Oligomeric isoflavonoids. Part 4. Synthesis of the daljanelin class of isoflavonoid-neoflavonoid dimers

Article abstract of DOI:10.1039/a904944d

A protocol of introducing an electrophilic C₁ fragment to a pterocarpan nucleus, followed by anionic coupling of a C₆-C₂ benzofuranoid precursor and late introduction of the final C₆ fragment, permitted the synt

Full text of DOI:10.1039/a904944d

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Oligomeric isoflavonoids. Part 4.† Synthesis of the daljanelin class
of isoflavonoid–neoflavonoid dimers
Mark B. Rohwer,a Pieter S. van Heerden,a E. Vincent Brandt,a Barend C. B. Bezuidenhoudta
and Daneel Ferreira*b
a Department of Chemistry, University of the Orange Free State, PO Box 339,
Bloemfontein, 9300 South Africa
b National Center for Natural Products Research, Research Institute of Pharmaceutical
Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA
Received (in Cambridge, UK) 21st June 1999, Accepted 9th September 1999
A protocol of introducing an electrophilic C1 fragment to a pterocarpan nucleus, followed by anionic coupling of a
C6–C2 benzofuranoid precursor and late introduction of the final C6 fragment, permitted the syntheses of daljanelins
B 3 and D 5. The feasibility of introducing the same electrophilic C1 fragment to C-2 of the pterocarpan moiety to
obtain a precursor to daljanelin A 2 was also demonstrated.
Iso- and neoflavonoids are less abundant in nature than the
corresponding flavonoids, and a similar distorted distribution
exists between isoflavonoid- and flavonoid-based oligomers.1–3
Mono- and oligomeric iso- and neoflavonoids are credited with
the biological activity of some of the plants used in traditional
medicine.4,5 Our recent identification of the first isoflavonoid–
neoflavonoid dimers and the synthesis of a single member,
daljanelin C 4,4 prompted us to synthesize the remaining
analogues in order to obtain unequivocal confirmation of their
molecular frameworks and absolute configurations.
The structures of the four isoflavonoid–neoflavonoid dimers,
daljanelins A–D 2–5 were established by means of spectro-
scopic methods.4 Owing to the preferential bromination and
hence facile introduction of the C1 fragment at C-8 (D-ring) of
the pterocarpan, (ϩ)-(6aS,11aS)-medicarpin 1,6 daljanelin C 4
was selected as the initial synthetic target.4 The deactivating
effect of the benzylic C-11a oxygen function on the susceptibil-
ity of the A-ring of (ϩ)-medicarpin 1 towards electrophilic
aromatic substitution necessitated a different approach to
introduce the C1 fragment at C-2 and C-4 to that used to
functionalize the same pterocarpan at C-8 in the synthesis of
daljanelin C 4.4 Cognizance also had to be taken of the acid
lability of the C-11a–O-11 bond4 and hence the risk of racemiz-
ation at C-6a and C-11a of the pterocarpan.
Thus, (ϩ)-medicarpin 1 was converted into the 3-O-allyl
ether 8 (87% yield) using allyl bromide–K2CO3 in anhydrous
acetone (Scheme 1). The allyl ether 8 was subjected to regio-
selective Claisen rearrangement7 by refluxing in N,N-dimethyl-
aniline to give (6aS,11aS)-4-allylmedicarpin 9 in 47% yield.
Alkylation at C-4 (see also ref. 6) of the pterocarpan nucleus
[the equivalent of C-8 of flavonoids/isoflavonoids without the
pterocarpan C-ring, e.g. (ϩ)-vestitol 6] is unique since it repre-
sents the only method hitherto to functionalize this site of
analogues with resorcinol-type A-rings.
The (6aS,11aS)-4-allylmedicarpin 9 was purified by crystal-
lization of its 3,5-dinitrobenzoate 10 (51%). The 4-(prop-2-enyl)
substituent of benzoate 10 was then converted to the 4-(prop-1-
enyl) group in compound 11 (92%) via facile Pd()-catalyzed
olefin isomerization.8,9 The olefinic double bond of benzoate 11
resisted all efforts at dihydroxylation with osmium tetroxide.
Thus, 11 was first debenzoylated and the resulting phenol 12
(84%) protected as methoxymethyl derivative 13 (59%). Oxid-
ation of 13, using the Upjohn method,10 gave the glycol 14
Scheme 1 Introduction of the methylene function at C-4 of (ϩ)-
medicarpin 1. Reagents and conditions: i, CH2᎐᎐CHCH2Br, Me2CO,
K2CO3, reflux; ii, reflux in N,N-dimethylaniline; iii, 3,5-di-NO2-benzoyl
chloride–pyridine; iv, Pd(PhCN)2Cl2, reflux in benzene; v, KOH–
MeOH; vi, NaH, THF, then ClCH2OMe; vii, OsO4–NMO in Me2CO at
0 ЊC; viii, NaIO4; ix, LiBr, Ms2O, 2,6-lutidine.
(59%) which was then oxidatively cleaved with sodium period-
ate. Subsequent reduction of the ensuing aldehyde 15 (73%)
with sodium borohydride afforded the hydroxymethyl com-
pound 16 (86%). Substitution at C-4 in compounds 9–16 was
confirmed by 1H NMR data (Table 1) reflecting an AB-system
† For Part 3, see ref. 4.
