Total synthesis of milbemycins: A synthesis of (6R)-6-hydroxy-3,4- dihydromilbemycin E

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A R T I C L E

Total synthesis of milbemycins: a synthesis of

(6R)-6-hydroxy-3,4-dihydromilbemycin E

Madeleine Helliwell, Suﬁa Karim, Emma R. Parmee 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 20th June 2005, Accepted 8th August 2005

First published as an Advance Article on the web 14th September 2005

Following studies using benzyloxymethyl isopropenyl ketone 5 and ethyl 3-(3-furyl)-3-oxopropanoate 6, Robinson

reactions between aryloxymethyl isopropenyl ketones 19 and 5 and ethyl 3-(2-trimethylsilyl-3-furyl)-3-oxopropanoate

20 were found to be stereoselective giving cyclohexanones 21 and 41, in which the 3-(arylmethoxy) substituents were

cis to the 2-hydroxyl groups, as the major products. After reduction and protection of ketone 21, selective

PMB-deprotection, oxidation and stereoselective reduction inverted the conﬁguration at C(3) to give the diol 30.

Protection of the secondary 3-hydroxyl group followed by modiﬁcation of the protected 4-alcohol then gave the

hydroxybutenolides 36 and 37 after oxidation of the silylated furan using singlet oxygen. The

3-benzyloxycyclohexanone 41 was also converted into the hydroxybutenolide 37 via the

(2-trimethylsilylethoxy)methyl (SEM) ether 35.

The Wittig reaction between the ylid generated from 2-methylpropyl(triphenyl)phosphonium salt and

hydroxybutenolide 36 gave predominantly the (2Z,4Z)-dienyl acid 38 which was taken through to the butenolide 40.

Similarly, the racemic hydroxybutenolide 37 was condensed with the racemic ylid derived from phosphonium salt 53

to give, after SEM-deprotection and 5-membered lactone formation, a mixture of the (9Z,2^ꢀZ)-dienyl lactones 58 and

59 containing ca. 10% of the corresponding (9Z,2^ꢀE)-isomers 60 and 61. (2^ꢀZ)/(2^ꢀE)-Isomerisation of the dienes 58

and 59 using iodine followed by deprotection gave a mixture of the seco-acids 62 and 63. Selective macrocyclisation

of the seco-acid 62 in which the relative conﬁguration of the C(1)–C(7) and C(17)–C(19) fragments (milbemycin

numbering) corresponded to that present in the natural milbemycins, gave the b-milbemycin analogue 65 after

butenolide reduction. The hydroxybutenolide 37 was also condensed with the ylid derived from the phosphonium salt

1 and the product taken through to (6R)-6-hydroxy-3,4-dihydromilbemycin E 77.

Preliminary attempts to convert the b-milbemycin analogues 65 and 77 into tetrahydrofurans corresponding to

analogues of a-milbemycins by treatment with toluene p-sulfonyl chloride under basic conditions gave the primary

allylic chlorides 78 and 79.

the a-milbemycins, by oxidation of precursors of the hydrox-

Introduction

ybutenolide 2 were not encouraging. The Robinson annelation

The milbemycins and avermectins are important natural prod-

using alkoxymethyl isopropenyl ketones and ethyl 3-(3-furyl)-3-

ucts with potent and useful biological activities.¹Their chemistry

oxopropanoates was therefore investigated.

has been widely studied and several total syntheses have been

The Robinson reaction between benzyloxymethyl isopropenyl

reported.^2–4One problem that was encountered in the early

syntheses of avermectins was the regioselective introduction

of the 3,4-double-bond since deconjugation of 2,3-unsaturated

ketone 5 and the b-keto-ester 6^5ain aqueous ethanol was usefully

stereoselective and gave the hydroxyketone 7, in which the

benzyloxymethyl group at C(3) was cis to the hydroxyl group at

C(2), as the major product (70%), together with minor amounts

of the epimers at C(1) and C(5), 8 (13%) and 9 (8%), which

isomers was complicated by the formation of mixtures of epimers

at C(2).^3,4To avoid this problem, a synthesis of the non-aromatic

b-milbemycins was developed in which the 3,4-double-bond was

introduced regioselectively into the C(1)–C(10) fragment early

in the synthesis and this approach was applied to complete a

were isolated by chromatography, see Scheme 1. Structures

1

were assigned to these compounds on the basis of H NMR

studies. For example, for the major product 7, strong NOEs were

observed between the three, cis-disposed, axial hydrogens, 1-H,

convergent total synthesis of milbemycin E 3 using the ylid

derived from phosphonium salt 1 and the hydroxybutenolide 2.⁵

3-H and 5-H. For the minor product 8, signiﬁcant deshielding

It would be of interest to apply this strategy to complete a

of the axial hydrogens 3-H and 5-H was observed consistent

synthesis of the more common a-milbemycins, e.g. milbemycin

with the axial disposition of the ethoxycarbonyl group at C(1),

and strong NOEs were still observed between 3-H and 5-H. For

the third product 9, no NOE was observed between 3-H and

5-H, instead irradiation of the 5-methyl group caused a large

G 4,⁶which are characterised by the presence of an extra oxygen

functionality at C(6) incorporated into a tetrahydrofuran ring.

We now provide full details of a synthesis of (6R)-6-hydroxy-

3,4-dihydromilbemycin E 77 as a prelude to a total synthesis of

enhancement of the 3-H which in turn exhibited an NOE

milbemycin G.⁷

1

with 1-H. H NMR coupling constants also supported these

stereochemical assignments (see experimental).

The stereoselective formation of the adduct 7 as the major

Results and discussion

product was probably due to thermodynamic control and by

its crystallization out of the reaction mixture. Indeed adducts

8 and 9 tended to isomerize to 7 on storage. In other solvents,

e.g. in a mixture of ethanol and dichloromethane, the yields and

stereoselectivities were lower and, in some cases, mixtures of

diasteroisomeric open-chain Michael adducts were also isolated

as minor products (ca. 7% in dichloromethane–ethanol).

The hydroxybutenolide 2 had been prepared using a Robinson

reaction of methyl isopropenyl ketone to assemble the six-

membered ring, with the cyclohexenyl double-bond introduced

via a selenoxide elimination and the hydroxybutenolide by

singlet oxygen oxidation of a 2-trimethylsilylfuran.^5cHowever,

preliminary studies on the introduction of the additional oxygen

functionality at C(3), the precursor of the ether at C(6) in

3 6 3 6

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

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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Scheme 1 Reagents and conditions: i, NaOH, EtOH, r.t., 24 h (7, 70%; 8, 13%; 9, 8%); ii, NaBH₄, AcOH, 30 min, r.t., then ketone added (10, 95%;

11, 77%; 12, 87%); iii, NaBH₄, EtOH, 3 h, r.t. (85%); iv, carbonyl diimidazole, benzene, NaH (trace), r.t., 6 h (67%).

Following earlier studies during the milbemycin E synthesis,^5c

reduction of the ketones 7, 8 and 9 using sodium triacetoxyboro-

hydride, was highly stereoselective and gave the trans-diols 10, 11

and 12 by intramolecular delivery of hydride via intermediates

in which the acetoxyborohydride was attached to the 2-hydroxyl

group. In contrast, reduction of the hydroxyketone 7 by sodium

borohydride proceeded via equatorial approach of the hydride

to give the 1,3-cis-diol 13.

methoxybenzyl ether 16, epoxidation, base induced rearrange-

ment of the epoxide 17 so formed into the allylic alcohol

18 and a Swern oxidation,⁸see Scheme 2. The Robinson

annelation between ketone 19 and ethyl 3-(2-trimethylsilyl-3-

furyl)-3-oxopropanoate 20^5awas carried out using aqueous

sodium hydroxide in ethanol and gave hydroxycyclohexanone

21 as the major product together with a small amount of its 1-

epimer 22. The conﬁguration shown was assigned to the major,

crystalline, adduct 21 by analogy with the earlier work, and on

the basis of NOEs between the cis-conﬁgured axial hydrogens,

1-H, 3-H and 5-H. Its structure was subsequently conﬁrmed

by an X-ray analysis of a later intermediate, vide infra. The

conﬁguration of the minor adduct 22 was assigned on the

basis of NMR data including the characteristic downﬁeld shifts

observed for the axial hydrogens 3-H and 5-H induced by the

axial ethoxycarbonyl group.

The Robinson reaction of the alkoxymethyl ketone 19 had

been usefully stereoselective, but again the major product had

the opposite conﬁguration at C(3) from that required for

incorporation into a milbemycin synthesis. The conﬁguration

at this centre therefore had to be inverted.

Whereas the hydroxyketones 7, 8 and 9 had been reduced

stereoselectively by sodium triacetoxyborohydride prepared in

situ from sodium borohydride and acetic acid, reduction of

the hydroxyketone 21 under these conditions was very slow

Structures were assigned to diols 10–13 by analogy with earlier

1

work^5aand were consistent with H NMR studies including

NOE data and vicinal coupling constants (see experimental).

The conﬁguration shown for the sodium borohydride reduction

product was conﬁrmed by formation of the cyclic carbonate 14

on reaction with carbonyl diimidazole.

These preliminary studies had shown that the incorporation

of a benzyloxy substituent into the methyl group of isopropenyl

methyl ketone was compatible with a stereoselective Robinson

annelation, albeit giving rise to the unwanted conﬁguration

at C(3), at least as far as incorporation into an a-milbemycin

synthesis was concerned. The next step was to check the

compatibility of silylated furans, the preferred^5aprecursors of

the hydroxybutenolides to be used in the crucial Wittig assembly

step, with these reactions.

Isopropenyl p-methoxybenzyloxymethyl ketone 19 was pre-

pared by conversion of 3-methylbut-2-en-1-ol 15 into its p-

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

3 6 3 7

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Scheme 2 Reagents and conditions: i, PMBCl, NaH, THF, TBAI, 16 h, r.t. (89%); ii, mCPBA, CH₂Cl₂, 0 ^◦C, 2 h (85%); iii, Al(OⁱPr)₃, xylene, reﬂux,

3 h (87%); iv, (COCl)₂, CH₂Cl₂, DMSO, −78 ^◦C then Et₃N, r.t. (80%); v, NaOH, EtOH, 16 h, r.t. (21, 64%; 22, 10%); vi, Me₄NBH(OAc)₃, AcOH,

MeCN (1 : 1), 96 h, r.t. (89%); vii, Ac₂O, Et₃N, DMAP, CH₂Cl₂, 16 h, r.t. (93%); viii, DDQ, CH₂Cl₂, 3 h, r.t. (80%); ix, DDQ, H₂O, CH₂Cl₂, 3 h, r.t.

(96%); x, Me₄NBH(OAc)₃, AcOH, MeCN (1 : 1), 1 h, r.t. (27, 51%; 28, 16%).

and was often accompanied by unchanged starting material.

Prolonged reaction with tetramethylammonium triacetoxyboro-

hydride, 48 h, was required but did lead to a highly stereoselective

reduction giving the alcohol 23 via intramolecular delivery of

hydride from the acetoxyborohydride co-ordinated to the 2-

hydroxyl group.⁹After acetylation of the 4-hydroxyl group, the

p-methoxybenzyl group was removed oxidatively to give the

alcohol 25.

As the reduction of the hydroxyketone 21 had been slow,

perhaps due to the additional steric hindrance of the trimethylsi-

lyl group, reduction of the dihydroxyketone 26 prepared by

oxidative removal of the p-methoxybenzyl group from the

hydroxyketone 21 was brieﬂy investigated. However, although

reduction using tetramethylammonium triacetoxyborohydride

was now complete in less than 1 h, two products were isolated

in a 75 : 25 ratio and the major product was identiﬁed as the

all-cis-triol 27 from ¹H NMR data (27, J_3,4= J_4,5= 2.7 Hz; 28,

J_3,4= J_4,5= 9 Hz). It would appear that delivery of hydride from

the acetoxyborohydride when attached to the more accessible

hydroxyl group at C(3) provides the preferred reaction pathway,

and that this delivery can take place from the equatorial direction

despite this being on the opposite face of the ring from the 3-

hydroxyl group.

Swern oxidation of the alcohol 25 gave the ketone 29 which

was reduced stereoselectively, again using tetramethylammo-

nium triacetoxyborohydride, to give the alcohol 30 which

now had the required conﬁguration at C(3) for the proposed

milbemycin synthesis, see Scheme 3. Following protection of

the 3-hydroxyl group as its 2-trimethylsilylethoxymethyl (SEM)

ether, simultaneous hydrolysis of the ethyl ester and the acetyl

group gave the hydroxy acid 32. The acid was converted into its 2-

trimethylsilylethyl ester 33 and the 4-hydroxyl group protected as

its tert-butyldimethylsilyl ether to give 34. The analogous methyl

ether 35 was also prepared, the latter conversion being best

effected using lithium hexamethyldisilazide, cetyltrimethylam-

monium bromide (CTAB) and methyl iodide. Oxidation of the

Scheme 3 Reagents and conditions: i, DMSO, (COCl)₂, CH₂Cl₂, −78 ^◦C then Et₃N, r.t. (100%); ii, Me₄NBH(OAc)₃, AcOH, MeCN, 16 h, r.t. (85%);

iii, ⁱPr₂NEt, SEMCl, CH₂Cl₂, 16 h, r.t. (90%); iv, NaOH, EtOH, THF, 72 h, r.t.; v, DCC, CH₂Cl₂, Me₃SiCH₂CH₂OH, 16 h, r.t. (87% from 31); vi,

2,6-lutidine, TBSOTf, CH₂Cl₂, 3 h, r.t. (99%); vii, CTAB, MeI, THF, LHMDS in hexane, 0 ^◦C, 15 min (93%); viii, tetraphenylporphine (TPP) (trace),

CH₂Cl₂, MeOH, O₂, hm, 4 h, −78 ^◦C, (36, 95%; 37, 97%); ix, ⁱPrCH₂PPh₃I, LHMDS, −78 ^◦C to −10 ^◦C, 90 min. (89%); x, I₂, benzene, 3 h, hm (70%);

xi, DCC, DMAP (cat.), CH₂Cl₂, 3 h, r.t. (90%).

3 6 3 8

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

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trimethylsilylfurans 34 and 35 then gave the hydroxybutenolides

36 and 37 ready for incorporation into milbemycin syntheses,

albeit racemic at this stage.

substituents. For example, the 5-methyl substituent gave rise to

a doublet at d1.08 in the ¹H NMR spectrum of the more polar

isomer 43 and at d0.57 for the less polar isomer 44.¹¹

To check procedures for the Wittig reactions, the ylid prepared

from 2-methylpropyl(triphenyl)phosphonium bromide was con-

densed with the hydroxybutenolide 36 to give the (2Z,4Z)-dienyl

acid 38. Very little of the analogous (2Z,4E)-isomer could be

detected in the crude product mixture from the Wittig reaction,

but treatment of the (2Z,4Z)-isomer 38 with a mole equivalent

of iodine in benzene in the presence of a sun-lamp led to clean

(4Z)/(4E)-isomerisation and simultaneous loss of the SEM

group to give the (2Z,4E)-dihydroxy acid 39. Lactonisation

was then carried out using dicyclohexylcarbodiimide and 4-

dimethylaminopyridine to give the butenolide 40.

Before investigating the application of these procedures for

the synthesis of macrocyclic analogues of milbemycins, a slightly

modiﬁed synthesis of the hydroxybutenolide 37, which provided

for a resolution of the racemic material, was investigated, see

Scheme 4. In this case, the Robinson reaction between the

benzyloxymethyl isopropenyl ketone 5 and the b-keto ester

20 gave the hydroxycyclohexanone 41 which was reduced to

the diol 42 using tetramethylammonium triacetoxyborohydride.

Resolution of this diol was carried out by esteriﬁcation with

(R)-acetylmandelic acid^5d,10to give a mixture of the crystalline

diastereoisomeric esters 43 and 44. These could be separated by

chromatography but, more conveniently, the less polar isomer

44 could be isolated free of the more polar isomer 43 by selective

crystallization from the mixture. Following this procedure, but

using the (S)-acetyl mandelate, the enantiomer of 44, which had

incorporated the required enantiomer of diol 42, was isolated in

a 35% yield based on the racemic diol 42.

Although this resolution provided access to enantiomerically

enriched intermediates, further preliminary work was carried

out using racemic compounds. Thus hydrogenolysis of a mixture

of the esters 43 and 44 gave the racemic phenylacetate 46 in which

both the acetoxy substituent in the mandelate and the benzyl

ether at C(3) had been cleaved. This racemic phenylacetate was

also prepared by esteriﬁcation of diol 42 using phenylacetic acid

followed by hydrogenolysis of the benzyl ether 45.

The relative conﬁguration of the alcohol at C(3) in the racemic

ester 46 was inverted by oxidation to the ketone 47 followed

by triacetoxyborohydride reduction, and the product alcohol

48 protected as its SEM-ether 49. Selective hydrolysis of the

phenylacetate followed by O-methylation, in this case using silver

oxide and methyl iodide, gave the methyl ether 51, which was

converted into the 2-trimethylsilyl ester 35, an intermediate in

the previous synthesis, by hydrolysis and esteriﬁcation using 2-

trimethylsilylethanol.

The Wittig reaction between the racemic hydroxybutenolide

37 and the racemic phosphonium salt 53^5awas carried out by

adding an excess of lithium hexamethyldisilazide to a mixture of

the hydroxybutenolide and phosphonium salt in tetrahydrofuran

at −78 ^◦C and gave a mixture of the (2Z,4Z)-dienes 54

and 56 together with ca. 10% of the corresponding (2Z,4E)-

isomers. Apart from the presence of these minor (2Z,4E)-

alkenes, the product appeared to be homogeneous, but as no

kinetic resolution was to be expected in the Wittig process it was

assumed that a 50 : 50 mixture of the racemic diastereoisomers

54 and 56 had been formed. No attempt was made to separate

this mixture, since it was known from earlier work^5athat only

the seco-acid with the relative conﬁguration corresponding to

that in the natural products would cyclise, vide infra, Scheme 5.

Structures were assigned to esters 43 and 44 on the basis of

the inﬂuence of the (R)-acetylmandelate group on the relative ¹H

NMR chemical shifts of the six-membered ring hydrogens and

Scheme 4 Reagents and conditions: i, 20, NaOH, EtOH, 20 h, r.t. (50%); ii, Me₄NBH(OAc)₃, AcOH–MeCN (1 : 1), 96 h, r.t. (84%); iii,

(R)-acetylmandelic acid, DMAP, DCC, CH₂Cl₂, 16 h, r.t. (43 + 44, 64%); iv, phenylacetic acid, DMAP, DCC, CH₂Cl₂(85%); v, H₂, Pd/C,

EtOH (73% from 43/44; 91% from 45); vi, DMSO, (COCl)₂, CH₂Cl₂, −78 ^◦C then Et₃N (99%); vii, Me₄NBH(OAc)₃, AcOH–MeCN (99%); viii,

ⁱPr₂NEt, SEMCl, CH₂Cl₂(91%); ix, K₂CO₃, EtOH, 48 h, r.t. (70%); x, Ag₂O, MeI (62%); xi, NaOH, EtOH; xii, Me₃SiCH₂CH₂OH, DMAP, DCC,

CH₂Cl₂(80%).

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

3 6 3 9

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Scheme 5 Reagents and conditions: i, ( )-37, LHMDS, −78 ^◦C to −10 ^◦C, 90 min (90%); ii, BuSH, MgBr₂, K₂CO₃, Et₂O, 10 min (88%); iii, DCC,

DMAP, CH₂Cl₂, 3 h, r.t. (80%); iv, I₂, benzene, K₂CO₃, hm, 3 h, r.t. (75%); v, TBAF, THF, 16 h, r.t. (97%); vi, Cl₃C₆H₂CO·Cl, Et₃N, xylene, 2 d then

DMAP, xylene, 1 h (26% : 52% based on 62); vii, DIBAL-H, toluene, −78 ^◦C, 30 min (70%).

In this series, attempted simultaneous (4Z)/(4E)-

isomerisation and removal of the SEM group from the

acids 54 and 56 using iodine gave rise to mixtures of products

with only partial SEM-deprotection. It was found to be

more efﬁcient to remove the SEM group ﬁrst by treatment

with magnesium(II) bromide and n-butanethiol¹²in the

presence of potassium carbonate to prevent adventitious

addition of hydrogen bromide to the 8,9-double-bond.

