Oligomeric flavanoids. Part 26. Structure and synthesis of the first profisetinidins with epifisetinidol constituent units

Article abstract of DOI:10.1039/a701334e

The natural occurrence of the first oligomeric profisetinidins with (2R,3R)-2,3-cis-epifisetinidol chain extender units is demonstrated in the bark of Pithecellobium dulce (Guamuchil). Semi-synthesis using the appropriate flavan-3-ol and flavan-3,4-diol precursors permits unequivocal structural and stereochemical assignment of the novel dimeric epifisetinidol-(4β,8)-catechin and epicatechins 16 and 18, the trimeric bis-epifisetinidol-(4β,6:4β,8)-catechin and epicatechins 33 and 35, the fisetinidol-(4α,8)-catechin-(6,4β)-epifisetinidol 37 and fisetinidol-(4α,8)-epicatechin-(6,4β)-epifisetinidol 39.

Full text of DOI:10.1039/a701334e

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Oligomeric flavanoids. Part 26.† Structure and synthesis of the first
profisetinidins with epifisetinidol constituent units
Petrus J. Steynberg,a Jan P. Steynberg,a E. Vincent Brandt,a Daneel Ferreira *,a
and Richard W. Hemingway*,b
a
Department of Chemistry, University of the Orange Free State, PO Box 339, Bloemfontein,
9300 South Africa
b Southern Research Station, USDA Forest Service, 2500 Shreveport Highway, Pineville,
Louisiana 71360, USA
The natural occurrence of the first oligomeric profisetinidins with (2R,3R)-2,3-cis-epifisetinidol chain
extender units is demonstrated in the bark of P ithecellobium dulce (G uamúchil). Semi-synthesis using the
appropriate flavan-3-ol and flavan-3,4-diol precursors permits unequivocal structural and stereochemical
assignment of the novel dimeric epifisetinidol-(4â,8)-catechin and epicatechins 16 and 18, the trimeric bis-
epifisetinidol-(4â,6 :4â,8)-catechin and epicatechins 33 and 35, the fisetinidol-(4á,8)-catechin-(6,4â)-
epifisetinidol 37 and fisetinidol-(4á,8)-epicatechin-(6,4â)-epifisetinidol 39.
The profisetinidins, with their 3Ј,4Ј,7-trihydroxyflavan-3-ol
extender units, are the most important polyflavanoids of com-
5′
OH
OR1
OR1
6′
B
8
merce, forming the major constituents of wattle and quebracho
tannins.1–7 Their genesis presumably involves coupling of the
flavan-3,4-diols, fisetinidol-4α-ol and ent-fisetinidol-4β-ol as
incipient electrophiles, to a variety of nucleophilic flavan-3-ols
and related compounds.8 Naturally occurring oligomers exhibit
predominantly 2,3-trans relative stereochemistry and possess
either 2R,3S (Acacia mearnsii1–5,7,9 and Colophospermum
mopane10–13) or 2S,3R (Schinopsis spp. or Rhus lancea 6,9) abso-
lute configurations. 5-Deoxy (A-ring) analogues exhibiting a
2,3-cis relative configuration of the chain extender moieties are
extremely rare and are hitherto restricted to two tentative (4,6)-
bis-fisetinidols which occur in very low concentrations in the
heartwood of C. mopane,13 a promelacacinidin 14 from Acacia
melanoxylon, and four proteracacinidins15 from A. galpinii and
A. caffra. Results relevant to the abundant occurrence of
mono-, di- and tri-meric profisetinidins with a 2,3-cis relative
stereochemistry of extender units from the bark of Pith-
ecellobium dulce (Roxb.) Benth (Guamúchil, Madras thorn), a
member of the Leguminosae (Mimosoideae) reputed for its
effectiveness as a leather tannage,16 are discussed here.
HO
O
C
R1O
O
2
OH
2′
A
3
6
OH
OR2
5
4
OR2
1
2
≡
≡
3
4
5
≡
≡
≡
, R1 = R2 = H
, R1 = R2 = H
, R1 = Me, R2 = Ac
OR1
OR1
OR1
OR1
R1O
O
R1O
O
OR1
OR2
OR2
OR2
6
≡
≡
≡
≡
, R1 = R2 = H
10 R1 = R2 = H
7
8
9
, R1 = Me, R2 = Ac
, R1 = R2 = H
11 R1 = Me, R2 = Ac
OR1
, R1 = Me, R2 = Ac
Results and discussion
B
R1O
O
2
OR1
The two fisetinidols 1 and 2 were named (Ϫ)-fisetinidol17 and
(ϩ)-epifisetinidol18 respectively, some thirty years ago. In order
to be consistent with the latest nomenclature proposals,19 com-
pound 2 should be designated ent-epifisetinidol (see also ref. 8).
The natural products from Guamúchil with (2R,3R)-2,3-cis
fisetinidol constituent units will thus accordingly be named as
epifisetinidol-derived profisetinidins in this paper.
The methanol extract of Guamúchil bark afforded a series of
mono-, di- and tri-meric profisetinidins exhibiting both 2,3-
trans and 2,3-cis relative configurations of the constituent
fisetinidol moieties. The monomeric compounds comprised of
the 3Ј,4Ј,7-trihydroxy-flavan-3,4-diols, epifisetinidol-4β-ol 3,20
epifisetinidol-4α-ol 4,20 the fisetinidol-4β- and 4α-ols 6 and 820
and the 3Ј,4Ј,5Ј,7-tetrahydroxyflavan-3-ol, robinetinidol 10.21
A
C
3
OR1
OR1
OR2
4
E
R1O
O
F
8
2
D
OR2
OR1
≡
12
13
14
15
, R1 = R2 = H
≡
, R1 = Me, R2 = Ac
, R1 = R2 = H
≡
≡
, R1 = Me, R2 = Ac
and 13C NMR spectra (Tables 1 and 2) and CD data (see
Experimental section) with those of authentic samples,20–22
either as free phenol 3, or as permethylaryl ether acetates 5, 7, 9
1
These compounds were identified by comparison of their H
1
and 11. H NMR and CD data of the derivatives 13 and 15 of
† For Part 25, see P. J. Steynberg, A. Cronjé, J. P. Steynberg, B. C. B.
Bezvidenhoudt, E. V. Brandt and D. Ferreira, Tetrahedron, 1997, 53,
2591.
the known fisetinidol-(4α,8)-catechin and -epicatechin dimers
121 and 1411 similarly permitted definition of their structures.
J. Chem. Soc., Perkin Trans. 1, 1997
1943

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Table 1 1H NMR peaks (δH , 300 MHz) of flavan-3,4-diols and derivatives at 296 K. Splitting patterns and J values (Hz) are given in square brackets.
