Stereocontolled synthesis of (-)-afzelechin: General route to catechin-class polyphenols by solving an SN2 vs. SN1 problem

Article abstract of DOI:10.1246/cl.2009.934

Stereocontrolled synthesis of (-)-afzelechin was achieved via the Mitsunobu reaction, where complete stereospecificity was observed when an electron-withdrawing group was introduced to the para-position of the B-ring fragment. Copyright

Full text of DOI:10.1246/cl.2009.934

934
Chemistry Letters Vol.38, No.9 (2009)
Stereocontolled Synthesis of (À)-Afzelechin:
General Route to Catechin-class Polyphenols by Solving an SN2 vs. SN1 Problem
Ken Ohmori, Megumi Takeda, Takashi Higuchi, Tomohiro Shono, and Keisuke Suzukiꢀ
Department of Chemistry, Tokyo Institute of Technology, SORST-JST Agency, O-okayama, Meguro-ku, Tokyo 152-8551
(Received July 8, 2009; CL-090642; E-mail: ksuzuki@chem.titech.ac.jp)
Stereocontrolled synthesis of (ꢁ)-afzelechin was achieved
tetramethylazodicarboxamide (TMAD) and n-Bu3P (eq 1).4b Re-
sults of this test case, allowing the stereoselective synthesis of
(ꢁ)-gallocatechin (1), made us believe that less oxygenated sub-
strates would be more easily subject to stereochemical control.
via the Mitsunobu reaction, where complete stereospecificity
was observed when an electron-withdrawing group was intro-
duced to the para-position of the B-ring fragment.
However, this naıve perception proved wrong, as the stereo-
¨
specificity became disrupted for less oxidized substrates. When
the Mitsunobu reaction of epoxy alcohol 6 and phenol 3 was at-
tempted (eq 2), the reaction proceeded much faster, within 1 h, to
give ether 7 in 71% yield, but as a mixture of diastereomers (93:7
ratio).7
In spite of increasing interest in the catechin-class polyphe-
nols,1 progress of biochemical studies are limited by the poor
availability of pure samples, because natural materials are ob-
tained as a hardly separable mixture of closely related com-
pounds. At this juncture, organic synthesis of catechins and re-
lated compounds has been gaining increasing importance
(Figure 1).2
OBn
OBn
TMAD
BnO
OBn
OBn
BnO
OH
OBn
OBn
n
-Bu3P
B
ð1Þ
ð2Þ
+
B
O
HO
toluene
0 °C, 10 h
I
OH
BnO
I
BnO
>99 : <1
OH
OH
O
OH
O
3
4
5
B
93%
2
3
2
3
HO
O
C
HO
O
A
BnO
TMAD
OBn
OH
OBn
OH
BnO
OH
+
n
-Bu3P
B
HO
B
HO
O
HO
toluene
I
(−)-gallocatechin (1)
(−)-afzelechin (2)
0 °C, 1 h
BnO
I
BnO
93 : 7
O
O
Figure 1. Structures of (ꢁ)-gallocatechin and (ꢁ)-afzelechin.
6
71%
7
3
This communication reports problems and solutions found
in the general application of our recent synthetic approach to
various catechin congeners.3
This unexpected result prompted us to study the dependence
of the stereospecificity on the oxidation state of the B-ring.
It turned out that the ratio was not linearly related to the number
of the oxy-functions (Table 1): A single diastereomer is pro-
duced when the B-ring is a simple phenyl, while the dioxy con-
gener results in a 97:3 ratio.7 Thus, the extent of the competing
SN1 pathway relative to the number of oxy-group(s) is in the or-
der of 1 > 2 > 3 ’ 0.
Scheme 1 outlines the synthetic route, which we hoped to be
generally applicable to various catechins sharing the 2,3-trans
stereochemistry, but differing in the oxygenation pattern of the
A/B rings. We reasoned that a narrow window would be the
stereospecificity of step 1, i.e. the Mitsunobu etherification.4
Given an electron-rich B-ring, the stereochemical integrity
may be lost due to SN1 ionization at the benzylic 2-position.5
This issue is relevant to the well-known tendency of catechins
to epimerize at the 2-positions,6 as well as being a fundamental
problem in organic chemistry, SN2 vs. SN1 mechanism.
