Enantiospecific syntheses of pseudopterosin aglycones. Part 2. Synthesis of pseudopterosin K-L aglycone and pseudopterosin A-F aglycone via a B→BA→BAC annulation strategy

Article abstract of DOI:10.1039/b102961b

The enantiomeric aglycones of pseudopterosins K-L and A-F are synthesised from (-)- and (+)-isopulegol respectively. Key features are (a) the construction of the C3 stereogenic centre by a directed epoxidation-reduction sequence (K-L); (b) the creation of

Full text of DOI:10.1039/b102961b

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Enantiospecific syntheses of pseudopterosin aglycones. Part 2.
Synthesis of pseudopterosin K–L aglycone and pseudopterosin
A–F aglycone via a B BA BAC annulation strategy
1
Philip J. Kocienski,*a Alessandro Pontirolib and Liu Qunc
a Department of Chemistry, Leeds University, Leeds, UK LS2 9JT
b Department of Chemistry, Glasgow University, Glasgow, UK G12 8QQ
c Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
Received (in Cambridge, UK) 2nd April 2001, Accepted 27th July 2001
First published as an Advance Article on the web 7th September 2001
The enantiomeric aglycones of pseudopterosins K–L and A–F are synthesised from (Ϫ)- and (ϩ)-isopulegol
respectively. Key features are (a) the construction of the C3 stereogenic centre by a directed epoxidation–reduction
sequence (K–L); (b) the creation of the C3 stereogenic centre by a Pfaltz asymmetric conjugate reduction (A–F);
(c) benzannulation of a cyclic ketone starting with an α-oxoketene-S,S-acetal to give a tetrahydronaphthol ether; and
(d) a diastereoselective intramolecular electrophilic aromatic substitution using an allylic sulfone as the electrophilic
trigger to complete the hexahydro-1H-phenalene core. An X-ray structure of compound 50 was determined.
Introduction
Results and discussion
The pseudopterosins are a family of 12 diterpene glycosides
whose aglycones are anti-inflammatory and analgesic.1,2 The
family comprises 3 sets based on the structure of the hexa-
hydro-1H-phenalene core. In the preceding paper, we described
a synthesis of the putative pseudopterosin G–J aglycone.3
We now present complementary routes to the enantiomeric
aglycones of pseudopterosins K–L (3, Scheme 1), the least
Pseudopterosin K–L aglycone
Construction of the C3 stereogenic centre. The principal
attraction to the B BA BAC annulation strategy is the
opportunity to use a cheap monoterpene for ring B which
harbours two of the four stereogenic centres of the final target.
A further enticement to begin with a monoterpene was the
prospect of introducing a third stereogenic centre early in the
synthesis. Schulte-Elte and Ohloff4 had reported that (ϩ)-
neoisopulegol (7) undergoes diastereoselective hydroboration
to give a mixture of diols (100%, dr 9 : 1) in favour of the diol 9
(Scheme 2) having the stereochemistry corresponding to C3, C4
and C6 of pseudopterosins K–L. (ϩ)-Neoisopulegol was easily
synthesised in 70% yield (dr ≥ 20 : 1) from technical grade iso-
pulegol by Jones oxidation followed by stereoselective reduction
with L-Selectride.5 Unfortunately, in our hands the diastereo-
selectivity of the hydroboration was unfavourable (2.5 : 1 at
best) despite extensive variations in time, temperature, solvent,
order of addition and hydroborating agent. A further attempt
at hydroboration of the corresponding methoxymethyl ether
was likewise disappointing.6
We next investigated the possibility of introducing the C3
stereogenic centre by a sequence involving directed epoxidation
followed by regioselective oxirane ring opening. Thus, treat-
ment of (ϩ)-neoisopulegol (7) with tert-butyl hydroperoxide in
the presence of a catalytic amount of vanadyl bis(acetylaceto-
nate)7 returned the known5 crystalline oxirane 8 in 88% yield.
1H and 13C NMR spectroscopic analysis of the crude product
indicated >20 : 1 diastereoselectivity in the epoxidation in
accord with a hydroxy-directed delivery of oxygen to the alkene
as depicted in Scheme 3. The crucial reductive cleavage of the
oxirane occurred with clean inversion of configuration by the
procedure of Hutchins8 involving addition of BF3ؒOEt2 to
a solution of the substrate, sodium cyanoborohydride and
bromocresol green at a rate sufficient to maintain a yellow
colour. The desired diol 9 was obtained as a single diastereo-
isomer in 79% yield. After protection of the primary hydroxy
group as its TBS ether 10, the secondary hydroxy group was
oxidised to the ketone 11.
Scheme 1
abundant members of the family, and pseudopterosins A–F (6),
the most abundant. The strategy we adopt (Scheme 1) is based
on the annulation sequence B BA BAC beginning with the
enantiomeric isopulegols 1 and 4. The two routes share a num-
ber of key features including (a) the benzannulation chemistry
whereby the aromatic ring A is appended to a monocyclic
α-oxoketene-S,S-acetal intermediate and (b) the use of allylic
sulfones 2 and 5 as the electrophilic trigger in the creation of
ring C. The two routes differ primarily in the methods used to
construct the stereogenic centre at C3.
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This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102961b

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Scheme 5
mechanism depicted in Scheme 5, the process depends on
intramolecular capture of the carbocationic intermediate 17 by
an alkene followed by loss of an alkylthio group with concom-
itant aromatisation. Since the corresponding methoxy analogue
of 16 was our target, we tried to capture the carbocation inter-
mediate 17 by conducting the benzannulation in methanol
using a variety of protic and Lewis acid catalysts but in every
case, the intramolecular cyclisation 17 18 was favoured.
We tried a variety of methods ranging from the brutal to the
exotic to replace the methylthio group in 16 with a methoxy or
hydroxy group. Scheme 6 shows the most successful sequence
Scheme 2
Scheme 3
Construction of the arene ring. In 1984 Dieter,9 Junjappa and
Ila10 reported independently that 1,2-addition of methyl-
allylmagnesium chloride to α-oxoketene-S,S-acetals followed
by treatment of the carbinol with HBF4 or a Lewis acid in THF
leads to benzannulation reactions in good yield.11,12 Application
of the sequence to our ketone 11 (Scheme 4) gave the benz-
annulated product 16 in 69% overall yield. According to the
Scheme 6
based on reductive cleavage of an aryl–sulfone bond. Direct
reductive cleavage of the methyl sulfone 20 was impossible
owing to preferential cleavage of the alkyl–sulfur bond. A simi-
lar fate befell the isopropyl sulfone 21. However, the lithiated
sulfone 22 cleaved with lithium 4,4Ј-di-tert-butylbiphenylide
(LDBB)13 to give the aryllithium 23 which could be con-
verted to the phenol 24 by oxidation of a borate intermediate.
The length of the route, its experimental difficulty and the low
overall yield were good reasons to seek alternatives.
Scheme 4
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Relief came from an unexpected quarter. A fresh trek
through the benzannulation chemistry discovered a trivial
modification of the structure of the α-oxoketene-S,S-acetal
that allowed a detour down paths leading to the desired meth-
oxyarene 27 (Scheme 7). The lithium enolate of ketone 11 was
condensed with carbon disulfide as before but this time, the
adduct was quenched with 1,3-dibromopropane to give the
dithianylidene derivative 25. Addition of methylallylmag-
nesium chloride gave a sensitive adduct 26 which was immedi-
ately treated with BF3ؒOEt2 in a mixture of THF and methanol
to give the desired methoxyarene 27 shorn of its TBS protector.
It would appear that the dithiane ring reduces the rate of cyclis-
ation of 32 (Scheme 8) so that the intermediate carbocation can
be captured by methanol to give the dithio orthoester inter-
mediate 29. Now cleavage of the dithiane ring leads to the oxo-
nium ion 30 whose cyclisation is followed by expulsion of
propane-1,3-dithiol leading to the desired product 27 in 63%
yield for the two steps from the α-oxoketene-S,S-acetal 25. An
alternative mechanism which would account for the introduc-
tion of methanol allows an initial rapid cyclisation of carbo-
cation 32 to the spirocyclic S,S-acetal 33. Subsequent cleavage
to the thionium ion 34 followed by addition of methanol leads
to the same intermediate 31 and thence the methoxyarene 27.
Scheme 8
ethanethiolate in hot DMF.14 The final oxidation of the phenol
38 to the catechol in 3 was precedented in the work of
McCombie et al.15 but the best we could obtain was 22% yield
using freshly prepared potassium nitrosodisulfonate (Fremy’s
salt) and KH2PO4 buffer in acetone–H2O at rt followed by
reduction of the red o-quinone with sodium dithionite.16
Unreacted starting material and a number of side products
were always recovered. Similar problems were encountered by
Corey and Carpino17 during their synthesis of pseudopterosin
A. However, by simply using aqueous DMF as the solvent,
the final step of the synthesis, oxidation of the phenol to the
catechol, was achieved in a very satisfactory 86% yield.
Scheme 7
Construction of ring C. The third and final phase of the syn-
thesis of the pseudopterosin K–L aglycone (Scheme 9) entailed
construction of ring C using an allylic sulfone strategy
described in our synthesis of the putative pseudopterosin G
aglycone. Reaction of the crystalline toluene-p-sulfonate 35
with the lithiated sulfone derived from 36 afforded the allylic
sulfone 2 in 76% yield. Without separation of the diastereo-
isomers (ca. 2.5 : 1), the mixture was treated with EtAlCl2 (10
equiv.) in dichloromethane at low temperature to give the
hexahydro-1H-phenalene ring system as a mixture of diastereo-
isomers (37a : 37b = 10 : 1). The structure and stereochemistry
of the major crystalline diastereoisomer 37a were established by
X-ray crystallography (see Experimental). The stereoselectivity
of the electrophilic aromatic substitution reaction was sensitive
to Lewis acid and solvent. For example, AlCl3 (Et2O, reflux)
and Et2AlCl (dichloromethane, Ϫ78 ЊC) both returned 37a,b as
a 1 : 1 mixture of diastereoisomers.
Pseudopterosin A–F aglycone
All of the syntheses of the pseudopterosins reported thus far
have identified the construction of the C3 stereogenic centre
as an obstacle. Solutions to the problem have generally been
inefficient or expensive. In our synthesis of pseudopterosin K–L
aglycone described above, we presented a two-step procedure
which was effective and cheap. We now suggest an alternative
solution to the problem (Scheme 10) in the context of a syn-
thesis of the pseudopterosin A–F aglycone 6. As before, the
synthesis began with isopulegol but we now require the (ϩ)-
enantiomer which is not available in a cheap commercial grade.
However, (ϩ)-isopulegol can be conveniently prepared in high
yield and stereoselectivity by a ZnCl2-catalysed intramolecular
ene-reaction on (Ϫ)-citronellal according to the procedure of
Nakatani and Kawashima.18 After protection of the hydroxy
group as its acetate derivative 39, the alkene was ozonolysed
To complete the synthesis, cleavage of the methoxy group of
37a was achieved in good yield using BBr3 and 2,6-di-tert-
butylpyridine over 30 min. Longer exposure to these reac-
tion conditions resulted in partial epimerisation at the C6
benzylic centre. The epimerisation reaction could be suppressed
by nucleophilic cleavage of the methyl ether using sodium
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to afford the β-acetoxy ketone 40. A Horner–Wadsworth–
Emmons reaction then accomplished the synthesis of the
α,β-unsaturated ester 41 in 64% yield as a mixture of isomers
(E : Z = 9 : 1) which were easily separable by column chrom-
atography. The key step of the sequence was an asymmetric
conjugate reduction using sodium borohydride and CoCl2 cat-
alysed by Pfaltz’s semicorrin 42.19,20 The reaction was very slow
requiring up to 10 days at room temperature but the yield of 43
was 90% and the diastereoselectivity excellent (dr ≥ 97 : 3). The
reaction requires rigorous exclusion of oxygen and our failure
to do so was probably responsible for the long reaction time and
the relatively high (8 mol%) catalyst loading. In more favour-
able circumstances as little as 1–2 mol% of catalyst is all that is
required.
