Synthesis and biological evaluation of flavan-3-ol derivatives as positive modulators of GABAA receptors

Bioorganic & Medicinal Chemistry 17 (2009) 7156–7173

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Bioorganic & Medicinal Chemistry

journal homepage: w ww.elsevier.com/locate/bmc

Synthesis and biological evaluation of ﬂavan-3-ol derivatives as positive

modulators of GABA_Areceptors

Kenneth N. Mewett ^a, Sebastian P. Fernandez ^a, Anmol K. Pasricha ^b, Alice Pong ^a, Steven O. Devenish ^a,b

,

David E. Hibbs ^b, Mary Chebib ^b, Graham A. R. Johnston ^a, Jane R. Hanrahan ^b,

*

^aAdrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, Faculty of Medicine, The University of Sydney, NSW 2006, Australia

^bPharmaceutical Chemistry, Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia

a r t i c l e i n f o

a b s t r a c t

Article history:

We herein describe the synthesis and positive modulatory activities of a small library of ﬂavan-3-ol deriv-

atives on ₁b₂c_2LGABA_Areceptors. Structure–activity relationships of various substituents on the A, B

and C rings were evaluated in a functional electrophysiological assay. A trans conﬁguration and a 3-acet-

oxy moiety are essential for activity. Substitution of the B ring appears to be well tolerated, with substit-

uents on the A ring playing a major role in determining activity.

Received 12 June 2009

Revised 21 August 2009

Accepted 29 August 2009

Available online 4 September 2009

a

Keywords:

GABA_A

Flavan-3-ol

Positive modulator

Structure–activity

1. Introduction

tors. Subsequently, functional electrophysiological studies using

recombinant receptors demonstrated that ﬂavonoids modulate

GABA_Areceptors are ligand-gated chloride channels consisting

of a heteropentameric assembly of proteins derived from a family

GABA_Areceptors at a site independent of the classical high-afﬁnity,

ﬂumazenil-sensitive benzodiazepine binding site.^6–10

of 16 genes:

a_1–6, b_1–3

,

c_1–3, d,

p

,

e

and h.¹Although there are a vast

Catechins are a group of naturally-occurring ﬂavonoids that

share the ﬂavan (3,4-dihydro-2-phenyl-2H-1-benzopyran) basic

backbone. Compared to ﬂavones, catechins have a saturated bond

between C2 and C3 of the C-ring (Fig. 1), which makes the mole-

cule less planar and reportedly less able to bind to the high-afﬁnity

benzodiazepine binding site.^6,11–13However, a number of cate-

chins have demonstrated modulatory activity at GABA_Areceptors.

(+)-Catechin and (ꢀ)-epicatechin, as well as their 3-gallate deriva-

tives, have been reported to exhibit negative modulatory action at

number of possible subunit combinations, only 20 native combina-

tions occur in the mammalian central nervous system; the most

common receptor subtypes contain

a₁, b₂and c₂subunits in a

2:2:1 ratio.²GABA_Areceptors have a diverse range of allosteric

binding sites and enhancement of the GABAergic responses at GA-

BA_Areceptors is the mechanism of action for a range of important

therapeutic agents such as benzodiazepines, barbiturates and some

general anesthetics. Other allosteric modulators include steroids,

ethanol and an extensive range of natural compounds including

ﬂavonoids.

a

₁b₂GABA_Areceptors.¹⁴Subsequently, (ꢀ)-epigallocatechin gallate

(EGCG), a major component of green tea, was shown to inhibit

Flavonoids were ﬁrst linked to GABA_Areceptors as a result of

their ability to inhibit the binding of benzodiazepines to brain

membranes.³Many subsequent studies demonstrated that a range

of naturally-occurring and synthetic ﬂavonoids bind to this site

with nanomolar afﬁnity, displacing radiolabelled benzodiazepines

from rat and bovine brain tissue.^4,5These results in combination

with behavioural studies, which indicated that many ﬂavonoids

exhibit anxiolytic activity in rodents, suggested that ﬂavonoids

mediate their activity via the benzodiazepine site at GABA_Arecep-

GABA-elicited currents at a₁b₂c_2LGABA_Areceptors in addition to

* Corresponding author. Tel.: +61 2 93512078; fax: +61 2 93514391.

E-mail address: janeh@pharm.usyd.edu.au (J.R. Hanrahan).

Figure 1. Structure and numbering of ﬂavan skeleton.

doi:10.1016/j.bmc.2009.08.062

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

7157

enhancing the positive modulatory effect of diazepam.¹⁵Recently,

we described the ﬂumazenil-insensitive positive modulatory ac-

Treatment of the MOM-protected (E)-propenes (19–27) at ini-

tially 0 °C, then 2–4 °C, for P2 days with AD-mix-b²¹in the stan-

dard 2-phase t-BuOH/water system afforded the (1R,2R)-syn-diols

(28a–35a) in good yields (Scheme 1). On some occasions, small

quantities of a second product, tentatively identiﬁed as the over-

oxidised hydroxyketone by analysis of the ¹H and ¹³C NMR spectra,

could be isolated. The corresponding (1S,2S)-syn-diols (28b, 29b,

31b, 33b, 35b and 36b) were obtained similarly using AD-mix-

tion of 3-acetoxy-4⁰-methoxyﬂavans at human recombinant a₁

,

a₂

,

a₃and a₅containing

abc

GABA_Areceptors.⁷

Many structure–activity studies of ﬂavonoids acting at GABA_A

receptors have been described. However, these studies have been

based on the results of ligand-binding assays on brain tissue, which

includes a mixture of receptor subtypes that have different binding

afﬁnities for benzodiazepines.^{11,12,16–18}The present study charac-

terises the structure–activity of a series of relatively simple ﬂa-

a.

²¹Initially, the absolute conﬁguration of the diols was tentatively

assigned according to the Sharpless model.^21,22However, the later

determination of the absolute conﬁguration of trans-(2S,3R)-3⁰-

bromo-4⁰,5⁰-dimethoxyﬂavan-3-ol (41a) by X-ray analysis (vide in-

fra) conﬁrmed this tentative assignment, and, by extrapolation, the

other assignments.

van-3-ol derivatives in

a

functional assay using human

recombinant

oocytes.

a₁b₂c_2LGABA_Areceptors expressed in Xenopus laevis

As observed by van Rensburg et al.,¹⁹the simultaneous depro-

tection and cyclisation of the diols (28–36) in the presence of

3 M HCl yielded a mixture of the trans- (37–45) and cis-ﬂavan-3-

ols (46–54) (Scheme 1).¹⁹While the ratio of trans:cis isomers var-

ied slightly depending on the substitution patterns, a ratio of

approximately 3:1 was obtained. Although the acetate derivatives

of these compounds have been the most thoroughly investigated in

our pharmacological assays to date, our eventual aims include the

possible preparation of ﬂavan-3-ol esters with a variety of acyl and

aryl groups. Consequently, the trans- (37–45) and cis-ﬂavan-3-ols

(46–54) were separated with difﬁculty by chromatography at this

stage rather than by the in situ conversion to and separation of the

acetates derivatives. The acetates (55–70) were subsequently ob-

tained from the corresponding isolated ﬂavan-3-ols in near quan-

titative yields by treatment of the ﬂavan-3-ols with acetic

anhydride/pyridine. Following the precedent of van Rensburg

et al.,¹⁹the optical purity of the acetates was determined by ¹H

NMR spectroscopy using [Eu(hcf)₃] as the chiral shift reagent; as

observed by the South African group, the acetates consistently

showed the presence of only one detectable enantiomer, thereby

indicating an excellent enantiomeric excess (nominally 99%).

Deprotection of the benzyl ether protected acetates (61a, 62a,b,

2. Results and discussion

The ﬂavan-3-ol acetates were prepared by the synthetic route

previously developed by van Rensberg et al.,¹⁹with some early

modiﬁcations for the preparation of intermediate MOM-protected

(E)-1,3-diarylpropenes. (E)-2⁰-Hydroxy-4-methoxychalcone (1)

and a number of substituted analogues (2–9) were prepared by

the base catalysed condensation of the appropriately substituted

acetophenones and benzaldehdes. The chalcones were reduced to

the unprotected (E)-1,3-diarylpropenes (10–18) as previously re-

ported for 10;²⁰via protection of the 2⁰-hydroxy function, subse-

quent reduction with NaBH₄and ﬁnally treatment with dilute

acid (Scheme 1). While this reduction frequently afforded small

yields of both the over-reduced product and the positional ene iso-

mer, these could be removed by a combination of preparative chro-

matography and recrystallisation. Treatment of the unprotected

(E)-1,3-diarylpropenes with methoxymethyl chloride (MOMCl)

and an organic base afforded the corresponding MOM protected

(E)-1,3-diarylpropenes (19–27) in high yields (Scheme 1). In the

case of (19), NMR data were identical to those reported for this

compound by van Rensburg, thereby establishing that the assign-

ment of the position of the double bond was correct.

Scheme 1. Reagents and conditions: (i) EtOC(O)Cl/TEA/THF, then NaBH₄/H₂O, then H⁺; (ii) MOMCl/(i-Pr)₂NEt/THF; (iii) AD-mix-b or AD-mix-

a/MeSO₂NH₂/H₂O/BuOH, 0–4 °C;

(iv) 3 M HCl/MeOH–H₂O; (v) Ac₂O/pyridine. 1, 10, 19, 28a,b, 37a,b, 46a,b, 55a,b, 64,a,b R¹= R³= R⁴= R⁵= H, R²= OMe; 2, 11, 20, 29a,b, 38a,b, 47a,b, 56a,b, 65,a,b

R³= R⁴= R⁵= H, R¹= R²= OMe; 3, 12, 21, 30a, 39a, 48a, 57a, 66a R¹= R³= R⁵= H, R²= R⁴= OMe; 4, 13, 22, 31a,b, 40a,b, 49a,b, 58a,b, 67b R³= R⁵= H, R¹= R²= OMe, R⁴= Me; 5,

14, 23, 32a, 41a, 50a, 59a R⁴= R⁵= H, R²= R³= OMe, R¹= Br; 6, 15, 24, 33a,b, 42a,b, 51a,b, 60a,b, 68a,b R³= R⁴= R⁵= H, R¹= R²= OCH₂O; 7, 16, 25, 34a, 43a, 52a, 61a, 69a

R

¹= R³= R⁴= H, R²= OMe, R⁵= OBn; 8, 17, 26, 35a,b, 44a,b, 53a,b, 62a,b R³= R⁴= H, R¹= R²= OMe, R⁵= OBn; 9, 18, 27, 36b, 45b, 54b, 63b, 70b R¹= R³= R⁴= R⁵= H, R²= OBn.

a: conﬁguration shown, b: enantiomer.

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K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

63b, 69a, 70b) by hydrogenolysis over Pearlman’s catalyst afforded

(71a, 72a,b, 73b, 74a, 75b) (Scheme 2).

Analytical and spectroscopic data was consistent with the pro-

posed structures. However, it is worth noting that although the

enantiomerically pure trans-acetates (56a) and (56b) which had

identical ¹H and ¹³C NMR spectra gave different melting points. A

repeat synthesis of both 56a and 56b from diols prepared using dif-

ferent batches of AD-mixes also resulted in products with melting

points that were consistent with the original observations, and no

problems were found with the melting points of either the parent

3-ols (38a and 38b) or the corresponding cis-enantiomers. As a re-

sult, the different melting points of 56a and 56b were ascribed to

polymorphism. However, this has not been conﬁrmed as crystals

suitable for X-ray diffraction have been unobtainable.

van Rensburg et al.¹⁹have proposed that the cyclisation of

methoxylated diol (76) proceeds stepwise (Scheme 3); initially

via a mixture of the syn:anti isomers (77) generated by an S_N1-type

acid-catalysed methanolysis of the C-1 benzylic hydroxy group, a

subsequent acid catalysed deprotection of the MOM ether on 77

to yield 78 and, in a ﬁnal step, an S_N1 cyclisation of an incipient

carbocation derived from 78 to afford predominantly the thermo-

dynamically more stable trans-ﬂavan-3-ol isomer (79) and smaller

amounts of the cis-isomer (80). In the case of more highly substi-

tuted

polymethoxylated

compounds

such

as

(76;

R¹= R³= R⁴= OMe, R²= H), intermediates (77; R¹= R³= R⁴= OMe,

R²= H) and (78; R¹= R³= R⁴= OMe, R²= H) were reported as read-

ily separated.

In the course of our investigation, we have found that with a

syn-diol having both an unsubstituted A-ring and a highly substi-

tuted B-ring such as (32a (76; R¹= Br, R²= OMe, R³= R⁴= H)

Scheme 3), the cyclisation reaction, besides requiring protracted

reaction times of up to several weeks to accomplish even a moder-

ate conversion to the ﬂavan-3-ol, appears to follow a different

pathway with the ‘triol’ (81; R¹= Br, R²= OMe, R³= R⁴= H) being

both the ﬁrst intermediate isolated and the major product after

3–5 days heating; (81; R¹= Br, R²= OMe, R³= R⁴= H) was subse-

Scheme 3.

X-ray analyses of trans-(2S,3R)-4⁰-methoxyﬂavan-3-ol (37a),

trans-(2S,3R)-3-acetoxy-4⁰-methoxyﬂavan (55a) and cis-(2R,3R)-

3-acetoxy-4⁰-methoxyﬂavan (64a) conﬁrmed the structure and

relative stereochemistry for these products (Fig. 2A, C and D,

respectively). In view of the fact that the absolute conﬁguration of

trans-(2S,3R)-3⁰-bromo-4⁰,5⁰-dimethoxyﬂavan-3-ol (41a, Fig. 2B),

prepared by an identical route, was unambiguously established by

X-ray analysis, it is reasonable to infer that the absolute conﬁgura-

tions of both 37a and 55a are indeed trans-(2S,3R)- and that the

assigned absolute conﬁgurations of other acetates are also correct.

The fused ring system of structures reported for 37a and 41a

both exhibit similar features to the structure previously reported

for 8-bromotetra-O-methyl-(+)-catechin.²³The six aromatic car-

bons of the A-ring all lie close to their mean plane, with the max-

imum deviation of 0.6 picometres (pm) from the plane of ring A

quently shown to be

a

precursor of (78; R¹= Br, R²= OMe,

R³= R⁴= H), and (78; R¹= Br, R²= OMe, R³= R⁴= H) to be a precur-

sor of the ﬂavanols (41a (79; R¹= Br, R²= OMe, R³= R⁴= H)) and

(50a (80; R¹= Br, R²= OMe, R³= R⁴= H)) by independent reactions.

No species such as (77; R¹= Br, R²= OMe, R³= R⁴= H) could be de-

tected and this would suggest that, with these more hindered com-

pounds, the acid catalysed hydrolysis of the MOM ether

functionality, despite the suggestion by van Rensburg et al.¹⁹of a

remarkably high stability towards acid hydrolysis in the com-

pounds investigated, proceeds far more rapidly than methoxyla-

tion at C(1).

Scheme 2. Reagents: (i) Pd(OH)₂–C/H₂in MeOH/THF.

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

7159

Figure 2. Structures of (A) 37a, (B) 41a, (C) 55a and (D) 64a. Displacement ellipsoids are drawn at the 50% probability level.

in compound 41a. The puckering of the heterocyclic ring is

most evident at C(2) and C(3). These two atoms lie on opposite

sides of the mean plane of the aromatic ring with C(2) below

the mean plane and C(3) above the plane. Equatorial positions

are adopted by both the aromatic ring bonded to C(2) and the

hydroxyl group bonded to C(3). In the solid state, 8-bromotetra-

O-methyl-(+)-catechin exists in a conformation between a C(2)-

sofa and a C-2,C-3-half-chair.²³Similarly, both 37a and 41a exist

in a conformation between a reverse C(2),C(3)-half-chair and a

reverse C(2)-sofa.

In the case of 64a, the six aromatic carbons also lie close to their

mean plane with a maximum deviation of 1.5 pm. However, in

contrast to compounds 37a and 41a, the C(2) lies above the mean

plane and C(3) below the plane. The aromatic ring bonded to C(2) is

in the equatorial position with the acetoxy group bonded to the

C(3) position axial. This is consistent with the structure of (ꢀ)-epi-

catechin, which exists in the solid state in a half-chair distorted to-

wards a C(2)-sofa.²⁴Interestingly, the presence of an acetoxy group

in the C3 position of 64a results in a solid state structure that is clo-

ser to a half-chair conformation than (ꢀ)-epicatechin; with C(2)

and C(3) deviations from the plane of 44.3 pm and ꢀ37.3 pm in

64a compared to 26.3 pm and ꢀ49.5 pm in (ꢀ)-epicatechin.²⁴

The six aromatic carbons of 55a lie close to their mean plane

with a maximum deviation of 1.0 pm, with the C(2) and C(3) lying

below and above the plane, respectively. Both the aromatic ring

bonded to C(2) and the acetoxy group bonded to the C(3) are in

the axial positions, which is consistent with the structure reported

for penta-O-acetyl-(+)-catechin,²⁵indicating that the presence of

the acetoxy group leads to the axial–axial conformation. In the so-

lid state. The conformation of heterocyclic ring of 55a is a reverse

half-chair distorted towards a reverse C(3)-sofa, similar to that of

37a and 41a. However, penta-O-acetyl-(+)-catechin adopts a con-

formation that is close to a reverse half-chair.²⁵

These structures conﬁrm that the conformation of the heterocy-

clic ring in the solid state is determined by the nature of the C(2)

and C(3) substituents. However, in solution, it has been demon-

strated that it is likely that the heterocyclic ring undergoes a rapid

interconversion of conformations,²⁵and this is supported by the

coupling constants determined for J_2,3, J_3,4aand J_3,4bof 37a (8.3,

5.6 and 9.4 Hz, respectively), 41a (8.3, 5.5 and 9.4 Hz, respectively),

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K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

64a (unresolved, 4.6 and 2.0 Hz, respectively) and 55a (6.4, 5.0 and

6.6 Hz, respectively).

To determine the structural requirements for positive modula-

tion of the GABA response at a₁b₂c_2LGABA_Areceptors by ﬂavans,

the current study examines the effects of varying substitutions

on simpliﬁed analogues of (ꢀ)-epigallocatechin gallate by deter-

mining the potentiation of the GABA EC₅responses elicited by

the coapplication of 30

dose of 30 M was selected as some compounds used in this study

were insoluble at higher doses. To account for inter-cell variability,

all responses were normalised to the response of 30 M 55a, our

lead compound, which enhances the response of the GABA EC₅

dose by 700%, with an EG₅₀of 13.7 0.9

M.⁷

lM ﬂavan-3-ols and acetate derivatives. A

l

Previous studies have indicated that EGCG is a negative modu-

lator at GABA_Areceptors.¹⁵In contrast, all ﬂavan compounds in this

study were found to be positive modulators of

a₁b₂c_2LGABA_A

Figure 4. Enhancement of the response to EC₅GABA dose GABA at

receptors by 56a (d), 57a (N), 59a (.), 71a (h) and 72a (s) in the presence of GABA

at ₁b_{2 2L}. Data are expressed as mean SEM.

a₁b₂c_2L

receptors and to effectively potentiate currents elicited by a low

concentration (EC₅) of GABA (Fig. 3). Previous research on all four

stereoisomers of 3-acetoxy-4⁰-methoxyﬂavan demonstrated that

the trans isomers are more active than their cis counterparts with

the trans-(2S,3R)-isomer being the most active stereoisomer.⁷

Without exception, the trans-(2S,3R)-isomer was also found to be

the most active isomer for all compounds in the current study.

