An enantioselective total synthesis of the stilbenolignan (-)-aiphanol and the determination of its absolute stereochemistry

Article abstract of DOI:10.1016/j.tetasy.2005.02.035

The title natural product (-)-aiphanol has been prepared by total synthesis. A key step involved the asymmetric dihydroxylation of (E)-3,5-dimethoxy-4-(methoxymethoxy)cinnamyl alcohol with the AD-mix-β to give triol (1R,2R)-1-(3′,5′-dimethoxy-4′-methoxymethoxyphenyl) -2,3-dihydroxypropanol, the absolute stereochemistry of which was confirmed by single-crystal X-ray analysis of a readily available bromo-derivative. These studies have established that the naturally occurring enantiomer of aiphanol possesses the (S)-configuration at each of C-2′ and C-3′.

Full text of DOI:10.1016/j.tetasy.2005.02.035

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1645–1654
An enantioselective total synthesis of the stilbenolignan
(ꢀ)-aiphanol and the determination of its absolute stereochemistry
Martin G. Banwell,a,* Satish Chanda and G. Paul Savageb
aResearch School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
bCSIRO Division of Molecular Science, Clayton, VIC 3165, Australia
Received 27 January 2005; accepted 8 February 2005
Abstract—The title natural product (ꢀ)-aiphanol has been prepared by total synthesis. A key step involved the asymmetric dihydr-
oxylation of (E)-3,5-dimethoxy-4-(methoxymethoxy)cinnamyl alcohol with the AD-mix-b to give triol (1R,2R)-1-(30,50-dimethoxy-
40-methoxymethoxyphenyl)-2,3-dihydroxypropanol, the absolute stereochemistry of which was confirmed by single-crystal X-ray
analysis of a readily available bromo-derivative. These studies have established that the naturally occurring enantiomer of aiphanol
possesses the (S)-configuration at each of C-20 and C-30.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
reaction between ortho-benzoquinone and a TBS-
protected sinapyl alcohol to construct the 1,4-benzodi-
oxane framework. We have recently shown6 that ( )-
aiphanol 1 can be assembled through an oxidative and
biomimetic coupling of a cinnamyl alcohol derivative
with the tetrahydroxystilbene piceatannol, itself a natu-
ral product that has been isolated from A. aculeata1 as
well as other sources.7 The oxidative coupling reaction
was promoted by an Ag(I) species.8 A related synthesis
of ( )-aiphanol has also been described by Pan et al.9
Some of the preliminary biological testing of
synthetically-derived ( )-aiphanol6 suggested that there
might be variations in the properties of the two
In 2001, Kinghorn and co-workers reported the bio-
assay-guided isolation of the polyphenolic compound
(ꢀ)-aiphanol 1 from the seeds of Aiphanes aculeata
Willd. (Arecaceae) collected in Peru.1 This natural prod-
uct possesses an unprecedented stilbenolignan skeleton
in which a hydroxylated stilbene unit is connected to a
phenylpropane moiety via a 1,4-dioxane bridge. Aipha-
nol is an optically active and levorotatory compound
{[a]D = ꢀ21.8 (c 0.13, MeOH)} but its absolute configu-
ration has not yet been determined.1 It shows potent
inhibition of the cyclooxygenase enzymes COX-1 and
COX-2 with IC50 values of 1.9 and 9.9 lM, respec-
tively.1 Since compounds exhibiting COX-2 inhibitory
properties can also act as anti-angiogenic agents,2–4 we
have pursued the syntheses of aiphanol and various con-
geners with the intention of establishing a structure–activ-
ity profile for this novel natural product. Such synthetic
studies are also necessary because aiphanol only occurs
in very low natural abundance, comprising just
0.00008% w/w of the dried seeds of A. aculeata.1
OH
2'
O
HO
OMe
OH
O
3'
OH
OMe
(–)-1
The intriguing biological properties and novel structural
features of aiphanol 1 have already attracted the atten-
tion of other groups and, in a recent study, Ohira
et al.5 have reported the total synthesis of a racemic
material. This group employed a [4+2]-cycloaddition
OH
2'
O
O
HO
OMe
OH
3'
OH
OMe
*
Corresponding author. Tel.: +61 2 61258202; fax: +61 2 6125
8114; e-mail: mgb@rsc.anu.edu.au
(+)-1
0957-4166/$ - see front matter ꢀ 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.035

1646
M. G. Banwell et al. / Tetrahedron: Asymmetry 16 (2005) 1645–1654
enantiomeric forms of compound 1. As such it became
necessary to establish unequivocal access to both
enantiomeric forms of aiphanol. Accordingly, we now
report the establishment of a quite distinct and
enantioselective total syntheses of (ꢀ)- and (+)-1 that
have enabled the unequivocal determination of the
absolute stereochemistry of the natural product.
lined in Scheme 1. After reviewing the various methods
available for preparing 1,4-benzodioxans, we ultimately
settled on that reported by Pan et al.10 since this
allows for the control of the absolute stereochemistry
of the substituents attached at C-20 and C-30 (see
structure 1). Thus, by following protocols established
by this group, the phenolic unit of commercially avail-
able syringealdehyde 2 was protected as the correspond-
ing MOM-ether, 3,11 which was subsequently engaged in
a Horner–Wadsworth–Emmon12 (HWE) reaction using
triethyl phosphonoacetate and NaH to afford the E-con-
figured a,b-unsaturated ester 413 in 79% yield over two
steps. Consistent with expectations,12 the Z-isomer was
2. Results and discussion
2.1. Synthesis of (20S,30S)-aiphanol (ꢀ)-1
The initial stages of the route that has culminated in the
synthesis of the natural or (ꢀ)-form of aiphanol is out-
1
not detected as judged by 300 MHz H NMR spectral
analysis of the crude product. DIBAL-H reduction of
compound 4 afforded the cinnamyl alcohol 513 in 81%
yield. Sharpless asymmetric dihydroxylation (AD)14
of the latter compound with AD mix-b then gave
triol 6 in 80% yield. The absolute stereochemistry of
compound 6 was assigned, in a preliminary fashion, as
(1R,2R) using the Sharpless mnemonic15 but in order
to unequivocally confirm the configuration of the
anticipated dioxane system, this triol was brominated
with pyridinium hydrobromide perbromide16 to afford
compound 7 after which the MOM group was removed
using methanolic HCl to give bromide 8 as a crystalline
solid in 77% yield over these two steps. X-ray analysis
of this material and exploitation of the presence of the
heavy atom allowed the absolute stereochemistry at
C-1 and C-2 to be determined,17 unequivocally, as R
in each case, an outcome consistent with that predicted
using the Sharpless mnemonic.15 (1R,2R)-Triol 6 was
converted, via tosylate 9, into epoxy-alcohol 10, which
was obtained in 63% yield and >95% ee as established
by chiral HPLC analysis.
O
OMe
EtOCOCH2P(O)(OEt)2,
OR
NaH, THF, 0—18 °C
OMe
O
MOM-Cl,
DIPEA,DCM,
0—18 °C
2 R=H
3 R=MOM
EtO
OMe
OMOM
OMe
OH
4
DIBAL-H,
toluene
OMe
—10 °C
OMOM
OMe
5
OH
OH
AD-mix-β, 1:1 v/v
t-BuOH/water,
0 °C
2
In the closing and pivotal stages (Scheme 2) of the form-
ation of the target 1,4-benzodioxane, Mitsunobu
coupling18 of compound 10 with the known19 phenol
11 using DIAD and PPh3 afforded adduct 12 in 60%
yield and >95% ee as determined by chiral HPLC
analysis.
OMe
HO
1
OMOM
OMe
6
.
.
TsCl, pyridine
0—18 °C
Pyr HBr Br2, DCM
18 °C, 10 min
Removal of the benzyl group was carried out by hydro-
genolysis over 5% Pd on C and using ethyl acetate as
solvent to afford epoxide 13 in 71% yield. The most
conspicuous feature in the 300 MHz 1H NMR spectrum
of this compound was, as expected, the lack of proton
resonances associated with the benzyl-protecting group.
The proton of the free phenolic hydroxyl group ap-
peared as a broad singlet at d 8.10 while H-10 resonated
as a doublet at d 4.99 (J = 2.3 Hz) and the H-20 proton
appeared as a multiplet at d 3.38. Singlets observed at d
5.14 (2H) and at d 3.61 (3H) are assigned to the methyl-
ene and methyl protons, respectively, of the MOM-
ether. The 75MHz 13C NMR spectrum of compound
13 showed signals due to seventeen non-equivalent
carbons, as expected for the illustrated structure. The
stereochemistry at C-10 within this compound was
assigned as S on the basis that the Mitsunobu reaction
between compounds 10 and 11 proceeded with inversion
of configuration at the electrophilic center, that is, at
C-1 within the former.
