HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 1, 2014, pp. 143-169
Received, 9th November, 2013, Accepted, 4th December, 2013, Published online, 13th December, 2013.
DOI: 10.3987/COM-13-12881

■ Preparation of Cyclic β-Amino Acid Derivatives with Quaternary Carbon Center via a Radical Addition-Cyclization Sequence

Norihiko Takeda, Masafumi Ueda, Seiko Kajisa, Kenji Matsuno, Takeaki Naito, and Okiko Miyata*

Department of Medicinal Chemistry, Kobe Pharmaceutical University, 4-19-1, Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan

Abstract

A new method has been developed for the construction of α,α-disubstituted cyclic β-amino acid derivatives via the sulfanyl radical addition-cyclization reaction of oxime ether connected with acrylate. This reaction proceeded smoothly to give the cyclized products that contained a quaternary carbon center. Furthermore, the use of carbon centered radicals in the reaction allowed for the formation of cyclic amines containing various alkyl chains. The cyclized product with a quaternary carbon center could also be converted to sterically congested cyclic β-amino acid.

INTRODUCTION
Cyclic amino acids have recently attracted considerable attention because their incorporation into peptides can affect the conformational freedom of the resulting peptides, which can affect their bioactivity. Furthermore, cyclic amino acids can be used for the construction of peptidomimetics, which could be used as potential therapeutic agents. Among the different types of cyclic amino acids known in the literature, cyclic β-amino acid structures in particular can be found in number of biologically active compounds, including the potent antifungal agent cispentacin 1,1 the potent bacterial isoleucyl-tRNA synthetase inhibitor PLD-118 2,2 and the potent influenza neuraminidase inhibitor A-192558 33 (Figure 1). In addition, cyclic β-amino acids such as trans-2-aminocyclopentanecarboxylic acid (ACPC) 4,4 trans-4-amino-3-pyrrolidinecarboxylic acid (APC) 5,4 and trans-2-aminocyclohexanecarboxylic acid (ACHC) 65 have been used as building blocks for the construction of biologically active and water-soluble β-peptides, which can fold into stable helical structures. β-Peptides, which are composed of ACPC 4 and APC 5, tend to form 12-helical structures, whereas the oligomer of ACHC 6 is capable of forming a 14-helical structure in aqueous solution. For this reason, β-amino acid oligomers (β-peptides) have attracted increasing levels of interest from organic and medicinal chemists over the past decade. Some β-peptides consisting of the conformationally rigid alicyclic and heterocyclic β-amino acids, in particular, such as the antimicrobial 17 residue β-peptide 74a (called β-17) and the water-soluble short chain β-peptide 8,4b display 12-helical secondary structures. In general, β-peptides show greater chemical stability than the corresponding α-peptides, as well as better stability towards enzymatic degradation, and are therefore cleared from the systemic circulation at a slower rate (i.e. longer half-lives in vivo). In contrast, however, they generally posses poorer solubility properties and may require intravenous administration.

While it is well known that the incorporation of amino acids containing a quaternary carbon center into peptide chains generally leads to greater stability against metabolic degradation, changes of this type can also have a significant impact of the conformational rigidity, lipophilicity, and selectivity properties of the resulting peptides.6 With this in mind, the synthesis of conformationally restricted cyclic β-amino acids containing a quaternary carbon center that could be embedded in β-peptides would be of considerable interest, and could give rise to a new class of polypeptide helices.
Although a variety of synthetic approaches have been described in the literature for the synthesis of α-monosubstituted cyclic β-amino acids,7 the synthesis of α,α-disubstituted cyclic β-amino acids are relatively scarce,8 and research towards the development of an effective synthetic method for the construction of sterically congested cyclic β-amino acids remains a major challenge. With this in mind, it was envisaged that the radical addition-cyclization reaction of the acrylate-tethered-oxime ether 9 would provide alicyclic amine 10 with a quaternary carbon center which could be readily converted to the α,α-disubstituted cyclic β-amino acid 11 using standard transformations (Scheme 1). Herein, we report the synthesis of cyclic β-amino acid derivatives containing a quaternary carbon center via the radical addition-cyclization reaction of oxime ether 9 involving sulfanyl as well as variety of alkyl radicals.9,10

RESULTS AND DISCUSSION
The requisite substrates 12a-d for the radical reaction were prepared as follows (Scheme 2). The alkylation of sulfonamide 13 with ethyl 2-(bromomethyl)acrylate 14 gave dimethyl acetal 15, which was subsequently hydrolyzed with 2 M HCl before being treated with methoxyamine to give the oxime ether 12a. The oxime ether 12b, which contained a quaternary carbon center instead of an NTs group was prepared by the sequential alkylation of diethyl malonate with α-chloro oxime ether 16 and ethyl 2-(bromomethyl)acrylate 14 under basic conditions. The O-alkylation of the α-hydroxy oxime ether 18 with 14 afforded the oxime ether 12c. The N-Boc tosylamine 19 was converted to ketoxime ether 12d11 via a four step linear sequence as follows. The alkylation of 19 with bromoacetone gave 20, which was Boc-deprotected with 2 M HCl before being treated with methoxyamine to give the oxime ether. Subsequent alkylation of the oxime ether with 14 gave the 12d in good yield.

We initially studied the sulfanyl radical addition-cyclization reactions of the oxime ethers 12a-d (Table 1). The sulfanyl radical addition-cyclization reaction of 12a with PhSH and AIBN proceeded smoothly to give a 60 : 40 separable mixture of the cis- and trans-pyrrolidines 21a and 22a in 94% combined yield (Table 1, entry 1). The reactions of 12b (X = C(CO2Et)2) and 12c (X = O) proceeded in a similar manner to that of 12a to give cis-21b and trans-22b, and cis-21c and trans-22c in 78 and 86% yields, respectively (entries 2 and 3). When the ketoxime ether 12d was subjected to the same conditions, the sterically congested cyclic amines 21d and 22d were obtained in low yield together with recovered 12d (entry 4). This method therefore provided access to the substituted pyrrolidines 21a and 22a, tetrahydrofurans 21c and 22c, and carbocyclic amines 21b and 22b, which all contained a quaternary carbon center, in good yields via the sulfanyl radical addition-cyclization reaction of the corresponding oxime ethers 12a-c, although the stereoselectivities of these reactions were unsatisfied.

We then proceeded to examine the ethyl radical addition-cyclization reactions of the oxime ethers 12a-d using triethylborane as an ethyl radical source (Table 2). The reaction of 12a with Et3B in toluene at 0 °C for 1 h afforded the cyclized products cis-23a and trans-24a in 84% combined yield with 76 : 24 stereoselectivity (Table 2, entry 1). Changing the reaction temperature from 0 to –78 °C showed significant effect in the stereoselectivity to predominately give cis-23a with high stereoselectivity (entry 2). In contrast, the application of the same reaction conditions to oxime ether 12b resulted in the formation of the carbocyclic amines cis-23b and trans-24b in good yields with a reversal in the cis/trans ratio (entry 3). The oxime ether 12c also reacted smoothly under these conditions to give the tetrahydrofurans cis-23c and trans-24c in a slightly lower yield compared with 12a and 12b (entry 4). In general, the reactivity of the ketoxime ether for the radical addition reaction was very low and therefore less developed than that of the aldoxime ether.12 Surprisingly, the ethyl radical addition-cyclization reaction of ketoxime ether 12d proceeded smoothly even at –40 °C to give the C,N-diethylated product 25 containing a vicinal quaternary carbon center in 98% yields with none of the corresponding cis-23d or trans-24d being isolated (entry 5). The diethylated product 25 was presumably formed as a result of the in situ trapping of an N-centered radical by an ethyl radical.
Based on our current results, as well as previous results from the literature, we have proposed a possible reaction pathway for this transformation (Scheme 3).13 The addition of both sulfanyl and ethyl radicals to the β-position of the alkene moiety followed by a 5-exo-trig cyclization onto the oxime ether via the generation of the α-carbonyl radical A would proceed regioselectively to give the aminyl radical B (12→A→B). In the sulfanyl radical addition-cyclization, the aminyl radical B would then be reduced by thiophenol to give the sulfanylated products 21a-d and 22a-d. The Et3B induced radical reaction is well known to work not only as a radical initiator but also as a chain transfer agent. Therefore, when Et3B is used as an ethyl radical source, aminyl radical B is then trapped by Et3B to form the borylamine C. The desired products 23a-c and 24a-c would then be obtained following a work up procedure. In the case of ketoxime ether 12d (R = Me), the corresponding B species was trapped by an ethyl radical to give the C,N-diethylated products 25. The formation of this product was attributed to the sterically congested aminyl radical B, which presumably prevented the trapping of B with Et3B.

The conversion of cis-23a to the α,α-disubstituted cyclic β-amino acid 26 was readily achieved via the conventional reaction sequence (Scheme 4). The hydrolysis of the ethoxycarbonyl group followed by the reductive cleavage of the methyloxy group with concomitant deprotection of the tosyl group under Birch reduction conditions gave the desired cyclic β-amino acid 26 containing a quaternary carbon center in 74% yield (2 steps). This conformationally restricted β-amino acid 26 represents an attractive building block that could give rise to a new class of polypeptide helices.
The sulfanyl and ethyl radical addition-cyclization reactions of acrylate tethered oxime ethers can be summarized as follows: (a) this reaction sequence proceeded in a regioselective manner to afford the desired cyclization products containing a quaternary carbon center via a 5-exo-trig cyclization reaction exclusively, with none of the 6-endo-trig products being obtained; (b) the sulfanyl radical addition-cyclization reactions of 12a-c proceeded smoothly to give cyclized products in high yields; (c) the addition reactions of the ethyl radical to 12a-c were more efficient than those of the sulfanyl radical, especially in terms of the high degree of stereocontrol observed in the ethyl radical addition-cyclization reaction of 12a at –78 °C, where cis-23a was obtained as the major product; and (d) the ethyl radical reaction of ketoxime 12d proceeded smoothly even at –40 °C to afford the cyclic amine 25 with a vicinal quaternary carbon centers. Thus, we have established that the sulfanyl and ethyl radical cyclization reactions represent effective methods for the formation of 5-membered products containing a quaternary carbon center. Moreover, the synthesis of the sterically congested cyclic β-amino acid 26 from cis-23a was easily achieved.

