Enantioselctive syntheses of sulfur analogues of flavan-3-ols

Article abstract of DOI:10.3390/molecules15085595

The first enantioselective syntheses of sulfur flavan-3-ol analogues 1-8 have been accomplished, whereby the oxygen atom of the pyran ring has been replaced by a sulfur atom. The key steps were: (a) Pd(0) catalyzed introduction of -S t-butyl group, (b) Sh

Full text of DOI:10.3390/molecules15085595

Molecules 2010, 15, 5595-5619; doi:10.3390/molecules15085595
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Enantioselctive Syntheses of Sulfur Analogues of Flavan-3-Ols
Pradeep K. Sharma 1,2,*, Min He 1, Jurjus Jurayj 1, Da-Ming Gou 1, Richard Lombardy 1,
Leo J. Romanczyk Jr. 3 and Hagen Schroeter 3
1
Chemical Process Research & Development and Analytical Development, Johnson Matthey
Pharmaceutical Materials Inc., 25 Patton Road, Devens, MA 01434, USA
2
Chemical Process R&D and CMC Regulatory, ARIAD Pharmaceuticals Inc., Cambridge, MA
02139, USA
3
MARS Incorporated, 6885 Elm Street, McLean, VA 22101, USA
* To whom correspondence should be addressed; E-Mail: sharmap76@yahoo.com;
Tel.: 978 394 9341.
Received: 26 July 2010; in revised form: 12 August 2010 / Accepted: 12 August 2010 /
Published: 13 August 2010
Abstract: The first enantioselective syntheses of sulfur flavan-3-ol analogues 1–8 have
been accomplished, whereby the oxygen atom of the pyran ring has been replaced by a
sulfur atom. The key steps were: (a) Pd(0) catalyzed introduction of –S t-butyl group, (b)
Sharpless enantioselective dihydroxylation of the alkene, (c) acid catalyzed ring closure to
produce the thiopyran ring, and (d) removal of benzyl groups using N,N-dimethylaniline
and AlCl3. The compounds were isolated in high chemical and optical purity.
Keywords:
flavan-3-ols;
5,7-dideoxythiocatechin;
5,7-dideoxythioepicatechin;
thiocatechin; thioepicatechin; asymmetric dihydroxylation
1. Introduction
Oligomeric and polymeric proanthocyanidins are some of the most ubiquitous groups of all the
plant phenolics [1] and their health benefits are well known. A large number of in vitro studies have
characterized flavanols as powerful antioxidants capable of efficient scavenging of both reactive
oxygen and reactive nitrogen species [2-8]. The mechanism of their action as radical scavengers
involves the donation of a hydrogen atom and/or electron to stabilize the radical species [9]. Until
recently, the ability of flavanols, and indeed other flavonoids, to act as classical H-donating

Molecules 2010, 15
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antioxidants was believed to underlie many of their reported health benefits [10-16]. However, it is
now clear that their ultimate antioxidant potential, and indeed their resulting potential in vivo
bioactivity is dependent on the absorption, metabolism, distribution, reducing properties of the
resulting metabolites, and excretion of these compounds within the body after ingestion. An
understanding of the processes involved in the absorption and distribution of flavonoids is essential to
determine their potential bioactivities in vivo and their overall significance in disease prevention [17].
The building blocks for most of these oligomeric and polymeric proanthocyanidins are the flavan-3-ols
(+)-catechin and (-)-epicatechin, whose stereochemistry allows for a large array of structural
possibilities [1]. In nature, (+)-catechin is widely distributed, whereas (-)-epicatechin, (-)-catechin, and
(+)-epicatechin are much less abundant (Figure 1).
Figure 1. Structures of catechin and epicatechin enantiomers.
OH
OH
B
HO
HO
O
HO
HO
O
C
2
7
OH
OH
A
3
OH
OH
5
OH
OH
(-)-Epicatechin
(+)-Catechin
OH
OH
OH
OH
O
O
OH
OH
OH
(-)-Catechin
OH
(+)-Epicatechin
This structural diversity of polyphenols is a subject of interest because of their varied biological
activities [18-23]. Included are an interesting group of sulfur conjugated flavan-3-ols that are derived
from cysteine and cysteamine [24-31]. Replacement of oxygen with sulfur is particularly appealing
because of the isovalent and isosteric relationship between sulfur and oxygen with minimal structural
disruption and possibly impacting the activity and the metabolism of the molecule. Sulfur exists in a
variety of oxidation states including -2, +4, and +6. The sulfur can undergo single oxidation to the
sulfoxide or it may be further oxidized to sulfone. The replacement of oxygen in the pyran ring with
sulfur might offer profound changes in the pharmacological action of the molecules. We are unaware
of any reports which describe the occurrence of thiocatechins or its analogues, whereby the oxygen in
the pyran ring is replaced with sulfur, although the synthesis of thioflavones and their methoxy
derivatives have been described [31,32]. Wang et al. [33] also reported two novel sulfur containing
flavanols isolated from the leaves of Glycosmis montana. Additionally, Lonano et al. [34] has reported
that 4-(S-cysteinyl)epicatechin-3-O-gallate has a free radical scavenging capacity as strong as that of
(-)-epigallocatechin gallate and causes significant S-phase cell cycle arrest in certain cell lines at doses
higher than 100 M. The other cysteinyl compounds do not affect normal cell cycle distribution. The
gallate derivatives also induce apoptosis in melanoma cells more strongly than the other derivatives
and (-)-epicatechin. The gallate compound seems to trigger nuclear condensation and fragmentation,
which was confirmed by DNA laddering. However, they do not induce apoptosis in
keratinocytes (HaCaT).

Molecules 2010, 15
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In this report, we wish to describe the first syntheses of sulfur analogues for all four isomers and A-
ring dideoxy analogues of naturally occurring catechin. These are 5,7-dideoxy-(+)-thiocatechin (1),
5,7-dideoxy-(-)-thioepicatechin (2), 5,7-dideoxy-(-)-thiocatechin (3), 5,7-dideoxy-(+)-thioepicatechin
(4) and fully substituted analogues namely (+)-thiocatechin (5), (-)-thioepicatechin (6), (-)-thiocatechin
(7), and (+)-thioepicatechin (8), as depicted in Figure 2.
Figure 2. Structures of analogues of catechin and epicatechin enantiomers.
OH
OH
S
S
OH
OH
OH
OH
5,7-Dideoxy-(-)-thioepicatechin
5,7-Dideoxy-(+)-thiocatechin
2
1
OH
OH
S
S
OH
OH
OH
OH
5,7-Dideoxy-(-)-thiocatechin
5,7-Dideoxy-(+)-thioepicatechin
3
4
OH
OH
HO
S
HO
S
OH
OH
OH
OH
OH
OH
(+)-Thiocatechin
(-)-Thioepicatechin
5
6
OH
OH
OH
OH
HO
S
HO
S
OH
OH
OH
OH
(+)-Thioepicatechin
(-)-Thiocatechin
8
7
2. Results and Discussion
Our aim was to initially develop a methodology for the synthesis of 1 to 4 and then apply the same
methodology for the analogues 5 to 8. The retro-synthetic approach for the construction of 1 is
depicted in Figure 3, which we envisioned as a direct approach. We contemplated the use of C as a
starting material where enantio-selective -hydroxylation of the 4-position ketone could be achieved
via Davis methodology [35,36] or by converting the ketone in situ to a silyl enol ether followed by
Sharpless asymmetric dihydroxylation [37]. Initially, we explored the methodology on a commercially
available model compound, namely phenylthiochroman-3-one (R1=H). Thus, attempts to introduce the
3-position hydroxyl group to phenylthiochroman-3-one using Mn(OAc)3•2H2O either in benzene or

Molecules 2010, 15
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toluene at reflux or in a mixture of benzene/glacial AcOH or CH2Cl2 with or without glacial AcOH
resulted in a complex and inseparable mixture [38].
Figure 3. Initial retrosynthetic approach.
R1
R1
R1
R1
R1
R1
S
S
S
OR
OR
O
B
O
A
C
R= protecting group
R1= OBn or OMe or OTBDMS
Alternatively, attempts to react phenylthiochroman-3-one with TMSCl or TBDMSCl in the
presence of Et3N/DMAP in MTBE or Et3N/DMAP in CH2Cl2 at ambient temperature in situ followed
by reaction under Sharpless asymmetric dihdyroxylation did not produce the desired compound. In all
the attempts, the starting material was recovered. Having been unsuccessful in the direct approach for
the construction of the desired compounds via the introduction of hydroxyl group  to the ketone, we
modified our approach as depicted in Figure 4.
Figure 4. Modified retrosynthetic approach.
R1
R1
R1
R1
R1
R1
P
S
P
S
S
OR
OR
OR
D
A
E
R1
R1
OH
O
R1
R1
R or P= H or a protecting group
R1= OBn or OMe or OTBDMS
OH
X = H2, O
OHC
X
H
G
F
In Figure 4, the challenge resides in converting the phenolic group to a suitably protected thiol
group, which could then be deprotected to form the desired intermediate A. An additional challenge
would be to retain the stereochemistry at the benzylic 2-position under the deprotection conditions.
The use of the benzyl group was chosen to protect the phenolic groups because of the ease of removal
under mild conditions.
2.1. Synthesis of 16 and 17
In Scheme 1, the base catalyzed condensation between 2-hydroxyacetophenone 9 and 3,4-bis-
(benzyloxy)benzaldehyde 10 furnished the chalcone 11 in quantitative yield via a Claisen-Schmidt
reaction. Selective reduction of the keto group of 11 with NaBH4 and CeCl3•7H2O in a mixture of THF

Molecules 2010, 15
5599
and water resulted in the desired compound 12 in low yield after chromatography [39]. Alternatively,
when 11 was subjected to treatment with ethyl chloroformate in the presence of Et3N in THF at 0 °C,
the corresponding ethyl carbamate intermediate was formed and reacted with NaBH4 in aqueous media
after removal of the salts. After workup and purification, 12 was furnished in 66% yield [40].
Scheme 1. Synthesis of 16 and 17.
OBn
NaH, DMF
0-5 oC
EtOCOCl
NaBH4, THF
OBn
OBn
OH
O
OH
OBn
+
100%
66%
OHC
O
10
9
11
OBn
OBn
OBn
Pd(OAc)2, NaN(TMS)2,
(R)-Tol-BINAP, PhMe,
tBuSH
Tf
O
Tf2O, Pyridine
0 oC to RT
76%
OH
OBn
98%
12
13

