One-pot asymmetric synthesis of acyclic chiral epoxy alcohols via tandem vinylation - Epoxidation with dioxygen

Article abstract of DOI:10.1021/jo048345d

(Chemical Equation Presented) We have developed a one-pot procedure for the asymmetric synthesis of a synthetically challenging class of acylic secondary epoxy alcohols with three contiguous stereocenters from simple achiral starting materials. The epoxy alcohols are synthesized via a tandem catalytic asymmetric vinylation of an aldehyde coupled with a diastereoselective epoxidation reaction. A vinylzinc reagent generated in situ undergoes enantioselective addition to an aldehyde in the presence of a zinc catalyst to provide an allylic zinc alkoxide. This species is then epoxidized by addition of dioxygen and a titanium tartrate catalyst to give epoxy alcohols with excellent enantioselectivities, in most cases, and with diastereoselectivities up to 4.5:1 in favor of the threo-diastereomer. The system described herein represents a significant advance in terms of synthetic efficiency and selectivity.

Full text of DOI:10.1021/jo048345d

One-Pot Asymmetric Synthesis of Acyclic Chiral Epoxy Alcohols
via Tandem Vinylation-Epoxidation with Dioxygen
Alice E. Lurain, Patrick J. Carroll, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
231 South 34th Street, Philadelphia, Pennsylvania 19104-6323
pwalsh@sas.upenn.edu
Received September 17, 2004
We have developed a one-pot procedure for the asymmetric synthesis of a synthetically challenging
class of acylic secondary epoxy alcohols with three contiguous stereocenters from simple achiral
starting materials. The epoxy alcohols are synthesized via a tandem catalytic asymmetric vinylation
of an aldehyde coupled with a diastereoselective epoxidation reaction. A vinylzinc reagent generated
in situ undergoes enantioselective addition to an aldehyde in the presence of a zinc catalyst to
provide an allylic zinc alkoxide. This species is then epoxidized by addition of dioxygen and a
titanium tartrate catalyst to give epoxy alcohols with excellent enantioselectivities, in most cases,
and with diastereoselectivities up to 4.5:1 in favor of the threo-diastereomer. The system described
herein represents a significant advance in terms of synthetic efficiency and selectivity.
SCHEME 1. Sharpless Asymmetric Epoxidation
Introduction
Chiral epoxy alcohols are versatile synthetic building
blocks that have found extensive utility in natural
product synthesis, particularly due to their potential for
undergoing regioselective ring-opening reactions.1,2 Much
effort has been directed, therefore, toward the develop-
ment of methods for the regio- and stereoselective
construction of this class of compounds.3,4 Chiral epoxy
alcohols are typically synthesized by selective epoxidation
of the corresponding allylic alcohols, a process which can
take place under reagent control, in the case of achiral
allylic alcohols,4 or under substrate control, in the case
of chiral allylic alcohols.5
The Sharpless asymmetric epoxidation reaction, using
catalytic titanium tetraisopropoxide, tartrate ester ligands,
and tert-butyl hydroperoxide (TBHP) in the presence of
4 Å molecular sieves is the premier method for the
construction of epoxy alcohols from achiral substrates
(Scheme 1).6-10 This methodology exhibits high enanti-
oselectivity for a range of structurally diverse achiral
allylic alcohols and has been successfully employed in
many natural product syntheses, as well as in the
preparation of numerous small molecules and chiral
building blocks.4
In contrast to the synthesis of epoxy alcohols from
achiral allylic alcohols, the direct synthesis of epoxy
alcohols containing a stereogenic center at the carbanol
carbon from achiral reagents requires that three contigu-
ous stereocenters be established with high enantio- and
diastereoselectivity. This transformation, therefore, is
typically performed in a multistep procedure involving
synthesis of a secondary allylic alcohol with high en-
antioselectivity, or racemic synthesis and resolution of
(6) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-
5976.
(1) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-299.
(2) Bonini, D.; Righib, G. Tetrahedron 2002, 58, 4981-5021.
(3) Methods of Organic Chemistry; Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; Thieme: New York, 1995; Vol. E.
(4) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993.
(7) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922-
1925.
(8) Klunder, J. M.; Ko, S. Y.; Sharpless, K. B. J. Org. Chem. 1986,
51, 3710-3712.
(9) Rossiter, B. E.; Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc.
1981, 103, 464-465.
(5) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307-1370.
