A synthesis of herboxidiene

Article abstract of DOI:10.1039/a900185i

The natural herbicide herboxidiene was constructed from two key fragments using a modified Julia olefination based on the benzothiazolyl sulfone activator. Key steps in the synthesis of the C1-C10 oxane fragment were (a) a modified Julia olefination using

Full text of DOI:10.1039/a900185i

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A synthesis of herboxidiene
Paul R. Blakemore,a Philip J. Kocien´ski,*a Andrew Morleyb and Kenneth Muira
a Chemistry Department, Glasgow University, Glasgow, UK G12 8QQ
b Rhône-Poulenc Rorer Ltd, Dagenham Research Centre, Rainham Road South, Dagenham,
Essex, UK RM10 7XS
Received (in Cambridge) 6th January 1999, Accepted 3rd February 1999
The natural herbicide herboxidiene was constructed from two key fragments using a modified Julia olefination based
on the benzothiazolyl sulfone activator. Key steps in the synthesis of the C1–C10 oxane fragment were (a) a modified
Julia olefination using a 1-phenyl-1H-tetrazolyl sulfone as activator and (b) an intramolecular addition of an
alkoxide to an α,β-unsaturated ester. Key steps in the synthesis of the C11–C19 polyketide fragment were (a) a
directed aldol reaction using a camphor-10,2-sultam as auxiliary; (b) an Ireland–Claisen rearrangement and (c) a
hydroxy-directed epoxidation.
Introduction
3
7
Screening of microbial fermentation broths for herbicidal
activity led to the discovery of a metabolite from Streptomyces
sp. A7847 which displays exceptional phytotoxicity towards a
broad range of broadleaf weeds such as oilseed rape (Brassica
napus), wild buckwheat (Polygonum convolvulus), morning glory
(Ipomoea sp.) and hemp sesbania (Sesbania exaltata).1 At doses
of 35 g hectareϪ1 90% inhibition of the aforementioned weeds
was observed and as little as 7 g hectareϪ1 secured a 75% inhib-
ition; however, even at doses of 5.6 kg hectareϪ1, the active
agent, herboxidiene (1),† was innocuous towards wheat (Tri-
ticum aestivum). Early structural studies established the poly-
ketide nature of the metabolite, its connectivity and the relative
configuration of 5 of the 9 stereogenic centres.2 A full assign-
ment of the relative and absolute stereochemistry was reported
by a Novartis group in 1997 through a combination of selective
degradation of the natural product and asymmetric synthesis
of the respective fragments and their conclusions corroborated
by X-ray analysis.3 The potent herbicidal activity of herboxid-
iene and the recent discovery that it up-regulates gene expres-
sion of low density lipoprotein receptors4 has spurred interest
in its total synthesis. Our first approach to herboxidiene and its
analogues was launched before the complete stereochemistry
had been assigned and culminated in herboxidiene A (2), a
diastereoisomer differing from the natural product at C12, C17
and C18.5 Asymmetric syntheses of major fragments have also
been recorded by the Banwell6–8 and Novartis3 groups. We now
report the first total synthesis of herboxidiene (1) based on the
union of the benzothiazolyl sulfone 4 and the aldehyde 3
(Scheme 1) using a modified Julia olefination.9,10 Our synthesis
also incorporates the first synthetic application of a new variant
of the modified Julia olefination based on the use of 1-phenyl-
1H-tetrazol-5-yl sulfones.11
O
CO2H
10
1
O
11
MeO
19
O
CO2All
O
HO
3
Herboxidiene (1)
+
N
S
O
CO2H
SO2
O
MeO
MeO
O
HO
(+)-Herboxidiene A (2)
PCBO
4 (PCB = p-chlorobenzoyl)
Scheme 1
detectable isomeric contaminants in 80% yield. Ozonolysis of 6
in MeOH–CH2Cl2 (1:3) yielded a mixture of the corresponding
aldehyde (minor) and dimethyl acetal (major) after reductive
work-up and the mixture was converted to the crystalline acetal
7 on treatment with 2,2-dimethylpropane-1,3-diol in the pres-
ence of p-TsOH. Acetal 7 again only needed recrystallisation to
yield pure product in 72% overall yield from 6. Alcohol 8
derived from reductive removal of the chiral auxiliary was the
most sensitive intermediate in the entire synthesis owing to easy
acid-catalysed intramolecular transacetalisation but with due
care, it could be purified by distillation and oxidised to the
corresponding aldehyde 9 in 96% yield.
Results and discussion
Synthesis of the C1–C10 aldehyde fragment 3
Our previous synthesis of aldehyde 35 was substantially modi-
fied in the quest for a more practical route. α-Alkylation of the
hex-5-enoyl bornane-10,2-sultam 5 (Scheme 2) afforded the
alkylation product 6 with excellent stereoselectivity.12 A simple
recrystallisation yielded analytically pure product with no
The next step of the sequence required a 2-carbon chain
extension of aldehyde 9 with concomitant generation of the
trans-alkene 11. We chose this and a later transformation (vide
infra) as vehicles for displaying the advantages of the modified
Julia olefination in fragment linkage reactions. Recent detailed
studies have revealed that the yield and stereoselectivity of
the modified Julia olefination is sensitive to the base used to
deprotonate the sulfone and solvent polarity.13–15 A noteworthy
new development is the discovery11 that 1-phenyl-1H-tetrazolyl
† The IUPAC name for herboxidiene is: 2-[3,4,5,6-tetrahydro-5-methyl-
6-(7,8-epoxy-11-hydroxy-10-methoxy-1,5,7,9-tetramethyldodec-1,3-
dienyl)-2H-pyran-2-yl]ethanoic acid.
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968
955

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O
O
O
E
A
B
C
O
O
O
R
Xc
O
Xc
O
Xc
O
8
9
11
R = CH2OH
5
6
7
D
mp 95-97 °C
mp 124-126 °C
R = CHO
F
O
J,K
M
I
G
HO
O
R1O
O
O
O
O
H
H
H
H
H
CO2All
OPMB
OR2
CO2All
16
17
OR
HO
OH
R = PMB
R = H
13
14
R
1 = Me, R2 = H
1 = Me, R2 = PMB
O
15
3
12
L
H
R
N
N
N
N
PMB = p-methoxybenzyl
All = allyl
SO2Et
O2S
N
Ph
Xc (2S)
10
Scheme 2 Reagents and conditions:
A
80% (a) BuLi, THF, Ϫ80 ЊC, 2 h; (b) MeI, DMPU,
Ϫ80 ЊC→rt, 12 h
72% (a) O3, MeOH–CH2Cl2 (1:3), Ϫ78 ЊC, 2 h; (b) Me2S,
Ϫ78 ЊC→rt, 12 h; (c) 2,2-dimethylpropane-1,3-diol,
p-TsOH, PhMe, ∆ (ϪH2O), 12 h
G
H
73% TsOH, MeOH, rt, 3 d, α:β = 3:1
93% (a) KHMDS, THF, 0 ЊC, 20 min; (b) PMBCl, TBAI, 0 ЊC→rt,
24 h
74% AcOH–THF–H2O (3:2:2), 65 ЊC, 2 h, α:β = 3:2
82% allyl diethylphosphonoacetate, Cs2CO3, THF, ∆, 18 h
89% t-BuOK, THF, Ϫ65 ЊC, 10 min, pure cis isomer
95% DDQ, H2O–CH2Cl2 (1:15), rt, 30 min
54% 4 steps (see ref. 5).
B
I
J
K
L
M
C
D
E
F
93% LiAlH4, Et2O, rt, 12 h
96% PyrؒSO3, Et3N, DMSO, rt, 30 min
93% sulfone 10, KHMDS, DME, Ϫ60 ЊC, 45 min
83% AD-mix α, MeSO2NH2, t-BuOH–H2O (2:3), 0 ЊC, 18 h
sulfones can give superior yields and stereoselectivity for the
synthesis of simple alkenes compared with the benzothiazolyl
sulfones advocated by Julia.9,10 In the case at hand, addition of
potassium hexamethyldisilazide (KHMDS) to a mixture of
sulfone 10 and aldehyde 9 in 1,2-dimethoxyethane (DME) at
Ϫ60 ЊC gave a 93% yield of the alkene 11 with good stereo-
selectivity (E:Z = 93:7). A highly stereoselective Sharpless
asymmetric dihydroxylation16 returned the diol 12 together
with an inseparable minor diastereoisomer (dr = 93:7) in 83%
yield. The identical dr for the last two steps indicates there was
no racemisation in the Julia olefination.‡
detour beginning with slow methanolysis of the acetal 12 at
room temperature in the presence of p-TsOH to give an
inseparable mixture of 2 major anomeric acetals 13 (α:β = 3:1)
in 73% yield. After protection of the remaining free hydroxy
group as its p-methoxybenzyl ether 14, the acetals were then
hydrolysed with aqueous acetic acid to a mixture of anomeric
lactols 15. The requisite 2-carbon chain extension was accom-
plished using a Horner–Wadsworth–Emmons reaction with
allyl diethylphosphonoacetate in the presence of caesium
carbonate whereupon the intermediate unsaturated ester under-
went ring closure to a mixture of 2 isomeric oxaneacetic
esters (dr = 2:3) in which the desired isomer 16 was the minor
component. Protracted heating of the mixture with caesium
carbonate led to no change in ratio suggesting that the oxanes
were the products of a kinetically controlled conjugate addi-
tion.¶ However, on treatment with potassium tert-butoxide at
Ϫ65 ЊC, the mixture isomerised rapidly and efficiently to give
the desired isomer 16 as the exclusive product.|| At this stage,
a chromatographic purification removed all minor diastereo-
isomeric impurities accrued since the Julia olefination 7 steps
previous to give the oxaneacetic ester 16 in 73% overall yield
from 15 and 28% overall from aldehyde 9. To complete the
sequence, oxidative cleavage of the p-methoxybenzyl ether with
DDQ17 gave alcohol 17 which was converted to the desired
fragment 3 in four further steps as described previously.5
As a prelude to another 2-carbon chain extension, we
required deprotection of acetal 12 to the corresponding alde-
hyde (or its cyclic lactol congener). Unfortunately all attempts
to achieve a mild hydrolysis failed.§ We therefore resorted to a
‡ Further proof that the modified Julia olefination proceeded without
racemisation was gleaned by oxidative cleavage of alkene 11 according
to the following sequence. Comparison of the 1H and 13C NMR spectra
of the mandelate 37 with a sample prepared from partially racemised
olefin revealed a dr of у94:6.
O
(a) OsO4, NaIO4
acetone-H2O, rt, 12 h
(b) LiAlH4, Et2O, rt
O
Ph
OAc
O
O
11
(c) (R)-PhCH(OAc)CO2H
DCC, DMAP, CH2Cl2
Synthesis of the C11–C19 sulfone fragment 4
37
Construction of sulfone 4 began with a highly stereoselective
§ Under strongly acidic conditions (1 M HCl in THF, reflux, 3 h),
cyclodehydration occurred to give a pleasant smelling, volatile bicyclic
acetal 38.
¶ Banwell and co-workers29 showed that under non-equilibrating con-
ditions, the stereochemistry of oxaneacetic esters formed by the intra-
molecular Michael addition of O-nucleophiles to tethered acrylates is a
kinetic process whose stereochemistry is governed by the double bond
geometry of the acrylate.
|| The equilibration of oxaneacetic esters with alkoxide bases was
reported by Maurer and co-workers in 197930 and has been used by
others.5,31,32
HCl (1M)-THF (1:9)
12
O
∆, 3 h
O
38
956
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968

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O
HO
O
A
N
XC
SO2
TBSO
O
20 mp 92-95 °C
(2R)-18
TBSO
B
19
MeO
OH
MeO
O
C
XC
TBSO
TBSO
21 mp 106-108 °C
22
D
Fig. 1 X-Ray crystal structure of the diol 26.
MeO
O
MeO
O
analysis of the corresponding diol 26 (Fig. 1) revealed that
the reduction had proceeded with 1,3-anti-stereoselectivity.**
Finally, esterification of the pure alcohol under standard
conditions then afforded the propionate ester 27 in 97%
yield.
E
TBSO
TBSO
23
24
Like Banwell before us,7 we chose the chirality transfer
inherent in the well-organised chair transition state typical of
the Ireland–Claisen rearrangement23 to introduce the C14–C15
trisubstituted alkene and the stereogenic centre at C12. Thus,
the lithium enolate of propionate ester 27 (Scheme 4) was
treated with TBSCl in hexanes followed by DMPU†† to give
(E)-silyl ketene acetal 28. Rearrangement of 28 followed by acid
hydrolysis of the intermediate silyl esters lead to the formation
of a diastereoisomeric mixture of carboxylic acids in 68% yield
(dr = 86:14). After reduction to the corresponding alcohols, the
diastereoisomers were easily separated by flash chromatography
and the major isomer 30 subjected to a Mitsunobu reaction
with 2-mercaptobenzothiazole24 to give the thioether 31 in
good yield. Oxidation of the thioether 31 to the corresponding
sulfone by ammonium heptamolybdate tetrahydrate [(NH4)6-
Mo7O24ؒ4H2O] catalysis25 required over 48 h for complete
conversion. Furthermore, attempted TBS deprotection of the
resulting sulfone with TBAFؒ3H2O lead to complete decom-
position: only benzothiazolone was isolated in 86% yield.
Simply reversing the order of the aforementioned steps solved
both problems. TBS deprotection of the thioether 31 with
TBAFؒ3H2O occurred in excellent yield with no detectable
decomposition and the sulfur atom of the resulting alcohol
32 was then rapidly converted to the sulfone 33 via treatment
with ammonium heptamolybdate tetrahydrate and H2O2 in
EtOH.
The directed epoxidation reaction used in our synthesis of
herboxidiene A5 was redeployed for the oxidation of olefin
33. The reactivity of an olefinic alcohol towards VO(acac)2
catalysed epoxidation depends on the proximity of the hydroxy
group to the alkene.26 As a consequence, the oxidation of
bishomoallylic alcohol 33 was extremely slow at sub-ambient
temperatures and low catalyst loadings. Unfortunately, con-
ducting the epoxidation in toluene at 60 ЊC [3 mol% VO(acac)2,
1.5 equiv. tert-butyl hydroperoxide (TBHP)] resulted in ring
closure to a tetrahydrofuran in 63% yield. Alternatively the
reaction could be hurried at 0 ЊC if repeated portions of
catalyst (total 40 mol%) were added but then acetates of the
product 34 and starting material 31 were also formed. Success
was eventually achieved using just 1 mol% of catalyst in a cold
(Ϫ8 ЊC) solution of the olefin 33 in CH2Cl2 with addition of
TBHP via a syringe pump over 48 h. After the addition was
complete, the oxidation was allowed a further 24 h whereupon
F
O
MeO
OH
MeO
O
G
RO
TBSO
25
26
R = TBS
27
mp 46-47 °C
H
mp 63-65 °C
R = H (X-ray)
mp 128-130 °C
Scheme 3 Reagents and conditions:
A
75% (a) Et2BOTf, CH2Cl2, Ϫ5 ЊC; (b) i-Pr2NEt, 30 min;
(c) 19, Ϫ78 ЊC, 3 h
B
C
D
E
90% MeOTf, proton sponge, PhMe, 80 ЊC, 24 h
99% LiAlH4, Et2O, 0 ЊC, 15 min
91% Dess–Martin periodinane, CH2Cl2, 0 ЊC→rt, 2 h
80% (a) CH2᎐᎐C(Me)MgBr, Et2O, 0 ЊC, 1 h;
(b) DMP, CH2Cl2, rt, 4 h
F
G
H
75% LiAlH4, LiI, Et2O, Ϫ100 ЊC, 1 h
97% (EtCO)2O, DMAP, pyridine, rt, 16 h
72% TBAFؒ3H2O, THF, rt, 15 min.
boron-mediated aldol reaction between propionyl sultam 18
and the (S)-aldehyde 19 (Scheme 3).12,18 Adduct 20 was
obtained enantiopure in 75% yield after a single recrystallis-
ation from hexanes as befits the conjunction of a matched pair.
To effect methylation of the aldol 20, a combination of proton
sponge [1,8-bis(dimethylamino)naphthalene] and methyl tri-
flate was employed. These conditions represent a cheap hybrid
formulation of two other costly mild methylation procedures
popularised by Evans:19 (a) methyl triflate (inexpensive) with
1,6-di-tert-butyl-4-methylpyridine (very expensive) and, (b)
trimethyloxonium tetrafluoroborate (expensive) with proton
sponge (inexpensive). Methyl triflate and proton sponge are
compatible partners and produced the methylated adduct 21 in
90% yield with no trace of retroaldolisation.
Following reductive removal of the chiral auxiliary the alco-
hol 22 was oxidised with the Dess–Martin periodinane20,21 to
afford aldehyde 23 in excellent yield. Addition of isopropenyl-
magnesium bromide to aldehyde 23 was not stereoselective
giving a mixture of allylic alcohols (syn:anti = 57:43) which
was immediately oxidised to enone 24 in 80% overall yield.
Reduction of enone 24 at Ϫ100 ЊC with lithium aluminium
hydride in the presence of lithium iodide22 was stereoselective
affording a solid product which, according to NMR spectro-
scopic analysis, was a mixture of diastereoisomers (dr = 85:15).
After recrystallisation of the solid product and careful chrom-
atography of the residual mother liquors, a combined yield of
75% of enantiopure 25 was obtained. A single crystal X-ray
** The chelation-controlled reduction of β-alkoxy ketones lacking a
substituent on the intervening carbon using LiI–LiAlH4 occurs with
syn-stereoselectivity.22
†† The use of DMPU to assist enolate silylation at low temperature by
TBSCl does not affect the enolate geometry.33
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968
957