Proton
3a
4a(5)b
6a(7)b
8a(9)b
5-H(A)
6-H(A)
8-H(A)
2-H(B)
5-H(B)
6-H(B)
2-H(C)
3-H(C)
4-H(C)
OMec
7.12 [d, 8.5]
6.41 [dd, 2.5, 8.8]
6.32 [d, 2.5]
7.05 [d, 2.0]
6.79 [d, 8.0]
6.84 [dd, 2.0, 8.00]
5.05 [d, 1.0]
3.86 [dd, 1.0, 3.0]
4.45 [d, 3.0]
7.27 (7.10) [d, 8.5]
6.41 (6.58) [dd, 2.5, 8.5]
6.25 (6.54) [d, 2.5]
7.07 (6.99) [d, 2.0]
6.78 (6.84) [d, 8.5]
6.48 (6.97) [dd, 2.0, 8.5]
5.0 (5.26) [br s]
3.97 (5.62) [dd, 1.0, 4.5]
4.90 (6.28) [d, 4.5]
7.12 (7.18) [d, 8.5]
6.42 (6.54) [dd, 2.5, 8.5]
6.25 (6.46) [d, 2.5]
6.92 (6.94) [d, 2.0]
6.80 (6.85) [d, 8.5]
6.75 (6.99) [dd, 2.0, 8.5]
4.86 (5.19) [d, 9.0, 10.5]
3.91 (5.47) [dd, 3.5, 9.0, 10.5]
4.48 (6.15) [d, 3.5]
7.27 (7.05) [d, 8.5]
6.43 (6.56) [dd, 2.5, 8.5]
6.19 (6.46) [d, 2.5]
6.93 (6.94) [d, 2.0]
6.79 (6.84) [d, 8.5]
6.75 (6.95) [dd, 2.0, 8.5]
4.60 (5.02) [d, 10.0, 9.5]
3.75 (5.54) [dd, 8.0, 10.0; 7.5, 9.5]
4.66 (6.24) [d, 8.0, 7.5]
3.75 (7-A), 3.87 (3-B), (4-B), each s
3.79 (7-A), 3.86 (3-B), 3.88
3.75 (7-A), 3.87 (3-B), (4-B),
(4-B), each s
1.93 (3-C), 2.09 (4-C), each s
each s
OAc c
1.84 (3-C), 2.13 (4-C), each s
1.84 (3-C), 2.03 (4-C), each s
a
b
c
In (CD3)2CO ϩ 5% D2O. Chemical shift values for derivatives in CDCl3 in parentheses. Positions of the groups on the ring are given in
parentheses.
Table 2 13C NMR peaks (δC, 300 MHz) of flavan-3,4-diols at 296 K in
(CD3)2CO ϩ 5% D2O
OR1
B
R1O
O
C
2
OR1
E
Carbon
3
4
6
8
A
3
OR1
OR1
OR2
5-C(A)
6-C(A)
8-C(A)
2-C(B)
5-C(B)
6-C(B)
2-C(C)
3-C(C)
4-C(C)
133.2
109.3
103.1
115.2
115.4
119.2
75.4
129.6
109.1
102.7
115.2
115.3
119.2
79.2
129.3
109.3
102.6
115.7
115.5
120.6
82.0
132.3
109.2
102.8
115.6
115.5
120.2
77.4
4
R1O
O
F
8
2
D
OR2
OR1
72.2
68.3
70.0
67.7
74.2
72.1
71.2
66.5
16
17
18
19
≡
≡
≡
≡
, R1 = R2 = H
, R1 = Me, R2 = Ac
, R1 = R2 = H
1
At ambient temperatures the H NMR spectra (Table 3) of
the derivatives 17 and 19 of the second pair of profisetinidin
biflavanoids 16 and 18 exhibited broadened resonances remin-
iscent of the effects of dynamic rotational isomerism about
the interflavanyl bond. At elevated temperatures (343 K) the
protons of the heterocyclic rings displayed an AMX-
[J2,3(C) = 2.5, 2.6, J3,4(C) = 3.5, 4.2 Hz for 17 and 19, respectively]
and an ABMX-system [J2,3(F ) = 7.5 and 1.0 Hz for 17 and 19
respectively] suggesting the possibility of either a 2,3-cis-3,4-
trans or a 2,3-cis-3,4-cis relative configuration of the C-ring in
both products and with either 2,3-trans or 2,3-cis stereo-
chemistry of the F-ring in 17 and 19, respectively. Long range
COSY experiments using the 2-H (for ABX-systems of rings B
and E) and 4-H (for ABX-system of ring A) resonances as
reference signals, permitted definition of the constitution of the
‘upper’ fisetinidol and ‘lower’ catechin and epicatechin units in
derivatives 17 and 19 respectively. In addition to the afore-
mentioned ABX-systems, the aromatic region of each spectrum
displayed a one-proton singlet (δ 6.23, 6.24 for 17 and 19,
respectively). The chemical shifts of these singlets are remin-
iscent of the A-ring proton of a C-8 substituted catechin or
epicatechin unit respectively.23 This was confirmed by the strong
NOE interaction of the ‘residual’ proton with both 5-OMe (6.3,
5.9% for 17 and 19, respectively) and 7-OMe (8.6, 9.1% for 17
and 19, respectively) of the ‘lower’ flavan-3-ol units. The high-
amplitude positive Cotton effects in the 220–245 nm region of
the CD spectra ([θ]241.9 ϩ51 690, [θ]243.6 ϩ44 590 for 17 and 19,
respectively), strongly indicated a 4β substituted ABC moiety in
each instance.24
, R1 = Me, R2 = Ac
OH
B
HO
O
2
OH
A
C
OMe
OMe
OH
O
4
E
8
MeO
D
F
OH
OMe
20
21
≡
≡
OR1
B
R1O
S
1
OR1
E
A
2
OMe
3
OR2
O
R2O
MeO
OMe
D
F
OR2
OMe
22 R1 = R2 = H
23 R1 = Me, R2 = Ac
Since the 1H NMR coupling constants did not permit
unequivocal differentiation between 2,3-cis-3,4-trans- and 2,3-
cis-3,4-cis-configurations of the ‘upper’ flavan-3-ol units, in
both 17 and 19, we embarked on the synthesis of compounds 16
and 18 from precursors of known absolute stereochemistry to
obtain sufficient proof of the absolute configuration of both
the upper and lower units in these compounds. Initial attempts
were aimed at the selective C-2 (C-ring) epimerization of the
ent-fisetinidol-(4,8)-tetra-O-methylcatechins 20 and 21, avail-
able by acid-catalysed condensation of ent-fisetinidol-4β-ol
(enantiomer of 8)and 3Ј,4Ј,5,7-tetra-O-methylcatechin.Whereas
efforts at converting the 2,3-trans-3,4-cis diastereomer 21 into
its C-2(C) epimer by heating at alkaline pH (ca. 12)25 under
pressure invariably failed, the 3,4-trans isomer 20 could be
epimerized at C-2, albeit in low yield (ca. 0.5%) and after pro-
longed reaction times. These poor results may presumably be
attributed to stereoselective recyclization of an intermediate
1944
J. Chem. Soc., Perkin Trans. 1, 1997

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Table 3 1H NMR peaks (δH , 300 MHz) of dimeric profisetinidin derivatives 17, 19, 30 and 32, and of the propan-2-ol derivative 23 in CDCl3
a
Proton
17 (343 K)
19 (343 K)
