Catalytic asymmetric generation of (Z)-disubstituted allylic alcohols

Article abstract of DOI:10.1021/ja0762285

A one-pot method for the direct preparation of enantioenriched (Z)-disubstituted allylic alcohols is introduced. Hydroboration of 1-halo-1-alkynes with dicyclohexylborane, reaction with t-BuLi, and transmetalation with dialkylzinc reagents generate (Z)-disubstituted vinylzinc intermediates. In situ reaction of these reagents with aldehydes in the presence of a catalyst derived from (-)-MIB generates (Z)-disubstituted allylic alcohols. It was found that the resulting allylic alcohols were racemic, most likely due to a rapid addition reaction promoted by LiX (X = Br and Cl). To suppress the LiX-promoted reaction, a series of inhibitors were screened. It was found that 20-30 mol % tetraethylethylenediamine inhibited LiCl without inhibiting the chiral zinc-based Lewis acid. In this fashion, (Z)-disubstituted allylic alcohols were obtained with up to 98% ee. The asymmetric (Z)-vinylation could be coupled with tandem diastereoselective epoxidation reactions to provide epoxy alcohols and allylic epoxy alcohols with up to three contiguous stereogenic centers, enabling the rapid construction of complex building blocks with high levels of enantio- and diastereoselectivity.

Full text of DOI:10.1021/ja0762285

Published on Web 12/04/2007
Catalytic Asymmetric Generation of (Z)-Disubstituted Allylic
Alcohols
Luca Salvi, Sang-Jin Jeon, Ethan L. Fisher, Patrick J. Carroll, and Patrick J. Walsh*
Contribution from the P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry,
UniVersity of PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received August 17, 2007; E-mail: pwalsh@sas.upenn.edu
Abstract: A one-pot method for the direct preparation of enantioenriched (Z)-disubstituted allylic alcohols
is introduced. Hydroboration of 1-halo-1-alkynes with dicyclohexylborane, reaction with t-BuLi, and
transmetalation with dialkylzinc reagents generate (Z)-disubstituted vinylzinc intermediates. In situ reaction
of these reagents with aldehydes in the presence of a catalyst derived from (-)-MIB generates
(Z)-disubstituted allylic alcohols. It was found that the resulting allylic alcohols were racemic, most likely
due to a rapid addition reaction promoted by LiX (X ) Br and Cl). To suppress the LiX-promoted reaction,
a series of inhibitors were screened. It was found that 20-30 mol % tetraethylethylenediamine inhibited
LiCl without inhibiting the chiral zinc-based Lewis acid. In this fashion, (Z)-disubstituted allylic alcohols
were obtained with up to 98% ee. The asymmetric (Z)-vinylation could be coupled with tandem
diastereoselective epoxidation reactions to provide epoxy alcohols and allylic epoxy alcohols with up to
three contiguous stereogenic centers, enabling the rapid construction of complex building blocks with high
levels of enantio- and diastereoselectivity.
Enantioenriched allylic alcohols are among the most com-
monly used chiral building blocks and have been widely applied
in natural and non-natural product synthesis.1-4 They are also
precursors to enantioenriched epoxy alcohols,1,4-10 allylic
amines,11-14 R- and â-amino acids,13,15 and cyclopropyl
alcohols.16-19 Enantioenriched allylic alcohols are often isolated
from kinetic resolution (KR) with the Sharpless-Katsuki
asymmetric epoxidation catalyst.4-7 Although (E)-allylic alco-
hols are excellent substrates for KR, (Z)-disubstituted allylic
alcohols are not (Scheme 1).4-7 Other drawbacks to KR include
the need to separate the desired allylic alcohol from the epoxy
alcohol product and a maximum yield of 50%.20
More efficient methods to prepare allylic alcohols include
asymmetric vinylation of aldehydes8-10,13,15,21-28 or ketones29,30
(Scheme 2) and reductive coupling of alkynes and carbonyl
compounds.31-36 These methods simultaneously generate the
C-C bond and a stereogenic center in a single step. Almost all
vinylation methods are initiated by hydrometalation of terminal
alkynes, via hydroboration21-23,37 or hydrozirconation,24,25,38
followed by addition of the resulting (E)-vinyl organometallic
reagents to aldehydes or ketones to furnish (E)-allylic alcohols
(Scheme 2). Similar methods to prepare (Z)-allylic alcohols
(1) Katsuki, T.; Martin, V. S. Org. React. 1996, 1.
(2) Bonini, C.; Righib, G. Tetrahedron 2002, 58, 4981-5021.
(3) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703-710.
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A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, pp 621-648.
(5) Mart´ın, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.;
Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237-6240.
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S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodard, S. S. Pure Appl.
Chem. 1983, 55, 589-604.
(20) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 1,
5-26.
