A dynamic kinetic resolution of allyl alcohols by the combined use of lipases and [VO(OSiPh3)3]

Article abstract of DOI:10.1002/anie.200503765

(Chemical Equation Presented) Mix and match: A new type of dynamic kinetic resolution of racemic allyl alcohols uses a combination of lipases and [VO(OSiPh₃)₃] (1). The 1,3-transposition of allyl alcohols catalyzed by 1 gave thermody

Full text of DOI:10.1002/anie.200503765

Communications
Asymmetric Synthesis
interconversion of allylic alcohols (2 and 3) through the
formation of the allyl vanadates A [Eq. (1)].[13]
DOI: 10.1002/anie.200503765
However, because the reactions are usually performed at
high temperatures (150–1708C) and afford thermodynamic
A Dynamic Kinetic Resolution of Allyl
Alcohols by the Combined Use of Lipases and
[VOACHTREUNG(OSiPh3)3]**
Shuji Akai,* Kouichi Tanimoto, Yukiko Kanao,
Masahiro Egi, Tomoko Yamamoto, and
Yasuyuki Kita*
mixtures of two regioisomers (2 and 3), this isomerization has
found limited application.[14,15] If these vanadium-catalyzed
isomerization reactions could be combined with the lipase-
catalyzed KR, a new DKR method would be established by
virtue of the high enantio- and chemoselective abilities of the
lipases.[16] To examine the feasibility of this idea, a lipase-
catalyzed KR of (Æ )-2a was examined first without and then
The lipase-catalyzed dynamic kinetic resolution (DKR) of
racemic alcohols has drawn increasing attention over the last
few years. The DKR protocol combines the lipase-catalyzed
kinetic resolution (KR) of racemic alcohols[1] with an in situ
racemization of the less reactive enantiomers, thus producing
optically enriched esters in up to quantitative yields,[2–4]
whereas the original KR has the inherent limitation of 50%
product yield at best. In previously reported DKRs, ruthe-
nium complexes were used as effective catalysts to bring
about the racemization of optically active alcohols through
oxidation/reduction reactions. Similarly, the combined use of
lipases with other transition-metal-based racemization cata-
lysts has the potential to produce diverse DKR methods.
However, although some rhodium, iridium, ruthenium, and
aluminum complexes are known to catalyze the racemization
of alcohols,[5] only a few have proven to be compatible with
enzymatic reactions.[5a,6]
with
[VO
a
catalytic amount of the stable compound,
AHCTRE(UGN OSiPh3)3] (1a).
First, after screening a number of commercially available
lipases and organic solvents, we found that ordinary KR took
place effectively. For instance, Candida antarctica lipase fr.B
(CAL-B, Roche Diagnostics) and the acyl donor ethoxyvinyl
acetate[17] (4a, 2 equiv) in acetone at 258C for 21 h completed
the resolution to give (R)-5a (92% ee, 51% yield) and (S)-2a
(97% ee, 49% yield) (Table 1, entry 1).
Table 1: KR and DKR of (Æ)-2a.[a]
Optically enriched allyl alcohols and their derivatives are
especially important as useful intermediates in the synthesis
of natural and non-natural compounds.[7] Therefore, their
asymmetric synthesis has been extensively investigated, with
much of the attention focused on the transition-metal-
catalyzed KR and DKR of allyl alcohols and their esters[8,9]
and the asymmetric reduction of enones.[10,11] From the
viewpoint of the synthetic utility of the allyl alcohols as well
as the extension of the lipase-catalyzed DKR methodology,
we report herein a very different DKR of allylic alcohols by
Entry
4
1a
t
(R)-5a[b]
(S)-2a[b]
3a
AHCTRE[UNG mol%] [h] ee [%] Yield [%] ee [%] Yield [%] Yield [%]
1
2
3
4
4a
–
21 92
16 99
60 98
72 93
51[c]
66[d]
95[c]
89[c]
97
5
–
49[c]
5[d]
–
4a 10
4a 10
4b 10
29[d]
<5[d]
6[d]
trace
the combination of lipases with [VO
H
–
<5[d]
It has been known for more than three decades that the
oxovanadium(v) compounds, [VO(OR)3] (1), catalyze the
[a] The reaction was carried out as stated in the text. [b] The optical
purities of 2a and 5a were determined by GC with a chiral column, TCI
Chiraldex G-TA. The absolute stereochemistry of the recovered 2a was
determined to be S by the modified Mosher method, and thereby that of
5a to be R. [c] Yield of isolated product after SiO2-column chromatog-
raphy. [d] Yield based on 1H NMR spectroscopic data.