Fortunately, substrate 4 with a trioxygenated B-ring, seem-
ingly highly susceptible to SN1 reaction, underwent the
Mitsunobu reaction with clean inversion by using N,N,N0,N0-
Table 1. Stereospecificity of the Mitsunobu reaction
OBn
OBn
OBn
OBn
OBn
OBn
B
B
B
B
n(p-oxy)a)
n(m-oxy)b)
ratio
0
1
0
93:7
1
1
97:3
1
0
>99:<1
2
>99:<1
a) Number of p-oxy substituents. b) Number of m-oxy sub-
stituents.
(OR)n
(OR)n
(RO)n
(RO)n
OH
I
B
step 1
B
A
O
2
A
+
HO
Apparently, one is required to separate the inductive and the
mesomeric effects (Figure 2). While the p-oxygen works to sta-
bilize the benzylic cation, the m-oxy group(s), out of conjuga-
tion, leads to destabilization (ꢁI effect). This accounts for the re-
covery of the SN2 pathway with increment in the m-oxygen(s).
An additional factor to be considered, particularly for the tri-
oxy substrate, is the steric inhibition of the resonance,5b as sup-
ported by the following experiment (eq 3). Mono-oxy substrate 8
with two m-methyl groups underwent the reaction in an SN2
fashion.
I
O
O
I
(OR)n
step 2
Ar
step 3
B
(RO)n
O
O
O
Ar
A
C
OR
I
Met
OH
OR
IV
Br
Br
III
II
Scheme 1. Synthetic route to catechin-class flavans.
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.9 (2009)
935
BnO
BnO
BnO
1) −I effect
2) Steric inhibition of resonance
OBoc
OBoc
+
+
+
R
R
R
a
c
O
10
O
O
1
I
BnO
b
I
RO
RO
•
•
OR
OR
•
RO
OR
•
•
•
O
OR
Br
O
R
O
RO
•
•
R
11: R1 = H
12: R1 = TES
OR2
OH
Figure 2. Two possible rationales.
f
HO
O
BnO
CH3
CH3
B
1
OH
OR
TMAD
BnO
OBn
CH3
OBn
HO
BnO
BnO
OH
+
n
-Bu4P
B
13: R1 = TES, R2 = Boc
14: R1 = TES, R2 = H
15: R1 = H, R2 = H
2
(−)-afzelechin (2)
HO
ð3Þ
O
CH3
d
e
toluene
0 °C
I
BnO
I
BnO
O
O
86%, >99 : <1
3
8
9
Scheme 2. Synthesis of (ꢁ)-afzelechin (2). Conditions: (a)
Li2NiBr4, THF, 0 ꢂC, 87%; (b) TESCl, imidazole, DMF, 0 ꢂC,
97%; (c) Ph3MgLi, HMPA, THF, 0 ꢂC, 88%; (d) DIBAL,
CH2Cl2, ꢁ78 ꢂC, 96%; (e) TBAF, THF, 0 ꢂC, 84%; (f) H2,
Pd(OH)2, THF, MeOH (1:1), rt, 76%.
To suppress the SN1 reaction in the most challenging mono-
oxy substrates, the choice of protecting group proved to be effec-
tive (Table 2). While the use of bulky protective groups, aiming
at the steric inhibition of resonance, proved ineffective (Runs 1–
4), use of an electron-withdrawing protective group, for decreas-
ing the n-electron donation, gave promising results (Runs 5–8).
Among others, t-butoxycarbonyl (Boc) gave the best result
(Run 8).
strated by the stereoselective synthesis of (ꢁ)-afzelechin (2),
scarcely obtained from nature.
This work was partially supported by Grant-in-Aid for Sci-
entific Research (Nos. 17685007 and 21350050) from MEXT,
Japan, Shorai Foundation for Science and Technology, and
Global COE Program (Chemistry).
Table 2. Effect of protecting group
OR
BnO
OR
TMAD
BnO
OH
HO
n
-Bu3P
+
O
toluene
I
conditions
d.r.
O
BnO
I
OBn
References and Notes
O
1
a) The Handbook of Natural Flavonoids, ed. by J. B. Harborne,
H. Baxter, Wiley, Chichester, 1999. b) D. Ferreira, D. Slade,
Nat. Prod. Rep. 2002, 19, 517.
Run
R
Conditions
0 ꢂC, 1.5 h
Yield/%
d.r.
