Lipase-catalyzed kinetic resolution of Z-configured homoallylic alcohols

Article abstract of DOI:10.1016/S0957-4166(98)00511-4

Racemic Z homoallylic alcohols were prepared by the BuSnCl₃-catalyzed addition of aldehydes to 1-(tributylstannyl)-2-butene. These alcohols were resolved for the first time by lipase-catalyzed enantioselective acetylation in up to 98% enantiomeric purity.

Full text of DOI:10.1016/S0957-4166(98)00511-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 315–322
Lipase-catalyzed kinetic resolution of Z-configured homoallylic
alcohols
Waldemar Adam,∗ Chantu R. Saha-Möller and Katharina S. Schmid
Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany
Received 13 November 1998; accepted 22 December 1998
Abstract
Racemic Z homoallylic alcohols were prepared by the BuSnCl3-catalyzed addition of aldehydes to 1-
(tributylstannyl)-2-butene. These alcohols were resolved for the first time by lipase-catalyzed enantioselective
acetylation in up to 98% enantiomeric purity. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The Z-configured homoallylic alcohol functionality is found in numerous natural products and biolo-
gically active compounds, a few representatives are given in Fig. 1.1–4 To date the only known enantio-
and Z-selective synthesis of optically active homoallylic alcohols utilized the laborious resolution of
diastereomeric phosphonium salts by fractional crystallization and subsequent Wittig olefination with
appropriate aldehydes.5 Alternatively, racemic ketene thioacetals with a homoallylic alcohol functiona-
lity have been kinetically resolved by lipase-catalyzed hydrolysis of the acetates in high enantiomeric
excess.6
Figure 1. Representative natural products and biologically active compounds with a Z-configured homoallylic alcohol functio-
nality
∗
Corresponding author. Fax: +49-931-888-4756; e-mail: adam@chemie.uni-wuerzburg.de
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00511-4

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Since simple optically active Z-configured homoallylic alcohols should serve as potentially useful
building blocks in the asymmetric synthesis and no convenient and efficient preparation is known so far,
we have employed the kinetic resolution by lipase-catalyzed transesterification for this purpose. Presently
we report that this method is convenient and effective for the preparation of these optically active building
blocks.
2. Results and discussion
The racemic homoallylic alcohols 1a–d were prepared in a two-step sequence (Scheme 1). The Pd(0)-
catalyzed hydrostannation of butadiene afforded (Z)-1-tributylstannyl-2-butene in high yields,7 the Z-
selective conversion of this allylic tin derivative with aldehydes under Lewis acid catalysis followed the
literature procedure for benzaldehyde.8 The formation of the regioisomer with a terminal double bond
was suppressed (≤5%) by choosing short reaction times and low temperatures.8 Acetylation gave the
acetates 2a–d, and the catalytic hydrogenation of the homoallylic alcohols 1a,d led to the saturated
alcohols 3a,d (Scheme 1).
Scheme 1. Synthesis of the homoallylic alcohols 1a–d, their acetylation and catalytic hydrogenation
The racemic homoallylic alcohols 1a–d were submitted to enzyme-catalyzed acetylation9 (Eq. 1), for
which a variety of lipases were screened (Boehringer screening set of lipases, L-1 to L-9, E-1 and E-2).
The lipases, which gave conversions below 20% within 14 days were not further considered, the others
are listed in Table 1. The isopropyl 1b and tert-butyl 1c derivatives were not acetylated by any of the
available lipases and were not further studied. Also the enzymatic hydrolysis of the acetate 2c failed by
all lipases that were used in 0.1 M phosphate buffer (pH 7) with 40% MeOH as cosolvent at 37°C for 4
days.
(1)
The most effective enzyme for the smallest homoallylic alcohol 1a is lipase CAL-2 (from Candida
antarctica, fraction B; CHIRAZYME® L-2, Boehringer Mannheim). On the analytical scale (100 µmol),
the reaction of alcohol rac-1a with isopropenyl acetate and CAL-2 gave at ca. 50% conversion an

W. Adam et al. / Tetrahedron: Asymmetry 10 (1999) 315–322
317
Table 1
Kinetic resolution of the homoallylic alcohols 1a,d and of the saturated alcohol 3d by lipase-catalyzed
acetylation
enantiomeric excess (ee) of 94% for the (S)-1a alcohol and >98% for the (R)-2a acetate (entry 1). The
nearly enantiomerically pure homoallylic derivatives (S)-1a and (R)-2a were easily separated by silica
gel chromatography. The lipase BSL (Burkholderia sp., CHIRAZYME® L-1, Boehringer Mannheim)
was also reactive, but much less enantioselective than CAL-2 (entry 2).
