A total synthesis of milbemycin G: Approaches to the C(1)-C(10)-fragment and completion of the synthesis

Article abstract of DOI:10.1039/b508675b

A synthesis of the hydroxybutenolide (-)-6 required for synthesis of α-milbemycins and the completion of a total synthesis of milbemycin G 7 is reported. Following preliminary studies, an optimised synthesis of the hydroxybutenolide (-)-6 from the hydroxy

Full text of DOI:10.1039/b508675b

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A R T I C L E
A total synthesis of milbemycin G: approaches to the
C(1)–C(10)-fragment and completion of the synthesis
Simon Bailey, Madeleine Helliwell, Aphiwat Teerawutgulrag and Eric J. Thomas*
The School of Chemistry, The University of Manchester, Manchester, UK M13 9PL.
E-mail: e.j.thomas@manchester.ac.uk; Fax: 0161 275 4939; Tel: 0161 275 4614
Received 22nd June 2005, Accepted 8th August 2005
First published as an Advance Article on the web 14th September 2005
A synthesis of the hydroxybutenolide (−)-6 required for synthesis of a-milbemycins and the completion of a total
synthesis of milbemycin G 7 is reported.
Following preliminary studies, an optimised synthesis of the hydroxybutenolide (−)-6 from the hydroxyketone 38 was
developed which involved the resolution of 38 by separation of the 3-(O-chloroacetyl)-(S)-mandelates 80 and 83.
Ester 80, which corresponded to the required enantiomer of the hydroxyketone 38, crystallized from the mixture of
the diastereoisomeric esters 80 and 83 giving the (−)-hydroxyketone (−)-38 in an overall yield of 47% (based on
racemic 38) after ethanolysis. Hydroxyketone (−)-38 was oxidised to the enolic diketone (−)-39 and phenylselenation
and stereoselective reduction gave the trihydroxycyclohexyl selenide (−)-43. The regioselective introduction of the
non-conjugated double-bond into the six-membered ring was then achieved by esterification of the 4-hydroxyl group
using trichloroacetic acid to give the trichloroacetate (−)-69. Oxidative elimination from the trichloroacetate using
tert-butyl hydroperoxide was highly regioselective and gave the endo- and exocyclic alkenes (−)-44 and (−)-46 in a
ratio of 95 : 5 after ethanolysis of the trichloroacetates. Selective O-methylation of the 4-hydroxyl group via the cyclic
stannylene 55 and protection of the 3-hydroxyl group as its 2-trimethylsilylethoxymethyl (SEM) ether gave the ester
(−)-57. Following saponification of the ethyl ester, re-esterification using 2-trimethylsilylethanol and oxidation of the
2-trimethylsilylfuryl fragment using singlet oxygen gave the required hydroxybutenolide (−)-6.
The Wittig reaction between the phosphonium salt 2 and the hydroxybutenolide (−)-6 gave a ca. 2 : 1 mixture of the
(4Z)- and (4E)-isomers of the ester 84 which on treatment with a catalytic amount of iodine was converted into the
(4E)-isomer (4E)-84. Deprotection gave the seco-acid 85 but attempts to macrocyclise this were unsuccessful, the
elimination product 86 being the only product isolated. The Wittig product 84 was taken through to the butenolide
(2ꢀE)-91 by removal of the SEM group, cyclisation to form the butenolide ring and diene isomerization, but this
could not be converted into the corresponding seco-acid 92. However, removal of the SEM group from the seco-acid
85 gave the trihydroxy-acid 93 which was cyclized under modified Yamaguchi conditions to give the macrolide 94
together with a small amount of the macrocyclic butenolide 95. Reduction of this mixture using diisobutylaluminium
hydride gave (6R)-6-hydroxymilbemycin E 96 which was converted to milbemycin G 7 by cyclisation of the primary
chloride 97. The synthetic milbemycin G 7 was identical to a sample prepared by methylation of a commercial sample
of milbemycin D 98, 7-O-methylmilbemycin G 99 being a side-product of this methylation.
together with functional group interconversions and oxidation
Introduction
of the 2-trimethylsilylfuran using singlet oxygen, gave the hy-
The total synthesis of milbemycins and avermectins has attracted
droxybutenolide 3.4 In the synthesis of hydroxybutenolide 1, the
much interest from synthetic chemists.1 We completed a conver-
3,4-double-bond had been introduced by phenylselenation of the
thermodynamic trimethylsilyl enol ether of a Robinson product
followed by oxidative elimination. However, the regioselectivity
gent synthesis of milbemycin E 4, a non-aromatic b-milbemycin,
using the Wittig reaction between the hydroxybutenolide 1 and
the ylid derived from the phosphonium salt 2, as a key step.2 It
of the oxidative elimination was found to be sensitive to the
was of interest to see whether this approach could be applied
functionality at C(4). For example, oxidative elimination of the
to complete a synthesis of the a-milbemycins as represented by
a-phenyl selanyl ketone 11 gave an 85 : 15 mixture of the endo-
milbemycin G 7.3 This would require the introduction of an extra
and exocyclic alkenes 12 and 13 whereas oxidative elimination
oxygen functionality at C(6) and formation of the tetrahydro-
of the corresponding phenyl selanyl alcohol 14, albeit at a higher
furan ring. In the preceding paper,4 a synthesis of the hydrox-
temperature, gave more of the exocyclic alkene, 15 : 16 = 11 : 89.6
ybutenolide 3, which has this additional oxygen functionality
but which lacks the 3,4-double-bond (milbemycin numbering),
is described, together with its incorporation into a synthesis
of (6R)-hydroxy-3,4-dihydromilbemycin E 5. We now report
studies leading to the synthesis of the hydroxybutenolide (−)-6
which has both the oxygen functionality at C(3) (corresponding
to C(6) in the milbemycins) and the incipient 3,4-double-bond,
and the completion of a synthesis of milbemycin G 7.5
The racemic hydroxybutenolide 3 had been prepared from
the keto-ester 8 and the alkoxymethyl isopropenyl ketones
9 (Ar = C6H5–, 4-MeOC6H4–) using Robinson reactions to
prepare the 2-hydroxycyclohexan-4-ones 10. The major products
from these reactions had the undesired configuration at C(3)
but stereoselective reduction at C(4) and inversion of the
configuration at C(3) by deprotection and oxidation–reduction,
Results and discussion
Preliminary studies
The Robinson products 10 would appear to be suitable precur-
sors of the required hydroxybutenolide 6 with the inversion of the
configuration at C(3) and the introduction of the cyclohexenyl
double-bond as key steps. However, in view of the sensitivity of
the regioselectivity of the selenoxide elimination to structure, it
was decided to check procedures for this process first.
The 3-benzyloxycyclohexan-4-one 174 was converted regiose-
lectively into the silyl enol ether 18,2 with concomitant silylation
of the 2-hydroxyl group, using an excess of trimethylsilyl tri-
fluoromethanesulfonate and triethylamine in dichloromethane,
3 6 5 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
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see Scheme 1. Reaction of this silyl enol ether with ben-
zene selenenyl chloride gave the phenyl selanyl ketone 19 as
a single diastereoisomer which was desilylated to give the
hydroxyketone 20. Oxidative elimination was then achieved
using a two-phase dichloromethane/aqueous hydrogen peroxide
system7 to give the cyclohexenone 21 as the only isolable material
in 50% yield, the regioselectivity of elimination being established
by 1H NMR (see experimental).
This sequence was then repeated using the 3-p-methoxybenzyl
protected ketone 224 since procedures were available for removal
of the p-methoxybenzyl group which should be compatible with
the cyclohexenyl double-bond, but attempts to convert the 3-p-
methoxybenzyloxycyclohexanone 22 into its trimethylsilyl enol
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
3 6 5 5

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predominantly. As expected,6 oxidative elimination from the
hydroxyselenide 28 gave a mixture of the endo- and exocyclic
alkenols 26 and 29, but the endocyclic alkene 26 was the major
product, 26 : 29 = 65 : 35, and the two alcohols 26 and 29
could be separated relatively easily by column chromatography
so providing a more convenient route to the alkenol 26.
These preliminary studies had shown that phenylselena-
tion/oxidative elimination could be used to introduce the incipi-
ent 3,4-double-bond into precursors of the hydroxybutenolide 6
albeit with variable regioselectivity. It remained to invert the con-
figuration at C(3). In the synthesis of the hydroxybutenolide 3,
this inversion had been carried out using an oxidation–reduction
sequence.4 However, it was thought this procedure would not be
suitable for the present case, vide infra, and so a Mitsunobu
inversion protocol was investigated first. The 4-hydroxyl group
in the diol 26 was protected as its tert-butyldimethylsilyl ether 30
and oxidation to the hydroxybutenolide 31 using singlet oxygen12
confirmed the stability of the cyclohexenyl double-bond to the
singlet oxygen reaction conditions, see Scheme 3. A Wittig
reaction with 2-methylpropyl(triphenyl)phosphorane then gave
a ca. 80 : 20 mixture of the (4Z)- and (4E)-dienyl acids 32.
These were not separated, instead the 3-alcohol was deprotected
by oxidative removal13 of the p-methoxybenzyl group to give
the (4Z)- and (4E)-dihydroxy acids 33, but attempts to cyclise
these using a Mitsunobu procedure to the corresponding five-
membered lactones with inversion of configuration at C(3), were
unsuccessful.
To check the compatibility of the incipient 3,4-double-
bond with the oxidation–reduction sequence, the diol 26 was
converted into the monomethyl ether 34 and the 3-hydroxyl
group deprotected to give the diol 35. Oxidation using Swern
conditions gave the ketone 36 but this was found to be unstable
and isomerised on standing to the a,b-unsaturated ketone
37. Attempts to reduce the non-conjugated ketone 36 were
unsuccessful. Tetramethylammonium triacetoxyborohydride in
acetic acid–acetonitrile led to rapid double-bond migration
giving the conjugated ketone 37 and complex mixtures of
products were obtained using other hydride reducing agents.
Attempts to convert the alcohol 35 with inversion into the
corresponding 4-nitrobenzoate under Mitsunobu conditions14
were also unsuccessful.
Scheme 1 Reagents and conditions: i, TMSOTf, Et3N, DCM (70%);
ii, PhSeCl, DCM (79%); iii, TBAF, THF, −50 ◦C (87%); iv, 30% aqu.
H2O2, DCM (50%).
ether using trimethylsilyl trifluoromethanesulfonate and triethy-
lamine led to complex mixtures of products possibly due to loss
of the p-methoxybenzyl group under the reaction conditions.8
However, tert-butyldimethylsilyl trifluoromethanesulfonate gave
the silyl enol ether 23 cleanly with just traces of the correspond-
ing bis-silylated ether, see Scheme 2. The enol ether 23 was
treated with phenyl selenenyl chloride to give the phenyl selanyl
ketone 24 which could also be obtained, albeit in only modest
yield, 36%, by direct phenyl selenation of the ketone 22 using
phenyl selenenyl chloride.9 Oxidative elimination using tert-
butyl hydroperoxide10 gave better yields of the cyclohexenone
25 than using hydrogen peroxide but was slow giving only 64%
of the product after 72 h at room temperature together with 18%
recovered starting material. This was resubjected to the reaction
conditions to give an overall yield of 76%.
Having prepared the cyclohexenone 25, the next step was
to reduce the ketone to the required alcohol 26. In earlier
work, the reduction of such 2-hydroxycyclohexen-4-ones using
sodium and tetramethylammonium triacetoxyborohydride had
been highly stereoselective due to intramolecular delivery of
the hydride to the ketone from the acetoxyborohydride reagent
when co-ordinated to the 2-hydroxyl group.11 However, in
the present case, the reduction using tetramethylammonium
triacetoxyborohydride showed only modest stereoselectivity and
a ca. 2 : 1 mixture of the alcohols 26 and 27, which were
difficult to separate by column chromatography, was obtained,
Scheme 2. In contrast, reduction of the phenyl selanyl ketone 24
using tetramethylammonium triacetoxyborohydride was highly
stereoselective for directed reduction and gave the alcohol 28
Synthesis and chemistry of the racemic hydroxybutenolide 6
In the preliminary investigations outlined above, useful proce-
dures had been developed for the regioselective introduction
of the cyclohexenyl double-bond, but the required inversion
of the configuration at C(3) by oxidation–reduction had been
hampered by double-bond migration at the ketone stage. It
was therefore clear that the configuration at C(3) had to be
corrected before the double-bond was introduced. Oxidation
Scheme 2 Reagents and conditions: i, TBSOTf, Et3N, DCM (95%); ii, PhSeCl, DCM (54%); iii, 30% aqu. H2O2, r.t., 10 min. (25, 27%) or tBuOOH,
DCM (25, 64%; recovered 24, 18%; 26/29, 88%; 26 : 29 = 65 : 35); iv, NMe4BH(OAc)3, MeCN, AcOH (26/27, 50%, 26 : 27 = 66 : 34; 28, 78%).
3 6 5 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7

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Scheme 3 Reagents and conditions: i, TBSOTf, 2,6-lutidine, DCM (97%); ii, O2, tetraphenylporphine (TPP), MeOH, DCM, hm (96%);
iii, (CH3)2CHCH2PPh3, nBuLi, −78 to −20 ◦C (68%, 4E : 4Z = 20 : 80); iv, DDQ (33, 78%; 35, 92%); v, LiHMDS, cetyltrimethylammonium
bromide (CTAB), MeI, THF, 0 ◦C (81%); vi, (COCl)2, DMSO, then Et3N (77%).
of the hydroxyketone 384 under Swern conditions gave the
enol 39 of the a-diketone which was converted into the tert-
butyldimethylsilyl enol ether 40 using tert-butyldimethylsilyl
trifluoromethanesulfonate and triethylamine, Scheme 4. It was
intended to reduce the ketone moiety in 40 to give the diol 41
which would be protected and the enol ether used to introduce
the required double-bond via phenylselenation–oxidative elimi-
nation, but conditions could not be found for a stereoselective
reduction of the ketone to the diol 41. Mild reducing agents, e.g.
sodium borohydride–cerium(III) chloride or tetramethylammo-
nium triacetoxyborohydride, gave unchanged starting material
and stronger reducing agents gave complex mixtures of products.
However, treatment of the enolic a-diketone 39 with phenyl se-
lenenyl chloride gave the phenylselanyl-a-diketone 42 which was
reduced using tetramethylammonium triacetoxyborohydride15
to the triol 43. This reduction was highly stereoselective, the triol
43 being the only product isolated, but was a little capricious in
that freshly prepared reagent was necessary for good yields to be
achieved. The cis-configuration of the 3- and 4-hydroxyl groups
in triol 43 was assigned on the basis of NMR data and was
confirmed by the formation of a cyclic derivative, vide infra.
Oxidative elimination was then carried out on the trihydroxy-
selenide 43 and gave a mixture of the endo- and exocyclic alkenes
44 and 46, ratio ca., 40 : 60, respectively, see Scheme 4. These
alkenes were not separated at this stage (but see later). Instead
the mixture of alkenes was silylated using tert-butyldimethylsilyl
trifluoromethanesulfonate to give the monosilyl ethers 45 and
47. These could be separated by chromatography, but a more
convenient procedure was developed which involved prolonged
treatment of the triols 44 and 46 with an excess of the
silylating agent. Under these conditions, the endo-alkenol 44 was
converted into its monosilyl ether 45 but the exocyclic alkene 46
gave the bis-silyl ether 48, these products being easy to separate
by chromatography.
At this point it was decided to check the compatibility
of the Wittig chemistry with the functionality present in the
cyclohexenediol 45 and its exocyclic isomer 47, see Scheme 5.
Oxidation of the endocyclic alkenol 45 using singlet oxygen12
gave the hydroxybutenolide 49 which was condensed with 2-
methylpropyl(triphenyl)phosphorane to give the dienyl acids
50 as a 75 : 25 mixture of the (4Z)- and (4E)-isomers. In
this reaction, an excess of ylid was used but the additional
Scheme 4 Reagents and conditions: i, (COCl)2, DMSO, Et3N (95%); ii, TBSOTf, Et3N (ca. 100%); iii, PhSeCl, pyridine (96%); iv, NMe4BH(OAc)3,
MeCN, AcOH (82%); v, tBuOOH, DCM (80%, 44 : 46 = 40 : 60); vi, TBSOTf, 2,6-lutidine, 0 ◦C, 5.5 h (45, 37%); vii, TBSOTf, 2,6-lutidine, r.t., 16 h
(45, 40%; 48, 44%).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
3 6 5 7

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Scheme 5 Reagents and conditions: i, TPP, O2, −78 ◦C, hm (49, 98%; 52, 98%); ii, (CH3)2CHCH2PPh3Br, nBuLi (50, 77%); iii, DCC, DMAP; iv, I2,
K2CO3, benzene, hm (51, 89% from 50; 54, 60% from 52).
3-hydroxyl group didn’t interfere and an acceptable, 77%, yield
was obtained. Cyclisation using dicyclohexylcarbodiimide and
4-dimethylaminopyridine followed by iodine catalysed alkene
isomerisation4 gave the lactone 51 in an 89% yield. An analogous
series of reactions on the exocyclic alkene 47 gave the isomeric
lactone 54.
(racemic) hydroxybutenolide 6. The exocyclic alkene 46 was
similarly taken through to the isomeric hydroxybutenolide 65,
see Scheme 6.
Optimisation of the synthesis of hydroxybutenolide (−)-6
In order to complete a synthesis of the racemic hy-
droxybutenolide 6 from the cyclohexenyl triol 44 it was
necessary to convert the 4-hydroxyl group selectively into
its methyl ether, protect the 3-hydroxyl group as a 2-
trimethylsilylethoxymethyl (SEM) ether and exchange the ethyl
ester for a 2-trimethylsilylethyl ester. Firstly, however, an im-
proved separation of the endo- and exocyclic alkenols 44 and 46
had to be achieved. This was carried out by chromatography
on silica gel impregnated with silver nitrate. The 4-hydroxyl
group of the endocyclic alkenol 44 was then methylated via
the cyclic stannylene 55,16 Scheme 6. This methylation was
very regioselective and gave the required dihydroxycyclohexenyl
methyl ether 56 in a 96% yield, the regioselectivity of the
methylation being checked by oxidation of the alcohol 56 to
the ketone 36 which was identical to a sample prepared from
the epimeric alcohol 35 (see Scheme 3). The diol 56 was now
converted into its SEM-ether 57 which was saponified and the
acid 58 so obtained esterified using 2-trimethylsilylethanol to
give the ester 59. Oxidation using singlet oxygen then gave the
The synthesis of the hydroxybutenolide 6 now needed to be
improved since the oxidative elimination used to introduce the
3,4-double-bond had given an unfavourable 40 : 60 mixture of
the endo- and exo-isomers 44 and 46, see Scheme 4. Moreover, a
resolution step had to be developed to prepare the enantiomer-
ically enriched 6 for incorporation into a milbemycin synthesis.
The use of different conditions for the oxidative elimination
of selenide 43, e.g. the use of tert-butyl hydroperoxide or m-
chloroperoxybenzoic acid at temperatures from −78 ◦C to
ambient temperature did not lead to a significant improvement
in the endo–exo ratio of the alkenes 44 and 46. To evaluate the
effect of substituents, the trihydroxyselenide 43 was converted
into its mono- and bis-tert-butyldimethylsilylated derivatives 66
and 67 but the oxidation of these using tert-butyl hydroperoxide
also gave more of the exocyclic alkene with endo–exo ratios of,
typically, 35 : 65, see Scheme 7. Since improved regioselectivity in
favour of the endocyclic alkenes had been observed with ketones
rather than alcohols at C(4), it was decided to see whether other
electron withdrawing substituents at C(4) would lead to better
i
Scheme 6 Reagents and conditions: i, n-Bu2SnO, MeOH, heat; ii, MeI, Bu4NI (56, 96% from 44; 61, 96% from 46); iii, SEMCl, Pr2NEt (57, ca.
100%; 62, 99%); iv, NaOH, EtOH; v, TMSCH2CH2OH, DCC, DMAP (59, 80% from 57; 64, 92% from 62); vi, TPP, O2, hm, −78 ◦C (6, 99%; 65, 96%).
3 6 5 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7

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Scheme 7 Reagents and conditions: i, TBSOTf, 2,6-lutidine, DCM, 0 ◦C, 1 h (66, 82%); ii, TBSOTf, 2,6-lutidine, DCM, r.t., 18 h (67, 97%);
iii, tBuOOH, DCM, r.t. (45/47, 75%; 45 : 47 = 40 : 60; 68/48, 78%; 68 : 48 = 35 : 65); iv, CCl3COCl, pyr., THF, 0 ◦C (88%); v, tBuOOH, benzene,
r.t. (81%, 70 : 71 : 72 = 80 : 15 : 5); vi, DMAP, EtOH (99%; 44 : 46 = 95 : 5).
selectivity for the endocyclic alkene. For this reason, the triol 43
was converted into its trichloroacetate 69 and the oxidative elim-
ination investigated on this substrate. m-Chloroperoxybenzoic
acid in dichloromethane led to the formation of the endo- and
exocyclic alkenes 70 and 72 in an indifferent 60 : 40 ratio.
However, the use of tert-butyl hydroperoxide in benzene gave rise
to the formation of three products. These could not be separated
but were identified as the two endocyclic alkenes 70 and 71
(in which the trichloroacetate had migrated) and the exocyclic
isomer 72, ratio 70 : 71 : 72 = 80 : 15 : 5. Transesterification of
this mixture using 4-dimethylaminopyridine in ethanol removed
the trichloroacetyl groups and gave the required alkenes 44 and
46 in an excellent, 99%, yield with a very satisfactory ratio of
44 : 46 = 95 : 5. Interestingly, when lithium hydroxide was
used for the attempted saponification of the trichloroacetate,
the major product was the cyclic carbonate 73 (47%) together
with the required cyclohexenetriol 44 (35%). The formation of
the cyclic carbonate 73 confirmed the cis-disposition of the 3-
Fig. 1 Projection of the acetylmandelate 76 as determined by X-ray
and 4-hydroxyl groups in triol 43.
crystallography showing the crystallographic numbering scheme used.
It remained to find a procedure for the resolution of one of
the intermediates in the synthesis of the hydroxybutenolide 6. A
procedure for resolution of the diol 74, prepared by reduction of
the hydroxycyclohexanone 17, by separating the corresponding
4-(O-acetyl)-(S)-mandelates, is described in the previous paper.
The p-methoxybenzyl ether 75, prepared by reduction of the
ketone 22 using tetramethylammonium triacetoxyborohydride,
was also resolved using this procedure, the diastereoisomeric
esters 76 and 77 being separated by chromatography and
recrystallisation. Structure 76 was assigned to the less polar
isomer on the basis of the relative chemical shifts of the 5-methyl
substituents (5-Me: dH 0.52 for 76 and 1.08 for 77) and was
confirmed by a single crystal X-ray structure determination of
isomer 76, see Fig. 1. However, the separation of 76 and 77 was
difficult to scale up and as neither of the diols 74 and 75 was now
an intermediate in the preferred route to the hydroxybutenolide
6, see the summary in Scheme 9, it was decided to develop a
resolution of the 2,3-dihydroxyketone 38.
the mixture of esters 78 and 81 was subjected to mild hydrolysis
conditions but only the starting hydroxyketone 38 was isolated
from this reaction. Since chloroacetates are easier to hydrolyse
than the corresponding acetates,20 the dihydroxyketone 38 was
esterified with O-chloroacetyl-(S)-mandelic acid to give esters
80 and 83 with the intention of studying the selective hydrolysis
of the chloroacetyl group to give the free hydroxymandelates.
However, this was found not to be necessary since the di-
astereoisomeric esters 80 and 83 were found to be easy to sepa-
rate by crystallisation. The required isomer 80 was isolated from
the mixture by a single crystallisation from ethyl acetate–light
petroleum in 47% yield (based on racemic 38). Concentration of
the filtrate under reduced pressure and chromatography of the
residue then gave the other isomer 83 as an amorphous glass.
Structures were initially assigned to the esters 80 and 83 on
1
the basis of the relative H NMR chemical shifts of their 5-
methyl substituents19 (5-Me: dH 1.11 in 80 and 1.18 in 83). They
were confirmed by correlation with the O-acetylmandelates 76,
see Scheme 8. Thus the (−)-enantiomer of dihydroxyketone 38
was obtained by hydrolysis of the 3-chloroacetylmandelate
which had been identified as isomer 80 and from the 4-O-
acetylmandelate 76 by hydrolysis, oxidation and deprotection.
The structure of the crystalline chloroacetylmandelate 80 was
also finally confirmed by an X-ray structure determination, see
Fig. 2.
Esterification of the 3-hydroxy group of the diol 38 with
(−)-camphanic chloride,17 endo-bornyloxyacetic acid or D-
camphorsulfonyl chloride gave mixtures of diastereoisomers
which could not be easily separated. O-Acetyl-(S)-mandelic
acid18 led to the diastereoisomers 78 and 81 which could be
separated by chromatography with the more polar isomer being
1
assigned as structure 78 on the basis of the relative H NMR
shifts of the 5-methyl substituents.19 To see whether the non-
acetylated mandelic esters 79 and 82 might be easier to separate,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
3 6 5 9

