Synthetic studies of proanthocyanidins. Part 2: Stereoselective gram-scale synthesis of procyanidin-B3

Article abstract of DOI:10.1016/S0040-4020(02)00936-5

A stereoselective synthesis of procyanidin-B3, a condensed catechin dimer, is described. Condensation of benzylated catechin with various 4-O-alkylated flavan-3,4-diol derivatives as an electrophile in the presence of a Lewis acid led to protected procyanidin-B3 and its diastereomer. In particular, the reaction using (2R,3S,4S)-3-acetoxy-5,7,3′,4′-tetrabenzyloxy-4-(2″- ethoxyethoxy)flavan as an electrophile in the presence of TMSOTf at -78°C afforded octa-O-benzylated procyanidin-B3 with high levels of stereoselectivity and in excellent isolation yields. Furthermore, we succeeded in a stereoselective gram-scale synthesis of protected procyanidin-B3.

Full text of DOI:10.1016/S0040-4020(02)00936-5

Tetrahedron 58 (2002) 7829–7837
Synthetic studies of proanthocyanidins. Part 2:
Stereoselective gram-scale synthesis of procyanidin-B3q
Akiko Saito,a Noriyuki Nakajima,b Akira Tanakac and Makoto Ubukatab
,
*
aJapan Society for the Promotion of Science, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan
bBiotechnology Research Center, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan
cCollege of Technology, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan
Received 28 June 2002; accepted 29 July 2002
Abstract—A stereoselective synthesis of procyanidin-B3, a condensed catechin dimer, is described. Condensation of benzylated catechin
with various 4-O-alkylated flavan-3,4-diol derivatives as an electrophile in the0presence of a Lewis acid led to protected procyanidin-B3 and
its diastereomer. In particular, the reaction using (2R,3S,4S)-3-acetoxy-5,7,30,4 -tetrabenzyloxy-4-(200-ethoxyethoxy)flavan as an electrophile
in the presence of TMSOTf at 2788C afforded octa-O-benzylated procyanidin-B3 with high levels of stereoselectivity and in excellent
isolation yields. Furthermore, we succeeded in a stereoselective gram-scale synthesis of protected procyanidin-B3. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Proanthocyanidins are a ubiquitous family of polyphenolic
natural products and are characterized by the oligomeric
structures including an interflavanyl bond between the
C4–C8 or C4–C6 position of the flavan-3-ol units.2,3 The
biological activities of proanthocyanidins are very interest-
ing in that they have powerful free-radical scavenging
activity,4 antioxidant activity5 and anti-tumor-promoting
effect.6 For this reason, a number of synthetic efforts have
been made to access oligomeric proanthocyanidins. Recent
investigations concerning the synthesis of isotopically
labeled proanthocyanidins to get direct proof of their gut
resorption and their metabolism in humans have appeared in
the literature.7,8 In a previous paper,1 we described a highly
stereoselective synthesis of benzylated (2)-procyanidin-B3,
(þ)-catechin-(408)-(þ)-catechin dimer, in which (2R,3S,4S)-
3-acetoxy-5,7,3 ,40-tetrabenzyloxy-4-methoxyflavan 10 was
employed as an electrophile in the presence of TiCl4. In this
paper, we report further investigations of the condensation
reaction with various 4-O-alkylated flavan-3,4-diol deriva-
tives as electrophiles and describe the details of the
synthesis of authentic samples and a diastereoselectivity
determination method. In addition, the reaction succeeded
in the stereoselective gram-scale synthesis of benzylated
procyanidin-B3.
2.1. Synthesis of 4-substituted catechin derivatives
DDQ oxidation at the C-4 carbon of a catechin derivative
in CHCl3/MeOH was first studied by Roux et al. to give
4-methoxy catechin.9 Tu¨ckmantel et al.10 reported DDQ
oxidation of an epicathechin derivative. DDQ oxidation of
the epicathechin derivative in CHCl3/MeOH gave generally
low yield, and improved result was obtained by the use of
ethylene glycol instead of MeOH to give flavan 3,4-diol
hydroxy ethyl ether derivatives in 52% yield. They also
described the formation of 2,4-bis-oxidized products in the
reaction using methanol or isopropyl alcohol as a nucleo-
phile. We re-examined the benzylic DDQ oxidation of a
catechin derivative, 5,7,30,40-tetrabenzylcatechin 6, using
five alcohols as nucleophiles. The results are summarized in
Table 1. Although the DDQ oxidation using MeOH or
isopropyl alcohol as a nucleophile resulted in the formation
of many by-products including bis-oxidized products, the
desired 4-O-methyl derivative 9 and 4-O-isopropyl deriva-
tive 11 were isolated in 52 and 58%, respectively, as
indicated by Tu¨ckmantel et al.10 (entries 1 and 2). When
tert-butyl alcohol was used, 2,4-bis-oxidation occurred in
preference to mono-oxidation. In the presence of ethylene
glycol in CH2Cl2, DDQ oxidation proceeded smoothly to
give a 74% yield of 4-O-hydroxyethyl derivative 13 (entry
3). DDQ oxidation of 3-acetylated catechin derivative 7 was
slower than that of 3-hydroxy catechin derivatives.
However, the isolation yield was relatively good, 70%
yield (entry 4). DDQ oxidation in the presence of
2-ethoxyethanol (ethyl cellosolve) led to smooth disappear-
ance of 6 and the desired 4-O-ethoxyethyl derivative 15 was
q For Part 1, see Ref. 1.
Keywords: proanthocyanidin; stereoselective synthesis; procyanidin-B3.
*
Corresponding author. Tel.: þ81-766-56-7500; fax: þ81-766-56-2498;
e-mail: ubukata@pu-toyama.ac.jp
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00936-5

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A. Saito et al. / Tetrahedron 58 (2002) 7829–7837
Table 1. DDQ oxidation
Entry
Nucleophile
Catechin
Time (h)
Products
Isolation yield (%)
R3
R4
No.
1
2
3
4
5
6
Methanola
6
6
6
7
6
6
4
8
6
12
2
12
CH3
CH(CH3)2
CH2CH2OH
CH2CH2OH
CH2CH2OCH2CH3
CH2Ph
9
52
58
74
70
98
86
Isopropyl alcohol
Ethylene glycol
Ethylene glycol
2-Ethoxyethanol
Benzyl alcohol
11
13
14
15
17
a
Ref. 9.
obtained in excellent 98% yield (entry 5). Fortunately,
this 4-O-ethoxyethyl derivative 15 crystallized from the
hexane/EtOAc and, therefore, purification was very easy.
4-O-Benzyl derivative 17 was also isolated in 86% yield in
the presence of benzyl alcohol even though long reaction
time was required at 08C (entry 6).11
(4b)-2 in 84% coupling yield in a 2.1:1 ratio. The ratio of
(4a)-2 and (4b)-2 was determined by the isolation yields of
each compound from silica gel preparative TLC separation
(Merck 1.0 mm, CHCl3/AcOEt, 1/3, 3 times development).
(4a)-2 and (4b)-2 were separately acetylated with Ac2O,
pyridine in the presence of DMAP to give 3,30-O-diacetyl-
octa-O-benzyl procyanidin-B3 (4a)-4 and (4b)-4 in 99 and
98% yield, respectively. Eight benzyl protecting groups
were submitted to hydrogenolysis with Pd(OH)2 in
THF/MeOH/H2O,7 and procyanidin-B3 (4a)-1 and its
diastereomer (4b)-1 were obtained in 60 and 67% yield,
respectively (Fig. 1). Full acetylation of ten hydroxy groups
of (4a)-1 afforded decaacetyl derivative (4a)-5 in 77% yield
and also (4b)-5 was obtained from (4b)-1 in 95% yield.
2.2. Diastereoselectivity determination
Lewis acid catalysts have been employed in the literature to
synthesize proanthocyanidins, e.g. TiCl4 for epicatechin10
and catechin dimer,8 SnCl4 and BF3·OEt2 for catechin
oligomer.12,13 The derivatives of catechin and epicathechin
containing a hydroxyl group at the C-4 position were used as
the electrophile in these condensation studies and few
reports employed the 4-O-alkyl derivatives. Further, the
stereoselectivity at the condensation is not sufficient. In this
paper, we describe further improvement in the stereoselec-
tivity of the condensation reaction over that attained in our
previous studies.1
In NMR studies of (4a)-2 and (4b)-2 in CDCl3 two
rotational isomers were observed with 2:1 ratio for (4a)-2
and 2.5:1 ratio for (4b)-2. Rotamers were also observed for
(4a)-4 (1:1), (4b)-4 (2:1) in CDCl3, (4a)-114 in acetone-d6
(1:1) and in CD3OD (2.5:1) solvent. Since all the NMR
peaks of (4b)-1 broadened, it was not possible to confirm
the existence of the rotamer. Interestingly, no rotational
isomer was observed in decaacetyl derivatives (4a)-512,15,16
and (4b)-5.12,17 All peaks containing the rotamers for 4a
and 4b of 2 and 4 except for the benzyl protecting group
were assigned by 2D NMR measurement on the basis of
literature values. We were pleased to find that a significant
We first synthesized octa-O-benzyl procyanidin-B3 (4a)-2
and its diastereomer (4b)-2 as the authentic samples by
Vercauteren’s method8 (Scheme 1). Condensation of tetra-
O-benzylated catechin 6 and (2R,3S,4S)-5,7,30,40-tetra-
benzyloxy-4-methoxyflavan 9 proceeded in the presence
of 1 equiv. TiCl4 at 08C to afford a mixture of (4a)-2 and
OR1
OR1
OR1
R1O
O
R1O
O
OR1
4
4
a, b
OR2
O
OR2
O
OR1
OR1
OR1
OR1
+
+
9
6
OR1
R1O
OR1
R1O
OR2
OR2
OR1
OR1
(4α)-2: R1 = Bn, R2 = H
(4β)-2: R1 = Bn, R2 = H
(4β)-4: R1 = Bn, R2 = Ac
d
d
(4α)-4: R1 = Bn, R2 = Ac
c
67 %
c
60 %
99 %
77%
98 %
(4α)-1: R1 = R2 = H
(4α)-5: R1 = R2 = Ac
(4β)-1: R1 = R2 = H
(4β)-5: R1 = R2 = Ac
95 %
Scheme 1. Synthesis of authentic samples. Reagents and conditions: (a) TiCl4, 08C, 83%; (b) silica gel TLC separation; (c) H2, Pd(OH)2, THF–MeOH–H2O;
(d) Ac2O, DMAP, Py.