OH
OH
OTs
OH
OMe
OMe
HO
Br
HO
OMOM
OMOM
OMe
OMe
9
7
K2CO3,
MeOH,
18 °C
HCl (trace),
MeOH,
18 °C, 18 h
OH
O
OH
OMe
OH
OMe
OMOM
HO
Br
HO
1
OMe
OMe
8
10
Scheme 1.

M. G. Banwell et al. / Tetrahedron: Asymmetry 16 (2005) 1645–1654
1647
and in an outcome consistent with earlier observ-
ations,20 the K2CO3-mediated cyclization reaction of
compound 13 did not give any seven-membered ring
product through attack of the phenoxyanion at C-30 of
the epoxide ring within this substrate.
DIAD, PPh3,
THF-toluene,
18 °C, 24 h
Bn
OBn
OH
O
O
10 +
O
O
OMe
O
11
OMOM
Based on the absolute configuration of the Sharpless
asymmetric dihydroxylation product 6, as determined
by X-ray analysis of derivative 8,17 and by virtue of
the involvement of a Mitsunobu reaction, a process
known18 to occur with inversion of configuration, as
well as the subsequent application of an intramolecular
epoxide ring-opening reaction that delivers a trans-2,3-
disubstituted 1,4-benzodioxane, the absolute configur-
ations at the two stereogenic centers associated with
the heterocyclic ring within compound 14 were assumed
to be S in each case.
OMe
12
H
O
O
H2, 5% Pd on C,
EtOAc, 18 °C, 9 h
3'
2'
O
OMe
O
1'
OMOM
13
OMe
OH
O
K2CO3, MeOH,
18 °C, 0.75 h
O
OMe
O
3'
With the desired dioxane system 14 in hand, the final
stages of the synthesis of the first enantiomeric form of
aiphanol could be contemplated. Following the work
of Ohira et al.,5 phosphonium salt 155 was prepared
and then treated, in refluxing toluene and using CsF as
base, with the readily derived MOM-ether, 16 (85%),
of compound 14. In this manner, the fully protected
(20S,30S)-aiphanol derivative 17 was obtained in 41%
yield. Global removal of the MOM groups associated
with compound 17 was achieved using MeOH and AcCl
and then the crude reaction product subjected to pre-
parative HPLC to afford (20S,30S)-aiphanol (ꢀ)-1 in
65% yield and >95% ee as determined by chiral HPLC
analysis. The diagnostic features associated with the
OMOM
14
OMe
MOM-Cl, DIPEA,
DMAP, DCM,
0–18 °C, 3 h
Cl
OMOM
OMe
MOMO
O
PPh3
O
+
O
OMOM
OMOM
OMe
1
15
16
500 MHz H NMR spectrum of synthetic (ꢀ)-aiphanol
include the doublet at d 4.99 corresponding to the H-
30 proton. The magnitude of the coupling observed
(J = 7.8 Hz) for this signal implies there is a trans-rela-
tionship between the aromatic substituent at C-30 and
the hydroxymethyl group at C-20. The mutually coupled
doublets at d 7.04 and 6.96 are attributed to the protons
associated with the ethylenic bridge of the stilbene and
the magnitude (J = 16.3 Hz) of the observed coupling
implies an E-configuration about this double bond. All
other features within both the 1H and 13C NMR spectra
were consistent with the data reported for the natural
product1 and essentially identical to those obtained for
the racemic material.6 Of course, most critically, an opti-
cal rotation measurement revealed this compound to be
levorotatory {[a]D = ꢀ20.1 (c 0.2, MeOH)} implying
that the 20S,30S-configured material corresponds to the
natural product {lit.1 [a]D = ꢀ21.8 (c 0.1, MeOH)}.
CsF, toluene,
112 °C, 6 h
OMOM
OMe
O
AcCl,
MeOH,
(–)-1
MOMO
OMe
OMOM
O
18 °C,
20 h
OMOM
17
Scheme 2.
With the structure of the required cyclization precursor
13 established, the formation of the 1,4-benzodioxane
system could now be pursued. Treatment of the epoxide
13 with K2CO3 afforded the anticipated cyclization
product, viz. compound 14 in 70% yield, and in an enan-
tiomeric purity of >95% ee as determined by chiral
2.2. Synthesis of (20R,30R)-aiphanol (+)-1
The synthesis of (20R,30R)-aiphanol (+)-1 was carried
out in the same manner as described above for the syn-
thesis of the natural product but using an AD mix-a in
the Sharpless asymmetric dihydroxylation14 of cinnamyl
alcohol 5 at the start of the reaction sequence. The prod-
uct triol ent-6 was converted into bromide ent-8 with the
latter then being subject to single-crystal X-ray analysis
for the purposes of the determination of its absolute
configuration.17 From such beginnings (+)-(20R,30R)-
aiphanol (+)-1 was ultimately obtained in >91% ee as
1
HPLC analysis. In the 300 MHz H NMR spectrum of
compound 14, H-3 resonated as a doublet at d 4.95
and the magnitude of the observed coupling
(J = 8.9 Hz) implied a trans-relationship exists be-
tween the aromatic substituent at C-30 and the hydroxy-
methyl unit on the adjacent center. This together with
the appearance of other resonances in the proton and
also in the 75MHz 13C NMR spectrum, were in full
accordance with the assigned structure. Interestingly,

1648
M. G. Banwell et al. / Tetrahedron: Asymmetry 16 (2005) 1645–1654
1
determined by chiral HPLC analysis. The 500 MHz H
NMR and 125MHz 13C NMR spectra of compound
(+)-1 were identical to the equivalent spectra of syntheti-
cally-derived (ꢀ)-(20S,30S)-aiphanol (ꢀ)-1. However, the
specific rotation of (+)-1 was, of course, dextrorotatory
{[a]D = +19.3 (c 0.2, MeOH)} implying that it was the
non-natural isomer.
trated under reduced pressure. The residue thus
obtained was subjected to flash chromatography (2:3
v/v ethyl acetate/hexane elution) to afford, after con-
centration of the appropriate fractions [Rf 0.2(5)], the
title compound 311 (2.90 g, 95%) as a white, crystalline
solid: mp 50–52 ꢁC (lit.11 mp 52–53 ꢁC); IR: mmax 2990,
2964, 2841, 1686, 1592, 1470, 1327, 1083, 951, 926, 828,
1
723 cmꢀ1; H NMR (300 MHz, CDCl3): d 9.81 (s, 1H,
CHO), 7.08 (s, 2H, ArH), 5.17 (s, 2H), 3.87 (s, 6H),
3.54 (s, 3H); 13C NMR (75MHz, CDCl 3): d 190.9
(CHO), 153.6 (C), 139.8 (C), 132.0 (C), 106.3 (CH),
98.0 (CH2), 57.1 (OCH3), 56.0 (OCH3); MS (EI,
3. Conclusions
The reaction sequences described above and leading, in a
predictable fashion, to each enantiomeric form of the
stilbenolignan aiphanol 1 have allowed for the determi-
nation of the absolute stereochemistry of this natural
product. This work serves to highlight the utility of PanÕs
protocols in the enantioselective construction of trans-
2,3-disubstituted 1,4-benzodioxanes, as well as, in a more
general sense, the value of combinations of AD and
Mitsunobu reactions in the construction of stereochemi-
cally well defined and polyfunctionalized arrays. The
acquisition of both enantiomeric forms of aiphanol
now provides the opportunity to study, in a definitive
manner, the impact of the absolute configuration of this
novel compound on its biological profile. The outcomes
of such a study will be reported in due course.
70 eV): m/z 226 (M+Å, 100%), 196 (92), 195(30), 181
+Å
(39), 180 (23), 125(2)5, 95(31); HRMS: M
calcd
for C11H14O5: 226.0841; found: 226.0842. Anal. Calcd
for C11H14O5: C, 58.40; H, 6.24. Found: C, 58.45; H,
6.34.
