HETEROCYCLES

Paper | Special issue | Vol. 77, No. 1, 2009, pp. 417-432
Received, 2nd July, 2008, Accepted, 18th August, 2008, Published online, 21st August, 2008.
DOI: 10.3987/COM-08-S(F)37

■ Synthesis of 5-Amino and 4-Hydroxy-2-phenylsulfonylmethylpiperidines

Julien Massé and Nicole Langlois*

Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France

Abstract

Suitable protected 5-amino- and 4-hydroxy- 2-phenylsulfonylmethylpiperidines were synthesized from functionalized N-benzyloxycarbonylpiperidin-2-ones through the opening of lactam ring by methyl phenyl sulfone carbanion followed by reductive aminocyclization.

INTRODUCTION
Many functionalized piperidines constitute structural subunits in natural as well as synthetic products which could exhibit interesting biological activities and a wide range of methodologies have been reported for their syntheses.1 In this context, 5-amino and 4-hydroxy- 2-phenylsulfonylmethylpiperidines 1 and 2 are interesting targets as scaffolds to synthesize, respectively, simplified deoxy- or deamino-analogues of pseudodistomins such as 4, by further elaboration of poly-unsaturated chains at C-2. Pseudodistomin C (4) is an all cis 2,4,5-trisubstituted piperidine of marin origin which displays cytotoxic activities.2 We developed some years ago a stereoselective and original access to the intermediate 3,3 which has been previously converted into 4,4 through Julia or Julia-Kocienski olefination to generate the 2-(1E,3E)-dienyl chain at C-2.5, 6
In addition, O-protected 4-hydroxy-2-phenylsulfonylmethylpiperidines 2 could also be the precusors of 4-hydroxy-2-(1,3-pentadienyl)piperidines 5. Several diastereomers of 5 have been isolated from Streptomyces strains.7 Whereas trans (2S,4S)-5 exhibits antibacterial and anticonvulsant activities, DNA-binding properties have been attributed to its enantiomer,7b and the cis derivative (2S,4R) was proposed as an intermediate in the biosynthesis of the potent antimicrobial agent streptazolin.7a,8 Therefore, the synthesis of these compounds have attracted much interest.9

We report herein the preparation of substituted 2-arylsulfonylmethylpiperidines of general structure 1 and 2 by a similar route depicted in the Scheme 1. This involved the opening of appropriate functionalized N-alkoxycarbonylpiperidinones A with anion of a methyl sulfone such as 6 or 7, and reductive aminocyclization of the corresponding β-ketosulfones B, leading to target substituted piperidines.

RESULTS AND DISCUSSION
Accordingly, our investigations began with the preparation of appropriate protected 5-amino- and 4-hydroxy-piperidinones 15, 16 and 21.
The protected 1-alkoxycarbonyl-5-aminopiperidinones 15 and 16 were prepared from enantiopure (S)-5-tert-butoxycarbonylaminopiperidin-2-one 12, following the Scheme 2. The intermediate 12 has been obtained from (S)-pyroglutaminol derivative 810 by a convenient, short and efficient route previously developed in our labortory.3,11 It involved an intramolecular transamidation of 1-alkoxycarbonyl-5-aminomethylpyrrolidin-2-one 11 obtained from 8 through the mesylate (9) (95%) and the azidomethyl derivative (10) (96%). Without isolation of 11, the conversion of 10 into 12 was almost quantitative. We demonstrated the superiority of this route to the pathways involving intramolecular Mitsunobu reactions,12,13 and its interest has been confirmed afterwards by several recent examples.14

Dually protected 5-amino group was needed to prevent side reactions. Accordingly, N,N’-tricarbamates 15 and 16 were stepwise prepared. These sequential protections are not obvious since the possibility of ring contraction could not be excluded. Thus, the 5-substituted piperidinone 12 was first protected as 1-tert-butylcarbamate 13 or 1-benzylcarbamate 14. N-tert-Butylcarbamate 13 was obtained in 90% yield under classical conditions (DMAP, Boc2O in MeCN), whereas orthogonally protected 1-benzyloxycarbonyl compound 14 could be isolated only in moderate yield (60%) under Kikugawa’s conditions using LiHMDS as base and benzyl chloroformate at –78 °C.15 Subsequent N-Boc protections to provide 15 and 16 were introduced respectively with 77% and 67% yield. The presence of six-membered ring in 15 and 16 was confirmed by IR absorption in the range of carbonyl, excluding a reverse transamidation reaction.

In the 4-hydroxypiperidine series, we chose to focus our study toward the synthesis of racemic cis-4-tert-butyldimethylsilyloxy-2-phenylsulfonylmethylpiperidine 33 from 1-benzyloxycarbonyl-4-tert- butyldimethylsilyloxypiperidin-2-one 21. Starting from inexpensive piperidinone monohydrate hydrochloride 17, the piperidinone 21 was prepared in high yields as outlined in the Scheme 3.

In our hands, benzyl chloroformate was shown to be more efficient than N-benzyloxycarbonyloxysuccinimide to protect nitrogen,16 affording 18 in 99% yield. Further reduction with NaBH4 under classical conditions provided the known N-Cbz-piperidin-4-ol 19 in 99% yield.17 The corresponding TBS ether 2017c,18 was oxidized into lactam 2119 in 78%, with RuCl3/NaIO4 under biphasic conditions.20
With the piperidinones 15, 16 and 21 in hands, we investigated their conversion into acyclic β-ketosulfones.
N-tert-Butoxycarbonylvalerolactam 22 was used as a model to compare the ring opening step with carbanions of methyl phenyl sulfone 6 and methyl 1-phenyl-1H-tetrazol-5-yl sulfone 7, respectively. As we observed in the cases of 1-alkoxycarbonylpyrrolidinone nucleophilic opening,21 methyl sulfones 6 and 7 in THF were deprotonated with nBuLi, at –78 °C and the N-alkoxycarbonylpiperidinone gave rise rapidly at the same temperature to the expected acyclic β-ketosulfones 2322 and 24 (Scheme 4).

