The synthesis of (-)-varitriol and (-)-3′-epi-varitriol via a Ramberg-B?cklund route

Article abstract of DOI:10.1016/j.tet.2007.09.057

A concise route to the anti-tumour natural product (-)-varitriol, together with its novel isomer (-)-3′-epi-varitriol, is described using a Horner-Wadsworth-Emmons (HWE)/conjugate addition/Ramberg-B?cklund sequence as the cornerstone. The flexibility of t

Full text of DOI:10.1016/j.tet.2007.09.057

Tetrahedron 63 (2007) 12123–12130
The synthesis of (L)-varitriol and (L)-30-epi-varitriol via
€
a Ramberg–Backlund route
*
Graeme D. McAllister, James E. Robinson and Richard J. K. Taylor
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 28 August 2007; revised 24 September 2007; accepted 25 September 2007
Abstract—A concise route to the anti-tumour natural product (ꢀ)-varitriol, together with its novel isomer (ꢀ)-30-epi-varitriol, is described
€
using a Horner–Wadsworth–Emmons (HWE)/conjugate addition/Ramberg–Backlund sequence as the cornerstone. The flexibility of the
synthetic route has been demonstrated by the preparation of novel varitriol analogues.
Ó 2007 Elsevier Ltd. All rights reserved.
OMe OH
OMe OP
1. Introduction
O
O
(+)-Varitriol 1 was isolated from a marine-derived strain of
the fungus Emericella variecolor and its structure reported
by Malmstrøm et al. in 2002.1 (+)-Varitriol 1 exhibits signifi-
cant activity against a variety of tumours, most notably with
selected renal, CNS and breast cancer cell lines, although its
mode of action remains to be elucidated.1,2
SO2
PO
OP
HO
(+)-Varitriol 1
OH
2
In 2006 Jennings and Clemens reported the total synthesis of
(ꢀ)-varitriol in approximately 14 steps from D-(ꢀ)-ribose
utilising alkene metathesis to link together the carbohydrate
and aromatic portions of the molecule.3 This synthesis pro-
vided structural confirmation and established the absolute
configuration of (+)-varitriol 1.
OMe OP
OMe OP
O
HO
+
PO
O2
S
HO
SO2
PO
P(O)(OEt)2
OP
OP
5
4
3
Scheme 1.
2. Results and discussion
Thus, it was envisaged that HWE reaction between benzyl-
sulfonyl phosphonate 5 and lactol 4 would transiently
produce vinyl sulfone 3 which would give sulfone 2 after
The combination of potent biological properties and a rela-
tively straightforward molecular structure make the develop-
ment of synthetic routes to varitriol and its analogues an
enticing prospect with SAR studies in mind. We have an inter-
€
re-cyclisation. Ramberg–Backlund reaction of sulfone 2
should then lead to (+)-varitriol 1. Indeed, the earlier studies
had shown that in some cases it was possible to combine the
Horner–Wadsworth–Emmons (HWE)/conjugate addition/
€
est intheapplicationofthe Ramberg–Backlundreactiontothe
synthesis of biologically active compounds4–6 and have re-
cently reported its use for the preparation of stilbenoid anti-
cancer agents such as combretastatin A-4, DMU-212 and
novelsyntheticanalogues.5 Giventhatwehavealsodeveloped
a Horner–Wadsworth–Emmons (HWE)/conjugate addition/
€
Ramberg–Backlund sequence in a one-pot operation. Lactol
4 is accessible from L-(+)-ribose7 but in view of its prohibi-
tive cost the following studies utilised D-(ꢀ)-ribose,
ultimately producing (ꢀ)-varitriol 1 (the same financial
rationale was followed in the earlier3 study).
€
Ramberg–Backlund sequence to prepare styrenyl C-glyco-
sides,6 it was hoped that this novel methodology could be
appliedtothesynthesisof(+)-varitriol1asshown inScheme1.
This analysis prompted us to investigate the feasibility of
the approach in a model study using the readily available
benzylsulfonyl reagent 66 (Scheme 2). The known lactol 8
was easily prepared from D-(ꢀ)-ribose 7 using a published7
* Corresponding author. Tel.: +44 1904 432606; e-mail: rjkt1@york.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.057

12124
G. D. McAllister et al. / Tetrahedron 63 (2007) 12123–12130
O
S2 P(O)(OEt)2
6
Ph
O
O
O
Ph
HO
HO
HO
4 steps7
(28%)
i. 6, THF, NaH, 0 °C to rt
OH
16 h
O
O
O
O
OH
7
ii. CBr2F2, tBuOH, KOH-Al2O3
9
8
0 °C, 2 h
75% overall
(α:β ca. 1:3)
Scheme 2.
procedure involving acetonide formation, tosylation, iodide
displacement and hydrogenolysis (28% overall yield, 32%
in lit.7).
As 11a and 11b were inseparable, and as the NOE studies
were inconclusive, the ratio was determined by conversion
back to the corresponding isopropylidene derivatives 9
(Scheme 3). The isomers of 9 could be separated by chroma-
tography and pure samples of 11a and 11b obtained by
deprotection using dilute hydrochloric acid in methanol.
With the key components 6 and 8 in hand, the one-pot HWE/
€
conjugate addition/Ramberg–Backlund reaction was carried
out. Thus, sodium hydride was employed to generate the an-
ionic HWE reagent from phosphonate 6 and then lactol 8
was added. After completion of the HWE/conjugate addition
€
Having established the viability of the Ramberg–Backlund
approach to prepare novel varitriol analogues, the next objec-
tive was to prepare the functionalised benzylsulfonyl reagent
5 needed for the synthesis of varitriol itself. Eventually, the
route shown in Scheme 4 proved successful. Thus, the
known10 benzoate 12 was brominated under radical condi-
tions and the product 13 was reduced to give bromo alcohol
14. Treatment ofcompound14with phosphonylmethanethiol
15,11 followed by oxidation, gave the requisite HWE reagent
5a in good yield (Scheme 4). This could easily be silylated
to produce phosphonate 5b in essentially quantitative yield.
€
phase (16 h), the tandem halogenation/Ramberg–Backlund
sequence was carried out in situ using the conditions devised
by Chan et al.8 (CF2Br2, tBuOH, KOH–Al2O3). We were de-
lighted to observe that this one-pot procedure produced the
desired styryl C-glycoside 9 cleanly in 75% yield as a sepa-
rable mixture (9a:9b ca. 1:3) of a- and b-isomers [in this pa-
per the a/b descriptors are employed to indicate the lower
face (a) and the upper face (b) with the molecules drawn
as illustrated—this is clearly seen in structures 11a and
11b]. The trans-alkene structure was confirmed by 1H
NMR spectroscopy (9a, J 15.9 Hz; 9b, J 16.1 Hz). This ap-
proach had therefore furnished the non-natural b-styrenyl
isomer as the major product. The thermodynamic preference
for the 1,2-cis-relationship in 2,3-O-isopropylidene deriva-
tives of furanosyl C-glycosides is well precedented.6,9
NBS,
OMe
OMe
DIBAL-H,
toluene
benzoyl peroxide
CO2Me
Me
CO2Me
Br
CCl4, reflux, 1.5 h
86%
0 °C, 3 h
70%
13
12
In an attempt to enhance the selectivity of the reaction for the
required a-styrenyl substituent, the isopropylidene protect-
ing group of lactol 8 was removed using Amberlyst
120(H) resin in water to give the corresponding diol lactol
10 (Scheme 3). Without purification, lactol 10 was subjected
i. HSCH2P(O)(OEt)2 15
OMe OH
OMe OP
K2CO3, EtOH, 78%
ii. mCPBA, 79%
O2
S
Br
P(O)(OEt)2
€
to the HWE/conjugate addition/Ramberg–Backlund se-
14
5a, P = H
5b, P = TBS
TBSOTf,
2,6-lutidine
98%
quence. The desired diols 11 were obtained as an inseparable
mixture in an unoptimised 21% yield over the sequence of
steps from acetonide 8, gratifyingly with the required a-styr-
enyl derivative 11a predominating (a:b ca. 7:3).
