Diastereoselective conjugate addition of cyanide to α,β- unsaturated oxazolidinones: Enantioselective synthesis of ent-pregabalin and baclofen

Article abstract of DOI:10.1055/s-2006-941584

Conjugate addition of cyanide to chiral α,β-unsaturated oxazolidinones catalyzed by samarium(III) isopropoxide proceeds with good diastereoselectivity. The addition products can be converted into the biologically active targets ent-pregabalin and baclofen

Full text of DOI:10.1055/s-2006-941584

LETTER
1589
Diastereoselective Conjugate Addition of Cyanide to a,b-Unsaturated
Oxazolidinones: Enantioselective Synthesis of ent-Pregabalin and Baclofen
D
iastereoselective
l
C
onjug
a
ate Additio
n
n of
C
yanide Armstrong,*a Nicola J. Convine,a Matthew E. Popkinb
a
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
Fax +44(20)75945804; E-mail: A.Armstrong@imperial.ac.uk
b
Chemical Development, GSK Tonbridge, Old Powder Mills, Tonbridge, Kent TN11 9AN, UK
Received 9 March 2006
cases. With a view to eventual use of chiral auxiliaries, we
were pleased to find that this chemistry was effective
with a,b-unsaturated oxazolidinones, using commercial
acetone cyanohydrin and Sm(Oi-Pr)3 as catalyst
(Equation 1).
Abstract: Conjugate addition of cyanide to chiral a,b-unsaturated
oxazolidinones catalyzed by samarium(III) isopropoxide proceeds
with good diastereoselectivity. The addition products can be
converted into the biologically active targets ent-pregabalin and
baclofen.
Key words: conjugate addition, cyanide, samarium, oxazolidinone
10 mol%
O
O
O
CN
O
Sm(OiPr)3
NC
2
OH
+
N
O
N
O
toluene
r.t., 15 h
84%
The asymmetric conjugate addition of cyanide to a,b-un-
saturated carboxylic acid derivatives has great potential
value in synthesis, particularly because the cyanide group
can be manipulated (e.g. by reduction or hydrolysis) to
provide access to several important compound classes.1
Recently, two groups have reported catalytic asymmetric
conjugate additions of cyanide.2,3 Jacobsen has described
the use of chiral aluminium salen catalysts for cyanide ad-
dition to a,b-unsaturated imides,2a and has noted coopera-
tive dual catalysis when (pybox)erbium complexes are
also present.2b Shibasaki has reported catalytic asym-
metric addition to a,b-unsaturated N-acylpyrroles using a
chiral gadolinium complex as catalyst.3 While these re-
present outstanding advances, they have practical limita-
tions. The Jacobsen chemistry is not effective for b-aryl
substrates, while the Shibasaki chemistry uses a relatively
complex chiral catalyst. Both systems employ a relatively
expensive cyanide source, TMSCN. Whilst conceptually
less appealing, an auxiliary-based diastereoselective sys-
tem for cyanide conjugate addition would allow simpler
analysis of diastereomeric ratios and the possibility of im-
provement of product stereoisomeric purity through dias-
tereomer separation. Although there are scattered reports
in the literature of diastereoselective cyanide conjugate
additions,4 there appears to be no systematic study of the
use of a practical chiral auxiliary. Here we report such a
system and the application of the chemistry to the synthe-
sis of two drug molecules.
1
2
Equation 1
Preliminary screening of chiral oxazolidinones suggested
that the isopropyl-substituted auxiliary afforded best
results. A range of substrates 3 was therefore prepared by
acylation of the auxiliary with the appropriate acid
chloride,6 and these substrates were tested in the samari-
um-catalysed hydrocyanation conditions (Equation 2).
The results are presented in Table 1.7 Reaction of 3a
with two equivalents of acetone cyanohydrin under 10%
Sm(Oi-Pr)3 catalysis in toluene at room temperature was
complete within 30 minutes. The hydrocyanated product
4a was obtained in 73% yield and the diastereomeric
products could be separated by flash chromatography
(entry 1). The relative configuration of the products was
confirmed by X-ray crystallography of the minor diaste-
reomer.8 Although the precise mechanism of the addition
process has not yet been established, the configuration of
the major diastereomer is consistent with bidentate co-
ordination of the samarium to the carbonyl groups and
delivery of cyanide on the less hindered face, anti to the
isopropyl substituent on the auxiliary, with the enone in an
s-cis conformation.