A. Saito et al. / Tetrahedron 58 (2002) 7829–7837
7831
OR1
OR1
OR1
8
B
8
B
2
2
R1O
O
C
R1O
O
C
OR1
E
A
A
3
3
6
6
OR2
OR2
OR1
OR1
OR1
OR1
4
4
OR1
OR1
E
R1O
O
F
R1O
O
F
D
D
OR3
OR3
OR1
OR1
(4α)-1 : R1 = R2 = R3 = H (procyanidin-B3)
(4α)-2 : R1 = Bn, R2 = R3 = H
(4α)-3 : R1 = Bn, R2 = Ac, R3 = H
(4α)-4 : R1 = Bn, R2 = R3 = Ac
(4α)-5 : R1 = R2 = R3 =Ac
(4β)-1 : R1 = R2 = R3 = H
(4β)-2 : R1 = Bn, R2 = R3 = H
(4β)-3 : R1 = Bn, R2 = Ac, R3 = H
(4β)-4 : R1 = Bn, R2 = R3 = Ac
(4β)-5 : R1 = R2 = R3 =Ac
Figure 1. Structure of procyanidin and its diastereomer derivatives.
difference is observed in the chemical shift of the C3-proton.
The C3-proton d 5.83 and d 5.80 in (4a)-4 with 3,4-trans
configuration appear at about 0.25 ppm lower than the
C3-proton d 5.53 and d 5.58 in (4b)-4 with 3,4-cis
configuration. These peaks appear in isolated regions
without interference from other peaks even if the sample
exists as a mixture. Thus, the diastereomeric ratio of (4a)-2
to (4b)-2 could be directly determined by 1H NMR
measurement of (4a)-4 and (4b)-4. The 2.1:1 ratio on
comparison of the peaks at the C3-protons perfectly agreed
with the TLC separation rate.
2.3. Condensation studies
With the simple diastereoselectivity determination method
in hand, we re-examined the condensation reaction of 4-O-
alkyl derivatives with tetra-O-benzylated catechin deriva-
tive 6 (Fig. 2) under various conditions as summarized
in Table 2. The neighboring group participation of the
3-O-acetyl moiety was effective in attaining significant
improvement in the selectivity as shown in entries 1 and 2.
Reaction conditions were first checked using 4-O-methyl
substituent 10. The used nucleophilic tetra-O-benzylated
catechin 6 was in 4.5-fold excess to avoid higher oligomer
OBn
BnO
O
OBn
OR3
OBn
6: R3 = H
7: R3 = Ac
Figure 2. Structure of protected catechins.
Table 2. Condensation studies of 4-O-alkyl derivatives and tetra-O-benzylated catechin derivative 6 in the presence of Lewis acid
Entry
Electrophile
R2
Solvent
Lewis acid
Temperature (8C)
Couplinga yield (%)
Selectivityb (4a)-4/(4b)-4
No.
R4
1
2
3
4
5
6
7
8
9
H
Me
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
TiCl4
TiCl4
TiCl4
BF3·OEt2
SnCl4
TMSOTf
BF3·OEt2
SnCl4
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
0
0
84
81
35
55
87
quant.
85
Quant.
89
Quant.
Quant.
Quant.
88
2.1:1
7.4:1
55:1
10:1
11:1
10
10
10
10
10
10
10
10
12
14
16
18
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Me
Me
Me
Me
Me
Me
Me
Me
iPr
240
278
278
278
0
0
0
278
278
278
278
32:1
4.0:1
4.4:1
7.0:1
40:1
46:1
.48:1
25:1
9
10
11
12
13
(CH2)2OH
EEc
Bn
a
Isolation yield of the dimer mixture.
Selectivities were determined by the 1H NMR of the acetylated dimer mixture.
EE represents ethoxyethyl group.
b
c

7832
A. Saito et al. / Tetrahedron 58 (2002) 7829–7837
OBn
OBn
OH
OH
BnO
O
HO
O
16
+
4
c, d, e
a
4
OAc
O
OBn
OBn
OH
O
OH
OH
OBn
BnO
OH
HO
e
6
OH
OH
OBn
OH
(4 )-3
(4 )-4
b
(4 )-1
97% d.e.
Scheme 2. Gram-scale stereoselective synthesis of procyanidin-B3. Reagents and conditions: (a) TMSOTf, CH2Cl2, 2788C, 97%; (b) Ac2O, DMAP, Py;
(c) KCN 95%–EtOH, 98%; (d) silica gel column separation .99% de; (e) H2, Pd(OH)2, THF–MeOH–H2O, 67%.
OBn
OBn
The condensation between 16 (0.68 g, 0.87 mmol) and 6
(2.55 g, 3.92 mmol) in the presence of 1.0 equiv. TMSOTf
at 2788C was carried out to afford dimerization product
(4a)-3 (1.11 g, 0.83 mmol) in 95% yield in a 66:1 ratio.
BnO
O
OR3
OBn
OR4
The acetyl group of (4a)-3 thus obtained was hydrolyzed
with 10 equiv. KCN in 95% EtOH18 (Rf value of benzylated
B3 is 0.11, and its diastereomer is 0.27 in CH2Cl2 containing
1.6% AcOEt), in which no epimerization product was
detected. The eight remaining benzyl protecting groups
were then submitted to hydrogenolysis with Pd(OH)2 and
purification in the usual way to give procyanidin-B3 1.
13 : R3 = H, R4 = (CH2)2OH
14 : R3 = Ac, R4 = (CH2)2OH
15 : R3 = H, R4 = EE
16 : R3 = Ac, R4 = EE
17 : R3 = H, R4 =Bn
8 : R3 = R4 = H
9 : R3 = H, R4 = Me
10 : R3 = Ac, R4 = Me
11 : R3 = H, R4 = iPr
12 : R3 =Ac, R4 = iPr
18 : R3 = Ac, R4 =Bn
[a]D24¼2221 (c 0.38, EtOH) {lit.7 [a]2D5¼2202 (c 1.0,
Figure 3. Structure of 4-substituted catechin derivatives.
EtOH), lit.19 [a] ¼2244.7 (c 2.0, EtOH)}.
20
578
formation. One equivalent of Lewis acid, TiCl4, BF3·OEt2,
SnCl4 and TMSOTf, was added dropwise to a solution of
4-O-alkyl derivatives (Fig. 3) and 6 in CH2Cl2 at each
temperature, and the mixture was allowed to react for 5 min.
TiCl4-catalyzed reaction of 6 and 9 at 08C provided 84%
yield of products with 2.1:1 ratio (entry 1 and Scheme 1).
The ratio of the reaction at 2408C condensation dramatic-
ally increased to 55:1; however, the isolation yield
decreased to only 35% (entry 3). When BF3·OEt2 and
SnCl2 were used as catalyst at 2788C, isolation yield
increased up to 55 and 87% with moderate 10:1 ratio
(entries 4 and 5). The best results were obtained by using
TMSOTf as catalyst; 100% yield with 32:1 selectivity was
achieved at 2788C (entry 6). No dimerization product was
detected in the reaction with Et2AlCl and Ti(Oi-Pr)4 at any
temperature. In all reactions in toluene, the benzyl catechin
6 was precipitated below 08C; therefore, the selectivities
obtained at 08C were maximum 7:1 ratio (entries 7–9)
because TMSOTf-catalyzed reaction achieved quantitative
yield with excellent selectivity, the differentiation of the
4-O-alkyl substituent, Me into iPr, (CH2)2OH, EE and Bn,
was next investigated using TMSOTf as catalyst (entries
10–13). All reactions were accomplished within 5 min. As
shown in entry 12, the best result was0 obtained from the
reac0t0ion of (2R,3S,4S)-3-acetoxy-5,7,3 ,40-tetrabenzyloxy-
4-(2 -ethoxyethoxy)flavan 16 with 6 at 2788C; quantitative
yield of product in more than 48:1 selectivity was obtained.
3. Conclusion
In conclusion, we were able to synthesize octa-O-benzyl-
ated procyanidin-B3 (4a)-3 in high diastereomeric
excess. Condensation of benzylated catechin with various
4-O-alkylated flavan-3,4-diol derivatives as an electrophile
in the presence of a Lewis acid led to protected procyanidin-
B3 and0its diastereomer. The use of (2R,3S,4S)-3-acetoxy-
5,7,30,4 -tetrabenzyloxy-4-(200-ethoxyethoxy)flavan as an
electrophile in the presence of TMSOTf afforded octa-O-
benzylated procyanidin-B3 with high levels of stereoselec-
tivity. Furthermore, we succeeded in the stereoselective
gram-scale synthesis of procyanidin-B3.