Scheme 4.
i. Amberlyst
O
ii. 6, THF, NaH
O
O
Ph
HO
HO
120(H), H2O
reflux, 1 h
0 °C to rt, 16 h
iii. CBr2F2, tBuOH,
KOH-Al2O3
OH
O
O
HO
HO
OH
0 °C, 2 h
8
10
11
21% from 8
(α:β ca: 7:3)
PPTS, CuSO4
acetone, 18 h,
quant.
O
O
O
Ph
Ph
Ph
i. separate
ii. 10% aq. HCl
MeOH, Δ, 0.5 h
95-99%
O
O
OH
HO
OH
HO
9
11
11
Scheme 3.

G. D. McAllister et al. / Tetrahedron 63 (2007) 12123–12130
12125
OMe OTBS
O
OMe OTBS
HO
NaH, THF
0 °C-rt
+
O2
S
O
88%
α:β = 2:3
O
O
SO2
P(O)(OEt)2
O
O
5b
8
16
/
OMe OTBS
OMe OH
1'
1M aq. HCl
THF, 18 h
2'
3'
O
O
72%
KOH-Al2O3,
DCM-tBuOH
CBr2F2
O
O
HO
OH
17
(-)- varitriol 1
+
78%
α:β = 1:3
OMe OTBS
OMe OH
2'
1M aq. HCl
THF, 7 d
O
O
83%
3'
1'
O
O
HO
OH
17
(-)-3'-epi-varitriol 18
Scheme 5.
The key one-pot HWE/RBR sequence was first carried out
using unprotected phosphonate 5a and lactol 8. Unfortu-
nately, this reaction proved to be capricious and furnished
upon work-up a complex mixture of products none of which
(ꢀ)-Varitriol 1 and (ꢀ)-30-epi-varitriol 18 were fully charac-
terised and were easily distinguishable by 1H and 13C NMR
spectroscopy (Table 1).
Table 1. Key 1H and 13C NMR data comparisona
1
resembled by H NMR spectroscopy the desired (ꢀ)-vari-
Natural (+)-11
Synthetic (ꢀ)-1
(ꢀ)-30-epi-18
d 7.12 (d, J 15.5) d 7.05 (d, J 15.5)
triol 1. We therefore next investigated the sequential proce-
dure using the silylated phosphonate 5b (Scheme 5). Thus,
reaction of compound 5b and lactol 8 under standard
HWE/conjugate addition conditions gave an inseparable
mixture of sulfones 16a and 16b (a:b ca. 2:3). Ramberg–
H-10 d 7.14 (d, J 15.8)
H-20 d 6.19 (dd, J 6.7, 15.8) d 6.20
d 6.32
(dd, J 6.8, 15.5)
d 132.4
d 85.3
(dd, J 7.5, 15.5)
d 130.8
d 82.1
C-20 d 132.3
C-30 d 85.2
€
Backlund reaction of this mixture of sulfones gave an excel-
lent yield of trans-alkene products 17a and 17b (a:b ca. 1:3)
(Scheme 5). Fortunately, the two epimers could be separated
by careful chromatography on silica. Global deprotection
of each isomer using the published conditions3,12 gave (ꢀ)-
varitriol 1 and its 30-epimer 18 in excellent yield. It is inter-
esting to note that, while deprotection of 17a was complete
in 18 h, deprotection of its epimer 17b took much longer
to achieve completion (7 days).
a
All spectra were recorded in acetone-d6. The spectra of natural (+)-1 were
obtained at 300 MHz (1H) and 100 MHz (13C).1 The NMR data for syn-
thetic (ꢀ)-1 and 18 were obtained at 500 MHz (1H) and 125 MHz (13C).
The spectroscopic data for (ꢀ)-varitriol 1 closely matched
those in the literature.1,3 However, somewhat surprisingly,
the measured [a]D value for (ꢀ)-varitriol 1 was markedly
different from those published {[a]D ꢀ40.6 (c 1.6, MeOH),
cf. lit.1 (enant.) +18.5 (c 2.3, MeOH), lit.3 ꢀ18.2 (c 3.3,
MeOH)}. In order to clarify this issue, the known triacetate
19, previously reported by Malmstrøm et al.,1 was prepared
(Scheme 7). We were delighted to observe that the specific
rotation value for our peracetylated product agreed with
that reported, thereby providing final confirmation for the
authenticity of synthetic (ꢀ)-varitriol 1.13
We then went on to establish that the HWE/conjugate addi-
€
tion/Ramberg–Backlund sequence could be carried out as
a one-pot operation with the protected phosphonate 5b and
lactol 8 (Scheme 6). However, despite producing alkenes
17 directly in reasonable overall yield, the stereo-control
was again disappointing (a:b ca. 1:1.3).
OMe OTBS
OMe OTBS
i. NaH, THF
then
O
O2
S
HO
P(O)(OEt)2
+
O
ii. KOH-Al2O3,
CBr2F2
O
O
47%
α:β = 1:1.3
5b
17
8
O
O
Scheme 6.

12126
OMe OH
G. D. McAllister et al. / Tetrahedron 63 (2007) 12123–12130
OMe OAc
(CI), electron ionisation (EI) or fast atom bombardment
Ac2O,
pyridine
(FAB) mode or on a Bruker Daltronics microTOF spectrom-
eter operating in electrospray ionisation (ESI) mode.
O
O
96%
Diethyl benzylsulfonylmethylphosphonate 6,6 lactol 8,7
benzoate 1210 and thiol 1511 were prepared by published
methods.
HO
OH
(-)-1
AcO
OAc
19
[α]D22 -17.2 (c. 0.58, CHCl3)
Lit.1 [α]D25(enant.) +16.9 (c. 0.33, CHCl3)
3.1.1. (E)-20-(40,50-O-Isopropylidene-70-deoxy-D-ribofur-
anosyl)styrene 9. A solution of phosphonate 66 (224 mg,
0.73 mmol) in THF (2.5 mL) was added to a stirred suspen-
sion of sodium hydride (19 mg, 0.80 mmol) in THF
(2.5 mL) at 0 ꢁC under an atmosphere of argon. After stirring
for 15 min a solution of lactol 87 (127 mg, 0.73 mmol) in
THF (2.5 mL) was added and the mixture allowed to warm
to rt. The mixture was stirred for 20 h before the addition
of tert-butanol (2.92 mL). Potassium hydroxide on alumina8
(1.46 g) was added and the suspension cooled to 0 ꢁC before
the addition of CBr2F2 (0.27 mL, 2.92 mmol). After stirring
for 3 h, water (10 mL) was added and the aqueous layer ex-
tracted with diethyl ether (3ꢂ20 mL). The combined organic
extracts were dried over magnesium sulfate, filtered and the
solvent removed under reduced pressure. The resultant resi-
due was purified by careful flash column chromatography
using pet. ether–EtOAc (9:1) to give styrenes 9a (31 mg,
18% over two steps) and 9b (109 mg, 57% over two steps)
as colourless oils.