AD-mix
OBn
OBn
OBn
OBn
MeSO2NH2
tBuOH, H2O
CH2Cl2
tBu
S
tBu
TFA, CH2Cl2,
0 - 5 oC
S
OH
OH
86%
73%
14
S
15
OBn
OBn
OBn
OBn
S
OH
OH
16
17
The reaction of 12 with Tf2O in pyridine at ambient temperature yielded 13 in 76% yield after
chromatography. The use of other bases such as Et3N, DMAP or DIPEA in THF or CH2Cl2 did not
result in complete reaction. We envisioned the introduction of an –STIPS group [41] where the TIPS
could be removed under mild acidic conditions or by nBu4NF to generate the thiol. Our attempts to
effect Pd catalyzed coupling of TIPSSH with triflate 13 using Pd(PPh3) 4, Pd(OAc) 2, (R)-Tol-BINAP
and TIPSH in the presence of a base (NaH or NaN(TMS)2) in toluene did not produce the desired
compound and the starting material was recovered. Alternatively, the introduction of an
–S t-butyl group was accomplished using the methodology reported by McWilliams et al. [42]. Under
the conditions, triflate 13 was treated with NaSt-Bu or KSt-Bu (generated in situ by reacting HSt-Bu
with NaHDMS or KHDMS at ambient temperature in the presence of Pd(OAc) 2, (R)-Tol-BINAP in
toluene at 100 °C for 18h to produce 14 in 98% yield after chromatography. Attempts to replace
Pd(OAc)2, (R)-Tol-BINAP with Pd(PPh3)4 under similar conditions did not produce the desired
compound. Sharpless asymmetric dihydroxylation of 14 with AD-mix- and CH3SO2NH2 in the
t
presence of BuOH, H2O and CH2Cl2 at 0 °C resulted in 15 in 86% yield [43]. Attempts to replace
CH2Cl2 with acetone or toluene did produce 15 but in low yield and ee. Literature precedence and

Molecules 2010, 15
5600
conversion of 15 to 16 established the stereochemical assignment of 15. The ee of 15 was 100% as
determined by chiral HPLC. The dihydroxylation of 14 also furnished ~5% of a sulfoxide by product,
which was easily removed by chromatography. Having the key intermediate 15, we focused our
attention at the removal of the tert-butyl group followed by cyclization under acidic conditions. The
treatment of 15 with excess TFA in CH2Cl2 at ambient temperature for 24 h resulted in a complex
mixture. However, LCMS indicated the presence of only a trace of the desired compound. These
results revealed product formation, but additional by products were also formed. LCMS showed that t-
butylation of the oxygenated phenyl group was a side reaction which prompted the examination of
cationic scavengers. Reacting 15 with TFA in CH2Cl2 in the presence of iPr3SiH or anisole as
scavengers at 0 °C resulted in the formation of two non-polar major products as determined by HPLC.
However, when the workup was performed at ambient temperature, multiple products were obtained
probably the result of product decomposition. A modification was made in the reaction work up
conditions where 15 was treated with TFA in CH2Cl2 at 0 °C for 24h. Under these modified
conditions, the reaction was quenched with an equimolar amount of Et3N at 0 °C followed by the
addition of cold water (<5 °C) before bringing the reaction mixture to ambient temperature for thin
layer separation. The crude product was purified by chromatography producing 16 and 17 in 93:7 ratio,
respectively. The enantiomeric excess of 16 and 17 were determined to be 96% and 100% respectively
by chiral HPLC analysis. Compound 16 having trans-2,3-orientation was isolated as the major
component along with the cis-isomer 17 as a minor product. The formation of 17 under these
conditions suggested that the activated benzylic 2-position in the sequence could not maintain its
stereochemical integrity, thus producing 17 as a minor diastereomer.
2.2. Proposed mechanism for the formation of 16 and 17
The proposed mechanism for the formation of 16 and 17 is outlined in Scheme 2. The benzylic
carbocations generated in situ might form the epoxide which is followed by ring closure (Approach 1)
in the presence of an acid. Alternatively, the attack of the sulfur atom to close the ring (Approach 2)
followed by loss of the tert-butyl group as isobutene would lead to product formation. Thus, the
carbocation generated at benzylic 2-position would lose its stereochemical integrity and thus form the
minor isomer 17. Formation of both catechin and epicatehin derivatives is explicable in terms of the
generation of an incipient benzylic 2-position carbocation via protonation of the benzylic alcohol
functionality, and subsequent SN1 cyclization that leads to the predominant formation of the
thermodynamically more stable trans-isomer along with the cis isomer. If the formation of the
diastereomer occurs via carbocation scrambling, then the diastereomeric ratio would be 1:1. Note that
other mechanisms are possible for the formation of the diastereomers. No kinetic studies were
performed at this time to determine the stability of the benzylic 2-position carbocation. However, from
the ratio of the major and minor isomer it was concluded that temperature might play an important role
[44-46].
The use of other acids such as 6N HCl or CH3SO3H in either CH2Cl2 or THF in place of TFA at
0 °C were investigated and resulted in only < 50% conversion after 48 h.

Molecules 2010, 15
5601
Scheme 2. Proposed mechanism of the cyclization of 15.
OBn
OBn
OBn
cation
S
OBn
formation
OH
OH
S
Approach 2
OH
Epoxide formation
Approach 1
OBn
OBn
OBn
S
OBn
O
S
OH
loss of
OBn
OBn
OBn
S
OBn
O H
S
OH
2.3. Synthesis of 19 and 20
For the synthesis of 19 and 20 (Scheme 3), alkene 14 was reacted with AD-mix- under Sharpless
asymmetric dihydroxylation conditions giving 18 in 83% yield, and 100% ee.
Scheme 3. Synthesis of 19 and 20.
OBn
OBn
OBn
OBn

AD-mix- ,
TFA
CH3SO2NH2,
tBuOH, H2O
S
S
CH2Cl2, 0 oC
OH
OH
73%
83%
14
18
OBn
OBn
OBn
S
S
OBn
OH
OH
19
20
Compound 18 has a similar NMR spectrum to 15 but opposite optical rotation. The presence of
~5% sulfoxide, which was efficiently removed by chromatography, was observed during the formation
of 18. The treatment of 18 with TFA in CH2Cl2 at 0 °C resulted in the major 19 and a minor
diasteromer 20 after chromatographic purification. The enantiomeric excess of 19 and 20 were found
to be 99% and 99.5%, respectively.

Molecules 2010, 15
5602
2.4. Synthesis of 1, 2, 3, and 4
Once the synthesis of the penultimate intermediates 16, 17, 19, and 20 were accomplished, our
attention was turned to optimizing the debenzylation conditions. The catalytic hydrogenation of 16
with 20% Pd/C or 10% Pd(OH)2/C in CH3OH, EtOAc or CH3OH/EtOAc (1/4, v/v) resulted in an
incomplete reaction. Increasing catalyst loading, extending the reaction time (up to 72 h) or increasing
the hydrogen pressure (up to 50 psi) did not change the course of the reaction. Use of Pd black along
with 1,4-cyclohexadiene with or without the presence of a scavenger (N,N-dimethylaniline) or
5%Pd/Al2O3 at 15 psi H2 pressure in EtOAc/CH3OH (3/2, v/v) did result in an incomplete reaction.
The reaction mixture consisted of debenzylated product, partially benzylated intermediates, and the
starting material. The incomplete reaction was thought to be due to the poisoning of the catalyst in the
presence of the sulfur atom in the molecule. A non-catalytic deprotection method using BCl3 with
nBu4NI was not successful. Finally, compound 16 was treated with AlCl3 at 0 °C in the presence of
N,N-dimethylaniline in CH2Cl2 to produce 1 in 54% yield after purification by preparative HPLC [47]
(Scheme 4).
Scheme 4. Debenzylation of 16.
OBn
OBn
OH
OH
AlCl3
N.N-dimethylaniline
S
S
54%
OH
OH
1
16
Under similar conditions, 17, 19, and 20 produced 2, 3, and 4 respectively in 50 to 64% yield.
The ee of 1 to 4 were further determined by preparing their peracetylated derivatives. It was found that
no loss in optical purity could be observed (≥98% ee) for these compounds during the deprotection and
isolation stages of preparation. These isomers were found to have similar optical rotation when
compared to natural catechin and epicatechin enantiomers.
2.5. Synthesis of 27 and 28
Encouraged by the successful synthesis of 1 to 4, we then pursued the synthesis of the sulfur
catechin analogues and their epimers, 5 to 8. Our synthetic approach for these compounds is depicted
in Scheme 5.
The base catalyzed condensation between 21 and 10 produced chalcone 22 via Claisen-Schmidt
reaction in 92% yield, and >98% AUC purity. Attempts to reduce the conjugated ketone of 22 by ethyl
chloroformate and NaBH4 either at 0 °C or at ambient temperature did not produce 23 and the starting
material was recovered. Luche reduction of 22 at 0 to 5 °C resulted in 23 in 83% yield after
chromatography. It was essential to perform the reaction at low temperature [39] to avoid the
formation of the cyclic byproduct 29. Reaction of 23 with Tf2O in pyridine at ambient temperature
produced triflate 24 in good yield after chromatography. The triflate 24 was subjected to Pd(OAc)2 and
(R)-Tol-BINAP in the presence of t-BuSH and NaN(TMS)2 in toluene at 100 °C to give 25. The
asymmetric dihydroxylation of 25 under Sharpless conditions using AD-mix- along with methane

Molecules 2010, 15
5603
sulfonamide in a mixture of tert-butanol, water and CH2Cl2 produced 26 in 86% yield. It was again
observed that ~5% of corresponding sulfoxide was obtained, which was removed during purification
by chromatography. When 26 was subjected to TFA in CH2Cl2 at 0–5 °C for 24 h, 27 and 28 were
obtained as the major and minor diastereomers, respectively after chromatography in 96% ee.
Scheme 5. Synthesis of 27 and 28 intermediates.
OBn
CeCl3.6H2O
NaH, DMF
0-5 oC
NaBH4, THF
EtOH
OBn
OBn
BnO
OH
O
BnO
OH
OBn
+
92%
76%
OHC
O
OBn
21
OBn
10
OBn
22
OBn
OBn
Pd(OAc)2, NaN(TMS)2,
(R)-Tol-BINAP, PhMe,
tBuSH, 100 oC
Tf
O
Tf2O, Pyridine
0 oC to RT
82%
BnO
OH
BnO
OBn
73%
OBn
OBn
23
24

AD-mix
OBn
OBn
OBn
OBn
MeSO2NH2
tBuOH, H2O
CH2Cl2
tBu
tBu
S
TFA, CH2Cl2,
0 - 5 oC
BnO
S
BnO
OH
OH
100%
71%
OBn
OBn
26
25
OBn
OBn
OBn
OBn
OBn
BnO
S
BnO
S
BnO
O
OBn
OH
OH
OBn
OBn
OBn
28
27
29
2.6. Synthesis of 31 and 32
Having established the syntheses of 27 and 28 for 5 and 8, respectively alkene 25 was subjected to
AD-mix- along with methane sulfonamide in a mixture of tert-butanol, water and CH2Cl2 producing
30 in 83% yield (Scheme 6). The diol 30 has the same spectroscopic properties as 26 but opposite
optical rotation.