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(22) Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993, 115, 1593-1594.
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36, 2607-2610.
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Chem. 1997, 69, 639-644.
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Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
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Chem. Soc. 2004, 126, 13608-13609.
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R. E. Synlett 2004, 2647-2669.
(27) Richmond, M. L.; Sprout, C. M.; Seto, C. T. J. Org. Chem. 2005, 70, 8835-
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8840.
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127, 14668-14674.
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103, 977-1050.
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9
10.1021/ja0762285 CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 16119-16125
16119

A R T I C L E S
Salvi et al.
Scheme 1. Application of the Sharpless-Katsuki Catalyst to the Kinetic Resolution of (E)- and (Z)-Allylic Alcohols
Scheme 2. Catalytic Asymmetric Vinylation of Aldehydes and
Ketones via Hydrometalation of Terminal Alkynes,
Transmetalation, and Addition
We recently reported a one-pot stereospecific method for the
synthesis of (Z)-disubstituted allylic alcohols based on synthon
B (Scheme 4).46 Initial hydroboration of 1-bromo-1-alkynes with
dicyclohexylborane furnishes 1-bromo-1-alkenylboranes regi-
oselectively. It is known that nucleophiles react with 1-bromo-
1-alkenylboron derivatives via addition of the nucleophile to
the open coordination site on boron followed by migration of
the nucleophile47,48 or a boron alkyl to the vinylic position with
inversion at the vinylic center.42,48-52 In our investigations we
chose to use t-BuLi, which had been shown to be an excellent
hydride source by Molander48 for the formation of (Z)-
vinylboranes. Vinylboranes are fairly unreactive toward carbonyl
additions. We envisioned that the (Z)-vinyl group would undergo
boron to zinc transmetalation with dialkylzinc reagents to
generate more reactive vinylzinc reagents. In fact, the increased
reactivity of the vinylzinc reagent enabled additions to aldehydes
to proceed smoothly to generate (Z)-allylic alcohols.46 Using
this method, a variety of racemic (Z)-allylic alcohols were
prepared in high yields. Additions of (Z)-vinyl groups to
enantioenriched protected R- and â-hydroxy aldehydes resulted
in formation of (Z)-allylic alcohols with high diastereoselec-
tivity.46 Unfortunately, attempts at enantioselective versions of
this transformation afforded only racemic products.
would require trans hydrometalations, which are rarely ob-
served.39,40 One direct (Z)-vinylation of aldehydes has been
reported involving the Nozaki-Hiyama-Kishi reaction with
(Z)-vinyl halides. The only (Z)-vinyl halide in this study,
however, underwent addition with 30% enantioselectivity.41
Progress toward the generation of enantioenriched (Z)-dienyl
alcohols has recently been reported by the Krische group36
employing acetylene, hydrogen, and an aldehyde or R-ketoester
in the presence of a rhodium catalyst (Scheme 3). Preliminary
studies directed toward enantioselective versions of this dieny-
lation reaction are promising.
We have been interested in the development and applications
of vinyl organometallic reagents that enable the construction
of di- and trisubstituted olefins and allylic alcohols.8-10,13,15,19,29,30,42
Synthons for these species are shown in Figure 1. The synthon
for the (E)-disubstituted vinyl groups represented in Scheme 2
(A, Figure 1) is readily derived from hydrometalation of terminal
alkynes. A synthon for a (Z)-di- or trisubstituted vinyl group
(Figure 1, B), on the other hand, contains two reactive positions,
a nucleophilic site cis to R1 and an electrophilic site trans to
R1.43-45 For generation of (Z)-disubstituted allylic alcohols, the
nucleophilic reagent added to the electrophilic site is a hydride.
In the development of reagents for synthon B, it is critical that
the double bond stereochemistry be preserved during bond-
forming processes.
We now disclose the first general and direct catalytic
asymmetric synthesis of (Z)-allylic alcohols. The application
of this method to the one-pot preparation of highly function-
alized epoxy alcohols and allylic epoxy alcohols is also
demonstrated. These reactions lead to a rapid increase in
molecular complexity and enable the synthesis of highly
functionalized chiral building blocks.
Experimental Section
General Methods. All reactions were performed under a nitrogen
atmosphere with oven-dried glassware using standard Schlenk or
vacuum line techniques. The progress of all reactions was monitored
by thin-layer chromatography which was performed on Whatman
precoated silica gel 60 K6F plates and visualized by ultraviolet light
or by staining with phosphomolybdic acid. t-BuOMe was distilled from
Na/benzophenone and hexanes was dried through alumina columns.
(42) Chen, Y. K.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 3702-3703.
(43) Kocienski, P.; Barber, C. Pure Appl. Chem. 1990, 62, 1933-1940.
(44) Kocienski, P., Klein, W., Eds.; Wieweg, 1993; p 203.