4. Experimental
All melting points (mp) are uncorrected. Optical rotation
was measured with a HORIBA SEPA-300 spectrometer. 1H
NMR spectra were measured with a JEOL JNM-LA400
spectrometer, and mass spectra were recorded with a JEOL
JMS-AX500 instrument.
4.1. A typical procedure for DDQ oxidation
4.1.1. (2S,3S,4S)-5,7,30,40-Tetrabenzyloxy-4-isopropoxy-
flavan-3-ol 11. To a solution of tetra-O-benzylated catechin
6 (200 mg, 0.31 mmol) and isopropyl alcohol (2 mL) in
CH2Cl2 (6 mL) was added slowly DDQ (2 equiv., 140 mg,
0.61 mmol) at 08C. After stirring for 8 h at rt, excess of
4-(dimethylamino)pyridine was added to the solution at 08C
and the mixture was stirred for 10 min. The resulting purple
solid was removed by filtration and the filtrate was washed
with water and brine, and dried (Na2SO4). Filtration,
2.4. Gram-scale stereoselective synthesis of (4a)-3 and its
deprotection
The condensation conditions were applied to a gram-scale
synthesis of procyanidin-B3. Gram order of electrophile 16
was synthesized from tetra-O-benzyl catechin 6, and the
reaction was carried out under the optimized conditions.

A. Saito et al. / Tetrahedron 58 (2002) 7829–7837
7833
concentration and short silica gel column chromatography
(CHCl3) gave 11 (128 mg, 0.18 mmol, 58%) as white foam:
[a]2D4¼þ55.1 (c 1.20, CHCl3); 1H NMR (400 MHz, CDCl3)
7.51–7.24 (20H, m), 7.09 (1H, d, J¼1.7 Hz), 7.01 (1H, dd,
J¼1.7, 8.3 Hz), 6.96 (1H, d, J¼8.3 Hz), 6.25 (1H, d, J¼
2.3 Hz), 6.17 (1H, d, J¼2.3 Hz), 5.17 (4H, s), 5.04 (1H, d,
J¼11.2 Hz), 5.01 (1H, d, J¼11.2 Hz), 4.98 (2H, s), 4.95
(1H, d, J¼10.2 Hz), 4.87 (1H, d, J¼3.4 Hz), 4.07 (1H,
heptet, 6.1 Hz), 3.81 (1H, ddd, J¼3.4, 10.0, 10.2 Hz), 2.96
(1H, d, J¼10.0 Hz, OH), 1.04 (6H, d, J¼6.1 Hz). FAB-MS
(m/z) 731 ([MþNa]þ, 7), 710 (6), 709 ([MþH]þ, 12), 708
(18); FAB-HRMS calcd for C46H45O7 [MþH]þ, 709.3165;
found: 709.3186.
3.45 (4H, m), 1.18 (3H, t, J¼7.1 Hz). FAB-MS (m/z) 761
([MþNa]þ, 11), 740 (4), 739 ([MþH]þ, 10), 738 (11);
FAB-HRMS calcd for C47H46O8 [MþH]þ, 739.3271;
found, 739.3268.
4.1.5. (2R,3S,4S)-4,5,7,30,40-Pentabenzyloxyflavan-3-ol
17. DDQ oxidation according to the general procedure
using 6 (500 mg, 0.78 mmol), DDQ (350 mg, 1.54 mmol)
and benzyl alcohol (0.8 mL) in CH2Cl2 (20 mL) for 12 h
afforded 568 mg (86%) of 17 as a colorless prism: mp
1
124.0–125.58C; [a]D24¼þ56.4 (c 0.48, CHCl3); H NMR
(400 MHz, CDCl3) 7.45–7.18 (25H, m), 7.07 (1H, d, J¼
2.0 Hz), 6.99 (1H, dd, J¼2.0, 8.3 Hz), 6.94 (1H, d, J¼
8.3 Hz), 6.28 (1H, d, J¼2.2 Hz), 6.18 (1H, d, J¼2.2 Hz),
5.13 (4H, s), 5.05 (1H, d, J¼11.2 Hz), 5.01 (1H, d, J¼
11.2 Hz), 5.00 (1H, d, J¼9.7 Hz), 4.98 (2H, s), 4.96 (1H, d,
J¼3.4 Hz), 4.78 (1H, d, J¼11.5 Hz), 4.66 (1H, d, J¼
11.5 Hz), 3.90 (1H, dt, J¼3.4, 9.7 Hz), 2.35 (1H, d, J¼
9.7 Hz); FAB-MS (m/z) 780 (11), 779 ([MþNa]þ, 16), 758
(10), 757 ([MþH]þ, 26), 756 (38); FAB-HRMS calcd for
C50H45O7 [MþH]þ, 757.3165; found: 757.3151.
4.1.2. (2R,3S,4S)-5,7,30,40-Tetrabenzyloxy-4-(200-hydroxy-
ethyloxy)flavan-3-ol 13. DDQ oxidation according to the
general procedure using 6 (300 mg, 0.46 mmol), DDQ
(209 mg, 0.92 mmol) and ethylene glycol (1 mL) in CH2Cl2
(8 mL) for 6 h afforded 260 mg (75%) of 11 as a white
1
foam: [a]2D4¼þ28.3 (c 0.38, CHCl3); H NMR (400 MHz,
CDCl3) 7.45–7.26 (20H, m), 7.08 (1H, d, J¼1.7 Hz), 7.00
(1H, dd, J¼1.7, 8.3 Hz), 6.93 (1H, d, J¼8.3 Hz), 6.26 (1H,
d, J¼2.2 Hz), 6.15 (1H, d, J¼2.2 Hz), 5.17 (1H, d, J¼
12.2 Hz), 5.14 (2H, s), 5.13 (1H, d, J¼12.2 Hz), 5.07 (1H, d,
J¼11.5 Hz), 5.02 (1H, d, J¼11.5 Hz), 4.97 (2H, s), 4.95
(1H, d, J¼12.0 Hz), 4.80 (1H, d, J¼3.4 Hz), 3.90–3.86 (2H,
m), 3.76 (1H, ddd, J¼3.7, 6.6, 15.1 Hz), 3.65–3.60 (2H, m),
2.96 (1H, br, OH), 2.74 (1H, br, OH); FABMS (m/z) 733
([MþNa]þ, 31), 712 (5), 711 ([MþNa]þ, 12), 710 (21),
FAB-HRMS calcd for C45H43O8 [MþH]þ, 711.2958;
found, 711.2943.
4.2. Condensation reaction and diastereoselectivity
determination
4.2.1. (2R,3S,4S)-3-Acetoxy-5,7,30,40-tetrabenzyloxy-4-
isopropoxyflavan 12. To a solution of 11 (45 mg,
0.063 mmol) in dry pyridine (1 mL) was added Ac2O
(45 mL, 0.126 mmol) and 4-(dimethylamino)pyridine
(1 mg) at 08C. After stirring for 12 h at rt, the reaction
mixture was quenched with water, and extracted with ethyl
acetate. The organic phase was washed with water and
brine, and dried (Na2SO4). Filtration, concentration and
short silica gel column chromatography (hexane/EtOAc)
gave each 3-acetyl-tetra-benzyl catechin 12 (45 mg,
0.061 mmol, 97%) as a white foam: [a]2D1¼þ57.1 (c 0.44,
CHCl3); 1H NMR (400 MHz, CDCl3) 7.46–7.23 (20H, m),
7.05 (1H, d, J¼1.7 Hz), 6.97 (1H, dd, J¼1.7, 8.3 Hz), 6.91
(1H, d, J¼8.3 Hz), 6.21 (1H, d, J¼2.2 Hz), 6.13 (1H, d,
J¼2.2 Hz), 5.30 (1H, J¼10.7 Hz), 5.19 (1H, dd, J¼2.9,
10.7 Hz), 5.15 (2H, s), 5.14 (2H, s), 5.04 (1H, d, J¼
11.9 Hz), 5.00 (1H, d, J¼11.9 Hz), 4.98 (1H, d, J¼11.7 Hz),
4.94 (1H, d, J¼11.7 Hz), 4.90 (1H, d, J¼2.9 Hz), 3.84 (1H,
heptet, J¼6.3 Hz), 1.75 (3H, s), 1.10 (3H, d, J¼6.3 Hz),
1.03 (3H, d, J¼6.3 Hz); FAB-MS (m/z) 774 (12), 773
([MþNa]þ, 24), 752 (13), 751 ([MþH]þ, 31), 750 (35);
FAB-HRMS calcd for C48H47O8 [MþH]þ, 751.3271;
found: 751.3267.
