Stereoselective formation of chiral trans-4-hydroxy-5-substituted 2-pyrrolidinones: syntheses of streptopyrrolidine and 3-epi-epohelmin A

Abstract

A highly diastereoselective approach for the synthesis of trans-4-hydroxy-5-substituted 2-pyrrolidinones has been developed through an intramolecular cascade process of α-chiral aldimines using alkyl, aryl, alkynyl, and alkenyl Grignard reagents. The stereochemistry at the C-5 position of 2-pyrrolidinone after reaction with alkyl, aryl, and alkenyl Grignard reagents was solely controlled by α-alkoxy substitution. For alkynyl Grignard reagents, the stereochemistry was controlled by coordination of the α-alkoxy substitution and the stereochemistry of the sulfinamide. The utility of this one-pot cascade protocol is demonstrated by the asymmetric synthesis of streptopyrrolidine 5 and 3-epi-epohelmin A 3-epi-6.

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Introduction

The development of efficient and stereoselective reactions and methodologies for carbon–carbon bond formation is one of the major pursuits in organic synthesis and medicinal chemistry.¹ Ellman and Davis reported, respectively, an effective method to prepare chiral amines through the addition reaction of imines bearing chiral auxiliaries (e.g., N-tert-butanesulfinamide and N-toluenesulfinamide) with nucleophilic reagents.^2,3 Nowadays, the addition of corresponding Grignard reagents to chiral N-tert-butanesulfinyl imines is widely applied in organic synthesis.⁴ Our group has also explored the utility of chiral N-tert-butanesulfinyl imines, and successfully accomplished the divergent synthesis of several bioactive natural products.⁵ In addition, we observed an interesting stereoselective tert-butyl migration from sulfur to carbon when N-tert-butanesulfinyl iminoacetate was treated with various benzylzinc bromides.⁶

More recently, we discovered an intramolecular cascade process for the highly diastereoselective synthesis of versatile trans-5-hydroxy-6-substituted 2-piperidinones 2.⁷ In this case, the stereoselectivity of C-5 and C-6 strongly favored the trans form and the new stereogenic center at the C-6 position was solely controlled by the tert-butyldimethylsilyl ether (α-OTBS) group of imine 1. Encouraged by this highly stereoselective imine addition and the subsequent in situ formation of 2-piperidinones 2, as a continuous work, we became interested in a similar imine substrate 3 with one less carbon, which would potentially produce trans-4-hydroxy-5-substituted 2-pyrrolidinones 4 (Fig. 1).

Fig. 1 Formation of chiral 2-piperidinones and 2-pyrrolidinones.

Chiral functionalized trans-4-hydroxy-5-substituted 2-pyrrolidinones and the ring-opened form γ-amino-β-hydroxybutyric acids are present as a core structure or subfeature in many biologically relevant alkaloids^8,9 isolated from marine and terrestrial plants and animals, as well as in pharmaceutical agents.¹⁰ For example, streptopyrrolidine 5, isolated from the fermentation broth of marine Streptomyces sp. KORDI-3973,¹¹ could significantly block the capillary tube formation of cells at the same potency as the known angiogenesis inhibitor SU11248, whereas epohelmin A 6, isolated from an unidentified fungus (strain FKI-0929), could inhibit recombinant lanosterol synthase (IC₅₀ = 10 μM).¹² Ring-opened form, (3R,4S)-γ-amino-β-hydroxybutyric acid unit,¹³ exists in hapalosin 7 and symplocin A 8. The former showed multi-drug resistance reversing activity in cancer cells,¹⁴ and the latter displayed very potent cathepsin E inhibition (IC₅₀ = 300 pM)¹⁵ (Fig. 2).

Fig. 2 The structure of several bioactive molecules.

In the past few decades, a wide range of synthetic methods for the stereoselective construction of trans-4-hydroxyl-5-substituted 2-pyrrolidinones 4 and the ring-opened form have been developed.⁹ The common approaches among them are based on reductive alkylation^9d–f,k and nucleophilic substitution,^9c which usually require multiple steps and lead to an unsatisfactory overall yield. Therefore, an efficient and stereoselective approach for direct preparation of 4 remains a challenge.¹⁶ Herein we report our results of the one-pot cascade process starting from α-chiral aldimine 3 and Grignard reagents to generate chiral 2-pyrrolidinones 4, as well as the application in the asymmetric syntheses of streptopyrrolidine 5 and 3-epi-epohelmin A (3-epi-6).

Results and discussion

The synthesis of aldimine 3 is demonstrated in Scheme 1. D-Malic acid was conveniently converted to ester 9 according to the known procedure in 74% overall yield.¹⁷ The subsequent regioselective desilylation from the primary hydroxyl group was achieved by controlling the reaction temperature at −40 °C in the presence of camphorsulfonic acid (CSA) to produce alcohol 10 in 65% yield. Oxidation of 10 with Dess–Martin periodinane (DMP)¹⁸ and subsequent condensation with 2-methylpropane-2-sulfinamide in the presence of anhydrous copper sulfate¹⁹ led to N-tert-butanesulfinyl imines 3 in 84% overall yield (Scheme 1).

Scheme 1 Preparation of N-tert-butanesulfinyl aldimines 3. Reagents and conditions: (a) CSA, MeOH/DCM, −40 °C, 8 h, 65%; (b) DMP, DCM, room temperature (rt), 0.5 h, quantitative yield; (c) 2-methylpropane-2-sulfinamide, CuSO₄, pyridinium p-toluenesulfonate, DCM, 24 h, 84%.

With the desired precursor 3 in hand, we started to investigate the intramolecular tandem sequence by reacting it with Grignard reagents. When optically pure (R,S_R)-3 was treated with phenyl magnesium bromide at −78 °C, the desired product 12a was obtained. Because of its co-elution with the sulfoxide by-product 13a in silica gel chromatography, the lactam-NH was protected as the N-tert-butoxycarbonyl (N-Boc) form, and the pure imide 4a was obtained with high diastereoselectivity (dr = 99 : 1) in spite of low yield (40%, Table 1, entry 1). Like the tandem process involving imine 1,⁷ the yield of 4a was greatly improved to 74% when the reaction was conducted from −78 °C to room temperature and maintained at room temperature overnight, the diastereoselectivity remained unchanged (dr = 99 : 1, Table 1, entry 2). Regardless of the chirality of sulfur in the imine substrate, both (R,S_S)-3 and (R,S_R)-3, as well as (R,S_RS)-3, led to the same product 4a with high diastereoselectivities (dr = 99 : 1, Table 1, entries 2–4), indicating that the stereochemistry of the new chiral center at C-5 was solely controlled by the α-OTBS group. Use of different solvents was also investigated for the reaction with (R,S_RS)-3, and the results are summarized in Table 1 (entries 5–7). The reaction in tetrahydrofuran (THF) offered better conversion than in tetrahydrofuran/dichloromethane (Table 1, entries 4 and 5). Different amounts of Grignard reagents were also assessed. The use of less than three equivalents of phenylmagnesium bromide also produced the desired product 4a with high diastereoselectivity, albeit in much lower yields (Table 1, entries 8 and 9).

Table 1 Optimization of the tandem process

Entry^a	Imine	T (°C)	Solvent	Yield^b (%)	trans : cis^c
a The reactions were performed with α-chiral substituted aldimines 3 (1.0 mmol), phenyl magnesium bromide (3 mL, 1.0 M in THF) from −78 °C to rt overnight, crude product was treated with Boc2O (2.0 mmol), DMAP (1.0 mmol), and triethylamine (5.0 mmol) in DMF for 24 h. b Isolated yield. c Determined by HPLC or ^1H NMR. d Phenyl magnesium bromide (1 mL, 1.0 M in THF). e Phenyl magnesium bromide (2 mL, 1.0 M in THF).
1	(R,SR)-3	−78	THF	40	99 : 1
2	(R,SR)-3	−78 to rt	THF	74	99 : 1
3	(R,SS)-3	−78 to rt	THF	69	99 : 1
4	(R,SRS)-3	−78 to rt	THF	71	99 : 1
5	(R,SRS)-3	−78 to rt	THF/DCM (3/5)	45	99 : 1
6	(R,SRS)-3	−78 to rt	THF/Et2O (3/5)	62	99 : 1
7	(R,SRS)-3	−78 to rt	THF/PhMe (3/5)	65	99 : 1
8^d	(R,SRS)-3	−78 to rt	THF	25	99 : 1
9^e	(R,SRS)-3	−78 to rt	THF	47	99 : 1

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Next, we turned our attention to investigate the scope and limitation of this method in the preparation of trans-4-hydroxy-5-substituted 2-pyrrolidinones. A survey of different Grignard reagents was conducted by reaction with (R,S_RS)-3 under the established optimal conditions, as summarized in Table 2. When substituted phenyl Grignard reagents were used, the intramolecular tandem addition–cyclization proceeded smoothly with high diastereoselectivities and in excellent yields (Table 2, entries 2–9) except that the m-fluoro-phenylmagnesium reagent led to a slightly lower diastereoselectivity of the desired product 4f (Table 2, entry 6). Bicyclic Grignard reagents, including α- and β-naphthyl magnesium bromides, also afforded the desired lactams 4j,k, and the less hindered β-naphthyl magnesium bromide provided better diastereoselectivity and higher yield for this tandem process (Table 2, entries 10 and 11). Several alkyl-chain Grignard reagents were also investigated, and the yields of products 4l–p were slightly lower than those of substituted phenyl Grignard reagents (Table 2, entries 12–16). It is noteworthy that saturated cyclic Grignard reagents also gave the desired lactams 4q,r in 66–68% yield (Table 2, entries 17 and 18). Although benzylmagnesium bromide could give the corresponding product 4s in 70% yield (Table 2, entry 19), the reaction with allylMgBr was very messy (Table 2, entry 20). All the above-mentioned results indicate that the tandem sequence of α-chiral aldimine 3 was quite suitable for different substituted alkyl and aryl Grignard reagents and the stereogenic center at C-5 was solely controlled by the α-OTBS group.

Table 2 Reactions of different Grignard reagents with (R,S_RS)-3

Entry^a	R	4a–s	Yield^b (%)	trans : cis^c
a Reactions were performed with (R,SRS)-3 (1.0 mmol), Grignard reagents (3 mL, 1.0 M in THF) in dry THF (5 mL) at −78 °C to rt overnight, crude product was treated with Boc2O (2.0 mmol), DMAP (1.0 mmol), and triethylamine (5.0 mmol) in DMF for 24 h. b Isolated yield. c Determined by HPLC or ^1H NMR.
1	C6H5	4a	71	99 : 1
2	o-CH3C6H4	4b	62	99 : 1
3	m-CH3C6H4	4c	73	98 : 2
4	p-CH3C6H4	4d	68	99 : 1
5	p-CH3OC6H4	4e	74	99 : 1
6	m-FC6H4	4f	80	96 : 4
7	p-FC6H4	4g	81	90 : 10
8	m-CF3C6H4	4h	59	99 : 1
9	p-PhC6H4	4i	81	94 : 6
10	α-Naphthyl	4j	59	96 : 4
11	β-Naphthyl	4k	70	99 : 1
12	Ethyl	4l	65	99 : 1
13	CH2=CHCH2CH2	4m	69	94 : 6
14	Isopropyl	4n	52	99 : 1
15	Isobutyl	4o	61	99 : 1
16	CH3(CH2)4	4p	72	99 : 1
17	Cyclopropyl	4q	68	99 : 1
18	Cyclohexyl	4r	66	99 : 1
19	Bn	4s	70	97 : 3
20	Allyl	4t	—	—

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The stereochemistry of product 4a was unambiguously determined as the trans form by X-ray crystallography.²⁶ Other compounds 4b–s were accordingly assigned as the trans forms based on the similar coupling constant (J) between the protons C4-H (CH̲-OTBS) and C5-H (CH̲-alkyl or aryl).

