A conjugate reduction pathway to chiral silanes using CuH

Article abstract of DOI:10.1055/s-2007-983830

Experimental details concerning asymmetric 1,4-reduction of β-silylated-β,β-disubstituted enoates catalyzed by CuH are described. High yields and enantiomeric excesses are to be expected when Solvias' JOSIPHOS bis-phosphine PPF-P(t-Bu)₂ is used as a non-racemic ligand. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983830

PRACTICAL SYNTHETIC PROCEDURES
3257
A Conjugate Reduction Pathway to Chiral Silanes Using CuH
A
R
eduction Path
r
w
ay to C
u
hiral Silane
c
s
U
sing Cu
e
H
H. Lipshutz,* Ching-Tien Lee, Benjamin R. Taft
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA
Fax +1(805)8938265; E-mail: Lipshutz@chem.ucsb.edu
Received 28 March 2007
Dedicated to Prof. Madeleine M. Joullie on the occasion of her 80th birthday.
PSP
No99
Abstract: Experimental details concerning asymmetric 1,4-reduction of b-silylated-b,b-disubstituted enoates catalyzed by CuH are de-
scribed. High yields and enantiomeric excesses are to be expected when Solvias’ JOSIPHOS bis-phosphine PPF-P(t-Bu)2 is used as a non-
racemic ligand.
Key words: chiral silanes, CuH, asymmetric conjugate reduction
O
SiR3
O
O
3
"Pd"
"Rh"
C–C
R1
R2
R1
SiR3
3
R1
R2
*
C–Si
C–Si
O
"Rh"
R1 = aryl, alkyl, O-alkyl
R2 = aryl, alkyl
R3 = chloride, aryl, alkyl
R1
R2
Scheme 1
Chiral organosilanes are valued intermediates in organic this novel and potentially useful technology for synthesis
synthesis.1 The Si–C bond is not only commonly used as of chiral organosilanes in high yields and enantioselectiv-
an equivalent to the hydroxyl group using a Tamao2/ ities.
Fleming3 oxidation, but also provides many inroads for
Acyl silane precursors to b-silylated-b,b-disubstituted
asymmetric C–C bond construction.4 Due to their wide
enoates are easily prepared by treatment of morpholine
utility, a number of efforts have been dedicated to the syn-
amides with Fleming’s PhMe2SiLi (a deep red-colored so-
thesis of enantioenriched organosilanes (Scheme 1).5
lution in THF; path A, Scheme 2).7 It is important to
These routes involve enantioselective C–Si5a,cor C–C5b quench the initially formed tetrahedral intermediate at
bond formation under rhodium or palladium catalysis, re- –78 °C to avoid the Brook rearrangement. b-Aryl-substi-
spectively. Recently,6 we disclosed a versatile method for tuted enoates were made by 1,2-addition of PhMe2SiLi to
preparing nonracemic silanes that relies on copper-cata- a benzaldehyde, followed by Swern oxidation (path B).
lyzed asymmetric hydrosilylations of b-silylated-b,b-di- Subsequent conversion to the corresponding educts useful
substituted enoates (Scheme 2). Herein, we summarize for copper hydride-catalyzed asymmetric hydrosilylation
R
O
R
L*CuH
CO2R'
PhMe2Si
N
R
PhMe2Si
CO2R'
O
O
Z
E
A
B
C
D
ent-L*CuH
PhMe2Si
R
O
R
R
L*CuH
CO2R'
CO2R'
H
FG
PhMe2Si
PhMe2Si
[L* = Ligand 1]
Scheme 2
SYNTHESIS 2007, No. 20, pp 3257–3260
x
x.
x
x
.
2
0
0
7
Advanced online publication: 30.07.2007
DOI: 10.1055/s-2007-983830; Art ID: Z08007SS
© Georg Thieme Verlag Stuttgart · New York

3258
B. H. Lipshutz et al.
PRACTICAL SYNTHETIC PROCEDURES
followed from either Peterson olefination (path C) or Hor- Although ligand-accelerated CuH reductions are not usu-
ner–Wadsworth–Emmons reaction (HWE, path D) of in- ally sensitive to neutral water,11 exposure to oxygen
termediate acyl silanes, giving rise to Z- and E-enoates, should be minimized to avoid (presumably) oxidation at
respectively.8 Pure geometrical isomers can be obtained the ligand to phosphine oxides. Nonracemic JOSIPHOS
by silica gel chromatographic purification affording sta- analogue PPF-P(t-Bu)2 (1, Scheme 3),14 supplied by
ble materials as colorless oils.
