Improved synthesis of structural analogues of (-)-epicatechin gallate for modulation of staphylococcal β-lactam resistance

Article abstract of DOI:10.1016/j.tet.2014.03.052

The high-yielding synthesis of enantiomerically pure epicatechin gallate analogues where the A and/or B-ring hydroxylation is reduced or altered has been achieved by optimising routes to the catechin stereochemistry. The B-ring analogues were synthesised by using an electrophilic ring closure onto an enantiomerically enriched epoxide as a key step. The A and B-ring hydroxyl-deleted analogues were synthesised through a Mitsunobu cyclisation. For the B-ring analogues, the anti- (catechin) stereochemistry was converted to the syn- (epicatechin) stereochemistry by a known oxidation/reduction protocol. Absolute stereochemistry was derived from either a Sharpless epoxidation or asymmetric dihydroxylation.

Full text of DOI:10.1016/j.tet.2014.03.052

Tetrahedron 70 (2014) 3485e3490
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Improved synthesis of structural analogues of (ꢀ)-epicatechin
gallate for modulation of staphylococcal b
-lactam resistanceq
,
a
a
b
James C. Anderson a , Helen Grounds , Suzanna Reeves , Peter W. Taylor
*
a Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
b School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1, 1AX, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The high-yielding synthesis of enantiomerically pure epicatechin gallate analogues where the A and/or
B-ring hydroxylation is reduced or altered has been achieved by optimising routes to the catechin ste-
reochemistry. The B-ring analogues were synthesised by using an electrophilic ring closure onto an
enantiomerically enriched epoxide as a key step. The A and B-ring hydroxyl-deleted analogues were
synthesised through a Mitsunobu cyclisation. For the B-ring analogues, the anti- (catechin) stereo-
chemistry was converted to the syn- (epicatechin) stereochemistry by a known oxidation/reduction
protocol. Absolute stereochemistry was derived from either a Sharpless epoxidation or asymmetric
dihydroxylation.
Received 13 January 2014
Received in revised form 10 March 2014
Accepted 17 March 2014
Available online 26 March 2014
Keywords:
(ꢀ)-Epicatechin gallate analogues
Asymmetric synthesis
Cyclisation
Ó 2014 The Authors. Published by Elsevier Ltd. All rights reserved.
Mitsunobu
MRSA
1. Introduction
may increase bilayer affinity, withconsequent increases inbioactivity.
We therefore synthesized a number of unnatural ECg analogues dif-
Galloyl catechins, such as (ꢀ)-epicatechin gallate (ECg), (ꢀ)-epi-
gallocatechin gallate (EGCg) and (ꢀ)-catechin gallate (Cg) are natural
polyphenols, which constitute around 10% of the dry leaf weight of
the green tea plant Camellia sinensis.1 They have negligible antibac-
terial activity themselves, but show the capacity, at relatively low
fering in B-ring hydroxylation and in hydroxyl substitution of the
fused AeC-ring moiety (Fig. 1).7,8 We demonstrated that while
monohydroxylated 3-hydroxy B-ring 1 and dihydroxylated 3,5-
dihydroxy B-ring 2 ECg analogues sensitized MRSA strains to the b-
lactam antibiotic oxacillin to a comparable extent compared to the
natural product, the complete deletion of all B-ring hydroxyl groups
gave a compound 3 that displayed an enhanced capacity to reduce
oxacillin resistance in EMRSA-16 (Fig. 1).8 Complete deletion of A and
B ring hydroxyl groups in either epicatechin 4 or catechin (ꢀ)-5
concentrations, to disrupt the
methicillin-resistant strains of Staphylococcus aureus (MRSA), in-
ducing complete but reversible susceptibility to a wide range of
b-lactam resistance machinery of
b-
lactamdrugs.2e4 There isstrongevidence that thiseffect isdependent
on the intercalation of the bioactive polyphenols into the bacterial
cytoplasmic membrane (CM): the most potent modifier, ECg (Fig. 1),
inserts into the staphylococcal bilayer, inducing a series of complex
changes to the phospholipid palisade and leading to reduction in the
efficiency of function of CM-embedded proteins, such as the
penicillin-binding proteins responsible for peptidoglycan bio-
resulted in a reduction in b-lactam resistance-modifying potential
and an increase in intrinsic anti-staphylococcal activity, with the
catechin derivative (ꢀ)-5 showing an enhanced effect. We reported
that further reduction of B-ring hydroxyl substitution led to lower
synthetic yields.8 In order to investigate the capacity of natural and
synthetic galloyl catechins, as well as combinations of galloyl and
non-galloyl catechins, to interact with artificial membrane bilayers
and indicate the potential for creating therapeutic catechin combi-
synthesis and b
-lactam resistance.5,6 ECg differs from EGCg only by
the absence of a hydroxyl function at one of the meta positions on the
B-ring(Fig.1), suggestingthatreducingthedegreeofhydroxylation or
alteringthe positionof hydroxyl groups ontheB-ringpharmacophore
nations for modulation of staphylococcal b-lactam resistance, we
requireda morerobust synthesis of thesehydroxyl deleted analogues.
Here we report an improved synthesis of these analogues, as well as
the synthesis of the novel enantiomerof (ꢀ)-5 [(þ)-5], which we have
used in further studies of our own9 and we hope will be of use to
others investigating the wide range of other biological effects
exhibited by catechins in general.10
q
This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/3.0/).
* Corresponding author. Tel.: þ44 (0)2076795585; e-mail address: j.c.anderson@
ucl.ac.uk (J.C. Anderson).
0040-4020/$ e see front matter Ó 2014 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.052

3486
J.C. Anderson et al. / Tetrahedron 70 (2014) 3485e3490
Fig. 1. Naturally occurring galloyl catechins and non-natural targets.
2. Results and discussion
Our previous synthesis of these compounds, which was also
developed by Chan,11 introduced the desired stereochemistry using
a Sharpless dihydroxylation followed by a four-step cyclisation
(Scheme 1).7,8 We have since found that the reproducibility of the
cyclisation to form ring C is highly dependent on the purity of the
acetyl bromide used. This must be freshly distilled and the presence
of any HBr leads to a large mixture of often inseparable compounds,
erosion of stereochemical integrity and low yields (typically less
than 10%).
ð1Þ
It was thought that this methodology could be applied to the
synthesis of our analogues. Use of benzyl protecting groups on the
phenolic hydroxyls would enable the synthesis of the ECg ana-
logues with free phenolic hydroxyl groups after hydrogenolysis. We
are not aware of any examples of the deprotection of methoxy
groups on either (epi)catechins or the corresponding gallate esters.