[*] Prof. Dr. S. Akai, Dr. M. Egi, T. Yamamoto
School of Pharmaceutical Sciences
University of Shizuoka
52-1, Yada, Suruga-ku, Shizuoka 422-8526 (Japan)
Fax: (+81)54-264-5672
E-mail: akai@u-shizuoka-ken.ac.jp
Next, 1a in acetone was found to effect 1,3-transposition
at 258C. The reaction of (S)-2a (98% ee) with 1a (10 mol%)
reached thermodynamic equilibrium after about 12 h to give a
mixture of (Æ )-2a and 3a (15:85), while the racemization of
(S)-2a proceeded [Eq. (2)] (Figure 1).
Dr. K. Tanimoto, Y. Kanao, Prof. Dr. Y. Kita
Graduate School of Pharmaceutical Sciences
Osaka University
1-6, Yamadaoka, Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-8229
E-mail: kita@phs.osaka-u.ac.jp
[**] This work was supported by Grants-in-Aid for Scientific Research
(S and C) from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan. We thank Roche Diagnostics K. K., Japan
and Amano Enzyme Inc., Japan for the generous gift of the lipases.
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lipase immobilized on diatomaceous earth (PS-D, Amano
Enzyme) in toluene was suitable for ordinary KR, and DKR
using these lipases with 1a produced (R)-5b (91–95% ee) in
83–93% yield [Eq. (3)].[20,21] Although a related DKR of the
racemic acetate (Æ )-5b, in which the lipase-catalyzed hydrol-
ysis and the palladium(ii)-catalyzed racemization were com-
bined to yield optically enriched 2b (96% ee, 81% yield), was
previously reported, the reaction took 19 days for comple-
tion.[22]
Figure 1. Time course of the isomerization of (S)-2a (98% ee) cata-
&
*
lyzed by 1a in acetone at 258C. Mol ratio 2a/(2a + 3a), optical
purity of (S)-2a.
We then investigated the DKR of 2a by the combined use
of CAL-B and 1a. A mixture of 2a, 4a (2 equiv), 1a
(10 mol%), and CAL-B was stirred in anhydrous acetone at
258C. After 16 h, a mixture of (R)-5a (99 ee, 66% yield),
(S)-2a (5% ee, 5% yield), and 3a (29%
The DKR protocol was successfully applied to other
racemic secondary alcohols (Æ )-2c–g as well as the tertiary
alcohol 3e with either 4a or 4b (Table 2). All reactions were
carried out at around room temperature to produce the esters
yield) was obtained (Table 1, entry 2).
Table 2: DKR of (Æ)-2 and 3 to give (R)-5.[a]
These results indicated that the lipase and
1a had little adverse affect on each other.
Prolonged stirring for 2.5 days resulted in
the conversion of 3a into (R)-5a (98% ee,
95% yield) (Table 1, entry 3). The use of
vinyl acetate (4b, 2 equiv), currently the
most popular acyl donor, also brought about
Entry Alcohol
4
Lipase Solvent
T
[8C]
t
5[b]
ee
Yield
A
[%] [%]
1
2
4a CAL-B acetone 25
4b CAL-B acetone 25
2
2
97[c] 88
98[c] 94
3
4
4a CAL-B acetone 10
4b CAL-B acetone 10
2
2
97[c] 88
98[c] 80
a
similar DKR that produced (R)-5a
(93% ee, 89% yield) after 3 days (Table 1,
entry 4), although its optical and chemical
yields were slightly lower than those
obtained using 4a (Table 1, entry 3). In
these reactions, the formation of the acetate
of the tertiary alcohol 3a was not observed,
which was expected from the high chemo-
selectivity of the lipase-catalyzed reac-
tions.[16]
5
6
4a CAL-B acetone 25
4b CAL-B acetone 25
3
3
99[d] 91
99[d] 85
7
8
4a CAL-B acetone 25
4b CAL-B acetone 25
4
4
98[d] 93
99[d] 93
The
preparation
of
the
ester
(R)-5a from the tertiary alcohol 3a is a
unique feature of this DKR protocol. The
alcohol, which is readily available by the
alkynylation of cyclohexanone followed by
reduction,[18] can be converted into (R)-5a
(99% ee, 91% yield) under the same con-
ditions as entry 3 of Table 1 (Scheme 1).[19]
This DKR method was also effective for
the cyclic allylic alcohol (Æ )-2b. In this case,
both Pseudomonas fluorescens lipase (AK,
Amano Enzyme) and Burkholderia cepacia
9
10
4a PS-D toluene 35
4b PS-D toluene 35
2
2
97[e] 91
99[e] 96
(R)-5g: R=C CSiMe3 91[c] 81
ꢀ
ꢀ
11
(Æ)-2g R=C CSiMe3 4a PS-D toluene 35
4
[a] The reaction was carried out as stated in the text. [b] Yield of isolated product after SiO2-column
chromatography. [c] Optical purity was determined by HPLC with a Daicel Chiralcel OD-H column (for
5c and 5g) or a Daicel Chiralpak AD-H column (for 5d), after conversion into the corresponding alcohol
2. [d] Optical purity was determined by GC with a chiral column, TCI Chiraldex G-TA, after conversion
into the corresponding alcohol 2e. [e] Optical purity was determined by HPLC with a Daicel Chiralcel
OD-H column.
