Synthesis of 5-amino- and 4-hydroxy-2-phenylsulfonylmethylpiperidines

Article abstract of DOI:10.3987/COM-08-S(F)37

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

Full text of DOI:10.3987/COM-08-S(F)37

HETEROCYCLES, Vol. 77, No. 1, 2009
417
HETEROCYCLES, Vol. 77, No. 7, 2009, pp. 417 - 432. © The Japan Institute of Heterocyclic Chemistry
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,
France
E-mail: nicole.langlois@icsn.cnrs-gif.fr
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
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

418
HETEROCYCLES, Vol. 77, No. 1, 2009
O
OP
NBoc
NP
O
S
O
S
O
S
Ar
Ph
Ar
N
H
N
N
H
H
O
O
O
3
2
1
OH
OH
NH2
N
H
R
N
H
R =
5
4 pseudodistomin C
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.
R
R
R
ArSO2Me-BuLi
NHCO2Alk
ArO2S
ArO2S
N
O
6 : Ar = Ph
H
O
N
N
N
N
7 : Ar =
B
CO2Alk
1 R = 5-amino
N
Ph
A
2 R = 4-hydroxy
Scheme 1
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

HETEROCYCLES, Vol. 77, No. 1, 2009
419
NHBoc
NH2
X
O
N
O
N
H
O
N
8 : X = OEVE, OH
9 : X = OMs
10 : X = N3
Boc
11
Boc
12
NHBoc
N(Boc)2
O
N
O
N
CO2R
CO2R
13 R = t-Bu
14 R = Bn
15 R = t-Bu
16 R = Bn
Scheme 2
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.
O
OR
OTBS
OTBS
HO OH
Na2CO3
CbzCl
NaBH4
MeOH
RuCl3-NaIO4
78%
99%
99%
PhO2S
N
H
N
O
N
N
N
, HCl
H
Cbz
Cbz
Cbz
33
21
17
18
19 R = H
TBSCl-Im
100%
20 R = TBS
Scheme 3

420
HETEROCYCLES, Vol. 77, No. 1, 2009
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).
ArSO2Me-BuLi
NHBoc
ArO2S
O
O
N
6 : Ar = Ph
7 : Ar =
N
N
N
N
Boc
23 Ar = Ph
24 Ar =
N
N
N
N
22
Ph
Ph
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.
N(Boc)2
NBoc2
PhSO2Me-BuLi
NHCO2R
PhO2S
N
CO2R
O
O
27 R = t-Bu
28 R = Bn
15 R = t-Bu
16 R = Bn
OTBS
NHCO2Bn
PhSO2Me-BuLi
PhO2S
O
OTBS
29
O
N
CO2Bn
21
Scheme 5

HETEROCYCLES, Vol. 77, No. 1, 2009
421
Table 1. Preparation of β-ketosulfones by opening lactams with methyl phenyl sulfone 6 carbanion
OTBS
NBoc2
NBoc2
Piperidinones
O N
Cbz
25
O N
Boc
15
O N
Boc
22
O N
O N
Cbz
16
Cbz
21
Ketosulfones
(yield)
23
(91%)
26
(75%)
27
(74%)
28
(67%)
29
(78%)
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.

422
HETEROCYCLES, Vol. 77, No. 1, 2009
H3ax
NH
H5ax
N(Boc)2
H4ax
H6ax
PhO2S
H2
R
R
31 (2,5-trans)
H2-Pd/C
5
Figure 1
NHCO2Bn
2
PhO2S
PhO2S
N
O
H
N(Boc)2
NH
26 R = H
28 R = N(Boc)2
30 R = H
H4ax
31 R = N(Boc)2
32 R = N(Boc)2
H6ax
PhO2S
32 (2,5-cis)
Figure 2
OTBS
4
2
H2-Pd/C
NHCO2Bn
PhO2S
H2
PhO2S
H4
H6ax
N
H
O
OTBS
PhO2S
OTBS
29
33
HN
H3ax
33
Figure 3
Scheme 6
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

HETEROCYCLES, Vol. 77, No. 1, 2009
423
EXPERIMENTAL
General. Melting points were uncorrected. NMR spectra were recorded on a Bruker spectrometer at 300
1
13
or 500 MHz for H NMR, 75 or 125 MHz for C 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
1
cm–1. H 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
26
usual workup (4.10 g, 96%). [α]D – 43 (c 0.65, CHCl3). IR: 2990, 2111, 1786, 1746, 1711 cm–1. MS
1
(ESI, CH2Cl2-MeOH) m/z: 263 [(MNa)+, 100%]. H 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

