Application of the aza-Achmatowicz oxidative rearrangement for the stereoselective synthesis of the Cassia and Prosopis alkaloid family

Article abstract of DOI:10.1021/jo0616714

cis-2-Methyl-6-substituted piperidin-3-ol alkaloids of the Cassia and Prosopis species are readily prepared by a combination of an aza-Achmatowicz oxidative rearrangement and dihydropyridone reduction followed by a stereoselective allylsilane addition to

Full text of DOI:10.1021/jo0616714

Application of the Aza-Achmatowicz Oxidative Rearrangement
for the Stereoselective Synthesis of the Cassia and Prosopis
Alkaloid Family
Carolyn A. Leverett, Michael P. Cassidy, and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
ReceiVed August 11, 2006
cis-2-Methyl-6-substituted piperidin-3-ol alkaloids of the Cassia and Prosopis species are readily prepared
by a combination of an aza-Achmatowicz oxidative rearrangement and dihydropyridone reduction followed
by a stereoselective allylsilane addition to a N-sulfonyliminium ion. The stereochemical outcome of the
reduction reaction can be attributed to steric hindrance between the pseudoaxially oriented 2,6-substituents
and the equatorially approaching hydride reagent which explains the exclusive formation of the cis-
alcohol by axial approach of the hydride. The unsaturation present in the (E)-methyl-pent-3-enoate side
chain was removed by catalytic reduction, and the remaining ester group was converted to the
corresponding Weinreb’s amide. This key intermediate was utilized for the synthesis of azimic acid,
deoxocassine, cassine, and spicigerine. The facile preparation of (S)-N-tosylamidofuran 16 and its
conversion to the chiral Achmatowicz oxidation product 18 provide a formal chiral synthesis of these
alkaloids.
Introduction
2,6-dialkylpiperidines.5 The stereoselective synthesis of more
complex polysubstituted piperidines still remains a substantial
challenge in organic chemistry.6 Among this class of products,
2,6-disubstituted 3-piperidinol alkaloids are frequently encoun-
tered in biologically active natural products (Figure 1).7
A small yet important subgroup of the piperidin-3-ol alkaloids
which are of continuing interest to synthetic chemists are those
of the Cassia and Prosopis species, found in leaves and twigs
throughout the world.8 The characteristic framework of these
natural products is the cis-2-methyl-6-substituted piperidin-3-
The piperidine ring system is a frequently encountered
heterocyclic unit found in many naturally occurring and
biologically important compounds.1 In particular, 2,6-disubsti-
tuted piperidines have attracted much attention because they
often appear in various ring forms and exhibit a broad range of
biological activities.2 As a consequence, numerous synthetic
methods have been developed for the stereoselective synthesis
of 2,6-disubstituted piperidines.3 Most of the earlier procedures
have been directed toward the synthesis of simple cis-4 or trans-
(1) (a) Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S.
W., Ed.; Wiley: New York, 1985; Vol. 3. (b) Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon: Oxford, U.K.,
1996; Vol. 10. (c) Michael, J. P. Nat. Prod. Rep. 2001, 18, 520. (d) Rubiralta,
M.; Giralt, E.; Diez, A. Piperidine: Structure, Preparation and Synthetic
Applications of Piperidine and its DeriVatiVes; Elsevier: Amsterdam, 1991.
(2) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
(3) For recent reviews on the synthesis of piperidines, see: (a) Buffat,
M. G. P. Tetrahedron 2004, 60, 1701. (b) Felpin, F.-X.; Lebreton, J. Eur.
J. Org. Chem. 2003, 3693. (c) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953. (d) Bailey, P. D.; Millwood,
P. A.; Smith, P. D. Chem. Commun. 1998, 633. (e) Baliah, V.; Jeyaraman,
R.; Chandrasekaran, L. Chem. ReV. 1983, 83, 379.
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(b) Jefford, C. W.; Wang. J. B. Tetrahedron Lett. 1993, 34, 2911. (c) Ciblat,
S.; Besse, P.; Papastergion, V.; Veschambre, H.; Canrt, J. L.; Troin, Y.
Tetrahedron: Asymmetry 2000, 11, 2221. (d) Makabe, H.; Kong, L. K.;
Hirota, M. Org. Lett. 2003, 5, 27. (e) Shu, C.; Liebeskind, L. S. J. Am.
Chem. Soc. 2003, 125, 2878.
(5) (a) Gallagher, T.; Lathbury, D. Tetrahedron Lett. 1985, 26, 6249.
(b) Tufariello, J.; Puglis, J. Tetrahedron Lett. 1986, 27, 1489. (c) Carruthers,
W.; Williams, M. Chem. Commun. 1986, 1287. (d) Wasserman, H. H.;
Rodriques, K.; Kucharczyk, R. Tetrahedron Lett. 1989, 30, 6077. (e) Beak,
P.; Lee, W.-K. J. Org. Chem. 1990, 55, 2578. (f) Bertin, B. G.; Compere,
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10.1021/jo0616714 CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/27/2006
J. Org. Chem. 2006, 71, 8591-8601
8591

Leverett et al.
Because of their medicinal potential and characteristic all-
cis relative stereochemistry, the Cassia and Prosopis alkaloids
are of special synthetic significance, and many have been
prepared using a wide variety of methods.15,16 Methods also
exist for the synthesis of the corresponding trans isomers.17 One
of the earliest routes to (()-carpamic acid (6) relied on singlet
oxygen addition to a functionalized pyridine as the key step.18
More recently, Lee and co-workers demonstrated the usefulness
of a two-carbon homologation of â-lactams to access the
piperidine core.19 Kumar and Datta reported a stereoselective
total synthesis of (+)-azimic acid (5) starting with L-alanine.20
Kibayashi demonstrated an elegant route to azimic acid (5)
employing a hetero Diels-Alder cycloaddition.21 Finally, Trost
and co-workers reported a route to (+)-spectaline (1) using a
hydrosilylation-oxidation strategy.22
Despite the availability of many synthetic methods for this
class of compounds, there still exists a need to develop
procedures more efficient than those currently in existence. In
connection with our ongoing studies on natural product synthesis
based on amidofuran chemistry,23 we became interested in
employing N-tosylaminofurans for the synthesis of various cis-
2,3,6-trisubstituted piperidine alkaloids. Pioneering work by the
Ciufolini group24 demonstrated that the aza-Achmatowicz
reaction can be used for the preparation of various nitrogenous
ring systems. This novel oxidative ring expansion reaction has
been employed for the synthesis of azasaccharides,25 izidine
structures,26 â-lactam intermediates,27 and unusual amino acids28
and, we believe, possesses significant potential for the prepara-
tion of a variety of piperidinol alkaloids. In an earlier study
from our laboratory,29 we showed that the aza-Achmatowicz
oxidation of a furyl-substituted benzenesulfonamide could be
used for the synthesis of the putative indolizidine alkaloid 223A,
FIGURE 1. Some representative 2,6-disubstituted piperidin-3-ol
alkaloids.
ol skeleton.9,10 Structural variation is found in the long aliphatic
side chain appended at C6 which provides for a number of
different stereochemical and oxygenation patterns (Figure 1).
Typical representatives of this family include spectaline (1),
julifloridine (2), azimine (3), and carpaine (4). The latter two
structures correspond to macrocyclic dilactones containing two
molecules of the characteristic 2-methyl-3-piperidinol skeleton
with a carboxyl group as a terminal substituent at the C6
position.11,12 They are readily hydrolyzed to azimic (5) and
carpamic acid (6), which are presumably their biological
precursors. Since their discovery in the 1960s, much effort has
been directed to the synthesis of these and other related alkaloids
such as cassine (8) and deoxocassine (9).13 Besides the interest-
ing structural features, these alkaloids are also of pharmaceutical
interest as they exhibit a wide range of biological activities.14
The physiological effects stem from their ability to mimic
carbohydrate substrates in a variety of enzymatic processes.
(15) For the synthesis of azimic acid, see: (a) Brown, E.; Dhal, R.
Tetrahedron Lett. 1974, 15, 1029. (b) Brown, E.; Dhal, R. J. Chem. Soc.,
Perkin Trans. 1 1976, 2190. (c) Natsume, M.; Ogawa, M. Heterocycles
1980, 14, 169. (d) Hanessian, S.; Frenette, R. Tetrahedron Lett. 1979, 20,
3391. (e) Lu, Z.-H.; Zhou, W.-S. Tetrahedron 1993, 49, 4659. (f) Kiguchi,
T.; Shirakawa, M.; Ninomiya, I.; Naito, T. Chem. Pharm. Bull. 1996, 44,
1282. (g) Kiguchi, T.; Shirakawa, M.; Honda, R.; Ninomiya, I.; Naito, T.
Tetrahedron 1998, 54, 15589.
(16) For the synthesis of carpamic acid, see: (a) Brown, E.; Bourgouin,
A. Chem. Lett. 1974, 109. (b) Brown, E.; Bourgouin, A. Tetrahedron 1975,
31, 1047. (c) Holmes, A. B.; Swithenbank, C.; Williams, S. F. Chem.
Commun. 1986, 265.
(17) For the synthesis of other hydroxylated piperidine alkaloids, see:
(a) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org. Chem. 2002,
67, 1982. (b) Dransfield, P. J.; Gore, P. M.; Shipman, M.; Slawin, A. M.
Z. J. Chem. Soc., Chem. Commun. 2002, 150. (c) Jourdant, A.; Zhu, J.
Tetrahedron Lett. 2001, 42, 3431. (d) Comins, D. L.; Sandelier, M. J.; Grillo,
T. A. J. Org. Chem. 2001, 66, 6829. (e) Cook, G. R.; Beholz, L. G.; Stille,
J. R. J. Org. Chem. 1994, 59, 3575.
(18) Natsume, M.; Ogawa, M. Heterocycles 1979, 12, 159.
(19) Lee, H. K.; Chun, J. S.; Pak, C. S. Tetrahedron 2003, 59, 6445.
(20) Kumar, K. K.; Datta, A. Tetrahedron 1999, 55, 13899.
(21) Sato, T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2003, 5, 3839.
(22) Trost, B. M.; Ball, Z. T.; Laemmerhold, K. M. J. Am. Chem. Soc.
2005, 127, 10028.
(23) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998,
63, 5304. (b) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515. (c) Wang,
Q.; Padwa, A. Org. Lett. 2004, 6, 2189. (d) Lynch, S. M.; Bur, S. K.; Padwa,
A. Org. Lett. 2002, 4, 4643. (e) Wang, Q.; Padwa, A. Org. Lett. 2006, 8,
601. (f) Zhang, H.; Padwa, A. Org. Lett. 2006, 8, 247.
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W.; Dong, Q.; Shimiizu, T.; Swaminathan, S.; Xi, N. Synlett 1998, 105.
(25) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401.
(26) Harris, J. M.; Padwa, A. Org. Lett. 2002, 4, 2029.
(27) Ciufolini, M. A.; Dong, Q. J. Chem. Soc., Chem. Commun. 1996,
881.
(28) Ciufolini, M. A.; Shimizu, T.; Swaminathan, S.; Xi, N. Tetrahedron
Lett. 1997, 38, 4947.
(6) For some recent examples involving polysubstituted piperidines,
see: (a) Wang, X.; Dong, Y.; Sun, J.; Xu, X.; Li, R.; Hu, Y. J. Org. Chem.
2005, 70, 1897. (b) Lemire, A.; Charette, A. B. Org. Lett. 2005, 7, 2747.
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Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2004, 126, 11808. (e) Shintani, R.; Tokunaga, N.; Doi,
H.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240. (f) Comins, D. L.;
Goehring, R. R.; Joseph, S. P.; O’Connor, S. J. Org. Chem. 1990, 55, 2574.
(g) Ge’nisson, Y.; Marazano, C.; Das, B. C. J. Org. Chem. 1993, 58, 2052.
(7) (a) Numata, A.; Ibuka, T. In The Alkaloids; Brossi, A., Ed.; Academic
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Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1985; Vol. 26, pp
89-174.
