Synthesis and evaluation of a broad range of chiral sulfides for asymmetric sulfur ylide epoxidation of aldehydes

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Synthesis and evaluation of a broad range of chiral sulﬁdes for

asymmetric sulfur ylide epoxidation of aldehydes

Varinder K. Aggarwal,*^a,bRémy Angelaud,^aDominique Bihan,^aPaul Blackburn,^a

Robin Fieldhouse,^cSilvia J. Fonquerna,^aGair D. Ford,^aGeorge Hynd,^bElfyn Jones,^a

Ray V. H. Jones,^cPhilippe Jubault,^aMatthew J. Palmer,^aPaul D. Ratcliﬀe^aand Harry Adams^a

1

^aDepartment of Chemistry, University of Sheﬃeld, Brook Hill, Sheﬃeld, UK S3 7HF

^bSchool of Chemistry, Bristol University, Cantock’s Close, Bristol, UK BS8 1TS

^cZENECA Process Technology Dept., Earls Road, Grangemouth, Stirlingshire, UK FK3 8XG

Received (in Cambridge, UK) 20th June 2001, Accepted 6th August 2001

First published as an Advance Article on the web 24th September 2001

We have recently developed a catalytic, sulfur ylide mediated process for converting aldehydes into epoxides using

benzaldehyde tosylhydrazone sodium salt which decomposes to generate phenyldiazomethane in situ. Although

chiral 1,3-oxathianes gave good yields and excellent diastereo- and enantio-control when phenyldiazomethane

was employed, only low yields were obtained when using the simpliﬁed procedure employing benzaldehyde

tosylhydrazone sodium salt. Thus, a range of more robust chiral sulﬁdes based on thianes, thiolanes, and 1,4-

oxathianes were designed to achieve high yield and high enantioselectivity. The sulﬁdes all possessed the following

features: conformationally locked cyclic sulﬁde in which only one of the two lone pairs was accessible (not relevant

for C₂symmetric substrates); ylide conformation and face selectivity was to be controlled through non-bonded

steric interactions. Chirality was introduced from chiral pool materials (camphor, amino acids, lactic acid, limonene,

carvone, glyceraldehyde), through enzyme mediated reduction/hydrolysis and through the use of chiral reagents

(hydroboration). The sulﬁde catalysts were tested in the reaction between benzaldehyde tosylhydrazone salt and

benzaldehyde to give trans-stilbene oxide. The range of chiral sulﬁde catalysts derived from camphor gave trans-

stilbene oxide in generally good yield (23–95%) and with moderate enantioselectivity (40–76% ee). The range of novel

chiral thianes and 1,4-oxathianes gave trans-stilbene oxide again in generally good yield (9–92%) and with moderate

enantioselectivity (20–77% ee). The range of C₂symmetric chiral sulﬁde catalysts based on 5 and 6 membered rings

gave trans-stilbene oxide in moderate yield (10–78%) and with variable enantioselectivity (8–87% ee). In none of the

cases could high enantioselectivity and high yield be achieved simultaneously. Analysis of the results led us to the

conclusion that the moderate enantioselectivity was a result of poor control in the ylide conformation and this led

to the design of completely rigid [2.2.1] bicyclic sulﬁdes which ﬁnally gave high enantioselectivity and high yield in

the epoxidation process.

Introduction

The development of methods for the asymmetric synthesis of

epoxides continues to warrant intense research eﬀort, despite

the seminal contributions of Sharpless,¹Jacobsen,²Shi³and

others.⁴We have focused on epoxidation of carbonyl com-

pounds as a complementary method to the oxidative processes

cited above.⁵Indeed, we have developed a catalytic, sulfur ylide

mediated process operating under neutral conditions which,

Fig. 1

with 1,3-oxathiane 1, gave good yields and excellent diastereo-

in the new in situ process. In the design of new catalysts we

were guided by our experiences using oxathiane 1, from which

we learnt that three features were required to achieve good

enantiocontrol. These comprised: (i) formation of a single

sulfur ylide by blocking one of the two sulfur lone pairs, (ii)

control in the conformation of the ylide and (iii) control in the

face selectivity of the ylide (Fig. 1).

and enantio-control (Scheme 1).^5,6More recently, we have

In this paper we describe the synthesis of a broad range

of sulﬁdes, which fulﬁl these criteria, their application in

epoxidation and how additional criteria were eventually

required to ﬁnally arrive at sulﬁde catalysts which gave high

enantioselectivity.

Scheme 1

achieved a simpliﬁed process, whereby phenyldiazomethane is

generated in situ from tosylhydrazone salt 2, thus eliminating

the need for the preparation and handling of this potentially

explosive compound (Scheme 2).^5b,7However, 1,3-oxathiane 1

proved to be unstable under these modiﬁed conditions, and

only gave trans-stilbene oxide in low yield, albeit with high

enantioselectivity.^5bWe therefore embarked on the preparation

of a broader range of more stable chiral sulﬁde catalysts, for use

Results and discussion

Sulﬁdes derived from camphor

We initially synthesized camphor derived sulﬁdes 3–8 as it was

felt that these would fulﬁl the three criteria required: the axial

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This journal is © The Royal Society of Chemistry 2001

DOI: 10.1039/b105416n

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Scheme 2

Scheme 3 Reagents and conditions: i Br(CH₂)₂CH(OMe)₂, Mg, THF, rt, then CeCl₃, THF, Ϫ78 ЊC, then 10, THF, Ϫ78 ЊC to rt, 80%; ii BF₃ؒEt₂O,

CH₂Cl₂, 0 ЊC, 40%; iii Li, naphthalene, THF, then (CH₃)₂C᎐CHCH₂SPh, then CeCl₃, 50%; iv AIBN, C₆H₆, 56%; v (COCl)₂, C₆H₆, 81%; vi H₂, Pd S/C,

᎐

MeOH, 88%; vii N-trimethylsilylimidazole; viii HCCSiMe₃, n-BuLi, THF, 91%; ix TBAF, THF, 90%; x N-trimethylsilylimidazole, 94%.

resulted from an intramolecular transacetalization between the

ketal group of the organocerium reagent and the exo alcohol

obtained after addition of this organometallic reagent into

the ketone. When 11 was treated with BF₃ؒEt₂O, formation of

the third cycle occurred to aﬀord the expected sulﬁde 3. The

synthesis of sulﬁde 4 proceeded from the regio- and stereo-

selective addition to ketone 10 of the allylcerium reagent,

derived from 3,3-dimethylprop-2-enyl phenyl sulﬁde by the

method of Cohen,¹¹which aﬀorded the exo alcohol 12 in 50%

yield. Radical cyclisation of the thiol onto the pendant alkene

in 12 was achieved using catalytic AIBN, giving hydroxy sulﬁde

13. Attempts to remove the hydroxy group of 13 using the

radical decomposition of the mixed oxalate ester with N-

hydroxypyridine-2-thione were unsuccessful, as initial treat-

Fig. 2

ment with oxalyl chloride resulted in rapid elimination to give

the unsaturated sulﬁde 14.¹²However, we were able to use this

lone pair would be blocked by the gem dimethyl bridge and

ylide conformation and face selectivity would be controlled by

non-bonding interactions, such as those shown for the generic

sulﬁde structure in Fig. 1.

