Lipase-catalyzed transesterification of methyl 2-substituted 3-hydroxy-4-pentenoates and its synthetic application to the taxol side chain

Article abstract of DOI:10.1055/s-2002-34247

Syn-and anti-methyl 2-substituted 3-hydroxy-4-pentenoates were efficiently resolved in lipase-catalyzed transesterification. This protocol was successfully applied to the synthesis of the taxol side chain.

Full text of DOI:10.1055/s-2002-34247

LETTER
1665
Lipase-catalyzed Transesterification of Methyl 2-Substituted 3-Hydroxy-4-
pentenoates and its Synthetic Application to the Taxol Side Chain
T
ransesterificat
a
ion of
M
eth
d
yl 2-Substitu
a
ted-3-Hyd
k
roxy-4-Pente
a
noates tsu Mandai,* Tetsuta Oshitari, Masafumi Susowake
Department of Chemistry and Bioscience, Kurashiki University of Science and the Arts, 2640 Nishinoura, Tsurajima, Kurashiki 712-8505,
Japan
Fax +81(86)4401062; E-mail: ted@chem.kusa.ac.jp
Received 20 August 2002
1-ethoxycarbonyl-2-hydroxycyclohexane,8 tert-butyl 3-
Abstract: Syn-and anti-methyl 2-substituted 3-hydroxy-4-pen-
hydroxy-4-pentenoate,9 4-aryloxy-3-hydroxy esters,10
tenoates were efficiently resolved in lipase-catalyzed transesterifi-
cation. This protocol was successfully applied to the synthesis of the
and syn- and anti-2-substituted 3-hydroxy esters11 whose
substituents at the C-2 position were severely limited to
Ph-, MeS-, and PhS- groups. To the best of our know-
ledge, there has not been reported to date a general and ef-
ficient lipase-catalyzed transesterification for acyclic 2-
substituted 3-hydroxy esters.12
taxol side chain.
Key words: syn- and anti-methyl 2-substituted 3-hydroxy-4-pen-
tenoates, lipase-catalyzed kinetic resolution, 1,2-amino alcohols,
the taxol side chain
In this context, we designed syn- and anti- methyl 2-sub-
stituted 3-hydroxy-4-pentenoates 113 and 413 as enzymati-
cally acceptable substrates of high synthetic flexibility,
disclosing that (3R)-alcohols14 for both isomers were
acetylated with exceedingly high enantioselectivities in li-
pase-catalyzed transesterification as shown in Scheme 1.
Acyclic 1,2-amino alcohols are not only important con-
stituents of natural products such as sphingosine,1 statine,2
and phenylisoserine3 as the taxol side chain, but also sig-
nificant chiral auxiliaries for diverse asymmetric synthe-
ses.4 Among a number of synthetic methods for acyclic
1,2-amino alcohols reported hitherto, the sequence of
Evans’ asymmetric aldol reaction/the release of a 2-sub-
stituted 3-hydroxycarboxylic acid/Curtius rearrangement5
has been well recognized as a useful method owing to the
reliability of stereochemistry throughout the process. For
these reasons we wanted to devise a more straightforward
access to both syn- and anti-2-substituted 3-hydroxy es-
ters with high optical purities that takes the place of
Evans’ asymmetric aldol reaction.6
The reaction with syn-racemates 1 was executed as fol-
lows. Stirring a solution of 1 (7~38 mmol) and 2-propenyl
acetate (3 equiv) in toluene (1.5 mL per mmol of 1) with
Chirazyme® (Candida antarctica, fraction B, 0.5 g per
g of 1)15 at room temperature ~70 °C for 40~72 hours re-
sulted in the clean acetylation of one enantiomer to give
(2S,3R)-acetates 2.16 The unsolved lipase was filtered off
and the filtrate was concentrated and purified by column
chromatography (SiO2). Gratifyingly, both the enantiose-
lectivity and the chemical yield of the unreacted (2R,3S)-
alcohols 316 were also found to be excellent. Similarly, the
reaction with anti-racemates 4 proceeded quite efficiently
under the same reaction conditions to afford both (2R,3R)-
To this end, we envisioned to utilize lipase-catalyzed
transesterification7 of 2-substituted 3-hydroxy esters. A
very few related studies were reported so far on lipase-cat-
alyzed transesterifications of 3-hydroxy esters such as cis-
R
R
R
Lipase
CH2=C(OAc)Me
2R
3S
2S
3R
+
+
MeO2C
MeO2C
MeO2C
toluene
OH
OAc
OH
syn-racemate 1
2
3
R
R
R
Lipase
CH2=C(OAc)Me
2S
2R
3S
3R
MeO2C
MeO2C
MeO2C
toluene
OH
OAc
OH
anti-racemate 4
5
6
Scheme 1
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1665,1668,ftx,en;U05702ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1666
T. Mandai et al.
LETTER
acetates 516 and the unreacted (2S,3S)-alcohols 616 in a To demonstrate the synthetic utility of our method, we ex-
highly enantioselective manner, the results being summa- ecuted the synthesis of the taxol side chain. Anti-aldol iso-
rized in Tables 1 and Table 2.