β-Ketosulfone 23 obtained by using methyl phenyl sulfone 6 was isolated in better yields (91%) than 24 (71%) formed with methyl sulfone 7, the difference being significant. For this reason, the other functionalized N-alkoxycarbonylpiperidinones 15, 16 and 21 were opened with 6 carbanion (Scheme 5), and the results are summarized in the Table 1.

The opening of N-Boc protected piperidinone 22 and 25 occurred with high regioselectivity, and the β-ketosulfones 23 and 26 were the sole products obtained. In the case of 15, some nucleophilic attack of one of nitrogen Boc protecting groups was also observed (probably N1Boc) with the formation of an acyclic disulfone (ca 9%), while the treatment of 21 afforded 29 in 78% yield, together with small amount (less than 4%) of 4-tert-butyldimethylsilyloxypiperidin-2-one by loss of the Cbz protecting group.

Reductive aminocyclizations were investigated on the N-Cbz ketosulfones 26, 28 and 29.
With the model ketosulfone 26, one-pot hydrogenolysis of benzyl carbamate (H2, 10% Pd/C) and cyclization–reduction into 30 occurred in good yields after 30 h (80%). With substituted ketosulfone 28, the reaction was much slower under the same conditions and some starting material was recovered after 48 h (ca 20%). An equilibrium between the imine intermediate and a conjugate enamine could be involved during this aminocyclization step.22 Two diastereomers of 2,5-disubstituted piperidines 31 and 32 were formed (70% yield) in ca 1:2 ratio. Their configurations were deduced from NMR spectroscopy. To avoid overlapping of several signals, C6D6 was used as solvent for 1H and 2D experiments with minor diastereomer 31. The doublet of doublet at 3.23 ppm (with two large coupling constants J = J’ = 10.9 Hz) could be assigned to H-6ax confirming the axial position of vicinal H-5. The coupling pattern of the signal at 3.03 ppm attributed to H-2 is also compatible with an axial position, and NOE were observed between H-5 and H-3ax, H-6ax and H-4ax, H-4ax and H-2, supporting a trans 2,5 configuration as shown in Figure 1. In the major diastereomer 32, a small NOE effect between H-4ax and the methylene of the phenylsulfonylmethyl group is compatible with an axial position of this group and a cis 2,5 relative configuration as shown in Figure 2.

With benzyl 3-(tert-butyldimethylsilyloxy)-5-oxo-6-(phenylsulfonyl)hexylcarbamate 29, the cis-2,4-substituted piperidine 33 was isolated only in moderate yield (53%), together with starting material. It is worthy of note that the product of O-desilylation was not identified under these conditions of hydrogenolysis.23 The attribution of relative cis configuration of 4-tert-butyldimethylsilyloxy-2- phenylsulfonylmethylpiperidinone 33 was based on steric factors and supported by the comparison of the chemical shifts and coupling constants with the data described for the two diastereomers of 4-hydroxy-2-(1,3-pentadienyl)piperidines 5.7,9a,b NOESY experiment indicated correlations between H-6ax and H-4 and between H-6ax and H-2 as shown in Figure 3.

In conclusion, cis and trans 5S-(bis(tert-butoxycarbonyl)amino)-2-phenylsulfonylmethylpiperidines were prepared through opening of appropriate substituted N-Cbz-lactam, followed by reductive aminocyclization. These polysubstituted piperidines constitute interesting building blocks for the synthesis of pseudodistomin deoxy analogues owing to the presence of a phenyl sulfone function which would allow the introduction of various polyunsaturated side chains at position α to the nitrogen. Starting from 21, the synthesis of 33 occurred with good stereoselectivity, and this work could be extended to the synthesis of enantiopure counterparts.24

EXPERIMENTAL
General. Melting points were uncorrected. NMR spectra were recorded on a Bruker spectrometer at 300 or 500 MHz for 1H NMR, 75 or 125 MHz for 13C NMR; chemical shifts are given in ppm relative to residual CHCl3 (7.27 ppm for 1H NMR and 77.14 ppm for the middle line in 13C NMR); s, d, t, dd and m indicate singlet, doublet, triplet, doublet of doublets, and multiplet, respectively. Mass spectra and high-resolution mass spectra (m/z) were measured using ESI. All moisture sensitive reactions were performed under argon. THF was freshly distilled from the sodium complex of benzophenone before use. Dichloromethane was freshly distilled from CaH2. Column chromatography was performed on silica gel (SDS 230-400 mesh) and preparative thin layer chromatography (TLC) on silica gel (Merck HF 254 + 366).

(S)-tert-Butyl 2-(methylsulfonyloxy)methyl-5-oxopyrrolidine-1-carboxylate (9)
Mesyl chloride (3.3 mL, 42.4 mmol) was added dropwise under inert atmosphere to a stirred solution of N-Bocpyroglutaminol (4.563 g, 21.2 mmol) in dry pyridine (100 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h and at rt for 3 h. After cooling at 0 °C, the mixture was diluted with CH2Cl2 and aqueous Na2CO3 (10% w/v, 150 mL), was added. The mesylate was extracted with CH2Cl2, purified by filtration on silica gel (eluent : EtOAc-MeOH 9 : 1) and obtained as colorless crystals (5.91 g, 95%). Mp 80-81 °C. [α]D26 – 65 (c 2.0, CHCl3) lit.,25 ent-9: + 64.4 (c 1.00, EtOH). IR: 3030, 2933, 1787, 1748(sh), 1707, 1364 cm–1. 1H NMR (300 MHz, CDCl3): 4.60, 4.35 (2 dd, 2H, H2-6), 4.41 (masked m, 1H, H-5), 3.03 (s, 3H, SMe), 2 .70, 2.50, 2.25, 2.07 (4 m, 4H, H2-3, H2-4), 1.54 (s, 9H, t-Bu) ppm.

