2
J . Org. Chem. 1998, 63, 2-3
Communications
benzyl bromide and trimethylsilyl chloride electrophiles, 7
and 8, were established by X-ray crystallography.6 Reaction
with benzaldehyde as the electrophile followed by cyclization
provides (4S,5R)-10 with an er of 77.73.7 The configurations
of 6 and 9 are assigned by analogy to 7 and 8. It is notable
that the carbonyl and alkyl halide electrophiles provide
products with an opposite sense of configuration at the new
carbon-carbon bond.8
Com p lex-In d u ced P r oxim ity Effects:
Ster eoselective Ca r bon -Ca r bon Bon d
F or m a tion in Ch ir a l Au xilia r y Med ia ted
â-Lith ia tion -Su bstitu tion Sequ en ces of
â-Su bstitu ted Secon d a r y Ca r boxa m id es
Daniel J . Pippel, Michael D. Curtis, Hua Du, and
Peter Beak*
Department of Chemistry, University of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
Received November 6, 1997
The central hypothesis of the complex-induced proximity
effect (CIPE), that remote groups can influence the formation
and reactivity of organolithium intermediates, has been
demonstrated for a number of functional groups.1,2 Reac-
tions in which lithiated secondary amides provide CIPE
control of regioselectivity and stereoselectivity have been a
recurrent theme in this area.3-5
A recent investigation from our laboratories established
6
by Li, 13C, and 15N NMR that a lithium atom bridges the
amide nitrogen and benzylic carbon in dilithiated intermedi-
ate 1.3c This placement of the nitrogen proximal to the
reactive carbanionic center suggests that a nitrogen-bound
chiral auxiliary could influence the stereochemical course
of â-lithiation-substitution sequences with derivatives of 1.
We now wish to report that the chiral homoenolate equiva-
lents readily formed by dilithiation of 2-4 serve as nucleo-
philes for diastereoselective carbon-carbon bond-forming
reactions. We demonstrate this approach for the synthesis
of an enantiomerically pure 4-substituted dihydrocoumarin
and provide evidence that favors a dynamic kinetic resolu-
tion as the diastereodetermining step.
The diastereomers are readily separated, and hydrolysis
of the major diastereomer 7, via ester 11b, provides the
enantiomerically pure carboxylic acid (R)-11a in 70% yield.
The procedure also permits recovery of the chiral auxiliary
as the hydrochloride (S)-12.
Both yields and selectivity increase when the â-substitu-
ent is an o-methoxy aryl group. Treatment of (R)-N-(1′-
phenylethyl)-3-(o-methoxyphenyl)propionamide (3) with 2.2
equiv of s-BuLi and TMEDA in diethyl ether at -78 °C for
4 h followed by addition of the electrophile at -78 °C with
warming to -10 °C over 4 h gives products 13-15 in 63-
72% yield and 93:7-98:2 dr. The configuration for the major
diastereomer (3S,1′R)-15 was determined by X-ray crystal-
lography;6 configurations for 13 and 14 are based on analogy
to 15.
Treatment of (S)-N-(1′-phenylethyl)-3-phenylpropiona-
mide (2) in diethyl ether at -78 °C with 2.2 equiv of s-BuLi
and TMEDA for 4.5 h followed by addition of an electrophile,
stirring at -78 °C for 4 h, and addition of MeOH affords
the products 6-9 in 46-55% yield and 88:12-94:6 diaster-
eomeric ratios (dr). The absolute configurations of the major
diastereomers for products arising from reactions with
(1) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res 1986, 19, 356. (b) Beak,
P.; Basu, A.; Gallagher, D. J .; Park, Y. S.; Thayumanavan, S. Acc. Chem.
Res 1996, 29, 552.
The amide 15 can be used for the preparation of the
enantiomerically pure 4-substituted dihydrocoumarin (S)-
16. Preparatory HPLC separation of (3S,1′R)-15, followed
(2) Snieckus, V. Chem. Rev. (Washington, D.C.) 1990, 90, 879.
(3) (a) Beak, P.; Du, H. J . Am. Chem. Soc. 1993, 115, 2516. (b) Lutz, G.
P.; Du, H.; Gallagher, D. J .; Beak, P. J . Org. Chem. 1996, 61, 4542. (c)
Gallagher, D. J .; Du, H.; Long, S. A.; Beak, P. J . Am. Chem. Soc. 1996,
118, 11391.
(4) (a) Fuhrer, W.; Gschwend, H. W. J . Org. Chem. 1979, 44, 1133. (b)
Houlihan, W. J .; Parrino, V. A.; Uike, Y. J . Org. Chem. 1981, 46, 4511. (c)
Yates, P.; Schwartz, D. A. Can. J . Chem. 1983, 61, 509. (d) Clark, R. D.;
Muchowski, J . M.; Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M.
Synthesis 1991, 871. (e) Denmark, S. E.; Marble, L. K. J . Org. Chem. 1990,
55, 1984.
(5) (a) Frost, C.; Linnane, P.; Magnus, P.; Spyvee, M. Tetrahedron Lett.
1996, 37, 9139. (b) Magnus, N.; Magnus, P. Tetrahedron Lett. 1997, 38,
3491. (c) Linnane, P.; Magnus, N.; Magnus, P. Nature 1997, 385, 799.
(6) The authors have deposited atomic coordinates for structures 7, 8,
15, and 17 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, CB2 1EZ, U.K.
(7) Chang, C.-J .; Fang, J .-M.; Liao, L.-F. J . Org. Chem. 1993, 58, 1754.
(8) (a) Carstens, A.; Hoppe, D. Tetrahedron 1994, 50, 6097. (b) Weisen-
burger, G. A.; Beak, P. J . Am. Chem. Soc. 1996, 118, 12218 and references
therein.
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Published on Web 01/09/1998