Solvias,15 was found to be particularly effective [sub-
strate-to-ligand (S/L) ratios up to 1000:1] as the derived
CuH complex at promoting asymmetric hydrosilylation of
several b-silyl enoates.16
Using 1% CuCl and 1% t-BuONa, active CuH can be gen-
erated in situ in the presence of polymethylhydrosiloxane
(PMHS), purchased from Lancaster.9,10 Copper can also
be introduced in the form of Stryker’s reagent [hexameric A variety of b-silyl unsaturated esters were smoothly re-
(Ph3P)CuH],11 although care should be exercised to en- duced under mild conditions in good yields and high ee
sure that commercial material is of good quality, easily (Scheme 3). As expected from prior observations,16 the
done by 1H NMR analysis in C6D6.12 A third alternative is presence of t-BuOH was crucial in these cases, noticeably
to use Cu(OAc)2·H2O as the copper(I) source, also form- accelerating the reduction. Thus, using 1.1 equivalents of
ing CuH upon introduction of PMHS in toluene at room t-BuOH, reduction of 2 was complete within 24 hours at
temperature.13
–78 °C, while without t-BuOH seven days at room tem-
Me
cat. CuCl, t-BuONa
Me
Ligand 1
CO2Et
PhMe2Si
PhMe2Si
PMHS, PhMe,
t-BuOH, –30 °C, 9 h
CO2Et
96%, 95% ee (S)
(Z)-2
cat. CuCl, t-BuONa
Ligand
Me
Me
CO2Et
CO2Et
PhMe2Si
PhMe2Si
*
PMHS, PhMe
t-BuOH
(E)-2
a. Ligand 1, –78 °C, 18 h:
98%, >95% ee (R)
b. ent-1, –78 °C, 24 h:
Me
95%, >95% ee (S)
H
P(t-Bu)2
PPh2
Fe
1
(R,S)-PPF-P(t-Bu)2
OMe
MeO
MeO
MeO
SiMe2Ph
CO2Me
O
CO2Me
3
SiMe2Ph
98% yield, 83% ee
83% yield, >95% ee
Cl
CO2Me
CO2Me
SiMe2Ph
SiMe2Ph
82% yield, 97% ee
89% yield, 91% ee
Me
CO2Et
CO2C8H17
SiMe2Ph
PhMe2Si
76% yield, 98% ee
95% yield, 92% ee
Scheme 3
Synthesis 2007, No. 20, 3257–3260 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
A Reduction Pathway to Chiral Silanes Using CuH
3259
the phases separated, and the aqueous layer extracted with Et2O
(2 × 5 mL). The combined organics were washed with H2O (2 × 20
mL) and brine (1 × 20 mL), dried (MgSO4), filtered, and concentrat-
ed in vacuo. The residue was purified by flash column chromatog-
raphy using silica gel yielding pure acylsilane as clear oils.
perature were needed to reach full conversion. In general,
the nature of olefin geometry (E vs Z) does not affect the
rate of reduction, or the level of enantioselectivity. When
a stereodefined nonracemic ligand such as 1 is used with
either E- or Z-isomer, complementary chirality in the 1,4-
adduct is obtained. Likewise, using the enantiomeric
ligand (such as ent-1) on an enoate of defined olefin ge-
ometry can dictate complimentary chirality in the product.
By comparison with known products derived from initial
saponification and then imide derivatization with a non-
racemic oxazolidinone,17 the sense of chirality and levels
of induction (observed as dr) could be ascertained with
confidence.