(45) Shibli, A.; Varghese, J. P.; Knochel, P.; Marek, I. Synlett 2001, 818-820.
(46) Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc.
2006, 128, 9618-9619.
Figure 1. Synthon A represents (E)-disubstituted vinyl organometallics,
while synthon B represents (Z)-di- or trisubstituted reagents.
(47) Corey, E. J.; Albonico, S. M.; Koelliker, U.; Schaaf, T. K.; Varma, R. K.
J. Am. Chem. Soc. 1971, 93, 1491-1493.
(48) Campbell, J. B. J.; Molander, G. A. J. Organomet. Chem. 1978, 156, 71-
79.
(39) Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000, 122,
4990-4991.
(40) Alexakis, A.; Duffault, J. M. Tetrahedron Lett. 1988, 29, 6243-6246.
(41) Wan, Z.-K.; Choi, H.-w.; Kang, F.-A.; Nakajima, K.; Demeke, D.; Kishi,
Y. Org. Lett. 2002, 4, 4431-4434.
(49) Zweifel, G.; Arzoumanian, H. J. Am. Chem. Soc. 1967, 89, 5086-5088.
(50) Negishi, E.; Yoshida, T. J. Chem. Soc., Chem. Commun. 1973, 606-607.
(51) Negishi, E.; Williams, R. M.; Lew, G.; Yoshida, T. J. Organomet. Chem.
1975, 92, C4-C6.
(52) Brown, H. C.; Imai, T.; Bhat, N. G. J. Org. Chem. 1986, 51, 5277-5282.
9
16120 J. AM. CHEM. SOC. VOL. 129, NO. 51, 2007

Generation of (Z)-Disubstituted Allylic Alcohols
A R T I C L E S
Scheme 3. Generation of (Z)-Dienyl Alcohols and Proposed Intermediates by Krische and Co-Workers
Scheme 4. Our Stereospecific Method for the Synthesis of (Z)-Allylic Alcohols
Tetraethylethylenediamine (TEEDA) was distilled and stored under
nitrogen. The 1H NMR and 13C{1H} NMR spectra were obtained on a
Bru¨ker AM-500 Fourier transform NMR spectrometer at 500 and 125
under reduced pressure. The crude product was purified by column
chromatography on silica gel (hexanes/EtOAc, 95:5) to give 3ac (83.8
mg, 61% yield) as an oil: ee was determined by HPLC equipped with
a Chiralcel AD-H column (hexanes/2-propanol, 99:1; flow rate 0.5 mL/
1
MHz, respectively. H NMR spectra were referenced to tetramethyl-
min), tR(1) ) 38.2 min, tR(2) ) 44.6 min; [R]20 ) +131.11 (c )
silane in CDCl3 or residual protonated solvent; 13C{1H} NMR spectra
were referenced to residual solvent. Analysis of the enantiomeric excess
was performed using a Hewlett-Packard 1100 Series HPLC and a chiral
column specific for each compound. The optical rotations were recorded
using a JASCO DIP-370. Infrared spectra were obtained using a Perkin-
Elmer Spectrum 100 series spectrometer. All reagents were purchased
from Aldrich or Acros unless otherwise described. 1-Bromo-1-alkynes53
and 1-chloro-1-alkynes54 were made according to a known procedure.
All commercially available aldehyde substrates were distilled prior to
use. Silica gel (Silicaflash P60, 40-63 µm, Silicycle) was used for
air-flashed chromatography, and deactivated silica gel was prepared
by addition of 15 mL of NEt3 to 1 L of silica gel. Complete experimental
procedures and characterization are located in the Supporting Informa-
tion.
D
1
0.001, CHCl3, 95% ee); H NMR (CDCl3, 500 MHz) δ 1.12 (s, 9H),
2,20 (br, 1H), 2.45-2.51 (m, 1H), 2.58-2.65 (m, 1H), 3.73-3.80 (m,
2H), 5.50-5.51 (dd, J ) 1.9, 8.0 Hz, 1H), 5.60-5.67 (dt, J ) 7.8,
11.2 Hz, 1H), 5.77-5.81 (dd, J ) 8.5, 10.9 Hz, 1H), 7.40 (m 10H),
7.71 (m, 5H) ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ 19.4, 27.1,
31.4, 63.5, 69.9, 126.1, 127.6, 127.9, 128.7, 128.8, 129.9, 133.8, 134.5,
135.8, 143.7 ppm; IR (neat) 3369, 3069, 2931, 1958, 1890, 1824, 1656,
1589, 1472, 1427, 1389 cm-1; HRMS m/z calcd for C27H32NaO2Si (M
+ Na)+ 439.2069, found 439.2054.