Reduction of the ketoester 43 gave a crystalline diol 44 whose
primary hydroxy was protected as its TBS ether 45 before oxid-
ation of the secondary hydroxy was achieved in 80% yield using
the Swern method. Thenceforth the synthesis bears a close
resemblance to the route used to synthesise pseudopterosin K–L
aglycone; viz. the arene was appended using an α-oxoketene-
S,S-acetal benzannulation and ring C was constructed using the
sulfone-based electrophilic aromatic substitution. The pseudo-
pterosin A–F aglycone 6 thus obtained was identical to the one
prepared as described in Scheme 9 except for the sign of the
optical rotation.
Conclusions
Our syntheses of the pseudopterosin aglycones represent
another rendition of the popular B BA BAC annulation
strategy based on monoterpene precursors.21–24 Pseudopterosin
K–L aglycone was prepared in 7.8% overall yield (15 steps)
from commercial (ϩ)-isopulegol but the synthesis of pseudo-
pterosin A–F aglycone was less efficient giving the target in only
2.3% overall yield from citronellal in 17 steps. An important
milestone in our approach was the successful diversion of the
Dieter–Junjappa–Ila benzannulation to produce a methoxy-
arene rather than the usual methylthioarene. Our solutions to
the vexing problem of creating the C3 stereogenic centre are
noteworthy too for their general efficiency and stereoselectivity.
The reductive cleavage of the oxirane 8 has been applied
Scheme 9
Scheme 10
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in similar circumstances previously25–27 but the Pfaltz asym-
metric conjugate reduction has rarely been exploited in natural
product synthesis.28 It served our purposes well.
(2S,5R)-2-[(S)-2-(tert-Butyldimethylsilyloxy)-1-methylethyl]-5-
methylcyclohexan-1-one (11)
DMSO (1.0 g, 93 µl, 13.0 mmol, 2.5 equiv.) in CH2Cl2 (15 ml)
was added dropwise to a solution of oxalyl chloride (0.8 g, 0.55
ml, 6.3 mmol, 1.2 equiv.) in dry CH2Cl2 (8 ml) at Ϫ72 ЊC over
7 min. After 5 min the alcohol 10 (1.50 g, 5.23 mmol) in CH2Cl2
(4 ml) was slowly added over 4 min at Ϫ65 ЊC. After 90 min
stirring at Ϫ65 ЊC, Et3N (2.18 g, 3 ml, 21.5 mmol, 4.1 equiv.)
was added over 8 min and mixture allowed to warm to rt over
2 h. The white suspension was poured into vigorously stirred
aq. NH4Cl (15 ml) and extracted into hexanes (3 × 20 ml). The
combined organic phases were washed with HCl (1.5 M, 10 ml)
followed by brine (10 ml). The residue obtained on concen-
tration in vacuo was purified by column chromatography (SiO2,
hexanes–Et2O 95 : 5) to give the ketone 11 (1.31 g, 4.60 mmol,
88%) as a pale yellow oil: [α]D Ϫ7.4 (c 2.5, CHCl3); νmax film/
cmϪ1 2955 s, 2857 s, 1710 s, 1471 m, 1387 m, 1256 m, 1087 s, 836
s, 776 s; δH (300 MHz, CDCl3) 3.45 (2H, AB part of an ABX
system, JAB 9.9, JBX 7.3, JAX 5.5, C2H2), 2.43–2.2 (3H, m), 2.05–
1.80 (4H, m), 1.41–1.10 (2H, m), 1.02 (3H, d, J 6.2, C3Me), 0.88
(9H, s, t-Bu), 0.80 (3H, d, J 7.0, C5Me), 0.04 and 0.03 (3H each,
s, SiMe2); δC (75 MHz, CDCl3) 212.6 (0), 66.0 (2), 51.0 (2), 50.0
(1), 35.4 (1), 34.1 (2), 33.3 (1), 27.0 (2), 26.1 (3C, 3), 22.5 (3),
18.4 (0), 12.9 (3), Ϫ5.4 (3), Ϫ5.5 (3); m/z (CIϩ mode, NH3) 285
[(M ϩ H)ϩ, 100%], 227 (66), 153 (33); Found (M ϩ H)ϩ,
285.2249; C20H33O2Si requires M, 285.2250.
Experimental
For general experimental details see the previous paper in this
issue.3
(؉)-Neoisopulegol (7)
Technical grade isopulegol (Aldrich), a mixture of four dia-
stereoisomers including (Ϫ)-isopulegol (ca. 65–80%) and
(ϩ)-neoisopulegol (ca. 10–25%), can be separated by column
chromatography but the oxidation–reduction sequence of
Friedrich and Bohlmann5 is a more convenient procedure
giving (ϩ)-neoisopulegol in ca. 70% overall yield (120 mmol
scale) and >90% purity. If necessary, the (ϩ)-neoisopulegol
can be further purified by crystallisation of its p-nitrobenzoate
(mp 88–89 ЊC).29
(1S,2R,5R)-2-[(R)-1-Methyl-1,2-epoxyethyl]-5-methylcyclo-
hexan-1-ol (8)
Epoxidation of (ϩ)-isopulegol 7 (5.93 ml, 5.40 g, 35.0 mmol) by
the procedure of Friedrich and Bohlmann.5 gave the epoxide
8 (5.25 g, 30.8 mmol, 88%) as white crystals, mp 55–56 ЊC;
[α]D ϩ3.2 (c 3, CHCl3). Lit.5 mp 56–58 ЊC.
(2S,5R)-2-[(S)-2-(tert-Butyldimethylsilyloxy)-1-methylethyl]-5-
methyl-6-bis(methylsulfanyl)methylenecyclohexan-1-one (14)
(1R,2S,5R)-2-[(S)-2-Hydroxy-1-methylethyl]-5-
methylcyclohexan-1-ol (9)
To a solution of LHMDS in THF (6.0 ml, 1.0 M, 6 mmol)
cooled to Ϫ85 ЊC was added a solution of ketone 11 (1.55 g,
5.47 mmol) in THF (10 ml) over 16 min. After 50 min, HMPA
(0.5 ml, 3.2 mmol) and CS2 (0.35 ml, 5.82 mmol) were added.
The solution was allowed to warm to 0 ЊC over 100 min, stirred
at 0 ЊC for 15 min and then cooled again to Ϫ82 ЊC whereupon
LHMDS (6.0 ml, 1.0 M, 6 mmol) was added over 7 min. After
40 min, iodomethane (0.8 ml, 10.2 mmol) was added at Ϫ55 ЊC
and the cooling bath removed. After 15 h, the reaction was
quenched with saturated aqueous NH4Cl (10 ml) and diluted
with water (10 ml). The mixture was extracted into hexanes (50
ml) and the organic extract washed successively with 20 ml
aliquots of water, HCl (2 M), water, and brine. The organic
layer was dried over MgSO4, concentrated in vacuo, and the
residue purified by column chromatography (SiO2, with ether–
hexanes 5 : 95) to give the ketene-S,S-acetal 14 (1.74 g, 4.49
mmol, 82%) as a bright yellow oil: [α]D ϩ2.0 (c 2.36, CHCl3);
νmax film/cmϪ1 1683 s, 1259 s, 1098 s, 847 s; δH (270 MHz,
CDCl3) 3.55 (1H, dd, J 10.0, 6.0, CHAHBOSi), 3.54 (1H, appar-
ent sextet, J 6.0), 3.35 (1H, dd, J 9.9, 7.4, CHAHBOSi), 2.36 and
2.29 (3 H each, s, SMe), 2.4–2.3 (1H, m), 2.17 (1H, apparent
septet J 7.0), 2.02 (1H, ddt, J 15.2, 9.4, 3.0), 1.91–1.76 (1H, m),
1.71–1.58 (1H, m), 1.38–1.25 (1H, m), 1.06 (3H, d, J 6.9,
C3Me), 0.88 (9H, s, But), 0.84 (3H, d, J 6.6, C6Me), 0.04 and
0.02 (3H each, s, SiMe2); δC (67.5 MHz, CDCl3) 206.1 (0), 148.6
(0), 140.4 (0), 66.4 (2), 52.1 (1), 37.2 (1), 36.4 (1), 30.0 (2), 26.1
(3), 22.0 (2), 20.7 (3), 18.4 (0), 17.75 (3), 17.7 (3), 13.2 (3), Ϫ5.25
(3), Ϫ5.2 (3); m/z (CI mode, NH3) 389 [(M ϩ H)ϩ, 100%], 331
[(M Ϫ But), 76], 257 [(M Ϫ OTBS), 80].
Sodium cyanoborohydride (4.47 g, 71.2 mmol, 3 equiv.) was
added to a solution of epoxide 8 (4.04 g, 23.7 mmol) and a drop
of bromocresol green in dry THF (5 ml). A solution of
BF3ؒOEt2 in dry THF (0.8 M) was added dropwise until the
colour changed to yellow. The reaction mixture was stirred for
12 h maintaining the yellow colour by dropwise addition of the
BF3ؒOEt2 solution. The mixture was diluted with brine (35 ml)
and extracted with EtOAc (5 × 35 ml). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (SiO2, EtOAc–
hexanes 1 : 1) to give the diol 9 (3.24 g, 18.8 mmol, 79%) as a
pale yellow oil having [α]D, IR, H NMR (300 MHz), and 13C
1
NMR (75 MHz) spectra consistent with data published by
Schulte-Elte and Ohloff.4
(2S,5R)-2-[(S)-2-(tert-Butyldimethylsilyloxy)-1-methylethyl]-5-
methylcyclohexan-1-ol (10)
To a solution of the diol 9 (3.50 g, 20.3 mmol) and imidazole
(3.18 g, 46.74 mmol, 2.3 equiv.) in dry DMF (15 ml) was added
tert-butyldimethylsilyl chloride (3.37 g, 22.35 mmol, 1.1 equiv.).
After 15 min the reaction mixture was poured into NH4Cl (20
ml) and the product extracted into hexanes. The organic layer
was washed with brine, dried over MgSO4 and concentrated
in vacuo. The residue was purified by column chromatography
(SiO2, Et2O–hexanes 1 : 25) to give the TBS ether 10 (4.89 g,
17.05 mmol, 84%) as a colourless oil: [α]D ϩ7.1 (c 3.9, CHCl3);
νmax film/cmϪ1 3440 br, 2927 s, 2858 s, 1472 m, 1461 m, 1354 s,
1071 s, 961 m, 937 m, 836 s, 776 s, 666 m; δH (270 MHz, CDCl3)
4.07 (1H, m, C11H), 3.66 (2H, overlapping br s, OH, and dd, A
portion of an ABX system, JAB 10.4, JAX 2.4, C2HA), 3.52 (1H,
dd, B portion of an ABX system, JAB 10.4, JBX 6.2, C2HB),
1.92–1.59 (6H, m), 1.29–0.98 (3H, m), 0.94 (3H, d, J 6.4,
C3Me), 0.91 (9H, s, t-Bu), 0.85 (3H, d, J 6.4, C6Me), 0.08 (6H,
s, SiMe2); δC (75 MHz, CDCl3) 66.3 (2), 66.2 (1), 46.9 (1), 41.9
(2), 38.4 (1), 35.6 (2), 26.3 (1), 26.0 (3C, 3), 25.8 (2), 22.6 (3),
18.4 (0), 16.3 (3), Ϫ5.5 (2C, 3); m/z (CI mode, NH3) 287 (MHϩ,
100%), 137 (48); Found (MH)ϩ, 287.2414; C16H35O2Si requires
M, 287.2406.