Subsequent lactonization using dicyclohexylcarbodiimide and

4-dimethylaminopyridine gave the butenolides 58 and 59,

still as a ca. 90 : 10 mixture of the (2^ꢀZ)- and (2^ꢀE)-isomers.

(2^ꢀZ)/(2^ꢀE)-Isomerisation was then achieved using a catalytic

amount of iodine in benzene to give the (9Z,2^ꢀE)-dienes 60

and 61. Conversion into the, now distinguishable, seco-acids

62 and 63 was carried out using tetrabutylammonium ﬂuoride

in tetrahydrofuran, and macrocyclisation was achieved using

the modiﬁed Yamaguchi procedure.¹³As expected, only the

Fig. 1 Projection of the conformation of the macrolide 64 as deter-

mined by X-ray crystallography.

seco-acid with the conﬁguration corresponding to the natural

products cyclised, and the required macrolide 64 was isolated

as a single isomer in a 52% yield (based on seco-acid 62). As

this bis-lactone was crystalline, its structure was conﬁrmed as

shown by X-ray diffraction, see Fig. 1. Selective reduction of

the 5-membered lactone over the macrolide was then achieved

using diisobutylaluminium hydride in toluene and gave the

b-milbemycin analogue 65.

Having established a strategy for the assembly of macrolides

in this series, the racemic hydroxybutenolide 37 was condensed

with the enantiomerically enriched phosphonium salt 1 followed

in this more complex case by esteriﬁcation of the acid so formed

3 6 4 0

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

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Scheme 6 Reagents and conditions: i, ( )-37, LHMDS, THF, −78 to −10 ^◦C, 90 min then CH₂N₂, Et₂O, r.t. (66%); ii, I₂(50 mol%), benzene, hm

(90%); iii, TBAF, THF, 10 h (99%).

using diazomethane to give a ca. 2 : 1 mixture of the (4Z)-

and (4E)-dienyl esters 66, together with their diastereoisomers

67 which had incorporated the wrong enantiomer of the

hydroxybutenolide. In this case an attempt was made to effect

macrocyclisation of the seco-acids 68 and 69 formed by (4Z)-

to (4E)-isomerisation of the dienes 66 and 67 using a sub-

stoichiometric amount of iodine without removal of the SEM

group, and desilylation with removal of the trimethylsilylethyl

ester, but no large-ring product could be isolated, see Scheme 6.

A stoichiometric amount of iodine was therefore used to carry

out simultaneous (4Z)- to (4E)-diene isomerisation and SEM

group removal from the Wittig products 66 and 67 to give the

dihydroxydienes 70 and 71, see Scheme 7. Treatment of this

mixture of hydroxy methyl esters with silica gel in chloroform

effected intramolecular transesteriﬁcation to give the buteno-

lides 72 and 73 and desilylation using tetrabutylammonium

ﬂuoride in tetrahydrofuran removed both the 2-trimethylsilyl

ester and the tert-butyldimethylsilyl ether protecting groups to

give a mixture of the distinguishable, but not separable, seco-

acids 74 and 75. As in the earlier series, macrocyclisation,

in this case using dicyclohexylcarbodiimide, was successful

only for the seco-acid which had the conﬁguration of the

natural milbemycins, and gave the required macrolide 76 (46%

based on seco-acid 74). Selective reduction of the 5-membered

lactone then gave (6R)-6-hydroxy-3,4-dihydromilbemycin

E 77.

Since the ultimate objective of this work was to complete

a synthesis of an a-milbemycin, preliminary attempts were

made to convert the b-milbemycin analogues 65 and 77 into

tetrahydrofurans corresponding to analogues of a-milbemycins.

However, treatment of these triols with an excess of lithium

diisopropylamide and one equivalent of toluene p-sulfonyl

chloride gave rise to the formation of the primary allylic

chlorides 78 and 79, rather than the required tetrahydrofurans.

Structures were assigned to these chlorides by comparison of

their ¹H NMR data with those of milbemycin G 4 and its

synthetic precursor, the chloride 80.^14,15In particular the peaks

due to 9-H and 10-H in chloride 79 are at d6.14 (d, J 11) and

d6.26 (dd, J 15, 11) with the corresponding peaks in chloride

80 being at d6.38 (d, J 11) and at d6.26 (dd, J, 15, 11). For

comparison, in milbemycin G 4, 9-H and 10-H overlap as a

complex multiplet at d5.69–5.77.¹⁵†

Summary and conclusions

This work has shown that the approach used previously to

prepare non-aromatic b-milbemycins as typiﬁed by a synthesis

of milbemycin E 3,⁵can be applied to synthesize milbemycins

with a hydroxyl group at C(6) (milbemycin numbering). The

Robinson reactions used to assemble the six-membered ring

leading to the C(1)–C(10)-fragments were stereoselective but

gave the unwanted conﬁguration at C(6). Nevertheless, the

conﬁguration at this centre could be inverted by a redox

process, and procedures were developed for the resolution of this

fragment and for its incorporation into macrocyclic analogues

of milbemycins culminating in a total synthesis of (6R)-6-

hydroxy-3,4-dihydromilbemycin E 77. During these studies it

was observed that the macrocyclisation reactions were more

efﬁcient if carried out on intermediates in which a butenolide

had been incorporated between the side-chain acid and the 6b-

hydroxyl group, perhaps because of more limited degrees of

freedom in this system.

The next stage in this programme was to show that the

chemistry used to introduce the 6b-hydroxyl substituent was

compatible with the 3,4-double-bond (milbemycin numbering)

and to ﬁnd procedures to effect the formation of the tetrahydro-

furan ring found in the a-milbemycins. The results of this work

and the completion of a total synthesis of milbemycin G 4

including the successful introduction of the tetrahydrofuran ring

are described in the accompanying paper.^14,15

† At the time of our preliminary communication on this work,^7bit was

thought that the triols 65 and 77 had been cyclised on treatment with

lithium diisopropylamide and toluene p-sulfonyl chloride. It was only

after the synthesis of milbemycin G was complete and the allylic chloride

80 identiﬁed^14,15did it become apparent that the chlorides 78 and 79 had

been formed in the present study.

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

3 6 4 1

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Scheme 7 Reagents and conditions: i, I₂, benzene, ht, 1.5 h (92%); ii, silica, CHCl₃(98%); iii, TBAF, THF, 10 h (78%); iv, DCC, DMAP, CH₂Cl₂,

21 h (23% of 76, 46% based on 74); v, DIBAL-H, toluene, −78 ^◦C, 1 h (74%).

32 mmol) in ethanol (70 cm³) and aqueous sodium hydroxide

Experimental

(10%; 2.2 cm³) and the mixture stirred at ambient temperature

Melting points were recorded on a Kofﬂer heated stage micro-

for 24 h. The solid which had separated out was ﬁltered off

scope and are uncorrected. Proton NMR spectra were recorded

in deuteriated chloroform unless otherwise indicated on Bruker

AC300, Varian XXL300 and Varian Unity 500 spectrometers;

coupling constants are given in Hz and chemical shifts relative

to Me₄Si. IR spectra were recorded on a Perkin Elmer 1710FT

spectrometer and were run as liquid ﬁlms, KBr discs or as

solutions in chloroform. Mass spectra were measured on a

Kratos MS25 spectrometer coupled to a DS55 data system.

and recrystallized from ether–hexane to give the title compound

7 (70%), mp 94–95 ^◦C. (Found: C, 67.5; H, 6.4%. C₂₁H₂₄O₆

requires C, 67.75; H, 6.50%), m_max(CHCl₃) 3478, 1723, 1053 and

1030 cm⁻¹; d_H(300 MHz, CDCl₃) 1.12 (3 H, t, J 7, CH₂CH₃),

1.15 (3 H, d, J 6, 5-CH₃), 2.12 (2 H, m, 6-H₂), 2.5 (1 H, m,

5-H), 3.2 (1 H, dd, J 7.5, 8, 1-H), 3.8 (1 H, s, 3-H), 3.9 (1

H, s, OH), 4.05 (2 H, m, CH₂CH₃), 4.3 and 4.8 (each 1 H, d,

J 12.5, OHCHPh), 6.3 (1 H, s, 4^ꢀ-H), 7.0 (2 H, m, ArH, 7.2 (3

Optical rotations were measured on an Optical Activity AA100

H, m, ArH) and 7.4 (2 H, m, 2^ꢀ-H and 5^ꢀ-H); m/z (EI) 372 (M⁺,

polarimeter at ambient temperature, typically 20 ^◦C.

1%), 263 (4) and 95 (100). The ﬁltrate was concentrated under

Chromatography refers to ﬂash chromatography¹⁶using

reduced pressure and the residue taken up in ether (30 cm³).

Merck silica gel 60H (40–63 mm³, 230–300 mesh). Light

The ether solution was washed with brine, dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

◦

petroleum refers to the fraction boiling at 40–60 C and ether

to diethyl ether. All solvents and reagents were puriﬁed before

residue using light petroleum–ether (3 : 1) as eluant gave ﬁrst

use by standard techniques.¹⁷All non-aqueous reactions were

the title compound 8 (13%), mp 78–80 ^◦C. (Found: C, 67.65; H,

performed under an atmosphere of dry argon or nitrogen.

6.5%. C₂₁H₂₄O₆requires C, 67.75; H, 6.50%), m_max(KBr) 3474,

1713, 1455, 1373 and 1195 cm⁻¹; d_H(300 MHz, C₆D₆) 0.88 (3

Ethyl (1RS,2SR,3RS,5SR)-2-(3-furyl)-2-hydroxy-5-methyl-3-

H, t, J 7.5, CH₂CH₃), 1.1 (3 H, d, J 7.5, 5-CH₃), 1.8 (1 H, ddd,

phenylmethoxy-4-oxocyclohexane-1-carboxylate 7,

J 13, 7, 1, 6-H), 2.25 (1 H, dt, J 6, 13, 6-H^ꢀ), 3.1 (2 H, m, 5-H,

(1SR,2SR,3RS,5SR)-2-(3-furyl)-2-hydroxy-5-methyl-3-

OH), 3.2 (1 H, dd, J 6, 1.5, 1-H), 3.85 (2 H, m, CH₂CH₃), 4.3

phenylmethoxy-4-oxocyclohexane-1-carboxylate 8 and

(1RS,2SR,3RS,5RS)-2-(3-furyl)-2-hydroxy-5-methyl-3-

and 5.0 (each 1 H, d, J 11, OHCHPh), 5.15 (1 H, s, 3-H), 6.3

(1 H, s, 4^ꢀ-H) and 7.2 (7 H, m, ArH, 2^ꢀ-H, 5^ꢀ-H); m/z (EI) 372

phenylmethoxy-4-oxocyclohexane-1-carboxylate 9

(M⁺, 5%) and 95 (100). Further elution gave the title compound

9 (8%), mp 85 ^◦C. (Found: C, 68.0; H, 6.5%. C₂₁H₂₄O₆requires

The benzyloxymethyl ketone 5 (6.8 g, 38 mmol) in ethanol

(19 cm³) was added to a mixture of the keto ester 6^5a(5.77 g,

C, 67.75; H, 6.50%), m_max(KBr) 3416, 1710, 1187, 1164, 1026 and

3 6 4 2

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

View Article Online

965 cm⁻¹; d_H(300 MHz, CDCl₃) 1.08 (3 H, t, J 7.5, CH₂CH₃),

1.15 (3 H, d, J 7.5, 5-CH₃), 1.52 and 2.47 (each 1 H, m, 6-H),

3.0 (1 H, m, 5-H), 3.1 (1 H, dd, J 8, 3, 1-H), 3.98 (2 H, m,

CH₂CH₃), 4.02 (1 H, s, 3-H), 4.42 and 4.6 (each 1 H, d, J 12,

OHCHPh), 4.78 (1 H, br. s, OH), 6.3 (1 H, s, 4^ꢀ-H) and 7.05–7.4

(7 H, m, ArH, 2^ꢀ-H, 5^ꢀ-H); m/z (CI) 390 (M⁺+ 18, 66%), 355

(98), 265 (57), 208 (79) and 95 (100). Finally a further small

amount of the major product 7 (ca. 5%) was eluted from the

column.

and the mixture stirred for 3 h. Ether (5 cm³) was added

and the mixture washed with water (3 × 5 cm³). After re-

extraction of the aqueous phase, the combined organic phases

were dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue gave the title compound 13

(112 mg, 85%), as a white solid, mp 113–114 ^◦C. (Found: C,

67.3; H, 7.0%. C₂₁H₂₆O₆requires C, 67.35; H, 7.0%); m_max(CHCl₃)

3419, 3064, 1707 and 1191 cm⁻¹; d_H(300 MHz, C₆D₆) 0.68 (3

H, t J 6.5, CH₂CH₃), 1.05 (4 H, m, 5-CH₃, 5-H), 1.22 (1 H, m,

6-H), 1.97 (1 H, q, J 12, 6-H^ꢀ), 2.35 (1 H, dd, J 12, 4, 1-H), 2.78

(1 H, d, J 3, 3-H), 3.61 (2 H, m, CH₂CH₃), 3.85 (1 H, br. d, J

9, OH), 4.05 (1 H, d, J 3, 4-H), 4.1 and 4.45 (each 1 H, d, J 11,

OHCHPh), 4.92 (1 H, s, OH), 6.19 (1 H, s, 4^ꢀ-H), 6.9–7.1 (6 H,

m, ArH, 5^ꢀ-H) and 7.5 (1 H, m, 2^ꢀ-H); m/z (EI) 374 (M⁺, 1%)

and 91 (100).

Carbonyl diimidazole (153 mg, 0.94 mmol) was added to the

cis-diol 13 (88 mg, 0.235 mmol) in anhydrous benzene (2 cm³)

containing a trace of sodium hydride and the mixture stirred

for 36 h at ambient temperature. Ethyl acetate (5 cm³) was

added and the mixture washed with water (3 × 3 cm³). After re-

extraction of the aqueous phase, the combined organic phases

were dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue gave the cyclic carbonate 14

(63 mg, 67%) as a white solid, mp 184–185 ^◦C; m_max(CHCl₃)

3020, 1748, 1630, 1602 and 1154 cm⁻¹; d_H(300 MHz, CDCl₃)

1.13 (3 H, t J 7.5, CH₂CH₃), 1.2 (3 H, d, J 6, 5-CH₃), 1.9 (3 H,

m, 5-H, 6-H₂), 2.9 (1 H, m, 1-H), 3.46 (1 H, d, J 2, 3-H), 3.98 (2

H, m, CH₂CH₃), 4.4 and 4.5 (each 1 H, d, J 12.5, OHCHPh),

4.53 (1 H, m, 4-H), 6.3 (1 H, s, 4^ꢀ-H), 7.1–7.3 (5 H, m, ArH),

7.42 (1 H, m, 5^ꢀ-H) and 7.5 (1 H, m, 2^ꢀ-H); m/z (CI) 418 (M⁺+

18, 100%).

Ethyl (1RS,2SR,3SR,4RS,5SR)-3-benzyloxy-2,4-dihydroxy-2-

(3-furyl)-5-methylcyclohexane-1-carboxylate 10

Sodium borohydride (23 mg, 0.62 mmol) was added to acetic

acid (1.7 cm³) portionwise over 20 min maintaining a tempera-

ture of 15–18 ^◦C and the mixture stirred at ambient temperature

for 30 min then added to the hydroxycyclohexanone 7 (57 mg,

0.154 mmol). The mixture was stirred for 3 h then concentrated

under reduced pressure. The residue was dissolved in ethyl

acetate (5 cm³) and the solution washed with aqueous sodium

hydroxide (3 M, 3 × 5 cm³). The aqueous phase was re-extracted

and the combined organic extracts washed with brine, dried

(MgSO₄) and concentrated under reduced pressure. The residue

was recrystallized from ether–hexane to give the title compound

◦

10 (100%), mp 98–99 C. (Found: C, 67.0; H, 6.9%. C₂₁H₂₆O₆

requires C, 67.35; H, 7.0%); m_max(KBr) 3430, 1712 and 1187 cm⁻¹;

d_H(300 MHz, CDCl₃) 1.1 (3 H, t, J 7, CH₂CH₃), 1.12 (3 H, d,

J 7.5, 5-CH₃), 1.6 (1 H, m, 5-H), 1.8 (2 H, m, 6-H₂), 2.15 (1 H,

br. s, OH), 2.82 (1 H, dd, J 12, 1.5, 1-H), 3.2 (1 H, d, J 9, 3-H),

3.65 (1 H, t, J 9, 4-H), 4.0 (3 H, m, OH, CH₂CH₃), 4.15 and

4.32 (each 1 H, d, J 11, OHCHPh), 6.45 (1 H, s, 4^ꢀ-H), 7.1–7.3

(5 H, m, ArH), 7.44 (1 H, m, 5^ꢀ-H) and 7.5 (1 H, m, 2^ꢀ-H); m/z

(EI) 374 (M⁺, 1.6%), 250 (60), 174 (51) and 91 (100).

1-p-Methoxybenzyloxy-3-methylbut-2-ene 16

Ethyl (1SR,2SR,3SR,4RS,5SR)-3-benzyloxy-2,4-dihydroxy-2-

(3-furyl)-5-methylcyclohexane-1-carboxylate 11

Sodium hydride (3 g, 128 mmol) was washed with THF (3 ×

20 cm³), suspended in THF (50 cm³) and a solution of 3-

methylbut-2-en-1-o1 15 (10 g, 116 mmol) in THF (50 cm³) was

added slowly. The mixture was stirred for 30 min before cooling

to 0 ^◦C and tetra-n-butylammonium iodide (4.28 g, 11.6 mmol)

and p-methoxybenzyl chloride (19.9 g, 128 mmol) were added.

The reaction was stirred for 16 h at room temperature, cooled to

Following the procedure outlined above for the preparation of

diol 10, the hydroxyketone 8 (105 mg, 0.28 mmol) gave the title

compound 11 (81 mg, 77%), as an oil. [Found (EI): M⁺, 374.1729.

C₂₁H₂₆O₆requires M, 374.1729]; m_max(CHCl₃) 3495, 1726 and

1188 cm⁻¹; d_H(300 MHz, CDCl₃) 1.05 (3 H, d, J 7.5, 5-CH₃),

1.15 (3 H, t, J 7, CH₂CH₃), 1.17 (1 H, m, 6-H_eq), 1.95 (1 H, dt, J

5.5, 14, 6-H_ax), 2.1 (1 H, m, 5-H), 2.9 (1 H, dd, J 5.5, 1.5, 1-H),

3.05 (1 H, br. s, OH), 3.5 (1 H, dd, J 7.5, 8.5, 4-H), 4.05 (2 H, q,

J 7, CH₂CH₃), 4.3 (1 H, d, J 8.5, 3-H), 4.45 and 4.65 (each 1 H,

d, J 10, OHCHPh), 6.45 (1 H, s, 4^ꢀ-H), 7.1–7.3 (5 H, m, ArH),

7.35 (1 H, m, 5^ꢀ-H) and 7.5 (1 H, m, 2^ꢀ-H); m/z (EI) 374 (M⁺,

2%), 357 (30), 339 (39), 250 (47) and 91 (100).

◦

0 C, then water (20 cm³) was added. The mixture was diluted

with ether (100 cm³), washed with water (2 × 20 cm³) and the

aqueous phase was re-extracted. The combined organic phases

were dried (MgSO₄) and concentrated under reduced pressure to

give the ether 16 (21.3 g, 89%) as a yellow oil. Chromatography

of a sample using light petroleum–ether (9 : 1) as eluant gave

the title compound 16. [Found (EI): M⁺, 206.1296. C₁₃H₁₈O₂

requires M, 206.1307]; m_max(CHCl₃) 1613, 1514, 1448, 1379,

1176 and 1074 cm^−l; d_H(300 MH; CDC1₃) 1.65 and 1.79 (each

3 H, s, CH₃), 3.8 (3 H, s, OCH₃), 3.98 (2 H, d, J 7, 1-H₂),

4.45 (2 H, s, CH₂Ar), 5.4 (1 H, m, 2-H), 6.9 (2 H, m, ArH)

and 7.3 (2 H, m, ArH); m/z (EI) 206 (M⁺, 32%), 156 (21) and

121 (100).

