Asymmetric total synthesis of B-ring modified (-)-epicatechin gallate analogues and their modulation of β-lactam resistance in Staphylococcus aureus

Article abstract of DOI:10.1016/j.tet.2005.05.086

Two enantiomerically pure B-ring modified analogues of (-)-epicatechin gallate were synthesised and their modulation of β-lactam resistance using three strains of methicillin resistant Staphylococcus aureus (BB 568, EMRSA-15 and EMRSA-16) evaluated. Sub-i

Full text of DOI:10.1016/j.tet.2005.05.086

Tetrahedron 61 (2005) 7703–7711
Asymmetric total synthesis of B-ring modified (K)-epicatechin
gallate analogues and their modulation of b-lactam resistance in
Staphylococcus aureus
a
b
b,
James C. Anderson,a, Catherine Headley, Paul D. Stapleton and Peter W. Taylor
*
*
aSchool of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
bMicrobiology Group, School of Pharmacy, University of London, 29-39 Brunswick Square, London, WC1, 1AX, UK
Received 20 April 2005; revised 10 May 2005; accepted 26 May 2005
Available online 20 June 2005
Abstract—Two enantiomerically pure B-ring modified analogues of (K)-epicatechin gallate were synthesised and their modulation of
b-lactam resistance using three strains of methicillin resistant Staphylococcus aureus (BB 568, EMRSA-15 and EMRSA-16) evaluated. Sub-
inhibitory concentrations (12.5 and 25 mg/L) of the two analogues fully sensitised each of the three MRSA strains to oxacillin, reducing the
MIC to less than 0.5 mg/L, identical to levels achieved with ECg. Lower concentrations demonstrated that the position and degree of
hydroxylation of the B-ring is important for activity.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The benefits to health of green tea (Camellia sinensis) are
well documented1 and are attributable, in the main, to
polyphenolic constituents that include (K)-epicatechin
(EC), (K)-epigallocatechin (EGC), (K)-epicatechin gallate
(ECg) and (K)-epigallocatechin gallate (EGCg), the four
most abundant catechins present in green tea (w10% of dry
weight, Fig. 1).2 In addition to their capacity to inhibit the
development of tumours,3 catechins possess weak anti-
bacterial properties4 and catechin gallates are able to reduce
the resistance of the opportunistic human pathogen
Staphylococcus aureus to a wide spectrum of b-lactam
antibiotics, such as methicillin, oxacillin and flucloxacillin.5
Strains of methicillin-resistant S. aureus (MRSA) have
emerged in recent years as a major cause of hospital-
acquired infection and the difficulty in treating these
infections is compounded by the fact that they are often
also resistant to a wide range of other antibiotics.6 The
recent introduction of two novel antibacterial agents,
quinupristin/dalfopristin and linezolid, has provided effica-
cious and safe therapeutic options for MRSA but there
remains an urgent need for new treatments of these
infections, in particular with agents that suppress or
Figure 1.
The resistance modifying capacity of catechin gallates
abrogate the emergence of drug resistance.
raises the possibility that such molecules could be used in
combination with b-lactam agents that are currently of
Keywords: Epicatechin gallate; Asymmetric synthesis; Oxacillin; MRSA.
limited use in the treatment of MRSA infections. Naturally
occurring catechin gallates, such as the potent modifier
ECg,7 are rapidly degraded in vivo to inactive products due
*
Corresponding authors. Tel.: C44 1159514194; fax: C44 1159513564
(J.C.A.); fax: C44 2077535867 (P.W.T.); e-mail addresses:
j.anderson@nottingham.ac.uk; peter.taylor@ulsop.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.086

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J. C. Anderson et al. / Tetrahedron 61 (2005) 7703–7711
Scheme 1.
to the presence of esterase-susceptible linkage groups.8
In addition, ECg and other catechin gallates are also known
to undergo C-2 epimerisation in hot water or dilute
hydroxide.9–11 We have determined that the presence of
the galloyl moiety is essential for b-lactam resistance
modification by ECg.7 In order to prevent the esterase-
mediated removal of the galloyl moiety from catechin
gallates, the initial step in the metabolism of these
molecules, we have designed, synthesised and evaluated
an amide ECg analogue 1 (Fig. 1) in which the
hydrolytically susceptible ester bond was replaced with an
inherently more stable amide linkage.12 This compound
reduced the oxacillin resistance of MRSA strains to levels
that are comparable to those achieved with ECg.12 In order
to further improve the pharmacological profile of ECg, we
have examined the effect of the degree of hydroxylation of
the B-ring (Fig. 1) on modification of b-lactam resistance in
MRSA: although the mechanism of modification is at
present only partially understood, it is likely to involve a
reduction in efficiency of membrane-associated cell wall
synthesis as a result of intercalation of ECg into the
staphylococcal cytoplasmic membrane.13 Recent work has
shown that catechins in the nanomole range are able to
modulate the structure and function of model membranes
due to their capacity to partition into the phospholipid
palisade.14 Galloyl catechins bound more avidly than either
EC or EGC to small unilamellar vesicles produced from
phosphatidyl choline, and ECg had a greater affinity for the
membrane bilayer than EGCg.14 The relative affinity of
catechins for membrane bilayers is reflected in their
capacity to modulate b-lactam resistance and their partition
coefficients in n-octanol-saline. ECg differs from EGCg
only by the absence of a hydroxyl function at one of the
other meta- position of the B-ring; we surmised that a
further reduction in the degree of hydroxylation of the
B-ring would enhance anti-MRSA effects by increasing the
affinity of these analogues for lipid bilayers.
bilayers. Specifically, modified ECg molecule 2 that did not
possess the para-hydroxyl group would also be less prone to
epimerization via a quinine methide-like intermediate due
to the removal of this anchimeric substituent. We have
synthesized this compound (2) in enantiomerically pure
form, as well as the 3,5-dihydroxy B-ring (3) to compare
their capacity to suppress the resistance of MRSA isolates to
the b-lactam antibiotic oxacillin.
2. Chemical synthesis
We desired a flexible total synthesis that would allow access
to analogues of ECg with respect to the number and location
of the hydroxyl groups and also to individual stereoisomers.
During the initial stages of our work there appeared two
total syntheses of EGCg,17,18 both forming the gallate ester
bond at a late stage in the synthesis. The synthesis15 by Li
and Chan was enantioselective based upon the Sharpless
asymmetric dihydroxylation19 of 5 followed by subsequent
cyclisation via an ortho ester to give the C-ring catechin 2,3-
trans stereochemistry (Scheme 2).15 Using a published
stereochemical inversion of the C-3 hydroxyl of catechin
derivatives,20 oxidation of the C-3 hydroxyl group and
reduction furnished the epicatechin 2,3-cis stereochemistry.
Our attempts at an analogous route using a 3-hydroxylated
or 3,5-dihydroxylated B-ring failed at the acid induced
coupling stage in an attempt to give the analogue of 5.
Presumably the para-oxygen functionality is important for
the success of this coupling. It was also noted in Li and
Chan’s work17 that under cyclisation conditions to give
directly the cis-2,3 C-ring, the integrity at the benzylic C-2
position was compromised by the oxygenation of the B-ring,
again most probably due to the para-hydroxyl group. We
decided to access 6, the 3-hydroxylated and 3,5-dihydroxyl-
ated B-ring analogue of 5 (Scheme 3), by using an aldol
The facility for epimerization may also be due to the extent
of hydroxylation of the aromatic B-ring. Rate measurements
of epimerization of tea catechins in tea infusion indicated
that the presence of hydroxyl groups on the B-ring of
catechin structures promoted epimerization.11 The most
reasonable mechanism for epimerization involves the
intermediate quinine methide 4, proposed by Mehta and
Whalley,15 which is also supported by the fact that
epimerization only affects the stereochemistry at C-2.