The presence of an acetoxy group at the C3 position has been

found to be a necessary requirement for activity. The parent hydro-

xy compounds, 37a and 46a, exhibited a 75% decrease in enhance-

ment of the GABA_AEC₅response compared to the corresponding

acetylated compounds 55a and 55b, respectively. A possible expla-

nation for this is that the carbonyl of the acetoxy moiety interacts

with the same residue in the binding site as the carbonyl of the

pyranone ring in ﬂavones and ﬂavanones that are also positive

modulators at GABA_Areceptors.^8,9

a

c

the 3⁰,4⁰-dimethoxy substituents with the 3⁰,4⁰methylenedioxy

moiety results in a decrease in activity of approximately 20% for

60a and 60b compared to 56a and 56b, respectively. Compound

59a, which is essentially the 3⁰4⁰-dimethoxy compound 56a with

a bromo substituent ortho to the 4⁰-methoxy, showed a maximal

efﬁcacy similar to that of 55a, but with increased potency

(Fig. 4), having an EC₅₀of 3.17 1.1

13.15 1.00

M.⁷

However, replacement of the 4⁰-methoxyl with a benzyloxy

moiety resulted in a signiﬁcant decrease in activity, with 30

63b and 70b resulting in a maximal enhancement of 10% and

15%, respectively, of the enhancement resulting from 30 M 55a.

lM compared with

l

M

l

This indicates that there are no large lipophilic pockets in the bind-

ing site surrounding the B-ring of the ﬂavan. Replacement of the 4⁰-

methoxyl of 55b with a hydroxyl (73b) also resulted in signiﬁcant

loss of activity with 73b only enhancing the GABA EC₅response by

43% compared to 77% maximal enhancement by 55b. Interestingly,

in the case of the cis-(S,S) compound 64b replacement of the 4⁰-

methoxyl with a hydroxyl (75b) resulted in a fourfold increase in

enhancement.

The substitution pattern of the B-ring of the ﬂavan was also

found to be important for activity. The 3⁰,4⁰-dimethoxyl com-

pounds 56a, 56b and 65b demonstrated increased activity com-

pared to that of the corresponding enantiomer of the 4⁰-methoxy

compounds 55a, 55b and 64b, respectively. One of the most efﬁca-

cious compounds is 56a, which elicited a maximal potentiation of

approximately 1.2 times that of 55a at a dose of 30 lM, when com-

pared to the potentiation of 55a on the same oocyte. The dose–re-

In the case of the trans-(2S,3R)-isomer, the presence of a methyl

group at the C6 position, (58a), or a methoxyl group at the C6 posi-

tion (57a), resulted in a decrease in the potentiation of the GABA

EC₅response, when compared to the potentiation of the corre-

sponding compounds without a C6-substituent, 56a and 55a,

respectively. However, there was little effect on the EC₅₀value

sponse curve of 56a demonstrates a maximal enhancement of 13.9

times the EC₅of GABA with an EC₅₀value of 6.68 1.38 lM (Fig. 4),

approximately 1.7 times the maximal response of 55a. This dis-

crepancy is attributed to the receptors becoming unstable at max-

imal potentiation resulting in high variability. However, replacing

for compound 57a (EC₅₀= 14.95 1.28

lM

compared to

EC₅₀=13.15 1.00 M for 55a). In the case of the enantiomeric

l

(2R,3S)-isomer (58b), C6 methyl substitution resulted in a 60% de-

crease in activity compared to that of (2R,3S)-3-acetoxy-3⁰,4⁰-dim-

ethoxyﬂavan (56b).

In the trans-(2S,3R) compounds, a hydroxyl substituent at C7 is

well tolerated, if not advantageous, with 71a being equivalent in

efﬁcacy to 55a at 30

ment than 55a at a dose of 50

l

M and exerting a higher maximal enhance-

M (10.5 vs 8.5-fold enhancement).

l

Compound 72a demonstrates a 10% increase in efﬁcacy when com-

pared to 56a, the corresponding compound without the C7-hydro-

xyl. However, the dose–response curve of 72a demonstrates a

maximal enhancement of 12 times the EC₅of GABA with an EC₅₀

value of 12.15 1.1

ment of 14.7 times the EC₅of GABA with an EC₅₀value of

6.68 1.4 M. These discrepancies are again attributed to the

lM (Fig. 4), compared to a maximal enhance-

l

receptors becoming unstable at maximal potentiation resulting in

high variability. Conversely, the trans-(2R,3S) compound 72b

exhibits a signiﬁcant reduction in efﬁcacy, having a maximal

enhancement of 27% compared to the maximal enhancement by

Figure 3. Comparison of enhancement of GABA EC₅dose by compounds (30

GABA_{A 1}b₂c_2Lreceptors relative to the effect of 55a at 30 M.

lM) at

a

l

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

7161

56b of 100%. This suggests that the (2S,3R)- and the (2R,3S)-com-

pounds bind in different orientations to each other. In the case of

74a, the addition of a hydroxyl at the C-7 position resulted in a

twofold increase in activity compared to compound 64a.

non-hydrogen atoms were reﬁned anisotropically. All hydrogen

atoms were reﬁned in idealised positions, and given isotropic ther-

mal parameters equal to 1.2 (or 1.5 for methyl groups) times the

equivalent isotropic displacement parameter of the atom to which

it is attached. For 41a (Fig. 2B) the Flack Parameter (X) reﬁned to

0.0000 with an esu of 0.0009, indicating the correct absolute con-

ﬁguration was reﬁned. Material for publication was prepared using

the ^WINGXsuite of programs.²⁷

Interestingly, 71a displayed a bell-shaped dose–response curve

with concentrations above 60

the GABA EC₅response. Compound 55a has previously been shown

to exert a similar effect at high doses (>300 M), possibly through

lM decreasing the potentiation of

l

open channel blockade.⁷The fact that 71a exerts this blocking ef-

fect at lower concentrations suggests that manipulation of the

afﬁnity to this ‘secondary’ site may be achieved through appropri-

ate substitutions at the C7 position. However, the precursor 7-ben-

zyloxy compound 61a and the other compounds incorporating a

benzyloxy substituent, 62a, 62b and 69a all displayed signiﬁcantly

4.3. General procedure for the preparation of (E)-4-

methoxychalcones (1–9)

Aqueous KOH (7.0 g in 10 mL of H₂O) was added to a rapidly

stirred solution of the appropriate 2⁰-hydroxyacetophenone

(40 mmol) and the appropriately substituted 4-methoxybenzalde-

hyde (40 mmol) in EtOH (50–125 mL depending on solubility) at

room temperature (or occasionally warmed slightly to facilitate

solution). The mixture, which rapidly acquired a deep reddish col-

our and frequently deposited a copious, orange or orange-red pre-

cipitate, was stirred at room temperature for P24 h, then poured

into H₂O/ice (ca. 800 mL) and the mixture acidiﬁed (pH 64) with

vigorous stirring.

Where the resulting product was a yellow-orange precipitate,

this was ﬁltered, washed thoroughly with water and air-dried.

Puriﬁcation either by direct recrystallisation from EtOH or by CC

and subsequent recrystallisation from EtOH gave the pure

chalcone.

decreased activity at 30 lM with a maximal enhancement of less

than 12% of the activity of 55a at the same concentration.

3. Conclusion

We have described the structure–activity relationships of a ser-

ies of ﬂavan-3-ol derivatives that enhance the response of a₁b₂c_2L

GABA receptors to GABA. Evaluation of the biological activity in a

functional electrophysiological assay indicates that a trans conﬁg-

uration and a 3-acetoxy moiety is essential for activity. Although,

substitution of the B ring appears to be well tolerated, substitution

of the A ring plays a major role in determining activity. Compounds

56a and 72a are two of the most efﬁcacious positive modulators at

Where the resulting product was an oil or gum, the mixture was

extracted with several portions of DCM, the combined DCM ex-

tracts washed in turn with H₂O and saturated brine, and the solu-

tion dried (MgSO₄). The residue obtained on concentration of the

solution was puriﬁed as before by a combination of column chro-

matography and recrystallisation from EtOH to afford pure chal-

cone. Frequently, quantities of the corresponding ﬂavanone could

be recovered from the column upon further elution with a more

polar solvent.

GABA_A

a₁b₂c_2Lreceptors. Further structure–activity studies and

evaluation of ﬂavan-3-ol derivatives as modulators of the GABA re-

sponse is currently under investigation in our laboratories.

4. Experimental

4.1. General experimental

¹H NMR spectra were recorded at 300 MHz on a Varian Gemini-

300 BB spectrometer at room temperature; for solutions in CDCl₃,

TMS was employed as an internal standard. ¹³C NMR spectra were

recorded on the same instrument at 75.5 MHz, referenced to the

residual CDCl₃signal at 77.0 ppm. Melting points were determined

on a Reichert hot-stage apparatus and are uncorrected. High reso-

lution mass spectra were recorded using atmospheric pressure

chemical ionisation (APCI) on a Bruker 7T FTICR at The Mass Spec-

trometry Unit of the School of Chemistry, University of Sydney or

electron ionisation (EI) on a Micromass Autospec at the Australian

National University. All solvents were distilled before use. Anhy-

drous tetrahydrofuran (THF) was obtained by distillation from so-

dium/benzophenone ketal under an atmosphere of nitrogen. Thin

layer chromatography was performed on Merck Kieselgel 60 F₂₅₄

TLC aluminium plates; spots were visualised by UV light or by

alkaline KMnO₄spray. Short column vacuum chromatography

(CC) was performed on Merck Kieselgel 60 H at water pump

vacuum.

4.3.1. (E)-2⁰-Hydroxy-4-methoxychalcone (1)

Yellow-orange crystals; yield 79%; mp 93–94 °C (lit. mp

92 °C);^{28 1}H NMR (CDCl₃, 300 MHz) d 12.97 (1H, d of small coupling

constant, OH), 7.93 (1H, dd, J = 1.7, 8.0 Hz, H-6⁰), 7.91 (1H, d,

J = 15.5 Hz, CH@CHAr), 7.64 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2 and H-

6), 7.55 (1H,

d with additional ﬁne coupling, J = 15.5 Hz,

CH@CHCO), 7.50 (1H, ddd with additional ﬁne coupling, J = 1.7,

7.2, 8.3 Hz, H-4⁰), 7.03 (1H, dd with additional ﬁne coupling,

J = 1.2, 8.3 Hz, H-3⁰), 6.96 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3 and H-5),

6.95 (1H, ddd, J = 1.2, 7.2, 8.0 Hz, H-5⁰), 3.87 (3H, s, OCH₃); ¹³C

NMR (CDCl₃, 75.46 MHz) d 193.7, 163.6, 162.1, 145.3, 136.1,

130.5, 129.5, 127.5, 120.3, 118.72, 118.62, 117.9, 114.6, 55.4.

4.3.2. (E)-2⁰-Hydroxy-3,4-dimethoxychalcone (2)

Yellow-orange crystals; yield 83%; mp 116–117 °C (lit. mp 115–

117 °C);^{29 1}H NMR (CDCl₃, 300 MHz) d 12.95 (1H, s, OH), 7.95 (1H,

partly superimposed m (dd, J = 1.6, 8.2 Hz), H-6⁰), 7.90 (1H, d,

J = 15.4 Hz, COCH@CH), 7.53 (1H, d, J = 15.4 Hz, COCH@CH), 7.50

(1H, partly superimposed m (ddd, J = 1.6, ca. 7.9, 8.4 Hz), H-4⁰),

7.28 (1H, dd, J = 2.1, 8.4 Hz, H-6), 7.18 (1H, d, J = 2.1 Hz, H-2),

7.04 (1H, dd, J = 1.1, 8.4 Hz, H-3⁰), 6.95 (1H, ddd, J = 1.2, ca. 7.9,

8.2 Hz, H-5⁰), 6.92 (1H, d, J = 8.4 Hz, H-5), 3.98 (3H, s, OCH₃), 3.95

(3H, s, OCH₃); ¹³C NMR (CDCl₃, 75.45 MHz) d 193.7, 163.6, 152.0,

149.6, 145.6, 136.1, 129.6, 127.8, 123.5, 120.2, 118.73, 118.69,

118.1, 111.5, 110.8, 56.13, 56.09.

4.2. Crystallisation, data collection and reﬁnement

X-ray crystallographic measurements were made with a Bruker

Apex II diffractometer equipped with an Oxford Cryosystems Co-

bra. Graphite monochromated Mo K

a

radiation (k = 0.71073 Å)

–2h mode. Unit cell

was used to collect the intensity data in the

x

parameters and orientation matrix were obtained by least-squares

reﬁnement of the setting angles of 200 reﬂections. The structures

were solved by direct methods (using ^SHELXS-97)²⁶and reﬁned

using full-matrix least-squares on F²(using SHELXL-97),²⁶using all

unique data corrected for Lorentz and polarisation factors. All

4.3.3. (E)-2⁰-Hydroxy-4,5⁰-dimethoxychalcone (3)

Orange crystals; yield 67%; mp 90–91 °C; ¹H NMR (CDCl₃,

300 MHz) d 12.51 (1H, s, OH), 7.91 (1H, d, J = 15.4 Hz, COCH@CH),

7162

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

7.64 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2 and H-6), 7.48 (1H, dd, J = 15.4,

<0.5 Hz, COCH@CH), 7.37 (1H, d, J = 3.0 Hz, H-6⁰), 7.14 (1H, dd,

J = 3.0, 9.0 Hz, H-4⁰), 6.98 (1H, dd, J = <0.5, 9.0 Hz, H-3⁰), 6.96 (2H,

aa⁰bb⁰‘d’, J = 8.8 Hz, H-3 and H-5), 3.88 (3H, s, OCH₃), 3.85 (3H, s,

OCH₃); ¹³C NMR (CDCl₃, 75.45 MHz): d 193.4, 162.2, 158.0, 151.8,

145.5, 130.5, 127.5, 123.6, 119.9, 119.3, 117.9, 114.6, 113.2, 56.2,

55.5.

(2H, s, OCH₂), 3.97 (3H, s, OCH₃), 3.95 (3H, s, OCH₃); ¹³C NMR

(CDCl₃, 75.45 MHz) d 191.9, 166.6, 165.2, 151.8, 149.5, 144.6,

136.0, 131.2, 128.7, 128.3, 128.0, 127.5, 123.3, 118.2, 114.5,

111.4, 110.7, 108.1, 102.3, 70.3, 56.10, 56.06.

4.3.9. (E)-2⁰-Hydroxy-4-(phenylmethoxy)chalcone (9)

Yellow-orange crystals; yield 79%; mp 116.5–117 °C; ¹H NMR

(CDCl₃, 300 MHz) d 12.95 (1H, s, OH), 7.92 (1H, dd, J = 1.5, ca.

8.1 Hz, H-6⁰), 7.91 (1H, d, J = 15.6 Hz, COCH@CH), 7.64 (2H, aa⁰bb⁰

‘d’, J = 8.8 Hz, H-2 and H-6), 7.55 (1H, d, J = 15.6 Hz, COCH@CH),

7.49 (1H, ddd, J = 1.5, ca. 7.5, ca. 7.5 Hz, H-4⁰), 7.46–7.32 (5H, m,

5 ꢁ benzyl Ar-H), 7.03 (1H, superimposed m (dd, J = 1.2, ca.

7.5 Hz), H-3⁰), 7.03 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3 and H-5), 6.94

(1H, ddd, J = 1.2, ca. 7.5, ca. 8.1 Hz, H-5⁰), 5.13 (2H, s, OCH₂); ¹³C

NMR (CDCl₃, 75.45 MHz): d 193.7, 163.7, 161.3, 145.2, 136.5,

136.1, 130.5, 129.6, 128.7, 128.2, 127.8, 127.5, 120.3, 118.73,

118.65, 118.0, 115.5, 70.3.

4.3.4. (E)-2⁰-Hydroxy-3,4-dimethoxy-5-methylchalcone (4)

Yellow-orange solid; yield 67%; mp 143–145 °C; ¹H NMR

(CDCl₃, 300 MHz) d 12.77 (1H, s, OH), 7.89 (1H, d, J = 15.3 Hz,

C@CH-Ar), 7.70 (1H, dm (from decoupling experiment dq),

J = 2.2 Hz, H-6⁰), 7.52 (1H, d, J = 15.3 Hz, C@CHCO), 7.32 (1H, dd

(from decoupling experiment ddm), J = 2.2, 8.5 Hz, H-4⁰), 7.30

(1H, dd, J = 2.0, 8.3 Hz, H-6), 7.18 (1H, d, J = 2.0 Hz, H-2), 6.94

(1H, d, J = 8.5 Hz, H-3⁰), 6.93 (1H, d, J = 8.3 Hz, H-5), 3.98 (3H, s,

OCH₃), 3.95 (3H, s, OCH₃), 2.37 (3H, s, ArCH₃); ¹³C NMR (CDCl₃,

75.45 MHz) d 193.6, 161.6, 152.0, 149.5, 145.4, 137.2, 129.2,

127.9, 127.8, 123.4, 119.9, 118.4, 118.2, 111.5, 111.0, 56.2, 56.1,

20.6.

4.4. General procedure for ene (10–18) preparation

Ethyl chloroformate (2.6 g, 24 mmol) in THF (5 mL) was added

dropwise with stirring to a solution of TEA (2.4 g, 24 mmol) and

the appropriate chalcone (20 mmol) in THF (25–70 mL depending

on solubility) under N₂at 0–5 °C over ca. 20 min. The resulting

mixture was then stirred at the same temperature for P30 min

(a small amount of product intermediate (or other) occasionally

precipitated early in a small minority of reactions; in these cases

additional solvent was then added to dissolve as much precipitated

material as possible, the stirring was immediately discontinued

and the mixture ﬁltered). The insoluble amine salt was ﬁltered,

the ﬁlter cake washed with an additional volume of THF

(P25 mL) and the ﬁltrate added slowly to a vigorously stirred solu-

tion of NaBH₄(3.04 g, 80 mmol) in H₂O (ꢂ50 mL) over ca. 10 min.

with the temperature being maintained at less than 15 °C. The

mixture was stirred at <15 °C for 1–2 h, then allowed to warm

slowly to room temperature (the yellow/orange colour rapidly fad-

ing to creamy/colourless) and stirred at room temperature over-

night. The reaction mixture was diluted with H₂O, cooled and

acidiﬁed/neutralised (to pH 3.0–4.0) with dilute HCl, and extracted

with DCM (several portions). The combined DCM extracts were

washed in turn with H₂O and brine, and dried (MgSO₄). Concentra-

tion under reduced pressure afforded crude product as a colourless

or faintly coloured solid that consisted predominantly of product

(P90%) with smaller quantities of both the C@C positional isomer

and the fully reduced product; reported ratios were determined

from the ¹H NMR spectra of crude samples. One or several CC sep-

arations (solvent systems varied for individual compounds) of the

crude material afforded impurity free product but recovery was

rarely, if ever, complete and consequently yields are reported as to-

tal recovered mixture after the ﬁrst separation. Where possible, so-

lid products were recrystallised from either hexane or hexane/

EtOAc to afford pure product as colourless crystals. Fortunately,

incompletely separated mixtures obtained from CC consisting only

of product and fully reduced product could be protected concur-

rently in the subsequent protection step and the unreactive satu-

rated impurity (as its protected derivative) removed during

chromatography of the later dihydroxylation product.

4.3.5. (E)-2⁰-Hydroxy-3-bromo-4,5-dimethoxychalcone (5)

Yellow-orange crystals; yield 37%; mp 131–133 °C; ¹H NMR

(CDCl₃, 300 MHz) d 12.77 (1H, s, OH), 7.93 (1H, dd, J = 1.6, 8.1 Hz,

H-6⁰), 7.79 (1H, d, J = 15.4 Hz, COCH@CH), 7.55 (1H, d, J = 15.4 Hz,

COCH@CH), 7.52 (1H, superimposed m (ddd, J = 1.6, ca. 7.4,

8.4 Hz), H-4⁰), 7.51 (1H, d, J = 2.0 Hz, H-2), 7.09 (1H, d, J = 2.0 Hz,

H-6), 7.04 (1H, dd, J = 1.2, 8.4 Hz, H-3⁰), 6.97 (1H, ddd, J = 1.2, ca.

7.4, 8.1 Hz, H-5⁰), 3.95 (3H, s, OCH₃), 3.92 (3H, s, OCH₃); ¹³C NMR

(CDCl₃, 75.46 MHz) d 193.3, 163.6, 153.9, 148.7, 143.7, 136.5,

131.7, 129.6, 125.1, 120.4, 119.9, 118.9, 118.7, 118.3, 112.0, 60.8,

56.3.

4.3.6. (E)-2⁰-Hydroxy-3,4-methylenedioxychalcone (6)

Yellow crystals (EtOH); yield 62%, mp 139–141 °C; ¹H NMR

(CDCl₃, 300 MHz) d 12.92 (1H, s, OH), 7.92 (1H, dd, J = 1.6, 8.1 Hz,

H-6⁰), 7.90 (1H, d, J = 15.4 Hz, COCH@CH), 7.50 (1H, superimposed

m (ddd, J = 1.6, ca. 7.2, 8.4 Hz), H-4⁰), 7.50 (1H, d, J = 15.4 Hz,

COCH@CH), 7.19 (1H, d, J = 1.6 Hz, H-2), 7.17 (1H, dd, J = 1.6,

8.1 Hz, H-6), 7.03 (1H, dd, J = 1.1, 8.4 Hz, H-3⁰), 6.95 (1H, ddd,

J = 1.1, ca. 7.2, 8.1 Hz, H-5⁰), 6.87 (1H, d, J = 8.1 Hz, H-5), 6.05 (2H,

s, OCH₂O); ¹³C NMR (CDCl₃, 75.46 MHz) d 193.6, 163.6, 150.3,

148.6, 145.3, 136.2, 129.5, 129.2, 125.7, 120.2, 118.8, 118.7,

118.2, 108.8, 106.8, 101.8.