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Table 2 1H NMR peaks (ppm) of the synthetic intermediates 19 and 20 (27 ЊC) at 300 MHz. Splitting patterns and J-values (Hz) are given in
parentheses
Ring
Proton
19
20
A
B
1
2
6ax
6eq
6a
11a
7
8
10
CH2
7.44 (2 × d, 9.0 each)
6.92 and 6.91 (2 × d, 9.0 each)
3.68–3.57 (m)
4.35–4.25 (2 × m)
3.68–3.57 (m)
5.57 and 5.56 (2 × d, 7.0 each)
7.15 (2 × d, 9.0 each)
6.47 (2 × dd, 3.0, 9.0 each)
6.47 and 6.44 (2 × d, 3.0 each)
3.27 and 3.26 (2 × dd, 5.0, 14.0 each)
3.14 and 3.12 (dd, 10.0, 14.0 each)
7.39 and 7.38 (2 × s)
6.51 and 6.48 (2 × s)
—
4.91 and 4.88 (2 × dd, 5.0, 10.0 each)
3.94, 3.90, 3.79 and 3.78 (4 × s)
5.24, 5.22, 5.20 and 5.19 (4 × s)
3.53, 3.52 and 3.48 (×2) (3 × s)
—
7.35–7.29 and 7.26–7.11 (overlapped)
6.74 (2 × d, 9.0 each)
3.63–3.46 (m)
4.23–4.20, 4.16 and 4.13 (2 × ddd, 1.0, 5.0, 10.0 each)
3.63–3.46 (m)
5.44 and 5.42 (2 × d, 7.0 each)
7.35–7.29 and 7.26–7.11 (overlapped)
6.51–6.44
D
6.51–6.44
3.33–3.20 (m)
E
4
7
6.78 (s)
6.54 and 6.45 (2 × s)
7.35–7.29 and 7.26–7.11 (m)
5.11–4.92 (m)
3.87, 3.86, 3.79 and 3.78 (4 × s)
5.05, 5.04 and 5.02 (×2) (3 × s)
3.45, 3.44, 3.38 and 3.35 (4 × s)
2.91 (s)
F
G
OMe
OCH2OMe
OCH2OMe
OH
Scheme 2 Coupling of neoflavonoid precursor 18 to bromomethylmedicarpin 17 and conversion of daljanelin B 3 to daljanelin D 5. Reagents and
conditions: i, TASF–HMPA, then aq. NH4Cl; ii, PhMgBr–THF, then 3 M HCl, 0 ЊC; iii, 0.1 M HCl–MeOH, reflux; iv, Na(CN)BH3–TFA, 0 ЊC.
for H-1 and H-2 (e.g. δ 7.33, 6.60, respectively, J = 8.0 Hz for 9)
and indicating long-range coupling between H-1 and the C-11a
benzylic proton. A similar observation of benzylic coupling
between H-1 and H-11a and/or between H-7 and H-6a was also
used to define structures 21–28 (vide infra).
The last steps of the synthesis of daljanelin B 3 are out-
lined in Scheme 2 and are similar to those utilized in the syn-
thesis of daljanelin C 4.4 Preparation of the highly labile benzyl
bromide 17 from the corresponding hydroxymethyl compound
16 was accomplished in quantitative yield via the Collington–
Meyers protocol11 using a mixture of methanesulfonic anhy-
dride, lithium bromide and 2,6-lutidine in THF.‡ Coupling
of the bromide 17 and the stable silyl enol ether 18, prepared
by the literature procedure,4 was effected in 32% yield via
the TASF [tris(dimethylamino)sulfonium difluorotrimethyl-
silicate]–HMPA procedure4,12 to give the C-alkylated product
19 as a diastereoisomeric mixture, as was evident from the
double set of resonances in its H NMR spectrum (Table 2).
1
Grignard reaction of compound 19 with phenylmagnesium
bromide in THF afforded a diastereoisomeric mixture (22%) of
alcohol 20. This mixture was refluxed in methanol containing
0.1 mol dmϪ3 hydrochloric acid to effect simultaneous deprotec-
1
tion and dehydration, affording daljanelin B 3 (24%), the H
NMR and CD data identical to those of the natural product.4
Daljanelin D 5 should, in principle, be accessible via reduc-
tive cleavage of the benzylic C-11a–O-11 ether bond of daljan-
elin B 3. Owing to the presence of the electron-rich olefinic bond
in the G-ring of daljanelin B 3 and in view of our experience
with the relative inertia of (ϩ)-medicarpin 1 towards catalytic
hydrogenation under a variety of conditions,13 we were hesitant
to employ the hydrogenolysis protocol. Utilization of sodium
cyanoborohydride [Na(CN)BH3] in TFA14,15 to reduce (ϩ)-
medicarpin 1, led to the formation of (ϩ)-(3S)-vestitol 6 (85%)
1
‡ The H NMR spectrum used to monitor the reaction indicated the
4-methylene protons of 17 as an AB system in contrast to the broad-
ened multiplet in benzyl alcohol 16.
1
in optically pure form (see Experimental for H NMR data of
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its Mosher’s ester). Such cleavage of the pterocarpan C-ring
with retention of configuration at C-3 of (ϩ)-vestitol 6 was
effected by maintaining an excess of Na(CN)BH3 while slowly
adding a dilute solution of TFA in THF. Daljanelin B 3 was
subsequently subjected to the same conditions leading to facile
conversion into daljanelin D 5 in 70% yield (Scheme 2). Its 1H
NMR and CD data were identical to those of the natural
product.4
Finally, we explored methods to introduce the requisite C1
fragment at C-2 of (ϩ)-medicarpin 1 in order to produce the
precursor 28 to the synthesis of daljanelin A 2 (Scheme 3)
Fig. 1 CD curves of (ϩ)-(6aS,11aS)-medicarpin 1 and (6aS,11aS)-2-
ethoxycarbonyl-3-O-methoxymethylmedicarpin 28.
in the syntheses of daljanelins B 3 and C 4. Compound 28 had
a CD spectrum which was virtually identical to that of (ϩ)-
medicarpin (Fig. 1).
Although the synthetic sequences in Schemes 2 and 3 resulted
in low overall yields, our objective to functionalize (ϩ)-
medicarpin 1 at C-2 and C-4 of its deactivated A-ring, without
affecting the C-6a and C-11a stereocentres, and hence to pro-
vide precursors to the syntheses of the natural products 2, 3 and
5, was indeed realized.
