Self-condensation of N-tert-butanesulfinyl aldimines: Application to the rapid asymmetric synthesis of biologically important amine-containing compounds

Article abstract of DOI:10.1021/ol048458j

(Chemical Equation Presented) Highly diastereoselective intra- and intermolecular self-condensation reactions of N-tert-butanesulfinyl aldimines have been developed and applied to the rapid, asymmetric synthesis of frans-2-aminocyclopentanecarboxylic acid and the drug candidate SC-53116. Key to both syntheses is a novel microwave-assisted reaction in which N-sulfinyl aldimines are cleanly converted into nitrites in high-yielding concerted elimination processes.

Full text of DOI:10.1021/ol048458j

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3621-3624
Self-Condensation of
N-tert-Butanesulfinyl Aldimines:
Application to the Rapid Asymmetric
Synthesis of Biologically Important
Amine-Containing Compounds
Laurie B. Schenkel and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California, Berkeley, California 94720
jellman@berkeley.edu
Received August 3, 2004
ABSTRACT
Highly diastereoselective intra- and intermolecular self-condensation reactions of N-tert-butanesulfinyl aldimines have been developed and
applied to the rapid, asymmetric synthesis of trans-2-aminocyclopentanecarboxylic acid and the drug candidate SC-53116. Key to both syntheses
is a novel microwave-assisted reaction in which N-sulfinyl aldimines are cleanly converted into nitriles in high-yielding concerted elimination
processes.
Diastereoselective additions of nucleophiles to N-tert-
butanesulfinyl imines have proven to be among the most
effective methods for the asymmetric synthesis of amines.1
The deprotonation of N-sulfinyl ketimines to provide met-
alloenamines, which then add with high diastereoselectivity
to electrophiles, has significantly enhanced the utility of this
chemistry. In particular, metalloenamines derived from
N-tert-butanesulfinyl ketimines have been added to aldehydes
to provide â-hydroxy N-sulfinyl imines. Stereoselective
reduction then provides access to either syn- or anti-1,3-
amino alcohols.2
Attempts to add metalloenamines derived from tert-
butanesulfinyl aldimines to electrophiles have been unsuc-
cessful as a result of competitive self-condensation during
the deprotonation step.3 However, it became apparent that a
high-yielding, diastereoselective self-condensation reaction
would enable the rapid construction of a variety of amine-
containing compounds bearing two new contiguous stereo-
centers. Herein we report the development of highly dia-
stereoselective intra- and intermolecular self-condensation
(1) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984. (b) McMahon, J. P.; Ellman, J. A. Org. Lett. 2004, 6, 1645 and
references therein. (c) Higashibayashi, S.; Kohno, M.; Goto, T.; Suzuki,
K.; Mori, T.; Hashimoto, K.; Nakata, M. Tetrahedron Lett. 2004, 45, 3707.
(d) deSolms, S. J.; Ciccarone, T. M.; MacTough, S. C.; Shaw, A. W.; Buser,
C. A.; Ellis-Hutchings, M. E.; Fernandes, C.; Hamilton, K. A.; Huber, H.
E.; Kohl, N. E.; Lobell, R. B.; Robinson, R. G.; Tsou, N. N.; Walsh, E. S.;
Graham, S. L.; Beese, L. S.; Taylor, J. S. J. Med. Chem. 2003, 46, 2973.
(e) Kells, K. W.; Chong, J. M. Org. Lett. 2003, 5, 4215. (f) Cooper, I. R.;
Grigg, R.; Hardie, M. J.; MacLachlan, W. S.; Sridharan, V.; Thomas, W.
A. Tetrahedron Lett. 2003, 44, 2283. (g) Rech, J. R.; Floreancig, P. E.
Org. Lett. 2003, 5, 1495. (h) Jung, P. M.; Beaudegnies, E.; DeMesmaeker,
A.; Wendeborn, S. Tetrahedron Lett. 2003, 44, 293.
(2) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 6518. (b) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc.
2003, 125, 11276.
(3) Kochi, T. Unpublished results.
10.1021/ol048458j CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/04/2004