4.3.7. (E)-2⁰-Hydroxy-4-methoxy-4⁰-(phenylmethoxy)chalcone

(7)

Yellow-orange crystals (EtOH); yield 35%; mp 135–136.5 °C; ¹H

NMR (CDCl₃, 300 MHz) d 13.56 (1H, s, OH), 7.87 (1H, d, J = 15.5 Hz,

C@CH-Ar), 7.85 (1H, d, J = 9.7 Hz, H-6), 7.62 (2H, aa⁰bb⁰‘d’,

J = 8.8 Hz, H-2⁰and H-6⁰), 7.46 (1H, d, J = 15.5 Hz, C@CHCO), 7.46–

7.28 (5H, m, 5 ꢁ benzyl Ar-H), 6.95 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰

and H-5⁰), 6.56 (1H, dd, J = 2.5, 9.7 Hz, H-5), 6.56 (1H, d,

J = 2.5 Hz, H-3), 5.11 (2H, s, OCH₂), 3.87 (3H, s, OCH₃); ¹³C NMR

(CDCl₃, 75.45 MHz) d 192.0, 166.6, 165.2, 161.9, 144.3, 136.1,

131.2, 130.4, 128.7, 128.3, 127.7, 127.5, 118.1, 114.6, 114.5,

108.1, 102.3, 70.3, 55.4.

4.3.8. (E)-2⁰-Hydroxy-3,4-dimethoxy-4⁰-

(phenylmethoxy)chalcone (8)

4.4.1. 2-[(2E)-3-(4-Methoxyphenyl)-2-propen-1-yl]phenol (10)

Colourless needles (hexane); yield mixed products 83%, mole

ratio product/positional isomer/saturated 100:5:5; mp 96.5–

97.5 °C [lit mp 98.5–99.5 °C];³⁰¹H NMR (CDCl₃, 300 MHz) d 7.29

(aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰⁰and H-6⁰⁰), 7.16 (1H, superimposed m

(non-resolved dd), H-3), 7.15 (1H, superimposed m (non-resolved

ddd, J = 1.7, 7.5, n/m Hz), H-5), 6.90 (1H, ddd, J = 1.2, 7.5, 7.5 Hz,

H-4), 6.83 (1H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰⁰and H-5⁰⁰), 6.82 (1H, super-

Yellow/orange crystals (EtOH); yield 68%; mp 131–133 °C; ¹H

NMR (CDCl₃, 300 MHz) d 13.55 (1H, s, OH), 7.86 (1H, m, H-6⁰),

7.855 (1H, d, J = 15.3 Hz, CH@CHCO), 7.46–7.32 (5H, m, 5 ꢁ benzyl

Ar-H), 7.44 (1H, d, J = 15.3 Hz, CH@CHCO), 7.25 (1H, dd, J = 2.0,

8.3 Hz, H-6), 7.16 (1H, d, J = 2.0 Hz, H-2), 6.91 (1H, d, J = 8.3 Hz,

H-5), 6.59–6.55 (2H, 2 ꢁ superimposed m, H-3⁰and H-5⁰), 5.12

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

7163

imposed m (dd), H-6), 6.46 (1H, incompletely resolved td, J = ca.

1.1, 15.9 Hz, H-3⁰), 6.24 (1H, td, J = 6.6, 15.9 Hz, H-2⁰), 5.01 (1H, s,

OH), 3.79 (3H, s, OCH₃), 3.54 (2H, dd, J = 1.1, 6.6 Hz, CH₂-1⁰); ¹³C

NMR (CDCl₃, 75.46 MHz) d 159.2, 154.2, 131.1, 130.5, 130.1,

127.9, 127.4, 126.0, 125.7, 121.0, 115.9, 114.1, 55.3, 34.1.

94 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.16 (1H, unresolved superim-

posed m, H-3), 7.15 (1H, unresolved superimposed m (ddd,

J = 1.8, ca. 7.6, n/m Hz), H-5), 6.90 (1H, superimposed m (ddd,

J = ca. 1.2, n/m, n/m Hz), H-4), 6.90 (1H, superimposed m (d,

J = 1.6 Hz), H-2⁰⁰), 6.82 (1H, dm, H-6), 6.78 (1H, dd, J = 1.6, 8.0 Hz,

H-6⁰⁰), 6.73 (1H, dd, J = 60.5, 8.0 Hz, H-5⁰⁰), 6.42 (1H, td, J = ca. 1.0,

15.9, Hz, H-3⁰), 6.21 (1H, td, J = 6.6, 15.9 Hz, H-2⁰), 5.94 (2H, s,

OCH₂O), 4.98 (1H, s, OH), 3.54 (2H, dd, J = 1.0, 6.6 Hz, CH₂-1⁰); ¹³C

NMR (CDCl₃, 75.46 MHz) d 154.1, 148.0, 147.0, 131.7, 131.1,

130.5, 127.9, 126.2, 125.8, 121.0, 120.7, 115.8, 108.3, 105.7,

101.0, 34.0. n/m not measurable.

4.4.2. 2-[(E)-3-(3,4-Dimethoxyphenyl)-2-propen-1-yl]phenol

(11)

Colourless solid (hexane/EtOAc); yield 83%, mole ratio product/

positional isomer/saturated 100:4:5; ¹H NMR (CDCl₃, 300 MHz); d

7.18 (1H, superimposed m (dd, J = 1.7, ca. 7.4 Hz), H-3), 7.16 (1H,

superimposed m (ddd, J = 1.7, 7.4, 8.1 Hz), H-5), 6.91 (1H, superim-

posed m (ddd, J = 1.2, ca. 7.4, ca. 7.4 Hz), H-4), 6.91 (1H, superim-

posed m (d, J = 2.0 Hz), H-2⁰⁰), 6.89 (1H, superimposed m (dd,

J = 2.0, 8.1 Hz), H-6⁰⁰), 6.83 (1H, dd, J = 1.2, 8.1 Hz, H-6), 6.79 (1H,

d, J = 8.1 Hz, H-5⁰⁰), 6.46 (1H, td, J = ca. 1.1 15.7, Hz, H-3⁰), 6.25

(1H, td, J = 6.5, 15.7 Hz, H-2⁰), 5.04 (1H, s, OH), 3.88 (3.876) (3H,

s, OCH₃), 3.87(3.872) (3H, s, OCH₃), 3.56 (2H, dd, J = 1.1, 6.5 Hz,

CH₂-1⁰); ¹³C NMR (CDCl₃, 75.46 MHz) d 154.2, 149.3, 148.8, 131.2,

130.53, 130.47, 127.9, 126.1, 126.0, 121.0, 119.4, 115.8, 111.6,

109.2, 56.0, 55.9, 34.0.

4.4.7. 2-[(E)-3-(4-Methoxyphenyl)-2-propen-1-yl]-5-(phenyl-

methoxy)phenol (16)

Off-white solid (hexane/EtOAc); yield mixed products 83% mole

ratio product/positional isomer/saturated 100:2:8; mp 101–

103 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.45–7.30 (5H, m, 5 ꢁ benzyl

Ar-H), 7.28 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰⁰and H-6⁰⁰), 7.04 (1H, d,

J = 8.3 Hz, H-3), 6.83 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰⁰and H-5⁰⁰),

6.54 (1H, dd, J = 2.5, 8.3 Hz, H-4), 6.50 (1H, d, J = 2.5 Hz, H-6),

6.45 (1H, td, J = 1.1, 15.8 Hz, H-3⁰), 6.21 (1H, td, J = 6.5, 15.8 Hz,

H-2⁰), 5.06 (1H, s, OH), 5.03 (2H, s, OCH₂), 3.80 (3H, s, OCH₃), 3.48

(2H, dd, J = 1.1, 6.5 Hz, CH₂-1⁰); ¹³C NMR (CDCl₃, 75.45 MHz) d

159.1, 158.9, 155.1, 137.1, 130.88, 130.85, 130.0, 128.6, 127.9,

127.5, 127.4, 126.0, 118.3, 114.0, 107.3, 103.1, 70.2, 55.3, 33.6.

4.4.3. 2-[(E)-3-(4-Methoxyphenyl)-2-propen-1-yl)-4-

methoxyphenol (12)

Colourless oil; yield 90%, mole ratio product/positional isomer/

saturated 100:5:5; ¹H NMR (CDCl₃, 300 MHz) d 7.29 (2H, aa⁰bb⁰‘d’,

J = 8.8 Hz, H-2⁰⁰and H-6⁰⁰), 6.83 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰⁰and

H-5⁰⁰), 6.76 (1H, ‘d’ (unresolved dd), J = 8.5 Hz, H-6), 6.74 (1H, ‘d’

(unresolved dd, J = 2.9 Hz, H-3), 6.69 (1H, dd, J = 2.9, 8.5 Hz, H-5),

6.45 (1H, td, J = ca. 1.3, 15.8 Hz, H-3⁰), 6.22 (1H, td, J = 6.5,

15.8 Hz, H-2⁰), 4.70 (1H, br s, OH), 3.80 (3H, s, OCH₃), 3.76 (3H, s,

OCH₃), 3.03 (2H, dd, J = 1.3, 6.5 Hz, CH₂-1⁰); ¹³C NMR (CDCl₃,

75.46 MHz) d 159.1, 154.0, 148.1, 131.1, 130.1, 127.4, 127.2,

125.5, 116.5, 116.1, 114.1, 112.7, 55.8, 55.3, 34.3.

4.4.8. 2-[(E)-3-(3,4-Dimethoxyphenyl)-2-propen-1-yl]-5-

(phenylmethoxy)phenol (17)

Colourless solid; yield 80%, mole ratio product/positional

isomer/saturated 100:5:5; mp 124–125 °C; ¹H NMR (CDCl₃,

300 MHz);

d 7.45–7.29 (5H, m, benzyl Ar-H). 7.06 (1H, d,

J = 8.3 Hz, H-3), 6.90 (1H, d, J = 1.9 Hz, H-2⁰⁰), 6.89 (1H, dd, J = 1.9,

8.0 Hz, H-6⁰⁰), 6.79 (1H, d, J = 8.0 Hz, H-5⁰⁰), 6.55 (1H, dd, J = 2.5,

8.3 Hz, H-4), 6.51 (1H, d, J = 2.5 Hz, H-6), 6.44 (1H, td, J = ca. 1.1,

15.8 Hz, H-3⁰), 6.22 (1H, td, J = 6.5, 15.8 Hz, H-2⁰), 5.12 (1H, s,

OH), 5.03 (2H, s, OCH₂), 3.88 (3.875) (3H, s, OCH₃), 3.87 (3.870)

(3H, s, OCH₃), 3.56 (2H, dd, J = 1.1, 6.5 Hz, CH₂-1⁰); ¹³C NMR (CDCl₃,

75.46 MHz) d 158.9, 155.1, 149.2, 148.8, 137.2, 131.1, 130.9, 130.4,

128.6, 127.9, 127.4, 126.4, 119.4, 118.3, 111.5, 109.1, 107.4, 103.2,

70.2, 56.0, 55.9, 33.5.

4.4.4. 2-[(E)-3-(3,4-Dimethoxyphenyl)-2-propen-1-yl]-4-

methylphenol (13)

Colourless solid; yield mixed products 82%, mole ratio product/

positional isomer/saturated 100:4:4; mp 121–123 °C; ¹H NMR

(CDCl₃, 300 MHz) d 6.98 [1H, superimposed m (d, J = ca. 2.1 Hz),

H-3], 6.95 [1H, superimposed m (dd, J = 2.1, 8.0 Hz), H-5]. 6.91

(1H, superimposed m (d, J = ca. 1.9 Hz), H-2⁰⁰], 6.89 (1H, dd,

J = 1.9, 8.0 Hz, H-6⁰⁰), 6.80 (1H, d, J = 8.0 Hz, H-5⁰⁰), 6.73 (1H, d,

J = 8.0 Hz, H-6), 6.45 (1H, td, J = ca. 1.0, 15.7 Hz, H-3⁰), 6.24 (1H,

td, J = 6.5, 15.7 Hz, H-2⁰), 4.88 (1H, s, OH), 3.87 (3.874) (3H, s,

OCH₃), 3.87 (3.870) (3H, s, OCH₃), 3.52 (2H, dd, J = 1.0, 6.5 Hz,

CH₂-1⁰), 2.27 (1H, s, ArCH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 151.9,

149.1, 148.7, 131.03, 130.99, 130.4, 130.1, 128.2, 126.2, 125.6,

119.3, 115.7, 111.3, 108.9, 56.0, 55.9, 34.1, 20.5.

4.4.9. 2-[(E)-3-[(4-Phenylmethoxy)phenyl]-2-propen-1-

yl]phenol (18)

Off-white solid (hexane/EtOAc); yield mixed products 84% mole

ratio product/positional isomer/saturated 100:2:6; 92–93.5 °C; ¹H

NMR (CDCl₃, 300 MHz) d 7.44–7.30 (5H, m, 5 ꢁ benzyl Ar-H),

7.28 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰⁰and H-6⁰⁰), 7.16 (1H, d (or super-

imposed, non-resolved dd), J = ca. 7.5 Hz, H-3), 7.14 (1H, superim-

posed m (ddd, J = ca. 1.5, ca. 7.5, ca. 7.8 Hz), H-5), 6.90 (2H, aa⁰bb⁰

‘d’, J = 8.8 Hz, H-3⁰⁰and H-5⁰⁰), 6.90 (1H, superimposed m (ddd,

J = 1.2, 7.5, 7.5 Hz), H-4), 6.82 (1H, dm, J = ca. 7.8 Hz, H-6), 6.46

(1H, td, J = 1.0, 15.9 Hz, H-3⁰), 6.24 (1H, td, J = 6.6, 15.9 Hz, H-2⁰),

5.05 (2H, s, OCH₂) 4.99 (1H, s, OH), 3.54 (2H, dd, J = 1.0, 6.6 Hz,

CH₂-1⁰), ¹³C NMR (CDCl₃, 75.45 MHz): d 158.3, 154.1, 137.0,

131.0, 130.4, 130.3, 128.6, 128.0, 127.9, 127.5, 127.4, 125.9,

125.8, 121.0, 115.8, 115.0, 70.1, 34.1.

4.4.5. 2-[(E)-3-(3-Bromo-4,5-dimethoxyphenyl)-2-propen-1-

yl]phenol (14)

Colourless oil; mole ratio product/positional isomer/saturated

100:5:5 ¹H NMR (CDCl₃, 300 MHz) d 7.18–7.12 (3H, 3 ꢁ superim-

posed m, unassigned H-3, H-5 and H-2⁰⁰), 6.91 (1H, ddd, J = 1.2,

7.5, ca. 8.2 Hz, H-4), 6.82 (1H, d, J = 2.0 Hz, H-6⁰⁰), 6.81 (1H, dd,

J = 1.2, 8.0 Hz, H-6), 6.40–6.25 (2H, m, H-3⁰and H-2⁰), 4.97 (1H,

br s, OH), 3.86 (3H, s, OCH₃), 3.84 (3H, s, OCH₃), 3.55 (2H, d,

J = 4.8 Hz, CH₂-1⁰); ¹³C NMR (CDCl₃, 75.46 MHz) d 153.9, 153.6,

145.7, 134.6, 130.5, 129.6, 129.0, 127.9, 125.6, 122.6, 121.0,

117.8, 115.7, 109.4, 60.7, 56.1, 33.8.

4.5. General procedure for the preparation of MOM protected

propenes (19–27)

Di-isopropylethylamine (5 mL, 29 mmol) was added dropwise

with stirring to a solution of the appropriate MOM-protected

unsaturated precursor (12.5 mmol) in anhydrous THF (ca.

25 mL) under N₂at room temperature and the resulting solution

was stirred at this temperature for 15–20 min. A solution of

MOM-Cl (1.85 mL, 24.3 mmol) in anhydrous THF (5 mL) was

4.4.6. 2-[(2E)-3-(4-Methylenedioxyphenyl)-2-propen-1-

yl]phenol (15)

Colourless needles (hexane/EtOAc); yield mixed products 88%

mole ratio product/positional isomer/saturated 100:5:5; mp 93–

7164

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

then added dropwise at room temperature under N₂and the

solution stirred at room temperature for 1 h, then reﬂuxed for

P4 d. The reaction mixture was cooled and concentrated under

reduced pressure. The residue was partitioned between H₂O (ca.

75 mL) and DCM (50 mL) and the aq layer extracted further with

DCM (3 ꢁ 25 mL). The combined DCM extracts were washed in

turn with H₂O and brine, and dried (MgSO₄). Concentration gave

a tan, viscous oil. Puriﬁcation of the crude product by short col-

umn vacuum chromatography (hexane/DCM mixtures with the

polarity later increased to speed elution) afforded the desired

compound as a colourless oil or occasionally as a colourless

solid.

4.5.5. 1-(Methoxymethoxy)-2-[(E)-3-(3-bromo-4,5-dimethoxy-

phenyl)-2-propen-1-yl]benzene (23)

Colourless oil; yield 88%; ¹H NMR (CDCl₃, 300 MHz) d 7.20 (1H,

unresolved superimposed m (ddd), H-5), 7.19 (1H, unresolved

superimposed m (dd), H-3), 7.11 (1H, d, J = 2.0 Hz, H-2⁰⁰), 7.10

(1H, superimposed dm, J = ca. 8.0 Hz, H-6), 6.98 (1H, ddd, J = 1.2,

7.4, 8.0 Hz, H-4), 6.81 (1H, d, J = 2.0 Hz, H-6⁰⁰), 6.39–6.25 (2H, m,

H-3⁰and H-2⁰), 5.19 (2H, s, OCH₂O), 3.85 (3H, s, OCH₃), 3.83 (3H,

s, OCH₃), 3.55 (2H, m, CH₂-1⁰), 3.48 (3H, s, CH₂OCH₃); ¹³C NMR

(CDCl₃, 75.45 MHz) d 155.0, 153.6, 145.6, 135.1, 130.2, 129.8,

129.1, 128.9, 127.6, 122.5, 121.9, 117.7, 114.1, 109.3, 94.5, 60.6,

56.1, 56.1, 33.5.

4.5.1. 1-(Methoxymethoxy)-2-[(E)-3-(4-methoxyphenyl)-2-

propen-1-yl]benzene (19)

4.5.6. 1-(Methoxymethoxy)-2-[(E)-3-(3,4-methylenedioxy-

phenyl)-2-propen-1-yl]benzene (24)

Colourless oil; yield 92–99%; ¹H NMR (CDCl₃, 300 MHz) d 7.27

(2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰⁰and H-6⁰⁰), 7.20 (1H, unresolved

superimposed dd, H-3) 7.19 (1H, unresolved superimposed ddd,

H-5), 7.08 (1H, dd, J = ca. 1.2, 8.2 Hz, H-6), 6.96 (1H, ddd, J = ca.

1.2, 7.3, 7.3 Hz, H-4), 6.82 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰⁰and H-

5⁰⁰), 6.37 (1H, d (unresolved t of d), J = 15.8 Hz, H-3⁰), 6.23 (1H, td,

J = 6.6, 15.8 Hz, H-2⁰), 5.22 (2H, s, OCH₂O), 3.79 (3H, s, ArOCH₃);

3.54 (2H, d, J = 6.6 Hz, H-1⁰), 3.48 (3H, s, CH₂OCH₃); ¹³C NMR

(CDCl₃, 75.45 MHz): d 158.9, 155.1, 130.7, 130.2, 130.1, 129.7,

127.4, 127.2, 126.8, 121.9, 114.2, 114.0, 94.6, 56.1, 55.3, 33.5.

