Synthesis and lipase-catalyzed enantiotope selective acetylation of 2- benzoyloxy-1,3-propanediol

Article abstract of DOI:10.1055/s-1999-2720

Preparation and porcine pancreatic lipase (PPL)-catalyzed enantiotope selective acetylation of the prochiral 2-benzoyloxy-1,3-propanediol (1a) is described. The reaction with PPL and vinyl acetate gave monoacetate (2a) of 96 % e.e.

Full text of DOI:10.1055/s-1999-2720

LETTER
759
Synthesis and Lipase-Catalyzed Enantiotope Selective Acetylation of
2-Benzoyloxy-1,3-propanediol
Viktória Bódaia, Lajos Nováka, László Poppe*b
aInstitute for Organic Chemistry, Technical University of Budapest, H-1111 Budapest, Gellért tér 4., Hungary
bChemical Research Centre of the Hungarian Academy of Sciences, H-1025 Budapest, Pusztaszeri út 59-67, Hungary;
E-mail: poppe.szk@chem.bme.hu
Received 3 April 1999
Abstract: Preparation and porcine pancreatic lipase (PPL)-cata-
lyzed enantiotope selective acetylation of the prochiral 2-benzo-
yloxy-1,3-propanediol (1a) is described. The reaction with PPL and
vinyl acetate gave monoacetate (2a) of 96 % e.e.
Key words: 2-O-benzoylglycerol, enantiotope selective, acetyla-
tion, lipase
Chiral glycerol derivatives are considered to be useful C3
building blocks for the preparation of homochiral biolog-
ically active molecules such as phospholipids1, phospho-
lipase A2 inhibitors2, PAF (platelet-activating factor)3,
and many others4.
Biocatalytical preparation of these chiral C3 units were
carried out either by enantiomer selective or enantiotope
selective manner. The kinetic resolution of racemic glyc-
erol derivatives such as glycerol acetonide5,6 , glycerol-
7
2,3-carbonate provided moderate selectivity and 50%
theoretical limit of the desired enantiomer. On the other
hand, enantiotope selective transformation of prochiral
1,3-propanediols (1) or their diacyl derivatives (3) provide
theoretically 100% of a single enantiomer (2 or ent-2).
(a) cat. cc. H2SO4, RT, 4 h, 28%; (b) BzCl (1.1 eq.), Et3N (1.2 eq.), cat.
DMAP, CH2Cl2, RT, 2 h, 96 %; (c) H2, cat. 10 %Pd/C, EtOAc, RT, 8
h, 73 %.
Scheme 1
Enzyme-catalyzed acylation of several 2-O-alkylglycerol
derivatives (1, R1,R2= O-alkyl, H), such as the 2-O-meth-
yl-,8,9 2-O-ethyl-, 8,9 or 2-O-benzylglycerol8 gave optical-
ly active monoacetates (2). Hydrolyses of the
corresponding diacyl compound (3, R1, R2= OBn, H) with
different enzymes under various conditions were also per-
formed.11-15 In the case of the 2-O-alkyl substituents, the
lipase-catalyzed process proved to be pro-S selective.
Consequently, acylation of the 2-O-benzylglycerol (1, R1,
R2= OBn, H) provided (S)-1-O-acetyl-2-O-benzylglycer-
ol (2, R1= H, R2= OBn) 11 and hydrolyses of the corre-
sponding diacyl derivative (3, R1= H, R2= OBn) gave the
(R)-enantiomer (ent-2, R1= OBn, R2= H).11,12 The slow ra-
* According to TLC data, most of the diol 1a was converted to
diacetate.
(a) 1a (300 mg), enzyme, vinyl acetate (1 ml), THF (3 ml), hexane
(3 ml), RT
Scheme 2
Synlett 1999, No. 6, 759–761 ISSN 0936-5214 © Thieme Stuttgart · New York