4.1.2. Ethyl (E)-3,5-dimethoxy-4-(methoxymethoxy)-cin-
namate 4. A magnetically stirred suspension of NaH
(480 mg, 60% suspension washed free of oil with hexane,
12 mmol) in THF (50 mL) maintained at 0 ꢁC (ice-water
bath) under an atmosphere of nitrogen was treated,
dropwise, with triethyl phosphonoacetate (2.2 mL,
11 mmol). The resulting suspension was warmed to
18 ꢁC and stirred until no further evolution of H2 gas
was observed (ca. 0.25h). Next, a solution of aldehyde
3 (2.40 g, 10.6 mmol) in THF (15mL) was slowly intro-
duced, via cannula, to the reaction mixture, which was
then stirred at 18 ꢁC for 4 h before being diluted with
water (40 mL) and extracted with diethyl ether
(3 · 60 mL). The combined organic phases were then
dried over Na2SO4 filtered, and concentrated under re-
duced pressure. The residue thus obtained was subjected
to flash chromatography (2:3 v/v ethyl acetate/hexane
elution) and thereby affording, after concentration of
the appropriate fractions [Rf 0.4(5)], title compound
413 (2.60 g, 83%) as a white, crystalline solid: mp 64–
66 ꢁC; IR: mmax 2953, 2840, 1691, 1586, 1463, 1424,
4. Experimental
4.1. General
1
Unless otherwise specified, H and 13C NMR spectra
were recorded on a Varian Gemini 300 Spectrometer
using deuterochloroform as solvent. Infrared spectra
were recorded on either a Perkin–Elmer 683 or 1800
FTIR instrument. Mass spectral analyses were generally
carried out in electron-impact (EI) mode on a VG Micro-
mass 7070F Double-Focusing Spectrometer or, in cer-
tain cases, in electrospray (ES) mode on a VG Quattro
II triple quadrupole liquid chromatograph-MS instru-
ment. Thin layer chromatographic analyses were carried
out on aluminum-backed 0.2 mm thick silica gel 60
GF254 plates supplied by Merck while flash chromato-
graphic purifications were conducted according to the
method of Still et al.21 and using Merck silica gel 60
(230–400 mesh) as adsorbent. All solvents and common
reagents were purified by established procedures.22
1250, 1153, 1124, 1074, 979, 817 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 7.55 (d, J = 15.9 Hz, 1H), 6.71
(s, 2H, ArH), 6.31 (d, J = 15.9 Hz, 1H), 5.12 (s, 2H),
4.21 (q, J = 7.1 Hz, 2H), 3.83 (s, 6H), 3.56 (s, 3H),
1.30 (t, J = 7.1 Hz, 3H); 13C NMR (75MHz, CDCl 3):
d 166.8 (C@O), 153.3 (C), 144.4 (CH), 136.2 (C), 130.2
(C), 117.4 (CH), 104.8 (CH), 98.0 (CH2), 60.3 (CH2),
57.0 (OCH3), 55.9 (OCH3), 14.2 (CH3); MS (EI,
70 eV): m/z 296 (M+Å, 98%), 266 (95), 251 (100), 206
(62), 191 (42), 177 (33), 163 (20), 135(17), 77 (1)5;
HRMS: M+Å calcd for C15H20O6: 296.1260; found:
296.1260. Anal. Calcd for C15H20O6: C, 60.80; H, 6.80.
Found: C, 61.09; H, 6.99.
4.1.1. 3,5-Dimethoxy-4-(methoxymethoxy)benzaldehyde
3. A magnetically stirred mixture of aldehyde 2
(2.50 g, 14 mmol), DIPEA (3.8 mL, 22 mmol), and
DMAP (15mg, ca. 1 mol %) in DCM (40 mL) main-
tained at 0 ꢁC (ice-water bath) under an atmosphere
of nitrogen was treated, dropwise, with MOM-Cl
(1.3 mL, 17 mmol). After addition was complete, the
reaction mixture was allowed to warm to 18 ꢁC and
then stirred at this temperature for 6 h before being
treated with cold HCl (50 mL of a 0.1 M aqueous solu-
tion). The DCM layer was separated, and the aqueous
layer extracted with additional DCM (2 · 50 mL). The
combined organic phases were washed with water
(1 · 50 mL), dried over Na2SO4, filtered, and concen-
4.1.3. (E)-3,5-Dimethoxy-4-(methoxymethoxy)cinnamyl
alcohol 5. A magnetically stirred solution of ester 4
(2.30 g, 7.8 mmol) in toluene (40 mL) maintained at
ꢀ10 ꢁC (ice-salt bath) under an atmosphere of nitrogen
was treated, dropwise, with DIBAL-H (19.5mL of a
1 M solution in hexane, 19.5mmol). After addition
was complete, the reaction mixture was stirred at
ꢀ10 ꢁC for a further 45min, at which point TLC analy-
sis indicated that no starting material remained. Conse-
quently, the reaction mixture was slowly quenched

M. G. Banwell et al. / Tetrahedron: Asymmetry 16 (2005) 1645–1654
1649
(CAUTION), at ꢀ10 ꢁC, with ethanol (ca. 5mL), and
then most of the solvent removed under reduced pres-
sure. The residue thus obtained was treated with water
(15mL), and the resulting gelatinous precipitate ex-
tracted with ethyl acetate (5 · 30 mL). The combined
organic phases were washed with water (1 · 50 mL) and
brine (1 · 50 mL), then dried over Na2SO4, filtered,
and concentrated under reduced pressure to give a
light-yellow oil. Subjection of this material to flash chro-
matography (3:2 v/v ethyl acetate/hexane elution) afford-
ed, after concentration of the appropriate fractions (Rf
0.3), title compound 513 (1.60 g, 81%) as a white, crystal-
line solid: mp 54–56 ꢁC; IR: mmax 3425(broad), 2939,
1585, 1505, 1463, 1419, 1335, 1242, 1155, 1127,
70 eV): m/z 288 (M+Å, 10%), 227 (45), 197 (15), 195
(20), 169 (17), 167 (9), 123 (11), 45(100); HRMS: M
calcd for C13H20O7: 288.1209; found: 288.1207. Anal.
Calcd for C13H20O7: C, 54.16; H, 6.99. Found: C,
54.57; H, 7.23.
+Å
4.1.5. (1R,2R)-1-(20-Bromo-40-hydroxy-30,50-dimethoxy-
phenyl)-2,3-dihydroxypropanol 8. A magnetically stir-
red solution of compound 6 (25mg, 0.1 mmol) in
DCM (5mL) maintained at 18 ꢁC was treated, in one
portion, with pyridinium hydrobromide perbromide16
(32 mg, 0.1 mmol) and the ensuing mixture stirred for
a further 10 min at which time TLC analysis indicated
no starting material remained. Consequently, the reac-
tion mixture was quenched with NaHSO4 (0.5mL of a
1 M aqueous solution) then NaHCO3 (2 mL of a satu-
rated aqueous solution) was added. The DCM layer
was separated, and the aqueous layer extracted with
DCM (2 · 5mL). The combined organic phases were
washed with brine (1 · 10 mL), dried over Na2SO4, fil-
tered, and the filtrate concentrated under reduced pres-
sure. The resulting oil was subjected to high vacuum
for 5h to afford compound 7 (28 mg, 85%) as a clear,
colorless oil. A solution of compound 7 (28 mg,
0.1 mmol) in MeOH (5mL) was treated with concd
HCl (one drop) and the ensuing mixture was stirred
magnetically at 18 ꢁC for 18 h. Methanol was then re-
moved under reduced pressure, water (10 mL) was
added to the residue and the resulting mixture extracted
with ethyl acetate (3 · 10 mL). The combined organic
phases were then dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The residue thus ob-
tained was subjected to flash chromatography (19:1 v/v
ethyl acetate/methanol elution) to afford, after concen-
tration of the appropriate fractions (Rf 0.4), a white so-
lid. Recrystallization (methanol–DCM) of this material
afforded the title compound 8 (20 mg, 91%) as colorless
crystals: mp 172–174 ꢁC; [a]D ꢀ51.7 (c 0.5, MeOH); IR:
mmax 3365 (broad), 2938, 1594, 1495, 1410, 1314, 1176,
1
967 cmꢀ1; H NMR (300 MHz, CDCl3): d 6.60 (s, 2H,
ArH), 6.52 (dt, J = 15.8 and 1.4 Hz, 1H), 6.26 (dt,
J = 15.8 and 5.6 Hz, 1H), 5.11 (s, 2H), 4.29 (broad d,
J = 5.6 Hz, 2H), 3.84 (s, 6H), 3.59 (s, 3H), 1.76 (broad
s, 1H, OH); 13C NMR (75MHz, CDCl 3): d 153.3 (C),
134.1 (C), 132.8 (C), 130.9 (CH), 128.1 (CH), 103.4
(CH), 98.1 (CH2), 63.5(CH 2), 57.1 (OCH3), 55.9
(OCH3); MS (EI, 70 eV): m/z 254 (M+Å, 100%), 224
(52), 209 (58), 181 (30), 164 (30), 149 (83), 121 (30), 77
(26); HRMS: M+Å calcd for C13H18O5: 254.1154; found:
254.1155. Anal. Calcd for C13H18O5: C, 61.40; H, 7.14.
Found: C, 61.22; H, 7.33.