Colourless, viscous oil; yield 97%; ¹H NMR (CDCl₃, 300 MHz) d

7.20 (1H, superimposed m (dd, J = 1.7, ca. 7.4 Hz), H-3), 7.19 (1H,

superimposed m (ddd, J = 1.7, ca. 7.4, ca. 8.3 Hz), H-5], 7.09 (1H,

dd, J = 1.2, 8.3 Hz, H-6), 6.96 (1H, ddd, J = 1.2, 7.4, 7.4 Hz, H-4),

6.90 (1H, d, J = 1.5 Hz, H-2⁰⁰), 6.76 (1H, dd, J = 1.5, 8.0 Hz, H-6⁰⁰),

6.72 (1H, d, J = 8.0 Hz, H-5⁰⁰), 6.34 (1H, d (unresolved t of d),

J = 15.8 Hz, H-3⁰), 6.20 (1H, td, J = 6.5, 15.8 Hz, H-2⁰), 5.93 (2H, s,

OCH₂O), 5.23 (2H, s, OCH₂OCH₃), 3.53 (2H, d, J = 6.5 Hz, CH₂-1⁰),

3.48 (3H, s, CH₂OCH₃); ¹³C NMR (CDCl₃, 75.45 MHz): d 155.0,

148.0, 146.7, 132.4, 130.4, 130.1, 129.5, 127.5, 127.2, 121.9,

120.4, 114.2, 108.2, 105.6, 100.9, 94.5, 56.1, 33.5.

4.5.2. 1-(Methoxymethoxy)-2-[(E)-3-(3,4-dimethoxyphenyl)-2-

propen-1-yl]benzene (20)

4.5.7. 1-(Methoxymethoxy)-2-[(E)-3-(4-methoxyphenyl)-2-

propen-1-yl]-5-(phenylmethoxy)benzene (25)

Colourless oil; yield 94%; ¹H NMR (CDCl₃, 300 MHz) d 7.23 (1H,

superimposed m (dd, J = 1.7, 7.4 Hz), H-3), 7.20 (1H, ddd, J = 1.7,

7.4, 8.3 Hz, H-5), 7.09 (1H, dd, J = 1.2, 8.3 Hz, H-6), 6.97 (1H, ddd,

J = 1.2, 7.4, 7.4 Hz, H-4), 6.90 (1H, d, J = 1.9 Hz, H-2⁰⁰), 6.87 (1H,

dd, J = 1.9, 8.2 Hz, H-6⁰⁰), 6.79 (1H, d, J = 8.2 Hz, H-5⁰⁰), 6.37 (1H, d

(probably d of unresolved t), J = 15.8 Hz, H-3⁰), 6.24 (1H, td,

J = 6.4, 15.8 Hz, H-2⁰), 5.23 (2H, s, OCH₂O), 3.88 (3H, s, OCH₃),

3.87 (3H, s, OCH₃), 3.55 (2H, d, J = 6.4 Hz, CH₂-1⁰), 3.48 (3H, s,

CH₂OCH₃); ¹³C NMR (CDCl₃, 75.45 MHz): d 155.1, 149.2, 148.6,

131.1, 130.5, 130.2, 129.7, 127.5, 127.1, 121.9, 119.1, 114.3,

111.6, 109.1, 94.6, 56.1, 56.0, 55.9, 33.5.

Colourless, extremely viscous oil; yield 88%; ¹H NMR (CDCl₃,

300 MHz) d 7.46–7.29 (5H, m, 5 ꢁ benzyl Ar-H), 7.27 (2H, aa⁰bb⁰

‘d’, J = 8.8 Hz, H-2⁰⁰and H-6⁰⁰), 7.09 (1H, d, J = 8.3 Hz, H-3), 6.82

(2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰⁰and H-5⁰⁰), 6.79 (1H, d, J = 2.5 Hz,

H-6), 6.58 (1H, dd, J = 2.5, 8.4 Hz, H-4), 6.34 (1H, d, J = 15.8 Hz, H-

3⁰), 6.21 (1H, dt, J = 15.8, 6.5 Hz, H-2⁰), 5.19 (2H, s, OCH₂O), 5.03

(2H, s, OCH₂Ar), 3.79 (3H, s, OCH₃), 3.46 (3H, s, CH₂OCH₃), 3.46

(2H, broadened d, J = 6.5 Hz, CH₂-1⁰); ¹³C NMR (CDCl₃,

75.45 MHz) d 158.8, 158.5, 155.8, 137.2, 130.7, 130.3, 129.9,

128.6, 127.9, 127.6, 127.1, 127.1, 122.2, 114.0, 107.2, 102.5, 94.6,

70.2, 56.1, 55.3, 33.0.

4.5.3. 1-(Methoxymethoxy)-2-[(E)-3-(4-methoxyphenyl)-2-

propen-1-yl]-4-methoxybenzene (21)

4.5.8. 1-(Methoxymethoxy)-2-[(E)-3-(3,4-dimethoxyphenyl)-2-

propen-1-yl]-5-(phenylmethoxy)benzene (26)

Colourless, viscous oil; yield 90%; ¹H NMR (CDCl₃, 300 MHz) d

7.28 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰⁰and H-6⁰⁰), 7.02 (1H, d,

J = 8.9 Hz, H-6), 6.82 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰⁰and H-5⁰⁰),

6.78 (1H, d, J = 3.1 Hz, H-3), 6.70 (1H, dd, J = 3.1, 8.9 Hz, H-5),

6.38 (1H, d (d of unresolved t), J = 15.8, Hz, H-3⁰), 6.21 (1H, td,

J = 6.7, 15.8 Hz, H-2⁰), 5.13 (2H, s, OCH₂O), 3.78 (3H, s, OCH₃),

3.74 (3H, s, OCH₃), 3.51 (2H, (d)d, J = (ca. 0.7), 6.4 Hz, CH₂-1⁰),

3.47 (3H, s, CH₂OCH₃); ¹³C NMR (CDCl₃, 75.45 MHz): d 158.9,

154.7, 149.3, 131.3, 130.6, 130.4, 127.2, 126.5, 116.1 115.9, 114.0,

111.8, 95.6, 56.0, 55.7, 55.3, 33.7.

Colourless oil; yield 93%; ¹H NMR (CDCl₃, 300 MHz) d 7.46–7.29

(5H, m, 5 ꢁ benzyl Ar-H), 7.10 (1H, d, J = 8.3 Hz, H-3), 6.90 (1H, d,

J = 1.9 Hz, H-2⁰⁰), 6.87 (1H, dd, J = 1.9, 8.2 Hz, H-6⁰⁰), 6.80 (1H, d,

J = 2.5 Hz, H-6), 6.78 (1H, d, J = 8.2 Hz, H-5⁰⁰), 6.59 (1H, dd, J = 2.5,

8.3 Hz, H-4), 6.34 (1H, d (unresolved td), J = 15.7 Hz, H-3⁰), 6.21

(1H, td, J = 6.4, 15.7 Hz, H-2⁰), 5.19 (2H, s, OCH₂O), 5.04 (2H, s,

OCH₂Ph), 3.88 (3H, s, OCH₃), 3.87 (3H, s, OCH₃), 3.48 (2H, d (unre-

solved dd), J = 6.4 Hz, CH₂-1⁰), 3.47 (3H, s, CH₂OCH₃); ¹³C NMR

(CDCl₃, 75.45 MHz): d 158.6, 155.9, 149.2, 148.5, 137.2, 131.2,

130.4, 130.1, 128.5, 127.9, 127.54, 127.49, 122.1, 119.1, 111.5,

109.1, 107.4, 102.6, 94.7, 70.3, 56.06, 56.03, 55.91, 32.9.

4.5.4. 1-(Methoxymethoxy)-2-[(E)-3-(3,4-dimethoxyphenyl)-2-

propen-1-yl]-4-methylbenzene (22)

Colourless oil; yield 98%; ¹H NMR (CDCl₃, 300 MHz) d 6.98 (1H,

superimposed m (d, J = ca. 2.1 Hz), H-3), 6.95 (1H, superimposed m

(dd, J = 2.1, 8.0 Hz), H-5). 6.91 (1H, superimposed m (d, J = ca.

2.1 Hz), H-2⁰⁰), 6.89 (1H, dd, J = 1.9, 8.0 Hz, H-6⁰⁰), 6.80 (1H,

J = 8.0 Hz, H-5⁰⁰), 6.73 (1H, d, J = 8.0 Hz, H-6), 6.45 (1H, td, J = ca.

1.0, 15.7 Hz, H-3⁰), 6.24 (1H, td, J = 6.5, 15.7 Hz, H-2⁰), 4.88 (1H, s,

OH), 3.87 (3.874) (3H, s, OCH₃), 3.87 (3.870) (3H, s, OCH₃), 3.52

(2H, dd, J = 1.0, 6.5 Hz, CH₂-1⁰), 2.27 (1H, s, ArCH₃); ¹³C NMR (CDCl₃,

75.46 MHz) d 151.9, 149.1, 148.7, 131.03, 130.99, 130.4, 130.1,

128.2, 126.2, 125.6, 119.3, 115.7, 111.3, 108.9, 56.0, 55.9, 34.1,

20.5.

4.5.9. 1-(Methoxymethoxy)-2-[(E)-3-[4-(phenylmethoxy)-

phenyl]-2-propen-1-yl]benzene (27)

Colourless solid; yield 93%; mp 67–68 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.45–7.30 (5H, m, 5 ꢁ benzyl Ar-H), 7.27 (2H, aa⁰bb⁰

‘d’, J = 8.8 Hz, H-2⁰⁰and H-6⁰⁰), 7.20 (1H, unresolved superimposed

m (dd), H-6) 7.18 (1H, unresolved superimposed m (ddd), H-4),

7.08 (1H, dd, J = ca. 1.0, 8.2 Hz, H-3), 6.96 (1H, ddd, J = ca. 1.0, 7.3,

7.3 Hz, H-5), 6.89 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰⁰and H-5⁰⁰), 6.37

(1H, d (unresolved t of d), J = 15.8 Hz, H-3⁰), 6.24 (1H, td, J = 6.6,

15.8 Hz, H-2⁰), 5.22 (2H, s, OCH₂O), 5.05 (2H, s, OCH₂Ph), 3.54

(2H, d, J = 6.6 Hz, H-1⁰), 3.48 (3H, s, OCH₃); ¹³C NMR (CDCl₃,

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

7165

75.45 MHz): d 158.0, 155.0, 137.1, 130.9, 130.2, 130.1, 129.7, 128.6,

4.6.3. (1R,2R)-syn-1-(3,4-Dimethoxyphenyl)-3-[2-(methoxy-

127.9, 127.45, 127.41, 127.2, 126.9, 121.8, 115.0, 114.1, 94.5, 70.1,

56.1, 33.5.

methoxy)phenyl]propan-1,2-diol (29a)

Colourless solid; yield 94%; mp 130–132 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.20 (1H, ddd, J = 1.8, 7.3, 8.2 Hz, H-4⁰⁰), 7.12 (1H, dd,

J = 1.8, 7.5 Hz, H-6⁰⁰), 7.06 (1H, dd, J = 1.2, 8.2 Hz, H-3⁰⁰), 6.96 (1H,

superimposed m (ddd, J = 1.2, 7.3, 7.5 Hz), H-5⁰⁰), 6.96 (1H, super-

imposed m (d, J = 2.0 Hz), H-2⁰), 6.93 (1H, dd, J = 2.0, 8.0 Hz, H-6⁰),

6.86 (1H, d, J = 8.0 Hz, H-5⁰), 5.16 (2H, s, OCH₂O), 4.48 (1H, dd

(when coupled to OH), J = 2.9, 6.2 Hz, H-1), 3.96 (1H, sym m (dddd

(when coupled to OH), J = 4.2, 4.4, 6.2, 8.6 Hz), H-2), 3.90 (3H, s,

OCH₃), 3.89 (3H, s, OCH₃), 3.43 (3H, s, CH₂OCH₃), 3.07 (1H, d,

J = 2.9 Hz, ArCH(OH)), 2.82 (1H, dd, J = 4.2, 13.7 Hz, H-3a), 2.72

(1H, dd, J = 8.6, 13.7 Hz, H-3b), 2.63 (1H, d, J = 4.4 Hz, CH₂CH(OH));

¹³C NMR (CDCl₃, 75.45 MHz) d 155.3, 149.3, 149.0, 133.8, 131.4,

128.0, 127.4, 122.1, 119.5, 114.4, 111.4, 110.5, 94.9, 76.9, 76.1,

56.2, 56.04, 56.02, 34.6.

4.6. General procedure for the asymmetric dihydroxylation of

the MOM-protected propenes (19–27)

AD-mix-b or AD-mix-a (11.2 g) in t-BuOH (40 mL) and H₂O

(40 mL) was vigorously stirred at room temperature to give a

2-phase mixture. MeSO₂NH₂(760 mg, ca. 8 mmol) was added

at room temperature to the stirred mixture and stirring contin-

ued for ca. 5 min. At this stage the mixture was cooled to 0 °C

and treated with a solution of the appropriate propene (15–21)

(8 mmol) in acetone (ca. 4–5 mL) in one portion. The viscous

reaction mixture was stirred vigorously at 0 °C for P8 h then

at 2–4 °C (cold room) for ca. 72 h (longer in the case of highly

substituted ene compounds). Na₂SO₃(12 g) was then added,

the mixture allowed to warm to room temperature, and ﬁnally

stirred at rt for P30 min. EtOAc (P60 mL) was added (extra

H₂O may also required to dissolve all inorganics) and the organic

layer separated. The aqueous phase was extracted further with

EtOAc (3 ꢁ ca. 60 mL), the combined organic extracts washed

in turn with H₂O and brine, and dried (MgSO₄). The solvent

was removed in vacuo to afford crude product (22–28) as either

a colourless/pale yellow solid or a viscous oil. The crude product

was puriﬁed by short column vacuum chromatography (eluting

with DCM/EtOAc mixtures) followed, where possible with solid

products, by recrystallisation from hexane/EtOAc. In some cases,

4.6.4. (1S,2S)-syn-1-(3,4-Dimethoxyphenyl)-3-[2-(methoxy-

methoxy)phenyl]propan-1,2-diol (29b)

Colourless solid; yield 91%; mp 130–131 °C; NMR spectra corre-

spond to those reported above for the (1R,2R)-enantiomer (29a).

4.6.5. (1R,2R)-syn-1-(4-Methoxyphenyl)-3-[2-(methoxy-

methoxy)-5-methoxyphenyl]propan-1,2-diol (30a)

Colourless, viscous oil; yield 85%; ¹H NMR (CDCl₃, 300 MHz) d

7.32 (2H, aa⁰bb⁰‘d’, J = 8.6 Hz, H-2⁰and H-6⁰), 7.00 (1H, d,

J = 8.8 Hz, H-3⁰⁰), 6.90 (2H, aa⁰bb⁰‘d’, J = 8.6 Hz, H-3⁰and H-5⁰)

6.71 (1H, dd, J = 3.1, 8.8 Hz, H-4⁰⁰), 6.67 (1H, d, J = 3.1 Hz, H-6⁰⁰),

5.07 (2H, s, OCH₂O), 4.48 (1H, d, J = 6.5 Hz, H-1), 3.94 (1H, sym m

(ddd, J = 4.4, 6.5, 8.5 Hz), H-2), 3.81 (3H, s, OCH₃), 3.74 (3H, s,

OCH₃), 3.42 (3H, s, CH₂OCH₃), 3.01 (1H, br s, OH), 2.75 (1H, dd,

J = 4.4, 13.7 Hz, H-3a), 2.67 (1H, dd, J = 8.5, 13.7 Hz, H-3b), 1.64

(1H, br s, OH); ¹³C NMR (CDCl₃, 75.45 MHz): d 159.5, 154.8,

149.5, 133.2, 129.0, 128.2, 117.1, 116.0, 113.9, 112.5, 95.7, 76.7,

76.2, 56.1, 55.7, 55.3, 34.7.

a

small quantity of hydroxyketone eluted prior to the diol

product.

4.6.1. (1R,2R)-syn-1-(4-Methoxyphenyl)-3-[2-(methoxyme-

thoxy)phenyl]propan-1,2-diol (28a)

Colourless oil; yield 92%; ¹H NMR (CDCl₃, 300 MHz) d 7.32

(2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 7.19 (1H, ddd, J = 1.8,

7.5, 8.2 Hz, H-4⁰⁰), 7.12 (1H, dd, J = 1.8, 7.5 Hz, H-6⁰⁰), 7.06 (1H,

dd, J = 1.2, 8.2 Hz, H-3⁰⁰), 6.95 (1H, ddd as apparent ‘dt’, J = 1.2,

7.5, 7.5 Hz, H-5⁰⁰), 6.90 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and H-5⁰),

ca. 5.15 and 5.14 merging to non-resolved br central peak (each

1H, each d of AB system, J = 6.7 Hz, OCH₂O), 4.48 (1H, dm,

J = 6.5 Hz, H-1), 3.95 (1H, sym m (unresolved dddd), H-2), 3.81

(3H, s, OCH₃), 3.42 (3H, s, CH₂OCH₃), 3.02 (1H, d, J = ca. 2.5 Hz,

ArCH(OH)), 2.79 (1H, dd, J = 4.0, 13.8 Hz, CH₂-3a), 2.69 (1H, dd,

J = 8.8, 13.8 Hz, CH₂-3b), 2.62 (1H, d, J = 4.3 Hz, CH(OH)); ¹³C

NMR (CDCl₃, 75.46 MHz) d 159.4, 155.2, 133.1, 131.4, 128.2,

127.9, 127.5, 122.1, 114.2, 114.0, 94.6, 76.7, 76.1, 56.2, 55.3,

34.4.

4.6.6. (1R,2R)-syn-1-(3,4-dimethoxyphenyl)-3-[2-

(methoxymethoxy)-5-methylphenyl]-propan-1,2-diol (31a)

Colourless solid; yield 91%; mp 112.5–114 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.01–6.90 (5H, 5 ꢁ superimposed m, unassigned H-

3⁰⁰, H-4⁰⁰, H-6⁰⁰, H-2⁰and H-6⁰), 6.86 (1H, d, J = 8.0 Hz, H-5⁰), 5.13

(2H, s, OCH₂), 4.48 (1H, d, J = 6.4 Hz, H-1), 3.94 (1H, sym m (dddd,

J = 4.6, 6.4, 6.2, 8.4 Hz, H-2], 3.90 (3H, s, OCH₃), 3.89 (3H, s, OCH₃),

3.42 (3H, s, CH₂OCH₃), 3.12 (1H, br s, ArCH(OH)), 2.77 (1H, dd,

J = 4.6, 13.7 Hz, H-3a), 2.69 (1H, dd, J = 8.4, 13.7 Hz, H-3b), 2.69

(1H, br s, CH₂CH(OH)), 2.26 (3H, s, Ar-CH₃); ¹³C NMR (CDCl₃,

75.45 MHz) d 153.1, 149.1, 148.9, 133.7, 132.0, 131.5, 128.3,

127.1, 119.5, 114.4, 111.2, 110.3, 95.0, 76.9, 76.2, 56.2, 55.99,

55.96, 34.5, 20.5.

4.6.2. (1S,2S)-syn-1-(4-Methoxyphenyl)-3-[2-(methoxymeth-

oxy)phenyl]propan-1,2-diol (22b) and (2S)-1-(4-methoxy-

phenyl)-2-hydroxy-3-[2-(methoxymethoxy)phenyl]propan-1-

one diol (28b)

Oil; yield 91%; NMR spectra of (28b) correspond to those re-

ported above for the (1R,2R)-enantiomer (28a).

4.6.7. (1S,2S)-syn-1-(3,4-Dimethoxyphenyl)-3-[2-(methoxy-

methoxy)-5-methylphenyl]-propan-1,2-diol (31b)

Colourless solid; yield 88%; mp 112–114 °C; NMR spectra of

(31b) correspond to those reported above for the (1R,2R)-enantio-

mer (31a).

2-Hydroxypropan-1-one: colourless solid, yield 5%; ¹H NMR

(CDCl₃, 300 MHz) d 8.09 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰),

7.22 (1H, superimposed m (unresolved dm, J = ca. 7.5 Hz), H-6⁰⁰),

7.21 (1H, superimposed m (ddd, J = 1.6, 7.5, n/d), H-4⁰⁰), 7.06 (1H,

dm, J = ca. 8.1 Hz, H-3⁰⁰), 6.97 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and

H-5⁰), 6.96 (1H, superimposed m (ddd), H-5⁰⁰), 5.30 (1H, ddd,

J = 3.4, 7.2, 8.9 Hz, H-2), 5.22 and 5.17 (each 1H, each d of AB sys-

tem, J = 6.6 Hz, OCH₂O), 3.90 (3H, s, OCH₃), 3.73 (1H, d, J = 7.2 Hz,

OH), 3.48 (3H, s, CH₂OCH₃), 3.35 (1H, dd, J = 3.4, 13.6 Hz, H-3a),

2.65 (1H, dd, J = 8.9, 13.6 Hz, H-3b); ¹³C NMR (CDCl₃, 75.46 MHz)

d 199.8, 164.2, 155.2, 131.9, 131.2, 128.1, 126.9, 126.5, 121.8,

114.0, 113.7, 94.7, 72.5, 56.2, 55.5, 38.1.