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Scheme 8 Reagents and conditions: i, 10% aqu. LiOH, EtOH, r.t., 48 h (97%); ii, (COCl)2, DMSO, then Et3N (90%); iii, DDQ (88%); iv, K2CO3,
EtOH, 0 ◦C (92%).
nenylation gave the diketoselenide (−)-42 which was converted
into the trichloroacetate (−)-69 by reduction and esterification.
Regioselective selenoxide elimination and hydrolysis then gave
the required cyclohexene triol (−)-44 and selective methylation
of the 4-hydroxyl group followed by protection of the 3-hydroxyl
group as its SEM ether gave the required hydroxybutenolide (−)-
6 after ester exchange and oxidation of the 2-trimethylsilylfuran.
This synthesis was repeated to give nearly 1.9 grammes of the
hydroxybutenolide (−)-6.
Completion of a synthesis of milbemycin G
The Wittig reaction between the ylid derived from phosphonium
salt 22 (10% excess) and the hydroxybutenolide (−)-6 was carried
out using 3.5 molar equivalents of lithium hexamethyldisilazide
as base and gave the dienyl ester 84 (48%) as a 2 : 1 mixture
of the (4Z)- and (4E)-isomers (1H NMR) after reaction of the
crude product with diazomethane, see Scheme 10. No attempt
was made to separate this mixture. Instead treatment with
a catalytic amount of iodine in daylight instigated (4Z)- to
(4E)-isomerisation to give the required (4E)-isomer (4E)-84.
Removal of the tert-butyldimethylsilyl protecting group and
cleavage of the 2-trimethylsilylethyl ester was then achieved using
tetrabutylammonium fluoride to give the seco-acid 85. However,
attempts to effect macrolactonisation using dicyclohexylcar-
bodiimide and 4-dimethylaminopyridine in dichloromethane
or using 2,4,6-trichlorobenzoyl chloride under the Yamaguchi
conditions21 were unsuccessful, the only product isolated being
tentatively identified as the elimination product 86.
During the synthesis of (6R)-3,4-dihydromilbemycin E 5, it
had been observed that macrolactonisation of the 3,4-dihydro
seco-acid corresponding to 85, i.e. 87, was also unsuccessful,4
and so the difficulties encountered in trying to cyclise 85 were
not unexpected. However, in the dihydro-series, macrolactoni-
sation of butenolide 88 using dicyclohexylcarbodiimide gave the
macrolide 89 in a 46% yield. The Wittig product 84, as the mix-
ture of (4Z)- and (4E)-isomers, was therefore taken through to
the protected butenolide 91 by removal of the SEM-group using
anhydrous magnesium dibromide and n-butanethiol in ether22
to give the hydroxy-ester 90, followed by lactonisation to form
Fig. 2 Projection of the chloroacetylmandelate 80 as determined by
X-ray crystallography showing the crystallographic numbering scheme
used. Only one of the disordered components of the structure is shown
for clarity.
˚
the butenolide 91 which was carried out using silica gel and 4 A
molecular sieves, see Scheme 11. Iodine catalysed (2ꢀZ)- to (2ꢀE)-
isomerisation was then effected using a trace of iodine in daylight
to give (2ꢀE)-91. However, in this series, attempts to remove the
tert-butyldimethylsilyl group and the 2-trimethylsilyl ester using
tetrabutylammonium fluoride to prepare the seco-acid 92 were
unsuccessful, only complex product mixtures being obtained.
Following the resolution of the dihydroxyketone 38 via the
chloroacetyl mandelates 80 and 83, the laevorotatory enan-
tiomer of the ketone 38 was taken through to the laevorotatory
hydroxybutenolide 6, see Scheme 9. Oxidation and phenylsele-
Scheme 9 Reagents and conditions: i, (COCl)2, DMSO, Et3N (90%); ii, PhSeCl, py. (88%); iii, Me4NBH(OAc)3 (75%); iv, CCl3COCl, py. (87%);
t
i
v, BuOOH, benzene (82%); vi, EtOH, DMAP (94%); vii, nBu2SnO then MeI, Bu4NI (93%); viii, SEMCl, Pr2NEt (96%); ix, NaOH, EtOH; x,
Me3SiCH2CH2OH, DCC, DMAP (82% from (−)-57); xi, TPP, O2, hm (98%).
3 6 6 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7

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Scheme 10 Reagents and conditions: i, (a) LHMDS, −78 ◦C to r.t., 3 h (b) CH2N2, ether, r.t., 20 min (48%); ii, I2 (5 mol%), benzene (95%); iii, TBAF,
THF, r.t., 13 h (93%); iv, DCC, DMAP (cat.), CH2Cl2, 5 ◦C, 69 h (19%) or Cl3C6H2COCl, Et3N, xylene, r.t., 24 h, then DMAP, r.t., 2 h (70%).
Scheme 11 Reagents and conditions: i, MgBr2, n-BuSH, Et2O (78%); ii, silica gel, 4A mol. sieves (98%); iii, I2, benzene (91%); iv, TBAF, THF, r.t.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
3 6 6 1

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At this point, it was decided to remove the SEM-group
from the seco-acid 85, to see whether macrocyclisation was
compatible with a smaller, H-bond donating, group at C(6).
This selective deprotection was carried out using anhydrous
magnesium bromide and n-butanethiol and gave the trihydroxy-
acid 93 (90%), see Scheme 12. Fortunately, cyclisation of this acid
using the Yamaguchi conditions21 gave the required macrolide
94 in a 33% yield together with a small amount of the analogous
butenolide 95, ratio 94 : 95 = 80 : 20. Reduction of this
mixture using diisobutylaluminium hydride in toluene, with an
aqueous quench, gave (6R)-6-hydroxymilbemycin E 96 as the
only isolable product in a 45% yield.
At this point, it remained to dehydrate the triol 96 to introduce
the required tetrahydrofuran ring and complete a synthesis of
milbemycin G 7. The triol was treated with lithium diisopropy-
lamide (2 molar equivalents) followed by the addition of toluene
p-sulfonyl chloride. Under these conditions it was intended
to generate the toluene p-sulfonate of the primary alcohol
which it was hoped would cyclise under the basic reaction
conditions to give milbemycin G. However, the primary chloride
97 was isolated, not milbemycin G 7. It would appear that
displacement of the toluene p-sulfonate by the chloride anions
in solution had competed with the required cyclisation and that
cyclisation by intramolecular displacement of the allylic chloride
was slow. Since the displacement of the primary chloride by
the hydroxyl group at C(6) would be expected to be promoted
by silver(I) salts under basic conditions, the chloride 97 was
treated with freshly prepared silver(I) oxide in tetrahydrofuran.
Under these conditions, the required displacement did indeed
take place to give milbemycin G 7, [a]D 101 (c 0.195, acetone),
lit.3b [a]D 108 (c 0.25, acetone), which was isolated in a 71%
yield.
sample of milbemycin G 7 prepared by total synthesis was found
to be identical to that prepared by methylation of milbemycin D
98 by TLC, MS, IR and 1H NMR.
Summary and conclusions
This work delivered a total synthesis of milbemycin G 7, an a-
milbemycin, by a synthesis in which the 3,4-double-bond was
introduced into the C(1)–C(10) fragment before assembly of the
macrolide. During this synthesis, no migration of the double-
bond was observed nor was any epimerisation at C(2) detected.
Of interest is the control of the regioselectivity of the oxidative
elimination by use of the trichloroacetate 69.23 The origin of
the influence of the C(4)-substituent on the regioselectivity of
the oxidative elimination of a phenylselanyl group at C(5) was
not investigated. These eliminations are believed to be subject
to kinetic control and the regioselectivity must be determined at
the selenoxide stage. It may be that the 4-substituent influences
the diastereoselectivity of selenide oxidation and hence the
regioselectivity of elimination. However, configurationally de-
fined selenoxides racemize within minutes at room temperature
in the presence of traces of acid and moisture.24
Although
anhydrous tert-butyl hydroperoxide in benzene was used for the
regioselective oxidative elimination of trichloroacetate 69, no
rigorous precautions were taken to avoid the presence of traces
of moisture and so the rapid equilibration of diastereoisomeric
selenoxides with different configurations at selenium may well
have taken place under our reaction conditions. As an alternative
explanation, perhaps through space, dipolar, effects are involved.
Such effects have been postulated to explain the regioselec-
tivity of analogous sulfoxide eliminations.25 The conformation
required for elimination to give the exocyclic alkene may intro-
duce a repulsive dipolar interaction with a strongly electron-
withdrawing, cis-orientated substituent at C(4) which should be
more influential for more polar 4-substituents, i.e. for ketones
and the trichloroacetate, and in less polar solvents, i.e. in benzene
rather than in dichloromethane. In the conformation required
for the endocyclic elimination, this dipolar field effect should
be less effective, see Fig. 3, although it may be that half-boat
The successful completion of a synthesis of milbemycin G
was confirmed by comparison of the synthetic material with an
authentic sample prepared by O-methylation of a commercial
sample of milbemycin D 98. Thus treatment of milbemycin
D 98 with an excess of methyl iodide and silver(I) oxide gave
milbemycin G 7 (64%), [a]D 113 (c 0.75, acetone) together with
a small amount, ca. 20%, of 7-O-methyl milbemycin G 99. The
Scheme 12 Reagents and conditions: i, MgBr2, n-BuSH, Et2O (90%); ii, 2,4,6-Cl3C6H2COCl, Et3N then DMAP (33%; 94 : 95 = 80 : 20); iii, DIBAL-H,
toluene (45%); iv, LDA, THF–HMPA, p-TsCl (74%); v, Ag2O, THF, r.t. 24 h then heat under reflux, 1 h (71%); vi, Ag2O, MeI, r.t., 24 h (7, 64%; 99,
20%).
3 6 6 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7

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Ethyl (1RS,2SR,3RS,5RS)-3-benzyloxy-2-hydroxy-5-methyl-5-
phenylselanyl-2-(2-trimethylsilyl-3-furyl)-4-oxocyclohexane-1-
carboxylate 20
Tetra-n-butylammonium fluoride (1.0 M solution in THF,
0.16 cm3, 0.16 mmol) was added to a solution of the selenide 19
(110 mg, 0.16 mmol) in THF (3 cm3) at −50 ◦C and the mixture
stirred at −50 ◦C for 1 h. Saturated aqueous ammonium chloride
(2 cm3) was added and the mixture warmed to room temperature
and partitioned between water (5 cm3) and ether (5 cm3). The
aqueous phase was extracted with ether (3 × 5 cm3) and the
combined organic phase dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using 5 : 1 light
petroleum–ether as eluant afforded the title compound 20 (85 mg,
87%) as an amorphous glass; mmax 3475, 1719, 1377, 1250 and
845 cm−1; dH (300 MHz; CDCl3) 0.23 [9 H, s, Si(CH3)3], 1.06
(3 H, t, J 7, CH2CH3], 1.56 (3 H, s, 5-CH3), 2.20 (1 H, dd, J 13,
4, 6-Heq), 2.62 (1 H, dd, J 15, 13, 6-Hax), 3.61 (1 H, dd, J 13, 4,
1-H), 3.77 (1 H, br. s, 2-OH), 4.00 (2 H, m, CH2CH3), 4.23 and
4.56 (each 1 H, d, J 12, PhHCHO), 4.94 (1 H, s, 3-H), 6.29
(1 H, br. s, 4ꢀ-H), 7.01 (3 H, m, ArH), 7.22 (2 H, m,
ArH), 7.40 (5 H, m, PhSe) and 7.59 (1 H, d, J 2, 5ꢀ-H); m/z
(FAB) 599 (M+ + 1, 0.1%), 443 (4), 353 (7), 167 (26) and
91 (100).
Fig. 3 Transition structures for selenoxide elimination from the
trichloroacetate 69.
conformations are required for the endocyclic process to take
place.
Experimental
All IR spectra were recorded as evaporated films and all optical
rotations were measured at ambient temperature, ca. 20 ◦C. For
other general experimental details see the preceding paper in this
issue.4
Ethyl (1RS,2SR,3RS)-3-benzyloxy-5-methyl-2-(2-
trimethylsilyl-3-furyl)-2,4-bis(trimethylsilyloxy)cyclohex-
4-ene-1-carboxylate 18
Trimethylsilyl trifluoromethanesulfonate (0.48 cm3, 2.50 mmol)
was added to a solution of cyclohexanone 17 (222 mg,
0.50 mmol) and triethylamine (0.48 cm3, 3.50 mmol) in
dichloromethane (1 cm3) at 0 ◦C. The reaction mixture was
warmed to room temperature, stirred for 22 h, then diluted
with dichloromethane (20 cm3) and washed with saturated
aqueous sodium bicarbonate (20 cm3). The aqueous phase
was extracted with dichloromethane, and the combined organic
phase dried (K2CO3) and concentrated under reduced pressure.
Chromatography of the residue using 25 : 1 light petroleum–
ether as eluant gave the title compound 18 (205 mg, 70%) as
a viscous oil. [Found (FAB): M − CH3, 573.2515. C29H45O6Si3
requires M, 573.2524]; mmax 1727, 1250, 1204, 1168 and 840 cm−1;
dH (300 MHz, CDCl3) −0.02 [9 H, s, 2-OSi(CH3)3], 0.19 [9 H, s,
4-OSi(CH3)3], 0.40 [9 H, s, Si(CH3)3], 0.98 (3 H, t, J 7, CH2CH3),
1.49 (3 H, br. s, 5-CH3), 2.00 (1 H, dd, J 16, 5, 6-Heq), 2.63 (1 H,
m, 6-Hax), 3.00 (1 H, m, 1-H), 3.81 (2 H, q, J 7, CH2CH3), 4.22
(1 H, s, 3-H), 4.58 (2 H, m, PhHCHO), 6.47 (1 H, d, J 2, 4ꢀ-H),
7.25 (5 H, m, ArH) and 7.54 (1 H, d, J 2, 5ꢀ-H); m/z (FAB) 588
(M+, 1%), 573 (6), 481 (21), 319 (32), 262 (100) and 171 (99).
Ethyl (1RS,2SR,3RS)-3-benzyloxy-2-hydroxy-5-methyl-2-(2-
trimethylsilyl-3-furyl)-4-oxocyclohex-5-ene-1-carboxylate 21
Aqueous hydrogen peroxide (30%, 15 cm3, 1.4 mmol) was
added to a solution of selenide 20 (82 mg, 0.14 mmol) in
dichloromethane at room temperature. The mixture was stirred
for 1.5 h, diluted with ether (10 cm3) and washed with water.
The combined aqueous phase was extracted with ether and
the combined organic phase dried (Na2SO4) and concentrated
under reduced pressure. Chromatography of the residue using
3 : 1 light petroleum–ether gave the title compound 21 (30 mg,
50%) as a viscous oil; mmax 3466, 1697, 1249, 1184 and 843 cm−1;
dH (300 MHz; CDCl3) 0.24 [9 H, s, Si(CH3)3], 1.11 (3 H, t, J
7, CH2CH3), 1.81 (3 H, m, 5-CH3), 3.82 (1 H, m, 1-H), 3.98
(1 H, s, 3-H), 4.07 (2 H, m, CH2CH3), 4.20 (1 H, s, 2-OH), 4.43
and 4.74 (each 1 H, d, J 12, PhHCHO), 6.16 (1 H, d, J 2, 4ꢀ-H),
6.48 (1 H, m, 6-H), 7.03 (2 H, m, ArH) and 7.22 (3 H, m, ArH),
7.56 (1 H, d, J 2, 5ꢀ-H); m/z (Cl) 460 (M+ + 17, 40%), 335 (54)
and 90 (100).
Ethyl (1RS,2SR,3RS,5RS)-3-benzyloxy-5-methyl-5-
phenylselanyl-2-trimethylsilyloxy-2-(2-trimethylsilyl-3-furyl)-4-
oxocyclohexane-1-carboxylate 19
Ethyl (1RS,2SR,3RS)-4-tert-butyldimethylsilyloxy-2-hydroxy-
3-(4-methoxy)benzyloxy-5-methyl-2-(2-trimethylsilyl-3-
furyl)cyclohex-4-ene-1-carboxylate 23
Benzene selenenyl chloride (72 mg, 0.37 mmol) was added
to a solution of the silyl enol ether 18 (200 mg, 0.34 mmol)
in dichloromethane (5 cm3) at room temperature and the
reaction mixture stirred for 2 h. Saturated aqueous am-
monium chloride was added and the mixture diluted with
dichloromethane (10 cm3). The aqueous phase was extracted
with dichloromethane and the combined organic phase dried
(MgSO4) and concentrated under reduced pressure. Chromatog-
raphy of the residue using 50 : 1 light petroleum–ether as eluant
gave the title compound 19 (180 mg, 79%) as a white crystalline
solid, mp 88 ◦C. [Found: C, 58.6; H, 6.6. C33H44O6SeSi2
requires C, 59.0; H, 6.6%. Found (FAB): M+–CH3, 657.1601.
C32H41O6SeSi2 requires M, 657.16071]; mmax 1738, 1714, 1250,
1173 and 841 cm−1; dH (300 MHz; CDCl3) − 0.01 [9 H, s,
OSi(CH3)3], 0.48 [9 H, s, Si(CH3)3], 1.01 (3 H, t, J 7, CH2CH3),
1.56 (3 H, s, 5-CH3), 2.13 (1 H, dd, J 14, 3, 6-Heq), 2.75 (1 H, dd, J
16, 14, 6-Hax), 3.40 (1 H, dd, J 14, 3,1-H), 3.88(2H, m, CH2CH3),
4.42 and 4.99 (each 1 H, d, J 12, PhHCHO), 5.24 (1 H,
s, 3-H), 6.48 (1 H, d, J 2, 4ꢀ-H), 7.14 (2 H, m, ArH), 7.22 (3 H,
m, ArH), 7.30–7.52 (5 H, m, PhSe) and 7.55 (1 H, d, J 2, 5ꢀ-H);
m/z FAB 672 (M+, 0.6%), 657 (2), 425 (54), 397 (19), 311 (19)
and 167 (100).
tert-Butyldimethylsilyl trifluoromethanesulfonate (2.10 cm3,
9.00 mmol) was added to a solution of cyclohexanone 22
(854 mg, 1.8 mmol) and triethylamine (1.75 cm3, 12.6 mmol) in
dichloromethane (10 cm3) at 0 ◦C and the mixture stirred for 6 h.
Saturated aqueous sodium bicarbonate (10 cm3) was added and
the mixture warmed to room temperature. The aqueous phase
was extracted with dichloromethane and the combined organic
phase dried (Na2CO3) and concentrated under reduced pressure.
Chromatography of the residue using 39 : 1 light petroleum–
ether gave the title compound 23 (1.01 g, 95%) as a viscous oil.
[Found (FAB): M+ − OH, 571.2912. C31H47O6Si2 requires M,
571.2911]; mmax 3530, 1739, 1687, 1515, 1249 and 839 cm−1; dH
(300 MHz; CDCl3) 0.14 and 0.16 (each 3 H, s, SiCH3), 0.26
[9 H, s, Si(CH3)3], 0.98 (3 H, t, J 7, CH2CH3), 0.99 [9 H, s,
SiC(CH3)3], 1.70 (3 H, s, 5-CH3), 2.00 (1 H, dd, J 15, 4, 6-Heq),
2.69 and 2.77 (each 1 H, m, 1-H, 6-Hax), 3.80 (3 H, s, OCH3),
3.86 (2 H, q, J 7, CH2CH3), 3.92 (1 H, s, OH), 4.33 (1 H, s, 3-H),
4.44 and 4.62 (each 1 H, d, J 10, ArHCHO), 6.32 (1 H, d, J 2,
4ꢀ-H), 679 and 7.12 (each 2 H, d, J 10, ArH) and 7.56 (1 H, d, J
2,5ꢀ-H); m/z (FAB) 589 (M+ + 1, 0.7%), 588 (0.5), 571 (4), 451
(21), 277 (18) and 121 (100).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
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Ethyl (1RS,2SR,3RS,5RS)-2-hydroxy-3-(4-
methoxy)benzyloxy-5-methyl-5-phenylselanyl-2-(2-
trimethylsilyl-3-furyl)-4-oxocyclohexane-1-carboxylate 24
Ethyl (1RS,2SR,3SR,4RS)-2,4-dihydroxy-3-(4-methoxy)-
benzyloxy-5-methyl-2-(2-trimethylsilyl-3-furyl)cyclohex-5-ene-
1-carboxylate 26 and ethyl (1RS,2SR,3SR,4RS)-2,4-dihydroxy-
3-(4-methoxy)benzyloxy-5-methylene-2-(2-trimethylsilyl-3-
furyl)cyclohexane-1-carboxylate 29
Following the procedure outlined for the preparation of selenide
19, benzene selenenyl chloride (2.35 g, 12.2 mmol) and the silyl
enol ◦ether 23 (3.60 g, 6.12 mmol) in dichloromethane (90 cm3) at
−50 C for 1.25 h followed by extraction into ether (3 × 25 cm3)
and chromatography using 9 : 1 light petroleum–ether as eluant
gave the title compound 24 (1.92 g, 50%) as an amorphous glass;
mmax 3474, 1717, 1612, 1586, 1513, 1249, 1180, 1032 and 844 cm−1;
dH (300 MHz; CDCl3) 0.26 [9 H, s, Si(CH3)3], 1.06 (3 H, t, J 7,
CH2CH3), 1.51 (3 H, s, 5-CH3), 2.20 (1 H, dd, J 16, 4, 6-Heq),
2.60 (1 H, dd, J 16, 14, 6-Hax), 3.60 (1 H, dd, J 14, 4, 1-H), 3.75
(1 H, s, OH), 3.79 (3 H, s, OCH3), 4.00 (2 H, m, CH2CH3), 4.20
and 4.44 (each 1 H, d, J 12, ArHCHO), 4.93 (1 H, s, 3-H), 6.28
(1 H, s, 4ꢀ-H), 6.78 and 6.94 (each 2 H, d, J 10, ArH), 7.30 (2 H,
m, ArH), 7.40 (3 H, m, ArH) and 7.58 (1 H, d, J 2, 5ꢀ-H); m/z
(FAB) 631 (M+ + 1, 0.2%), 630 (0.1), 456 (1), 337 (7) and 121
(100).
tert-Butyl hydroperoxide (ca. 6.5 M in CH2Cl2, l cm3, 6.5 mmol)
was added to a solution of the hydroxyselenide 28 (420 mg,
0.66 mmol) in dichloromethane (5 cm3) at 0 ◦C. The reaction
mixture was warmed to room temperature and stirred for 6.5 h.
Saturated aqueous sodium sulfite (10 cm3) was added and the
mixture stirred for 30 min then diluted with dichloromethane
(5 cm3). The aqueous phase was extracted with dichloromethane
(3 × 10 cm3) and the combined organic phase dried (Na2SO4)
and concentrated under reduced pressure. Chromatography of
the residue using 4 : 1 light petroleum–ether as eluant gave the
title ◦compound 26 (179 mg, 57%) as a white solid, mp 133–
134 C; mmax 3472, 1713, 1613, 1514, 1249, 1179 and 844 cm−1;
dH (300 MHz; CDCl3) 0.29 [9 H, s, Si(CH3)3], 1.11 (3 H, t, J 7,
CH2CH3), 1.85 (3 H, br. s, 5-CH3), 2.07 (1 H, br. s, 4-OH), 3.52
(1 H, d, J 8, 3-H), 3.65 (1 H, m, 1-H), 3.78 (3 H, s, OCH3), 4.04
(4 H, m, CH2CH3, ArCH2O), 4.28 (1 H, s, 2-OH), 4.42 (1 H, br.
d, J 8, 4-H), 5.28 (1 H, s, 3-H), 6.33 (1 H, br. s, 4ꢀ-H), 6.81 and
7.00 (each 2 H, d, J 8, ArH) and 7.63 (1 H, d, J 2, 5ꢀ-H); m/z (EI)
474 (M+, 0.3%), 459 (16), 339 (22), 277 (10), 248 (17) and 121
(100). The title compound 29 (98 mg, 31%) was also isolated as
a white solid, mp 129–130 ◦C; mmax (EF) 3475, 1709, 1613, 1587,
1515, 1250, 1186 and 844 cm−1; dH (300 MHz; CDCl3) 0.30
[9 H, s, Si(CH3)3], 1.06 (3 H, t, J 7, CH2CH3), 1.65 (1 H, br. s,
4-OH), 2.43 (l H, m, 6-Heq), 2.80 (2 H, m, 1-H, 6-Hax), 3.22
(1 H, d, J 10, 3-H), 3.80 (3 H, s, OCH3), 4.00 (3 H, m, CH2CH3,
2-OH), 4.10 (2 H, s, ArCH2O), 4.49 (1 H, d, J 10, 4-H), 4.97 and
5.20 (each 1 H, s, 5-CH), 6.28 (1 H, br. s, 4ꢀ-H), 6.81 and 7.00
(2 H, d, J 9, ArH) and 7.62 (1 H, d, J 2, 5ꢀ-H); m/z (EI) 474
(M+, 7%), 459 (24), 457 (57), 439 (18), 383 (44) and 121 (100).
Ethyl (1RS,2SR,3RS)-2-hydroxy-3-(4-methoxy)benzyloxy-5-
methyl-2-(2-trimethylsilyl-3-furyl)-4-oxocyclohex-5-ene-1-
carboxylate 25
tert-Butyl hydroperoxide (ca. 6.5 M in CH2Cl2, 1.1 cm3,
7.3 mmol) was added to a solution of phenyl selenide 24 (461 mg,
0.73 mmol) in dichloromethane (5 cm3) at 0 ◦C and the mixture
warmed to room temperature and stirred for 72 h. Saturated
aqueous sodium sulfite (10 cm3) was added and the mixture
stirred for 30 min then diluted with dichloromethane (5 cm3).
The aqueous phase was extracted with dichloromethane (3 ×
10 cm3) and the combined organic phase dried (Na2SO4) and
concentrated under reduced pressure. Chromatography of the
residue using 6 : 1 light petroleum–ether as eluant gave the
title compound 25 (222 mg, 64%) as a viscous oil; mmax 3471,
1696, 1613, 1587, 1514, 1249, 1183 and 845 cm−1; dH (300 MHz;
CDCl3) 0.24 [9 H, s, Si(CH3)3], 1.10 (3 H, t, J 7, CH2CH3), 1.91
(3 H, m, 5-CH3), 3.77 (3 H, s, OCH3), 3.81 (1 H, m, 1-H), 3.96
(1 H, s, 3-H), 4.06 (2 H, m, CH2CH3), 4.14 (1 H, s, OH), 4.37
and 4.64 (each 1 H, d, J 12, ArHCHO), 6.14 (1 H, d, J 2, 4ꢀ-H),
6.48 (1 H, m, 6-H), 6.75 and 6.96 (each 2 H, d, J 10, ArH) and
7.56 (1 H, d, J 2, 5ꢀ-H); m/z (CI) 490 (M+ + 18, 11%), 455 (18),
335 (39), 319 (10) and 121 (100).
Ethyl (1RS,2SR,3SR,4RS)-4-tert-butyldimethylsilyloxy-2-
hydroxy-3-(4-methoxy)benzyloxy-5-methyl-2-(2-trimethylsilyl-
3-furyl)cyclohex-5-ene-1-carboxylate 30
tert-Butyldimethylsilyl trifluoromethanesulfonate (115 ll,
0.5 mmol) was added to a solution of the cyclohexenol 26
(158 mg, 0.33 mmol) and 2,6-lutidine (80 ll, 0.67 mmol)
in dichloromethane (3 cm3) at 0 ◦C and the mixture stirred
for 2 h. Saturated aqueous sodium bicarbonate (3 cm3) was
added and the aqueous phase extracted with dichloromethane
(3 × 3 cm3). The combined organic phase was dried (Na2SO4)
and concentrated under reduced pressure, and the residue was
chromatographed using 9 : 1 light petroleum–ether as eluant to
afford the title compound 30 (190 mg, 97%) as a viscous oil; mmax
3536, 1714, 1614, 1515, 1249, 1086 and 839 cm−1; dH (300 MHz;
CDCl3) 0.11 and 0.15 (each 3 H, s, SiCH3), 0.19 [9 H, s, Si(CH3)3],
0.94 [9 H, s, SiC(CH3)3], 1.10 (3 H, t, J 7, CH2CH3), 1.82 (3 H, s,
5-CH3), 3.56 (1 H, d, J 8, 3-H), 3.63 (1 H, m, 1-H), 3.77 (3 H, s,
OCH3), 3.94 (1 H, d, J 10, ArHCHO), 4.03 (2 H, m, CH2CH3),
4.18 (1 H, s, 2-OH), 4.49 (2 H, m, 4-H, ArHCHO), 5.30 (1 H,
br. s, 6-H), 6.34 (1 H, d, J 2, 4ꢀ-H), 6.74 and 6.79 (each 2 H, d,
J 10, ArH) and 7.59 (1 H, d, J 2,5ꢀ-H); m/z (CI) 589 (M+ + 1,
9%), 339 (47), 137 (19) and 121 (100).
Ethyl (1RS,2SR,3SR,4SR,5RS)-2,4-dihydroxy-3-(4-
methoxy)benzyloxy-5-methyl-5-phenylselanyl-2-(2-
trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 28
Tetramethylammonium triacetoxyborohydride (1.92 g,
7.3 mmol) was added to a solution of the phenyl selenide 24
(0.575 g, 0.91 mmol) in acetonitrile (8 cm3) and acetic acid
(8 cm3) and the mixture stirred at room temperature for 48 h
then concentrated under reduced pressure. The residue was
dissolved in ether (50 cm3) and washed with saturated aqueous
sodium bicarbonate (2 × 25 cm3). The combined aqueous phase
was extracted with ether (3 × 25 cm3) and the combined organic
phase was dried (MgSO4) and concentrated under reduced
pressure. The residue was chromatographed using 3 : 1 light
petroleum–ether as eluant to afford the title compound 28 as an
amorphous glass (451 mg, 78%); mmax 3476, 1711, 1612, 1586,
1514, 1250, 1182 and 843 cm−1; dH (300 MHz; CDCl3) 0.30
[9 H, s, Si(CH3)3], 1.06 (3 H, t, J 7, CH2CH3), 1.50 (1 H, dd,
J 16, 4, 6-Heq), 1.55 (3 H, s, 5-CH3), 1.62 (1 H, br. s, 4-OH),
1.90 (1 H, dd, J 16, 14, 6-Hax), 3.56 (1 H, dd, J 14, 4, 1-H), 3.77
(1 H, d, J 9, 3-H), 3.79 (3 H, s, OCH3), 3.83 (1 H, d, J 9, 4-H),
3.97 (3 H, m, CH2CH3, 2-OH), 4.02 and 4.16 (each 1 H, d, J
11, ArHCHO), 6.53 (1 H, d, J 1, 4ꢀ-H), 6.83 and 7.05 (each
2 H, d, J 6, ArH), 7.35 (3 H, m, ArH), 7.66 (2 H, m, ArH) and
7.69 (1 H, br. s, 5ꢀ-H); m/z (FAB) 632 (M+, 0.6%), 457 (1), 321
(2), 249 (22), 167 (69) and 121 (100).
Ethyl (1RS,2SR,3SR,4RS)-4-tert-butyldimethylsilyloxy-2-
hydroxy-2-(5-hydroxy-2-oxo-1-oxacyclopent-3-en-3-yl)-3-(4-
methoxy)benzyloxy-5-methylcyclohex-5-ene-1-carboxylate 31
A solution of the silylated furan 30 (185 mg, 0.31 mmol) in
dichloromethane (5 cm3) and methanol (5 cm3) containing a
trace amount of tetraphenylporphine was cooled to −78 ◦C
and irradiated for 1.5 h with a 250 W sunlamp whilst a
stream of oxygen was passed through the solution. The mixture
was concentrated under reduced pressure and the residue
chromatographed using 1 : 2 light petroleum–ether as eluant
3 6 6 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7