(8) Viegas, C., Jr.; Bolzani, V. da S.; Furlan, M.; Barreiro, E. J.; Young,
M. C. M.; Tomazela, D.; Eberlin, M. N. J. Nat. Prod. 2004, 67, 908.
(9) (a) Schneider, M. J. In Alkaloids: Chemical and Biological Perspec-
tiVes; Pelletier, W. S., Ed.; Wiley: New York, 1996; Vol. 10, pp 155-
355. (b) Michael, J. P. Nat. Prod. Rep. 1999, 16, 675-696.
(10) For reviews, see: (a) Nadin, A. J. Chem. Soc., Perkin Trans. 1 1998,
3493. (b) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(11) Rall, G. J. H.; Smalberger, T. M.; de Waal, H. L. Tetrahedron Lett.
1967, 36, 3465.
(12) (a) Rapoport, H.; Baldridge, H. D., Jr. J. Am. Chem. Soc. 1951, 73,
343. (b) Govindachari, T. R.; Pai, B. R.; Narasimhan, N. S. J. Chem. Soc.
1954, 1847.
(13) (a) Bonte´, A. Bull. Soc. Chem. Fr. 1981, 7, 281. (b) Hasseberg, H.
A.; Gerlach, H. Liebigs Ann. Chem. 1989, 255. (c) Ma, D.; Ma, N.
Tetrahedron Lett. 2003, 44, 3963.
(14) (a) Fodor, G. B.; Colasanti, B. The Pyridine and Piperidine
Alkaloids: Chemistry and Pharmacology. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley-Interscience: New
York, 1985; Vol. 3, pp 1-90.
(29) Harris, J. M.; Padwa, A. J. Org. Chem. 2003, 68, 4371.
8592 J. Org. Chem., Vol. 71, No. 22, 2006

Synthesis of the Cassia and Prosopis Alkaloid Family
SCHEME 1. Synthesis of epi-Indolizidine 223A Using an
Aza-Achmatowicz Oxidation
SCHEME 2. Key Disconnections for the Synthesis of the
3-Piperidinol Alkaloid System
2,6-cis-disubstituted dihydropyridinones.34 Consequently, we
chose to work with several related N-tosyl systems because of
their robust nature, ease of purification of the resulting
products,35 and high stereoselectivity of reaction with an
assortment of nucleophiles. Our retrosynthetic strategy for the
synthesis of a 3-piperidinol alkaloid system such as spicigerine
(7) is based on the earlier Hiemstra/Speckamp report34 and
envisages initial construction of the functionalized piperidino
Weinreb amide 19 from a 6-alkoxy-2-methyl-1-(toluene-4-
sulfonyl)-1,6-dihydro-2H-pyridin-3-one intermediate (i.e., 17 or
18). The required dihydropyridone 17 (or 18) is easily procured
by the aza-Achmatowicz oxidation of furyl sulfonamide 16
(Scheme 2). The availability of the Weinreb amide intermediate
19 would also allow for the ready synthesis of cassine (8),
deoxocassine (9), and spicigerine (7) by its reaction with an
appropriate lithiate derived from either commercially available
or easily synthesized alkyl halides.
(()-Azimic Acid Synthesis. Our studies began by subjecting
the readily available furyl sulfonamide 1636 to the aza-
Achmatowicz oxidative ring expansion37 with mCPBA. The
initially formed hemiaminal was immediately treated with
trimethyl orthoformate and catalytic BF3‚OEt2 which furnished
aminal 17 in 85% yield. Whereas the hemiaminal was difficult
to purify, the resulting N-tosyl-O-methylaminal 17 was a stable
crystalline solid that could be stored for extended periods of
time. A similar procedure was also utilized to transform 16 into
the corresponding O-ethyl aminal 18 by making use of triethyl
orthoformate. Even though both procedures worked well, the
synthesis of 18 from 16 proceeded in a somewhat higher yield
(95% vs 85%). Also, the synthetic steps following the aza-
Achmatowicz oxidation were higher yielding with the ethoxy
substituent, leading us to routinely adopt this more efficient
protocol over our previously reported conditions.35 The exclusive
cis orientation of the substituent group in 17/18 can be
rationalized by assuming that A1,3-strain of the tosyl group forces
the alkoxy and methyl groups to adopt a pseudoaxial orientation.
Reduction of 17 with NaBH4 in the presence of CeCl3‚7H2O
(Luche conditions)38 stereoselectively produced alcohol 20
(Scheme 3), whose configuration was elucidated by NMR
which had been isolated from the skin secretion of a neotropical
frog.30 The approach that we employed is shown in Scheme 1
and involved a flexible combination of an aza-Achmatowicz
oxidative rearrangement followed by a stereoselective allylsilane
addition to a N-sulfonyliminium ion and a subsequent 1,4-
conjugate addition.
In this paper, we further describe the utility of the aza-
Achmatowicz oxidation for the preparation of several members
of the Cassia and Prosopis alkaloid family such as (()-azimic
acid. The synthesis also includes the generation of a versatile
Weinreb amide that readily allows for the introduction of various
side chains thereby providing quick access to several piperidinol
alkaloids such as (()-deoxocassine, (()-cassine, and (()-
spicigerine. By making use of Davis’ sulfilimine chemistry,31
we were also able to generate a chiral N-tosylaminofuran
allowing for a formal asymmetric synthesis of these alkaloids.
Results and Discussion
aza-Achmatowicz products incorporate functionality that is
easily modified and can be utilized to construct complex nitrogen
heterocycles. In his early studies of the aza-Achmatowicz
reaction, Ciufolini reported that carbamate-protected furfury-
lamines are somewhat unstable and readily hydrolyze to
3-hydroxypiperidines under typical oxidation conditions.24
Subsequent studies by Zhou32 and Altenbach,33 however,
showed that a sulfonamide protecting group was completely
compatible with the aza-Achmatowicz oxidation reaction. The
earlier work by Hiemstra and Speckamp with N-tosyl-6-alkoxy-
2,6-dihydro-1H-pyridin-3-ones also demonstrated that these
systems undergo reaction with great stereoselectivity with
various nucleophiles under the influence of BF3‚OEt2 to furnish
(34) Hopman, J. C. P.; van der Berg, E.; Ollero, L. O.; Hiemstra, H.;
Speckamp, W. N. Tetrahedron Lett. 1995, 36, 4315.
(35) Cassidy, M. P.; Padwa, A. Org. Lett. 2004, 6, 4029.
(36) Padwa, A.; Zanka, A.; Cassidy, M.; Harris, J. M. Tetrahedron 2003,
59, 4939.
(37) (a) Ciufolini, M. A.; Wood, C. Y. Tetrahedron Lett. 1986, 27, 5085.
(b) See also: Georgiadis, M. P.; Couladouros, E. A. J. Org. Chem. 1986,
51, 2725.
(30) (a) Garraffo, H. M.; Jain, P.; Spande, T. F.; Daly, J. W. J. Nat.
Prod. 1997, 60, 2. (b) Toyooka, N.; Fukutome, A.; Nemoto, H.; Daly, J.
W.; Spande, T. F.; Garraffo, H. M.; Kaneko, T. Org. Lett. 2002, 4, 1715.
(31) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(32) Yang, C. F.; Xu, Y. M.; Liao, L. X.; Zhou, W. S. Tetrahedron Lett.
1998, 39, 9227.
(33) Altenbach, H. J.; Wischnat, R. Tetrahedron Lett. 1995, 36, 4983.
(38) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
J. Org. Chem, Vol. 71, No. 22, 2006 8593

Leverett et al.
SCHEME 4. Total Synthesis of (()-Azimic Acida
SCHEME 3. Synthesis of the Cis-Trisubstituted Corea
a Reagents: (a) LiAlH4, THF, 0 °C, 97%; (b) MsCl, Et3N, CH2Cl2, 0
°C; (c) NaCN, DMF, 50 °C, 68% (two steps); (d) NaOH, MeOH, 70 °C,
89%; (e) Li, NH3, THF, -78 °C, 70%.
SCHEME 5. Total Synthesis of (()-Deoxocassine (9)a
a Reagents: (a) NaBH4, CeCl3, MeOH, -40 °C, 60%; (b) TBSCl,
imidazole, DMAP, CH2Cl2, 25 °C, 86%; (c) methyl 3-(trimethylsilyl)-4-
pentenoate (24), BF3OEt2, CH2Cl2, -78 °C; (d) H2, PtO2, MeOH, 87%
(two steps).
studies. The reduction proved to be remarkably stereospecific,
providing the desired cis-alcohol 20 in pure diastereomeric form
and in 60% isolated yield. This result may be attributed to the
steric hindrance between the pseudoaxially oriented 2,6-bulky
substituents and the incoming hydride reagent thus favoring
formation of the cis-alcohol by the less sterically demanding
axial attack.39 Alcohol 20 was converted into the corresponding
TBS ether 22 using TBSCl and imidazole in 86% yield. A
similar set of experiments was also carried out with 18, and
this compound was easily converted in the TBS ether 23 in
66% overall yield (vs 49% overall yield for formation of 22).
The reaction of the TBS ether 22 or 23 with methyl
3-(trimethylsilyl)-4-pentenoate (24) in the presence of BF3‚OEt2
led to the somewhat labile allylic ester 25, which was im-
mediately hydrogenated (H2, PtO2, MeOH) to give the key
intermediate 26 in 57% or 87% yield, respectively. The choice
of the hydrogenation catalyst proved to be crucial for the success
of the reduction. Our first attempts used palladium on carbon
(Pd/C) as in ethanol; however, the desired product was only
isolated in low yield with a nearly equal amount of the
isomerized N-tosyl enamine. On the other hand, the use of PtO2
(Adams catalyst) afforded the desired saturated piperidine 26
as the exclusive product, with no evidence of epimerization at
C6. As suggested by Hiemstra and Speckamp,34 the preference
for the cis substitution pattern in 26 can be rationalized by
assuming that the steric bulk associated with the tosyl group
directs the attack of the allylsilane on the iminium ion to the
side of the C2-methyl group, thereby leading to the formation
of the all-cis stereochemistry.
Having achieved a reliable preparation of the key piperidine
intermediate 26, we proceeded to use this compound for the
synthesis of azimic acid (5). Our approach to 5 began with the
LiAlH4 reduction of ester 26 which afforded the corresponding
alcohol 27 in 97% yield (Scheme 4). Conversion of 27 to the
mesylate followed by cyanide displacement (NaCN, DMF)
provided nitrile 28 which was hydrolyzed to carboxylic acid
29 in 89% yield. Deprotection of the TBS group occurred during
the basic hydrolysis conditions used to convert 28 into 29
(NaOH, MeOH). Removal of the tosyl group with Li/NH3 gave
(()-azimic acid (5) in 70% yield. The spectral data were in
good agreement with those reported in the literature.15
a Reagents: (a) MeNH(OMe)‚HCl, i-PrMgCl, THF, -20 °C, 85%; (b)
CH2dCH(CH2)5I, t-BiLi, heptane, -78 °C, 56%; (c) TsNHNH2, EtOH, 25
°C; (d) DIBAL-H, NaOH, CH2Cl2, 0 °C, 40% (two steps); (e) H2 PtO2,
MeOH; (f) TBAF, THF, 0 °C, 92% (two steps); (g) Li, NH3, THF, -78
°C, 100%.
