Ring closing metathesis for the asymmetric synthesis of (S)-homopipecolic acid, (S)-homoproline and (S)-coniine

Article abstract of DOI:10.1055/s-2002-32580

Diastereoselective conjugate addition of lithium (S)-N-allyl-N-α-methylbenzylamide to α,β-unsaturated esters or Weinreb amides, followed by ring closing metathesis is used to afford the cyclic β-amino acids (S)-homopipecolic acid and (S)-homoproline and the amine (S)-coniine in high ee.

Full text of DOI:10.1055/s-2002-32580

1146
LETTER
Ring Closing Metathesis for the Asymmetric Synthesis of (S)-Homopipecolic
Acid, (S)-Homoproline and (S)-Coniine
Asymmetric
S
t
ynthesi
e
s
of
(
S
)-H
o
p
mopipecolic
h
A
cid,
(
S
)
-Ho
e
moproline
n
a
nd (
S
)-Coniine G. Davies,* Keiji Iwamoto, Christian A. P. Smethurst, Andrew D. Smith, Humberto Rodriguez-Solla
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, OX1 3QY, UK
E-mail: steve.davies@chem.ox.ac.uk
Received 7 May 2001
Abstract: Diastereoselective conjugate addition of lithium (S)-N-
allyl-N- -methylbenzylamide to , -unsaturated esters or Weinreb
amides, followed by ring closing metathesis is used to afford the cy-
clic -amino acids (S)-homopipecolic acid and (S)-homoproline and
the amine (S)-coniine in high ee.
NH
N
Ph
CO2R
CO2R
n
n
Key words: lithium amide, conjugate addition, ring closing met-
athesis, asymmetric synthesis, cyclic -amino acids
1
N
Ph
Li
N
Ph
The synthesis of conformationally constrained amino acid
derivatives has received much recent attention due to their
ability to act as conformational probes when incorporated
into peptides and peptidomimetics.1 Asymmetric ap-
proaches toward these targets have largely focused upon
the production of novel -amino acid derivatives,2 with
the preparation of homochiral cyclic -amino acids rela-
tively less studied, although these attractive synthetic tar-
gets have previously been constructed by homologation of
-amino acids,3 intramolecular ring closure4 and stereose-
lective hydrogenation.5 Previous investigations from our
laboratory have shown that the highly diastereoselective
conjugate addition of homochiral lithium N-alkyl-N- -
methylbenzylamides to a range of , -unsaturated esters
and subsequent N-deprotection offers an efficient route to
the asymmetric synthesis of -amino acid derivatives.6 In
order to extend the utility of this methodology, a protocol
involving functionalisation, rather than deprotection, of
the N-alkyl groups of the chiral lithium amide used in the
conjugate addition reaction was desired. The N-allyl func-
tionality contained within (S)-N-allyl-N- -methylbenzy-
lamide 1 was selected for this purpose and we describe
herein the use of ring closing olefin metathesis7 for the
synthesis of cyclic -amino acids and amines (Figure).8
CO2R
CO2R
n
n
Figure
catalytic hydrogenation afforded -amino ester 5 in 93%
yield and >95% ee,12 with subsequent ester hydrolysis
26
giving (S)-homopipecolic acid 6 {[ ]D +24.0 (c 0.87,
H2O); lit.13 [ ]D +22.1 (c 0.6, H2O)} in 92% yield after ion
exchange chromatography (Scheme 1).
(i)
N
Ph
CO2Me
69%, >95% d.e.
CO2Me
2
3
49%,
>95% d.e.
(ii)
(iii)
NH
N
Ph
CO2Me
CO2Me
93%, >95% e.e.
The initial target for this methodology was the synthesis
of (S)-homopipecolic acid 6.9 Thus, conjugate addition of
lithium (S)-N-allyl-N- -methylbenzylamide 1 to (E,E)-
methyl heptan-2,5-dieneoate 2 gave (3S, S)-methyl 3-(N-
allyl-N- -methylbenzylamino)hept-5-enoate 3 in 69%
yield and >95% de.10 Treatment of -amino ester 3 with
Grubbs’ ruthenium alkylidene catalyst11 furnished cyclic
N-protected -amino ester 4 in 49% yield and in >95% de,
indicating that no epimerisation had taken place during
the ring closing metathesis protocol. N-deprotection via
5
4
(iv), (v)
92%
NH
CO2H
6
Scheme 1 Reagents and conditions: (i) (S)-1, THF, –78 °C; (ii) 4
mol% RuCl2(=CHPh)(PCy3)2, DCM, , 12 hours; (iii) 10% Pd-C, H2;
(iv) 2 M HCl; (v) Dowex 50WX8-200.
Synlett 2002, No. 7, Print: 01 07 2002.
Art Id.1437-2096,E;2002,0,07,1146,1148,ftx,en;D09102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Asymmetric Synthesis of (S)-Homopipecolic Acid, (S)-Homoproline and (S)-Coniine
1147
Further application of this procedure to the synthesis of
(S)-homoproline 1314 was investigated. Thus, addition of
(S)-1 to (E,E)-tert-butyl hexa-2,4-dieneoate 7 gave
(ii)
N
Ph
N
Ph
86%, >95% d.e.,
>95% e.e.
(3R, S)-tert-butyl
3-(N-allyl-N- -methylbenzylami-
t
CO2 Bu
t
CO2 Bu
no)hex-4-enoate 8 in 78% yield and >95% de.10 Treat-
ment of -amino ester 8 with Grubbs’ ruthenium
alkylidene catalyst gave the desired N- -methylbenzyl-
protected cyclic -amino acid 915 in 77% yield as a single
diastereoisomer (Scheme 2).
9
11
(i)
(iii) 92%
NH
N
Ph
(i)
t
N
Ph
t
CO2 Bu
CO2 Bu
t
CO2 Bu
t
CO2 Bu
78%, >95% d.e.
10
12
7
8
(iv)
96%
77%,
>95% d.e.
(ii)
NH
CO2H
N
Ph
13
t
Scheme 3 Reagents and conditions: (i) Pd(OH)2 on C, H2 (5 atm);
(ii) Rh(PPh3)3Cl, H2 (2 atm), MeCN, r.t.; (iii) Pd(OH)2 on C, H2 (1
atm), MeOH–H2O–AcOH (40:4:1), r.t.; (iv) HCl (aq) then Dowex
50WX8-200.
CO2 Bu
9
Scheme 2 Reagents and conditions: (i) (S)-1, THF, –78 °C; (ii) 4
mol% RuCl2(=CHPh)(PCy3)2, DCM, , 12 hours.
Attempted Pd-mediated hydrogenation of cyclic -amino
ester 9 proved problematic, resulting in the predominant
formation of pyrrole 10. An alternative deprotection pro-
tocol was therefore followed, involving initial hydrogena-
tion of the alkene with Wilkinson’s catalyst to furnish N-
-methylbenzyl -amino ester 11 in 86% yield as a single
diastereoisomer in >95% ee.16 Subsequent N-benzyl
deprotection via catalytic hydrogenation, a protocol
O
(i)
Ph
N
O
Me
N
Me
65%, >95% d.e.
N
OMe
OMe
14
15
62%,
>95% d.e.
(ii), (iii)
known to proceed without racemisation,6 furnished
-
amino ester 12 in 92% yield with ester hydrolysis afford-
(iv)
91%, >95% d.e.
23
ing (S)-homoproline 13 {[ ]D +3.4 (c 1.0, H2O); lit.17
Ph
N
Ph
N
[ ]D25 +4.0 (c 1.0, H2O)} in excellent yield after purifica-
tion by ion exchange chromatography (Scheme 3).
17
16
Having shown the utility of this approach for the synthesis
of cyclic -amino acids, a related protocol for the synthe-
sis of (S)-coniine, a simple cyclic alkaloid known to have
potent neurotoxic effects18 was developed.19 Thus, conju-
gate addition of lithium (S)-1 to (E)-N-methoxy-N-methyl
hex-2-enamide 14 gave (3S, S)-N-methoxy-N-methyl 3-
(N-allyl-N- -methylbenzylamino)hexanamide 15 in 65%
yield and >95% de.10 Reduction with DIBAL and subse-
quent Wittig reaction furnished diene 16 in 62% yield
over two steps in >95% de. Ring closing metathesis pro-
duced the N-protected cyclic amine 17 in 91% yield,
which, after hydrogenation and treatment with HCl, fur-
nished (S)-coniine hydrochloride 18 in 95% yield, with
(v)
95%
HCl.HN
18
Scheme 4 Reagents and Conditions: (i) (S)-1, THF, –78 °C; (ii) DI-
BAL, THF, –78 °C; (iii) NaNH2, PPh3CH3Br, DCM, –40 °C to r.t.;
(iv) 4 mol% RuCl2(=CHPh)(PCy3)2, DCM, , 12 hours; (v) 10% Pd-
C, H2 (5 atm), MeOH, r.t.; then HCl.
21
25
specific rotation {[ ]D +8.3 (c 0.7, EtOH); lit, [ ]D
In conclusion, we have demonstrated that conjugate addi-
tion of (S)-N-allyl-N- -methylbenzylamide to an , -un-
saturated acceptor, followed by functionalisation of the
25
+9.4 (c 0.32, EtOH)20; [ ]D +8.1 (c 0.6, EtOH)21} and
spectroscopic properties consistent with those of the liter-
ature (Scheme 4).
Synlett 2002, No. 7, 1146–1148 ISSN 0936-5214 © Thieme Stuttgart · New York

