Synthesis of macrocyclic precursors of phomactins using 2,3-Wittig rearrangements

Article abstract of DOI:10.1039/b903256h

The combination of a 2,3-Wittig rearrangement of a suitably substituted cyclohexenylmethyl propargyl ether with a subsequent conversion of the alkyne to a trisubstituted alkene and cyclisation via intramolecular sulfone alkylation has proved to be a usefu

Full text of DOI:10.1039/b903256h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of macrocyclic precursors of phomactins using [2,3]-Wittig
rearrangements†
Graham McGowan and Eric J. Thomas*
Received 17th February 2009, Accepted 27th March 2009
First published as an Advance Article on the web 27th April 2009
DOI: 10.1039/b903256h
The combination of a [2,3]-Wittig rearrangement of a suitably substituted cyclohexenylmethyl
propargyl ether with a subsequent conversion of the alkyne to a trisubstituted alkene and cyclisation via
intramolecular sulfone alkylation has proved to be a useful stereoselective approach to advanced
macrocyclic intermediates for a projected synthesis of phomactins. Thus Luche reduction of methyl
(1RS,6SR)-2-(bromomethyl)-1,6-dimethyl-4-oxocyclohex-2-ene-1-carboxylate 24 gave methyl
(1RS,4RS,6SR)-2-bromomethyl-4-hydroxy-1,6-dimethylcyclohex-2-ene-1-carboxylate 26 which was
protected as its (2-trimethylsilylethoxy)methyl ether 27. O-Alkylation of (E)-8-tert-
butyldiphenylsilyloxy-7-methyloct-6-en-2-yn-1-ol 17 using this bromide gave the corresponding ether
28. This was reduced and the resulting primary alcohol 29 converted into a phenylsulfonyl group by
displacement of the corresponding mesylate by sodium thiophenoxide followed by oxidation. A [2,3]
-Wittig rearrangement of the resulting propargylic ether 31 was stereoselective and gave predominantly
(2RS,3SR,5RS,6SR)-2-[(1RS,6E)-8-tert-butyldiphenylsilyloxy-1-hydroxyoct-6-en-2-yn-1-yl)]-5,6-
dimethyl-6-(phenylsulfonyl)methyl-3-(trimethylsilylethoxy)methoxy-1-methylenecyclohexane 37
together with its epimer at C(1¢) 38. Following protection as its 4-methoxybenzyl ether 39 with
O-desilylation and conversion of the primary alcohol 40 into the corresponding bromide 41, cyclisation
by intramolecular allylation of the sulfone gave (1SR,2RS,11SR,12RS,14SR,7E)-10-phenylsulfonyl-
8,11,12-trimethyl-15-methylene-2-(4-methoxybenzyl)-14-(2-trimethylsilylethoxy)methoxybicyclo-
[9.3.1]pentadec-7-en-3-yne 42 and reductive desulfonylation and O-deprotection gave (1RS,2RS,
11SR,12RS,14SR,7E)-8,11,12-trimethyl-15-methylene-14-(2-trimethylsilylethoxy)methoxybicyclo-
[9.3.1]pentadec-7-en-3-yn-2-ol 44. Analogous chemistry was carried out following protection of the
Wittig rearrangement product as its tri-isopropylsilylether 45. To prepare the corresponding
(3E,7E)-3,7-dienol, the Wittig rearrangement products 37 and 38 were oxidised to the corresponding
ketone 54. Conjugate addition of thiophenol followed by substitution of the major phenylthio adduct
56 using lithium dimethylcuprate gave the corresponding (E)-conjugated enone 57 which was reduced
using sodium borohydride and the resulting alcohol 58 converted into its benzyloxymethoxy ether 59.
This was taken through to give (1RS,2RS,11SR,12RS,14SR,3E,6E)-4,8,11,12-tetramethyl-
15-methylene-14-(2-trimethylsilylethoxy)methoxybicyclo[9.3.1]pentadeca-3,7-dien-2-ol 63 which has
the full carbon skeleton of the phomactins.
Introduction
The phomactins, e.g. 1–4, are a group of diterpenes isolated from
the marine fungus Phoma sp. which have interesting biological
activities including platelet activating factor antagonism.1 Struc-
turally they are characterised by a bicyclo[9.3.1]pentadec-7-enyl
framework with two cis-disposed methyl substituents at the 11-
and 12-positions. In the case of phomactin A 2, an ethereal group
bridges the 4- and 14-positions to form a tetrahydropyranyl ring.
The phomactins have attracted considerable interest from
synthetic organic chemists because of their novel structures and
biological activities. Phomactin D 1 is the most active member of
the series, and was the first naturally occurring phomactin to be
prepared by total synthesis.2 Since then two syntheses of the more
The School of Chemistry, The University of Manchester, Manchester, M13
9PL, UK. E-mail: e.j.thomas@manchester.ac.uk
complex phomactin A 2,3,4 and syntheses of phomactins G 35 and
† Electronic supplementary information (ESI) available: General experi-
mental details and for procedures relating to Schemes 2 and 5. See DOI:
10.1039/b903256h
B2 4,6 have been described. In addition many other approaches
to the synthesis of phomactins have been disclosed7 and the
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biogenesis of the phomactins and their structural homology to
taxanes have been discussed.8 The chemistry of phomactins has
recently been reviewed.8
In this work, propargylic ethers were used to control the regios-
electivity of the [2,3]-Wittig rearrangements with deprotonation
taking place next to the alkyne, see Fig. 1.9a However, mixtures
of stereoisomers at C(2) and C(1¢), e.g. 6a,b and 7, were formed
and mixtures of (E)- and (Z)-conjugated alkenes 8 and 9, were
obtained on addition of lithium dimethylcuprate to the ketones
prepared by oxidation of the Wittig rearrangement products.
The stereoselectivities of these reactions therefore needed to be
improved and, as the synthesis of the more advanced Wittig
precursor 11 was rather long, a better synthesis of analogous
intermediates was required.
We now report the results of further investigations into
this synthetic approach to phomactins, including stereoselec-
tive Wittig rearrangements of sulfones analogous to 11, the
development of an (E)-stereoselective synthesis of the required
conjugated enones, and a synthesis of a bicyclic intermediate
with the (3E,7E)-4,8,11,12-tetramethylbicyclo[9.3.1]pentadeca-
3,7-dienyl framework of the phomactins.10
Preliminary studies have been carried out on a possible syn-
thetic approach to phomactins using [2,3]-Wittig rearrangements
to assemble methylenecyclohexanes suitably functionalised for
subsequent formation of the bicyclo[9.3.1]pentadecenyl structure.9
In particular, the propargylic ether 5 was found to rearrange
on deprotonation using n-butyllithium to give a mixture of the
alcohols 6a,b and 7 which were taken through to mixtures of (E)-
and (Z)-isomers of the conjugated enones 8 and 9 by oxidation
and reaction with lithium dimethylcuprate (Scheme 1).9b The more
advanced Wittig precursor 11 has also been prepared from the
simpler propargylic ether 10.9b
Results and discussion
Hex-4-ynol 13 was prepared by alkylation of 3-tert-
butyldimethylsilyloxypropyne 12 using oxetane,11 see Scheme 2.
Oxidation and an in situ Wittig reaction of the resulting alde-
hyde gave ester 14 which was converted to the alcohol 17
by reduction, further protection and selective removal of the
tert-butyldimethylsilyl group.12 Alkylation of alcohol 17 using
the cyclohexenylmethyl bromide 189b gave the ether 19 which
was reduced to the alcohol 20. This was protected as its tert-
butyldimethylsilyl ether 21 which was treated with n-butyllithium
to effect a [2,3]-Wittig rearrangement. This gave an inseparable
mixture of two diastereoisomers of the methylenecyclohexanes
22, ratio 70:30, shown to be epimeric at C(2) as oxidation gave
a mixture of the two ketones 23a,b The formation of just two
diastereoisomers of the methylenecyclohexane 22 is precedented
in earlier studies.9b
Rather than take this mixture through the next stages of
the synthesis, it was decided to convert alcohol 20 into the
corresponding sulfone in anticipation of macrocyclisation by
sulfone allylation. However, attempts to convert alcohol 20 into
the corresponding thio-ether by displacement of its mesylate using
sodium thiophenoxide were unsuccessful. Complex mixtures of
products were obtained possibly because of neighbouring group
participation involving the acetal as indicated in Fig. 2.
To avoid this neighbouring group participation the ketone 24
was reduced under Luche conditions.13 At room temperature,
◦
mixtures of epimers 25 and 26 were formed, but at -78 C only
isomer 26 was isolated, the configuration shown being assigned on
1
the basis of H NMR data, e.g. a significant NOE enhancement
Scheme 1 Early studies of the synthesis of methylenecyclohexanes using
[2,3]-Wittig rearrangements.
of H(6) on irradiation of H(4) and vice versa. This alcohol was
Fig. 1 Regioselectivity of the [2.3]-Wittig rearrangement of ether 5.
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Scheme 2 Reagents and conditions: i, nBuLi, oxetane, BF3.Et2O, THF, -78 ◦C, 2 h (85%); ii, DMSO, (COCl)2, Et3N, DCM, -78 ◦C to r.t.,
Ph3PC(CH3)CO2Et, -78 ◦C-r.t., DCM, r.t., 16 h (90%); iii, LiEt3BH, THF, -78 ◦C, 1 h (84%); iv, TBDPSCl, imid., DCM, 0 ◦C, 16 h (67%); v,
MeOH, CCl4, sonicated, 50 ◦C, 4 h (86%); vi, NaH, TBAI, 15-c-5, 5 min, add 18, r.t., 16 h (42%); vii, LiEt3BH, THF, 0 ◦C, 50 min (93%); viii, TBSOTf,
Et3N, DCM, r.t., 45 min (67%); ix, nBuLi, THF, -78 ◦C, 3 h (70:30, 83%); x, Dess–Martin periodinane, DCM, r.t., 30 min (23a, 33%; 23b, 55%).
diphenyl disulfide and tributylphosphine14 was difficult to scale
up. However, substitution of the corresponding mesylate using
sodium thiophenoxide gave a good yield, 85%, of the required
thio-ether 30. Initial attempts to oxidise thio-ether 30 to its sulfone
R
using 3-chloroperoxybenzoic acid or OXONEꢀ gave appreciable
amounts of the epimeric sulfoxides 32 as well as the required
sulfone, and the use of magnesium monoperoxyphthalate was
accompanied by partial epoxidation of the side-chain double-
Fig. 2 Possible neighbouring group participation leading to loss of the
mesylate derived from alcohol 20.
bond. However, the use of hydrogen peroxide in the presence of
ammonium molybdate15 gave a 65% yield of the sulfone 31 together
with small amounts of the sulfoxides 32, which could be oxidised
separately to the sulfone, see Scheme 3.
converted into its (trimethylsilylethoxy)methyl ether 27 which was
treated with the sodium salt of alcohol 17 to give the ether 28.
This was reduced using lithium triethylborohydride to the alcohol
29. The direct conversion of alcohol 29 into thio-ether 30 using
Scheme 3 Reagents and conditions: i, NaBH4, CeCl3.7H2O, MeOH, -78 ◦C, 1.5 h (26, 91%); ii, iPr2NEt, SEMCl, DCM, r.t., 16 h (80%); iii, TBAI, NaH,
17, 0 ◦C, 20 min, add 15-c-5 and 27, r.t., 16 h (65%); iv, LiEt3BH, THF, 0 ◦C to r.t. (88%); v, (a) MesCl, Et3N, DCM, 0 ◦C, 30 min (b) PhSH, NaH, DMF,
0
◦C, 20 min, add the mesylate of 29, heat under reflux, 16 h (85%); vi, ammonium molybdate, H2O2, EtOH, -10 ◦C, 5 min then r.t., 24 h (31, 65%)
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Sulfone 31 is suitably substituted for a [2,3]-Wittig rearrange-
ment to form a methylenecyclohexane which could be incorpo-
rated into a synthesis of a phomactin. However, the option of
carrying out the rearrangement on a macrocyclic ether, i.e. 36, was
investigated at this point since it was thought that steric constraints
introduced by the bicyclic system could direct the facial selectivity
of the Wittig rearrangement and hence control the configuration
of the product at C(2). Moreover, such a rearrangement would
lead directly to the bicyclo[9.3.1]pentadecenyl system present in
the phomactins.
Selective removal of the tert-butyldiphenylsilyl ether from 31
gave the primary alcohol 33 which was converted into the bromide
34 by mesylation and substitution using lithium bromide, see
Scheme 4. Macrocyclisation of this bromide using sodium hex-
amethyldisilazide was more efficient after chromatographic purifi-
cation of the bromide and gave a mixture of the epimeric sulfones
35a,b. Reductive removal of the phenylsulfonyl group to give the
macrocyclic ether 36 was then achieved using sodium amalgam.16
However, all attempts to effect a [2,3]-Wittig rearrangement of
the macrocyclic propargylic ether 36 using n-butyllithium or
amide bases at various temperatures using different solvents were
unsuccessful. In all cases complex mixtures of ill-defined products
were obtained. The [2,3]-Wittig rearrangement of the sulfone 31
was therefore investigated and, somewhat unexpectedly, was found
to be stereoselective with respect to C(2). Two methylenecyclo-
hexanes 37 and 38 were isolated in isolated yields of 59% and 13%,
respectively, and were found to have the same configuration at
C(2).
The C(2) configurations of the rearrangement products 37 and
1
38 were assigned on the basis of H NMR data. For isomer 37
the diaxial coupling of 10 Hz observed between H(2) and H(3)
established this configuration and for isomer 38, a significant NOE
enhancement of H(2) was observed on irradiation of 6-CH3. That
these compounds had the same configuration at C(2) was also
confirmed later in the synthesis when they both gave the same
ketone on oxidation, vide infra.
