Novozym-435-catalyzed enzymatic separation of racemic propargylic alcohols. A facile route to optically active terminal aryl propargylic alcohols

Article abstract of DOI:10.1016/S0040-4039(03)01528-4

Novozym-435 (a form of Candida antarctica lipase B) was found to be an effective biocatalyst for the kinetic resolution of a variety of racemic terminal aryl propargylic alcohols affording highly optically active (S)-propargylic alcohols and (R)-propargylic alcohol acetates in high yields and good ees. The advantages of this reaction are the easy availability of starting materials and the biocatalyst, simple reaction conditions, easy operation and high stereoselectivity.

Full text of DOI:10.1016/S0040-4039(03)01528-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6343–6346
Novozym-435-catalyzed enzymatic separation of racemic
propargylic alcohols. A facile route to optically active terminal
aryl propargylic alcohols
Daiwang Xu,a Zuyi Lib and Shengming Maa,*
aState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, PR China
bState Key Laboratory of Bio-Organic & Natural Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, PR China
Received 22 April 2003; revised 26 May 2003; accepted 9 June 2003
Abstract—Novozym-435 (a form of Candida antarctica lipase B) was found to be an effective biocatalyst for the kinetic resolution
of a variety of racemic terminal aryl propargylic alcohols affording highly optically active (S)-propargylic alcohols and
(R)-propargylic alcohol acetates in high yields and good ees. The advantages of this reaction are the easy availability of starting
materials and the biocatalyst, simple reaction conditions, easy operation and high stereoselectivity.
© 2003 Published by Elsevier Ltd.
Optically active propargylic alcohols are very important
intermediates for the enantioselective synthesis of vari-
ous natural products and precursors of otherwise
difficult-to-make optically active compounds,1 for
example, eicosanoids,2 macrolides3 and enediyne antibi-
otics.4 They are also useful starting materials for the
synthesis of allenes,5 benzo[b]furan (1-benzofuran) and
derivatives.6 Many methods have been reported for the
synthesis of optically active propargylic alcohols;7 how-
ever, those for terminal propargylic alcohols are limited
due to the presence of the terminal proton. The opti-
cally active propargylic alcohols with terminal protons
are usually prepared by the asymmetric reduction of
1-alkynyl-3-one using chiral lithium aluminum hydride
reagent8 or organoboranes,9 the enantioselective
hydrolysis of propargylic alcohol acetates using
microorganisms10 or enzymes,11 and the kinetic esterifi-
cation of propargylic alcohols.12 Some optically active
terminal 1-aryl-2-alkynols are prepared via lipase-cata-
lyzed kinetic resolution,12a,b but the enantioselectivities
were strongly dependent on the substitution pattern of
the benzene moiety, regarding to both the type of the
substituent and its position on the aromatic ring. Some
of the results were unsatisfactory. The reduction proto-
col requires more than stiochiometric amount of enan-
tiomerically pure chiral reagents under non-convenient
reaction conditions. Some examples of terminal alkyl
propargylic alcohols using Candida antarctica lipase B
as the catalyst in organic solvent have been reported.13
2,3-Allenols are important starting materials for the
synthesis of oxiranes,14 2,5-dihydrofurans,15 a-
methylenelactones,16 a- or g-amino alcohols,17 and a,b-
unsaturated ketones.18 Thus, the syntheses of optically
active 2,3-allenols are of current interest. Using the
optically active terminal propargylic alcohols as the
starting materials, the optically pure 2,3-allenols can be
easily obtained.19 During the course of our systematic
study of allenes, we found that Novozym-435 (a form
of Candida antarctica lipase B) is an efficient biocatalyst
for the kinetic resolution of a series of racemic 2,3-
allenols affording highly optically active (S)-2,3-allenols
and (R)-2,3-allenyl acetates in high yields and excellent
ees.20 However, when it was applied to the resolution of
aryl-substituted or 2-unsubstituted 2,3-allenols, the
result was rather disappointing. In an attempt to
develop a general and facile route to optically active
1-aryl-2,3-allenols,19 we decided to develop an efficient
route to optically active terminal 1-aryl-2-alkynols. In
this paper, we wish to report the Novozym-435-cata-
lyzed efficient kinetic resolution of racemic 1-aryl-2-
alkylnols in an organic solvent.
In order to identify the best suited enzyme for the
present class of compounds, extensive screening experi-
* Corresponding author.
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/S0040-4039(03)01528-4

