Asymmetric CuH-catalyzed 1,4-reductions in water at room temperature

Article abstract of DOI:10.1055/s-0030-1258540

Taking advantage of micellar catalysis in water, asymmetric hydrosilylation reactions can now be conducted at ambient temperatures using water, and only water, as the global medium. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258540

CLUSTER
2041
Asymmetric CuH-Catalyzed 1,4-Reductions in Water at Room Temperature
Asymmetric
C
h
uH-Catalyze
e
d 1, 4-Redu
n
ctions in
W
a
l
ter in Huang, Karl R. Voigtritter, John B. Unger, Bruce H. Lipshutz*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, USA
Fax +1(805)8938265; E-mail: lipshutz@chem.ucsb.edu
Received 18 June 2010
was observed (Table 1, entry 1). Although phenylsilane
Abstract: Taking advantage of micellar catalysis in water, asym-
metric hydrosilylation reactions can now be conducted at ambient
temperatures using water, and only water, as the global medium.
was indicative of the potential for excellent enantiocon-
trol, PMHS seemed to be the only effective hydride source
leading to both high enantioselectivity and significantly
reduced levels of hydride needed to achieve full conver-
sion.
Key words: copper hydride, hydrosilylations, reduction, asymmet-
ric catalysis, micellar catalysis, green chemistry
t-Bu
Advances in asymmetric conjugate reductions of activat-
ed olefins catalyzed by nonracemically ligated copper hy-
dride have led to remarkably effective methodologies for
controlling stereocenters b to electron-withdrawing
groups.1 The source of stoichiometric hydride, fortunate-
ly, is commonly an environmentally unoffensive silane,
such as polymethylhydrosiloxane (PMHS; a 29mer),2
PhSiH3,3 or diethoxymethylsilane (DEMS).4 In all reac-
tions studied to date, however, organic solvents (e.g., tol-
uene) have been used, and oftentimes at low temperatures
in order to maximize enantioselectivities. From the envi-
ronmental perspective, use of organic media, as well as
energy for purposes of cooling to temperatures as low as
–78 °C, are far from ideal. As stated in the monograph
Green Chemistry and Catalysis,5 ‘The best solvent is no
solvent and if a solvent (diluent) is needed then water is
preferred.’ Reactions run at room temperature offer, in ad-
dition to an element of energy savings, considerable con-
venience, increased throughput, and perhaps most
interesting to the fine chemical and pharmaceutical are-
nas, a potentially significantly improved impurity profile.
In this report we describe new technology that, for the first
time, allows valued asymmetric hydrosilylation reactions
to be conducted at ambient temperatures using water, and
only water, as the global medium. These aqueous condi-
tions serve mainly to force self-aggregation of a ‘design-
er’ surfactant into nanoparticles (i.e., nanomicelles) in
which homogeneous catalysis is occurring.6
OMe
O
O
P
P
t-Bu
t-Bu
2
2
MeO
MeO
P
P
2
2
O
O
OMe
t-Bu
L1: (R)-DTBM-SEGPHOS
L2: (R)-3,5-Xyl-MeO-BIPHEP
(Takasago)
(Roche)
Me
Me
H
H
PCy2
P(t-Bu)2
Fe
Fe
PPh2
PPh2
L4: Josiphos
(Solvias)
L3: (R,S)-PPF-P(t-Bu)2
(Solvias)
Figure 1 Nonracemic ligands used in this study
The corresponding reaction performed ‘on water’10 using
nine hydride equivalents of PMHS suggested that PTS is
not an effective surfactant for these hydrosilylations
(Table 1, entries 2 vs. 3). Hence, a distinct combination of
silane, surfactant, and ligand was needed such that hy-
drosilylation would be favored over competing hydrolysis
of the silane in water.
PMHS was chosen for further optimization studies for
several reasons. It is inexpensive and relatively air and
moisture stable. Recently, it has been prepared under mi-
cellar catalysis, for example, using sodium dodecylbenze-
nesulfonate (NaDBSA).11 A solution containing PMHS in
NaDBSA was attempted, however, only a slightly higher
conversion to the desired reduced ketone was obtained
compared to the control reaction performed ‘on water’
(Table 1, entry 4). Our new surfactant TPGS-750-M12
also gave a similar 45% conversion (Table 1, entry 5).