Experimental
1H NMR spectra were recorded on a Bruker Avance DPX 300
spectrometer for solutions in CDCl3 with TMS as internal
standard. MS and accurate mass estimations were obtained
using a VG 70-70E instrument. Since the majority of the syn-
thetic intermediates are isomeric to those described in the
Scheme 3 Introduction of the C1 fragment at C-2 of (ϩ)-medicarpin
1. Reagents and conditions: i, HBr–DMSO; ii, NaH–THF, then
ClCH2OMe; iii, n-BuLi, then aq. NH4Cl; iv, BuLi–TMEDA, then
ClCO2Et, then aq. NH4Cl.
1
synthesis of daljanelin C 4 (see ref. 4), we regarded H NMR
(Table 3 for 1H NMR data of analogues 21–28). Thus, bromin-
ation of (ϩ)-medicarpin 1 using hydrogen bromide in DMSO16
afforded both the 8-bromo- 21 (39%) and 2,8-dibromo- 22
(16%) derivatives. Since conditions permitting dibromination
invariably led to ca. 50% loss of material, we persisted with
HBr–DMSO because the 8-bromo derivative 21 could eventu-
ally be recycled. The 2,8-dibromomedicarpin 22 was protected
as the 3-O-methoxymethyl ether 23 (79%), this compound
being available for preparative purposes in a combined yield of
30%. Treatment of the protected derivative 23 with butyllithium
and subsequent protic quenching gave a mixture comprising the
starting material 23 (17%), the 2-debromo analogue 24 (20%)
and the fully debrominated compound 25 (13%). The formation
of the (6aS,11aS)-8-bromo-3-O-methoxymethylmedicarpin
24 indicates the feasibility of regioselective metal–halogen
exchange at C-2 of the dibromo analogue 23 in order to intro-
duce the electrophilic C1 fragment at this site.
However, when the (6aS,11aS)-2,8-dibromomedicarpin 23
was reacted for 30 min with 1.1 eq. of n-BuLi, solvated with
2.5 eq. of TMEDA, and 6 eq. of ethyl chloroformate, only the
2,8-dibromo-4-ethoxycarbonylmedicarpin derivative 26 (14%)
could be isolated. Its formation was unexpected since lithium–
halogen exchange with n-BuLi is usually a fast and facile reac-
tion capable of competing with protonation of the aryllithium
by H2O (D2O) or even an intramolecular carboxylic acid. The
preferential lithiation at C-4 may be facilitated by extensive
complexation of the resulting aryllithium 29, i.e. a resorcylic
directed ortho metalation process.17,18 The 8-bromo-2-ethoxy-
carbonylmedicarpin 27 was eventually formed in low yield
(14%) by adding the ethyl chloroformate ca. 3 min after addi-
tion of the n-BuLi–TMEDA to the 2,8-dibromomedicarpin
derivative 23. Debromination of the 8-bromo compound 27
using n-BuLi–TMEDA and an aqueous workup afforded the
2-ethoxycarbonylmedicarpin 28 (40%), i.e. a precursor to the
synthesis of daljanelin A by implementing the protocol utilized
and HRMS data as sufficient for confirmation of these struc-
tures. CD data were obtained in MeOH on a Jasco J710
spectropolarimeter. TLC was performed on precoated Merck
plastic sheets (silica gel 60 PF254) which were sprayed with
H2SO4–HCHO (40:1) after development. Preparative TLC
plates (PLC) (Kieselgel PF254, 1.0 mm) were air-dried and used
without prior activation. Flash column chromatography (CC)
was carried out in a glass column of appropriate diameter
charged with Merck Kieselgel 60 (230–400 mesh) at a flow rate
of 30 mm minϪ1 under N2 pressure.
(6aS,11aS)-3-O-Allylmedicarpin 8
A solution of (ϩ)-(6aS,11aS)-medicarpin 1 (500 mg; 1.85
mmol) and allyl bromide (ca. 10 eq.) in anhydrous acetone (ca.
10 eq. v/m) was refluxed over anhydrous K2CO3 (2–5 eq. m/m)
under N2 until TLC indicated complete conversion of the start-
ing material. The K2CO3 was filtered off, the precipitate washed
with anhydrous acetone, the filtrates combined and the acetone
removed under reduced pressure. PLC (n-hexane–benzene–
acetone, 5:4:1, v/v) gave the title compound 8 (457 mg, 80%) as
a viscous light yellow oil (Rf 0.6) (Found: Mϩ, 310.1204.
C19H18O4 requires M, 310.1205); 1H NMR (Table 1).
(6aS,11aS)-4-Allylmedicarpin 9
A solution of (6aS,11aS)-3-O-allylmedicarpin 8 (1 g, 3.22
mmol) in N,N-dimethylaniline (ca. 10 eq. v/m) was refluxed
under Ar until TLC indicated complete or near-complete con-
version of the starting material. A copious amount of ice was
added to the cooled reaction mixture, and 3 M HCl (ca. 10
volumes) was added slowly. The aqueous phase was extracted
with ethyl acetate, and the combined organic extracts were
washed successively with ice-cold 3 M HCl, sat. aq. NaHCO3
and brine. The extract was dried (MgSO4) and the solvent
removed under reduced pressure. Flash CC (n-hexane–ethyl
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acetate, 8:2, v/v) gave the title compound 9 (553 mg, 55%) as
a viscous light brown oil (Rf 0.3); (Found: Mϩ, 310.1203.
C19H18O4 requires M, 310.1205); 1H NMR (Table 1).
6:4, v/v) gave (E/Z)-(6aS,11aS)-3-O-methoxymethyl-4-(prop-
1-enyl)medicarpin 13 (201 mg, 61%) as an amorphous white
solid (Rf 0.6) (Found: Mϩ, 354.1466. C21H22O5 requires M,
354.1467); 1H NMR (Table 1).