The stereoselectivity at C(2) observed in the formation of
epimers 37 and 38 in this Wittig rearrangement contrasted with
the lack of stereoselectivity with respect to C(2) which had been
observed earlier.9b As the rearrangement of sulfone 31 required two
equivalents of base, it may be that the facial selectivity with respect
to the six-membered ring leading to the configuration shown at
C(2) is due to lithiation a to the sulfone and co-ordination of
the lithiated sulfone with the oxygen of the propargylic ether, see
Fig. 3.
The configurations at C(1¢) were not formally confirmed at
this stage, but were assigned on the basis that the alkynyl moiety
would prefer to adopt the less hindered outside position during
the rearrangement leading to isomer 37 as the major product.9b 1H
NMR studies later in the synthesis confirmed these assignments.
Scheme◦4 Reagents and conditions: i, TBAF, THF, r.t., 2 h (88%); ii, E3N, MesCl, DCM, r.t., 30 min, LiBr, acetone, r.t., 30 min (83%); iii, NaHMDS,
THF, 0 C, 2 h (35a, 26%; 35b, 49%); iv, Na-Hg, Na2HPO4, THF, MeOH, r.t., 1 h (62%); v, nBuLi, THF, -78 ◦C, 2.5 h (37, 59%; 38, 13%); vi, NaH, DMF,
r.t., 30 min, 4-MeOC6H4CH2Cl, r.t., 16 h (58%); vii, TBAF, THF, r.t., 1.5 h (87%); viii, E3N, MesCl, DCM, r.t., 30 min, LiBr, acetone, r.t., 30 min (92%);
ix, NaHMDS, THF, r.t., 30 min (68%); x, NaHPO4, THF, MeOH, Na-Hg, 0 ◦C to r.t., 1.5 h (93%); xi, DDQ, pH 7 phosphate buffer, DCM, 0 ◦C, 10 min
(72%).
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be better to use the tert-butyldimethylsilyl analogue of the tert-
butyldiphenylsilyl ether 17 in the synthesis since rearrangement
of the corresponding propargyl ether would lead to the alcohol
47 directly. However, this option has not yet been investigated
although the primary alcohol 49 was converted into the bromide
50 via its mesylate and cyclisation of the bromide using sodium
hexamethyldisilazide gave the bicyclic alkyne 51 as a single epimer
at C(10). Removal of the tri-isopropylsilyl group using tetra-n-
butylammonium fluoride then gave the alcohol 52 and reductive
removal of the sulfone group from 51 gave the bicyclic phomactin
precursor 53 which was deprotected to give the alcohol 44.
This work has shown that the [2,3]-Wittig rearrangement
can be used to prepare methylenecyclohexanes which can be
taken through to bicyclo[9.3.1]pentadec-7-en-3-ynes reminiscent
of phomactins with overall useful levels of stereoselectivity.
To complete a synthesis of intermediates with the full carbon
skeleton of phomactins it remained to convert the alkyne moiety
into the corresponding methyl substituted (E)-alkene regio- and
stereoselectively. Propargylic alcohols can be converted into the
corresponding (Z)-3-iodoalkenes, possible precursors of (E)-3-
methylalkenes, by reduction using lithium aluminium hydride
or Red-Al followed by treatment with iodine.21 However, in
our hands, attempts to convert the propargylic alcohol 44 into
the corresponding (Z)-vinyl iodide using these procedures were
unsuccessful, unchanged starting material being recovered, and
similar studies using the Wittig rearrangement product 37 gave
a mixture of unstable products possibly formed by competing
iodination a to the sulfone. Attention was therefore directed
towards conjugate addition reactions of the ketone 54 prepared
by oxidation of alcohols 37 and 38 using the Dess Martin
periodinane.22
Fig. 3 Influence of the lithiated sulfone on the facial selectivity of the
[2,3]-Wittig rearrangement of propargylic ether 31.
At this point it was necessary to protect the free hydroxyl
group before attempting macrocyclisation and so the major
rearrangement product 37 was converted into its p-methoxybenzyl
ether 39 albeit in only a modest, 58%, yield. Following selective
deprotection to give the primary alcohol 40 and conversion into
the bromide 41, macrocyclisation was achieved using sodium
hexamethyldisilylazide to give the bicyclic sulfone 42 essentially
as a single epimer at C(10). The configuration at C(2) was now
established as shown on the basis of the small H(1)-H(2) coupling
constant of ca. 4 Hz, and a strong NOE enhancement of H(2)
on irradiation of H(1). The configuration of the sulfonyl bearing
stereogenic centre, C(10), was not established.17
To complete a synthesis of a potential macrocyclic precursor of
phomactins, the sulfone 42 was subjected to reductive sulfonyla-
tion using sodium-amalgam to give the macrocyclic alkyne 43 and
the p-methoxybenzyl group removed using DDQ under buffered
conditions19 to give the alcohol 44, see Scheme 4.
As the protection of the alcohol 37 as its 4-methoxybenzyl
ether had not been particularly efficient, the use of silyl protecting
groups was investigated. Alcohol 37 was converted into its tri-
isopropylsilyl ether 4520 (Scheme 5) but attempts to remove
selectively the tert-butyldiphenylsilyl group using 5% sodium
hydroxide in ethanol gave only a 54% yield of the corresponding
primary alcohol. Both silyl protecting groups were therefore
cleaved using tetra-n-butylammonium fluoride to give the diol
46 which was silylated selectively on the primary alcohol using
tert-butyldimethylsilyl chloride to give the monosilyl ether 47 and
further silylated using tri-isopropylsilyl triflate to give the bis-silyl
ether 48. Selective removal of the tert-butyldimethyl silyl group
was now possible using acetic acid in aqueous tetrahydrofuran to
give the primary alcohol 49. This sequence showed that it would
Preliminary studies of the conjugate addition of lithium
dimethylcuprate to the alkynone 54 gave rise to a (E,Z)-mixture
of conjugated alkenes which could not be separated and which did
not appear to isomerise to the required (E)-isomer on treatment
with thiols. However, reaction of ketone 54 with thiophenol under
basic conditions23,24 gave a mixture of the separable vinyl sulfides
55 and 56, from which the (Z)-isomer 56 could be isolated in a
69% yield, and treatment of this with lithium dimethyl cuprate
gave the required (E)-alkene 57 in a 97% yield (Scheme 6).25 The
geometries of the alkenes 55–57 were confirmed by 1H NMR NOE
Scheme 5 Reagents and conditions: i, TIPSOTf, 2,6-lutidine, DCM, 0 ◦C, 30 min (45, 87%; 48, 97%); ii, TBAF, THF, r.t., 1.5 h (93%); iii, TBSCl, imid.,
DCM, r.t., 30 min (89%); iv, AcOH, THF, H2O, 0 ◦C, r.t., 24 h (82%); v, MesCl, Et3N, DCM, r.t., 30 min, then LiBr, acetone, r.t., 30 min (86%); vi,
NaHMDS, THF, 0 ◦C, 1 h (64%); vii, TBAF, THF, r.t., 1.5 h (73%); viii, Na-Hg, NaHPO4, r.t., 2 h (69%); ix, TBAF, THF, r.t. (43% from 50).
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Scheme 6 Reagents and conditions: i, Dess–Martin periodinane, DCM, r.t., 30 min (89%); ii, PhSH, Et3N, THF, -20 ◦C, 2 h (55, 26%; 56, 69%); iii, CuI,
MeLi, Et2O, 0 ◦C, 30 min, then add to 56, -78 ◦C, 30 min (97%); iv, NaBH4, EtOH, r.t., 18 h (59%); v, iPr2NEt, BOMCl, TBAI, r.t., 16 h (85%); vi, TBAF,
THF, r.t., 2 h (79%); vii, MesCl, Et3N, DCM, 0 ◦C, 30 min, then LiBr, acetone, 0 ◦C, 30 min (69%); viii, NaHMDS, THF, 0 ◦C, syringe pump, 40 min,
then 30 min; ix, Na, liq. NH3, THF, EtOH, -60 ◦C (45% from 61).
and chemical shift studies, e.g. the observation of an enhancement
of 4¢-H2 on irradiation of 2¢-H for the (Z)-isomer 56. Since the
enone 57 would be incompatible with the strongly basic conditions
required for macrocyclisation, it was reduced to the alcohol 58
using sodium borohydride, the configuration of the alcohol at C(1¢)
being assigned by 1H NMR studies later in the synthesis. Although
this reduction was somewhat capricious, alternative procedures
including the use of Luche conditions, gave unchanged starting
material, and more reactive hydride reducing agents gave complex
mixtures of products. Following protection of the alcohol 58 as
its benzyloxymethyl (BOM) derivative 59, desilylation gave the
alcohol 60. This taken through to the bromide 61 via its mesylate
and cyclisation of the bromide was carried out under the usual
conditions to give the macrocyclic sulfone 62. This was immedi-
ately subjected to a Birch reduction2,26 to remove both the BOM
and phenylsulfonyl groups giving the 2-hydroxy-15-methylene-
4,8,11,12-tetramethylbicyclo[9.3.1]pentadeca-3,7-diene 63 which
has the full carbon skeleton of the phomactins.
cyclisation would appear to provide useful stereoselective access
to the phomactin system. The need for a propargylic ether for
control of the regioselectivity of the Wittig rearrangements meant
that a stereoselective procedure had to be developed to convert
the 3-alkyne into an (E)-alkene later in the synthesis. Although a
procedure was devised to achieve this, some improvements to this
part of the synthesis are necessary. Further work is on-going to
improve the overall synthesis and to bring through larger amounts
of material to enable the completion of a synthesis of phomactin
A 2.18
Experimental
Methyl (1SR,4SR,6RS)-2-bromomethyl-4-hydroxy-1,
6-dimethylcyclohex-2-ene-1-carboxylate 26
Cerium(III) chloride heptahydrate (1.043 g, 2.805 mmol) was
added to the enone 24 (7.0 g, 2.55 mmol) in methanol (210 cm3) at
room temperature and the resulting suspension was stirred until
the solid had dissolved. The mixture was then cooled to -78 ◦C and
sodium borohydride (1.16 g, 3.07 mmol) was added. The solution
was stirred for 1.5 h then warmed to room temperature and
concentrated under reduced pressure. Dichloromethane (30 cm3)
and silica powder were added and the dichloromethane removed
under reduced pressure. The solid residue was dried under
reduced pressure and loaded onto a silica gel column. Flash
chromatography, with 5–40% ether in petrol as eluent, afforded
the title compound 26 as an oil (6.4 g, 91%), Rf = 0.075 (50% ether
in petrol) (Found; M+ + NH4, 294.0706. C11H21O379BrN requires
M, 294.0705); nmax/cm-1 3424 (br), 2949, 2875, 1729, 1451, 1434
1384, 1254, 1118, 1022 and 967; dH (300 MHz, CDCl3) 6.07 (1 H, s,
3-H), 4.42 (1 H, t, J 8, 4-H), 3.96 and 3.83 (each 1 H, d, J 11,
2-CH), 3.74 (3 H, s, 1-CO2CH3), 2.36 (1 H, dqd, J 13, 7, 2.5, 6-H),
Summary and conclusions
This work has achieved a synthesis of 15-methylenebicyclo[9.3.1]-
pentadec-7-en-4-ynes and related dienes which have the bicyclic
framework present in the phomactins. The [2,3]-Wittig rear-
rangement of cyclohexenyl propargylic ethers7 has proved to
be useful for the synthesis of methylenecyclohexanes and the
effect of a phenylsulfonyl group on the stereoselectivity of these
rearrangements is of interest. The macrocyclisation procedure
involving an intramolecular allylation of a sulfone using an allylic
bromide, which was used in the early synthesis of phomactin
D,1 has proved to be generally useful in this system and has
delivered quite acceptable yields of macrocycles. Indeed the
combination of a [2,3]-Wittig rearrangement and subsequent
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2.01 (1 H, br s, OH), 1.93 (1 H, ddd, J 12.5, 2.5, 1, 5-H), 1.38 (1 H,
m, 5-H¢), 1.30 (3 H, s, 1-CH3) and 0.91 (3 H, d, J 7, 6-CH3); dC
(75 MHz, CDCl3) 175.5, 138.7, 135.0, 67.1, 52.3, 50.9, 35.3, 34.5,
31.6, 16.7 and 16.5; m/z (CI) 296 (M+ + 18, 30%), 294 (M+ + 18,
30), 261 (100) and 259 (95).
(3 H, s, 7¢-CH3), 1.47 (1 H, m, 5-H¢), 1.26 (3 H, s, 1-CH3), 1.11
[9 H, s, OSiC(CH3)3], 0.99 (2 H, m, CH2Si), 0.91 (3 H, d, J 6.5,
6-CH3) and 0.07 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3) 175.9,
139.2, 135.5, 135.3, 133.7, 129.5, 128.6, 127.5, 122.4, 93.3, 86.6,
75.8, 72.2, 69.8, 68.7, 65.0, 57.7, 52.0, 49.6, 35.3, 34.4, 33.0, 26.8,
19.2, 19.0, 18.0, 16.8, 16.0, 13.5 and -1.4; m/z (CI) 736 (M+ + 18,
10%), 360 (12) and 90 (100).
