A versatile access to vicinal diamine motifs by highly anti-selective asymmetric vinylogous Mannich reactions: an efficient total synthesis of (+)-absouline

Abstract

We report the asymmetric vinylogous Mannich reactions (VMRs) of N-Boc-2-tert-(butyldimethylsilyloxy)pyrrole (TBSOP) with N-tert-butanesulfinylimines. The reaction is highly anti-diastereoselective and shows good generality for the direct construction of a variety of vicinal anti-diamine motifs that are found in a number of biologically active alkaloids and medicinal agents. A VMR adduct was elaborated in six steps into the 1-aminopyrrolizidine alkaloid (+)-absouline, which constitutes the second and also the most efficient total synthesis of the natural enantiomer of the title alkaloid.

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Introduction

anti-Vicinal diamines in general,¹ and 1-aminopyrrolizidines^2–6 in particular are structural motifs found in many biologically active alkaloids and medicinal agents.^1–6 For example, 1-aminopyrrolizidine alkaloids (+)-absouline (E-1), (+)-isoabsouline (Z-1) (Fig. 1) and their N-oxides are found in two Caledonian plants Hugonia oreogena and Hugonia penicillanthemum,^2a which were reported to exhibit modest antiviral activity.^2a,b (+)-Laburnamine (2),³ which differs only at the acyl group from (+)-absouline (1), is found in Cytisus laburnum seeds^3a,b and in Laburnum anagyroides seeds,^3c and showed middle to high affinity to the α3β4, α7 and α4β2 nicotinic receptor subtype.^3c Loline (3) is a representative of a group of thirteen alkaloids produced by mutualistic fungal endophytes living on forage grasses, which play a range of biological roles.⁴ Unnatural SC52246 (4) is a potent and selective 5HT3 serotonin receptor antagonist.⁵ Unnatural influenza neuraminidase inhibitor A-315675 (5) is a potent inhibitor of influenza A and B viral replication developed by the Abbott scientists.⁶

Fig. 1 Representative natural products and medicinal agents bearing an anti-vicinal diamine motif.

The unique structural feature and interesting bioactivities exhibited by 1-aminopyrrolizidine alkaloids make them attractive synthetic targets. However, although several syntheses of absouline⁷ (E-1), laburnamine⁸ (2), loline (3),⁹ and SC-52246⁵ (4) have been reported, efficient enantioselective total syntheses are rare.^7d–f,9e,g Specifically, for absouline (E-1), aza-conjugate addition-based highly efficient enantioselective total syntheses of (−)-absouline (E-1) have been achieved by Scheerer et al. (eight steps, 10% overall yield)^7e and Davies et al. (eight steps, 20% overall yield),^7f respectively. Surprisingly, the lengthy asymmetric synthesis of (+)-absouline (E-1), reported several years ago from these laboratories,^7c remains the sole total synthesis of the natural enantiomer of this alkaloid. It is thus desirable to develop an alternative strategy for the efficient asymmetric total synthesis of (+)-absouline (E-1).

In recent years, we have been engaged in developing efficient methodologies for the asymmetric total syntheses of natural products^9g,10 based on the vinylogous Mannich reaction (VMR)¹¹ and the vinylogous Mukaiyama reaction (VMAR).^11a,b Although the resulting heterocyclic amino alcohols can be converted into the corresponding vicinal diamines,^9g a direct approach would be more efficient and more attractive. It was envisioned that the addition of a 2-silyloxypyrrole such as N-tert-butoxycarbonyl-2-(tert-butyldimethylsiloxy)pyrrole (TBSOP,¹²7) to an imine such as 6 would afford the functionalized vicinal diamino adduct 8, which could be elaborated in a straightforward manner into 1-aminopyrrolizidine 9a or 1-aminoindolizidine 9b, and related alkaloids (Scheme 1).

Scheme 1 Vinylogous Mannich reaction-based approach to anti-vicinal diamine motifs.

Thanks to the seminal work of Casiraghi/Rassu and Martin, the heterocyclic silyloxydiene-based VMRs and VMARs have become powerful methodologies for the syntheses of functionalized bioactive heterocycles and natural products. However, direct construction of the anti-vicinal diamine motif by asymmetric addition of a 2-silyloxypyrrole with an imine was less explored.^6,13,14 The most significant advance in this field is undoubtedly the catalytic enantioselective VMR, developed independently by Casiraghi/Zanardi,^14a,b and Hoveyda.^14c Nevertheless, this methodology is still in its infancy. In fact, the reported methods are largely limited to aromatic¹⁴ and alkyne-substituted N-arylaldimines.^14c When aliphatic N-arylimines were used as substrates, the cleavage of the N-aryl group of the resulting diamine products led to low yields.^14b On the other hand, the chemistry developed during the synthesis of A-315675⁶ (5) is restricted to substrates 10 derived from a specific chiral non-racemic aldehyde (Scheme 2). Moreover, use of the Ellman N-tert-butanesulfinimine 10b led to 11b in a low yield (36%).^6a In view of the widespread use of Ellman N-tert-butanesulfinimines (t-BS-imines 6) as versatile chiral and reliable amine templates,¹⁵ development of the Ellman sulfinimine-based asymmetric VMR would pave an avenue for the asymmetric synthesis of anti-vicinal diamine-containing bioactive molecules and alkaloids (Scheme 1). We report herein the asymmetric VMR of Ellman chiral sulfinimines (6) and TBSOP (7), and its application to the efficient asymmetric total synthesis of the naturally occurring (+)-(1S,7aR)-absouline (E-1).

Scheme 2 The VMRs investigated during the syntheses of A-315675.

We first investigated the asymmetric VMRs of Ellman sulfinimines (6) with commercially available TBSOP (7). In view of the total synthesis of (+)-absouline (E-1), the known (R_S)-t-BS-imine 6a,^16a prepared in high yield from (R_S)-N-tert-butanesulfinamide (13) and the known aldehyde 14a^16b by Ellman's method,¹⁷ was selected as a model compound for investigating the asymmetric VMR. After screening the reaction conditions including Lewis acids (BF₃·Et₂O, TiCl₄, Sm(OTf)₃, Bi(OTf)₃, Cu(OTf)₂, TMSOTf), molar equivalents of both Lewis acids and TBSOP (7), optimal reaction conditions were determined, from which TMSOTf turned out to be the Lewis acid of choice (cf. ESI†). In the event, a mixture of TBSOP (7, 1.4 equiv.) and t-BS-imine 6a (1.0 equiv.) in CH₂Cl₂ was treated with TMSOTf (1.0 equiv.) at −78 °C for 7 h. In this manner, the desired addition product 8a was obtained in 96% yield as a single diastereomer (Scheme 3). The stereochemistry of 8a was determined to be R_S,5R,6S (5,6-anti) by single-crystal X-ray diffraction crystallographic analysis (Scheme 3).¹⁸

Scheme 3 Synthesis and X-ray structure of 8a.

To extend the scope of the asymmetric VMR, the reactions of TBSOP (7) with other (R_S)-t-BS-imines 6b–o were examined, and the results are listed in Table 1. t-BS-imines 6b–o were prepared in high yields from (R_S)-t-butanesulfinamide (13) and the corresponding aldehydes using either CuSO₄¹⁷ (for aliphatic aldehydes) or Ti(OEt)₄¹⁷ (for aromatic aldehydes) as a dehydrating agent (Table 1, col. 1). As in the case of 6a, the asymmetric VMRs of aliphatic t-BS-imines 6b–h produced the corresponding adducts 8b–h in excellent yields and anti-diastereoselectivities (86–98%, dr > 99 : 1, entries 2–8). The reactions of aromatic t-BS-imines 6i–o afforded the corresponding adducts 8i–o in 86–93% yields, and in 82 : 18 to >99 : 1 anti-diastereoselectivities (entries 9–15). A strong electron-donating group (MeO) at the para-position of the phenyl group decreased the anti-diastereoselectivity (86%, dr = 82 : 18, entry 12), while a strong electron-withdrawing group (NO₂) seems to be beneficial for both the yield and anti-selectivity (93%, dr = 95 : 5, entry 14). The highest anti-diastereoselectivity (92%, >99 : 1) among the tested aromatic t-BS-imines was observed for the reaction of sterically hindered 1-naphthyl t-BS-imine 6o (entry 15).