(5S,8R)-1-Methylthio-3,8-dimethyl-5-[(S)-2-hydroxy-1-
methylethyl]-5,6,7,8-tetrahydronaphthalene (16)
To a magnetically stirred solution of the ketene-S,S-acetal 14
(1.24 g, 3.19 mmol) in THF (7 ml) was added methylallyl-
magnesium chloride (5 ml, 0.9 M, 4.5 mmol) over 30 min at
0 ЊC. After 1 h, saturated aqueous NH4Cl (10 ml) was added.
The organic layer was extracted into Et2O (30 ml) and washed
with brine. After evaporation of the solvent the crude alcohol
15 was dissolved in THF (2 ml) and nitromethane (4 ml) and
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cooled to 0 ЊC whereupon BF3ؒOEt2 (1.0 ml, 3.4 mmol) was
added. The mixture was stirred at 0 ЊC for 1 h and then
quenched by the addition of saturated aqueous NH4Cl (10 ml).
The organic material was extracted into Et2O (30 ml) and
washed with brine. The extract was dried over MgSO4, concen-
trated in vacuo and the residue purified by column chrom-
atography (SiO2, CH2Cl2) to give the methylthioarene 16 (0.71
g, 2.68 mmol, 84%) as a colourless oil: νmax film/cmϪ1 3356 br,
1598 m, 1560 m, 1040 s, 850 m; δH (270 MHz, CDCl3) 6.84 and
6.68 (1H each, s), 3.65 (1H, dd, J 10.8, 5.0), 3.56 (1H, dd, J 10.8,
6.2), 3.25 (1H, quintet, J 5.7), 2.87 (1H, t, J 4.8), 2.47 and 2.31
(3H each, s), 2.1–2.0 (1H, m), 2.0–1.9 (2H, m), 1.75–1.55
(2H ϩ OH, m), 1.2 (3H, d, J 6.75), 0.86 (3H, d, J 7.0); δC (67.5
MHz, CDCl3) 138.9 (0), 137.9 (0), 137.2 (0), 135.05 (0), 126.9
(1), 123.8 (1), 66.9 (2), 42.1 (1), 37.6 (1), 29.4 (1), 27.3 (2), 21.42
(3), 21.39 (3), 18.8 (2), 16.0 (3), 14.25 (3); m/z (EI mode) 265
130.1 (1), 66.30 (2), 55.95 (1), 42.6 (1), 35.5 (1), 29.8 (1), 27.0 (2),
26.1 (3), 24.5 (3), 21.1 (3), 18.5 (0), 17.2 (2), 16.2 (3), 15.1 (3),
12.7 (3), Ϫ5.1 (3), Ϫ5.2 (3); m/z (CI mode, NH3) 456
[(Mϩ ϩ NH4), 100%], 439 [(Mϩ ϩ H), 15], 381 [(Mϩ Ϫ But, 27].
(5S,8R)-[(S)-2-(tert-Butyldimethylsilyloxy)-1-methylethyl]-3,8-
dimethyl-1-hydroxy-5,6,7,8-tetrahydronaphthalene (24)
To a solution of the isopropylsulfone 21 (0.140 g, 0.32 mmol) in
THF (1.5 ml) was added BuLi (0.3 ml, 1.6 M, 0.48 mmol)
dropwise at Ϫ78 ЊC. A deep yellow colour formed immediately.
After 1 h, a solution of lithium 4,4-di-tert-butylbiphenylide in
THF (3 ml, 0.25 M, 0.75 mmol) was added over 1 min. The
solution changed from green to red–brown. Trimethyl borate
(0.3 ml, 2.6 mmol) was added at Ϫ78 ЊC over 30 s. The solution
was allowed to warm gradually to Ϫ10 ЊC over 2.5 h whereupon
NaOH (2 ml, 2 M, 4 mmol) and H2O2 (3 ml, 15%) were added.
After 16 h the solution was acidified with HCl (2 M) until the
pH was approximately 1. The organic phase was extracted into
ether (30 ml) and washed with water (20 ml) and brine (20 ml).
After drying over MgSO4, the mixture was concentrated
in vacuo and the residue purified by column chromatography
(SiO2, ether–hexanes 4 : 96 10 : 90) to give the phenol 24
(0.047 g, 0.134 mmol, 42%) as a pale yellow oil: [α]D 1.3 (c 4.35,
CHCl3); νmax film/cmϪ1 3586 m, 3418 br, 1618 s, 1579 s, 1264 s,
1088 s, 1036 s, 837 s, 776 s, 741 s; δH (270 MHz, CDCl3) 6.67
(1H, s, C10H), 6.45 (1H, s, C8H), 3.56 (2H, d, J 5.8, CH2OSi),
3.09 (1H, dquintets, J 6.0, 2.0), 2.91 (1H, dt, J 6.0, 3.0), 2.25
(3H, s), 2.08–1.87 (2H, m), 1.81 (1H, ddd, J 13.0, 5.9, 2.5), 1.75–
1.66 (2H, m), 1.53 (1H, dquintets, J 12.5, 2.5), 1.22 (3H, d, J
7.0), 0.95 (9H, s), 0.83 (3H, d, J 7), 0.10 and 0.08 (3H each, s);
δC (67.5 MHz, CDCl3) 153.2 (0), 141.1 (0), 135.4 (0), 126.4 (0),
122.70 (1), 113.4 (1), 66.65 (2), 41.1 (1), 36.9 (1), 27.3 (2), 26.65
(1), 26.2 (3), 21.3 (3), 21.23 (3), 18.9 (2), 18.5 (0), 14.2 (3), Ϫ5.13
(3), Ϫ5.2 (3).
(Mϩ , 52%), 205 (100).
ؒ
(5S,8R)-1-Methylsulfonyl-3,8-dimethyl-5-[(S)-2-(tert-butyl-
dimethylsilyloxy)-1-methylethyl]-5,6,7,8-tetrahydro-
naphthalene (20)
To a solution of alcohol 16 (0.36 g, 1.35 mmol) in DMF (2 ml)
were added imidazole (0.225 g, 3.31 mmol) and TBSCl (0.250 g,
1.66 mmol). After 1 h at rt, hexanes (5 ml) and water (5 ml) were
added. The organic phase was diluted with hexanes (25 ml) and
the organic layer washed with water and brine. The mixture was
dried over MgSO4 and concentrated in vacuo and the residue
dissolved in CH2Cl2 (10 ml). NaHCO3 (235 mg, 2.8 mmol) and
m-chloroperbenzoic acid (0.60 g, ca. 80%, 2.8 mmol) were
added and the mixture stirred at rt for 1 h whereupon water (10
ml) and saturated aqueous NaHCO3 (10 ml) were added. The
organic layer was diluted with CH2Cl2 (25 ml) and washed with
Na2S2O3 (1 M, 10 ml), NaHCO3 (10 ml) and brine (10 ml).
After drying over MgSO4, the mixture was concentrated
in vacuo and the residue purified by column chromatography
(SiO2, CH2Cl2) to give sulfone 20 (0.405 g, 0.99 mmol, 73%) as a
pale yellow oil: νmax film/cmϪ1 1471 s, 1310 s, 1265 s, 1149 s, 1088
s, 958 s, 838 s, 777 s, 739 s; δH (270 MHz, CDCl3) 7.72 (1H, s,
C8H), 7.32 (1H, s, C10H), 3.90–3.75 (1H, m), 3.54 (2H, d, J 6.2,
CH2OSi), 3.2–3.1 (1H, m), 3.06 (3H, s, SO2Me), 2.36 (3H, s,
C9Me), 2.2–2.1 (1H, m), 2.06–1.6 (4H, m), 1.26 (3H, d, J 7,
C3Me), 0.93 (9H, s, But), 0.71 (3H, d, J 7, C6Me), 0.09 (6H, s,
SiMe2); δC (67.5 MHz, CDCl3) 142.2 (0), 140.1 (0), 137.5 (0),
135.6 (0), 135.2 (1), 128.3 (1), 66.2 (2), 45.3 (3), 42.0 (1), 35.3 (1),
29.5 (1), 27.0 (2), 26.1 (3), 24.0 (3), 21.15 (3), 18.5 (0), 17.3 (2),
(2S,5R)-2-[(S)-2-(tert-Butyldimethylsilyloxy)-1-methylethyl]-6-
(1,3-dithian-2-ylidene)-5-methylcyclohexan-1-one (25)
A solution of HMDS (1.8 ml, 1.40 g, 8.7 mmol, 1.05 equiv.) in
THF (7 ml) was cooled to Ϫ78 ЊC and BuLi (1.58 M in hexanes,
5.5 ml, 8.7 mmol, 1.05 equiv.) was added slowly over 7 min. The
mixture was warmed to rt over 30 min, then the clear solution
was cooled again to Ϫ78 ЊC and DMPU (1.06 ml, 1.11 g, 8.67
mmol, 1.05 equiv.) was added dropwise over 5 min. After stir-
ring for 20 min at the same temperature, a solution of the
ketone 11 (2.35 g, 8.26 mmol) in THF (12 ml) was added drop-
wise over 10 min and the solution stirred at Ϫ78 ЊC for a further
30 min before rapid addition of CS2 (522 µl, 660 mg, 8.67 mmol,
1.05 equiv.). The orange solution was allowed to warm to
Ϫ20 ЊC over 2 h, stirred at this temperature for 90 min, and
cooled again to Ϫ78 ЊC before addition of a second portion of
LHMDS solution in THF (1.05 equiv.) prepared as above. 1,3-
Dibromopropane (885 µl, 1.75 g, 8.67 mmol, 1.05 equiv.) in
THF (28 ml) was added after 30 min, the solution was allowed
to warmed to rt over 13 h and then poured into aq. NH4Cl (60
ml). The aqueous phase was separated, extracted with Et2O
(3 × 40 ml) and the combined organic layers washed with brine
(20 ml) before drying over Na2SO4. The residue obtained on
concentration in vacuo was purified by column chromatography
(SiO2, hexanes–Et2O 4 : 1) to give the ketene-S,S-acetal 25 (2.35
g, 5.86 mmol, 71%) as a dark orange oil: [α]D ϩ14.3 (c 12,
CHCl3); νmax film/cmϪ1 2928 s, 2856 s, 1643s, 1472 s, 1418 m,
1281 m, 1255 m, 1087 s, 837 s, 775 s, 668 s; δH (300 MHz,
CDCl3) 3.40 (2H, m, AB portion of ABX system, JAB 7.1,
C3H2), 3.21 (1H, app. sextet, J 6.4, C13H), 2.98 (2H, ddd, A2
portion of A2BBЈXY system, JAB 13.9, S-CH2), 2.83 (1H, ddd,
B portion of A2BBЈXY system, JAB 13.9, JBX 7.7, JBY 7.3,
S-CHB), 2.75 (1H, ddd, BЈ portion of A2BBЈXY system, JABЈ
13.9, JBЈX 6.6, JBЈY 5.5, S-CHB), 2.43 (1H, dd, J 12.9, 6.2, C4H or
C5H), 2.35 (1H, dd, J 12.5, 6.6, C4H or C5H), 2.22–2.09 (2H,
12.6 (3), Ϫ5.2 (3), Ϫ5.1 (3); m/z (EI mode) 410 (Mϩ , 0.1%), 395
ؒ
ϩ
t
[(Mϩ Ϫ Me), 10], 353 [M Ϫ Bu ), 100].
