A diastereoselective approach to amino alcohols and application for divergent synthesis of dolastatin 10

Abstract

A diastereoselective approach to obtain amino alcohols 10 through SmI₂-induced radical addition of chiral imine 8 with 2-(benzyloxymethylsulfonyl)pyridine 9 is described. This approach was easily used for the synthesis of non-natural amino acid 15, a flexible key fragment whose utility was demonstrated in the divergent synthesis of dolastatin 10 (1) and its nine analogues 31a, 31c, 31d, 31e, 31f, 31g, 40a, 40b and 40c were obtained.

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Introduction

Bioactive small peptides derived from peptidic secondary metabolites are a promising class of compounds for drug discovery,¹ due to their interesting biological activities, including antimalarial, antifungal, antimicrobial, cytotoxic and neurotoxic properties.² Among them, linear peptides displaying a variety of physiological activities and possessing attractive structures have attracted significant attention in recent years.³ Several of these bioactive peptides or cyclodepsipeptides were selected as novel pharmaceuticals and are currently being evaluated in human clinical trials for cancer treatment.⁴ As a prime instance, dolastatins, a large family of compounds named star molecules, were gradually isolated from the marine mollusk Dolabella auricularia over the last 30 years.⁵ Among the family, several are of the linear peptide form⁶ and several are of the cyclodepsipeptide form (Fig. 1).⁷ Most of them exhibit strong activity against a variety of cancers, and the mechanism of action is through a unique mode of action, which is different from that of paclitaxel, vinblastine and epothilones.⁸

Fig. 1 Several structures of dolastatins.

Dolastatin 10 (1) is one of the star molecules of its family compounds, which shows strong antitumor activity in sub-nanomolar concentrations against a wide range of tumor cell lines.⁹ Structurally, dolastatin 10 (1) led to five subunits (Fig. 2): N,N-dimethyl valine (Dov), L-valine (Val), (3R,4S,5S)-dolaisoleucine (Dil), (2R,3R,4S)-dolaproine (Dap) and protected (S)-dolaphenine (Doe) fragments. Due to the extensive biological activity against a variety of cancers and easily modified chemical structures, the synthetic dolastatin 10 (1) and its analogues have attracted significant attention and several important synthetic methods have been achieved.¹⁰ But most of the modifications of dolastatin 10 are focused on the Doe and Dov units. As a result, dolastatin 10 (1) and its analogues have inspired the design of auristatin as the potent ‘warhead’ component of antibody–drug conjugates (ADC) which has been approved as the antineoplastic agent for cancer chemotherapy and was evaluated in clinical trials in recent years.¹¹ There are also a few modifications for Dap fragments.¹² However, to the best of our knowledge, structural modifications for the Dil unit are not well studied, and the main reason is that the Dil fragment is difficult to synthesize. Moreover, another tricky reason for the synthesis of dolastatin 10 is the effective condensation between the Dil and Dov-Val fragments.^10c

Fig. 2 The structures of dolastatin 10 and its analogues.

In recent years, we have been focusing on the divergent synthesis of bioactive secondary metabolites,¹³ and very recently, we have established a diverse approach to obtain dolastatin 10 through a SmI₂-induced cross-coupling process to obtain the Dap fragment.^13d As a continuation of our interest in developing the divergent synthesis of dolastatins and investigating their structure–activity relationships, herein, we present an asymmetric approach to obtain the Dil fragment and divergent synthesis of more analogues of dolastatin 10 (1).

Results and discussion

As shown in Table 1, our investigation started with an effective method to obtain the Dil subunit of dolastatin 10. Commercialized chiral N-tert-butanesulfinamide has been undoubtedly one of the most efficient classes of auxiliaries in the past decade,¹⁴ and we decided to investigate an asymmetric process through the SmI₂-induced radical addition of chiral imine 8a with 2-(benzyloxymethylsulfonyl)pyridine 9. The imine 8a was easily prepared through oxidation and following condensation with N-tert-butanesulfinamide,¹⁵ and 2-(benzyloxymethylsulfonyl)pyridine 9 was synthesized through a known procedure.¹⁶ When a mixture of 8a (0.5 mmol) and 2-(benzyloxymethylsulfonyl)pyridine 9 (0.75 mmol) was treated with newly prepared SmI₂ (0.1 M in THF), the desired product 10a was not produced (Table 1, entry 1). Even when the amount of 9 (1.0 mmol) or SmI₂ was increased, the results were still fruitless (Table 1, entries 2 and 3). When a solution of 2-(benzyloxymethylsulfonyl)pyridine 9 in THF was dropped into the mixture of imine 8a with SmI₂ and stirred for 30 min, the desired product was obtained in 42% yield with high diastereoselectivity (Table 1, entry 4). Different amounts of 2-(benzyloxymethylsulfonyl)pyridine 9 and SmI₂ were screened, and the results are summarized in Table 1 (Table 1, entries 5–8). Although the best yield is 67%, the diastereoselectivity is excellent (Table 1, entry 6).

Table 1 Optimization of reaction conditions

Entry^a	SmI2 (equiv.)	9 (equiv.)	Yield^b (%)	dr^c
a 2-(Benzyloxymethylsulfonyl)pyridine 9 (in THF) was dropped into the mixture of imine 8a (0.5 mmol) with SmI2, and then stirred for 30 min at room temperature. b Isolated yield. c dr values were determined by ^1H NMR of crude products. d The new prepared SmI2 (0.1 M in THF) was dropped into a mixture of 8a with 2-(benzyloxymethylsulfonyl)pyridine 9.
1^d	4.0	1.5	Trace	—
2^d	4.0	3.0	Trace	—
3^d	6.0	3.0	Trace	—
4	4.0	1.5	42	99 : 1
5	4.0	3.0	47	99 : 1
6	6.0	3.0	67	99 : 1
7	6.0	2.0	45	99 : 1
8	6.0	2.5	56	99 : 1

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Next, we turned to investigate the scope and limitation of this asymmetric radical addition of imines 8b–8w with 2-(benzyloxymethylsulfonyl)pyridine 9. Different substituted linear alkyl imines 8a–8h were surveyed under the optimal conditions, as summarized in Scheme 1. In general, the reactions with various substituted linear alkyl imines 8a–8h proceeded smoothly in moderate yields with excellent diastereoselectivities (dr > 99 : 1). When tert-butyl type imines 8i and 8j were investigated, the results showed that the desired 10i–10j could be produced in moderate yields with low diastereoselectivities. Cyclic alkyl substituted imines 8k–8m were also studied, and it was found that the diastereoselectivities of 10k–10m are still low. Several aryl including furan substituted linear alkyl imines 8n–8t were also examined, affording the desired products in moderate yields with excellent diastereoselectivities. When 8u, a compound containing chiral α-methyl imine, was investigated, the desired 10u was obtained with low diastereoselectivity. To confirm the effect of different chiral auxiliaries in imine, 8v was also studied and the result suggested that the chiral sulfinamide moiety determined the stereocontrol of this addition process in this example (10v). Imine 8w derived from a ketone was also examined, and the desired product 10w was obtained in moderate yield with high diastereoselectivity. Despite our great efforts to determine the stereochemistry of the newly generated chiral center, the result is fruitless.

Scheme 1 The addition of imines 8 with 2-(benzyloxymethylsulfonyl)pyridine 9. The reactions were performed with 8 (0.5 mmol), 9 (1.5 mmol) and SmI₂ (3.0 mmol, 0.1 M in THF) in dry THF (2 mL) at room temperature for 30 min. Isolated yield. dr values were determined by ¹H NMR of crude products or column chromatography.

To confirm the stereochemistry of 10a–10v, compound 10d was easily transformed to the known 13. The treatment of 10d with HCl/dioxane in methanol and subsequent protection (Boc₂O) afforded ester 11 in 67% overall yield (Scheme 2). The deprotection (Pd/C, H₂) of 11 gave alcohol 12 in 81% yield. Dess–Martin oxidation¹⁷ and subsequent Pinnick oxidation (NaH₂PO₄·2H₂O, NaClO₂)¹⁸ gave the known 13 {[α]²²_D = −29.0 (c, 1.00, DMF), lit.¹⁹ [α]²⁵_D = −29.8 (c 1.00, DMF)} in 70% overall yield. The spectroscopic and physical data of the synthetic 13 were identical to the reported data.¹⁹ Thus the new stereochemistry of product 10d was unambiguously determined as the S-form.

Scheme 2 The synthesis of known compound 13. Reagents and conditions: a. (1) HCl/dioxane, MeOH, 30 min; (2) Boc₂O, TEA, DCM, overnight, 67%, two steps; b. Pd/C, H₂, MeOH, rt, 4 h, 81%; c. (1) Dess–Martin periodinane, DCM, rt, 30 min; (2) NaH₂PO₄·2H₂O, NaClO₂, 2-methyl-2-butene/t-BuOH, rt, 8 h, 70%, two steps.

With 10o in hand, another non-natural amino acid 15 was considered as shown in Scheme 3. The removal of the chiral auxiliary (HCl/dioxane) of 10o and protection (Boc₂O) gave an ester, which was deprotected with hydrogen (H₂) in the presence of Pd/C to obtain alcohol 14 in 88% overall yield (Scheme 3). Dess–Martin oxidation and subsequent Pinnick oxidation (NaH₂PO₄·2H₂O, NaClO₂) generated a crude acid without further purification, which was treated with dry hydrogen chloride in methanol to obtain the desired amino acid hydrochloride 15 {[α]²⁵_D = −33.6 (c 0.50, MeOH)} in 66% overall yield.

Scheme 3 The synthesis of non-natural amino acid 15. Reagents and conditions: a. (1) HCl/dioxane, MeOH, 30 min; (2) Boc₂O, TEA, DCM, overnight; (3) Pd/C, H₂, MeOH, 4 h, 88%, three steps; b. (1) Dess–Martin periodinane, DCM, rt, 30 min; (2) NaH₂PO₄·2H₂O, NaClO₂, 2-methyl-2-butene/t-BuOH, rt, 8 h; (3) HCl/MeOH (3 M), 2 h, 66%, three steps.

We turned our attention to utilize this diastereoselective approach in the synthesis of Dov-Val–Dil fragments of dolastatin 10 (1) analogues (Scheme 4). The deprotection (HCl/dioxane) of 10n and subsequent protection (Boc₂O/TEA) gave ester 16a in 65% yield. The methylation of 16a with methyl trifluoromethanesulfonate (MeOTf)^10c in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) produced the desired compound 17a in 81% yield. The deprotection (TFA/DCM) of 17a and condensation (HATU/DIPEA) with N-Boc-L-Val-OH gave the desired amide 18a in 94% yield. The crude amine salt, prepared by the removal of the Boc group in 18a (TFA), was directly coupled with N-Boc-L-Val-OH (HATU/DIPEA) to give tripeptide 19a in 87% yield. The hydrogenation (Pd/C, H₂) of 19a gave alcohol 20a in 82% yield. Upon the Dess–Martin oxidation of the hydroxy group in 20a, the subsequent addition with benzyl acetate in the presence of lithium diisopropylamide (LDA) gave the desired alcohol 21a in 73% yield with low diastereoselectivity (dr = 66 : 34). Following the similar synthetic sequence described above, two analogues of Dov-Val–Dil fragment precursors 21b and 21c (dr = 54 : 46 for 21b, dr = 72 : 28 for 21c) in 24% and 32% respective overall yields were successfully achieved in parallel.

Scheme 4 The synthesis of Dov-Val–Dil fragment precursors 21a, 21b, and 21c. Reagents and conditions: a. (1) HCl/dioxane, MeOH, 30 min; (2) Boc₂O, TEA, DCM, overnight, 65% for 16a, 75% for 16b, 76% for 16c, two steps; b. LiHMDS, HMPA, THF, −78 °C, 30 min, and then MeOTf, −15 °C, 20 min, 81% for 17a, 95% for 17b, 93% for 17c; c. (1) TFA, DCM, rt, 3 h; (2) N-Boc-L-Val-OH, HATU, DIPEA, DCM, rt, 7 h, 94% for 18a, 80% for 18b, 85% for 18c; d. (1) TFA, DCM, rt, 3 h; (2) N-Boc-L-Val-OH, HATU, DIPEA, DCM, rt, 7 h, 87% for 19a, 86% for 19b, 88% for 19c; e. Pd/C, H₂, MeOH, 4 h, 82% for 20a, 80% for 20b, 83% for 20c; f. (1) Dess–Martin periodinane, DCM, rt, 30 min; (2) LDA, benzyl acetate, THF, −78 °C, 30 min, 53% for 21a (dr = 66 : 34), 61% for 21b (dr = 54 : 46), 72% for 21c (dr = 72 : 28), two steps.

To obtain more diverse fragments of Dov-Val–Dil, several commercial amino acids 22a, 22b, 22c and 22d were also selected as the starting material. As shown in Scheme 5, continuous sequential protection of amino acids gave esters 23a, 23b, 23c and 23d in 40%, 42%, 41%, and 40% respective yields. Then through the key condensation and asymmetric addition as described in Scheme 4, four other analogues of Dov-Val–Dil fragment precursors 27a–27d (dr = 75 : 25 for 27a, dr = 70 : 30 for 27b, dr > 99 : 1 for 27c, dr > 99 : 1 for 27d) in 44%, 33%, 27%, 25% respective overall yields were also successfully obtained in parallel.

Scheme 5 The synthesis of Dov-Val–Dil fragment precursors 27a, 27b, 27c, and 27d. Reagents and conditions: a. (1) Boc₂O, NaOH, H₂O/dioxane, overnight; (2) NaH, MeI, THF, rt, 48 h; (3). BnBr, K₂CO₃, DMSO, rt, overnight, 40% for 23a, 42% for 23b, 41% for 23c, 40% for 23d, three steps; b. (1) TFA, DCM, rt, 3 h; (2) N-Boc-L-Val-OH, HATU, DIPEA, DCM, rt, 7 h, 82% for 24a, 70% for 24b, 77% for 24c, 68% for 24d, two steps; c. (1) TFA, DCM, rt, 3 h; (2) N-Boc-L-Val-OH, HATU, DIPEA, DCM, rt, 7 h, 94% for 25a, 92% for 25b, 90% for 25c, 87% for 25d, two steps; d. LiHBEt₃, THF, 0 °C–rt., 90% for 26a, 90% for 26b, 60% for 26c, 59% for 26d; e. (1) Dess–Martin periodinane, DCM, rt, 30 min; (2) LDA, benzyl acetate, THF, −78 °C, 30 min, 63% for 27a (dr = 75 : 25), 57% for 27b (dr = 70 : 30), 65% for 27c (dr > 99 : 1), 71% for 27d (dr > 99 : 1), two steps.

With a series of Dov-Val–Dil fragment precursors in hand, we then turned our attention to synthesize the dolastatin 10 (1) analogues. As shown in Scheme 6, 27b was firstly methylated with methyl trifluoromethanesulfonate (MeOTf) in the presence of bis(trimethylsilyl)amine lithium (LiHMDS) to give protected dipeptide 28a in 55% yield. The removal (TFA/DCM) of Boc in 28a and subsequent dimethylation²⁰ (40% HCHO, Na(BH₃)CN) gave Dov-Val–Dil fragment 29a in 70% yield. Upon the hydrogenation (Pd/C, H₂) of Bn in 29a, the crude acid was directly amidated with our previously prepared Dap–Doe amine 30^13d in the presence of HATU and DIPEA to give dolastatin 10 analogue 31a as a viscous liquid, which was further treated with acetone/hexane to give a white powder {mp 94–95 °C; [α]²²_D = −214.4 (c 0.125, CHCl₃)} in 50% isolated yield. Finally, following a similar synthetic sequence described above, five other analogues of dolastatin 10 31b {[α]²⁶_D = −39.2 (c 0.25, CHCl₃)}, 31c {[α]²⁶_D = −35.2 (c 0.25, CHCl₃)}, 31d {[α]²⁶_D = −41.5 (c 1.00, CHCl₃)}, 31e {[α]²³_D = −5.6 (c 0.50, CHCl₃)}, and 31f {[α]²³_D = −26.4 (c 0.125, CHCl₃)}were successfully achieved in 25%, 22%, 27%, 14%, and 12% respective overall yields in parallel. The structures of analogues 31a, 31b, 31c, 31d, 31e and 31f were overall confirmed by spectroscopic data.

Scheme 6 The divergent synthesis of dolastatin 10 (1). Reagents and conditions: a. LiHMDS, HMPA, THF, −78 °C, 30 min, and then MeOTf, −15 °C, 15 min, 55% for 28a, 53% for 28b, 77% for 28c, 73% for 28d, 67% for 28e, 50% for 28f, 44% for 28g; b. (1) TFA, DCM, rt, 2 h; (2) 40% HCHO, Na(BH₃)CN, MeCN, rt, 10 h, 70% for 29a, 70% for 29b, 77% for 29c, 89% for 29d, 91% for 29e, 65% for 29f, 60% for 29g, two steps; c. (1) Pd/C, H₂, MeOH, 4 h; (2) HATU, DIPEA, DCM, rt, 12 h, 50% for 31a, 42% for 31b, 34% for 31c, 45% for 31d, 42% for 31e, 45% for 31f, two steps.

In light of our interest in diversity-oriented synthesis,²¹ we decided to prepare several analogues of dolastatin 10 containing a cyclopropane skeleton. As shown in Scheme 7, the cyclopropanated amino alcohol 33 was easily prepared from the commercialized (S)-(+)-5-hydroxymethyl-2-pyrrolidinone 32 by a known procedure.²² The hydroxy group in 33 was oxidized to the corresponding aldehyde without further purification, which was directly converted to compound 34 with two stereocenters according to a known procedure using the well-established Evans’ asymmetric aldol methodology²³ in 60% yield with excellent diastereoselectivity (dr > 99 : 1). Hydrolysis (LiOH, H₂O₂), protection (BnBr/K₂CO₃) and following methylation (MeOTf/LiHMDS) produced the protected ether 35 in 81% yield. The hydrogenation (Pd/C, H₂) of 35 gave crude acid 36 without further purification, which was directly coupled with our previously prepared chiral salt 37 ^13d in the presence of HATU and DIPEA to generate 38 in 75% yield. Upon the deprotection (TFA, DCM) of Boc in 38, the crude amine was directly condensed separately with free acids of 29b, 29c and 29e to obtain three analogues of dolastatin 10 40a {[α]²⁴_D = −38.0 (c 0.10, CHCl₃)}, 40b {[α]²⁶_D = −22.0 (c 0.25, CHCl₃)}, and 40c {[α]²⁴_D = −30.2 (c 0.50, CHCl₃)} in 31%, 28%, and 45% respective yields in parallel. The structures of analogues 40a, 40b and 40c were overall confirmed by spectroscopic data.

Scheme 7 The synthesis of three analogues 40a, 40b, and 40c. Reagents and conditions: a. (1) Dess–Martin periodinane, DCM, rt, 30 min; (2) Bu₂BOTf, TEA, DCM, −78 °C to rt, 60%, two steps; b. (1) LiOH, H₂O₂, THF/H₂O; (2) BnBr, K₂CO₃, DMF; (3) LiHMDS, HMPA, MeOTf, THF, 81%, three steps; c. Pd/C, H₂, MeOH, 4 h; d. HATU, DIPEA, DCM, rt, 7 h, 75%; e. TFA, DCM, 2 h; f. (1) 29b, 29c, 29e, Pd/C, H₂, MeOH, 4 h; (2) HATU, DIPEA, DCM, rt, 12 h, 31% for 40a, 28% for 40b, 45% for 40c.

Conclusions

In summary, a diastereoselective approach to obtain amino alcohols 10 which were easily converted to non-natural amino acids through SmI₂-induced radical addition of chiral imines 8 with 2-(benzyloxymethylsulfonyl)pyridine 9 has been developed. Moreover, this novel approach was used to prepare the key fragment-Dil of dolastatin 10 analogues. Using this strategy, nine dolastatin 10 analogues 31a, 31b, 31c, 31d, 31e, 31f, 40a, 40b and 40c have been synthesized. It is worth mentioning that several analogues containing divergent Dil subunits have been synthesized for the first time. Further chemistry and related biological data will be published in due course.

Experimental

General

THF was distilled from sodium/benzophenone. The reactions were monitored by thin layer chromatography (TLC) on glass plates coated with silica gel with a fluorescent indicator. Flash chromatography was performed on silica gel (300–400 mesh). Optical rotations were measured on a polarimeter with a sodium lamp. HRMS were measured on an LTQ-Orbitrap-XL apparatus. IR spectra were recorded using a film on a Fourier transform infrared spectrometer. NMR spectra were recorded at 400 MHz or 600 MHz, and chemical shifts are reported in δ (ppm) referenced to the appropriate residual solvent peaks unless otherwise noted.

General procedure for the synthesis of 8a–8u

To a solution of (S)-2-methyl-2-propane-sulfinamide (606 mg, 5.00 mmol) and aldehyde (5.00 mmol) in DCM (100 mL) was added anhydrous cupric sulfate (1.59 g, 10 mmol) and PPTS (63 mg, 0.25 mmol) in one portion, and the mixture was stirred for 24 h. The resulting mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by flash chromatography on silica gel (PE/EA = 15 : 1) to give the title product (8a–8u).

(S,E)-N-Butylidene-2-methylpropane-2-sulfinamide (8a)

Colorless oil (572 mg, 65%); [α]²⁵_D +267 (c 1.00, CHCl₃), lit.²⁴{[α]²⁰_D +303.5 (c 1.00, CHCl₃)}; IR (film): ν_max 2961, 1622, 1363, 1085, 587 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.07 (dd, J = 5.2, 4.4 Hz, 1H), 2.53–2.48 (m, 2H), 1.71–1.65 (m, 2H), 1.20 (s, 9H), 1.00 (t, J = 7.6 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 169.6, 56.5, 38.0, 22.3, 18.9, 13.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₈H₁₈NOS⁺, 176.1104, found: 176.1102.

(S,E)-N-Hexylidene-2-methylpropane-2-sulfinamide (8b)

Colorless oil (755 mg, 74%); [α]²⁵_D +282 (c 1.00, CHCl₃), lit.²⁵{[α]_D +240.3 (c 1.00, CHCl₃)}; IR (film): ν_max 2957, 1622, 1363, 1087, 583 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.10–8.03 (m, 1H), 2.55–2.47 (m, 2H), 1.67–1.58 (m, 2H), 1.37–1.32 (m, 4H), 1.20 (s, 9H), 0.94–0.86 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 169.9, 56.6, 36.2, 31.5, 25.3, 22.5, 14.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₀H₂₂NOS⁺, 204.1417, found: 204.1419.

(S,E)-2-Methyl-N-octylidenepropane-2-sulfinamide (8c)

Colorless oil (720 mg, 62%); [α]²⁵_D +207 (c 1.00, CHCl₃), lit.²⁴{[α]²⁰_D +177.0 (c 1.00, CHCl₃)}; IR (film): ν_max 2926, 1621, 1455, 1087, 583 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.07 (dd, J = 5.2, 4.4 Hz, 1H), 2.54–2.49 (m, 2H), 1.67–1.57 (m, 2H), 1.38–1.26 (m, 8H), 1.20 (s, 9H), 0.88 (t, J = 6.8 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 169.9, 56.5, 36.2, 31.7, 29.3, 29.1, 25.6, 22.7, 22.4, 14.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₂H₂₆NOS⁺, 232.1730, found: 232.1730.

(S,E)-2-Methyl-N-(3-methylbutylidene)propane-2-sulfinamide (8d)

Colorless oil (789 mg, 83%); [α]²⁵_D +282 (c 1.00, CHCl₃); IR (film): ν_max 2959, 1621, 1363, 1085, 586 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.06 (dd, J = 5.2, 4.4 Hz, 1H), 2.44–2.38 (m, 2H), 2.13–2.01 (m, 1H), 1.21 (s, 9H), 1.02–1.00 (m, 3H), 1.00–0.98 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 169.4, 56.5, 45.0, 26.2, 22.6, 22.5, 22.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₉H₂₀NOS⁺, 190.1260, found: 190.1262.

