Titanocene-catalyzed asymmetric ketone hydrosilylation: The effect of catalyst activation protocol and additives on the reaction rate and enantioselectivity

Article abstract of DOI:10.1021/ja990450v

The efficient asymmetric hydrosilylation of ketones with a chiral titanocene catalyst has been realized. In this procedure, (R,R)-ethylenebis(tetrahydroindenyl) titanium difluoride (1) was used as the precatalyst, and alcohol additives were employed. Arom

Full text of DOI:10.1021/ja990450v

5640
J. Am. Chem. Soc. 1999, 121, 5640-5644
Titanocene-Catalyzed Asymmetric Ketone Hydrosilylation: The
Effect of Catalyst Activation Protocol and Additives on the Reaction
Rate and Enantioselectivity
Jaesook Yun and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed February 12, 1999
Abstract: The efficient asymmetric hydrosilylation of ketones with a chiral titanocene catalyst has been realized.
In this procedure, (R,R)-ethylenebis(tetrahydroindenyl) titanium difluoride (1) was used as the precatalyst,
and alcohol additives were employed. Aromatic and R,â-unsaturated ketones were reduced to the corresponding
alcohols with a high level of enantioselectivity.
Introduction
hydride is highly effective in the asymmetric hydrosilylation
of prochiral imines (eq 2).7,8 We also found that the substrate
The asymmetric hydrosilylation of ketones provides an
effective route to optically active secondary alcohols. While the
asymmetric hydrosilylation of prochiral ketones using late
transition-metal catalysts has been extensively explored,1 we
reported only recently the first hydrosilylation of ketones with
a chiral titanocene catalyst which afforded the corresponding
alcohols in high enantiomeric purity (eq 1).2 Since our report,
scope in this process could be significantly increased if certain
primary amines were slowly added to the reaction mixture. We
therefore chose to reinvestigate the ketone hydrosilylation
reaction using (R,R)-1 with and without the inclusion of
additives. Herein, we report the results of those studies.
Results
In our previous study, (EBTHI)Ti-catalyzed hydrosilylation
of aromatic ketones afforded the product alcohols with a high
enantiomeric excess, but it was necessary to use high catalyst
loadings (4.5-10 mol %) to obtain complete conversion of
substrate to product in a reasonable reaction time (1-4.5 days).
Since the (EBTHI)Ti-catalyzed imine hydrosilylation was
facilitated by added primary amines,8 we surmised that the
analogous ketone hydrosilylation reaction might also be pro-
moted by additives. In preliminary studies on the hydrosilylation
of 4-methylacetophenone and isobutyrophenone,9 we screened
a number of possibilities and found that primary alcohols are
more effective as additives than either secondary alcohols or
primary amines (Table 1). Among the primary alcohols we
examined, MeOH was eventually chosen because its low boiling
other asymmetric hydrosilylation reactions of ketones using
chiral titanium catalysts have been reported.3-6 However, the
enantioselectivity realized in these studies was very low even
with aromatic ketones,3-5 which were the optimal substrates
for our catalytic system.
Recently, we have shown that the precatalyst (S,S)-(EBTHI)-
TiF2 (EBTHI ) ethylenebis(tetrahydroindenyl)) 1 can be
activated with phenylsilane and that the resulting titanocene
(1) (a) Brunner, H.; Nishiyama, H.; Itoh, K. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993; Chapter 6. (b) Lee, S.;
Lim, C. W.; Song, C. E.; Kim, I. O. Tetrahedron: Asymmetry 1997, 8,
4027. (c) Hayashi, T.; Hayashi, C.; Uozumi, Y. Tetrahedron: Asymmetry
1995, 6, 2503. (d) Nishiyama, H.; Kondo, M.; Nakamura, T.; Itoh, K.
Organometallics 1991, 10, 500.
(2) Carter, M. B.; Schiøtt, B.; Gutie´rrez, A.; Buchwald, S. L. J. Am.
Chem. Soc. 1994, 116, 11667.
(3) Halterman, R. L.; Ramsey, T. M.; Chen, Z. J. Org. Chem. 1994, 59,
2642.
(7) Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald, S. L. J.