ؒ
ؒ
(5S,8R)-5-[(S)-2-(tert-Butyldimethylsilyloxy)-1-methylethyl]-
3,8-dimethyl-1-(2-isopropylsulfonyl)-5,6,7,8-tetrahydro-
naphthalene (21)
To a solution of the methylsulfone 20 (97.5 mg, 0.24 mmol) in
THF (2.5 ml) was added LHMDS (0.61 ml, 1.0 M, 0.61 mmol)
at Ϫ50 ЊC. After 80 min, the solution was cooled to Ϫ78 ЊC
whereupon iodomethane (0.1 ml, 1.6 mmol) was added and the
mixture allowed to warm slowly to ambient temperature over
22 h. The reaction was quenched by adding saturated aqueous
NH4Cl (6 ml). The organic phase was extracted into Et2O (20
ml) and washed with HCl (2 M) and brine. After drying over
MgSO4, the mixture was concentrated in vacuo and the residue
purified by column chromatography (SiO2, hexanes–CH2Cl2
1 : 1) to give the isopropylsulfone 21 (0.105 g, 0.24 mmol, 100%)
as a colourless oil: νmax film/cmϪ1 1309 s, 1257 s, 1123 s, 1089 s,
1052 s, 837 s, 776 s, 677 s; δH (270 MHz, CDCl3) 7.66 (1H, s,
C8H), 7.31 (1H, s, C10H), 3.86–3.72 (1H, m), 3.60–3.49 (2H,
m), 3.26–3.09 (1H, m), 2.35 (3H, s, C9Me), 2.15–1.60 (6H, m),
1.34 (3H, d, J 6.8), 1.23 (3H, d, J 6.95), 1.28 (3H, d, J 6.8), 0.93
(9H, s, But), 0.69 (3H, d, J 6.95), 0.08 (6H, s, SiMe2); δC (67.5
MHz, CDCl3) 142.0 (0), 141.9 (0), 135.4 (1), 135.3 (0), 133.8 (0),
J. Chem. Soc., Perkin Trans. 1, 2001, 2356–2366
2361

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m, S-C-CH2), 2.03–1.93 (1H, m, C6H or C3H), 1.89–1.77 (1H,
m, C6H or C13H), 1.61–1.49 (1H, m), 1.46–1.34 (1H, m), 1.11
(3H, d, J 7.2, C3Me), 0.86 (9H, s, But), 0.75 (3H, d, J 6.5,
C6Me), 0.02 and 0.01 (3H each, s, SiMe2); δC (67.5 MHz,
CDCl3) 200.4 (0), 150.8 (0), 137.1 (0), 66.1 (2), 48.7 (1), 36.1 (1),
33.9 (1), 29.3 (2), 29.1 (2), 28.9 (2), 26.1 (3), 23.9 (2), 20.3 (3),
19.8 (2), 18.4 (0), 12.7 (3), Ϫ5.2 (3), Ϫ5.3 (3); Found (M ϩ H)ϩ,
401.2018; C20H36O2SiS2 requires M, 400.1926.
m), 1.11 (3H, d, J 7.0, C3Me), 0.84 (3H, d, J 7.0, C6Me); δC
(75 MHz, CDCl3) 157.4 (0), 144.8 (0), 138.6 (0), 135.3 (0), 133.4
(0), 130.0 (2C, 1), 128.7 (0), 128.1 (2C, 1), 121.9 (1), 109.1 (1),
74.3 (2), 55.3 (3), 38.1 (1), 37.4 (1), 26.8 (2), 26.5 (1), 21.8 (3),
21.6 (3), 21.5 (3), 19.0 (2), 14.1 (3); m/z (EI mode) 402 (Mϩ , 59),
ؒ
230 [(M Ϫ C7H8O3S)ϩ , 35], 215 (41), 189 (100%), 173 (38), 91
ؒ
(25); Found: C, 68.40; H, 7.7%. C23H30O4S requires C, 68.63; H,
7.51; O, 15.90; S, 7.96.
(5S,8R)-3,8-Dimethyl-5-[(S)-2-hydroxy-1-methylethyl]-1-
methoxy-5,6,7,8-tetrahydronaphthalene (27)
(4RS,5S,8R)-3,8-Dimethyl-5-[(1S)-1,5-dimethyl-3-phenylsulf-
onylhex-4-enyl]-1-methoxy-5,6,7,8-tetrahydronaphthalene (2)
To a solution of ketene-S,S-acetal 25 (4.09 g, 10.2 mmol) in
THF (120 ml) was added dropwise methylallylmagnesium
chloride [prepared from methylallyl chloride (7.03 ml, 6.46 g,
71.4 mmol, 7.0 equiv.) and Mg turnings (5.27 g, 217 mmol, 21
equiv.) in dry THF (286 ml)] over 15 min at 0 ЊC. The cooling
bath was removed and the mixture stirred at ambient temper-
ature for 90 min. The reaction mixture was poured into satur-
ated aqueous NH4Cl (200 ml), extracted with ether (3 × 40 ml)
and dried over Na2SO4. Concentration in vacuo gave alcohol 26
as a pale yellow oil (4.46 g) which was used immediately in the
next step.
To a solution of 3-methyl-1-(phenylsulfonyl)but-2-ene30 (2.78 g,
13.2 mmol, 4 equiv.) in THF (40 ml) at Ϫ78 ЊC was added BuLi
(1.58 M solution in hexanes, 8.36 ml, 13.2 mmol, 4 equiv.) over
10 min. The orange solution was warmed to Ϫ30 ЊC over 2 h,
then cooled again to Ϫ78 ЊC, and a solution of toluene-p-
sulfonate 35 (1.33 g, 3.30 mmol, 1 equiv.) in THF (24 ml) slowly
added via a cannula. The solution was allowed to warm to rt
over 4 h and then poured into vigorously stirred saturated
aqueous NH4Cl (80 ml). The product was extracted into Et2O
(3 × 50 ml), and the combined organic layers washed with brine
(25 ml) and dried over MgSO4. The residue obtained after
filtration and concentration in vacuo was purified by column
chromatography (SiO2, Et2O–hexanes 5 : 95) to give the sul-
fones 2 (1.10 g, 2.50 mmol, 76%) as a 2.5 : 1 mixture of epimers
at C14 (1H, 13C NMR). Discernible signals attributed to the
minor isomer are marked with an asterisk (*). [α]D ϩ13.2 (c 6,
CHCl3); νmax film/cmϪ1 3048 m, 2956 s, 2869 s, 1613 m, 1580 s,
1447 s, 1304 s, 1273 m, 1147 s, 1086 s, 743 s, 690 s; δH (300 MHz,
CDCl3) 7.90–7.78 (2H, m, Ph), 7.65–7.59 (1H, m, Ph), 7.58–
7.48 (2H, m, Ph), 6.51 and 6.42* (2H, s, C8H and C10H), 5.00
and 4.92* (1H, dm, J 10.3, C14H), 3.88* and 3.79 (3H, s, OMe),
3.57 (1H, dt, J 10.3, 3.3, C1H), 3.05–2.98 (1H, m), 2.56–2.52*
and 2.51–2.48 (1H, m), 2.30–2.10 (5H, m), 1.90–1.88 (1H, m,
C3H), 1.73 and 1.69* (3H, s, C16H3), 1.69 and 1.59* (2H, m),
1.52–1.46 (2H, m, C2H2), 1.19* and 1.08 (3H, d, J 1.1, C17Me),
1.13* and 1.11 (3H, d, J 7.7, C3Me), 0.80 and 0.68* (3H, d,
J 7.7, C6Me); δC (75 MHz, CDCl3) 157.2* and 157.1 (0), 142.5*
and 142.3 (0), 139.7 and 139.6* (0), 138.2 (0), 135.6 and 135.2*
(0), 135.2 (0), 133.5* and 133.4, 133.4 (1), 129.4 (2C, 1), 128.8
(2C, 1), 121.8 (1), 117.8 and 117.5* (1), 108.8* and 108.7 (1),
64.0*, 63.3 (1), 55.3 (3), 41.8* and 38.1 (1), 36.5 and 36.2* (1),
33.4* and 32.0 (2), 29.9 (1), 27.6* and 27.4 (2), 26.0 (3), 21.9 (3),
To a solution of BF3ؒOEt2 (11.1 g, 9.83 ml, 78.2 mmol, 8
equiv.) in methanol (40 ml) at Ϫ40 ЊC was added slowly crude
alcohol 26 (4.46 g) in THF (10 ml). The mixture was allowed to
warm to rt over 18 h. Saturated NaHCO3 solution (45 ml) was
added slowly and the mixture concentrated in vacuo to a slurry
which was diluted with brine (15 ml) and extracted with ether
(3 × 15 ml). The combined organic layers were dried over
Na2CO3–Na2SO4, filtered, and concentrated in vacuo. The resi-
due was purified by column chromatography (SiO2, hexanes–
Et2O 7 : 3) to give the methoxyarene 27 (1.61 g, 6.48 mmol, 63%
from 25) as a yellow oil: [α]D Ϫ25.0 (c 0.62, CHCl3); νmax film/
cmϪ1 3354 s, br (OH), 2954 s, 2869 s, 1612 s, 1579 s, 1462 s, 1373
m, 1344 m, 1272 s, 1096 s, 1029 s, 893 m, 832 m; δH (300 MHz,
CDCl3) 6.64 (1H, s, C10H), 6.53 (1H, s C8H), 3.82 (3H, s,
OMe), 3.67 (1H, dd, J 10.7, 6.6, C2H), 3.56 (1H, dd, J 10.7, 5.9,
C2H), 3.23–3.13 (1H, m), 2.84–2.74 (1H, m), 2.31 (3H, s,
C9Me), 2.12–2.04 (1H, m), 1.91–1.65 (3H, m), 1.58–1.68 (2H,
m), 1.15 (3H, d, J 6.8, C3Me), 0.89 (3H, d, J 7.0, C6Me); δC (75
MHz, CDCl3) 157.4 (0), 139.9 (0), 135.3 (0), 128.9 (0), 122.1 (1),
109.0 (1), 67.0 (2), 55.2 (3), 41.4 (1), 38.4 (1), 27.1 (2), 26.6 (1),
21.7 (3), 21.6 (3), 19.5 (2), 14.7 (3); m/z (EI mode) 248 (Mϩ , 37),
ؒ
ϩ
189 [(M Ϫ C3H7O)ϩ , 100%], 175 (26); Found M , 248.1774;
21.2 (3), 19.2 (2), 18.7 and 18.1* (3), 17.9 and 15.7* (3);
ؒ
ؒ
ϩ
m/z (EI mode) 440 (Mϩ , 29%), 299 [(M Ϫ PhSO2) , 100%],
ؒ
ؒ
C16H24O2 requires M, 248.1776.
