Enantioselective synthesis of flavan-3-ols using a mitsunobu cyclization

Article abstract of DOI:10.1055/s-0028-1083361

The synthesis of four flavan-3-ols with different substitution patterns and electron densities has been achieved in high stereo- and regioselectivity by a one-step Mitsunobu reaction from the corresponding diols, which were prepared by enantioselective Sharpless dihydroxylation of suitable olefins. The six-membered flavan-3-ols were the only cyclization products and the theoretically possible formation of five-membered rings during the Mitsunobu cyclization was not observed. The flavanols are important starting materials for the synthesis of dimers such as the procyanidins or other coupling products such as the flavan part of the potent DNA polymerase β inhibitor myristinin A. The enantioselectivities of both the Sharpless dihydroxylation and the Mitsunobu cyclization steps were monitored by chiral HPLC. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0028-1083361

PAPER
779
Enantioselective Synthesis of Flavan-3-ols Using a Mitsunobu Cyclization
E
nantioselective
S
a
ynthesis of
r
Flavan-3
s
-ols ten Krohn,*a, Ishtiaq Ahmed,a Markus Johnb
a
Department of Chemistry, University of Paderborn, Warburger Straße 100, 33098 Paderborn, Germany
Fax +44(5251)603245; E-mail: k.krohn@uni-paderborn.de
Macherey-Nagel GmbH & Co. KG, Neumann-Neander-Straße 6-8, 52355 Düren, Germany
b
Received 9 September 2008; revised 10 November 2008
OH
Abstract: The synthesis of four flavan-3-ols with different substi-
tution patterns and electron densities has been achieved in high ste-
reo- and regioselectivity by a one-step Mitsunobu reaction from the
corresponding diols, which were prepared by enantioselective
Sharpless dihydroxylation of suitable olefins. The six-membered
flavan-3-ols were the only cyclization products and the theoretically
possible formation of five-membered rings during the Mitsunobu
cyclization was not observed. The flavanols are important starting
materials for the synthesis of dimers such as the procyanidins or
other coupling products such as the flavan part of the potent DNA
polymerase b inhibitor myristinin A. The enantioselectivities of
both the Sharpless dihydroxylation and the Mitsunobu cyclization
steps were monitored by chiral HPLC.
OH
OH
HO
O
OH
OH
OH
O
OH
OH
HO
HO
O
OH
OH
OH
OH
(+)-catechin (1)
procyanidin B3 (2)
OH
Key words: myristinin A, Sharpless dihydroxylation, flavanol syn-
thesis, Mitsunobu reaction
HO
O
HO
OH
Polyphenols are ingredients of agricultural products such
as wine, tea, fruit, vegetables and herbal medicines, and
play an important role due to their multitude of biological
functions.1 The specific interactions of polyphenols with
biomolecules such as proteins have stimulated the search
for new pharmaceutical entities derived from polyphenol-
ic compounds.2 Among them, flavanoids are considered
to be particularly important secondary metabolites due to
their antibacterial,3 anticancer,4 antioxidant5 and antiviral6
properties. Flavan-3-ols such as (+)-catechin (1) or their
dimers such as procyanidin B3 (2; Figure 1) occur in fresh
fruits, tea, cocoa and chocolate,7 and have been shown to
have beneficial effects on health.8 Other kinds of bioactiv-
ity were recently discovered in the naturally occurring
flavanoid myristinin A (3; Figure 1), which is a DNA
polymerase b inhibitor capable of blocking the repair of
DNA damage induced by clinically used damaging agents
and thereby potentiates their cytotoxicity.9–13
O
OH
n-C11H23
myristinin A (3)
Figure 1 Structures of (+)-catechin (1), procyanidin B3 (2), and my-
ristinin A (3)
ranging from one to five oxygen substituents (Scheme 1).
The flavan-3-ols thus prepared generally serve as precur-
sors in procyanidin synthesis.16
We started with the formation of chalcones 6a–d by
Claisen–Schmidt condensation of 2-hydroxyacetophen-
ones 4a–d with benzaldehydes 5a–d to afford chalcones
6a–d in nearly quantitative yields (Scheme 1). Deoxygen-
ation of the ketones 6a–d to the olefins 7a–d was per-
formed by employing ethyl chloroformate and sodium
borohydride in a two-step sequence.12,17 This procedure is
shorter than the two-step hydrogenation–elimination pro-
cedure used by van Rensburg et al.15 However, the fla-
venes 8b–d and, in the case of 6d, the saturated phenol 9d,
were formed as side products in this reduction. To im-
prove the yield of the deoxygenation reaction, the temper-
ature dependency of the reduction was studied carefully.
When the borohydride reduction was performed at 0–
5 °C, the formation of the flavenes was almost entirely
avoided and the substituted alkenes 7a–d were isolated in
improved yields of 57–86% (Starck et al.12 produced 7b in
74% yield).
The key step in many syntheses of flavan-3-ols such as 13
is the Sharpless dihydroxylation14 of diaryl propenes 10 to
the diols 11.12,15 In connection with an improvement of the
myristinin A synthesis,12 we now report on a new and
shorter variation of the flavan-3-ol synthesis, using a Mit-
sunobu reaction for the one-step cyclization of phenolic
diol precursors 12, as outlined in Scheme 1. In order to
probe the generality of this one-step Mitsunobu cycliza-
tion, we conducted the reaction with four olefins 10a–d
with different substitution patterns and electron densities,
SYNTHESIS 2009, No. 5, pp 0779–0786
x
x
.
x
x
.2
0
0
9
The phenolic hydroxy group of the substituted propenes
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1083361; Art ID: T15908SS
© Georg Thieme Verlag Stuttgart · New York
7a–d was then protected with the tert-butyldimethylsilyl

780
K. Krohn et al.
PAPER
R3
3''
R4
R5
2''
R3
4''
5''
3'
R1
OH
R1
OH
R4
R5
4'
5'
2'
40% (w/v) KOH in MeOH
3
6''
+
MeOH, reflux
(93–97%)
CH3
2
H
6'
1
R2
O
R2
O
6a–d
O
6–13:
a R1–R5 = H
b R1 = R4 = OCH3, R2 = R3 = R5 = H
c R1 = R4 = OBn, R2 = R3 = R5 = H
d R1–R5 = OBn
4a: R1 = R2 = H
5a: R3 = R4 = R5 = H
5b: R4 = OMe, R3 = R5 = H
5c: R4 = OBn, R3 = R5 = H
5d: R3 = R4 = R5 = OBn
4b: R1 = OMe, R2 = H
4c: R1 = OBn, R2 = H
4d: R1 = R2 = OBn
R3
R3
3'
R4
R3
3''
R4
2'
R4
4'
1
O
2''
R1
OH
8
4''
5''
R1
7
R5
3'
R5
5'
R1
OH
2
3
a) THF, Et3N, ClCOOEt
4'
2'
6'
R5
+
+
1
2
6''
6
b) NaBH4, H2O–EtOH,
0–5 °C (57–86%)
5
5'
4
9d
R2
R3
6'
R2
3
8b–d
R2
7a–d
R3
R4
R5
R4
R5
R1
OTBS
R1
OTBS
TBSCl, DMF
7a–d
AD-mix α
OH
OH
imidazole
t-BuOH–H2O (1:1)
(82–89%)
(93–97%)
R2 11a–d
R2
10a–d
R3
R3
R4
R5
R4
R5
R1
OH
R1
O
TBAF
DEAD, Ph3P
(71–82%)
OH
OH
(92–95%)
OH
R2
R2 13a–d
12a–d
Scheme 1 Improved synthesis of flavan-3-ols 13a–d via Mitsunobu reaction of 12a–d
(TBS) group to afford the TBS-protected substituted 1,3- observed optical rotation also compared favorably to that
diphenylpropenes 10a–d in almost quantitative yields. reported in the literature12 after additional protection and
20
Asymmetric dihydroxylation of the diphenylpropenes deprotection steps {13b: [a]D –17.4 (c 1.11, CHCl3)
10a–d proceeded smoothly using AD-mix a14 in a mixture [Lit.12 –16.1 (c 1.11, CHCl3)]}. The optical rotation also
of tert-butyl alcohol and water (1:1), to afford the TBS- confirmed the presence of the 2R,3S-isomer, leading to
protected diols 11a–d. In the next step, instead of forming the natural configuration of myristinin A (3).13
an orthoester as described, for example, by Wan et al.18 or
In order to confirm the enantioselectivity indicated by the
specific optical rotation, the products 11b and 13a–d were
subjected to chiral HPLC. The two crucial steps: the enan-
tioselective dihydroxylation of olefins 10a–d to the diols
Hecht and co-workers,12 we investigated whether it was
possible to achieve a direct cyclization using either acidic
conditions or, preferably, SN2-type Mitsunobu condi-
tions.19 Therefore, the TBS-ether of diols 11a–d were
11a–d, and the Mitsunobu reaction of the phenols 12a–d
cleaved using tetrabutylammonium fluoride (TBAF) to
to the flavanols 13a–d, were analyzed by chiral HPLC.