(R)-5c–g with 91–99% ee in 80–96% yields, which demon-
strates the similar high efficacy of both 4a and 4b. The use of
ethoxyvinyl esters, in particular, will enable us to apply the
DKR method to the domino-type reactions that we recently
developed.[3,17] Among the products, (R)-5g was reported to
Scheme 1. Preparation of 3a and its conversion into (R)-5a by DKR.
be a key synthetic intermediate of medicinally important
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Communications
compounds.[23] It was previously prepared by the ordinary KR
2004, 69, 1972 – 1977; b) M. Edin, J. Steinreiber, J.-E. Bäckvall,
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of (Æ )-2g to give (R)-5g and (S)-2g, followed by Mitsunobu
reaction of the mixture. Although the enantioselectivity of the
KR was excellent (99% ee for both products), the Mitsunobu
inversion suffered partial racemization to give (R)-5g with
88% ee.[23a] Our DKR method produced (R)-5g (91% ee,
81% yield) directly (Table 2, entry 11).
In conclusion, we have shown that the combination of the
oxovanadium compound 1a with lipases produces a novel
DKR process with excellent enantiomer resolution and
chemical yields. The 1,3-transposition of allyl alcohols was
catalyzed by 1a and resulted in a thermodynamic equilibrium
of two regioisomers, which underwent highly enantio- and
chemoselective esterification under the action of the lipases.
Because the 1a-catalyzed 1,3-transposition reactions are not
very sensitive to oxygen and moisture, this DKR method
offers the advantage of a facile experimental procedure
without the need for special apparatus.[24] Furthermore, it
features a unique preparation of optically active esters of
secondary alcohols from the corresponding ketones via the
readily available tertiary alcohols; this synthesis is not
attainable by existing DKRs with ruthenium complexes.
[5] a) P. M. Dinh, J. A. Howarth, A. R. Hudnott, J. M. J. Williams,
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[6] For a related DKR of racemic secondary amines with palla-
dium(0) on carbon as a racemization catalyst, see: M. T. Reetz,
K. Schimossek, Chimia 1996, 50, 668 – 669; see also: Y. K. Choi,
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[7] For examples, see: R. M. Hanson, Org. React. 2002, 60, 1 – 156.
[8] For a recent review, see: E. Vedejs, M. Jure, Angew. Chem. 2005,
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Experimental Section
[11] For other recent examples based on different methodologies,
see: H. Li, P. J. Walsh, J. Am. Chem. Soc. 2004, 126, 6538 – 6539;
S. F. Kirsch, L. E. Overman, J. Am. Chem. Soc. 2005, 127, 2866 –
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[12] The first preparation of 1a was reported independently by two
groups: a) N. F. Orlov, B. N. Dolgov, M. G. Voronkov, Dokl.
Akad. Nauk SSSR 1958, 122, 246 – 249; b) F. E. Granchelli, G. B.
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[13] a) P. Chabardes, E. Kuntz, J. Varagnat, Tetrahedron 1977, 33,
1775 – 1783; for a review, see: b) S. Bellemin-Laponnaz, J.-P.