(S)-tert-Butyl 2-(azidomethyl)-5-oxopyrrolidine-1-carboxylate (10)
NaN3 (5.78 g, 89.0 mmol) was added to a solution of mesylate 9 (5.214 g, 17.8 mmol) in DMF (53.4 mL). The mixture was stirred under argon at 50 °C for 10 h, cooled to rt, diluted with H2O and extracted with Et2O. The organic layers were washed with H2O and afforded azido-derivative 10 as colorless gum after usual workup (4.10 g, 96%). [α]D26 – 43 (c 0.65, CHCl3). IR: 2990, 2111, 1786, 1746, 1711 cm–1. MS (ESI, CH2Cl2-MeOH) m/z: 263 [(MNa)+, 100%]. 1H NMR (300 MHz, CDCl3): 4.27 (m, 1H, H-5), 3.67 (dd, 1H, J = 12.3, J’ = 5.7 Hz, Ha-6), 3.54 (dd, 1H, J = 12.3, J’ = 3.0 Hz, Hb-6), 2.70, 2.43, 2.16, 1.93 (4m, 4H, H2-3, H2-4), 1.55 (s, 9H, t-Bu) ppm. 13C NMR (75 MHz, CDCl3): 173.9, 149.8, 83.5, 56.6, 53.7, 31.4, 28.0, 21.3 ppm. HRMS (ESI, CH2Cl2-MeOH) m/z: calcd for C10H16N4O3Na (MNa)+: 263.1120, found 263.1116.

(S)-5-N-tert-Butoxycarbonylaminopiperidin-2-one (12)
A solution of compound 10 (706 mg, 2.94 mmol) in dry MeOH (14 mL) and 10% Pd/C (180 mg) were stirred under H2 (1 atm.) for 26 h. The catalyst was filtered off on Celite® and washed with MeOH. Evaporation to dryness under reduced pressure gave rise to the crude product which was heated in MeOH at 65 °C for 24 h to afford (S)-5-N-tert-butoxycarbonylaminopiperidin-2-one 12 (623 mg, 99%) as colorless crystals. Mp 128-129 °C. [α]D25 – 36.4 (c 0.72, CHCl3). IR: 3687, 3631, 3031, 1718, 1662, 1506 cm–1. MS (CI, isobutane) m/z: 215 (MH)+, 159, 115. 1H NMR (300 MHz, CDCl3): 6.12 (broad s, NH), 4.74 (broad s, 1H, NHCO2), 3.97 (m, 1H, H-5), 3.56 (broad d, 1H, J = 11.5 Hz, Ha-6), 3.16 (dd, 1H, J = 11.5, J’ = 6.6 Hz, Hb-6), 2.47 (m, 2H, H2-3), 2.03 (m, 1H, Ha-4), 1.87 (m, 1H, Hb-4), 1.45 (s, 9H, t-Bu) ppm. 13C NMR (75 MHz, CDCl3): 171.73, 155.26, 79.98, 46.89, 44.22, 28.62, 28.44, 26.49 ppm. Anal. Calcd for C10H18N2O3: C, 56.06; H, 8.47; N, 13.07. Found: C, 55.90; H, 8.07; N, 12.87.

(S)-tert-Butyl 5-(bis(tert-butoxycarbonyl)amino)-2-oxopiperidine-1-carboxylate (15)
a) (S)-tert-Butyl 5-(tert-butoxycarbonylamino)-2-oxopiperidine-1-carboxylate (13)
To a solution of lactam 12 (749 mg, 3.5 mmol) in MeCN (10 mL) were successively added DMAP (214 mg, 1.75 mmol) and Boc2O (1.146g, 5.25 mmol) in MeCN (4 mL) and the mixture was stirred at rt for 8 h. After evaporation of the solvent at rt, the residue was purified by chromatography on silica gel (eluent : Et2O) to afford 13 (988 mg, 90%). MS (ESI, MeOH) m/z: 337 (MNa)+, 237 (100%). 1H NMR (300 MHz, CDCl3): 4.65 (broad d, 1H, NH), 4.03 (m, 1H, H-5), 3.80 (d, 1H, J = 12.5, J’ = 4 Hz, Ha-6), 3.57 (dd, 1H, J = 12.5, J’ = 6 Hz, Hb-6), 2.56 (m, 2H), 2.12 (m, 1H), and 1.75 (m, 1H): H2-3 and H2-4, 1.52 and 1.45 (2s, 18H, 2 t-Bu) ppm. The compound 13 was further protected as tricarbamate 15.
To a solution of tert-butyl 5-(tert-butoxycarbonyl)amino-2-oxopiperidine-1-carboxylate 13 (941 mg, 2.99 mmol) in MeCN (9.5 mL) were successively added DMAP (208 mg, 1.7 mmol) and Boc2O (1.028g, 4.5 mmol) in MeCN (4.0 mL) and the mixture was stirred at rt for 18 h. After evaporation of the solvent at rt, the product was purified by chromatography on silica gel (eluent : heptane-Et2O 3 : 7 to give 15 as colorless crystals (955 mg, 77%). Mp 100 °C. [α]D26 + 13.2 (c 3.17, CHCl3). IR: 2980, 2937, 1727, 1716, 1690, 1477, 1453, 1413, 1391, 1364, 1297 cm–1. MS (ESI, MeOH) m/z: 437 (MNa+, 100%), 337. 1H NMR (300 MHz, CDCl3): 4.50 (m, 1H, H-5), 3.96 (dd, 1H, J = 12.5, J’ = 6.1 Hz, Ha-6), 3.86 (dd, 1H, J = 12.5, J’ = 10.9 Hz, Hb-6), 2.78 and 2.47 (2m, 2H , H2-3), 2.17 and 2.06 (2m, 2H, H2-4), 1.50-1.49 (27H, 3x t-Bu) ppm. 13C NMR (75 MHz, CDCl3): 171.24, 152.84, 151.96, 83.31, 83.23, 50.74, 46.04, 33.90, 28.12, 23.77 ppm. Anal. Calcd for C20 H34N2O7: C, 57.95; H, 8.27; N, 6.76. Found: C, 57.68; H, 8.26; N, 6.54.