Am. Chem. Soc. 1996, 118, 6784.
(8) Verdaguer, X.; Lange, U. E. W.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1998, 37, 1103.
(4) Xin, S.; Harrod, J. F. Can. J. Chem. 1995, 73, 999.
(5) Imma, H.; Mori, M.; Nakai, T. Synlett 1996, 1229.
(6) Rahimian, K.; Harrod, J. F. Inorg. Chim. Acta 1998, 270, 330.
(9) In our previous report, isobutyrophenone was reduced to the alcohol
product (92% ee, 79% isolated yield) with 10 mol % catalyst and 10 equiv
PMHS in 4.5 days.2.
10.1021/ja990450v CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/02/1999

Titanocene-Catalyzed Ketone Hydrosilylation
J. Am. Chem. Soc., Vol. 121, No. 24, 1999 5641
Table 2. Enantioselective Hydrosilylation of Ketonesa
Table 1. Effect of Different Additives on the Assymetric
Hydrosilylation of Ketones
a Determined by GC after aqueous work-up upon completion of
addition of indicated amounts of additives. b Reaction was carried out
at 60 °C. c Time of reaction with no additive. d 10 equiv PMHS was
used instead of 6 equiv. e 1 mol % of 1 was used.
point facilitates product isolation. It is important to note that
the use of different alcohol additives did not affect the
enantioselectivity of the process. This is in contrast to imine
hydrosilylation for which different amine additives produced
secondary amine product with varying levels of enantiomeric
excess.8
Slow addition of MeOH, using a syringe pump, to the
homogeneous reaction mixture over 4-13 h resulted in a great
enhancement of the reaction rate, compared to that previously
reported, allowing the reduction of the catalyst greatly to 0.5-2
mol % (Table 2).10 In addition, the alcohol products were found
to have a higher ee than those in our previous study. Bulky
aromatic ketones such as isobutyrophenone (entry 3) and
cyclohexylphenyl ketone (entry 4) were reduced with excellent
levels of enantioselectivities within 12 h and R,â-unsaturated
ketones (entries 6-8) were reduced in 1,2-fashion to afford the
corresponding allylic alcohols of high ee.
a Reactions were run using (R,R)-(EBTHI)TiF2. All data represent
the average of at least two runs except entry 2. b MeOH (3-7 equiv)
was added during the course of the reaction time. c Percent ee was
determined by chiral GC analysis (Chiraldex GTA or BPH column).
d >95% pure by 1H NMR and GC. e Toluene was used instead of THF.
f Percent ee was determined by HPLC analysis using a Chiralcel OJ
column. g Contaminated with 5% 1-cyclohexylethanol.
Table 3. Hydrosilylation of Dialkyl Ketonesa
Most of the reactions in this work were conducted in THF;
in our previous study the use of THF as solvent afforded
products with variable levels of ee. In the present study, the ee
of the product was the same for reactions conducted in either
THF or toluene (entry 2). Additionally, the current procedure
does not require that the activating agent (in the previous
instance, n-BuLi) be added to the center of the reaction mixture.2
The hydrosilylation reactions of dialkyl ketones were also
briefly investigated. The product secondary alcohols, however,
were formed with only low to moderate levels of enantiomeric
excess (Table 3). Cyclohexylmethyl ketone was reduced to the
corresponding alcohol of the same ee (23% ee) as in our
previous study.2 As expected, as the steric bulk of the alkyl
a 1 mol% (R,R)-1, 5 equiv PMHS, slow addition of MeOH. b MeOH
was added until the catalyst was deactivated.
side chain increased, the rate of reaction was found to decrease.
With tert-butylmethyl ketone, the reaction rate becomes so slow
that the addition of methanol had no beneficial effect.
