Enantioselective synthesis of α-hydroxylated enterolactone and analogs

Article abstract of DOI:10.1016/S0040-4039(01)00907-8

A short and general synthesis of enantiomerically pure α-hydroxylated lactone lignans starting from commercially available ⁱPr malate is presented. Key reactions are two stereoselective alkylations of malic acid derivatives. Some enhancements of the alkylation of malic acid esters and a general extension of the alkylation of dioxolanones is reported. Proof of the stereochemical outcome of the alkylation reactions is provided by X-ray diffraction analysis of α-hydroxy-α,β-dibenzyl-γ-butyrolactone, the first crystal structure of an enantiomerically pure α-hydroxylated lactone lignan.

Full text of DOI:10.1016/S0040-4039(01)00907-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5101–5104
Enantioselective synthesis of a-hydroxylated enterolactone
and analogs
Michael Sefkow,a,* Alexandra Kellingb and Uwe Schildeb
aUniversita¨t Potsdam, Institut fu¨r Organische Chemie und Strukturanalytik, Karl-Liebknecht-Straße 24-25,
D-14476 Golm, Germany
bUniversita¨t Potsdam, Institut fu¨r Anorganische Chemie und Didaktik der Chemie, Karl-Liebknecht-Straße 24-25,
D-14476 Golm, Germany
Received 16 March 2001; revised 27 March 2001; accepted 28 May 2001
Abstract—A short and general synthesis of enantiomerically pure a-hydroxylated lactone lignans starting from commercially
i
available Pr malate is presented. Key reactions are two stereoselective alkylations of malic acid derivatives. Some enhancements
of the alkylation of malic acid esters and a general extension of the alkylation of dioxolanones is reported. Proof of the
stereochemical outcome of the alkylation reactions is provided by X-ray diffraction analysis of a-hydroxy-a,b-dibenzyl-g-butyro-
lactone, the first crystal structure of an enantiomerically pure a-hydroxylated lactone lignan. © 2001 Elsevier Science Ltd. All
rights reserved.
a-Hydroxylated lactone lignans1 possess many biologi-
cal activities.2 Plants containing these lignans are con-
stituents of many Asian traditional medicines.
Enantioselective syntheses of a-hydroxylated lactone
lignans have been reported in the past. They were based
on three general strategies: (a) a-hydroxylation of a,b-
dibenzyl-g-butyrolactone (eight steps/3–6% overall
yield);3 (b) conversion of (+)-arabinose (20/0.5%)4 or (c)
a-alkylation of protected a-hydroxy-b-benzyl-g-butyro-
lactones (8/3%).5 Major drawbacks of these routes were
a multistep sequence (b) or a non-selective introduction
of either the hydroxy group (a) or the benzyl moiety (c)
in a-position to the carbonyl group. Herein we report a
short and general synthesis of optically active a-hydroxy-
lated lactone lignans. Key reactions are two stereoselec-
tive alkylations of malic acid derivatives at C(2) and
C(3) (Fig. 1).
First, commercially available malic acid esters were
alkylated stereoselectively according to the procedure
described by Seebach and Wasmuth.6 Modifications of
the reaction procedure involving the ester group of
malic acid (iPr malate was used instead of Et or Me
malate)7 and the base (LDA was substituted by
LHMDS)8 have been described. Better yields and/or
higher anti-selectivity were achieved following these
changes.
We have submitted both commercially available malic
i
acid ester, Me and Pr malate (1 and 2), in a series of
parallel experiments to the standard alkylation condi-
tions. Different bases were employed in order to exam-
ine their influence on yield and selectivity (Scheme 1
and Table 1).
We found that neither yield nor selectivity was
improved using LHMDS instead of LDA although side
reactions were more effectively suppressed with
LHMDS as base (indicated by a better mass recovery).
The base system s-BuLi/TMEDA caused almost com-
plete decomposition of the starting material.
OH
2
3
CO2R
8'
8
RO2C
R
OH
O
R
O
stereoselective
alkylations
i
The influence of the alkyl ester was more important: Pr
Figure 1.
malate (2) was alkylated faster and more selective than
Me malate (1) providing benzylation products 5 and 6
in about 50% yield and 95:5 selectivity compared to
ꢀ20% yield and 90:10 selectivity for compounds 3 and
* Corresponding author. Fax: +49 331 977 5067; e-mail: sefkow@
i
rz.uni-potsdam.de
4. Furthermore, the diastereoisomers of alkylated Pr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00907-8