424
HETEROCYCLES, Vol. 77, No. 1, 2009
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
1
cm–1. MS (CI, isobutane) m/z: 215 (MH)+, 159, 115. H 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)
13
ppm. C 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,
1
1690, 1477, 1453, 1413, 1391, 1364, 1297 cm–1. MS (ESI, MeOH) m/z: 437 (MNa+, 100%), 337. H
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,
13
3x t-Bu) ppm. C 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

HETEROCYCLES, Vol. 77, No. 1, 2009
425
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
1
(2MNa)+, 471 (MNa+, 100%). H 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,
13
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. C 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,
13
4H), 2.47 (m, 4H) ppm. C 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,

426
HETEROCYCLES, Vol. 77, No. 1, 2009
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,
13
6H, 2 SiMe) ppm. C 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%).

HETEROCYCLES, Vol. 77, No. 1, 2009
427
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,
1
1292, 1270, 1249, 1161 cm–1. MS (ESI, MeOH) m/z: 446 (MNa+). H 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
13
(s, 9H, t-Bu) ppm. C 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 :
1
heptane-Et2O 1 :1) affording 25 (895 mg, 89% yield). H 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,

428
HETEROCYCLES, Vol. 77, No. 1, 2009
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
22
colorless gum. [α]D + 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

HETEROCYCLES, Vol. 77, No. 1, 2009
429
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

430
HETEROCYCLES, Vol. 77, No. 1, 2009
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%)
25
and 32 (29.0 mg, 47%). 31: Mp 71 °C. [α]D + 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.
24
32: [α]D + 24 (c 0.82, CHCl3). IR: 2977, 2931, 1736, 1694, 1446, 1392, 1366, 1340, 1304, 1238, 1140
1
cm–1. MS (ESI, CH2Cl2-MeOH) m/z : 477 (MNa+, 100%), 455, 377, 299, 255. H 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’
13
~ J” ~ 11 Hz, Hb-3), 0.96 (s, 9H, Sit-Bu), 0.01 (s, 6H, 2 SiMe) ppm. C (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.

HETEROCYCLES, Vol. 77, No. 1, 2009
431
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.
REFERENCES
1. for reviews see: a) P. D. Bayley, P. A. Millwood, and P. D. Smith, Chem. Comm., 1998, 633. b) S.
Laschat and T. Dickner, Synthesis, 2000, 1781. c) F.-X. Felpin and J. Lebreton, Eur. J. Org. Chem.,
2003, 3693. d) P. M. Weintraub, J. S. Sabol, J. M. Kane, and D. R. Borcherding, Tetrahedron, 2003,
59, 2953. e) M. G. P. Buffat, Tetrahedron, 2004, 60, 1701.
2. I. Ninomiya, T. Kiguchi, and T. Naito, The Alkaloids, vol 50, ed. by G. A. Cordell, Academic Press,
Inc., London 1998, pp. 317-342.
3. N. Langlois, Org. Lett., 2002, 4, 185.
4. Y. Doi, M. Ishibashi, and J. Kobayashi, Tetrahedron, 1996, 52, 4573.
5. a) J. B. Baudin, G. Hareau, S. A. Julia, and O. Ruel, Bull. Soc. Chim. Fr., 1993, 336. b) J. B. Baudin,
G. Hareau, S. A. Julia, R. Lorne, and O. Ruel, Bull. Soc. Chim. Fr., 1993, 856.
6. P. R. Blakemore, W. J. Cole, P. J. Kocienski, and A. Morley, Synlett, 1998, 26.
7. a) S. Grabley, P. Hammann, H. Kluge, J. Wink, P. Kricke, and A. Zeek, J. Antibiot., 1991, 44, 797. b)
C. Maul, I. Sattler, M. Zerlin, C. Hinze, C. Koch, A. Maier, S. Grabley, and R. Thiericke, J. Antibiot.,
1999, 52, 1124.
8. M. Mayer and R. Thiericke, J. Org. Chem., 1993, 58, 3486.
9. a) Y. Takemoto, S. Ueda, J. Takeuchi, Y. Baba, and C. Iwata, Chem. Pharm. Bull., 1997, 45, 1906. b)
I. Ripoche, J.-L. Canet, B. Aboab, J. Gelas, and Y. Troin, J. Chem. Soc., Perkin Trans 1, 1998, 3485.
c) H. Yokoyama, K. Otaya, S. Yamaguchi, and Y. Hirai, Tetrahedron Lett., 1998, 39, 5971. d) F. A.
Davis, B. Chao, T. Fang, and J. M. Szewczyk, Org. Lett., 2000, 2, 1041. e) M. Sabat and C. R.
Johnson, Terahedron Lett., 2001, 42, 1209. f) P. Celestini, B. Danieli, G. Lesma, A. Sacchetti, A.
Silvani, D. Passarella, and A. Virdis, Org. Lett., 2002, 4, 1367.
10. N. Langlois, N. Van Bac , N. Dahuron, J.-M. Delcroix, A. Deyine, D. Griffart-Brunet, A. Chiaroni,
and C. Riche, Tetrahedron, 1995, 51, 3571.
11. a) N. Langlois, IXth Conference French-American Chemical Society, June 2-6th 2002, Saint-Malo,
France. b) N. Langlois, Tetrahedron Lett., 2002, 43, 9531.
12. S. K. Panday and N. Langlois, Tetrahedron Lett., 1995, 36, 8205.
13. N. Langlois and O. Calvez, Tetrahedron Lett., 2000, 41, 8285.
14. a) K.-i. Tanaka, H. Nemoto, and H. Sawanishi, Tetrahedron: Asymmetry, 2005, 16, 809. b) K.-i.