View Online
to give the title compound 31 (165 mg, 96%) as a white solid,
mp 104–106 ◦C. [Found: C, 61.4; H, 7.1. C28H40O9Si requires C,
61.3; H, 7.35%. Found (CI): M+ + NH4, 566.2754. C28H44O9NSi
requires M, 566.2785]; mmax 3423, 1760, 1740, 1613, 1515, 1250,
1108 and 1020 cm−1; dH (300 MHz; CDCl3) 0.11, 0.12, 0.50 and
0.55 (each 1.5 H, s, SiCH3), 0.97 [9 H, s, SiC(CH3)3], 1.23 (3 H,
m, CH2CH3), 1.82 (3 H, s, 5-CH3), 3.80 (3 H, s, OCH3), 3.94
(0.55 H, d, J 8, 3-H), 3.99 (0.45 H, d, J 8, 3-H), 4.05–4.25 (5 H,
m, CH2CH3, PhHCHO, 4-H, 2-OH), 4.55 (1 H, m, 5-OH), 4.85
(0.45 H, d, J 11, ArHCHO), 4.95 (0.55 H, d, J 11, ArHCHO),
5.33 and 5.35 (each 0.5 H, br. s, 6-H), 5.65 (0.45 H, s, 5ꢀ-H), 5.83
(0.55 H, br. s, 5ꢀ-H), 6.84, 6.88, 7.12 and 7.14 (each 1 H, d, J 10,
ArH), 7.21 (0.45 H, s, 4ꢀ-H) and 7.24 (0.55 H, s, 4ꢀ-H); m/z (CI)
566 (M+, 7%), 531 (7) and 121 (100).
1, 10%), 468 (20), 451 (45), 433 (76), 319 (50), 301 (100) and
271 (74).
Ethyl (1RS,2SR,3SR,4RS)-2-hydroxy-4-methoxy-3-(4-
methoxy)benzyloxy-5-methyl-2-(2-trimethylsilyl-3-
furyl)cyclohex-5-ene-1-carboxylate 34
Lithium hexamethyldisilazide (0.56 cm3, 1.0 M solution in THF,
0.56 mmol) was added dropwise to a solution of the alcohol
26 (53 mg, 0.112 mmol), cetyltrimethylammonium bromide
(49 mg, 0.134 mmol) and methyl iodide (0.14 cm3, 2.24 mmol)
in THF (1 cm3) at 0 ◦C. The resultant solution was stirred at
0
◦C for 25 min then quenched by the addition of saturated
aqueous ammonium chloride. The aqueous phase was extracted
with ether and the combined organic phase was dried and
concentrated under reduced pressure. Chromatography of the
residue (4 : 1 light petroleum–ether) gave the title compound
(2Z,4EZ)-2-[(1RS,2SR,3SR,4RS)-4-tert-Butyldimethylsilyloxy-
1-ethoxycarbonyl-2-hydroxy-3-(4-methoxy)benzyloxy-5-
methylcyclohex-5-en-2-yl]-6-methylhepta-2,4-dienoic acid 32
◦
34 (44 mg, 81%) as a white solid, mp 115–116 C. [Found: C,
63.7; H, 7.7. C26H36O7Si requires C, 63.91; H, 7.43%. Found
(CI): M+ + H, 489.2325. C26H37O8Si requires M, 489.2309];
mmax 3473, 1715, 1613, 1515, 1249, 1189, 1097 and 843 cm−1;
dH (300 MHz; CDCl3) 0.23 [9 H, s, Si(CH3)3], 1.09 (3 H, t, J
7, CH2CH3), 1.85 (3 H, s, 5-CH3), 3.56 (3 H, s, 4-OCH3), 3.61
(1 H, m, 1-H), 3.69 (1 H, d, J 8, 3-H), 3.78 (3 H, s, ArOCH3),
3.95–4.10 (5 H, m, CH2CH3, 2-OH, 4-H, ArCH), 4.37 (1 H, d,
J 10, ArCH), 5.28 (1 H, br. s, 6-H), 6.32 (1 H, d, J 2, 4ꢀ-H), 6.77
and 6.98 (each 2 H, d, J 9, ArH) and 7.62 (1 H, d, J 2, 5ꢀ-H);
dC (75 MHz; CDCl3) 0.0, 13.9, 19.3, 51.8, 55.4, 60.2, 75.0, 76.4,
83.1, 85.5, 109.2, 113.4, 117.9, 129.9, 130.6, 138.6, 146.1, 158.9
and 172.9; m/z (CI; NH3) 506 (M+ + 18, 68%), 489 (28), 339
(100) and 231 (32).
n-Butyllithium (0.23 cm3, 1.6 M in hexanes, 0.36 mmol) was
added to a solution of 2-methylpropyl(triphenyl)phosphonium
bromide (146 mg, 0.36 mmol) in THF (1 cm3) at 0 ◦C. The
resultant orange solution was stirred at 0 ◦C for 30 min, cooled
to −78 ◦C and added to a solution of the hydroxybutenolide 31
(40 mg, 0.073 mmol) in THF (1 cm3) at −78 ◦C. The resultant
solution was warmed to −20 ◦C over 1 h, then saturated aqueous
ammonium chloride was added, and the mixture warmed to
room temperature before being extracted with ethyl acetate. The
combined organic phase was dried (Na2SO4) and concentrated
under reduced pressure. Chromatography of the residue (65 : 34 :
1 light petroleum–ether–acetic acid) gave the title compound
32 (29 mg, 68%), an 80 : 20 mixture ◦of the (4Z)- and (4E)-
isomers, as a white solid, mp 171–172 C. [Found: C, 65.3; H,
8.3. C32H48O8Si requires C, 65.28; H, 8.22%. Found (CI): M+ −
1, 587.3041. C32H47O8Si requires M, 587.3040]; mmax 3371, 1743,
1613, 1514, 1249, 1176 and 1105 cm−1; dH (300 MHz; CDCl3)
(4Z)-isomer: 0.09 and 0.14 (each 3 H, s, SiCH3), 0.98 [9 H, s,
SiC(CH3)3], 1.03 (3 H, d, J 7, 6-CH3), 1.08 (3 H, d, J 7, 7-H3),
1.21 (3 H, t, J 7, CH2CH3), 1.85 (3 H, s, 5ꢀ-CH3), 2.93 (1 H, m,
6-H), 3.78 (3 H, s, OCH3), 3.95–4.28 (5 H, m, CH2CH3, 3ꢀ-H,
4ꢀ-H, 1ꢀ-H), 4.52 (2 H, br. d, J 11, 2-OH, ArCH), 4.69 (1 H, d,
J 11, ArCH), 5.34 (1 H, s, 6ꢀ-H), 5.67 (1 H, t, J 11, 5-H), 6.65
(1 H, t, J 11, 4-H), 6.79 and 7.18 (each 2 H, d, J 8, ArH) and
7.35 (1 H, d, J 11, 3-H); (4E)-isomer: 2.49 (1 H, m, 6-H), 6.08
(1 H, dd, J 15, 7, 5-H), 6.94 (1 H, dd, J 15, 11, 4-H); m/z
(FAB) 588 (M+, 43%), 587 (100), 437 (54), 393 (80), 347 (39) and
131 (78).
Ethyl (1RS,2SR,3SR,4RS)-2,3-dihydroxy-4-methoxy-5-methyl-
2-(2-trimethylsilyl-3-furyl)cyclohex-5-ene-1-carboxylate 35
5,6-Dichloro-2,3-dicyanobenzo-1,4-quinone (84 mg, 0.37 mmol)
was added to a solution of p-methoxybenzyl ether 34 (50 mg,
0.085 mmol) in dichloromethane (3 cm3) and water (0.3 cm3)
and the resultant dark red solution was stirred at room temper-
ature for 2 h. The mixture was diluted with dichloromethane
and washed with saturated aqueous sodium bicarbonate. The
aqueous phase was extracted with dichloromethane and the
combined organic phase was dried and concentrated under
reduced pressure. Chromatography of the residue (3 : 1 light
petroleum–ether) gave the title compound 35 (84 mg, 92%) as a
white solid, mp 80.5–82 ◦C. [Found: C, 59.0; H, 7.6. C18H28O6Si
requires C, 58.67; H, 7.66%. Found (EI): M+ + NH4, 386.1995.
C18H32NO6Si requires M, 386.1999]; mmax 3460, 1716, 1333, 1249,
1188, 1097 and 843 cm−1; dH (300 MHz; CDCl3) 0.32 [9 H, s,
Si(CH3)3], 1.11 (3 H, t, J 7, CH2CH3), 1.84 (4 H, br. s, 5-CH3,
3-OH), 3.57 (4 H, br. s, 4-OCH3, 1-H), 3.77 (1 H, d, J 8, 3-H),
3.96 (1 H, br. d, J 8, 4-H), 4.05 (2 H, m, CH2CH3), 4.38 (1 H, s,
2-OH), 5.29 (1 H, br. s, 6-H), 6.22 (1 H, d, J 2, 4ꢀ-H) and 7.59
(1 H, d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3) 0.0, 13.8, 19.2, 51.1, 59.5,
61.2, 76.5, 77.3, 82.7, 108.0, 118.0, 136.9, 138.2, 147.1, 158.6 and
173.5; m/z (CI; NH3) 386 (M+ + 18, 14%), 351 (9), 296 (70), 279
(23) and 219 (100).
(2Z,4EZ)-2-[(1RS,2SR,3SR,4RS)-4-tert-Butyldimethylsilyloxy-
1-ethoxycarbonyl-2,3-dihydroxy-5-methylcyclohex-5-en-2-yl]-6-
methylhepta-2,4-dienoic acid 33
5,6-Dichloro-2,3-dicyanobenzo-1,4-quinone (29 mg, 0.13 mmol)
was added to a solution of the dienyl acid 32 (50 mg, 0.085 mmol)
in dichloromethane (0.8 cm3) and water (0.08 cm3) and the
resultant dark red solution was stirred at room temperature
for 5 h. The mixture was diluted with ethyl acetate and washed
with saturated aqueous ammonium chloride. The aqueous phase
was extracted with ethyl acetate and the combined organic
phase was dried and concentrated under reduced pressure.
Chromatography of the residue (75 : 24 : 1 light petroleum–
ether–acetic acid) gave the title compound 33 (31 mg, 78%) as
an amorphous glass, mainly the (4Z)-isomer. [Found (EI): M+,
468.2525. C24H40O7Si requires M, 468.2543]; mmax 3377, 1705,
1691, 1261, 1180, 1164 and 1053 cm−1; dH (300 MHz; CDCl3)
0.14 [6 H, s, Si(CH3)2], 0.92 [9 H, s, SiC(CH3)3], 0.97 and 0.98
(each 3 H, d, J 7, 6-CH3, 7-H3), 1.20 (3 H, t, J 7, CH2CH3), 1.80
(3 H, br. s, 5ꢀ-CH3), 2.89 (1 H, m, 6-H), 3.86 (1 H, m, 1ꢀ-H), 3.95
(1 H, d, J 7, 3ꢀ-H), 4.05–4.43 (4 H, m, CH2CH3, 4ꢀ-H, 2ꢀ-OH),
5.28 (1 H, br. s, 6ꢀ-H), 5.60 (1 H, t, J 10, 5-H), 6.43 (1 H, t, J
10, 4-H) and 7.09 (1 H, d, J 10, 3-H); m/z (CI; NH3) 469 (M+ +
Ethyl (1RS,2SR,4RS)-2-hydroxy-4-methoxy-5-methyl-2-(2-
trimethylsilyl-3-furyl)-3-oxocyclohex-5-ene-1-carboxylate 36
Dimethyl sulfoxide (0.3 cm3, 4.2 mmol) in dichloromethane
(1 cm3) was added to a solution of oxalyl chloride (0.18 cm3,
2.1 mmol) in dichloromethane (1 cm3) at −78 ◦C and the
resultant solution stirred for 10 min. The alcohol 35 (153 mg,
0.42 mmol) in dichloromethane (1.5 cm3) was added and the mix-
ture stirred at −78 ◦C for 20 min before triethylamine (1.2 cm3,
8.4 mmol) was added and the mixture allowed to warm to room
temperature. The mixture was diluted with dichloromethane
and washed with saturated aqueous sodium bicarbonate. The
aqueous phase was extracted with dichloromethane and the
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
3 6 6 5

View Online
combined organic phase was dried and concentrated under
reduced pressure. Chromatography of the residue (9 : 1 light
petroleum–ether) on base-washed silica provided the title com-
pound 36 (117 mg, 77%) as an amorphous glass; mmax 3462, 1715,
1249, 1187, 1098, 1020 and 843 cm−1; dH (300 MHz; CDCl3)
0.39 [9 H, s, Si(CH3)3], 1.28 (3 H, t, J 7, CH2CH3), 1.90 (3 H, s,
5-CH3), 3.42 (3 H, s, OCH3), 3.93 (1 H, d, J 6, 1-H), 4.15 (2 H,
q, J 7, CH2CH3), 4.45 (1 H, s, 4-H), 4.66 (1 H, s, 2-OH), 5.34
(1 H, br. d, J 6, 6-H), 6.40 (1 H, d, J 2, 4ꢀ-H) and 7.55 (1 H, d, J
2, 5ꢀ-H).
0.17 and 0.20 (each 3 H, s, SiCH3), 0.32 [9 H, s, Si(CH3)3], 0.98
[9 H, s, SiC(CH3)3], 1.22 (3 H, t, J 7, CH2CH3), 1.94 (3 H, s,
5-CH3), 2.50 (1 H, dd, J 19, 1.5, 6-Heq), 2.66 (1 H, ddd, J 19, 6,
1.5, 6-Hax), 3.23 (1 H, dd, J 6, 3, 1-H), 4.14 (2 H, m, CH2CH3),
4.28 (1 H, br. s, 2-OH), 6.15 (1 H, d, J 2, 4ꢀ-H) and 7.44 (1 H,
d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3) −4.0, −3.7, −0.3, 14.0, 17.9,
18.8, 31.4, 51.8, 60.7, 75.3, 109.0, 134.9, 135.7, 143.7, 145.9,
158.7, 172.6 and 192.6; m/z (CI; NH3) 484 (M+ + 18, 48%) and
394 (100).
On standing, the b,c-unsaturated ketone 36 isomerised to
the a,b-unsaturated ketone 37, an amorphous glass. [Found
(CI): M+, 366.1487. C18H26O6Si requires M, 366.1499]; mmax 3468,
1736, 1688, 1641, 1248, 1189, 1140 and 843 cm−1; dH (300 MHz;
CDCl3) 0.35 [9 H, s, Si(CH3)3], 1.24 (3 H, t, J 7, CH2CH3), 1.99
(3 H, s, 5-CH3), 2.50 (1 H, dd, J 19, 2, 6-Heq), 2.69 (1 H, dd, J
19, 6, 6-Hax), 3.28 (1 H, dd, J 6, 2, 1-H), 3.78 (3 H, s, OCH3),
4.17 (2 H, m, CH2CH3), 4.30 (1 H, s, 2-OH), 6.18 (1 H, d, J
2, 4ꢀ-H) and 7.50 (1 H, d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3) 0.0,
14.1, 17.5, 31.2, 51.9, 59.8, 61.0, 75.2, 108.5, 135.1, 142.1, 146.0,
147.7, 159.2, 172.2 and 192.7; m/z (EI) 366 (M+, 8%), 351 (22),
307 (14), 266 (26), 248 (21) and 167 (100).
Ethyl (1RS,2SR,5RS)-2-hydroxy-5-methyl-5-phenylselanyl-2-
(2-trimethylsilyl-3-furyl)-3,4-dioxocyclohexane-1-carboxylate 42
Pyridine (1.13 cm3, 14.0 mmol) was added to a solution of
benzene selenenyl chloride (1.34 g, 7.00 mmol) in THF (35 cm3)
at 0 ◦C and the resultant solution was warmed to room temper-
ature and stirred for 15 min. The enolic a-diketone 39 (2.24 g,
6.36 mmol) in THF (30 cm3) was added and the resultant mixture
was stirred for 5 min before saturated aqueous ammonium
chloride was added. The mixture was extracted with ether and
the combined organic phase was washed with brine, dried and
concentrated under reduced pressure. Chromatography of the
residue (9 : 1 then 4 : 1 light petroleum–ether) gave the title
compound 42 (3.10 g, 96%) as a pale yellow solid, mp 140–
141 ◦C. (Found: C, 54.5; H, 5.6. C23H28O6SeSi requires C, 54.43;
H, 5.56%); mmax 3402, 1749, 1710, 1376, 1184 and 843 cm−1; dH
(300 MHz; CDCl3) 0.25 [9 H, s, Si(CH3)3], 1.16 (3 H, t, J 7,
CH2CH3), 1.60 (3 H, s, 5-CH3), 2.30 (1 H, dd, J 14, 4, 6-Heq),
2.86 (1 H, dd, J 14, 13, 6-Hax), 3.70 (1 H, dd, J 13, 4, 1-H),
4.11 (2 H, m, CH2CH3), 4.89 (1 H, s, 2-OH), 6.34 (1 H, d, J
2, 4ꢀ-H), 7.30–7.55 (5 H, m, ArH) and 7.63 (1 H, d, J 2, 5ꢀ-H);
dC (75 MHz; CDCl3) 0.0, 13.8, 22.2, 30.9, 35.6 46.6, 62.0, 80.3,
108.9, 124.2, 129.5, 130.4, 132.8, 137.7, 146.4, 173.5, 189.4 and
193.1; m/z (FAB) 509 (M+ + 1, 2%), 389 (4), 351 (18), 198 (20),
167 (67) and 73 (100).
Ethyl (1RS,2SR)-2,4-dihydroxy-5-methyl-2-(2-trimethylsilyl-3-
furyl)-3-oxocyclohex-4-ene-1-carboxylate 39
Dimethyl sulfoxide (3.00 cm3, 42.2 mmol) in dichloromethane
(50 cm3) was added to a solution of oxalyl chloride (1.77 cm3,
20.2 mmol) in dichloromethane (50 cm3) at −78 ◦C and the
resultant solution was stirred for 10 min before the hydroxyke-
tone 38 (5.97 g, 16.9 mmol) in dichloromethane (50 cm3) was
added dropwise. The resultant mixture was stirred at −78 ◦C for
30 min before triethylamine (11.7 cm3, 84.3 mmol) was added.
The mixture was allowed to warm to room temperature, diluted
with dichloromethane and washed with saturated aqueous
sodium bicarbonate. The aqueous phase was extracted with
dichloromethane and the combined organic phase was dried
and concentrated under reduced pressure. Chromatography of
the residue (2 : 1 light petroleum–ether) gave the title compound
39 (5.65 g, 95%) as a white solid, mp 72–73 ◦C. [Found: C, 57.8;
H, 6.9. C17H24O6Si requires C, 57.93; H, 6.86%. Found (EI): M+,
352.1356. C17H24O6Si requires M, 352.1342]; mmax 3462, 1735,
1686, 1654, 1248, 1195 and 843 cm−1; dH (300 MHz; CDCl3)
0.34 [9 H, s, Si(CH3)3], 1.21 (3 H, t, J 7, CH2CH3), 1.97 (3 H, s,
5-CH3), 2.61 (2 H, m, 6-H2), 3.27 (1 H, dd, J 5, 3, 1-H), 4.14
(2 H, m, CH2CH3), 4.19 (1 H, s, 2-OH), 5.93 (1 H, s, 4-OH), 6.11
(1 H, d, J 2, 4ꢀ-H) and 7.49 (1 H, d, J 2, 5ꢀ-H); dC (75 MHz;
CDCl3) −0.3, 14.0, 16.7, 30.7, 51.9, 61.1, 74.6, 108.6, 127.3,
134.5, 142.7, 146.0, 159.2, 172.5 and 192.2; m/z (EI) 352 (M+,
4%), 337 (36), 335 (30), 291 (10) and 43 (100).
Following this procedure, the a-diketone (−)-39 (5.39 g,
15.3 mmol) gave the phenyl selanyl diketone (−)-42 (6.85 g,
88%), as a white solid, [a]D −188.8 (c 1.75, CHCl3).
Ethyl (1RS,2SR,3RS,4SR,5RS)-5-methyl-5-phenylselanyl-
2,3,4-trihydroxy-2-(2-trimethylsilyl-3-furyl)-cyclohexane-1-
carboxylate 43
Acetic acid (7.50 cm3, 172 mmol) was added dropwise to a solu-
tion of tetramethylammonium borohydride (5.12 g, 57.5 mmol)
in acetonitrile (15 cm3) at 0 ◦C. The resultant solution was
warmed to room temperature, stirred for 30 min and added
to a suspension of the diketone 42 (3.65 g, 7.19 mmol) in
acetonitrile (10 cm3) and acetic acid (17.5 cm3) at 5 ◦C. The
resultant mixture was warmed to room temperature, stirred for
1 h, diluted with ethyl acetate and slowly poured onto a large
volume of saturated aqueous potassium carbonate (ca. 750 cm3)
at ca. 5 ◦C. The aqueous phase was extracted with ethyl acetate
and the combined organic phase was washed with brine, dried
and concentrated under reduced pressure. Chromatography of
the residue (9 : 1 then 3 : 1 light petroleum–ether) gave the title
compound 43 as a colourless foam (3.01 g, 82%); mmax 3461, 1707,
1377, 1248, 1186, 1035 and 842 cm−1; dH (300 MHz; CDCl3)
0.40 [9 H, s, Si(CH3)3], 1.17 (3 H, t, J 7, CH2CH3), 1.27 (3 H, s,
5-CH3), 1.95–2.20 (4 H, m, 6-H2, 3-OH, 4-OH), 3.74 (1 H, d, J
3, 3-H), 3.83 (1 H, dd, J 10, 6, 1-H), 3.88 (1 H, d, J 3, 4-H), 4.08
(2 H, m, CH2CH3), 4.49 (1 H, s, 2-OH), 6.45 (1 H, d, J 2, 4ꢀ-H),
7.25–7.45 (3 H, m, ArH), 7.57 (1 H, d, J 2, 5ꢀ-H) and 7.83 (2 H,
m, ArH); dC (75 MHz; CDCl3) −0.1, 14.0, 29.0, 37.6 43.5, 53.2,
61.0, 74.1, 74.7, 110.2, 127.2, 128.8, 128.9, 138.6, 139.4, 146.0,
157.7 and 175.9; m/z (EI) 512 (M+, 13%), 337 (36), 265 (58), 247
(67), 219 (60) and 167 (100).
Following this procedure, the hydroxyketone (−)-38 (2.95 g,
8.33 mmol) gave the diketone (−)-39 (2.63 g, 90%), as a white
solid, [a]D −120.8 (c 1.23, CHCl3).
Ethyl (1RS,2SR)-4-tert-butyldimethylsilyloxy-2-hydroxy-5-
methyl-2-(2-trimethylsilyl-3-furyl)-3-oxocyclohex-4-ene-1-
carboxylate 40
tert-Butyldimethylsilyl trifluoromethanesulfonate (30 ll,
0.131 mmol) was added to a solution of the a-diketone 39
(20 mg, 0.057 mmol) and triethylamine (40 ll, 0.288 mmol) in
dichloromethane (0.5 cm3) at room temperature. The resultant
mixture was stirred at room temperature for 30 min, then diluted
with dichloromethane and washed with saturated aqueous
sodium bicarbonate. The aqueous phase was extracted with
dichloromethane and the combined organic phase was dried
and concentrated under reduced pressure. Chromatography of
the residue (19 : 1 light petroleum–ether) gave the title compound
40 as a viscous oil (26 mg, 98%). [Found (EI): M+ + NH4,
484.2547. C23H42NO6Si2 requires M, 484.2551]; mmax 3463, 1738,
1690, 1251, 1190, 1146 and 840 cm−1; dH (300 MHz; CDCl3)
Following this procedure, the diketone (−)-42 (6.54 g,
12.9 mmol) gave the triol (−)-43 (4.94 g, 75%), as a white solid,
[a]D −68.5 (c 0.89, CHCl3).
3 6 6 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7