(Z)-b-Silyl Enoates from Acyl Silanes; General Peterson Olefi-
nation Procedure (Scheme 2, Path C)
To a THF (3 mL) solution of 1,1,1,3,3,3-hexamethyldisilazane (194
mg, 1.2 mmol) was added a hexane solution of n-BuLi (l.6 M, 0.75
mL, 1.2 mmol) at 0 °C and the mixture was stirred for 20 min. After
cooling to –78 °C, ethyl (trimethylsilyl)acetate (192 mg, 1.2 mmol)
in THF (1 mL) was added, and stirring was continued for 15 min. A
THF (1 mL) solution of acylsilane (1 mmol) was added, and the
mixture was stirred at the same temperature for 1 h. The cooling
bath was removed, and the mixture was allowed to warm to r.t. Sat.
aq NH4Cl (10 mL) was added, and the organic materials were ex-
tracted with Et2O (2 × 15 mL), dried (Na2SO4), and concentrated
under reduced pressure. The residue, which consisted of both E- and
Z-isomers, was purified by flash column chromatography using sil-
ica gel yielding pure Z-enoate.
In summary, the combination of catalytic CuH and Sol-
vias’ nonracemic (R,S)- or (S,R)-PPF-P(t-Bu)2 together
with stoichiometric silane (PMHS) effects asymmetric
conjugate reduction of b-silylated-b,b-disubstituted
enoates. This method can be applied to a wide range of
substrates (b-aryl- and b-alkyl-b-silyl enoates) that are
readily prepared in either E- or Z-form. Absolute stere-
ochemistry in the products is controlled by substrate ge-
ometry or ligand axial chirality. Good yields and high ee’s
of the resulting nonracemic silanes are typical, and turn-
over numbers range from 100 to 1000.
(E)-b-Silyl Enoates from Acyl Silanes; General HWE Procedure
(Scheme 2, Path D)
To a mineral oil dispersion of NaH (2 mmol) was added a THF (2
mL) solution of triethyl phosphonoacetate (2.0 mmol) at r.t. with
stirring. After 30 min, acylsilane (2.0 mmol) was added dropwise
and the mixture was stirred overnight. The mixture was quenched
with deionized H2O (5 mL) and diluted with Et2O (5 mL). The aque-
ous phase was further extracted with Et2O (2 × 5 mL). The com-
bined organics were washed with NaHCO3 (2 × 20 mL), brine (1 ×
20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The
residue, which consisted of both E- and Z-isomers, was purified by
flash column chromatography using silica gel yielding pure
E-enoate.
Reactions were performed in oven-dried glassware under argon
containing a Teflon coated stir bar and dry septum. THF and toluene
were freshly distilled from Na/benzophenone ketyl prior to use. All
commercially available reagents were distilled either from CaH2 or
molecular sieves under an inert atmosphere before use. PMHS can
be used directly from the bottle, purchased from Lancaster, and
should be stored under an inert atmosphere. (R,S)-PPF-P(t-Bu)2 and
(S,R)-PPF-P(t-Bu)2 were generously supplied by Solvias. Column
chromatography was performed using Davisil Grade 633 Type 60A
silica gel. TLC analyses were performed on commercial Kieselgel
60 F254 silica gel plates. NMR spectra were obtained on Varian In-
ova systems using CDCl3 as solvent, with proton and carbon reso-
nances at 400 MHz and 100 MHz, respectively. Mass spectral data
were acquired on a VF Autospec or an analytical VG-70-250 HF in-
strument.
Catalytic Asymmetric CuH Hydrosilylation of b-Silyl Enoates;
Ethyl(S)-3-(Dimethylphenylsilyl)butanoate;TypicalProcedure
(Scheme 3)
To a 50 mL round-bottomed flask, flame dried and purged with ar-
gon, was added CuCl (1.5 mg, 0.015 mmol), (R,S)-PPF-P(t-Bu)2
(2.7 mg, 0.005 mmol), and t-BuONa (1.4 mg, 0.015 mmol). Tolu-
ene (1 mL) was added and the solution was stirred at 0 °C for 30
min, followed by the addition of t-BuOH (52 mL, 0.55 mmol). The
solution was cooled to –30 °C before the addition of PMHS (65 mL,
1.0 mmol), and was further stirred at –30 °C for 10 min. Z-Enoate 2
(124 mg, 0.50 mmol) was added via a syringe. The mixture was
stirred at –30 °C until complete by TLC (9 h; Et2O–hexanes, 1:9).