Molecules 2010, 15
5604
Scheme 6. Synthesis of intermediates 31 and 32.

AD-mix
OBn
OBn
OBn
OBn
MeSO2NH2
tBuOH, H2O
CH2Cl2
tBu
tBu
TFA, CH2Cl2,
0 - 5 oC
BnO
S
BnO
S
OH
OH
98%
72%
OBn
OBn
30
OBn
OBn
25
OBn
OBn
BnO
S
BnO
S
OH
OH
OBn
OBn
32
31
The reaction of 30 with TFA in CH2Cl2 at 0–5 °C for 24 h resulted in the major and minor
diastereomer 31 and 32 respectively after chromatography, and in >96% ee.
2.7. Synthesis of 5, 6, 7, and 8
The treatment of a cold solution of 27, 32, 31 and 28 in CH2Cl2 with an excess of AlCl3 in the
presence of N,N-dimethylaniline as a scavenger resulted in 5, 6, 7, and 8, respectively after HPLC
purification in 50 to 65% yield. A comparison of optical rotations of newly synthesized thiocatechin
and thioepicatechin enantiomers (1 to 8) against naturally occurring catechin and epicatechin
enantiomers are summarized in Table 1.
Table 1. Optical rotations of the sulfur analogues of flavan-3-ols.
Compounds
(+)-Catechin
Optical rotations*
+ 56.6
5,7-Dideoxy-(+)-thiocatechin (1)
(+)-Thiocatechin (5)
+ 22.2
+ 32.2
(-)-Epicatechin
- 33.9
5,7-Dideoxy-(-)-thioepicatechin (2)
(-)-Thioepicatechin (6)
(-)-Catechin
- 28.6
- 28.9
- 34.8
5,7-Dideoxy-(-)-thiocatechin (3)
(-)-Thiocatechin (7)
- 21.3
- 28.6
(+)-Epicatechin
+ 37.7
5,7-Dideoxy-(+)-thioepicatechin (4)
(+)-Thioepicatechin (8)
+ 28.4
+ 29.7
* (c 1, acetone).

Molecules 2010, 15
5605
3. Experimental
3.1. General
All the solvents were purchased from Aldrich Chemical Company in Sure/Seal™ bottles and were
1
13
used as received. H-NMR spectra were recorded on a 300 MHz Bruker whereas C-NMR spectra
were recorded on a 75 MHz Bruker NMR and TMS was used as an internal standard. Specific
rotations were determined for solutions by irradiating with the sodium D line (= 589 nm) using a
Perkin Elmer 341 polarimeter: specific rotation, []D values are given in units 10-1deg•cm2g-1 where
the concentration c is given in g/100 mL. The chemical purity (Method A) was determined by standard
HPLC (containing a PDA detector) using a Phenomenex Synergi 4  Fusion-RP 80 Å
(150 mm × 4.6 mm) column at wavelength of 280 nm, using a gradient of 5 to 90% of acetonitrile
(containing 0.01% TFA) with water (containing 0.01% TFA) up to 20 min, the column temperature
was 25 °C, and the flow rate was 1 mL/min. The enantiomeric purity (Method B) was determined by
chiral HPLC equipped with a PDA detector using a Chiralpak AD-RH 5 (150 mm × 4.6 mm) column.
The solvent for isocratic programs was acetonitrile/water (65/35, v/v) containing 0.01% TFA, run time
40 min, detection wavelength was 210 nm, column temperature was 60 °C, and the flow rate was
1 mL/min.
(E)-3-(3’,4’-Bis(benzyloxy)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (11). To a suspension of NaH
(60% dispersion in oil, 3.82 g, 95.48 mmol, 1.3 eq.) in dry DMF (100 mL) was slowly added 9 (10 g,
73.45 mmol, 1 eq.) keeping the internal temperature ≤ 2 °C throughout the addition. The resulting
mixture was stirred at this temperature for 10 minutes. A solution of 10 (23.38 g, 73.45 mmol, 1 eq.) in
DMF (100 mL) was added over a period of 20 minutes to the reaction mixture via an addition funnel
keeping the internal temperature ≤ 2 C. The resulting red brown solution was stirred at this
temperature for an additional 30 minutes before stirring at RT for 4 hours. The reaction mixture was
quenched with H2O (50 mL) and diluted with EtOAc (500 mL). The organic layer was separated,
washed with H2O (50 mL), sat. NaHCO3 (2 × 50 mL), brine (100 mL), dried (Na2SO4), filtered and the
solvent removed in vacuo to afford a yellow solid. The solid was triturated with heptane (100 mL) at
RT for 1h and filtered. The solids were dried under high vacuum at RT for 18 h to produce 11 (33.3 g,
1
100%) as a yellow solid with 100% AUC purity. H-NMR (CDCl3)  5.32 (s, 4H), 6.2 (dd, 2H,
J = 2.2 and 19Hz), 6.9–7.1 (m, 4H, Ar), 7.2–7.6 (m, 9H, Ar), 7.8–8.0 (m, 4H, Ar); 13C-NMR
(CDCl3)  = 31.1, 37.2, 47.3, 51.5, 117.4, 118.2, 118.4, 126.3, 127.3, 127.4, 127.5, 127.8, 128.4,
128.7, 129.1, 129.3, 130.2, 131.7, 132.1, 137.4, 138.9, 139.9, 148.6, 149.9, 150.3, 181.6; MS (m/z):
437 (M++1); HRMS calcd for C29H24O4 [M+H] 437.1753, Found: 437.1748.
(E)-2-(3-(3’,4’-Bis(benzyloxy)phenyl)allylphenol (12). To a solution of 11 (12 g, 27.6 mmol, 1 eq.) in
THF (100 mL) was added Et3N (5 mL, 35.8 mmol, 1.3 eq.) and the mixture cooled to 0 C. Ethyl
chloroformate (3.2 mL, 33 mmol, 1.2 eq.) was slowly added keeping the internal temperature at 0 C.
The resulting mixture was allowed to stir at 0 C for 1.5 h and the progress of the reaction was
monitored by TLC. The reaction mixture was suction filtered to remove the salts and the salts washed
with THF (2 × 50 mL). The combined filtrate was added slowly to a cold solution of NaBH4 in water
at 0 C over 45 minutes. The resulting mixture was slowly warmed to room temperature and allowed

Molecules 2010, 15
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to stir for 18h. The reaction mixture was acidified with 1N HCl (pH ~2 with a pH paper) and extracted
with EtOAc (2 × 300 mL). The combined organic layers were dried (MgSO4), filtered and the solvent
was removed in vacuo to afford an oil. The crude product was purified by silica gel chromatography
(5–10% ethyl acetate in heptane) to afford 12 (7.7 g, 66%) as a colorless oil with 100% AUC purity.
1H-NMR (CDCl3)  = 3.58 (d, 2H, J = 6.0 Hz), 5.2 (s, 4H), 6.1–6.25 (m, 1H), 6.33 (d, 1H,
13
J = 8.4 Hz), 6.8–7.0 (m, 4H), 7.2–7.6 (m, 13H); C-NMR (CDCl3)  = 34.0, 71.5, 71.9, 71.7, 77.5,
112.9, 115.3, 115.8, 115.9, 119.9, 120.8, 120.9, 125.8, 126.3, 127.3, 127.4, 127.8, 127.8, 127.8, 128.2,
128.5, 130.4, 131.4, 131.1, 131.4, 137.2, 148.6, 148.2, 154.1; MS (m/z) = 423.1 (M++1); HRMS calcd
for C29H26O3 [M+H] 423.1962, Found: 423.1959
(E)-2-(3-(3’,4’-Bis(benzyloxy)phenyl)allyl)phenyl trifluoromethane sulfonate (13). To an ice cold
solution (<5 C) of 12 (4 g, 9.46 mmol, 1 eq.) in dry pyridine (40 mL) was slowly added Tf2O (3.22 g,
11.4 mmol, 1.2 eq.). The resulting mixture was allowed to warm to RT and allowed to stir for 18h. The
reaction mixture was diluted with EtOAc (200 mL), washed with 1N HCl (4 × 100 mL), brine
(100 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo to give an oil. The oil was
purified by silica gel chromatography (5-10% ethyl acetate in heptane) to give 13 (4 g, 76%) as a
1
colorless oil with 100% AUC purity. H-NMR (CDCl3)  = 3.6 (d, 2H, J = 6.3 Hz), 5.2 (s, 4H),
6.0–6.15 (m, 1H), 6.33 (d, 1H, J = 8.4 Hz), 6.8 (s, 2H), 7.0 (s, 1H), 7.2–7.6 (m, 14H); HRMS calcd for
C30H25F3O5S [M+H] 555.1455, Found: 555.1451
(E)-2-(3-(3’,4’-Bis(benzyloxy)phenyl)allyl)phenyl-(tert-butyl)sulfane (14). To a degassed solution of 13
(8 g, 14.43 mmol, 1 eq.) in dry toluene (80 mL) was added Pd(OAc)2 (0.194 g, 0.866 mmol, 0.06 eq.)
and (R)-Tol-BINAP (0.685 g, 1.01 mmol, 0.07 eq.) at RT. The resulting reaction mixture was degassed
again for an additional 15 minutes at RT. In a separate flask, a solution of NaN(TMS)2 (0.6M solution
in toluene, 33.7 mL, 202.2 mmol, 1.4 eq.) was added slowly to t-BuSH (2.3 mL, 2.2 mmol, 1.4 eq.) in
dry toluene (10 mL) at RT and the mixture stirred at RT under N2 for 15 minutes. This solution was
transferred under N2 to the above solution. The red colored solution was heated at 100 C under N2 for
18h. The reaction mixture was diluted with H2O (100 mL) and EtOAc (100 mL). The organic layer
was separated, washed with brine (50 mL), dried (Na2SO4), filtered and the solvent was removed in
vacuo to give a red viscous oil. The oil was purified by silica gel chromatography (5% EtOAc in
heptane) to afford 14 (6.98g, 98%) as a yellow viscous oil with 99.8% AUC purity. 1H-NMR (CDCl3)
 = 1.22 (s, 9H), 3.88 (d, 2H, J = 6.7 Hz), 5.12 (s, 4H), 6–6.2 (m, 1H), 6.3 (d, 1H,
J = 6.7 Hz), 6.77 (s, 2H), 7.0 (s, 1H), 7.1–7.6 (m, 14H); 13C-NMR (CDCl3)  = 31.2, 37.9, 47.2, 71.5,
112.1, 115.4, 119.9, 126.2, 127.3, 127.4, 127.7, 127.8, 127.9, 128.5, 128.6, 129.2, 129.9, 130.6, 131.7,
132.1, 137.4, 138.9, 143.8, 145.1, 146.4; MS (m/z) = 495 (M++1), 439.3 (M+-t-Bu); HRMS calcd for
C33H34O2S [M+H] 495.2358, Found: 495.2353
(1S,2S)-1-(3’,4’-Bis(benzyloxy)phenyl)-3-(2-(tert-butylthio)phenyl)propane-1,2-diol
(15).
A
suspension of AD-mix- (18g) in tBuOH/H2O (60 mL, 1/1, v/v) was stirred at RT for 15 minutes until
a clear yellow solution was obtained followed by the addition of a solution of 14 (3.6 g, 7.29 mol, 1
eq.) in CH2Cl2 (15 mL). The resulting reaction mixture was cooled to 0 ºC with stirring. Then,
MeSO2NH2 (0.833 g, 8.76 mmol, 1.2 eq.) was added and the mixture stirred at this temperature for