Scheme 7.
€
Insummary, theRamberg–Backlundreactionhasbeenutilised
as part of a short and flexible route to the anti-cancer natural
product (ꢀ)-varitriol 1 and its novel 30-epimer 18. This route
is operationally straightforward, and is considerably shorter
(seven steps, 14% from D-ribose; three steps, 49% from lactol
8) than the one previously reported.3 We have also shown that
this approach can be used in the synthesis of novel varitriol
analogues. The low a/b-stereoselectivity observed is dis-
appointing—but it does ensure rapid access to both ‘anomeric’
series, and this is useful in structure–activity studies.
3. Experimental
3.1. General details
All reagents were purchased from commercial sources and
used without further purification. All reactions were carried
out in oven-dried or flame-dried glassware under a nitrogen
or argon atmosphere using standard syringe and septum
techniques unless otherwise stated. Diethyl ether and THF
were freshly distilled from sodium/benzophenone. Di-
chloromethane and dimethylformamide were dried using
an MBraun Solvent Purification System. Thin layer chroma-
tography was performed on precoated 0.2 mm Merck Kie-
selgel 60 F254 silica plates and compounds were visualised
under 245 nm ultraviolet irradiation followed by staining
in either alkaline potassium permanganate or ethanolic
vanillin solution. Flash column chromatography was per-
formed using Fluka Kieselgel 60 F (220–440 mesh) with
the indicated solvents. Petroleum ether refers to the fractions
with boiling range 40–60 ꢁC.
3.1.1.1. Minor (30,40)-trans isomer 9a (less polar iso-
mer). Rf (7:3 pet. ether–EtOAc) 0.69; [a]2D0 ꢀ21.5 (c 0.89,
CHCl3); nmax(film)/cmꢀ1 2980, 2931, 1599, 1493, 1450,
1375, 1210, 1157, 1078, 967, 863 and 746; dH (400 MHz,
CDCl3) 1.28 (3H, s, Me), 1.31 (3H, d, J 6.4, H70), 1.51
(3H, s, Me), 3.97 (1H, qd, J 6.4 and 4.9, H60), 4.27 (1H, dd,
J 7.0 and 4.9, H50), 4.37 (1H, app. t, J 6.4, H30), 4.47 (1H,
dd, J 7.0 and 4.9, H40), 6.17 (1H, dd, J 15.9 and 6.7, H20),
6.64 (1H, d, J 15.9, H10), 7.16 (1H, t, J 7.1, H4), 7.24 (2H,
t, J 7.1, H3) and 7.32 (2H, d, J 7.1, H2); dC (100 MHz,
CDCl3) 19.0 (C70), 25.4 (CMe2), 27.3 (CMe2), 80.2 (C60),
84.8 (C30), 85.6 (C40), 86.2 (C50), 115.1 (CMe2), 126.6
(C3), 127.0 (C20), 127.8 (C4), 128.5 (C2), 132.5 (C10) and
136.4 (C1); m/z (ESI): 261 (MH+, 98%) and 203; HRMS
(ESI): found MH+, 261.1484. C16H21O3 requires, 261.1485.
Melting points were determined on a Gallenkamp melting
point apparatus. Optical rotations were measured using
a Jasco DIP 370 Digital Polarimeter at l¼598 nm and are
given in 10ꢀ1 deg cm2 gꢀ1. Infrared spectra were recorded
with a ThermoNicolet IR100 spectrophotometer as thin
films between sodium chloride plates. Absorption maxima
are expressed in wavenumbers (cmꢀ1).
3.1.1.2. Major (30,40)-cis isomer 9b (more polar iso-
mer). Rf (7:3 pet. ether–EtOAc) 0.57; [a]2D0 ꢀ21.5 (c 0.55,
CHCl3); nmax(film)/cmꢀ1 2981, 2934, 1451, 1375, 1266,
1209, 1163, 1108, 1068, 969, 902, 862, 752 and 693; dH
(400 MHz, CDCl3) 1.12 (3H, d, J 7.0, H70), 1.25 (3H, s,
Me), 1.46 (3H, s, Me), 4.24 (1H, q, J 7.0, H40), 4.39 (1H, dd,
J 7.5 and 4.0, H30), 4.44 (1H, dd, J 6.1 and 0.9, H50), 4.66
(1H, dd, J 6.1 and 4.0, H40), 6.28 (1H, dd, J 16.1 and 7.5,
H20), 6.62 (1H, d, J 16.1, H10), 7.15 (1H, t, J 7.3, H4), 7.22
(2H, d, J 7.3, H3) and 7.34 (2H, J 7.3, H2); dC (100 MHz,
CDCl3) 17.0 (C70), 24.9 (CMe2), 26.2 (CMe2), 79.5 (C60),
80.3 (C30), 82.8 (C40), 86.5 (C50), 112.4 (CMe2), 124.0 (C20),
126.7 (C3), 127.7 (C4), 128.4 (C2), 133.6 (C10) and 136.6
(C1); m/z (ESI): 261 (MH+, 36%), 259 and 203; HRMS
(ESI): found MH+, 261.1485. C16H21O3 requires, 261.1485.
1H and 13C NMR spectra were obtained using either a JEOL
400 MHz spectrophotometer operating at either 400 MHz or
100 MHz or a Bruker AMX 500 spectrometer operating at
500 MHz or 125 MHz, respectively. Data are expressed in
parts per million downfield shift from tetramethylsilane as
an internal standard or relative to CDCl3. All J values are
given in hertz. Assignments are made with the aid of
DEPT 135, COSY and HSQC experiments.
3.1.2. (E)-20-(40,50-O-Isopropylidene-70-deoxy-D-ribofur-
anosyl)styrene 11. (a) A mixture of lactol 8 (106 mg,
0.61 mmol) and Amberlyst 120(H) resin (catalytic amount)
Mass spectra were recorded using a Fisons Analytical VG-
Autospec spectrometer operating in chemical ionisation

G. D. McAllister et al. / Tetrahedron 63 (2007) 12123–12130
12127
in H2O (2 mL) was heated to reflux for 1 h then cooled to rt.