Methyl (1SR,4SR,6RS)-2-bromomethyl-1,6-dimethyl-4-(2-
trimethylsilylethoxy)methoxycyclohex-2-ene-1-carboxylate 27
N,N -Di-isopropylethylamine (12.1 cm3, 6.96 mmol) and 2-
trimethylsilylethoxymethyl chloride (6.2 cm3, 3.5 mmol) were
added to the alcohol 26 (6.4 g, 2.32 mmol) in dichloromethane
(20 cm3) at 0 ◦C and the solution allowed to warm to room
temperature. After 16 h, the solution was diluted with ethyl acetate
(20 cm3) and water (40 cm3). The aqueous phase was extracted
with ethyl acetate (4 ¥ 20 cm3) and the organic extracts washed
with brine (40 cm3), dried (MgSO4) and concentrated under
reduced pressure. Flash column chromatography of the residue
on silica gel, eluted with 1–15% ether in petrol, afforded the title
compound 27 as a clear oil (7.5 g, 80%), Rf = 0.75 (20% ether
in petrol) (Found; M+ + NH4, 424.1519. C17H35O4BrSiN requires
M, 424.1519); nmax/cm-1 2951, 2878, 1732, 1459, 1378, 1249, 1101,
1035, 860 and 836; dH (300 MHz, CDCl3) 6.06 (1 H, s, 3-H), 4.83
and 4.78 (each 1 H, d, J 7, OCHHO), 4.37 (1 H, m, 4-H), 4.03
and 3.95 (each 1 H, d, J 11.5, 2-CH), 3.74 (3 H, s, CO2CH3), 3.68
(2 H, m, OCH2CH2Si), 2.35 (1 H, dqd, J 13, 7, 2, 6-H), 1.95 (1 H,
ddd, J 13, 2.5, 1, 5-H), 1.47 (1 H, m, 5-H¢), 1.29 (3 H, s, 1-CH3),
0.98 (2 H, m, CH2Si), 0.92 (3 H, d, J 7, 6-CH3) and 0.01 [9 H, s,
Si(CH3)3]; dC (75 MHz, CDCl3) 175.5, 138.9, 131.4, 93.5, 72.2,
65.1, 52.2, 50.7, 44.4, 34.5, 32.7, 18.0, 16.8, 16.3 and -1.5; m/z
(CI) 426 (M+ + 18, 2%), 424 (M+ + 18, 2), 380 (60), 232 (45), 215
(100) and 181 (34).
(3SR,5RS,6SR)-1-[(6E)-8-tert-Butyldiphenylsilyloxy-7-
methyloct-6-en-2-yn-1-yloxy]methyl-5,6-dimethyl-6-
hydroxymethyl-3-(2-trimethylsilylethoxy)methoxycyclohex-
1-ene 29
Lithium triethylborohydride (1.0 M in tetrahydrofuran, 14.5 cm3,
14.6 mmol) was added to the ester 28 (4.17 g, 5.85 mmol) in
tetrahydrofuran (47 cm3) at 0 ◦C. The solution was stirred at
◦
room temperature for 3 h then cooled to 0 C and more lithium
triethylborohydride (1.0 M in THF, 5.85 cm3, 5.85 mmol) was
added. After 1 h, saturated aqueous ammonium chloride (30 cm3)
was added and the mixture diluted with ethyl acetate (20 cm3)
then stirred at room temperature for 1 h. The aqueous phase
was extracted with ether (4 ¥ 20 cm3), and the organic extracts
washed with water (30 cm3) and brine (30 cm3), dried (MgSO4) and
concentrated under reduced pressure. Column chromatography of
the residue on silica gel, eluted with 1–40% ether in petrol, afforded
the title compound 29 (3.57 g, 88%) as a clear, viscous oil, Rf = 0.15
(50% ether in petrol) (Found; M+ + NH4, 708.4487. C41H66O5Si2N
requires M, 708.4479); nmax/cm-1 3468 (br), 2954, 2862, 1465, 1428,
1375, 1249, 1106, 1055 and 835; dH (500 MHz, CDCl3) 7.62 (4 H,
dt, J 7, 1.5, Ar-H), 7.40 (6 H, m, Ar-H), 5.93 (1 H, s, 2-H), 5.40
(1 H, m, 6¢-H), 4.79 and 4.74 (each 1 H, d, J 7, OCHHO), 4.27
(1 H, ddd, J 10, 5, 2, 3-H), 4.19 (1 H, d, J 15.5, 1¢-CH), 4.16 (1 H,
d, J 9.5, 1-CH), 4.11 (1 H, d, J 15.5, 1¢-CH¢), 4.06 (2 H, s, 8¢-CH2),
3.80 (1 H, d, J 10, 1-CH¢), 3.65 (2 H, m, OCH2CH2Si), 3.56 (1 H,
dd, J 12, 4.5, 6-CH), 3.38 (1 H, t, J 11.5, 6-CH¢), 2.91 (1 H, dd, J
11, 4.5, OH), 2.64 (4 H, m, 4¢-CH2 and 5¢-CH2), 2.20 (1 H, dqd,
J 14, 4, 2.5, 5-H), 1.91 (1 H, dd, J 11.5, 2, 4-H), 1.61 (3 H, s,
7¢-CH3), 1.47 (1 H, m, 4-H¢), 1.07 [9 H, s, SiC(CH3)3], 0.95 (2 H,
m, CH2Si), 0.92 (3 H, d, J 7.5, 5-CH3), 0.77 (3 H, s, 6-CH3) and
0.03 [9 H, s, Si(CH3)3]; dC (100 MHz, CDCl3) 140.9, 136.3, 135.5,
133.8, 129.5, 127.6, 122.2, 93.3, 87.6, 77.2, 75.1, 72.3, 71.1, 68.6,
65.0, 64.9, 58.4, 43.2, 33.7, 30.2, 26.8, 19.3, 19.0, 18.0, 16.4, 15.8,
13.5 and -1.4; m/z (CI) 708 (M+ + 18, 5%), 410 (4), 167 (15), 151
(12), 123 (20) and 90 (100).
Methyl (1SR,4SR,6RS)-2-[(6E)-8-tert-butyldiphenylsilyloxy-7-
methyloct-6-en-2-yn-1-yloxy]methyl-1,6-dimethyl-4-(2-
trimethylsilylethoxy)methoxycyclohex-2-ene-1-carboxylate 28
Sodium hydride (60% dispersion in mineral oil, 1.49 g, 37.2 mmol)
and tetra-n-butylammonium iodide (4.6 g, 21.4 mmol) were
added to tetrahydrofuran (12.5 cm3) and the suspension cooled
to 0 ◦C. Alcohol 17 (13.4 g, 34.1 mmol) in tetrahydrofuran
(25 cm3) was added and the suspension stirred for 20 min before
the addition of 15-crown-5 (7.4 cm3) and bromide 27 (12.6 g,
31.0 mmol) in tetrahydrofuran (20 cm3). The brown suspension
was warmed to room temperature and stirred for 16 h. Saturated
aqueous ammonium chloride (40 cm3) was then added and
the aqueous phase extracted into ethyl acetate (4 ¥ 30 cm3).
The organic extracts were washed with brine (40 cm3), dried
(MgSO4) and concentrated under reduced pressure. Flash column
chromatography of the residue afforded the title compound 28 as a
clear oil (14.5 g, 65%), Rf = 0.5 (20% ether in petrol) (Found; M+ +
NH4, 736.4425; C42H66O6Si2N requires M, 736.4428); nmax/cm-1
2951, 2857, 1732, 1461, 1428, 1249, 1110, 1055, 836 and 707; dH
(300 MHz, CDCl3) 7.73 (4 H, m, Ar-H), 7.41 (6 H, m, Ar-H), 5.88
(1 H, s, 3-H), 5.53 (1 H, m, J 5, 6¢-H), 4.82 and 4.81 (each 1 H, d, J
7, OCHHO), 4.39 (1 H, m, 4-H), 4.10 (2 H, s, 8¢-H2), 4.07 (2 H, s,
1¢-H2), 4.01 and 3.93 (each 1 H, d, J 12.5, 2-CH), 3.67–3.72 (5 H,
m, CO2CH3 and OCH2CH2Si), 2.38 (1 H, m, 6-H), 2.28 (4 H,
m, 4¢-H2 and 5¢-H2), 1.97 (1 H, ddd, J 13.5, 6.5, 2, 5-H), 1.65
(3SR,5RS,6SR)-1-[(6E)-8-tert-Butyldiphenylsilyloxy-7-
methyloct-6-en-2-yn-1-yloxy]methyl-5,6-dimethyl-6-
phenylthiomethyl-3-(2-trimethylsilylethoxy)methoxycyclohex-
1-ene 30
Triethylamine (2.54 cm3, 18.2 mmol) and methanesulfonyl chloride
(0.8 cm3, 10.4 mmol) were added to the alcohol 29 (3.6 g,
5.21 mmol) i◦n dichloromethane (90 cm3) at 0 ◦C and the solution
stirred at 0 C for 0.5 h. Ethyl acetate (90 cm3) and saturated
aqueous sodium bicarbonate (50 cm3) were added and the aqueous
phase extracted with ethyl acetate (4 ¥ 30 cm3). The organic
extracts were washed with saturated aqueous sodium bicarbonate
3
(50 cm ) and brine (50 cm3), dried (MgSO4) and concentrated
2582 | Org. Biomol. Chem., 2009, 7, 2576–2590
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under reduced pressure to afford the mesylate as a pale orange oil
used without further purification.
(3 H, m, 1-CH¢ and 1¢-CH2), 4.05 (2 H, s, 8¢-CH2), 3.65 (2 H,
m, CH2CH2Si), 3.50 and 3.29 (each 1 H, d, J 14.5, 6-CH), 2.66
(1 H, dqd, J 14, 6.5, 2, 5-H), 2.23 (4 H, m, 4¢-H2 and 5¢-H2), 1.95
(1 H, dd, J 11.5, 5.5, 4-H), 1.60 (3 H, s, 7¢-CH3), 1.55 (1 H, m,
4-H¢), 1.11 (3 H, s, 6-CH3), 1.07 [9 H, s, SiC(CH3)3], 0.99 (3 H, d,
J 6.5, 5-CH3), 0.95 (2 H, m, CH2Si) and 0.04 [9 H, s, Si(CH3)3]; dC
(75 MHz, CDCl3) 141.8, 139.4, 135.5, 135.4, 133.7, 133.3, 130.95,
129.5, 129.1, 127.7, 127.5, 127.4, 122.3, 93.3, 86.7, 75.9, 71.8, 68.7,
65.0, 60.5, 57.4, 41.9, 33.6, 33.0, 26.9, 26.8, 21.5, 19.2, 19.0, 18.0,
16.1, 13.5 and -1.4; m/z (CI) 831 (M+ + 17, 1%), 322 (26), 196
(62), 160 (62) and 90 (100).
Sodium hydride (1.04 g, 26 mmol) was added to anhydrous
N◦,N-dimethylformamide (90 cm3) and the suspension cooled to
0 C. Benzenethiol (2.67 cm3, 26 mmol) was added dropwise and
the yellow solution stirred for 20 min at 0 ◦C. The mesylate in
anhydrous N,N-dimethylformamide (80 cm3) was added, and the
solution heated under reflux for 16 h. After being allowed to
cool to room temperature, the reaction mixture was diluted with
ethyl acetate (50 cm3) and washed with aqueous sodium hydroxide
(50 cm3). The aqueous phase was extracted with ethyl acetate
(3 ¥ 40 cm3) and the organic extracts were washed with water
(50 cm3) and brine (50 cm3), dried (MgSO4) and concentrated
under reduced pressure. Column chromatography of the residue
using 0–25% ether in petrol as eluent afforded the title compound
30 (3.41 g, 85%) as a pale yellow, viscous oil, Rf = 0.6 (50% ether
in petrol) (Found; M+ + NH4, 800.4555. C47H70O4Si2SN requires
M, 800.4563); nmax/cm-1 3070, 2954, 2857, 1471, 1428, 1361, 1249,
1109, 1056, 836, 740 and 707; dH (500 MHz, CDCl3) 7.69 (4 H,
d, J 6.5, Ar-H), 7.14–7.45 (10 H, m, Ar-H), 7.16 (1 H, t, J 7.5,
Ar-H), 5.89 (1 H, s, 2-H), 5.47 (1 H, t, J 6, 6¢-H), 4.79 and 4.77
(each 1 H, d, J 7, OCHHO), 4.29 (1 H, t, J 7.5, 3-H), 4.19 (1 H,
d, J 12.5, 1-CH), 4.13 and 4.07 (each 1 H, d, J 15.5, 1¢-CH),
4.06 (2 H, s, 8¢-CH2), 4.01 (1 H, d, J 12.5, 1-CH¢), 3.66 (2 H, m,
OCH2CH2), 3.15 and 3.09 (each 1 H, d, J 12, 6-CH), 2.14–2.24
(5 H, m, 5-H, 4¢-H2 and 5¢-H2), 1.88 (1 H, dd, J 11.5, 5.5, 4-H),
1.57 (3 H, s, 7¢-CH3), 1.51 (1 H, m, 4-H¢), 1.11 (3 H, s, 6-CH3),
1.06 [9 H, s, SiC(CH3)3], 0.96 (2 H, m, CH2Si), 0.87 (3 H, d, J 7, 4-
CH3) and 0.04 [9 H, s, Si(CH3)3]; dC (91 MHz, CDCl3) 142.3, 139.5,
137.4, 137.2, 135.7, 132.1, 131.4, 131.1, 130.7, 129.4, 127.6, 124.4,
95.1, 88.5, 77.9, 74.1, 72.1, 70.6, 66.8, 59.5, 43.4, 42.9, 35.5, 34.7,
28.8, 28.7, 22.8, 21.1, 20.9, 19.9, 17.5, 15.4 and 0.4; m/z (CI) 800
(M+ + 18, 1%), 407 (20), 261 (30), 259 (30), 123 (45), 196 (25) and
90 (100).