Ethyl (1RS,2SR,3SR,4RS,5RS)-3-benzyloxy-2,4-dihydroxy-2-

(3-furyl)-5-methylcyclohexane-1-carboxylate 12

Following the procedure outlined above for the preparation

of diol 10, the hydroxyketone 9 (50 mg, 0.13 mmol) gave the

title _◦compound 12 (42 mg, 87%), as a white solid, mp 130–

132 C. (Found: C, 67.0; H, 7.0%. C₂₁H₂₆O₆requires C, 67.35;

H, 7.0%); m_max(KBr) 3489, 1710, 1500, 1188, 1109, 1079, 1030

and 1002 cm⁻¹; d_H(300 MHz, C₆D₆) 0.8 (3 H, t, J 7, CH₂CH₃),

1.12 (3 H, d, J 7.5, 5-CH₃), 1.52 (1 H, dt, J 13.5, 3, 6-H_eq), 2.25

(2 H, m, 5-H, OH), 2.42 (1 H, dt, J 4, 13.5, 6-H_ax), 3.0 (1 H, dd,

J 13.5, 4, 1-H), 3.37 (1 H, d, J 10, 3-H), 3.79 (2 H, m, CH₂CH₃),

4.24 and 4.34 (each 1 H, d, J 11, OHCHPh), 4.35 (1 H, m, OH),

4.42 (1 H, dd, J 10, 5.5, 4-H), 6.28 (1 H, s, 4^ꢀ-H), 7.1–7.3 (6 H,

m, ArH, 5^ꢀ-H) and 7.45 (1 H, m, 2^ꢀ-H); m/z (EI) 374 (M⁺, 4%)

and 250 (100).

1-p-Methoxybenzyloxy-3-methylbut-2-ene epoxide 17

A solution of oleﬁn 16 (21.3 g, 103 mmol) in dichloromethane

(100 cm³) was added to a suspension of m-chloroperbenzoic acid

◦

(43.6 g, 140 mmol) in dichloromethane (250 cm³) at 0 C. The

mixture was stirred at this temperature for 2 h before ﬁltering

through celite, washing with aqueous sodium bicarbonate (3 ×

50 cm³) and re-extracting the aqueous phase. The combined

organic phases were dried (MgSO₄) and concentrated to give the

epoxide 17 (19.4 g, 85%) as a yellow oil. Chromatography of a

sample using light petroleum–ether (9 : 1) as eluant gave the title

compound 17. [Found (EI): M⁺, 222.1259. C₁₃H₁₈O₃requires M,

222.1256]; m_max(CHCl₃) 1727, 1613, 1587, 1514, 1463, 1380, 1303,

1175, 1083, 1036 and 907 cm^−l; d_H(200 MHz, CDC1₃) 1.26 and

1.35 (each 3 H, s, CH₃), 3.0 (1 H, t, J 5, 2-H), 3.55 (1 H, dd,

J 11, 5 Hz, 1-H), 3.65 (1 H, dd, J 11, 5 Hz, 1-H), 3.82 (3 H, s,

Ethyl (1RS,2SR,3SR,4SR,5SR)-3-benzyloxy-2,4-dihydroxy-2-

(3-furyl)-5-methylcyclohexane-1-carboxylate 13

Sodium borohydride (133 mg, 3.5 mmol) was added portionwise

to the hydroxyketone 7 (131 mg, 0.352 mmol) in ethanol (1 cm³)

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

3 6 4 3

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OCH₃), 4.48 and 4.6 (each l H, d, J 12, HCHAr) and 6.9 and

7.3 (each 2 H, m, ArH); m/z (EI) 222 (M⁺, 0.5%), 156 (7), 137

(59) and 121 (100).

475.2152]; m_max(CHCl₃) 3398, 1727, 1613, 1515, 1460, 1377, 1094

and 946 cm⁻¹; d_H(300 MHz; CDCl₃), 0.32 [9 H, s, Si(CH₃)₃], 1.16

(3 H, d, J 6.5, 5-CH₃), 1.18 (3 H, t, J 7, CO₂CH₂CH₃), 2.02 (1

H, ddd J 13.5, 6, 1.7 Hz, 6-H), 2.2 (1 H, td, J 13.5, 5.5 Hz,

6-H), 3.07 (1 H, s, 3-H), 3.12 (2 H, m, 1-H, 5-H), 3.82 (3 H, s,

OCH₃), 4.05 (2 H, m, CO₂CH₂), 4.45 and 4.82 (each 1 H, d, J

11, HCHAr), 5.02 (1 H, s, 2-OH), 6.03 (1 H, d, J 1.8, 4^ꢀ-H), 6.84

and 7.12 (each 2 H, d, J 7, ArH) and 7.48 (1 H, d, J 1.8, 5^ꢀ-H);

m/z (CI) 492 (M⁺+ 18, 40), 475 (M⁺+ 1, 85), 429 (57) and 385

(21). Further elution of the column gave a further small amount

(ca. 5%) of the major product 21.

1-p-Methoxybenzyloxy-3-methylbut-3-en-2-ol 18

Epoxide 17 (19.4 g, 87.4 mmol) and aluminium isopropoxide

(25 g, 122 mmol) were heated under reﬂux in xylene (100 cm³) for

3 h. The mixture was cooled and washed with aqueous hydrogen

chloride (3 M; 2 × 20 cm³). The aqueous phase was re-extracted

and the combined organic phases dried (MgSO₄). Concentration

under reduced pressure and chromatography of the residue using

light petroleum–ether (3 : 1) as eluant gave the title compound 18

(16.53 g, 87%) as a clear oil. [Found (EI): M⁺, 222.1257. C₁₃H₁₈O₃

requires M, 222.1256]; m_max(CHCl₃) 3400, 3075, 1653, 1613,

1587, 1514, 1463, 1363, 1175, 1035 and 902 cm⁻¹; d_H(300 MHz;

CDCl₃) 1.75 (3 H, s, 3-CH₃), 2.5 (1 H, br. s, OH), 3.4 (1 H, dd,

J 9.5, 8, 1-H), 3.55 (1 H, dd, J 9.5, 3, 1-H), 3.82 (3 H, s, OCH₃),

4.28 (1 H, dd, J 8, 3, 2-H), 4.52 (2 H, s, CH₂Ar), 4.95 (1 H, s,

4-H), 5.08 (1 H, s, 4-H) and 6.88 and 7.3 (each 2 H, m, ArH);

m/z (EI) 222 (M⁺, 5%), 152 (5), 137 (25) and 121 (100).

Ethyl (1RS,2SR,3SR,4RS,5SR)-3-p-methoxybenzyloxy-2,4-

dihydroxy-5-methyl-2-(2-trimethylsilyl-3-furyl)cyclohexane-

1-carboxylate 23

The ketone 21 (4 g, 8.44 mmol) was dissolved in acetonitrile

and acetic acid (1 : 1; 60 cm³), tetramethylammonium triace-

toxyborohydride (17.71 g, 67.64 mmol) was added and the

mixture stirred for 96 h. After concentration under reduced

pressure, the residue was dissolved in ether (100 cm³) and the

solution washed with aqueous sodium hydroxide (1 M; 20 cm³).

The aqueous phase was re-extracted and the combined organic

phases were dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue using light petroleum–

ether (4 : 1) as eluant gave the title compound 23 (3.57 g, 89%) as a

white solid, mp 128–129 ^◦C. (Found: C, 62.8; H, 7.7. C₂₅H₃₆O₇Si

requires C, 63.0; H, 7.6%); m_max(CHCl₃) 3455, 1780, 1710, 1613,

1514, 1463, 1377, 1098, 1057, 1034 and 918 cm⁻¹; d_H(300 MHz,

CDC1₃), 0.03 [9 H, s, Si(CH₃)₃], 1.02 (3 H, t, J 7, OCH₂CH₃),

1.07 (3 H, d, J 6.5, 5-CH₃), 1.59 (1 H, m, 5-H), 1.7 (1 H, m, 6-H),

1.8 (1 H, q, J 12, 6-H), 2.19 (1 H, d, J 1.5, 4-OH), 2.8 (1 H, dd,

J 7 and 2 Hz, 1-H), 3.19 (1 H, d, J 9, 3-H), 3.55 (1 H, td, J 9,

1.5 Hz, 4-H), 3.75 (3 H, s, OCH₃), 3.85–4.12 (5 H, m, CH₂Ar,

OCH₂CH₃, 2-OH), 6.3 (1 H, d, J 2, 4^ꢀ-H), 6.78 and 6.98 (each 2

H, m, ArH) and 7.6 (1 H, d, J 2, 5^ꢀ-H); m/z (CI) 477 (M⁺+ 1,

12.5%), 459 (27), 387 (22), 337 (13) and 121 (100).

1-p-Methoxybenzyloxy-3-methylbut-3-en-2-one 19

Dimethyl sulfoxide (1.07 g, 13.6 mmol) in dichloromethane

(6 cm³) was added to oxalyl chloride (0.95 g, 7.5 mmol) in

dichloromethane (10 cm³) at −78 ^◦C followed by the alcohol

18 (1.5 g, 6.8 mmol) in dichloromethane (6 cm³). The mixture

was stirred for 15 min before triethylamine (4.75 cm³, 34 mmol)

was added and the mixture warmed to room temperature. The

solution was diluted with ether (100 cm³), washed with saturated

aqueous ammonium chloride (30 cm³) and the organic phase

dried (MgSO₄). After concentration under reduced pressure, the

residue was chromatographed using light petroleum–ether (4 :

1) as eluant to give the title compound 19 (1.19 g, 80%) as a

clear oil. [Found (EI): M⁺− H, 219.1028. C₁₃H₁₅O₃requires M,

219.1021]; m_max(CHCl₃) 1690, 1613, 1586, 1513, 1461, 1374, 1301,

1175, 1060, 1034 and 943 cm⁻¹; d_H(200 MHz, CDCl₃) 1.9 (3 H, s,

3-CH₃), 3.8 (3 H, s, OCH₃), 4.45 (2 H, s, CH₂Ar), 4.55 (2 H, s,

1-H₂), 5.75 (1 H, s, 4-H), 5.9 (1 H, s, 4-H) and 6.9 and 7.3 (each

2 H, m, ArH); m/z (CI) 220 (M⁺, 5%), 219 (33), 138 (28) and

121(100).

Ethyl (1RS,2SR,3SR,4RS,5SR)-4-acetoxy-2-hydroxy-3-

p-methoxybenzyloxy-5-methyl-2-(2-trimethylsilyl-

3-furyl)cyclohexane-1-carboxylate 24

Triethylamine (352 mg, 3.45 mmol), DMAP (a trace) and acetic

anhydride (266 mg, 2.66 mmol) were added to a solution of

diol 23 (0.86 g, 1.8 mmol) and the mixture stirred for 16 h.

The mixture was diluted with ether (150 cm³), washed with

brine (45 cm³), dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue using light petroleum–

ether (3 : 1) as eluant gave the title compound 24 (0.87 g, 93%) as a

white solid, mp 154–156 ^◦C. (Found: C, 62.7; H, 7.6. C₂₇H₃₈O₈Si

requires C, 62.55; H, 7.4%); m_max(CHCl₃) 3469, 1736, 1613, 1514,

1433, 1373, 1072, 1036 and 905 cm⁻¹; d_H(300 MHz, CDCl₃) 0.25

[9 H, s, Si(CH₃)₃], 1.02 (3 H, d, J 6, 5-CH₃), 1.07 (3 H, t, J 7,

OCH₂CH₃), 1.8 (2 H, m, 5-H, 6-H), 2.0 [3 H, s, OC(O)CH₃],

2.02 (1 H, q, J 13, 6-H), 2.84 (1 H, dd, J 12.7, 3.7 Hz, 1-H),

3.43 (1 H, d, J 9.7, 3-H), 3.81 (3 H, OCH₃), 3.83 (1 H, s, 2-OH),

3.9–4.18 (4 H, m, CH₂Ar, OCH₂CH₃), 5.18 (1 H, t, J 9.7, 4-H),

6.34 (1 H, d, J 1.7, 4^ꢀ-H), 6.81 and 6.92 (each 2 H, m, ArH) and

7.65 (1 H, d, J 1.7, 5^ꢀ-H); m/z (CI) 519 (M⁺+ 1, 5%), 501 (13),

441 (20), 429 (9) and 121 (100).

Ethyl (1RS,2SR,3RS,5SR)-3-p-methoxybenzyloxy-2-hydroxy-

5-methyl-2-(2-trimethylsilyl-3-furyl)-4-oxocyclohexane-1-

carboxylate 21 and ethyl (1SR,2SR,3RS,5SR)-3-p-

methoxybenzyloxy-2-hydroxy-5-methyl-2-(2-trimethylsilyl-

3-furyl)-4-oxocyclohexane-1-carboxylate 22

A solution of ketone 19 (0.85 g, 3.89 mmol), keto-ester 20 (0.99 g,

3.89 mmol) and aqueous sodium hydroxide (3 M; 0.26 cm³) was

stirred in ethanol (6 cm³) for 16 h at room temperature then

◦

allowed to stand for a further 16 h at −30 C. Crystals of the

cyclohexanone 21 were ﬁltered off and washed with ice-cold

ethanol. The washings were diluted with ether (50 cm³) and

washed with brine (10 cm³) and dried (MgSO₄). Concentration

under reduced pressure gave more of the title compound 21

(1.17 g, 64% in total) as a crystalline solid, mp 127–128 ^◦C;

m_max(CHCl₃) 3553, 3469, 3418, 1722, 1638, 1588, 1515, 1467,

1399, 1380, 1349, 1302, 1274, 1148, 1099, 1036 and 914 cm⁻¹;

d_H(300 MHz, CDCl₃) 0.22 [9 H, s, Si(CH₃)₃], 1.02 (3 H, t, J 7,

CO₂CH₃),1.13 (1 H, d, J 6.5, 5-CH₃), 2.03–2.19 (2 H, m, 6-H₂),

2.48 (1 H, m, 5-H), 3.19 (1 H, m, 1-H), 3.75 (3 H, s, OCH₃), 3.82

(1 H, s, 3-H), 3.86 (1 H, s, 2-OH), 3.88–4.07 (2 H, m, CO₂CH₂),

4.18 and 4.54 (each 1 H, d, J 12, HCHAr), 6.17 (1 H, s, 4^ꢀ-H),

6.7 and 6.85 (each 2 H, d, J 8, ArH) and 7.53 (1 H, d, J 2, 5^ꢀ-H);

m/z (CI) 492 (M⁺+ 18, 48), 475 (M⁺+ 1, 20%), 457 (19), 429

(18), 385 (16) and 337 (30). After concentration of the ﬁltrate,

chromatography of the residue using light petroleum–ether (2 : 1)

as eluant gave the title compound 22 (0.19 g, 10%) as a solid, mp

104 ^◦C. [Found (EI): M⁺+ H, 475.2167. C₂₅H₃₅O₇Si requires M,

Ethyl (1RS,2SR,3SR,4RS,5SR)-4-acetoxy-2,3-dihydroxy-5-

methyl-2-(2-trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 25

The p-methoxybenzyl ether 24 (40 mg, 0.07 mmol) was depro-

tected following the procedure outlined for ketone 21 to give

the title compound 25 (24 mg, 80%) as a white solid, mp 103–

104 ^◦C. (Found: C, 57.4; H, 7.7. C₁₉H₃₀O₇Si requires C, 57.25; H,

7.6%); m_max(CHCl₃) 3466, 1735, 1604, 1566, 1512, 1461, 1373,

1111, 1067, 943 and 881 cm⁻¹; d_H(300 MHz; CDCl₃) 0.03 [9

H, s, Si(CH₃)₃], 1.0 (3 H, d, J 6, 5-CH₃), 1.08 (3 H, t, J 7.5,

3 6 4 4

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

View Article Online

OCH₂CH₃), 1.75–1.9 (4 H, m, 6-H₂, 5-H, 3-OH), 2.1 [3 H, s,

OC(O)CH₃], 2.85 (1 H, dd, J 12, 6 Hz, 1-H), 3.38 (1 H, t, J

9.5, 3-H), 3.9–4.1 (2 H, m, OCH₂CH₃), 4.5 (1 H, s, 2-OH), 5.02

(1 H, t, J 9.5, 4-H), 6.2 (1 H, d, J 1.5, 4^ꢀ-H), 7.55 (1 H, d, J 1.5,

5^ꢀ-H); m/z (CI) 416 (M⁺+ 18, 6%), 397 (1), 381 (15), 321 (14)

and 309 (50).

saturated aqueous ammonium chloride (10 cm³). The organic

phase was dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue using light petroleum–

ether (3 : 1) as eluant gave the title compound 29 (0.49 g) as a

white solid, mp 113–114 ^◦C. (Found: C, 57.5; H, 7.2. C₁₉H₂₈O₇Si

requires C, 57.55; H, 7.1%); m_max(CHCl₃) 3447, 1742, 1708, 1565,

1462, 1373, 1342, 1287, 1136, 1071, 1060 and 985 cm⁻¹; d_H

(300 MHz, CDCl₃) 0.3 [9 H, s, Si(CH₃)₃], 1.18 (3 H, t, J 7,

OCH₂CH₃), 1.13 (3 H, d, J 7, 5-CH₃), 2.05 (2 H, m, 6-H, 5-H),

2.18 [3 H, s, OC(O)CH₃], 2.35 (1 H, q, J 12.5, 6-H^ꢀ), 3.03 (1 H,

dd, J 13, 4, 1-H), 4.1 (2 H, m, OCH₂CH₃), 4.9 (1 H, s, 2-OH),

5.71 (1 H, d, J 11, 4-H), 6.22 (1 H, d, J 1.7, 4^ꢀ-H), 7.6 (1 H, d, J

1.7, 5^ꢀ-H); m/z (CI) 414 (M⁺+ 18, 9), 397 (M⁺+ 1, 11%), 379

(16), 337 (71), 324 (43) and 247 (100).

Ethyl (1RS,2SR,3RS,5SR)-2,3-dihydroxy-5-methyl-2-(2-

trimethylsilyl-3-furyl)-4-oxocyclohexane-1-carboxylate 26

Dichlorodicyanoquinone (72 mg, 0.32 mmol) was added to the

ketone 21 (100 mg, 0.21 mmol) in dichloromethane (1 cm³) and

water (0.2 cm³) and the mixture was stirred for 3 h. Aqueous

sodium bicarbonate (0.5 cm³) was added and the mixture was

diluted with ether (20 cm³) and washed with brine (2 cm³).

The organic phase was dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue using light

petroleum–ether (3 : 1) as eluant gave the title compound 26

(75 mg, 96%) as a white solid, mp 84–86 ^◦C. (Found: C, 58.0, H,

7.5. C₁₇H₂₆O₆Si requires C, 57.6; H, 7.4%); m_max(CHCl₃) 3300,

1781, 1722, 1658, 1461, 1378, 109 and 915 cm⁻¹; d_H(300 MHz,

CDCl₃) 0.3 [9 H, s, Si(CH₃)₃], 1.05 (3 H, t, J 7, CO₂CH₃), 1.2 (3

H, d, J 6, 5-CH₃), 2.1 (1 H, q, J 12.5, 6-H), 2.25 (1 H, m, 6-H^ꢀ),

2.65 (1 H, m, 5-H), 3.32 (1 H, dd, J 12.5, 4, 1-H), 3.52 (1 H, d,

J 6, 3-OH), 3.9–4.1 (3 H, m, CO₂CH₂, 2-OH), 4.15 (1 H, d, J 6,

3-H), 6.31 (1 H, d, J 1.7, 4^ꢀ-H) and 7.58 (1 H, d, J 1.7, 5^ꢀ-H);

m/z (CI) 372 (M⁺+ 18, 11), 355 (M⁺+ 1, 29%) and 337 (100).

Ethyl (1RS,2SR,3RS,4RS,5SR)-4-acetoxy-2,3-dihydroxy-5-

methyl-2-(2-trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 30

Tetramethylammonium triacetoxyborohydride (1.38 g,

5.2 mmol) was added to a solution of the ketone 29 (0.41 g,

1.05 mmol) in acetic acid (4 cm³) and acetonitrile (4 cm³) and

the mixture was stirred for 16 h. After concentration under

reduced pressure, chromatography of the residue using light

petroleum–ether (2 : 1) as eluant gave the title compound 30

(0.35 g, 85%) as a white solid, mp 175–177 ^◦C. (Found: C, 57.3;

H, 7.5. C₁₉H₃₀O₇Si requires C, 57.25; H, 7.6%); m_max(CHCl₃)

3454, 1708, 1465, 1374, 1345, 1283, 1263, 1100, 1045, 914 and

879 cm⁻¹; d_H(300 MHz, CDCl₃), 0.35 [9 H, s, Si(CH₃)₃], 1.2 (3

H, d, J 6.5, 5-CH₃), 1.18 (3 H, t, J 7.25, OCH₂CH₃), 1.8 (1 H,

d, J 3, 3-OH), 1.85 (2 H, m, 6-H₂), 2.12 [3 H, s, OC(O)CH₃],

2.2 (1 H, m, 5-H), 3.34 (1 H, dd, J 12, 5, 1-H), 3.88 (1 H, t, J

3, 3-H), 4.08 (2 H, qd, J 7.25, 1.5, OCH₂CH₃), 4.52 (1 H, s,

2-OH), 5.22 (1 H, dd, J 11, 3, 4-H), 6.38 (1 H, d, J 1.5, 4^ꢀ-H)

and 7.75 (1 H, d, J 1.5, 5^ꢀ-H); m/z (EI) 398 (M⁺, 7%), 383 (38),

323 (14), 321 (11), 305 (22) and 91 (100).

