Synthesis of (+)-wikstromol by double alkylation of malic acid

Article abstract of DOI:10.1016/S0957-4166(01)00188-4

The synthesis of (+)-wikstromol in six steps, based on two stereoselective benzylations of unnatural malic acid derivatives, is presented. The influence of the alkyl ester on yield and selectivity in the alkylation of malic acid esters is examined.

Full text of DOI:10.1016/S0957-4166(01)00188-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 987–989
Synthesis of (+)-wikstromol by double alkylation of malic acid
Michael Sefkow
Institut fu¨r Organische Chemie und Strukturanalytik, Universita¨t Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Golm, Germany
Received 30 March 2001; accepted 26 April 2001
Abstract—The synthesis of (+)-wikstromol in six steps, based on two stereoselective benzylations of unnatural malic acid
derivatives, is presented. The influence of the alkyl ester on yield and selectivity in the alkylation of malic acid esters is examined.
© 2001 Elsevier Science Ltd. All rights reserved.
(+)-Wikstromol 11 (Scheme 1) is an a hydroxylated
lactone lignan possessing anti-leukemic activity in
vivo.2 Despite its attractive biological properties, only
one enantioselective synthesis of (+)-wikstromol 1 has
been published so far.3 The overall yield from eight
steps was only 5% due to the resolution of a racemic
precursor and a non-selective oxygenation reaction a
to the carbonyl group in the penultimate step.3 ( )-
Wikstromol was prepared more efficiently, although the
hydroxy group was similarly introduced by oxygenation
of the corresponding lactone enolate.4
by Seebach and Wasmuth,7 is frequently used to pre-
pare enantiopure alkyl succinic acids,8 although yields
and selectivities were very dependent on the electrophile
employed.8 Some years ago Dugger et al. reported that
the yield of benzylation of malates was dependent on
the ester used.9 The alkylations of Me and Et malates
were less efficient than that of the iso-propyl analog,
which was attributed to reduced self-condensation of
iso-propyl malate due to the protection of the carboxyl
moieties by sterically demanding iso-propyl groups. We
reasoned that ester condensation might be efficiently
suppressed when a solution of the base is added to a
mixture of malate and electrophile at low temperature
followed by gradually warming to rt. Additionally,
LHMDS was used instead of LDA because Norman
and Morris have reported that better yields and selec-
tivities were obtained with this base.10 Using these
conditions we re-examined the steric effects of the ester
on the yield and selectivity of the benzylation of malic
acid. A series of malic ester analogs 2a–2d (R=Me, Et,
iso-Pr, tert-Bu11) were reacted with 4-benzyloxy-3-
methoxy-benzyl bromide 3 after addition of two equiv.
of LHMDS at −78°C. Subsequent warming to about
10°C afforded the alkylation products 4a–4d and their
syn-isomers (Scheme 2). The selectivities and yields
Two alternative strategies for the synthesis of a-hydrox-
ylated lactone lignans have been described. One is
based on the conversion of arabinose5 and the other on
the alkylation of a protected a-hydroxy-b-benzyl-g-
butyrolactone.6 The first strategy suffers from a lengthy
synthesis (20 steps, 0.5% overall yield) whereas the
non-selective alkylation of the g-butyrolactone is the
major drawback of the second route (eight steps, 3%
overall yield). Herein, we report a short and efficient
synthesis of (+)-wikstromol 1 involving two diastereose-
lective alkylations of (+)-malic acid (Scheme 1).
The first stereoselective alkylation was the benzylation
at C(3) of malic acid ester. This reaction, first reported
MeO
HO
OMe
OH
OH
2
CO2R
3
RO2C
8'
8
OH
O
stereoselective
alkylations
O
1
Scheme 1. (+)-Wikstromol and malic acid ester as suitable precursor.
E-mail: sefkow@rz.uni-potsdam.de
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00188-4

988
M. Sefkow / Tetrahedron: Asymmetry 12 (2001) 987–989
OH
2
OH
2
MeO
3
CO2R
Br
LHMDS
THF
RO2C
MeO
3
CO2R
syn
+
+
RO2C
BnO
2a-d
R = Me,Et,iPr,tBu
3
BnO
4a-d
R = Me,Et,iPr,tBu
Scheme 2. Conditions: 1.4 equiv. 3, 2.1 equiv. LHMDS, 13 h, −75 to 14°C (for 2a, 2b); −75 to 9°C (for 2c, 2d). Esters of (−)-malic
acid were employed for these experiments.
obtained after chromatographic purification are sum-
marized in Fig. 1. Interestingly, all esters gave reason-
ably high yields of alkylation product (75–90%). As
expected, the lowest yield of 75% was achieved with Me
malate 2a good anti-selectivity of 89:11 was also
observed. Reaction of Et malate 2b gave a very good
91% yield of the alkylated product 4b and a slightly
better ratio than with the methyl analog (90:10) was
achieved. As described, iso-Pr malate 2c reacted more
slowly than the Me and Et analogs and the reaction did
not proceed to completion (80% yield + ꢀ10% starting
material) although the stereoselectivity of the reaction
of 2c was very good (95:5). Curiously, the more steri-
cally encumbered tert-Bu malate reacted efficiently
under identical conditions to afford 4d in 94% yield,
however the stereoselectivity was lower (86:14). There-
fore, 2c was chosen for the actual synthesis of (+)-1
from (+)-malic acid. The low reactivity of 2c was cir-
cumvented easily by increasing the reaction time and
elevating the temperature of the reaction. Thus, com-
pound
5 was obtained in 85% yield and 95:5
diastereoselectivity from (+)-iso-Pr malate (−75°C to
+14°C, 16 h, Scheme 3).
Saponification of ester 5 using an excess of KOH in
EtOH afforded the diacid 6 in 80% yield. Alkylation at
C(2) was accomplished by analogy to the methodology
developed by Seebach et al.12 First, acetalization of
diacid 6 to 1,3-dioxolan-4-one 7 was effected with
pivaldehyde and catalytic amounts of recrystallized
TsOH in benzene. Dioxolanone 7 was obtained in 59%
yield and ca. 8:1 cis:trans ratio. Since it is known that
acetalization under those conditions generally yielded
mixtures of cis- and trans-dioxolanone an alternative
procedure based on the kinetic acetalization of the
corresponding tris-trimethylsilyl ether was examined.13
Unfortunately, no reaction occurred under these condi-
Figure 1. Yields and percent anti-isomers of alkylation prod-
ucts 4a–4d.
OH
2
3
OMe
CO2R
tBuCHO
CO2H
O
RO2C
1'
5
OBn
O
OMe
OBn
TsOH
59%
R
2
O
tBu
5 R = iPr
7 R = H
LHMDS
71%
KOH,
EtOH
80%
3
8 R = CH2Ar
6 R = H
1) BH3•Me2S
71%
2) 4 M HCl
MeO
RO
OMe
OR
8'
8
OH
O
O
9 R = Bn
1 R = H
H2,
Pd/C
99%
Scheme 3. Synthesis of (+)-wikstromol from malic acid derivative 4c.

