From isoxazolidines to tetrahydro-1,3-oxazines for the synthesis of chiral pyrrolidines

Abstract

A novel approach for the synthesis of chiral tetrasubstituted pyrrolidines has been developed. The rearrangement of isoxazolidines into tetrahydro-1,3-oxazines using reactive organic bromides is herein described for the first time. The subsequent opening reaction of these tetrahydro-1,3-oxazines with nucleophiles probes the usefulness of the method for the synthesis of biologically active compounds.

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Introduction

Nitrones and sulfones are two of the most important functional groups in organic chemistry due to their versatility.¹ Nitrones undergo several synthetically useful reactions such as 1,3-dipolar cycloadditions and nucleophilic additions, which make them ideal tools for the construction of highly functionalized nitrogen heterocycles.² Especially important are the cyclic nitrones, as they have been applied to the synthesis of many biologically active natural products.³ The excellent properties of the sulfone group as well as its being easily removable, have made it increasingly important in synthetic chemistry, for example in the synthesis of demanding and sophisticated complex molecules such as peptide-based inhibitors.⁴ Although there is very extensive literature dedicated to the study of cyclic nitrones⁵ and vinyl sulfones,⁶ studies of the reactivity of both together are scarce.⁷ Recently, we studied the reactivity of several cyclic nitrones with phenylvinylsulfone (Scheme 1).⁸

Scheme 1 Reaction of cyclic nitrones with phenylvinylsulfone.

This study started with the aim of obtaining pyrrolidine-based organocatalysts with a phenylsulfone group. In order to synthesize the required organocatalysts it was necessary to open the isoxazolidine ring. This step has usually been achieved by cleavage of the N–O bond, mainly by reduction,⁹ oxidation¹⁰ with m-CPBA or alkylation of the nitrogen atom followed by treatment with base.¹¹

Results and discussion

We initially focused our attention on the ring opening reaction of compounds 2a–c and 3a–c (Scheme 2), as they are the straightforward precursors for the organocatalysts.

Scheme 2 Ring opening reaction of isoxazolidines 2a–c and 3a–c (details of reaction conditions A or B are given in Table 1).

Treatment of isoxazolidines 2a,2b and 3a,3b with Mo(CO)₆, for the reductive cleavage of the N–O bond^9c (Table 1, entries 1, 3, 5 and 7) gave the expected products, 4a,4b and 5a,5b, respectively. Surprisingly, when compounds 2c and 3c were submitted to these conditions, not only were the corresponding pyrrolidines 4c and 5c obtained, but two other rearranged products, identified as the corresponding bicyclic tetrahydro-1,3-oxazines 10 and 11 respectively (entries 9 and 11), were obtained.

Table 1 Ring opening reaction of isoxazolidines 2a–c and 3a–c

Entry	Compound	Conditions^a	Product (% yield)^b
a Conditions A: Mo(CO)6, H2O–MeCN, reflux, 24 h; conditions B: BnBr, CHCl3, reflux, 20 h. b Yield of isolated product.
1	2a	A	4a(35)
2	2a	B	6a (24)
3	3a	A	5a (35)
4	3a	B	7a (55)
5	2b	A	4b (20)
6	2b	B	8b (10)
7	3b	A	5b (—)
8	3b	B	9b (10)
9	2c	A	4c (50), 10 (50)
10	2c	B	12a (46)
11	3c	A	5c (20), 11 (53)
12	3c	B	13a (67)

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As we were aware of the importance of this rearrangement, we focused our attention on the alkylation conditions, in order to see if this rearrangement takes place with alkylating agents (Table 1). When isoxazolidines 2a–c and 3a–c were submitted to treatment with benzyl bromide it was observed that pyrrolidines with no substituents in the 3 or 4 positions (entries 2 and 4) undergo alkylation of the nitrogen atom with neither ring opening nor rearrangement. Pyrrolidines 2b and 3b, protected with benzyl groups (entries 6 and 8), gave products resulting from alkylation, followed by ring opening (8b and 9b respectively) in low yield by transformation in the work up or chromatography. To our delight, for compounds with an acetonide group (entries 10 and 12) the rearrangement was the only reaction, producing tetrahydro-1,3-oxazines 12a and 13a in moderate and good yields respectively. The stereochemistry of the rearranged compounds was easily established by the observation of no coupling between the H-5 and H-4 hydrogens in the ¹H NMR spectra and corroborated by X-ray analysis for compound 13a (Fig. 1).¹²

Fig. 1 X-ray crystal structure of compound 13a. Displacement ellipsoids are drawn at the 30% probability level. Hydrogen atoms are shown as spheres of arbitrary radius.

This rearrangement could be understood as a 1,3-hydride shift from the C–H in the α-position with regard to the tertiary amine (tert-amino effect) to the oxygen of the isoxazolidine (Pathway A in Scheme 3). The structural rigidity of the tricyclic derivatives 2c and 3c could be responsible for their unique reactivity, forcing the topology required in the transition state. Therefore, this could represent a nice example of a 1,3-hydride shift triggered reaction cascade involving ring opening–ring closure sequences which, to the best of our knowledge, are quite uncommon. Related intramolecular hydride shift–ring closure transformations are known, including some recent advances through catalytic approaches.¹³ It could also be considered a deprotonation–ring opening followed by the cyclization step (Pathway B in Scheme 3). More synthetic studies to better understand the mechanism are being conducted.

Scheme 3 Suggested mechanisms for the synthesis of tetrahydro-1,3-oxazines.

This kind of behaviour of the isoxazolidine moiety for these kinds of compounds has rarely been observed. The related formation of oxazines from isoxazolidines has been observed by Uccella and co-workers through alkylation of the isoxazolidines to give isoxazolidinium salts, followed by treatment with a base.¹⁴

The novelty of the reactions reported herein rests in their occurrence under thermal conditions with no reagent added, which would further support a 1,3-hydride shift mechanism. Formation of tetrahydro-1,3-oxazines from tertiary amines bearing an OH group able to trap the intermediate iminium ion is a well established process occurring usually by oxidation or under photochemical conditions.¹⁵ The particular structure of adducts 2c and 3c seems to suggest kinetic lability of the C–H α to N for stereoelectronic reasons, according to similar observations reported for the oxidation of the parent hydroxylamines to the corresponding nitrones.¹⁶

Having obtained bicyclic aminals 12 and 13, and taking into account the importance of nitrones such as 1c, which has been used in the synthesis of many natural and biologically active compounds,^3b,3c we decided to explore the scope of the reaction using different alkylating agents (Table 2). The rearrangement of isoxazolidines 2c and 3c to the bicyclic system only works with very effective alkylating agents such as allylic or benzylic species, and in higher yields with bromides than with chlorides (entries 5–8 and 9, 10). When geranyl bromide was employed, no reaction with 2c occurred due to the steric hinderence of the sulfonyl group; the yield was low with 3c (entry 11). Moreover, no reaction occurred in any case with either saturated alkyl bromides or acyl compounds.

Table 2 Isoxazolidine to oxazine rearrangement^a

Entry	S. M.	RX	Product		Yield (%)
a Isoxazolidine (1 mmol) in CHCl3 (0.06 M); RX (1 mmol), 60 °C for 20 h. b In this case, only the alkylation product was isolated in 30% yield.
1	2c		12a	46
2	2c		12b	60
3	2c		^b	30
4	2c		12d	25
5	3c		13a	67
6	3c		13a	20
7	3c		13b	74
8	3c		13b	—
9	3c		13c	25
10	3c		13c	—
11	3c		13d	30
12	3c		13e	80
13	3c		13f	35
14	3c		13g	20

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To demonstrate the importance of this reaction, we decided to open the bicyclic system with different nucleophiles as has been done with other aminals, in particular by Bosch and Amat.¹⁷ Compounds 12a and 13a were chosen as starting materials. First of all, 12a and 13a were treated with methylmagnesium bromide. When the reaction was performed using 1, 3 or even 5 equivalents of the Grignard reagent, ring opening either did not occur or only occurred in poor yield. The desired products (14a and 15a) were formed in high yield only when using at least 10 equivalents of the nucleophile (Table 3, entries 1 and 2). Moreover, lithium nucleophiles resulted in quite poor yields or no reaction, irrespective of the number of equivalents used (entries 3 and 4). Other Grignard reagents led to the opening of the aminal in high yields when 10 equivalents were used (entries 5–10). In this manner, pyrrolidines with four chiral centers were obtained in high yield in a simple way.

