Enantioselective Michael addition of nitromethane to α,β-enones catalyzed by chiral quaternary ammonium salts. A simple synthesis of (R)-baclofen

Article abstract of DOI:10.1021/ol0068344

(equation presented) R/S = 85/15, 97.5/2 after recryst. Enantioselective Michael addition of nitromethane to an α,β-enone is a key step in the synthesis of (R)-baclofen.

Full text of DOI:10.1021/ol0068344

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4257-4259
Enantioselective Michael Addition of
Nitromethane to r,â-Enones Catalyzed
by Chiral Quaternary Ammonium Salts.
A Simple Synthesis of (R)-Baclofen
E. J. Corey* and Fu-Yao Zhang
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received November 7, 2000
ABSTRACT
Enantioselective Michael addition of nitromethane to an r,â-enone is a key step in the synthesis of (R)-baclofen.
Advances in understanding the three-dimensional pathways
and transition states for the cinchona alkaloid catalyzed
asymmetric dihydroxylation of olefins by osmium tetroxide1
led to the development of rigid, structurally defined, chiral
quaternary ammonium salts of type 1 for a variety of catalytic
phase transfer reactions. With catalysts of type 1, enantio-
catalysts can also be used to control diastereoselectivity, as
demonstrated by highly effective and practical syntheses of
HIV protease inhibitors by nitro aldol reactions of aldehydes
with nitromethane.9 This Letter describes another new and
useful reaction of nitromethane, the enantioselective Michael
addition to R,â-enones to form chiral γ-nitro ketones. These
versatile intermediates can serve as starting materials for a
variety of further elaborated structures. Demonstrated herein
is a route for the synthesis of the therapeutically useful
GABAB receptor agonist (R)-baclofen hydrochloride (3),10
a chiral γ-amino acid, via the corresponding γ-lactam.
Racemic baclofen is used therapeutically to treat spasms
caused by spinal cord injury or disease; however, the (S)-
(5) Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett.
1999, 40, 3843.
(6) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287.
(7) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097.
(8) For earlier work on the enantioselective alkylation of the benzophe-
none Schiff base of tert-butyl glycinate, see: (a) O’Donnell, M. J.; Bennett,
W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353. (b) O’Donnell, M. J.;
Wu, S.; Huffman, J. C. Tetrahedron 1994, 50, 4507. (c) Lipkowitz, K. B.;
Cavanaugh, M. W.; Baker, B.; O’Donnell, M. J. J. Org. Chem. 1991, 56,
5181.
(9) Corey, E. J.; Zhang, F.-Y. Angew. Chem., Intl. Ed. 1999, 38, 1931.
(10) (a) Bowery, N. E. Trends Pharm. Sci. 1982, 31, 400. (b) Olpe, H.
R.; Demie´ville, H.; Baltzer, V.; Bencze, E. L.; Koella, W. P.; Wolf, P.;
Haas, H. L. Eur. J. Pharmacol. 1978, 52, 133.
selectivities of >20:1 were obtained in numerous alkylation,2-4
aldol,5 epoxidation,6 and Michael7,8 reactions. These chiral
(1) (a) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 11038.
(b) Corey, E. J.; Noe, M. C.; Ting, A. Tetrahedron Lett. 1996, 37, 1735.
(2) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
(3) Corey, E. J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1998,
120, 13000.
(4) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347.
10.1021/ol0068344 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/23/2000