4.1.4. (1R,2R)-1-(30,50-Dimethoxy-40-methoxymethoxy-
phenyl)-2,3-dihydroxypropanol 6.
A mixture of t-
BuOH (15mL) and water (15mL) was treated with
AD mix-b (3.10 g) and methanesulfonamide (200 mg,
0.7 mmol), then stirred magnetically at 18 ꢁC until the
two phases observed were both clear. The ensuing
mixture was cooled to 0 ꢁC (ice-water bath), treated
with cinnamyl alcohol 5 (550 mg, 2.2 mmol) and then
stirred vigorously at 0 ꢁC for 48 h. The reaction mixture
was quenched, at 0 ꢁC, by the addition of Na2SO3
(3.20 mg), warmed to 18 ꢁC, stirred at this temperature
for 0.5h and then extracted with ethyl acetate
(4 · 50 mL). The combined organic extracts were
washed with KOH (1 · 50 mL of a 2 M aqueous solu-
tion) and water (1 · 50 mL) and then dried over
Na2SO4, filtered, and concentrated under reduced
pressure. Subjection of this material to flash chromato-
graphy (9:1 v/v diethyl ether/methanol elution) afforded,
after concentration of the appropriate fractions [Rf
0.2(5)], an off-white solid. Recrystallization (methanol–
DCM) of this material then gave title compound 6
(490 mg, 80%) as a white, crystalline solid, mp 73–
75 ꢁC, in >95% ee (as determined by chiral HPLC anal-
ysis using CHIRALPAKꢂ AS-H 250 · 4.6 mm column,
1:3 v/v isopropyl alcohol/hexane elution at a solvent
flow rate of 1.0 mL/min and with UV peak detection
at 254 nm, tR 13.3 min): [a]D = ꢀ24 (c 1.0, CHCl3); IR:
mmax 3401 (broad), 2940, 1594, 1506, 1462, 1422, 1329,
1
1097, 856 cmꢀ1; H NMR (300 MHz, CD3OD): d 7.05
(s, 1H, ArH), 5.04 (d, J = 3.8 Hz, 1H), 3.89 (s, 3H),
3.80 (s, 3H), 3.75(m, 1H), 3.60 (m, 2H); 13C NMR
(75MHz, CD 3OD): d 148.2, 144.5, 139.8, 132.1, 108.1,
107.5, 74.9, 72.0, 63.6, 59.5 55.4; MS (EI, 70 eV): m/z
288 (M+Å, 10%), 227 (45), 195 (20), 169 (17), 123 (11),
+Å
45(100); HRMS: M
324.0032; found: 324.0032.
calcd for C11H1581BrO6:
4.1.6. (1R,2R)-1-(30,50-Dimethoxy-40-methoxymethoxy-
phenyl)-1,2-dihydroxypropyl tosylate 9. A magnetically
stirred solution of triol 6 (350 mg, 1.2 mmol) in dry pyr-
idine (15mL) maintained at 0 ꢁC (ice-water bath) under
an atmosphere of nitrogen was treated, in one portion,
with TsCl (250 mg, 1.3 mmol). The cooling bath was re-
moved and the mixture allowed to warm to 18 ꢁC and
stirred at this temperature for 18 h, then diluted with
ethyl acetate (35mL) and washed with cold HCl
(2 · 30 mL of a 0.1 M aqueous solution). The organic
phase was then dried over Na2SO4, filtered, and the fil-
trate concentrated under reduced pressure. Subjection
of the resulting gum to flash chromatography (7:3 v/v
ethyl acetate/hexane elution) afforded, after concentra-
tion of the appropriate fractions [Rf 0.2(5)], title
1
1233, 1125, 1078, 968, 836 cmꢀ1; H NMR (300 MHz,
CDCl3): d 6.60 (s, 2H, ArH), 5.09 (s, 2H), 4.60 (d,
J = 6.5Hz, 1H), 3.82 (s, 6H), 3.73 (m, 1H), 3.61 (dd,
J = 11.4 and 3.3 Hz, 1H), 3.58 (s, 3H), 3.55 (dd,
J = 11.4 and 4.8 Hz, 1H), 2.99 (broad s, 3H, OH); 13C
NMR (75MHz, CDCl 3): d 153.4 (C), 136.7 (C), 133.9
(C), 103.4 (CH), 98.0 (CH2), 75.7 (CH), 74.8 (CH),
63.3 (CH2), 57.1 (OCH3), 56.1 (OCH3); MS (EI,

1650
M. G. Banwell et al. / Tetrahedron: Asymmetry 16 (2005) 1645–1654
compound 9 (380 mg, 72%) as a white, crystalline solid:
mp 68–70 ꢁC; [a]D = ꢀ14 (c 1.0, CHCl3); IR: mmax 3422
(broad), 2940, 1595, 1462, 1422, 1357, 1235, 1189,
1176, 1126, 967, 815cm ꢀ1; 1H NMR (300 MHz, CDCl3):
d 7.75(d, J = 8.2 Hz, 2H, ArH), 7.34 (d, J = 8.2 Hz, 2H,
ArH), 6.57 (s, 2H, ArH), 5.09 (s, 2H), 4.63 (d, J = 6.2 H,
1H), 4.04–3.86 (m, 3H), 3.82 (s, 6H), 3.58 (s, 3H), 2.60
(broad s, 2H, OH), 2.44 (s, 3H); 13C NMR (75MHz,
CDCl3): d 153.4 (C), 145.2 (C), 135.7 (C), 134.1 (C),
132.3 (C), 129.9 (CH), 127.9 (CH), 103.3 (CH), 98.0
extracted with ethyl acetate (4 · 20 mL). The combined
organic extracts were then dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue
thus obtained was subjected to flash chromatography
(7:3 v/v diethyl ether/hexane elution) to afford, after con-
centration of the appropriate fractions (Rf 0.5), a white
solid. Recrystallization (ethanol) of this material gave
the title compound 1119 (320 mg, 39%) as colorless crys-
tals: mp 120–121 ꢁC (lit.19b mp 121–122 ꢁC); IR: mmax
3210 (broad), 2870, 1674, 1605, 1580, 1513, 1344,
1
(CH2), 73.6 (CH), 73.5(CH), 70.1 (CH ), 57.1 (OCH3),
2
1288, 1259, 1117, 1016, 1008, 812, 728 cmꢀ1; H NMR
56.0 (OCH3), 21.6 (CH3); MS (EI, 70 eV): m/z 442
(M+Å, <1%), 410 (7), 380 (4), 227 (20), 208 (22), 183
(25), 155 (48), 167 (65), 91 (92), 45 (100); HRMS: M+Å
calcd for C20H26O9S: 442.1298; found: 442.1293.
(300 MHz, CD3COCD3): d 9.83 (s, 1H, CHO), 8.40
(broad s, 1H, OH), 7.53 (dm, J = 8.2 Hz, 1H), 7.45–
7.32 (complex m, 6H, ArH), 7.24 (d, J = 8.2 Hz, 1H),
5.26 (s, 2H); 13C NMR (75MHz, CD 3COCD3): d
190.9 (CHO), 152.3 (C), 147.6 (C), 136.6 (C), 131.1
(C), 128.7 (CH), 128.4 (CH), 128.3 (CH), 124.3 (CH),
114.4 (CH), 112.7 (CH), 70.8 (CH2); MS (EI, 70 eV):
m/z 228 M+Å, 17%, 137 (3), 109 (3), 91 (100), 81 (6), 65
(21); HRMS: M+Å calcd for C14H12O3: 228.0786; found:
228.0789.
4.1.7. (1R,2R)-2,3-Epoxy-1-(30,50-dimethoxy-40-methoxy-
methoxyphenyl)propanol 10. A solution of tosylate 9
(301 mg, 0.7 mmol) in dry methanol (20 mL) was treated
with K2CO3 (98 mg of anhydrous material, 0.7 mol) and
the resulting suspension stirred vigorously at 18 ꢁC under
an atmosphere of nitrogen for 3 h, then poured into
water (20 mL) and extracted with ethyl acetate
(3 · 20 mL). The combined organic phases were washed
with brine (1 · 30 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure to give a light-yel-
low oil. Subjection of this material to flash chromatogra-
phy (7:3 v/v ethyl acetate/hexane elution) gave, after
concentration of the appropriate fractions [Rf 0.3(5)],
an off-white solid. Recrystallization (DCM–hexane) of
this material then afforded title compound 10 (160 mg,
88%) as a white, crystalline solid, mp 71–73 ꢁC, in
>95% ee (as determined by chiral HPLC analysis using
CHIRALPAKꢂ AS-H 250 · 4.6 mm column, 1:3 v/v iso-
propyl alcohol/hexane elution at a solvent flow rate of
1 mL/min and with UV peak detection at 254 nm, tR
16.1 min): [a]D = ꢀ5.4 (c 1.3, CHCl3); IR: mmax 3433
(broad), 2940, 1593, 1505, 1462, 1420, 1331, 1230,
4.1.9.