To examine the scope of the transformation for various alkyl radials, we investigated the radical addition-cyclization of oxime ether 12a using a wide variety of alkyl iodides as radical precursors (Table 3). Pleasingly, various alkyl radicals resulting from the iodine atom-transfer reaction reacted successfully with 12a to give the desired cyclization products, even at low temperatures. For example, the isopropyl radical addition-cyclization reaction proceeded smoothly at 0 °C using isopropyl iodide (10 eq.) and Et3B (2.5 eq.) to give a 77 : 23 mixture of the isopropylated products cis-27A and trans-28A in 80% combined yield, accompanying with a 3% yield of the ethylated product cis-23a resulting from the addition of the ethyl radical (Table 3, entry 1). To improve the stereoselectivity, the reaction was carried out at –78 °C. At this temperature, the reaction proceeded with a higher level of stereoselectivity to give cis-27A, although the yield for the transformation was decreased with the starting material 12a being recovered (entry 2). When the reaction was conducted with other secondary alkyl radical, such as sec-butyl and cyclohexyl radicals, the corresponding alkylated products 27B and 28B, and 27C and 28C were formed, respectively, along with a significant amounts of the ethylated products 23a and 24a (entries 3 and 4). In contrast, the use of a tert-butyl radical species gave a much higher yield of the tert-butylated products 27D and 28D, with none of the ethylated product being formed because stable tertiary alkyl radical is formed by efficient iodine atom-transfer process (entry 5). We also examined the introduction of several longer alkyl chains according to this process and found that the use of large excesses of the alkyl iodides (60 eq.) allowed for the formation of the desired alkylated and cyclized products 27E-G and 28E-G in moderate yields (entries 6-8). The use of this strategy, however, also led to formation of the ethylated products 23 and 24 because the iodine atom-transfer reactions of primary decanyl, tridecanyl, and undecanyl iodides were less efficient than those of secondary and tertiary alkyl iodides. As expected, the addition-cyclization reaction of the secondary alkyl radical generated from 2-iododecane gave the four cyclized products 27H, 27H’, 28H, and 28H’ in 72% combined yield, with 3,4-cis-27H and 27H’ being formed as the major diastereomers and the formation of the ethylated products being suppressed (entry 9). We had succeeded in developing a method for the synthesis of cyclic β-amino acid analogues bearing not only secondary and tertiary alkyl groups but also longer alkyl groups via our radical addition-cyclization reaction.

CONCLUSION
In conclusion, we have successfully developed a radical addition-cyclization method for the preparation of various heterocyclic compounds containing a quaternary carbon center. In particular, the radical addition-cyclization reaction of oxime ether containing a nitrogen atom afforded α,α-disubstituted cyclic β-amino acid derivatives bearing a wide variety of alkyl groups, including longer alkyl chains. This new methodology could be used to provide access to various cyclic β-amino acids containing a quaternary carbon center.

EXPERIMENTAL
Melting points are uncorrected 1H and 13C NMR spectra were recorded at 300 or 500 MHz and at 75 or 125 MHz, respectively. IR spectra were recorded using FTIR apparatus. Mass spectra were obtained by EI method. Flash column chromatography (FCC) was preformed using E. Merck Kieselgel 60 (230-400 mesh). Medium-pressure column chromatography (MCC) was performed using Lober Größe B (E. Merck 310-25, Lichroprep Si60).

Ethyl (E/Z)-2-[[[2-(Methoxyimino)ethyl][(4-methylphenyl)sulfonyl]amino]methyl]propenoate (12a)
To a solution of N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamid 1314 (2.00 g, 7.7 mmol) in acetone (11 mL) were added K2CO3 (3.21 g, 15.5 mmol) and ethyl 2-(bromomethyl)acrylate 14 (1.50 g, 7.7 mmol) in acetone (20 mL) at room temperature. After being stirred at reflux for 5 h, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure to give the residue. 1H NMR spectrum of the residue proved the formation of desired acrylate 15, which was subjected to the following reaction without further purification. Ethyl 2-[(2,2-dimethoxyethyl)[(4-methylphenyl)sulfonyl]amino]methyl]propenoate (15) 1H NMR (300 MHz, CDCl3): δ: 7.71 (2H, br d, J = 8 Hz), 7.30 (2H, br d, J = 8 Hz), 6.32 (1H, br d, J = 1 Hz), 5.79 (1H, br d, J = 1 Hz), 4.43 (1H, t, J = 5 Hz), 4.17 (2H, q, J = 7 Hz), 4.16 (2H, s), 3.32 (6H, s), 3.27 (2H, d, J = 5 Hz), 2.43 (3H, s), 1.28 (3H, t, J = 7 Hz). To a solution of 15 prepared above (2.86 g, 7.7 mmol) in acetone (70 mL) was added 2M HCl (90 mL) at room temperature. After being stirred at the same temperature for 24 h, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure to give desired aldehyde. This structure was confirmed by 1H NMR in which the aldehyde proton signal was observed at 9.53 ppm (1H, s). The aldehyde was used to next reaction without further purification. To a solution of aldehyde prepared above (2.50 g, 7.7 mmol) in CH2Cl2 (120 mL) were added AcONa (1.47 g, 17.9 mmol) and MeONH2∙HCl (756.2 mg, 8.94 mmol) at room temperature. After being stirred at the same temperature for 20 h, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by FCC (n-hexane:AcOEt = 3 : 1) to afford 12a (2.72 g, 93%) as a colorless oil and a 4:3 mixture of E- and Z-isomers. IR (CHCl3) 1709 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.71 (2H, br d, J = 8 Hz), 7.33 (2H, br d, J = 8 Hz), 7.13 (4/7H, t, J = 6 Hz), 6.55 (3/7H, t, J = 6 Hz), 6.38 (1H, br dd, J = 3.5, 1 Hz), 5.88 (1H, br dd, J = 6, 1 Hz), 4.20 (2H, br q, J = 7 Hz), 4.04 (6/7H, d, J = 6 Hz), 4.04 (2H, br s), 3.91 (8/7H, d, J = 6 Hz), 3.83 (9/7H, s), 3.77 (12/7H, s), 2.44 (3H, s), 1.29 (3H, br t, J = 7 Hz); 13C NMR (75 MHz, CDCl3) δ: 165.4, 147.3, 144.8, 143.8, 143.6, 136.4, 136.0, 135.5, 135.4, 129.8, 129.7, 127.5, 127.3, 127.15, 127.12, 61.9, 61.5, 60.9, 60.8, 49.2, 47.8, 46.8, 43.9, 21.3, 14.0; HRMS (EI, m/z) calcd for C16H22N2O5S (M+) 354.1248, found 354.1257.

Diethyl (E/Z)-2-[2-(Methoxyimino)ethyl]propanedioate (17)
To a mixture of NaH (60% w/w in mineral oil) (164.5 mg, 4.11 mmol) in dry THF (7.8 mL) was added diethyl malonate (598 mg, 3.74 mmol) under a nitrogen atmosphere at room temperature. After being stirred at the same temperature for 20 min, 2-chloroacetaldehyde O-methyloxime 16 (400 mg, 3.74 mmol) was added and the reaction mixture was stirred at reflux for 27 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by FCC (n-hexane:AcOEt = 9:1) to give 17 (511 mg, 59%) as a colorless oil and a 2:1 mixture of E- and Z-isomers. IR (CHCl3) 1730 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.41 (2/3H, t, J = 5 Hz), 6.73 (1/3H, t, J = 5 Hz), 4.22 (4H, br q, J = 7 Hz), 3.89 (3/3H, s), 3.80 (6/3H, s), 3.65 (2/3H, t, J = 8 Hz), 3.61 (1/3H, t, J = 7 Hz), 2.86 (2/3H, dd, J = 7, 5 Hz), 2.78 (4/3H, dd, J = 8, 5 Hz), 1.28 (6H, br t, J = 7 Hz); 13C NMR (75 MHz, CDCl3) δ: 168.35, 168.32, 146.9, 146.5, 61.61, 61.55, 61.46, 61.3, 49.0, 48.6, 28.5, 24.8, 13.9; HRMS (EI, m/z) calcd for C10H17NO5 (M+) 231.1106, found 231.1123.

Triethyl (E/Z)-1-[2-(Methoxyimino)ethyl]-3-butene-1,1,3-tricarboxylate (12b)
To a mixture of NaH (60% w/w in mineral oil) (136.4 mg, 3.41 mmol) in dry THF (16.4 mL) was added 17 (715.3 mg, 3.1 mmol) under a nitrogen atmosphere at room temperature. After being stirred at the same temperature for 20 min, ethyl 2-(bromomethyl)acrylate 14 (598.3 mg, 3.1 mmol) was added and the reaction mixture was stirred at reflux for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MCC (n-hexane:AcOEt = 15:1) to give 12b (942.8 mg, 89%) as a colorless oil and a 2:1 mixture of E- and Z-isomers. IR (CHCl3) 1724 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.37 (2/3H, t, J = 6 Hz), 6.71 (1/3H, t, J = 5 Hz), 6.30 (2/3H, d, J = 1.5 Hz), 6.30 (1/3H, d, J = 1.5 Hz), 5.70 (2/3H, br d, J = 1.5 Hz), 5.63 (1/3H, br d, J = 1.5 Hz), 4.27-4.10 (6H, m), 3.86 (3/3H, s), 3.80 (6/3H, s), 3.03 (2H, br s), 2.83 (2/3H, d, J = 5 Hz), 2.69 (4/3H, d, J = 6 Hz), 1.29 (3H, t, J = 7 Hz), 1.26 (6H, t, J = 7 Hz); 13C NMR (50 MHz, CDCl3) δ: 169.2, 166.0, 145.9, 135.3, 128.7, 60.9, 60.6, 60.2, 56.0, 55.2, 33.9, 33.5, 32.2, 28.5, 13.4, 13.3. HRMS (EI, m/z) calcd for C16H25NO7 (M+) 343.1629, found 343.1627.