Ethyl (1RS,2SR,3SR,4SR,5SR)-5-methyl-2,3,4-trihydroxy-2-

(2-trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 27 and ethyl

(1RS,2SR,3SR,4RS,5SR)-5-methyl-2,3,4-trihydroxy-2-

(2-trimethylsilyl-3-furyl)-cyclohexane-1-carboxylate 28

Tetramethylammonium triacetoxyborohydride (170 mg,

0.65 mmol) was added to a solution of hydroxy ketone 26

(120 mg, 0.32 mmol) in acetonitrile (1 cm³) and acetic acid

(1 cm³) and the mixture was stirred for 1 h. The solvents

were removed under reduced pressure and chromatography

of the residue, using light petroleum–ether (1 : 1) as eluant,

gave the title compound 27 (62 mg, 51%), as a white solid, mp

124–125 ^◦C. (Found: C, 57.3; H, 8.0. C₁₇H₂₈O₆Si requires C,

57.3; H, 7.92%); m_max(CHCl₃) 3402, 1710, 1462, 1377, 1150, 1116

and 1064 cm⁻¹; d_H(300 MHz, CDC1₃) 0.3 [9 H, s, Si(CH₃)₃],

1.05 (3 H, t, J 7.5, OCH₂CH₃), 1.15 (3 H, d, J 6, 5-CH₃), 1.65

(1 H, m, 6-H), 1.8 (1 H, m, 5-H), 1.95 (1 H, q, J 12.5, 6-H^ꢀ),

2.5 (1 H, d, J 7.5, 3-OH), 2.82 (1 H, dd, J 12.5, 4.5, 1-H), 3.4

(1 H, dd, J 7.5, 2.7 Hz, 3-H), 3.57 (1 H, d, J 9.5, 4-OH), 3.9 (1

H, dt, J 9.5, 2.7 Hz, 4-H), 4.0 (2 H, m, CO₂CH₂), 5.08 (1 H, s,

2-OH), 6.15 (1 H, d, J 1.5, 4^ꢀ-H) and 7.58 (1 H, d, J 1.5, 5^ꢀ-H);

m/z (EI) 356 (M⁺, 7%), 323 (10), 267 (22) and 255 (100). On

further elution, the title compound 28 (18 mg, 16%) was isolated

as an oil. [Found (EI): M⁺, 356.1669. C₁₇H₂₈O₆Si requires M,

356.1655]; m_max(CHCl₃) 3400, 1711, 1461, 1377, 1278, 1150,

1104, 1056 and 896 cm⁻¹; d_H(300 MHz, CDCl₃) 0.35 (9 H, s,

TMS), 1.03 (3 H, t, J 7.2, OCH₂CH₃), 1.15 (3 H, d, J 6.5,

5-CH₃), 1.6–1.85 (4 H, m, 6-H₂, 5-H, 3-OH), 2.5 (1 H, s, 4-OH),

2.85 (1 H, m, 1-H), 3.25 (1 H, t, J 9, 4-H), 3.55 (1 H, t, J 9,

3-H), 4.0 (2 H, m, OCH₂CH₃), 4.5 (1 H, s, 2-OH), 6.32 (1 H, d,

J 1.5, 4^ꢀ-H) and 7.49 (1 H, d, J 1.5, 5^ꢀ-H); m/z (EI) 357 (M⁺+

1, 58%), 343 (24), 255 (14) and 245 (32).

Ethyl (1RS,2SR,3RS,4RS,5SR)-4-acetoxy-2-hydroxy-5-

methyl-3-(2-trimethylsilylethoxy)methoxy-2-(2-trimethylsilyl-

3-furyl)cyclohexane-1-carboxylate 31

Hunig^ꢀs base (2.67 g, 20.7 mmol) and SEM chloride (2.06 g,

12.37 mmol) were added to d_◦iol 30 (3.05 g, 7.66 mmol) in

dichloromethane (7.5 cm³) at 0 C and the reaction was stirred

for 16 h. Water (5 cm³) and ether (100 cm³) were added and the

aqueous phase extracted with more ether. The combined organic

extracts were dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue using light petroleum–

ether (2 : 1) as eluant gave the title compound 31 (3.61 g, 90%) as

◦

a solid, mp 71–74 C. [Found (EI): M⁺, 528.2591. C₂₅H₄₄O₈Si₂

requires M, 528.2575]; m_max(CHCl₃) 3468, 1739, 1710, 1463,

1371, 1337, 1292, 1100, 1052 and 1026 cm⁻¹; d_H(300 MHz,

CDCl₃) 0.0 and 0.3 [each 9 H, s, Si(CH₃)₃], 0.8 (2 H, m, CH₂Si),

0.97 (3 H, d, J 6.5, 5-CH₃), 1.13 (3 H, t, J 7, OCH₂CH₃), 1.75 (1

H, q, J 12, 6-H), 1.85 (1 H, m, 6-H), 2.05 [3 H, s, OC(O)CH₃],

2.15 (1 H, m, 5-H), 3.22 (2 H, m, 1^ꢀꢀ-H, 1-H), 3.48 (1 H, m,

1^ꢀꢀ-H^ꢀ), 3.8 (1 H, d, J 2.5, 3-H), 4.2 (2 H, m, OCH₂CH₃), 4.42

(1 H, d, J 6.25, OHCHO), 4.41 (1 H, s, 2-OH), 4.46 (1 H, d, J

6.25, OHCHO), 5.17 (1 H, dd, J 11, 2.5, 4-H), 6.28 (1 H, d, J

1.5, 4^ꢀ-H) and 7.45 (1 H, d, J 1.5, 5^ꢀ-H); m/z (FAB) 529 (M⁺+

1, 1%), 513 (0.5), 483 (0.5) and 453 (0.5).

Ethyl (1RS,2SR,4RS,5SR)-4-acetoxy-2-hydroxy-5-methyl-2-

(2-trimethylsilyl-3-furyl)-3-oxocyclohexane-1-carboxylate 29

(1RS,2SR,3RS,4RS,5SR)-2,4-Dihydroxy-5-methyl-3-(2-

trimethylsilylethoxy)methoxy-2-(2-trimethylsilyl-

3-furyl)cyclohexane-1-carboxylic acid 32

Sodium hydroxide (15 M, 0.75 cm³) was added to a solution of

ester 31 (0.5 g, 0.95 mmol) in ethanol (2 cm³) and THF (1 cm³)

and the mixture was stirred for 72 h. The solution was acidiﬁed

to pH 2 by the addition of aqueous hydrogen chloride (3 M). The

mixture was extracted with ether (5 × 25 cm³), dried (MgSO₄)

and concentrated to give title compound 32 as a clear oil.

Dimethyl sulfoxide (0.19 g, 2.39 mmol) in dichloromethane

(1 cm³) followed by alcohol 25 (0.5 g, 1.25 mmol) in

dichloromethane (1 cm³) were added to oxalyl chloride (0.18 g,

1.25 mmol) in dichloromethane (3 cm³) at −78 ^◦C. The mixture

was stirred for 15 min, triethylamine (0.63 g, 6.3 mmol) was

added and the mixture allowed to warm to room temperature.

The mixture was diluted with ether (50 cm³) and washed with

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

3 6 4 5

View Article Online

[Found (EI): M⁺, 458.2178. C₂₁H₃₈O₇Si₂requires M, 458.2156];

m_max(CHCl₃) 3435, 1708, 1382, 1155, 1058 and 1019 cm⁻¹; d_H

(300 MHz, CDCl₃) 0.0 and 0.3 [9 H, s, Si(CH₃)₃], 0.92 (2 H, m,

CH₂Si), 1.1 (3 H, d, J 6, 5-CH₃), 1.6–1.9 (3 H, m, 6-H₂, 5-H), 3.2

(1 H, dd, J 12, 2.5 Hz, 1-H), 3.45 (1 H, m, 1^ꢀꢀ-H), 3.5 (1 H, d, J

2.5, 3-H), 3.7 (2 H, m, 4-H, 1^ꢀꢀ-H), 4.03 (1 H, d, J 6, OHCHO),

4.22 (1 H, s, 2-OH), 4.58 (1 H, d, J 6, OHCHO), 6.28 (1 H, d, J

1.5, 4^ꢀ-H) and 7.5 (1 H, d, J 1.7, 5^ꢀ-H); m/z (CI) 459 (M⁺+ 1,

4%), 413 (3), 411 (2), 383 (6), 341 (10) and 90 (100).

residue using light petroleum–ether (9 : 1) as eluant gave the title

compound 35 (0.782 g, 93%) as a viscous oil, m_max(CHCl₃) 3459,

1738, 1709, 1454, 1381, 1335, 1171, 1102 and 1047 cm⁻¹; d_H

(300 MHz, CDCl₃) −0.8, 0.05 and 0.32 [each 9 H, s, Si(CH₃)₃],

0.78 and 0.89 (each 2 H, m, CH₂Si), 1.03 (3 H, d, J 7, 5-CH₃),

1.68 (1 H, q, J 13.5, 6-H), 1.78 (1 H, dt, J 13.5, 4.5, 6-H^ꢀ), 2.0

(1 H, m, 5-H), 3.12 (1 H, m, 1^ꢀꢀ-H), 3.21 (1 H, dd, J 13, 4, 1-H),

3.38 (3 H, s, OCH₃), 3.33–3.48 (2 H, m, 1^ꢀꢀ-H, 4-H), 3.94 (1 H,

d, J 2.5, 3-H), 4.05 (2 H, m, OCH₂CH₂), 4.22 (1 H, d, J 6.5,

OHCHO), 4.47 (1 H, s, 2-OH), 4.61 (1 H, d, J 6.5, OHCHO),

6.28 (1 H, d, J 1.5, 4^ꢀ-H) and 7.46 (1 H, d, J 1.5, 5^ꢀ-H). All other

data were identical to those of a sample prepared via the acid

52, vide infra.

2-Trimethylsilylethyl (1RS,2SR,3RS,4RS,5SR)-2,4-dihydroxy-

5-methyl-3-(2-trimethylsilylethoxy)methoxy-2-(2-trimethylsilyl-

3-furyl)cyclohexane-1-carboxylate 33

Dicyclohexylcarbodiimide (244 mg, 1.14 mmol) in

dichloromethane (2 cm³) was added to a solution of acid

32 (0.95 mmol), 2-trimethylsilylethanol (0.68 cm³, 4.75 mmol)

and DMAP (trace) in dichloromethane (3 cm³) and the mixture

stirred for 16 h. The mixture was diluted with ether (30 cm³),

washed with saturated aqueous citric acid (10 cm³) and

dried (MgSO₄). After concentration under reduced pressure,

chromatography of the residue using light petroleum–ether (3 :

1) as eluant gave the title compound 33 (0.455 g, 87% based on

31), as a clear oil, m_max(CHCl₃) 3449, 1708, 1460, 1384, 1337,

1173, 1099, 1062 and 1021 cm⁻¹; d_H(300 MHz, CDCl₃) 0.0 [18

H, s, 2 × Si(CH₃)₃], 0.3 [9 H, s, Si(CH₃)₃], 0.9 (4 H, m, 2 ×

CH₂Si), 1.1 (3 H, d, J 6, 5-CH₃), 1.72 (3 H, m, 6-H₂, 5-H), 3.12

(1 H, dd, J 12, 4, 1-H), 3.3 (1 H, d, J 9, 4-OH), 3.45 (1 H, m,

1^ꢀꢀ-H), 3.51 (1 H, d, J 3, 3-H), 3.7 (2 H, m, 4-H, 1^ꢀꢀ-H), 4.03 (3

H, m, OHCHO, OCH₂CH₂), 4.53 (1 H, s, 2-OH), 4.55 (1 H, d,

J 6.5, OHCHO), 6.25 (1 H, d, J 1.5, 4^ꢀ-H), 7.48 (1 H, d, J 1.5,

5^ꢀ-H); m/z (FAB) 559 (M⁺+ 1, 0.2%) and 442 (10).

2-Trimethylsilylethyl (1RS,2SR,3RS,4RS,5SR)-4-(1-tert-

butyldimethylsilyloxy)-2-hydroxy-2-[5(RS,SR)-5-hydroxy-2-

oxo-1-oxacyclopent-3-en-3-yl]-5-methyl-3-(2-trimethylsilylethoxy)-

methoxycyclohexane-1-carboxylate 36

A trace of tetraphenylporphine was added to a solution of

furan 34 (0.368 g, 0.55 mmol) in dichloromethane (12.5 cm³)

and methanol (12.5 cm³) and the mixture was cooled to

◦

−78 C. A stream of O₂was bubbled through in the presence

of a sun-lamp for 4 h, then the mixture was allowed to warm

to ambient temperature. After concentration under reduced

pressure, chromatography of the residue using light petroleum–

ether (2 : 1) as eluant gave the title compound 36 (0.33 g, 95%) as

a foamy solid, m_max(CHCl₃) 3442, 1771, 1707, 1463, 1412, 1343,

1286, 1172, 1158, 1089 and 1023 cm⁻¹; d_H(300 MHz, CDCl₃)

−0.9 [9 H, s, Si(CH₃)₃], 0.02 and 0.03 (each 4.5 H, s, 2 × TMS),

0.09 [6 H, s, Si(CH₃)₂], 0.88 [9 H, s, SiC(CH₃)₃], 0.85–1.0 (7 H,

m, 5-CH₃, 2 × CH₂Si), 1.5–1.9 (3 H, m, 6-H₂, 5-H), 3.08 (0.5 H,

dd, J 12, 4, 1-H), 3.3–3.85 (4.5 H, m, 1^ꢀꢀ-H, 5^ꢀ-OH, 3-H, 4-H,

1-H), 4.14 (2 H, m, OCH₂CH₂), 4.31 (0.5 H, s, 2-OH), 4.55 (2.5

H, m, 1^ꢀꢀ-H, OHCHO, 2-OH), 4.85 (1 H, m, OHCHO), 5.95 (1

H, m, 5^ꢀ-H), 7.0 (0.5 H, s, 4^ꢀ-H) and 7.28 (0.5 H, s, 4^ꢀ-H).

2-Trimethylsilylethyl (1RS,2SR,3RS,4RS,5SR)-

4-(tert-butyldimethylsilyloxy)-2-hydroxy-5-methyl-3-

(2-trimethylsilylethoxy)methoxy-2-(2-trimethylsilyl-

3-furyl)cyclohexane-1-carboxylate 34

2,6-Lutidine (0.15 cm³, 1.33 mmol) was added dropwise to solu-

tion of the alcohol 33 (212 mg, 0.38 mmol) in dichloromethane

(4 cm³) at 0 ^◦C, followed by tert-butyldimethylsilyl triﬂate

(0.18 cm³, 0.76 mmol). The mixture was stirred at room

temperature for 3 h before diluting with ether (25 cm³) and

washing with brine (5 cm³). The organic layer was dried (MgSO₄)

and concentrated under reduced pressure. Chromatography of

the residue using light petroleum–ether (10 : 1) as eluant gave the

title compound 34 (0.254 g, 99%) as a clear oil. [Found (CI): M⁺+

H, 673.3835. C₃₂H₆₅O₇Si₄requires M, 673.3808]; m_max(CHCl₃)

3458, 1709, 1463, 1386, 1338, 1173, 1085 and 1031 cm⁻¹; d_H

(300 MHz, CDCl₃) 0.03 [18 H, s, 2 × Si(CH₃)₃], 0.15 [6 H, s,

Si(CH₃)₂], 0.32 [9 H, s, Si(CH₃)₃], 0.75 (4 H, m, 2 × CH₂Si), 0.92

[9 H, s, SiC(CH₃)₃]), 1.0 (3 H, d, J 6.5, 5-CH₃), 1.62 (1 H, q, J

12, 6-H), 1.75 (1 H, dt, J 12, 3, 6-H), 2.05 (1 H, m, 5-H), 3.2 (3

H, m, OCH₂CH₂, 1-H), 3.62 (1 H, d, J 2.25, 3-H), 3.95 (1 H,

dd, J 11.25, 2.25, 4-H), 4.05 (2 H, m, OCH₂CH₂), 4.5 (1 H, s,

2-OH), 4.58 and 4.27 (each 1 H, d, J 6, OHCHO), 6.32 (1 H, d,

J 1.5, 4^ꢀ-H) and 7.45 (1 H, d, J 1.5, 5^ꢀ-H); m/z (FAB) 673 (M⁺+

1, 0.1%), 569 (0.5), 555 (0.75) and 511 (0.5).

2-Trimethylsilylethyl (1RS,2SR,3RS,4RS,5SR)-2-hydroxy-

2-[5(RS,SR)-5-hydroxy-2-oxo-1-oxacyclopent-3-en-3-yl]-4-

methoxy-5-methyl-3-(2-trimethylsilylethoxy)methoxycyclo-

hexane-1-carboxylate 37

Following the procedure outlined for the preparation of hydrox-

ybutenolide 36, the 2-trimethylsilylfuran 35 (110 mg, 0.19 mmol)

gave the title compound 37 (99 mg, 97%) as a mixture of epimers,

m_max(CHCl₃) 3431, 1771, 1704, 1456, 1387, 1338, 1288, 1109,

1059, 1019, 975 and 862 cm⁻¹; d_H(300 MHz, CDCl₃) 0.0 and

0.03 [each 9 H, s, Si(CH₃)₃], 0.8–1.05 (4 H, m, 2 × CH₂Si), 1.03

(3 H, d, J 6, 5-CH₃), 1.5–2.0 (3 H, m, 6-H₂, 5-H), 3.2 (1.5 H, m,

1-H, 4-H), 3.38 (0.5 H, m, 4-H), 3.4 (3 H, s, OCH₃), 3.5 (1 H, m,

1^ꢀꢀ-H), 3.62–3.92 (2 H, m, 3-H, 1^ꢀꢀ-H), 4.15 (2 H, m, OCH₂CH₂),

4.38–4.62 (2 H, m, 2-OH, OHCHO), 4.83 (1 H, m, OHCHO),

6.0 (1 H, d, J 13, 5^ꢀ-H), 7.03 (0.5 H, d, J 1.5, 4^ꢀ-H) and 7.32 (0.5

H, d, J 1.5, 4^ꢀ- H); m/z (FAB) 555 (M⁺+ 23, 2%), 475 (8), 459

(2), 447 (10) and 429 (15).