216 [(M Ϫ C10H15SO2)ϩ ,48]; Found M , 440.2377; C27H36O3S
ϩ
ؒ
ؒ
(5R,8R)-3,8-Dimethyl-1-methoxy-5-[(S)-1-methyl-2-( p-tolyl-
sulfonyl)oxyethyl]-5,6,7,8-tetrahydronaphthalene (35)
requires M, 440.2385.
Cyclisation of the sulfones 2
To a solution of alcohol 27 (1.45 g, 5.84 mmol, 1 equiv.),
DMAP (0.78 g, 6.42 mmol, 1.1 equiv.) and NEt3 (2.04 ml, 1.48
g, 14.6 mmol, 2.5 equiv.) in CH2Cl2 (40 ml) at 0 ЊC was added
solid toluene-p-sulfonyl chloride (1.56 g, 8.18 mmol, 1.4 equiv.)
portionwise over 10 min. The cooling bath was removed and
the clear yellow solution stirred at rt for 18 h before pouring
into saturated aqueous NH4Cl (50 ml). The organic layer was
separated, the aqueous phase extracted with CH2Cl2 (3 × 25
ml). The combined organic layers were washed with HCl (2 M,
10 ml) and brine (10 ml), dried over Na2CO3–Na2SO4, filtered
and concentrated in vacuo. The residue was purified by column
chromatography (SiO2, hexanes–CH2Cl2 1 : 4) to give the
toluene-p-sulfonate 35 (2.02 g, 5.02 mmol, 86%) as colourless
needles, mp 69–70 ЊC (hexanes): [α]D ϩ22.5 (c 1.25, CHCl3);
νmax film/cmϪ1 2932 s, 2870 s, 1612 m, 1579 m, 1463 s, 1360 s,
1274 m, 1176 s, 1097 s, 965 s, 836 s, 791 s, 666 s; δH (300 MHz,
CDCl3) 7.81 and 7.36 (2H each, d, J 8.3, Ar AAЈBBЈ system),
6.51 (1H, s, C10H), 6.44 (1H, s, C8H), 3.99 (2H, apparent d,
J 5.9, C2H2), 3.82 (3H, s, OMe), 3.12–3.08 (1H, m, C13H),
2.76–2.71 (1H, m, C6H), 2.47 (3H, s, ArMe), 2.25 (3H, s,
C9Me), 2.10 (1H, m, C3H), 1.81–1.75 (2H, m), 1.58–1.44 (2H,
To a solution of sulfones 2 (264 mg, 0.6 mmol) in CH2Cl2
(15 ml) cooled to Ϫ78 ЊC was added dropwise EtAlCl2 (1 M
in hexanes, 2.4 ml, 2.4 mmol, 4 equiv.) over 5 min. The brown
solution was allowed to warm to rt overnight and then poured
into HCl (2 M, 25 ml). The product was extracted into CH2Cl2
(3 × 25 ml) and the combined organic layers washed with satur-
ated aqueous NaHCO3 (5 ml), brine (5 ml) and dried over
1
Na2SO4. After filtration and concentration in vacuo, H NMR
spectroscopic analysis of the crude reaction mixture before
chromatography revealed a 10 : 1 mixture of C1 epimers. The
isomers were isolated by column chromatography (SiO2, hex-
anes) to give (1S,3R,6R,13S)-7-methoxy-1-(2-methylprop-1-
enyl)-3,6,9-trimethyl-2,3,3a,4,5,6-hexahydro-1H-phenalene 37a
(142 mg, 0.48 mmol, 79%) as white needles, mp 95–96 ЊC
(propan-2-ol); [α]D ϩ16.8 (c 0.57, CHCl3); νmax CHCl3/cmϪ1
2923 s, 2856 s, 1593 s, 1575 s, 1464 s, 1379 m, 1320 m, 1273 m,
1216 m, 1177 m, 1101 m, 836 s; δH (300 MHz, CDCl3) 6.63
(1H, s, C8H), 5.19 (1H, dm, J 9.2, C14H), 3.86 (3H, s, OMe),
3.69–3.64 (1H, m, C1H), 3.43 (1H, app. sextet, J 7.0, C6H), 2.22
(3H, s, C9Me), 2.21–2.10 (3H, m), 1.80 (3H, d, J 1.3, C15H3),
2362
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1.73–1.60 (6H, m), 1.58–1.45 (2H, m, C4H2), 1.24 (3H, d, J 7.0,
C6Me), 1.12 (3H, d, J 5.5, C3Me); δC (75 MHz, CDCl3) 154.9
(0), 138.7 (0), 134.6 (0), 129.8 (1), 129.6 (2C, 0), 128.4 (0), 110.8
(1), 55.4 (3), 43.5 (1), 39.4 (2), 35.2 (1), 30.6 (2), 30.1 (1), 28.2
After addition of water (150 ml) and Et2O (150 ml) the aqueous
phase was separated, extracted with Et2O (2 × 60 ml) and the
organic phase washed with brine (30 ml) and dried on MgSO4.
The mixture was concentrated in vacuo and the residue purified
by column chromatography (SiO2, hexanes–Et2O 3 : 1) to give
the ketone 40 (8.13 g, 41.0 mmol, 89%) as a colourless oil: [α]D
ϩ76.3 (c 2, CHCl3); νmax film/cmϪ1 2930 s, 2870 m, 1738 s, 1715
s, 1455 m, 1371 s, 1241 s, 1204 m; δH (360 MHz, CDCl3) 4.91
(1H, td, J 11.0, 4.4, C11H), 2.55 (1H, ddd, J 10.9, 10.7, 3.8,
C13H), 2.16–2.08 (4H, m), 1.97 (3H, s, OCOMe), 1.91 (1H, dq,
J 13.4, 3.4, C5H or C4H), 1.79–1.69 (1H, m, C4H or C5H),
1.65–1.53 (1H, m, C6H), 1.33 (1H, app. dq, J 13.1, 3.6, C4H
or C5H), 1.00–0.89 (2H, m), 0.93 (3H, d, J 6.6, C6Me); δC
(90 MHz, CDCl3) 210.0 (0), 170.3 (0), 73.4 (1), 55.7 (1), 39.6 (2),
33.5 (2), 31.0 (1), 29.2 (3), 27.9 (2), 22.0 (3), 21.3 (3); Found
(MH)ϩ, 199.1332; C11H19O3 requires M, 199.1334.
(2), 26.6 (1), 25.9 (3), 23.3 (3), 21.3 (3), 19.7 (3), 17.8 (3);
ϩ
m/z (EI mode) 298 (Mϩ , 87), 283 [(M Ϫ CH3) , 100%],
ؒ
ؒ
242 [(M Ϫ C4H8)ϩ , 30], 227 [(M Ϫ C5H11) , 33]; Found M
,
ϩ
ϩ
ؒ
ؒ
ؒ
298.2295; C21H30O requires M, 298.2297.
A small amount of the minor isomer 37b was obtained
sufficiently pure (ca. 90%) to allow the following assignments:
δH (300 MHz, CDCl3) 6.60 (1H, s, C8H), 4.99 (1H, dm, J 9.6,
C14H), 3.86 (3H, s, OMe), 3.78–3.72 (1H, m, C1H), 3.43 (1H,
app. sextet, J 7.0, C6H), 2.23 (3H, s, C9Me), 2.21–2.10 (3H, m),
1.77 (3H, d, J 1.5, C15Me), 1.73–1.60 (6H, m), 1.58–1.45 (2H,
m, C4H2), 1.26 (3H, d, J 6.6, C6Me), 1.08 (3H, d, J 5.9, C3Me);
δC (75 MHz, CDCl3) 155.6 (0), 140.7 (0), 135.1 (0), 131.3 (1),
130.0 (0) 129.8 (0), 127.9 (0), 111.1 (1), 55.2 (3), 45.0 (1), 40.2
(2), 36.7 (1), 34.2 (2), 31.9 (1), 28.3 (2), 27.8 (1), 25.6 (3), 23.8
(3), 20.8 (3), 20.3 (3), 17.7 (3).
Ethyl 3-[(1R,2S,4S)-2-acetoxy-4-methyl-1-cyclohexyl]but-2-
enoate (41)
NaH (60% suspension in mineral oil, 706 mg, 17.6 mmol, 3.5
equiv.) was washed with dry hexane to remove the oil, sus-
pended in dry THF (25 ml) and cooled to 0 ЊC in an ice bath.
Triethyl phosphonoacetate (4.0 ml, 4.52 g, 20.2 mmol, 4 equiv.)
was slowly added over 35 min. The ice bath was removed and
the clear solution stirred at rt for 20 min before addition via a
cannula to a solution of ketone 40 (1.00 g, 5.04 mmol) in dry
THF (25 ml). The solution was heated at reflux for 12 h, then
poured into water (50 ml). The aqueous phase was extracted
with ether (3 × 25 ml) and dried on MgSO4. The solvent was
removed in vacuo and the residue purified by column chrom-
atography (SiO2, hexanes–ether 9 : 1) to give the α,β-unsatur-
ated ester 41 (872 mg, 3.22 mmol, 64%) as a yellow oil: [α]D
Ϫ3.4 (c 2, CHCl3). The compound was obtained as 9 : 1 mix-
ture of isomers. The stereochemistry of the major product was
confirmed by NOE experiments. νmax film/cmϪ1 2930, 2870 m,
1736 s, 1646 s, 1453 m, 1373 s, 1242 s, 1154 s, 1027 s, 868 s; δH
(360 MHz, CDCl3) 5.66 (1H, d, J 1.3, C2H), 4.83 (1H, dt,
J 10.8, 4.4, C11), 4.11 (2H, q, J 7.2, CH2CH3), 2.18–2.08 (1H,
m, C13H), 2.06 (3H, d, J 1.1, C3Me), 2.04–1.92 (4H, m,
C12H ϩ COOMe), 1.76–1.64 (2H, m), 1.61–1.35 (2H, m), 1.23
(3H, t, J 7.2, CH2CH3), 1.1–0.85 (1H, m), 0.98–0.80 (1H, m),
0.90 (3H, d, J 6.6, C6Me); δC (75 MHz, CDCl3) 170.5 (0), 166.8
(0), 160.0 (0), 117.3 (1), 73.2 (2), 59.7 (2), 53.4 (1), 40.3 (2), 33.9
(2), 31.3 (1), 30.1 (2), 22.0 (3), 21.2 (3), 16.0 (3), 14.4 (3); Found
(M ϩ H)ϩ, 269.1769; C15H25O4 requires M, 269.1753.
(1S,3R,6R,13S)-7-Hydroxy-1-(2-methylprop-1-enyl)-3,6,9-
trimethyl-2,3,3a,4,5,6-hexahydro-1H-phenalene (38)
A suspension of NaH (121 mg, 5 mmol, 20 equiv.) in dry DMF
(2 ml) was added EtSH (311 mg, 0.37 ml, 5 mmol, 20 equiv.)
in DMF (0.37 ml) at a rate sufficient to maintain slow gas
evolution at 0 ЊC. After 30 min from the end of the addition, a
solution of methoxyarene 37a (75 mg, 0.25 mmol) in dry DMF
(4 ml) was added via a cannula. The clear yellow solution was
heated at 155 ЊC for 16 h before cooling to rt, diluting with Et2O
and pouring into saturated aqueous NH4Cl (10 ml). After
extraction of the aqueous phase with Et2O (2 × 10 ml), and
drying of the organic phase over Na2SO4, the solvent was
removed in vacuo and column chromatography of the residue
(SiO2, hexanes–Et2O 4 : 1) gave the phenol 38 (56 mg, 0.197
mmol, 78%) as a colourless oil.