Ethyl (E/Z)-2-[[[2-(Methoxyimino)ethyl]oxy]methyl]propenoate (12c)
To a mixture of NaH (60% w/w in mineral oil) (42 mg, 1.04 mmol) in dry THF (1.6 mL) was added oxime ether 18 (92.6 mg, 1.04 mmol) under a nitrogen atmosphere at 0 °C. After being stirred at the same temperature for 1 h, ethyl 2-(bromomethyl)acrylate 14 (100 mg, 0.52 mmol) in dry THF (1.6 mL) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MCC (n-hexane:AcOEt = 9:1) to give 12c (91.1 mg, 87%) as a colorless oil and a 3:2 mixture of E- and Z-isomers. IR (CHCl3) 1713 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.45 (3/5H, t, J = 6 Hz), 6.86 (2/5H, t, J = 4 Hz), 6.34-6.31 (1H, m), 5.88-5.86 (1H, m), 4.32 (4/5H, d, J = 4 Hz), 4.27-4.19 (4H, m), 4.13 (6/5H, d, J = 6 Hz), 3.874 (6/5H, s), 3.867 (9/5H, s), 1.31 (3H, br t, J = 7 Hz); 13C NMR (75 MHz, CDCl3) δ: 165.2, 149.4, 146.4, 136.9, 136.8, 136.5, 125.5, 69.1, 68.3, 67.1, 64.7, 61.7, 61.3, 60.4, 13.9; HRMS (EI, m/z) calcd for C9H15NO4 (M+) 201.1000, found 201.0998.

1,1-Dimethylethyl N-[4-Methylphenyl]sulfonyl]-N-(2-oxopropyl)carbamate (20)
To a solution of N-(tert-butoxycarbonyl)-p-toluenesulfonamide 19 (626 mg, 2.3 mmol) in acetone (43 mL) were added K2CO3 (952 mg, 6.9 mmol) and bromoacetone (315 mg, 2.3 mmol) at room temperature. After being stirred at reflux for 4 h, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by FCC (n-hexane:AcOEt = 3:1) to give ketone 20 (731.1 mg, 97%) as colorless crystals. mp 73.5-74.5 °C (n-hexane/AcOEt); IR (CHCl3) 1728 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.91 (2H, br d, J = 8 Hz), 7.31 (2H, br d, J = 8 Hz), 4.62 (2H, s), 2.43 (3H, s), 2.21 (3H, s), 1.29 (9H, s); 13C NMR (75 MHz, CDCl3) δ: 201.1, 150.1, 144.1, 136.3, 128.8, 128.2, 84.3, 54.2, 27.3, 26.3, 21.2; HRMS (EI, m/z) calcd for C15H21NO5S (M+) 327.1139, found 327.1135. Anal. Calcd for C15H21NO5S : C, 55.03; H, 6.47; N, 4.28. Found : C, 55.13; H, 6.42; N, 4.28.

Ethyl (E/Z)-2-[[[2-(Methoxyimino)propyl][(4-methylphenyl)sulfonyl]amino]methyl]propenoate (12d)
To a solution of ketone 20 (2.47 g, 7.54 mmol) in 1,4-dioxane (56.7 mL) was added conc. HCl (37.8 mL) at room temperature. After being stirred at the same temperature for 2 h, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure to give sulfonamide. The formation of the sulfonamide was confirmed by the 1H NMR spectrum in which the t-butyl signal of the Boc group (δ: 1.29 (9H, s) in ketone 20) was not observed. The sulfonamide was used to next reaction without further purification. To a solution of sulfonamide prepared above (1.70 g, 7.50 mmol) in CH2Cl2 (115 mL) were added AcONa (2.48 g, 30.2 mmol) and MeONH2∙HCl (1.26 g, 15.1 mmol) at room temperature. After being stirred at the same temperature for 28 h, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by FCC (n-hexane:AcOEt = 2:1) to give ketoxime ether (1.81 g, 93%) as colorless crystals and a 5:1 mixture of geometric isomers. (E/Z)-N-[2-(Methoxyimino)propyl]-4-methylphenylsulfonamide: 1H NMR (300 MHz, CDCl3) δ: 7.74 (2H, br d, J = 8 Hz), 7.32 (2H, br d, J = 8 Hz), 5.31 (1/6H, br t, J = 6 Hz), 5.17 (5/6H, br t, J = 5.5 Hz), 3.78 (3H, br s), 3.73 (2/6H, d, J = 6 Hz), 3.62 (10/6H, d, J = 5.5 Hz), 2.43 (3H, s), 1.82 (3/6H, s), 1.76 (15/6H, s). The stereostructures have not been established. To a solution of ketoxime ether prepared above (353.5 mg, 1.38 mmol) in acetone (28 mL) were added K2CO3 (571 mg, 4.14 mmol) and ethyl 2-(bromomethyl)acrylate 14 (266.7 mg, 1.38 mmol) at room temperature. After being stirred at reflux for 4 h, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by FCC (n-hexane:AcOEt = 3:1) to give 12d (475.8 mg, 94%) as a colorless oil and a 5:1 mixture of geometric isomers. The stereostructures have not been established. IR (CHCl3) 1710 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.69 (2H, br d, J = 8 Hz), 7.31 (2H, br d, J = 8 Hz), 6.32 (5/6H, br s), 6.29 (1/6H, br s), 5.84 (5/6H, br s), 5.74 (1/6H, br s), 4.17 (2H, br q, J = 7 Hz), 4.04 (2/6H, br s), 3.99 (10/6H, br s), 3.83 (10/6H, br s), 3.79 (2/6H, br s), 3.75 (3H, br s), 2.43 (3H, s), 1.89 (3/6H, s), 1.79 (15/6H, s), 1.28 (3H, br t, J = 7 Hz); 13C NMR (75 MHz, CDCl3) δ: 165.7, 152.5, 143.6, 136.1, 135.5, 135.4, 129.73, 129.67, 128.5, 127.5, 127.32, 127.26, 61.6, 61.0, 60.9, 52.8, 49.9, 48.1, 21.5, 14.1, 12.5; HRMS (EI, m/z) calcd for C17H24N2O5S (M+) 368.1405, found 368.1389.

General procedure for radical addition-cyclization reactions of oxime ethers 12a-d with PhSH-AIBN combination
To a boiling solution of the oxime ethers 12a-d (0.20 mmol) in benzene (3 mL) under a nitrogen atmosphere was added a solution of thiophenol (29 mg, 0.26 mmol) and AIBN (16mg, 0.10 mmol) in benzene (5 mL) by syringe pump (5 mL/h) over 1 h. After the reaction mixture was heated at reflux for a further 3 h, the reaction mixture was diluted with H2O and extracted with CHCl3. The organic phase was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by MCC (n-hexane:AcOEt = 5:1) to afford the cyclized products 21a-d and 22a-d as shown in Table 1.

Ethyl (3R*,4R*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-(phenylsulfanyl)methyl-3-pyrrolidinecarboxylate (cis-21a)
A yellow oil; IR (CHCl3) 3670, 1731 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.72 (2H, br d, J = 8 Hz), 7.34-7.19 (7H, m), 5.78 (1H, br d, J = 5 Hz), 3.96-3.85 (2H, m), 3.67 (1H, d, J = 10 Hz), 3.57 (1H, d, J = 10 Hz), 3.60-3.52 (2H, m), 3.31 (1H, d, J = 13 Hz), 3.27 (1H, dd, J = 10, 3 Hz), 3.17 (3H, s), 2.98 (1H, d, J = 13 Hz), 2.41 (3H, s), 1.13 (3H, t, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 170.3, 143.6, 135.4, 133.3, 130.6, 129.7, 129.0, 127.7, 126.9, 65.3, 61.9, 61.4, 56.4, 52.5, 50.0, 40.3, 21.5, 13.9; HRMS (EI, m/z) calcd for C22H28N2O5S2 (M+) 464.1438, found 464.1432.

Ethyl (3R*,4S*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-(phenylsulfanyl)methyl-3-pyrrolidinecarboxylate (trans-22a)
A yellow oil; IR (CHCl3) 3350, 1730 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.70 (2H, br d, J = 8 Hz, ArH), 7.34-7.19 (7H, m), 5.72 (1H, br d, J = 5 Hz), 3.91-3.81 (3H, m), 3.73 (1H, d, J = 10 Hz), 3.57 (1H, dd, J = 10.5, 7 Hz), 3.47 (1H, d, J = 10 Hz), 3.36 (1H, dd, J = 10.5, 5 Hz), 3.32 (1H, d, J = 13 Hz), 3.31 (3H, s), 3.09 (1H, d, J = 13 Hz), 2.41 (3H, s), 1.10 (3H, t, J = 7 Hz). NOE was observed between 4-NH (δ 5.72) and 3-CH2 (δ 3.32, 3.09) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 171.7, 143.6, 135.4, 133.6, 130.6, 129.6, 129.0, 127.6, 127.0, 62.9, 62.2, 61.7, 56.5, 54.2, 50.6, 35.6, 21.5, 13.8; HRMS (EI, m/z) calcd for C22H28N2O5S2 (M+) 464.1438, found 464.1441.

