Asymmetric 1,4-hydrosilylations of α,β-unsaturated esters

Article abstract of DOI:10.1021/ja049135l

Complexing catalytic amounts of CuH with a nonracemic JOSIPHOS or SEGPHOS ligand, together with stoichiometric PMHS, leads to exceedingly efficient and highly enantioselective 1,4-reductions of β,β-disubstituted enoates and lactones. An unprecedented subs

Full text of DOI:10.1021/ja049135l

Published on Web 06/18/2004
Asymmetric 1,4-Hydrosilylations of r,â-Unsaturated Esters
Bruce H. Lipshutz,* Jeff M. Servesko, and Benjamin R. Taft
Department of Chemistry & Biochemistry, UniVersity of California, Santa Barbara, California 93106
Received February 17, 2004; E-mail: lipshutz@chem.ucsb.edu
Asymmetric 1,4-hydrosilylations of conjugated carbonyl systems
at the acid oxidation level are especially challenging. As amply
demonstrated by the Buchwald group in their study in 1999,1a as
well as in very recent work,1b enoates respond to selected
nonracemically ligated CuH/PMHS reagent combinations and
typically afford ee’s in the 80-92% range. No other competing
reductive process irrespective of the metal involved, to our
knowledge, is currently known.2 The notion that stereochemistry
â- to an ester could be highly controlled in an absolute sense has
obvious merit, as such products offer access to a wealth of structural
arrays both acyclic and cyclic in nature.3 In this communication,
we describe methodology based on two nonracemic ligands of
recent vintage (1 and 2) which chelate Cu(I), presumably as CuH,
and lead to exceptionally reactive reagents and remarkably selective
conjugate reductions of enoates as well as unsaturated lactones.
lar levels of induction, albeit with products of opposite (R) chirality.
Raising the temperature of the 1,4-addition from 0 °C to room tem-
perature (entry d), resulted in a decrease in selectivity to 91% ee.7a
On the other hand, â,â-dialkyl-substituted enoates did not respond
in the same fashion using CuH-SEGPHOS technology. Although
E-enoate 5 (entry a; eq 2) still gave a respectable 90% ee of S-6,
results with the Z-isomer (entry b; 65% ee) clearly indicated that
limitations exist with this substrate/ligand combination. Fortunately,
the di-tert-butyl analogue (2) of the (R,S)-JOSIPHOS series of
ligands, as provided in the Solvias “kit”,8 displayed outstanding
facial discrimination in the dialkyl enoate cases. Indeed, E- and/or
Z isomers of three substrates 5 (entries c-g) could be individually
converted at 0 °C to their enantiomerically enriched derivatives 6
in high yields and ee’s.7b The previously reported difficult case of
an enoate akin to E-5 (R ) Et, R′ ) Me; entry e) was also found
to give the product (S)-6 in 95% ee (vs 81% ee).1a
Although substrate to ligand (S/L) ratios typically on the order
of 500-1000:1 were used for convenience, much lower levels of
ligand can be employed. For example, reduction of 2.5 g of ester
Z-3 was accomplished (0 °C, 12 h) in the presence of only 2 mg of
ligand R,S-2 (S/L ) ∼7700:1; eq 3).
Initially, â-substituted ethyl cinnamate derivatives were studied
using small percentages of Stryker’s reagent [(Ph3P)CuH]64 in the
presence of excess polymethylhydrosiloxane (PMHS). Takasago’s
ligand, (R)-(-)-DTBM-SEGPHOS5 was tested given our prior success
with this system for asymmetric hydrosilylations of aryl ketones,6a
imines,6b and cyclic enones.6c Although educt Z-3 (R′ ) Me; eq 1)
With availability of the enantiomeric JOSIPHOS derivative of
ligand 2, (S,R)-PPF-P(t-Bu)2 (ent-2), absolute stereochemistry in
the product could be controlled from either olefin geometry of the
educt or ligand configuration. Thus, E-5 reacts with CuH ligated
by R,S-2 to give S-6 (cf. eq 2, entry c), while the S,R form of 2
gives R-6 (eq 4).
afforded the corresponding product 4 with an ee of 95%, after 17
h at 0 °C the reaction had progressed only to the extent of 85%.
By simply supplying 1.1 equiv of t-BuOH to the original reagent
mix,1b,4,6b complete reduction could be effected within 1 h to give
(S)-4 in 99% ee (92% isolated yield; entry a). Geometrically iso-
meric cinnamate derivatives E-3 (entries b-d), likewise led to simi-
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10.1021/ja049135l CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Since JOSIPHOS 2 possesses elements of central and planar
chirality, it was of particular interest to ascertain the effect of an
available diastereomeric version (i.e., the R,R-isomer)8 on the level
of induction. Using E-3 (R′ ) Me), a very modest selectivity
resulted (<10% ee) along with a diminution in reaction rate (54%
conversion after 24 h at room temperature).
and t-BuOD, it would seem that the rate enhancement may well be
due to more rapid quenching of a copper enolate by alcohol than
by the silane.
The influence of an existing stereocenter at the γ-carbon in an
enoate, as in educt 7, has also been examined given the inherently
