General and convenient approach to flavan-3-ols: Stereoselective synthesis of (-)-gallocatechin

Article abstract of DOI:10.1246/cl.2006.1006

General synthetic route to flavan-3-ols was developed. Union of two fragments was accomplished by an efficient three-step protocol, enabling the stereoselective synthesis of (-)-gallocatechin. Copyright

Full text of DOI:10.1246/cl.2006.1006

1006
Chemistry Letters Vol.35, No.9 (2006)
General and Convenient Approach to Flavan-3-ols:
Stereoselective Synthesis of (À)-Gallocatechin
Takashi Higuchi, Ken Ohmori, and Keisuke Suzukiꢀ
Department of Chemistry, Tokyo Institute of Technology, SORST-JST Agency,
O-okayama, Meguro-ku, Tokyo 152-8551
(Received June 9, 2006; CL-060668; E-mail: ksuzuki@chem.titech.ac.jp)
General synthetic route to flavan-3-ols was developed.
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
Union of two fragments was accomplished by an efficient
three-step protocol, enabling the stereoselective synthesis of
(ꢁ)-gallocatechin.
a
c
HO
HO
OH
O
HO
RO
b
4
3
5: R = H
6: R =
i-Pr
SO2
i-Pr
i-Pr
Considerable attention has recently been centered at the po-
tential bioactivities of flavan-3-ols (catechins). However, de-
tailed studies at molecular levels are hampered by their scarce
availability of pure samples, because the natural sources are gen-
erally comprised of hardly separable mixture of closely related
compounds. At this juncture, development of reliable synthetic
methods is of keen necessity.1,2
We have developed a concise synthetic route to this class
of compounds based on the assembly of two fragments for con-
structing the central pyran ring (Scheme 1). This communication
features the generality and the efficiency of the route by the
stereoselective synthesis of a highly oxygenated congener,
(ꢁ)-gallocatechin (1).3
Scheme 3. Conditions: (a) (DHQD)2PHAL (1 mol %), K3Fe-
(CN)6, K2CO3, K2OsO2(OH)4 (0.5 mol %), t-BuOH, H2O,
MeSO2NH2, 0 ꢂC, 92%, 99% ee; (b) 2,4,6-triisopropylbenzene-
1-sulfonyl chloride, pyridine, rt, 89%; (c) K2CO3, MeOH, 1,4-di-
oxane, 0 ꢂC, 90%; (DHQD)2PHAL = hydroquinidine 1,4-phthal-
azinediyl diether.
Conversely, we hoped that halohydrin II would be a good
substrate for Step 3, that is, the C–C bond formation to construct
the pyran ring (6-exo-tet). Two critical processes are relevant,
(1) the halogen–metal exchange (X ! Met) to generate aryl
anion species III, (2) displacement to form the pyran ring. The
first stage requires the chemoselectivity in that the other halogen
Y needs to remain intact.5,6
OH
OH
Scheme 3 shows the preparation of epoxide 3.7 Asymmetric
dihydroxylation of allyl alcohol 4 by using (DHQD)2PHAL8 as
the chiral ligand gave the corresponding triol 5 (92% yield, 99%
ee).9 Selective sulfonylation of the prim-hydroxy group in 510
followed by treatment with K2CO3 gave epoxide 3 in high yield.
Union of epoxyalcohol 3 with phenol 2 (X ¼ I) posed a ster-
eochemical challenge by the potentially facile loss of stereospe-
cificity (vide supra). Delightedly, however, the Mitsunobu reac-
tion11 gave us a clean solution to this issue. When epoxyalcohol
3 was allowed to react with Bu3P and TMAD,12 ether 7 was ob-
tained in 93% yield as a single diastereomer. Complete inversion
of the benzylic stereocenter was proven at a later stage.13 Oxir-
ane 7 was then regioselectively cleaved by Li2NiBr4,14 giving 8
in 98% yield, and the resulting alcohol was masked with TBS
group to afford bromide 9 in 93% yield (Scheme 4).
HO
O
O
OH
+
OH
OR
HO
(−)-gallocatechin (1)
Scheme 1. Retrosynthetic analysis.