An initial investigation focused on the asymmetric hy-
drosilylation of isophorone in water using catalytic CuH,
ligated by Takasago’s nonracemic bisphosphine (R)-
DTBM-SEGPHOS (L1, Figure 1).7 Excellent results have
typically been observed using this ligand system, albeit in
organic solvent.8 Among several silanes screened under
these aqueous conditions, a large excess of phenylsilane
was required to give full conversion in 2 wt% PTS/H2O at
room temperature (PTS = polyoxyethanyl-a-tocopheryl
sebacate).9 Remarkably, nearly perfect stereoinduction
Since the choice of ligand is crucial although as yet still
empirically determined, an alternative combination in-
volving the Roche ligand (R)-3,5-Xyl-MeO-BIPHEP (L2,
Figure 1)13 was investigated. Full conversion and high
isolated yield, along with excellent enantioselectivity was
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Advanced online publication: 02.08.2010
DOI: 10.1055/s-0030-1258540; Art ID: Y01910ST
© Georg Thieme Verlag Stuttgart · New York

2042
S. Huang et al.
CLUSTER
Table 1 Optimization of Reaction Conditionsa
O
O
Cu(OAc)2⋅H2O (3 mol%)
L* (3 mol%), silane
surfactant, H2O
18 h, r.t.
*
Entry
L*b
L1
L1
L1
L1
L1
L2
L2
L2
L2
L2
Silane
PhSiH3
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
Hydride (equiv) Surfactant
Conv. (%)c
ee (%)d
99
1
2
36
9
2 wt% PTS
100 (89)e
2 wt% PTS
27
44
n. d.f
n. d.f
n. d.f
n. d.f
94
3
9
only H2O
4
9
2 wt% NaDBSA
2 wt% TPGS-750-M
2 wt% TPGS-750-M
2 wt% TPGS-750-M
2 wt% TPGS-750-M
2 wt% NaDBSA
only H2O
45
5
9
45
6
9
100 (88)e
27
7
3
94
8
6
93
94
9
9
trace
18
n.d.
n.d.
10
9
a Performed on a 0.5 mmol scale in 2 mL of solvent.
b L1 = (R)-DTBM-SEGPHOS, L2 = (R)-3,5-Xyl-MeO-BIPHEP.
c Determined by GC/FID.
d Determined by Chiral GC.
e Isolated yield.
f Not determined.
realized using ca. 0.31 equivalents of PMHS in 2 wt% (Table 1, entry 2). Another noteworthy example is the
TPGS-750-M/H2O at room temperature (Table 1, entry case of b,b-diaryl enoate 1c, which afforded the corre-
6). Surprisingly, only trace amounts of the desired product sponding reduced ester 2c in 94% ee (87% isolated yield).
was observed using NaDBSA as surfactant under the This case seems to indicate that the pattern of olefin sub-
same conditions (Table 1, entry 9). The control experi- stitution is crucial to enantioselectivity (i.e., recognizing
ment performed ‘on water’ further highlighted the crucial an enoate and its cis-disposed substituent, rather than the
role of TPGS-750-M (Table 1, entry 10). Reducing the nature and position of substituents on an aromatic ring;
amount of PMHS to three equivalents of effective hydride Table 2, entry 3). The substituted thiophene 1d was re-
unfortunately only afforded an unacceptable 27% conver- duced to 2d with a respectable 88% ee (Table 2, entry 4).
sion (Table 1, entry 7). Ultimately, it was determined that Similarly, the acrylonitrile (1e)16 was reduced using
six or more hydride equivalents are required to achieve ligand L4, which proceeded relatively efficiently
full consumption of educt (Table 1, entry 8). This may re- (Table 2, entry 5). The a,b-unsaturated lactone 1f also ap-
sult from the nature of PMHS, where intermediate silyl pears to react in a manner comparable to the correspond-
enol ether products generated on its polymeric backbone ing 1,4-hydrosilylation reported earlier in organic solvent
render sites bearing hydride inaccessible within a highly at 0 °C (Table 2, entry 6).1d,17
concentrated micelle.