(S,E)-N-(3,3-Dimethylbutylidene)-2-methylpropane-2-sulfinamide (8e)

Colorless oil (887 mg, 87%); [α]²⁵_D +267 (c 1.00, CHCl₃); IR (film): ν_max 2958, 1619, 1364, 1092, 672 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.12 (dd, J = 10.8, 5.4 Hz, 1H), 2.45–2.38 (m, 2H), 1.23–1.19 (m, 9H), 1.05–1.01 (m, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 169.0, 56.7, 49.9, 31.5, 29.9, 22.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₀H₂₂NOS⁺, 204.1417, found: 204.1416.

(S,E)-N-(2-Ethylbutylidene)-2-methylpropane-2-sulfinamide (8f)

Colorless oil (898 mg, 88%); [α]²⁵_D +279 (c 1.00, CHCl₃); IR (film): ν_max 2963, 1619, 1458, 1086, 686 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.91 (dd, J = 6.0, 2.0 Hz, 1H), 2.42–2.33 (m, 1H), 1.64–1.57 (m, 4H), 1.23–1.21 (m, 9H), 0.94–0.89 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.3, 56.5, 48.8, 24.6, 22.5, 11.7, 11.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₀H₂₂NOS⁺, 204.1417, found: 204.1416.

(S,E)-N-((R)-2-Ethylpent-4-enylidene)-2-methylpropane-2-sulfinamide (8g)

Colorless oil (799 mg, 74%); [α]²⁵_D +270 (c 1.00, CHCl₃); IR (film): ν_max 2963, 1619, 1363, 1086, 915 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.96–7.90 (m, 1H), 5.81–5.68 (m, 1H), 5.12–5.01 (m, 2H), 2.60–2.49 (m, 1H), 2.40–2.27 (m, 2H), 1.66–1.58 (m, 2H), 1.20 (s, 9H), 0.94 (t, J = 7.6 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.4, 135.4, 117.0, 56.5, 46.7, 35.8, 24.5, 22.4, 11.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₁H₂₂NOS⁺, 216.1417, found: 216.1415.

(S,E)-N-((Z)-Hept-4-enylidene)-2-methylpropane-2-sulfinamide (8h)

Colorless oil (929 mg, 86%); [α]²⁵_D +247 (c 1.00, CHCl₃); IR (film): ν_max 2961, 1622, 1456, 1086, 583 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.09–8.04 (m, 1H), 5.48–5.39 (m, 1H), 5.38–5.28 (m, 1H), 2.62–2.55 (m, 2H), 2.40–2.33 (m, 2H), 2.10–2.01 (m, 2H), 1.21–1.18 (m, 9H), 1.00–0.94 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 169.2, 133.4, 126.9, 56.6, 36.3, 23.2, 22.4, 20.7, 14.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₁H₂₂NOS⁺, 216.1417, found: 216.1414.

(S,E)-N-(2,2-Dimethylpropylidene)-2-methylpropane-2-sulfinamide (8i)

Colorless oil (799 mg, 84%); [α]²⁵_D +287 (c 1.00, CHCl₃), lit.²⁶{[α]_D +267.1 (c 0.70, CHCl₃)}; IR (film): ν_max 2963, 1620, 1474, 1363, 1086, 586 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (brs, 1H), 1.18 (s, 9H), 1.16 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 175.6, 56.4, 37.9, 26.7, 22.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₉H₂₀NOS⁺, 190.1260, found: 190.1262.

(S,E)-2-Methyl-N-(2,2,5-trimethylhex-4-enylidene)propane-2-sulfinamide (8j)

Colorless oil (781 mg, 64%); [α]²⁵_D +212 (c 1.00, CHCl₃); IR (film): ν_max 2965, 1619, 1385, 1089, 588 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.93–7.90 (m, 1H), 5.15–5.07 (m, 1H), 2.23–2.16 (m, 2H), 1.70–1.68 (m, 3H), 1.62–1.60 (m, 3H), 1.20–1.18 (m, 9H), 1.14–1.12 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 175.7, 134.5, 119.6, 56.6, 42.1, 38.5, 26.1, 24.6, 24.3, 22.4, 18.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₃H₂₆NOS⁺, 244.1730, found: 244.1731.

(S,E)-N-(Cyclopropylmethylene)-2-methylpropane-2-sulfinamide (8k)

Colorless oil (714 mg, 82%); [α]²⁵_D +410 (c 1.00, CHCl₃), lit.²⁷{[α]_D +332 (c 0.50, CH₂Cl₂)}; IR (film): ν_max 2960, 1616, 1363, 1080, 695 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 7.6 Hz, 1H), 2.02–1.96 (m, 1H), 1.19 (s, 9H), 1.12–1.07 (m, 2H), 0.98–0.94 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.8, 56.7, 22.3, 17.6, 8.6, 8.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₈H₁₆NOS⁺, 174.0947, found: 174.0945.

(S,E)-N-(Cyclopentylmethylene)-2-methylpropane-2-sulfinamide (8l)

Colorless oil (717 mg, 71%); [α]²⁵_D +261 (c 1.00, CHCl₃); IR (film): ν_max 2956, 1619, 1474, 1084, 584 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.01–7.98 (m, 1H), 2.99–2.92 (m, 1H), 1.94–1.85 (m, 2H), 1.73–1.65 (m, 6H), 1.20–1.18 (m, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.6, 56.5, 45.7, 30.0, 29.9, 25.6, 25.6, 22.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₀H₂₀NOS⁺, 202.1260, found: 202.1262.

(S,E)-tert-Butyl 4-((2-methylpropan-2-ylsulfinamido)methyl)piperidine-1-carboxylate (8m)

Colorless oil (1.14 g, 72%); [α]²⁵_D +138 (c 1.00, CHCl₃); IR (film): ν_max 3444, 2975, 1692, 1423, 1170 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J = 4.0 Hz, 1H), 4.15–4.02 (m, 2H), 2.94–2.82 (m, 2H), 2.67–2.56 (m, 1H), 1.92–1.84 (m, 2H), 1.59–1.49 (m, 2H), 1.46 (s, 9H), 1.19 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.8, 154.8, 79.8, 56.7, 42.2, 28.5, 28.4, 22.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₅H₂₉N₂O₃S⁺, 317.1893, found: 317.1899.

(S)-N-((R,E)-2-Benzylbutylidene)-2-methylpropane-2-sulfinamide (8n)

Colorless oil (1.16 g, 87%); [α]²⁵_D +143 (c 1.00, CHCl₃); IR (film): ν_max 2961, 1620, 1495, 1363, 1124, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.88 (m, 1H), 7.30–7.21 (m, 2H), 7.19–7.12 (m, 3H), 2.93–2.81 (m, 3H), 1.68–1.56 (m, 2H), 1.06–0.99 (m, 9H), 0.99–0.91 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.2, 139.2, 129.1, 128.5, 126.3, 56.6, 48.9, 38.1, 25.0, 22.3, 11.6 ppm; HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₂₄NOS⁺, 266.1573, found: 266.1576.

(S)-N-((R,E)-2-(3-Fluorobenzyl)butylidene)-2-methylpropane-2-sulfinamide (8o)

Colorless oil (1.16 g, 82%); [α]²⁵_D +141 (c 1.00, CHCl₃); IR (film): ν_max 2963, 1619, 1589, 1488, 1363, 1083, 693 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 5.6 Hz, 1H), 7.25–7.16 (m, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.91–6.83 (m, 2H), 2.91–2.78 (m, 3H), 1.69–1.57 (m, 2H), 1.05 (s, 9H), 0.95 (t, J = 7.6 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.8, 163.0 (d, J = 244.3 Hz), 141.9 (d, J = 7.2 Hz), 130.0 (d, J = 8.3 Hz), 124.8 (d, J = 2.2 Hz), 116.0 (d, J = 20.9 Hz), 113.3 (d, J = 20.9 Hz), 56.7, 48.7, 37.8, 25.1, 22.3, 11.6 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.6 ppm; HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₂₃FNOS⁺, 284.1479, found: 284.1480.

(S)-N-((R,E)-2-(4-Methoxybenzyl)butylidene)-2-methylpropane-2-sulfinamide (8p)

Colorless oil (1.23 g, 83%); [α]²⁵_D +130 (c 1.00, CHCl₃); IR (film): ν_max 3447, 2960, 1698, 1661, 1513, 1363, 1247, 1180 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 5.6 Hz, 1H), 7.10–7.05 (m, 2H), 6.82–6.77 (m, 2H), 3.77 (s, 3H), 2.88–2.80 (m, 1H), 2.80–2.73 (m, 2H), 1.65–1.55 (m, 2H), 1.05 (s, 9H), 0.94 (t, J = 7.6 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.5, 158.3, 131.3, 130.1, 114.1, 56.7, 55.4, 49.2, 37.4, 25.0, 22.4, 11.7 ppm; HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₂₆NO₂S⁺, 296.1679, found: 296.1680.

(S,E)-N-((R)-2-(4-tert-Butylbenzyl)butylidene)-2-methylpropane-2-sulfinamide (8q)

Colorless oil (1.21 g, 75%); [α]²⁵_D +104 (c 1.00, CHCl₃); IR (film): ν_max 2961, 1620, 1363, 1086, 589 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.91–7.87 (m, 1H), 7.28–7.24 (m, 2H), 7.12–7.07 (m, 2H), 2.84–2.81 (m, 3H), 1.66–1.58 (m, 2H), 1.28 (s, 9H), 0.99 (s, 9H), 0.95 (t, J = 7.6 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.4, 149.1, 136.0, 128.8, 125.4, 56.5, 49.0, 37.8, 34.4, 31.4, 25.3, 22.3, 11.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₉H₃₂NOS⁺, 322.2199, found: 322.2203.

(S,E)-2-Methyl-N-(3-(5-methylfuran-2-yl)propylidene)propane-2-sulfinamide (8r)

Yellow oil (944 mg, 78%); [α]²⁵_D +208 (c 1.00, CHCl₃); IR (film): ν_max 2957, 1623, 1363, 1086, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (dd, J = 4.0, 3.2 Hz, 1H), 5.90–5.87 (m, 1H), 5.84–5.82 (m, 1H), 2.96–2.92 (m, 2H), 2.88–2.84 (m, 2H), 2.23 (s, 3H), 1.16 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 168.3, 152.2, 150.7, 106.2, 106.0, 56.7, 34.5, 23.9, 22.3, 13.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₂H₂₀NO₂S⁺, 242.1209, found: 242.1211.

(S,E)-2-Methyl-N-(3-phenylpropylidene)propane-2-sulfinamide (8s)

Colorless oil (964 mg, 81%); [α]²⁵_D +196 (c 1.00, CHCl₃); IR (film): ν_max 2958, 1622, 1453, 1079, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.13–8.08 (m, 1H), 7.30–7.25 (m, 2H), 7.22–7.17 (m, 3H), 2.99–2.94 (m, 2H), 2.88–2.83 (m, 2H), 1.12 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 168.5, 140.3, 128.6, 128.4, 126.3, 56.6, 37.5, 31.4, 22.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₃H₂₀NOS⁺, 238.1260, found: 238.1261.

(S,E)-2-Methyl-N-(3-(3-(trifluoromethyl)phenyl)propylidene)propane-2-sulfinamide (8t)

Colorless oil (1.03 g, 67%); [α]²⁵_D +145 (c 1.00, CHCl₃); IR (film): ν_max 2961, 1623, 1328, 1124, 1075, 703 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.13–8.08 (m, 1H), 7.50–7.45 (m, 2H), 7.43–7.38 (m, 2H), 3.08–3.04 (m, 2H), 2.94–2.89 (m, 2H), 1.11 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.8, 141.4, 131.9, 131.0 (d, J = 31.9 Hz), 129.1, 125.2 (d, J = 3.6 Hz), 124.2 (d, J = 270.7 Hz), 123.3 (d, J = 3.5 Hz), 56.7, 37.0, 31.0, 22.3 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₄H₁₉F₃NOS⁺, 306.1134, found: 306.1130.

(S,E)-2-Methyl-N-((S)-2-methylbutylidene)propane-2-sulfinamide (8u)

Colorless oil (865 mg, 91%); [α]²⁵_D +296 (c 1.00, CHCl₃), lit.²⁸{[α]²⁷_D +208.7 (c 1.00, CHCl₃)}; IR (film): ν_max 2964, 2929, 1620, 1457, 1086 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.91–7.89 (m, 1H), 2.53–2.45 (m, 1H), 1.65–1.57 (m, 1H), 1.47–1.37 (m, 1H), 1.13 (s, 9H), 1.08–1.05 (m, 3H), 0.91–0.86 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.3, 56.5, 41.6, 26.7, 22.3, 16.5, 11.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₉H₂₀NOS⁺, 190.1260, found: 190.1261.

(R,E)-2-Methyl-N-((S)-2-methylbutylidene)propane-2-sulfinamide (8v)

To a solution of (S)-(−)-2-methyl-1-butanol (176 mg, 2.00 mmol) in DCM (8 mL) was added Dess–Martin periodinane (1.70 g, 4.00 mmol). After being stirred for 30 min, the reaction mixture was carefully quenched with a saturated aqueous solution of NaHCO₃ and solid Na₂S₂O₃. The resulting mixture was extracted with DCM (20 mL × 3) and the combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to give a crude aldehyde without further purification. To a solution of the crude aldehyde in DCM (10 mL) was added (R)-2-methyl-2-propane-sulfinamide (266 mg, 2.20 mmol), anhydrous cupric sulfate (636 mg, 4.00 mmol) and PPTS (25 mg, 0.10 mmol), and after being stirred for 24 h, the reaction mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 15 : 1) to give the imine 8v. Colorless oil (282 mg, 75%, two steps); [α]²⁵_D −268 (c 1.00, CHCl₃); IR (film): ν_max 2964, 2875, 1621, 1086, 587 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J = 5.2, 4.4 Hz, 1H), 2.58–2.50 (m, 1H), 1.71–1.64 (m, 1H), 1.52–1.47 (m, 1H), 1.21–1.19 (m, 9H), 1.16–1.13 (m, 3H), 0.97–0.92 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.5, 56.5, 41.7, 26.7, 22.4, 16.5, 11.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₉H₂₀NOS⁺, 190.1260, found: 190.1261.

(S,E)-2-Methyl-N-(4-methylpentan-2-ylidene)propane-2-sulfinamide (8w)

To a solution of 4-methyl-2-pentanone (350 mg, 5 mmol) in THF (14 mL) was added (S)-2-methyl-2-propane-sulfinamide (462 mg, 3.85 mmol) and Ti(OEt)₄ (1.45 mL, 7.00 mmol). After the mixture was refluxed for 12 h, water was added. The resulting mixture was extracted with EtOAc (60 mL × 3), and the combined organic layers were dried over MgSO₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 15 : 1) to give the imine 8w. Colorless oil (504 mg, 50%); [α]²⁵_D +160 (c 1.00, CHCl₃); IR (film): ν_max 2957, 1620, 1463, 1387, 1074 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 2.33–2.30 (m, 3H), 2.29–2.27 (m, 1H), 2.15–2.08 (m, 1H), 1.25 (s, 9H), 1.01–0.97 (m, 1H), 0.97–0.95 (m, 3H), 0.95–0.93 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 185.2, 56.2, 52.5, 25.7, 23.3, 22.6, 22.5, 22.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₀H₂₂NOS⁺, 204.1417, found: 204.1419.

General procedure for the synthesis of 10a–10u

A solution of 2-(benzyloxymethylsulfonyl)-pyridine 9 (395 mg, 1.50 mmol) in THF (1 ml) was dropped into the mixture of imine 8 (0.50 mmol) with SmI₂ (30 ml, 3.00 mmol, 0.1 M in THF) at room temperature under an Ar atmosphere. The reaction mixture was quenched with H₂O (0.2 ml), then the organic layer was washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 3 : 1) to give 10a–10u.

(S)-N-((S)-1-(Benzyloxy)pentan-2-yl)-2-methylpropane-2-sulfinamide (10a)

Colorless oil (99 mg, 67%); [α]²⁰_D +45.0 (c 1.00, CHCl₃); IR (film): ν_max 2956, 2869, 1589, 1454, 1387, 1362, 1114, 1056 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.27 (m, 5H), 4.60 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 3.67–3.62 (m, 2H), 3.56–3.48 (m, 1H), 3.47–3.36 (m, 1H), 1.63–1.53 (m, 1H), 1.52–1.44 (m, 1H), 1.43–1.28 (m, 2H), 1.22 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.3, 128.5, 127.9, 127.8, 73.4, 73.2, 55.9, 55.8, 35.2, 22.8, 22.7, 19.1, 14.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₆H₂₈NO₂S⁺, 298.1835, found: 298.1836.

(S)-N-((S)-1-(Benzyloxy)heptan-2-yl)-2-methylpropane-2-sulfinamide (10b)

Colorless oil (104 mg, 64%); [α]²¹_D +43.5 (c 1.00, CHCl₃); IR (film): ν_max 2954, 2928, 2859, 1454, 1362, 1098, 735, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.27 (m, 5H), 4.65–4.45 (m, 2H), 3.68–3.60 (m, 1H), 3.56–3.48 (m, 1H), 3.46–3.32 (m, 2H), 1.73–1.61 (m, 1H), 1.60–1.48 (m, 1H), 1.42–1.37 (m, 1H), 1.35–1.26 (m, 5H), 1.22–1.20 (m, 9H), 0.93–0.83 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.3, 138.2, 128.5, 127.9, 127.8, 73.4, 73.2, 56.6, 55.9, 55.8, 33.0, 32.8, 31.8, 25.7, 25.5, 22.8, 22.7, 22.6, 22.5, 14.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₈H₃₂NO₂S⁺, 326.2148, found: 326.2150.

(S)-N-((S)-1-(Benzyloxy)nonan-2-yl)-2-methylpropane-2-sulfinamide (10c)

Colorless oil (92 mg, 52%); [α]²¹_D +40.7 (c 1.00, CHCl₃); IR (film): ν_max 2924, 2855, 1454, 1362, 1113, 1057, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.27 (m, 5H), 4.54 (d, J = 12.0 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H), 3.53–3.43 (m, 2H), 3.42–3.39 (m, 1H), 3.38–3.33 (m, 1H), 1.71–1.59 (m, 2H), 1.33–1.25 (m, 10H), 1.20 (s, 9H), 0.91–0.84 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.3, 128.5, 127.8, 73.4, 73.3, 56.6, 55.9, 32.8, 31.9, 29.6, 29.3, 26.1, 22.8, 22.7, 14.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₀H₃₆NO₂S⁺, 354.2461, found: 354.2462.

(S)-N-((S)-1-(Benzyloxy)-4-methylpentan-2-yl)-2-methylpropane-2-sulfinamide (10d)

Colorless oil (98 mg, 63%); [α]²⁰_D +35.0 (c 1.00, CHCl₃); IR (film): ν_max 2955, 2927, 2867, 1587, 1454, 1386, 1114, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃,) δ 7.39–7.28 (m, 5H), 4.60 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 3.69–3.64 (m, 1H), 3.64–3.59 (m, 1H), 3.55–3.48 (m, 1H), 3.47–3.44 (m, 1H), 1.84–1.65 (m, 1H), 1.62–1.46 (m, 2H), 1.23–1.18 (m, 9H), 0.94–0.86 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.3, 128.5, 127.9, 127.8, 74.0, 73.4, 73.3, 56.0, 54.6, 42.5, 41.7, 24.6, 23.3, 23.1, 22.8, 22.7, 22.3, 22.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₇H₃₀NO₂S⁺, 312.1992, found: 312.1993.

(S)-N-((S)-1-(Benzyloxy)-4,4-dimethylpentan-2-yl)-2-methylpropane-2-sulfinamide (10e)

Colorless oil (105 mg, 65%); [α]²¹_D +48.6 (c 1.00, CHCl₃); IR (film): ν_max 2953, 1587, 1474, 1454, 1388, 1117, 1069, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.25 (m, 5H), 4.60 (d, J = 11.8 Hz, 1H), 4.49 (d, J = 11.8 Hz, 1H), 3.74–3.69 (m, 1H), 3.69–3.64 (m, 1H), 3.53–3.46 (m, 2H), 1.51–1.46 (m, 1H), 1.46–1.39 (m, 1H), 1.23–1.19 (m, 9H), 0.96–0.91 (m, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.3, 128.5, 127.9, 127.8, 127.7, 75.4, 74.9, 73.3, 73.2, 55.8, 53.6, 53.0, 47.2, 45.6, 30.5, 30.1, 30.0, 22.8, 22.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₈H₃₂NO₂S⁺, 326.2148, found: 326.2149.

(S)-N-((S)-1-(Benzyloxy)-3-ethylpentan-2-yl)-2-methylpropane-2-sulfinamide (10f)

Colorless oil (115 mg, 71%); [α]²¹_D +26.7 (c 1.00, CHCl₃); IR (film): ν_max 2960, 2927, 1591, 1454, 1362, 1074, 1028 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.26 (m, 5H), 4.58 (d, J = 11.6 Hz, 1H), 4.49 (d, J = 11.6 Hz, 1H), 3.67–3.62 (m, 2H), 3.60 (d, J = 8.0 Hz, 1H), 3.46–3.37 (m, 1H), 1.57–1.49 (m, 1H), 1.46–1.38 (m, 2H), 1.36–1.26 (m, 2H), 1.24 (s, 9H), 0.90–0.82 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.3, 128.5, 127.9, 127.8, 73.2, 71.2, 57.6, 56.1, 42.8, 22.9, 21.9, 21.7, 11.7, 11.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₈H₃₂NO₂S⁺, 326.2148, found: 326.2148.

(S)-N-((2S,3R)-1-(Benzyloxy)-3-ethylhex-5-en-2-yl)-2-methylpropane-2-sulfinamide (10g)

Colorless oil (98 mg, 58%); [α]²¹_D +37.7 (c 1.00, CHCl₃); IR (film): ν_max 2958, 1638, 1454, 1100, 911, 736, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.36–7.29 (m, 5H), 5.88–5.67 (m, 1H), 5.10–5.04 (m, 1H), 5.03–4.97 (m, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 3.67–3.62 (m, 0.7H), 3.60–3.56 (m, 0.3H), 3.53–3.48 (m, 3H), 2.26–2.16 (m, 1H), 2.15–2.07 (m, 1H), 1.83–1.76 (m, 0.7H), 1.74–1.69 (m, 0.3H), 1.59–1.49 (m, 1H), 1.46–1.35 (m, 1H), 1.24–1.18 (m, 9H), 0.97–0.89 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 138.2, 137.2, 137.1, 128.5, 127.9, 127.8, 116.8, 116.5, 73.3, 73.2, 71.9, 71.0, 57.9, 57.5, 56.1, 56.0, 41.3, 41.2, 34.0, 33.9, 22.9, 22.7, 22.1, 11.7, 11.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₉H₃₂NO₂S⁺, 338.2148, found: 338.2149.

(S)-N-((S,Z)-1-(Benzyloxy)oct-5-en-2-yl)-2-methylpropane-2-sulfinamide (10h)

Colorless oil (138 mg, 82%); [α]²⁰_D +41.4 (c 1.00, CHCl₃); IR (film): ν_max 2959, 2929, 1454, 1362, 1069, 735, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.26 (m, 5H), 5.42–5.34 (m, 1H), 5.33–5.25 (m, 1H), 4.65–4.57 (m, 0.6H), 4.57–4.53 (m, 0.4H), 4.53–4.49 (m, 0.4H), 4.49–4.45 (m, 0.6H), 3.71–3.66 (m, 1H), 3.65–3.64 (m, 0.4H), 3.57–3.53 (m, 0.6H), 3.53–3.51 (m, 0.4H), 3.50–3.45 (m, 0.6H), 3.44–3.37 (m, 1H), 2.19–2.04 (m, 2H), 2.04–1.96 (m, 2H), 1.78–1.70 (m, 1H), 1.66–1.56 (m, 1H), 1.24–1.19 (m, 9H), 0.95 (t, J = 7.6 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 138.2, 132.7, 132.6, 128.5, 128.2, 127.9, 127.8, 73.4, 73.3, 73.2, 56.2, 55.9, 55.8, 33.4, 32.7, 23.8, 23.6, 22.8, 22.7, 20.7, 14.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₉H₃₂NO₂S⁺, 338.2148, found: 338.2149.

