Vanadium-catalyzed enantioselective desymmetrization of meso secondary allylic alcohols and homoallylic alcohols

Article abstract of DOI:10.1002/anie.200802523

(Chemical Equation Presented) Desymmetrization isn't complex: The substrate scope for vanadium-catalyzed epoxidation has been extended. In addition to various allylic alcohols, homoallylic alcohols can also be desymmetrized by using vanadium/bishydroxamic

Full text of DOI:10.1002/anie.200802523

Communications
DOI: 10.1002/anie.200802523
Asymmetric Catalysis
Vanadium-Catalyzed Enantioselective Desymmetrization of meso
Secondary Allylic Alcohols and Homoallylic Alcohols**
Zhi Li, Wei Zhang, and Hisashi Yamamoto*
Kinetic resolution of secondary allylic alcohols and homo-
allylic alcohols is one of the most important synthetic
protocols used to provide enantiomerically enriched epox-
ides, especially those carrying several contiguous stereogenic
centers. These chiral building blocks would be very useful for
the asymmetric synthesis of natural products and biologically
active substances. Many efficient protocols have been devel-
oped to satisfactorily mediate the kinetic resolution of allylic
alcohols.[1] Recently, we reported new bishydroxamic acid
(BHA) ligands for the enantioselective vanadium-catalyzed
asymmetric epoxidation and kinetic resolution of allylic
alcohols and homoallylic alcohols (Scheme 1).[2,3]
However, the intrinsic problem of kinetic resolution is
that the maximum yield is 50%, and half of the starting
material turns out to be a by-product after the reaction. On
the other hand, the desymmetrization of meso secondary
allylic alcohols and homoallylic alcohols, which shares the
same principle of facial discrimination of olefins with kinetic
resolution, does not have this limitation because in theory all
of the starting material can participate in the reaction.
Therefore, this approach should be more efficient than
kinetic resolution in providing optically pure epoxy alcohols
bearing at least two stereocenters.
Several meso secondary allylic alcohols have been suc-
cessfully desymmetrized by using the Sharpless asymmetric
epoxidation reaction,[1b,4] and this method has been applied in
Scheme 1. Structures of BHA ligands 1a–1c. Asymmetric epoxidation
and kinetic resolution of allylic and homoallylic alcohols catalyzed by
stereoselective natural product synthesis.[5] However, cis-
substituted meso secondary allylic alcohols did not provide
satisfactory enantioselectivities. Additionally, the catalyst
loadings necessary for desymmetrization by Sharpless systems
vanadium/BHA complexes. acac=acetylacetonate, CHP=cumene
hydroperoxide, iPr=2-propyl, TBHP=tert-butyl hydroperoxide.
are usually high, often greater than
a stoichiometric
amount.[1b] Our vanadium/BHA catalyst system has several
features that would facilitate this type of reaction, such as low
catalyst loading, tolerance of aqueous peroxy oxidants, mild
reaction conditions, and easy work-up procedures. By using
our catalyst system, several typical meso secondary allylic
alcohols such as trans- and cis-1,1-disubstituted and unsub-
stituted divinyl carbinols were all desymmetrized to give the
corresponding epoxy allylic alcohols in high stereoselectivi-
ties and good yields (Table 1).
We used the optimized reaction conditions for the
vanadium-catalyzed asymmetric epoxidation developed in
our previous study, and then applied ligands 1a–c and a
1.0 mol% catalyst loading to the desymmetrization reactions.
As was found previously, ligand 1a provided trans-substituted
and 1,1-disubstituted substrates with excellent enantioselec-
tivities (Table 1, entries 1–3), while 1b was suitable for cis-
substituted substrates (Table 1, entry 4). The reactions also
provided high diastereoselectivities and good yields. The
simplest product in this category, 1,2-epoxy-4-penten-3-ol
(3e), was generated with 95% ee when the sterically more
demanding ligand 1c was used (Table 1, entry 5). The trans-
formation for 3e was more diastereoselective in the presence
of CHP than in aqueous TBHP. The absolute configuration of
[*] Z. Li, Prof. Dr. H. Yamamoto
Department of Chemistry
The Universityof Chicago
5735 South Ellis Avenue, Chicago, IL 60637 (USA)
Fax: (+1)773-702-0805
E-mail: yamamoto@uchicago.edu
Homepage: http://yamamotogroup.uchicago.edu/
Dr. W. Zhang
Department of Chemistry, Northwestern University
2145 Sheridan Road, Evanston, IL 60208 (USA)
[**] Support for this research was provided bythe National Institutes of
Health (NIH) (grant no. GM068433-01) and the Merck Research
Laboratories.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802523.