(Scheme 1).16 It has also been noted that under basic
reaction conditions epimerization of epicatechin type
molecules (2,3-cis) reaches an equilibrium in which the
catechin type skeleton (2,3-trans) predominates.10
We proposed that a further reduction in the degree of
hydroxylation of the B-ring would enhance anti-MRSA
effects by increasing the affinity of these analogues for lipid
Scheme 2.

J. C. Anderson et al. / Tetrahedron 61 (2005) 7703–7711
7705
Selective 2,4-benzylation21 of 2,4,6-trihydroxybenzalde-
hyde (7), by treatment with K2CO3 and BnBr, was followed
by standard MOM protection of the remaining 6-hydroxyl
group to give 8 (Scheme 4). We planned that the MOM
group would be orthogonal to the benzyl groups and could
be selectively removed under acidic conditions that may
facilitate cyclisation to form the C-ring. Condensation22 of 8
with 3-benzyloxyacetophenone (9) gave enone 10 unevent-
fully in good yield. Reduction of the enone system to the
alcohol and subsequent elimination to give the alkene was
surprisingly capricious. Protocols for one step reduction23 of
the enone to the alcohol gave mixtures of reduction products
and it was more efficient for material throughput to perform
a two step reduction of the enone alkene with catechol
borane24 and then the resultant ketone with NaBH4. Direct
dehydration using acidic reagents was prohibited due to the
lability of the MOM ether. The use of activating dehydration
reagents; Burgess’ reagent and DCC,25 were slow and
unable to give complete conversion. Elimination was
achieved by conversion of the benzyl alcohol 11 to the
corresponding bromide and then heating in the presence of
DBU. The overall reductive isomerisation of enone 10 to
alkene 12 was achieved in a four steps with an overall yield
of 42% (Scheme 4).
Scheme 3. Retrosynthesis.
dehydration/reduction protocol. We were confident that the
reported loss of stereochemical integrity at C-2 upon
cyclisation to form the C-ring would be impeded due to
the lack of B-ring para-oxygenation. Both of the published
syntheses17,18 had shown that global debenzylation was
high yielding and so we opted to use the benzyl protecting
group except for the orthogonal protecting group P. Our
retrosynthesis is detailed in Scheme 3.
Dihydroxylation of 12 using AD-mix-bw19gave 13 with an
initial 75% ee (65%).26 Recrystallisation gave a 48%
isolated yield of enantiomerically pure 13. Removal of the
MOM ether (3 M HCl) gave triol 14, but attempts at direct
acid catalysed cyclisation (3 M HCl) proved impossible.
Scheme 4. Reagents: (i) K2CO3, BnBr, DMF, rt, 16 h, 69%; (ii) NaH, MOMCl, THF 0 8C to rt, 88%; (iii) KOH aq. (50%), EtOH, THF, rt, 16 h, RZH 69%,
RZOBn 94%; (iv) Catechol borane, THF, K78 8C to rt, RZH 86% crude, RZOBn 86% crude; (v) NaBH4, MeOH, rt, RZH 99% crude, RZOBn 99% crude;
(vi) PPh3, Br2, Et3N, CH2Cl2, 0 8C to rt, RZH 85%, RZOBn 99%; (vii) DBU, PhMe, 110 8C, 16 h, RZH 57%, RZOBn 53%; (viii) AD-mix-bw, t-BuOH,
H2O, MeSO2NH2, 0 8C, 5 days, RZH 65% @75% ee, 48% @O99% ee, RZOBn 82% @75% ee, 46% @O99% ee; (ix) HCl, MeOH, Et2O, reflux, 5 h, RZH
100% crude, RZOBn 100% crude; (x) HC (OMe)3, PPTS cat., CH2Cl2, rt; w/up then AcBr, CH2Cl2, rt, RZH 88% crude, RZOBn 91% crude; (xi) K2CO3,
acetone, rt, 5 h; w/up then K2CO3, MeOH rt, 16 h, RZH 61%, RZOBn 45%; (xii) DCC, tri-OBn gallic acid, DMAP, CH2Cl2, rt, 16 h, RZH 64%, RZOBn
67%; (xiii) H2, 10% Pd(OH)2/C, EtOAc, rt, 12 h, RZH 94%, RZOH 37%.

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J. C. Anderson et al. / Tetrahedron 61 (2005) 7703–7711
Presumably similar cyclisations in the literature17,27 have
relied upon the ring B para-hydroxyl group activating the
benzylic hydroxyl group toward cyclisation. Although, this
meant we had to adopt an alternative and longer synthetic
route to form ring C, this was again circumstantial evidence
to support our hypothesis that ECg analogues 2 and 3 would
be more stable toward possible epimerization (Scheme 1).
Cyclisation to the 2,3-cis substituted C-ring followed Li and
Chan’s protocol17 whereby the corresponding cyclic
orthoformate of 14 was ring opened with acetyl bromide28
to give benzylic bromide 15 as a single diastereoisomer by
1H NMR. Immediate treatment with K2CO3 caused
cyclisation and deformylation to give the cis-2,3 substituted
C-ring compound 16. Completion of the synthesis was
achieved by DCC induced coupling with 3,4,5-tribenzyloxy
benzoic acid (55%) and subsequent global debenzylation by
hydrogenolysis with Pd(OH)2 catalysis (48%) to give the
enantiomerically pure 3-hydroxy B-ring analogue (K)-2 of
ECg. The stereochemical integrity of the 2,3-cis substitution
1
was proven from the multiplicity of the H NMR signal of
C–1H (2, d 5.27, s) that compares favourably with the
analogous signal in (K)-EGCg (d 5.36, d, JZ1.2 Hz)17 and
5,7,30,40-tetra-O-benzyl-(K)-epicatechin (d 4.91, s).29 Con-
trasting signals in similar molecules possessing the 2,3-
trans relationship also support this; 5,7,30,40,50-penta-O-
benzyl-gallocatechin (d 4.65, d, JZ8.1 Hz)17 and 5,7,30,40-
tetra-O-benzyl-(C)-catechin (d 4.63, d, JZ8.5 Hz).21
Absolute stereochemistry was assumed from the Sharpless
mnemonic for AD-mix-bw19 and the fact that the final
compound exhibits the same sense of optical rotation as
naturally occurring (K)-ECg.
Repetition of this synthesis starting with 3,5-dibenzyloxy-
acetophenone 17 led to the enantiomerically pure 3,5-
dihydroxy B-ring analogue (K)-3 of ECg uneventfully in
similar yield. The 2,3-cis stereochemical relationship was
again verified from the multiplicity of the 1H NMR signal of
C–1H (3, d 4.99, s) that compares favourably with the above
data.