We had previously demonstrated that the reactions of α-chiral aldimines 1 with alkynyl Grignard reagents could lead to 2-piperidinones 2 with different stereoselectivities depending on the chirality of sulfur.^7b The α-chiral aldimine 3, with one less carbon in the chain, also performed in a similar way. When (R,S_R)-3 was treated with (2-phenylethynyl)magnesium bromide and followed by N-Boc protection, the desired imide 14a was produced in 76% yield with high diastereoselectivity (dr = 99 : 1) (Table 3, entry 1). Other aryl- and alkyl-substituted alkynyl Grignard reagents were also investigated for the reaction with (R,S_R)-3, and the desired imides 14b–e were produced with high diastereoselectivities (dr = 99 : 1) (Table 3, entries 2–5). The reactions of α-chiral aldimine (R,S_S)-3 with alkynyl Grignard reagents also afforded the desired products in comparable combined yields of both trans and cis isomers, but with significantly lower diastereoselectivities. When (R,S_S)-3 was treated with (2-phenylethynyl)magnesium bromide, the desired imide 14a was obtained in 73% combined yield with low diastereoselectivity (dr = 38 : 62), favoring the cis form (Table 3, entry 6). Both (2-m-tolylethynyl)magnesium bromide and [2-(4-fluorophenyl)ethynyl]magnesium bromide also yielded the imides 14b and 14c with low diastereoselectivities, predominantly in the cis forms (Table 3, entries 7 and 8). Interestingly, when (3,3-dimethylbut-1-ynyl)magnesium bromide and hept-1-ynylmagnesium bromide were subjected to the reaction sequence, the major isomer of the resulting imides 14d and 14e were the trans forms (Table 3, entries 9 and 10). Our results indicate that the stereochemistry outcome of the reactions with alkynyl Grignard reagents was controlled by both the α-alkoxy substitution and the chiral sulfinamide. When α-chiral aldimine (R,S_R)-3 was used, imide 14 was obtained with high diastereoselectivity (dr = 99 : 1) in the trans form. However, the reactions with α-chiral aldimine (R,S_S)-3 gave poor diastereoselectivities, with the aryl-substituted alkynyl Grignard reagents producing the major imides 14 in the cis forms and alkyl-substituted alkynyl Grignard reagents favoring trans products.

Table 3 Reactions of different alkynyl Grignard reagents with 3

Entry^a	R	3	14a–e	Yield^b (%)	trans : cis^c
a Reactions were performed with 3 (1.0 mmol), Grignard reagents (3 mL, 1.0 M in THF) in dry THF (5 mL) at −78 °C to rt overnight, crude product was treated with Boc2O (2.0 mmol), DMAP (1.0 mmol), and triethylamine (5.0 mmol) in DMF for 24 h. b Isolated yield. c Determined by ^1H NMR.
1	C6H5	(R,SR)	(2S,3R)-14a	76	99 : 1
2	3-Me-C6H4	(R,SR)	(2S,3R)-14b	80	99 : 1
3	4-F-C6H4	(R,SR)	(2S,3R)-14c	77	99 : 1
4	CH3(CH2)3CH2	(R,SR)	(2S,3R)-14d	79	99 : 1
5	C(CH3)3	(R,SR)	(2S,3R)-14e	70	99 : 1
6	C6H5	(R,SS)	(2R,3R)-14a	73	38 : 62
7	3-Me-C6H4	(R,SS)	(2R,3R)-14b	75	35 : 65
8	4-F-C6H4	(R,SS)	(2R,3R)-14c	72	34 : 66
9	CH3(CH2)3CH2	(R,SS)	(2R,3R)-14d	71	61 : 39
10	C(CH3)3	(R,SS)	(2R,3R)-14e	63	68 : 32

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The tandem process of reacting α-chiral aldimine 3 with alkenyl Grignard reagents was also investigated. Like the reaction with imine substrate 1,^7b the generation of the stereogenic center at C-5 was solely controlled by the α-OTBS group (Table 4, entries 1–5).

Table 4 Reactions of different alkenyl Grignard reagents with 3

Entry^a	3	R1	17	Yield^b (%)	trans : cis^c
a Reactions were performed with α-chiral substituted aldimines 3 (1.0 mmol), alkenyl Grignard reagents (3 mL, 1.0 M in THF) in dry THF (5 mL) at −78 °C to rt overnight, crude product was treated with Boc2O (2.0 mmol), DMAP (1.0 mmol), and triethylamine (5.0 mmol) in DMF for 24 h. b Isolated yield. c Determined by HPLC or ^1H NMR.
1	(R,SRS)	H	17a	69	99 : 1
2	(R,SR)	H	17a	74	99 : 1
3	(R,SS)	H	17a	65	99 : 1
4	(R,SR)	Et-	17b	68	98 : 2
5	(R,SS)	Et-	17b	59	96 : 4

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With this effective method for the preparation of trans-4-hydroxy-5-substituted 2-pyrrolidinones in hand, we decided to use it in the total syntheses of natural products. The synthesis of streptopyrrolidine 5 only requires a chiral inversion at the C-4 position of 4s. After the deprotection (tetra-n-butylammonium fluoride, TBAF) of 4s, oxidation (DMP) and subsequent reduction (NaBH₄) generated 18 in 89% overall yield, which was treated with trifluoroacetic acid (TFA) to afford streptopyrrolidine 5 in 83% yield (Scheme 2) {[α]²⁵_D = −44.5 (c 0.15, MeOH); lit.^9j [α]²⁵_D = −44.6 (c 0.05, MeOH); lit.¹¹ [α]²⁵_D = −12 (c 0.05, MeOH); lit.^20a [α]²⁰_D = −44 (c 1.0, MeOH); lit.^20b [α]²⁰_D = −43.5 (c 1.0, MeOH)}. The spectroscopy and physical data of the synthetic streptopyrrolidine 5 were identical to the reported data.^9j,11,20

Scheme 2 Asymmetric synthesis of streptopyrrolidine 5. Reagents and conditions: (a) (1) TBAF, THF, 3 h; (2) DMP, DCM, 30 min; (3) NaBH₄, MeOH, 0 °C–rt, 2 h, 89% (3 steps); (b) TFA, 0 °C–rt, 4 h, 83%.

Next, we focused on the total synthesis of epohelmin A 6, a novel lanosterol synthase inhibitor that was isolated from a fungal strain FKI-0929.^12a The chemical structure of 6 was revised from the originally proposed monocyclic core to a bicyclic skeleton by Snider after their asymmetric synthesis in 2005.^12b,c Our retrosynthetic analysis is shown in Fig. 3, hoping to introduce the C-3 chiral center through nucleophilic addition of lactam by allylmagnesium chloride and subsequent stereoselective reduction sequence.

Fig. 3 Retrosynthetic analysis of epohelmin A 6.

Thus, the intramolecular cascade reaction of α-chiral aldimines (R,S_RS)-3 with [3-(benzyloxy)propyl]magnesium bromide was initially considered. To our disappointment, the yield of 19a and its diastereoselectivity were very low (38 : 62) (Table 5, entry 1). Moreover, the major imide 19a was in the cis form (Table 5, entry 1). Although several conditions including (R,S_R)-3 and (R,S_S)-3 were investigated, the stereochemistry was still low (Table 5, entries 2 and 3). The use of (3-[(tert-butyl)dimethylsilyloxy]propyl)magnesium bromide was also investigated, but the intramolecular tandem process did not proceed (Table 5, entry 4). To further investigate this abnormal result, different [(benzyloxy)alkyl]magnesium bromides were studied. When (R,S_RS)-3 was treated with [2-(benzyloxy)ethyl]magnesium bromide, no desired product was produced (Table 5, entry 5). Using [4-(benzyloxy)butyl]magnesium bromide, the yield of desired imide 19d improved to 53%, and the ratio of diastereoselectivity of trans to cis changed to 50 : 50 (Table 5, entry 6). Interestingly, when (R,S_RS)-3 was treated with [6-(benzyloxy)hexyl]magnesium bromide, the desired product 19e was generated in 60% yield and the diastereoselectivity returned to normal, with 90 : 10 ratio favoring the trans (Table 5, entry 7).

Table 5 Reactions of (benzyloxy) or (silaneoxy) Grignard reagents with 3

Entry^a	3	n	P	19	Yield^b (%)	trans : cis^c
a Reactions were performed with α-chiral substituted aldimines 3 (1.0 mmol), Grignard reagents (3 mL, 1.0 M in THF) in dry THF (5 mL) at −78 °C to rt overnight, crude product was treated with Boc2O (2.0 mmol), DMAP (1.0 mmol), and TEA (5.0 mmol) in DMF for 24 h. b Isolated yield. c Determined by HPLC or ^1H NMR. d No reaction.
1	(R,SRS)	3	Bn	19a	32	38 : 62
2	(R,SR)	3	Bn	19a	35	41 : 59
3	(R,SS)	3	Bn	19a	29	35 : 65
4	(R,SRS)	3	TBS	19b	NR^d	—
5	(R,SRS)	2	Bn	19c	NR^d	—
6	(R,SRS)	4	Bn	19d	53	50 : 50
7	(R,SRS)	6	Bn	19e	60	90 : 10

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In understanding why the intramolecular cascade reaction of (R,S_RS)-3 with [3-(benzyloxy)propyl]magnesium bromide gave different results, we presumed that the strong coordination of magnesium with oxygen produced the cyclic form as stable intermediates (Fig. 4, structure A)²¹ that weakly produced B to attack the C=N bond. It is likely that steric hindrance caused the abnormal result. For (3-[(tert-butyl)dimethylsilyloxy]propyl)magnesium bromide D, we presume that the steric hindrance of the more stable structure C is predominant. Thus it could not attach the C=N bond. However, there is balance between the coordination structure E and [4-(benzyloxy)butyl]magnesium bromide F, and the steric hindrance of E caused the cis-result. Thus, the ratio of diastereoselectivity for imine 19d is close to 50 : 50. For [6-(benzyloxy)hexyl]magnesium bromide H, the coordination structure G is very weak, so the intramolecular cascade reaction of (R,S_RS)-3 gave the normal trans product.

Fig. 4 The proposed coordination structures of magnesium with oxygen.

To obtain 19b, lactam 4m was selected as a key intermediate for the synthesis of epohelmin A 6. Thus, the dihydroxylation of alkene 4m with 4-methylmorpholine 4-oxide (NMO) in the presence of 0.1 equivalents of K₂Os₂O₂(OH)₄ ²² and continuous oxidation with NaIO₄ ²³ as well as subsequent reduction with NaBH₄ gave desired alcohol 20 in 87% overall yield (Scheme 3). The hydroxyl group in 20 was then converted to TBS ether in 93% yield.

Scheme 3 Synthesis of 19b. Reagents and conditions: (a) (1) NMO, K₂OsO₄, t-BuOH/H₂O, overnight; (2) NaIO₄, THF/H₂O, 1.5 h; (3) NaBH₄, MeOH, 0 °C, 87% (3 steps); (b) TBSCl, DMAP, imidazole, DMF, 24 h, 93%.

Imine 19b was treated with a solution of allylmagnesium chloride in dichloromethane at −20 °C; additive product 21 and the tautomeric amidoketone 22 were generated²⁴ (Scheme 4). Without further purification, the crude mixture of compounds 21 and 22 was treated with sodium borohydride (ethanol/NaBH₄) in the presence of cerous chloride to afford the crude alcohol 23, which was directly treated with methanesulfonyl chloride and potassium tert-butoxide to give 25 in 70% overall yield with diastereoselectivity (dr = 50 : 50). Methanol was also used as a solvent, but the result remained the same (dr = 50 : 50). To obtain diastereoselectivity in 25, the diastereoselective nucleophilic addition of organic boronic ester to N-acyliminium ions^24b was investigated. Reduction of 19b with lithium triethylhydridoborate gave N,O-acetals 24 in quantitative yield, which was directly treated with 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to afford desired product 2,5-cis-25 in 69% overall yield with high diastereoselectivity (dr > 99 : 1). The stereochemistry of 25 prepared by the addition–reduction–cyclization process was assigned as the 2,5-trans form by comparing data with 2,5-cis-25.^24b

Scheme 4 Asymmetric allylation of 19b. Reagents and conditions: (a) allylmagnesium chloride, DCM; (b) NaBH₄, CeCl₃, EtOH; (c) (1) MsCl, TEA, DCM; (2) t-BuOK, THF, 70% (3 steps); (d) LiBEt₃H, THF, −78 °C; (e) 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, BF₃·Et₂O, −78 °C to −40 °C, DCM, 69% (2 steps from 19b).

