Efficient preparation of highly optically active (S)-(-)-2,3-allenols and (R)-(+)-2,3-allenyl acetates by a clean novozym-435-catalyzed enzymatic separation of racemic 2,3-allenols.

Article abstract of DOI:10.1002/1521-3765(20021104)8:21<5012::AID-CHEM5012>3.0.CO;2-2

Novozym-435 has been found to be an effective 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 with excellent ee values. The reaction of 3-(n-butyl)-3,4-pentadien-2-ol (1 a) was successfully performed on a 10 g scale to afford the corresponding (S)-(-)-2,3-allenol (1 a) and (R)-(+)-2,3-allenyl acetate (2 a) in synthetically useful amounts and with high ee values. The advantages of this reaction are the ready availability of the starting materials, high stereoselectivities for both (-)-2,3-allenols and (+)-2,3-allenyl acetates, the use of a relatively high substrate concentration, and a lower catalyst loading. The resulting (S)-(-)-2,3-allenol 1 a can be converted into the corresponding chiral 2,5-dihydrofuran and the vinylic epoxide.

Full text of DOI:10.1002/1521-3765(20021104)8:21<5012::AID-CHEM5012>3.0.CO;2-2

FULL PAPER
Efficient Preparation of Highly Optically Active (S)-(À)-2,3-Allenols and
(R)-(‡)-2,3-Allenyl Acetates by a Clean Novozym-435-Catalyzed Enzymatic
Separation of Racemic 2,3-Allenols**
Daiwang Xu,[a] Zuyi Li,[b] and Shengming Ma*[a]
Abstract: Novozym-435 has been found
to be an effective biocatalyst for the
kinetic resolution of a series of racemic
2,3-allenols, affording highly optically
active (S)-(À)-2,3-allenols and (R)-(‡)-
2,3-allenyl acetates in high yields and
with excellent ee values. The reaction of
3-(n-butyl)-3,4-pentadien-2-ol (1a) w as
successfully performed on a 10 g scale to
afford the corresponding (S)-(À)-2,3-
allenol (1a) and (R)-(‡)-2,3-allenyl ace-
tate (2a) in synthetically useful amounts
and with high ee values. The advantages
of this reaction are the ready availability
of the starting materials, high stereo-
selectivities for both (À)-2,3-allenols
and (‡)-2,3-allenyl acetates, the use of
a relatively high substrate concentra-
tion, and a lower catalyst loading. The
resulting (S)-(À)-2,3-allenol 1a can be
converted into the corresponding chiral
2,5-dihydrofuran and the vinylic epox-
ide.
Keywords: allenes
¥
alcohols
¥
enzymes ¥ kinetic resolution
from 2,3-allenols. Thus, it is highly desirable to develop
efficient methodologies for the synthesis of highly optically
active 2,3-allenols. We have investigated some protocols for
the synthesis of optically active 2,3-allenols with high ee, but
the efficiency proved to be lowdue to the lengthy proce-
dure.[7, 9, 13] For chiral alcohols, enzymes or other biosystems
are usually used to resolve the racemates, leading to both
enantiomers with one isomer in the form of an alcohol and the
corresponding opposite enantiomer in the form of an ester,
which makes the separation very easy due to the huge
difference in the physical properties of these two classes of
products.[14] For these enzymatic processes, the common
problems are: 1) the very limited scope of the substrates,
2) the enantiopurities of both the alcohols and esters, 3) the
loading of the biocatalysts, 4) the concentration of the
substrates, and 5) the reaction rate. Here, we wish to report
an enzymatic protocol for the efficient synthesis of (S)-2,3-
allenols and (R)-2,3-allenyl acetates of high ee values with a
certain range of substrates by means of a kinetic resolution
process employing a lowcatalyst loading and relatively high
substrate concentrations.[15]
Introduction
It is well known that stereoisomers can show rather different
bioactivities, and hence much attention has been focused on
the formation or recognition of chemical bonds in a three-
dimensional manner leading to the highly stereoselective
preparation of enantiomers with one or more chiral center(s)
(element(s)).[1, 2] Allenes are a class of compounds with
interesting properties such as unique reactivity, chirality,
etc.[3] The synthesis of the first allene was reported in 1887[4]
and its structure was confirmed in 1954.[5] Allenes can also be
found in many natural sources.[6] Due to the notion that these
compounds would not be thermally stable, for a long time
their chemistry and synthetic routes remained relatively
unexplored. Thus, methodologies for the efficient synthesis
of highly optically active allenes are quite limited. Recently,
9]
12]
ourselves[7 and others[10
have developed some method-
ologies for the synthesis of 2,5-dihydrofurans, a-methylene
lactones, vinylic epoxides, and a- or g-amino alcohols starting
[a] Prof. S. Ma, D. Xu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (P.R. China)
E-mail: masm@pub.sioc.ac.cn
Results and Discussion
[b] Prof. Z. Li
Synthesis of starting racemic 2,3-allenols: Racemic 2,3-
allenols can be synthesized very conveniently by a one-step
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences
reaction of a propargylic bromide and an aldehyde (for 1a
e
354 Fenglin Lu, Shanghai 200032 (P.R. China)
and 1g l)[16] or by the reduction of 1-benzylpropadienyl
methyl ketone with LiAlH4 for (1 f) (Scheme 1).[17]
[**] China patent pending (02112225.3)
5012
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0821-5012 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 21

5012 5018
the biocatalyst,[18] the yields of both the alcohols and esters
were good and the ee values for both products were excellent!
These results stimulated our considerable interest in this
enzymatic resolution reaction. Some typical results are
presented in Table 2. From the results shown in Table 2, it
can clearly be seen that the enzymatic resolution process is
high-yielding and provides the (À)-2,3-allenols and (‡)-2,3-
allenyl acetates with excellent ee. This methodology can
accommodate a wide range of different R2 groups (entries 1 8,
Table 2); with R1 ˆ Me, Et, the results are excellent. The
absolute configurations of the products were determined by
comparison of the sign of specific rotation of (À)-3-propyl-
pentadien-2-ol (1b) with that of the known (R)-(‡)-1b.[13c]
R2
OH
SnCl2, NaI
DMF, 0oC
R2
R1CHO +
Br
R1
1a: R1 = CH3, R2 = n-C4H9; 1b: R1 = CH3, R2 = n-C3H7
1c: R1 = CH3, R2 = n-C5H11; 1d: R1 = CH3, R2 = n-C6H13
1e: R1 = CH3, R2 = n-C7H15; 1g: R1 = CH3, R2 = PhCH2CH2
1h: R1 = CH3, R2 = 2-propenyl; 1i: R1 = CH2CH3, R2
=
n-C4H9
1j: R1 = CH2CH3, R2
1l: R1 = CH2CH3, R2
=
=
n-C3H7; 1k: R1 = CH2CH3, R2
=
n-C5H11
n-C7H15
CH2Ph
O
LiAlH4
THF
CH2Ph
OH
1f
Scheme 1. Synthesis of the racemic 2,3-allenols.
Table 2. Novozym-435-catalyzed resolution of racemic 2,3-allenols.[a]
R2
Kinetic resolution of racemic 2,3-allenols: The resolution of
3-(n-butyl)-3,4-pentadien-2-ol (1a) with vinyl acetate was
studied using various enzymes. Some typical results are listed
in Table 1. With Novozym 871L and lipolase, no reaction was
observed (entries 1 and 2, Table 1). With lipases AY, PS, and
CCL, the results were rather disappointing (entries 3 5,
Table 1). With lipase AK, which was used by Burgess to
resolve 3-(trimethylsilyl)-3,4-pentadien-2-ol with good selec-
tivity in favor of the corresponding ester (>95% ee) and 81%
ee for the alcohol,[15] (À)-1a was obtained in 26% yield and
99% ee and (‡)-2a in 39% yield and 79% ee (entry 6,
Table 1). Fortunately, however, when we used an immobilized
preparation of Candida antartica lipase B (Novozym-435) as
R2
R2
Novozym-435
+
+
30 o
C
R1
R1
R1
OAc
HO
HO
AcO
1 (racemate)
(S)-(-)-1
(R)-(+)-2
Entry
1
t [h]
(S)-(À)-1
(R)-(‡)-2
Yield[b] ee[c]
R1
R2
Yield[b] ee[c]
[%]
[%]
[%]
[%]
1
2
3
4
5
6
7
8
9
Me nBu (1a)
Me nPr (1b)
96
72
100
39 (1a) 99.0
36 (1b) 99.7
41 (1c) 99.5
31
36
39
31
49
45
44
38
98.9 (2a)
95.4 (2b)
99.0 (2c)
99.1 (2d)
99.2 (2e)
99.2 (2f)
94.3 (2g)
98.8 (2h)
99.5 (2i)
96.4 (2j)
99.7 (2k)
99.4 (2l)
Me n-C5H11 (1c)
Me n-C6H13 (1d)
Me n-C7H15 (1e)
Me PhCH2 (1f)
Me Ph(CH2)2 (1g)
Me allyl (1h)
82.5 40 (1d) 99.1
82.5 45 (1e) 99.0
72
42 (1f) 95.9
82.5 50 (1g) 98.6
82.5 31 (1h) 99.7
Et
Et
Et
Et
n-C4H9 (1i)
n-C3H7 (1j)
n-C5H11 (1k)
n-C7H15 (1l)
102
74
49 (1i)
99.0[d] 43
Table 1. Screening of various enzymes for the resolution of 3-(n-butyl)-3,4-
pentadien-2-ol (1a) with vinyl acetate.[a]
10
11
12
45 (1j) 99.7[d] 37
84
39 (1k) 99.4[d] 38
n-C4H9
n-C4H9
n-C4H9
enzyme
102
49 (1l)
99.7[d] 47
+
+
30 o
C
OAc
CH3
CH3
CH3
[a] The reaction was carried out at 308C using the alcohol (100 mg), vinyl
acetate (5 mL), and Novozym-435 (70 mg). [b] Isolated yield based on alcohol.
