Total synthesis of milbemycin E: Resolution of the C(1)-C(10) fragment and final assembly

Article abstract of DOI:10.1039/a605894i

The racemic hydroxycyclohexanone (±)-7, prepared by the Robinson addition of the keto ester 5 to 3-methylbut-3-enone 6, has been reduced stereoselectively to give the racemic cyclohexanediol (±)-8. This has been resolved by fractional crystallisation of t

Full text of DOI:10.1039/a605894i

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Total synthesis of milbemycin E: resolution of the C(1)–C(10)
fragment and final assembly
Patrick G. Steel,a (the late) Owen S. Mills,b Emma R. Parmeeb and
Eric J. Thomas*,b
a
The Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, UK
b The Department of Chemistry, The University of Manchester, Manchester M13 9PL, UK
The racemic hydroxycyclohexanone (±)-7, prepared by the Robinson addition of the keto ester 5 to 3-
methylbut-3-enone 6, has been reduced stereoselectively to give the racemic cyclohexanediol (±)-8. This
has been resolved by fractional crystallisation of the acetylmandelate esters 10 and 11. With (S)-acetyl
mandelic acid 9, diastereoisomer 11 crystallises out. The required, dextrorotatory, enantiomer of the
cyclohexanediol (±)-8 has been obtained by selective saponification of the mixture of the diastereo-
isomers 10 and 11, to give the mandelates 12 and 13, followed by crystallisation of the required
diastereoisomer 12. Saponification of 12 gives the dextrorotatory enantiomer of the cyclohexanediol (+)-8
[which could alternatively have been obtained directly from the racemic diol (±)-8 using (R)-acetyl-
mandelate ent-9]. Oxidation of the dextrorotatory diol (+)-8 gives the laevorotatory hydroxy ketone (Ϫ)-7.
The 3,4-double bond has been introduced into this ketone by regioselective enol trimethylsilyl ether
formation, phenylselanation and oxidative elimination, followed by reduction to give the cyclohexenediol
18. M ethylation, saponification and re-esterification give the 2-furylcyclohexenoate 23, which on oxidation
using singlet oxygen is converted into the hydroxybutenolide 3. The dextrorotatory diol (+)-8 has also been
converted into the hydroxybutenolide 29 which lacks the 3,4-double bond. Conditions have been
developed for the Wittig reactions between the hydroxybutenolides 29 and 3 and the phosphonium salt 2 to
give the esters 32 and 37 after esterification using diazomethane and iodine induced isomerisation of the
10,11-double bond. D eprotection gives the hydroxy acids 33 and 39 which have been cyclised to give the
macrolides 34 and 40. Selective reduction of these methyl esters gives 3,4-dihydromilbemycin E 35 and
milbemycin E 1.
A convergent approach to non-aromatic β-milbemycins, e.g.
milbemycin E 1, has been proposed in which a key step is the
Wittig reaction between the phosphonium salt 2 and the
hydroxybutenolide 3.1 We have reported syntheses of the phos-
phonium salt 22 and the racemic hydroxybutenolide (±)-4,3 and
shown that this hydroxybutenolide can be used in Wittig con-
densations. We now describe the resolution of a synthetic pre-
cursor of hydroxybutenolide 3, and the completion of a total
synthesis of milbemycin E 1.4
Results and discussion
The racemic hydroxycyclohexanone (±)-7 was prepared from
the keto ester 5 and 3-methylbut-3-enone 6 (Scheme 1).3 Pre-
liminary attempts at resolution by saponification to the corre-
sponding acid and esterification using a chiral alcohol, e.g.
menthol or borneol, were unsuccessful. However, reduction
using sodium triacetoxyborohydride5 gave the racemic cyclo-
hexanediol (±)-8 which was esterified with (S)-(+)-acetyl-
mandelic acid 9 to give the diastereoisomers 10 and 11.6 One of
these diastereoisomers, the isomer 11, crystallised out on tritur-
ation of the mixture with hexane. A sample of the other isomer
10 was isolated as an oil by chromatography.
The structures of isomers 10 and 11, and hence the absolute
configurations of products derived from them, were assigned by
1H NMR spectroscopy. In particular, the 5-CH3 for the crystal-
line isomer was observed at δ 1.03, whereas it was observed at δ
0.63 for the non-crystalline isomer.6 Following the mnemonic
for the assignment of absolute configuration to secondary
alcohols from the relative chemical shifts of their acetyl-
mandelates,7 it followed that the crystalline isomer was 11, the
non-crystalline isomer being 10. These assignments were con-
firmed by the successful incorporation of the laevorotatory
hydroxycyclohexanone (Ϫ)-7 into a total synthesis of milbemy-
cin E 1. (Indeed, had the wrong enantiomer of this hydroxy
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391

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Scheme 1 Reagents: i, NaOH, ethanol (58%);3 ii, NaBH(OAc)3, acetic acid (94%);3 iii, dicyclohexylcarbodiimide, 4-dimethylaminopyridine (83% of
the mixture of 10 and 11, 33% of 11 after recrystallisation); iv, K2CO3, ethanol, 0 ЊC, 2 h (39% of 12 from the 1:1 mixture of acetates 10 and 11); v,
K2CO3, ethanol, room temperature, 16 h (99%); vi, oxalyl chloride, dimethyl sulfoxide, triethylamine [(Ϫ)-7, 85%; (+)-7, 82%]; vii, K2CO3, ethanol,
room temperature, 16 h (97%)
ketone been taken through the synthesis, the macrocyclisation
reaction would have been unsuccessful.1)†
crystalline acetylmandelate ent-11 could be saponified directly
to the required enantiomer (+)-8.]
Selective saponification of the acetylmandelate 10, contain-
ing ca. 20% of its isomer 11, gave the mandelate esters 12 and
13. In this case, the required diastereoisomer 12 could be crys-
tallised out of the mixture, and further treatment with potas-
sium carbonate in ethanol gave the required diol, which turned
out to be the dextrorotatory, enantiomer of the cyclohexanediol
(+)-8. Oxidation of (+)-8 using Swern conditions8 gave the
laevorotatory hydroxycyclohexanone (Ϫ)-7. Saponification of
the crystalline acetylmandelate 11 gave the laevorotatory
cyclohexanediol (Ϫ)-8 which gave the dextrorotatory ketone
(+)-7 on oxidation. [Following the confirmation of structures
for the acetylmandelates, (R)-acetylmandelic acid ent-9 was
used for the resolution of the cyclohexanediol (±)-8, since the
The laevorotatory hydroxycyclohexanone (Ϫ)-7 was con-
verted into its enol trimethylsilyl ether (Ϫ)-14 which gave the
phenylselanyl ketone (Ϫ)-15 after sequential treatment with
phenylselenenyl chloride and tetrabutylammonium fluoride
(Scheme 2).3 Oxidative elimination gave a mixture of the endo-
and exo-cyclic alkenes 16 and 17 which was reduced to give the
cyclohexenediol (Ϫ)-18 together with the isomeric methylene-
cyclohexanediol 19. The ratio of these two isomers tended to
vary with scale, being 90:10 in favour of the endo-isomer 18 on
a small scale, but dropping to 78:22 on a multi-gram scale.3
Spectroscopic data for the enantiomerically enriched products
prepared along this sequence were identical to those obtained
earlier for the racemic compounds.
At this stage it was necessary to effect selective methylation
of the 5-hydroxy group (milbemycin numbering). During model
work this had been achieved using trimethyloxonium tetra-
fluoroborate in the presence of potassium carbonate.1 However,
during the present work this procedure gave mixtures of prod-
ucts including the bis-methyl ether 21. Conditions for this and
subsequent steps were first developed using the racemic alcohol
(±)-18.3
Selective monomethylation to the methyl ether (±)-20 was
achieved using silver oxide which had been freshly prepared,
stored in the dark, and rigorously dried under reduced pressure
together with methyl iodide which was filtered through silica gel
before use. The ethyl ester (±)-20 was then converted into the
2-trimethylsilylethyl ester (±)-23 in anticipation of the macro-
cyclisation step which would require prior deprotection of the
acid at C(1) in the presence of the methoxycarbonyl group at
C(8).1 The transesterification was carried out by saponification
† The structures assigned to the acetylmandelates 10 and 11, and hence
the absolute configurations of the cyclohexanediols (+)-8 and (Ϫ)-8
and the hydroxycyclohexanones (Ϫ)-7 and (+)-7, were confirmed by X-
ray crystallography of the crystalline acetylmandelate 11 (carried out
by O. S. Mills). Fig. 1 shows a projection of the molecular structure of
11 as established by the crystal structure determination. Crystal data:
C27H36O8Si. Mr = 516.36, monoclinic, spacegroup P21, Z = 2. At
T = 293 K, a = 10.034(8), b = 11.837(7), c = 12.640(9) Å, β = 102.18(3)Њ,
V = 1467.5(3) Å3, λ(Mo-Kα) = 0.710 69 Å, Dx = 1.18 g cmϪ3, µ = 1.28
cmϪ1. Colourless needles, crystal dimensions 0.3 × 0.15 × 0.15 mm.