reactions of N-tert-butanesulfinyl aldimines, which, to our
knowledge, represent the first examples of stereoselective
imine self-condensation.4 The utility of these self-condensa-
tion reactions is further demonstrated via the concise
asymmetric syntheses of trans-2-aminocyclopentanecarboxy-
lic acid 1 and SC-53116, a serotonin 5-HT4 agonist (Figure
1).
3 (Scheme 1). Optimization of the intramolecular self-
condensation reaction of imine 3 began with a survey of
bases (Table 1). Previous observation of self-condensation
Table 1. Optimization of Intramolecular Self-Condensation
entry
base
yield (%)a
drb
1
2
3
4
5
6c
7
2-MePhMgBr
2-MeOPhMgBr
t-BuMgBr
25
50
80
60
60
81
34
52:0:38:10
66:0:26:8
50:0:37:13
76:0:12:12
80:2:7:11
78:3:8:11
77:0:19:4
LHMDSd
NaHMDSd
NaHMDSd
KHMDSd
Figure 1. Biologically important compounds prepared utilizing
self-condensation methodology.
a Isolated yield after column chromatography. b Determined by 1H NMR
(see Supporting Information). Only the stereochemistry of the major
diastereomer was determined. c Reaction run with 2.0 equiv of DMPU as
additive. d 1.0 M in THF.
The potential utility of an intramolecular N-sulfinyl
aldimine self-condensation reaction was evident upon ex-
amination of the literature. There are several cyclic drug
candidates5 and biologically relevant compounds6 that exhibit
a core structure that could be accessed via aldimine self-
condensation. One such compound, â-amino acid 1 (Scheme
1), is particularly useful because it has been incorporated
to provide oligomeric products as an undesired side reaction
in the addition of Grignard reagents to sulfinyl aldimines9
suggested that magnesium bases might effect the desired
transformation. Imine 3, which was prepared in 80% yield
by condensation of (R)-tert-butanesulfinamide with hex-
anedial, was deprotonated with several sterically hindered
Grignard reagents to provide the desired self-condensation
product, albeit with poor diastereoselectivity (entries 1-3).
Use of sodium and lithium hexamethyldisilazide (HMDS)
improved both the yield and selectivity (entries 4-6).
Optimization showed that NaHMDS with 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) as an addi-
tive significantly improved the reaction yield (entry 6).
Notably, a single recrystallization of self-condensation
product 2, obtained according to the conditions listed in entry
6, provides the diastereomerically enriched product (g95%
dr) in 50% yield from 3.10 The absolute stereochemistry of
2 was determined by X-ray crystallography, establishing that
the thermodynamically favored trans isomer was formed
preferentially in the self-condensation reaction.
Scheme 1. Retrosynthesis for 1
into unnatural homo- and heterogeneous foldamers that
exhibit discrete folding properties.7 Very recently, foldamers
prepared from 1 were reported to display promising anti-
microbial activity.8
We envisioned a rapid synthesis of 1 via intermediate 2,
which is the self-condensation product of bis-sulfinyl imine
(4) The self-condensation of 3,4,5,6-tetrahydropyridine is the only
reported example of imine self-condensation. The stereochemical outcome
of the reaction was not determined: Scho¨pf, C.; Braun, F.; Komzak, A.
Chem. Ber. 1956, 89, 1821.
(5) (a) Babu, Y. S.; Chand, P.; Montgomery, J. A. U.S. Patent 6,562,-
861, 2000. (b) Berge, J. M.; Brown, P.; Elder, J. S.; Forrest, A. K.;
Hamprecht, D. W.; Jarvest, R. L.; McNair, D. J.; Sheppard, R. J. U.S. Patent
6,320,051, 2000. (c) McIver, J. M.; Degenhardt, C. R.; Eickhoff, D. J. U.S.
Patent 6,307,049, 1999.
(6) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Strijowski,
U.; Sewald, N. Org. Biomol. Chem. 2004, 2, 1105. (c) Yamazaki, T.; Zhu,
Y.-F.; Probstl, A.; Chadha, R. K.; Goodman, M. J. Org. Chem. 1991, 56,
6644.
With the self-condensation product 2 in hand, conversion
to â-amino acid 1 was rapidly completed in two high-yielding
steps (Scheme 2). Previous work in these laboratories led to
the observation that at temperatures above 130 °C, tert-
butanesulfinyl aldimines undergo a concerted elimination of
tert-butanesulfenic acid to provide nitriles.11 Optimization
of this novel reaction for the present work showed that the
(7) (a) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Richards, M.
R.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 7574. (b)
Hayen, A.; Schmitt, M. A.; Ngassa, F. N.; Thomasson, K. A.; Gellman, S.
H. Angew. Chem., Int. Ed. 2004, 43, 505. (c) LePlae, P. R.; Fisk, J. D.;
Porter, E. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2002, 124,
6820.
(9) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.; Nantermet,
P. G. Tetrahedron Lett. 2001, 42, 2051.
(10) A short survey of solvents revealed that THF is required for high
yield and selectivity, as both Et2O and toluene gave inferior results.
(11) (a) Mukade, T.; Dragoli, D. R.; Ellman, J. A. J. Comb. Chem. 2003,
5, 590. (b) Decomposition of a p-toluenesulfinyl imine has also been
reported: Davis, F. A.; Friedman, A. J.; Kluger, E. W. J. Am. Chem. Soc.
1974, 96, 5000.
(8) Schmitt, M. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc.
2004, 126, 6848.
3622
Org. Lett., Vol. 6, No. 20, 2004