Table 1 The VMRs of t-BS-imines 6 with TBSOP (7)

Entry	Aldehyde	t-BS-imine 6 (% yield)^d	Major diastereomer (anti/syn)^c (% yield)^d
a Prepared by Method A: CuSO4, CH2Cl2, rt, 12 h. b Prepared by Method B: Ti(OEt)4, CH2Cl2, rt, 12 h. c Ratio determined by ^1H NMR analysis of crude mixture. d Isolated yield.
1	TIPSO(CH2)2CHO	(RS)-6a (94)^a	8a (>99 : 1) (96)
2	EtCHO	(RS)-6b (93)^a	8b (>99 : 1) (91)
3	n-PrCHO	(RS)-6c (90)^a	8c (>99 : 1) (98)
4	n-C5H11CHO	(RS)-6d (95)^a	8d (>99 : 1) (91)
5	Ph(CH2)2CHO	(RS)-6e (94)^a	8e (>99 : 1) (94)
6	3-Cl-n-PrCHO	(RS)-6f (85)^a	8f (>99 : 1) (87)
7	i-PrCHO	(RS)-6g (94)^a	8g (>99 : 1) (86)
8	c-HexCHO	(RS)-6h (94)^a	8h (>99 : 1) (88)
9	PhCHO	(RS)-6i (95)^b	8i (93 : 7) (88)
10	p-i-PrC6H4CHO	(RS)-6j (94)^b	8j (92 : 8) (87)
11	4-Ph-C6H4CHO	(RS)-6k (95)^b	8k (88 : 12) (88)
12	p-MeOC6H4CHO	(RS)-6l (94)^b	8l (82 : 18) (86)
13	p-ClC6H4CHO	(RS)-6m (91)^b	8m (88 : 12) (88)
14	p-O2NC6H4CHO	(RS)-6n (90)^b	8n (95 : 5) (93)
15	1-NaphthylCHO	(RS)-6o (93)^b	8o (>99 : 1) (92)

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Single-crystal X-ray diffraction crystallographic analysis (Fig. 2) showed that the stereochemistry of aromatic 8m is the same as that of aliphatic 8a, namely, R_S,5R,6S (5,6-anti).¹⁸ Comparison of the diagnostic resonances (cf. S3 in the ESI†) of the ¹H NMR spectra of aliphatic 8b–h and aromatic 8i–o with those of 8a and 8m allowed concluding that they all possess the same 5,6-anti-stereochemistry as 8a and 8m.

Fig. 2 X-Ray structure of 8m.

Interestingly, the stereochemical outcome including asymmetric induction at C5 of this anti-selective VMR (between TBSOP 7 and t-BS-imines 6) is in agreement not only with other VMRs of 2-silyloxypyrroles,^6,14 but also with that observed for the VMR between 2-(tert-butyldimethylsiloxy)furan (TBSOF) and t-BS-imines 6.^10a Thus, the same model^10a (A in Fig. 3) could be used to account for the observed anti-selectivities of the VMRs, namely, according to the Cram–Davis’ open transition model,^19,20 TBSOP (7) approaches t-BS-imines 6 by the si-face of the former and re-face of the latter, and the facial selectivity on the chiral sulfinimine is total. On the basis of this model, the lower diastereoselectivities and/or yields obtained from the branched t-BS-imines including isobutyl, cyclohexylmethyl and aromatic t-BS-imine could be attributed to the unfavorable steric interaction between those groups and the N-Boc group. The opposite effects of phenyl substituents OMe and Cl compared with that of NO₂ might implicate a favorable secondary orbital interaction between the aromatic ring and the carbonyl group in Boc. The higher diastereoselectivity observed for the 1-naphthyl t-BS-imine 6o also supports this assumption.

Fig. 3 Plausible transition state for the anti-selective VMR leading to (R_S,5R,6S)-8.

After establishing a versatile and highly anti-diastereoselective approach to (R_S,5R,6S)-8, we turned our attention to the total synthesis of (+)-absouline (E-1). Thus (R_S,5R,6S)-8a, the required stereoisomer for the synthesis of (+)-absouline (E-1), was subjected to catalytic hydrogenation (10% Pd/C, H₂ 1 atm, 5 h, rt) of 8a, which produced 15 in 97% yield (Scheme 4). Chemoselective reduction of imide 15 was achieved by treating with BH₃·SMe₂ (4 equiv.) at −30 °C for 18.5 h, which produced N-Boc-pyrrolidine 16 in 85% yield. Treatment of the silyl ether 16 with 1.5 equiv. of TBAF at 0 °C for 1 h provided the alcohol 17 in 97% yield. Compound 17 was mesylated (MsCl, NEt₃, CH₂Cl₂, 0 °C to rt, 3 h) to afford mesylate 18 in 90% yield. Successive treatment of 18 with TFA and K₂CO₃ in MeCN produced, in one-pot, the 1-aminopyrrolizidine derivative 19 in 90% yield. Finally, cleavage of the chiral auxiliary (conc. HCl, MeOH),^17,21 followed by coupling of the resulting 1-aminopyrrolizidine with (E)-4-methoxycinnamic acid (DCC, DMAP) produced (+)-absouline (E-1) in 60% yield. The spectroscopy and optical rotation data of our synthetic (+)-absouline (E-1) matched well with those previously reported {[α]²⁰_D +51.3 (c 0.3, EtOH), [α]²⁰_D +40.0 (c 1.0, CHCl₃); lit. natural (+)-absouline: [α]_D +56 (c 1, EtOH);^2a synthetic (+)-absouline: [α]²⁰_D +26 (c 1.05, CHCl₃);^7a [α]²⁰_D +46.0 (c 1.2, CHCl₃);^7c synthetic (−)-absouline: [α]²⁰_D −49 (c 0.2, EtOH)^7f}.

Scheme 4 The synthesis of (+)-absouline (E-1).

Conclusion

In summary, on the basis of the asymmetric vinylogous Mannich reactions (VMRs) between TBSOP and t-BS-imines, we have developed a direct, highly anti-stereoselective and versatile approach to anti-vicinal diamine structural motifs. The reaction is versatile for t-BS-imines bearing both linear and branched alkyl groups, as well as aromatic groups. Running under mild conditions, the reaction tolerates several functional groups, which allows further elaboration of adducts into bicyclic ring systems such as 1-aminopyrrolizidine. The power of this method has been demonstrated by a highly efficient total synthesis of the natural (+)-absouline (E-1). The method is applicable for the rapid construction of 1-aminoindolizidine ring system 9b and for the synthesis of other 1-aminopyrrolizidine-containing alkaloids such as (+)-isoabsouline (Z-1), (+)-laburnamine (2), and loline (3). Research along this line is in progress and the results will be reported in due course.

Experimental section

General methods

¹H NMR and ¹³C NMR spectra were recorded on a Bruker 400 or Bruker 500 (¹H/400 or 500 MHz, ¹³C/100 or 125 MHz) spectrometer. Chemical shifts are expressed in parts per million (δ) relative to an internal standard of residual chloroform (7.26 ppm for ¹H NMR and 77.0 ppm for ¹³C NMR) or DMSO-d₆ (2.50 ppm for ¹H NMR and 39.5 ppm for ¹³C NMR). ESI-mass spectra were recorded on a Bruker Dalton ESquire 3000 Plus LC-MS apparatus. Optical rotations were measured with a Perkin-Elmer 341 automatic polarimeter or an Anton Paar MCP 500 polarimeter. Melting points were uncorrected. Infrared spectra were recorded with a Nicolet Avatar 330 FT-IR spectrometer using the film KBr pellet technique. Silica gel (300–400 mesh) was used for flash column chromatography. THF was distilled over sodium benzophenone ketyl under Ar. Dichloromethane was distilled over calcium hydride under Ar.