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Table 1: Desymmetrization of meso secondaryallylic alcohols.
Table 2: Desymmetrization of meso secondaryhomoallylic alcohols.
Entry[a] Epoxyalcohol
Ligand T [8C] t [h] d.r.
Yield ee
Entry[a]
Epoxyalcohol
T [8C]
t [d]
d.r.
Yield
[%][b]
ee
[%][b] [%][c]
[%][c]
1
2
3
0
0
0
0
RT
0
3
8
11.8
5
2
4
87:13
90:10
93:7
92:8
95:5
97:3
23
56
53
51
53
69
93
94
95
97
92
97
1
2
1a
1a
0
0
10
12
94:6 52
95
95
4[d]
5
95:5 60
99:1 62
6
[a] All reactions were carried out in toluene in the presence of 88% CHP
(1.2 equiv). [b] Yield of isolated product after chromatographic purifica-
tion. [c] The d.r. and ee values were determined byHPLC or GC analysis
on a chiral stationaryphase, see the Supporting Information for details.
[d] VO(OiPr)3 (2 mol%) and 1c (4 mol%) were used.
3
1a
À10 96
À10 96
95
4
1b
1c
87:13 73
98:2 52
97
95
5[d]
0
24
applied a 2 mol% catalyst loading to the system. The
combination of lower temperature and higher catalyst loading
provided the best result (Table 2, entry 4).
Stereospecific base-catalyzed epoxide hydrolysis of epoxy
alcohol 5a provided a 1,2,4-triol, the absolute configuration of
which was established as 2R,4R (Scheme 2).[8] These results
further support our previously described mechanism for the
vanadium/BHA catalyst system.[3]
[a] All reactions were carried out in CH2Cl2 in the presence of 70%
aqueous TBHP (1.2 equiv), unless otherwise indicated. [b] Yield of
isolated product after chromatographic purification. [c] The d.r. and
ee values were determined byHPLC or GC analysis on a chiral stationary
phase, see the Supporting Information for details. [d] Reaction was
carried out in CH2Cl2 in the presence of 88% CHP (1.2 equiv).
epoxy alcohol 3e was determined as 2S,3R by comparison
with NMR spectroscopic data and optical rotation data.[6] The
absolute configurations of 3a–d were assigned by comparison
of the structures with that of 3e, as well as from the kinetic
resolution of secondary allylic alcohols.[2]
Scheme 2. Determination of the absolute configuration of 5a.
With these results in hand, we next applied this catalyst
system to the asymmetric epoxidation of meso secondary
homoallylic alcohols, which has been an unsolved problem in
asymmetric synthesis (Table 2). Substrates bearing cis sub-
stituents on the double bonds provided excellent yields and
ee values, while the reactions of the trans counterparts did not
proceed satisfactorily.
Although our previous study showed that temperature
does not significantly affect the enantioselectivity of homo-
allylic alcohol epoxidation,[3] here, a lower temperature (08C)
was necessary to achieve excellent ee values. As a result, the
reaction time required was longer (Table 2, entries 5 and 6).
These substrates are typical examples of a “combination
of enantiotopic groups and diastereotopic faces”.[4b] Studies
from Schreiber and co-workers showed that these reactions
could provide higher stereoselectivities but lower yields after
a longer reaction time.[4b,7] This observation is also applicable
to our reaction. Here, the enantiotopic groups are the two
double bonds, while the diastereotopic faces are the two faces
of each double bond. As the reaction time for the desymmet-
rization of substrate 4a increased, the ee values and diaste-
reomeric ratios increased, while the yield reached a maximum
after 8 days (Table 2, entries 1–3).