The enzyme CAL-2 acetylates the phenyl-substituted homoallylic alcohol 1d very slowly (in 19 d,
only 2% conversion). This substrate, with two relatively large substituents, is not well accepted by this
lipase, but good conversions are obtained with BSL (entries 3–6). The best enantiomeric excess (>98%)
for the alcohol 1d was achieved at 67% conversion (entry 6); unfortunately, under these conditions only
a moderate ee value (48%) was obtained for the acetate 2d product. At nearly 50% conversion, the ee
values are 44% for the alcohol 1d and 52% for the acetate 2d (entry 4). The lipase PSL (Pseudomonas
sp.; CHIRAZYME® L-6, Boehringer Mannheim) also acetylated the substrate 1d, but at 39% conversion
only moderate enantiomeric excesses were observed for both the alcohol and acetate (entry 7). These

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W. Adam et al. / Tetrahedron: Asymmetry 10 (1999) 315–322
analytical results for the kinetic resolution of the homoallylic alcohols 1a,d are reproducible on the semi-
preparative scale (1–3 mmol).
The saturated alcohol 3d was also enantiomerically acetylated by BSL to compare the efficacy of
enantioselection between the n-butyl chain and the Z-crotyl group. At nearly 50% conversion, the ee
values were 88% for the alcohol 3d and 80% for the corresponding acetate 4d (entry 8).
As reference samples for the MDGC and HPLC analysis, it was necessary to synthesize the racemic
acetates 2 by acetylation of the homoallylic alcohols 1 with acetic anhydride under basic conditions
(Scheme 1). All four homoallylic acetates 2a–d are new and have been completely characterized.
To assign the absolute configuration of the homoallylic alcohols (+)-1a and (−)-1d obtained in the
enzymatic resolution, these optically active compounds were hydrogenated11 on the palladium-on-
carbon catalyst to afford the known saturated alcohols (+)-3a and (−)-3d (Scheme 1).12 The chemical
correlation for both homoallylic substrates 1a,d and the saturated alcohol 3d revealed that the lipases
convert preferentially the (R) enantiomer. This sense in the enantioselection is in good accord with
the established empirical rule proposed by Kazlauskas et al.13 for the kinetic resolution of secondary
alcohols, which is based on the relative size of the substituents at the stereogenic carbon center (Fig. 2).
In the homoallylic alcohol 1a, the small substituent is methyl and the large one is the Z-crotyl group.
This small substrate was converted very quickly and highly selectively by CAL-2 (3 h). In the phenyl-
substituted alcohol 1d, the crotyl group takes the place of the small substituent, but this substrate is
presumably too large to fit into the active site of the CAL-2 enzyme so that the conversion is very
slow (19 days, 2% convn). However, the lipase from Burkholderia sp. (BSL) accepts the alcohol 1d
with moderate enantiodifferentiation, which implies that the latter enzyme may possess a bigger enzyme
pocket. Unfortunately, this enzyme does not distinguish well between the crotyl and phenyl groups and
the enantioselectivity values are only moderate (E≤20, Table 1, entries 3–6).
Figure 2. Selected enantiomers in the lipase-catalyzed acetylation of the alcohols 1a,d and 3d
The lipase-catalyzed kinetic resolution of the saturated alcohol 3d was much better than that of the
homoallylic alcohol 1d at comparable conversion. The reason for this may be that the more flexible
n-butyl chain fits better in the active site of the enzyme than the Z-crotyl group.
3. Conclusion
The homoallylic alcohols 1a,d and the acetates 2a,d were obtained optically active for the first time
by lipase-catalyzed kinetic resolution. This is a convenient and effective preparation of optically active
Z-configured homoallylic alcohols. By hydrolysis of the optically active acetates 2a,d, which are the
products of the lipase-catalyzed acetylation, both enantiomers of these potentially useful building blocks
are now available for asymmetric synthesis.