(S)-N-((S)-1-(Benzyloxy)-3,3-dimethylbutan-2-yl)-2-methylpropane-2-sulfinamide (10i)

Colorless oil (64 mg, 66%, dr = 62 : 38); [α]²¹_D +36.2 (c 1.00, CHCl₃); IR (film): ν_max 2955, 2868, 1586, 1474, 1388, 1115, 735, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.27 (m, 5H), 4.61 (d, J = 11.6 Hz, 1H), 4.44 (d, J = 11.6 Hz, 1H), 3.95 (d, J = 8.0 Hz, 1H), 3.83–3.77 (m, 1H), 3.72–3.63 (m, 1H), 3.10–2.96 (m, 1H), 1.25 (s, 9H), 0.94 (s, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.4, 128.4, 127.7, 127.6, 73.3, 71.1, 64.4, 56.4, 35.3, 27.4, 23.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₇H₃₀NO₂S⁺, 312.1992, found: 312.1997.

(S)-N-((R)-1-(Benzyloxy)-3,3-dimethylbutan-2-yl)-2-methylpropane-2-sulfinamide ((1R)-10i)

Colorless oil (39 mg, 25%); [α]²¹_D +22.4 (c 1.00, CHCl₃); IR (film): ν_max 2955, 2867, 1473, 1454, 1364, 1117, 1070 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.28 (m, 5H), 4.56–4.47 (m, 2H), 3.63–3.57 (m, 1H), 3.55–3.50 (m, 1H), 3.50–3.45 (m, 1H), 3.64–3.57 (m, 1H), 3.56–3.50 (m, 1H), 3.18–3.09 (m, 1H), 1.24–1.18 (m, 7H), 1.05–0.99 (m, 9H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 138.2, 128.5, 127.7, 73.3, 71.6, 64.7, 56.3, 34.3, 27.4, 22.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₇H₃₀NO₂S⁺, 312.1992, found: 312.1998.

(S)-N-((S)-1-(Benzyloxy)-3,3,6-trimethylhept-5-en-2-yl)-2-methylpropane-2-sulfinamide (10j)

Colorless oil (70 mg, 57%, dr = 67 : 33); [α]²⁰_D +33.6 (c 0.50, CHCl₃); IR (film): ν_max 2960, 2923, 1587, 1453, 1385, 1180, 1113, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.27 (m, 5H), 5.15 (dd, J = 8.0, 7.2 Hz, 1H), 4.61 (d, J = 11.8 Hz, 1H), 4.44 (d, J = 11.8 Hz, 1H), 3.96 (d, J = 8.8 Hz, 1H), 3.83–3.77 (m, 1H), 3.67 (dd, J = 9.8, 4.2 Hz, 1H), 3.15–3.07 (m, 1H), 2.00–1.95 (m, 2H), 1.73–1.69 (m, 3H), 1.57–1.53 (m, 3H), 1.25 (s, 9H), 0.93–0.88 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.5, 133.6, 128.5, 127.8, 127.6, 120.5, 73.4, 71.2, 63.1, 56.4, 39.0, 38.1, 26.3, 24.9, 24.4, 23.1, 18.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₁H₃₆NO₂S⁺, 366.2461, found: 366.2467.

(S)-N-((R)-1-(Benzyloxy)-3,3,6-trimethylhept-5-en-2-yl)-2-methylpropane-2-sulfinamide ((1R)-10j)

Colorless oil (34 mg, 19%); [α]²²_D +20.4 (c 0.25, CHCl₃); IR (film): ν_max 2917, 2849, 1649, 1454, 1386, 1180, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.28 (m, 5H), 5.26–5.15 (m, 1H), 4.50–4.48 (m, 2H), 3.64–3.59 (m, 2H), 3.54–3.49 (m, 1H), 3.25–3.20 (m, 1H), 2.06–2.00 (m, 2H), 1.73–1.70 (m, 3H), 1.59–1.57 (m, 3H), 1.19 (s, 9H), 1.00–0.98 (m, 3H), 0.98–0.96 (m, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 134.1, 128.5, 127.8, 127.7, 120.4, 73.3, 71.7, 63.8, 56.2, 38.1, 37.9, 26.3, 25.4, 24.9, 22.8, 18.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₁H₃₆NO₂S⁺, 366.2461, found: 366.2465.

(S)-N-((S)-2-(Benzyloxy)-1-cyclopropylethyl)-2-methylpropane-2-sulfinamide (10k)

Colorless oil (60 mg, 61%, dr = 67 : 33); [α]²⁰_D +54.3 (c 1.00, CHCl₃); IR (film): ν_max 2923, 2862, 1587, 1454, 1387, 1117, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.27 (m, 5H), 4.60 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 3.91 (d, J = 2.8 Hz, 1H), 3.69 (dd, J = 9.1, 3.6 Hz, 1H), 3.53 (dd, J = 9.1, 8.2 Hz, 1H), 2.81–2.74 (m, 1H), 1.23 (s, 9H), 0.82–0.73 (m, 1H), 0.66–0.59 (m, 1H), 0.50–0.43 (m, 2H), 0.24–0.14 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.1, 128.6, 127.8, 73.4, 73.0, 59.2, 55.4, 22.7, 13,1, 4.6, 2.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₆H₂₆NO₂S⁺, 296.1679, found: 296.1676.

(S)-N-((R)-2-(Benzyloxy)-1-cyclopropylethyl)-2-methylpropane-2-sulfinamide ((1R)-10k)

Colorless oil (30 mg, 20%); [α]²⁰_D +34.2 (c 0.50, CHCl₃); IR (film): ν_max 2923, 1594, 1454, 1387, 1362, 1072 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.28 (m, 5H), 4.58 (d, J = 11.8 Hz, 1H), 4.54 (d, J = 11.8 Hz, 1H), 3.64–3.58 (m, 3H), 2.60–2.53 (m, 1H), 1.21 (s, 9H), 1.10–1.03 (m, 1H), 0.67–0.59 (m, 2H), 0.46–0.40 (m, 1H), 0.36–0.27 (m, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 138.4, 128.5, 127.8, 127.7, 73.8, 73.4, 61.8, 55.8, 22.7, 14.3, 4.6, 4.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₆H₂₆NO₂S⁺, 296.1679, found: 296.1682.

(S)-N-((S)-2-(Benzyloxy)-1-cyclopentylethyl)-2-methylpropane-2-sulfinamide (10l)

Colorless oil (53 mg, 61%, dr = 54 : 46); [α]²⁰_D +19.4 (c 0.50, CHCl₃); IR (film): ν_max 2952, 1587, 1454, 1387, 1071, 735.6, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.27 (m, 5H), 4.62 (d, J = 11.8 Hz, 1H), 4.46 (d, J = 11.8 Hz, 1H), 3.78 (d, J = 8.4 Hz, 1H), 3.69 (dd, J = 9.5, 3.8 Hz, 1H), 3.63 (dd, J = 9.5, 3.2 Hz, 1H), 3.19–3.11 (m, 1H), 2.21–2.06 (m, 1H), 1.85–1.71 (m, 1H), 1.62–1.56 (m, 2H), 1.56–1.50 (m, 2H), 1.24 (s, 9H), 1.22–1.20 (m, 1H), 1.20–1.10 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.4, 128.5, 127.9, 127.8, 73.4, 72.8, 61.6, 56.2, 42.8, 30.3, 29.8, 25.6, 25.4, 22.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₈H₃₀NO₂S⁺, 324.1992, found: 324.1993.

(S)-N-((R)-2-(Benzyloxy)-1-cyclopentylethyl)-2-methylpropane-2-sulfinamide ((1R)-10l)

Colorless oil (46 mg, 28%); [α]²²_D +43.6 (c 0.25, CHCl₃); IR (film): ν_max 2952, 2920, 2865, 1650, 1453, 1362, 1066, 736, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.29 (m, 5H), 4.58–4.44 (m, 2H), 3.63–3.46 (m, 3H), 3.25–3.14 (m, 1H), 2.26–2.10 (m, 1H), 1.97–1.81 (m, 1H), 1.80–1.70 (m, 1H), 1.60–1.50 (m, 3H), 1.43–1.29 (m, 2H),1.29–1.25 (m, 1H), 1.23–1.19 (m, 9H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 138.4, 128.5, 127.9, 127.8, 76.8, 73.4, 73.3, 61.1, 56.0, 41.8, 30.2, 25.7, 25.3, 22.9, 22.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₈H₃₀NO₂S⁺, 324.1992, found: 324.1994.

tert-Butyl-4-((S)-2-(benzyloxy)-1-(((S)-tert-butylsulfinyl)amino)ethyl)piperidine-1-carboxylate (10m)

Colorless oil (101 mg, 69%, dr = 67 : 33); [α]²⁰_D +10.1 (c 1.00, CHCl₃); IR (film): ν_max 3439, 2922, 1691, 1423, 1364, 1172, 1071, 772 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.28 (m, 5H), 4.58 (d, J = 11.8 Hz, 1H), 4.46 (d, J = 11.8 Hz, 1H), 4.25–3.97 (m, 2H), 3.73–3.60 (m, 3H), 3.18–3.02 (m, 1H), 2.72–2.54 (m, 2H), 1.86–1.73 (m, 2H), 1.56 (d, J = 11.2 Hz, 1H), 1.45 (s, 9H), 1.23 (s, 9H), 1.19–1.04 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.9, 138.0, 128.6, 128.0, 127.9, 79.5, 77.5, 77.2, 76.8, 73.5, 71.0, 56.2, 38.6, 28.9, 28.6, 22.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₃H₃₉N₂O₄S⁺, 439.2625, found: 439.2624.

tert-Butyl-4-((R)-2-(benzyloxy)-1-(((S)-tert-butylsulfinyl)amino)ethyl)piperidine-1-carboxylate ((1R)-10m)

Colorless oil (50 mg, 23%); [α]²⁰_D +27.1 (c 1.00, CHCl₃); IR (film): ν_max 3259, 2922, 1691, 1453, 1364, 1170, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.30 (m, 5H), 4.55 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.26–4.08 (m, 2H), 3.61–3.55 (m, 1H), 3.54–3.45 (m, 2H), 3.24–3.10 (m, 1H), 2.76–2.58 (m, 2H), 1.97–1.79 (m, 2H), 1.67–1.61 (m, 1H), 1.47 (s, 9H), 1.36–1.23 (m, 2H), 1.20 (s, 9H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 154.9, 138.0, 128.6, 128.0, 127.9, 79.5, 73.5, 71.0, 56.2, 38.6, 28.9, 28.6, 22.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₃H₃₉N₂O₄S⁺, 439.2625, found: 439.2626.

(S)-N-((2S,3R)-3-Benzyl-1-(benzyloxy)pentan-2-yl)-2-methylpropane-2-sulfinamide (10n)

Colorless oil (145 mg, 75%); [α]²²_D +12.5 (c 1.00, CHCl₃); IR (film): ν_max 2958, 2925, 2870, 1637, 1454, 1362, 1100, 1071, 735, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.40–7.24 (m, 7H), 7.23–7.12 (m, 3H), 4.57–4.39 (m, 2H), 3.66–3.63 (m, 1H), 3.61–3.60 (m, 0.28H), 3.55–3.52 (m, 1H), 3.52–3.47 (m, 0.72H), 2.81–2.73 (m, 1H), 2.58–2.42 (m, 1H), 2.11–2.05 (m, 0.28H), 2.04–1.94 (m, 0.72H), 1.58–1.46 (m, 0.28H), 1.45–1.33 (m, 1H), 1.33–1.26 (m, 0.72H), 1.26–1.12 (m, 9H), 0.94–0.86 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 141.3, 138.2, 129.3, 129.2, 128.5, 127.9, 127.8, 127.7, 126.0, 73.3, 73.1, 71.8, 71.0, 57.3, 56.6, 56.1, 44.0, 43.6, 36.1, 36.0, 22.9, 22.7, 22.1, 11.7, 11.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + Na]⁺ calcd for C₂₃H₃₃NO₂SNa⁺, 410.2124, found: 410.2129.

(S)-N-((2S,3R)-1-(Benzyloxy)-3-(3-fluorobenzyl)pentan-2-yl)-2-methylpropane-2-sulfinamide (10o)

Colorless oil (131 mg, 65%); [α]²²_D +12.2 (c 1.00, CHCl₃); IR (film): ν_max 2959, 1587, 1453, 1362, 1068, 743, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.39–7.27 (m, 5H), 7.27–7.18 (m, 1H), 6.98–6.82 (m, 3H), 4.54 (d, J = 12.0 Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 3.66–3.59 (m, 2.5H), 3.57–3.51 (m, 0.5H), 3.49–3.40 (m, 1H), 2.70 (dd, J = 13.6, 6.8 Hz, 1H), 2.47 (dd, J = 13.6, 6.8 Hz, 1H), 1.98 (d, J = 6.0 Hz, 1H), 1.46–1.35 (m, 1H), 1.35–1.27 (m, 1H), 1.25 (s, 7.5H), 1.18 (s, 1.5H), 0.89 (t, J = 7.4 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 163.0 (d, J = 243.9 Hz), 143.9 (d, J = 2.0 Hz), 138.1, 129.9 (d, J = 8.2 Hz), 127.9, 127.8, 124.9, 115.9 (d, J = 20.7 Hz), 112.9 (d, J = 20.9 Hz), 73.4, 73.2, 71.7, 70.9, 57.2, 56.6, 56.1, 43.9, 43.5, 35.9, 35.8, 22.9, 22.7, 22.0, 11.5 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −114.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₃H₃₃FNO₂S⁺, 406.2211, found: 406.2214.

(S)-N-((2S,3R)-1-(Benzyloxy)-3-(4-methoxybenzyl)pentan-2-yl)-2-methylpropane-2-sulfinamide (10p)

Colorless oil (170 mg, 82%); [α]²⁰_D +14.0 (c 1.00, CHCl₃); IR (film): ν_max 2957, 1611, 1512, 1246, 1179, 1071, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.38–7.26 (m, 5H), 7.10–7.01 (m, 2H), 6.87–6.77 (m, 2H), 4.56–4.40 (m, 2H), 3.78 (s, 3H), 3.70–3.54 (m, 2H), 3.63–3.46 (m, 1.67H), 3.42–3.38 (m, 0.33H), 2.75–2.60 (m, 1H), 2.53–2.36 (m, 1H), 2.03–1.87 (m, 1H), 1.55–1.48 (m, 0.33H), 1.44–1.34 (m, 1H), 1.34–1.27 (m, 0.67H), 1.27–1.20 (m, 6H), 1.17–1.15 (m, 3H), 0.96–0.84 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 158.0, 157.9, 138.2, 133.2, 132.6, 130.2, 130.1, 128.5, 127.9, 127.8, 127.7, 113.9, 73.3, 73.1, 71.9, 71.1, 57.3, 56.6, 56.1, 56.0, 55.4, 44.2, 43.7, 35.1, 35.0, 22.9, 22.7, 22.6, 22.0, 11.8, 11.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₄H₃₆NO₃S⁺, 418.2410, found: 418.2412.

(S)-N-((2S,3R)-1-(Benzyloxy)-3-(4-(tert-butyl)benzyl)pentan-2-yl)-2-methylpropane-2-sulfinamide (10q)

Colorless oil (145 mg, 66%); [α]²²_D +7.7 (c 1.00, CHCl₃); IR (film): ν_max 2959, 1587, 1455, 1363, 1073, 735, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.25 (m, 7H), 7.10–7.04 (m, 2H), 4.52 (d, J = 11.6 Hz, 1H), 4.41 (d, J = 11.6 Hz, 1H), 3.65–3.62 (m, 1H), 3.59 (d, J = 8.4 Hz, 1H), 3.54–3.48 (m, 1H), 2.79–2.60 (m, 1H), 2.56–2.37 (m, 1H), 2.07–1.89 (m, 1H), 1.45–1.36 (m, 1H), 1.31 (s, 9H), 1.24 (s, 9H), 1.20–1.19 (m, 1H), 1.15–1.13 (m, 1H), 0.95–0.86 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 148.8, 138.2, 138.1, 128.9, 128.5, 127.9, 127.8, 127.7, 125.4, 73.1, 71.1, 56.7, 56.1, 44.2, 35.5, 34.5, 31.5, 22.9, 22.7, 22.4, 11.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₇H₄₂NO₂S⁺, 444.2931, found: 444.2932.

(S)-N-((S)-1-(Benzyloxy)-4-(5-methylfuran-2-yl)butan-2-yl)-2-methylpropane-2-sulfinamide (10r)

Colorless oil (98 mg, 54%); [α]²¹_D +33.0 (c 1.00, CHCl₃); IR (film): ν_max 2922, 1570, 1454, 1362, 1072, 1021, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.28 (m, 5H), 5.92–5.88 (m, 0.37H), 5.85–5.81 (m, 1.63H), 4.62–4.46 (m, 2H), 3.71–3.65 (m, 1H), 3.59–3.52 (m, 1H), 3.51–3.39 (m, 2H), 2.78–2.67 (m, 1H), 2.67–2.53 (m, 1H), 2.24 (s, 3H), 2.09–1.92 (m, 1H), 1.91–1.87 (m, 1H), 1.24–1.19 (m, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 153.5, 153.3, 150.6, 138.2, 128.5, 127.9, 127.8, 106.2, 106.0, 105.9, 73.4, 73.3, 56.1, 56.0, 55.8, 31.8, 24.6, 22.8, 22.7, 13.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₀H₃₀NO₃S⁺, 364.1941, found: 364.1944.

(S)-N-((S)-1-(Benzyloxy)-4-phenylbutan-2-yl)-2-methylpropane-2-sulfinamide (10s)

Colorless oil (114 mg, 64%); [α]²⁰_D +30.8 (c 0.50, CHCl₃); IR (film): ν_max 2924, 1602, 1454, 1363, 1071, 745, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.30 (m, 5H), 7.30–7.27 (m, 2H), 7.20–7.13 (m, 3H), 4.59 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 3.73 (d, J = 7.6 Hz, 1H), 3.68 (dd, J = 9.4, 4.2 Hz, 1H), 3.56 (dd, J = 9.6, 4.4 Hz, 1H), 3.47–3.40 (m, 1H), 2.75–2.68 (m, 1H), 2.66–2.56 (m, 1H), 1.96–1.80 (m, 2H), 1.26–1.23 (m, 7.6H), 1.20–1.19 (m, 1.4H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 141.8, 138.2, 128.7, 128.6, 128.5, 128.0, 126.1, 73.4, 73.3, 56.1, 55.8, 35.2, 32.2, 22.9, 22.8, 22.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₁H₃₀NO₂S⁺, 360.1992, found: 360.1996.

(S)-N-((S)-1-(Benzyloxy)-4-(3-(trifluoromethyl)phenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (10t)

Colorless oil (119 mg, 56%); [α]¹⁹_D +31.7 (c 1.00, CHCl₃); IR (film): ν_max 2921, 1454, 1328, 1163, 1123, 1073, 799, 701 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.47–7.39 (m, 3H), 7.39–7.36 (m, 1H), 7.35–7.28 (m, 5H), 4.63–4.55 (m, 0.68H), 4.53–4.52 (m, 0.32H), 4.52–4.50 (m, 0.32H), 4.49–4.45 (m, 0.68H), 3.79–3.69 (m, 1H), 3.68–3.66 (m, 0.32H), 3.60–3.56 (m, 0.68H), 3.54–3.45 (m, 1H), 3.44–3.36 (m, 1H), 2.89–2.83 (m, 0.32H), 2.81–2.73 (m, 1H), 2.71–2.61 (m, 0.68H), 2.08–1.95 (m, 1H), 1.94–1.86 (m, 1 H), 1.26 (s, 6H), 1.21 (s, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 142.7, 142.5, 138.1, 132.0 (d, J = 23.6 Hz), 130.8 (d, J = 31.8 Hz), 129.0, 128.6, 127.9 (d, J = 5.6 Hz), 125.2 (d, J = 3.5 Hz), 123.0, 73.4, 73.3, 73.2, 56.2, 56.1, 56.0, 55.9, 34.9, 34.3, 32.1, 22.8, 22.7 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₂H₂₉F₃NO₂S⁺, 428.1866, found: 428.1867.

(S)-N-((2S,3S)-1-(Benzyloxy)-3-methylpentan-2-yl)-2-methylpropane-2-sulfinamide (10u)

Colorless oil (79 mg, 75%, dr = 68 : 32); [α]²⁰_D +41.4 (c 1.00, CHCl₃); IR (film): ν_max 2959, 2924, 2874, 1591, 1454, 1362, 1074 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.28 (m, 5H), 4.59 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 3.69 (d, J = 7.2 Hz, 1H), 3.65–3.61 (m, 2H), 3.29–3.17 (m, 1H), 1.83–1.72 (m, 1H), 1.57–1.48 (m, 1H), 1.23 (s, 9H), 1.15–1.05 (m, 1H), 0.97–0.88 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.3, 128.5, 127.9, 127.8, 73.2, 70.7, 59.9, 56.0, 36.5, 25.5, 22.9, 15.1, 11.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₇H₃₀NO₂S⁺, 312.1992, found: 312.1997.

(S)-N-((2R,3S)-1-(Benzyloxy)-3-methylpentan-2-yl)-2-methylpropane-2-sulfinamide ((2R)-10u)

Colorless oil (37 mg, 24%); [α]²¹_D +44.2 (c 1.00, CHCl₃); IR (film): ν_max 2959, 2926, 2872, 1590, 1454, 1362, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.28 (m, 5H), 4.54 (d, J = 12 Hz, 1H), 4.48 (d, J = 12 Hz, 1H), 3.52–3.44 (m, 2H), 3.43–3.38 (m, 1H), 3.30 (d, J = 6.0 Hz, 1H), 1.83–1.78 (m, 1H), 1.62–1.47 (m, 1H), 1.31–1.26 (m, 1H), 1.19 (s, 9H), 0.96–0.88 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 138.3, 128.5, 127.8, 73.3, 72.0, 59.4, 56.0, 36.4, 26.2, 22.7, 14.6, 11.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₇H₃₀NO₂S⁺, 312.1992, found: 312.1993.

(R)-N-((2R,3S)-1-(Benzyloxy)-3-methylpentan-2-yl)-2-methylpropane-2-sulfinamide (10v)

A solution of 2-(benzyloxymethylsulfonyl)-pyridine 9 (395 mg, 1.50 mmol) in THF was dropped into the mixture of imine 8v (94 mg, 0.50 mmol) with SmI₂ (30 ml, 3.00 mmol, 0.1 M in THF) at room temperature under an Ar atmosphere. The reaction mixture was quenched with H₂O (0.20 ml), then the organic layer was washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 3 : 1) to give 10v. Colorless oil (99 mg, 80%, dr = 80 : 20); [α]²⁰_D −38.4 (c 1.00, CHCl₃); IR (film): ν_max 2959, 2924, 2873, 1454, 1362, 1067, 736, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.27 (m, 5H), 4.57 (d, J = 12.0 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H), 3.69–3.62 (m, 1H), 3.62–3.57 (m, 1H), 3.49 (d, J = 8.0 Hz, 1H), 3.40–3.30 (m, 1H), 1.79–1.68 (m, 1H), 1.50–1.42 (m, 1H), 1.23 (s, 9H), 1.17–1.10 (m, 1H), 0.91–0.85 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 138.3, 128.5, 127.9, 127.8, 73.3, 71.5, 59.6, 56.2, 36.7, 26.1, 22.9, 14.9, 11.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₇H₃₀NO₂S⁺, 312.1992, found: 312.1995.