Scheme 1
enantiomer is essentially inactive. As a consequence there
6 with R/S selectivity of 85/15 in 89% yield. Recrystallization
of this product from EtOAc-hexane furnished 6 of 95% ee
with good recovery. Baeyer-Villiger oxidation of this
material afforded the γ-nitro ester 7 as a colorless solid, mp
have been many studies on the synthesis of (R)-baclofen,
including syntheses from (S)-glutamic acid11 and (S)-trans-
4-hydroxyproline,12 syntheses involving resolution,13,14 and
syntheses involving enzymatic reactions.15-17
99-100 °C, [R]23 -19 (c ) 1, CH2Cl2), in 90% yield.
D
Reduction of 7 in methanol with 10 equiv of sodium
borohydride in the presence of nickel boride (prepared in
situ from 1 equiv of NiCl2 and 5 equiv of NaBH4) at 23 °C
The pathway of the present catalytic enantioselective
synthesis of (R)-baclofen is outlined in Scheme 1. Reaction
of 10 equiv of nitromethane with 4-chlorobenzylidine-
acetophenone, the cinchoninium salt 5 (10 mol %), and
powdered cesium fluoride (10 equiv) in toluene at -40 °C
with stirring for 36 h produced the crystalline Michael adduct
for 30 min gave the (R)-γ-lactam 8, mp 116-117 °C, [R]23
D
-37 (c ) 1, CH3OH) (65%), the spectral and physical data
for which matched those previously reported.13 Hydrolysis
of γ-lactam 8 in 5 N aqueous HCl at reflux for 4 h afforded
(R)-baclofen hydrochloride (3), [R]23 -1.5 (c ) 1, H2O),
D
(11) Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry 1992, 3,
1213.
(12) Yoshifuji, S.; Kaname, M. Chem. Pharm. Bull. 1995, 43, 1302.
(13) Langlois, N.; Dahuron, N.; Wang, H.-S. Tetrahedron 1996, 52,
15117.
(14) Allan, R. D.; Bates, M. C.; Drew, C. A.; Duke, R. K.; Hambley, T.
W.; Johnston, G. A. R.; Mewett, K. N.; Spence, I. Tetrahedron 1990, 46,
2511.
(15) Mazzini, C.; Lebreton, J.; Alphand, V.; Furstoss, R. Tetrahedron
Lett. 1997, 38, 1195.
mp 200 °C (dec).
The enantiomer of 3 has also been synthesized enantio-
selectively by the approach outlined in Scheme 1 using as
the initial step the Michael reaction of nitromethane to the
R,â-enone 4 with the cinchonidium salt 2 as catalyst and
CsF as base in toluene at -40 °C for 36 h to afford the
(16) Cheˆnevert, R.; Desjardins, M. Tetrahedron Lett. 1991, 32, 4249.
(17) Brenna, E.; Caraccia, N.; Fuganti, C.; Fuganti, D.; Grasselli, P.
Tetrahedron: Asymmetry 1997, 8, 3801.
(18) The Michael reaction of nitromethane with benzalacetophenone is
similar to the examples described above, the (S) adduct predominating with
the cinchonidium catalyst 2 and the R adduct predominating with the
diastereomeric cinchoninium catalyst 5.
(19) A mixture of powdered, flame-dried CsF (1.52 g, 10.0 mmol), the
chiral cinchoninium salt 5 (66 mg, 0.1 mmol), and chlorochalcone 4 (243
mg, 1.0 mmol) in toluene (2.5 mL) was cooled to -40 °C and treated with
nitromethane (0.54 mL, 10 mmol). The mixture was stirred at -40 °C for
36 h and then diluted with 10 mL of Et2O and 10 mL of water. The organic
phase was separated, concentrated, and purified by flash chromatography
(silica gel, 3:1 hexanes:ethyl acetate) to afford (R)-6 (270 mg, 89% yield,
70% ee) as a colorless solid: mp 110-112 °C; [R]23 ) +17.9 (c ) 1,
D
CH2Cl2); FTIR (film) 1682.9 cm-1
;
1H NMR (400 MHz, CDCl3) 7.91-
7.21 (m, 9H), 4.83 (dd, J ) 12.4 and 6.4 Hz, 1H), 4.65 (dd, J ) 12.4 and
8.0 Hz, 1H), 4.21 (m, 1H), 3.45 (dd, J ) 17.6 and 6.8 Hz, 1H), 3.39 (dd,
J ) 17.6 and 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 196.3, 137.6,
136.2, 133.7, 129.2, 129.0, 128.9, 128.8, 128.0, 79.5, 41.5, 38.9 ppm; HRMS
(CI+) calcd [C16H14ClNO3 + NH4]+ 321.1006, found 321.1002. Enantio-
selectivity was determined by HPLC analysis with a Chiralcel AD column,
10% isopropyl alcohol in hexanes, 1.0 mL/min, λ ) 254 nm, retention times
minor 18.1 min, major 25.9 min. One recrystallization from ethyl acetate-
hexane gave colorless crystals: mp 121-122 °C; [R]23 +24.3 (c ) 1,
Figure 1.
D
CH2Cl2); ee 95%.
4258
Org. Lett., Vol. 2, No. 26, 2000

(S)-enantiomer of 6 of 95% ee after a single recrystallization
from EtOAc-hexane.18
The simplicity of the enantioselective methodology de-
scribed herein is illustrated by the conversion of 4 to 6 using
catalyst 5.19
The absolute stereochemical course of the enantioselective
Michael addition of nitromethane to 4 catalyzed by the chiral
quaternary ammonium salts 2 and 5 can be explained by the
same type of pre-transition state assembly as previously
discussed for other Michael reactions involving ClO- or
enolates as nucleophiles.6,7 Figure 1 shows two views (related
by a 180° rotation about a vertical axis) of the transition
state assembly for the addition of the contact ion pair of
-
CH2NO2 and 2 to 4 forming ent-6.
OL0068344
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