The reaction was filtered and the resin washed with H2O
(3ꢂ5 mL), then the solvent evaporated in vacuo and the res-
idue dried by azeotrope with EtOH (3ꢂ10 mL). After drying
under high vacuum for 4 h, crude lactol 10 (80 mg,
0.60 mmol, 98%) was obtained as colourless oil. This was
used in the next step without further purification. A solution
of phosphonate 6 (183 mg, 0.60 mmol) in N,N-dimethylfor-
mamide (3 mL) was added to a stirred suspension of sodium
hydride (29 mg, 0.72 mmol) in N,N-dimethylformamide
(4 mL) at 0 ꢁC under an atmosphere of argon. After stirring
for 0.5 h, a solution of diol lactol 10 (80 mg, 0.60 mmol) in
N,N-dimethylformamide (3 mL) was added and the mixture
allowed to warm to rt. The mixture was stirred for 16 h be-
fore the addition of tert-butanol (1.20 mL). Potassium hy-
droxide on alumina (1.20 g) was added and the suspension
cooled to 0 ꢁC before the addition of CBr2F2 (0.22 mL,
2.39 mmol). After stirring for 12 h, aqueous hydrochloric
acid (10 mL, 10%) was added followed by CH2Cl2 (20 mL).
The aqueous layer was extracted with CH2Cl2 (3ꢂ20 mL)
and the combined organic extracts dried over magnesium
sulfate. Filtration and removal of the solvent under reduced
pressure gave a residue that was purified by careful flash
column chromatography using pet. ether–EtOAc (9:1–1:9)
to give an inseparable mixture of isomers of styrenes 11
(28 mg, 21% over two steps) as a yellow oil; Rf (9:1
CH2Cl2–MeOH) 0.32; nmax(film)/cmꢀ1 3368 (br) (OH),
2970, 2924, 1493, 1449, 1376, 1089s, 967, 898, 746 and
691; m/z (ESI): 243 (M+Na+, 73%), 221 (MH, 100) and
177; HRMS (ESI): found MH+, 221.1175. C13H17O3 re-
quires, 221.1172.
saturated aqueous sodium hydrogen carbonate (2ꢂ30 mL)
and brine (2ꢂ30 mL), and dried over magnesium sulfate.
Filtration and removal of the solvent under reduced pressure
furnished a crude orange residue that was purified by flash
column chromatography using pet. ether–diethyl ether
(8:2) as the eluent to give bromide 13 (4.65 g, 86%) as an
orange oil; Rf (1:1 pet. ether–Et2O) 0.50; nmax(film)/cmꢀ1
3006, 2949, 2840, 1728s (CO), 1588, 1471, 1435, 1272s,
1115, 1071, 959, 936 and 742; dH (400 MHz, CDCl3) 3.82
(3H, s, OMe), 3.94 (3H, s, OMe), 4.48 (2H, s, CH2Br),
6.88 (1H, dd, J 8.1 and 0.7, H3), 6.99 (1H, dd, J 8.1 and
0.7, H5) and 7.32 (1H, td, J 8.1 and 0.7, H4); dC
(100 MHz, CDCl3) 30.0 (CH2Br), 52.5 (OMe), 56.1
(OMe), 111.5 (C5), 122.2 (C3), 123.1 (C1), 131.1 (C4),
136.5 (C2), 156.8 (C6) and 167.5 (CO2Me); m/z (ESI):
281 (M[79Br]+Na+, 66%), 259 (MH, 100), 227 and 179;
HRMS (ESI): found M[79Br]H+, 258.9966. C10H12BrO3
requires, 258.9964.
3.1.4. 2-(Bromomethyl)-6-methoxybenzyl alcohol 14. To
a stirred solution of ester 13 (4.65 g, 17.93 mmol) in toluene
(45 mL) at 0 ꢁC under an atmosphere of argon was added
dropwise diisobutylaluminum hydride (1 M in toluene,
39.45 mL, 39.45 mmol). After stirring for 3 h, aqueous hy-
drochloric acid (10%) was cautiously added and the mixture
allowed to warm to rt. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (3ꢂ50 mL).
The combined organic extracts were dried over magnesium
sulfate and the solvent removed under reduced pressure.
Purification of the resultant residue by flash column chroma-
tography using pet. ether–diethyl ether (7:3–1:1) as the elu-
ent afforded alcohol 14 (2.92 g, 70%) as a colourless solid;
mp 69–71 ꢁC; Rf (1:1 pet. ether–Et2O) 0.29; nmax(film)/
cmꢀ1 3364 (br) (OH), 2931, 2838, 1587, 1468, 1267, 1070,
1003 and 747; dH (400 MHz, CDCl3) 3.81 (3H, s, OMe),
4.54 (2H, s, CH2Br), 4.78 (2H, br s, CH2O), 6.83 (1H, d,
J 8.1, H3), 6.91 (1H, dd, J 8.1 and 0.9, H5) and 7.19 (1H, t,
J 8.1, H4); dC (100 MHz, CDCl3) 31.0 (CH2Br), 55.7
(OMe), 56.6 (OMe), 111.3 (C5), 122.7 (C3), 127.7 (C1),
129.3 (C4), 137.4 (C2) and 158.4 (C6); m/z (ESI): 253
(M[79Br]+Na+, 12%), 230 and 213 (M-OH, 100); HRMS
(ESI): found M[79Br]+Na+, 252.9840. C9H11BrO2Na
requires, 252.9835.
(b) Pure samples of the separated isomers 11a and 11b were
obtained by separate hydrolyses of 9a and 9b.
3.1.2.1. Major (30,40)-trans isomer 11a. dH (400 MHz,
CDCl3) 1.29 (3H, d, J 6.4, H70), 2.53 (1H, d, J 4.9, OH),
2.58 (1H, d, J 5.2, OH), 3.71 (1H, br q, J 4.9, H50), 3.85
(1H, app. p, J 6.4, H60), 3.89 (1H, br q, J 5.8, H40), 4.24
(1H, ddd, J 6.1, 6.1 and 0.6, H30), 6.14 (1H, dd, J 15.9 and
7.0, H20), 6.63 (1H, d, J 15.9, H10), 7.15–7.19 (1H, m,
H4), 7.24 (2H, t, J 7.6, H2) and 7.30–7.35 (2H, m, H3); dC
(100 MHz, CDCl3) 19.0 (C70), 75.5 (C40), 76.1 (C50), 79.7
(C60), 84.1 (C30), 126.6 (C3), 127.4 (C20), 127.9 (C4),
128.5 (C2), 132.6 (C10) and 136.3 (C1).
3.1.5. Diethyl [(2-hydroxymethyl)-3-methoxybenzyl-
sulfonyl]methylphosphonate 5a. (a) A solution of thiol
1511 (1.87 g, 10.14 mmol) in degassed ethanol (20 mL)
was added dropwise to a stirred suspension of K2CO3
(1.54 g, 11.15 mmol) in degassed ethanol (10 mL) at 0 ꢁC
under an atmosphere of argon. To this mixture was added
dropwise a solution of bromide 14 (2.34 g, 10.14 mmol) in
degassed ethanol (20 mL). After stirring for 24 h the solvent
was removed and the residue taken up in CH2Cl2 (50 mL).