Sulﬁdes 3, 4, 5, 6a and 6b (Fig. 2) were prepared from their

common precursor ketone 10, readily available in one step

from camphorsulfonyl chloride (Scheme 3).⁸The addition of

the organocerium() reagent⁹generated by transmetallation

of cerium chloride with the Grignard reagent derived from

1-bromo-3,3-dimethoxypropane,¹⁰to the sterically hindered

mercaptoketone 10 provided the bicyclic compound 11 as a

70 : 30 mixture of acetal diastereoisomers. The formation of 11

material as hydrogenation aﬀorded the target sulﬁde 4 diastereo-

merically pure. X-Ray crystallographic analysis of the corre-

sponding sulfoxide 15 (prepared from 4 with MCPBA, 92%)

(Fig. 3) revealed that the isopropyl substituent occupied the

axial position in the thiane ring. Treatment of alcohol 13 with

N-trimethylsilylimidazole provided sulﬁde 5. Sulﬁdes 6a and

6b were prepared from the addition of lithium trimethylsilyl-

acetylide to ketone 10 to give exo alcohol 16 in good yield.

Treatment of 16 with tetrabutylammonium ﬂuoride gave the

thiolane 6a. This product is presumed to arise from initial

desilylation of 16 to give anion 17, which undergoes proton

transfer to form thiolate 18 (the pKa of the thiol is 10–11 com-

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

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Table 1 Yields and enantioselectivities for epoxidation

Entry

Sulﬁde

Yield (%)^a

trans : cis^b

ee (%)^c

1

2

3

4

5

6

7

8

9

1

9

10

83

42

23

78

95

62

100

98 : 2

95 : 5

57 : 43

85 : 15

92 : 8

93 : 7

84 : 16

90 (R,R)

12 (R,R)

40 (S,S)

30 (S,S)

63 (R,R)

76 (R,R)

45 (S,S)

72 (S,S)

64 (R,R)

3

4

5

6a

6b

7

8

9

^aIsolated yield. ^bBy ¹H NMR. ^cMeasured on a Chiralcel OD column.

Fig. 3 ORTEP drawing of sulfoxide 15.

Scheme 6

pared with the pKa of the acetylene of 25). Ring closure of the

thiolate onto the acetylene provides thiolane 6a after protic

work up.¹³Sulﬁde 6b was obtained from 6a by treatment with

N-trimethylsilylimidazole.

The remaining target sulﬁdes, 7 and 8, were both obtained

from camphor derivatives (Schemes 4 and 5). It should be noted

Results of epoxidation. Sulﬁdes 3–8 were tested in the cata-

lytic cycle with benzaldehyde, using the new in situ conditions

(Scheme 6, Table 1). The bridged 1,3-oxathiane 3 was expected

to be more robust to the reaction conditions than 1,3-oxathiane

1 (entry 1) as there is no longer the entropic driving force

for hydrolysis. However, in the event, 1,3-oxathiane 3 behaved

similarly to 1,3-oxathiane 1, providing only a low yield of

stilbene oxide but also with very low enantioselectivity (entry

2). The low enantioselectivity relative to 1 is probably due to

replacement of the equatorial methyl group for a proton. How-

ever, as the yield was low, further work with 1,3-oxathianes was

terminated¹⁹and alternative chiral sulﬁdes 4–8 were prepared

and tested in the epoxidation process. As expected, by com-

parison with 1,3-oxathiane 1, sulﬁdes 4–8 were signiﬁcantly

more robust in the in situ reaction conditions and gave sub-

stantially higher yields in all cases. However, in no case did the

enantioselectivities obtained with catalysts 4–8 approach those

aﬀorded by 1,3-oxathiane 1. The most likely explanation for

this is incomplete control of ylide conformation, as illustrated

for sulﬁde 4 (Scheme 7). The ylide formed from reaction of

Scheme

4

Reagents and conditions: i EtOCH᎐CH₂, Pd(OAc)₂,

᎐

phenanthroline, CH₂Cl₂, 40%; ii AcSH, AIBN, hν, C₆H₆; iii LiOHؒH₂O,

MeOH; iv BF₃ؒOEt₂, Et₃SiH, CH₂Cl₂, 52% over three steps.

Scheme 5 Reagents and conditions: i AcSH, AIBN, C₆H₆; ii LiOHؒ

H₂O, MeOH; iii BF₃ؒOEt₂, Et₃SiH, CH₂Cl₂, 63% over three steps.

that oxathiane 9, which has the sulfur and oxygen atoms trans-

posed, had been prepared previously and tested in our epoxid-

ation process but gave only moderate enantioselectivity (Fig. 2)

(Table 1, entry 9).¹⁴It was felt that oxathiane 7 would provide

higher face selectivity in the ylide reaction than 9 because of the

blocking methyl substituent and thereby lead to higher enantio-

selectivity. 1,4-Oxathiane 7 was prepared in four steps starting

from exo-hydroxy camphor 19¹⁵(Scheme 4), which was con-

verted to the vinyl ether 20 using a Pd(OAc)₂–phenanthroline

catalyst.¹⁶Radical addition of thioacetic acid to the terminal

alkene in 20 was achieved with catalytic AIBN and under

irradiation. Performing the same reaction only in the presence

of AIBN did aﬀord 21 in lower yield, but it was also less pure.

Hydrolysis of thioacetate 21 was followed by cyclisation of

thiol 22 with boron triﬂuoride–diethyl ether and triethylsilane

to give 1,4-oxathiane 7.¹⁷A similar procedure was implemented

to prepare the unsaturated sulﬁde 8 (Scheme 5). Radical

addition of the thioacetic acid to allylcamphor 23¹⁸(7 : 3 exo :

endo), followed by hydrolysis and subsequent cyclisation with

boron triﬂuoride–diethyl ether aﬀorded sulﬁde 8 in good

overall yield. We were not able to reduce the double bond in

sulﬁde 8 but it was nevertheless tested as a potential catalyst.

Scheme 7

the more sterically accessible equatorial lone pair can adopt

conformations 26a or 26b, but 26a should be favoured due to

1,3-diaxial interactions in 26b. The facial selectivity of 26a

should dictate that benzaldehyde attacks the Re face of the

ylide, aﬀording (R,R)-epoxide. However, this was not the sense

of asymmetric induction observed. NOE experiments on 4

revealed that it preferred to adopt the boat conformation,

presumably to avoid the 1,3-diaxial interactions between the

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Fig. 4

Fig. 6

Fig. 7

ate the three criteria required for high enantioselectivity as

described in the introduction. In addition, sulﬁdes 29–32 are

conformationally locked, thus providing a rigid framework for

the sulfur ylide.