30 (343 K)
32 (343 K)
23 (297 K)
5-H(A)/6-H(A)
6-H(A)/5-H(A)
8-H(A)/3-H(A)
2-H(B)
5-H(B)
6-H(B)
2-H(C)/1-H
3-H(C)/2-H
4-H(C)/3-H
6-H(D)
6.72 (dd, 1.0, 8.5)
6.37 (dd, 2.5, 8.5)
6.29 (d, 2.5)
6.94 (d, 2.0)
6.79 (d, 8.5)
6.87 (dd, 2.0, 8.5)
5.43 (d, 2.5)
5.54 (dd, 2.5, 3.5)
4.60 (d, 3.5)
6.76 (dd, 1.0, 8.5)
6.35 (dd, 2.5, 8.5)
6.26 (br d, ca. 2.5)
7.00 (d, 2.0)
6.80 (d, 8.5)
6.92 (dd, 2.0, 8.5)
5.58 (d, 2.6)
5.65 (dd, 2.6, 4.2)
4.68 (d, 4.2)
6.24 (s)
6.73 (dd, 1.0, 8.5)
6.44 (dd, 2.5, 8.5)
6.63 (d, 2.5)
7.02 (d, 2.0)
6.88 or 6.86 (d, 8.0)
6.97–6.92 (m)
5.59 (d, 3.0)
5.71 (dd, 3.0, 5.0)
4.57 (dd, 1.0, 5.0)
—
6.73 (dd, 1.0, 8.5)
6.44 (dd, 2.5, 8.5)
6.63 (d, 2.5)
7.02 (d, 2.5)
6.86 (d, 8.5)
6.96 (dd, 2.5, 8.5)
5.59 (d, 3.0)
5.72 (dd, 3.0, 5.0)
4.54 (dd, 1.0, 5.0)
—
6.96 (d, 9.0)
6.08 (dd, 2.5, 9.0)
6.46 (d, 2.5)
6.83 (d, 2.0)
6.70 (d, 8.0)
6.46 (dd, 2.0, 8.0)
5.39 (d, 11.5)
6.26 (dd, 2.0, 11.5)
3.68 (d, 2.0)
6.23 (s)
6.06 (s)
8-H(D)
—
—
6.41 (s)
6.42 (s)
—
2-H(E)
5-H(E)
6-H(E)
2-H(F)
6.77 (d, 2.0)
6.78 (d, 8.5)
6.74 (dd, 2.0, 8.5)
4.57 (d, 7.5)
5.27 (m)
6.87 (d, 2.0)
6.77 (d, 8.5)
6.70 (dd, 2.0, 8.5)
4.66 (br s, ca. 1.0)
5.37 (m)
6.95 (d, 2.0)
6.88 or 6.86 (d, 8.0)
6.97–6.92 (m)
5.13 (d, 6.0)
5.40 (m)
7.05 (d, 2.5)
6.89 (d, 8.5)
6.98 (dd, 2.5, 8.5)
5.15 (d, 2.0)
5.50 (m)
7.25 (d, 2.0)
6.77 (d, 8.5)
6.82 (dd, 2.0, 8.5)
4.35 (d, 9.5)
4.99 (m)
3-H(F)
4-Hα(F)
4-Hβ(F)
PhCH2
3.08 (dd, 5.8, 16.7)
2.70 (dd, 7.5, 16.7)
—
2.93 (dd, 2.1, 17.7)
3.01 (dd, 5.0, 17.7))
—
2.95 (dd, 5.5, 17.0)
2.84 (dd, 6.0, 17.0)
—
2.98 (dd, 3.0, 18.0)
3.14 (dd, 5.0, 18.0)
—
3.14 (dd, 6.0, 16.0)
2.34 (dd, 10.0, 16.0)
3.34, 3.20 (both d, 13.0)
6.89–7.04
Ph
—
—
—
—
OMe
3.70 (7-A), 3.74 (5-D),
3.76, 3.82, 3.86 (7-D),
3.86, 3.87, each s
3.65, 3.74, 3.75,
3.83, 3.85, 3.86, 3.87
(7-D), each s
3.89, 3.88, 3.87,
3.86, 3.81, 3.64,
3.38, each s
3.40 (×2), 3.88, 3.86,
3.81, 3.62, 3.43 (br),
each s
3.92 (4-E), 3.90 (7-D),
3.86 (4-B), 3.74 (3-B),
3.73 (5-D), 3.70 (4-A),
3.44 (3-E), each s
2.34 (2-A), 1.76 (3-F),
1.66 (2), each s
OAc
1.87, 1.81, each s
1.94, 1.81, each s
2.00, 1.87, each s
1.95, 1.86, each s
a
Splitting patterns and J values (Hz) are given in parentheses.
quinomethane of type 24. The addition of an external nucleo-
phile to scavenge the quinomethane may then possibly enhance
product formation via an addition–substitution mechanism.
Thus, treatment of profisetinidin 20 with base in the presence of
phenylmethanethiol followed by the appropriate derivatiz-
ations, afforded the epifisetinidol-(4β,8)-catechin derivative 17
(ca. 5% yield) and the 2-acetoxy-1,3,3-triaryl-1-benzylthio-
propane derivative 23 (1H NMR data—Table 3). The 1H NMR
and CD spectra of the synthetic derivative 17 were identical to
those of the same derivative of the natural product 16, hence
confirming the 2R,3R,4S absolute configuration of the upper
epifisetinidol chain extender unit as well as the 2R,3S absolute
configuration of the catechin DEF unit.
Formation of both the epimerized profisetinidin and the
thioether 22 is explicable by the dual trapping of an intermedi-
ate quinomethane 24, either intramolecularly by the A-ring
phenoxide or intermolecularly by the sulfur nucleophile
(Scheme 1). The former process regenerates the starting
material 20 by rapid and highly stereoselective ring closure,
while the latter affords the benzyl thioether 25, both processes
involving the π antibonding orbital at the si-face of C-2. Con-
former 26 then permits the formation of the natural product
analogue 28 with inversed C-2(C) configuration, either via SN 2
displacement of thiolate anion or by generation of the inter-
mediate quinomethane 27 and subsequent cyclization involving
the re-face at C-2.
Conformational preferences appear to control the remark-
able stereoselectivity of the pyran ring closure of quino-
methanes of type 24, and also reaction of the latter with thiol.
In solution both the (4α,8)- and (4β,8)-profisetinidins 20 and 21
preferentially adopt compressed conformations about the
interflavanyl bonds in which 4-H(C) and 7-OMe(D) are approxi-
mately eclipsed.25,26 These conformations permit an offset face-
to-face arrangement of the B- and E-rings hence leading to
stabilizing π-stacking27 of these rings. Such π–π interactions are
especially prevalent in profisetinidin 21, with its 3,4-cis (C-ring)
configuration thus effectively preventing attack of the A-ring
phenoxide ion at the re-face of C-2 in an intermediate quino-
methane of type 24. The increased distance between the B- and
E-rings in the 3,4-trans profisetinidin 20, partially alleviates the
π–π interactions, thus permitting a low degree of attack at the
re-face of C-2 in quinomethane 24, and subsequent epimeriz-
ation at this stereocentre with formation of the natural product
derivative 28 in low yield. The formation of the benzyl thioether
26 presumably opens up the conformation hence allowing
increased accessibility at the equivalent of the re-face of quino-
methane 27 and permitting an SN 2 displacement of the thio-
ether functionality.
