Zirconium(IV)- and hafnium(IV)-catalyzed highly enantioselective epoxidation of homoallylic and bishomoallylic alcohols

Article abstract of DOI:10.1021/ja100951u

In this report, zirconium(IV)- and hafnium(IV)-bishydroxamic acid complexes were utilized in the highly enantioselective epoxidation of homoallylic alcohols and bishomoallylic alcohols, which used to be quite difficult substrates for other types of asymmetric epoxidation reactions. The performance of the catalyst was improved by adding polar additive and molecular sieves. For homoallylic alcohols, the reaction could provide epoxy alcohols in up to 83% yield and up to 98% ee, while, for bishomoallylic alcohols, up to 79% yield and 99% ee of epoxy alcohols rather than cyclized tetrahydrofuran compounds could be obtained in most cases.

Full text of DOI:10.1021/ja100951u

Published on Web 05/19/2010
Zirconium(IV)- and Hafnium(IV)-Catalyzed Highly Enantioselective Epoxidation
of Homoallylic and Bishomoallylic Alcohols
Zhi Li and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received February 8, 2010; E-mail: yamamoto@uchicago.edu
Despite the tremendous success of asymmetric epoxidations,1
more efficient epoxidation reactions are still of great importance.
Scheme 1. Zr(IV)- and Hf(IV)-BHA Catalyzed Asymmetric
Epoxidation of Homoallylic and Bishomoallylic Alcohols
For example, there are only sporadic reports of catalytic
enantioselective epoxidation of challenging substrates such as
homoallylic alcohols and bishomoallylic alcohols to date.2 In
recent years, our group has developed highly efficient vanadium-
hydroxamic acid and -bishydroxamic acid (BHA) catalyst
systems for the asymmetric epoxidation of allylic alcohols and
homoallylic alcohols.3 However, asymmetric epoxidation of
bishomoallylic alcohols is an even more challenging problem
because the longer carbon chain is much more flexible in the
transition state.4 Although syntheses of epoxides, tetrahydrofuran
(THF), and tetrahydropyran (THP) derivatives via epoxidation
of bishomoallylic alcohols are well established using either
achiral metal catalyst5 or Shi’s chiral-ketone-catalyzed epoxi-
dation procedures,2f,6 a highly efficient metal-catalyzed enan-
tioselective direct epoxidation is still missing from the list.
Herein, we would like to report a zirconium(IV)- and hafnium(IV)-
catalyzed highly enantioselective epoxidation of homoallylic
alcohols and bishomoallylic alcohols (Scheme 1).
Since we depleted the catalytic ability of the vanadium-BHA
system with a very bulky BHA ligand,3d,e we began to consider
Scheme 2. Comparison of V-, Zr-, and Hf-Catalyzed Reactions
solving the problem using another approach. For example, we
postulated that using a larger center ion would provide more space
around it so that even a smaller ligand could arrange a proper cavity
for stereoselective recognition of the substrate and oxidant mol-
ecules. There are many transition metals reported to efficiently
catalyze epoxidation of alkenyl alcohols, especially group 4 and 5
metals such as Ti, Zr, and V.7 Additionally, as a strong Lewis
gave a much higher selectivity (entries 1 and 2). The simpler ligand
acid,8 Zr(IV) has been applied in asymmetric epoxidation of
homoallylic alcohols.2b,e Enlightened by this pioneering work,
we therefore chose Ti, Zr, Hf, V, and Nb as candidate metal
species for our initial experiments. As we examined the candidate
metal sources, Zr(OtBu)4 and Hf(OtBu)4 proved to be superior
compared to other metals such as Ti(OiPr)4, Nb(OEt)5, and
VO(acac)2 in terms of both reactivity and enantioselectivity. An
explanation is presented in Scheme 2. In vanadium-catalyzed
reactions, the transition state is believed to involve hexacoor-
dinate vanadium species,3d while, in zirconium and hafnium-
catalyzed reactions, the transition state should be a mononuclear
pentacoordinate complex7,9 because (1) the ligand binds with
the metal using two hydroxamate oxygens and the size of the
ligand prevents catalyst oligomerization;10 (2) the substrate binds
with the metal using one alkoxide; and (3) the alkylhydroper-
oxide binds with the metal as a bidentate ligand using both
oxygens of the peroxy group as ligand donors.9 Nonlinearity
experiments showed the linear relationship between the enan-
tiomer excess of ligand and product, which supported our
hypothesis.
1a showed the best reactivity and selectivity (entries 2 and 3). A
1:1 ratio of metal to ligand was crucial; while 2 equiv of ligand
completely inactivated the catalyst (entry 4),11 and Zr(acac)4 did
not work at all as the metal source (entry 5). Since using toluene
and dichloromethane as solvent both gave similar levels of
enantioselectivity, we chose to use toluene because it is more
environment friendly. Interestingly, we also found that the results