The number of peaks in 13C NMR reflects the fact that the two phenyl
groups attached to silicon are too far from the stereocenter to be seen
as diastereotopic; thus, only four signals are present for those two phenyl
groups.
Caution. Dialkylzinc reagents and t-BuLi are pyrophoric. Care must
Asymmetric Addition/Diastereoselective Epoxidation Reactions.
Preparation of [3-(4-Chlorobutyl)oxiranyl]phenylmethanol (4cc).
Dicyclohexylborane (88 mg, 0.5 mmol) was weighed into a Schlenk
flask under nitrogen, and dry t-BuOMe (1 mL) was added. 1,6-Dichloro-
hex-1-yne (66 µL, 0.5 mmol) was then added slowly to the reaction
mixture at 0 °C. After 15 min, the solution was warmed to room
temperature and stirred for 45 min. t-BuLi (0.37 mL, 0.55 mmol, 1.5
M pentane solution) was added dropwise at -78 °C and the solution
stirred for 60 min. The reaction mixture was then warmed to room
temperature and stirred for an additional 60 min. During this time, a
white precipitate formed. Diethylzinc (0.28 mL, 0.55 mmol, 2 M
hexanes solution) was slowly added to the reaction mixture at -78 °C
and the solution stirred for 20 min. Addition of TEEDA (14 µL, 0.066
mmol) and hexanes (4 mL) was performed at -78 °C and the solution
warmed to 0 °C. Addition of (-)-MIB (166 µL, 0.017 mmol, 0.1 M
hexanes solution) was followed by addition of benzaldehyde (34 µL,
0.332 mmol). The reaction mixture was then slowly warmed to room
temperature and stirred for 16 h. After the reaction was complete by
TLC analysis, the temperature was brought to -20 °C and ZnEt2 (0.28
mL, 0.55 mmol, 2 M solution in hexanes) was added. The reaction
was stirred for 30 min, and then TBHP (tert-butyl hydroperoxide; 0.30
mL, 1.68 mmol, 5.5 M solution in decane) was added. After an
additional 30 min at -20 °C, Ti(O-i-Pr)4 (48 µL, 0.067 mmol, 1.4 M
solution in hexanes) was added and the mixture stirred until the allylic
alkoxide had been consumed (TLC, ∼16 h). The reaction mixture was
then quenched with 2 mL of saturated aqueous NH4Cl, stirred for 30
be used when handling solutions of these reagents.
Synthesis of (Z)-Disubstituted Allylic Alcohols. Preparation of
(Z)-5-(tert-Butyldiphenylsilanyloxy)-1-phenylpent-2-en-1-ol (3ac).
Dicyclohexylborane (88 mg, 0.5 mmol) was weighed into a Schlenk
flask under nitrogen, and dry t-BuOMe (1 mL) was added. tert-Butyl-
(4-chlorobut-3-ynyloxy)diphenylsilane (1a; 160 µL, 0.5 mmol) was then
added slowly to the reaction mixture at 0 °C. After 15 min, the solution
was warmed to room temperature and stirred for 45 min, resulting in
a clear solution. t-BuLi (0.37 mL, 0.55 mmol, 1.5 M pentane solution)
was added dropwise at -78 °C and stirred for 60 min before the solution
was warmed to room temperature and stirred for 60 min. During this
time, a precipitate, presumably LiCl, formed. Diethylzinc (0.28 mL,
0.55 mmol, 2 M hexanes solution) was slowly added to the reaction
mixture at -78 °C, and the solution was stirred for 20 min. Next,
TEEDA (14 µL, 0.066 mmol) and hexanes (4 mL) were added at
-78 °C, the solution was warmed to 0 °C, and (-)-MIB (166 µL,
0.017 mmol, 0.1 M hexanes solution) and benzaldehyde (34 µL, 0.33
mmol) were added. The reaction was then slowly warmed to room
temperature and stirred for 16 h. After the reaction was complete by
TLC analysis, the mixture was diluted with 3 mL of hexanes and
quenched with H2O. The organic layer was separated, and the aqueous
solution was extracted with EtOAc (2 × 10 mL). The combined organic
layer was dried over MgSO4 and filtered, and the solvent was removed
(53) Leroy, J. Org. Synth. 1997, 74, 212-216.
(54) Murray, R. E. Synth. Commun. 1980, 10, 345-349.
9
J. AM. CHEM. SOC. VOL. 129, NO. 51, 2007 16121

A R T I C L E S
Salvi et al.