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TBSO
O
SO2BT
O
O
MeO
MeO
A
MeO
O
O
CO2R2
A(a),(b)
PCBO
TBSO
TBSO
MeO
4
(E)-28
A(c),(d)
27
O
R1O
O
X
O
35
36
1
R
R
R
1 = PCB, R2 = All
CO2All
MeO
HO
B
MeO
CHO
1 = H, R2 = Me
1 = R2 = H
B
3
C
TBSO
TBSO
Scheme 5 Reagents and conditions:
29
30
31
X = OH
A
B
C
81% (a) LDA, THF, Ϫ78 ЊC, 15 min; (b) 3, Ϫ78 ЊC→Ϫ20 ЊC, 1.5 h
72% K2CO3, MeOH, ∆, 2 h
84% K2CO3, H2O–MeOH (1:4), ∆, 1 h.
C
BT = Benzothiazol-2-yl
X = SBT
D
of the alcohol 34, triphenylphosphine and p-chlorobenzoic acid
(PCBOH) in THF at 0 ЊC was treated with either diethyl azo-
dicarboxylate (DEAD) or diisopropyl azodicarboxylate
(DIAD) and allowed to warm. Although these simple experi-
ments afforded the desired ester 4, yields were low to moderate
(23–66%) and the product was very difficult to separate from
the hydrazodicarboxylate by-product. To solve the purification
problem the azodicarboxylate component was changed to the
rarely used dimethyl congener which gives a water soluble
hydrazodicarboxylate derivative but now significant quantities
of acylated hydrazine adducts were formed and the yield of the
product ester 4 was disappointing (30%). These problems were
circumvented by forming the adduct between triphenyl-
phosphine and dimethyl azodicarboxylate (DMAD)28 in THF
at 0 ЊC. The alcohol 34 was then added followed by the slow
portionwise addition of the PCBOH. With the new protocol,
ester 4 was produced rapidly in good yield (74%) and was easily
separated from the hydrazodicarboxylate by-product by
aqueous extraction.
SBT
SO2BT
MeO
MeO
E
HO
HO
32
33
F
SO2BT
O
SO2BT
O
MeO
MeO
G
PCBO
HO
4
34
Scheme 4 Reagents and conditions:
A
68% (a) LDA, THF, Ϫ78 ЊC, 30 min; (b) TBSCl, DMPU;
(c) Ϫ78 ЊC→∆, 1 h; (d) aq. HCl
Completion of synthesis—union of sulfone 4 and aldehyde 3
B
C
D
E
F
G
90% LiAlH4, Et2O, 0 ЊC, 10 min
The one-pot Julia reaction between sulfone 4 and the aldehyde 3
(Scheme 5) yielded 81% of the protected herboxidiene deriv-
ative 35 with excellent selectivity (10E:Z = 91:9). Although
direct double deprotection of 35 was possible by simple
saponification, we favoured a two step deprotection protocol
via the previously reported methyl ester of herboxidiene 362
because separation of minor impurities and the (10Z)-isomer
from allyl ester 35 by chromatography proved very difficult,
as was direct purification of herboxidiene itself.§§ How-
ever, purification of the methyl ester 36 was straightforward
99% BTSH, Ph3P, DIAD, THF, 0 ЊC→rt, 2 h
98% TBAFؒ3H2O, THF, rt, 32 h
88% Mo(), H2O2, H2O–EtOH, rt, 24 h
69% VO(acac)2, TBHP, CH2Cl2, Ϫ8 ЊC, 72 h
74% (a) Ph3P, DMAD, THF, 0 ЊC; (b) PCBOH, 0 ЊC→rt, 3 h.
oxirane 34 was obtained in 69% yield as a single diastereoisomer
together with 26% of recovered starting material 33.‡‡ Concomi-
tant oxidation of the thioether and olefin in 32 was also
achieved with MCPBA to yield 46% of the epoxysulfone 34
directly (dr = 85:15).
To complete the synthesis of the fragment 4, all that
remained was to invert the stereogenic centre at C18 and to
protect the resultant hydroxy group. Reasoning that an ester
function would be a sufficiently robust protecting group for the
imminent Julia olefination, a Mitsunobu reaction was the
logical choice for the inversion operation.27 Initial experiments
employed the standard Mitsunobu conditions: viz., a mixture
1
and the high field H and 13C NMR spectra of our synthetic
material compared favourably with the data reported by Isaac.2
Finally, hydrolysis of pure methyl ester 36 with potassium
carbonate in aqueous methanol gave herboxidiene in 84%
yield.
Comparison of 1H and 13C NMR spectroscopic data for our
synthetic herboxidiene with the data for the natural material
reported by Isaac2 revealed significant discrepancies in the C1–
C3 region (see Tables 1 and 2). However, the sodium salt of our
synthetic material (prepared by treatment with Na2CO3 in
‡‡ The model 39 we used to predict the stereochemistry of the hydroxy-
directed epoxidation was based on earlier work by Sharpless34 and
Mihelich.35
1
CD3OD) provided H and 13C NMR data in complete agree-
ment with those of Isaac. Therefore, the data reported for
natural herboxidiene likely pertains to a carboxylate derivative
rather than the free acid.
In conclusion, we have completed the first total synthesis of
(ϩ)-herboxidiene which features two variants of the modified
L
R
MeO
O
L
O
V
O
tBu
§§ Herboxidiene was not separable from p-chlorobenzoic acid or its
minor (10Z)-isomer by simple flash chromatography.
39
958
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968

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Table 1 1H NMR data for natural and synthetic herboxidiene (1)
Natural herboxidienea
Synthetic herboxidieneb
Position
δ
Multiplicity
J/Hz
δ
Multiplicity
J/Hz
H2A
H2B
H3
H4A
H4B
H5A
H5B
H6
2.45
2.25
3.76
1.86–1.68
1.30
1.86–1.68
1.26–1.12
1.55
0.66
3.34
dd
dd
m
m
m
m
m
m
d
14.1, 6.6
14.1, 7.5
—
—
—
—
—
—
6.6
2.46
2.38
dd
dd
m
m
m
m
m
m
d
15.6, 7.2
15.3, 5.7
—
—
—
—
—
—
6.6
3.80–3.70
1.90–1.82
1.40–1.22
1.74–1.65
1.40–1.22
1.60–1.43
0.68
C6-Me
H7
d
9.9
3.34
d
9.9
C8-Me
H9
H10
H11
H12
C12-Me
H13A
H13B
C14-Me
H15
1.68
5.90
6.29
5.45
2.44
1.03
1.91
1.26–1.12
1.27
s
d
—
1.69
5.92
6.30
5.47
2.50–2.38
1.04
1.92
1.18
1.28
s
d
—
11.1
15.0, 10.8
15.0, 9.0
—
6.6
13.1, 4.3
—
10.8
15.0, 10.8
15.0, 9.1
—
dd
dd
m
d
dd
m
s
dd
dd
m
d
dd
dd
s
6.7
13.4, 4.3
13.0, 11.2
—
—
9.6
2.65
d
2.65
d
9.4
H16
C16-Me
H17
H18
H19
1.45
0.83
2.96
3.78
m
d
dd
dq
d
—
6.9
6.0, 4.5
6.6, 6.3
6.6
1.60–1.43
0.83
2.97
3.78
1.10
m
d
dd
quintet
d
—
6.9
6.1, 4.3
6.4
6.4
1.11
OMe
3.52
s
—
3.52
s
—
a Recorded in CD3OD at 300 MHz (data taken from ref. 2). b Recorded in CD3OD at 360 MHz.
Table 2 13C NMR data for natural and synthetic herboxidiene (1)
Position
Naturala δ
Syntheticb δ
∆δ
Position
Naturala δ
Syntheticb δ
∆δ
C1
C2
C3
C4
C5
C6
C6-Me
C7
C8
C8-Me
C9
C10
C11
179.8
46.4
77.0
33.1
33.7
33.5
18.2
92.2
136.5
12.1
175.3
42.3
75.5
32.8
33.4
33.4
18.1
92.2
136.2
12.1
Ϫ4.5
Ϫ4.1
Ϫ1.5
Ϫ0.3
Ϫ0.3
Ϫ0.1
Ϫ0.1
0.0
Ϫ0.3
0.0
ϩ0.1
Ϫ0.1
ϩ0.2
C12
C12-Me
C13
C14
C14-Me
C15
C16
C16-Me
C17
C18
C19
36.5
22.7
48.1
62.6
16.8
67.8
36.4
11.7
88.6
69.8
19.9
61.9
36.6
22.7
48.1
62.6
16.8
67.9
36.4
11.5
88.5
69.9
19.8
61.9
ϩ0.1
0.0
0.0
0.0
0.0
ϩ0.1
0.0
Ϫ0.2
Ϫ0.1
ϩ0.1
Ϫ0.1
0.0
129.5
126.6
140.5
129.6
126.5
140.7
OMe
a Recorded in CD3OD at 75 MHz (data taken from ref. 2). b Recorded in CD3OD at 90 MHz.
Julia olefination in key fragment linkage reactions. We have
shown that, depending on the nature of the olefinic linkage,
variation of the heterocyclic sulfone can be used to optimise
yield and stereoselectivity. Thus, in the case at hand, the benzo-
thiazolyl sulfone unit is superior for the construction of the
conjugated (E,E)-diene moiety whereas a 1-phenyl-1H-tetrazol-
5-yl sulfone gave high yields and trans-selectivity in the con-
struction of a simple alkene.
are described using the following abbreviations: 0 = singlet
(due to quaternary carbon), 1 = doublet (methine), 2 = triplet
(methylene), 3 = quartet (methyl). For the sake of consistency,
all NMR assignments refer to herboxidiene numbering. 5-
Mercapto-1-phenyl-1H-tetrazole and 2-mercapto-1,3-benzo-
thiazole were obtained from Aldrich.
(2S)-N-(Hex-5-enoyl)bornane-10,2-sultam 5
To a mechanically stirred suspension of sodium hydride (6.0 g,
60 wt%, 150 mmol) in PhMe (125 ml) at rt under N2 was added
dropwise a solution of (2S)-bornane-10,2-sultam (25 g, 116
mmol) in PhMe (250 ml) over 30 min. The mixture was stirred
for a further 1 h before being treated dropwise with hex-5-enoyl
chloride36 (17.4 g, 131 mmol) in PhMe (125 ml) over 30 min and
then allowed to stir overnight. The reaction mixture was then
quenched by the addition of sat. aqueous NH4Cl (100 ml) and
the layers shaken and then separated. The aqueous phase was
extracted with Et2O (2 × 50 ml) and the combined organic
extracts washed successively with NaOH (1 M, 2 × 20 ml),
brine (40 ml), dried (MgSO4) and then concentrated in vacuo.
The residue was purified by column chromatography eluting
Experimental
For a description of general experimental details including
spectroscopic information and solvent purification see reference
1
5. H NMR and 13C NMR spectra were recorded on Bruker
AM 360 or Aspect 400 spectrometers with chemical shift values
being reported in ppm relative to residual chloroform (δH = 7.27
or δC = 77.2) as internal standard unless otherwise stated. All
coupling constants (J) are reported in Hertz (Hz). The multi-
plicities in the 13C NMR spectra refer to the signals in the off-
resonance spectra and were elucidated using the Distortionless
Enhancement by Polarisation Transfer (DEPT) spectral editing
technique, with secondary pulses at 90Њ and 135Њ. Multiplicities
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968
959