(()-Deoxocassine Synthesis. Having successfully obtained
azimic acid (5) from piperidine 26, we extended the above
strategy to the synthesis of deoxocassine (9). Accordingly, the
ester functionality present in piperidine 26 was converted (85%
yield) into the corresponding Weinreb amide 19 with meth-
oxymethylamine hydrochloride and isopropylmagnesium chlo-
ride. Although N-methoxy-N-methylamides are generally pre-
pared from the ester using an aluminum-based reagent,40 we
found that the use of i-PrMgCl41 gave higher yields and resulted
in a cleaner overall reaction. Treatment of 19 with 6-heptenyl-
lithium in heptane at -78 °C provided the expected ketone 30
in 56% unoptimized yield (Scheme 5). The terminal π-bond
present in 30 can be utilized for a synthesis of either deoxo-
cassine (9) or cassine (8) depending on the experimental
conditions. Reduction of the carbonyl group in 30 proved more
difficult than we originally anticipated. A Wolff-Kishner
reduction of 30 provided a complex, intractable mixture of
products. Instead, ketone 30 was converted to the corresponding
tosylhydrazone and then treated with DiBAL-H/NaOH42 which
afforded 31 in reasonable yield. After hydrogenation of the
double bond with PtO2, the TBS protecting group was removed
with TBAF and the tosyl group was cleaved using Li/NH3 to
furnish deoxocassine (9) in 92% yield for the three-step
sequence.
(40) Levin, J. L.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,
989.
(41) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(42) Marcantoni, E.; Torregiani, E.; Bosica, G.; Bartolacci, M.; Ballini,
R.; Badioli, M. J. Org. Chem. 2002, 67, 8938.
(39) For a related stereospecific reduction, see: Koulocheri, S. D.;
Magiatis, P.; Skaltsounis, A.-L.; Haroutounian, S. A. Tetrahedron 2000,
56, 6135.
8594 J. Org. Chem., Vol. 71, No. 22, 2006

Synthesis of the Cassia and Prosopis Alkaloid Family
SCHEME 6. First-Generation Synthesis of (()-Cassine (8)a
SCHEME 7. Second-Generation Synthesis of (()-Cassine
(8)a
a Reagents: (a) t-BuLi, pentane/TBME, -78 °C, 72%; (b) TsNHNH2,
EtOH, rt, then DIBAL-H, NaOH, CH2Cl2, 0 °C, 67%.
ceeded in good yield to give ketone 36. Conversion of the keto
group to the corresponding tosylhydrazone was followed by
reduction with DiBAL-H/NaOH to give the same piperidinyl
dioxolane 34 as had previously been prepared. This latter route
represents a considerable improvement over the earlier approach.
Thus, a complete synthesis of (()-cassine (8) is now possible
in four short steps starting from the Weinreb amide intermed-
iate 19.
a Reagents: (a) MeLi, THF, -78 °C, 65%; (b) HSCH2CH2SH, BF3‚OEt2,
CH2Cl2, rt, 89%; (c) t-BuLi, pentane/TBME, -78 °C, 70%; (d) TsNHNH2,
EtOH, rt, then DIBAL-H, NaOH, CH2Cl2, 0 °C, 57%; (e) MeI, CaCO3,
CH3CN/H2O, 55 °C, quantitative; (f) ethylene glycol, BF3‚OEt2, CH2Cl2,
rt, 93%; (g) Li, NH3, THF, -78 °C, 94%; (h) 3 N HCl, THF, rt, 59%.
(()-Cassine Synthesis. With these encouraging results in
hand, the total synthesis of (()-cassine (8) was next undertaken.
We realized that it should be possible to obtain 8 by a Wacker
oxidation43 of the piperidinyl-substituted alkene 31 but thought
it would be more convergent to employ a side chain that already
contained a protected keto group. With this in mind, we prepared
2-(5-bromopentyl)-2-methyl-[1,3]dithiolane (32) in two steps
from commercially available 6-bromohexanoic acid. Thus, slow
addition of 2.2 equiv of methyllithium to the above acid at -78
°C in THF afforded 65% yield of the requisite bromopentyl
methyl ketone.44 The ketone was then allowed to react with
1,2-ethanedithiol in CH2Cl2 with BF3‚OEt2 to give bromo-
dithiolane 32 in 89% yield. Treating 32 with t-BuLi at -78 °C
followed by reaction of the resulting lithiate with Weinreb’s
amide 19 afforded the expected coupled ketone which was
subsequently reduced with TsNHNH2-DiBAL-H/NaOH42 to
furnish [1,3]-dithiolane 33 in 45% overall yield. Hydrolysis of
33 afforded the expected methyl ketone in quantitative yield
which was subsequently protected as the dioxolane 34 by
reaction with ethylene glycol. Conversion of 34 to (()-cassine
(8) was then accomplished by a series of reactions involving
Li/NH3 removal of the tosyl group and deprotection of the TBS
ether in 55% overall yield (Scheme 6).
Although the above synthesis served to define the viability
of the critical Weinreb amide coupling step, the added protec-
tion-deprotection steps and the modest yield in formation of
the lithiate derived from dithiolane 32 resulted in a sequence
that was less efficient than what we had envisioned. In
considering a more direct approach to piperidinyl-ketal 34, we
became intrigued by the prospect of generating a lithium reagent
directly from 2-(5-bromopentyl)-2-methyl-1,3-dioxolane (35).45
This led us to reinvestigate the key coupling step using ketal
35 and the Weinreb amide 19 (Scheme 7). Although the critical
coupling step required some optimization, it ultimately pro-
(()-Spicigerine Synthesis. (()-Spicigerine (7) represents
another member of the piperidinol alkaloid family, was isolated
in minute amounts from Prosopis spicigera, and possesses
noteworthy antibiotic and anesthetic properties.46 Surprisingly,
only two syntheses of (()-spicigerine have been reported to
date,47 perhaps as a consequence of the presence of the terminal
carboxylic acid functionality. The considerable potential of using
Weinreb’s amide 19 for the synthesis of various Prosopis
alkaloids motivated us to undertake the synthesis of spicigerine.
We reasoned that an efficient approach toward this particular
alkaloid would involve an oxidative cleavage of the piperidinyl
alkene 38, which in turn should be easily available from
Weinreb’s amide 19 (Scheme 8). Thus, we extended our earlier
two-step strategy and treated Weinreb’s amide 19 with 8-octe-
nyllithium, and this was followed by reduction of the resulting
ketone 37 via its tosylhydrazone to give 38. Several different
conditions were examined for the oxidation of the terminal
π-bond of 38 into the carboxylic acid functionality of 40. The
most successful method was a one-pot dihydroxylation/oxidation
step using OsO4 and Oxone.48 Although this method allowed
for a one-step synthesis of 40 from 38, the yields were generally
poor with the highest being only 53%. Instead, a much higher
yield of 40 was obtained (92%) using a two-step sequence where
38 was first oxidized to aldehyde 3949 followed by a subsequent
oxidation to 40 with sodium chlorite.50 In line with our
expectations, exposure of 40 to the TBAF and Li/NH3 conditions
effects deprotection of the TBS and tosyl groups producing (()-
spicigerine in 64% isolated yield.
Asymmetric Approach. The construction of versatile chiral
building blocks for the efficient synthesis of biologically active
(46) Jewers, K.; Nagler, M. J.; Zirvi, K. A.; Amin, F. Phytochemistry
1976, 15, 238.
(47) (a) Paterne, M.; Brown, E. J. Chem. Res. 1985, 9, 278. (b) Hasseberg,
H. A.; Gerlach, H. Liebigs Ann. Chem. 1989, 255.
(48) Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002,
124, 3824.
(49) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217.
(50) Lindgren, B. P.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
(43) Tsuji, J. Synthesis 1984, 369.
(44) (a) Rubottom, G. M.; Kim, C. J. Org. Chem. 1983, 48, 1550. (b)
Jorgenson, M. J. Org. React. 1970, 18, 1.
(45) Rudler, H.; Durand-Reville, T. J. Organomet. Chem. 2001,
617-618, 571.
J. Org. Chem, Vol. 71, No. 22, 2006 8595

Leverett et al.
SCHEME 8. Total Synthesis of (()-Spicigerine (7)a
SCHEME 9. Synthetic Route to Chiral
(S)-N-Tosylaminofuran 16a
a Reagents: Ti(OEt)4, CHCl3, reflux, 69%; (b) LiAlH(OtBu)3, THF, -78
to -55 °C; (c) mCPBA, CH2Cl2, -30 to 0 °C, 35% (two steps); (d) mCPBA,
CH2Cl2, rt, CH(OEt)3, p-TsOH, rt, 95%.
sulfilimine was carried out at low temperatures (-78 to -55
°C) with LiAlH(OtBu)3, and this was followed by an immediate
oxidation with mCPBA to give the desired N-tosylaminofuran
16 in >75% ee as determined by chiral HPLC. Comparison of
the optical rotation of (S)-16 ([R]20D -63.5 (c 1.0, EtOH)) with
that reported by Zhou and co-workers58 clearly indicates that
hydride delivery occurred on the si face of the imine as expected
for a sulfoxide-directed addition.56 Having a sample of (S)-16
on hand, it was then submitted to the aza-Achmatowicz protocol,
thereby providing a formal chiral synthesis of azimic acid (5),
deoxocassine (9), cassine (8), and spicigerine (7).
In conclusion, we have developed a useful and efficient
protocol for the preparation of several hydroxylated piperidine
alkaloids. The approach involves a flexible combination of an
aza-Achmatowicz oxidative rearrangement, dihydropyridone
reduction, and a subsequent stereoselective allylsilane addition
to a N-sulfonyliminium ion. Catalytic reduction of the olefinic
π-bond followed by conversion of the ester group to the
corresponding Weinreb amide provided an extremely useful
intermediate which was utilized for the eventual synthesis of
azimic acid, deoxocassine, cassine, and spicigerine. These
synthetic studies have allowed us to further define the scope of
the aza-Achmatowicz reaction and to optimize the introduction
of various substituents at the 6-position of the Cassia and
Prosopis alkaloid frameworks. The facile preparation of (S)-
N-tosylamidofuran 16 and its conversion to the chiral Achma-
towicz oxidation product 18 demonstrates the promise of using
this method for the efficient asymmetric synthesis of other
members of the piperidinol class of alkaloids.
a Reagents: (a) CH2dCH(CH2)6Br, t-BuLi, heptane, -78 °C, 59%; (b)
TsNHNH2, EtOH, 25 °C; (c) DIBaH, NaOH, CH2Cl2, 0 °C, 76% (two steps);
(d) OsO4, NaIO4, dioxane/H2O, 25 °C, 93%; (e) OsO4, Oxone, DMF, 25
°C, 53%; (f) NaClO2, t-BuOH, 25 °C, 99%; (g) TBAF, THF, 0 °C, 77%;
(h) Li, NH3, THF, -78 °C, 64%.
natural products is a topic of current interest.51 A large number
of methods leading to the synthesis of chiral piperidine,
decahydroquinoline, indolizidine, and quinolizidine systems
have already been developed.52 Several methods for the ste-
reoselective construction of 2,6-disubstituted piperidinols have
also been reported.53 In earlier work, the Ciufolini group
demonstrated that a chemoenzymatic hydrolysis of N-protected
furanylglycine methyl esters could be used to prepare chiral
furan derivatives.54 The resolved furylglycines were shown to
be excellent substrates for the synthesis of trans-2,6-disubstituted
piperidines by subjecting them to an aza-Achmatowicz oxidation
reaction.55 However, no example of an asymmetric synthesis
of a cis-2,6-disubstituted piperidin-3-ol has appeared to date.
As a consequence of our earlier synthetic work in this area, we
wondered whether the aza-Achmatowicz oxidation could also
be used for the enantiocontrolled synthesis of various members
of the Cassia and Prosopis family of alkaloids. To this end, we
examined a new strategy for the asymmetric construction of
tosylaminofuran 16 by making use of the elegant sulfilimine
chemistry developed independently by the Davis31 and Ellman
groups.56 Our synthesis of (S)-16 (Scheme 9) began by condens-
ing (S)-(+)-p-toluenesulfinimide with 2-acetylfuran in the
presence of Ti(OEt)4 using a modification of the conditions
reported by Davis.5757 Stereoselective reduction of the resulting
Experimental Section
(51) Huang, P.-Q. Synlett 2006, 1133.
(52) Momose, T.; Toyooka, N.; Jin, M. J. Chem. Soc., Perkin Trans. 1
1997, 2005.