General procedure for the synthesis of compound (8)

To a cooled (−78 °C) solution of (R_S)-t-BS-imine 6²² (0.50 mmol) and commercially available tert-butyl-2-[(tert-butyldimethylsilyl)oxy]-1H-pyrrole-1-carboxylate (TBSOP) 7 (0.70 mmol) in CH₂Cl₂ (5 mL) was added dropwise TMSOTf (0.50 mmol) under an atmosphere of nitrogen. After being stirred for 7 h at the same temperature, the reaction was quenched with saturated aqueous NaHCO₃ solution. The mixture was extracted with CH₂Cl₂ (5 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide adduct 8. The diastereomeric ratio was determined by ¹H NMR.

tert-Butyl (R)-2-{(S)-[(R)-1,1-dimethylethylsulfinamido](2-triisopropylsilyloxyethyl)methyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8a]. Following the general procedure, the VMR between TBSOP (416 mg, 1.4 mmol) and (R_S)-t-BS-imine 6a (333 mg, 1.0 mmol) produced, after flash chromatography (eluent: EtOAc/hexane = 2/1), compound 8a (496 mg, yield: 96%) (dr > 99 : 1, ¹H NMR) as a white solid. Mp: 93–95 °C; [α]²⁰_D +116.4 (c 1.0, CHCl₃); IR (film) ν_max: 3345, 2943, 2886, 1776, 1743, 1718, 1368, 1317, 1161, 1102, 1054, 883, 772 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.00–1.10 (m, 18H, 6Me, superposed), 1.10–1.20 (m, 12H including a singlet at 1.12 (s, 9H)), 1.53 (s, 9H), 1.93–1.99 (m, 2H), 2.96 (d, J = 8.9 Hz, 1H), 3.89–4.01 (m, 2H), 4.28 (ddd, J = 3.2, 7.4, 16.1 Hz, 1H), 4.87 (t, J = 1.5 Hz, 1H), 6.21 (dd, J = 1.4, 6.2 Hz, 1H), 7.18 (dd, J = 2.0, 6.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 11.9 (3C), 18.0 (6C), 22.7 (3C), 28.1 (3C), 38.0, 55.3, 56.3, 60.6, 66.1, 83.2, 129.5, 145.8, 149.0, 169.1; HRMS calcd for C₂₅H₄₈N₂O₅SSiNa [M + Na]⁺: 539.2945; found: 539.2947.

tert-Butyl (R)-2-{(S)-1-[(R)-1,1-dimethylethylsulfinamido]propyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8b]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6b (80 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc/hexane = 3/1), compound 8b (156 mg, yield: 91%) (dr > 99 : 1, ¹H NMR) as a white solid. Mp: 110–111 °C; [α]²⁰_D +183.0 (c 1.0, CHCl₃); IR (film) ν_max: 3268, 2923, 2852, 1566, 1462, 1453, 1366, 1185, 1150, 1036, 964, 890, 791, 736 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.13 (s, 9H), 1.17 (t, J = 7.6 Hz, 3H), 1.57 (s, 9H), 1.70–1.77 (m, 2H), 2.79 (d, J = 8.4 Hz, 1H), 4.01–4.04 (m, 1H), 4.68–4.69 (m, 1H), 6.22 (dd, J = 1.6, 6.2 Hz, 1H), 7.10 (dd, J = 2.0, 6.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 11.2, 22.8 (3C), 28.05, 28.14 (3C), 56.3, 58.0, 65.4, 83.3, 129.9, 144.9, 149.0, 168.8; HRMS calcd for C₁₆H₂₈N₂O₄SNa [M + Na]⁺: 367.1662; found: 367.1663.

tert-Butyl (R)-2-{(S)-1-[(R)-1,1-dimethylethylsulfinamido]butyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8c]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6c (88 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc), compound 8c (177 mg, yield: 98%) (dr > 99 : 1, ¹H NMR) as a white solid. Mp: 167–168 °C; [α]²⁰_D +249.2 (c 1.0, CHCl₃); IR (film) ν_max: 3296, 2959, 2929, 2872, 2359, 2340, 1774, 1741, 1712, 1461, 1368, 1342, 1317, 1293, 1255, 1160, 1104, 1052, 911, 847, 794, 770, 752 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.02 (t, J = 6.8 Hz, 3H), 1.13 (s, 9H), 1.57 (s, 9H), 1.60–1.70 (m, 3H), 1.86–1.95 (m, 1H), 2.75 (d, J = 8.5 Hz, 1H), 4.10–4.18 (m, 1H), 4.62–4.66 (m, 1H), 6.21 (dd, J = 1.6, 6.3 Hz, 1H), 7.10 (dd, J = 1.9, 6.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 13.7, 19.5, 22.7 (3C), 28.1 (3C), 36.9, 55.9, 56.2, 65.7, 83.3, 129.8, 145.0, 149.0, 168.9; HRMS calcd for C₁₇H₃₀N₂O₄SNa [M + Na]⁺: 381.1819; found: 381.1823.

tert-Butyl (R)-2-{(S)-1-[(R)-1,1-dimethylethylsulfinamido]hexyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8d]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6d (102 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc), compound 8d (181 mg, yield: 91%) (dr > 99 : 1, ¹H NMR) as a white solid. Mp: 152–154 °C; [α]²⁰_D +210.2 (c 1.0, CHCl₃); IR (film) ν_max: 3226, 2956, 2928, 2861, 1775, 1742, 1714, 1458, 1369, 1319, 1293, 1256, 1161, 1106, 1053, 894, 846, 826, 795, 773, 752 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 0.91 (t, J = 7.0 Hz, 3H), 1.13 (s, 9H), 1.30–1.40 (m, 4H), 1.47–1.70 (m, 4H), 1.58 (s, 9H), 2.67 (d, J = 8.8 Hz, 1H), 4.07–4.16 (m, 1H), 4.62–4.67 (m, 1H), 6.22 (dd, J = 1.4, 6.2 Hz, 1H), 7.09 (dd, J = 1.9, 6.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 13.9, 22.3, 22.6 (3C), 25.9, 28.1 (3C), 31.4, 34.9, 56.1, 56.2, 65.6, 83.2, 129.8, 145.0, 149.0, 168.8; HRMS calcd for C₁₉H₃₄N₂O₄SNa [M + Na]⁺: 409.2131; found: 409.2130.

tert-Butyl (R)-2-{(S)-1-[(R)-1,1-dimethylethylsulfinamido]-3-phenylpropyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8e]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6e (119 mg, 0.50 mmol) produced, after flash chromatography (eluent: MeOH/CH₂Cl₂ = 1/80), compound 8e (198 mg, yield: 94%) (dr > 99 : 1, ¹H NMR) as a white solid. Mp: 149–152 °C; [α]²⁰_D +125.6 (c 1.0, CHCl₃); IR (film) ν_max: 3291, 2979, 2941, 1774, 1742, 1723, 1603, 1477, 1453, 1369, 1317, 1294, 1196, 1157, 1132, 1076, 1051, 885, 752 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.15 (s, 9H), 1.43 (s, 9H), 1.85–1.96 (m, 1H), 1.97–2.08 (m, 1H), 2.82 (d, J = 8.6 Hz, 1H), 2.84–2.93 (m, 1H), 2.94–3.04 (m, 1H), 3.98–4.08 (m, 1H), 4.56 (dd, J = 2.0, 3.3 Hz, 1H), 6.21 (dd, J = 1.5, 6.2 Hz, 1H), 7.08 (dd, J = 2.0, 6.2 Hz, 1H), 7.20 (dd, J = 4.4, 8.8 Hz, 1H), 7.29–7.32 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 22.8 (3C), 28.0 (3C), 31.9, 36.5, 55.8, 56.4, 66.3, 83.3, 126.3, 128.6, 129.9, 140.6, 144.9, 148.8, 168.9; HRMS calcd for C₂₂H₃₂N₂O₄SNa [M + Na]⁺: 443.1975; found: 443.1977.

tert-Butyl (R)-2-{(S)-4-chloro-1-[(R)-1,1-dimethylethylsulfinamido]butyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8f]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6f (105 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc/hexane = 4/1), compound 8f (171 mg, yield: 87%) (dr > 99 : 1, ¹H NMR) as a white solid. Mp: 140–142 °C; [α]²⁰_D +182.3 (c 1.0, CHCl₃); IR (film) ν_max: 3277, 2978, 2928, 2870, 1775, 1741, 1713, 1475, 1456, 1369, 1318, 1294, 1257, 1160, 1105, 1053, 955, 896, 845, 825, 795, 753, 643, 611 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.14 (s, 9H), 1.57 (s, 9H), 1.63–1.72 (m, 1H), 1.93–2.07 (m, 2H), 2.11–2.26 (m, 1H), 2.77 (d, J = 8.6 Hz, 1H), 3.61–3.71 (m, 2H), 4.09–4.17 (m, 1H), 4.62–4.65 (m, 1H), 6.24 (dd, J = 1.6, 6.2 Hz, 1H), 7.15 (dd, J = 2.0, 6.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 22.7 (3C), 28.2 (3C), 29.0, 31.5, 44.4, 55.7, 56.4, 66.0, 83.5, 130.1, 144.7, 149.2, 168.5; HRMS calcd for C₁₇H₂₉ClN₂O₄SNa [M + Na]⁺: 415.1429; found: 415.1426.