(2Z,4Z)-2-[(1RS,2SR,3RS,4RS,5SR)-4-tert-

Butyldimethylsilyloxy-2-hydroxy-5-methyl-3-(2-

trimethylsilylethoxy)methoxy-1-(2-trimethylsilylethoxy-

carbonyl)cyclohexan-2-yl]-6-methylhepta-2,4-dienoic acid 38

2-Trimethylsilylethyl (1RS,2SR,3RS,4RS,5SR)-2-hydroxy-4-

methoxy-5-methyl-3-(2-trimethylsilylethoxy)methoxy-2-

(2-trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 35

A solution of lithium hexamethyldisilazide (1 M in hexanes,

0.31 cm³, 0.31 mmol) in THF (1 cm³) was cooled to −78 ^◦C and

added via a cannula to a solution of the hydroxybutenolide 36

(64 mg, 0.1 mmol) and 2-methylpropyl(triphenyl)phosphonium

Cetyltrimethylammonium bromide (CTAB) (0.595 g,

1.61 mmol) and methyl iodide (1.66 cm³) were added to

a solution of the alcohol 33 (0.818 g, 1.47 mmol) in THF (7 cm³)

and the mixture was cooled to 0 ^◦C. LHMDS (1 M in hexanes,

3 cm³, 3 mmol) was added and the reaction mixture was stirred

for 15 min. Water (2 cm³) was added, the mixture extracted with

ether (3 × 25 cm³), and the extracts were dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

◦

iodide (49 mg, 0.12 mmol) in THF (2.5 cm³) at −78 C. Over

◦

1 h, the mixture was slowly warmed to −10 C and stirred at

this temperature for 30 minutes. Saturated aqueous ammonium

chloride (1 cm³) was added and the mixture diluted with

ether (10 cm³). The organic extracts were dried (MgSO₄) and

3 6 4 6

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

View Article Online

concentrated under reduced pressure. Chromatography of the

residue using light petroleum–ether (1 : 1) with 1% acetic acid

as eluant gave the title compound 38 (62 mg, 89%) as a viscous

oil. [Found (EI): M⁺− H, 671.3836. C₃₃H₆₃O₈Si₃requires M,

671.3831]; m_max(CHCl₃) 3856–2400, 2363, 1708, 1640, 1511,

1463, 1388, 1173, 1087, 1029 and 861 cm⁻¹; d_H(300 MHz,

CDCl₃) −0.4 and 0.01 [9 H, s, Si(CH₃)₃], 0.09 and 0.091 (each

3 H, s, 2 × SiCH₃), 0.8–1.0 [22 H, m, SiC(CH₃)₃, 6-CH₃, 7-H₃,

2 × CH₂Si, 5^ꢀ-CH₃), 1.55 (1 H, q, J 12.5, 6^ꢀ-H), 1.8 (1 H, dt, J

12.5, 4 Hz, 6^ꢀ-H^ꢀ), 1.9 (1 H, m, 5^ꢀ-H), 2.82 (1 H, m, 6-H), 3.0

(1 H, dd, J 12.5, 4 Hz, 1^ꢀ-H), 3.5 (2 H, m, 1^ꢀꢀ-H₂), 3.58 (1 H, d,

J 2.5, 3^ꢀ-H), 3.79 (1 H, dd, J 10, 2.5 Hz, 4^ꢀ-H), 4.15 (2 H, m,

OCH₂), 4.81 and 4.83 (each 1 H, d, J 11, HCHO), 4.9 (1 H, s,

2^ꢀ-OH), 5.51 (1 H, t, J 11.5, 5-H), 6.22 (1 H, t, J 11.5, 4-H)

and 6.81 (1 H, d, J 11.5, 3-H); m/z (FAB) 671 (M⁺− 1, 100%)

and 631 (25).

Ethyl (lRS,2SR,3RS,5SR)-3-benzyloxy-2-hydroxy-5-methyl-2-

(2-trimethylsilyl-3-furyl)-4-oxocyclohexane-1-carboxylate 41

The b-ketoester 20 (8.1 g, 31.9 mmol) was dissolved in ethanol

(63 cm³) and aqueous sodium hydroxide (2 M, 2 cm³) was added.

The benzyloxymethyl ketone 5 (6.05 g, 31.9 mmol) in ethanol

(15.4 cm³) was added and stirring was continued for 20 h. The

solvent was removed under reduced pressure and the residue

partitioned between ether (200 cm³) and brine (75 cm³). The

organic layer was dried (MgSO₄), concentrated under reduced

pressure, and the residue puriﬁed by ﬂash chromatography,

using light petroleum–ether (4 : 1) as eluant, to yield the title

compound 41 (7 g, 50%) as a white powder, mp 107–109 ^◦C.

[Found (EI): M⁺, 444.1968. C₂₄H₃₂O₅Si requires M, 444.1965];

m_max(ﬁlm) 3463, 1726, 1497, 1454, 1397, 1378, 1346, 1303, 1274,

1149, 1099 and 1050 cm⁻¹; d_H(300 MHz; CDCl₃) 0.25 [9 H, s,

Si(CH₃)₃], 1.04 (3 H, t, J 7.5, CH₂CH₃), 1.16 (3 H, d, J 7, 5-

CH₃), 2.05–2.19 (2 H, m, 6-H₂), 2.51 (1 H, m, 5-H), 3.22 (1 H,

m, 1-H), 3.86 (1 H, s, 2-OH), 3.12 (1 H, s, 3-H), 3.99 (2 H, m,

CH₂CH₃), 4.25 and 4.67 (each 1 H, d, J 13, PhHCHO), 6.18 (1

H, s, 4^ꢀ-H), 6.92 (2 H, m, ArH), 7.20 (3 H, m, ArH) and 7.56 (1

H, d, J 2 Hz, 5^ꢀ-H); m/z (EI) 444 (M⁺, 2%), 190 (23), 167 (88)

and 91 (100).

(2Z,4E)-2-[(1RS,2SR,3RS,4RS,5SR)-4-tert-

Butyldimethylsilyloxy-2,3-dihydroxy-5-methyl-1-(2-

trimethylsilylethoxycarbonyl)cyclohexan-2-yl]-6-methylhepta-

2,4-dienoic acid 39

Iodine (17 mg, 0.07 mmol) in benzene (0.5 cm³) was added to a

solution of the diene 38 (41 mg, 0.06 mmol) in benzene (1.2 cm³)

and the mixture was stirred for 3 h in the presence of a sun-lamp.

The mixture was then diluted with ether (10 cm³), washed with

saturated aqueous sodium thiosulfate (1 cm³) and the aqueous

phase re-extracted with ether. The combined organic extracts

were dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue using light petroleum–ether (1

: 1) with 1% acetic acid as eluant gave the title compound 39

(23 mg, 70%) as a viscous oil. [Found (EI): M⁺− H, 541.3028.

C₂₇H₄₉O₇Si₂requires M, 541.3017]; m_max(CHCl₃) 3905–2400,

1708, 1639, 1562, 1462, 1342, 1176, 1135, 1069 and 978 cm⁻¹;

d_H(200 MHz, CDCl₃) 0.05 [9 H, s, Si(CH₃)₃], 0.15 [6 H, s,

Si(CH₃)₂], 0.9 [9 H, s, Si(CH₃)₃], 1.05 (11 H, m, 6-CH₃, 7-H₃,

5^ꢀ-CH₃, CH₂Si), 1.75 (3 H, m, 5^ꢀ-H, 6^ꢀ-H₂), 2.4 (1 H, m, 6-H),

3.1 (1 H, dd, J 11.5, 4, 1^ꢀ-H), 3.6 (1 H, d, J 3, 3^ꢀ-H), 3.74 (1 H,

dd, J 10, 3, 4^ꢀ-H), 4.18 (2 H, m, O₂CH₂CH₂), 4.7 (1 H, s, 2^ꢀ-OH),

5.97 (1 H, dd, J 15, 7, 5-H), 6.54 (1 H, ddd, J 15, 11, 1, 4-H) and

6.74 (1 H, d, J 11, 3-H); m/z (FAB) 541 (M⁺− 1, 100%) and

153 (40).

Ethyl (lRS,2SR,3SR,4RS,5SR)-3-benzyloxy-2,4-dihydroxy-5-

methyl-2-(2-trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 42

The hydroxycyclohexanone 41 (3 g, 6.76 mmol) was dissolved

in acetonitrile (24 cm³) and acetic acid (24 cm³) at ambient

temperature and tetramethylammonium triacetoxyborohydride

(14 g, 53.2 mmol) was added. The mixture was stirred for 96 h

and the solvent removed under reduced pressure. The residue

was dissolved in ether (100 cm³), washed with saturated aqueous

sodium hydrogen carbonate (2 × 30 cm³) and the aqueous

phase extracted with ether (3 × 50 cm³). The combined organic

phases were washed with brine (100 cm³), dried (MgSO₄) and

concentrated to give the title compound 42 (2.52 g, 84%) as a

viscous oil. [Found (EI): M⁺, 446.2131. C₂₄H₃₄O₆Si requires M,

446.2125]; m_max(ﬁlm) 3471, 1710, 1455, 1377, 1346, 1249, 1187,

1149, 1100, 1074 and 843 cm⁻¹; d_H(300 Mz; CDCl₃) 0.3 [9 H, s,

Si(CH₃)₃], 1.03 (3 H, t, J 7, CH₂CH₃), 1.1 (3 H, d, J 7, 5-CH₃),

1.58–1.91 (3 H, m, 5-H and 6-H₂), 2.21 (1 H, d, J 1.5, 4-OH),

2.32 (1 H, dd, J 13, 4.5, 1-H), 3.23 (1 H, d, J 9, 3-H), 3.61 (1

H, t, J 9, 4-H), 3.87–4.07 (4 H, m, 2-OH, CH₂CH₃, PhHCHO),

4.18 (1 H, d, J 11, PhHCHO), 6.32 (1 H, s, 4^ꢀ-H), 7.10 (2 H, m,

ArH), 7.29 (3 H, m, ArH) and 7.62 (1 H, s, 5^ꢀ-H); m/z (EI) 446

(M⁺, 0.7%), 250 (32), 174 (53), 167 (28) and 91(100).

2-Trimethylsilylethyl (1SR,2RS,4SR,5RS,6RS,9Z)-

5-tert-butyldimethylsilyloxy-1-hydroxy-4-methyl-9-[(2E)-4-

methylpent-2-enylidene]-8-oxo-7-oxabicyclo[4.3.0]nonane-2-

carboxylate 40

Ethyl (1R,2S,3S,4R,5S)-3-benzyloxy-4-[(2R)-2-ethanoyloxy-2-

phenylethanoyloxy]-2-hydroxy-5-methyl-2-(2-trimethylsilyl-3-

furyl)cyclohexane-1-carboxylate 43 and ethyl (1S,2R,3R,4S,5R)-

3-benzyloxy-4-[(2R)-2-ethanoyloxy-2-phenylethanoyloxy]-2-

hydroxy-5-methyl-2-(2-trimethylsilyl-3-furyl)cyclohexane-1-

carboxylate 44

4-Dimethylaminopyridine (a trace) and dicyclohexylcarbodi-

imide (25 mg, 0.12 mmol) in dichloromethane (1 cm³) were

added to a solution of the hydroxy acid 39 (22 mg, 0.04 mmol)

in dichloromethane (4 cm³) and the mixture was stirred for 3 h.

The reaction mixture was then diluted with ether (10 cm³) and

washed with aqueous saturated citric acid (1 cm³). The organic

extracts were dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue using light petroleum–

ether (3 : 1) as eluant gave the title compound 40 (19 mg, 90%)

as a clear oil. [Found (CI): M⁺+ H, 525.3078. C₂₇H₄₉O₆Si₂

requires M, 525.3068]; m_max(CHCl₃) 3400, 1762, 1704, 1653,

1546, 1463, 1361, 1178, 1140, 1113, 1057 and 987 cm⁻¹; d_H

(300 MHz, CDCl₃) 0.05 [9 H, s, Si(CH₃)₃], 0.1 [6 H, s, Si(CH₃)₂],

0.9 [9 H, s, SiC(CH₃)₃], 1.0 (2 H, m, CH₂Si), 1.12 (9 H, m,

4^ꢀ-CH₃, 5^ꢀ-H₃, 4-CH₃), 1.3 (l H, m, 4-H), 1.55 (1 H, m, 3-H),

1.9 (1 H, m, 3-H^ꢀ), 2.47 (1 H, m, 4^ꢀ-H), 2.65 (1 H, dd, J 13,

3, 2-H), 3.64 (1 H, dd, J 9, 4, 5-H), 4.13 (1 H, d, J 4, 6-H),

4.19 (2 H, m, OCH₂CH₂), 5.35 (1 H, s, 1-OH), 6.06 (1 H, dd,

J 15, 7 Hz, 3^ꢀ-H), 6.53 (1 H, d, J 11, 1^ꢀ-H), 7.2 (1 H, dd,

J 15, 11 Hz, 2^ꢀ-H); m/z (FAB) 525 (M⁺+ 1, 50%), 507 (75)

and 479 (100).

The diol 42 (120 mg, 0.27 mmol), (R)-acetylmandelic acid

(78 mg, 0.41 mmol) and DMAP (1.7 mg, 0.014 mmol) were

dissolved in dichloromethane (1 cm³) at 0 ^◦C, and dicyclo-

hexylcarbodiimide (83 mg, 0.41 mmol) in dichloromethane

(0.5 cm³) was added. The reaction mixture was stirred at ambient

temperature for 16 h, diluted with ether (5 cm³) and ﬁltered

through celite. The solvent was removed under reduced pressure

and the residue chromatographed using light petroleum–ether

(4 : 1) as eluant to yield the title compounds 43 and 44 (107 mg,

64%). Recrystallization of the mixture from hot hexane gave

the less polar isomer 44 (44.8 mg, 42% of the mixture) as white

needles, mp 131–133 ^◦C (82–85 ^◦C phase change). (Found C,

65.8; H, 7.1. C₃₄H₄₂O₉Si requires C, 65.6; H, 6.8%); [a]_D+8.4 (c

0.57 in CHCl₃); m_max(ﬁlm) 3472, 1744, 1706, 1374, 1234, 1209,

1183, 1048 and 843 cm⁻¹; d_H(300 MHz; CDCl₃) 0.12 [9 H, s,

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

3 6 4 7

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Si(CH₃)₃], 0.53 (3 H, d, J 7, 5-CH₃), 1.0 (3 H, t, J 7, CH₂CH₃),

1.51–1.68 (2 H, m, 5-H, 6-H), 1.91 (1 H, q, J 13, 6-H), 2.20 (3

H, s, OAc), 2.72 (1 H, dd, J 13, 4, 1-H), 3.42 (1 H, d, J 9, 3-H),

3.65 (1 H, s, 2-OH), 3.92 (3 H, m, CH₂CH₃, PhHCHO), 4.41 (1

H, d, J 10.5, PhHCHO), 5.13 (1 H, t, J 9, 4-H), 5.95 (1 H, s, 2^ꢀꢀ-

H), 6.31 (1 H, d, J 2, 4^ꢀ-H), 6.90–7.45 (10 H, m, ArH) and 7.65

(1 H, d, J 2, 5^ꢀ-H); m/z (El) 622 (M⁺, 0.5%), 174 (75), 167 (26)

and 91 (100). Chromatography of the mother liquor, using light

petroleum–ether (4 : 1) as eluant gave the more polar isomer 43

as a white crystalline solid, mp 130–132 ^◦C. (Found: C, 65.6;

H, 7.3. C₃₄H₄₂O₉Si requires C, 65.6; H, 6.8%); [a]_D−84 (c 0.83

in CHCl₃); m_max(ﬁlm) 3468, 1743, 1712, 1456, 1374, 1349, 1235,

1209, 1182, 1049 and 843 cm⁻¹; d_H(300 MHz; CDCl₃) 0.0 [9

H, s, Si(CH₃)₃], 1.01 (3 H, t, J 7.5, CH₂CH₃), 1.08 (3 H, d, J 7,

5-CH₃), 1.70–1.90 (2 H, m, 5-H, 6-H), 1.98 (1 H, q, J 13, 6-H^ꢀ),

2.20 (3 H, s, OAc), 2.77 (1 H, dd, J 13, 4, 1-H), 3.30 (1 H, d,

J 9, 3-H), 3.39 and 3.48 (each 1 H, d, J 10.5, PhHCHO), 3.58

(1 H, s, 2-OH), 3.93 (2 H, m, CH₂CH₃), 5.20 (1 H, t, J 9, 4-H),

5.92 (1 H, s, 2^ꢀꢀ-H), 6.22 (1 H, d, J 2, 4^ꢀ-H), 6.43–7.48 (10 H, m,

ArH) and 7.52 (1 H, d, J 2, 5^ꢀ-H); m/z (EI) 622 (M⁺, 1%), 174

(81), 167 (32) and 91 (100).

Using the diol 42 (690 mg, 1.55 mmol) and (S)-acetylmandelic

acid, the enantiomeric esters ent-43 and ent-44 (0.81 g, 84%)

were obtained. Recrystallization of the mixture (400 mg,

0.643 mmol) from hot hexane gave ent-44 (140 mg, 35%) as a

white crystalline solid, mp 133–135 ^◦C (85–87 ^◦C phase change).

(Found C, 65.3; H, 7.1. C₃₄H₄₃O₉Si requires C, 65.6; H, 6.8%);

[a]_D−7.9 (c 1.01 in CHCl₃); all other data were identical to those

reported for 44. Chromatography of the mother liquor yielded

the more polar isomer ent-43 as a white crystalline solid, mp

128–133 ^◦C. (Found: C, 66.0; H, 7.0. C₃₄H₄₂O₉Si requires C,

65.6; H, 6.8%); [a]_D+77 (c 1.03 in CHCl₃); all other data were

identical to those of 43.

843 cm⁻¹; d_H(300 MHz; CDCl₃) 0.31 [9 H, s, Si(CH₃)₃], 0.91 (3

H, d, J 6, 5-CH₃), 1.06 (3 H, t, J 7.5, CH₂CH₃), 1.58 (1 H, br. s,

3-OH), 1.72–1.93 (3 H, m, 5-H, 6-H₂), 2.82 (1 H, m, 1-H), 3.39

(1 H, d, J 9, 3-H), 3.68 (2 H, s, PhCH₂), 4.0 (2 H, m, CH₂CH₃),

4.48 (1 H, d, J 1.5, 2-OH), 5.03 (1 H, t, J 9, 4-H), 6.20 (1 H, d,

J 2, 4^ꢀ-H), 7.30 (5 H, m, ArH) and 7.56 (1 H, d, J 2, 5^ꢀ-H); m/z

(CI; NH₃) 492 (M⁺+ 18, 16%), 474 (M⁺, 2), 462 (84), 457 (33),

402 (27), 356 (26), 339 (28), 337 (62), 327 (67), 321 (34), 255 (30)

and 249 (100).

Following this procedure, the benzyl ether 45 (2.70 g,

4.8 mmol) gave the diol 46 (2.07 g, 91%).

Ethyl (lRS,2SR,4RS,5SR)-2-hydroxy-5-methyl-4-

phenylethanoyloxy-2-(2-trimethylsilyl-3-furyl)-3-oxo-

cyclohexane-1-carboxylate 47

◦

The diol 46 (2 g, 4.2 mmol) was oxidized at −50 C using the

procedure outlined for alcohol 25 with chromatography using

light petroleum–ether (3 : 1) as eluant to give the title compound

◦

47 (2 g, ca. 100%) as a white crystalline solid, mp 148–150 C.

(Found: C, 63.3; H, 6.8. C₂₅H₃₂O₇Si requires C, 63.55; H, 6.8%);

m_max(ﬁlm) 3444, 1739, 1709, 1457, 1378, 1343, 1249, 1190, 1140

and 843 cm⁻¹; d_H(300 MHz; CDCl₃) 0.25 [9 H, s, Si(CH₃)₃], 1.10

(3 H, d, J 7, 5-CH₃), 1.12 (3 H, t, J 7.5, CH₂CH₃), 1.92–2.10 (2

H, m, 5-H, 6-H), 2.26 (1 H, q, J 13, 6-H^ꢀ), 3.02 (1 H, dd, J 13,

4, 1-H), 3.72 (2 H, s, PhCH₂), 4.07 (2 H, m, CH₂CH₃), 4.83 (1

H, s, 2-OH), 5.68 (1 H, d, J 11, 4-H), 6.19 (1 H, d, J 2, 4^ꢀ-H),

7.18 (5 H, m, ArH) and 7.57 (1 H, d, J 2, 5^ꢀ-H); m/z (CI; NH₃)

490 (M⁺+ 18, 40%), 473 (M⁺+ 1, 39), 400 (32), 383 (36), 337

(76) and 247 (100).

Ethyl (lRS,2SR,3RS,4RS,5SR)-2,3-dihydroxy-5-methyl-4-

phenylethanoyloxy-2-(2-trimethylsilyl-3-furyl)cyclohexane-1-

carboxylate 48

Ethyl (1RS,2SR,3SR,4RS,5SR)-3-benzyloxy-2-hydroxy-5-

methyl-4-phenylethanoyloxy-2-(2-trimethylsilyl-3-

furyl)cyclohexane-1-carboxylate 45

The ketone 47 (2 g, 4.24 mmol) was dissolved in acetonitrile

(15 cm³) and acetic acid (15 cm³). Tetramethylammonium

triacetoxyborohydride (5 g, 19 mmol) was added and the mixture

stirred for 16 h. Work-up as outlined for the preparation of

diol 42, with chromatography using light petroleum–ether (4

: 1) as eluant, gave the title compound 48 (1.99 g, 99%) as a

white crystalline solid, mp 90–92 ^◦C. (Found C, 63.2; H, 7.3.