Reflection intensities were collected on a CAD4 diffractometer using
the θ–2θ scan method. Index limits were 0 ≤ h ≤ 13, 0 ≤ k ≤ 16 and
Ϫ16 ≤ l ≤ 17. The structure was solved by direct methods (MULTAN 16
)
and difference Fourier series. The structure was refined by our own full-
matrix, least squares program and converged to a final R = 7.0% for
2628 reflections, |F| > 3σ(|F|), for 324 parameters (anisotropic thermal
parameters for non-H atoms and fixed parameters for H with B = 4.5
Å2).
392
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Scheme 2 Reagents: i, triethylamine, trimethylsilyl trifluoromethanesulfonate, carbon tetrachloride (85%); ii, phenylselenenyl chloride, tetrahydro-
furan (82%); iii, tetrabutylammonium fluoride, tetrahydrofuran (93%); iv, 30% hydrogen peroxide, dichloromethane, room temperature, 30 min; v,
sodium triacetoxyborohydride, acetic acid (18, 57%; 19, 17% from 15); vi, silver() oxide, methyl iodide (79%); vii, aqueous sodium hydroxide, ethanol
(75%); vii, 2-trimethylsilylethanol, 4-dimethylaminopyridine, dicyclohexylcarbodiimide (78%); ix, oxygen, tetraphenylporphyrin, dichloromethane,
methanol (24, 98%; 3, 95%)
of the ethyl ester using sodium hydroxide in ethanol to give the
carboxylic acid (±)-22, followed by esterification of the acid
using 2-trimethylsilylethanol and dicyclohexylcarbodiimide.
This synthesis of the racemic trimethylsilyl ester (±)-23 was
followed by a synthesis of the homochiral material (Ϫ)-23 from
the laevorotatory cyclohexenol (Ϫ)-18.
The final step for the synthesis of the required hydroxy-
butenolide 3 was the oxidation of the furan using singlet oxy-
gen.9 Previously, this had been carried out using dichlorometh-
ane as solvent. When this procedure was followed using the
racemic 2-trimethylsilylfuran (±)-20, two products were isolated
which were separated and identified as the required hydroxybu-
tenolide (±)-24 together with the Diels–Alder adduct (±)-25.
The isolation of this latter product was avoided using a mixture
of dichloromethane and methanol as solvent.10 Repetition of
this procedure with the laevorotatory 2-trimethylsilylethyl ester
(Ϫ)-23 gave the required hydroxybutenolide 3 (95%).
It was decided to synthesise 3,4-dihydromilbemycin E as a
more accessible interim target in order to develop conditions for
the later stages of the synthesis of milbemycin E. The dextro-
rotatory cyclohexanediol (+)-8 was monomethylated to give the
methyl ether (+)-26 (Scheme 3). This was saponified to give the
Scheme 3 Reagents: i, silver() oxide, methyl iodide (100%); ii, sodium
hydroxide, ethanol (99%); iii, 2-trimethylsilylethanol, 4-dimethylamino-
pyridine, dicyclohexylcarbodiimide (82%); iv, oxygen, tetraphenylpor-
phyrin, dichloromethane, ethanol (91%)
acid 27 which was coupled with 2-trimethylsilylethanol to give
the ester (+)-28. Oxidation with singlet oxygen in dichloro-
methane and methanol gave the hydroxybutenolide 29 which
lacked the crucial double bond, but which was more readily
available than its unsaturated analogue 3, and was used in
studies to establish conditions for the Wittig reaction and
macrocyclisation.
Preliminary attempts at the Wittig condensation between the
phosphonium salt 2 and the hydroxybutenolide 29 were carried
out by treatment of the phosphonium salt with either butyl-
lithium or lithium hexamethyldisilazide at 0 ЊC, followed by the
addition of two mole equivalents of lithium hexamethyl-
J. Chem. Soc., Perkin Trans. 1, 1997
393

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disilazide, and the addition of the mixture to the hydroxy-
butenolide. However, the major product under these conditions
was the phosphine oxide 30 together with only traces of the
required Wittig product. Slightly better results were obtained
using tert-butyllithium at Ϫ40 ЊC. The addition of tert-
butyllithium to the phosphonium salt 2 at Ϫ40 ЊC gave a red
solution. Two mole equivalents of lithium hexamethyldisilazide
were added and the solution was added to the hydroxybuteno-
lide 29 at Ϫ78 ЊC. The mixture was then allowed to warm to
Ϫ15 ЊC before being quenched. The crude product, presumably
the acid 31, was immediately treated with diazomethane and
isomerised using a trace of iodine in benzene to give the methyl
ester 32 as a single diastereoisomer in 54% overall yield from
the phosphonium salt (Scheme 4). Treatment with tetrabutyl-
ammonium fluoride11 gave the hydroxy acid 33 which was
cyclised using dicyclohexylcarbodiimide and 4-dimethylamino-
pyridine to give the macrolide 34 in 34% yield over the two
steps.12 Reduction using Red-Al, which had been used success-
fully in model studies, gave 3,4-dihydromilbemycin E 35 which
was identified on the basis of its spectroscopic data.
However, attempts to carry out the Wittig reaction following
the above procedure, but using the unsaturated hydroxybuteno-
lide 3, gave only low yields of products and were non-
reproducible. An alternative, somewhat simpler, procedure was
therefore developed in which three mole equivalents of lithium
hexamethyldisilazide were added to a mixture of the phos-
phonium salt 2 and the hydroxybutenolide 3 at Ϫ78 ЊC and the
mixture allowed to warm to Ϫ15 ЊC, before being quenched to
give the dienyl acid 36 as a mixture of (E)- and (Z)-isomers,
ratio (E):(Z) ca. 1:2 (Scheme 5). The crude acid was treated
with diazomethane and isomerised using a trace of iodine to
give the ester 37 together with a trace of an aromatic side-
product, possibly 38, formed by elimination from the hydroxy-
cyclohexenoate. Deprotection and macrocyclisation were
carried out as before to give the macrolide 40 in a 37% yield
over the two steps.
Scheme 4 Reagents: i, tert-butyllithium, lithium hexamethyldisilazide; ii, diazomethane; iii, iodine (cat.), benzene (54% of 32 based on 2); iv,
tetrabutylammonium fluoride, tetrahydrofuran; v, 4-dimethylaminopyridine, dicyclohexylcarbodimide (34% of 34 based on 32); vi, sodium bis(2-
methoxyethoxy)aluminium hydride (68%)
Fig. 1 Projection of the molecular structure of acetylmandelate 11 showing the crystallographic numbering scheme used
394
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Scheme 5 Reagents: i, lithium hexamethyldisilazide; ii, diazomethane; iii, iodine (cat.), benzene (42% of 37 based on 2); iv, tetrabutylammonium
fluoride, tetrahydrofuran; v, 4-dimethylaminopyridine, dicyclohexylcarbodiimide (37% of 40 based on 37); vi, diisobutylaluminium hydride (87%)
It now remained to reduce the methoxycarbonyl substituent
to complete a synthesis of milbemycin E 1. Attempts to effect
this transformation using Red-Al, which had proved success-
ful for the preparation of the dihydromilbemycin E 35, were
unsuccessful and gave rise to the formation of complex mix-
tures of products; perhaps the Red-Al is too basic. Diisobutyl-
aluminium hydride in hexane and tetrahydrofuran gave no reac-
tion, but the use of diisobutylaluminium hydride in toluene
gave rise to the formation of a single product which was iso-
lated in a yield of 87% and identified as milbemycin E 1 by
comparison of its chromatographic and spectroscopic data
with a sample of the authentic material.
This work completed a total synthesis of the non-aromatic
milbemycin, milbemycin E 1, by a convergent approach in
which the labile 3,4-double bond is introduced early in the syn-
thesis. The Wittig reaction between the phosphonium salt 2 and
the hydroxybutenolide 3 is the key step. By having the nucle-
ophilic component of this coupling step in the C(11)–C(25)
fragment, the use of protecting groups is minimised. The ylide
reacts selectively with the aldehyde derived from the hydroxy-
butenolide component of 3 rather than with the alkoxycarbonyl
group at C(1). This selectivity is important since it means that
the alkoxycarbonyl group at C(1) can be introduced early in the
synthesis and avoids problems associated with migration of the
3,4-double bond which complicate attempts to oxidise either a
hydroxymethyl or formyl group at C(1).12
The preferred procedure for the Wittig reaction is that in
which lithium hexamethyldisilazide is added to a mixture of
the hydroxybutenolide and the phosphonium salt at Ϫ78 ЊC. It
would appear that the ylide derived from the phosphonium
salt has to be generated in the presence of the aldehyde or else
it fragments to give the phosphine oxide 30. The early successes
in using tert-butyllithium as base during condensations with
the hydroxybutenolide 29 were probably due to formation of
the ylide by the lithium hexamethyldisilazide in the presence
of the hydroxybutenolide and not by the tert-butyllithium
itself.