Substrates possessing proximal heteroatoms are poorer sub-
strates for the hydrosilylation reaction. The presence of a
potential coordinating heteroatom close to the ketone carbonyl
significantly slows the reaction, leading to low levels of
conversion to product.11 However, the enantioselectivity of the
reaction was still high. Ketones 2 and 3 having â-hydroxy and
(10) For analysis by GC, an aliquot was removed from the reaction
mixture and subjected to aqueous workup. It was found that, even under
more forcing reaction conditions (prolonged reaction time, higher catalyst
loadings, high temperatures), the ketone (<3%) was observable after aqueous
workup except in the case of isobutyrophenone where ∼5% of the starting
ketone was observed. This starting ketone may arise from the corresponding
silyl enol ether, a side product invoked in several ketone hydrosilylation
reports.1b-1d To investigate this further, an experiment using infrared
spectroscopy was carried out. The progress of the hydrosilylation reaction
of 4-methylacetophenone with (R,R)-1 (5 mol %) was monitored over 6 h
with an ASI 1000React IR probe, following the CdO stretching band of
the ketone (1686 cm-1). The absorbance of the CdO stretching decreased
to baseline in 4 h, and the reaction was continued for another 2 h. There
was no change in the intensity during the next 2 h. However, ketone was
still detected by GC after hydrolysis of the reaction mixture, and the ratio
of alcohol product and ketone was 98:2.
â-methoxy groups, respectively, were reduced to the corre-

5642 J. Am. Chem. Soc., Vol. 121, No. 24, 1999
Yun and Buchwald
Figure 1.
sponding alcohols under the standard reaction conditions using
PMHS (∼50% conversion) with the same level of enantiose-
lectivity (96% and 98% ee, respectively) as for ketones with
similar steric demands in Table 2.
explained in an alternative manner. Pentavalent silicon species
formed by the reaction of hydrosilanes with a nucleophile such
as F- or an alkali metal alkoxide are capable of hydrosilylating
ketones13 and this nonselective hydrosilylation reaction is known
to be dependent on both the solvent and silane employed.13d
Such a reduction pathway catalyzed by pentavalent hydrosilicate
species formed from lithium binaphtholate in the reaction
mixture may be a major factor in the reaction which utilized
MeLi in THF. This would explain the lower ee’s in THF solution
observed by Harrod and Rahimian, as well as the lower ee’s
that we had observed in solvents other than benzene utilizing
our previous activation protocol (n-BuLi, (EBTHI)-Ti(binaph-
tholate)).
Harrod and Rahimian also proposed that the active silane
species in our previously reported catalytic system is actually
MeSiH3, not PMHS. We have confirmed their observation that
PMHS undergoes a partial redistribution reaction to MeSiH3
and new polymeric materials in the presence of a titanocene
catalyst. (Caution: MeSiH3 is generated in these procedures.
Due precaution should be taken including a consideration of
the possible buildup of pressure.)14 However, we are unsure
whether methylsilane is the active silane species in the hydrosi-
lylation reaction. When the hydrosilylation of 2 was carried out
with different silanes, we found that the ee of the product
depended on whether PhSiH3 (∼0% ee) or PMHS (96% ee)
was used, indicating that a nonselective pathway was taking
place in the protocol involving PhSiH3. We reason that, in the
Discussion
As in the previous study, we observed that conjugation of
the carbonyl group is necessary to achieve high levels of
enantioselectivity. To explain this phenomenon, we proposed a
transition-state model for the reaction in which the ketone
approaches the titanium complex from the side(Figure 1).2 For
substrates in which the carbonyl is conjugated to an aromatic
ring or a double bond (e.g., aromatic ketones and R,â-
unsaturated ketones), the enone moiety is in a coplanar
arrangement. As a result, transition state A is disfavored because
of unfavorable steric interactions between the aromatic ring and
the tetrahydroindenyl ring (Figure 1). In contrast, no such
interaction exists for transition state B, and thus it is preferred.
In saturated ketones such a conjugation does not exist, allowing
the alkyl side chain to rotate to minimize steric interactions.
This resulted in a very small energy difference between the two
transition states.
Harrod and Rahimian recently reported that the enantiose-
lectivity for the (EBTHI)Ti-catalyzed hydrosilylation of ac-
etophenone was consistently much higher (∼99% ee) when they
generated active catalyst by adding n-BuLi rather than MeLi
(7-53% ee) to the precatalyst (EBTHI)-Ti(binaphtholate).6
They attributed the difference in ee to the formation of different
catalytic species when the different modes of activation were
employed. In their study, benzene was used for the hydrosily-
lation reaction utilizing n-BuLi, while THF was used for the
hydrosilylation reaction using MeLi. We previously observed
that variable levels of enantioselectivity were seen for reactions
run in different solvents in the n-BuLi based activation
protocol.12 We therefore felt that the difference in ee might be
(13) (a) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. ReV.