Table 3 Opening of aminals^a

Entry	S. M.	Nucleophile	Product	Yield (%)
a 12a or 13a (1 mmol) , Et2O (0.08 M); NuMgBr (10 mmol) or NuLi (10 mmol), −60 °C for 2 h.
1	12a	MeMgBr	14a Nu = Me	85
2	13a	MeMgBr	15a Nu = Me	98
3	13a	MeLi	15a Nu = Me	40
4	13a	n-BuLi	15b Nu = Bu	—
5	13a	EtMgBr	15c Nu = Et	98
6	13a	PhMgBr	15d Nu = Ph	70
7	13a	AllylMgBr	15e Nu = Allyl	85
8	13a	2-NaphCH2MgBr	15f Nu = 2-NaphCH2-	80
9	13a	c-hexCH2MgBr	15g Nu = c-hexCH2-	90
10	13a	VinylMgBr	15h Nu = Vinyl	54

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It can be observed that the configuration of the sulfone group does not influence the stereochemistry of the incoming nucleophile; in all cases, the same α-Nu were obtained independently of the starting material 12a or 13a. The stereochemistry of the ring opened product was established by analysis of the NMR experiments (bidimensional and NOE, see ESI†) and confirmed by transformation of 14a and 15a into pyrrolidine 16 by treatment with Na(Hg) amalgam as shown in Scheme 4. Since the stereochemistry of 16 is known,¹⁸ it could be established that the nucleophile had entered through the α side. The stereochemistry was also corroborated by transformation of compound 15h in the same manner to form meso diolefin 17.

Scheme 4 a. Na(Hg) 5%, MeOH, r.t., 2 h, 100%; b. 9-BBN, THF, NaBO₃, r.t., 30%; c. Na(Hg) 5%, MeOH, r.t., 2 h, 100%.

In order to further extend the applicability of this methodology, compound 16, which had previously been transformed by Palmer and Jäger into biologically active pyrrolidines,¹⁸ was submitted to hydroboration and oxidation affording pyrrolidine 18, the C-5 epimer of which has been previously transformed into a fucosidase inhibitor by Defoin et al..¹⁹

As depicted in Scheme 4, both compounds 14a and 15a led to the same olefin 16, which increased the yield of the final product (18).

Conclusions

A new method for the synthesis of chiral pyrrolidines is described. This approach is based on the rearrangement of chiral isoxazolidines into tetrahydro-1,3-oxazines by treatment with reactive organic bromides. Opening of the obtained tetrahydro-1,3-oxazines with different nucleophiles affords the corresponding chiral pyrrolidines in a diastereoselective manner. These compounds can be used for diversity oriented synthesis of biologically active compounds.

Experimental section

N–O cleavage of isoxazolidines using Mo(CO)₆: standard procedure

To a stirred solution of isoxazolidine (1 mmol) in 1 mL of H₂O and 15 mL of MeCN was added 0.7 mmol of Mo(CO)₆ and the mixture was heated at reflux. The solution was stirred for 24 h then concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, hexane–EtOAc 1 : 1) to obtain rearranged compound.

(1′R*,2R*)-2-(1-Phenylsulfonyl-2-hydroxyethyl)pyrrolidine 4a. IR (film): 3299, 29589, 2924, 1447, 1304, 1144, 691 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.99–7.58 (5H, m, H_Ar), 4.11–4.04 (1H, m, H_A-2′), 3.89–3.84 (1H, m, H_B-2′), 3.50–47 (1H, m, H-1′), 3.00–2.93 (3H, m, H-2 and H-5), 2.10–1.74 (4H, m, H-3 and H-4); ¹³C NMR (50 MHz, CDCl₃) δ 139.0, 134.2, 129.5, 128.7, 67.3, 59.1, 56.1, 45.8, 31.3, 25.5; HRMS (EI) calcd for C₁₂H₁₇NO₃S (M + H)⁺ 256.0929; found 256.1017.

(1′R,2R,4S,5S)-2-(1-Phenylsulfonyl-2-hydroxyethyl)-4,5-bis(benzyloxy)pyrrolidine 4b. [α]²⁰_D −22.0 (c 0.4, MeOH); IR (film): 3431, 2922, 2851, 1628, 1449, 1148, 1086, 698 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.87–7.22 (15H, m, H_Ar), 4.56–4.34 (4H, m, CH₂–Bn), 4.34 (1H, d, J = 2.2 Hz, H-3), 4.03–3.87 (3H, m, H-2 and H-2′), 3.88 (1H, t, J = 5.8 Hz, H-4), 3.57–3.43 (1H, m, H-1′), 3.89–3.84 (1H, m, H_B-2′), 3.50–47 (1H, m, H-1′), 3.25 (1H, dd, J = 5.6 and 12.0 Hz, H_B-5), 3.07 (1H, dd, J = 1.8 and 12.0 Hz, H_A-5), 2.07 (2H, bs, NH and OH); ¹³C NMR (50 MHz, CDCl₃) δ 138.4, 137.9, 137.8, 134.1, 129.5, 128.8, 128.7, 128.5, 128.2, 128.1, 128.0, 127.9, 85.5, 82.5, 71.9, 71.6, 61.9, 60.2, 50.4; HRMS (EI) calcd for C₂₆H₃₀NO₅S (M + H)⁺ 468.1815; found 468.1819.

(1′R,2R,3S,4R)-2-(1-Phenylsulfonyl-2-hydroxyethyl)-3,4-isopropylidenedioxypyrrolidine 4c. [α]²⁰_D = +2.1 (c = 2.5, CHCl₃); IR (film): 3481, 3334, 2987, 2909, 2840, 1434, 1144, 1042 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.91 (2H, d, J = 8.2 Hz, Hortho), 7.69 (1H, t, J = 7.4 Hz, Hpara), 7.59 (2H, d, J = 7.4 Hz, Hmeta), 5.15 (1H, d, J = 5.6 Hz, H-3), 4.75 (1H, t, J = 4.7 Hz, H-4), 3.90 (1H, dd, J = 3.4 and 11.8 Hz, H_A-2′), 3.80 (1H, dd, J = 7.7 and 13.2 Hz, H_B-2′), 3.69 (1H, d, J = 10.0 Hz, H-2), 3.15–3.06 (1H, m, H-1′), 3.08 (1H, d, J = 13.6 Hz, H_B-5), 2.97 (1H, dd, J = 13.6 Hz, H_A-5), 1.45 (3H, s, Me-acetonide), 1.33 (3H, s, Me-acetonide); ¹³C NMR (100 MHz, CDCl₃) δ 137.5, 134.2, 129.3, 128.9, 111.4, 84.8, 81.0, 65.4, 63.4, 61.6, 51.6, 26.3, 24.1; HRMS (EI) calcd for C₁₅H₂₂NO₅S (M + H)⁺ 328.1213; found 328.1218.