(6aS,11aS)-4-Allyl-3-O-(3Ј,5Ј-dinitrobenzoyl)medicarpin 10
(6aS,11aS)-4-(1,2-Dihydroxypropyl)-3-O-methoxymethyl-
Impure (6aS,11aS)-4-allylmedicarpin 9 (553 mg) was dissolved
in a minimal volume of pyridine, 3,5-dinitrobenzoyl chloride
(1.5 eq.) added, and the mixture was left standing at ca. 30 ЊC
for ca. 12 h. The reaction was quenched by addition of ice and
the crude product was taken up in ethyl acetate. The organic
phase was washed successively with H2O, sat. aq. CuSO4
(twice), H2O, sat. aq. NaHCO3 and H2O, dried (MgSO4), and
the solvent was removed under reduced pressure. Crystalliz-
ation from ethyl acetate gave the title compound 10 (429 mg;
26% based on 1 g of (6aS,11aS)-3-O-allylmedicarpin 8) as
orange needles (mp, 186–187 ЊC) (Found: Mϩ, 504.116.
C26H20O9 requires M, 504.1169); 1H NMR (Table 1).
medicarpin 14
(E/Z)-(6aS,11aS)-3-O-Methoxymethyl-4-(prop-1-enyl)medi-
carpin 13 (180 mg, 508 µmol) was added to a mixture of
N-methylmorpholine N-oxide (NMO) (1.1 eq. based on 1 mmol
of olefin), H2O (15 cm3), acetone (30 cm3), tert-butyl alcohol
(3 cm3) and OsO4 (5–20 mol%). The mixture was stirred at rt
under N2 until TLC indicated no further conversion of start-
ing material (typically 3–18 h). The reaction was quenched by
the addition of a slurry of NaHSO3 (100 mg) and commercial
Florisil (1 g) in H2O (50 cm3). After filtration and washing
(acetone, 3 × 10 cm3) of the Florisil, the combined filtrates
were neutralized to pH 7 with 3 M HCl, the acetone removed
under reduced pressure, the aqueous residue cooled by the addi-
tion of ice and acidified further to pH 2. The solution was
saturated with NaCl and extracted with ethyl acetate (3 × 50
cm3), the combined extracts washed successively with sat. aq.
NaHCO3 and H2O, dried (MgSO4) and the solvent removed
under reduced pressure. Flash CC (n-hexane–ethyl acetate, 6:4,
v/v) gave the title compound 14 (121 mg, 61%) as an amorph-
ous white solid (Rf 0.4) (Found: Mϩ, 388.1522. C21H24O7
requires M, 388.1522); 1H NMR (Table 1).
(E/Z)-(6aS, 11aS)-3-O-(3Ј,5Ј-Dinitrobenzoyl)-4-(prop-1-enyl)-
medicarpin 11
PdCl2(PhCN)2 was prepared by heating PdCl2 (500 mg; 2.82
mmol) in PhCN (ca. 8 cm3) under Ar to 100 ЊC until dis-
solution. The mixture was cooled and the solids filtered. A
second crop of product was precipitated from the mother liquor
with petroleum ether (bp 40–60 ЊC) and filtered. The combined
precipitates were washed with petroleum ether (bp 40–60 ЊC),
dried in a vacuum oven at ca. 35 ЊC and stored under Ar until
use. Yield: 792 mg (73%).
(6aS,11aS)-4-Formyl-3-O-methoxymethylmedicarpin 15
A solution of (6aS,11aS)-4-allyl-3-O-(3Ј,5Ј-dinitrobenzoyl)-
medicarpin 10 (306 mg, 607 µmol) and PdCl2(PhCN)2 (5–10 eq.
m/m) was refluxed in benzene under Ar until 1H NMR spectra
of reaction aliquots indicated complete or near-complete con-
version of the allyl group to a prop-1-enyl group. The catalyst
was removed by elution with acetone through a short silica gel
plug, and the eluate was concentrated under reduced pressure.
Flash CC (n-hexane–benzene–acetone, 60:35:5, v/v) gave an
inseparable E:Z-mixture (302 mg, 99%; Rf 0.25) of the
title compound 11 as yellow needles (Found: Mϩ, 504.1168.
C26H20N2O9 requires M, 504.1169); 1H NMR (Table 1).
A solution of NaIO4 (2.5 eq.) in H2O (ca. 1 cm3) was added
slowly to a solution of (6aS,11aS)-4-(1,2-dihydroxypropyl)-3-
O-methoxymethylmedicarpin 14 (110 mg, 283 µmol) in meth-
anol (ca. 10 cm3) and the mixture was stirred at rt until TLC
indicated complete conversion of the starting material. The
methanol was evaporated under reduced pressure, the residue
taken up in H2O and the aqueous phase extracted with ether.
The combined organic extracts were dried (MgSO4) and the
solvent removed under reduced pressure. PLC (n-hexane–ethyl
acetate, 6:4, v/v) gave the title compound 15 (71 mg, 73%) as a
viscous light yellow oil (Rf 0.3) (Found: Mϩ, 342.1102. C19H18O6
requires M, 342.1103); 1H NMR (Table 1).
(E/Z)-(6aS,11aS)-4-(Prop-1-enyl)medicarpin 12
(E/Z)-(6aS,11aS)-3-O-(3Ј,5Ј-Dinitrobenzoyl)-4-(prop-1-enyl)-
medicarpin 11 (623 mg, 1.24 mmol) was dissolved in methanol
(ca. 10 eq. v/m) and a 2% solution of KOH in methanol
(ca. 10 eq. v/m) was added slowly. The mixture was stirred
at gentle reflux until TLC indicated no further conversion of
starting material. The cooled mixture was poured into an excess
of ice–H2O, and the aqueous phase was acidified to pH 5 and
extracted with ethyl acetate. The combined organic extracts
were washed with sat. aq. NaHCO3 and H2O, dried (MgSO4)
and the solvent removed under reduced pressure. PLC
(n-hexane–ethyl acetate, 7:3, v/v) gave (E/Z)-(6aS,11aS)-4-
(prop-1-enyl)medicarpin 12 (283 mg; 74%) as a light green
oil (Rf 0.35) (Found: Mϩ, 310.1206. C19H18O4 requires M,
310.1205); 1H NMR (Table 1).