View Article Online
with 30% Et2O in hexanes to yield the desired product con-
taminated by hex-5-enoic acid. The impurity was subsequently
removed by dissolving the material in Et2O (250 ml), washing
with sat. aqueous NaHCO3 (4 × 75 ml), drying (MgSO4) and
then concentrating in vacuo to yield the pure unsaturated acyl
sultam 5 (34.0 g, 109 mmol, 94%) as a clear oil: bp (Kugelrohr
oven) 250 ЊC/0.2 mmHg, [α]D ϩ91.8 (c 1.02, CHCl3); νmax(film)/
cmϪ1 2962s, 1701s, 1457m, 1414m, 1385m, 1335s, 1269s, 1238s,
1212s, 1112m, 1083m, 1057m, 1039m, 989m, 912m, 771m;
δH(360 MHz, CDCl3) 5.78 (1H, ddt, J 17.0, 10.3, 6.7, H3), 5.02
catalytic quantity of p-TsOHؒH2O (ca. 10 mg). The mixture was
then stirred at reflux overnight with removal of water using
a Dean–Stark apparatus. The cooled reaction mixture was
diluted with Et2O (100 ml) and washed successively with sat.
aqueous NaHCO3 (50 ml), H2O (4 × 30 ml) and brine (30 ml).
The organic layer was then dried (MgSO4) and concentrated in
vacuo to yield 7.25 g of a crude solid which was recrystallised
(30 ml cyclohexane) to yield the pure dioxane product 7 (5.20 g,
12.6 mmol, 72%) as a white solid: mp 124–126 ЊC; [α]D ϩ75.0
(c 1.11, CHCl3); νmax(film)/cmϪ1 2956s, 1692s, 1328s, 1133m,
1113m, 547m, 536m; δH(360 MHz, CDCl3) 4.43 (1H, t, J 4.9,
H3), 3.89 (1H, t, J 6.3, CHN), 3.58 (2H, d, J 11.0, CHAHBO),
3.49 (1H, d, J 13.7, CHAHBSO2), 3.43 (1H, d, J 13.8, CHAHB-
SO2), 3.41 (2H, d, J 11.3, CHAHBO), 3.08 (1H, sextet of m, 6.8,
H6), 2.08–2.03 (2H, m), 1.97–1.82 (4H, m), 1.75–1.48 (3H, m),
1.44–1.30 (2H, m), 1.22 (3H, d, J 6.9, C6-Me), 1.17 and 0.70
(3H each, s, acetal CMe2), 1.15 and 0.97 (3H each, s, bornane
CMe2); δC(90 MHz, CDCl3) 176.0 (0), 101.8 (1), 77.2 (2), 77.2
(2), 65.1 (1), 53.2 (2), 48.4 (0), 47.8 (0), 44.7 (1), 39.9 (1), 38.5
(2), 32.9 (2), 32.3 (2), 30.2 (0), 26.9 (2), 26.5 (2), 23.1 (3), 22.0
(3), 20.9 (3), 20.0 (3), 19.1 (3); m/z (CI mode, NH3) 431
(100%), 414 (26), 350 (16), 250 (14), 233 (49) (Found: C, 60.84;
H, 8.49; N, 3.28. C21H35NO5S requires C, 60.99; H, 8.53; N,
3.39%).
(1H, dq, J 17.1, 1.7, CH᎐CH H ), 4.96 (1H, ddt, J 10.2, 1.9,
᎐
Z
E
1.1, CH᎐CH H ), 3.85 (1H, dd, J 7.3, 5.3, CHN), 3.49 (1H, d,
᎐
Z
E
J 13.8, CHAHBSO2), 3.42 (1H, d, J 13.8, CHAHBSO2), 2.78–2.63
(2H, m), 2.15–2.03 (4H, m), 1.95–1.83 (3H, m), 1.77 (2H, quin-
tet, J 7.5), 1.44–1.30 (2H, m), 1.14 and 0.96 (3H each, s, CMe2);
δC(90 MHz, CDCl3) 171.9 (0), 137.8 (1), 115.5 (2), 65.3 (1), 53.1
(2), 48.5 (0), 47.9 (0), 44.8 (1), 38.6 (2), 34.9 (2), 33.0 (2), 32.9
(2), 26.6 (2), 23.7 (2), 21.0 (3), 20.0 (3); m/z (EI mode) 311
(92%), 257 (31), 135 (100), 97 (47), 69 (69) (Found: C, 61.62; H,
8.05; N, 4.51. C16H25NO3S requires C, 61.70; H, 8.09; N,
4.50%).
(2S)-N-[(S)-2-Methylhex-5-enoyl]bornane-10,2-sultam 6
To a stirred solution of the acyl sultam 5 (15.6 g, 50.2 mmol)
in anhydrous THF (250 ml) at Ϫ80 ЊC (internal temperature)
under N2 was added BuLi (21.7 ml, 2.31 M in hexanes, 50.1
mmol) via a syringe-pump over 1 h. After the addition was
complete, the reaction mixture was stirred at Ϫ80 ЊC for a
further 1 h before being treated dropwise with a solution of
methyl iodide (9.4 ml, 21.4 g, 151 mmol) in anhydrous dimethyl-
propylene urea (DMPU, 18.2 ml, 19.3 g, 151 mmol) over 25
min. The reaction mixture was then allowed to warm slowly to
Ϫ60 ЊC, stirred for 1 h and then allowed to warm to rt over-
night. After this time the mixture was diluted with H2O (200 ml)
and Et2O (200 ml) and the layers shaken and then separated.
The aqueous phase was then extracted with Et2O (3 × 50 ml)
and the combined organic extracts washed successively with
H2O (3 × 50 ml), brine (50 ml), dried (MgSO4) and then con-
centrated in vacuo to yield 16.0 g of a white solid. The solid was
further purified by recrystallisation (50 ml cyclohexane) to yield
the methylated adduct 6 (13.0 g, 40.0 mmol, 80%) as a white
solid: mp 95–97 ЊC; [α]D ϩ98.0 (c 1.09, CHCl3); νmax(film)/cmϪ1
2935m, 1685s, 1327s, 1272m, 1220m, 1134m, 1057m, 534m;
δH(360 MHz, CDCl3) 5.81 (1H, ddt, J 17.0, 10.3, 6.7, H3), 5.02
(2S)-4-(5,5-Dimethyl-1,3-dioxan-2-yl)-2-methylbutan-1-ol 8
To a stirred suspension of lithium aluminium hydride (0.81 g,
21.3 mmol) in anhydrous Et2O (50 ml) at rt under N2 was added
dropwise a solution of the acyl sultam 7 (3.50 g, 8.47 mmol) in
anhydrous Et2O–THF (3:1) over 10 min. The resultant mixture
was then allowed to stir at rt overnight. After this time the
reaction was quenched by the dropwise addition of 20% KOH
(50 ml) and then stirred vigorously for 1 h. The biphasic mix-
ture was then filtered through a pad of Celite and the residue
washed well with Et2O (3 × 10 ml). The layers of the filtrate and
combined washings were then separated and the organic phase
washed successively with 20% KOH (5 × 20 ml), H2O (20 ml)
and brine (20 ml). The organic layer was then dried (MgSO4)
and concentrated in vacuo to yield essentially pure alcohol 8
(1.59 g, 7.87 mmol, 93%) as a clear oil: bp (Kugelrohr oven)
170 ЊC/0.3 mmHg; [α]D Ϫ7.3 (c 1.05, CHCl3); νmax(film)/cmϪ1
3424br s, 2954s, 2870s, 1472m, 1394m, 1116s, 1078m, 1042m,
1018s; δH(360 MHz, CDCl3) 4.43 (1H, t, J 4.9, H3), 3.61 (2H, d,
J 11.2, Me2CCHAHBO), 3.52 (1H, dd, J 10.6, 5.9, H7A), 3.45
(1H, dd, J 10.6, 6.2, H7B), 3.43 (2H, d, J 11.4, Me2CCHAHBO),
1.78–1.49 (4H, m), 1.27 (1H, dddd, J 12.8, 10.3, 7.3, 5.1),
1.20 and 0.72 (3H each, s, CMe2), 0.93 (3H, d, J 6.7, C6-Me);
δC(90 MHz, C6D6) 103.3 (1), 77.6 (2C, 2), 68.1 (2), 36.4 (1), 33.2
(2), 30.5 (0), 28.1 (2), 23.6 (3), 22.1 (3), 17.4 (3); m/z (CIϩ mode,
NH3) 220 (100%), 203 (3), 133 (17), 122 (64), 116 (44). The
alcohol is unstable under mildly acidic conditions: appreciable
decomposition was noted after just 30 min in CDCl3.
(1H, dq, J 17.2, 1.8, CH᎐CH H ), 4.95 (1H, dm, J 10.2,
᎐
Z
E
CH᎐CH H ), 3.90 (1H, t, J 6.3, CHN), 3.51 (1H, d, J 13.8,
᎐
Z
E
CHAHBSO2), 3.44 (1H, d, J 13.8, CHAHBSO2), 3.09 (1H, sextet,
J 6.8, H6), 2.13–2.02 (4H, m), 1.97–1.84 (4H, m), 1.50–1.32
(3H, m), 1.22 (3H, d, J 6.9, C6-Me), 1.16 and 0.98 (3H each, s,
CMe2); δC(90 MHz, CDCl3) 176.1 (0), 138.2 (1), 114.8 (2), 65.1
(1), 53.2 (2), 48.4 (0), 47.8 (0), 44.7 (1), 39.9 (1), 38.5 (2), 32.9
(2), 32.0 (2), 31.5 (2), 26.5 (2), 20.9 (3), 19.9 (3), 19.0 (3); m/z (EI
mode) 325 (46%), 271 (100), 214 (17), 191 (22), 135 (88), 111
(50), 93 (23), 83 (99), 67 (18), 55 (78), 41 (52) (Found: C, 62.76;
H, 8.41; N, 4.27. C17H27NO3S requires C, 62.74; H, 8.36; N,
4.30%).
(2S)-4-(5,5-Dimethyl-1,3-dioxan-2-yl)-2-methylbutanal 9
A biphasic mixture of the alcohol 8 (860 mg, 4.26 mmol)
and triethylamine (3.55 ml, 2.58 g, 25.5 mmol) in anhydrous
DMSO (20 ml) at rt under N2 was treated portionwise with
sulfur trioxide–pyridine complex (2.03 g, 12.8 mmol) and
stirred vigorously for 30 min. The mixture was then poured into
10% aqueous NaHSO4 (200 ml), stirred for 10 min and then
extracted with CH2Cl2 (4 × 50 ml). The combined organic
extracts were then washed successively with H2O (2 × 50 ml)
and brine (50 ml) and then dried (MgSO4) and concentrated in
vacuo. The residue was then further purified by column chrom-
atography eluting with 20% Et2O in hexanes to yield the alde-
hyde 9 (816 mg, 4.08 mmol, 96%) as a clear oil: bp (Kugelrohr
oven) 140 ЊC/0.3 mmHg; [α]D ϩ12.8 (c 1.07, CHCl3); νmax(film)/
cmϪ1 2956s, 2848s, 1726s, 1472m, 1394m, 1120s, 1018m, 984m;
δH(360 MHz, CDCl3) 9.62 (1H, d, J 1.8, H7), 4.43 (1H, t, J 4.8,
(2S)-N-[(S)-4-(5,5-Dimethyl-1,3-dioxan-2-yl)-2-methyl-
butanoyl]bornane-10,2-sultam 7
Ozone was bubbled through a stirred solution of the olefin 6
(5.64 g, 17.4 mmol) in CH2Cl2 (100 ml) and MeOH (30 ml) at
Ϫ78 ЊC for 2 h. After this time the ozone flow was stopped and
N2 bubbled through the cold solution for 10 min to remove
excess ozone. Dimethyl sulfide (30 ml) was then added and the
mixture allowed to warm slowly to rt overnight. All solvent
was then removed in vacuo to yield 8.33 g of an oily residue
which was subsequently dissolved in PhMe (100 ml). Following
a negative starch–iodide paper test, the solution was treated
with 2,2-dimethylpropane-1,3-diol (1.90 g, 18.3 mmol) and a
960
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968

View Article Online
H3), 3.59 (2H, d, J 11.1, CHAHBO), 3.41 (2H, d, J 11.1, CHA-
HBO), 2.36 (1H, sextet of d, J 6.9, 1.7, H6), 1.92–1.82 (1H, m),
1.75–1.60 (2H, m), 1.55–1.44 (1H, m), 1.18 and 0.72 (3H, s,
CMe2), 1.10 (3H, d, J 7.0, C6-Me); δC(90 MHz, CDCl3) 204.9
(1), 101.7 (1), 77.2 (2C, 2), 46.1 (1), 32.2 (2), 30.2 (0), 24.7 (2),
23.1 (3), 21.9 (3), 13.4 (3); m/z (CI mode, NH3) 218 (100%), 201
(10) (Found: C, 65.81; H, 9.99. C11H20O3 requires C, 65.97; H,
10.07%).
(2S,3S,4S)-6-(5,5-Dimethyl-1,3-dioxan-2-yl)-4-methylhexane-
2,3-diol 12
To a mechanically stirred solution of AD-mix α38 (25.0 g) in
t-BuOH (70 ml) and H2O (80 ml) was added methanesulfon-
amide (1.70 g, 17.9 mmol). The mixture was then cooled to 0 ЊC
and a solution of the olefin 11 (3.76 g, 17.7 mmol, E:Z = 93:7)
in t-BuOH (10 ml) added. The reaction was then stirred vigor-
ously at 0 ЊC for 24 h. Solid Na2SO3 (26 g) was added and the
mixture allowed to stir for 1 h whilst being allowed to warm to
rt. The biphasic system was then extracted with CH2Cl2 (4 × 50
ml) and the combined organic extracts washed successively with
KOH (2 M, 60 ml) and brine (50 ml). The organic phase was
then dried (MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography eluting with Et2O to yield
the diol 12 (3.62 g, 14.7 mmol, 83%, dr ~ 93:7) as a clear oil:
[α]D Ϫ13.5 (c 0.48, CHCl3); νmax(film)/cmϪ1 3424br s, 2954s,
1472s, 1334s, 1120s, 1042m, 1018m, 984m; δH(360 MHz,
CDCl3) 4.41 (1H, t, J 7.6, H3), 3.85 (1H, quintet, J 6.0, H8),
3.60 (2H, d, J 11.1, CHAHBO), 3.42 (2H, d, J 11.0, CHAHBO),
3.13 (1H, t, J 5.2, H7), 2.40–2.15 (2H, m, OH), 1.80–1.52 (4H,
m), 1.37–1.28 (1H, m), 1.20 (3H, d, J 6.3, C8-Me), 1.18 and 0.72
(3H each, s, CMe2), 0.96 (3H, d, J 6.8, C6-Me); δC(90 MHz,
CDCl3) 102.6 (1), 79.9 (1), 77.3 (2C, 2), 67.9 (1), 35.0 (1), 32.2
(2), 30.3 (0), 25.1 (2), 23.1 (3), 21.9 (3), 20.2 (3), 16.7 (3); m/z (CI
mode, NH3) 264 (36%), 247 (71), 160 (11), 143 (21), 122 (100),
105 (22) (Found: (M ϩ H)ϩ, 247.1911. C13H27O4 requires M
247.1909).
5-Ethylsulfonyl-1-phenyl-1H-tetrazole 10
To a suspension of powdered potassium hydroxide (3.3 g, 58.9
mmol) in EtOH (100 ml) was added 1-phenyl-1H-tetrazole-
5-thiol (Aldrich, 10 g, 56.2 mmol) and the resulting mixture
stirred at reflux for 1 h. After this time ethyl bromide (4.4 ml,
6.42 g, 58.9 mmol) was added dropwise and the reaction stirred
at reflux for a further 18 h. The solvent was then removed in
vacuo and the residue partitioned between H2O (100 ml) and
Et2O (100 ml). The layers were then separated and the organic
phase washed successively with sat. NaHCO3 (2 × 75 ml) and
brine (75 ml). After drying (MgSO4) the solvent was removed
in vacuo to yield essentially pure 5-ethylthio-1-phenyl-1H-
tetrazole (9.86 g, 47.9 mmol, 86%) as a brown oil. A mechanic-
ally stirred suspension of the thioether (9.86 g, 47.9 mmol) and
NaHCO3 (20 g, 238 mmol) in CH2Cl2 (200 ml) was treated
portionwise with 3-chloroperoxybenzoic acid (41.0 g, 50 wt%,
119 mmol) and stirred vigorously for 18 h. After this time the
reaction mixture was poured into sat. NaHCO3–Na2S2O3 (200
ml) and stirred vigorously for 3 h. The layers were then separ-
ated and the aqueous phase extracted with CH2Cl2 (2 × 50 ml).
The combined organic extracts were then washed with sat.
NaHCO3 (3 × 75 ml), brine (75 ml), dried (MgSO4) and concen-
trated in vacuo. The residue was purified by column chrom-
atography eluting with 40–55% Et2O in hexanes to yield
5-ethylsulfonyl-1-phenyl-1H-tetrazole (10, 8.33 g, 35.0 mmol,
73%) as a white solid: mp 70-71 ЊC (10% EtOAc–hexanes) (lit.
37 mp 73–74 ЊC; CAS No. 3206-46-0); δH(360 MHz, CDCl3)
7.71–7.65 (2H, m), 7.64–7.55 (3H, m), 3.75 (2H, q, J 7.4), 1.52
(3H, t, J 7.4); δC(90 MHz, CDCl3) 153.2 (0), 133.1 (0), 131.6 (1),
129.8 (2C, 1), 125.2 (2C, 1), 50.9 (2), 7.0 (3).
(2S,3S,6S)-2-[(1S)-1-Hydroxyethyl]-6-methoxy-3-methyloxane
13á and (2S,3S,6R)-2-[(1S)-1-hydroxyethyl]-6-methoxy-3-
methyloxane 13â
A solution of the diol 12 (3.62 g, 14.7 mmol) and p-TsOHؒH2O
(40 mg) in MeOH (60 ml) was stirred at rt for 3 d. After this
time the mixture was diluted with Et2O (100 ml) and shaken
with sat. NaHCO3 (100 ml). The layers were then separated and
the aqueous phase extracted with Et2O (4 × 20 ml). The com-
bined organic extracts were then washed with brine (50 ml),
dried (MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography eluting with 40% Et2O in
hexanes to yield the methyl glycoside 13 (1.88 g, 10.8 mmol,
73%, α:β = 3:1) as a white solid: mp 36–40 ЊC; bp (Kugelrohr
oven) 100 ЊC/0.3 mmHg; [α]D ϩ101.8 (c 0.50, CHCl3); νmax(film)/
cmϪ1 3474br s, 2930s, 1458m, 1374m, 1233m, 1211m, 1158m,
1129m, 1047m, 1026m, 997m, 964m, 908m; δH(360 MHz,
CDCl3) 4.77 (1Hα, t, J 2.4, H3), 4.33 (1Hβ, dd, J 9.7, 2.1, H3),
4.00–3.90 (1H, m, H8), 3.50 (3Hβ, s, OMe), 3.34 (3Hα, s, OMe),
3.17 (1Hα, dd, J 9.4, 0.8, H7), 2.86 (1Hβ, dd, J 9.8, 1.5, H7),
2.00–1.39 (5H, m), 1.29 (3Hβ, d, J 6.6, C8-Me), 1.27 (3Hα, d,
J 6.5, C8-Me), 0.88 (3Hα, d, J 6.5, C6-Me), 0.87 (3Hβ, d, J 6.5,
C6-Me); δC(90 MHz, CDCl3) α 98.5 (1), 77.2 (1), 66.3 (1), 54.5
(3), 30.7 (1), 30.1 (2), 26.9 (2), 20.8 (3), 17.7 (3); β 103.7 (1), 84.2
(1), 66.5 (1), 56.2 (3), 31.6 (2), 31.4 (2), 30.5 (1), 20.8 (3), 16.9
(3); m/z (CI mode, NH3) 192 (75%), 160 (100), 143 (75), 96 (22),
79 (40) (Found: C, 62.04; H, 10.22. C9H18O3 requires C, 62.04;
H, 10.41%).
5,5-Dimethyl-2-[(E,3S)-3-methylhex-4-enyl]-1,3-dioxane 11
To a stirred solution of the aldehyde 9 (3.82 g, 19.1 mmol) and
sulfone 10 (5.95 g, 25.0 mmol) in anhydrous 1,2-dimethoxy-
ethane (80 ml) at Ϫ60 ЊC (bath temperature) under N2 was
added dropwise via a cannula a solution of potassium hexa-
methyldisilazane (KHMDS, 7.0 g, 80 wt%, 28.1 mmol) in
anhydrous DME (40 ml) over 45 min. After this time H2O (10
ml) was added and the mixture stirred vigorously whilst warm-
ing to rt. The mixture was then diluted with Et2O (150 ml) and
H2O (80 ml) and the layers shaken and then separated. The
aqueous phase was then extracted with Et2O (3 × 50 ml) and
the combined organic extracts washed successively with H2O
(3 × 50 ml) and brine (50 ml). The organic phase was then dried
(MgSO4) and concentrated in vacuo. The residue was purified
by column chromatography eluting with 0–10% Et2O in hex-
anes to yield the olefin 11 (3.76 g, 17.7 mmol, 93%, E:Z = 93:7)
as a clear oil: [α]D ϩ7.2 (c 1.01, CHCl3); νmax(film)/cmϪ1 2956s,
1454m, 1394m, 1122s, 1044m, 1020s, 966s; δH(360 MHz,
CDCl3) 5.40 (1H, ddq, J 15.2, 6.2, 0.7, H8), 5.26 (1H, ddq,
J 15.2, 7.6, 1.3, H7), 4.39 (1H, t, J 5.1, H3), 3.60 (2H, d, J 9.9,
CHAHBO), 3.42 (2H, d, J 10.6, CHAHBO), 2.04 (1H, septet,
J 7.0, H6), 1.63 (3H, dm, J 6.3, C8-Me), 1.70–1.52 (2H, m),
1.44–1.27 (2H, m), 1.19 and 0.72 (3H each, s, CMe2), 0.96 (3H,
d, J 6.7, C6-Me); δC(90 MHz, CDCl3) 137.1 (1), 123.5 (1), 102.6
(1), 77.4 (2C, 2), 36.9 (1), 33.0 (2), 31.3 (2), 30.3 (0), 23.1 (3),
22.0 (3), 21.0 (3), 18.1 (3); m/z (CI mode, NH3) 230 (100%), 213
(25), 126 (36), 96 (86), 79 (26) (Found: C, 73.36; H, 11.13.
C13H24O2 requires C, 73.54; H, 11.39%).
(2S,3S,6S)-6-Methoxy-2-[(1S)-1-(4-methoxybenzyloxy)ethyl]-
3-methyloxane 14á and (2S,3S,6R)-6-methoxy-2-[(1S)-1-(4-
methoxybenzyloxy)ethyl]-3-methyloxane 14â
A
stirred solution of potassium hexamethyldisilazide
(KHMDS, 1.88 g, 80 wt%, 7.54 mmol) in anhydrous THF (45
ml) under N2 at 0 ЊC was treated dropwise with a solution of the
alcohol 13α,β (1.01 g, 5.80 mmol, α,β = 3:1) in anhydrous THF
(15 ml). After complete addition the mixture was stirred for 20
min; neat p-methoxybenzyl chloride (PMBCl, 1.02 ml, 1.18 g,
7.56 mmol) was then added dropwise. A small portion of
tetrabutylammonium iodide (TBAI, 60 mg) was added and the
mixture allowed to warm to rt and stirred for 24 h. The reaction
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968
961