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319
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in CDCl3 on a Bruker AC 250 (1H: 250 MHz; 13C: 63 MHz),
with CHCl3 contained in CDCl3 as reference standard. Multi-dimensional gas chromatography (MDGC)
was performed on a HRGC MEGA 2, Series 8560 Fisons Instruments chromatograph, equipped with
two columns and two EL 980 detectors from CE Instruments. The stationary phase of the achiral column
A was OV 1701 (30 m, 0.25 mm), for the chiral column B it was 30% permethylated β-cyclodextrin on
DB 1701 (CYCLODEX-B from J&W, 30 m, 0.25 mm) or dimethylpentyl β-cyclodextrin on OV 1701
(DMEPEBETA from MEGA, 25 m, 0.25 mm). The carrier was hydrogen gas with pressures of 150
kPa (column A) and 100 kPa (column B). The injection temperature was 190°C. HPLC analyses were
carried out on Kontron equipment, furnished with a spectrophotometer UVIKON 720 and CHIRALYSER
1.6 from IBZ Messtechnik. The stationary phase was a chiral column (CHIRACEL OD-H from Daicel
Chemical Industries Ltd). IR spectra were recorded on a Perkin–Elmer 1420 ratio recording infrared
spectrophotometer. The specific rotation [α]D20 was determined on a Perkin–Elmer 241 MC polarimeter
by using CHCl3 as solvent. TLC analysis was conducted on precoated silica gel foils Polygram SIL
G/UV254 from Machery and Nagel. Spots were visualized by phosphomolybdic acid. Silica gel (32–64
µm, Woelm) was used for flash chromatography. The lipases were obtained as gift samples from
Boehringer Mannheim and used as received.
4.2. General procedure for the synthesis of the homoallylic alcohols 1a–d8
To a solution of 5.00 g (14.5 mmol) of (Z)-tributyltin-2-butene7 and 15.9 mmol of aldehyde in 30
mL CH2Cl2 under a nitrogen atmosphere were added 2.42 mL (14.5 mmol) of butyltin trichloride in 10
mL of CH2Cl2 over a period of 45 min at −78°C. After an additional 30 min stirring, the mixture was
allowed to warm up to 0°C, stirred at that temperature for 1 h, treated with H2O (10 mL), and extracted
with Et2O (3×10 mL). The combined organic phases were dried over MgSO4 and purified by distillation
to give the homoallylic alcohols 1a–d as colorless oils, which contained about 5% of the regioisomers
with the terminal double bond. Yields are given in Scheme 1. For the lipase-catalyzed kinetic resolution,
the homoallylic alcohols were purified by flash chromatography (4:1 petroleum ether:Et2O).
4.2.1. (Z)-4-Hexen-2-ol 1a
Colorless oil; bp 52°C/15 torr (lit.14 50°C/15 torr); 1H NMR: δ 1.21 (d, 3H, 1-H), 1.59 (br s, 1H, OH),
1.64 (ddt, J=5.8, 1.8, 0.9 Hz, 3H, 6-H), 2.22 (dd, J=7.6, 0.9 Hz, 2H, 3-H), 3.84 (sext, J=6.1 Hz, 1H, 2-H),
5.43 (dtq, J=10.7, 7.0, 1.5 Hz, 1H, 4-H), 5.65 (dqt, J=10.7, 6.7, 1.5 Hz, 1H, 5-H); 13C NMR: δ 13.0 (q,
C-6), 22.7 (q, C-1), 36.7 (t, C-3), 67.7 (d, C-2), 126.0 (d, C-5), 127.3 (d, C-4); GC (CYCLODEX-B): tR
(45°C isothermal)=28.4 (−), 28.8 (+).
