A new synthetic strategy for catechin-class polyphenols: Concise synthesis of (-)-epicatechin and its 3-O-gallate

Article abstract of DOI:10.1039/c2cc33704e

Concise synthesis of (-)-epicatechin and its 3-O-gallate is described, illustrating efficacy of the new strategy for catechin-class polyphenols based on assembly of lithiated fluorobenzene and epoxy alcohol followed by a pyran cyclization. 1,3,5-Trifluorobenzene serves as the A-ring equivalent for functionalization and the pyran annulation.

Full text of DOI:10.1039/c2cc33704e

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COMMUNICATION
A new synthetic strategy for catechin-class polyphenols: concise synthesis
of (ꢀ)-epicatechin and its 3-O-gallatew
Sven Stadlbauer, Ken Ohmori, Fumihiko Hattori and Keisuke Suzuki*
Received 23rd May 2012, Accepted 25th June 2012
DOI: 10.1039/c2cc33704e
Concise synthesis of (ꢀ)-epicatechin and its 3-O-gallate is
described, illustrating efficacy of the new strategy for catechin-
class polyphenols based on assembly of lithiated fluorobenzene
and epoxy alcohol followed by a pyran cyclization. 1,3,5-Trifluoro-
benzene serves as the A-ring equivalent for functionalization and
the pyran annulation.
Increasing interests are currently focussed on the catechin-
class polyphenols,1 such as (ꢀ)-epicatechin (EC, 1) and
(ꢀ)-epicatechin 3-O-gallate (ECg, 2) (Fig. 1). Besides these
major ingredients in green tea, the Nature produces a huge
Scheme 1 Instability of free flavans.
‘‘catechin library’’ consisting of enormous numbers of related
In our current study on catechin oligomers,5 scarce avail-
polyphenols, differing in oxygenation, stereochemistry, and
degree of oligomerization.4 Despite a potentially rich source of
ability of various catechin monomers is retarding the progress.
compounds of biological or pharmaceutical relevance, such a
Except for (+)-catechin, other congeners are expensive or not
natural library has been hardly explored due to difficulty in
commercially available, and thus we started trying to establish
a facile and flexible synthetic method of monomers.6
obtaining pure samples of individual compounds: natural
sources such as plant extracts are highly complex mixtures
previous approach6c based on an intermolecular SNAr reaction7
of closely related compounds (vide supra), hardly separable
Scheme 2 (the upper sequence) is the polarity analysis of our
even by modern separation techniques.
to form the C–O bond followed by intramolecular C–C bond
Although chemical synthesis has the potential for supplying
formation via aryl anion species to close the central pyran ring.
the requisite samples, reported methods have certain limitations
Seeking for other possibilities, we were interested in the
in the relative/absolute stereocontrol.2 In addition, the real
optional sequence of two-bond formations, i.e., the C–C bond first
issues emerge after deprotection: handling of free polyphenols
followed by the C–O bond (the lower sequence in Scheme 2).
is difficult due to their high sensitivity to oxidants, acid, base,
Pleasingly, this simple reversal allowed us to develop a new
light, and metallic species. Scheme 1 exemplifies the vulnerability
efficient synthetic route discussed in this communication.
to basic conditions: facile deterioration of C(2)–C(3) stereogenic
Promising potentials as facile and rapid access to catechin-
centers or skeletal rearrangements.3
class polyphenols will be featured by concise syntheses of
(ꢀ)-epicatechin (EC, 1) and its 3-O-gallate (ECg, 2).
Scheme 3 outlines the access to (ꢀ)-EC (1) starting from
1,3,5-trifluorobenzene (3), which was treated with sodium
Fig. 1 Two representative green tea catechins.
Department of Chemistry, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8551, Japan.
E-mail: ksuzuki@chem.titech.ac.jp
w Electronic supplementary information (ESI) available: Experimental
procedures for the preparation and spectral data of all compounds.
See DOI: 10.1039/c2cc33704e
Scheme 2 Polarity analysis.
c