(1′S*,2R*)-2-(1-Phenylsulfonyl-2-hydroxyethyl)pyrrolidine 5a. IR (film): 3343, 3065, 2961, 2874, 1304, 1144, 1049, 760, 691, 565 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.99–7.58 (5H, m, H_Ar), 4.13–3.95 (1H, m, H_A-2′), 3.87–3.81 (1H, m, H_B-2′), 3.50–3.47 (1H, m, H-1′), 3.02–2.85 (3H, m, H-2 and H-5), 2.13–1.74 (4H, m, H-3 and H-4); ¹³C NMR (50 MHz, CDCl₃) δ 139.0, 134.3, 129.6, 128.7, 68.2, 59.7, 56.2, 46.5, 31.3, 25.4; HRMS (EI) calcd for C₁₂H₁₇NO₃S (M + H)⁺ 256.0929; found 256.1017.

(1′S,2R,3S,4R)-2-(1-Phenylsulfonyl-2-hydroxyethyl)-3,4-isopropylidenedioxypyrrolidine 5c. [α]²⁰_D −32.0 (c 1.5, CHCl₃); IR (film): 3501, 3326, 2983, 2913, 1446, 1283 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.94 (2H, d, J = 7.4 Hz, Hortho), 7.65 (1H, t, J = 7.4 Hz, Hpara), 7.58 (2H, d, J = 7.4 Hz, Hmeta), 4.75–4.70 (2H, m, H-3 and H-4), 4.06 (1H, dd, J = 4.9 and 13.2 Hz, H_B-2′), 3.99 (1H, dd, J = 3.5 and 13.2 Hz, H_A-2′), 3.52 (1H, dd, J = 2.5 and 8.4 Hz, H-2), 3.19–3.18 (1H, m, H-1′), 3.02 (1H, dd, J = 4.6 and 11.8 Hz, H_A-5), 2.97 (1H, d, J = 11.8 Hz, H_B-5), 2.82 (1H, s, N–H), 1.44 (3H, s, Me-acetonide), 1.30 (3H, s, Me acetonide); ¹³C NMR (100 MHz, CDCl₃) δ 138.7, 133.4, 129.1, 128.9, 112.7, 83.6, 80.8, 67.9, 62.3, 59.4, 51.8, 26.8, 24.6; HRMS (EI) calcd for C₁₅H₂₂NO₅S (M + H)⁺ 328.1213; found 328.1202.

(1R,4R,5R,6S,7S)-4-Phenylsulfonyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 10. [α]²⁰_D −2.7 (c 0.7, CHCl₃); IR (film): 2982, 2934, 2882, 1301, 1148, 733 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.94 (2H, d, J = 8.0 Hz, Hortho), 7.70–7.56 (3H, m, Hmeta and Hpara), 4.86 (1H, s, H-1), 4.75 (1H, dd, J = 1.2 and 5.4 Hz, H-6), 4.55, 4.48 (2H, m, H-7 and H_B-3), 3.87 (1H, dd, J = 5.8 and 14.2 Hz, H_A-3), 3.77 (1H, bs, H-5), 2.73 (1H, dd, J = 3.0 and 5.8 Hz, H-4), 1.45 (3H, s, Me-acetonide), 1.31 (3H, s, Me acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 137.5, 134.6, 129.8, 128.9, 112.9, 88.8, 81.9, 78.7, 59.1, 57.9, 56.5, 26.1, 24.9; HRMS (EI) calcd for C₁₅H₂₀NO₅S (M + H)⁺ 326.1056; found 326.1067.

(1R,4S,5R,6S,7S)-4-Phenylsulfonyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 11. [α]²⁰_D = +20.0 (c = 0.9, CHCl₃); IR (film): 3412, 3338, 2974, 2929, 1373, 1140, 1033 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.82 (2H, d, J = 8.0 Hz, Hortho), 7.70 (1H, t, J = 7.6 Hz, Hpara), 7.60 (2H, d, J = 7.6 Hz, Hmeta), 5.32 (1H, d, J = 5.4 Hz, H-6), 4.77 (1H, s, H-1), 4.72 (1H, d, J = 5.4 Hz, H-7), 4.01 (1H, dd, J = 5.8 and 11.8 Hz, H_B-3), 3.87 (1H, t, J = 11.8 Hz, H_A-3), 3.77 (1H, sa, H-5), 3.50 (1H, ddd, J = 2.6, 5.8 and 8.4 Hz, H-4), 1.45 (3H, s, Me-acetonide), 1.38 (3H, s, Me acetonide); ¹³C NMR (100 MHz, CDCl₃) δ 137.7, 134.4, 129.6, 128.2, 111.7, 88.8, 81.8, 78.7, 61.3, 59.6, 57.9, 25.7, 24.4; HRMS (EI) calcd for C₁₅H₂₀NO₅S (M + H)⁺ 326.1056; found 326.1068.

Alkylation of heterocycles: standard procedure

To a stirred solution of isoxazolidine (1 mmol) in CHCl₃ (0.06 M) was added dropwise RBr (1 mmol) and the solution heated at 60 °C. The solution was stirred at 60 °C for 20 h. Then it was quenched with saturated aqueous solution of NH₄Cl and the product was extracted with DCM (3×15 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, hexane–EtOAc 8 : 2) to obtain the rearranged compound.

(3R*,3aR*)-N-Benzyl-3-phenylsulfonylhexahydropyrrolo[1,2-b]-isoxazole 6a. IR (film): 3314, 2928, 2872, 1447, 1306, 1049, 916, 691, 600 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.89–7.15 (10H, m, HAr), 4.23–3.96 (1H, m, H_A-2), 3.90–3.88 (1H, m, H_B-2 and H-3), 3.60–3.24 (3H, m, H-3a, H_A-6 and H_A–CH₂Bn), 3.03–2.95 (1H, m, H_B-6), 2.95 (1H, d, J = 12.3 Hz, H_B–CH₂Bn), 2.33–2.05 (2H, m, H-4), 1.95–1.87 (1H, m, H_A-5), 1.78-1.13 (1H, m, H_B-5); ¹³C NMR (50 MHz, CDCl₃) δ 138.7, 134.3, 129.5, 129.4, 129.2, 128.9, 128.2, 127.9, 63.3, 62.1, 59.4, 58.6, 53.7, 26.0, 24.5; HRMS (EI) calcd for C₁₉H₂₂NO₅S (M + H)⁺ 344.1314;

(3S*,3aR*)-N-Benzyl-3-phenylsulfonylhexahydropyrrolo[1,2-b]-isoxazole 7a. IR (film): 3397, 2993, 2882, 1449, 1152, 723, 602 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 8.08–7.26 (10H, m, HAr), 5.90 (1H, d, J = 12.8 Hz, H_B–CH₂Bn), 5.45–5.42 (1H, m, H-3a), 5.29–4.99 (3H, m, H-2 and H_A–CH₂Bn), 4.72–4.64 (1H, m, H-3), 4.39–4.28 (1H, m, H_B-6), 3.66–3.62 (1H, m, H_A-6), 3.46–3.38 (1H, m, H_B-4), 2.98–2.94 (1H, m, H_A-5), 2.27–2.11 (2H, m, H_A-4 and H_B-5); ¹³C NMR (50 MHz, CDCl₃) δ 136.6, 135.6, 132.7, 131.1, 130.4, 129.3, 129.0, 127.8, 79.3, 71.2, 10.8, 66.7, 66.0, 31.7, 23.9; HRMS (EI) calcd for C₁₉H₂₂NO₅S (M + H)⁺ 344.1314; found 344.1328.