3. Microbiological evaluation
With the B-ring modified analogues 2 and 3 in hand, their
efficacy as modulators for b-lactam resistance in S. aureus
was evaluated by determining their capacity to reduce the
minimum inhibitory concentration (MIC) of oxacillin
against MRSA strains BB 568, EMRSA-15 and EMRSA-
16 (Table 1). The monohydroxylated B-ring analogue 2
possessed little or no intrinsic antibacterial activity against
the three MRSA strains and in this respect was comparable
to ECg (Table 1). Interestingly, the 3,5-dihydroxy B-ring
analogue 3 showed weak to moderate anti-staphylococcal
activity that was significantly higher than that shown by
ECg and analogue 2, suggesting that the position of
hydroxyl groups on the B-ring may influence the intrinsic
antibacterial activity of ECg analogues. Sub-inhibitory
concentrations (6.25, 12.5 and 25 mg/L) of both compounds
were effective in reducing the MIC of all three strains
examined. At a concentration of 25 mg/L, ECg and the two
analogues (2 and 3) fully sensitised each of the three MRSA
strains to oxacillin, reducing the MICs to less than 0.5 mg/L,
a figure well below the clinically-relevant breakpoint for

J. C. Anderson et al. / Tetrahedron 61 (2005) 7703–7711
7707
b-lactam antibiotics. At 6.25 mg/L of catechin gallate, the
lowest concentration used in this study, both the mono-
hydroxylated B-ring analogue and the 3,5-dihydroxy B-ring
analogue were less potent than the natural compound
(Table 1).
allowed to warm to rt. Brine (5.0 mL) was then added and
the reaction partitioned between Et2O (100 mL) and H2O
(100 mL), the organic layer was dried (MgSO4), filtered and
concentrated in vacuo to yield aldehyde 8 as a brown oil
1
(11 g, 88%); IR nmax 3063, 3031, 2875 cmK1; H NMR
(400 MHz, CDCl3) d 3.53 (s, 3H, OCH2OCH3), 5.09 (s, 2H,
OCH2Ph), 5.15 (s, 2H, OCH2Ph), 5.27 (s, 2H, OCH2OCH3),
6.30 (d, 1H, JZ2.1 Hz, ArH), 6.48 (d, 1H, JZ2.1 Hz, ArH),
7.35–7.48 (m, 10H, ArH), 10.49 (s, 1H, CHO); 13C NMR
(100 MHz, CDCl3) d 56.9, 70.8, 71.0, 94.5, 95.1, 95.4,
110.5, 127.4, 127.5, 128.1, 128.4, 128.8, 128.9, 129.0,
129.1, 129.2, 136.2, 136.5, 161.8, 163.3, 165.3, 188.0; MS
(ES, m/z) 378 (MC, 10%), 91 (BnC, 100%); HRMS (ES,
m/z) found 378.1456, C23H22O5 requires 378.1467.
4. Conclusion
A flexible asymmetric synthesis of two B-ring modified
ECg analogues has been developed that originates from an
aldol dehydration/reduction protocol to form a key A,B-ring
styrene precursor. We believe this strategy could be used to
synthesise other B and A ring modified ECg analogues for
biological evaluation. The control of absolute stereo-
chemistry by the Sharpless asymmetric dihydroxylation,
and subsequent stereoselective cyclisation to form the
C-ring is an analogous strategy to that reported by Li and
Chan17 in their synthesis of EGCg. As demonstrated by
them this route can provide either enantiomer of the desired
analogues. Biological evaluation showed that at concen-
trations of 12.5 and 25 mg/L, ECg and the two B-ring
analogues (2 and 3) fully sensitised each of the three MRSA
strains to oxacillin, reducing the MICs to less than 0.5 mg/L.
Results at lower concentration of catechin suggests that not
only the degree, but the relative position of hydroxylation of
the B-ring is important for optimal interaction with
biological membranes in MRSA. We are currently
investigating the intrinsic stability of ECg, 2 and 3, and
their capacity to intercalate into staphylococcal membranes,
the results of which will be reported in due course.
5.1.2. 30,4,6-Tribenzyloxy-2-O-methoxymethyl-E-retro-
chalcone (10). To a solution of acetophenone 9 (6.9 g,
32 mmol) in EtOH (100 mL) was added aq. KOH solution
(10 mL of 50% m/v) and the mixture stirred at rt for 20 min.
A solution of benzaldehyde 8 (11 g, 29 mmol) in THF
(50 mL) was then added, and the mixture stirred overnight.
The precipitate, which had formed was then filtered and
washed with Et2O to yield chalcone 10 (12 g, 69%), as a fine
yellow powder; mp 108–110 8C; IR nmax 3064, 3032, 2933,
1
1601, 1566, 1159 cmK1; H NMR (500 MHz, CDCl3) d
3.60 (s, 3H, OCH2OCH3), 5.16 (s, 2H, OCH2Ph), 5.17 (s,
2H, OCH2Ph), 5.19 (s, 2H, OCH2Ph), 5.35 (s, 2H,
OCH2OCH3), 6.46 (d, 1H, JZ2.2 Hz, ArH), 6.62 (d, 1H,
JZ2.2 Hz, ArH), 7.19–7.21 (m, 1H, ArH), 7.28–7.30 (m,
2H, ArH), 7.42–7.57 (m, 15H, ArH), 7.66 (d, 1H, ArH), 7.99
(d, 1H, JZ16 Hz, ArCH]CHCO), 8.41 (d, 1H, JZ16 Hz,
ArCH]CHCO); 13C NMR (100 MHz, CDCl3) d 56.9, 70.5,
70.7, 71.4, 94.5, 94.9, 95.3, 108.2, 114.0, 119.9, 121.7,
122.5, 128.1, 128.5, 128.6, 128.7, 128.8, 129.0, 129.1,
129.3, 129.8, 136.2, 136.5, 136.7, 137.2, 140.9, 159.4,
159.9, 161.3, 162.5, 191.5; MS (ES, m/z) 586 (MC, 7%), 91
(BnC, 100%); HRMS (ES, m/z) found 586.2340, C38H34O6
requires 586.2355.
5. Experimental
5.1. General
Our general experimental details have been reported.30
5.1.1. 4,6-Dibenzyloxy-2-O-methoxymethylbenzalde-
hyde (8). To a stirred solution of aldehyde 7 (5.0 g,
35 mmol) in DMF (50 mL) was added K2CO3 (9.7 g,
70 mmol) followed by BnBr (8.4 mL, 70 mmol) and the
mixture was stirred at rt overnight. The mixture was then
diluted with Et2O (100 mL) and washed with H2O
(100 mL), dried (MgSO4), filtered and concentrated in
vacuo to yield a yellow solid, which was recrystallised from
Et2O to furnish the 4,6-dibenzyl protected aldehyde as a
pale yellow semi-solid (8.1 g, 69%); IR nmax 2922,
5.1.3. 1-(30-Benzyloxyphenyl)-3-(200-O-methoxymethyl-
400,600-dibenzyloxyphenyl)propan-1-ol (11). Catechol
borane (1 M solution in THF, 10 mL, 10 mmol) was
added dropwise to a stirred solution of chalcone 10 (5.0 g,
8.5 mmol) in THF (80 mL) at K78 8C. The mixture was
allowed to warm to rt and stirred for a further 1 h before
acetone (10 mL) and sat. aq. NH4Cl (10 mL) were added.