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[14] The related isomerization of propargyl and allenyl alcohols has
found synthetic use for producing conjugated carbonyl com-
pounds after irreversible enol–keto transformation (for an
example, see: C. Tode, Y. Yamano, M. Ito, J. Chem. Soc.
Perkin Trans. 1 2001, 3338 – 3345) and was applied to the aldol
reaction of the intermediate vanadium enolates.[12c]
Typical procedure: (Æ )-2a (50 mg, 0.36 mmol), 4a (93 mg,
0.71 mmol), 1a (32 mg, 0.036 mmol), CAL-B (150 mg), and anhy-
drous acetone (4 mL) were added to a round-bottomed flask. The
flask was sealed and the reaction mixture was stirred at 258C for
2.5 days. The reaction mixture was then filtered and concentrated in
vacuo. The residue was purified by flash column chromatography on
SiO2 (hexane/Et2O, 20:1 to 2:1) to give (R)-5a as a colorless oil
(62 mg, 95% yield, 98% ee (GC analysis with TCI chiraldex G-TA)).
[a]2D0 = + 35.0 (c = 0.96, CHCl3); 1H NMR (300 MHz, CDCl3): d = 1.26
(d, J = 7.0 Hz, 3H), 1.48–1.58 (m, 6H), 2.02 (s, 3H), 2.06–2.09 (m,
2H), 2.18–2.23 (m, 2H), 5.11 (br d, J = 9.0 Hz, 1H), 5.63 ppm (qd, J =
7.0, 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 21.3, 21.5, 26.6,
27.7, 28.4, 29.4, 36.8, 67.4, 121.5, 144.1, 170.5 ppm; IR (KBr): n =
1715 cmÀ1; elemental analysis: calcd (%): C 72.49, H 9.95; found: C
72.26, H 9.89.
Received: October 24, 2005
Revised: January 13, 2006
Published online: March 17, 2006
[15] The vanadium catalyst prepared in situ from [VOACHTRE(UNG acac)2] and
Keywords: allyl alcohols · asymmetric synthesis ·
dynamic kinetic resolution · lipases · vanadium
Me3SiOOSiMe3 caused isomerization at room temperature: S.
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.
[16] The lipase-catalyzed reactions of tertiary alcohols are usually
slow, probably due to steric hindrance: U. T. Bornscheuer, R. J.
Kazlauskas, Hydrolases in Organic Synthesis: Regio- and Ste-
reoselective Biotransformations, Wiley-VCH, Weinheim, 1999,
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[17] For a review, see: Y. Kita, S. Akai, Chem. Rec. 2004, 4, 363 – 372;
for a recent example, see: S. Akai, K. Tanimoto, Y. Kanao, S.
Ohmura, Y. Kita, Chem. Commun. 2005, 2369 – 2371.
[18] For the E-selective reduction of alkynes with LiAlH4/NaOMe,
see: I. Fleming, N. K. Terrett, J. Organomet. Chem. 1984, 264,
99 – 118.
[1] For recent reviews, see: a) S. M. Roberts, J. Chem. Soc. Perkin
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[4] For some recent improvements and applications of the lipase–
ruthenium(ii)-catalyzed DKRs, see: a) J. H. Choi, Y. K. Choi,
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[19] The reaction of 3a with 1a (10 mol%) in acetone at 258C
reached equilibrium after about 6 h to afford a mixture of 2a and
3a (15:85).
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[20] The optical purity was determined by HPLC with a Daicel
Chiralpak AD-H column; [a]2D2 = + 169 (c = 1.0, CHCl3) (lit:
[a]D25 = À157 (c = 0.57, CHCl3) for (S)-5b with 96% ee).[21]
[21] M. Frohn, X. Zhou, J.-R. Zhang, Y. Tang, Y. Shi, J. Am. Chem.
Soc. 1999, 121, 7718 – 7719.
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´
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118 – 124.
[24] The ruthenium-catalyzed racemization reported so far needed
strict anaerobic conditions because the interfusion of oxygen
often caused the formation of significant amounts of side
products, that is, ketones.[2–4] However, just before submitting
this Communication, a novel ruthenium complex was reported
to produce the DKR of alcohols with a lipase in air (N. Kim, S.-B.
Ko, M. S. Kwon, M.-J. Kim, J. Park, Org. Lett. 2005, 7, 4523 –
4526).
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