Scheme 5. Optimization of the Catalytic Asymmetric Generation of (Z)-Allylic Alcohols
Scheme 6. Asymmetric Arylation of Aldehydes with TEEDA To Inhibit LiCl
Table 1. Enantioselective Addition of (Z)-Vinylzinc Reagents to
Aldehydes in the Presence of Various Inhibitors (Scheme 5)
min at room temperature, and quenched with an aqueous solution of
Na2S2O3. The organic and aqueous layers were separated, and the
aqueous layer was extracted with diethyl ether (3 × 5 mL). The
combined organic layers were then washed with 5 mL of brine and 5
mL of H2O, dried over MgSO4, and filtered. The filtrate was collected
and concentrated in vacuo, and the crude product was purified by
column chromatography on deactivated silica gel (hexanes/EtOAc, 90:
10) to give 4cc (53.6 mg, 67% yield) as an oil: [R]2D0 ) +56.03 (c )
additive
ee
entry
(concn, mol %)
X
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
DiMPEG (5.5)
DiMPEG (6)
DiMPEG (6.5)
DiMPEG (7)
tetraglyme (90)
tetraglyme (110)
tetraglyme (220)
TEEDA (20)
TEEDA (20)
none
TEEDA (10)
TEEDA (15)
TEEDA (20)
TEEDA (25)
TEEDA (30)
TEEDA (40)
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
75
79
86
80
10
26
5
10
10
0
82
89
90
90
90
45
1
0.041, CHCl3); H NMR (CDCl3, 500 MHz) δ 1.64 (m, 6H), 2.46 (d,
J ) 2.9 Hz, 1H), 3.1 (m, 1H), 3.20 (dd, J ) 4.4, 8.4 Hz, 1H), 3.56 (t,
J ) 6.8 Hz, 2H), 4.58 (dd, J ) 2.8, 8.0 Hz, 1H), 7.31 (m, 5H) ppm;
13C{1H} NMR (CDCl3, 125 MHz) δ 24.5, 28.0, 32.3, 44.9, 58.3, 61.4,
72.5, 126.4, 128.6, 129.0, 140.1 ppm; IR (neat) 3419, 3062, 3031, 2955,
2866, 1807, 1604, 1492, 1454, 1278, 1195, 1040 cm-1; HRMS m/z
calcd for C13H16OCl (M - OH)+ 223.08897, found 223.08883. Analysis
1
of the diastereomeric ratio was performed by H NMR spectroscopy.
Results and Discussion
reaction to proceed via the ligand-accelerated59 Lewis acid-
catalyzed pathway.60
When our (Z)-vinylation of aldehydes (Scheme 4) was
conducted in the presence of the amino alcohol-based catalyst
derived from (-)-MIB,55,56 the (Z)-allylic alcohol product was
isolated in good yields, but the product was found to be racemic.
This was surprising because the zinc-based catalyst derived from
(-)-MIB is one of the most efficient and enantioselective amino
alcohol-based catalysts known for carbonyl additions. The
absence of enantioselectivity was attributed to the rapid addition
reaction promoted by the liberated Lewis acid byproduct, LiBr
(Scheme 4). Rather than attempt to remove the LiBr byproduct
by filtration57 or centrifugation,58 which would be impractical
on a large scale, we decided to deactivate it.
To suppress the LiBr-promoted vinyl addition to aldehydes,
we employed DiMPEG as an inhibitor (Scheme 5). Addition
of 5-7 mol % DiMPEG (MW 2000) proved most effective,
with enantioselectivities in the (Z)-vinylation reaching 86%
(Table 1, entries 1-4). Although this result was exciting and
promising, we found that the reactions were very sensitive to
the concentration (mol %) of DiMPEG and enantioselectivities
were difficult to reproduce. Tetraglyme was used as a DiMPEG
analogue but was significantly less effective at inhibiting LiBr
(Table 1, entries 5-7). After significant effort to identify reliable
polyether inhibitors, this strategy was abandoned.
Our first attempts to inhibit the salt byproduct were based
on observations reported by Bolm. In a study involving the
addition of Ph2Zn to aldehydes, Bolm and co-workers empha-
sized the beneficial effect of dimethoxypoly(ethylene glycol)
(DiMPEG) on the reaction enantioselectivity.57 They proposed
that DiMPEG suppressed reactions catalyzed by trace achiral
Lewis acids, including LiBr, allowing most of the arylation
Instead, we turned to a diamine inhibitor that we had
successfully used to solve a similar problem in our development
of the first highly enantioselective one-pot asymmetric synthesis
of enantioenriched diarylmethanols beginning from aryl bro-
mides (Scheme 6).61 Like the vinylation in Scheme 4, initial
attempts at the asymmetric arylation reactions also resulted in
formation of essentially racemic products. In the transmetalation
(55) Chen, Y. K.; Jeon, S. J.; Walsh, P. J.; Nugent, W. A. Org. Synth. 2005,
82, 87-92.
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(57) Rudolph, J.; Hermanns, N.; Bolm, C. J. Org. Chem. 2004, 69, 3997-4000.
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1995, 34, 1059-1070.