A more expensive procedure which avoids the obnoxious
smell of ethanethiol entailed dropwise addition of BBr3 (1.0 M
solution in CH2Cl2, 2.46 ml, 2.46 mmol, 2 equiv.) to methoxy-
arene 37a (366 mg, 1.23 mmol) and freshly distilled 2,6-di-
tert-butyl-4-methylpyridine (303 mg, 1.48 mmol, 1.2 equiv.) in
CH2Cl2 (15 ml). The brown suspension was stirred for 30 min,
whereupon the mixture was poured into H2O (50 ml), extracted
with Et2O (3 × 25 ml) and dried over Na2CO3–Na2SO4. The
mixture was filtered, concentrated in vacuo, and the residue
purified by column chromatography (SiO2, hexanes hexanes–
Et2O 95 : 5) to give the phenol 38 (270 mg, 0.95 mmol, 77%) as
a pale yellow oil: [α]D ϩ14.5 (c 0.5, CHCl3); νmax CHCl3/cmϪ1
3406 br (OH), 2922 s, 2868 s, 1585 s, 1455 s, 1096 m, 1043 m,
909 s, 843 s, 735 s; δH (300 MHz, CDCl3) 6.49 (1H, s, C8H), 5.15
(1H, dm, J 8.0, C14H), 5.05 (1H, s, OH), 3.61–3.58 (1H, m,
C1H), 3.32–3.28 (1H, app. sextet, J 7.0, C6H), 2.24–2.08 (6H,
m), 1.81 (3H, s, C16H3), 1.75–1.72 (5H, m), 1.60–1.42 (3H, m),
1.24 (3H, d, J 7.0, C6Me), 1.10 (3H, d, J 5.8, C3Me); δC (75
MHz, CDCl3) 151.0 (0), 139.0 (0), 135.0 (0), 130.0 (2 C, 0 and
1), 129.7 (0), 126.0 (0), 115.4 (1), 43.6 (1), 39.3 (2), 35.1 (1), 30.8
(2), 29.9 (1), 28.1 (2), 26.9 (1), 25.8 (3), 23.1 (3), 21.1 (3), 19.1
(3), 17.7 (3); m/z (CI mode, NH3) 285 [(M ϩ H)ϩ, 100%], 134
Data for the minor isomer: δH (270 MHz, CDCl3) 5.65 (1H, s,
C2H), 4.82 (1H, dt, J 10.6, 4.4, C11H), 4.15 (2H, q, J 7.1,
CH2CH3), 2.18–2.08 (1H, m, C13H), 2.06 (3H, d, J 1.1, C3Me),
2.04–1.92 (4H, m, C12H ϩ COMe), 1.76–1.64 (2H, m), 1.61–
1.35 (2H, m), 1.28 (3H, t, J 7.1, CH3CH2), 1.05–0.80 (2H, m),
0.92 (3H, d, J 6.6, C6Me); δC (75 MHz, CDCl3) 170.7 (0), 166.2
(0), 160.0 (0), 118.5 (1), 73.3 (1), 59.7 (2), 53.4 (1), 43.8 (2), 33.8
(2), 31.4 (1), 29.5 (2), 22.0 (3), 20.4 (3), 15.3 (3), 14.4 (3).
(3S)-Ethyl 3-[(1R,2S,4S)-2-acetoxy-4-methyl-1-cyclohexyl]-
butanoate (43)
In a flask fitted with a vacuum-tight Teflon stopper, a solution
of the α,β-unsaturated ester 41 (670 mg, 2.5 mmol) in ethanol
(1.0 ml) under N2 was treated successively with CoCl2ؒ6H2O
(42 mg, 0.175 mmol, 0.07 equiv.) in EtOH (0.27 ml) and semi-
corrin ligand 4219,31 (93 mg, 0.2 mmol, 0.08 equiv.) in EtOH
(0.52 ml) causing the colour to turn from blue–violet to dark
blue. A solution of NaBH4 (189 mg, 5.0 mmol, 2 equiv.) in
DMF (1.5 ml) was then added whereupon the colour changed
to brown. The suspension was then degassed at 0.01 mmHg by
repeated (6) freeze–thaw cycles. The reaction mixture was
stirred at 25 ЊC for 6 days in the vacuum-sealed flask, then water
(10 ml) was added and the mixture extracted with CH2Cl2
(4 × 15 ml). The combined organic extracts were washed with
(65), 35 (48); Found Mϩ , 284.2141; C20H28O requires M,
ؒ
284.2140.
(1S,2S,5S)-1-Acetoxy-2-acetyl-5-methylcyclohexane (40)
(ϩ)-Isopulegyl acetate 39 [9.15 g, 46.1 mmol, [α]D ϩ17.3 (c 2,
CHCl3)] prepared from (ϩ)-isopulegol18 was dissolved in dry
methanol (75 ml) and dry CH2Cl2 (25 ml), cooled to Ϫ78 ЊC
and O3 was bubbled through the solution until the formation of
a persistent blue colour. The mixture was flushed with N2 for
15 min at Ϫ78 ЊC before addition of SMe2 (16.8 ml, 14.3 g,
230.5 mmol, 5 equiv.). The solution was allowed to warm to rt
over 10 h and the solvent was removed under reduced pressure.
J. Chem. Soc., Perkin Trans. 1, 2001, 2356–2366
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H2O (15 ml) and dried over Na2SO4. After evaporation of the
solvent in vacuo, the residue was purified by column chrom-
atography (SiO2, hexanes–Et2O 4 : 1) to give the diester 43 (592
mg, 2.2 mol, 90%) as a colourless oil: [α]D ϩ35.7 (c 2.5, CHCl3);
νmax film/cmϪ1 2953 s, 2929 s, 2870 s, 1735 s, 1373 m, 1244 s, 1184
m, 1027 m; δH(300 MHz, CDCl3) 4.63 (1H, dt, J 10.7, 4.4,
C11H), 4.10 (2H, q, J 7.0, CH2CH3), 2.36 (1H, dd, J 14.9, 4.2,
C5H), 2.27–2.19 (1H, m, C6H), 2.05 (3H, s, COCH3), 2.03–1.93
(2H, m), 1.76–1.64 (2H, m), 1.53–1.40 (2H, m), 1.24 (3H, t,
J 7.0, CH3CH2), 1.02–0.82 (3H, m), 0.93 (3H, d, J 7.0, C6Me
or C3Me), 0.90 (3H, d, J 6.6, C6Me or C3Me); δC (75 MHz,
CDCl3) 173.8 (0), 170.8 (0), 73.6 (1), 60.6 (2), 46.6 (1), 40.7 (2),
37.5 (2), 34.4 (2), 31.4 (1), 29.3 (1), 25.8 (2), 22.9 (3), 21.4 (3),
17.6 (3), 14.4 (3); Found (M ϩ H)ϩ, 271.1926; C15H27O4
requires M, 271.1909.
The combined organic phases were washed with HCl (1.5 M,
30 ml) followed by brine (20 ml). The residue obtained on con-
centration in vacuo was purified by column chromatography
(SiO2, hexanes–Et2O (95 : 5)) to give the ketone 45 (5.13 g, 17.2
mmol, 80%) as a pale yellow oil: [α]D ϩ27.6 (c 1.1, CHCl3); νmax
film/cmϪ1 2928 s, 2858 s, 1712 s, 1462 s, 1255 s, 1104 s, 836 s, 775
s; δH (360 MHz, CDCl3) 3.68–3.56 (2H, m, C2H2), 2.30 (1H,
ddd, J 12.9, 3.7, 2.2, C13H), 2.15–2.09 (1H, m), 2.06–1.77 (5H,
m), 1.64–1.56 (1H, m), 1.43 (1H, dq, J 12.6, 3.0, C3H), 1.33–
1.22 (2H, m), 0.98 (3H, d, J 6.3, C6Me or C3Me), 0.90 (3H, d,
J 6.9, C6Me or C3Me), 0.86 (9H, s, t-Bu), 0.03 and 0.02 (3H
each, s, SiMe2); δC (90 MHz, CDCl3) 211.9 (0), 62.1 (1), 55.2 (2),
51.0 (2), 36.4 (2), 35.3 (1), 34.1 (2), 28.6 (2), 28.4 (1), 26.1 (3,
3C), 22.4 (3), 18.4 (0), 17.7 (3), Ϫ5.2 (3, 2C); m/z (CI mode,
NH3) 316 [(M ϩ NH4)ϩ, 15], 299 [(M ϩ H)ϩ, 100%], 241
[(M Ϫ C4H9)ϩ, 15]; Found (M ϩ H)ϩ, 299.2416; C17H35O2Si
requires M, 299.2406.
(1S,2R,5S)-2-[(S)-3-Hydroxy-1-methylpropyl]-5-methylcyclo-
hexan-1-ol (44)
(2R,5S)-2-[(R)-3-(tert-Butyldimethylsilyloxy)-1-methylpropyl]-
Diester 43 (0.56 g, 2.08 mmol) was dissolved in dry CH2Cl2
(15 ml) and cooled to Ϫ70 ЊC. A 1.0 M solution of DIBAL-H
in hexanes (11.3 ml, 11.3 mmol, 4.5 equiv.) was added dropwise
over 15 min and the solution allowed to warm to 0 ЊC over 1 h.
The mixture was then poured into an ice cold solution of
sodium potassium tartrate (10.5 g, 3.3 equiv. with respect to
DIBAL-H) in water (15 ml) and CH2Cl2 (5 ml) and vigorously
stirred for 1 h. The aqueous layer was separated and extracted
with CH2Cl2 (3 × 10 ml), the combined organic extracts washed
with brine (5 ml) and dried over Na2SO4. The solvent was
removed in vacuo and the residue purified by column chrom-
atography (SiO2, EtOAc–CH2Cl2 7 : 3) to give the diol 44 (0.29
g after recrystallisation from hexanes, 1.56 mmol, 75%) as a
white crystalline solid, mp 93–94 ЊC: [α]D ϩ75.2 (c 0.5, CHCl3);
νmax CHCl3/cmϪ1 3265 br s, 2923 s, 2868 s, 1455 m, 1216 m, 1033
m, 758 s; δH (300 MHz, CDCl3) 3.77 (1H, ddd, J 10.6, 5.9, 4.6,
C1HAHB), 3.77 (1H, app. dt, J 9.9, 5.1, C1HAHB), 3.48 (1H, dt,
J 10.4, 4.6, C11H), 2.90–2.50 (2H, br s, OH), 2.22–2.09 (1H, m,
C6H), 2.01–1.95 (1H, m, C12H), 1.78–1.62 (3H, m), 1.50–1.38
(1H, m, C2HAHB), 1.29–1.12 (2H, m), 1.08–0.80 (3H, m), 0.95
(3H, d, J 7.0, C6Me or C3Me), 0.92 (3H, d, J 6.2, C6Me or
C3Me); δC (90 MHz, CDCl3) 71.0 (1), 61.4 (2), 50.5 (1), 44.7 (2),
34.8 (2), 33.7 (2), 31.9 (1), 27.7 (1), 24.2 (2), 22.4 (3), 18.4 (3);
Found: C, 70.98; H, 11.75%. C11H22O2 requires C, 70.92; H,
11.90; O, 17.18.