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mixture was then partitioned between Et2O (40 ml) and brine
(50 ml). The layers were then shaken and separated and the
aqueous layer extracted with Et2O (3 × 10 ml). The combined
organic extracts were then dried (MgSO4) and concentrated in
vacuo. The crude residue was then purified by column chrom-
atography eluting with 20–50% Et2O in hexanes to yield the
ether 14α,β (1.58 g, 5.37 mmol, 93%, α,β = 3:1) as a clear oil:
[α]D ϩ103.1 (c 0.52, CHCl3); νmax(film)/cmϪ1 2932s, 1613m,
1514s, 1458m, 1373m, 1302m, 1248s, 1172m, 1128s, 1057s,
1035s, 998m, 906m, 821m; δH(360 MHz, CDCl3) 7.27 (2H, d,
J 8.7, Ar), 6.85 (2H, d, J 8.6, Ar), 4.78 (1Hα, d, J 3.1, H3), 4.64
(1H, d, J 11.8, CHAHBAr), 4.34 (1Hβ, J 11.9, CHAHBAr), 4.33
(1Hα, d, J 11.8, CHAHBAr), 4.21 (1Hβ, dd, J 9.6, 2.0, H3), 3.78
(3H, s, MeOAr), 3.65 (1H, dq, J 6.3, 1.6, H8), 3.47 (3Hβ, s,
OMe), 3.32 (3Hα, s, OMe), 3.19 (1Hα, dd, J 10.1, 1.6, H7), 2.87
(1Hβ, dd, J 9.6, 2.1, H7), 1.93–1.61 (3H, m), 1.55–1.36 (2H, m),
1.27 (3Hβ, d, J 6.4, C8-Me), 1.27 (3Hα, d, J 6.4, C8-Me), 0.64
(3H, d, J 6.6, C6-Me); δC(90 MHz, CDCl3) α 159.2 (0), 130.9
(0), 129.8 (2C, 1), 113.7 (2C, 1), 98.6 (1), 77.1 (1), 71.8 (1), 70.4
(2), 55.3 (3), 54.5 (3), 30.4 (1), 29.9 (2), 27.2 (2), 17.4 (3), 15.5
(3); β 159.2 (0), 131.0 (0), 129.7 (2C, 1), 113.7 (2C, 1), 104.0 (1),
83.9 (1), 72.4 (1), 70.1 (2), 56.0 (3), 55.3 (3), 31.7 (2), 31.5 (2),
30.2 (1), 16.6 (3), 15.3 (3); m/z (CI mode, isobutane) 312 (100%),
280 (14), 155 (37), 138 (55), 121 (36) (Found: C, 69.22; H, 8.98.
C17H26O4 requires C, 69.36; H, 8.90%).
extracted (3 × 10 ml Et2O). The combined organic extracts were
washed with brine (20 ml), dried (MgSO4) and concentrated
in vacuo. The residue was then purified by column chrom-
atography eluting with 40% Et2O in hexanes to afford 1.30 g of
tetrahydropyran isomers 16 (cis:trans = 4:6, 82%). A solution
of the isomers (1.30 g, 3.59 mmol) in anhydrous THF (30 ml) at
Ϫ65 ЊC under N2 was then treated dropwise with a solution of
potassium tert-butoxide (485 mg, 4.33 mmol) in anhydrous
THF (10 ml). After stirring for 10 min, sat. NH4Cl (2 ml) was
added and the mixture allowed to warm to rt. The reaction
mixture was then partitioned between Et2O (40 ml) and H2O
(20 ml) and the aqueous phase extracted with Et2O (3 × 10 ml).
The combined organic extracts were washed with brine (15 ml),
dried (MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography eluting with 20% Et2O in
hexanes to yield the pure cis tetrahydropyran 16 (1.15 g, 3.18
mmol, 73% overall) as a clear oil: [α]D ϩ29.8 (c 0.60, CHCl3);
νmax(film)/cmϪ1 2928s, 1738s, 1613m, 1514s, 1456m, 1372m,
1302m, 1276m, 1248s, 1194m, 1170m, 1084m, 1036m; δH(360
MHz, CDCl3) 7.27 (2H, d, J 8.6, Ar), 6.86 (2H, d, J 8.7, Ar),
5.92 (1H, ddt, J 17.2, 10.4, 5.7, CH CH᎐CH ), 5.31 (1H,
᎐
2
2
dq, J 17.2, 1.5, CH CH᎐CH H ), 5.22 (1H, dq, J 10.4, 1.3,
᎐
2
Z
E
CH CH᎐CH H ), 4.63 (1H, d, J 11.9, CH H Ar), 4.58 (2H, dt,
᎐
2
Z
E
A
B
J 5.7, 1.3, CH CH᎐CH ), 4.33 (1H, d, J 11.9, CH H Ar), 3.80
᎐
2
2
A
B
(3H, s, OMe), 3.70 (1H, dddd, J 11.2, 8.5, 5.6, 3.0, H3), 3.61
(1H, dq, J 6.4, 2.1, H8), 2.84 (1H, dd, J 9.5, 3.1, H7), 2.68 (1H,
dd, J 15.3, 8.1, H2A), 2.43 (1H, dd, J 15.3, 5.3, H2B), 1.85–1.75
(2H, m), 1.62 (1H, ddt, J 12.9, 4.2, 2.1), 1.39 (1H, tdd, J 12.9,
11.1, 3.7, H4ax), 1.28–1.15 (1H, signal obscured), 1.20 (3H, d,
J 6.4, C8-Me), 0.63 (3H, d, J 6.3, C6-Me); δC(90 MHz, CDCl3)
171.5 (0), 159.3 (0), 132.4 (1), 131.1 (0), 129.8 (2C, 1), 118.2 (2),
113.8 (2C, 1), 86.5 (1), 75.3 (1), 72.2 (1), 70.2 (2), 65.2 (2), 55.4
(3), 41.4 (2), 33.0 (2), 31.7 (2), 30.4 (1), 17.2 (3), 15.3 (3); m/z
(2S,3S,6S)-6-Hydroxy-2-[(1S)-1-(4-methoxybenzyloxy)ethyl]-
3-methyloxane 15á and (2S,3S,6R)-6-hydroxy-2-[(1S)-1-(4-
methoxybenzyloxy)ethyl]-3-methyloxane 15â
A solution of the methyl glycoside 14α,β (1.73 g, 5.88 mmol,
α:β = 3:1) in AcOH–THF–H2O (3:2:2, 30 ml) was stirred at
65 ЊC for 2 h. The cooled mixture was diluted with Et2O (40 ml)
and H2O (20 ml). The layers were then shaken and separated
and the aqueous phase extracted with Et2O (3 × 15 ml). The
combined organic extracts were successively washed with H2O
(4 × 15 ml), sat. NaHCO3 (3 × 15 ml), dried (MgSO4) and then
concentrated in vacuo. The residue was purified by column
chromatography eluting with 40% Et2O in hexanes to afford
some recovered starting material (311 mg, 1.06 mmol, 18%) and
the lactol 15α,β (1.22 g, 4.36 mmol, 74%, α:β = 1.4:1) as a clear
oil: [α]D ϩ73.1 (c 0.54, CHCl3); νmax(film)/cmϪ1 3405br m, 2930s,
2855s, 1612m, 1514s, 1459m, 1376m, 1247s, 1173m, 1112m,
1035s, 1001s, 821m; δH(360 MHz, CDCl3) 7.28 (2Hβ, d, J 8.6,
Ar), 7.27 (2Hα, d, J 8.6, Ar), 6.87 (2H, d, J 8.7, Ar), 5.40 (1Hα,
m, H3), 4.64 (1Hβ, d, J 11.8, CHAHBAr), 4.64 (1Hα, d, J 11.8,
CHAHBAr), 4.67–4.60 (1Hβ, signal obscured, H3), 4.36 (1Hβ,
d, J 11.8, CHAHBAr), 4.35 (1Hα, d, J 11.8, CHAHBAr), 3.81
(3H, s, OMe), 3.70–3.60 (1H, m, H8), 3.46 (1Hα, dd, J 10.3, 2.0,
H7), 2.97 (1Hβ, dd, J 9.4, 2.0, H7), 2.80–2.65 (1Hβ, br s, OH),
2.32–2.23 (1Hα, br s, OH), 1.92–1.65 (3H, m), 1.60–1.33
(2H, m), 1.28 (3Hβ, d, J 6.4, C8-Me), 1.23 (3Hα, d, J 6.4,
C8-Me), 0.68 (3Hα, d, J 6.4, C6-Me), 0.66 (3Hβ, d, J 6.4,
C6-Me); δC(90 MHz, CDCl3) α 159.3 (0), 130.9 (0), 129.8 (2C,
1), 113.7 (2C, 1), 91.9 (1), 77.2 (1), 72.0 (1), 70.4 (2), 55.4 (3),
30.7 (1), 30.1 (2), 26.5 (2), 17.6 (3), 15.7 (3); β 159.3 (0), 130.9
(0), 129.8 (2C, 1), 113.8 (2C, 1), 97.2 (1), 84.3 (1), 72.3 (1), 70.3
(2), 55.4 (3), 33.8 (2), 31.6 (2), 30.0 (1), 16.7 (3), 15.5 (3); m/z (CI
mode, NH3) 298 (100%), 280 (19), 155 (27), 138 (44), 121 (34)
(Found: (M ϩ NH4)ϩ, 298.2013. C16H24O4 ϩ NH4 requires M
298.2018).
ϩ
ؒ
(CI mode, NH3) 380 (100%), 121 (36) (Found: M , 362.2095.
C21H30O5 requires M 362.2093).
Prop-2-enyl {(2S,3S,6R)-2-[(1S)-1-hydroxyethyl]-3-methyloxan-
6-yl}ethanoate 17
A vigorously stirred solution of the PMB ether 16 (508 mg, 1.40
mmol) in a mixture of CH2Cl2 (30 ml) and H2O (2 ml) at rt was
treated with 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone (470
mg, 2.07 mmol) and the resulting brown mixture stirred for
30 min. Anhydrous MgSO4 (ca. 20 g) was then added and the
mixture stirred for a further 10 min. The thick suspension was
filtered and the filtrate concentrated in vacuo. The resulting
residue was purified by column chromatography eluting with
30% Et2O in hexanes to yield the alcohol 17 (321 mg, 1.33
mmol, 95%) as a clear oil: [α]D ϩ7.8 (c 0.97, CHCl3) [lit. 5 [α]D
ϩ5.7 (c 0.7, CHCl3)]; 1H and 13C NMR in complete agreement
with that previously reported.5
(2R)-N-[(2R,3R,4S)-4-(tert-Butyldimethylsilyloxy)-3-hydroxy-
2-methylpentanoyl]bornane-10,2-sultam 20
To a stirred solution of triethylborane (32.0 ml, 1.0 M in hex-
anes, 32.0 mmol) at rt under N2 was added dropwise triflic acid
(2.83 ml, 4.80 g, 32.0 mmol). Evolution of ethane was noted
and the temperature of the reaction mixture rose to 38 ЊC. The
mixture was then stirred for 15 min before being cooled to
Ϫ10 ЊC and treated dropwise with (2R)-N-propanoylbornane-
10,2-sultam18 (18, 4.34 g, 16.0 mmol) in anhydrous CH2Cl2 (60
ml) at such a rate that the internal temperature did not rise
above Ϫ5 ЊC. After 5 min diisopropylethylamine (5.90 ml, 4.40
g, 33.9 mmol) was added dropwise and the reaction stirred for
30 min at Ϫ5 ЊC before cooling to Ϫ78 ЊC. The neat aldehyde
195 (9.14 g, 48.6 mmol) was added dropwise and stirring con-
tinued for 3 h. The reaction mixture was quenched by the add-
ition of sat. NH4Cl (50 ml), allowed to warm to rt and diluted
with Et2O (100 ml). The layers were separated and the aqueous
phase extracted with Et2O (3 × 30 ml). The combined organic
Prop-2-enyl {(2S,3S,6R)-2-[(1S)-1-(4-methoxybenzyloxy)ethyl]-
3-methyloxan-6-yl}ethanoate 16
A stirred suspension of the lactol 15α,β (1.22 g, 4.36 mmol,
α:β = 1.4:1) and caesium carbonate (2.90 g, 8.90 mmol) in
anhydrous THF (20 ml) under N2 was treated with allyl diethyl-
phosphonoacetate (1.85 ml, 2.07 g, 8.77 mmol) and heated at
reflux overnight. The cooled reaction mixture was partitioned
between Et2O (40 ml) and H2O (20 ml) and the aqueous phase
962
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extracts were dried (MgSO4) and concentrated in vacuo to yield
15.2 g of a crude oil. The residue was purified by column chrom-
atography eluting with 20% Et2O in hexanes followed by
recrystallisation (hexanes) to yield the aldol 20 (5.50 g, 12.0
mmol, 75%) as a white solid: mp 92–95 ЊC; [α]D Ϫ65.8 (c 1.20,
CHCl3); νmax(KBr)/cmϪ1 3517br, 2967s, 1680m, 1335s, 1139m;
δH(400 MHz, CDCl3) 3.86 (1H, dd, J 5.9, 5.9, CHN), 3.80–3.71
(2H, m, H17, H18), 3.47 (1H, d, J 13.8, CHAHBSO2), 3.40 (1H,
d, J 13.8, CHAHBSO2), 3.36 (1H, dq, J 7.1, 4.2, H16), 2.04–1.99
(2H, m), 1.91–1.82 (3H, m), 1.42–1.36 (1H, m), 1.35–1.29 (1H,
m), 1.27 (3H, d, J 7.1, H19), 1.17 (3H, d, J 5.9, C16-Me), 1.15
and 0.96 (3H each, s, CMe2), 0.90 (9H, s, CMe3), 0.09 and 0.08
(3H each, s, SiMe2); δC(100 MHz, CDCl3) 176.7 (0), 75.0 (1),
68.1 (1), 64.7 (1), 53.0 (2), 48.3 (0), 47.7 (0), 44.5 (1), 40.4 (1),
38.2 (2), 32.8 (2), 26.4 (2), 25.8 (3, 3C), 20.7 (3), 19.8 (3), 19.1
(3), 17.9 (0), 12.9 (3), Ϫ4.2 (3), Ϫ5.0 (3); m/z (CI mode, NH3)
460 (12%), 442 (4), 328 (100), 289 (3), 272 (3), 245 (5) (Found:
C, 57.51; H, 8.98; N, 2.97. C22H41NO5SSi requires C, 57.48; H,
8.99; N, 3.05%).
solid and the alcohol 22 (1.11 g, 4.24 mmol, 99%) as a clear oil:
[α]D ϩ25.5 (c 1.07, CHCl3); νmax(film)/cmϪ1 3410br, 2941s,
1476m, 1385m, 1265m, 1110s, 1065m, 836s, 776s; δH(400 MHz,
CDCl3) 3.84 (1H, dq, J 6.1, 6.1, H18), 3.62–3.54 (2H, m, H15),
3.47 (3H, s, OMe), 3.07 (1H, dd, J 6.0, 3.5, H17), 1.99 (1H,
dddq, J 6.8, 6.8, 5.6, 3.4, H16), 1.19 (3H, d, J 6.1, H19), 0.89
(3H, d, J 7.1, C16-Me), 0.85 (9H, s, CMe3), 0.05 and 0.03 (3H
each, s, SiMe2); δC(100 MHz, CDCl3) 87.2 (1), 69.0 (1), 66.3 (2),
60.3 (3), 36.8 (1), 25.8 (3, 3C), 20.4 (3), 18.0 (0), 11.3 (3), Ϫ4.2
(3), Ϫ4.8 (3); m/z (CI mode, NH3) 606 (31%), 492 (100), 263
(48), 131 (19), 117 (21) (Found: C, 59.57; H, 11.41. C13H30O3Si
requires C, 59.49; H, 11.52%).
(2S,3R,4S)-4-(tert-Butyldimethylsilyloxy)-3-methoxy-2-methyl-
pentanal 23
A stirred solution of the alcohol 22 (6.80 g, 26.0 mmol) in
anhydrous CH2Cl2 (120 ml) at 0 ЊC under N2 was treated in one
portion with Dess–Martin reagent20,21 (13.4 g, 31.6 mmol). The
resulting solution was allowed to warm to rt and stirred for 2 h
whereupon the reaction mixture was poured into sat. Na2S2O3–
NaHCO3 (200 ml) and stirred vigorously for 30 min. The bi-
phasic system was diluted with Et2O (100 ml) and the layers
shaken and then separated. The aqueous phase was then
extracted with Et2O (2 × 20 ml) and the combined organic
extracts washed with sat. NaHCO3 (4 × 30 ml), dried (MgSO4)
and then concentrated in vacuo. The residue was purified by
column chromatography eluting with 10% Et2O in hexanes) to
yield the aldehyde 23 (6.15 g, 23.7 mmol, 91%) as a clear oil:
[α]D Ϫ7.5 (c 1.0, CHCl3); νmax(film)/cmϪ1 2932s, 1728s, 1472m,
1258m, 1114s, 1004m, 940m, 836s, 812m, 776m; δH(360 MHz,
CDCl3) 9.81 (1H, s, H15), 3.76 (1H, quintet, J 6.3, H18), 3.47
(1H, dd, J 7.1, 3.0, H17), 3.34 (3H, s, OMe), 2.78 (1H, dq, J 7.2,
3.0, H16), 1.25 (3H, d, J 6.0, H19), 1.04 (3H, d, J 7.0, C16-Me),
0.88 (9H, s, CMe3), 0.08 and 0.06 (3H each, s, SiMe2); δC(90
MHz, CDCl3) 204.8 (1), 84.9 (1), 68.7 (1), 59.7 (3), 48.3 (1), 25.9
(3, 3C), 20.9 (3), 18.0 (0), 7.6 (3), Ϫ3.9 (3), Ϫ4.8 (3); m/z (CI
mode, NH3) 278 (100%), 261 (48), 249 (16).
(2R)-N-[(2R,3R,4S)-4-(tert-Butyldimethylsilyloxy)-3-methoxy-
2-methylpentanoyl]bornane-10,2-sultam 21
To a stirred solution of the aldol 20 (12.1 g, 26.4 mmol) and 1,8-
bis(dimethylamino)naphthalene (proton sponge, 17.0 g, 79.4
mmol) in anhydrous PhMe (100 ml) at rt under N2 was added
methyl triflate (9.0 ml, 13.1 g, 79.6 mmol). The resulting mix-
ture was heated to 80 ЊC and stirred for 24 h whereupon the
suspension was allowed to cool to rt, treated with conc.
NH4OH (15 ml) and then stirred for 30 min. The biphasic mix-
ture was diluted with CH2Cl2 (100 ml) and H2O (50 ml) and the
layers shaken well and then separated. The aqueous phase was
extracted with CH2Cl2 (2 × 30 ml) and the combined organic
extracts washed successively with HCl (2 M, 4 × 50 ml) and
brine (50 ml). The organic phase was dried (MgSO4) and con-
centrated in vacuo. The resulting crude residue was purified by
column chromatography eluting with 20% Et2O in hexanes to
yield the methyl ether 21 (11.3 g, 23.9 mmol, 90%) as a white
solid: mp 106–108 ЊC (hexanes); [α]D Ϫ74.9 (c 0.39, CHCl3);
νmax(KBr)/cmϪ1 2971m, 1691m, 1342s, 1142m, 1107s, 776m;
δH(400 MHz, CDCl3) 3.84 (1H, dd, J 7.5, 5.1, CHN), 3.79 (1H,
dq, J 6.4, 2.6, H18), 3.52 (3H, s, OMe), 3.46 (1H, dd, J 8.4, 2.6,
H17), 3.45 (1H, d, J 13.6, CHAHBSO2), 3.39 (1H, d, J 14.0,
CHAHBSO2), 3.07 (1H, dq, J 8.3, 7.0, H16), 2.04 (1H, dd,
J 13.7, 7.8), 1.98 (1H, dm, J 14.0), 1.93–1.81 (3H, m), 1.42–1.36
(1H, m), 1.35–1.29 (1H, m), 1.27 (3H, d, J 7.0, H19), 1.12 and
0.94 (3H each, s, CMe2), 1.11 (3H, d, J 6.1, C16-Me), 0.87 (9H,
s, CMe3), 0.06 and 0.02 (3H each, s, SiMe2); δC(100 MHz,
CDCl3) 174.7 (0), 85.5 (1), 70.1 (1), 64.9 (1), 61.2 (3), 53.1 (2),
48.3 (0), 47.7 (0), 44.6 (1), 42.4 (1), 38.3 (2), 32.7 (2), 26.4 (2),
25.8 (3, 3C), 20.8 (3), 19.9 (3), 17.9 (0), 17.3 (3), 15.7 (3), Ϫ4.7
(3, 2C); m/z (CI mode, NH3) 474 (4%), 342 (100), 310 (1), 278
(2) (Found: C, 58.34; H, 9.12; N, 2.92. C23H43NO5SSi requires
C, 58.31; H, 9.15; N, 2.96%).
(4R,5R,6S)-2,4-Dimethyl-6-(tert-butyldimethylsilyloxy)-5-
methoxyhept-1-en-3-one 24
A stirred suspension of magnesium (2.7 g, 113 mmol) in
anhydrous Et2O (130 ml) at rt under N2 was provided with 1
crystal of re-sublimed iodine. The brown mixture was then
treated with one quarter of a solution of 2-bromopropene (10
g, 82.6 mmol) in anhydrous Et2O (20 ml). The resultant suspen-
sion was heated to reflux until the brown colour had dissipated
and Grignard formation had initiated. The remainder of the
solution of bromide was then added at such a rate as to main-
tain a gentle reflux (ca. 30 min). After the complete addition the
cloudy solution of prop-2-enylmagnesium bromide was heated
at reflux for an additional 2.5 h before being cooled to 0 ЊC. A
solution of the freshly prepared aldehyde 23 (6.15 g, 23.7 mmol)
in anhydrous Et2O (50 ml) was then added dropwise over 10
min and the reaction mixture stirred at 0 ЊC for 1 h. H2O (50 ml)
was then added cautiously followed by 1 M HCl (50 ml) and the
biphasic mixture stirred for 10 min. The layers were then separ-
ated and the aqueous phase extracted (3 × 30 ml Et2O). The
combined organic extracts were then washed with sat. NaHCO3
(50 ml), dried (MgSO4) and concentrated in vacuo. The residue
was then further purified via column chromatography (eluting
with 10% Et2O in hexanes) to afford a mixture of allylic alco-
hols (6.51 g, 21.6 mmol, 91%, dr = 57:43 in favour of the syn
isomer). The alcohols (6.37 g, 21.1 mmol) were then dissolved
in anhydrous CH2Cl2 (100 ml) and the resulting solution treated
with Dess–Martin reagent20,21 (DMP, 11.0 g, 25.9 mmol) and
stirred at rt under N2 for 4 h. After this time the mixture was
poured into sat. Na2S2O3–NaHCO3 (100 ml) and stirred vigor-
ously for 1 h. The biphasic mixture was then diluted with Et2O
(100 ml) and the layers separated. The aqueous phase was
(2S,3R,4S)-4-(tert-Butyldimethylsilyloxy)-3-methoxy-2-methyl-
pentan-1-ol 22
A solution of the acyl sultam 21 (2.03 g, 4.3 mmol) in
anhydrous Et2O (20 ml) was added dropwise to a stirred sus-
pension of lithium aluminium hydride (0.50 g, 13.2 mmol) in
Et2O (10 ml) at 0 ЊC under N2. After 15 min the reaction was
quenched by the careful addition of sat. NH4Cl (10 ml) and
stirred vigorously for 10 min. The mixture was filtered through
a Celite pad and the residue washed well with Et2O (3 × 5 ml).
The layers of the filtrate and combined washings were then
separated and the aqueous layer extracted with Et2O (2 × 10
ml). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo. The residue was purified by column
chromatography eluting with 40% Et2O in hexanes to yield
(2R)-bornane-10,2-sultam (0.87 g, 4.05 mmol, 94%) as a white
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968
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extracted (3 × 30 ml Et2O) and the combined organic extracts
washed with brine (30 ml), dried (MgSO4) and then concen-
trated in vacuo. The crude ketone was then further purified via
column chromatography (eluting with 5% Et2O in hexanes) to
yield pure 24 (5.58 g, 18.6 mmol, 88%, 80% from 23) as a clear
oil: [α]D Ϫ35.2 (c 1.02, CHCl3); νmax(film)/cmϪ1 2956s, 2931s,
2858s, 1676s, 1462m, 1380m, 1257s, 1115s, 1058m, 932s, 835s,
776s; δH(360 MHz, CDCl3) 5.97 (1H, m, H13E), 5.80 (1H, m,
H13Z), 3.66 (1H, quintet, J 6.0, H18), 3.52 (1H, dq, J 6.9, 5.1,
H16), 3.37–3.34 (1H, signal obscured, H17), 3.35 (3H, s, OMe),
1.88 (3H, m, C14-Me), 1.13 (3H, d, J 6.1, H19), 1.09 (3H, d,
J 6.8, C16-Me), 0.88 (9H, s, CMe3), 0.06 and 0.05 (3H each, s,
SiMe2); δC(90 MHz, CDCl3) 205.3 (0), 143.8 (0), 124.9 (2), 87.6
(1), 69.4 (1), 60.6 (3), 41.4 (1), 26.0 (3C, 3), 19.8 (3), 18.3 (3),
18.1 (0), 11.8 (3), Ϫ4.2 (3), Ϫ4.7 (3); m/z (CI mode, isobutane)
301 (100%), 285 (3), 269 (5), 243 (16), 169 (63) (Found: C, 63.73;
H, 10.53. C16H32O3Si requires C, 63.95; H, 10.73%).
50% EtOAc in hexanes) to yield the diol 26 (45 mg, 0.24 mmol,
72%) as a white solid: mp 128–130 ЊC (EtOAc); [α]D ϩ3 (c 0.34,
CHCl3); νmax(film)/cmϪ1 3328m, 2926m, 1460m, 1097s, 1018s,
902m, 733 (m); δH(360 MHz, CDCl3) 5.07 (1H, m, H13E), 4.94
(1H, m, H13Z), 4.03 (1H, quintet, J 6.2, H18), 3.99 (1H, d, J 7.0,
H15), 3.47 (3H, s, OMe), 3.36 (1H, dd, J 5.8, 2.1, H17), 2.67–
2.60 (1H, m, OH), 2.05 (1H, quintet of d, J 7.1, 2.0, H16), 1.98–
1.90 (1H, m, OH), 1.70 (3H, s, C14-Me), 1.25 (3H, d, J 6.4,
H19), 0.98 (3H, d, J 7.1, C16-Me); δC(90 MHz, CDCl3) 146.6
(0), 113.0 (2), 84.0 (1), 79.4 (1), 67.2 (1), 58.9 (3), 35.5 (1), 19.6
(3), 17.7 (3), 11.9 (3) (Found: (M ϩ H)ϩ, 189.1490. C10H21O3
requires M, 189.1491).
Crystal data. C10H20O3, M = 188.26, crystallises fom ethyl
acetate as extremely fine needles which invariably shattered on
cutting. Finally data were collected at 20 ЊC an uncut crystal of
dimensions 3.0 × 0.15 × 0.02 mm and a beam diameter of
0.80 mm. Monoclinic, space group P21, a = 7.3028(10), b =
19.019(3), c = 8.1976(12) Å, β = 90.816(12)Њ, V = 1138.5(3) Å3,
Z = 4, µ(Mo-Kα) = 0.079 mmϪ1. The intensities of 3957 reflec-
tions were corrected for 25% crystal decomposition and
for variations in the irradiated volume (correction factors
1.000–0.921).39–41 Averaging gave 3115 unique reflections
(Rint = 0.049); of these 1620 were deemed observed [I > 2σ(I)].
Final agreement indices were R[I > 2θ(I)] = 0.054 and wR2(all
data) = 0.14 and in the final difference map |∆ρ| < 0.24 e ÅϪ3.
The absolute configuration of the model could not be reliably
determined and was therefore assigned from the known abso-
lute stereochemistry of atoms C4n, C5n and C6n (n = 1,2).
Scattering factors and dispersion corrections were those
incorporated in the least squares refinement program
SHELXL97 and the WINGX package was used for other
calculations.42,43
(3R,4S,5R,6S)-2,4-Dimethyl-6-(tert-butyldimethylsilyloxy)-5-
methoxyhept-1-en-3-ol 25
To a stirred solution of anhydrous lithium iodide (25.0 g, 187
mmol) in anhydrous Et2O (200 ml) at Ϫ30 ЊC under N2 was
added the enone 24 (5.58 g, 18.6 mmol) in anhydrous Et2O (20
ml). The resulting mixture was stirred vigorously for 20 min and
then further cooled to Ϫ95 ЊC (internal temperature). A solu-
tion of lithium aluminium hydride (20 ml, 1.0 M in Et2O, 20
mmol) was then added dropwise via a syringe pump over 30
min. The reaction mixture was then quenched by the careful
addition of MeOH (20 ml) followed by H2O (50 ml) and then
allowed to warm to rt. The biphasic system was then filtered
through a Celite pad and the residue washed well (3 × 50 ml
Et2O). The layers of the filtrate and combined washings were
then separated and the aqueous phase extracted (2 × 20 ml
Et2O). The combined organic extracts were then washed succes-
sively with H2O (2 × 50 ml), brine (50 ml), dried (MgSO4) and
then concentrated in vacuo. The resulting crude solid product
(5.22 g, ca. 93%, dr (C15) = 85:15) was then further purified via
recrystallisation (5% H2O–EtOH 30 ml) to afford 3.46 g of the
title compound 25 as a white crystalline solid: mp 63–65 ЊC.
The mother liquor was concentrated in vacuo and the residue
(1.65 g) further purified via column chromatography (eluting
with 7% Et2O in hexanes) to yield an additional 0.76 g of pure
product as a white solid (desired isomer is the less polar com-
ponent). The above procedure yielded in total 4.22 g of dia-
stereoisomerically pure 25 (14.0 mmol, 75%): [α]D ϩ9.2 (c 1.07,
CHCl3); νmax(KBr)/cmϪ1 3444br s, 2953s, 2858s, 1655m, 1373m,
1257m, 1115s, 1086m, 1043m, 993m, 934s, 899m, 835s, 810m,
772s; δH(360 MHz, CDCl3) 5.06 (1H, m, H13E), 4.92 (1H, m,
H13Z), 3.95 (1H, d, J 7.4, H15), 3.81 (1H, quintet, J 6.2, H18),
3.46 (3H, s, OMe), 3.30 (1H, dd, J 6.9, 2.0, H17), 2.66–2.59
(1H, m, OH), 2.08 (1H, ddq, J 7.2, 7.1, 1.9, H16), 1.68 (3H, s,
C14-Me), 1.22 (3H, d, J 6.1, H19), 0.88 (3H, d, J 7.1, C16-Me),
0.87 (9H, s, CMe3), 0.07 and 0.05 (3H each, s, SiMe2); δC(90
MHz, CDCl3) 146.7 (0), 112.8 (2), 85.4 (1), 79.3 (1), 68.9 (1),
59.9 (3), 35.7 (1), 26.0 (3C, 3), 21.1 (3), 18.1 (0), 17.5 (3), 11.3
(3), Ϫ3.9 (3), Ϫ4.7 (3); m/z (CI mode, NH3) 303 (100%), 285
(13), 253 (8), 132 (7), 96 (28) (Found: C, 63.48; H, 11.26.
C16H34O3Si requires C, 63.52; H, 11.33%).
Full crystallographic details, excluding structure factor
tables, have been deposited in the Cambridge Crystallographic
Data Centre (CCDC). For details of the deposition scheme, see
‘Instructions for Authors’, J. Chem. Soc., Perkin Trans. 1, avail-
able via the RSC Web page (http://www.rsc.org/authors). Any
request to the CCDC for this material should quote the full
literature citation and the reference number 207/303.
(3R,4S,5R,6S)-2,4-Dimethyl-6-(tert-butyldimethylsilyloxy)-5-
methoxyhept-1-en-3-yl propionate 27
A stirred solution of the alcohol 26 (4.0 g, 13.2 mmol) in
anhydrous pyridine (30 ml) at rt under N2 was treated with
propionic anhydride (3.4 ml, 3.45 g, 26.5 mmol) followed by
4-(dimethylamino)pyridine (30 mg, 0.25 mmol) and then stirred
for 16 h. The mixture was then diluted with Et2O (250 ml) and
the organic phase washed successively with 2 M HCl (5 × 50
ml) and sat. NaHCO3 (2 × 50 ml). The ethereal liquor was then
dried (MgSO4) and concentrated in vacuo. The crude residue
was then further purified via column chromatography (eluting
with 5% Et2O in hexanes) to yield the ester 27 (4.60 g, 12.8
mmol, 97%) as a clear oil which later crystallised upon stand-
ing: mp 46–47 ЊC; bp (Kugelrohr oven) 160 ЊC/0.8 mmHg;
[α]D Ϫ5.1 (c 0.60, CHCl3); νmax(film)/cmϪ1 2932s, 2858m, 1740s,
1463m, 1361m, 1257m, 1185s, 1108s, 1003m, 958m, 926m, 835s,
775m; δH(360 MHz, CDCl3) 5.11 (1H, d, J 10.0, H15), 5.04 (1H,
m, H13E), 4.96 (1H, quintet, J 1.7, H13Z), 3.74 (1H, dq, J 7.7,
6.0, H18), 3.38 (3H, s, OMe), 2.99 (1H, dd, J 7.8, 1.5, H17), 2.36
(2H, dq, J 7.7, 1.4, H12), 2.23 (1H, ddq, J 10.0, 7.1, 1.5, H16),
1.66 (3H, br s, C14-Me), 1.22 (3H, d, J 6.1, H19), 1.16 (3H, t,
J 7.5, C12-Me), 0.89 (9H, s, CMe3), 0.75 (3H, d, J 7.1, C16-Me),
0.07 and 0.05 (3H each, s, SiMe2); δC(90 MHz, CDCl3) 173.8
(0), 142.1 (0), 115.8 (2), 84.7 (1), 79.5 (1), 69.0 (1), 60.9 (3), 34.9
(1), 28.2 (2), 25.9 (3C, 3), 21.2 (3), 18.1 (0), 17.3 (3), 9.5 (3), 9.4
(3), Ϫ3.7 (3), Ϫ4.8 (3); m/z (CI mode, NH3) 376 (100%), 359
(15), 285 (70), 277 (25), 253 (15), 188 (10), 132 (10), 96 (30)
(3R,4S,5R,6S)-2,4-Dimethyl-5-methoxyhept-1-en-3,6-diol 26
A stirred solution of the silyl ether 25 (100 mg, 0.33 mmol)
in anhydrous THF (5 ml) at rt under N2 was treated with
tetrabutylammonium fluoride trihydrate (520 mg, 1.65 mmol).
After stirring for 15 min the mixture was partitioned between
EtOAc (20 ml) and H2O (20 ml) and the layers shaken and then
separated. The aqueous phase was extracted (3 × 10 ml EtOAc)
and the combined organic extracts washed with brine (10 ml),
dried (MgSO4) and then concentrated in vacuo. The residue was
then further purified via column chromatography (eluting with
964
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968