Unequivocal structural proof for the novel compounds 16
and 18 followed from a small scale acid-catalysed condensa-
tion of epifisetinidol-4β-ol 3, available via epimerization at C-
2 of ent-fisetinidol-4β-ol,22 and catechin and epicatechin
respectively. The former reaction afforded the epifisetinidol-
(4β,8)-catechin 16 and epifisetinidol-(4β,6)-catechin 29, and
the latter one the epifisetinidol-(4β,8)-epicatechin 18 and the
(4β,6)-regioisomer 31, both couplings occurring stereo-
selectively.1 The 1H NMR and CD data of the hepta-O-methyl
ether acetate derivatives 17 and 19 were identical to those of the
corresponding derivatives of the naturally occurring profiseti-
nidins 16 and 18. These compounds accordingly represent the
first profisetinidins with (2R,3R)-2,3-cis fisetinidol (epifisetini-
dol) constituent units for which structural proof via synthesis is
available. Analogue 18 complements the rate series of profiseti-
1
nidins associated with epicatechin.11 The same H NMR and
CD parameters that were used above to establish the structures
of the hepta-O-methyl ether acetates 17 and 19, were also
applied to the structure elucidation of the same derivatives 30
1
and 32 of the (4β,6)-regioisomers 29 and 31. Their H NMR
and CD data are collated in Table 3 and in the Experimental
section, respectively.
The 1H NMR spectra (Table 4) of the trimeric derivatives 34,
36, 38 and 40 were also characterized by severe line-broadening
at ambient temperatures. At elevated temperatures (343 K) the
spectra displayed ten methoxy and three acetoxy signals, five
aromatic ABX patterns as well as an ABMX and two AMX
spin systems in the heterocyclic region, reminiscent of the pro-
tons of the permethylaryl ether triacetates of bis-fisetinidol-
catechin/epicatechin triflavanoids.4 Owing to the small chemical
shift differences of some key reference signals, e.g. H-4 of both
the C- and I-rings in all four isomers, the spin systems of the
constituent units could not be differentiated using a variety of
NMR techniques, e.g. HMBC. Differentiation of these spin sys-
J. Chem. Soc., Perkin Trans. 1, 1997
1945

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OR1
OR1
E
PhCH SH
• •
2
(b)
O
B
R1O
O
C
OH
(a)
O–
H
B–
A
3
OR1
OR1
2
20
(a) Si-face
OR2
O
4
OH
H
R1O
R1O
R1O
R2O
(DEF)
H
D
F
24
OR2
I
OR1
(b) Si-face
O
, R1 = R2 = H
OH
33
≡
≡
≡
≡
G
• •
, R1 = Me, R2 = Ac
, R1 = R2 = H
H
H
O–
• •
O–
34
35
36
SCH2Ph
OH
H
R
OH
OR1
OH
, R1 = Me, R2 = Ac
H
(DEF)
(DEF)
OR1
25 R = SCH2Ph
OH
B
R1O
O
C
OH
OR1
E
A
26
OR1
-SCH2Ph
SN
OR2
O
OH
2
R1O
R1O
R1O
-SCH2Ph
R2O
OR1
HO
O
H
O–
OH
E
D
F
H
• •
H
OR2
3
OMe
OMe
OH
O
I
Re-face
O
OR1
OH
2
4
MeO
37
≡
≡
≡
≡
, R1 = R2 = H
G
(DEF)
D
F
38
39
40
, R1 = Me, R2 = Ac
, R1 = R2 = H
OH
OH
OR1
OMe
O
, R1 = Me, R2 = Ac
27
28
Scheme
1
Epimerization of ent-fisetinidol-(4β,8)-tetra-O-methyl-
ABC and GHI moieties of 33 and 35, GHI moieties of 37 and
39) and (2R,3S)-2,3-trans-fisetinidol units (ABC moieties of 37
and 39). Since the circular dichroism method does not permit
reliable stereochemical assignment at this molecular level we
took recourse to the semi-synthetic approach 1,4 in order to
establish configuration at the eight stereocentres, and especially
the stereochemistry at C-4 of both the C- and the I-rings.
Thus, acid-catalysed condensation of epifisetinidol-4β-ol 3
with either catechin or epicatechin in a 1:6 molar ratio, stereo-
selectively afforded, in addition to the dimeric profisetinidins 16
or 18, the angular trimeric profisetinidins 33 or 35. The
appropriate derivatizations gave the permethylaryl ether tri-
acetes 34 and 36, with 1H NMR and CD data identical to those
of the same derivatives of the natural products 33 and 35.
Although all naturally occurring (2R)-proanthocyanidins with
2,3-cis relative configuration have been assigned a 3,4-trans 4β-
linkage, evidence for such an assignment is entirely based upon
the upfield shift of the C-2 (C-ring) carbon resonances (γ
gauche effect)28 and chiroptical data.29 Evidence for the 4β-
orientation of both the C- and I-rings in derivatives 34 and 36
was obtained from the high intensity positive Cotton effects
[ϩ104 700 (245.8 nm), ϩ108 700 (245.7 nm) for 34 and 36,
respectively] in the CD spectra of these compounds. The
dimeric profisetinidins 16 and 17 accompanying the trimers 33
and 35 were identical to those synthesized by acid-catalysed
condensation of epifisetinidol-4β-ol 3 with catechin and epi-
catechin, respectively, thus proving the 4β linkage between the
C- and D-rings.
catechin 20, in the presence of phenylmethanethiol
OR1
R1O
O
OR1
OR2
OR1
R1O
29
30
31
32
≡
≡
≡
≡
, R1 = R2 = H
, R1 = Me, R2 = Ac
, R1 = R2 = H
O
R2O
, R1 = Me, R2 = Ac
OR2
OR1
tems became possible for derivatives 38 and 40 (see Table 4)
however, once the structures were confirmed by a concise syn-
thesis (see below).