432
HETEROCYCLES, Vol. 77, No. 1, 2009
Tanaka, T. Maesoba, and H. Sawanishi, Heterocycles, 2006, 68, 183.
15. a) H. Li, T. Sakamoto, M. Kato, and Y. Kikugawa, Synth. Commun., 1995, 24, 4045. b) X.-L. Qiu and
F.-L. Qing, Synthesis, 2004, 334.
16. V. Semetey, D. Moustakas, and G. M. Whitesides, Angew. Chem. Int. Ed. 2006, 45, 588.
17. a) K. Hattori, H. Sajiki, and K. Hirota, Tetrahedron, 2000, 56, 8433. b) D. Chang, H.-J. Feiten, K.-H.
Engesser, J. B. van Beilen, B. Witholt, and Z. Li, Org. Lett., 2002, 4, 1859. c) C.-E. Yeom, Y. J. Kim,
S. Y. Lee, Y. J. Shin, and B. M. Kim, Tetrahedron, 2005, 61, 12227.
18. R. K. Boeckman, Jr and J. C. Potenza, Tetrahedron Lett., 1985, 26, 1411.
19. D. I. MaGee, M. Ramaseshan, and J. D. Leach, Canad. J. Chem., 1995, 73, 2111.
20. a) J. C. Sheehan and R. W. Tulis, J. Org. Chem., 1974, 39, 2264. b) G. Bettoni, C. Franchini, F.
Morlacchi, N. Tangari, and V. Tortorella, J. Org. Chem., 1976, 41, 2780. c) N. K. Sharma and K. N.
Ganesh, Tetrahedron Lett., 2004, 45, 1403.
21. A. J. Mota, A. Chiaroni, and N. Langlois, Eur. J. Org. Chem., 2003, 4187.
22. L. A. Arias, D. Arbelo, A. Alzérreca, and J. A. Prieto, J. Heterocycl. Chem., 2001, 38, 29.
23. a) J. F. Cormier, Tetrahedron Lett., 1991, 32, 187. b) S. Kim, S. M. Jacobo, C.-T. Chang, S. Bellone,
W. S. Powell, and J. Rokach Tetrahedron Lett., 2004, 45, 1973. c) T. Ikawa, K. Hattori, H. Sajiki, and
K. Hirota , Tetrahedron 2004, 60, 6901.
24. a) D. Chang, H.-J. Feiten, B. Witholt, and Z. Li, Tetrahedron: Asymmetry, 2002, 13, 2141 and
ref. cited therein. b) M. K. S. Vink, C. A. Schortinghuis, J. Luten, J. H. van Maarseveen, H. E.
Schoemaker, H. Hiemstra, and F. P. J. T. Rutjes, J. Org. Chem., 2002, 67, 7869.
25. J. Ackermann, M. Matthes, and C. Tamm, Helv. Chim. Acta, 1990, 73, 122.
26. A. Giovannini, D. Savoia, and A. Umani-Ronchi, J. Org. Chem., 1989, 54, 228.
27. D. J. Hart, J. Li, W.-L. Wu, and A. P. Kozikowski, J. Org. Chem., 1997, 62, 5023.