(1′R,2R,4S,5S)-N-Benzyl-2-(1-phenylsulfonyl-2-hydroxyethyl)-4,5-bis(benzyloxy)pyrrolidine 8b. [α]²⁰_D −35.7 (c 0.4, MeOH); IR (film): 3422, 2955, 2922, 2851, 1701, 1609, 1497, 1364, 1146, 1086, 802, 698 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.85–7.12 (20H, m, HAr), 4.46–4.39 (6H, m, H-3, H-4 and CH₂–Bn), 4.05 (1H, dd, J = 8.8 and 11.8 Hz, H_A-2′), 3.99 (1H, dd, J = 3.8 and 11.8 Hz, H_B-2′), 3.87–3.79(1H, m, H-2), 3.85 (1H, d, J = 12.8 Hz, H_A–NCH₂), 3.68–3.58 (1H, m, H-1′), 3.58 (1H, d, J = 12.8 Hz, H_B–NCH₂), 3.05 (1H, d, J = 11.4 Hz, H_A-5), 2.70 (1H, dd, J = 4.4 and 11.4 Hz, H_B-5), 1.50 (1H, bs, OH); ¹³C NMR (50 MHz, CDCl₃) δ 138.7, 138.5, 138.2, 137.6, 134.1, 129.6, 129.1, 128.7, 128.1, 127.9, 127.8, 127.6, 87.7, 81.8, 77.3, 71.5, 71.3, 66.9, 61.9, 59.7, 57.1; HRMS (EI) calcd for C₃₃H₃₆NO₅S (M + H)⁺ 558.2308; found 558.2296.

(1′S,2R,4S,5S)-N-Benzyl-2-(1-phenylsulfonyl-2-hydroxyethyl)-4,5-bis(benzyloxy)pyrrolidine 9b. [α]²⁰_D −15.7 (c 0.2, MeOH); IR (film): 3404, 3059, 2916, 1603, 1560, 1306, 1084, 689, 573 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.91–7.12 (10H, m, HAr), 4.78–4.41 (6H, m, H-3, H-4 and CH₂–Bn), 4.26 (1H, dd, J = 8.0 and 11.8 Hz, H_A-2′), 4.12 (1H, dd, J = 3.8 and 11.8 Hz, H_B-2′), 4.07–3.87(1H, m, H-2), 3.82 (1H, d, J = 12.8 Hz, H_A–NCH₂), 3.49–3.45 (1H, m, H-1′), 3.30 (1H, d, J = 12.8 Hz, H_B–NCH₂), 3.05 (1H, d, J = 10.2 Hz, H_A-5), 2.46 (1H, dd, J = 3.6 and 10.2 Hz, H_B-5) 1.56 (1H, bs, OH); HRMS (EI) calcd for C₃₃H₃₆NO₅S (M + H)⁺ 558.2308; found 558.2296.

(1R,4R,5R,6S,7S)-8-Benzyl-4-phenylsulfonyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 12a. [α]²⁰_D −31.7 (c 0.6, CHCl₃); IR (film): 3391, 3060, 2970, 2921, 1446, 1385, 1152 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.85–7.30 (10H, m, HAr), 4.71 (1H, s, H-1), 4.62 (1H, d, J = 5.0 Hz, H-7), 4.52 (1H, d, J = 5.0 Hz, H-6), 4.38 (1H, d, J = 12.0 Hz, H_A–CH₂Bn), 4.26–4.23 (1H, m, H_A-3), 4.20 (1H, d, J = 12.0 Hz, H_B–CH₂Bn), 4.13 (1H, s, H-5), 3.85–3.75 (1H, m, H_B-3), 3.10 (1H, t, J = 6.2 Hz, H-4), 1.52 (3H, s, Me-acetonide), 1.29 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 138.9, 138.5, 134.4, 129.8, 128.7, 128.4, 127.3, 113.3, 90.1, 84.6, 83.1, 61.8, 59.6, 58.4, 52.6, 25.9, 24.8; HRMS (EI) calcd for C₂₂H₂₅NO₅S (M + H)⁺ 416.1526; found 416.1538.

(1R,4R,5R,6S,7S)-4-Phenylsulfonyl-8-propenyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 12b. [α]²⁰_D −31.7 (c 0.6, CHCl₃); IR (film): 3069, 2982, 2932, 2860, 1447, 1306, 1209, 1450, 1072, 731, 606 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.89 (2H, d, J = 8.2 Hz, Hortho), 7.70–7.52 (3H, m, Hpara and Hmeta), 5.75–5.58 (1H, m, H-2′), 5.31 (1H, dd, J = 1.8 and 13.6 Hz, H_A-3′), 5.14 (1H, dd, J = 1.8 and 13.6 Hz, H_B-3′), 4.70 (1H, s, H-1), 4.62 (1H, d, J = 5.4 Hz, H-6), 4.51 (1H, d, J = 5.4 Hz, H-7), 4.20–4.09 (2H, m, 2H-3), 4.05 (1H, s, H-5), 3.80–3.55 (2H, m, H-4 and H_A-1′), 3.07–3.01 (1H, m, H_B-1′), 1.48 (3H, s, Me-acetonide), 1.26 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 138.7, 135.3, 134.3, 129.7, 128.8, 117.3, 113.4, 90.3, 84.7, 83.5, 62.3, 59.8, 58.4, 51.9, 26.1, 25.0; HRMS (EI) calcd for C₁₈H₂₄NO₅S (M + H)⁺ 366.1369; found 366.1351.

(3R,3aR,4S,5R)-3-Phenylsulfonyl-N-propargyl-4,5-isopropylidenedioxyhexahydropyrrolo[1,2-b]isoxazole 12c. [α]²⁰_D = +5.5 (c = 0.2, CHCl₃); IR (film): 3275, 2955, 2924, 2851, 1260, 1145, 758, 689, 584 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.90 (2H, d, J = 7.8 Hz, Hortho), 7.66–7.53 (3H, m, Hpara and Hmeta), 5.08 (1H, dd, J = 3.0 and 6.6 Hz, H-4), 4.76–4.72 (1H, m, H-5), 4.12 (1H, dd, J = 5.4 and 12.4 Hz, H_B-2), 3.98 (1H, dd, J = 6.6 and 12.4 Hz, H_A-2), 3.57–3.31 (1H, m, H-3a, H-3, 2H-1′), 3.08 (1H, dd, J = 3.0 and 13.2 Hz, H_B-5), 2.98 (1H, dd, J = 5.6 and 13.2 Hz, H_A-5), 2.18 (1H, t, J = 2.4 Hz, H-3′), 1.47 (3H, s, Me-acetonide), 1.31 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 139.1, 134.2, 129.3, 129.2, 112.4, 84.2, 79.4, 77.8, 73.9, 67.3, 65.0, 60.6, 56.7, 43.4, 27.4, 24.9; HRMS (EI) calcd for C₁₈H₂₃NO₅NaS (M + Na) 388.1189; found 388.1195.

(1R,4R,5R,6S,7S)-8-Methylcrotonate-4-phenylsulfonyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 12d. [α]²⁰_D −23.6 (c 1.4, CHCl₃); IR (film): 3429, 2980, 2851, 1719, 1447, 1152, 978, 691 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.88 (2H, d, J = 8.0 Hz, Hortho), 7.67 (1H, m, Hpara), 7.57 (H, m, Hmeta), 6.80 (1H, dt, J = 4.8 and 16.0 Hz, H-3′), 6.15 (1H, dt, J = 1.8 and 16.0 Hz, H-2′), 4.67 (1H, s, H-1), 4.63 (1H, d, J = 5.4 Hz, H-7), 4.51 (1H, d, J = 5.4 Hz, H-6), 4.14 (1H, dd, J = 5.4 and 12.6 Hz, H_B-3), 4.10 (1H, s, H-5), 4.03 (1H, ddd, J = 1.9, 4.8 and 6.4 Hz, H_B-1′), 3.88 (1H, ddd, J = 1.9, 4.8 and 6.4 Hz, H_A-1′), 3.76 (1H, dd, J = 6.5 and 12.6 Hz, H_A-3), 3.04–3.01 (1H, m, H-4), 3.75 (3H, s, CO₂CH₃), 1.49 (3H, s, Me-acetonide), 1.26 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 167.2, 145.6, 138.6, 134.4, 129.8, 128.7, 121.9, 113.4, 90.0, 84.3, 83.0, 61.7, 60.0, 58.5, 51.7, 49.4, 25.9, 24.8; HRMS (EI) calcd for C₂₀H₂₆NO₇S (M + H)⁺ 424.1424.; found 424.1434.