The influence exerted by the substrate/ligand combination
To explore the scope of this CuH-catalyzed hydrosilyla- is further highlighted in the case of the E/Z isomers of
tion methodology, various Michael acceptors were exam- enoate 3. Although (E)-3 [entry (a); Scheme 1] gave a
ined (Table 2). In addition to the results involving 99% ee of 4 using L2, results for the Z-isomer [entry (b);
isophorone (88% yield, 94% ee; Table 1, entry 6), acyclic 86% ee] clearly indicated a match/mismatch case. Fortu-
enone 1a afforded 2a in good yield with excellent enanti- nately, the di-tert-butyl analogue (L3) of (R,S)-
oselectivity by switching to the Josiphos analogue, ligand JOSIPHOS14 displayed outstanding facial discrimination
L3.14 Remarkably, this complex of CuH utilized under for the (Z)-3 case (entry c; 98% ee).
micellar catalysis conditions at room temperature leads to
In order to highlight the potential applications of this
an even higher degree of stereoinduction than that ob-
asymmetric hydrosilylation in water at room temperature,
tained previously for the same reaction in organic solvent
introduction of the C-15 stereocenter of the natural prod-
run at –78 °C (Table 2, entry 1).15 Enoates and lactones
uct amphidinoketide I (8; Scheme 2)18 was chosen as a
worked very well, as expected from the related reactions
representative example.19 Asymmetric 1,4-reduction of E-
in toluene. b-Substituted ethyl cinnamate derivative 1b
enoate 5 occurred efficiently at 0 °C using ligated CuH
was reduced smoothly with an ee of 95% using L2
Synlett 2010, No. 13, 2041–2044 © Thieme Stuttgart · New York

CLUSTER
Asymmetric CuH-Catalyzed 1,4-Reductions in Water
2043
Table 2 Cu-Catalyzed Asymmetric 1,4-Reductionsa
derived from Cu(OAc)2, PMHS, and Solvias ligand L3 in
2 wt% TPGS-750-M/H2O. The enantioselectivity of this
reduction (>99% ee; 83% yield) was best determined after
conversion of product 6 to Weinreb amide 7, which can
ultimately be transformed into amphidinoketide I (8) us-
ing known methods.19
EWG
EWG
Cu(OAc)2⋅H2O (3 mol%)
L* (3 mol%), PMHS (0.31 equiv)
*
2 wt% TPGS-750-M (0.25 M)
18 h, r.t.
R1
R2
R1
R2
1
2
Entry Substrate
Ligand Yield (%)b ee (%)c
Cu(OAc)2⋅H2O (3 mol%)
L3 (3 mol%)
O
93 (87)15
PMHS (0.31 equiv)
n-BuO
n-BuO
1
L3
L2
80
Ph
2 wt% TPGS-750-M/H2O
18 h, 0 °C
O
5
1a
(83%)
O
95 (91)1d
OEt
O
2
94
MeO(Me)NH2Cl
Me3Al (92%)
Ph
O
6, >99% ee
1b
99% ee19
Me
ref. 19
15
Me
N
O
OEt
3
L2
L3
87
87
94
88
O
7
O
O
Cl
15
9
1c
12
1
O
O
O
amphidinoketide I (8)
OEt
4
Scheme 2
S
1d
In summary, CuH-catalyzed enantioselective hydrosilyla-
tion of b,b-disubstituted Michael acceptors has been real-
ized under environmentally attractive conditions, taking
advantage of micellar catalysis to perform reactions in
water at room temperature.20 The combination of silane
PMHS, nonracemic ligand, and amphiphile has led to a vi-
able, ‘greener’ method for this otherwise well-established
transformation.