tert-Butyl (R)-2-{(S)-1-[(R)-1,1-dimethylethylsulfinamido]-2-methylpropyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8g]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6g (88 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc), compound 8g (154 mg, yield: 86%) (dr > 99 : 1, ¹H NMR) as a white solid. Mp: 158–159 °C; [α]²⁰_D +249.2 (c 1.0, CHCl₃); IR (film) ν_max: 3222, 2964, 2928, 2872, 1775, 1741, 1712, 1475, 1392, 1368, 1318, 1292, 1257, 1161, 1127, 1107, 1052, 891, 848, 816, 791, 752 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.14 (s, 9H), 1.19 (d, J = 6.4 Hz, 6H), 1.58 (s, 9H), 1.69–1.79 (m, 1H), 2.77 (d, J = 8.0 Hz, 1H), 3.78–3.84 (m, 1H), 4.81–4.84 (m, 1H), 6.20 (dd, J = 1.5, 6.2 Hz, 1H), 7.09 (dd, J = 1.8, 6.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 20.2, 21.0, 22.8 (3C), 28.2 (3C), 32.2, 56.3, 61.9, 64.6, 83.3, 129.8, 145.2, 148.9, 169.0; HRMS calcd for C₁₇H₃₀N₂O₄SNa [M + Na]⁺: 381.1819; found: 381.1814.

tert-Butyl (R)-2-{(S)-cyclohexyl[(R)-1,1-dimethylethylsulfinamido]methyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8h]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6h (108 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc/hexane = 3/1), compound 8h (175 mg, yield: 88%) (dr > 99 : 1, ¹H NMR) as a white solid. Mp: 158–159 °C; [α]²⁰_D +134.8 (c 1.0, CHCl₃); IR (film) ν_max: 3233, 2926, 2853, 1777, 1738, 1711, 1368, 1344, 1321, 1296, 1161, 1052, 729 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.14 (s, 9H), 1.20–1.50 (m, 6H), 1.57 (s, 9H), 1.70–2.12 (m, 5H), 2.75 (d, J = 8.0 Hz, 1H), 3.86–3.92 (m, 1H), 4.82–4.85 (m, 1H), 6.19 (dd, J = 1.5, 6.2 Hz, 1H), 7.08 (dd, J = 2.0, 6.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 22.8 (3C), 25.5, 25.8, 25.9, 28.1 (3C), 30.3, 30.7, 41.2, 56.2, 60.4, 64.2, 83.2, 129.6, 145.5, 148.8, 169.2; HRMS calcd for C₂₀H₃₄N₂O₄SNa [M + Na]⁺: 421.2132; found: 421.2136.

tert-Butyl (R)-2-{(S)-[(R)-1,1-dimethylethylsulfinamido](phenyl)methyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8i]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6i (105 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc/hexane = 3/1), compound 8i (174 mg, yield: 88%) (dr = 93 : 7, ¹H NMR) as a diastereomeric mixture, which was separated by repeated flash chromatography on silica gel (eluent: EtOAc/hexane = 3/1) to give (R_S,5R,6S)-8i as a white solid. Mp: 149–150 °C; [α]²⁰_D +130.3 (c 1.0, CHCl₃); IR (film) ν_max: 3242, 2978, 2925, 2359, 2343, 1778, 1743, 1709, 1478, 1453, 1366, 1321, 1284, 1258, 1158, 1053, 894, 846, 815, 790, 772, 701 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.19 (s, 9H), 1.63 (s, 9H), 3.63 (d, J = 9.4 Hz, 1H), 4.89–4.92 (m, 1H), 5.40 (dd, J = 3.5, 9.4 Hz, 1H), 6.20 (d, J = 6.2 Hz, 1H), 6.85 (dd, J = 1.9, 6.2 Hz, 1H), 7.32–7.48 (m, 5H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 28.2 (3C), 56.7, 58.6, 67.4, 83.7, 126.3, 128.3, 129.1, 129.7, 138.3, 145.2, 149.2, 168.7; HRMS calcd for C₂₀H₂₈N₂O₄SNa [M + Na]⁺: 415.1662; found: 415.1658.

tert-Butyl (R)-2-{(S)-[(R)-1,1-dimethylethylsulfinamido](4-isopropylphenyl)methyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8j]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6j (126 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc), compound 8j (189 mg, yield: 87%) (dr = 92 : 8, ¹H NMR) as a diastereomeric mixture, which was separated by repeated flash chromatography on silica gel (eluent: MeOH/CH₂Cl₂ = 1/80) to give (R_S,5R,6S)-8j as a colorless oil. [α]²⁰_D +177.6 (c 1.0, CHCl₃); IR (film) ν_max: 3246, 2961, 2926, 2869, 1783, 1745, 1709, 1460, 1366, 1321, 1260, 1159, 1054, 896, 794; ¹H NMR (400 MHz, CDCl₃): δ 1.18 (s, 9H), 1.25 (d, J = 6.9 Hz, 6H), 1.63 (s, 9H), 2.92 (sept, J = 6.9 Hz, 1H), 3.53 (d, J = 9.3 Hz, 1H), 4.88 (ddd, J = 1.8, 2.0, 3.6 Hz, 1H), 5.36 (dd, J = 3.5, 9.3 Hz, 1H), 6.20 (dd, J = 1.6, 6.2 Hz, 1H), 6.88 (dd, J = 2.0, 6.2 Hz, 1H), 7.24–7.30 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 22.83, 22.87, 28.2 (3C), 33.8, 55.4, 56.6, 58.5, 67.4, 83.5, 126.3 (2C), 127.1 (2C), 129.6, 135.6, 145.4, 149.2, 168.7; HRMS calcd for C₂₃H₃₄N₂O₄SNa [M + Na]⁺: 457.2132; found: 457.2136.

tert-Butyl (R,S)-2-{(S)-[1,1′-biphenyl]-4-yl[(R)-1,1-dimethylethylsulfinamido]methyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8k] and [(R_S,5S,6S)-8k]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6k (143 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc), compound 8k (205 mg, yield: 88%) (dr = 88 : 12, ¹H NMR) as a diastereomeric mixture, which was separated by repeated flash chromatography on silica gel (eluent: MeOH/CH₂Cl₂ = 1/80) to give compound (R_S,5R,6S)-8k (180 mg) and (R_S,5S,6S)-8k (25 mg).

(R_S,5R,6S)-8k: pale yellow solid. Mp: 131–133 °C; [α]²⁰_D +184.1 (c 1.0, CHCl₃); IR (film) ν_max: 3242, 2976, 2926, 2866, 1781, 1743, 1709, 1601, 1485, 1468, 1366, 1322, 1283, 1258, 1196, 1180, 1132, 1076, 896, 750; ¹H NMR (400 MHz, CDCl₃): δ 1.20 (s, 9H), 1.64 (s, 9H), 3.67 (d, J = 9.5 Hz, 1H), 4.95 (ddd, J = 1.8, 2.0, 3.6 Hz, 1H), 5.44 (dd, J = 3.4, 9.5 Hz, 1H), 6.22 (dd, J = 1.6, 6.2 Hz, 1H), 6.91 (dd, J = 2.0, 6.2 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.41–7.48 (m, 4H), 7.57 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 7.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 28.2 (3C), 56.6, 58.5, 67.4, 83.7, 126.8 (2C), 127.1 (2C), 127.6, 127.7 (2C), 128.9 (2C), 129.8, 137.3, 140.3, 141.3, 145.2, 149.3, 168.6; HRMS calcd for C₂₆H₃₂N₂O₄SNa [M + Na]⁺: 491.1975; found: 491.1978.