The thiourea catalyst used in Eq. 1 is not commercially available and
the synthesis of this compound involves multiple steps, in addition
to the use of an expensive gold catalyst. In contrast to this the HFIP
cyclisation requires no additional catalyst and the solvent can be
recycled and reused by a simple distillation at the end of the re-
action. Although the reaction for the methoxy-substituted catechin
analogous to 3 was slow (72 hd51% conversion) we decided to
pursue this reaction in favour of the gold-catalysed cyclisation.
For the synthesis of analogue 3 we initially attempted to syn-
thesise the desired racemic epicatechin 7 with the correct syn-
relative stereochemistry directly from the diastereomeric epoxide 8
compared to Yang14 and Qu15 (Scheme 2). However all attempts at
cyclising 8 utilising HFIP failed, starting material and HFIP addition
to the epoxide was detected in the crude reaction mixture by 1H
NMR spectroscopy. The failure of 8 to cyclise under these reaction
conditions is in direct contrast to the literature example (Fig. 1).
Inspection of molecular models reveals steric crowding between
each of the aromatic rings and the methylene of the epoxide in the
reactive conformation required for ring closure. For the di-
astereoisomer in Fig. 1, the C6H5-group is orientated exo- to the
bond forming event in the same conformation.
Scheme 1. Reagents and conditions (i) AD-mix-b
Ò. (ii) HCl, MeOH. (iii) HC(OMe)3,
PPTS cat. (iv) AcBr; K2CO3. (v) NaBH4.
As 100 mg quantities of each compound were required for
membrane bilayer studies we set about to develop a more reliable
and reproducible synthesis of the desired analogues. Natural EGCg
can be readily synthesised using a Mitsunobu cyclisation to form
ring C to give the catechin followed by an oxidation and reduction
to give the epicatechin.12 We investigated a range of conditions for
the Mitsunobu cyclisations of the B-ring diminished hydroxyl
compounds (1, 2, 3) along the same route, but found that in the
absence of the para-hydroxy group on the B ring no desired product
formation occurred. Since our publication of the synthesis of 2 and
3 in 20057 and the synthesis of 1 and 4 in 20118 a number of
publications have appeared on the synthesis of various other epi-
catechin analogues (with or without the gallate ester), which do not
have a para-hydroxyl group on the B-ring. A recent method replaces
the capricious acetyl bromide used in our previous cyclisations
with BF3$OEt2 to good effect, although only cyclises substrates to
the anti-stereochemistry (catechin like) and in racemic form.13 We
were drawn to the more efficient route of Yang et al. who reported
the synthesis of a range of catechins using a thiourea/AuCl3/AgOTf
catalysed diastereoselective annulation of aryl epoxides (Eq. 1).14
Qu et al. have reported a similar strategy for the synthesis of 3-
chromanol analogues, in this case the cyclisation of a similar ep-
oxide was performed by refluxing the substrate in hexa-
fluoroisopropanol (HFIP), but again only on substrates, which gave
the (anti-) catechin relative stereochemistry.15 They also had one
example of the synthesis of a catechin analogous to 3 but with
methyl ether protecting groups performed using enantiopure
epoxide.
Scheme 2. Reagents and conditions (i) mcpba, CH2Cl2,
4 h, 52%. (ii) 3,5-
Dibenzoxyphenol, NaH, THF, H2O, reflux, 14 h, 61%. (iii) Et3N, TMSCl, EtOAc, ꢀ20 ꢁC,
25 min, then MsCl, Et3N, 20 min followed by 2 M HCl (used crude in next step). (iv)
NaOH, Bu4NCl, H2O, THF, 14 h, 73% over two steps.

J.C. Anderson et al. / Tetrahedron 70 (2014) 3485e3490
3487
We therefore reverted to the diastereomeric epoxide 10a anal-
ogous to Qu’s compound.15 The enantiomerically pure epoxide 6a
(96% ee) was generated by Sharpless epoxidation16 of cinnamoyl
alcohol and the epoxide synthesised for this substrate in an anal-
ogous way to epoxides synthesised by Qu. Heating 10a in HFIP gave
the desired cyclised catechin 11a in 46% yield (56% b.r.s.m), al-
though long reaction times were needed (15 d). The desired epi-
catechin relative stereochemistry was attained by oxidation of the
alcohol with DesseMartin periodinane and reduction of the gen-
erated ketone with L-Selectride to give 7a in high overall yield.17
The desired gallate ester product 3 was synthesised using our
previously published procedure8 involving the DMAP-catalysed
coupling of the benzyl-protected gallate acid chloride followed by
global hydrogenolysis to remove the benzyl protecting groups. By
changing the solvent of the hydrogenation to a mixture of EtOAc
and MeOH (compared to previously using just EtOAc) and in-
creasing the reaction time to 12 h the yield of this step could be
increased from 37 to 95% (depending on analogue) to near quan-
titative conversion in all cases.
Scheme 4. Reagents and conditions (i) PPh3, DEAD, THF, 14 h (12: 46%, 13: 64%). (ii)
BzCl, Et3N, DMAP (cat.), CH2Cl2, 15 h. (iii) Pd(OH)2/C, EtOAc/MeOH, 2.5 h ((ꢀ)-5: 57%),
(þ)-5: 53% over two steps).
3. Conclusion
Reducing the degree of hydroxylation or altering the position of
hydroxyl groups on the A and/or B-ring pharmacophore has a pro-
found effect on the ability of non-natural epicatechin gallate ana-
logues to modulate staphylococcal b-lactam resistance, and also on
their syntheses. The syntheses of these molecules have proven low-
yielding due to decreased activation of the aromatic rings.7,8 We
have optimised synthetic routes to prepare these compounds in
high yielding procedures, which allows for their synthesis in
quantities sufficient for further studies to explore and quantify
interactions with artificial membrane bilayers and indicate the
potential for creating therapeutic catechin combinations for mod-
This synthesis was also successful for the mono- and di-
hydroxy-substituted B ring analogues (1 and 2). In these cases
enantiopurity was determined by the formation of the Mosher
ester of the epoxides 6b,c as no separation was seen of the ra-
cemic epoxides using chiral HPLC. In both cases the enantio-
purity was found to be >95% by 1H NMR analysis. The
enantiopurity of all the epicatechin compounds and gallate es-
ters was judged to be maintained through the synthetic se-
quence (Scheme 3) by comparison to our previously reported
specific rotations.8
ulation of staphylococcal b
-lactam resistance.9 The synthetic routes
to the B-ring analogues rely upon formation of the anti- (catechin)
stereochemistry, which was then converted to the syn- (epi-
catechin) stereochemistry by a known oxidation/reduction pro-
tocol.17 Absolute stereochemistry was derived from either
a Sharpless epoxidation16 or asymmetric dihydroxylation.19 The
synthetic routes will be of use to others investigating the wide
range of biological effects exhibited by catechin analogues in
general.