Investigation of the intermolecular variant thus focused
on self-condensation of sulfinyl imine 5, which was prepared
in 89% yield via CuSO4-catalyzed condensation of (R)-tert-
butanesulfinamide and the corresponding aldehyde. As in
the intramolecular case, hindered Grignard reagents were less
effective bases for this transformation, and both KHMDS
and NaHMDS failed to provide the desired product in
synthetically useful yields or selectivities. Use of LHMDS
proved to be critical, and we were pleased to find that, under
optimized conditions, the desired intermolecular self-
condensation product could be isolated in 55% yield and with
an excellent 91:5:4:0 diastereomeric ratio (Scheme 4). Again,
Scheme 2. Synthesis of 1
microwave-assisted transformation can be carried out in high
yield in the presence of a sulfinamide moiety and other
protected functionalities (vide infra).12 The highest yields
were obtained by heating at 150 °C for 15 min in acetonitrile
in a microwave reactor. Incomplete conversion was observed
at lower temperatures, and significant amounts of undesired
decomposition products were obtained at temperatures higher
than 150 °C.
Scheme 4. Intermolecular Self-Condensation
Conversion of 4 to 1 was then carried out in quantitative
yield via acid-catalyzed hydrolysis of the nitrile with
concomitant removal of the sulfinyl protecting group (Scheme
2). Under these conditions, the stereochemical integrity of 1
was maintained as confirmed by preparation and GC analysis
of the corresponding (R)- and (S)-Mosher amides. This
synthesis of enantiomerically pure â-amino acid 1 was
accomplished in four steps in 31% overall yield from
hexanedial and represents one of the most efficient syntheses
of 1 reported to date.13
The diastereoselective self-condensation of tert-butane-
sulfinyl aldimines was further applied to an intermolecular
variant of the reaction. One powerful application of this
method is the rapid construction of the pyrrolizidine scaffold
(Scheme 3), an alkaloid motif that is present in multiple drug
DMPU as an additive was beneficial, which in this case
served to improve the diastereoselectivity from 87:7:6:0 in
the case where LHMDS alone was employed. Notably, the
intermolecular self-condensation reaction does not require a
sulfinyl imine bearing a coordinating group for high selectiv-
ity, as self-condensation of imine 7 also provides a syntheti-
cally useful diastereoselectivity and yield (Scheme 4). In this
case, however, additives did not improve either yield or
selectivity.
The pyrrolizidine benzamide SC-5311614a seemed an ideal
synthesis target for displaying the utility of the intermolecular
aldimine self-condensation methodology (Scheme 5). SC-
53116 is the first selective serotonin 5-HT4 receptor agonist
Scheme 3. Retrosynthesis for Preparation of Pyrrolizidines
(13) For other asymmetric syntheses, see: (a) LePlae, P. R.; Umezawa,
N.; Lee, H.-S.; Gellman, S. H. J. Org. Chem. 2001, 66, 5629. (b)
Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R. M.; Smethurst,
C. A. P.; Smith, A. D.; Rodriguez-Solla, H. Tetrahedron 2003, 59, 3253.
(c) Enders, D.; Weidemann, J. Liebigs Ann./Recueil 1997, 699. (d) Davies,
S. G.; Ichihara, O.; Lenoir, I.; Walters, I. A. S. J. Chem. Soc., Perkin Trans.
1 1994, 1411. (e) Perlmutter, P.; Rose, M.; Vounatsos, F. Eur. J. Org. Chem.
2003, 756.
(14) Representative examples include: (a) Flynn, D. L.; Zabrowski, D.
L.; Becker, D. P.; Nosal, R.; Villamil, C. I.; Gullikson, G. W.; Moummi,
C.; Yang, D.-C. J. Med. Chem. 1992, 35, 1489. (b) Becker, D. P.; Flynn,
D. L.; Villamil, C. I. Biorg. Med. Chem. Lett. 2004, 14, 3073. (c) Zabrowski,
D. L.; Flynn, D. L. U.S. Patent 4,992,461, 1989. (d) Becker, D. P.; Flynn,
D. L.; Moormann, A. E.; Nosal, R.; Villamil, C. I. U.S. Patent 5,137,893,
1991.
(15) For representative natural product syntheses, see: (a) Ledoux, S.;
Marchalant, E.; Ce´le´rier, J.-P.; Lhommet, G. Tetrahedron Lett. 2001, 42,
5397. (b) Bertrand, S.; Hoffman, N.; Pete, J.-P. Eur. J. Org. Chem. 2000,
2227. (c) David, O.; Blot, J.; Bellec, C.; Fargeau-Bellassoued, M.-C.;
Haviari, G.; Ce´le´rier, J.-P.; Lhommet, G.; Gramain, J.-C.; Gardette, D. J.
Org. Chem. 1999, 64, 3122. (d) Nagao, Y.; Dai, W.-M.; Ochiai, M.;
Tsukagoshi, S.; Fujita, E. J. Org. Chem. 1990, 55, 1148.
candidates14 and natural products.15 It was envisioned that
the pyrrolizidine framework could be prepared via function-
alization of intermediate 6, which is the product of inter-
molecular self-condensation of sulfinyl imine 5 (Scheme 3).
(12) tert-Butanesulfinamides also undergo concerted eliminations of tert-
butanesulfenic acid to provide unsubstituted imines, but this transformation
apparently has a higher activation barrier than for conversion of N-tert-
butanesulfinyl imines to nitriles.
Org. Lett., Vol. 6, No. 20, 2004
3623