By completing a synthesis of milbemycin E 1, we had
achieved what we had originally set out to accomplish in this
area. However, the biological activities of the α-milbemycins
and avermectins are more interesting and useful than those of
the β-milbemycins and so the strategy for milbemycin synthe-
sis reported in this paper has been adapted to complete a total
synthesis of an α-milbemycin, milbemycin G.13,14 Work on
completing a synthesis of the aglycone of an avermectin is in
progress.15
Experimental
For general experimental details, see the first paper in this
series.2
The following compounds were prepared as described pre-
viously1,3 but starting with the laevorotatory ketone (Ϫ)-7;
ethyl
(1R,6S)-4,6-bis(trimethylsilyloxy)-3-methyl-6-(2-tri-
methylsilyl-3-furyl)cyclohex-3-enecarboxylate (Ϫ)-14, [α]D
Ϫ35.0 (c 0.98 in CHCl3); ethyl (1R,2S,5R)-5-methyl-4-oxo-
5-phenylselanyl-2-trimethylsilyloxy-2-(2-trimethylsilyl-3-furyl)-
cyclohexanecarboxylate, [α]D Ϫ57.1 (c 0.38 in CHCl3); ethyl
(1R,2S,5R)-2-hydroxy-5-methyl-4-oxo-5-phenylselanyl-2-(2-
trimethylsilyl-3-furyl)cyclohexanecarboxylate (Ϫ)-15, [α]D
Ϫ109 (c 0.445 in CHCl3); ethyl (1R,4S,6S)-2,6-dihydroxy-3-
methyl-6-(2-trimethylsilyl-3-furyl)cyclohex-2-enecarboxylate
(Ϫ)-18, [α]D Ϫ112.9 (c 0.89 in CHCl3).
Ethyl (1R,2S,4S,5S)-4-[(2S)-2-acetoxy-2-phenylacetoxy]-2-
hydroxy-5-methyl-2-(2-trimethylsilyl-3-furyl)cyclohexane-
carboxylate 10 and ethyl (1S,2R,4R,5R)-4-[(2S)-2-acetoxy-2-
phenylacetoxy]-2-hydroxy-5-methyl-2-(2-trimethylsilyl-3-
furyl)cyclohexanecarboxylate 11
Dicyclohexylcarbodiimide (4.45 g, 21.6 mmol) in dichloro-
methane (35 cm3) was added to the cyclohexanediol (±)-81,3 (7
g, 20.6 mmol), (S)-(+)-acetylmandelic acid 9 (4.8 g, 24.7 mmol)
and 4-dimethylaminopyridine (DMAP) (246 mg, 2 mmol) in
dichloromethane (75 cm3) at 0 ЊC. The reaction mixture was
stirred for 16 h at ambient temperature, filtered and the residue
washed with ether (3 × 50 cm3). Concentration under reduced
pressure and chromatography of the residue using light
petroleum–ether (4:1) as eluent, gave the two diastereoisomers
10 and 11 as a thick gum (8.86 g, 83%). Warm hexane (100 cm3)
was added and the mixture triturated at ambient temperature to
induce crystallisation. Filtration gave the title compound 11 (3.6
g, 33%) as white crystals, mp 131–134 ЊC (Found: C, 62.75; H,
7.3. C27H36O8Si requires C, 62.77; H, 7.02%); [α]D +27.7 (c 0.88
in CHCl3); νmax/cmϪ1 3470, 1745, 1709, 1374, 1233, 1210, 1181,
J. Chem. Soc., Perkin Trans. 1, 1997
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1094, 1056 and 843; δH 0.3 [9 H, s, Si(CH3)3], 1.03 (3 H, d, J 6,
5-CH3), 1.10 (3 H, t, J 6, CH2CH3), 1.29 (1 H, m, 3-Hax), 1.72
(1 H, m, 5-H), 1.87 (2 H, m, 6-H2), 2.02 (1 H, dd, J 14, 5, 3-Heq),
2.2 (3 H, s, CH3CO), 2.81 (1 H, m, 1-H), 4.01 (2 H, m,
CH2CH3), 4.32 (1 H, br s, 2-OH), 5.03 (1 H, td, J 10, 7, 4-H),
5.86 (1 H, s, CHPh), 6.10 (1 H, d, J 2, 4Ј-H), 7.37 (5 H, m,
aromatic H) and 7.42 (1 H, d, J 2, 5Ј-H); m/z (EI) 516 (M+,
4.5%) and 501 (12). Chromatography of a small portion of the
residue, using light petroleum–ether (4:1) as eluent, gave the
title compound 10 as a viscous oil (Found: M+, 516.2180.
C27H36O8Si requires M, 516.2179); [α]D +55.2 (c 0.42 in
CHCl3); νmax/cmϪ1 3360, 1746, 1709, 1383, 1233, 1181, 1095,
1057 and 843; δH 0.31 [9 H, s, Si(CH3)3], 0.63 (3 H, d, J 6,
5-CH3), 1.11 (3 H, t, J 7.5, CH2CH3), 1.48 (1 H, m, 3-Hax), 1.63
(1 H, m, 5-H), 1.84 (2 H, m, 6-H2), 2.18 (3 H, s, CH3CO), 2.32 (1
H, dd, J 14, 4.5, 3-Heq), 2.83 (1 H, m, 1-H), 3.97 (2 H, m,
CH2CH3), 4.32 (1 H, d, J 2, 2-OH), 4.91 (1 H, td, J 11.3, 4.5,
4-H), 5.85 (1 H, s, CHPh), 6.15 (1 H, d, J 2, 4Ј-H), 7.41 (5 H, m,
aromatic H) and 7.53 (1 H, d, J 2, 5Ј-H); m/z (CI) 534 (M+ + 18,
2%), 516 (M+, 0.2), 323 (80), 305 (31) and 233 (100).
the solvent removed under reduced pressure. The residue was
dissolved in ether (100 cm3) and washed with water (2 × 50
cm3). The aqueous phase was extracted with ether (3 × 50 cm3)
and the organic extracts washed with brine (50 cm3), dried
(MgSO4) and concentrated under reduced pressure. The residue
was distilled using a Kugelrohr at 130 ЊC/0.05 mmHg to leave
behind the title compound (+)-8 (2.25 g, 99%) which was used
without further purification, [α]D +14.18 (c 0.51 in CHCl3); all
spectroscopic data were identical to those of the racemic
compound.3
Ethyl (1S,2R,4R,5R)-2,4-dihydroxy-5-methyl-2-(2-trimethyl-
silyl-3-furyl)cyclohexanecarboxylate (Ϫ)-8
Following the procedure used for the synthesis of the dextro-
rotatory cyclohexanediol (+)-8, the acetylmandelate 11 (2.9 g,
5.6 mmol) gave the laevorotatory enantiomer (Ϫ)-8 (1.85 g,
97%), [α]D Ϫ14.6 (c 0.9 in CHCl3).3
Ethyl (1R,2S,5S)-2-hydroxy-5-methyl-4-oxo-2-(2-trimethylsilyl-
3-furyl)cyclohexanecarboxylate (Ϫ)-7
Dimethyl sulfoxide (1.70 cm3, 24 mmol) in dichloromethane
(10 cm3) was added to oxalyl chloride (1.21 cm3, 13.9 mmol)
in dichloromethane (10 cm3) at Ϫ78 ЊC. After 15 min, the
cyclohexanediol (+)-8 (4.28 g, 12.6 mmol) in dichloromethane
(30 cm3) was added. After a further 30 min, triethylamine (8.8
cm3, 63 mmol) was added, and the mixture stirred for 15 min,
before warming to room temperature over a period of 1 h. Dilu-
tion with ether (100 cm3) was followed by washing with satur-
ated aqueous ammonium chloride (2 × 50 cm3). The aqueous
phase was extracted with ether (3 × 75 cm3) and the organic
extracts were washed with brine (100 cm3), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using light petroleum–ether (4:1) as eluent, gave the
title compound (Ϫ)-7 (3.6 g, 85%), [α]D Ϫ16.7 (c 0.4 in CHCl3),
with spectroscopic data identical to those of the racemic
compound.3
Ethyl (1R,2S,4S,5S)-2-hydroxy-4-[(2S)-2-hydroxy-2-phenyl-
acetoxy]-5-methyl-2-(2-trimethylsilyl-3-furyl)cyclohexane-
carboxylate 12 and ethyl (1S,2R,4R,5R)-2-hydroxy-4-[(2S)-2-
hydroxy-2-phenylacetoxy]-5-methyl-2-(2-trimethylsilyl-3-furyl)-
cyclohexanecarboxylate 13
The mixture of acetates 10 and 11 (5 g, 9.69 mmol) recovered
from crystallisation of 11, ratio 10:11 = ca. 5:1, was dissolved
in ethanol (90 cm3) and potassium carbonate (7 g, 50 mmol)