The coupling constants of the protons constituting the
heterocyclic AMX systems tentatively indicated 2,3-cis-3,4-
trans(C):2,3-trans(F):2,3-cis-3,4-trans(I) [J2,3(C) = 3.2, J3,4(C)
=
5.1; J2,3(F ) = 5.1; J2,3(I) = 3.2, J3,4(I) = 4.9 Hz] relative configur-
ation for derivative 34 and 2,3-cis-3,4-trans(C):2,3-cis(F):
2,3-cis-3,4-trans(I) [J2,3(C) = 3.2; J3,4(C) = 5.3; J2,3(F ) = ca. 1.0;
J2,3(I) = 3.5, J3,4(I) = 6.2 Hz] relative stereochemistry for deriv-
ative 36. Compounds 38 and 40 are apparently based on the
same flavan-3-ol DEF units [J2,3(F ) = 6.5, ca. 1.0 Hz for 38 and
40 respectively] as was indicated for 34 and 36. These deriv-
atives, however, possess chain extender units with 2,3-trans-3,4-
trans(C) and presumably 2,3-cis-3,4-trans(I) [J2,3(C) = 9.5,
J3,4(C) = 9.5; J2,3(I) = ca. 3.0, J3,4(I) = ca. 5.0 Hz] relative configur-
ations. When taken in conjunction with the structures of the
dimeric analogues 12, 14, 16 and 18, the triflavanoids presum-
ably also comprise (2R,3R)-2,3-cis-epifisetinidol units (both
A similar approach was used in assigning the structures of
the trimeric profisetinidins 37 and 39. Since CD data were
inconclusive due to the presence of both 4α and 4β interflavanyl
bonds, the trimer 37 was synthesized by acid-catalysed reaction
of fisetinidol-(4α,8)-catechin 12 and epifisetinidol-4β-ol 3. The
appropriate derivatizations afforded the decamethyl ether tri-
1
acetate 38 with H NMR and CD data identical to those of the
same derivative of the natural product. Trimer 39 was syn-
thesized by condensation of epifisetinidol-(4β,6)-epicatechin
31, available from the reaction between epifisetinidol-4β-ol 3
1946
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
Table 4 1H NMR peaks (δH , 300 MHz) of trimeric profisetinidin derivatives 34, 36, 38 and 40
Proton
34*
36*
38
40
5-H(A)
6-H(A)
8-H(A)
2-H(B)
5-H(B)
6-H(B)
2-H(C)
3-H(C)
4-H(C)
2-H(E)
5-H(E)
6-H(E)
2-H(F)
3-H(F)
4-Hα(F)
4-Hβ(F)
5-H(G)
6-H(G)
8-H(G)
2-H(H)
5-H(H)
6-H(H)
2-H(I)
7.06 (dd, 1.0, 8.2)
6.58 (dd, 2.5, 8.2)
6.94 (d, 2.5)
7.32 (d, 2.0)
6.78 (d, 8.2)
7.24 (dd, 2.0, 8.2)
6.13 (d, 3.2)
6.26 (dd, 3.2, 5.1)
5.01 (dd, 1.0, 5.1)
7.03 (d, 2.2)
6.74 (d, 8.0)
6.97 (dd, 2.2, 8.0)
4.97 (d, 5.1)
7.08 (d, 8.5)
6.60 (dd, 2.5, 8.5)
6.94 (d, 2.5)
7.32 (d, 2.0)
6.79 (d, 8.5)
7.25 (dd, 2.0, 8.5)
6.10 (d, 3.2)
6.28 (dd, 3.2, 5.3)
5.01 (d, 5.3)
7.11 (d, 2.0)
6.76 (d, 8.0)
7.19 (dd, 1.0, 8.0)
7.15 (dd, 1.0, 8.5)
6.69 (dd, 2.5, 8.5)
6.81 (d, 2.5)
7.04 (d, 2.0)
6.69 (d, 8.0)
6.94 (dd, 2.0, 8.0)
5.05 (d, 9.5)
6.75 (t, 9.5)
5.09 (dd, 1.0, 9.5)
6.85 (d, 2.0)
6.81 (d, 8.2)
6.74–6.64
·
7.12 (d, 2.0)
6.75 (d, 8.0)
7.01 (dd, 2.0, 8.0)
4.97 (d, 9.5)
6.68 (t, 9.5)
5.07 (dd, 1.0, 9.5)
6.87 (br s)
6.74–6.64
·
6.84 (dd, 2.0, 8.0)
4.66 (br s)
5.46 (m)
6.74 (dd, 2.0, 8.2)
5.33 (br s)
5.50 (m)
5.49 (d, 6.5)
5.53 (m)
5.42 (m)
3.07 (dd, 5.0, 16.0)
2.95 (dd, 6.5, 16.0)
7.11 (dd, 1.0, 8.5)
6.63 (dd, 2.5, 8.5)
6.98 (d, 2.5)
7.32 (d, 2.1)
6.78 (d, 8.0)
7.23 (dd, 2.1, 8.0)
6.15 (d, 3.0)
2.99 (d, 5.1)
3.08 (d, 4.6)
3.34 (d, 3.5)
·
·
·
7.09 (dd, 1.0, 8.5)
6.65 (dd, 2.5, 8.5)
6.76 (d, 2.5)
7.05 (d, 8.5)
7.14 (dd, 1.0, 8.5)
6.62 (dd, 2.5, 8.5)
6.99 (d, 2.5)
6.59 (dd, 2.5, 8.5)
6.66 (d, 2.5)
7.23 (d, 2.0)
6.74 (d, 8.5)
7.14 (dd, 2.0, 8.5)
5.94 (d, 3.5)
7.18 (d, 2.0)
6.75 (d, 8.2)
7.13 (dd, 2.0, 8.2)
5.79 (d, 3.2)
7.32 (d, 2.0)
6.79 (d, 8.2)
7.25 (dd, 2.0, 8.2)
6.16 (d, 2.8)
3-H(I)
4-H(I)
OMe
6.30 (dd, 3.2, 4.9)
4.97 (d, 4.9)
3.73, 3.64, 3.62, 3.56, 3.55,
3.54, 3.50, 3.49, 3.28 (br),
each s
6.39 (dd, 3.5, 6.2)
5.03 (d, 6.2)
3.84, 3.65, 3.62, 3.57 (×2),
3.55, 3.51, 3.47 (br), 3.44,
3.39 (br), each s
1.79, 1.77, 1.72, each s
6.25 (dd, 3.0, 4.5)
5.05 (dd, 1.0, 4.5)
3.76 (br), 3.69, 3.67, 3.65,
3.56, 3.55, 3.55, 3.51, 3.48,
3.22 (br), each s
1.78, 1.72, 1.61, each s
6.26 (dd, 2.8, 5.0)
5.06 (dd, 1.0, 5.0)
3.74, 3.72 (br), 3.65, 3.57,
3.56 (×2), 3.55, 3.52 (×2),
3.35 (br), each s
1.71, 1.59, 1.56, each s
OAc
1.75, 1.73 (×2), each s
* The allocations of the protons of the ABC- and GHI-moieties may be interchanged.
and epicatechin (see above), and fisetinidol-4α-ol 8 under mild
acidic conditions. Its permethylaryl ether triacetate 40 proved
to be identical to the natural product derivative by comparison
pressure at ambient temperature in a rotary evaporator, and
freeze drying of aqueous solutions on a Virtis 12SL freeze-
mobile.
1
of H NMR and CD data. The absolute configuration at C-4 of
Isolation of phenolic compounds
the ABC moiety is then defined by the coupling constants
(3J2,3 = 3J3,4 = 9.5 Hz) reminiscent of 2,3-trans-3,4-trans stereo-
chemistry.
A Craig enriched fraction (20 g) (top and bottom phases of
tubes 7–13) from a 20 tube countercurrent assembly [water–
butan-2-ol–hexane (5:4:1, v/v), 100 ml underphase] of the
methanol extract of Guamúchil bark was separated on Seph-
adex LH-20 in ethanol (5 × 160 cm column, flow rate 1 ml
minϪ1, 16 min fractions, first 2.0 l of eluent discarded) to give
the following fractions: GA (tubes 60–90, 139 mg), GB (105–
130, 74 mg), GC (137–170, 72 mg), GD (171–200, 80 mg), GE
(201–258, 182 mg), GF (259–300, 167 mg), GG (301–380, 570
mg), GH (381–420, 430 mg), GI (421–520, 3.17 g), GJ (521–
620, 2.13 g), GK (621–760, 2.8 g), GL (761–800, 540 mg), GM
(801–1000, 2.48 g) and GN (1001–1130, 1.01 g).