6-Methoxy-2-methyl-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-
pyridin-3-one (17). A 0.39 g (1.1 mmol) sample of furyl sulfona-
mide 16,35 4 mL of CH2Cl2, and mCPBA (0.39 g, 2.3 mmol) were
placed in a round-bottom flask, and the mixture was stirred for 2
h at room temperature. The reaction mixture was quenched with a
saturated aqueous NaHCO3 solution (15 mL), and 15 mL of ether
was added. The solution was extracted with ether. The layers were
separated, and the organic layer was dried (MgSO4). Concentration
under reduced pressure and purification by silica gel chromatog-
(53) Singh, R.; Ghosh, S. K. Tetrahedron Lett. 2002, 43, 7711.
(54) Drueckhammer, D. G.; Barbas, C. F.; Nozaki, K.; Wong, C.-H.;
Wood, C. Y.; Ciufolini, M. A. J. Org. Chem. 1988, 53, 1607.
(55) Ciufolini, M. A.; Hermann, C. W.; Whitmire, K. H.; Byrne, N. E.
J. Am. Chem. Soc. 1989, 111, 3473.
(56) For some recent reviews on the chemistry of sulfilimines, see: (a)
Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(b) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I.
Aldrichimica Acta 2005, 38, 93.
(57) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
(58) Zhou, W.-S.; Lu, Z.-H.; Wang, Z.-M. Tetrahedron Lett. 1991,
32, 1467.
8596 J. Org. Chem., Vol. 71, No. 22, 2006

Synthesis of the Cassia and Prosopis Alkaloid Family
raphy gave 0.27 g (0.96 mmol, 85%) of the labile hemiaminal as
a clear oil: IR (thin film) 1686, 1597, 1449, 1332, 1165, 1110,
chromatography to give 0.82 g (86% yield) of the title compound
22 as a colorless oil: IR (thin film) 2935, 1469, 1382, 1159, and
1073 cm-1; 1H NMR (400 MHz, CDCl3) δ -0.12 (d, 6H, J ) 5.6
Hz), 0.80 (s, 9H), 1.17 (d, 3H, J ) 7.2 Hz), 2.42 (s, 3H), 3.49 (s,
3H), 3.69 (m, 1H), 3.84 (dq, 1H, J ) 6.8 and 6.8 Hz), 5.36 (m,
1H), 5.50 (dd, 1H, J ) 10.8 and 1.6 Hz), 5.72 (ddd, 1H, J ) 10.0,
7.2, and 7.2 Hz), 7.29 (d, 2H, J ) 8.4 Hz), and 7.70 (d, 2H, J )
8.4 Hz); 13C NMR (100 MHz, CDCl3) δ -5.01, -4.85, 13.2, 18.2,
21.7, 25.8, 50.3, 56.1, 65.6, 80.9, 124.2, 127.3, 129.9, 132.0, 138.5,
and 143.8; HRMS calcd for C20H33NSiSO4 411.1899, found
411.1903.
1
and 1006 cm-1; H NMR (400 MHz, CDCl3) δ 1.59 (d, J ) 7.2
Hz, 3H), 2.38 (s, 3H), 3.82 (brs, 1H), 4.36 (q, 1H, J ) 7.2 Hz),
5.90 (dd, 1H, J ) 4.8 and 1.2 Hz), 5.96 (dd, 1H, J ) 10.0 and 1.2
Hz), 6.86 (dd, 1H, J ) 10.4 and 4.8 Hz), 7.25 (d, 2H, J ) 8.4 Hz),
and 7.62 (d, 2H, J ) 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ
21.5, 22.1, 57.0, 73.3, 126.2, 126.7, 130.0, 136.5, 143.5, 144.3,
and 195.3.
A 1.0 g (3.5 mmol) sample of the above 6-hydroxy-2H-pyridin-
3-one was dissolved in 20 mL of CH2Cl2, and trimethyl orthofor-
mate (777 µL, 7.1 mmol) and BF3‚OEt2 (45 µL, 0.36 mmol) were
added to the solution. The solution was stirred for 3 h at 0 °C and
quenched with a saturated aqueous NaHCO3 solution (25 mL), and
40 mL of ether was added. The solution was extracted with ether.
The layers were separated, and the organic layer was dried (MgSO4).
Concentration under reduced pressure and purification by silica gel
chromatography gave 0.89 g (3.0 mmol, 85%) of 17 as a white
solid: mp 113-115 °C; IR (thin film) 1692, 1597, 1453, 1340,
3-(tert-Butyldimethyl-silanyloxy)-6-ethoxy-2-methyl-1-(toluene-
4-sulfonyl)-1,2,3,6-tetrahydropyridine (23). To a solution of
6-ethoxy-2H-pyridin-3-one 18 (0.78 g, 2.5 mmol) at -50 °C in
MeOH (30 mL) was added CeCl3‚7H2O (0.95 g, 2.5 mmol)
followed by the portionwise addition of NaBH4 (0.1 g, 2.5 mmol)
over a 20 min period. The reaction mixture was stirred at -40 to
-50 °C for an additional 30 min and was then diluted with H2O
and extracted with EtOAc. The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure. Silica
gel chromatography gave 0.64 g of 21 as a clear oil which was
immediately used in the next step. The oil was taken up in CH2Cl2
(20 mL) and cooled to 0 °C, and then TBSCl (0.37 g, 2.4 mmol)
was added, followed by imidazole (0.28 g, 4.0 mmol) and a catalytic
amount of DMAP. The solution was stirred from 0 °C to 25 °C
over 16 h, diluted with H2O, and extracted with CH2Cl2. The organic
layer was dried over MgSO4, filtered, and concentrated to an oil
which was purified by silica gel chromatography to provide 0.7 g
(66%) of 23 as a clear oil: IR (thin film) 2929, 2853, 1470, 1393,
1
1168, 1080, and 1014 cm-1; H NMR (400 MHz, CDCl3) δ 1.56
(d, 3H, J ) 7.6 Hz), 2.38 (s, 3H), 3.57 (s, 3H), 4.30 (q, 1H, J )
7.6 Hz), 5.58 (dd, 1H, J ) 4.8 and 0.8 Hz), 5.82 (dd, 1H, J ) 10.4
and 0.8 Hz), 6.82 (dd, 1H, J ) 10.4 and 4.8 Hz), 7.24 (dd, 2H, J
) 8.0 and 1.2 Hz), and 7.56 (dd, 2H, J ) 8.0 and 1.2 Hz); 13C
NMR (100 MHz, CDCl3) δ 20.8, 21.5, 56.0, 57.2, 80.7, 126.6,
126.8, 130.0, 136.1, 142.5, 144.1, and 195.5. Anal. Calcd for C14H17-
NO4S: C, 56.93; H, 5.81; N, 4.75. Found: C, 56.81; H, 5.69; N,
4.70.
6-Ethoxy-2-methyl-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-py-
ridin-3-one (18). A procedure similar to that described above was
used to prepare 18 (95%): mp 94-96 °C; IR (thin film) 2981,
1690, 1357, 1335, 1169, 1072, 1012, 815, and 677 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.26 (t, 3H, J ) 7.2 Hz), 1.58 (d, 2H, J )
7.6 Hz), 2.38 (s, 3H), 3.71 (dq, 1H, J ) 14.0 and 7.2 Hz), 4.02
(dq, 1H, J ) 14.0 and 7.2 Hz), 4.30 (q, 1H, J ) 7.2 Hz), 5.68 (d,
1H, J ) 4.8 Hz), 5.82 (d, 1H, J ) 10.4 Hz), 6.82 (dd, 1H, J ) 4.8
and 4.8 Hz), 7.24 (d, 2H, J ) 8.4 Hz), and 7.56 (d, 2H, J ) 8.4
Hz); 13C NMR (100 MHz, CDCl3) δ 15.1, 21.1, 21.7, 57.4, 64.2,
79.4, 126.7, 127.0, 130.2, 136.4, 143.1, 144.3, and 195.8. Anal.
Calcd for C15H19NO4S: C, 58.23; H, 6.19; N, 4.53. Found: C,
58.17; H, 6.17; N, 4.44.
1
1343, 1171, 1114, 1076, 987, 885, and 835 cm-1; H NMR (400
MHz, CDCl3) δ -0.15 (d, 6H, J ) 6.0 Hz), 0.78 (s, 9H), 1.19 (m,
6H), 2.40 (s, 3H), 3.64 (m, 2H), 3.85 (m, 2H), 5.47 (m, 2H), 5.71
(m, 1H), 7.27 (d, 2H, J ) 8.0 Hz), and 7.68 (d, 2H, J ) 8.0 Hz);
13C NMR (100 MHz, CDCl3) δ -5.0, -4.9, 13.3, 15.3, 18.2, 21.6,
25.8, 50.3, 63.8, 65.5, 79.5, 124.7, 127.3, 129.9, 131.8, 138.5, and
143.7; HRMS calcd for [(C21H35NO4SSi) + H+] 426.2056, found
426.2129.
5-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-sul-
fonyl)-piperidin-2-yl]-pentanoic Acid Methyl Ester (26). To a
solution of 0.7 g of TBS ether 22 or 23 (1.7 mmol) in 20 mL of
CH2Cl2 at -78°C was added 0.6 g (2.9 mmol) of methyl-3-
(trimethylsilyl)-4-pentenonate (24) followed by 4 drops of BF3‚
OEt2. The reaction was stirred at -78° for 7 h and was then
quenched with a saturated sodium bicarbonate solution. After
warming to room temperature, the layers were separated and the
aqueous layer was extracted with CH2Cl2. The combined organic
layer was dried over MgSO4 and concentrated under reduced
pressure. The crude unsaturated ester 25 was dissolved in 20 mL
of methanol, and a catalytic amount of platinum(IV) oxide was
added. The flask was purged with hydrogen gas three times before
being allowed to stir under a hydrogen balloon for 17 h. The
solution was filtered through a pad of Celite, concentrated under
reduced pressure, and subjected to flash silica gel chromatography
to give 0.72 g (87%) of 26 as a white solid: mp 75-76 °C; IR
(thin film) 2950, 1739, 1463, 1339, and 1109 cm-1; 1H NMR (400
MHz, CDCl3) δ -0.08 (d, 6H, J ) 3.6 Hz), 0.80 (s, 9H), 1.22 (d,
3H, J ) 7.2 Hz), 1.50 (m, 10H), 2.32 (t, 2H, J ) 7.2 Hz), 2.41 (s,
3H), 3.19 (m, 1H), 3.67 (s, 3H), 3.96 (m, 3H), 7.28 (d, 2H, J )
7.4 Hz), and 7.69 (d, 2H, J ) 7.4 Hz); 13C NMR (100 MHz, CDCl3)
δ -4.8, -4.6, 14.9, 18.1, 21.6, 23.6, 24.9, 25.9, 26.9, 27.5, 34.1,
34.9, 51.7, 51.9, 53.1, 69.4, 126.9, 129.8, 139.1, 143.1, and 174.3.
Anal. Calcd for C25H43NO5SSi: C, 60.32; H, 8.71; N, 2.81.
Found: C, 60.21; H, 8.58; N, 2.81.
