Synthesis of Enantiomerically Pure 2,2,3,4,5-Pentasubstituted Pyrrolidines by Phenylsulfanyl Migration

Article abstract of DOI:10.1021/ol0268384

(Matrix Presented) Enantiomerically pure 2,2,3,4,5-pentasubstituted pyrrolidines can be prepared, in high overall yield, from α,β-unsaturated esters. Asymmetry is introduced via a Michael addition, and additional stereogenic centers are introduced by an a

Full text of DOI:10.1021/ol0268384

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4381-4384
Synthesis of Enantiomerically Pure
2,2,3,4,5-Pentasubstituted Pyrrolidines
by Phenylsulfanyl Migration†
I. Craig Baldwin,‡ Paul Briner,‡ Martin D. Eastgate,§ David J. Fox,§ and
,§
Stuart Warren*
OSI Pharmaceuticals, Watlington Road, Cowley, Oxford, OX4 5LY, England, and
UniVersity Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, England
sw134@cam.ac.uk
Received September 2, 2002
ABSTRACT
Enantiomerically pure 2,2,3,4,5-pentasubstituted pyrrolidines can be prepared, in high overall yield, from r,â-unsaturated esters. Asymmetry
is introduced via a Michael addition, and additional stereogenic centers are introduced by an aldol reaction. A novel stereospecific ring-
forming reaction, proceeding via a thiiranium (episulfonium) ion, yields pyrrolidines from â-hydroxy sulfides. In this manner, 2,2,3,4,5-
pentasubstituted pyrrolidines, containing three contiguous stereogenic centers around the ring, can be prepared in 44% overall yield from
ethyl crotonate.
We have shown that thiiranium (episulfonium) ions, gener-
ated by the treatment of â-hydroxy sulfides with acid, are
useful intermediates in the synthesis of both oxygen- and
nitrogen-containing heterocycles.1 Thus, when the diol 1 is
heated with p-toluenesulfonic acid (TsOH), an intermediate
thiiranium ion 3 is formed; capture by the internal oxygen
nucleophile gives the tetrahydrofuran (THF) 2.2 Both of the
substitution steps in this mechanism proceed with clean
inversion of stereochemistry (Scheme 1).1
leads to the allylic sulfide 6 (with an unsubstituted amine).
Specific protection is required to reduce the basicity of the
nitrogen atom. Thus, the N-tosyl derivative 4 undergoes
Scheme 1
However, the use of acidic methods for the synthesis of
similar nitrogen-containing heterocycles is precluded by
nitrogen protonation; removal of the internal nucleophile
† This paper is dedicated to Dr. R. Bolton on the occasion of his
retirement. He is an exceptional teacher of organic chemistry and an
inspiration to many. We wish him a very long and enjoyable retirement.
‡ OSI Pharmaceuticals.
cyclization to give the pyrrolidine 5, with only small
quantities of the allylic sulfide 6 being produced. TMSOTf
was a more efficient activating agent for this reaction than
TsOH (Scheme 2).3
§ University Chemical Laboratory.
(1) Fox, D. J.; House, D.; Warren, S. Angew Chem., Int. Ed. 2002, 41,
2462 and references contained therein.
(2) Aggarwal, V. K.; Eames, J.; Villa, M.-J.: McIntre, S.; Sansbury, F.
H.; Warren, S. J. Chem. Soc., Perkin Trans. 1 2000, 533.
(3) Coldham, I.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1993, 1637.
10.1021/ol0268384 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/15/2002