Molecules 2010, 15
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24h. The reaction was quenched by the addition of 10% Na2S2O3 (50 mL) and then extracted with
CH2Cl2 (2 × 100 mL). The combined organic layers were washed with H2O (2 × 50 mL), brine (1 × 75
mL), dried (Na2SO4), filtered, and the solvent removed in vacuo to afford the crude product. The crude
product was purified by silica gel chromatography using 20% to 30% EtOAc/heptane to produce 15
1
(3.3g, 86%) as an oil with 100% AUC purity. []20 D = +34. 9 (c 1, acetone); H-NMR (CDCl3)
 = 1.15 (s, 9H), 2.21 (d, 1H, J = 4.45 Hz), 2.82 (dd, 1H, J = 9, 9.5 Hz), 2.88 (d, 1H, J = 4.5 Hz), 3.07
(dd, 1H, J = 4 Hz), 3.81-3.9 (m, 1H), 4.4 (dd, 1H, J = 3.4 Hz), 5.13 (s, 2H), 5.18 (s, 2H), 6.8 (s, 2H),
13
7.03 (s, 1H), 7.1–7.52 (m, 14H); C-NMR (CDCl3)  = 30.9, 38.5, 47.6, 71.3, 71.5, 113.9, 115.1,
120.4, 126.6, 127.3, 127.5, 127.7, 127.9, 128.5, 129.1, 130.9, 132.4, 134.8, 137.3, 137.4, 139.1, 143.8,
148.8, 149.2; Optical purity = 100% ee. HRMS calcd for C33H36O4S [M+H] 529.2412, Found:
529.2338.
3’,4’-Bis(benzyloxy)-5,7-dideoxy-(+)-thiocatechin (16) and 3’,4’-Bis(benzyloxy)-5,7-dideoxy-(+)-
thioepicatechin (17). To a cold solution of 15 (1.42 g, 2.7 mmol, 1 eq.) in CH2Cl2 (50 mL) was slowly
added TFA (494 L, 2.4 eq.). The resulting mixture was kept at 0 °C. The reaction was quenched by
addition of Et3N (890 L, 2.4 eq.) followed by cold H2O (15 mL). The organic layer was separated and
washed with brine solution (15 mL), dried (Na2SO4), filtered, and the solvent removed in vacuo. The
crude product was then purified by silica gel chromatography (10–30% EtOAc in heptane) to produce
the desired major diastereomer 16 (830 mg, 68%) and the minor diastereomer 17 (60 mg, 4.9%).
1
3’,4’-Bis(benzyloxy)-5,7-dideoxy-(+)-thiocatechin (16). []20 = +108.9 (c 1, acetone); H-NMR
D
(CDCl3) = 1.98 (d, 2H, J = 4.8 Hz), 2.52 (dd, 1H, H4a, J = 8.4, 7.3 Hz), 3.08 (dd, 1H, H4b,
J = 4, 3.9 Hz), 4.16–4.3 (m, 1H), 5.1 (s, 2H), 5.16 (s, 2H), 6.85–7.2 (m, 6H), 7.22–7.5 (m, 11H);
13C-NMR (CDCl3) = 36.6, 51.7, 56.4, 70.1, 71.3, 77.5, 115.2, 121.8, 124.6, 124.8, 127.3, 127.5,
127.9, 127.9, 128.5, 128.5, 130.5, 130.9, 131.2, 131.9, 132.7, 136.9, 137.5, 148.4, 149.2; Optical
purity = 96% ee; Chemical purity = 100% (AUC); MS (m/z) = 455.1 (M++1), 437.2 (M+-OH), 345.3
(M+-OH-Bn); HRMS calcd for C29H26O3S [M+H] 455.1681, Found: 455.1677.
1
3’,4’-Bis(benzyloxy)-5,7-dideoxy-(+)-thioepicatechin (17). []20 D = +38.6 (c 1, Acetone); H NMR
(300 MHz, CDCl3) = 2.2 (d, 1H, J = 9.4 Hz), 2.96 (dd, 1H, H4a, J = 5, 17 Hz), 3.1 (dd, 1H, H4b,
J = 3.5, 17 Hz), 4.3–4.42 (m, 1H), 4.45 (d, 1H, J = 1.6 Hz), 5.12 (s, 2H), 5.14 (s, 2H), 6.85–7.2 (m,
13
6H), 7.28–7.5 (m, 11H); C NMR (75 MHz, CDCl3) = 37.9, 50.1, 66.4, 71.3, 76.6, 114.9, 115.6,
121.7, 124.8, 125.9, 126.8, 127.3, 127.5, 127.8, 128.5, 128.5, 130.1, 131.2, 131.4, 132.4, 137.1, 137.3,
148.9, 148.9; Optical purity = 100% ee; HPLC purity = 100% (AUC); MS (m/z) = 455.1 (M++1),
437.2 (M+-OH), 345.3 (M+-OH-Bn); HRMS calcd for C29H26O3S [M+H] 455.1681, Found: 455.1679.
(1R,2R)-1-(3’,4’-Bis(benzyloxy)phenyl)-3-(2-(tert-butylthio)phenyl)propane-1,2-diol
(18).
A
suspension of AD-mix- (18 g) in tBuOH/H2O (60 mL, 1/1, v/v) was stirred at RT for 15 minutes until
a clear yellow solution was obtained. This was followed by the addition of a solution of 14 (3.6g,
7.29 mol, 1 eq.) in CH2Cl2 (15 mL). The resulting reaction mixture cooled to 0 °C with stirring. Then,
MeSO2NH2 (0.833 g, 8.76 mmol, 1.2 eq.) was added and the mixture stirred at this temperature for
24 h. The reaction was quenched by the addition of 10% Na2S2O3 (50 mL) and then extracted with