The results for one example (13b) are shown in Figure 2
and relevant results for compounds 13a–d are given in the
experimental section. The enantiomeric ratio found after
the enantioselective Sharpless dihydroxylation of 11b
was 96.8:3.2 [93.6% ee; Figure 2 (left)]. After cleavage of
the TBS-ether of 11b to give phenol 12b and purification
by flash chromatography, the enantiomers formed in the
afford the triols 12a–d with a free phenolic hydroxy
group. The cyclization of these triols was first tried using
methanolic hydrogen chloride.15 However, not unexpect-
edly, acidic treatment resulted in formation of the racemic
flavan-3-ols. Next, the standard SN2-type Mitsunobu reac-
tion conditions17 were employed in an attempt to convert
the triols 12a–d in one step into the enantiomerically pure
flavan-3-ols 13a–d. In the first experiment, the flavanol
13b was not only formed in excellent yield (77%) and in
the expected 2,3-trans-configuration, but remarkably, no
one-step Mitsunobu reaction were found in a ratio of
98.8:1.2 [97.7% ee; Figure 2 (right)]. The slight increase
in ee may be due to the purification step.
five-membered cyclization products were observed. The
Synthesis 2009, No. 5, 779–786 © Thieme Stuttgart · New York

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Enantioselective Synthesis of Flavan-3-ols
781
Figure 2 HPLC traces showing the enantiomeric excess for diol 11b (left) and flavanol 13b (right); for details, see the experimental section
and text
ture was diluted with ice-cold H2O (150 mL) until the yellow solid
dissolved. The reaction mixture was acidified by addition of dilute
HCl (20 mL), maintaining the temperature at 0 °C. The precipitates
formed were filtered off, dried, and crystallized (aq EtOH) to give
yellow needles of 2¢-hydroxychalcones 6a and 6b.
In conclusion, the number of reaction steps required for
the synthesis of enantiomerically enriched flavan-3-ols
13a–d was reduced by omitting the protection (and later
deprotection) of the diol 12a–d and instead employing a
direct Mitsunobu cyclization of 12a–d to selectively af-
ford the 2,3-trans-flavan-3-ols (13a–d) in excellent yield
and enantioselectivity measured by chiral HPLC. This
strategy may prove to be generally useful in flavonoid and
catechin synthesis.
2¢-Hydroxychalcone (6a)20,21
Yield: 93%; yellow needles; mp 87–88 °C (Lit.19,20 88–89 °C).
1H NMR (200 MHz, CDCl3): d = 6.95–7.99 (m, 10 H, 2-H, ArH),
8.01 (d, J = 15.5 Hz, 1 H, 3-H), 13.9 (s, 1 H, 2¢-OH).
13C NMR (50 MHz, CDCl3): d = 119.0 (3¢-C), 119.2 (C-2), 120.4,
120.5, 129.0, 129.4, 130.0, 131.3, 135.0, 136.8 (Ar), 145.9 (C-3),
164.0 (C-2¢), 194.1 (C-1).
TLC was performed on precoated TLC plates (silica gel). Melting
points were measured with a Gallenkamp apparatus and are not cor-
rected. NMR spectra were recorded on a Bruker Avance 500 instru-
ment at 500.13 MHz (1H) and 125.76 MHz (13C). Chemical shifts
(d) for 1H and 13C NMR spectra are reported in ppm downfield from
TMS as an internal standard. Optical rotations were measured at
25 °C on a Perkin–Elmer Polarimeter 241. Mass spectra were re-
corded using a Finnigan MAT 8430 spectrometer in the electron-
impact mode at 70 eV and chemical ionization, and are reported as
m/z values and relative abundances. The infrared spectra were re-
corded using a Nicolet 510 P FT-IR Spectrometer. HPLC system:
Summit (Dionex); pump: P 580 A (Dionex); detector: UVD 170S;
autosampler: ASI 100 (Dionex); column oven: STH 585 (Dionex).
Petroleum ether (PE), where used, was the fraction boiling in the
range 40–60 °C.
4,4¢-Dimethoxy-2¢-hydroxychalcone (6b)22,23
Yield: 91%; yellow needles; mp 91–93 °C (Lit.21,22 89–91 °C).
1H NMR (200 MHz, CDCl3): d = 3.88 (s, 6 H, OCH3), 6.49 (s, 1 H,
3¢-H), 6.53 (d, J = 8.8 Hz, 1 H, 5¢-H), 6.98 (d, J = 8.8 Hz, 2 H, 3¢¢-
H, 5¢¢-H), 7.51 (d, J = 15.6 Hz, 1 H, 2-H), 7.67 (d, J = 8.8 Hz, 2 H,
2¢¢-H, 6¢¢-H), 7.87 (d, J = 15.9 Hz, 1 H, 3-H), 7.97 (d, J = 8.8 Hz,
1 H, 6¢-H), 13.61 (s, 1 H, 2¢-OH).
13C NMR (50 MHz, CDCl3): d = 55.8 (OCH3), 55.9 (OCH3), 101.4
(C-3¢), 108.0 (C-5¢), 114.5 (C-3), 114.8 (C-1¢), 118.1 (C-2), 127.9
(C-2¢¢), 130.7 (C-1¢¢), 131.5 (C-6¢), 144.6 (C-3), 162.2 (C-4¢¢), 166.4
(C-2¢), 167.0 (C-4¢), 192.2 (C-1).
(E)-1-(4-Benzyloxy-2-hydroxyphenyl)-3-(4-benzyloxyphe-
nyl)propenone (6c)12
HPLC Conditions for Compounds 11b and 13a–d
Retention times for the enantiomers were first determined on race-
mic mixtures.
Yield: 97%; mp 136–137 °C (Lit.12 140–142 °C).
11b: Column: EC 250 × 4.6 mm NUCLEOCEL Alpha RP-S;
MeCN–H2O, 80:20; 0.5 mL/min; 25 °C; detection: 230 nm; pres-
sure: 35 bar; injection volume: 3 mL. Retention time for enantiomer
1: 16.84 min; enantiomer 2: 18.48 min; integration for enantiomer
1: 42.283; integration for enantiomer 2: 1.3788.
(E)-1-[2,4-Bis(benzyloxy)-6-hydroxyphenyl]-3-[3,4,5-tris(ben-
zyloxy)phenyl]propenone (6d)24
To a stirred solution of 2,4-bis(benzyloxy)-6-hydroxyacetophenone
(4d; 2.00 g, 5.70 mmol) in DMF (34 mL), NaH (60% in oil, 1.00 g,
25.00 mmol) was added. The mixture was stirred for 15 min at 0 °C,
then a solution of 3,4,5-tris(benzyloxy)benzaldehyde (5d; 2.60 g,
6.12 mmol) in DMF (15 mL) was added dropwise over a period of
25 min at 0 °C. After stirring for 5 h at 0 °C, the reaction was
quenched with H2O (2 mL). The solvent was evaporated under vac-
uum, and the residue was dissolved in CH2Cl2 (200 mL). The organ-
ic layer was washed with H2O (50 mL) and brine (50 mL), then the
extract was concentrated and the residue was crystallized (Et2O) to
give 6d.
13c: As described for 11b, except pressure: 70 bar. Retention time
for enantiomer 1: 36.44 min; enantiomer 2: 44.69 min; integration
for enantiomer 1: 932.481; integration for enantiomer 2: 10.895.
Identical conditions were used for the analysis of 13a, 13b and 13d.