(3SR,5RS,6SR)-5,6-Dimethyl-1-[(6E)-8-hydroxy-7-methyloct-6-
en-2-yn-1-yloxy]methyl-6-phenylsulf-onylmethyl-3-
(2-trimethylsilylethoxy)methoxycyclohex-1-ene 33
tetra-n-Butylammonium fluoride (1.0 M in tetrahydrofuran,
0.34 cm3, 0.34 mmol) was added to th◦e sulfone 31 (0.25 g,
0.31 mmol) in tetrahydrofuran (8 cm3) at 0 C and the pale orange
solution stirred at room temperature for 2 h. After concentration
under reduced pressure, column chromatography of the residue
on silica gel, eluted with 10–50% ether in petrol, afforded the
title compound 33 (0.157 g, 88%) as a clear, viscous oil, Rf = 0.1
(50% ether in petrol) (Found; M+ + NH4, 594.3290. C31H52O6SSiN
requires M, 594.3284); nmax/cm-1 3468 (br), 2949, 2894, 2874, 1447,
1378, 1361, 1308, 1248, 1149, 1030, 836 and 748; dH (300 MHz,
CDCl3) 7.92 (2 H, d, J 8.5, Ar-H), 7.63 (1 H, m, Ar-H), 7.55 (2 H,
m, Ar-H), 5.85 (1 H, s, 2-H), 5.47 (1 H, m, 6¢-H), 4.79 and 4.75
(each 1 H, d, J 7, OCHHO), 4.32 (2 H, m, 1-CH and 3-H), 4.09
(3 H, m, 1-CH¢ and 1¢-H2), 4.00 (2 H, s, 8¢-H2), 3.65 (2 H, m,
CH2CH2Si), 3.50 and 3.30 (each 1 H, d, J 14.5, 6-CH), 2.64 (1 H,
m, 5-H), 2.26 (4 H, m, 4¢-H2 and 5¢-H2), 1.94 (1 H, dd, J 11.5, 6.5,
4-H), 1.70 (1 H, br s, OH), 1.67 (3 H, s, 7¢-CH3), 1.54 (1 H, dt,
12.5, 9.5, 4-H¢), 1.11 (3 H, s, 6-CH3), 0.97 (3 H, d, J 7, 5-CH3),
0.93 (2 H, m, CH2Si) and 0.04 [9 H, s, Si(CH3)3]; dC (75 MHz,
CDCl3) 141.8, 139.4, 136.3, 133.3, 130.9, 129.1, 127.4, 123.5, 93.3,
86.6, 71.8, 71.5, 68.3, 65.0, 60.1, 57.3, 41.9, 33.5, 33.0, 29.6, 26.7,
21.4, 18.9, 18.0, 16.1, 13.7 and -1.5; m/z (CI) 594 (M+ + 18, 3%),
456 (2), 293 (21), 170 (30), 137 (32) and 90 (100).
(3SR,5RS,6SR)-1-[(6E)-8-tert-Butyldiphenylsilyloxy-7-
methyloct-6-en-2-yn-1-yloxy]methyl-5,6-dimethyl-6-
phenylsulfonylmethyl-3-(2-trimethylsilylethoxy)methoxycyclohex-
1-ene 31
Sulfide 30 (0.55 g, 0.0703 mmol) and ammonium molybdate
(0.13 g, 0.105 mmol) in ethanol (7.4 cm3) were cooled to -10 ◦C,
and hydrogen peroxide (30% solution in water, 0.21 cm3) was added
(3SR,5RS,6SR)-1-[(6E)-8-Bromo-7-methyloct-6-en-2-yn-1-
yloxy]methyl-6-phenylsulfonylmethyl-5,6-dimethyl-3-
(2-trimethylsilylethoxy)methoxycyclohex-1-ene 34
◦
over 5 min. The suspension was stirred at -10 C for 5 min and
at room temperature for 24 h then water (10 cm3) was added.
The solution was partitioned with ether and the aqueous phase
was extracted with ether (6 ¥ 10 cm3). The organic extracts were
washed with aqueous iron(II) sulfate (20 cm3), brine (20 cm3),
dried (Na2SO4) and concentrated under reduced pressure. Column
chromatography of the residue on silica gel, eluted with 1–30%
ether in petrol, afforded the title compound 31 (0.372 g, 65%) as
a clear, viscous oil, Rf = 0.5 (50% ether in petrol) (Found; M+ +
NH4, 832.4455. C47H70O6Si2SN requires M, 832.4462); nmax/cm-1
2955, 2894, 1727, 1447, 1308, 1249. 1149, 1109, 1056, 836 and
745; dH (500 MHz, CDCl3) 7.92 (2 H, d, J 7, Ar-H), 7.73 (2 H,
dd, 6, 1.5, Ar-H), 7.68 (3 H, dd, J 6.5, 1.5, Ar-H), 7.62 (1 H, t, J
7.5, Ar-H), 7.54 (2 H, t, J 7.5, Ar-H), 7.37–7.44 (5 H, m, Ar-H),
5.85 (1 H, s, 2-H), 5.47 (1 H, t, J 6, 6¢-H), 4.78 and 4.75 (each
1 H, d, J 6.5, OCHHO), 4.33 (2 H, m, 3-H and 1-CH), 4.07–4.13
Triethylamine (0.06 cm3, 0.417 mmol) then methanesulfonyl
chloride (0.02 cm3, 0.26 mmol) were added to alcohol 33 (0.06 g,
◦
0.104 mmol) in dichloromethane (1.5 cm3) at 0 C and the pale
orange solution was stirred at room temperature for 30 min. After
cooling to 0 ◦C, lithium bromide (0.135 g, 1.56 mmol) in acetone
(0.5 cm3) was added and, after 30 min at ambient temperature, the
suspension was filtered through a pad of celite, the filter cake was
washed with dichloromethane and the filtrate concentrated under
reduced pressure. The residue was taken up in ethyl acetate (5 cm3)
and washed with saturated aqueous sodium bicarbonate solution
(5 cm3). The aqueous phase was washed with ethyl acetate (3 ¥
5 cm3) and the organic extracts were washed with brine (10 cm3),
dried (MgSO4) and concentrated under reduced pressure. Column
chromatography of the residue on silica gel, eluted with 1–20%
ether on petrol, afforded the title compound 34 (0.55 g, 83%) as a
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clear, viscous oil, Rf = 0.5 (50% ether in petrol) (Found; M+ + NH4,
656.2435. C31H51O5SSi79BrN requires M, 656.2441); nmax/cm-1
2948, 2878, 1446, 1361, 1313, 1248, 1149, 1087, 1053 1032, 837
and 748; dH (300 MHz, CDCl3) 7.92 (2 H, d, J 7, Ar-H), 7.63
(1 H, t, J 7, Ar-H), 7.55 (2 H, t, J 7.5, Ar-H), 5.84 (1 H, s, 2-H),
5.56 (1 H, m, 6¢-H), 4.79 and 4.75 (each 1 H, d, J 7, OCHHO),
4.32 (2 H, m, 3-H and 1¢-H), 4.11–3.95 (5 H, m, 1-CH2, 1¢-H¢ and
8¢-H2), 3.65 (2 H, m, CH2CH2Si), 3.50 and 3.30 (each 1 H, d, J 15,
6-CH), 2.65 (1 H, m, 5-H), 2.25 (4 H, br s, 4¢-H2 and 5¢-H2), 1.95
(1 H, dd, J 12, 6.5, 4-H), 1.75 (3 H, s, 7¢-CH3), 1.54 (1 H, td, J 13,
9.5, 4-H¢), 1.12 (3 H, s, 6-CH3), 0.98 (3 H, d, J 6.5, 5-CH3), 0.93
(2 H, m, CH2Si) and 0.04 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3)
142.2, 139.7, 133.7, 131.4, 129.5, 129.4, 128.9, 127.8, 93.6, 86.3,
72.1, 65.3, 60.8, 57.7, 42.3, 41.4, 33.9, 33.4, 27.8, 27.5, 21.8, 18.9,
18.8, 18.3, 16.4, 15.1 and -1.1; m/z (CI) 658 (M+ + 18, 1.5%), 656
(M+ + 18, 1.5%), 612 (2), 578 (1), 493 (2), 391 (35) and 90 (100).
1.56 (1 H, td, J 12.5, 10.5, 15-H¢), 1.36 (3 H, s, 10-CH3), 1.21 (3 H,
d, J 7, 14-CH3), 1.20 (3 H, s, 13-CH3), 0.96 (2 H, m, CH2Si) and
0.03 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3) 142.9, 140.5, 135.5,
134.0, 133.1, 129.2, 128.8, 124.8, 93.2, 86.6, 79.0, 72.2, 72.0, 70.5,
65.0, 58.4, 45.1, 35.3, 34.1, 33.8, 24.3, 19.9, 18.6, 18.2, 18.0 and
-1.4; m/z (CI) 576 (M+ + 18, 10%), 411 (40), 359 (12), 271 (42),
215 (30) and 90 (100).
(13SR,14RS,16SR,9E)-10,13,14-Trimethyl-16-
(2-trimethylsilylethoxy)methoxy-3-oxabicyclo[11.4.0]-
heptadeca-9,17-dien-5-yne 36
Sodium-mercury amalgam (10%, 0.12 g, 0.538 mmol) was added
to a suspension of the sulfones 35a,b (50 mg, 0.0896 mmol) and
disodium hydrogen phosphate in tetrahydrofuran (0.3 cm3) and
anhydrous methanol (0.5 cm3) at 0 ◦C and the suspension stirred
at ambient temperature for 1 h. Saturated aqueous ammonium
chloride (1.5 cm3) and ethyl acetate (2 cm3) were added and the
mixture decanted from the residues which were washed with ethyl
acetate (3 ¥ 5 cm3). The aqueous phase was extracted with ethyl
acetate (3 ¥ 2 cm3) and the organic extracts washed with brine
(10 cm3), dried (MgSO4) and concentrated under reduced pressure.
Column chromatography of the residue, eluted with 0–5% ether
in petrol, afforded the title compound 36 (0.023 g, 62%) as a clear,
viscous oil, Rf = 0.8 (50% ether in petrol) (Found; M+ + NH4,
436.3238. C25H46O3SiN requires M, 436.3247); nmax/cm-1 2924,
2855, 1735, 1459, 1376, 1147 and 1037; dH (300 MHz, CDCl3) 5.86
(1 H, s, 17-H), 5.24 (1 H, m, 9-H), 4.78 (2 H, s, OCH2O), 4.37
(1 H, dt, J 13, 2, 2-H), 4.26 (1 H, m, 16-H), 4.25 (1 H, dt, J 16, 2,
4-H), 4.04 (1 H, dt, J 16, 2, 4-H¢), 3.87 (1 H, dt, J, 13, 2, 2-H¢),
3.66 (2 H, m, CH2CH2Si), 2.37 (2 H, m, 7-H2), 2.28 (1 H, m, 8-H),
2.13 (1 H, dd, J 12.5, 5.5, 8-H¢), 2.04 and 1.80 (each 1 H, m, 11-H),
1.70 (2 H, m, 14-H and 15-H), 1.61 (3 H, s, 10-CH3), 1.52 (1 H, m,
12-H), 1.26–1.36 (2 H, m, 15-H¢ and 12-H¢), 0.97 (3 H, s, 13-CH3),
0.89 (3 H, d, J 7, 14-CH3), 0.88 (2 H, m, CH2Si) and 0.04 [9 H, s,
Si(CH3)3]; dC (75 MHz, CDCl3) 142.9, 137.6, 124.8, 123.5, 92.9,
87.7, 78.5, 72.5, 68.2, 64.8, 58.2, 40.9, 34.1, 33.8, 33.4, 32.3, 24.5,
21.7, 18.5, 18.0, 15.6, 15.3 and -1.5; m/z (CI) 436 (M+ + 18, 1%),
288 (3), 271 (45), 178 (50) 161 (45) and 146 (100).