(10S,20R)-4-Benzyloxy-3-[20,30-epoxy-10-(300,500-
dimethoxy-400-methoxymethoxyphenyl)-propoxy]-benzal-
dehyde 12. A magnetically stirred solution of aldehyde
11 (111 mg, 0.5mmol) and DIAD (98 lL, 0.5mmol) in
dry toluene (10 mL) maintained at 18 ꢁC under an atmo-
sphere of nitrogen was treated, dropwise, with a solution
of PPh3 (130 mg, 0.5mmol) and epoxide 10 (101 mg,
0.4 mmol) in dry THF–toluene (2 mL of a 1:1 v/v mix-
ture). The ensuing mixture was stirred at 18 ꢁC for
24 h and then solvent removed under reduced pressure.
Subjection of the residue thus obtained to flash chroma-
tography (3:2 v/v ethyl acetate/hexane elution) then
gave, after concentration of the appropriate fractions
(Rf 0.3), title compound 12 (99 mg, 60%) as a white,
crystalline solid, mp 50–52 ꢁC, in >95% ee (as deter-
mined by chiral HPLC analysis using CHIRALPAKꢂ
AS-H 250 · 4.6 mm column, 1:3 v/v isopropyl alcohol/
hexane elution at a solvent flow rate of 0.8 mL/min
and with UV peak detection at 254 nm, tR 39.9 min):
[a]D = +11.9 (c 0.6, CHCl3); IR: mmax 2939, 2840, 1687,
1596, 1507, 1462, 1436, 1337, 1272, 1128, 967, 739,
1
1155, 1126, 1078, 969, 924 cmꢀ1; H NMR (300 MHz,
CDCl3): d 6.63 (s, 2H), 5.11 (s, 2H), 4.40 (d,
J = 4.9 Hz, 1H), 3.85(s, 6H), 3.95 (s, 3H), 3.20 (m,
1H), 2.84 (m, 2H), 2.56 (broad s, 1H, OH); 13C NMR
(75MHz, CDCl 3): d 153.5 (C), 136.3 (C), 134.1 (C),
103.2 (CH), 98.1 (CH2), 74.4 (CH), 57.1 (CH), 56.0
(OCH3), 55.8 (OCH3), 45.4 (CH2); MS (EI, 70 eV): m/z
1
698 cmꢀ1; H NMR (300 MHz, CDCl3): d 9.77 (s, 1H,
CHO), 7.48–7.34 (complex m, 7H, ArH), 7.02 (d,
J = 8.7 Hz, 1H, ArH), 6.68 (s, 2H, ArH), 5.24–5.14
(complex m, 3H), 5.10 (s, 2H), 3.77 (s, 6H), 3.58 (s,
3H), 3.34 (m, 1H), 2.89 (dd, J = 5.2 and 2.6 Hz, 1H),
2.80 (dd, J = 5.2 and 3.8 Hz, 1H); 13C NMR (75MHz,
CDCl3): d 190.5 (CHO), 154.8 (C), 153.5 (C), 147.8
(C), 136.0 (C), 134.4 (C), 133.2 (C), 130.1 (C), 128.6
(CH), 128.2 (CH), 127.1 (CH), 115.8 (CH), 113.0
(CH), 103.7 (CH), 98.1 (CH2), 80.3 (CH), 70.7 (CH2),
57.1 (CH), 56.0 (OCH3), 54.2 (OCH3), 45.1 (CH2) (one
signal obscured or overlapping); MS (EI, 70 eV): m/z
270 (M+Å, 27%), 240 (10), 197 (16), 195(17), 177 (23),
+Å
165(32), 109 (12), 45(100); HRMS: M
calcd for
C13H18O6: 270.1103; found: 270.1102. Anal. Calcd for
C13H18O6: C, 57.77; H, 6.71. Found: C, 57.90; H, 7.00.
4.1.8. 4-Benzyloxy-3-hydroxybenzaldehyde 11. A mag-
netically stirred suspension of NaH (160 mg, 60% sus-
pension washed free of oil with hexane, 4.0 mmol) in
DMSO (5mL) maintained at 18 ꢁC under an atmo-
sphere of nitrogen was treated, in portions over
10 min, with 3,4-dihydroxybenzaldehyde (499 mg,
3.6 mmol). The resulting mixture was stirred at 18 ꢁC
for 1 h then benzyl chloride (410 lL, 3.6 mmol) was
added dropwise to the reaction mixture. Stirring was
continued for 18 h then the ensuing mixture diluted with
water (15mL) and the basic solution washed with
diethyl ether (3 · 10 mL). The aqueous phase was acid-
ified with HCl (0.5M aqueous solution) to pH ꢁ4 then
480 (M+Å, 7%), 450 (6), 272 (11), 253 (96), 223 (27),
+Å
195(47), 91 (9)5, 45(100); HRMS: M
calcd for
C27H28O8: 480.1784; found: 480.1777. Anal. Calcd for
C27H28O8: C, 67.49; H, 5.87. Found: C, 67.07; H, 5.66.
4.1.10.
(1S,2R)-4-Hydroxy-3-[20,300-epoxy-10-(300,500-
dimethoxy-400-methoxymethoxyphenyl)-propoxy]-benzal-
dehyde 13. A solution of compound 12 (60 mg,

M. G. Banwell et al. / Tetrahedron: Asymmetry 16 (2005) 1645–1654
1651
0.1 mmol) in ethyl acetate (5mL) was treated with 5%
Pd on C (6 mg) and the resulting mixture stirred mag-
netically under a hydrogen atmosphere at 18 ꢁC for
9 h. The reaction mixture was then filtered and the fil-
trate concentrated under reduced pressure. The residue
thus obtained was subjected to flash chromatography
(3:2 v/v ethyl acetate/hexane elution) to afford, after con-
centration of the appropriate fractions [Rf 0.3(5)], title
compound 13 (35mg, 71%) as an amorphous solid
and in >95% ee (as determined by chiral HPLC analysis
using CHIRALPAKꢂ AS-H 250 · 4.6 mm column, 1:3
v/v isopropyl alcohol/hexane elution at a solvent flow
rate of 1 mL/min and with UV peak detection at
254 nm, tR 25.5 min): [a]D = +142.4 (c 0.4, CHCl3); IR:
mmax 3360 (broad), 2939, 1684, 1595, 1507, 1462, 1443,
121.3 (CH), 103.6 (CH), 98.1 (CH2), 85.7 (CH), 74.9
(CH), 74.8 (CH2), 57.2 (OCH3), 56.1 (OCH3); MS (EI,
70 eV): m/z 390 (M+Å, 95%), 346 (16), 345 (15), 316
(11), 253 (18), 195 (83), 149 (73), 57 (100); HRMS:
M+Å calcd for C20H22O8: 390.1315; found: 390.1310.
4.1.12. 3,5-Bis-(methoxymethoxy)benzyltriphenyl-phos-
phonium chloride 15
4.1.12.1. Step (i): Formation of methyl 3,5-bis-meth-
oxymethoxybenzoate. A magnetically stirred mixture
of methyl 3,5-dihydroxybenzoate (501 mg, 3.0 mmol),
DMAP (5mg, 14 mol %), and DIPEA (1.6 mL, 9 mmol)
in DCM (20 mL) maintained at 0 ꢁC (ice-water bath)
under an atmosphere of nitrogen was treated, dropwise,
with MOM-Cl (600 lL, 8 mmol). The ensuing reaction
mixture was allowed to warm to 18 ꢁC, stirred at this
temperature for 18 h and then poured into cold HCl
(20 mL of a 0.1 M aqueous solution). The separated
aqueous layer was extracted with DCM (2 · 20 mL)
and the combined organic extracts washed with water
(1 · 40 mL) and brine (1 · 40 mL) then dried over
Na2SO4, filtered, and concentrated under reduced pres-
sure. The resulting gum was subjected to flash chroma-
tography (2:3 v/v ethyl acetate/hexane elution) to
afford, after concentration of the appropriate fractions
(Rf 0.5), methyl 3,5-bis-methoxymethoxybenzoate23
(700 mg, 91%) as a clear, colorless oil: IR: mmax 2955,
2905, 1724, 1597, 1438, 1302, 1146, 1032, 924, 770,
1287, 1238, 1154, 1126, 964 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 9.71 (s, 1H, CHO), 8.10 (broad
s, 1H, OH), 7.52 (dd, J = 8.2 and 1.9 Hz, 1H, ArH),
7.32 (d, J = 1.9 Hz, 1H, ArH), 7.05(d, J = 8.2 Hz, 1H,
ArH), 6.63 (s, 2H, ArH), 5.14 (s, 2H), 4.99 (d,
J = 2.3 Hz, 1H), 3.85(s, 6H), 3.61 (s, 3H), 3.38 (m,
1H), 3.25(m, 1H), 2.96 (t, J = 4.4 Hz, 1H); 13C NMR
(75MHz, CDCl 3): d 190.4 (CHO), 154.5 (C), 153.8
(C), 145.9 (C), 134.8 (C), 132.2 (C), 129.4 (C), 128.8
(CH), 119.8 (CH), 116.6 (CH), 103.5(CH), 98.1
(CH2), 81.9 (CH), 57.1 (CH), 56.1 (OCH2), 54.7
(OCH3), 44.7 (CH2); MS (EI, 70 eV): m/z 390 (M+Å,
100%), 345(12), 253 (40), 195(49), 149 (41), 137 (30),
99 (28); HRMS: M+Å calcd for C20H22O8: 390.1315;
found: 390.1312.
