Lithium amide conjugate addition for the asymmetric synthesis of 3-aminopyrrolidines

Article abstract of DOI:10.1039/b604835h

Conjugate addition of homochiral lithium amides to methyl 4-(N-benzyl-N-allylamino)but-2-enoate, chemoselective N-deprotection and concomitant cyclisation, followed by enolate functionalisation and deprotection allows access to syn- and anti-3,4-disubstituted aminopyrrolidines in > 98% d.e. and > 98% e.e. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b604835h

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Lithium amide conjugate addition for the asymmetric synthesis of
3-aminopyrrolidines
Stephen G. Davies,* A. Christopher Garner, Euan C. Goddard, Dennis Kruchinin, Paul M. Roberts,
Humberto Rodriguez-Solla and Andrew D. Smith
Received (in Cambridge, UK) 4th April 2006, Accepted 28th April 2006
First published as an Advance Article on the web 18th May 2006
DOI: 10.1039/b604835h
aminopyrrolidines and report herein our preliminary investigations
within this area.
Conjugate addition of homochiral lithium amides to
methyl 4-(N-benzyl-N-allylamino)but-2-enoate, chemoselective
N-deprotection and concomitant cyclisation, followed by
enolate functionalisation and deprotection allows access to
syn- and anti-3,4-disubstituted aminopyrrolidines in . 98% d.e.
and . 98% e.e.
Initial studies were directed toward the delineation of a simple,
high yielding and scaleable route to homochiral aminopyrrolidines,
with the preparation of (R)-3-aminopyrrolidine dihydrochloride 7
chosen as a model for optimization of this methodology.
Conjugate addition of homochiral lithium (S)-N-benzyl-N-(a-
methylbenzyl)amide 3 to methyl 4-(N-benzyl-N-allylamino)but-2-
enoate 410 gave b-amino ester (3R,aS)-5 in . 98% d.e.,11 and in
91% yield (. 98% d.e.) after chromatographic purification.12
Chemoselective N-allyl deprotection upon treatment with
Pd(PPh3)4 and 1,3-dimethylbarbituric acid (DMBA)13 and con-
comitant intramolecular cyclisation furnished aminopyrrolidinone
6 (. 98% d.e., . 98% e.e.)14 in 97% yield on a . 30 gram scale.
Global N-deprotection of aminopyrrolidinone 6 was achieved
following an efficient two-step protocol, with LiAlH4 reduction
followed by hydrogenolysis and treatment with HCl (6 M, aq)
giving the homochiral dihydrochloride salt (R)-7 in 52% overall
yield, with spectroscopic properties consistent with those of a
commercially available sample15 {[a]D23 21.7 (c 0.9 in H2O); lit.15
[a]2D3 21.7 (c 1.3 in H2O)} (Scheme 1).
Substituted homochiral aminopyrrolidines are common subunits
found in a plethora of natural products. A variety of molecular
classes are encompassed by this structural motif, which have
become attractive synthetic targets due to their increasing demand
as building blocks in bioactive compounds.1 For example,
hydroxylated aminopyrrolidines constitute one of the main classes
of naturally occurring sugar mimics,2 with much attention focused
upon their potential therapeutic applications due to their role as
glycosidase inhibitors.3 Within this structural family, (3S,4S)-3-
methoxy-4-methylaminopyrrolidine 1 is an important fragment of
the quinolone antitumour agent AG-7352 2 which shows high
in vivo and excellent in vitro antibacterial activity against both
Gram positive and Gram negative bacteria, as well as potent
cytotoxic activity against Murine P388 leukaemia cells (Fig. 1).4
Typical synthetic routes to enantiomerically enriched pyrrolidine
derivatives include the enantioselective cycloaddition of azo-
methine ylides5 or the diastereoselective cycloaddition of ynoates
to chiral nitrones,6 with hydroxylated aminopyrrolidines usually
prepared using carbohydrates as starting materials,7 or resolution
of the racemates.8 Previous investigations from this laboratory
have shown that conjugate addition of homochiral lithium amides
derived from a-methylbenzylamine to a,b-unsaturated esters may
be used for the asymmetric synthesis of b-amino acid derivatives.9
We wished to apply this versatile methodology to the
stereodivergent asymmetric synthesis of enantiomerically pure
Fig. 1 Structure of (3S,4S)-3-methoxy-4-methylaminopyrrolidine 1 and
AG-7352 2.