Fig. 5

proton and isopropyl group on the thiane ring (Fig. 4). Ylide 27,

formed from the boat conformation of 4 should then adopt

the conformation shown and the Si face selectivity leads to the

observed (S,S)-product. Similar arguments can be advanced

for the observed absolute stereochemistry of the trans-stilbene

oxide obtained from sulﬁdes 5, 6, 7 and 8 (entries 4–8), with the

major ylide conformation and facial selectivity shown in Fig. 5.

Whilst we were able to account for the sense of asymmetric

induction observed, we were surprised at the low level of enan-

tioselectivity and particularly surprised that sulﬁde 7 only gave

45% ee in the epoxidation reaction as: (i) only one of the two

lone pairs should react, (ii) the ylide conformation should be

controlled by 1,3-diaxial interactions and (iii) the face selec-

tivity of the ylide should be completely controlled. As points (i)

and (iii) should be completely controlled, it must be ylide

conformation that is poorly controlled.

The 1,4-oxathianes 28a and 28b were prepared as shown in

Scheme 8. Alkylation of the known hydroxythiols 34a and 34b,²⁰

accessible from methyl (S)-lactate and -valine respectively,

with methallyl bromide provided the allylic sulﬁdes 35a and 35b

in good yields.²¹We had originally hoped to apply an acid-

mediated cyclisation²²of 35a and 35b to aﬀord sulﬁdes 28a

and 28b, but with all reagents tried we obtained either decom-

position or return of starting material. Alternatively, when 35a

was treated with triﬂuoroacetic acid, sulﬁde 37 was obtained

in high yield, presumably via regioselective opening of the epi-

sulfonium ion 36.²³Consequently, we subjected 35a and 35b to

iodocyclisation²⁴to aﬀord the 1,4-oxathianes 38a and 38b in an

inconsequential 1 : 1 ratio of diastereomers. Excision of the

iodine with either LiEt₃BH or LiAlH₄completed the synthesis

of sulﬁdes 28a and 28b. Subsequent chiral GC analysis of

sulﬁdes 28a and 28b indicated that although 28a was prepared

in 98% ee, sulﬁde 28b was only 66% ee.²⁵The partial racemis-

ation of 28b is presumed to emanate from hydroxythiol 34b,

which is reported to be prepared in only 81% ee from -valine.^20a

The key intermediate in the synthesis of sulﬁdes 29a, 29b

and 29c was β-hydroxyester 40, accessible from β-ketoester 39

as shown in Scheme 9. The procedure of Fehnel was used to

prepare 39 in two steps,²⁶which was subjected to Baker’s yeast

reduction, following the precedent of the enantioselective

yeast reduction of the carbocyclic analogue of 39 reported by

Seebach and other groups.^27–29The desired product 40 was

obtained with complete syn diastereoselectivity and good

enantioselectivity (82% ee), which could be raised to 100%

enantiopurity by crystallisation from ether–hexane (Fig. 8). The

ﬁrst target sulﬁde 29a was prepared in two simple steps as

shown in Scheme 10. Reduction of 40 with lithium aluminium

hydride to aﬀord diol 41, followed by reaction with 2,2-

dimethoxypropane and catalytic PPTS provided acetal 29a.³⁰

The geminal dimethyl sulﬁde 29b was obtained by reaction of

methylmagnesium bromide with 40 to provide diol 42, followed

by acetalisation (Scheme 11). During the course of this work,

These results demonstrated the need to simultaneously

control the formation of a single diastereomeric ylide, its con-

formation and face selectivity. We therefore embarked on the

synthesis of alternative chiral sulﬁdes but this time without

being constrained to the camphor skeleton.

Novel chiral thianes and 1,4-oxathianes

In the previous section we described the use of a variety

of chiral sulﬁde catalysts derived from camphor in the catalytic

in situ epoxidation of aldehydes (Scheme 1). Although we

achieved higher yields than we had with 1,3-oxathiane 1,

none of the new catalysts approached the high level of enantio-

selectivity obtained with 1. Consequently, it seemed necessary

to prepare a range of chiral sulﬁdes derived from materials

other than camphor which all incorporated the basic structural

features of 1,3-oxathiane 1. As depicted in Fig. 6, we sought

conformationally locked cyclic sulﬁdes in which the axial lone

pair would be hindered by an axial substituent. In addition,

ylide conformation and face selectivity needed to be controlled

and we proposed to achieve this through non-bonded steric

interactions. Sulﬁdes 28–32 (Fig. 7) were designed to incorpor-

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

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i

Scheme 8 Reagents and conditions: i methallyl bromide, NaOMe, MeOH, 72% (R = Me) or 64% (R = Pr); ii TFA, CH₂Cl₂, 86% (R = Me); iii I₂,

NaHCO₃, CCl₄, H₂O, 80% (R = Me) or I₂, Na₂CO₃, MeCN, 55% (R = ⁱPr); iv LiEt₃BH, THF, 60% (R = Me) or LiAlH₄, THF, 64% (R = ⁱPr).

Scheme 10 Reagents and conditions: i LiAlH₄, Et₂O, 76%; ii (MeO)₂-

CMe₂, PPTS, CH₂Cl₂, 86%.

Scheme 9 Reagents and conditions: i NaOEt, EtOH; ii NaOEt, Et₂O;

iii Baker’s yeast, H₂O, 66%.

Scheme 11 Reagents and conditions: i MeMgBr, THF, 75%; ii (MeO)₂-

CH₂, PPTS, CH₂Cl₂, 29%.

Scheme 12 Reagents and conditions: i LDA, THF, then MeI, HMPA,

81% (6 : 1 mixture of diastereoisomers); ii LiAlH₄, Et₂O, 77%; iii

(MeO)₂CMe₂, PPTS, CH₂Cl₂, 82% (mixture of diastereoisomers).

ated by chromatography to provide sulﬁde 29c as the major

product.

Sulﬁde 30 was synthesised from trans-limonene oxide 45

(Scheme 13). Thus, treatment of 45 with the sodium thiolate

Fig. 8 ORTEP drawing of β-hydroxyester 40.

