A R T I C L E S
Lipshutz et al.
temperature for 20 min. To a flame-dried 5 mL PBF were added toluene
(2 mL) and then acetophenone (0.23 mL, 2.0 mmol). The RBF was
then charged with TMDS (0.88 mL, 10 mmol, 5.0 equiv) and
immediately cooled to -78 °C followed by addition of ketone via
cannula. The reaction was monitored by TLC (10% ether:hexanes).
Upon completion (11 h), the reaction was filtered through a pad of
Celite/charcoal and rinsed with EtOAc (ca. 50 mL). The solvents were
concentrated in vacuo, and the silyl ether was dissolved in THF (3
mL) to which was added TBAF (0.7 mL, 1.0 M in THF). The
corresponding alcohol was isolated (239.6 mg, 98%) after flash
chromatography (20% ether:hexanes). Treatment of the alcohol (1.45
mmol) with Ac2O (1.4 mL, 15 mmol, 10 equiv) and NEt3 (2 mL, 15
mmol, 10 equiv) in CH2Cl2 (7 mL, 0.2 M) afforded the corresponding
acetate which was determined to be 94% ee by chiral capillary GC.
Conversion of the alcohol product to its acetate derivative and chiral
GC analysis (Chiraldex G-TA column, 60 °C) indicated an ee of 50%.
(R)-(S)-cy2PF-PCy2. We followed the general procedure above using
CuCl (3.6 mg, 0.0364 mmol, 3.5 mol %), NaO-t-Bu (3.6 mg, 0.0375
mmol, 4 mol %), (R)-(S)-cy2PF-PCy2 (19.1 mg, 0.0315 mmol, 3 mol
%), PMHS (0.65 mL, 10 mmol, 10 equiv), toluene (2 mL, 0.5 M), and
acetophenone (0.12 mL, 1.0 mmol). The reaction was run at -78 °C
for 2 h. Conversion of the alcohol product to its acetate derivative and
chiral GC analysis (Chiraldex G-TA column, 60 °C) indicated an ee
of 88%.
(R)-(S)-PPF-P(Xyl)2. We followed the general procedure above
using CuCl (3.3 mg, 0.0333 mmol, 3.5 mol %), NaO-t-Bu (3.7 mg,
0.0385 mmol, 3 mol %), (R)-(S)-PPF-PXyl2 (20.8 mg, 0.0326 mmol,
3 mol %), PMHS (0.65 mL, 10 mmol, 10 equiv), toluene (2 mL, 0.5
M), and acetophenone (0.12 mL, 1.0 mmol). The reaction was run at
-78 °C for 20 h. Conversion of the alcohol product to its acetate
derivative and chiral GC analysis (Chiraldex G-TA column, 60 °C)
indicated an ee of 42%.
Asymmetric Hydrosilylations Using other Ligands; (R,R)-Me-
DuPHOS. We followed the general procedure above using CuCl (3.5
mg, 0.0354 mmol, 3 mol %), NaO-t-Bu (3.5 mg, 0.0364 mmol, 3 mol
%), (R,R)-Me-DuPHOS (10 mg, 0.0326 mmol, 3 mol %), PMHS (0.16
mL, 2.5 mmol, 2.5 equiv), toluene (2 mL, 0.5 M), and propiophenone
(0.13 mL, 1.0 mmol). The reaction was run at 0 °C for 4 h. Conversion
of the alcohol product to its acetate derivative and chiral GC analysis
(Chiraldex G-TA column) indicated an ee of 45%.
(-)-BITIANP. We followed the general procedure above using CuCl
(6.4 mg, 0.0646 mmol, 3 mol %), NaO-t-Bu (6.2 mg, 0.0645 mmol, 3
mol %), (-)-BITIANP (39.3 mg, 0.0619 mmol, 3 mol %), PMHS (1.34
mL, 20.5 mmol, 10 equiv), toluene (4 mL, 0.5 M), and acetophenone
(0.24 mL, 2.05 mmol). The reaction was run at -50 °C for 8 h.