Preparation of Chalcones 6a and 6b; General Procedure
A mixture of equimolar amounts of 2¢-hydroxyacetophenones 4a or
4b (44.10 mmol) and benzaldehydes 5a or 5b (44.10 mmol) in
EtOH (40 mL) was warmed to 50 °C, then aq NaOH (50%, 20 mL)
was added dropwise to the reaction mixture during 30 min. The re-
action mixture was further stirred for 5 h at 50 °C and then kept at
r.t. for 24 h. Yellow precipitates were formed and the reaction mix-
Yield: 3.1 g (72%); yellow crystals; mp 148–149 °C.
1H NMR (200 MHz, CDCl3): d = 4.89 (s, 4 H, OCH2Ph), 5.13 (s,
6 H, 2 × OCH2Ph), 6.23 (d, J = 2.4 Hz, 1 H, 3¢-H), 6.31 (d, J = 2.4
Synthesis 2009, No. 5, 779–786 © Thieme Stuttgart · New York

782
K. Krohn et al.
PAPER
Hz, 1 H, 5¢-H), 6.70 (s, 2 H, 2¢¢-H, 6¢¢-H), 7.16–7.49 (m, 25 H,
ArH), 7.64 (d, J = 15.3 Hz, 1 H, 2-H), 7.86 (d, J = 14.7 Hz, 1 H, 3-
H), 14.32 (s, 1 H, 6¢-OH).
13C NMR (50 MHz, CDCl3): d = 70.7 (4-, 4¢-OCH2Ph), 71.4, (3-, 5-,
2¢-OCH2Ph), 95.5 (C-3¢, C-5¢), 107.2 (C-1¢), 108.6 (C-5¢), 114.4 (C-
2¢¢), 121.4 (C-6¢¢), 125.9 (C-2), 127.4, 127.8, 128.1, 128.3, 128.6,
128.7, 128.8, 128.9, 129.0, 129.1, 129.2 (Ar), 131.0 (C-1¢¢), 136.1,
136.2, 137.2, 138.0, 140, 7 (Ar), 142.7 (C-3), 153.2 (C-3¢¢), 150.8
(C-4¢¢), 161.9 (C-6¢), 165.6 (C-4¢), 168.5 (C-2¢), 193.0 (C-1).
MS (EI): m/z (%) = 754 (1) [M+], 738 (1), 663 (4), 573 (1), 555 (1),
440 (2), 436 (2), 333 (4), 306 (5), 243 (4), 181 (14), 91 (100), 44
(12).
HRMS: m/z [M]+ calcd for C50H42O7: 754.29303; found:
754.29604.
HRMS: m/z [M]+ calcd for C17H18O3: 270.12561; found:
270.12566.
( )-7-Methoxy-2-(4-methoxyphenyl)-2H-chromene (8b)26
Reduction at r.t. afforded the racemic cyclization product 8b in ad-
dition to the desired olefin 7b.
Yield: 11%; yellow solid; mp 81–82 °C (Lit.26 82–83 °C).
IR (film): 2931, 2838, 1610, 1511, 1251, 1170, 1112, 1025.
1H NMR (200 MHz, CDCl3): d = 3.78 (s, 3 H, OCH3), 3.84 (s, 3 H,
OCH3), 5.71 (dd, J = 9.5, 3.2 Hz, 1 H, 3-H), 5.87 (br s, 1 H, 2-H),
6.40 (br s, 1 H, 8-H), 6.49 (dd, J = 9.5, 1.8 Hz, 1 H, 4-H), 6.56 (d,
J = 8.3 Hz, 1 H, 6-H), 6.91–7.03 (m, 3 H, 5-H, 3¢-H, 5¢-H), 7.39–
7.44 (m, 2 H, 2¢-H, 6¢-H).
13C NMR (50 MHz, CDCl3): d = 55.6 (OCH3), 81.3 (C-2), 102.2 (C-
8), 107.3 (C-6), 114.4 (C-4a), 115.1 (C-3¢), 122.3 (C-4), 124.0 (C-
3), 127.5 (C-2¢), 129.0 (C-6), 133.4 (C-1¢), 159.3 (C-8a), 160.1 (C-
4¢), 161.2 (C-7).
MS (EI, 70 eV): m/z (%) = 268 (100) [M+], 237 (66), 224 (26), 181
(12), 161 (78), 134 (60), 89 (12), 77 (13), 51 (6), 28 (21).
HRMS: m/z [M]+ calcd for C17H16O3: 268.10995; found:
268.10995.
Deoxygenation of Chalcones; General Procedure
Et3N (1.81 g, 2.50 mL, 17.90 mmol) was added to a solution con-
taining the corresponding chalcones 6a–d (13.79 mmol) in anhy-
drous THF (50 mL). The reaction mixture was cooled to 0 °C in an
ice bath and stirred for 15 min. ClCO2Et (1.79 g, 1.58 mL, 16.50
mmol) was then added dropwise over a period of 20 min. After stir-
ring at 0 °C for 1.5 h, the mixture was filtered and the precipitate ob-
tained was washed with THF (2 × 20 mL). The filtrate, which
contained the phenolic carbonate, was then added dropwise at 0 °C
over a period of 45 min to a solution of NaBH4 (2.00 g, 52.87 mmol)
in H2O (80 mL). The reaction mixture was stirred at 0–5 °C over-
night, then acidified with 1N HCl, diluted with H2O (200 mL), and
extracted with Et2O (3 × 50 mL). The organic layers were com-
bined, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by flash chromatography on a silica gel
column (EtOAc–PE, 1:9) to afford the substituted propenes 7a–d.
(E)-1-(4-Benzyloxyphenyl)-3-(4-benzyloxy-2-hydroxyphe-
nyl)propene (7c)12
Yield: 86%; mp 106–107 °C.
( )-7-Benzyloxy-2-[4-benzyloxyphenyl]-2H-chromene (8c)
Reduction at r.t. afforded the racemic cyclization product 8c in ad-
dition to the desired olefin 7c.
Yield: 19%; yellow solid; mp 76–77 °C.
IR (KBr): 3027, 2888, 1610, 1508, 1378, 1166, 1112, 1027 cm–1.
(E)-3-(2-Hydroxyphenyl)-1-phenylpropene (7a)25
Yield: 84%; colorless oil.
IR (film): 3532, 3025, 2900, 1592, 1454, 1349, 1211 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.09 (s, 2 H, OCH2Ph), 5.13 (s,
2 H, OCH2Ph), 5.81 (dd, J = 9.8, 3.7 Hz, 1 H, 3-H), 5.97 (br s, 1 H,
2-H), 6.62 (br s, 1 H, 8-H), 6.68 (dd, J = 9.8, 1.9 Hz, 1 H, 4-H), 6.75
(d, J = 8.3 Hz, 1 H, 6-H), 7.05–7.20 (overlapped, 3 H, 5-H, 3¢-H, 5¢-
H), 7.41–7.72 (overlapped, 12 H, 2¢-H, 6¢-H, ArH).
13C NMR (125 MHz, CDCl3): d = 70.5 (OCH2Ph), 70.9 (OCH2Ph),
82.1 (C-2), 103.3 (C-8), 108.3 (C-6), 115.3 (C-4a), 115.4 (C-3¢),
115.5 (C-4), 122.6 (C-3), 124.2 (C-2¢), 127.8, 128.0, 128.4, 129.0,
129.1, 129.2, 129.9, 131.1, 133.8, 137.4, 137.4 (Ar), 154.9 (C-4¢),
159.4 (C-8a), 160.6 (C-7).
MS (EI): m/z (%) = 420 (46) [M+], 362 (5), 329 (38), 300 (60), 228
(54), 180 (12), 150 (14), 91 (100), 65 (62), 29 (28).
HRMS: m/z [M]+ calcd for C29H24O3: 420.17255; found:
420.17254.
1H NMR (200 MHz, CDCl3): d = 3.68 (d, J = 5.6 Hz, 2 H, 3-H),
6.53 (dt, J = 15.9, 6.5 Hz, 1 H, 2-H), 6.62 (d, J = 15.9 Hz, 1 H, 1-
H), 6.92 (dd, J = 8.0, 1.1 Hz, 1 H, 3¢-H), 7.06 (ddd, J = 8.0, 7.4, 1.1
Hz, 1 H, 4¢-H), 7.26 (ddd, J = 7.4, 8.2, 1.5 Hz, 1 H, 5¢-H), 7.23–7.49
(m, 6 H, Ar).