were significantly improved when a polar aprotic ligand such as
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was
added (entry 7). The additive may serve two functions in the system.
First, as seen in Scheme 2, there are vacant coordination sites on
Zr and Hf metal during the reaction. These vacant sites could
possibly facilitate a slow but significant oligomerization of Zr and
Hf species by bridging two or more metals with a primary alkoxide
anion generated from the substrate or product. Adding DMPU could
help the catalyst stay in its monomeric form by occupying these
vacant sites on the metals as well as regeneration of the monomeric
catalytic species.8b,12 Second, the nucleophilic oxygen of DMPU
may help release the coordinated product from the metal and
complete the catalytic cycle. Final screening showed Hf(IV) gave
more promising results than Zr(IV) as the center metal ion (entry
We then started conditions optimization with the Zr(IV)-BHA
system (Table 1). Compared with the V(V)-BHA system, Zr-BHA
9
7878 J. AM. CHEM. SOC. 2010, 132, 7878–7880
10.1021/ja100951u  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Screening of Reaction Conditions
Table 3. Zr(IV)- and Hf(IV)-Catalyzed Asymmetric Epoxidation of
Bishomoallylic Alcohols
entrya
metal
ligand
additive
solvent
%yieldb %eec
1
2
3
4
5
6
7
8
9f
VO(OiPr)3
Zr(OtBu)4
Zr(OtBu)4
Zr(OtBu)4
Zr(acac)4
Zr(OtBu)4
Zr(OtBu)4
Hf(OtBu)4
Hf(OtBu)4
1ad
1a
1b
1ae
1a
1a
1a
1a
1a
-
-
-
-
-
-
toluene
toluene
toluene
toluene
toluene
CH2Cl2
toluene
toluene
29
25
28
N.R.
N.R.
48
56
60
69
90
71
-
-
90
90
95
97
DMPU
DMPU
DMPU MS 4 Å toluene
81
a All reactions were performed in the presence of 1.0 equiv of
cumene hydroperoxide (CHP) (1 mmol) unless otherwise noted.
b Isolated yield after chromatographic purification. c Enantiomeric excess
values were determined by chiral gas chromatography. d 1.5 mol %
ligand was used. e 2.0 mol % ligand was used. f Conditions: 2 mol %
metal, 2 mol % ligand, 4 mol % DMPU, 1.5 equiv of CHP, and 100 mg
MS were used in a 0.5 mmol scale reaction. The reaction is initially
cooled to 0 °C for 4 h then left at room temperature for the next 36 h.
Table 2. Zr(IV)- and Hf(IV)-Catalyzed Asymmetric Epoxidation of
Homoallylic Alcohols
a All reactions were performed in the presence of 1.5 equiv of CHP.
b Isolated yield after chromatography purification. c Enantiomeric excess
values were determined by chiral HPLC. d 42% of 4e was recovered.
e 30 mol % catalyst loading was used and the reaction was stirred for
72 h. 52% starting material 4h was recovered. Absolute configuration is
determined as (R, R). See ref 14.
8). Furthermore, addition of molecular sieves (MS) also greatly
improved the results, especially the 4 Å powdered molecular sieves
(entry 9).13
A variety of homoallylic alcohols with different substituted
patterns were subjected to the optimum epoxidation conditions of
both Zr(IV) and Hf(IV). The results are summarized in Table 2. In
general, Hf is better than Zr in terms of reactivity and selectivity.
1,1-Disubstituted (entries 1, 3, and 5) and (Z)-substituted substrates
(entries 7 and 8) provide higher reactivities and selectivities. It is
a All reactions were performed in the presence of 1.5 equiv of CHP.
b Isolated yield after chromatographic purification. c Enantiomeric excess values
were determined by chiral GC and chiral HPLC. d 61% of 2e was recovered.
9
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C O M M U N I C A T I O N S
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Entries 1 and 2 indicated that, without (Z)-substituent, the epoxi-
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The reactivity of epoxidation of bishomoallylic alcohols was
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2, 3, and 4). Electron-rich but sterically hindered substrate 4e gave
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therefore facilitating the SN1 type racemizing cyclization. (Z)-
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selective epoxidation of homoallylic alcohols and bishomoallylic
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employed to investigate the reaction mechanism and potential
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Acknowledgment. National Institutes of Health (NIH) is greatly
appreciated for providing financial support (GM068433-05).
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Supporting Information Available: Representative experimental
procedures and necessary characterization data for all compounds are
provided. Results of nonlinear effect experiments are provided. This
material is available free of charge via the Internet at http://pubs.acs.org.
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