Conversion of the alcohol product to its acetate derivative and chiral
GC analysis (Chiraldex G-TA column, 80 °C) indicated an ee of 84%.
(R,R)-Et-FerroTANE. We followed the general procedure above
using (PPh3)CuH (12.2 mg, 0.00625 mmol, 3.75 mol %), (R,R)-Et-
FerroTANE (16.1 mmol, 0.0342 mmol, 3.5 mol %), PMHS (0.16 mL,
2.5 mmol, 2.5 equiv), toluene (2.0 mL, 0.5 M), and propiophenone
(0.13 mL, 1.0 mmol). The reaction was run at 0 °C for 18 h. Conversion
of the alcohol product to its acetate derivative and chiral GC analysis
(Chiraldex G-TA column) indicated an ee of 27%.
Asymmetric Hydrosilylation of Cyclohexyl Phenyl Ketone (Scheme
4).47 We followed the general procedure above using cyclohexyl phenyl
ketone (800 mg, 4.25 mmol), CuCl (4.2 mg, 0.043 mmol), NaO-t-Bu
(4.1 mg, 0.043 mmol), R-(-)-DTBM-SEGPHOS (2.5 mg, 2.13 × 10-3
mmol), PMHS (1.11 mL, 17.0 mmol), and toluene (4.25 mL).
Conversion of the alcohol product to its acetate derivative and chiral
GC analysis (Chiraldex B-DM column 90 °C) indicated an ee of 93%.
(R,R)-Trost Ligand. We followed the general procedure above using
(PPh3)CuH (11.3 mg, 0.00583 mmol, 3.5 mol %), (R,R)-Trost ligand
(20.9 mmol, 0.0303 mmol, 3 mol %), PMHS (0.16 mL, 2.5 mmol, 2.5
equiv), toluene (2.0 mL, 0.5 M), and propiophenone (0.13 mL, 1.0
mmol). The reaction was run at 0 °C for 9 h and then warmed to room
temperature and stirred for 2 d. Conversion of the alcohol product to
its acetate derivative and chiral GC analysis (Chiraldex G-TA column)
indicated an ee of 21%.
Asymmetric Hydrosilylation of Acetophenone; Comparison of
Substituted BIPHEP versus SEGPHOS Ligands: (R)-4-MeO-3,5-
DTB-MeO-BIPHEP. We followed the general procedure above using
CuCl (3.5 mg, 0.0355 mmol, 3.5 mol %), NaO-t-Bu (3.7 mg, 0.0385
mmol, 3 mol %), (R)-4-MeO-3,5-DTB-MeO-BIPHEP (34.7 mg, 0.0301
mmol, 3 mol %), PMHS (0.65 mL, 10 mmol, 10 equiv), toluene (2
mL, 0.5 M), and acetophenone (0.12 mL, 1.0 mmol). Conversion of
the alcohol product to its acetate derivative and chiral GC analysis
(Chiraldex G-TA column, 60 °C) indicated an ee of 90%.
(R,R)-DIOP. We followed the general procedure above using (PPh3)-
CuH (11.3 mg, 0.00583 mmol CuH, 3.5 mol %), (R,R)-DIOP (20.2
mmol, 0.0405 mmol, 4 mol %), PMHS (0.16 mL, 2.5 mmol, 2.5 equiv),
toluene (2.0 mL, 0.5 M), and acetophenone (0.12 mL, 1.0 mmol). The
reaction was run at 0 °C for 1 h. Conversion of the alcohol product to
its acetate derivative and chiral GC analysis (Chiraldex G-TA column)
indicated an ee of 0%.
R-(+)-DM-SEGPHOS. We followed the general procedure above
using CuCl (6.3 mg, 0.0636 mmol, 3 mol %), NaO-t-Bu (6.1 mg, 0.0635
mmol, 3 mol %), R-(+)-DM-SEGPHOS (45.1 mg, 0.0624 mmol, 3
mol %), PMHS (1.34 mL, 20.5 mmol, 10 equiv), toluene (4 mL, 0.5
M), and acetophenone (0.24 mL, 2.05 mmol). Conversion of the alcohol
product to its acetate derivative and chiral GC analysis (Chiraldex G-TA
column, 80 °C) indicated an ee of 95%.