Scheme 1 Reagents and conditions: (i) lithium (S)-N-benzyl-N-(a-methyl-
benzyl)amide 3, THF, 278 uC, 2 h; (ii) Pd(PPh3)4, 1,3-DMBA, DCM, rt,
16 h; (iii) LiAlH4, THF, reflux, 12 h; (iv) H2 (5 atm), Pd(OH)2/C, MeOH,
rt, 40 h, then HCl (6 M, aq).
Department of Organic Chemistry, University of Oxford, Chemical
Research Laboratory, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: steve.davies@chem.ox.ac.uk
2664 | Chem. Commun., 2006, 2664–2666
This journal is ß The Royal Society of Chemistry 2006

View Article Online
The extension of this protocol to the preparation of 3,4-
disubstituted pyrrolidines was next investigated, with functionali-
sation of pyrrolidinone 6 via enolate alkylation expected to lead to
the corresponding 3,4-anti-aminopyrrolidine. Treatment of pyrro-
lidinone 6 with LiTMP at 278 uC, followed by addition of benzyl
bromide at 278 uC gave complete conversion to anti-3-benzyl-4-
aminopyrrolidinone (3R,4R,aS)-8 in . 98% d.e.,11 giving 8 in
. 98% d.e. and 94% isolated yield after purification. The relative
3,4-anti-configuration within 8 was confirmed unambiguously by
homogeneity by chromatography, gave syn-3-benzyl-4-aminopyr-
rolidinone 11 as a single diastereoisomer in 94% yield. Subsequent
LiAlH4 reduction and hydrogenolysis gave (3R,4S)-12 in 83%
yield over two steps (Scheme 3).
X-ray
crystallographic
analysis,
with
the
absolute
(3R,4R,aS)-configuration known relative to the (S)-N-a-methyl-
benzyl stereocentre (Fig. 2).{16,17 LiAlH4 reduction of pyrrolidi-
none 8, followed by hydrogenolysis gave (3R,4R)-9 in . 98% d.e.
and 87% yield (Scheme 2).
Scheme 3 Reagents and conditions: (i) lithium (S)-N-benzyl-N-(a-methyl-
benzyl)amide 3, THF, 278 uC, 2 h, then BnBr (2 eq), 278 uC, 16 h; (ii)
Pd(PPh3)4, 1,3-DMBA, DCM, rt, 16 h; (iii) LiAlH4, THF, reflux, 12 h; (iv)
H2 (5 atm), Pd(OH)2/C, MeOH, 24 h.
Scheme 2 Reagents and conditions: (i) LiTMP, THF, 278 uC, 2 h, then
BnBr (2 eq), 278 uC, 16 h; (ii) LiAlH4, THF, reflux, 12 h; (iii) H2 (5 atm),
Pd(OH)2/C, MeOH, 40 h.
Fig. 2 Chem 3D representation of the X-ray crystal structure of
(3R,4R,aS)-8 (some H atoms omitted for clarity).
The utility of this methodology for the synthesis of the
corresponding 3,4-syn-aminopyrrolidine was next established, with
conjugate addition of lithium amide (S)-3 to a,b-unsaturated ester
4, followed by alkylation of the resulting (Z)-b-amino enolate with
benzyl bromide giving anti-3-amino-2-benzyl 10 in 94% d.e., and in
94% yield (94% d.e.) after purification.18 Deallylation of 10 (94%
d.e.) and concomitant cyclisation, followed by purification to
Scheme 4 Reagents and conditions: (i) lithium (S)-N-methyl-N-(a-methyl-
benzyl)amide 13, THF, 278 uC, 2 h; (ii) Pd(PPh3)4, 1,3-DMBA, DCM, rt,
16 h; (iii) LiTMP, THF, 278 uC, 2 h, then (+)-CSO, THF, 278 uC to rt, 16
h; (iv) NaH, THF, 0 uC, 1 h, then MeI, rt, 12 h; (v) LiAlH4, THF, reflux,
12 h; (vi) H2 (5 atm), Pd(OH)2/C, MeOH, 48 h, then pTSA.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2664–2666 | 2665

View Article Online
Ajish Kumar, V. D. Chaudhari, T. Sharma, S. G. Sabharwal and
J. PrakashaReddy, Org. Biomol. Chem., 2005, 3, 3720.
8 For examples see: Y. Tzuzuki, K. Chiba, K. Mizuno, K. Tomita and
K. Suzuki, Tetrahedron: Asymmetry, 2001, 12, 2989; Y. Tzuzuki,
K. Chiba and K. Hino, Tetrahedron: Asymmetry, 2001, 12, 1793;
A. Madhan and B. Venkateswara Rao, Tetrahedron Lett., 2005, 46, 323.
9 S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 2, 183;
S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1, 1994,
1129; S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron:
Asymmetry, 2005, 16, 2833.