4.2.2. (Z)-2-Methyl-5-hepten-3-ol 1b15
1
Colorless oil; bp 90°C/38 torr; H NMR (200 MHz): δ 0.95 (dd, J=6.7, 2.3 Hz, 6H, 1-H), 1.55 (br
s, 1H, OH), 1.65 (dt, J=6.6, 1.2 Hz, 3H, 7-H), 1.70 (m, 1H, 2-H), 2.22 (t, J=7.1 Hz, 2H, 4-H), 3.47 (q,
7.1 Hz, 1H, 3-H), 5.44 (dtq, J=10.9, 7.2, 1.7 Hz, 1H, 5-H), 5.70 (dqt, J=10.9, 6.6, 1.2 Hz, 1H, 6-H); 13
C
NMR: δ 13.0 (q, C-7), 17.5 (q, C-1), 18.8 (q, C-1), 31.8 (t, C-4), 33.1 (d, C-2), 76.2 (d, C-3), 126.6 (d,
C-6), 127.2 (d, C-5); GC (DMEPEBETA): tR [40°C (25 min) -→ 70°C (5°C/min)]=41.9, 42.1.

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4.2.3. (Z)-2,2-Dimethyl-5-hepten-3-ol 1c15
Colorless oil, bp 94°C/38 torr; 1H NMR: δ 0.94 (s, 9H, 1-H), 1.58 (br s, 1H, OH), 1.64 (d, J=6.7 Hz,
3H, 7-H), 2.19 (m, 2H, 4-H), 3.24 (dd, J=9.8, 3.4 Hz, 1H, 3-H), 5.46 (dtq, J=10.1, 8.9, 1.8 Hz, 1H, 5-H),
5.67 (dqt, J=10.1, 6.7, 1.2 Hz, 1H, 6-H); 13C NMR: δ 13.0 (q, C-7), 25.8 (3×q, C-1), 29.4 (t, C-4), 34.7
(s, C-2), 79.1 (d, C-3), 127.2 (d, C-6), 127.8 (d, C-5); GC (DMEPEBETA): tR [40°C (25 min) -→ 70°C
(20°C/min)]=38.9, 39.4.
4.2.4. (Z)-1-Phenyl-3-penten-1-ol 1d8
Colorless oil; Rf (3:1 petroleum ether:Et2O)=0.33; 1H NMR: δ 1.61 (ddt, J=6.70, 1.53, 0.91 Hz, 3H, 5-
H), 2.06 (br s, 1H, OH), 2.55 (m, 2H, 2-H), 4.72 (dd, J=7.60, 5.50 Hz, 1H, 1-H), 5.43 (dtq, J=10.7, 5.40,
1.50 Hz, 1H, 3-H), 5.65 (dqt, J=10.7, 6.70, 1.50 Hz, 1H, 4-H), 7.35–7.38 (m, 5H, Ph-H); 13C NMR:
δ 13.4 (q, C-5), 37.3 (t, C-2), 74.6 (d, C-1), 126.1 (d, C-4), 126.2 (2×d, Ph-C), 127.9 (d, C-3), 128.0
(d, Ph-C), 128.8 (2×d, Ph-C), 144.5 (s, Ph-C); HPLC (OD-H, 98:2 n-Hex:i-PrOH, flow 0.35 mL/min):
tR=41.8 (+), 48.3 (−).
4.3. General procedure for the acetylation of the homoallylic alcohols 1a–d
To a solution of 2.50 mmol of the homoallylic alcohol 1 in 50 mL of CH2Cl2 were added 2.75 mmol
of acetic anhydride, 3.75 mmol of triethylamine and 1.00 mg of 4-(dimethylamino)pyridine (DMAP) and
stirred at 20°C for 24 h. After concentration (20°C, 15 torr), flash chromatography (100:1 ratio of silica
gel to substrate, petroleum ether:Et2O) gave the esters 2a–d. Yields are given in Scheme 1.
4.3.1. (Z)-2-Acetoxy-4-hexene 2a
Colorless oil; Rf (4:1 petroleum ether:Et2O)=0.60; 1H NMR: δ 1.21 (d, J=6.4 Hz, 3H, 1-H), 1.61 (ddt,
J=6.7, 1.8, 0.9 Hz, 3H, 6-H), 2.02 (s, 3H, OCOCH3), 2.22–2.35 (m, 2H, 3-H), 4.91 (sext, J=6.4 Hz, 1H,
2-H), 5.36 (dtq, J=11.0, 7.3, 1.8 Hz, 1H, 4-H), 5.59 (dqt, J=11.0, 6.7, 1.5 Hz, 1H, 5-H); 13C NMR: δ 12.9
(q, C-6), 19.4 (q, C-1), 21.3 (q, OCOCH3), 33.2 (t, C-3), 70.6 (d, C-2), 125.1 (d, C-5), 126.7 (d, C-4),
169.3 (s, OCOCH3); IR (CCl4): ν 1730, 1380 cm−1; GC (CYCLODEX-B): tR (45°C isothermal)=35.4
(−), 42.9 (+). Anal. calcd for C8H14O2 (142.2): C, 67.57; H, 9.92. Found: C, 67.15; H, 9.50.
