Iterative multifunctionalization of unactivated C-H bonds in piperidines by way of intramolecular Rh(II)-catalyzed aminations

Article abstract of DOI:10.1021/jo702350u

(Chemical Equation Presented) Efficient stereocontrolled synthesis of di-, tri-, tetra-, and pentasubstituted piperidines from simple 2-sulfamoyloxymethyl piperidine derivatives has been performed by way of intramolecular Rh-catalyzed amination of saturated C-H bonds. In this process, the sulfamoyloxymethyl arm was directly or indirectly involved in the functionalization of every saturated methylene group of the piperidine ring at C-3, C-4, C-5, and C-6. Direct application to the total synthesis of iminosugars and related compounds demonstrated the synthetic potential of this strategy.

Full text of DOI:10.1021/jo702350u

Iterative Multifunctionalization of Unactivated C-H Bonds in
Piperidines by Way of Intramolecular Rh(II)-Catalyzed Aminations
Sylvestre Toumieux, Philippe Compain,* and Olivier R. Martin
Institut de Chimie Organique et Analytique, CNRS UMR 6005, UniVersite´ d’Orle´ans, BP 6759,
45067 Orle´ans, France
philippe.compain@uniV-orleans.fr
ReceiVed October 31, 2007
Efficient stereocontrolled synthesis of di-, tri-, tetra-, and pentasubstituted piperidines from simple
2-sulfamoyloxymethyl piperidine derivatives has been performed by way of intramolecular Rh-catalyzed
amination of saturated C-H bonds. In this process, the sulfamoyloxymethyl arm was directly or indirectly
involved in the functionalization of every saturated methylene group of the piperidine ring at C-3, C-4,
C-5, and C-6. Direct application to the total synthesis of iminosugars and related compounds demonstrated
the synthetic potential of this strategy.
Introduction
stimulated the development of efficient catalytic methods for
the amination of unactivated C-H bonds.3 The major recent
advances in this field have involved catalyzed intramolecular
C-H insertion reactions using carbamate or sulfamate ester
substrates (Figure 1).4,5 The high regioselectivity usually
observed in these processes is mainly controlled by electronic
factors. Benzylic, allylic, and tertiary C-H bonds as well as
sites adjacent to electron-donating groups are generally favored.
Amination reactions performed with sulfamate esters lead
generally to the formation of the corresponding six-membered
ring insertion product (Figure 1), whereas carbamates afforded
only five-membered rings.3
Conquering molecular complexity and diversity using the
simplest means is a major challenge in organic chemistry that
combines economic with environmental goals.1 Catalyzed
functionalization of unreactive C-H bonds is probably one of
the most promising strategies toward this end.2 The direct and
selective introduction of functional groups into saturated
hydrocarbons is indeed expected to shorten the syntheses of
pharmaceuticals and other relevant targets by reducing the
number of steps usually required for protective group manipula-
tion and prefunctionalization via C-X bonds (X ) OTf,
halogens, etc.). In addition, unlocking the potential of inert C-H
bonds offers a major simplification of synthetic sequences and
unprecedented chemical possibilities. The importance of nitrogen-
based functional groups in natural and synthetic products has
(3) (a) Davies, H. M. L.; Long, M. S. Angew. Chem., Int. Ed. 2005, 44,
3518. (b) Espino, C. G.; Du Bois, J. in Modern Rhodium-catalyzed Organic
Reaction; Evans, P. A. Ed.; Wiley-VCH, Weinheim, 2005, pp 379-416.
(c) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905. (d) Dauban, P.; Dodd,
R. H. Synlett 2003, 1571.
(4) (a) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935. (b) Espino, C. G.; Du Bois, J. Angew. Chem., Int.
Ed. 2001, 40, 598. (c) Du Bois, J. Chemtracts, 2005, 18, 1.
* To whom correspondence should be addressed. Tel: ++ 33 2 38 49 48
55. Fax: ++ 33 2 38 41 72 81.
(1) Compain, P.; Desvergnes, V.; Ollivier, C.; Robert, F.; Suzenet, F.;
Barboiu, M.; Belmont, P.; Ble´riot, Y.; Bolze, F.; Bouquillon, S.; Bourguet,
E.; Braida, B.; Constantieux, T.; De´saubry, L.; Dupont, D.; Gastaldi, S.;
Je´rome, F.; Legoupy, S.; Marat, X.; Migaud, M.; Moitessier, N.; Papot, S.;
Peri, F.; Petit, M.; Py, S.; Schulz, E.; Tranoy-Opalinski, I.; Vauzeilles, B.;
Vayron, P.; Vergnes, L.; Vidal, S.; Wilmouth, S. New J. Chem. 2006, 30,
823.
(5) For examples of related work see: (a) Breslow, R.; Gellman, S. H.
J. Am. Chem. Soc. 1983, 105, 6728. (b) Fruit, C.; Mu¨ller, P. HelV. Chim.
Acta. 2004, 87, 1607. (c) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-
Y.; Che, C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465. (d) Liang, J.-L.;
Yuan, S.-X.; Huang, J.-S.; Che, C.-M. J. Org. Chem. 2004, 69, 3610. (e)
Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198. (f)
Cui, Y.; He, C. Angew. Chem., Int. Ed. 2004, 43, 4210. (g) Liang, C.;
Robert-Peillard, F.; Fruit, C.; Mu¨ller, P.; Dodd, R. H.; Dauban, P. Angew.
Chem., Int. Ed. 2006, 45, 4641. (h) Reddy, R. P.; Davies, H. M. L. Org.
Lett. 2006, 8, 5013. (i) Fructos, M. R.; Trofimenko, S.; Mar Diaz-Requejo,
M.; Pe´rez, P. J. J. Am. Chem. Soc. 2006, 128, 11784. (j) Li, Z.; Capretto,
D. A.; Rahaman, R.; He, C. Angew. Chem., Int. Ed. 2007, 46, 5184.
(2) (a) Bergman, R. G. Nature, 2007, 446, 391. (b) Godula, K.; Sames,
D. Science 2006, 312, 67. (c) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal.
2003, 345, 1077. (d) Davies, H. M. L.; Beckwith, E. J. Chem. ReV. 2003,
103, 2861. (e) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911. (e)
Murai S. in ActiVation of UnreactiVe Bonds and Organic Synthesis,
Springer: Berlin 1999.
10.1021/jo702350u CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/15/2008
J. Org. Chem. 2008, 73, 2155-2162
2155

Toumieux et al.
FIGURE 1. Rh-catalyzed oxidative cyclization of sulfamic esters.
SCHEME 1 a
FIGURE 2. Toward multifunctionalization of unactivated C-H bonds
in piperidine derivatives.
for further intramolecular C-H amination. Based on this
working hypothesis, we have devised molecular systems for
selective and iterative multifunctionalization of unactivated C-H
bonds in nitrogen-containing heterocycles. In this process, the
sulfamoyloxymethyl group is used several times as a “molecular
activating arm” allowing the formation of C-C, C-N, or Cd
C double bonds.9 The ultimate goal of this strategy would be
the diversity-oriented synthesis of bioactive azacycloalkanes by
iterative and direct heterocyclic scaffold decoration. We wish
to report here our first exploration of the synthetic potential of
this new concept in the piperidine series. This major class of
biologically active compounds10 is found in many natural
products, glycomimetics (iminosugars),6d and drug candidates.
Their impact on medicinal science has been superbly highlighted
by the fact that, during a recent 10-year period, there were over
12000 piperidine compounds mentioned in clinical and pre-
clinical studies.11
a Reagents and conditions: (a) PhI(OAc)2 (1.1 equiv), MgO (2.3 equiv),
Rh2(OAc)4 (0.05 equiv), CH2Cl2, 40 °C (ref 7); (b) Et3SiD (3 equiv) or
allylTMS (4 equiv), BF3‚OEt2 (1 equiv), CH2Cl2, -78 °C; (c) propargylTMS
(4 equiv), SnCl4 (0.2 equiv ), CH2Cl2, -78 to 0 °C; (d) H2, 10% Pd/C,
MeOH, rt; (e) PhI(OAc)2 (1.1 equiv), MgO (2.3 equiv), Rh2(esp)2 (0.02
equiv), CH2Cl2, 40 °C; (f) CbzCl (2.5 equiv), t-BuOK (1.5 equiv), DME,
0 °C to rt; (g) KOAc (2 equiv), DMF, rt; (h) PhSH (2.4 equiv), K2CO3 (2.4
equiv), CH3CN, -20 °C to rt; (i) NaN3 (2 equiv), DMSO, 0 °C to rt.
[Rh2(esp)2 ) Rh2(R,R,R′,R′-tetramethyl-1,3-benzenedipropionate)2].
Results and Discussion
Synthetic Route to 2,6-Disubstituted 3-Aminopiperidines.
We first investigated the activating arm concept for the general
synthesis of 2,6-disubstituted 3-aminopiperidines (Scheme 1).
In contrast to the nucleophilic addition to N,O-acetals,12,13 the
reactivity of aminals as precursors of N-tosyliminium ions has
been almost unexplored.14 To evaluate the synthetic scope of
this reaction, a systematic study was performed with aminal 2
over a broad range of conditions (Table 1). We were pleased to
find that treatment of aminal 2 with 4 equiv of allylsilane and
BF3‚OEt2 or SnCl4 afforded the expected 2,6-disubstituted
piperidine 3a in good yields and as a single diastereoisomer.