was added. The mixture was stirred for 2 h at 0 ЊC, diluted with
ether (150 cm3) and washed with water (2 × 75 cm3). The aque-
ous phase was extracted with ether (3 × 100 cm3) and the
organic extracts were washed with brine (100 cm3), dried
(MgSO4) and concentrated under reduced pressure. The residue
crystallised on trituration with warm hexane (70 cm3) and the
crystals were washed with cold hexane (50 cm3) to give the
alcohol 12 (2.4 g, 52%). Chromatography of the mother liquor
using light petroleum–ether (4:1) as eluent gave a second crop
of the alcohol 12 (0.75 g, 16%). The two batches of alcohol
were combined to give the title compound 12 (3.15 g, 68%; 39%
from the 50:50 mixture of acetates 10 and 11), mp 78–82 ЊC
(Found: C, 63.0; H, 6.95. C25H34O7Si requires C, 63.27; H,
7.22%); [α]D +14.3 (c 0.83 in CHCl3); νmax/cmϪ1 3380, 1733,
1715, 1383, 1250, 1185, 1096, 1030 and 843; δH 0.32 [9 H, s,
Si(CH3)3], 0.52 (3 H, d, J 7.5, 5-CH3), 1.11 (3 H, t, J 7.5,
CH2CH3), 1.52 (2 H, m, 3-Hax and 5-H), 1.79 (2 H, m, 6-H2),
2.32 (1 H, dd, J 13.5, 5, 3-Heq), 2.83 (1 H, m, 1-H), 3.50 (1 H, br
s, OH), 4.0 (2 H, m, CH2CH3), 4.36 (1 H, d, J 2, 2-OH), 4.97 (1
H, td, J 11.3, 4.5, 4-H), 5.07 [1 H, s, CH(OH)Ph], 6.13 (1 H, d, J
2, 4Ј-H), 7.28–7.42 (5 H, m, aromatic H) and 7.49 (1 H, d, J 2,
5Ј-H); m/z (EI) 474 (M+, 2.3%) and 459 (13). A sample of the
other isomer 13 of the title compound (550 mg, 12%) was iso-
lated from the column (Found: M+, 474.2074. C25H34O7Si
requires M, 474.2079); [α]D Ϫ8.5 (c 0.71 in CHCl3); νmax/cmϪ1
3340, 1735, 1715, 1384, 1250, 1185, 1096, 1031 and 843; δH 0.3
[9 H, s, Si(CH3)3], 1.02 (3 H, d, J 7, 5-CH3), 1.11 (3 H, t, J 7.5,
CH2CH3), 1.24 (1 H, m, 3-Hax), 1.70 (1 H, m, 5-H), 1.86 (2 H,
m, 6-H2), 2.06 (1 H, dd, J 14.3, 5, 3-Heq), 2.79 (1 H, m, 1-H), 3.5
(1 H, br s, OH), 4.0 (2 H, m, CH2CH3), 4.36 (1 H, d, J 2, 2-OH),
5.04 (1 H, td, J 11.3, 4.5, 4-H), 5.13 [1 H, s, CH(OH)Ph], 6.10 (1
H, d, J 2, 4Ј-H), 7.34 (5 H, m, aromatic H) and 7.45 (1 H, d, J 2,
5Ј-H); m/z (EI) 474 (M+, 2.7%) and 459 (10). A sample of the
cyclohexanediol 8 (230 mg, 7%) was also isolated from the
column.
Following the same procedure the laevorotatory cyclohex-
anediol (Ϫ)-8 (200 mg, 0.59 mmol) gave the dextrorotatory
cyclohexanone (+)-7 (164 mg, 82%), [α]D +15.98 (c 1.77 in
CHCl3).
Ethyl (1RS,4SR,6SR)-6-hydroxy-4-methoxy-3-methyl-6-(2-tri-
methylsilyl-3-furyl)cyclohex-2-enecarboxylate (±)-20
Aqueous sodium hydroxide (4 ; 40 cm3) was added to silver
nitrate (8 g, 47 mmol) in water (80 cm3), and the mixture stirred
vigorously in the absence of light for 30 min. The mixture was
filtered, and the fine brown powder washed sequentially with
water (100 cm3), acetone (100 cm3) and ether (200 cm3) before
being dried under reduced pressure in the dark for 48 h to give
silver oxide (5 g, 92%).
The cyclohexanediol (±)-18 (750 mg, 2.22 mmol) was dis-
solved in methyl iodide (42 cm3) which had been dried by pass-
ing through silica gel, and silver() oxide (4 g, 17.4 mmol) was
added. The mixture was stirred vigorously, whilst being heated
under reflux, in the absence of light, for 48 h. After cooling, the
silver() oxide was removed by filtration through Celite and was
washed with ether (4 × 50 cm3). Concentration under reduced
pressure gave a residue, which was chromatographed, using
light petroleum–ether (5:1) as eluent, to give the title compound
(±)-20 (620 mg, 79%) as white crystals, mp 78–70 ЊC (Found: C,
61.3; H, 8.2. C18H28O5Si requires C, 61.33; H, 8.01%); νmax/cmϪ1
3450, 1705, 1370, 1330, 1180, 1090 and 840; δH 0.35 [9 H, s,
Si(CH3)3], 1.17 (3 H, t, J 7, CH2CH3), 1.68 (1 H, m, 5-Hax), 1.84
(3 H, br s, 3-CH3), 2.41 (1 H, dd, J 13, 6, 5-Heq), 3.37 (3 H, s,
4-OCH3), 3.61 (1 H, m, 1-H), 4.10 (2 H, q, J 7, CH2CH3), 4.13
(1 H, m, 4-H), 4.66 (1 H, d, J 2, 6-OH), 5.35 (1 H, m, 2-H),
6.20 (1 H, d, J 2, 4Ј-H) and 7.53 (1 H, d, J 2, 5Ј-H); m/z
(CI) 370 (M+ + 18, 1%), 353 (M+ + 1, 3), 352 (M+, 2) and 335
(100).
Ethyl (1R,2S,4S,5S)-2,4-dihydroxy-5-methyl-2-(2-trimethylsilyl-
3-furyl)cyclohexanecarboxylate (+)-8
The mandelate 12 (3.15 g, 6.6 mmol) was dissolved in ethanol
(70 cm3) and potassium carbonate (7 g, 50 mmol) was added.
The mixture was stirred for 16 h at ambient temperature and
The (1R,4S,6S)-enantiomer (Ϫ)-20 was similarly prepared
and had [α]D Ϫ90.48 (c 2.48 in CHCl3).
396
J. Chem. Soc., Perkin Trans. 1, 1997

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(1RS,4SR,6SR)-6-Hydroxy-4-methoxy-3-methyl-6-(2-trimethyl-
silyl-3-furyl)cyclohex-2-enecarboxylic acid (±)-22
3.56 (3 H, s, OCH3), 3.69 (0.5 H, m, 1-H), 4.08 (4.5 H, m,
1-H, OCH2CH3, 4-H, OH), 4.25 and 4.56 (each 0.5 H, d, J 2.5,
6-OH), 5.42 (1 H, m, 2-H), 6.09 (1 H, m, 5Ј-H) and 7.23 and
7.15 (each 0.5 H, s, 4Ј-H); m/z (CI) 330 (M+ + 18, 43%), 313
(M+ + 1, 23) and 281 (100).
Aqueous sodium hydroxide (15 , 1.4 cm3) diluted with ethanol
(3 cm3) was added to the ethyl ester (±)-20 (760 mg, 2.16 mmol)
in ethanol (7 cm3) at 0 ЊC. The resulting orange solution was
stirred at 0 ЊC for 16 h, diluted with ether (20 cm3) and washed
with saturated aqueous sodium hydrogen carbonate (5 × 10
cm3). The aqueous extracts were acidified to pH 2 using 3 
hydrochloric acid and extracted with ethyl acetate (4 × 30 cm3).
The organic extracts were washed with brine (2 × 30 cm3), dried
(MgSO4) and concentrated under reduced pressure. The residue
was further dried by azeotropic distillation with benzene
(3 × 25 cm3) to give the title compound (±)-22 (533 mg, 75%), as
a pale yellow solid, which was used without further purifi-
cation, mp 138–40 ЊC; νmax/cmϪ1 3600–2400, 2880, 1700, 1090
and 840; δH 0.30 [9 H, s, Si(CH3)3], 1.70 (1 H, m, 5-Hax), 1.85
(3 H, br s, 3-CH3), 2.38 (1 H, dd, J 13, 5, 5-Heq), 3.37 (3 H, s,
4-OCH3), 3.66 (1 H, m, 1-H), 4.10 (2 H, m, 4-H and CO2H),
4.30 (1 H, br s, 6-OH), 5.40 (1 H, m, 2-H), 6.20 (1 H, d, J 2,
4Ј-H) and 7.53 (1 H, d, J 2, 5Ј-H); m/z (CI) 324 (M+, 4%),
303 (33) and 275 (18). The ether phase was washed with brine
(5 cm3), dried (MgSO4) and concentrated under reduced pres-
sure to give ethyl 5-methyl-2-(2-trimethylsilyl-3-furyl)benzoate
(126 mg, 19%).