With the 2,5-cis-25 in hand, the asymmetric synthesis of 3-epi-epohelmin A (3-epi-6) was considered as shown in Scheme 5. The carbon chain extension of 2,5-cis-25 through Grubbs’ second-generation catalyst²⁵ successfully afforded olefin 26 in 95% yield with excellent selectivity (E : Z = 95 : 5). Reduction (Pd/C, H₂) of 26 gave ester 27 in 92% yield. Compound 27 was treated with a large excess of LiCH₂PO(OMe)₂ in THF from −78 °C to −50 °C to obtain keto phosphonate 28 in 97% isolated yield.^12b Treatment of 28 with NaH in THF, followed by the addition of hexanal gave enone 29 in 88% yield with good selectivity (E : Z = 98 : 2).^12b Selective deprotection of 29 with CSA in a mixture of DCM and methanol at −50 °C for 8 h gave alcohol 30 in 93% yield. Finally, mesylation of compound 30 with methanesulfonyl chloride in the presence of triethylamine and subsequent treatment with triethylsilyl triflate (TESOTf)/2,6-lutidine generated the bicyclic product, which was subjected to desilylation with HCl/methanol in one pot, affording 3-epi-epohelmin A (3-epi-6) in 49% yield {[α]²⁵_D = +7.8 (c 0.80, CHCl₃)}. The structure of the synthetic 3-epi-6 was further confirmed by the spectroscopy and physical data.

Scheme 5 Asymmetric synthesis of 3-epi-epohelmin A (3-epi-6). Reagents and conditions: (a) methyl acrylate, Grubbs 2^nd generation catalyst, DCM, reflux, 7 h, 95%; (b) Pd/C, H₂, MeOH, 92%; (c) dimethyl methylphosphonate, n-BuLi, THF, −78 °C, 1 h, then (5R)-27, −50 °C, 2 h, 97%; (d) NaH, (5R)-28, THF, 1 h, then caproaldehyde, 0 °C, 3 h, 88%; (e) CSA, DCM/MeOH, −50 °C, 8 h, 93%; (f) (1) MsCl, TEA, DCM, 100%; (2) 2,6-lutidine, TESOTf, DCM, −78 °C–rt, overnight; (3) HCl/MeOH, 24 h, 49% (2 steps).

Conclusions

We established a convenient one-pot method for highly diastereoselective synthesis of trans-4-hydroxy-5-substituted 2-pyrrolidinones 4a–s, 14a–e, and 17a,b by an intramolecular cascade process of (R,S_RS)-3 with alkyl, aryl, alkynyl, and alkenyl Grignard reagents. For the reaction of (R,S_RS)-3 with alkyl, aryl, and alkenyl Grignard reagents, the stereochemistry at the C-5 stereogenic center of the trans-4-hydroxy-5-substituted 2-pyrrolidinones was solely controlled by α-alkoxy substitution. In contrast, in reactions of (R,S_RS)-3 with alkynyl Grignard reagents, the stereochemistry at the C-5 stereogenic center was controlled by coordination of the α-alkoxy substitution and the stereochemistry of the sulfinamide. The synthetic application of this methodology was demonstrated by the asymmetric syntheses of streptopyrrolidine 5 and 3-epi-epohelmin A (3-epi-6).

Experimental section

General

THF was distilled from sodium/benzophenone. The reactions were monitored by thin layer chromatography (TLC) on glass plates coated with silica gel with a fluorescent indicator. Flash chromatography was performed on silica gel (300–400) with petroleum/EtOAc as the eluent. Optical rotations were measured on a polarimeter with a sodium lamp. HRMS were measured on a LCMS-IT-TOF apparatus. IR spectra were recorded using film on a Fourier Transform Infrared Spectrometer. NMR spectra were recorded at 400 MHz or 500 MHz, and chemical shifts are reported in δ (ppm) referenced to an internal TMS standard for ¹H NMR and CDCl₃ (77.0 ppm) for ¹³C NMR.

(R)-Methyl 3-(tert-butyldimethylsilyloxy)-4-hydroxybutanoate 10. A solution of 9 (40.0 g, 110.42 mmol) and CSA (20.9 g, 88.34 mmol) was stirred in DCM (200 mL) and MeOH (200 mL) at −40 °C for 8 h. Then a solution of TEA (15.3 mL, 110.42 mmol) was added and the mixture was warmed to room temperature. After being concentrated, the residue was purified by flash chromatography on a silica gel column (PE/EA = 6/1) to give alcohol 10 (17.8 g, 65%) as a colorless oil. [α]²⁵_D = +12.8 (c 1.02, CHCl₃); IR (film): ν_max 3462, 2954, 2930, 2887, 2858, 1740, 1438, 1256, 1169, 1115, 1071, 838, 779 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.24–4.16 (m, 1H), 3.67 (s, 3H), 3.63–3.57 (m, 1H), 3.56–3.50 (m, 1H), 2.60–2.50 (m, 2H), 2.03 (dd, J = 7.6, 5.2 Hz, 1H), 0.87 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 171.9, 69.7, 66.2, 51.6, 39.2, 25.7, 18.0, −4.7, −4.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₁₁H₂₄O₄SiNa: 271.1342, found: 271.1354.

(E,3R,S_RS)-Methyl 3-(tert-butyldimethylsilyloxy)-4-(2-methylpropan-2-ylsulfinamido)butanoate 3. Then the above alcohol 10 was dissolved in DCM (200 mL) and treated with freshly prepared DMP (36.5 g, 86.14 mmol) at room temperature for 30 min. The mixture was quenched carefully with a saturated solution of NaHCO₃ and Na₂S₂O₃. The resulted mixture was separated and the aqueous layer was extracted with DCM three times. The combined organic layers were washed with brine, dried, filtered and concentrated to give crude aldehyde 11, which was dissolved in DCM (200 mL). Then 2-methyl-2-propanesulfinamide (8.7 g, 71.78 mmol), cupric sulphate anhydrous (22.9 g, 143.56 mmol) and PPTS (0.9 g, 3.59 mmol) were added in one portion. After being stirred for 24 h, the reaction was filtered and concentrated to give the crude product, which was purified by flash chromatography on a silica gel column (PE/EA = 10/1) to give 3 (21.1 g, 2 steps for 84%) as a colorless oil. For the mixture: IR (film): ν_max 2955, 2930, 2898, 2858, 1742, 1624, 1473, 1462, 1437, 1364, 1256, 1173, 1090, 1005, 838, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.06–8.02 (m, 0.33H), δ 7.96–7.94 (m, 0.67H), 4.90–4.84 (m, 0.67H), 4.58–4.54 (m, 0.33H), 3.68–3.67 (m, 1H), 3.65–3.63 (m, 2H), 2.98–2.85 (m, 0.66H), 2.78–2.71 (m, 0.67H), 2.62–2.54 (m, 0.67H), 1.16–1.14 (m, 6H), 1.14–1.12 (m, 3H), 0.86–0.82 (m, 9H), 0.07–0.02 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 170.7, 169.4, 165.7, 71.2, 69.3, 57.0, 56.8, 52.0, 51.8, 40.9, 40.3, 25.6, 22.3, 22.2, 18.2, 18.0, −4.5, −4.9, −5.1, −5.4 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₅H₃₂NO₄SSi: 350.1821, found: 350.1821.