(13SR,14RS,16SR,9E)-12-Phenylsulfonyl-10,13,14-trimethyl-16-
(2-trimethylsilylethoxy)methoxy-3-oxabicyclo[11.4.0]heptadeca-
9,17-dien-5-yne 35,a,b
Sodium hexamethylsilazide (1.0 M in tetrahydrofuran, 0.19 cm3,
0.186 mmol) was added to the bromide 34 (39 mg, 0.0619 mmol)
◦
in tetrahydrofuran (1.24 cm3) at 0 C using a syringe pump over
1 h and the mixture stirred for 1 h. Saturated aqueous ammonium
chloride (2 cm3) and ethyl acetate (2 cm3) were added and the
aqueous phase extracted into ethyl acetate (3 ¥ 5 cm3). The organic
extracts were washed with brine (10 cm3), dried (MgSO4) and
concentrated under reduced pressure. Column chromatography
of the residue, eluted with 0–10% ether in petrol, gave the title
compound 35a (9 mg, 26%) as a clear oil, Rf = 0.52 (50% ether
in petrol) (Found; M+ + NH4, 576.3196. C31H50O5SSiN requires
M, 576.3179); nmax/cm-1 2925, 2857, 1719, 1670, 1449, 1310, 1246,
1149, 1085, 1029, 838 and 749; dH (300 MHz, CDCl3) 7.88 (2 H, d,
J 6.5, Ar-H), 7.45–7.57 (3 H, m, Ar-H), 6.04 (1 H, s, 17-H), 4.74
(2 H, s, OCH2O), 4.20 (2 H, d, J 16, 2-H and 4-H), 4.15 (1 H, m,
9-H), 3.92 (1 H, m, 16-H), 3.86 (1 H, d, J 15, 4-H¢), 3.68 (1 H, d,
J 15.5, 2-H¢), 3.50 (2 H, m, CH2CH2Si), 3.38 (1 H, t, J 4, 12-H),
2.65 (1 H, d, J 19.5, 11-H), 2.46 (1 H, m, 14-H), 2.19 (1 H, dd, J
19, 4, 11-H¢), 2.12 (1 H, m, 15-H), 1.96–2.06 (4 H, m, J 9, 7-H2
and 8-H2), 1.54 (3 H, s, 10-CH3), 1.44 (1 H, m, 15-H¢), 1.33 (3 H, s,
13-CH3), 1.27 (3 H, d, J 6.5, 14-CH3), 0.92 (2 H, m, CH2Si) and
0.00 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3) 141.2, 139.3, 133.6,
133.2, 129.0, 128.9, 126.0, 120.7, 93.1, 87.9, 78.3, 70.3, 70.1, 66.0,
65.0, 58.0, 47.9, 35.4, 35.1, 31.1, 25.9, 22.6, 19.7, 18.6, 18.4, 18.1
and -1.4; m/z (CI) 576 (M+ + 18, 5%), 411 (100), 269 (50), 160 (35)
and 90 (72). The second fraction was recovered starting material
34 (5 mg, 13%) followed by the title compound 35b (17 mg, 49%)
as a clear oil, Rf = 0.48 (50% ether in petrol) (Found; M+ + NH4,
576.3178; C31H50O5SSiN requires M, 576.3179); nmax/cm-1 2925,
2859, 2234, 1720, 1669, 1449, 1378, 1311, 1247, 1149, 1084, 1030,
936, 838 and 749; dH (500 MHz, CDCl3) 8.05 (2 H, d, J 7, Ar-H),
7.61 (1 H, t, J 7.5, Ar-H), 7.54 (2 H, t, J 8, Ar-H), 5.92 (1 H, s,
17-H), 4.78 and 4.74 (each 1 H, d, J 7, OCHHO), 4.66 (1 H, t, J
6.5, 9-H), 4.42 (1 H, dd, J 10, 6, 16-H), 4.32 (1 H, d, J 16, 2-H),
4.28 (1 H, dd, J 6, 2, 12-H), 4.25 and 4.07 (each 1 H, d, J 10, 4-H),
4.03 (1 H, d, J 16, 2-H¢), 3.64 (2 H, m, CH2CH2Si), 3.03 (1 H,
dqd, J 12.5, 7, 2.5, 14-H), 2.68 (1 H, d, J 17, 11-H), 2.49 (1 H, dd,
J 17, 6, 11-H¢), 2.22 (1 H, m, 15-H), 2.00 (2 H, m), 1.85 (2 H, m),
(1¢RS)- and (1¢SR)-(2RS,3SR,5RS,6SR)-2-[(6E)-8-tert-
Butyldiphenylsilyloxy-1-hydroxy-7-methyloct-6-en-2-yn-1-yl]-
5,6-dimethyl-6-phenylsulfonylmethyl-3-(2-trimethylsilylethoxy)-
methoxy-1-methylenecyclohexanes 37 and 38
n-Butyllithium(1.6 M in tetrahydrofuran, 0.31 cm3, 0.491 mmol)
was added dropwise over 10 min to the sulfone 31 (0.16 g,
0.197 mmol) in tetrahydrofuran (3.9 cm3) at -78 ◦C and the
mixture stirred for 2.5 h before saturated aqueous ammonium
chloride (4 cm3) was added. After allowing to warm to room
temperature, ethyl acetate (10 cm3) was added, the aqueous phase
was extracted with ethyl acetate (4 ¥ 10 cm3), and the organic
extracts were washed with brine (15 cm3), dried (Na2SO4) and
concentrated under reduced pressure. Column chromatography of
the residue, eluting with 0–30% ether in petrol, afforded the title
compound 37 (94 mg, 59%) as a pale yellow oil, Rf = 0.45 (50% ether
in petrol) (Found; M+ + NH4, 832.4485. C47H70O6Si2SN requires
M, 832.4462); nmax/cm-1 3493 (br), 3069, 2953, 2857, 1462, 1447,
1319, 1248, 1151, 1110, 1027, 859, 836, 743 and 707; dH (400 MHz,
2584 | Org. Biomol. Chem., 2009, 7, 2576–2590
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CDCl3) 7.93 (2 H, d, J 7, Ar-H), 7.68 (4 H, dd, J 7.5, 1.5, Ar-H),
7.64 (1 H, m, Ar-H), 7.57 (2 H, t, J 7.5, Ar-H), 7.36–7.42, (6 H,
m, Ar-H), 5.46 (1 H, m, 6¢-H), 5.33 and 5.17 (each 1 H, s, 1-CH),
4.84 and 4.80 (each 1 H, d, J 7, OCHHO), 4.62 (1 H, br d, J 9,
1¢-H), 4.09 (1 H, d, J 10, OH), 4.05 (2 H, s, 8¢-H2), 3.89 (1 H, td,
J 10, 5, 3-H), 3.74 (1 H, td, J 10, 5, OCHHCH2Si), 3.57 (1 H,
td, J 10, 6, OCHH¢CH2Si), 3.47 and 3.36 (each 1 H, d, J 15, 6-
CH), 2.70 (1 H, dd, J 9, 2, 2-H), 2.27 (4 H, m, 4¢-H2 and 5¢-H2),
2.09 (1 H, dt, J 12.5, 4.5, 4-H), 1.84 (1 H, m, 5-H), 1.62 (3 H, s,
7¢-CH3), 1.56 (1 H, m, 4-H¢), 1.27 (3 H, s, 6-CH3), 1.06 [9 H, s,
SiC(CH3)3], 0.95 (2 H, m, CH2Si), 0.91 (3 H, d, J 7, 5-CH3) and
0.03 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3) 147.5, 142.5, 135.5,
135.3, 133.7, 133.3, 129.5, 129.3, 127.5, 127.3, 122.5, 111.7, 94.6,
86.7, 79.5, 79.4, 68.7, 65.6, 64.4, 63.2, 51.0, 45.3, 36.7, 36.1, 30.2,
27.2, 26.8, 19.2, 19.1, 18.0, 16.5, 13.6 and -1.5; m/z (CI) 832 (M+ +
18, 12%), 442 (12), 408 (73), 391 (32), 365 (26), 294 (46) and 277
(100). The second fraction was the title compound 38 (22 mg, 13%)
as a pale yellow oil, Rf = 0.42 (50% ether in petrol) (Found; M+ +
NH4, 832.4450. C47H70O6Si2SN requires M, 832.4462); nmax/cm-1
3421 (br), 2953, 2929, 1719, 1695, 1560, 1318, 1150 and 1030; dH
(300 MHz, CDCl3) 7.93 (2 H, d, J 8, Ar-H), 7.68 (4 H, d, J 8,
Ar-H), 7.62 (1 H, t, J 7, Ar-H), 7.55 (2 H, dd, J 8, 6.5, Ar-H),
7.39 (6 H, m, Ar-H), 5.49 and 5.44 (each 1 H, s, 1-CH), 5.38 (1 H,
m, 6¢-H), 4.82 (1 H, m, 1¢-H), 4.73 (2 H, s, OCH2O), 4.05 (2 H, s,
8¢-H2), 3.70 (1 H, m, 3-H), 3.66 (2 H, t, J 8.5, CH2CH2Si), 3.53
and 3.41 (each 1 H, d, J 15, 6-CH), 3.27 (1 H, d, J 7.5, OH), 2.76
(1 H, dd, J 7, 5.5, 2-H), 2.21 (4 H, m, 4¢-H2 and 5¢-H2), 1.96 (1 H,
dt, J 13, 4, 4-H), 1.81 (1 H, m, 5-H), 1.60 (3 H, s, 7¢-CH3), 1.50
(1 H, m, 4-H¢), 1.33 (3 H, s, 6-CH3), 1.07 [9 H, s, SiC(CH3)3], 0.97
(2 H, m, CH2Si), 0.90 (3 H, d, J 6.5, 5-CH3) and 0.03 [9 H, s,
Si(CH3)3]; dC (75 MHz, CDCl3) 147.1, 142.9, 135.8, 135.7, 134.1,
133.6, 129.8, 129.5, 128.6, 127.8, 127.7, 122.9, 114.7, 94.3, 86.9,
80.8, 69.1, 65.8, 63.9, 63.4, 52.8, 44.9, 37.3, 36.2, 27.3, 27.1, 19.5,
19.4, 18.3, 16.9, 13.8 and -1.2; m/z (CI) 832 (M+ + 18, 2%), 498
(2), 294 (36), 277 (100), 196 (32), 135 (28) and 90 (61).
6¢-H), 5.34 (1 H, s, 1-CH¢), 4.73 (1 H, d, J 11.5, CHHAr), 4.66
and 4.59 (each 1 H, d, J 7, OCHHO), 4.54 (1 H, m, 1¢-H), 4.35
(1 H, d, J 11, CHH¢Ar), 4.08 (2 H, s, 8¢-H2), 3.82 (3 H, s, OCH3),
3.70 (2 H, m, 3-H and OCHHCH2Si), 3.55 (1 H, d, J 14.5, 6-CH),
3.48 (1 H, m, OCHH¢CH2Si), 3.34 (1 H, d, J 14.5, 6-CH¢), 2.62
(1 H, dd, J 8, 4, 2-H), 2.29 (4 H, m, 4¢-H2 and 5¢-H2), 2.00 (1 H,
dt, J 13, 5, 4-H), 1.91 (1 H, m, 5-H), 1.65 (3 H, s, 7¢-CH3), 1.52
(1 H, m, 4-H¢), 1.32 (3 H, s, 6-CH3), 1.08 [9 H, s, SiC(CH3)3],
0.94 (3 H, d, J 6.5, 5-CH3), 0.90 (2 H, m, CH2Si) and 0.03 [9 H, s,
Si(CH3)3]; dC (75 MHz, CDCl3) 146.6, 143.0, 142.3, 135.81, 135.80,
134.1, 133.4, 130.4, 129.8, 129.4, 127.9, 127.7, 123.0, 120.8, 114.7,
113.9, 103.6, 95.0, 91.7, 88.4, 78.2, 77.2, 70.3, 69.1, 69.0, 65.2,
63.9, 55.5, 52.1, 45.1, 36.4, 35.2, 27.5, 27.1, 19.5, 18.3, 17.2, 13.9
and -1.2.
(2SR,3SR,5RS,6SR)-2-[(1RS,6E)-8-Hydroxy-1-(4-methoxy)-
benzyloxy-7-methyloct-6-en-2-ynyl]-5,6-dimethyl-6-
phenylsulfonylmethyl-3-(2-trimethylsilylethoxy)methoxy-
1-methylenecyclohexane 40
tetra-n-Butylammonium fluoride (1.0 M solution in tetrahydro-
furan, 0.0192 cm3, 0.0192 mmol) was added to the silylether
39 (18 mg, 0.0192 mmol) in tetrahydrofuran (0.4 cm3) at room
temperature and the solution stirred for 1.5 h. After concentration
under reduced pressure, chromatography of the residue, eluting
with 5–50% ether in petrol, afforded the title compound 40 (0.012 g,
87%) as a clear oil, Rf = 0.1 (50% ether in petrol) nmax/cm-1 3509
(br), 2930, 1612, 1513, 1448, 1376, 1313, 1248, 1149, 1031 and 835;
dH (300 MHz, C6D6) 7.84 (2 H, br d, J 8, Ar-H), 7.36 (2 H, d, J
8.5, Ar-H), 7.12 (1 H, m, Ar-H), 6.94 (2 H, m, Ar-H), 6.80 (2 H,
m, Ar-H), 5.95 (1 H, s, 1-CH), 5.64 (2 H, m, 6¢-H and 1-CH¢),
4.99 (1 H, d, J 11, CHHAr), 4.91 (1 H, d, J 4, 1¢-H), 4.81 and 4.68
(each 1 H, d, J 7, OCHHO), 4.47 (1 H, d, J 11, CHH¢Ar), 4.34
(1 H, br s, OH), 3.98 (1 H, m, 3-H), 3.94 (2 H, s, 8¢-H2), 3.80 and
3.59 (each 1 H, q, J 8.5, CHHCH2Si), 3.43 (1 H, d, J 15, 6-CH),
3.29 (3 H, s, OCH3), 3.24 (1 H, d, J 15, 6-CH¢), 2.92 (1 H, dd, J
8, 4, 2-H), 2.21 (4 H, br s, 4-H2 and 5-H2), 2.10 (1 H, m, 4-H),
1.86 (1 H, m, 5-H), 1.55 (3 H, s, 7¢-CH3), 1.57 (1 H, m, 4-H¢), 1.36
(3 H, s, 6-CH3), 0.98 (2 H, m, CH2Si), 0.78 (3 H, d, J 6.5, 5-CH3)
and 0.00 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3) 159.4, 147.1,
142.9, 136.7, 133.5, 130.4, 129.8, 129.5, 127.7, 123.6, 114.0, 95.0,
88.4, 78.4, 70.3, 69.2, 68.5, 65.2, 63.8, 55.5, 51.6, 45.3, 37.2, 37.1,
27.0, 19.3, 18.6, 18.2, 17.0, 4.1 and -1.2; m/z (ES+) 719 (M+ + 23,
47%) and 105 (100); (APCI-) 731 (M+ + 35, 100%), 712 (12) and
612 (21).