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(Found: C, 63.72; H, 10.61. C19H38O4Si requires C, 63.64; H,
10.68%).
2,4,6-trimethylnon-4-en-1-ol 30. [α]D ϩ1.5 (c 0.62, CHCl3);
νmax(film)/cmϪ1 3365br m, 2956s, 2929s, 2857s, 1461m, 1256m,
1103m, 1047m, 836m, 775m; δH(360 MHz, CDCl3) 5.00 (1H,
dm, J 10.0, H15), 3.85 (1H, dq, J 6.2, 3.4, H18), 3.52 (3H, s,
OMe), 3.48 (1H, dd, J 10.5, 5.8, H11A), 3.41 (1H, dd, J 10.6,
5.9, H11B), 2.86 (1H, dd, J 7.7, 3.4, H17), 2.42 (1H, ddq, J 9.9,
8.0, 6.7, H16), 2.11 (1H, dd, J 12.2, 5.1, H13A), 1.88–1.79 (1H,
m, H12), 1.79–1.70 (2H, m, H13B, OH), 1.58 (3H, d, J 1.3,
C14-Me), 1.08 (3H, d, J 6.2, H19), 0.95 (3H, d, J 6.6, C16-Me),
0.87 (9H, s, CMe3), 0.84 (3H, d, J 6.5, C12-Me), 0.03 (6H, s,
SiMe2); δC(90 MHz, CDCl3) 133.0 (0), 130.0 (1), 90.4 (1), 70.4
(1), 68.6 (2), 61.5 (3), 44.5 (2), 35.3 (1), 33.8 (1), 26.0 (3C, 3),
18.1 (0), 17.6 (3), 17.2 (3), 16.7 (3), 16.0 (3), Ϫ4.3 (3), Ϫ4.7 (3);
m/z (CI mode, isobutane) 345 (100%), 313 (45), 213 (82), 181
(34) (Found: C, 66.07; H, 11.61. C19H40O3Si requires C, 66.22;
H, 11.70%).
(E,2S,6S,7R,8S)-8-(tert-Butyldimethylsilyloxy)-7-methoxy-2,4-
6-trimethylnon-4-enoic acid 29
To a stirred solution of diisopropylamine (0.65 ml, 0.47 g, 4.6
mmol) in anhydrous THF (10 ml) at 0 ЊC under N2 was added
dropwise n-butyllithium (1.85 ml, 2.27 M in hexanes, 4.2
mmol). The resulting solution of lithium diisopropylamide was
stirred for 5 min and then further cooled to Ϫ78 ЊC. A solution
of the ester 27 (1.0 g, 2.79 mmol) in anhydrous THF (5 ml) was
then added continuously down the cold flask side-wall over 5
min whilst the base solution was vigorously stirred. The clear
reaction mixture was stirred for 30 min and then treated
dropwise with tert-butyldimethylsilyl chloride (TBSCl, 3.0 ml,
1.03 M in hexanes, 3.1 mmol) followed by anhydrous dimethyl-
propylene urea (DMPU, 4 ml). After stirring for 5 min the
solution was allowed to warm to rt (cold bath removed) and
then heated at reflux for 1 h. The colourless mixture was then
allowed to cool to rt, treated with 2 M HCl (10 ml) and stirred
vigorously for 30 min. The layers were then separated and the
aqueous phase extracted with CH2Cl2 (5 × 10 ml). The com-
bined organic extracts were dried (MgSO4) and concentrated in
vacuo. The crude residue was then further purified via column
chromatography (eluting with 25–50% Et2O in hexanes) to yield
the acid 29 (835 mg, 82 wt% (contaminated by TBSOH), 1.91
mmol, 68%, dr (C12) Å 6:1 determined by integration of OMe
(E,2R,6S,7R,8S)-8-(tert-Butyldimethylsilyloxy)-7-methoxy-
2,4,6-trimethylnon-4-en-1-ol 12-epi-30. [α]D ϩ6.9 (c 0.58,
CHCl3); νmax(film)/cmϪ1 3373br m, 2955s, 2928s, 2857s, 1462m,
1382m, 1256m, 1102s, 1047s, 932m, 835m, 775m; δH(360 MHz,
CDCl3) 5.02 (1H, d, J 9.9), 3.84 (1H, dq, J 6.0, 3.5), 3.53 (3H,
s), 3.50 (1H, dd, J 10.5, 5.6), 3.41 (1H, dd, J 10.5, 6.0), 2.87 (1H,
dd, J 7.7, 3.5), 2.47 (1H, ddq, J 9.6, 7.3, 7.3), 2.10 (1H, dd,
J 12.1, 5.1), 1.90–1.74 (2H, m), 1.60 (3H, m), 1.51 (1H, br s),
1.11 (3H, d, J 6.2), 0.97 (3H, d, J 6.6), 0.92 (9H, s), 0.90–0.87
(3H, m), 0.05 (6H, s, SiMe2); δC(90 MHz, CDCl3) 132.8 (0),
130.1 (1), 90.4 (1), 70.3 (1), 68.5 (2), 61.4 (3), 44.3 (2), 35.2 (1),
33.9 (1), 26.0 (3C, 3), 18.2 (0), 17.9 (3), 17.1 (3), 16.7 (3), 16.3
(3), Ϫ4.2 (3), Ϫ4.7 (3); m/z (CI mode, NH3) 344 (3%), 287 (4),
255 (12), 229 (3), 203 (100), 181 (34), 159 (40), 123 (39), 89 (43),
1
resonances in the H NMR (360 MHz, CDCl3): δmajor = 3.52,
δminor = 3.50) as a clear oil. An analytical sample of the acid free
from TBSOH was obtained by repeated chromatography, but
diastereoisomers were not separated: [α]D Ϫ0.8 (c 0.51, CHCl3);
νmax(film)/cmϪ1 2957s, 2930s, 2857s, 1709s, 1462m, 1255m,
1104m, 835m, 775m; δH(360 MHz, CDCl3) 5.06 (1H, dm, J 9.2,
H15), 3.83 (1H, dq, J 6.2, 3.5, H18), 3.52 (3H, s, OMe), 2.86
(1H, dd, J 7.8, 3.6, H17), 2.70–2.59 (1H, m, H12), 2.50–2.38
(2H, m, H16, H13B), 2.05 (1H, dd, J 13.5, 8.4, H13A), 1.60 (3H,
d, J 1.2, C14-Me), 1.12 (3H, d, J 6.9, C12-Me), 1.09 (3H, d,
J 6.2, H19), 0.95 (3H, d, J 6.6, C16-Me), 0.89 (9H, s, CMe3),
0.04 (6H, s, SiMe2); δC(90 MHz, CDCl3) 182.8 (0), 131.2 (1),
131.2 (0), 90.3 (1), 70.4 (1), 61.5 (3), 44.0 (2), 37.9 (1), 35.2 (1),
26.0 (3C, 3), 18.2 (0), 17.8 (3), 17.0 (3), 16.4 (3), 15.8 (3), Ϫ4.3
(3), Ϫ4.7 (3); m/z (CI mode, NH3) 375 (31%), 358 (34), 327 (9),
ϩ
ؒ
73 (96), 69 (41) (Found: M , 344.2744. C19H40O3Si requires M
344.2747).
2-{[(E,2S,6S,7R,8S)-8-(tert-Butyldimethylsilyloxy)-7-methoxy-
2,4,6-trimethylnon-4-enyl]thio}-1,3-benzothiazole 31
To a stirred solution of the alcohol 30 (1.47 g, 4.27 mmol) in
anhydrous THF (25 ml) at rt under N2 was added 2-mercapto-
1,3-benzothiazole (BTSH, 0.86 g, 5.15 mmol) and triphenyl-
phosphine (1.34 g, 5.11 mmol). The resulting solution was
cooled to 0 ЊC and diisopropyl azodicarboxylate (DIAD, 1.10
ml, 1.13 g, 5.59 mmol) added dropwise. The cooling bath was
then removed and the mixture allowed to stir for 2 h. After this
time the solvent was removed in vacuo and the residue further
purified via column chromatography (eluting with 3% EtOAc
in hexanes) to yield the sulfide 31 (2.08 g, 4.21 mmol, 99%) as
a clear oil: [α]D ϩ0.3 (c 0.65, CHCl3); νmax(film)/cmϪ1 2956s,
2928s, 2894s, 2856s, 1461s, 1428s, 1255m, 1103m, 995m, 836m,
775m, 755m; δH(360 MHz, CDCl3) 7.86 (1H, dm, J 8.1), 7.75
(1H, dm, J 8.0), 7.41 (1H, ddd, J 8.5, 7.3, 1.3), 7.29 (1H, ddd,
J 8.1, 7.4, 1.2), 5.06 (1H, dm, J 9.9, H15), 3.87 (1H, dq, J 6.2,
3.4, H18), 3.54 (3H, s, OMe), 3.45 (1H, dd, J 12.9, 5.3, H11A),
3.12 (1H, dd, J 12.9, 7.5, H11B), 2.88 (1H, dd, J 7.9, 3.4,
H17), 2.47 (1H, ddq, J 9.9, 7.8, 6.7, H16), 2.27–2.10 (2H, m,
H12, H13A), 1.93 (1H, dd, J 12.8, 8.0, H13B), 1.62 (3H, d, J 1.2,
C14-Me), 1.11 (3H, d, J 6.2, H19), 1.03 (3H, d, J 6.5, C12-Me),
1.00 (3H, d, J 6.6, C16-Me), 0.90 (9H, s, CMe3), 0.05 (6H, s,
SiMe2); δC(90 MHz, CDCl3) 167.6 (0), 153.4 (0), 135.3 (0), 132.2
(0), 130.7 (1), 126.1 (1), 124.2 (1), 121.5 (1), 121.0 (1), 90.3 (1),
70.4 (1), 61.5 (3), 47.2 (2), 40.4 (2), 35.3 (1), 31.5 (1), 26.0 (3C,
3), 19.4 (3), 18.2 (0), 17.7 (3), 17.2 (3), 16.1 (3), Ϫ4.3 (3), Ϫ4.7
(3); m/z (CI mode, NH3) 493 (10%), 446 (6), 436 (4), 330 (47),
ϩ
ؒ
227 (100), 212 (18), 195 (15), 172 (10) (Found: M , 358.2538.
C19H38O4Si requires M 358.2539).
(E,2S,6S,7R,8S)-8-(tert-Butyldimethylsilyloxy)-7-methoxy-
2,4,6-trimethylnon-4-en-1-ol 30
A stirred suspension of lithium aluminium hydride (0.35 g, 9.2
mmol) in anhydrous Et2O (15 ml) at 0 ЊC under N2 was treated
dropwise with a solution of the acid 29 (1.64 g, 82 wt%, 3.76
mmol, dr (C12) Å 6:1) in anhydrous Et2O (5 ml). A vigorous
reaction ensued and after stirring for 10 min the reaction mix-
ture was quenched by the careful addition of sat. NH4Cl (10
ml). The biphasic system was then filtered through a Celite pad
and the residue washed well (4 × 10 ml Et2O). The layers of the
combined washings and filtrate were then separated and the
aqueous phase extracted (10 ml Et2O). The combined organic
extracts were then dried (MgSO4) and concentrated in vacuo.
The crude residue was then further purified via column chrom-
atography (eluting with 30% Et2O in hexanes) to yield the alco-
hol 30 (1.17 g, 3.40 mmol, 90%, dr (C12) ≈ 6:1) as a clear oil.
The two diastereoisomers (at C12) can be separated as
follows: 1.0 g of 30 (dr (C12) > 4:1) was loaded onto a silica
column (id 7 cm, depth 12 cm) and eluted with 15% Et2O
in hexanes taking a pre-fraction of 2.2 l followed by 20 ml
fractions to yield in order of elution, 303 mg of mixed
material (dr ≈ 3:1) followed by 590 mg of pure material
(dr у 95:5).
ϩ
ؒ
203 (97), 159 (33), 123 (63), 73 (100) (Found: M , 493.2508.
C26H43NO2S2Si requires m/z 493.2505) (Found: C, 63.36; H,
8.84; N, 2.82. C26H43NO2S2Si requires C, 63.23; H, 8.78; N,
2.84%).
(E,2S,6S,7R,8S)-1-(1,3-Benzothiazol-2-ylthio)-7-methoxy-
2,4,6-trimethylnon-4-en-8-ol 32
(E,2S,6S,7R,8S)-8-(tert-Butyldimethylsilyloxy)-7-methoxy-
A stirred solution of the silyl ether 31 (631 mg, 1.28 mmol)
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968
965