C₂₅H₃₄O₇Si requires C, 63.25; H, 7.20%); m_max(ﬁlm) 3465, 1730,

1709, 1260, 1186, 1097, 1016, 841 and 799 cm⁻¹; d_H(300 MHz;

CDCl₃) 0.30 [9 H, s, Si(CH₃)₃], 0.91 (3 H, d, J 7, 5-CH₃), 1.11

(3 H, t, J 7.5, CH₂CH₃), 1.65 (1 H, br. s, 3-OH), 1.81 (2 H, m,

6-H₂), 2.13 (1 H, m, 5-H), 3.25 (1 H, dd, J 13, 7, 1-H), 3.65 (2

H, s, PhCH₂), 3.80 (1 H, d, J 2, 3-H), 4.01 (2 H, m, CH₂CH₃),

4.46 (1 H, s, 2-OH), 5.16 (1 H, dd, J 11, 2, 4-H), 6.31 (1 H, s,

4^ꢀ-H), 7.30 (5 H, m, ArH) and 7.52 (1 H, s, 5^ꢀ-H); m/z (EI) 474

(M⁺, 6%), 459 (22), 255 (64), 167 (30), 137 (34) and 91 (100).

Following the procedure outlined for the preparation of esters

43 and 44, the diol 42 (2.5 g, 5.6 mmol) and phenylacetic acid

(1.14 g, 8.38 mmol) gave the title compound 45 (2.70 g, 85%)

as a white crystalline solid, after chromatography using light

petroleum–ether (4 : 1) as eluant, mp 81–83 ^◦C. (Found: C,

68.2; H, 7.2; M⁺, 564.2548. C₃₂H₄₀O₇Si requires C, 68.05; H,

7.15%; M, 564.2543); m_max(ﬁlm) 3464, 1736, 1708, 1250, 1188

and 842 cm⁻¹; d_H(300 MHz; CDCl₃) 0.18 [9 H, s, Si(CH₃)₃], 0.9

(3 H, d, J 6, 5-CH₃), 1.01 (3 H, t, J 7.5, CH₂CH₃), 1.73 (2 H, m,

5-H and 6-H), 1.97 (1 H, q, J 13, 6-H^ꢀ), 2.80 (1 H, dd, J 13, 4,

1-H), 3.39 (1 H, d, J 9, 3-H), 3.47 (2 H, s, PhCH₂), 3.72 (1 H, s,

2-OH), 3.95 (4 H, m, CH₂CH₃and PhCH₂O), 5.18 (1 H, t, J 9,

4-H), 6.30 (1 H, s, 4^ꢀ-H), 6.9–7.22 (10 H, m, ArH) and 7.61(1

H, d J 2, 5^ꢀ-H); m/z (EI) 564 (M⁺, 0.1%), 174 (29) and 91 (100);

(CI; NH₃) 582 (M⁺+ 18, 100%).

Ethyl (lRS,2SR,3RS,4RS,5SR)-2-hydroxy-5-methyl-4-

phenylethanoyloxy-3-(2-trimethylsilylethoxy)methoxy-2-

(2-trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 49

Ethyl (lRS,2SR,3SR,4RS,5SR)-2,3-dihydroxy-5-methyl-4-

phenylethanoyloxy-2-(2-trimethylsilyl-3-furyl)cyclohexane-1-

carboxylate 46

The diol 48 (1 g, 2.1 mmol) and diisopropylethylamine (1 cm³,

◦

5.75 mmol) were dissolved in dichloromethane (2 cm³) at 0 C

A mixture of the esters 43 and 44 (400 mg, 0.64 mmol)

was dissolved in ethanol (10 cm³) with a suspension of 10%

palladium on charcoal (68 mg, 0.064 mmol). The mixture

was stirred vigorously under an atmosphere of hydrogen until

complete consumption of starting material (several days). The

reaction mixture was diluted with dichloromethane (20 ml),

ﬁltered through celite, and the ﬁlter cake was washed with

dichloromethane (3 × 10 cm³). The solvent was removed under

reduced pressure and chromatography of the residue, using light

petroleum–ether (4 : 1) as eluant, gave the title compound 46

(220 mg, 73%) as a white crystalline solid, mp 102–103 ^◦C.

(Found: C, 63.0; H, 7.3. C₂₅H₃₄O₇Si requires C, 63.25; H, 7.20%);

m_max(ﬁlm) 3460, 1735, 1709, 1379, 1250, 1188, 1044, 1003 and

and 2-trimethylsilylethoxymethyl chloride (0.6 cm³, 3.39 mmol)

was added. The reaction mixture was stirred for 16 h at ambient

temperature, quenched with water (2 cm³) and diluted with

ether (5 cm³). The aqueous layer was extracted with ether

(3 × 5 cm³) and the combined organic phases washed with

brine (10 cm³), dried (MgSO₄), and concentrated under reduced

pressure. Chromatography of the residue using light petroleum–

ether (10 : 1) as eluant, gave the title compound 49 (1.16 g,

91%) as a viscous oil. [Found (EI): M⁺, 604.2898. C₃₁H₄₈O₈Si₂

requires M, 604.2888]; m_max(ﬁlm) 3467, 1737, 1710, 1250, 1186,

1156, 1098, 1013 and 839 cm⁻¹; d_H(300 MHz; CDCl₃) 0.0

[9 H, s, Si(CH₃)₃], 0.31 (9 H, s, 2^ꢀ-TMS), 0.81 (2 H, m, CH₂Si),

0.83 (3 H, d, J 7, 5-CH₃), 1.13 (3 H, t, J 7, CH₂CH₃), 1.77

3 6 4 8

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

View Article Online

(2 H, m, 6-H₂), 2.12 (1 H, m, 5-H), 3.19 (1 H, m, 1^ꢀꢀ-H), 3.25 (1

H, dd, J 9, 4, 1-H), 3.43 (1 H, m, 1^ꢀ-H), 3.64 (2 H, s, PhCH₂),

3.79 (1 H, d, J 3, 3-H), 4.02 (2 H, q, J 7, CH₂CH₃), 4.09 and

4.37 (each 1 H, d, J 6, OHCHO), 4.38 (1 H, s, 2-OH), 5.15 (1

H, dd, J 11, 3, 4-H), 6.28 (1 H, d, J 2, 4^ꢀ-H), 7.30 (5 H, m, ArH)

and 7.46 (1 H, d, J 2, 5^ꢀ-H); m/z. (EI) 604 (M⁺, 5%), 413 (53),

337 (48), 277 (43), 249 (57), 193 (27), 167 (37), 156 (85), 91 (92)

and 73 (100).

2-Trimethylsilylethyl (1RS,2SR,3RS,4RS,5SR)-2-hydroxy-4-

methoxy-5-methyl-3-(2-trimethylsilylethoxy)methoxy-2-(2-

trimethylsilyl-3-furyl)cyclohexane-1-carboxylate 35 via acid 52

The ethyl ester 51 (1.55 g, 3.1 mmol) was dissolved in ethanol

(10 cm³) and aqueous sodium hydroxide (15 M, 2.16 cm³) diluted

with ethanol (5.5 cm³) was added. The mixture was stirred at

ambient temperature for 48 h then acidiﬁed to pH 2 with aqueous

hydrogen chloride (3 M). The aqueous phase was extracted

with ethyl acetate (5 × 25 cm³) and the combined organic

phase washed with brine (2 × 30 cm³), dried (MgSO₄), and

concentrated under reduced pressure. Azeotropic distillation

with benzene (3 × 50 cm³) gave the carboxylic acid 52 (1.45 g,

99%) as a sticky gum; m_max(ﬁlm) 3600–2400, 1711, 1249, 1183,

1155, 1104, 1058, 1020 and 840 cm⁻¹; d_H(300 MHz; CDCl₃)

0.02 [9 H, s, Si(CH₃)₃], 0.31 [9 H, s, 2^ꢀ-Si(CH₃)₃], 0.76 (2 H, m,

CH₂Si), 1.03 (3 H, d, J 7, 5-CH₃), 1.65 (1 H, q, J 13, 6-H), 1.87

(1 H, dt, J 13, 4.5, 6-H), 1.98 (1 H, m, 5-H), 3.11 (1 H, m, 1^ꢀꢀ-H),

3.28 (1 H, dd, J 13, 4.5, 1-H), 3.35 (1 H, m, 4-H), 3.38 (3 H, s,

4-OCH₃), 3.43 (1 H, m, 1^ꢀ-H), 3.91 (1 H, d, J 2, 3-H), 4.10 (1

H, s, 2-OH), 4.20 and 4.61 (each 1 H, d, J 7, OHCHO), 6.29 (1

H, d, J 1.5, 4^ꢀ-H) and 7.49 (1 H, d, J 1.5, 5^ꢀ-H); m/z (FAB) 495

(M⁺+ 23, 2%), 472 (M⁺, 4), 247 (36), 226 (93), 203 (25), 175 (26)

and 167 (100).

Ethyl (lRS,2SR,3RS,4RS,5SR)-2,4-dihydroxy-5-methyl-3-

(2-trimethylsilylethoxymethoxy)-2-(2-trimethylsilyl-

3-furyl)cyclohexane-1-carboxylate 50

The ester 49 (3.6 g, 5.96 mmol) was dissolved in ethanol (51 cm³)

and anhydrous potassium carbonate (8 g, 57.9 mmol) was

added. The mixture was stirred at ambient temperature for 48 h,

the solvent removed under reduced pressure, and the residue

partitioned between ether (100 cm³) and water (50 cm³). The

aqueous phase was extracted with ether (3 × 30 cm³) and the

combined organic phases were washed with brine (50 cm³), dried

(MgSO₄) and concentrated. Chromatography of the residue

using light petroleum–ether (20 : 1 then 4 : 1) as eluant, gave

the title compound 50 (2.03 g, 70%) as a white crystalline solid,

mp 83–85 ^◦C. (Found: C, 56.95; H, 8.9. C₂₃H₄₂O₇Si₂requires C,

56.75; H, 8.7%); m_max(ﬁlm) 3457, 1709, 1376, 1250, 1185, 1099,

1061, 1020 and 841 cm⁻¹; d_H(300 MHz; CDCl₃) 0.01 [9 H, s,

Si(CH₃)₃], 0.31 (9 H, s, 2^ꢀ-TMS), 0.92 (2 H, m, CH₂TMS), 1.11

(3 H, d, J 7, 5-CH₃), 1.12 (3 H, t, J 7, CH₂CH₃), 1.75 (3 H, m,

5-H, 6-H₂), 3.18 (1 H, m, 1-H), 3.33 (1 H, d, J 9, 4-OH), 3.45 (1

H, m, 1^ꢀꢀ-H), 3.51 (1 H, d, J 3, 3-H), 3.71 (2 H, m, 4-H, 1^ꢀꢀ-H),

4.01 (2 H, q, J 7, CH₂CH₃), 4.04 (1 H, d, J 5.5, OHCHO), 4.48

(1 H, s, 2-OH), 4.57(1 H, d, J 5.5, OHCHO), 6.28 (1 H, d, J 1.5,

4^ꢀ-H) and 7.5 (1 H, d, J 1.5, 5^ꢀ-H); m/z (EI) 486 (M⁺, 1%), 370

(25), 267 (35), 249 (37), 167 (39) and 156 (100). Some of the ester

49 (1.08 g, 30%) was recovered and resubjected to the reaction

conditions to yield further alcohol 50 (500 mg, 17%; total yield

2.53 g, 87%).

Acid 52 (1.4 g, 2.9 mmol), 2-trimethylsilylethanol (2.12 cm³,

14.8 mmol) and DMAP (18 mg, 0. 15 mmol) were dissolved in

dichloromethane (10 cm³) at 0 ^◦C, and dicyclohexylcarbodiimide

(737 mg, 3.6 mmol) in dichloromethane (6.6 cm³) was added.

Stirring was continued at ambient temperature for 16 h and

the reaction mixture diluted with ether (30 cm³) and washed

with water (15 cm³). The aqueous phase was extracted with

ether (3 × 15 cm³) and the combined organic phases washed

with brine (20 cm³), dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue using light

petroleum–ether (10 : 1) as eluant gave the title compound 35

(1.35 g, 80%) as a viscous oil. [Found (CI): M⁺+ H, 573.3072.

C₂₇H₅₃O₇Si₃requires M, 573.3099]; m_max(ﬁlm) 3464, 1708, 1250,

1172, 1106, 1036 and 839 cm⁻¹; m/z (FAB) 573 (M⁺+ 1,

0.2%), 226 (7), 167 (7) and 73 (100). All other data were

identical to those of a sample prepared from the alcohol 33,

vide supra.

Ethyl (lRS,2SR,3RS,4RS,5SR)-2-hydroxy-4-methoxy-5-

methyl-3-(2-trimethylsilylethoxymethoxy)-2-(2-trimethylsilyl-

3-furyl)cyclohexane-1-carboxylate 51

To silver nitrate (16 g, 94 mmol) in water (80 cm³) was added

aqueous sodium hydroxide (4 M, 160 cm³) and the mixture

stirred in the absence of light for 0.5 h. The mixture was ﬁltered

and the brown powder washed with water (200 cm³), acetone

(200 cm³) and ether (400 cm³) before being dried under reduced

pressure in the dark for 48 h to give silver oxide (10 g, 92%).

The alcohol 50 (2.5 g, 4.12 mmol) was dissolved in methyl

iodide (78 cm³) which had been dried by passing through silica

gel and silver(I) oxide (7.42 g, 32.2 mmol) was added. The

mixture was stirred while heating under reﬂux in the absence of

light for 48 h then cooled and ﬁltered through celite. The residue

was washed with ether and the organic extracts combined and

concentrated under reduced pressure. Chromatography using

light petroleum–ether (20 : 1 then 4 : 1) as eluant, gave the title

compound 51 (1.59 g, 62%) as a white crystalline solid, mp 52–

(2Z,4Z,8E)-10-[(1RS,3RS)-1-tert-Butyldimethylsilyloxycy-

clohexan-3-yl]-2-[(1RS,2SR,3RS,4RS,5SR)-2-hydroxy-4-

methoxy-5-methyl-1-(2-trimethylsilylethoxycarbonyl)-3-(2-

trimethylsilylethoxy)methoxycyclohexan-2-yl]-8-methyldeca-

2,4,8-trienoic acid 54 and (2Z,4Z,8E)-10-[(1SR,3SR)-1-tert-

butyldimethylsilyloxycyclohexan-3-yl]-2-[(1RS,2SR,3RS,4RS,

5SR)-2-hydroxy-4-methoxy-5-methyl-1-(2-trimethylsilylethoxy-

carbonyl)-3-(2-trimethylsilylethoxy)methoxycyclohexan-2-yl)-8-

methyldeca-2,4,8-trienoic acid 56

Following the procedure outlined for the synthesis of the diene

38, the racemic hydroxybutenolide 37 (0.254 g, 0.48 mmol) and

racemic phosphonium salt 53 (0.4 g, 0.57 mmol) gave a mixture

of the title compounds 54 and 56 (0.353 g, 90%) together with

their (4E)-isomers, ratio ca. 90 : 10, as a viscous oil. [Found

(CI): M⁺− H, 823.5039. C₄₃H₇₉O₉Si₃requires M, 823.5032];

m_max(CHCl₃) 3800–2400, 1710, 1463, 1386, 1172, 1098, 1030 and

861 cm⁻¹; d_H(300 MHz, CDCl₃) (4Z)-isomers: −0.9 and 0.02

[each 9 H, s, Si(CH₃)₃], 0.04 [6 H, Si(CH₃)₂], 0.8 (1 H, m, 2^ꢀ-

H_ax), 0.9 [9 H, s, SiC(CH₃)₃], 0.9–1.0 (4 H, m), 1.05 (3 H, d, J 6,

5^ꢀꢀ-CH₃), 1.1–1.38 (6 H, m, 2 × CH₂Si, 2 × CH), 1.63 (3 H, s,

8-CH₃), 1.5–1.9 (5 H, m), 1.95 (2 H, m, 10-H₂), 2.08 (2 H, m,

7-H₂), 2.33 (2 H, m, 6-H₂), 3.05 (1 H, dd, J 12.5, 4, 1^ꢀꢀ-H), 3.25

(1 H, dd, J 11, 2, 4^ꢀꢀ-H), 3.43 (3 H, s, OCH₃), 3.55 (3 H, m, 1^ꢀ-H,

OCH₂CH₂Si), 3.91 (1 H, d, J 2, 3^ꢀꢀ-H), 4.18 (2 H, m, OCH₂CH₂),

4.73 and 4.8 (each 1 H, d, J 6, OHCHO), 4.8 (1 H, s, 2^ꢀꢀ-OH),

5.18 (1 H, t, J 7.5, 9-H), 5.72 (1 H, m, 5-H), 6.35 (1 H, t, J 11.5,

◦

54 C. (Found: C, 57.55; H, 8.9; M⁺, 500.2624. C₂₄H₄₄O₇Si₂

requires C, 57.55, H, 8.85%; M, 500.2625); m_max(ﬁlm) 3468,

1710, 1376, 1240, 1183, 1106 1032 and 841 cm⁻¹; d_H(300 MHz;

CDCl₃) 0.02 (9 H, s, TMS), 0.32 (9 H, s, 2^ꢀ-TMS), 0.76 (2 H,

m, CH₂TMS), 1.04 (3 H, d, J 7, 5-CH₃), 1.13 (3 H, t, J 7,

CH₂CH₃), 1.67 (1 H, q, J 12.5, 6-H), 1.80 (1 H, dt, J 12.5, 4.5,

6-H^ꢀ), 1.97 (1 H, m, 5-H), 3.12 (1 H, m, 1^ꢀꢀ-H), 3.25 (1 H, dd, J

12.5, 4.5, 1-H), 3.40 (3 H, s, 4-OCH₃), 3.32–3.48 (2 H, m, 4-H,

1^ꢀꢀ-H), 3.92 (1 H, d, J 3, 3-H), 4.02 (2 H, q, J 7, CH₂CH₃), 4.22

(1 H, d, J 5.5, OHCHO), 4.4 (1 H, s, 2-OH), 4.62 (1 H, d, J

5.5, OHCHO), 6.30 (1 H, d, J 1.5, 4^ꢀ-H and 7.48 (1 H, d, J

1.5, 5^ꢀ-H); m/e (EI) 500 (M⁺, 1%), 231 (35), 179 (24), 167 (36),

156 (65) and 73 (100). Some alcohol 50 (0.53 g, 21%) was also

recovered.

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

3 6 4 9

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4-H) and 6.85 (1 H, d, J 11.5, 3-H); (4E)-isomers: 5.95 (1 H, dt,

J 15, 6, 5-H) and 6.55 (2 H, m, 3-H, 4-H); m/z (FAB) 823 (M⁺−

1, 100%), 723 (25) and 661 (30).