Molecules 2010, 15
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CH2Cl2 (2 × 100 mL). The combined organic layers were washed with H2O (2 × 50 mL), brine
(1 × 75 mL), dried (Na2SO4), filtered, and the solvent removed in vacuo to afford the crude product.
The crude product was purified by silica gel chromatography using 20% to 30% EtOAc/heptane to
1
produce 18 (3.2g, 83%) as an oil with 99.8% AUC purity. []20 D = -34.3 (c 1, acetone); H-NMR
(CDCl3)  = 1.15 (s, 9H), 2.21 (d, 1H, J = 4.5 Hz), 2.82 (dd, 1H, J = 9, 9.5 Hz), 2.88 (d, 1H,
J = 4.5 Hz), 3.07 (dd, 1H, J = 3.4, 4 Hz), 3.81-3.9 (m, 1H), 4.4 (dd, 1H, J = 3.4, 4 Hz), 5.13 (s, 2H),
13
5.18 (s, 2H), 6.8 (s, 2H), 7.03 (s, 1H), 7.1–7.52 (m, 14H); C-NMR (CDCl3)  = 30.9, 38.6, 47.6,
71.4, 71.5, 113.9, 115.1, 120.3, 126.7, 127.3, 127.5, 127.8, 127.8, 128.5, 129.2, 130.9, 132.4, 134.8,
137.3, 137.4, 139.1, 143.8, 148.8, 149.2; Optical purity = 100% ee; HRMS calcd for C33H36O4S
[M+H] 529.2412, Found: 529.2337.
3’,4’-Bis(benzyloxy)-5,7-dideoxy-(-)-thiocatechin (19) and 3’,4’-bis(benzyloxy)-5,7-dideoxy-(-)-thio-
epicatechin (20). To a cold solution of 18 (1.6 g, 3.04 mmol, 1 eq.) in CH2Cl2 (60 mL) was slowly
added TFA (617 L, 3.0 eq.). The resulting mixture was kept at 0 °C. The reaction was quenched by
addition of Et3N (1.1 mL, 2.4 eq.) followed by cold H2O (25 mL). The organic layer was separated and
washed with brine solution (25 mL), dried (Na2SO4), filtered, and the solvent removed in vacuo. The
crude product was then purified by silica gel chromatography (10–30% EtOAc in heptane) to produce
the desired major diastereomer 19 (925 mg, 68%), and minor diastereomer 20 (72 mg, 4.8%).
1
3’,4’-Bis(benzyloxy)-5,7-dideoxy-(-)-thiocatechin (19). []20
= -110.4 (c 1, acetone); H-NMR
D
(CDCl3) = 1.98 (d, 1H, J = 4.3 Hz), 2.9 (dd, 1H, H4a, J = 8.3, 14.2, 17 Hz), 3.08 (dd, 1H, H4b,
J = 4, 16.5 Hz), 4.15–4.32 (m, 2H), 5.12 (s, 2H), 5.16 (s, 2H), 6.8–7.15 (m, 6H), 7.2–7.5 (m, 11H);
13C-NMR (CDCl3) = 31.8, 51.6, 70.1, 71.3, 71.4, 77.2, 115.1, 115.3, 121.8, 124.5, 125.3, 126.8,
127.3, 127.5, 127.9, 127.9, 128.1, 128.5, 128.5, 130.5, 130.9, 131.9, 132.7, 136.9, 137.1, 148.1, 148.1;
Optical purity = 99% ee; Chemical purity = 100% (AUC); MS (m/z) = 455.1 (M++1), 345.3 (M+-OH-
Bn); HRMS calcd for C29H26O3S [M+H] 455.1681, Found: 455.1678.
1
3’,4’-Bis(benzyloxy)-5,7-dideoxy-(-)-thioepicatechin (20). []20 = -74.2 (c 1, acetone); H-NMR
D
(CDCl3) = 2.2 (d, 1H, J = 9.4Hz), 2.95 (dd, 1H, H4a, J = 5, 17 Hz), 3.1 (dd, 1H, H4b, J = 3.5, 17 Hz),
4.3–4.41 (m, 1H), 4.42 (d, 1H, J = 1.4 Hz), 5.1 (s, 2H), 5.12 (s, 2H), 6.8–7.2 (m, 6H), 7.28–7.5 (m,
13
11H); C-NMR (CDCl3) = 37.9, 50.1, 66.4, 71.3, 76.6, 114.9, 115.6, 121.7, 124.8, 125.9, 126.7,
127.2, 127.9, 127.8, 128.0, 128.5, 128.5, 130.1, 131.2, 131.4, 132.4, 137.1, 137.3, 148.9, 148.9;
Optical purity = 99.5% ee; Chemical purity = 100% (AUC); MS (m/z) = 455.1 (M++1), 345.3 (M+-OH-
Bn); HRMS calcd for C29H26O3S [M+H] 455.1681, Found: 455.1679.
5,7-Dideoxy-(+)-thiocatechin (1). To an ice cold solution of compound 16 (614 mg, 1.35 mmol, 1 eq.)
in dry CH2Cl2 (50 mL) was added N,N-dimethylaniline (1.37 mL, 10.82 mol, 8 eq.) under N2. The
solution was stirred at this temperature for ~10 minutes before AlCl3 (1.8 g, 13.52 mmol, 10 eq.) was
added in one portion. The flask was covered with aluminum foil to protect it from light and stirred at
ice bath temperature for 3h. EtOAc (100 mL) and silica gel (8.5 g) were added to the reaction mixture
and stirred for 15 minutes. The reaction mixture was filtered through a pad of silica gel. The silica gel
pad was washed with EtOAc (5 × 50 mL). The filtrates were combined and the solvent was removed in

Molecules 2010, 15
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vacuo to ~5 mL of volume keeping the bath temperature < 25 C. The crude mixture was diluted with
purified water (50 mL), frozen and lyophilized to give the crude product. The crude product was
further purified by preparative HPLC to give the desired compound 1 (180mg, 54%, 100% AUC) as an
off-white solid. []20 D = + 22.2 (c 1, acetone); 1H-NMR (acetone-d6) = 2.9 (dd, 1H, J = 9, 16.1 Hz),
3.1 (dd, 1H, J = 4, 16.2 Hz), 4.1 – 4.35 (m, 2H), 6.7 (s, 2H, Ar), 6.9 (s, 1H, Ar), 6.92–7.2 (m, Ar, 4H),
13
7.4–8.3 (br s, 2H); C-NMR (acetone-d6) = 39.2, 52.7, 70.9, 116.0, 116.5, 121.3, 124.9, 125.7,
127.3, 130.9, 131.7, 134.3, 134.8, 145.6, 145.9; MS= 255.2 [M+-H2O-H, 100%]; HRMS calcd for
C15H14O3S [M+H] 275.0742, Found: 275.0737.
5,7-Dideoxy-(-)-thioepicatechin (2). To an ice cold solution of compound 17 (790 mg, 1.74 mmol, 1
eq.) in dry CH2Cl2 (80 mL) was added N,N-dimethylaniline (1.76 mL, 13.92 mol, 8 eq.) under N2. The
solution was stirred at this temperature for ~10 minutes before AlCl3 (2.32 g, 17.4 mmol, 10 eq.) was
added in one portion. The flask was covered with aluminum foil to protect it from light and stirred at
the ice bath temperature for 3h. EtOAc (50 mL) and silica gel (10 g) were added to the reaction
mixture and stirred for 15 minutes. The reaction mixture was filtered through a pad of silica gel. The
silica gel pad was washed with EtOAc (4 × 50 mL). The filtrates were combined and the solvent
removed in vacuo to ~20 mL of volume keeping the bath temperature < 25 C. The crude mixture was
diluted with purified water (100 mL), cooled and lyophilized to give the crude product. The crude
product was further purified by preparative HPLC to give the desired compound 2 (270 mg, 64%,
1
98.5% AUC) as an off-white solid. []20 D = -28.6 (c 1, acetone); H-NMR (acetone-d6) = 2.88 (dd,
1H, J = 5.9 and 16.7 Hz), 3.04 (d, 1H, J = 14.5 Hz), 4.25–4.4 (m, 2H), 6.5–7.2 (m, 7H, Ar), 7.4–8.3
(br s, 2H); 13C-NMR (acetone-d6) = 37.9, 49.3, 66.4, 114.5, 116.1, 120.5, 123.8, 124.9, 126.1, 130.7,
130.9, 131.1, 133.3, 144.3, 144.4; MS= 255.2 [M+-H2O-H, 100%]; HRMS calcd for C15H14O3S [M+H]
275.0742, Found: 275.0739.
5,7-Dideoxy-(-)-thiocatechin (3). To an ice cold solution of compound 19 (506 mg, 1.11 mmol, 1 eq.)
in dry CH2Cl2 (40 mL) was added N, N-dimethylaniline (1.13 mL, 8.92 mol, 8 eq.) under N2. The
solution was stirred at this temperature for ~10 minutes before AlCl3 (1.5 g, 11.14 mmol, 10 eq.) was
added in one portion. The flask was covered with aluminum foil to protect it from light and stirred at
the ice bath temperature for 2.5h. EtOAc (100 mL) and silica gel (8 g) were added to the reaction
mixture and stirred for 15 minutes. The reaction mixture was filtered through a pad of silica gel. The
silica gel pad was washed with EtOAc (3 × 50 mL). The filtrates were combined and the solvent was
removed in vacuo to ~20 mL of volume keeping the bath temperature < 25 C. The crude mixture was
diluted with purified water (50 mL), cooled and lyophilized to give the crude product. The crude
product was further purified by preparative HPLC to give the desired compound 3 (180 mg, 59%, 99%
1
AUC) as an off-white solid. []20 D = -21.3 (c 1, acetone); H-NMR (acetone-d6) = 2.9 (dd, 1H,
J = 9, 16.1 Hz), 3.1 (dd, 1H, J = 4, 16.2 Hz), 4.1–4.35 (m, 2H), 6.7 (s, 2H, Ar), 6.9 (s, 1H, Ar),
13
6.92–7.2 (m, Ar, 4H), 7.4–8.3 (br s, 2H); C-NMR (acetone-d6) = 39.2, 52.7, 70.9, 116.0, 116.5,
121.3, 124.9, 125.7, 127.3, 130.9, 131.7, 134.3, 134.8, 145.6, 145.9; MS = 255.2 [M+-H2O-H, 100%];
HRMS calcd for C15H14O3S [M+H] 275.0742, Found: 275.0735.