General procedure for synthesis of 4a–s, 14a–e and 17a–b. Compound 3 (350 mg, 1.00 mmol) was dissolved in anhydrous THF (5 mL) and cooled to −78 °C. Then a solution of Grignard reagent (3 mL, 1 M in THF) was slowly added. After stirring for 3 h, the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a saturated NH₄Cl aqueous solution and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried, filtered and concentrated to give crude amide, which was directly dissolved in dry DMF (4 mL), then TEA (0.70 mL, 5.00 mmol), Boc₂O (0.46 mL, 2 mmol) and DMAP (122 mg, 1.00 mmol) were added. After stirring for 24 h, the reaction was diluted with water and extracted with EtOAc for three times. The combined organic layers were washed with water and brine two times respectively. The organic layer was dried, filtered and concentrated. Then the residue was purified by flash chromatography on a silica gel column (PE/EA = 15/1) to give imide 4a–s, 14a–e and 17a–b.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-phenylpyrrolidine-1-carboxylate 4a. White solid (277 mg, 71%), m.p. 112–113 °C. [α]²⁵_D = −5.4 (c 1.40, CHCl₃); IR (film): ν_max 2948, 2931, 2855, 1794, 1458, 1367, 1306, 1255, 1151, 1101, 839, 780 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.41–7.30 (m, 3H), 7.22–7.18 (m, 2H), 5.00–4.95 (m, 1H), 4.12 (ddd, J = 5.6, 2.4, 1.6 Hz, 1H), 2.87 (dd, J = 17.2, 5.6 Hz, 1H), 2.43 (dd, J = 17.2, 1.6 Hz, 1H), 1.32 (s, 9H), 0.91 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.9, 149.6, 139.1, 129.0, 128.0, 125.2, 83.0, 72.0, 71.4, 41.0, 27.7, 25.7, 18.0, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₁H₃₃NO₄SiNa: 414.2077, found: 414.2066.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-o-tolylpyrrolidine-1-carboxylate 4b. Pale yellow oil (251 mg, 62%). [α]²⁵_D = −8.2 (c 2.50, CHCl₃); IR (film): ν_max 2959, 2931, 2849, 1789, 1753, 1721, 1463, 1370, 1307, 1249, 1153, 1079, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.24–7.16 (m, 3H), 7.06–7.01 (m, 1H), 5.23–5.21 (m, 1H), 4.07 (ddd, J = 5.6, 2.4, 1.6 Hz, 1H), 2.87 (dd, J = 17.2, 5.6 Hz, 1H), 2.45–2.39 (m, 4H), 1.28 (s, 9H), 0.90 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 173.0, 149.4, 137.1, 134.9, 130.8, 127.7, 126.6, 123.2, 82.8, 71.1, 67.9, 41.1, 27.6, 25.6, 19.3, 17.8, −4.6, −4.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₂H₃₅NO₄SiNa: 428.2233, found: 428.2231.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-m-tolylpyrrolidine-1-carboxylate 4c. Pale yellow oil (296 mg, 73%). [α]²⁵_D = −2.4 (c 2.78, CHCl₃); IR (film): ν_max 2959, 2931, 2849, 1789, 1753, 1715, 1359, 1307, 1154, 1079, 838, 778 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.24–7.17 (m, 1H), 7.08–7.04 (m, 1H), 6.95–6.90 (m, 2H), 4.90–4.87 (m, 1H), 4.05 (ddd, J = 5.6, 2.4, 1.6 Hz, 1H), 2.81 (dd, J = 17.6, 5.6 Hz, 1H), 2.35 (dd, J = 17.6, 1.6 Hz, 1H), 2.29 (s, 3H), 1.26 (s, 9H), 0.84 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 173.0, 149.6, 138.9, 138.7, 128.9, 128.7, 125.6, 122.3, 82.9, 72.0, 71.4, 41.1, 27.7, 25.7, 21.4, 18.0, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₂H₃₅NO₄SiNa: 428.2233, found: 428.2233.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-p-tolylpyrrolidine-1-carboxylate 4d. White solid (276 mg, 68%), m.p. 98–99 °C. [α]²⁵_D = −4.6 (c 1.43, CHCl₃); IR (film): ν_max 2953, 2932, 2855, 1789, 1726, 1370, 1307, 1153, 1068, 921, 838, 777 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.19–7.17 (m, 2H), 7.08–7.06 (m, 2H), 4.97–4.93 (m, 1H), 4.09 (ddd, J = 5.6, 2.0, 1.2 Hz, 1H), 2.86 (dd, J = 17.6, 5.6 Hz, 1H), 2.40 (ddd, J = 17.6, 2.0, 0.8 Hz, 1H), 2.36 (s, 3H), 1.33 (s, 9H), 0.90 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 173.0, 149.7, 137.7, 136.0, 129.6, 125.1, 82.9, 72.1, 71.3, 41.0, 27.7, 25.7, 21.1, 18.0, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₂H₃₅NO₄SiNa: 428.2233, found: 428.2222.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(4-methoxyphenyl)-5-oxopyrrolidine-1-carboxylate 4e. Pale yellow oil (312 mg, 74%). [α]²⁵_D = −5.7 (c 1.66, CHCl₃); IR (film): ν_max 2953, 2932, 2849, 1787, 1715, 1512, 1364, 1306, 1251, 1153, 1079, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.03–7.09 (m, 2H), 6.93–6.89 (m, 2H), 4.94–4.92 (m, 1H), 4.08 (ddd, J = 5.6, 2.0, 1.2 Hz, 1H), 3.82 (s, 3H), 2.87 (dd, J = 17.6, 5.6 Hz, 1H), 2.41 (dd, J = 17.6, 1.6 Hz, 1H), 1.34 (s, 9H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.9, 159.3, 149.6, 131.1, 126.4, 114.3, 82.9, 72.1, 70.1, 55.3, 41.0, 27.8, 25.7, 18.0, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₂H₃₅NO₅SiNa: 444.2182, found: 444.2172.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)-5-oxopyrrolidine-1-carboxylate 4f. White solid (327 mg, 80%), m.p. 51–53 °C. [α]²⁵_D = −6.0 (c 1.9, CHCl₃); IR (film): ν_max 2954, 2931, 2858, 1790, 1758, 1721, 1589, 1453, 1367, 1305, 1258, 1153, 1082, 919, 839, 779 cm⁻¹; ¹⁹F NMR (376 MHz, CDCl₃) δ −111.82 ppm; ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.33 (m, 1H), 7.05–6.98 (m, 2H), 6.93–6.88 (m, 1H), 4.97–4.93 (m, 1H), 4.10 (ddd, J = 5.6, 2.8, 2.0 Hz, 1H), 2.86 (dd, J = 17.6, 5.6 Hz, 1H), 2.44 (dd, J = 17.6, 2.4 Hz, 1H), 1.34 (s, 9H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.4, 163.2 (d, J = 246.1 Hz), 149.4, 141.9 (d, J = 6.7 Hz), 130.7 (d, J = 8.2 Hz), 120.7 (d, J = 2.2 Hz), 114.9 (d, J = 21.0 Hz), 112.4 (d, J = 22.2 Hz), 83.3, 71.9, 70.9, 41.0, 27.7, 25.6, 18.0, −4.5, −4.8, −5.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₁H₃₂FNO₄SiNa: 432.1982, found: 432.1985.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(4-fluorophenyl)-5-oxopyrrolidine-1-carboxylate 4g. White solid (331 mg, 81%), m.p. 111–112 °C. [α]²⁵_D = −6.9 (c 0.78, CHCl₃); IR (film): ν_max 2948, 2926, 2849, 1789, 1715, 1518, 1370, 1306, 1249, 1151, 1085, 839 cm⁻¹; ¹⁹F NMR (376 MHz, CDCl₃) δ −114.11 ppm; ¹H NMR (400 MHz, CDCl₃) δ 7.21–7.15 (m, 2H), 7.12–7.06 (m, 2H), 4.95–4.92 (m, 1H), 4.08 (ddd, J = 5.6, 2.8, 2.0 Hz, 1H), 2.86 (dd, J = 17.6, 6.0 Hz, 1H), 2.45 (dd, J = 17.6, 2.4 Hz, 1H), 1.34 (s, 9H), 0.90 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.5, 162.3 (d, J = 245.2 Hz), 149.4, 135.0 (d, J = 2.8 Hz), 126.9 (d, J = 8.1 Hz), 116.0 (d, J = 21.5 Hz), 83.2, 72.0, 70.7, 41.0, 27.7, 25.6, 18.0, −4.5, −4.8, −5.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₁H₃₂FNO₄SiNa: 432.1982, found: 432.1977.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-(3-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate 4h. Pale yellow oil (271 mg, 59%). [α]²⁵_D = −4.1 (c 0.92, CHCl₃); IR (film): ν_max 2948, 2931, 2866, 1801, 1452, 1364, 1333, 1255, 1167, 1130, 1096, 893, 839, 780 cm⁻¹; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.78 ppm; ¹H NMR (400 MHz, CDCl₃) δ 7.63–7.38 (m, 4H), 4.97 (d, J = 2.4 Hz, 1H), 4.11 (ddd, J = 6.4, 3.2, 2.8 Hz, 1H), 2.86 (dd, J = 17.2, 6.4 Hz, 1H), 2.49 (dd, J = 17.6, 3.2 Hz, 1H), 1.31 (s, 9H), 0.89 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.2, 149.3, 140.5, 131.5 (d, J = 43.1, 21.6 Hz), 129.6, 128.5, 124.8 (d, J = 23.0 Hz), 123.8 (d, J = 361.0, 180.4 Hz), 122.3 (d, J = 22.0 Hz), 83.5, 72.0, 70.8, 41.0, 27.7, 25.6, 17.9, −4.8, −4.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₂H₃₂F₃NO₄SiNa: 482.1950, found: 482.1951.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(4-phenyl)-5-oxopyrrolidine-1-carboxylate 4i. Colorless oil (378 mg, 81%). [α]²⁵_D = −5.8 (c 2.75, CHCl₃); IR (film): ν_max 2953, 2937, 2849, 1788, 1721, 1359, 1306, 1255, 1152, 1079, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.64–7.61 (m, 4H), 7.49–7.45 (m, 2H), 7.40–7.36 (m, 1H), 7.27–7.25 (m, 2H), 5.05–5.03 (m, 1H), 4.17 (ddd, J = 5.2, 3.2, 1.2 Hz, 1H), 2.92 (dd, J = 17.6, 5.6 Hz, 1H), 2.40 (dd, J = 17.6, 1.6, Hz, 1H), 1.36 (s, 9H), 0.93 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.8, 149.7, 140.9, 140.3, 138.0, 128.9, 127.7, 127.6, 127.0, 125.6, 83.1, 72.0, 71.2, 41.1, 27.8, 25.7, 18.0, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₇H₃₇NO₄SiNa: 490.2390, found: 490.2381.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(naphthalen-1-yl)-5-oxopyrrolidine-1-carboxylate 4j. Colorless oil (260 mg, 59%). [α]²⁵_D = +42.2 (c 1.80, CHCl₃); IR (film): ν_max 2953, 2932, 2860, 1788, 1759, 1726, 1370, 1308, 1153, 1074, 921, 838, 778 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.07–8.05 (m, 1H), 7.95–7.92 (m, 1H), 7.84–7.82 (m, 1H), 7.62–7.54 (m, 2H), 7.47–7.43 (m, 1H), 7.28–7.25 (m, 1H), 5.87–5.85 (m, 1H), 4.24 (ddd, J = 5.6, 1.6, 1.2 Hz, 1H), 2.85 (dd, J = 17.6, 5.2 Hz, 1H), 2.43 (d, J = 17.6 Hz, 1H), 1.26 (s, 9H), 0.96 (s, 9H), 0.10 (s, 3H), 0.04 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 173.2, 149.7, 134.3, 134.0, 130.2, 129.1, 128.5, 126.6, 126.1, 125.3, 122.6, 120.8, 83.0, 70.8, 68.2, 41.3, 27.7, 25.7, 17.9, −4.5, −4.7 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₅H₃₅NO₄SiNa: 464.2233, found: 464.2223.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(naphthalen-2-yl)-5-oxopyrrolidine-1-carboxylate 4k. White solid (309 mg, 70%), m.p. 116–117 °C. [α]²⁵_D = −2.6 (c 0.44, CHCl₃); IR (film): ν_max 2953, 2932, 2866, 1789, 1748, 1715, 1468, 1370, 1306, 1255, 1153, 1068, 838, 779 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.91–7.82 (m, 3H), 7.63 (s, 1H), 7.56–7.50 (m, 2H), 7.35–7.33 (m, 1H), 5.17–5.15 (m, 1H), 4.20 (ddd, J = 5.2, 2.0, 1.2 Hz, 1H), 2.94 (dd, J = 17.4, 5.6 Hz, 1H), 2.47 (dd, J = 17.4, 1.6 Hz, 1H), 1.31 (s, 3H), 0.93 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 173.0, 149.7, 136.3, 133.3, 133.0, 129.1, 127.9, 127.7, 126.7, 126.3, 123.6, 123.3, 83.1, 71.8, 71.5, 41.1, 27.7, 25.7, 18.0, −4.7, −4.7 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₅H₃₅NO₄SiNa: 464.2233, found: 464.2231.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidine-1-carboxylate 4l. Colorless oil (223 mg, 65%). [α]²⁵_D = +28.6 (c 1.28, CHCl₃); IR (film): ν_max 2948, 2926, 2866, 1797, 1753, 1714, 1463, 1370, 1309, 1249, 1156, 1074, 926, 837, 777 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.00 (d, J = 5.2 Hz, 1H), 3.79 (dd, J = 9.6, 3.6 Hz, 1H), 2.68 (dd, J = 17.6, 5.2 Hz, 1H), 2.27 (d, J = 17.6 Hz, 1H), 1.74–1.61 (m, 1H), 1.46 (s, 9H), 1.39–1.28 (m, 1H), 0.94–0.88 (m, 3H), 0.80 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.7, 150.1, 82.7, 69.2, 67.9, 41.8, 28.0, 25.7, 24.9, 17.9, 10.3, −4.6, −4.7 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₁₇H₃₃NO₄SiNa: 366.2077, found: 366.2067.