1993, 93, 1371. (b) Furin, G. G.; Vyazankina, O. A.; Gostevsky, B. A.;
Vyazankin, N. S. Tetrahedron 1988, 44, 2675. (c) Schiffers, R.; Kagan, H.
B. Synlett 1997, 1175. (d) The reactivity of silanes has been shown to
decrease in the order: (EtO)3SiH > (EtO)2Si(Me)H > PMHS13a or (EtO)3-
SiH > (EtO)2Si(Me)H > Ph2SiH2.13b The reactivity of silanes increases as
the coordinating ability of the solvent increases: HMPA > DMF > THF
13a
. CH2Cl2. It has been reported that ketones could be reduced asym-
metrically by a catalytic amount of the monolithio salt of (R)-binol in the
presence of (MeO)3SiH or (EtO)3SiH. When THF was used as solvent, the
reduction of acetophenone proceeded faster but with a lower enantioselec-
tivity (0% ee, 88% yield) than when diethyl ether was used (31% ee, 33%
yield). Other solvents were not effective in this reaction catalyzed by
hypervalent trialkoxysilanes.13c
(11) With 2 mol % 1 and 5 equiv PMHS, we observed ∼50% conversion
for both ketones 2 and 3 before catalyst deactivation. When a solution of
ketone 2 in THF was added slowly via syringe pump, we obtained ∼90%
conversion with no change in the ee of the product.
(12) With PMHS as the silane, the alcohol product which was isolated
had a 2-30% ee when the reaction was carried out in THF and 14% ee
when diethyl ether was used as solvent: Carter, M. B., unpublished results.
(14) (a) Urben, P. G. Bretherick’s Handbook of ReactiVe Chemical
Hazards, 5th ed.; Butterworth-Heinemann: Boston, 1995; Vol. I, p 205.
(b) Lewis, R. J., Sr. Sax’s Dangerous Properties of Industrial Materials,
8th ed.; Van Nostrand Reinhold: New York, 1994; Vol. III, p 2397.

Titanocene-Catalyzed Ketone Hydrosilylation
J. Am. Chem. Soc., Vol. 121, No. 24, 1999 5643
Scheme 1
presence of PhSiH3, the primary hydroxyl group of 2 initially
reacts with the silane producing the silyl ether.15 Reduction of
the carbonyl group to the corresponding diol product via
intramolecular hydrogen transfer16 from the silane subsequently
occurs with no selectivity. It is possible that this intramolecular
reduction takes place faster than the asymmetric reduction
pathway catalyzed by the titanocene catalyst. To the extent that
methylsilane and phenylsilane should behave similarly, if
methylsilane were the active silane species in our reactions with
PMHS, we would expect that the ee of the product alcohol
would be closer to that seen when PhSiH3 is employed. This
finding, of course, does not shed light on what the actual silane
group participating in the σ-bond metathesis is, but is suggestive
of what it is not.
hydrosilylation reaction, whereas nonselective reduction path-
ways are minimized when the new activation protocol is
employed.
In summary, by applying a protocol which involves the slow
addition of a primary alcohol to the titanocene-catalyzed
asymmetric hydrosilylation reaction of ketones, improved
turnover numbers and high enantioselectivities were realized.
The use of the new activation protocol obviates the need to use
alkyllithium reagents for catalyst activation and broadens the
choice of solvent by minimizing other deleterious nonselective
pathways for ketone reduction.
Experimental Section
General Methods. Toluene and THF were distilled under argon or
nitrogen from sodium benzophenone ketyl. Polymethylhydrosiloxane
(PMHS) was used after filtration through a plug of alumina under argon.