Molecules 2010, 15
5610
5,7-Dideoxy-(+)-thioepicatechin (4). To an ice cold solution of compound 20 (790 mg, 1.74 mmol,
1 eq.) in dry CH2Cl2 (80 mL) was added N, N-dimethylaniline (1.76 mL, 13.92 mol, 8 eq.) under N2.
The solution was stirred at this temperature for ~10 minutes before AlCl3 (2.32 g, 17.4 mmol, 10 eq.)
was added in one portion. The flask was covered with aluminum foil to protect it from light and stirred
at the ice bath temperature for 3 h. EtOAc (50 mL) and silica gel (10 g) were added to the reaction
mixture and stirred for 15 minutes. The reaction mixture was filtered through a pad of silica gel. The
silica gel pad was washed with EtOAc (4 × 50 mL). The filtrates were combined and the solvent was
removed in vacuo to ~20 mL of volume keeping the bath temperature < 25 C. The crude mixture was
diluted with purified water (100 mL), cooled and lyophilized to give the crude product. The crude
product was further purified by preparative HPLC to give the desired compound 4 (270mg, 64%,
1
98.5% AUC) as an off-white solid. []20 D = +28.4 (c 1, acetone); H-NMR (acetone-d6) = 2.88 (dd,
1H, J = 5.9 and 16.7 Hz), 3.04 (d, 1H, J = 14.5 Hz), 4.25–4.4 (m, 2H), 6.5–7.2 (m, 7H, Ar), 7.4–8.3
(br s, 2H); 13C-NMR (acetone-d6) = 37.9, 49.3, 66.4, 114.5, 116.1, 120.5, 123.7, 124.9, 126.1, 130.7,
130.9, 131.1, 133.3, 144.3, 144.4; MS = 255.2 [M+-H2O-H, 100%]; HRMS calcd for C15H14O3S
[M+H] 275.0742, Found: 275.0736.
(E)-1-(2,4-Bis(benzyloxy)-6-hydroxyphenyl)-3-(3’,4’-bis(benzyloxy)phenyl)prop-2-en-1-one (22). To a
cold solution (<5 °C) of NaH (60% dispersion in oil, 0.69 g, 17.23 mmol, 1.2 eq.) in DMF (50 mL)
was added 21 (5 g, 14.36 mmol, 1 eq.) keeping the internal temperature < 5 °C throughout the
addition. The resulting mixture was allowed to stir at this temperature for 20 minutes before addition
of a solution of 10 (4.57g, 14.36 mmol, 1 eq.) in DMF (75 mL) over 15 minutes. The resulting mixture
was allowed to warm to RT and stirred for 16 h. A gel was obtained. Water (75 mL) and EtOAc (75
mL) were added with stirring whereupon a solid started to appear. Heptane (200 mL) was then added,
the solids were suction filtered and washed with heptane (2 × 50 mL). The solids were dried under
high vacuum at 40–45 °C for 24 h to produce 22 (8.6g, 92%) as a yellow solid with 100% AUC purity.
1H- NMR (CDCl3)  4.93 (s, 2H), 5.06 (s, 2H), 5.09 (s, 2H), 5.2 (s, 2H), 6.2 (dd, 2H, J = 1.6 and 4.6
13
Hz), 6.6–6.8 (m, 2H), 6.9 (s, 1H), 7.2–7.42 (m, 25H), 7.71 (q, 2H, J = 15.5 Hz); C-NMR (CDCl3)
 = 70.3, 70.8, 70.9, 71.4, 96.2, 97.8, 105.8, 114.1, 114.9, 123.1, 125.3, 126.9 (2C), 127.3 (2C), 127.2
(2C), 127.6 (2C), 127.8, 127.9, 128.0, 128.3 (2C), 128.4, 128.5 (4C), 128.6 (2C), 136.2, 136.3, 136.8,
136.9, 142.8, 149.5, 149.6, 161.1, 164.7, 166.3, 191.5. Anal. calcd for C43H36O6, C 79.61, H 5.59
Found C 79.58, H 5.36.
(E)-3,5-Bis(benzyloxy)-2-(3’,4’-bis(benzyloxy)phenyl)allyl)phenol (23). To a solution of ethanol (236
mL) and THF (800 ml) was added CeCl3.7H2O (74 g, 198.0 mmol, 2.5 eq.) at room temperature and
the mixture was stirred at this temperature until a clear solution was obtained. To this was added
chalcone 22 (51.4 g, 79.23 mmol, 1 eq.) followed by THF (500 mL). The solution was stirred at room
temperature for ~10 minutes and then cooled to −1.5 to −0.2 C (internal temperature) with agitation.
Solid NaBH4 (7.5 g, 197.37 mmol, 2.5 eq.) was added in portions over 0.5 h keeping the internal
temperature ≤ 0.3 C throughout the addition. The mixture was stirred at this temperature (−0.8 to
−0.3 C) for ~2.5 h. The reaction mixture was quenched with 5% aqueous citric acid (167 mL)
followed by EtOAc (1.5 L). The mixture was stirred as the internal temperature rose to ~12 C. The
organic layer was separated and washed with H2O (2 × 1L, 1 × 800 mL), brine (1 × 500 mL), dried

Molecules 2010, 15
5611
(Na2SO4), filtered and the solvent was removed in vacuo to give a semi solid. HPLC analysis of the
crude product indicated 86% product and 14% by-product (AUC). The crude product was purified by
silica gel chromatography using heptane/CH2Cl2/EtOAc (25/25/0.5, v/v/v) to give 23 (38g, 76%) as
an-off white solid with 99.5% AUC purity. 1H-NMR (CDCl3) = 3.55 (d, J = 5.4 Hz, 2H), 4.94–5.08
(m, 5H), 5.12 (d, J = 4.4 Hz, 4H), 6.04–6.2 (m, 2H), 6.22–6.4 (m, 2H), 6.82 (s, 2H), 6.97 (d,
13
J = 1.2 Hz, 1H), 7.18–7.5 (m, 20H); C-NMR (CDCl3) = 26.4, 70.2, 70.4, 71.5, 93.6, 95.3, 107.0,
112.9, 115.3, 119.9, 126.7, 127.3, 127.3, 127.4, 127.5, 127.8, 127.8, 127.9, 128.0, 128.5, 128.6, 128.5,
128.6, 130.9, 136.5, 137.3, 137.4, 146.6, 148.2, 155.8, 157.9, 158.8. Anal. calcd for C43H38O5, C
81.36, H 6.03, Found C 81.22, H 5.86.
(E)-3,5-Bis(benzyloxy)-2-(3’,4’-bis(benzyloxy)phenyl)allylphenyl trifluoromethane sulfonate (24). To
an ice cold solution of 23 (6 g, 9.45 mmol, 1 eq.) in pyridine (35 mL) was slowly added Tf2O (1.75
mL, 10.4 mmol, 1.1 eq). The resulting mixture was allowed to warm to RT and stirred for 18h. The
reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (250 mL) and
washed with 1N HCl (2 × 100 mL). The aqueous layer was back washed with EtOAc (100 mL). The
organic layers were combined and washed with brine (2 × 75 mL), dried (Na2SO4), filtered and the
solvent removed in vacuo to produce the crude product. The crude product was purified by silica gel
chromatography (10–15% EtOAc in heptane) to produce the 24 (4.1 g, 82%) as an off-white solid with
1
100% AUC purity. H-NMR (CDCl3) = 3.55 (d, 2H, J = 6.4 Hz), 5.0 (s, 2H), 5.05 (s, 2H), 5.08 (s,
2H), 5.1 (s, 2H), 5.95–6.1 (m, 1H), 6.28 (d, 1H, J = 16 Hz), 6.5 (d, 1H, J = 2.3 Hz), 6.6 (d, 1H, J = 2.3
13
Hz), 6.7–6.86 (m, 2H), 6.9 (d, 1H, J = 1.8 Hz), 7.3–7.5 (m, 20H); C-NMR (CDCl3) = 70.7, 71.5,
77.4, 100.4, 115.3, 125.1, 127.3, 127.4, 127.5, 127.6, 128.19, 128.5, 125.7, 128.8. Anal. calcd for
C44H37F3O7S, C 68.92, H 4.86, F 7.43 Found C 68.89, H 4.77, F 7.22.
(E)-(3,5-Bis(benzyloxy)-2-(3-(3’,4’-bis(benzyloxy)phenyl)allyl)phenyl) (tert-butyl)sulfane (25). To a
degassed solution of triflate 24 (1.86 g, 2.4 mmol, 1 eq.) in toluene (50 mL) was added Pd(OAc)2 (33
mg, 0.14 mmol, 0.06 eq.) and (R)-Tol-BINAP (115 mg, 0.17 mmol, 0.07 eq.) at room temperature. The
mixture was again degassed for an additional 15 minutes at room temperature. In a separate flask,
KN(TMS)2 (0.5M solution in toluene, 7 mL, 3.4 mmol, 1.4 eq.) was added to t-BuSH (0.39 mL)
followed by stirring the mixture at RT for 15 minutes before adding this solution to the mixture of
triflate containing catalyst. The resulting reaction mixture was kept at 100–105 ºC (bath temperature)
for 36 h. The reaction was quenched by adding H2O (50 mL) and extracted with EtOAc (2 × 100 mL).
The combined organic layers were washed with H2O (50 mL), brine (50 mL), dried, (Na2SO4), filtered
and the solvent removed in vacuo to give the crude product. The crude product was then purified by
silica gel chromatography (20–40% CH2Cl2 in heptane) to afford 25 (1.25 g, 73%) as an off-white
1
solid with 98.3% AUC purity; H-NMR (CDCl3) = 1.28 (s, 9H), 3.85 (d, 2H, J = 5.9 Hz), 4.98 (s,
2H), 5.01 (s, 2H), 5.06 (s, 2H), 5.12 (s, 2H), 6.05–6.25 (m, 2H), 6.6 (d, 1H, J = 2.4 Hz), 6.7–6.85 (m,
13
3H), 6.9 (d, 1H, J = 1.8 Hz), 7.2–7.5 (m, 20H); C-NMR (CDCl3) = 31.3, 31.6, 47.4, 70.3, 70.3,
71.5, 71.6, 77.5, 101.8, 112.7, 113.4, 115.5, 119.7, 127.1, 127.4, 127.5, 127.5, 127.7, 127.7, 127.9,
128.1, 128.4, 128.4, 128.5, 128.6, 129.6, 132.3, 133.8, 136.9, 137.5, 139.5, 148.1, 149.2, 156.1, 157.1;
MS (m/z) = 707.1 (M++1), 651.2 (M+-tBu). Anal. calcd for C47H46O4S, C 79.85, H 6.56, Found C
79.64, H 6.49.