4.6.8. (1R,2R)-syn-1-(3-Bromo-4,5-dimethoxyphenyl)-3-[2-

(methoxymethoxy)phenyl]propan-1,2-diol (32a)

Colourless, viscous gum; yield 93%; ¹H NMR (CDCl₃, 300 MHz) d

7.21 (1H, ddd, J = 1.8, 7.4, 8.3 Hz, H-4⁰⁰), 7.15 (1H, d, J = 1.9 Hz, H-2⁰),

7.15 (1H, dd, J = 1.8, 7.4 Hz, H-6⁰⁰), 7.08 (1H, dd, J = 1.1, 8.3 Hz, H-

3⁰⁰), 6.97 (1H, ddd, J = 1.1, 7.4, 7.4 Hz, H-5⁰⁰), 6.92 (1H, d,

J = 1.9 Hz, H-6⁰), 5.18 (2H, s, OCH₂), 4.45 (1H, d, J = 5.9 Hz, H-1),

3.95 (1H, sym m (ddd, J = 4.5, 5.9, 8.5 Hz), H-2), 3.88 (3H, s,

OCH₃), 3.85 (3H, s, OCH₃), 3.45 (3H, s, CH₂OCH₃), 3.14 (1H, br s,

ArCH(OH)), 2.86 (1H, dd, J = 4.5, 13.6 Hz, H-3a), 2.74 (1H, dd,

7166

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

J = 8.5, 13.6 Hz, H-3b), 2.58 (1H, br s, CH₂CH(OH)); ¹³C NMR (CDCl₃,

75.45 MHz) d 155.2, 153.6, 146.0, 138.3, 131.4, 128.2, 126.9, 123.2,

122.1, 117.5, 114.2, 110.5, 94.7, 76.0, 75.8, 60.6, 56.3, 56.1, 34.7.

7.19 (1H, ddd, J = 1.8, 7.3, 8.3 Hz, H-4⁰⁰), 7.12 (1H, dd, J = 1.8, 7.5 Hz,

H-6⁰⁰), 7.06 (1H, dd, J = 1.2, 8.3 Hz, H-3⁰⁰), 6.98 (2H, aa⁰bb⁰‘d’,

J = 8.8 Hz, H-3⁰and H-5⁰), 6.95 (1H, ddd, J = 1.2, 7.3, 7.5 Hz, H-5⁰⁰),

5.14 and 5.12 (each 1H, d, J = 6.6 Hz, OCH₂O), 5.08 (2H, s, OCH₂Ar),

4.49 (1H, d, J = 6.3 Hz, H-1), 3.96 (1H, sym m (ddd with no coupling

to OH, J = 4.2, 6.3, 8.7 Hz), H-2), 3.41 (3H, s, CH₂OCH₃), 2.98 (1H, br

s or d (J = 2.2 Hz), ArCH(OH)), 2.80 (1H, dd, J = 4.2, 13.7 Hz, H-3a),

2.70 (1H, dd, J = 8.7, 13.7 Hz, H-3b), 2.6 (1H, br s or d (J = 4.0 Hz),

CH₂CH(OH)); ¹³C NMR (CDCl₃, 75.45 MHz) d 158.7, 155.3, 137.1,

133.6, 131.4, 128.6, 128.3, 128.0, 128.0, 127.5, 127.4, 122.1,

115.0, 114.4, 94.8, 76.7, 76.1, 70.2, 56.2, 34.6.

4.6.9. (1R,2R)-syn-1-(3,4-Methylenedioxyphenyl)-3-[2-

(methoxymethoxy)phenyl]propan-1,2-diol (33a)

Colourless solid (needles ex hexane/EtOAc); yield 89%; mp 93–

95 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.20 (1H, ddd, J = 1.7, 7.5, 8.3 Hz,

H-4⁰⁰), 7.13 (1H, dd, J = 1.7, 7.5 Hz, H-6⁰⁰), 7.07 (1H, dd, J = 1.0,

8.3 Hz, H-3⁰⁰), 6.95 (1H, ddd, J = 1.0, 7.5, 7.5 Hz, H-5⁰⁰), 6.92 (1H, d,

J = 1.2 Hz, H-2⁰), 6.85 (1H, dd, J = 1.2, 8.0 Hz, H-6⁰), 6.80 (1H,

d, J = 8.0 Hz, H-5⁰), 5.963 and 5.960 (each 1H (of ‘ab’ system), d,

J = 1.5 Hz, OCH₂O), 5.17 and 5.155 (each 1H (of ‘ab’ system), d, J =

6.8 Hz, OCH₂OCH₃), 4.45 (1H, d, J = 6.3 Hz, H-1), 3.93 (1H, sym m

(ddd, J = 4.0, 6.3, 8.8 Hz), H-2), 3.44 (3H, s, OCH₃), 3.04 (1H, br s,

ArCH(OH)), 2.81 (1H, dd, J = 4.0, 13.8 Hz, H-3a), 2.69 (1H, dd,

J = 8.8, 13.8 Hz, H-3b), 2.60 (1H, br s, CH₂CH(OH)); ¹³C NMR (CDCl₃,

75.45 MHz) d 155.2, 147.8, 147.3, 135.0, 131.4, 128.0, 127.2, 122.1,

120.6, 114.2, 108.1, 107.4, 101.0, 94.7, 76.9, 76.1, 56.2, 34.5.

4.7. General procedure for the preparation of trans- (37–45)

and cis-ﬂavan-3-ols (46–54)

Aqueous HCl (11 mL of 3 M) was added to a solution of the

diol (28–36) (ca. 6.25 mmol) in MeOH/H₂O (3:1, total 120 mL;

dissolved in MeOH prior to addition of H₂O) and the solution

was heated at 75–80 °C for P48 h (longer reaction times were re-

quired for compounds having a highly substituted precursor B

ring. The mixture was cooled, diluted with ice-H₂O (ca. 600 mL)

4.6.10. (1S,2S)-syn-1-(3,4-Methylenedioxyphenyl)-3-[2-

(methoxymethoxy)phenyl]propan-1,2-diol (33b)

Colourless solid (needles ex hexane/EtOAc); yield 95%; mp 93–

95 °C; NMR spectra correspond to those reported above for the

(2R,3R)-enantiomer (33a).

(giving

a

white precipitate) and extracted with Et₂O (1 ꢁ

>120 mL, 3 ꢁ ꢂ75 mL). The combined extracts were washed in

turn with H₂O and brine, dried (MgSO₄), and concentrated under

reduced pressure to afford crude products as a colourless or

slightly coloured (usually pinkish increasing in intensity with

time) gum or solid. Initial CC (eluting solvent DCM/hexane/EtOAc

mixtures) separated the closely eluting mixed cis- and trans-iso-

mers (yield, ratio) from impurities with the cis-isomer eluting

immediately before, but partly overlapping with, the trans-iso-

mer. Further repetitive CC employing the same solvent system

gave a separation of adequate quantities of the cis- and trans-iso-

mers that could be further puriﬁed by recrystallisation from

hexane/EtOAc.

4.6.11. (1R,2R)-syn-1-(4-Methoxyphenyl)-3-[2-(methoxyme-

thoxy)-4-(phenylmethoxy)phenyl]propan-1,2-diol (34a)

Colourless oil; yield 89%; ¹H NMR (CDCl₃, 300 MHz) d 7.45–7.29

(5H, m, benzyl Ar-H), 7.31 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰),

7.01 (1H, d, J = 8.3 Hz, H-6⁰⁰), 6.90 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and

H-5⁰), 6.76 (1H, d, J = 2.5 Hz, H-3⁰⁰), 6.57 (1H, dd, J = 2.5, 8.3 Hz, H-

5⁰⁰), 5.115 and 5.105 (each 1H of ab system, d, J = 6.7 Hz, OCH₂O),

5.02 (2H, s, OCH₂Ar), 4.47 (1H, dd, J = 3.3, 6.5 Hz, H-1), 3.91 (1H,

sym m, H-2), 3.81 (3H, s, OCH₃), 3.41 (3H, s, CH₂OCH₃), 2.97 (1H,

d, J = 3.3 Hz, ArCH(OH)), 2.72 (1H, dd, J = 4.2, 13.8 Hz, H-3a), 2.62

(1H, dd, J = 8.7, 13.8 Hz, H-3b), 2.54 (1H, d, J = 4.3 Hz, CH₂CH(OH));

¹³C NMR (CDCl₃, 75.45 MHz) d 159.4, 158.8, 156.0, 137.0, 133.3,

131.6, 128.5, 128.2, 128.0, 127.5, 119.7, 113.8, 107.5, 102.6, 94.8,

76.6, 76.1, 70.2, 56.2, 55.3, 33.9.

4.7.1. (2S,3R)-trans-4⁰-Methoxyﬂavan-3-ol (37a)

Colourless solid; yield for combined trans:cis 94%, ratio 3:1; mp

1

104–105 °C; H NMR (CDCl₃, 300 MHz) d 7.38 (2H, aa⁰bb⁰‘d’,

J = 8.8 Hz, H-2⁰and H-6⁰), 7.15 (1H, superimposed m (ddd), H-7),

7.12 (1H, superimposed

m

(dd), H-5), 6.96 (2H, aa⁰bb⁰‘d’,

J = 8.8 Hz, H-3⁰and H-5⁰), 6.92 (1H, m (superimposed ddd), H-6),

6.91 (1H, ‘d’ (superimposed/unresolved dd), J = 7.7 Hz, H-8), 4.74

(1H, d, J = 8.3 Hz, H-2), 4.11 (1H, sym m (dddd, J = 3.5, 5.6, 8.3,

9.4 Hz), H-3), 3.83 (3H, s, OCH₃), 3.12 (1H, dd, J = 5.6, 16.2 Hz, H-

4a), 2.93 (1H, dd, J = 9.4, 16.2 Hz, H-4b), 1.73 variable (1H, d,

J = 3.5 Hz variable, OH); ¹³C NMR (CDCl₃, 75.45 MHz) d 160.0,

154.0, 130.0, 129.9, 128.5, 127.7, 121.0, 120.2, 116.5, 114.3, 81.7,

68.1, 55.3, 33.1.

4.6.12. (1R,2R)-syn-1-(3,4-Dimethoxyphenyl)-3-[2-(methoxy-

methoxy)-4-(phenylmethoxy)phenyl]propan-1,2-diol (35a)

Colourless solid; yield 82%; ¹H NMR (CDCl₃, 300 MHz) d 7.45–

7.29 (5H, m, benzyl Ar-H). 7.02 (1H, d, J = 8.3 Hz, H-6⁰⁰), 6.95 (1H,

d, J = 1.9 Hz, H-2⁰), 6.93 (1H, dd, J = 1.9, 8.2 Hz, H-6⁰), 6.85 (1H, d,

J = 8.2 Hz, H-5⁰), 6.77 (1H, d, J = 2.5 Hz, H-3⁰⁰), 6.57 (1H, dd, J = 2.5,

8.3 Hz, H-5⁰⁰), 5.12 (2H, s, OCH₂O), 5.02 (2H, s, OCH₂Ph), 4.47 (1H,

dd, J = 3.0, 6.2 Hz, H-1), 3.91 (1H, superimposed sym m (dddd,

J = 4.1, 4.3, 6.2, 8.6 Hz), H-2)), 3.90 (3H, s, OCH₃), 3.89 (3H, s,

OCH₃), 3.42 (3H, s, CH₂OCH₃), 3.04 (1H, d, J = 3.0 Hz, ArCH(OH)),

2.75 (1H, dd, J = 4.3, 13.9 Hz, H-3a), 2.65 (1H, dd, J = 8.6, 13.9 Hz,

H-3b), 2.56 (1H, d, J = 4.1 Hz, CH₂CH(OH)); ¹³C NMR (CDCl₃,

75.45 MHz) d 158.9, 156.1, 149.2, 148.9, 137.0, 133.9, 131.6,

128.5, 128.0, 127.5, 119.7, 119.5, 111.3, 110.4, 107.7, 102.7, 94.9,

76.8, 76.1, 70.3, 56.2, 56.03, 56.01, 33.9.

4.7.2. Crystal data for trans-(2S,3R)-4⁰-methoxyﬂavan-3-ol (37a)

C₁₆H₁₆O₃,

M = 256.29.

Orthorhombic,

a = 5.8927(11),

b = 10.2670(19), c = 21.264(4) Å (by least-squares reﬁnement of

the setting angles for 200 reﬂections within h = 1.92–28.20),

V = 1286.5(4) Å³, space group P2₁2₁2₁, Z = 4, D_m= 1.323 g cm^ꢀ1

,

F(0 0 0) = 544. Colourless prisms. Crystal dimensions 0.15 ꢁ

0.12 ꢁ 0.12 mm, (Mo K

l

a

) = 0.0091 mm^ꢀ1

.

4.6.13. (1S,2S)-syn-1-(3,4-Dimethoxyphenyl)-3-[2-(methoxy-

methoxy)-4-(phenylmethoxy)phenyl]propan-1,2-diol (35b)

Colourless solid; yield 89%; mp 120–121.5 °C; NMR spectra cor-

respond to those reported above for the (1R,2R)-enantiomer (35a).

4.7.3. (2R,3R)-cis-4⁰-Methoxyﬂavan-3-ol (46a)

Colourless solid; mp 116–117 °C; ¹H NMR (CDCl₃, 300 MHz) d

7.45 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 7.17 (1H, non-re-

solved superimposed m (ddd), H-7), 7.13 (1H, non-resolved super-

imposed m (dd), H-5), 6.97 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and H-5⁰),

6.97 (1H, superimposed m (dd), H-8), 6.93 (1H, ddd, J = 1.2, 7.4,

7.4 Hz, H-6), 5.06 (1H, m as broadened s, H-2), 4.28 (1H, sym m

(dddd, J = 61.0, 2.4, 4.2, 6.0 Hz), H-3), 3.83 (3H, s, OCH₃), 3.26

(1H, dd, J = 4.2, 16.9 Hz, H-4a), 2.98 (1H, dd, J = 2.4, 16.9 Hz, H-

4.6.14. (1S,2S)-syn-1-[4-(Phenylmethoxy)phenyl]-3-[2-

(methoxymethoxy)phenyl]propan-1,2-diol (36b)

Colourless oil; yield 89%; ¹H NMR (CDCl₃, 300 MHz) d 7.46–7.30

(5H, m, benzyl Ar-H), 7.32 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰),

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

7167

4b), 1.80 variable (1H, d, J = ca. 6.0 Hz variable, OH); ¹³C NMR

(CDCl₃, 75.45 MHz) d 159.6, 154.2, 130.3, 130.3, 127.61, 127.59,

121.3, 118.9, 116.8, 114.1, 78.4, 66.7, 55.3, 33.5.

OCH₃), 3.26 (1H, dd, J = 4.3, 17.0 Hz (possibly more accurately ddd

with a further small J = ca. 0.5 Hz), H-4a), 2.95 (1H, dd, J = 2.2,

17.0 Hz, H-4b), 1.84 variable (1H, d, J = 6.2 Hz variable, OH); ¹³C

NMR (CDCl₃, 75.45 MHz) d 159.6, 154.2, 148.3, 130.5, 127.6, 119.6,

117.4, 114.8, 114.1, 113.9, 78.4, 66.8, 55.8, 55.3, 34.0.

4.7.4. (2R,3S)-trans-4⁰-Methoxyﬂavan-3-ol (37b)

Colourless solid; yield for combined trans:cis 89%, ratio 2.7:1;

mp 104–105 °C; NMR spectra correspond to those reported above

for the trans-(2S,3R)-enantiomer (37a).

4.7.12. (2S,3R)-trans-3⁰,4⁰-Dimethoxy-6-methylﬂavan-3-ol (40a)

Colourless solid; yield for combined trans:cis 85%, ratio 2.6:1;

mp 120–122 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.02 (1H, dd, J = 2.0,

8.1 Hz, H-6⁰), 6.99 (1H, d. J = 2.0 Hz, H-2⁰), 6.96 (1H, superimposed

m (dd), H-7), 6.94 (1H, superimposed m (d), H-5), 6.91 (1H, d,

J = 8.1 Hz, H-5⁰), 6.83 (1H, d, J = 8.0 Hz, H-8), 4.68 (1H, d,

J = 8.5 Hz, H-2), 4.10 (1H, ddd, J = 5.5, 8.5, 9.4 Hz, H-3), 3.899 (3H,

s, OCH₃), 3.896 (3H, s, OCH₃), 3.10 (1H, dd, J = 5.5, 16.0 Hz, H-4a),

2.91 (1H, dd, J = 9.4, 16.0 Hz, H-4b), 2.29 (3H, s, ArCH₃), 1.74 vari-

able (1H, br s, OH); ¹³C NMR (CDCl₃, 75.45 MHz) d 152.0, 149.4,

149.4, 130.5, 130.3, 130.2 128.3, 119.94, 119.91, 116.2, 111.3,

110.0, 81.9, 68.3, 56.0, 55.9, 33.2, 20.5.

4.7.5. (2S,3S)-cis-4⁰-Methoxyﬂavan-3-ol (46b)

Colourless solid; mp 115–117 °C; NMR spectra correspond to

those reported above for the cis-(2R,3R)-enantiomer (46a).

4.7.6. (2S,3R)-trans-3⁰,4⁰-Dimethoxyﬂavan-3-ol (38a)

Colourless solid; yield for combined trans:cis 94%, ratio 2.7:1;

mp 110–112 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.15 (1H, superim-

posed m (ddd), H-7), 7.14 (1H, superimposed m (dd), H-5), 7.02

(1H, superimposed m (dd, J = 2.0, 8.1 Hz), H-6⁰), 6.99 (1H, superim-

posed m (d, J = 2.0), H-2⁰), 6.96–6.89 (2H, 2 ꢁ superimposed m, H-6

and H-8), 6.91 (1H, d, J = 8.1 Hz, H-5⁰), 4.71 (1H, d, J = 8.3 Hz, H-2),

4.11 (1H, ddd, J = 5.6, 8.3, 9.5 Hz, H-3), 3.901 (3H, s, OCH₃), 3.896

(3H, s, OCH₃), 3.14 (1H, dd, J = 5.6, 16.0 Hz, H-4a), 2.94 (1H, dd,

J = 9.5, 16.0 Hz, H-4b), 1.74 variable (1H, br s, OH); ¹³C NMR (CDCl₃,

75.45 MHz) d 154.2, 149.6, 149.6, 130.6, 129.9, 127.7, 121.1, 120.3,

119.9, 116.5, 111.6, 110.4, 82.0, 68.2, 56.1, 56.0, 33.2.

4.7.13. (2R,3R)-cis-3⁰,4⁰-Dimethoxy-6-methylﬂavan-3-ol (49a)

Glassy solid (not recrystallised); ¹H NMR (CDCl₃, 300 MHz) d

7.08 (1H, d, J = 2.0 Hz, H-2⁰) 7.05 (1H, ddd, J = ca. 0.6, 2.0, 8.1 Hz,

H-6⁰), 6.98 (1H, dd (or ddm with possible additional coupling to

ring methyl) J = ca. 1.8, ca. 8.2 Hz, H-7), 6.94 (1H, superimposed

and unresolved d, J = ca. 1.8 Hz, H-5), 6.92 (1H, d, J = 8.1 Hz. H-5⁰),

6.88 (1H, d, J = 8.2 Hz, H-8), 5.01 (1H, sl. br s, H-2), 4.27 (1H, sym

m (ddd, J = ca. 1.0, 2.4, 4.2 Hz), H-3), 3.92 (3H, s, OCH₃), 3.90 (3H,

s, OCH₃), 3.24 (1H, dd, J = 4.2, 16.9 Hz, H-4a), 2.94 (1H, dd, J = 2.4,

16.9 Hz, H-4b), 2.28 (3H, s, ArCH₃), 1.74 variable (1H, br s, OH);

¹³C NMR (CDCl₃, 75.45 MHz) d 151.8, 149.2, 148.8, 130.9, 130.6,

130.5, 128.2, 118.5, 118.4, 116.4, 111.3, 109.7, 78.3, 66,9, 55.93,

55.92, 33.4, 20.5.