6344
D. Xu et al. / Tetrahedron Letters 44 (2003) 6343–6346
ened from 4 days to one day (entry 1, Table 2) and the
loading of the enzyme decreased from 70 mg to 18 mg
(entry 4, Table 2). The absolute configuration of the
major enantiomer was determined to be S by compari-
son of the sign of the specific rotation of the obtained
(+)-1-phenyl-prop-2-yn-1-ol (1a) with the known (R)-
(−)-1a.12a The absolute configurations of compounds in
Table 3 were tentatively assigned based on this result.
ments were performed. Some typical results listed in
Table 1 show that with Lipase G (lipase from penicil-
lium camembertii ) and PPL (porcine pancreatic lipase)
the occurrence of the reaction could not be observed
(entries 1 and 2, Table 1). With CRL (Candida rugosa
lipase) and Lipase Ak (lipase from pseudomonas fluores-
cens), the results are disappointing (entries 3 and 4,
Table 1). In addition, with lipase Ps (lipase from pseu-
domonas cepacia), acetate 2a was formed in a low yield
with a good ee while the ee of the alcohol is very low.
Fortunately, when we used Novozym-435 as the cata-
lyst, the result is encouraging: the yields and ees of both
the alcohol and the acetate are good (entry 6, Table 1).
With these results in hand, we went on to optimize the
reaction conditions. To our surprise, the reaction could
be carried out at 60°C even with higher ees. At this
temperature, the time of the reaction could be short-
In order to investigate the scope of the reaction, the
standard conditions for the kinetic resolution reaction
of racemic 1a was established (entry 4, Table 2). The
results of a series of racemic aryl-substituted propar-
gylic alcohols under standard reaction conditions were
summarized in Table 3. The reaction can proceed with
the substrates bearing either electron-rich or electron-
deficient aryl groups. In most cases of this experiment,
we could obtain the expected products with high enan-
Table 1. Screening of enzymes for the resolution of 1a with vinyl acetatea
Entry
Enzyme
Time (days)
1a
2a
Ed
Absolute
Yield (%)b
ee (%)c
Absolute
Yield (%)b
ee (%)c
configuration
configuration
1
2
3
4
5
6
Lipase G
PPL
CRL
Lipsase AK
Lipase Ps
Novozym 435
3
3
3
3
3
4
NRe
NRf
S
R
S
S
S
44
32
59
43
5
69
31
93
42
56
21
47
5
40
92
92
1.2
R
R
R
4.5
32.5
81.8
a The reaction was carried out at 30°C using 1a (100 mg), vinyl acetate (5 mL), and enzyme (70 mg).
b Isolated yield based on 1a.
c Determined by HPLC.
d E=ln[eeP(1−eeS)]/(eeP+eeS)/ln[eeP(1+eeS)]/(eeP+eeS).
e 1a was recovered in 94% yield.
f 1a was recovered in 92% yield.
Table 2. Optimization of Novozym-435-promoted kinetic resolution of 1a
Entry
Solvent (mL) Substrate
(mg)
Enzyme (mg) T (°C)
Time (h)
(S)-1a
(R)-2a
Ea
Yield (%)
ee (%)
Yield (%)
ee (%)
1
2
3
4
5
5
2.5
2.5
100
101
101
100
70
70
35
18
30
60
60
60
96
24
24
24
43
41
36
36
93
>99
>99
95
47
50
35
35
92
79
80
96
81.8
>43.6
>46.1
183.3
a E=ln[eeP(1−eeS)]/(eeP+eeS)/ln[eeP(1+eeS)]/(eeP+eeS).