Scheme 2 shows three critical steps. Step 1 involves union
of two building blocks, 2 and 3, through the C–O bond formation
in an inversion of the C(2) center. The anxiety was loss of the
stereochemical integrity, since the electron-rich aromatic ring
in 3 could strongly facilitate the SN1 ionization. Step 2 is the
opening of the oxirane ring to the corresponding halohydrin II,
since consideration of the Baldwin’s rule4 suggested the inade-
quacy of epoxide I as a substrate for the pyran ring closure
(6-endo-tet).
Faced with the pivotal transformation, i.e., construction of
the flavan skeleton from 9, we examined various reaction condi-
OBn
BnO
OBn
BnO
OH
X
step 1
O
Ar
2
OBn
+
HO
OBn
OBn
BnO
2
BnO
BnO
OBn
OBn
OBn
OBn
BnO
X
(X = I)
b
a
BnO
O
O
2
O
O
2
3
I
BnO
c
I
I
OR
3
step 2
Ar
step 3
O
Br
BnO
O
Ar
OR
7
8: R = H
9: R = TBS
i)
ii)
O
O
Ar
X
Met
OH
Scheme 4. Conditions: (a) TMAD, n-Bu3P, toluene, 0 ꢂC, 93%.
(b) Li2NiBr4, THF, 0 ꢂC, 98%; (c) TBSOTf, 2,6-di-t-butyl-
pyridine, CH2Cl2, 0 ꢂC, 93%; TMAD = N,N,N0,N0-tetramethyl-
azodicarboxamide, TBS = t-butyldimethylsilyl.
OR
BnO
Y
Y
III
IV
II
Scheme 2. Synthetic plan.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.9 (2006)
1007
Table 1. Cyclizaiton via halogen–metal exchange
product 10 exclusively. Thus, upon addition of 9 into a mixture
of 2.5 mole equiv. of Ph3MgLi and 10 mole equiv. of HMPA
in THF, the desired product 10 was obtained in 96% yield
(Run 6).17
Scheme 5 shows the final stage of the synthesis. After re-
moval of the silyl group in 10, all the benzyl protecting groups
in the resulting alcohol 13 were removed by hydrogenolysis over
20% Pd(OH)2 in a mixed solvent (THF, MeOH, H2O = 4:4:1)
for 12 h to give (ꢁ)-gallocatechin (1) as an amorphous solid in
82% yield. All the physical data of the synthetic sample 1 (1H
and 13C NMR, IR, ½ꢀꢃD) coincided with those of the natural
product.3
OBn
OBn
OBn
OBn
BnO
OBn
OBn
1) reagent
/ THF
BnO
O
O
2) CH3OD
←
OTBS
BnO
I
OTBS
−78 0 °C
BnO
Br
9
10
Yield/%
Run Reagent (equiv.) Additive (equiv.) 10 11 (D%) Recovery of 9
1
2
3
4
5
6
n-BuLi (1.0)a
t-BuLi (2.0)a
—
77
53c
5 (0)
—
6
—
72
—
—
—
—
i-PrMgCl (1.2)b
n-Bu3MgLi (1.2)
Ph3MgLi (1.2)
Ph3MgLi (2.5)
—
—
28 (100)
In summary, a convergent, stereoselective synthesis of (ꢁ)-
gallocatechin (1) was achieved, which opened a flexible synthet-
ic approach to various flavan analogs.
—
—
84 12 (0)
76 14 (86)
HMPA (10)
96
—
BnO
BnO
BnO
This work was partially supported by a Grant-in-Aid for
Scientific Research (No. 17685007) from MEXT, Japan, Kurata
Memorial Hitachi Science and Technology Foundation, and 21st
Century COE Program (Chemistry).
O
Ar
O
H
Ar
OTBS
BnO
H
H
OTBS
(D)
Br
11
12
aAt ꢁ78 ꢂC. bAt ꢁ40 ꢂC. c13% yield of byproduct 12 was obtained;
References and Notes
HMPA = hexamethylphosphoramide.
1
2
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.
tions by using alkylmetals for the chemoselective halogen–lithi-
um exchange (Table 1). All the reactions were quenched by add-
ing CH3OD in order to assess the amount of ‘‘living’’ anionic
species.