4.7.7. (2R,3R)-cis-3⁰,4⁰-Dimethoxyﬂavan-3-ol (47a)

Colourless solid; mp 96.5–98 °C; ¹H NMR (CDCl₃, 300 MHz) d

7.17 (1H, superimposed m, H-7), 7.14 (1H, superimposed m, H-5),

7.08 (1H, superimposed m (d, J = ca. 2.0 Hz), H-2⁰), 7.06 (1H, super-

imposed m (ddd, J = ca. 0.7, 2.0, 8.1 Hz), H-6⁰), 6.99 (1H. superim-

posed m (dd), H-8), 6.97 (1H, superimposed m (ddd), H-6), 6.93

(1H, superimposed m (d, J = 8.1 Hz), H-5⁰), 5.05 (1H, m as slightly

br s, H-2), 4.30 (1H, m, H-3), 3.93 (3H, s, OCH₃), 3.91 (3H, s,

OCH₃), 3.28 (1H, dd, J = 4.2, 16.8 Hz, H-4a), 2.99 (1H, dd, J = 2.2,

16.8 Hz, H-4b), 1.71 variable (1H, br s, OH); ¹³C NMR (CDCl₃,

75.45 MHz) d 154.2, 149.4, 149.1, 131.0, 130.3, 127.6, 121.3,

118.9, 118.7, 116.8, 111.6, 110.0, 78.5, 66.9, 56.1, 56.1, 33.5.

4.7.14. (2R,3S)-trans-3⁰,4⁰-Dimethoxy-6-methylﬂavan-3-ol

(40b)

Fine, colourless needles (hexane/EtOAc); yield for combined

trans:cis 85%, ratio 2.6:1; mp 119–121 °C; NMR spectra correspond

to those reported above for the trans-(2S,3R)-enantiomer (40a).

4.7.8. (2R,3S)-trans-3⁰,4⁰-Dimethoxyﬂavan-3-ol (38b)

Colourless solid; yield for combined trans:cis 94%, ratio 2.5:1;

mp 109–111 °C; NMR spectra correspond to those reported above

for the trans-(2S,3R)-enantiomer (38a).

4.7.15. (2S,3S)-cis-3⁰,4⁰-Dimethoxy-6-methylﬂavan-3-ol (49b)

Colourless solid; mp 102–103 °C; NMR spectra correspond to

those reported above for the cis-(2R,3R)-enantiomer (49a).

4.7.16. (2S,3R)-trans-3⁰-Bromo-4⁰,5⁰-Dimethoxyﬂavan-3-ol

(41a)

4.7.9. (2S,3S)-cis-3⁰,4⁰-Dimethoxyﬂavan-3-ol (47b)

Colourless solid; mp 97–98 °C; NMR spectra correspond to

those reported above for the cis-(2R,3R)-enantiomer (47a).

Reaction time >15 d, colourless crystals (hexane/EtOAc); com-

bined trans:cis ratio not determined with minimal cis isolated;

mp 164–165 °C; ¹H NMR (CDCl₃, 300 MHz)

d 7.25 (1H, d,

4.7.10. (2S,3R)-trans-4⁰,6-Dimethoxyﬂavan-3-ol (39a)

J = 1.8 Hz, H-2⁰), 7.16 (1H, non-resolved ddd, H-7), 7.13 (1H, non-

resolved dd, H-5), 6.96 (1H, d, J = 1.8 Hz, H-6⁰), 6.94 (1H. superim-

posed ddd, H-6) 6.93 (1H, superimposed dd, H-8), 4.68 (1H, d,

J = 8.3 Hz, H-2), 4.09 (1H, ddd, J = 5.5, 8.3, 9.4 Hz, H-3), 3.87 (3H,

s, OCH₃), 3.86 (3H, s, OCH₃), 3.14 (1H, dd, J = 5.5, 16.0 Hz, H-4a),

2.94 (1H, dd, J = 9.4, 16.0 Hz, H-4b), 1.74 variable (1H, br s, OH);

¹³C NMR (CDCl₃, 75.45 MHz) d 153.8, 153.7, 146.4, 135.3, 129.9,

127.8, 123.4, 121.3, 120.2, 117.8, 116.4, 110.5, 81.4, 68.0, 60.5,

56.1, 33.3.

Colourless solid; yield for combined trans:cis 88%, ratio 2.3:1;

1

mp 117–118 °C; H NMR (CDCl₃, 300 MHz) d 7.38 (2H, aa⁰bb⁰‘d’,

J = 8.8 Hz, H-2⁰and H-6⁰), 6.94 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and

H-5⁰), 6.84 (1H, d, J = 8.9 Hz, H-8), 6.72 (1H, dd, J = 3.0, 8.9 Hz, H-

7), 6.64 (1H, d, J = 3.0, H-5), 4.69 (1H, d, J = 8.2 Hz, H-2), 4.11 (1H,

ddd, J = 5.4, 8.2, 9.0 Hz, H-3), 3.83 (3H, s, OCH₃), 3.77 (3H, s,

OCH₃), 3.09 (1H, dd, J = 5.4, 16.2 Hz, H-4a), 2.91 (1H, dd, J = 9.0,

16.2 Hz, H-4b), 1.55 variable (1H, br s, OH); ¹³C NMR (CDCl₃,

75.45 MHz) d 160.0, 154.0, 148.3, 130.3, 128.5, 121.0, 117.2,

114.39, 114.35, 113.9, 81.7, 68.2, 55.8, 55.4, 33.4.

4.7.17. Crystal data for trans-(2S,3R)-3⁰-bromo-4⁰,5⁰-

dimethoxyﬂavan-3-ol (41a)

4.7.11. (2R,3R)-cis-4⁰,6-Dimethoxyﬂavan-3-ol (48a)

C₁₇H₁₇BrO₄,

M = 365.22.

Orthorhombic,

a = 7.9341(3),

Colourless solid; mp 153–155 °C; ¹H NMR (CDCl₃, 300 MHz) d

7.45 (2H, aa⁰bb⁰‘d’, J = 8.9 Hz, H-2⁰and H-6⁰), 6.96 (2H, aa⁰bb⁰‘d’,

J = 8.9 Hz, H-3⁰and H-5⁰), 6.90 (1H, d, J = 8.9 Hz, H-8), 6.74 (1H, dd,

J = 2.9, 8.9 Hz, H-7), 6.66 (1H, d, J = 2.9, H-5), 4.99 (1H, m as broad-

ened s, H-2), 4.25 (1H, sym m, H-3), 3.83 (3H, s, OCH₃), 3.77 (3H, s,

b = 10.4401(4), c = 18.6699(8) Å (by least-squares reﬁnement of

the setting angles for 200 reﬂections within h = 2.18–28.25),

V = 1546.48(11) Å³, space group P2₁2₁2₁, Z = 4, D_m= 1.569 g cm^ꢀ3

,

F(0 0 0) = 744.

0.30 ꢁ 0.20 ꢁ 0.20 mm,

Colourless

(Mo K

needles.

Crystal

dimensions

l

a

) = 0.2673 mm^ꢀ1

.

7168

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

4.7.18. (2R,3R)-cis-3⁰-Bromo-4⁰,5⁰-dimethoxyﬂavan-3-ol (50a)

Colourless, viscous gum; ¹H NMR (CDCl₃, 300 MHz) d 7.28 (1H,

dd, J = ca. 0.6, 1.8 Hz, H-2⁰), 7.18 (1H, non-resolved ddd, H-7), 7.14

(1H, non-resolved dd, H-5), 7.06 (1H, d, J = 1.8 Hz, H-6⁰), 6.99 (1H,

dd, J = 1.2, 8.1 Hz, H-8), 6.96 (1H, ddd, J = 1.2, 7.5, 7.5 Hz, H-6),

5.00 (1H, broadened s, H-2), 4.31 (1H, incompletely resolved sym

m, H-3), 3.91 (3H, s, OCH₃), 3.87 (3H, s, OCH₃), 3.29 (1H, dd,

J = 4.0, 16.9 Hz, H-4a), 3.00 (1H, dd, J = 1.8, 16.9 Hz, H-4b), 1.67 var-

iable (1H, br s, OH); ¹³C NMR (CDCl₃, 75.45 MHz) d 153.9, 153.7,

146.3, 135.5, 130.4, 127.8, 122.6, 121.7, 118.6, 117.9, 116.8,

109.9, 77.9, 66.7, 60.6, 56.3, 33.6.

(1H, ‘d’, J = 9.1 Hz, H-5), 6.96 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and H-

5⁰), 6.61 (1H, d, J = 2.6 Hz, H-8), 6.61 (1H, dd, J = 2.6, 9.1 Hz, H-6),

5.04 (2H, s, OCH₂), 5.04 (1H, s, H-2), 4.25 (1H, sym m, H-3), 3.83

(3H, s, OCH₃), 3.19 (1H, dd, J = 4.0, 16.5 Hz, H-4a), 2.91 (1H, dd,

J = 2.5, 16.5 Hz, H-4b), 1.77 (1H, d, J = 6.0 Hz, OH); ¹³C NMR (CDCl₃,

75.45 MHz) d 159.6, 158.7, 154.9, 137.2, 130.8 130.4, 128.5, 127.9,

127.7, 127.4, 114.1, 111.2, 109.3, 102.8, 78.5, 70.2, 66.8, 55.3, 33.0.

4.7.25. (2S,3R)-trans-3⁰,4⁰-Dimethoxy-7-(phenylmethoxy)-

ﬂavan-3-ol (44a)

Colourless solid; yield for combined trans:cis 70%, ratio 3:1; mp

124–125 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.46–7.28 (5H, m, benzyl

Ar-H), 7.02 (1H, d, J = 8.3 Hz, H-5), 7.01 (1H, dd, J = 2.0, 8.1 Hz, H-

6⁰), 6.97 (1H, d, J = 2.0, H-2⁰), 6.91 (1H, d, J = 8.1 Hz, H-5⁰), 6.60 (1H,

dd, J = 2.5, 8.3 Hz, H-6), 6.57 (1H, d, J = 2.5 Hz, H-8), 5.02 (2H, s,

CH₂O), 4.70 (1H, d, J = 8.3 Hz, H-2), 4.09 (1H, ddd, J = 5.5, 8.3,

9.4 Hz, H-3), 3.90 (3H, s, OCH₃), 3.89 (3H, s, OCH₃), 3.07 (1H, dd,

J = 5.5, 15.7 Hz, H-4a), 2.86 (1H, dd, J = 9.4, 15.7 Hz, H-4b), ca. 1.70

variable (1H, variable d to br s, variable J = 3.5 to 0 depending on sol-

vent acidity and dryness, OH); ¹³C NMR (CDCl₃, 75.45 MHz) d 158.7,

154.9, 149.6, 149.6, 137.1, 130.5, 130.4, 128.6, 127.9, 127.4, 119.9,

112.6, 111.6, 110.3, 109.0, 102.5, 82.0, 70.2, 68.3, 56.1, 56.0, 32.6.

4.7.19. (2S,3R)-trans-3⁰4⁰-Methylenedioxyﬂavan-3-ol (42a)

Colourless crystals (hexane/EtOAc); yield for combined trans:cis

92%, ratio 2.6:1; mp 102–103 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.15

(1H, unresolved superimposed m, H-7), 7.12 (1H, unresolved

superimposed m, H-5), 6.97–6.89 (3H, 3 ꢁ superimposed m, unas-

signed H-6, H-8, and H-2⁰), 6.92 (1H, superimposed m (ddd, J = ca.

0.5, 1.8, 8.0 Hz), H-6⁰), 6.84 (1H, d, J = 8.0 Hz, H-5⁰), 5.99 (2H, s,

OCH₂O, 4.69 (1H, d, J = 8.3 Hz, H-2), 4.07 (1H, sym. m (dddd,

J = 3.6, 5.5, 8.3, 9.4 Hz, H-3), 3.12 (1H, dd, J = 5.5, 16.0 Hz, H-4a),

2.92 (1H, dd, J = 9.2, 16.0 Hz, H-4b), 1.74 variable (1H, d,

J = 3.6 Hz, OH); ¹³C NMR (CDCl₃, 75.45 MHz) d 154.0, 148.2,

148.0, 131.8, 129.9, 127.7, 121.2, 121.1, 120.2, 116.5, 108.4,

107.3, 101.3, 81.9, 68.1, 33.1.

4.7.26. (2R,3R)-cis-3⁰,4⁰-Dimethoxy-7(phenylmethoxy)ﬂavan-3-

ol (53a)

Colourless solid; mp 114–115 °C; ¹H NMR (CDCl₃, 300 MHz) d

7.45–7.29 (5H, m, benzyl Ar-H), 7.07 (1H, superimposed d, J = ca.

2.0 Hz, H-2⁰), 7.05 (superimposed m (dd with additional ﬁne cou-

pling), H-6⁰), 7.02 (1H, superimposed d (or md), H-5), 6.92 (1H, d,

J = 8.2 Hz, H-5⁰), 6.63 (1H, superimposed d, J = 2.6 Hz, H-8), 6.61

(1H, superimposed dd, J = ca. 8.2, 2.6 Hz, H-6), 5.04 (2H, s, OCH₂),

5.03 (1H, s, H-2), 4.27 (1H, sym m, H-3), 3.92 (3H, s, OCH₃), 3.90

(3H, s, OCH₃), 3.20 (1H, dd, J = 4.1, 16.5 Hz, H-4a), 2.91 (1H, dd,

J = 2.3, 16.5 Hz, H-4b), ca. 1.7 variable (1H, br s, OH); ¹³C NMR

(CDCl₃, 75.45 MHz) d 158.7, 154.9, 149.4, 149.2, 137.2, 130.9,

130.8, 128.6, 127.9, 127.4, 118.8, 111.6, 111.2, 110.1, 109.3,

102.9, 78.6, 70.2, 66.9, 56.1, 56.1, 32.9.

4.7.20. (2R,3R)-cis-3⁰4⁰-Methylenedioxyﬂavan-3-ol (51a)

Colourless solid; mp 78–79 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.17

(1H, unresolved superimposed m (ddd), H-7), 7.13 (1H, unresolved

superimposed m (dd), H-5), 7.05 (1H, d, J = 1.7 Hz, H-2⁰), 6.97 (1H,

superimposed m (ddd, J = ca. 0.6, 1.7, 8.0 Hz), H-6⁰), 6.95 (1H.

superimposed m (dd), H-8), 6.94 (1H, superimposed m (ddd), H-

6), 6.86 (1H, d, J = 8.0 Hz, H-5⁰), 5.99 (2H, s, OCH₂O), 5.01 (1H, m

as slightly br s, H-2), 4.26 (1H, m, H-3), 3.27 (1H, dd, J = 4.0,

17.0 Hz, H-4a), 2.98 (1H, dd, J = 2.2, 17.0 Hz, H-4b), 1.71 variable

(1H, br s, OH); ¹³C NMR (CDCl₃, 75.45 MHz) d 154.0, 148.0, 147.4,

132.2, 130.4, 127.7, 121.4, 119.6, 118.7, 116.7, 108.4, 107.1,

101.2, 78.4, 66.8, 33.5.

4.7.27. (2R,3S)-trans-3⁰,4⁰-Dimethoxy-7-

4.7.21. (2R,3S)-trans-3⁰4⁰-Methylenedioxyﬂavan-3-ol (42b)

Colourless crystals (hexane/EtOAc); yield for combined trans:cis

95%, ratio 2.6:1; mp 101–102.5 °C; NMR spectra correspond to

those reported above for the trans-(2S,3R)-enantiomer (42a).

(phenylmethoxy)ﬂavan-3-ol (44b)

Colourless solid; yield for combined trans:cis 68%, ratio 3:1; mp

125–126 °C; NMR spectra correspond to those reported above for

the trans-(2S,3R)-enantiomer (44a).

4.7.22. (2S,3S)-cis-3⁰4⁰-Methylenedioxyﬂavan-3-ol (51b)

Colourless solid; mp 77–78 °C; NMR spectra correspond to

those reported above for the cis-(2R,3R)-enantiomer (51a).

4.7.28. (2S,3S)-cis-3⁰,4⁰-Dimethoxy-7-(phenylmethoxy)ﬂavan-3-

ol (53b)

Colourless solid; mp 113–114.5 °C; NMR spectra correspond to

those reported above for the cis-(2R,3R)-enantiomer (53a).

4.7.23. trans-(2S,3R)-4⁰-Methoxy-7-(phenylmethoxy)ﬂavan-3-

ol (43a)

4.7.29. trans-(2R,3S)-4⁰-(Phenylmethoxy)ﬂavan-3-ol (45b)

Colourless solid; yield for combined trans:cis 86%, ratio 2.7:1; mp

119–120 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.46–7.30 (5H, m, benzyl

Ar-H), 7.38 (2H, superimposed aa⁰bb⁰‘d’, J = 8.7 Hz, H-2⁰and H-6⁰),

7.15 (1H, superimposed m (unresolved ddd), H-7), 7.12 superim-

posed m (unresolved dd), H-5), 7.03 (2H, aa⁰bb⁰‘d’, J = 8.7 Hz, H-3⁰

and H-5⁰), 6.92 (1H, superimposedm (ddd), H-6), 6.91 (1H, ‘d’ (super-

imposed dd), J = P7.5 Hz, H-8), 5.09 (2H, s, OCH₂), 4.73 (1H, d,

J = 8.3 Hz, H-2), 4.11 (1H, ddd, J = 5.5, 8.3, 9.3 Hz, H-3), 3.12 (1H,

dd, J = 5.4, 16.0 Hz, H-4a), 2.93 (1H, dd, J = 9.3, 16.0 Hz, H-4b), ca.

1.6 variable (1H, br s, OH); ¹³C NMR (CDCl₃, 75.45 MHz) d 159.3,

154.3, 137.0, 130.5, 130.0, 128.6, 128.5, 128.0, 127.7, 127.4, 121.0,

120.3, 116.5, 115.3, 81.7, 70.2, 68.2, 33.1.

Colourless solid; yield for combined trans:cis 83%, ratio 2.8:1;

mp 117–118 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.44–7.28 (5H, m,

benzyl Ar-H), 7.36 (2H, aa⁰bb⁰‘d’, J = 8.7 Hz, H-2⁰and H-6⁰), 7.00

(1H, d, J = 8.3 Hz, H-5), 6.95 (2H, aa⁰bb⁰‘d’, J = 8.7 Hz, H-3⁰and H-

5⁰), 6.59 (1H, dd, J = 2.5, 8.3 Hz, H-6), 6.55 (1H, d, J = 2.5 Hz, H-8),

5.01 (2H, s, OCH₂), 4.73 (1H, d, J = 8.1 Hz, H-2), 4.09 (1H, incom-

pletely resolved sym m, H-3), 3.82 (3H, s, OCH₃), 3.05 (1H, dd,

J = 5.4, 15.8 Hz, H-4a), 2.84 (1H, dd, J = 9.0, 15.8 Hz, H-4b), 1.71

(1H, d, J = 3.8 Hz, OH); ¹³C NMR (CDCl₃, 75.45 MHz) d 160.0,

158.6, 154.9, 137.1, 130.4, 130.0, 128.54, 128.49, 127.9, 127.4,

114.3, 112.5, 108.9, 102.4, 81.7, 70.1, 68.3, 55.3, 32.4.

4.7.24. cis-(2S,3R)-4⁰-Methoxy-7-(phenylmethoxy)ﬂavan-3-ol

(52a)

4.7.30. cis-(2S,3S)-4⁰-(Phenylmethoxy)ﬂavan-3-ol (54b)

Colourless solid; mp 103–105 °C; ¹H NMR (CDCl₃, 300 MHz) d

7.47–7.30 (5H, m, benzyl Ar-H), 7.45 (2H, superimposed aa⁰bb⁰

Colourless solid; ¹H NMR (CDCl₃, 300 MHz) d 7.45–7.29 (5H, m,

benzyl Ar-H), 7.44 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 7.02

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

7169

‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 7.17 (1H, unresolved superimposed

ddd, H-7), 7.13 (1H, unresolved superimposed dd, H-5), 6.97 (2H,

aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and H-5⁰), 6.96 (1H, dd, J = ca. 1.2,

8.0 Hz, H-8), 6.93 (1H, ddd, J = ca. 1.2, ca. 7.4, ca. 7.4 Hz, H-6),

5.10 (2H, s, OCH₂), 5.05 (1H, s, H-2), 4.28 (1H, sym m as broadened

s, H-3), 3.27 (1H, dd, J = 4.1, 17.0 Hz, H-4a), 2.98 (1H, dd, J = 2.4,

17.0 Hz, H-4b), 1.76 variable (1H, br s, OH); ¹³C NMR (CDCl₃,

75.45 MHz) d 158.8, 154.3, 137.1, 130.7, 130.4, 128.6, 128.0,

127.67, 127.65, 127.4, 121.3, 118.9, 116.8, 115.2, 78.4, 70.2, 66.8,

33.6.