The mixture was acidified with dilute aqueous hydrochloric
acid (10%) and the aqueous layer extracted with CH2Cl2
(4ꢂ50 mL). The combined organic extracts were dried
over magnesium sulfate, filtered and the solvent removed
under reduced pressure. Purification of the resultant residue
by flash column chromatography using pet. ether–EtOAc–
MeOH (9:10:1) gave the sulfide (2.63 g, 78%) as a viscous
colourless oil; Rf (4.5:5:1 pet. ether–EtOAc–MeOH) 0.25;
nmax(film)/cmꢀ1 3395 (br) (OH), 2982, 1586, 1468, 1265s,
1051, 1024s, 968, 826 and 731; dH (400 MHz, CDCl3)
3.1.2.2. Minor (30,40)-cis isomer 11b. dH (400 MHz,
CDCl3) 1.27 (3H, d, J 6.4, H70), 3.77–3.81 (1H, m, H50),
3.94 (1H, dq, J 6.4 and 6.4, H60), 4.12 (1H, br t, J 4.3,
H40), 4.62 (1H, ddd, J 6.7, 4.3 and 1.2, H30), 6.25 (1H, dd,
J 16.1 and 6.7, H20), 6.62 (1H, d, J 16.1, H10), 7.15–7.19
(1H, m, H4), 7.24 (2H, t, J 7.6, H2) and 7.30–7.35 (2H, m,
H3); dC (100 MHz, CDCl3) 18.8 (C70), 73.4 (C40), 77.9
(C60), 78.6 (C50), 80.7 (C30), 124.6 (C20), 126.7 (C2),
128.0 (C4), 128.6 (C3), 133.5 (C10) and 136.2 (C1).
3.1.3. Methyl 2-(bromomethyl)-6-methoxybenzoate 13. A
degassed mixture of benzoate 1210 (3.75 g, 20.81 mmol),
N-bromosuccinimide (4.07 g, 22.89 mmol) and benzoyl per-
oxide (0.36 g, 1.04 mmol) in carbon tetrachloride (50 mL)
was heated under reflux for 1.5 h. The mixture was allowed
to cool to rt and saturated aqueous sodium hydrogen carbon-
ate (30 mL) was added. The organic layer was washed with

12128
G. D. McAllister et al. / Tetrahedron 63 (2007) 12123–12130
1.26 (6H, t, J 7.0, OCH2CH3), 2.51 (2H, d, J 12.5, SCH2P),
3.78 (3H, s, OMe), 3.99 (2H, d, J 0.6, CH2SCH2P), 4.08
(2H, q, J 7.0, OCH2CH3), 4.10 (2H, q, J 7.0, OCH2CH3),
4.72 (2H, s, CH2O), 6.77 (1H, d, J 7.9, H4), 6.89 (1H, dd,
J 7.9 and 0.6, H6) and 7.15 (1H, t, J 7.9, H5); dC
(100 MHz, CDCl3) 16.3 (OCH2CH3), 16.3 (OCH2CH3),
22.7 (SCH2P), 24.2 (SCH2P), 33.8 (CH2SCH2P), 33.8
(CH2SCH2P), 55.5 (OMe), 55.6 (CH2O), 62.6 (OCH2CH3),
62.7 (OCH2CH3), 110.0 (C4), 122.7 (C6), 128.1 (C2), 128.5
(C5), 136.5 (C1) and 158.4 (C3); m/z (ESI): 357 (M+Na+,
13%), 335 (MH, 10) and 317; HRMS (ESI): found
M+Na+, 357.0893. C14H23O5PSNa requires, 357.0896.
(b) To a solution of this sulfide (2.63 g, 7.86 mmol) in
CH2Cl2 (100 mL) at 0 ꢁC, was added sodium hydrogen car-
bonate (1.98 g, 23.58 mmol) under a stream of nitrogen.
This was followed by m-chloroperoxybenzoic acid (4.84 g,
19.65 mmol, ca. 70%). After stirring for 20 h, saturated
aqueous sodium hydrogen carbonate (50 mL) was added
and the aqueous layer extracted with CH2Cl2 (4ꢂ100 mL).
The combined organic extracts were dried over magnesium
sulfate, filtered and the solvent removed under reduced
pressure. Purification of the resultant residue using pet.
ether–EtOAc–MeOH (4:5:1) afforded sulfone 5a (2.27 g,
79%) as a colourless solid; mp 86–88 ꢁC; Rf (4:5:1 pet.
ether–EtOAc–MeOH) 0.16; nmax(film)/cmꢀ1 3431 (br) (OH),
2982, 2913, 1588, 1470, 1319 (SO2), 1267, 1151 (SO2),
1020, 833, 804 and 733; dH (400 MHz, CDCl3) 1.29 (6H,
t, J 7.0, OCH2CH3), 3.55 (2H, d, J 16.2, SO2CH2P), 3.79
(3H, s, OMe), 4.17 (2H, q, J 7.0, OCH2CH3), 4.19 (2H, q,
J 7.0, OCH2CH3), 4.73 (2H, s, CH2O), 4.75 (2H, s,
CH2SO2CH2P), 6.88 (1H, d, J 7.9, H4), 7.04 (1H, dd, J 7.9
and 0.6, H6) and 7.23 (1H, t, J 7.9, H5); dC (100 MHz,
CDCl3) 16.1 (OCH2CH3), 16.2 (OCH2CH3), 48.2 (SO2CH2P),
49.6 (SO2CH2P), 55.7 (OMe), 56.0 (CH2O), 57.3
(CH2SO2CH2P), 63.7 (OCH2CH3), 63.7 (OCH2CH3),
111.6 (C4), 124.3 (C6), 127.0 (C2), 129.1 (C5), 129.8 (C1)
and 158.6 (C3); m/z (ESI): 389 (M+Na+, 30%), 367 (MH,
6) and 349; HRMS (ESI): found M+Na+, 389.0781.
C14H23O7PSNa requires, 389.0794.
7.10 (1H, d, J 7.8, H6) and 7.22 (1H, td, J 7.9 and 1.5,
H5); dC (100 MHz, CDCl3) ꢀ5.5 (SiMe2), 16.1 (OCH2CH3),
16.2 (OCH2CH3), 18.1 (SitBu), 25.7 (SitBu), 47.9
(SO2CH2P), 49.3 (SO2CH2P), 55.3 (OMe), 55.8 (CH2O),
57.3 (CH2SO2CH2P), 63.4 (OCH2CH3), 63.4 (OCH2CH3),
111.4 (C4), 123.9 (C6), 128.8 (C5), 129.0 (C2), 129.6 (C1)
and 157.4 (C3); m/z (ESI): 595 (MH+C6H15Si+, 15%), 498
(M+NH4, 44), 481 (MH, 31) and 349; HRMS (ESI): found
M+NH+4, 498.2104. C20H41NO7PSSi requires, 498.2105.