The mixture was extracted into Et2O (2!50 mL), the
combined organic layers washed with 2 M NaOH (50 mL)
and brine (50 mL), then dried (MgSO4) filtered, and
concentrated in vacuo to afford the corresponding ketone
(4.3 g, 86%). The crude ketone was immediately dissolved
in methanol (30 mL) and NaBH4 (310 mg, 8.0 mmol) was
added at rt. The mixture was stirred for 1 h before all
volatile material was removed in vacuo, H2O (50 mL) added
and the mixture extracted into Et2O (3!30 mL). The
combined organic layers were dried (MgSO4) filtered, and
concentrated in vacuo to give alcohol 11 (5.0 g, 99%) as a
pale yellow solid; mp 120–122 8C; IR nmax 3500, 2931,
1
1635 cmK1; H NMR (400 MHz, CDCl3) d 5.04 (s, 2H,
OCH2Ph), 5.06 (s, 2H, OCH2Ph), 6.14 (d, 1H, JZ2.1 Hz,
ArH), 6.17 (d, 1H, JZ2.1 Hz, ArH), 7.37–7.50 (m, 10H,
ArH), 10.24 (s, 1H, CHO); 13C NMR (100 MHz, CDCl3) d
70.9, 80.1, 92.8, 94.6, 106.8, 127.5, 127.9, 128.0, 128.1,
128.8, 128.9, 129.0, 129.2, 129.3, 136.1, 163.1, 166.6,
166.8, 192.4; MS (ES, m/z) 334 (MC, 20%), 91 (BnC,
100%); HRMS (ES, m/z) found 334.1215, C21H18O4
requires 334.1205.
1
1604 cmK1; H NMR (400 MHz, CDCl3) d 1.95–2.08 (m,
To a stirred solution of NaH (2.6 g, 66 mmol) in THF
(100 mL) at 0 8C was added the 4,6-dibenzyl protected
aldehyde (11 g, 33 mmol), in THF (30 mL). After 5 min
MOMCl (5.0 mL, 33 mmol) was added and the mixture
2H, ArCH2CH2CHOH), 2.90–2.92 (m, 2H, ArCH2CH2-
CHBr), 3.52 (s, 3H, OCH2OCH3), 4.61 (dd, 1H, JZ8.8,
4.3 Hz, ArCH2CH2CHOH), 5.07 (s, 2H, OCH2Ph), 5.08 (s,
2H, OCH2Ph), 5.09 (s, 2H, OCH2Ph), 5.23 (s, 2H,

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J. C. Anderson et al. / Tetrahedron 61 (2005) 7703–7711
OCH2OCH3), 6.41 (d, 1H, JZ2.2 Hz, ArH), 6.55 (d, 1H,
JZ2.2 Hz, ArH), 6.90 (ddd, 1H, JZ8.2, 2.6, 0.8 Hz, ArH),
6.93 (d, 1H, JZ8.2 Hz, ArH), 7.06 (apt, 1H, JZ2.6 Hz,
ArH), 7.26 (t, 1H, JZ8.2 Hz, ArH), 7.35–7.50 (m, 15H,
ArH); 13C NMR (100 MHz, CDCl3) d 19.7, 39.3, 56.7, 70.3,
70.7, 70.9, 73.4, 94.8, 95.0, 95.3, 112.1, 112.8, 113.9, 118.9,
127.7, 128.0, 128.1, 128.3, 128.4, 128.5, 129.0, 129.1,
129.7, 137.3, 137.6, 146.9, 156.9, 158.3, 158.9, 159.3; MS
(ES, m/z) 613 (MCCNa, 80%), 523 (MCK67, 100%);
HRMS (ES, m/z) found 613.2578, C38H38O6Na requires
613.2566.
(270 mg, 2.9 mmol) followed by styrene 12 (1.5 g,
2.6 mmol) in THF (30 mL) and the mixture stirred at 0 8C
for 5 days. Solid sodium sulfite (5 g) was added and the
product was extracted into EtOAc (3!30 mL), the
combined organics dried (MgSO4), filtered and concen-
trated in vacuo to yield the crude product, which was
purified by flash chromatography (Silica, 80% Et2O/
hexanes) to yield the desired product 13 as a white solid
(1.0 g, 65%, 75% ee by HPLC26) that was then
recrystallised (80% Et2O/EtOAc) to give enantiomerically
pure 13 (740 mg, 48%); mp 114–116 8C; IR nmax 3405,
2964, 2923, 2851, 1605 cmK1; 1H NMR (500 MHz, CDCl3)
d 2.60 (br s, 1H, OH), 2.97 (dd, 1H, JZ14, 5.8 Hz,
ArCH2CH(OH)CH(OH)), 3.03 (dd, 1H, JZ14, 8.1 Hz,
ArCH2CH(OH)CH(OH)), 3.36 (br s, 1H, OH), 3.53 (s,
3H, OCH2OCH3), 4.02–4.05 (m, 1H, ArCH2-
CH(OH)CH(OH)), 4.60 (d, 1H, JZ4.8 Hz, ArCH2-
CH(OH)CH(OH)), 5.11–5.13 (m, 6H, 3!OCH2Ph), 5.22
(dd, 2H, JZ11, 6.7 Hz, OCH2OCH3), 6.47 (d, 1H, JZ
2.2 Hz, ArH), 6.58 (d, 1H, JZ2.2 Hz, ArH), 6.98 (dd, 1H,
JZ8.2, 2.0 Hz, ArH), 7.03 (d, 1H, JZ8.2 Hz, ArH), 7.15
(apt, 1H, JZ2.0 Hz, ArH), 7.32 (t, 1H, JZ8.2 Hz, ArH),
7.40–7.53 (m, 15H, ArH); 13C NMR (100 MHz, CDCl3) d
27.9, 56.7, 70.4, 70.7, 71.0, 76.1, 76.7, 94.9, 95.1, 95.2,
108.7, 113.8, 114.3, 119.8, 127.7, 128.0, 128.1, 128.4,
128.5, 128.6, 129.0, 129.2, 129.7, 137.2, 137.5, 143.4,
157.2, 158.5, 159.3, 159.4; MS (ES, m/z) 629 (MCCNa,
100%); HRMS (ES, m/z) found 629.2629, C38H38O7Na
requires 629.2515; [a]D C9.9 (c 0.1, CH2Cl2, at 21 8C).
5.1.4. (E)-1-(30-Benzyloxyphenyl)-3-(200-O-methoxy-
methyl-400,600-dibenzyloxyphenyl)propene (12). To a
stirred solution of PPh3 (1.4 g, 5.4 mmol) in CH2Cl2
(20 mL) at 0 8C was added Br2 (0.30 mL, 5.4 mmol)
dropwise and after 5 min, Et3N (0.90 mL, 9.7 mmol) was
added and the mixture stirred for a further 5 min. A solution
of the alcohol 11 (2.1 g, 3.6 mmol) in CH2Cl2 (10 mL) was
then added dropwise and the mixture allowed to warm to rt.
After 2 h the mixture was concentrated in vacuo and purified
by flash chromatography (neutral alumina, 50% Et2O/
hexanes) to afford the bromide as a yellow oil (2.0 g, 85%);
IR nmax 2931, 1594, 1150 cmK1 1H NMR (400 MHz,
;
CDCl3) d 2.50–2.58 (m, 2H, ArCH2CH2CHBr), 2.74–2.76
(m, 1H, ArCH2CH2CHBr), 2.89–2.93 (m, 1H, ArCH2CH2-
CHBr), 3.52 (s, 3H, OCH2OCH3), 5.05–5.09 (m, 7H, 3!
OCH2Ph and ArCH2CH2CHBr), 5.21 (dd, 2H, JZ8.0,
6.7 Hz, OCH2OCH3), 6.37 (d, 1H, JZ2.3 Hz, ArH), 6.53 (d,
1H, JZ2.2 Hz, ArH), 6.89 (ddd, 1H, JZ8.2, 2.5, 0.8 Hz,
ArH), 7.00 (d, 1H, JZ7.8 Hz, ArH), 7.07 (t, 1H, JZ2.2 Hz,
ArH), 7.20–7.23 (m, 1H, ArH), 7.33–7.47 (m, 15H, 15!