Hayakawa and Shimizu described the synthesis of a related

sulﬁde 33 (Fig. 7) using a similar strategy, which gave 78% ee in

the epoxidation of benzaldehyde using conventional conditions

(BnBr, NaOH, MeCN).^6mThe preparation of α-methyl substi-

tuted 29c was accomplished as shown in Scheme 12, utilising the

procedure of Fráter for the α-alkylation of β-hydroxyesters.³¹

Scheme 13 Reagents and conditions: i NaH, DMF; ii BF₃ؒOEt₂, Et₂O,

Thus, treatment of 40 with lithium diisopropylamide at Ϫ50 ЊC,

slow warming of the dianion to Ϫ15 ЊC over two hours,

followed by alkylation with methyl iodide in HMPA furnished

sulﬁde 43 in 81% yield and as an inseparable 6 : 1 mixture of

diastereomers in favour of the product shown. Subsequent

reduction with LiAlH₄and acetalisation proceeded well

to aﬀord a diastereomeric mixture of acetals, which were separ-

80% over two steps; iii H₂, Pd–S/C, EtOH, 80%.

derived from mercaptoacetaldehyde diethyl acetal 46³²aﬀorded

the epoxide-opened product which was immediately cyclised

under the mediation of BF₃ؒOEt₂to give unsaturated 1,4-

oxathiane 47. It was not possible to use cis-limonene oxide as

no reaction occurred with the thiolate derived from 46. Hydro-

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Table 2 Yields and enantioselectivities for epoxidation

genation of 47 furnished the desired 1,4-oxathiane 30 in good

yield. The synthesis of 31 proceeded from (ϩ)-dihydrocarvone

48, which was converted to silyl enol ether 49 using a known

method as shown in Scheme 14.³³Treatment of 49 with methyl-

Entry

Sulﬁde

Yield (%)^a

trans : cis^b

ee (%)^c

1

2

3

4

5

6

7

8

28a

28b

29a

29b

29c

30

80

75

92

62

65

45

77

9

95 : 5

92 : 8

90 : 10

92 : 8

95 : 5

70 (R,R)

48 (R,R)^d

77 (S,S)

20 (S,S)

68 (S,S)

41 (S,S)

66 (S,S)

60 (R,R)

31

32

^aIsolated yield. ^bBy ¹H NMR. ^cMeasured on a Chiralcel OD column.

^dSulﬁde 28b only 66% ee by chiral GC.

(entries 4 and 8). However, the enantioselectivities observed

were only moderate for sulﬁdes 28a, 28b, 29a, 29c, 31 and 32

and low for 29b and 30, contrasting with those obtained with

1,3-oxathiane 1, where concerted steric and electronic factors

contribute to the high enantioselectivity. The following ration-

ale, illustrated for related sulﬁdes 29a or 29c, can be invoked to

account for the asymmetric induction observed (Scheme 16).

Scheme 14 Reagents and conditions: i CH₃CN, Et₃N, TMSCl, NaI,

80 ЊC, ii MeLi, THF, then BnSS(O)₂C₆H₄(CH₃), HMPA, THF, 82%

(4 : 1 mixture of diastereomers); iii DIBAL-H, CH₂Cl₂, 67%; iv Na,

NH₃, THF, used crude in next step; v BrCH₂CH(OEt)₂, KOH, EtOH,

39% from 51; vi BF₃ؒOEt₂, Et₂O, 50%; vii H₂, Pd–S/C, EtOH, 60%.

lithium at 0 ЊC generated the enolate which was transferred

by cannula into a solution of benzyl toluene-p-thiosulfonate

and HMPA to give the benzyl sulﬁde 50 as a 4 : 1 mixture of

diastereoisomers in favour of 50, which could not be separated

at this stage.^14,34–36Reduction of ketone 50 with DIBAL-H gave

the corresponding alcohol 51 in an isolated yield of 67%.

Debenzylation of 51 proceeded well to provide hydroxythiol 52,

which was immediately coupled with bromoacetaldehyde

diethyl acetal under basic conditions to furnish hydroxyacetal

53.¹⁴Attempts to form sulﬁde 31 directly from 53 with boron

triﬂuoride–diethyl ether–triethylsilane were unsuccessful, with a

signiﬁcant by-product being unsaturated 1,4-oxathiane 54.

Consequently, treatment of 53 with excess boron triﬂuoride–

diethyl ether furnished 54 cleanly in moderate yield, which was

hydrogenated to aﬀord 1,4-oxathiane 31. Sulﬁde 32 has been

prepared previously from thiol 56 and 3-hydroxy-3-methyl-

butan-2-one, although only in racemic form.³⁷We utilised this

procedure employing enantiomerically pure thiol 56, derived

from acetonide 55 by the method of Chu,³⁸to aﬀord sulﬁde 32

(Scheme 15).

Scheme 16

Only the equatorial sulfur lone pair of 29a or 29c should be

accessible, and hence only one diastereomer of the ylide should

be formed upon reaction of the sulﬁde with the rhodium carb-

enoid. This ylide can adopt conformations 57a or 57b, but 57b

should be favoured due to 1,3-diaxial interactions in 57a. The

facial selectivity of 57b should then dictate that the Si face be

more accessible to benzaldehyde, leading to the formation of

the (S,S)-epoxide, which was the observed major enantiomer.

We were surprised that 29c gave lower enantioselectivity

than 29a especially because both ylide conformation and face

selectivity should be better controlled in 29c. We cannot

account for this observation at present.

Similar arguments can be advanced for the observed absolute

stereochemistry of the trans-stilbene oxide obtained from

sulﬁdes 28a, 28b, 30, 31, and 32, with the major ylide con-

formation and facial selectivity shown in Fig. 9. Sulﬁde 29b,

containing a blocking equatorial methyl group, was further

evaluated. The asymmetric induction observed was consider-

ably lower than that previously seen but can be accounted for

by the following model (Scheme 17). In this case, it is possible

that both sulfur lone pairs may be equally hindered: the axial

lone pair by the axial oxygen and the equatorial lone pair by the

equatorial methyl group. This would produce a diastereomeric

mixture of sulfur ylides 58 and 59. Conformations 58b and 59b

should be favoured on consideration of 1,3-diaxial interactions,

but the respective facial selectivity of ylides 58b and 59b would

give rise to enantiomeric products.

Scheme 15 Reagents and conditions: i TsCl, NEt₃, CHCl₃, 71%;

ii BnSH, NaOEt, EtOH, 69%; iii Na–NH₃, 60%; iv AcOH, 58%;

v 3-hydroxy-3-methylbutan-2-one, TsOH, o-xylene, 25%.

Results of epoxidation. Sulﬁdes 28–32 were tested in the cata-

lytic cycle with benzaldehyde, using the new in situ conditions

(Scheme 6, Table 2). Good to excellent yields were obtained

using sulﬁdes 28a, 28b, 29a, 29c and 31 (entries 1, 2, 3, 5 and 7),

whilst somewhat lower yields using 29b and, particularly, 32

reﬂected the more sterically hindered nature of these sulﬁdes

We were surprised that the sulﬁdes we had carefully designed,

which we believed would largely control ylide formation, con-

formation and face selectivity, were still inferior to the camphor

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

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Fig. 10

Fig. 9

Fig. 11

Scheme 17

derived 1,3-oxathiane 1. As we were clearly unable to control

all three features that we perceived were required to achieve

high enantiocontrol we decided to eliminate one of them. We

decided to avoid the possibility of formation of diastereomeric

mixtures of sulfur ylides by using C₂symmetric sulﬁdes.

