6090
J . Org. Chem. 1998, 63, 6090-6091
solution of the active catalyst 3b can be made simply by
mixing 5 mol % of CuClO4‚(MeCN)4 with 5.5 mol % of
Dia ster eo- a n d En a n tioselective Alk yla tion of
r-Im in o Ester s w ith En ol Sila n es Ca ta lyzed
by (R)-Tol-BINAP -Cu ClO4‚(MeCN)2
Dana Ferraris, Brandon Young, Christopher Cox,
William J . Drury III, Travis Dudding, and
Thomas Lectka*
Department of Chemistry, J ohns Hopkins University,
3400 North Charles Street, Baltimore, Maryland 21218
Received J une 8, 1998
8
commercially available (R)- or (S)-Tol-BINAP in CH2Cl2.
This catalyst solution is stirred for 30 min, at which time 1
equiv of imino ester 1 is added at room temperature. As
part of our standard procedure, slow addition of a CH2Cl2
solution of 1.1 equiv of 2a over 1 h to the catalyst-imine
mixture at 0 °C afforded product 4a with good yield (86%),
excellent ee (98%), and diastereoselection (anti/syn ) 25:1;
Table 1, entry 1). The yield, enantioselectivity, and diaste-
reoselectivity all decreased slightly with the use of (S)-
BINAP-CuClO4‚(MeCN)2 3a , an unexpected result that
mirrors the recent findings of Carreira in a Cu(II) phosphine-
catalyzed asymmetric aldol reaction.9 Not surprisingly, the
enol silane 2b10 reacted under these conditions to yield 75%
of 4b in 95% ee and a 25:1 anti/syn ratio (entry 2). The
absolute and relative stereochemistries of 4a and 4b were
determined by diastereoselective reduction/cyclization to
yield an intermediate lactone which was converted to known
compound 5 (eq 2).11 This methodology provides a conve-
nient way to synthesize asymmetrically trisubstituted lac-
tones that are building blocks for many natural products.12
The past few years have witnessed a profusion of highly
efficient, catalytic, enantio- and diastereoselective alkyla-
tions of carbonyl compounds.1 At the present time, the
alkylation of the imino functional group presents a timely
challenge in asymmetric catalysis, and recent work has
focused on enol silanes, silyl ketene acetals, and TMSCN
as carbon-based nucleophiles.2 We recently reported a
means to alkylate R-imino ester 1 in up to 98% ee with enol
silanes using chiral catalytic late-transition-metal phosphine
complexes based on Ag(I), Cu(I), Ni(II), and Pd(II) (eq 1, R′
) H).3 The best results were obtained with the easy-to-
prepare catalyst (R)-Tol-BINAP-CuClO4‚(MeCN)2. In this
paper, we extend the utility of our reaction to include
diastereo- and enantioselective variants that yield precur-
sors for a number of pharmacologically active classes of
compounds.4 Regardless of the geometry of the enol silane,
in many cases, excellent anti diastereoselectivity as well as
enantioselectivity (up to 99% ee) can be obtained in the
reaction (eq 1).5 In fact, the precise nature of the chiral
phosphines we employ is responsible for the diastereoselec-
tivity, as certain achiral bis(triphenylphosphine)-Cu(I)
complexes lead to equal amounts of anti and syn products.
1) H2/Pd 15 psi
2) HBr/Phenol
O
3) (BOC)2
42% overall yield
We were interested in whether an E-enol silane could
reverse the stereochemistry at the â-carbon leading to the
syn product. Simple E-enol silanes, however, are difficult
to synthesize isomerically pure without laborious purifica-
tion.13 One way to approach the problem of diastereoselec-
tive enolization is to enforce E-geometry by using a cyclic
framework. The cyclic enol silane 2e affords a 20/1 anti/
syn ratio of product 4e in >99% ee (entry 5).14 Enol silane
2f, derived from the corresponding known ketone,15 can be
viewed as a masked equivalent of E-enol silane 2b. The silyl
tetralone 2f afforded the product 4f with anti stereochem-
istry in 99% ee at -78 °C (15:1 anti/syn, entry 6, Table 1).16
We found that higher reaction temperatures drastically
eroded the enantio- and diastereoselectivity of 4f due to an
appreciable nonselective background rate between 1 and 2f.
Other cyclic enol silanes yielded somewhat lower enantio-
and diastereoselectivities. For example, the enol silane 2c
Initial screening focused on the reaction of Z-enol silane
2a (R′ ) Me)6 with R-imino ester 1.7 A pale straw yellow
(1) (a) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J . Am. Chem.