4. Experimental section
4.1. General
Melting points were recorded on a Stuart Scientific SMP3 ap-
paratus and are uncorrected. Optical rotations were recorded on
a PerkineElmer 343 digital polarimeter at 22 ꢁC and are reported in
deg cm2 ꢀ1. Infrared spectra were recorded on a PerkineElmer
g
1600 FTIR instrument as thin films or solids. The NMR spectra were
recorded on Bruker AVANCE III 600 MHz spectrometer as a solution
in CDCl3 unless otherwise stated. Chemical shifts are reported in
parts per million relative to CHCl3 (1H: 7.27), (13C: 77.2). Coupling
constants are reported in Hertz and rounded to the nearest 0.1 Hz.
Signal assignments are as follows: br (broad), s (singlet), d (dou-
blet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets),
etc. Mass spectra were recorded using Thermo Finnigan Mat900xp
(EI/CI) and Waters LCT Premier XE (ES) instruments. HPLC analysis
was acquired on a Hewlett Packard Capillary HP4890A GC analyser.
For all non-aqueous chemistry, glassware was rigorously flame-
dried and an inert (N2) atmosphere maintained throughout. All
solvents and chemicals were used as received unless stated. Chro-
matographic separations were performed using Merck GeduranÒ
silica gel 60. Petroleum ether with a boiling range 40e60 ꢁC was
used.
Scheme 3. Reagents and conditions (i) DiethyleL-tartrate, Ti(OiPr)4, t-BuOOH, sieves,
CH2Cl2, ꢀ20 ꢁC (6a: 40%, 6b: 70%, 6c: 79%). (ii) 3,5-Dibenzoxyphenol, NaH, THF, H2O,
reflux, 14 h (9a: 61%, 9b: 61%, 9c: 78%). (iii) 10a: Pyridine, p-tosyl chloride, rt, 2 d then
K2CO3 (67%); 10b,c: Et3N, DMAP, p-tosyl chloride, CH2Cl2, rt, o/n then K2CO3 (10b: 46%,
10c: 56%). (iv) HFIP, reflux 12e15 d (11a: 46%, 11b: 42%, 11c: 33%). (v) DesseMartin
periodinane, wet CH2Cl2, 0 ꢁC, o/n (a: 63%, b: 57%, c: 68%). (vi) L-Selectride, THF,
ꢀ78 ꢁC, 2 h (7a: 72%, 7b: 68%, 7c: 74%).
The synthesis of our last analogues 5 was more facile. The
Mitsunobu cyclisation of requisite triols has been reported by
Krohn to give (ꢀ)-catechin.18 We repeated this reaction using both
4.2. ( )-(S)-2-(S)-Phenyl-(3,5-dibenzyloxyphenoxy)-methyl
oxirane (8)
the known triols8,18 synthesised using
a
-AD mixÒ and
b
-AD mixÒ to
give cyclised compounds 12 and 13.19 Subsequent coupling with
the benzyl-protected gallate acid chloride and hydrogenolysis gave
(ꢀ)-5 and the novel (þ)-5 (Scheme 4).
A suspension of (ꢂ)-9a (90 mg, 0.197 mmol) and Et3N (30
mL,
0.197 mmol) in EtOAc (1 mL) was cooled to ꢀ20 ꢁC and treated with

3488
J.C. Anderson et al. / Tetrahedron 70 (2014) 3485e3490
a solution of TMSCl (26
m
L, 0.197 mmol) in EtOAc (0.4 mL) added
C4H2), 5.07 (2H, s, OCH2PH), 6.91e6.94 (3H, m, ArH), 7.26e7.29 (1H,
m, ArH), 7.32e7.36 (1H, m, ArH), 7.38e7.46 (4H, m, ArH); 13C NMR
dropwise over 10 min. The resultant solution was stirred at ꢀ20 ꢁC
for 15 min and then treated with Et3N (30
by a solution of MsCl (17
mL, 0.197 mmol) followed
d 55.5, 61.2, 62.4, 70.1, 111.9, 115.0, 118.5, 127.6, 128.2, 128.7, 129.8,
m
L, 0.217 mmol) in EtOAc (0.4 mL) and
136.9, 138.5, 159.2; m/z (CI) 257 (22%, MþþH), 239 (41%, MþꢀOH),
stirred for 20 min at ꢀ20 ꢁC. After this time HCl (2 M, 0.4 mL) was
added and the reaction mixture stirred at rt for 1 h. The reaction
mixture was washed with H2O (2 mL), NaHCO3(aq) (5 mL), brine
(5 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid
was taken up in THF (1 mL) and treated with a mixture of NaOH
(35 mg, 0.450 mmol) and Bu4NCl (3 mg, 0.010 mmol) in H2O (1 mL).
The resultant solution was stirred vigorously o/n. The reaction
mixture was extracted into EtOAc (2ꢃ5 mL), separated, dried
(MgSO4), filtered and concentrated in vacuo. Purification was ach-
ieved by flash column chromatography (20% EtOAc/Pet. Ether) to
give 8 as a white solid (63 mg, 73%); mp 101e102 ꢁC; Rf (10% EtOAc/
Pet. Ether) 0.28; IR nmax 3025, 1594, 1451, 1375, 1144, 1057 cmꢀ1; 1H
227 (61%), 213 (26%), 181 (26%), 161 (22%), 149 (41%, MþþHꢀOH,
Bn), 137 (24%), 119 (39%), 91 (100%, Bn); HRMS
C16H17O3
calcd 257.1172, found 257.1161. By comparison of the diastereotopic
peaks 6c was found to have an enantiopurity of >20:1.
4.4. General procedure for the synthesis of diols (9)
A solution of 3,5-dibenzoxyphenol21 (1.1 equiv) in anhydrous THF
(6 mL) was cooled to 0 ꢁC and treated with NaH (1.1 equiv). The re-
sultant suspension was stirred at rt for 90 min, after this time H2O
(9.5 mL) was added dropwise over 5 min followed by a solution of 6
(2.40e2.98 mmol, 1 equiv) in THF (6 mL). The resultant solution was
heated to reflux for 1e3 d until complete by TLC. The reaction mixture
was cooled to rt and concentrated in vacuo. Purification was achieved
by flash column chromatography (20e70% EtOAc/Pet. Ether).
NMR
d
2.74 (1H, dd, J¼4.8, 2.6, C4H2), 2.84 (1H, appt, J¼4.4, C4H2),
3.38 (1H, ddd, J¼6.4, 4.1, 3.3, C3H), 4.82 (1H, d, J¼6.0, C2H), 4.94 (4H,
s, 2ꢃOCH2Ph), 6.19 (2H, d, J¼2.4, ArH), 6.21 (1H, t, J¼2.4, ArH),
7.31e7.39 (15H, m, ArH); 13C NMR
d 45.1, 55.1, 70.2, 81.6, 95.4, 96.1,
126.6, 127.7, 128.1, 128.5, 128.7, 129.0, 136.8, 137.3, 159.6, 160.6; m/z
(EI) 438 (Mþ), 408 (MþꢀH2CO), 347 (MþꢀBn), 133, 91; HRMS m/z
(EI) C29H26O4 calcd 438.1831, found 438.1822.