(S)-Benzyl 5-(bis(tert-butoxycarbonyl)amino)-2-oxopiperidine-1-carboxylate (16)
(S)-Benzyl 5-(tert-butoxycarbonyl)amino-2-oxopiperidine-1-carboxylate (14)
LiHMDS (1M in THF, 2.4 mL) was added under argon to a solution of lactam 12 (512 mg, 2.39 mmol) in dry THF (30 mL) under stirring at –78 °C. The mixture was stirred for 0.25 h at the same temperature before the addition of benzyl chloroformate (0.39 mL, 2.75 mmol). After being stirred for additional 0.5 h at –78 °C, a saturated aqueous NH4Cl solution was added, and the cooling bath was removed. The dicarbamate was extracted with EtOAc and purified by filtration on silica gel (eluent : Et2O) to give 14 (500 mg, 60%). MS (ESI, MeOH) m/z: 371 (MNa)+, HRMS calcd for C18H24N2O5Na: 371.1583, found: 371.1584. The compound 14 was further protected as tricarbamate 16, by treatment with DMAP and Boc2O under the conditions described for 13 and the tricarbamate 16 was isolated after chromatography on silica gel (eluent : heptane-Et2O 3 : 7) as colorless crystals (431 mg, 67%). Mp 124-125 °C. [α]D26 + 16 (c 3.08, CHCl3). IR: 2985, 2936, 1723, 1691, 1458, 1386, 1336 cm–1. MS (ESI, CH2Cl2-MeOH) m/z: 919 (2MNa)+, 471 (MNa+, 100%). 1H NMR (300 MHz, CDCl3): 7.44 and 7.35 (2m, 5H, H-Ar), 5.30 (s, 2H, OCH2), 4.55 (m, 1H, H-5), 4.08 (dd, 1H, J = 12, J’ = 6 Hz, Ha-6), 3.96 (dd, 1H, J = 12, J’ = 9.7 Hz, Hb-6), 2.84 and 2.51 (2m, 2H, H2-3), 2.21 and 2.08 (2m, 2H, H2-4), 1.49 (s, 18H, t-Bu) ppm. 13C NMR (75 MHz, CDCl3): 171.06, 153.41, 152.76, 135.38, 128.62, 128.34, 128.10, 68.68, 50.52, 46.26, 33.88, 27.98, 23.61 ppm. HRMS (ESI, CH2Cl2-MeOH) m/z: calcd for C23H32N2O7Na (MNa)+: 471.2107, found 471.2078.

N-Benzyloxycarbonylpiperidin-4-one (18)
Na2CO3 (711 mg, 6.77 mmol) was added at rt to a mixture of 4-piperidone monohydrate hydrochloride (825 mg, 4.81 mmol) in THF-H2O 1:1 (20 mL). Then, benzyl chloroformate (0.57 mL, 3.99 mmol) was added under stirring. After 70 min., the mixture was diluted with CH2Cl2 and aqueous solution of Na2CO3 (5% w/v). The organic layer was separated and the aqueous layer was further extracted 3 times with CH2Cl2 to afford, after usual workup and filtration on silica gel (eluent: Et2O) the N-Cbz derivative 18 (922 mg, 99%) as a colorless oil. IR: 3031, 2960, 2879, 1693, 1497, 1473, 1426, 1362, 1352, 1310, 1271, 1226, 1116 cm–1. 1H NMR (300 MHz, CDCl3): 7.37 (5H, H-Ar), 5.19 (apparent s, 2H, CH2Ph), 3.81 (dd, 4H), 2.47 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3): 207.24, 155.14, 136.34, 128.54, 128.24, 128.14, 67.74, 43.04, 41.04 ppm (in full agrement with described data).17a

N-Benzyloxycarbonylpiperidin-4-ol (19)
To a solution of 18 (533 mg, 2.29 mmol) in MeOH (4.6 mL) was added NaBH4 (42 mg, 1.11 mmol) and the mixture was stirred at rt for 30 min before addition of CH2Cl2 and H2O. The aqueous phase was extracted with CH2Cl2 and the organic phases were washed with H2O to afford after usual workup the alcohol 19 pure enough for the next step (532 mg, 99%). IR: 3397, 2942, 2862, 1672, 1428, 1363, 1270, 1221, 1128, 1069 cm–1. 1H NMR (300MHz, CDCl3): 7.35 (m, 5H, H-Ar), 5.13 (s, 2H, OCH2Ph), 3.93 and 3.88 (2m, 3H, 2xCHaN, H-4), 3.15 (ddd, 2H, J = 13.6, J’ = 9.5, J” = 3.5 Hz, 2 x CHbN), 2.00 (m, 1H, OH), 1.85 (m, 2H) and 1.49 (m, 2H): H2-3 and H2-5. 13C NMR (75 MHz, CDCl3): 155.37, 136.85, 128 .56, 128.07, 127.90, 67.38, 67.21, 41.44, 34.10 ppm.17a,b