Triethyl (3R*,4S*)-4-(Methoxyamino)-3-(phenylsulfanyl)methyl-1,1,3-cyclopentanetricarboxylate (cis-21b)
A yellow oil; IR (CHCl3) 3691, 1726 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.41-7.16 (5H, m), 5.89 (1H, br s), 4.20 (2H, q, J = 7 Hz), 4.14 (2H, br q, J = 7 Hz), 4.05 (2H, br q, J = 7 Hz), 3.63 (1H, dd, J = 9, 7 Hz), 3.58 (1H, d, J = 13 Hz), 3.42 (3H, s), 3.17 (1H, d, J = 13 Hz), 3.04 (1H, d, J = 15 Hz), 2.56 (1H, dd, J = 14, 7 Hz), 2.52 (1H, d, J = 15 Hz), 2.44 (1H, dd, J = 14, 9 Hz), 1.25 (3H, t, J = 7 Hz), 1.21 (3H, t, J = 7 Hz), 1.20 (3H, t, J = 7 Hz). NOE was observed between 4-H (δ 3.63) and 2-H (δ 2.52), 2-H (δ 2.52) and CH2SPh (δ 3.58, 3.17) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 172.7, 172.5, 171.3, 136.7, 130.4, 128.8, 126.4, 67.6, 61.9, 61.8, 61.6, 61.2, 57.1, 57.0, 41.5, 39.8, 36.7, 13.98, 13.96, 13.93; HRMS (EI, m/z) calcd for C22H31NO7S (M+) 453.1820, found 453.1821.

Triethyl (3R*,4R*)-4-(Methoxyamino)-3-(phenylsulfanyl)methyl-1,1,3-cyclopentanetricarboxylate (trans-22b)
A yellow oil; IR (CHCl3) 3545, 1727 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.23-7.16 (5H, m), 5.95 (1H, br s), 4.17 (2H, q, J = 7 Hz), 4.15 (2H, q, J = 7 Hz), 3.97 (2H, br q, J = 7 Hz), 3.85 (1H, t, J = 7 Hz), 3.48 (3H, s), 3.44 (1H, d, J = 13 Hz), 3.22 (1H, d, J = 13 Hz), 2.96 (1H, d, J = 15 Hz), 2.67 (1H, dd, J = 15, 7 Hz), 2.66 (1H, d, J = 15 Hz), 2.44 (1H, dd, J = 15, 7 Hz), 1.24 (3H, t, J = 7 Hz), 1.23 (3H, t, J = 7 Hz), 1.16 (3H, t, J = 7 Hz). NOE was observed between 4-H (δ 3.85) and 2β-H (δ 2.96), 2α-H (δ 2.66) and CH2SPh (δ 3.44, 3.22) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 173.6, 171.9, 171.6, 136.4, 130.4, 128.8, 126.5, 65.4, 62.0, 61.8, 61.7, 61.3, 57.4, 57.2, 40.7, 37.9, 36.9, 14.0, 13.9; HRMS (EI, m/z) calcd for C22H31NO7S (M+) 453.1820, found 453.1833.

Ethyl (3R*,4R*)-Tetrahydro-4-(methoxyamino)-3-(phenylsulfanyl)methyl-3-furancarboxylate (cis-21c)
A colorless oil; IR (CHCl3) 3691, 1726 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.39-7.17 (5H, m), 4.13 (1H, dd, J = 9, 1 Hz), 4.11 (1H, dd, J = 10, 7 Hz), 4.10-4.01 (2H, m), 3.99 (1H, d, J = 9 Hz), 3.75 (1H, dd, J = 10, 5 Hz), 3.62 (1H, dd, J = 7, 5 Hz), 3.46 (1H, dd, J = 13, 1 Hz), 3.45 (3H, s), 3.15 (1H, d, J = 13 Hz), 1.22 (3H, t, J = 7 Hz). NOE was observed between 4-H (δ 3.62) and 2β-H (δ 3.99), 4-H (δ 3.62) and CH2SPh (δ 3.46, 3.15), 2β-H (δ 3.99) and CH2SPh (δ 3.46, 3.15) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 170.1, 136.2, 130.2, 128.9, 126.6, 72.7, 70.7, 67.8, 61.9, 61.2, 57.5, 40.5, 14.0; HRMS (EI, m/z) calcd for C15H21NO4S (M+) 311.1190, found 311.1180.

Ethyl (3R*,4S*)-Tetrahydro-4-(methoxyamino)-3-(phenylsulfanyl)methyl-3-furancarboxylate (trans-22c)
A colorless oil; IR (CHCl3) 3700, 1726 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.41-7.19 (5H, m), 4.20 (1H, d, J=9 Hz), 4.10 (1H, dd, J=12, 7 Hz), 4.09 (1H, dd, J=8, 7 Hz), 4.09-3.99 (2H, m), 3.86 (1H, d, J=9 Hz), 3.82 (1H, dd, J = 12, 8 Hz), 3.52 (3H, s), 3.48 (1H, d, J = 12.5 Hz), 3.30 (1H, d, J = 12.5 Hz), 1.19 (3H, t, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 172.7, 136.1, 130.4, 129.0, 126.7, 74.6, 71.3, 64.8, 62.2, 61.5, 57.9, 35.2, 14.0; HRMS (EI, m/z) calcd for C15H21NO4S (M+) 311.1190, found 311.1205.

Ethyl 4-(Methoxyamino)-4-methyl-1-[(4-methylphenyl)sulfonyl]-3-(phenylsulfanyl)methyl-3-pyrrolidinecarboxylate (21d and 22d)
According to the procedure given for the preparation of pyrrolidines 21a and 22a, the reaction was carried out for 6 h to afford cyclized products 21d and 22d. The stereostructures of the cis- and trans-isomer (52:48) have not been established. The major less polar product; A yellow oil; IR (CHCl3) 3694, 1731 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.74 (2H, br d, J = 8 Hz), 7.30-7.18 (7H, m), 5.68 (1H, br s), 3.92 (1H, dq, J = 11, 7 Hz), 3.83 (1H, d, J = 11 Hz), 3.80 (1H, dq, J = 11, 7 Hz), 3.73 (1H, dd, J = 11, 2 Hz), 3.54 (1H, d, J = 10 Hz), 3.52 (1H, dd, J = 13, 2 Hz), 3.46 (3H, s), 3.34 (1H, d, J = 10 Hz), 2.74 (1H, d, J = 13 Hz), 2.39 (3H, s), 1.11 (3H, t, J = 7 Hz), 0.96 (3H, s); 13C NMR (125 MHz, CDCl3) δ: 170.5, 143.6, 135.5, 133.7, 130.6, 129.7, 128.9, 127.4, 126.8, 66.5, 62.9, 61.4, 59.5, 56.0, 51.7, 36.8, 21.5, 20.1, 14.0; HRMS (CI, isobutane, m/z) calcd for C23H31N2O5S2 (QM+) 479.1673, found 479.1667. The minor more polar product; A yellow oil; IR (CHCl3) 3650, 1729 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.74 (2H, br d, J = 8 Hz), 7.32-7.20 (7H, m), 5.14 (1H, br s), 3.97 (1H, dq, J = 11, 7 Hz), 3.87 (1H, dd, J = 11, 2 Hz), 3.82 (1H, dd, J = 11, 2 Hz), 3.80 (1H, dq, J = 11, 7 Hz), 3.59 (1H, d, J = 11 Hz), 3.38 (1H, dd, J = 13, 2 Hz), 3.16 (3H, s), 3.06 (1H, d, J = 11 Hz), 2.70 (1H, d, J = 13 Hz), 2.39 (3H, s), 1.28 (3H, s), 1.13 (3H, t, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 169.8, 143.5, 135.3, 133.5, 130.8, 129.7, 129.0, 127.7, 127.0, 69.3, 62.4, 61.2, 58.0, 54.5, 52.0, 38.6, 21.5, 16.7, 14.0; HRMS (CI, isobutane, m/z) calcd for C23H31N2O5S2 (QM+) 479.1673, found 479.1673.

General procedure for radical addition-cyclization reactions of oxime ethers 12a-c with Et3B
Oxime ethers 12a-c (0.15 mmol) was dissolved in toluene (10 mL) under air atmosphere. To a solution of oxime ethers 12a-c in toluene was added Et3B (1.01M in n-hexane) (0.37 mL, 0.375 mmol) under a nitrogen atmosphere at –78 °C. After being stirred at the same temperature for 15 min, Three further portions of Et3B (1.01M in n-hexane) (each 0.37 mL, 0.375 mmol) were added at 15 min intervals. After being stirred at the same temperature for 1 h, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with CHCl3. The organic phase was washed with brine, dried over MgSO4, and concentrated under reduced pressure. Purification of the residue by MCC (n-hexane:AcOEt = 5:1-3:1) afforded cyclized products 23a-c and 24a-c as shown in Table 2.

Ethyl (3R*,4R*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-propyl-3-pyrrolidinecarboxylate (cis-23a)
Colorless crystals; mp 79.0-79.5 °C (n-hexane/AcOEt); IR (CHCl3) 3560, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.75 (2H, br d, J = 8 Hz), 7.34 (2H, br d, J = 8 Hz), 5.75 (1H, br s), 4.11 (2H, br q, J = 7 Hz), 3.55 (1H, dd, J = 11, 6 Hz), 3.52 (1H, d, J = 10 Hz), 3.42 (1H, d, J = 10 Hz), 3.41-3.37 (1H, m), 3.32 (1H, dd, J = 11, 3 Hz), 3.16 (3H, s), 2.43 (3H, s) 1.61-1.54 (1H, m), 1.33 (1H, br td, J = 12, 5 Hz), 1.22 (3H, t, J = 7 Hz), 1.27-1.08 (2H, m), 0.81 (3H, t, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 172.1, 143.7, 133.9, 129.8, 127.9, 66.3, 62.2, 61.2, 55.8, 52.2, 50.2, 38.3, 21.7, 18.1, 14.33, 14.31; HRMS (EI, m/z) calcd for C18H28N2O5S (M+) 384.1717, found 384.1716; Anal. Calcd for C18H28N2O5S : C, 56.23; H, 7.34; N, 7.29. Found : C, 56.17; H, 7.55; N, 7.32.