Alcohols (MeOH, EtOH, i-PrOH, n-BuOH) were purchased from
Aldrich in sure-seal bottles, transferred via cannula into a Schlenk tube
and degassed using three freeze-pump-thaw cycles. Substrate ketones
were commercially available with the following exceptions: 5-methyl-
1-phenylhex-4-en-1-one (Table 2, entry 5) was prepared by the literature
procedure.20 Ketone 2 was obtained from ethyl benzoyl acetate by
protection of the ketone carbonyl (ethylene glycol, p-TsOH), reduction
of the ester moiety (LiAlH4) to afford a hydroxy ketal, followed by
deketalization (PPTS, aqueous acetone). Ketone 3 was obtained in a
similar fashion as for 2 by methylation of the hydroxy ketal (NaH,
MeI) followed by cleavage of the ketal. These ketones were purified
by column chromatography and/or Kugelrohr distillation. Commercial
ketones were passed through a plug of alumina and stored over 3 Å
molecular sieves prior to use. Phenylsilane and pyrrolidine were stored
under argon in a Schlenk tube and were manipulated under an argon
atmosphere. Flash chromatography was performed on ICN SiliTech
In analogy to what we have proposed for the imine hydrosi-
lylation carried out with slow addition of primary amine, a
possible catalytic cycle for the modified ketone hydrosilylation
process is shown in Scheme 1.17 In this mechanism, the
enantioselectivity-determining step and the rate-determining step
are different, as they are in the titanocene-catalyzed hydrogena-
tion of imines.19 That -OR′ is smaller than -O(CH(R1)(R2))
increases the rate of σ-bond metathesis in the rate-determining
step; the rate of the process is enhanced. The additive is not
involved in the enantioselectivity-determining step; thus, it does
not change the inherent selectivity of the process. We believe
that the uniformly consistent ee’s arise because use of the
additive greatly enhances the rate of the catalytic asymmetric
(15) Bedard, T. C.; Corey, J. Y. J. Organomet. Chem. 1992, 428, 315.
(16) Fujita, M.; Hiyama, T. J. Org. Chem. 1988, 53, 5405.
(17) We have been unable to identify the exact nature of the catalytic
species. It is possible that several titanium species are present in the solution
including titanium(III) hydrides, silyl titanium(IV) hydrides, and bimetallic
titanium hydrides which have been reported in the literature.18.
(18) (a) Spaltenstein, E.; Palma, P.; Kreutzer, K. A.; Willoughby, C. A.;
Davis, W. M.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 10308. (b)
Xin, S.; Harrod, J. F.; Samuel, E. J. Am. Chem. Soc. 1994, 116, 11562. (c)
Aitken, C. T.; Harrod, J. F.; Samuel, E. J. Am. Chem. Soc. 1986, 108, 4059.
(19) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
11703.
1
32-63D, 60A. All H NMR spectra are reported in δ units, parts per
million (ppm) downfield from tetramethylsilane. 13C NMR spectra are
reported in ppm referenced to the center peak of deuteriochloroform
(77 ppm). Infrared spectra (IR) were obtained on ASI ReactIR 1000
and are recorded in cm-1. Optical rotations were recorded on a Perkin-
Elmer 241 polarimeter.
(20) Michael, J. P.; Nkwelo, M. M. Tetrahedron 1990, 46, 2549.