D. Xu et al. / Tetrahedron Letters 44 (2003) 6343–6346
6345
Table 3. Novozym-435-catalyzed resolution of racemic propargylic alcoholsa
Entry
R
Time (h)
(S)-1
(R)-2
Ed
Yieldb (%)
eec (%)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
H
4-CH3
4-F
4-Cl
3,4-Cl2
2-Cl
4-i-Pr
3-Cl
4-Et
2,3-Cl2
4-CN
3,4-CH3O2
2,4-Cl2
4-CH3O
24
22
22
22
36 (1a)
35 (1b)
39 (1c)
30 (1d)
42 (1e)
40 (1f)
47 (1g)
37 (1h)
40 (1i)
42 (1j)
23 (1k)
44 (1l)
40 (1m)
42 (1o)
95
>99
99
>99
99
>99
70
>99
97
35 (2a)
39 (2b)
48 (2c)
52 (2d)
49 (2e)
44 (2f)
47 (2g)
39 (2h)
48 (2i)
45 (2j)
50 (2k)
38 (2l)
47 (2m)
41 (2o)
96
183.3
ND
66
24.2
347.7
525.0
>205.0
35.9
>81.6
35.0
205.8
6.6
97e
98
22
18.5
17.5
14.5
17.5
22.5
24
55
11
21.5
95e
89
88e
79
9
10
11
12
13
14
99
98
88
95
28
75
98
27.6
354.3
26.6
94
91f
79
a The reaction was carried out at 60°C using alcohols (ꢀ100 mg), vinyl acetate (2.5 mL), and Novozym-435 (18 mg).
b Isolated yield.
c Determined by HPLC.
d E=ln[eeP(1−eeS)]/(eeP+eeS)/ln[eeP(1+eeS)]/(eeP+eeS).
e Determined by HPLC after its conversion to the corresponding alcohol.
f Determined by HPLC after its conversion to the corresponding acetate.
tiomeric purity. When the substituent of the aromatic
ring was a chlorine atom, the yields of the alcohols and
esters were mostly good and the ees for both products
were excellent (entries 4, 5, 6, 8, 10 and 13, Table 3).
For some substrates, the products with very high enan-
tiomeric purities could be obtained with only extended
conversions (entries 3, 9, 11 and 12, Table 3). When we
turned to 1-(2%,6%-dichlorophenyl)prop-2-yn-1-ol and 1-
(2%-trifluoromethylphenyl)prop-2-yn-1-ol, the reaction
did not occur. When we used 1-(1%-naphthyl)prop-2-yn-
1-ol as the substrate, (R)-2n was obtained in 36% yield
with 99% ee (Eq. (1)). It is notable that this reaction
was carried out in organic solvents, which has made the
current procedure practical for organic substrates. The
crude products can be obtained by simple filtration and
washing with diethyl ether.
The prepared propargylic alcohol can be easily con-
verted to the corresponding optically active 2,3-allenol
(Eq. (2)).19
(2)
Under the current reaction conditions, the highly opti-
cally active alkyl-substituted propargylic alcohol (R)-1p
can also be obtained with an extended conversion (Eq.
(3)).
From the above results, we can also conclude that
Candida antarctica lipase
B has demonstrated R
stereoselectivity toward the aryl-substituted terminal
alcohols. By analogy to the conventional models21 for
the lipase-catalyzed reaction of secondary alcohols, aryl
moiety is the large substituent at the hydroxymethine
center as ethynyl is the medium group (Fig. 1).
(1)
(3)

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D. Xu et al. / Tetrahedron Letters 44 (2003) 6343–6346
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In conclusion, we have developed an efficient and facile
method for the preparation of optically active terminal
propargylic alcohols at 60°C. Due to the easy availabil-
ity of both the biocatalyst and racemic terminal propar-
gylic alcohols, this methodology will be useful in
organic synthesis. Further studies on this reaction are
being carried out in our laboratory
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Acknowledgements
Financial support from the Major State Basic Research
Development Program (Grant No. G2000077500),
National Science Foundation of China, and Shanghai
Municipal Committee of Science and Technology are
greatly appreciated. S.M. is the recipient of 1999 Qiu
Shi Award for Young Scientific Workers issued by
Hong Kong Qiu Shi Foundation of Science and Tech-
nology (1999-2003). Novozym 435 is a gift from Novo
Nordisk Inc. (Danburg, CT).
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