2-Trimethylsilylethyl (1R,4S,6S)-6-hydroxy-6-(5-hydroxy-2-
oxo-1-oxacyclopent-3-en-3-yl)-4-methoxy-3-methylcyclohex-2-
enecarboxylate 3
Following the procedure outlined for the synthesis of hydroxy-
butenolide (±)-24, the 2-trimethylsilylfuran (Ϫ)-23 (210 mg,
0.495 mmol) gave, after chromatography, the hydroxybuteno-
lide 3 as a hygroscopic gum. This was recrystallised from
hexane–dichloromethane to yield the title compound 3 (181
mg, 95%) as a mixture of epimers; νmax/cmϪ1 3391, 1767,
1735, 1251, 1177, 1112, 1073, 929, 861 and 838; δH 0.06 [9 H,
s, Si(CH3)3], 0.98 [2 H, m, CH2Si(CH3)3], 1.80 (3 H, br s, 3-
CH3), 2.15 (2 H, m, 5-H2), 3.36 (3 H, s, 4-OCH3), 3.63 and
3.73 (each 0.5 H, d,
J
9, 5Ј-OH), 4.06 [4 H, m,
CH2CH2Si(CH3)3, 1-H and 4-H], 4.33 and 4.65 (each 0.5 H, s,
6-OH), 5.37 and 5.42 (each 0.5 H, d, J 2, 2-H), 6.1 (1 H, m,
5Ј-H) and 7.16 and 7.22 (each 0.5 H, s, 4Ј-H); m/z (CI) 402
(M+ + 18, 45%), 384 (M+, 8.4) and 357 (20).
The (1R,4S,6S)-enantiomer (Ϫ)-22 was similarly prepared
and had [α]D Ϫ85.06 (c 0.79 in CHCl3).
Ethyl (1R,2S,4S,5S)-2-hydroxy-4-methoxy-5-methyl-2-(2-tri-
methylsilyl-3-furyl)cyclohexanecarboxylate (+)-26
Following the procedure outlined for the synthesis of the
methyl ether 20, the diol (+)-8 (354 mg, 1.04 mmol) gave the
title compound (+)-26 (370 mg, 100%) as a white crystalline
solid, mp 83–85 ЊC (Found: C, 61.0; H, 8.6. C18H30O5Si requires
C, 60.98; H, 8.53%); [α]D +34.1 (c 0.9 in CHCl3); νmax/cmϪ1
3471, 1711, 1464, 1376, 1249, 1184, 1102 and 844; δH 0.32 [9 H,
s, Si(CH3)3], 1.10 (3 H, d, J 7.5, 5-CH3), 1.12 (3 H, t, J 7,
CH2CH3), 1.28 (1 H, m, 3-Hax), 1.52 (1 H, m, 5-H), 1.8 (2 H, m,
6-H2), 2.34 (1 H, dd, J 13.5, 4.5, 3-Heq), 2.84 (1 H, m, 1-H), 3.23
(1 H, td, J 11.3, 4.5, 4-H), 3.33 (3 H, s, 4-OCH3), 4.02 (2 H, m,
CH2CH3), 4.43 (1 H, br s, 2-OH), 6.18 (1 H, d, J 2, 4Ј-H) and
7.50 (1 H, d, J 2, 5Ј-H); m/z (EI) 354 (M+, 9%), 339 (14) and 307
(11).
2-Trimethylsilylethyl (1RS,4SR,6SR)-6-hydroxy-4-methoxy-3-
methyl-6-(2-trimethylsilyl-3-furyl)cyclohex-2-enecarboxylate
(±)-23
2-Trimethylsilylethanol (1.1 cm3, 7.7 mmol) was added to the
crude acid (±)-22 (533 mg, 1.65 mmol) and 4-dimethyl-
aminopyridine (10 mg, 0.08 mmol) in dichloromethane (5.7
cm3) and the mixture cooled to 0 ЊC. Dicyclohexylcarbodiimide
(445 mg, 2.16 mmol) in dichloromethane (3.7 cm3) was added
dropwise, and the resultant mixture stirred at ambient temper-
ature for 16 h. The reaction mixture was diluted with ether (20
cm3), filtered through Celite and the solvent removed under
reduced pressure. The residue was purified by flash chroma-
tography, using light petroleum–ether (20:1) as eluent, to give
the title compound (±)-23 (548 mg, 78%) as a viscous oil
(Found: C, 59.55; H, 8.85. C21H36O5Si2 requires C, 59.39; H,
8.55%); νmax/cmϪ1 3420, 1700, 1375, 1330, 1085 and 835; δH 0.02
and 0.34 [each 9 H, s, Si(CH3)3], 0.90 [2 H, m, CH2Si(CH3)3],
1.66 (1 H, m, 5-Hax), 1.84 (3 H, br s, 3-CH3), 2.40 (1 H, dd, J 13,
6, 5-Heq), 3.37 (3 H, s, 4-OCH3), 3.58 (1 H, m, 1-H), 4.12 [3 H,
m, 4-H and CH2CH2Si(CH3)3], 4.73 (1 H, d, J 2, 6-OH), 5.34 (1
H, m, 2-H), 6.18 (1 H, d, J 2, 4Ј-H) and 7.52 (1 H, d, J 2, 5Ј-H);
m/z (CI) 424 (M+).
(1R,2S,4S,5S)-2-Hydroxy-4-methoxy-5-methyl-2-(2-trimethyl-
silyl-3-furyl)cyclohexanecarboxylic acid (+)-27
Following the procedure used for the preparation of the carb-
oxylic acid 22, the ester (+)-26 (220 mg, 0.62 mmol) after 48 h at
5 ЊC, gave the title compound (+)-27 (200 mg, 99%) as a pale
yellow crystalline solid, mp 122–125 ЊC; [α]D +35.7 (c 0.92 in
CHCl3); νmax/cmϪ1 3440–2520, 1710, 1383, 1249, 1182, 1097
and 843; δH 0.3 [9 H, s, Si(CH3)3], 1.08 (3 H, d, J 7.5, 5-CH3),
1.27 (1 H, dd, J 14, 11, 3-Hax), 1.54 (1 H, m, 5-H), 1.82 (3 H,
m, 6-H2 and CO2H), 2.31 (1 H, dd, J 14, 5, 3-Heq), 2.91 (1 H,
dd, J 14, 3.7, 1-H), 3.23 (1 H, td, J 11, 5, 4-H), 3.33 (3 H, s,
4-OCH3), 4.2 (1 H, br s, 2-OH), 6.19 (1 H, d, J 2, 4Ј-H) and
7.50 (1 H, d, J 2, 5Ј-H); m/z (EI) 326 (M+, 14%), 293 (13) and
225 (100).
The (1R,4S,6S)-enantiomer (Ϫ)-23 was similarly prepared
and had [α]D Ϫ78.68 (c 0.91 in CHCl3).