(6aS,11aS)-4-Hydroxymethyl-3-O-methoxymethylmedicarpin
16
Finely powdered NaBH4 (2.5 eq.) was added in small portions
to a stirred solution of (6aS,11aS)-4-formyl-3-O-methoxy-
methylmedicarpin 15 (60 mg, 175 µmol) in a mixture of THF
(ca. 1 cm3) and ethanol (ca. 1 cm3). The resulting mixture was
stirred at rt until TLC indicated complete conversion of the
starting material. The excess of borohydride was quenched by
the slow addition of acetone (ca. 2 cm3) and the mixture was
concentrated under reduced pressure. The residue was taken up
in H2O, the aqueous phase extracted with ether and the com-
bined organic extracts dried (MgSO4). Evaporation of the sol-
vent under reduced pressure gave the title compound 16 (51 mg,
85%) as an amorphous white solid (Found: Mϩ, 344.1261.
C19H20O6 requires M, 344.1260); 1H NMR (Table 1).
(E/Z)-(6aS,11aS)-3-O-Methoxymethyl-4-(prop-1-enyl)-
medicarpin 13
(6aS,11aS)-4-Bromomethyl-3-O-methoxymethylmedicarpin 17
The phenolic medicarpin 12 (300 mg, 967 µmol) was dissolved
in anhydrous THF and added under N2 to an ice-cooled, stirred
suspension of NaH (1.5 eq.) in the same anhydrous solvent.
The mixture was stirred for 10 min, chloromethyl methyl ether
(1.2 eq.) added and stirring continued on ice until TLC indi-
cated complete conversion of the starting material. Crushed
ice was added slowly to the mixture and the aqueous phase
extracted with ethyl acetate. The organic extracts were com-
bined, washed with H2O, dried (MgSO4) and the solvent
removed under reduced pressure. PLC (n-hexane–ethyl acetate,
2,6-Lutidine (2 eq.) was added to a stirred solution of (6aS,
11aS)-4-hydroxymethyl-3-O-methoxymethylmedicarpin 16 (45
mg; 131 µmol) and oven-dried LiBr (3 eq.) in anhydrous THF
(ca. 2 cm3) under Ar, and stirring was continued at rt until all
LiBr had dissolved. The mixture was cooled to 0 ЊC and a solu-
tion of methanesulfonic anhydride (1.5 eq.) in anhydrous THF
(ca. 2 cm3) was added under Ar. The resulting suspension was
stirred at rt until 1H NMR of reaction aliquots indicated com-
plete conversion of the benzylic alcohol 16 into the correspond-
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ing bromide 17; 1H NMR: δH 7.42 (d, J 9.0, H-1), 6.82 (d, J 9.0,
H-2), 6.58 (dd, J 9.0, 2.0, H-8), 5.20 (d, J 7.0, 3-OCH2-), 3.52 (s,
3-OCH3), 4.93, 4.83 (2 × d, each J 3.0, -CH2Br).
(dd, J 11.0, 11, H-6 ax), 3.34 and 3.14 [2 × s, 9(A)-OCH3 and
6(E)-OCH3] and 3.12–3.01 (m, H-6a).
(؉)-(3S)-Vestitol 6
(6aS,11aS)-4-(6-Methoxy-5-methoxymethoxy-2,3-dihydro-3-
oxo-1-benzofuran-2-ylmethyl)-3-O-methoxymethylmedicarpin
19
TFA (17 µl, 1.2 eq.) was added slowly via microsyringe to a
stirred suspension of (ϩ)-(6aS,11aS)-medicarpin 1 (50 mg, 185
µmol) and Na(CN)BH3 (17 mg, 1.5 eq.) in anhydrous DCM
(2 cm3) at Ϫ10 ЊC under N2. Stirring was continued (1 h,
Ϫ10→0 ЊC), the reaction quenched with H2O (excess), the mix-
ture neutralized with sat. aq. NaHCO3 and extracted with ethyl
acetate (3 × 5 cm3). The combined organic extracts were dried
(MgSO4) and the solvent removed under reduced pressure. PLC
(n-hexane–benzene–acetone, 4:4:2, v/v) of the residue gave the
title compound 6 (43 mg, 85%) as a light brown solid (Rf 0.25)
(Found: Mϩ, 272.1046. C16H16O4 requires M, 272.1049); 1H
NMR: δH 7.03 (d, J 9.0, H-6Ј), 6.96 (d, J 8.0, H-5), 6.50 (dd,
J 9.0, 2, H-5Ј), 6.41 (dd, J 8.0, 2, H-6), 6.38 (d, J 2.0, H-8), 6.37
(d, J 2.0, H-3Ј), 4.96 and 4.70 (2 × br s, 7-OH and 2Ј-OH), 4.35
(dd, J 0.11, 4, H-2 eq), 4.06 (dd, J 10.0, 10, H-2 ax), 3.79 (s, 4Ј-
OCH3), 3.57–3.47 (m, H-3), 3.02 (dd, J 16.0, 10, H-4 ax) and
2.91 (dd, J 16.0, 6, H-4 eq).