4.4.1. (2S,3R)-3-(3,5-Dibenzyloxyphenoxy)-3-phenylpropane-1,2-
diol (9a). Yield (629 mg, 57%) as a yellow solid; mp 135e137 ꢁC; Rf
(40% EtOAc/Pet. Ether) 0.25; [
a
]
22 ꢀ8.7 (c 0.35, CHCl3); IR nmax 3532,
D
3371, 1595, 1451, 1154, 1053 cmꢀ1; 1H NMR
d
1.99 (1H, dd, J¼7.4, 5.1,
4.3. General procedure for the synthesis of epoxy alcohols (6)
C4OH), 2.21 (1H, d, J¼5.9, C3OH), 3.79e3.83 (2H, m, C4H2),
3.94e3.98 (1H, m, C3H), 4.93 (4H, s, 2ꢃOCH2Ph), 5.17 (1H, d, J¼6.0,
C2H), 6.13 (2H, d, J¼2.1, ArH), 6.20 (1H, t, J¼2.1, ArH), 7.30e7.41 (15H,
ꢀ
A suspension of CH2Cl2 (30 mL) over molecular sieves (4 g, 4 A,
powdered) was cooled to ꢀ20 ꢁC and treated with diethyl-
L-tartrate
m, ArH); 13C NMR
d 62.9, 70.2, 74.8, 81.1, 95.4, 96.0, 126.8, 127.7,
(0.08 equiv) followed by titanium isopropoxide (0.05 equiv) and t-
butyl hydroperoxide (2.1 equiv). The resultant solution was stirred at
ꢀ20 ꢁC for 40 min and then treated with a solution of 3,5-
dibenzyloxycinnamyl alcohol14 (for 6b) or 3-benzyloxycinnamyl al-
cohol20 (for 6c) (2.47e4.16 mmol) in CH2Cl2 (20 mL), added dropwise
over 1 h. After stirring for 2 h the reaction was quenched NaOH
(0.21e0.33 mL,10% aqueous solution saturated with NaCl) anddiethyl
ether added (6 mL). The reaction mixture was removed from the cold
bath, warmed to 10 ꢁC and stirred for 10 min after this time MgSO4
(0.21e0.33 g) and Celite (50 mg) were added, stirring was continued
for 15 min. The reaction mixture was then filtered through Celite,
washed with diethyl ether (20 mL) and concentrated in vacuo. Puri-
fication was achieved by flash column chromatography (30e50%
EtOAc/Pet. Ether). Enantiopurity was checked by conversion of the
alcohol to the Mosher ester. A solution of 6 (0.04 mmol) in CH2Cl2
128.2, 128.5, 128.7, 129.0, 136.7, 137.6, 159.4, 160.6; m/z (CI) 457
(53%, MþþH), 439 (23%), 307 (100%); HRMS m/z (CI) C29H29O5
calcd 457.2015, found 457.2003.
4.4.2. (2S,3R)-3-(3,5-Dibenzyloxyphenoxy)-3-(3,5-dibenzyloxyphen
yl)-propane-1,2-diol (9b). Yield (919 mg, 61%) as a white solid; mp
66e68 ꢁC; Rf (40% EtOAc/Pet. Ether) 0.20; [
a
]
22 ꢀ2.3 (c 1.10, CHCl3);
IR nmax 3403, 1597, 1454, 1377, 1156, 1056 cmꢀ1D; 1H NMR
d 2.00e2.02
(1H, m, C4OH), 2.50 (1H, d, J¼5.9, C3OH), 3.73e3.81 (2H, m, C4H2),
3.89e3.94 (1H, m, C3H), 4.94 (4H, s, 2ꢃOCH2Ph), 5.01 (4H, s,
2ꢃOCH2Ph), 5.07 (1H, d, J¼5.9, C2H), 6.14 (1H, s, ArH), 6.14 (1H, s,
ArH), 6.23 (1H, br, ArH), 6.57 (1H, br, ArH), 6.61 (1H, s, ArH), 6.62 (1H,
s, ArH), 7.27e7.41 (20H, m, ArH); 13C NMR
d 62.9, 70.2, 70.3, 74.7, 81.0,
95.4, 96.0, 101.9, 105.8, 127.7, 127.8, 128.21, 128.24, 128.69, 128.72,
136.6, 136.8, 140.1, 159.4, 160.4, 160.6; m/z (CI) 669 (62%, Mþ), 363
(28%, Mþꢀ3ꢃBn, OH2), 352 (82%), 207 (100%), 181 (25%), 91 (26%,
Bn); HRMS m/z (ES) C43H39O7 calcd 667.2696, found 667.2755.
(0.3 mL) was treated with a pre-mixed solution of Et3N (27
0.04 mmol) and DMAP (5 mg, 0.04 mmol) in CH2Cl2 (0.3 mL) followed
by (S)- -methoxy- -(trifluoromethyl)phenylacetyl chloride (9 L,
mL,
a
a
m
0.044 mmol) and stirred for 5 min, TLC analysis indicated reaction
completion. The solution was concentrated and submitted for 1H
NMR analysis (CDCl3). The analogous reaction was performed using
racemic-3-(3-methoxy)-phenyl)-oxiran-2-yl) methanol and the dis-
tinctive double-doublets for the C4 peak compared.
4.4.3. (2S,3R)-3-(3,5-Dibenzyloxyphenoxy)-3-(3-benzyloxyphenyl)-
propane-1,2-diol (9c). Yield (1.30 g, 78%) as a white solid; mp
78e80 ꢁC; Rf (30% EtOAc/Pet. Ether) 0.25; [
a
]
D
22 ꢀ14.8 (c 1.14, CHCl3);
IR nmax 3406, 1594, 1450, 1378, 1260, 1154, 1060 cmꢀ1
;
1H NMR
d
2.00e2.02 (1H, m, C4OH), 2.23 (1H, d, J¼5.4, C3OH), 3.75e3.81
(2H, m, C4H2), 3.91e3.94 (1H, m, C3H), 4.92 (4H, s, 2ꢃOCH2Ph), 5.03
(2H, s, OCH2Ph), 5.11 (1H, d, J¼5.9, C2H), 6.13 (1H, s, ArH), 6.13 (1H, s,
ArH), 6.91 (1H, dd, J¼8.1, 1.7, ArH), 6.94 (1H, d, J¼7.6, ArH), 6.98 (1H,
4.3.1. (2S,3S)-3-(3,5-Bis(benzyloxy)-phenyl)-oxiran-2-yl
methanol
(6b). Yield (804 mg, 70%) as a sticky white solid; Rf (40% EtOAc/Pet.