In connection with our studies on iminosugars,6 we have
recently reported the first examples of seven- and eight-
membered rings generated by way of the intramolecular-
catalyzed amination of saturated C-H bonds.7,8 This reaction,
which further expands the synthetic scope of C-H amination,
provides access to bicyclic aminals such as 2 (Scheme 1),
allowing the functionalization of a C-H bond in a 1,7-
relationship with respect to the activating group (Figure 2). It
was anticipated that these compounds, as potential precursors
of N-tosyliminium ions, could react with various reagents to
form versatile enamine intermediates or a new bond at C-6
(Figure 2). The major advantage of these processes is the
regeneration of the sulfamoyloxy group that may be used again
(9) An example of sequential directed C-H bond functionalizations has
been reported in the literature. This process was based on Pd-catalyzed
cyclometallation and transmetallation: Dangel, B. D.; Godula, K.; Youn,
S. W.; Sezen, B.; Sames, D. J. Am. Chem. Soc. 2002, 124, 11856.
(10) For a review see for example: Weintraub, P. M.; Sabol, J. S.; Kane,
J. M.; Borchedering, D. R. Tetrahedron 2003, 59, 2953 and references cited.
(11) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
(12) See for example: (a) Myers, E. L.; de Vries, J. G.; Aggarwal, V.
K. Angew. Chem., Int. Ed. 2007, 46, 1893. (b) Armstrong, A.; Cumming,
G. R.; Pike, K. Chem. Commun. 2004, 812. (c) Åhman, J.; Somfai, P.
Tetrahedron 1992, 48, 9537. (d) Ungureanu, I.; Bologa, C.; Chayer, S.;
Mann, A. Tetrahedron Lett. 1999, 40, 5315. (e) Matsumura, Y.; Ikeda, T.;
Onomura, O. Heterocycles 2006, 67, 113. (f) Burgess, L. E.; Gross, E. K.
M.; Jurka, J. Tetrahedron Lett. 1996, 37, 3255.
(6) See for example: (a) Godin, G.; Compain, P.; Masson, G.; Martin,
O. R. J. Org. Chem. 2002, 67, 6960. (b) Godin, G.; Compain, P.; Martin,
O. R. Org. Lett. 2003, 5, 3269. (c) Compain, P.; Martin, O. R.; Boucheron,
C.; Godin, G.; Yu, L.; Ikeda, K.; Asano, N. ChemBioChem 2006, 7, 1356.
(d) Iminosugars: from Synthesis to Therapeutic Applications, (Eds.: P.
Compain, O. R. Martin), Wiley-VCH: Weinheim, 2007.
(7) Toumieux, S.; Compain, P.; Martin, O. R.; Selkti, M. Org. Lett. 2006,
8, 4493.
(13) For reviews on the chemistry of N-Acyliminiums ions and related
intermediates see: (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron
2000, 56, 3817. (b) Royer, J.; Bonin, M.; Micouin, L. Chem. ReV. 2004,
104, 2311.
(8) For the first example of a metal-catalyzed amination of pseudo-
anomeric C-H bond see: Toumieux, S.; Compain, P.; Martin, O. R.
Tetrahedron Lett. 2005, 46, 4731.
(14) Berry, C. R.; Hsung, R. P. Tetrahedron 2004, 60, 7629.
2156 J. Org. Chem., Vol. 73, No. 6, 2008

Multifunctionalization of UnactiVated C-H Bonds in Piperidines
SCHEME 2 a
TABLE 1. Addition of Allylsilane to N-Tosyliminium Ions Derived
from Aminal 2a
entry
acid
equiv reaction time (h)
T (°C)
yieldb (%)
1
2
3
4
5
6
7
BF3‚OEt2
1
16
28
3
-78 to -40
-78 to -40
-78 to -40
-78 to rtc
-78 to -40
-78 to rt
78
13
77
86c
d
BF3‚OEt2 0.5
SnCl4
SnCl4
TMSOTf
ZnCl2
p-TsOH
1.5
0.7c
1
1.5
0.2
24c
22
16
20
a Reagents and conditions: (a) AcOH, 60 °C; (b) (i) I2 (1.9 equiv),
MeONa (2 equiv), MeOH, -78 °C; (ii) DBU (2 equiv), toluene, 60 °C, 20
h; (c) PhI(OAc)2 (1.1 equiv), MgO (2.3 equiv), Rh2(esp)2 (0.01 equiv),
CH2Cl2, 40 °C.
d
d
0 to rt
a All compounds are racemic. b Isolated yield after purification on silica
gel. c 0.2 equiv of Lewis acid was first introduced in the flask, and then an
additional 0.5 equiv of Lewis acid was added after 16 h at 0 °C.
d Degradation products were observed on TLC and NMR spectra along with
various amount of enamine 8.
group at C-6 afforded the bicyclic piperidine 4b in 46% yield.
Exposure of 6-allyl piperidine 3a to PhI(OAc)2, MgO, and
catalytic Rh2(esp)2 led to a mixture of unidentifiable products,
arising probably from side reactions such as amination of allylic
C-H bonds or aziridination. The last step of our strategy, which
allowed the introduction of a second diversity point, the creation
of a new bond and the removal of the “activating arm”, was
evaluated on 6-propyl piperidine 4d to access alkaloids related
to coniine.16 After activation of the oxathiazinane by carbony-
lation of the NH moiety, ring-opening of compound 6 proceeded
in very good yields with various heteroatomic nucleophiles
(Scheme 1).4a,17 It is noteworthy that 3-amino 2,6-disubstituted
piperidines are known to display anti-allergic and anti-inflam-
matory activities.18
General Access to Polysubstituted 3-Aminopiperidines.
Armed with the first successful results, we further expanded
the scope of our iterative strategy with a double objective. First,
our aim was to design an approach in which the sulfamoyloxy
activating arm would be directly or indirectly involved in the
functionalization of every saturated methylene of monosubsti-
tuted piperidine 1. Second, to extend the flexibility of our
strategy by avoiding possible chemo- and regioselectivity issues,
amination reaction at C-3 was performed before introducing
structural diversity at C-6. Our approach exploited the reactivity
of enamine 8 which was readily obtained from 2 by reaction in
AcOH in 90% yield (Scheme 2).19,20 The use of a stronger
Brønsted acid (TFA) or of Lewis acid conditions (SnCl4 in CH2-
Cl2) led to lower yields.
14
The use of other Lewis acids, such as TMSOTf12f or ZnCl2
(entries 5 and 6), or of a Brønsted acid12e (entry 7) led to
degradation products and to various amounts of enamine 8.
The reaction of aminal 27 with propargyltrimethylsilane or
triethylsilane afforded the expected piperidines in good to
excellent yield, whereas the addition of 1-phenyl-1-trimethyl-
silyloxyethylene was unsuccessful. High levels of diastereose-
lectivity were observed for the addition of propargyltrimethyl-
silane in favor of the 2,6-cis derivative (Scheme 1). The addition
of the less sterically demanding deuteride ion led to piperidine
3c with a lower degree of diastereoselectivity (60% de). The
cis stereoselectivity may be rationalized by preferential axial
addition of the nucleophile to a half-chair conformation of the
cyclic iminium intermediate 5 in which the substituent at C-2
is pseudoaxial to avoid pseudo A1,3 strain with the N-tosyl group
(Scheme 1).6a,7,15 Delivery of nucleophiles in the axial direction
minimizes torsional strain during the transition to the final chair
conformation of piperidine ring. The stereochemistry of the
newly formed bond was established by extensive NMR analysis
and definitively assigned by X-ray crystallographic analysis.7
The next key step of our strategy was the second C-H bond
amination using the sulfamoyloxymethyl arm regenerated by
nucleophilic ring-opening of aminal 2 (Scheme 1).
One of the pivotal issues of this process was the regioselec-
tivity of the insertion reaction at C-2 or C-3, position 6 being
at this stage unavailable as a result of the formation of a 2,6-
cis isomer. It is indeed known that amination reactions
performed with sulfamate esters lead generally to the formation
of the corresponding six-membered ring insertion products but
that electron-donating groups generally activate the R-C-H
bond toward insertion.3b The Rh-catalyzed amination was first
investigated with 6-propyl piperidine 3d obtained by hydrogena-
tion of 3a in the presence of 10% Pd/C in MeOH (Scheme 1).
The amination reaction was found to be highly regioselective
and afforded the desired oxathiazinane 4d as a single diaste-
reoisomer. The nature of the Rhodium catalyst was found to be
critical since the use of Rh2(esp)2 provided 4d in 71% yield
whereas the use of Rh2(OAc)4 led to a much lower yield of
24%. More challenging structures such as 3b bearing an allenic
Iodomethoxylation of R,â-unsaturated N-tosylpiperidine 8
using I2 and MeONa in MeOH, followed by DBU-mediated
(16) See for example: Boto, A.; Herna´ndez, D.; Herna´ndez, R.; Montoya,
A.; Sua´rez, E. Eur. J. Org. Chem. 2007, 325.
(17) For the synthesis of piperidine derivatives by nucleophilic ring-
opening of cyclic sulfamidates see for example: Bower, J. F.; Szeto, P.;
Gallagher, T. Org. Lett. 2007, 9, 4909.
(18) Takahashi, M.; Miyake, T.; Yamakita, H.; Saito, A.; Asai H. (Tanabe
Seiyaku Co., Ltd.), PCT Int. Appl. WO 2002026710, 2002.
(19) Rossen, K.; Kolarovic, A.; Baskakov, D.; Kiesel, M. Tetrahedron
Lett. 2004, 45, 3023.
(20) N-acyl- or N-sulfonyl-1,2,3,4-tetrahydropyridine derivatives have
been used as versatile intermediates in the general synthesis of polyfunc-
tionalized piperidines, see for example: (a) Comins, D. L.; Sandelier, M.
J.; Grillo, T. A. J. Org. Chem. 2001, 66, 6829. (b) Comins, D. L.; Kuethe,
J. T.; Hong, H.; Lakner, F. J. J. Am. Chem. Soc. 1999, 121, 2651. (c)
Adelbrecht, J.-C; Craig, D.; Dymock, B. W.; Thorimbert, S. Synlett 2000,
467. (d) Craig, D.; McCague, R.; Potter, G. A.; Williams, R. V. Synlett
1998, 55.