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Ethyl (1RS,2SR,3RS,4RS)-5-methyl-2,3,4-trihydroxy-2-(2-
trimethylsilyl-3-furyl)cyclohex-5-ene-1-carboxylate 44 and ethyl
(1RS,2SR,3RS,4RS)-5-methylene-2,3,4-trihydroxy-2-(2-
trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 46
dd, J 13, 4, 6-Heq), 2.70 (1 H, t, J 13, 6-Hax), 3.22 (1 H, dd, J 13,
4, 1-H), 3.70 (1 H, d, J 3, 3-H), 4.03 (2 H, m, CH2CH3), 4.58
(1 H, s, 2-OH), 4.74 (1 H, m, 4-H), 5.05 and 5.15 (each 1 H, br. s,
5-CH), 6.32 (1 H, d, J 2, 4ꢀ-H) and 7.51 (1 H, d, J 2, 5ꢀ-H); dC
(75 MHz; CDCl3) −5.1, −5.0, 0.0, 13.9, 18.2, 25.8, 32.4, 46.4,
60.9, 71.2, 74.7, 77.9, 110.3, 110.4, 139.9, 143.3, 145.5, 156.8 and
175.7; m/z (CI; NH3) 469 (M+ + 1, 1%), 451 (15), 379 (35), 321
(49) and 247 (100).
tert-Butyl hydroperoxide (2 cm3, 5 M in dichloromethane,
10 mmol) was added to a solution of the trihydroxyselenide
43 (540 mg, 1.05 mmol) in dichloromethane (10 cm3) at room
temperature and the resultant solution was stirred for 3 h.
Saturated aqueous sodium sulfite was added and the resultant
mixture was stirred vigorously for 30 min. The aqueous phase
was extracted with dichloromethane and the combined organic
phase was dried and concentrated under reduced pressure.
Chromatography of the residue (2 : 1 light petroleum–ether)
gave the alkenols 44 and 46 (300 mg, 80%), ratio 40 : 60,
as an amorphous glass. Chromatography of this mixture on
silica gel impregnated with silver nitrate (5% w/w) (2 : 1 light
petroleum–et◦her) gave the title compound 44 as a white solid,
mp 162–163 C. (Found: C, 57.45; H, 7.5. C17H26O6Si requires
C, 57.60; H, 7.39%); mmax 3461, 1711, 1248, 1190 and 843 cm−1;
dH (300 MHz; CDCl3) 0.30 [9 H, s, Si(CH3)3], 1.17 (3 H, t, J 7,
CH2CH3), 1.86 (3 H, s, 5-CH3), 2.26 (2 H, br. s, 3-OH, 4-OH),
3.82 (2 H, d, J 4, 3-H, 1-H), 4.09 (2 H, q, J 7, CH2CH3), 4.50
(1 H, m, 4-H), 4.80 (1 H, s, 2-OH), 5.34 (1 H, br. s, 6-H), 6.36
(1 H, d, J 2, 4ꢀ-H) and 7.54 (1 H, d, J 2, 5ꢀ-H); dC (75 MHz;
CDCl3) −0.1, 14.0, 19.3, 46.2, 61.4, 69.3, 74.7, 75.0, 109.9,
117.7, 137.0, 140.0, 146.2, 157.6 and 174.9; m/z (CI; NH3) 355
(M+ + 1, 2%), 337 (11) and 265 (100). Further elution gave the
title compound 46 (216 mg, 54%) as a colourless foam. [Found
(CI): M+, 354.1502. C17H26O6Si requires M, 354.1499]; mmax 3454,
1709, 1249, 1187, 1094 and 842 cm−1; dH (300 MHz; CDCl3) 0.33
[9 H, s, Si(CH3)3], 1.12 (3 H, t, J 7, CH2CH3), 2.00 (2 H, br. s,
3-OH, 4-OH), 2.50 (1 H, d, J 13, 4, 6-Heq), 2.71 (1 H, t, J 13,
6-Hax), 3.19 (1 H, dd, J 13, 4, 1-H), 3.79 (1 H, d, J 3, 3-H), 4.04
(2 H, m, CH2CH3), 4.68 (1 H, s, 2-OH), 4.70 (1 H, m, 4-H), 5.09
and 5.19 (each 1 H, br. s, 5-CH), 6.29 (1 H, d, J 2, 4ꢀ-H) and 7.53
(1 H, d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3) −0.5, 14.1, 33.3, 46.0,
60.9, 70.0, 75.0, 77.4, 109.4, 110.0, 139.5, 144.4, 146.0, 158.2 and
175.4; m/z (EI) 354 (M+, 3%), 336 (9), 290 (18), 247 (24), 173
(72) and 167 (100).
Ethyl (1RS,2SR,3RS,4RS)-3,4-bis(tert-butyldimethylsilyloxy)-
2-hydroxy-5-methylene-2-(2-trimethylsilyl-3-furyl)cyclohexane-
1-carboxylate 48
tert-Butyldimethylsilyl trifluoromethanesulfonate (0.81 cm3,
3.51 mmol) was added to a solution of the alcohols 44 and
46 (594 mg, 1.68 mmol, ratio 40 : 60) and 2,6-lutidine (0.82 cm3,
7.02 mmol) in dichloromethane (8 cm3) at 0 ◦C. The reaction
mixture was warmed to room temperature, stirred for 16 h,
diluted with dichloromethane and washed with saturated aque-
ous sodium bicarbonate. The aqueous phase was extracted with
dichloromethane and the combined organic phase was dried
and concentrated under reduced pressure. Chromatography of
the residue (99 : 1 hexane–ether) afforded the title compound
48 (343 mg, 44%) as a white solid, mp 64–65 ◦C. [Found: C,
60.0; H, 9.5. C29H54O6Si3 requires C, 59.75; H, 9.34%. Found
(CI): M+ − OH, 565.3206. C29H53O5Si3 requires M, 565.3201];
mmax 3472, 1711, 1250, 1183, 897 and 840 cm−1; dH (300 MHz;
CDCl3) −0.42, 0.00, 0.10 and 0.11 (each 3 H, s, SiMe), 0.32
[9 H, s, Si(CH3)3], 0.78 and 0.99 [each 9 H, s, SiC(CH3)3], 1.16
(3 H, t, J 7, CH2CH3), 2.45 (1 H, dd, J 13, 4, 6-Heq), 2.59 (1 H,
t, J 13, 6-Hax), 3.23 (1 H, dd, J 13, 4, 1-H), 3.60 (1 H, d, J 3,
3-H), 4.06 (2 H, q, J 7, CH2CH3), 4.42 (1 H, s, 2-OH), 4.87
(1 H, m, 4-H), 5.00 and 5.05 (each 1 H, br. s, 5-CH), 6.20 (1 H,
d, J 2, 4ꢀ-H) and 7.41 (1 H, d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3)
−5.1, −4.8, −4.7, −3.2, 0.0, 14.0, 18.4, 18.9, 26.1, 26.4, 33.1,
46.7, 60.7, 72.9, 75.8, 80.6, 109.4, 111.8, 141.1, 143.6, 144.9,
156.8 and 176.1; m/z (CI; NH3) 565 (M+ − 17, 44%), 493 (77),
361 (69) and 90 (100). Further elution gave the silyl ether 45
(251 mg, 40%) as a viscous oil.
Ethyl (1RS,2SR,3RS,4RS)-4-tert-butyldimethylsilyloxy-2,3-
dihydroxy-2-(5-hydroxy-2-oxo-1-oxacyclopent-3-en-3-yl)-5-
methylcyclohex-5-ene-1-carboxylate 49
Ethyl (1RS,2SR,3RS,4RS)-4-tert-butyldimethylsilyloxy-2,3-
dihydroxy-5-methyl-2-(2-trimethylsilyl-3-furyl)cyclohex-5-ene-1-
carboxylate 45 and ethyl (1RS,2SR,3RS,4RS)-4-tert-
butyldimethylsilyloxy-2,3-dihydroxy-5-methylene-2-(2-
trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 47
A solution of the 2-silylfuran 45 (89 mg, 0.190 mmol)
and 5,10,15,20-tetraphenyl-21H,23H-porphine (0.5 mg) in
dichloromethane (3 cm3) and methanol (3 cm3) was cooled to
tert-Butyldimethylsilyl trifluoromethanesulfonate (0.58 cm3,
2.53 mmol) was added to a mixture of the alcohols 44 and
46 (300 mg, 0.847 mmol, ratio 40 : 60) and 2,6-◦lutidine
(0.49 cm3, 4.21 mmol) in dichloromethane (6 cm3) at 0 C. The
reaction mixture was stirred at 0 ◦C for 5.5 h, diluted
with dichloromethane and washed with saturated aqueous
sodium bicarbonate. The aqueous phase was extracted with
dichloromethane and the combined organic phase was dried
and concentrated under reduced pressure. Chromatography of
the residue (49 : 1 hexane–ether) afforded the title compound 45
(147 mg, 37%) as a viscous oil. [Found (EI): M+ + H, 469.2444.
C23H41O6Si2 requires M, 469.2442]; mmax 3457, 1712, 1250, 1188
and 840 cm−1; dH (300 MHz; CDCl3) 0.12 and 0.19 (each 3 H, s,
SiMe), 0.31 [9 H, s, Si(CH3)3], 0.92 [9 H, s, SiC(CH3)3], 1.17
(3 H, t, J 7, CH2CH3), 1.78 (3 H, s, 5-CH3), 3.74 (1 H, d, J 4,
3-H) 3.88 (1 H, m, 1-H), 4.10 (2 H, q, J 7, CH2CH3), 4.61 (1 H,
m, 4-H), 4.84 (1 H, s, 2-OH), 5.35 (1 H, br. s, 6-H), 6.39 (1 H, d,
J 2, 4ꢀ-H and 7.54 (1 H, d, J 2, 5ꢀ-H); m/z (CI; NH3) 469 (M+ +
1, 2%), 451 (5), 379 (60), 247 (44) and 219 (100). Further elution
gave the title compound 47. [Found (CI): M+ − OH, 451.2321.
C23H39O5Si2 requires M, 451.2336]; mmax 3467, 1710, 1251, 1185,
1111 and 840 cm−1; dH (300 MHz; CDCl3) 0.10 and 0.12 (each
3 H, s, SiMe), 0.32 [9 H, s, Si(CH3)3], 0.92 [9 H, s, SiC(CH3)3],
1.13 (3 H, t, J 7, CH2CH3), 2.34 (1 H, br. s, 3-OH), 2.48 (1 H,
◦
−78 C and irradiated with a 250 W sunlamp whilst a stream
of oxygen was passed through the solution for 45 min. The
reaction mixture was concentrated under reduced pressure and
chromatography of the residue (98 : 2 then 95 : 5 chloroform–
ether) gave the title compound 49 (80 mg, 98%, ca. a 1 : 1 mixture
of epimers) as a colourless foam. [Found (CI): M+ + H, 429.1941.
C20H33O8Si requires M, 429.1945]; mmax 3427, 1739, 1255, 1113,
1054 and 867 cm−1; dH (300 MHz; CDCl3) 0.15 and 0.17 (each
3 H, s, SiMe), 0.93 [9 H, s, SiC(CH3)3], 1.27 (3 H, m, CH2CH3),
1.79 (3 H, s, 5-CH3), 3.80 and 3.87 (each 0.5 H, d, J 4, 3-H),
3.94 (1 H, m, 1-H), 4.18 (3 H, m, CH2CH3, 2-OH), 4.54 (1 H, m,
4-H), 4.85 and 5.08 (each 0.5 H, br. s, 5ꢀ-OH), 5.49 (1 H, br. s,
6-H), 6.11 (1 H, m, 5ꢀ-H) and 7.32 and 7.38 (each 0.5 H, d, J
1, 4ꢀ-H); m/z (CI; NH3) 429 (M+ + 1, 37%), 411 (19) and 297
(100).
(2Z,4EZ)-2-[(1RS,2SR,3RS,4RS)-4-tert-Butyldimethylsilyloxy-
2,3-dihydroxy-1-ethoxycarbonyl-5-methylcyclohex-5-en-2-yl]-6-
methylhepta-2,4-dienoic acid 50
n-Butyllithium (0.23 cm3, 1.6
M solution in hexanes,
0.36 mmol) was added to a solution of 2-methylpropyl-
(triphenyl)phosphonium bromide (144 mg, 0.36 mmol) in THF
(1 cm3) at 0 ◦C. The resultant orange solution was stirred for
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
3 6 6 7

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30 min, cooled to −60 ◦C and added to a solution of the
hydroxybutenolide 49 (31 mg, 0.072 mmol) in THF (0.5 cm3)
at −60 ◦C. The resultant solution was warmed to −20 ◦C over
30 min, stirred for 30 min then saturated aqueous ammonium
chloride was added. The mixture was warmed to room temper-
ature, extracted with ethyl acetate and the combined organic
phase was dried and concentrated under reduced pressure.
Chromatography of the residue (99 : 1 chloroform–acetic acid)
gave the title compound 50 (26 mg, 77%), a 75 : 25 mixture of the
(4Z)- and (4E)-isomers, as an amorphous glass; mmax 3450, 1712,
1254, 1189 and 867 cm−1; dH (300 MHz; CDCl3) (4Z)-isomer:
0.17 and 0.19 (each 3 H, s, SiMe), 0.92 [9 H, s, SiC(CH3)3], 1.02
(6 H, m, 7-H3, 6-CH3), 1.28 (3 H, t, J 7, CH2CH3), 1.78 (3 H, s,
5ꢀ-CH3), 2.90 (1 H, m, 6-H), 3.54 (1 H, br. s, 3ꢀ-OH), 3.80 (2 H,
m, 3ꢀ-H, 1ꢀ-H), 4.21 (2 H, m, CH2CH3), 4.55 (1 H, m, 4ꢀ-H), 5.08
(1 H, s, 2ꢀ-OH), 5.47 (1 H, s, 6ꢀ-H), 5.62 (1 H, t, J 11, 5-H), 6.39
(1 H, t, J 11, 4-H) and 7.12 (1 H, d, J 11, 3-H); (4E)-isomer:
5.98 (1 H, dd, J 15, 6, 5-H), 6.58 (1 H, dd, J 15, 11, 4-H) and
6.80 (1 H, d, J 11, 3-H); m/z (FAB) 469 (M+ + 1, 1%), 319 (20)
and 73 (100).
5.12 (each 1 H, s, 5-CH), 6.37 (1 H, br. s, 5ꢀ-H) and 7.20 (1 H,
d, J 2, 4ꢀ-H); m/z (CI; NH3) 429 (M+ + 1, 87%), 411 (33), 297
(67), 102 (49) and 75 (100).
(2Z,4EZ)-2-[(1RS,2SR,3RS,4RS)-4-tert-Butyldimethylsilyloxy-
2,3-dihydroxy-1-ethoxycarbonyl-5-methylenecyclohexan-2-yl]-6-
methylhepta-2,4-dienoic acid 53
Following the procedure outlined for the synthesis of the Wittig
product 50, 2-methylpropyl(triphenyl)phosphonium bromide
(188 mg, 0.47 mmol) and the hydroxybutenolide 52 (40 mg,
0.093 mmol) gave the title compound 53 (30 mg, 69%), an 80 : 20
mixture of the (4Z)- and (4E)-isomers, as an amorphous glass,
after chromatography (99 : 1 chloroform–acetic acid); mmax 3450,
1710, 1253, 1184, 1122 and 867 cm−1; dH (200 MHz; CDCl3)
(4Z)-isomer: 0.12 [6 H, s, Si(CH3)2], 0.92 [9 H, s, SiC(CH3)3],
1.02 (6 H, d, J 7, 6-CH3, 7-H3), 1.28 (3 H, t, J 7, CH2CH3), 2.67
(2 H, m, 6ꢀ-H2), 2.89 (1 H, m, 6-H), 3.18 (1 H, dd, J 13, 4, 1ꢀ-H),
3.72 (1 H, d, J 4, 3ꢀ-H), 4.16 (2 H, m, CH2CH3), 4.62 (2 H, br. s,
4ꢀ-H, 2ꢀ-OH), 5.06 and 5.12 (each 1 H, s, 5ꢀ-CH), 5.57 (1 H, t, J
11, 5-H), 6.29 (1 H, t, J 11, 4-H) and 7.14 (1 H, d, J 11, 3-H);
(4E)-isomer: 5.96 (1 H, dd, J 15, 7, 5-H), 6.48 (1 H, dd, J 15, 11,
4-H) and 6.75 (1 H, d, J 11, 3-H).
Ethyl (1SR,2RS,5RS,6RS,9Z)-5-tert-butyldimethylsilyloxy-1-
hydroxy-4-methyl-9-[(2E)-4-methylpent-2-enylidene]-8-oxo-7-
oxabicyclo[4.3.0]non-3-ene-2-carboxylate 51
Ethyl (1SR,2RS,5RS,6RS,9Z)-5-tert-butyldimethylsilyloxy-1-
hydroxy-4-methylene-9-[(2E)-4-methyl-pent-2-enylidene]-8-oxo-
7-oxabicyclo[4.3.0]nonane-2-carboxylate 54
A
solution of N,Nꢀ-dicyclohexylcarbodiimide (9 mg,
0.045 mmol) in dichloromethane (0.4 cm3) was added to
a solution of the hydroxyacid 50 (7 mg, 0.015 mmol) and
4-N,N-dimethylaminopyridine (0.2 mg, 0.002 mmol) in
dichloromethane (0.6 cm3) at room temperature. The resultant
mixture was stirred for 2 h then concentrated under reduced
pressure. The residue was suspended in ether, filtered and the
filtrate concentrated under reduced pressure. The residue was
dissolved in benzene (1 cm3) containing iodine (trace) and
potassium carbonate (ca. 10 mg) and the resultant mixture
was vigorously stirred whilst being irradiated with a 250 W
sunlamp for 1 h. Saturated aqueous sodium thiosulfate was
added and the mixture was extracted with ethyl acetate. The
combined organic phase was dried and concentrated under
reduced pressure. Chromatography of the residue (3 : 1 light
petroleum–ether) gave the title compound 51 as an amorphous
glass (6 mg, 89%). [Found (CI): M+ + H, 451.2514. C24H39O6Si
requires M, 451.2516]; mmax 3389, 1760, 1739, 1641, 1256, 1095
and 1063 cm−1; dH (300 MHz; CDCl3) 0.06 and 0.11 (each
3 H, s, SiMe), 0.81 [9 H, s, SiC(CH3)3], 1.05 (6 H, d, J 7, 5ꢀ-H3,
4ꢀ-CH3), 1.35 (3 H, t, J 7, CH2CH3), 1.88 (3 H, s, 4-CH3), 2.51
(1 H, m, 4ꢀ-H), 3.78 (1 H, m, 2-H), 3.98 (1 H, br. s, 1-OH), 4.28
(2 H, m, CH2CH3), 4.38 (2 H, m, 5-H, 6-H), 5.74 (1 H, m, 3-H),
6.11 (1 H, dd, J 15, 7, 3ꢀ-H), 7.01 (1 H, d, J 11, 1ꢀ-H) and 7.45
(1 H, ddd, J15, 11, 1, 2ꢀ-H); m/z (CI; NH3) 451 (M+ + 1, 43%)
and 271 (100).
Following the procedure outlined for the synthesis of the lactone
51, treatment of the hydroxyacid 53 (25 mg, 0.053 mmol) with
N,Nꢀ-dicyclohexylcarbodiimide (33 mg, 0.16 mmol) followed by
isomerisation of the crude product with iodine using a sunlamp
gave the title compound 54 (21 mg, 87%) as an amorphous
glass after chromatography (3 : 1 light petroleum–ether). [Found
(CI): M+ + H, 451.2522. C24H39O6Si requires M, 451.2516]; mmax
3411, 1760, 1738, 1645, 1188 and 1133 cm−1; dH (300 MHz;
CDCl3) 0.07 and 0.11 (each 3 H, s, SiCH3), 0.85 [9 H, s,
SiC(CH3)3], 1.05 (6 H, d, J 7, 4ꢀ-CH3, 5ꢀ-H3), 1.29 (3 H, t, J
7, CH2CH3), 2.50 (2 H, m, 3-Hax, 4ꢀ-H), 2.68 (1 H, dd, J 14, 5,
3-Heq), 3.11 (1 H, dd, J 10, 5, 2-H), 4.22 (2 H, q, J 7, CH2CH3),
4.32 (1 H, d, J 4, 5-H), 4.46 (1 H, d, J 4, 6-H), 4.75 (1 H, br. s,
1-OH), 5.08 and 5.20 (each 1 H, s, 4-CH), 6.07 (1 H, dd, J 16,
7, 3ꢀ-H), 6.59 (1 H, d, J 11, 1ꢀ-H) and 7.33 (1 H, ddd, J 16, 11,
1, 2ꢀ-H); dC (75 MHz; CDCl3) −5.1, −5.0, 14.0, 18.1, 21.8, 25.7,
30.4, 31.8, 46.4, 61.6, 71.4, 75.9, 83.6, 113.6, 122.8, 127.9, 139.1,
141.6, 153.7, 168.2 and 174.7; m/z (CI; NH3) 451 (M+ + 1, 57%)
and 434 (100).
Ethyl (1RS,2SR,3RS,4RS)-2,3-dihydroxy-4-methoxy-5-methyl-
2-(2-trimethylsilyl-3-furyl)cyclohex-5-ene-1-carboxylate 56
A suspension of the triol 44 (316 mg, 0.893 mmol) and di-
n-butyltin oxide (222 mg, 0.893 mmol) in methanol (18 cm3)
was heated under reflux for 24 h, then cooled, concentrated
under reduced pressure and the residue dissolved in benzene
(3.5 cm3). Tetra-n-butylammonium iodide (330 mg, 0.893 mmol)
and methyl iodide (565 ll, 8,9 mmol) were added and the
solution heated under reflux for 36 h. After concentration under
reduced pressure, the residue was dissolved in chloroform and
the solution washed with saturated aqueous sodium thiosulfate.
The aqueous phase was extracted with chloroform and the
combined organic phase was dried and concentrated under
reduced pressure. Chromatography of the residue (4 : 1 light
petroleum–ether) gave the title compound 56 (312 mg, 96%) as a
Ethyl (1RS,2SR,3RS,4RS)-4-tert-butyldimethylsilyloxy-2,3-
dihydroxy-2-(5-hydroxy-2-oxo-1-oxacyclopent-3-en-3-yl)-5-
methylenecyclohexane-1-carboxylate 52
A solution of the 2-silylfuran 47 (107 mg, 0.229 mmol)
and 5,10,15,20-tetraphenyl-21H,23H-porphine (0.2 mg) in
dichloromethane (3 cm3) and methanol (3 cm3) was cooled
to −78 ◦C and irradiated with a 250 W sunlamp whilst a
stream of oxygen was passed through the solution for 2 h. The
reaction mixture was concentrated under reduced pressure and
the residue purified by chromatography (98 : 2 chloroform–
methanol) to give the title compound 52 (96 mg, 98%) as a
colourless foam. [Found (CI): M+ + H, 429.1948. C20H33O8Si
requires M, 429.1945]; mmax 3397, 1741, 1189, 1115 and 864 cm−1;
dH (300 MHz; CDCl3) 0.12 [6 H, s, Si(CH3)2], 0.93 [9 H, s,
SiC(CH3)3], 1.26 (3 H, t, J 7, CH2CH3), 2.52 (1 H, dd, J 13, 4,
6-Heq), 2.67 (1 H, t, J 13, 6-Hax), 2.70 (1 H, br. s, 5ꢀ-OH), 3.34
(1 H, dd, J 13, 4, 1-H), 3.79 (1 H, d, J 3, 3-H), 4.14 (2 H, q, J
7, CH2CH3), 4.65 (1 H, m, 4-H), 4.68 (1 H, s, 2-OH), 5.04 and
◦
white solid; mp 158–159 C. [Found (CI): C, 58.4; H, 7.9; M+,
368.1650. C18H28O6Si requires C, 58.67; H, 7.66%; M, 368.1655];
mmax 3461, 1712, 1328, 1248, 1172, 1190, 1095 and 843 cm−1; dH
(300 MHz; CDCl3) 0.31 [9 H, s, Si(CH3)3], 1.16 (3 H, t, J 7,
CH2CH3), 1.82 (3 H, s, 5-CH3), 2.59 (1 H, br. s, 3-OH), 3.47
(3 H, s, OCH3), 3.88 (1 H, m, 1-H), 3.98 (1 H, d, J 4, 3-
H), 4.10 (3 H, m, CH2CH3, 4-H), 4.77 (1 H, s, 2-OH), 5.36
3 6 6 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7