22
Ether) 0.25; [
a
]
ꢀ25.9 (c 1.03, CHCl3). 1H NMR data agrees with
s, ArH), 7.26e7.42 (17H, m, ArH); 13C NMR
d 62.9, 70.1, 70.2, 74.8,
D
that published in the literature for the racemic compound.14 By
comparison of the diastereotopic peaks 6b was found to have an
enantiopurity of >20:1.
80.9, 95.4, 96.0, 113.2, 114.8, 119.4, 127.71, 127.74, 128.18, 128.22,
128.71, 128.73, 130.1, 136.8 (ꢃ2), 139.3, 159.3, 159.4, 160.6; m/z (CI)
563 (16%, MþþH), 545 (10%, MþꢀOH), 338 (10%), 308 (21%), 307
(100%), 306 (12%), 239 (17%), 223 (13%); HRMS
calcd 563.2428, found 563.2427.
C36H35O6
4.3.2. ((2S,3S)-3-(3-Benzyloxy)-phenyl)-oxiran-2-yl
methanol
(6c). Yield (840 mg, 79%) as a white solid; mp 70e73 ꢁC; Rf (30%
22
EtOAc/Pet. Ether) 0.25; [
a
]
ꢀ34.2 (c 1.03, CHCl3); IR nmax 3413,
4.5. (S)-2-(R)-Phenyl-(3,5-dibenzyloxyphenoxy)-methyl oxir-
ane (10a)
D
3034, 2868, 1598, 1591, 1493, 1454, 1382, 1320, 1291, 1274, 1268,
1205, 1155, 1078, 1026 cmꢀ1
;
1H NMR
d
1.72 (1H, dd, J¼7.9, 5.2,
C4OH), 3.20 (1H, ddd, J¼4.0, 2.2, 1.9, C3H), 3.81 (1H, ddd, J¼12.4, 7.9,
A solution of 9a (450 mg, 0.980 mmol) in pyridine (2.5 mL) was
cooled to 0 ꢁC and treated with p-tosyl chloride (186 mg,
3.7, C4H2), 3.92 (1H, d, J¼1.9, C2H), 4.05 (1H, ddd, J¼12.4, 5.2, 2.2,

J.C. Anderson et al. / Tetrahedron 70 (2014) 3485e3490
3489
0.98 mmol). The resultant reaction mixture was stirred at rt for 2 d.
1 M HCl(aq) (20 mL) was added to the reaction mixture and the
solution was extracted wit EtOAc (3ꢃ15 mL). The organics were
washed with brine (2ꢃ20 mL), NaHCO3(aq) solution (30% wt,
2ꢃ20 mL), brine (2ꢃ15 mL), separated, dried (Na2SO4), filtered and
concentrated in vacuo. The residue was taken up in MeOH (8 mL),
treated with K2CO3 (145 mg, 1.40 mmol) and stirred at rt o/n. After
this time H2O (20 mL) was added and the solution extracted Et2O
(3ꢃ20 mL), washed with brine (3ꢃ20 mL), dried (Na2SO4), filtered
and concentrated in vacuo. Purification was achieved by flash col-
umn chromatography (10e50% EtOAc/Pet. Ether) to give 10a
(289 mg, 67%, (90% b.r.s.m.)) as a pale yellow solid; mp 90e93 ꢁC; Rf
was distilled off and the residue purified by flash column chro-
matography (5e25 % Et2O/Pet. Ether).
4.7.1. (2R,3S)-2-Phenyl-5,7-dibenzyloxy-chroman-3-ol (11a). Yield
(203 mg, 46%, 56% b.r.s.m.) as a white solid; mp 134e135 ꢁC; Rf (30%
22
EtOAc/Pet. Ether) 0.50; [
a
]
D
þ10.2 (c 0.29, CH2Cl2), (lit.5 (other
enantiomer) no mp reported, [
data agrees with those published in the literature for the other
a
]
ꢀ8.7 (c 0.30, CH2Cl2)). 1H NMR
D
enantiomer.8
4.7.2. (2R,3S)-2-(3,5-Bis-benzyloxy-phenyl)-5,7-dibenzyloxy-chro-
man-3-ol (11b). Yield (167 mg, 42%, 74% b.r.s.m.) as a white solid;
22
(30% EtOAc/Pet. Ether) 0.64; [
a
]
22 ꢀ2.8 (c 1.16, CHCl3); IR nmax 1595,
mp 100e102 ꢁC; Rf (25% EtOAc/Pet. Ether) 0.50; [
a]
ꢀ2.0 (c 1.04,
D
D
1450, 1378, 1260, 1153, 1060 cmꢀ1
;
1H NMR
d
2.79 (1H, dd, J¼5.2,
CHCl3); IR nmax 3567, 3064, 3032, 2916,1594, 1498, 1455, 1375, 1346,
2.5, C4H2), 2.83 (1H, dd, J¼5.0, 4.0, C4H2), 3.32 (1H, dt, J¼4.0, 4.0,
C3H), 4.94 (4H, s, 2ꢃOCH2Ph), 5.08 (1H, d, J¼4.1, C2H), 6.16 (2H, d,
J¼2.1, ArH), 6.21 (1H, t, J¼2.1, ArH), 7.27e7.40 (15H, m, ArH); 13C
1291, 1216, 1150, 1118, 1053, 1029 cmꢀ1; 1H NMR
d
1.72 (1H, d, J¼3.6,
C3OH), 2.67 (1H, dd, J¼16.4, 8.8, C4H2), 3.10 (1H, dd, J¼16.4, 5.6,
C4H2), 4.03e4.90 (1H, m, C3H), 4.69 (1H, d, J¼8.0, C2H), 5.00 (2H, s,
OCH2Ph), 5.03 (4H, s, 2ꢃOCH2Ph), 5.04 (2H, s, OCH2Ph), 6.24 (1H, d,
J¼2.2, ArH), 6.27 (1H, d, J¼2.2, ArH), 6.61 (1H, t, J¼2.2, ArH), 6.69
NMR
d 45.1, 54.4, 70.2, 79.2, 95.4, 96.2, 126.8, 127.7, 128.1, 128.5,
128.7, 128.8, 136.8, 137.4, 159.5, 160.6; m/z (CI) 439 (100%, Mþ), 414
(71%), 240 (22%), 229 (42%), 87 (36%), 85 (75%); HRMS C29H27O4
calcd 439.1909, found 439.1893.
(2H, d, J¼2.2, ArH), 7.32e7.39 (20H, m, ArH); 13C NMR
d 27.6, 68.3,
70.0, 70.2, 70.3, 77.3, 81.8, 93.9, 94.4, 102.2, 102.4, 106.3, 127.3, 127.7,
127.7,128.0,128.1,128.2,128.6,128.7,128.7,136.7,136.9,137.0,140.4,
155.2, 157.9, 158.9, 160.4; m/z (EI) 650 (20%, MþꢀH), 369 (32%), 355
(21%), 319 (17%), 242 (16%), 91 (100%, Bn); HRMS m/z (EI) C43H38O6
calcd 650.2663, found 650.2666.