The reaction was quenched with sat. aq NaHCO3 (5 mL) and diluted
with Et2O (5 mL). The aqueous layer was extracted with Et2O (5 ×
5 mL) and the organic layer was washed with brine (5 mL), dried
(MgSO4), filtered, and concentrated by rotary evaporation. The res-
idue was purified by flash chromatography (Et2O–hexanes, 1:10) to
afford the title product (120 mg, 96%) as a clear oil. The de was de-
termined by 1H NMR spectrum of the corresponding imide deriva-
tive to be 95%;17 Rf = 0.36 (Et2O–hexanes, 1:9).
Morpholine Amides from Acid Chlorides; General Procedure
The acid chloride (1 equiv) was added to a flask containing CH2Cl2
(enough to make a 1.0 M solution of the acid chloride). The flask
was cooled to 0 °C, and morpholine (3 equiv) was added dropwise
via syringe. The reaction was allowed to warm to r.t. and stirred for
30 min at which time it was diluted with EtOAc (5 mL), then
washed with 1 M HCl (5 mL), sat. aq NaHCO3 (5 mL), and brine (5
mL). The organic layer was dried (Na2SO4), filtered, and concen-
trated in vacuo. The resulting amides were used without further pu-
rification.
IR (neat): 3070, 2956, 1734, 1428, 1368, 1208 cm–1.
Acyl Silanes from Morpholine Amides; General Procedure
(Scheme 2, Path A)
1H NMR (400 MHz, CDCl3): d = 0.29 (s, 6 H), 0.98 (d, J = 7.4 Hz,
3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.45 (m, 1 H), 2.05 (dd, J = 15.2, 11.4
Hz, 1 H), 2.38 (dd, J = 15.2, 4.0 Hz, 1 H), 4.09 (q, J = 7.1 Hz, 2 H),
7.33–7.40 (m, 3 H), 7.47–7.54 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = –5.14, –4.84, 14.44, 14.63, 16.66,
37.04, 60.37, 127.96, 129.26, 134.11, 137.49, 174.14.
The morpholine amide (2 mmol) was added to a flame-dried 50 mL
round-bottomed flask under dry N2. To this amide, THF (3 mL) was
added, and the solution was then cooled to –78 °C. Dimethylphenyl-
silyllithium (1.0 M solution in THF, 3 mL) was added dropwise via
a syringe, and the reaction was allowed to stir for 1.5 h, after which
time it was quenched at –78 °C (to prevent decomposition) by the
addition of sat. aq NH4Cl (4 mL). The resulting mixture was al-
lowed to warm to r.t. and then stirred for an additional 30 min. The
mixture was then partitioned between H2O (5 mL) and Et2O (5 mL),
MS-EI: m/z (%) = 250 (5.4, [M+]), 235 (23), 205 (16), 145 (27), 135
(100).
Synthesis 2007, No. 20, 3257–3260 © Thieme Stuttgart · New York

3260
B. H. Lipshutz et al.
PRACTICAL SYNTHETIC PROCEDURES
HRMS-EI: m/z calcd for C14H22O2Si [M+]: 250.1389; found:
250.1390.
(5) (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc.
1988, 110, 5579. (b) Hayashi, T.; Shintani, R.; Okamoto, K.
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Acknowledgment
We sincerely thank the NSF CHE 05-50232 for financial support,
and Solvias for supplying PPF-P(t-Bu)2 (Dr. H.-U. Blaser and Dr.
M. Thomen).
(8) Fujiwara, T.; Sawabe, K.; Takeda, T. Tetrahedron 1997, 53,
8349.
(9) Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower, A. J. Am.
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(10) Catalog # L14561. PMHS purchased from Acros does not
give the same results.
(11) Stryker, J. M.; Mahoney, W. S. J. Am. Chem. Soc. 1989, 111,
8818.
(12) Lipshutz, B. H.; Chrisman, W.; Noson, K.; Papa, P.;
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2000, 56, 2779.
(13) (a) Lipshutz, B. H.; Frieman, B. A. Angew. Chem. Int. Ed.
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(15) See http://www.solvias.com/.
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Synthesis 2007, No. 20, 3257–3260 © Thieme Stuttgart · New York