ArH); 13C NMR (100 MHz, CDCl3) d 22.5, 39.8, 56.0, 56.5,
56.6, 70.5, 70.6, 70.7, 94.6, 94.9, 95.1, 111.8, 114.7, 120.5,
127.6, 127.7, 127.9, 128.0, 128.1, 128.3, 128.5, 129.0,
130.0, 137.3, 137.4, 137.6, 144.3, 157.0, 158.3, 159.0,
159.3; MS (FAB, m/z) 654 (MC, 100%); HRMS (FAB, m/z)
found 654.1809, C38H37O5Br requires 654.1804.
5.1.6. (1R,2R)-1-(30Benzyloxyphenyl)-3-(200hydroxy-
400,600-dibenzyloxyphenyl)propane-1,2-diol (14). To a
solution of diol 13 (740 mg, 1.2 mmol) in MeOH (10 mL)
and Et2O (10 mL) was added conc. HCl (5 drops) and the
mixture heated at reflux for 5 h. The mixture was then
concentrated in vacuo, diluted with EtOAc and washed with
H2O, the organic layer was dried (MgSO4), filtered and
concentrated in vacuo to yield the product 14 as a white
solid (730 mg, 100%); mp 120–122 8C; IR nmax 3436, 2923,
1
A solution of bromide (3.3 g, 5.0 mmol) in DBU and
toluene (25 mL, 4:1), was heated to reflux overnight. The
mixture was then allowed to cool and extracted into Et2O
(3!25 mL). The combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. Purification
by flash chromatography (Silica, 20% Et2O/hexanes) gave
styrene 12 (1.68 g, 57%) as a colourless oil; IR nmax 3031,
1739 cmK1; H NMR (400 MHz, CDCl3) d 2.81 (dd, 1H,
JZ15, 8.5 Hz, ArCH2CH(OH)CH(OH)), 2.97 (dd, 1H, JZ
15, 3.8 Hz, ArCH2CH(OH)CH(OH)), 4.00–4.04 (m, 1H,
ArCH2CH(OH)CH(OH)), 4.50 (d, 1H, JZ6.3 Hz, ArCH2-
CH(OH)CH(OH)), 4.90 (dd, 2H, JZ14, 12 Hz, OCH2Ph),
4.99–5.01 (m, 4H, 2!OCH2Ph), 6.26 (d, 1H, JZ2.3 Hz,
ArH), 6.31 (d, 1H, JZ2.3 Hz, ArH), 6.88–6.92 (m, 1H,
ArH), 6.99–7.00 (m, 1H, ArH), 7.17–7.20 (m, 2H, ArH),
7.33–7.47 (m, 15H, ArH); 13C NMR (100 MHz, CDCl3) d
27.1, 70.4, 70.5, 77.2, 77.3, 93.9, 96.3, 106.7, 119.8, 127.2,
127.3, 128.0, 128.1, 128.4, 128.9, 129.0, 130.1, 137.3,
137.4, 142.6, 157.7, 158.3, 159.3, 159.5; MS (ES, m/z) 585
(MCCNa, 40%), 563 (MHC, 100%); HRMS (ES, m/z)
found 563.2358, C36H35O6 requires 563.2434; [a]D K15.6
(c 3.7, CH2Cl2, at 24 8C).
1
2929, 1592 cmK1; H NMR (400 MHz, CDCl3) d 3.53 (s,
3H, OCH2OCH3), 3.63–3.64 (m, 2H, ArCH2CH]CH),
5.08–5.10 (m, 6H, 3!OCH2Ph), 5.24 (s, 2H, OCH2OCH3),
6.38–6.41 (m, 3H, ArCH2CH]CH and ArH), 6.55 (d, 1H,
JZ2.3 Hz, ArH), 6.95–7.00 (m, 1H, ArH), 7.24 (t, 1H, JZ
4.3 Hz, ArH), 7.33–7.50 (m, 16H, ArH); 13C NMR
(100 MHz, CDCl3) d 27.0, 56.5, 70.3, 70.4, 70.7, 94.7,
95.0, 95.1, 110.9, 112.7, 113.6, 127.7, 127.9, 128.0, 128.1,
128.2, 128.3, 128.5, 129.0, 129.7, 129.8, 130.2, 137.4,
137.6, 140.1, 156.8, 158.3, 159.1, 159.4; MS (ES, m/z) 573
(MHC, 100%); HRMS (ES, m/z) found 573.2556, C38H37O5
requires 573.2641.
5.1.7. (1S,2R)-1-Bromo-2-formate (15). To a solution of
triol 14 (730 mg, 1.3 mmol) in CH2Cl2 (15 mL) was added
trimethyl orthoformate (1.4 mL, 13 mmol) followed by
PPTS (5.0 mg) and the mixture stirred at rt for 10 min. The
mixture was then washed with satd. aq. NaHCO3 (10 mL),
dried (MgSO4), filtered and concentrated to in vacuo. The
crude cyclic orthoformate was then redissolved in CH2Cl2
(15 mL), treated with AcBr (0.14 mL, 1.9 mmol) and stirred
5.1.5. (1R,2R)-1-(30Benzyloxyphenyl)-3-(200-O-methoxy-
methyl-400,600-dibenzyloxyphenyl)propane-1,2-diol (13).
To a solution of AD-mix-bw (5.0 g) in t-BuOH (30 mL)
and H2O (30 mL) at 0 8C was added methane sulfonamide

J. C. Anderson et al. / Tetrahedron 61 (2005) 7703–7711
7709
for 10 min at rt. The mixture was then washed with satd. aq.
NaHCO3 (10 mL) and concentrated in vacuo to afford
bromo formate 15 as a brown foam (750 mg, 88%). This
compound was used immediately without purification or
characterisation.
was stirred under an atmosphere of H2 (balloon) for 12 h.
The mixture was then filtered through celite, concentrated in
vacuo and purified by flash chromatography (Silica, Et2O)
to yield the product (K)-2 (72 mg, 94%) as an off-white
solid; mp O200 8C; IR nmax 3329 (br), 2950, 1607 cmK1
;
1H NMR (500 MHz, (CD3)2CO) d 2.99 (dd, 1H, JZ18,
2.0 Hz, ArCH2CHCHO), 3.12 (dd, 1H, JZ18, 4.6 Hz,
ArCH2CHCHO), 3.15 (br s, 1H, OH), 5.27 (s, 1H,
ArCH2CHCHO), 5.64–5.66 (m, 1H, ArCH2CHCHO), 6.11
(d, 1H, JZ2.3 Hz, ArH), 6.12 (d, 1H, JZ2.3 Hz, ArH), 6.77
(ddd, 1H, JZ8.0, 2.5, 0.9 Hz, ArH), 7.07–7.20 (m, 5H,
ArH), 8.36 (br s, 5H, OH); 13C NMR (125 MHz, (CD3)2O) d
13.5, 68.4, 77.2, 94.9, 95.7, 98.0, 109.0, 113.9, 114.6, 117.7,
120.8, 129.0, 138.0, 140.4, 145.1, 156.0, 156.6, 157.0,
157.2, 165.1; MS (ES, m/z) 449 (MCCNa, 65%), 257
(MCK151, 100%); HRMS (ES, m/z) found 449.0818,
C22H18O9Na requires 449.0846; [a]D K130.8 (c 0.3,
(CH3)2CO, at 23 8C).