(10) Burns, C. J.; Martin, C. A.; Sharpless, K. B. J. Org. Chem. 1989,
54, 2826-2834.
10.1021/jo048345d CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/19/2005
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J. Org. Chem. 2005, 70, 1262-1268

Asymmetric Synthesis of Acyclic Epoxy Alcohols
the allylic alcohol, followed by a directed epoxidation
reaction. The epoxidation of chiral secondary allylic
alcohols is generally carried out using an organic peracid,
such as mCPBA, or with a transition-metal catalyst in
combination with a stoichiometric oxidant.5
the substituent at the stereogenic center (R1) in the
transition state. Therefore, the preferred diastereomer
of the product epoxy alcohol and the extent to which it
dominates may differ for a given allylic alcohol substrate,
depending upon the epoxidizing agent used. For any
given epoxidizing agent, the favored diastereomer is
dictated by the substitution pattern of the allylic alcohol,
which determines whether A1,2 or A1,3 strain is the
dominant steric interaction in the transition state. As
illustrated in Scheme 2, there is no strong steric bias
disfavoring formation of either the threo- or erythro-epoxy
alcohol in the case of E-disubstituted olefins (where R2
and R3 ) H), and we are unaware of general substrate-
directed methods for the synthesis of chiral epoxy alco-
hols derived from these substrates with high diastereo-
selectivity. Epoxidation with VO(acac)2/TBHP slightly
favors the erythro-product, and Ti(OiPr)4/TBHP and
mCPBA slightly favor the threo-product (entry 4, Table
1).
The diastereoselectivity of the directed epoxidation step
ranges from poor to excellent, depending on the nature
of the allylic alcohol. Good to excellent diastereoselec-
tivities have been achieved with cyclic allylic alcohols and
with acyclic allylic alcohols having substitution on the
olefin such that significant A1,3 or A1,2 strain exists in
one of the diastereomeric transition states (Table 1).
Thus, A1,3 strain encountered in the transition state
leading to the minor diastereomer can result in high
diastereoselectivity for allylic alcohols that are Z-substi-
tuted with respect to the carbanol moiety (entries 1 and
2, Table 1). Likewise, substrates with substitution gemi-
nal to the carbanol group can exhibit A1,2 strain in one
of the diastereomeric transition states and be epoxidized
with high diastereoselectivity (entry 3, Table 1). On the
other hand, allylic alcohols containing disubstituted (E)-
olefins are among the most difficult substrates for
directed epoxidation. In the absence of significant A1,3
and/or A1,2 strain in the diastereomeric transition states,
diastereoselectivities for these substrates are typically
less than 2:1 with both peracid- and transition-metal-
catalyzed epoxidation reactions (entry 4, Table 1).11-16
Sharpless kinetic resolution17-19 of racemic secondary
allylic alcohols with a titanium tartrate catalyst can, in
principle, be used to afford the corresponding chiral epoxy
alcohol products with good selectivity, regardless of the
substitution pattern on the olefin. As with all kinetic
resolutions, however, this approach is limited to a
maximum yield of 50%. The enantioselectivity of the
kinetic resolution is controlled by the difference in the
relative rates of reaction of the two enantiomers of the
allylic alcohol and by the extent of conversion. If the
difference in rate is large enough, and the reaction is
quenched at low conversion, the ee of the epoxy alcohol
can be very high. Diastereoselectivity in the Sharpless
system strongly favors the erythro-product, leading to
erythro:threo ratios as high as 49:1.18,19 As such, it is the
only existing method that achieves high diastereoselec-
tivities in the synthesis of trans-disubstituted erythro-
epoxy alcohols. To our knowledge, no method exists for
achieving high threo selectivity for this class of com-
pounds.