Ethyl (3R*,4S*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-propyl-3-pyrrolidinecarboxylate (trans-24a)
Colorless crystals; mp 90.5-91.0 °C (n-hexane/AcOEt); IR (CHCl3) 3540, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.72 (2H, br d, J = 8 Hz), 7.33 (2H, br d, J = 8 Hz), 5.60 (1H, br s), 4.11-4.00 (2H, m), 3.77-3.73 (1H, m), 3.73 (1H, d, J = 10 Hz), 3.47 (1H, dd, J=10, 6 Hz), 3.39 (1H, dd, J = 10, 4 Hz), 3.35 (3H, s), 3.25 (1H, d, J = 10 Hz), 2.43 (3H, s), 1.64-1.56 (1H, m), 1.44-1.36 (1H, m), 1.20 (3H, t, J = 7 Hz), 1.20-1.08 (2H, m), 0.84 (3H, t, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 173.2, 143.4, 133.9, 129.6, 127.6, 62.8, 62.0, 61.3, 55.7, 53.6, 50.7, 32.1, 21.5, 18.5, 14.3, 14.0; HRMS (EI, m/z) calcd for C18H28N2O5S (M+) 384.1717, found 384.1725; Anal. Calcd for C18H28N2O5S : C, 56.23; H, 7.34; N, 7.29. Found : C, 56.06; H, 7.51; N, 7.20.

Triethyl (3R*,4S*)-4-(Methoxyamino)-3-propyl-1,1,3-cyclopentanetricarboxylate (cis-23b)
A yellow oil; IR (CHCl3) 3540, 1727 cm-1; 1H NMR (500 MHz, CDCl3) δ: 5.91 (1H, br s), 4.24-4.10 (6H, m), 3.45 (3H, s), 3.41 (1H, dd, J = 7, 6.5 Hz), 2.91 (1H, d, J = 14.5 Hz), 2.54 (1H, dd, J = 14, 6.5 Hz), 2.48 (1H, dd, J = 14, 7 Hz), 2.35 (1H, d, J = 14.5 Hz), 1.87 (1H, br td, J = 13.5, 4.5 Hz), 1.40 (1H, br td, J = 13.5, 4.5 Hz), 1.35-1.18 (2H, m), 1.26 (6H, t, J = 7 Hz), 1.25 (3H, t, J = 7 Hz), 0.89 (3H, t, J = 7 Hz). NOE was observed between 4-H (δ 3.41) and 2β-H (δ 2.35), 4-H (δ 3.41) and CH2Et (δ 1.87, 1.40), 2β-H (δ 2.35) and CH2Et (δ 1.87, 1.40) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 174.0, 172.8, 171.8, 68.5, 61.83, 61.77, 61.6, 60.7, 57.3, 56.3, 39.38, 39.35, 36.8, 18.4, 14.4, 14.1, 13.99, 13.97; HRMS (EI, m/z) calcd for C18H31NO7 (M+) 373.2098, found 373.2103.

Triethyl (3R*,4R*)-4-(Methoxyamino)-3-propyl-1,1,3-cyclopentanetricarboxylate (trans-24b)
A yellow oil; IR (CHCl3) 3541, 1728 cm-1; 1H NMR (500 MHz, CDCl3) δ: 5.83 (1H, br s), 4.25-4.10 (6H, m), 3.74 (1H, dd, J = 6.5, 6 Hz), 3.49 (3H, s), 2.82 (1H, d, J = 14.5 Hz), 2.64 (1H, dd, J = 14.5, 6 Hz), 2.50 (1H, d, J = 14.5 Hz), 2.34 (1H, dd, J = 14.5, 6.5 Hz), 1.72 (1H, ddd, J = 13.5, 12, 5 Hz), 1.45 (1H, ddd, J = 13.5, 12, 4.5, Hz), 1.30-1.11 (2H, m), 1.25 (6H, t, J = 7 Hz), 1.24 (3H, t, J = 7 Hz), 0.90 (3H, t, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 175.2, 172.3, 171.9, 65.3, 61.9, 61.7, 61.6, 60.9, 57.3, 56.6, 40.0, 36.9, 34.1, 18.6, 14.5, 14.1, 14.0; HRMS (EI, m/z) calcd for C18H31NO7 (M+) 373.2098, found 373.2104.

Ethyl (3R*,4R*)-Tetrahydro-4-(methoxyamino)-3-propyl-3-furanecarboxylate (cis-23c)
A colorless oil; IR (CHCl3) 3526, 1723 cm-1; 1H NMR (500 MHz, CDCl3) δ: 6.09 (1H, br s), 4.19 (2H, q, J = 7 Hz), 4.11 (1H, d, J = 9 Hz), 4.05 (1H, dd, J = 10, 6 Hz), 3.84 (1H, dd, J = 10, 4 Hz), 3.75 (1H, d, J = 9 Hz), 3.47 (3H, s), 3.45 (1H, dd, J = 6, 4 Hz), 1.75 (1H, br td, J = 13.5, 5 Hz), 1.56 (1H, br td, J = 13.5, 5 Hz), 1.35-1.18 (2H, m), 1.29 (3H, t, J = 7 Hz), 0.91 (3H, t, J = 7 Hz). NOE was observed between 4-H (δ 3.45) and 3-CH2 (δ 1.75, 1.56) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 172.7, 72.5, 70.7, 68.0, 62.1, 60.8, 56.5, 38.8, 18.2, 14.3, 14.2; HRMS (EI, m/z) calcd for C11H21NO4 (M+) 231.1469, found 231.1489.

Ethyl (3R*,4S*)-Tetrahydro-4-(methoxyamino)-3-propyl-3-furanecarboxylate (trans-24c)
A colorless oil; IR (CHCl3) 3515, 1724 cm-1; 1H NMR (500 MHz, CDCl3) δ: 5.70 (1H, br s), 4.25 (1H, d, J = 9 Hz), 4.19 (2H, br q, J = 7 Hz), 4.01 (1H, dd, J = 9, 6 Hz), 3.96 (1H, dd, J = 6, 4 Hz), 3.80 (1H, dd, J = 9, 4 Hz), 3.65 (1H, d, J = 9 Hz), 3.53 (3H, s), 1.72 (1H, ddd, J = 13, 12, 5 Hz), 1.64-1.54 (1H, m), 1.34-1.18 (2H, m), 1.27 (3H, t, J = 7 Hz), 0.93 (3H, t, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 174.4, 74.2, 71.6, 64.3, 62.0, 61.1, 57.1, 31.8, 19.1, 14.6, 14.2; HRMS (EI, m/z) calcd for C11H21NO4 (M+) 231.1469, found 231.1486.

Ethyl 4-[(Ethyl)(methoxy)amino]-4-methyl-1-[(4-methylphenyl)sulfonyl]-3-propyl-3-pyrrolidinecarboxylate (25)
According to the procedure for given for the preparation of pyrrolidines 23a and 24a, the reaction was carried out at –40 °C to afford cyclized products 25 and isomer. The stereostructures of the cis-25 and trans-25 (52:48) have not been established. The major less polar product; A colorless oil; IR (CHCl3) 1721 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.50 (2H, br d, J = 8 Hz), 7.35 (2H, br d, J = 8 Hz), 4.08 (2H, br q, J = 7 Hz), 3.85 (1H, dd, J = 11, 1.5 Hz), 3.59 (3H, s), 3.48 (1H, d, J=10 Hz), 3.45 (1H, d, J = 11 Hz), 3.30 (1H, d, J = 10 Hz), 3.07-2.95 (1H, m), 2.58-2.49 (1H, m), 2.45 (3H, s), 1.85-1.78 (1H, m), 1.21 (3H, t, J = 7 Hz), 1.14 (3H, t, J = 7 Hz), 1.14-0.95 (3H, m), 0.89 (3H, s), 0.79 (3H, t, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 171.9, 143.6, 133.6, 129.7, 127.5, 72.3, 64.4, 61.0, 59.4, 57.9, 52.9, 48.0, 33.4, 21.5, 18.3, 14.9, 14.4, 14.0, 13.8; HRMS (EI, m/z) calcd for C21H34N2O5S (M+) 426.2186, found 426.2198. The minor more polar product; A colorless oil; IR (CHCl3) 1724 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.76 (2H, br d, J = 8 Hz), 7.34 (2H, br d, J = 8 Hz), 4.03 (1H, dq, J = 11, 7 Hz), 3.75 (1H, d, J = 10 Hz), 3.79-3.72 (1H, m), 3.57 (1H, br d, J = 9 Hz), 3.45 (1H, d, J = 9 Hz), 3.45 (3H, s), 3.31 (1H, d, J = 10 Hz), 2.75-2.68 (1H, m), 2.68-2.60 (1H, m), 2.44 (3H, s), 1.88-1.78 (1H, m), 1.28-1.20 (3H, m), 1.15 (3H, s), 1.06 (3H, t, J = 7 Hz), 1.05 (3H, t, J = 7 Hz), 0.86 (3H, t, J = 7 Hz), 13C NMR (125 MHz, CDCl3) δ: 172.5, 143.2, 134.7, 129.5, 127.5, 73.1, 64.1, 60.6, 58.5, 58.2, 54.9, 48.5, 35.6, 21.5, 19.1, 14.7, 14.0, 13.6, 13.4. HRMS (EI, m/z) calcd for C21H34N2O5S (M+) 426.2186, found 426.2181.