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in anhydrous THF (15 ml) at rt under N2 was treated with
TBAFؒ3H2O (2.0 g, 6.3 mmol) and the resulting clear mixture
stirred for 28 h. After this time TLC analysis indicated
incomplete consumption of the silyl ether; additional TBAFؒ
3H2O (0.5 g, 1.6 mmol) was then added and the reaction stirred
for a further 4 h. The solution was then partitioned between
Et2O (30 ml) and H2O (30 ml) and the layers shaken well and
then separated. The aqueous phase was extracted with Et2O
(3 × 15 ml) and the combined organic extracts washed with
brine (20 ml), dried (MgSO4) and then concentrated in vacuo.
The residue was purified via column chromatography (eluting
with 30% EtOAc in hexanes) to yield the alcohol 32 (475 mg,
1.25 mmol, 98%) as a clear oil: [α]D Ϫ22.1 (c 1.00, CHCl3);
νmax(film)/cmϪ1 3441br s, 2979s, 2829s, 1458s, 1427s, 1239m,
1126m, 1096s, 994s, 904m, 756s, 727s; δH(360 MHz, CDCl3)
7.85 (1H, dm, J 8.1), 7.75 (1H, dm, J 8.0), 7.40 (1H, ddd, J 8.2,
7.3, 1.3), 7.28 (1H, ddd, J 8.0, 7.4, 1.2), 5.07 (1H, dm, J 9.9,
H15), 3.84 (1H, m, H18), 3.53 (3H, s, OMe), 3.44 (1H, dd,
J 12.9, 5.1, H11A), 3.09 (1H, dd, J 12.9, 7.4, H11B), 2.96 (1H,
dd, J 8.2, 3.8, H17), 2.51 (1H, ddq, J 9.8, 8.2, 6.7, H16), 2.23–
2.09 (2H, m, H12, H13A), 1.98–1.89 (2H, m, H13B, OH), 1.63
(3H, d, J 1.3, C14-Me), 1.14 (3H, d, J 6.4, H19), 1.05 (3H, d,
J 6.7, C12-Me), 1.01 (3H, d, J 6.5, C16-Me); δC(90 MHz,
CDCl3) 167.6 (0), 153.4 (0), 135.3 (0), 132.6 (0), 130.1 (1), 126.1
(1), 124.2 (1), 121.5 (1), 121.0 (1), 89.6 (1), 69.4 (1), 61.6 (3), 47.0
(2), 40.3 (2), 35.7 (1), 31.5 (1), 19.4 (3), 17.7 (3), 17.5 (3), 16.2
(3); m/z (EI mode) 379 (3%), 332 (14), 290 (18), 248 (7), 223 (6),
208 (10), 167 (73), 123 (100%), 89 (41), 81 (37) (Found: C, 63.13;
H, 7.62; N, 3.61. C20H29NO2S2 requires C, 63.28; H, 7.70; N,
3.69%).
the slow addition of a solution of tert-butyl hydroperoxide
(TBHP, 0.71 ml, 5.32 M in isooctane, 3.8 mmol) in anhydrous
CH2Cl2 (9 ml) via a syringe pump over 48 h. After the complete
addition of the stoichiometric oxidant the colourless solution
was allowed to stir for a further 24 h at Ϫ8 ЊC. After this time
the mixture was diluted with Et2O (20 ml) and H2O (20 ml) and
the layers shaken well and then separated. The aqueous phase
was then extracted (2 × 10 ml) and the combined organic
extracts washed with brine (10 ml), dried (MgSO4) and then
concentrated in vacuo. The residue was further purified via
column chromatography (eluting with 35–60% EtOAc in
hexanes) to afford in order of elution: the tetrahydrofuran by-
product 40 (25 mg, 0.06 mmol, 5%), recovered starting material
S
O
O2S
N
MeO
OH
40
33 (136 mg, 0.33 mmol, 26%) and the epoxide 34 (373 mg, 0.87
mmol, 69%) all as clear oils. 1H and 13C NMR analysis revealed
the latter compound to be a single diastereoisomer.
(2S,4R,5R,6S,7R,8S)-1-(1,3-Benzothiazol-2-ylsulfonyl)-4,5-
epoxy-7-methoxy-2,4,6-trimethylnon-8-ol 34. [α]D Ϫ4.0 (c
1.98, CHCl3); νmax(film)/cmϪ1 3452br s, 2966s, 2932s, 1471m,
1318s, 1148s, 1097s, 763m; δH(360 MHz, CDCl3) 8.18 (1H, dm,
J 7.6), 8.01 (1H, dm, J 7.5), 7.66–7.56 (2H, m), 3.94 (1H, quin-
tet, J 5.8, H18), 3.61 (1H, dd, J 14.2, 4.7, H11A), 3.48 (3H, s,
OMe), 3.34 (1H, dd, J 14.3, 7.9, H11B), 3.06 (1H, t, J 5.0, H17),
2.61 (1H, d, J 9.5, H15), 2.62–2.50 (1H, m), 2.08–2.00 (1H, m),
1.80 (1H, dd, J 14.2, 7.3, H13A), 1.67–1.55 (1H, m), 1.59 (1H,
dd, J 14.2, 7.4, H13B), 1.27 (3H, s, C14-Me), 1.22 (3H, d, J 6.8,
H19), 1.20 (3H, d, J 6.5, C12-Me), 1.01 (3H, d, J 6.9, C16-Me);
δC(90 MHz, CDCl3) 166.6 (0), 152.7 (0), 136.8 (0), 128.2 (1),
127.9 (1), 125.5 (1), 122.5 (1), 86.6 (1), 68.1 (1), 64.9 (1), 60.5 (3),
60.3 (2), 60.2 (0), 45.4 (2), 34.7 (1), 26.1 (1), 20.9 (3), 19.1 (3),
16.4 (3), 11.8 (3); m/z (CI mode, isobutane) 428 (11%), 410 (15),
378 (100), 322 (14), 298 (12), 213 (14), 136 (27) (Found:
(M ϩ H)ϩ, 428.1561. C20H30NO5S2 requires M, 428.1565)
(Found: C, 56.19; H, 6.84; N, 3.23. C20H29NO5S2 requires C,
56.18; H, 6.84; N, 3.28%).
(2S,3S,4R,5S)-3,5-Dimethyl-2-[(1R,3S)-4-(1,3-benzothiazol-
2-ylsulfonyl)-1,3-dimethyl-1-hydroxybutyl]-4-methoxyoxolane
40. δH(360 MHz, CDCl3) 8.22 (1H, dm, J 7.5 Hz), 8.03 (1H, dm,
J 7.9 Hz), 7.68–7.55 (2H, m), 3.80 (1H, dq, J 6.7, 2.6 Hz), 3.57
(1H, dd, J 14.3, 6.7 Hz), 3.57 (1H, d, J 4.6 Hz), 3.48 (1H, dd,
J 14.3, 6.0 Hz), 3.29 (3H, s), 3.08 (1H, d, J 2.5 Hz), 2.73–2.60
(1H, m), 2.20–2.10 (2H, m), 1.77 (1H, dd, J 14.1, 3.4 Hz), 1.65
(1H, dd, J 14.2, 8.8 Hz), 1.31 (3H, d, J 6.6 Hz), 1.28 (3H, d,
J 6.8 Hz), 1.27 (3H, s), 1.03 (3H, d, J 7.4 Hz); δC(90 MHz,
CDCl3) 166.9 (0), 152.8 (0), 136.8 (0), 128.2 (1), 127.8 (1), 125.6
(1), 122.5 (1), 95.1 (1), 85.6 (1), 79.8 (1), 73.3 (0), 62.1 (2), 56.9
(3), 42.9 (2), 40.2 (1), 26.2 (3), 25.3 (1), 22.3 (3), 20.7 (3), 15.0
(3).
(E,2S,6S,7R,8S)-1-(1,3-Benzothiazol-2-ylsulfonyl)-7-methoxy-
2,4,6-trimethylnon-4-en-8-ol 33
To a stirred solution of the sulfide 32 (870 mg, 2.30 mmol) in
EtOH (20 ml) at rt was added dropwise a yellow solution of
ammonium molybdate tetrahydrate (280 mg, 0.23 mmol) in
aqueous hydrogen peroxide (2.6 g, 30 wt%, 22.9 mmol). The
resultant mixture was stirred vigorously for 24 h and then par-
titioned between Et2O (30 ml) and H2O (20 ml). The layers were
shaken and then separated and the aqueous phase extracted
(3 × 10 ml Et2O). The combined organic extracts were washed
with H2O (2 × 20 ml), dried (MgSO4) and then concentrated in
vacuo. The crude residue was then further purified via column
chromatography (eluting with 40% EtOAc in hexanes) to yield
the sulfone 33 (835 mg, 2.03 mmol, 88%) as a clear oil: [α]D
Ϫ24.0 (c 1.09, CHCl3); νmax(film)/cmϪ1 3447br s, 2962s, 2929s,
1472m, 1458m, 1318m, 1146m, 1097m, 763m, 731m, 632m;
δH(360 MHz, CDCl3) 8.19 (1H, dm, J 7.8), 8.01 (1H, dm,
J 8.11), 7.63 (1H, ddd, J 8.1, 7.2, 1.4), 7.58 (1H, ddd, J 7.9, 7.2,
1.4), 5.02 (1H, dm, J 9.9, H15), 3.79 (1H, dq, J 6.4, 3.8, H18),
3.58 (1H, dd, J 14.4, 3.7, H11A), 3.50 (3H, s, OMe), 3.23 (1H,
dd, J 14.4, 8.7, H11B), 2.92 (1H, dd, J 8.0, 3.8, H17), 2.50–2.39
(2H, m, H16, H12), 2.07 (1H, ddd, J 13.4, 7.9, 1.1, H13A), 1.98
(1H, dd, J 13.6, 6.8, H13B), 2.0–1.80 (1H, br, OH), 1.49 (3H, d,
J 1.3, C14-Me), 1.10 (6H, d, J 6.4, C12-Me, H19), 1.01 (3H, d,
J 6.7, C16-Me); δC(90 MHz, CDCl3) 166.7 (0), 152.8 (0), 136.8
(0), 131.6 (0), 131.3 (1), 128.2 (1), 127.8 (1), 125.5 (1), 122.5 (1),
89.4 (1), 69.2 (1), 61.4 (3), 60.0 (2), 47.4 (2), 35.5 (1), 26.6 (1),
20.2 (3), 17.6 (3), 17.5 (3), 15.9 (3); m/z (CI mode, isobutane)
412 (100%), 380 (26), 362 (42), 322 (54) (Found: (M ϩ H)ϩ,
412.1614. C20H30NO4S2 requires M 412.1616) (Found: C, 58.17;
H, 7.15; N, 3.42. C20H29NO4S2 requires C, 58.36; H, 7.10; N,
3.40%).
(1R,2R,3R,4R,5R,7S)-8-(1,3-Benzothiazol-2-ylsulfonyl)-4,5-
epoxy-2-methoxy-1,3,5,7-tetramethyloctyl 4-chlorobenzoate 4
A solution of triphenylphosphine (393 mg, 1.50 mmol) in
anhydrous THF (3 ml) at 0 ЊC under N2 was treated with neat
dimethyl azodicarboxylate28 (207 mg, 1.42 mmol) and the
resultant colourless suspension stirred for 5 min. A solution of
the alcohol 34 (304 mg, 0.71 mmol) in anhydrous THF (3 ml)
was then added dropwise and the mixture stirred for a further 5
min. One third of a solution of p-chlorobenzoic acid (138 mg,
0.88 mmol) in anhydrous THF (1.8 ml) was then added drop-
wise and the cooling bath removed. After 1 h a further one third
of the acid solution was added, followed by the remainder after
a subsequent hour. The reaction was then stirred for a final 1 h
(2S,4R,5R,6S,7R,8S)-1-(1,3-Benzothiazol-2-ylsulfonyl)-4,5-
epoxy-7-methoxy-2,4,6-trimethylnon-8-ol 34
A stirred solution of the hydroxy olefin 33 (519 mg, 1.26 mmol)
in anhydrous CH2Cl2 (10 ml) at Ϫ8 ЊC under N2 was treated
with vanadyl bis(acetylacetonate) (3.4 mg, 13 µmol) followed by
966
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968