6-Methoxy-2-methyl-1-(toluene-4-sulfonyl)-1,2,3,6-tetrahydro-
pyridin-3-ol (20). To a solution of 4.7 g (12.5 mmol) of cerium
trichloride heptahydrate in 100 mL of MeOH was added 3.7 g (12.5
mmol) of N-tosylaminal 17. The solution was chilled to -40 °C,
and 0.5 g (14 mmol) of NaBH4 was added. The solution was stirred
for 10 min at -40 °C and was then quenched with a saturated
NaHCO3 solution. The solution was extracted with CH2Cl2, and
the combined extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by silica gel chromatography to give 2.2 g (60% yield) of
the title compound 20 as a colorless oil: IR (thin film) 2939, 1332,
1
and 1167 cm-1; H NMR (400 MHz, CDCl3) δ 1.20 (d, 3H, J )
6.8 Hz), 1.68 (d, 1H, J ) 7.6 Hz), 2.42 (s, 3H), 3.49 (s, 3H), 3.87
(m, 1H), 4.03 (dq, 1H, J ) 7.2 and 7.2 Hz), 5.37 (m, 1H), 5.62
(ddd, 1H, J ) 10.8, 3.2, and 1.6 Hz), 5.81 (ddd, 1H, J ) 10.4, 3.6,
and 2.4 Hz), 7.28 (d, 2H, J ) 8.0 Hz), and 7.69 (d, 2H, J ) 8.0
Hz); 13C NMR (100 MHz, CDCl3) δ 13.2, 21.7, 49.8, 56.3, 65.5,
80.9, 125.3, 127.2, 129.9, 130.7, 138.1, and 143.9; HRMS calcd
for C14H19NSO4 297.1035, found 297.1033.
3-(tert-Butyldimethyl-silanyloxy)-6-methoxy-2-methyl-1-(tolu-
ene-4-sulfonyl)-1,2,3,6-tetrahydropyridine (22). To a solution of
0.7 g (2.3 mmol) of 20 in 25 mL of CH2Cl2 was added 0.3 g (4.6
mmol) of imidazole and a catalytic amount of 4-(dimethylamino)-
pyridine followed by 0.4 g (2.8 mmol) of tert-butyldimethylchlo-
rosilane. The resulting solution was stirred at room temperature
for 30 min. Water was added, and the solution was extracted with
ether and dried over MgSO4. After removal of the solvent under
reduced pressure, the crude product was purified by silica gel
5-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-sul-
fonyl)-piperidin-2-yl]-pentan-1-ol (27). To a solution of 0.13 g
(0.26 mmol) of piperidino ester 26 at 0 °C was slowly added 0.3
mL of a solution of lithium aluminum hydride (1M in THF). After
the addition was complete, the reaction was quenched by the careful
addition of Na2SO4‚10H2O. After stirring for 30 min at room
J. Org. Chem, Vol. 71, No. 22, 2006 8597

Leverett et al.
temperature, MgSO4 was added and the solution was filtered. The
solution was concentrated under reduced pressure, and the crude
product was subjected to flash silica gel chromatography to give
0.12 g (97%) of the title compound 27 as a clear oil: IR (thin
2H, J ) 7.4 Hz), 3.03 (bs, 1H), 3.21 (q, 1H, J ) 6.4 Hz), and 3.83
(brs, 1H); 13C NMR (150 MHz, CDCl3) δ 16.4, 24.0, 26.1, 27.3,
30.4, 31.4, 35.0, 39.0, 57.6, 58.7, 66.3, and 182.9; FAB HRMS
calcd for [(C12H23NO3) + H+] 230.1756, found 230.1759.
film) 3418, 2855, 1462, and 1095 cm-1 1H NMR (400 MHz,
;
5-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-sul-
fonyl)-piperidin-2-yl]-pentanoic Acid Methoxymethylamide (19).
To a solution of 0.3 g (0.6 mmol) of piperidino ester 26 in THF
(1.2 mL) was added methoxymethylamine hydrochloride. The
resulting slurry was chilled to approximately -20 °C, and iso-
propylmagnesium chloride (0.9 mL of a 2 M solution in THF (1.8
mmol)) was added. The solution was stirred at this temperature
for 20 min and was then quenched by addition of a saturated
ammonium chloride solution. The reaction mixture was extracted
with CH2Cl2, dried over MgSO4, and concentrated under reduced
pressure. The crude product was subjected to flash silica gel
chromatography to give 0.27 g (85% yield) of the title compound
19 as a white solid: mp 77-78 °C; IR (thin film) 2947, 2848,
CDCl3) δ -0.08 (d, 6H, J ) 3.6 Hz), 0.82 (s, 9H), 1.23 (d, 3H, J
) 7.2 Hz), 1.30-1.80 (m, 13H), 2.43 (s, 3H), 3.19 (m, 1H), 3.66
(dt, 2H, J ) 2.8, and 6.8 Hz), 3.98 (m, 2H), 7.28 (d, 2H, J ) 8.0
Hz), and 7.70 (d, 2H, J ) 8.4 Hz); 13C NMR (100 MHz, CDCl3)
δ -4.8, -4.6, 14.9, 18.2, 21.7, 23.6, 25.6, 25.9, 27.0, 27.5, 32.8,
35.2, 51.9, 53.1, 63.0, 69.4, 126.9, 129.8, 139.1, and 143.0; HRMS
calcd for C24H43NSiSO4 469.2682, found 469.2675.
6-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-sul-
fonyl)-piperidin-2-yl]-hexanenitrile (28). To a solution of 0.26 g
(0.6 mmol) of alcohol 27 in 5.5 mL of CH2Cl2 was added
methanesulfonyl chloride (0.09 g, 0.8 mmol). The solution was
cooled to 0 °C, and 0.09 g of triethylamine was added dropwise.
After warming to room temperature over 30 min, the reaction was
quenched by the addition of water. The solution was extracted with
CH2Cl2, dried over MgSO4, and concentrated under reduced
pressure. The crude product was dissolved in 2 mL of DMF, and
0.05 g of sodium cyanide was added. The reaction mixture was
heated at 50 °C for 15 h. After cooling to room temperature, water
was added, and the mixture was extracted with ether. The ether
extracts were washed three time with brine, dried over MgSO4,
and concentrated under reduced pressure. The crude product was
subjected to flash silica gel chromatography to give 0.18 g (68%)
of the title compound 28 as a clear oil: IR (thin film) 2943, 2242,
1592, 1150, and 1104 cm-1; 1H NMR (400 MHz, CDCl3) δ -0.08
(d, 6H, J ) 3.6 Hz), 0.82 (s, 9H), 1.24 (d, 3H, J ) 7.2 Hz), 1.30-
1.74 (m, 12H), 2.36 (t, 2H, J ) 7.2 Hz), 2.43 (s, 3H), 3.17 (m,
1H), 3.96 (m, 1H), 7.29 (d, 2H, J ) 8.4 Hz), and 7.70 (d, 2H, J )
8.4 Hz); 13C NMR (100 MHz, CDCl3) δ -4.8, -4.6, 14.9, 17.3,
18.1, 21.7, 23.6, 25.5, 25.9, 26.4, 27.6, 28.6, 35.0, 51.8, 53.2, 69.3,
120.0, 126.9, 129.8, 139.0, and 143.1; HRMS calcd for C25H42N2-
SiSO3 478.2685, found 478.2677.
6-[5-Hydroxy-6-methyl-1-(toluene-4-sulfonyl)-piperidin-2-yl]-
hexanoic Acid (29). To a solution of 0.09 g (0.19 mmol) of nitrile
28 in 2 mL of methanol was added 2 mL of a 50% NaOH solution.
The mixture was heated at reflux for 3 h and cooled to room
temperature. The solution was extracted once with ether, and then
the aqueous portion was acidified to pH 2 using a 6 N HCl solution.
The acidified solution was extracted with CHCl3, and the combined
extracts were dried over MgSO4 and concentrated under reduced
pressure. The crude product contained 0.06 g (89%) of the title
compound 29 as a clear oil: IR (thin film) 3453, 2934, 2871, 1705,
1328, and 1155 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.25 (d, 4H,
J ) 7.2 Hz), 1.35-1.64 (m, 13H), 2.36 (t, 2H, J ) 7.6 Hz), 2.42
(s, 3H), 3.37 (m, 1H), 3.94 (q, 1H, J ) 6.8 Hz), 4.17 (dq, 1H, J )
6.8 and 6.8 Hz), 7.28 (d, 2H, J ) 8.4 Hz), and 7.70 (d, 2H, J )
8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 14.7, 21.7, 23.0, 24.7,
27.1, 27.3, 29.0, 34.1, 35.0, 51.9, 52.4, 69.1, 126.9, 129.9, 138.9,
143.2, and 179.2; HRMS calcd for C19H29NSO5 383.1766, found
383.1772.
1
1663, 1461, 1161, and 999 cm-1; H NMR (400 MHz, CDCl3) δ
-0.10 (d, 6H, J ) 3.6 Hz), 0.79 (s, 9H), 1.21 (d, 3H, J ) 7.2 Hz),
1.29-1.73 (m, 10H), 2.40 (s, 3H), 2.43 (m, 2H), 3.16 (m, 4H),
3.67 (s, 3H), 3.95 (m, 2H), 7.26 (d, 2H, J ) 8.0 Hz), and 7.67 (d,
2H, 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ -4.9, -4.7, 14.8,
18.0, 21.6, 23.5, 24.6, 25.8, 27.2, 27.4, 31.9, 32.2, 35.0, 51.9, 53.1,
61.4, 69.3, 126.8, 129.7, 139.0, 143.0, and 174.7; HRMS calcd for
C26H46N2SiSO5 526.2897, found 526.2889.
1-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-sul-
fonyl)-piperidin-2-yl]-dodec-11-en-5-one (30). To a solution of
0.1 g (0.6 mmol) of 1-iodo-6-heptene in 0.5 mL of heptane at -78
°C was added 1.6 mL of a 1.4 M solution of tert-butyllithium in
pentane. The mixture was stirred for 5 min, and then a solution of
0.17 g (0.3 mmol) of Weinreb’s amide 19 was added slowly. After
warming to 0 °C over 30 min, the reaction was quenched by the
addition of a saturated NH4Cl solution. The mixture was extracted
with ether, dried over MgSO4, and concentrated under reduced
pressure. The crude product was subjected to flash silica gel
chromatography to give 0.1 g (56%) of the title compound 30 as a
colorless oil: IR (thin film) 2932, 2857, 1712, 1337, and 1162 cm-1
;
1H NMR (400 MHz, CDCl3) δ -0.12 (d, 6H, J ) 4.0 Hz), 0.77 (s,
9H), 1.18 (d, 3H, J ) 7.2 Hz), 1.23-1.72 (m, 16H), 2.00 (q, 2H,
J ) 6.8 Hz), 2.36 (t, 2H, J ) 7.6 Hz), 2.38 (m, 5H), 3.14 (m, 1H),
3.92 (m, 2H), 4.92 (m, 2H), 5.75 (m, 1H), 7.24 (d, 2H, J ) 8.0
Hz), and 7.65 (d, 2H, J ) 7.6 Hz); 13C NMR (100 MHz, CDCl3)
δ -4.8, -4.6, 14.2, 14.9, 18.1, 21.6, 23.6, 23.7, 23.9, 25.9, 27.0,
27.5, 28.8, 28.9, 33.8, 35.1, 42.8, 42.9, 51.9, 53.1, 69.4, 114.5,
126.9, 129.8, 139.1, 143.0, and 211.6; HRMS calcd for C31H53-
NSiSO4 563.3464, found 563.3472.
3-(tert-Butyldimethyl-silanyloxy)-6-dodec-11-enyl-2-methyl-
1-(toluene-4-sulfonyl)-piperidine (31). To a solution of 0.1 g (0.18
mmol) of ketone 30 in 1.5 mL of absolute ethanol was added 0.037
g (0.19 mmol) of p-toluenesulfonylhydrazide. The solution was
stirred for 15 h at room temperature and then was concentrated
under reduced pressure. To the residue was added 1.5 mL of CH2-
Cl2, and the resulting solution was cooled to 0 °C. To this solution
was added 0.35 mL (0.34 mmol) of diisobutylaluminum hydride
solution (1 M in hexane). The solution was warmed to room
temperature over 30 min and was quenched with a 3.0 M solution
of NaOH. The solution was extracted with ether, dried over MgSO4,
and concentrated under reduced pressure. The crude product was
subjected to flash silica gel chromatography to give 0.04 g (40%
yield) of the title compound 31 as a colorless oil: IR (thin film)
2852, 1640, 1598, and 1163 cm-1; 1H NMR (400 MHz, CDCl3) δ
-0.07 (d, 6H, J ) 4.0 Hz), 0.82 (s, 9H), 1.22 (d, 3H, J ) 7.6 Hz),
1.27-1.72 (m, 22H), 2.04 (q, 2H, J ) 7.6 Hz), 2.42 (s, 3H), 3.23
(m, 1H), 3.98 (m, 2H), 4.96 (m, 2H), 5.82 (m, 1H), 7.28 (d, 2H, J
) 8.0 Hz), and 7.70 (d, 2H, J ) 7.6 Hz); 13C NMR (100 MHz,
CDCl3) δ -4.8, -4.6, 14.2, 14.9, 18.1, 21.6, 23.6, 23.7, 23.9, 25.9,
26.5, 27.0, 27.5, 28.8, 28.9, 33.8, 35.1, 52.0, 53.1, 69.4, 114.3,
126.9, 129.8, 139.2, 139.5, and 142.9; HRMS calcd for C31H55-
NSiSO3 549.3672, found 549.3661.