(3R*,4R*)-4-Amino-3-propyl-3-pyrrolidinecarboxylic Acid (26)
To a solution of cis-23a (166 mg, 0.43 mmol) in THF (12.2 mL) was added a solution of LiOH·H2O (902 mg, 21.5 mmol) in H2O (18 mL) at room temperature under a nitrogen atmosphere. After being stirred at reflux for 24 h, the reaction mixture was acidified to pH 3 and extracted with CHCl3. The organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by FCC (n-hexane:AcOEt (2:1)→AcOEt:MeOH (95:5) to give desired (±)-carboxylic acid (120 mg, 78%) as pale yellow crystals. mp 110-111 °C (Et2O); IR (CHCl3) 3500-2300, 1708 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.74 (2H, br d, J = 8 Hz), 7.34 (2H, br d, J = 8 Hz), 3.59 (1H, d, J = 10 Hz), 3.56 (1H, dd, J = 10, 4 Hz), 3.44-3.39 (1H, m), 3.39 (1H, d, J = 10 Hz), 3.31 (1H, dd, J = 10, 3 Hz), 3.21 (3H, s), 2.43 (3H, s), 1.66-1.56 (1H, m), 1.44-1.16 (3H, m), 0.83 (3H, t, J = 7 Hz); 13C NMR (75 MHz, CDCl3) δ: 176.9, 143.6, 133.2, 129.6, 127.5, 65.9, 61.8, 55.5, 51.9, 49.8, 37.8, 21.4, 17.8, 13.9; HRMS (EI, m/z) calcd for C16H24N2O5S (M+) 356.1405, found 356.1413. Sodium (20 mg, 0.87 mmol) was added slowly to liquid ammonia (15 mL) at –78 °C until the color of the mixture remaind dark blue. A solution of (±)-carboxylic acid (45.8 mg, 0.13 mmol) in THF (2 mL) was added slowly to the sodium/liquid ammonia mixture. The reaction was stirred for 30 min at the same temperature. The reaction mixture was quenched with isoprene (1 mL) and allowed to reach to room temperature in order to allow the ammonia to fully evaporate. The residue was acidified by aqueous 2 M HCl and loaded on resin (Amberlite IR-120B) in a column and washed with water and then 0.5 M NH4OH. After concentration of the elute under reduced pressure, cyclic β-amino acid 26 (21 mg, 95%) was obtained as white solid. IR (Nujol) 3700-2500, 1670, 1627, 1461 cm-1; 1H NMR (300 MHz, CD3OD) δ: 3.89 (1H, br d, J = 11 Hz), 3.66-3.52 (2H, m), 3.18-3.10 (1H, m), 3.04 (1H, br d, J = 11 Hz), 1.98-1.80 (1H, m), 1.52-1.20 (3H, m), 0.95 (3H, br t, J = 7 Hz); HRMS (CI, isobutane, m/z) calcd for C8H17N2O2 (QM+) 173.1289, found 173.1282.

General procedure for alkyl radical addition-cyclization reactions of oxime ether 12a
(Table 3, entries 2, 3, and 5)
Oxime ether 12a (50 mg, 0.14 mmol) was dissolved in toluene (6 mL) under air atmosphere. To a solution of oxime ether 12a in toluene were added corresponding alkyl iodide (1.4 or 2.8 mmol) and Et3B (1.01M in n-hexane) (0.35 or 0.70 mmol) under a nitrogen atmosphere at –78 °C. After being stirred at the same temperature for 1 h, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with CHCl3. The organic phase was washed with brine, dried over MgSO4, and concentrated under reduced pressure. Purification of the residue by MCC (n-hexane:AcOEt = 3:1) afforded cyclized products 27A, B, D and 28A, B, D as shown in Table 3.

Ethyl (3R*,4R*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-(2-methylpropyl)-3-pyrrolidinecarboxylate (cis-27A)
A colorless oil; IR (CHCl3) 3552, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.75 (2H, br d, J = 8 Hz), 7.34 (2H, br d, J = 8 Hz), 5.73 (1H, br d, J = 4 Hz), 4.16-4.06 (2H, m), 3.56 (1H, dd, J = 11, 6 Hz), 3.55 (1H, d, J = 10 Hz), 3.45 (1H, d, J = 10 Hz), 3.38-3.33 (1H, m), 3.29 (1H, dd, J = 11, 3 Hz), 3.16 (3H, s), 2.43 (3H, s), 1.68-1.58 (2H, m), 1.40-1.36 (1H, m), 1.23 (3H, t, J = 7 Hz), 0.84 (3H, d, J = 6 Hz), 0.79 (3H, d, J = 6 Hz); 13C NMR (125 MHz, CDCl3) δ: 172.2, 143.4, 133.6, 129.5, 127.6, 66.5, 61.8, 61.0, 55.0, 52.0, 49.7, 44.1, 24.8, 24.0, 23.0, 21.4, 13.9; HRMS (EI, m/z) calcd for C19H30N2O5S (M+) 398.1873, found 398.1885.

Ethyl (3R*,4S*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-(2-methylpropyl)-3-pyrrolidinecarboxylate (trans-28A)
A colorless oil; IR (CHCl3) 3690, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.73 (2H, br d, J = 8 Hz), 7.32 (2H, br d, J = 8 Hz), 5.55 (1H, br s), 4.10-3.98 (2H, m), 3.82 (1H, d, J = 10 Hz), 3.77-3.73 (1H, m), 3.44 (1H, dd, J = 10, 4 Hz), 3.39 (1H, dd, J = 10, 6 Hz), 3.33 (3H, s), 3.24 (1H, d, J = 10 Hz), 2.43 (3H, s), 1.62 (1H, dd, J = 13.5, 6 Hz), 1.56-1.47 (1H, m), 1.44 (1H, dd, J = 13.5, 6 Hz), 1.20 (3H, t, J = 7 Hz), 0.84 (3H, d, J = 6 Hz), 0.83 (3H, d, J = 6 Hz); 13C NMR (125 MHz, CDCl3) δ: 173.5, 143.3, 134.0, 129.6, 127.5, 63.6, 62.0, 61.3, 55.5, 53.9, 50.4, 38.5, 25.5, 23.5, 23.3, 21.5, 13.9. HRMS (EI, m/z) calcd for C19H30N2O5S (M+) 398.1873, found 398.1899.

Ethyl (3R*,4R*)-4-(Methoxyamino)-3-(2-methylbutyl)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinecarboxylate (cis-27B)
A colorless oil; IR (CHCl3) 3546, 1724 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.75 (2H, br d, J = 8 Hz), 7.34 (2H, br d, J = 8 Hz), 4.16-4.06 (2H, m), 3.58 (1/2H, dd, J = 10.5, 6 Hz), 3.57 (1/2H, dd, J = 13, 7 Hz), 3.53 (1H, br d, J = 10 Hz), 3.44 (1/2H, d, J = 10 Hz), 3.43 (1/2H, d, J = 10 Hz), 3.38-3.35 (1H, m), 3.33 (1/2H, dd, J = 13, 5 Hz), 3.30 (1/2H, dd, J = 10.5, 3 Hz), 3.15 (3/2H, s), 3.14 (3/2H, s), 2.42 (3H, s), 1.68 (1/2H, dd, J = 14, 4 Hz), 1.56 (1/2H, dd, J = 14, 7.5 Hz), 1.49 (1/2H, dd, J = 14, 4 Hz), 1.41-1.33 (1H, m), 1.32 (1/2H, dd, J = 14, 7 Hz), 1.239 (3/2H, t, J = 7 Hz), 1.236 (3/2H, t, J = 7 Hz), 1.25-1.15 (1H, m), 1.13-1.02 (1H, m), 0.84 -0.75 (6H, m). NOE was observed between 4-H (δ 3.38-3.35) and 3-CH2 (δ 1.68, 1.56, 1.49, 1.3) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 172.4, 172.3, 143.4, 133.72, 133.66, 129.59, 129.58, 127.66, 127.65, 66.5, 66.1, 61.91, 61.85, 61.0, 55.1, 55.0, 52.7, 51.8, 49.79, 49.78, 42.5, 42.4, 31.1, 30.9, 30.8, 30.3, 21.5, 20.6, 19.7, 14.00, 13.98, 11.14, 11.10; HRMS (EI, m/z) calcd for C20H32N2O5S (M+) 412.2030, found 412.2051.

Ethyl (3R*,4S*)-4-(Methoxyamino)-3-(2-methylbutyl)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidine- carboxylate (trans-28B)
A colorless oil; IR (CHCl3) 3660, 1724 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.73 (2H, br d, J = 8 Hz), 7.32 (2H, br d, J = 8 Hz), 4.10-3.97 (2H, m), 3.84 (5/11H, d, J = 10 Hz), 3.79 (6/11H, d, J = 10 Hz), 3.77 (5/11H, dd, J = 6, 3 Hz), 3.74 (6/11H, dd, J = 6, 4 Hz), 3.47-3.35 (2H, m), 3.35 (18/11H, s), 3.33 (15/11H, s), 3.25 (6/11H, d, J = 10 Hz), 3.24 (5/11H, d, J = 10 Hz), 2.43 (3H, s), 1.73 (6/11H, dd, J = 14, 4 Hz), 1.57 (5/11H, dd, J = 14, 5 Hz), 1.51 (5/11H, dd, J = 14, 7 Hz), 1.37 (6/11H, dd, J = 14, 7.5 Hz), 1.30-1.18 (3H, m), 1.21 (18/11H, t, J = 7 Hz), 1.20 (15/11H, t, J = 7 Hz), 0.83-0.78 (6H, m); 13C NMR (125 MHz, CDCl3) δ: 173.5, 173.4, 143.4, 143.3, 134.1, 134.0, 129.58, 129.57, 127.6, 63.7, 63.5, 62.08, 62.05, 61.4, 55.7, 55.4, 54.2, 53.7, 50.5, 50.3, 37.1, 36.2, 31.7, 31.6, 30.5, 30.4, 21.5, 20.0, 19.6, 13.9, 11.24, 11.20; HRMS (EI, m/z) calcd for C20H32N2O5S (M+) 412.2030, found 412.2041.