[c] Enantiomeric excess was determined by GC or HPLC. [d] Determined after
conversion to the corresponding acetate.
HO
AcO
HO
(R)-(+)-2a
(S)-(-)-1a
1a
Entry Catalyst
t [d]
(S)-(À)-1a
(R)-(‡)-2a
Yield [%][b] ee [%][c] Yield [%][b] ee [%][c]
This methodology can be efficiently applied to the synthesis
of highly optically active (À)-2,3-allenols and (‡)-2,3-allenyl
acetates in large quantities. For example, after the treatment
of 1a (10.005 g, 71 mmol) with Novozym-435 (7.000 g) in vinyl
acetate (500 mL) for 47 h at 308C, crude products were
obtained following filtration, washing the solids with diethyl
ether, and concentration of the combined filtrate and wash-
ings. The crude products could be easily separated by flash
chromatography on silica gel (column length 12 cm, diameter
6.5 cm; petroleum ether/diethyl ether 20:1 (300 mL) ! 10:1
(400 mL) ! 5:1 (350 mL) ! 3:1 (500 mL)) to afford 4.622 g
of (S)-(À)-1a and 5.723 g of (R)-(‡)-2a. It only took 55 min
from packing of the column to complete the elution,
illustrating the potential of this methodology [Eq. (1)].
1
2
3
4
5
6
7
Novozym 871L
Lipolase
CCL
Lipase AY
Lipase PS
Lipase AK
Novozym-435
4
4
4
4
4
4
4
NR
NR
40
24
34
NR
NR
17
35
20
9
1
39
99
22
38
96
79
99
26
39
39
31
[d]
[a] The reaction was carried out at 308C using 1a (100 mg), vinyl acetate
(5 mL), and enzyme (70 mg). [b] Isolated yield based on 1a. [c] Enantio-
meric excess determined by GC. [d] (‡)-1a was not detected by GC.
Abstract in Chinese:
n-C4H9
n-C4H9
n-C4H9
Novozym-435
30 oC
+
+
(1)
OAc
CH3
CH3
CH3
HO
AcO
HO
(S)-(-)-1a
(R)-(+)-2a
1a
10.005 g
4.662 g (46%)
(R)-isomer
not detected
by GC
5.723 g (44%)
98.7% ee
Chem. Eur. J. 2002, 8, No. 21
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0821-5013 $ 20.00+.50/0
5013

S. Ma et al.
FULL PAPER
Table 4. Novozym-435-catalyzed resolution of racemic 2,3-allenols at
different substrate concentrations and catalyst loadings.
Typical drawbacks of biocatalyzed reactions are a low
working concentration of the substrate, a high catalyst
loading, and long reaction times. Further studies showed that
this Novozym-435-catalyzed kinetic resolution could be
performed at higher concentrations of the substrates and
lower loadings of the catalyst (entries 1 3, Table 3). The
immobilized enzyme showed much higher activity even at
608C, without any obvious loss of the enantioselectivity
(entry 5, Table 3). At this temperature, the catalyst loading
may be as lowas 23 mgg À1 of substrate without obvious loss of
stereoselectivity, and the reaction is complete within 24 h
(entry 9, Table 3).
R2
R2
R2
Novozym-435
+
+
60 o
C
R1
R1
R1
OAc
HO
HO
(S)-(-)-1
AcO
(R)-(+)-2
1 (racemate)
Entry
1
Conc.
[mLgÀ1
Cat.
[mggÀ1
t
(S)-(À)-1
(R)-(‡)-2
]
]
[h]
Yield
ee
Yield
ee
[%]
[%] [%]
[%]
[a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
1a 1.5
1b 1.5
23
23
92
92
23
46
23
46
46
23
23
92
46
23
46
92
23
92
23
23
92
24
20
36 (1a)
39 (2a) 95.2
30 (1b) 82.2 38 (2b) 98.4
21.5 31 (1b) 99.3 43 (2b) 95.8
1b
1b
6
6
19
24
26
28
30
28
28
24
22
21
49
34 (1b) 96.3 41 (2b) 97.4
1c 1.5
1c
1d 1.5
41 (1c) 85.0 40 (2c) 98.2
[a]
3
41 (1c)
48 (2c) 97.7
Table 3. Optimization of Novozym-435-promoted kinetic resolution of 1a.
43 (1d) 91.2 43 (2d) 96.8
1d
1d
3
3
41 (1d) 99.4 43 (2d) 96.5
C4H9
C4H9
C4H9
OH
Novozym-435
[a]
+
45 (1d)
51 (2d) 99.0
+
OAc
1e 1.5
1f 1.5
50 (1e) 98.7 50 (2e) 98.4
HO
(S)-(-)-1a
AcO
(R)-(+)-2a
48 (1f) 89.7 31 (2f) 99.3
[a]
1a
1f
1h
1i
1i
1i
6
3
1.5
3
6
38 (1f)
41 (2f) 96.7
35 (1h) 90.0 34 (2h) 98.3
60 (1i) 28.5 24 (2i) 94.0
44.5 52 (1i) 73.6 36 (2i) 97.9
Entry Solvent Substrate Enzyme
T
t
(S)-(À)-1a
(R)-(‡)-2a
Yield ee
[%] [%] [%]
[mL]
[mg]
[mg]
[8C] [h] Yield ee
[%]
41
26
27
43
28
43
54 (1i) 96.4 41 (2i) 97.3
58 (1j) 49.4 30 (2j) 98.0
44 (1j) 74.7 38 (2j) 97.7
39 (1k) 98.5 45 (2k) 99.1
31 (1l) 70.7 40 (2l) 99.3
48 (1l) 66.0 38 (2l) 97.0
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
1j 1.5
1j
1k 1.5
1
2
3
4
5
6
7
8
9
2.5
1.25
5
5
5
1.25
3
1.5
1.5
100
100
100
100
100
100
500
500
1000
35
18
70
70
70
18.5
46
23
23
30
30
40
50
60
60
60
60
60
96
95
48
40
37
32
40
40
32
35
45
43
39
36
41
39
39
97.2
99.6
99.1
6
1l
1l
1.5
6
97.8
[a]
24.5 36
23
24
24
24
33
40
35
36
96.2
96.0
95.6
95.2
[a] The opposite enantiomer was not detected by GC.
C4H9
CH3
[a] The opposite enantiomer was not detected by GC.
AgNO3
H2O / acetone
O
reflux, 60%
(S)-3a
(>99% ee)
Some typical results for this kinetic resolution, on a scale of
1.0 g at higher concentrations and lower catalyst loadings, are
summarized in Table 4. From Table 4, it is interesting to note
that: 1) at a lower catalyst loading, in some cases the
stereoselectivity in favor of 2,3-allenyl acetate is of no
practical value, while that for (À)-2,3-allenols is still reason-
able (entries 2, 5, 11, 13, 14, 15, 17, 18, 20, and 21, Table 4);
2) for the same substrate, reaction at a lower concentration
and a higher catalyst loading affords the products with higher
ee values.