(R)-N-((2S,3S)-1-(Benzyloxy)-3-methylpentan-2-yl)-2-methylpropane-2-sulfinamide ((2S)-10v)

Colorless oil (25 mg, 16%); [α]²⁰_D −26.4 (c 1.00, CHCl₃); IR (film): ν_max 2959, 2924, 2873, 1454, 1362, 1067, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.27 (m, 5H), 4.53 (d, J = 12.2 Hz, 1H), 4.49 (d, J = 12.2 Hz, 1H), 3.55–3.47 (m, 2H), 3.44 (d, J = 6.4 Hz, 1H), 3.30–3.25 (m, 1H), 1.84–1.76 (m, 1H), 1.63–1.51 (m, 1H), 1.20 (s, 9H), 1.18–1.12 (m, 1H), 0.98–0.86 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 138.3, 128.5, 127.8, 73.4, 71.6, 60.4, 56.0, 37.2, 25.6, 22.7, 15.5, 11.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₇H₃₀NO₂S⁺, 312.1992, found: 312.1995.

(S)-N-(1-(Benzyloxy)-2,4-dimethylpentan-2-yl)-2-methylpropane-2-sulfinamide (10w)

A solution of 2-(benzyloxymethylsulfonyl)-pyridine 9 (395 mg, 1.50 mmol) in THF was dropped into the mixture of imine 8w (102 mg, 0.50 mmol) with SmI₂ (30 ml, 3.00 mmol, 0.1 M in THF) at room temperature under an Ar atmosphere. The reaction mixture was quenched with H₂O (0.20 ml), then the organic layer was washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 3 : 1) to give 10w. Colorless oil (84 mg, 52%); [α]²³_D +36.0 (c 0.25, CHCl₃); IR (film): ν_max 2955, 1455, 1362, 1200, 1099, 919, 736, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.27 (m, 5H), 4.61 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 3.72–3.69 (m, 1H), 3.45–3.68 (m, 2H), 1.75–1.70 (m, 1H), 1.52–1.42 (m, 2H), 1.34–1.30 (m, 3H), 1.20 (s, 9H), 0.96–0.88 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 137.6, 127.5, 126.8, 126.7, 77.5, 72.5, 57.8, 54.7, 47.1, 24.3, 24.2, 22.7, 21.9, 21.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₈H₃₂NO₂S⁺, 326.2148, found: 326.2149.

tert-Butyl (S)-(1-(benzyloxy)-4-methylpentan-2-yl)carbamate (11)

A cooled (0 °C) solution of 10d (1.00 g, 3.22 mmol) in MeOH (14 mL) was treated with a solution of HCl/dioxane (2.80 mL). After being stirred for 30 min, the reaction mixture was concentrated. The resulting mixture was diluted with DCM (13 mL), and Boc₂O (1.18 g, 6.44 mmol) and TEA (1.80 mL, 12.88 mmol) were added. After being stirred overnight, the mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 10 : 1) to give 11. Colorless oil (662 mg, 67%, two steps); [α]²³_D −34.6 (c 1.00, CHCl₃); IR (film): ν_max 3348, 2956, 1713, 1498, 1365, 1171, 1101, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.27 (m, 5H), 4.67 (d, J = 7.6 Hz, 1H), 4.55 (d, J = 12.2 Hz, 1H), 4.48 (d, J = 12.2 Hz, 1H), 3.89–3.77 (m, 1H), 3.50–3.41 (m, 2H), 1.68–1.56 (m, 1H), 1.44 (s, 9H), 1.42–1.35 (m, 2H), 0.94–0.89 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 155.7, 138.5, 128.5, 127.7, 127.6, 79.1, 73.3, 72.6, 48.7, 41.4, 28.6, 25.0, 23.1, 22.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + Na]⁺ calcd for C₁₈H₂₉NO₃Na⁺, 330.2040, found: 330.2038.

tert-Butyl (S)-(1-hydroxy-4-methylpentan-2-yl)carbamate (12)

Compound 11 (500 mg, 1.52 mmol) and 10% Pd/C (50 mg) were stirred in MeOH (50 mL) for 4 h under a H₂ atmosphere. Then the mixture was filtered to give a crude alcohol, which was purified by flash chromatography on silica gel (PE/EA = 4 : 1) to give 12. Colorless oil (267 mg, 81%); [α]²³_D −20.3 (c 1.00, CHCl₃); IR (film): ν_max 3348, 2956, 1713, 1171, 1101, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.68–4.53 (m, 1H), 3.77–3.62 (m, 1H), 3.67–3.60 (m, 1H), 3.54–3.42 (m, 1H), 2.83–2.60 (m, 1H), 1.68–1.62 (m, 1H), 1.44 (s, 9H), 1.34–1.27 (m, 2H), 0.97–0.87 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 156.7, 79.8, 66.7, 51.2, 40.7, 28.5, 24.9, 23.2, 22.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₁H₂₄NO₃⁺, 218.1681, found: 218.1685.

(tert-Butoxycarbonyl)-L-leucine (13)

To a cooled (0 °C) solution of 12 (180 mg, 0.83 mmol) in DCM (4 mL) was slowly added Dess–Martin periodinane (880 mg, 2.08 mmol). After being stirred for 30 min, the reaction mixture was carefully quenched with a saturated aqueous solution of NaHCO₃ and solid Na₂S₂O₃. The resulting mixture was extracted with DCM (20 mL × 3) and the combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to give a crude aldehyde without further purification. A solution of the above crude aldehyde in t-BuOH/2-methyl-2-butene (1/3 mL) was treated with a solution of NaClO₂ (224 mg, 2.49 mmol) and NaH₂PO₄·2H₂O (388 mg, 2.49 mmol) in water (3 mL). After being stirred for 8 h, the reaction mixture was extracted with EtOAc (30 mL × 3) and the combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to give a crude acid. The residue was purified by flash chromatography on silica gel (DCM/MeOH = 100 : 1–50 : 1) to give 13. Colorless oil (134 mg, 70%, two steps); [α]²²_D −29.0 (c 1.00, DMF); IR (film): ν_max 3387, 2956, 1714, 1649, 1251, 1019, 750, 697 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.94–4.79 (m, 1H), 4.35–4.25 (m, 1H), 1.79–1.63 (m, 2H), 1.57–1.50 (m, 1H), 1.44 (s, 9H), 0.98–0.91 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 177.7, 155.9, 80.4, 52.1, 41.4, 28.4, 24.9, 23.0, 21.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₁H₂₂NO₄⁺, 232.1543, found: 232.1549.

tert-Butyl ((2S,3R)-1-(benzyloxy)-3-(3-fluorobenzyl)pentan-2-yl)carbamate (14)

To a cooled (0 °C) solution of 10o (1.90 g, 4.69 mmol) in MeOH (20 mL) was added dropwise a solution of HCl/dioxane (4.00 mL). After being stirred for 30 min, the reaction mixture was concentrated. The resulting mixture was diluted with DCM (20 mL), and then Boc₂O (2.04 g, 9.38 mmol) and TEA (2.6 ml, 18.76 mmol) were added. After stirring overnight, the mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to give a crude middle compound without further purification. Above crude middle compound and 10% Pd/C (190 mg) were stirred in MeOH (100 mL) for 4 h under a H₂ atmosphere, and filtered to give a crude alcohol, which was purified by flash chromatography on silica gel (PE/EA = 4 : 1) to give 14. Colorless oil (1.28 g, 88%, three steps); [α]²²_D −6.4 (c 1.00, CHCl₃); IR (film): ν_max 3356, 2967, 1689, 1589, 1488, 1366, 1170 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.26–7.19 (m, 1H), 6.98–6.93 (m, 1H), 6.91–6.85 (m, 2H), 4.84–4.63 (m, 1H), 3.77–3.68 (m, 1H), 3.67–3.59 (m, 2H), 2.75 (dd, J = 13.6, 4.2 Hz, 1H), 2.70–2.64 (m, 0.3H), 2.60 (d, J = 6.8 Hz, 1H), 2.57–2.42 (m, 0.7H), 1.90–1.79 (m, 1H), 1.45 (s, 9H), 1.40–1.28 (m, 2H), 0.97–0.88 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.0 (d, J = 243.9 Hz), 156.8, 143.6, 129.9 (d, J = 8.0 Hz), 124.8 (d, J = 8.1 Hz), 115.9 (d, J = 20.7 Hz), 113.0 (d, J = 20.9 Hz), 79.9, 64.5, 54.5, 54.3, 43.2, 42.5, 36.5, 35.9, 28.5, 22.6, 11.8, 10.8 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + Na]⁺ calcd for C₁₇H₂₆FNO₃Na⁺ (M + Na)⁺, 334.1789, found: 334.1789.

(2S,3R)-2-Amino-3-(3-fluorobenzyl)pentanoic acid hydrochloride (15)

Dess–Martin periodinane (2.05 g, 4.83 mmol) was carefully added to a cooled (0 °C) solution of 14 (600 mg, 1.93 mmol) in DCM (8 mL) and stirred for 30 min. Then the reaction mixture was carefully quenched with a saturated aqueous solution of NaHCO₃ and solid Na₂S₂O₃. The mixture was extracted with DCM (30 mL × 3) and the combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to give a crude aldehyde without further purification. The above aldehyde was dissolved in t-BuOH/2-methyl-2-butene (2.3/7.0 mL) and NaClO₂ (589 mg, 5.79 mmol) and NaH₂PO₄·2H₂O (902 mg, 5.79 mmol) in water (7 mL) was added dropwise. After stirring for 8 h, the reaction mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to give a crude acid without further purification. The above crude acid was dissolved in MeOH (8 mL) and treated with a solution of HCl/MeOH (2.00 mL, 3 M) for 2 h. The mixture was directly concentrated to give a crude salt, which was recrystallized to give 15. White solid (287 mg, 66%, three steps); mp 103.6–105.6 °C; [α]²⁰_D −33.6 (c 0.50, MeOH); IR (film): ν_max 3421, 2966, 1732, 1589, 1489, 1253, 784, 691 cm⁻¹; ¹H NMR (400 MHz, CD₃OD) δ 7.41–7.31 (m, 1H), 7.14–7.07 (m, 1H), 7.07–6.95 (m, 2H), 3.8–3.82 (m, 1H), 2.87–2.67 (m, 2H), 2.32–2.12 (m, 1H), 1.65–1.48 (m, 1H), 1.43–1.30 (m, 1H), 1.07–0.95 (m, 3H) ppm; ¹³C{¹H} NMR (150 MHz, CD₃OD) δ 171.0, 164.4 (d, J = 243.3 Hz), 143.3 (d, J = 7.1 Hz), 131.5 (d, J = 8.3 Hz), 126.2, 117.0 (d, J = 21.5 Hz), 113.2 (d, J = 21.2 Hz), 55.3, 44.8, 44.5, 36.7, 36.6, 23.4, 23.0, 12.1, 11.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₂H₁₇FNO₂⁺, 226.1238, found: 226.1239.

General procedure for the synthesis of 16a, 16b and 16c

A cooled (0 °C) solution of 10n/10o/10p (10.12 mmol) in MeOH (40 mL) was treated with a solution of HCl/dioxane (8.00 mL) for 30 min. The reaction mixture was concentrated and the resulting mixture was dissolved in DCM (40 mL). Boc₂O (4.41 g, 20.24 mmol) and TEA (5.63 mL, 40.48 mmol) were added. After being stirred overnight, the mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with DCM (60 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 10 : 1) to give the title product (16a, 16b and 16c).

tert-Butyl ((2S,3R)-3-benzyl-1-(benzyloxy)pentan-2-yl)carbamate (16a)

Colorless oil (2.52 g, 65%, two steps); [α]²³_D −9.1 (c 3.00, CHCl₃); IR (film): ν_max 3446, 2965, 1699, 1496, 1365, 1170, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.31 (m, 2H), 7.31–7.22 (m, 5H), 7.19–7.13 (m, 3H), 4.79–4.65 (m, 1H), 4.52–4.36 (m, 2H), 3.97–3.78 (m, 1H), 3.57–3.41 (m, 2H), 2.85–2.74 (m, 0.3H), 2.70–2.60 (m, 0.7H), 2.58–2.48 (m, 0.7H), 2.44–2.37 (m, 0.3H), 2.03–1.85 (m, 1H), 1.44 (s, 9H), 1.38–1.20 (m, 2H), 0.95–0.78 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 156.0, 155.8, 141.3, 138.3, 129.2, 129.1, 128.4, 128.3, 127.8, 127.7, 125.9, 79.1, 73.2, 73.0, 70.8, 70.4, 51.7, 51.5, 43.2, 42.4, 36.7, 35.8, 28.5, 22.3, 11.5, 10.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₄H₃₄NO₄⁺, 384.2533, found: 384.2536.

tert-Butyl ((2S,3R)-1-(benzyloxy)-3-(4-methoxybenzyl)pentan-2-yl)carbamate (16b)

Colorless oil (3.13 g, 75%, two steps); [α]²³_D −12.7 (c 1.00, CHCl₃); IR (film): ν_max 3344, 2964, 1635, 1512, 1246, 1173, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.26 (m, 5H), 7.12–7.05 (m, 2H), 7.85–7.78 (m, 2H), 4.79–4.65 (m, 0.8H), 4.53–4.51 (m, 0.2H), 4.50–4.36 (m, 2H), 3.92–3.80 (m, 1H), 3.78 (s, 3H), 3.57–3.42 (m, 2H), 2.77–2.71 (m, 0.2H), 2.63–2.52 (m, 0.8H), 2.52–2.45 (m, 0.8H), 2.42–2.30 (m, 0.2H), 1.95–1.82 (m, 1H), 1.44 (s, 9H), 1.34–1.17 (m, 2H), 0.98–0.81 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 157.9, 156.0, 155.8, 138.3, 133.3, 130.2, 130.1, 128.5, 127.7, 113.8, 79.2, 73.3, 73.1, 70.8, 70.5, 55.4, 51.4, 43.4, 35.7, 34.9, 28.6, 22.3, 11.6, 10.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₅H₃₆NO₄⁺, 414.2639, found: 414.2641.

tert-Butyl ((2S,3R)-1-(benzyloxy)-3-(3-fluorobenzyl)pentan-2-yl)carbamate (16c)

Colorless oil (3.25 g, 76%, two steps); [α]²²_D −8.3 (c 1.00, CHCl₃); IR (film): ν_max 3447, 2964, 1699, 1614, 1488, 1390, 1248, 1099, 747 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.36–7.25 (m, 5H), 7.25–7.19 (m, 1H), 6.97–6.84 (m, 3H), 4.78–4.70 (m, 0.75H), 4.54–4.41 (m, 0.25H), 4.51–4.38 (m, 2H), 3.92–3.76 (m, 1H), 3.59–3.43 (m, 2H), 2.86–2.73 (m, 0.25H), 2.72–2.59 (m, 0.75H), 2.59–2.45 (m, 0.75H), 2.46–2.39 (m, 0.25H), 2.00–1.89 (m, 1H), 1.45 (s, 9H), 1.33–1.20 (m, 2H), 0.94–0.84 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 162.5 (d, J = 243.7 Hz), 156.0, 155.8, 144.1, 138.2, 129.7 (d, J = 8.3 Hz), 128.5, 127.8 (d, J = 4.0 Hz), 125.0, 124.8, 116.0 (d, J = 20.6 Hz), 112.8 (d, J = 20.9 Hz), 79.3, 73.3, 73.2, 70.7, 70.3, 51.8, 51.5, 43.1, 42.4, 36.5, 35.7, 29.8, 28.5, 22.3, 11.6, 10.5 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −114.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + Na]⁺ calcd for C₂₄H₃₂FNO₃Na⁺, 424.2258, found: 424.2258.

General procedure for the synthesis of 17a, 17b and 17c

Compounds 16a/16b/16c (6.50 mmol) were stirred in HMPA (1.35 ml, 7.80 mmol) and THF (28 mL) at −78 °C, and then a solution of LiHMDS (7.80 ml, 7.80 mmol, 1 M in THF) was slowly added dropwise and stirred for 30 min. The reaction mixture was allowed to warm to −15 °C and MeOTf (1.47 ml, 13.00 mmol) was added. The resulting mixture was stirred for an additional 15 min. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 10 : 1) to give the desired product (17a, 17b and 17c).

tert-Butyl ((2S,3R)-3-benzyl-1-(benzyloxy)pentan-2-yl)(methyl)carbamate (17a)

Colorless oil (2.09 g, 81%); [α]²³_D +4.8 (c 1.00, CHCl₃); IR (film): ν_max 3444, 2970, 1688, 1454, 1365, 1149, 737, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.28 (m, 5H), 7.27–7.23 (m, 2H), 7.20–7.12 (m, 3H), 4.62–4.48 (m, 1H), 4.46–4.41 (m, 0.5H), 4.41–4.38 (m, 0.5H), 4.38–4.02 (m, 1H), 3.68–3.56 (m, 2H), 2.84–2.73 (m, 3H), 2.72–2.63 (m, 1H), 2.55–2.38 (m, 1H), 2.17–1.93 (m, 1H), 1.49–1.42 (m, 9H), 1.31–1.17 (m, 2H), 0.90–0.79 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 156.9, 156.5, 141.2, 140.7, 138.6, 138.4, 129.1, 128.5, 128.4, 127.7, 127.6, 126.0, 125.9, 125.8, 79.6, 79.4, 79.3, 72.9, 70.4, 70.2, 69.7, 69.5, 56.4, 56.1, 39.8, 39.4, 39.2, 36.0, 35.7, 35.6, 30.5, 29.8, 28.7, 28.6, 21.6, 21.2, 9.3, 8.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₅H₃₆NO₃⁺, 398.2690, found: 398.2688.

tert-Butyl ((2S,3R)-1-(benzyloxy)-3-(4-methoxybenzyl)pentan-2-yl)(methyl)carbamate (17b)

Colorless oil (2.64 g, 95%); [α]²⁴_D +5.1 (c 1.00, CHCl₃); IR (film): ν_max 3448, 2966, 1680, 1512, 1246, 1149, 1037, 737 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.39–7.25 (m, 5H), 7.10–7.01 (m, 2H), 6.85–6.75 (m, 2H), 4.65–4.50 (m, 1H), 4.47–4.33 (m, 1H), 4.37–3.96 (m, 1H), 3.79 (s, 3H), 3.67–3.66 (m, 2H), 2.85–2.71 (m, 3H), 2.68–2.57 (m, 1H), 2.47–2.35 (m, 1H), 2.12–1.83 (m, 1H), 1.49–1.41 (m, 9H), 1.27–1.16 (m, 2H), 0.91–0.81 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 157.9, 156.5, 138.6, 138.4, 133.1, 132.7, 129.9, 128.5, 128.4, 127.7, 127.6, 113.8, 79.6, 79.2, 72.9, 70.4, 69.7, 55.4, 39.5, 39.3, 35.0, 34.6, 28.7, 28.6, 21.5, 21.1, 21.0, 9.3, 8.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₆H₃₈NO₄⁺, 428.2795, found: 428.2796.

tert-Butyl-((2S,3R)-1-(benzyloxy)-3-(3-fluorobenzyl)pentan-2-yl)(methyl)carbamate (17c)

Colorless oil (2.51 g, 93%); [α]²⁵_D +1.3 (c 1.00, CHCl₃); IR (film): ν_max 3445, 2969, 1689, 1452, 1365, 1251, 1142, 697 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.38–7.26 (m, 5H), 7.24–7.16 (m, 1H), 6.97–6.78 (m, 3H), 4.62–4.48 (m, 1H), 4.47–4.35 (m, 1H), 4.37–4.00 (m, 1H), 3.68–3.53 (m, 2H), 2.85–2.70 (m, 3H), 2.68–2.5 8 (m, 1H), 2.56–2.37 (m, 1H), 2.17–1.98 (m, 1H), 1.49–1.42 (m, 9H), 1.32–1.15 (m, 2H), 0.92–0.78 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 163.0 (d, J = 243.8 Hz), 156.4, 156.3, 144.3, 143.8, 143.4, 138.4 (d, J = 19.1 Hz), 129.7, 128.5, 128.4, 127.7 (d, J = 7.3 Hz), 124.8, 115.9 (d, J = 20.6 Hz), 112.9 (d, J = 19.9 Hz), 79.7, 79.5, 79.3, 73.0, 70.5, 70.2, 69.7, 58.6, 56.3, 39.7, 39.3, 39.2, 35.8, 35.7, 35.4, 30.6, 29.8, 28.6, 21.5, 21.4, 21.2, 9.3, 8.8 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₅H₃₅FNO₃⁺, 416.2596, found: 416.2596.

General procedure for the synthesis of 18a, 18b, 18c, 24a, 24b, 24c and 24d

Compounds 17a/17b/17c/23a/23b/23c/23d (5.00 mmol) were stirred in DCM (20 mL) at 0 °C and were treated with TFA (4.00 mL) for 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM (20 mL). HATU (2.85 g, 7.50 mmol), DIPEA (2.61 mL, 15.00 mmol), and N-Boc-L-Val-OH (1.19 g, 5.50 mmol) were added in turn and the resulting mixture was stirred overnight. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 8 : 1) to give the desired product (18a, 18b, 18c, 24a, 24b, 24c and 24d).

tert-Butyl-((S)-1-(((2S,3R)-3-benzyl-1-(benzyloxy)pentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (18a)

Colorless oil (2.33 g, 94%, two steps); [α]²³_D +10.0 (c 1.00, CHCl₃); IR (film): ν_max 3434, 2966, 1636, 1495, 1171, 739, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.30 (m, 2H), 7.30–7.23 (m, 5H), 7.20–7.06 (m, 3H), 5.41–5.15 (m, 1H), 4.84–4.66 (m, 1H), 4.59–4.50 (m, 1H), 4.47–4.36 (m, 2H), 3.66–3.52 (m, 2H), 3.13–2.98 (m, 3H), 2.83–2.80 (m, 0.5H), 2.72–2.67 (m, 0.5H), 2.56–2.45 (m, 1H), 2.21–2.07 (m, 1H), 2.03–1.87 (m, 1H), 1.45–1.40 (m, 9H), 1.31–1.26 (m, 1H), 1.22–1.12 (m, 1H), 0.93–0.85 (m, 6H), 0.79 (t, J = 7.4 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.4, 156.2, 140.8, 138.1, 129.1, 128.5, 128.4, 128.0, 127.9, 127.8, 126.1, 79.5, 73.2, 73.1, 69.8, 55.7, 38.8, 38.3, 35.9, 35.4, 31.3, 31.1, 28.5, 28.4, 21.5, 20.5, 19.7, 17.7, 17.0, 9.4, 8.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₀H₄₅N₂O₄⁺, 497.3374, found: 497.3370.

tert-Butyl-((S)-1-(((2S,3R)-1-(benzyloxy)-3-(4-methoxybenzyl)pentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (18b)

Colorless oil (2.10 g, 80%, two steps); [α]²⁴_D +8.0 (c 1.00, CHCl₃); IR (film): ν_max 3438, 2965, 1636, 1512, 1365, 1247, 1175, 1109 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.38–7.23 (m, 5H), 7.13–7.01 (m, 2H), 6.87–6.77 (m, 2H), 5.42–5.13 (m, 1H), 4.83–4.69 (m, 0.76H), 4.56–4.53 (m, 0.24H), 4.52–4.43 (m, 1H), 4.43–4.27 (m, 2H), 3.78 (s, 3H), 3.65–3.50 (m, 2H), 3.13–2.89 (m, 3H), 2.81–2.78 (m, 0.24H), 2.68–2.59 (m, 0.76H), 2.54–2.42 (m, 1H), 2.19–1.88 (m, 2H), 1.41 (s, 9H), 1.24–1.13 (m, 2H), 0.96–0.83 (m, 6H), 0.82–0.74 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.4, 157.9, 156.2, 138.1, 132.7, 130.0, 128.5, 128.4, 128.0, 127.9, 127.8, 113.8, 79.4, 73.1, 69.7, 55.7, 55.3, 38.9, 34.8, 31.1, 28.5, 28.4, 21.3, 19.6, 17.7, 9.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₁H₄₇N₂O₅⁺, 527.3480, found: 527.3480.

tert-Butyl ((S)-1-(((2S,3R)-1-(benzyloxy)-3-(3-fluorobenzyl)pentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (18c)

Colorless oil (2.18 g, 85%, two steps); [α]²⁶_D +6.7 (c 1.00, CHCl₃, rotamers); IR (film): ν_max 3320, 2965, 1708, 1637, 1488, 1390, 1172, 774 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.27 (m, 5H), 7.26–7.23 (m, 1H), 6.94–6.82 (m, 3H), 5.40–5.14 (m, 1H), 4.83–4.66 (m, 0.7H), 4.56–4.53 (m, 0.3H), 4.50–4.42 (m, 1H), 4.42–4.29 (m, 2H), 3.63–3.48 (m, 2H), 3.13–2.96 (m, 3H), 2.83–2.81 (m, 0.3H), 2.73–2.65 (m, 0.7H), 2.58–2.48 (m, 1H), 2.20–2.06 (m, 1H), 2.02–1.87 (m, 1H), 1.41 (s, 9H), 1.27–1.14 (m, 2H), 0.97–0.87 (m, 6H), 0.85–0.75 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.3, 162.9 (d, J = 244.0 Hz), 156.0, 143.3 (d, J = 7.0 Hz), 137.8, 129.7 (d, J = 8.1 Hz), 128.4, 128.3, 127.9, 127.7, 127.6, 124.6, 115.7 (d, J = 20.6 Hz), 112.9 (d, J = 20.8 Hz), 79.4, 73.1, 69.7, 55.6, 38.6, 35.5, 31.0, 28.4, 28.3, 21.3, 19.5, 17.6, 9.3 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₀H₄₄FN₂O₄⁺, 515.3280, found: 515.3281.