(2S,3R)-tert-Butyl 2-(but-3-enyl)-3-(tert-butyldimethylsilyloxy)-5-oxopyrrolidine-1-carboxylate 4m. White solid (255 mg, 69%), m.p. 51–53 °C. [α]²⁵_D = +30.0 (c 1.00, CHCl₃); IR (film): ν_max 2955, 2930, 2857, 1787, 1754, 1716, 1468, 1369, 1311, 1258, 1155, 1081, 915, 837 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.86–5.75 (m, 1H), 5.12–5.00 (m, 2H), 4.10–4.06 (m, 1H), 3.98–3.92 (m, 1H), 2.82–2.74 (m, 1H), 2.38–2.30 (m, 1H), 2.23–2.05 (m, 2H), 1.84–1.75 (m, 1H), 1.55–1.52 (m, 9H), 1.51–1.43 (m, 1H), 0.88–0.85 (m, 9H), 0.09–0.06 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.4, 149.8, 136.7, 115.6, 82.7, 68.0, 67.2, 41.5, 30.9, 29.9, 27.9, 25.5, 17.7, −4.8, −4.9 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₉H₃₆NO₄Si: 370.2414, found: 370.2408.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-isopropyl-5-oxopyrrolidine-1-carboxylate 4n. Colorless oil (186 mg, 52%). {[α]²⁵_D = +31.8 (c 1.82, CHCl₃), lit.^9j [α]²⁵_D = +45.17 (c = 1 in CHCl₃)}; IR (film): ν_max 2964, 2926, 2860, 1787, 1752, 1717, 1474, 1370, 1306, 1157, 1068, 915, 837, 777 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.14 (d, J = 5.2 Hz, 1H), 3.89 (d, J = 5.6 Hz, 1H), 2.72 (dd, J = 18.0, 5.6 Hz, 1H), 2.34 (d, J = 17.6 Hz, 1H), 2.06–1.95 (m, 1H), 1.53 (s, 9H), 1.01 (d, J = 6.8 Hz, 2H), 0.90–0.86 (m, 12H), 0.09 (s, 3H), 0.08 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 173.1, 150.3, 82.8, 72.9, 65.9, 43.0, 29.8, 29.7, 28.0, 25.6, 19.3, 17.9, 17.6, −4.6, −4.7 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₁₈H₃₅NO₄SiNa: 380.2233, found: 380.2241.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-isobutyl-5-oxopyrrolidine-1-carboxylate 4o. Colorless oil (226 mg, 61%). {[α]²⁵_D = +36.8 (c 1.00, CHCl₃), lit.^9j [α]²⁵_D = +36.06 (c 1.02, CHCl₃); lit.^10c [α]²⁵_D = −35.9 (c 2.3, CHCl₃)}; IR (film): ν_max 2957, 2931, 2855, 1787, 1754, 1716, 1463, 1368, 1312, 1257, 1157, 1078, 915, 836, 776 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.06 (d, J = 4.8 Hz, 1H), 4.01 (dd, J = 10.8, 3.2 Hz, 1H), 2.79 (dd, J = 17.6, 5.2 Hz, 1H), 2.34 (d, J = 17.6 Hz, 1H), 1.71–1.62 (m, 1H), 1.55 (s, 9H), 1.53–1.45 (m, 1H), 1.28 (ddd, J = 14.8, 10.8, 4.0 Hz, 1H), 1.04–0.96 (m, 6H), 0.88 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.3, 149.9, 82.8, 68.5, 66.4, 41.5, 41.1, 28.1, 25.6, 25.3, 23.8, 21.7, 17.9, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₁₉H₃₇NO₄SiNa: 394.2390, found: 394.2390.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-pentylpyrrolidine-1-carboxylate 4p. Colorless oil (277 mg, 72%). [α]²⁵_D = +20.7 (c 1.55, CHCl₃); IR (film): ν_max 2953, 2926, 2855, 1787, 1748, 1704, 1463, 1370, 1310, 1155, 1074, 836, 777 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.09–4.05 (m, 1H), 3.95–3.89 (m, 1H), 2.76 (dd, J = 17.6, 5.2 Hz, 1H), 2.34 (d, J = 17.6 Hz, 1H), 1.71–1.64 (m, 1H), 1.56–1.52 (m, 9H), 1.43–1.26 (m, 7H), 0.95–0.85 (m, 12H), 0.10–0.05 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.7, 150.1, 82.7, 68.3, 68.0, 41.7, 32.0, 31.6, 28.0, 25.7, 25.6, 22.5, 17.9, 13.9, −4.6, −4.7 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₀H₃₉NO₄SiNa: 408.2546, found: 408.2555.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-cyclopropyl-5-oxopyrrolidine-1-carboxylate 4q. Colorless oil (241 mg, 68%). [α]²⁵_D = +22.5 (c 1.95, CHCl₃); IR (film): ν_max 2955, 2930, 2849, 1787, 1754, 1717, 1463, 1368, 1307, 1255, 1156, 1081, 930, 838, 777 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.15 (d, J = 4.8 Hz, 1H), 3.40 (d, J = 9.2 Hz, 1H), 2.76 (dd, J = 17.2, 4.8 Hz, 1H), 2.27 (d, J = 17.2 Hz, 1H), 1.46 (s, 9H), 0.79 (s, 9H), 0.72–0.62 (m, 1H), 0.60–0.44 (m, 3H), 0.24–0.14 (m, 1H), 0.00 (s, 3H), −0.01 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.8, 150.3, 82.7, 71.4, 70.3, 41.8, 27.9, 25.6, 17.9, 13.6, 4.5, 1.8, −4.8, −4.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₁₈H₃₃NO₄SiNa: 378.2077, found: 378.2083.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-cyclohexyl-5-oxopyrrolidine-1-carboxylate 4r. Colorless oil (262 mg, 66%) {[α]²⁵_D = +46.2 (c 3.33, CHCl₃), lit.^9j [α]²⁵_D = +40.73 (c 0.88, CHCl₃)}; IR (film): ν_max 2930, 2855, 1785, 1748, 1715, 1370, 1305, 1255, 1154, 1068, 932, 833, 777 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.09 (d, J = 5.2 Hz, 1H), 3.80 (d, J = 5.6 Hz, 1H), 2.65 (dd, J = 17.6, 5.2 Hz, 1H), 2.25 (d, J = 18.0 Hz, 1H), 1.77–1.68 (m, 2H), 1.66–1.57 (m, 3H), 1.56–1.49 (m, 1H), 1.46 (s, 9H), 1.23–1.01 (m, 4H), 0.87–0.81 (m, 1H), 0.79 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 173.2, 150.4, 82.7, 72.5, 66.6, 42.9, 40.2, 29.8, 28.0, 26.3, 26.2, 25.6, 17.9, −4.5, −4.6 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₁H₃₉NO₄SiNa: 420.2546, found: 420.2549.

(2S,3R)-tert-Butyl 2-benzyl-3-(tert-butyldimethylsilyloxy)-5-oxopyrrolidine-1-carboxylate 4s. Pale yellow oil (284 mg, 70%). {[α]²⁵_D = +10.4 (c 1.00, CHCl₃) lit.^9j [α]²⁵_D = +8.67 (c 1.07, CHCl₃); lit.^10b [α]²³_D = +37.9 (c 1.20, CHCl₃)}; IR (film): ν_max 2959, 2926, 2860, 1787, 1704, 1370, 1312, 1148, 926, 821 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.31 (m, 2H), 7.30–7.24 (m, 1H), 7.23–7.18 (m, 2H), 4.16 (dd, J = 10.4, 3.2 Hz, 1H), 4.07 (d, J = 5.2 Hz, 1H), 3.17 (dd, J = 13.2, 4.0 Hz, 1H), 2.65 (dd, J = 17.6, 5.2 Hz, 1H), 2.51 (dd, J = 13.2, 10.4 Hz, 1H), 2.31 (d, J = 17.6 Hz, 1H), 1.60 (s, 9H), 0.74 (s, 9H), −0.23 (s, 3H), −0.24 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.8, 150.0, 136.6, 129.3, 128.9, 127.1, 83.0, 69.1, 66.9, 41.4, 38.0, 28.1, 25.5, 17.8, −5.2, −5.3 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₂H₃₅NO₄SiNa: 428.2233, found: 428.2221.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-(2-phenylethynyl)pyrrolidine-1-carboxylate (2S,3R)-14a. Pale yellow oil (316 mg, 76%). [α]²⁵_D = +19.5 (c 1.50, CHCl₃); IR (film): ν_max 2959, 2926, 2860, 2205 (very weak), 1790, 1764, 1715, 1468, 1348, 1308, 1255, 1148, 1074, 1019, 915, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.44–7.38 (m, 2H), 7.37–7.30 (m, 3H), 4.81–4.78 (m, 1H), 4.43 (d, J = 5.2 Hz, 1H), 3.01 (dd, J = 17.2, 5.2 Hz, 1H), 2.45 (d, J = 17.2 Hz, 1H), 1.58 (s, 9H), 0.92 (s, 9H), 0.16 (s, 3H), 0.14 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 171.7, 149.4, 131.7, 128.8, 128.4, 121.9, 85.5, 84.2, 83.4, 70.5, 59.2, 41.9, 28.1, 25.7, 18.0, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₃H₃₄NO₄Si: 416.2257, found: 416.2253.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-(2-m-tolylethynyl)pyrrolidine-1-carboxylate (2S,3R)-14b. Pale yellow oil (343 mg, 80%). [α]²⁵_D = +25.6 (c 1.00, CHCl₃); IR (film): ν_max 2959, 2920, 2855, 2367 (very weak), 1792, 1766, 1718, 1369, 1348, 1307, 1148, 1079, 1021, 918, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.26–7.15 (m, 4H), 4.81–4.78 (m, 1H), 4.42 (d, J = 4.8 Hz, 1H), 3.02 (dd, J = 17.2, 5.2 Hz, 1H), 2.45 (d, J = 17.2 Hz, 1H), 2.35 (s, 3H), 1.58 (s, 9H), 0.92 (s, 9H), 0.16 (s, 3H), 0.14 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 171.8, 149.4, 138.1, 132.3, 129.7, 128.8, 128.3, 121.7, 85.7, 83.8, 83.4, 70.5, 59.3, 41.9, 28.1, 25.7, 21.2, 18.0, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₄H₃₆NO₄Si: 430.2414, found: 430.2408.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(2-(4-fluorophenyl)ethynyl)-5-oxopyrrolidine-1-carboxylate (2S,3R)-14c. Yellow oil (334 mg, 77%). [α]²⁵_D = +18.2 (c 2.00, CHCl₃); IR (film): ν_max 2959, 2937, 2860, 2227 (very weak), 1791, 1760, 1721, 1600, 1508, 1364, 1307, 1257, 1149, 1090, 1014, 921, 837 cm⁻¹; ¹⁹F NMR (376 MHz, CDCl₃) δ −109.88 ppm; ¹H NMR (400 MHz, CDCl₃) δ 7.42–7.36 (m, 2H), 7.06–6.99 (m, 2H), 4.79–4.76 (m, 1H), 4.41 (d, J = 5.2 Hz, 1H), 2.99 (dd, J = 17.2, 5.2 Hz, 1H), 2.44 (d, J = 17.2 Hz, 1H), 1.57 (s, 9H), 0.91 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 171.7, 162.8 (d, J = 248.9 Hz), 149.4, 133.7, 133.6, 118.0 (d, J = 3.2 Hz), 115.8, 115.6, 84.5, 83.9, 83.5, 70.4, 59.1, 41.9, 28.0, 25.6, 18.0, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₃H₃₃FNO₄Si: 434.2163, found: 434.2159.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(hept-1-ynyl)-5-oxopyrrolidine-1-carboxylate (2S,3R)-14d. Pale yellow oil (323 mg, 79%). [α]²⁵_D = +26.4 (c 1.00, CHCl₃); IR (film): ν_max 2957, 2926, 2855, 2090 (very weak), 1793, 1760, 1720, 1472, 1352, 1306, 1256, 1149, 1085, 927, 828 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.56–4.52 (m, 1H), 4.26 (d, J = 5.2 Hz, 1H), 2.92 (dd, J = 17.2, 5.2 Hz, 1H), 2.36 (d, J = 17.2 Hz, 1H), 2.21–2.15 (m, 2H), 1.56 (s, 9H), 1.52–1.45 (m, 2H), 1.39–1.29 (m, 4H), 0.93–0.87 (m, 12H), 0.11 (s, 3H), 0.10 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 171.9, 149.5, 86.4, 83.1, 75.4, 70.7, 59.0, 41.8, 30.9, 28.1, 28.0, 25.6, 22.1, 18.6, 18.0, 13.9, −4.9 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₂H₄₀NO₄Si: 410.2727, found: 410.2722.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(3,3-dimethylbut-1-ynyl)-5-oxopyrrolidine-1-carboxylate (2S,3R)-14e. Pale yellow oil (277 mg, 70%). [α]²⁵_D = +22.7 (c 1.50, CHCl₃); IR (film): ν_max 2968, 2931, 2866, 2209 (very weak), 1793, 1764, 1723, 1364, 1348, 1306, 1255, 1149, 1085, 938, 821 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.53–4.50 (m, 1H), 4.25–4.22 (m, 1H), 2.90 (dd, J = 16.8, 5.2 Hz, 1H), 2.36 (d, J = 17.2 Hz, 1H), 1.55 (s, 9H), 1.20 (s, 9H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.1, 149.3, 94.4, 83.0, 73.9, 70.7, 59.0, 41.7, 30.8, 28.0, 27.3, 25.6, 18.0, −4.9 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₁H₃₈NO₄Si: 396.2570, found: 396.2560.

(2R,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-(2-phenylethynyl)pyrrolidine-1-carboxylate (2R,3R)-14a. Pale yellow solid (303 mg, 73%), m.p. 133–134 °C. [α]²⁵_D = −37.7 (c 1.00, CHCl₃); IR (film): ν_max 2953, 2926, 2849, 2370 (very weak), 1781, 1698, 1326, 1288, 1255, 1158, 1093, 937, 840 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.40 (m, 2H), 7.36–7.30 (m, 3H), 5.05 (d, J = 6.8 Hz, 1H), 4.49 (ddd, J = 14.0, 7.2, 6.4 Hz, 1H), 2.80 (dd, J = 16.4, 9.2 Hz, 1H), 2.67 (dd, J = 16.4, 7.2 Hz, 1H), 1.58 (s, 9H), 0.94 (s, 9H), 0.16 (s, 3H), 0.14 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 170.6, 149.0, 131.7, 128.5, 128.3, 122.6, 86.3, 83.6, 83.3, 66.1, 55.6, 40.8, 28.0, 25.6, 18.0, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₃H₃₄NO₄Si: 416.2257, found: 416.2257.