View Article Online
period after complete addition of the acid component and then
worked-up as follows: the mixture was diluted with EtOAc (20
ml) and washed successively with sat. NaHCO3 (15 ml), H2O
(4 × 10 ml) and brine (10 ml). The resulting organic phase was
dried (MgSO4) and then concentrated in vacuo. The residue was
then further purified via column chromatography (eluting with
20% EtOAc in hexanes) to afford the p-chlorobenzoate 4 (297
mg, 0.52 mmol, 74%) as a white foam: [α]D Ϫ17.3 (c 1.60,
CHCl3); νmax(film)/cmϪ1 2964s, 2933s, 1712s, 1594m, 1472m,
1459m, 1321s, 1273s, 1148s, 1090s, 1015m, 760m, 730m, 632m;
δH(360 MHz, CDCl3) 8.19 (1H, dm, J 7.2), 8.02 (1H, dm, J 7.6),
7.99 (2H, d, J 8.7), 7.65 (1H, ddd, J 7.3, 7.3, 1.4), 7.60 (1H, ddd,
J 7.3, 7.3, 1.4), 7.40 (2H, d, J 8.7), 5.29 (1H, quintet, J 6.6,
H18), 3.61 (1H, dd, J 14.2, 4.7, H11A), 3.51 (3H, s, OMe), 3.37
(1H, dd, J 6.8, 4.2, H17), 3.34 (1H, dd, J 14.2, 7.9, H11B), 2.65
(1H, d, J 9.3, H15), 2.64–2.51 (1H, m, H16), 1.80 (1H, dd,
J 14.1, 7.3, H13A), 1.62 (1H, dd, J 14.1, 7.5, H13B), 1.63–1.52
(1H, m, H12), 1.30 (3H, d, J 6.5, H19), 1.27 (3H, s, C14-Me),
1.24 (3H, d, J 6.7, C12-Me), 1.02 (3H, d, J 6.9, C16-Me); δC(90
MHz, CDCl3) 166.6 (0), 165.2 (0), 152.7 (0), 139.4 (0), 136.8 (0),
131.1 (2C, 1), 129.2 (0), 128.8 (2C, 1), 128.3 (1), 127.9 (1), 125.5
(1), 122.5 (1), 84.5 (1), 73.1 (1), 64.6 (1), 61.5 (3), 60.3 (2), 59.9
(0), 45.5 (2), 35.0 (1), 26.1 (1), 20.9 (3), 16.8 (3), 16.4 (3), 10.8
(3); m/z (CI mode, NH3) 583 (8%), 548 (23), 378 (67), 213
(92), 136 (100) (Found: (M ϩ H)ϩ, 566.1433. C27H33ClNO6S2
requires M, 566.1438).
δC(90 MHz, CDCl3) 171.2 (0), 165.3 (0), 139.4 (1), 139.4 (0),
135.3 (0), 132.3 (1), 131.2 (2C, 1), 129.3 (0), 128.8 (2C, 1), 128.3
(1), 125.3 (1), 118.0 (2), 90.8 (1), 84.7 (1), 74.0 (1), 73.3 (1),
66.0 (1), 65.1 (2), 61.5 (3), 60.9 (0), 47.1 (2), 41.6 (2), 35.4 (1),
35.2 (1), 32.4 (2), 32.2 (1), 31.8 (2), 22.3 (3), 17.7 (3), 16.8 (3),
16.8 (3), 12.0 (3), 10.8 (3); m/z (CI mode, NH3) 616
(0.6%), 460 (2), 361 (4), 304 (16), 290 (24), 227 (46), 183 (15),
139 (100), 95 (41) (Found: Mϩ, 616.3169. C35H49ClO7 requires
M, 616.3167).
Herboxidiene methyl ester 36
A stirred suspension of the benzoate 35 (223 mg, 0.36 mmol)
and potassium carbonate (100 mg, 0.72 mmol) in anhydrous
MeOH (5 ml) was heated at reflux for 2 h. The mixture was
allowed to cool to rt and subsequently diluted with EtOAc (20
ml) and H2O (10 ml). The layers were then shaken and separ-
ated and the aqueous phase extracted with EtOAc (3 × 5 ml).
The combined organic extracts were washed with brine (5 ml),
dried (MgSO4) and then concentrated in vacuo. The residue was
further purified via column chromatography (eluting with 35%
EtOAc in hexanes) to yield the pure methyl ester 36 (117 mg,
0.26 mmol, 72%) as a clear oil. The 10E:Z ratio of this material
reflected that of the starting material [E:Z = 91:9, determined
by integration of the H11 resonance in the 1H NMR spectrum;
δH11 (10E) = 5.44 (1H, dd, J 15.0, 8.7), δH11 (10Z) = 5.21 (1H, t,
J 10.0)]. The pure natural isomer could be isolated by sub-
sequent careful column chromatography eluting with 20%
EtOAc in hexanes, the 10E isomer being the less polar compon-
18O-(4-Chlorobenzoyl)herboxidiene allyl ester 35
1
ent. H and 13C NMR data were in complete agreement with
To a stirred solution of the sulfone 4 (331 mg, 0.58 mmol) in
anhydrous THF (6 ml) at Ϫ78 ЊC under N2 was added dropwise
a solution of freshly prepared lithium diisopropylamide (LDA,
1.3 ml, 0.41 M in THF, 0.53 mmol) and the resulting deep
yellow solution stirred for 15 min. A solution of the enal 3 (131
mg, 0.49 mmol, prepared in 4 steps from 17 as previously
described5) in anhydrous THF (2 ml) was then added dropwise.
The colour of the reaction mixture lightened. The mixture was
stirred for 30 min at Ϫ78 ЊC and then allowed to warm slowly to
Ϫ20 ЊC over 1 h. The resulting colourless solution was then
quenched by the addition of sat. NH4Cl (2 ml) and allowed to
warm to rt with vigorous stirring. After further dilution with
EtOAc (15 ml) and H2O (15 ml) the layers were well shaken and
separated. The aqueous phase was then extracted (3 × 5 ml
EtOAc) and the combined organic extracts washed with brine
(5 ml), dried (MgSO4) and concentrated in vacuo. The residue
was further purified via column chromatography (eluting with
15% EtOAc in hexanes) to yield the diene 35 (246 mg, ca. 0.40
mmol, 81%) as a clear oil. 1H NMR analysis indicated the pres-
ence of a small quantity of the associated 10Z isomer together
with other minor impurities (<5%). Conversion to the methyl
ester 36 as outlined below facilitated purification and enabled
accurate measurement of the E:Z ratio for the olefination step
as 91:9 in favour of the natural 10E geometry. Repeated chro-
matography (eluting with 20% Et2O in hexanes) provided a
good purity sample of 35 for characterisation purposes: [α]D
Ϫ25 (c 0.4, CHCl3); νmax(film)/cmϪ1 2927m, 1720s, 1091m;
δH(360 MHz, CDCl3) 8.00 (2H, d, J 8.7, Ar), 7.41 (2H, d, J 8.7,
Ar), 6.22 (1H, dd, J 15.0, 10.9, H10), 5.94–5.82 (1H, m,
those previously reported by Isaac et al.2 DEPT data and pro-
ton resonance coupling constants were not reported by Isaac
and so are listed here: [α]D ϩ0.9 (c 0.66, CHCl3); νmax(film)/cmϪ1
3501br m, 2954s, 2925s, 2849m, 1740s, 1455m, 1067m; δH(360
MHz, CDCl3) 6.24 (1H, dd, J 15.0, 10.8, H10), 5.90 (1H, d,
J 11.0, H9), 5.45 (1H, dd, J 14.9, 8.8, H11), 3.90–3.83 (1H, m,
H18), 3.82–3.73 (1H, m, H3), 3.67 (3H, s, CO2Me), 3.55 (3H, s,
OMe), 3.33 (1H, d, J 9.8, H7), 2.98 (1H, t, J 5.3, H17), 2.60
(1H, dd, J 15.2, 6.2, H2A), 2.60–2.53 (1H, m, OH), 2.56 (1H, d,
J 9.7, H15), 2.45–2.37 (1H, m, H12), 2.41 (1H, dd, J 15.2, 6.7,
H2B), 1.90 (1H, dd, J 13.6, 4.7, H13A), 1.88–1.81 (1H, m, H5A),
1.71 (3H, s, C8-Me), 1.70–1.50 (3H, m, H4A, H6, H16), 1.40–
1.20 (3H, m, H4B, H5B, H13B), 1.29 (3H, s, C14-Me), 1.19 (3H,
d, J 6.4, H19), 1.05 (3H, d, J 6.7, C12-Me), 0.88 (3H, d, J 6.9,
C16-Me), 0.67 (3H, d, J 6.6, C6-Me); δC(90 MHz, CDCl3) 172.0
(0), 139.4 (1), 135.4 (0), 128.3 (1), 125.4 (1), 90.8 (1), 87.8 (1),
74.0 (1), 68.4 (1), 66.2 (1), 61.5 (0), 61.5 (3), 51.7 (3), 47.1 (2),
41.5 (2), 35.5 (1), 35.3 (1), 32.4 (2), 32.3 (1), 31.8 (2), 22.2 (3),
19.2 (3), 17.8 (3), 16.7 (3), 12.1 (3), 12.0 (3); m/z (CI mode, NH3)
452 (28%), 434 (9), 351 (12), 305 (10), 278 (22), 265 (19), 237
(12), 211 (11), 197 (15), 173 (44), 157 (42), 129 (100), 123 (55),
95 (56), 69 (50) (Found: Mϩ, 452.3136. C26H44O6 requires M,
452.3138).
Herboxidiene 1
A solution of the methyl ester 36 (16 mg, 35 µmol) in MeOH (2
ml) was treated with an aqueous solution of potassium
carbonate (24 mg, 174 µmol in 0.5 ml H2O) and the resultant
mixture stirred at reflux for 1 h whereupon the reaction was
allowed to cool and diluted with EtOAc (10 ml) and H2O
(5 ml). The aqueous layer was then acidified to pH 2–3 by
the careful addition of HCl (2 M, ca. 0.5 ml) and the layers
shaken well and then separated. The aqueous phase was
extracted with EtOAc (4 × 5 ml) and the combined organic
extracts washed with brine (5 ml), dried (Na2SO4) and then
concentrated in vacuo. The residue was further purified via
column chromatography (eluting with 7% MeOH in CH2Cl2) to
CH CH᎐CH ), 5.88 (1H, dm, J 10.4, H9), 5.42 (1H, dd, J 15.0,
᎐
2
2
8.9, H11), 5.30 (1H, dm, J 17.9, CH CH᎐CH H ), 5.27 (1H,
᎐
2
Z
E
quintet, J 6.9, H18), 5.20 (1H, dm, J 10.5, CH CH᎐CH H ),
᎐
2
Z
E
4.58 (2H, d, J 5.5, CH CH᎐CH ), 3.83–3.74 (1H, m, H3),
᎐
2
2
3.52 (3H, s, OMe), 3.37 (1H, dd, J 6.9, 3.9, H17), 3.31 (1H, d,
J 9.9, H7), 2.62 (1H, d, J 9.7, H15), 2.61 (1H, dd, J 15.1,
6.5, H2A), 2.43 (1H, dd, J 15.2, 6.5, H2B), 2.47–2.34 (1H, m,
H12), 1.91 (1H, dd, J 13.5, 4.6, H13A), 1.88–1.80 (1H, m, H5A),
1.72–1.65 (1H, m, H4A), 1.69 (3H, s, C8-Me), 1.57–1.46 (2H,
m, H6, H16), 1.40–1.15 (3H, m, H4B, H5B, H13B), 1.29 (3H, d,
J 6.5, H19), 1.24 (3H, s, C14-Me), 1.03 (3H, d, J 6.6, C12-
Me), 0.88 (3H, d, J 6.9, C16-Me), 0.64 (3H, d, J 6.6, C6-Me);
1
yield herboxidiene (1, 13 mg, 30 µmol, 84%) as a clear oil. H
and 13C NMR data recorded in CD3OD are listed in Tables 1
and 2 respectively. νmax(film)/cmϪ1 3470br w, 2962s, 2919s,
J. Chem. Soc., Perkin Trans. 1, 1999, 955–968
967