(1R,4S,5R,6S,7S)-8-Benzyl-4-phenylsulfonyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 13a. [α]²⁰_D −28.3 (c 0.7, CHCl₃); IR (film): 3387, 2978, 2864, 1589, 1397, 1140 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.84–7.52 (10H, m, HAr), 5.34 (1H, d, J = 5.8 Hz, H-6), 4.72 (1H, d, J = 5.8 Hz, H-7), 4.50 (1H, s, H-1), 4.14–3.97 (3H, m, CH₂Bn and 1H-3), 3.84 (1H, t, J = 14.8 Hz, H-3), 3.73 (1H, ddd, J = 2.6, 6.2 and 8.8 Hz, H-4), 3.56 (1H, s, H-5), 1.52 (3H, s, Me-acetonide), 1.37 (3H, s, Me acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 138.1, 137.3, 134.4, 129.8, 128.7, 128.3, 127.5, 112.5, 89.6, 81.4, 77.4, 59.9, 59.8, 54.1, 48.3, 26.4, 25.4; HRMS (EI) calcd for C₂₂H₂₅NO₅NaS (M + Na) 438.1345; found 438.1349.

(1R,4S,5R,6S,7S)-4-Phenylsulfonyl-8-propenyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 13b. [α]²⁰_D −13.7 (c 0.6, CHCl₃); IR (film): 3067, 2982, 2936, 1310, 1246, 1101, 903, 866, 731, 604 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.85 (2H, d, J = 8.0 Hz, Hortho), 7.72–7.52 (3H, m, Hpara and Hmeta), 5.71–5.63 (1H, m, H-2′), 5.33 (1H, d, J = 5.4 Hz, H-6), 5.20 (1H, dd, J = 1.8 and 7.2 Hz, H_A-3′), 5.02 (1H, dd, J = 1.8 and 7.2 Hz, H_B-3′), 4.70 (1H, d, J = 5.4 Hz, H-7), 4.51 (1H, s, H-1), 4.02–3.87 (2H, m, 2H-3), 3.60 (1H, s, H-5), 3.59–3.42 (2H, m, H-4 and H_A-1′), 3.29–3.19 (1H, m, H_B-1′), 1.45 (3H, s, Me-acetonide), 1.36 (3H, s, Me-acetonide).); ¹³C NMR (50 MHz, CDCl₃) δ 138.1, 134.5, 134.3, 129.9, 128.4, 117.6, 112.6, 89.5, 81.5, 77.9, 59.9, 59.8, 53.9, 46.9, 26.4, 25.5; HRMS (EI) calcd for C₁₈H₂₄NO₅S (M + H)⁺ 366.1369; found 366.1372.

(1R,4S,5R,6S,7S)-4-Phenylsulfonyl-8-propargyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 13c. [α]²⁰_D = +8.4 (c = 1.6, CHCl₃); IR (film): 3275, 2957, 2924, 2853, 1381, 1319, 885, 727, 604 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.88 (2H, d, J = 8.0 Hz, Hortho), 7.70–7.57 (3H, m, Hpara and Hmeta), 5.36 (1H, d, J = 6.0 Hz, H-6), 4.72 (1H, d, J = 6.0 Hz, H-7), 4.56 (1H, s, H-1), 4.02 (1H, dd, J = 1.8 and 11.6 Hz, H_B-3), 3.91 (1H, d, J = 11.6 Hz, H_A-3), 3.81 (1H, s, H-5), 3.66 (1H, ddd, J = 1.8, 6.6 and 9.6 Hz, H-4), 2.05 (1H, t, J = 2.6 Hz, H-3′), 1.46 (3H, s, Me-acetonide), 1.37 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 139.0, 134.5, 129.9, 128.5, 112.9, 89.6, 81.6, 78.2, 77.9, 59.8, 59.7, 53.8, 34.3, 26.4, 25.7; HRMS (EI) calcd for C₁₈H₂₂NO₅S (M + H)⁺ 364.1210; found 364.1211.

(1R,4S,5R,6S,7S)-8-Geranyl-4-phenylsulfonyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 13d. [α]²⁰_D −7.3 (c 0.5, CHCl₃); IR (film): 2963, 2926, 2855, 1458, 1375, 1153, 885, 604 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.87 (2H, d, J = 8.0 Hz, Hortho), 7.69–7.55 (3H, m, Hpara and Hmeta), 5.32 (1H, d, J = 5.8 Hz, H-6), 5.09–5.02 (2H, m, H-2′′ and H-6′′), 4.68 (1H, d, J = 5.8 Hz, H-7), 4.48 (1H, s, H-1), 4.02–3.87 (2H, m, H-3), 3.64–3.59 (2H, m, H-4 and H-5), 3.36 (1H, dd, J = 6.2 and 12.8 Hz, H_A-1′′), 3.25 (1H, dd, J = 7.2 and 12.8 Hz, H_B-1′′), 2.03–1.28 (13H, m, geranyl), 1.45 (3H, s, Me-acetonide), 1.36 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 139.6, 138.3, 134.4, 131.9, 129.8, 128.4, 120.2, 112.7, 89.6, 81.6, 78.4, 59.8, 59.7, 41.7, 39.7, 34.5, 26.6, 26.4, 25.9, 25.7, 17.9, 16.8; HRMS (EI) calcd for C₂₅H₃₆NO₅S (M + H)⁺ 462.2308; found 462.2318.

(1R,4S,5R,6S,7S)-4-Phenylsulfonyl-8-((E)-4-bromobut-2-en-1-yl)-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 13e. [α]²⁰_D −8.0 (c 0.3, CHCl₃); IR (film): 3348, 2984, 2928, 2853, 1447, 1373, 1207, 725, 604 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.82 (2H, d, J = 8.0 Hz, Hortho), 7.72–7.57 (3H, m, Hpara and Hmeta), 5.97–5.93 (2H, m, H-3′), 5.90–5.57 (1H, m, H-2′), 5.33 (1H, d, J = 6.0 Hz, H-6), 4.84 (1H, s, H-1), 4.69 (1H, d, J = 6.0 Hz, H-7), 3.97–3.82 (3H, m, H-4 and 2H-3), 3.58 (1H, s, H-5), 3.57–3.20 (4H, m, 2H-1′ and 2H-4′), 1.44 (3H, s, Me-acetonide), 1.21 (3H, s, Me-acetonide). ¹³C NMR (50 MHz, CDCl₃) δ 138.1, 134.6, 131.3, 129.4, 128.4, 128.2, 112.6, 89.5, 81.4, 78.3, 60.1, 59.8, 54.1, 45.3, 32.1, 26.3, 25.5; HRMS (EI) calcd for C₁₉H₂₆NO₅SBr (M + H)⁺ 458.0631; found 458.0644.

(1R,4S,5R,6S,7S)-8-Methylcrotonate-4-phenylsulfonyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 13f. [α]²⁰_D −13.1 (c 0.9, CHCl₃); IR (film): 3412, 2988, 2951, 1719, 1375, 1319, 1308, 1086, 723 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.82 (2H, d, J = 8.0 Hz, Hortho), 7.64 (1H, m, Hpara), 7.55 (H, m, Hmeta), 6.74 (1H, dt, J = 1.8 and 15.0 Hz, H-3′), 6.04 (1H, dt, J = 5.0 and 15.0 Hz, H-2′), 5.29 (1H, d, J = 5.8 Hz, H-6), 4.66 (1H, d, J = 5.8 Hz, H-7), 4.45 (1H, s, H-1), 3.91–3.88 (2H, m, H-3), 3.66 (3H, s, CO₂CH₃), 3.63 (1H, ddd, J = 1.8, 5.0 and 16.0 Hz, H_B-1′), 3.62 (1H, s, H-5), 3.59–3.54 (1H, m, H-4), 3.35 (1H, ddd, J = 1.8, 5.0 and 16.0 Hz, H_A-1′), 1.44 (3H, s, Me-acetonide), 1.21 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 166.7, 144.2, 137.9, 134.6, 129.9, 128.3, 122.7, 112.6, 89.6, 81.3, 78.3, 60.4, 59.8, 54.3, 51.7, 44.7, 26.2, 25.3; HRMS (EI) calcd for C₂₀H₂₅NO₇NaS (M + Na) 446.1243; found 446.1249.