13C NMR (50 MHz, CDCl3): d = 34.0 (C-3), 115.0, 116.0, 121.1,
124.9, 125.5, 126.2, 127.1, 127.4, 127.8, 127.9, 128.4, 129.0, 130.4
(Ar, C-1, C-2), 152.7 (C-2¢).
MS (EI): m/z (%) = 210 (100) [M+], 165 (20), 130 (40), 91 (55), 58
(48), 29 (18).
HRMS: m/z [M]+ calcd for C15H14O: 210.10446; found: 210.10455.
(E)-1-(4-Methoxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)pro-
pene (7b)26
(E)-1-[3,4,5-Tris(benzyloxy)phenyl]-3-[2,4-bis(benzyloxy)-6-
hydroxyphenyl]propene (7d)27
Yield: 82%; mp 97–98 °C (Lit.26 99–100 °C).
Yield: 57%; mp 129–131 °C (no mp or spectral data given in Lit.27).
IR (KBr): 3436, 2929, 1608, 1511, 1440, 1398, 1220, 833 cm–1.
IR (film): 3492, 3029, 1621, 1506, 1374, 1116, 997 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.50 (d, J = 5.1 Hz, 2 H, 3-H),
3.77 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 5.41 (br s, 1 H, OH), 6.26
(dt, J = 15.8, 6.5 Hz, 1 H, 2-H), 6.44–6.51 (m, 3 H, 3¢-H, 5¢-H, 1-H),
6.86 (dt, J = 8.6, 2.1 Hz, 2 H, 3¢¢-H, 5¢¢-H), 7.07 (d, J = 8.4 Hz, 1 H,
6¢-H), 7.31 (dt, J = 8.6, 2.1 Hz, 2 H, 2¢¢-H, 6¢¢-H).
13C NMR (50 MHz, CDCl3): d = 34.6 (C-3), 55.32 (OCH3), 55.35
(OCH3), 102.1 (C-3¢), 106.3 (C-5¢), 114.3 (C-5¢¢), 118.2 (C-1¢),
126.2, 127.3, 129.3, 129.5, 120.0, 130.5, 130.8 (Ar, C-1, C-2),
155.0 (C-2¢), 159.0 (C-4¢), 159.5 (C-4¢¢).
1H NMR (200 MHz, CDCl3): d = 3.62 (d, J = 5.4 Hz, 2 H, CH2),
5.03 (s, 2 H, 4¢-OCH2Ph), 5.10 (s, 4 H, 3¢¢-H, 5¢¢-OCH2Ph), 5.11 (s,
4 H, 4¢¢-H, 2¢-OCH2Ph), 6.15–6.38 (m, 4 H, 1-H, 2-H, 3¢-H, 5¢-H),
6.70 (s, 2 H, 2¢¢-H, 6¢¢-H), 7.31–7.55 (m, 25 H, ArH).
13C NMR (50 MHz, CDCl3): d = 32.0 (CH2), 70.5 (4¢-OCH2Ph),
70.7 (4¢¢-OCH2Ph), 71.7 (3¢¢-H, 5¢¢-H, 2¢-OCH2Ph), 94.1 (C-3¢),
95.5 (C-5¢), 106.4 (C-2¢¢, C-6¢¢), 107.4 (C-1¢), 127.3 (C-2), 127.7,
127.9, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 128.9, 128.9, 128.8,
128.9, 129.0, 129.6, 130.6 (C-1), 133.3, 137.3, 137.6, 137.8 (Ar),
138.2 (C-4¢¢), 153.0 (C-5¢¢), 153.3 (C-3¢¢), 156.0 (C-OH), 158.4 (C-
4¢), 159.2 (C-2¢).
MS (EI): m/z (%) = 270 (100) [M+], 226 (20), 210 (98), 167 (18),
134 (90), 91 (62), 57 (24), 29 (5).
Synthesis 2009, No. 5, 779–786 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of Flavan-3-ols
783
MS (EI): m/z (%) = 740 (1) [M+], 650 (2), 634 (2), 560 (1), 541 (1),
467 (1), 422 (2), 396 (1), 306 (7), 227 (2), 181 (7), 108 (4), 91 (100),
39 (5).
(E)-1-Phenyl-3-[2-(tert-butyldimethylsilyloxy)phenyl]propene
(10a)
Yield: 95%; colorless oil.
HRMS: m/z [M]+ calcd for C50H44O6: 740.31378; found:
IR (film): 3060, 2929, 1614, 1598, 1490, 1255 cm–1.
740.31219.
1H NMR (200 MHz, CDCl3): d = 0.39 [s, 6 H, Si(CH3)2], 1.17 [s,
9 H, SiC(CH3)3], 3.68 (d, J = 5.5 Hz, 2 H, 3-H), 6.47–6.53 (m, 2 H,
2¢¢-H, 6¢¢-H), 6.96 (dd, J = 8.1, 1.1 Hz, 1 H, 6¢-H), 7.03 (ddd,
J = 8.1, 7.5, 1.2 Hz, 1 H, 5¢-H), 7.17–7.47 (m, 7 H, ArH),
13C NMR (50 MHz, CDCl3): d = –3.7 [Si(CH3)2], 18.4 [SiC(CH3)3],
25.9 [SiC(CH3)3], 33.7 (C-3), 118.5, 121.5, 126.1, 126.8, 127.9,
128.3, 128.5, 128.9, 129.2, 130.4 (Ar), 130.9 (C-1¢), 137.9 (C-1),
153.5 (C-2¢).
5,7-Dibenzyloxy-2-[3,4,5-tris(benzyloxy)phenyl]-2H-chromene
(8d)24
Reduction at r.t. afforded the racemic cyclization product 8d and
saturated 9d in addition to the desired olefin 7d.
Yield: 25%; yellow solid; mp 105–107 °C (no mp given in Lit.27).
IR (film): 3124, 3021, 1614, 1376, 1182, 782, 732 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.99 (s, 2 H, OCH2Ph), 5.03 (s,
2 H, OCH2Ph), 5.05 (s, 4 H, OCH2Ph), 5.09 (s, 2 H, OCH2Ph), 5.53
(dd, J = 9.95, 3.29 Hz, 1 H, 3-H), 5.72 (dd, J = 3.2, 2.0, 5 Hz, 1 H,
2-H), 6.13 (d, J = 2.2 Hz, 1 H, H-8), 6.20 (d, J = 2.17 Hz, 1 H, H-
6), 6.78 (s, 2 H, 2¢-H, 6¢-H), 6.86 (dd, J = 9.86, 1.57 Hz, 1 H, 4-H),
7.25–7.41 (m, 25 H, ArH).
13C NMR (50 MHz, CDCl3): d = 70.1 (OCH2Ph), 70.3 (OCH2Ph),
70.7 (OCH2Ph), 71.3 (OCH2Ph), 71.3 (OCH2Ph), 77.0 (C-2), 93.9
(C-6), 95.2 (C-8), 105.0 (4a), 114.3 (C-2¢, C-6¢), 114.9 (C-5¢), 118.9
(C-4), 119.7 (C-3), 120.5, 127.2, 127.3, 127.4, 127.5, 127.7, 127.9,
128.0, 128.4, 128.5 (Ar), 134.2 (C-1¢), 136.7, 136.9, 137.2, 137.3
(Ar), 149.1 (C-3¢), 149.2 (C-4¢), 154.9 (C-8a), 155.3 (C-5), 160.3
(C-7).
MS (EI): m/z (%) = 324 (22) [M+], 267 (88), 249 (5), 189 (20), 163
(98), 147 (34), 91 (100), 71 (54).
HRMS: m/z [M]+ calcd for C21H28OSi: 324.19095; found:
324.19098.
(E)-1-(4-Methoxyphenyl)-3-[4-methoxy-2-(tert-butyldimethyl-
silyloxy)phenyl]propene (10b)
Yield: 93%; colorless oil.
