Synthesis of C1-C6 fragment for epothilone A via lipase-catalyzed optical resolution

Article abstract of DOI:10.1081/SCC-100107003

Synthesis of 5-oxo-(3S)-hydroxy-4,4-dimethylheptanoic acid (1), C1-C6 fragment of epothilone A, is described. Racemic tert-butyl 5-oxo-(3S)-acetoxy-4,4-dimethylheptanoate (5) was prepared by acylation of enamine followed by aldol condensation. Optical resolution of the heptanoate 5 was carried out by lipase catalyzed hydrolysis (yield 50%, > 98% e.e.).

Full text of DOI:10.1081/SCC-100107003

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SYNTHESIS OF C1–C6 FRAGMENT FOR EPOTHILONE A
VIA LIPASE-CATALYZED OPTICAL RESOLUTION
Kosei Shioji a , Hitomi Kawaoka a , Asami Miura a & Kentaro Okuma a
a Department of Chemistry, Faculty of Science , Fukuoka University , Jonan-ku, Fukuoka,
814-0180, Japan
Published online: 16 Aug 2006.
To cite this article: Kosei Shioji , Hitomi Kawaoka , Asami Miura & Kentaro Okuma (2001) SYNTHESIS OF C1–C6 FRAGMENT
FOR EPOTHILONE A VIA LIPASE-CATALYZED OPTICAL RESOLUTION, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 31:23, 3569-3575, DOI: 10.1081/SCC-100107003
To link to this article: http://dx.doi.org/10.1081/SCC-100107003
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SYNTHETIC COMMUNICATIONS, 31(23), 3569–3575 (2001)
SYNTHESIS OF C1–C6
FRAGMENT FOR EPOTHILONE A
VIA LIPASE-CATALYZED
OPTICAL RESOLUTION
Kosei Shioji,* Hitomi Kawaoka,
Asami Miura,and Kentaro Okuma
Department of Chemistry, Faculty of Science,
Fukuoka University, Jonan-ku,
Fukuoka 814-0180, Japan
ABSTRACT
Synthesis of 5-oxo-(3S )-hydroxy-4,4-dimethylheptanoic acid
(1), C1–C6 fragment of epothilone A, is described. Racemic
tert-butyl 5-oxo-(3S )-acetoxy-4,4-dimethylheptanoate (5) was
prepared by acylation of enamine followed by aldol conden-
sation. Optical resolution of the heptanoate 5 was carried out
by lipase catalyzed hydrolysis (yield 50%, >98% e.e.).
Epothilones represent a new class of natural products with taxol-like
effects. They are greater advantage than taxol for effect on taxol-resistant
tumors and water solubility without solbilizing additives.1 Having interest-
ing molecular architecture and considerable potential in medicine, total
syntheses of these macrolides have been reported by many chemists.2
*Corresponding author.
3569
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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SHIOJI ET AL.
Nicolaou et al. have been reported that the total synthesis of epothilone A
was completed by assembling enantiomerically enriched three fragments
called Nicolaou’s key intermediates (C1–C6, C7–C12, and C13–C21).3
The construction of C1–C6 fragment (1) in optically active form was
succeeded by asymmetric allylboration using (þ)-Ipc2B(allyl) at low tem-
perature (>98% e.e.).4,5 It was also reported that enantiomerically enriched
C1–C6 fragment was synthesized by chromium (II)-mediated Reformasky
reaction (84% d.e.) and/or ‘‘acetate’’ aldol reaction using bornane-10,2-
sultam as a chiral auxiliary (88% e.e.).6,7 However, these methods require
severe reaction conditions or accompany poor stereoselectivity. In this com-
munication, we report a concise and high stereoselective synthesis of C1–C6
fragment for epothilone A using lipase catalyzed optical resolution.
O
H
OTBS
O
O
(S)–1
Racemic tert-butyl 5-oxo-3-hydroxy-4,4-dimethylheptanoate (2),
C1–C6 fragment, was synthesized as follows. 1-N-morpholinoisobutene (3)
was prepared from iso-butylaldehyde and morpholine (yield 82%).8
Acylation of enamine 3 with propionyl chloride gave 3-oxo-2,2-dimethyl-
pentanal (4) (yield 62%).9 Aldol condensation of 4 with tert-butyl acetate
provided racemic heptanoate 2 (yield 47%) (Scheme 1).
Cl
morpholine
H
O
benzene
reflux
ether
N
H
H
O
O
O
O
O
3
4
1) LDA at –78˚C
2)
O
4
t
Bu
t
Bu
O
OH
O
O
2
Scheme 1.