Triflavanoids 33, 35, 37 and 39 accordingly represent the first
trimeric profisetinidins with epifisetinidol chain extender units.
Together with the dimeric analogues 16 and 18 they are hitherto
the only profisetinidins with a 2,3-cis relative configuration
whose structures have been rigorously established by synthesis.
We have thus demonstrated an extended stereochemical
diversity among the economically important group of pro-
fisetinidin oligomers. The compounds with epifisetinidol
constituent units, e.g. 16 and 18 represent the 5-deoxy (A-ring)
analogues of the epicatechin-(4β,6/8)-catechin or -epicatechin
oligomers which are ubiquitous in the class of procyanidin
condensed tannins.
Fraction GA gave epifisetinidol-4β-ol 318 as a white solid
(139 mg); δH (Table 1); CD [θ]328.8 Ϫ53, [θ]286.2 Ϫ1700, [θ]267.3 75,
[θ]237.3 Ϫ1100, [θ]229.8 190, [θ]221.7 Ϫ770, [θ]215.8 Ϫ32 and [θ]209.1
1600.
Fraction GB (74 mg) was methylated and subsequently sep-
arated by PLC in benzene–acetone (7:3, v/v) to give two bands,
RF 0.31 (17 mg) and 0.27 (19 mg). Acetylation of the RF 0.31
band followed by PLC in benzene–acetone (9:1, v/v) gave tri-O-
methyl-3,4-di-O-acetylfisetinidol-4β-ol 7 (15 mg, RF 0.51).20
Similar treatment of the RF 0.27 band afforded the same deriv-
ative 9 of fisetinidol-4α-ol 8 (RF 0.49, 17 mg).20
Fraction GC (72 mg) was methylated and purified by PLC
in benzene–acetone (7:3, v/v) to give a methyl ether (RF 0.45,
25 mg) which was acetylated and eventually purified by PLC
in benzene–acetone (9:1, v/v) to afford tetra-O-methyl-3-O-
acetylrobinetinidol 1121 as a white solid, CD [θ]320 15, [θ]298
Ϫ320, [θ]283.3 Ϫ9600, [θ]264.3 Ϫ101, [θ]256.7 11, [θ]242.8 5900, [θ]235
1500, [θ]229 3500, [θ]224.4 Ϫ170, [θ]221.5 Ϫ3100, [θ]216.5 1500, [θ]212.3
Ϫ1600 and [θ]206.5 3500.
Experimental
1H NMR Spectra were recorded on a Bruker AM-300 spec-
trometer for solutions as indicated, with Me4Si as internal
standard. FAB Mass spectra were recorded on a VG 70-70E
instrument with a VG 11-250J data system and an iontech
saddlefield FAB gun. TLC was performed on precoated Merck
plastic sheets (silica gel 60 PF254, 0.25 mm) and the plates were
sprayed with H2SO4–HCHO (40:1 v/v) after development.
Preparative plates (PLC) [20 × 20 cm, Kieselgel PF254 (1.0 mm)]
were air dried and used without prior activation. Column
chromatography was performed on Sephadex LH-20 or Cellu-
lose (Avicell, 20–100 µm particle size) in various columns, sol-
vent systems and flow rates (to be specified in each instance).
Methylations were performed with an excess of diazomethane
in MeOH–diethyl ether over a period of 48 h at Ϫ15 ЊC, while
acetylations were conducted in acetic anhydride–pyridine at
ambient temperature. Evaporations were done under reduced
Fraction GD (80 mg) was subjected to the same derivatiz-
ations and purifications as above to eventually give tri-O-
J. Chem. Soc., Perkin Trans. 1, 1997
1947

View Article Online
methyl-3,4-di-O-acetylepifisetinidol-4α-ol 520 (RF 0.31, 20
mg); δH (Table 1); CD [θ]320 Ϫ250, [θ]295.2 Ϫ430, [θ]282.2 Ϫ6700,
[θ]252.2 Ϫ570, [θ]240.3 Ϫ14 000, [θ]228.5 2500, [θ]222.4 Ϫ290, [θ]215.2
1400 and [θ]208.5 6400.
vessel at a steam pressure of 200 kPa. The vessel was rapidly
cooled in a waterbath and the reaction mixture was freeze-dried
and separated on Sephadex LH-20 in ethanol–water (1:4, v/v)
(5 × 140 cm column, flow rate 1 ml minϪ1, 16 min fractions, first
1 l of eluent discarded) to give the following fractions: A (tubes
141–164, 1.1 g), B (165–178, 1.23 g), C (178–189, 500 mg), D
(190–210, 1.04 g), E (211–245, 2.31 g), F (246–290, 1.80 g) and
G (291–326, 1.02 g). Fraction B, comprising a mixture of ent-
fisetinidol-4α-ol (enantiomer of 6), epifisetinidol-4β-ol 3 and
epifisetinidol-4α-ol 4 (10:25:12 by 1H NMR analysis), was
further resolved by flash column chromatography on cellulose
in water to give the following fractions: B-1 (tubes 8–17, 523
mg), B-2 (19–21, 209 mg) and B-3 (24–26, 251 mg). Fractions A
(see above) and B-2 afforded epifisetinidol-4β-ol 3;‡ δH (Table 1);
δC(Table 2); CD [θ]336.9 Ϫ3.8, [θ]298.7 Ϫ54, [θ]286 Ϫ1300, [θ]270.7
Ϫ2.3, [θ]266.7 32, [θ]254.7 Ϫ30, [θ]247.6 Ϫ9.3, [θ]237.4 Ϫ660, [θ]230.4 58,
[θ]222.9 230, [θ]216.5 Ϫ130, [θ]212.5 38, [θ]208.5 Ϫ280 and [θ]205.7 Ϫ1.8.
Fraction F gave the starting material ent-fisetinidol-4β-ol;
δH (Table 1); δC(Table 2); CD [θ]330 56, [θ]229.6 160, [θ]290.6 1100,
[θ]277.6 Ϫ200, [θ]254.6 170, [θ]241.5 8600, [θ]233.3 Ϫ250, [θ]220.1 930
and [θ]203.9 Ϫ100. Fractions B-1 and C afforded ent-fisetinidol-
4α-ol (enantiomer of 6); δH (Table 1); δC(Table 2); CD [θ]330 10,
[θ]301.2 Ϫ30, [θ]290.7 1500, [θ]283.4 Ϫ140, [θ]279.4 Ϫ180, [θ]269.3
Ϫ1800, [θ]251.6 Ϫ270, [θ]242.2 Ϫ1400, [θ]236.9 Ϫ35, [θ]234.9 170,
[θ]230.9 11, [θ]220.2 512, [θ]213.7 Ϫ170, [θ]208.3 390 and [θ]202.6 Ϫ370.