IR (film): 2954, 1605, 1509, 1483, 1249, 1162 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.34 [s, 6 H, Si(CH3)2], 1.11 [s,
9 H, SiC(CH3)3], 3.52 (d, J = 6.6 Hz, 2 H, 3-H), 3.81 (s, 3 H,
OCH3), 3.83 (s, 3 H, OCH3), 6.29 (dt, J = 15.7, 6.6 Hz, 1 H, 2-H),
6.41 (d, J = 15.7 Hz, 1 H, 1-H), 6.50 (d, J = 2.5 Hz, 1 H, 3¢-H), 6.54
(d, J = 8.4, 2.5 Hz, 1 H, 5¢-H), 6.89 (dt, J = 8.8, 2.1 Hz, 2 H, 3¢¢-H,
5¢¢-H), 7.14 (d, J = 8.4 Hz, 1 H, 6¢-H), 7.33 (dt, J = 8.8, 2.1 Hz, 2 H,
2¢¢-H, 6¢¢-H).
13C NMR (50 MHz, CDCl3): d = –3.7 [Si(CH3)2], 18.3 [SiC(CH3)3],
25.9 [SiC(CH3)3], 33.0 (C-3), 55.24 (OCH3), 55.28 (OCH3), 105.5
(C-3¢), 106.9 (C-5¢), 114.1 (C-3¢¢, C-5¢¢), 123.4 (C-2), 127.0, 127.1,
127.3, 129.7, 129.9, 130.0, 130.2 (Ar, C-1), 154.2 (C-2¢), 158.6 (C-
4¢), 159.8 (C-4¢¢).
MS (EI): m/z (%) = 738 (6) [M+], 647 (24), 557 (1), 465 (8), 396 (2),
306 (8), 229 (1), 181 (12), 91 (100), 65 (7).
HRMS: m/z [M]+ calcd for C50H42O6: 738.29816; found:
738.29721.
1-[3,4,5-Tris(benzyloxy)phenyl]-3-[2,4-bis(benzyloxy)-6-hy-
droxyphenyl]propane (9d)
Yield: 7%; white solid; mp 102–103 °C.
IR (film): 3318, 2923, 1623, 1434, 1274, 1128, 871 cm–1.
MS (EI): m/z (%) = 384 (12) [M+], 324 (22), 267 (88), 251 (5), 209
(34), 163 (98), 121 (66), 91 (100), 73 (26).
HRMS: m/z [M]+ calcd for C23H32O3Si: 384.21207; found:
384.21223.
1H NMR (200 MHz, CDCl3): d = 1.93 (m, 2 H, 2-CH2), 2.68 (t,
J = 7.5 Hz, 2 H, 3-CH2), 2.79 (t, J = 7.5 Hz, 2 H, 1-CH2), 5.09 (s,
2 H, OCH2Ph), 5.12 (s, 4 H, OCH2Ph), 5.14 (s, 4 H, OCH2Ph), 6.21
(d, J = 2.0 Hz, 1 H, 5¢-H), 6.39 (d, J = 2.0 Hz, 1 H, 6-H), 6.59 (s,
2 H, 2¢-H, 6¢-H), 7.30–7.50 (m, 25 H, ArH).
13C NMR (50 MHz, CDCl3): d = 18.7 (CH2), 26.8 (CH2), 31.9
(CH2), 70.5 (4¢¢-, 4¢-OCH2Ph), 71.7 (3¢¢-, 5¢¢-, 2¢-OCH2Ph), 94.3 (C-
3¢), 97.7 (C-5¢), 108.6 (C-2¢, C-4¢), 115.0 (C-1¢), 127.3, 127.8,
127.9, 127.9, 128.1, 128.2, 128.4, 128.5, 128.7, 128.8, 128.8, 128.9,
128.9, 129.0, 129.6, 137.0, 133.6, 137.8, 137.9, 137.9, 138.6, 139.3
(Ar, C-4¢¢), 152.8 (C-5¢¢, C-3¢¢), 154.7 (C-6¢), 158.1 (C-2¢), 158.4
(C-4¢).
(E)-1-(4-Benzyloxyphenyl)-3-[4-benzyloxy-2-(tert-butyldimeth-
ylsilyloxy)phenyl]propene (10c)12
Yield: 97%; colorless oil.
(E)-3-[2,4-Bis(benzyloxy)-6-(tert-butyldimethylsilyloxy]-1-
[3,4,5-tris(benzyloxy)phenyl]propene (10d)27
Yield: 96%; mp 88–90 °C (no mp given in Lit.27).
IR (film): 2929, 1600, 1427, 1288, 1108, 889, 696 cm–1.
MS (EI): m/z (%) = 742 (2) [M+], 651 (20), 561 (1), 469 (1), 409 (2),
319 (15), 229 (7), 181 (18), 91 (100), 44 (4).
HRMS: m/z [M]+ calcd for C50H46O6: 742.32947; found:
742.32957.
1H NMR (500 MHz, CDCl3): d = 0.20 [s, 6 H, Si(CH3)2], 1.00 [s,
9 H, SiC(CH3)3], 3.52 (d, J = 4.9 Hz, 2 H, CH2), 5.02 (s, 2 H, 7-
OCH2Ph), 5.05 (s, 4 H, 3¢-, 6¢-OCH2Ph), 5.10 (s, 4 H, 4¢-, 5-
OCH2Ph), 6.19–6.35 (m, 4 H, 2-H, 3-H, 6-H, 8-H), 6.60 (s, 2 H, 2¢-
H, 6¢-H), 7.30–7.47 (m, 25 H, ArH).
13C NMR (125 MHz, CDCl3): d = –4.0 [Si(CH3)2], 18.3
[SiC(CH3)3], 25.8 [SiC(CH3)3], 26.8 (C-3), 70.2 (4¢-OCH2Ph), 70.1
(4¢¢-OCH2Ph), 71.3 (3¢¢-, 5¢¢-, 2¢-OCH2Ph), 93.9 (C-3¢), 98.5 (C-5¢),
105.9 (C-2¢, C-4¢), 112.1 (C-4), 127.3 (C-3), 127.4, 127.4, 127.7,
128.1, 128.4, 128.5, 128.5, 128.7, 128.7, 128.8, 128.9, 128.9, 129.0,
129.6, 130.6, 133.3, 137.1, 137.3, 137.6, 138.0 (Ar), 152.1 (C-4¢¢),
153.8 (C-3¢¢, C-5¢¢), 154.7 (C-6¢), 158.1 (C-4¢), 158.4 (C-2¢).
TBS Protection; General Procedure
To a solution containing the substituted propenes 7a–d (4.75 mmol)
in anhydrous DMF (30 mL), was added imidazole (960 mg, 14.10
mmol, 3 equiv). The solution was stirred at r.t. for 15 min, then
TBDMSCl (1.10 g, 7.30 mmol, 1.5 equiv) was added. The reaction
mixture was stirred overnight at r.t., then poured into H2O (100 mL)
and extracted with EtOAc (3 × 50 mL). The combined organic
phase was dried over MgSO4, concentrated under reduced pressure
and the residue was purified by flash chromatography on silica gel
(EtOAc–PE, 1:9) to afford the corresponding TBS-ethers 10a–d.
MS (EI): m/z (%) = 854 (1) [M+], 763 (8), 745 (1), 672 (1), 581 (4),
512 (3), 444 (2), 434 (22), 343 (8), 271 (2), 211 (1), 181 (18), 91
(100), 51 (4).
Synthesis 2009, No. 5, 779–786 © Thieme Stuttgart · New York

784
K. Krohn et al.
PAPER
HRMS: m/z [M]+ calcd for C56H58O6Si: 854.40027; found:
854.40052.
(1S,2S)-1-(4-Benzyloxyphenyl)-3-[4-benzyloxy-2-(tert-butyl-
dimethylsilyloxy)phenyl]propane-1,2-diol (11c)12
Yield: 88%; mp 66–68 °C (no mp given in Lit.12); [a]D +4.91 (c
0.77, CHCl3) [Lit.12 +4.77 (c 0.77, CHCl3)].
Sharpless Asymmetric Dihydroxylation; General Procedure
To a solution containing the TBS ethers 10a–d (8.00 mmol) in t-
BuOH–H2O (1:1, 12 mL), was added AD-mix a (11.2 g) in portions.
The heterogeneous mixture was cooled to 0 °C in an ice bath and
methanesulfonamide (0.95 g, 10 mmol) was also added in portions.