There are two approaches by which this type of strategy
can be implemented, termed the tandem and stepwise
procedures (Scheme 4). The tandem approach uses the (Z)-
enolate 13, selectively generated by the Michael addition,6
directly in the aldol reaction; the â-amino ester is not isolated.
In the stepwise procedure, deprotonation of the isolated
â-amino ester 10, selectively generates the (E)-enolate 11,6
this can be used in a boron-mediated aldol reaction (Scheme
4); this is based on a procedure employed by Davies in his
formal synthesis of thienamycin, the sense of stereoinduction
is the same.7
Thus, the amino alcohols 12 and 14 are produced in
excellent overall yield, from ethyl crotonate, and in good
diastereomeric excess; although a 4:1 mixture of two
diastereoisomers is produced by the tandem procedure, three
new stereogenic centers have been introduced in a one-pot
reaction sequence. Aldehyde 15, used in both aldol reactions,
is easily prepared from the trimethylsilyl enol ether of
isobutyraldehyde and phenylsulfenyl chloride. This procedure
has been used in similar cases.8
Scheme 2
Recently, we have developed methods of forming thiira-
nium ions that avoid the need for strong Brønsted acids,
turning instead to weak Lewis acids. Pyrrolidines can be
formed in high yield from suitably substituted cyclic car-
bamates. Treatment of carbamate 8 with chromatography
silica, in refluxing chloroform, results in complete conversion
to the N-unsubstituted pyrrolidine 9 (Scheme 3).4 We now
Scheme 3
The stereochemical outcomes of the aldol reactions are
slightly counterintuitive; the boron-mediated aldol reaction,
via an (E)-enolate, produces a syn-aldol product, and a (Z)-
enolate yields an anti-aldol product. If a Zimmerman-
Traxler chair transition state structure applies,9 the R-group
of the aldehyde may be forced into an axial position by the
steric bulk of the benzylamine fragment of the molecule;
however, a boatlike transition state cannot be discounted.
Yamamoto noted identical stereochemical outcomes in
similar work.6
report our attempts to apply this methodology to the synthesis
of enantiomerically enriched pyrrolidines. This work has
resulted in a novel method of generating thiiranium ions,
unusually proceeding under basic conditions.
To prepare enantiomerically enriched pyrrolidines, opti-
cally active derivatives of the amino alcohol 7 were required.
These can be easily prepared from R,â-unsaturated esters
via a consecutive Michael addition-aldol reaction strategy
(Figure 1). The stereochemical outcome of the Michael
The absolute stereochemistry of the anti-aldol amino
alcohol 14 was determined by X-ray crystallography via
reduction of the ester with LiAlH4 to provide the crystalline
diol 16 (Figure 2).
Figure 1. Strategy for the synthesis of enantiomerically enriched
amino alcohols.
Figure 2. Chem3D representation of the crystal structure of diol
16.10a Protons have been removed for clarity.
addition is controlled using methodology developed by
Davies.5 Addition of lithium R-methylbenzyl amide to an
R,â-unsaturated ester produces the â-amino ester with
excellent stereochemical control (Scheme 4); the (S)-R-
methylbenzyl amide generates (S)-stereochemistry at the
nitrogen-bearing center (C3) (Figure 1). This stereochemical
information can then be used to control the absolute
stereochemistry of the subsequent aldol reaction.
To apply our silica methodology (Scheme 3),4 deprotection
of the nitrogen atoms of the amino alcohols 12 and 14 was
(6) Asao, N.; Uyehara, T.; Yamamoto, Y. Tetrahedron 1990, 46, 4563.
(7) Davies, S.; Fenwick, D. J. Chem. Soc., Chem. Commun. 1997, 565.
(8) Aggarwal, V. K.; Coldham, I.; McIntyre, S.; Warren, S. J. Chem.
Soc., Perkin Trans. 1 1991, 451.
(9) Zimmerman, H.; Traxler, M. J. Am. Chem. Soc. 1957, 79, 1920.
(10) (a) Crystal data or diol 16: C29H37NO2S, M ) 463.66 gmol-1
,
monoclinic, P21, a ) 10.5006 Å, b ) 10.1426 Å, c ) 12.5752 Å, â )
104.610°. Absolute structure parameter -0.1(6). Structure was solved with
SHELXS-97 and refined with SHELXL-97.10b (b) Sheldrick, G. M. SHELXS-
97/SHELXL-97. University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(4) Caggiano, L.; Fox, D. J.; Warren, S. Chem. Commun. 2002, 2528.
(5) Davies, S.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183.
4382
Org. Lett., Vol. 4, No. 25, 2002