4.6. General procedure for the synthesis of epoxides (10)
A solution of 9 (1.33e1.42 mmol) in CH2Cl2 (30 mL) was treated
with Et3N (1.5 equiv), DMAP (0.025 equiv) and p-tosyl chloride
(1.2 equiv). The resultant reaction mixture was stirred at rt o/n. The
reaction mixture was washed with H2O (20 mL), separated, dried
(Na2SO4), filtered and concentrated in vacuo. The residue was taken
up in MeOH (50 mL), treated with K2CO3 (1.3 equiv) and stirred at rt
for 2 h. The solvent was removed in vacuo and the residue taken up
in EtOAc (40 mL), washed with H2O (20 mL), dried (MgSO4), filtered
and concentrated in vacuo. Purification was achieved by flash col-
umn chromatography (10e50% EtOAc/Pet. Ether).
4.7.3. (2R,3S)-2-(3-Benzyloxyphenyl)-5,7-dibenzyloxy-chroman-3-ol
(11c). Yield (150 mg, 33%, 71% b.r.s.m.) as a white solid; mp
86e88 ꢁC; Rf (25% EtOAc/Pet. Ether) 0.47; [
a]
22 ꢀ4.0 (c 0.98, CHCl3);
D
IR nmax 3417, 3032, 2907, 1617, 1592, 1496, 1441, 1377, 1289, 1218,
1150, 1118, 1049, 1029 cmꢀ1; 1H NMR 1.72 (1H, s, C3OH), 2.69 (1H,
d
dd, J¼16.4, 8.6, C4H2), 3.10 (1H, dd, J¼16.4, 5.6, C4H2), 4.09e4.10 (1H,
m, C3H), 4.75 (1H, d, J¼7.9, C2H), 5.00 (2H, s, OCH2Ph), 5.03 (2H, s,
OCH2Ph), 5.07 (2H, s, OCH2Ph), 6.24 (1H, d, J¼2.2, ArH), 6.28 (1H, d,
J¼2.2, ArH), 6.97 (1H, dd, J¼8.3, 2.3, ArH), 7.03 (1H, d, J¼7.7, ArH),
4.6.1. (S)-2-(R)-(3,5-Bis(benzyloxy)-phenyl)-(3,5-dibenzyloxypheno
7.07 (1H, m, ArH), 7.31e7.40 (16H, m, ArH); 13C NMR
d 27.6, 68.3,
xy)-methyl oxirane (10b). Yield (402 mg, 46%, (58% b.r.s.m.)) as
70.0, 70.1, 70.2, 77.3, 81.8, 93.9, 94.4, 102.2, 113.6, 115.2, 119.8, 127.3,
127.7, 127.7, 128.0, 128.1, 128.2, 128.7, 128.7, 128.7, 130.1, 136.8, 137.0,
137.0, 139.7, 155.3, 157.9, 158.9, 159.2; m/z (CI) 545 (100%, MþꢀH),
545 (18%, Mþ), 527 (16%), 319 (16%); HRMS m/z (CI) C36H32O5
calcd 545.2323, found 545.2328.
20
a white solid; mp 64e66 ꢁC; Rf (30% EtOAc/Pet. Ether) 0.46; [
a]
D
ꢀ16.1 (c 1.30, CHCl3); IR nmax 3063, 2864, 1594, 1444, 1379, 1354,
1290, 1158, 1080, 1056, 1028 cmꢀ1 1H NMR
; d 2.80e2.82 (2H, m,
C4H2), 3.27e3.29 (1H, dt, J¼3.6, 3.2, C3H), 4.95 (4H, s, 2ꢃOCH2Ph),
4.99 (1H, d, J¼4.0, C2H), 5.02 (4H, s, 2ꢃOCH2Ph), 6.16 (2H, d, J¼1.9,
ArH), 6.23 (1H, t, J¼1.9, ArH), 6.58 (1H, t, J¼1.9, ArH), 6.67 (2H, d,
J¼1.9, ArH), 7.31e7.43 (20H, m, ArH); 13C NMR
d 45.1, 54.5, 70.2,
4.8. General procedure for the synthesis of epicatechins (7)
70.3, 79.1, 95.5, 96.1, 101.9, 105.8, 127.2, 127.3, 127.8, 128.5, 128.9,
137.2, 143.0, 159.6, 160.3, 160.6; m/z (CI) 651 (100%, MþþH), 621
(15%), 414 (16%), 345 (21%), 307 (23%), 181 (17%); HRMS m/z (CI)
Step 1: A solution of 11 (0.150e0.460 mmol) in wet CH2Cl2
(3e15 mL) was cooled to 0 ꢁC and treated with DesseMartin
periodinane (1.2 equiv). The resultant solution was stirred at rt o/n.
The reaction mixture was washed with 1 M NaOH(aq), back
extracted with CH2Cl2, organics combined and washed with brine,
dried (MgSO4), filtered and concentrated in vacuo. Purification was
achieved by flash column chromatography (10% EtOAc/Pet. Ether).
Step 2: A solution of ketone (0.142e0.330 mmol) in anhydrous
THF (5 mL) was cooled to ꢀ78 ꢁC and treated with L-Selectride
(1.4 equiv, 1 M in THF). The resultant solution was stirred at ꢀ78 ꢁC
for 2 h. The reaction mixture was taken up in EtOAc (10 mL) washed
with H2O (5 mL), back extracted with EtOAc (10 mL), organics
combined and dried (Na2SO4), filtered and concentrated in vacuo.
Purification was achieved by flash column chromatography (15%
EtOAc/Pet. Ether).
C
43H39O6 calcd 651.2747, found 651.2739.
4.6.2. (S)-2-(R)-(3-Benzyloxyphenyl)-(3,5-dibenzyloxyphenoxy)-
methyl oxirane (10c). Yield (433 mg, 56%, (81% b.r.s.m.)) as a waxy
pale yellow solid; Rf (25% EtOAc/Pet. Ether) 0.60; [
a
]
22 ꢀ12.1 (c 0.73,
D
CHCl3); IR nmax 3032, 1598, 1454, 1379, 1262, 1156, 1056 cmꢀ1
;
1H
NMR d
2.76e2.81 (2H, m, C4H2), 3.27e3.30 (1H, m, C3H), 4.93 (4H, s,
2ꢃOCH2Ph), 5.04 (3H, s, C2H, OCH2Ph), 6.15 (2H, d, J¼2.1, ArH), 6.21
(1H, t, J¼2.1, ArH), 6.92 (1H, dd, J¼8.1, 2.2, ArH), 6.98 (1H, d, J¼7.7,
ArH), 7.02 (1H, m, ArH), 7.27e7.48 (16H, m, ArH); 13C NMR
d 45.1,
54.4, 70.1, 70.2, 79.0, 95.4, 96.1, 113.2, 114.8, 119.4, 127.7, 127.8, 128.1,
128.7, 129.9, 136.8, 136.9, 139.1, 159.2, 159.5, 160.6; m/z (EI) 544 (6%,
Mþ), 149 (30%), 123 (24%),111 (31%), 97 (52%), 83 (53%), 81 (61%), 69
(100%); HRMS C36H32O5 calcd 544.2244, found 544.2248.