View Article Online
20 D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
2849m, 1731m, 1456m, 1068m; m/z (EI mode) 438 (10%), 420
(4), 337 (7), 293 (7), 251 (58), 183 (18), 173 (34), 129 (85), 95
(100), 69 (82) (Found: Mϩ, 438.2980. C25H42O6 requires M,
438.2981).
21 R. E. Ireland and L. Liu, J. Org. Chem., 1993, 58, 2899.
22 Y. Mori, M. Kuhara, A. Takeuchi and M. Suzuki, Tetrahedron Lett.,
1988, 29, 5419.
23 P. Wipf, in Claisen Rearrangements, in Comprehensive Organic
Synthesis, ed. B. M. Trost and I. Fleming, Pergamon Press,
Oxford, 1991, vol. 5, p. 827.
24 H. Loibner and E. Zbiral, Helv. Chim. Acta, 1976, 59, 2100.
25 H. S. Schultz, H. B. Freyermuth and S. R. Buc, J. Org. Chem., 1963,
28, 1140.
Acknowledgements
We thank Rhône-Poulenc Rorer for a CASE studentship.
26 D. A. Evans, A. H. Hoveyda and G. C. Fu, Chem. Rev., 1993, 93,
1307.
27 D. L. Hughes, Org. React., 1992, 42, 335.
28 J. C. Kauer, Org. Synth., 1963, 4, 411.
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