(2SR,3SR,5RS,6SR)-2-[(1RS,6E)-8-tert-Butyldiphenylsilyloxy-1-
(4-methoxy)benzyloxy-7-methyloct-6-en-2-yn-1-yl]-5,6-dimethyl-
6-phenylsulfonylmethyl-3-(2-trimethylsilylethoxy)methoxy-1-
methylenecyclohexane 39
Sodium hydride (2.5 mg, 0.062 mmol) was suspended in anhydrous
N,N-dimethylformamide (0.25 cm3) and the suspension cooled
◦
to 0 C. The alcohol 37 (42 mg, 0.052 mmol) in tetrahydrofuran
(0.25 cm3) was added and the resulting yellow solution was allowed
to warm to room temperature and stirred for 30 min. The solution
◦
was cooled to 0 C and 4-methoxybenzyl chloride (0.008 cm3,
(2SR,3SR,5RS,6SR)-2-[(1RS,6E)-8-Bromo-1-(4-methoxy)
benzyloxy-7-methyloct-6-en-2-yn-1-yl]-5,6-dimethyl-6-
phenylsulfonylmethyl-3-(2-trimethylsilylethoxy)methoxy-
1-methylenecyclohexane 41
0.062 mmol) was added. After 16 h at room temperature, water
(2 cm3) and ethyl acetate (2 cm3) were added and the aqueous
phase extracted into ethyl acetate (3 ¥ 3 cm3). The organic extracts
were washed with brine (5 cm3), dried (MgSO4) and concentrated
under reduced pressure. Column chromatography of the residue,
eluting with 1–10% ether in petrol, afforded the title compound 39
(28 mg, 58%) as a pale yellow oil, Rf = 0.65 (50% ether in petrol);
Triethylamine (0.03 cm3, 0.22 mmol) and methanesulfonyl chloride
(0.01 cm3) were added to the alco◦hol 40 (0.038 g, 0.0545 mmol)
in dichloromethane (0.8 cm3) at 0 C and the solution allowed to
warm to room temperature and stirred for 30 min. The mixture was
cooled to 0 ◦C and lithium bromide (0.07 g, 0.88 mmol) in acetone
(0.4 cm3) was added. After 30 min at room temperature, the
suspension was filtered through a pad of celite and the filter-cake
washed with dichloromethane. The filtrate was concentrated under
n
max/cm-1 2952, 2932, 2859, 1612, 1513, 1465, 1317, 1249, 1150,
1108, 1108, 1052, 1034 and 833; dH (300 MHz, CDCl3) 7.89 (2 H,
d, J 8, Ar-H), 7.70 (4 H, d, J 7.5, Ar-H), 7.61 (1 H, t, J 8, Ar-H),
7.51 (2 H, t, J 7.5, Ar-H), 7.41 (6 H, m, Ar-H), 7.24 (2 H, d, J
8.5, Ar-H), 6.86 (2 H, d, J 8, Ar-H), 5.50 (2 H, br s, 1-CH and
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reduced pressure and the residue was taken up in ethyl acetate
(5 cm3) and washed with saturated aqueous sodium bicarbonate
(5 cm3). The aqueous phase was extracted with ethyl acetate (3 ¥
5 cm3), the organic extracts were washed with brine (5 cm3),
dried (MgSO4) and concentrated under reduced pressure. Column
chromatography of the residue, eluted with 1–10% ether in petrol,
afforded the title compound 41 (0.035 g, 92%) as a clear oil, Rf =
0.5 (50% ether in petrol); nmax/cm-1 2950, 2837, 1612, 1513, 1446,
1316, 1248, 1149, 1032 and 835; dH (300 MHz, CDCl3) 7.89 (2 H,
d, J 7, Ar-H), 7.62 (1 H, t, J 7.5, Ar-H), 7.53 (2 H, t, J 7.5, Ar-H),
7.24 (2 H, d, J 8.5, Ar-H), 6.87 (2 H, d, J, 9, Ar-H), 5.69 (1 H, t,
J 6.5, 6¢-H), 5.51 and 5.36 (each 1 H, s, 1-CH), 4.73 (1 H, d, J 11,
CHHAr), 4.63 and 4.56 (each 1 H, d, J 7, OCHHO), 4.55 (1 H,
m, 1¢-H), 4.35 (1 H, d, J 11.5, CHH¢Ar), 3.98 (2 H, s, 8¢-H2), 3.81
(3 H, s, OCH3), 3.63–3.72 (2 H, m, 3-H and CHHCH2Si), 3.53
(1 H, d, J 15, 6-CH), 3.45 (1 H, m, CHH¢CH2Si), 3.35 (1 H, d, J
15, 6-CH¢), 2.60 (1 H, dd, J 9, 3.5, 2-H), 2.26–2.33 (4 H, m, 4¢-H2
and 5¢-H2), 1.98 (1 H, dt, J 13, 4.5, 4-H), 1.84 (1 H, m, 5-H), 1.77
(3 H, s, 7¢-CH3), 1.49 (1 H, m, 4-H¢), 1.31 (3 H, s, 6-CH3), 0.91
(3 H, d, J 6.5, 5-CH3), 0.87 (2 H, m, CH2Si) and 0.01 [9 H, s,
Si(CH3)3]; dC (75 MHz, CDCl3) 159.1, 146.2, 142.7, 133.2, 130.0,
129.5, 129.2, 128.3, 127.4, 114.1, 113.7, 94.8, 87.3, 78.5, 70.1, 68.3,
64.9, 63.6, 55.3, 51.5, 45.0, 41.3, 36.8, 36.4, 27.6, 18.7, 18.6, 18.0,
16.8, 14.9 and -1.5; m/z (ES+) 783 (M+ + 23, 71%), 767 (100), 765
(93), 737 (44) and 721 (94).
(1SR,2RS,7E,11SR,12RS,14SR)-2-(4-Methoxy)benzyloxy-15-
methylene-8,11,12-trimethyl-14-(2-trimethylsilylethoxymethoxy)-
bicyclo[9.3.1]pentadec-7-en-3-yne 43
Disodium hydrogen phosphate (23 mg, 0.16 mmol) was added to
the sulfone 42 (10 mg, 0.016 mmol) in tetrahydrofuran (0.1 cm3)
and anhydrous methanol (0.4 cm3) was added. The suspension
was cooled to 0 ◦C, sodium-mercury amalgam (5%, 0.074 g,
0.16 mmol) was added portionwise, and the mixture allowed to
warm to room temperature. After stirring for 1.5 h, saturated
aqueous ammonium chloride (1 cm3) was added, and the mixture
diluted with ethyl acetate (3 cm3) and decanted from the residue
which was washed with ethyl acetate (2 ¥ 2 cm3). The aqueous
phase was extracted into ethyl acetate (3 ¥ 3 cm3), and the
organic extracts washed with brine (5 cm3), dried (Na2SO4) and
concentrated under reduced pressure. Column chromatography
of the residue, eluted with 0–5% ether in petrol, afforded the title
compound 43 (8 mg, 93%) as a clear oil, Rf = 0.6 (50% ether in
petrol) (Found; M+ + NH4, 556.3821. C33H54O4NSi requires M,
556.3822); nmax/cm-1 2952, 2926, 1727, 1639, 1613, 1514, 1461,
1380, 1249, 1106, 1054, 1036 and 836; dH (300 MHz, CDCl3) 7.30
and 6.89 (each 2 H, d, J 8.5, Ar-H), 5.45 (1 H, s, 15-CH), 5.02
(1 H, br d, J 7.5, 7-H), 4.92 (1 H, s, 15-CH¢), 4.78 (1 H, d, J 11.5,
CHHAr), 4.67 and 4.56 (each 1 H, d, J 6.5, OCHHO), 4.45 (1 H,
d, J 4, 2-H), 4.28 (1 H, d, J 11.5, CHH¢Ar), 3.82 (3 H, s, OCH3),
3.73 (1 H, td, J 10.5, 6, CHHCH2Si), 3.60 (1 H, td, J 10.5, 6,
14-H), 3.42 (1 H, td, J 10, 6.5, CHH¢CH2Si), 2.64 (1 H, dd, J
10.5, 4, 1-H), 2.40–2.20 (4 H, m), 1.90–2.10 (4 H, m), 1.62 (3 H, s,
8-CH3), 1.42–1.52 (2 H, m), 1.27 (1 H, m, 12-H), 1.04 (3 H, s,
11-CH3), 0.89 (2 H, m, CH2Si), 0.77 (3 H, d, J 6.5, 12-CH3) and
0.00 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3) 158.8, 150.4, 135.9,
130.4, 129.1, 126.3, 113.5, 109.1, 95.1, 86.9, 81.4, 79.6, 70.5, 68.0,
64.7, 55.2, 51.8, 44.2, 42.9, 39.5, 35.2, 30.1, 29.6, 27.2, 18.7, 17.9,
16.3, 15.5 and -1.5; m/z (CI) 556 (M+, 0.5%), 391 (6), 361 (5), 257
(4), 154 (43), 137 (29), 121 (100) and 90 (33).
(1SR,2RS,11SR,12RS,14SR,7E)-10-Phenylsulfonyl-8,11,12-
trimethyl-15-methylene-2-(4-methoxy)-benzyloxy-14-(2-
trimethylsilylethoxy)methoxybicyclo[9.3.1]pentadec-7-en-3-yne 42
Sodium hexamethyldisilazide (1.0
M
in tetrahydrofuran,
0.356 cm3, 0.356 mmol) was added to the bromide 41 (0.09 g,
◦
0.19 mmol) in tetrahydrofuran (1.5 cm3) at 0 C using a syringe
pump over 1 h and the mixture stirred for 30 min before saturated
ammonium chloride (2 cm3) and ethyl acetate (5 cm3) were
added. The aqueous phase was extracted with ethyl acetate (3 ¥
5 cm3) and the organic extracts were washed with brine (10 cm3),
dried (Na2SO4) and concentrated under reduced pressure. Column
chromatography of the residue, eluted with 1–10% ether in petrol,
afforded the title compound 42 (0.055 g, 68%) as a clear oil, Rf = 0.6
(50% ether in petrol) (Found; M+ + NH4, 696.3749. C39H58O6SSiN
requires M, 696.3754); nmax/cm-1 2923, 2871, 1613, 1514, 1446,
1303, 1249, 1142, 1050, 1035, 923 and 836; dH (300 MHz, CDCl3)
7.97 (2 H, d, J 7, Ar-H), 7.56–7.66 (3 H, m, Ar-H), 7.31 (2 H, d,
J 8, Ar-H), 6.90 (2 H, d, J 8.5, Ar-H), 6.05 (1 H, s, 15-CH), 6.00
(1 H, s, 15-CH¢), 5.53 (1 H, m, 7-H), 4.80 (1 H, d, J 11.5, CHHAr),
4.65 and 4.55 (each 1 H, d, J 6.5, OCHHO), 4.54 (1 H, m, 2-H),
4.29 (1 H, d, J 11, CHH¢Ar), 3.83 (3 H, s, OCH3), 3.71 (2 H, m,
14-H and CHHCH2Si), 3.59 (1 H, m, 10-H), 3.43 (1 H, td, J 10,
7, CHH¢CH2Si), 3.17 (1 H, t, J 13, 9-H), 2.91 (1 H, m, 12-H),
2.41 (1 H, dd, J 11, 4, 1-H), 2.29 (2 H, m), 2.06–2.19 (4 H, m),
1.44 (3 H, s, 8-CH3), 1.25 (1 H, m, 13-H¢), 1.09 (6 H, m, 11-CH3
and 12-CH3), 0.91 (2 H, m, CH2Si) and 0.00 [9 H, s, Si(CH3)3]; dC
(75 MHz, CDCl3) 158.6, 145.4, 142.1, 133.1, 133.0, 130.2, 130.0,
129.0, 128.1, 115.6, 113.6, 95.1, 85.9, 82.2, 78.6, 72.3, 70.7, 67.8,
64.9, 55.2, 53.5, 52.9, 39.8, 39.2, 37.6, 29.6, 26.2, 22.4, 18.3, 18.1,
17.9, 17.3 and -1.5; m/z (CI) 690 (M+ + 18, 0.3%), 154 (37), 177
(100) and 100 (49).
(1RS,2RS,7E,11SR,12RS,14SR)-2-Hydroxy-15-methylene-
8,11,12-trimethyl-14-(2-trimethylsilylethoxymethoxy)-
bicyclo[9.3.1]pentadec-7-en-3-yne 44
An aqueous pH 7 phosphate buffer (0.054 cm3) was added to
a rapidly stirred solution of the ether 43 (32 mg, 0.0594 mmol)
in dichloromethane (0.4 cm3) and the mixture was cooled to
0 ◦C. Dichlorodicyanoquinone (0.015 g, 0.0654 mmol) was added
and, after 10 min, dichloromethane (2 cm3) and aqueous pH 7
buffer (5 cm3) were added. The aqueous phase was extracted into
dichloromethane (4 ¥ 5 cm3) and the organic extracts were washed
with aqueous pH 7 buffer (2 ¥ 5 cm3), water (5 cm3) and brine
(5 cm3), dried (Na2SO4), and concentrated under reduced pressure.
Column chromatography of the residue, eluted with 1–15% ether
in petrol, afforded the title compound 44 (18 mg, 72%) as a clear
oil, Rf = 0.55 (50% ether in petrol) (Found; M+ + H, 419.2973.
C25H43O3Si requires M, 419.2981); nmax/cm-1 3454 (br), 2920, 2851,
1731, 1462, 1379, 129, 1054, 1037, 859 and 838; dH (400 MHz,
CDCl3) 5.50 (1 H, s, 15-CH), 4.98 (1 H, br d, J 9, 7-H), 4.91
(1 H, s, 15-CH¢), 4.82 (1 H, br s, 2-H), 4.70 and 4.67 (each 1 H, d,
J 6.5, OCHHO), 3.75 (2 H, m, OH and CHHCH2Si), 3.51 (2 H,
m, 14-H and CHH¢CH2Si), 2.52 (1 H, dd, J 11, 4, 1-H), 2.28–2.38
(3 H, m, 5-H, 6-H and 9-H), 2.23 (1 H, td, J 13, 2, 5-H¢), 1.98
2586 | Org. Biomol. Chem., 2009, 7, 2576–2590
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(2 H, m, 6-H¢ and 9-H¢), 1.86 (1 H, m, 13-H), 1.61 (3 H, s, 8-CH3),
1.46 (1 H, dt, J 14, 3.6, 10-H), 1.42 (1 H, m, 13-H¢), 1.23–1.34
(2 H, m, 10-H¢and 12-H), 1.02 (3 H, s, 11-CH3), 0.97 (2 H, m,
CH2Si), 0.77 (3 H, d, J 7, 12-CH3) and 0.02 [9 H, s, Si(CH3)3];
dC (100 MHz, CDCl3) 150.6, 135.8, 126.5, 108.9, 95.3, 86.5, 81.4,
76.3, 65.9, 61.4, 52.0, 44.4, 42.9, 38.6, 35.1, 30.0, 27.1, 18.8, 18.0,
17.9, 16.5, 15.4 and -1.6; m/z (CI) 419 (M+ + 1, 3%), 343 (12) and
271 (100).