4.3.2. (Z)-3-Acetoxy-2-methyl-4-heptene 2b
Colorless oil; Rf (30:1 petroleum ether:Et2O)=0.38; 1H NMR: δ 0.91 (d, J=6.7 Hz, 6H, 1-H), 1.62 (dt,
J=6.7, 0.9 Hz, 3H, 7-H), 1.83 (sept, J=6.7 Hz, 1H, 2-H), 2.04 (s, 3H, OCOCH3), 2.30 (t, J=7.3 Hz, 2H,
4-H), 4.75 (dt, J=7.0, 5.8 Hz, 1H, 3-H), 5.35 (dqt, J=10.7, 7.3, 1.5 Hz, 1H, 5-H), 5.55 (dqt, J=10.7, 6.7,
1.5 Hz, 1H, 6-H); 13C NMR: δ 12.9 (q, C-7), 17.6 (q, C-1), 18.7 (q, C-1), 21.1 (q, OCOCH3), 28.9 (t,
C-4), 31.0 (d, C-2), 78.1 (d, C-3), 125.5 (d, C-6), 126.3 (d, C-5), 170.9 (s, OCOCH3); IR (neat): ν 1720,
1360, 1020 cm−1; GC (DMEPEBETA): tR [40°C (25 min) -→ 70°C (5°C/min)]=42.3, 43.8. Anal. calcd
for C10H18O2 (170.3): C, 70.55; H, 10.66. Found: C, 70.73; H, 10.44.
4.3.3. (Z)-3-Acetoxy-2,2-dimethyl-4-heptene 2c
Colorless oil; Rf (20:1 petroleum ether:Et2O)=0.33; 1H NMR: δ 0.92 (s, 9H, 1-H), 1.60 (dt, J=6.7, 0.9
Hz, 3H, 7-H), 2.02 (s, 3H, OCOCH3), 2.25 (m, 2H, 4-H), 4.76 (dd, J=8.5, 4.6 Hz, 1H, 3-H), 5.33 (dtq,
J=11.0, 7.6, 1.8 Hz, 1H, 5-H), 5.51 (dqt, J=11.0, 6.7, 1.2 Hz, 1H, 6-H); 13C NMR: δ 12.8 (q, C-7), 21.0
(q, OCOCH3), 25.9 (3×q, C-1), 27.3 (t, C-4), 34.5 (s, C-2), 80.2 (d, C-3), 125.9 (d, C-6), 126.7 (d, C-5),
170.9 (s, OCOCH3); IR (neat): ν 1725, 1360, 1230, 1020, 705, 630 cm−1; GC (DMEPEBETA): tR [40°C

W. Adam et al. / Tetrahedron: Asymmetry 10 (1999) 315–322
321
(25 min) -→ 70°C (20°C/min)]=43.0, 43.3. Anal. calcd for C11H20O2 (184.3): C, 71.70; H, 10.94. Found:
C, 71.11; H, 10.43.