Fraction B-3 gave epifisetinidol-4α-ol 4; δH (Table 1); δC(Table
2); CD [θ]330 Ϫ120, [θ]310 220, [θ]296 260, [θ]292.9 Ϫ4.1, [θ]285.9
Ϫ1600, [θ]278.9 Ϫ1900, [θ]253.3 Ϫ170, [θ]240.1 Ϫ6000, [θ]233 Ϫ18,
[θ]231.1 380, [θ]226.3 Ϫ340, [θ]213.7 1100 and [θ]204.7 Ϫ370.
Methylation of fraction GG (570 mg) and PLC in benzene–
acetone (8:2, v/v) gave a main band at RF 0.26 (105 mg) which
was further resolved by PLC in benzene–acetone (17:3, v/v, ×4)
into two bands at RF 0.42 (45 mg) and 0.35 (42.5 mg). The RF
0.42 band was acetylated and purified by PLC in benzene–
acetone (19:1, v/v, ×3) to give epifisetinidol-(4β,8)-catechin
hepta-O-methyl ether diacetate 17 as a white amorphous solid
(RF 0.24, 28 mg) (Found: Mϩ, 744.2780. C41H44O13 requires M,
744.2781); δH (Table 3); CD [θ]291.5 Ϫ1200, [θ]285.4 390, [θ]275.1
Ϫ5400, [θ]241.9 52 000, [θ]214.7 Ϫ1300 and [θ]208.6 8700. Acetyl-
ation of the RF 0.35 band followed by PLC purification in
benzene–acetone (9:1, v/v) gave epifisetinidol-(4β,8)-epicatechin
hepta-O-methyl ether diacetate 19 as a white amorphous solid
(RF 0.27, 35 mg) (Found: Mϩ, 744.2779. C41H44O13 requires M,
744.2781); δH (Table 3); CD [θ]291 Ϫ2100, [θ]275.2 Ϫ6400, [θ]243.6
45 000, [θ]230 Ϫ1700, [θ]219 50 000 and [θ]201 Ϫ4700.
Fraction GH (430 mg) was methylated and the mixture was
resolved by PLC in benzene–acetone (8:2, v/v) to give a main
band at RF 0.34 (126 mg). Acetylation of this fraction followed
by PLC in benzene–acetone (9:1, v/v) afforded two main bands
at RF 0.28 (28 mg) and 0.24 (23 mg). The former band afforded
fisetinidol-(4α,8)-catechin hepta-O-methyl ether diacetate 131
and the latter one, fisetinidol-(4α,8)-epicatechin hepta-O-
methyl ether diacetate 15.1
A portion (200 mg) of fraction GI was methylated and the
mixture was separated by PLC in benzene–acetone (7:3, v/v) to
give two main bands at RF 0.35 (51 mg) and 0.11 (23 mg).
Acetylation of the former band followed by PLC in benzene–
acetone (17:3, v/v) afforded bis(epifisetinidol)-(4β,6:4β,8)-
catechin deca-O-methyl ether triacetate 34 as a white amorph-
ous solid (RF 0.42, 34 mg) (Found: Mϩ 1099.3960. C61H63O19
requires M, 1099.3963; δH (Table 4); CD [θ]300 Ϫ420, [θ]290
Ϫ7400, [θ]281.1 420, [θ]259.1 7800, [θ]245.8 100 000, [θ]236.4 Ϫ2900,
[θ]230.4 11 000, [θ]225.4 4100, [θ]220.4 8800, [θ]214.8 2.6 and [θ]208.7
15 000. The RF 0.11 band was acetylated and purified by PLC in
benzene–acetone (7:3, v/v) to give bis(epifisetinidol)-(4β,6:
4β,8)-epicatechin deca-O-methyl ether triacetate 36 as a white
amorphous solid (RF 0.26, 17 mg) (Found: Mϩ, 1099.3959.
C61H63O19 requires M, 1099.3963); δH (Table 4); CD [θ]300 Ϫ610,
[θ]290 Ϫ7100, [θ]280.2 130, [θ]274.2 5800, [θ]259.2 8500, [θ]245.7
110 000, [θ]233.7 Ϫ2100, [θ]228 7500, [θ]222.5 Ϫ5100 and [θ]209.5
16 000.
A portion (200 mg) of fraction GJ was methylated and the
mixture was resolved by PLC in benzene–acetone (7:3, v/v) to
give a main band at RF 0.29 (80 mg). This was acetylated and
purified by PLC in benzene–acetone (17:3, v/v, ×2) to give
epifisetinidol-(4β,6)-epicatechin-(8,4α)-fisetinidol deca-O-methyl
ether triacetate 40 as a white amorphous solid (RF 0.33, 20 mg)
(Found: Mϩ, 1099.3962. C61H63O19 requires M, 1099.3963);
δH (Table 4); CD [θ]300 Ϫ440, [θ]287.5 Ϫ6900, [θ]281.6 Ϫ230, [θ]272.6
7600, [θ]257.6 3300, [θ]243.9 4100, [θ]228.9 Ϫ37, [θ]222.9 180, [θ]212.9
6300 and [θ]206.9 Ϫ5900.
Synthesis of ent-fisetinidol-(4â,8)- and -(4á,8)-catechin tetra-O-
methyl ether 20 and 21
Tetra-O-methylcatechin (14 g) and ent-fisetinidol-4β-ol (enan-
tiomer of 8, 5.8 g) were dissolved in 75% aq. methanol (700 ml),
the pH was adjusted to 3 with 1  HCl and the mixture was
stirred at 60 ЊC for 48 h. Water (500 ml) was added, the mixture
was neutralized with 2% aqueous NaHCO3 and the methanol
was evaporated. The aqueous solution was freeze-dried and the
mixture was resolved on Sephadex LH-20 in ethanol–hexane
(3:1, v/v) (4 × 130 cm column, flow rate 1 ml minϪ1, 16 min
fractions for tubes 1–120 and then 32 min fractions, first 1 l of
eluent discarded) to give three fractions: A (tubes 1–80, 8.3 g), B
(170–259, 5.1 g) and C (260–350, 5.8 g). Fraction A consisted of
tetra-O-methylcatechin. Fractions B and C gave the title com-
pounds 20 and 21 respectively by comparison of the physical
data of the permethylaryl ether diacetates with those of authen-
tic specimens.1
Base-catalysed C-2 epimerization of ent-fisetinidol(4â,8)-
catechin tetra-O-methyl ether 20
The profisetinidin 20 (1 g) was dissolved in ‘argon degassed’
water (80 ml) and the pH was adjusted to ca. 12 with 1  NaOH
under an argon atmosphere. This mixture was heated at 90 ЊC
for 25 h in a ‘capped’ reaction vial, cooled and the pH was
adjusted to ca. 3 with 1  HCl. Extraction with ethyl acetate
(3 × 200 ml), drying (Na2SO4) and evaporation of the solvent
followed by chromatography on Sephadex LH-20 in ethanol–
hexane (7:3, v/v) (3 × 100 cm column, 1 ml minϪ1 flow rate,
16 min fractions) afforded two fractions: A (tubes 1–32, 17
mg) and B (tubes 33–80, 900 mg). Fraction B gave the start-
ing material. Methylation of fraction A followed by PLC in
benzene–acetone (7:3, v/v) gave a main band at RF 0.3 (2
mg). This was acetylated and purified by PLC in benzene–
acetone (9:1, v/v) to give epifisetinidol-(4β,8)-catechin
hepta-O-methyl ether diacetate 17 with 1H NMR and CD
data identical to those of the same derivative of the natural
product 16.