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(1 H, br. s, 6-H), 6.42 (1 H, d, J 2, 4ꢀ-H) and 7.54 (1 H,
d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3) −0.2, 13.8, 19.1, 46.4,
57.2, 61.1, 70.9, 74.5, 79.1, 110.6, 116.5, 134.7, 140.6, 145.7,
157.4 and 174.7; m/z (EI) 368 (M+, 3%), 171 (24) and 167
(100).
Following this procedure, the cyclohexenol (−)-44 (630 mg,
1.78 mmol) gave (−)-56 (606 mg, 93%), as a white solid, [a]D
−85.0 (c 1.60, CHCl3).
2-Trimethylsilylethyl (1RS,2SR,3RS,4RS)-2-hydroxy-4-
methoxy-5-methyl-3-(2-trimethylsilylethoxy)methoxy-2-(2-
trimethylsilyl-3-furyl)cyclohex-5-ene-1-carboxylate 59
N,Nꢀ-Dicyclohexylcarbodiimide (214 mg, 1.04 mmol) in
dichloromethane (3 cm3) was added to the acid 58 (325 mg,
0.691 mmol), 2-trimethylsilylethanol (0.30 cm3, 2.1 mmol)
and 4-N,N-dimethylaminopyridine (8 mg, 0.07 mmol) in
dichloromethane (4 cm3) and the mixture stirred at room
temperature for 18 h then concentrated under reduced pressure.
The residue was suspended in ether, filtered and the filtrate
concentrated under reduced pressure. Chromatography of the
residue (49 : 1 light petroleum–ether) gave the title compound 59
(336 mg, 80% from 57) as a viscous oil. [Found (CI): M+ + NH4,
588.3192. C27H54NO7Si3 requires M, 588.3208]; mmax 3452, 1710,
1250, 1170, 1111 and 839 cm−1; dH (300 MHz; CDCl3) −0.02,
0.01 and 0.33 [each 9 H, s, Si(CH3)3], 0.78 (2 H, m, CH2Si),
0.92 (2 H, m, CO2CH2CH2), 1.84 (3 H, s, 5-CH3), 3.20 (1 H, m,
OCH2OCHH), 3.45 (3 H, s, OCH3), 3.60 (1 H, m, OCH2CHH),
3.85 (1 H, m, 1-H), 4.05 (1 H, d, J 3, 3-H), 4.12 (2 H, m,
CO2CH2), 4.25 (1 H, m, 4-H), 4.33 and 4.67 (each 1 H, d, J 7,
OHCHO), 5.00 (1 H, s, 2-OH), 5.34 (1 H, br. s, 6-H), 6.28 (1 H,
d, J 2, 4ꢀ-H) and 7.49 (1 H, d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3)
−1.4, 0.0, 17.1, 18.0, 19.8, 46.9, 57.9, 63.6, 65.6, 74.2, 77.3, 79.9,
95.6, 110.5, 117.3, 137.0, 140.7, 145.3, 157.6 and 175.1; m/z (CI;
NH3) 588 (M+ + 18, 7%), 395 (36), 335 (72) and 90 (100).
Following this procedure, the acid (−)-58 (391 mg,
0.832 mmol) gave the 2-trimethylsilyl ester (−)-59 [390 mg, 82%
from (−)-57], as a viscous oil, [a]D −60.3 (c 0.68, CHCl3).
Ethyl (1RS,2SR,3RS,4RS)-2-hydroxy-4-methoxy-5-methyl-3-
(2-trimethylsilylethoxymethoxy)-2-(2-trimethylsilyl-3-
furyl)cyclohex-5-ene-1-carboxylate 57
2-Trimethylsilylethoxymethyl chloride (225 ll, 1.27 mmol) was
added to a solution of the diol 56 (312 mg, 0.848 mmol) and
ethyldiisopropylamine (440 ll, 2.43 mmol) in dichloromethane
(420 ll) at room temperature and the resultant mixture was
stirred for 24 h. Methanol (0.5 cm3) was added and the mixture
was stirred for 30 min, then diluted with dichloromethane
and washed with saturated aqueous sodium bicarbonate. The
aqueous phase was extracted with dichloromethane and the
combined organic phase was dried and concentrated under
reduced pressure. Chromatography of the residue (9 : 1 light
petroleum–ether) gave the title compound 57 (417 mg, 99%) as
a viscous oil. [Found (EI): M+ + NH4, 516.2808. C24H46NO7Si2
requires M, 516.2813]; mmax 3454, 1713, 1327, 1249, 1191, 1176,
1111, 1020 and 841 cm−1; dH (300 MHz; CDCl3) −0.03 and 0.35
[each 9 H, s, Si(CH3)3], 0.78 (2 H, m, CH2Si), 1.18 (3 H, t, J 7,
CH2CH3), 1.82 (3 H, s, 5-CH3), 3.20 (1 H, m, OCH2OCHH),
3.45 (3 H, s, OCH3), 3.60 (1 H, m, OCH2OCHH), 3.88 (1 H,
m, 1-H), 4.10 (3 H, m, CH2CH3, 3-H), 4.24 (1 H, m, 4-H), 4.34
and 4.67 (each 1 H, d, J 7, OHCHO), 4.90 (1 H, s, 2-OH), 5.32
(1 H, br. s, 6-H), 6.30 (1 H, d, J 2, 4ꢀ-H) and 7.44 (1 H, d, J
2, 5ꢀ-H); dC (75 MHz; CDCl3) −1.5, 0.0, 13.8, 18.1, 19.3, 46.9,
57.8, 61.1, 66.0, 74.5, 76.2, 79.6, 96.2, 110.1, 117.0, 136.8, 140.4,
145.5, 157.6 and 174.8; m/z (CI; NH3) 516 (M+ + 18, 20%), 351
(21), 291 (64) and 90 (100).
2-Trimethylsilylethyl (1RS,2SR,3RS,4RS)-2-hydroxy-2-(5-
hydroxy-2-oxo-1-oxacyclopent-3-en-3-yl)-4-methoxy-5-methyl-3-
(2-trimethylsilylethoxy)methoxycyclohex-5-ene-1-carboxylate 6
A solution of the 2-trimethylsilylfuran 59 (330 mg, 0.580 mmol)
and 5,10,15,20-tetraphenyl-21H,23H-porphine (0.5 mg) in
dichloromethane (2 cm3) and methanol (2 cm3) was cooled to
◦
−78 C and irradiated with a 250 W sunlamp whilst a stream
Following this procedure, the diol (−)-56 (180 mg,
0.489 mmol) gave the SEM–ether (−)-57 (234 mg, 96%), as a
viscous oil, [a]D −73.2 (c 1.15, CHCl3).
of oxygen was passed through the solution for 40 min. The
reaction mixture was concentrated under reduced pressure and
chromatography of the residue (98 : 2 chloroform–methanol)
gave the title compound 6 (294 mg, 99%) as a colourless foam.
[Found (CI): M+ + NH4, 548.2705. C24H46NO9Si2 requires M,
548.2711]; mmax 3428, 1767, 1700, 1251, 1192, 1114, 1023, 861
and 838 cm−1; dH (300 MHz; CDCl3) −0.01 and 0.04 [each 9 H,
s, Si(CH3)3], 0.88 [4 H, m, 2 × CH2Si), 1.80 (3 H, m, 5-CH3),
3.40–3.70 (5 H, m, OCH3, OCH2OCH2), 3.89 (0.5 H, m, 1-H),
4.00–4.20 (4 H, m, CO2CH2, 3-H, 4-H), 4.35 (0.5 H, m, 1-H),
4.55–4.85 (3 H, m, OCH2O, 2-OH), 5.02 (1 H, br. s, 5ꢀ-OH), 5.44
(1 H, br. s, 6-H), 6.01 and 6.05 (each 0.5 H, br. s, 5ꢀ-H) and 7.14
and 7.33 (each 0.5 H, d, J 1, 4ꢀ-H); m/z (CI; NH3) 548 (M+ +
18, 71%), 418 (41), 390 (22), 215 (42) and 90 (100).
(1RS,2SR,3RS,4RS)-2-Hydroxy-4-methoxy-5-methyl-3-(2-
trimethylsilylethoxy)methoxy-2-(2-trimethylsilyl-3-
furyl)cyclohex-5-enoic acid 58
Aqueous sodium hydroxide (0.49 cm3, 15 M, 7.33 mmol) in
ethanol (3 cm3) was added to a solution of the ethyl ester 57
(365 mg, 0.733 mmol) in ethanol (4 cm3) at 0 ◦C. The solution
was stirred at 0 ◦C for 24 h, then diluted with aqueous pH 4 buffer
(15 cm3) and acidified to ca. pH 4 by the dropwise addition of
3 M HCl. The mixture was extracted with ethyl acetate and
the combined organic phase was washed with brine, dried and
concentrated under reduced pressure. Chromatography of the
residue (85 : 15 light petroleum–ethyl acetate then 99 : 1 ethyl
acetate–acetic acid) gave the title compound 58 (325 mg) as a
viscous oil. [Found (CI): M+ + NH4, 488.2502. C22H42NO7Si2
requires M, 488.2500]; mmax 3407, 1711, 1249, 1195, 1020 and
840 cm−1; dH (300 MHz; CDCl3) −0.02 and 0.32 [9 H, s,
Si(CH3)3], 0.78 (2 H, m, CH2Si), 1.82 (3 H, s, 5-CH3), 3.20
(1 H, OCH2OCHH), 3.45 (3 H, s, OCH3), 3.60 (1 H, m,
OCH2OCHH), 3.91 (1 H, br. s, 1-H), 4.03 (1 H, d, J 3, 3-H),
4.27 (1 H, m, 4-H), 4.32 (1 H, d, J 7, OHCHO), 4.65 (2 H, m,
OHCHO, 2-OH), 5.32 (1 H, br. s, 6-H), 6.29 (1 H, d, J 2, 4ꢀ-H)
and 7.50 (1 H, d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3) −1.5, −0.1,
18.0, 19.3, 46.8, 58.0, 65.9, 74.0, 76.1, 79.7, 95.7, 110.3, 116.7,
137.2, 140.6, 145.6, 157.5 and 179.3; m/z (CI; NH3) 488 (M+ +
18, 20%), 225 (42) and 90 (100).
Following this procedure, the 2-trimethylsilylfuran (−)-59
(390 mg, 0.684 mmol) gave the hydroxybutenolide (−)-6 (356 mg,
98%), as a viscous oil, [a]D −64.6 (c 0.92, CHCl3).
Ethyl (1RS,2SR,3RS,4RS)-2,3-dihydroxy-4-methoxy-5-
methylene-2-(2-trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 61
A suspension of the triol 46 (415 mg, 1.18 mmol) and di-
n-butyltin oxide (294 mg, 1.18 mmol) in methanol (30 cm3)
was heated under reflux for 24 h. The reaction mixture was
cooled, concentrated under reduced pressure and the residue
dissolved in benzene (12 cm3). Tetra-n-butylammonium iodide
(482 mg, 1.30 mmol) and methyl iodide (740 ll, 11.8 mmol)
were added and the resultant solution was heated under reflux
for 72 h. The mixture was concentrated under reduced pressure,
dissolved in chloroform and washed with saturated sodium
thiosulfate solution. The aqueous phase was extracted with chlo-
roform and the combined organic phase was dried and concen-
trated under reduced pressure. Chromatography of the residue
Following this procedure, the ethyl ester (−)-57 (417 mg,
0.837 mmol) gave the acid (−)-58 (391 mg), as a colourless foam,
[a]D −57.3 (c 1.10, CHCl3).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
3 6 6 9

View Online
(4 : 1 light petroleum–ether) gave the title compound 61 (415 mg,
96%) as a colourless oil. [Found (EI): M+, 368.1663. C18H28O6Si
requires M, 368.1665]; mmax 3461, 1707, 1248, 1185, 1072 and
842 cm−1; dH (300 MHz; CDCl3) 0.34 [9 H, s, Si(CH3)3], 1.14
(3 H, t, J 7, CH2CH3), 2.07 (1 H, br. s, 3-OH), 2.47 (1 H, dd,
J 13, 5, 6-Heq), 2.67 (1 H, t, J 13, 6-Hax), 3.23 (1 H, dd, J
13, 5, 1-H), 3.45 (3 H, s, OCH3), 3.91 (1 H, d, J 3, 3-H), 4.03
(2 H, m, CH2CH3), 4.29 (1 H, m, 4-H), 4.58 (1 H, s, 2-OH), 5.07
and 5.14 (each 1 H, m, 5-CH), 6.32 (1 H, d, J 2, 4ꢀ-H) and 7.50
(1 H, d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3) 0.0, 13.9, 32.7, 46.4, 57.2,
60.9, 74.4, 74.6, 79.4, 110.1, 110.4, 139.9, 141.0, 145.6, 156.9 and
176.2; m/z (CI; NH3) 386 (M+ + 18, 4%), 351 (20), 296 (38) and
279 (100).
2-Trimethylsilylethyl (1RS,2SR,3RS,4RS)-2-hydroxy-4-
methoxy-5-methylene-3-(2-trimethylsilylethoxy)methoxy-2-(2-
trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 64
A
solution of N,Nꢀ-dicyclohexylcarbodiimide (351 mg,
1.70 mmol) in dichloromethane (1.7 cm3) was added to a solution
of the acid 63 (400 mg, 0.851 mmol), 2-trimethylsilylethanol
(0.61 cm3, 4.3 mmol) and 4-N,N-dimethylaminopyridine (10 mg,
0.09 mmol) in dichloromethane (2.5 cm3) and the resultant mix-
ture was stirred at room temperature for 3 h then concentrated
under reduced pressure. The residue was suspended in ether,
filtered and the filtrate concentrated under reduced pressure.
Chromatography of the residue (49 : 1 light petroleum–ether)
gave the title compound 64 (472 mg, 92% from 62) as a viscous oil.
[Found (CI): M+ + NH4, 588.3214. C27H54NO7Si3 requires M,
588.3208]; mmax 3455, 1711, 1250, 1169, 1111 and 838 cm−1; dH
(300 MHz; CDCl3) −0.02, 0.01 and 0.35 [each 9 H, s, Si(CH3)3],
0.87 (4 H, m, 2 × CH2Si), 2.50 (1 H, dd, J 13, 5, 6-Heq), 2.63
(1 H, t, J 13, 6-Hax), 3.18 (1 H, m, 1-H, OCH2OCHH), 3.40–
3.65 (4 H, m, OCH3, OCH2OCHH), 3.96 (1 H, d, J 3, 3-H), 4.03
(2 H, m, CO2CH2), 4.17 (1 H, d, J 7, OHCHO), 4.31 (1 H, m,
4-H), 4.62 (1 H, d, J 7, OHCHO), 4.68 (1 H, s, 2-OH), 5.04 and
5.11 (each 1 H, br. s, 5-CH), 6.35 (1 H, d, J 2, 4ꢀ-H) and 7.44
(1 H, d, J 2, 5ꢀ-H); m/z (CI; NH3) 588 (M+ + 18, 1%), 395 (6),
335 (14), 118 (16) and 90 (100).
Ethyl (1RS,2SR,3RS,4RS)-2-hydroxy-4-methoxy-5-methylene-
3-(2-trimethylsilylethoxy)methoxy-2-(2-trimethylsilyl-3-
furyl)cyclohexane-1-carboxylate 62
2-Trimethylsilylethoxymethyl chloride (217 ll, 1.23 mmol) was
added to a solution of the diol 61 (301 mg, 0.822 mmol) and
ethyldiisopropylamine (420 ll, 2.47 mmol) in dichloromethane
(1.7 cm3) at room temperature and the mixture was stirred
for 24 h. More 2-trimethylsilylethoxymethyl chloride (70 ll,
0.395 mmol) was added, the mixture stirred at room temperature
for 24 h then more 2-trimethylsilylethoxymethyl chloride (70 ll,
0.395 mmol) was added and the mixture heated under reflux
for 8 h. The mixture was cooled, diluted with dichloromethane
and washed with saturated aqueous sodium bicarbonate. The
aqueous phase was extracted with dichloromethane and the
combined organic phase was dried and concentrated under
reduced pressure. Chromatography of the residue (9 : 1 light
petroleum–ether) gave the title compound 62 (405 mg, 99%)
as a viscous oil. [Found (CI): M+ + H, 499.2548. C24H43O7Si2
requires M, 499.2547]; mmax 3462, 1710, 1249, 1185, 1118, 1020
and 840 cm−1; dH (300 MHz; CDCl3) −0.03 and 0.34 [each 9 H, s,
Si(CH3)3], 0.78 (2 H, m, CH2Si), 1.12 (3 H, t, J 7, CH2CH3), 2.50
(1 H, dd, J 13, 5, 6-Heq), 2.64 (1 H, t, J 13, 6-Hax), 3.15 (1 H,
m, OCH2OCHH), 3.24 (1 H, dd, J 13, 5, 1-H), 3.45 (3 H, s,
OCH3), 3.56 (1 H, m, OCH2OCHH), 3.95 (1 H, d, J 3, 3-H),
4.02 (2 H, m, CH2CH3), 4.17 (1 H, d, J 7, OHCHO), 4.33
(1 H, m, 4-H), 4.57 (1 H, s, 2-OH), 4.63 (1 H, d, J 7, OHCHO),
5.04 and 5.10 (each 1 H, m, 5-CH), 6.27 (1 H, d, J 2, 4ꢀ-H) and
7.45 (1 H, d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3) −1.5, 0.0, 13.9,
17.9, 33.0, 47.0, 57.4, 60.8, 65.3, 74.8, 79.1, 80.4, 95.3, 108.6,
110.6, 140.2, 141.8, 145.3, 157.1 and 175.8; m/z (CI; NH3) 499
(M+ + 1, 4%), 451 (6), 381 (21), 351 (63), 319 (38), 291 (90) and
90 (100).
2-Trimethylsilylethyl (1RS,2SR,3RS,4RS)-2-hydroxy-2-
(5-hydroxy-2-oxo-1-oxacyclopent-3-en-3-yl)-4-methoxy-5-
methylene-(2-trimethylsilylethoxy)methoxycyclohexane-1-
carboxylate 65
A solution of the 2-trimethylsilylfuran 64 (450 mg, 0.789 mmol)
and 5,10,15,20-tetraphenyl-21H,23H-porphine (0.5 mg) in
dichloromethane (5 cm3) and methanol (5 cm3) was cooled to
◦
−78 C and irradiated with a 250 W sunlamp whilst a stream
of oxygen was passed through the solution for 40 min. The
reaction mixture was concentrated under reduced pressure then
chromatography of the residue (98 : 2 chloroform–methanol)
gave the title compound 65 (400 mg, 96%, a 1 : 1 mixture
of epimers) as a colourless foam. [Found (CI): M+ + NH4,
548.2696. C24H46NO9Si2 requires M, 548.2711]; mmax 3417, 1767,
1251, 1191, 1023, 861 and 838 cm−1; dH (300 MHz; CDCl3) 0.01
and 0.06 [each 9 H, s, Si(CH3)3], 0.75–1.05 (4 H, m, 2 × CH2Si),
2.45–2.75 (2 H, m, 6-H2), 3.16 (0.5 H, dd, J 13, 5, 1-H), 3.30–
3.75 (5.5 H, m, OCH3, OCH2OCH2, 1-H), 3.81 and 3.92 (each
0.5 H, d, J 3, 3-H), 4.18 (3 H, m, CO2CH2, 4-H), 4.50–4.85 (4 H,
m, OCH2O, 2-OH, 5ꢀ-OH), 5.04 (2 H, br. s, 5-CH2), 6.00 (1 H, s,
5ꢀ-H) and 7.07 and 7.32 (each 0.5 H, s, 4ꢀ-H); m/z (CI; NH3) 548
(M+ + 18, 5%), 215 (18), 118 (22) and 90 (100).
(1RS,2SR,3RS,4RS)-2-Hydroxy-4-methoxy-5-methylene-3-(2-
trimethylsilylethoxy)methoxy-2-(2-trimethylsilyl-3-
furyl)cyclohexanoic acid 63
Preparation and oxidative elimination of ethyl
(1RS,2SR,3RS,4SR,5RS)-4-tert-butyldimethylsilyloxy-2,3-
dihydroxy-5-methyl-5-phenylselanyl-2-(2-trimethylsilyl-3-
furyl)cyclohexane-1-carboxylate 66
Following the procedure outlined for the preparation of acid 58,
the ethyl ester 62 (450 mg, 0.907 mmol) gave the title compound
63 (400 mg) after chromatography of the residue (85 : 15 light
petroleum–ethyl acetate then 99 : 1 ethyl acetate–acetic acid) as
a viscous oil. [Found (CI): M+ + NH4, 488.2513. C22H42NO7Si2
requires M, 488.2500]; mmax 3584, 1712, 1250, 1119, 1022 and
840 cm−1; dH (300 MHz; CDCl3) −0.04 and 0.31 [each 9 H, s,
Si(CH3)3], 0.86 (2 H, m, CH2Si), 2.52 (2 H, m, 6-H2), 3.14
(2 H, m, 1-H, OCH2OCHH), 3.43 (3 H, s, OCH3), 3.67 (1 H,
m, OCH2OCHH), 3.92 (1 H, d, J 3, 3-H), 4.13 (1 H, d, J 7,
OHCHO), 4.29 (1 H, m, 4-H), 4.40 (1 H, br. s, 2-OH), 4.60
(1 H, d, J 7, OHCHO), 5.03 and 5.10 (each 1 H, m, 5-
CH), 6.24 (1 H, br. s, 4ꢀ-H) and 7.42 (1 H, d, J 2, 5ꢀ-H);
dC (75 MHz; CDCl3) −1.5, 0.0, 17.8, 33.1, 46.9, 57.4, 65.4,
74.5, 79.1, 80.2, 95.2, 108.9, 110.5, 118.3, 140.1, 141.4, 145.5,
157.0 and 180.7; m/z (CI; NH3) 488 (M+ + 18, 32%) and
90 (100).
tert-Butyldimethylsilyl trifluoromethanesulfonate (17 ll,
0.076 mmol) was added to a solution of the trihydroxy selenide
43 (26 mg, 0.051 mmol) and 2,6-lutidine (18 ll, 0.15 mmol) in
dichloromethane (0.5 cm3) at 0 ◦C. The solution was stirred at
0
◦C for 1 h, diluted with dichloromethane and washed with
saturated aqueous sodium bicarbonate. The aqueous phase
was extracted with dichloromethane and the combined organic
phase was dried and concentrated under reduced pressure.
Chromatography of the residue (49 : 1 light petroleum–ether)
gave the title compound 66 (26 mg, 82%) as an amorphous glass;
mmax 3469, 1711, 1250, 1186, 1110 and 841 cm−1; dH (300 MHz;
CDCl3) 0.12 and 0.16 (each 3 H, s, SiCH3), 0.31 [9 H, s,
Si(CH3)3], 0.97 [9 H, s, SiC(CH3)3], 1.12 (3 H, t, J 7, CH2CH3),
1.46 (3 H, s, 5-CH3), 1.68 (1 H, dd, J 14, 4, 6-Heq), 1.83 (1 H,
dd, J 14, 13, 6-Hax), 3.04 (1 H, br. s, 3-OH), 3.73 (2 H, m, 1-H,
3-H), 3.98 (2 H, q, J 7, CH2CH3), 4.07 (1 H, d, J 3, 4-H), 4.38
3 6 7 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7

