Enzyme assisted syntheses of chiral building blocks for isosters of diglycerides, phospholipids and PAF

Article abstract of DOI:10.1016/j.tetasy.2004.07.047

Lipase catalyzed desymmetrizations of suitably substituted, achiral 1,3-diols lead to the corresponding chiral building blocks of high enantiomeric purities, starting materials for the synthesis of isosteric carba-analogues of 1,2-sn-diglycerides and phospholipids with interesting biological activities. Lipase catalyzed resolutions of the corresponding ether derivatives lead to the corresponding building blocks for carba-analogues of PAF.

Full text of DOI:10.1016/j.tetasy.2004.07.047

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2811–2815
Enzyme assisted syntheses of chiral building blocks for isosters of
diglycerides, phospholipids and PAF
Karsten Lange and Manfred P. Schneider*
FB C––Bergische Universita¨t Wuppertal, D-42097 Wuppertal, Germany
Received 1 June 2004; accepted 6 July2004
Available online 11 September 2004
Abstract—Lipase catalyzed desymmetrizations of suitably substituted, achiral 1,3-diols lead to the corresponding chiral building
blocks of high enantiomeric purities, starting materials for the synthesis of isosteric carba-analogues of 1,2-sn-diglycerides and
phospholipids with interesting biological activities. Lipase catalyzed resolutions of the corresponding ether derivatives lead to the
corresponding building blocks for carba-analogues of PAF.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
siderablyhigher stabilityand lifetime as compared to
the native second messengers. Furthermore, certain
derivatives of PAF, e.g. Ilmofosine (BM 41.440)9 or
(ET-18-OCH3)10––Edelfosine are claimed to be promis-
ing anti-tumoractive compounds and anti-proliferation
active derivatives.11–13
Molecules with a glyceride substructure are among the
most important and at the same time ubiquitous biolog-
icallyactive compounds in living organisms. While cer-
tain phospholipids are essential constituents of cell
membranes,1 others are involved in highlyimportant
processes of cell regulation and signal transduction,
resulting––due to specificallyacting phospholipases––in
the formation of important second messengers such as
arachidonic acid, 1,2-sn-diglycerides and inositol phos-
phates.2 Platelet activating factor (PAF), an ether lipid
displays a wide variety of biological (physiological) prop-
erties and is, among others, an important mediator of
platelet aggregation, inflammation and anaphylaxis.3,4
O
O
O
H
H
O
O
P
O
P
O
O
O
O
O
N+
H37C18
N+
H37C18
O-
O-
PAF Analogues
PAF
O
O
O
CnH2n+1
O
CnH2n+1
In view of our continuing interest in molecules of the
inositolphospholipid pathway,5,6 indications in the liter-
ature that carba-analogues of phospholipids could be
interesting substrates and––possibly––effective inhibi-
tors of phospholipase A2,7,8 prompted us to synthesize
a series of such molecules in which the sp3––oxygens
of the 2-positions are replaced bysp 3––carbons (Fig. 1).
H
O
H
O
P
H2n+1Cn
O
P
O
H2n+1Cn
O
O
O
N+
N+
O-
O-
O
O
Phosphatidylcholine
Phosphatidylcholine-Analogues
Figure 1. Isosters of phospholipids and PAF.
These changes result in isosteric mimics of the natural
molecules with minimal deviations regarding bond an-
gles and distances. Moreover, it can be expected that
carba-analogous 1,2-sn-diglycerides would display con-
While a number of such molecules and related deriva-
tives have been described in the past7,14 in onlyfew cases
theyhave been prepared as single enantiomers.
The frequentlyobserved close relationship between
absolute configurations and biological activities––
together with their proven or potential properties––
provided sufficient motivation to develop a general
*
Corresponding author. Tel.: +49 0202 439 2775; fax: +49 0202 439
2535; e-mail: schneid@uni-wuppertal.de
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.047