Ethyl (1RS,4SR,6SR)-6-hydroxy-6-(5-hydroxy-2-oxo-1-oxa-
cyclopent-3-en-3-yl)-4-methoxy-3-methylcyclohex-2-ene-
carboxylate (±)-24
A solution of the 2-trimethylsilylfuran (±)-20 (87 mg, 0.25
mmol) in dichloromethane–methanol (50:50; 10 cm3) contain-
ing a trace of 5,10,15,20-tetraphenyl-21H,23H-porphine (tetra-
phenylporphyrin) was cooled to Ϫ78 ЊC and irradiated for 20
min by a 250 W tungsten light source whilst oxygen was
bubbled through the solution. The reaction was allowed to
warm to room temperature, then concentrated under reduced
pressure to give a residue which was taken up in ether. The
mixture was filtered and the filtrate concentrated under
reduced pressure. Chromatography of the resultant gum using
gradient elution with light petroleum–ether (66:34 to 25: 75)
as eluent, gave the title compound (±)-24 (75 mg, 98%) as a
mixture of epimers; νmax/cmϪ1 3570–3160, 1764, 1705, 1442,
1369, 1382, 1305, 1194, 1103, 1055 and 1018; δH 1.27 (3 H,
m, OCH2CH3), 1.83 (3 H, s, 3-CH3), 2.24 (2 H, d, J 7, 5-H2),
2-Trimethylsilylethyl (1R,2S,4S,5S)-2-hydroxy-4-methoxy-5-
methyl-2-(2-trimethylsilyl-3-furyl)cyclohexanecarboxylate-
(+)-28
Following the procedure outlined for the preparation of the
ester 23, the carboxylic acid (+)-27 (145 mg, 0.445 mmol) gave,
after chromatography using light petroleum–ether (12:1) as
eluent, the title compound (+)-28 (155 mg, 82%) as a viscous oil
(Found: M+, 426.2258. C21H38O5Si requires M, 426.2258);
[α]D +31.68 (c 1.25 in CHCl3); νmax/cmϪ1 3463, 1709, 1385,
1251, 1173, 1102 and 841; δH 0.00 and 0.33 [each 9 H, s,
Si(CH3)3], 0.85 [2 H, m, CH2Si(CH3)3], 1.08 (3 H, d, J 7.5,
5-CH3), 1.27 (1 H, m, 3-Hax), 1.55 (1 H, m, 5-H), 1.8 (2 H, m,
6-H2), 2.32 (1 H, dd, J 14.3, 4, 3-Heq), 2.82 (1 H, dd, J 12, 4.5,
1-H), 3.23 (1 H, td, J 10, 4, 4-H), 3.33 (3 H, s, 4-OCH3), 4.03 [2
H, m, CH2CH2Si(CH3)3], 4.50 (1 H, s, 2-OH), 6.18 (1 H, d, J 2,
J. Chem. Soc., Perkin Trans. 1, 1997
397

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4Ј-H) and 7.50 (1 H, d, J 2, 5Ј-H); m/z (EI) 426 (M+, 5%), 383
[3 H, m, CH2CH2Si(CH3)3 and 4Љ-H], 4.36 (1 H, d, J 2, 1Ј-OH),
(8), 351 (7) and 225 (75).
5.22 (1 H, br t, J 7, 9-H), 5.92 (1 H, dd, J 15, 7, 5-H), 6.36 (1 H,
dd, J 15, 11, 4-H) and 6.68 (1 H, d, J 11, 3-H); m/z (CI) 852
(M+ + 18, 4%), 835 (M+ + 1, 5), 834 (M+, 5), 817 (5), 703 (18)
and 685 (31).
2-Trimethylsilylethyl (1R,2S,4S,5S)-2-hydroxy-2-(5-hydroxy-
2-oxo-1-oxacyclopent-3-en-3-yl)-4-methoxy-5-methylcyclo-
hexanecarboxylate 29
Following the procedure outlined for the preparation of the
hydroxybutenolide 24, the 2-trimethylsilylfuran (+)-28 (200 mg,
0.47 mmol) gave, after chromatography with gradient elution
using light petroleum–ether (2:1 to 1:3) as eluent, the title
compound 29 (165 mg, 91%), a mixture of epimers, as a highly
crystalline solid (Found: C, 56.1; H, 7.9. C18H30O7Si requires C,
55.94; H, 7.82%); νmax/cmϪ1 3620–3200, 1765, 1705, 1252, 1176,
1106, 1013 and 838; δH 0.02 [9 H, s, Si(CH3)3], 0.92 [2 H, m,
CH2Si(CH3)3], 1.07 (3 H, d, J 7, 5-CH3), 1.67 (3 H, m, 6-H,
3-Hax and 5-H), 1.88 (1 H, m, 6-H), 2.10 (1 H, m, 3-Heq), 3.17 (1
H, td, J 11.3, 4.5, 4-H), 3.25 and 3.3 (each 0.5 H, m, 1-H), 3.32
and 3.33 (each 1.5 H, s, 4-OCH3), 3.65 and 3.73 (each 0.5 H, m,
5Ј-OH), 4.10 [2 H, m, CH2CH2Si(CH3)3], 4.45 and 4.57 (each
0.5 H, d, J 2, 2-OH), 6.03 and 6.07 (each 0.5 H, d, J 6, 5Ј-H) and
7.18 and 7.2 (each 0.5 H, s, 4Ј-H); m/z (CI) 359 (100%) and 341
(82).
(1R,2S,4S,5S)-2-{(6R,2Z,4E,8E)-6,8-Dimethyl-10-[(2R,4S,6R,-
8R,9S)-4-hydroxy-9-methyl-8-isopropyl-1,7-dioxaspirol[5.5]-
undecan-2-yl]-1-methoxy-1-oxodeca-2,4,8-trien-2-yl}-2-
hydroxy-4-methoxy-5-methylcyclohexanecarboxylic acid 33
Tetrabutylammonium fluoride (1  in tetrahydrofuran; 0.55
cm3, 0.55 mmol) was added to the ester 32 (90 mg, 0.108 mmol)
in tetrahydrofuran (5 cm3) at 0 ЊC. The solution was stirred at
room temperature for 10 h, and ethyl acetate (15 cm3) and
aqueous hydrogen chloride (3 ; 5 cm3) were added. The aque-
ous layer was extracted with ethyl acetate (3 × 5 cm3) and the
organic extracts were washed with brine (10 cm3), dried
(MgSO4) and concentrated under reduced pressure. Chroma-
tography of the residue using light petroleum–ether–propan-2-
ol–acetic acid (1:1:0.02:0.01) as eluent, gave the title com-
pound 33 (67 mg, ~100%) (Found: M+ Ϫ H2O, 602.3824.
C35H56O9 requires M, 602.3818); νmax/cmϪ1 3630–2540, 1712,
1680, 1631, 1553, 1384, 1092 and 1011; δH 0.78 (3 H, d, J 6, 9Љ-
CH3), 0.82 and 0.95 (each 3 H, d, J 7, CH3CHCH3), 1.05 (6 H,
m, 5-CH3 and 6Ј-CH3), 1.15–1.39 (3 H, overlapping m, 3-Hax,
3Љ-Hax and 5Љ-Hax), 1.60 (3 H, br s, 8Ј-CH3), 1.39–1.76 (8 H,
overlapping m, 5-H, 6-H2, 9Љ-H, 10Љ-H2 and 11Љ-H2), 1.76–2.03
(4 H, m, 7Ј-H, 3Љ-Heq, 5Љ-Heq and 8Љ-CH), 2.03–2.36 (4 H, m,
3-Heq, 7Ј-HЈ and 10Ј-H2), 2.48 (1 H, m, 6Ј-H), 3.03 (1 H, d, J 10,
8Љ-H), 3.17 (2 H, m, 1-H and 4-H), 3.35 (3 H, s, 4-OCH3), 3.51
(1 H, m, 2Љ-H), 3.81 (3 H, s, CO2CH3), 4.18 (1 H, m, 4Љ-H),
4.45–4.76 (3 H, br s, 2-OH, 4Љ-OH and CO2H), 4.98 (1 H, m,
9Ј-H), 5.73 (1 H, dd, J 15, 7.5, 5Ј-H), 6.32 (1 H, dd, J 15, 11, 4Ј-
H) and 6.66 (1 H, d, J 11, 3Ј-H); m/z (CI) 620 (M+, 3.5%), 602
(M+ Ϫ 18, 99) and 585 (100).