C4H9
CH3
C4H9
CH3
PdCl2, DMA
allyl bromide
rt, 68%
O
HO
(S)-4a
(>99% ee)
(S)-(-)-1a
(>99% ee)
C4H9
CH3
[Pd(PPh3)4 ]/ PhI
O
K2CO3, DMF
75-80oC, 59%
Ph
(S,S)-5a
(d.r. 35:1;
99.4% ee)
The prepared 2,3-allenols can be easily converted to
optically active 2,5-dihydrofurans[8] and vinylic epoxide de-
rivatives[7] (Scheme 2).
Scheme 2. Different reactions of (S)-(À)-1a.
In conclusion, we have established a protocol for the
preparation of (S)-(À)-2,3-allenols and (R)-(‡)-2,3-allenyl
acetates with ee values of practical value. The reaction can be
carried out on a large scale to afford the pure products with
high ee values following an efficient flash chromatographic
separation. Due to the ready availability of racemic 2,3-
allenols, high stereoselectivity for both products, a relatively
high working concentration, a lower catalyst loading, and the
synthetic potential of the products, this methodology should
be useful in organic synthesis and provide information for
studies of the interaction of 2,3-allenols with biosystems.
Further studies on this reaction are being carried out in our
laboratory.
Experimental Section
General procedures: All solvents were distilled prior to use. 1H and
13C NMR spectra were recorded from samples in CDCl3 on a Varian
300 MHz spectrometer. IR spectra were obtained using a Perkin-Elmer 983
instrument. Mass spectra were obtained using a HP 5989A instrument.
High-resolution mass spectra (HRMS) were obtained using a Finnigan
MAT 8430 instrument. GC analyses were performed on a Perkin-Elmer
Autosystem XL gas chromatograph instrument. HPLC was carried out
using a Perkin-Elmer 200 pump/785A instrument.
Synthesis of racemic 2,3-allenols 1a l: The racemic 2,3-allenols 1a e and
1g l were obtained by the reaction of propargylic bromide, the aldehyde,
5014
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0821-5014 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 21

Enzymatic Separation of Racemic 2,3-Allenols
5012 5018
and SnCl2[16]; 1 f was prepared by the reduction of the corresponding allenic
CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 203.72, 108.67, 78.50, 67.58,
ketone with LiAlH4.[17]
29.69, 27.53, 22.37, 21.89, 13.84; IR (neat): nÄ ˆ 3332 cmÀ1 (OH), 1956 cmÀ1
‡
ˆ ˆ
(C C C); MS (70 eV): m/z (%): 140 (2) [M ]. (R)-(‡)-2a: 98.9% ee (GC
Synthesis of (Æ)-3-(n-butyl)penta-3,4-dien-2-ol (1a): Typical procedure: A
suspension of tin(ii) chloride (4.70 g, 25.0 mmol), 1-bromo-hept-2-yne
(3.90 g, 22.5 mmol), and sodium iodide (3.75 g, 25.0 mmol) in N,N-
dimethylformamide (50 mL) was stirred at room temperature for 1 h.
The reaction mixture was then cooled to 08C and acetaldehyde (2.20 g,
50 mmol) was added. The resulting mixture was stirred at this temperature
for 12 h, quenched with water, and extracted with diethyl ether. The
combined organic layers were washed with water, and dried over
anhydrous magnesium sulfate. After evaporation of the solvent, the
residue was purified by flash chromatography on silica gel (petroleum
ether/diethyl ether 20:1) to afford 1a (1.63 g, 50%).
conditions: column: RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier:
N2, 10 psi; injector: 2508C; detector (FID, H2, 0.218 MPa): 2508C; oven
temperature: 1008C (35 min)); liquid; 1H NMR (300 MHz, CDCl3, 258C):
d ˆ 5.32 5.20 (m, 1H; CH), 4.80 4.75 (m, 2H; CH2), 1.97 1.78 (m, 5H;
3
CH2 and CH3), 1.49 1.00 (m, 4H; 2CH2), 1.22 (d, J(H,H) ˆ 6.6 Hz, 3H;
CH3), 0.81 (t, 3J(H,H) ˆ 6.7 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3,
258C): d ˆ 205.96, 170.69, 105.03, 78.36, 70.47, 29.81, 28.25, 22.55, 21.44,
19.08, 14.10; IR (neat): nÄ ˆ 1958 cmÀ1 (C C C), 1739 cm (C O); APCI
À1
ˆ ˆ
ˆ
‡
‡
MS: m/z: 183 [M ‡H]; HRMS: calcd for C9H15O [M À COCH3]:
139.1123, found: 139.1130.
Synthesis of (S)-(À)-3-(n-propyl)penta-3,4-dien-2-ol and (R)-(‡)-3-(n-
propyl)penta-3,4-dien-2-yl acetate: Treatment of racemic 3-(n-propyl)pen-
ta-3,4-dien-2-ol (101 mg) with Novozym-435 (70 mg) afforded (S)-(À)-1b
(36 mg, 36%) and (R)-(‡)-2b (48 mg, 36%). (S)-(À)-1b: 99.7% ee (GC
conditions: column: RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier:
N2, 10 psi; injector: 2508C; detector (FID, H2, 0.218 MPa): 2508C; oven
temperature: 1008C (35 min)); liquid; 1H NMR (300 MHz, CDCl3, 258C):
d ˆ 4.93 4.80 (m, 2H; CH2), 4.29 4.13 (m, 1H; CH), 2.09 1.84 (m, 2H,
CH2), 1.68 (s, 1H, OH), 1.57 1.40 (m, 2H, CH2), 1.30 (d, 3J(H,H) ˆ 6.7 Hz,
3H; CH3), 0.93 (t, 3J(H,H) ˆ 7.3 Hz, 3H; CH3); 13C NMR (75.4 MHz,
CDCl3, 258C): d ˆ 203.66, 108.75, 78.90, 67.70, 30.17, 22.07, 20.88, 13.89; IR
(Æ)-3-(n-Propyl)penta-3,4-dien-2-ol (1b): Reaction of 1-bromo-hex-2-yne
(6.78 g, 42.4 mmol) with acetaldehyde (3.70 g, 84.8 mmol) afforded 1b
(2.41 g, 45%).
(Æ)-3-(n-Pentyl)penta-3,4-dien-2-ol (1c): Reaction of 1-bromo-oct-2-yne
(11.1 g, 59 mmol) with acetaldehyde (5.20 g, 118.0 mmol) afforded 1c
(7.20 g, 79%).
(Æ)-3-(n-Hexyl)penta-3,4-dien-2-ol (1d): Reaction of 1-bromo-non-2-yne
(4.06 g, 20.0 mmol) with acetaldehyde (1.76 g, 40.0 mmol) afforded 1d
(2.16 g, 64%).
(Æ)-3-(n-Heptyl)penta-3,4-dien-2-ol (1e): Reaction of 1-bromo-dec-2-yne
(6.48 g, 30.0 mmol) with acetaldehyde (2.64 g, 60.0 mmol) afforded 1e
(3.70 g, 67%).
(neat): nÄ ˆ 3350 cmÀ1 (OH), 1955 cmÀ1 (C C C); MS (70 eV): m/z (%): 126
ˆ ˆ
‡
(1) [M ].
(Æ)-3-(2'-Phenylethyl)penta-3,4-dien-2-ol (1g): Reaction of 1-bromo-5-
phenylpent-2-yne (4.01 g, 18.0 mmol) with acetaldehyde (3.70 g,
84.8 mmol) afforded 1g (2.03 g, 60%).
(R)-(‡)-2b: 95.4% ee (GC conditions: column: RT-bDEXcst (30 m, Æ
0.25 m, 0.25 mm DF); carrier: N2, 10 psi; injector: 2508C; detector (FID,
H2, 0.218 MPa): 2508C; oven temperature: 858C (20 min), then
1.0 8CminÀ1 to 1008C); liquid; 1H NMR (300 MHz, CDCl3, 258C): d ˆ
5.38 5.22 (m, 1H; CH), 4.93 4.80 (m, 2H; CH2), 2.04 (s, 3H; CH3),
2.00 1.80 (m, 2H; CH2), 1.58 1.36 (m, 4H; 2CH2), 1.32 (d, 3J(H,H) ˆ
5.7 Hz, 3H; CH3), 0.91 (t, 3J(H,H) ˆ 7.3 Hz, 3H; CH3); 13C NMR
(Æ)-3-Allylpenta-3,4-dien-2-ol (1h): Reaction of 6-bromo-hex-1-en-4-yne
(3.18 g, 20 mmol) with acetaldehyde (1.76 g, 40.0 mmol) afforded 1h
(1.10 g, 44%).
(Æ)-4-(n-Butyl)hexa-4,5-dien-3-ol (1i): Reaction of 1-bromo-hept-2-yne
(6.68 g, 38.4 mmol) with acetaldehyde (3.38 g, 76.8 mmol) afforded 1i
(3.68 g, 62%).