mer 1021 (1.26 g, 5.2 mmol) was subjected to the
transesterification [Chirazyme® (0.6 g), 2-propenyl ace-
tate (1.72 mL, 15.6 mmol), toluene (7.8 mL)], providing
acetate 11 (44%, 98.5%ee) and unreacted alcohol 12
(49%, >99%ee) (Scheme 3).
To determine the absolute configuration of alcohols 6, 6a
(>99% ee, 4.76 mmol) was transformed into alcohol 9, an
aggregation pheromone of the smaller European elm bark
beetle (Scolytus multistriatus),18 as depicted in Scheme 2.
Hydrogenation of the terminal olefin (HN=NH/MeOH,19 Compound 12 thus obtained was transformed into cyclic
96%) provided saturated alcohol 7. Protection of the hy- carbamate 13 in 80% yield via Curtius rearrangement of
droxyl group (CH2=CHOEt, 93%) followed by reduction the free acid released by palladium-catalyzed
of the methyl ester (LiAlH4, 98%) gave rise to alcohol 8. hydrogenolysis22 of the allyl ester. Protection of the nitro-
Tosylation of 8 (p-TsCl, 91%), reduction (LiAlH4, 92%) gen with (Boc)2O and oxidative cleavage (RuO2/NaIO4)23
and deprotection (3 M HCl, 82%) afforded 9 {[ ]D24 –22.7 of the double bond furnished carboxylic acid 14 in 88%
19
(c 1.00, hexane), Lit.20 [ ]D –21.4 (c 1.02, hexane)} in yield. Ring opening (2 M NaOH/MeOH, r.t., 2 h), depro-
60% overall yield.
tection of the Boc group, and ensuing benzoylation pro-
vided N-benzoyl-(2R,3S)-3-phenylisoserine (15) in 71%
Table 1 Lipase-catalyzed Kinetic Resolution of syn-Racemate 1
Temp. (°C)/Time (h)
Entry
1: R-
Yield (%ee)
Acetate 2
Alcohol 3
E value17
>1000
136
1
2
3
4
5
6
7
n-C3H7-
1a
1b
1c
1d
1e
1f
70/72
70/72
70/40
70/72
70/72
50/40
r.t./72
40 (99): 2a
41 (96): 2b
48 (99): 2c
49 (>99): 2d
43 (99): 2e
48 (>99): 2f
48 (89): 2g
47 (>99): 3a
45 (86): 3b
49 (99): 3c
48 (>99): 3d
51 (98): 3e
50 (>99): 3f
42 (>99): 3g
(CH3)2CHCH2-
trans-EtCH=CH-
(CH3)2C=CHCH2-
CH2=CH(CH2)7-
PhSCH2CH2-
CH3-
>1000
>1000
922
>1000
90
1g
Table 2 Lipase-catalyzed Kinetic Resolution of anti-Racemate 4
Entry
4: R-
Temp. (°C)/Time (h)
Yield (%ee)
Acetate 5
Alcohol 6
E value17
170
1
2
3
4
5
6
7
n-C3H7-
4a
4b
4c
4d
4e
4f
70/72
70/72
70/40
70/72
70/72
50/40
r.t./72
45 (94): 5a
43 (96): 5b
48 (96): 5c
48 (93): 5d
49 (>99): 5e
50 (98): 5f
46 (96): 5g
46 (>99): 6a
45 (>99): 6b
46 (97): 6c
46 (>96): 6d
48 (>99): 6e
50 (>99): 6f
44 (>99): 6g
(CH3)2CHCH2-
trans-EtCH=CH-
(CH3)2C=CHCH2-
CH2=CH(CH2)7-
PhSCH2CH2-
CH3-
259
207
145
>1000
525
4g
259
OH
b, c
d, e, f
a
MeO2C
MeO2C
OH
OH
OEE
OH
6a
7
8
9
Scheme 2 (a) KO2CN=NCO2K/HOAc/MeOH, 0 °C to r.t., 12 h, 96%; (b) CH2=CHOEt/cat. PPTS/CH2Cl2, r.t., 6 h, 93%; (c) LiAlH4/THF,
0 °C, 0.5 h, 98%; (d) p-TsCl/cat. DMAP/pyridine, r.t., 20 h, 91% (e) LiAlH4/THF, 0 °C to r.t., 12 h, 92%; (f) 3 M HCl/EtOH, r.t., 4 h, 82%
Synlett 2002, No. 10, 1665–1668 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Transesterification of Methyl 2 Substituted 3-Hydroxy-4-pentenoates