(R_S,5S,6S)-8k: pale yellow oil. [α]²⁰_D −252.9 (c 1.0, CHCl₃); IR (film) ν_max: 3243, 2977, 2926, 2867, 1776, 1745, 1713, 1602, 1488, 1456, 1367, 1319, 1285, 1259, 1158, 1076, 1052, 844, 824, 752; ¹H NMR (400 MHz, CDCl₃): δ 1.32 (s, 9H), 1.67 (s, 9H), 3.78 (d, J = 2.7 Hz, 1H), 5.14 (ddd, J = 1.8, 2.1, 5.1 Hz, 1H), 5.31 (dd, J = 2.7, 5.1 Hz, 1H), 5.98 (dd, J = 1.6, 6.2 Hz, 1H), 7.16 (dt, J = 1.8, 8.2 Hz, 1H), 7.29 (dd, J = 2.0, 6.2 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.39–7.45 (m, 2H), 7.46–7.55 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 28.2 (3C), 56.2, 58.4, 64.9, 83.8, 127.1 (2C), 127.2 (2C), 127.6, 128.0 (2C), 128.7, 128.8 (2C), 134.6, 140.2, 141.8, 146.5, 149.3, 168.6; HRMS calcd for C₂₆H₃₂N₂O₄SNa [M + Na]⁺: 491.1975; found: 491.1978.

tert-Butyl (R)-2-{(S)-[(R)-1,1-dimethylethylsulfinamido](4-methoxyphenyl)methyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8l] and [(R_S,5S,6S)-8l]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6l (120 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc), compound 8l (182 mg, yield: 86%) (dr = 82 : 18, ¹H NMR) as a diastereomeric mixture, which was separated by repeated flash chromatography on silica gel (eluent: MeOH/CH₂Cl₂ = 1/80) to give compound (R_S,5R,6S)-8l (149 mg) and compound (R_S,5S,6S)-8l (33 mg).

(R_S,5R,6S)-8l: colorless oil. [α]²⁰_D +103.5 (c 1.0, CHCl₃); IR (film) ν_max: 3242, 2977, 2929, 1777, 1742, 1709, 1612, 1515, 1461, 1392, 1366, 1321, 1284, 1251, 1159, 1106, 1051, 1033, 936, 894, 818, 798, 753 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.18 (s, 9H), 1.62 (s, 9H), 3.56 (d, J = 9.2 Hz, 1H), 3.81 (s, 3H), 4.84–4.91 (m, 1H), 5.33 (dd, J = 3.2, 9.2 Hz, 1H), 6.20 (dd, J = 1.3, 6.2 Hz, 1H), 6.88 (dd, J = 1.9, 6.2 Hz, 1H), 6.93 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 28.2 (3C), 55.3, 56.6, 58.1, 67.5, 83.6, 114.4 (2C), 127.5 (2C), 129.6, 130.3, 145.3, 149.3, 159.5, 168.7. HRMS calcd for C₂₁H₃₀N₂O₅SNa [M + Na]⁺: 445.1768; found: 445.1773.

(R_S,5S,6S)-8l: colorless oil. [α]²⁰_D −279.3 (c 1.0, CHCl₃); IR (film) ν_max: 3234, 2976, 2928, 1775, 1744, 1712, 1612, 1515, 1458, 1393, 1338, 1319, 1283, 1252, 1180, 1158, 1106, 1051, 891, 841, 819, 757, 727 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.31 (s, 9H), 1.65 (s, 9H), 3.66 (d, J = 2.4 Hz, 1H), 3.76 (s, 3H), 5.07–5.12 (m, 1H), 5.23 (dd, J = 2.0, 5.0 Hz, 1H), 5.96 (dd, J = 1.5, 6.1 Hz, 1H), 6.78 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 7.24 (dd, J = 1.9, 6.1 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 28.2 (3C), 55.2, 56.1, 58.0, 64.8, 83.7, 113.9 (2C), 127.4, 128.6, 128.8 (2C), 146.6, 149.2, 159.8, 168.7. HRMS calcd for C₂₁H₃₀N₂O₅SNa [M + Na]⁺: 445.1768; found: 445.1773.

tert-Butyl (R,S)-2-{(S)-(4-chlorophenyl)[(R)-1,1-dimethylethylsulfinamido]methyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8m] and [(R_S,5S,6S)-8m]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6m (122 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc), compound 8m (188 mg, yield: 88%) (dr = 88 : 12, ¹H NMR) as a diastereomeric mixture, which was separated by repeated flash chromatography on silica gel (eluent: MeOH/CH₂Cl₂ = 1/80) to give (R_S,5R,6S)-8m (165 mg) and (R_S,5S,6S)-8m (23 mg).

(R_S,5R,6S)-8m: white solid. Mp: 130–132 °C; [α]²⁰_D +197.8 (c 1.0, CHCl₃); IR (film) ν_max: 3270, 2977, 2928, 2866, 1779, 1744, 1710, 1493, 1461, 1367, 1322, 1281, 1259, 1196, 1158, 1132, 1076, 894, 810, 752; ¹H NMR (400 MHz, CDCl₃): δ 1.19 (s, 9H), 1.62 (s, 9H), 3.70 (d, J = 9.9 Hz, 1H), 4.90 (ddd, J = 1.8, 2.0, 3.6 Hz, 1H), 5.37 (dd, J = 3.6, 9.9 Hz, 1H), 6.22 (dd, J = 1.6, 6.2 Hz, 1H), 6.84 (dd, J = 2.0, 6.2 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 28.2 (3C), 56.8, 58.2, 67.2, 83.8, 127.8 (2C), 129.2 (2C), 130.0, 134.3, 136.8, 144.7, 149.4, 168.2; HRMS calcd for C₂₀H₂₇ClN₂O₄SNa [M + Na]⁺: 449.1272; found: 449.1273.

(R_S,5S,6S)-8m: colorless oil. [α]²⁰_D −247.7 (c 1.0, CHCl₃); IR (film) ν_max: 3243, 2961, 2924, 2854, 1772, 1747, 1717, 1558, 1457, 1366, 1318, 1260, 1157, 1076, 1051, 801; ¹H NMR (400 MHz, CDCl₃): δ 1.31 (s, 9H), 1.64 (s, 9H), 3.70 (d, J = 2.7 Hz, 1H), 5.11 (ddd, J = 1.8, 2.3, 5.2 Hz, 1H), 5.25 (dd, J = 2.7, 5.2 Hz, 1H), 5.99 (dd, J = 1.5, 6.2 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 7.22 (dd, J = 2.0, 6.2 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 28.2 (3C), 56.3, 58.1, 64.6, 84.0, 128.8 (2C), 128.88 (2C), 128.94, 134.1, 134.9, 146.2, 149.3, 168.3. HRMS calcd for C₂₀H₂₇ClN₂O₄SNa [M + Na]⁺: 449.1272; found: 449.1273.

tert-Butyl (R)-2-{(S)-[(R)-1,1-dimethylethylsulfinamido](4-nitrophenyl)methyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8n]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6n (127 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc), compound 8n (204 mg, yield: 93%) (dr = 95 : 5, ¹H NMR) as a diastereomeric mixture, which was separated by repeated flash chromatography on silica gel (eluent: MeOH/CH₂Cl₂ = 1/80) to give compound (R_S,5R,6S)-8n as a yellow solid. Mp: 100–102 °C; [α]²⁰_D +184.9 (c 1.0, CHCl₃); IR (film) ν_max: 3285, 2980, 2930, 2866, 1779, 1744, 1710, 1606, 1523, 1475, 1459, 1349, 1322, 1285, 1196, 1157, 1076, 893, 845, 754; ¹H NMR (400 MHz, CDCl₃): δ 1.19 (s, 9H), 1.62 (s, 9H), 4.02 (d, J = 10.3 Hz, 1H), 4.98 (ddd, J = 1.8, 1.9, 5.1 Hz, 1H), 5.47 (dd, J = 5.1, 10.4 Hz, 1H), 6.24 (dt, J = 1.6, 6.2 Hz, 1H), 6.84 (dd, J = 2.0, 6.2 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 8.25 (dd, J = 2.0, 8.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 28.2 (3C), 57.1, 58.4, 66.9, 84.1, 124.0 (2C), 127.7 (2C), 130.3, 144.3, 145.5, 147.8, 149.7, 167.8; HRMS calcd for C₂₀H₂₇N₃O₆SNa [M + Na]⁺: 460.1513; found: 460.1515.