TABLE 1. Diastereomeric Ratios for the Directed
Epoxidation of Chiral Secondary Allylic Alcohols with
Various Oxidizing Agents12
In practice, the Sharpless kinetic resolution is more
often used as a method to isolate resolved allylic alcohols.4
Resolved 2- and 3-Z-substituted allylic alcohol substrates
can then undergo directed epoxidation with an appropri-
ate oxidizing agent. If the product of such a resolution is
an E-disubstituted allylic alcohol, however, obtaining
high diastereoselectivity in a second substrate-directed
epoxidation step remains a challenge for the reasons
outlined above. Under reagent control, using the Sharp-
less system, enantioenriched allylic alcohol substrates of
this type can be epoxidized in good yield and with high
erythro selectivity, but one is still left with the task of
first synthesizing and/or resolving the enantioenriched
allylic alcohol substrates.18,20,21
Proposed transition states illustrating the formation
of the threo- and erythro-epoxy alcohols with peracids and
vanadium or titanium catalysts are depicted in Scheme
2. The peracid is proposed to associate with the allylic
alcohol via hydrogen bonding with a dihedral angle of
approximately 120°, while in the case of vanadium- and
titanium-based peroxide catalysts, the binding of the
allylic alkoxide to the metal is proposed to favor a
dihedral angle of 40-50° and 70-90°, respectively.11 This
dihedral angle determines the spatial relationships be-
tween the substituents on the olefin (R2, R3, and R4) and
We have sought to address the limitations of existing
methods for the enantio- and diastereoselective synthesis
of acyclic epoxy alcohols with three contiguous stereo-
(11) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703-710.
(12) Adam, W.; Corma, A.; Reddy, T. I.; Renz, M. J. Org. Chem. 1997,
62, 3631-3637.
(13) Adam, W.; Alsters, P. L.; Neumann, R.; Saha-Moller, C. R.;
Sloboda-Rozner, D.; Zhang, R. J. Org. Chem. 2003, 68, 1721-1728.
(14) Adam, W.; Kumar, R.; Reddy, T. I.; Renz, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 880-882.
(15) Cui, M.; Adam, W.; Shen, J. H.; Luo, X. M.; Tan, X. J.; Chen,
K. X.; Ji, R. Y.; Jiang, H. L. J. Org. Chem. 2002, 67, 1427-1435.
(16) Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharpless, K. B.;
Michaelson, R. C.; Cutting, J. D. J. Am. Chem. Soc. 1974, 96, 5254-
5255.
(17) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(18) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237-6240.
(19) McKee, B. H.; Kalantar, T. H.; Sharpless, K. B. J. Org. Chem.
1991, 56, 6966-6968.
(20) Roush, W. R.; Brown, R. J. J. Org. Chem. 1983, 48, 5093-5101.
(21) Warmerdam, E. G. J. C.; van den Nieuwendijk, A. M. C. H.;
Brussee, J. Tetrahedron: Asymmetry 1996, 7, 2539-2550.
J. Org. Chem, Vol. 70, No. 4, 2005 1263

Lurain et al.
SCHEME 2. Transition States for the Directed Epoxidation of Chiral Allylic Alcohols via a Peracid or a
Transition-Metal Peroxide
centers by developing a one-pot tandem vinylation-
epoxidation approach to these compounds from simple
achiral starting materials.22 In a separate study on the
addition of diethylzinc to cyclic enones in the presence
of a titanium catalyst, we discovered that exposure of the
newly formed allylic alkoxide to dioxygen led to smooth
epoxidation, providing the corresponding epoxy alcohols
with high enantioselectivity. As would be expected for
cyclic allylic alkoxides, the reaction proceeded with high
diastereoselectivity. We proposed that diethylzinc or an
ethylzinc alkoxide and dioxygen react to give an inter-
mediate zinc peroxide, EtZn(OOEt) or ROZn(OOEt).23-32
In this way, the dialkylzinc reagent acts in the dual roles
of nucleophile and oxidant precursor. Transfer of the
peroxy group to the titanium allylic alkoxide intermediate
provides the activated complex. Intramolecular atom
transfer to the allylic alkoxide and hydrolysis of the
reaction mixture afford the epoxy alcohols.33 Our research
group has also generated acyclic chiral allylic zinc al-
koxides with substitution on the olefin R to the carbanol
carbon or cis to the carbanol via amino alcohol-promoted
asymmetric alkylzinc addition to R,â-unsaturated alde-
hydes or addition of divinylzinc reagents A and B
(Scheme 3) to simple aldehydes. We have shown that
these zinc alkoxide intermediates will undergo directed
epoxidation upon exposure to dioxygen and a catalytic
amount of Ti(OiPr)4.34 As a result of their substitution
patterns, these substrates exhibit A1,2 or A1,3 strain in
one of their two diastereomeric epoxidation transition
states. Therefore, the epoxidation step proceeds with
moderate to high levels of diastereoselectivity.