The survey of b-substituents (Table 1) demonstrates that
alkyl groups (entries 1–4) are well tolerated in the reaction
conditions with increasing steric bulk having little impact
on the yield and leading to a slight increase in dr. Aryl b-
substituents, which are unreactive in Jacobsen’s enantio-
selective conjugate addition of cyanide,2 are also tolerated
albeit with reduced reactivity (entries 5–7). Elevating the
reaction temperature to 50 °C (entry 8) for the electron-
rich substrate 3g greatly improved the conversion with lit-
tle impact on the dr. The TBS-protected oxygenated b-
substituent 3h (entry 9) also had reduced reactivity even
at 50 °C, but the product was formed as a single
In evaluating alternatives to the use of TMSCN, we were
attracted to a report by Ishii in 1999 that cyanide conju-
gate addition to a,b-unsaturated ketones, esters and ni-
triles could be effected using acetone cyanohydrin.5
Cp*2Sm(THF)2 or Sm(Oi-Pr)3 was employed as catalyst,
with the former giving markedly better results in most
SYNLETT 2006, No. 10, pp 1589–1591
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941584; Art ID: D07706ST
© Georg Thieme Verlag Stuttgart · New York

1590
A. Armstrong et al.
LETTER
Table 1 Sm(Oi-Pr)3-Catalysed Reaction of Oxazolidinones 3 with Acetone Cyanohydrina (Equation 2)
Entry
1
3
R1
R2
H
Time (h)
0.5
Yield 4d (%)
73
dre
81:19
3a
3b
3c
3d
3e
3f
Me
2
Et
H
0.83
0.5
71
83:17
87:13
88:12
89:11
84:16
81:19
82:18
100:0
78:22
–
3
i-Pr
H
70
4
i-Bu
H
1
75
5
Ph
H
5.75
23.5
49
68 (2)
74 (1)
22 (63)
73 (1)
46 (31)
80
6
p-ClC6H4
p-MeOC6H4
p-MeOC6H4
(CH2)2OTBS
(CH2)2OMe
Me
H
7
3g
3g
3h
3i
H
8b
9
H
4
H
69
10
11b
12c
H
3.75
47
3j
Me
Me
74 (6)
40 (40)
3k
Ph
96
82:18
a Acetone cyanohydrin (2 equiv), 10 mol% Sm(Oi-Pr)3.
b Reaction run at 50 °C.
c 20 mol% Sm(Oi-Pr)3 employed and reactant order of addition reversed.
d Combined yield of isolated diastereomers of 4 after flash chromatography. Isolated yield of recovered starting material in parentheses.
e Estimated from the isolated yields of the separated diastereomers.
diastereomer. Interestingly, the analogous OMe substrate inhibitory neurotransmitter g-amino butyric acid
3i displayed reactivity and stereoselectivity (entry 10) (GABA). Baclofen is commercially administered in race-
similar to the alkyl-substituted substrates (entries 1–4) mic form but the biological activity is reported to lie in the
and not the OTBS substrate 3h (entry 9). The b-disubsti- R-enantiomer.11 The viability of this approach to pregaba-
tuted substrate 3j (entry 11) requires an elevated reaction lin was demonstrated with the enantiomeric series
temperature to produce a good yield and proves that a qua- (Scheme 1). The hydrocyanation of 3d proceeded under
ternary centre can be formed in the product with this the standard reaction conditions7 to yield 66% of the
methodology which is an improvement in substrate scope major diastereomer 4d. Hydrogenation of the nitrile with
to that shown by Jacobsen2 and Shibasaki3 for asymmetric concomitant auxiliary cleavage to yield the lactam 7d was
conjugate addition of cyanide. An aryl-alkyl b-disubsti- accomplished over platinum oxide. Acidic hydrolytic
tuted substrate 3k (entry 12) demonstrated that this meth- opening of the lactam12 gave the g-amino acid 5 in excel-
odology can generate a chiral quaternary centre although lent yield and with retention of the enantiomeric purity.
currently only with a moderate yield. An a-substituted
substrate underwent decomposition under the reaction
conditions.
O
O
O
CN
O
a
N
O
N
O
10 mol%
R2
O
O
CN
O
O
R2
R1
Sm(OiPr)3
NC
OH
3d
4d
+
R1
N
O
N
O
toluene
r.t.
O
HCl·H2N
O
c
b
3
4
HN
OH
Equation 2 Major diastereomer of 4 pictured.