A solution of the silyloxybenzofuran 18, prepared by a liter-
ature procedure4 (112 mg, 328 µmol; 2.5 eq. relative to the
benzyl bromide 17) in anhydrous THF (1 cm3) was added slowly
to a stirred suspension of TASF (95 mg, 1.05 eq. relative to the
silyloxybenzofuran 18) in anhydrous THF (1 cm3) at Ϫ78 ЊC
under Ar. The mixture was stirred for 15 min, HMPA (300 µl;
5 eq. relative to the silyloxybenzofuran 18) added and stirring
continued for 15 min. The suspension containing (6aS,11aS)-
4-bromomethyl-3-O-methoxymethylmedicarpin 17 (452 µmol,
1 eq.) was added slowly to the mixture by filtration under Ar
through a septum-capped syringe (5 cm3) charged with cotton
wool. The cotton wool was rinsed once with anhydrous THF
(2 cm3), and the resulting mixture was stirred (1 h, Ϫ78 to
Ϫ30 ЊC; 15 h, Ϫ30 ЊC), quenched at Ϫ30 ЊC with sat. aq. NH4Cl
(2 cm3), warmed to rt, diluted with H2O, extracted with ether
(5 × 10 cm3) and the combined organic extracts dried (MgSO4).
Evaporation of the solvent under reduced pressure and PLC
(first CHCl3–methanol, 98:2, v/v, Rf 0.4, then n-hexane–
benzene–acetone, 5:4:1, v/v, Rf 0.25) gave the title compound
19 (20 mg, 28%) as a viscous colorless oil (Found: Mϩ,
(3S)-{2Ј-O,7-O-Bis-[(ꢀR)-ꢀ-trifluoromethyl-ꢀ-methoxyphenyl-
acetyl]}vestitol
Vestitol 6 (11 mg, 40.4 µmol) from the preceding experiment,
triethylamine (60 µl, 5.3 eq. per phenol) and DMAP (8 mg, 0.8
eq. per phenol) were dissolved in anhydrous DCM (2 cm3)
under N2. The mixture was added to S-(ϩ)-α-methoxy-α-
trifluoromethylphenylacetyl chloride (MTPACl) (7 cm3 of a
21.4 mM solution in anhydrous DCM; 1.9 eq. per phenol),
stirred at rt under N2 for 2 h, neutralized with 0.1 M HCl and
extracted with ethyl acetate (4 × 5 cm3). The combined extracts
were washed with sat. aq. NaHCO3, dried (MgSO4), the solvent
evaporated under reduced pressure and the residue purified
with PLC (n-hexane–benzene–acetone, 5:4:1, v/v) to give the
1
550.1836. C30H30O10 requires M, 550.1839); H NMR (unre-
solved diastereoisomeric mixture) (Table 2).
(6aS,11aS)-4-(3-Hydroxy-6-methoxy-5-methoxymethoxy-3-
phenyl-2,3-dihydro-1-benzofuran-2-ylmethyl)-3-O-methoxy-
methylmedicarpin 20
A standardized solution of PhMgBr in THF (2 eq.) was added
slowly via a microsyringe to a stirred solution of (6aS,11aS)-
4-(6-methoxy-5-methoxymethoxy-2,3-dihydro-3-oxo-1-benzo-
furan-2-ylmethyl)-3-O-methoxymethylmedicarpin 19 (20 mg,
36.3 µmol) in anhydrous THF (ca. 1 cm3) under N2 at 0 ЊC, and
the resulting mixture was stirred at rt until TLC of reaction
aliquots indicated complete conversion of the starting material.
Crushed ice and an excess of sat. aq. NH4Cl was added to the
mixture which was then extracted with ethyl acetate. The com-
bined organic extracts were washed with sat. aq. NaHCO3,
dried (MgSO4) and concentrated under reduced pressure. PLC
(benzene–acetone, 9:1, v/v) gave the title compound 20 (5 mg,
22%; Rf 0.25), and 3 mg (15%) of the starting material 19 (Rf
0.4) was recovered (Found: Mϩ, 628.2306. C36H36O10 requires
M, 628.2308); 1H NMR (unresolved diastereoisomeric mixture)
(Table 2).
1
title compound (13 mg, 44%) as a colorless oil (Rf 0.55); H
NMR: δH 7.70–7.66, 7.64–7.60, 5.52–7.47, 7.32–7.28 (4 × m,
2 × C6H5), 7.10 (d, J 9.0, H-6Ј), 6.99 (d, J 8.0, H-5), 6.84 (dd,
J 9.0, 3, H-5Ј), 6.69 (d, J 3.0, H-3Ј), 6.64 (dd, J 8.0, 2, H-6), 6.62
(d, J 2.0, H-8), 4.16 (dd, J 11.0, 4, H-2 eq), 3.91 (dd, J 11.0, 10,
H-2 ax), 3.82 (s, 4Ј-OCH3), 3.73 and 3.69 (2 × q, J 1.0, 2 × PhC-
(CF3)OCH3), 2.95–2.86 (m, H-3), 2.85–2.67 (m, H-4 ax and H-4
eq).