3.1.7. {[2-(tert-Butyldimethylsilyloxy)methyl]-3-methoxy-
benzylsulfonyl}methyl-40,50-O-isopropylidene-70-deoxy-
D-ribofuranose 16. To a stirred suspension of sodium
hydride (20 mg, 0.50 mmol, 60%) in THF (1 mL) at 0 ꢁC un-
der an atmosphere of argon was added a solution of phospho-
nate 5b (0.20 g, 0.42 mmol) in THF (2 mL). The mixture
was allowed to warm to rt and was stirred for 0.5 h. The
solution was cooled back to 0 ꢁC and a solution of lactol 8
(0.07 g, 0.42 mmol) in THF (2 mL) added dropwise. After
stirring for 24 h, brine (5 mL) was added and the aqueous
layer extracted with diethyl ether (3ꢂ10 mL). The combined
organic extracts were dried over magnesium sulfate, filtered
and the solvent removed under reduced pressure. Purifica-
tion of the resultant oil by flash column chromatography
using pet. ether–EtOAc (7:3) as the eluent afforded a
42:58 inseparable mixture of sulfones 16 (0.16 g, 79%) as
a colourless oil; Rf (7:3 pet. ether–EtOAc) 0.35; nmax(film)/
cmꢀ1 2932, 2856, 1588, 1467, 1378, 1310 (SO2), 1253,
1115, 1061s, 1006 (SO2), 837 and 776; m/z (ESI): 523
(M+Na+, 85%), 501 (MH, 42) and 369; HRMS (ESI): found
MH+, 501.2339. C24H41O7SSi requires, 501.2337.
3.1.7.1. Minor (30,40)-trans isomer 16a. dH (400 MHz,
CDCl3) 0.01 (3H, s, SiMe2), 0.03 (3H, s, SiMe2), 0.85 (9H,
s, SitBu), 1.32 (3H, s, Me), 1.36 (3H, d, J 6.4, H70), 1.53
(3H, s, Me), 3.25–3.27 (2H, m, H20), 3.80 (3H, s, OMe),
4.05 (1H, qd, J 6.4 and 4.8, H60), 4.28–4.35 (2H, m, H30
and H50), 4.55 (1H, dd, J 7.1 and 5.7, H40), 4.60 (1H, d, J
14.2, H10), 4.78 (1H, d, J 14.2, H10), 4.98 (2H, s, CH2O),
6.86 (1H, d, J 8.0, H6), 7.06 (1H, dd, J 8.0 and 0.9, H5)
and 7.23 (1H, t, J 8.0, H4); dC (100 MHz, CDCl3) ꢀ5.4
(SiMe2), 18.2 (SitBu), 18.8 (C70), 25.5 (CMe2), 25.9 (SitBu),
27.3 (CMe2), 54.9 (C20), 55.5 (OMe), 55.9 (CH2O), 57.4
(C10), 78.7 (C30), 80.9 (C60), 84.0 (C40), 85.6 (C50), 111.3
(C3), 115.6 (CMe2), 124.2 (C5), 128.6 (C4), 129.0 (C1 or
C6), 129.8 (C6 or C1) and 157.5 (C2).
3.1.6. Diethyl {[2-(tert-butyldimethylsilyloxy)methyl]-
3-methoxybenzylsulfonyl}methylphosphonate 5b. To a
stirred solution of sulfone 5a (0.30 g, 0.89 mmol) in dry
CH2Cl2 (5 mL) at ꢀ78 ꢁC under an atmosphere of nitrogen
was added dropwise 2,6-lutidine (0.11 mL, 0.98 mmol), fol-
lowed by tert-butyldimethylsilyl trifluoromethane–sulfonate
(0.21 mL, 0.90 mmol). The solution was allowed to warm to
rt over 1 h before the addition of ammonium chloride
(5 mL). The aqueous layer was extracted with CH2Cl2
(3ꢂ10 mL) and the combined organic extracts dried over
magnesium sulfate, filtered and the solvent removed under
reduced pressure. Purification of the resultant oil by flash
column chromatography using pet. ether–EtOAc–MeOH
(4:5:1) as the eluent afforded sulfone 5b (0.38 g, 98%) as
a colourless oil; Rf (4:5:1 pet. ether–EtOAc–MeOH) 0.53;
nmax(film)/cmꢀ1 2930, 2856, 1589, 1468, 1322 (SO2),
1255, 1053s (SO2), 975, 836 and 732; dH (400 MHz,
CDCl3) 0.00 (3H, s, SiMe2), 0.00 (3H, s, SiMe2), 0.82 (9H,
s, SitBu), 1.31 (6H, td, J 7.0 and 0.9, OCH2CH3), 3.49
(2H, d, J 16.5, SO2CH2P), 3.76 (3H, s, OMe), 4.19 (2H,
qd, J 7.0 and 1.5, OCH2CH3), 4.21 (2H, q, J 7.0 and 1.5,
OCH2CH3), 4.84 (2H, s, CH2O or CH2SO2CH2P), 4.92
(2H, s, CH2SO2CH2P or CH2O), 6.84 (1H, d, J 7.8, H4),
3.1.7.2. Major (30,40)-cis isomer 16b. dH (400 MHz,
CDCl3) ꢀ0.01 (3H, s, SiMe2), 0.04 (3H, s, SiMe2), 0.85
(9H, s, SitBu), 1.17 (3H, d, J 7.2, H70), 1.29 (3H, s, Me),
1.46 (3H, s, Me), 3.11 (1H, ddd, J 15.2, 3.2 and 1.2, H20),
3.50 (1H, dd, J 15.2 and 9.1, H20), 3.79 (3H, s, OMe),
4.28–4.36 (1H, m, H60), 4.39 (1H, dt, J 9.1 and 3.2, H30),
4.50 (1H, d, J 6.1, H50), 4.64 (1H, d, J 14.1, H10), 4.72
(1H, dd, J 5.8 and 4.0, H40), 4.84 (1H, dd, J 14.1 and 1.2,
H10), 4.95 (2H, s, CH2O), 6.86 (1H, d, J 8.0, H6), 7.12
(1H, dd, J 8.0 and 1.1, H5) and 7.23 (1H, t, J 8.0, H4); dC
(100 MHz, CDCl3) ꢀ5.4 (SiMe2), 16.6 (C70), 18.2 (SitBu),
24.6 (CMe2), 25.8 (SitBu), 26.0 (CMe2), 52.0 (C30), 55.5
(OMe), 55.9 (CH2O), 57.0 (C10), 73.8 (C30), 80.1 (C60),
81.5 (C40), 85.8 (C50), 111.2 (C3), 112.7 (CMe2), 124.4
(C5), 128.5 (C4), 129.3 (C1 or C6), 129.9 (C6 or C1) and
157.4 (C2).