SCHEME 3. One-Pot Synthesis of 2- and
3-Z-Substituted Epoxy Alcohols
(22) For recent examples of tandem processes using catalytic asym-
metric reactions, see: (a) Zhong, G. Chem. Commun. 2004, 606-607.
(b) Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc.
2004, 126, 5962-5963. (c) Du, H.; Ding, K. Org. Lett. 2003, 5, 1091-
1093. (d) Alexakis, A.; March, S. J. Org. Chem. 2002, 67, 8753-8759.
(e) Alexakis, A.; Croset, K. Org. Lett. 2002, 4, 4147-4149.
(23) Seyferth, D. Organometallics 2001, 20, 2940-2955.
(24) Porter, M. J.; Skidmore, J. Chem. Commun. 2000, 1215-1225.
(25) Lewinski, J.; Ochal, Z.; Bojarski, E.; Tratkiewicz, E.; Justyniak,
I.; Lipkowski, J. Angew. Chem., Int. Ed. 2003, 42, 4643-4646.
(26) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed. Engl.
1996, 35, 1725-1728.
In the present study, we have addressed the enantio-
and diastereoselective synthesis of trans-disubstituted
epoxy alcohols, a class of compounds that cannot be
synthesized via traditional directed epoxidation methods.
Our method begins with in situ generation of a vinylzinc
species via hydroboration of a terminal alkyne, followed
by transmetalation to zinc.35 Asymmetric addition of the
vinylzinc intermediate to an aldehyde in the presence of
Nugent’s morpholino isoborneol ligand36-38 (MIB; Scheme
4) affords the chiral allylic alkoxide intermediate. Replac-
(27) Enders, D.; Kramps, L.; Zhu, J. Tetrahedron: Asymmetry 1998,
9, 3959-3962.
(28) Yu, H.-B.; Zheng, X.-F.; Lin, Z.-M.; Hu, Q.-S.; Huang, W.-S.;
Pu, L. J. Org. Chem. 1999, 64, 8149-8155.
(29) van der Deen, H.; Kellogg, R. M.; Feringa, B. L. Org. Lett. 2000,
2, 1593-1595.
(30) Lewinski, J.; Marciniak, W.; Lipkowski, J.; Justyniak, I. J. Am.
Chem. Soc. 2003, 125, 12698-12699.
(33) Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544-
9545.
(34) Lurain, A. E.; Maestri, A.; Kelly, A. R.; Carroll, P. J.; Walsh,
P. J. J. Am. Chem. Soc. 2004, 126, 13608-13609.
(35) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170-
173.
(31) Yamamoto, K.; Yamamoto, N. Chem. Lett. 1989, 1989, 1149-
1152.
(32) Enders, D.; Zhu, J. Q.; Kramps, L. Liebigs Ann. Chem. 1997,
1101-1113.
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Asymmetric Synthesis of Acyclic Epoxy Alcohols
SCHEME 4. One-Pot Asymmetric Synthesis of Chiral Epoxy Alcohols
TABLE 2. Diastereoselectivities for One-Pot Synthesis
ing the nitrogen atmosphere with dioxygen followed by
addition of a titanium tartrate catalyst promotes clean
and efficient epoxidation of the allylic alkoxide (Scheme
4). In this fashion, epoxy alcohols can be isolated directly
in good to excellent yields without the need to prepare
and isolate the enantioenriched allylic alcohol precursors.
Enantioselectivities are excellent, in most cases, and
diastereoselectivities are moderate, typically ranging
from 3:1 to 4:1 in favor of the threo-diastereomer. In
addition, we are able to use molecular oxygen as the
oxidant in these epoxidations, thereby avoiding the need
to dry or handle TBHP or other peroxides.
of Epoxy Alcohols with Different Catalysts and Catalyst
Loadings
Results and Discussion
In previous work on the synthesis of R- and â-amino
acid derivatives,39,40 we have demonstrated the highly
enantioselective addition of various vinylzinc species to
aromatic and aliphatic aldehydes catalyzed by Nugent’s
MIB ligand.35 In an effort to improve synthetic efficiency
and diastereoselectivity in the formation of epoxy alcohols
derived from secondary E-disubstituted allylic alcohols,
we aimed to combine this asymmetric vinylation protocol
with a selective epoxidation using diethylzinc and dioxy-
gen to generate the stoichiometric oxidant.