1671, 1562, 1472, 1445, 1428, 1320, 1248, 1150, 1110, 1056, 1030,
859, 835, 745 and 705; dH (300 MHz, CDCl3) 7.89 (2 H, d, J 6.5,
Ar-H), 7.74 (4 H, dd, J 7.5, 2, Ar-H), 7.50 (4 H, m, Ar-H), 7.45
(4 H, m, Ar-H), 7.39 (6 H, m, Ar-H), 5.70 (1 H, s, 2¢-H), 5.51 (1 H,
t, J 7.5, 6¢-H), 5.15 and 4.70 (each 1 H, s, 1-CH), 4.63 and 4.60
(each 1 H, d, J 7, OCHHO), 4.67 (2 H, br s, 8¢-H2), 3.92 (1 H,
td, J 8, 6, 3-H), 3.65–3.45 (2 H, m, CH2CH2Si), 3.38 (1 H, d, J
14.5, 6-CH), 3.15 (1 H, d, J 8, 2-H), 3.05 (1 H, d, 6-CH¢), 2.72
(2 H, m, 4¢-H2), 2.30 (2 H, m, 5¢-H2), 1.96 (1 H, m, 4-H and 5-H),
1.66 (3 H, s, 7¢-CH3), 1.43 (1 H, m, 4-H¢), 1.25 (3 H, s, 6-CH3),
1.08 [9 H, br s, SiC(CH3)3], 0.93 (2 H, m, CH2Si), 0.88 (3 H, d,
J 6.5, 5-CH3) and 0.00 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3)
195.6, 165.8, 147.3, 142.8, 135.8, 135.5, 135.0, 134.1, 133.6, 130.0,
129.9, 129.6, 129.5, 127.9, 127.5, 123.2, 118.0, 114.4, 94.8, 75.6,
69.2, 65.3, 62.8, 61.3, 45.2, 36.1, 35.1, 34.2, 27.9, 27.2, 27.0, 26.8,
19.6, 18.2, 17.0, 13.8 and -1.2; m/z (ES+) 945 (M+ + 23, 7%),
923 (M+ + 1, 8), 517 (9) and 145 (100). The second fraction was
the title compound 56 (0.152 g, 69%), as a pale yellow oil Rf =
0.4 (50% ether in petrol); nmax/cm-1 3068, 2925, 2855, 1735, 1664,
1543, 1446, 1318, 1149, 1109, 1030, 835 and 747; dH (400 MHz,
C6D6) 7.83 (2 H, m, Ar-H), 7.74 (3 H, m, Ar-H), 7.45 (2 H, m,
Ar-H), 7.22 (7 H, m, Ar-H), 6.92 (6 H, m, Ar-H), 6.62 (1 H, s,
2¢-H), 5.39 and 5.26 (each 1 H, d, J 1, 1-CH), 5.18 (1 H, m, 6¢-H),
4.84 and 4.73 (each 1 H, d, J 7, OCHHO), 4.45 (1 H, td, J 8.5, 4.5,
3-H), 3.97 (2 H, s, 8¢-H2), 3.75 (1 H, d, J 6.5, 2-H), 3.72 (2 H, m,
CH2CH2Si), 3.29 and 3.10 (each 1 H, d, J 14.5, 6-CH), 2.17–2.07
(5 H, m, 4-H, 4¢-H2 and 5¢-H2), 1.98 (1 H, m, 5-H), 1.57 (1 H, td,
J H 13.5, 5.5, 4-H¢), 1.36 (3 H, s, 7¢-CH3),1.34 (3 H, s, 6-CH3),
1.15 [9 H, s, SiC(CH3)3], 1.01 (2 H, m, CH2Si), 0.80 (3 H, d, J 7,
5-CH3) and 0.04 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3) 197.3,
162.3, 147.4, 142.5, 135.6, 135.4, 135.2, 133.7, 133.3, 131.0, 129.5,
129.2, 129.0, 127.5, 127.3, 121.8, 119.9, 114.0, 94.6, 75.7, 68.5,
65.0, 62.7, 59.8, 44.9, 36.5, 36.3, 35.3, 28.0, 26.8, 19.3, 19.2, 18.0,
16.7, 13.5, 13.3 and -1.4; m/z (ES+) 945 (M+ + 23, 38%) and 923
(M+ + 1, 53).
(2SR,3SR,5RS,6SR)-2-[(6E)-8-tert-Butyldiphenylsilyloxy-7-
methyl-1-oxo-oct-6-en-2-yn-1-yl]-5,6-dimethyl-6-
phenylsulfonylmethyl-3-(2-trimethylsilylethoxy)methoxy-
1-methylenecyclohexane 54
Dess–Martin periodinane (0.14 g, 0.33 mmol) was added to a
mixture of the alcohols 37 and 38 (0.225 g, 0.277 mmol) in
dichloromethane (15 cm3) at room temperature and the suspension
stirred for 30 min. Aqueous sodium hydroxide (1.6 M, 10 cm3)
and ether (20 cm3) were added and the aqueous phase extracted
with ether (4 ¥ 10 cm3). The organic extracts were washed with
aqueous sodium hydroxide (1.6 M, 20 cm3), brine (20 cm3),
dried (Na2SO4) and concentrated under reduced pressure. Column
chromatography of the residue, eluting with 1–25% ether in petrol,
afforded the title compound 54 (0.201 g, 89%) as a clear oil,
Rf = 0.5 (50% ether in petrol) (Found; M+ + NH4, 830.4304.
C47H68O6Si2SN requires M, 830.4306); nmax/cm-1 3069, 2952, 2893,
2857, 2212, 1672, 1447, 1428, 1320, 1248, 1150, 1110, 1058, 1032,
835, 741 and 707; dH (400 MHz, C6D6), 7.45–7.81 (6 H, m, Ar-H),
7.26 (6 H, m, Ar-H), 6.91 (3 H, m, Ar-H), 5.39 (2 H, m, 6¢-H
and 1-CH), 5.30 (1 H, s, 1-CH¢), 4.82 and 4.74 (each 1 H, d, J 7,
OCHHO), 4.37 (1 H, td, J 10, 5, 3-H), 4.08 (2 H, s, 8¢-CH2), 3.78
(1 H, d, J 9.5, 2-H), 3.71 (2 H, m, CH2CH2Si), 3.18 and 3.01 (each
1 H, d, J 15, 6-CH), 2.18 (1 H, m, 5-H), 2.09 (3 H, m, 4¢-H2 and
4-H), 1.97 (2 H, t, J 7, 5¢-H2), 1.48 (3 H, s, 7-CH3), 1.44 (1 H, m,
4-H¢), 1.19 [9 H, s, SiC(CH3)3], 1.0 (3 H, s, 6-CH3), 1.01 (2 H, m,
CH2Si), 0.76 (3 H, d, J 6.5, 5-CH3) and 0.03 [9 H, s, Si(CH3)3]; dC
(75 MHz, CDCl3) 187.7, 146.1, 142.5, 136.2, 135.5, 133.7, 133.4,
129.5, 129.3, 128.3, 127.6, 127.3, 121.5, 113.1, 95.1, 94.5, 81.0,
76.0, 68.6, 65.2, 62.5, 61.6, 45.2, 35.6, 35.2, 26.8, 26.1, 19.9, 19.4,
19.2, 17.9, 16.7, 13.6, and -1.4; m/z (CI) 830 (M+ + 18, 0.4%), 682
(1.3) and 90 (100).
(2SR,3SR,5RS,6SR)-2-[(2E,6E)-8-tert-Butyldiphenylsilyloxy-3,
7-dimethyl-1-oxo-oct-2,6-dien-1-yl]-5,6-dimethyl-6-
phenylsulfonylmethyl-3-(2-trimethylsilylethoxy)methoxy-
1-methylenecyclohexane 57
Methyllithium (1.6 M in ether, 0.26 cm3, 0.428 mmol) was added to
a suspension of copper(I) iodide (0.041 g, 0.214 mmol) in diethyl
ether (0.75 cm3) at 0 ◦C and the suspension stirred for 30 min.
(2SR,3SR,5RS,6SR)-2-[(2E,6E)- and -2-[(2Z,6E)-8-tert-
Butyldiphenylsilyloxy-7-methyl-3-phenylthio-1-oxo-oct-2,6-dien-1-
yl]-5,6-dimethyl-6-phenylsulfonylmethyl-3-(2-
◦
The solution was cooled to -78 C and a precooled solution of
the thioether 56 (0.152 g, 1.65 mmol) in diethyl ether (0.75 cm3)
was added using a cannula. After 30 min, saturated aqueous
ammonium chloride and saturated aqueous ammonia (1:1, 2 cm3)
was added and the mixture allowed to warm to room temperature.
Ether (5 cm3) was added, the aqueous phase extracted with ether
(4 ¥ 5 cm3) and the organic extracts combined and washed with
brine (10 cm3), dried (Na2SO4) and concentrated under reduced
pressure. Column chromatography of the residue, eluting with
1–25% ether in petrol, afforded the title compound 57 (0.13 g,
97%) as a clear oil, Rf = 0.3 (50% ether in petrol) (Found; M+ +
trimethylsilylethoxy)methoxy-1-methylenecyclohexane 55 and 56
Triethylamine (0.07 cm3, 0.504 mmol) and thiophenol (0.5 M
solution in methanol, 0.52 cm3, 0.26 mmol) were added to the
alkynone 53 (0.195 g, 0.24 mmol) in tetrahydrofuran (2.2 cm3)
at -20 ◦C and the solution stirred for 2 h. Saturated aqueous
ammonium chloride (2.5 cm3) was added and the mixture allowed
to warm to room temperature. Ethyl acetate (3 cm3) was added,
the aqueous layer extracted with ethyl acetate (4 ¥ 3 cm3) and
the organic extracts combined and washed with brine (5 cm3),
dried (Na2SO4) and concentrated under reduced pressure. Column
chromatography of the residue, eluted with 0–25% ether in petrol,
afforded the title compound 55 (0.058 g, 26%) as a pale yellow oil,
Rf = 0.5 (50% ether in petrol); nmax/cm-1 3069, 2953, 2930, 2857,
+
NH4 , 846.4628. C48H72O6NSSi2 requires M, 846.4619); nmax/cm-1
3069, 2931, 2893, 2857, 1685, 1615, 1471, 1446, 1428, 1320, 1248,
1150, 1110, 1056, 1032, 859 and 835; dH (400 MHz, C6D6) 7.80
(6 H, m, Ar-H), 7.26 (6 H, m, Ar-H), 6.91 (3 H, m, Ar-H), 6.33
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(1 H, s, 2¢-H), 5.43 (1 H, t, J 6.5, 6¢-H), 5.34 and 5.13 (each 1 H, s,
1-CH), 4.82 and 4.72 (each 1 H, d, J 7, OCHHO), 4.35 (1 H, td,
J 9, 5, 3-H), 4.11 (2 H, s, 8¢-H2), 3.70 (2 H, m, CH2CH2Si), 3.62
(1 H, d, J 9, 2-H), 3.24 and 3.02 (each 1 H, d, J 15, 6-CH), 2.19
(3 H, s, 3¢-CH3), 2.15 (1 H, dt, J 13.5, 4.5, 4-H), 2.09 (2 H, t, J 7.5,
5¢-H2), 2.02 (1 H, m, 5-H), 1.94 (2 H, t, J 7.5, 4¢-H2), 1.55 (1 H,
m, 4-H¢), 1.52 (3 H, s, 7¢-CH3), 1.23 (3 H, s, 6-CH3), 1.20 [9 H, s,
SiC(CH3)3], 0.99 (2 H, m, CH2Si), 0.77 (3 H, d, J 6.5, 5-CH3) and
0.02 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3) 200.0, 158.9, 147.4,
142.5, 135.5, 135.0, 133.8, 133.3, 129.5, 129.2, 128.3, 127.6, 127.3,
123.8, 122.9, 113.2, 94.4, 75.7, 68.8, 65.0, 62.7, 60.3, 45.0, 41.1,
36.0, 35.5, 26.8, 25.8, 19.5, 19.3, 18.0, 16.7, 13.5 and -1.4; m/z
(CI) 846 (M+ + 18, 0.1%), 426 (3), 408 (3.5), 405 (3) and 90 (100).
0.6 (50% ether in petrol); nmax/cm-1 2927, 2889, 2862, 1470, 1316,
1253, 1152, 1105, 1029 and 833; dH (300 MHz, CDCl3) 7.90 (2
H, dd, J 7, 2, Ar-H), 7.71 (4 H, dd, J 7, 1.5, Ar-H), 7.60–7.20
(14 H, m, Ar-H), 5.42 (1 H, t, J 7, 6¢-H), 5.34 and 5.23 (each 1
H, s, 1-CH), 5.20 (1 H, m, 2¢-H), 4.73 (3 H, br s, OCH2O and
CHHAr), 4.69 (1 H, m, 1¢-H), 4.60 (1 H, d, J 12, OCHHO), 4.56
(1 H, d, J 7, CHH¢Ar), 4.48 (1 H, d, J 12, OCHH¢O), 4.06 (2 H,
br s, 8¢-H2), 3.79 (1 H, m, 3-H), 3.76 (1 H, d, J 14.5, 6-CH), 3.63
(2 H, m, CH2CH2Si), 3.33 (1 H, d, J 14.5, 6-CH¢), 2.54 (1 H, t,
J 5, 2-H), 2.15–1.95 (6 H, m, 4¢-H2, 5¢-H2, 4-H and 5-H), 1.73 (3
H, s, 3¢-CH3), 1.63 (3 H, s, 7¢-CH3), 1.59 (1 H, m, 4-H¢), 1.42 (3
H, s, 6-CH3), 1.09 [9 H, s, SiC(CH3)3], 1.00 (3 H, d, J 7, 5-CH3),
0.94 (2 H, m, CH2Si) and 0.04 [9 H, s, Si(CH3)3]; dC (75 MHz,
CDCl3) 147.3, 140.7, 138.2, 135.8, 134.6, 134.1, 133.4, 129.8, 129.4,
128.8, 128.7, 127.9, 127.7, 127.3, 124.2, 123.7, 117.4, 94.1, 92.0,
73.5, 70.0, 69.3, 65.6, 65.3, 64.1, 55.7, 44.3, 41.1, 39.9, 35.9, 35.2,
27.1, 26.6, 24.1, 19.6, 18.3, 17.5, 17.0, 13.8 and -1.1; m/z (ES+)
973 (M+ + 23, 100%), 933 (18), 827 (31), 372 (81), 341 (93) and
311 (73).