1
2
3
4
5
C(CH3)2Ph
CH(CH3)Ph 0 ꢂC, 1.5 h
SiPh2(t-Bu)
Si(i-Pr)3
CH2C6F5
74
66
61
83
44
93:7
93:7
96:4
91:9
2
a) B. Nay, V. Arnaudinaud, J. F. Peyrat, A. Nuhrich, G. Deffieux,
´
0 ꢂC, 1.8 h
0 ꢂC, 3 h
J. M. Merillon, J. Vercauteren, Eur. J. Org. Chem. 2000, 1279. b)
L. Li, T. H. Chan, Org. Lett. 2001, 3, 739. c) N. T. Zaveri, Org.
Lett. 2001, 3, 843. d) S.-S. Jew, D.-Y. Lim, S.-Y. Bae, H.-A.
Kim, J.-H. Kim, J. Lee, H.-G. Park, Tetrahedron: Asymmetry
2002, 13, 715. e) S. B. Wan, T. H. Chan, Tetrahedron 2004,
60, 8207. f) J. C. Anderson, C. Headley, P. D. Stapleton, P. W.
Taylor, Tetrahedron 2005, 61, 7703. g) M. Kitade, Y. Ohno,
H. Tanaka, T. Takahashi, Synlett 2006, 2827.
0 ꢂC, 0.5 h
0 ꢂC, 1.5 h
then rt, 1.3 h
0 ꢂC, 1.5 h
then rt, 5 h
0 ꢂC, 0.5 h
then rt, 2 h
>99:<1
6
7
8
Bz
Ms
68
65
77
>99:<1
>99:<1
>99:<1
Boc
3
4
T. Higuchi, K. Ohmori, K. Suzuki, Chem. Lett. 2006, 35, 1006.
a) O. Mitsunobu, Synthesis 1981, 1. b) T. Tsunoda, J. Otsuka, Y.
ˆ
Yamamiya, S. Ito, Chem. Lett. 1994, 539.
Having fixed the problem, we carried out the stereocontrol-
led synthesis of (ꢁ)-afzelechin (2), the less abundant enantiomer
of this natural product (Scheme 2).8,9 Boc-ether 10 (Run 8,
Table 2) was converted to the corresponding bromohydrin 11
by using Li2NiBr4. After protection of alcohol 11 to give tri-
ethylsilyl (TES) ether 12, the pyran ring formation was carried
out by treatment with Ph3MgLi (2.5 equiv) and HMPA (10
equiv) in THF to afford the desired product 13 in 88% yield.
The Boc group was removed with DIBAL (2.9 equiv, THF,
ꢁ78 ꢂC, 1 h) to give phenol 14, and subsequent treatment with
n-Bu4NF gave alcohol 15 in 84% yield. Finally, the benzyl
groups were detached by catalytic hydrogenolysis to afford
(ꢁ)-afzelechin (2) {½ꢀꢃD ꢁ18 (c 0.28, acetone); lit. ½ꢀꢃD ꢁ20
(c 0.63, acetone)9} as snow-white amorphous solid in high
yield.10,11
In conclusion, an efficient synthetic approach to catechin de-
rivatives is described that allows access to various congeners
sharing the 2,3-trans stereochemistry. The efficiency is demon-
5
6
a) H. Iida, N. Yamazaki, C. Kibayashi, Tetrahedron Lett. 1985,
26, 3255. b) T. S. Kaufman, Tetrahedron Lett. 1996, 37, 5329.
a) A. J. Birch, J. W. Clark-Lewis, A. V. Robertson, J. Chem. Soc.
1957, 3586. b) P. Kiatgrajai, J. D. Wellons, L. Gollob, J. D.
White, J. Org. Chem. 1982, 47, 2910. c) R. Seto, H. Nakamura,
F. Nanjo, Y. Hara, Biosci. Biotechnol. Biochem. 1997, 61, 1434.
The relative stereochemistry of C(2) and C(3) stereogenic centers
was assigned by NMR analysis after conversion to the corre-
sponding cyclized product (J2;3 ¼ 8:4 Hz).
7
8
9
(+)-Afzelechin: a) W. E. Hillis, A. Carle, Aust. J. Chem. 1960,
13, 390. b) W. E. Hillis, T. Inoue, Phytochemistry 1967, 6, 59.
(ꢁ)-Afzelechin: V. S. S. Rao, S. Rajadurai, Leather Sci. 1968,
15, 114.
31
25
10 All spectroscopic means (1H, 13C NMR, IR, MS) and combina-
tion analysis was identical to those of natural product.
11 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.
html.
Published on the web (Advance View) September 5, 2009; doi:10.1246/cl.2009.934