the pure major diastereomer 9 in 84% yield. Absolute
stereochemistry was established via X-ray crystallographic
analysis of 9. Mild reduction of the nitrile with borane-
dimethyl sulfide complex was accomplished in 90% yield,
followed by coupling of amine 10 with 4-amino-5-chloro-
2-methoxybenzoic acid under standard amide bond forming
conditions, to provide intermediate 11 in 80% yield. Under
acidic reducing conditions, the sulfinyl and acetal protecting
groups were removed, allowing for cyclization and reduction
in a single step, which furnished SC-53116 in 88% isolated
yield. This sequence is significantly more efficient than the
prior synthesis, providing SC-53116 in 29% overall yield in
only five steps from sulfinyl imine 5.
Scheme 5. Synthesis of Pyrrolizidine Alkaloid SC-53116
The self-condensation reactions of N-tert-butanesulfinyl
aldimines reported here are the first examples of stereose-
lective imine self-condensation processes and provide ver-
satile, functionalized intermediates with multiple stereo-
centers. The diastereoselective intra- and intermolecular self-
condensation reactions were applied to the rapid total
syntheses of trans-2-aminocyclopentanecarboxylic acid 1 and
serotonin 5-HT4 agonist SC-53116, both of which featured
a novel microwave-assisted thermal decomposition to cleanly
convert N-sulfinyl imines to nitriles. The prevalence of
structural motifs and scaffolds that are easily accessible via
this strategy suggests that this self-condensation methodology
may enjoy widespread use for a variety of applications.
to be identified14b and surpasses the potency and selectivity
of other benzamides, such as metoclopramide, zacopride,
renzapride, and cisapride.14a The reported synthesis of SC-
53116 requires over 10 steps, with the key step being a highly
diastereoselective alkylation of a cyclic acyl imine by a chiral
tin enolate.14a,15d
The highly diastereoselective synthesis of self-condensa-
tion product 6 enables a significantly more efficient synthesis
of SC-53116 (Scheme 5). Microwave-assisted sulfinyl imine
decomposition was again key to the success of the sequence,
as it allowed for selective functionalization of the self-
condensation product in the presence of both the sulfinyl
amine and cyclic acetal protecting groups. Microwave
reaction of a 91:5:4:0 diastereomeric mixture of self-
condensation product 6, followed by chromatographic sepa-
ration of the corresponding diastereomeric nitriles, provided
Acknowledgment. This work was supported by the
National Science Foundation (CHE0139468). L.B.S grate-
fully acknowledges Boehringer Ingelheim for a graduate
fellowship. The authors thank Dr. Allen G. Oliver and Dr.
Frederick J. Hollander for solving the X-ray crystal struc-
tures. The Center for New Directions in Organic Synthesis
is supported by Bristol-Myers-Squibb as sponsoring member
and Novartis as supporting member.
Supporting Information Available: Crystallographic
data in CIF format, full experimental details, and character-
ization for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL048458J
3624
Org. Lett., Vol. 6, No. 20, 2004