(15) Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68, 8867.
J. Org. Chem, Vol. 73, No. 6, 2008 2157

Toumieux et al.
SCHEME 3. Addition of Various Nucleophiles to
SCHEME 4
N-Tosyliminium Ions Derived from 10a
SCHEME 5 a
a All compounds are racemic. bIsolated yield after purification on silica
c
gel. Determined from 1H and 13C NMR analysis on the crude products.
dehydroiodination, provided the desired 6-methoxytetrahydro-
pyridine 9 with a double bond tactically positioned at C(4)-
C(5).21 Remarkably, this three-step process can be performed
without purification of the intermediates providing compound
9 in 73% yield from 2. Rh-catalyzed amination of allylic C-H
bond at C-3 was then favored and provided in 87% yield
oxathiazinane 10 as an advanced intermediate for the general
synthesis of pentasubstituted piperidines. As a potential precur-
sor of the R,â-unsaturated iminium ion A with three electrophilic
sites of orthogonal reactivity at C-4, C-6, and C-1′, bicyclic
compound 10 displays a unique reactivity pattern. The different
reactivity of the three electrophilic sites was confirmed by
treatment of 10 with SnCl4 and various silylated nucleophiles
according to conditions described for ring opening of 2 (Scheme
3).21,22
This process provided piperidines 11a-d, corresponding to
the 1,2-adducts, with good to high diastereoselectivity and with
complete regioselectivity. It was established by 2D COSY and
NOESY NMR experiments that the relative configurations of
the major epimers obtained are cis,cis. For example, the definite
NOE interactions in 11a between -CH2SO2- and -CH2CHd
CH2, and between H-2 and H-3, indicated that these substituents
were on the same side of the piperidine rings. Contrary to results
obtained with aminal 2, addition of silylated enol ethers, such
as 1-phenyl-1-trimethylsilyloxyethylene, could be performed
successfully. The diastereoselectivity observed in favor of the
cis products may be explained as a result of a strong stereo-
electronic preference for a pseudoaxial attack of the nucleophile
on the intermediate iminium ion A (Scheme 2) with a pseudo-
axial sulfamoyloxymethyl substituent.22d Equatorial attack would
indeed generate torsional and pseudo A1,3 strain during the
transition from a sp2 to a sp3 carbon at C-6. Also, the versatile
synthon 11e21,23 was obtained in 89% yield by way of an SN2′
(or SN1′)-like reaction at C-4 upon treatment of 9 with BF3‚
a Reagents and conditions: (a) Ac2O (5 equiv), DMAP (0.1 equiv),
t-BuOK (1.1 equiv), CH2Cl2, -20 °C; (b) OsO4 (0.2 equiv), NMO (4 equiv),
acetone/water (9/1), rt; (c) Ac2O (15 equiv), DMAP (0.3 equiv), CH2Cl2,
rt; (d) KOAc (2 equiv), DMF, 40 °C; (e) Boc2O (2 equiv), DMAP (0.2
equiv), pyridine (14 equiv), CH2Cl2, 0 °C, 70% (two steps from 10); (f)
KOAc (2 equiv), DMF, 40 °C; (g) Na/naphthalene (9 equiv), THF,
-78 °C.
OEt2 (Scheme 4). Addition of allysilane onto 11e in the presence
of SnCl4 afforded the 2,6-disubstituted piperidine 11f in modest
yield (not optimized) but as a single cis diastereoisomer,
demonstrating the synthetic potential of such an intermediate.
The stereochemistry of 11f was determined by its conversion
to piperidine 3d via hydrogenation in the presence of 10% Pd/C
in MeOH.
To further probe the versatility of bicyclic intermediate 10,
stepwise functionalization into more complex structures related
to iminosugars was then performed with compounds 11a (R1
) allyl) and 11d (R1 ) H) (Scheme 5). The electrophilic activity
of the oxathiazinane was enhanced by the addition of an N-acyl
substituent. Formation of 15, the N-Boc derivatives of sulfamate
11a, followed by ring-opening with potassium acetate provided
16 in good yield. Deprotection of the N-tosylpiperidines with
sodium naphthalenide afforded the advanced intermediates 17
which resulted from O f N-acetyl group migration.
(21) Shono, T.; Terauchi, J.; Ohki, Y.; Matsumura, Y. Tetrahedron Lett.
1990, 31, 6385.
(22) For a related process see: (a) Torii, S.; Inokuchi, T.; Takagishi, S.;
Akahoshi, F.; Uneyama, K. Chem. Lett. 1987, 639. (b) Tjen, K. C. M. F.;
Kinderman, S. S.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T.
Chem. Commun. 2000, 699. (c) Kinderman, S. S.; Doodeman, R.; Van
Beijma, J. W.; Russcher, J. C.; Tjen, K. C. M. F.; Kooistra, T. M.;
Mohaselzadeh, H.; Van Maarseveen, J. H.; Hiemstra, H.; Shoemaker, H.
E.; Rutjes, F. P. J. T. AdV. Synth. Catal. 2002, 344, 736. (d) Kennedy, A.;
Nelson, A.; Perry, A. Belstein J. Org. Chem. 2005, 1:2, doi:10.1186/1860-
5397-1-2.
Synthesis of the fully protected amino iminosugar 14 (in
racemic form) began with the N-acetylation of oxathiazinane
11d, and the highly diastereoselective dihydroxylation of the
endocyclic double bond of 12, which occurred anti to the
oxathiazinane ring under Upjohn reaction conditions.24 It is
noteworthy that the same reaction performed with the unacylated
(23) Kozikowski, A. P.; Park, P.-U. J. Org. Chem. 1984, 49, 1674.
(24) Kennedy, A.; Nelson, A.; Perry, A. Chem. Commun. 2005, 1646.
2158 J. Org. Chem., Vol. 73, No. 6, 2008

Multifunctionalization of UnactiVated C-H Bonds in Piperidines
1163 cm-1. HRMS: calcd for C16H26N2O5S2Na [M + Na]+
413.1181, found 413.1182 (0 ppm).
analog of 12, compound 11d, led only to degradation products.
Direct acetylation of the resulting product followed by nucleo-
philic ring-opening with potassium acetate afforded the expected
protected iminosugar 14.
General Cyclization Procedure. To a ∼0.04 M solution of
sulfamate ester dissolved in degassed dichloromethane were suc-
cessively added MgO (2.3 equiv), PhI(OAc)2 (1.1 equiv), and Rh2-
(esp)2 or Rh2(OAc)4 (0.02-0.05 equiv). The solution was stirred
at 40 °C until TLC indicated total conversion of starting material
(4-24 h). After cooling at room temperature, the solution was
filtered through a pad of Celite and washed three times with
dichloromethane and acetone. The filtrate was evaporated to dryness
under reduced pressure. The crude mixture was purified by
chromatography on silica gel.
Conclusion
In conclusion, these preliminary studies demonstrate that the
iterative multifunctionalization of unactivated C-H bonds is
an attractive strategy for the general synthesis of polyfunction-
alized piperidines. Efficient stereocontrolled preparations of di-,
tri-, tetra-, and penta-substituted piperidines from simple 2-sul-
famoyloxymethyl piperidine derivatives have been performed.
In this process, the “sulfamoyloxymethyl activating arm” was
directly or indirectly involved in the functionalization of every
saturated methylene of the piperidine ring at C-3, C-4, C-5, and
C-6. Direct application to the total synthesis of iminosugars and
related compounds demonstrates the synthetic potential of this
strategy which should become a useful tool for the diversity-
oriented synthesis of various bioactive azacycloalkanes by
iterative and direct heterocyclic scaffold decoration. Recent
studies have for example shown the interest of grafting
pharmacophore groups at selected positions on piperidine
scaffolds.25 Following these lines, we are currently devising
various nitrogen-containing systems (cyclic or acyclic) to further
expand the synthetic scope of this chemistry.
(4aS*,6R*,8aR*)-6-Propadienyl-5-(toluene-4-sulfonyl)octahy-
dro-3-oxa-2-thia-1,5-diazanaphthalene 2,2-Dioxide (4b). Com-
pound 3b (50 mg, 0.134 mmol) was treated as described in the
general cyclization procedure using MgO (13 mg, 0.309 mmol, 2.3
equiv), PhI(OAc)2 (49 mg, 0.148 mmol, 1.1 equiv), and Rh2(esp)2
(2 mg, 0.003 mmol, 0.02 equiv). The resulting crude product was
purified by silica gel chromatography (PE/AcOEt 7/3) to provide
1
4b (24 mg, 46%, de g 98%) as a colorless oil. H NMR (CDCl3,
500 MHz): δ 1.38 (m, 1H, H5), 1.77 (m, 1H, H4eq), 2.01 (br d,
1H, H5eq), 2.44 (s, 3H, Me), 2.66 (dq, 1H, J ≈ 3.5 Hz, J ≈ 3 ×
14.0 Hz, H4ax), 3.16 (m, 1H, H3), 4.34 (ddd, 1H, J ≈ 1.5 Hz, J ≈
6.5 Hz, J ≈ 11.3 Hz, CHAOSO2), 4.49 (dt, 1H, J ≈ 2 × 5.4 Hz, J
≈ 11.0 Hz, H2), 4.68 (narrow m, 1H, H6), 4.96 (m, 3H, CH2dCd
CH, NH), 5.10-5.18 (m, 2H, CHBOSO2, CH2dCdCH), 7.32 (d,
2H, J ≈ 8.0 Hz, HAr), 7.72 (d, 2H, J ≈ 8.2 Hz, HAr). 13C NMR
(CDCl3, 62.5 MHz): δ 20.2 (C4), 21.7 (Me), 26.6 (C5), 48.6 (C6),
48.7 (C2), 53.6 (C3), 69.2 (CH2OSO2), 79.12 (CH2dCdCH), 93.1
(CH2dCdCH), 126.9 (CHAr), 130.3 (CHAr), 137.3 (Cq), 144.4 (Cq),
207.3 (CH2dCdCH). IR (neat) 3273, 1956, 1161 cm-1. HRMS:
calcd for C16H20N2O5NaS2 [M + Na]+ 407.07114, found 407.0702
(2 ppm).