5.1.8. (2R,3R)-30-Benzyloxy-400,600-dibenzyloxyflavan
(16). Crude bromo formate 15 (750 mg, 1.1 mmol) was
treated with K2CO3 (170 mg, 1.1 mmol) in acetone (10 mL)
and stirred at rt over 5 h. The mixture was diluted with H2O
(5.0 mL), extracted into EtOAc (3!10 mL), the combined
organics dried with (MgSO4), filtered and concentrated to
dryness. The resulting compound was then redissolved in
MeOH (10 mL), treated with K2CO3 (170 mg, 1.1 mmol)
and the mixture stirred at rt overnight. The mixture was then
concentrated in vacuo, extracted into EtOAc (3!15 mL),
the combined organics dried (MgSO4), filtered, concen-
trated to dryness and the product purified by flash
chromatography (Silica, 50% Et2O/hexanes) to give 16 as
a colourless oil (310 mg, 61%); IR nmax 3439, 3031, 2924,
1619, 1592 cmK1; 1H NMR (500 MHz, CDCl3) d 3.06 (dd,
1H, JZ17, 4.4 Hz, ArCH2CHCHO), 3.11 (dd, 1H, JZ9.8,
2.1 Hz, ArCH2CHCHO), 4.39 (br s, 1H, ArCH2CHCHO),
5.10–5.15 (m, 5H, ArCH2CHCHO, and 2!OCH2Ph), 5.19
(s, 2H, OCH2Ph), 6.38 (d, 1H, JZ2.3 Hz, ArH), 6.40 (d, 1H,
JZ2.3 Hz, ArH), 7.06 (dd, 1H, JZ8.2, 2.5 Hz, ArH), 7.18
(dd, 1H, JZ8.2, 0.6 Hz, ArH), 7.29 (s, 1H, ArH), 7.41–7.56
(m, 16H, ArH); 13C NMR (100 MHz, CDCl3) d 28.3, 66.5,
69.9, 70.1, 70.2, 78.6, 94.2, 94.7, 101.0, 113.0, 114.4, 118.8,
127.2, 127.3, 127.7, 128.0, 128.1, 128.6, 128.7, 129.8,
136.9, 137.1, 139.9, 155.2, 158.4, 158.8, 159.1; MS (ES,
m/z) 567 (MCCNa, 20%), 545 (MHC, 100%); HRMS (ES,
m/z) found 567.2111, C36H32O5Na requires 567.2147; [a]D
K25.7 (c 3.4, CH2Cl2, at 23 8C).
5.1.10. 30,4,50,6-Tetrabenzyloxy-2-O-methoxymethyl-E-
retro-chlacone (18). Acetophenone 17 (3.3 g, 13 mmol)
and benzaldehyde 8 (4.2 g, 11 mmol) were condensed in an
identical manner to the preparation of 10 to give 18 (6.5 g,
94%), as a fine yellow powder; mp 108–110 8C; IR nmax
2933, 2872, 1650, 1585, 1568, 1454 cmK1 1H NMR
;
(400 MHz, CDCl3) d 3.59 (s, 3H, OCH2OCH3), 5.09 (s,
4H, 2!OCH2Ph), 5.16 (s, 2H OCH2Ph), 5.20 (s, 2H,
OCH2Ph), 5.34 (s, 2H, OCH2OCH3), 6.28 (d, 1H, JZ
2.2 Hz, ArH), 6.60 (d, 1H, JZ2.2 Hz, ArH), 6.84, (t, 1H,
JZ2.3 Hz, ArH), 7.23 (t, 1H JZ2.3 Hz, ArH), 7.35–7.53
(m, 21H, ArH), 7.94 (d, 1H JZ16 Hz, ArCH2CH]CHCO),
8.41 (d, 1H JZ16 Hz, ArCH2CH]CHCO); 13C NMR
(125 MHz, CDCl3) d 56.1, 70.1, 70.3, 70.9, 94.4, 94.5, 94.7,
95.0, 106.9, 107.4, 107.7, 122.3, 126.7, 127.3, 127.5, 127.6,
127.7, 127.8, 128.1, 128.3, 128.7, 128.9, 136.1, 139.7,
159.5, 159.6, 160.7, 162.1, 191.4; MS (ES, m/z) 693 (MHC,
20%); HRMS (ES, m/z) found 693.2817, C45H41O7 requires
693.2852.
5.1.9. (K)-3-Hydroxy B-ring modified (K)-ECg (2). To a
solution of tri-O-benzyl gallic acid (54 mg, 0.12 mmol) in
CH2Cl2 (5.0 mL) was added DCC (25 mg, 0.12 mmol) and
the mixture was stirred at rt for 5 min. Alcohol 16 (42 mg,
0.081 mmol) was then added in CH2Cl2 (5.0 mL) followed
by DMAP (5.0 mg) and the mixture was stirred at rt
overnight. The mixture was then filtered, concentrated in
vacuo and purified by flash chromatography (Silica, 10%
Et2O/hexanes) to yield the globally protected gallate ester as
a colourless oil (49 mg, 64%); IR nmax 2923, 2851, 1707,
1590 cmK1; 1H NMR (400 MHz, CDCl3) d 3.19 (d, 2H, JZ
3.4 Hz, ArCH2CHCHO), 4.82 (d, 1H, JZ11 Hz, OCH2Ph),
4.91 (d, 1H, JZ11 Hz, OCH2Ph), 5.08–5.10 (m, 11H,
ArCH2CHCHO, and 5!OCH2Ph), 5.70–5.71 (m, 1H,
ArCH2CHCHO), 6.39 (d, 1H, JZ2.3 Hz, ArH), 6.47 (d,
1H, JZ2.3 Hz, ArH), 6.93 (dd, 1H, JZ7.9, 2.2 Hz, ArH),
7.06 (d, 1H, JZ7.9 Hz, ArH), 7.20–7.21 (m, 1H, ArH),
7.33–7.52 (m, 33H, ArH); 13C NMR (100 MHz, CDCl3) d
26.5, 69.2, 70.4, 70.6, 71.4, 71.9, 75.0, 78.1, 94.4, 95.2, 101.4,
109.5, 110.6, 113.7, 114.9, 119.6, 127.7, 128.0, 128.1, 128.2,
128.4, 128.5, 128.6, 128.7, 129.0, 129.1, 129.9, 137.0, 137.3,
137.9, 139.9, 142.9, 152.8, 156.0, 158.5, 159.3, 165.6; MS
(ES, m/z) 967 (MC, 5%), 647 (MHCK318, 100%); HRMS
(ES, m/z) found 967.3859, C64H55O9 requires 967.3846; [a]D
K31.4 (c 3.3, CH2Cl2, at 23 8C).
5.1.11. 1-(30,50-Dibenzyloxyphenyl)-3-(200-O-methoxy-
methyl-400,600-dibenzyloxyphenyl)propan-1-ol (19). In an
identical manner to the preparation of 11 chalcone 18 (5.9 g,
9.5 mmol) was converted into crude ketone (4.7 g, 86%) and
then alcohol 19 (4.7 g, 99%) as a pale yellow solid; mp 119–
1
120 8C; IR nmax 3575, 2946, 1594, 1497, 1453 cmK1; H
NMR (400 MHz, CDCl3) d 1.99 (m, 2H, ArCH2CH2-
CHOH), 2.87 (m, 3H, ArCH2CH2CHOH and OH), 3.50 (s,
3H, OCH2OCH3), 4.53 (m, 1H, CHOH), 5.02 (s, 4H, 2!