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Scheme 4 Access to (ꢀ)-ECg (2).
Scheme 5 Previous approach.
Scheme 3 Reaction conditions: (a) BnOH, NaH, NMP, 100 1C, 2 h
(79%). (b) n-BuLi, THF, ꢀ78 1C, 1 h; then 5, BF3ꢁOEt2, ꢀ78 1C, 15 min
(88%). (c) MEMCl, i-Pr2NEt, n-Bu4NI, CH2Cl2, room temp., 15 h
(92%). (d) n-Bu4NF, THF, room temp., 14 h (99%). (e) KH, DMF,
0 1C, 5 h (91%). (f) p-TsOHꢁH2O, 11, CH2Cl2, room temp., 6 d (87%).
(g) H2, Pd(OH)2/C, MeOH, THF, H2O, room temp., 2.5 h (quant.).
NMP = N-methylpyrrolidone, MEM = methoxyethoxymethyl.
It should be noted that alcohol 10 is readily convertible to
(ꢀ)-ECg (2)14 as reported previously6c (Scheme 4).
What makes the present approach so concise and effective?
Scheme 5 shows key aspects of the previous approach,6c
featured by the dual roles of a sulfinyl group: (1) to ease the
SNAr attack of alkoxide b to the electrophilic unit a at the
fluorine-bearing carbon center, and (2) to serve as a carbanion
precursor via sulfinyl–lithium exchange15 for the SN2 pyran
cyclization. The sulfinyl group also caused cumbersome handling
of diastereomeric intermediates. In addition, there was a trajectory
issue at the pyran cyclization (c0),16,17 requiring extra steps for
converting epoxide c into bromo ether d as a viable seco-precursor.
The present approach is free from these complications
simply by reversing the order of C–O and C–C bond formations
(Scheme 6). A primary difference is that the sulfinyl group is not
required because of the following reasons: (1) the aryl anion
formation uses the high C–H acidity of fluorobenzene e,7 (2) the
intramolecular nature of the SNAr reaction allows smooth
replacement of aryl fluoride by an internal alkoxide derived
from g. Furthermore, epoxide f could be used, as the reaction
with aryllithium e is intermolecular (no trajectory issue).
In conclusion, an effective approach has been developed
that would enable the synthesis of a wide range of catechin-
class polyphenols and their unnatural congeners. Work is now
in progress along these lines.
benzyl oxide (2.5 mol equiv.) at 100 1C to give 79% yield of
3,5-dibenzyloxy-1-fluorobenzene (4) as the A-ring surrogate.
Fluorobenzene 4 was regioselectively lithiated (n-BuLi, ꢀ78 1C),8,9
and then treated with enantiomerically enriched epoxide 5
(499% ee)10 in the presence of BF3ꢁOEt2 to give adduct 6 in
88% yield. After protection as MEM ether 7, removal of the
silyl group (n-Bu4NF) gave alcohol 8 in 91% yield from 6,
ready for pyran cyclization.
Screening of basic conditions11 revealed that KH (DMF,
0 1C, 5 h) allowed clean cyclization of pyran 9 in excellent
yield. The C(2)–C(3) cis relationship in 9 was verified by
1H NMR analysis (J2,3 = o0.5 Hz). Notably, the intramolecular
SNAr reaction nicely proceeded without help by an electron-
withdrawing group (vide infra).
The next stage was to detach the MEM group in 9 under
acidic conditions, which was troublesome. Exposure of 9 to
acids gave uniformly many unidentified products. We assumed
that the issues came from the formaldehyde12 that is liberated
during deprotection. Among additives tested for scavenging
formaldehyde, phloroglucinol (11) proved to be most effective:
Treatment of ether 9 with p-toluenesulfonic acid in the
presence of 11 realized slow, but clean deprotection, giving
alcohol 10 in 87% yield.
Finally, four benzyl groups in 10 were removed by hydro-
genolysis [5% Pd(OH)2/C, MeOH–THF–H2O (v/v/v = 1 : 1 : 1),
2.5 h]. After careful anaerobic filtration through a Celites pad
(argon), concentration and lyophilization quantitatively gave
(ꢀ)-EC (1) as a snow-white solid, which was identical to an
authentic specimen.13
Scheme 6 Present approach.
c
Chem. Commun.
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This work was supported by Grant-in-Aid for Specially
Promoted Research (No. 23000006) from JSPS. SS thanks
the Japan Society for the Promotion of Science (JSPS) for a
postdoctoral fellowship (10708).
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c
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Chem. Commun.