G. D. McAllister et al. / Tetrahedron 63 (2007) 12123–12130
12129
3.1.8. 2-[(E)-2-(2-tert-Butyldimethylsilyloxymethyl-
3-methoxyphenyl)-styryl]-40,50-O-isopropylidene-70-de-
oxy-D-ribofuranose 17. (a) Sulfones 16 (500 mg,
1.00 mmol) were dissolved in CH2Cl2 (15 mL) and tert-
BuOH (2 mL) and cooled to 0 ꢁC under argon. Potassium
hydroxide on alumina (2.00 g) was added, followed by
CBr2F2 (0.46 mL, 5.00 mmol). The reaction was allowed
to warm to rt and stirred overnight. The mixture was filtered
through a plug of CeliteÓ, and the plug washed with CH2Cl2
(2ꢂ30 mL). Concentration in vacuo, followed by chromato-
graphy on silica eluting with pet. ether–EtOAc (9:1) gave the
two styrene products 17a3 (82 mg, 0.19 mmol, 19%) and
17b (256 mg, 0.59 mmol, 59%) as colourless oils. 17a: Rf
(9:1 pet. ether–EtOAc) 0.53; [a]2D0 ꢀ25.7 (c 0.8, CHCl3);
nmax(film)/cmꢀ1 2930, 2856, 1579, 1471, 1380, 1252 and
1079; dH (400 MHz, acetone-d6) 0.14 (6H, s, SiMe2), 0.98
(9H, s, SitBu), 1.43 (3H, s, Me), 1.44 (3H, d, J 6.5, H70),
1.65 (3H, s, Me), 3.89 (3H, s, OMe), 4.13 (1H, q, J 6.5,
H60), 4.41 (1H, dd, J 4.5 and 7.0, H30), 4.55 (1H, app. t, J
6.0, H50), 4.62 (1H, dd, J 5.5 and 6.5, H40), 4.89 (2H, s,
CH2OSi), 6.28 (1H, dd, J 6.5 and 16.0, H20), 6.86 (1H, d,
J 8.0, H6), 7.18 (1H, d, J 8.0, H5), 7.24 (1H, d, J 16.0,
H10) and 7.27 (1H, app. t, J 8.0, H4); dC (100 MHz, ace-
tone-d6) ꢀ5.3 (SiMe2), 18.4 (SitBu), 19.1 (C70), 25.5 (SitBu),
26.0 (CMe2), 27.4 (CMe2), 55.6 (OMe), 55.9 (CH2O), 80.2
(C40), 84.8 (C50), 85.7 (C60), 86.3 (C30), 110.0 (C3), 114.8
(CMe2), 118.7 (C5), 126.6 (C1), 128.5 (C4), 129.4 (C10),
130.1 (C20), 138.5 (C6) and 157.4 (C2); m/z (ESI): 457
[(M+Na)+, 100%], 303, 245, 227, 199 and 159; found
(M+Na)+, 457.2387. C24H38O5SiNa requires, 457.2381.
17b: Rf 9:1 pet. ether–EtOAc) 0.44; [a]2D0 ꢀ95.7 (c 1.1,
CHCl3); nmax(film)/cmꢀ1 2931, 2856, 1579, 1471, 1374,
1256 and 1067; dH (400 MHz, acetone-d6) 0.11 (3H, s,
SiMe2), 0.12 (3H, s, SiMe2), 0.96 (9H, s, SitBu), 1.27 (3H,
d, J 7.0, H70), 1.40 (3H, s, Me), 1.60 (3H, s, Me), 3.88
(3H, s, OMe), 4.38 (1H, q, J 7.0, H60), 4.55 (1H, dd, J 4.0
and 7.5, H30), 4.58 (1H, d, J 6.0, H50), 4.81 (1H, dd, J 4.0
and 6.0, H40), 4.90 (2H, AB q, J 11.5, CH2OSi), 6.34 (1H,
dd, J 8.0 and 16.0, H20), 6.84 (1H, dd, J 2.5 and 7.0, H6)
and 7.23–7.33 (3H, m, H10,4,5); dC (100 MHz, acetone-d6)
ꢀ5.2 (SiMe2), 17.2 (C70), 18.4 (SitBu), 25.0 (SitBu), 26.0
(two signals), 26.4, 55.6 (OMe), 56.0 (CH2O), 79.7 (C40),
80.7 (C50), 83.1 (C60), 86.7 (C30), 110.0 (C3), 112.5
(CMe2), 119.1 (C5), 126.3 (C1), 126.5 (C4), 128.5 (C10),
131.8 (C20), 138.7 (C6) and 157.3 (C2); m/z (ESI): 457
[(M+Na)+, 100%], 303, 245, 227, 189 and 159; found
(M+Na)+, 457.2394. C24H38O5SiNa requires, 457.2381.
over two steps) as colourless oils. Data matched those
reported above.
3.1.9. (L)-Varitriol 1. A solution of styrene 17a (70 mg,
0.16 mmol) in THF (6 mL) and aqueous HCl (1 M, 3 mL)
was stirred at rt for 18 h. The reaction was neutralised by
the addition of saturated aqueous sodium bicarbonate
(5 mL) and extracted into CH2Cl2 (3ꢂ20 mL). The com-
bined organic extracts were dried over magnesium sulfate,
filtered and concentrated under reduced pressure. Chromato-
graphy on silica eluting with CH2Cl2–acetone (3:2) gave
(ꢀ)-varitriol 1 (32 mg, 0.12 mmol, 72%) as a colourless
oil; Rf (3:2 CH2Cl2–acetone) 0.30; [a]2D0 ꢀ40.6 (c 1.6,
MeOH) [lit.1 [a]D25 (enant.) +18.5 (c 2.3, MeOH)]; nmax
-
(film)/cmꢀ1 3321, 2897, 1576 and 1472; dH (500 MHz, ace-
tone-d6) 1.27 (3H, d, J 6.5, H70), 2.92 (1H, br s, OH), 3.65
(1H, br s, OH), 3.69 (1H, app. t, J 5.5, H50), 3.82 (3H, s,
OMe), 3.84 (1H, app. t, J 6.5, H60), 3.91 (1H, app. t, J 5.5,
H40), 4.05 (1H, br s, OH), 4.29 (1H, app. t, J 6.0, H30), 4.72
(2H, s, OCH2), 6.20 (1H, dd, J 6.8 and 15.5, H20), 6.89
(1H, d, J 8.0, H6), 7.12 (1H, d, J 15.5, H10), 7.13 (1H, d, J
8.0, H5) and 7.22 (1H, app. t, J 8.0, H4); dC (125 MHz,
acetone-d6) 19.5 (C70), 55.4 (OCH2), 56.0 (OMe), 76.4
(C40), 77.1 (C50), 80.0 (C60), 85.3 (C30), 110.6 (C3), 119.3
(C5), 127.9 (C1), 129.2 (C4), 129.3 (C10), 132.4 (C20),
139.0 (C6) and 158.9 (C2); m/z (ESI): 303 [(M+Na)+,
100%]; found (M+Na)+, 303.1213. C15H20O5Na requires,
303.1203. These data were in broad accord with those
published in the literature (see text).1,3
3.1.10. (L)-30-epi-Varitriol 18. A solution of styrene 17b
(104 mg, 0.24 mmol) in THF (9 mL) and aqueous HCl
(1 M, 4.5 mL) was stirred at rt for 7 days. The reaction
was neutralised by the addition of saturated aqueous sodium
bicarbonate (10 mL) and extracted into CH2Cl2 (3ꢂ50 mL).
The combined organic extracts were dried over magnesium
sulfate, filtered and concentrated under reduced pressure.