In our initial experiments, the asymmetric vinyl ad-
dition reaction was performed by hydroborating a ter-
minal alkyne with Cy2BH, transmetalating it with Et2Zn
at -10 °C, and adding it to an aldehyde in the presence
of (-)-MIB at 0 °C. Upon completion of the vinylation
reaction, as determined by thin-layer chromatography,
dioxygen was introduced by capping the reaction flask
with a balloon containing dioxygen at 0 °C. No epoxida-
tion product was detected, even after warming to room
temperature and stirring for 2 days, indicating that zinc
did not promote the epoxidation reaction under these
conditions.
mixture to dioxygen led cleanly to the epoxy alcohol
product with a diastereomeric ratio (dr) of approximately
2:1. Comparison of the ee’s of the epoxy alcohol products
and the allylic alcohols formed on quenching the alkoxide
intermediates with dilute acid led us to conclude that the
enantioselectivity set in the vinyl addition step was not
eroded during the epoxidation.
After observing the formation of the chiral epoxy
alcohol product in the presence of stoichiometric
Ti(OiPr)4, we investigated the possibility of a catalytic
reaction. It was found that no significant change in
diastereoselectivity occurred at catalyst loadings down
to 20 mol % Ti(OiPr)4 (Table 2). At 10 mol % Ti(OiPr)4, a
slight decrease in dr was observed, along with lower
yields of the epoxy alcohol products. Changing the size
of the alkoxide ligands on titanium by using Ti(OtBu)4
led also to a slight decrease in diastereoselectivity (entry
5, Table 2). When catalytic VO(acac)2 was added to the
vinyl addition reaction mixture, the vanadium species
rapidly changed from green to dark purple, and no
epoxidation product was observed (entry 6, Table 2).
Presumably, the VO(acac)2 was reduced by the orga-
nozinc reagent under these reaction conditions.
Screening of Transition-Metal Catalysts. A series
of transition-metal complexes were then examined to
determine their ability to promote the epoxidation and
their diastereoselectivity. We found that addition of 1
equiv of Ti(OiPr)4 directly after exposing the reaction
(36) Chen, Y. K.; Costa, A. M.; Walsh, P. J. J. Am. Chem. Soc. 2001,
123, 5378-5379.
Screening of Tartrates and Other Chiral and
Achiral Diol Ligands. Given the success of tartrate-
based complexes at promoting both enantio- and diaste-
reoselectivity in the Sharpless epoxidation system with
allylic alcohol substrates, we decided to explore the use
of such ligands with Ti(OiPr)4 and our allylic zinc
(37) Nugent, W. A. Chem. Commun. 1999, 1369-1370.
(38) Rosner, T.; Sears, P. J.; Nugent, W. A.; Blackmond, D. G. Org.
Lett. 2000, 2, 2511-2513.
(39) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002,
124, 12225-12231.
(40) Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 10677-
10683.
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Lurain et al.
TABLE 3. Effects of Different Ligands on
Diastereoselectivity in the One-Pot Epoxy Alcohol
Synthesis
SCHEME 5. Optimized Conditions for Tandem
Asymmetric Vinylation-Epoxidation
dioxygen and addition of a premixed titanium tartrate
complex, the epoxy alcohols were formed in high enan-
tiopurity and with diastereoselectivities ranging from
2.9:1 to 4.5:1 (Scheme 5 and Table 4).
X-ray crystal structures of the minor diastereomer of
epoxy alcohols 19 and 21 in Table 4 (see structures in
the Supporting Information) indicate that the major
diastereomer formed in these reactions is the threo-
diastereomer, and comparison of the 1H NMR spectra for
all other substrates tested showed the predominance of
the threo-diastereomer to be general.