(()-Azimic Acid (5). To a solution of 0.02 g (0.044 mmol) of
carboxylic acid 29 in 0.6 mL of THF at -78 °C was condensed 3
mL of NH3 using a dry ice condenser. To this solution was added
lithium chips which resulted in the formation of a deep blue color.
The mixture was allowed to stir at -78 °C for 30 min, and then
0.5 mL of isoprene was added to quench the reaction. The solution
was warmed to room temperature, and water was added to the
resulting residue. The solution was brought to pH 7 by the addition
of 6 N HCl, and the solvent was subsequently removed under
reduced pressure. Methanol was added to precipitate any inorganic
salts, and the resulting solution was filtered and concentrated under
reduced pressure to give 0.007 g (70%) of (()-azimic acid (5) as
a white solid: mp 217-218 °C (lit.15d 214-215 °C); IR (thin film)
3344, 1633, and 1551 cm-1; 1H NMR (400 MHz, CD3OD) δ 1.33
(d, 2H, J ) 6.8 Hz), 1.22-1.81 (m, 11H), 1.96 (m, 1H), 2.17 (t,
8598 J. Org. Chem., Vol. 71, No. 22, 2006

Synthesis of the Cassia and Prosopis Alkaloid Family
6-Dodecyl-2-methyl-1-(toluene-4-sulfonyl)-piperidin-3-ol. To
a solution of 0.03 g (0.06 mmol) of alkene 31 in 0.1 mL of methanol
was added a catalytic amount of platinum(IV) oxide. After purging
the reaction vessel three times with hydrogen gas, the mixture was
stirred for 1 h under a hydrogen balloon. The reaction mixture was
filtered through a pad of Celite and concentrated under reduced
pressure. The crude reaction mixture was taken up in 0.6 mL of
THF, and a solution of tetrabutylammonium fluoride (66 µL of a
1 M solution in THF) was added at 0 °C. After warming to room
temperature over 30 min, water was added and the reaction mixture
was extracted with ether. The ether extracts were dried over MgSO4
and concentrated under reduced pressure. The crude product was
subjected to preparative thin-layer chromatography to give 0.024
g (92%) of the title compound as a clear oil: IR (thin film) 3444,
-0.10 (d, 6H, J ) 4.0 Hz), 0.81 (s, 9H), 1.22 (d, 3H, J ) 7.2 Hz),
1.49 (m, 16H), 1.74 (s, 3H), 1.92 (m, 2H), 2.41 (m, 7H), 3.17 (m,
1H), 3.32 (m, 4H), 3.95 (m, 2H), 7.28 (d, 2H, J ) 8.6 Hz), and
7.68 (d, 2H, J ) 8.6 Hz); 13C NMR (100 MHz, CDCl3) δ -4.8,
-4.6, 15.0, 18.2, 21.7, 23.6, 23.8, 23.9, 25.9, 27.0, 27.3, 27.5, 29.5,
32.5, 35.1, 40.0, 42.9, 45.8, 51.9, 53.2, 67.0, 69.4, 126.9, 129.8,
139.1, 143.1, and 211.5; HRMS calcd for [(C33H57NO4S3Si) + H+]
656.3219, found, 656.3298.
3-(tert-Butyldimethyl-silanyloxy)-2-methyl-6-[10-(2-methyl-
[1,3]dithiolan-2-yl)-decyl]-1-(toluene-4-sulfonyl)piperidine (33).
To a solution of the above ketone (0.07 g, 0.1 mmol) in absolute
EtOH (1.2 mL) was added p-toluenesulfonylhydrazide (0.02 g, 0.11
mmol), and the reaction mixture was stirred at room temperature
for 17 h. The solvent was removed under reduced pressure, and
the residue was taken up in CH2Cl2 (1.2 mL). The solution was
cooled to 0 °C, and DIBAL-H (0.5 mL, 0.5 mmol, 1.0 M in hexane)
was slowly added over a 15 min period. The reaction mixture was
stirred at 0 °C and then gradually warmed to room temperature
over 1 h. The solution was quenched by the dropwise addition of
an aqueous 3 M NaOH solution. The mixture was extracted with
ether, and the organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting residue was
subjected to silica gel chromatography to give 0.04 g (57%) of the
title compound 33 as a clear oil: IR (thin film) 2924, 2848, 1470,
1163, 1107, 999, 881, and 835 cm-1; 1H NMR (400 MHz, CDCl3)
δ -0.08 (d, 6H, J ) 4.0 Hz), 0.81 (s, 9H), 1.20 (d, 3H, J ) 6.8
Hz), 1.26-1.72 (m, 22H), 1.75 (s, 3H), 1.94 (m, 2H), 2.41 (s, 3H),
3.22 (ddd, 1H, J ) 11.2, 6.0, and 4.0 Hz), 3.32 (m, 4H), 3.97 (m,
2H), 7.27 (d, 2H, J ) 8.4 Hz), and 7.70 (d, 2H, J ) 8.4 Hz); 13C
NMR (100 MHz, CDCl3) δ -4.8, -4.6, 14.9, 18.1, 21.7, 23.6, 25.9,
27.4, 27.56, 27.64, 29.7, 29.8, 29.9, 30.0, 32.5, 35.3, 39.9, 46.1,
52.2, 53.1, 67.2, 69.6, 126.9, 129.8, 139.2, and 142.9; HRMS calcd
for [(C33H59NO3S3Si) + H+] 642.3426, found 642.3490.
1
2923, 2852, and 1460 cm-1; H NMR (600 MHz, CDCl3) δ 0.89
(t, 3H, J ) 7.2 Hz), 1.25-1.66 (m, 30H), 2.42 (s, 3H), 3.40 (m,
1H), 3.95 (q, 1H, J ) 6.6 Hz), 4.18 (dq, 1H, J ) 6.6 and 6.6 Hz),
7.28 (d, 2H, J ) 9.0 Hz), and 7.70 (d, 2H, J ) 8.4 Hz); 13C NMR
(150 MHz, CDCl3) δ 14.3, 14.7, 21.7, 22.9, 23.2, 27.3, 27.7, 29.6,
29.7, 29.8, 29.9, 32.1, 35.3, 52.1, 52.4, 69.2, 126.9, 129.9, 139.1,
and 143.1; HRMS calcd for C25H43NSO4 453.2913, found 453.2924.
(()-Deoxocassine (9). To a solution of 0.05 g of the above
alcohol in 0.5 mL of THF at -78 °C was condensed 2 mL of NH3
using a dry ice condenser. To this mixture was added lithium chips
(approximately 2 mg), and the solution immediately turned a deep
blue color. The reaction mixture was allowed to stir at -78 °C for
30 min, and then 0.5 mL of isoprene was added to quench the
reaction. The mixture was warmed to room temperature, and water
was added followed by a drop of 50% NaOH solution and CHCl3.
After extracting the aqueous layer with additional CHCl3, the
combined organic layer was dried over MgSO4 and concentrated
under reduced pressure to give 0.03 g (100%) of (()-deoxocassine
1
(9): IR (thin film) 3394, 2916, 2848, and 1455 cm-1; H NMR
(400 MHz, CDCl3) δ 0.89 (t, 3H, J ) 7.2 Hz), 1.15, (d, 3H, J )
6.8 Hz), 1.22-1.36 (m, 22H), 1.46 (m, 2H), 1.90 (m, 2H), 2.50
(m, 2H), 2.72 (qd, 1H, J ) 6.8 and 1.2 Hz), and 3.52 (d, 1H, J )
4.8 Hz); 13C NMR (150 MHz, CDCl3) δ 14.3, 18.9, 22.9, 26.0,
26.4, 29.6, 29.8, 29.9, 30.0, 32.1, 32.3, 37.2, 56.0, 57.5, and 68.3;
FAB HRMS calcd for [(C18H37NO) + H+] 284.2953, found
284.2941.
12-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-
sulfonyl)-piperidin-2-yl]-dodecan-2-one. To a solution of dithi-
olane 33 (0.03 g, 0.04 mmol) in a 2:1 CH3CN/H2O mixture (2.1
mL) was added CaCO3 (0.05 g, 0.45 mmol) and MeI (0.5 mL).
The solution was heated at 60 °C for 12 h, cooled to room
temperature, and diluted with H2O and brine. The aqueous layer
was extracted with ether, and the organic phase was dried over
MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography to give
0.02 g (100%) of the title compound as a clear oil: IR (thin film)
2937, 2855, 1717, 1463, 1339, 1253, 1163, 838, and 776 cm-1; 1H
NMR (400 MHz, CDCl3) δ -0.09 (d, 6H, J ) 3.6 Hz), 0.81 (s,
9H), 1.22 (d, 3H, J ) 7.2 Hz), 1.44 (m, 22H), 2.13 (s, 3H), 2.39
(m, 5H), 3.20 (ddd, 1H, J ) 11.2, 6.0, and 4.2 Hz), 3.96 (m, 2H),
7.27 (d, 2H, J ) 8.4 Hz), and 7.69 (d, 2H, J ) 8.4 Hz); 13C NMR
(100 MHz, CDCl3) δ -4.8, -4.6, 14.9, 18.2, 21.7, 23.6, 24.1, 25.9,
27.4, 27.5, 29.4, 29.6, 29.64, 29.68, 29.7, 30.1, 35.3, 44.0, 52.2,
53.1, 69.6, 127.0, 129.8, 139.2, 143.0, and 209.7; HRMS calcd for
[(C31H55NO4SSi) + H+] 566.3621, found 566.3700.
2-(5-Bromopentyl)-2-methyl-[1,3]dithiolane (32). A mixture of
BF3‚OEt2 (0.04 mL) and 1,2-ethanedithiol (0.3 mL, 4.0 mmol) was
added to a solution of 7-bromo-2-heptanone (0.5 g, 2.7 mmol) in
12 mL of CH2Cl2, and the reaction mixture was stirred for 18 h at
room temperature. The resulting solution was then quenched with
an aqueous 1 M NaOH solution, and the organic layer was washed
with H2O, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel chroma-
tography to give 0.65 g (89%) of the title compound 32 as a pale
1
yellow oil: IR (thin film) 2935, 2856, 1445, and 1374 cm-1; H
NMR (400 MHz, CDCl3) δ 1.51 (m, 4H), 1.75 (s, 3H), 1.90 (m,
4H), 3.33 (m, 4H), and 3.42 (t, 2H, J ) 6.8 Hz); 13C NMR (100
MHz, CDCl3) δ 26.6, 28.3, 32.5, 32.7, 33.9, 40.0, 45.6, and 66.8;
HRMS calcd for [(C9H17BrS2) + H+] 268.9955, found 269.0028.