4.1.3. (2S,3S,4S)-3-Acetoxy-5,7,30,40-tetrabenzyloxy-4-
(200-hydroxyethyloxy)flavan 14. DDQ oxidation according
to the general procedure using 7 (339 mg, 0.49 mmol), DDQ
(222 mg, 0.98 mmol) and ethylene glycol (1 mL) in CH2Cl2
(10 mL) for 12 h afforded 258 mg (70%) of 14 as a white
1
foam: [a]2D4¼þ45.4 (c 0.56, CHCl3); H NMR (400 MHz,
CDCl3) 7.47–7.28 (20H, m), 7.05 (1H, d, J¼2.0 Hz), 6.97
(1H, dd, J¼2.0, 8.3 Hz), 6.92 (1H, d, J¼8.3 Hz), 6.26 (1H,
d, J¼2.2 Hz), 6.15 (1H, d, J¼2.2 Hz), 5.27 (1H, dd, J¼3.2,
10.7 Hz), 5.20 (1H, d, J¼10.7 Hz), 5.16 (2H, s), 5.15 (2H,
s), 5.07 (1H, d, J¼11.5 Hz), 5.02 (1H, d, J¼11.5 Hz), 4.99
(1H, d, J¼11.7 Hz), 4.96 (1H, d, J¼11.7 Hz), 4.83 (1H, d,
J¼3.2 Hz), 3.79–3.71 (2H, m), 3.60 (2H, br), 2.33 (1H, br,
OH), 1.79 (3H, s); FAB-MS (m/z) 775 ([MþNa]þ, 8), 754
(4), 753 ([MþH]þ, 8), 752 (12); FAB-HRMS calcd for
C47H45O9 [MþH]þ, 753.3064; found, 753.3062.
4.1.4. (2R,3S,4S)-5,7,30,40-Tetrabenzyloxy-4-(200-ethoxy-
ethoxy)flavan-3-ol 15. DDQ oxidation according to the
general procedure using 6 (500 mg, 0.78 mmol), DDQ
(350 mg, 1.54 mmol) and 2-ethoxyethanol (1.5 mL) in
CH2Cl2 (15 mL) for 2 h afforded 15 as a pale yellow
solid, which was crystallized from hexane/EtOAc to give
560 mg (98%) of 15 as colorless needles: mp 144.5–
145.08C; [a]2D3¼þ29.5 (c 1.60, CHCl3); 1H NMR
(400 MHz, CDCl3) 7.47–7.27 (20H, m), 7.11 (1H, d,
J¼2.0 Hz), 7.00 (1H, dd, J¼2.0, 8.3 Hz), 6.96 (1H, d,
J¼8.3 Hz), 6.26 (1H, d, J¼2.2 Hz), 6.15 (1H, d, J¼2.2 Hz),
5.16 (4H, s), 5.08 (1H, d, J¼11.4 Hz), 5.03 (1H, d, J¼
11.4 Hz), 4.98 (2H, s), 4.89 (1H, d, J¼10.5 Hz), 4.77 (1H, d,
J¼3.4 Hz), 4.13 (1H, brs, OH), 3.96–3.83 (3H, m), 3.56–
4.2.2. (2S,3S,4S)-3-Acetoxy-5,7,30,40-tetrabenzyloxy-4-
(200-ethoxyethoxy)flavan 16. Acetylation using 15
(300 mg, 0.41 mmol), Ac2O (45 mL, 0.126 mmol) and
4-(dimethylamino)pyridine (1 mg) in CH2Cl2 (15 mL)
afforded 310 mg (98%) of 16 as a white foam: [a]2D0¼
þ64.1 (c 0.22, CHCl3); 1H NMR (400 MHz, CDCl3) 7.46–
7.27 (20H, m), 7.06 (1H, d, J¼1.7 Hz), 6.96 (1H, dd, J¼1.7,
8.3 Hz), 6.92 (1H, d, J¼8.3 Hz), 6.24 (1H, d, J¼2.2 Hz),
6.14 (1H, d, J¼2.2 Hz), 5.26 (1H, d, J¼10.7 Hz), 5.21 (1H,
dd, J¼2.9, 10.7 Hz), 5.16 (2H, s), 5.14 (2H, s), 5.05 (1H, d,
J¼11.5 Hz), 5.01 (1H, d, J¼11.5 Hz), 4.99 (1H, d, J¼
11.7 Hz), 4.96 (1H, d, J¼11.7 Hz), 4.87 (1H, d, J¼2.9 Hz),
3.82–3.71 (2H, m), 3.48–3.36 (4H, m), 1.97 (3H, s), 1.14
(3H, t, J¼7.0 Hz); FAB-MS (m/z) 804 (10), 803 ([MþNa]þ,

7834
A. Saito et al. / Tetrahedron 58 (2002) 7829–7837
19), 782 (5), 781 ([MþH]þ, 11), 780 (14); FAB-HRMS
16.3 Hz, 4Fb), 1.70–1.30 (0.68H, m, br, OH); 13C NMR
(100 MHz, CDCl3, 2:1 mixture of rotational isomers) major
isomer: 157.9, 157.7, 156.9, 155.50, 155.46, 153.8, 149.2,
149.0, 148.9, 148.5, 137.3, 137.2 (£2), 137.14, 137.09 (£2),
137.0, 136.6, 131.8, 130.6, 128.6, 128.51, 128.47, 128.40
(£4), 128.37 (£2), 128.34, 128.26, 128.1, 127.9, 127.8,
127.70, 127.60, 127.5, 127.45 (£2), 127.43, 127.2 (£2),
127.1 (£2), 121.2, 120.0, 114.8, 114.7, 113.6, 113.5, 111.9,
108.6, 102.4, 94.8, 94.1, 91.7, 82.0, 80.6, 76.6, 73.2, 71.2
(£2), 71.1 (£2), 70.3, 70.0, 69.9, 68.5, 37.2, 28.0; minor
isomer: 157.9, 157.5, 156.8, 155.4 (£2), 152.8, 149.2, 149.0,
148.9, 148.7, 137.6, 137.3, 137.2, 137.14, 137.09 (£2),
137.0, 136.9, 131.9, 130.5, 128.50, 128.40 (£2), 128.37,
128.35, 128.27, 128.0, 127.9, 127.8, 127.75 (£2), 127.70,
127.66, 127.60, 127.5 (£2), 127.22, 127.18 (£2), 127.1
(£3), 127.0, 126.9, 120.7, 120.6, 115.0, 114.4, 114.0, 113.7,
112.0, 108.4, 103.2, 94.8, 94.1, 91.7, 81.7, 81.2, 77.2, 73.3,
71.2, 71.1, 71.0, 70.9, 69.83, 69.79, 69.78, 68.3, 372, 28.1.
Data for (4b)-2: Rf 0.27 (CH2Cl2 containing 1.6% AcOEt);
[a]D24¼þ96.5 (c 0.20, CHCl3) {lit.12 [a]3D0¼þ106.8 (c 1.4,
calcd for C49H49O9 [MþH]þ, 781.3377; found: 781.3391.
4.2.3. (2S,3S,4S)-3-Acetoxy-4,5,7,30,40-pentabenzyloxy-
flavan 18. Acetylation using 17 (22 mg, 0.029 mmol),
Ac2O (14 mL, 0.126 mmol) and 4-(dimethylamino)pyridine
(1 mg) in CH2Cl2 (1 mL) afforded 23 mg (100%) of 18 as a
1
colorless foam: [a]D24¼þ74.1 (c 0.28, CHCl3); H NMR
(400 MHz, CDCl3) 7.46–7.20 (25H, m), 7.07 (1H, d, J¼
2.0 Hz), 6.98 (1H, dd, J¼2.0, 8.3 Hz), 6.92 (1H, d, J¼
8.3 Hz), 6.26 (1H, d, J¼2.2 Hz), 6.15 (1H, d, J¼2.2 Hz),
5.32 (1H, d, J¼10.7 Hz), 5.24 (1H, dd, J¼3.2, 10.7 Hz),
5.16 (2H, s), 5.15 (2H, s), 5.05 (1H, d, J¼11.2 Hz), 5.01
(1H, d, J¼11.2 Hz), 5.02–5.00 (1H, m), 5.00 (1H, d, J¼
11.7 Hz), 4.97 (1H, d, J¼11.7 Hz), 4.66 (2H, s), 1.72 (3H,
s). FAB-MS (m/z) 822 (15), 821 ([MþNa]þ, 25), 800 (14),
799 ([MþH]þ, 37), 798 (42); FAB-HRMS calcd for
C52H47O8 [MþH]þ, 799.3271; found: 799.3286.
4.2.4. [4,8]-2,3-trans-3,4-cis:2,3-trans-Octa-O-benzyl-bi-
(1)-catechin and [4,8]-2,3-trans-3,4-trans:2,3-trans-
octa-O-benzyl-bi-(1)-catechin (Scheme 1). (4a)-2 and
its diastereomer (4b)-2. To a solution of tetra-O-benzyl-
ated catechin 6 (323 mg, 0.50 mmol, 4.5 equiv.) and
(2R,3S,4S)-5,7,30,40-tetrabenzyloxy-4-methoxyflavan-3-ol
9 (75 mg, 0.11 mmol) in CH2Cl2 (20 mL) was added
dropwise TiCl4 at 08C. After stirring for 5 min, the reaction
mixture was quenched with sat. sodium hydrogen carbonate.