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(1 H, s, 2-OH), 6.45 (1 H, d, J 2, 4ꢀ-H), 7.33 (3 H, m, ArH),
7.55 (1 H, d, J 2, 5ꢀ-H) and 7.71 (2 H, m, ArH); dC (75 MHz;
CDCl3) −4.7, − 4.1, 0.0, 13.9, 18.2, 25.8, 30.8, 35.7, 43.2, 51.2,
60.8, 74.6, 75.8, 77.2, 110.7, 127.0, 128.7, 128.8, 138.9, 140.4,
145.5, 156.7 and 176.0; m/z (FAB) 626 (M+, 2%), 611 (2), 451
(35), 379 (38), 321 (43), 247 (76) and 167 (100).
tert-Butyl hydroperoxide (50 ll, 5 M in dichloromethane,
0.25 mmol) was added to a solution of the selenide 66 (16 mg,
0.026 mmol) in dichloromethane (0.1 cm3) at room temperature
and the mixture was stirred for 1 h. Saturated aqueous sodium
sulfite was added and the resultant two-phase mixture stirred
vigorously for 30 min. The mixture was partitioned between
dichloromethane and water and the aqueous phase extracted
with dichloromethane. The combined organic phase was dried
and concentrated under reduced pressure. Chromatography of
the residue (9 : 1 light petroleum–ether) gave the alkenes 45 and
47 (9 mg, 75%, ratio 40 : 60) as a viscous oil.
aqueous sodium bicarbonate. The aqueous phase was extracted
with ether and the combined organic phase was washed with
brine, dried and concentrated under reduced pressure. Chro-
matography of the residue (9 : 1 light petroleum–ether) gave the
title compound 69 (226 mg, 88%) as a colourless foam. [Found
(FAB): M+, 656.0080. C25H31O7Cl3SeSi requires M, 656.0070];
mmax 3465, 1765, 1710, 1248, 1188, 1129, 1003 and 842 cm−1; dH
(300 MHz; CDCl3) 0.34 [9 H, s, Si(CH3)3], 1.17 (3 H, t, J 7,
CH2CH3), 1.42 (3 H, s, 5-CH3), 1.93 (1 H, dd, J 14, 4, 6-Heq),
2.11 (1 H, dd, J 14, 13, 6-Hax), 2.74 (1 H, br. d, J 7, 3-OH), 3.85
(1 H, dd, J 13, 4, 1-H), 4.05 (3 H, m, CH2CH3, 3-H), 4.50
(1 H, s, 2-OH), 5.44 (1 H, d, J 3, 4-H), 6.46 (1 H, d, J 2, 4ꢀ-H), 7.35
(3 H, m, ArH), 7.56 (1 H, d, J 2, 5ꢀ-H) and 7.72 (2 H,
m, ArH); dC (75 MHz; CHCl3) −0.2, 14.2, 15.5, 29.4,
36.7, 43.2, 46.8, 61.2, 66.0, 73.8, 74.7, 82.4, 110.3, 126.4,
129.2, 138.9, 146.0, 157.6, 161.3 and 175.4; m/z (FAB)
656 (M+, 11%), 567 (5), 409 (11), 337 (13), 247 (55) and
167 (100).
Preparation and oxidative elimination of ethyl
Following this procedure, the trihydroxy selenide (−)-43
(578 mg, 1.13 mmol) gave the trichloroacetate (−)-69 (646 mg,
87%), as a colourless foam, [a]D −30.3 (c 1.19, CHCl3).
(1RS,2SR,3RS,4SR,5RS)-3,4-bis-(tert-butyldimethylsilyloxy)-
2-hydroxy-5-methyl-5-phenylselanyl-2-(2-trimethylsilyl-3-
furyl)cyclohexane-1-carboxylate 67
3-Chloroperbenzoic acid (0.29 cm3, 0.25
M
in
dichloromethane, 0.073 mmol) was added dropwise to the
selenide 69 (24 mg, 0.0365 mmol) in dichloromethane (0.4 cm3)
at −78 ◦C and the mixture was stirred at −78 ◦C for 20 min
then warmed to room temperature over 0.5 h and stirred for
1 h. The mixture was partitioned between dichloromethane and
saturated aqueous sodium bicarbonate and the aqueous phase
was extracted with dichloromethane. The combined organic
phase was dried and concentrated under reduced pressure.
Chromatography of the residue (9 : 1 light petroleum–ether)
gave a mixture of the alkenes 70 and 72 (16 mg, 88%, ratio 40 :
60) as a colourless foam; mmax 3462, 1763, 1712, 1250, 1021 and
844 cm−1; dH (300 MHz; CDCl3) endo-isomer 70: 0.30 [9 H, s,
Si(CH3)3], 1.22 (3 H, t, J 7, CH2CH3), 1.89 (3 H, br. s, 5-CH3),
3.95 (1 H, m, 1-H), 4.12 (3 H, m, CH2CH3, 3-H), 4.98 (1 H, s,
2-OH), 5.57 (1 H, m, 6-H), 5.94 (1 H, m, 4-H), 6.40 (1 H, d, J
2, 4ꢀ-H), 7.55 (1 H, d, J 2, 5ꢀ-H); exo-isomer 72: 2.48 (1 H, dd,
J 13, 4, 6-Heq), 2.68 (1 H, t, J 13, 6-Hax), 3.20 (1 H, dd, J 13,
4 Hz, 1-H), 5.13 and 5.27 (each 1 H, br. s, 5-CH) and 6.30 (1 H,
d, J 2, 4ꢀ-H); m/z (CI; NH3) 516 (M+ + 18, 2%), 426 (10), 398
(13) and 264 (100).
tert-Butyldimethylsilyl trifluoromethanesulfonate (30 ll,
0.13 mmol) was added to a solution of the trihydroxy
selenide 43 (27 mg, 0.053 mmol) and 2,6-lutidine (31 ll,
0.26 mmol) in dichloromethane (1 cm3) at 0 ◦C. The solution
was warmed to room temperature, stirred for 18 h, diluted
with dichloromethane and washed with saturated aqueous
sodium bicarbonate. The aqueous phase was extracted with
dichloromethane and the combined organic phase was dried
and concentrated under reduced pressure. Chromatography of
the residue (49 : 1 light petroleum–ether) gave the title compound
67 (38 mg, 97%) as an amorphous glass; mmax 3475, 1711, 1249,
1183, 1097 and 839 cm−1; dH (300 MHz; CDCl3) −0.48, 0.13,
0.17 and 0.18 (each 3 H, s, SiCH3), 0.33 [9 H, s, Si(CH3)3],
0.90 and 1.07 [each 9 H, s, SiC(CH3)3], 1.21 (6 H, m, CH2CH3,
5-CH3), 1.90 (2 H, m, 6-H2), 3.81 (1 H, d, J 3, 3-H), 3.98 (1 H,
dd, J 12, 5, 1-H), 4.07 (2 H, m, CH2CH3), 4.25 (2 H, m, 4-H,
2-OH), 6.39 (1 H, d, J 2, 4ꢀ-H), 7.32 (3 H, m, ArH), 7.48
(1 H, d, J 2, 5ꢀ-H) and 7.68 (2 H, m, ArH); dC (75 MHz; CDCl3)
−5.6, −3.8, −1.8, −1.7, −0.1, 14.1, 18.5, 18.8, 26.9, 27.1, 29.9,
38.2, 43.9, 50.0, 60.7, 75.6, 76.5, 79.4, 112.3, 128.2, 128.9, 139.4,
141.3, 145.0, 157.0 and 176.5; m/z (FAB) 723 (M+ − 17, 1%),
683 (4), 525 (6), 493 (3), 451 (35), 215 (35), 167 (85) and 73
(100).
A solution of tert-butyl hydroperoxide (0.82 cm3, 6 M in
benzene, 4.91 mmol) was added to a solution of the selenide 69
(646 mg, 0.982 mmol) in benzene (1 cm3) at room temperature
and the resultant mixture was stirred for 18 h. Saturated sodium
sulfite solution was added and the resultant two-phase mixture
was stirred vigorously for 30 min, then partitioned between
ether and water. The aqueous phase was extracted with ether
and the combined organic phase was washed with brine, dried
and concentrated under reduced pressure. Chromatography of
the residue (9 : 1 light petroleum–ether) gave a mixture of
the alkenes 70, 71 and 72 (453 mg, 92%), ratio 85 : 15 : 5,
respectively, as a colourless foam. Partial assignment of the C-3
endo-trichloroacetate 71: dH (300 MHz; CDCl3) 3.83 (1 H, m,
1-H), 5.42 (1 H, m, 6-H), 6.39 (1 H, d, J 2, 4ꢀ-H) and 7.49 (1 H,
d, J 2, 5ꢀ-H).
tert-Butyl hydroperoxide (35 ll, 5 M in dichloromethane,
0.18 mmol) was added to a solution of the selenide 67 (13 mg,
0.018 mmol) in dichloromethane (0.1 cm3) at room temperature
and the resultant mixture was stirred for 16 h. Saturated aqueous
sodium sulfite was added and the resultant two-phase mixture
was stirred vigorously for 30 min. The mixture was partitioned
between dichloromethane and water and the aqueous phase
extracted with dichloromethane. The combined organic phase
was dried and concentrated under reduced pressure. Chromatog-
raphy of the residue (98 : 2 light petroleum–ether) gave a mixture
of the alkenes 68 and 48 (8 mg, 78%, ratio 35 : 65) as a viscous oil.
The endo-isomer 68 was distinguished by the following peaks in
Following this procedure, the trichloroacetyl selenide (−)-
69 (1.43 g, 2.17 mmol) gave the alkene (−)-70 (895 mg, 82%),
together with its isomers 71 and 72, ratio 85 : 15 : 5, respectively,
as a colourless foam, [a]D −83.3 (c 0.81, CHCl3).
1
the H NMR spectrum of the mixture; dH (300 MHz; CDCl3)
1.83 (3 H, s, 5-CH3), 3.84 (1 H, m, 1-H), 5.34 (1 H, br. s, 6-H)
and 6.32 (1 H, d, J 2, 4ꢀ-H).
4-N,N-Dimethylaminopyridine (22 mg, 0.18 mmol) was
added to a mixture of the trichloroacetates 70, 71 and 72 (895 mg,
1.79 mmol, ratio 80 : 15 : 5, respectively) in ethanol (18 cm3) at
room temperature and the solution was stirred for 16 h. The
reaction mixture was concentrated under reduced pressure and
the residue chromatographed (2 : 1 light petroleum–ether) to
give the cyclohexenetriol 44 (630 mg, 99%), as a white solid,
together with a small amount (<5%) of the exo-isomer 46. All
data were in accord with those reported above.
Preparation and oxidative elimination of ethyl
(1RS,2SR,3RS,4SR,5RS)-2,3-dihydroxy-5-methyl-5-
phenylselanyl-4-trichloroacetoxy-2-(2-trimethylsilyl-3-
furyl)cyclohexane-1-carboxylate 69
Trichloroacetyl chloride (65 ll, 0.586 mmol) was added to a
solution of the triol 43 (200 mg, 0.391 mmol) and pyridine (95 ll,
1.17 mmol) in THF at 0 ◦C and the mixture was stirred at 0 ◦C
for 20 min then diluted with ether and washed with saturated
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
3 6 7 1

View Online
Following this procedure, a mixture of the trichloroacetates
(−)-70, 71 and 72 (615 mg, 1.23 mmol, ratio 85 : 15 : 5,
respectively) gave the triol (−)-44 (410 mg, 94%), as a white
solid, containing less than 5% of the exo-isomer 46, [a]D −152.8
(c 0.99, CHCl3).
38 (690 mg, 1.95 mmol), (S)-(+)-O-acetylmandelic acid
(382 mg, 2.14 mmol) and 4-N,N-dimethylamin◦opyridine (24 mg,
0.195 mmol) in dichloromethane (2 cm3) at 0 C. The resultant
mixture was warmed to room temperature and stirred for 16 h,
then concentrated under reduced pressure. The residue was
suspended in ether, filtered and the filtrate concentrated under
reduced pressure to give the esters 78 and 81 (1.00 g, 100%)
as a colourless foam. Chromatography of the mixture (4 : 1
light petroleum–ether) gave first the title compound 81, as a
white solid, mp 110–111 ◦C (ether–light petroleum); [a]D +59.3
(c 1.19, CHCl3). [Found: C, 61.4; H, 6.5. C27H34O9Si requires C,
61.11; H, 6.46%. Found (FAB): M+ + H, 531.2056. C27H35O9Si
requires M, 531.2050]; mmax 3460, 1755, 1710, 1250, 1228, 1191,
1096, 1047 and 844 cm−1; dH (300 MHz; CDCl3) 0.35 [9 H, s,
Si(CH3)3], 1.05 (3 H, t, J 7, CH2CH3), 1.12 (3 H, d, J 7, 5-CH3),
2.12 (5 H, m, 6-H2, CH3CO2), 2.62 (1 H, m, 5-H), 3.41 (1 H, dd,
J 13, 5, 1-H), 4.02 (2 H, m, CH2CH3), 4.38 (1 H, s, 2-OH), 5.40
(1 H, s, 3-H), 5.96 (1 H, s, PhCH), 6.18 (1 H, br. s, 4ꢀ-H), 7.40
(5 H, m, ArH) and 7.50 (1 H, d, J 2, 5ꢀ-H); dC (75 MHz; CDCl3)
0.0, 13.6, 13.9, 20.8, 32.8, 42.1, 50.0, 61.5, 74.3, 78.6, 81.0, 108.0,
128.1, 128.9, 129.5, 133.4, 135.7, 146.5, 158.1, 167.9, 169.6, 173.4
and 200.1; m/z (FAB) 531 (MH+, 7%), 455 (12), 353 (29), 217
(63), 167 (92) and 149 (100). The more polar product was the
title compound 78, a white solid, mp 125–126 ◦C (ether–light
petroleum); [a]D +0.1 (c 0.97, CHCl3). [Found: C, 61.5; H, 6.6.
C27H34O9Si requires C, 61.11; H, 6.46%. Found (FAB): M+ +
H, 531.2009. C27H35O9Si requires M, 531.2050]; mmax 3461, 1755,
1739, 1710, 1190, 1049 and 844 cm−1; dH (300 MHz; CDCl3) 0.18
[9 H, s, Si(CH3)3], 1.03 (3 H, t, J 7, CH2CH3), 1.19 (3 H, d, J 7,
5-CH3), 2.07 (3 H, s, CH3CO2), 2.18 (2 H, m, 6-H2), 2.68 (1 H,
m, 5-H), 3.31 (1 H, dd, J 13, 5, 1-H), 4.00 (2 H, m, CH2CH3),
4.20 (1 H, s, 2-OH), 5.25 (1 H, s, 3-H), 6.08 (1 H, s, PhCH), 6.20
(1 H, br. s, 4ꢀ-H), 7.09 (2 H, m, ArH), 7.28 (3 H, m, ArH) and
7.48 (1 H, br. s, 5ꢀ-H); dC (75 MHz; CDCl3) −0.3, 13.6, 13.7,
20.7, 32.9, 42.2, 50.1, 61.6, 74.3, 78.1, 81.4, 108.0, 128.1, 128.7,
129.0, 133.2, 135.1, 146.6, 157.8, 168.4, 169.6, 173.3 and 199.8;
m/z (FAB) 531 (MH+, 10%), 217 (35), 167 (71) and 149 (100).
Ethyl (1RS,2SR,3RS,4RS)-3,4-carbonyldioxy-2-hydroxy-5-
methyl-2-(2-trimethylsilyl-3-furyl)-5-cyclohexene-1-carboxylate 73
Aqueous lithium hydroxide (520 ll, 5% w/v, 1.1 mmol) was
added to a solution of the trichloroacetates 70, 71 and 72
(182 mg, 0.364 mmol, ratio 80 : 15 : 5) in THF at 0 ◦C. The
resultant solution was stirred for 10 min at 0 ◦C then partitioned
between ether and water. The aqueous phase was extracted with
ether and the combined organic phase was washed with brine,
dried and concentrated under reduced pressure. Chromatogra-
phy of the residue (3 : 1 light petroleum–ether) gave the title
compound 73 (65 mg, 47%) as an amorphous glass. [Found
(EI): M+ + NH4, 398.1639. C18H28NO7Si requires M, 398.1635];
mmax 3451, 1816, 1711, 1249, 1193, 1173, 1094, 1072, 1055, 1018
and 843 cm−1; dH (300 MHz; CDCl3) 0.32 [9 H, s, Si(CH3)3], 1.16
(3 H, t, J 7, CH2CH3), 1.95 (3 H, s, 5-CH3), 3.79 (1 H, m, 1-H),
4.12 (2 H, m, CH2CH3), 4.60 (1 H, d, J 7, 3-H), 4.89 (1 H, s,
2-OH), 5.08 (1 H, br. d, J 7, 4-H), 5.55 (1 H, s, 6-H), 6.40 (1 H,
d, J 2, 4ꢀ-H) and 7.57 (1 H, d, J 2, 5ꢀ-H); m/z (CI; NH3) 398
(M+ + 18, 100%). The endo-allylic alcohol 44 (50 mg, 39%) was
also isolated.
Ethyl (1R,2S,3S,4R,5S)-4-[(S)-O-acetylmandeloyloxy]-2-
hydroxy-3-(4-methoxy)benzyloxy-5-methyl-2-(2-trimethylsilyl-
3-furyl)cyclohexane-1-carboxylate 76
N,Nꢀ-Dicyclohexylcarbodiimide (3.1 g, 15 mmol) in
dichloromethane (14 cm3) was added slowly to the diol 75
(3.6 g, 7.6 mmol), (S)-O-acetylmandelic acid (2.92 g, 15 mmol)
and 4-N,N-dimethylaminopyridine (100 mg, 0.8 mmol) in
◦
dichloromethane (28 cm3) at 0 C. A white suspension formed
and the mixture was allowed to warm to ambient temperature
and stirred for 16 h before being diluted with ether (60 cm3).
The mixture was filtered through a pad of celite and the filtrate
concentrated under reduced pressure. Chromatography of the
residue (4 : 1 light petroleum–ether) gave the required ester
76 as the first eluted product and this was recrystallised from
light petroleum and ether. Mixed fractions from the column
were rechromatographed to give, after final recrystallisation,
the title compound 76 (1.87 g, 38%), as a white solid, mp 134 ◦C
(ether–light petroleum); [a]D −12 (c 0.95, CHCl3). (Found:
C, 64.2; H, 7.0. C35H44O10Si requires C, 64.4; H, 6.8%); mmax
3400, 1745, 1613, 1249, 1209, 1180, 1069, 912 and 844 cm−1;
dH (300 MHz, CDCl3) 0.1 [9 H, s, Si(CH3)3], 0.52 (3 H, d, J 5,
5-CH3), 1.0 (3 H, t, J 5, CH2CH3), 1.6 (2 H, m, 5-H, 6-Heq),
1.9 (1 H, q, J 9, 6-Hax), 2.2 (3 H, s, CH3CO), 2.7 (1 H, dd, J
13, 3, 1-H), 3.42 (1 H, d, J 10, 3-H), 3.6 (1 H, s, 2-OH), 3.79
(3 H, s, OCH3), 3.80–4.05 (3 H, m, CH2CH3, ArHCHO), 4.35
(1 H, d, J 10, ArHCHO), 5.1 (1 H, t, J 7.5, 4-H), 6.0 (1 H, s,
PhCHCO2), 6.3 (1 H, d, J 1, 4ꢀ-H), 6.75 and 6.82 (each 2 H,
d, J 9, ArH), 7.35 (3 H, m, ArH), 7.45 (2 H, m, ArH) and 7.6
(1 H, d, J 1, 5ꢀ-H); dC (75 MHz, CDCl3) 0.0, 13.8, 17.2, 21.0,
30.8, 35.5, 50.5, 55.4, 60.7, 74.5, 75.5, 76.3, 79.2, 84.6, 108.9,
113.5, 127.7, 128.8, 129.3, 130.2, 130.5, 134.4, 138.5, 146.2,
158.4, 159.3, 168.4, 170.1 and 172.7; m/z (FAB) 653 (M+ + 1,
1%), 441 (4), 250 (4.5) and 121 (100).
(S)-(+)-O-Chloroacetylmandelic acid
A mixture of (S)-(+)-mandelic acid (10.0 g, 65.8 mmol) and
chloroacetyl chloride (26 cm3, 330 mmol) was stirred at 100 ◦C
for 1 h. The mixture was cooled, diluted with ethyl acetate
(300 cm3) and washed with water (20 × 100 cm3). The organic
phase was dried and concentrated under reduced pressure.
Crystallisation of the residue from benzene–hexane gave the
◦
title compound (11.2 g, 75%) as a white solid, mp 102–103 C;
[a]D +133.9 (c 2.08, acetone). [Found (CI): M+ + NH4, 246.0532.
C10H13NO435Cl requires M, 246.0533]; mmax 3037 (br), 1738, 1166,
1081 and 1027 cm−1; dH (200 MHz; CDCl3) 4.20 (2 H, m, CH2Cl),
6.02 (1 H, s, PhCH) and 7.45 (5 H, m, ArH); dC (50 MHz; CDCl3)
41.0, 75.7, 128.2, 129.5, 130.4, 132.8, 167.4 and 174.4; m/z (CI;
+
NH3) 246 (MNH4 , 100%), 212 (83) and 154 (58).
Ethyl (1R,2S,3R,5S)-3-[(S)-O-(chloroacetyl)mandeloyloxy]-2-
hydroxy-5-methyl-2-(2-trimethylsilyl-3-furyl)-4-oxocyclohexane-
1-carboxylate 80 and ethyl (1S,2R,3S,5R)-3-[(S)-O-
(chloroacetyl)-mandeloyloxy]-2-hydroxy-5-methyl-2-(2-
trimethylsilyl-3-furyl)-4-oxocyclohexane-1-carboxylate 83
N,Nꢀ-Dicyclohexylcarbodiimide (4.86 g, 23.6 mmol) in
dichloromethane (100 cm3) was added to the hydroxyketone
38 (7.60 g, 21.5 mmol), 4-N,N-dimethylaminopyridine (260 mg,
2.15 mmol) and (S)-(+)-O-(chloroacetyl)mandelic acid (5.40 g,
23.6 mmol) in dichloromethane (100 cm3) at 0 ◦C. The mixture
was warmed to room temperature and stirred for 16 h then
diluted with ether and filtered. The filtrate was concentrated
under reduced pressure to give a mixture of the esters 80 and 83
(12.0 g, 100%). Crystallisation from ethyl acetate–hexane gave
the title compound 80 (5.72 g, 47%) as a white solid, mp 116–
117 ◦C; [a]D −1.8 (c 1.01, CHCl3). [Found: C, 57.6; H, 6.05;
Ethyl (1R,2S,3R,5S)-3-[(S)-O-acetylmandeloyloxy]-2-hydroxy-
5-methyl-2-(2-trimethylsilyl-3-furyl)-4-oxocyclohexane-1-
carboxylate 78 and ethyl (1S,2R,3S,5R)-3-[(S)-O-
acetylmandeloyloxy]-2-hydroxy-5-methyl-2-(2-trimethylsilyl-3-
furyl)-4-oxocyclohexane-1-carboxylate 81
N,Nꢀ-Dicyclohexylcarbodiimide (803 mg, 3.90 mmol) in
dichloromethane (2 cm3) was added to the hydroxyketone
3 6 7 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7