7d
5
ent-Pregabalin
Next we wished to illustrate auxiliary cleavage and
manipulation of the cyanide group by application of the
methodology to two drugs: pregabalin9 ent-5 [(S)-3-ami-
nomethyl-5-methyl-hexanoic acid], an anticonvulsant,
and baclofen10 6 [4-amino-3-(4-chlorophenyl)butanoic
acid], a treatment for spasms, which are related to the
Scheme 1 Reagents and conditions: a) Acetone cyanohydrin (2
equiv), Sm(Oi-Pr)3 (10 mol%), toluene, r.t., 1 h, 66% major diastereo-
mer; b) PtO2 (10 mol%), H2, EtOH, 70 h, 75%, 96% ee; c) 4 N HCl,
125 °C, 20 h, 95%, 96% ee.
Synlett 2006, No. 10, 1589–1591 © Thieme Stuttgart · New York

LETTER
Diastereoselective Conjugate Addition of Cyanide
1591
Castro, A. M.; Rodriguez Ramos, J. H. Angew. Chem. Int.
Ed. 2001, 40, 2507. (c) Acherki, H.; Alvarez-Ibarra, C.;
Dios, A.; Quiroga, M. L. Tetrahedron 2002, 58, 3217.
(d) Benedetti, F.; Berti, F.; Garau, G.; Martinuzzi, I.;
Norbedo, S. Eur. J. Org. Chem. 2003, 1973. (e) Steurer, S.;
Podlech, J. Eur. J. Org. Chem. 2002, 899.
A similar pathway can be followed to synthesise (S)-ba-
clofen (Scheme 2), which demonstrates the applicability
of aryl b-substituted substrates to this methodology. The
cyanide adduct (4f) was produced in a 62% yield of the
major diastereomer. Selective nitrile reduction with NiCl2
13
and NaBH4 gave the lactam 7f after in situ auxiliary
(5) Kawasaki, Y.; Fujii, A.; Nakano, Y.; Sakaguchi, S.; Ishii, Y.
J. Org. Chem. 1999, 64, 4214.
(6) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1988, 110, 1238.
cleavage. Again acidic hydrolytic opening of the lactam13a
gave the g-amino acid 6 in excellent yield and with reten-
tion of the enantiomeric purity.
(7) Typical Procedure.
The substrate 3 (1 mmol) in toluene (1 mL) was added to
Sm(Oi-Pr)3 (0.1 mmol) under N2 at 0 °C followed by
commercial acetone cyanohydrin (2 mmol). The reaction
mixture was warmed to r.t. and stirred for the indicated time.
Upon completion, wet Et2O (5 mL) was added and the
reaction mixture filtered through Celite®, washing with Et2O
and CH2Cl2. The filtrate was concentrated in vacuo and the
resulting crude material purified by silica flash column
chromatography to yield the separated diastereomers of 4.
Major diastereomer of 4a (132 mg, 59%) isolated as a
colourless oil; [a]D20 +60 (c 1, CHCl3). IR: nmax = 2965,
2243, 1779, 1703, 1390, 1209 cm–1. 1H NMR (250 MHz,
CDCl3): d = 0.89 (d, J = 7.0 Hz, 3 H, MeCHMe), 0.93 (d,
J = 7.0 Hz, 3 H, MeCHMe), 1.41 (d, J = 7.0 Hz, 3 H, Me),
2.41 (sept of d, J = 7.0, 4.0 Hz, 1 H, MeCHMe), 3.07–3.24
(m, 2 H, NCCHCH2), 3.41 (m, 1 H, NCCHCH2), 4.25 (dd,
J = 9.2, 3.4 Hz, 1 H, OCH2), 4.31 (dd, J = 9.2, 7.9 Hz, 1 H,
OCH2), 4.46 (dt, J = 7.9, 3.7 Hz, 1 H, NCH). 13C NMR (62.5
MHz, CDCl3): d = 14.7 (CH3, MeCHMe), 17.7 (CH3), 17.8
(CH3), 21.1 (CH, NCC), 28.3 (CH, MeCHMe), 39.6 (CH2,
COCH2), 58.4 (CH, NCH), 63.8 (CH2, OCH2), 122.1 (C,
CN), 154.0 [C, NC(O)O], 169.0 (C, COCH2). MS (CI):
O
O
O
CN
O
a
N
O
N
O
Cl
Cl
3f
4f
O
HCl·H2N
O
b
c
HN
OH
7f
6
Cl
(S)-Baclofen
Cl
Scheme 2 Reagents and conditions: a) Acetone cyanohydrin (2
equiv), Sm(Oi-Pr)3 (10 mol%), toluene, r.t., 23.5 h, 62% major dia-
stereomer; b) NiCl2·6H2O, NaBH4, MeOH, r.t., 1.5 h, 51%, 99% ee;
c) 4 N HCl, 100 °C, 24.5 h, 98%, 99% ee.