1667
Chirazyme®
Ph
Ph
Ph
CH2=C(OAc)Me
+
AllylO2C
AllylO2C
AllylO2C
PhMe, 70 °C, 90 h
OH
OH
OAc
10
11
12
48% (98.5%ee)
49% (>99%ee)
Scheme 3
O
O
NHBz
BocN
Ph
HN
e, f , g
71%
a, b
80%
c, d
CO2H
Ph
12
O
O
Ph
88%
OH
CO2H
13
14
15
Scheme 4 (a) Pd(OAc)2/PPh3, HCO2H/Et3N/THF, r.t., 10 h; (b) DPPA/Et3N/toluene, r.t., 40 min, then 80 °C, 1.5 h; (c) (Boc)2O/Et3N/DMAP/
THF, r.t., 2 h; (d) RuO2/NaIO4, CCl4/MeCN/H2O = 2:2:3, r.t., 15 h; (e) 2 M NaOH/MeOH, r.t., 1 h; (f) TFA, r.t., 2 h; (g) BzCl/aq NaHCO3, r.t.,
6 h
25
(7) For a review: Carrea, G.; Riva, S. Angew. Chem. Int. Ed.
2000, 39, 2226.
(8) Panunzio, M.; Camerini, R.; Mazzoni, A.; Donati, D.;
Marchioro, C.; Pachera, R. Tetrahedron: Asymmetry 1997,
8, 15.
(9) Vrielynck, S.; Vandewalle, M. Tetrahedron Lett. 1995, 36,
9023.
(10) Wünsche, K.; Schwaneberg, U.; Bornscheuer, U. T.; Meyer,
H. H. Tetrahedron: Asymmetry 1996, 7, 2017.
(11) Kaga, H.; Hirosawa, K.; Takahashi, T.; Goto, K. Chirality
1998, 10, 693.
(12) Lipase-catalyzed enantioselective hydrolysis of 2-methy-3-
acetoxy esters has been reported, see: (a) Akita, H.;
Matsuura, H.; Oishi, T. Tetrahedron Lett. 1986, 27, 5241.
(b) Akita, H.; Chen, C. Y.; Nagumo, S. Tetrahedron:
Asymmetry 1994, 5, 1207.
yield {[ ]D –35.3 (c 1.03, EtOH), mp 173.5–176 °C,
Lit.24 [ ]D20 –35.5 (c 1.07, EtOH), mp 175.5–177 °C} as
outlined in Scheme 4.
In summary, we have established a practical method for
obtaining syn- and anti-methyl 2-substituted 3-hydroxy-
4-pentenoates with high optical purities by means of the
lipase-catalyzed transesterification, which would offer ac-
cess to other synthetically useful intermediates involving
1,2-amino alcohols less available from natural amino ac-
ids.
Acknowledgement
We thank Prof. Kaoru Nakamura (Kyoto University) for his helpful
discussions. We also thank The Promotion and Mutual Aid Corpo-
ration for Private Schools of Japan for financial support (The Sci-
ence Research Promotion Fund).
(13) For instance, compounds 1b and 4b were prepared as
follows. A solution of methyl 4-methylvalerate (7.48 g, 57.5
mmol) in THF (20 mL) was added dropwise to a solution of
LDA (60.3 mmol) in hexane (38.7 mL)/THF (50 mL) at
–78 °C and the mixture was stirred for 1 h. Then, acrolein
(4.61 mL, 68.9 mmol) was added and the mixture was stirred
at –78 °C for 2 min. After usual workup, the oil obtained was
purified by medium-pressure column chromatography
References
(1) Gargano, J. M.; Lees, W. J. Tetrahedron Lett. 2001, 42,
5845.
(Yamazen, Ultra PackTM
,
50 300 mm, hexane/ethyl
(2) (a) Sakaitani, M.; Ohfune, Y. Tetrahedron Lett. 1987, 28,
3987. (b) Sakaitani, M.; Ohfune, Y. J. Am. Chem. Soc. 1990,
112, 1150. (c) Alemany, C.; Bach, J.; Farràs, J.; Garcia, J.