strong facial preference associated with ligand 2 toward â,â-
disubstituted enoates. Energetically dissimilar conformations might
create opportunities for a “matched/mismatched” situation mani-
fested in the observed de’s. By contrast, the innate bias of this
CuH-ligand system could overshadow such internal preferences
(i.e., exerting reagent, rather than substrate control). In the event,
treatment of optically pure 7 with catalytic CuH complexed by
ligand R,S-2 led to a 99:1 ratio of diastereomers favoring 8 via si
face attack (eq 5). The enantiomeric CuH complex using S,R-2,
In summary, ligands in the SEGPHOS and JOSIPHOS families
of nonracemic bis-phosphines, when complexed with CuH, have
been found to exert remarkably high degrees of facial selectivity
in 1,4-reductions of â,â-disubstituted enoates. Levels of product
ester ee’s and chemical yields routinely in excess of 95% are
observed employing high S/L ratios and are independent of
substitution pattern in the substrate. These results suggest that this
new technology is not only operationally straightforward but is also
of considerable generality.
Acknowledgment. We warmly thank the NSF (CHE 02-13522)
for financial support. We are also indebted to Drs. Hans-Ulrich
Blaser and Marc Thommen (Solvias), and Dr. Takao Saito and Mr.
Hideo Shimizu (Takasago), for supplying the JOSIPHOS and
SEGPHOS ligands, respectively, used in this study, and to Ms. Nina
Freienstein for expert technical assistance.
Supporting Information Available: Procedures and spectral data
for all conjugate reductions. This material is available free of charge
via the Internet at http://pubs.acs.org.
however, afforded only a -40% de (70% conversion) of the
diastereomeric product (i.e., the 3S isomer) under identical condi-
tions (0 °C, 36 h), suggesting that facial delivery of hydride onto
7 as drawn from the re face, while favored (70:30), is a mismatched
situation.
R,â-Unsaturated lactones, represented by 9 and studied previously
in a related context,1b appear to be especially prone toward this
type of asymmetric 1,4-hydrosilylation (eq 6). Thus, educt 9 could
be converted to butyrolactone 10 in high yield at 0 °C in 3 h under
the influence of minimal DTBM-SEGPHOS (1000:1 S/L) in 99%
ee.
References
(1) (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473. (b) Hughes, G.; Kimura, M.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11253.
(2) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171.
(3) For selected examples, see ref 1b.
(4) Chen, J.-X.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M. Tetrahedron
2000, 56, 2153.
(5) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.;
Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(6) (a) Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower, A. J. Am. Chem.
Soc. 2003, 125, 8779. (b) Lipshutz, B. H.; Shimizu, H. Angew. Chem.,
Int. Ed. 2004, published online February 16, http://dx/doi.org/10.1002/
anie.200353294. (c) Lipshutz, B. H.; Servesko, J. M.; Peterson, T. B.;
Papa, P. P.; Lover, A. L. Org. Lett. 2004, 6, 1273.
(7) (a) Product R-4 (R′ ) Me) was saponified to the known, commercially
available acid (Fluka). (b) Product S-6, R ) Et, is known; Norsikian, S.;
Marek, I.; Klein, S.; Poisson, J. F.; Normant, J. F. Chem. Eur. J. 1999, 5,
2055.
(8) R,S-2, S,R-2, and R,R-2 are all available from Solvias, Inc.; cf. Blaser,
H.-U.; Brieden, W.; Pugin, B.; Spindler, F.; Studer, M.; Togni, A. Top.
Catal. 2002, 19, 3.
(9) Product 8 was deprotected and cyclized to the corresponding γ-lactone
with mild acid (1% H2SO4/dioxane).The resulting cis-disubstitued buty-
rolactone, indicative of the R-stereochemistry at the â-site, was readily
confirmed by NMR (cf. Supporting Information).
(10) It is likely that CuH (20 mol % present) and t-BuOH (1.1 equiv) undergo
facile H/D-exhange at room temperature, which accounts for the (16%)
deuterium incorporation at the â-site. If copper hydride remains deuterated
given excess t-BuOD and thus accounts for 20 mol % of the deuterium
present, the maximum level of D incorporation is 90% (1.1 equiv t-BuOD
) 110% D available - 20% in the form of CuD). Thus, 77% (29% +
32% + 16% D incorporation, based on NMR integrations) of this 90%,
or 85.5% deuteration has occurred.
Last, the rate-accelerating role of the alcohol1,4b in this sequence
was briefly investigated. In the absence of this additive, silyl ketene
acetal derivatives are initially formed.6a Reduction of unsaturated
lactone 9 (cf. eq 6) in benzene-d6 at room temperature was analyzed
directly by proton NMR, the spectrum from which showed only
lactone 10. A second experiment using t-BuOD followed by careful
integration of the three proton signals at the R- and â-sites revealed
that most of the deuterium was incorporated as expected at the
R-position (eq 7).10 Thus, since no exchange occurs between PMHS
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