Diastereo- and Enantioselective Alkylation of α-Imino Esters with Enol Silanes Catalyzed by (R)-Tol-BINAP-CuClO4*(MeCN)2

Full text of DOI:10.1021/jo981079h

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

Communications
J . Org. Chem., Vol. 63, No. 18, 1998 6091
Ta ble 1. Dia ster eoselective Alk yla tion s of r-Im in o Ester 1
F igu r e 1. Crystal structure of (S)-BINAP-CuClO4‚(MeCN)2 (50%
ellipsoids).
was added to (S)-BINAP in a THF solution to which a slight
excess of water enriched in H218O had been added. Workup
and MS analysis of the BINAPO byproduct showed corre-
sponding isotopic incorporation of 18O into the phosphine
oxide moiety,19 implying that a small amount of adventitious
water is the oxygen source when BINAP is oxidized by Cu-
(ClO4)2.20 Consequently, the use of Cu(I)- or Cu(II)-
BINAPO complexes in the alkylation of 1 led to racemic
products 4h (R ) Ph, R′ ) H), implying that only Cu(I)-
BINAP is the active catalyst in our system, albeit present
in reduced amounts when a Cu(II) salt is employed as a
starting material.
The UV spectra of catalysts derived from either Cu(I) or
Cu(II) salts appeared virtually identical, with features
characteristic of Cu(I), including the lack of d-d absorption
bands indicative of Cu(II).17 Similarly, NMR spectra showed
none of the expected paramagnetic broadening associated
with the use of Cu(II), even when Cu(ClO4)2 was the starting
copper salt. The catalyst’s composition was determined by
an X-ray crystal structure of the catalyst (S)-BINAP-
CuClO4‚(MeCN)2 (Figure 1), showing conclusively that a
tetrahedral complex of Cu(I) is involved in our reactions.21
Some interesting structural features of the crystal include
one of the largest bite angles (P-Cu-P ) 98.98°) of any
BINAP-M complex,22 apparently due to its approximate
tetrahedral geometry. When single crystals of catalyst 3a
were redissolved in THF or CH2Cl2, a fully competent
catalyst solution was formed.
a
b
Reactions carried out at 0 °C f rt. Reactions carried out at
-78 °C. c %ee determined by Chiralcel OD chiral HPLC column.
%ee determined by chiral shift reagent (+)-Pr(hfc)3.
d
derived from cyclohexanone affords product 4c in 71% yield
(88% ee, 11:1 anti/syn, entry 3) with catalyst 3b. Once
again, both the enantioselectivity and diastereoselectivity
diminished slightly with the use of catalyst 3a (78% ee, 7:1
anti/syn ratio). The cycloheptanone-derived enol silane 2d
led to a lower ee and anti/syn ratio (entry 4). Not surpris-
ingly, the aliphatic enol silane 2g led to similar diastereo-
selectivity and enantioselectivity regardless of the purity of
enol silane (entry 7).
Ack n ow led gm en t. T.L. thanks the American Cancer
Society and the Petroleum Research Fund for financial
support. The authors thank Dr. Victor G. Young, J r.,
director of the X-ray Crystallographic Laboratory at the
University of Minnesota, for obtaining the crystal struc-
tures of 3a and 4e.
Intriguing reports on the intermediacy of Pd(II)- and Cu-
(II)-based enolates in catalytic asymmetric imine additions
and aldol reactions2b,9 prompted us to examine whether they
might be involved in our system. Treatment of a 1 mM
solution of enol silane 2h (R ) Ph, R′ ) H) in CD2Cl2 with
1 equiv of catalyst produced no discernible change in the
Su p p or tin g In for m a tion Ava ila ble: General procedures for
the conduct of catalytic reactions, spectroscopic details for all new
compounds, and proof of absolute configuration (37 pages).
J O981079H
(17) Hathaway, B. J . In Comprehensive Coordination Chemistry; Wilkin-
son, G., Fillard, R. D., McCleverty, J . A., Eds.; Pergamon: New York, 1987;
Vol. 5.
1
13C and H NMR spectra of the enolate over the course of 2
days, whereas previously we had demonstrated a chelate-
based interaction between imino ester 1 and the catalyst 3b
by IR spectroscopy.3 Thus, our results are consistent with
the catalyst 3b working as a classical Lewis acid. We were
also aware of the potential ease of interconversion between
Cu(I) and Cu(II).17 To our surprise, a similar, although
somewhat less effective, catalyst could also be generated by
mixing Cu(ClO4)2 with (R)- or (S)-BINAP in THF. This
catalyst afforded product 4h (R ) Ph, R′ ) H) in 85% ee
under the conditions of our screen. In addition, a major
ligand-based byproduct of this reaction was identified as the
bis(phosphine) oxide of BINAP (BINAPO).18 To determine
the source of oxygen in this phosphine oxidation, Cu(ClO4)2
(18) For the synthesis and characterization of BINAPO see: Tayaka, H.;
Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.; Taketomi, T.;
Akutagawa, S.; Noyori, R. J . Org. Chem. 1986, 51, 629.
(19) Mass spectral analysis indicated an isotopic enrichment at the M +
2 and M + 4 peaks of BINAPO.
(20) Phosphine oxidation by Cu(SO4)2 is precedented: Berners-Price, S.
J .; J ohnson, R. K.; Mirabelli, C. K.; Faucette, L. F.; McCabe, F. L.; Sadler,
P. J . Inorg. Chem. 1987, 26, 3383.
(21) Crystals of 3a were obtained by slow evaporation of THF. Crystal
data for 3a : monoclinic, C2; a ) 39.263(2), b ) 10.8841(4), c ) 11.0147 Å;
V ) 4705.4(3) Å3; Z ) 4; dcalcd ) 1.225 Mg/m3; F(000) ) 1792; µ(Mo KR) )
0.120 mm-1; µ(Mo KR) ) 0.710 73 Å; 17 316 reflections measured, 8125
observed; (I > 2σ(I)) ) 6800; 107 variables; R ) 0.0570, RW ) 0.1015, GOF
) 1.045.
(22) Tayaka, H.; Ohta, T.; Mashima, K.; Noyori, R. Pure Appl. Chem.
1990, 62, 1135.