5-methyl-6-(1,3-dithian-2-ylidene)cyclohexan-1-one (46)
A solution of HMDS (4.30 ml, 3.33 g, 20.6 mmol, 1.1 equiv.) in
THF (25 ml) was cooled to Ϫ78 ЊC and BuLi (1.38 M in hex-
anes, 14.9 ml, 20.6 mmol, 1.1 equiv.) was added slowly over
10 min. The mixture was warmed to rt over 30 min, then the
clear solution was cooled again to Ϫ78 ЊC and DMPU (2.5 ml,
2.6 g, 20.6 mmol, 1.1 equiv.) was added dropwise over 5 min.
After stirring for 20 min at the same temperature, a solution
of ketone 45 (5.6 g, 18.8 mmol) in THF (20 ml) was added
dropwise over 10 min and the solution stirred at Ϫ78 ЊC for a
further 30 min before rapid addition of CS2 (1.24 ml, 1.57 g,
20.6 mmol, 1.1 equiv.). The orange solution was allowed to
warm to Ϫ20 ЊC over 2 h, stirred at this temperature for 90 min,
and cooled again to Ϫ78 ЊC before addition of a second portion
of LHMDS solution in THF (1.05 equiv.) prepared as above.
1,3-Dibromopropane (885 µl, 1.75 g, 8.67 mmol, 1.05 equiv.) in
THF (28 ml) was added after 30 min at the same temperature,
whereupon the solution was warmed to rt over 16 h and then
poured into saturated aqueous NH4Cl (80 ml). The aqueous
phase was separated, extracted with Et2O (3 × 40 ml) and the
combined organic layers washed with brine (30 ml) before dry-
ing over Na2SO4. The residue obtained after concentration in
vacuo was purified by column chromatography (SiO2, hexanes–
Et2O 4 : 1) to give the ketene-S,S-acetal 46 (3.92 g, 9.45 mmol,
50%) as a dark orange oil: [α]D Ϫ46.2 (c 1.1, CHCl3); νmax film/
cmϪ1 2928 s, 2857 s, 1644 m, 1471 s, 1283 m, 1255 s, 1093 s, 836
s, 775 s; δH (360 MHz, CDCl3) 3.64–3.50 (2H, m, C1H2), 3.18
(1H, app. sextet, J 6.4, C13H), 3.01 (2H, AAЈ part of an
AAЈBBЈXY system, JAB 13.8, JAЈB 13.8, SCH2), 2.91 (1H, ddd,
B part of an AAЈBBЈXY system, JAB 13.8, JBX 8.6, JBY 7.2,
SCH2), 2.71 (1H, ddd, BЈ part of an AAЈBBЈXY system, JAB
13.8, JBX 6.6, JBY 4.8, SCH), 2.19–2.10 (2H, m, SCH2CH2),
2.04–1.96 (1H, m), 1.90–1.71 (1H, m), 1.67–1.54 (3H, m), 1.42–
1.24 (2H, m), 1.10 (3H, d, J 6.9, C3Me), 0.90–0.36 (13H, m),
0.03 and 0.02 (3H each, s, SiMe2); δC (90 MHz, CDCl3) 200.6
(01), 150.0 (0), 137.4 (0), 61.9 (2), 53.5 (1), 36.7 (2), 34.2 (1), 31.1
(1), 29.1 (2), 28.8 (2), 26.1 (3, 3C), 23.9 (2), 22.7 (2), 21.3 (2),
20.2 (3), 18.4 (0), 18.0 (3), Ϫ5.1 (3, 2C); m/z (ESIϩ mode,
CH3CN) 846 [(2M ϩ NH4)ϩ, 82], 415 [(M ϩ H)ϩ, 100]; Found
(M ϩ H)ϩ, 415.2141; C21H39O2S2Si requires M, 415.2161.
(1S,2S,5R)-2-[(R)-3-(tert-Butyldimethylsilyloxy)-1-methyl-
propyl]-5-methylcyclohexan-1-one (45)
Diol 44 (4.2 g, 22.5 mmol) and imidazole (3.52 g, 51.7 mmol,
2.3 equiv.) were dissolved in dry DMF (35 ml) and solid tert-
butyldimethylsilyl chloride (3.74 g, 24.8 mmol, 1.1 equiv.) was
then added. After 15 min, the reaction mixture was poured into
saturated aqueous NH4Cl (40 ml) and the product extracted
into hexanes (3 × 30 ml). The organic layer was washed with
brine (5 ml), dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography (SiO2, Et2O–
hexanes 1 : 25) to give (1S,2S,5R)-2-[(R)-3-(3-tert-butyldimethyl-
silyloxy)-1-methylpropyl]-5-methylcyclohexan-1-ol (6.42 g, 21.5
mmol, 95%) as a colourless oil which was used in the next step
without further purification.
DMSO (4.36 g, 3.96 ml, 55.8 mmol, 2.6 equiv.) in CH2Cl2
(15 ml) was added dropwise to a solution of oxalyl chloride
(3.54 g, 2.40 ml, 27.9 mmol, 1.3 equiv.) in dry CH2Cl2 (80 ml)
at Ϫ72 ЊC over 10 min. After 20 min, the crude (1S,2S,5R)-2-
[(R)-3-(3-tert-butyldimethylsilyloxy)-1-methylpropyl]-5-methyl-
cyclohexan-1-ol (6.42 g, ca. 21,5 mmol) in CH2Cl2 (35 ml)
was slowly added over 4 min at Ϫ65 ЊC. After 90 min stirring
at Ϫ65 ЊC, Et3N (8.90 g, 12.3 ml, 88.0 mmol, 4.1 equiv.) was
added over 8 min and mixture allowed to warm to over 2 h. The
white suspension was poured into vigorously stirred saturated
aqueous NH4Cl (50 ml) and extracted into hexanes (3 × 40 ml).
(5R,8S)-3,8-Dimethyl-5-[(R)-3-hydroxy-1-methylpropyl]-1-
methoxy-5,6,7,8-tetrahydronaphthalene (47)
To a solution of ketene-S,S-acetal 46 (3.90 g, 9.4 mmol) in THF
(100 ml) was added methylallylmagnesium chloride [prepared
from methylallyl chloride (7.4 ml, 6.8 g, 75.2 mmol, 8.0 equiv.)
and Mg turnings (5.4 g, 226 mmol, 24 equiv.) in dry THF
(320 ml)] over 15 min at 0 ЊC via a cannula. The cooling bath
was removed and the mixture stirred at rt for 2 h. The reaction
mixture was poured into saturated aqueous NH4Cl (400 ml),
2364
J. Chem. Soc., Perkin Trans. 1, 2001, 2356–2366

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extracted with ether (3 × 80 ml) and dried over Na2SO4. Con-
centration in vacuo gave a pale yellow oil (4.80 g) which was
dissolved in THF (40 ml) and added slowly to a solution of
BF3ؒOEt2 (13.3 g, 11.6 ml, 94 mmol, 10 equiv.) in methanol
(40 ml) at Ϫ40 ЊC. The mixture was allowed to warm to rt over
18 h. Saturated aqueous NaHCO3 (60 ml) was added slowly and
the mixture concentrated in vacuo to a slurry which was diluted
with brine (40 ml) and extracted with ether (3 × 45 ml). The
combined organic layers were dried over Na2CO3–Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography (SiO2, hexanes–Et2O 7 : 3) to give the
methoxyarene 47 (1.12 g, 4.27 mmol, 45% over the two steps) as
a pale yellow oil: [α]D ϩ32.9 (c 3.0, CHCl3). The compound was
contaminated with impurities (ca. 8%) that could not be
removed by column chromatography.
extracts were washed with brine (2 ml) and dried over Na2SO4
before removal of the solvent in vacuo and column chrom-
atography of the residue (SiO2, hexanes–NEt2O 4 : 1 1 : 1).
The title alcohol 49 (150 mg, 0.47 mmol, 80%) was obtained as
1
a 2 : 1 mixture of epimers by H and 13C NMR spectroscopy.
Discernible signals attributed to the minor isomer are marked
with an asterisk (*).
νmax film/cmϪ1 3360 br (OH), 2927 s, 2863 s, 1612 s, 1580 s,
1462 s, 1416 s, 1370 m, 1344 m, 1271 s, 1097 s, 1043 s, 1016 s, 820
m, 800; δH (360 MHz, CDCl3) 6.66 and 6.60* (1H, s, C10H),
6.51 (1H, s, C8H), 5.09 (0.67H, dt, J 8.5, 1.4, C14H), 4.86*
(0.33H, dt, J 9.0, 1.4, C14H), 4.34–4.26 (1H, m, C1H), 3.82
(3H, s, OMe), 3.17–3.14 (1H, m), 2.69–2.60 (1H, m), 2.31 (3H,
s, C9Me), 2.23–2.18 (1H, m), 1.94–1.86 (2H, m), 1.78–1.73 (2H,
m), 1.72* and 1.69 (3H, d, J 1.2, C16H3 or C17H3), 1.67* and
1.66 (3H, d, J 1.2, C16H3 or C17H3), 1.50–1.43 and 1.40–1.33*
(2H, m), 1.15 (3H, d, J 6.9, C3Me), 1.05 and 1.03* (3H, d,
J 6.8, C6Me); δC (90 MHz, CDCl3) 157.2 (0), 140.3* and
140.2 (0), 135.7 and 135.1 (0), 135.0 (0), 131.3 (0), 129.0 and
128.3* (1), 122.1 and 121.0* (1), 108.7 (1), 67.7* and 67.0 (1),
55.3 (3), 42.4 (1), 41.8 and 41.4* (2), 35.3* and 34.9 (1), 27.8*
and 27.7 (2), 26.6 (1), 26.0* and 25.9 (3), 21.8 (3), 21.5 (3), 19.7
νmax film/cmϪ1 3361 s, br, 2933 s, 2869 s, 1612 m, 1579 m, 1462
s, 1272 s, 1098 s, 1055 m, 832 m, 787 s, 764 m; δH (300 MHz,
CDCl3) 6.66 (1H, s, C10H), 6.53 (1H, s, C8H), 3.83 (3H, s,
OMe), 3.64–3.56 (1H, A portion of an ABXY system, JAB 10.5,
JBY 8.2, JAY 5.1, C3HA), 3.50–3.42 (1H, B portion of an ABXY
system, JAB 10.5, JBX, JBY 7.3, C3HB), 3.20–3.17 (1H, m), 2.73–
2.62 (1H, m), 2.33 (3H, s, C9Me), 2.22–1.70 (4H, m), 1.65–1.49
(2H, m), 1.41–1.28 (2H, m), 1.18 (3H, d, J 7.0, C3Me), 1.04
(3H, d, J 7.0, C6Me); δC (75 MHz, CDCl3) 157.1 (1), 140.1 (0),
135.0 (0), 128.8 (0), 121.9 (1), 108.6 (1), 61.8 (2), 55.1 (3),
42.2 (1), 36.4 (2), 35.4 (1), 27.5 (2), 26.5 (1), 21.7 (3), 21.4 (3),
19.2 (3), 18.9 (2); Found Mϩ, 263.2028; C17H27O2 requires M,
263.2011.
and 19.3* (3), 19.2* and 19.0 (2), 18.3* and 18.2 (3); m/z
ϩ
(EI mode) 298 [(M Ϫ H2O)ϩ , 8], 216 [(M Ϫ C6H12O) , 67],
ؒ
ؒ
189 [(M Ϫ C8H15O)ϩ , 100]; Found M , 316.2402; C21H32O2
ϩ
ؒ
ؒ
requires M, 316.2402.