In order to allow complete dissolution of the starting material,
CHCl3 (0.5 mL) was added and the reaction mixture was allowed to
warm to r.t. and stirred for 16 h. When the starting material was
completely consumed (reaction monitored by TLC), the reaction
was quenched by addition of Na2SO3 (1 M, 4 mL) and diluted with
EtOAc (100 mL) and H2O (100 mL). The organic layer was sepa-
rated and washed with KOH (2 M, 2 × 100 mL), followed by H2O
(100 mL). The organic layer was dried over MgSO4, concentrated
under reduced pressure and the residue was purified by flash chro-
matography on a silica gel column (EtOAc–PE, 1:3) to afford TBS-
protected diols 11a–d.
(1S,2S)-3-[2,4-Bis(benzyloxy)-6-(tert-butyldimethylsilyl-
oxy)phenyl]-1-[3,4,5-tris(benzyloxy)phenyl]propane-1,2-diol
(11d)27
Yield: 82%; sticky oil; [a]D –6.5 (c 1.0, CHCl3).
IR (film): 3505, 3145, 2929, 1590, 1409 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.17 (s, 3 H, SiCH3), 0.19 (s, 3 H,
SiCH3), 1.11 [s, 9 H, SiC(CH3)3], 2.75 (dd, J = 14.8, 8.4 Hz, 1 H, 3-
Ha), 2.90 (dd, J = 14.8, 3.6 Hz, 1 H, 3-Hb), 3.92 (ddd, J = 8.4, 5.6,
3.6 Hz, 1 H, 2-H), 4.43 (d, J = 5.6 Hz, 1 H, 1-H), 4.89 (s, 2 H,
OCH2Ph), 4.95–5.05 (m, 8 H, OCH2Ph), 6.21 (d, J = 2.0 Hz, 1 H,
5¢-H), 6.26 (d, J = 2.0 Hz, 1 H, 3¢-H), 6.59 (s, 2 H, 2¢¢-H, 6¢¢-H),
7.25–7.45 (m, 25 H, ArH).
13C NMR (50 MHz, CDCl3): d = –3.8 [Si(CH3)2], 18.5 [SiC(CH3)3],
25.7 [SiC(CH3)3], 26.9 (C-3), 70.0 (OCH2Ph), 71.3 (OCH2Ph), 79.4
(C-1), 82.1 (C-2), 93.9 (C-3¢), 98.5 (C-5¢), 105.9 (C-2¢¢, C-6¢¢),
112.1 (C-1¢), 127.3, 127.4, 127.4, 127.7, 128.1, 128.4, 128.5, 128.5,
128.7, 128.7, 128.8, 128.9, 128.9, 129.0, 129.6, 130.6, 133.3, 137.1,
137.3, 137.6, 138.0 (Ar), 152.8 (C-3¢¢,C-5¢¢), 154.7 (C-6¢), 158.1 (C-
4¢), 158.4 (C-2¢).
(1S,2S)-1-Phenyl-3-[2-(tert-butyldimethylsilyloxy)phenyl]pro-
pane-1,2-diol (11a)
Yield: 89%; colorless oil; [a]D –4.7 (c 1.0, CH2Cl2).
IR (film): 3405, 3062, 2892, 1581, 1490, 1452, 1253 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.21 (s, 3 H, SiCH3), 0.23 (s, 3 H,
SiCH3), 1.00 [s, 9 H, SiC(CH3)3], 2.75 (dd, J = 9.2, 4.4 Hz, 1 H, 3-
Ha), 2.79 (dd, J = 8.5, 4.2 Hz, 1 H, 3-Hb), 2.91 (br, 1 H, 2-OH), 3.97
(m, 1 H, 2-H), 4.51 (d, J = 5.7 Hz, 1 H, 1-H), 6.84 (dd, J = 8.1, 1.1
Hz, 1 H, 3¢-H), 6.92 (ddd, J = 8.1, 7.5, 1.1 Hz, 1 H, 5¢-H), 7.13 (ddd,
J = 7.8, 7.7, 1.8 Hz, 1 H, 4¢-H), 7.18 (dd, J = 7.5, 1.8 Hz, 1 H, 6¢-H),
7.29–7.39 (m, 5 H, ArH).
MS (EI): m/z (%) = 888.4 (0.40) [M+], 753 (1), 723 (1), 665 (1), 525
(1), 463 (10), 433 (8), 343 (2), 253 (2), 181 (12), 91 (100), 65 (3).
HRMS: m/z [M]+ calcd for C56H60O8Si: 888.40576; found:
888.40467.
TBS Deprotection; General Procedure
13C NMR (50 MHz, CDCl3): d = –3.8 [Si(CH3)2], 18.2 [SiC(CH3)3],
25.9 [SiC(CH3)3], 34.5 (C-3), 75.6 (C-2), 77.3 (C-1), 118.3, 121.4,
126.9, 127.6, 127.8, 128.0, 128.2, 128.4, 128.6, 131.6 (Ar), 141.1
(C-1¢¢), 153.8 (C¢-2).
MS (EI): m/z (%) = 358 (2) [M+], 325 (4), 283 (96), 265 (37), 251
(42), 205 (12), 177 (24), 165 (18), 119 (60), 91 (100), 73 (71), 45
(4).
To a solution of TBS-protected diols 11a–d (0.87 mmol) in anhy-
drous THF (16 mL), was added TBAF·3H2O (250 mg, 0.79 mmol).
The reaction mixture was stirred at r.t. for 1.5 h. After complete con-
version (monitored by TLC), the reaction mixture was quenched by
addition of sat. aq NaHCO3 (3 mL). The reaction mixture was dilut-
ed with H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The
combined organic layer was washed with brine (25 mL) and H2O
(25 mL). The organic layer was then dried (MgSO4) and concentrat-
ed under reduced pressure to obtain a brown residue which was pu-
rified by flash chromatography on a silica gel column (EtOAc–PE,
1:3) to obtain triols 12a–d.
HRMS: m/z [M]+ calcd for C21H30O3Si: 358.19641; found:
358.19617.
(1S,2S)-1-(4-Methoxyphenyl)-3-[4-methoxy-2-(tert-butyldi-
methylsilyloxy)phenyl]propane-1,2-diol (11b)
Yield: 84%; mp 74–76 °C; [a]D +4.5 (c 1.0, CH2Cl2).
(1S,2S)-3-(2-Hydroxyphenyl)-1-phenylpropane-1,2-diol (12a)
Yield: 95%; mp 108–109 °C; [a]D +36.6 (c 1.0, CH2Cl2).
IR (KBr): 3396, 3019, 1610, 1504, 1489, 1288, 1245, 1162, 1041,
835, 700 cm–1.
IR (KBr): 3415, 2886, 1581, 1509, 1488, 1398, 1240, 1039, 844,
757 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.18 (s, 3 H, SiCH3), 0.20 (s, 3 H,
SiCH3), 0.95 [s, 9 H, SiC(CH3)3], 2.59 (dd, J = 9.2, 3.7 Hz, 1 H, 3-
Ha), 2.68 (dd, J = 9.2, 3.7 Hz, 1 H, 3-Hb), 3.74 (s, 3 H, OCH3), 3.79
(s, 3 H, OCH3), 3.85 (m, 1 H, 2-H), 4.50 (d, J = 6.1 Hz, 1 H, 1-H),
6.38 (d, J = 2.6 Hz, 1 H, 3¢-H), 6.46 (dd, J = 8.4, 2.5 Hz, 1 H, 5¢-H),
6.89 (dt, J = 6.8, 2.5 Hz, 2 H, 3¢¢-H, 5¢¢-H), 7.03 (d, J = 8.4 Hz, 1 H,
6¢-H), 7.28 (dt, J = 6.8, 1.8 Hz, 2 H, 2¢¢-H, 6¢¢-H).
13C NMR (50 MHz, CDCl3): d = –3.9 [Si(CH3)2], 18.2 [SiC(CH3)3],
25.8 [SiC(CH3)3], 33.7 (C-3), 55.24 (OCH3), 55.26 (OCH3), 75.8
(C-2), 76.8 (C-1), 105.7 (C-3¢), 106.1 (C-5¢), 113.8, 113.9 (C-3¢¢, C-
5¢¢), 120.8 (C-1¢), 128.1 (C-2¢¢), 128.5 (C-6¢¢), 131.7 (C-6¢), 133.2
(C-1¢¢), 154.5 (C-2¢), 159.1 (C-4¢), 159.2 (C-4¢¢).