Benzyl N-((tert-butoxycarbonyl)-L-valyl)-N-methyl-L-isoleucinate (24a)^13d

Colorless oil (1.78 g, 82%, two steps).

Benzyl N-((tert-butoxycarbonyl)-L-valyl)-N-methyl-L-valinate (24b)

Colorless oil (1.47 g, 70%, two steps); [α]²³_D −80.8 (c 1.00, CHCl₃); IR (film) ν_max 2965, 1736, 1654, 1497, 1366, 1175, 1130, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.31 (m, 5H), 5.25–5.20 (m, 1H), 5.17–5.13 (m, 1H), 5.07–5.03 (m, 1H), 5.00 (d, J = 10.8 Hz, 1H), 4.35 (dd, J = 9.2, 6.8 Hz, 1H), 2.99–2.96 (m, 3H), 2.27–2.17 (m, 1H), 1.88–1.78 (m, 1H), 1.41 (s, 9H), 1.03–1.00 (m, 3H), 0.98–0.88 (m, 1H), 0.86–0.82 (m, 8H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.6, 170.8, 156.1, 135.6, 128.7, 128.6, 128.6, 79.6, 66.8, 61.6, 55.5, 31.4, 31.2, 28.4, 27.2, 20.0, 19.4, 18.7, 17.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₃H₃₇N₂O₅⁺, 421.2697, found: 421.2694.

Benzyl N-((tert-butoxycarbonyl)-L-valyl)-N-methyl-L-leucinate (24c)

Colorless oil (1.67 g, 77%, two steps); [α]²³_D −39.9 (c 1.00, CHCl₃); IR (film) ν_max 2960, 1738, 1711, 1498, 1456, 1367, 1265, 694 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.30 (m, 5H), 5.43 (dd, J = 10.8, 5.2 Hz, 1H), 5.20–5.05 (m, 3H), 4.39 (dd, J = 9.2, 6.4 Hz, 1H), 2.99–2.95 (m, 3H), 1.95–1.87 (m, 1H), 1.80–1.70 (m, 2H), 1.52–1.45 (m, 1H), 1.42 (s, 9H), 0.94–0.88 (m, 9H), 0.87–0.84 (m, 3H) ppm; ¹³C{¹H} NMR (CDCl₃, 100 MHz) δ 173.5, 171.7, 156.1, 135.5, 128.7, 128.6, 79.6, 67.2, 55.4, 54.6, 37.0, 31.3, 31.1, 28.4, 24.8, 23.4, 21.5, 19.5, 17.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₄H₃₉N₂O₅⁺, 435.2854, found: 435.2849.

Benzyl N-((tert-butoxycarbonyl)-L-valyl)-N-methyl-L-phenylalaninate (24d)

Colorless oil (1 g, 68%, two steps); [α]²³_D −72.4 (c 1.00, CHCl₃); IR (film) ν_max 2968, 1741, 1649, 1498, 1407, 1366, 1012, 696 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.32 (m, 3H), 7.31–7.28 (m, 2H), 7.25–7.16 (m, 5H), 5.41 (dd, J = 9.6, 5.6 Hz, 1H), 5.22–5.18 (m, 1H), 5.11–5.06 (m, 1H), 5.06–5.02 (m, 1H), 4.32 (dd, J = 9.2, 6.0 Hz, 1H), 3.40 (dd, J = 14.4, 5.6 Hz, 1H), 2.99 (dd, J = 14.4, 10.0 Hz, 1H), 2.90–2.86 (m, 3H), 1.90–1.80 (m, 1H), 1.40 (s, 9H), 0.90–0.86 (m, 3H), 0.84–0.80 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.9, 170.6, 155.8, 136.9, 135.4, 129.0, 128.7, 128.6, 128.6, 126.9, 79.5, 67.3, 58.4, 55.1, 34.7, 32.8, 31.3, 28.5, 19.6, 17.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₇H₃₇N₂O₅⁺, 469.2697, found: 469.2692.

General procedure for the synthesis of 19a, 19b, 19c, 25a, 25b, 25c and 25d

Compounds 18a/18b/18c/24a/24b/24c/24d (3.20 mmol) were dissolved in DCM (16 mL) at 0 °C and treated with TFA (3.20 mL) for 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM (16 mL). HATU (1.82 g, 4.8 mmol), DIPEA (1.67 ml, 9.6 mmol), and N-Boc-L-Val-OH (0.76 g, 3.52 mmol) were added in turn and the resulting mixture was stirred overnight. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 3 : 1) to give the desired product (19a, 19b, 19c, 25a, 25b, 25c and 25d).

tert-Butyl ((S)-1-(((S)-1-(((2S,3R)-3-benzyl-1-(benzyloxy)pentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (19a)

Colorless oil (1.66 g, 87%, two steps); [α]²³_D −6.4 (c 1.00, CHCl₃); IR (film): ν_max 3444, 2963, 1633, 1517, 1454, 1174, 739, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.35–7.29 (m, 3H), 7.29–7.24 (m, 5H), 7.19 (d, J = 7.2 Hz, 1H), 7.15–7.10 (m, 2H), 6.69–6.55 (m, 1H), 5.13–5.08 (m, 0.7H), 4.94–4.87 (m, 0.3H), 4.79–4.75 (m, 1H), 4.53–4.47 (m, 0.3H), 4.45–4.30 (m, 1.7H), 3.99–3.84 (m, 1H), 3.69–362 (m, 0.3H), 3.60–3.52 (m, 1.7H), 3.16–2.97 (m, 3H), 2.84–2.76 (m, 0.3H), 2.75–2.64 (m, 0.7H), 2.59–2.48 (m, 1H), 2.25–2.17 (m, 0.3H), 2.10–1.97 (m, 2.7H), 1.45–1.43 (m, 9H), 1.04–0.94 (m, 2H), 0.92–0.85 (m, 12H), 0.75 (t, J = 7.2 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 172.4, 171.5, 155.8, 140.7, 138.0, 129.0, 128.5, 128.4, 128.0, 127.8, 126.1, 79.8, 73.3, 73.2, 69.6, 63.2, 60.1, 58.6, 54.2, 38.7, 35.8, 31.5, 31.3, 30.9, 28.4, 21.5, 19.6, 19.3, 17.7, 9.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₅H₅₄N₃O₅⁺, 596.4058, found: 596.4059.

tert-Butyl ((S)-1-(((S)-1-(((2S,3R)-1-(benzyloxy)-3-(4-methoxybenzyl)pentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (19b)

Colorless oil (1.72 g, 86%, two steps); [α]²³_D −4.7 (c 1.00, CHCl₃); IR (film): ν_max 3325, 2962, 1650, 1512, 1455, 1247, 1176, 1039 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.36–7.26 (m, 5H), 7.07–6.98 (m, 2H), 6.82–6.77 (m, 2H), 6.62–6.47 (m, 1H), 5.13–5.03 (m, 1H), 4.77 (dd, J = 8.8, 6.8 Hz, 1H), 4.52–4.43 (m, 1H), 4.40–4.32 (m, 1H), 3.98–3.86 (m, 1H), 3.78 (s, 3H), 3.65–3.51 (m, 2H), 3.15–2.97 (m, 2.7H), 2.84–2.79 (m, 0.3H), 2.76–2.70 (m, 0.3H), 2.66–2.59 (m, 0.7H), 2.54–2.41 (m, 1H), 2.20–1.96 (m, 3H), 1.45–1.42 (m, 9H), 1.15–0.95 (m, 2H), 0.93–0.85 (m, 12H), 0.82–0.72 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 172.4, 171.5, 158.0, 155.8, 138.1, 132.6, 130.0, 128.5, 128.4, 127.9, 127.8, 113.9, 79.8, 73.1, 69.6, 60.2, 55.4, 54.2, 38.8, 34.8, 31.5, 31.3, 28.4, 21.4, 20.1, 19.6, 19.3, 18.0, 17.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₆H₅₆N₃O₆⁺, 626.4164, found: 626.4164.

tert-Butyl ((S)-1-(((S)-1-(((2S,3R)-1-(benzyloxy)-3-(3-fluorobenzyl)pentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (19c)

Colorless oil (1.73 g, 88%, two steps); [α]²⁶_D −11.2 (c 1.00, CHCl₃); IR (film): ν_max 3296, 2962, 1693, 1630, 1524, 1417, 1249, 1174 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.26 (m, 5H), 7.26–7.24 (m, 1H), 7.23–7.17 (m, 1H), 6.94–6.81 (m, 3H), 6.63–6.48 (m, 1H), 5.10–5.06 (m, 0.7H), 4.79–4.70 (m, 1.3H), 4.50–4.34 (m, 2H), 3.98–3.87 (m, 1H), 3.68–3.48 (m, 2H), 3.14–3.01 (m, 2.7H), 2.85–2.81 (m, 0.3H), 2.81–2.72 (m, 0.3H), 2.71–2.61 (m, 0.7H), 2.57–2.45 (m, 1H), 2.22–2.15 (m, 0.3H), 2.14–1.98 (m, 2.7H), 1.45–1.42 (m, 9H), 1.27–1.04 (m, 2H), 0.93–0.85 (m, 12H), 0.82–0.71 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 172.6, 172.4, 171.5, 163.0 (d, J = 243.9 Hz), 155.8, 143.3 (d, J = 6.8 Hz), 137.9, 129.9, 129.8 (d, J = 8.0 Hz), 128.5, 128.4, 128.0, 127.9, 127.8, 124.7, 115.8 (d, J = 20.8 Hz), 113.0 (d, J = 20.8 Hz), 79.8, 73.2, 69.7, 60.1, 54.1, 38.5, 35.6, 31.5, 31.3, 28.4, 21.4, 20.5, 20.1, 19.6, 19.3, 18.0, 17.7, 17.2, 9.2, 8.6 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −114.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₅H₅₃FN₃O₅⁺, 614.3964, found: 614.3967.

Benzyl N-(tert-butoxycarbonyl)-L-valyl-L-valyl-N-methyl-L-isoleucinate (25a)

Colorless oil (1.60 g, 94%, two steps); [α]²²_D −88.1 (c 1.00, CHCl₃); IR (film) ν_max 3322, 2964, 1738, 1690, 1525, 1179, 845 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.30 (m, 5H), 6.50–6.43 (m, 1H), 5.22–5.04 (m, 4H), 4.75–4.69 (m, 1H), 3.93–3.88 (m, 1H), 3.00–2.97 (m, 3H), 2.08–1.97 (m, 2H), 1.96–1.88 (m, 1H), 1.45–1.42 (m, 9H), 1.30–1.24 (m, 1H), 1.03–0.96 (m, 1H), 0.95–0.93 (m, 3H), 0.92–0.88 (m, 6H), 0.85–0.80 (m, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.6, 171.6, 170.8, 155.8, 135.6, 128.7, 128.7, 128.6, 79.9, 66.8, 60.5, 60.1, 54.0, 33.1, 31.5, 31.4, 31.2, 28.4, 24.9, 19.4, 19.2, 18.0, 17.8, 15.9, 10.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₉H₄₈N₃O₆⁺, 534.3538, found: 534.3531.

Benzyl N-(tert-butoxycarbonyl)-L-valyl-L-valyl-N-methyl-L-valinate (25b)

Colorless oil (1.53 g, 92%, two steps); [α]²³_D −92.0 (c 1.00, CHCl₃); IR (film) ν_max 3322, 2964, 1738, 1692, 1525, 1366, 1178, 845 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.30 (m, 5H), 6.53–6.40 (m, 1H), 5.24–5.18 (m, 1H), 5.08–5.02 (m, 2H), 4.98 (d, J = 10.4 Hz, 1H), 4.71 (dd, J = 8.8, 7.2 Hz, 1H), 3.94–3.88 (m, 1H), 2.97 (brs, 3H), 2.26–2.18 (m, 1H), 2.08–2.00 (m, 1H), 1.95–1.86 (m, 1H), 1.43 (s, 9H), 1.01–0.99 (m, 3H), 0.97–0.92 (m, 1H), 0.90–0.87 (m, 5H), 0.85–0.82 (m, 6H), 0.80–0.77 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.5, 171.5, 170.5, 155.7, 135.4, 128.6, 128.5, 128.5, 79.8, 66.7, 61.5, 60.0, 53.9, 31.3, 31.3, 31.0, 28.3, 27.0, 19.8, 19.3, 19.2, 18.6, 17.8, 17.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₈H₄₆N₃O₆⁺, 520.3381, found: 520.3377.

Benzyl N-(tert-butoxycarbonyl)-L-valyl-L-valyl-N-methyl-L-leucinate (25c)

Colorless oil (1.54 g, 90%, two steps); [α]²¹_D −53.6 (c 1.00, CHCl₃); IR (film) ν_max 3321, 2959, 1739, 1689, 1525, 1367, 1179, 833 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.32–7.29 (m, 5H), 6.53–6.46 (m, 1H), 5.42 (dd, J = 10.8, 5.2 Hz, 1H), 5.17–5.05 (m, 3H), 4.76 (dd, J = 8.4, 7.2 Hz, 1H), 3.91 (dd, J = 8.4, 6.8 Hz, 1H), 2.97–2.95 (m, 3H), 2.09–2.02 (m, 1H), 2.02–1.96 (m, 1H), 1.79–1.67 (m, 2H), 1.43 (s, 9H), 1.41–1.35 (m, 1H), 0.92–0.88 (m, 12H), 0.87–0.84 (m, 6H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.5, 171.5, 171.4, 155.7, 135.3, 128.6, 128.5, 79.8, 67.1, 60.0, 54.4, 53.8, 36.8, 31.3, 31.1, 31.1, 28.3, 24.7, 23.3, 21.3, 19.4, 19.1, 17.9, 17.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₉H₄₈N₃O₆⁺, 534.3538, found: 534.3530.

Benzyl N-(tert-butoxycarbonyl)-L-valyl-L-valyl-N-methyl-L-phenylalaninate (25d)

Colorless oil (1.58 g, 87%, two steps); [α]²³_D −66.2 (c 0.50, CHCl₃); IR (film) ν_max 3321, 2963, 1739, 1525, 1366, 1247, 696 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.33 (m, 3H), 7.31–7.28 (m, 2H), 7.25–7.20 (m, 2H), 7.19–7.14 (m, 3H), 6.41–6.36 (m, 1H), 5.48 (dd, J = 10.4, 5.6 Hz, 1H), 5.19–5.09 (m, 2H), 5.02–4.98 (m, 1H), 4.66 (dd, J = 8.8, 5.6 Hz, 1H), 3.84 (dd, J = 8.0, 6.8 Hz, 1H), 3.42 (dd, J = 14.8, 5.6 Hz, 1H), 2.98 (dd, J = 14.8, 10.4 Hz, 1H), 2.89–2.87 (m, 3H), 2.00–1.88 (m, 2H), 1.44–1.43 (m, 9H), 0.90–0.87 (m, 3H), 0.85–0.79 (m, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.0, 171.4, 170.5, 155.8, 136.6, 135.4, 128.8, 128.7, 128.6, 128.6, 127.0, 79.9, 67.4, 60.1, 58.0, 53.6, 34.5, 32.5, 31.5, 31.1, 28.4, 19.7, 19.4, 18.0, 17.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₂H₄₆N₃O₆⁺, 568.3381, found: 568.3377.

General procedure for the synthesis of 20a, 20b and 20c

Compounds 19a/19b/19c (2.60 mmol) and 10% Pd/C (800 mg) were stirred in MeOH (50 mL) for 4 h under a H₂ atmosphere. Then, the mixture was filtered to give a crude alcohol, which was purified by flash chromatography on silica gel (PE/EA = 1 : 1) to give the title product (20a, 20b and 20c).

tert-Butyl ((S)-1-(((S)-1-(((2S,3R)-3-benzyl-1-hydroxypentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (20a)

Colorless oil (1.08 g, 82%); [α]²⁴_D −11.1 (c 1.00, CHCl₃); IR (film): ν_max 3434, 2965, 1625, 1496, 1417, 1300, 1247, 745 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.84–7.70 (m, 0.5H), 7.38–7.24 (m, 3H), 7.23–7.16 (m, 2H), 7.15–7.08 (m, 1H), 7.07–6.87 (m, 0.5H), 5.25–5.05 (m, 1H), 4.87–4.67 (m, 1H), 4.67–4.47 (m, 1H), 4.27–4.15 (m, 0.5H), 4.15–4.02 (m, 0.5H), 4.02–3.91 (m, 1H), 3.72–3.46 (m, 1H), 3.16–2.93 (m, 3H), 2.85–2.78 (m, 0.5H), 2.75–2.70 (m, 0.5H), 2.58–2.53 (m, 0.5H), 2.51–2.33 (m, 0.5H), 2.11–1.96 (m, 3H), 1.42 (s, 9H), 1.26–1.06 (m, 2H), 1.00–0.84 (m, 12H), 0.83–0.68 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 174.0, 173.6, 172.2, 171.8, 140.6, 140.5, 129.5, 129.0, 128.7, 128.5, 126.2, 79.9, 61.8, 61.3, 59.8, 58.9, 58.7, 55.2, 54.6, 39.1, 38.7, 35.9, 35.6, 32.0, 31.6, 31.5, 31.2, 31.3, 28.4, 21.5, 19.9, 19.4, 19.3, 18.4, 18.1, 17.9, 9.1, 8.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₈H₄₈N₃O₅⁺, 506.3589, found: 506.3590.

tert-Butyl-((S)-1-(((S)-1-(((2S,3R)-1-hydroxy-3-(4-methoxybenzyl)pentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (20b)

Colorless oil (1.11 g, 80%); [α]²³_D −13.7 (c 1.00, CHCl₃); IR (film): ν_max 3326, 2963, 1624, 1513, 1466, 1366, 1246, 1039 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.17–7.09 (m, 1H), 7.09–7.01 (m, 2H), 6.90–6.84 (m, 0.5H), 6.84–6.80 (m, 2H), 6.75–6.69 (m, 0.5H), 5.18–5.07 (m, 1H), 4.83–4.70 (m, 1H), 4.60–4.54 (m, 0.5H), 4.49–4.42 (m, 0.5H), 4.07–4.03 (m, 0.5H), 4.00–3.95 (m, 0.5H), 3.93–3.85 (m, 1H), 3.79 (s, 3H), 3.69–3.59 (m, 1H), 3.14–3.01 (m, 3H), 2.70–2.59 (m, 1H), 2.56–2.50 (m, 1H), 2.38–2.32 (m, 0.5H), 2.12–2.08 (m, 0.5H), 2.06–1.96 (m, 2H), 1.45–1.42 (m, 9H), 1.25–1.08 (m, 2H), 0.97–0.88 (m, 12H), 0.85–0.77 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.9, 173.6, 172.2, 171.8, 158.0, 155.9, 132.4, 132.3, 130.5, 129.9, 114.0, 79.9, 61.9, 61.3, 59.9, 58.7, 55.4, 55.2, 54.6, 39.2, 38.8, 34.9, 34.6, 31.7, 31.3, 31.1, 28.4, 20.5, 19.9, 19.5, 19.4, 18.0, 17.9, 9.2, 8.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₉H₅₀N₃O₆⁺, 536.3694, found: 536.3695.

tert-Butyl ((S)-1-(((S)-1-(((2S,3R)-3-(3-Fluorobenzyl)-1-hydroxypentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (20c)

Colorless oil (1.13 g, 83%); [α]²⁶_D −12.4 (c 0.50, CHCl₃); IR (film): ν_max 3292, 2964, 1623, 1525, 1417, 1366, 1173, 779 cm⁻¹;¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.46–7.27 (m, 1H), 7.26–7.18 (m, 1H), 7.04–6.83 (m, 3H), 6.83–6.60 (m, 1H), 5.19–4.95 (m, 1H), 4.87–4.67 (m, 1H), 4.64–4.39 (m, 1H), 4.16–3.94 (m, 1H), 3.93–3.83 (m, 1H), 3.74–3.51 (m, 1H), 3.15–3.01 (m, 3H), 2.77–2.65 (m, 1H), 2.58–2.45 (m, 1H), 2.13–2.03 (m, 2H), 2.02–1.81 (m, 1H), 1.47–1.41 (m, 9H), 1.25–1.06 (m, 2H), 1.03–0.91(m, 12H), 0.76 (t, J = 7.2 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.6, 171.8, 169.1, 163.0 (d, J = 245.4 Hz), 155.9, 143.1, 130.0 (d, J = 8.1 Hz), 124.7, 115.8 (d, J = 20.6 Hz), 113.2 (d, J = 21.0 Hz), 80.0, 62.0, 61.4, 60.0, 59.5, 54.7, 38.9, 35.7, 32.2, 31.8, 31.4, 31.1, 28.4, 21.5, 19.3, 18.0, 9.2 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₈H₄₇FN₃O₅⁺, 524.3494, found: 524.3497.

General procedure for the synthesis of 21a, 21b, 21c, 27a, 27b, 27c and 27d

Compounds 20a/20b/20c/26a/26b/26c/26d (1.50 mmol) in DCM (8 mL) were added to Dess–Martin periodinane (672 mg, 3.00 mmol) and stirred for 30 min at room temperature. The mixture was carefully quenched with a solution of saturated aqueous NaHCO₃ and solid Na₂S₂O₃. The resulting mixture was extracted with DCM (30 mL × 3), and the combined organic layers were washed with brine, and then dried and concentrated to give the aldehyde without further purification. To a solution of benzyl acetate (0.51 ml, 3.60 mmol) in THF was added dropwise a solution of LDA (1.73 ml, 3.45 mmol, 2 M in THF) at −78 °C and stirred for 30 min. The solution of the above aldehyde in THF (2 ml) was added dropwise, and the reaction mixture was stirred for 30 min at −78 °C. The mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 2 : 1) to give the title product (21a, 21b, 21c, 27a, 27b, 27c and 27d).