Experimental Section
(2S*,6R*)-6-Propadienyl-2-sulfamoyloxymethyl-1-(toluene-4-
sulfonyl)piperidine (3b). To a 0.1 M solution of 27 (50 mg, 0.144
mmol) in CH2Cl2 were added at -78 °C propargyltrimethylsilane
(0.086 mL, 0.576 mmol, 4 equiv) and SnCl4 (1M in CH2Cl2) (0.028
mL, 0.028 mmol, 0.2 equiv). The solution was rapidly warmed to
0 °C and stirred for 6 h at this temperature. The reaction mixture
was quenched with saturated aqueous NaHCO3, extracted with CH2-
Cl2, dried over MgSO4, and concentrated under reduced pressure.
Purification on silica gel (PE/AcOEt 6:4) gave 3b as a colorless
(4aS*,6S*,8aR*)-6-Propyl-5-(toluene-4-sulfonyl)octahydro-3-
oxa-2-thia-1,5-diazanaphthalene 2,2-Dioxide (4d). Compound 3d
(71 mg, 0.182 mmol) was treated as described in the general
cyclization procedure using MgO (16.7 mg, 0.419 mmol, 2.3 equiv),
PhI(OAc)2 (64.6 mg, 0.20 mmol, 1.1 equiv), and Rh2(esp)2 (6.84
mg, 0.009 mmol, 0.02 equiv). The resulting crude product was
purified by silica gel chromatography (PE/AcOEt 7/3) to provide
1
1
oil (54 mg, 99%, de g 98%). H NMR (CDCl3, 400 MHz): δ
4d (50 mg, 71%, de g 98%) as a white solid. H NMR (CDCl3,
1.22-1.42 (m, 3H, H3A, 2H5), 1.56-1.89 (m, 3H, H3B, 2H4), 2.44
(s, 3H, Me), 4.35-4.42 (m, 3H, CH2OSO2, H2), 4.64 (m, 1H, H6),
4.86 (dd, 2H, J ≈ 4.4, 6.4 Hz, CHdCdCH2), 5.04 (s, 2H, NH2),
5.25-5.31 (m, 1H, CHdCdCH2), 7.31 (d, 2H, J ≈ 8.0 Hz, HAr),
7.72 (d, 2H, J ≈ 8.3 Hz, HAr). 13C NMR (CDCl3, 62.5 MHz): δ
14.1 (C4), 21.6 (Me), 24.2 (C3 or C5), 26.0 (C3 or C5), 49.4 (C6),
50.8 (C2), 69.7 (CH2OSO2), 78.4 (CH2dCdCH), 93.8 (CH2d
C)CH), 127.0 (CHAr), 130.0 (CHAr), 137.9 (Cq), 143.8 (Cq), 207.0
(CH2)C)CH). IR (neat) 3268, 1952 cm-1. HRMS: calcd for
C16H23N2O5S2 [M + H]+ 387.10484, found 387.1040 (2 ppm).
(2S*,6S*)-6-Propyl-2-sulfamoyloxymethyl-1-(toluene-4-sulfo-
nyl)piperidine (3d). To 3a7 (920 mg, 2.37 mmol) in MeOH (20
mL) was added 10% Pd/C (0.2 equiv). The flask was purged three
times with Ar and then filled with H2. The reaction mixture was
stirred at rt. After 15 h, the solids were removed by filtration and
washed with MeOH. The filtrate was concentrated under reduced
pressure. Purification on silica gel (PE/AcOEt 7/3) gave 3d as a
colorless oil (763 mg, 72%, de g 98%): 1H NMR (CDCl3, 250
MHz): δ 0.92 (t, 3H, J ≈ 7.2 Hz, CH3CH2CH2), 1.16-1.71 (m,
10H, 2H3, 2H4, 2H5, CH3CH2CH2), 2.42 (s, 3H, Me), 3.91 (q, 1H,
J ≈ 5.6 Hz, H6), 4.40 (br s, 3H, CH2OSO2, H2), 5.37 (s, 2H, NH2),
7.30 (d, 2H, J ≈ 8.2 Hz, HAr), 7.72 (d, 2H, J ≈ 8.2 Hz, HAr). 13C
NMR (CDCl3, 62.5 MHz): δ 13.7 (C4), 13.9 (CH2CH2CH3), 20.4
(CH2CH2CH3), 21.6 (Me), 24.0 (C3 or C5), 26.6 (C3 or C5), 37.7
(CH2CH2CH3), 50.5 (C2), 52.5 (C6), 70.7 (CH2OSO2), 126.9 (CHAr),
129.9 (CHAr), 137.9 (CqAr), 143.5 (CqAr). IR (neat) 3281, 1377,
500 MHz): δ 0.95 (t, 3H, J ≈ 7.25 Hz, CH3CH2CH2), 1.15-1.45
(m, 3H), 1.53-1.58 (m, 2H), 1.66-1.73 (m, 2H) (CH3CH2CH2,
H
4eq, 2H5), 2.42 (s, 3H, Me), 2.51 (br q, 1H, J ≈ 13.0 Hz, H4ax),
3.01 (m, 1H, H3), 3.91 (q, 1H, J ≈ 6.5 Hz, H6), 4.44 (dd, 1H, J ≈
4.0 Hz, J ≈ 11.0 Hz, CHAOSO2), 4.50 (dt, 1H, J ≈ 2 × 5.5, 11.6
Hz, H2), 4.88 (t, 1H, J ≈ 11.3 Hz, CHBOSO2), 5.35 (d, 1H, J ≈
6.0 Hz, NH), 7.31 (d, 2H, J ≈ 8.0 Hz, HAr), 7.71 (d, 2H, J ≈ 8.0
Hz, HAr). 13C NMR (CDCl3, 62.5 MHz): δ 13.9 (CH2CH2CH3),
19.8 (CH2CH2CH3), 20.5 (C4), 21.7 (Me), 27.0 (C5), 37.5 (CH2-
CH2CH3), 48.2 (C2), 51.8 (C6), 53.45 (C3), 70.1 (CH2OSO2), 126.8
(CHAr), 130.3 (CHAr), 137.4 (CqAr), 144.2 (CqAr). IR (neat) 1265,
1163 cm-1. HRMS: calcd for C16H25N2O5S2 [M + H]+ 389.1205,
found 389.1221 (4 ppm).
(4aS*,6S*,8aR*)-1-Benzyloxycarbonyl-6-propyl-5-(toluene-4-
sulfonyl)octahydro-3-oxa-2-thia-1,5-diazanaphthalene 2,2-Di-
oxide (6). To a solution of 4d (290 mg, 0.747 mmol) in DME (15
mL) was added t-BuOK (127 mg, 1.12 mmol, 1.5 equiv) at 0 °C.
The mixture was stirred during 1.5 h at this temperature. CbzCl
(0.266 mL, 1.868 mmol, 2.5 equiv) was added, and the reaction
was stirred overnight at rt. The reaction mixture was quenched with
H2O, extracted with CH2Cl2, dried over MgSO4, and concentrated
under reduced pressure. Purification on silica gel (PE/AcOEt 8/2)
1
gave 6 as a colorless oil (280 mg, 72%, de g 98%). H NMR
(CDCl
3, 250 MHz): δ 0.96 (t, 3H, J ≈ 7.2 Hz, CH2CH2CH3), 1.20-
1.48 (m, 3H, H5A, CH2CH2CH3), 1.52-1.76 (m, 4H, H4eq, H5B, CH2-
CH
2CH3), 2.21 (m, 1H, H4ax), 2.43 (s, 3H, Me), 3.97 (q, 1H, J ≈
6.6 Hz, H6), 4.19 (m, 1H, H3), 4.56 (q, 1H, J ≈ 6.9 Hz, H2), 4.65-
4.83 (m, 2H, CH2OSO2), 5.29 (AB, 2H, J ≈ 12.2 Hz, OCH2Ph),
(25) Murphy, P. V.; Dunne, J. L. Curr. Org. Synth. 2006, 3, 403.
J. Org. Chem, Vol. 73, No. 6, 2008 2159

Toumieux et al.
7.25-7.40 (m, 7H, HAr), 7.67 (d, 2H, J ≈ 8.2 Hz, HAr). 13C NMR
(CDCl3, 62.5 MHz): δ 13.9 (CH2CH2CH3), 20.4 (C4, CH2CH2-
CH3), 21.7 (Me), 26.3 (C5), 36.0 (CH2CH2CH3), 48.2 (C2), 51.8
(C6), 55.9 (C3), 69.9 (OCH2Ph), 73.4 (CH2OSO2), 126.0 (CHAr),
126.7 (CHAr), 127.8 (CHAr), 128.8 (CHAr), 130.3 (CHAr), 134.5 (Cq),
137.3 (Cq), 144.3 (Cq), 151.6 (CdO). IR (neat) 2960, 1740, 1291,
1165 cm-1. HRMS: calcd for C24H31N2O7NaS2 [M + Na]+
545.13921, found 545.1394 (0 ppm).