(2RS,3SR,5RS,6SR)-2-[(1SR,2E,6E)-8-tert-
Butyldiphenylsilyloxy-3,7-dimethyl-1-hydroxyoct-2,6-dien-1-yl]-
5,6-dimethyl-6-phenylsulfonylmethyl-3-(2-
trimethylsilylethoxy)methoxy-1-methylenecyclohexane 58
Sodium borohydride (20 mg, 0.504 mmol) was added to the
ketone 57 (0.278 g, 0.34 mmol) in ethanol (1.67 cm3) at room
temperature and the solution stirred for 18 h. The mixture was
concentrated under reduced pressure and column chromatography
of the residue, eluting with 0–20% ether in petrol, afforded the title
compound 58 (0.165 g, 59%) as a clear oil, Rf = 0.25 (50% ether in
petrol); nmax/cm-1 3499 (br), 2954, 2930, 2858, 1626, 1448, 1428,
1382, 1312, 1250, 1149, 1108, 1055, 1027, 936, 859, 834, 743 and
709; dH (300 MHz, C6D6) 7.80 (6 H, m, Ar-H), 7.24 (6 H, m, Ar-
H), 6.92 (3 H, m, Ar-H), 5.65 (1 H, d, J 8, 2¢-H), 5.57 (1 H, t, J
7, 6¢-H), 5.49 and 5.39 (each 1 H, s, 1-CH), 4.75 (1 H, td, J 8, 3.5,
1¢-H), 4.61 and 4.57 (each 1 H, d, J 7, OCHHO), 4.14 (2 H, br s,
8¢-H2), 3.92 (1 H, m, 3-H), 3.85 (1 H, d, J 3.5, OH), 3.62 (2 H, m,
CH2CH2Si), 3.19 and 3.12 (each 1 H, d, J 14, 6-CH), 2.82 (1 H,
dd, J 8, 4, 2-H), 2.23–2.09 (4 H, m, 4¢-H2 and 5¢-H2), 2.00 (1 H,
m, 5-H), 1.88 (1 H, dt, J 14, 5.5, 4-H), 1.70 (3 H, s, 3¢-CH3), 1.62
(3 H, s, 7¢-CH3), 1.53 (1 H, m, 4-H¢), 1.25 (3 H, s, 6-CH3), 1.17 [9
H, s, SiC(CH3)3], 0.95 (2 H, m, CH2Si), 0.89 (3 H, d, J 6.5, 5-CH3)
and 0.00 [9 H, s, Si(CH3)3]; dC (75 MHz, C6D6) 147.2, 143.0, 138.9,
135.9, 134.5, 134.2, 132.9, 129.8, 129.1, 124.7, 117.6, 93.4, 74.6,
69.5, 67.9, 65.3, 64.2, 56.4, 43.7, 39.9, 34.9, 34.7, 27.0, 26.6, 22.7,
19.5, 18.2, 17.2, 16.7, 13.6, 1.3 and -1.4.
(2SR,3SR,5RS,6SR)-2-[(1SR,2E,6E)-3,7-Dimethyl-1-
benzyloxymethoxy-8-hydroxyoct-2,6-dien-1-yl]-5,6-dimethyl-
6-phenylsulfonylmethyl-3-(2-trimethylsilylethoxy)methoxy-
1-methylenecyclohexane 60
tetra-n-Butylammonium fluoride (1.0 M in tetrahydrofuran,
0.16 cm3) was added to the silyl ether 59 (0.15 g, 0.16 mmol)
in tetrahydrofuran (1.5 cm3) at room temperature and the solution
stirred for 2 h. After concentration under reduced pressure, column
chromatography of the residue, eluted with 10–50% ether in petrol,
gave the title compound 60 (0.089 g, 79%) as a pale yellow oil, Rf =
0.05 (50% ether in petrol); nmax/cm-1 3443 (br), 2925, 2886, 1587,
1447, 1380, 1312, 1149, 1027 and 836; dH (300 MHz, C6D6) 7.89 (2
H, m, Ar-H), 7.35 (2 H, d, J 7.5, Ar-H), 7.19 and 7.09 (each 1 H,
m, Ar-H), 6.92 (4 H, m, Ar-H), 5.57 (1 H, m, 2¢-H), 5.53 and 5.51
(each 1 H, s, 1-CH), 5.37 (1 H, t, J 6.5, 6¢-H), 4.97 (1 H, dd, J 9,
4.5, 1¢-H), 4.80 (1 H, d, J 6.5, CHHAr), 4.72 (2 H, br s, OCH2O),
4.62 (1 H, d, J 12, OCHHO), 4.61 (1 H, d, J 6.5, CHH¢Ar), 4.46
(1 H, d, J 12, OCHH¢O), 4.01 (1 H, m, 3-H), 3.86 (2 H, br s, 8¢-
H2), 3.69 (1 H, d, J 14.5, 6-CH), 3.63–3.71 (2 H, m, CH2CH2Si),
3.38 (1 H, d, J 14.5, 6-CH¢), 2.78 (1 H, t, J 5, 2-H), 2.25–1.95 (6
H, m, 4-H, 5-H, 4¢-H2, 5¢-H2), 1.65 (3 H, s, 3¢-CH3), 1.61 (1 H,
m, 4-H), 1.55 (3 H, s, 7¢-CH3), 1.50 (3 H, s, 6-CH3), 0.95 (2 H,
CH2Si), 0.92 (3 H, d, J 7, 5-CH3) and 0.00 [9 H, s, Si(CH3)3]; dC
(75 MHz, CDCl3) 147.4, 143.8, 139.5, 138.5, 135.8, 132.6, 129.0,
128.5, 127.7, 124.8, 124.3, 117.4, 94.1, 92.1, 76.9, 73.6, 69.8, 68.4,
65.1, 64.1, 54.1, 44.4, 39.5, 36.1, 35.4, 30.3, 25.7, 20.8, 18.2, 17.3,
16.4, 13.7, 1.3 and -1.4; m/z (ES+) 735 (M+ + 23, 100%), 640
(23), 589 (23), 140 (42) and 126 (44).
(2SR,3SR,5RS,6SR)-2-[(1SR,2E,6E)-8-tert-
Butyldiphenylsilyloxy-3,7-dimethyl-1-benzyloxymethoxyoct-2,
6-dien-1-yl]-5,6-dimethyl-6-phenylsulfonylmethyl-3-(2-
trimethylsilylethoxy)methoxy-1-methylenecyclohexane 59
Di-isopropylethylamine (0.16 cm3), benzyloxymethyl chloride
(0.11 cm3) and tetra-n-butylammonium iodide (0.005 g,
0.0127 mmol) were added to the alcohol 58 (0.105 g, 0.127 mmol)
in tetrahydrofuran (0.16 cm3) at room temperature and the
solution stirred for 16 h. Methanol (0.025 cm3) and, after 1 h,
ethyl acetate (10 cm3) and water (10 cm3) were added. The aqueous
layer was extracted with ethyl acetate (4 ¥ 5 cm3) and the organic
extracts were washed with aqueous sodium hydrogen sulfate
(0.5 M, 15 cm3), aqueous pH 7 buffer (15 cm3) and brine (15 cm3),
dried (Na2SO4) and concentrated under reduced pressure. Column
chromatography of the residue, eluting with 0–20% ether in petrol,
gave the title compound 59 (0.104 g, 85%) as a pale yellow oil, Rf =
(2SR,3SR,5RS,6SR)-2-[(1SR,2E,6E)-8-Bromo-3,7-dimethyl-1-
benzyloxymethoxyoct-2,6-dien-1-yl]-5,6-dimethyl-6-
phenylsulfonylmethyl-3-(2-trimethylsilylethoxy)methoxy-
1-methylenecyclohexane 61
Triethylamine (0.016 cm3, 0.112 mmol) and methanesulfonyl
chloride (0.006 cm3, 0.0702 mmol) were added to the alcohol
60 (20 mg, 0.028 mmol) in dichloromethane (0.41 cm3) at 0 ◦C
and the solution stirred at room temperature for 0.5 h. After
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cooling to 0 ◦C, lithium bromide (0.036 g, 0.422 mmol) in acetone
(0.3 cm3) was added, and the mixture stirred at room temperature
for 0.5 h then filtered through a pad of celite. The filter cake
was washed with dichloromethane and the filtrate concentrated
under reduced pressure. The residue was taken up in ethyl acetate
(2 cm3) and washed with saturated aqueous sodium bicarbonate
(2 cm3). The aqueous layer was extracted with ethyl acetate (4 ¥
2 cm3) and the organic extracts were washed with brine (4 cm3),
dried (Na2SO4) and concentrated under reduced pressure. Column
chromatography of the residue, eluting with 0–15% ether in petrol,
afforded the title compound 61 (0.015 g, 69%) as a clear oil, Rf =
0.5 (50% ether in petrol); nmax/cm-1 2926, 2892, 1663, 1633, 1449,
1381, 1315, 1251, 1150, 1093, 1030, 854 and 836; dH (300 MHz,
CDCl3) 7.91 (2 H, d, J 7.5, Ar-H), 7.74 (1 H, dd, J 7, 2, Ar-H),
7.56 (3 H, m, Ar-H), 7.37 (4 H, m, Ar-H), 5.57 (1 H, t, J 6, 6¢-
H), 5.37 (1 H, s, 1-CH), 5.30 (1 H, d, J 7.5, 2¢-H), 5.25 (1 H, s,
1-CH¢), 4.75–4.65 (4 H, m, OCH2O, OCHHO and 1¢-H), 4.60 (1
H, d, J 12, CHHAr), 4.58 (1 H, d, J 6.5, OCHH¢O), 4.50 (1 H,
d, J 12, CHH¢Ar), 3.96 (2 H, br s, 8¢-H2), 3.79 (1 H, m, 3-H),
3.71 (1 H, d, J 14.5, 6-CH), 3.62 (2 H, m, OCH2CH2Si), 3.35 (1
H, d, J 14.5, 6-CH¢), 2.52 (1 H, t, J 5, 2-H), 2.17–2.00 (5 H, m,
4¢-H2, 5¢-H2 and 4-H), 1.97 (1 H, m, 5-H), 1.76 (3 H, s, 3¢-CH3),
1.70 (3 H, s, 7¢-CH3), 1.55 (1 H, m, 4-H¢), 1.41 (3 H, s, 6-CH3),
0.95 (5 H, m, CH2Si and 5-CH3) and 0.03 [9 H, s, Si(CH3)3]; dC
(75 MHz, CDCl3) 147.2, 143.0, 139.6, 138.1, 135.1, 133.4, 130.9,
129.9, 129.4, 128.7, 127.9, 127.6, 124.3, 117.1, 94.2, 92.2, 73.5,
70.0, 65.3, 64.0, 53.5, 44.4, 41.9, 39.1, 36.2, 35.3, 26.8, 24.1, 20.4,
18.3, 17.4, 16.8, 15.0 and -1.2; m/z (ES+) 799 (M+ + 23, 100%),
797 (M+ + 23, 80), 753 (22) and 652 (25).
15-CH¢), 4.89 (2 H, m, 2-H and 7-H), 4.74 (2 H, s, OCH2O),
3.90–3.50 (4 H, m, CH2CH2Si, OH and 14-H), 2.54 (1 H, dt, J
14, 7, 13-H), 2.42 (1 H, dd, J 11, 4.5, 1-H), 1.98–2.20 (6 H, m,
5-H2, 6-H2 and 9-H2), 1.87 (1 H, m, 13-H¢), 1.73 (2 H, m, 10-H2),
1.57 (3 H, s, 4-CH3), 1.54 (3 H, s, 8-CH3), 1.34 (1 H, m, 12-H),
0.98 (2 H, m, CH2Si), 0.84 (3 H, s, 11-CH3), 0.75 (3 H, d, J 6.5,
12-CH3) and 0.09 [9 H, s, Si(CH3)3]; dC (75 MHz, CDCl3) 153.0,
133.6, 131.4, 130.7, 130.2, 109.8, 96.6, 82.6, 67.5, 66.2, 51.0, 47.3,
43.8, 39.2, 38.8, 35.4, 29.9, 25.5, 19.0, 18.2, 17.9, 17.3, 15.4 and
-1.3; m/z (ES+) 458 (M+ + 23, 81%), 419 (23), 391 (72), 359 (22),
272 (31) and 271 (44).
Acknowledgements
We thank Dr. D. J. Holt for preparing compounds 22 and 23, Dr.
A. Balnaves for preliminary work on the Wittig rearrangement of
sulfone 31, and Merck, Sharpe and Dohme at Terlings Park for
support (to G.M.) under the CASE scheme.
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M
in tetrahydrofuran,
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(300 MHz, CDCl3) 5.57 (2 H, s, 15-CH and 3-H), 4.93 (1 H, m,
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2590 | Org. Biomol. Chem., 2009, 7, 2576–2590
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©