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9
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Generation of (Z)-Disubstituted Allylic Alcohols
A R T I C L E S
(Table 1, entries 10-16). The highest enantioselectivities were
obtained with 20-30 mol % TEEDA. Further increases in the
concentration (mol %) of diamine caused a decrease in both
enantioselectivity and yield. This observation is likely due to
inhibition of the chiral zinc-based catalyst by the diamine,
allowing the uncatalyzed background reaction to become
competitive with the catalyzed addition, eroding the product
ee. Note that less than 1 equiv of diamine/equiv of LiCl is
needed. Much of the LiCl precipitates from solution and is not
active in promoting the addition reaction.
Figure 2. Possible structure of the coordinatively saturated TEEDA adduct
of LiCl.
reactions used to generate the aryl group donor, Ar-Zn(n-Bu),
over 4 equiv of LiCl was formed. As seen in the vinylation
reactions, this Lewis acidic byproduct was significantly faster
at promoting the aryl addition to provide diarylmethanols than
the chiral amino alcohol-based catalyst, resulting in formation
of racemic product. Another possible mechanism for the LiCl
accelerated addition to aldehydes is via formation of a more
reactive zincate by interaction of the LiCl with the organozinc
to generate R2ZnCl-Li+.45,62 Although this mechanism cannot
be ruled out at this time, we favor the Lewis acid activation of
the aldehyde on the basis of the results in the following
paragraph.
The key to our successful development of an asymmetric
arylation system was inhibition of the LiCl byproduct with
TEEDA. The diamine is believed to chelate the LiCl to form a
chloride-bridged dimer, [(TEEDA)LiCl]2, that is coordinatively
saturated and catalytically inactive (Figure 2).63,64 Using this
technique, the racemic background reaction was completely
suppressed, resulting in formation of diarylmethanols with
enantioselectivities as high as 97%.
When our diamine-based strategy in Scheme 6 was applied
to the synthesis of (Z)-allylic alcohols in Scheme 5, enantiose-
lectivities peaked at 10% under our best conditions (Table 1,
entries 8 and 9). These results suggested to us that inhibition
of LiBr would be significantly different from inhibition of LiCl.
We speculate that the bromide analogues of [(TEEDA)LiCl]n
(Figure 2) dissociate more readily to generate an open coordina-
tion site capable of aldehyde activation. Rather than search for
a new inhibitor for LiBr, we chose to examine 1-chloro-1-
alkynes in this process, which would generate LiCl.
Examination of 1-chloro-1-alkynes was approached in a
fashion similar to that of the optimization of 1-bromo-1-alkynes.
When 1-bromo-1-alkynes were employed in our previous study46
(Scheme 4), we found it necessary to perform the addition of
t-BuLi in THF. A solvent switch was then needed, because the
vinylzinc addition proceeds in low yield in THF. Using the
1-chloro-1-alkynes, however, the entire reaction could be
performed in t-BuOMe solvent, without the need to switch
solvents. Hydroboration of 1-chloro-1-alkynes (1.5 equiv) with
Cy2BH (1.5 equiv) proceeded in 1 h at 0 °C to room temperature
with excellent regioselectivity. Reaction of the resulting 1-chloro-
1-vinylborane with t-BuLi (1.65 equiv) occurred with inversion
at the vinylic center, generating the (Z)-vinylborane. Trans-
metalation with diethylzinc (1.65 equiv) and addition to an
aldehyde (1 equiv) in the presence of the (-)-MIB-based catalyst
provided the racemic allylic alcohol. Repeating the sequence
with the addition of increasing amounts of TEEDA resulted in
the formation of enantioenriched (Z)-allylic alcohol products
With the optimized conditions in Table 1, we examined the
scope of the asymmetric vinylation (Table 2). Employing 20-
30 mol % TEEDA, a variety of 1-chloro-1-alkynes and
aldehydes underwent the addition in good yields (61-93%,
based on aldehyde as the limiting reagent) and good to excellent
enantioselectivities (75-98%). 1-Chloro-1-alkynes bearing a
TBDPS-protected alcohol (entries 1-6), alkyl (entries 7 and
8), chloroalkyl (entries 9-16), or phenyl (entries 17 and 18)
group were successfully employed in the asymmetric vinylation
reaction. Although aliphatic aldehydes with R-branching un-
derwent addition with high enantioselectivity (84-90%, entries
1, 8, and 11), â-branched isovaleraldehyde was a more chal-
lenging substrate, undergoing addition with 76% enantioselec-
tivity (entry 2). Likewise, dihydrocinnamaldehyde underwent
addition with 75% enantioselectivity (entry 6). R,â-Unsaturated
aldehydes reacted to form dienols with 88-94% enantioselec-
tivity (entries 15 and 16). Aryl aldehydes were also good
substrates for the vinylation reaction, providing benzylic alcohols
with enantioselectivities between 86% and 98%. The electron-
withdrawing trifluoromethylbenzaldehyde exhibited the lowest
enantioselectivity of this class of substrates, possibly due to an
earlier transition state with less bond formation and reduced
steric bias (entry 12). The heterocyclic aldehyde, 2-thiophen-
ecarboxaldehyde, proved to be an excellent substrate for (Z)-
vinylations proceeding in 92-94% enantioselectivity (entries
5, 10, and 18). This route to thiophene-containing allylic alcohols
avoids potential problems with catalyst poisoning that can arise
inhydrogenationofthiophene-containingpropargylicalcohols.65-70
Beyond catalyst poisoning, over-reduction and contamination
with the undesired (E)-isomer have been reported to be
problematic.70 Similarly, the alkyne-bearing product in entry 4
would be difficult to prepare by selective Lindlar reduction.