10 Methyl 4-(N-benzyl-N-allylamino)but-2-enoate 4 can be prepared
readily on a multigram scale by addition of N-benzyl-N-allylamine to
methyl 4-bromocrotonate.
11 As indicated by 400 MHz 1H NMR spectroscopic analysis of the crude
reaction product.
12 The absolute configuration of 5 was assigned as (3R,aS) by analogy
with previous models developed to explain the stereoselectivity observed
during addition of lithium amide 3 to a,b-unsaturated acceptors; see
J. F. Costello, S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry,
1994, 5, 3919.
13 F. Garro-Helion, A. Merzouk and G. Guibe´, J. Org. Chem., 1993, 58,
6109.
1
14 The e.e. of aminopyrrolidinone 6 was inferred by H NMR studies of
With an efficient stereodivergent route to functionalised syn-
and anti-3-amino-4-benzylpyrrolidines 9 and 12 in hand, the
application of this strategy to the synthesis of (3S,4S)-3-methoxy-
4-methylaminopyrrolidine 1 was investigated, with incorporation
of the desired N-methyl fragment within 1 deriving from conjugate
addition of lithium (S)-N-methyl-N-(a-methylbenzyl)amide 13.
Conjugate addition of lithium amide (S)-13 to butenoate 4 gave
b-amino ester (3R,aS)-14 in . 98% d.e., and in 93% yield and
. 98% d.e. after purification. N-Deallylation and cyclisation gave
pyrrolidinone 15 in 96% yield, with deprotonation of 15 with
LiTMP followed by enolate oxygenation with (+)-camphorsulfo-
nyloxaziridine (CSO) giving exclusively 3,4-anti-(3R,4S,aS)-16,
furnishing 16 in 86% yield and . 98% d.e. after purification.
O-Methylation, LiAlH4 reduction and hydrogenolysis furnished
the desired (3S,4S)-pyrrolidine 1 in 62% overall yield (3 steps) as its
di-p-toluenesulfonic acid salt with comparable spectroscopic
properties to the literature {[a]2D4 10.1 (c 1.1 in MeOH); lit.19 [a]2D9
+10.4 (c 1.0 in MeOH)} (Scheme 4).
In conclusion, lithium amide conjugate addition has been used
as the key step for the development of a simple and efficient
protocol for the preparation of polysubstituted aminopyrrolidines
in high d.e. and e.e. This protocol provides a stereodivergent route
to both anti- and syn-3-alkyl-4-aminopyrrolidines, and has been
applied to the synthesis of (3S,4S)-3-methoxy-4-methylaminopyr-
rolidine 1 in . 98% d.e. The further application of this
methodology to the synthesis of a variety of natural product
targets is currently under investigation in this laboratory.
the corresponding Mosher’s amides of pyrrolidinone 17, obtained in
89% yield via hydrogenolysis of 6, and comparison with an authentic
racemic standard.
Notes and references
15 (R)-(+)-3-Aminopyrrolidine (. 98% e.e.) is commercially available from
Aldrich.
{ CCDC 602326. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b604835h
16 X-ray crystal structure determination for 8. Data were collected using an
Enraf-Nonius k-CCD diffractometer with graphite monochromated
Mo-Ka radiation using standard procedures at 190 K. The structure
was solved by direct methods (SIR92), all non-hydrogen atoms were
refined with anisotropic thermal parameters. Hydrogen atoms were
added at idealised positions. The structure was refined using
CRYSTALS.17 X-ray crystal structure data for 8: [C33H34N2O]:
1 T. Rosen, D. T. W. Chu, I. M. Lico, P. B. Fernandez, K. Marsh,
L. Shen, V. G. Gepa and A. G. Pernet, J. Med. Chem., 1988, 31, 1598;
T. Rosen, D. T. W. Chu, I. M. Lico, P. B. Fernandez, L. Shen,
S. Borodkin and A. G. Penet, J. Med. Chem., 1988, 31, 1586; A. B.
Attygalle and D. E. Morgan, Chem. Soc. Rev., 1984, 13, 245; M. Pichon
and B. Figadere, Tetrahedron: Asymmetry, 1996, 7, 927.