(2ЈR,5R,8S)-3,8-Dimethyl-5-(1,5-dimethyl-3-phenylsulfonylhex-
4-enyl)-1-methoxy-5,6,7,8-tetrahydronaphthalene (5)
(5R,8S)-3,8-Dimethyl-5-[(R)-3-oxo-1-methylpropyl]-1-methoxy-
Solid PhSO2Na (579 mg, 3.52 mmol, 7.5 equiv.) was added to a
solution of allylic alcohol 49 (150 mg, 0.47 mmol) in propan-2-
ol (5 ml). Glacial AcOH (0.5 ml) was added dropwise over
2 min and the suspension stirred for 30 min at rt until all the
solid had dissolved whereupon the mixture was heated at reflux
for 16 h. The pale yellow solution was then allowed to cool to
rt, diluted with EtOAc (6 ml) and neutralised with saturated
aqueous NaHCO3 (5 ml). The aqueous layer was extracted with
EtOAc (2 × 5 ml) and the organic phases dried over MgSO4
before concentrating in vacuo. The residue was purified by
column chromatography (SiO2, hexanes–Et2O 1 : 1) to afford
the title sulfones 5 (0.132 g, 0.3 mmol, 64%) as a 2 : 1 mixture of
epimers giving 1H and 13C NMR spectroscopic data consistent
with those reported for the enantiomers 2.
5,6,7,8-tetrahydronaphthalene (48)
DMSO (204 mg, 0.19 ml, 2.6 mmol, 2.6 equiv.) in CH2Cl2
(0.5 ml) was added dropwise to a solution of oxalyl chloride
(166 mg, 0.112 ml, 1.31 mmol, 1.3 equiv.) in dry CH2Cl2 (1.5 ml)
at Ϫ70 ЊC over 5 min. After 20 min alcohol 47 (262 mg,
1.0 mmol) in CH2Cl2 (2.6 ml) was slowly added over 4 min
at Ϫ65 ЊC. After 90 min stirring at Ϫ65 ЊC, Et3N (417 mg,
0.575 ml, 4.12 mmol, 4.1 equiv.) was added over 8 min and the
mixture was allowed to warm to rt over 2 h. The white suspen-
sion was poured into vigorously stirred saturated aqueous
NH4Cl (10 ml) and extracted into hexanes (3 × 10 ml). The
combined organic phases were washed with HCl (2 M, 3 ml)
followed by brine (2 ml). The solvent was removed in vacuo and
the residue purified by column chromatography (SiO2, hexanes–
Et2O 95 : 5); to give the aldehyde 48 (230 mg, 0.88 mmol, 88%)
as a pale yellow oil: [α]D ϩ32.9 (c 3.0, CHCl3); νmax film/cmϪ1
2928 s, 2870 s, 1725 s, 1612 m, 1579 m, 1463 s, 1273 s, 1098 s, 833
m, 733 m; δH (300 MHz, CDCl3) 9.57 (1H, dd, J 3.1, 1.2, CHO),
6.65 (1H, s, C10H), 6.53 (1H, s, C8H), 3.82 (3H, s, OMe), 3.20–
3.12 (1H, m), 2.74–2.69 (1H, m), 2.64–2.57 (1H, m), 2.34–2.29
(4H, m), 2.17 (1H, ddd, J 16.0, 10.3, 3.1, C2H), 1.97–1.68 (3H,
m), 1.58–1.49 (1H, m), 1.14 (3H, d, J 6.9, C3H), 1.08 (3H, d, J
6.8, C6Me); δC (75 MHz, CDCl3) 203.2 (0), 157.3 (0), 139.2 (0),
135.6 (0), 129.0 (0), 121.9 (1), 109.1 (1), 55.3 (3), 48.0 (2), 41.5
(1R,3S,6S,13R)-7-Methoxy-1-(2-methylprop-1-enyl)-3,6,9-
trimethyl-2,3,3a,4,5,6-hexahydro-1H-phenalene (50)
A mixture of sulfones 5 (110 mg, 0.25 mmol) in CH2Cl2 (10 ml)
was treated with EtAlCl2 (1 M in hexanes, 1.0 ml, 1.0 mmol) as
described above for the synthesis of the enantiomer 37a. The
crude product was purified by column chromatography (SiO2,
hexanes) followed by crystallisation from propan-2-ol to give
the title compound 50 (56 mg, 0.19 mmol, 75%) as white
needles, mp 92–95 ЊC; [α]D Ϫ17.0 (c 0.6, CHCl3). Compound 50
1
was identical by H and 13C NMR spectroscopy with the data
(1), 33.9 (1), 27.5 (2), 26.5 (1), 21.8 (3), 21.4 (3), 19.6 (3), 18.8
reported for the enantiomer 37a. The relative configuration
(Fig. 1) was established by X-ray diffraction on a Rigaku
AFC7S diffractometer using Mo X-rays.
(2); m/z (EI mode) 260 (Mϩ , 22), 216 [(M Ϫ C2H4O) , 16], 189
ϩ
ؒ
ؒ
ϩ
[(M Ϫ C4H7O)ϩ ,100]; Found M , 260.1781; C17H24O2 requires
ؒ
ؒ
M, 260.1776.
Crystal data† C21H30O, M = 298.47, monoclinic, a =
10.653(5), b = 9.082(7), c = 18.57(1) Å, β = 101.27(5)Њ, U =
1762(1) Å3, T = 150 K, space group P21/c, Z = 4, µ(Mo-Kα)
(2ЈR,5R,8S)-1-Methoxy-3,8-dimethyl-5-(1,5-dimethyl-3-
hydroxyhex-4-enyl)-5,6,7,8-tetrahydronaphthalene (49)
0.066 mmϪ1
, 3083 reflections measured, 2894 unique,
To a solution of aldehyde 48 (153 mg, 0.59 mmol) in dry THF
(2 ml) at 0 ЊC was added 2-methylprop-1-enylmagnesium chlor-
ide prepared from 1-bromo-2-methylprop-1-ene (398 mg, 2.95
mmol, 5 equiv.) and Mg turnings (142 mg, 5.9 mmol, 10 equiv.)
in dry THF (2 ml) via a cannula over 5 min. The clear solution
was allowed to warm to rt and stirred over 2 h; then saturated
aqueous NH4Cl (5 ml) was added and the aqueous phase separ-
ated and extracted with Et2O (3 × 5 ml). The combined organic
Rint = 0.041. Refinement on F using 1481 reflections with I > 2.5
σ(I ) gave R = 0.061. Data were processed using the TeXsan
Crystal Structure Analysis Package, Molecular4 Structure
Corporation, New Trails Drive, The Woodlands, Texas 77381,
USA, 1985 and 1992.
† CCDC reference number 144022.
J. Chem. Soc., Perkin Trans. 1, 2001, 2356–2366
2365

View Online
scholarship (A. P.) and Dr Andrew Kohler and Dr Simon Gill
for crucial preliminary experiments.
References
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Verlag, Berlin Heidelberg, 1989, pp. 198–448.
Fig. 1 Molecular drawing of 50 showing the atom numbering and
50% probability ellipsoids for non-hydrogen atoms.
(1R,3S,6S,13R)-7,8-Dihydroxy-1-[2-methylprop-1-enyl]-3,6,9-
trimethyl-2,3,3a,4,5,6-hexahydro-1H-phenalene
(pseudopterosins A–F aglycone) (6)
Compound 50 was converted to pseudopterosins A–F aglycone
6 by a 2-step procedure identical to that described above for the
synthesis of the enantiomer. The catechol 6 was obtained as a
1
yellow oil: [α]D ϩ30.5 (c 0.3, CHCl3). IR and H NMR data
are in agreement with those reported by Carpino32 and
McCombie:33 νmax film/cmϪ1 3449 br (OH), 2923 s, 2857 s, 1446
s, 1374 m, 1295 s, 1189 m, 1106 m, 1041 m, 810 m; δH (360 MHz,
CDCl3) 5.12 (1H, d, J 9.1, C14H), 5.07 (1H, br s, OH), 4.87
(1H, br s, OH), 3.62–3.55 (1H, m, C1H), 3.23 (1H, app. sextet,
J 7.3, C6H), 2.25–2.13 (3H, m, C5H2 and C13H), 2.04 (3H, s,
C9Me), 1.76 (3H, s, C16H3), 1.70 (3H, s, C17H3), 1.71–1.41
(4H, m), 1.26 (3H, d, J 7.1, C6Me), 1.31–1.20 (1H, m, C3H),
1.05 (3H, d, J 6.1, C3Me); δC (90 MHz, CDCl3) 140.0 (0), 139.9
(0), 130.4 (1), 130.3 (0), 130.0 (0), 126.0 (0), 125.7 (0), 120.0 (0),
43.3 (1), 39.7 (2), 35.5 (1), 31.1 (2), 30.1 (1), 28.4 (2), 27.5 (1),
25.8 (3), 23.2 (3), 21.2 (3), 17.8 (3), 11.0 (3); m/z (EI mode) 300
20 A. Pfaltz, Acc. Chem. Res., 1993, 26, 339.
21 C. A. Broka, S. Chan and B. Peterson, J. Org. Chem., 1988, 53, 1584.
22 E. J. Corey and P. Carpino, Tetrahedron Lett., 1990, 31, 3857.
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12777.
24 A. P. Kozikowski and J. P. Wu, Synlett, 1991, 465.
25 D. F. Taber and J. B. Houze, J. Org. Chem., 1994, 59, 4004.
26 H. Tone, T. Nishi, Y. Oikawa, M. Hikota and O. Yonemitsu,
Tetrahedron Lett., 1987, 28, 4569.
27 H. B. Wood and B. Ganem, Tetrahedron Lett., 1993, 34, 1403.
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29 S. P. Chavan, P. K. Zubaidha and V. D. Dhondge, Tetrahedron, 1993,
49, 6429.
ϩ
ϩ
(Mϩ , 100), 285 [(M Ϫ CH3) , 75], 245 [(M Ϫ C4H7) , 68], 244
ؒ
ؒ
ؒ
[(M Ϫ C4H8)ϩ , 52], 229 [(M Ϫ C5H11) , 36], 218 (28); Found
ϩ
ؒ
ؒ
Mϩ , 300.2071; C20H28O2 requires M, 300.2089.
ؒ
30 B. M. Trost and N. R. Schmuff, J. Am. Chem. Soc., 1985, 107, 396.
31 U. Leutenegger, A. Madin and A. Pfaltz, Angew. Chem., Int. Ed.
Engl., 1989, 28, 60.
32 P. Carpino, PhD Thesis, Harvard, Cambridge, MA, USA, 1989.
33 S. W. McCombie, B. Cox and A. K. Ganguly, Tetrahedron Lett.,
1991, 32, 2087.
Acknowledgements
We thank GlaxoWellcome for financial support. We also thank
the Collegio Ghislieri di Pavia and the Università di Pavia for a
2366
J. Chem. Soc., Perkin Trans. 1, 2001, 2356–2366