(1R,4S,5R,6S,7S)-8-Methylacetate-4-phenylsulfonyl-6,7-isopropylidendioxy-2-oxa-8-azabicyclo[3.2.1]octane 13g. [α]²⁰_D −11.0 (c 0.5, CHCl₃); IR (film): 2980, 2955, 2918, 2872, 2849, 1751, 1431, 1379, 1287, 1086, 885, 735 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.86 (2H, d, J = 7.8 Hz, Hortho), 7.71–7.61 (3H, m, Hpara and Hmeta), 5.35 (1H, d, J = 6.0 Hz, H-6), 4.72 (1H, d, J = 6.0 Hz, H-7), 4.63 (1H, s, H-1), 3.91–3.79 (2H, m, H-3), 3.79 (1H, s, H-5), 3.75 (1H, d, J = 16.4 Hz, H_A-1′), 3.65 (3H, s, CO₂CH₃), 3.56–3.45 (1H, m, H-4), 3.41 (1H, d, J = 16.4 Hz, H_B-1′), 1.48 (3H, s, Me-acetonide), 1.37 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 170.1, 138.1, 134.6, 129.9, 128.4, 113.2, 90.6, 81.6, 78.6, 61.5, 59.8, 54.8, 52.2, 46.6, 26.4, 25.9; HRMS (EI) calcd for C₁₈H₂₄NO₇S (M + H)⁺ 398.1268; found 398.1261.

Addition of organometallic reagents: standard procedure

To a stirred solution of rearranged compound (1 mmol) in Et₂O (0.08 M) was added dropwise RMgBr or RLi (10 mmol) at −60 °C. The solution was stirred at −60 °C for 2 h. Then the mixture was allowed to warm slowly to room temperature. It was quenched with a saturated aqueous solution of NH₄Cl and the product was extracted with DCM (3×15 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, hexane–EtOAc 1 : 1) to obtain the pyrrolidine product.

(1′R,2R,3S,4R,5R)-1-Benzyl-5-methyl-2-(1-phenylsulfonyl-2-hydroxyethyl)-3,4-isopropylidenedioxypyrrolidine 14a. [α]²⁰_D −4.3 (c 0.4, CHCl₃); IR (film): 2959, 2920, 2851, 1144, 1051, 800, 584 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.92–7.25 (10H, m, HAr), 5.04 (1H, dd, J = 2.6 and 6.0 Hz, H-3), 4.35 (1H, dd, J = 3.2 and 6.0 Hz, H-4), 4.01 (1H, dd, J = 4.4 and 12.0 Hz, H_A-2′), 3.89 (1H, d, J = 13.2 Hz, H_A-CH₂Bn), 3.66–3.56 (2H, m, H-2 and H_B-2′), 3.64 (1H, d, J = 13.2 Hz, H_B- CH₂Bn), 3.42–3.36 (1H, m, H-1′), 3.12 (1H, dq, J = 3.2 and 7.0 Hz, H-5), 1.45 (3H, s, Me-acetonide), 1.30 (3H, s, Me-acetonide), 1.20 (3H, d, J = 7.0 Hz, Me–C-5); ¹³C NMR (50 MHz, CDCl₃) δ 138.0, 135.7, 134.2, 129.8, 129.4, 128.8, 128.7, 127.8, 112.5, 86.4, 84.2, 69.0, 66.9, 64.1, 60.0, 59.4, 27.6, 25.3, 19.8; HRMS (EI) calcd for C₂₃H₃₀NO₅NaS (M + Na) 454.1658; found 454.1640.

(1′S,2R,3S,4R,5R)-1-Benzyl-5-methyl-2-(1-phenylsulfonyl-2-hydroxyethyl)-3,4-isopropylidenedioxypyrrolidine 15a. [α]²⁰_D = +5.8 (c = 0.7, CHCl₃); IR (film): 3474, 2986, 2965, 2934, 1449, 1381, 1308, 1043, 691 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.94–7.55 (10H, m, HAr), 4.76 (1H, d, J = 6.0 Hz, H-3), 4.09 (1H, t, J = 6.5 Hz, H-4), 4.06 (1H, ddd, J = 1.0, 4.7 and 11.6 Hz, H_A-2′), 3.96 (1H, dd, J = 7.5 and 11.6 Hz, H_B-2′), 3.82 (1H, d, J = 13.6 Hz, H_A–CH₂Bn), 3.59 (1H, s, H-2), 3.49 (1H, d, J = 13.6 Hz, H_B–CH₂Bn), 3.03–2.99 (1H, m, H-1′), 2.70–2.67 (1H, m, H-5), 1.41 (3H, s, Me-acetonide), 1.29 (3H, s, Me-acetonide), 1.20 (3H, d, J = 6.0 Hz, Me–C-5); ¹³C NMR (100 MHz, CDCl₃) δ 138.0, 135.7, 133.9, 129.5, 129.2, 128.8, 128.6, 127.7, 112.5, 84.6, 78.6, 65.7, 63.5, 63.3, 58.4, 56.3, 27.9, 25.8, 17.6; HRMS (EI) calcd for C₂₃H₃₀NO₅S (M + H)⁺ 432.1815; found 432.1824.

(1′S,2R,3S,4R,5R)-1-Benzyl-5-ethyl-2-(1-phenylsulfonyl-2-hydroxyethyl)-3,4-isopropylidenedioxypyrrolidine 15c. [α]²⁰_D = +4.4 (c = 0.9, CHCl₃); IR (film): 3412, 2963, 2932, 2876, 1449, 1308, 1065, 733, 689 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.79–6.98 (10H, m, Ar), 4.79 (1H, dd, J = 1.8 and 6.2 Hz, H-3), 4.26 (1H, t, J = 6.2 Hz, H-4), 4.09–3.95 (2H, m, H-2′), 3.87 (1H, d, J = 13.6 Hz, H_A–CH₂Bn), 3.58 (1H, bs, H-2), 3.50 (1H, d, J = 13.6 Hz, H_B–CH₂Bn), 2.95–2.92 (1H, m, H-1′), 2.69–2.60 (1H, m, H-5), 1.77–1.67 (2H, m, –CH₂–C-5), 1.41 (3H, s, Me-acetonide), 1.30 (3H, s, Me-acetonide), 0.97 (3H, t, J = 7.8 Hz, CH₃–CH₃CH₂–C-5). ¹³C NMR (50 MHz, CDCl₃) δ 138.3, 136.3, 134.2, 129.7, 129.4, 128.9, 128.0, 112.6, 83.3, 79.1, 69.2, 66.1, 63.8, 58.5, 57.3, 23.5, 26.1, 25.3, 9.4; HRMS (EI) calcd for C₂₄H₃₁NO₅NaS (M + Na)⁺ 468.1815; found 468.1805.