682 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.35(d,
;
J = 2.3 Hz, 2H, ArH), 6.91 (t, J = 2.3 Hz, 1H, ArH),
5.17 (s, 4H), 3.88 (s, 3H), 3.46 (s, 6H); 13C NMR
(75MHz, CDCl 3): d 166.5(C @O), 158.0 (C), 132.1
4.1.11. (2S,3S)-3-(30,50-Dimethoxy-40-methoxymethoxy-
phenyl)-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxin-6-
carbaldehyde 14. A solution of compound 13 (26 mg,
0.1 mmol) in dry methanol (5mL) was treated with
K2CO3 (10 mg of anhydrous material, 0.1 mmol) and
the resulting suspension stirred magnetically at 18 ꢁC
for 0.75h. The methanol was then removed under re-
duced pressure and the residue treated with cold HCl
(2 mL of a 0.1 M aqueous solution), extracted with ethyl
acetate (4 · 5mL), washed with brine (1 · 10 mL) then
dried over Na2SO4, filtered, and concentrated under re-
duced pressure. The residue thus obtained was purified
by column chromatography (3:2 v/v ethyl acetate/hex-
ane elution) to afford, after concentration of the appro-
priate fractions (Rf 0.4), title compound 14 (17 mg, 70%)
as an amorphous solid in >95% ee (as determined by
chiral HPLC analysis using CHIRALPAKꢂ AS-H
250 · 4.6 mm column, 1:3 v/v isopropyl alcohol/hexane
elution at a solvent flow rate of 1 mL/min and with
UV peak detection at 254 nm, tR 27.2 min): [a]D =
ꢀ48.4 (c 0.3, CHCl3); IR: mmax 3436 (broad), 2925,
2853, 1690, 1595, 1502, 1463, 1314, 1279, 1263, 1155,
(C), 110.5(CH), 109.6 (CH), 94.3 (CH ), 56.1 (OCH3),
2
52.2 (OCH3); MS (EI, 70 eV): m/z 256 (M+Å, 100%),
225(80), 196 (18), 193 (17), 139 (16), 63 (38); HRMS:
M+Å calcd for C12H16O6: 256.0947; found: 256.0944.
Anal. Calcd for C12H16O6: C, 56.24; H, 6.29. Found:
C, 56.40; H, 6.46.
4.1.12.2. Step (ii): Formation of 3,5-bis-methoxymeth-
oxybenzyl alcohol. A magnetically stirred solution of
methyl
3,5-bis-methoxymethoxybenzoate
(502 mg,
2.0 mmol) in dry THF (25mL) maintained at 0 ꢁC
(ice-water bath) under an atmosphere of nitrogen was
treated, dropwise, with LiAlH4 (2.8 mL of a 1 M solu-
tion in THF, 2.8 mmol). After addition was complete,
the reaction mixture was warmed to 18 ꢁC and stirred
at this temperature for 2 h, then treated sequentially
with water (200 lL), NaOH (200 lL of a 15% w/v aque-
ous solution) and, again, with water (200 lL). The ensu-
ing mixture was stirred for a further 2 h and the
resulting granular mixture then filtered through a pad
of CeliteTM and the filtrate concentrated under reduced
pressure. The residue thus obtained was subjected to
flash chromatography (2:3 v/v ethyl acetate/hexane elu-
tion) to afford, after concentration of the appropriate
fractions [Rf 0.2(5)], 3,5-bis-methoxymethoxybenzyl
alcohol23 (430 mg, 97%) as an amorphous, white solid:
IR: mmax 3418 (broad), 2955, 2903, 1599, 1459, 1291,
1
1128, 959 cmꢀ1; H NMR (300 MHz, CDCl3): d 9.83
(s, 1H, CHO), 7.53–7.49 (complex m, 2H, ArH), 7.12
(dm, J = 8.7 Hz, 1H, ArH), 6.74 (s, 2H, ArH), 5.15 (s,
2H), 4.95(d, J = 8.9 Hz, 1H), 4.72 (dd, J = 13.0 and
3.0 Hz, 1H), 4.41 (dd, J = 13.0 and 1.5Hz, 1H), 4.23
(dm, J = 8.9 Hz, 1H), 3.88 (s, 6H), 3.62 (s, 3H) (signal
due to OH not observed); 13C NMR (75MHz, CDCl 3):
d 190.5 (CHO), 155.4 (C), 153.5 (C), 149.3 (C), 134.5
(C), 134.0 (C), 131.9 (C), 125.5 (CH), 122.9 (CH),
1
1145, 1083, 1034, 923, 846 cmꢀ1; H NMR (300 MHz,
CDCl3): d 6.69 (d, J = 2.2 Hz, 2H, ArH), 6.63 (t,
J = 2.2 Hz, 1H, ArH), 5.14 (s, 4H), 4.59 (s, 2H), 3.45

1652
M. G. Banwell et al. / Tetrahedron: Asymmetry 16 (2005) 1645–1654
(s, 6H), 2.28 (broad s, 1H, OH); 13C NMR (75MHz,
CDCl3): d 158.3 (C), 143.6 (C), 107.8 (CH), 103.9
(CH), 94.3 (CH2), 64.9 (CH2), 56.0 (OCH3); MS (EI,
70 eV): m/z 228 (M+Å, 80%), 211 (12), 198 (23), 168
(40), 152 (23), 107 (16), 77 (17), 45 (100); HRMS: M+Å
calcd for C11H16O5: 228.0998; found: 228.0997. Anal.
Calcd for C11H16O5: C, 57.88; H, 7.07. Found: C,
58.00; H, 7.30.
4.1.13. (1E,20S,30S)-5-{20-[20,30-Dihydro-30-(400-hydroxy-
300,500-dimethoxyphenyl)-20-(hydroxymethyl)-10,40-benzo-
dioxin-60-yl]ethenyl}-1,3-benzenediol [(ꢀ)-aiphanol] (ꢀ)-
1. A magnetically stirred solution of compound 14
(11 mg, 0.03 mmol), DIPEA (20 lL, 0.1 mmol), and
DMAP (0.5mg, catalyst) in DCM (2 mL) maintained
at 0 ꢁC (ice-water bath) under an atmosphere of nitrogen
was treated with MOM-Cl (8 lL, 0.1 mmol). The result-
ing mixture was warmed to 18 ꢁC, stirred at this temper-
ature for 3 h, poured into water (5mL), and the DCM
layer separated. The aqueous layer was extracted with
additional DCM (2 · 5mL) and the combined organic
phases washed with brine (1 · 10 mL) and then dried
over Na2SO4, filtered, and concentrated under reduced
pressure. The residue thus obtained was passed through
a short pad of silica (3:2 v/v ethyl acetate/hexane elution).
The eluent was concentrated under reduced pressure
then dried under high vacuum to afford compound 16
(11 mg, 85%) as a light-brown gum. A solution of com-
pound 16 (11 mg, 0.02 mmol) in dry toluene (5mL)
was treated with phosphonium salt 15 (20 mg,
0.04 mmol) and CsF (8 mg, 0.05mmol). The ensuing sus-
pension was heated at reflux for 6 h then cooled to 18 ꢁC
and treated with water (5mL). The aqueous phase was
extracted with ethyl acetate (3 · 10 mL), and the com-
bined organic phases washed with brine (1 · 10 mL) then
dried over Na2SO4, filtered, and concentrated under re-
duced pressure. The residue thus obtained was passed
through a short pad of silica (3:2 v/v ethyl acetate/hexane
elution) and concentration of the highly UV active eluent
(Rf 0.5) afforded compound 17 (6 mg, 41%), which was
used directly in the next step of the reaction sequence.