1H NMR (200 MHz, CDCl3): d = 2.66 (m, 1 H, 3-Ha), 2.74 (m, 1 H,
3-Hb), 4.08 (m, 1 H, 2-H), 4.51 (d, J = 7.7 Hz, 1 H, 1-H), 6.75–6.90
(m, 2 H, ArH), 7.11–7.41 (m, 7 H, ArH).
13C NMR (50 MHz, CDCl3): d = 34.7 (C-3), 76.7 (C-2), 77.3 (C-1),
117.2, 120.2, 124.4, 127.1, 128.5, 128.6, 128.6, 128.6, 129.3, 131.7
(Ar), 140.1 (C-1¢¢), 155.5 (C¢-2).
MS (EI): m/z (%) = 244 (48) [M+], 207 (3), 165 (5), 137 (44), 108
(100), 65 (12), 28 (5).
HRMS: m/z [M]+ calcd for C15H16O3: 244.10994; found:
244.10980.
(1S,2S)-3-(2-Hydroxy-4-methoxyphenyl)-1-(4-methoxy-
phenyl)propane-1,2-diol (12b)
Yield: 94%; mp 103–104 °C; [a]D –1.6 (c 1.0, CH2Cl2).
MS (EI): m/z (%) = 418 (12) [M+], 350 (8), 313 (5), 281 (60), 251
(28), 223 (35), 167 (24), 149 (100), 75 (58), 73 (56), 928 (47).
HRMS: m/z [M]+ calcd for C23H34O5Si: 418.21756; found:
418.21733.
IR (KBr): 3546, 3465, 3361, 2965, 1641, 1444, 1206, 1176, 1076,
827 cm–1.
Synthesis 2009, No. 5, 779–786 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of Flavan-3-ols
785
1H NMR (200 MHz, CDCl3): d = 2.51 (dd, J = 14.8, 7.3 Hz, 1 H, 3-
Ha), 2.60 (dd, J = 14.8, 3.2 Hz, 1 H, 3-Hb), 3.68 (s, 3 H, OCH3),
3.77 (s, 3 H, OCH3), 3.93 (m, 1 H, 2-H), 4.29 (d, J = 7.8 Hz, 1 H, 1-
H), 6.33 (dd, J = 8.3, 2.5 Hz, 1 H, 5¢-H), 6.44 (d, J = 2.6 Hz, 1 H, 3¢-
H), 6.61 (d, J = 8.3 Hz, 1 H, 6¢-H), 6.84 (dt, J = 7.0, 1.8 Hz, 2 H, 3¢¢-
H, 5¢¢-H), 7.28 (dt, J = 7.0, 1.7 Hz, 2 H, 2¢¢-H, 6¢¢-H).
13C NMR (50 MHz, CDCl3): d = 34.1 (C-3), 55.22 (OCH3), 55.26
(OCH3), 76.1 (C-2), 77.3 (C-1), 102.3 (C-3¢), 106.0 (C-5¢), 113.9
(C-1¢), 114.0 (C-3¢¢), 114.3 (C-5¢¢), 128.2 (C-2¢¢), 128.4 (C-6¢¢),
131.9 (C-6¢), 132.2 (C-1¢¢), 156.3 (C-2¢), 159.5 (C-4¢), 159.8 (C-4¢¢).
MS (EI): m/z (%) = 304 (34) [M+], 286 (54), 167 (32), 137 (100),
109 (33), 65 (6).
HRMS: m/z [M]+ calcd for C17H20O5: 304.13107; found:
304.13115.
wise to the reaction mixture. After stirring for 3 h at r.t. (reaction
monitored by TLC), the reaction mixture was diluted with EtOAc
(40 mL) and washed with H2O (30 mL) and brine (30 mL). The or-
ganic phase was dried over MgSO4, filtered and concentrated under
reduced pressure to give a brown residue. The residue obtained was
purified by silica gel column chromatography (EtOAc–PE, 1:3) to
afford of the cyclized products 13a–d as white solids.
2,3-trans-Flavan-3-ol (13a)28
Yield: 75%; mp 107–109 °C; 91.2% ee (HPLC); [a]D –7.9 (c 1.0,
CH2Cl2).
IR (KBr): 3403, 3031, 2911, 1583, 1488, 1301, 1247, 1114, 1037,
750, 701 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.86 (d, J = 3.8 Hz, 1 H, 3-OH),
2.93 (dd, J = 16.1, 8.8 Hz, 1 H, 4-Ha), 3.09 (dd, J = 16.1, 5.3 Hz,
1 H, 4-Hb), 4.12 (m, 1 H, 3-H), 4.65 (d, J = 7.8 Hz, 1 H, 2-H), 6.87–
6.95 (m, 2 H, 6-H, 8-H), 7.11–7.20 (m, 2 H, 5-H, 7-H), 7.33–7.46
(m, 5 H, ArH).
13C NMR (50 MHz, CDCl3): d = 32.8 (C-4), 68.6 (C-3), 81.9 (C-2),
116.5, 120.1, 121.0, 127.1, 127.7, 128.6, 128.8, 129.6, 130.0, 131.0,
138.2 (Ar), 154.0 (C-8a).
MS (EI): m/z (%) = 226.17 (44) [M+], 177 (8), 176 (48), 149 (56),
107 (100), 91 (78), 57 (28), 43 (42).
HRMS: m/z [M]+ calcd for C15H14O2: 226.09938; found:
226.09947.
(1S,2S)-3-(4-Benzyloxy-2-hydroxyphenyl)-1-(4-benzyloxy-
phenyl)propane-1,2-diol (12c)
Yield: 95%; mp 122–124 °C; [a]D –1.28 (c 1.0, CHCl3).
IR (KBr): 3426, 3033, 2892, 1614, 1509, 1440, 1286, 1168, 1024
cm–1.
1H NMR (500 MHz, CDCl3): d = 2.55 (dd, J = 15.2, 8.3 Hz, 1 H, 3-
Ha), 2.71 (dd, J = 14.2, 6.1 Hz, 1 H, 3-Hb), 4.07 (br, 1 H, 2-H), 4.41
(d, J = 7.2 Hz, 1 H, 1-H), 5.04 (s, 2 H, OCH2Ph), 5.11 (s, 2 H,
OCH2Ph), 6.47 (dd, J = 8.3, 2.4 Hz, 1 H, 5¢-H), 6.62 (d, J = 2.4 Hz,
1 H, 3¢-H), 6.69 (d, J = 8.7 Hz, 1 H, 6-H), 7.04 (d, J = 8.7 Hz, 2 H,
3¢¢-H, 5¢¢-H), 7.24–7.46 (m, 12 H, 2¢¢-H, 6¢¢-H, ArH).
13C NMR (125 MHz, CDCl3): d = 34.6 (C-3), 70.4 (OCH2Ph), 70.5
(OCH2Ph), 76.1 (C-2), 76.1 (C-1), 104.1 (C-3¢), 107.3 (C-5¢), 115.5
(C-3¢¢, C-5¢¢), 117.1 (C-1¢), 127.9 (C-1¢), 127.6, 127.8, 127.7, 128.3,
128.5, 128.9, 129.0, 132.7, 133.8, 137.1, 137.5 (Ar), 157.1 (C-2¢),
159.4 (C-4¢), 159.6 (C-4¢¢).
2,3-trans-7,4¢-Dimethoxyflavan-3-ol (13b)26,29
Yield: 82%; mp 89–90 °C (Lit.26 86–88 °C); 75.7% ee [>98% after
one recrystallization (EtOAc–PE, 1:7)]; [a]D –9.2 (c 1.0, CH2Cl2).
IR (KBr): 3440, 2933, 1619, 1506, 1398, 1247, 1157 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.01 (br, 1 H, 3-OH), 2.81 (dd,
J = 15.7, 8.9 Hz, 1 H, 4-Ha), 3.01 (dd, J = 15.7, 5.3 Hz, 1 H, 4-Hb),
3.75 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 4.06 (m, 1 H, 3-H), 4.72
(d, J = 8.0 Hz, 1 H, 2-H), 6.48 (d, J = 2.5 Hz, 1 H, 8-H), 6.53 (dd,
J = 8.4, 2.5 Hz, 1 H, 6-H), 6.94 (dt, J = 6.7, 2.0 Hz, 2 H, 3¢-H, 5¢-H),
7.00 (d, J = 8.4 Hz, 1 H, 5-H), 7.36 (dt, J = 6.7, 2.0 Hz, 2 H, 2¢-H,
6¢-H).