C₂symmetric chiral sulﬁdes

C₂symmetric sulﬁdes have been utilised previously in stoichio-

metric sulfonium ylide epoxidations, notably by Durst^6band

Metzner.^6k,6lAs shown for the generic sulﬁde structure in

Fig. 10, ylide conformation and face selectivity should be

controlled by non-bonded interactions. We therefore embarked

on the synthesis and application of a variety of C₂symmetric

sulﬁdes 60–65 (Fig. 11) in the new in situ catalytic epoxidation

cycle.

Scheme 18 Reagents and conditions: i ^tBuLi, HMPA, THF, 67; ii

TBAF, THF, 63% over two steps; iii Raney Ni, EtOH, 27%; iv MsCl,

pyridine, CH₂Cl₂; v Li₂S, DMSO, 43% over two steps.

formationally locked 63 and this was accomplished as shown

in Scheme 20. Dialkylation of sulfone 70 with (S)-propylene

oxide according to the procedure of Najdi and Kurth⁴³gave

the required diol 78 in 58% yield, together with some

monoalkylated product 77. Subsequent mesylation of 78 and

cyclisation with lithium sulﬁde furnished the cyclic sulﬁde 63.

Sulﬁdes 60a,^6l64,³⁹65a⁴⁰and 65b⁴¹were prepared as

described in the literature. The synthesis of sulﬁde 61 was

achieved as shown in Scheme 18. Following the procedure of

Smith and Boldi,⁴²dithiane 66 was dialkylated with (S)-

glycidyl† methyl ether 67 to furnish diol 68 following desilylation

with TBAF in 63% yield over two steps. Cleavage of the dithiane

moiety in 68 with Raney nickel was slow, providing diol 69 in

low yield. Subsequent mesylation and cyclisation with lithium

sulﬁde aﬀorded sulﬁde 61.^6lThe corresponding cyclic diol 62

was prepared in a similar manner to 61, starting from the

dialkylation of sulfone 70 with (R)-glycidyl benzyl ether 69

(Scheme 19) reported by Najdi and Kurth,⁴³which gave diol 73

in 50% yield, together with monoalkylated 72. Desulfonylation

of diol 73 with sodium–mercury amalgam, tosylation, sub-

sequent cyclisation with lithium sulﬁde and debenzylation

gave the required sulﬁde 62. We also wished to prepare con-

Results of epoxidation

Sulﬁdes 60–65 were tested in the catalytic cycle with benzalde-

hyde, using the new in situ conditions (Scheme 6, Table 3).

However, in general, low enantioselectivities were observed.

2,5-Dimethylthiolane 60a gave trans-stilbene oxide in moderate

yield and enantioselectivity (entry 1). However, this result

stands in contrast to the work of Metzner and co-workers who

employed a stoichiometric amount of 60a together with benzyl

bromide and benzaldehyde under basic conditions in

acetonitrile–water (9 : 1) to aﬀord trans-stilbene oxide in 84%

ee.^6k,6lThe wide discrepancy in enantioselectivities using 60a

under the Metzner conditions and our in situ reaction, which

† The IUPAC name for glycidyl is 2,3-epoxypropyl.

2610

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

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a radical stabilising group (Ph) α to sulfur, furnished no epoxide

(entry 3), perhaps because of the intervention of a facile

competitive Stevens rearrangement.

The sulfur lone pairs on 61 are equivalent through ring

inversion as shown in Scheme 21. The ylide formed upon

Scheme 19 Reagents and conditions: i n-BuLi, HMPA, THF, then 71,

50% (plus 40% of 72); ii Na–Hg, 73%; iii TsCl, Et₃N, CH₂Cl₂, 88%; iv

Li₂S, DMF, 43%; v Na–NH₃, 54%.

Scheme 21

reaction of the equatorial sulfur lone pair with the rhodium

carbenoid can adopt conformations 80a or 80b, but 80b

should be favoured due to 1,3-diaxial interactions in 80a. Ring

inversion of 80a and 80b leads to conformation 81a or 81b

respectively, which is equivalent to formation of the ylide

through reaction of the axial lone pair. Conformation 81b

should be favoured over 81a due to less stringent 1,3-diaxial

interactions. The conformational freedom of 61 means that a

mixture of conformers 80b and 81b will be present. The facial

selectivity of 80b should dictate that the Re face be more access-

ible to benzaldehyde, leading to the formation of the (R,R)-

epoxide. Conversely, ylide 81b should lead to the formation

of the (S,S)-epoxide. This could account for the low enantio-

selectivity observed with this catalyst.

Scheme 20 Reagents and conditions: i n-BuLi, HMPA, THF, then (S)-

propylene oxide, 58% (plus 24% of 77); ii MsCl, pyridine, CH₂Cl₂, 41%;

iii Li₂S, DMF, 81%.

Although the axial conformer 81b may seem to be highly

disfavoured on the basis of 1,3-diaxial interactions, it needs to

be considered given that Eliel and Willer have shown that the

C₂symmetric thiane 82 has a small preference for the axial

S-methyl conformer 83a (Scheme 22).⁴⁴Thermal equilibration

Table 3 Yields and enantioselectivities for epoxidation

Entry

Sulﬁde

Yield (%)^a

trans : cis^b

ee (%)^c

1

2

3

4

5

6

7

8

9

60a

60b

61

55

40

0

10

41

64

73

78

0

92 : 8

—

95 : 5

98 : 2

97 : 3

95 : 5

—

48 (R,R)

87 (R,R)^d

—

43 (S,S)

8 (S,S)

3 (S,S)

18 (S,S)

11 (R,R)

—

62

63

64

65a

65b

^aIsolated yield. ^bBy ¹H NMR. ^cMeasured on a Chiralcel OD column.

Scheme 22

^dIn MeCN–H₂O (9 : 1).

at sulfur occurred by heating at 100 ЊC in CD₃CN for several

hours. Evidently, the two gauche interactions in 83e are greater

than the sum of a single gauche interaction with 1,3-diaxial

interactions present in 83a. Similar arguments can be advanced

for sulﬁdes 61 and 62 (entries 4 and 5).

In order to restrict the ring inversion observed for sulﬁdes 61

and 62, we tested the conformationally locked thiane 63

(Scheme 23). The ylide formed upon reaction of the equatorial

lone pair should adopt conformation 84a, based on similar

arguments detailed above for 61. Ring inversion to form con-

former 84b should be negligible. Similarly, ylide 85a, formed

through reaction of the axial lone pair, should be the major

conformer. Ylides 84a and 85a have opposite facial selectivities

and based on the very low enantioselectivity observed (entry 6),

it seems likely that a diastereomeric mixture of ylides 84a and

85a was present. There is evidence in the literature which sug-

gests that this scenario is likely. Alkylation of the conforma-

presumably share a common benzyl ylide species, was not easy

to reconcile. However, Metzner reported a substantial depend-

ence of the yield and enantioselectivity on the particular solv-

ent mixture employed in his process. In order to probe whether

a similar eﬀect operated in our in situ reaction employing 60a as

catalyst, we conducted an in situ epoxidation in acetonitrile–

water (9 : 1). In test reactions with tetrahydrothiophene, this

solvent mixture gave superior yields compared to tert-BuOH–

water (9 : 1), EtOH–water (9 : 1) and 1,4-dioxane–water (9 : 1).