Thus, a magnetically stirred solution of compound 17
(6 mg, 0.01 mmol) in MeOH (2 mL) maintained under
an atmosphere of nitrogen was treated with AcCl
(10 lL) and the ensuing mixture stirred at 18 ꢁC for
20 h then the MeOH removed under reduced pressure.
HCl (5mL of a 0.1 M aqueous solution) was added to
the residue, which was then extracted with ethyl acetate
(3 · 5mL). The combined organic phases were dried
over Na2SO4, filtered, and concentrated under reduced
pressure. The residue thus obtained was subjected to
flash chromatography (4:1 v/v ethyl acetate/hexane elu-
tion) to afford, upon concentration of a highly UV active
band [Rf 0.3(5)], a brown solid. Purification of this mate-
rial by HPLC (using a 300 · 7.8 mm C18 Alltech Alltima
column, 50:49.95:0.05 v/v/v H2O/MeOH/AcOH elution,
solvent flow rate of 5mL/min, UV peak detection at
325nm, tR 15.05 min), afforded the title compound (+)-11
(2.7 mg, 65%) as a light-brown solid in >95% ee (as deter-
mined by chiral HPLC analysis using CHIRALPAKꢂ
AS-H 250 · 4.6 mm column, 1:1 v/v isopropyl alcohol/
hexane elution at a solvent flow rate of 1.2 mL/min and
with UV peak detection at 325nm, tR 12.1 min):
[a]D = ꢀ20.1 (c 0.2, MeOH) [lit.1 ꢀ21.8 (c 0.1, MeOH)];
IR: mmax 3370 (broad), 2925, 1595, 1505, 1463, 1345,
4.1.12.3. Step (iii): Formation of 3,5-bis-methoxymeth-
oxybenzyl chloride. A magnetically stirred solution of
3,5-bis-methoxymethoxybenzyl
alcohol
(350 mg,
1.5mmol) and TEA (240 lL, 1.7 mmol) in DCM
(20 mL) maintained at 0 ꢁC (ice-water bath) under an
atmosphere of nitrogen was treated, dropwise, with
MsCl (130 lL, 1.7 mmol). After addition was complete,
the mixture was allowed to warm to 18 ꢁC, stirred at this
temperature for 18 h, poured into cold water (20 mL),
the DCM layer separated, and the aqueous layer
extracted with additional DCM (2 · 15mL). The com-
bined organic phases were then dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The
residue thus obtained was subjected to column chroma-
tography (2:3 v/v ethyl acetate/hexane elution) to afford,
after concentration of the appropriate fractions (Rf 0.7),
3,5-bis-methoxymethoxybenzyl chloride5 (301 mg, 79%)
as a clear, colorless oil: IR: mmax 2958, 2903, 1599, 1461,
1
1296, 1146, 1083, 1034, 933, 850, 717 cmꢀ1; H NMR
(300 MHz, CDCl3): d 6.73 (d, J = 2.2 Hz, 2H, ArH),
6.69 (t, J = 2.2 Hz, 1H, ArH), 5.16 (s, 4H), 4.50 (s,
2H), 3.47 (s, 6H); 13C NMR (75MHz, CDCl 3): d
158.3 (C), 139.6 (C), 109.7 (CH), 104.7 (CH), 94.3
(CH2), 56.0 (OCH3), 46.0 (CH2); MS (EI, 70 eV): m/z
248 and 246 (M+Å, 55 and 100%), 211 (61), 186 (16),
77 (46); HRMS: M+Å calcd for C11H15ClO4: 246.0659;
found: 246.0659. Anal. Calcd for C11H15ClO4: C,
53.56; H, 6.13; Cl, 14.37. Found: C, 53.71; H, 6.22;
Cl, 14.20.
4.1.12.4. Step (iv): Formation of 3,5-bis-(methoxy-
methoxy)benzyltriphenylphosphonium chloride 15.
A
solution of 3,5-bis-methoxymethoxybenzyl chloride
(250 mg, 1.0 mmol) in toluene (30 mL) was treated with
PPh3 (301 mg, 1.2 mmol) and the resulting mixture
heated at reflux for 18 h. The mixture was then cooled
to ca. 18 ꢁC and the white precipitate formed was fil-
tered off, washed thoroughly with diethyl ether and then
dried at 80 ꢁC for 3 h to afford the title salt 155 (401 mg,
76%) as a white, crystalline solid: mp 188–190 ꢁC; IR:
mmax 3594, 3378, 2902, 1595, 1435, 1135, 1036, 879,
746, 693 cmꢀ1 1H NMR (300 MHz, CD3SOCD3): d:
;
7.88 (m, 3H), 7.80–7.60 (complex m, 12 H), 6.57 (ABq,
J = 2.1 Hz, 1H, ArH), 6.33 (t, J = 2.2 Hz, 2H, ArH),
5.20 (d, J = 15.7 Hz, 2H), 4.91 (s, 4H), 3.21 (s, 6H);
13C NMR (75MHz, CD 3SOCD3):
d
158.4 (d,
JC,P = 3.4 Hz), 135.7, 134.7 (d, JC,P = 9.7 Hz), 130.7(5),
130.7(4) (d, JC,P = 12.6 Hz), 119.1, 117.9, 112.9, 105.1,
94.4, 56.2; MS (EI, 70 eV): m/z 472 [(MꢀHCl)+, 34%],
427 (8), 262 (100), 183 (66), 108 (26); HRMS:
(MꢀHCl)+ calcd for C29H30ClO4P: 472.1803; found:
472.1801. Anal. Calcd for C29H30ClO4P: C, 68.43; H,
5.94; Cl, 6.97; P, 6.09. Found: C, 68.17; H, 6.07; Cl,
6.98; P, 5.86.
1
1270, 1216, 1115, 1048, 831 cmꢀ1; H NMR (500 MHz,
CD3COCD3): d 8.25(broad s, 2H, OH), 7.42 (broad s,
1H, OH), 7.15(d, J = 1.9 Hz, 1H, ArH), 7.10 (dd,
J = 8.3 and 2.0 Hz, 1H, ArH), 7.04 (d, J = 16.3 Hz,
1H), 6.96 (d, J = 16.3 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H,
ArH), 6.84 (s, 2H, ArH), 6.57 (d, J = 1.9 Hz, 2H,
ArH), 6.30 (t, J = 1.9 Hz, 1H, ArH), 4.99 (d,

M. G. Banwell et al. / Tetrahedron: Asymmetry 16 (2005) 1645–1654
1653
J = 7.8 Hz, 1H), 4.16 (ddd, J = 8.3, 4.4 and 2.3 Hz, 1H),
4.06 (tm, J = 6.8 Hz, 1H, OH), 3.87 (s, 6H), 3.77 (ddd,
J = 12.3, 3.9 and 2.3 Hz, 1H), 3.55 (ddd, J = 12.3, 6.8
and 4.4 Hz, 1H); 13C NMR (125MHz, CD 3COCD3): d
159.3 (C), 148.5 (C), 144.5 (C), 144.4 (C), 140.3 (C),
137.0 (C), 131.7 (C), 128.4 (CH), 127.8 (CH and C),
120.3 (CH), 117.6 (CH), 115.0 (CH), 105.8 (CH), 105.5
(CH), 102.6 (CH), 79.2 (CH), 77.3 (CH), 61.6 (CH2),
56.4 (OCH3); MS (EI, 70 eV): m/z 452 (M+Å, 100%),
438 (40), 346 (18), 255 (30), 210 (82), 167 (60), 149 (32),
121 (43), 91 (67); HRMS: M+Å calcd for C25H24O8:
452.1471; found: 452.1466.
with UV peak detection at 254 nm, tR 20.4 min):
[a]D = +5 .3 (c 0.7, CHCl3); HRMS: M+Å calcd for
C13H18O6: 270.1103; found: 270.1101. Anal. Calcd for
C13H18O6: C, 57.77; H, 6.71. Found: C, 58.31; H, 6.96.
1
The IR, H NMR, 13C NMR, and mass spectral data
derived from this material matched those reported
above for enantiomer 10.