4.8.4. (2R,3R)-cis-3-Acetoxy-4⁰-methoxyﬂavan (64a)

Colourless crystals (hexane/EtOAc); yield 99%; mp 145–146 °C

1

[lit. mp 140 °C];¹⁹H NMR (CDCl₃, 300 MHz) d 7.38 (2H, aa⁰bb⁰

‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 7.18 (1H, unresolved ddd, H-7), 7.10

(1H, unresolved dd, J = ca. 7.5 Hz, H-5), 6.97 (1H, unresolved dd,

J = ca. 8.4 Hz, H-8), 6.93 (1H, superimposed m (presumed ddd),

H-6), 6.91 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and H-5⁰), 5.40 (1H, sym

m (ddd), H-3), 5.11 (1H, br s, H-2), 3.82 (3H, s, OCH₃), 3.31 (1H,

dd, J = 4.6, 17.6 Hz, H-4a), 2.99 (1H, dd, J = 2.0, 17.6 Hz, H-4b),

1.91 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 170.3,

159.6, 154.4, 130.1, 129.8, 127.8, 127.7, 121.1, 118.5, 116.9,

113.8, 77.3, 68.3, 55.3, 30.9, 20.9; APCI-MS (C₁₈H₁₈O₄requires

MH⁺, m/z 299.1278, found: MH⁺, m/z 299.1275).

4.8. General procedure for the preparation of trans- (43–49)

and cis-acetates (64–70)

4.8.5. Crystal data for cis-(2R,3R)-3-acetoxy-4⁰-methoxyﬂavan

(64a)

To the precursor trans- (37–45) or cis-ﬂavan-3-ol (46–49, 51, 52

and 54) (1.0 mmol) was added a mixture of pyridine (1 mL) and

Ac₂O (1 mL) and the resulting solution was allowed to stand at

room temperature for >24 h. The solution was poured into sat.

NaHCO₃solution (P75 mL) and the product extracted into EtOAc

(3 ꢁ 25 mL). The combined organic extracts were washed in turn

with H₂O and brine, dried (MgSO₄) and concentrated under re-

duced pressure to afford crude product trans- (55–63) and cis-ace-

tates (64–70) (usually in high to quantitative yield) as either a

colourless solid or a colourless, extremely viscous gum that could

not be induced to crystallise. Crude material was often sufﬁciently

pure for pharmacological evaluation and was occasionally tested as

the crude product.

More frequently, the crude material was puriﬁed by short col-

umn vacuum chromatography (various solvent systems including

hexane/DCM/EtOAc) to afforded pure product as either a colourless

solid or alternatively as a viscous gum that, with a few exceptions,

slowly crystallised to a colourless or off-white solid. Where possi-

ble, solid products were puriﬁed further by recrystallisation from

hexane or hexane/EtOAc.

C₁₈H₁₈O₄,

M = 298.32.

Orthorhombic,

a = 5.6430(12),

b = 14.644(3),c = 18.586(4) Å(byleast-squaresreﬁnementoftheset-

ting angles for 200 reﬂections within h = 1.77–26.84),

V = 1535.9(6) Å³, space group P2₁2₁2₁, Z = 4, D_m= 1.290 g cm^ꢀ3

,

F(0 0 0) = 632.

0.20 ꢁ 0.15 ꢁ 0.15 mm,

Colourless

(Mo K

prisms.

Crystal

dimensions

l

a

) = 0.0091 mm^ꢀ1

.

4.8.6. (2S,3S)-cis-3-Acetoxy-4⁰-methoxyﬂavan (64b)

Colourless solid, yield 99%; mp 144–145.5 °C [lit. mp 142 °C];¹⁹

NMR spectra correspond to those reported above for the cis-

(2R,3R)-enantiomer (64a); APCI-MS (C₁₈H₁₈O₄requires MH⁺, m/z

299.1278, found: MH⁺, m/z 299.1274).

4.8.7. (2S,3R)-trans-3-Acetoxy-3⁰,4⁰-dimethoxyﬂavan (56a)

Colourless solid; yield 98%; mp 76–77 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.18 (1H, ddd (with additional ﬁne structure), J = ca.

1.5, 7.3, 8.2 Hz, H-7), 7.06 (1H, dd (with additional ﬁne structure),

J = ca. 1.5, 7.5 Hz, H-5), 6.97 (1H, dd, J = ca. 1.0, 8.2 Hz, H-8), 6.92

(1H, superimposed m (ddd, J = ca. 1.0, 7.3, 7.5 Hz), H-6), 6.92 (1H,

superimposed m (ddd, J = ca. 0.5, 2.0, 8.1 Hz), H-6⁰), 6.89 (1H, d,

J = 2.0 Hz, H-2⁰), 6.84 (1H, d, J = 8.1 Hz, H-5⁰), 5.38 (1H, ddd,

J = 5.1, 6.4, 6.8 Hz, H-3), 5.11 (1H, broadened d (d of unresolved

m), J = 6.4 Hz, H-2), 3.87 (3H, s, OCH₃), 3.85 (3H, s, OCH₃), 3.07

(1H, dd, J = 5.1, 16.5 Hz, H-4a), 2.89 (1H, dd, J = 6.8, 16.5 Hz, H-

4b), 1.97 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 170.0,

153.8, 149.25, 149.22, 130.8, 129.7, 127.9, 121.0, 119.24, 119.17,

116.5, 111.4, 109.9, 78.5, 69.4, 56.0, 56.0, 29.3, 21.0; APCI-MS

(C₁₉H₂₀O₅requires MH⁺, m/z 329.1384, found: MH⁺, m/z 329.1380).

When the amount of material available for acetylation was

greater or less than 1 mmol, the amounts of acetic anhydride and

pyridine were scaled accordingly.

4.8.1. (2S,3R)-trans-3-Acetoxy-4⁰-methoxyﬂavan (55a)

Colourless crystals; yield 95%; mp 77–78 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.29 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 7.18

(1H, ddd (with additional ﬁne structure), J = ca. 1.5, 7.5, 8.1 Hz,

H-7), 7.05 (1H, dd, J = ca. 1.2, 7.5 Hz, H-5), 6.96 (1H, dd, J = ca.

1.2, 8.1 Hz, H-8), 6.92 (1H, superimposed m (possibly ddd, J = ca.

1.2, 7.5, 7.5 Hz), H-6), 6.88 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and H-

5⁰), 5.35 (1H, incompletely resolved sym m (ddd, J = 5.0, 6.4,

6.6 Hz), H-3), 5.12 (1H, d, J = 6.4 Hz, H-2), 3.80 (3H, s, OCH₃), 3.05

(1H, dd, J = 5.0, 16.5 Hz, H-4a), 2.88 (1H, dd, J = 6.6, 16.5 Hz, H-

4b), 1.97 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃, 75.45 MHz) d 170.1,

159.7, 153.9, 130.3, 129.7, 127.9, 127.7, 121.0, 119.2, 116.6,

114.0, 78.3, 69.4, 55.3, 29.2, 21.0; APCI-MS (C₁₈H₁₈O₄requires

MH⁺, m/z 299.1278, found: MH⁺, m/z 299.1287).

4.8.8. (2R,3S)-trans-3-Acetoxy-3⁰,4⁰-dimethoxyﬂavan (56b)

Colourless solid; quantitative yield; mp 92–93 °C; NMR spectra

correspond to those reported above for the trans-(2S,3R)-enantio-

mer (56a); APCI-MS (C₁₉H₂₀O₅requires MH⁺, m/z 329.1384, found:

MH⁺, m/z 329.1376).

4.8.9. (2R,3R)-cis-3-Acetoxy-3⁰,4⁰-dimethoxyﬂavan (65a)

Colourless solid; yield 92%; mp 93.5–95 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.19 (1H, incompletely resolved ddm (or ddd with

additional ﬁne structure), J = ca. 7.4, 8.2 Hz, H-7), 7.10 (1H, incom-

pletely resolved dm (or dd with additional ﬁne structure), J = ca.

7.4 Hz, H-5), 7.05 (1H, d, J = 2.0 Hz, H-2⁰), 6.99 (1H, dd, J = ca. 1.2,

4.8.2. Crystal data for trans-(2S,3R)-3-acetoxy-4⁰-

methoxyﬂavan (55a)

C₁₈H₁₈O₄, M = 298.34. Monoclinic, a = 6.1915(9), b = 8.2754(12),

*

8.2 Hz, H-8), 6.98 (1H, ddd, J = ca. 0.6 , 2.0, 8.3 Hz, H-6⁰), 6.94

c = 15.049(2) Å,

a = 99.092(2) (by least-squares reﬁnement of the

(1H, ddd, J = ca. 1.2, 7.4, 7.4 Hz, H-6), 6.87 (1H, d, J = 8.3 Hz, H-5⁰),

5.42 (1H, sym m (ddd, J = 1.4, 2.2, 4.4 Hz), H-3), 5.10 (1H, m as br

s, H-2), 3.91 (3H, s, OCH₃), 3.90 (3H, s, OCH₃), 3.32 (1H, dd,

J = 4.4, 17.7 Hz, H-4a), 2.99 (1H, dd, J = 2.2, 17.7 Hz, H-4b), 1.93

(3H, s, C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 170.2, 154.3,

149.11, 149.06, 130.6, 129.8, 127.7, 121.2, 119.0, 118.5, 116.9,

111.2, 110.3, 77.3, 68.3, 56.02, 56.00, 31.0, 20.9; APCI-MS

(C₁₉H₂₀O₅requires MH⁺, m/z 329.1384, found: MH⁺, m/z 329.1380).

setting angles for 200 reﬂections within h = 1.37– 24.87),

V = 761.40(19) Å³, space group P2₁, Z = 2, D_m= 1.301 g cm³,

F(0 0 0) = 316.

0.25 ꢁ 0.20 ꢁ 0.20 mm,

Colourless

(Mo K

prisms

a

Crystal

dimensions

l

) = 0.0091 mm^ꢀ1

.

4.8.3. (2R,3S)-trans-3-Acetoxy-4⁰-methoxyﬂavan (55b)

Yield 88%; mp 76–77 °C; NMR spectra correspond to those re-

ported above for the trans-(2S,3R)-enantiomer (55a); APCI-MS

(C₁₈H₁₈O₄requires MH⁺, m/z 299.1278, found: MH⁺, m/z 299.1276).

*

shown to be coupled to H-2 by decoupling experiment.

7170

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

4.8.10. (2S,3S)-cis-3-Acetoxy-3⁰,4⁰-dimethoxyﬂavan (65b)

Colourless solid; yield 95%; mp 94–95 °C; NMR spectra corre-

spond to those reported above for the cis-(2R,3R)-enantiomer

(65a); EI-MS (C₁₉H₂₀O₅requires MH⁺, m/z 328.1311, found: MH⁺,

m/z 328.1131).

31.0, 21.0, 20.6; EI-MS (C₂₀H₂₂O₅requires MH⁺, m/z 342.1467,

found: MH⁺, m/z 342.1471). n/m not measurable.

4.8.16. (2S,3R)-trans-3-Acetoxy-3⁰-bromo-4⁰,5⁰-

dimethoxyﬂavan (59a)

Colourless solid (glass); yield 93%; ¹H NMR (CDCl₃, 300 MHz) d

7.19 (1H, ddm, J = ca. 7.5, ca. 8.1, n/m Hz, H-7), 7.15 (1H, dd, J = ca.

0.6, 2.0 Hz, H-2⁰), 7.07 (1H, dd (or md) J = ca. 1.2, 7.5 Hz, H-5), 6.97

(1H, dd, J = ca. 1.2, ca. 8.1 Hz, H-8), 6.94 (1H, ddd, J = 1.2, 7.5, 7.5 Hz,

H-6), 6.89 (1H, d, J = 2.0 Hz, H-6⁰), 5.32 (1H, ddd, J = 5.1, 6.5, 6.8 Hz,

H-3), 5.07 (1H, d, J = 6.5 Hz, H-2), 3.85 (3H, s, OCH₃), 3.82 (3H, s,

OCH₃), 3.08 (1H, dd, J = 5.1, 16.5 Hz, H-4a), 2.89 (1H, dd, J = 6.8,

16.5 Hz, H-4b), 2.00 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃,

75.46 MHz) d 170.1, 153.8, 153.3, 146.4, 135.2, 129.8, 128.1,

123.0, 121.4, 119.0, 117.6, 116.5, 109.8, 77.7, 69.2, 60.6, 56.1,

29.2, 21.1; APCI-MS (C₁₉H₁₉BrO₅requires MH⁺, m/z 407.0489,

found: MH⁺, m/z 407.0489).

4.8.11. (2S,3R)-trans-3-Acetoxy-4⁰,6-dimethoxyﬂavan (57a)

Colourless solid; quantitative yield; mp 84–85 °C; ¹H NMR

(CDCl₃, 300 MHz) d 7.28 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰),

6.89 (1H, d, J = 8.9 Hz, H-8), 6.87 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰

and H-5⁰), 6.75 (1H, dd, J = 3.0, 8.9 Hz, H-7), 6.58 (1H, d,

J = 3.0 Hz, H-5), 5.33 (sym m as apparent td (ddd, J = 5.0, 6.5,

6.5 Hz), H-3), 5.06 (1H, d, J = 6.5 Hz, H-2), 3.80 (3H, s, OCH₃), 3.76

(3H, s, OCH₃), 3.03 (1H, dd, J = 5.0, 16.6 Hz, H-4a), 2.85 (1H, dd,

J = 6.5, 16.6 Hz, H-4b), 1.97 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃,

75 MHz) d 170.1, 159.6, 154.0, 147.9, 130.4, 127.8, 119.9, 117.2,

114.2, 114.1, 114.0, 78.2, 69.5, 55.8, 55.3, 29.5, 21.0; EI-MS

(C₁₉H₂₀O₅requires MH⁺, m/z 328.1311, found: MH⁺, m/z 328.1312).

4.8.17. (2S,3R)-trans-3-Acetoxy-3⁰,4⁰-methylenedioxyﬂavan

(60a)

4.8.12. (2R,3R)-cis-3-Acetoxy-4⁰,6-dimethoxyﬂavan (66a)

Colourless solid; yield 98%; mp 130–132 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.19 8.8 Hz, H-2⁰and H-6⁰), 6.91 (2H, aa⁰bb⁰‘d’,

J = 8.8 Hz, H-3⁰and H-5⁰), 6.91 (1H, d, J = 8.9 Hz, H-8), 6.75 (1H,

dd, J = 3.0, 8.9 Hz, H-7), 6.62 (1H, d, J = 3.0 Hz, H-5), 5.38 (1H,

sym m (ddd), H-3), 5.04 (1H, unresolved m as broadened s, H-2)),

3.82 (3H, s, OCH₃), 3.77 (3H, s, OCH₃), 3.31 (1H, dd with additional

ﬁne coupling, J = 4.6, 17.7 Hz, H-4a), 2.95 (1H, dd, J = ca. 1.8,

17.7 Hz, H-4b), 1.92 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃,

75.46 MHz) d 170.3, 159.5, 154.1, 148.4, 130.2, 127.8, 119.0,

117.5, 114.3, 113.9, 113.8, 77.3, 68.3, 55.8, 55.3, 31.3, 20.9; EI-MS

(C₁₉H₂₀O₅requires MH⁺, m/z 328.1311, found: MH⁺, m/z 328.1316).

Colourless, viscous gum; yield 97%; ¹H NMR (CDCl₃, 300 MHz) d

7.18 (1H, ddm, J = 7.5, 8.1 Hz, H-7), 7.05 (1H, dm, J = 7.5 Hz, H-5),

6.95 (1H, dd, J = ca. 1.2, 8.1 Hz, H-8), 6.92 (1H, ddd, J = ca. 1.2, 7.5,

7.5 Hz, H-6), 6.86 (1H, dm, J = 1.7 Hz, H-2⁰), 6.84 (1H, ddd, J = ca.

0.6, 1.7, 7.9 Hz, H-6⁰), 6.78 (1H, d (with additional ﬁne coupling),

J = 7.9 Hz, H-5⁰), 5.958 and 5.956 (each 1H, d, J = ca. 1.4 Hz, OCH₂O),

5.31 (1H, sym m (ddd, J = 5.1, 6.4, 6.6 Hz), H-2), 5.07 (1H, broad-

ened d (unresolved m of d), J = 6.4 Hz, H-3), 3.06 (1H, dd, J = 5.1,

16.4 Hz, H-4a), 2.87 (1H, dd, J = 6.6, 16.4 Hz, H-4b), 1.98 (3H, s,

C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 170.1, 153.6, 147.9,

147.5, 132.0, 129.7, 128.0, 121.1, 120.1, 119.1, 116.5, 108.2,

106.9, 101.2, 78.3, 69.3, 29.1, 21.1; APCI-MS (C₁₈H₁₆O₅requires

MH⁺, m/z 313.1071, found: MH⁺, m/z 313.1072).

4.8.13. (2S,3R)-trans-3-Acetoxy-3⁰,4⁰-dimethoxy-6-

methylﬂavan (58a)

Colourless solid; quantitative yield; mp 84–85 °C; ¹H NMR

(CDCl₃, 300 MHz) d 6.98 (1H, dd, J = 1.8, 8.3 Hz, H-7), 6.92 (1H, ddd,

J = <0.5, ca. 1.8, 8.2 Hz, H-6⁰), 6.90–6.84 (3H, 3 ꢁ superimposed m,

H-5, H-2⁰and H-8), 6.82 (1H, d, J = 8.2 Hz, H-5⁰), 5.37 (1H, ddd,

J = 5.1, 6.4, 6.7 Hz, H-3), 5.11 (1H, d, J = 6.4 Hz, H-2), 3.87 (3H, s,

OCH₃), 3.85 (3H, s, OCH₃), 3.02 (1H, dd, J = 5.1, 16.6 Hz, H-4a), 2.84

(1H, dd, J = 6.7, 16.6 Hz, H-4b), 2.28 (3H, s, ArCH₃), 1.97 (3H, s,

C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 170.1, 151.5, 149.06,

149.00, 130.7, 130.2, 130.0, 128.5, 119.1, 118.8, 116.2, 111.1, 109.7,

78.3, 69.4, 55.9, 55.9, 29.2, 21.1, 20.5; EI-MS (C₂₀H₂₂O₅requires

MH⁺, m/z 342.1467, found: MH⁺, m/z 342.1464).

4.8.18. (2R,3S)-trans-3-Acetoxy-3⁰,4⁰-methylenedioxyﬂavan

(60b)

Colourless, viscous gum; yield 96%; NMR spectra correspond to

those reported above for the trans-(2S,3R)-enantiomer (60a); APCI-

MS (C₁₈H₁₆O₅requires MH⁺, m/z 313.1071, found: MH⁺, m/z

313.1069).

4.8.19. (2R,3R)-cis-3-Acetoxy-3⁰,4⁰-methylenedioxyﬂavan (68a)

Colourless solid; yield 82%; mp 95–96 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.38 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 7.18 (1H,

unresolved ddd, H-7), 7.10 (1H, unresolved dd, J = ca. 7.5 Hz, H-5),

6.97 (1H, unresolved dd, J = ca. 8.4 Hz, H-8), 6.93 (1H, superimposed

m (presumed ddd), H-6), 6.91 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and H-

5⁰), 5.40 (1H, sym m (ddd), H-3), 5.11 (1H, m as broadened s, H-2),

3.82 (3H, s, OCH₃), 3.31 (1H, dd, J = 4.6, 17.6 Hz, H-4a), 2.99 (1H,

dd, J = 2.0, 17.6 Hz, H-4b), 1.91 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃,

75.46 MHz) d 170.3, 159.6, 154.4, 130.1, 129.8, 127.8, 127.7, 121.1,

118.5, 116.9, 113.8, 77.3, 68.3, 55.3, 30.9, 20.9; APCI-MS (C₁₈H₁₆O₅

requires MH⁺, m/z 313.1071, found: MH⁺, m/z 313.1069).