Under these new conditions, a substantially improved enantio-

selectivity was indeed achieved, although in lower yield

(entry 2). Alternative solvents (THF, toluene, 1,4-dioxane) were

investigated with 60a, but in no case did the enantioselectivities

approach those observed in acetonitrile–water, nor could yields

be improved using this solvent mixture. Sulﬁde 60b, which has

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

2611

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may be due to the anomeric eﬀect.^5bIndeed, Solladié-Cavallo’s

sulﬁde 88,^6gwhich is the only other sulﬁde that gives high

enantioselectivity, is also a 1,3-oxathiane (Scheme 26). The

Scheme 26 Reagents and conditions: i BnOH, pyridine, Tf₂O; ii NaH,

CH₂Cl₂, PhCHO, Ϫ40 ЊC.

oxygen of the 1,3-oxathiane will stabilise the ylide through over-

lap of its equatorial lone pair with the C–S σ* orbital. This

stabilisation will be maximal if the oxathiane retains its chair

conformation. In doing so, 1,3-diaxial interactions between the

ring and substituents on the ylide carbon are maintained,

leading to the formation of essentially a single ylide conformer.

High face selectivity in the reactivity of the ylide then leads

to high enantioselectivity in epoxidation. Without anomeric

stabilisation, we now believe that ﬂattening of the ring in the

ylides derived from the thianes and 1,4-oxathianes occurs and

this would lead to reduced 1,3-diaxial interactions. Such

reduced interactions would result in the presence of signiﬁcant

amounts of both ylide conformers, leading to lower enantio-

selectivity. There is substantial evidence that torsional deform-

ation of substituted thianes occurs upon alkylation resulting in

ﬂattening of the ring. This has been observed in both X-ray and

NMR analysis of S-methylthiolanium salts.^44,45Furthermore,

Barbarella and Dembech⁴⁶found from detailed NMR studies

that thiane and substituted derivatives actually exist in half

chair conformations and that upon alkylation signiﬁcant

deformation to quasi-envelope conformations occurred. Thus,

the erosion in enantioselectivity most likely originates from

facile deformation of the chair conformation of thianes leading

to poor control in the conformation of the ylide. Clearly what

was required were conformationally much more rigid sulﬁdes.

This analysis led to the design and synthesis of the conform-

ationally locked bridged bicyclic sulﬁde 89 (Scheme 27). This

Scheme 23

Scheme 24

tionally locked thiane 86 was reported to proceed in a 65 : 35

ratio in favour of the equatorial diastereomer 87e (Scheme 24).⁴⁴

The proposed reason for the greater than expected proportion

of the axial S-methyl diastereomer 87a was a large interaction

between the axial 2-methyl and the equatorial S-methyl in

87e, which is absent in 87a. The interaction between the axial

2-methyl and the equatorial S-methyl in 87e, which is absent in

87a is manifested in equilibration studies (heating at 100 ЊC in

CD₃CN for several hours), which resulted in a small preference

for the axial conformer 87a. Facile ﬂattening of the ring at

sulfur upon alkylation bends the axial 2-methyl group towards

the vicinal equatorial S-methyl accentuating this interaction.

The same arguments can be applied in ylide formation from

sulﬁde 63 leading to a low diastereomeric ratio of 84a : 85a.

The bicyclic thiane 64 contains equivalent lone pairs and the

conformation of the ylide should be controlled by non-bonded

interactions between the phenyl group and thiane ring (Scheme

25). The low enantioselectivity observed (entry 7) is probably

due to the methyl groups not being able to eﬀectively block one

face of the ylide. The binaphthyl group has proven to be an

excellent scaﬀold for numerous successful asymmetric catalysts,

but in the case of the binaphthyl sulﬁde 65a a poor enantio-

selectivity was observed (entry 8).⁴⁰This is most likely attrib-

utable to the formation of a diastereomeric mixture of ylides

coupled with some conformational freedom of the ylide.

Scheme 27 Reagents and conditions: i 1 mol% Rh₂(OAc)₄, 5 mol%

BnEt₃N^ϩCl^Ϫ, CH₃CN, 40 ЊC.

sulﬁde retained the three criteria described in the Introduction

but in addition was completely rigid, and so could not undergo

any subtle changes in bond angles and therefore ﬂattening of

the ring upon ylide formation. As such, ylide conformation was

much better controlled. This sulﬁde ﬁnally led to high enantio-

selectivity in the epoxidation process.⁷

Conclusions

We have recently described a new method for converting

carbonyl compounds into epoxides using tosylhydrazone salts

and catalytic quantities of Rh₂(OAc)₄and sulﬁde. The reaction

occurs via the corresponding diazo compound. However, 1,3-

oxathianes derived from camphorsulfonyl chloride, which

previously gave high yield and high enantioselectivity when

phenyldiazomethane was employed, only gave low yields in the

new process. A broad range of more robust, chiral sulﬁdes were

therefore prepared based on thianes, thiolanes, 1,4-oxathianes

and other bicyclic ring systems. The sulﬁdes were largely

Scheme 25

Unfortunately, the less conformationally mobile sulﬁde 65b

was not soluble in a range of solvents and gave no epoxide

(entry 9).⁴¹

The strategies described above have not been successful in

delivering sulﬁdes which give high yields and high enantio-

selectivities in epoxidation. We now believe the much higher

enantioselectivity observed with 1,3-oxathiane derived ylides

2612

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

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designed based on the following criteria: (i) only one of the two

lone pairs should be accessible so that a single diastereomer of

the sulfur ylide was formed (this of course did not apply to the

C₂symmetric thianes/thiolanes); (ii) the conformation of the

ylide should be controlled through 1,3-diaxial type interactions;

(iii) the face selectivity of the ylide should be controlled by

blocking substituents on the ring, making one face much more

hindered than the other. The sulﬁdes all proved to be stable to

the reaction conditions and gave high yields of epoxides. Even

though most sulﬁdes conformed to the above criteria the

enantioselectivity was only modest. This has been attributed to

poor control in the conformation of the ylide due to the ﬂexible

nature of the sulﬁde as thianes and thiolanes are particularly

prone to facile ﬂattening of the ring to avoid steric repulsions.