This one-pot method avoids the need to synthesize and
isolate chiral allylic alcohol substrates of high enantiopu-
rity and achieves improved threo diastereoselectivities for
this class of chiral epoxy alcohols, as compared to
substrate-directed epoxidation reactions with Ti(OiPr)4/
TBHP, VO(acac)2/TBHP, and mCPBA. In addition, it
precludes the handling of TBHP or other peroxides by
employing molecular oxygen to generate a peroxide
species in situ. For comparison with the results obtained
in our one-pot system, allylic alcohol 2 (Table 4) was
isolated with 94% ee by working up the allylic alkoxide
intermediate with satd aq NH4Cl solution, and it was
then subjected to substrate-directed epoxidation condi-
tions. Reaction with 1.5 mol % VO(acac)2 and 1.5 equiv
of TBHP resulted in a 1.8:1 erythro:threo ratio of dia-
stereomers. Epoxidations with 1.6 equiv of mCPBA and
with 5 mol % Ti(OiPr)4/2.0 equiv of TBHP both led to a
predominance of the threo-diastereomer in ratios of 1.4:1
and 1.6:1, respectively. In no case was the diastereomeric
ratio in the epoxy alcohol product 16 (Table 4) higher
than the 3.5:1 threo:erythro ratio achieved in our one-
pot reaction. Although diastereoselectivities are not
nearly as high as those obtained with the Sharpless
kinetic resolution, our system represents complimentary
chemistry. We have eliminated the need to synthesize
and isolate the allylic alcohol substrates; yields are not
limited to a maximum of 50%, and our system provides
access to the opposite diastereomer of the epoxy alcohol
products.
A range of simple achiral starting aldehydes and
terminal alkynes can be used successfully in our system.
Electron-rich or -poor aromatic aldehydes with ortho or
para substitution, as well as aliphatic aldehydes with R
or â substitution, give products of high ee. In addition,
the substituent at the propargyl position of the alkyne
can be sterically demanding, as in the case of tert-
butylacetylene, or not, as in the case of 1-hexyne. Straight
chain aliphatic aldehydes give allylic alcohol products
with ee’s around 80%, and we had hoped to observe
enhancement of the ee via kinetic resolution during the
in situ epoxidation. Unfortunately, the difference in the
rates of reaction for the two enantiomers of the allylic
alkoxide intermediate turned out to be too small for such
a kinetic resolution to take place.
alkoxide system. To begin, we stirred a 1:1 mixture of
Ti(OiPr)4 and (+)-diisopropyl tartrate (DIPT) in dichlo-
romethane for 45 min at room temperature and then
removed the solvent and the liberated 2-propanol under
reduced pressure. When the resulting titanium tartrate
catalyst (20 mol % with respect to the allylic alkoxide
intermediate) was redissolved in dichloromethane and
added to the reaction flask containing the allylic zinc
alkoxide at -10 °C under an oxygen atmosphere, epoxi-
dation occurred cleanly, and diastereoselectivity in-
creased to almost 4:1 (entry 3, Table 3). This can be
compared to diastereoselectivities of about 2:1 with
Ti(OiPr)4 in the absence of ligand. Chiral tartrate ligands
(+)-dimethyl tartrate (DMT) and (+)-diethyl tartrate
(DET), bearing smaller alkyl groups, gave lower selectivi-
ties, as did the opposite enantiomer of the isopropyl
derivative, (-)-DIPT (entries 1, 2, and 5, Table 3). Adding
meso-DIPT as an achiral ligand led to lower diastereo-
selectivity than in the case of (+)- or (-)-DIPT (entry 6,
Table 3), and use of (R)- or (S)-BINOL as a chiral ligand
on titanium resulted in only trace amounts of the
epoxidation product (entries 7 and 8, Table 3). When
Ti(OiPr)4 and (+)-DIPT were added directly to the
reaction flask containing the allylic zinc alkoxide inter-
mediate without premixing the catalyst or without
removal of the liberated 2-propanol, lower diastereose-
lectivities were observed. Increasing the premixing time
of the Ti(OiPr)4 and (+)-DIPT, addition of 4 Å molecular
sieves in the premixing process, or increasing the ratio
of tartrate ligand to Ti(OiPr)4 did not improve the ratio
of epoxide diastereomers formed.
Substrate Scope. Ultimately, our best results for the
one-pot synthesis of chiral trans-disubstituted epoxy
alcohols were achieved using 20 mol % Ti(OiPr)4 and 20
mol % (+)-DIPT. These operationally simple reactions
were run using 1.1 equiv of vinylborane, generated from
the in situ hydroboration of a terminal alkyne with
Cy2BH, 3.1 equiv of Et2Zn, 4 mol % (-)-MIB, and 1.0
equiv of aldehyde to form the chiral allylic zinc alkoxide.
Upon capping of the reaction flask with a balloon of
1266 J. Org. Chem., Vol. 70, No. 4, 2005

Asymmetric Synthesis of Acyclic Epoxy Alcohols
TABLE 4. Enantio- and Diastereoselectivities for the One-Pot Asymmetric Synthesis of trans-Disubstituted Epoxy
Alcohols
a Determined by chiral HPLC analysis. b Determined by chiral GC analysis. c Diastereomeric ratio of threo to erythro determined by
1H NMR analysis. d Total isolated yield for both diastereomers.