5644 J. Am. Chem. Soc., Vol. 121, No. 24, 1999
Yun and Buchwald
General Procedure for the Asymmetric Hydrosilylation of
Ketones. To a solution of (R,R)-1 (7.0 mg, 0.02 mmol) in anhydrous
THF (1 mL) were added phenylsilane (12 µL, 0.1 mmol), pyrrolidine
(8 µL, 0.1 mmol), and MeOH (4 µL, 0.1 mmol) sequentially under an
atmosphere of argon in a resealable Schlenk tube. The reaction mixture
was then heated at 60 °C until the color of the solution turned from
yellow to green. The Schlenk tube was removed from the oil bath and
cooled to room temperature. PMHS (5 equiv relative to ketone) and
ketone (1 or 2 mmol) were added successively. The Schlenk tube was
resealed and transferred to a glovebox. A gastight syringe was charged
with methanol (>7 equiv) and slow addition of the methanol into the
Schlenk tube was initiated by means of a syringe pump. During the
course of the addition, the progress of the reaction was monitored by
GC and/or TLC. The addition of methanol was allowed to continue
until the ratio of product to staring material did not change, and at this
point the reaction was stopped. Typically this occurred before 5 equiv
of MeOH had been added. (CAUTION: The evolution of gas was
observed in this reaction. Therefore, it is advised that the addition be
carried out in a system open to an inert atmosphere to avoid the buildup
of pressure). Workup: The reaction mixture was diluted with THF (10
mL), and the resulting solution was added to an aqueous solution of
NaOH (10 mL, 2 M) with vigorous stirring. The biphasic mixture was
stirred until the organic layer became clear (several hours). The aqueous
layer was extracted with ether (3 × 20 mL), and the combined organic
layers were washed with brine, dried over MgSO4, and concentrated
in vacuo. The product was purified by column chromatography, and
its 1H spectrum was compared against either the literature data or that
of authentic material (derived from sodium borohydride or Luche21
reduction of the corresponding ketone). The reported isolated yields
are the average of at least two runs, and the products were of >95%
purity by GC and 1H NMR. The absolute configuration of the alcohol
was determined by optical rotation in the cases where it had previously
been determined. The ee was determined by GC analysis of the alcohol
itself or the corresponding acetate derivative using a Chiraldex BPH
or GTA column or by HPLC analysis using a Chiralcel OB or OJ
column as indicated below.
1.81 (m, 5H), 1.36-1.40 (br d, 1H), 0.91-1.27 (m, 5H); [R]D -29.2°
(c 0.22, benzene) (lit.25 [R]D -28.27° (c 3.29, benzene), (S)).
(S)-1-Phenyl-5-methylhex-4-en-1-ol:26 84% yield; 97% ee was
1
measured by HPLC on a OJ column; H NMR (CDCl3, 300 MHz)
7.26-7.36 (m, 5H), 5.15 (br t, J ) 7.2 Hz, 1H), 4.68 (dd, J ) 5.5 Hz,
7.7 Hz, 1H), 1.95-2.06 (m, 2H), 1.73-1.87 (m, 3H), 1.70 (s, 3H),
1.59 (s, 3H); 13C NMR (CDCl3, 75 MHz) 144.95, 132.52, 128.61,
127.66, 126.10, 123.98, 74.45, 39.21, 25.96, 24.68, 17.94; IR (neat)
3354, 2968, 2926, 2860, 1494, 1451, 1378, 1061, 1015, 833 cm-1; [R]D
-13.9° (c 1.73, CHCl3) (lit.26 [R]D -10.7° (c 1.60, CHCl3), 96% ee
(S)).
(S)-1-(1-Cyclohexenyl)ethanol:2 87% yield; 96% ee was measured
1
by GC on a GTA column; H NMR (CDCl3, 300 MHz) 5.67 (br s,
1H), 4.17 (q, J ) 6.4 Hz, 1H), 2.02 (m, 4H), 1.50-1.70 (m, 4H), 1.39
(br s, 1H), 1.26 (d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
141.41, 121.67, 72.32, 25.07, 23.82, 22.83, 22.78, 21.67; [R]D -11.2°
(c 0.36, CHCl3) (lit.27 [R]D 7.60° (c 1.54, CHCl3), 61% ee (R)).
1-(2-Methyl-cyclopent-1-enyl)ethanol:28 90% yield; 97% ee was
measured by GC on a GTA column; 1H NMR (CDCl3, 300 MHz) 4.71
(q, J ) 6.5 Hz, 1H), 2.35-2.44 (m, 2H), 2.30 (t, J ) 7.5 Hz, 2H),
1.73-1.84 (m, 2H), 1.68 (s, 3H), 1.36 (br s, 1H), 1.26 (d, J ) 6.5 Hz,
3H); 13C NMR (CDCl3, 75 MHz) 137.86, 134.28, 64.60, 39.03, 30.51,
21.82, 21.75, 13.90; IR (neat) 3335, 2972, 2953, 2926, 2895, 2841,
1675, 1444, 1405, 1382, 1336, 1289, 1185, 1069, 1015, 984, 880 cm-1
;
[R]D -27.6° (c 1.01, CHCl3).