(75.4 MHz, CDCl3, 258C): d ˆ 206.03, 170.87, 104.89, 78.42, 70.55, 30.72,
À1
21.53, 20.95, 19.14, 14.07; IR (neat): nÄ ˆ 1958 cmÀ1 (C C C), 1738 cm
ˆ ˆ
‡
ˆ
(C O); MS (70 eV): m/z (%): 126 (25) [M À COCH2]; HRMS: calcd for
‡
(Æ)-4-(n-Propyl)hexa-4,5-dien-3-ol (1j): Reaction of 1-bromo-hex-2-yne
(6.90 g, 43.2 mmol) with propionaldehyde (2.01 g, 34.6 mmol) afforded 1j
(4.10 g, 67%).
C8H13O [M À COCH3]: 125.0966, found: 125.0946.
Synthesis of (S)-(À)-3-(n-pentyl)penta-3,4-dien-2-ol and (R)-(‡)-3-(n-
pentyl)penta-3,4-dien-2-yl acetate: Treatment of racemic 3-(n-pentyl)pen-
ta-3,4-dien-2-ol (l01 mg) with Novozym-435 (70 mg) afforded (S)-(À)-1c
(41 mg, 41%) and (R)-(‡)-2c (50 mg, 39%). (S)-(À)-1c: 99.5% ee (GC
conditions: column: RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier:
N2, 10 psi; injector: 2508C; detector (FID, H2, 0.218 MPa): 2508C; oven
temperature: 1208C (50 min), then 1.08CminÀ1 to 1358C); liquid; 1H NMR
(300 MHz, CDCl3, 258C): d ˆ 4.93 4.80 (m, 2H; CH2), 4.27 4.07 (m, 1H;
CH), 2.13 1.87 (m, 2H; CH2), 1.68 (s, 1H; OH), 1.60 1.11 (m, 6H; 3CH2),
(Æ)-4-(n-Pentyl)hexa-4,5-dien-3-ol (1k): Reaction of 1-bromo-dec-2-yne
(7.10 g, 37.5 mmol) with propionaldehyde (1.74 g, 30.0 mmol) afforded 1k
(3.40 g, 68%).
(Æ)-4-(n-Heptyl)hexa-4,5-dien-3-ol (1l): Reaction of 1-bromo-dec-2-yne
(7.08 g, 37.5 mmol) with propionaldehyde (1.74 g, 30.0 mmol) afforded 1l
(3.40 g, 68%).
Synthesis of (Æ)-3-benzylpenta-3,4-dien-2-ol (1 f): A solution of 3-benzyl-
penta-3,4-dien-2-one (1.60 g, 9.30 mmol) in THF (20 mL) was added
dropwise to a suspension of LiAlH4 (0.38 g, 10.0 mmol) in THF (20 mL)
with cooling (ice bath). After the addition, the reaction mixture was stirred
for a further 20 min at 08C. The excess LiAlH4 was then decomposed by the
dropwise addition of water until the gray slurry turned into white granules.
The mixture was then filtered and the residual solid was washed with
diethyl ether. The combined organic phases were washed with brine and
dried over anhydrous sodium sulfate. After evaporation of the solvent, the
residue was purified by flash chromatography on silica gel (petroleum ether
(30 608C)/diethyl ether 8:1) to afford 1 f (1.17 g, 72%).
3
3
1.25 (d, J(H,H) ˆ 6.6 Hz, 3H; CH3), 0.88 (t, J(H,H) ˆ 6.7 Hz, 3H; CH3);
13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 204.27, 108.81, 78.36, 67.82, 31.78,
27.98, 27.48, 22.67, 22.07, 14.16; IR (neat): nÄ ˆ 3346 cmÀ1 (OH), 1956 cmÀ1
‡
ˆ ˆ
(C C C); APCI MS: m/z: 155 [M ‡H]; HRMS: calcd for C10H19O
‡
[M ‡H]: 155.1436, found: 155.1436.
(R)-(‡)-2c: 99.0% ee (GC conditions: column: RT-bDEXcst (30 m, Æ
0.25 m, 0.25 mm DF); carrier: N2, 10 psi; injector: 2508C; detector (FID,
H2, 0.218 MPa): 2508C; oven temperature: 1008C (30 min)); liquid;
1H NMR (300 MHz, CDCl3, 258C): d ˆ 5.32 5.20 (m, 1H; CH), 4.80
4.75 (m, 2H; CH2), 1.98 (s, 3H; CH3), 1.97 1.80 (m, 2H; CH2), 1.49 1.00
(m, 9H; 3CH2 and CH3), 0.84 (t, 3J(H,H) ˆ 6.7 Hz, 3H; CH3); 13C NMR
(75.4 MHz, CDCl3, 258C): d ˆ 205.99, 170.72, 105.08, 78.38, 70.49, 31.70,
Kinetic resolution of racemic 2,3-allenols 1a l and allenyl acetates 2a
l
Synthesis of (S)-(À)-(3-n-butyl)penta-3,4-dien-2-ol and (R)-(‡)-(3-n-bu-
tyl)penta-3,4-dien-2-yl acetate: Typical procedure: Novozym-435 (70 mg)
was added to a racemic mixture of (3-n-butyl)penta-3,4-dien-2-ol (l00 mg)
and vinyl acetate (5 mL). After stirring at 308C for 96 h, the reaction
mixture was worked-up by filtration. After evaporation of the solvent,
purification of the residue by flash chromatography on silica gel (petroleum
ether/diethyl ether 40:1 ! 10:1) afforded (S)-(À)-1a (39 mg, 39%) and
(R)-(‡)-2a (40 mg, 31%). (S)-(À)-1a: 99.0% ee (GC conditions: column:
RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier: N2, 10 psi; injector:
2508C; detector (FID, H2, 0.218 MPa): 2508C; oven temperature: 1008C
(35 min)); liquid; 1H NMR (300 MHz, CDCl3, 258C): d ˆ 4.82 4.78 (m,
2H; CH2), 4.20 4.02 (m, 1H; CH), 2.02 1.80 (m, 2H; CH2), 1.60 (s, 1H,
OH), 1.50 1.05 (m, 7H; 2CH2 and CH3), 0.82 (t, 3J(H,H) ˆ 6.7 Hz, 3H;
28.53, 27.34, 22.69, 21.44, 19.09, 14.25; IR (neat): nÄ ˆ 1958 cmÀ1 (C C C),
ˆ ˆ
‡
1740 cmÀ1 (C O); APCI MS: m/z: 197 [M ‡H]; HRMS: calcd for C10H17O
ˆ
‡
[M À COCH3]: 153.1279, found: 153.1269.
Synthesis of (S)-(À)-3-(n-hexyl)penta-3,4-dien-2-ol and (R)-(‡)-3-(n-hex-
yl)penta-3,4-dien-2-yl acetate: Treatment of racemic 3-(n-hexyl)penta-3,4-
dien-2-ol (l00 mg) with Novozym-435 (70 mg) afforded (S)-(À)-1d (40 mg,
40%) and (R)-(‡)-2d (39 mg, 31%). (S)-(À)-1d: 99.1% ee (GC con-
ditions: column: RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier: N2,
10 psi; injector: 2508C; detector (FID, H2, 0.218 MPa): 2508C; oven
temperature: 1208C (50 min), then 1.08CminÀ1 to 1358C); liquid; 1H NMR
(300 MHz, CDCl3, 258C): d ˆ 4.96 4.80 (m, 2H; CH2), 4.33 4.09 (m, 1H;
CH), 2.13 1.83 (m, 2H; CH2), 1.65 (s, 1H; OH), 1.57 1.04 (m, 11H; 4CH2
Chem. Eur. J. 2002, 8, No. 21
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0821-5015 $ 20.00+.50/0
5015

S. Ma et al.
FULL PAPER
and CH3), 0.87 (t, 3J(H,H) ˆ 6.7 Hz, 3H; CH3); 13C NMR (75.4 MHz,
CDCl3, 258C): d ˆ 203.64, 108.83, 78.71, 67.62, 31.62, 28.98, 27.93, 27.52,
3H; CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 203.95, 141.91, 128.38,
128.25, 125.83, 108.24, 79.33, 67.83, 33.95, 29.63, 21.95; IR (neat): nÄ ˆ 3368
‡
22.54, 21.96, 13.98; IR (neat): nÄ ˆ 3339 (OH), 1956 cmÀ1 (C C C); APCI
(OH), 1955 cmÀ1 (C C C); APCI MS: m/z: 189 [M ‡H]; HRMS: calcd
ˆ ˆ
ˆ ˆ
‡
‡
‡
MS: m/z: 169 [M ‡H]; HRMS: calcd for C11H21O [M ‡H]: 169.1592,
for C13H17O [M ‡H]: 189.1279, found: 189.1280.
found: 169.1596.