Soc. 1997, 119, 10859. (b) Yangisawa, A.; Matsumoto, Y.; Nakashima, H.;
Asakawa, K.; Yamamoto, H. J . Am. Chem. Soc. 1997, 119, 9319. (c) Evans,
D. A.; Murry, J . A.; Kozlowski, M. C. J . Am. Chem. Soc. 1996, 118, 5814.
(d) Carreira, E. M.; Singer, R. A.; Lee, W. J . Am. Chem. Soc. 1994, 116,
8837.
(2) (a) Sigman, M. S.; J acobsen, E. N. J . Am. Chem. Soc. 1998, 120, 4901.
(b) Hagiwara, E.; Fujii, A.; Sodeoka, M. J . Am. Chem. Soc. 1998, 120, 2474.
(c) Kobayashi, S.; Ishitani, H.; Ueno, M. J . Am. Chem. Soc. 1998, 120, 431.
(d) Kobayashi, S.; Nagayama, S. J . Am. Chem. Soc. 1997, 119, 10049. (e)
Ishitani, H.; Ueno, M.; Kobayashi, S. J . Am. Chem. Soc. 1997, 119, 7153.
(3) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J . Am. Chem. Soc.
1998, 120, 4548.
(4) Oxo-R-amino acids are a class of kynurenine-3-hydroxylase inhibi-
tors: (a) Rover, S.; Cesura, A. M.; Huguenin, P.; Kettler, R.; Szente, A. J .
Med. Chem. 1997, 40, 4378. (b) Pellicciari, R.; Natalini, B.; Costantino, G.;
Mohmoud, M. R.; Mattoli, L.; Sadeghpour, B. M.; Moroni, F.; Chiarugi, A.;
Carpendo, R. J . Med. Chem. 1994, 37, 647. (c) Nikkomycins and neopoly-
oxins are a potent class of antifungals and antibiotics: Barrett, A. G. M.;
Lebold, S. A. J . Org. Chem. 1991, 56, 4875. (d) Helms, G. L.; Moore, R. E.;
Niemczura, W. P.; Patterson, G. M. L.; Tomer, K. B.; Gross, M. L. J . Org.
Chem. 1988, 53, 1298.
(5) Mukaiyama and co-workers also note predominant anti addition to
aldehydes regardless of double-bond geometry in the presence of a Lewis
acid catalyst: Mukaiyama, T.; Kobayashi, S.; Murakami, M. Chem. Lett.
1985, 447.
(6) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn,
J . E.; Lampe, J . J . Org. Chem. 1980, 45, 1066.
(7) Tschaen, D. H.; Turos, E.; Weinreb, S. M. J . Org. Chem. 1984, 49,
5058.
(8) For preparation of Cu(ClO4)‚(MeCN)4, see: Kubas, G. J . Inorganic
Synthesis; Shriver, D. F., Ed.; Plenum: New York, 1979; Vol. XIX, p 90.
(9) Kruger, J .; Carreira, E. M. J . Am. Chem. Soc. 1998, 120, 837.
(10) Schumacher, R.; Reissig, H.-U. Liebigs Ann. Recueil 1997, 521.
(11) Experimental details are reported in the Supporting Information.
(a) Barluenga, J .; Viado, A. L.; Aguilar, E.; Fustero, S.; Olano, B. J . Org.
Chem. 1993, 58, 5972. (b) Gair, S.; J ackson, R. F. W.; Brown, P. A.
Tetrahedron Lett. 1997, 38, 3059.
(12) J ackson, R. F. W.; Rettie, A. B.; Wood, A.; Wythes, M. J . J . Chem.
Soc., Perkin Trans. 1 1994, 1719.
(13) Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A. J . Org.
Chem. 1986, 51, 3027.
(14) The absolute and relative stereochemistry of product (2S,1′R)-4e was
determined by X-ray crystallography as shown in the Supporting Informa-
tion. Stereoregularity was inferred for the cyclic products 4c, 4d , and 4f.
(15) Barcza, S.; Hoffman, C. W. Tetrahedron 1975, 31, 2363.
(16) For desilylation of 4f, see: Hayes, M. A. In Comprehensive Organic
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees,
C. W., Eds.; Pergamon: New York, 1995; Vol. 1, p 447.
S0022-3263(98)01079-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/20/1998