7.45 (m, 7H, HAr), 7.71 (d, 2H, J ≈ 8.2 Hz, HAr). 13C NMR (DMSO-
d6, 62.5 MHz): δ 14.0 (CH2CH2CH3), 19.2 (C4 or CH2CH2CH3),
19.5 (C4 or CH2CH2CH3), 20.4 (Me), 26.0 (C5), 35.7 (CH2CH2-
CH3), 48.6 (C3), 50.3 (C6 or C2), 50.8 (C6 or C2), 53.3 (CH2N3),
65.2 (OCH2Ph), 126.3 (CHAr), 127.2 (CHAr), 127.3 (CHAr), 127.8-
(CHAr), 129.3 (CHAr), 136.6 (Cq), 137.8 (Cq), 142.5 (Cq). IR (neat)
3365, 2101, 1715, 1162 cm-1. HRMS: calcd for C24H31N5O4NaS
[M + Na]+ 508.1994, found 508.1994 (0 ppm).
2-Sulfamoyloxymethyl-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahy-
dropyridine (8). A solution of 2 (3.89 g, 11.2 mmol) in AcOH
(80 mL) was stirred for 6 h at 60 °C. The solvent was removed by
coevaporation with toluene. The crude product was used directly
(2S*,3R*,6S*)-2-Acetoxymethyl-3-benzyloxycarbonylamino-
6-propyl-1-(toluene-4-sulfonyl)piperidine (7a). To a solution of
6 (50 mg, 0.0957 mmol) in DMF (1 mL) was added KOAc (19
mg, 0.192 mmol, 2 equiv) at rt. The mixture was stirred for 15 h,
and aqueous HCl 1 N solution was then added; the mixture was
stirred for 1 h at rt, extracted with CH2Cl2, dried over MgSO4, and
concentrated under reduced pressure. Purification on silica gel (PE/
1
in the next steps. H NMR (CDCl3, 250 MHz): δ 0.98 (m, 1H,
H4A), 1.71-2.07 (m, 3H, 2H3, H4B), 2.41 (s, 3H, Me), 4.10 (dd,
1H, J ≈ 7.7 Hz, J ≈ 10.0 Hz, CHAOSO2), 4.24-4.30 (m, 3H, CHB-
OSO2, H2), 5.07 (m, 1H, H5), 5.39 (s, 2H, NH2), 6.58 (d, 1H, J ≈
8.2 Hz, H6), 7.31 (d, 2H, J ≈ 8.2 Hz, HAr), 7.67 (d, 2H, J ≈ 8.2
Hz, HAr). 13C NMR (CDCl3, 62.5 MHz): δ 17.0 (C3), 20.3 (C4),
21.7 (Me), 51.0 (C2), 68.3 (CH2OSO2), 109.3 (C5), 123.3 (C6), 127.1
(CHAr), 130.1 (CHAr), 135.3 (Cq), 144.2 (Cq). MS-IS m/z 369.0
1
AcOEt 7/3) gave 7a as a colorless oil (37 mg, 77%). H NMR
(DMSO-d6, 80 °C, 250 MHz): δ 0.88 (t, 3H, J ≈ 7.0 Hz, CH2-
CH2CH3), 1.09-1.75 (m, 8H, 2H4, 2H5, CH2CH2CH3, CH2CH2-
CH3), 1.95 (s, 3H, CH3), 2.39 (s, 3H, Me), 3.37 (m, 1H, H3), 3.81
(q, 1H, J ≈ 6.2 Hz, H6), 3.98 (dd, 1H, J ≈ 7.2 Hz, J ≈ 11.5 Hz,
CHAOSO2), 4.32 (dd, 1H, J ≈ 6.0 Hz, J ≈ 11.5 Hz, CHBOSO2),
4.55 (q, 1H, J ≈ 6.2 Hz, H2), 5.07 (s, 2H, OCH2Ph), 7.14 (br s,
1H, NH), 7.34-7.38 (m, 7H, HAr), 7.69 (d, 2H, J ≈ 7.75 Hz, HAr).
13C NMR (CDCl3, 62.5 MHz): δ 14.0 (CH2CH2CH3), 20.4 (C4 or
CH2CH2CH3), 20.9 (CH3), 21.2 (C4 or CH2CH2CH3), 21.7 (Me),
26.9 (C5), 36.8 (CH2CH2CH3), 49.1 (C3), 51.5 (C6), 52.6 (C2), 63.2
(CH2OAc), 67.0 (OCH2Ph), 126.7 (CHAr), 128.3 (CHAr), 128.4
(CHAr), 128.7 (CHAr), 136.2 (Cq), 138.5 (Cq), 143.3 (Cq), 151.6
(CdO), 170.9 (CdO). IR (neat) 3359, 1735, 1715, 1520, 1165
cm-1. HRMS: calcd for C26H34N2O6NaS [M + Na]+ 525.2035,
found 525.2046 (2 ppm).
[M + Na]+, 347.0 [M + H]+. IR (neat) 3281, 1346, 1162 cm-1
.
(2S*,6S*)-6-Methoxy-2-sulfamoyloxymethyl-1-(toluene-4-sul-
fonyl)-1,2,3,6-tetrahydropyridine (9). To a solution of crude 8
(3.890 g, 11.2 mmol) in MeOH (130 mL) was added NaOMe
(1.17 g, 22.480 mmol, 2 equiv). The mixture was cooled to
-78 °C, and I2 (5.425 g, 21.36 mmol, 1.9 equiv) was added. The
mixture was stirred for 1.25 h at this temperature. The reaction
mixture was quenched with saturated aqueous Na2S2O3, extracted
with AcOEt, dried over MgSO4, and concentrated under reduced
pressure to afford the iodomethoxylation product as a single
diastereoisomer which was used directly in the next step with no
1
further treatment. H NMR (CDCl3, 250 MHz): δ 1.60-1.85 (m,
(2S*,3R*,6S*)-2-Phenylthiomethyl-3-benzyloxycarbonylamino-
6-propyl-1-(toluene-4-sulfonyl)piperidine (7b). To a solution of
6 (50 mg, 0.0957 mmol) in CH3CN (5 mL) were added K2CO3 (32
mg, 0.229 mmol, 2.4 equiv) and thiophenol (0.023 mL, 0.229 mmol,
2.4 equiv) at -20 °C to rt over 24 h. The mixture was then stirred
for 15 h at rt. Aqueous 1 N HCl solution (10 mL) and AcOEt (10
mL) were added to the reaction mixture, which was stirred for 1 h
at rt and then extracted with CH2Cl2, dried over MgSO4, and
concentrated under reduced pressure. Purification on silica gel (PE/
AcOEt 7/3) gave 7b as colorless oil (44 mg, 83%). 1H NMR
(DMSO-d6, 80 °C, 250 MHz): δ 0.86 (m, 3H, CH2CH2CH3), 1.13-
1.42 (m, 5H, H4A, CH2CH2CH3, CH2CH2CH3), 1.46-1.80 (m, 3H,
H4B, H5), 2.38 (s, 3H, Me), 2.94-3.09 (m, 1H, CHASPh), 3.27-
3.41 (m, 2H, H3, CHBSPh), 3.81 (m, 1H, H6), 4.60 (m, 1H, H2),
5.07 (m, 2H, OCH2Ph), 7.20 (m, 2H, CHar, NH), 7.29-7.40 (m,
11H, HAr), 7.65-7.73 (m, 2H, HAr). 13C NMR (DMSO-d6, 80 °C,
100 MHz): δ 12.9 (CH2CH2CH3), 19.4 (C4 or CH2CH2CH3), 19.3
(C4 or CH2CH2CH3), 20.3 (Me), 26.2 (C5), 33.4 (CH2S), 35.7 (CH2-
CH2CH3), 49.5 (C3), 50.9 (C6), 53.8 (C2), 65.1 (OCH2Ph), 125.2
(CHAr), 126.2 (CHAr), 127.1 (CHAr), 127.2 (CHAr), 127.7 (CHAr),
128.1 (CHAr), 128.2 (CHAr), 128.3 (CHAr), 129.1 (CHAr), 136.6 (Cq),
137.9 (Cq), 142.4 (Cq), 154.3 (CdO). IR (neat) 3366, 1714, 1158
cm-1. HRMS: calcd for C30H36N2O4NaS2 [M + Na]+ 575.20142,
found 575.2005 (2 ppm).
(2S*,3R*,6S*)-2-Azidomethyl-3-benzyloxycarbonylamino-6-
propyl-1-(toluene-4-sulfonyl)piperidine (7c). To a solution of 6
(50 mg, 0.0957 mmol) in DMSO (2 mL) was added NaN3 (12.5
mg, 0.191 mmol, 2 equiv) at 0 °C to rt over 8 h. Aqueous 1 N HCl
(2 mL) solution and Et2O (2 mL) were added to the reaction
mixture, which was stirred for 1 h at rt, extracted with Et2O, dried
over MgSO4, and concentrated under reduced pressure. Purification
on silica gel (PE/AcOEt 8/2) gave 7c as colorless oil (40 mg, 87%).
1H NMR (DMSO-d6, 80 °C, 250 MHz): δ 0.90 (t, 3H, CH2-
CH2CH3), 1.10-1.69 (m, 8H, 2H4, 2H5, CH2CH2CH3), 2.40 (s, 3H
Me), 3.23 (m, 1H, H3), 3.39 (dd, 1H, J ≈ 7.0 Hz, J ≈ 13.0 Hz,
CHAN3), 3.60 (dd, 1H, J ≈ 6.0 Hz, J ≈ 13.0 Hz, CHBN3), 3.81 (q,
1H, J ≈ 6.5 Hz, H6), 4.46 (q, 1H, J ≈ 6.3 Hz, H2), 5.06 (AB, 2H,
J ≈ 12.7 Hz, OCH2Ph), 7.14 (br d, 1H, J ≈ 6.0 Hz, NH), 7.28-
3H, 2H3, H4A), 2.14 (m, 1H, H4B), 2.44 (s, 3H, Me), 3.46 (s, 3H,
OMe), 3.92 (m, 1H, H2), 4.40-4.52 (m, 3H, CH2OSO2, H5), 5.15
(s, 2H, NH2), 5.30 (s, 1H, H6), 7.32 (d, 2H, J ≈ 8.2 Hz, Har), 7.90
(d, 2H, J ≈ 8.2 Hz, Har). 13C NMR (CDCl3, 62.5 MHz): δ 20.4
(C3), 21.7 (Me), 22.7 (C4), 27.2 (C5), 50.3 (C2), 56.5 (OMe), 68.9
(CH2OSO2), 88.3 (C6), 128.6 (CHAr), 129.6 (CHAr), 135.6 (Cq),
144.4 (Cq).