4.1.18. (10R,20S)-4-Benzyloxy-3-[20,30-epoxy-10-(300,500-
dimethoxy-400-methoxymethoxyphenyl)-propoxy]benzal-
dehyde ent-12. Compound ent-10 was transformed into
the title compound in the same manner as used for the
conversion 10 ! 12. In this way title compound ent-12
was obtained in 70% yield and as a white, crystalline so-
lid, mp 50–52 ꢁC, in >95% ee (as determined by chiral
HPLC analysis using CHIRALPAKꢂ AS-H 250 ·
4.6 mm column, 1:3 v/v isopropyl alcohol/hexane elu-
tion at a solvent flow rate of 0.8 mL/min and with UV
peak detection at 254 nm, tR 41.2 min): [a]D = ꢀ14.2 (c
1.9, CHCl3); HRMS: M+Å calcd for C27H28O8:
480.1784; found: 480.1772. Anal. Calcd for C27H28O8:
C, 67.49; H, 5.87. Found: C, 66.96; H, 5.90. The IR,
1H NMR, 13C NMR, and mass spectral data derived
from this material matched those reported above for
enantiomer 12.
4.1.14. (1S,2S)-1-(30,50-Dimethoxy-40-methoxymethoxy-
phenyl)-2,3-dihydroxypropanol ent-6. The title com-
pound was prepared by the asymmetric dihydroxylation
of cinnamyl alcohol 5 in the same manner as employed
in the preparation of enantiomer 6 except that AD
mix-a was used. Recrystallization (methanol–DCM) of
the solid obtained on work-up afforded the title com-
pound ent-6 (78%) as a white, crystalline solid, mp 73–
75 ꢁC, in >95% ee (as determined by chiral HPLC
analysis using CHIRALPAKꢂ AS-H 250 · 4.6 mm
column, 1:3 v/v isopropyl alcohol/hexane elution at a
solvent flow rate of 1 mL/min and with UV peak detec-
tion at 254 nm, tR 14.1 min): [a]D = +23.9 (c 1.0, CHCl3);
HRMS: M+Å calcd for C13H20O7: 288.1209; found:
288.1209. Anal. Calcd for C13H20O7: C, 54.16; H, 6.99.
Found: C, 54.20; H, 7.10. The IR, 1H NMR, 13C
NMR, and mass spectral data derived from this material
matched those reported above for enantiomer 6.
4.1.19.
(10R,20S)-4-Hydroxy-3-[20,30-epoxy-10-(300,500-
dimethoxy-400-methoxymethoxyphenyl)-propoxy]benzal-
dehyde ent-13. Compound ent-12 was transformed into
the title compound in the same manner as used for the
conversion 12 ! 13. In this way the title compound
ent-13 was obtained in 70% yield, as an amorphous so-
lid, and in >95% ee (as determined by chiral HPLC anal-
ysis using CHIRALPAKꢂ AS-H 250 · 4.6 mm column,
1:3 v/v isopropyl alcohol/hexane elution at a solvent
flow rate of 1.0 mL/min and with UV peak detection
at 254 nm, tR 50.7 min): [a]D = ꢀ139.2 (c 0.6, CHCl3);
HRMS: M+Å calcd for C20H22O8: 390.1315; found:
390.1315. The IR, 1H NMR, 13C NMR, and mass spec-
tral data derived from this material matched those re-
ported above for enantiomer 13.
4.1.15. (1S,2S)-1-(20-Bromo-40-hydroxy-30,50-dimethoxy-
phenyl)-2,3-dihydroxypropanol ent-8. Compound ent-6
was transformed into the title derivative in the same
manner as used for the conversion 6 ! 8. In this way
title compound ent-8 was obtained in 93% yield and as
colorless crystals: mp 172–174 ꢁC; [a]D = +5 1.2 (c 0.3,
1
MeOH). The H and 13C NMR spectral data derived
from this material matched those reported above for
enantiomer 8.
4.1.16. (1S,2S)-1-(30,50-Dimethoxy-40-methoxymethoxy-
phenyl)-1,2-dihydroxypropyl tosylate ent-9. Compound
ent-6 was transformed into the title compound in the
same manner as used for the conversion 6 ! 9. In this
way the title compound ent-9 was obtained in 73%
yield and as colorless crystals: mp 67–69 ꢁC;
[a]D = +13.5( c 0.8, CHCl3); HRMS: M+Å calcd for
C20H26O9S: 442.1298; found: 442.1295. The IR, 1H
NMR, 13C NMR, and mass spectral data derived from
this material matched those reported above for enan-
tiomer 9.
4.1.20. (2R,3R)-3-(30,50-Dimethoxy-40-methoxymethoxy-
phenyl)-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxin-6-
carbaldehyde ent-14. Compound ent-13 was trans-
formed into the title compound in the same manner
as used for the conversion 13 ! 14. In this way, title
compound ent-14 was obtained in 68% yield, as an
amorphous solid, and in >91% ee (as determined by
chiral HPLC analysis using CHIRALPAKꢂ AS-H
250 · 4.6 mm column, 1:3 v/v isopropyl alcohol/hexane
elution at a solvent flow rate of 1.0 mL/min and with
UV peak detection at 254 nm, tR 47.1 min):
[a]D = +43.6 (c 0.3, CHCl3); HRMS: M+Å calcd for
C20H22O8: 390.1315; found: 390.1314. The IR, 1H
NMR, 13C NMR, and mass spectral data derived from
this material matched those reported above for
enantiomer 14.
4.1.17. (1S,2S)-2,3-Epoxy-1-(30,50-dimethoxy-40-methoxy-
methoxyphenyl)propanol ent-10. Compound ent-10
was transformed into the title compound in the same
manner as used for the conversion 9 ! 10. In this way
the compound ent-10 was obtained in 82% yield and
as colorless crystals, mp 71–73 ꢁC, in >95% ee (as deter-
mined by chiral HPLC analysis using CHIRALPAKꢂ
AS-H 250 · 4.6 mm column, 1:3 v/v isopropyl alcohol/
hexane elution at a solvent flow rate of 1 mL/min and
4.1.21. (1E,20R,30R)-5-{20-[20,30-Dihydro-30-(400-hydroxy-
300,500-dimethoxyphenyl)-20-(hydroxymethyl)-10,40-benzo-
dioxin-60-yl]ethenyl}-1,3-benzenediol [(+)-aiphanol] (+)-
1. Compound ent-14 was transformed into title

1654
M. G. Banwell et al. / Tetrahedron: Asymmetry 16 (2005) 1645–1654
8. Guz, N. R.; Stermitz, F. R.; Johnson, J. B.; Beeson, T. D.;
Willen, S.; Hsiang, J.-F.; Lewis, K. J. Med. Chem. 2001,
44, 261, and references cited therein.
9. Wang, X. L.; Feng, J. P.; Xie, X. G.; Cao, X. P.; Pan, X.
F. Chin. Chem. Lett. 2004, 15, 1036.
10. Gu, W.; Chen, X.; Pan, X.; Chan, A. S. C.; Yang, T.-K.
Tetrahedron: Asymmetry 2000, 11, 2801.
11. Arcoleo, A.; Bellino, A.; Venturella, P. Ann. Chim. 1957,
47, 66.
12. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89,
863.
13. Toshio, W.; Takatoshi, F.; Setsuya, O.; Seiitsu, M.
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Chem. Rev. 1994, 94, 2483.
compound in the same manner as used for the conver-
sion 14 ! (ꢀ)-1. In this way the title compound (+)-1
was obtained in 18% yield, as a light-brown solid, and
in >91% ee (as determined by chiral HPLC analysis
using CHIRALPAKꢂ AS-H 250 · 4.6 mm column, 1:1
v/v isopropyl alcohol/hexane elution at a solvent flow
rate of 1.2 mL/min and with UV peak detection at
325nm, tR 15.1 min): [a]D = +19.3 (c 0.2, CHCl3);
HRMS: M+Å calcd for C25H24O8: 452.1471; found:
452.1469. The IR, 1H NMR, 13C NMR, and mass spec-
tral data derived from this material matched those re-
ported above for enantiomer (ꢀ)-1.
15. (a) Becker, H.; Ho, P. T.; Kolb, H. C.; Loren, S.; Norrby,
P.-O.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 7315;
(b) Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. J. Am.
Chem. Soc. 1994, 116, 1278.
16. Moon, M. P. Pyridinium Hydrobromide Perbromide In
Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; John Wiley and Sons: Chichester, 1995; Vol. 6,
pp 4370–4373.
Acknowledgements
We thank the Institute of Advanced Studies (IAS) and
the CSIRO Molecular Science for financial support
and Dr. Alison Edwards for carrying out single-crystal
X-ray analyses.
17. Details of the X-ray structure analysis will be published
elsewhere.
18. Mitsunobu, O. Synthesis 1981, 1, and references cited
therein.
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