2812
K. Lange, M. P. Schneider / Tetrahedron: Asymmetry 15 (2004) 2811–2815
synthetic strategy towards the preparation of the title
compounds in enantiomericallypure form. In order to
compare biological activities, both enantiomeric series
had to be made available for everytarget structure.
2CH2O
H2O
O
O
O
O
O
O
acetone
PTSA
O
O
NaHCO3
MeO
OMe
MeO
OMe
MeO
OMe
85%
75%
OH OH
1
2
DMSO
NaCl
2. Retrosynthesis
76%
O
160°C
Retrosynthetic analysis (Scheme 1) of an enantiomeri-
callypure 2- sn-carba-analogous phospholipid I leads––
via formal removal of the phosphocholine head
group––to the corresponding carba-analogues of 1,2-
sn-diglycerides II, which in turn, can be correlated to
the corresponding diols III, which are clearlyequivalent
to the thioketals IV. It can easilybe envisaged that both
III and IV could possiblybe desymmetrized via lipase
catalyzed asymmetric hydrolyses or acylations.
LG
O
OH
OMe
LAH
75%
60-80%
O
O
O
O
O
4
3
5: LG = Cl
6: LG = Br
7: LG = Tos
Scheme 2. Synthesis of central building blocks V.
O
O
SH SH
R´
R´
BF3etherate
H
O
H
CH2Cl2
O
+
S
R
S
H
5
R
H
>90%
O
O
P
O
R
N+
O
OH
R
O-
I
II
8: R = C11H23
R = C11H23
R = C15H31
R = Me
R = Acyl; Alkyl
R´= CH3, Alkyl
9: R = C15H31
10: R = Me
O
BuLi
S
S
R´
THF
60-70%
R´
H
-50°C
H
HO
OH
HO
OH
S
S
R
S
S
R
EtOH/H2O
p-TsOH
IV
III
quant.
LG
OH OH
O
O
H
O
+
S
H
S
R´
14: R = C11H23
11: R = C11H23
12: R = C15 31
13: R = Me
H
R´
HO
OH
15: R = C15 31
H
H
V
VI
16: R = Me
Scheme 1. Retrosynthesis of the title compounds.
Scheme 3. Synthesis of building blocks IV.
Disconnection of IV leads directlyto building blocks V
and VI. While V can serve as a central building block for
the ÔglycerolÕ backbone in all of the title compounds, VI
can be individuallyprepared from readilyavailable alde-
hydes via a simple protection step. Consequently, a ser-
ies of compounds with the general structure of IV were
prepared as follows (Schemes 2 and 3).
derivatives 5–7, respectively. It turned out that the cor-
responding chloro-compound 5 is best suited as the
electrophile for the following coupling reactions with
the 2-alkyl-1,3 dithiane building blocks. Thus 4 was
transformed into 5 using CCl4/PPh3 in 72% yield. Com-
pound 5 constitutes the central building block for con-
struction of the ÔglycerolÕ backbone.
3. Synthesis of the central building block V
4. Syntheses of building blocks VI
Condensation of formaldehyde with dimethylmalonate
leads to the diol 1 which, after protection as acetonide
2 (85%) is submitted to a Krapcho reaction (concomi-
tant hydrolysis and decarboxylation15) leading to the
protected ester derivate 3 (76%) which, byreduction
with LiAlH4 leads to the protected diol 4 in 75% yield.
The overall yield, starting from dimethylmalonate is
39%. A successful application of this building block de-
pends, of course on the introduction of a suitable leav-
ing group such as Cl, Br or Tosyl leading to the
Using the classical Corey–Seebach methodology16 alde-
hydes of wide structural variety can be converted into
the corresponding 2-substituted -1,3 dithianes, building
blocks VI. Thus n-dodecanal and n-hexadecanal
(prepared from n-hexadecanol using a Swern-type
oxidation17,18 were converted in the presence of 1,3-pro-
panedithiol/BF3 · Et2O into the corresponding deriva-
tives 8–10, with 10 being a potential building block for
PAF analogues (Scheme 3).