(R)-(‡)-2g: 94.3% ee (HPLC conditions: Chiralcel OJ column
(Æ 0.46 cm  25 cm); l ˆ 254 nm; rate: 0.7 mLminÀ1
; hexane/iPrOH
(R)-(‡)-2d: 99.1% ee (GC conditions: column: RT-bDEXcst (30 m, Æ
0.25 m, 0.25 mm DF); carrier: N2, 10 psi; injector: 2508C; detector (FID,
H2, 0.218 MPa): 2508C; oven temperature: 1208C (50 min), then
1.0 8CminÀ1 to 1358C); liquid; 1H NMR (300 MHz, CDCl3, 258C): d ˆ
5.37 5.20 (m, 1H; CH), 4.89 4.71 (m, 2H; CH2), 1.98 (s, 3H; CH3),
1.97 1.80 (m, 2H; CH2), 1.44 1.09 (m, 11H; 4CH2 and CH3), 0.81 (t,
3J(H,H) ˆ 7.3 Hz, 3 H ; CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ
97:3); liquid; 1H NMR (300 MHz, CDCl3, 258C): d ˆ 7.42 7.04 (m, 5H;
C6H5), 5.44 5.24 (m, 1H; CH), 4.96 4.84 (m, 2H; CH2), 2.74 (t, 3J(H,H) ˆ
7.9 Hz, 2H; CH2), 2.40 2.11 (m, 2H; CH2), 2.03 (s, 3H; CH3), 1.34 (d,
3J(H,H) ˆ 6.3 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ
205.72, 170.28, 141.68, 128.26, 128.16, 125.75, 104.30, 78.72, 70.12, 33.71,
À1
ˆ ˆ
ˆ
29.98, 21.07, 18.74; IR (neat): nÄ ˆ 1958 (C C C), 1737 cm (C O); APCI
‡
‡
MS: m/z: 231 [M ‡H]; HRMS: calcd for C13H15O [M À COCH3]:
204.76, 169.59, 103.87, 77.20, 69.33, 30.65, 27.94, 27.37, 26.41, 21.60, 20.28,
À1
ˆ ˆ
ˆ
187.1123, found: 187.1118.
17.89, 13.07; IR (neat): nÄ ˆ 1958 (C C C), 1740 cm (C O); APCI MS:
‡
‡
m/z: 211 [M ‡H]; HRMS: calcd for C11H19O [M À COCH3]: 167.1436,
Synthesis of (S)-(À)-3-allylpenta-3,4-dien-2-ol and (R)-(‡)-3-allylpenta-
3,4-dien-2-yl acetate: Treatment of racemic 3-allylpenta-3,4-dien-2-ol
(l00 mg) with Novozym-435 (70 mg) afforded (S)-(À)-1h (31 mg, 31%)
and (R)-(‡)-2h (51 mg, 38%). (S)-(À)-1h: 99.7% ee (GC conditions:
column: RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier: N2, 10 psi;
injector: 2508C; detector (FID, H2, 0.218 MPa): 2508C; oven temperature:
1208C (50 min), then 1.08CminÀ1 to 1358C); liquid; 1H NMR (300 MHz,
CDCl3, 258C): d ˆ 5.84 5.64 (m, 1H; CH), 5.09 4.96 (m, 2H; CH2), 4.84
4.76 (m, 2H; CH2), 4.29 4.04 (m, 1H; CH), 2.84 2.60 (m, 2H; CH2), 1.57
found: 167.1441.
Synthesis of (S)-(À)-3-(n-heptyl)penta-3,4-dien-2-ol and (R)-(‡)-3-(n-
heptyl)penta-3,4-dien-2-yl acetate: Treatment of racemic 3-(n-heptyl)pen-
ta-3,4-dien-2-ol (l00 mg) with Novozym-435 (70 mg) afforded (S)-(À)-1e
(45 mg, 45%) and (R)-(‡)-2e (60 mg, 49%). (S)-(À)-1e: 99.0% ee (GC
conditions: column: RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier:
N2, 10 psi; injector: 2508C; detector (FID, H2, 0.218 MPa): 2508C; oven
temperature: 1208C (50 min), then 1.08CminÀ1 to 1358C); liquid; 1H NMR
(300 MHz, CDCl3, 258C): d ˆ 4.89 4.76 (m, 2H; CH2), 4.20 4.00 (m, 1H;
CH), 2.09 1.78 (m, 2H; CH2), 1.63 (s, 1H; OH), 1.53 1.00 (m, 13H; 5CH2
and CH3), 0.78 (t, 3J(H,H) ˆ 6.1 Hz, 3H; CH3); 13C NMR (75.4 MHz,
CDCl3, 258C): d ˆ 204.18, 108.94, 78.58, 67.87, 32.03, 29.56, 29.37, 28.11,
3
(s, 1H; OH), 1.23 (d, J(H,H) ˆ 6.7 Hz, 3H; CH3); 13C NMR (75.40 MHz,
CDCl3, 258C): d ˆ 204.70, 135.90, 116.24, 107.01, 78.63, 67.61, 33.34, 22.10;
IR (neat): nÄ ˆ 3342 (OH), 1957 cmÀ1 (C C C); MS (70 eV): m/z (%): 124
ˆ ˆ
‡
‡
(0.7) [M ]; HRMS: calcd for C8H11 [M À OH]: 107.0861, found 107.0856.
27.85, 22.82, 22.14, 14.21; IR (neat): nÄ ˆ 3341 (OH), 1956 cmÀ1 (C C C);
ˆ ˆ
(R)-(‡)-2h: 98.8% ee (GC conditions: column: RT-bDEXcst (30 m, Æ
0.25 m, 0.25 mm DF); carrier: N2, 10 psi; injector: 2508C; detector (FID,
H2, 0.218 MPa): 2508C; oven temperature: 1008C (35 min)); liquid;
1H NMR (300 MHz, CDCl3, 258C): d ˆ 5.89 5.67 (m, 1H; CH), 5.40 5.23
(m, 1H; CH), 5.10 5.00 (m, 2H; CH2), 4.91 4.78 (m, 2H; CH2), 2.84 2.63
(m, 2H; CH2), 2.05 (s, 3H; CH3), 1.32 (d, 3J(H,H) ˆ 6.1 Hz, 3H; CH3);
13C NMR (75.40 MHz, CDCl3, 258C): d ˆ 206.06, 170.55, 135.08, 116.17,
‡
‡
APCI MS: m/z: 183 [M ‡H]; HRMS: calcd for C12H23O [M ‡H]:
183.1749, found: 183.1749. (R)-(‡)-2e: 99.2% ee (GC conditions: column:
RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier: N2, 10 psi; injector:
2508C; detector (FID, H2, 0.218 MPa): 2508C; oven temperature: 1208C
(50 min), then 1.08CminÀ1 to 1358C); liquid; 1H NMR (300 MHz, CDCl3,
258C): d ˆ 5.37 5.16 (m, 1H; CH), 4.89 4.64 (m, 2H; CH2), 1.98 (s, 3H;
CH3), 1.96 1.84 (m, 2H; CH2), 1.53 1.04 (m, 13H; 5CH2 and CH3), 0.81 (t,
3J(H,H) ˆ 6.1 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ
ˆ ˆ
103.10, 78.31, 69.77, 33.53, 21.18, 18.74; IR (neat): nÄ ˆ 1959 (C C C),
‡
1738 cmÀ1 (C O); APCI MS: m/z: 167 [M ‡H]; HRMS: calcd for C8H12O
ˆ
‡
204.76, 169.58, 103.87, 77.19, 69.32, 30.81, 28.25, 28.11, 27.37, 26.46, 21.63,
[M À COCH2]: 124.0889, found: 124.0864.