OCH2Ph), 5.05 (s, 2H, OCH2Ph), 5.07 (s, 2H, OCH2Ph),
5.21 (s, 2H, OCH2OCH3), 6.37 (s, 1H, ArH), 6.57 (s, 2H,
ArH), 6.68 (s, 2H, ArH), 7.24–7.47 (m, 20H, ArH); 13C
NMR (100 MHz, CDCl3) d 0.7, 39.2, 56.6, 70.5, 70.8, 73.5,
94.8, 95.0, 95.3, 101.1, 105.4, 112.0, 127.6, 128.0, 128.1,
128.3, 128.4, 128.5, 129.0, 129.1, 137.3, 147.8, 156.158.3,
160.3; MS (ES, m/z) 719 (MCCNa, 30%), 239 (MCK480,
100%); HRMS (ES, m/z) found 719.2916 C45H44O7Na
requires 719.2985.
5.1.12. (E)-1-(30,50-Dibenzyloxyphenyl)-3-(200-O-methoxy-
methyl-400,600-dibenzyloxyphenyl)propene (20). In an
identical manner to the preparation of 12, alcohol 19
(2.5 g, 4.0 mmol) gave the corresponding bromide (2.8 g,
99%) as a white solid; mp 114–115 8C; IR nmax 3062, 2932,
A solution of the globally protected gallate ester (170 mg,
0.18 mmol) and 10% Pd (OH)2 (10 mg) in EtOAc (10 mL)

7710
J. C. Anderson et al. / Tetrahedron 61 (2005) 7703–7711
1595, 1497, 1453 cmK1; H NMR (400 MHz, CDCl3) d
2.51 (m, 2H, ArCH2CH2CHBr), 2.78 (m, 1H, ArCH2CH2-
CHBr), 2.93 (m, 1H, ArCH2CH2CHBr), 3.52 (s, 3H,
OCH2OCH3), 5.06 (m, 9H, 4!OCH2PhCCHBr), 5.21 (s,
2H, OCH2OCH3), 6.36 (d, 1H, JZ2.2 Hz, ArH), 5.85 (d,
1H, JZ2.2 Hz, ArH), 6.59 (t, 1H, JZ2.2 Hz, ArH), 6.75 (d,
2H, JZ2.2 Hz, ArH), 7.33–7.53 (m, 20H, ArH); 13C NMR
(100 MHz, CDCl3) d 22.5, 39.7, 56.1, 56.6, 70.6, 94.7, 94.9,
95.2, 102.1, 107.2, 111.8, 127.4, 127.7, 128.0, 128.1, 128.2,
128.4, 128.5, 129.0, 137.2, 137.6, 145.0, 157.0, 158.3,
159.0, 160.4; MS (ES, m/z) 760 (MC, 10%), 723 (MCK37,
100%); HRMS (ES, m/z) found 760.2229, C45H44O6Br
requires 760.2222.
ArCH2CH(OH)CH(OH)), 4.89–5.00 (m, 8H, 4!
OCH2Ph), 6.26 (d, 1H, JZ2.3 Hz, ArH), 6.31 (d, 1H, JZ
2.3 Hz, ArH), 6.56 (t, 1H, JZ2.1 Hz, ArH), 6.63 (s, 1H,
ArH), 6.64 (s, 1H, ArH), 7.18–7.48 (m, 20H, ArH); 13C
NMR (100 MHz, CDCl3) d 27.2, 70.4, 70.5, 77.1, 94.0,
96.3, 102.3, 106.4, 106.7, 127.1, 128.0, 128.1, 128.4, 128.5,
128.9, 129.0, 129.1, 137.2, 137.4, 143.5, 157.6, 158.3,
159.5, 160.4; MS (ES, m/z) 669 (MHC, 100%); HRMS (ES,
m/z) found 669.2855, C43H41O7 requires 669.2852; [a]D
K7.5 (c 4.2, CH2Cl2, at 24 8C).
1
5.1.15. (1S,2R)-1-Bromo-2-formate (23). In an identical
manner to the preparation of 15 triol 22 (550 mg,
0.93 mmol) gave bromo formate 23 as a brown foam
(580 mg, 91%). This compound was used immediately
without purification or characterisation.
The bromide (2.8 g, 4.0 mmol) gave styrene 20 (1.3 g, 53%)
as a white solid; mp 103–104 8C; IR nmax 3087, 2932, 1676,
1
1593, 1497, 1453 cmK1; H NMR (400 MHz, CDCl3) d
5.1.16. (2R,3R)-30,50-Dibenzyloxy-400,600-dibenzyloxy-
flavan (24). In an identical manner to the preparation of
16 crude bromo formate 23 (580 mg, 0.90 mmol) gave 24 as
a colourless oil (222 mg, 45%); IR nmax 3562, 3064, 3032,
3.53 (s, 3H, OCH2OCH3), 3.65–3.66 (m, 2H, CH2-
CH]CH), 5.09 (s, 4H, 2!OCH2Ph), 5.11 (s, 2H,
OCH2Ph), 5.14 (s, 2H, OCH2Ph), 5.25 (s, 2H, OCH2OCH3),
6.37–6.38 (m, 2H, ArCH2CH]CH), 6.42 (d, 1H, JZ
2.2 Hz, ArH), 6.54 (t, 1H, JZ2.2 Hz, ArH), 6.57 (d, 1H, JZ
2.2 Hz, ArH), 6.64 (s, 1H, ArH), 6.65 (s, 1H, ArH), 7.34–
7.56 (m, 20H, ArH); 13C NMR (100 MHz, CDCl3) d 27.0,
56.6, 70.4, 70.5, 70.6, 70.7, 94.7, 95.0, 95.1, 101.1, 105.8,
108.3, 110.9, 127.6, 127.7, 128.0, 128.1, 128.3, 128.4,
128.5, 129.0, 129.1, 129.9, 130.5, 137.3, 137.4, 137.5,
137.7, 140.7, 156.9, 158.4, 159.1, 160.5; MS (ES, m/z) 679
(MHC, 10%), 576 (MCK103, 100%); HRMS (ES, m/z)
found 679.3167 C45H43O6 requires 679.3060.
1
2925, 1593, 1150 cmK1; H NMR (400 MHz, CDCl3) d
1.65 (d, 1H, JZ5.2 Hz, OH), 2.87 (dd, 1H, JZ18, 4.4 Hz,
ArCH2CHCHO), 2.97 (dd, 1H, JZ18, 2.0 Hz, ArCH2-
CHCHO), 4.19–4.23 (m, 1H, ArCH2CHCHO), 4.86 (s, 1H,
ArCH2CHCHO), 4.88–5.02 (m, 8H, 4!OCH2Ph), 6.21 (d,
1H, JZ2.4 Hz, ArH), 6.23 (d, 1H, JZ2.4 Hz, ArH), 6.53 (t,
1H, JZ2.4 Hz, ArH), 6.70 (s, 1H, ArH), 6.71 (s, 1H, ArH),
7.21–7.30 (m, 20H, ArH); 13C NMR (100 MHz, CDCl3) d
28.2, 66.5, 70.0, 70.2, 77.2, 78.6, 94.1, 94.7, 101.0, 101.6,
105.4, 127.2, 127.6, 127.9, 128.1, 128.5, 128.6, 136.7,
136.9, 137.0, 140.7, 155.1, 158.3, 158.8, 160.2; MS (ES,
m/z) 651 (MHC, 80%), 225 (MK426, 100%); HRMS (ES,
m/z) found 651.2741, C43H39O6 requires 651.2747; [a]D
K17.2 (c 0.8, CH2Cl2, at 24 8C).