tert-Butyl (R)-2-{(S)-[(R)-1,1-dimethylethylsulfinamido](naphthalen-1-yl)methyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate [(R_S,5R,6S)-8o]. Following the general procedure, the VMR between TBSOP (208 mg, 0.70 mmol) and (R_S)-6o (130 mg, 0.50 mmol) produced, after flash chromatography (eluent: EtOAc), compound 8o (204 mg, yield: 92%) (dr > 99 : 1, ¹H NMR) as a diastereomeric mixture, which was separated by repeated flash chromatography on silica gel (eluent: MeOH/CH₂Cl₂ = 1/80) to give compound (R_S,5R,6S)-8o as a pale yellow wax. [α]²⁰_D +55.8 (c 1.0, CHCl₃); IR (film) ν_max: 3284, 2979, 2929, 2866, 1780, 1743, 1705, 1601, 1514, 1474, 1457, 1358, 1322, 1258, 1195, 1156, 1076, 895, 796; ¹H NMR (400 MHz, CDCl₃): δ 1.22 (s, 9H), 1.72 (s, 9H), 3.80 (d, J = 9.5 Hz, 1H), 5.10 (ddd, J = 2.0, 2.1, 3.8 Hz, 1H), 6.18 (dd, J = 3.1, 10.7 Hz, 1H), 6.18 (dd, J = 1.6, 6.2 Hz, 1H), 6.70 (dd, J = 1.9, 6.2 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.47–7.58 (m, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 8.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 28.4 (3C), 55.3, 56.8, 65.3, 83.9, 123.0, 123.9, 125.2, 126.2, 127.0, 129.0, 129.1, 129.6, 130.5, 133.9, 134.3, 145.6, 149.8, 168.4; HRMS calcd for C₂₄H₃₀N₂O₄SNa [M + Na]⁺: 465.1819; found: 465.1821.

tert-Butyl (R)-2-{(S)-1-[(R)-1,1-dimethylethylsulfinamido](2-triisopropylsilyloxyethyl)methyl}-5-oxopyrrolidine-1-carboxylate (15). To a solution of compound 8a (52 mg, 0.10 mmol) in EtOAc (10 mL) were added NaOAc (9 mg, 0.01 mmol) and 10% Pd/C (52 mg). The reaction vessel was degassed under vacuum and thoroughly purged with hydrogen. The mixture was stirred under an atmosphere of hydrogen for 5 h. The solid was filtered off and the filtrate was washed with water (3 mL × 2) and brine (3 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/hexane = 2 : 1) to give compound 15 (51 mg, yield: 97%) as a colorless oil. [α]²⁰_D +27.0 (c 1.0, CHCl₃); IR (film) ν_max: 3245, 2943, 2866, 1782, 1749, 1718, 1368, 1307, 1289, 1154, 1098, 1070, 1050, 882, 773 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 0.95–1.15 (m, 21H), 1.17 (s, 9H), 1.55 (s, 9H), 1.79–1.88 (m, 2H), 1.89–2.11 (m, 2H), 2.40–2.57 (m, 2H), 3.33 (d, J = 7.2 Hz, 1H), 3.83–3.97 (m, 2H), 4.04 (ddd, J = 2.4, 7.2, 14.4 Hz, 1H), 4.27 (dt, J = 3.0, 9.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 11.5, 11.8, 17.1, 17.9 (6C), 22.6 (3C), 28.0 (3C), 32.1, 36.7, 55.7, 56.4, 60.7, 61.0, 83.1, 149.6, 174.3; HRMS calcd for C₂₅H₅₀N₂O₅SSiNa [M + Na]⁺: 541.3102; found: 541.3106.

tert-Butyl (R)-2-{(S)-1-[(R)-1,1-dimethylethylsulfinamido](2-triisopropylsilyloxyethyl)methyl}pyrrolidine-1-carboxylate (16). To a cooled (0 °C) solution of compound 15 (96 mg, 0.20 mmol) in THF (4 mL) was added borane dimethyl sulfide (2.0 M in THF, 0.4 mL, 0.8 mmol) and the mixture was stirred for 20 h at 30 °C. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (5 mL) and washed successively with water (3 mL) and brine (3 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/hexane = 1 : 1) to give compound 16 (79 mg, yield: 85%) as a white wax. [α]²⁰_D +12.0 (c 1.0, CHCl₃); IR (film) ν_max: 3309, 2942, 2866, 1697, 1463, 1398, 1364, 1166, 1101, 882, 772, 682 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 0.92–1.16 (m, 21H), 1.19 (s, 9H), 1.45 (s, 4.6H), 1.49 (s, 4.4H), 1.60–1.90 (m, 5H), 1.97 (br s, 1H), 3.07–3.23 (m, 1.5H), 3.45–3.71 (m, 1H), 3.76–4.04 (m, 4H), 4.10–4.25 (m, 0.5H), 4.12–4.31 (m, 1H); ¹H NMR (400 MHz, DMSO-d₆, temp = 80 °C): δ 1.00–1.15 (m, 21H), 1.17 (s, 9H), 1.42 (s, 9H), 1.60–1.85 (m, 5H), 1.90–2.00 (m, 1H), 3.05–3.14 (m, 1H), 3.35–3.43 (m, 1H), 3.65–3.90 (m, 4H), 4.50 (d, J = 8.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 11.9 (3C), 18.0 (6C), 22.8 (3C), 23.7, 24.1, 26.5, 27.5, 28.5 (3C), 36.2, 37.6, 47.2, 47.7, 55.6, 55.9, 56.1, 60.6, 60.9, 62.2, 79.3, 79.7, 154.4, 155.0; ¹³C NMR (100 MHz, DMSO-d₆, temp = 80 °C): δ 11.2 (3C), 17.4 (6C), 22.3 (3C), 22.9, 25.2, 27.8 (3C), 36.5, 46.5, 54.5, 55.0, 60.3, 60.6, 77.7, 153.1; HRMS calcd for C₂₅H₅₂N₂O₄SSiNa [M + Na]⁺: 527.3309; found: 527.3309.

tert-Butyl (R)-2-{(S)-1-[(R)-1,1-dimethylethylsulfinamido]-3-hydroxypropyl}pyrrolidine-1-carboxylate (17). To a cooled (0 °C) solution of compound 16 (776 mg, 1.54 mmol) in THF (30 mL) was added dropwise TBAF (1.0 M in THF, 2.3 mL, 2.3 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. The resultant mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: EtOAc) to give compound 17 (520 mg, yield: 97%) as a colorless oil. [α]²⁰_D +54.0 (c 1.0, CHCl₃); IR (film) ν_max: 3408, 2969, 2927, 1692, 1400, 1364, 1166, 1048, 772 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.23 (s, 9H), 1.36–1.66 (m, 10H), 1.66–2.03 (m, 5H), 3.07–3.23 (m, 1H), 3.38–3.54 (m, 1H), 3.54–3.68 (m, 1H), 3.69–3.96 (m, 3H), 3.96–4.12 (m, 1H), 4.12–4.31 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 22.7 (3C), 23.7, 24.1, 26.5, 28.5 (3C), 35.1, 35.9, 47.1, 47.5, 55.6, 56.9, 57.2, 60.3, 60.5, 61.7, 62.0, 79.4, 79.9, 154.3, 154.8; HRMS calcd for C₁₆H₃₂N₂O₄SNa [M + Na]⁺: 371.1975; found: 371.1975.

tert-Butyl (R)-2-{(S)-1-[(R)-1,1-dimethylethylsulfinamido]-3-(methylsulfonyl)oxypropyl}pyrrolidine-1-carboxylate (18). To a cooled (0 °C) mixture of compound 17 (208 mg, 0.60 mmol) and Et₃N (0.21 mL, 1.5 mmol) in CH₂Cl₂ (12 mL) was added MsCl (0.10 mL, 1.2 mmol). The mixture was allowed to warm up to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO₃ solution (3 mL). The mixture was extracted with CH₂Cl₂ (5 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc) to give compound 18 (229 mg, yield: 90%) as a white solid. Mp: 117–118 °C; [α]²⁰_D −11.0 (c 1.0, CHCl₃); IR (film) ν_max: 3296, 2975, 2930, 1689, 1476, 1456, 1399, 1364, 1174, 1054, 929, 528 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.09–1.32 (m, 9H), 1.35–1.57 (m, 9H), 1.61–1.93 (m, 4H), 1.93–2.16 (m, 2H), 3.13 (s, 3H), 3.16–3.27 (m, 1.3H), 3.45–3.77 (m, 2H), 3.83 (br s, 0.6H), 4.06 (br s, 0.4H), 4.39–4.65 (m, 2H), 4.65–4.85 (m, 0.6H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 23.5, 23.8, 26.2, 28.3 (3C), 31.6, 33.4, 36.9, 47.1, 47.7, 54.8, 55.8, 56.3, 61.2, 62.2, 67.2, 67.8, 79.5, 79.8, 154.0, 155.2; HRMS calcd for C₁₇H₃₄N₂O₆S₂Na [M + Na]⁺: 449.1751; found: 449.1754.