À1
20.28, 17.89, 13.08; IR (neat): nÄ ˆ 1958 cmÀ1 (C C C), 1739 cm (C O);
ˆ ˆ
ˆ
Synthesis of (S)-(À)-4-(n-butyl)hexa-4,5-dien-3-ol and (R)-(‡)-4-(n-bu-
tyl)hexa-4,5-dien-3-yl acetate: Treatment of racemic 4-(n-butyl)hexa-4,5-
dien-3-ol (l01 mg) with Novozym-435 (70 mg) afforded (S)-(À)-1i (49 mg,
49%) and (R)-(‡)-2i (55 mg, 43%). (S)-(À)-1i: 99.0% ee (GC conditions:
column: RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier: N2, 10 psi;
injector: 2508C; detector (FID, H2, 0.218 MPa): 2508C; oven temperature:
1008C (30 min), then 1.08CminÀ1 to 1808C (20 min)); liquid; 1H NMR
(300 MHz, CDCl3, 258C): d ˆ 4.93 4.76 (m, 2H; CH2), 4.04 3.99 (m, 1H;
CH), 2.09 1.80 (m, 2H; CH2), 1.80 1.16 (m, 7H; 3CH2 and OH), 1.00
0.71 (m, 6H; 2CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 204.64,
‡
‡
APCI MS: m/z: 225 [M ‡H]; HRMS: calcd for C12H22O [M À COCH2]:
182.1671, found: 182.1680.
Synthesis of (S)-(À)-3-benzylpenta-3,4-dien-2-ol and (R)-(‡)-3-benzylpen-
ta-3,4-dien-2-yl acetate: Treatment of racemic 3-benzylpenta-3,4-dien-2-ol
(l00 mg) with Novozym-435 (70 mg) afforded (S)-(À)-1 f (42 mg, 42%) and
(R)-(‡)-2 f (55 mg, 45%). (S)-(À)-1 f: 95.9% ee (HPLC conditions:
Chiralpak AD column (Æ 0.46 cm  25 cm); l ˆ 254 nm; rate:
0.7 mLminÀ1; hexane/iPrOH 100:1.5); liquid; 1H NMR (300 MHz, CDCl3,
258C): d ˆ 7.36 7.12 (m, 5H; C6H5), 4.84 4.80 (m, 2H; CH2), 4.24 4.16
(m, 1H; CH), 3.50 3.30 (m, 2H; CH2), 1.60 (s, 1H; OH), 1.20 (d,
3J(H,H) ˆ 6.7 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ
205.59, 139.76, 129.33, 128.58, 126.56, 108.33, 78.40, 67.19, 35.97, 22.40; IR
107.52, 78.70, 73.38, 30.04, 28.54, 27.76, 22.72, 14.17, 9.92; IR (neat): nÄ ˆ 3342
‡
(OH), 1956 cmÀ1 (C C C); APCI MS: m/z: 155 [M ‡H]; HRMS: calcd
ˆ ˆ
‡
for C10H19O [M ‡H]: 155.1436, found: 155.1431.
(neat): nÄ ˆ 3363 (OH), 1956 cmÀ1 (C C C); MS (70 eV): m/z (%): 174 (0.1)
ˆ ˆ
(R)-(‡)-2i: 99.5% ee (determined after conversion to the corresponding
acetate); liquid; 1H NMR (300 MHz, CDCl3, 258C): d ˆ 5.20 5.04 (m, 1H;
CH), 4.93 4.68 (m, 2H; CH2), 2.04 (s, 3H; CH3), 2.00 1.80 (m, 2H; CH2),
1.76 1.64 (m, 2H; CH2), 1.49 1.20 (m, 4H; 2CH2), 1.00 0.71 (m, 6H;
2CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 206.33, 170.75, 103.50,
77.89, 75.56, 29.80, 28.00, 26.08, 22.55, 21.31, 14.08, 10.05; IR (neat): nÄ ˆ
‡
[M ].
(R)-(‡)-2 f: 99.2% ee (HPLC conditions: Chiralcel OJ column
(Æ0.46 cm  25 cm); l ˆ 254 nm; rate: 0.7 mLminÀ1; hexane/iPrOH 97:3);
liquid; 1H NMR (300 MHz, CDCl3, 258C): d ˆ 7.37 7.09 (m, 5H; C6H5),
5.36 5.24 (m, 1H; CH), 4.89 4.80 (m, 2H; CH2), 3.40 3.27 (m, 2H; CH2),
1.99 (s, 3H; CH3), 1.30 (d, 3J(H,H) ˆ 6.7 Hz, 3H; CH3); 13C NMR
(75.4 MHz, CDCl3, 258C): d ˆ 207.25, 170.74, 139.23, 129.16, 128.49,
126.54, 104.52, 78.31, 69.93, 36.45, 21.37, 19.22; IR (neat): nÄ ˆ 1958
À1
‡
ˆ ˆ
ˆ
1958 (C C C), 1740 cm (C O); APCI MS: m/z: 197 [M ‡H]; HRMS:
‡
calcd for C10H18O [M À COCH2]: 154.1357, found: 154.1346.
Synthesis of (S)-(À)-4-(n-propyl)hexa-4,5-dien-3-ol (1j) and (R)-(‡)-4-(n-
propyl)hexa-4,5-dien-3-yl acetate: Treatment of racemic 4-(n-propyl)hexa-
4,5-dien-3-ol (l01 mg) with Novozym-435 (70 mg) afforded (S)-(À)-1j
(45 mg, 45%) and (R)-(‡)-2j (48 mg, 37%). (S)-(À)-1j: 99.7% ee (GC
conditions: column: RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier:
N2, 10 psi; injector: 2508C; detector (FID, H2, 0.218 MPa): 2508C; oven
temperature: 1008C (30 min), then 1.08CminÀ1 to 1808C (20 min)); liquid;
1H NMR (300 MHz, CDCl3, 258C): d ˆ 4.96 4.74 (m, 2H; CH2), 4.00 3.82
(m, 1H; CH), 2.02 1.80 (m, 2H; CH2), 1.80 1.24 (m, 5H; 2CH2 and OH),
1.02 0.80 (m, 6H; 2CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 204.64,
À1
‡
ˆ ˆ
ˆ
(C C C), 1737 cm (C O); APCI MS: m/z: 217 [M ‡H]; elemental
analysis calcd (%) for C14H16O2: C 77.78, H 7.40; found C 77.75, H 7.30.
Synthesis of (S)-(À)-3-(2'-phenylethyl)penta-3,4-dien-2-ol and (R)-(‡)-3-
(2'-phenyl)ethylpenta-3,4-dien-2-yl acetate: Treatment of racemic 3-(2'-
phenylethyl)penta-3,4-dien-2-ol (l00 mg) with Novozym-435 (70 mg) af-
forded (S)-(À)-1g (50 mg, 50%) and (R)-(‡)-2g (54 mg, 44%). (S)-(À)-
1g: 98.6% ee (HPLC conditions: Chiralcel AD column (Æ0.46 cm Â
25 cm); l ˆ 254 nm; rate: 0.7 mLminÀ1
; hexane/iPrOH 95:5); liquid;
1H NMR (300 MHz, CDCl3, 258C): d ˆ 7.44 7.04 (m, 5H; C6H5), 5.00
4.80 (m, 2H; CH2), 4.33 4.09 (m, 1H; CH), 2.79 (t, 3J(H,H) ˆ 7.3 Hz, 2H;
CH2), 2.40 2.22 (m, 2H; CH2), 1.84 (s, 1H; OH), 1.32 (d, 3J(H,H) ˆ 3.7 Hz,
107.30, 78.63, 73.36, 30.15, 28.52, 21.08, 14.14, 9.91; IR (neat): nÄ ˆ 3361
‡
(OH), 1955 cmÀ1 (C C C), MS (70 eV): m/z (%): 140 (8) [M ].
ˆ ˆ
5016
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0821-5016 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 21

Enzymatic Separation of Racemic 2,3-Allenols
5012 5018
(R)-(‡)-2j: 96.4% ee (determined after conversion to the corresponding
acetate); liquid; 1H NMR (300 MHz, CDCl3, 258C): d ˆ 5.19 5.06 (m, 1H;
CH), 4.89 4.63 (m, 2H; CH2), 2.02 (s, 3H; CH3), 1.97 1.74 (m, 2H; CH2),
1.74 1.52 (m, 2H; CH2), 1.41 (q, 3J(H,H) ˆ 7.2 Hz, 2H, CH2), 1.00 0.70
(m, 6H; 2CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 206.02, 170.49,
103.01, 77.61, 75.25, 30.11, 25.77, 21.06, 20.59, 13.73, 9.79; IR (neat): nÄ ˆ 1958
PdII-catalyzed coupling cyclization of 1a with allylic bromide: Synthesis of
(S)-4-allyl-3-butyl-2-methyl-2,5-dihydrofuran [(S)-4a]: A mixture of (S)-1a
(ee > 99%) (140 mg, 1 mmol), allylic bromide (5 mmol), and PdCl2 (8.9 mg,
0.05 mmol) was stirred in N,N-dimethylacetamide (6 mL) at room temper-
ature. When the reaction was complete, as monitored by TLC, diethyl ether
was added. The resulting mixture was washed with brine (three times) and
dried over anhydrous sodium sulfate. The product was purified by column
chromatography on silica gel (petroleum ether/diethyl ether 100:1) to
afford (S)-4-allyl-3-butyl-2-methyl-2,5-dihydrofuran (122 mg, 68%) with
>99% ee (GC conditions: column: g-cyclodextrin butyryl (20 m Â
0.25 mm); carrier: N2, 6 psi; injector: 2508C; detector (FID, H2,
0.218 MPa): 2508C; oven temperature: 808C (40 min), then 1.08CminÀ1
À1
‡
ˆ ˆ
ˆ
(C C C), 1740 cm (C O); MS (70 eV): m/z (%): 140 (3) [M À COCH2];
‡
HRMS: calcd for C9H16O [M À COCH2]: 140.1201, found: 140.1192.