4.3.4. (Z)-1-Acetoxy-1-phenyl-3-pentene 2d
Colorless oil; Rf (4:1 petroleum ether:Et2O)=0.49; 1H NMR: δ 1.55 (ddt, J=6.70, 1.83, 0.93 Hz, 3H,
5-H), 2.07 (s, 3H, OCOCH3), 2.44–2.76 (m, 2H, 2-H), 5.30 (dtq, J=11.0, 7.33, 1.83 Hz, 1H, 3-H), 5.53
(dqt, J=11.0, 6.70, 1.53 Hz, 1H, 4-H), 5.76 (dd, J=6.40, 7.33 Hz, 1H, 1-H), 7.30–7.38 (m, 5H, Ph-H);
13C NMR: δ 12.8 (q, C-5), 21.2 (q, OCOCH3), 33.9 (t, C-2), 75.5 (d, C-1), 124.6 (d, C-3), 126.5 (2×d,
Ph-C), 127.1 (d, Ph-C), 127.9 (d, C-4), 128.3 (2×d, Ph-C), 140.3 (s, Ph-C), 170.3 (s, OCOCH3); IR
(neat): ν=1740, 1495, 1455, 1375, 1240, 1030, 810 cm−1; HPLC (OD-H, 98:2 n-Hex:i-PrOH, flow 0.35
mL/min): tR=13.9 (+), 15.0 (−). Anal. calcd for C13H16O2 (204.3): C, 76.44; H, 7.90. Found: C, 76.3; H,
8.06.
4.4. General procedure for the lipase-catalyzed transesterification
To a solution of 100 µmol of the homoallylic alcohol 1a–d in 2.0 mL of t-BuOMe was added the
appropriate lipase and isopropenyl acetate (5.0 equiv.). The mixture was vigorously stirred at ca. 20°C
for the time indicated in Table 1, the enzyme was removed by filtration and the solvent evaporated at
reduced pressure (20°C/12 torr). The crude samples were analyzed by gas chromatography or by HPLC.
In the case of semi-preparative-scale reactions, the homoallylic alcohols and acetates were separated by
flash chromatography (4:1 petroleum ether:Et2O).
4.4.1. (S)-(+)-(Z)-4-Hexen-2-ol [(S)-(+)-1a]
[α]D20=+3.48 (c=0.71, CHCl3) for 94% ee.
4.4.2. (R)-(+)-(Z)-2-Acetoxy-4-hexene [(R)-(+)-2a]
[α]D20=+25.7 (c=0.80, CHCl3) for >98% ee.
4.4.3. (S)-(−)-(Z)-1-Phenyl-3-penten-1-ol [(S)-(−)-1d]
[α]D20=−43.2 (c=0.50, CHCl3) for >98% ee.
4.4.4. (R)-(+)-(Z)-1-Acetoxy-1-phenyl-3-pentene [(R)-(+)-2d]
[α]D20=+34.2 (c=0.74, CHCl3) for 48% ee.
4.5. Lipase-catalyzed hydrolysis of the acetate 2c
The acetate 2c (100 µmol) was dissolved in 0.1 M phosphate buffer (1 mL, pH 7), which contained
40% methanol as a cosolvent. The lipase powder was added, the mixture was heated to 37°C for 4
days, extracted with Et2O (5×2 mL), dried over Na2SO4, and the solvent evaporated at reduced pressure
(20°C/12 torr). The crude samples were analyzed by gas chromatography. No conversion was observed
with any of the lipases employed in this work.
4.6. General procedure for the hydrogenation of 1a,d11
A suspension of 1.00 mmol of homoallylic alcohol 1a,d in 30 mL of methanol and 5.00 mg of
palladium-on-carbon catalyst was stirred at room temperature (ca. 20°C) for 68 h under a hydrogen

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W. Adam et al. / Tetrahedron: Asymmetry 10 (1999) 315–322
atmosphere. After filtration over Celite and removal of the solvent (50°C/250 torr), the saturated alcohols
3a,d were obtained as colorless oils. Yields are given in Scheme 1.
4.7. General procedure for the hydrolysis of the acetates 2
To a solution of 1.45 mmol of acetate 2 in 30 mL of methanol were added 150 mg (1.08 mmol) of
potassium carbonate. After stirring for 6 h, the solvent was removed (40°C/250 torr). The residue was
taken up in 5 mL of CH2Cl2 and the solid material removed by filtration. Flash chromatography (100:1
ratio of silica gel to substrate, petroleum ether:Et2O) gave the corresponding alcohol 1.
Acknowledgements
This work was generously supported by the Deutsche Forschungsgemeinschaft (SFB 347, ‘Selektive
Reaktionen Metall-aktivierter Moleküle’), the Bayerische Forschungsstiftung (Bayerischer Forschungs-
verbund Katalyse-FORKAT), and the Fonds der Chemischen Industrie. We also thank the Boehringer
Mannheim GmbH for the generous gift of enzymes.
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