1-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-sul-
fonyl)-piperidin-2-yl]-10-(2-methyl-[1,3]dithiolan-2-yl)-decan-5-
one. To a solution of the above bromide 32 (0.7 g, 0.27 mmol) in
pentane (2.5 mL) and tert-butyl methyl ether (1.25 mL) at -78 °C
was added t-BuLi (0.22 mL, 0.38 mmol, 1.7 M in pentane) over
15 min, and the resulting solution was stirred for an additional 25
min at -78 °C. A 0.1 g (0.19 mmol) sample of Weinreb’s amide
19 in ether (1.8 mL) was added over a 15 min period, and the
reaction mixture was stirred at -78 °C for 2.2 h before being
quenched with an aqueous NH4Cl solution. The aqueous layer was
extracted with ether, and the organic layer was dried over MgSO4,
filtered, and concentrated under reduced pressure. The resulting
oil was purified by silica gel chromatography to give 0.09 g (70%)
of the title compound as a clear oil: IR (thin film) 2935, 2857,
1713, 1463, 1338, and 1253 cm-1; 1H NMR (400 MHz, CDCl3) δ
3-(tert-Butyldimethyl-silanyloxy)-2-methyl-6-[10-(2-methyl-
[1,3]dioxolan-2-yl)-decyl]-1-(toluene-4-sulfonyl)piperidine (34).
To a solution of the above ketone (0.02 g, 0.03 mmol) in CH2Cl2
(0.5 mL) was added ethylene glycol (0.5 mL) and BF3‚OEt2 (8
drops), and the resulting solution was stirred at room temperature
for 27 h. The reaction mixture was then diluted with 1 M NaOH
and extracted with CH2Cl2. The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography to give
0.02 g (93%) of the title compound 34 as a clear oil: IR (thin
film) 2929, 2855, 1463, 1339, 1254, 1163, 1107, 1055, 879, 839,
1
and 776 cm-1; H NMR (400 MHz, CDCl3) δ -0.09 (d, 6H, J )
4.0 Hz), 0.81 (s, 9H), 1.22 (d, 3H, J ) 7.2 Hz), 1.31 (s, 3H), 1.48
(m, 24H), 2.41 (s, 3H), 3.22 (ddd, 1H, J ) 10.0, 6.0, and 4.0 Hz),
3.94 (m, 6H), 7.27 (d, 2H, J ) 8.4 Hz), and 7.69 (d, 2H, J ) 8.4
Hz); 13C NMR (100 MHz, CDCl3) δ -4.8, -4.6, 14.9, 18.2, 21.7,
23.6, 23.9, 24.3, 25.9, 27.4, 27.6, 29.6, 29.7, 29.8, 30.1, 35.3, 39.4,
J. Org. Chem, Vol. 71, No. 22, 2006 8599

Leverett et al.
52.2, 53.1, 64.8, 69.6, 110.4, 127.0, 129.8, 139.2, and 142.9; HRMS
calcd for [(C33H59NO5SSi) + H+] 610.3883, found 610.3962.
3-(tert-Butyldimethyl-silanyloxy)-2-methyl-6-[10-(2-methyl-
[1,3]dioxolan-2-yl)decyl]piperidine. To a solution of 34 (0.03 g,
0.04 mmol) in THF (3 mL) at -78 °C was added 5 mg of lithium
wire. The flask was fitted with an acetone/dry ice condenser, and
3 mL of NH3 was added which resulted in a dark blue solution.
The reaction mixture was stirred at -78 °C for 30 min, warmed to
room temperature, and quenched by the careful dropwise addition
of methanol. The solution was diluted with aqueous NH4Cl and
extracted with EtOAc. The organic layer was dried over MgSO4,
filtered, and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography to give 0.02 g
(94%) of the title compound as a clear oil: IR (thin film) 2927,
2854, 1463, 1373, 1252, 1070, 1032, and 837 cm-1; 1H NMR (400
MHz, CDCl3) δ -0.04 (d, 6H, J ) 6.0 Hz), 0.91 (s, 9H), 1.01 (d,
3H, J ) 6.8 Hz), 1.30 (s, 3H), 1.44 (m, 22H), 1.81 (m, 2H), 2.49
(brs, 1H), 2.68 (m, 1H), 3.55 (brs, 1H), and 3.93 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ -4.7, -4.3, 18.4, 19.5, 23.9, 24.3, 26.0, 26.1,
26.2, 29.8, 29.9, 30.1, 32.7, 37.6, 39.4, 55.6, 56.5, 64.8, 68.4, 77.5,
and 110.4; HRMS calcd for [(C26H53NO3Si) + H+] 456.3795, found
456.3863.
the residue was taken up in CH2Cl2 (1.0 mL). The solution was
cooled to 0 °C, and DIBAL-H (0.35 mL, 0.35 mmol, 1.0 M in
hexane) was added slowly over 10 min. The solution was stirred
at 0 °C and then gradually warmed to room temperature over 1 h.
The mixture was quenched by the dropwise addition of an aqueous
3 M NaOH solution and was extracted with ether. The organic layer
was dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting residue was subjected to silica gel chro-
matography to give 0.02 g (41%) of compound 34 which was
subsequently converted to cassine (8) as described above.
1-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-sul-
fonyl)piperidin-2-yl]-tridec-12-en-5-one (37). To a solution of
8-bromo-1-octene (0.25 mL, 0.29 g, 1.5 mmol) in tert-butyl methyl
ether (4.2 mL) at -78 °C was added t-BuLi (1.1 mL, 1.9 mmol,
1.7 M in pentane) over 15 min. The reaction mixture was stirred at
-78 °C for 25 min, and then a solution of Weinreb’s amide 19
(0.5 g, 0.95 mmol) in ether (8.8 mL) was added over 15 min. The
resulting solution was stirred at -78 °C for 3 h and then quenched
with an aqueous NH4Cl solution, and the mixture was warmed to
room temperature. The aqueous layer was extracted with ether, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue was subjected to silica gel chromatography to
afford 0.33 g (59%) of the title compound 37 as a clear oil: IR
(thin film) 2936, 2856, 1713, 1463, 1339, 1163, 1107, 934, 838,
(()-Cassine (8). To a solution of the above acetal (0.02 g, 0.04
mmol) in THF (3.3 mL) was added a 3 N HCl solution (0.33 mL,
1.0 mmol), and the solution was stirred at room temperature for
27 h. The reaction mixture was then quenched with 1 M NaOH
(5.0 mL, 5.0 mmol), and the aqueous layer was extracted with
EtOAc. The organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography over basic alumina to afford 0.007 g (59%)
of (()-cassine (8) as a white solid: mp 63-65 °C (lit.59 mp 59-
60 °C); IR (thin film) 3405, 2926, 2852, 1716, 1464, 1363, 1166,
and 967 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.11 (d, 3H, J ) 6.8
Hz), 1.39 (m, 20H), 1.90 (m, 2H), 2.13 (s, 3H), 2.41 (t, 2H, J )
7.6 Hz), 2.54 (m, 1H), 2.76 (m, 1H), and 3.55 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 18.7, 24.0, 26.0, 26.1, 29.4, 29.60, 29.63,
29.7, 29.8, 30.0, 30.1, 32.2, 37.0, 44.0, 56.0, 57.4, 68.1, and 209.7;
HRMS calcd for [(C18H35NO2) + H+] 298.2668, found 298.2740.
1-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-sul-
fonyl)piperidin-2-yl]-10-(2-methyl-[1,3]dioxolan-2-yl)-decan-5-
one (36). To a solution of 2-(5-bromopentyl)-2-methyl-1,3-
dioxolane (35)45 (0.06 g, 0.27 mmol) in tert-butyl methyl ether (1.25
mL) at -78 °C was added t-BuLi (0.22 mL, 0.38 mmol, 1.7 M in
pentane) over a 15 min period. The reaction mixture was then stirred
at -78 °C for 25 min, and a solution of Weinreb’s amide 19 (0.1
g, 0.19 mmol) in tert-butyl methyl ether (1.8 mL) was added over
15 min. The resulting solution was stirred at -78 °C for 2.5 h and
was subsequently quenched with an aqueous NH4Cl solution and
allowed to warm to room temperature. The aqueous layer was
extracted with ether, dried over MgSO4, filtered, and concentrated
under reduced pressure. The resulting residue was subjected to silica
gel chromatography to give 0.07 g (72%) of the title compound 36
as a clear oil: IR (thin film) 2941, 1713, 1464, 1338, 1254, 1107,
1
and 776 cm-1; H NMR (400 MHz, CDCl3) δ -0.10 (d, 6H, J )
3.6 Hz), 0.81 (s, 9H), 1.22 (d, 3H, J ) 6.8 Hz), 1.50 (m, 18H),
2.03 (m, 2H), 2.39 (m, 7H), 3.17 (ddd, 1H, J ) 10.0, 6.0, and 4.0
Hz), 3.95 (m, 2H), 4.89 (bd, 1H, J ) 10.0 Hz), 4.98 (dq, 1H, J )
17.2 and 1.6 Hz), 5.79 (ddt, 1H, J ) 17.2, 10.0, and 6.8 Hz), 7.27
(d, 2H, J ) 8.4 Hz) and 7.68 (d, 2H, J ) 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ -4.8, -4.6, 15.0, 18.1, 21.7, 23.6, 23.8, 24.0, 25.9,
27.0, 27.5, 28.9, 29.1, 29.3, 33.9, 35.1, 42.8, 43.0, 51.9, 53.1, 69.4,
114.4, 126.9, 129.8, 139.1, 139.3, 143.0, and 211.6; HRMS calcd
for [(C32H55NO4SSi) + H+] 578.3621, found 578.3697.
3-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-sulfo-
nyl)-piperidin-2-yl-6-tridec-12-enyl-piperidine (38). To a solution
of ketone 37 (0.06 g, 0.095 mmol) in absolute EtOH (1.0 mL) was
added p-toluenesulfonhydrazide (0.02 g, 0.1 mmol), and the reaction
mixture was stirred at room temperature for 18.5 h. The solvent
was removed under reduced pressure, and the residue was taken
up in CH2Cl2 (0.9 mL). The solution was cooled to 0 °C, and
DIBAL-H (0.3 mL, 0.34 mmol, 1.0 M in hexane) was slowly added
over 15 min. The solution was stirred at 0 °C and was gradually
warmed to room temperature over 1 h. The mixture was diluted
with CH2Cl2, quenched by the dropwise addition of an aqueous
3.0 M NaOH solution, and extracted with ether. The organic layer
was dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting residue was subjected to silica gel chro-
matography to give 0.04 g (76%) of the title compound 38 as a
clear oil: IR (thin film) 2928, 2855, 1463, 1340, 1254, 1164, 1105,
880, 838, 776, and 611 cm-1; 1H NMR (400 MHz, CDCl3) δ -0.08
(d, 6H, J ) 4.0 Hz), 0.82 (s, 9H), 1.22 (d, 3H, J ) 7.6 Hz), 1.49
(m, 24H), 2.04 (m, 2H), 2.41 (s, 3H), 3.22 (ddd, 1H, J ) 11.2, 6.0,
and 4.0 Hz), 3.98 (m, 2H), 4.92 (dt, 1H, J ) 10.0 and 1.2 Hz),
4.99 (dt, 1H, J ) 16.8 and 1.6 Hz), 5.80 (ddt, 1H, J ) 17.2, 10.4,
and 6.8 Hz), 7.27 (d, 2H, J ) 8.4 Hz), and 7.70 (d, 2H, J ) 8.4
Hz); 13C NMR (100 MHz, CDCl3) δ -4.8, -4.6, 14.9, 18.2, 21.1,
21.7, 23.6, 25.9, 26.2, 27.4, 27.6, 29.2, 29.4, 29.7, 29.8, 29.9, 34.0,
35.3, 52.2, 53.1, 69.6, 114.3, 127.0, 129.8, 139.2, 139.5, and 142.9;
HRMS calcd for [(C32H57NO3SSi) + H+] 564.3828, found 564.3903.