Molecules 2010, 15
5612
(1S,2S)-(3-(2,4-Bis(benzyloxy)-6-(tert-butylthio)phenyl)-1-(3’,4’-bis(benzyloxy)phenyl)propane-1,2-
t
diol (26). To a solution of BuOH/H2O (1/1, v/v, 100 mL) was added AD-mix- (16.5 g) and the
suspension was stirred at RT until a clear solution was obtained. The solution was then cooled to
0-5 ºC and a solution of 25 (3.3 g, 4.67 mmol) in CH2Cl2 (100 mL) was added in one portion followed
by CH3SO2NH2 (0.533 g, 5.6 mol, 1.2 eq.). The resulting reaction mixture was stirred at this
temperature for 24 h. After 24h and 30h, additional amounts of AD-mix- (16.5 g) and CH3SO2NH2
(0.533 g, 5.6 mol, 1.2 eq.) were added respectively and the stirring was continued for an additional 24h
at this temperature. HPLC analysis indicated the completion of the reaction. To the reaction mixture
was added H2O (100 ml) and EtOAc (150 mL). The organic layer was separated and washed with 10%
aqueous sodium metabisulfite (2 x 100 mL), H2O (100 mL), brine (50 mL), dried (Na2SO4), filtered
and the solvent removed in vacuo to afford the crude product as an off-white solid. The solid was
triturated with heptane (50 mL) at room temperature and filtered to give 26 (3.48 g, 100%) as an off-
1
white solid with 97% AUC purity; []20 D = -17.4 (c 1, acetone); Optical purity = 95% ee; H-NMR
(CDCl3)0.2 (s, 6H), 1.2 (s, 9H), 2.4 (d, 2H, J = 6 Hz), 3.1 (d, 2H, J = 6.05 Hz), 3.15 (s, 1H),
3.8–3.95 (m, 1H), 4.35 (d, 1H, J = 4.5 Hz), 4.96 (s, 2H), 5.0 (s, 2H), 5.05 (s, 2H), 6.65 (d, 1H,
13
J = 2.4 Hz), 6.75–6.9 (m, 2H), 7.05 (d, 1H, J = 1.4 Hz), 7.25–7.5 (m, 20H); C-NMR (CDCl3)
 31.1, 41.9, 70.3, 70.8, 71.4, 71.6, 77.5, 102.1, 115.2, 116.1, 120.2, 125.2, 127.3, 127.4, 127.5,
127.5 127.7, 128.1, 128.2, 129.4, 128.4, 128.7, 128.8, 134.5, 135.3, 137.4, 149.1; MS (m/z) = 723.1
(M+-OH). Anal. calcd for C47H48O6S, C 76.19, H 6.53, Found C 75.98, H 6.44.
(1R,2R)-(3-(2,4-Bis(benzyloxy)-6-(tert-butylthio)phenyl)-1-(3’,4’-bis(benzyloxy)phenyl)propane-1,2-
t
diol (30). To a solution of BuOH/H2O (1/1, v/v, 90 mL) was added AD-mix- (6.1 g) and the
suspension was stirred at RT until a clear solution was obtained. The solution was then cooled to
0–5 ºC and a solution of 25 (1.22 g, 1.73 mmol) in CH2Cl2 (60 mL) was added in one portion followed
by CH3SO2NH2 (0.197 g, 2.07 mol, 1.2 eq.). The resulting reaction mixture was stirred at this
temperature for 24 h and the progress of the reaction monitored by HPLC. After 24 h and 30 h,
additional amounts of AD-mix- (6.1 g) and CH3SO2NH2 (0.197 g, 2.07 mol, 1.2 eq.) were added
respectively and stirring continued for an additional 24h at this temperature. To the reaction mixture
was added H2O (50 mL) and EtOAc (100 mL). The organic layer was separated and washed with 10%
aqueous sodium metabisulfite (2 × 100 mL), H2O (50 mL), brine (50 mL), dried (Na2SO4), filtered and
the solvent removed in vacuo to afford the crude product as an off-white solid. The solid was purified
by silica gel chromatography (30% EtOAc in heptane) to give 30 (1.2 g, 98%) as an off-white solid
1
with 99.4% AUC purity. []20 D = +16.4 (c 1, acetone); Optical purity =95% ee; H-NMR (CDCl3)
= 0.2 (s, 6H), 1.2 (s, 9H), 2.4 (d, 1H, J = 6.2 Hz), 3.05 (d, 2H, J = 6.2 Hz), 3.15 (d, 1H,
J = 3.1 Hz), 3.75–3.82 (m, 1H), 4.3–4.4 (m, 1H), 4.95 (s, 2H), 5.0 (s, 2H), 5.1 (s, 4H), 6.6 (d, 1H,
J = 2.4 Hz), 6.7–6.85 (m, 2H), 7.0 (s, 1H), 7.15–7.5 (m, 20H); 13C-NMR (CDCl3) = 31.1, 41.9, 70.3,
70.8, 71.4, 71.6, 77.5, 102.1, 115.2, 116.1, 120.2, 125.2, 127.3, 127.4, 127.5, 127.5, 127.7, 128.1,
128.2, 129.4, 128.4, 128.7, 128.8, 134.5, 135.3, 137.4, 149.1; MS (m/z) = 723.1 (M+-OH). Anal. calcd
for C47H48O6S, C 76.19, H 6.53, Found C 76.11, H 6.39.
5,7,3’,4’-Tetra-O-benzyl-(+)-thiocatechin (27) and 5,7,3’,4’-Tetra-O-benzyl-(+)-thioepicatechin (28).
To a cold solution (0–5 °C) of 26 (3.46 g, 4.68 mmol, 1 eq.) in CH2Cl2 (150 mL) was added TFA

Molecules 2010, 15
5613
(1.28 g, 11.22 mmol, 2.4 eq.). The mixture was kept at 0–5 °C for 24 hours. Upon consumption of the
starting material, the reaction was quenched by addition of Et3N (1.5 mL) and cold H2O (50 mL). The
organic layer was separated and washed with brine (50 mL), dried (Na2SO4), filtered and the solvent
removed in vacuo. The crude product was then purified by silica gel chromatography
(heptane/CH2Cl2/EtOAc, 25/25/1, v/v/v) to afford 27 (1.75 g, 57%), and 28 (440 mg, 14%).
5,7,3’,4’-Tetra-O-benzyl-(+)-thiocatechin (27). []20 D = +55.2 (c 1, CH2Cl2); Chemical purity = 97%
1
(AUC); Optical purity = 96% ee; H-NMR (CDCl3) = 2.0 (d, 1H, J = 5.5 Hz), 2.7 (dd, 1H, J = 8.4,
17.2 Hz), 3.1 (dd, 1H, J = 4.5, 17.2 Hz), 4.1 (d, 1H, J = 8.5 Hz), 4.15-4.3 (m, 1H), 4.95 (s, 4H), 5.1 (s,
2H), 5.12 (s, 2H), 6.4 (s, 2H), 6.85–6.95 (m, 2H), 7.01 (d, 1H, J = 1.5 Hz), 7.2–7.5 (m, 20H);
13C-NMR (CDCl3) = 29.8, 31.9, 51.3, 70.0, 70.2, 70.3, 71.3, 71.4, 77.5, 97.4, 103.3, 113.8, 115.2,
115.4, 121.9, 127.3, 127.5, 127.6, 127,9, 127.9, 127.9, 128.1, 128.5, 128.5, 128.6, 128.6, 130.62,
133.9, 136.8, 136.8, 137.0, 137.2, 148.1, 149.2, 157.1, 158.1; MS (m/z) = 667.5 (M++1). Anal. calcd
for C43H38O5S, C 77.45, H 5.74, S 4.81 Found C 77.36, H 5.59, S 4.62.
5,7,3’,4’-Tetra-O-benzyl-(+)-thioepicatechin (28). []20
= +61.3 (c 1, CH2Cl2); Optical
D
purity = 96.6% ee; Chemical purity = 100% (AUC); 1H-NMR (CDCl3) = 2.2 (d, 1H, J = 9.6 Hz), 2.9
(q, ABq, JA = 3.9, 4.1, 17.4 Hz, JB = 4.9, 5.3 Hz), 4.3–4.42 (m, 2H), 4.95 (s, 2H), 5.12 (s, 2H), 5.14 (s,
2H), 6.3 (s, 2H), 6.82 (d, 1H, J = 8.3 Hz), 6.98 (dd, 1H, J = 2, 8.3 Hz), 7.12 (d, 1H, J = 2 Hz), 7.2–7.5
(m, 20H); 13C-NMR (CDCl3) = 31.4, 31.9, 49.8, 66.4, 70.0, 70.3, 71.3, 71.4, 77.5, 97.7, 102.3, 112.3,
114.9, 115.65, 121.7, 127.2,. 127.3, 127.5, 127.6, 127.8, 127.9, 128.1, 128.5, 128.5, 128.6, 128.6,
131.4, 133.7, 136.8, 136.8, 137.2, 137.3, 148.4, 148.9, 158.1, 158.5; MS (m/z) = 667.5 (M++1). Anal.
calcd for C43H38O5S, C 77.45, H 5.74, S 4.81 Found C 77.28, H 5.63, S 4.66.
5,7,3’,4’-Tetra-O-benzyl-(-)-thiocatechin (31) and 5,7,3’,4’-tetra-O-benzyl-(-)-thioepicatechin (32). To
a cold solution (0–5 °C) of 30 (1.26 g, 1.62 mmol, 1 eq.) in CH2Cl2 (60 mL) was added TFA
(300 L, 3.89 mmol, 2.4 eq.). The mixture was kept at 0–5 °C. Upon consumption of the starting
material, the reaction was quenched by addition of Et3N (515 L) and cold H2O (25 mL). The organic
layer was separated and washed with brine (25 mL), dried (Na2SO4), filtered and the solvent removed
in vacuo. The crude product was then purified by silica gel chromatography (heptane/CH2Cl2/EtOAc,
1/1/0 to 25/25/1, v/v/v) to afford the desired compounds 31 (0.82 g, 76%), and 32 (170 mg, 16%).
5,7,3’,4’-Tetra-O-benzyl-(-)-thiocatechin (31). []20 D= -62.5 (c 1, CH2Cl2); Chemical purity = 98.6%
(AUC); Optical purity = 96% ee; 1H-NMR (CDCl3)  = 1.95 (d, 1H, J = 4.4 Hz), 2.7 (dd, 1H, J = 8.4,
17.2 Hz), 3.12 (dd, 1H, J = 4.5, 17.2 Hz), 4.15 (d, 1H, J = 8.5 Hz), 4.18–4.32 (m, 1H), 4.98 (s, 4H), 5.1
(s, 2H), 5.12 (s, 2H), 6.3 (s, 2H), 6.8–6.92 (m, 2H), 7.02 (d, 1H, J = 1.5 Hz), 7.2–7.5 (m, 20H);
13C-NMR (CDCl3) = 29.8, 51.3, 70.0, 70.2, 70.3, 71.3, 71.4, 77.5, 97.4, 102.3, 113.8, 115.4, 121.9,
127.3, 127.5, 127.6, 127.9, 127.9, 127.9, 128.1, 128.2, 128.5, 128.5, 128.6, 128.6, 129.1, 130.6, 133.9,
136.8, 136.9, 137., 137.2, 149.2, 149.2, 157.8, 159.0; MS (m/z) = 667.5 (M++1). Anal. calcd for
C43H38O5S, C 77.45, H 5.74, S 4.81 Found C 77.41, H 5.66, S 4.78.