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EPOTHILONE A
3571
In order to obtain optically active 2, we tried lipase catalyzed acylation
of 2. The attempted lipase catalyzed acylation of 2 was recovered racemic
2 almost completely. Next, we have carried out lipase catalyzed hydrolysis
of tert-butyl 5-oxo-3-acetoxy-4,4-dimethylheptanoate (5) prepared from 2
and acetic anhydride in phosphate buffer at 36ꢀC for 24 h (Scheme 2). By
use of lipase from Candida rugosa, stereoselective hydrolysis of 5 was
succeeded to give an enantiomerically pure 2 (Table 1).
Scheme 2.
The preparative scale (6 mmol) of this resolution afforded enantomeri-
cally pure 2* in 49% yield ([a]D20 þ 42.5(c 0.57 CHCl 3)). Optically active
5 was recovered in 48% ([a]2D0 À 7.53 (c 3.32 CHCl3)). Hydrolysis of optically
pure 2 with trifluoroacetic acid afforded 6 in 94% yield ([a]2D0 þ 9.0 (c 1.25
CHCl3)).13 Protection of hydroxy group with tert-butyldimethylsilyl tri-
fluorometanesulfonate gave optically pure 1, C1–C6 fragment of epothilone
A, in 75% yield ([a]2D0 þ 15.7 (c 1.10 CHCl3)) (Scheme 3).
Absolute configuration of 1* was determined by comparison with
the sign of the optical rotation of the reported (S )-1 ([a]2D0 þ 16.1 (c 1.00
CHCl3)).4 Optical purity of (S )-1 was retained throughout this hydrolysis
Table 1. Hydrolase Catalyzed Hydrolysis of 5 a
Origins of Hydrolase
Time/h
Conversion of 5/%b
Ee of 2/%b
Ec
Porcine liver
Candida rugosa
21
21
40d
21
21
43
49
50
0
352.4
>98
>98
–
>100
>100
Pseudomonas cepacia
Candida antarctica
–
–
0
–
a5; 5mg, hydrolase; 10 mg, in 1 ml phosphate buffer (pH 7.4) at 36 ꢀC. Determined
by GC (CD-b-236 M-19, 25M). cE values were calculated from conversion and
b
d
product’s ee value. Hydrolase; 7.5mg.

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SHIOJI ET AL.
Scheme 3.
and protecting process. At a conversion of 50%, (R)-5 was recovered in an
enantiomerically pure state in 48% yield. Enantiomerically pure (R)-5
was hydrolyzed by trifluoloacetic acid to give (R)-6. In order to obtain
enantiomerically enriched b-hydroxy ester, the reduction of b-keto ester
by using of baker’s yeast was a convenient method. Due to the bulkiness
of two methyl groups at the 4 position, the reduction of tert-butyl 3,5-dioxo-
4,4-dimethylheptanoate, derived from racemic 2, was not accomplished by
baker’s yeast. Thus, lipase-catalyzed optical resolution of 5 was practically
useful for the synthesis of chiral building blocks, (S )-2 and (R)-5, with high
optical purity.
EXPERIMENTAL
General
Melting points are uncorrected. 1H and 13C NMR spectra were
obtained with a JEOL GX-400 spectrometer. Chemical shifts are
given in ppm units down field from tetramethylsilane. The enantiomeric
excess (ee) was determined by GC analysis. GC was performed on GL
sciences GC353B (column: CD-b-236 M-19, 25M). TLC analyses were
done using Merck Silica gel 60 F254 aluminium plates. Lipase from
Candida rugosa (Sigma L1754) and esterase from porcine liver were pur-
chased from Sigma. Lipase from Candida antarctica (Chirazymeꢀ L-2,
c.-f., C2, lyo.) was purchased from Roche Molecular Biochemicals. Lipase
from Pseudomonas cepacia (Amano P) was purchased from Amano
Pharmaceutical Co., Ltd.
1-N-morpholinoisobutene (3)
1-N-morpholinoisobutene (3) was prepared by the method of
Benzing.8 Yield; 82%. colorless oil. bp 64–65ꢀC (20 mmHg). 1H NMR;
(CDCl3) d 1.62 (s, 3H, CH3), 1.68 (s, 3H, CH3), 2.59 (t, J ¼ 2.0 Hz, 4H,