N-Benzyloxycarbonyl-4-tert-butyldimethylsilyloxypiperidine (20)
Imidazole (409 mg, 6.0 mmol) and TBSCl (446 mg, 2.96 mmol) were successively added to a solution of 19 (489 mg, 2.08 mmol) in DMF (1.18 mL) and the mixture was stirred at rt for 24 h. After addition of aqueous Na2CO3 (10% w:v) and Et2O, the product was extracted with Et2O. The organic layers were washed twice with H2O and gave rise to 20 after usual workup (728 mg, 100%). IR: 2949, 2928, 2855, 1698, 1428, 1358, 1272, 1253, 1222, 1098, 1043 cm–1. 1H NMR (300 MHz, CDCl3): 7.37 (m, 5H, H-Ar), 5.14 (s, 2H, OCH2Ph), 3.92 (m, 1H, H-4), 3.69 (m, 2H, 2 x CHaN) and 3.40 (m, 2H, 2 x CHbN): H2-2 and H2-6), 1.72 (m, 2H) and 1.53 (m, 2H): H2-3 and H2-5, 0.91 (s, 9H, t-Bu), 0.07 (s, 6H, 2 SiMe) ppm. 13C NMR (75 MHz, CDCl3): 155.45, 137.10, 128.57, 128.01, 127.91, 67.08, 66.93, 40.77, 34.27, 25.90, 18.18, –4.62 ppm.17c

N-Benzyloxycarbonyl-4-tert-butyldimethylsilyloxypiperidin-2-one (21)
EtOAc (13 mL) and H2O (9 mL) were added to piperidine 20 (380 mg, 1.09 mmol). To the mixture stirred at rt were successively added Na2CO3 (340 mg, 3.2 mmol), NaIO4 (1.10 g, 5.14 mmol) and RuCl3, H2O (40 mg, 0.177 mmol). After stirring for 4 h, NaIO4 (550 mg, 2.57 mmol) was added and the mixture was stirred for 20 h before extraction with EtOAc. The crude product was purified by chromatography on silica gel (eluent : heptane-EtOAc 1 : 1) affording 21 (308 mg, 78%) as a colorless gum. IR: 2953, 2928, 2855, 1774 (sh), 1713, 1471, 1462, 1378, 1276, 1219, 1106, 1076 cm–1. MS (ESI, CH2Cl2 - MeOH) m/z: 386 (MNa)+. 1H NMR (300 MHz, CDCl3): 7.43 and 7.36 (2m, 5H, H-Ar), 5.30 (centre of 2d, J = 12.6 Hz, OCH2Ph), 4.21 (m, 1H, H-4), 3.89 (m, 1H, Ha-6), 3.72 (m, 1H, Hb-6), 2.70 (dd, 1H, J = 17.2, J’ = 4.5 Hz, Ha-3), 2.55 (dd, 1H, J = 17, J’ = 5.3 Hz, Hb-3), 1.94 and 1.85 (2m, 2H, H2-5), 0.89 (s, 9H, t-Bu), 0.07 (s, 6H, 2 SiMe) ppm. 13C NMR (75 MHz, CDCl3): 169.74, 154.20, 135.54, 128.67, 128.38, 128.16, 68.61, 64.95, 44.39, 42.29, 31.35, 25.82, 18.12, –4.75 ppm.19 HRMS (ESI, CH2Cl2-MeOH) m/z: calcd for C19H29NO4NaSi (MNa)+: 386.1764, found 386.1765.

1-Boc valerolactam (22)
To a solution of valerolactam (420.0 mg, 4.24 mmol) in MeCN (15 mL) were successively added DMAP (270.0 mg, 2.21 mmol) and Boc2O (1.157 g, 5.3 mmol) and the mixture was stirred at rt for 1h. After evaporation of the solvent at rt under reduced pressure, the residue was purify by chromatography on silica gel (eluent : heptane-Et2O 4 : 1) to give 22 as colorless crystals (810 mg, 96%).

tert-Butyl 5-oxo-6-(phenylsulfonyl)hexylcarbamate (23)
nBuLi (1.88 mL, 1.6 M, 3.0 mmol) was added under argon to a stirred solution of PhSO2Me (484.2 mg, 3.1 mmol) in dry THF (8 mL) at –78 °C. The mixture was stirred at the same temperature for 45 min before the addition of a solution of 22 (299 mg, 1.5 mmol) in THF (4.6 mL). The mixture was then stirred at – 78 °C for 1.5 h. A saturated aqueous solution of NH4Cl was added and the cooling bath was removed. After extraction with CH2Cl2 and usual workup, the product was purified by chromatography on silica gel (eluent : heptane-EtOAc 1 : 1) to give 23 (485 mg, 91%) as colorless crystals. Mp 82-3 °C. IR: 3338, 2976, 2928, 1716, 1686, 1525, 1446, 1361, 1322, 1290 cm–1. MS (ESI, CH2Cl2-MeOH) m/z: 378 (MNa+, 100%). 1H NMR (300 MHz, CDCl3): 7.89 (d, 2H), H-Ar, 7.70 (dd, 1H, H-Ar), 7.59 (dd, 2H, H-Ar), 4.58 (NH), 4.15 (s, 2H, SO2CH2), 3.10 (m, 2H, NCH2) and 2.74 (dd, J ~J’~ 7.0 Hz, COCH2), 1.58 (m, 2H) and 1.46 (masked m): H2-3 and H2-2, 1.46 (s, 9H, t-Bu) ppm. 13C NMR (75 MHz, CDCl3): 197.93, 156.07, 138.85, 134.41, 129.47, 128.35 79.27, 66.95, 43.99, 40.11, 29.26, 28.52, 20.28, ppm.22 HRMS (ESI, CH2Cl2-MeOH) m/z: calcd for C17H25NO5SNa: 378.1351, found: 378.1358.

tert-Butyl 5-oxo-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexylcarbamate (24)
The same protocol was applied to 22 (2.5 mmol) and 7, leading to β-ketosulfone 24 as colorless crystals (71% yield). Mp 78 °C. IR: 3368, 2948, 2911, 2876, 1731, 1682, 1595, 1517, 1501, 1456, 1366, 1344, 1292, 1270, 1249, 1161 cm–1. MS (ESI, MeOH) m/z: 446 (MNa+). 1H NMR (300 MHz, CDCl3): 7.68-7.14 (H-Ar), 4.73 (s, 2H, SO2CH2), 4.57 (NH), 3.10 (CH2), 2.68 (CH2), 1.62 (CH2), 1.48 (CH2), 1.44 (s, 9H, t-Bu) ppm. 13C NMR (75MHz, CDCl3): 196.54, 156.16, 131.7-125.6, 79.66, 64.83, 43.71, 39.90, 29.18, 28.51, 20.09 ppm. HRMS (ESI, CH2Cl2-MeOH) m/z: calcd for C18H25N5O5SNa: 446.1474, found: 446.1495.