12-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-
sulfonyl)-piperidin-2-yl]-dodecanal (39). To a solution of 38 (0.1
g, 0.17 mmol) in a 2:1 dioxane/H2O mixture (5.5 mL) was added
2,6-lutidine (0.05 mL, 0.43 mmol), OsO4 (7 drops, 2.5% in
t-BuOH), and NaIO4 (0.16 g, 0.75 mmol). After stirring for 3.5 h
at room temperature, an aqueous mixture of Na2SO3 was added
and the aqueous layer was then extracted with CH2Cl2. The organic
layer was washed with 1 N HCl, dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting residue was
1
and 839 cm-1; H NMR (400 MHz, CDCl3) δ -0.10 (d, 6H, J )
3.6 Hz), 0.80 (s, 9H), 1.21 (d, 3H, J ) 6.8 Hz), 1.30 (s, 3H), 1.50
(m, 16H), 2.40 (m, 7H), 3.17 (ddd, 1H, J ) 10.8, 6.0, and 4.0 Hz),
3.84 (m, 6H), 7.27 (d, 2H, J ) 8.4 Hz), and 7.68 (d, 2H, J ) 8.4
Hz); 13C NMR (100 MHz, CDCl3) δ -4.8, -4.6, 14.9, 18.1, 21.6,
23.6, 23.7, 23.9, 24.0, 24.1, 25.9, 27.0, 27.5, 29.6, 35.1, 39.2, 42.8,
42.9, 51.9, 53.1, 64.8, 69.4, 110.3, 126.9, 129.8, 139.1, 143.0, and
211.5; HRMS calcd for [(C33H57NO6SSi) + H+] 624.3676, found
624.3763.
To a solution of the above ketone (0.06 g, 0.09 mmol) in absolute
EtOH (1.0 mL) was added p-toluenesulfonylhydrazide (0.02 g, 0.01
mmol), and the reaction mixture was stirred at room temperature
for 18 h. The solvent was removed under reduced pressure, and
(59) Oetting, J.; Holzkamp, J.; Meyer, H. H.; Pahl, A. Tetrahedron:
Asymmetry 1997, 8, 477.
8600 J. Org. Chem., Vol. 71, No. 22, 2006

Synthesis of the Cassia and Prosopis Alkaloid Family
purified by silica gel to give 0.09 g (93%) of the title compound
of lithium wire. The flask was fitted with an acetone/dry ice
condenser, and 3 mL of ammonia was added which gave rise to a
dark blue solution. The mixture was stirred at -78 °C for 0.5 h,
allowed to warm to room temperature, and quenched by the careful
dropwise addition of methanol. The solution was diluted with an
aqueous NH4Cl solution and extracted with EtOAc. The aqueous
layer was acidified to pH ) 2 with 6 N HCl and extracted with
EtOAc. The aqueous layer was further extracted with a 3:1 mixture
of CHCl3/i-PrOH. The resulting organic layer was dried over Na2-
SO4, filtered, and concentrated under reduced pressure to provide
0.02 g (64%) of (()-spicigerine (7) as a white solid requiring no
further purification: mp 168-169 °C; IR (thin film) 3416, 2914,
39 as a yellow oil: IR (thin film) 2933, 2854, 1725, 1463, 1338,
1
1254, 1164, 1107, 879, 838, 776, and 660 cm-1; H NMR (400
MHz, CDCl3) δ -0.10 (d, 6H, J ) 3.6 Hz), 0.81 (s, 9H), 1.22 (d,
3H, J ) 7.2 Hz), 1.48 (m, 24H), 2.42 (m, 5H), 3.21 (ddd, 1H, J )
10.4, 5.6, and 4.0 Hz), 4.00 (m, 2H), 7.27 (d, 2H, J ) 8.4 Hz),
7.70 (d, 2H, J ) 8.4 Hz), and 9.76 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ -4.8, -4.7, 14.9, 18.1, 21.6, 22.3, 23.6, 25.9, 27.4, 27.5,
29.3, 29.5, 29.6, 29.7, 29.9, 35.3, 44.1, 52.2, 53.1, 69.5, 127.0,
129.8, 139.2, 142.9, and 203.2; HRMS calcd for [(C31H55NO4SSi)
+ H+] 566.3621, found 566.3698.
12-[5-(tert-Butyldimethyl-silanyloxy)-6-methyl-1-(toluene-4-
sulfonyl)-piperidin-2-yl]-dodecanoic Acid (40). To a solution of
aldehyde 39 (0.36 g, 0.64 mmol) in t-BuOH (4.5 mL) was added
resorcinol (0.09 g, 0.83 mmol) followed by an acetate buffer (pH
) 3.6, 1.3 mL). To the resulting mixture was added a solution of
NaClO2 (0.07 g, 0.8 mmol) in H2O (5 mL), and the mixture was
stirred at room temperature for 6 h. The organic layer was diluted
with brine and extracted with ether, dried over MgSO4, filtered,
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography to give 0.37 g (99%) of the
title compound 40 as a yellow oil: IR (thin film) 2936, 2854, 1709,
1463, 1338, 1254, 1164, 1105, 838, and 777 cm-1; 1H NMR (400
MHz, CDCl3) δ -0.09 (d, 6 H, J ) 3.6 Hz), 0.81 (s, 9H), 1.25 (m,
24H), 1.22 (d, 3H, J ) 6.8 Hz), 2.34 (t, 2H, J ) 7.6 Hz), 2.41 (s,
3H), 3.22 (ddd, 1H, J ) 11.2, 5.6, and 4.0 Hz), 3.97 (m, 2H), 7.27
(d, 2H, J ) 8.4 Hz), and 7.69 (d, 2H, J ) 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ -4.8, -4.6, 14.9, 18.2, 21.7, 23.6, 24.9, 25.9, 27.4,
27.6, 29.3, 29.4, 29.6, 29.7, 34.2, 35.3, 52.2, 53.1, 69.6, 127.0,
129.8, 139.2, 143.0, and 180.0; HRMS calcd for [(C31H55NO5SSi)
+ H+] 582.3570, found 582.3643.
1
2848, 1726, 1460, 1408, 1173, 1102, and 1010 cm-1; H NMR
(400 MHz, CD3OD) δ 1.61 (m, 27H), 2.26 (t, 2H, J ) 8.0 Hz),
3.05 (brs, 1H), 3.22 (m, 1H), and 3.82 (m, 1H); 13C NMR (100
MHz, CD3OD) δ 16.1, 23.7, 26.2, 26.5, 30.4, 30.5, 30.6, 30.7,
30.8, 30.9, 31.1, 34.9, 35.1, 57.6, 58.8, 66.0, and 177.9; HRMS
calcd for [(C18H35NO3) + H+] 314.2617, found 314.2685.
(S,E)-N-(1-Furan-2-yl-ethyl)toluene p-Sulfinamide (41). A
mixture of (S)-(+)-p-toluenesulfinamide57 (0.03 g, 0.19 mmol),
2-acetylfuran (0.02 g, 0.19 mmol), and Ti(OEt)4 (0.3 mL, 1.5 mmol)
in CHCl3 (4 mL) was heated at reflux for 41 h. The reaction mixture
was then cooled to 0 °C. H2O was added, and the resulting
suspension was filtered over Celite. The filtrate was extracted with
CH2Cl2, dried over MgSO4, and concentrated under reduced
pressure. The resulting residue was purified by silica gel chroma-
tography to give 0.03 g (69%) of the title compound 41 as a yellow
solid: mp 65-67 °C; IR (thin film) 3129, 2925, 2243, 1581, 1479,
1
1397, 1307, 1168, 1099, 1066, 1029, 907, 813, and 727 cm-1; H
NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 2.66 (s, 3H), 6.48 (s,
1H), 7.09 (d, 1H, J ) 3.6 Hz), 7.29 (d, 2H, J ) 8.0 Hz), 7.53 (s,
1H) and 7.69 (d, 2H, J ) 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ
19.2, 21.6, 112. 7, 115.9, 125.3, 130.0, 142.0, 143.4, 146.4, 152.5,
and 164.2.
The same carboxylic acid 40 was prepared by the direct oxidation
of piperidinyl alkene 38. To a solution of alkene 38 (0.03 g, 0.05
mmol) in DMF (1.2 mL) was added OsO4 (3 drops, 2.5% in
t-BuOH), and the reaction mixture was stirred at room temperature
for 5 min. Oxone was added in one portion, and the mixture was
stirred at room temperature for an additional 35 min and then diluted
with EtOAc. The aqueous layer was acidified with 10% HCl and
extracted with EtOAc. The organic layer was dried over MgSO4,
filtered, and concentrated to give a clear oil which was purified by
silica gel chromatography to give 0.02 g (53%) of 40.
(S)-N-(1-Furan-2-yl-ethyl)toluene p-Sulfonamide ((S)-16). To
a -78 °C solution of the above sulfinimine 41 (0.08 g, 0.33 mmol)
in 4.7 mL of THF was added LiAlH(OtBu)3 (0.11 g, 0.43 mmol)
in 2.5 mL of THF over a 15 min period. The mixture was stirred
at -78 °C for 2 h and then warmed and stirred between -50 and
-55 °C for 20 h. The solution was quenched with a saturated
aqueous NH4Cl solution, warmed to room temperature, and
extracted with EtOAc. The organic layer was dried over MgSO4,
filtered, and concentrated under reduced pressure to provide a 1:1
inseparable mixture of 41 and 42, which was used immediately in
the next step. A solution of the crude mixture in 5 mL of CH2Cl2
was added to a solution of mCPBA in 5 mL of CH2Cl2 at -30 °C.
The mixture was stirred and allowed to warm to 0 °C over 1.5 h.
A saturated aqueous NaHCO3 solution was added, and the aqueous
layer was extracted with CH2Cl2. The resulting organic layer was
dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting clear oil was purified by silica gel
chromatography to give 0.03 g (35%) of the title compound: [R]D
-63.5 (c 1.0, EtOH) 0.58
12-[5-Hydroxy-6-methyl-1-(toluene-4-sulfonyl)piperidin-2-
yl] Dodecanoic Acid. To a solution of carboxylic acid 40 (0.37 g,
0.6 mmol) in THF (8 mL) at 0 °C was added TBAF (0.8 mL, 0.76
mmol, 1.0 M in THF), and the mixture was gradually warmed to
room temperature over 40 min. The solution was stirred at room
temperature for an additional 3 h, over which time an additional
2.0 equiv (1.3 mL) of TBAF was added in portions. The mixture
was then diluted with H2O and brine and extracted with EtOAc.
The organic layer was dried over MgSO4, filtered, and concentrated
under reduced pressure. The resulting residue was purified by silica
gel chromatography to give 0.23 g (77%) of the title compound as
a yellow oil: IR (thin film) 3448, 2927, 2853, 1709, 1458, 1404,
1
1330, 1166, 1098, 985, 911, 814, 732, and 664 cm-1; H NMR
(400 MHz, CDCl3) δ 1.47 (m, 27H), 2.34 (t, 2H, J ) 7.2 Hz), 2.40
(s, 3H), 3.38 (ddd, 1H, J ) 10.4, 6.0, and 4.4 Hz), 3.93 (q, 1H, J
) 6.8 Hz), 4.17 (p, 1H, J ) 6.8 Hz), 7.26 (d, 2H, J ) 8.4 Hz), and
7.69 (d, 2H, J ) 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 14.7,
21.7, 23.1, 24.9, 27.3, 27.6, 29.2, 29.4, 29.56, 29.65, 29.70, 29.90,
34.2, 35.2, 52.1, 52.4, 69.2, 126.9, 129.9, 139.0, 143.1, and 179.5;
HRMS calcd for [(C25H41NO5S) + H+] 468.2705, found 468.2779.
(()-Spicigerine (7). To a solution containing 0.04 g (0.08 mmol)
of the above compound in THF (3 mL) at -78 °C was added 5 mg
Acknowledgment. This research was supported by the
National Institutes of Health (GM 0539384) and the National
Science Foundation (CHE-0450779).
Supporting Information Available: 1H and 13C NMR data of
various key compounds lacking CHN analyses. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0616714
J. Org. Chem, Vol. 71, No. 22, 2006 8601