This crude product (5.17 g, 10.25 mmol) was dissolved in toluene
(200 mL). DBU (3.05 mL, 20.5 mmol, 2 equiv) was added and the
solution was stirred 20 h at 60 °C. The reaction mixture was
quenched with 5% aqueous NaHCO3, extracted with AcOEt, dried
over Na2SO4, and concentrated under reduced pressure. Purification
on silica gel (CH2Cl2/Acetone 95/5) gave 9 as a colorless oil
1
(3.070 g, 73%, three steps from 2, de g 98%). H NMR (CDCl3,
250 MHz): δ 1.70 (m, 1H, H3A), 1.91 (dd, 1H, J ≈ 5.5 Hz, J ≈
18.7 Hz, H3B), 2.43 (s, 3H, Me), 3.50 (s, 3H, OMe), 4.29 (m, 3H,
CH2OSO2, H2), 5.17 (s, 2H, NH2), 5.35 (br s, 1H, H6), 5.64-5.87
(m, 2H, H4, H5), 7.30 (d, 2H, J ≈ 8.2 Hz, HAr), 7.67 (d, 2H, J ≈
8.2 Hz, HAr). 13C NMR (CDCl3, 62.5 MHz): δ 21.7 (Me), 23.2
(C3), 48.2 (C2), 56.0 (OMe), 70.2 (CH2OSO2), 80.9 (C6), 123.9
(C4 or C5), 125.6 (C4 or C5), 127.0 (CHAr), 130.0 (CHAr), 137.4
(Cq), 144.2 (Cq). IR (neat) 3285, 1361, 1162, 958 cm-1. HRMS:
calcd for C14H20N2O6NaS2 [M + Na]+ 399.0660, found 399.0663
(1 ppm).
(4aS*,6S*,8aR*)-6-Methoxy-5-(toluene-4-sulfonyl)-1,4,4a,5,6,-
8a-hexahydro-3-oxa-2-thia-1,5-diazanaphthalene 2,2-Dioxide (10).
Compound 9 (1.008 g, 2.681 mmol) was treated as described in
the general cyclization procedure using MgO (246 mg, 4.756 mmol,
2.3 equiv), PhI(OAc)2 (952 mg, 2.274 mmol, 1.1 equiv), and Rh2-
(esp)2 (20.1 mg, 0.020 mmol, 0.01 equiv). The resulting crude
product was purified by silica gel chromatography (EP/AcOEt 7/3)
1
to provide 10 (863 mg, 87%, de g 98%) as a colorless oil. H
NMR (CDCl3, 400 MHz): δ 2.43 (s, 3H, Me), 3.48 (s, 3H, OMe),
3.67 (t, 1H, J ≈ 6.0 Hz, H3), 4.20 (dt, 1H, J ≈ 2 × 5.0 Hz, J ≈
10.0 Hz, H2), 4.26 (dd, 1H, J ≈ 4.8 Hz, J ≈ 11.6 Hz, CHAOSO2),
5.13 (d, 1H, J ≈ 6.4 Hz, NH), 5.19 (dd, 1H, J ≈ 10.5 Hz, J ≈ 11.6
Hz, CHBOSO2), 5.33 (d, 1H, J ≈ 2.8 Hz, H6), 5.99 (narrow AB,
2160 J. Org. Chem., Vol. 73, No. 6, 2008

Multifunctionalization of UnactiVated C-H Bonds in Piperidines
2H, H4, H5), 7.32 (d, 2H, J ≈ 8.4 Hz, HAr), 7.70 (d, 2H, J ≈ 8.4
Hz, HAr). 13C NMR (CDCl3, 100 MHz): δ 21.7 (Me), 45.2 (C2),
50.5 (C3), 56.4 (OMe), 69.5 (CH2OSO2), 80.3 (C6), 126.3 (C4 or
C5), 127.2 (CHAr), 127.9 (C4 or C5), 130.4 (CHAr), 136.5 (Cq), 145.0
(Cq). IR (neat) 3269, 1351, 1190, 1166 cm-1. HRMS: calcd for
C14H18N2O6NaS2 [M + Na]+ 397.05040, found 397.0499 (1 ppm).
(4aS*,6R*S*,8aR*)-6-Allyl-5-(toluene-4-sulfonyl)-1,4,4a,5,6,-
8a-hexahydro-3-oxa-2-thia-1,5-diazanaphthalene 2,2-Dioxides
(11a). To a solution of 10 (50 mg, 0.134 mmol) in CH2Cl2 (3 mL)
were added at -78 °C allyltrimethylsilane (0.087 mL, 0.535 mmol,
4 equiv) and SnCl4 (1M in CH2Cl2, 0.134 mL, 0.134 mmol, 1
equiv). The solution was stirred for 1.5 h at this temperature and
was quenched with saturated aqueous NaHCO3, extracted with CH2-
Cl2, dried over MgSO4, and concentrated under reduced pressure.
Purification on silica gel (PE/AcOEt 8/2) gave 11a as a mixture of
epimers (colorless oil, 46 mg, 90%, de 61%). NMR analysis given
with pure CH2Cl2 followed by PE/AcOEt 9/1 to 7/3 gave 11c as a
colorless oil (105 mg, 65%, de g 95%). H NMR (CDCl3, 400
1
MHz): δ 2.41 (s, 3H, Me), 3.26 (dd, 1H, J ≈ 10.8 Hz, J ≈ 17.2
Hz, CHACdO), 3.56 (br s, 1H, H3), 3.65 (dd, 1H, J ≈ 2.8 Hz, J ≈
17.2 Hz, CHBCdO), 4.48 (dd, 1H, J ≈ 5.2 Hz, J ≈ 10.8 Hz, CHA-
OSO2), 4.66 (q, 1H, J ≈ 5.6 Hz, H2), 4.83 (t, 1H, J ≈ 10.8 Hz,
CHBOSO2), 4.89 (m, 1H, H6), 5.32 (d, 1H, J ≈ 6.0 Hz, NH), 5.92
(m, 2H, H4, H5), 7.31 (d, 1H, J ≈ 8.0 Hz, HAr), 7.48 (t, 2H, J ≈
8.0 Hz, HAr), 7.60 (t, 1H, J ≈ 7.6 Hz, HAr), 7.73 (d, 1H, J ≈ 8.0
Hz, HAr), 7.96 (d, 2H, J ≈ 7.6 Hz, HAr). 13C NMR (CDCl3, 100
MHz): δ 21.7 (Me), 45.3 (C2), 46.8 (CH2CdO), 48.5 (C6), 50.1
(C3), 69.5 (CH2OSO2), 124.5 (C4 or C5), 126.8 (CHAr), 127.7 (C4
or C5), 128.2 (CHAr), 128.9 (CHAr), 130.6 (CHAr), 133.8 (CHAr),
136.2 (Cq), 144.8 (Cq), 196.8 (CdO). IR (neat) 3282, 1681, 1353,
1191, 1162 cm-1. HRMS: calcd for C21H22N2O6NaS2 [M + Na]+
485.0817, found 485.0819 (0 ppm).
1
for a 2:1 cis/trans mixture of epimers 11a. H NMR (acetone-d6,
(1S*,6S*)-4-Oxa-7-(toluene-4-sulfonyl)-3-thia-2,7-diazabicyclo-
[4.3.1]dec-8-ene 3,3-Dioxide (11e). To a solution of 9 (54 mg,
0.144 mmol) in CH2Cl2 (3 mL), was added at -78 °C BF3‚OEt2
(0.028 mL, 0.144 mmol, 1 equiv). The solution was allowed to
return slowly to rt to complete conversion of starting material
(nearly 1 h) and was quenched with saturated aqueous NaHCO3,
extracted with CH2Cl2, dried over MgSO4, and concentrated under
reduced pressure. Purification by filtration on a pad of silica gel
(CH2Cl2/acetone 9/1) gave 11e as a colorless oil (44 mg, 89%, de
g 98%). 1H NMR (CDCl3, 400 MHz): δ 1.68 (dt, 1H, J ≈ 2 × 4.3
Hz, J ≈ 14.8 Hz, H3A), 2.39-2.47 (m, 4H, Me, H3B), 3.73 (t, 1H,
J ≈ 4.3 Hz, H4), 4.28-4.44 (m, 2H, H2, CHAOSO2), 4.51 (dd, 1H,
J ≈ 2.5 Hz, J ≈ 12.5 Hz, CHBOSO2), 4.98 (s, 1H, NH), 5.10 (m,
1H, H5), 7.03 (d, 1H, J ≈ 8.4 Hz, H6), 7.33 (d, 2H, J ≈ 8.4 Hz,
HAr), 7.67 (d, 2H, J ≈ 8.4 Hz, HAr). 13C NMR (CDCl3, 100 MHz):
δ 21.7 (Me), 29.3 (C3), 42.6 (C4), 51.5 (C2), 74.5 (CH2OSO2), 104.6
(C5), 126.9 (CHAr), 128.7 (C6), 130.3 (CHAr), 135.7 (Cq), 144.8
(Cq). IR (neat) 3286, 1355, 1215, 1169 cm-1. HRMS: calcd for
C13H16N2O5NaS2 [M + Na]+ 367.03984, found 367.0408 (3 ppm).