(1′S,2R,3S,4R,5R)-1-Benzyl-2-(1-phenylsulfonyl-2-hydroxyethyl)-5-phenyl-3,4-isopropylidenedioxypyrrolidine 15d. [α]²⁰_D = +6.2 (c = 0.3, CHCl₃); IR (film): 3497, 3063, 3030, 2988, 2934, 2872, 2857, 1493, 1308, 1217, 1030, 596 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.86–6.81 (15H, m, Ar), 4.81 (1H, dd, J = 1.6 and 6.0 Hz, H-3), 4.31 (1H, t, J = 6.7 Hz, H-4), 4.25 (1H, dd, J = 5.6 and 11.9 Hz, H_A-2′), 4.14 (1H, dd, J = 5.6 and 11.9 Hz, H_B-2′), 3.73 (1H, d, J = 13.7 Hz, H_A–CH₂Bn), 3.60–3.58 (2H, m, H-2 and H-5), 3.34 (1H, d, J = 13.7 Hz, H_B–CH₂Bn), 3.11–3.07 (1H, m, H-1′), 1.50 (3H, s, Me-acetonide), 1.28 (3H, s, Me-acetonide); ¹³C NMR (100 MHz, CDCl₃) δ 139.2, 138.0, 135.1, 134.1, 129.6, 129.2, 128.5, 128.1, 127.7, 127.3, 112.7, 85.3, 78.9, 72.1, 64.3, 58.0, 55.4, 27.9, 25.8; HRMS (EI) calcd for C₂₈H₃₁NO₅NaS (M + Na)⁺ 516.1833; found 516.1805.

(1′S,2R,3S,4R,5R)-1-Benzyl-2-(1-phenylsulfonyl-2-hydroxyethyl)-5-propenyl-3,4-isopropylidenedioxypyrrolidine 15e. [α]²⁰_D = +4.3 (c = 0.5, CHCl₃); IR (film): 3503, 2982, 2916, 2848, 1449, 1150, 1070, 737, 590 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.91–7.24 (10H, m, Ar), 5.90–5.76 (1H, m, H-2′′), 5.20–5.03 (2H, m, H-3′′), 4.78 (1H, dd, J = 2.0 and 6.2 Hz, H-3), 4.31 (1H, t, J = 6.2 Hz, H-4), 4.09–3.98 (2H, m, H-2′), 3.91 (1H, d, J = 13.2 Hz, H_A–CH₂Bn), 3.58 (1H, s, H-2), 3.56 (1H, d, J = 13.2 Hz, H_B–CH₂Bn), 3.09–2.95 (1H, m, H-1′), 2.48–2.16 (3H, m, H-5, H-1′′), 1.42 (3H, s, Me-acetonide), 1.29 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 138.8, 138.3, 136.2, 135.7, 134.3, 129.7, 129.4, 129.3, 128.5, 127.3, 118.4, 112.7, 82.4, 79.0, 67.6, 65.4, 64.1, 58.4, 57.1, 36.2, 28.1, 26.0; HRMS (EI) calcd for C₂₅H₃₂NO₅S (M + H)⁺ 458.1995; found 458.1978.

(1′S,2R,3S,4R,5R)-1-Benzyl-5-naphthalenylmethyl-2-(1-phenylsulfonyl-2-hydroxyethyl)-3,4-isopropylidenedioxypyrrolidine 15f. [α]²⁰_D = +30.4 (c = 2.6, CHCl₃); IR (film): 3449, 2986, 2932, 1449, 1306, 1148, 752, 689 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.81–7.09 (17H, m, Ar), 4.78 (1H, dd, J = 1.8 and 5.4 Hz, H-3), 4.38 (1H, t, J = 5.4 Hz, H-4), 3.99–3.86 (2H, m, H-2′), 3.80 (1H, d, J = 13.2 Hz, H_A–CH₂Bn), 3.77 (1H, bs, H-2), 3.50 (1H, d, J = 13.2 Hz, H_B–CH₂Bn), 3.20–3.26 (2H, m, H-1′′), 3.09–3.04 (1H, m, H-1′), 2.85–2.80 (1H, m, H-5), 1.36 (3H, s, Me-acetonide), 1.26 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 138.3, 136.5, 135.4, 133.7, 129.8, 129.4, 129.1, 128.3, 127.9, 127.7, 126.4, 125.7, 112.5, 83.3, 79.4, 69.4, 66.5, 64.5, 58.5, 39.5, 28.2, 26.1; HRMS (EI) calcd for C₃₃H₃₅NO₅NaS (M + Na)⁺ 580.2128; found 580.2131.

(1′S,2R,3S,4R,5R)-1-Benzyl-5-cyclohexylmethyl-2-(1-phenylsulfonyl-2-hydroxyethyl)-3,4-isopropylidenedioxypyrrolidine 15g. [α]²⁰_D = +7.8 (c = 0.4, CHCl₃); IR (film): 3462, 2986, 2851, 1449, 1308, 1063, 754, 592 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.77–7.02 (10H, m, Ar), 4.82 (1H, dd, J = 1.8 and 6.0 Hz, H-3), 4.23 (1H, t, J = 6.0 Hz, H-4), 4.05–3.92 (2H, m, H-2′), 3.85 (1H, d, J = 13.2 Hz, H_A–CH₂Bn), 3.53 (1H, bs, H-2), 3.48 (1H, d, J = 13.2 Hz, H_B–CH₂Bn), 3.46 (2H, d, J = 6.6 Hz, H-1′′), 2.95–2.79 (2H, m, H-5 and H-1′), 1.86–1.53 (11H, m, cyclohexyl), 1.31 (3H, s, Me-acetonide), 1.41 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 138.3, 136.3, 134.2, 129.9, 129.4, 129.1, 128.1, 112.5, 84.9, 79.4, 69.1, 66.0, 65.4, 63.5, 58.7, 57.4, 41.9, 40.7, 34.9, 34.3, 32.9, 28.1, 26.8, 26.4, 26.1; HRMS (EI) calcd for C₂₉H₃₉NO₅NaS (M + Na)⁺ 536.2440; found 536.2441.

(1′S,2R,3S,4R,5R)-1-Benzyl-2-(1-phenylsulfonyl-2-hydroxyethyl)-5-vinyl-3,4-isopropylidenedioxypyrrolidine 15h. [α]²⁰_D = +40.0 (c = 0.3, CHCl₃); IR (film): 2984, 2920, 2849, 1449, 1215, 1070, 690 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.97–6.95 (10H, m, Ar), 5.79–5.61 (1H, m, H-1′′), 5.40–5.29 (2H, m, H-2′′), 4.79 (1H, dd, J = 1.2 and 5.6 Hz, H-3), 4.26 (1H, t, J = 7.0 Hz, H-4), 4.07 (1H, dd, J = 4.2 and 11.8 Hz, H_A-2′), 3.93 (1H, dd, J = 5.8 and 11.8 Hz, H_B-2′), 3.89 (1H, d, J = 13.2 Hz, H_A–CH₂Bn), 3.60 (1H, s, H-2), 3.35 (1H, d, J = 13.2 Hz, H_B–CH₂Bn), 3.08 (1H, t, J = 7.8 Hz, H-1′′), 2.93–2.95 (1H, m, H-1′), 1.46 (3H, s, Me-acetonide), 1.30 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 138.2, 137.3, 135.8, 134.4, 129.9, 129.5, 129.2, 128.8, 128.1, 120.1 112.8, 83.2, 79.3, 72.4 64.9, 63.7, 58.5, 56.1, 28.2, 26.1; HRMS (EI) calcd for C₂₅H₃₂NO₅NaS (M + Na), 466.1658; found 466.1660.