K. Lange, M. P. Schneider / Tetrahedron: Asymmetry 15 (2004) 2811–2815
2813
5. Coupling of building blocks V and VI
a flexible synthesis of a particular target molecule and,
in order to avoid protection/deprotection steps for a
possiblyrequired inversion of configuration it seemed
attractive to screen for lipases, which could produce
both enantiomers at will––starting from the same diol
substrate (Scheme 4).
Deprotonation of the 1,3-dithiane moieties in 8–10 was
achieved with n-BuLi (THF, À50ꢁC) and the resulting
anions were reacted with the central building block 5
leading to the protected 1,3-diols 11–13, respectivelyin
yields of 70%. Deprotection 11–13 was achieved quanti-
tativelyusing p-TsOH leading to achiral diols 14–16,
respectively( Scheme 3).
After some screening effort we were indeed able to real-
ize this expectation. Using the 1,3 dithiane derivative 14
as model compound we were indeed able to identifytwo
different lipases, which produced opposite enantiomers.
6. Lipase-catalyzed desymmetrizations of alkyl-1,3
dithiane derivates 14 and 15
The transformations can be followed directlybyHPLC
on a chiral support (Chiralcel OD-H). While the lipase
from Candida antarctica B produces the (S)––configu-
rated monoester 17 (Fig. 2B), the (R)-enantiomer was ob-
tained byusing the lipase from Mucor miehei (Fig. 2C).
It was confirmed with the 1,3-dithiane derivatives that
enantioselective acylations in general produced higher
chemical yields than the corresponding hydrolyses. For
S
S
R
Candida antarctica B
H
O
HO
O
C11H23
S
S
R
O
C11H23
(S)-
O
17: R = C11H23
18: R = C15H31
H
Lipase from
MTBE
HO
OH
S
S
R
14: R = C11H23
15: R = C15 31
H
H
Mucor miehei
HO
O
C11H23
O
(R)-
17: R = C11H23
18: R = C15 31
H
Scheme 4. Desymmetrization of achiral 1,3 diols by lipases––production of opposite enantiomers.
Figure 2. HPLC Multichromatogram of racemic compound (A), (S)-17 (B), (R)-17 (C). Conditions: Column: Daicel Chiralcel OD-H; n-heptane/
2-propanol 99:1; flow: 1ml/min; UV-249nm.

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K. Lange, M. P. Schneider / Tetrahedron: Asymmetry 15 (2004) 2811–2815
The absolute configurations were tentativelyassigned
based on the resulting carba-analogous phospholipids
(see Section 8) derived thereof, while attempting to ob-
tain a crystalline derivate for an X-ray structure, the
ultimate confirmation.
of opposite absolute configurations. The here obtained
chiral building blocks are now available as mimics of
1,2-sn- and 2,3-sn-diglycerides for coupling reactions
with inositol phosphates to the corresponding carba-
analogues of inositol phospholipids. Theywere also
converted into the corresponding, enantiomeric carba-
analogues of phospholipids and ether lipids (PAF
analogues) (Scheme 7).19
7. Building blocks for PAF analogues
For the synthesis of the corresponding ether lipids we
had to resort to the lipase-catalyzed resolution of the
corresponding racemic ether derivate ( )-20. Thus,
mono alkylation of the 1,3-dithiane building block 16
led to racemic 19 from which 20 was obtained via clas-
sical chemical acylation (Scheme 5).
O
S
S
R
R
*
*
O
O
O-
OR´
N+
HO
OR´
P
O
BrC12H25
R = Me, C11H23, C16H33
R´= C12H25, COC11H23
KO-t-but
18-crown-6
THF
reflux
AcCl
NEt3
S
S
S
S
S
S
CH2Cl2
Scheme 7. Syntheses of carba-analogues of phospholipids and ether-
lipids from the enzymatically prepared chiral building blocks.
H
quant.
75%
HO
OH
HO
OC12H25
O
OC12H25
O
( )-19
( )-20
16
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