The aqueous solution was extracted with CHCl3 and the
organic phase was washed with water and brine, and dried
(Na2SO4). Filtration, concentration and silica gel column
chromatography (hexane/ethyl acetate, 6/1–1.5/1) afforded
a mixture of octabenzylated procyanidin-B3 (4a)-2 and its
diastereomer (4b)-2 (120 mg, 84%). Sixty-nine milligrams
(0.053 mmol) of the dimer mixture was separated on
preparative silica gel thin-layer chromatography (Merck
1.0 mm, CHCl3/AcOEt, 60/1, 3 times development) to give
pure 40 mg of (4a)-2 as a white foam and 20 mg of its
diastereomer (4b)-2 as a white foam. Data for (4a)-2: Rf
0.11 (CH2Cl2 containing 1.6% AcOEt); [a]2D6¼2106 (c
0.80, CHCl3) {lit.12 [a]D30¼2102.9 (c 1.9, CHCl3)}; 1H
NMR (400 MHz, CDCl3, 2:1 mixture of rotational isomers)
major isomer: 7.46–7.48 (22.44, m, Bn), 7.15–7.11 (1.32H,
m, Bn), 7.01–6.97 (1.32H, m, 20£2), 6.93–6.81 (4.62H, m,
4Bn, 50, 50, 60), 6.78 (0.66H, dd, J¼2.0, 8.3 Hz, 60), 6.23
(0.66H, s, 6D), 6.17 (0.66H, d, J¼2.4 Hz, 8A), 6.09 (0.66H,
d, J¼2.4 Hz, 6A), 5.20–4.86 (7.92H, m, Bn), 4.83–4.79
(1.32H, m, Bn), 4.72–4.63 (0.66H, m, Bn), 4.66 (0.66H,
d, J¼8.8 Hz, 2C), 4.53 (0.66H, d, J¼10.7 Hz, Bn), 4.49
(0.66H, d, J¼9.8 Hz, 4C), 4.28 (0.66H, dd, J¼8.8, 9.8 Hz,
3C), 3.67–3.61 (0.66H, m, 3F), 3.58 (0.66H, d, J¼8.8 Hz,
2F), 3.04 (0.66H, dd, J¼5.8, 16.3 Hz, 4Fa), 2.37 (0.66H, dd,
J¼9.2, 16.3 Hz, 4Fb), 1.70–1.30 (1.32H, m, br, OH); minor
isomer: 7.46–7.48 (11.9H, m, Bn), 7.150–7.11 (0.68H, m,
Bn), 6.93–60.81 (2.04H, m, 3Bn, 20, 50, 6 ), 06.70 (0.34H, d,
J¼8.3 Hz, 5 ), 6.59 (0.34H, d, J¼2.0 Hz, 2 ), 6.43 (0.34H,
dd, J¼2.0, 8.3 Hz, 60), 6.19 (0.34H, d, J¼2.4 Hz, 8A), 6.08
(0.34H, s, 6D), 6.00 (0.34H, d, J¼2.4 Hz, 6A), 5.20–4.86
(4.08H, m, Bn), 4.83–4.79 (0.68H, m, Bn), 4.77 (0.34H, d,
J¼8.2 Hz, 2C), 4.72–4.63 (0.68H, m, Bn), 4.49 (0.34H, d,
J¼9.8 Hz, 4C), 4.45 (0.34H, d, J¼8.2 Hz, 2F), 4.14 (0.34H,
dd, J¼8.2, 9.8 Hz, 3C), 3.67–3.61 (0.34H, m, 3F), 3.16
(0.34H, dd, J¼5.8, 16.3 Hz, 4Fa), 2.64 (0.34H, dd, J¼9.5,
1
CHCl3)}; H NMR (400 MHz, CDCl3, 2.5:1 mixture of
rotational isomers) major isomer0: 7.49–7.15 (25.56H, m,
Bn),7.25 (0.71H, d, J¼1.7 Hz, 2 ), 7.10–7.05 (1.42H, m,
Bn), 7.03 (0.71H, dd, J¼1.7, 8.3 Hz, 60), 6.98–6.97 (1.42H,
m, Bn), 6.92 (0.71H, d, J¼8.3 Hz, 50), 6.86 (0.71H, d,
J¼1.7 Hz, 20), 6.82 (0.71H, d, J¼8.3 Hz, 50), 6.57 (0.71H,
dd, J¼1.7, 8.3 Hz, 60), 6.36 (0.71H, s, 6D), 6.05 (0.71H, d,
J¼2.2 Hz, 8A), 5.44 (0.71H, d, J¼2.2 Hz, 6A), 5.13 (0.71H,
d, J¼9.5 Hz, 2C), 5.12–4.79 (9.94H, m, Bn), 5.07 (0.71H,
d, J¼6.1 Hz, 4C), 4.61 (0.71H, d, J¼11.4 Hz, Bn), 4.50
(0.71H, d, J¼11.4 Hz, Bn), 4.21 (0.71H, dd, J¼6.1, 9.5 Hz,
3C), 3.86 (0.71H, ddd, J¼6.6, 9.0, 9.6 Hz, 3F), 3.72 (0.71H,
d, J¼9.0 Hz, 2F), 3.28 (0.71H, dd, J¼6.6, 16.8 Hz, 4Fa),
2.74 (0.71H, brs, OH), 2.65 (0.71H, dd, J¼9.6, 16.8 Hz,
4Fb), 1.55 (0.71H, br, OH); minor isomer: 7.49–7.15
(10.73H, m, 0Bn), 7.10–7.05 (0.87H, m, Bn),06.97 (0.29H, d,
J¼1.7 Hz, 2 ), 6.94 (0.29H, d, J¼8.0 Hz, 5 ), 6.90 (0.29H,
dd, J¼1.7, 8.0 Hz, 60), 6.85 (0.29H, d, J¼1.7 Hz, 20), 6.80
(0.29H, d, J¼8.0 Hz, 50), 6.76 (0.29H, dd, J¼1.7, 8.0 Hz,
60), 6.23 (0.29H, d, J¼2.1 Hz, 8A), 6.24 (0.29H, s, 6D), 6.03
(0.29H, d, J¼2.1 Hz, 6A), 5.12–4.79 (4.06H, m, Bn), 5.07
(0.29H, d, J¼8.7 Hz, 2C), 4.94 (0.29H, d, J¼6.9 Hz, 4C),
4.75 (0.29H, d, J¼12.2 Hz, Bn), 4.55 (0.29H, d, J¼8.5 Hz,
2F), 4.46 (0.29H, d, J¼12.2 Hz, Bn), 4.16 (0.29H, dd,
J¼6.9, 8.7 Hz, 3C), 3.54 (0.29H, ddd, J¼5.6, 8.5, 9.6 Hz,
3F), 3.17 (0.29H, dd, J¼5.6, 16.4 Hz, 4Fa), 2.66 (0.29H, dd,
J¼9.6, 16.4 Hz, 4Fb), 2.48 (0.29H, brs, OH), 1.55 (0.29H,
br, OH); 13C NMR (100 MHz, CDCl3, 2.5:1 mixture of
rotational isomers) major isomer: 158.4, 156.7, 156.2 (£2),
155.9, 153.5, 149.3, 149.22, 149.16, 148.9, 135.5, 137.3,
137.2 (£2), 137.0 (£3), 136.7, 132.9, 130.4, 128.6 (£2),
128.41 (£2), 128.38, 128.35 (£2), 128.33, 128.1, 128.0
(£2), 127.74, 127.71, 127.65, 127.5 (£4), 127.4, 127.3,
127.22, 127.19, 127.15, 127.05, 121.0, 120.4, 114.6, 114.2,
114.0, 112.4, 109.2, 105.4, 105.2, 93.3, 92.5, 91.7, 82.0
(£2), 77.7, 77.2, 72.0, 71.3, 71.2, 70.4, 69.9, 69.6, 69.4,
68.7, 33.4, 29.1; minor isomer: 158.5, 157.21, 157.16,
156.0, 155.6, 153.5, 149.4, 149.3, 149.1, 148.9, 137.4, 137.3
(£2), 137.2, 137.1 (£3), 136.8, 132.6, 120.7, 128.6 (£2),
128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.93, 127.90,
127.8, 127.69 (£3), 127.53, 127.47 (£2), 127.4, 127.3,
127.22, 127.19 (£2), 127.15, 127.1, 120.7, 120.5, 114.9,
114.5, 114.1, 113.0, 109.0, 105.8, 102.7, 94.3, 93.0 (£2),

A. Saito et al. / Tetrahedron 58 (2002) 7829–7837
7835
82.1, 81.5, 77.8, 76.8, 71.3 (£2), 71.2, 71.1, 70.8, 69.9, 69.8,
ddd, J¼5.6, 7.8, 9.1, 10.0 Hz, 3Fb), 5.09–4.91 (8.5H, m,
Bn), 4.98 (0.5H, d, J¼9.1 Hz, 3Fb), 4.91 (0.5H, d, J¼
9.1 Hz, 2b), 4.83–4.77 (1H, m, Bn), 4.82 (0.5H, ddd, J¼3.7,
8.8, 9.0 Hz, 3Fa), 4.74–4.68 (1H, m, Bn), 4.67–4.61 (1H,
m, Bn), 4.644 (0.5H, d, J¼10.0 Hz, 4Ca), 4.638 (0.5H, d,
J¼10.0 Hz, 4Cb), 4.57–4.51 (1H, m, Bn), 3.63 (0.5H, d,
J¼8.8 Hz, 2Fa), 3.01 (0.5H, dd, J¼3.7, 16.4 Hz, 4Faa),
2.98 (0.5H, dd, J¼5.6, 16.6 Hz, 4Fba), 2.70 (0.5H, dd,
J¼7.8, 16.6 Hz, 4Fbb), 2.38 (0.5H, dd, J¼9.0, 16.4 Hz,
4Fab),1.83 (1.5H, s, CH3), 1.75 (1.5H, s, CH3), 1.57 (1.5H,
s, CH3), 1.53 (1.5H, s, CH3); 13C NMR (100 MHz, CDCl3,
1(a):1(b) mixture of rotational isomers) 170.2, 169.6, 169.1,
169.0, 158.2, 158.1, 157.7, 157.6, 156.9, 156.7, 156.6,
156.0, 155.5, 155.4, 153.6, 152.8, 149.0, 148.93, 148.90,
148.87, 148.78 (£2), 148.6, 148.5, 138.0, 137.4, 137.30
(£2), 137.27 (£3), 137.25 (£3), 137.19, 137.17, 137.03,
136.96, 136.90, 136.76, 131.7, 131.10, 131.05, 130.8,
128.60, 128.56 (£2), 128.54, 128.50, 128.43 (£4), 128.38
(£7), 128.33, 128.29, 128.15, 128.12 (£2), 127.96, 127.91
(£3), 127.80, 127.77 (£2), 127.73, 127.71, 127.69, 127.63
(£3), 127.5 (£3), 127.44, 127.41 (£2), 127.30 (£4), 127.26
(£2), 127.0, 126.8, 121.2, 120.9, 120.3, 120.2, 114.72,
114.69, 114.60, 114.2 (£2), 114.0, 113.9, 113.6, 110.9,
110.7, 108.3, 108.1, 102.1, 101.5, 94.8 (£2), 94.5, 94.3,
91.3, 90.9, 80.1, 79.9, 77.9, 77.6, 77.2 (£2), 73.0, 72.8, 71.5,
71.4, 71.3, 71.2 (£3), 71.1, 71.0, 70.3, 70.0 (£3), 69.9, 69.8
(£2), 69.6, 35.1, 29.7, 26.4, 25.1, 20.9, 20.8, 20.7, 20.5.