Daljanelin D 5
TFA (200 µl of a 0.1% solution in DCM, 1.4 eq.) was added
slowly via microsyringe to a stirred suspension of daljanelin B 3
(1 mg, 1.91 µmol) and Na(CN)BH3 (ca. 0.5 mg, 4.2 eq.) in
anhydrous DCM (1 cm3) at Ϫ10 ЊC under N2. Stirring was
continued (1 h, Ϫ10→0 ЊC), the reaction quenched with H2O
(excess), the mixture neutralized with sat. aq. NaHCO3 and
extracted with ethyl acetate (3 × 5 cm3). The combined extracts
were dried (MgSO4) and the solvent removed under reduced
pressure. PLC (benzene–acetone, 8:2, v/v) of the residue gave
(6aS,11aS)-4-(5-Hydroxy-6-methoxy-3-phenyl-1-benzofuran-2-
ylmethyl)medicarpin 3
(6aS,11aS)-4-(3-Hydroxy-6-methoxy-5-methoxymethoxy-3-
phenyl-2,3-dihydro-1-benzofuran-2-ylmethyl)-3-O-methoxy-
methylmedicarpin 20 (5 mg, 7.95 µmol) was refluxed for 3 h in a
mixture of 0.1 M HCl (1 cm3) and methanol (1 cm3). The mix-
ture was cooled to rt, neutralized with sat. aq. NaHCO3 and
extracted with ether (5 × 5 cm3). The combined moist organic
extracts were homogenized with ethanol (ca. 0.5 cm3), concen-
trated under reduced pressure and the residue subjected directly
to PLC (benzene–acetone, 8:2, v/v) to give the title compound
34 (1 mg, 24%; Rf 0.55) (Found: Mϩ, 522.1680. C32H26O7
1
daljanelin D 54 (0.7 mg, 70%, Rf 0.3); H NMR: δH 7.62–7.59,
7.50–7.44 and 7.37–7.33 [3 × m, 5 × H(E)], 7.06 [s, H-4(D)],
7.02 [s, H-7(D)], 6.99 [d, J 9.0, H-6Ј(B)], 6.88 [d, J 8.0, H-5(A)],
6.50 [d, J 8.0, H-6(A)], 6.45 [dd, J 8.0, 3, H-5Ј(B)], 6.38 [d, J 3.0,
H-3Ј(B)], 4.24–4.18 [m, 4(A)-CH2 and H-2 eq], 3.94 and 3.78
[2 × s, 4Ј(B)-OCH3 and 6(D)-OCH3], 3.98 (dd, J 10.0, 10, H-2
ax), 3.49–3.41 [m, H-3(C)] and 3.05–2.87 (m, H-4 ax and H-4
eq).
1
requires M, 522.1679); H NMR: δH 7.67–7.63 [m, 2 × H(F)],
(6aS,11aS)-8-Bromomedicarpin 21 and (6aS,11aS)-2,8-
dibromomedicarpin 22
A solution of HBr (conc.) (3 cm3) in DMSO (4 cm3) was added
dropwise to a stirred solution of (ϩ)-(6aS,11aS)-medicarpin 1
(300 mg, 1.11 mmol) in DMSO (5 cm3) kept just above freezing
7.45 [s, H-4(E)], 7.41 [d, J 8.0, H-1(A)], 7.39–7.29 [m,
3 × H(F)], 6.81 [d, J 8.0, H-7(D)], 6.66 [d, J 2.0, H-10(D)], 6.60
[s, H-7(E)], 6.53 [d, J 8.0, H-2(A)], 6.51 [dd, J 8.0, 2, H-8(D)],
5.52 and 5.46 (2 × br s, 3(A)-OH and 5(E)-OH), 5.30 (d, J 7.0,
H-11a), 4.36 [s, 4(A)-CH2], 3.92 (ddd, J 11.0, 5, 1, H-6 eq), 3.45
J. Chem. Soc., Perkin Trans. 1, 1999, 3367–3374
3373

View Article Online
point (ca. 5 ЊC). The mixture was stirred at rt for 1 h, diluted
with H2O, carefully neutralized with Na2CO3 (s), its pH
adjusted to 6 with 3 M HCl, and extracted with ethyl acetate
(3 × 20 cm3). The combined organic extracts were washed with
H2O (3 × 10 cm3), dried (MgSO4) and the solvent removed
under reduced pressure. PLC (n-hexane–benzene–acetone,
5:4:1, v/v) gave 21 (151 mg, 39%; Rf 0.3) (Found: Mϩ,
347.9996. C16H13BrO4 requires M, 347.9998) and 22 (74 mg,
16%; Rf 0.4) (Found: Mϩ, 425.9105. C16H12Br2O4 requires M,
425.9104), both as cream-colored solids; 1H NMR (Table 3).
(Found: Mϩ, 541.9575. C21H20Br2O7 requires M, 541.9576 for
26. Found: Mϩ, 464.0472. C21H21BrO7 requires M, 464.0471 for
27); 1H NMR (Table 3).
(6aS,11aS)-2-Ethoxycarbonyl-3-O-methoxymethylmedicarpin
28
(6aS,11aS)-8-Bromo-2-ethoxycarbonyl-3-O-methoxymethyl-
medicarpin 27 (3.5 mg, 7.52 µmol) was dissolved in anhydrous
THF (ca. 0.5 cm3) and the solution was cooled under N2 to
Ϫ78 ЊC. n-BuLi (10 µl of a 1.64 M solution in hexanes; 2.2 eq.)
and TMEDA (3 µl, 2.6 eq.) were added successively via
microsyringe to the stirred solution. The resulting mixture was
stirred at Ϫ78 ЊC for 10 min, warmed to 0 ЊC and quenched
immediately with sat. aq. NH4Cl (excess), warmed to rt, diluted
with H2O and extracted with ethyl acetate (3 × 5 cm3). The
combined organic extracts were dried (MgSO4) and the solvent
removed under reduced pressure. PLC (benzene–acetone, 95:5,
v/v) gave the title compound 28 (1 mg, 34%, Rf 0.6) (Found:
Mϩ, 386.1365. C21H22O7 requires M, 386.1365); 1H NMR
(Table 3); CD: [θ]231.9 ϩ12920, [θ]244.9 ϩ20140, [θ]270.7 Ϫ30.2,
[θ]285.5 Ϫ5101, [θ]299.6 ϩ3213 (Fig. 1).
(6aS,11aS)-2,8-Dibromo-3-O-methoxymethylmedicarpin 23
(6aS,11aS)-2,8-Dibromomedicarpin 22 (30 mg; 70.1 µmol) was
dissolved in anhydrous THF and added under N2 to an ice-
cooled, stirred suspension of NaH (1.5 eq.) in the same solvent.