Conclusions
method involves in situ generation of a vinylzinc reagent
that undergoes enantioselective addition to an aldehyde
in the presence of a zinc catalyst to provide an allylic zinc
alkoxide. This species is then epoxidized by addition of
dioxygen and a titanium tartrate catalyst to give the
threo-diastereomer with up to 4.5:1 diastereselectivity.
In addition to its synthetic efficiency, the catalytic system
reported herein represents the most threo selective
We have introduced a new one-pot catalytic asym-
metric approach to a synthetically challenging class of
acyclic chiral secondary epoxy alcohols containing three
contiguous stereocenters. The reactivity of dialkylzinc
species has been exploited such that these reagents have
served in the same reaction flask as nucleophiles and as
oxidant precursors in conjunction with dioxygen. Our
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Lurain et al.
for 1 h. In a separate 10 mL Schlenk flask (B), 1 mL of
dichloromethane, Ti(OiPr)4 (100 µL, 1.0 M in hexanes), and
(+)-DIPT (21 µL, 0.10 mmol) were combined. After its contents
were stirred at room temperature for 45 min, flask B was
evacuated for 1 h to strip off the solvent. The contents of flask
B were then redissolved in 1 mL of dichloromethane and
stripped again for 1 h. Finally, the contents of flask B were
taken up in 1 mL of dichloromethane and transferred to
reaction flask A. The reaction continued to stir at -10 °C under
an O2 atmosphere for 18 h. It was then quenched with 2 mL
of 15% tartaric acid solution and allowed to stir for 45 min
before the organic and aqueous layers were separated, and the
aqueous layer was extracted with hexanes (3 × 5 mL). The
combined organic layers were then washed with 5 mL of H2O
and dried over MgSO4. The filtrate was concentrated in vacuo,
and the residue was chromatographed on silica (5% ethyl
acetate in hexanes) to afford the title compound in 77% yield
(110 mg, 0.39 mmol). Data for the threo-diastereomer: color-
system for the synthesis of secondary trans-disubstituted
epoxy alcohols. Further study on the nature of the
catalyst and the origin of selectivity in the system
continues in our group.
Experimental Section
General procedures for the synthesis of allylic alcohols and
epoxy alcohols are presented below. Synthesis and full char-
acterization of all compounds are provided in the Supporting
Information.
Caution! Caution should be used when handling organozinc
reagents and exposing them to oxygen.
(S)-1-(2-Bromophenyl)hept-2-en-1-ol (4). General Pro-
cedure A. A 10 mL Schlenk flask was charged with Cy2BH
(98 mg, 0.55 mmol), prepared according to Oppolzer’s proce-
dure,35 and 1.5 mL of hexanes. 1-Hexyne (64 µL, 0.55 mmol)
was added dropwise, and the homogeneous reaction mixture
was stirred for 30 min at room temperature. After the reaction
flask was cooled to -10 °C, (-)-MIB (4.8 mg, 0.02 mmol) was
added, followed by Et2Zn (0.55 mL, 2.0 M) and then o-
bromobenzaldehyde (58 µL, 0.50 mmol) dropwise. The reaction
was stirred at -10 °C for 2 h and quenched with 2 mL of H2O.