68.2, 32.5, 28.0.
4.2.5. [4,8]-2,3-trans-3,4-cis:2,3-trans-Octa-O-benzyl-3-
O-acetyl-bi-(1)-catechin and [4,8]-2,3-trans-3,4-
trans:2,3-trans-octa-O-benzyl-3-O-acetyl-bi-(1)-catechin
(Scheme 2). (4a)-3 and its diastereomer (4b)-3. To a
solution of tetra-O-benzylated catechin
6
(2.505 g,
3.92 mmol, 4.5 equiv.) and (2S,3S,4S)-3-acetoxy-5,7,3 ,40-
tetrabenzyloxy-4-(200-ethoxy-ethoxy)flavan 16 (0.68 g,
0.87 mmol) in CH2Cl2 (160 mL) was added dropwise
TMSOTf (1.74 mL, 0.87 mmol, 0.5 M solution in CH2Cl2)
at 2788C. After stirring for 5 min, the pale yellow reaction
mixture was quenched with sat. sodium hydrogen carbonate.
The aq. solution was extracted with CHCl3 and the organic
phase was washed with water and brine, and dried
(Na2SO4). Filtration, concentration and silica gel column
chromatography (hexane/EtOAc, 6/1–1.5/1) afforded a
1.11 g (95%) of a mixture of (4a)-3 and its diastereomer
(4b)-3. A part of the reaction mixture (10 mg) was
acetylated in pyridine (1 mL), acetic anhydride (4 mL,
0.043 mmol), 4-(dimethylamino)pyridine (0.5 mg) to
afford a 10 mg (97%) of (4a)-4 and (4b)-4 mixture. The
stereoselectivity of the condensation reaction was deter-
mined by 1H NMR as 66:1 ratio. Data for (4a)-3: 1H NMR
(400 MHz, CDCl3, 1:1 mixture of rotational isomers) 7.49–
6.37 (46H, m), 6.22 (0.5H, s), 6.19 (0.5H, d, J¼2.2 Hz),
6.16 (0.5H, d, J¼2.4 Hz), 6.10 (0.5H, d, J¼2.2 Hz), 6.07
(0.5H, d, J¼2.4 Hz), 5.95 (0.5H, t, J¼9.8 Hz), 5.94 (0.5H,
s), 5.82 (0.5H, t, J¼9.5 Hz), 4.91 (0.5H, d, J¼9.8 Hz), 4.78
(0.5H, d, J¼9.5 Hz), 4.70 (0.5H, d, J¼9.8 Hz), 4.62 (0.5H,
d, J¼9.5 Hz), 5.35–4.52 (16.5H, m), 3.90 (0.5H, m), 3.53
(0.5H, dd, J¼5.1, 9.0 Hz), 3.29 (0.5H, d, J¼9.0 Hz), 3.01
(0.5H, dd, J¼5.9, 16.1 Hz), 2.82 (0.5H, dd, J¼5.1, 16.3 Hz),
2.69 (0.5H, dd, J¼7.1, 16.3 Hz), 2.31 (0.5H, dd, J¼9.8,
16.1 Hz), 2.16 (0.5H, br), 1.59 (1.5H, s), 1.50 (1.5H, s), 1.30
(0.5H, br); FAB-MS (m/z): 1365 (7), 1364 ([MþNa]þ, 9),
1344 (6), 1343 ([MþH]þ, 10), 1342 (11).
4.2.7. [4,8]-2,3-trans-3,4-cis:2,3-trans-Octa-O-benzyl-
3,30-di-O-acetyl-bi-(1)-catechin. (4b)-4. Acetylation
according to the above procedure using 22 mg of (4b)-2
(0.017 mmol) in pyridine (4 mL), acetic anhydride (16 mL,
0.17 mmol), 4-(dimethylamino)pyridine (0.5 mg) afforded
23 mg (98%) of the (4b)-4 as a colorless amorphous;
[a]2D7¼þ110 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3,
2:1 mixture of rotational isomers) major isomer: 7.46–7.19
(22.44H, m, Bn), 7.18–7.01 (3.96H, m, Bn), 6.94 (0.66H,
dd, J¼1.9, 8.3 Hz, 60), 6.92 (0.66H, d, J¼1.9 Hz, 20), 6.84
(0.66H, d, J¼8.3 Hz, 50), 6.83 (0.66H, dd, J¼1.7 Hz, 20),
6.78 (0.66H, d, J¼8.3 Hz, 50), 6.56 (0.66H, dd, J¼1.7,
8.3 Hz, 60), 6.28 (0.66H, s, 6D), 6.03 (0.66H, dd, J¼2.2 Hz,
8A), 5.58 (0.66H, dd, J¼6.4, 10.0 Hz, 3C), 5.46 (0.66H, d,
J¼2.2 Hz, 6A), 5.39 (0.66H, d, J¼10.0 Hz, 2C), 5.16
(0.66H, d, J¼6.4 Hz, 4C), 5.14 (0.66H, ddd, J¼6.6, 8.6,
8.8 Hz, 3F), 5.12–4.82 (6.60H, m, Bn), 4.81 (0.66H, d,
J¼11.9 Hz, Bn), 4.80 (1.32H, s, Bn), 4.74 (0.66H, d, J¼
11.9 Hz, Bn), 4.62 (0.66H, d, J¼11.2 Hz, Bn), 4.54 (0.66H,
d, J¼11.2 Hz, Bn), 3.47 (0.66H, d, J¼8.8 Hz, 2F), 3.23
(0.66H, dd, J¼6.6, 16.9 Hz, 4Fa), 2.96 (0.66H, dd, J¼8.6,
16.9 Hz, 4Fb), 1.74 (1.98H, s, CH3), 1.59 (1.98H, s, CH3);
minor isomer: 7.46–7.19 (11.56H, m, Bn), 7.18–7.01
(2.04H, m, Bn), 6.910 (0.34H, d, J¼1.9 Hz, 20), 6.91
(0.34H, d, J¼8.1 Hz, 5 ), 6.90 (0.34H, dd, J¼1.9, 8.1 Hz,
60), 6.81 (0.34H, d, J¼1.7 Hz, 20), 6.76 (0.34H, dd, J¼1.7,
8.5 Hz, 60), 6.58 (0.34H, d, J¼8.5 Hz, 50), 6.22 (0.34H, s,
6D), 6.12 (0.34H, d, J¼2.2 Hz, 8A), 5.96 (0.34H, d, J¼
2.2 Hz, 6A), 5.53 (0.34H, dd, J¼6.3, 10.0 Hz, 3C), 5.34
(0.34H, d, J¼10.0 Hz, 2B), 5.12 (0.34H, d, J¼6.3 Hz, 4C),
5.12–4.82 (4.76H, m, Bn), 5.03 (0.34H, ddd, J¼5.3, 6.6,
10.0 Hz, 3F), 4.88 (0.34H, d, J¼10.0 Hz, 2F), 4.71 (0.34H,
d, J¼12.2 Hz, Bn), 4.36 (0.34H, d, J¼12.2 Hz, Bn), 2.93
(0.34H, dd, J¼5.3, 16.8 Hz, 4Fa), 2.76 (0.34H, dd, J¼6.6,
16.8 Hz, 4Fb), 1.92 (1.02H, s, CH3), 1.67 (1.02H, s, CH3);
4.2.6. [4,8]-2,3-trans-3,4-trans:2,3-trans-Octa-O-benzyl-
3,30-di-O-acetyl-bi-(1)-catechin. (4a)-4. To a solution of
(4a)-2 (43 mg, 0.033 mmol) in dry pyridine (2 mL) was
added Ac2O (7.3 mL, 0.066 mmol) and 4-(dimethylamino)-
pyridine (1 mg) at 08C. After stirring for 12 h at rt, the
reaction mixture was quenched with water, and extracted
with ethyl acetate. The organic phase was washed with
water and brine, and dried (Na2SO4). Filtration, concen-
tration and short silica gel column chromatography
(hexane/EtOAc, 5/1) gave (4a)-4 (45 mg, 99%) as a
colorless amorphous; [a]2D7¼299.6 (c 0.46, CHCl3); 1H
NMR (400 MHz, CDCl3, 1(a):1(b) mixture of rotational
isomers) 7.54–7.18 (37H, m, Bn), 7.15–7.12 (1.5H, m, Bn),
6.94–6.92 (1.5H, m, Bn)0, 6.90 (0.5H, d, J¼1.9 Hz, 200a),
6.89 (0.5H, d, J¼1.9 Hz, 20b), 6.88 (0.5H, d, J¼8.5 Hz, 50b),
6.83 (0.5H, d, J¼8.5 Hz, 50a), 6.82 (0.5H, d, J¼1.8 Hz, 2 b),
6.79 (0.5H, d, J¼9.1 Hz, 5 b), 6.77–6.73 (1.5H, m, 60b, 60a,