(R)-N-[(1S,7aR)-Hexahydro-1H-pyrrolizin-1-yl]-2-methyl-propane-2-sulfinamide (19). To a cooled (0 °C) solution of compound 18 (90 mg, 0.21 mmol) in CH₂Cl₂ (4.0 mL) was added TFA (1.0 mL). The mixture was allowed to warm up to room temperature and stirred for 1 h. The solvent and TFA were removed under reduced pressure, and the residue was dissolved in MeCN (12 mL). K₂CO₃ (80 mg, 1.6 mmol) was added to the resulting solution and stirred at room temperature for 10 h under a nitrogen atmosphere. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: CH₂Cl₂/MeOH = 10 : 1) to give compound 19 (44 mg, yield: 90%) as a yellow wax. [α]²⁰_D −25.5 (c 1.0, CHCl₃); IR (film) ν_max: 3438, 3200, 2961, 2514, 1676, 1458, 1416, 1366, 1200, 1177, 1129, 1054, 831, 799, 720 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.24 (s, 9H), 1.71–1.81 (m, 1H), 1.90–2.11 (m, 2H), 2.29–2.43 (m, 3H), 2.78–2.97 (m, 2H), 3.62–3.69 (m, 1H), 3.76–3.83 (m, 1H), 3.87–3.95 (m, 1H), 4.01–4.09 (m, 1H), 4.62 (d, J = 8.3 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 22.6 (3C), 25.2, 29.9, 32.9, 52.7, 54.9, 56.5, 60.5, 72.2; HRMS calcd for C₁₁H₂₃N₂OS [M + H]⁺: 231.1526; found: 231.1526.

(+)-Absouline (E-1). To a cooled (0 °C) solution of compound 19 (30 mg, 0.13 mmol) in dioxane (2.5 mL) was added conc. HCl (0.13 mL). The mixture was stirred for 1 h at the same temperature, and then concentrated under reduced pressure. The residue was dissolved in CH₂Cl₂ (4 mL), and DMAP (8.5 mg, 0.07 mmol) and trans-4-methoxycinnamic acid (46 mg, 0.25 mmol) were added sequentially. The mixture was cooled to 0 °C before adding DCC (54 mg, 0.26 mmol) in one portion. The resulting mixture was stirred at 0 °C for 15 min, then allowed to warm up to room temperature and stirred for 30 min at the same temperature. The resulting mixture was filtered and saturated NaHCO₃ aqueous solution (2 mL) was added to the filtrates. The aqueous layer was extracted with CH₂Cl₂ (5 mL × 3) and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on basic alumina (eluent: CH₂Cl₂/MeOH = 20 : 1) to give (+)-absouline (E-1) (22 mg, yield: 60%) as a white powder. Mp: 164–166 °C [lit.: synthetic (−)-absouline: mp: 165 °C^7d]; [α]²⁰_D +51.3 (c 0.3, EtOH), [α]²⁰_D +40.0 (c 1.0, CHCl₃) {lit.: natural (+)-absouline: [α]_D +56 (c 1, EtOH);^2a synthetic (+)-absouline: [α]²⁰_D +26 (c 1.05, CHCl₃);^7a [α]²⁰_D +46.0 (c 1.2, CHCl₃);^7c synthetic (−)-absouline: [α]²⁰_D −34 (c 0.91, CHCl₃);^7a [α]²⁰_D −37 (c 1.8, CHCl₃), [α]²⁰_D −51 (c 0.4, EtOH);^7d [α]²⁵_D −28 (c 1.17, CHCl₃), [α]²⁵_D −48 (c 0.8, EtOH);^7e [α]²⁰_D −49 (c 0.2, EtOH)^7f}; IR (film) ν_max: 3270, 2959, 2868, 1656, 1603, 1575, 1545, 1512, 1304, 1288, 1256, 1223, 1173, 1031, 828 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 1.65–1.95 (m, 4H), 1.97–2.08 (m, 1H), 2.23–2.30 (m, 1H), 2.60–2.68 (m, 2H), 2.85–3.04 (m, 1H), 3.21–3.32 (m, 2H), 3.82 (s, 3H), 4.21–4.27 (m, 1H), 6.18 (d, J = 6.0 Hz, 1H), 6.29 (d, J = 15.6 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 15.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 25.4, 30.7, 33.0, 53.4, 55.2, 55.3, 55.5, 71.0, 114.2, 118.2, 127.6, 129.3, 140.7, 160.9, 166.1; HRMS calcd for C₁₇H₂₃N₂O₂ [M + H]⁺: 287.1754; found: 287.1758.

Acknowledgements

The authors are grateful for financial support from the NSF of China (21332007), the National Basic Research Program (973 Program) of China (Grant No. 2010CB833200), the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of Ministry of Education.