(2R,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-(2-m-tolylethynyl)pyrrolidine-1-carboxylate (2R,3R)-14b. Pale yellow oil (322 mg, 75%). [α]²⁵_D = −27.2 (c 1.50, CHCl₃); IR (film): ν_max 2961, 2928, 2855, 2359, 1792, 1721, 1304, 1146, 1107, 932, 827 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.10–7.03 (m, 3H), 7.01–6.97 (m, 1H), 4.88 (d, J = 4.8 Hz, 1H), 4.33 (ddd, J = 9.2, 5.2, 4.4 Hz, 1H), 2.63 (dd, J = 11.2, 6.4 Hz, 1H), 2.51 (dd, J = 11.2, 4.4 Hz, 1H), 2.18 (s, 3H), 1.41 (s, 9H), 0.78 (s, 9H), 0.00 (s, 3H), −0.02 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 170.5, 149.0, 137.9, 132.3, 129.3, 128.8, 128.2, 122.4, 86.5, 83.5, 82.9, 66.1, 55.6, 40.8, 28.0, 25.7, 21.2, 18.0, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₄H₃₆NO₄Si: 430.2414, found: 430.2402.

(2R,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(2-(4-fluorophenyl)ethynyl)-5-oxopyrrolidine-1-carboxylate (2R,3R)-14c. Pale yellow solid (312 mg, 72%), m.p. 105–106 °C. [α]²⁵_D = −29.7 (c 1.00, CHCl₃); IR (film): ν_max 2953, 2930, 2855, 2200 (very weak), 1791, 1721, 1507, 1304, 1255, 1147, 1101, 836 cm⁻¹; ¹⁹F NMR (376 MHz, CDCl₃) δ −110.55 ppm; ¹H NMR (400 MHz, CDCl₃) δ 7.43–7.37 (m, 2H), 7.06–6.98 (m, 2H), 5.03 (d, J = 7.2 Hz, 1H), 4.49 (ddd, J = 14.0, 7.6, 6.8 Hz, 1H), 2.78 (dd, J = 16.4, 9.2 Hz, 1H), 2.67 (d, J = 16.4, 7.2 Hz, 1H), 1.57 (s, 9H), 0.93 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 170.5, 162.6 (d, J = 248.2 Hz), 149.0, 133.6, 133.5, 118.6 (d, J = 3.2 Hz), 115.7, 115.5, 85.2, 83.6, 83.0, 66.0, 55.5, 40.8, 28.0, 25.6, 18.0, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₃H₃₃FNO₄Si: 434.2163, found: 434.2157.

(2R,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(hept-1-ynyl)-5-oxopyrrolidine-1-carboxylate (2R,3R)-14d. Pale yellow oil (290 mg, 71%). [α]²⁵_D = −25.2 (c 1.00, CHCl₃); IR (film): ν_max 2957, 2931, 2858, 2245 (very weak), 1793, 1760, 1725, 1332, 1305, 1256, 1142, 904, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.78 (ddd, J = 7.2, 2.4, 1.6 Hz, 1H), 4.36 (ddd, J = 14.0, 7.2, 6.4 Hz, 1H), 2.72 (dd, J = 16.4, 10.0 Hz, 1H), 2.58 (dd, J = 16.4, 7.2 Hz, 1H), 2.24–2.18 (m, 2H), 1.55 (s, 9H), 1.53–1.47 (m, 2H), 1.40–1.31 (m, 4H), 0.94–0.88 (m, 12H), 0.13 (s, 3H), 0.11 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 170.8, 149.2, 87.0, 83.3, 73.8, 66.0, 55.1, 40.6, 31.0, 28.2, 28.0, 25.6, 22.2, 18.7, 18.0, 13.9, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₂H₄₀NO₄Si: 410.2727, found: 410.2721.

(2R,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(3,3-dimethylbut-1-ynyl)-5-oxopyrrolidine-1-carboxylate (2R,3R)-14e. Pale yellow solid (249 mg, 63%), m.p. 120–121 °C. [α]²⁵_D = −29.4 (c 0.50, CHCl₃); IR (film): ν_max 2967, 2931, 2855, 2044 (very weak), 1780, 1697, 1342, 1297, 1255, 1149, 1023, 839 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.78 (d, J = 7.2 Hz, 1H), 4.36 (ddd, J = 14.4, 7.6, 6.8 Hz, 1H), 2.71 (dd, J = 16.4, 10.4 Hz, 1H), 2.57 (dd, J = 16.4, 7.2 Hz, 1H), 1.56 (s, 9H), 1.22 (s, 9H), 0.94 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 170.9, 149.0, 95.0, 83.2, 72.2, 65.8, 55.1, 40.5, 30.9, 28.0, 27.4, 25.7, 18.0, −4.7, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₁H₃₈NO₄Si: 396.2570, found: 396.2565.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-oxo-2-vinylpyrrolidine-1-carboxylate 17a. Pale yellow oil (252 mg, 74%). [α]²⁵_D = −0.45 (c 2.80, CHCl₃); IR (film): ν_max 2953, 2926, 2860, 1787, 1715, 1364, 1309, 1255, 1154, 1079, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.82 (ddd, J = 17.2, 10.4, 6.0 Hz, 1H), 5.25–5.17 (m, 2H), 4.47–4.43 (m, 1H), 4.07–4.04 (m, 1H), 2.74 (dd, J = 17.6, 5.2 Hz, 1H), 2.37–2.30 (m, 1H), 1.50 (s, 9H), 0.88 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 149.8, 133.9, 116.6, 82.9, 69.5, 69.4, 41.1, 27.9, 25.6, 18.0, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₁₇H₃₁NO₄SiNa: 364.1920, found: 364.1915.

(2S,3R)-tert-Butyl 2-(but-1-en-2-yl)-3-(tert-butyldimethylsilyloxy)-5-oxopyrrolidine-1-carboxylate 17b. Pale yellow oil (251 mg, 68%). [α]²⁵_D = +2.6 (c 0.50, CHCl₃); IR (film): ν_max 2957, 2931, 2859, 1790, 1755, 1721, 1474, 1368, 1306, 1257, 1154, 1087, 920, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.90–4.88 (m, 1H), 4.84–4.82 (m, 1H), 4.38–4.34 (m, 1H), 4.04–4.01 (m, 1H), 2.77 (dd, J = 17.6, 5.6 Hz, 1H), 2.30 (d, J = 17.2 Hz, 1H), 2.20–2.00 (m, 2H), 1.48 (s, 9H), 1.16–1.11 (m, 3H), 0.89 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 173.1, 149.7, 147.3, 108.1, 82.7, 71.5, 68.6, 41.1, 27.9, 26.5, 25.6, 17.9, 12.1, −4.6, −4.7 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₁₉H₃₅NO₄SiNa: 392.2233, found: 392.2232.

(2S,3S)-tert-Butyl 2-benzyl-3-hydroxy-5-oxopyrrolidine-1-carboxylate 18. A solution of 4s (240 mg, 0.59 mmol) was stirred in dry THF (3 mL) at room temperature, and then a solution of TBAF (3 mL, 1.0 mol in THF) was added. After stirring for 3 hours, the mixture was quenched with water and extracted with EtOAc for three times. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated, the residue was purified by chromatography on a silica gel column to give a crude intermediate (172 mg), which was treated with DMP (502 mg, 1.18 mmol) in dry CH₂Cl₂ (5 mL) for 30 min. Then the mixture was quenched carefully with a saturated solution of NaHCO₃ and Na₂S₂O₃ and separated. The aqueous layer was extracted with DCM three times and the combined organic layers were washed with brine. The organic layer was dried, filtered and concentrated to give crude ketone, which was directly used without further purification. The above crude mixture was dissolved in MeOH (5 mL) and cooled to 0 °C. Then NaBH₄ (22 mg, 0.59 mmol) was added in three portions. After stirring for 2 hours from 0 °C–room temperature, the reaction was quenched with aqueous NaHCO₃ solution and extracted with DCM three times. The combined organic layers were concentrated and the residue was purified by chromatography on a silica gel column to give 18 (153 mg, 89%) as a white solid. M.p. 122–123 °C; lit.^10d m.p. 122–124 °C. {[α]²⁵_D = +26.9 (c 1.00, CHCl₃), lit.^10b [α]²⁴_D = +25.1 (c 0.85, CHCl₃); lit.^10d [α]²⁵_D = +25.2 (c 0.86, CHCl₃); lit.^9j [α]²⁵_D = +27.7 (c 1.12, CHCl₃)}; IR (film): ν_max 3403, 2975, 1770, 1676, 1366, 1287, 1167 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.35–7.22 (m, 5H), 4.56–4.44 (m, 2H), 3.24–3.09 (m, 2H), 2.63 (dd, J = 17.0, 7.2 Hz, 1H), 2.43 (dd, J = 17.0, 8.0 Hz, 1H), 1.51 (s, 9H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 171.8, 149.8, 137.8, 129.9, 128.6, 126.7, 83.3, 65.6, 62.7, 40.1, 40.0, 28.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₁₆H₂₁NO₄Na: 314.1368, found: 314.1372.

Streptopyrrolidine 5. A solution of 18 (120 mg, 0.41 mmol) in CF₃COOH (1.5 mL) was stirred for 4 h from 0 °C to room temperature. Then the mixture was concentrated and the residue was purified by chromatography on a silica gel column to give 5 (65 mg, 83%) as a white solid. M.p. 133–134 °C. lit.^9j m.p. 132–134 °C; lit.^20a m.p. 134–135 °C; lit.^20b m.p. 133–135 °C {[α]²⁵_D = −44.5 (c 0.15, MeOH); lit.^9j [α]²⁵_D = −44.6 (c 0.05, MeOH); lit.¹¹ [α]²⁵_D = −12 (c 0.05, MeOH)}; lit.^20a [α]²⁰_D = −44 (c 1.0, MeOH)}; lit.^20b [α]²⁰_D = −43.5 (c 1.0, MeOH)}; IR (film): ν_max 3455, 3229, 1693, 1346, 1044 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.32 (m, 2H), 7.30–7.24 (m, 3H), 5.78 (brs, 1H), 4.51–4.43 (m, 1H), 3.91 (ddd, J = 10.4, 5.6, 4.8 Hz, 1H), 3.07 (dd, J = 13.6, 5.6 Hz, 1H), 2.98 (d, J = 4.8 Hz, 1H), 2.86 (dd, J = 13.6, 8.8 Hz, 1H), 2.68 (dd, J = 17.2, 6.0 Hz, 1H), 2.42 (dd, J = 17.2, 2.4 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 175.6, 137.7, 129.0, 128.9, 126.9, 68.7, 60.8, 41.0, 35.4 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₁H₁₄NO₂: 192.1025, found: 192.1010.

(2S,3R)-tert-Butyl 2-(3-(benzyloxy)propyl)-3-(tert-butyldimethylsilyloxy)-5-oxopyrrolidine-1-carboxylate (2S,3R)-19a. Pale yellow oil (56 mg, 12%). [α]²⁵_D = +23.0 (c 0.20, CHCl₃); IR (film): ν_max 2959, 2924, 2854, 1782, 1717, 1457, 1364, 1309, 1260, 1152, 1076, 1019, 921, 828 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.31 (m, 5H), 4.55–4.48 (m, 2H), 4.09 (d, J = 5.2 Hz, 1H), 3.96 (dd, J = 9.2, 3.2 Hz, 1H), 3.57–3.47 (m, 2H), 2.78 (dd, J = 17.6, 5.2 Hz, 1H), 2.36 (d, J = 17.6 Hz, 1H), 1.84–1.62 (m, 4H), 1.54 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 150.1, 138.3, 128.4, 127.7, 82.9, 73.1, 69.8, 68.3, 67.9, 28.9, 28.0, 26.4, 25.7, 17.9, −4.6, −4.7 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₅H₄₁NO₅SiNa: 486.2652, found: 486.2653.