Benzyl (6S,9S,12S,13R)-13-hydroxy-6,9-diisopropyl-2,2,11-trimethyl-4,7,10-trioxo-12-((R)-1-phenylbutan-2-yl)-3-oxa-5,8,11-triazapentadecan-15-oate (21a)

Colorless oil (519 mg, 53%, dr = 66 : 34, two steps); [α]²⁴_D −10.6 (c 1.00, CHCl₃); IR (film): ν_max 3439, 2963, 1636, 1496, 1390, 1301, 1167, 748 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.32 (m, 5H), 7.31–7.27 (m, 1H), 7.27–7.22 (m, 2H), 7.20–7.14 (m, 3H), 6.75 (d, J = 8.0 Hz, 1H), 5.16–5.11 (m, 2H), 5.08 (d, J = 8.4 Hz, 1H), 4.78 (dd, J = 8.0, 7.2 Hz, 1H), 4.46–4.39 (m, 1H), 3.97 (dd, J = 8.0, 7.2 Hz, 1H), 3.10–3.01 (m, 3H), 2.96–2.87 (m, 1H), 2.57–2.48 (m, 3H), 2.35–2.21 (m, 1H), 2.07–1.98 (m, 2H), 1.44 (s, 9H), 1.38–1.26 (m, 2H), 1.14–1.04 (m, 1H), 1.02–0.96 (m, 3H), 0.98–0.87 (m, 9H), 0.76 (t, J = 7.2 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃,) δ 173.3, 172.3, 171.7, 155.9, 140.8, 135.7, 129.1, 128.7, 128.6, 128.5, 128.4, 126.1, 79.9, 69.5, 66.8, 60.2, 54.3, 40.3, 39.2, 36.2, 31.3, 31.2, 28.4, 22.2, 19.9, 19.4, 18.0, 17.6, 10.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₇H₅₆N₃O₇⁺, 654.4113, found: 654.4114.

Benzyl(6S,9S,12S,13R)-13-hydroxy-6,9-diisopropyl-12-((R)-1-(4-methoxyphenyl)butan-2-yl)-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (21b)

Colorless oil (625 mg, 61%, dr = 54 : 46, two steps); [α]²⁴_D −10.7 (c 1.00, CHCl₃); IR (film): ν_max 3433, 2963, 1626, 1512, 1366, 1247, 1173, 697 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.31 (m, 5H), 7.20–7.10 (m, 1H), 7.10–7.02 (m, 2H), 6.88–6.81 (m, 1H), 6.81–6.69 (m, 2H), 5.15–5.12 (m, 2H), 5.11–5.00 (m, 1H), 4.78 (dd, J = 7.2, 6.4 Hz, 1H), 4.47–4.39 (m, 1H), 4.42–3.95 (m, 1H), 3.78 (s, 3H), 3.10–2.98 (m, 3H), 2.90–2.79 (m, 1H), 2.57–2.48 (m, 2H), 2.48–2.40 (m, 1H), 2.26–2.14 (m, 1H), 2.10–1.96 (m, 2H), 1.44 (s, 9H), 1.37–1.22 (m, 2H), 1.12–1.03 (m, 1H), 1.02–0.96 (m, 3H), 0.93–0.85 (m, 9H), 0.78–0.75 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.4, 172.3, 171.7, 158.0, 155.8, 135.7, 132.7, 130.0, 128.7, 128.5, 128.4, 113.9, 79.9, 69.5, 66.8, 60.1, 58.6, 55.3, 54.3, 40.4, 39.1, 35.2, 31.3, 31.2, 28.4, 22.2, 19.9, 19.3, 18.6, 18.1, 17.6, 10.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₈H₅₈N₃O₈⁺, 684.4218, found: 684.4219.

Benzyl(6S,9S,12S,13R)-12-((R)-1-(3-fluorophenyl)butan-2-yl)-13-hydroxy-6,9-diisopropyl-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (21c)

Colorless oil (725 mg, 72%, dr = 72 : 28, two steps); [α]²⁶_D −11.8 (c 0.50, CHCl₃); IR (film): ν_max 3323, 2963, 1626, 1524, 1386, 1169, 773 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.42–7.32 (m, 5H), 7.25–7.17 (m, 1H), 6.99–6.95 (m, 1H), 6.94–6.82 (m, 2H), 6.61 (d, J = 8.8 Hz, 1H), 5.18–5.11 (m, 2H), 5.05 (d, J = 8.4 Hz, 1H), 4.77 (dd, J = 7.2, 6.4 Hz, 1H), 4.42–4.32 (m, 1H), 3.99–3.88 (m, 1H), 3.09–3.01 (m, 3H), 2.98–2.87 (m, 1H), 2.56–2.51 (m, 2H), 2.51–2.44 (m, 1H), 2.37–2.20 (m, 1H), 2.07–2.00 (m, 2H), 1.41 (s, 9H), 1.39–1.27 (m, 2H), 1.16–1.04 (m, 1H), 1.01–0.94 (m, 3H), 0.94–0.83 (m, 9H), 0.77 (t, J = 7.2 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.2, 172.4, 171.7, 162.5 (d, J = 243.7 Hz), 155.9, 135.6, 129.8 (d, J = 8.3 Hz), 128.7, 128.6, 128.5, 124.8, 115.9 (d, J = 20.7 Hz), 113.0 (d, J = 20.8 Hz), 80.0, 69.5, 66.9, 60.2, 54.3, 40.4, 39.3, 36.0, 31.3, 31.1, 28.4, 22.2, 20.0, 19.4, 18.0, 17.5, 10.2 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₇H₅₅FN₃O₇⁺, 672.4019, found: 672.4017.

Benzyl(6S,9S,12S,13R)-12-((S)-sec-butyl)-13-hydroxy-6,9-diisopropyl-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (27a)

Colorless oil (545 mg, 63%, dr = 75 : 25, two steps); [α]²³_D −21.4 (c 1.00, CHCl₃); IR (film) ν_max 3302, 2964, 1693, 1525, 1417, 1297, 870 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.32 (m, 5H), 7.34–7.30 (m, 1H), 6.87–6.71 (m, 1H), 5.17–5.12 (m, 2H), 5.10–5.05 (m, 1H), 4.77 (d, J = 9.2, 7.2 Hz, 1H), 4.40–4.32 (m, 1H), 4.03–3.94 (m, 1H), 3.73–3.48 (m, 1H), 3.04–3.02 (m, 2.7H), 2.79–2.78 (m, 0.3H), 2.58–2.52 (m, 2H), 2.07–1.99 (m, 2H), 1.96–1.85 (m, 1H), 1.44–1.42 (m, 9H), 1.42–1.36 (m, 2H), 1.00–0.97 (m, 6H), 0.92–0.88 (m, 9H), 0.83 (t, J = 7.4 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.6, 172.3, 171.7, 155.8, 135.7, 128.7, 128.5, 128.5, 128.4, 79.9, 69.8, 66.8, 60.0, 54.3, 39.2, 33.6, 31.4, 31.3, 28.4, 26.1, 19.8, 19.3, 18.1, 18.0, 17.7, 17.5, 16.2, 11.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₁H₅₂N₃O₇⁺, 578.3800, found: 578.3796.

Benzyl (6S,9S,12S,13R)-13-hydroxy-6,9,12-triisopropyl-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (27b)

Colorless oil (481 mg, 57%, dr = 70 : 30, two steps); [α]²³_D +4.0 (c 0.50, CHCl₃); IR (film) ν_max 2971, 2920, 1668, 1396, 1202, 1135, 936, 870 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.34 (m, 5H), 7.34–7.31 (m, 1H), 5.21–5.13 (m, 3H), 4.79 (dd, J = 8.8, 7.2 Hz, 1H), 4.36 (dd, J = 12.0, 6.4 Hz, 1H), 4.10–3.95 (m, 1H), 3.08–3.03 (m, 3H), 2.59–2.50 (m, 2H), 2.25–2.11 (m, 1H), 2.20–1.98 (m, 3H), 1.45–1.43 (m, 9H), 1.04–1.01 (m, 3H), 1.00–0.98 (m, 3H), 0.95–0.92 (m, 3H), 0.91–0.88 (m, 6H), 0.86–0.83 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.7, 172.2, 155.9, 135.7, 128.7, 128.5, 128.5, 128.4, 80.0, 69.8, 66.8, 60.1, 54.5, 39.3, 31.3, 31.2, 28.4, 27.4, 20.5, 20.4, 19.7, 19.3, 18.2, 17.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₀H₅₀N₃O₇⁺, 564.3643, found: 564.3646.

Benzyl(6S,9S,12S,13R)-13-hydroxy-12-isobutyl-6,9-diisopropyl-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (27c)

Colorless oil (563 mg, 65%, two steps); [α]²³_D −31.6 (c 1.00, CHCl₃); IR (film) ν_max 3319, 2961, 1690, 1525, 1417, 1172, 771 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.30 (m, 5H), 6.69–6.58 (m, 1H), 5.15–5.11 (m, 2H), 5.10–5.04 (m, 1H), 4.87–4.74 (m, 2H), 4.09–4.01 (m, 1H), 3.96–3.91 (m, 1H), 3.08–3.04 (m, 2H), 3.00–2.99 (m, 1H), 2.53–2.49 (m, 1H), 2.12–2.00 (m, 3H), 1.78–1.58 (m, 2H), 1.44–1.43 (m, 9H), 1.40–1.34 (m, 1H), 1.03–0.99 (m, 2H), 0.98–0.95 (m, 3H), 0.94–0.93 (m, 2H), 0.91–0.88 (m, 9H), 0.84–0.81 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 199.1, 198.9, 173.3, 172.8, 172.7, 172.6, 171.8, 171.6, 155.8, 135.6, 128.7, 128.5, 128.5, 128.4, 80.0, 79.9, 70.4, 66.8, 63.3, 60.1, 54.2, 54.0, 38.9, 37.4, 35.1, 34.5, 33.3, 31.5, 31.4, 31.3, 31.3, 31.1, 28.4, 25.0, 24.9, 24.0, 23.4, 21.6, 19.9, 19.8, 19.6, 19.3, 18.0, 17.8, 17.6, 17.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₁H₅₂N₃O₇⁺, 578.3800, found: 578.3795.

Benzyl(6S,9S,12S,13R)-12-benzyl-13-hydroxy-6,9-diisopropyl-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (27d)

Colorless oil (651 mg, 71%, two steps); [α]²³_D −32.8 (c 1.00, CHCl₃); IR (film) ν_max 3333, 2959, 1633, 1533, 1180, 937, 844 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.33 (m, 5H), 7.26–7.10 (m, 5H), 6.61–6.48 (m, 1H), 5.18–5.09 (m, 2H), 5.08–5.02 (m, 1H), 4.63–4.54 (m, 1H), 4.32–4.10 (m, 2H), 3.94–3.83 (m, 1H), 3.34–3.12 (m, 1H), 3.08–2.96 (m, 1H), 2.94–2.74 (m, 3H), 2.57–2.42 (m, 2H), 2.03–1.95 (m, 1H), 1.91–1.81 (m, 1H), 1.45–1.40 (m, 9H), 0.92–0.88 (m, 3H), 0.87–0.78 (m, 9H), 0.48–0.34 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.7, 172.7, 172.6, 172.3, 171.6, 171.5, 155.8, 138.3, 138.2, 135.6, 135.5, 129.4, 128.9, 128.9, 128.7, 128.7, 128.6, 128.5, 128.4, 128.4, 127.7, 127.1, 126.9, 126.6, 79.9, 70.1, 69.6, 66.9, 66.8, 63.6, 60.2, 60.0, 54.0, 53.1, 39.0, 34.1, 32.6, 31.1, 30.7, 30.4, 29.2, 28.4, 20.2, 19.3, 18.0, 17.9, 17.0, 16.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₄H₅₀N₃O₇⁺, 612.3643, found: 612.3645.

General procedure for the synthesis of 23a, 23b, 23c and 23d

Compounds 22a/22b/22c/22d (20.00 mmol) were stirred in H₂O/dioxane (35 ml/30 ml), then NaOH (1.60 g, 40.00 mmol) and Boc₂O (4.80 g, 22.00 mmol) were added and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with EtOAc (50 mL × 1). The water phase was acidified with hydrochloric acid to pH = 2–3 and the resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to give a crude acid without further purification. To a cooled (0 °C) solution of the above crude acid in THF (70 mL) was added NaH (1.23 g, 51.30 mmol) three portions and stirred for 30 min. MeI (4.36 mL, 70.00 mmol) was slowly added dropwise and stirred for 48 h. The mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated to give a crude acid without further purification. A solution of the above acid in DMSO (70 mL) was treated with K₂CO₃ (4.24 g, 40.00 mmol) and BnBr (2.37 mL, 20.00 mmol) overnight. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with water and brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 15 : 1) to give the desired product (23a, 23b, 23c and 23d).

Benzyl N-(tert-butoxycarbonyl)-N-methyl-L-isoleucinate (23a)^13d

Colorless oil (2.68 g, 40%, three steps).

Benzyl N-(tert-butoxycarbonyl)-N-methyl-L-valinate (23b)

Colorless oil (2.70 g, 42%, three steps); [α]²³_D −67.3 (c 1.00, CHCl₃); IR (film) ν_max 2967, 1739, 1455, 1392, 1258, 1144, 774 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.38–7.28 (m, 5 H), 5.19–5.11 (m, 2H), 4.51 (d, J = 10.4 Hz, 0.5 H), 4.15 (d, J = 10.4 Hz, 0.5 H), 2.85–2.76 (m, 3H), 2.25–2.13 (m, 1H), 1.46–1.41 (m, 9H), 0.97–0.94 (m, 3H), 0.91–0.87 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 171.5, 171.1, 156.4, 155.8, 136.0, 135.8, 128.7, 128.6, 128.4, 128.2, 128.1, 80.4, 80.1, 66.5, 66.3, 65.2, 63.4, 30.7, 30.6, 28.5, 27.9, 27.7, 20.1, 19.9, 19.2, 18.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₈H₂₈NO₄⁺, 322.2013, found: 322.2009.

Benzyl N-(tert-butoxycarbonyl)-N-methyl-L-leucinate (23c)

Colorless oil (2.75 g, 41%, three steps); [α]²¹_D −29.3 (c 1.00, CHCl₃); IR (film) ν_max 2959, 1698, 1455, 1391, 1367, 1151, 972, 848 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.31 (m, 5H), 5.16–5.13 (m, 2H), 4.93 (dd, J = 8.8, 7.2 Hz, 0.5H), 4.63 (dd, J = 10.8, 4.8 Hz, 0.5H), 2.80–2.74 (m, 3H), 1.78–1.67 (m, 2H), 1.60–1.51 (m, 1H), 1.46–1.40 (m, 9H), 0.96–0.91 (m, 6H) ppm; ¹³C{¹H} NMR (CDCl₃, 100 MHz, rotamers) δ 172.5, 172.3, 156.4, 155.8, 136.0, 135.8, 128.7, 128.6, 128.4, 128.3, 128.1, 128.0, 80.4, 80.0, 66.7, 66.6, 57.4, 56.2, 38.0, 37.5, 30.6, 30.5, 28.5, 28.4, 25.0, 24.7, 23.4, 23.4, 21.4, 21.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₁₉H₃₀NO₄⁺, 336.2169, found: 336.2162.

Benzyl N-(tert-butoxycarbonyl)-N-methyl-L-phenylalaninate (23d)

Colorless oil (2.95 g, 40%, three steps); [α]²³_D −47.5 (c 1.00, CHCl₃); IR (film) ν_max 1743, 1693, 1455, 1142, 849, 696 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.36–7.31 (m, 5H), 7.29–7.26 (m, 1.5H), 7.24–7.15 (m, 3.5H), 5.22–5.12 (m, 2H), 4.95 (dd, J = 10.4, 5.2 Hz, 0.5H), 4.62 (dd, J = 10.8, 4.4 Hz, 0.5H), 3.37–3.26 (m, 1H), 3.08–2.99 (m, 1H), 2.72–2.67 (m, 3H), 1.37–1.29 (m, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 171.4, 171.1, 155.9, 155.1, 137.7, 137.5, 135.8, 135.6, 129.1, 129.1, 128.7, 128.7, 128.5, 128.3, 128.2, 126.8, 126.6, 80.4, 80.1, 67.0, 66.9, 61.7, 59.9, 35.6, 35.1, 32.6, 32.3, 28.4, 28.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₂H₂₈NO₄⁺, 370.2013, found: 370.2007.

General procedure for the synthesis of 26a, 26b, 26c and 26d

To a solution of 25a/25b/25c/25d (2.70 mmol) in THF (11 ml) was added dropwise LiHBEt₃ (8.10 ml, 8.10 mmol, 1 M in THF) at 0 °C before gradually warming to room temperature, and the reaction mixture was stirred overnight. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 1 : 1) to give the title product (26a, 26b, 26c and 26d).

tert-Butyl-((S)-1-(((S)-1-(((2S,3S)-1-hydroxy-3-methylpentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (26a)

Colorless oil (1.04 g, 90%); [α]²³_D −30.6 (c 0.50, CHCl₃); IR (film) ν_max 3290, 2964, 1693, 1366, 1175, 1016, 870 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.49–7.44 (m, 0.75H), 6.77–6.73 (m, 0.25H), 5.15–5.12 (m, 0.75H), 5.01–4.97 (m, 0.25H), 4.83–4.77 (m, 1H), 4.36–4.28 (m, 1H), 4.17–4.11 (m, 1H), 3.97–3.82 (m, 2H), 3.61–3.50 (m, 1H), 3.02–3.01 (m, 2.25H), 2.94–2.87 (m, 1H), 2.78–2.77 (m, 0.75H), 2.09–2.01 (m, 2H), 1.69–1.62 (m, 1H), 1.59–1.47 (m, 1H), 1.44–1.42 (m, 9H), 1.02–1.00 (m, 3H), 0.94–0.91 (m, 12H), 0.80 (t, J = 7.4 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.7, 171.8, 155.9, 79.9, 64.5, 61.5, 61.3, 60.3, 59.8, 54.6, 54.2, 53.6, 35.4, 32.8, 31.9, 31.7, 31.4, 30.9, 28.4, 27.6, 25.7, 20.3, 19.4, 19.3, 19.2, 18.4, 18.2, 18.1, 16.3, 15.9, 11.9, 10.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₂H₄₄N₃O₅⁺, 430.3276, found: 430.3273.

tert-Butyl-((S)-1-(((S)-1-(((S)-1-hydroxy-3-methylbutan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (26b)

Colorless oil (1.01 g, 90%); [α]²⁰_D −37.9 (c 1.00, CHCl₃); IR (film) ν_max 3302, 2964, 1693, 1533, 1367, 1247, 844 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.74–7.65 (m, 0.76H), 7.10–7.03 (m, 0.24H), 5.23–5.02 (m, 1H), 4.84–4.74 (m, 1H), 4.36–4.28 (m, 0.76H), 4.25–4.19 (m, 0.76H), 4.02–3.96 (m, 0.24H), 3.91–3.84 (m, 1H), 3.75–3.68 (m, 0.24H), 3.59–3.40 (m, 1H), 3.24–3.10 (m, 1H), 3.04–3.02 (m, 2.24H), 2.80–2.79 (m, 0.76H), 2.16–2.06 (m, 0.76H), 2.03–1.94 (m, 1.24H), 1.86–1.76 (m, 1H), 1.44–1.41 (m, 9H), 1.04–1.01 (m, 3H), 0.98–0.90 (m, 13H), 0.81–0.79 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.8, 173.2, 172.8, 171.9, 155.9, 80.1, 79.8, 65.4, 62.8, 61.3, 60.5, 60.2, 59.7, 54.6, 54.2, 32.0, 31.7, 31.5, 31.0, 30.9, 28.6, 28.4, 27.5, 27.0, 21.2, 21.0, 20.3, 20.1, 20.0, 19.3, 19.2, 19.2, 18.5, 18.2, 18.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₁H₄₂N₃O₅⁺, 416.3119, found: 416.3120.

tert-Butyl-((S)-1-(((S)-1-(((S)-1-hydroxy-4-methylpentan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (26c)

Colorless oil (695 mg, 60%); [α]²²_D −24.5 (c 1.00, CHCl₃); IR (film) ν_max 3293, 2959, 1696, 1535, 1468, 1366, 1173, 757 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.65–7.57 (m, 0.73H), 6.90–6.82 (m, 0.27H), 5.20–5.15 (m, 0.73H), 5.07–5.01 (m, 0.27H), 4.88–4.70 (m, 2H), 4.27–4.12 (m, 1H), 4.00–3.84 (m, 0.27H), 3.68–3.56 (m, 1H), 3.54–3.41 (m, 1H), 3.25–3.03 (m, 0.73H), 2.98–2.97 (m, 2.27H), 2.79–2.78 (m, 0.73H), 2.11–2.05 (m, 0.73H), 2.04–1.96 (m, 1.27H), 1.93–1.74 (m, 0.73H), 1.62–1.56 (m, 0.27H), 1.44–1.41 (m, 9H), 1.39–1.36 (m, 1H), 1.21–1.11 (m, 1H), 1.02–1.00 (m, 2H), 0.99–0.95 (m, 3H), 0.95–0.93 (m, 3H), 0.92–0.87 (m, 7H), 0.87–0.84 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.6, 172.8, 172.7, 171.7, 155.8, 80.0, 79.7, 63.1, 62.4, 60.0, 59.6, 57.2, 54.5, 54.3, 54.0, 39.1, 36.6, 31.9, 31.7, 31.3, 30.9, 29.7, 28.3, 26.9, 24.9, 24.8, 23.5, 23.3, 22.8, 22.0, 19.7, 19.2, 19.0, 18.4, 18.2, 18.1, 17.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₂H₄₄N₃O₅⁺, 430.3276, found: 430.3277.

tert-Butyl-((S)-1-(((S)-1-(((S)-1-hydroxy-3-phenylpropan-2-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (26d)

Colorless oil (738 mg, 59%); [α]²³_D −57.8 (c 1.00, CHCl₃); IR (film) ν_max 3310, 2965, 1686, 1523, 1366, 1247, 760 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.32–7.27 (m, 1H), 7.25–7.22 (m, 1H), 7.21–7.15 (m, 3H), 7.01–6.95 (m, 0.5H), 6.77–6.72 (m, 0.5H), 5.13–5.08 (m, 0.5H), 5.05–5.02 (m, 0.5H), 4.72–4.64 (m, 1H), 4.51–4.46 (m, 0.5H), 4.43–4.36 (m, 0.5H), 4.06–3.99 (m, 0.5H), 3.95–3.88 (m, 0.5H), 3.73–3.69 (m, 1.5H), 3.61–3.52 (m, 0.5H), 3.16–3.03 (m, 1H), 2.97–2.96 (m, 1.5H), 2.91–2.90 (m, 1.5H), 2.89–2.83 (m, 1H), 2.81–2.77 (m, 1H), 2.03–1.95 (m, 1H), 1.68–1.58 (m, 1H), 1.44–1.41 (m, 9H), 0.97–0.94 (m, 1.5H), 0.92–0.89 (m, 4.5H), 0.88–0.86 (m, 3H), 0.78–0.75 (m, 1.5H), 0.48–0.45 (m, 1.5H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.0, 172.8, 172.8, 171.7, 155.9, 137.8, 137.7, 129.2, 129.0, 128.9, 128.6, 127.1, 126.7, 80.2, 79.9, 62.7, 62.4, 61.3, 60.2, 59.9, 59.7, 54.6, 54.2, 36.0, 34.5, 32.7, 31.6, 31.3, 30.9, 30.8, 28.4, 28.4, 19.7, 19.4, 19.3, 19.2, 18.2, 18.0, 17.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₅H₄₂N₃O₅⁺, 464.3119, found: 464.3117.

General procedure for the synthesis of 28a, 28b, 28c, 28d, 28e, 28f and 28g

Compounds 21a/21b/21c/27a/27b/27c/27d (0.49 mmol) and HMPA (94 μL, 0.54 mmol) were stirred in THF (2 mL) at −78 °C, then a solution of LiHMDS (0.49 ml, 0.49 mmol, 1 M in THF) was slowly added dropwise and stirred for 30 min. The reaction mixture was warmed to −15 °C and MeOTf (111 μL, 0.98 mmol) was added and stirred for an additional 15 min. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 2 : 1) to give the title product (28a, 28b, 28c, 28d, 28e, 28f and 28g).