View Online
Cl, 6.4. C27H33O9ClSi requires C, 57.39; H, 5.89; Cl, 6.27%.
Found (CI): M+ + NH4, 582.1922. C27H37NO935ClSi requires M,
582.1926]; mmax 3463, 1756, 1737, 1710, 1250, 1191, 1159, 1026
and 844 cm−1; dH (300 MHz; CDCl3) 0.15 [9 H, s, Si(CH3)3],
1.03 (3 H, t, J 7, CH2CH3), 1.18 (3 H, d, J 7, 5-CH3), 2.12
(2 H, m, 6-H2), 2.68 (1 H, m, 5-H), 3.32 (1 H, dd, J 13, 5, 1-H),
4.01 (4 H, m, CH2CH3, CH2Cl), 4.22 (1 H, s, 2-OH), 5.27
(1 H, s, 3-H), 6.17 (1 H, s, PhCH), 6.21 (1 H, d, J 2, 4ꢀ-H), 7.07
(2 H, m, ArH), 7.29 (3 H, m, ArH) and 7.49 (1 H, br. s, 5ꢀ-H);
dC (75 MHz; CDCl3) −0.4, 13.6, 13.7, 32.8, 40.4, 42.1, 50.0,
61.4, 75.3, 78.3, 81.7, 107.8, 127.9, 128.7, 129.4, 132.5, 135.5,
146.6, 158.0, 166.2, 167.6, 173.4 and 199.6; m/z (CI; NH3) 582
pressure. Chromatography of the residue (2 : 1 light petroleum–
ether) gave the hydroxyketone (−)-38 (1.74 g, 92%) as a white
solid. [a]D −13.1 (c 1.10, CHCl3). All other data were in accord
with the racemate.4
Deprotection of the cyclohexanone (−)-22 (3.10 g, 6.51 mmol)
following the procedure outlined for the racemic compound,4
gave the dihydroxyketone (−)-38 (2.03 g, 88%), as a white solid,
[a]D −12.7 (c 1.10, CHCl3).
Methyl (6R,2Z,4EZ,8E)-l0-{(2R,3S,6R,8R,l0S)-l0-tert-
butyldimethylsilyloxy-3-methyl-2-(1-methylethyl)-l,7-
dioxaspiro[5.5]undecan-8-yl}-2-[(lR,2S,3R,4R)-2-hydroxy-4-
methoxy-5-methyl-1-(2-trimethylsilylethoxycarbonyl)-3-(2-
trimethylsilylethoxy)methoxycyclohex-5-en-2-yl]-6,8-
dimethyldeca-2,4,8-trienoate 84
+
(MNH4 , 14%), 356 (28), 321 (53), 249 (61), 225 (82) and 100
(100). Concentration of the filtrate under reduced pressure and
chromatography of the residue (4 : 1 light petroleum–ether) gave
the title compound 83 as an amorphous glass, [a]D +46.8 (c 1.18,
CHCl3). [Found (CI): M+ + NH4, 582.1919. C27H37NO935ClSi
requires M, 582.1926]; mmax 3463, 1757, 1738, 1710, 1251, 1190,
1023 and 845 cm−1; dH (300 MHz; CDCl3) 0.30 [9 H, s, Si(CH3)3],
1.09 (3 H, t, J 7, CH2CH3), 1.11 (3 H, d, J 7, 5-CH3), 2.12 (2 H,
m, 6-H2), 2.64 (1 H, m, 5-H), 3.35 (1 H, dd, J 13, 5, 1-H), 3.85–
4.25 (4 H, m, CH2CH3, CH2Cl), 4.32 (1 H, s, 2-OH), 5.34 (1 H, s,
3-H), 6.02 (1 H, s, PhCH), 6.22 (1 H, br. s, 4ꢀ-H), 7.32 (5 H, m,
ArH) and 7.55 (1 H, br. s, 5ꢀ-H); dC (75 MHz; CDCl3) −0.1, 13.7,
14.3, 32.9, 40.7, 42.2, 50.1, 61.6, 75.5, 78.4, 81.5, 108.0, 128.3,
128.9, 129.4, 132.8, 135.7, 147.0, 158.2, 166.7, 167.5, 173.8 and
n-Butyllithium (1.6 M in hexane, 0.31 cm3, 4.98 mmol) was
added to hexamethyldisilazane (0.096 cm3, 4.59 mmol) in
tetrahydrofuran (0.86 cm3) at 0 ◦C. After 30 min the solution
was cooled to −78 ◦C and added to the hydroxybutenolide (−)-
6 (69 mg, 1.31 mmol) and the phosphonium◦salt 2 (124 mg,
1.48 mmol) in tetrahydrofuran (2.5 cm3) at −78 C. The reaction
mixture was warmed to −10 ◦C over 1 h and left at this
temperature for 2 h. Saturated aqueous ammonium chloride
(0.5 cm3) and ethyl acetate (7 cm3) were added, and the mixture
acidified with aqueous hydrochloric acid (1.2 M) to pH 4. The
aqueous layer was extracted with ethyl acetate (6 × 10 cm3), and
the combined organic phases were washed with brine (4 cm3)
and dried (MgSO4). After concentration under reduced pressure,
the residue was dissolved in ether (3 cm3) and an excess of
ethereal diazomethane was added over a period of 20 min before
glacial acetic acid was added until no further gas evolution was
observed. Ether (15 cm3) was added and the solution washed
with saturated aqueous sodium hydrogen carbonate (3 cm3).
The aqueous phase was extracted with ether (2 × 5 cm3)
and the combined organic phases were dried (MgSO4). After
concentration under reduced pressure, chromatography of the
residue (7 : 1 light petroleum–ether) gave the title compound
84 (61 mg, 48%), a ca. 65 : 35 mixture of the (4Z)- and (4E)-
isomers, as a viscous oil. [Found (CI): M+ + NH4, 996.6373.
C52H98NO11Si3 requires M, 996.6448]; mmax 3369, 1726, 1457,
1251, 1168, 1072, 861 and 837 cm−1; dH (300 MHz, CDCl3)
(4Z)-isomer 0.02 and 0.07 [each 9 H, s, Si(CH3)3], 0.09 [6 H, s,
Si(CH3)2], 0.81 (3 H, d, J 6, 3ꢀ-CH3), 0.85 (3 H, d, J 7, 2ꢀ-
CHCH3), 0.92 [9 H, s, SiC(CH3)3], 0.96–1.06 (13 H, m, 6-CH3,
4ꢀ-H2, 2ꢀ-CHCH3, 2 × CH2Si), 1.19–1.36 (3 H, m, 3ꢀ-H, 5ꢀ-H2),
1.46–1.70 (2 H, m, 9ꢀ-Hax, 11ꢀ-Hax), 1.61 (3 H, s, 8-CH3), 1.79–
1.91 (2 H, m, 9ꢀ-Heq, 11ꢀ-Heq), 1.82 (3 H, s, 5ꢀꢀ-CH3), 1.99–2.30
(4 H, m, 7-H2 and 10-H2), 2.84 (1 H, m, 6-H), 3.06 (1 H, br.
d, J 9, 2ꢀ-H), 3.42–3.59 (2 H, m, 1ꢀꢀ-H, OCHHCH2Si), 3.51
(3 H, s, OCH3), 3.81–3.92 (2 H, m, 8ꢀ-H, OCHHCH2Si), 3.84
(3 H, s, CO2CH3), 4.11–4.37 (5 H, m, 10ꢀ-H, 3ꢀꢀ-H, 4ꢀꢀ-H,
CO2CH2), 4.72 and 4.77 (each 1 H, d, J 7, OHCHO), 5.04
(1 H, s, 2ꢀꢀ-OH), 5.25–5.32 (2 H, m, 9-H, 6ꢀꢀ-H), 5.48 (1 H, t, J
11, 5-H), 5.97 (1 H, t, J 11, 4-H) and 6.65 (1 H, d, J 11, 3-H);
(4E)-isomer 5.86 (1 H, dd, J 15, 7, 5-H), 6.15 (1 H, dd, J 15, 11,
4-H) and 6.38 (1 H, d, J 11, 3-H); m/z (CI/NH3) 996 (M+ +
18, 18%), 961 (M+ − 17, 5), 878 (5), 462 (11), 399 (15) and 295
(100).
+
200.0; m/z (CI; NH3) 582 (MNH4 , 100%) and 548 (31).
Ethyl (1R,2S,3S,4R,5S)-2,4-dihydroxy-3-(4-
methoxy)benzyloxy-5-methyl-2-(2-trimethylsilyl-3-
furyl)cyclohexane-1-carboxylate (−)-75
Aqueous lithium hydroxide (10 cm3, 10% w/v) was added to
the acetylmandelate 76 (4.00 g, 6.13 mmol) in ethanol (400 cm3)
at room temperature and the resultant mixture stirred for 48 h.
The mixture was diluted with ethyl acetate and washed with
water then brine. The organic phase was concentrated under
reduced pressure and the residue was chromatographed (2 : 1
light petroleum–ether) to give the diol (−)-75 (2.83 g, 97%) as
◦
a white solid, mp 139–140 C; [a]D −95.6 (c 0.98, CHCl3). All
other data were in accord with those of the racemate.4
Ethyl (1R,2S,3R,5S)-2-hydroxy-3-(4-methoxy)benzyloxy-5-
methyl-2-(2-trimethylsilyl-3-furyl)-4-oxocyclohexane-1-
carboxylate (−)-22
Dimethyl sulfoxide (0.935 cm3, 13.27 mmol) in dichloromethane
(25 cm3) was added to oxalyl chloride (0.632 cm3, 7.31 mmol)
in dichloromethane (25 cm3) at −78 ◦C and the mixture stirred
for 10 min before the alcohol (−)-75 (3.16 g, 6.64 mmol) in
dichloromethane (25 cm3) was added. The solution was stirred
at −78 ◦C for 30 min, then triethylamine (4.55 cm3, 33.12 mmol)
was added and the mixture warmed to room temperature, diluted
with dichloromethane and washed with saturated aqueous
sodium bicarbonate. The aqueous phase was extracted with
dichloromethane and the combined organic phase was dried
and concentrated under reduced pressure. Chromatography of
the residue (2 : 1 light petroleum–ether) gave the hydroxyketone4
(−)-22 (3.10 g, 90%) as a white solid, [a]D −85.1 (c 0.94, CHCl3);
mp 125–126 ◦C. All other data were in accord with those of the
racemate.4
Methyl (6R,2Z,4E,8E)-l0-{(2R,3S,6R,8R,l0S)-l0-tert-
butyldimethylsilyloxy-3-methyl-2-(1-methylethyl)-l,7-
dioxaspiro[5.5]undecan-8-yl}-2-[(lR,2S,3R,4R)-2-hydroxy-4-
methoxy-5-methyl-1-(2-trimethylsilylethoxycarbonyl)-3-(2-
trimethylsilylethoxy)methoxycyclohex-5-en-2-yl]-6,8-
dimethyldeca-2,4,8-trienoate (4E)-84
Ethyl (1R,2S,3R,5S)-2,3-dihydroxy-5-methyl-2-(2-
trimethylsilyl-3-furyl)-4-oxocyclohexane-1-carboxylate (−)-38
Potassium carbonate (1.49 g, 10.7 mmol) was added to a solution
of the chloroacetylmandelate 80 (3.00 g, 5.3◦3 mol) in ethanol
(25 cm3) at 0 ◦C. The mixture was stirred at 0 C for 1 h, diluted
with ethyl acetate and washed with water. The aqueous phase
was extracted with ethyl acetate and the combined organic phase
was washed with brine, dried and concentrated under reduced
To the ester 84 (75 mg, 0.768 mmol) in degassed benzene
(2.2 cm3) was added iodine (0.2 M in benzene, 0.02 cm3,
0.0384 mmol) and potassium carbonate (50 mg, 3.69 mmol).
The suspension was stirred in daylight for 6.5 h then diluted
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
3 6 7 3

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with ether (10 cm3) and washed with saturated aqueous sodium
thiosulfate (2 cm3). The aqueous phase was extracted with
ether (5 × 5 cm3) and the combined organic phases were
dried (MgSO4). After concentration under reduced pressure,
chromatography of the residue (9 : 1 light petroleum–ether)
gave the title compound (4E)-84 (71 mg, 95%) as a viscous oil.
[Found (CI): M+ + NH4, 996.6387. C52H98NO11Si3 requires M,
Methyl (2Z,4E,8E)-10-{(2R,3S,6R,8R,10S)-10-hydroxy-2-(2-
methyl)propyl-3-methyl-1,7-dioxaspiro-[5.5]undec-8-yl}-2-
[(5R,6S)-5-methoxy-4-methyl-6-(2-trimethylsilylethoxy)-
methoxycyclohexa-1,3-dien-1-yl]-6,8-dimethyldeca-2,4,8-
trienoate 86
Triethylamine (0.1 M in xylene, 0.18 cm3, 0.18 mmol) and
2,4,6-trichlorobenzoyl chloride (0.1 M in xylene, 0.15 cm3,
0.151 mmol) in xylene (1.3 cm3) were added to the acid 85
(11 mg, 0.151 mmol) at room temperature. After 44 h, 4-N,N-
dimethylaminopyridine (4.7 mg, 0.341 mmol) in xylene (1.3 cm3)
was added and the reaction mixture was stirred for 2 h. After
concentration under reduced pressure, chromatography (2 : 1
light petroleum–ether) of the residue afforded the title compound
86 (7.5 mg, 70%) as a viscous oil. [Found (FAB): M+ + Na-H,
724.4316. C40H65O8SiNa requires M, 724.4346]; mmax 3399, 1728,
1632, 1454, 1383, 1249, 1196, 1117, 1062, 1011, 980, 860 and
836 cm−1; dH (300 MHz, CDCl3) 0.01 [9 H, s, Si(CH3)3], 0.82
(3 H, d, J 6, 3ꢀ-CH3), 0.85 (3 H, d, J 7, 2ꢀ-CHCH3), 0.89–1.12
(11 H, m, 6-CH3, 4ꢀ-H2, 2ꢀ-CHCH3, CH2Si), 1.25–1.32 (3 H, m,
3ꢀ-H, 5ꢀ-H2), 1.48–1.70 (2 H, m, 9ꢀ-Hax 11ꢀ-Hax), 1.60 (3 H, s,
8-CH3), 1.87–2.11 (4 H, m, 10-H2, 9ꢀ-Heq, 11ꢀ-Heq), 1.96 (3 H, s,
4ꢀꢀ-CH3), 2.25 (2 H, m, 7-H2), 2.50 (1 H, m, 6-H), 3.08 (1 H, m,
2ꢀ-H), 3.51–3.61 (2 H, m, OCH2CH2Si), 3.54 (3 H, s, OCH3),
3.68 (1 H, m, 8ꢀ-H), 3.85 (3 H, s, CO2CH3), 3.99–4.09 (2 H, m,
10ꢀ-H, 6ꢀꢀ-H), 4.59 (1 H, d, J 5, 5ꢀꢀ-H), 4.71 and 4.86 (each 1 H,
d, J 7, OHCHO), 5.19 (1 H, m, 9-H), 5.82–5.95 (3 H, m, 5-H,
2ꢀꢀ-H, 3ꢀꢀ-H), 6.35 (1 H, dd, J 15, 11, 4-H) and 6.67 (1 H, d, J 11,
3-H); m/z (CI/NH3) 720 (M+ + 18, 4%), 703 (M+ + 1, 5), 555
(100) and 537 (92)
21
996.6448]; [a]D +10.6 (c 1.28, CHCl3); mmax 3439, 1722, 1643,
1384, 1098 and 836 cm−1; dH (300 MHz, CDCl3) 0.01 and 0.04
[each 9 H, s, Si(CH3)3], 0.08 [6 H, s, Si(CH3)2], 0.81 (3 H,
d, J 6, 3ꢀ-CH3), 0.85 (3 H, d, J 7, 2ꢀ-CHCH3), 0.93 [9 H, s,
SiC(CH3)3], 0.94–1.07 (13 H, m, 6-CH3, 4ꢀ-H2, 2ꢀ-CHCH3, 2 ×
CH2Si), 1.19–1.37 (3 H, m, 3ꢀ-H and 5ꢀ-H2), 1.46–1.58 (2 H,
m, 9ꢀ-Hax, 11ꢀ-Hax), 1.62 (3 H, s, 8-CH3), 1.82 (3 H, s, 5ꢀꢀ-CH3),
1.82–1.91 (2 H, m, 9ꢀ-Heq, 11ꢀ-Heq), 2.12–2.32 (4 H, m, 7-H2
and 10-H2), 2.42 (1 H, m, 6-H), 3.07 (1 H, m, 2ꢀ-H), 3.45–3.59
(2 H, m, 1ꢀꢀ-H, OCHHCH2Si), 3.50 (3 H, s, OCH3), 3.79–3.86
(2 H, m, 8ꢀ-H, OCHHCH2Si), 3.85 (3 H, s, CO2CH3), 4.12–
4.35 (5 H, m, 10ꢀ-H, 3ꢀꢀ-H, 4ꢀꢀ-H, CO2CH2), 4.72 and 4.77 (each
1 H, d, J 7, OHCHO), 4.97 (1 H, s, 2ꢀꢀ-OH), 5.25 (1 H, m, 9-H),
5.33 (1 H, m, 6ꢀꢀ-H), 5.86 (1 H, dd, J 15, 7, 5-H), 6.15 (1 H,
dd, J 15, 11, 4-H) and 6.38 (1 H, d, J 11, 3-H); dC (50 MHz,
CDCl3) −4.2, −1.0, −0.9, 14.6, 16.7, 17.8, 18.0, 18.7, 18.8, 19.2,
19.8, 21.4, 24.3, 26.5, 28.7, 28.8, 32.1, 34.9, 35.2, 36.2, 41.8,
45.6, 46.0, 47.4, 52.2, 58.7, 64.2, 66.3, 68.6, 68.7, 74.9, 76.5,
76.9, 78.1, 78.4, 79.9, 80.0, 96.6, 96.7, 97.7, 117.5, 123.6, 124.5,
133.4, 134.9, 135.9, 137.0, 147.4, 169.1 and 175.3; m/z (CI/NH3)
996 (M+ + 18, 22%), 979 (M+ + 1, 3), 829 (7), 411 (29) and
90 (100).
The acid 85 (11 mg, 0.146 mmol) and 4-dimethylamino-
pyridine (0.1 M in dichloromethane, 0.015 cm3, 0.0146 mmol)
in dichloromethane (2.3 cm3) were added to dicyclohexylcar-
bodiimide (0.1 M in dichlorometh◦ane, 0.22 cm3, 0.219 mmol)
in dichloromethane (2.0 cm3) at 0 C via a syringe pump over
6 h and the reaction mixture then stirred at 5 ◦C for 63 h. After
concentration under reduced pressure, the residue was dissolved
in ether (3 cm3) and filtered through silica gel. The combined
filtrate was then concentrated under reduced pressure and
chromatography (1 : 1 light petroleum–ether) of the residue gave
the cyclohexadiene 86 (2 mg, 19%) as a viscous oil. Further elu-
tion with light petroleum–ether–methanol–acetic acid 50 : 50 :
1 : 1 gave recovered acid 85 (1 mg).
(lR,2S,3R,4R)-2-[(5R,1Z,3E,7E)-1-Carbomethoxy-5,7-
dimethyl-9-{(2R,3S,6R,8R,10S)-10-hydroxy-3-methyl-2-(1-
methylethyl)-l,7-dioxaspiro[5.5]undecan-8-yl}nona-1,3,7-trien-1-
yl]-2-hydroxy-4-methoxy-5-methyl-3-(2-trimethylsilylethoxy)-
methoxycyclohex-5-ene-1-carboxylic acid 85
Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran,
0.28 cm3, 2.82 mmol) was added to the ester (4E)-84 (55 mg,
0.564 mmol) in tetrahydrofuran (2.6 cm3) at room temperature.
After 13 h, aqueous hydrogen chloride (1.2 M, 0.3 cm3) and
saturated aqueous ammonium chloride (2 cm3) were added.
The mixture was diluted with ethyl acetate (10 cm3), the
aqueous phase was extracted with chloroform (5 × 7 cm3)
and the combined organic phases were dried (MgSO4). After
concentration under reduced pressure, chromatography (50 : 50 :
1 : 1 light petroleum–ether–methanol–acetic acid) of the residue
gave the title compound 85 (40 mg, 93%) as a viscous oil. [Found
(CI): M+ − OH, 747.4517. C41H67O10Si requires M, 747.4504];
mmax 3419, 1721, 1435, 1250, 1198, 1121, 1099, 1075, 1057, 1023,
862 and 836 cm−1; dH (300 MHz, CDCl3) 0.02 [9 H, s, Si(CH3)3],
0.82 (3 H, d, J 6, 3ꢀꢀ-CH3), 0.85 (3 H, d, J 7, 2ꢀꢀ-CHCH3), 0.95–
1.10 (11 H, m, 5ꢀ-CH3, 4ꢀꢀ-H2, CH2Si, 2ꢀꢀ-CHCH3), 1.28–1.36
(3 H, m, 3ꢀꢀ-H, 5ꢀꢀ-H2), 1.48–1.57 (2 H, m, 9ꢀꢀ-Hax, 11ꢀꢀ-Hax), 1.64
(3 H, s, 7ꢀ-CH3), 1.83 (3 H, s, 5-CH3), 1.95–2.05 (2 H, m, 9ꢀꢀ-Heq,
11ꢀꢀ-Heq), 2.24–2.35 (4 H, m, 6ꢀ-H2, 9ꢀ-H2), 2.55 (1 H, m, 5ꢀ-H),
3.07 (1 H, m, 2ꢀꢀ-H), 3.45–3.52 (2 H, m, 8ꢀꢀ-H, OCHHCH2Si),
3.50 (3 H, s, OCH3), 3.68 (2 H, m, 10ꢀꢀ-H, 10ꢀꢀ-OH), 3.88–3.96
(2 H, m, 1-H, OCHHCH2Si), 3.91 (3 H, s, CO2CH3), 4.14–4.32
(3 H, m, 3-H, 4-H, 2-OH), 4.73 (2 H, s, OCH2O), 5.08 (1 H,
m, 8ꢀ-H), 5.34 (1 H, br. s, 6-H), 6.03 (1 H, dd, J 15, 7, 4ꢀ-H),
6.38 (1 H, dd, J 15, 11, 3ꢀ-H) and 6.60 (1 H, d, J 11, 2ꢀ-H); dC
(50 MHz, CDCl3) −0.9, 14.6, 16.6, 17.9, 18.5, 19.7, 19.9, 21.3,
28.7, 28.7, 30.2, 30.2, 32.0, 32.1, 34.4, 34.8, 36.2, 40.1, 45.2,
46.0, 47.7, 52.6, 58.9, 66.1, 66.3, 66.4, 68.4, 74.2, 76.9, 77.1,
78.1, 78.6, 80.3, 96.3, 97.8, 117.8, 122.8, 124.7, 131.9, 135.3,
136.7, 137.2, 149.2, 170.1, 176.2 and 258.6; m/z (CI/NH3) 765
(M+ + 1, 7%), 747 (M+ − 17, 19), 729 (22), 647 (50), 629 (74) and
90 (100).
Methyl (6R,2Z,4EZ,8E)-l0-{(2R,3S,6R,8R,l0S)-l0-tert-
butyldimethylsilyloxy-3-methyl-2-(1-methylethyl)-l,7-
dioxaspiro[5.5]undecan-8-yl}-2-[(lR,2S,3R,4R)-2,3-dihydroxy-
4-methoxy-5-methyl-1-(2-trimethylsilylethoxycarbonyl)-
cyclohex-5-en-2-yl]-6,8-dimethyldeca-2,4,8-trienoate 90
Magnesium bromide diethyl etherate (65 mg, 2.53 mmol),
potassium carbonate (31 mg, 2.21 mmol) and n-butanethiol
(0.027 cm3, 2.53 mmol) were added to the 2-trimethyl-
silylethoxymethyl ether 84 (31 mg, 0.316 mol) in ether (0.9 cm3)
at room temperature. After 2.5 h, water (1.4 cm3), aqueous
hydrogen chloride (1.2 M, 0.2 cm3) and ether (22 cm3) were
added, the aqueous phase was extracted with ether (6 × 20 cm3)
and the combined organic phases were dried (MgSO4). After
concentration under reduced pressure, chromatography (8 : 1
then 2 : 1 light petroleum–ether) of the residue gave the title
compound 90 (21 mg, 78%), a ca. 2 : 1 mixture of the (4Z)-
and (4E)-isomers, as a viscous oil. [Found (CI): M+ + NH4,
866.5624. C46H84NO10Si2 requires M, 866.5634]; mmax 3369, 1726,
1457, 1168, 1072 and 837 cm−1; dH (300 MHz, CDCl3) (4Z)-
isomer 0.08 [9 H, s, Si(CH3)3], 0.10 [6 H, s, Si(CH3)2], 0.81
(3 H, d, J 6, 3ꢀ-CH3), 0.85 (3 H, d, J 7, 2ꢀ-CHCH3), 0.93
[9 H, s, SiC(CH3)3], 0.96–1.07 (11 H, m, 6-CH3, 4ꢀ-H2, 2ꢀ-
CHCH3, CH2Si), 1.19–1.38 (3 H, m, 3ꢀ-H, 5ꢀ-H2), 1.47–1.65
(2 H, m, 9ꢀ-Hax, 11ꢀ-Hax), 1.63 (3 H, s, 8-CH3), 1.81 (3 H, s, 5ꢀꢀ-
CH3), 1.86–1.92 (2 H, m, 9ꢀ-Heq, 11ꢀ-Heq), 1.98–2.28 (4 H, m,
3 6 7 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7