In conclusion, we have developed a diastereoselective
method for the hydrocyanation of a,b-unsaturated carbo-
nyl compounds bearing chiral oxazolidinone auxiliaries,
using catalytic Sm(Oi-Pr)3 and acetone cyanohydrin as
the cyanide source, and have applied the methodology to
syntheses of two drug molecules. Ongoing studies will
include further applications and extension of the samari-
um chemistry to asymmetric catalysis.
+
m/z (%) = 242 (100) [M + NH4 ]. HRMS: m/z calcd for
C11H20N3O3: 242.1505; found: 242.1498.
(8) Details will be provided in a full account of this work. We
thank Dr. A. J. P. White, Dept. of Chemistry, Imperial
College London, for this structure determination.
(9) (a) Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.;
Mulhern, T. A.; Grote, T. M.; Huckabee, B. K.;
Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Karrick,
G. L. Org. Process Res. Dev. 1997, 1, 26. (b) Burk, M. J.;
de Koning, P. D.; Grote, T. M.; Hoekstra, M. S.; Hoge, G.;
Jennings, R. A.; Kissel, W. S.; Le, T. V.; Lennon, I. C.;
Mulhern, T. A.; Ramsden, J. A.; Wade, R. A. J. Org. Chem.
2003, 68, 5731. (c) Burk, M. J.; Goel, O. P.; Hoekstra, M. S.;
Mich, T. F.; Mulhern, T. A.; Ramsden, J. A. WO01 55090,
2001. (d) Hoge, G. J. Am. Chem. Soc. 2003, 125, 10219.
(e) Brenner, M.; Seebach, D. Helv. Chim. Acta 1999, 82,
2365. (f) See also ref. 2a and 3.
Acknowledgment
We thank EPSRC and GlaxoSmithKline for financial support
(CASE award to NJC).
References and Notes
(1) (a) Review of conjugate addition of cyanide: Nagata, W.;
Nozaki, H. Org. React. 1977, 25, 255. (b) For cyanide
group manipulations, see: North, M. Tetrahedron:
Asymmetry 2003, 14, 147; and references therein. (c) For a
review of stereoselective conjugate addition, see:
Armstrong, A.; Convine, N. J. In Comprehensive Organic
Functional Group Transformations II, Vol. 1; Katritzky, A.
R.; Taylor, R. J. K.; Cossy, J., Eds.; Elsevier Pergamon:
Oxford, 2005, 287; and references therein.
(2) (a) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003,
125, 4442. (b) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J.
Am. Chem. Soc. 2004, 126, 9928.
(3) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 514.
(10) For selected approaches to (R)-baclofen employing
conjugate addition as the key step, see: (a) Corey, E. J.;
Zhang, F.-Y. Org. Lett. 2000, 2, 4257. (b) Baldoli, C.;
Maiorana, S.; Licandro, E.; Perdicchia, D.; Vandoni, B.
Tetrahedron: Asymmetry 2000, 11, 2007. (c) Licandro, E.;
Maiorana, S.; Baldoli, C.; Capella, L.; Perdicchia, D.
Tetrahedron: Asymmetry 2000, 11, 975. (d) Meyer, O.;
Becht, J.-M.; Helmchen, G. Synlett 2003, 1539. (e) Becht,
J.-M.; Meyer, O.; Helmchen, G. Synthesis 2003, 2805.
(11) Olpe, H.-R.; Demieville, H.; Baltzer, W. L.; Koella, W. P.;
Wolf, P.; Hass, H. L. Eur. J. Pharmacol. 1978, 52, 133.
(12) Puetz, C.; Przewosny, M. T. WO03 062185, 2003.
(13) (a) Thakur, V. V.; Nikalje, M. D.; Sudalai, A. Tetrahedron:
Asymmetry 2003, 14, 581. (b) Caddick, S.; Judd, D. B.; de
Lewis, A. K. K.; Reich, M. T.; Williams, M. R. V.
Tetrahedron 2003, 59, 5417.
(4) For selected diastereoselective approaches, see:
(a) Dahuron, N.; Langlois, N. Synlett 1996, 51. (b) Garcia
Ruano, J. L.; Cifuentes Garcia, M.; Laso, N. M.; Martin
Synlett 2006, No. 10, 1589–1591 © Thieme Stuttgart · New York