5.1.13. (1R,2R)-1-(30,50-Dibenzyloxyphenyl)-3-(200-O-
methoxymethyl-400,600-dibenzyloxyphenyl)propane-1,2-
diol (21). In an identical manner to the preparation of 13
styrene 20 (1.4 g, 2.3 mmol) gave 21 as a white solid (1.2 g,
82%, 75% ee by HPLC15) that was then recrystallised (80%
Et2O/EtOAc) to give enantiomerically pure 21 (670 mg,
5.1.17. (K)-3,5-Dihydroxy B-ring modified (K)-ECg (3).
In an identical manner to the preparation of 2, alcohol 24
(100 mg, 0.17 mmol) was converted to the globally
protected gallate ester (120 mg, 67%); IR nmax 3063,
46%); mp 84–86 8C; IR nmax 3520, 2928, 1594, 1151 cmK1
;
1H NMR (500 MHz, CDCl3) d 2.99–3.10 (m, 2H, ArCH2-
CH(OH)CH(OH)), 3.55 (s, 3H, OCH2OCH3), 4.06–4.09 (m,
1H, ArCH2CH(OH)CH(OH)), 4.60 (d, 1H, JZ4.5 Hz,
ArCH2CH(OH)CH(OH)), 5.11 (s, 4H, 2!OCH2Ph), 5.13
(s, 2H, OCH2Ph), 5.14 (s, 2H, OCH2Ph), 5.25 (dd, 2H, JZ
13, 6.7 Hz, OCH2OCH3), 6.47 (d, 1H, JZ2.2 Hz, ArH),
6.58 (d, 1H, JZ2.2 Hz, ArH), 7.00 (t, 1H, JZ2.1 Hz, ArH),
7.05 (s, 1H, ArH), 7.12 (s, 1H, ArH), 7.40–7.53 (m, 20H,
ArH); 13C NMR (100 MHz, CDCl3) d 27.6, 56.4, 70.1, 70.3,
70.6, 75.7, 76.2, 94.5, 94.7, 94.9, 101.2, 105.9, 108.3, 127.3,
127.8, 128.1, 128.2, 128.7, 128.9, 136.6, 136.8, 137.0,
143.9, 156.9, 158.1, 159.0, 160.0; MS (ES, m/z) 735 (MHC,
80%), 363 (MCK372, 100%); HRMS (ES, m/z) found
735.2970, C45H45O8 requires 735.2958; [a]D C3.0 (c 0.1,
CH2Cl2, at 24 8C).
1
3031, 1714, 1593 cmK1; H NMR (400 MHz, CDCl3) d
3.03 (d, 2H, JZ3.2 Hz, ArCH2CHCHO), 4.65 (d, 1H, JZ
12 Hz, OCH2Ph), 4.73 (d, 1H, JZ12 Hz, OCH2Ph), 4.86–
5.10 (m, 13H, ArCH2CHCHO, and 6!OCH2Ph), 5.56–5.57
(m, 1H, ArCH2CHCHO), 6.23 (d, 1H, JZ2.4 Hz, ArH),
6.31 (d, 1H, JZ2.4 Hz, ArH), 6.42 (t, 1H, JZ2.0 Hz, ArH),
6.64 (s, 1H, ArH), 6.65 (s, 1H, ArH), 7.13–7.24 (m, 37H,
ArH); 13C NMR (100 MHz, CDCl3) d 26.5, 68.7, 70.0, 70.1,
70.2, 71.0, 75.1, 77.9, 94.0, 94.8, 101.0, 101.2, 106.0 109.1,
125.1, 127.3, 127.5, 127.6, 127.7, 127.8, 127.9, 128.0,
128.2, 128.4, 128.6, 136.6, 136.7, 136.9, 137.5, 138.1,
142.6, 152.4, 155.6, 158.0, 158.9, 160.0, 165.1; [a]D K43.8
(c 2.4, CH2Cl2, at 24 8C).
5.1.14.
(1R,2R)-1-(30,50-Dibenzyloxyphenyl)-3-(200-
A solution of the globally protected gallate ester (120 mg,
0.11 mmol) was hydrogenolysed to give (K)-3 (18 mg,
37%) as an off-white solid; mp O200 8C; IR nmax 3332,
1608, 1237 cmK1; 1H NMR (400 MHz, (CD3)2CO) d 2.76–
2.95 (m, 2H, ArCH2CHCHO), 4.99 (s, 1H, ArCH2CHCHO),
5.46–5.48 (m, 1H, ArCH2CHCHO), 5.91–5.93 (m, 2H,
ArH), 6.11 (t, 1H, JZ2.4 Hz, ArH), 6.43–6.44 (m, 2H,
ArH), 6.88 (s, 2H, ArH), 8.01 (br s, 7H, OH); 13C NMR
(100 MHz, (CD3)2O) d 20.7, 26.6, 60.8, 66.6, 69.2, 78.1,
hydroxy-400,600-dibenzyloxyphenyl)propane-1,2-diol
(22). In an identical manner to the preparation of 14 diol 21
(670 mg, 1.0 mmol) gave triol 22 as a white solid (600 mg,
100%); mp 91–92 8C; IR nmax 3384, 3031, 2910, 1595,
1150 cmK1; H NMR (400 MHz, CDCl3) d 2.86 (dd, 1H,
JZ15, 12 Hz, ArCH2CH(OH)CH(OH)), 3.01 (dd, 1H, JZ
15, 3.7 Hz, ArCH2CH(OH)CH(OH)), 4.02–4.05 (m, 1H,
ArCH2CH(OH)CH(OH)), 4.50 (d, 1H, JZ5.9 Hz,
1

J. C. Anderson et al. / Tetrahedron 61 (2005) 7703–7711
7711
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141.0, 146.0, 156.9, 157.5, 157.8, 159.2, 166.1; MS (ES,
m/z) 443 (MHC, 80%), 273 (MCK169, 100%); HRMS (ES,
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5.2. Microbiological evaluation of 2 and 3. S. aureus BB
¨
568 was provided by Professor B. Berger-Bachi, University
of Zu¨rich, Switzerland. EMRSA-15 and EMRSA-16 were
clinical isolates obtained from the Royal Free Hospital
London. The capacity of the various compounds to
modulate b-lactam resistance was evaluated by determi-
nation of the MIC at a fixed concentration in combination
with oxacillin. Assays were performed in 96-well microtiter
trays with a bacterial inoculum of about 104 colony-forming
units in 100 ml of Mueller-Hinton broth (Oxoid,
Basingstoke, UK) supplemented with 2% w/v NaCl.
Doubling dilutions of oxacillin were employed. MIC values
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Acknowledgements
This work was supported by MRC Strategic Grant
G0000996. We thank S. Shah for undertaking the
antibacterial assays, Mr. T. Hollingworth and Mr. D.
Hooper for providing mass spectra and Mr. T. J. Spencer
for micro analytical data.
13. Taylor, P. W.; Stapleton, P. D.; Shah, S.; Anderson, J. C. ICOS
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