References

1. For reviews on the asymmetric syntheses of vicinal diamines, see: (a) D. Lucet, T. Le Gall and C. Mioskowski, Angew. Chem., Int. Ed., 1998, 37, 2580–2627; (b) H. Kim, S. M. So, J. Chin and B. M. Kim, Aldrichimica Acta, 2008, 41, 77–88; (c) E. Marques-Lopez, P. Merino, T. Tejero and R. P. Herrera, Eur. J. Org. Chem., 2009, 2401–2420; (d) A. Viso, R. Fernandez de la Pradilla, M. Tortosa, A. Garcia and A. Flores, Chem. Rev., 2011, 111, PR1–PR42; (e) S. De Jong, D. G. Nosal and D. J. Wardrop, Tetrahedron, 2012, 68, 4067–4105; (f) A. Noble and J. C. Anderson, Chem. Rev., 2013, 113, 2887–2939; (g) Y. Zhu, R. G. Cornwall, H. Du, B. Zhao and Y. Shi, Acc. Chem. Res., 2014, 47, 3665–3678.
2. (a) K. Ikhiri, A. Ahond, C. Poupat, P. Potier, J. Pusset and T. Sevenet, J. Nat. Prod., 1987, 50, 626–630; (b) The subsequent bio-tests on synthetic (+)-absouline showed no notable anti-viral activity, see: ref. 7a.
3. (a) F. Galinovsky, O. Vogl and H. Nesvadba, Sci. Pharm., 1953, 21, 256–258; (b) N. Neuner-Jehle, H. Nesvadba and G. Spiteller, Monatsh. Chem., 1965, 96, 321–338; (c) B. Tasso, F. Novelli, F. Sparatore, F. Fasoli and C. Gotti, J. Nat. Prod., 2013, 76, 727–731.
4. C. L. Schardl, R. B. Grossman, P. Nagabhyru, J. R. Faulkner and U. P. Mallik, Phytochemistry, 2007, 68, 980–996.
5. (a) D. L. Flynn, D. L. Zabrowski, D. P. Becker, R. Nosal, C. I. Villamil, G. W. Gullikson, C. Moummi and D. C. Yang, J. Med. Chem., 1992, 35, 1486–1489; (b) M. Langlois and R. Fischmeister, J. Med. Chem., 2003, 46, 319–344.
6. (a) D. A. DeGoey, H.-J. Chen, W. J. Flosi, D. J. Grampovnik, C. M. Yeung, L. L. Klein and D. J. Kempf, J. Org. Chem., 2002, 67, 5445–5453; (b) D. M. Barnes, M. A. McLaughlin, T. Oie, M. W. Rasmussen, K. D. Stewart and S. J. Wittenberger, Org. Lett., 2002, 4, 1427–1430; (c) D. M. Barnes, L. Bhagavatula, J. DeMattei, A. Gupta, D. R. Hill, S. Manna, M. A. McLaughlin, P. Nichols, R. Premchandran, M. W. Rasmussen, Z. Tian and S. J. Wittenberger, Tetrahedron: Asymmetry, 2003, 14, 3541–3551.
7. For racemic syntheses of absouline, see: (a) C. Christine, K. Ikhiri, A. Ahond, A. A. Mourabit, C. Poupat and P. Potier, Tetrahedron, 2000, 56, 1837–1850 (two enantiomers were separated by HPLC on a chiral column); (b) K. Muniz, J. Streuff, P. Chavez and C. H. Hovelmann, Chem. – Asian J., 2008, 3, 1248–1255. For an asymmetric synthesis of the natural enantiomer (+)-absouline, see: (c) T. Tang, Y.-P. Ruan, J.-L. Ye and P.-Q. Huang, Synlett, 2005, 231–234. For the asymmetric syntheses of unnatural enantiomer, see: (d) M. Vargas-Sanchez, F. Couty, G. Evano, D. Prim and J. Marrot, Org. Lett., 2005, 7, 5861–5864; (e) E. J. Eklund, R. D. Pike and J. R. Scheerer, Tetrahedron Lett., 2012, 53, 4644–4647; (f) S. G. Davies, A. M. Fletcher, C. Lebée, P. M. Roberts, J. E. Thomson and J. Yin, Tetrahedron, 2013, 69, 1369–1377. For an enantioselective synthesis of (−)-(1S,7aR)-1-aminopyrrolizidine, see: (g) N. Giri, M. Petrini and R. Profeta, J. Org. Chem., 2004, 69, 7303–7308.
8. For racemic synthesis of laburnamine, see: M. Norton Matos, C. A. M. Afonso and R. A. Batey, Tetrahedron, 2005, 61, 1221–1244.
9. For racemic total syntheses, see: (a) J. J. Tufariello, H. Meckler and K. Winzenberg, J. Org. Chem., 1986, 51, 3556–3557; (b) M. T. Hovey, E. J. Eklund, R. D. Pike, A. A. Mainkar and J. R. Scheerer, Org. Lett., 2011, 13, 1246–1249. For enantioselective total syntheses, see: (c) P. R. Blakemore, V. K. Schulze and J. D. White, Chem. Commun., 2000, 1263–1264; (d) P. R. Blakemore, S.-K. Kim, V. K. Schulze, J. D. White and A. F. T. Yokochi, J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1847; (e) M. Cakmak, P. Mayer and D. Trauner, Nat. Chem., 2011, 3, 543–545; (f) K. E. Miller, A. J. Wright, M. K. Olesen, M. T. Hovey and J. R. Scheerer, J. Org. Chem., 2015, 80, 1569–1576; (g) J.-L. Ye, Y. Liu, Z.-P. Yang and P.-Q. Huang, Chem. Commun., 2016, 52, 561–563.
10. (a) S.-T. Ruan, J.-M. Luo, Y. Du and P.-Q. Huang, Org. Lett., 2011, 13, 4938–4941; (b) L.-D. Guo, P. Liang, J.-F. Zheng and P.-Q. Huang, Eur. J. Org. Chem., 2013, 2230–2236; (c) X. Dai and P.-Q. Huang, Chin. J. Chem., 2012, 30, 1953–1956; (d) J.-L. Ye, Y.-F. Zhang, Y. Liu, J.-Y. Zhang, Y.-P. Ruan and P.-Q. Huang, Org. Chem. Front., 2015, 2, 697–704.
11. For comprehensive recent reviews on the heterocyclic silyloxydiene-based VMRs and VMARs and synthetic applications, see: (a) G. Casiraghi, L. Battistini, C. Curti, G. Rassu and F. Zanardi, Chem. Rev., 2011, 111, 3076–3154; (b) G. Casiraghi, F. Zanardi, L. Battistini and G. Rassu, Synlett, 2009, 1525–1542; (c) S. K. Bur and S. F. Martin, Tetrahedron, 2001, 57, 3221–3242; (d) S. F. Martin, Acc. Chem. Res., 2002, 35, 895–904.
12. (a) G. Rassu, G. Casiraghi, P. Spanu, L. Pinna, G. G. Fava, M. B. Ferrari and G. Pelosi, Tetrahedron: Asymmetry, 1992, 3, 1035–1048; (b) G. Casiraghi, G. Rassu, P. Spanu and L. Pinna, J. Org. Chem., 1992, 57, 3760–3763.
13. (a) F. Zanardi, L. Battistini, G. Rassu, L. Pinna, M. Mor, N. Culeddu and G. Casiraghi, J. Org. Chem., 1998, 63, 1368–1369; (b) F. Zanardi, L. Battistini, G. Rassu, L. Auzzas, L. Pinna, L. Marzocchi, D. Acquotti and G. Casiraghi, J. Org. Chem., 2000, 65, 2048–2064; (c) B. Dudot, A. Chiaroni and J. Royer, Tetrahedron Lett., 2000, 41, 6355–6359, correction: Tetrahedron Lett. 2000, 41, 8667; (d) B. Dudot, J. Royer, M. Sevrin and P. George, Tetrahedron Lett., 2000, 41, 4367–4371; (e) A. Sartori, L. Dell'Amico, C. Curti, L. Battistini, G. Pelosi, G. Rassu, G. Casiraghi and F. Zanardi, Adv. Synth. Catal., 2011, 353, 3278–3284; (f) A. Sartori, L. Dell'Amico, L. Battistini, C. Curti, S. Rivara, D. Pala, P. S. Kerry, G. Pelosi, G. Casiraghi, G. Rassu and F. Zanardi, Org. Biomol. Chem., 2014, 12, 1561–1569.
14. (a) C. Curti, L. Battistini, B. Ranieri, G. Pelosi, G. Rassu, G. Casiraghi and F. Zanardi, J. Org. Chem., 2011, 76, 2248–2252; (b) B. Ranieri, C. Curti, L. Battistini, A. Sartori, L. Pinna, G. Casiraghi and F. Zanardi, J. Org. Chem., 2011, 76, 10291–10298; (c) D. L. Silverio, P. Fu, E. L. Carswell, M. L. Snapper and A. H. Hoveyda, Tetrahedron Lett., 2015, 56, 3489–3493. For a syn-selective reaction, see: (d) N. E. Shepherd, H. Tanabe, Y. Xu, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2010, 132, 3666–3667.
15. For reviews, see: (a) J. A. Ellman, T. D. Owens and T. P. Tang, Acc. Chem. Res., 2002, 35, 984–995; (b) F. Ferreira, C. Botuha, F. Chemla and A. Pérez-Luna, Chem. Soc. Rev., 2009, 38, 1162–1186; (c) G.-Q. Lin, M.-H. Xu, Y.-W. Zhong and X.-W. Sun, Acc. Chem. Res., 2008, 41, 831–840; (d) M. T. Robak, M. A. Herbage and J. A. Ellman, Chem. Rev., 2010, 110, 3600–3740.
16. (a) J. S. Villadsen, H. M. Stephansen, A. R. Maolanon, P. Harris and C. A. Olsen, J. Med. Chem., 2013, 56, 6512–6520; (b) C. Hamdouchi and C. Sanchez-Martinez, Synthesis, 2001, 833–840.
17. G. Liu, D. A. Cogan, T. D. Owens, T. P. Tang and J. A. Ellman, J. Org. Chem., 1999, 64, 1278–1284.
18. CCDC 1046181 (8a) and 1445824 (8m) contain the supplementary crystallographic data for this paper.
19. F. A. Davis and W. McCoull, J. Org. Chem., 1999, 64, 3396–3397.
20. For theoretical studies on the origins of diastereoselectivity of the vinylogous Mannich reactions between 2-methoxyfuran and pyrrolinium ion, see: S. K. Bur and S. F. Martin, Org. Lett., 2000, 2, 3445–3447.
21. N. Plobeck and D. Powell, Tetrahedron: Asymmetry, 2002, 13, 303–310.
22. For the syntheses of (R_S)-t-BS-imines 6 see: ESI.†.

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Footnotes

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra of compounds 6j, 6k, 8a–8o, 15–19, and (+)-absouline (E-1); crystallographic structure files for 8a and 8m (CIF). CCDC 1046181 and 1445824. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00022c

‡ These authors contributed equally to this work.

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