(2S,3S,4R,5R)-1-Benzyl-3,4-isopropylidenedioxy-5-methyl-2-vinylpyrrolidine 16

a) To a solution of pyrrolidine 15a (40 mg, 0.09 mmol) in MeOH (1.5 mL) was added 128 mg (0.28 mmol) of 5% Na (Hg) amalgam at r.t. The mixture was stirred for 2 h at this temperature under an argon atmosphere. Next, it was filtered to remove the Hg residue and diluted with DCM (30 mL). The mixture was washed with brine, dried (Na₂SO₄), filtered, and concentrated. The resulting crude residue was purified by flash chromatography (silica gel, n-hexane–EtOAc 6 : 4) to obtain 16 (25 mg, 100%). [α]²⁰_D −5.0 (c 0.5, CH₂Cl₂); IR (film): 2980, 2965, 2930, 1449, 1246, 1148, 1070, 866 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.31–7.21 (5H, m, HAr), 5.84–5.66 (1H, m, H-1′), 5.39–5.20 (2H, m, H-2′), 4.29 (1H, dd, J = 5.0 and 6.8 Hz, H-3), 4.16 (1H, dd, J = 4.8 and 6.8 Hz, H-4), 3.84 (1H, d, J = 14.6 Hz, H_A–CH₂Bn), 3.49 (1H, d, J = 14.6 Hz, H_B–CH₂Bn), 3.09 (1H, dd, J = 5.0 and 8.4 Hz, H-2), 2.70–2.64 (1H, m, H-5), 1.43 (3H, s, Me-acetonide), 1.29 (3H, s, Me-acetonide), 1.22 (3H, d, J = 5.6 Hz, Me–C-5); ¹³C NMR (50 MHz, CDCl₃) δ 138.8, 137.6, 129.5, 128.2, 127.1, 118.9, 113.5, 85.4, 83.5, 72.9, 63.9, 53.4, 27.5, 25.6, 18.5; HRMS (EI) calcd for C₁₇H₂₄NO₂ (M + H)⁺ 274.1801; found 274.1800.

b) To a solution of pyrrolidine 14a (10 mg, 0.02 mmol) in MeOH (1 mL) was added 48 mg (0.06 mmol) of 5% Na (Hg) amalgam at r.t. The mixture was stirred for 2 h at this temperature under an argon atmosphere. Next, it was filtered to eliminate the Hg residue and diluted with DCM (30 mL). The mixture was washed with brine, dried (Na₂SO₄), filtered, and concentrated. The resulting crude residue was purified by flash chromatography (silica gel, n-hexane–EtOAc 6 : 4) to obtain 16 (6 mg, 100%).

(2S,3S,4R,5R)-1-Benzyl-2,5-divinyl-3,4-isopropylidenedioxypyrrolidine 17

To a solution of pyrrolidine 15h (24 mg, 0.06 mmol) in MeOH (1 mL) was added 75 mg (0.16 mmol) of 5% Na (Hg) amalgam at r.t. The mixture was stirred for 2 h at this temperature under an argon atmosphere. Next, it was filtered to remove the Hg residue and diluted with DCM (30 mL). The mixture was washed with brine, dried (Na₂SO₄), filtered, and concentrated. The resulting crude residue was purified by flash chromatography (silica gel, n-hexane–EtOAc 6 : 4) to obtain 17 (17 mg, 100%). IR (film): 2982, 2924, 1375, 1267, 1072, 922, 866, 704 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.26–7.21 (5H, m, HAr), 5.82–5.84 (2H, m, H-1′), 5.38 (2H, d, J = 1.8 Hz, H_A-2′), 5.20 (2H, dd, J = 5.0 and 6.8 Hz, H_B-2′), 4.30 (2H, dd, J = 1.2 and 3.0 Hz, H-3 and H-4), 3.70 (2H, bs, CH₂Bn), 3.12 (2H, dd, J = 1.8 and 7.8 Hz, H-2 and H-5), 1.42 (3H, s, Me-acetonide), 1.27 (3H, s, Me-acetonide); ¹³C NMR (50 MHz, CDCl₃) δ 138.5, 136.5, 130.1, 128.1, 127.1, 118.9, 113.7, 83.7, 77.3, 71.7, 52.6, 27.4, 25.6; HRMS (EI) calcd for C₁₈H₂₄NO₂ (M + H)⁺ 286.1803; found 286.1801.

(2S,3S,4R,5R)-1-Benzyl-3,4-isopropylidenedioxy-5-methylpyrrolidine-2-ethanol 18

9-BBN (1.8 ml, 0.9 mmol) was added to a solution of vinylpyrrolidine 16 (50 mg, 0.18 mmol) in THF (1.50 mL) at 0 °C. The reaction mixture was stirred at r.t. for 4 h. A saturated aqueous solution of NaBO₃ was added and the resulting mixture was stirred at r.t. for 18 h. The reaction product was then extracted with DCM (3×15 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated. The resulting crude residue was purified by flash chromatography (silica gel, n-hexane–EtOAc 6 : 4) to obtain 18 (15 mg, 30%). [α]²⁰_D −12.8 (c 0.8, CH₃Cl); IR (film): 3397, 2980, 2932, 2866, 1452, 1341, 1028, 733, 702 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.33–7.17 (5H, m, HAr), 4.29 (1H, dd, J = 5.0 and 6.8 Hz, H-3), 4.16 (1H, dd, J = 4.6 and 6.8 Hz, H-4), 4.05–3.99 (1H, m, H_A-2′), 3.84 (1H, d, J = 14.3 Hz, H_A–CH₂Bn), 3.54–3.40 (1H, m, H_B-2′), 3.49 (1H, d, J = 14.3 Hz, H_B–CH₂Bn), 3.12–3.05 (1H, m, H-2), 2.70–2.64 (1H, m, H-5), 1.95–1.85 (1H, m, H_A-1′), 1.83–1.75 (1H, m, H_B-1′), 1.44 (3H, s, Me-acetonide), 1.29 (3H, s, Me-acetonide), 1.17 (3H, d, J = 5.6 Hz, Me–C-5); ¹³C NMR (50 MHz, CDCl₃) δ 135.2, 132.3, 130.4, 128.6, 113.2, 83.5, 81.2, 72.7, 68.663.5, 54.4, 27.6, 24.3, 17.6; HRMS (EI) calcd for C₁₇H₂₆NO₃ (M + H)⁺ 292.1907; found 292.1911.

Acknowledgements

The authors gratefully acknowledge the help of A. Lithgow (NMR) and C. Raposo (MS) of Universidad de Salamanca; FSE, MICINN CTQ2009-11172BQU, Junta de Castilla and León for financial support. MFF is grateful to the JCyL for her fellowship.

References

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12. Crystal data for 13a: C₂₂H₂₅NO₅S, CH₂Cl₂, M = 500.42, monoclinic, space group P2₁, a = 6.0659(2) Å, b = 15.5656(6) Å, c = 12.9608(5) Å, α = γ = 90°, β = 99.791(3)°, V = 1205.93(8) ų, Z = 2, D_c = 1.378 Mg m⁻³, μ(Cu-Kα) = 3.521 mm⁻¹, F(000) = 524. 6938 reflections were collected at 4.48 ≤ 2θ ≤ 67.01 and merged to give 3318 unique reflections (R_int = 0.0254), of which 3132 with I > 2σ(I) were considered to be observed. Final values are R₁ = 0.0379, wR₂ = 0.1017, GOF = 1.039, max/min residual electron density 0.355 and −0.352 e. Å⁻³. A suitable single crystal of the 13a compound was mounted on a glass fibre for data collection on a Bruker Kappa APEX II CCD (charge coupled device) diffractometer. Data were collected at 298 K using Cu-Kα radiation (λ = 1.54178 Å) and ω scan technique, and were corrected for Lorentz and polarization effects. Structure solution, refinement and data output were carried out with the SHELXTL^TM program package. The structure was solved by direct methods combined with difference Fourier synthesis and refined by full-matrix least-squares procedures, with anisotropic thermal parameters in the last cycles of refinement for all non-hydrogen atoms. Hydrogen atom positions were calculated by geometrical methods and refined as a riding model. CCDC 888605.
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Footnotes

† Electronic supplementary information (ESI) available: Detailed experimental procedures, optimization studies, complete characterization of products, NMR spectra, IR spectra, CCDC 888605. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra22110a

‡ This manuscript is dedicated to Prof. Arturo San Feliciano on the occasion of his 65th birthday.

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