5102
M. Sefkow et al. / Tetrahedron Letters 42 (2001) 5101–5104
OH
2
OH
2
OH
2
BnBr
3 CO2R
3 CO2R
Ph
+
3
CO2R
Ph
RO2C
RO2C
RO2C
base
4 R = Me
6 R = iPr
3 R = Me
5 R = iPr
1 R = Me
2 R = iPr
Scheme 1.
Table 1. Dependence of yield and selectivity on base and alkyl ester
Entry
Base
Yield (%)
1
3+4 (d.r.)
2
5+6 (d.r.)
1
2
3
LDA
LHMDS
s-BuLi/TMEDA
30
41
10
18 (90:10)
17 (91:9)
0
9
16
15
45 (95:5)
48 (95:5)
0
method described by Seebach et al.11 Thus, diacids 9–11
were converted to the cis-1,3-dioxolan-4-ones 12–14
upon treatment with pivaldehyde and catalytic amounts
of freshly recrystallized TsOH in benzene (72–83%).
Since the solvent has a higher boiling point than the
aldehyde, continuous addition of pivaldehyde was nec-
essary for complete conversion of the diacids. Reaction
in lower boiling solvents like pentane or light petroleum
did not afford the dioxolanones. The diastereoisomeric
malate can be generally better seperated by column
chromatography than those of the corresponding Me
malate.10
Substituted benzyl bromides were also suitable elec-
i
trophiles for the alkylation of Pr malates. The alkyla-
tion products 7 and 89 were obtained in reasonable
yields (56 and 65%) using 2,4,6-trimethylbenzyl bro-
mide and 3-methoxybenzyl bromide, respectively (Fig.
2). The stereoselectivity, however, decreased with
increased sterical hindrance of the electrophile (anti:syn
83:17 for 7 and 97:3 for 8).
OH
2
OH
2
i
i
3 CO2 Pr
3
CO2 Pr
iPrO2C
iPrO2C
Me
OMe
Isomerically pure anti products 5, 7 and 8 were quanti-
tatively saponified to the diacids 9–11 using KOH in
EtOH (3 days, rt). Surprisingly, acids 9 and 11 were
isolated as mixtures of diastereoisomers (9 86:14, 11
90:10). The mixtures were used without separation for
the subsequent steps (Scheme 2). Diastereoselective
alkylation at C(2) was accomplished in analogy to the
Me
Me
7 (56%, d.r. 83:17)
8 (65%, d.r. 97:3)
Figure 2.
OH
2
KOH
3
CO2H
Ar
HO2C
5,7,8
isomerically
EtOH
pure
9
Ar = Ar1, 99%, d.r. 86:14
10 Ar = Ar2, 98%, d.r. 98:2
11 Ar = Ar3, 99%, d.r. 90:10
Ar1 = Ph
Ar2 = 2,4,6-Me-Ph
Ar3 = 3-MeO-Ph
tBuCHO
TsOH
CO2H
CO2H
O
O
1'
ArCH2Br,
LHMDS
1'
Ar
Ar
5
5
O
O
2
H
2
O
O
THF, -78 °C
Ar
15 Ar = Ar1, 52%
16 Ar = Ar2, 70%
17 Ar = Ar3, 48%
12 Ar = Ar1, 83%, d.r. 88:12
13 Ar = Ar2, 72%, d.r. 98:2
14 Ar = Ar3, 73%, d.r. 88:8:4
Scheme 2.