2-Trimethylsilylethyl (1SR,2RS,4SR,5RS,6RS,9Z)-9-{(2E,6E)-

8-[(1RS,3RS)-1-tert-butyldimethylsilyloxycyclohexan-3-yl]-6-

methylocta-2,6-dienylidene}-1-hydroxy-5-methoxy-4-methyl-8-

oxo-7-oxa-bicyclo[4.3.0]nonane-2-carboxylate 60 and 2-

trimethylsilylethyl (1SR,2RS,4SR,5RS,6RS,9Z)-9-{(2E,6E)-8-

[(1SR,3SR)-1-tert-butyldimethylsilyloxycyclohexan-3-yl]-6-

methylocta-2,6-dienylidene}-1-hydroxy-5-methoxy-4-methyl-8-

oxo-7-oxabicyclo[4.3.0]nonane-2-carboxylate 61

(2Z,4Z,8E)-l0-[(1RS,3RS)-l-tert-Butyldimethylsilyloxycy-

clohexan-3-yl[-2-[(1RS,2SR,3RS,4RS,5SR)-2,3-dihydroxy-4-

methoxy-5-methyl-1-(2-trimethylsilylethoxycarbonyl)cyclohexan-

2-yl]-8-methyldeca-2,4,8-trienoic acid 55 and (2Z,4Z,8E)-l0-

[(1SR,3SR)-tert-butyldimethylsilyloxycyclohexan-3-yl]-2-

[(1RS,2SR,3RS,4RS,5SR)-2,3-dihydroxy-4-methoxy-5-methyl-

1-(2-trimethylsilylethoxycarbonyl)cyclohexan-2-yl]-8-

methyldeca-2,4,8-trienoic acid 57

Iodine (1.5 mg, 5.9 × 10⁻³mmol) in benzene (0.3 cm³) was added

to a solution of the lactones 58 and 59 (77 mg, 0.12 mmol)

in benzene (9 cm³) with potassium carbonate (80 mg) and the

reaction stirred in the presence of a sun-lamp for 3 h. The mixture

was diluted with ether (25 cm³), washed with saturated aqueous

sodium thiosulfate (2 cm³) and the aqueous phase was extracted

with ether. The combined organic extracts were dried (MgSO₄)

and concentrated under reduced pressure. Chromatography of

the residue using light petroleum–ether (6 : 1) as eluant gave

a mixture of the title compounds 60 and 61 (57 mg, 75%) as

a viscous oil. [Found (CI): M⁺+ H, 677.4250. C₃₇H₆₅O₇Si₂

requires M, 677.4269]; m_max(CHCl₃) 3428, 1761, 1703, 1651,

1463, 1379, 1175, 1099, 1056 and 975 cm⁻¹; d_H(300 MHz,

CDCl₃) 0.05 (9 H, s, TMS), 0.08 [6 H, s, Si(CH₃)₂], 0.8 (1 H,

m, 2^ꢀꢀ-H_ax), 0.9 [9 H, s, SiC(CH₃)₃], 0.85–1.05 (6 H, m, CH₂Si,

4 × CH), 1.1 (3 H, d, J 6, 4-CH₃), 1.2 (2 H, m), 1.6 (3 H, s, 6^ꢀ-

CH₃), 1.5–1.8 (1 H, m), 1.85 (6 H, m), 2.1 (2 H, t, J 7.5, 5^ꢀ-H₂),

2.3 (2 H, m, 4^ꢀ-H₂), 2.6 (1 H, dd, J 12, 2, 2-H), 3.2 (1 H, dd, J

11, 3.5, 5-H), 3.5 (3 H, s, OCH₃), 3.52 (1 H, m, 1^ꢀꢀ- H), 4.2 (2 H,

m, OCH₂CH₂), 4.4 (1 H, d, J 3.5, 6-H), 5.15 (1 H, t, J 7, 7^ꢀ-H),

5.5 (1 H, s, 1-OH), 6.1 (1 H, dt, J 15, 7.5, 3^ꢀ-H), 6.55 (1 H, d, J

11, 1^ꢀ-H) and 7.25 (1 H, dd, J 15, 11, 2^ꢀ-H); m/z 677 (M⁺+ 1,

5%), 659 (5), 619 (10) and 499 (20). Minor amounts, ca. 1–2%,

of the (2^ꢀZ)-isomers 58 and 59 were detected by ¹H NMR.

Potassium carbonate (70 mg) was added to a solution of the 2-

trimethylsilylethoxymethyl ethers 54 and 56 (67 mg, 0.08 mmol)

in ether (1 cm³) and the mixture was stirred vigorously. An

ethereal solution of magnesium bromide (1 M, 0.66 cm³,

0.66 mmol) was added, followed by n-butanethiol (29 mg,

0.33 mmol) and the reaction was stirred for 10 min. Water (1 cm³)

was added, the mixture diluted with ether (10 cm³) and the

aqueous phase extracted with ether (3 × 5 cm³). The combined

organic extracts were dried (MgSO₄), and concentrated under

reduced pressure. Chromatography of the residue using light

petroleum–ether (2 : 1) and 1% acetic acid as eluant gave a

mixture of the title compounds 55 and 57 (50 mg, 88%) together

with their (4E)-isomers, ratio ca. 90 : 10, as a viscous oil. [Found

(CI): M⁺− H, 693.4230. C₃₇H₆₅O₈Si₂requires M, 693.4218];

m_max(CHCl₃) 3583–2400, 1707, 1627, 1450 and 1097 cm⁻¹; d_H

(300 MHz, CDCl₃) (4Z)-isomers: −0.9 (9 H, s, TMS), 0.07[6

H, s, Si(CH₃)₂], 0.8 (1 H, m, 2^ꢀ-H_ax), 0.9 [9 H, s, SiC(CH₃)₃], 1.05

(3 H, d, J 6, 5^ꢀꢀ-CH₃), 0.85–1.4 (8 H, m, CH₂Si, 6 × CH), 1.62 (3

H, s, 8-CH₃), 1.5–1.88 (6 H, m), 1.91 (2 H, m, 10-H₂), 2.1 (2 H,

t, J 7.5, 7-H₂), 2.49 (2 H, m, 6-H₂), 3.15 (1 H, dd, J 12, 4, 1^ꢀꢀ-H),

3.23 (1 H, dd, J 10, 2.5, 4^ꢀꢀ-H), 3.47 (3 H, s, OCH₃), 3.55 (1 H,

m, 1^ꢀ-H), 3.9 (1 H, d, J 2.5, 3^ꢀꢀ-H), 4.2 (2 H, m, OCH₂CH₂), 4.72

(1 H, br. s, 2^ꢀ-OH), 5.18 (1 H, t, J 7.5, 9-H), 5.75 (1 H, m, 5-H),

6.43 (1 H, t, J 11.5, 4-H), 7.1 (1 H, d, J 11.5, 3-H); (4E)-isomers:

5.98 (1 H, dt, J 15, 6, 5-H), 6.57 (1 H, dd, J 15, 12, 4-H) and

6.74 (1 H, d, J 12, 3-H); m/z (FAB) 694 (M⁺, 100%), 676 (5) and

594 (10).

(1SR,2RS,4SR,5RS,6RS,9Z)-9-{(2E,6E)-8-[(1RS,3RS)-1-

hydroxycyclohexan-3-yl]-6-methylocta-2,6-dienylidene}-1-

hydroxy-5-methoxy-4-methyl-8-oxo-7-oxabicyclo[4.3.0]nonane-

2-carboxylic acid 62 and (1SR,2RS,4SR,5RS,6RS,9Z)-9-

{(2E,6E)-8-[(1SR,3SR)-1-hydroxycyclohexan-3-yl]-6-

methylocta-2,6-dienylidene}-1-hydroxy-5-methoxy-4-methyl-8-

oxo-7-oxabicyclo[4.3.0]nonane-2-carboxylic acid 63

Tetrabutylammonium ﬂuoride (1 M in THF, 0.19 cm³,

0.19 mmol) was added to a solution of the esters 60 and 61

(30 mg, 0.04 mmol) in THF (0.5 cm³) and the mixture stirred at

ambient temperature for 16 h. Aqueous hydrogen chloride (3 M,

0.3 cm³) and chloroform (10 cm³) were added and the aqueous

phase extracted with more chloroform. The organic extracts

were dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue using ethyl acetate containing

acetic acid (1%) as eluant gave the title compounds 62 and 63

(20 mg, 97%) as a viscous oil. [Found (CI): M⁺− H, 461.2545.

C₂₆H₃₇O₇requires M, 461.2539]; m_max(CHCl₃) 3583–2400, 1757,

1710, 1650, 1446, 1396, 1371, 1166, 1099 and 1039 cm⁻¹; d_H

(300 MHz, CDCl₃) 0.8 (1 H, m, 2^ꢀꢀ-H_ax), 0.85–1.0 (4 H, m), 1.1

(3 H, d, J 6, 4-CH₃), 1.15–1.4 (2 H, m), 1.54 and 1.59 (each 1.5

H, s, 6^ꢀ-CH₃), 1.6–2.45 (11 H, m), 2.65 (1 H, m, 2-H), 3.2 (1 H,

dd, J 10, 4, 5-H), 3.45 (3 H, s, OCH₃), 3.62 and 3.75 (each 0.5

H, m, 1^ꢀꢀ-H), 4.42 (1 H, d, J 4, 6-H), 4.9–5.2 (4 H, m, 1^ꢀꢀ-OH,

1-OH, CO₂H, 7^ꢀ-H), 6.05 (1 H, m, 3^ꢀ-H), 6.57 and 6.58 (each 0.5

H, d, J 11, 1^ꢀ-H) and 7.25 (1 H, dd, J 15, 11, 2^ꢀ-H); m/z (FAB)

461 (M⁺− 1, 100%) and 241 (15).

2-Trimethylsilylethyl (1SR,2RS,4SR,5RS,6RS,9Z)-9-{(2Z,6E)-

8-[(1RS,3RS)-1-tert-butyldimethylsilyloxycyclohexan-3-yl]-6-

methylocta-2,6-dienylidene}-1-hydroxy-5-methoxy-4-methyl-8-

oxo-7-oxa-bicyclo[4.3.0]nonane-2-carboxylate 58 and 2-

trimethylsilylethyl (1SR,2RS,4SR,5RS,6RS,9Z)-9-{(2Z,6E)-8-

[(1SR,3SR)-1-tert-butyldimethylsilyloxycyclohexan-3-yl]-6-

methylocta-2,6-dienylidene}-1-hydroxy-5-methoxy-4-methyl-

8-oxo-7-oxabicyclo[4.3.0]nonane-2-carboxylate 59

Following the procedure outlined for the synthesis of the lactone

40, a mixture of the hydroxy acids 55 and 57 (0.29 g, 0.42 mmol)

gave a mixture of the title compounds 58 and 59 together with

their (2^ꢀE)-isomers, ratio ca. 80 : 20, as a viscous oil (0.226 g,

80%). [Found (CI): M⁺+ H, 677.4260. C₃₇H₆₅O₇Si₂requires M,

677.4269]; m_max(CHCl₃) 3425, 1763, 1737, 1703, 1648, 1461, 1386,

1349, 1174, 1115 and 976 cm⁻¹; d_H(300 MHz, CDCl₃) (2^ꢀZ)-

isomers: 0.03 (9 H, s, TMS), 0.09 [6 H, s, Si(CH₃)₂], 0.8 (1 H, m,

2^ꢀꢀ-H_ax), 0.9 [9 H, s, SiC(CH₃)₃], 0.85–1.05 (6 H, m, CH₂Si, 4 ×

CH), 1.1 (3 H, d, J 6, 4-CH₃), 1.15–1.35 (2 H, m), 1.6 (3 H, s,

6^ꢀ-CH₃), 1.5–1.65 (4 H, m), 1.8–2.0 (3 H, m), 2.08 (2 H, t, J 7,

5^ꢀ-H), 2.36 (2 H, m, 4^ꢀ-H), 2.61 (1 H, dd, J 12, 2.5, 2-H), 3.18 (1

H, dd, J 11, 3.5, 5-H), 3.45 (3 H, s, OCH₃), 3.52 (1 H, m, 1^ꢀꢀ-H),

4.18 (2 H, m, OCH₂CH₂), 4.43 (1 H, d, J 4.5, 6-H), 5.16 (1 H,

t, J 7.5, 7^ꢀ-H), 5.58 (1 H, br. s, 1-OH), 5.95 (1 H, m, 3^ꢀ-H), 6.95

(1 H, d, J 12, 1^ꢀ-H) and 7.15 (1 H, t, J 12, 2^ꢀ-H); (2^ꢀE)-isomers:

5.50 (1 H, br. s, 1-OH), 6.1 (1 H, dt, J 15, 7.5, 3^ꢀ-H), 6.55 (1 H,

d, J 11, 1^ꢀ-H) and 7.25 (1 H, dd, J 15, 11, 2^ꢀ-H); m/z (FAB) 677

(M⁺+ 1, 2%), 619 (10) and 499 (6).

(1RS,4SR,8RS,18SR,19RS,20RS,21SR,10E,14E,16Z)-

11,21-Dimethyl-18-hydroxy-20-methoxy-3,25-

dioxatetracyclo[16.4.0.1^4,8.2^17,19]pentacosa-10,14,16-

triene-2,24-dione 64

Triethylamine (7.5 ll, 0.05 mmol) and trichlorobenzoyl chloride

(7 ll, 0.045 mmol) were added to a solution of the hydroxy acids

62 and 63 (20 mg, 0.04 mmol) in anhydrous xylene (4.4 cm³)

3 6 5 0

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

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and the mixture stirred at ambient temperature for 2 days. 4-

Dimethylaminopyridine (11 mg, 0.086 mmol) in xylene (4.4 cm³)

was added and the mixture was stirred for a further hour before

concentrating under reduced pressure. Chromatography of the

residue using light petroleum–ether (1 : 1) as eluant gave the title

compound 64 (5 mg, 26%, 52% based 62) as a solid, mp 176–

178 ^◦C. [Found (CI): M⁺+ H, 445.2565. C₂₆H₃₇O₆requires M,

445.2590]; m_max(CHCl₃) 3437, 1759, 1737, 1698, 1652, 1581, 1549,

1454, 1385, 1315, 1277, 1135, 1099, 1059, 982 and 909 cm⁻¹; d_H

(300 MHz, CDCl₃) 0.65 (1 H, q, J 12, 23-H_ax), 0.8–0.92 (4 H,

m), 1.08 (3 H, d, J 6, 21-CH₃), 1.2–1.4 (4 H, m), 1.5 (3 H, s,

11-CH₃), 1.55–2.05 (5 H, m), 2.1–2.45 (4 H, m), 2.55 (1 H, dd, J

12.5, 3.5, 1-H), 3.2 (1 H, dd, J 11, 4, 20-H), 3.5 (3 H, s, OCH₃),

4.45 (1 H, d, J 4, 19-H), 4.87 (1 H, m, 4-H), 5.0 (1 H, m, 10-H),

5.13 (1 H, s, 18-OH), 5.9 (1 H, m, 14-H), 6.4 (1 H, d, J 11.5,

16-H) and 7.19 (1 H, dd, J 11, 15, 15-H); m/z (FAB) 445 (M⁺+

1, 6%), 427 (3) and 409 (1).

esters 66 and 67 (74 mg, 66%) as a 2 : 1 mixture of (4Z)- and

(4E)-isomers.

This mixture of (4Z)- and (4E)-dienyl esters 66 and 67 (70 mg,

0.071 mmol) was dissolved in degassed benzene (l cm³) and

iodine (0.18 cm³of an 0.2 M solution in benzene) was added. The

reaction mixture was left, without stirring, in sunlight until only

the 4E-isomers were visible by TLC. The solution was diluted

with ether (5 cm³) and washed with saturated aqueous sodium

thiosulfate (5 cm³). The aqueous phase was extracted with ether

(3 × 5 cm³) and the combined organic phases washed with

brine (10 cm³), dried (MgSO₄), and concentrated under reduced

pressure. Chromatography of the residue using light petroleum–

ether (5 : 1) as eluant, gave a mixture of the title compounds

(4E)-66 and (4E)-67 (63 mg, 90%). [Found (FAB): M⁺+ Na,

1003.6192. C₅₂H₉₆NaO₁₁Si₃requires M, 1003.6159]; m_max(ﬁlm)

3467, 1726, 1645, 1385, 1216, 1172, 1090, 1066, 1032, 1011, 861

and 837 cm⁻¹; d_H(300 MHz; CDCl₃) 0.0 and 0.03 [each 9 H, s,

Si(CH₃)₃], 0.06 [6 H, s, Si(CH₃)₂], 0.75 (3 H, d, J 7, 3^ꢀ-CH₃), 0.82

(3 H, d, J 7, CHCH₃), 0.90 [9 H, s, SiC(CH₃)₃], 0.85–1.02 (13 H,

m, CHCH₃, 6-CH₃, 5^ꢀꢀ-CH₃, 2 × CH₂Si), 1.09–1.70 (10 H, m),

1.59 (3 H, s, 8-CH₃), 1.75–1.95 [5 H, m, 9^ꢀ-H, 11^ꢀ-H, CH(CH₃)₂,

7-H₂], 2.05–2.40 (3 H, m, 10-H₂, 6-H), 3.04 (1 H, d, J 9, 2^ꢀ-H),

3.20 (2 H, m, 1^ꢀꢀ-H, 4^ꢀꢀ-H), 3.39 (3 H, s, 4^ꢀꢀ-OCH₃), 3.42–3.69 (2

H, m, 8^ꢀ-H, SiCH₂HCHO), 3.74 (1 H, m, SiCH₂HCHO), 3.80 (3

H, s, CO₂CH₃), 4.03–4.20 (4 H, m, SiCH₂CH₂O, 10^ꢀ-H, 3^ꢀꢀ-H),

4.44 (1 H, s, 2^ꢀꢀ-OH), 4.69 (2 H, m, OCH₂O), 5.22 (1 H, br. t, J

7, 9-H), 5.81 (1 H, m, 5-H), 6.12 (1 H, m, 4-H) and 6.30 (1 H, d,

J 10.8, 3-H); m/z FAB 1004 (M⁺+ 23, 2%), 980 (M⁺, 1%), 430

(18), 297 (67) and 226 (100).

(1RS,4RS,6SR,7RS,8RS,9SR,19RS,10E,12E,16E)-8,9-

Dihydroxy-6,16-dimethyl-10-hydroxymethyl-7-methoxy-2-

oxatricyclo[17.3.1.0^4,9]tricosa-10,12,16-trien-3-one 65

Diisobutylaluminium hydride in toluene (1 M, 0.23 cm³,

0.23 mmol) was added to a solution of lactone 64 (10 mg,

0.025 mmol) in toluene (1 cm³) at −78 ^◦C. The reaction was

stirred for 30 min then water (1 cm³) and ether (10 cm³) were

added. The aqueous phase was extracted with ether (6 × 5 cm³)

and the combined organic extracts were dried (MgSO₄). After

concentration under reduced pressure, chromatography of the

residue using ether as eluant gave the title compound 65 (7 mg,

The 4Z-isomers (4Z)-66 and (4Z)-67 could be distinguished

by the following peaks; d_H2.84 (1 H, m, 6-H), 5.43 (1 H, m,

5-H), 5.92 (1 H, m, 4-H) and 6.58 (1 H, d, J 11.5 Hz, 3-H).

◦

70%) as a solid, mp 184–188 C. [Found (EI): M⁺, 448.2845.

C₂₆H₄₀O₆requires M, 448.2825]; m_max(CHCl₃) 3344, 1705, 1451,

1380, 1173, 1095 and 1031 cm⁻¹; d_H(300 MHz, CDCl₃) 0.06 (1

H, q, J 12, 23-H_ax), 0.8 (4 H, m), 1.05 (3 H, d, J 6, 6-CH₃),

1.1–1.45 (4 H, m), 1.6 (3 H, s, 16-CH₃), 1.5–2.1 (5 H, m), 2.25 (4

H, m), 3.1 (1 H, dd, J 9, 7, 4-H), 3.3 (1 H, dd, J 10, 3.5, 7-H),

3.42 (3 H, s, OCH₃), 3.9 (1 H, d, J 3.5, 8-H), 3.95 (1 H, s, 9-OH),

4.18 and 4.28 (each 1 H, d, J 13, 10-CH), 4.75 (1 H, m, 1-H),

4.9 (1 H, m, 17-H), 5.7 (1 H, m, 13-H) and 6.35 (2 H, m, 11-H,

12-H); m/z (EI) 448 (M⁺, 3%), 430 (6), 412 (12) and 339 (7).