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EPOTHILONE A
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N(CH2)2), 3.73 (t, J ¼ 3.2 Hz, 4H, O(CH2)2), 5.32 (s, 1H, CH N). 13C NMR;
(CDCl3) d 17.3, 22.1, 53.0, 66.8, 123.3, 135.0.
3-Oxo-2,2-dimethylpentanal (4)
3-Oxo-2,2-dimethylpentanal (4) was prepared by the published pro-
cedure.9 Yield; 62%. colorless oil. bp 63–65ꢀC (16 mmHg). 1H NMR;
(CDCl3) d 1.05( t, J ¼ 8.0 Hz, 3H, CH2CH3), 1.34 (s, 6H, (CH3)2), 2.50 (q,
J ¼ 7.2 Hz, 2H, CH2CH3), 9.62 (s, 1H, CHO). 13C NMR; (CDCl3) d 7.4, 8.7,
19.2, 27.3, 32.3, 60.2.
Aldol Condensation of 4 with Tert-butyl Acetate
To a solution of tert-butyl acetate (14.3 g, 123 mmol) in THF (120 ml)
was added a solution of LDA (74 ml, 2.0 M cyclohexane solution) at À 78ꢀC.
After being stirred for 15min, a solution of aldehyde 4 (15.8 g, 123 mmol) in
THF (120 ml) was added to the solution. The reaction mixture was stirred
for 2 h at À 78ꢀC and warmed up to room temperature. The resulting
mixture was quenched by addition of saturated aqueous NH4Cl, and the
aqueous layer was extracted with CH2Cl2 (100 ml ꢁ 3). The combined
organic extracts were washed with brine and dried over sodium sulfate.
The solvent was removed under reduced pressure, and the residue was puri-
fied by distillation to give racemic 2. Yield; 47%. pale yellow oil; bp
119–120ꢀC (2.2 mHg). 1H NMR; (CDCl3) d 1.03 (t, J ¼ 7 Hz, 3H,
CH2CH3), 1.13 (s, 3H, CCH3), 1.19 (s, 3H, CCH3), 1.46 (s, 9H, C(CH3)3),
2.40–2.26 (m, 2H, CH2COOBut), 2.61–2.53 (m, 2H, CH2CH3), 4.20–4.18
(m, 1H, CHOH). 13C NMR; (CDCl3) d 7.8, 19.4, 21.5, 28.0, 31.3, 36.6,
50.7, 72.7, 81.3, 172.3, 215.7. HRMS; Calcd. For C13H24O4 m/z 245.1753.
Found 245.1752.
Tert-butyl 5-Oxo-3-acetoxy-4,4-dimethylheptanoate (5)
Acylation of 2 with acetic anhydride in the presence of 4,4-dimethyl-
aminopyridine in CH2Cl2 afforded 5. Yield; 86%. pale yellow oil. 1H NMR;
(CDCl3) d 1.03 (t, J ¼ 14, 3H, CH2CH3), 1.12 (s, 3H, CCH3), 1.15( s, 3H,
CCH3), 1.42 (s, 9H, C(CH3)3), 2.04 (S, 3H, OCOCH3), 2.63–2.48 (m, 2H,
CH2COOBut), 2.42–2.31 (m, 2H, CH2CH3), 5.90 (dd, J ¼ 4.0, 9.0 Hz, 1H,
CHOAc). 13C NMR; (CDCl3) d 7.9, 20.2, 20.8, 21.0, 27.9, 30.8, 37.1, 51.0,
73.4, 80.9, 169.2, 169.4, 212.8.

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SHIOJI ET AL.
Lipase-catalyzed Kinetic Resolution of
Tert-butyl 5-Oxo-3-Acetoxy-4,4-
dimethylheptanoate (5)
Hydrolysis was carried out at 36ꢀC by stirring a mixture of a substrate
5 (1.2 g, 4.0 mmol), lipase (1.8 g) and phosphate buffer (pH 7.4, 120 ml).
The lipase was removed by filtration with celite. The filtrate was extracted
with ether several times. The extract was washed with brine, dried
over sodium sulfate and concentrated in vacuo. The crude residue was pur-
ified by column chromatography (eluent: hexane-CH2Cl2). Yield; 49%
[a]2D0 þ 42.5(c 0.57 CHCl 3).
Hydrolysis of (S )-2 and (R)-5 with Trifluoroacetic Acid
To a solution of (S )-2 (4.15mmol) or ( R)-5 (1.0 g, 4.15mmol) in etha-
nol (5mmol) was added a solution of trifluoroacetic acid (472 mg,
4.15mmol) in H 2O (20 ml) and refluxed for 12 h. The resulting mixture
was extracted with ethyl acetate (30 ml ꢁ 2). The combined extracts were
dried over sodium sulfate. The solvent was removed under reduced pressure
to give (S )-6 or (R)-6 respectively. (S )-6: Yield; 94%. Pale yellow oil.
1H NMR; (CDCl3) d 4.21 (dd, J ¼ 2.4, 10.4 Hz, 1H, CHOH), 2.63–2.48 (m,
1H, CH2CH3), 2.61–2.53 (m, 2H, CH2COOH), 1.19 (s, 3H, CCH3), 1.17 (s,
3H, CCH3), 1.03 (t, J ¼ 14, 3H, CH2CH3). 13C NMR; (CDCl3) d 7.8, 19.5,
21.6, 31.3, 36.6, 50.8, 72.7, 175.9, 216.5. (R)-6: Yield; 98%. Pale yellow oil.
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Received in Japan October 20, 2000

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