CN
86 (96)16
N
5
L4
L2
87
89
1e
O
6
98 (99)1d
O
Ph
Acknowledgment
1f
a Reactions were carried out on a 0.25 mmol scale in 1 mL of solvent.
b Isolated yield.
Financial support provided by the NSF (CHE 09-48479) is warmly
acknowledged. We are most grateful for the generous supply of li-
gands by Roche (BIPHEP series) and Takasago (SEGPHOS series).
c Determined by chiral HPLC analyses.
References and Notes
O
O
Cu(OAc)2⋅H2O (3 mol%)
(1) (a) Review: Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem.
Rev. 2008, 108, 2916. (b) Rendler, S.; Oestreich, M. Angew.
Chem. Int. Ed. 2007, 46, 498. For selected cases, see:
(c) Yun, J.; Kim, D.; Lee, D. Angew. Chem. Int. Ed. 2006,
45, 2785. (d) Lipshutz, B. H.; Servesko, J. M.; Taft, B. R.
J. Am. Chem. Soc. 2004, 126, 8352. (e) Buchwald, S. L.;
Aye, Y.; Rainka, M. P. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5821. (f) Czekelius, C.; Carreira, E. M. Angew. Chem.
Int. Ed. 2003, 42, 4793.
L* (3 mol%), PMHS (0.31 equiv)
OEt
OEt
2 wt% TPGS-750-M (0.25 M)
18 h, r.t.
*
Ph
Ph
3
4
(a) L* = (R)-3,5-Xyl-MeO-BIPHEP (L2)
reaction as above in toluene with L1
(b) L* = (R)-3,5-Xyl-MeO-BIPHEP (L2)
(c) L* = (R,S)-PPF-P(t-Bu)2 (L3)
(95%) 99% ee (R)
(E)-3
(E)-3
(Z)-3
(Z)-3
1d
(90%) 95%
ee (R)
(91%) 86% ee (S)
(86%) 98% ee (S)
(2) Lawrence, N. J.; Drew, M. D.; Bushell, S. M. J. Chem. Soc.,
Perkin Trans. 1 1999, 3381.
(3) Hays, D. S.; Scholl, M.; Fu, G. C. J. Org. Chem. 1996, 61,
6751.
Scheme 1
(4) Nishiyama, H.; Shiomi, T.; Tsuchiya, Y.; Matsuda, I. J. Am.
Chem. Soc. 2005, 127, 6972.
Synlett 2010, No. 13, 2041–2044 © Thieme Stuttgart · New York

2044
S. Huang et al.
CLUSTER
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(17) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc.
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(20) General Procedure for a CuH-Catalyzed Asymmetric
1,4-Reduction in Water
To a 5 mL glass vial was added Cu(OAc)2·H2O (3 mg, 0.015
mmol) and (R)-3,5-Xyl-MeO-BIPHEP (10.4 mg, 0.015
mmol). After an atmosphere exchange with argon, 2 wt%
TPGS-750-M/H2O (2 mL) was added, and the mixture was
vigorously stirred for 2 h. Isophorone (75 mL, 0.5 mmol) was
added and the reaction continued with stirring for 10 min.
PMHS (0.3 mL) was added dropwise to the reaction over 6
h. The reaction was stirred vigorously overnight (12 h), then
quenched with sat. aq NH4F (0.3 mL) and stirred for an
additional 2 h. The resulting solution was filtered through a
short plug of silica gel and concentrated under vacuum. The
product was purified via silica gel flash chromatography
(10% Et2O–hexanes) to afford the desired 3,3,5-trimethyl-
cyclohexanone as a colorless oil (62 mg, 88%). The ee was
determined by chiral GC on a b-DEX SM column, 100 °C
isotherm, 1 mL/min; racemic tR = 13.67 and 14.81 min;
nonracemic tR = 13.65 (minor) and 14.85 (major), 94% ee.
The product spectral data matched those previously
reported: (a) Camps, F.; Coll, J.; Guitart, J. Tetrahedron
1986, 42, 4603. (b) Baker, B. A.; Boskovic, Z. V.; Lipshutz,
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polyoxyethanyl-a-tocopheryl succinate.
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