Org. Lett. 1999, 1, 1831; and references therein.
(3) Jost, S.; Gimbert, Y.; Green, A. E.; Fotiadu, F. J. Org. Chem.
1997, 62, 6672; and references therein.
(4) For a review on 1,2-amino alcohols as chiral auxiliaries in
asymmetric synthesis: Ager, D. J.; Prakash, I.; Schaad, D. R.
Chem. Rev. 1996, 96, 835.
(5) (a) Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62,
5864. (b) Ghosh, A. K.; Hussain, K. A.; Fidanze, S. J. Org.
Chem. 1997, 62, 6080. (c) Pais, G. C. G.; Maier, M. E. J.
Org. Chem. 1999, 64, 4551.
acetate = 6:1~4:1 as eluent) to afford the less polar syn-
racemate 1b (5.03 g, 27.0 mmol, 47% yield) and the more
polar anti-racemate 4b (4.70 g, 25.2 mmol, 44% yield). Each
compound can easily be discriminated by the chemical shifts
of methine protons at 2- and 3-positions in 1H NMR spectra
(CDCl3, 500 MHz) : 2.62–2.68 (m, 1 H, CHCOO) and
4.28–4.33 (m, 1 H, CHOH) for 1b, and 2.58–2.63 (m, 1 H,
CHCOO) and 4.14–4.20 (m, 1 H, CHOH) for 4b. The
chemical shifts of the methine protons at 2- and 3-positions
of 1 are generally observed in the down field compared with
those of 4. Additionally, syn-racemates 1 are generally less
polar than anti-racemates 4 on TLC analysis (hexane/ethyl
acetate = 5:1~3:1).
(6) For syn-aldol reactions: (a) Evans, D. A.; Taber, T. R.
Tetrahedron Lett. 1980, 21, 4675. (b) Evans, D. A.;
Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
(c) For anti-aldol reactions: Evans, D. A.; Tedrow, J. S.;
Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124,
392. (d) Also see: Evans, D. A.; Downey, C. W.; Shaw, J. T.;
Tedrow, J. S. Org. Lett. 2002, 4, 1127.
(14) Lipase-catalyzed enantioselective acylation of 1-alkene-3-
ols has been well examined, see: (a) Ito, T.; Akasaki, E.;
Kudo, K.; Shirakami, S. Chem. Lett. 2001, 262. (b) Ito, T.;
Kudo, K.; Tanaka, N.; Sakabe, K.; Takagi, Y.; Kihara, H.
Tetrahedron Lett. 2000, 41, 4591.
Synlett 2002, No. 10, 1665–1668 ISSN 0936-5214 © Thieme Stuttgart · New York

1668
T. Mandai et al.
LETTER
(15) The quantity of the lipase was not optimized. The lipase
collected was washed with ether, dried in air for 5 min and
stored below 5 °C. The lipase retains full activity and can be
reused at least three times.
(17) (a) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294. (b) Chen, C.-S.; Wu,
S.-H.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1987, 109,
2812.
(16) The enantiomeric purity of alcohols 3 and 6 were determined
by Chiralcel OD-H (hexane–2-propanol, 230 nm or 254 nm).
Acetates 2 and 5 were also analyzed by Chiralcel OD-H
(hexane/2-propanol, 230 nm or 254 nm) after having been
converted to the corresponding alcohols via methanolysis
(K2CO3/MeOH, r.t., 1 h). Some of them were transformed
into known 1,2-amino alcohols to confirm their absolute
configuration. For instance, acetates 2b (96% ee), 3b (90%
ee after resubjection to the lipase-catalyzed transesteri-
fication), 5b (>99% ee), and 6b (99% ee) were converted to
N-protected amino alcohols in 58%, 67%, 61%, and 56%
overall yields, respectively via sequential alkaline hydrol-
ysis (2 M NaOH/MeOH, r.t., 2 h), Curtius rearrangement
(DPPA/Et3N/toluene, r.t., 4 h and 80 °C, 1 h), N-protection
[(Boc)2O/Et3N/cat. DMAP/THF, r.t., 2 h], and ring opening
(0.4 equiv. of Cs2CO3/MeOH, r.t., 11 h),25 the results being
summarized below (Scheme 5). The optical rotation values
were compared with those of reported in the literatures. See:
(a) Leanna, M. R.; DeMattei, J. A.; Li, W.; Nichols, P. J.;
Rasmussen, M.; Morton, H. E. Org. Lett. 2000, 2, 3627.