4.8.1. (2R,3R)-2-Phenyl-5,7-dibenzyloxy-chroman-3-ol7 (7a)
4.7. General procedure for the synthesis of catechins (11)
4.8.1.1. Step 1: (2R)-2-(3,5-bis-benzyloxy-phenyl)-5,7-dibenzylo
xy-chroman-3-on. Yield (125 mg, 63%) as a white solid; mp
22
A solution of 10 (0.691e0.958 mmol) in HFIP (15 mL) was heated
to reflux in a sealed tube for 12e15 d. After this time the solvent
109e111 ꢁC; Rf (30% EtOAc/Pet. Ether) 0.75; [
a
]
þ16.5 (c 0.74,
D
CHCl3); IR nmax 2919, 2872, 1731, 1594, 1451, 1378, 1152, 1027 cmꢀ1
;

3490
J.C. Anderson et al. / Tetrahedron 70 (2014) 3485e3490
1H NMR
d
3.51 (1H, d, J¼22.4, C4H2), 3.67 (1H, d, J¼22.4, C4H2), 5.02
(1S,2S)-3-(2-hydroxyphenyl)-1-phenylpropane-1,2-diol to give the
(2H, s, OCH2Ph), 5.05 (2H, s, OCH2Ph), 5.36 (1H, s, C2H), 6.36 (1H, d,
J¼2.2, ArH), 6.41 (1H, d, J¼2.1, ArH), 7.33e7.45 (15H, m, ArH); 13C
opposite enantiomer.18 Yield (88 mg, 46%, (66% b.r.s.m)) as a white
20
solid; mp 70e72 ꢁC; [
a]
þ8.51 (c 1.32, CH2Cl2), (lit. mp and [
a]
D
D
NMR
d
33.9, 70.2, 70.4, 83.6, 95.2, 95.9, 102.0, 126.8, 127.3, 127.7,
not reported). 1H NMR agrees with literature data for racemic
material.22
128.2, 128.3, 128.7, 128.7, 128.8, 128.8, 135.2, 136.6, 136.7, 154.7,
157.2, 159.6, 205.2; m/z (CI) 437 (100%, MþþH), 414 (25%), 219
(20%), 181 (22%), 91 (85%, Bn); HRMS m/z (CI)
C29H25O4
4.10. Synthesis of hydroxyl deleted A and B ring catechin
gallates (5)
calcd 437.1753, found 437.1749.
4.8.1.2. Step 2: (2R,3R)-2-phenyl-5,7-dibenzyloxy-chroman-3-
4.10.1. (þ)-(2R,3S)-trans-Phenylflavan-3-yl-3,4,5-tris(benzyloxy)
benzoate. Synthesised according to the procedure of Anderson
et al. using (2S,3R)-trans-flavan-3-ol in place of (2R,3S)-trans-fla-
van-3-ol to give the opposite enantiomer.8 Yield (165 mg, 62%) as
ol.7 Yield (91 mg, 72%) as a waxy solid; Rf (25% Et2O/Pet. Ether)
0.21; [
a
]
22 ꢀ11.0 (c 0.45, CH2Cl3), (lit.7 [
a]
20 ꢀ10.5 (c 0.40, CH2Cl2)).
D
D
1H NMR data agrees with those published in the literature.7
a white solid; mp 121e123 ꢁC; [
a
]
D
20 þ60.5 (c 0.50, CH2Cl2), (lit.8 mp
4.8.2. (2R,3R)-2-(3,5-Bis-benzyloxy-phenyl)-5,7-dibenzyloxy-chro-
20
126e128 ꢁC, [
a
]
ꢀ65.0 (c 0.50, CH2Cl2) opposite enantiomer). 1H
D
man-3-ol7 (7b)
NMR agrees with literature data for opposite enantiomer.8
4.8.2.1. Step 1: (2R)-2-(3,5-bis-benzyloxy-phenyl)-5,7-
dibenzyloxy-chroman-3-one. Yield (94 mg, 57%, (73% b.r.s.m.)) as
4.10.2. (þ)-(2R,3S)-trans-Phenylflavan-3-yl-O-gallate (5). A solu-
tion of (þ)-(2R,3S)-trans-phenylflavan-3-yl-3,4,5-tris(benzyloxy)
benzoate (55 mg, 0.084 mmol) in EtOAc (10 mL) and MeOH (10 mL)
was treated with Pd(OH)2/C (42 mg) and back filled with H2 (three
times). Stirred at rt for 2.5 h, filtered through Celite, washed with
EtOAc (10 mL) and concentrated to give 5 (27 mg, 85%) as an off
22
a white solid; mp 112e114 ꢁC; Rf (10% EtOAc/Pet. Ether) 0.34; [
a]
D
þ24.6 (c 1.06, CHCl3); IR nmax 3032, 2919, 2872, 1732, 1619, 1595,
1498,1453,1441,1376,1348,1293,1217,1179,1152, 1099, 1081,1052,
1029 cmꢀ1; 1H NMR
d
3.49 (1H, d, J¼21.4, C4H2), 3.63 (1H, d, J¼21.4,
C4H2), 4.99 (4H, s, 2ꢃOCH2Ph), 5.02 (2H, s, OCH2Ph), 5.04 (2H, s,
OCH2Ph), 5.29 (1H, s, C2H), 6.35 (1H, d, J¼2.0, ArH), 6.40 (1H, d,
J¼1.9, ArH), 6.58 (1H, t, J¼1.9, ArH), 6.64 (2H, d, J¼2.0, ArH),
white solid; mp 210e212 ꢁC; [
a
]
20 þ95.1 (c 0.30, acetone), (lit.8 mp
D
not reported, [
a
]
20 ꢀ97.0 (c 0.3, acetone) opposite enantiomer). 1H
D
7.32e7.40 (20H, m, ArH); 13C NMR
d 33.8, 70.2, 70.2, 70.4, 83.3, 95.2,
NMR agrees with literature data for opposite enantiomer.8
95.8, 101.9, 102.3, 105.8, 127.4, 127.7, 127.8, 128.2, 128.3, 128.7, 128.8,
136.6, 136.7, 137.4, 154.5, 157.2, 159.6, 160.2, 204.8; m/z (CI) 649 (4%,
MþþH), 614 (28%), 414 (100%), 219 (74%), 91 (86%, Bn); HRMS m/z
(CI) C43H37O6 calcd 649.2590, found 649.2589.