2-Pentyl-cyclopent-2-enol: 90% yield; 84% ee was measured by
GC on a BPH column; 1H NMR (CDCl3, 300 MHz) 5.53 (s, 1H), 4.65
(br s, 1H), 2.08-2.46 (m, 5H), 1.65-1.74 (m, 1H), 1.42-1.56 (m,
2H), 1.26-1.39 (m, 5H), 0.90 (t, J ) 6.7 Hz, 3H); 13C NMR (CDCl3,
75 MHz) 146.71, 127.09, 79.10, 34.22, 32.03, 29.81, 28.19, 27.60,
22.76, 14.28; IR (neat) 3312, 2957, 2926, 2856, 1459, 1316, 1046,
926, 826 cm-1; [R]D -30.3° (c 1.26, CHCl3).
(S)-1-Phenyl-propane-1,3-diol:29 96% ee was measured by HPLC
1
on a OB column; H NMR (CDCl3, 300 MHz) 7.24-7.36 (m, 5H),
4.94 (dd, J ) 3.8 Hz, 8.5 Hz, 1H), 3.83 (t, J ) 5.5 Hz, 2H), 2.91 (br
s, 2H), 1.86-2.06 (m, 2H); [R]D -65.7° (c 1.67, CHCl3) (lit.29 [R]D
-70.5° (c 1.015, CHCl3), >98% ee (S)).
(S)-1-(4-Methylphenyl)ethanol:2 87% yield; 98% ee was measured
(S)-3-Methoxy-1-phenyl-1-propanol:30 98% ee was measured by
1
by GC on a GTA column; H NMR (CDCl3, 300 MHz) 7.27 (d, J )
1
GC on a GTA column; H NMR (CDCl3, 300 MHz) 7.24-7.38 (m,
7.9 Hz, 2H), 7.16 (d, J ) 7.8 Hz, 2H), 4.87 (q, J ) 6.5 Hz, 1H), 2.34
(s, 3H), 1.80 (br s, 1H), 1.48 (d, J ) 6.5 Hz, 3H); [R]D -63.0° (c 1.0,
CHCl3) (lit.22 [R]D 51.6° (c 1.0, CHCl3), 93.8% ee (R)).
5H), 4.91 (ddd, J ) 3.2 Hz, 3.9 Hz, 8.0 Hz, 1H), 3.53-3.62 (m, 2H),
3.37 (s, 3H), 3.32 (d, J ) 3.2 Hz, 1H), 1.90-2.05 (m, 2H); 13C NMR
(CDCl3, 125 MHz) 144.59, 128.56, 127.50, 125.88, 73.80, 71.43, 59.16,
38.75; [R]D -39.0° (c 1.77, cyclopentane) (lit.31 [R]D 30.1° (c 0.74,
cyclopentane), 80% ee (R)).
(S)-1-phenylpropanol:2 86% yield; 98% ee was measured by GC
1
on a BPH column; H NMR (CDCl3, 300 MHz) 7.25-7.35 (m, 5H),
4.59 (t, J ) 6.6 Hz, 1 H), 1.72-1.85 (m, 3H), 0.92 (t, J ) 7.4 Hz,
3H); [R]D -49.2° (c 1.18, CHCl3) (lit.23 [R]D 49.0° (c 1.0, CHCl3),
96% ee (R)).
Acknowledgment. We thank the National Institutes of
Health (GM-46059) for support of this work. We thank Dr.
Bryant Yang for help with the manuscript and Marcus C. Hansen
for the preparation of (R,R)-1 and for assistance in IR studies.
(S)-2-Methyl-1-phenylpropanol:2 86% yield; 99% ee was measured
1
by GC on a GTA column; H NMR (CDCl3, 300 MHz) 7.24-7.37
(m, 5H), 4.36 (d, J ) 6.9 Hz, 1H), 1.94 (d sept, J ) 6.9 Hz, 1H), 1.82
(s, 1H), 1.00 (d, J ) 7.2 Hz, 3H), 0.80 (d, J ) 6.9 Hz, 3H); [R]D
-50.9° (c 0.65, diethyl ether) (lit.24 [R]D 34.8° (c 4.90, diethyl ether),
73% ee (R)).
JA990450V
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