Ethyl (3R*,4R*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-(2,2-dimethylpropyl)-3-pyrrolidinecarboxylate (cis-27D)
A colorless oil; IR (CHCl3) 3548, 1724 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.75 (2H, br d, J = 8 Hz), 7.34 (2H, br d, J = 8 Hz), 4.15-4.03 (2H, m), 3.64 (1H, d, J = 10 Hz), 3.59 (1H, dd, J = 10.5, 6 Hz), 3.57 (1H, d, J = 10 Hz), 3.37 (1H, dd, J = 6, 4 Hz), 3.19 (1H, dd, J = 10.5, 4 Hz), 3.19 (3H, s), 2.43 (3H, s), 1.84 (1H, d, J = 14.5 Hz), 1.48 (1H, d, J = 14.5 Hz), 1.24 (3H, t, J = 7 Hz), 0.90 (9H, s); 13C NMR (125 MHz, CDCl3) δ: 172.4, 143.4, 133.9, 129.6, 127.6, 67.6, 61.9, 61.1, 54.7, 52.8, 49.2, 48.2, 31.7, 30.6, 21.5, 13.8; HRMS (EI, m/z) calcd for C20H32N2O5S (M+) 412.2030, found 412.2027.

Ethyl (3R*,4S*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-(2,2-dimethylpropyl)-3-pyrrolidinecarboxylate (trans-28D)
A colorless oil; IR (CHCl3) 3547, 1724 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.73 (2H, br d, J = 8 Hz), 7.32 (2H, br d, J = 8 Hz), 4.07-3.93 (2H, m), 3.99 (1H, d, J = 10 Hz), 3.79 (1H, br dd, J = 5, 2 Hz), 3.49 (1H, dd, J = 10.5, 2 Hz), 3.33 (3H, s), 3.26 (1H, dd, J = 10.5, 5.5 Hz), 3.21 (1H, d, J = 10 Hz), 2.43 (3H, s), 1.79 (1H, d, J = 14 Hz), 1.56 (1H, d, J = 14 Hz), 1.19 (3H, t, J = 7 Hz,), 0.88 (9H, s); 13C NMR (125 MHz, CDCl3) δ: 173.6, 143.2, 134.5, 129.5, 127.5, 64.9, 62.0, 61.4, 55.5, 54.3, 49.6, 43.0, 31.4, 30.3, 21.5, 13.7; HRMS (EI, m/z) calcd for C20H32N2O5S (M+) 412.2030, found 412.2026.

Ethyl (3R*,4R*)-3-Cyclohexylmethyl-4-(methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinecarboxylate (cis-27C) and ethyl (3R*,4S*)-3-cyclohexylmethyl-4-(methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinecarboxylate (trans-28C) (Table 3, entry 4)
Oxime ether 12a (50 mg, 0.14 mmol) was dissolved in toluene (6 mL) under air atmosphere. To a solution of oxime ether 12a in toluene were added cyclohexyl iodide (296.5 mg, 1.4 mmol) and Et3B (1.01M in n-hexane) (0.37 mL, 0.35 mmol) under a nitrogen atmosphere at –78 °C. After being stirred at the same temperature for 30 min, an additional cyclohexyl iodide (296.5 mg, 1.4 mmol) and Et3B (1.01M in n-hexane) (0.37 mL, 0.35 mmol) were added to the solution. After being stirred at the same temperature for 30 min, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with CHCl3. The organic phase was washed with brine, dried over MgSO4, and concentrated under reduced pressure. Purification of the residue by MCC (n-hexane:AcOEt = 3:1) afforded cyclized products 27C and 28C.
cis-27C. Colorless crystals; mp 100-101 °C (n-hexane/CHCl3); IR (CHCl3) 3552, 1724 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.75 (2H, br d, J = 8 Hz), 7.32 (2H, br d, J = 8 Hz), 4.16-4.05 (2H, m), 3.56 (1H, dd, J = 11, 6 Hz), 3.55 (1H, d, J = 10 Hz), 3.43 (1H, d, J = 10 Hz), 3.36 (1H, dd, J = 6, 3 Hz), 3.31 (1H, dd, J = 11, 3 Hz), 3.17 (3H, s), 2.42 (3H, s), 1.66-1.55 (3H, m), 1.60 (1H, dd, J = 14, 7 Hz), 1.52-1.46 (2H, m), 1.33 (1H, dd, J = 14, 5 Hz), 1.30-1.02 (4H, m), 1.23 (3H, t, J = 7 Hz), 0.91-0.77 (2H, m). NOE was observed between 4-H (δ 3.36) and 3-CH2 (δ 1.60, 1.33) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 172.3, 143.4, 133.7, 129.6, 127.6, 66.5, 61.9, 61.0, 54.8, 52.2, 49.8, 43.0, 34.5, 34.2, 33.7, 26.13, 26.12, 26.0, 21.5, 14.0; HRMS (EI, m/z) calcd for C22H34N2O5S (M+) 438.2186, found 438.2188; Anal. Calcd for C22H34N2O5S : C, 60.25; H, 7.81; N, 6.39. Found : C, 60.26; H, 7.81; N, 6.38.
trans-28C. A colorless oil; IR (CHCl3) 3551, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.73 (2H, br d, J = 8 Hz), 7.33 (2H, br d, J = 8 Hz), 4.12-3.98 (2H, m), 3.82 (1H, d, J = 10 Hz), 3.74 (1H, dd, J = 6, 4 Hz), 3.42 (1H, dd, J = 10, 4 Hz), 3.40 (1H, dd, J = 10, 6 Hz), 3.33 (3H, s), 3.23 (1H, d, J = 10 Hz), 2.43 (3H, s), 1.66-1.49 (5H, m), 1.41 (1H, dd, J = 14, 6 Hz), 1.28-1.04 (5H, m), 1.20 (3H, t, J = 7 Hz), 0.91-0.80 (2H, m); 13C NMR (125 MHz, CDCl3) δ: 173.5, 143.4, 134.1, 129.6, 127.6, 63.7, 62.1, 61.3, 55.3, 53.9, 50.4, 37.2, 34.8, 34.1, 33.8, 26.2, 26.1, 26.0, 21.5, 14.0; HRMS (EI, m/z) calcd for C22H34N2O5S (M+) 438.2186, found 438.2175.

General procedure for alkyl radical addition-cyclization reactions of oxime ether 12a
(Table 3, entries 6-9)
Oxime ether 12a (50 mg, 0.14 mmol) was dissolved in toluene (10 mL) under air atmosphere. To a solution of oxime ether 12a in toluene were added corresponding alkyl iodide (0.70 or 2.10 mmol) and Et3B (1.01M in n-hexane) (0.10 mL, 0.105 mmol) under a nitrogen atmosphere at 0 °C. After being stirred at the same temperature for 15 min, Three further portions of corresponding alkyl iodide (0.70 or 2.10 mmol) and Et3B (1.01M in n-hexane) (each 0.10 mL, 0.105 mmol) were added at 15 min intervals. After being stirred at the same temperature for 1 h, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with CHCl3. The organic phase was washed with brine, dried over MgSO4, and concentrated under reduced pressure. Purification of the residue by MCC (n-hexane:AcOEt = 7:1-5:1) afforded cyclized products 27E-H and 28E-H as shown in Table 3. 1-Iodotridecane, methyl 11-iodoundecanoate, and 2-iododecane were prepared according to the literature procedure.15

Ethyl (3R*,4R*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-undecanyl-3-pyrrolidinecarboxylate (cis-27E)
A colorless oil; IR (CHCl3) 3550, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.75 (2H, br d, J = 8 Hz), 7.33 (2H, br d, J = 8 Hz), 5.75 (1H, br s), 4.12 (2H, q, J = 7 Hz), 3.54 (1H, dd, J = 10.5, 6 Hz), 3.52 (1H, d, J = 10 Hz), 3.41 (1H, d, J = 10 Hz), 3.39 (1H, dd, J = 6, 3 Hz), 3.33 (1H, dd, J = 10.5, 3 Hz), 3.17 (3H, s), 2.42 (3H, s), 1.62-1.46 (1H, m), 1.38-1.00 (19H, m), 1.22 (3H, t, J = 7 Hz), 0.88 (3H, t, J = 7 Hz). NOE was observed between 4-H (δ 3.39) and 3-CH2 (δ 1.62-1.46) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 171.9, 143.4, 133.7, 129.6, 127.6, 66.0, 63.1, 61.9, 61.0, 55.5, 52.0, 50.0, 35.9, 29.62, 29.59, 29.58, 29.57, 29.53, 29.50, 29.4, 29.3, 24.5, 21.5, 14.1. HRMS (EI, m/z) calcd for C26H44N2O5S (M+) 496.2968, found 496.2966.

Ethyl (3R*,4S*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-undecanyl-3-pyrrolidinecarboxylate (trans-28E)
A colorless oil; IR (CHCl3) 3550, 1724 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.72 (2H, br d, J = 8 Hz), 7.32 (2H, br d, J = 8 Hz), 5.59 (1H, br s), 4.14-4.00 (2H, m), 3.75 (1H, dd, J = 6, 4.5 Hz), 3.73 (1H, d, J = 10 Hz), 3.47 (1H, dd, J=10, 6 Hz), 3.39 (1H, dd, J = 10, 4.5 Hz), 3.35 (3H, s), 3.24 (1H, d, J = 10 Hz), 2.43 (3H, s), 1.60 (1H, ddd, J = 13, 12, 4.5 Hz), 1.40 (1H, ddd, J = 13, 11, 5 Hz), 1.34-1.04 (18H, m), 1.20 (3H, t, J = 7 Hz), 0.88 (3H, t, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 173.2, 143.4, 133.9, 129.6, 127.5, 62.7, 62.0, 61.3, 55.7, 53.6, 50.7, 31.9, 30.0, 29.8, 29.6, 29.55, 29.46, 29.29, 29.27, 25.1, 22.6, 21.5, 14.1, 14.0; HRMS (EI, m/z) calcd for C26H44N2O5S (M+) 496.2968, found 496.2972.