Important in the development of practical methods with
potential utility in target-oriented synthesis is the evaluation of
scalability. With this in mind, we examined the substrate
combination in entry 14 using 5.0 mmol of the aldehyde. The
desired (Z)-allylic alcohol was obtained in 79% yield at this
scale with 96% ee. The high yield and enantioselectivity in this
reaction bode well for large-scale applications of these asym-
metric addition reactions.
Having developed a viable method for the catalytic asym-
metric synthesis of (Z)-disubstituted allylic alcohols, we wanted
to briefly examine the potential application of this process in
(65) Rylander, P. N. Catalytic Hydrogenation OVer Platinum Metal; Academic
Press: New York, 1967; p 22.
(66) Freifelder, M. Catalytic Hydrogenation in Organic Synthesis: Procedures
and Commentary; John Wiley & Sons: New York, 1978; p 184.
(67) Belen’kii, L. I.; Gol’dfarb, Y. L. In Thiophene and Its DeriVatiVes, The
Chemistry of Heterocyclic Compounds; Gronowitz, S., Ed.; John Wiley &
Son: New York, 1985; Vol. 44, Part 1, p 465.
(68) Maxted, E. B.; Evans, H. C. J. Chem. Soc. 1937, 603-606.
(69) Bateman, L.; Shipley, F. W. J. Chem. Soc. 1958, 2888-2890.
(70) de Sousa, P. T., Jr.; Taylor, R. J. K. J. Braz. Chem. Soc. 1993, 4, 64-68.
(62) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J.-F. Tetrahedron 1994,
50, 11665-11692.
(63) Chitsaz, S.; Pauls, J.; Neumuller, B. Z. Naturforsch., B 2001, 56, 245-
248.
(64) Hoffmann, D.; Dorigo, A.; Schleyer, P. v. R.; Reif, H.; Stalke, D.; Sheldrick,
G. M.; Weiss, E.; Geissler, M. Inorg. Chem. 1995, 34, 262-269.
9
J. AM. CHEM. SOC. VOL. 129, NO. 51, 2007 16123

A R T I C L E S
Salvi et al.
Scheme 7. Tandem Asymmetric Addition/Diastereoselective
Table 2. Scope of the Catalytic Asymmetric Synthesis of
(Z)-Allylic Alcohols
Epoxidation
Scheme 8. Epoxidation of the Isolated Allylic Alcohol with
VO(acac)2/TBHP and mCPBA
enals8-10 followed by diastereoselective epoxidation of the
resulting allylic alkoxide to provide epoxy alcohols with up to
three contiguous stereogenic centers. The oxidant in the epoxi-
dation was a zinc peroxide generated upon reaction of either
TBHP or dioxygen with dialkylzinc reagents. Adaptation of our
addition/epoxidation method to the (Z)-vinylation reagents is
illustrated in Scheme 7. Initially we were concerned that the
reaction would be hampered by the presence of the TEEDA,
due to its known coordination to titanium alkoxides73 or
oxidation to the N-oxide, as was observed in KR of racemic
â-amino alcohols by Sharpless.74 Fortunately, these side reac-
tions did not interfere with the epoxidation.
The generation of the allylic zinc alkoxide was performed as
outlined in Scheme 5. Rather than addition of water to quench
the allylic alkoxide intermediate, however, 1.65 equiv of
diethylzinc was injected into the flask. Dropwise addition of a
5.5 M solution of TBHP in decane was then followed by
titanium tetraisopropoxide (20 mol %). The epoxidations were
conducted at -20 °C and stirred for 24 h before workup. The
crude epoxy alcohols were chromatographed and isolated in 52-
67% yield with excellent dr (19:1 in each case, Scheme 7).