Chromatography on silica eluting with CH2Cl2–acetone
(3:2) gave (ꢀ)-30-epi-varitriol 18 (56 mg, 0.20 mmol,
83%) as a colourless oil; Rf (3:2 CH2Cl2–acetone) 0.30;
[a]D20 ꢀ9.7 (c 2.25, MeOH); nmax(film)/cmꢀ1 3356, 2966,
1696, 1575 and 1470; dH (500 MHz, acetone-d6) 1.24 (3H,
d, J 6.0, H70), 2.95 (1H, br s, OH), 3.82 (3H, s, OMe),
3.79–3.85 (2H, m, H50, OH), 3.94 (1H, dd, J 7.5 and 6.0,
H60), 4.05 (1H, br s, OH), 4.16 (1H, app. t, J 4.5, H40),
4.63 (1H, dd, J 6.5 and 4.0, H30), 4.72 (2H, s, OCH2), 6.32
(1H, dd, J 15.5 and 7.5, H20), 6.88 (1H, d, J 8.0, H6), 7.05
(1H, d, J 15.5, H10), 7.14 (1H, d, J 8.0, H5) and 7.22 (1H,
app. t, J 8.0, H4); dC (125 MHz, acetone-d6) 19.3 (C70),
55.4 (OCH2), 56.0 (OMe), 74.7 (C40), 78.1 (C50), 79.3
(C60), 82.1 (C30), 110.5 (C3), 119.5 (C5), 127.9 (C1),
129.3 (C4), 129.9 (C10), 130.8 (C20), 139.3 (C6) and 158.8
(C2); m/z (ESI): 303 [(M+Na)+, 100%], 189 and 159; found
(M+Na)+, 303.1199. C15H20O5Na requires, 303.1203.
(b) One-pot route to styrenes 17. A solution of phosphonate
5b (160 mg, 0.33 mmol) in THF (2.5 mL) was added to
a stirred suspension of sodium hydride (16 mg, 0.40 mmol,
60%) in THF (1.5 mL) at 0 ꢁC under an atmosphere of argon.
After stirring for 15 min a solution of lactol 8 (58 mg,
0.33 mmol) in THF (1.5 mL) was added and the mixture al-
lowed to warm to rt. The reaction was stirred for 20 h before
the addition of potassium hydroxide on alumina (663 mg).
The suspension was cooled to 0 ꢁC before the addition of
CBr2F2 (155 mL, 1.70 mmol). After stirring for 18 h, the re-
action was filtered through CeliteÓ washing with CH2Cl2
(25 mL). The solvent was removed under reduced pressure,
and the resultant residue was purified by careful flash col-
umn chromatography using pet. ether–EtOAc (9:1) to give
the styrenes 9a and 9b as a 1:1.3 mixture (68 mg, 47%
3.1.11. Triacetylvaritriol 19. (ꢀ)-Varitriol 1 (28 mg,
0.10 mmol) was dissolved in pyridine (0.7 mL) and Ac2O
(60 mL, 0.60 mmol) added. After stirring at rt for 4 h, the
reaction was diluted with CH2Cl2 (10 mL) and washed
with aqueous HCl (1 M, 5 mL), saturated aqueous sodium
bicarbonate (5 mL) and brine (5 mL). The organic solution
was dried over magnesium sulfate, filtered and concentrated
in vacuo. Chromatography on silica eluting with pet. ether–

12130
G. D. McAllister et al. / Tetrahedron 63 (2007) 12123–12130
3. Clemens, R. T.; Jennings, M. P. Chem. Commun. 2006, 2720–2721.
EtOAc (4:1) gave triacetate 19 (39 mg, 0.096 mmol, 96%) as
a colourless oil; Rf (4:1 pet. ether–EtOAc) 0.18; [a]2D0 ꢀ17.2
(c 0.58, CHCl3) [lit.1 [a]D25 (enant.) +16.9 (c 0.33, CHCl3)];
dH (400 MHz, CDCl3) 1.37 (3H, d, J 6.4, H70), 2.05, 2.08 and
2.09 (3ꢂ3H, 3ꢂs, 3ꢂOAc), 3.82 (3H, s, OMe), 4.12 (1H,
quintet, J 6.4, H60), 4.52 (1H, app. t, J 6.7, H30), 4.92 (1H,
app. t, J 5.8, H50), 5.07 (1H, app. t, J 5.8, H40), 5.24 (2H,
AB q, J 11.6, OCH2), 6.12 (1H, dd, J 6.7 and 15.6, H20),
6.84 (1H, d, J 8.0, H6), 6.97 (1H, d, J 15.6, H10), 7.12
(1H, d, J 8.0, H5) and 7.29 (1H, app. t, J 8.0, H4); dC
(100 MHz, CDCl3) 19.0 (C70), 20.6 (Me), 20.7 (Me), 21.0
(Me), 55.8 (OMe), 57.6 (CH2O), 74.7 (C40), 75.6 (C50),
77.5 (C60), 81.4 (C30), 110.2 (C3), 118.8 (C5), 129.7 (C4),
119.8 (C10), 129.9 (C20), 130.0 (C1), 138.3 (C6), 158.4
(C2), 169.9 (CO), 169.9 (CO) and 171.2 (CO). These data
were in agreement with those reported in the literature.1
€
4. For recent reviews on the Ramberg–Backlund reaction, see:
Taylor, R. J. K.; McAllister, G. D.; Franck, R. W. Carbohydr.
Res. 2006, 341, 1298–1311; Taylor, R. J. K.; Casy, G. Org.
React. 2003, 62, 357–475.
5. Robinson, J. E.; Taylor, R. J. K. Chem. Commun. 2007, 1617–
1619 and references therein.
6. (a) McAllister, G. D.; Paterson, D. E.; Taylor, R. J. K. Angew.
Chem., Int. Ed. 2003, 42, 1387–1391; (b) Jeanmart, S.;
Taylor, R. J. K. Tetrahedron Lett. 2005, 46, 9043–9048.
7. (a) Hughes, N. A.; Speakman, P. R. H. Carbohydr. Res. 1965, 1,
171–175; (b) Jensen, H. H.; Jensen, A.; Hazell, R. G.; Bols, M.
J. Chem. Soc., Perkin Trans. 1 2002, 1190–1198.
8. Chan, T.-L.; Fong, S.; Li, Y.; Man, T.-O.; Poon, C.-D. J. Chem.
Soc., Chem. Commun. 1994, 1771–1772.
9. (a) Davidson, A. H.; Hughes, L. R.; Qureshi, S. S.; Wright, B.
Tetrahedron Lett. 1988, 29, 693–696; (b) Ohrui, H.; Jones,
G. H.; Moffatt, J. G.; Maddox, M. L.; Christensen, A. T.;
Byram, S. K. J. Am. Chem. Soc. 1975, 97, 4602–4613 and refer-
ences therein.
Acknowledgements
10. Ronald, R. C.; Winkle, M. R. Tetrahedron 1983, 39, 2031–2042.
11. Mikolajczyk, M.; Grzejszczak, S.; Chefczynska, A.; Zatorski,
A. J. Org. Chem. 1979, 44, 2967–2972.
The University of York (G.D.M.), the EPSRC and the MOD
(J.E.R.) are thanked for financial assistance.
12. Clemens and Jennings reported the synthesis of 17a (Ref. 3).
However, no physical data were given.
References and notes
13. Saponification of 19 cleanly regenerated (ꢀ)-varitriol 1 (67%)
and the measured rotation was consistent with the value
obtained earlier in our study [a]D ꢀ41.2 (c 1.8, MeOH). This
finding indicates a possible error in the [a]D values originally
reported in the literature (Refs. 1 and 3).
1. Malmstrøm, J.; Christophersen, C.; Barrero, A. F.; Oltra, J. E.;
Justicia, J.; Rosales, A. J. Nat. Prod. 2002, 65, 364–367.
2. Mayer, A. M. S.; Gustafson, K. R. Eur. J. Cancer 2004, 40,
2676–2704.