Scheme 4
essential. Deallylation of alcohol 12 was easily achieved
carbonyldiimidazolide (CDI) at room temperature. When this
procedure was carried out on amino alcohol 17, no cyclic
carbamate was observed and only starting material was
recovered. However, heating the reaction mixture to reflux
led directly to the desired pyrrolidine 19, and no epimeriza-
tion was observed (Scheme 7).13
using a slightly modified palladium-catalyzed reaction
developed by Genet.11 The bidentate phosphine ligand [1,4-
bis-(diphenylphosphino)butane, DPPB] stabilizes the metal
center, preventing coordination by the sulfur atom present
in the alcohol 12 (presumably the thiol of o-mercaptobenzoic
acid also competes with the sulfide 12 for coordination to
the metal center). The reaction produces high yields of the
amino alcohol 17 (Scheme 5).
Scheme 7
Scheme 5
Debenzylation of the dibenzylamine 14 by palladium-
catalyzed hydrogenolysis proved to be difficult, presumably
due to deactivation of the metal center by sulfur ligation.
Monodebenzylation could be achieved using an oxidative
debenzylation procedure [mediated by ceric ammonium
nitrate (CAN)],12 to produce good yields of the desired amino
alcohol 18 (Scheme 6).
The reaction was also applicable to the other diastereo-
meric amino alcohol 18. However, the yield of pyrrolidine
20 was lower in this case, due perhaps to the developing
3,4-syn relationship between the migrating sulfur atom and
the ester substituent.14 These cyclization reactions proceed
Scheme 6
(11) Sandrine, L.; Savigac, M.; Genet, D. Tetrahedron Lett. 1995, 1267.
(12) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad,
R. S.; Smith, A. D. Chem. Commun. 2000, 337.
(13) Typical procedure: to an acetonitrile (10 mL) solution of the amino
alcohol (1 mmol) were added CDI (1.1 mmol) and DMAP (cat.). The
reaction was heated at reflux until TLC analysis (4:1 hexane/EtOAc)
indicated complete reaction. The solution was then concentrated onto silica
and chromatographed, eluting 5-10% EtOAc in hexane, to yield the
pyrrolidine as a clear colorless oil. NMR, HRMS, IR, and elemental analysis
confirmed the structures of novel compounds.
Previously, carbamates such as sulfide 8 could be prepared
by treatment of the corresponding amino alcohol with 1,1′-
Org. Lett., Vol. 4, No. 25, 2002
4383

stereospecifically via an intermediate thiiranium ion, with
an overall [1,2]-PhS migration.
We propose that the alcohol rather than the amine (of
sulfides 17 or 18) reacts initially with CDI, to form the
imidazolide 21, and that the role of the amine is surprisingly
that of a general base catalyst and not that of a nucleophile.
The resulting imidazolide is then displaced by sulfur,
liberating carbon dioxide and imidazole, to yield a thiiranium
ion 22; this is then captured by the internal nitrogen
nucleophile (Scheme 8). This reaction is applicable to a
Figure 3. Chem3D representation of the crystal structure of amide
23, derived from a tandem sequence.15 Compared to diol 16,
inversion at the migration terminus is observed.
Scheme 8
3). Enantiomeric excesses were measured via comparison
1
of the H NMR spectra of both pairs of the diastereomeric
amides derived from of each of the pyrrolidines 19 and 20
and the two enantiomers of Mosher’s acid.
Acknowledgment. M. D. E. thanks the BBSRC and
British Biotech Pharmaceuticals Ltd. for funding. The
assistance of Dr. J. E. Davies of the Cambridge University
Crystallographic laboratory is gratefully acknowledged.
Supporting Information Available: Procedures for the
preparation, and full characterization, of compounds 12, 14,
17, 18, 19, and 20. X-ray data for compounds 16 and 23.
This material is available free of charge via the Internet at
http://pubs.acs.org.
variety of substitution patterns around the migration origin
and terminus. This along with experiments on the mechanism
of this reaction will be the subject of future publications.
The stereospecificity of the migration reaction has been
confirmed by X-ray crystallography. Both pyrrolidines 19
and 20 can be debenzylated over Pearlman’s catalyst [Pd-
(OH)2] and reacted with 3,5-dinitrobenzoyl chloride to
provide crystalline derivatives such as the amide 23 (Figure
OL0268384
(14) Aggarwal, V. K.; Coldham, I.; McIntyre, S.; Sansbury, F. H.; Villa,
M. J.; Warren, S. Tetrahedron Lett. 1988, 29, 4885.
(15) Selected X-ray data for the amide 23: C23H25N3O7S, M ) 487.52,
orthorhombic, P212121, a ) 7.92010(10) Å, b ) 14.8135(5) Å, c ) 20.5852-
(7) Å, â ) 104.610°. Absolute structure parameter -0.11(8). Structure was
solved with SHELXS-97 and refined with SHELXL-97.10b
4384
Org. Lett., Vol. 4, No. 25, 2002