To aid in the assignment of the relative stereochemistry in
the epoxy alcohol products in Scheme 7, we examined the
diastereoselective epoxidation of an isolated allylic alcohol with
the complementary epoxidizing agents mCPBA and VO(acac)2/
TBHP (Scheme 8). It is well-known that VO(acac)2/TBHP
exhibits high diastereoselectivity with allylic alcohols that
possess A1,2 strain in one of the diastereomeric epoxidation
transition states. In contrast, mCPBA is known to be epoxidized
with high diastereoselectivity when allylic alcohols lead to A1,3
strain in one of the diastereomeric epoxidation transition states.3
Subjecting the preformed allylic alcohol in Scheme 8 to the
a Yields based on aldehyde as the limiting reagent.
tandem addition/epoxidation reactions. We recently developed
methods for tandem asymmetric alkylation of enones71,72 and
(73) Larsen, A. O.; White, P. S.; Gagne´, M. R. Inorg. Chem. 1999, 38, 4824-
(71) Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544-9545.
(72) Jeon, S.-J.; Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 16416-
16425.
4828.
(74) Miyano, S.; Lu, L. D. L.; Viti, S. M.; Sharpless, K. B. J. Org. Chem. 1985,
50, 4350-4360.
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16124 J. AM. CHEM. SOC. VOL. 129, NO. 51, 2007

Generation of (Z)-Disubstituted Allylic Alcohols
A R T I C L E S
Scheme 9. Tandem Asymmetric Addition/Diastereo- and Chemoselective Epoxidation
typical epoxidation conditions with VO(acac)2/TBHP and
mCPBA afforded the epoxy alcohols with 2.5:1 and 10:1 dr,
respectively. The mCPBA epoxidation resulted in high stereo-
selectivity and formed the same diastereomer as our one-pot
addition/epoxidation procedure. This observation indicates that
the syn diastereomer is formed in the tandem reaction, as shown
in Scheme 7. Furthermore, the stereochemistry of 4dc was
assigned by derivatization with (-)-camphanic acid chloride
to afford the expected ester, which was characterized by X-ray
crystallography (see the Supporting Information).
Having demonstrated that the epoxidation of the (Z)-allylic
alkoxide could be performed in the tandem addition/epoxidation
reaction, we wanted to explore the preferential epoxidation of
a more substituted double bond in the presence of the (Z)-vinyl
group. Thus, addition of the (Z)-vinylzinc reagent to cyclohex-
enecarboxaldehyde generated the intermediate dienyl alkoxide,
which was subsequently exposed to zinc peroxide and titanium
tetraisopropoxide to furnish the allylic epoxy alcohol derived
from oxidation of the more electron rich trisubstituted double
bond in 52% yield with 94% ee and 19:1 dr. The results in
Schemes 7 and 9 highlight a unique feature of this epoxidation
system: the ability to perform highly diastereoselective epoxi-
dations with either A1,2 or A1,3 strain in one of the diastereomeric
epoxidation transition states.10 In contrast, low diastereoselec-
tivity is observed with mCPBA when selectivity is dependent
on A1,2 strain in one of the diastereomeric transition states and
with VO(acac)2/THBP or Ti(Oi-Pr)4/TBHP when selectivity is
dependent on A1,3 strain.3
1-chloro-1-alkynes, hydroboration, addition of t-BuLi, and
transmetalation to zinc affords (Z)-vinylzinc intermediates. The
resulting (Z)-vinylzinc reagents undergo addition to aldehydes
with high enantioselectivity in the presence of a zinc-based
catalyst derived from (-)MIB. A variety of enantioenriched (Z)-
allylic alcohols can be accessed in this simple one-pot procedure,
including some that would be difficult to prepare using Lindlar
hydrogenations of enantioenriched propargylic alcohols due to
catalyst poisoning or functional group incompatibility.
Furthermore, we have found the conditions for the (Z)-
vinylation of aldehydes are compatible with our diastereose-
lective epoxidation procedure, allowing access to epoxy alcohols
and allylic epoxy alcohols with three contiguous stereogenic
centers with high ee and dr. Previous methods to prepare such
compounds required several synthetic steps and purifications.
Using the procedures introduced herein, such compounds can
be readily synthesized in a single flask without isolation or
purification of intermediates.
Given the rapid increase in molecular complexity with a
defined stereochemical outcome, we anticipate that these
methods will be very useful in enantioselective synthesis.
Acknowledgment. We thank the NSF (Grant CHE-065210)
and NIH (National Institute of General Medical Sciences Grant
GM58101) for partial support of this work. We are also grateful
to Akzo Nobel Polymer Chemicals for a gift of dialkylzinc
reagents.
Supporting Information Available: Procedures, full charac-
terization, and stereochemical assignments of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Outlook and Conclusions
Herein we have presented the first general highly enantiose-
lective addition of (Z)-vinyl groups to aldehydes to afford
enantioenriched (Z)-allylic alcohols. Employing readily available
JA0762285
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