CuH-catalyzed enantioselective 1,2-reductions of α,β-unsaturated ketones

Article abstract of DOI:10.1021/ja102689e

The first study on a general technology for arriving at valued nonracemic allylic alcohols using asymmetric ligand-accelerated catalysis by copper hydride is described.

Full text of DOI:10.1021/ja102689e

Published on Web 05/19/2010
CuH-Catalyzed Enantioselective 1,2-Reductions of r,ꢀ-Unsaturated Ketones
ˇ
Ralph Moser, Zarko V. Bosˇkovic´, Christopher S. Crowe, and Bruce H. Lipshutz*
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara, California 93106
Received March 31, 2010; E-mail: lipshutz@chem.ucsb.edu
Scheme 1. Pathways for Addition of CuH to Unsaturated Ketones
Asymmetric copper hydride chemistry has become an especially
powerful tool for controlling chirality in a variety of substrate types.1
Most notably, nonracemically ligated CuH can be used to direct
remarkably selective hydride delivery to the ꢀ-site in a variety of
Michael acceptors (Scheme 1, path A). In the absence of extended
conjugation, asymmetric 1,2-additions of CuH are now known for
aromatic ketones,2 diaryl3 and heteroaromatic ketones,4 and imines.5
Redirecting the natural tendency of copper complexes away from
additions in a 1,4-sense can be challenging. The potential to alter,
in the achiral manifold, such regioselectivity toward the 1,2-mode
by a “subtle interplay of steric and electronic factors” of the
phosphine ligand on copper was recognized years ago by Stryker.6
Overcoming the inherent mechanistic preference for initial d-π*
complexation associated with, for example, Cu(I)-olefin soft-soft
interactions in R,ꢀ-unsaturated ketones remains an unsolved
problem, notwithstanding the synthetic potential of the resulting
nonracemic allylic alcohols (Scheme 1, path B). While isolated
examples of copper-catalyzed enantioselective 1,2-reductions of
enones exist,7 any semblance of a general asymmetric protocol
resulting from the correlation of substrate substitution pattern with
ligand biases and/or tuning of reaction conditions for this important
transformation is still lacking. Herein, we describe a new methodol-
ogy for the enantioselective CuH-catalyzed 1,2-reduction of
R-substituted unsaturated ketones leading to secondary allylic
alcohols (Scheme 1).
Table 1. Selected Optimization Conditions for Regio- and
Stereocontrolled 1,2-Reductionsa
entry
ligand
solvent
T (°C)
yield of 2 (%)b
ee of 2 (%)c
1
2
3
L1
L2
L2
L2
THF
THF
THF
Et2O
Et2O
Et2O
Et2O
Et2O
THF
rt
rt
90
78
87
50 (S)
75 (S)
86 (S)
91 (S)
n.d.
89 (R)
91 (R)
90 (S)
-
-25
-25
-35
-25
-25
-25
rt
4
83 (98)d
n.d.
96
5e
6
L2
L3a
L3b
L3c
BDP
7
95
99
8
9f
-
As illustrated in Table 1, optimization studies using enone 1
revealed that (1) 1,2-addition to arrive at cinnamyl alcohol derivative
2 is strongly favored over conjugate addition; (2) enantiomeric
excesses (ee’s) on the order of 90% could be achieved; (3) ligands
in both the SEGPHOS8 and BIPHEP9 series give similar levels of
induction; (4) diethoxymethylsilane (DEMS) as the stoichiometric
source of hydride10 gives the best ee’s; (5) Et2O is the solvent of
choice; (6) reactions should be run at -25 °C for optimal conversion
and enantioselectivity; and (7) the sense of induction is such that
(L2)CuH11 produces the S-allylic alcohol while (L3b)CuH leads
to the enantiomeric product.
a Performed on a 0.1 mmol scale in 0.3 mL of solvent. See the
b
Supporting Information for full details. 1H NMR yield using Ph3CH as
internal standard. c Determined by chiral HPLC analysis. The absolute
stereochemistry was determined by comparing the optical rotation to that
of the known compound. d Isolated yield (0.25 mmol scale). e Low
conversion after prolonged reaction time. f A 1,2/1,4 ratio of 1:7 and a
60% isolated yield of the 1,4-reduced enone were obtained.
Several additional examples of acyclic and cyclic enones can
be found in Table 2. R′-Substitution with an alkyl group other than
methyl in 1 led to the desired product 3 in high ee using L3b,
while R-substitution with residues including ethyl and n-pentyl (4
and 5) gave consistently high yields and ee’s of 1,2-addition