Methyl (6R,2Z,4E,8E)-6,8-dimethyl-2-[(1S,2R,4S,5S)-1-
hydroxy-5-methoxy-4-methyl-2-(2-trimethylsilylethoxycarbonyl)-
cyclohexan-1-yl]-10-{(2R,4S,6R,8R,9S)-4-tert-butyldimethyl-
silyloxy-9-methyl-8-isopropyl-1,7-dioxaspiro[5.5]undecan-2-
yl}-deca-2,4,8-trienoate 32
tert-Butyllithium (0.27 mmol) was added to a solution of the
phosphonium salt 2 (200 mg, 0.24 mmol) in tetrahydrofuran (3
cm3) at Ϫ40 ЊC and the solution stirred at this temperature for
0.5 h. Lithium hexamethyldisilazide (0.61 mmol) in tetrahydro-
furan (2 cm3) was added, and the mixture cooled to Ϫ78 ЊC and
added to a solution of the hydroxybutenolide 29 (120 mg, 0.31
mmol) in tetrahydrofuran (2 cm3) at Ϫ78 ЊC. The mixture was
warmed to Ϫ15 ЊC over 3 h, and saturated aqueous ammonium
chloride (5 cm3) and ether (10 cm3) were added. The ethereal
extract was washed with water (5 cm3), the aqueous phase
extracted with ether (3 × 5 cm3) and the organic extracts
washed with brine (10 cm3), dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using
light petroleum–ether–acetic acid (1:1:0.01) as eluent gave the
acid 31 as a mixture of E- and Z-isomers. This was dissolved in
ether (10 cm3) and diazomethane in ether added until a yellow
colour persisted. Acetic acid was added to remove the excess of
diazomethane and the solution concentrated under reduced
pressure. Chromatography of the residue using light
petroleum–ether (6:1) as eluent, gave the esters as a mixture of
E- and Z-isomers. This was dissolved in benzene (3 cm3) and
iodine (6 mg, 0.024 mmol) in benzene (1 cm3) was added, and
the mixture exposed to sunlight for 8 h. Ether (5 cm3) was
added, and the solution washed with saturated aqueous sodium
thiosulfate (5 cm3) and extracted with ether (3 × 5 cm3). The
organic extracts were washed with brine (5 cm3), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue using light petroleum–ether (8:1) as eluent gave the
title compound 32 (108 mg, 54%) as a viscous oil (Found: M+,
834.5445. C46H82O9Si2 requires M, 834.5497: Found: M+ Ϫ
H2O, 816.5406. C46H80O8Si2 requires M, 816.5391); [α]D +42.8
(c 0.6 in CHCl3);νmax/cmϪ1 3408, 1712, 1630, 1462, 1385, 1252,
1173, 1091 and 1012; δH 0.02 [9 H, s, Si(CH3)3], 0.05 [6 H, s,
Si(CH3)2], 0.78 (3 H, d, J 6, 9Љ-CH3), 0.82 (3 H, d, J 7,
CH3CHCH3), 0.89 [9 H, s, SiC(CH3)3], 0.92 [8 H, m,
CH2Si(CH3)3, CH3CHCH3, 6-CH3], 1.05 (3 H, d, J 6, 4Ј-CH3),
1.25 (3 H, m, 3Љ-H, 5Љ-H and 6Ј-H), 1.59 (3 H, s, 8-CH3), 1.38–
1.73 (7 H, overlapping m, 9Љ-H, 10Љ-H2, 11Љ-H2, 3Ј-H and 4Ј-H),
1.74–1.91 (5 H, overlapping m, 7-H, 3Ј-HЈ, 3Љ-HЈ, 5Љ-HЈ and 8Љ-
CH), 2.15 (4 H, m, 7-HЈ, 6Ј-Heq and 10-H2), 2.41 (1 H, m, 6-H),
3.05 (2 H, m, 8Љ-H and 2Ј-H), 3.17 (1 H, td, J 10, 5, 5Ј-H), 3.35
(3 H, s, 5Ј-OMe), 3.52 (1 H, m, 2Љ-H), 3.78 (3 H, s, CO2CH3), 4.1
(4S)-8-Methoxycarbonyl-3,4-dihydro-8-norhydroxymethyl-
milbemycin E 34
The hydroxy acid 33 (36 mg, 0.058 mmol) and 4-dimethyl-
aminopyridine (0.72 mg, 5.8 µmol) in dichloromethane (5 cm3)
were added, over a period of 5 h using a syringe pump, to
dicyclohexylcarbodiimide (18 mg, 0.088 mmol) in dichloro-
methane (10 cm3) at 0 ЊC. On completion of the addition, the
reaction was stirred at 5 ЊC for 16 h, and the solvent removed
under reduced pressure. The residue was dissolved in ether (2
cm3), filtered and concentrated under reduced pressure. Chro-
matography of the residue using light petroleum–ether (4:1) as
eluent gave the title compound 34 (12 mg, 34%) (Found: M+,
602.3817. C35H54O8 requires M, 602.3818); [α]D +183.6 (c 0.61
in CHCl3); νmax/cmϪ1 3452, 1707, 1458, 1376, 1333, 1275, 1181,
1117, 1094 and 1010; δH 0.72 (1 H, q, J 12, 18-Hax), 0.79 (3 H, d,
J 6.5, 24-CH3), 0.83 and 1.01 (each 3 H, d, J 7, CH3CHCH3),
1.05 and 1.04 (each 3 H, d, J 6.55, 4-CH3 and 12-CH3), 1.43–
1.53 (6 H, overlapping m), 1.57 (3 H, s, 14-CH3), 1.58–1.91 (8
H, overlapping m), 2.12–2.30 (4 H, m, 6-H, 13-H, 16-H2), 2.47
(1 H, m, 12-H), 3.06 (1 H, dd, J 10, 2, 25-H), 3.21 (2 H, m, 2-H
and 5-H), 3.34 (3 H, s, 5-OCH3), 3.60 (1 H, m, 17-H), 3.78 (3 H,
s, CO2CH3), 4.70 (1 H, d, J 2.5, 7-OH), 4.82 (1 H, d, J 9, 15-H),
5.27 (1 H, m, 19-H), 5.60 (1 H, dd, J 15, 10, 11-H), 6.27 (1 H,
dd, J 15, 11, 10-H) and 6.56 (1 H, d, J 11, 9-H); m/z (CI) 620
(M+ + 18, 4%), 602 (M+, 24), 601 (47), 585 (98) and 408 (100).
(4S)-3,4-Dihydromilbemycin E 35
Red-Al [Sodium bis(2-methoxyethoxy)aluminium hydride;
0.085 ; 0.5 cm3, 0.042 mmol] was added to the ester 34 (4.6 mg,
7.6 µmol) in toluene (0.2 cm3) at 0 ЊC. The mixture was stirred for
2 h at 0 ЊC, and saturated aqueous ammonium chloride (0.5
cm3) and ether (5 cm3) were added. The aqueous phase was
extracted with ether (3 × 2 cm3) and the organic extracts
washed with brine (3 cm3), dried (MgSO4) and concentrated
398
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
under reduced pressure. Chromatography of the residue using
light petroleum–ether (1:1) as eluent, gave the title compound
35 (3 mg, 68%) (Found: M+, 574.3868. C34H54O7 requires M,
574.3869); [α]D +189.7 (c 0.66 in CHCl3); νmax/cmϪ1 3453, 1706,
1457, 1375, 1276, 1176, 1095 and 1009; δH 0.70 (1 H, q, J 11.7,
18-Hax), 0.80 (3 H, d, J 6.5, 24-CH3), 0.83 and 1.01 (each 3 H,
d, J 7, CH3CHCH3), 1.04 (3 H, d, J 6.5, 12-CH3), 1.06 (3 H, d, J
6.5, 4-CH3), 1.27 (1 H, br s, CH2OH), 1.38–1.67 (8 H, m, 4-H,
6-H, 20-H, 24-H, 22-H2 and 23-H2), 1.60 (3 H, s, 14-CH3), 1.81
(6 H, m, 3-H2, 13-H, 18-H, 20-H and 25-CH), 2.21 (4 H, m,
6-H, 13-H and 16-H2), 2.47 (1 H, m, 12-H), 2.70 (1 H, m, 2-H),
3.06 (1 H, dd, J 10, 2, 25-H), 3.24 (1 H, td, J 10, 4, 5-H), 3.36 (3
H, s, 5-OCH3), 3.61 (1 H, m, 17-H), 4.12 (1 H, d, J 2.5, 7-OH),
4.2 (2 H, m, CH2OH), 4.83 (1 H, m, 15-H), 5.33 (1 H, m, 19-H),
5.49 (1 H, dd, J 15, 10, 11-H), 6.21 (1 H, dd, J 15, 11, 10-H) and
6.31 (1 H, d, J 11, 9-H); m/z (CI) 575 (M+ + 1, 6%), 574 (M+, 2),
558 (46), 557 (100) and 539 (28).
H, overlapping m, 5-Heq, 7Ј-HЈ and 10Ј-H2), 2.47 (1 H, m,
6Ј-H), 3.04 (1 H, m, 8Љ-H), 3.37 (3 H, s, 4-OCH3), 3.53 (1 H, m,
2Љ-H), 3.80 (3 H, s, CO2CH3), 3.91 (1 H, m, 1-H), 4.08 (1 H, m,
4-H), 4.20 (1 H, m, 4Љ-H), 4.50–4.75 (3 H, br s, 6-OH, 4Љ-OH
and CO2H), 5.0 (1 H, m, 9Ј-H), 5.36 (1 H, m, 2-H), 5.78 (1 H,
dd, J 15, 8.6, 5Ј-H), 6.40 (1 H, dd, J 15, 12, 4Ј-H) and 6.76 (1 H,
d, J 12, 3Ј-H); m/z (FAB) 600 (M+ Ϫ 18, 10%).
8-Methoxycarbonyl-8-norhydroxymethylmilbemycin E 40
Following the procedure outlined above for the synthesis of the
lactone 34, the hydroxy acid 39 (15 mg, 0.024 mmol) gave the
title compound 40 (5.3 mg, 37%) (Found: M+, 600.3666.