This analysis led to the design of the conformationally rigid

[2.2.1] bridged bicyclic sulﬁde 89, which ﬁnally led to high enan-

tioselectivity. Note added in proof: oxathiane 7 has recently

been reported and employed in related sulfur ylide reactions.⁴⁷

over MgSO₄and the solvent was evaporated under reduced

pressure. The resulting residue was puriﬁed by ﬂash column

chromatography (petroleum ether–Et₂O 70 : 30) to aﬀord

sulﬁde 3 (0.22 g, 40%) as a white solid, mp 47 ЊC; [α]²_D²= Ϫ128.8

(c 1.7 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ11456, 1385, 1366, 1237, 1158,

1101 and 1076; δ_H(250 MHz; CDCl₃) 0.94 (3H, s, CH₃), 1.00

(3H, s, CH₃), 1.25–1.75 (8H, m), 2.01–2.24 (3H, m), 2.75 (1H, d,

J 10.0, CHHS), 3.19 (1H, d, J 10.0, CHHS) and 5.60 (1H, t,

J 2.0, SCHO); δ_C(63 MHz; CDCl₃) 23.5, 24.6, 24.8, 25.2, 31.4,

31.7, 32.0, 38.4, 42.9, 49.0, 51.4, 82.4 and 94.5; m/z (CI) 225

(MH^ϩ, 80%) (Found: MH^ϩ, 225.1304. C₁₃H₂₁OS requires MH^ϩ,

225.1313).

(1R,4R,6S,8R)-11,11-Dimethyl-4-(1-methylethyl)-3-thiatricyclo-

[6.2.1.0^1,6]undecane 4

A mixture of alkene 14 (172 mg, 0.73 mmol) and palladium

sulﬁde, 5% wt on carbon (1.72 g) in methanol (30 cm³) was

hydrogenated at 20 atm at RT for 22 h. The mixture was ﬁltered

through Celite, concentrated under reduced pressure and

puriﬁed by ﬂash column chromatography (petrol) to aﬀord 4

(151 mg, 88%) as ﬁne white needles; mp 54–56 ЊC; [α]¹_D⁸= Ϫ136.4

(c 0.60 in CHCl₃); ν_max(Nujol)/cm^Ϫ12955, 1459 and 1384;

δ_H(250 MHz; CDCl₃) 0.87 (3H, s, CH₃), 0.95 (3H, d, J 6.5,

CH₃), 1.05 (3H, d, J 6.5, CH₃), 1.14 (3H, s, CH₃), 1.10–1.29

(2H, m, 2CH), 1.44–2.00 (9H, m, CH₂and CH), 2.40–2.47 (1H,

m, CHS), 2.48 (1H, d, J 14.5, CHHS) and 2.62 (1H, d, J 14.5,

CHHS); δ_C(63 MHz; CDCl₃) 20.6, 21.0, 21.8, 22.1, 25.2, 27.2,

29.7, 34.9, 36.6, 38.8, 39.0, 44.9, 45.5, 46.9 and 47.6; m/z (EI)

238 (M^ϩ, 34%) and 195 (100) (Found: M^ϩ, 238.1758. C₁₅H₂₆S

requires M^ϩ, 238.1755).

Experimental

¹H and ¹³C magnetic resonance spectra were recorded using

a Bruker ACS-250 and a Bruker AMX-2 400 spectrometer

1

supported by an Aspect 2000 data system. The H chemical

shifts were recorded on the δ scale and were measured relative

to the residual signal of chloroform at δ 7.25. ¹³C chemical

shifts were measured from the central peak of chloroform at

δ 77.0. Coupling constants are measured in hertz. Mass spectra

were recorded using a Kratos instrument. Infrared spectra were

obtained on a Perkin-Elmer Paragon 1000 FTIR instrument.

Melting points were determined on a Gallenkamp apparatus

and stand uncorrected. Elemental microanalyses were carried

out using a Perkin-Elmer 2400 Elemental Analyser CHN,

involving classical analysis for sulfur. Optical rotations were

recorded on an Optical Activity AA-10 polarimeter at 589 nm

with a path length of 1 dm and are reported in units of 10^Ϫ1deg

cm²g^Ϫ1. Concentrations (c) are quoted in g 100 cm^Ϫ3. Thin

layer chromatography (TLC) was used routinely to monitor the

progress of reactions and purity of compounds. TLC was

performed on Merck Kieselgel 60 F₂₅₄aluminium backed TLC

plates containing ﬂuorescent indicator. Visualisation was

achieved with 254 nm UV light and by treatment with either

a solution of phosphomolybdic acid (5 g in 100 cm³of 95%

ethanol) or 1% w/v aqueous potassium permanganate, followed

by warming of the TLC plate with a heat gun. Chromato-

graphic puriﬁcation of compounds was achieved by ﬂash

chromatography using Kieselgel 60 F₂₅₄40–63 micron silica gel.

Reactions were generally run in oven dried glassware under

nitrogen. Liquid reagents were distilled before use, while solid

reagents were generally used as supplied. Solvents were dried

and distilled by conventional methods.

(1S,5R,7R)-10,10-Dimethyl-4-methylene-3-thiatricyclo-

[5.2.1.0^1,5]decan-5-ol 6a

To a solution of thiol 16 (65 mg, 0.23 mmol) in THF (5 cm³) at

RT was added TBAF (0.5 cm³, 0.5 mmol, 1.0 M in THF). After

2 h, water was added to the reaction mixture, which was then

extracted with CH₂Cl₂(3×). The combined extracts were

washed with brine, dried (MgSO₄), concentrated under reduced

pressure and puriﬁed by ﬂash column chromatography (ethyl

acetate–petrol 5 : 95) to aﬀord 6a (31 mg, 64%) as a colourless

oil; [α]²_D⁰= Ϫ90.5 (c 2.10 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ13483, 2942,

1701 and 1627; δ_H(250 MHz; CDCl₃) 0.97 (3H, s, CH₃), 1.01–

1.16 (1H, m), 1.27 (3H, s, CH₃), 1.50–1.83 (4H, m), 1.96–2.10

(2H, m), 2.14 (1H, br s, OH), 2.52 (1H, d, J 9.0, CHHS), 3.22

(1H, d, J 9.0, CHHS), 4.93 (1H, d, J 1.0, ᎐CHH) and 5.12 (1H,

᎐

d, J 1.0, ᎐CHH); δ (63 MHz; CDCl₃) 22.0, 22.1, 26.9, 32.0,

᎐

C

32.1, 37.4, 46.3, 50.8, 61.7, 93.2, 101.4 and 151.8; m/z (EI) 210

(M^ϩ, 30%), 108 (57), 95 (100) and 81 (27) (Found: M^ϩ,

210.1085. C₁₂H₁₈OS requires M^ϩ, 210.1078).

Enantiomeric excesses were determined by chiral HPLC

using a Chiralcel OD column (1% i-PrOH–hexane, 2 cm³min^Ϫ1

)

(1S,5R,7R)-10,10-Dimethyl-4-methylene-3-thia-5-trimethylsilyl-

oxytricyclo[5.2.1.0^1,5]decane 6b

for trans-stilbene oxide and a Chiralcel OJ column (2%

i-PrOH–hexane, 2 cm³min^Ϫ1) for β-hydroxyester 40. The

enantiomeric excesses of sulﬁdes 28a and 28b were determined

by chiral GC using a β-cyclodextrin column (100 ЊC iso-

thermal). (Retention times: (S)-28a 6.58, (R)-28a 6.73 min and

(S)-28b 15.42, (R)-28b 15.87 min.) Compounds 10,⁸19,⁴⁸23,⁴⁹

34a,²⁰34b,²⁰39,²⁶46,³²49,³³55,³⁸56,³⁸60a,^6l64,³⁹65a⁴⁰and

65b⁴¹were prepared as described in the literature.