(2R,3R)-tert-Butyl 2-(3-(benzyloxy)propyl)-3-(tert-butyldimethylsilyloxy)-5-oxopyrrolidine-1-carboxylate (2R,3R)-19a. White solid (93 mg, 20%), m.p. 80–82 °C. [α]²⁵_D = −38.9 (c 2.42, CHCl₃); IR (film): ν_max 2959, 2926, 2860, 1787, 1704, 1370, 1312, 1148, 926, 821 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.27 (m, 5H), 4.55–4.47 (m, 3H), 4.19–4.13 (m, 1H), 3.53–3.46 (m, 2H), 2.65–2.52 (m, 2H), 2.05–1.95 (m, 1H), 1.82–1.64 (m, 3H), 1.53 (s, 9H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 171.3, 149.8, 138.6, 128.3, 127.5, 127.4, 83.1, 72.8, 70.2, 66.4, 61.4, 40.8, 28.0, 26.7, 25.7, 25.5, 18.0, −4.7, −5.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]⁺ Calcd for C₂₅H₄₁NO₅SiNa: 486.2652, found: 486.2643.

(2S,3R)-tert-Butyl 2-(4-(benzyloxy)butyl)-3-(tert-butyldimethylsilyloxy)-5-oxopyrrolidine-1-carboxylate (2S,3R)-19d. Yellow oil (129 mg, 27%). [α]²⁵_D = +24.7 (c 1.50, CHCl₃); IR (film): ν_max 2959, 2930, 2856, 1786, 1753, 1714, 1368, 1310, 1256, 1152, 1102, 1076, 837 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.29–7.19 (m, 5H), 4.44–4.42 (m, 2H), 3.99 (d, J = 3.2 Hz, 1H), 3.85 (dd, J = 5.6, 2.8 Hz, 1H), 3.43–3.39 (m, 2H), 2.67 (dd, J = 12.0, 3.2 Hz, 1H), 2.28 (d, J = 12.0 Hz, 1H), 1.65–1.55 (m, 4H), 1.46 (s, 9H), 1.38–1.32 (m, 2H), 0.80 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 150.1, 138.5, 128.4, 127.6, 82.8, 73.0, 69.8, 68.3, 67.9, 41.7, 31.9, 29.7, 28.1, 25.7, 22.8, 17.9, −4.6, −4.7 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₆H₄₄NO₅Si: 478.2989, found: 478.2983.

(2R,3R)-tert-Butyl 2-(4-(benzyloxy)butyl)-3-(tert-butyldimethylsilyloxy)-5-oxopyrrolidine-1-carboxylate (2R,3R)-19d. Pale yellow oil (124 mg, 26%). [α]²⁵_D = +45.0 (c 0.40, CHCl₃); IR (film): ν_max 2953, 2930, 2855, 1789, 1755, 1717, 1368, 1305, 1255, 1162, 839 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.21–7.10 (m, 5H), 4.36–4.32 (m, 2H), 4.06 (dd, J = 5.2, 4.0 Hz, 1H), 3.79–3.73 (m, 1H), 3.36–3.28 (m, 2H), 2.15 (ddd, J = 10.0, 5.6, 4.8 Hz, 1H), 1.89–1.84 (m, 1H), 1.55–1.45 (m, 4H), 1.37 (s, 9H), 1.28–1.19 (m, 2H), 0.74 (s, 9H), 0.00 (s, 3H), −0.03 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.8, 150.3, 138.5, 128.4, 127.6, 127.5, 83.0, 73.0, 71.2, 70.1, 55.3, 34.6, 33.0, 29.6, 28.1, 25.7, 21.8, 18.2, −4.5, −5.3 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₆H₄₄NO₅Si: 478.2989, found: 478.2986.

(2R,3R)-tert-Butyl 2-(6-(benzyloxy)hexyl)-3-(tert-butyldimethylsilyloxy)-5-oxopyrrolidine-1-carboxylate (2S,3R)-19e. Yellow oil (303 mg, 60%). [α]²⁵_D = +22.7 (c 2.00, CHCl₃); IR (film): ν_max 2959, 2930, 2857, 1786, 1748, 1715, 1368, 1310, 1153, 1078, 921, 837 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.27 (m, 5H), 4.53–4.51 (m, 2H), 4.07 (d, J = 5.2 Hz, 1H), 3.95–3.90 (m, 1H), 3.51–3.46 (m, 2H), 2.78 (dd, J = 17.6, 5.2 Hz, 1H), 2.34 (d, J = 17.6 Hz, 1H), 1.73–1.60 (m, 3H), 1.55 (s, 9H), 1.46–1.34 (m, 7H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.7, 150.1, 138.6, 128.4, 127.6, 127.5, 82.8, 72.9, 70.3, 68.3, 67.9, 41.7, 29.7, 29.4, 28.1, 26.1, 26.0, 25.7, 17.9, −4.6, −4.7 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₈H₄₈NO₅Si: 506.3302, found: 506.3296.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(3-hydroxypropyl)-5-oxopyrrolidine-1-carboxylate 20. To a solution of 4m (4.9 g, 13.26 mmol) in t-BuOH/H₂O (60 mL, v/v = 3/1) were added N-methylmorpholine N-oxide (5.4 g, 39.79 mmol) and potassium osmate(VI) dihydrate aqueous (245 mg, 0.66 mmol). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHSO₄ and stirred for another 1 h. Then the resulted mixture was concentrated and residue was diluted with water. The mixture was extracted with EtOAc (150 mL × 3) and the combined organic extracts were washed with brine. The organic layer was dried, filtered and concentrated to give crude middle compound without further purification, which was dissolved in THF/H₂O (180 mL, v/v = 1/1) and cooled to 0 °C. Then sodium periodate (5.7 g, 26.52 mmol) was added in one portion. After stirring for 1.5 h, the reaction was quenched with Na₂S₂O₃. The mixture was extracted with EtOAc (150 mL × 3) and the combined organic extracts were washed with brine. The organic layer was dried, filtered and concentrated and the residue was purified by flash chromatography on a silica gel column (PE/EA = 1/1) to give 20 (4.31 g, 87%) as a colorless oil. [α]²⁵_D = +28.2 (c 1.00, CHCl₃); IR (film): ν_max 2953, 2932, 2849, 1770, 1715, 1364, 1293, 1140, 1074, 833 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.11–4.05 (m, 1H), 4.00–3.90 (m, 1H), 3.73–3.62 (m, 2H), 2.83–2.73 (m, 1H), 2.40–2.15 (m, 2H), 1.83–1.57 (m, 3H), 1.56–1.47 (m, 10H), 0.89–0.82 (m, 9H), 0.11–0.03 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.7, 150.2, 83.0, 68.3, 67.7, 61.9, 41.7, 28.8, 28.4, 28.0, 25.6, 17.9, −4.6, −4.7 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₈H₃₆NO₅Si: 374.2363, found: 374.2357.

(2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)propyl)-5-oxopyrrolidine-1-carboxylate trans-19b. To a cooled (0 °C) solution of 20 (4.0 g, 10.70 mmol) TBSCl (2.4 g, 16.05 mmol) and DMAP (1.3 g, 10.70 mmol) in DMF (45 mL) was added imidazole (2.2 g, 32.12 mmol) in one portion. After stirring for 24 h, the mixture was quenched with a saturated aqueous solution of NH₄Cl. The resulted mixture was separated and the aqueous phase was extracted with EA (60 mL × 4). The combined organic layers were washed with water (30 mL × 2) and brine, dried and concentrated. The residue was purified by flash chromatography on a silica gel column (PE/EA = 10/1) to give trans-19b (4.86 g, 93%) as a colorless oil. [α]²⁵_D = +26.1 (c 1.50, CHCl₃); IR (film): ν_max 2956, 2930, 2849, 1788, 1716, 1474, 1310, 1256, 1153, 1074, 836 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.08 (d, J = 5.2 Hz, 1H), 3.92 (dd, J = 9.6, 4.0 Hz, 1H), 3.68–3.59 (m, 2H), 2.78 (dd, J = 17.6, 5.2 Hz, 1H), 2.35 (d, J = 17.6 Hz, 1H), 1.81–1.71 (m, 1H), 1.62–1.55 (m, 2H), 1.57 (s, 9H), 1.51–1.42 (m, 1H), 0.89 (s, 9H), 0.88 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 150.0, 82.8, 68.4, 67.9, 62.5, 41.7, 29.3, 28.5, 28.0, 25.9, 25.7, 18.3, 17.9, −4.6, −4.7, −5.3 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₄H₅₀NO₅Si₂: 488.3228, found: 488.3229.

(2S,3R,5R)-tert-Butyl 5-allyl-3-(tert-butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)propyl)pyrrolidine-1-carboxylate 2,5-cis25. A solution of 19b (2.2 g, 4.52 mmol) in dry THF (20 mL) was treated with a solution of LiEt₃BH (13.5 mL, 13.56 mmol, 1.0 M in THF) at −78 °C. After stirring for 30 min, the reaction was carefully quenched with MeOH (5 mL) and stirred for another 5 min. Then a solution of sodium bicarbonate was added and the mixture was warmed to room temperature. The resulting mixture was extracted with EtOAc (50 mL × 3) and the combined organic layers were washed with brine. The dried organic layer was filtered and concentrated to give a crude mixture without further purification, which was dissolved in dry CH₂Cl₂ (40 mL) and cooled to −78 °C. Once 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 mL, 6.49 mmol) was added, a solution of BF₃·OEt₂ (2.2 mL, 17.31 mmol) was added slowly and the reaction mixture was stirred from −78 °C to −40 °C overnight. The mixture was quenched with a saturated NaHCO₃ solution (10 mL) and warmed to room temperature. The organic phase was separated and the aqueous layer was extracted with CH₂Cl₂ three times. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on a silica gel column (PE/EA = 25/1) to give 2,5-cis25 (1.53 g) in 69% yield as a colorless oil. [α]²⁵_D = +25.2 (c 0.50, CHCl₃); IR (film): ν_max 2956, 2930, 2858, 1472, 1391, 1257, 1175, 1078 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 5.82–5.68 (m, 1H), 5.11–5.00 (m, 2H), 4.10–4.05 (m, 1H), 3.88–3.82 (m, 0.5H), 3.75–3.52 (m, 3.5H), 3.00–2.90 (m, 0.5 H), 2.75–2.65 (m, 1H), 2.56–2.45 (m, 0.5H), 2.44–2.34 (m, 0.5H), 2.06–1.95 (m, 1H), 1.90–1.70 (m, 2H), 1.62–1.44 (m, 11H), 1.28–1.14 (m, 1H), 0.94–0.88 (m, 18H), 0.10–0.07 (m, 6H), 0.06–0.04 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃, rotamers) δ 154.0 (153.9), 136.4 (136.3), 116.6 (116.5), 79.0, 76.1 (75.2), 67.8, 63.0, 57.6 (57.3), 38.9 (37.6), 35.5 (34.6), 30.2 (30.1), 29.8 (28.0), 28.6, 25.9, 25.8, 18.3 (18.2), 17.9, −4.7, −4.8, −5.3 ppm; ¹H NMR (400 MHz, DMSO, 70 °C) δ 5.75–5.62 (m, 1H), 5.00–4.90 (m, 2H), 4.07–4.03 (m, 1H), 3.70–3.60 (m, 1H), 3.56–3.48 (m, 2H), 3.47–3.40 (m, 1H), 2.77–2.55 (m, 1H), 2.36–2.22 (m, 1H), 2.07–1.98 (m, 1H), 1.70–1.58 (m, 2H), 1.43–1.31 (m, 11H), 1.20–1.13 (m, 1H), 0.82 (s, 9H), 0.81 (s, 9H), 0.01 (s, 6H), −0.04 (s, 6H) ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₇H₅₆NO₄Si₂: 514.3748, found: 514.3742.