Benzyl-(6S,9S,12S,13R)-6,9,12-triisopropyl-13-methoxy-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (28a)

Colorless oil (156 mg, 55%); [α]²³_D −40.0 (c 0.50, CHCl₃); IR (film) ν_max 3288, 2964, 1739, 1525, 1417, 1390, 1170, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.33 (m, 5H), 6.56–6.49 (m, 1H), 5.20–5.08 (m, 3H), 4.78–4.64 (m, 2H), 3.97–3.90 (m, 2H), 3.33–3.29 (m, 3H), 2.99–2.76 (m, 3H), 2.60–2.44 (m, 2H), 2.07–1.99 (m, 2H), 1.43 (s, 9H), 1.01–0.97 (m, 6H), 0.93–0.88 (m, 9H), 0.83–0.79 (m, 3H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 172.4, 170.9, 170.9, 155.1, 135.1, 127.9, 127.8, 127.7, 79.1, 77.8, 77.3, 66.1, 66.0, 63.8, 59.3, 57.8, 57.6, 57.3, 53.5, 52.8, 36.6, 36.1, 31.0, 30.6, 30.6, 30.5, 27.7, 26.3, 20.2, 19.8, 19.4, 19.3, 18.9, 18.5, 17.2, 17.0, 15.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₁H₅₂N₃O₇⁺, 578.3800, found: 578.3799.

Benzyl-(6S,9S,12S,13R)-12-((S)-sec-butyl)-6,9-diisopropyl-13-methoxy-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (28b)^13d

Colorless oil (153 mg, 53%).

Benzyl-(6S,9S,12S,13R)-6,9-diisopropyl-13-methoxy-2,2,11-trimethyl-4,7,10-trioxo-12-((R)-1-phenylbutan-2-yl)-3-oxa-5,8,11-triazapentadecan-15-oate (28c)

Colorless oil (252 mg, 77%); [α]²³_D −9.7 (c 1.00, CHCl₃); IR (film): ν_max 3322, 2964, 1626, 1455, 1390, 1367, 1169, 752 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.32 (m, 5H), 7.28–7.25 (m, 2H), 7.25–7.22 (m, 1H), 7.20–7.13 (m, 3H), 6.49 (d, J = 8.8 Hz, 1H), 5.18–5.08 (m, 2H), 5.08–5.05 (m, 1H), 5.02–4.90 (m, 1H), 4.80–4.72 (m, 1H), 4.12–3.97 (m, 1H), 3.97–3.85 (m, 1H), 3.35–3.32 (m, 3H), 3.02–2.96 (m, 3H), 2.80–2.72 (m, 1H), 2.61–2.42 (m, 3H), 2.09–1.95 (m, 3H), 1.44 (s, 9H), 1.16–1.02 (m, 1H), 1.02–0.95 (m, 3H), 0.92–0.85 (m, 9H), 0.76 (t, J = 7.0 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃,) δ 172.8, 171.6, 171.5, 155.8, 140.5, 135.8, 129.1, 128.7, 128.5, 126.2, 79.9, 78.0, 66.8, 60.1, 58.0, 54.2, 39.9, 37.4, 35.9, 31.3, 31.2, 28.4, 22.1, 19.8, 19.3, 18.0, 17.5, 9.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₈H₅₈N₃O₇⁺, 668.4269, found: 668.4268.

Benzyl (6S,9S,12S,13R)-6,9-diisopropyl-13-methoxy-12-(1-(4-methoxyphenyl)butan-2-yl)-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (28d)

Colorless oil (249 mg, 73%); [α]²⁴_D −7.5 (c 1.00, CHCl₃); IR (film): ν_max 3322, 2961, 1636, 1512, 1455, 1247, 1095, 751 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.41–7.29 (m, 5H), 7.09–7.04 (m, 2H), 6.83–6.77 (m, 2H), 6.48 (d, J = 8.4 Hz, 1H), 5.19–5.08 (m, 2H), 5.08–5.03 (m, 1H), 5.01–4.85 (m, 1H), 4.76 (dd, J = 7.6, 6.8 Hz, 1H), 4.08–3.94 (m, 1H), 3.91 (dd, J = 7.6, 6.8 Hz, 1H), 3.78 (s, 3H), 3.34–3.31 (m, 3H), 2.99–2.96 (m, 3H), 2.72–2.63 (m, 1H), 2.60–2.41 (m, 3H), 2.08–1.94(m, 3H), 1.43 (s, 9H), 1.30–1.02 (m, 1H), 1.02–0.96 (m, 3H), 0.93–0.85 (m, 9H), 0.76 (t, J = 7.2 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.8, 171.5, 158.1, 155.8, 135.8, 132.4, 130.0, 128.7, 128.5, 113.9, 79.9, 78.0, 66.8, 60.2, 58.0, 55.4, 54.2, 40.1, 37.4, 34.9, 31.3, 28.5, 22.0, 19.8, 19.3, 18.0, 17.5, 9.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₉H₆₀N₃O₈⁺, 698.4375, found: 698.4376.

Benzyl (6S,9S,12S,13R)-12-((R)-1-(3-fluorophenyl)butan-2-yl)-6,9-diisopropyl-13-methoxy-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (28e)

Colorless oil (225 mg, 67%); [α]²⁶_D −14.4 (c 1.00, CHCl₃); IR (film): ν_max 3314, 2963, 1635, 1488, 1390, 1249, 1168, 1095 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.42–7.28 (m, 5H), 7.21 (dd, J = 14.0, 6.8 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.90–6.83 (m, 2H), 6.50 (d, J = 8.8 Hz, 1H), 5.20–5.09 (m, 2H), 5.08–5.03 (m, 1H), 4.99–4.84 (m, 1H), 4.76 (dd, J = 7.2, 6.4 Hz, 1H), 4.06–3.95 (m, 1H), 3.92 (dd, J = 8.0, 7.2 Hz, 1H), 4.06–3.96 (m, 1H), 3.34–3.32 (m, 3H), 3.01–2.98 (m, 3H), 2.79–2.71 (m, 1H), 2.59–2.46 (m, 3H), 2.08–1.97 (m, 3H), 1.43 (s, 9H), 1.16–1.02 (m, 1H), 1.00–0.94 (m, 3H), 0.90–0.87 (m, 9H), 0.76 (t, J = 7.2 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.9, 171.6, 171.5, 163.0 (d, J = 243.8 Hz), 155.8, 143.2, 135.8, 129.9 (d, J = 8.4 Hz), 128.7, 128.5, 124.8, 115.9 (d, J = 20.7 Hz), 113.1 (d, J = 20.9 Hz), 79.9, 78.0, 66.8, 60.2, 58.0, 54.2, 40.0, 37.6, 35.8, 31.3, 31.2, 28.4, 22.1, 19.8, 19.3, 18.0, 17.5, 10.0 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₈H₅₇FN₃O₇⁺, 686.4175, found: 686.4179.

Benzyl(6S,9S,12S,13R)-12-isobutyl-6,9-diisopropyl-13-methoxy-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (28f)

Colorless oil (145 mg, 50%); [α]²³_D −74.8 (c 0.25, CHCl₃); IR (film) ν_max 3319, 2960, 1690, 1525, 1416, 1247, 1173, 770 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.37–7.33 (m, 5H), 6.52–6.45 (m, 1H), 5.17–5.09 (m, 2H), 5.10–5.04 (m, 1H), 4.78–4.73 (m, 1H), 3.98–3.84 (m, 1.33H), 3.70–3.55 (m, 1H), 3.45–3.36 (m, 0.67H), 3.33–3.31 (m, 3H), 2.97–2.94 (m, 3H), 2.58–2.40 (m, 2H), 2.12–1.90 (m, 3H), 1.44 (s, 9H), 1.39–1.34 (m, 1H), 0.97–0.94 (m, 3H), 0.91–0.88 (m, 10H), 0.87–0.84 (m, 3H), 0.82–0.79 (m, 2H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 172.5, 171.6, 171.6, 171.5, 155.8, 135.8, 128.7, 128.6, 128.5, 128.5, 128.0, 127.9, 80.1, 79.9, 66.7, 60.1, 58.5, 54.1, 31.3, 28.4, 24.8, 24.0, 23.9, 21.7, 21.5, 19.9, 19.6, 19.2, 18.0, 17.8, 17.6, 17.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₂H₅₄N₃O₇⁺, 592.3956, found: 592.3953.

Benzyl (6S,9S,12S,13R)-12-benzyl-6,9-diisopropyl-13-methoxy-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate (28g)

Colorless oil (135 mg, 44%); [α]²²_D −25.3 (c 1.00, CHCl₃); IR (film) ν_max 3320, 2964, 1735, 1497, 1246, 1164, 772 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.32 (m, 5H), 7.34–7.29 (m, 1H), 7.23–7.18 (m, 2H), 7.16–7.10 (m, 3H), 6.43–6.35 (m, 1H), 5.16–5.13 (m, 2H), 5.04–4.98 (m, 1H), 4.55 (dd, J = 8.8, 4.8 Hz, 1H), 4.01–3.80 (m, 2H), 3.40–3.36 (m, 3H), 3.16 (dd, J = 14.8, 4.0 Hz, 1H), 2.93–2.75 (m, 3H), 2.66–2.51 (m, 2H), 2.03–1.92 (m, 1H), 1.90–1.81 (m, 1H), 1.44–1.41 (m, 9H), 0.99–0.92 (m, 1H), 0.91–0.88 (m, 3H), 0.85–0.80 (m, 9H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.5, 171.8, 171.2, 155.7, 138.1, 137.6, 135.7, 129.3, 128.8, 128.6, 128.5, 128.4, 128.4, 126.9, 126.5, 125.6, 79.9, 79.7, 79.5, 79.5, 66.7, 66.6, 62.6, 60.0, 59.9, 58.7, 58.5, 53.7, 53.0, 37.0, 33.8, 32.0, 31.1, 30.7, 30.4, 29.7, 28.3, 20.1, 19.5, 19.3, 19.2, 17.9, 17.8, 16.8, 16.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₅H₅₂N₃O₇⁺, 626.3800, found: 626.3798.

General procedure for the synthesis of 29a, 29b, 29c, 29d, 29e, 29f and 29g

A cooled (0 °C) solution of 28a/28b/28c/28d/28e/28f/28g (0.21 mmol) in DCM (1 mL) was treated with TFA (0.20 mL) for 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in CH₃CN (1 mL), then a solution of 40% HCHO (354 μL, 1.68 mmol) and Na(BH₃)CN (40 mg, 0.63 mmol) was added. After being stirred for 10 h, the reaction mixture was evaporated and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel (DCM/MeOH/NH₄OH = 50 : 1 : 0.01) to give the title product (29a, 29b, 29c, 29d, 29e, 29f and 29g).

Benzyl (3R,4S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylhexanoate (29a)

Colorless oil (74 mg, 70%, two steps); [α]²³_D −25.4 (c 0.50, CHCl₃); IR (film) ν_max 2961, 1738, 1517, 1455, 1163, 1098, 916 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.38–7.34 (m, 5H), 6.93–6.87 (m, 1H), 5.20–5.09 (m, 2H), 4.77–4.68 (m, 2H), 3.98–3.89 (m, 1H), 3.36–3.28 (m, 4H), 3.04–3.00 (m, 3H), 2.56–2.49 (m, 1H), 2.45–2.41 (m, 1H), 2.25–2.23 (m, 6H), 2.10–1.99 (m, 2H), 1.90–1.80 (m, 1H), 1.02–0.98 (m, 9H), 0.97–0.94 (m, 3H), 0.93–0.90 (m, 3H), 0.83–0.79 (m, 3H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃, rotamers) δ 173.6, 172.0, 171.7, 135.9, 128.7, 128.5, 128.5, 78.0, 76.7, 66.8, 58.2, 58.0, 54.0, 43.1, 43.0, 37.3, 31.9, 31.0, 27.8, 27.0, 20.3, 20.2, 20.1, 19.8, 18.3, 17.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₈H₄₈N₃O₅⁺, 506.3589, found: 506.3586.

Benzyl (3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoate (29b)^13d

Colorless oil (76 mg, 70%, two steps).

Benzyl (3R,4S,5R)-5-benzyl-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxyheptanoate (29c)

Colorless oil (96 mg, 77%, two steps); [α]²⁵_D −9.4 (c 1.00, CHCl₃); IR (film): ν_max 3336, 2961, 1623, 1454, 1164, 1084, 750, 669 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.32 (m, 5H), 7.29–7.24 (m, 2H), 7.20–7.14 (m, 3H), 6.92 (d, J = 9.2 Hz, 1H), 5.15 (d, J = 12.4 Hz, 1H), 5.08 (d, J = 12.4 Hz, 1H), 5.06–4.91 (m, 1H), 4.79 (dd, J = 8.8, 6.4 Hz, 1H), 4.08–3.94 (m, 1H), 3.35–3.31 (m, 3H), 3.04–2.98 (m, 3H), 2.79–2.70 (m, 1H), 2.62–2.47 (m, 3H), 2.43 (d, J = 6.4 Hz, 1H), 2.24–2.21 (m, 6H), 2.12–1.98 (m, 3H), 1.33–1.27 (m, 1H), 1.16–1.05 (m, 1H), 1.03–0.97 (m, 6H), 0.97–0.88 (m, 6H), 0.75 (t, J = 6.6 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃,) δ 173.3, 171.8, 171.5, 140.5, 135.9, 129.1, 128.7, 128.5, 126.1, 70.1, 66.8, 58.0, 53.8, 43.1, 37.4, 35.9, 31.0, 27.8, 22.0, 20.3, 20.0, 17.9, 9.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₅H₅₄N₃O₅⁺, 596.4059, found: 596.4060.

Benzyl (3R,4S,5R)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-(4-methoxybenzyl)heptanoate (29d)

Colorless oil (117 mg, 89%, two steps); [α]²⁵_D −7.3 (c 1.00, CHCl₃); IR (film): ν_max 3446, 2960, 1657, 1512, 1247, 1084, 772 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.41–7.29 (m, 5H), 7.11–7.04 (m, 2H), 6.93 (d, J = 8.8 Hz, 1H), 6.83–6.77 (m, 2H), 5.15 (d, J = 12.2 Hz, 1H), 5.09 (d, J = 12.2 Hz, 1H), 5.02–4.91 (m, 1H), 4.79 (dd, J = 6.8, 6.0 Hz, 1H), 4.11–3.93 (m, 1H), 3.78 (s, 3H), 3.44–3.38 (m, 1H), 3.35–3.32 (m, 3H), 3.05–2.98 (m, 3H), 2.75–2.63 (m, 1H), 2.58–2.48 (m, 2H), 2.46–2.43 (m, 1H), 2.29–2.19 (m, 6H), 2.12–1.96 (m, 3H), 1.77–1.69 (m, 2H), 1.03–0.97 (m, 6H), 0.96–0.89 (m, 6H), 0.79–0.71 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.3, 171.6, 158.0, 135.9, 132.4, 130.0, 128.7, 128.5, 113.9, 78.0, 76.6, 70.8, 66.8, 58.0, 55.4, 53.8, 43.0, 37.4, 34.9, 31.0, 27.8, 26.7, 22.0, 20.3, 20.0, 17.9, 9.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₆H₅₆N₃O₆⁺, 626.4164, found: 626.4165.

Benzyl (3R,4S,5R)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-5-(3-fluorobenzyl)-3-methoxyheptanoate (29e)

Colorless oil (117 mg, 91%, two steps); [α]²⁵_D −12.5 (c 1.00, CHCl₃); IR (film): ν_max 3443, 2962, 1624, 1454, 1124, 1084, 776 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.28 (m, 5H), 7.23–7.16 (m, 1H), 6.97–6.87 (m, 3H), 6.87–6.83 (m, 1H), 5.16 (d, J = 12.4 Hz, 1H), 5.10 (d, J = 12.4 Hz, 1H), 5.00–4.85 (m, 1H), 4.78 (dd, J = 6.8, 6.0 Hz, 1H), 4.07–3.87 (m, 1H), 3.36–3.29 (m, 3H), 3.07–3.00 (m, 3H), 2.78–2.70 (m, 1H), 2.58–2.47 (m, 3H), 2.44 (d, J = 6.4 Hz, 1H), 2.28–2.22 (m, 6H), 2.10–1.97 (m, 3H), 1.34–1.27 (m, 1H), 1.17–1.08 (m, 1H), 1.04–0.97 (m, 6H), 0.97–0.88 (m, 6H), 0.75 (t, J = 6.8 Hz, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.3, 171.8, 171.5, 163.0 (d, J = 243.9 Hz), 143.3 (d, J = 7.1 Hz), 135.8, 129.9 (d, J = 8.3 Hz), 128.7, 128.5, 124.8, 115.9 (d, J = 20.7 Hz), 113.0 (d, J = 20.9 Hz), 78.1, 76.6, 66.8, 58.0, 53.8, 43.1, 35.8, 30.9, 27.8, 22.1, 20.3, 20.0, 17.9, 9.9 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₅H₅₃FN₃O₅⁺, 614.3964, found: 614.3967.

Benzyl (3R,4S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-6-methylheptanoate (29f)

Colorless oil (71 mg, 65%, two steps); [α]²⁵_D −60.0 (c 0.50, CHCl₃); IR (film) ν_max 2959, 1738, 1456, 1197, 1103, 768 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.32 (m, 5H), 6.92–6.87 (m, 1H), 5.15–5.12 (m, 2H), 4.86–4.66 (m, 2H), 3.77–3.63 (m, 1H), 3.33–3.30 (m, 3H), 3.06–3.02 (m, 1H), 3.01–2.96 (m, 3H), 2.55–2.47 (m, 2H), 2.45–2.43 (m, 1H), 2.25–2.22 (m, 6H), 2.11–2.05 (m, 1H), 2.01–1.94 (m, 1H), 1.65–1.55 (m, 1H), 1.38–1.32 (m, 1H), 1.00–0.97 (m, 6H), 0.94–0.90 (m, 6H), 0.88–0.86 (m, 3H), 0.80–0.77 (m, 3H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 172.8, 171.7, 171.5, 135.7, 128.6, 128.4, 80.0, 76.5, 66.6, 58.4, 53.6, 53.4, 42.8, 37.7, 30.9, 27.7, 24.6, 24.6, 24.0, 21.3, 20.1, 19.9, 17.8, 17.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₉H₅₀N₃O₅⁺, 520.3745, found: 520.3744.

Benzyl-(3R,4S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-phenylpentanoate (29g)

Colorless oil (70 mg, 60%, two steps); [α]²³_D −21.2 (c 0.50, CHCl₃); IR (film) ν_max 2970, 1732, 1544, 1456, 1202, 936, 700 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.42–7.31 (m, 6H), 7.23–7.11 (m, 5H), 5.17–5.14 (m, 2H), 4.71–4.50 (m, 1H), 3.97–3.60 (m, 2H), 3.45–3.37 (m, 3H), 3.18–3.11 (m, 1H), 2.98–2.76 (m, 10H), 2.73–2.42 (m, 3H), 2.21–1.84 (m, 2H), 1.13–1.05 (m, 3H), 0.96–0.83 (m, 6H), 0.79–0.66 (m, 2H), 0.54–0.34 (m, 1H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃, rotamers) δ 171.9, 171.4, 171.2, 166.5, 166.5, 162.2, 162.0, 138.1, 135.7, 135.7, 129.3, 129.0, 128.8, 128.7, 128.6, 127.1, 126.6, 117.1, 115.2, 80.0, 79.7, 72.0, 66.9, 66.8, 63.1, 59.0, 58.6, 53.9, 53.6, 36.9, 33.9, 29.6, 29.6, 28.9, 28.2, 28.1, 20.4, 20.1, 19.4, 19.4, 19.3, 17.0, 16.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₃₂H₄₈N₃O₅⁺, 554.3589, found: 554.3583.

General procedure for the synthesis of 31a, 31b, 31c, 31d, 31e and 31f

Compounds 29a/29c/29d/29e/29f/29g (0.12 mmol) and 10% Pd/C (40 mg) were stirred in MeOH (10 mL) for 4 h under a H₂ atmosphere. Then, the mixture was filtered and concentrated to give a crude acid without further purification. HATU (68 mg, 0.18 mmol), DIPEA (63 μL, 0.36 mmol), and 30 (49 mg, 0.13 mmol) were added in turn. After being stirred for 12 h, the reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel to give the title product (31a, 31b, 31c, 31d, 31e and 31f) as a viscous liquid, which was further treated with acetone/hexane to give a white powder.

(S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3S,4R)-4-methoxy-6-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-2-methyl-6-oxohexan-3-yl)-N,3-dimethylbutanamide (31a)

White powder (46 mg, 50%, three steps), mp 94–95 °C; [α]²²_D −214.4 (c 0.125, CHCl₃); IR (film) ν_max 3292, 2965, 1622, 1498, 1100, 830, 749 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.78–7.74 (m, 1H), 7.26–7.16 (m, 6H), 7.12–7.06 (m, 1H), 5.68–5.51 (m, 1H), 4.86–4.64 (m, 2H), 4.21–4.02 (m, 2H), 3.92–3.86 (m, 1H), 3.81–3.53 (m, 1H), 3.44–3.37 (m, 3H), 3.36–3.31 (m, 6H), 3.29–3.23 (m, 1H), 3.18 (s, 1H), 3.05 (s, 2H), 2.74–2.65 (m, 1H), 2.50–2.41 (m, 2H), 2.40–2.36 (m, 6H), 2.25–2.19 (m, 1H), 2.14–2.07 (m, 2H), 2.05–1.99 (m, 1H), 1.97–1.86 (m, 2H), 1.83–1.71 (m, 2H), 1.68–1.60 (m, 1H), 1.50–1.43 (m, 3H), 1.29–1.20 (m, 2H), 1.17–1.11 (m, 3H), 1.03–1.00 (m, 6H), 0.98–0.95 (m, 2H), 0.92–0.90 (m, 2H), 0.84–0.81 (m, 2H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃, rotamers) δ 174.1, 173.4, 173.3, 171.9, 170.4, 170.1, 142.6, 137.0, 136.5, 129.5, 129.2, 128.8, 128.6, 127.2, 127.0, 119.4, 119.0, 85.7, 81.8, 78.5, 76.0, 64.6, 61.7, 60.6, 60.5, 59.3, 59.0, 58.7, 58.7, 58.2, 58.1, 55.8, 54.2, 53.6, 51.4, 47.8, 46.7, 44.9, 44.0, 43.8, 42.9, 42.8, 41.4, 41.3, 37.9, 36.3, 32.1, 31.1, 30.7, 29.8, 27.8, 27.2, 26.9, 25.9, 25.1, 24.8, 23.8, 20.8, 20.8, 20.4, 20.2, 20.1, 20.1, 19.8, 19.6, 18.4, 18.3, 17.9, 17.8, 15.4, 14.1, 12.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₄₁H₆₇N₆O₆S⁺, 771.4837, found: 771.4836.

(S)-N-((3R,4S,5R)-5-Benzyl-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (31b)

White powder (43 mg, 42%, three steps), mp 73.6–75.6 °C; [α]²⁶_D −39.2 (c 0.25, CHCl₃); IR (film): ν_max 3290, 2960, 1622, 1497, 1098, 749, 700 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.77–7.71(m, 1H), 7.26–7.21 (m, 5H), 7.20–7.04 (m, 6H), 7.00–6.92 (m, 1H), 5.63–5.53 (m, 1H), 5.02–4.86 (m, 1H), 4.82 (dd, J = 6.4, 5.6 Hz, 1H), 4.34–4.19 (m, 1H), 4.12–4.04 (m, 1H), 3.89 (d, J = 6.8 Hz, 1H), 3.44–3.42 (m, 1H), 3.38–3.36 (m, 2H), 3.33–3.33 (m, 2H), 3.30–3.28 (m, 1H), 3.21–3.17 (m, 1H), 3.08–3.05 (m, 2H), 2.83–2.76 (m, 1H), 2.53–2.41 (m, 4H), 2.28–2.22 (m, 6H), 2.12–2.00 (m, 4H), 1.95–1.90 (m, 1H), 1.84–1.74 (m, 2H), 1.68–1.64 (m, 6H), 1.44–1.32 (m, 2H), 1.15–1.12 (m, 3H), 1.04–0.98 (m, 6H), 0.96–0.92 (m, 6H), 0.77 (t, J = 7.0 Hz, 3H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 173.9, 173.3, 171.7, 170.1, 142.6, 140.8, 137.1, 130.0, 129.2, 129.1, 128.8, 129.0, 128.4, 127.2, 126.9, 126.0, 119.4, 118.9, 85.7, 81.9, 60.5, 59.3, 58.3, 53.8, 52.7, 51.4, 47.7, 46.7, 43.9, 43.1, 41.5, 41.3, 40.3, 38.2, 35.7, 32.3, 31.0, 29.8, 27.8, 25.9, 25.1, 24.8, 23.8, 22.0, 20.4, 18.0, 13.9, 10.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₄₈H₇₃N₆O₆S⁺, 861.5307, found: 861.5306.