(R)-(S)-JOSIPHOS. We followed the general procedure above using
CuCl (4.2 mg, 0.0424 mmol, 4 mol %), NaO-t-Bu (3.3 mg, 0.0343
mmol, 3 mol %), (R)-(S)-JOSIPHOS (18.8 mg, 0.0316 mmol, 3 mol
%), PMHS (0.65 mL, 10 mmol, 10 equiv), toluene (2 mL, 0.5 M), and
acetophenone (0.12 mL, 1.0 mmol). The reaction was run at -78 °C
for 20 h. Conversion of the alcohol product to its acetate derivative
and chiral GC analysis (Chiraldex G-TA column, 60 °C) indicated an
ee of 62%.
R-(-)-DTBM-SEGPHOS. We followed the general procedure
above using CuCl (7.3 mg, 0.0737 mmol, 3.5 mol %), NaO-t-Bu (6.1
mg, 0.0635 mmol, 3 mol %), R-(-)-DTBM-SEGPHOS (72.7 mg,
0.0616 mmol, 3 mol %), PMHS (1.34 mL, 20.5 mmol, 10 equiv),
toluene (4 mL, 0.5 M), and acetophenone (0.24 mL, 2.05 mmol).
Conversion of the alcohol product to its acetate derivative and chiral
GC analysis (Chiraldex G-TA column, 80 °C) indicated an ee of 96%.
Asymmetric Hydrosilylation of 4-Fluoropropiophenone.48 We
followed the general procedure above using CuCl (2.3 mg, 0.023 mmol),
NaO-t-Bu (2.2 mg, 0.023 mmol), R-(-)-DTBM-SEGPHOS (1.4 mg,
1.15 × 10-3 mmol), PMHS (0.60 mL, 9.20 mmol), toluene (2.30 mL),
and 4-fluoropropiophenone (0.32 mL, 2.30 mmol). Isolation afforded
330 mg (93%) of the corresponding alcohol product. Comparison of
spectral data with known literature values48 confirmed the identity of
(R)-(S)-PPF-P(t-Bu)2. We followed the general procedure above
using CuCl (3.3 mg, 0.0333 mmol, 3 mol %), NaO-t-Bu (3.6 mg, 0.0375
mmol, 3 mol %), (R)-(S)-PPF-P(t-Bu)2 (34 mg, 0.0627 mmol, 6 mol
%), PMHS (0.65 mL, 10 mmol, 10 equiv), toluene (2 mL, 0.5 M), and
acetophenone (0.12 mL, 1.0 mmol). The reaction was run at -78 °C
for 20 h. Conversion of the alcohol product to its acetate derivative
and chiral GC analysis (Chiraldex G-TA column, 60 °C) indicated an
ee of 42%.
(S)-(S)-WALPHOS. We followed the general procedure above using
CuCl (3.7 mg, 0.0374 mmol, 3.5 mol %), NaO-t-Bu (4.0 mg, 0.0416
mmol, 4 mol %), WALPHOS (31.5 mg, 0.0339 mmol, 3 mol %), PMHS
(0.65 mL, 10 mmol, 10 equiv), toluene (2 mL, 0.5 M), and acetophe-
none (0.12 mL, 1.0 mmol). The reaction was run at -78 °C for 2 h.
(47) Carter, M. B.; Schiott, B.; Gutierrez, A.; Buchwald, S. L. J. Am. Chem.
Soc. 1994, 116, 11667.
(48) Prasad, K. R. K.; Joshi, N. N. Tetrahedron: Asymmetry 1996, 7, 1957.
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8788 J. AM. CHEM. SOC. VOL. 125, NO. 29, 2003