(2S,3R,5R,E)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)propyl)-5-(4-methoxy-4-oxobut-2-enyl)pyrrolidine-1-carboxylate (5R)-26. To a solution of 25 (794 mg, 1.55 mmol) and methyl acrylate (2.1 mL, 23.18 mmol) in dry DCM (260 mL) was quickly added Grubbs 2^nd generation catalyst (110 mg) and heated to reflux for 7 h, then the mixture was concentrated and the crude was purified by flash chromatography on a silica gel column to give 26 (884 mg, 95%, E : Z = 95 : 5) as a colorless oil. [α]²⁵_D = +28.7 (c 1.50, CHCl₃); IR (film): ν_max 2955, 2930, 2860, 1750, 1704, 1391, 1255, 1172, 1097, 1057, 837 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 6.92–6.85 (m, 1H), 5.90–5.81 (m, 1H), 4.11–4.07 (m, 1H), 3.97–3.89 (m, 0.5H), 3.87–3.80 (m, 0.5H), 3.76–3.72 (m, 3H), 3.71–3.52 (m, 3H), 3.17–3.08 (m, 0.5H), 2.91–2.82 (m, 0.5H), 2.75–2.65 (m, 0.5H), 2.64–2.52 (m, 0.5H), 2.11–2.00 (m, 1H), 1.91–1.81 (m, 0.5H), 1.79–1.68 (m, 1.5H), 1.60–1.42 (m, 11H), 1.25–1.12 (m, 1H), 0.93–0.87 (m, 18H), 0.10–0.07 (m, 6H), 0.06–0.03 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃, rotamers) δ 167.0 (169.9), 154.0 (153.7), 147.0 (146.9), 122.6, 79.5 (79.3), 76.0 (75.1), 67.7, 63.0, 56.7 (56.5), 51.5 (51.4), 37.7 (36.3), 36.1 (35.2), 30.2 (30.1), 29.8 (28.0), 28.5, 25.9, 25.8, 18.3 (18.2), 17.9, −4.7, −4.8, −5.3 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₉H₅₈NO₆Si₂: 572.3803, found: 572.3804.

(2S,3R,5R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)propyl)-5-(4-methoxy-4-oxobutyl)pyrrolidine-1-carboxylate (5R)-27. Compound 26 (800 mg, 1.40 mmol) and 10% Pd/C (80 mg) were stirred overnight under a hydrogen atmosphere. Then the mixture was filtered and concentrated. The residue was purified by flash chromatography on a silica gel column (PE/EA = 10/1) to give 27 (739 mg, 92%) as a colorless oil. [α]²⁵_D = +23.4 (c 2.00, CHCl₃); IR (film): ν_max 2953, 2929, 2858, 1742, 1693, 1391, 1255, 1178, 1098, 1060, 835 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 4.10–4.05 (m, 1H), 3.80–3.48 (m, 7H), 2.42–2.22 (m, 2H), 2.12–2.00 (m, 1.5H), 1.89–1.82 (m, 1H), 1.77–1.68 (m, 2H), 1.67–1.43 (m, 13.5H), 1.24–1.10 (m, 1H), 0.92–0.85 (m, 18H), 0.09–0.03 (m, 12H) ppm; ¹³C NMR (100 MHz, CDCl₃, rotamers) δ 174.1 (174.0), 154.0 (153.9), 79.0, 76.1 (75.2), 67.5, 63.0, 57.6, 51.4, 36.0 (35.2), 34.0 (33.9), 33.8 (32.7), 30.2 (30.1), 29.8 (28.0), 28.6, 25.9, 25.7, 22.2, 18.3 (18.2), 17.9, −4.7, −4.9, −5.3 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₉H₆₀NO₆Si₂: 574.3959, found: 574.3954.

(2S,3R,5R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)propyl)-5-(5-(dimethoxyphosphoryl)-4-oxopentyl)pyrrolidine-1-carboxylate (5R)-28. A solution of dimethyl methylphosphonate (0.7 mL, 6.1 mmol) in dry THF (50 mL) was treated with a solution of n-BuLi (2.7 mL, 6.1 mmol, 2.4 M in hexane) at −78 °C for 1 h. Then a solution of compound 27 (500 mg, 0.87 mmol) in THF (10 mL) was slowly added, and the reaction was warmed to −50 °C and stirred for 2 h. The resulted mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on a silica gel column (PE/EA = 30/1) to give 28 (563 mg, 97%) as a colorless oil. [α]²⁵_D = +23.7 (c 1.50, CHCl₃); IR (film): ν_max 2955, 2932, 2855, 1750, 1709, 1463, 1393, 1255, 1179, 1035, 835 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 4.08–4.03 (m, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.74–3.47 (m, 4H), 3.15–3.08 (m, 1H), 3.07–3.02 (m, 1H), 2.72–2.50 (m, 2H), 2.08–1.98 (m, 1.5H), 1.88–1.66 (m, 3.5H), 1.60–1.44 (m, 13H), 1.22–1.11 (m, 1H), 0.92–0.83 (m, 18H), 0.08–0.02 (m, 12H) ppm; ¹³C NMR (100 MHz, CDCl₃, rotamers) δ 201.8 (201.4), 154.0 (153.9), 79.0, 76.1 (75.2), 67.5, 63.0, 57.7 (57.6), 53.0, 52.9, 44.1 (44.0), 42.0 (41.8), 40.7 (40.5), 35.2 (35.9), 32.3 (33.5), 30.2 (30.0), 29.8 (28.0), 28.6, 25.9, 25.7, 20.5, 17.9 (18.3), −4.7, −4.9, −5.3 ppm; ³¹P NMR (125 MHz, CDCl₃, rotamers) δ 22.89 (22.73) ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₃₁H₆₅NO₈PSi₂: 666.3986, found: 666.3983.

(2S,3R,5R,E)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)propyl)-5-(4-oxoundec-5-enyl)pyrrolidine-1-carboxylate 29. A solution of sodium hydride (36 mg, 0.90 mmol) in dry THF (8 mL) was carefully treated with a solution of compound 28 (543 mg, 0.75 mmol) at −0 °C. After stirring for 1 h from 0 °C to room temperature, hexaldehyde (0.11 mL, 0.90 mmol) was added and the resulted mixture was stirred for another 3 h. Then the reaction was quenched with a saturated aqueous solution of NH₄Cl and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on a silica gel column (PE/EA = 30/1) to give 29 (459 mg, 88%) as a colorless oil. [α]²⁵_D = +30.4 (c 0.50, CHCl₃); IR (film): ν_max 2953, 2928, 2857, 1692, 1458, 1391, 1356, 1175, 1096, 835 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 6.82–6.77 (m, 1H), 6.12–6.03 (m, 1H), 4.10–4.05 (m, 1H), 3.80–3.47 (m, 4H), 2.67–2.45 (m, 2H), 2.25–2.16 (m, 2H), 2.12–1.98 (m, 1.5H), 1.88–1.81 (m, 1H), 1.78–1.68 (m, 2H), 1.63–1.42 (m, 15.5H), 1.37–1.26 (m, 4H), 1.24–1.11 (m, 1H), 0.92–0.86 (m, 21H), 0.08–0.03 (m, 12H) ppm; ¹³C NMR (100 MHz, CDCl₃, rotamers) δ 200.8 (200.5), 154.1 (153.9), 147.4, 130.4, 79.0, 76.1 (75.2), 67.5, 63.0, 57.7, 39.9, 35.1 (35.9), 32.6 (33.9), 32.4, 31.3, 30.2 (30.1), 29.8 (28.0), 28.6, 27.8, 25.9, 25.7, 22.4, 21.4, 18.3, 17.9, 14.0, −4.7, −4.9, −5.3 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₃₅H₇₀NO₅Si₂: 640.4793, found: 640.4790.

(2S,3R,5R,E)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-(3-hydroxypropyl)-5-(4-oxoundec-5-enyl)pyrrolidine-1-carboxylate 30. Compound 29 (393 mg, 0.61 mmol) was dissolved in mixture of DCM/MeOH (4 mL, v : v = 50 : 50) and cooled to −51 °C. Then camphorsulfonic acid (100 mg, 0.43 mmol) was added in one portion and the reaction was stirred overnight. The mixture was quenched with TEA (0.61 mmol) and warmed to room temperature. The resulted mixture was extracted with DCM (20 mL × 3) and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on a silica gel column (PE/EA = 2/1) to give 30 (300 mg, 93%) as a colorless oil. [α]²⁵_D = +23.7 (c 1.00, CHCl₃); IR (film): ν_max 3449, 2956, 2929, 2858, 1688, 1670, 1631, 1393, 1255, 1173, 1054, 843 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, rotamers) δ 6.87–6.78 (m, 1H), 6.12–6.04 (m, 1H), 4.10–4.01 (m, 1H), 3.81–3.60 (m, 4H), 3.57–3.53 (m, 0.33H), 2.95–2.88 (m, 0.67H), 2.67–2.44 (m, 2H), 2.25–2.16 (m, 2H), 2.13–2.00 (m, 1.33H), 1.90–1.82 (m, 1H), 1.80–1.70 (m, 2H), 1.67–1.57 (m, 2H), 1.56–1.44 (m, 13.67H), 1.35–1.28 (m, 4H), 1.25–1.15 (m, 1H), 0.93–0.87 (m, 12H), 0.08–0.04 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃, rotamers) δ 200.4 (200.8), 154.3 (154.0), 147.5, 130.3, 79.4 (79.1), 75.7 (76.0), 66.1 (67.3), 61.4 (62.6), 57.8, 39.8, 35.8 (35.1), 33.8 (32.6), 32.4, 31.3, 29.0 (29.9), 28.5, 28.2 (29.5), 27.8, 25.7, 22.4, 21.4, 17.9, 13.9, −4.8, −4.9 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₉H₅₆NO₅Si: 526.3928, found: 526.3929.

3-epi-Epohelmin A 3-epi-6. A solution of alcohol 30 (102 mg, 0.19 mmol) and TEA (0.21 mL, 1.52 mmol) in dry CH₂Cl₂ (5 mL) was cooled to 0 °C. Then MsCl (43 μL, 0.57 mmol) was added and the mixture was stirred for 30 min. The reaction was quenched with a saturated NH₄Cl solution (20 mL) and extracted with CH₂Cl₂ (25 mL × 3). The combined organic layers were washed with brine for two times, dried and concentrated to give a crude product without further purification. The crude product and 2,6-lutidine (0.11 mL, 0.91 mmol) were dissolved in CH₂Cl₂ (15 mL) and cooled to −78 °C. The reaction was treated with TESOTf (0.2 mL, 0.87 mmol) and the mixture was allowed to warm to room temperature and the mixture was stirred overnight. The mixture was diluted with water and extracted with CH₂Cl₂ (30 mL × 3) and the combined organic layers were washed with brine. The resulted organic layer was dried and concentrated to give a crude product without further purification, which was stirred overnight in a mixture of MeOH/HCl (3 mL, v : v = 50 : 50). Then the mixture was concentrated to give a crude salt, which was dissolved in water (10 mL) and treated with potassium carbonate. The resulted mixture was extracted with CHCl₃ (15 mL × 5) and the combined organic layers were dried with MgSO₄. After being concentrated, the residue was purified by flash chromatography on a silica gel column (DCM/CH₃OH = 80/1–10/1) to give 3-epi-epohelmin A 3-epi-6 (28 mg, 49%), as a yellow oil, [α]²⁵_D = +7.8 (c 0.80, CHCl₃); IR (film): ν_max 3386, 2959, 2927, 2858, 1668, 1627, 1571, 1458, 1407, 1381, 1261, 1177, 1105, 1043 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.84 (ddd, J = 10.4, 5.2, 4.4 Hz, 1H), 6.07 (d, J = 10.8 Hz, 1H), 4.10–4.05 (m, 1H), 3.85–3.80 (m, 1H), 3.28–3.22 (m, 1H), 2.91–2.82 (m, 2H), 2.65–2.55 (m, 2H), 2.49–2.44 (m, 1H), 2.24–2.19 (m, 2H), 2.17–2.10 (m, 1H), 1.96–1.91 (m, 2H), 1.88–1.80 (m, 2H), 1.77–1.70 (m, 2H), 1.68–1.62 (m, 2H), 1.50–1.43 (m, 2H), 1.34–1.28 (m, 4H), 0.91–0.88 (m, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 200.0, 148.0, 130.2, 75.3, 73.2, 66.6, 53.5, 40.9, 39.4, 33.5, 32.4, 31.4, 29.1, 27.8, 24.6, 22.4, 21.3, 13.9 ppm; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₈H₃₂NO₂: 294.2433, found: 294.2424.

Acknowledgements

We thank the National Natural Science Foundation of China (21472022, 21272041, 21072034, 20832005), Key Laboratory for Chemical Biology of Fujian Province for financial support. The authors also thank Dr Han-Qing Dong for helpful suggestions and thank Xiao-Yun, Wei for initial exploration.

References

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26. CCDC 1417164 (compound trans-4a) contains the supplementary crystallographic data for this paper.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1417164. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00250h

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