760
V. Bódai et al.
LETTER
cemisation (ca. 2 %/h) found when optically active (S)-1-
O-acetyl-2-O-benzylglycerol (2, R1= H, R2= OBn) was
incubated in phosphate buffer pH 7 without enzyme is the
drawback of the hydrolytic method.11
Although the enantiotope selective biotransformations of
2-O-alkylglycerol derivatives (1 or 3, R1,R2= O-alkyl, H)
are well documented, no example of enzymic enantiotope
selective acylation of 2-O-acylglycerol derivatives (1, R1,
R2= O-acyl, H) was found.
(a) BzCl (1.1 eq.), Et3N (1.2 eq.), THF, 0-20oC, 2 h, 88 %.
Scheme 3
It is worthwile noting that two compounds of this family
(2, R1, R2= O-acyl, H), namely 1-O-acetyl-2-O-(16-meth-
yl)heptadecanoyl- and 1-O-acetyl-2-O-(18-methyl)nona-
decanoylglycerol, were isolated from Nicotina
benthamiana.16
The optical rotation of our dibenzoyl compound
(9)24 ([a]D= -2.78; c = 0.78, methanol) comparing to
the literature data for (S)-(9) ([a]D= -0.8; c = 0.13, metha-
nol) 25proved its (S)-configuration, and therefore (R)-con-
figuration of our enzymic product (2a).
As a part of our interest in exploring new stereoselective
biocatalytic methods, we decided to investigate the lipase-
catalyzed acetylation of the 2-O-acylglycerol derivatives
(1, R1,R2= O-acyl, H). Hence, 2-O-benzoyloxyglycerol
(1a, R1=OBz, R2=H) was selected as a representative of
this class.
Acknowledgement
We thank OTKA (No. T014894 and T025235) for financial support.
Preparation of the desired diol (1a) was straightforward
(Scheme 1). Condensation reaction 17 of glycerol (4) and
benzaldehyde (5) provided cis-5-hydroxy-2-phenyl-1,3-
dioxane (6).18 Consequent benzoylation and deprotection
of the benzylidene protected intermediate (8)19 by catalyt-
ic hydrogenation yielded the desired diol (1a)20 in pure
crystalline form.
References and Notes
(1) Caer, E.; Kindler, A. Biochemistry 1962, 1, 518.
(2) Dennis, E. A. Bio/Technology 1987, 5, 1294.
(3) Hirth, G.; Barner, R. Helv. Chim. Acta 1982, 65, 1059.
(4) Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447.
(5) Wang, Y. F.; Wong, C.-H. J. Org. Chem. 1988, 53, 3127.
(6) Bianchi, D.; Bosetti, A.; Golini, P.; Cesti, P.; Pina, C.
Tetrahedron:Asymmetry 1997, 8, 817.
(7) Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O. J. Org.
Chem. 1994, 59, 1751.
(8) Murata, M.; Terao, Y.; Achiwa, K.; Nishio, T.; Seto, K. Chem.
Pharm. Bull. 1989, 10, 2670.
(9) Terao, Y.; Murata, M.; Achiwa, K.; Nishio, T.; Akamtsu, M.;
Kamimura, M. Tetrahedron Lett. 1988, 29, 5173.
(10) Ghisalba, O.; Lattmann, R.; Gygax, D. Recl. Trav. Chim.
Pays-Bas 1991, 110, 263.
(11) Wang, Y. F.; Lalonde, J. J.; Momongan, M.; Bergbreiter, D.
E.; Wong, C. H. J. Am. Chem. Soc. 1988, 110, 7200.
(12) Breitgoff, D.; Laumen, K.; Schneider, M. P. J. Chem. Soc.
Chem. Commun. 1986, 1523.
(13) Wirz, B.; Schmid, R.; Foricher, J. Tetrahedron:Asymmetry
1992, 3, 137.
(14) Suemune, H.; Mizuhara, Y.; Akita, H.; Sakai, K. Chem.
Pharm. Bull. 1986, 34, 3440.
(15) Kerschner, V.; Kreiser, W.; Tetrahedron Lett. 1987, 28, 531.
(16) Tsuzaki, T.; Shinozaki, Y.; Hagimori, M.; Tobita, T.;
Shigematsu, H.; Koiwai, A. Biosci. Biotechnol. Biochem.
1992, 56, 1565.
(17) Carlsen, P. H. J.; Soerbye, K.; Ulven, T.; Aasboe, K. Acta
Chem. Scand. 1996, 50, 185.
(18) Data for cis-5-hydroxy-2-phenyl-1,3-dioxane (6): nmax (KBr)/
cm-1 3285, 3190, 2987, 2920, 2855, 1452, 1391, 1340, 1279,
1239, 1231, 1156, 1089, 1017,996, 977, 948, 930, 831, 808,
741; dH (500 MHz, CDCl3): 3.15 (1H, d, J= 10.0 Hz, OH),
3.58 (1 H, br d, J= 10.0 Hz), 4.09 (2H, dd, J= 12.0 and 1.5
Hz), 4.17 (2H, dd, J= 12.0 and 1.5 Hz), 5.54 (1H, s) , 7.36
(3H, m), 7.49 (2H, m). Spectra are in agreement with
literature data.17
With the desired prochiral diol (1a) in hand, the enan-
tiotope selectivity of acetylation by several commercially
available lipases was tested (Scheme 2).
Among the enzymes investigated, lipase from porcine
pancreas (PPL) proved to be the most selective providing
almost enantiomerically pure product (2a)21 in good yield
(Entry 7). The enantiomeric purity of the product (2a) was
determined from the 1H-NMR signals of its MTPA ester.22