1148
S. G. Davies et al.
LETTER
(9) For selected asymmetric syntheses and uses of homo-
N-allyl group by ring closing metathesis offers an efficient
route to the cyclic -amino acids (S)-homopipecolic acid
and (S)-homoproline and the amine (S)-coniine in high ee.
The application of this methodology to the synthesis of
other constrained amino derivatives is currently under in-
vestigation within our laboratory.
pipecolic acid in synthesis see: (a) Toone, E. J.; Jones, J. B.
Can. J. Chem. 1987, 65, 2722. (b) Wanner, K. T.; Kaertner,
A. Heterocycles 1987, 26, 921.
(10) As shown by 1H NMR spectroscopic analysis of the crude
reaction mixture.
(11) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100.
(12) By 1H NMR spectroscopic analysis in the presence of (R)-
2,2,2-trifluoro-1-(9-anthryl)-ethanol and comparison with
an authentic racemic standard.
Acknowledgement
We thank the EPSRC and Oxford Asymmetry International Plc for
support (C. A. P. S) through a CASE award and New College, Ox-
ford for a Junior Research Fellowship (A. D. S).
(13) Wakabayashi, T.; Watanabe, K.; Kato, Y. Synth. Commun.
1977, 7, 239.
(14) For selected asymmetric syntheses and uses of homoproline
in synthesis see: (a) Buchschacher, P.; Cassal, J. M.; Fuerst,
A.; Werner, M. Helv. Chim. Acta. 1977, 60, 2747. (b)Lang,
G.; Passreiter, C. M.; Medinilla, B.; Castillo, J. -J.; Witte, L.
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V. J. Biol. Res. 1996, 72, 29. (d) Cassal, J. M.; Fuerst, A.;
Meier, W. Helv. Chim. Acta 1976, 59, 1917.
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Synlett 2002, No. 7, 1146–1148 ISSN 0936-5214 © Thieme Stuttgart · New York