(2S*,6S*)-6-Allyl-2-sulfamoyloxymethyl-1-(toluene-4-sulfonyl)-
1,2,3,6-tetrahydropyridine (11f). To a solution of compound 11e
(72 mg, 0.209 mmol) in CH2Cl2 at -78 °C were added allyltrim-
ethylsilane (66 µL, 0.418 mmol, 2 equiv) and SnCl4 (1 M in CH2-
Cl2) (209 µL, 0.209 mmol, 1 equiv). The solution was stirred for
3 h at -78 °C and then 16 h at -35 °C. SnCl4 (42 µL, 0.042 mmol,
0.2 equiv) was added at -35 °C, and the reaction mixture was
stirred another 24 h at room temperature. The solution was then
quenched with NaHCO3, extracted with CH2Cl2, dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification on
silica gel (CH2Cl2/acetone 9/1) gave 11f as a colorless oil (30 mg,
400 MHz): δ 2.35-2.47 (s and m, 5.5H, Me, CHcisCHdCH2),
2.47-2.57 (m, 1H, CH2transCHdCH2), 2.57-2.67 (m, 1H, CHcis-
CHdCH2), 3.54 (m, 1H, H3cis), 4.23-4.38 (m, 2.5H, CHAcisOSO2,
H3trans, H6cis), 4.42-4.50 (m, 1H, H6trans, H2trans), 4.56 (dt, 1H, J ≈
5.6 Hz, J ≈ 11.2 Hz, H2cis), 4.64 (ddd, 0.5H, J ≈ 1.2 Hz, J ≈ 3 ×
4.4 Hz, CHAtransOSO2), 4.76 (t, 1H, J ≈ 11.2 Hz, CHBcisOSO2),
4.86-4.98 (m, 1.5H, CH2CHdCH2trans, CHBtransOSO2), 5.11-5.24
(m, 2H, CH2CHdCH2cis), 5.57 (m, 0.5H, CH2CHtransdCH2), 5.80-
6.02 (m, 4H, H4cis, H4trans, H5cis, H5trans, CH2CHcisdCH2), 6.22 (d,
0.5H, J ≈ 6.4 Hz, NHtrans), 6.92 (d, 1H, J ≈ 5.6 Hz, NHcis), 7.39-
7.46 (m, 3H, HAr), 7.77-7.86 (m, 3H, HAr). 13C NMR (acetone-d6,
100 MHz): δ 21.4 (Me), 38.7 (CH2transCHdCH2), 43.3 (CH2cis
-
CHdCH2), 46.2 (C2cis), 49.6 (C2trans), 50.4 (C3cis), 53.0 (C6cis), 53.9
(C3trans), 54.5 (C6trans), 70.1 (CH2cisOSO2), 70.3 (CH2transOSO2), 118.6
(CH2CHdCH2trans), 118.8 (CH2CHdCH2cis), 125.2 (C4trans or C5trans),
125.8 (C4cis or C5cis), 127.3 (C4cis or C5cis), 127.7 (CH2-CHcis)CH2),
127.8 (CHArcis), 130.5 (C4trans or C5trans), 130.7 (CHArtrans), 131.1
(CHArcis), 133.8 (CH2-CHtrans)CH2), 135.0 (CHArtrans), 137.9
(Cqcis), 140.0 (Cqtrans), 144.7 Cqtrans, 145.2 (Cqcis). IR (neat) 3271,
1352, 1191, 1163 cm-1. ESI: calcd for C16H20N2O5S2Na [M +
Na]+ 407.4, found 407.5.
(4aS*,6R*,8aR*)-6-Cyano-5-(toluene-4-sulfonyl)-1,4,4a,5,6,8a-
hexahydro-3-oxa-2-thia-1,5-diazanaphthalene 2,2-Dioxide (11b).
To a solution of 10 (100 mg, 0.268 mmol) in CH2Cl2 (2 mL) were
added at -78 °C trimethylsilyl cyanide (0.142 mL, 1.33 mmol, 5
equiv) and SnCl4 (1M in CH2Cl2, 0.187 mL, 0.187 mmol, 0.7
equiv). The solution was stirred for 2.5 h at this temperature. The
reaction mixture was quenched with saturated aqueous NaHCO3
at -78 °C, allowed to warm to rt, extracted with CH2Cl2, dried
over MgSO4, and concentrated under reduced pressure to afford
11b as a colorless oil (96 mg, 97%, de g 95%). It is important to
note that partial degradation occurred during purification on silica
gel. 1H NMR (acetone-d6, 250 MHz): δ 2.45 (s, 3H, Me), 3.94 (br
s, 1H, H3), 4.40 (ddd, 1H, J ≈ 1.2 Hz, J ≈ 5.2 Hz, J ≈ 11.2 Hz,
CHAOSO2), 4.68 (m, 1H, H2), 4.91 (t, 1H, J ≈ 11.0 Hz, CHBOSO2),
5.62 (m, 1H, H6), 6.00 (dt, 1H, J ≈ 2 × 3.5 Hz, J ≈ 10.5 Hz, H4),
6.20 (br d, 1H, J ≈ 10.4 Hz, H5), 7.10 (br d, 1H, J ≈ 5.6 Hz, NH),
7.48 (d, 2H, J ≈ 8.4 Hz, HAr), 7.86 (d, 2H HAr). 13C NMR (acetone-
d6, 62.5 MHz): δ 21.5 (Me), 42.0 (C6), 45.7 (C2), 50.6 (C3), 67.8
(CH2OSO2), 117.8 (CN), 120.6 (C4 or C5), 128.0 (CHAr), 130.2
(C4 or C5), 131.3 (CHAr), 136.6 (Cq), 146.2 (Cq). IR (neat) 3323,
2245, 1350, 1190, 1163 cm-1. HRMS calcd for C14H15N3O5S2Na
[M + Na]+ 392.03508, found 392.0341 (2 ppm).
(4aS*,6S*,8aR*)-6-Benzoylmethyl-5-(toluene-4-sulfonyl)-1,4,-
4a,5,6,8a-hexahydro-3-oxa-2-thia-1,5-diazanaphthalene 2,2-
Dioxide (11c). To a solution of 10 (134 mg, 0.358 mmol) in CH2Cl2
(3 mL) were added at -78 °C 1-phenyl-1-trimethylsiloxyethylene
(0.293 mL, 1.43 mmol, 4 equiv) and SnCl4 (1M in CH2Cl2, 0.429
mL, 0.429 mmol, 1.2 equiv). The solution was stirred for 20 h at
this temperature, quenched with saturated aqueous NaHCO3 at
-78 °C, warmed to rt, extracted with CH2Cl2, dried over MgSO4,
and concentrated under reduced pressure. Purification on silica gel
1
37%, de g 98%). H NMR (CDCl3, 400 MHz): δ 1.72 (m, 1H,
H
3A), 1.88 (m, 1H, H3B), 2.29 (ddd, 1H, J ≈ 2 × 8.7 Hz, J ≈ 17.2
Hz, CH2CHdCH2), 2.42 (s, 3H, Me), 2.65 (m, 1H, CH2CHdCH2),
4.16 (m, 2H, CH2OSO2), 4.29 (m, 1H, H6), 4.38 (m, 1H, H2), 5.15
(m, 2H, CH2CHdCH2), 5.29 (s, 2H, NH2), 5.60 (m, 1H, H4), 5.71
(m, 1H, H5), 5.88 (m, 1H, CH2CHdCH2), 7.29 (d, 2H, J ≈ 8.0
Hz, HAr), 7.29 (d, 2H, J ≈ 8.4 Hz, HAr). 13C NMR (CDCl3, 100
MHz): δ 21.7 (Me), 23.1 (C3), 43.0 (CH2CHdCH2), 48.6 (C2),
52.9 (C6), 70.4 (CH2OSO2), 118.5 (CH2CHdCH2), 121.7 (C4),
125.9 (C5), 126.9 (CHAr), 130.1 (CHAr), 134.2 (CH2CHdCH2),
137.3 (CqAr), 143.9 (CqAr). IR (neat) 3279, 1375, 1184, 1163 cm-1
.
HRMS: calcd for C12H22N2O5NaS2 [M + Na]+ 409.08679, found
409.0866 (0 ppm).
(4aS*,7S*,8R*,8aS*)-1-Acetyl-7,8-diacetoxy-5-(toluene-4-sul-
fonyl)-1,4,4a,5,6,8a-hexahydro-3-oxa-2-thia-1,5-diazanaphtha-
lene 2,2-Dioxide (13). To a solution of 12 (280 mg, 0.725 mmol)
in acetone/water 9/1 (10 mL), were added at room temperature
NMO (543 mg, 2.901 mmol, 4 equiv), a 2.5% solution of of OsO4
in t-BuOH (1.8 mL, 0.145 mmol, 0.2 equiv). The solution was
stirred 18 h at this temperature and was quenched with saturated
aqueous Na2S2O5, extracted with CH2Cl2, dried over MgSO4, and
concentrated under reduced pressure. To the crude mixture in CH2-
Cl2 (7 mL) were added at room-temperature acetic anhydride (1.05
J. Org. Chem, Vol. 73, No. 6, 2008 2161

Toumieux et al.
mL, 10.88 mmol, 15 equiv) and DMAP (26.5 mg, 0.217 mmol,
0.3 equiv). The solution was stirred for 4 h at this temperature.
The reaction was quenched with water; the mixture was extracted
with CH2Cl2, dried over MgSO4, and concentrated under reduced
pressure. Purification on silica gel (CH2Cl2/acetone 95/5) gave 13
as a colorless oil (225 mg, 66%, de g 98%, two steps from 12).