The organic and aqueous layers were separated, and the
aqueous layer was extracted with hexanes (3 × 5 mL). The
combined organic layers were then washed with 5 mL of H2O
and dried over MgSO4. The filtrate was concentrated in vacuo,
and the residue was chromatographed on silica (5% ethyl
acetate in hexanes) to afford the title compound in 77% yield
less oil; [R]D ) -40.5 (c ) 0.39, CHCl3); 1H NMR (CDCl3,
20
500 MHz) δ 0.87 (t, 3H, J ) 7.1 Hz), 1.27-1.44 (m, 4H), 1.53-
1.61 (m, 2H), 2.51 (d, 1H, J ) 5.4 Hz), 2.98 (dd, 1H, J ) 4.5,
2.1 Hz), 3.24 (dt, 1H, J ) 5.6, 2.0 Hz), 5.02 (t, 1H, J ) 4.9 Hz),
7.18 (t, 1H, J ) 7.6 Hz), 7.37 (t, 1H, J ) 7.5 Hz), 7.56 (d, 1H,
J ) 7.9 Hz), and 7.61 (d, 1H, J ) 7.7 Hz) ppm; 13C{1H} NMR
(CDCl3, 125 MHz) δ 13.9, 22.4, 27.9, 31.1, 57.7, 61.1, 71.6,
122.1, 127.9, 128.0, 129.5, 132.8, and 139.8 ppm; IR (neat)
3424, 3063, 2962, 2930, 2861, 1562, 1468, 1434, 1383, and 1260
cm-1; HRMS-CI m/z 285.0496 [MH+; calcd for C13H18BrO2,
285.0490]. Data for the erythro-diastereomer: colorless oil;
[R]D20 ) -55.9 (c ) 1.2, CHCl3); 1H NMR (CDCl3, 500 MHz) δ
0.82 (t, 3H, J ) 7.1 Hz), 1.20-1.33 (m, 4H), 1.44 (m, 1H), 1.55
(m, 1H), 2.51 (s, 1H), 3.03 (dt, 1H, J ) 5.6, 1.8 Hz), 3.20 (br t,
1H), 5.37 (br s, 1H), 7.17 (t, 1H, J ) 7.1 Hz), 7.34 (t, 1H, J )
7.5 Hz), 7.50 (d, 1H, J ) 7.6 Hz), and 7.54 (d, 1H, J ) 8.0 Hz)
ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ 13.8, 22.2, 27.9, 31.0,
54.8, 59.6, 69.1, 122.1, 127.7, 127.9, 129.4, 132.6, and 138.8
ppm; IR (neat) 3434, 3072, 2957, 2931, 2859, 1590, 1568, 1468,
1438, and 1378 cm-1; HRMS-CI m/z 285.0496 [MH+; calcd for
C13H18BrO2, 285.0490].
(104 mg, 0.39 mmol) as a colorless oil: [R]20 ) -31.3 (c )
D
3.2, CHCl3, 93% ee); 1H NMR (CDCl3, 500 MHz) δ 0.86 (t, 3H,
J ) 7.1 Hz), 1.25-1.37 (m, 4H), 2.03 (dt, 2H, J ) 7.0, 6.7 Hz),
2.11 (br s, 1H), 5.51 (d, 1 H, J ) 6.1 Hz), 5.58 (dd, 1H, J )
15.2, 6.4 Hz), 5.78 (dt, 1H, J ) 15.2, 6.7 Hz), 7.10 (t, 1H J )
7.6 Hz), 7.31 (t, 1H, J ) 7.4 Hz), 7.50 (d, 1H, J ) 7.9 Hz), and
7.53 (d, 1H, J ) 7.7 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz)
δ 13.9, 22.2, 31.3, 31.9, 73.5, 122.4, 127.70, 127.74, 128.8, 130.2,
132.7, 133.5, and 142.2 ppm; IR (neat) 3360, 3060, 2956, 2926,
2857, 1664, 1567, 1466, 1438, 1378, and 1193 cm-1; HRMS-
CI m/z 268.0471 [M+; calcd for C13H17BrO, 268.0463].
Acknowledgment. This work was supported by the
National Science Foundation (Grant CHE-0315913). We
also thank Professor M. G. Finn (The Scripps Research
Institute) for helpful discussions.
(2-Bromophenyl)(3-butyloxiranyl)methanol (18). Gen-
eral Procedure B. A 10 mL Schlenk flask (A) was charged
with Cy2BH (98 mg, 0.55 mmol), prepared according to
Oppolzer’s procedure,35 and 1.2 mL of hexanes. 1-Hexyne (64
µL, 0.55 mmol) was added dropwise, and the homogeneous
reaction mixture was stirred for 30 min at room temperature.
After the reaction flask was cooled to -10 °C, (-)-MIB (4.8
mg, 0.02 mmol) was added, followed by Et2Zn (0.78 mL, 2.0
M) and then o-bromobenzaldehyde (58 µL, 0.50 mmol) drop-
wise. The reaction was stirred at -10 °C for 4 h until vinyl
addition was complete by TLC. The reaction flask was then
capped with a balloon of oxygen and allowed to stir at -10 °C
Supporting Information Available: Synthesis and full
characterization of all compounds, X-ray crystal structures of
19 and 21, and conditions for the resolution of racemates (PDF,
CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JO048345D
1268 J. Org. Chem., Vol. 70, No. 4, 2005