Synthesis of (S)-(À)-4-(n-pentyl)hexa-4,5-dien-3-ol and (R)-(‡)-4-(n-pen-
tyl)hexa-4,5-dien-3-yl acetate: Treatment of racemic 4-(n-pentyl)hexa-4,5-
dien-3-ol (l01 mg) with Novozym-435 (70 mg) afforded (S)-(À)-1k (39 mg,
39%) and (R)-(‡)-2k (48 mg, 38%). (S)-(À)-1k: 99.4% ee (GC con-
ditions: column: RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier: N2,
10 psi; injector: 2508C; detector (FID, H2, 0.218 MPa): 2508C; oven
temperature: 1208C (40 min), then 1.08CminÀ1 to 1308C (20 min)); liquid;
1H NMR (300 MHz, CDCl3, 258C): d ˆ 5.00 4.76(m, 2H; CH2), 4.04 3.80
(m, 1H; CH), 2.04 1.80 (m, 2H; CH2), 1.80 1.08 (m, 9H; 4CH2 and OH),
1.08 0.80 (m, 6H; 2CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 204.36,
1
to 1208C (20 min)); liquid; H NMR (300 MHz, CDCl3, 258C): d ˆ 5.80
5.60 (m, 1H; CH), 5.11 4.90 (m, 2H; CH2), 4.90 4.71 (m, 1H; CH), 4.60
4.38 (m, 2H; CH2), 2.81 (d, 3J(H,H) ˆ 6.3 Hz, 2H; CH2), 2.26 2.03 (m, 1H;
CH), 2.00 1.83 (m, 1H; CH), 1.54 1.03 (m, 4H; 2CH2), 1.22 (d,
3J(H,H) ˆ 6.4 Hz, 3H; CH3), 0.89 (t, 3J(H,H) ˆ 6.3 Hz, 3H; CH3);
13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 136.53, 135.14, 128.97, 115.67,
83.87, 76.13, 30.17, 29.72, 24.51, 22.71, 20.59, 13.85; IR (neat): nÄ ˆ 1639
107.19, 78.28, 73.11, 31.56, 28.23, 27.65, 27.24, 22.46, 13.99, 9.64; IR (neat):
À1
‡
ˆ
À
(C C), 1071 cm (C O); MS (70 eV): m/z (%): 180 (3) [M ].
‡
nÄ ˆ 3353 (OH), 1955 cmÀ1 (C C C); MS (70 eV): m/z (%): 168 (2) [M ].
ˆ ˆ
Pd0-catalyzed coupling cyclization of 1a with PhI: Synthesis of (S,S)-2-
butyl-3-methyl-2-(1'-phenylvinyl)oxirane ((S,S)-5a): [Pd(PPh3)4] (58 mg,
0.05 mmol) was added to a mixture of (S)-1a (ee > 99%) (140 mg, 1 mmol),
phenyl iodide (216 mg, 1.06 mmol), and potassium carbonate (552 mg,
4.01 mmol) in DMF (4 mL) under Ar, and the resulting mixture was heated
at 75 808C for 18 h with monitoring by TLC. The reaction was then
quenched with brine (10 mL), the mixture was extracted with diethyl ether
(3 Â 20 mL), and the combined extracts were washed twice with brine and
dried over sodium sulfate. After evaporation of the solvent, the residue was
purified by flash chromatography on silica gel (petroleum ether/diethyl
ether 200:1) to afford (S,S)-2-butyl-3-methyl-2-(1'-phenylvinyl)oxirane
((S,S)-5a) (127 mg, 59%) with 99.4% ee (GC conditions: column: RT-
bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier: N2, 8 psi; injector: 2508C;
detector (FID, H2, 0.218 MPa): 2508C; oven temperature: 1408C (20 min),
then 1.08CminÀ1 to 1808C); liquid; 1H NMR (300 MHz, CDCl3, 258C): d ˆ
7.31 7.19 (m, 5H; C6H5), 5.35 (d, 3J(H,H) ˆ 1.5 Hz, 1H; CH), 5.25 (d,
3J(H,H) ˆ 1.5 Hz, 1H; CH), 3.07 (q, 3J(H,H) ˆ 5.4 Hz, 1H; CH), 1.80 1.60
(m, 1H; CH), 1.30 (d, 3J(H,H) ˆ 3.9 Hz, 3H; CH3), 1.31 1.02 (m, 4H;
2CH2), 0.80 (t, 3J(H,H) ˆ 2.6 Hz, 3H; CH3); 13C NMR (75.4 MHz, CDCl3,
258C): d ˆ 148.38, 138.49, 128.28, 127.69, 126.46, 112.73, 64.83, 60.84, 28.72,
(R)-(‡)-2k: 99.7% ee (determined after conversion to the corresponding
acetate); liquid; 1H NMR (300 MHz, CDCl3, 258C): d ˆ 5.03 4.97 (m, 1H;
CH), 4.74 4.57 (m, 2H; CH2), 1.93 (s, 3H; CH3), 1.91 1.79 (m, 2H; CH2),
1.75 1.50 (m, 2H; CH2), 1.47 1.00 (m, 6H; 3CH2), 0.96 0.59 (m, 6H;
2CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 206.03, 170.48, 103.26,
77.67, 75.29, 31.43, 27.99, 27.05, 25.81, 22.42, 21.07, 13.98, 9.81; IR (neat): nÄ ˆ
À1
‡
ˆ ˆ
ˆ
1958 (C C C), 1740 cm (C O); MS (70 eV): m/z (%): 168 (2) [M
À
‡
COCH2]; HRMS: calcd for C11H20O [M À COCH2]: 168.1514, found:
168.1497.
Synthesis of (S)-(À)-4-(n-heptyl)hexa-4,5-dien-3-ol and (R)-(‡)-4-(n-hept-
yl)hexa-4,5-dien-3-yl acetate: Treatment of racemic 4-(n-heptyl)hexa-4,5-
dien-3-ol (l02 mg) with Novozym-435 (70 mg) afforded (S)-(À)-1l (49 mg,
49%) and (R)-(‡)-2l (58 mg, 47%). (S)-(À)-1l: 99.7% ee (GC conditions:
column: RT-bDEXcst (30 m, Æ 0.25 m, 0.25 mm DF); carrier: N2, 10 psi;
injector: 2508C; detector (FID, H2, 0.218 MPa): 2508C; oven temperature:
1208C (40 min), then 1.08CminÀ1 to 1308C (20 min)); liquid; 1H NMR
(300 MHz, CDCl3, 258C): d ˆ 5.00 4.67 (m, 2H; CH2), 4.09 3.80 (m, 1H;
CH), 2.13 1.80 (m, 2H; CH2), 1.80 1.00 (m, 13H; 6CH2 and OH), 1.00
0.80 (m, 6H; 2CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 204.32,
107.34, 78.57, 73.10, 31.82, 29.36, 29.16, 28.30, 27.84, 27.63, 22.63, 14.09, 9.67;
27.13, 22.58, 13.87, 13.77; IR (neat): nÄ ˆ 1627 cmÀ1 (C C); MS (70 eV): m/z
ˆ
‡
‡
IR (neat): nÄ ˆ 3344 (OH), 1955 cmÀ1 (C C C); MS (70 eV): m/z (%): 196
(%): 216 (14) [M ]; HRMS: calcd for C15H20O [M ]: 216.1514, found:
ˆ ˆ
‡
‡
(5) [M ]; HRMS: calcd for C13H24O [M ]: 196.1827, found: 196.1781.
216.1513.