When n-BuLi was employed for the halogen–metal ex-
change, the cyclized product 10 was obtained in 77% yield along
with a small amount of non-cyclized product 11 (Run 1). t-BuLi
(2.0 equiv.) led to a poorer yield. Among various by-products,
compound 12 was obtained, showing that the double lithiation
occurred to some extent (Run 2).
Having only limited success with organolithium reagents,
we turned our attention to organomagnesium reagents, which
gave eventually an excellent result after thorough screening of
the reaction conditions. The initial attempt with i-PrMgCl15 only
effected slow halogen–metal exchange at ꢁ40 ꢂC, and gave no
cyclized product (Run 3). Notably, however, the non-cyclized
product 11 was completely deuterated, showing that the aryl
anion species was still present before the quenching. Further at-
tempts allowed us to find that the use of the Mg ate complexes16
improved the yield of 10 (Runs 4 and 5). Although the yields of
10 were similar, an important difference in these results was the
extent of deuterium incorporation in 11. Namely, 11 was highly
deuterated in the case of Ph3MgLi (Run 5), while no deuterium
atom was incorporated in the case of n-Bu3MgLi (Run 4). Thus,
we chose to use Ph3MgLi as the metalation agent.
a) L. Li, T. H. Chan, Org. Lett. 2001, 3, 739. b) N. T. Zaveri, Org.
Lett. 2001, 3, 843. c) 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.
3
R. Seto, H. Nakamura, F. Nanjo, Y. Hara, Biosci. Biotechnol.
Biochem. 1997, 61, 1434.
4
5
J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734.
Chemoselective halogen–metal exchange of aryl bromide in the
presence of aliphatic bromide has appeared: C. K. Bradsher,
D. C. Reames, J. Org. Chem. 1981, 46, 1384.
6
7
8
9
A similar approach was used in the simpler chroman synthesis:
a) K. J. Hodgetts, Tetrahedron Lett. 2000, 41, 8655. b) K. J.
Hodgetts, Tetrahedron 2005, 61, 6860.
Epoxyalcohol 3 was prepared by the Ren’s protocol: X. Ren, X.
Chen, K. Peng, X. Xie, Y. Xia, X. Pan, Tetrahedron: Asymmetry
2002, 13, 1799. See, also Supporting Information.
K. B. Sharpless, W. Amberg, Y. L. Bennni, G. A. Crispino, J.
Hartung, K. S. Jeong, H. L. Kwong, K. Morikawa, Z. M. Wang,
D. Xu, X. L. Zhang, J. Org. Chem. 1992, 57, 2768.
Enantiomeric purity of 5 was assessed by HPLC analysis. See
Supporting Information.
10 Tosyl chloride gave a mixture of mono-/di-sulfonylated products.
11 O. Mitsunobu, Synthesis 1981, 1.
12 T. Tsunoda, J. Otsuka, Y. Yamamiya, S. Ito, Chem. Lett. 1994, 539.
13 The relative stereochemistry of C(2) and C(3) stereogenic centers
was assigned by NMR analysis after conversion to cyclized product
10 (J2;3 ¼ 8:4 Hz).
Upon further experimentations, choice of an additive
offered us the optimal conditions for obtaining the cyclized
14 R. D. Dawe, T. F. Molinski, J. V. Turner, Tetrahedron Lett. 1984,
25, 2061.
OR
OBn
OR
OR
OBn
OBn
15 F. F. Kneisel, Y. Monguchi, K. M. Knapp, H. Zipse, P. Knochel,
Tetrahedron Lett. 2002, 43, 4875.
RO
O
BnO
O
a
16 a) K. Kitagawa, A. Inoue, H. Shinokubo, K. Oshima, Angew.
Chem., Int. Ed. 2000, 39, 2481. b) A. Inoue, K. Kitagawa, H.
Shinokubo, K. Oshima, J. Org. Chem. 2001, 66, 4333.
17 The amount of Ph3MgLi was important. For example, use in 1.2
equimolar amounts gave only 36% yield of 10 with recovery of 9
in 62% yield.
OH
OTBS
RO
BnO
10
13: R = Bn
1: R = H
b
Scheme 5. Conditions: (a) n-Bu4NF, THF, 0 ꢂC, 87%; (b) H2,
Pd(OH)2, THF, MeOH, H2O (4:4:1), rt., 82%.
Published on the web (Advance View) July 29, 2006; doi:10.1246/cl.2006.1006