M. Sefkow et al. / Tetrahedron Letters 42 (2001) 5101–5104
5103
purity of dioxolanones 12 and 14 was similar to that of
the diacids 9 and 11. Compound 14 was accompanied
by an additional stereoisomer, most likely by the corre-
sponding trans-dioxolanone. Dioxolanones 12–14 were
submitted to the second alkylation without further
purification. Addition of 2 equiv. LHMDS to a mixture
of the dioxolanone and a small excess of the corre-
sponding benzyl bromide at −78°C afforded the alkyla-
tion products 15–17 in 48–70% yield. Compounds
15–17 were obtained diastereoisomerically pure accord-
ing to the NMR spectra even when impure starting
materials 12 or 14 were employed. Apparently the
additional stereocenter in the side-chain caused
matched/ mismatched case in which the mismatched
dioxolanone did not (or did very slowly) react with the
electrophile (Scheme 2).
Reduction of the carboxyl group of compounds 15–17
using BH3·Me2S in refluxing diethyl ether followed by
acid catalyzed lactonization afforded the enantiomeri-
cally pure lignans in over 80% yield (19, 20), except
when THF was employed as solvent (18, 19% yield)
(Scheme 3).
Figure 3. ORTEP plot of compound 18.12 Selected distances
,
(A) and angles (°): C1ꢀC7 1.504(5), C7ꢀC8 1.544(5), C8ꢀC11
1.547(5), C11ꢀC10 1.512(5), C10ꢀO3 1.465(5), O3ꢀC9
1.347(4), C9ꢀC8 1.515(6), C8ꢀO1 1.417(4), C9ꢀO2 1.215(4),
C11ꢀC12 1.540(5), C12ꢀC13 1.509(5); C1ꢀC7ꢀC8 115.2(3),
C11ꢀC12ꢀC13 112.9(3), C8ꢀC11ꢀC10 100.8(3), C11ꢀC10ꢀO3
104.9(3), C9ꢀO3ꢀC10 109.4(3), O3ꢀC9ꢀC8 110.1(3),
C9ꢀC8ꢀC11 100.5(3), O1ꢀC8ꢀC7 112.0(3), O2ꢀC9ꢀC8
129.5(3); C2ꢀC1ꢀC7ꢀC8 81.9(5), C14ꢀC13ꢀC12ꢀC11−111.5-
(4), C1ꢀC7ꢀC8ꢀO1 −76.7(4), O2ꢀC9ꢀC8ꢀO1 31.7(5); angle
between best planes Cp (C1···C8)ꢀCp (C14···C18) 61.5(2).
Intermolecular hydrogen bonds were found between O1 and
O2 to form infinite chains in the a-direction (O1ꢀH2 0.86(4),
O1···O2 2.887(6), O1ꢀH1···O2 173(3), symmetry operator of
O2 is x−1, y, z).
Lignan 18 was crystalline and the trans relationship of
both benzyl groups of this compound was established
by X-ray diffraction, the first crystal structure of an
enantiomerically pure a-hydroxylated lactone lignan
(Fig. 3). The crystal structure also provides evidence for
the stereochemical course of the alkylation of di-
oxolanones having an additional stereocenter in the
side-chain.
Reduction of acid 15 with BH3·Me2S in refluxing THF
provided lactone 18 and several byproducts derived
from over-reduction or non-selective reduction proba-
bly due to a higher reaction temperature as compared
to diethyl ether. Some byproducts, compounds 21–23
(Scheme 4), have been characterized. Oxidation of lac-
tol 23 using PDC in CH2Cl2 gave formate 24 in 70%
yield and not, as expected, lactone lignan 18.13
malic acid esters and a general extension of the alkyla-
tion of dioxolanones is reported. Evaluation of the
biological properties of lignans presented herein and the
synthesis of unsymmetrically substituted lactone lignans
is in progress and will be reported in due course.
H
H
O
O
O
O
O
O
O
BBr3-mediated cleavage of the methylethers of lactone
20 gave the optically pure a-hydroxy analog of entero-
lactone (25) although the conditions were not optimized
and the yield was low (Scheme 5).
Ph
Ph
Ph
Ph
22 (10%)
21 (5%)
We have presented a short (five to six steps), efficient
(ꢀ20% overall yield) and general synthesis of optically
active a-hydroxylated lactone lignans. Key reactions
were two stereoselective alkylations of malic acid
derivatives. Some enhencements of the alkylation of
O
Ph
Ph
OH
PDC
8'
8
Ph
8'
8
Ph
CH2Cl2
70%
OH
O
OCHO
24
23 (20%)
1) BH3•Me2S
2) 4 M HCl
Scheme 4.
Ar
Ar
OH
8'
8
15 - 17
Et2O
(THF)
BBr3
O
O
8'
8
20
OH
O
18 Ar = Ar1, 19% (THF)
19 Ar = Ar2, 82% (Et2O)
20 Ar = Ar3, 85% (Et2O)
HO
OH
CH2Cl2
O
-78 °C → r.t.
25
Scheme 3.
Scheme 5.

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M. Sefkow et al. / Tetrahedron Letters 42 (2001) 5101–5104
4. Yamauchi, S.; Kinoshita, Y. Biosci. Biotechnol. Biochem.
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M.S. acknowledges the DFG for a habilitation fellow-
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Fonds der Chemischen Industrie is gratefully
acknowledged.
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