2 N. Asano, R. J. Nash, R. J. Molineux, G. W. J. Fleet, D. D. Long,
S. M. Frederiksen, D. G. Marquess, A. L. Lane, D. J. Watkin and
D. A. Winkler, Tetrahedron: Asymmetry, 2000, 11, 1645; E. S. H.
El Ashry, N. Rashed and A. H. S. Shobier, Pharmazie, 2000, 55, 331.
3 G. W. J. Fleet, A. Karpas, R. A. Dwek, L. E. Fellows, A. S. Tyms,
S. Petursson, S. K. Namgoong, N. G. Ramsden, P. W. Smith, J. C. Son,
F. X. Wilson, D. R. Witty, G. S. Jacob and T. W. Rademacher, FEBS
Lett., 1998, 237, 128.
4 P. Di Cesare, D. Bouzard, M. Essiz, J. P. Jacquet, B. Ledoussal,
J. R. Keichel, P. Remuzon, R. E. Kessler, J. Fung-Tomc and
J. Desiderio, J. Med. Chem., 1992, 35, 4205; K. Tomita, Y. Tzuzuki,
K. I. Shibamori, M. Tashima, F. Kajikawa, Y. Sato, S. Kashimoto,
K. Chiba and K. Hino, J. Med. Chem., 2002, 45, 5564; Y. Tzuzuki,
K. Tomita, K. I. Shibamori, Y. Sato, S. Kashimoto and K. Chiba,
J. Med. Chem., 2004, 47, 2097.
˚
M 5 474.65, monoclinic, space group C 1 2 1, a 5 17.1297(3) A,
3
˚
˚
˚
b 5 8.2098(2) A, c 5 19.4751(4) A, b 5 100.0736(8)u, V 5 2696.6(1) A ,
Z 5 4, m 5 0.070 mm21, colourless block, crystal dimensions 5 0.2 6
0.2 6 0.2 mm. A total of 3244 unique reflections were measured for 5 ,
h , 27 and 2894 reflections were used in the refinement. The final
parameters were wR2 5 0.032 and R1 5 0.032 [I . 3s(I)].
17 D. J. Watkin, C. K. Prout, J. R. Carruthers, P. W. Betteridge and
R. I. Cooper, CRYSTALS, 2003, Issue 12, Chemical Crystallography
Laboratory, Oxford, UK.
18 For the established anti-alkylation preference of b-amino enolates see
S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1, 1994,
1129; the high stereocontrol asserted upon protonation of an enolate
anti to an adjacent heteroatom is also well documented; H. M. L. Davies,
L. M. Hodges and T. M. Gregg, J. Org. Chem., 2001, 66, 7898;
H. E. Zimmerman, Acc. Chem. Res., 1987, 20, 263; J. E. Mohrig,
R. E. Rosenberg, J. W. Apostol, M. Bastienaansen, J. W. Evans,
S. J. Franklin, C. D. Frisbie, S. S. Fu, M. L. Hamm, C. B. Hirose,
D. A. Hunstad, T. L. James, R. W. King, C. J. Larson, H. A. Latham,
D. A. Owen, K. A. Stein and R. Warnet, J. Am. Chem. Soc., 1997, 119,
479; L. Banfi and G. Guanti, Tetrahedron: Asymmetry, 1999, 10, 439.
19 Y. Tzuzuki, K. Chiba and K. Hino, Tetrahedron: Asymmetry, 2001, 12,
1793.
5 S. Cabrera, R. G. Arrayas and J. C. Carretero, J. Am. Chem. Soc., 2005,
127, 16394.
6 M. Shindo, K. Ohtsuki and K. Shishido, Tetrahedron: Asymmetry,
2005, 16, 2821.
7 H. E. A. El Sayed and A. El Nemr, Carbohydr. Res., 2003, 338, 2265;
B. G. Davis, M. A. T. Maughan, T. M. Chapman, R. Villard and
S. Courtney, Org. Lett., 2002, 4, 1026; D. D. Dhavale, K. S.
2666 | Chem. Commun., 2006, 2664–2666
This journal is ß The Royal Society of Chemistry 2006