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7-H2, 10-H2), 2.66 (1 H, br. s, 3ꢀꢀ-OH), 2.90 (1 H, m, 6-H), 3.07
(1 H, d, J 9, 2ꢀ-H), 3.50 (3 H, s, OCH3), 3.53 (1 H, m, 1ꢀꢀ-H), 3.82
(3 H, s, CO2CH3), 3.83 (1 H, m, 8ꢀ-H), 3.97–4.31 (5 H, m, 10ꢀ-H,
3ꢀꢀ-H, 4ꢀꢀ-H, CO2CH2), 4.96 (1 H, s, 2ꢀꢀ-OH), 5.26 (1 H, m, 9-H),
5.36 (1 H, m, 6ꢀꢀ-H), 5.49 (1 H, d, J 10, 5-H), 6.03 (1 H, t, J 10,
4-H) and 6.91 (1 H, d, J 11, 3-H); (4E)-isomer 5.92 (1 H, dd, J
15, 7, 5-H), 6.19 (1 H, dd, J 15, 11, 4-H) and 6.62 (1 H, d, J 10,
3-H); m/z (CI/NH3) 866 (M+ + 18, 28), 849 (M+, 17), 831 (5)
and 717 (100).
(lR,2S,3R,4R)-2-[(5R,1Z,3E,7E)-1-Carbomethoxy-5,7-
dimethyl-9-{(2R,3S,6R,8R,10S)-10-hydroxy-3-methyl-2-(1-
methylethyl)-l,7-dioxaspiro[5.5]undecan-8-yl}nona-1,3,7-trien-1-
yl]-2,3-dihydroxy-4-methoxy-5-methylcyclohex-5-ene-1-
carboxylic acid 93
Following the procedure outlined for the preparation of the diol
90, the trimethylsilylethoxymethyl ether 85 (40 mg, 0.523 mmol),
magnesium bromide diethyl etherate (108 mg, 4.18 mmol),
potassium carbonate (50 mg, 3.66 mmol) and n-butanethiol
(0.022 cm3, 2.09 mmol) in ether (1.5 cm3), after chromatography
(25 : 25 : 2 : 1 light petroleum–ether–methanol–acetic acid) gave
the title compound 93 (30 mg, 90%) as a viscous oil. [Found
2-Trimethylsilylethyl (1S,2R,5R,6R,9Z)-9-[(4R,2Z,6E)-8-
{(2R,3S,6R,8R,10S)-10-tert-butyldimethylsilyloxy-3-methyl-2-
(1-methylethyl)-l,7-dioxaspiro[5.5]undecan-8-yl}-4,6-
dimethylocta-2,6-dienylidene]-1-hydroxy-5-methoxy-4-methyl-8-
oxo-7-oxabicyclo[4.3.0]non-3-ene-2-carboxylate 91
(CI): M+ − OH, 617.3689. C35H53O9 requires M, 617.3690]; [a]D
22
+15.7 (c 0.9, CHCl3); mmax 3421, 1715, 1454, 1384, 1198, 1085,
1009, 979, 883 and 737 cm−1; dH (300 MHz, CDCl3) 0.82 (3 H,
d, J 6, 3ꢀꢀ-CH3), 0.85 (3 H, d, J 7, 2ꢀꢀ-CHCH3), 0.92–1.08 (9 H,
m, 5ꢀ-CH3, 4ꢀꢀ-H2, 2ꢀꢀ-CHCH3), 1.25–1.34 (3 H, m, 3ꢀꢀ-H, 5ꢀꢀ-H2),
1.48–1.72 (2 H, m, 9ꢀꢀ-Hax, 11ꢀꢀ-Hax), 1.61 (3 H, s, 7ꢀ-CH3), 1.80
(3 H, s, 5-CH3), 1.87–2.02 (2 H, m, 9ꢀꢀ-Heq, 11ꢀꢀ-Heq), 2.12–2.31
(4 H, m, 6ꢀ-H2, 9ꢀ-H2), 2.51 (1 H, m, 5ꢀ-H), 3.07 (1 H, br. d, J
8, 2ꢀꢀ-H), 3.46 (1 H, m, 1-H), 3.48 (3 H, s, OCH3), 3.58 (1 H,
m, 8ꢀꢀ-H), 3.88 (3 H, s, CO2CH3), 4.01–4.21 (4 H, m, 3-H, 4-H,
10ꢀꢀ-H, 10ꢀꢀ-OH), 5.03 (1 H, m, 8ꢀ-H), 5.41 (1 H, m, 6-H), 5.84
(1 H, dd, J 15, 7, 4ꢀ-H), 6.19 (1 H, dd, J 15, 11, 3ꢀ-H) and 6.68
(1 H, d, J 11, 2ꢀ-H); m/z (CI/NH3) 635 (M+ + 1, 9%), 617 (8),
585 (7), 401 (90) and 219 (100).
˚
Silica gel (350 mg) and powdered molecular sieves 4 A (1 mg)
were added to the hydroxyester 90 (12 mg, 0.147 mmol) in
chloroform (0.7 cm3) at room temperature and the suspension
stirred for 29 h before being concentrated under reduced
pressure. Chromatography (2 : 1 light petroleum–ether) of the
residue gave the title compound 91 (11 mg, 98%), mainly the
(2ꢀZ)-isomers, as a viscous oil. [Found (CI): M+ + H, 817.5111.
C45H77O9Si2 requires M, 817.5106]; mmax 3421, 1754, 1639, 1459,
1252, 1187, 1122, 1069 and 837 cm−1; dH (300 MHz, CDCl3)
0.10 [9 H, s, Si(CH3)3], 0.11 [6 H, s, Si(CH3)2], 0.81 (3 H, d, J 6,
3ꢀꢀ-CH3), 0.85 (3 H, d, J 7, 2ꢀꢀ-CHCH3) 0.93 [9 H, s, SiC(CH3)3],
0.97–1.09 (11 H, m, 4ꢀ-CH3, 4ꢀꢀ-H2, 2ꢀꢀ-CHCH3, CH2Si), 1.30
(3 H, m, 3ꢀꢀ-H, 5ꢀꢀ-H2), 1.48–1.63 (2 H, m, 9ꢀꢀ-Hax, 11ꢀꢀ-Hax), 1.59
(3 H, s, 6ꢀ-CH3), 1.81–1.92 (2 H, m, 9ꢀꢀ-Heq, 11ꢀꢀ-Heq), 1.90 (3 H, s,
4-CH3), 2.05–2.21 (4 H, m, 5ꢀ-H2, 8ꢀ-H2), 2.98 (1 H, m, 4ꢀ-H),
3.06 (1 H, d, J 9, 2ꢀꢀ-H), 3.46 (3 H, s, OCH3), 3.53 (2 H, m, 8ꢀꢀ-H,
1-OH), 3.64 (1 H, m, 2-H), 4.15 (2 H, m, CO2CH2), 4.32 (2 H,
m, 5-H, 10ꢀꢀ-H), 4.70 (1 H, d, J 3, 6-H), 5.28 (1 H, m, 7ꢀ-H),
5.71 (1 H, m, 3-H), 5.85 (1 H, m, 3ꢀ-H) and 7.38 (2 H, m, 1ꢀ-H,
2ꢀ-H); m/z (CI/NH3) 817 (M+ + 1, 0.5%), 685 (1), 667 (1) and
215 (100).
(6R)-6-Hydroxymilbemycin E 96
Triethylamine (0.1 M in xylene, 0.62 cm3, 0.624 mmol) and
2,4,6-trichlorobenzoyl chloride (0.1 M in xylene, 0.52 cm3,
0.520 mmol) were added to the seco-acid 93 (33 mg, 0.52 mmol)
in xylene (4.4 cm3) at room temperature. After 46 h, 4-
N,N-dimethylaminopyridine (13 mg, 1.12 mmol) in xylene
(5.5 cm3) was added and the mixture stirred for 30 min.
After concentration under reduced pressure, chromatography
(1 : 1 light petroleum–ether) of the residue gave a mixture of
(6R)-6-hydroxy-28-(O-methyl)-28-oxomilbemycin E 94 and 28-
oxomilbemycin G 95 (11 mg, 33%) as a viscous oil. [Found for
94 (CI): M+ + H, 617.3683. C35H53O9 requires M, 617.3690]; mmax
3428, 1731, 1643, 1454, 1373, 1265, 1178, 1089, 1010, 880 and
805 cm−1; dH (200 MHz, CDCl3) for 94 1.80 (3 H, s, 4-CH3), 3.46
(3 H, s, OCH3), 3.80 (3 H, s, CO2CH3), 4.85 (1 H, m, 15-H) and
5.40 (1 H, m, 19-H); m/z (CI/NH3) 634 (M+ + 18, 2%), 617
(M+ + 1, 41) and 585 (M+ − 31, 100).
2-Trimethylsilylethyl (1S,2R,5R,6R,9Z)-9-[(4R,2E,6E)-8-
{(2R,3S,6R,8R,10S)-10-tert-butyldimethylsilyloxy-3-methyl-2-
(1-methylethyl)-l,7-dioxaspiro[5.5]undecan-8-yl}-4,6-
dimethylocta-2,6-dienylidene]-1-hydroxy-5-methoxy-4-methyl-
8-oxo-7-oxabicyclo[4.3.0]non-3-ene-2-carboxylate (2ꢀE)-91
Iodine (0.2 M in benzene, 0.01 cm3, 0.002 mmol) and potassium
carbonate (25 mg, 1.86 mmol) were added to the (2ꢀZ)-alkene
91 (32 mg, 0.388 mmol) in degassed benzene (1.1 cm3) at
room temperature and the mixture stirred in the presence of
daylight for 6.5 h before being diluted with ether (20 cm3) and
washed with saturated aqueous sodium thiosulfate (1.2 cm3).
The aqueous phase was extracted with ether (3 × 10 cm3) and
the combined organic phases were dried (MgSO4). After con-
centration under reduced pressure, chromatography (5 : 1 light
petroleum–ether) of the residue gave the title compound (2ꢀE)-91
(29 mg, 91%), as a viscous oil. [Found (EI): M+ + H, 817.5112.
Diisobutylaluminium hydride (1 M in toluene, 0.13 cm3,
1.29 mmol) was added to a mixture of the macrolides 94 and
95 (8 mg, 0.129 mmol) in toluene (0.58 cm3) at −78 ◦C. The
reaction mixture was warmed to −40 ◦C over 15 min, stirred
◦
for 2 h, then cooled to −78 C. Water (0.5 cm3) was added,
and the mixture warmed to room temperature and diluted with
ether (5 cm3). The aqueous phase was extracted with ether (3 ×
5 cm3) and dichloromethane (3 × 5 cm3) and the combined
organic phases dried (MgSO4). Concentration under reduced
pressure and chromatography (2 : 1 light petroleum–ether) of
the residue gave a mixture of the starting macrolides 94 and 95
(1 mg) followed by the title compound 96 (3 mg, 45%). [Found
20
C45H77O9Si2 requires M, 817.5106); [a]D −10.6 (c 0.34, CHCl3);
mmax 3437, 1751, 1734, 1641, 1383, 1251, 1121, 1068, 1009, 983
and 837 cm−1; dH (300 MHz, CDCl3) 0.09 [6 H, s, Si(CH3)2],
0.10 [9 H, s, Si(CH3)3], 0.81 (3 H, d, J 6, 3ꢀꢀ-CH3), 0.85 (3 H,
d, J 7, 2ꢀꢀ-CHCH3), 0.93 [9 H, s, SiC(CH3)3], 0.95–1.11 (11 H,
m, 4ꢀ-CH3, 4ꢀꢀ-H2, 2ꢀꢀ-CHCH3, CH2Si), 1.19–1.37 (3 H, m, 3ꢀꢀ-H,
5ꢀꢀ-H2), 1.45–1.60 (2 H, m, 9ꢀꢀ-Hax, 11ꢀꢀ-Hax), 1.63 (3 H, s, 6ꢀ-CH3),
1.81–1.95 (2 H, m, 9ꢀꢀ-Heq, 11ꢀꢀ-Heq), 1.89 (3 H, s, 4-CH3), 2.12–
2.30 (4 H, m, 5ꢀ-H2, 8ꢀ-H2), 2.58 (1 H, m, 4ꢀ-H), 3.07 (1 H, m,
2ꢀꢀ-H), 3.47 (3 H, s, OCH3), 3.52–3.65 (2 H, m, 2-H, 8ꢀꢀ-H), 4.10–
4.34 (5 H, m, 1-OH, 5-H, 10ꢀꢀ-H, CO2CH2), 4.75 (1 H, d, J 4,
6-H), 5.27 (1 H, m, 7ꢀ-H), 5.66 (1 H, m, 3-H), 6.16 (1 H, dd, J
15, 7, 3ꢀ-H), 6.93 (1 H, d, J 11, 1ꢀ-H) and 7.54 (1 H, dd, J 15, 11,
2ꢀ-H); m/z (CI/NH3) 817 (M+ + 1, 66%), 799 (21), 685 (100),
667 (72) and 215 (95).
(CI): M+ − OH, 571.3621. C34H51O7 requires M, 571.3635]; [a]D
23
+87.3 (c 0.47, acetone); mmax 3439, 1711, 1454, 1383, 1333, 1170,
1089, 1009 and 877 cm−1; dH (500 MHz, CDCl3) 0.77 (3 H, d, J
6, 24-CH3), 0.81 (3 H, d, J 7, 25-CHCH3), 0.84 (1 H, m, 18-Hax),
0.97 (3 H, d, J 7, 25-CHCH3), 1.01 (3 H, d, J 7, 12-CH3), 1.37–
1.68 (6 H, m, 20-Hax, 22-H2, 23-H2, 24-H), 1.58 (3 H, s, 14-CH3),
1.76 (3 H, s, 4-CH3), 1.78–1.87 and 2.10–2.24 (7 H, m, 13-H2,
16-H2, 18-Heq, 20-Heq, 25-CH), 2.45 (1 H, m, 12-H), 3.03 (1 H,
dd, J 10, 2, 25-H), 3.26 (1 H, br. s, OH), 3.43 (3 H, s, OCH3),
3.57 (1 H, m, 2-H), 3.73 (1 H, m, 17-H), 3.79 (1 H, m, OH), 3.81
(1 H, s, OH), 4.00 (2 H, m, 5-H, 6-H), 4.17 and 4.28 (each 1 H,
d, J 15, 28-H), 4.78 (1 H, m, 15-H), 5.30 (2 H, m, 3-H, 19-H),
5.45 (1 H, dd, J 15, 10, 11-H), 6.27 (1 H, dd, J 15, 11, 10-H)
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 5 4 – 3 6 7 7
3 6 7 5

View Online
and 6.46 (1 H, d, J 11, 9-H); m/z (CI/NH3) 588 (M+, 4%), 571
(M+ − 17, 100) and 553 (42).
(3 : 1 light petroleum–ether) of the residue gave a mixture of
milbemycin G 7 and 7-O-methylmilbemycin G 99. Reverse phase
HPLC (9 : 1 acetonitrile–water) gave milbemycin G 7 (7.5 mg,
21
(6R)-28-Chloro-28-deoxy-6-hydroxymilbemycin E 97
64%) as a viscous oil, [a]D +113.2 (c 0.75, acetone), all other
data were in accord with those recorded above, together with
7-O-methylmilbemycin G 99. [Found (CI): M+ + H, 585.3798.
C35H53O7 requires M, 585.3791]; mmax 3391, 1739, 1683, 1171,
1099, 836 and 776 cm−1; dH (500 MHz, CDCl3) 0.84 (3 H, d,
J 7, 24-CH3), 0.87 (3 H, d, J 7, 25-CHCH3), 0.91 (1 H, dd, J
7, 5, 18-Hax), 1.01 (3 H, d, J 7, 25-CHCH3), 1.02 (3 H, d, J 7,
12-CH3), 1.15 (1 H, t, J 12, 20-Hax), 1.39–1.67 (5 H, m, 22-H2,
23-H2, 24-H), 1.53 (3 H, s, 14-CH3), 1.81 (3 H, s, 4-CH3), 1.88
(3 H, m, 13-H, 18-Heq, 25-CH), 2.16–2.28 (4 H, m, 13-Hꢀ, 16-H2,
20-Heq), 2.46 (1 H, m, 12-H), 3.04 (1 H, dd, J 10, 2, 25-H), 3.26
(3 H, s, 7-OCH3), 3.35 (1 H, m, 2-H), 3.46 (3 H, s, 5-OCH3), 3.60
(1 H, m, 17-H), 3.91 (1 H, d, J 5, 5-H), 4.11 (1 H, m, 6-H), 4.59
and 4.66 (each 1 H, dd, J 14, 2, 28-H), 4.98 (1 H, m, 15-H), 5.0
and 5.52 (each 1 H, m), 5.65 (1 H, br. s, 3-H), 5.70 (1 H, d, J
11, 9-H) and 5.81 (1 H, dd, J 15, 11, 10-H); m/z (CI/NH3) 585
(M+ + 1, 7%) and 553 (M+ − 31, 100).
A solution of lithium diisopropylamine (0.6 M in tetrahy-
drofuran, 0.024 cm3, 0.0731 mmol) cooled to −78 ◦C was
added to (6S)-6-hydroxymilbemycin E 96 (4 mg, 0.0731 mmol)
in tetrahydrofuran–hexamethyldisilazane (3 : 1, 0.26 cm3) at
−78 ◦C. After 10 min, a solution of toluene p-sulfonyl chloride
(0.08 M in tetrahydrofuran–hexamethyldisilazane 3 : 1, 0.1 cm3,
0.0877 mmol) cooled to −78 ◦C was added and the mixture
stirred for 10 min. The reaction mixture was warmed to 0 ◦C
over 2 h and left at this temperature for 40 min. Brine (0.6 cm3)
and ether (10 cm3) were added, the aqueous phase was extracted
with ether (3 × 5 cm3) and the combined organic phases were
dried (MgSO4). After concentration under reduced pressure,
chromatography (20 : 1 light petroleum–ether) of the residue
gave the title compound 97 (3 mg, 74%) as a viscous oil. [Found
(CI): M+ + H, 607.3393. C34H52ClO7 requires M, 607.3402];
1172, 1120, 1088, 1055, 1009, 878 and 738 cm−1; dH (500 MHz,
CDCl3) 0.77 (3 H, d, J 7, 24-CH3), 0.81 (3 H, d, J 7, 25-CHCH3),
0.85 (1 H, m, 18-Hax), 0.97 (3 H, d, J 7, 25-CHCH3), 1.04 (3 H,
d, J 7, 12-CH3), 1.41–1.66 (6 H, m, 20-Hax, 22-H2, 23-H2, 24-H),
1.60 (3 H, s, 14-CH3), 1.72–1.87 (4 H, m, 13-H, 18-Heq, 20-Heq,
25-CH), 1.75 (3 H, s, 4-CH3), 2.14–2.28 (3 H, m, 13-Hꢀ, 16-H2),
2.53 (1 H, m, 12-H), 2.72 (1 H, s, 6-OH), 3.04 (1 H, dd, J 10, 2,
25-H), 3.44 (3 H, s, OCH3), 3.59 (1 H, m, 17-H), 3.68 (1 H, m,
2-H), 4.02 (1 H, m, 5-H), 4.11 (1 H, d, J 4, 6-H), 4.45 (1 H, d,
J 11, 28-H), 4.55 (1 H, s, 7-OH), 4.56 (1 H, d, J 11, 28-H), 4.83
(1 H, d, J 10, 15-H), 5.26 (1 H, d, J 2, 3-H), 5.33 (1 H, m, 19-H),
5.58 (1 H, dd, J 15, 9, 11-H), 6.26 (1 H, dd, J 15, 11, 10-H) and
6.38 (1 H, d, J 11, 9-H); m/z (CI/NH3) 609 [M+ + 1 (37Cl), 7%],
607 [M+ + 1 (35Cl), 21], 589 (M+ − 17, 21), 571 (41) and 553
(100).
25
[a]D +81.7 (c 0.14, acetone); mmax 3456, 1705, 1454, 1383, 1332,
Crystal data for acetylmandelate 76
C35H44O10Si, M = 652.81, orthorhombic, a = 14.792(2), b =
◦
3
˚
˚
28.300(4), c = 8.5666(9) A, U = 3586.1(7) A , T = 293(1) ,
space group P212121 (no. 19), Z = 4, l(CuKa) = 1.027 mm−1,
3060 unique reflections, 2565 reflections with I > 3.00 r(I) were
used in the final refinement. The final R(F) = 0.0484. X-Ray
data have been deposited with the Cambridge Crystallographic
Data Base, CCDC number 275136.†
Crystal data for chloroacetylmandelate 80
C27H33ClO9Si, M = 565.09, hexagonal, a = 14.153(1), c =
3
˚
˚
25.881(2) A, U = 4489.3(7) A , space group P61 (number 169),
Z = 6, l(CuKa) = 1.925 mm−1, 2592 reflections measured, 2292
unique reflections (Rint = 0.08139), 1156 reflections with I >
3.00 r(I) were used in the final refinement. The final R(F) =
0.0907. Since the number of observations was low, only the Cl,
Si and O atoms were refined anisotropically. C11 was disordered
over two sites each at 50% occupancy. H atoms were included in
calculated positions, except that bonded to O2, which could not
be located. X-Ray data have been deposited with the Cambridge
Crystallographic Data Base, CCDC number 275135.†
Milbemycin G 7
Freshly prepared silver(I) oxide (17 mg, 0.0247 mmol) was added
to a solution of (6R)-28-chloro-28-deoxy-6-hydroxymilbemycin
G 97 (1.5 mg, 0.0247 mmol) in tetrahydrofuran (0.5 cm3) at room
temperature. The suspension was stirred for 24 h, heated under
reflux for 1 h, then cooled and filtered through celite. The filter
cake was washed with ether (10 × 1 cm3) and dichloromethane
(10 × 1 cm3) and the combined organic phases were concentrated
under reduced pressure. Chromatography (3 : 1 light petroleum–
ether) of the residue gave milbemycin G 7 (1 mg, 71%) as a
viscous oil. [Found (EI): M+, 570.3555. C34H50O7 requires M,
Acknowledgements
We thank the EPSRC for a studentship (to S. B.) and the IPST
(Thailand) for a post-graduate scholarship (to A. T.). We should
also like to thank Dr C. Ellwood for the resolution of diol 75 and
we are very grateful indeed to Dr J. Ide of the Sankyo Company
Limited, Tokyo, Japan, for a sample of milbemycin D.
570.3557]; [a]D +101 (c 0.195, acetone) [lit.3b [a]D +108
(c 0.25, acetone)]; mmax 3461, 1713, 1454, 1367, 1308, 1265, 1165,
1119, 1097, 1010, 869, 805 and 737 cm−1; dH (500 MHz, CDCl3)
0.77 (3 H, d, J 7, 24-CH3), 0.83 (1 H, m, 18-Hax), 0.84 and 0.98
(each 3 H, d, J 7, 25-CHCH3), 1.02 (3 H, d, J 7, 12-CH3), 1.33
(1 H, t, J 12, 20-Hax), 1.42–1.64 (5 H, m, 22-H2, 23-H2, 24-H),
1.51 (3 H, s, 14-CH3), 1.74–1.90 (3 H, m, 13-H, 18-Heq, 25-CH),
1.79 (3 H, s, 4-CH3), 1.98 (1 H, m, 20-Heq), 2.15–2.21 (3 H, m,
13-Hꢀ, 16-H2), 2.40 (1 H, m, 12-H), 3.05 (1 H, dd, J 10, 2, 25-H),
3.28 (1 H, m, 2-H), 3.49 (3 H, s, OCH3), 3.57 (1 H, m, 17-H), 3.96
(1 H, m, 5-H), 4.01 (1 H, d, J 6, 6-H), 4.11 (1 H, s, 7-OH), 4.60
and 4.67 (each 1 H, d, J 14, 28-H), 4.93 (1 H, t, J 8, 15-H),
5.28–5.38 (3 H, m, 3-H, 11-H, 19-H) and 5.69–5.77 (2 H, m,
9-H, 10-H); m/z (EI) 570 (M+, 5%), 552 (M+ − 18, 1), 428 (14),
259 (17), 151 (43) and 49 (100); m/z (CI/NH3) 571 (M+ + 1,
2%), 554 (18), 181 (51) and 55 (100).
26
27
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3 6 7 7