products with one or both ligand systems.12 Modified educts with
either R-phenyl (6) or R-bromo (7) likewise led to 1,2-adducts, albeit
in somewhat lower ee’s. Replacing the ꢀ-phenyl group in 1 with
an alkyl moiety (as in 8) did not alter the outcome of the reaction.
The impact of varying the substituents on a ꢀ-aryl ring in an
educt was also investigated. Electron-donating as well as electron-
withdrawing groups were tolerated and gave secondary allylic
alcohols 9-14 in high yields and good ee’s. Surprisingly, a strong
electron-withdrawing group (e.g., a nitro group) led to a significant
amount of the corresponding 1,4-reduced product when L2 was
used (see the Supporting Information), whereas L3b gave the
desired alcohol 13 with excellent regio- and stereocontrol.12
Various cyclic arrays (15-17) fit into the anticipated pattern of
regio- and enantiocontrol using (DTBM-SEGPHOS)CuH. The mild
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7852 J. AM. CHEM. SOC. 2010, 132, 7852–7853
10.1021/ja102689e  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. CuH-Catalyzed Asymmetric 1,2-Reductions of
R-Substituted Enonesa
Scheme 3. One Reagent, Two Reactions: One-Pot Asymmetric
1,2-Reduction of an Enone and 1,4-Reduction of an Enoate
(1:1 ratio) to conditions first favoring enone 1,2-reduction gave 2,
with <5% conjugate reduction of 1 being observed. Without
isolation, addition of t-BuOH (1.1 equiv), as originally reported
by Stryker,6,15 was used to enhance the rate of catalyst regeneration.
The presence of this additive along with added silane (1.1 equiv)
led to the asymmetric 1,4-reduction of 21 to ester 22. Both processes
gave high isolated yields and excellent ee’s.
In summary, regioselectivity in reactions of nonracemicaly
ligated, in situ-generated CuH can be dramatically shifted to favor
asymmetric 1,2-reductions over the normally observed 1,4-reduc-
tions of R,ꢀ-unsaturated ketones. This powerful methodology
affords high yields and ee’s of the resulting allylic alcohols having
defined olefin geometries and central chirality.
Acknowledgment. Support of this work by the NIH is gratefully
acknowledged. We are indebted to Takasago and Roche for
supplying the SEGPHOS and BIPHEP ligands, respectively.
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
a Reactions were carried out on a 0.25 mmol scale in 0.5 mL of
Et2O. Isolated yields after column chromatography are given in
parentheses. The reported ee’s were determined by chiral HPLC or GC
analyses. The stereochemistry shown was determined by analogy to 2
(see Table 1). b Absolute stereochemistry determined by comparing the
optical rotation with that of the known compound. c See text. d See the
Supporting Information.
(1) (a) Review: Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. ReV. 2008,
108, 2916. (b) Yun, J.; Kim, D.; Lee, D. Angew. Chem., Int. Ed. 2006, 45,
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agents.13 While treatment of (R)-pulegone with catalytic [(R)-
L2]CuH gave the highly favored anticipated cis product (93%; 99:1
dr), CuH complexed by ent-L2 led predominantly to the less
common trans isomer 18 (88%; 4:1 dr).14
The influence exerted by an R-substituent is further highlighted by
the case of exocyclic olefin-containing enone 19. Notwithstanding full
accessibility of CuH to the ꢀ-site, delivery of hydride took place in a
1,2-fashion, giving allylic alcohol 20 in 78% ee (Scheme 2).
(4) Lipshutz, B. H.; Lower, A.; Noson, K. Org. Lett. 2002, 4, 4045.
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Scheme 2. (L3b)CuH-Catalyzed 1,2-Addition to a
ꢀ,ꢀ-Unsubstituted Enone
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(12) For results obtained using ligands other than the ones shown in Table 2,
see the Supporting Information.
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The potential for a ligated CuH complex to induce asymmetry
in two distinct functional groups within the same pot is illustrated
in Scheme 3. Simultaneous exposure of enone 1 and enoate 21
JA102689E
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J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010 7853