C35H52O8 requires M, 600.3662); [α]D +152.4 (c 0.37 in CHCl3);
νmax/cmϪ1 3445, 1707, 1625, 1339, 1192, 1120, 1098, 1067 and
1010; δH 0.78 (1 H, q, J 12, 18-Hax), 0.79 (3 H, d, J 6, 24-CH3),
0.85 and 1.01 (each 3 H, d, J 7, CH3CHCH3), 1.04 (3 H, d, J 6.8,
12-CH3), 1.46 (1 H, t, J 12, 20-Hax), 1.40–1.75 (9 H, overlap-
ping m, 6-Hax, 14-CH3, 22-H2, 23-H2 and 24-H), 1.80 (3 H, s,
4-CH3), 1.87 (3 H, m, 25-CH, 18-Heq and 20-Heq), 2.04 (1 H,
m, 13-H), 2.21 (4 H, m, 6-Heq, 13-H and 16-H2), 2.5 (1 H, m,
12-H), 3.05 (1 H, m, 25-H), 3.35 (3 H, s, 5-OCH3), 3.60 (1 H, m,
17-H), 3.80 (3 H, s, CO2CH3), 3.92 (1 H, m, 2-H), 4.06 (1 H, m,
5-H), 4.52 (1 H, d, J 2, 7-OH), 4.84 (1 H, d J 7.5, 15-H), 5.28 (1
H, s, 3-H), 5.32 (1 H, m, 19-H), 5.63 (1 H, dd, J 13.5, 8.3, 11-H),
6.39 (1 H, dd, J 13.5, 11.3, 10-H) and 6.71 (1 H, d, J 11.3, 9-H);
m/z (EI) 600 (M+, 1%).
Methyl (6R,2Z,4E,8E)-6,8-dimethyl-2-[(1S,2R,5S)-1-hydroxy-
5-methoxy-4-methyl-2-trimethylsilylethoxycarbonylcyclohex-
3-en-1-yl]-10-{(2R,4S,6R,8R,9S)-4-tert-butyldimethylsilyloxy-
9-methyl-8-isopropyl-1,7-dioxaspirol[5.5]undecan-2-yl}deca-
2,4,8-trienoate 37
Lithium hexamethyldisilazide (0.72 mmol) in tetrahydrofuran
(2 cm3) was added via a cannula to the phosphonium salt 2 (138
mg, 0.166 mmol) and the hydroxybutenolide 3 (90 mg, 0.28
mmol) in tetrahydrofuran (3 cm3) at Ϫ78 ЊC. The resulting
orange solution was warmed to Ϫ15 ЊC over 1 h and stirred at
this temperature a further 1 h. (The disappearance of the orange
colour was noted at Ϫ20 ЊC.) Saturated aqueous ammonium
chloride (3 cm3) and ether (5 cm3) were added. The organic
layer was washed with water (5 cm3) and the aqueous phase
extracted with ether (3 × 10 cm3). The organic extracts were
washed with brine (10 cm3), dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue, using
light petroleum–ether–acetic acid (1:1:0.01) as eluent, gave a
residue which was treated separately with diazomethane and
iodine, as outlined above for the synthesis of the ester 32, to
give the title compound 37 (58 mg, 42%) as a viscous oil (Found:
M+ Ϫ H2O, 814.5220. C48H78O8Si2 requires M, 814.5235);
[α]D Ϫ8.75 (c 0.64 in CHCl3); νmax/cmϪ1 3590, 1714, 1460, 1384,
1252, 1216, 1189, 1170, 1089, 1067, 1009, 983 and 837; δH 0.02
[9 H, s, Si(CH3)3], 0.07 [6 H, s, Si(CH3)2], 0.76 (3 H, d, J 6, 9Љ-
CH3), 0.81 (3 H, d, J 7, CH3CHCH3), 0.86–1.01 [17 H, over-
lapping m, CH2Si(CH3)3, CH3CHCH3, SiC(CH3)3, 6-CH3], 1.21
(2 H, m, 3Љ-Hax and 5Љ-Hax), 1.60 (3 H, s, 8-CH3), 1.40–1.69 (5
H, overlapping m, 9Љ-H, 10Љ-H2 and 11Љ-H2), 1.80 (3 H, s,
4Ј-CH3), 1.89 (5 H, m, 8Љ-CH, 7-H, 6Ј-Hax, 3Љ-Heq and 5Љ-Heq),
2.09–2.33 (4 H, m, 7-HЈ, 10-H2 and 6Ј-Heq), 2.44 (1 H, m, 6-H),
3.01 (1 H, m, 8Љ-H), 3.36 (3 H, s, 5Ј-OCH3), 3.51 (1 H, m, 2Љ-H),
3.80 (3 H, s, CO2CH3), 3.83 (1 H, m, 2Ј-H), 4.12 [4 H, m,
CH2CH2Si(CH3)3, 5Ј-H and 4Љ-H], 4.71 (1 H, br s, 1Ј-OH), 5.22
(1 H, br t, J 7, 9-H), 5.31 (1 H, m, 3Ј-H), 5.98 (1 H, dd, J 15, 7.5,
5-H), 6.43 (1 H, dd, J 15, 12, 4-H) and 6.79 (1 H, d, J 12, 3-H);
m/z (CI) 850 (M+ + 18, 4.5%), 832 (M+, 1.5), 815 (7) and 683
(80).
Milbemycin E 1
The ester 40 (3 mg, 5 µmol) was dissolved in toluene (0.3 cm3)
and cooled to Ϫ78 ЊC. Diisobutylaluminium hydride (1  in
toluene; 50 µl) was added and the reaction stirred at Ϫ78 ЊC
for 1 h. Water (0.1 cm3) and ethyl acetate (3 cm3) were added
and the mixture allowed to warm to room temperature. Aque-
ous hydrogen chloride (3 ; 0.5 cm3) was added and the aque-
ous phase was extracted with ethyl acetate (3 × 2 cm3). The
organic extracts were washed with brine (5 cm3), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue using light petroleum–ethyl acetate (2:1) as eluent
gave milbemycin E 1 (2.5 mg, 87%) as an amorphous glass,
[α]D +153 (c 0.15 in acetone) {lit.,14 [α]D +157 (c 0.25 in acet-
one)}; νmax/cmϪ1 3470, 1709, 1460, 1377, 1165, 1099 and 1010;
δH (500 MHz) 0.77 (1 H, q, J 12, 18-Hax), 0.80 (3 H, d, J 7,
24-CH3), 0.83 and 1.02 (each 3 H, d, J 7.5, CH3CHCH3), 1.04
(3 H, d, J 7, 12-CH3), 1.38 (1 H, t, J 12, 20-Hax), 1.42–1.69 (5
H, overlapping m, 22-H2, 23-H2 and 24-H), 1.59 (3 H, br s,
14-CH3), 1.73–1.95 (5 H, m, 6-H, 13-H, 18-Heq, 20-Heq and
25-CH), 1.82 (3 H, br s, 4-CH3), 2.22 (4 H, m, 6-H, 13-H,
16-H2), 2.48 (1 H, m, 12-H), 3.04 (1 H, dd, J 10, 2, 25-H), 3.38
(3 H, s, 5-OCH3), 3.50 (1 H, m, 2-H), 3.60 (1 H, m, 17-H), 3.75
(1 H, d, J 2, 7-OH), 4.03 (1 H, m, 5-H), 4.18 and 4.27 (each 1 H,
d, J 13.5, CHHOH), 4.85 (1 H, m, 15-H), 5.33 (1 H, narrow m,
3-H), 5.36 (1 H, m, 19-H), 5.51 (1 H, dd, J 14, 10, 11-H), 6.25 (1
H, dd, J 14, 11, 10-H) and 6.42 (1 H, d, J 11, 9-H); m/z (EI) 572
(M+, 23%).
Acknowledgements
We thank the EPSRC for studentships (to P. G. S. and E. R. P.)
and Dr J. Ide of the Sankyo Company Ltd for a sample of
authentic milbemycin E for comparison purposes.
(1R,4S,6S)-6-{(6R,2Z,4E,8E)-6,8-Dimethyl-10-[(2R,4S,6R,
8R,9S)-4-hydroxy-9-methyl-8-isopropyl-1,7-dioxaspirol[5.5]-
undecan-2-yl]-1-methoxy-1-oxodeca-2,4,8-trien-2-yl}-6-
hydroxy-4-methoxy-3-methylcyclohex-2-enecarboxylic acid 39
Following the procedure outlined above for the synthesis of the
carboxylic acid 33, the ester 37 (20 mg, 0.024 mmol) gave the
title compound 39 (15 mg, 100%); νmax/cmϪ1 3600–2400, 1714,
1636, 1385, 1261, 1191, 1090, 1011 and 983; δH 0.78 (3 H, d, J 6,
9Љ-CH3), 0.82 and 0.95 (each 3 H, d, J 7, CH3CHCH3), 1.03 (3
H, d, J 7.5, 6Ј-CH3), 1.27 (2 H, m, 3Љ-Hax and 5Љ-Hax), 1.60 (3
H, br s, 8Ј-CH3), 1.40–1.75 (5 H, overlapping m, 9Љ-H, 10Љ-H2
and 11Љ-H2), 1.81 (3 H, br s, 3-CH3), 1.81–2.02 (5 H, over-
lapping m, 5-Hax, 7Ј-H, 8Љ-CH, 3Љ-Heq and 5Љ-Heq), 2.02–2.34 (4
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Paper 6/05894I
Received 27th August 1996
Accepted 24th October 1996
400
J. Chem. Soc., Perkin Trans. 1, 1997