The composition of the solvent in this reaction catalyzed
by PPL played an important role. Since the crystalline diol
(1a) is poorly soluble in apolar solvents, the reaction was
slow in hexane. Enzymatic acetylations using vinyl ace-
tate as acylating agent in more polar solvents like chloro-
form, ethyl acetate or vinyl acetate gave decreased
enantiotope selectivity compared to that obtained in the
best solvent system (THF:hexane 1:1).
Prediction of the sense of enantiotopic selectivity seemed
to be not obvious for lipase-catalyzed acylation of this
new class of prochiral 1,3-propanediols. The lipase-cata-
lyzed acylation of 2-O-alkyl-1,3-propanediols (1, R1, R2=
O-alkyl, H) proved to be pro-S selective. In the case of 2-
alkyl-1,3-propanediols (1, R1, R2= alkyl, H) bearing apo-
lar substituent at position 2, enantiotope preference is in-
verted in a geometrical sense, although as a result of the
sequence rules, the affected group is still labelled pro-S.23
Acetylation of the diol bearing 2-N-benzyloxycarbonyl
group by PPL was found to be pro-R.11
(19) Data for cis-5-benzoyloxy-2-phenyl-1,3-dioxane (7): m.p. 92-
93oC (ethanol); nmax (KBr)/cm-1 3060, 2990, 2850, 1720,
1595, 1450, 1390, 1360, 1310, 1280, 1265, 1145, 1110, 1010,
The absolute configuration of our product (2a) was deter-
mined by chemical correlation (Scheme 3.).
Synlett 1999, No. 6, 759–761 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis and Lipase-Catalyzed Enantiotope Selective Acetylation of 2-Benzoyloxy-1,3-propanediol
761
790, 750, 710; dH (500 MHz, CDCl3): 4.27 and 4.43 (2H, d,
OH), 4.40 (m, 2H, CH2-OAc), 5.33 (m, 1H, CH-O), 7.43 (t,
2H, J= 7.5 Hz, 2 m-Ar-H), 7.56 (t, 1H, J= 7.5 Hz, 1 p-Ar-H),
8.04 (d, 2H, J= 7.5 Hz, 2 o-Ar-H).
J=12 Hz, 2 CH2), 4.96 (1H, s, CH-OBz), 5.72 (1H, s, CH-Ph),
7.39 (3H, m, Ar-H), 7.46 (2H, t, J= 7.5 Hz, Ar-H), 7.56 (3H,
m, Ar-H), 8.17 (2H, d, J= 7.5 Hz, Ar-H).
(22) Reaction of 2a with (R)-MTPA-Cl (1.2 eqv., CCl4, pyridine)
gave diastereomeric MTPA esters. Useful signals (dH, 500
MHz, CDCl3): 3.517 [s, OCH3, (R)-2a MTPA ester], 3.544 [s,
OCH3, (S)-2a MTPA ester].
(23) Poppe, L.; Novák, L. Selective Biocatalysis: A Synthetic
Approach; VCH: Weinheim-New York, 1992.
(24) Data for (S)-1-acetoxy-2,3-benzoyloxypropane (9):
[a]D= -2.78 (c 0.78, methanol); nmax (KBr)/cm-1 3050, 2950,
1740, 1720, 1600, 1580, 1485, 1450, 1360, 1315, 1250, 1175,
1100, 1070, 1045, 1025, 935, 850, 710, 680; dH (500 MHz,
CDCl3): 2.09 (3H,s), 4.47 (2H, mc, CH2OAc), 4.62 (2H, mc,
CH2OBz), 5.68 (1H, m, CH-OBz), 7.26 (4H, mc, 4 m-ArH),
7.44 (2H, mc, 2 p-Ar-H), 8.04 (4H, mc, 4 o-Ar-H). Spectra are
in agreement with literature data.25
(20) Data for 2-benzoyloxy-1,3-propanendiol (1a): m.p. 72-73oC
(toluene-hexane 2:1); nmax (KBr)/cm-1 3300, 2950, 2920,
2850, 1720, 1590, 1450, 1350, 1270, 1105, 1020, 955, 705; dH
(500 MHz, CDCl3): 2.59 (2H, 2 OH), 3.87 (m, 4H, 2 CH2-O),
5.08 (m, 1H, CH-O), 7.36 (t, 2H, J= 7.5 Hz, 2 m-Ar-H), 7.50
(t, 1H, J= 7.5 Hz, p-Ar-H), 7.89 (d, 2H, J= 7.5 Hz, 2 o-Ar-H).
(21) The prochiral diol (1a, 300 mg, 1.53 mmol) was dissoved in
dry THF (3 ml). To this solution vinyl acetate (1 ml), hexane
(3 ml) and lipase from porcine pancreas (PPL, 300 mg) were
added and the resulting suspension was stirred at RT for 1 h.
The lipase (which after washing by acetone and drying proved
to be active in a subsequent reaction) was removed by
filtration. The oily residue remaining after evaporation of the
filtrate was purified by low pressure chromatography on silica
gel using hexane - acetone 4 : 1 eluant mixture.
(25) Uzawa, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem.
1990, 55, 116.
Data for (R)-3-acetoxy-2-benzoyloxy-1-propanol (2a, 230
mg, 63 %): [a]D= -27.4 (c 1, ethanol), 96 %e.e.; nmax (KBr)/
cm-1 3400, 2960, 2910, 2850, 1730, 1720, 1590, 1470, 1450,
1350, 1270, 1110, 1020, 960, 705; dH (500 MHz, CDCl3): 2.04
(s, 3H, O=C-CH3), 3.32 (br s, 1H, OH), 3.85 (m, 2H, CH2-
Article Identifier:
1437-2096,E;1999,0,06,0759,0761,ftx,en;L03399ST.pdf
Synlett 1999, No. 6, 759–761 ISSN 0936-5214 © Thieme Stuttgart · New York