(lR,2S,3R,4R,5S)-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-

methoxy)cyclohexane-1-carboxylic acid 68 and (lS,2R,3S,4S,

5R)-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-trimethylsilylethoxymethoxy)-

cyclohexane-1-carboxylic acid 69

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,5S)-1-(2-

trimethylsilylethoxycarbonyl)-2-hydroxy-4-methoxy-5-methyl-

3-(2-trimethylsilylethoxy-methoxy)cyclohexan-2-yl]-6,8-

dimethyldeca-2,4,8-trienoate (4E)-66 and 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-

[(lS,2R,3S,4S,5R)-1-(2-trimethylsilylethoxycarbonyl)-2-

hydroxy-4-methoxy-5-methyl-3-(2-trimethylsilylethoxymeth-

oxy)cyclohexan-2-yl]-6,8-dimethyldeca-2,4,8-trienoate (4E)-67

Tetrabutylammonium ﬂuoride (0.102 cm³of a 1 M solution

in THF) was added to a solution of the esters (4E)-66 and

(4E)-67 (20 mg, 0.02 mmol) in THF (1 cm³) at 0 ^◦C. The

solution was stirred at ambient temperature for 10 h, diluted

with ethyl acetate (3 cm³) and aqueous hydrogen chloride

(3 M, 1 cm³) was added. The aqueous layer was extracted with

ethyl acetate (3 × 1 cm³) and the combined organic phases

washed with brine (2 cm³), dried (MgSO₄) and concentrated

under reducedpressure. Chromatographyusing lightpetroleum–

ether–isopropanol (1 : 0.02 : 0.01) gave a mixture of the title

The phosphonium salt 1 (115.6 mg, 0.138 mmol) and the racemic

hydroxybutenolide 37 (61 mg, 0.115 mmol) were dissolved in

THF (2.5 cm³) and cooled to −78 ^◦C. Lithium hexamethyldis-

ilazide (0.4 mmol in THF, 1.5 cm³) was cooled to −78 ^◦C, and

added to the reaction mixture via a cannula. The orange solution

was warmed to −10 ^◦C over 1 h, stirred at this temperature

for 0.5 h and then saturated aqueous ammonium chloride

(2 cm³) was added. The aqueous layer was extracted with ether

(3 × 5 cm³) and the combined organic phases washed with

brine (5 cm³), dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue using light petroleum–

ether–acetic acid (1 : 1 : 0.01) as eluant gave trienyl acids which

were immediately dissolved in ether (10 cm³) and treated with

an excess of ethereal diazomethane. The residual diazomethane

was quenched by the addition of acetic acid (0.5 cm³) and the

reaction mixture concentrated. Chromatography of the residue

using light petroleum–ether (4 : 1) as eluant gave the trienyl

compounds 68 and 69 (15.4 mg, 99%). [Found (FAB): M⁺

+

Na, 789.4550. C₄₁H₇₀O₁₁NaSi requires M, 789.4585]; m_max(ﬁlm)

3630–2400, 1716, 1648, 1456, 1384, 1250, 1188, 1117, 1092, 1058,

1031, 1011, 980, 861 and 836 cm⁻¹; d_H(300 MHz; CDCl₃) 0.0 [9

H, s, Si(CH₃)₃], 0.72–1.05 [17 H, m, (CH₃)₂CH, 5-CH₃, 5^ꢀ-CH₃,

3^ꢀꢀ-CH₃, CH₂Si], 1.1–1.71 (10 H, m), 1.55 and 1.59 (each 1.5 H, s,

7^ꢀ-CH₃), 1.78–2.10 (5 H, m), 2.10–2.30 (2 H, m, 9^ꢀ-H₂), 2.47 (1 H,

m, 5^ꢀ-H), 3.04 (1 H, d, J 9, 2^ꢀꢀ-H), 3.09–3.27 (2 H, m, 1-H, 4-H),

3.39 (3 H, s, 4-OCH₃), 3.40–3.80 (3 H, m, 8^ꢀꢀ-H, SiCH₂CH₂O),

3.82 (3 H, s, CO₂CH₃), 3.99 (0.5 H, d, J 2, 3-H), 4.02–4.20 (1.5

H, m, 3-H, 10^ꢀꢀ-H), 4.60–4.69 (2 H, m, OCH₂O), 5.04 (1 H, m,

8^ꢀ-H), 5.71 (0.5 H, dd, J 15, 8, 4^ꢀ-H), 5.90 (0.5 H, dd, J 15, 7,

4^ꢀ-H), 5.8–6.38 (3 H, br. s, CO₂H, 2-OH, 10^ꢀꢀ-OH), 6.09–6.24 (1

H, m, 3^ꢀ-H), 6.21 (0.5 H, d, J 11, 2^ꢀ-H) and 6.48 (0.5 H, d, J 10.5,

2^ꢀ-H); m/z (FAB) 789 (M⁺+ 23, 2%), 181 (10), 136 (10) and 73

(100).

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

3 6 5 1

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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,5S)-1-(2-

trimethylsilylethoxycarbonyl)-2,3-dihydroxy-4-methoxy-5-

methyl)cyclohexan-2-yl]-6,8-dimethyldeca-2,4,8-trienoate 4E-70

and 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-[(lS,2R,3S,4S,5R)-1-(2-

trimethylsilylethoxycarbonyl)-2,3-dihydroxy-4-methoxy-5-

methyl)cyclohexan-2-yl]-6,8-dimethyldeca-2,4,8-trienoate 4E-71

(lS,2R,4S,5R,6R,9Z)-9-[(4R,2E,6E)-8-{(2R,3S,6R,8R,10S)-

(10-Hydroxy-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]nonane-2-

carboxylic acid 74 and (lR,2S,4R,5S,6S,9Z)-9-[(4R,2E,6E)-8-

{(2R,3S,6R,8R,10S)-(10-hydroxy-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]nonane-2-carboxylic acid 75

Deprotection of a mixture of the esters 72 and 73 (33 mg,

0.04 mmol) following the procedure outlined for the deprotec-

tion of (4E)-66 and (4E)-67 gave a mixture of the title compounds

74 and 75 (19.1 mg, 78%). [Found (CI): M⁺+ H, 605.3710.

C₃₄H₅₃O₉requires M, 605.3689]; m_max(ﬁlm) 3500–2600, 1742,

1710, 1648, 1457, 1384, 1271, 1116, 1057, 1010, 979, 912 and

734 cm⁻¹; d_H(300 MHz; CDCl₃) 0.76–0.82 (6 H, m, 3^ꢀꢀ-CH₃,

CHCH₃), 0.93–1.10 (9 H, m, CHCH₃, 4-CH₃, 4^ꢀ-CH₃), 1.15–

1.70 (10 H, m), 1.55 and 1.62 (each 1.5 H, s, 6^ꢀ-CH₃), 1.78–2.04

(5 H, m), 2.11–2.30 (2 H, m, 8^ꢀ-H₂), 2.51–2.71 (2 H, m, 2-H,

4^ꢀ-H), 3.04 (1 H, d, J 9, 2^ꢀꢀ-H), 3.20 (1 H, dd, J 10.5, 3, 5-H), 3.47

and 3.48 (each 1.5 H, s, 5-OCH₃), 3.60 (1 H, m, 8^ꢀꢀ-H), 4.13 and

4.29 (each 0.5 H, m, 10^ꢀꢀ-H), 4.4 (1 H, d, J 3, 6-H), 4.91 (0.5 H,

m, 7^ꢀ-H), 4.99 (0.5 H, br. t, J 6.6, 7^ꢀ- H), 5.29 (3 H, br. s, CO₂H,

1-OH, 10^ꢀꢀ-OH), 5.86 (0.5 H, dd, J 15.5, 9, 3^ꢀ-H), 6.13 (0.5 H,

dd, J 15.5, 6, 3^ꢀ-H), 6.53 (0.5 H, d, J 11.5, l^ꢀ-H), 6.60 (0.5 H, d,

J 10.5, l^ꢀ-H) and 7.21 (l H, dd, J 15.5, 11.5, 2^ꢀ-H); m/z FAB 627

(M⁺+ 23, 10%), 605 (M⁺+ 1, 5), 587 (23), 569 (13), 181 (74),

139 (57) and 111 (100).

A mixture of the unisomerized Wittig products 66 and 67 (50 mg,

0.051 mmol) was dissolved in benzene (1 cm³) and iodine (14 mg,

0.055 mmol) in benzene (0.4 cm³) was added. The reaction

was stirred vigorously while irradiating with a lamp (250 W)

for 1.5 h and was then diluted with ether (5 cm³) and washed

with saturated aqueous sodium thiosulfate (3 cm³). The aqueous

phase was extracted with ether (3 × 5 cm³), and the combined

organic phases were washed with brine (5 cm³), dried (MgSO₄)

and concentrated under reduced pressure. Chromatography of

the residue using light petroleum–ether (2 : 1) as eluant gave

a mixture of the title compounds (4E)-70 and (4E)-71 (40 mg,

92%) which were used immediately; m_max(ﬁlm) 3468, 1722, 1645,

1385, 1252, 1217, 1173, 1131, 1089, 1068, 1010, 983, 940, 861

and 837 cm⁻¹; d_H(300 MHz; CDCl₃) 0.08 [9 H, s, Si(CH₃)₃], 0.09

[6 H, s, Si(CH₃)₂], 0.78 (3 H, d, J 7, 3^ꢀ-CH₃), 0.81 (3 H, d, J

7, CHCH₃), 0.89 [9 H, s, C(CH₃)₃], 0.90–1.0 (8 H, m, CH₃CH,

6-CH₃, CH₂Si), 1.01 (3 H, d, J 7, 5^ꢀꢀ-CH₃), 1.01–1.71 (10 H,

m), 1.60 (3 H, s, 8-CH₃), 1.72–1.90 (5 H, m), 2.0–2.48 (3 H, m,

6-H, 10-H₂), 3.04 (1 H, d, J 9, 2^ꢀ-H), 3.19 (1 H, dd, J 10, 3,

4^ꢀꢀ-H), 3.26 (1 H, dd, J 12, 4, 1^ꢀꢀ-H), 3.40 (3 H, s, 4^ꢀꢀ-OCH₃), 3.50

(1 H, m, 8^ꢀ-H), 3.81 (3 H, s, CO₂CH₃), 3.99 (1 H, br. s, 3^ꢀꢀ-H),

4.05–4.24 (3 H, m, SiCH₂CH₂O, 10^ꢀ-H), 4.42 (1 H, s, 2^ꢀꢀ-OH),

5.23 (1 H, br. t, J 7, 9-H), 5.88 (1 H, dd, J 15, 7, 5-H), 6.27 (1

H, dd, J 15, 11, 4-H) and 6.52 (1 H, d, J 11, 3-H); m/z (FAB)

874 (M⁺+ 23).

(4S)-3,4-Dihydro-28-oxomilbemycin G 76

The seco-acids 74 and 75 (16 mg, 0.026 mmol) and DMAP

(0.32 mg, 2.6 lmol) in dichloromethane (2.7 cm³) were added

over 5 h (syringe pump) to dicyclohexylcarbodiimide (10 mg,

0.049 mmol) in dichloromethane (5.5 cm³) at 0 ^◦C. Stirring

was continued at this temperature for 16 h, and the reaction

mixture was concentrated under reduced pressure, dissolved in

ether (5 cm³), ﬁltered and concentrated under reduced pressure.

Chromatography of the residue using light petroleum–ether (4 :

1) as eluant gave the title compound 76 (3.6 mg, 23%; 46% based

on 74); m_max(ﬁlm) 3420, 1762, 1705, 1652, 1456, 1376, 1273,

1242, 1178, 1118, 1095, 1058, 1010 and 981 cm⁻¹; d_H(300 MHz;

CDCl₃) 0.80 (3 H, d, J 6, 24-CH₃), 0.85 and 1.03 (each 3 H,

d, J 7, CHCH₃), 1.04 (3 H, d, J 7, 12-CH₃), 1.10 (3 H, d, J 6,

4-CH₃), 1.2–2.10 (15 H, m), 1.53 (3 H, s, 14-CH₃), 2.18–2.28

(2 H, m, 16-H₂), 2.57 (1 H, dd, J 12, 3, 2-H), 2.60 (1 H, m,

12-H), 3.08 (1 H, d, J 9.5, 25-H), 3.20 (1 H, dd, J 10, 3.5, 5-H),

3.48 (3 H, s, 5-OCH₃), 3.60 (1 H, m, 17-H), 4.43 (1 H, d, J 3.5,

6-H), 4.93 (1 H, m, 15-H), 5.26 (1 H, s, 7-OH), 5.4 (1 H, m,

19-H), 5.82 (1 H, dd, J 15, 10, 11-H), 6.40 (1 H, d, J 12, 9-H)

and 7.24 (1 H, dd, J 15, 12, 10-H); m/z (FAB) 609 (M⁺+ 23,

0.2%), 561 (M⁺− 17, 0.5), 503 (2.5), 459 (3), 281 (66), 221 (100)

and 207 (90).

Trimethylsilylethyl (1S,2R,4S,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]nonan-2-ylcarboxylate 72 and trimethylsilylethyl

(1R,2S,4R,5S,6S,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]nonan-

2-ylcarboxylate 73

A mixture of the hydroxy esters (4E)-70 and (4E)-71 (36 mg,

0.042 mol) was dissolved in chloroform (2 cm³), silica gel (1 g,

Merck, Kieselgel 60; 230–400 mesh) was added, and the mixture

was stirred for 16 h. The solvent was removed under reduced

pressure, and chromatography of the residue, pre-adsorbed onto

the silica, using light petroleum–ether (3 : 1) as eluant, gave a

mixture of the title compounds 72 and 73 (33.8 mg, 98%); m_max

(ﬁlm) 3433, 1763, 1704, 1650, 1459, 1385, 1252, 1175, 1090,

1011, 982, 938 and 837 cm⁻¹; d_H(300 MHz; CDCl₃) 0.03 [9 H, s,

Si(CH₃)₃], 0.08 [6 H, s, Si(CH₃)₂), 0.79 (3 H, d, J 6, 3^ꢀꢀ-CH₃), 0.81

(3 H, d, J 7, CHCH₃), 0.89 [9 H, s, C(CH₃)₂], 0.91–1.01 (8 H, m,

CHCH₃, 4^ꢀ-CH₃, CH₂Si), 1.09 (3 H, d, J 7, 4-CH₃), 1.14–1.70 (10

H, m), 1.6 (3 H, s, 6^ꢀ-CH₃), 1.75–1.98 (5 H, m), 2.0–2.31 (2 H, m,

8^ꢀ-H₂), 2.51 (1 H, m, 4^ꢀ-H), 2.60 (1 H, d, J 12, 2-H), 3.03 (1 H, d, J

9, 2^ꢀꢀ-H), 3.19 (1 H, dd, J 10, 3, 5-H), 3.47 (3 H, s, 5-OCH₃), 3.51

(1 H, m, 8^ꢀꢀ-H), 4.11 (1 H, m, 10^ꢀꢀ-H), 4.19 (2 H, m, SiCH₂CH₂),

4.40 (1 H, d, J 3, 6-H), 5.23 (1 H, m, 7^ꢀ-H), 5.49 and 5.51 (each

0.5 H, s, 1-OH), 6.07 and 6.09 (each 0.5 H, dd, J 15, 8, 3^ꢀ-H),

6.52 (0.5 H, d, J 11, l^ꢀ-H), 6.54 (0.5 H, d, J 11, 1 ^ꢀ-H) and 7.21 (1

H, m, 2^ꢀ-H); m/z (FAB) 841 (M⁺+ 23, 2%), 761 (3), 209 (9) and

73(100).

(4S,6R)-6-Hydroxy-3,4-dihydromilbemycin E 77

The lactone 76 (4 mg, 7 lmol) was dissolved in toluene (0.4 cm³),

◦

the solution cooled to −78 C, and DIBAL-H (70 ll of a 1 M

solution in toluene) was added. The reaction was stirred for

1 h, water (0.1 cm³) was added, and the mixture diluted with

ethyl acetate (3 cm³). Aqueous hydrogen chloride (3 M, 0.5 cm³)

was added and the layers separated. The aqueous phase was

extracted with ethyl acetate (3 × 2 cm³), and the combined

organic phase washed with brine (5 cm³), dried (MgSO₄), and

concentrated under reduced pressure. Chromatography of the

residue using light petroleum–ether (4 : 1 then 1 : 1) as eluant

gave the title compound 77 (3 mg, 74%). [Found (CI): M⁺− OH,

573.3791. C₃₄H₅₃O₇requires M, 573.3791]; m_max(ﬁlm) 3455, 1706,

1457, 1376, 1175, 1090 and 1009 cm⁻¹; d_H(300 MHz; CDCl₃)

3 6 5 2

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

View Article Online

0.70 (1 H, q, J 12, 18-H_ax), 0.75 and 0.80 (each 3 H, d, J 7.5,

24-CH₃, CHCH₃), 0.99 (3 H, d, J 7.5, CHCH₃), 1.03 (6 H, d, J

7, 4-CH₃, 12-CH₃), 1.41 (1 H, t, J 12, 20-H_ax), 1.38–1.53 (5 H,

m, 22-H₂, 23-H₂, 24-H), 1.60 (3 H, s, 14-CH₃), 1.55–1.97 [8 H,

m, (CH₃)₂CH, 3-H₂, 4-H, 13-H₂, 18-H, 20-H], 2.07–2.35 (3 H,

m, 16-H₂, OH), 2.49 (1 H, m, 12-H), 3.04 (1 H, d, J 9, 25-H),

3.11 (2 H, m, 2-H, 6-OH), 3.31 (1 H, dd, J 9, 3, 5-H), 3.40 (3

H, s, 5-OCH₃), 3.60 (1 H, m, 17-H), 3.87 (2 H, m, 6-H, 7-OH),

4.12 and 4.2 (each 1 H, d, J 13, HCHOH), 4.78 (1 H, d, J 9,

15-H), 5.24–5.38 (1 H, m, 19-H), 5.48 (1 H, dd J 15,10, 11-H),

6.27 (1 H, dd, J 15, 11, 10-H) and 6.42 (1 H, d, J 11, 9-H); m/z

(FAB) 613 (M⁺+ 23, 5%), 573 (M⁺− 17, 28), 307 (35), 289 (28),

209 (37) and 181 (100).

3.65 (1 H, m, 17-H), 4.01 (1 H, m, 6-H), 4.17 (1 H, s, 7-OH),

4.36 and 4.48 (each 1 H, d, J 11, HCHCl), 4.83 (1 H, d, J 10,

15-H), 5.32 (1 H, m, 19-H), 5.73 (1 H, dd, J 15, 8, 11-H), 6.14

(1 H, d, J 11, 9-H) and 6.26 (1 H, dd, J 15, 11, 10-H); m/z (EI)

572 [M⁺− 36(³⁵Cl), 38(³⁷Cl), 30%), 503 (25) and 459 (60).

Acknowledgements

We thank Aventis (formerly Rhone Poulenc Rorer) and the

EPSRC for studentships (to S. K. and E. R. P., respectively).

References

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Chloromethyl-8,9-dihydroxy-6,16-dimethyl-7-methoxy-2-

oxatricyclo[17.3.1.0^4,9]tricosa-10,12,16-trien-3-one 78

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1706, 1454, 1382, 1283, 1175, 1113, 1091,1029, 990, 969, 907

and 729 cm⁻¹; d_H(500 MHz, CDCl₃) 0.77 (1 H, q, J 12), 0.85–

0.95 (4 H, m), 1.05 (3 H, d, J 6, 6-CH₃), 1.25 (2 H, m), 1.45–1.95

(6 H, m), 1.58 (3 H, s, 16-CH₃), 2.1–2.5 (6 H, m), 3.15 (1 H, dd,

J 12, 4.5, 4-H), 3.27 (1 H, dd, J 10, 3, 7-H), 3.43 (3 H, s, OCH₃),

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H, d, J 12, HCHCl), 4.8 (1 H, m, 1-H), 5.0 (1 H, t, J 7, 17-H),

5.73 (1 H, m, 3-H), 6.15 (1 H, d, J 11, 11-H) and 6.32 (1 H, dd,

J 14, 11, 12-H); m/z (FAB) 468 [M⁺(³⁷Cl), 12%], 466 [M⁺(³⁵Cl),

36%], 451 [M⁺(³⁷Cl) − 17, 16], 449 [M⁺(³⁵Cl) − 17, 48), 432 (50)

and 414 (50).

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(4S,6R)-28-Chloro-6-hydroxy-28-deoxa-3,4-dihydromilbemycin

E 79

Following the procedure outlined for the synthesis of the

chloride 78, the triol 77 (5 mg, 0.0085 mmol) gave the title

compound 79 (5 mg, 100%). [Found (CI): M⁺− HCl, 572.3712.

C₃₄H₅₂O₇requires M, 572.3713]; [a]_D+17.5. (c 0.004 in CHCl₃);

m_max(CHCl₃) 3461, 1710, 1462, 1377, 1261, 1098 and 802 cm⁻¹;

d_H(500 MHz, CDCl₃) 0.77 and 0.79 (each 3 H, d, J 7, CH₃),

0.84 (1 H, m, 18-H_ax), 0.95 (3 H, d, J 7.5, CH₃), 1.01 (3 H, d, J

7, 12-CH₃), 1.09 (3 H, d, J 7, 4-CH₃), 1.4–1.53 (5 H, m, 22-H₂,

23-H₂, 24-H), 1.64 (3 H, s, 14-CH₃), 1.6–1.88 (8 H, m, 25-CH,

3-H₂, 4-H, 13-H₂, 18-H, 20-H), 2.15–2.35 (3 H, m, 16-H₂, 20-H),

2.56 (1 H, m, 12-H), 3.04 (1 H, dd, J 10, 2, 25-H), 3.08 (1 H, dd,

J 12, 4, 2-H), 3.25 (1 H, dd, J 10, 3, 5-H), 3.4 (3 H, s, OCH₃),

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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 6 3 6 – 3 6 5 3

3 6 5 3

Article Doi

Total synthesis of milbemycins: A synthesis of (6R)-6-hydroxy-3,4- dihydromilbemycin E

DOI: 10.1039/b508670a

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