1-Benzyloxycarbonylvalerolactam (25)
A solution of valerolactam (427.7 mg, 4.31 mmol) in THF (5 mL) was added under argon to a mixture of NaH (80%, 155.4 mg, 5.18 mmol) and KI (899 mg, 5.42 mmol) in THF (4 mL), stirred at 0 °C. The mixture was stirred at rt for 1 h, cooled again at 0 °C before the addition of benzyl chloroformate (0.614 mL, 4.3 mmol). After being stirred for additional 20 min, a saturated aqueous solution of NH4Cl was added. The product was extracted with EtOAc, and purified by chromatography on silica gel (eluent : heptane-Et2O 1 : 1) affording 25 (895 mg, 89% yield). 1H NMR data in full agreement with those of literature.26

Benzyl 5-oxo-6-(phenylsulfonyl)hexylcarbamate (26)
nBuLi (1.6 M, 5.73 mL, 9.17 mmol) was added under argon to a stirred solution of PhSO2Me (1.433 g, 9.17 mmol) in dry THF (22 mL) at – 78 °C. The mixture was stirred at the same temperature for 50 min before the addition of a solution of 25 (997.4 mg, 4.28 mmol) in THF (13 mL). The mixture was then stirred at – 78 °C for 1.5 h. A saturated aqueous solution of NH4Cl was added and the cooling bath was removed. After extraction with CH2Cl2 and usual workup, the product was purified by chromatography (eluent : heptane-EtOAc 55:45) to give 26 (1.247 g, 75%) as colorless crystals. Mp 83 °C. IR: 3451, 3021, 2944, 2871, 1720, 1516, 1448, 1325, 1216, 1222, 1156 cm–1. MS (ESI, MeOH) m/z: 412 (MNa+, 100%). 1H NMR (300 MHz, CDCl3): 7.88 (dd, 2H, H-Ar), 7.68 (dd, 1H, H-Ar), 7.58 (dd, 2H, H-Ar), 7.34 (m, 5H, H-Ar), 5.09 (2H, OCH2Ph), 4.89 (1H, NH), 4.13 (s, 2H, SO2CH2), 3.17 (m, 2H, NCH2), 2.72 (m, 2H, COCH2), 1.58 (2H), 1.48 (2H): H2-3, H2-2, ppm. 13C NMR (75 MHz, CDCl3): 197.91, 156.51, 138.79, 136.68, 134.40, 129.46, 128.59, 128.32, 128.17, 66.89, 66.69, 43.90, 40.59, 29.10, 20.15 ppm. HRMS (ESI, CH2Cl2-MeOH) m/z: calcd for C20H23NO5NaS (MNa)+: 412.1195, found: 412.1193.

tert-Butyl (S)-2-(bis(tert-butoxycarbonyl)amino)-5-oxo-6-(phenylsulfonyl)hexylcarbamate (27)
nBuLi (1.6 M, 0.39 mL, 0.62 mmol) was added under argon to a stirred solution of PhSO2Me (110 mg, 0.70 mmol) in dry THF (2.52 mL) at – 78 °C. The mixture was stirred at the same temperature for 50 min before the addition of a solution of 15 (166.0 mg, 0.40 mmol) in THF (0.73 mL). The mixture was then stirred at – 78 °C for 1 h. A saturated aqueous solution of NH4Cl was added at the same temperature. After extraction with CH2Cl2 and usual workup, the product was purified by chromatography (eluent : CH2Cl2-EtOAc 9 : 1) to give 27 (169 mg, 74%) as colorless gum. IR: 3389, 2978, 2933, 1697, 1510, 1448, 1392, 1366, 1246, 1232 cm–1. MS (ESI, MeOH) m/z: 593 (MNa+ , 100%). 1H NMR (300 MHz, CDCl3): 7.88 (d, 2H, J = 7.5 Hz, H-Ar), 7.68 (dd, 1H, J = J’ = 7.5 Hz, H-Ar), 7.57 (dd, 2H, J = J’ = 7.5 Hz, H-Ar), 4.83 (m, 1H, NH), 4.16 (m, 3H, NCH, SO2CH2), 3.5-3.2 (2m, 2H, NCH2), 2.75 (m, 2H, COCH2), 1.95, 1.81 (2m, 2H, CH2), 1.50, 1.42 (3 t-Bu) ppm. 13C NMR (75 MHz, CDCl3): 197.32, 155.83, 153.46, 138.82, 134.37, 129.44, 128.41, 82.90, 79.34, 67.09, 56.28, 43.27, 41.09, 28.47, 28.07, 23.72 ppm. HRMS (ESI, CH2Cl2-MeOH) m/z: calcd for C27H42N2O9SNa (MNa)+: 593.2509, found 593.2506.