(R)-(‡)-2l: 99.4% ee (determined after conversion to the corresponding
acetate); liquid; 1H NMR (300 MHz, CDCl3, 258C); d ˆ 5.20 5.12 (m, 1H;
CH), 4.86 4.65 (m, 2H; CH2), 2.05 (s, 3H; CH3), 1.97 1.83 (m, 2H; CH2),
1.80 1.57 (m, 2H; CH2), 1.51 1.07 (m, 10H; 5CH2), 0.96 0.74 (m, 6H;
2CH3); 13C NMR (75.4 MHz, CDCl3, 258C): d ˆ 206.05, 170.56, 103.29,
Acknowledgements
Financial support from the Major State Basic Research Development
Program (Grant No. G2000077500), the National Science Foundation of
China, and the Shanghai Municipal Committee of Science and Technology
is greatly appreciated. Shengming Ma is the recipient of a 1999 Qiu Shi
Award for Young Scientific Workers issued by Hong Kong Qiu Shi
Foundation of Science and Technology (1999 2003). Novozym-435 was a
gift from Novo Nordisk Inc. (Danburg, CT).
77.71, 75.34, 31.80, 29.23, 29.11, 28.06, 27.41, 25.84, 22.62, 21.13, 14.05, 9.86;
À1
ˆ ˆ
ˆ
IR (neat): nÄ ˆ 1958 (C C C), 1740 cm (C O); MS (70 eV): m/z (%): 196
‡
‡
(14) [M À COCH2]; HRMS: calcd for C13H24O [M À COCH2]: 196.1827,
found: 196.1849.
AgNO3-catalyzed cycloisomerization of 1a: Synthesis of (R)-3-butyl-2-
methyl-2,5-dihydrofuran ((S)-3a): AgNO3 (170 mg, 1 mmol) was added to
a solution of (S)-1a (ee > 99%) (140 mg, 1 mmol) in acetone/water (1:1)
(2 mL) under nitrogen. After refluxing for 8 h, with TLC monitoring, the
reaction was quenched with brine (10 mL), the mixture was extracted with
diethyl ether (3 Â 20 mL), and the combined extracts were washed twice
with brine and dried over sodium sulfate. After evaporation of the solvent,
the residue was purified by flash chromatography on silica gel (petroleum
ether/diethyl ether 100:1) to afford (S)-3-butyl-2-methyl-2,5-dihydrofuran
((S)-3a) (84 mg, 60%) with >99% ee (GC conditions: column: g-cyclo-
dextrin butyryl (20 m  0.25 mm); carrier: N2, 6 psi; injector: 2508C;
detector (FID, H2, 0.218 MPa): 2508C; oven temperature: 508C (40 min),
then 1.08CminÀ1 to 1208C); liquid; 1H NMR (300 MHz, CDCl3, 258C): d ˆ
5.40 5.26 (m, 1H; CH), 4.77 4.40 (m, 3H; OCH and OCH2), 2.09 1.77
(m, 2H; CH2), 1.54 1.20 (m, 4H; 2CH2), 1.14 (d, 3J(H,H) ˆ 5.4 Hz, 3H;
CH3), 0.83 (t, 3J(H,H) ˆ 6.6 Hz, 3H); 13C NMR (75.4 MHz, CDCl3, 258C):
[1] Chirality in Industry: The Commercial Manufacture and Applications
of Optically Active Compounds (Eds.: A. D. Collins, G. N. Sheldrake,
J. Crosby), Wiley, Chichester, 1992; Chirotechnology: Industrial
Synthesis of Optically Active Compounds (Ed.: R. A. Sheldon),
Marcel Dekker, NewYork, 1993.
[2] Catalytic Asymmetric Synthesis (Ed.: I. Ojima), 2nd ed., Wiley, New
York, 2000; Comprehensive Asymmetric Catalysis (Eds.: E. Jacobsen,
A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999; Asymmetric
Catalysis in Organic Synthesis (Ed.: R. Noyori), Wiley, NewYork,
1993.
[3] a) Allenes in Organic Synthesis (Eds.: H. F. Schuster, G. M. Coppola),
Wiley, NewYork, 1984; b) The Chemistry of Ketenes, Allenes, and
Related Compounds, Part 1 (Ed.: S. Patai), Wiley, NewYork, 1980.
[4] B. S. Burton, H. V. Pechman, Chem. Ber. 1887, 20, 145 149.
d ˆ 144.34, 118.24, 82.94, 74.06, 29.48, 26.47, 22.53, 20.43, 13.91; IR (neat):
‡
nÄ ˆ 1661 cmÀ1 (C C); MS (70 eV): m/z (%): 140 (8) [M ] HRMS: calcd for
ˆ
‡
C9H16O [M ]: 140.1201, found: 140.1219.
Chem. Eur. J. 2002, 8, No. 21
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0821-5017 $ 20.00+.50/0
5017

S. Ma et al.
FULL PAPER
[5] E. R. H. Jones, G. H. Mansfield, M. L. J. Whiting, J. Chem. Soc. 1954,
3208 3212.
see: a) E. J. Corey, C.-M. Yu, D.-H. Lee, J. Am. Chem. Soc. 1990, 112,
878 879; b) H. C. Brown, U. R. Khire, G. Narla, J. Org. Chem. 1995,
60, 8130 8131; c) S. V. Kulkarni, H. C. Brown, Tetrahedron Lett. 1996,
37, 4125 4128; d) C.-M. Yu, S.-K. Yoon, K. Baek, J.-Y. Lee, Angew.
Chem. 1998, 110, 2504 2506; Angew. Chem. Int. Ed. 1998, 37, 2392
2394.
[6] H. Staudinger, L. Ruzicka, Helv. Chim. Acta 1924, 7, 177 201.
[7] S. Ma, S. Zhao, J. Am. Chem. Soc. 1999, 121, 7943 7944.
[8] S. Ma, W. Gao, Tetrahedron Lett. 2000, 41, 8933 8936.
[9] S. Ma, S. Zhao, J. Am. Chem. Soc. 2001, 123, 5578 5579.
[10] For the Ru-catalyzed reaction of 2,3-allenols in the presence of CO to
afford a-methylene lactones, see: E. Yoneda, T. Kaneko, S. W. Zhang,
K. Onitsuka, S. Takahashi, Org. Lett. 2000, 2, 441 443.
[11] For catalytic cycloisomerization of 2,3-allenols, see: a) J. A. Marshall,
X. Wang, J. Org. Chem. 1990, 55, 2995 2998; b) L. I. Olsson, A.
Claesson, Synthesis 1979, 743; c) S. S. Nikam, K. H. Chu, K. K. Wang,
J. Org. Chem. 1986, 51, 745 747; d) J. A. Marshall, C. A. Sehon, J.
Org. Chem. 1995, 60, 5966 5968; e) J. A. Marshall, R. H. Yu, J. F.
Perkins, J. Org. Chem. 1995, 60, 5550 5555; f) N. Krause, A.
Hoffmann-Roder, Org. Lett. 2001, 3, 2537 2538.
[14] a) Enzymes in Synthetic Organic Chemistry (Eds.: C.-H. Wong, G. M.
Whitesides), Pergamon, Oxford, 1994; b) Biotransformations in
Organic Chemistry (Ed.: K. Faber), 3rd ed., Springer, Berlin, 1997;
c) Biocatalysis for Fine Chemical Synthesis (Ed.: S. M. Roberts),
Wiley, Chichester, 1999.
[15] For efficient kinetic resolutions of chiral allylic or propargyl alcohols,
see: K. Burgess, L. D. Jennings, J. Am. Chem. Soc. 1990, 112, 7434
7436; J. Am. Chem. Soc. 1991, 113, 6129 6139.
[16] T. Mukaiyama, T. Harada, Chem. Lett. 1981, 621 624.
[17] a) G. Buono, Synthesis 1981, 872; b) M. Bertrand, R. Maufin, Bull.
Soc. Chim. Fr. 1967, 2779 2784.
[18] For some typical examples of Novozym-435-catalyzed reactions, see:
A. K. Saksena, V. M. Girijavallabhan, R. G. Lovey, R. E. Pike, H.
Wang, Tetrahedron Lett. 1995, 36, 1787 1790; A. Kumar, R. A. Gross,
J. Am. Chem. Soc. 2000, 122, 11767 11770.
[12] For the Pd0-catalyzed coupling-cyclization reaction of 2,3-allenols
with aryl or vinyl halides, see: K. Uemura, D. Shiraishi, M. Noziri, Y.
Inoue, Bull. Chem. Soc. Jpn. 1999, 1063 1069; b) S.-K. Kang, T.
Yamaguchi, S.-J. Pyun, Y.-H. Lee, T.-G. Baik, Tetrahedron Lett. 1998,
39, 2127 2130.
[13] For the synthesis of optically active 2,3-allenols by the reaction of
chiral allenylic or propargylic boron or tin reagents with aldehydes,
Received: May 31, 2002 [F4147]
5018
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0821-5018 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 21