(S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3R,4S,5R)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-5-(4-methoxybenzyl)-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (31c)

White powder (36 mg, 34%), mp 72.5–74.5 °C; [α]²⁶_D −35.2 (c 0.25, CHCl₃); IR (film): ν_max 3290, 2962, 2874, 1623, 1512, 1453, 1247, 1100, 752 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76–7.71 (m, 1H), 7.25–7.17 (m, 6H), 7.12–7.07 (m, 2H), 7.08–6.94 (m, 1H), 6.82–6.77 (m, 2H), 5.63–5.51 (m, 1H), 5.16–4.87 (m, 1H), 4.86–4.76 (m, 1H), 4.32–4.15 (m, 1H), 4.12–4.02 (m, 1H), 3.93–3.84 (m, 1H), 3.77 (s, 3H), 3.76–3.71 (m, 1H), 3.46–3.39 (m, 2H), 3.38–3.35 (m, 3H), 3.32–3.30 (m, 3H), 3.28–3.23 (m, 2H), 3.21–3.16 (m, 1H), 3.09–3.01 (m, 3H), 2.77–2.70 (m, 1H), 2.49–2.42 (m, 3H), 2.34–2.22 (m, 6H), 2.15–2.02 (m, 3H), 2.02–1.88 (m, 2H), 1.85–1.79 (m, 1H), 1.43–1.29 (m, 1H), 1.28–1.24 (m, 2H), 1.17–1.12 (m, 3H), 1.06–1.10 (m, 6H), 0.97–0.93 (m, 6H), 0.81–0.72 (m, 3H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 173.9, 173.5, 171.8, 170.1, 157.9, 142.6, 137.1, 132.7, 130.1, 130.0, 129.6, 129.2, 128.8, 128.5, 126.9, 119.4, 118.9, 113.8, 85.7, 81.9, 70.8, 60.5, 59.3, 58.6, 58.3, 55.3, 53.8, 53.6, 52.7, 47.7, 44.9, 43.9, 43.1, 41.3, 38.2, 34.7, 31.0, 27.8, 25.1, 24.8, 23.7, 22.0, 20.3, 18.6, 18.0, 13.9, 10.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₄₉H₇₅N₆O₇S⁺, 891.5413, found: 891.5415.

(S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3R,4S,5R)-5-(3-fluorobenzyl)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (31d)

White powder (47 mg, 45%), mp 86.5–88.5 °C; [α]²⁶_D −41.5 (c 1.00, CHCl₃); IR (film): ν_max 3291, 2963, 1636, 1488, 1251, 1141, 1098, 697 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76–7.71 (m, 1H), 7.26–7.17 (m, 6H), 7.12–7.05 (m, 1H), 7.02–6.96 (m, 2H), 6.92–6.83 (m, 2H), 5.61–5.54 (m, 1H), 4.94–4.84 (m, 1H), 4.80 (dd, J = 8.4, 7.6 Hz, 1H), 4.27–4.19 (m, 1H), 4.11–4.04 (m, 1H), 3.89 (d, J = 7.2 Hz, 1H), 3.44–3.42 (m, 1H), 3.37–3.35 (m, 3H), 3.34–3.32 (m, 3H), 3.31–3.29 (m, 1H), 3.28–3.24 (m, 1H), 3.18–3.17 (m, 1H), 3.08–3.05 (m, 2H), 2.82–2.75 (m, 1H), 2.54–2.40 (m, 4H), 2.34–2.26 (m, 6H), 2.16–2.02 (m, 4H), 1.96–1.88 (m, 2H), 1.84–1.73 (m, 2H), 1.72–1.61 (m, 2H), 1.43–1.33 (m, 1H), 1.28–1.24 (m, 1H), 1.17–1.13 (m, 3H), 1.06–1.00 (m, 6H), 0.97–0.93 (m, 6H), 0.82–0.72 (m, 3H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 173.8, 173.2, 171.7, 170.3, 170.0 169.7, 162.9 (d, J = 243.8 Hz), 143.5, 142.6, 137.1, 136.6, 129.8 (d, J = 8.1 Hz), 129.5, 129.2, 128.8, 128.5, 127.2, 126.9, 124.9, 119.4, 118.9, 115.9 (d, J = 20.7 Hz), 113.0 (d, J = 20.9 Hz), 85.7, 81.9, 61.7, 60.5, 59.2, 58.9, 58.5, 58.3, 52.7, 51.4, 47.7, 46.7, 43.8, 43.1, 41.3, 40.4, 38.4, 35.6, 30.8, 27.8, 25.9, 25.1, 24.8, 23.7, 22.1, 20.3, 19.9, 18.0, 13.9, 10.3 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₄₈H₇₂FN₆O₆S⁺, 879.5213, found: 879.5212.

(S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3R,4S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-6-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (31e)

White powder (40 mg, 42%), mp 108–110 °C; [α]²³_D −5.6 (c 0.50, CHCl₃); IR (film) ν_max 2914, 1959, 1682, 1453, 1200, 936, 870 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.81–7.77 (m, 1H), 7.53–7.43 (m, 1H), 7.36–7.29 (m, 1H), 7.25–7.09 (m, 6H), 5.87–5.62 (m, 1H), 4.90–4.72 (m, 2H), 3.97–3.75 (m, 4H), 3.46–3.37 (m, 2H), 3.36–3.26 (m, 8H), 3.19–3.12 (m, 1H), 3.06–2.88 (m, 8H), 2.59–2.45 (m, 1H), 2.34–2.28 (m, 1H), 2.28–2.16 (m, 2H), 2.15–2.06 (m, 1H), 2.03–1.92 (m, 1H), 1.92–1.77 (m, 2H), 1.75–1.65 (m, 1H), 1.63–1.56 (m, 1H), 1.29–1.23 (m, 2H), 1.15–1.10 (m, 6H), 1.01–0.98 (m, 3H), 0.98–0.94 (m, 3H), 0.93–0.90 (m, 6H), 0.81–0.68 (m, 3H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 172.5, 166.6, 162.3, 162.1, 161.8, 130.5, 129.5, 129.3, 128.8, 128.7, 127.3, 127.2, 125.8, 117.2, 115.3, 81.8, 81.6, 72.2, 51.6, 47.8, 47.7, 47.6, 47.6, 47.5, 47.3, 47.2, 44.4, 44.3, 44.3, 44.2, 44.1, 30.7, 29.9, 28.1, 27.9, 26.9, 26.0, 25.3, 24.1, 24.0, 23.9, 21.2, 21.1, 18.9, 18.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₄₂H₆₉N₆O₆S⁺, 785.4994, found: 785.4999.

(S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((2S,3R)-3-methoxy-5-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-5-oxo-1-phenylpentan-2-yl)-N,3-dimethylbutanamide (31f)

White powder (44 mg, 45%), mp 112–114 °C.; [α]²³_D −26.4 (c 0.125, CHCl₃); IR (film) ν_max 2916, 1957, 1650, 1453, 1203, 936, 919, 870 cm⁻¹; ¹H NMR (600 MHz, CDCl₃, rotamers) δ 7.88–7.83 (m, 1H), 7.43–7.37 (m, 1H), 7.25–7.10 (m, 11H), 5.76–5.66 (m, 1H), 5.26–5.03 (m, 1H), 4.67–4.58 (m, 1H), 3.90–3.72 (m, 4H), 3.42–3.38 (m, 3H), 3.35–3.33 (m, 1H), 3.33–3.31 (m, 2H), 3.31–3.28 (m, 2H), 3.27–3.21 (m, 1H), 3.16–3.10 (m, 1H), 3.03–2.87 (m, 10H), 2.56–2.46 (m, 1H), 2.45–2.20 (m, 3H), 2.16–2.10 (m, 1H), 2.07–1.88 (m, 3H), 1.84–1.76 (m, 1H), 1.74–1.66 (m, 1H), 1.63–1.55 (m, 1H), 1.17–1.04 (m, 7H), 0.97–0.93 (m, 3H), 0.91–0.86 (m, 3H), 0.78–0.73 (m, 2H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃, rotamers) δ 175.0, 173.5, 173.0, 171.5, 166.2, 161.8, 161.5, 161.2, 135.9, 129.4, 129.4, 129.3, 129.2, 129.1, 128.9, 128.8, 128.7, 128.6, 127.3, 126.7, 120.5, 118.7, 116.7, 114.8, 81.8, 72.1, 72.0, 61.7, 61.0, 60.6, 59.9, 59.6, 59.1, 54.5, 54.5, 54.4, 54.3, 51.7, 47.8, 47.8, 44.1, 41.2, 30.8, 29.9, 29.7, 29.7, 29.5, 28.2, 28.0, 27.9, 25.2, 25.1, 25.1, 24.5, 24.3, 20.4, 20.1, 19.0, 18.9, 17.1, 17.0, 15.5, 14.5, 14.3, 14.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₄₅H₆₇N₆O₆S⁺, 818.4759, found: 818.4755.

tert-Butyl(1S,3S,5S)-3-((1R,2R)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-2-methyl-3-oxopropyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (34)

Compound 33 (1.74 g, 8.16 mmol) was stirred in DCM (30 ml). Then Dess–Martin periodinane (8.6 g, 20.4 mmol) was added and the resulting mixture was stirred for 30 min at room temperature. The reaction mixture was carefully quenched with a solution of saturated aqueous NaHCO₃ and solid Na₂S₂O₃. The mixture was extracted with DCM (50 mL × 3), and the combined organic layers were washed with brine, and dried and concentrated to give the aldehyde without further purification. To a stirred solution of (S)-4-benzyl-3-propionyloxazolidin-2-one (2.13 g, 8.98 mmol) in DCM (20 mL) at 0 °C was added dropwise n-Bu₂BOTf ( 9.8 mL, 9.79 mmol, 1 M in DCM) and stirred for 10 min. TEA (1.47 mL, 10.61 mmol) was added dropwise and the reaction mixture was stirred for 1 h at room temperature. Then a solution of the above crude aldehyde in DCM was added dropwise, and the reaction mixture was stirred at −78 °C for 2 h before gradually warming to room temperature. Then the mixture was quenched with a solution of 30% aqueous H₂O₂ (15 mL) and MeOH (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for additional 4 h and extracted with DCM (80 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 4 : 1) to give 34. Colorless oil (2.17 g, 60%, two steps); [α]²⁴_D −29.1 (c 1.00, CHCl₃); IR (film): ν_max 3443, 2976, 1782, 1617, 1405, 1211, 1117, 702 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.25 (m, 3H), 7.22–7.17 (m, 2H), 4.72–4.60 (m, 1H), 4.30–4.15 (m, 3H), 4.12–3.95 (m, 1H), 3.84–3.78 (m, 1H), 3.52–3.42 (m, 1H), 3.23 (dd, J = 13.2, 3.2 Hz, 1H), 2.77 (dd, J = 13.6, 9.6 Hz, 1H), 2.24–2.13 (m, 2H), 1.50 (s, 9H), 1.46–1.41 (m, 1H), 1.35–1.24 (m, 4H), 0.89–0.83 (m, 1H), 0.72–0.64 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 177.4, 155.4, 152.8, 135.2, 129.6, 129.1, 127.5, 66.2, 55.2, 40.8, 38.6, 37.9, 28.7, 27.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₄H₃₃N₂O₆⁺, 445.2333, found: 445.2337.

tert-Butyl-(1S,3S,5S)-3-((1R,2R)-3-(benzyloxy)-1-methoxy-2-methyl-3-oxopropyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (35)

Compound 34 (0.95 g, 4.80 mmol) was dissolved in a mixture of THF and H₂O (80 mL v/v = 3 : 1). Then a solution of 30% H₂O₂ (4 mL, 38.4 mmol) and LiOH·H₂O (604 mg, 14.4 mmol) was added in one portion. After being stirred for 7 h, the mixture was acidified with hydrochloric acid to pH = 2–3 and the resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over MgSO₄, filtered and concentrated to give a crude compound, which was dissolved in DMF (20 mL). Then K₂CO₃ (950 mg, 9.6 mmol) and BnBr (0.57 mL, 4.8 mmol) were added. After being stirred for 4 h, the reaction mixture was diluted with water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water and brine respectively, then dried over MgSO₄, filtered and concentrated to give the crude secondary alcohol. To a cooled (−78 °C) solution of the secondary alcohol in HMPA (926 μL, 5.3 mmol) and THF (20 mL) was added a solution of LiHMDS (4.8 ml, 4.8 mmol, 1 M in THF) dropwise. After being stirred for 30 min, the reaction mixture was warmed to −15 °C and MeOTf (1.08 mL, 9.6 mmol) was added, and then the mixture was stirred for an additional 15 min. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 5 : 1) to give 35. Colorless oil (1.51 g, 81%, three steps); [α]²³_D +4.8 (c 0.50, CHCl₃); IR (film): ν_max 3443, 2075, 1637, 1404, 1172, 1088, 582 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.42–7.30 (m, 5H), 5.18–5.01 (m, 2H), 4.18–4.07 (m, 0.5H), 4.04–3.90 (m, 1H), 3.76–3.71 (m, 0.5H), 3.54–3.48 (m, 0.5H), 3.38–3.34 (m, 3.5H), 2.50–2.39 (m, 1H), 2.18–2.08 (m, 1H), 2.02–1.90 (m, 1H), 1.50–1.44 (m, 9H), 1.41–1.37 (m, 1H), 1.25–1.20 (m, 3H), 0.84 (d, J = 13.6 Hz, 1H), 0.70–0.60 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 174.4, 154.7, 135.9, 128.7, 128.4, 82.4, 81.2, 80.2, 79.5, 66.5, 63.6, 63.4, 61.0, 60.6, 43.4, 38.8, 38.5, 31.6, 30.3, 28.7, 28.0, 27.2, 14.0, 13.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₂H₃₂NO₅⁺, 390.2275, found: 390.2278.

tert-Butyl-(1S,3S,5S)-3-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (38)

Compound 35 (1.48 g, 3.80 mmol) and 10% Pd/C (148 mg) were stirred in MeOH (60 mL) for 4 h under a H₂ atmosphere. The mixture was filtered and concentrated to give a crude acid, which was dissolved in DCM (16 mL). HATU (2.17 g, 5.70 mmol), DIPEA (1.98 mL, 11.40 mmol), and 37 (912 mg, 3.80 mmol) were added and stirred overnight. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA = 1 : 1) to give 38. Colorless oil (1.38 g, 75%, two steps); [α]²³_D −39.2 (c 1.00, CHCl₃); IR (film): ν_max 3443, 2975, 2076, 1646, 1408, 1175, 1114 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 7.77–7.72 (m, 1H), 7.25–7.15 (m, 5H), 6.92–6.86 (m, 0.5H), 6.26–6.19 (m, 0.5H), 5.67–5.58 (m, 1H), 4.09–4.03 (m, 0.5H), 3.87–3.77 (m, 0.5H), 3.74–3.68 (m, 0.5H), 3.66–3.61 (m, 0.5H), 3.54–3.44 (m, 0.5H), 3.40–3.33 (m, 3H), 3.32–3.28 (m, 2H), 3.27–3.18 (m, 1.5H), 2.28–2.22(m, 0.5H), 2.14–2.05 (m,0.5H), 2.00–1.90 (m, 0.5H), 1.88–1.86 (m, 0.5H), 1.82–1.74 (m, 1H), 1.50 (s, 9H), 1.37–1.32 (m, 1H), 1.16–1.09 (m, 3H), 0.81–0.74 (m, 1H), 0.67–0.62 (m, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃, rotamers) δ 173.7, 173.2, 171.6, 171.0, 154.8, 142.6, 137.0, 136.6, 129.5, 129.4, 128.7, 128.6, 127.2, 127.0, 119.1, 118.9, 82.4, 81.1, 80.3, 79.7, 63.2, 62.9, 60.5, 52.4, 44.8, 44.4, 41.5, 38.9, 38.3, 28.7, 27.7, 26.5, 15.0, 14.6, 14.2, 13.9, 13.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₂₆H₃₆N₃O₄S⁺, 486.2421, found: 486.2427.

General procedure for the synthesis of 40a, 40b and 40c

Compound 29b/29c/29e (0.1 mmol) and 10% Pd/C were stirred in MeOH (10 mL) for 4 h under a H₂ atmosphere. The mixture was filtered and concentrated to give a crude acid without further purification. Compound 38 (53.4 mg, 0.11 mmol) and TFA (0.2 mL) were stirred in DCM (1 mL) for 2 h at 0 °C and the mixture was directly concentrated. The residue was dissolved in DCM (1 mL), HATU (57 mg, 0.15 mmol), and DIPEA (52 μL, 0.3 mmol) and the above crude acid was added. After being stirred for 12 h, the reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (DCM/MeOH = 100 : 1 to 25 : 1) to give the title product (40a, 40b and 40c) as a viscous liquid, which was further treated with acetone/hexane to give a white powder.

(S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((1S,3S,5S)-3-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)-2-azabicyclo[3.1.0]hexan-2-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (40a)

White powder (25 mg, 31%), mp 92.5–94.5 °C; [α]²⁴_D −38.0 (c 0.10, CHCl₃); IR (film): ν_max 3344, 2965, 1634, 1454, 1210, 1096, 698 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.77–7.72 (m, 1H), 7.24–7.18 (m, 5H), 7.13–7.06 (m, 1H), 5.61–5.51 (m, 1H), 4.93–4.72 (m, 2H), 4.40–4.32 (m, 1H), 4.24–4.13 (m, 1H), 3.89 (d, J = 8.0 Hz, 1H), 3.43–3.35 (m, 2H), 3.35–3.31 (m, 3H), 3.29–3.26 (m, 3H), 3.26–3.21 (m, 1H), 3.20–3.09 (m, 2H), 3.07–3.00 (m, 3H), 2.67–2.57 (m, 1H), 2.51–2.40 (m, 2H), 2.27–2.22 (m, 6H), 2.15–2.07 (m, 1H), 2.06–1.93 (m, 3H), 1.92–1.85 (m, 1H), 1.44–1.31 (m, 3H), 1.12–1.09 (m, 3H), 1.04–1.00 (m, 6H), 0.98–0.95 (m, 6H), 0.93–0.91 (m, 3H), 0.84–0.82 (m, 3H), 0.79–0.64 (m, 2H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 173.6, 171.9, 165.5, 163.1, 158.4, 156.5, 142.6, 137.1, 132.4, 129.9, 129.6, 128.6, 127.0, 122.0, 121.9, 118.9, 118.8, 80.1, 63.3, 60.0, 58.0, 53.9, 53.3, 52.7, 52.5, 44.4, 43.0, 41.3, 38.3, 38.1, 33.4, 31.1, 27.8, 25.8, 20.2, 17.9, 16.4, 14.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₄₃H₆₉N₆O₆S⁺, 797.4994, found: 797.4999.

(S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N-((3R,4S,5R)-5-(3-fluorobenzyl)-3-methoxy-1-((1S,3S,5S)-3-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)-2-azabicyclo[3.1.0]hexan-2-yl)-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (40b)

White powder (25 mg, 28%), mp 87.5–89.5 °C; [α]²⁶_D −22.0 (c 0.25, CHCl₃); IR (film): ν_max 3291, 2928, 1639, 1453, 1252, 1096, 774, 696 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.77–7.72 (m, 1H), 7.23–7.18 (m, 5H), 7.04–6.96 (m, 3H), 6.94–6.83 (m, 3H), 5.61–5.52 (m, 1H), 4.95–4.75 (m, 2H), 4.40–4.32 (m, 1H), 4.32–4.23 (m, 1H), 3.93–3.86 (m, 1H), 3.38–3.35 (m, 3H), 3.29–3.26 (m, 3H), 3.11–3.07 (m, 3H), 2.80–2.62 (m, 3H), 2.53–2.42 (m, 3H), 2.31–2.23 (m, 6H), 2.12–1.98 (m, 5H), 1.91–1.84 (m, 1H), 1.53–1.47 (m, 2H), 1.39–1.36 (m, 1H), 1.29–1.24 (m, 3H), 1.13–1.10 (m, 3H), 1.05–0.99 (m, 6H), 0.96–0.91 (m, 6H), 0.82–0.77 (m, 3H), 0.76–0.68 (m, 2H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 173.5, 171.9, 169.5, 163.0 (d, J = 243.6 Hz), 143.6, 142.6, 137.0, 129.8 (d, J = 7.7 Hz), 129.5, 128.6, 127.0, 124.9, 118.9, 116.0 (d, J = 20.6 Hz), 112.9 (d, J = 20.9 Hz), 80.2, 63.3, 60.0, 58.0, 53.8, 52.6, 44.3, 43.1, 41.4, 40.7, 38.6, 38.3, 35.8, 30.9, 27.8, 25.7, 20.3, 18.0, 16.4, 14.3, 10.6 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₄₉H₇₂FN₆O₆S⁺, 891.5213, found: 891.5211.

(S)-N-((3R,4S,5R)-5-Benzyl-3-methoxy-1-((1S,3S,5S)-3-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)-2-azabicyclo[3.1.0]hexan-2-yl)-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide (40c)

White powder (39 mg, 45%), mp 76.5–78.5 °C; [α]²⁴_D −30.2 (c 0.50, CHCl₃); IR (film): ν_max 3423, 2930, 1637, 1535, 1454, 1096, 750, 700, cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.74–7.71 (m, 1H), 7.26–7.22 (m, 4H), 7.22–7.15 (m, 8H), 7.08 (d, J = 6.8 Hz, 1H), 6.95 (d, J = 9.2 Hz, 1H), 5.57 (dd, J = 14.0, 8.0 Hz, 1H), 5.02–4.86 (m, 1H), 4.83 (dd, J = 6.8, 6.0 Hz, 1H), 4.40–4.33 (m, 1H), 4.32–4.26 (m, 1H), 3.88 (d, J = 7.6 Hz, 1H), 3.48–3.38 (m, 1H), 3.37–3.35 (m, 3H), 3.32–3.28 (m, 1H), 3.28–3.26 (m, 3H), 3.10–3.07 (m, 3H), 2.82–2.75 (m, 1H), 2.72–2.58 (m, 1H), 2.55–2.49 (m, 1H), 2.44 (d, J = 6.4 Hz, 1H), 2.42–2.27 (m, 1H), 2.26–2.23 (m, 6H), 2.10–1.97 (m, 4H), 1.91–1.86 (m, 1H), 1.54–1.46 (m, 1H), 1.44–1.37 (m, 1H), 1.12–1.09 (m, 3H), 1.04–0.98 (m, 6H), 0.97–0.94 (m, 3H), 0.93–0.91 (m, 3H), 0.90–0.87 (m, 2H), 0.78 (t, J = 7.0 Hz, 3H), 0.75–0.67 (m, 2H) ppm; ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 173.6, 173.3, 171.9, 171.7, 169.5, 142.6, 140.9, 137.0, 129.5, 129.2, 128.6, 128.4, 118.9, 80.1, 76.7, 63.3, 60.0, 58.0, 53.8, 52.6, 44.3, 43.1, 41.3, 38.4, 38.3, 35.9, 31.0, 29.8, 27.8, 25.7, 22.2, 20.3, 19.9, 18.0, 17.9, 16.4, 14.4, 10.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]⁺ calcd for C₄₉H₇₃N₆O₆S⁺, 873.5307, found: 873.5309.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (21772027 to B.-G. Wei, and 21702032 to C.-M. Si) and the Open Research Fund Program of Beijing Key Lab of Plant Resource Research and Development, BTBU (No. PRRD-2018-ZD1) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9qo01292c

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