Benzyl (S)-2-(bis(tert-butoxycarbonyl)amino)-5-oxo-6-(phenylsulfonyl)hexylcarbamate (28)
The same protocol was applied to 16 (404 mg, 0.90 mmol) and 6 (299 mg, 1.91 mmol) leading after purification by chromatography (eluent : heptane-Et2O 2:8) to β-ketosulfone 28 (365 mg, 67%), as a colorless gum. [α]D22 + 9.8 (c 0.79, CHCl3). IR: 3382, 2978, 2930, 1714, 1697, 1519, 1448, 1393, 1367, 1345, 1322 cm–1. MS (ESI, MeOH) m/z: 627 (MNa+, 100%), 527. 1H NMR (300 MHz, CDCl3): 7.90 (d, 2H, J = 7.5 Hz, Ar-H), 7.69 (dd, 1H, J = J’ = 7.5 Hz, H-Ar), 7.57 (dd, 2H, J = J’ = 7.5 Hz, H-Ar), 7.33 (5H, CH2Ph), 5.13 (1H, NH), 5.08 (2d, 2H, CH2Ph), 4.19 (1H, NCH), 4.13 (2H, SO2CH2), 3.50, 3.41 (2m, 2H, NCH2), 2.77 (m, 2H, COCH2), 1.98, 1.85 (2m, 2H, CH2), 1.47 (s, 18H, 2 t-Bu) ppm. 13C NMR (75 MHz, CDCl3): 197.24, 156.36, 153.45, 138.83, 136.62, 134.35, 129.44, 128.58, 128.39, 128.16, 83.03, 67.10, 66.77, 56.04, 43.81, 40.99, 28.03, 23.67 ppm. HRMS (ESI, MeOH) m/z: calcd for C30H40N2O9NaS (MNa)+: 627.2352, found: 627.2373.

Benzyl 3-(tert-butyldimethylsilyloxy)-5-oxo-6-(phenylsulfonyl)hexylcarbamate (29)
nBuLi (1.6 M, 0.83 mL, 1.33 mmol) was added under argon to a stirred solution of PhSO2Me (207.0 mg, 1.33 mmol) in dry THF (3.0 mL) at – 78 °C. The mixture was stirred at the same temperature temperature for 55 min before the addition of a solution of 21 (211.0 mg, 0.58 mmol) in THF (2.0 mL). The mixture was then stirred at – 78 °C for 40 min. A saturated aqueous solution of NH4Cl was added and then, the cooling bath was removed. After extraction with CH2Cl2 and usual workup, the product was purified by chromatography (eluent : CH2Cl2-EtOAc 30 : 1) to afford 29 as a colorless gum (235.0 mg, 78%). IR: 3382, 2927, 2855, 1713, 1518, 1471, 1447, 1322, 1250, 1152, 1083, 1042 cm–1. MS (ESI, CH2Cl2-MeOH) m/z: 542 (MNa)+. 1H NMR (300 MHz, CDCl3): 7.89 (d, J = 7.9 Hz, 2H, H-Ar), 7.69 (dd, 1H, J = J’ = 7.9 Hz, H-Ar), 7.58 (dd, 2H, J = J’ = 7.9 Hz, H-Ar), 7.35 (m, 5H, CH2Ph), 5.10 (apparent s, 2H, OCH2Ph), 5.05 (broad, NH), 4.24 (m, 1H, H-3), 4.18 (s, 2H, SO2CH2), 3.25 (m, 2H, NCH2), 2.90 (2H, COCH2CH), 1.68 (m, 2H, H2-2), 0.86 (s, 9H, t-Bu), 0.06 (s, 3H, SiMe), 0.02 (s, 3H, SiMe) ppm. 13C NMR (75 MHz, CDCl3): 196.87, 156.37, 138.87, 136.75, 134.45, 129.50, 128.60, 128.35, 128.14, 67.91, 67.03, 66.70, 51.14, 37.60, 36.70, 25.88, 18.00, –4.65 ppm. HRMS (ESI, CH2Cl2-MeOH) m/z: calcd for C26H37NO6NaSSi (MNa)+ : 542.2033, found 542.2009.

2-(Phenylsulfonylmethyl)piperidine (30)
To a solution of β-ketosulfone 26 (1.13 g, 2.9 mmol) in MeOH (28 mL) was added 10% Pd/C (300 mg), and the mixture was stirred at rt under H2 (1 atm.) for 30 h. The catalyst was filtered off on Celite® and washed with MeOH. Evaporation of the solution under reduced pressure afforded 30 (557 mg, 80%) as a pale yellow oil. IR: 3336, 2929, 2853, 1698, 1446, 1332, 1300 cm–1. MS (IE) m/z: 239 (M+.), 238, 97, 84 (100%), 77. 1H NMR (300 MHz, CDCl3): 7.91 (d, 2H, J = 7.5 Hz, H-Ar), 7.66 (dd, 1H, J = J’ = 7.5 Hz, H-Ar), 7.57 (dd, 2H, J = J’ = 7.5 Hz, H-Ar), 3.20-3.12 (m, 2H, H-2, SO2CHa), 3.02 (2H, SO2CHb, Ha-6), 2.72 (exch, NH), 2.67 (ddd, 1H, Hb-6), 1.75 (m, 1H), 1.63-1.27 (5H): H2-3, H2-4, H2-5, ppm. 13C NMR (75 MHz, CDCl3): 139.80, 133.90, 129.47, 127.85, 62.44, 51.44, 46.49, 32.82, 25.50, 24.61 ppm. N-Boc derivative was prepared to compare spectroscopic data with literature.27