Ethyl (3R*,4R*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-tetradecanyl-3-pyrrolidinecarboxylate (cis-27F)
Colorless crystals; mp. 54-54.5 °C (n-hexane); IR (CHCl3) 3510, 1724 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.75 (2H, br d, J = 8 Hz), 7.33 (2H, br d, J = 8 Hz), 4.12 (2H, q, J = 7 Hz), 3.54 (1H, dd, J = 10.5, 6 Hz), 3.52 (1H, d, J = 10 Hz), 3.40 (1H, d, J = 10 Hz), 3.39 (1H, dd, J = 6, 3 Hz), 3.33 (1H, dd, J = 10.5, 3 Hz), 3.17 (3H, s), 2.42 (3H, s), 1.62-1.46 (1H, m), 1.38-1.00 (25H, m), 1.22 (3H, t, J = 7 Hz), 0.88 (3H, t, J = 7 Hz). NOE was observed between 4-H (δ 3.39) and 3-CH2 (δ 1.62-1.46) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 171.9, 143.5, 133.7, 129.6, 127.6, 66.0, 63.1, 62.0, 61.0, 55.5, 52.0, 50.0, 36.0, 32.8, 31.9, 29.67, 29.65, 29.59, 29.52, 29.4, 29.35, 29.32, 25.7, 24.5, 22.7, 21.5, 14.1; HRMS (EI, m/z) calcd for C29H50N2O5S (M+) 538.3438, found 538.3432; Anal. Calcd for C29H50N2O5S : C, 64.65; H, 9.35; N, 5.20. Found : C, 64.64; H, 9.30; N, 5.18.

Ethyl (3R*,4S*)-4-(Methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-tetradecanyl-3-pyrrolidinecarboxylate (trans-28F)
A colorless oil; IR (CHCl3) 3570, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.72 (2H, br d, J = 8 Hz), 7.32 (2H, br d, J = 8 Hz), 4.10-4.00 (2H, m), 3.75 (1H, dd, J = 6, 4 Hz), 3.73 (1H, d, J = 10 Hz), 3.47 (1H, dd, J = 10.5, 6 Hz), 3.39 (1H, dd, J = 10.5, 4 Hz), 3.35 (3H, s), 3.24 (1H, d, J = 10 Hz), 2.43 (3H, s), 1.60-1.54 (1H, m), 1.44-1.36 (1H, m), 1.36-1.00 (24H, m), 1.20 (3H, t, J = 7 Hz), 0.88 (3H, t, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 173.3, 143.4, 134.0, 129.6, 127.6, 63.1, 62.8, 62.0, 61.3, 55.8, 53.6, 50.7, 32.8, 30.0, 29.8, 29.7, 29.64, 29.61, 29.59, 29.5, 29.4, 29.35, 29.31, 25.7, 25.1, 21.5, 14.0. HRMS (EI, m/z) calcd for C29H50N2O5S (M+) 538.3438, found 538.3422.

Methyl 3-(Ethoxycarbonyl)-4-(methoxyamino)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinedodecanoate (27G and 28G)
Cyclized products 27G and 28G (70:30) were inseparable. A colorless oil; IR (CHCl3) 3527, 1729 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.75 (2H, br d, J = 8 Hz), 7.34 (2H, br d, J = 8 Hz), 4.18-4.00 (2H, m), 3.67 (3H, s), 3.60-3.10 (5H, m), 3.35 (9/10H, s), 3.16 (21/10H, s), 2.43 (3H, s), 2.35 (6/10H, t, J = 7 Hz), 2.30 (14/10H, t, J = 7 Hz), 1.80-1.00 (20H, m), 1.24 (9/10H, t, J = 7 Hz), 1.23 (21/10H, t, J = 7 Hz); 13C NMR (75 MHz, CDCl3) δ: 174.3, 172.2, 143.4, 135.5, 129.6, 127.6, 66.1, 61.9, 61.0, 55.5, 51.9, 51.4, 49.9, 49.7, 34.1, 33.7, 30.4, 29.4, 29.2, 29.1, 28.4, 26.7, 24.9, 21.5, 21.0, 14.1; HRMS (EI, m/z) calcd for C28H46N2O7S (M+) 554.3023, found 554.3029.

Ethyl (3R*,4R*)-4-(Methoxyamino)-3-(2-methyldecanyl)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinecarboxylate (cis-27G and cis-27G’)
The stereostructures of the cis-27G and cis-27G’ (59:41) have not been established. The minor less polar product; A colorless oil; IR (CHCl3) 3556, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.75 (2H, br d, J = 8 Hz), 7.33 (2H, br d, J = 8 Hz), 4.10 (2H, br q, J = 7 Hz), 3.56 (1H, dd, J = 10.5, 6 Hz), 3.54 (1H, d, J = 9.5 Hz), 3.45 (1H, d, J = 9.5 Hz), 3.36 (1H, dd, J = 6, 3 Hz), 3.30 (1H, dd, J = 10.5, 3 Hz), 3.16 (3H, s), 2.42 (3H, s), 1.67 (1H, dd, J = 14, 4.5 Hz), 1.50-1.36 (1H, m), 1.31 (1H, dd, J = 14, 7 Hz), 1.34-0.98 (14H, m), 1.24 (3H, t, J = 7 Hz), 0.88 (3H, t, J = 7 Hz), 0.82 (3H, d, J = 7 Hz). NOE was observed between 4-H (δ 3.36) and 3-CH2 (δ 1.67, 1.31) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 172.3, 143.4, 133.7, 129.6, 127.7, 66.2, 61.9, 61.0, 55.1, 52.7, 49.8, 42.9, 37.9, 31.9, 29.8, 29.6, 29.3, 26.8, 22.6, 21.5, 21.0, 14.1, 14.0. HRMS (EI, m/z) calcd for C26H44N2O5S (M+) 496.2969, found 496.2970. The major more polar product; A colorless oil; IR (CHCl3) 3530, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.75 (2H, br d, J = 8 Hz), 7.33 (2H, br d, J = 8 Hz), 5.75 (1H, br s), 4.15-4.06 (2H, m), 3.57 (1H, dd, J = 11, 6 Hz), 3.53 (1H, d, J = 10 Hz), 3.42 (1H, d, J = 10 Hz), 3.36 (1H, dd, J = 6, 3 Hz), 3.30 (1H, dd, J = 11, 3 Hz), 3.14 (3H, s), 2.42 (3H, s), 1.56 (1H, dd, J = 14, 8 Hz), 1.49 (1H, dd, J = 14, 4 Hz), 1.50-1.40 (1H, m), 1.32-1.00 (14H, m), 1.24 (3H, t, J = 7 Hz), 0.89 (3H, t, J = 7 Hz), 0.76 (3H, d, J = 7 Hz). NOE was observed between 4-H (δ 3.36) and 3-CH2 (δ 1.56, 1.49) in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) δ: 172.4, 143.4, 133.7, 129.6, 127.7, 66.5, 61.9, 61.1, 55.1, 52.0, 49.8, 42.8, 38.4, 31.9, 29.9, 29.6, 29.5, 29.3, 26.8, 22.7, 21.5, 20.2, 14.1, 14.0; HRMS (EI, m/z) calcd for C26H44N2O5S (M+) 496.2969, found 496.2975.

Ethyl (3R*,4S*)-4-(Methoxyamino)-3-(2-methyldecanyl)-1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinecarboxylate (trans-28G and trans-28G’)
The stereostructures of the trans-28G and trans-28G’ (57:43) have not been established. The minor less polar product; A colorless oil; IR (CHCl3) 3525, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.73 (2H, br d, J = 8 Hz), 7.32 (2H, br d, J = 8 Hz), 4.09-3.97 (2H, m), 3.84 (1H, d, J = 10 Hz), 3.76 (1H, dd, J = 6, 3.5 Hz), 3.44 (1H, dd, J = 11, 3.5 Hz), 3.37 (1H, dd, J = 11, 6 Hz), 3.33 (3H, s), 3.23 (1H, d, J = 10 Hz), 2.43 (3H, s), 1.72 (1H, dd, J = 13, 4 Hz), 1.35 (1H, dd, J = 13, 8 Hz), 1.36-1.14 (15H, m), 1.20 (3H, t, J = 7 Hz), 0.88 (3H, t, J = 7 Hz), 0.80 (3H, d, J = 6 Hz); 13C NMR (125 MHz, CDCl3) δ: 173.5, 143.3, 134.1, 129.6, 127.6, 63.8, 62.0, 61.4, 55.7, 54.2, 50.3, 38.0, 37.5, 31.9, 30.1, 29.8, 29.6, 29.3, 26.9, 22.6, 21.5, 20.4, 14.1, 13.9; HRMS (EI, m/z) calcd for C26H44N2O5S (M+) 496.2969, found 496.2966. The major more polar product; A colorless oi; IR (CHCl3) 3551, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ: 7.73 (2H, br d, J = 8 Hz), 7.32 (2H, br d, J = 8 Hz), 5.77 (1H, br s), 4.10-3.97 (2H, m), 3.79 (1H, d, J = 10 Hz), 3.74 (1H, dd, J = 6, 4 Hz), 3.44 (1H, dd, J = 10.5, 4 Hz), 3.41 (1H, dd, J = 10.5, 6 Hz), 3.33 (3H, s), 3.23 (1H, d, J = 10 Hz), 2.43 (3H, s), 1.54 (1H, dd, J = 14, 5 Hz), 1.34-1.00 (16H, m), 1.21 (3H, t, J = 7 Hz), 0.89 (3H, t, J = 7 Hz), 0.80 (3H, d, J = 7 Hz); 13C NMR (125 MHz, CDCl3) δ: 173.6, 143.3, 134.1, 129.6, 127.6, 63.5, 62.1, 61.4, 55.4, 53.8, 50.6, 38.0, 36.6, 31.9, 30.1, 29.8, 29.6, 29.3, 26.9, 22.7, 21.5, 20.0, 14.1, 13.9; HRMS (EI, m/z) calcd for C26H44N2O5S (M+) 496.2969, found 496.2975.

ACKNOWLEDGEMENTS
This work was supported by Grants-in Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and the MEXT-Supported Program for the Strategic Research Foundation at Private Universities.

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