4.8.14. (2R,3S)-trans-3-Acetoxy-3⁰,4⁰-dimethoxy-6-methylﬂavan

(58b)

Colourless solid; yield 98%; mp 83.5–85 °C; NMR spectra corre-

spond to those reported above for the trans-(2S,3R)-enantiomer

(58a); EI-MS (C₂₀H₂₂O₅requires MH⁺, m/z 342.1467, found: MH⁺,

m/z 342.1469).

4.8.15. (2S,3S)-cis-3-Acetoxy-3⁰,4⁰-dimethoxy-6-methylﬂavan

(67b)

4.8.20. (2S,3S)-cis-3-Acetoxy-3⁰,4⁰-methylenedioxyﬂavan (68b)

Colourless solid; quantitative yield; mp 95–96 °C; NMR spectra

correspond to those reported above for the trans-(2R,3R)-enantio-

mer (68a); APCI-MS (C₁₈H₁₆O₅requires MH⁺, m/z 313.1071, found:

MH⁺, m/z 313.1068).

Colourless solid; yield 88%; mp 123–124 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.05 (1H, d, J = 2.0 Hz, H-2⁰), 6.99 (1H, ddm (ddq,

J = ca. 1.9, 8.0, n/m Hz), H-7), 6.98 (1H, ddd, J = ca. 0.5, 2.0, 8.2 Hz,

H-6⁰), 6.90 (1H superimposed m (unresolved d), H-5), 6.89 (1H,

superimposed m (d, J = 8.0 Hz), H-8), 6.87 (1H, d, J = 8.2 Hz, H-5⁰),

5.40 (1H, sym m (ddd, J = 1.4, 2.2, 4.5 Hz), H-3), 5.06 (1H, m as

broadened s, H-2), 3.91 (3H, s, OCH₃), 3.89 (3H, s, OCH₃), 3.29

(1H, dd, J = 4.5, 17.7 Hz, H-4a), 2.95 (1H, dd, J = 2.2, 17.7 Hz, H-

4b), 2.29 (3H, s, ArCH₃), 1.92 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃,

75.46 MHz) d 170.4, 152.1, 148.90, 148.88, 130.6, 130.4, 130.1,

128.4, 118.9, 118.0, 116.6, 110.9, 109.9, 77.3, 68.5, 55.95, 55.94,

4.8.21. (2S,3R)-trans-3-Acetoxy-4⁰-methoxy-7-(phenylmeth-

oxy)ﬂavan (61a)

Off-white solid; quantitative yield; mp 111–113 °C; ¹H NMR

(CDCl₃, 300 MHz) d 7.46–7.30 (5H, m, benzyl Ar-H), 7.28 (2H, aa⁰bb⁰

‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 6.94 (1H, md (possibly td with cou-

pling to CH₂), J = 8.4 Hz, H-5), 6.88 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

7171

and H-5⁰), 6.60 (1H, d, J = 2.5 Hz, H-8), 6.59 (1H, dd, J = 2.5, 8.4 Hz,

H-6), 5.32 (1H, ddd, J = 5.0, 6.3, 6.6 Hz, H-3), 5.10 (1H, broadened d,

J = 6.3 Hz, H-2), 5.03 (2H, s, OCH₂), 3.80 (3H, s, OCH₃), 2.97 (1H, dd

(with additional ﬁne coupling), J = 5.0, 16.2 Hz, H-4a), 2.80 (1H, dd

(with possible additional ﬁne coupling), J = 6.6, 16.2 Hz, H-4b), 1.97

(3H, s, C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 170.1, 159.7, 158.9,

154.6, 137.2, 130.3, 130.2, 128.6, 127.9, 127.8, 127.5, 114.0, 111.6,

108.9, 102.6, 78.4, 70.2, 69.6, 55.3, 28.5, 21.0; APCI-MS (C₂₅H₂₄O₅

requires MH⁺, m/z 405.1697, found: MH⁺, m/z 405.1691).

4.8.26. cis-(2S,3S)-3-Acetoxy-4⁰-(phenylmethoxy)ﬂavan (70b)

Colourless solid; quantitative yield; mp 131–133 °C; ¹H NMR

(CDCl₃, 300 MHz) d 7.47–7.30 (5H, m, benzyl Ar-H), 7.38 (2H, aa⁰bb⁰

‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 7.18 (1H, m (unresolved ddd), H-7),

7.09 (1H, br

d

(unresolved dd), H-5), 6.98 (2H, aa⁰bb⁰‘d’,

J = 8.8 Hz, H-3⁰and H-5⁰), 6.97 (1H, superimposed m (dd), H-8),

6.93 (1H, apparent td (ddd, J = ca. 1.2, 7.4, 7.4 Hz), H-6), 5.41 (1H,

sym m, H-3), 5.10 (1H, m as broadened s, H-2), 5.08 (2H, s,

OCH₂), 3.31 (1H, dd, J = 4.4, 17.5 Hz, H-4a), 2.98 (1H, dd, J = 2.2,

17.5 Hz, H-4b), 1.91 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃,

75.46 MHz) d 170.3, 158.8, 154.4, 137.1, 130.4, 129.8, 128.6,

128.0, 127.8, 127.7, 127.5, 121.1, 118.5, 116.9, 114.8, 77.3, 70.2,

68.3, 30.9, 20.9; APCI-MS (C₁₉H₂₀O₅requires MH⁺, m/z 375.1591,

found: MH⁺, m/z 375.1591).

4.8.22. (2R,3R)-cis-3-Acetoxy-4⁰-methoxy-7-(phenylmethoxy)-

ﬂavan (69a)

Colourless solid (needles, hexane/EtOAc); yield 61%; mp 142–

143 °C; ¹H NMR (CDCl₃, 300 MHz) d 7.46–7.29 (5H, m, benzyl Ar-

H), 7.37 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 6.98 (1H, ‘m’ (dis-

torted d), H-5), 6.91 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and H-5⁰), 6.62

(1H, superimposed d, J = 2.5 Hz, H-8), 6.60 (1H, dd, J = 2.5, 7.5 Hz,

H-6), 5.38 (1H, sym m (ddd, J = 1.4, 2.3, 4.5 Hz), H-3), 5.08 (1H, m

(as broadened s), H-2), 5.04 (2H, s, OCH₂), 3.82 (3H, s, OCH₃),

3.23 (1H, dd, J = 4.5, 17.2 Hz, H-4a), 2.92 (1H, dd, J = 2.3, 17.2 Hz,

H₂-4b), 1.92 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d

170.3, 159.6, 158.8, 155.2, 137.2, 130.3, 130.1, 128.6, 127.9,

127.8, 127.5, 113.8, 110.9, 109.1, 102.9, 77.4, 70.3, 68.4, 55.3,

30.3, 20.9; APCI-MS (C₂₅H₂₄O₅requires MH⁺, m/z 405.1697, found:

MH⁺, m/z 405.1688).

4.9. General procedure for the deprotection of benzyloxy

substituted 3-acetoxyﬂavans

A mixture of the precursor benzyloxy compound (61a, 62a,b,

63b, 69a, 70a) (1.0 mmol) and Pd(OH)₂–C (50 mg, 20% on C) in

MeOH/THF (1:1, 20 mL) was stirred vigorously at room tempera-

ture under H₂(1 atm) for 6 h. The reaction mixture was ﬁltered

through Celite to remove catalyst and the ﬁltrate concentrated un-

der reduced pressure to yield a glassy off-white solid. Column

chromatography (DCM/EtOAc 19:1) afforded the pure product.

4.9.1. trans-(2S,3R)-3-Acetoxy-7-hydroxy-4⁰-methoxyﬂavan

(71a)

4.8.23. (2S,3R)-trans-3-Acetoxy-3⁰,4⁰-dimethoxy-7-(phenyl-

methoxy)ﬂavan (62a)

Colourless foam; yield 99%; ¹H NMR (CDCl₃, 300 MHz) d 7.27

(2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 6.89 (1H, md, J = 8.0 Hz,

H-5), 6.87 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and H-5⁰), 6.46 (1H, d,

J = 2.5 Hz, H-8), 6.43 (1H, dd, J = 2.5, 8.0 Hz, H-6), 5.32 (1H, sym

m (ddd, J = 5.0, 6.2, 6.5 Hz), H-3), 5.10 (1H, d, J = 6.2 Hz, H-2), 5.1

variable (1H, br s, OH), 3.80 (3H, s, OCH₃), 2.95 (1H, dd (with addi-

tional ﬁne coupling), J = 5.0, 16.2 Hz, H-4a), 2.79 (1H, dd, J = 6.5,

16.2 Hz, H-4b), 1.97 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃,

75.46 MHz) d 170.4, 159.6, 155.6, 154.6, 130.4, 130.2, 127.7,

114.1, 111.3, 108.8, 103.3, 78.3, 69.7, 55.3, 28.4, 21.0.

Colourless solid; yield 93%; mp 116–117.5 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.46–7.29 (5H, m, benzyl Ar-H), 6.95 (1H, dm, J = ca.

8.3 Hz, H-5), 6.91 (1H, partly superimposed m (ddd, J = ca. 0.5,

1.9, 8.5 Hz), H-6⁰), 6.87 (1H, d, J = 1.9 Hz, H-2⁰), 6.83 (1H, d,

J = 8.5 Hz, H-5⁰), 6.61 (1H, d, J = 2.6 Hz, H-8), 6.59 (1H, dd, J = 2.6,

8.3 Hz, H-6), 5.35 (1H, ddd, J = 5.1, 6.4, 6.7 Hz, H-3), 5.08 (1H,

broadened d (or d of unresolved m), J = 6.4 Hz, H-2), 5.04 (2H, s,

OCH₂), 3.87 (3H, s, OCH₃), 3.84 (3H, s, OCH₃), 2.98 (1H, dd, J = 5.1,

16.1 Hz, H-4a), 2.81 (1H, dd, J = 6.7, 16.1 Hz, H-4b), 1.97 (3H, s,

C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 170.1, 158.8, 154.5,

149.26, 149.24, 137.1, 130.7, 130.2, 128.6, 127.9, 127.4, 119.2,

111.6, 111.4, 109.9, 108.9, 102.5, 78.5, 70.2, 69.5, 56.0, 56.0, 28.6,

21.0; APCI-MS (C₂₅H₂₄O₅requires MH⁺, m/z 435.1802, found:

MH⁺, m/z 435.1802).

4.9.2. trans-(2S,3R)-3-Acetoxy-3⁰,4⁰-dimethoxy-7-

hydroxyﬂavan (72a)

Faintly pink solid; quantitative yield; mp 64–66 °C; ¹H NMR

(CDCl₃, 300 MHz) d 6.93–6.86 (3H, 3 ꢁ superimposed m, H-5, H-

2⁰and H-6⁰), 6.83 (1H, d, J = 8.2 Hz, H-5⁰), 5.47 (1H, d, J = 2.5 Hz,

H-8), 6.44 (1H, dd, J = 2.5, 8.2 Hz, H-6), 5.34 (1H, sym m (ddd,

J = 5.0, 6.3, 6.7 Hz), H-3), 5.10 (1H, br s, OH), 5.08 (1H, d,

J = 6.3 Hz, H-2), 3.87 (3H, s, OCH₃), 3.85 (3H, s, OCH₃), 2.96 (1H,

dd, J = 5.0, 16.3 Hz, H-4a), 2.80 (1H, dd, J = 6.7, 16.3 Hz, H-4b),

1.97 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 170.4,

155.5, 154.4, 149.01, 148.98, 130.5, 130.4, 119.1, 111.2, 111.1,

109.5, 108.8, 103.2, 78.4, 69.5, 55.92, 55.91, 28.5, 21.1.

4.8.24. (2R,3S)-trans-3-Acetoxy-3⁰,4⁰-dimethoxy-7-(phenyl-

methoxy)ﬂavan (62b)

Colourless solid; quantitative yield; mp 115–117 °C; NMR spec-

tra correspond to those reported above for the trans-(2S,3R)-enan-

tiomer (62a); APCI-MS (C₂₅H₂₄O₅requires MH⁺, m/z 435.1802,

found: MH⁺, m/z 435.1797).

4.8.25. trans-(2R,3S)-3-Acetoxy-4⁰-(phenylmethoxy)ﬂavan

(63b)

4.9.3. trans-(2R,3S)-3-Acetoxy-3⁰,4⁰-dimethoxy-7-

hydroxyﬂavan (72b)

Faintly pink solid; quantitative yield; mp 63–65 °C; NMR spec-

tra correspond to those reported above for the trans-(2S,3R)-enan-

tiomer (72a).

Colourless solid; yield 97%; mp 102–103 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.45–7.30 (5H, m, benzyl Ar-H), 7.29 (2H, aa⁰bb⁰‘d’,

J = 8.8 Hz, H-2⁰and H-6⁰), 7.18 (1H, ddd, J = ca. 1.6, 7.5, 8.1 Hz, H-

7), 7.05 (1H, dd, J = ca. 1.6, 7.5 Hz, H-5), 6.96 (1H, superimposed

m (dd), H-8), 6.95 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰and H-5⁰), 6.92

(1H, superimposed m (ddd, J = 1.2, 7.5, 7.5 Hz), H-6), 5.34 (1H, m

(ddd, J = 5.0, 6.2, 6.5 Hz), H-3), 5.13 (1H, d, J = 6.2 Hz, H-2), 5.05

(2H, s, OCH₂), 3.05 (1H, dd, J = 5.0, 16.5 Hz, H-4a), 2.85 (1H, dd,

J = 6.5, 16.5 Hz, H-4b), 1.96 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃,

75.45 MHz) d 170.1, 158.9, 153.9, 137.0, 130.7, 129.7, 128.6,

128.0, 127.9, 127.8, 127.5, 121.0, 119.2, 116.6, 115.1, 78.3, 70.2,

69.5, 29.2, 21.0; APCI-MS (C₁₉H₂₀O₅requires MH⁺, m/z 375.1591,

found: MH⁺, m/z 375.1591).

4.9.4. trans-(2R,3S)-3-Acetoxy-4⁰-hydroxyﬂavan (73b)

Faintly pink solid; yield 98%; mp 50–52 °C; ¹H NMR (CDCl₃,

300 MHz) d 7.24 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and H-6⁰), 7.18

(1H, m (non-resolved ddd), H-7), 7.06 (1H, non-resolved dd, H-5),

6.96 (1H, superimposed non-resolved dd, H-8), 6.92 (1H, superim-

posed non-resolved ddd, H-6), 6.79 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-3⁰

and H-5⁰), 5.44 (1H, br s, OH), 5.35 (1H, sym m (ddd, J = 5.2, 6.2,

6.9 Hz), H-3), 5.08 (1H, d, J = 6.5 Hz, H-2), 3.06 (1H, dd, J = 5.2,

7172

K. N. Mewett et al. / Bioorg. Med. Chem. 17 (2009) 7156–7173

16.0 Hz, H-4a), 2.89 (1H, dd, J = 6.9, 16.0 Hz, H-4b), 1.97 (3H, s,

C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 170.4, 155.7, 153.7,

130.2, 129.8, 127.9, 127.9, 121.0, 119.1, 116.6, 115.4, 78.3, 69.4,

29.2, 21.1.

tion in the perfusate was 0.6% and did not produce any alteration in

the recording. Current measurements were obtained using a Gene-

clamp 500 voltage clamp ampliﬁer (Axon Instruments INC, Foster

City, CA), a MacLab/8 recorder (ADInstruments, Sydney, NSW, Aus-

tralia) and Chart program v3.6. Responses were graphed as

mean SEM from at least three oocytes from at least two different

batches.

Modulation of GABA-elicited currents was tested by applying

the sample drugs at 30 lM with a concentration of GABA that pro-

duced 5% of maximal activation (EC₅). A 5–10 min washout period

was allowed between drug applications to avoid receptor desensi-

4.9.5. cis-(2S,3S)-3-Acetoxy-4⁰-methoxy-7-hydroxyﬂavan (74a)

Faintly pink solid; quantitative yield; mp 147–148.5 °C; ¹H

NMR (CDCl₃, 300 MHz) d 7.37 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz, H-2⁰and

H-6⁰), 6.94 (1H, d, J = 8.2 Hz, H-5), 6.91 (2H, aa⁰bb⁰‘d’, J = 8.8 Hz,

H-3⁰and H-5⁰), 6.46 (1H, superimposed m (d, J = 2.5 Hz), H-8),

6.44 (1H, dd, J = 2.5, 8.2 Hz, H-6), 5.38 (1H, sym m, H-3), 5.08

(1H, s, H-2), 5.02 (1H, br s, OH), 3.82 (3H, s, OCH₃), 3.23 (1H, dd,

J = 4.4, 17.2 Hz, H-4a), 2.90 (1H, dd, J = 2.2, 17.2 Hz, H-4b), 1.92

(3H, s, C(O)CH₃); ¹³C NMR (CDCl₃, 75.46 MHz) d 170.6, 159.5,

155.3, 155.1, 130.5, 129.9, 127.8, 113.7, 110.6, 108.8, 103.5, 77.3,

68.4, 55.3, 30.3, 21.0.

tisation. For comparison of doses at 30

lised to the response to 30

M 55a⁷on the same cell (n 6 5). For

the dose–response curves the responses were recorded and norma-

lM, responses were norma-

l

lised as: percentage potentiation = (I_drugꢀ I_GABA) ꢁ 100/I_GABA

,

where I_drugis the current in the presence of a given concentration

of the drug, and I_GABAis amplitude of the control GABA current

(n P 8).

4.9.6. cis-(2S,3S)-3-Acetoxy-4⁰-hydroxyﬂavan (75b)

Faintly pink solid; quantitative yield; mp 51–53 °C; ¹H NMR

(CDCl₃, 300 MHz) d 7.33 (2H, aa⁰bb⁰‘d’, J = 8.6 Hz, H-2⁰and H-6⁰),

7.18 (1H, m (non-resolved ddd), H-7), 7.10 (1H, non-resolved dd,

H-5), 6.96 (1H, superimposed non-resolved dd, H-8), 6.93 (1H,

ddd, J = 1.2, 7.4, 7.4 Hz, H-6), 6.82 (2H, aa⁰bb⁰‘d’, J = 8.6 Hz, H-3⁰

and H-5⁰), 5.43 (1H, sym m (ddd), H-3), 5.32 (1H, br s, OH), 5.10

(1H, s, H-2), 3.33 (1H, dd, J = 4.3, 17.5 Hz, H-4a), 2.98 (1H, dd,

J = 1.8, 17.5 Hz, H-4b), 1.92 (3H, s, C(O)CH₃); ¹³C NMR (CDCl₃,

75.46 MHz) d 170.7, 155.6, 154.3, 130.0, 129.8, 127.9, 127.7,

121.1, 118.4, 116.9, 115.2, 77.2, 68.3, 30.9, 21.0.

Acknowledgements

This research was supported by a Grant from the National

Health and Medical Research Council (NHMRC) of Australia.

S.O.D. is supported by an Australian Postgraduate Award.

Supplementary data

¹H NMR data for compounds. Crystallographic data (excluding

factors) for the structures in this paper have been deposited with

the Cambridge Crystallographic Data Centre as supplementary

publication Nos. CCDC 733419, 733420, 733421 and 733425 for

55a, 41a, 64a and 37a, respectively. Copies of the data can be ob-

tained, free of charge, on application to CCDC, 12 Union Road, Cam-

bridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:

deposit@ccdc.cam.ac.uk). Supplementary data associated with this

article can be found, in the online version, at doi:10.1016/

j.bmc.2009.08.062.

4.10. Biological protocol

cDNA for human

a₁, b₂and c_2LGABA_Areceptor subunits sub-

cloned into pCDM8 were provided by Dr. Paul Whiting (Merck,

Sharpe and Dohme Research Labs, Harlow, UK). The protocol for

in vitro transcription of cRNA has been previously described.^9,31

Brieﬂy, cDNA vectors were linearised with the appropriate restric-

tion endonucleases and capped transcripts were produced from

linearised plasmids using the mMessage mMachine T7 transcrip-

tion kit (Ambion, Austin, TX). cRNA was diluted and stored in

diethylpyrocarbonate treated water at –80 °C. The procedure

involving the extraction, separation, and enzymatic treatment of

X. laevis oocytes was identical to that previously described.⁹Stage

V–VI oocytes were selected and injected (Nanoject, Drummond

Scientiﬁc Co., Broomali, PA) with 2–3 ng of cRNA in a 1:1:2 ratio

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Synthesis and biological evaluation of flavan-3-ol derivatives as positive modulators of GABAA receptors

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