Acknowledgements
This work was supported by Research Grant G0801757 from the
Medical Research Council. We thank Mr. J. Hill and Mr. V. Gray for
providing mass spectra.
4.8.2.2. Step 2: (2R,3R)-2-(3,5-bis-benzyloxy-phenyl)-5,7-
dibenzyloxy-chroman-3-ol.7 Yield (63 mg, 68%) as a white solid;
22
mp 121e123 ꢁC; Rf (20% EtOAc/Pet. Ether) 0.64; [
a
]
ꢀ17.8 (c 0.8,
D
CH2Cl2), (lit.7
[a
]
ꢀ17.2 (c 0.8, CH2Cl2, no mp reported)). 1H NMR
References and notes
D
data agrees with literature data.7
1. (a) Chu, D. C. In Chemistry and Applications of Green Tea; Yamamoto, T., Juneja, L. R.,
Chu, D. C., Kim, M., Eds.; CRC: Boca Raton, FL,1997; pp 1e11; (b)Chu, D. C.; Juneja, L.
R. In Chemistry and Applications of Green Tea; Yamamoto, T., Juneja, L. R., Chu, D. C.,
Kim, M., Eds.; CRC: Boca Raton, FL, 1997; pp 13e32.
2. Taylor, P. W.; Hamilton-Miller, J. M. T.; Stapleton, P. D. Food Sci. Technol. Bull.
2005, 2, 71.
3. Stapleton, P. D.; Shah, S.; Anderson, J. C.; Hara, Y.; Hamilton-Miller, J. M. T.;
Taylor, P. W. Int. J. Antimicrob. Agents 2004, 23, 462.
4. Taylor, P. W. Int. J. Antimicrob. Agents 2013, 42, 195.
5. Stapleton, P. D.; Shah, S.; Ehlert, K.; Hara, Y.; Taylor, P. W. Microbiology 2007, 153,
2093.
6. Bernal, P.; Lemaire, S.; Pinho, M. G.; Mobashery, S.; Hinds, J.; Taylor, P. W. J. Biol.
Chem. 2010, 285, 24055.
7. Anderson, J. C.; Headley, C.; Stapleton, P. D.; Taylor, P. W. Tetrahedron 2005, 61,
7703.
8. Anderson, J. C.; McCarthy, R. M.; Paulin, S.; Taylor, P. W. Bioorg. Med. Chem. Lett.
2011, 21, 6996.
4.8.3. (2R,3R)-2-(3-Benzyloxy-phenyl)-5,7-dibenzyloxy-chroman-3-
ol7 (7c)
4.8.3.1. Step 1: (2R)-2-(3-benzyloxyphenyl)-5,7-dibenzyloxy-
chroman-3-one. Yield (36 mg, 44%, 68% b.r.s.m.) as a white solid;
mp 100e102 ꢁC; Rf (10% EtOAc/Pet. Ether) 0.36; [
a]
22 þ17.4 (c 1.25,
D
CHCl3); IR nmax 2921, 1733, 1620, 1595, 1498, 1454, 1441, 1377, 1293,
1217, 1179, 1152, 1099, 1081, 1052, 1029 cmꢀ1; 1H NMR
d 3.49 (1H, d,
J¼21.4, C4H2), 3.65 (1H, d, J¼21.4, C4H2), 5.01 (2H, s, OCH2Ph), 5.02
(2H, s, OCH2Ph), 5.04 (2H, s, OCH2Ph), 5.33 (1H, s, C2H), 6.35 (1H, d,
J¼2.2, ArH), 6.40 (1H, d, J¼2.1, ArH), 6.94 (1H, dd, J¼8.2, 2.3, ArH),
6.94 (1H, d, J¼7.8, ArH), 7.01 (1H, m, ArH), 7.26e7.48 (16H, m, ArH);
13C NMR
d 33.8, 70.1, 70.2, 70.3, 83.3, 95.2, 95.9, 113.2, 115.1, 119.3,
9. Palacios, L.; Rosado, H.; Micol, V.; Rosato, A. E.; Bernal, P.; Arroyo, R.; Grounds, H.;
Anderson, J. C.; Stabler, R. A.; Taylor, P. W. PLoS ONE 2014, 9, e93830, http://dx.doi.
org/10.1371/journal.pone.0093830
10. Rosen, T. J. Drugs Dermatol. 2012, 11, e55.
11. Wan, S. B.; Landis-Piwowar, K. R.; Kuhn, D. J.; Chen, D.; Dou, Q. P.; Chan, T. H.
Bioorg. Med. Chem. 2005, 13, 2177.
127.3, 127.7, 128.2, 128.2, 128.3, 128.7, 128.8, 129.9, 136.6, 136.7,
136.8, 154.6, 157.2, 159.1, 159.6, 205.0; m/z (CI) 543 (26%, MþþH),
414 (100%), 219 (72%), 111 (16%); HRMS C36H31O5 calcd 543.2172,
found 543.2175.
12. Wan, S. B.; Chen, D.; Dou, Q. P.; Chan, T. H. Bioorg. Med. Chem. 2004, 12, 3521.
13. Khandelwal, A.; Hall, J. A.; Blagg, B. S. J. J. Org. Chem. 2013, 78, 7859.
14. Liu, Y.; Li, L.; Lin, G.; Xiang, Z.; Xiang, J.; Zhao, M.; Chen, J.; Yang, Z. J. Org. Chem.
2008, 73, 4625.
4.8.3.2. Step 2: (2R,3R)-2-(3-benzyloxy-phenyl)-5,7-dibenzyloxy-
chroman-3-ol.7 Yield (66 mg, 74%) as a white solid; mp 112e114 ꢁC;
Rf (20% EtOAc/Pet. Ether) 0.58; [
a
]
22 ꢀ28.1 (c 1.06, CH2Cl2), (lit.7 [
a]
D
D
15. Li, G.-X.; Qu, J. Chem. Commun. 2010, 2653.
ꢀ25.7 (c 3.4, CH2Cl2, no mp reported)). 1H NMR data agrees with
16. Cherian, S. K.; Kumar, P. Tetrahedron: Asymmetry 2007, 18, 982.
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literature data.7
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4.9. Synthesis of (2S,3R)-trans-flavan-3-ol (12)8
Synthesised according to the procedure of Krohn et al. using
(1R,2R)-3-(2-hydroxyphenyl)-1-phenylpropane-1,2-diol in place of
22. Clark-Lewis, J. W.; McGarry, E. J.; Ilsley, A. H. Aust. J. Chem. 1974, 27, 865.