Methylation of a portion (200 mg) of fraction GK followed
by PLC in benzene–acetone–methanol (6:3:1, v/v) afforded
a main band at RF 0.26 (80 mg). Acetylation and subsequent
purification by PLC in benzene–acetone (17:3, v/v, ×2) gave
epifisetinidol-(4β,6)-catechin-(8,4α)-fisetinidol
deca-O-methyl
ether triacetate 38 as a white amorphous solid (RF 0.38, 35 mg)
(Found: Mϩ, 1099.3961. C61H63O19 requires M, 1099.3963);
δH (Table 4); CD [θ]300 Ϫ98, [θ]288 Ϫ8700, [θ]281.6 Ϫ210, [θ]272.2
9200, [θ]259.2 5300, [θ]244.4 49 000, [θ]235.4 3300, [θ]231.5 6600, [θ]227.9
Ϫ250, [θ]224.9 Ϫ5000, [θ]215.9 3600 and [θ]207.9 Ϫ8700.
C-2 Epimerization of ent-fisetinidol-4â-ol22
A solution of ent-fisetinidol-4β-ol (enantiomer of compound 8)
(10 g) in water (800 ml) was heated for 2 h in a pressure reaction
‡ 1H, 13C and CD data for flavan-3,4-diol 3 and the remaining flavan-
3,4-diols are presented for the first time.
1948
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
Base-catalysed C-2 epimerization of ent-fisetinidol-(4â,8)-
catechin tetra-O-methyl ether 20 in the presence of toluene-á-
thiol
4β-ol 3 (52 mg) were dissolved in 0.1  HCl (30 ml) and the
mixture was stirred for 12 h at room temperature under nitro-
gen. The mixture was extracted with ethyl acetate (4 × 50 ml),
the combined organic layers were dried (Na2SO4) and evapor-
ated to dryness. The residual material (145 mg) was methylated
and separated by PLC in benzene–acetone (8:2, v/v) to give two
main bands at RF 0.34 (41 mg) and 0.28 (92 mg). The former
band gave biflavanoid 12. Acetylation of the RF 0.28 band and
PLC in benzene–acetone (8:2, v/v) afforded the epifisetinidol-
(4β,6)-catechin-(8,4α)-fisetinidol derivative 38 with 1H NMR
and CD data identical to those of the same derivative of the
natural profisetinidin 37.
Profisetinidin 20 (1 g) and toluene-α-thiol (790 mg) were dis-
solved in ‘argon degassed’ water (80 ml), the pH of the solu-
tion was adjusted to ca. 12 with 1  NaOH under an argon
atmosphere and the mixture was heated at 90 ЊC for 25 h in a
‘capped’ reaction vial. The mixture was cooled to room tem-
perature and the resulting precipitate was filtered off and thor-
oughly washed with hexanes to remove the excess of toluene-α-
thiol. Separation on Sephadex LH-20 in ethanol–hexane (7:3,
v/v) (3 × 120 cm column, flow rate of 1 ml minϪ1, 16 min frac-
tions) afforded six fractions: A (tubes 26–36, 11 mg), B (46–56,
10.5 mg), C (58–68, 33 mg), D (72–82, 45 mg), E (86–94, 109
mg) and F (95–123, 560 mg). Fraction D was methylated and
purified by PLC in benzene–acetone (7:3, v/v) to give a band
at RF 0.46 (40 mg) which was acetylated and finally purified
by PLC in benzene–acetone (9:1, v/v) to give epifisetinidol-
(4β,8)-catechin hepta-O-methyl ether diacetate 17 (RF 0.30, 40
When the epifisetinidol-(4β,6)-epicatechin biflavanoid 31
(100 mg) and fisetinidol-4α-ol (52 mg) were treated as above, the
unchanged biflavanoid (42 mg) and epifisetinidol-(4β,6)-
epicatechin-(8,4α)-fisetinidol 39 was obtained. The latter was
methylated and purified by PLC in benzene–acetone (7:3, v/v)
to give a band at RF 0.28 (80 mg) which was acetylated and
purified by PLC in benzene–acetone (8:2, v/v) to give the
trimeric profisetinidin derivative 40 (RF 0.35, 73 mg) with iden-
1
mg) with H NMR and CD data identical to the same deriva-
1
tive of the natural profisetinidin 16. Fraction C was similarly
methylated and separated by PLC in benzene–acetone (4:1,
v/v) to give a main band at RF 0.23 (12 mg). This was
acetylated and purified by PLC in benzene–acetone (9:1, v/v)
to give (2R,3S)-2-acetoxy-1-benzylthio-3-(2,4-dimethoxyphenyl)
-3-[(2R,3S)-3-acetoxy-3Ј,4Ј,5,7-tetramethoxyflavan-8-yl]-
propane 23 as a white amorphous solid (RF 0.30, 8 mg)
(Found: Mϩ, 909.3150. C50H53O14S requires M, 909.3156);
δH (Table 3).
tical H NMR and CD to the same derivative of the natural
product 39.
Acknowledgements
Financial support by the Foundation for Research Develop-
ment, Pretoria, the Sentrale Navorsiongsfonds of this Uni-
versity and by the Marketing Committee, Wattle Bark Industry
of South Africa, is acknowledged. The work was also sup-
ported by USDA Competitive Grants 94-03395 and 91-37103-
6492.
Synthesis of di- and tri-meric profisetinidins
Catechin (3 g) and epifisetinidol-4β-ol (500 mg) were dissolved
in 0.1  HCl (200 ml) and the mixture was stirred for 12 h at
room temperature under a nitrogen atmosphere. The mixture
was extracted with ethyl acetate (4 × 200 ml), the combined
organic layers were dried (Na2SO4) and evaporated to dry-
ness. The light-brown residue (3.3 g) was subjected to column
chromatography on Sephadex LH-20 in ethanol (3 × 100 cm
column, flow rate 1 ml minϪ1, 16 min fractions, first 800 ml of
eluent discarded) to give four fractions: A (tubes 112–154, 2.4
g), B (205–270, 545 mg), C (332–370, 184 mg) and D (388–420,
28 mg). Fraction A comprised of catechin, fraction B of
epifisetinidol-(4β,8)-catechin 16, fraction C of epifisetinidol-
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D of bis(epifisetinidol)-
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Fisetinidol-(4α,8)-catechin 121 (100 mg) and epifisetindol-
J. Chem. Soc., Perkin Trans. 1, 1997
1949

View Article Online
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Paper 7/01334E
Received 25th February 1997
Accepted 17th March 1997
1950
J. Chem. Soc., Perkin Trans. 1, 1997