To the best of our knowledge, the highly stereoselective
synthesis of compound 5a is the first time that this promising
synthetic intermediate has been accessed.[9] Existing methods
for the direct epoxidation of 4a have only given poor
conversions.[10–13] Indirect approaches include: preparation
of a racemic mixture by iodo-lactonization,[14,15] a multiple-
step synthesis using compounds, such as (À)-(S)-malic acid
from the chiral pool,[16] or use of Jacobsenꢀs method for the
hydrolytic kinetic resolution of the racemic mixture.[9] Even
though 5a has been used in several academic and industrial
syntheses, including preparation of a racemic mixture of the
crucial intermediate of the famous medicine atorvastatin
(Lipitor) used to control cholesterol levels, poor conversions
are problematic.[9,14–16] Now that we have developed a highly
stereoselective desymmetrization synthesis of 5a, the above-
mentioned procedures can be circumvented. We believe that
more syntheses based on our approach will soon become
available.
In conclusion, we have successfully applied our vanadium/
BHA catalyst system to the highly enantioselective desym-
metrization of meso secondary allylic alcohols and homo-
allylic alcohols. Further studies focusing on improvements of
the catalytic conditions are in progress.
To decrease the reaction time while retaining a high
enantioselectivity and an acceptable yield of product 5a, we
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Communications
[2]W. Zhang, A. Basak, Y. Kosugi, Y. Hoshino, H. Yamamoto,
Angew.Chem. 2005, 117, 4463; Angew.Chem.Int.Ed. 2005, 44,
4389.
[3]W. Zhang, H. Yamamoto, J.Am.Chem.Soc. 2007, 129, 286.
[4]For studies toward desymmetrization through olefin epoxida-
tion, see: a) S. Hatakeyama, K. Sakurai, S. Takano, J.Chem.Soc.
Chem.Commun. 1985, 1759; b) S. L. Schreiber, T. S. Schreiber,
Experimental Section
Representative experimental procedure: VO(OiPr)3 (2.5 mL,
0.0104 mmol) was added to a solution of 1a (11.2 mg, 0.0210 mmol)
in CH2Cl2 (0.5 mL), and the reaction mixture was stirred for 1 h at RT.
The resulting solution was cooled to 08C, and (1E,4E)-1,5-diphenyl-
penta-1,4-dien-3-ol (2a; 250 mg, 1.06 mmol) and 70% aqueous TBHP
(0.17 mL, 1.23 mmol) were sequentially added, and the mixture was
stirred at the same temperature for 10 h (progress of the epoxidation
was monitored by TLC). Saturated aqueous Na2SO3 was then added
and the reaction mixture was stirred for 1 h at 08C before the reaction
mixture was warmed to room temperature, extracted with Et2O, dried
over Na2SO4, and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel to
provide the epoxy alcohol 3a (52% yield, 95% ee). Determination of
the ee values for the epoxy alcohols is provided in the Supporting
Information.
D. B. Smith, J.Am.Chem.Soc.
Schreiber, M. T. Goulet, G. Schulte, J.Am.Chem.Soc.
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[5]For synthetic applications of desymmetrization through Sharp-
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Sato, Tetrahedron Lett. 1988, 29, 6297; b) S. Hatakeyama, K.
Sakurai, H. Numata, N. Ochi, S. Takano, J.Am.Chem.Soc. 1988,
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[6]M. Nakatsuka, J. A. Ragan, T. Sammakia, D. B. Smith, D. E.
Uehling, S. L. Schreiber, J.Am.Chem.Soc. 1990, 109, 8120.
[7]D. B. Smith, Z. Wang, S. L. Schreiber, Tetrahedron 1990, 46,
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[8]Y. Mori, H. Furukawa, Tetrahedron 1995, 51, 6725.
[9]Y.-J. Kim, J. Tae, Synlett 2006, 61.
[10]R. Antonioletti, F. Bonadies, A. Lattanzi, E. S. Monteagudo, A.
Scettri, Tetrahedron Lett. 1992, 33, 5433.
[11]A. Zaks, D. R. Dodds, J.Am.Chem.Soc. 1995, 117, 10419.
[12]L. Palombi, F. Bonadies, A. Scettri, Tetrahedron 1997, 53, 11369.
[13]J. W. Kramer, D. Y. Joh, G. W. Coates, Org.Lett. 2007, 9, 5581.
[14]D. E. Butler, C. F. Deering, A. Millar, T. N. Nanninga, B. D. Roth
(Warner-Lambert Co.), US Patent 5245047, 1993.
Received: May 29, 2008
Published online: August 28, 2008
Keywords: asymmetric catalysis · desymmetrization ·
.
epoxidation · vanadium
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