13C NMR (50 MHz, CDCl3): d = 32.4 (C-4), 55.3 (OCH3), 68.6 (C-
3), 81.7 (C-2), 101.3 (C-8), 108.0 (C-6), 112.1 (C-4a), 114.2 (C-3¢,
C-5¢), 127.6, 128.5, 130.1, 130.3, 130.6 (Ar), 154.9 (C-8a), 159.4
(C-4¢), 159.9 (C-7).
MS (EI): m/z (%) = 456 (10) [M+], 438 (60), 362 (16), 243 (36), 213
(97), 137 (50), 123 (58), 91 (100), 65 (25).
HRMS: m/z [M]+ calcd for C29H28O5: 456.1937; found: 456.1934.
(1S,2S)-3-[2,4-Bis(benzyloxy)-6-hydroxyphenyl]-1-[3,4,5-
tris(benzyloxy)phenyl]propane-1,2-diol (12d)27
Yield: 92%; mp 144–145 °C (no mp given in Lit.27); [a]D +11.61 (c
1.0, CHCl3) [Lit.10 +11.54 (c 1.0, CHCl3)].
IR (film): 3426, 2965, 1436, 1376, 1272, 1112, 879, 777, 694 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.75 (dd, J = 14.8, 8.4 Hz, 1 H, 3-
Ha), 2.90 (dd, J = 14.8, 3.6 Hz, 1 H, 3-Hb), 3.92 (ddd, J = 8.4, 5.6,
3.6 Hz, 1 H, 2-H), 4.43 (d, J = 5.6 Hz, 1 H, 1-H), 4.89 (s, 2 H,
OCH2Ph), 4.95–5.05 (m, 8 H, OCH2Ph), 6.21 (d, J = 2.0 Hz, 1 H,
5¢-H), 6.26 (d, J = 2.0 Hz, 1 H, 3¢-H), 6.59 (s, 2 H, 2¢¢-H, 6¢¢-H),
7.25–7.45 (m, 25 H, ArH).
13C NMR (125 MHz, CDCl3): d = 26.9 (C-3), 70.0 (OCH2Ph), 71.3
(OCH2Ph), 75.3 (OCH2Ph), 76.9 (OCH2Ph), 77.1 (OCH2Ph), 79.4
(C-1), 82.1 (C-2), 93.9 (C-3¢), 98.5 (C-5¢), 105.9 (C-2¢¢, C-6¢¢),
112.1 (C-1¢), 127.3, 127.4, 127.4, 127.7, 128.1, 128.4, 128.5, 128.5,
128.7, 128.7, 128.8, 128.9, 128.9, 129.0, 129.6, 130.6, 133.3, 137.1,
137.3, 137.6, 138.0 (Ar), 152.1 (C-4¢¢), 152.8 (C-3¢¢, C-5¢¢), 154.7
(C-6¢), 158.1 (C-4¢), 158.4 (C-2¢).
MS (EI): m/z (%) = 286.12 (78) [M+], 233 (5), 176 (40), 150 (58),
137 (100), 121 (82), 91 (28), 75 (32).
HRMS: m/z [M]+ calcd for C17H18O4: 286.12051; found:
286.12047.
2,3-trans-7,4¢-Bis(benzyloxy)flavan-3-ol (13c)12
Yield: 77%; mp 96–98 °C (no mp given in Lit.12); 97.7% ee after
chromatography (EtOAc–PE, 1:3) and crystallization (EtOAc–PE,
1:7); [a]D –17.38 (c 1.11, CHCl3) [Lit.10 –16.1 (c 1.11, CHCl3)].
1H NMR (500 MHz, CDCl3): d = 2.13 (br, 1 H, 3-OH), 2.94 (dd,
J = 15.6, 9.0 Hz, 1 H, 4-Ha), 3.06 (dd, J = 15.6, 5.3 Hz, 1 H, 4-Hb),
4.13 (m, 1 H, 3-H), 4.65 (d, J = 8.0 Hz, 1 H, 2-H), 5.04 (s, 2 H,
OCH2Ph), 5.13 (s, 2 H, OCH2Ph), 6.67 (dd, J = 8.1, 2.4 Hz, 2 H, 3¢-
H, 5¢-H), 7.08 (m, 3 H, 5-H, 6-H, 8-H), 7.30–7.47 (m, 12 H, ArH).
13C NMR (125 MHz, CDCl3): d = 32.5 (C-4), 68.6 (C-3), 70.4
(OCH2Ph), 82.1 (C-2), 107.6, 137.2, 137.4 (Ar), 155.2 (C-8a),
158.9 (C-4¢), 159.5 (C-7).
MS (EI): m/z (%) = 774 (0.2) [M+], 665 (0.1), 542 (0.1), 450 (0.1),
396 (3), 348 (2), 306 (4), 227 (1), 142 (2), 91 (100), 51 (2).
HRMS: m/z [M]+ calcd for C50H46O8: 774.31927; found:
774.31266.
Mitsunobu Reaction; General Procedure
MS (EI): m/z (%) = 438 (98) [M+], 362 (8), 347 (24), 226 (34), 213
(88), 107 (26), 91 (100), 65 (22).
HRMS: m/z [M]+ calcd for C29H26O4: 438.18311; found:
438.18333.
To a solution of triols 12a–d (0.56 mmol) in anhydrous THF (6
mL), was added Ph3P (225 mg, 0.86 mmol). The mixture was stirred
for 15 min and DEAD (0.13 mL, 0.83 mmol) was then added drop-
Synthesis 2009, No. 5, 779–786 © Thieme Stuttgart · New York

786
K. Krohn et al.
PAPER
2,3-trans-5,7,3¢,4¢,5¢-Pentakis(benzyloxy)flavan-3-ol (13d)27
Yield: 71%; mp 116–118 °C (no mp given in Lit.27); 47.3% ee
[~85% ee after one crystallization (EtOAc–PE, 1:7)]; [a]D –8.96 (c
1.0, CHCl3) [Lit.11 –7.21 (c 1.0, CHCl3)].
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IR (film): 3550, 3029, 1592, 1536, 1374, 1295, 1116, 773 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.76 (br s, 1 H, 3-OH), 2.75 (dd,
J = 16.5, 9.0 Hz, 1 H, 4-Ha), 3.15 (dd, J = 16.5, 6.0 Hz, 1 H, 4-Hb),
4.01 (ddd, J = 9.0, 8.1, 6.0 Hz, 1 H, 3-H), 4.65 (d, J = 8.1 Hz, 1 H,
2-H), 5.04 (s, 2 H, OCH2Ph), 5.07 (s, 2 H, OCH2Ph), 5.10 (s, 2 H,
OCH2Ph), 5.11 (s, 2 H, OCH2Ph), 5.14 (s, 2 H, OCH2Ph), 6.29 (d,
J = 2.4 Hz, 1 H, 8-H), 6.34 (d, J = 2.4 Hz, 1 H, 6-H), 6.78 (s, 2 H,
2¢-H, 6¢-H), 7.30–7.55 (m, 25 H, ArH).
13C NMR (50 MHz, CDCl3): d = 27.9 (C-4), 68.5 (C-3), 70.2
(OCH2Ph), 70.4 (OCH2Ph), 71.4 (OCH2Ph), 82.1 (C-2), 94.2 (C-8),
94.6 (C-6), 102.6 (C-4a), 106.9 (C-2¢, C-6¢), 127.4, 127.8, 127.9,
128.0, 128.1, 128.2, 128.3, 128.5, 128.7, 128.8, 128.9, 129.0, 133.6,
137.1, 137.2, 138.0, 138.9 (Ar), 153.1 (C-4¢), 153.3 (C-3¢, C-5¢),
155.4 (C-5), 158.0 (C-8a), 159.1 (C-7).
MS (EI): m/z (%) = 756 (1) [M+], 725 (1), 665 (3), 575 (1), 528 (1),
463 (1), 433 (4), 319 (10), 306 (7), 215 (2), 181 (25), 91 (100), 44
(8).
HRMS: m/z [M]+ calcd for C50H44O7: 756.30872; found:
756.30645.
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Synthesis 2009, No. 5, 779–786 © Thieme Stuttgart · New York