5S-(bis(tert-Butoxycarbonyl)amino)-2-(phenylsulfonylmethyl)piperidines (31) and (32)
To a solution of 28 (81.3 mg, 0 .135 mmol) in MeOH (0.55 mL) was added 10% Pd/C (20 mg), and the mixture was stirred at rt under H2 (1 atm) for 56 h. The catalyst was filtered off on Celite® and washed with MeOH. The solution was evaporated under reduced pressure. Purification by preparative TLC (eluent Et2O) afforded, together with starting material (16.1 mg, 20%), compounds 31 (14.2 mg, 23%) and 32 (29.0 mg, 47%). 31: Mp 71 °C. [α]D25 + 8 (c 0.45, CHCl3). IR: 2976, 2931, 1736, 1697, 1447, 1392, 1366, 1347, 1303, 1235, 1140, 1120 cm–1. MS (ESI, CH2Cl2-MeOH) m/z: 477 (MNa+, 100%), 455, 377, 299. 1H NMR (500 MHz, C6D6 δ = 7.16 ppm): 7.73 (split d, 2H, J = 7.9 Hz, H-Ar), 6.93 (dd, 1H, J = 7.9 Hz, H-Ar), 6.86 (dd, 2H , J = J’ = 7.9 Hz, H-Ar), 4.31 (m, 1H, H-5), 3.23 (dd, 1H, J = J’ = 10.9 Hz, Ha-6), 3.03 (m, 1H, H-2), 2.97 (m, 1H, J = 10.9 Hz, Hb-6), 2.80 (dd, 1H, J = 14.0, J’ = 9.0, Ha-7), 2.54 (dd, 1H, J = 14.0, J’ = 3.0, Hb-7), 2.08 (dddd, 1H, J = 12.6, J’ ~ J” ~ 12, J’’’= 4 Hz, Ha-4), 1.70 (broad d, 1H, J = 12.6 Hz, Hb-4), 1.37 (s, 18H, 2 t-Bu), 1.18 (m, 1H, J ~ 12.5 Hz, Ha-3), 0.94 (m, 1H, Hb-3) ppm. 13C NMR (125 MHz, CDCl3): 153.20, 139.79, 133.99, 129.55, 128.00, 82.45, 62.01, 54.30, 50.91, 48.95, 33.04, 28.14 ppm. HRMS (ESI, CH2Cl2-MeOH) m/z: calcd for C22H34N2O6NaS (MNa)+: 477.2035, found 477.2021.
32: [α]D24 + 24 (c 0.82, CHCl3). IR: 2977, 2931, 1736, 1694, 1446, 1392, 1366, 1340, 1304, 1238, 1140 cm–1. MS (ESI, CH2Cl2-MeOH) m/z : 477 (MNa+, 100%), 455, 377, 299, 255. 1H NMR (500 MHz, CDCl3): 7.94 (d, 2H, J = 7.6 Hz, H-Ar), 7.67 (dd, 1H, J = J’ = 7.6 Hz, H-Ar), 7.58 (dd, 2H, J = J’ = 7.6 Hz, H-Ar), 4.02 (m, 1H, H-5), 3.62 (dd, 1H, J = 14.0, J’ = 7.9 Hz, Ha-7), 3.55 (m, 1H, H-2), 3.20 (dd, 1H, J = J’ = 11.4 Hz, Ha-6), 3.10 (dd, 1H, J = 14.0, J’ = 4.1 Hz, Hb-7), 2.76 (dd, 1H, J = 11.4, J’ = 3.8 Hz, Hb-6), 2.08 (m, 1H, Ha-4), 1.87-1.64 (m, 3H, Ha-3, Hb-3, Hb-4), 1.49 (s, 18H, 2 t-Bu) ppm. 13C NMR (125 MHz, CDCl3): 153.32, 140.00, 133.83, 129.46, 128.05, 82.43, 56.91, 54.16, 47.12, 43.05, 30.40, 28.16, 24.05 ppm. HRMS (ESI, CH2Cl2-MeOH) m/z: calcd for C22H34N2O6NaS (MNa)+: 477.2035, found 477.2046.

(2S*,4R*)-4-(tert-Butyldimethylsilyloxy)-2-(phenylsulfonylmethyl)piperidine (33)
To a solution of 29 (66.0 mg, 0 .127 mmol) in MeOH (0.5 mL) was added 10% Pd/C (16 mg), and the mixture was stirred at rt under H2 for 56 h. The catalyst was filtered off on Celite® and washed with MeOH. The solution was evaporated under reduced pressure. Purification by preparative TLC (eluent Et2O) afforded 33 as a colorless gum (24.8 mg, 53%), together with starting material (6.3 mg, ca 10%). IR: 3337, 2949, 2927, 2886, 2854, 1462, 1446, 1377, 1359, 1304, 1251, 1147, 1085 cm–1. MS (ESI, CH2Cl2-MeOH) m/z: 370 (MH)+. 1H NMR (500 MHz, C6D6): 7.75 (d, 2H, J = 7.5, H-Ar), 6.92 (2m, 3H, H-Ar), 3.42 (m, 1H, H-4), 3.23 (m, 1H, J ~ J’ ~ 10 Hz, H-2), 2.98 (broad dd, 1H, J = 14.0, J’ = 10 Hz, Ha-7), 2.71 (m, 1H, J ~ 12 Hz, Ha-6), 2.61 (dd, 1H, J = 14.0, J’ = 2.4 Hz, Hb-7), 2.26 (ddd, 1H, J ~ J’~ 12, J” = 2.4 Hz, Hb-6), 1.57 and 1.55 (2m, 2H, Ha-5 and Ha-3), 1.43 (m, 1H, Hb-5), 1.19 (ddd, 1H, J ~ J’ ~ J” ~ 11 Hz, Hb-3), 0.96 (s, 9H, Sit-Bu), 0.01 (s, 6H, 2 SiMe) ppm. 13C (75 MHz, C6D6 δ = 128.39 ppm): 141.48, 133.56, 129.52, 70.26, 62.45, 50.37, 44.21, 43.04, 36.37, 26.39, 18.57, –4.00, –4.10 ppm. HRMS: cald for C18H32NO3SSi (MH)+: 370.1872, found: 370.1895.

ACKNOWLEDGEMENTS
We thank the Institut de Chimie des Substances Naturelles (CNRS, Gif-sur-Yvette) for financial support to J. Massé.

This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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