600b), 6.71 (0.5H, d, J¼2.0 Hz, 20a), 6.59 (0.5H, d, J¼8.5 Hz,
5 a), 6.38 (0.5H, dd, J¼2.0, 8.5 Hz, 60a), 6.22 (0.5H, s, 6D),
6.19 (0.5H, d, J¼2.2 Hz, 8A), 6.15 (0.5H, d, J¼2.4 Hz, 8A),
6.10 (0.5H, d, J¼2.4 Hz, 6A), 6.01 (0.5H, d, J¼2.2 Hz, 6A),
5.97 (0.5H, s, 6D), 5.83 (0.5H, dd, J¼9.1, 10.0 Hz, 3Ca),
5.80 (0.5H, dd, J¼9.1, 10.0 Hz, 3Cb), 5.83 (0.5H, dd,
J¼9.1, 10.0 Hz, 3Ca), 5.16–5.07 (3.5H, m, Bn), 5.10 (0.5H,

7836
A. Saito et al. / Tetrahedron 58 (2002) 7829–7837
13C NMR (100 MHz, CDCl3, 2:1 mixture of rotational
isomers) major isomer: 169.9, 169.4, 158.4, 157.5, 156.2,
155.9, 155.8, 154.5, 149.0, 148.9 (£2), 148.5, 137.4, 137.3,
137.2 (£2), 137.1, 137.0 (£3), 131.9, 130.8, 128.7, 128.43
(£4), 128.38 (£3), 128.2, 128.1, 127.7 (£2), 127.6, 127.51
(£2), 127.47 (£2), 127.31 (£3), 127.29 (£3), 127.0, 121.2,
120.1, 114.8, 114.2, 114.0, 112.6, 110.0, 105.3, 103.8, 93.5,
92.8, 91.9, 79.3, 77.4, 77.3, 75.8, 71.6, 71.3, 71.2, 70.5,
70.0, 69.9, 69.7, 69.4, 31.1, 26.8, 20.8 (£2); minor isomer:
170.1, 169.2, 158.5, 157.6, 156.9, 156.0, 155.9, 153.4,
149.2, 148.9, 148.8, 148.6, 137.5, 137.4, 137.3 (£2), 137.2
(£2), 137.1, 137.0, 131.8, 131.1, 128.6, 128.5, 128.42 (£2),
128.38 (£2), 128.35, 128.3, 128.05, 128.00, 127.9, 127.8,
127.7, 127.6, 127.51 (£2), 127.47, 127.31, 127.29 (£2),
127.25, 127.19, 127.0, 126.6, 121.1, 119.5, 114.8 (£2),
114.2, 113.3, 109.4, 105.8, 101.2, 94.2, 93.2, 92.1, 78.5,
77.6, 76.9, 75.9, 71.6, 71.2, 71.0, 70.3, 69.9, 69.8, 69.5,
69.3, 29.7, 24.1, 21.1, 20.7.
8.50–7.49 (3H, br, OH), 8.08 (2H, br, OH), 7.91 (2H, brs,
OH), 7.49 (1H, brs, OH), 6.95 (0.5H, d, J¼1.7 Hz), 6.94
(0.5H, d, J¼1.7 Hz), 6.83 (0.5H, dd, J¼1.7, 8.3 Hz), 6.79
(0.5H, dd, J¼1.7, 8.3 Hz), 6.74 (0.5H, d, J¼8.3 Hz), 6.72
(0.5H, d, J¼8.3 Hz), 6.72 (0.5H, d, J¼2.0 Hz), 6.64 (0.5H,
d, J¼8.0 Hz), 6.62 (0.5H, d, J¼8.0 Hz), 6.59 (0.5H, d,
J¼2.0 Hz), 6.45 (0.5H, dd, J¼2.0, 8.0 Hz), 6.23 (0.5H, dd,
J¼2.0, 8.0 Hz), 6.13 (0.5H, s), 5.99 (0.5H, s), 5.88 (0.5H, d,
J¼2.2 Hz), 5.81 (0.5H, d, J¼2.4 Hz), 5.79 (0.5H, d, J¼
2.2 Hz), 5.77 (0.5H, d, J¼2.4 Hz), 4.67 (0.5H, d, J¼7.6 Hz),
4.52–4.47 (1.5H, m), 4.41 (0.5H, d, J¼7.6 Hz), 4.27–4.24
(1H, m), 4.23 (0.5H, d, J¼9.5 Hz), 4.05–3.99 (0.5H, m),
3.93 (0.5H, brs, OH), 3.87 (0.5H, brs, OH), 3.79 (1H, m),
3.61 (0.5H, brs, OH), 2.84 (0.5H, dd, J¼5.4, 16.3 Hz), 2.76
(0.5H, dd, J¼5.6, 16.3 Hz), 2.56 (0.5H, dd, J¼8.0, 16.3 Hz),
2.47 (0.5H, dd, J¼8.0, 16.3 Hz); 13C NMR (100 MHz,
CD3OD, 2:1 mixture of rotational isomers) major isomer:
158.62, 157.1 (£2), 155.9, 155.7, 154.9, 146.11, 146.05,
145.8, 145.46, 132.6, 131.9, 120.6, 119.9, 116.4, 116.21,
116.05, 115.5, 108.1, 107.2, 102.2, 97.3, 96.8, 96.0, 84.0,
82.5, 73.70, 68.9, 38.6, 28.8; minor isomer 159.94, 157.4,
157.3, 155.9, 155.8, 155.0, 146.4, 146.11, 145.6, 145.46,
132.4, 132.2, 121.0, 120.2, 120.2, 116.15 (£2), 115.9, 115.2,
108.3, 107.1, 100.5, 97.5, 97.5, 96.2, 84.1, 83.0, 73.70, 68.6,
38.6, 28.7; 13C NMR (100 MHz, acetone-d6, 1:1 mixture of
rotational isomers) 158.7, 158.5, 157.4, 157.2, 157.1, 157.0,
155.5, 155.5, 155.3, 155.0, 154.9, 154.69, 145.71 (£2),
145.6, 145.5, 145.4, 145.2, 145.0, 144.9, 132.6, 132.5,
131.8, 131.5, 120.8, 120.5, 120.1, 119.6, 116.1, 115.9,
115.7, 115.7, 115.6, 115.5, 115.3, 115.1, 107.7 (£2), 106.5,
106.1, 102.4, 100.7, 97.5, 97.2, 97.0, 96.7, 96.14, 96.09,
83.8, 83.6, 83.1, 82.3, 73.3, 73.1, 68.4, 68.1, 38.2, 38.0,
29.0, 28.8.
4.3. Synthesis of procyanidin-B3
4.3.1. [4,8]-2,3-trans-3,4-trans:2,3-trans-Octa-O-benzyl-
bi-(1)-catechin. (4a)-2. A solution of (4a)-3 and (4b)-3
(0.99 g, 0.74 mmol, 97% de) and KCN (0.97 g, 14.8 mmol,
20 equiv.) in 95% EtOH (30 mL) was refluxed for 24 h. The
cooled reaction mixture was concentrated, and the residue
was dissolved in EtOAc. The organic phase was washed
successively with water, sat. NH4Cl, water and brine, dried
over Na2SO4. After filtration and concentration of the
eluent, (4b)-2 was removed by silica gel column chroma-
tography (CH2Cl2/EtOAc, 60/1–30/1) as the first fraction
and 0.95 g of (4a)-2 (98%) was obtained from the second
fraction: [a]D24¼2119 (c 1.32, CHCl3) {lit.12 [a]3D0¼2102.9
(c 1.9, CHCl3)}.
4.3.3. [4,8]-2,3-trans-3,4-cis:2,3-trans-Bi-(1)-catechin,
(4b)-1. Hydrogenation according to the above procedure
using 19 mg of (4b)-2 (0.015 mmol) in THF/MeOH/H2O,
20/1/1 (1.0 mL) afforded 6 mg (67%) of the (4b)-1 as a
colorless amorphous solid: [a]2D7¼þ31.7 (c 0.10, EtOH); 1H
NMR (400 MHz, acetone-d6) 8.13 (2H, brs, OH), 8.10–7.50
(6H, br, OH), 7.09 (1H, brs), 6.83 (2H, brs), 6.72 (2H, brs),
6.61 (2H, brs), 6.02 (1H, brs), 5.88 (1H, brs), 5.05 (1H, d,
J¼7.1 Hz), 4.82 (1H, d, J¼4.9 Hz), 4.20 (1H, brs), 4.07
(1H, brs), 4.01 (1H, brs), 2.86–2.83 (1H, m), 2.57 (1H, dd,
J¼7.1, 13.9 Hz); 13C NMR (100 MHz, acetone-d6) 157.9,
157.0, 156.8, 155.7 (£2), 155.2, 145.5, 145.4 (£2), 145.3,
132.5, 131.8, 119.8, 119.5, 115.72, 115.65, 115.0, 114.9,
108.1, 105.4, 101.0, 97.5, 96.1, 95.8, 82.7, 79.2, 72.2, 67.9,
39.4, 28.5.