The mixture was stirred for 10 min, chloromethyl methyl ether
(1.2 eq.) added and stirring continued on ice until TLC indi-
cated complete conversion of the starting material. Crushed
ice was added slowly to the mixture and the aqueous phase
extracted with ethyl acetate. The organic extracts were com-
bined, washed with H2O, dried (MgSO4) and the solvent
removed under reduced pressure. PLC (n-hexane–benzene–
acetone, 5:4:1, v/v) gave the title compound 23 (26 mg, 79%) as
a colorless oil (Rf 0.75) (Found: Mϩ, 469.9366. C18H16Br2O5
requires M, 469.9366); 1H NMR (Table 3).
Acknowledgements
Financial support by the Foundation for Research Develop-
ment, Pretoria and Die Sentrale Navorsingsfonds of UOFS is
gratefully acknowledged.
(6aS,11aS)-8-Bromo-3-O-methoxymethylmedicarpin 24 and
(6aS,11aS)-3-O-methoxymethylmedicarpin 25
References
n-BuLi (20 µl of a 1.30 M solution in hexanes; 1.02 eq.) was
added via microsyringe to a stirred solution of (6aS,11aS)-2,8-
dibromo-3-O-methoxymethylmedicarpin 23 (12 mg, 25.4 µmol)
in anhydrous THF (ca. 1 cm3) under N2 at Ϫ78 ЊC. The mixture
was stirred at Ϫ78 ЊC for 30 min, quenched with sat. aq. NH4Cl
(excess), warmed to rt, diluted with H2O and extracted with
ethyl acetate (4 × 5 cm3). The combined organic extracts were
dried (MgSO4) and the solvent removed under reduced
pressure. PLC (benzene) gave the title compound 24 (2 mg,
20%; Rf 0.55) (Found: Mϩ, 392.0257. C18H17BrO5 requires M,
392.0260) and (6aS,11aS)-3-O-methoxymethylmedicarpin 25
(1 mg, 13%; Rf 0.45) (Found: Mϩ, 314.1155. C18H18O5 requires
M, 314.1154); 1H NMR (Table 3).
1 P. M. Dewick, in The Flavonoids. Advances in Research since 1986, ed.
J. B. Harborne, Chapman and Hall, London, 1994, p. 117.
2 D. M. X. Donnelly and G. Boland, in The Flavonoids. Advances in
Research since 1986, ed. J. B. Harborne, Chapman and Hall,
London, 1994, p. 240.
3 L. J. Porter, in The Flavonoids. Advances in Research since 1986,
ed. J. B. Harborne, Chapman and Hall, London, 1994, p. 23.
4 J. A. Ferreira, J. W. Nel, E. V. Brandt, B. C. B. Bezuidenhoudt and
D. Ferreira, J. Chem. Soc., Perkin Trans. 1, 1995, 1049.
5 L. Rastrelli, I. Berger, W. Kubelka, A. Caceres, N. De Tommasi and
F. De Simone, J. Nat. Prod., 1999, 62, 188.
6 S. Ito, Y. Fujise and A. Mori, Chem. Commun., 1965, 595.
7 M. Ishiguro, T. Tatsuoka and N. Nakatsuka, Tetrahedron Lett.,
1982, 23, 3859.
8 M. S. Kharasch, R. C. Seyler and F. R. Mayo, J. Am. Chem. Soc.,
1938, 60, 882.
9 P. Golborn and F. Scheinmann, J. Chem. Soc., Perkin Trans. 1, 1973,
2870.
10 V. VanRheenen, R. C. Kelly and D. Y. Cha, Tetrahedron Lett., 1976,
37, 1973.
2,8-Dibromo-4-ethoxycarbonyl-3-O-methoxymethylmedicarpin
26 and (6aS,11aS)-8-bromo-2-ethoxycarbonyl-3-O-methoxy-
methylmedicarpin 27
(6aS,11aS)-2,8-Dibromo-3-O-methoxymethylmedicarpin
23
(45 mg; 95.3 µmol) was dissolved in anhydrous THF (ca. 1 cm3)
and the solution was cooled under N2 to Ϫ78 ЊC. n-BuLi (64 µl
of a 1.64 M solution in hexanes, 1.1 eq.) and TMEDA (35 µl,
2.4 eq.) were added successively via microsyringe to the stirred
solution, and ethyl chloroformate (45 µl, 4.9 eq.) was added to
the mixture 3 min after the addition of the TMEDA. The result-
ing mixture was warmed to 0 ЊC and stirred for 90 min,
quenched with sat. aq. NH4Cl (excess), warmed to rt, diluted
with H2O and extracted with ethyl acetate (3 × 5 cm3). The
combined organic extracts were dried (MgSO4) and the solvent
removed under reduced pressure. PLC (benzene) gave com-
pound 27 (6 mg; 14%, Rf 0.15) and 2,8-dibromo-4-ethoxy-
carbonyl-3-O-methoxymethylmedicarpin 26 (3 mg, 6%, Rf 0.25)
11 E. W. Collington and A. I. Meyers, J. Org. Chem., 1971, 36, 3044.
12 E. J. Corey and B. B. Snider, J. Am. Chem. Soc., 1972, 94, 2549.
13 J. A. Ferreira, M. B. Rohwer, B. C. B. Bezuidenhoudt and
D. Ferreira, unpublished results.
14 C. F. Lane, Synthesis, 1975, 135.
15 P. J. Steynberg, J. P. Steynberg, B. C. B. Bezuidenhoudt and
D. Ferreira, J. Chem. Soc., Chem. Commun., 1994, 31; J. Chem. Soc.,
Perkin Trans. 1, 1995, 3005.
16 G. Majetich, R. Hicks and S. Reister, J. Org. Chem., 1997, 62, 4321.
17 A. V. Kalinin, A. J. M. da Silva, C. C. Lopes, R. S. C. Lopes and
V. Snieckus, Tetrahedron Lett., 1998, 39, 4995.
18 A. V. Kalinin and V. Snieckus, Tetrahedron Lett., 1998, 39, 4999.
Paper 9/04944D
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J. Chem. Soc., Perkin Trans. 1, 1999, 3367–3374