M. Sefkow / Tetrahedron: Asymmetry 12 (2001) 987–989
989
tions. Stereoselective alkylation of an 8:1 mixture of
cis- and trans-dioxolanone 7 was achieved when two
equiv. of LHMDS were added to a solution of 7 and
1.3 equiv. of 3 in THF at −78°C. Only one stereoiso-
mer, 8, was obtained after purification. Apparently the
additional stereocenter at C(1%) caused a matched/mis-
matched case in which the mismatched dioxolanone did
not react with the electrophile (or reacted very slowly)
(Scheme 3). Dioxolanone 8 was treated with BH3·Me2S
in refluxing ether to reduce selectively the carboxyl
group and acidic hydrolysis afforded g-lactone 9
directly in 71% yield. Hydrogenolysis of the two benzyl
ethers of lactone 9 provided (+)-wikstromol 1 in quanti-
tative yield.
2. (a) Torrance, S. J.; Hoffmann, J. J.; Cole, J. R. J. Pharm.
Sci. 1979, 68, 664–665; (b) Lee, K.-H.; Tagahara, K.;
Suzuki, H.; Wu, R.-Y.; Haruna, M.; Hall, I. H.; Huang,
H.-C.; Ito, K.; Iida, T.; Lai, J.-S. J. Nat. Prod. 1981, 44,
530–535; (c) Ji-Xian, G.; Handa, S. S.; Pezzuto, J. M.;
Kinghorn, A. D.; Farnsworth, N. R. Planta Med. 1984,
50, 264–265; (d) Lin, R. C.; Skaltsounis, A.-L.; Seguin,
E.; Tillequin, F.; Koch, M. Planta Med. 1994, 60, 168–
170.
3. (a) Khamlach, K.; Dhal, R.; Brown, E. Tetrahedron Lett.
1989, 30, 2221–2224; (b) Khamlach, M. K.; Dhal, R.;
Brown, E. Tetrahedron 1992, 46, 10115–10126.
4. (a) Belletire, J. L.; Fry, D. F. J. Org. Chem. 1988, 53,
4724–4729; (b) Belletire, J. L.; Ho, D. M.; Fry, D. F. J.
Nat. Prod. 1990, 53, 1587–1592.
In summary, (+)-wikstromol 1 was synthesized from
iso-Pr malate 4d in six steps and in 20% overall yield.
Two stereoselective alkylations of (+)-malic acid deriva-
tives were necessary. The dependence of yield and
stereoselectivity on the alkyl ester employed in the
alkylation of malic acid was examined. The synthesis of
a-hydroxylated lignans and analogs as well as other
classes of lignans is currently underway.
5. Yamauchi, S.; Kinoshita, Y. Biosci. Biotechnol. Biochem.
1998, 62, 521–525.
6. Takano, D.; Doe, M.; Morimoto, Y.; Yoshihara, K.;
Kinoshita, T. J. Heterocyclic Chem. 1999, 36, 221–224.
7. Seebach, D.; Wasmuth, D. Helv. Chim. Acta 1980, 63,
197–200.
8. Gawron´ski, J.; Gawron´ska, K. Tartaric and Malic Acid in
Synthesis; John Wiley: New York, 1999.
9. Dugger, R. W.; Ralbovsky, J. L.; Bryant, D.; Comman-
der, J.; Massett, S. S.; Sage, N. A.; Selvidio, J. R.
Tetrahedron Lett. 1992, 45, 6763–6766.
Acknowledgements
10. Norman, B. H.; Morris, M. L. Tetrahedron Lett. 1992,
45, 6803–6806.
M.S. thanks the DFG for a habilitation fellowship (Se
875/1-1). Financial support of this work by the Fonds
der Chemischen Industrie is gratefully acknowledged.
11. tert-Bu malate 4d was obtained in 46% yield after distilla-
tion from the reaction of malic acid and tert-butyl-dicy-
clohexylisourea in CH2Cl2 (5 days, rt): Kuo, C. H.;
Robichaud, A. J.; Rew, D. J.; Bergstrom, J. D.; Berger,
G. D. Bioorg. Med. Chem. Lett. 1994, 4, 1591–1594.
12. Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984,
40, 1313–1324.
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