4.3.2. [4,8]-2,3-trans-3,4-trans:2,3-trans-Bi-(1)-catechin,
procyanidin-B3. (4a)-1. A solution of (4a)-2 (0.23 g,
0.18 mmol) in THF/MeOH/H2O, 20/1/1 was hydrogenated
over 20% Pd(OH)2/C (10 mg) for 12 h at rt. Filtration and
concentration afforded a pale brown oil, which was purified
by Sephadexw LH-20 column chromatography (MeOH) and
normal phase HPLC (KANTO CHEMICAL CO., Mightysil
Si 60, AcOEt) to give 65 mg of pure procyanidin-B3 (4a)-1
(63%) as an amorphous solid. [a]2D4¼2221 (c 0.38, EtOH)
{lit.19 [a] ¼2244.7 (c 2.0, EtOH)}: 1H NMR (400 MHz,
20
578
CD3OD, 2:1 mixture of rotational isomers) major isomer:
6.73 (0.71H, d, J¼2.0 Hz), 6.67 (0.71H, d, J¼8.3 Hz), 6.66
(0.71H, d, J¼8.0 Hz), 6.58 (0.71H, d, J¼2.0 Hz), 6.46
(0.71H, dd, J¼2.0, 8.0 Hz), 6.25 (0.71H, dd, J¼2.0, 8.3 Hz),
6.06 (0.71H, s), 5.88 (0.71H, d, J¼2.2 Hz), 5.78 (0.71H, d,
J¼2.2 Hz), 4.57 (0.71H, d, J¼7.6 Hz), 4.40 (0.71H, d,
J¼7.8 Hz), 4.34 (0.71H, dd, J¼7.8, 9.8 Hz), 4.25 (0.71H, d,
J¼9.8 Hz), 3.78 (0.71H, ddd, J¼5.6, 7.6, 8.0 Hz), 2.75
(0.71H, dd, J¼5.6, 16.3 Hz), 2.48 (0.71H, dd, J¼8.1,
16.3 Hz); minor isomer d: 6.95 (0.58H, d, J¼2.0 Hz), 6.83
(0.29H, dd, J¼2.0, 8.0 Hz), 6.82 (0.29H, dd, J¼2.0, 8.0 Hz),
6.75 (0.58H, dd, J¼2.0, 8.0 Hz), 5.93 (0.29H, s), 5.83
(0.29H, d, J¼2.5 Hz), 5.80 (0.29H, d, J¼2.5 Hz), 4.74
(0.29H, d, J¼7.1 Hz), 4.40 (0.29H, d, J¼7.8 Hz), 4.34
(0.29H, dd, J¼7.8, 9.8 Hz), 4.25 (0.29H, d, J¼9.8 Hz), 4.06
(0.29H, ddd, J¼5.4, 7.1, 7.8 Hz), 2.81 (0.29H, dd, J¼5.4,
16.3 Hz), 2.57 (0.29H, dd, J¼7.8, 16.3 Hz); 1H NMR
(400 MHz, acetone-d6, 1:1 mixture of rotational isomers)
4.3.4. [4,8]-2,3-trans-3,4-trans:2,3-trans-Deca-O-acetyl-
bi-(1)-catechin. (4a)-5. A pyridine solution (3 mL) of
(4a)-1 (10 mg, 0.017 mmol), acetic anhydride (49 mL,
0.52 mmol), was stirred at room temperature for 2 h, and
the reaction mixture was quenched by adding sat. aqueous
NH4Cl solution (5 mL). The mixture was extracted with
EtOAc (20 mL£3), and the combined organic layers were
washed with brine, dried (Na2SO4), filtered, then concen-
trated under reduced pressure. The residue was purified by
preparative TLC (hexane/EtOAc, 1/1) to give 13 mg of
(4a)-5 (77%) as a colorless oil; [a]2D8¼2117 (c 0.12,
CHCl3) {lit.12 [a]D30¼2102 (c 0.51, CHCl3)}; 1H NMR
(400 MHz CDCl3) 7.14 (1H, d, J¼8.3 Hz), 7.12 (1H, d,

A. Saito et al. / Tetrahedron 58 (2002) 7829–7837
7837
J¼8.5 Hz), 7.02 (1H, d, J¼1.9 Hz), 6.95 (1H, dd, J¼1.9,
References
8.3 Hz), 6.92 (1H, d, J¼2.0 Hz), 6.72 (1H, dd, J¼2.0,
8.5 Hz), 6.64 (1H, s), 6.50 (1H, d, J¼2.4 Hz), 6.48 (1H, d,
J¼2.4 Hz), 5.63 (1H, dd, J¼9.3, 10.0 Hz), 5.03 (1H, dt,
J¼5.6, 7.8 Hz), 4.96 (1H, d, J¼7.8 Hz), 4.76 (1H, d, J¼
10.0 Hz), 4.48 (1H, d, J¼9.3 Hz), 2.93 (1H, dd, J¼5.6,
16.5 Hz), 2.66 (1H, dd, J¼7.8, 16.5 Hz), 2.34 (3H, s), 2.28
(3H, s), 2.27 (3H, s), 2.259 (3H, s), 2.257 (3H, s), 2.255 (3H,
s), 2.24 (3H, s), 1.97 (3H, s), 1.93 (3H, s), 1.64 (3H, s); 13C
NMR (100 MHz, CDCl3) 170.0, 169.1, 168.7, 168.51,
168.48, 168.1, 168.0, 167.9, 167.8 (£2), 155.9, 152.7, 149.5,
149.0, 147.9, 147.5, 142.1, 142.0, 141.50, 141.45, 135.2,
135.2, 125.0, 124.5, 123.5, 123.4, 122.7, 121.9, 116.9,
115.1, 111.5, 110.1, 109.5, 108.2, 78.9, 78.0, 70.4, 68.4,
36.6, 25.7, 21.1, 20.89, 20.86, 20.8, 20.7, 20.62, 20.58 (£2),
20.5, 20.3; FAB-MS (m/z) 1022 (6), 1021 ([MþNa]þ, 9),
100 (0.8), 999 ([MþH]þ, 1.3), 738 (11).
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4.3.5. [4,8]-2,3-trans-3,4-cis:2,3-trans-Deca-O-acetyl-bi-
(1)-catechin. (4b)-5. Acetylation according to the above
procedure using 5 mg of (4b)-2 (0.0086 mmol) in pyridine
(2 mL), acetic anhydride (24 mL, 0.26 mmol), 4-(dimethyl-
amino)pyridine (0.5 mg) afforded 8.2 mg (95%) of the
(4b)-5 as a colorless oil; [a]2D8¼þ154 (c 0.14, CHCl3) {lit.12
[a]3D0¼þ131.3 (c 1.4, CHCl3)}; 1H NMR (400 MHz,
CDCl3) 7.29 (1H, dd, J¼2.0, 8.3 Hz), 7.193 (1H, d, J¼
2.0 Hz), 7.192 (1H, d, J¼8.3 Hz), 7.08 (1H, d, J¼8.3 Hz),
6.98 (1H, dd, J¼2.0, 8.3 Hz), 6.67 (1H, s), 6.29 (1H, d,
J¼2.4 Hz), 5.95 (1H, d, J¼2.4 Hz), 5.33 (1H, dd, J¼6.6,
10.2 Hz), 5.27 (1H, d, J¼10.2 Hz), 5.12 (1H, ddd, J¼6.6,
9.0, 9.5 Hz), 4.71 (1H, d, J¼6.6 Hz), 4.38 (1H, d, J¼
9.5 Hz), 3.19 (1H, dd, J¼6.6, 16.6 Hz), 2.59 (1H, dd, J¼9.0,
16.6 Hz), 2.29 (3H, s), 2.28 (3H, s), 2.27 (3H, s), 2.25 (3H,
s), 2.24 (3H, s), 2.20 (3H, s), 2.11 (3H, s), 1.89 (3H, s), 1.85
(3H, s), 1.78 (3H, s); 13C NMR (100 MHz, CDCl3) 170.0,
169.9, 169.2, 168.8, 168.4, 168.3, 168.1, 168.0, 167.8,
167.8, 155.4, 153.9, 149.6, 148.3, 148.2, 147.8, 142.3,
142.2, 141.8, 141.7, 136.3, 134.6, 125.4, 125.3, 123.4,
123.2, 123.1, 122.3, 115.6, 113.3, 112.8, 110.0, 109.0,
107.2, 78.2, 74.7, 71.1, 68.4, 32.4, 27.1, 21.0, 20.8 (£2),
20.7 (£2), 20.64 (£2), 20.56, 20.3, 20.1.
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1985, 26, 3045–3048.
10. Tu¨ckmantel, W.; Kozikowski, A. P.; Romanczyk, Jr. L. J.
J. Am. Chem. Soc. 1999, 121, 12073–12081.
11. The reaction using benzyl alcohol as a nucleophile at room
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