1H NMR (CDCl3, 400 MHz): δ 1.89 (s, 3H, COMe), 1.95 (s, 3H,
COMe), 2.45 (s, 3H, Me), 2.50 (s, 3H, Me), 3.31 (d, 1H, J ≈ 15.0
Hz, H6), 4.03 (dd, 1H, J ≈ 2.0 Hz, J ≈ 15.0 Hz, H6), 4.59-4.79
(m, 3H, H2, CH2OSO2), 5.34 (s, 1H, H5), 5.48-5.59 (m, 2H, H4,
H3), 7.35 (d, 1H, J ≈ 8.0 Hz, HAr), 7.71 (d, 1H, J ≈ 8.0 Hz, HAr).
13C NMR (CDCl3, 62.5 MHz): δ 20.6 (Me), 20.7 (Me), 21.7 (Me),
24.8 (Me), 43.6 (C6), 49.4 (C2), 50.3 (C3), 66.4 (C4 or C5), 68.4
(C4 or C5), 70.3 (CH2OSO2), 127.3 (CHAr), 130.3 (CHAr), 136.6
(Cq), 144.6 (Cq), 168.1 (CdO), 169.6 (CdO), 169.9 (CdO). IR
(neat) 1751, 1713, 1178 cm-1. HRMS: calcd for C19H24N2O10NaS2
[M + Na]+ 527.0770, found 527.0774 (1 ppm).
(2S*,3S*,4R*,5S*)-4,5-Diacetoxy-2-acetoxymethyl-3-acetyl-
amino-1-(toluene-4-sulfonyl)piperidine (14). To a solution of 13
(26 mg, 0.0515 mmol) in dry DMF (1 mL) was added potassium
acetate (10.8 mg, 0.130 mmol, 2 equiv). The solution was warmed
at 40 °C during 2.5 h. THF (1 mL), H2SO4 98% (150 µL), and
water (50 µL) were then added at rt. The mixture was then stirred
for 1 h. The reaction was quenched with saturated aqueous NaHCO3
solution (pH ∼5). The mixture was extracted with CH2Cl2, dried
over MgSO4, and concentrated under reduced pressure. Purification
on silica gel (CH2Cl2/acetone 85/15) gave 14 as a colorless oil (12
mg, 48%). 1H NMR (CDCl3, 250 MHz): δ 1.79 (s, 3H, Me), 1.97
(s, 3H, Me), 2.01 (s, 3H, Me), 2.4 (s, 3H, Me), 2.34 (s, 3H, Me),
3.50 (d, 1H, J ≈ 15.5 Hz, H6), 4.00 (d, 1H, J ≈ 15.2 Hz, H6), 4.16
(dd, 1H, J ≈ 3.0 Hz, J ≈ 12.0 Hz, CHAOAc), 4.42-4.62 (m, 2H,
H3, CHBOAc), 4.74 (m, 1H, H2), 5.10-5.20 (m, 2H, H4, H5), 5.91
(d, 1H, J ≈ 7.7 Hz, NH), 7.31 (d, 1H, J ≈ 8.5 Hz, HAr), 7.77 (d,
1H, J ≈ 8.2 Hz, HAr). 13C NMR (CDCl3, 100 MHz): δ 20.7 (Me),
20.9 (Me), 21.1 (Me), 21.6 (Me), 23.3 (Me), 44.4 (C6), 47.9 (C3),
53.9 (C2), 61.6 (CH2OAc), 67.1 (C4 or C5), 68.3 (C4 or C5), 127.4
(CHAr), 129.8 (CHAr), 138.0 (Cq), 143.6 (Cq), 170.2 (CdO), 170.6
(CdO), 170.9 (CdO), 171.9 (CdO). IR (neat) 3280, 1744, 1667,
1155 cm-1. HRMS: calcd for C21H28N2O9NaS [M + Na]+
507.14132, found 507.1414 (0 ppm).
4.72 (m, 3.8H, H2cis, CH2cisOSO2, H3cis, H2trans, H3trans, CHtransOSO2),
4.82-5.02 (m, 0.6H, CH2CHdCH2trans, CHOSO2trans), 5.08-5.22
(m, 1.8H, H4trans, CH2CHdCH2cis), 5.44 (m, 0.2H, CH2CHtransd
CH2), 5.64 (d, 0.8H, J ≈ 10.8 Hz, H4cis), 5.77-5.92 (m, 1.8H, H5trans
,
H5cis, CH2CHcisdCH2), 7.33 (m, 2H, HAr), 7.62-7.77 (m, 2H, HAr).
13C NMR (CDCl3, 62.5 MHz): δ 21.6 (CH3), 27.8 (t-Bucis), 27.9
(t-Butrans), 38.2 (CH2transCHdCH2), 41.4 (CH2cisCHdCH2), 46.9
(C2cis + C2trans), 50.8 (C3trans or C6trans), 51.5 (C6cis), 52.2 (C3cis),
54.9 (C3trans or C6trans), 71.7 (CH2transOSO2), 72.1 (CH2cisOSO2), 86.1
(t-Bucis), 86.3 (t-Butrans), 119.1 (CH2CHdCH2cis), 119.3 (CH2CHd
CH2trans), 124.4 (C4cis + C4trans), 126.0 (C5trans or CH2CHtransdCH2),
126.8 (CHArcis), 127.0 (CHArtrans), 127.7 (C5cis or CH2CHcisdCH2),
128.7 (C4trans), 130.0 (CHArtrans), 130.3 (CHArcis), 131.7 (C5trans or
CH2CHtransdCH2), 133.5 (C5cis or CH2CHcisdCH2), 136.4 (Cqcis),
137.7 (Cqtrans), 144.5 (Cq), 150.0 (CdO). IR (neat) 1734, 1355,
1215, 1146 cm-1. HRMS: calcd for C21H28N2O7NaS2 [M + Na]+
507.12356, found 507.1225 (2 ppm).
(2S*,3R*,6R*S*)-N-Acetyl-6-allyl-3-tert-butyloxycarbonylamino-
1,2,3,6-tetrahydropyridine (17). To a solution of naphthalene (0.64
mg, 5 mmol, 1 equiv) in THF (10 mL) was added sodium (115
mg, 5 mmol, 1 equiv) at rt. The solution turned to dark green and
was stirred 4 h. To a solution of diastereoisomers 16 (44 mg, 0.0948
mmol) in THF (3 mL) at -78 °C was added the 0.5 M sodium/
naphthalenide solution (900 µL, 9 equiv). The mixture was stirred
for 20 min at -78 °C. The reaction was quenched with methanol
(2 mL) and water (2 mL) at -78 °C. The reaction mixture was
then allowed to warm to rt. The solution was then extracted with
CH2Cl2, washed with water, dried over MgSO4, and concentrated
under reduced pressure. Purification on silica gel (CH2Cl2/acetone
8/2) gave 17 as a colorless oil (18 mg, 61%). 1H NMR (DMSO-d6,
90 °C, 250 MHz) (mixture of rotamers): δ 1.43 (s, 9H, t-Bu), 2.01-
2.22 (m, 4H, CHCHdCH2, CH3), 2.50 (m partially masked by the
signal of solvent residual peak, 1H, CHCHdCH2), 3.43 (m, 1H,
CHAOAc), 3.65 (m, 1H, CHBOAc), 4.06 (br s, 1H, OH), 4.13-
4.56 (m, 3H, H2, H3, H6), 5.06 (m, 2H, CH2CHdCH2), 5.59 (d,
1H, J ≈ 10.5 Hz, H4), 5.67-5.94 (m, 2H, CH2CHdCH2, H5), 6.55
(br s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz) (mixture of
rotamers): 22.4 (Me), 23.3 (Me), 28.2 (Me), 29.6 (Me), 36.6 (CH2),
38.5 (CH2), 47.9 (CH), 48.4 (CH), 49.2 (CH), 50.5 (CH), 52.5 (CH),
55.0 (CH), 57.3 (CH), 57.8 (CH2), 59.6 (CH2), 78.3 (Cq), 117.1
(CH2), 117.4 (CH2), 124.8 (CH), 126.0 (CH), 126.9 (CH), 127.0
(CH), 129.2 (CH), 134.1 (CH), 135.6 (CH), 155.1 (CdO), 155.2
(CdO), 169.6 (CdO), 171.5 (CdO). HRMS: calcd for C16H26N2O4-
Na [M + Na]+ 333.17903, found 333.1790 (0 ppm). IR (neat):
(4aS*,6R*S*,8aR*)-6-Allyl-5-(toluene-4-sulfonyl)-1-(tert-bu-
tyloxycarbonyl)-4,4a,5,6,8ahexahydro-3-oxa-2-thia-1,5-diaza-
naphthalene 2,2-Dioxide (15). To the mixture of diastereoisomers
11a (335 mg, 0.872 mmol) in CH2Cl2 were added at 0 °C Boc2O
(380 mg, 1.74 mmol, 2 equiv), pyridine (1 mL), and DMAP (22
mg, 0.174 mmol, 0.2 equiv). After 1 h at this temperature, the
solvents were removed under reduced pressure, and pyridine was
coevaporated with toluene. The crude mixture was taken up with
CH2Cl2, and the solution was washed with water, dried over MgSO4,
and concentrated under reduced pressure. Purification on silica gel
(AcOEt/PE 2/8) gave 15 as a mixture of epimers (colorless oil,
3442, 1707, 1628 cm-1
.
Acknowledgment. Financial support of this study by grants
from CNRS and the French department of research is gratefully
acknowledged.
Supporting Information Available: Additional procedures and
characterization data for new compounds are included. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
298 mg, 70%, de 61%). H NMR (CDCl3, 400 MHz): δ 1.51 (s,
9H, (CH3)3), 2.35-2.47 (m, 3.8H, Me, CHcisCHdCH2), 2.52-2.58
(m, 0.4H, CH2transCHdCH2), 2.68 (m, 0.8H, CHcisCHdCH2), 4.30
(m, 0.8H, H3cis), 4.37-4.47 (m, 0.4H, H4trans, CH2transOSO2), 4.55-
JO702350U
2162 J. Org. Chem., Vol. 73, No. 6, 2008