Molecules 2010, 15
5614
5,7,3’,4’-Tetra-O-benzyl-(-)-thioepicatechin (32). []20 D= -58.4 (c 1, CH2Cl2); Chemical
1
purity = 100% (AUC); Optical purity = 97% ee; H-NMR (CDCl3)  = 2.2 (d, 1H, J = 10.5 Hz), 2.9
(ABq, JA = 4, 17.7 Hz, JB = 5, 17.9 Hz), 4.3–4.42 (m, 2H), 4.92 (s, 4H), 5.06 (s, 2H), 5.09 (s, 2H), 6.36
(s, 2H), 6.86 (d, 1H, J = 8.3 Hz), 6.95 (dd, 1H, J = 2.1, 8.3 Hz), 7.12 (d, 1H, J = 2 Hz),
13
7.2–7.5 (m, 20H); C-NMR (CDCl3) = 29.8, 51.3, 70.0, 70.2, 70.3, 71.3, 71.4, 76.6, 97.4, 102.3,
113.8, 115.2, 115.4, 121.9, 127.3, 127.5, 127.6, 127.9, 127.9, 127.9, 128.1, 128.2, 128.5, 128.5, 128.6,
128.6, 129.1, 130.6, 133.9, 136.8, 136.8, 137.0, 137.2, 140.2, 140.2, 157.3, 158.0;
MS (m/z) = 667.5 (M++1). Anal. Calcd for C43H38O5S, C 77.45, H 5.74, S 4.81 Found C 77.37, H 5.65,
S 4.58.
(+)-Thiocatechin (5). To an ice cold solution of 27 (1.43 g, 2.15 mmol, 1 eq.) in dry CH2Cl2 (60 mL)
was added N,N-dimethylaniline (1.63 mL, 12.88 mol, 8 eq.) under N2. The solution was stirred at this
temperature for ~10 minutes before AlCl3 (2.29 g, 17.18 mmol, 10 eq.) was added in one portion. The
flask was covered with aluminum foil to protect it from light and stirred at ice bath temperature for 2 h.
EtOAc (50 mL) and silica gel (5 g) were added to the reaction mixture and stirred for 5 minutes. The
reaction mixture was filtered through a pad of silica gel. The silica gel pad was washed with EtOAc
(5 × 50 mL). The filtrates were combined and the solvent was removed in vacuo to ~10 mL of volume,
keeping the bath temperature < 25 C. The crude mixture was diluted with purified water (50 mL),
cooled and lyophilized to give the crude product. The crude product was further purified by
preparative HPLC to give 5 (380 mg, 57%) as an off-white solid in 99% AUC purity. []20 D = +32.2
1
(c 1, Acetone); H-NMR (acetone-d6) = 2.58 (dd, 1H, J = 8.3, 15.5 Hz), 3.18 (d, 1H,
J = 16.3 Hz), 4.17 (d, 1H, J = 8.3 Hz), 4.32 (s, 1H), 6.08 (s, 1H), 6.2 (s, 1H), 6.8 (s, 2H), 6.92 (s, 1H);
13C-NMR (acetone-d6) = 32.3, 52.3, 71.1, 99.9, 103.6, 112.3, 116.0, 116.5, 121.4, 131.3, 135.7,
145.6, 145.8, 157.0; MS = 307.1 [M++H]; HRMS Calcd for C15H15O5S [M+H] 307.0642 Found
307.0644.
(-)-Thioepicatechin (6). To an ice cold solution of 32 (0.67 g, 1.01 mmol, 1 eq.) in dry CH2Cl2 (35 mL)
was added N,N-dimethylaniline (1.02 mL, 8.05 mol, 8 eq.) under N2. The solution was stirred at this
temperature for ~10 minutes before AlCl3 (1.37 g, 10.1 mmol, 10 eq.) was added in one portion. The
flask was covered with aluminum foil to protect it from light and stirred at the ice bath temperature for
2 h. EtOAc (50 mL) and silica gel (5 g) were added to the reaction mixture and stirred for 5 minutes.
The reaction mixture was filtered through a pad of silica gel. The silica gel pad was washed with
EtOAc (3 × 50 mL). The filtrates were combined and the solvent was removed in vacuo to ~10 mL of
volume keeping the bath temperature < 25 C. The crude mixture was diluted with purified water
(50 mL), cooled and lyophilized to give the crude product. The crude product was further purified by
preparative HPLC to give 6 (100 mg, 57%) as an off-white solid in 99.8% AUC purity. []20 D= -28.9
1
(c 1, acetone); H-NMR (acetone-d6)  = 2.7 (dd, 1H, J = 6.7, 17 Hz), 2.82 (dd, 1H, J = 4.1, 17 Hz),
4.32 (d, 1H, J = 2.3 Hz), 4.33–4.5 (br s, 1H), 6.16 (dd, 2H, J = 2.3, 11.8 Hz), 6.72 (d, 1H,
13
J = 8 Hz), 6.82 (dd, 1H, J = 2.3, 11.8 Hz), 7.08 (d, 1H, J = 2 Hz), 7.7–8.3 (br s, 4H); C-NMR
(acetone-d6)  = 50.0, 68.0, 99.9, 104.1, 110.6, 115.5, 117.1, 121.7, 133.0, 135.2, 145.3, 145.4, 156.9,
157.5; MS = 307.1 [M++H]; HRMS Calcd for C15H15O5S [M+H] 307.0642 Found 307.0634.

Molecules 2010, 15
5615
(-)-Thiocatechin (7). To an ice cold solution of 31 (0.92 g, 1.38 mmol, 1 eq.) in dry CH2Cl2 (40 mL)
was added N, N-dimethylaniline (1.08 mL, 8.5 mol, 6.2 eq.) under N2. The solution was stirred at this
temperature for ~10 minutes before AlCl3 (1.51 g, 11 mmol, 8.2 eq.) was added in one portion. The
flask was covered with aluminum foil to protect it from light and stirred at the ice bath temperature for
2 h. EtOAc (50 mL) and silica gel (5 g) were added to the reaction mixture and stirred for 5 minutes.
The reaction mixture was filtered through a pad of silica gel. The silica gel pad was washed with
EtOAc (3 × 50 mL). The filtrates were combined and the solvent was removed in vacuo to ~10 mL of
volume keeping the bath temperature < 25 C. The crude mixture was diluted with purified water (50
mL), cooled and lyophilized to give the crude product. The crude product was further purified by
preparative HPLC to give 7 (205 mg, 56%) as an off-white solid in 99% AUC purity. []20 D= -28.6 (c
1
1, acetone); H-NMR (acetone-d6)  = 2.58 (dd, 1H, J = 5.9, 16.7 Hz), 3.18 (dd, 1H,
J = 4.7, 16.7 Hz), 3.8–3.96 (br s, 1H), 4.1 (d, 1H, J = 9 Hz), 4.16–4.3 (m, 1H), 6.12 (d, 1H,
J = 2.2 Hz), 6.2 (d, 1H, J = 2.2 Hz), 6.72 (s, 2H, J = 0.8 Hz), 6.9 (s, 1H), 7.6–8.3 (br s, 4H); 13C-NMR
(acetone-d6)  = 32.4, 52.3, 71.1, 98.5, 103.5, 112.0, 115.9, 116.5, 121.4, 131.3, 135.8, 145.5, 145.8,
157.0; MS = 307.1 [M++H]; HRMS Calcd for C15H15O5S [M+H] 307.0642 Found 307.0633.
(+)-Thioepicatechin (8). To an ice cold solution of 28 (0.4 g, 0.6 mmol, 1 eq.) in dry CH2Cl2 (20 mL)
was added N,N-dimethylaniline (0.6 mL, 4.81 mol, 8 eq.) under N2. The solution was stirred at this
temperature for ~10 minutes before AlCl3 (0.8 g, 6.01 mmol, 10 eq.) was added in one portion. The
flask was covered with aluminum foil to protect it from light and stirred at the ice bath temperature for
2 h. EtOAc (50 mL) and silica gel (5 g) were added to the reaction mixture and stirred for 5 minutes.
The reaction mixture was filtered through a pad of silica gel. The silica gel pad was washed with
EtOAc (3 × 50 mL). The filtrates were combined and the solvent was removed in vacuo to ~10 mL of
volume keeping the bath temperature < 25 C. The crude mixture was diluted with purified water
(50 mL), cooled and lyophilized to give the crude product. The crude product was further purified by
preparative HPLC to give 8 (124 mg, 52%) as an off-white solid in 100% AUC purity. []20 D= +29.7
1
(c 1, acetone); H-NMR (acetone-d6) = 2.7 (dd, 1H, J = 6.7, 17 Hz), 2.82 (dd, 1H,
J = 4.1, 17 Hz), 4.32 (d, 1H, J = 2.3 Hz), 4.33–4.5 (br s, 1H), 6.16 (dd, 2H, J = 2.3, 11.8 Hz), 6.72 (d,
13
1H, J = 8 Hz), 6.82 (dd, 2H, J = 2.3, 11.8 Hz), 7.08 (d, 1H, J = 2 Hz), 7.7–8.3 (br s, 4H); C-NMR
(acetone-d6) = 50.0, 68.0, 99.9, 104.1, 110.6, 115.5, 117.1, 121.7, 133.0, 135.2, 145.3, 145.4, 156.9,
157.5; MS = 307.1 [M++H]; HRMS Calcd for C15H15O5S [M+H] 307.0642 Found 307.0631.
4. Conclusions
In conclusion, the first enantioselective syntheses of sulfur analogues of naturally occurring flavan-
3-ols were accomplished wherein the oxygen atom of the pyran ring has been replaced with a sulfur
atom in a stereoselective fashion. The key steps involved were:the introduction of a –St-Bu group via
Pd(0) chemistry, stereoselective dihydroxylation under Sharpless conditions, ring closure under acidic
conditions via the formation of benzylic carbocation, and the removal of benzyl group using AlCl3 and
N,N-dimethylaniline as a scavenger. The enantiomeric excess of the intermediates and the title
compounds were determined by a chiral HPLC method. The methodologies developed here are quite

Molecules 2010, 15
5616
modular and should permit the preparation of other analogues of flavan-3-ols and various
combinations of A-type and B-type proanthocyanidins [48,49].
Acknowledgements
The authors thank Daniel J. Coughlin, Heather Taft of JMPM and Harold H. Schmitz of MARS
Incorporated for their constant encouragement during the course of this work. We are grateful to the
analytical department of Johnson Matthey for analytical method development and the analyses.
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