(b) DeMattei, J. A.; Leanna, M. R.; Li, W.; Nichols, P. J.;
Rasmussen, M. W.; Morton, H. E. J. Org. Chem. 2001, 66,
3330.
(18) (a) Pearce, G. T.; Gore, W. E.; Silverstein, R. M.; Peacock,
J. W.; Cuthbert, R. A.; Lanier, G. N.; Simeone, J. B. J. Chem.
Ecol. 1975, 1, 115. (b) Mori, K. In The Total Synthesis of
Natural Products, Vol. 9; ApSimon, J., Ed.; Wiley: New
York, 1992, 101.
(19) Groves, J. T.; Ma, K. W. J. Am. Chem. Soc. 1977, 99, 4076.
(20) Sayo, N.; Azuma, K.; Mikami, K.; Nakai, T. Tetrahedron
Lett. 1984, 25, 565.
(21) (a) The attempted alkaline hydrolysis of the corresponding
methyl ester of 10 failed entirely due to the intensive retro-
aldol reaction. Thus we adopted the allyl ester 10 cleanly
convertible to the free carboxylic acid by the palladium-
catalyzed hydrogenolysis under a neutral condition. The
compound 10 was prepared according to the Mulzer’s
protocol: Mulzer, J.; Segner, J.; Brüntrup, G. Tetrahedron
Lett. 1977, 4651. (b) A solution of phenylacetic acid (13.6 g,
100 mmol) in THF (40 mL) was added dropwise to a stirred
solution of LDA (210 mmol) in THF–hexane (140 mL/135
mL) at 0 °C and the reaction mixture was stirred at 0 °C for
45 min and at r.t. for 2 h. The solvent was removed under
reduced pressure and the residual viscous material was dried
in vacuo at 70 °C for 2 h to give pale yellow solids. The
lithium enolate thus obtained was dispersed in THF (100
mL) and acrolein (8.02 mL, 120 mmol) was added dropwise
at 0 °C. After being stirred at r.t. for 48 h, the solvent was
evaporated and ice-cold 3 N HCl (120 mL) was added to the
residue. Extraction with CHCl3 gave 2-phenyl-3-hydroxy-4-
pentenoic acid (anti/syn = ca. 10:1) as a viscous oil (17.4 g)
which without purification was esterified with allyl alcohol
(14.9 mL, 220 mmol) in methanol-free CH2Cl2 (150 mL) in
the presence of concd H2SO4 (2 mL) at r.t. for 48 h to give a
diastereomeric mixture of allyl esters. The anti-ester 10 was
isolated in 60% overall yield (Scheme 6) by medium-
pressure column chromatography (SiO2, toluene–EtOAc =
10:1~5:1).
1) 2M NaOH
NHBoc
2) DPPA/Et3N
MeO2C
3) (Boc)2O
OAc
OH
2b
4) Cs2CO3/MeOH
58%
96%ee
[α]D24 -35.6 (c 1.1, MeOH)
Lit. [α]D25 -37.9 (c 9.54, MeOH)
[α]24D -42.1 (c 1.0, CHCl3)
25
Lit. [α]D -41.3 (c 1.01, CHCl3)
OLi
NHBoc
LDA (2.1 eq)
Ph
As above
67%
Ph
CO2H
-iPr2NH
MeO2C
3b
OLi
OH
OH
[α]D24 +34.9 (c 1.1, MeOH)
90% ee
[α]D24 +39.6 (c 1.0, CHCl3)
THF/acrolein
0 °C~r.t., 48 h
Ph
Ph
OH
NHBoc
OH
HO2C
AllylO2C
As above
61%
H2SO4/CH2Cl2
r.t., 48 h
OH
OH
ca. 60% overall yield
MeO2C
5b
anti/syn=10/1
OAc
>99%ee
[α]D24 +84.7 (c 1.0, MeOH)
[α]D24 +61.8 (c 1.0 , CDCl3)
Scheme 6
(22) For a review: Tsuji, J.; Mandai, T. Synthesis 1996, 1.
(23) Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis,
Vol. 7; Trost, B. M.; Fleming, I., Eds.; Pergamon Press:
Oxford, 1991, Chap. 3.8, 541.
(24) Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem.
1994, 59, 5104.
NHBoc
As above
56%
MeO2C
6b
OH
OH
[α]D24 -83.2 (c 1.1, MeOH)
(25) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185.
99%ee
[α]D24 -59.5 (c 1.1, CDCl3)
Lit. [α]D25 -54.8 (c 0.81, CDCl3)
Scheme 5
Synlett 2002, No. 10, 1665–1668 ISSN 0936-5214 © Thieme Stuttgart · New York