A mixture of alcohol 6a (95 mg, 0.45 mmol) and N-trimethyl-

silylimidazole (1.7 cm³, 11.6 mmol) was heated at 100 ЊC for

1.5 h. After cooling, the reaction mixture was diluted with

petroleum ether, washed with water, dried (MgSO₄), concen-

trated under reduced pressure and puriﬁed by ﬂash column

chromatography (petroleum ether) to aﬀord 6b (120 mg, 94%)

as a colourless oil; [α]²_D⁰= Ϫ172.7 (c 1.0 in CHCl₃); ν_max(ﬁlm)/

cm^Ϫ12941, 1622, 1247 and 1082; δ_H(250 MHz; CDCl₃) 0.10

(9H, s, Si(CH₃)₃), 0.80–1.10 (1H, m), 0.94 (3H, s, CH₃), 1.20–

2.05 (6H, m), 1.22 (3H, s, CH₃), 2.38 (1H, d, J 8.4, CHHS),

(1R,3R,6S,9S)-13,13-Dimethyl-12-oxa-8-thiatetracyclo-

[7.2.1.1^3,60^1,6]tridecane 3

To a solution of 11 (0.62 g, 2.40 mmol) in CH₂Cl₂(5 cm³) at

0 ЊC, was added dropwise BF₃ؒEt₂O (0.4 cm³, 3.10 mmol). The

resulting solution was stirred at 0 ЊC for 3.5 h then poured into

saturated NaHCO₃. The aqueous layer was extracted with

CH₂Cl₂. The combined extracts were washed with brine, dried

3.24–3.27 (1H, d, J 8.4, CHHS), 4.93 (1H, s, ᎐CHH) and 5.07

᎐

(1H, s, ᎐CHH); δ (63 MHz; CDCl ) 1.7, 22.2, 22.6, 26.7, 31.1,

᎐

C

3

32.3, 39.1, 46.1, 51.0, 62.8, 94.1, 102.0 and 152.7; m/z (EI) 282

(M^ϩ, 100%) and 267 (75) (Found: M^ϩ, 282.1479. C₁₅H₂₆OSSi

requires M^ϩ, 282.1474).

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

2613

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(1S,2R,7S,8R)-8,11,11-Trimethyl-3-oxa-6-thiatricyclo-

[6.2.1.0^2,7]undecane 7

(10 cm³). To this solution was added boron triﬂuoride–diethyl

ether (0.9 cm³, 7.2 mmol) at 0 ЊC. The reaction mixture was

stirred at RT for 16 h, after which it was quenched by the

addition of saturated ammonium chloride solution. The separ-

ated aqueous layer was extracted with CH₂Cl₂(3×) and the

combined extracts were washed with brine, dried (MgSO₄),

concentrated under reduced pressure and puriﬁed by ﬂash

column chromatography (petroleum ether) to aﬀord 8 (300 mg,

63% over three steps) as a clear oil; [α]²_D²= Ϫ104.0 (c 0.90

in CHCl₃); ν_max(ﬁlm)/cm^Ϫ12983, 2949, 2869, 1619 and 1473;

δ_H(250 MHz; CDCl₃) 0.77 (3H, s, CH₃), 0.83 (3H, s, CH₃), 0.94

(3H, s, CH₃), 0.98–1.04 (1H, m, CH), 1.12–1.22 (1H, m, CH),

1.47–1.58 (1H, m, CH), 1.75–2.00 (4H, m, 4CH), 2.05–2.14

(2H, m, CH₂) and 2.72–2.80 (2H, m, CH₂S); δ_C(63 MHz;

CDCl₃) 10.9, 19.2, 19.3, 23.6, 25.9, 27.1, 33.2, 54.5, 55.9, 56.4,

132.7 and 133.7; m/z (CI) 209 ([M ϩ H]^ϩ, 100%), 208 (M^ϩ, 85),

193 (30), 180 (32) and 113 (25) (Found: M^ϩ, 208.1284. C₁₃H₂₀S

requires M^ϩ, 208.1285).

To a solution of vinyl ether 20 (600 mg, 3.1 mmol) in benzene

(5 cm³) was added AIBN (20 mg, 0.12 mmol) and thioacetic

acid (0.66 cm³, 9.3 mmol). The reaction mixture was irradiated

with a sun lamp at RT for 2 h and then quenched by the add-

ition of sodium hydroxide solution (10% w/v). The solution was

extracted with ether (3×), dried (MgSO₄) and concentrated

under reduced pressure to aﬀord the crude thioacetate 21 (720

mg) [δ_H(250 MHz; CDCl₃) 0.89 (3H, s, CH₃), 0.90 (3H, s, CH₃),

0.95 (3H, s, CH₃), 1.22–1.42 (2H, m, 2CH), 1.51–1.71 (1H, m,

CH), 1.89–2.03 (1H, m, CH), 2.07 (1H, d, J 4.9, CH), 2.30 (3H,

s, SCOCH₃), 3.15 (2H, m, CH₂S), 3.39 (1H, s, CHO), 3.63 (1H,

dt, J 9.8 and 6.7, CHHO) and 3.87 (1H, dt, J 9.8 and 6.1,

CHHO)], which was used without further puriﬁcation. To a

solution of thioacetate 21 (700 mg, 2.59 mmol) in degassed

methanol (10 cm³) was added lithium hydroxide hydrate (140

mg, 3.4 mmol) at 0 ЊC and the mixture stirred for 20 min before

quenching by the addition of saturated ammonium chloride

solution. The mixture was diluted with ether (50 cm³), acidiﬁed

to pH 1 with a 1 M HCl solution and extracted with ether (3×).

The combined organics were washed with brine, dried (MgSO₄)

and concentrated under reduced pressure to aﬀord the crude

thiol 22 (550 mg) [δ_H(250 MHz; CDCl₃) 0.90 (3H, s, CH₃), 0.91

(3H, s, CH₃), 0.97 (3H, s, CH₃), 1.24–1.44 (2H, m, 2CH), 1.57

(1H, t, J 8.2, SH), 1.62 (1H, m, CH), 1.91–2.04 (1H, m, CH),

2.11 (1H, d, J 4.9, CH), 2.52 (2H, m, CH₂S), 3.41 (1H, s, CHO),

3.65 (1H, dt, J 9.8 and 6.7, CHHO) and 3.90 (1H, dt, J 9.8 and

5.8, CHHO)], which was used without further puriﬁcation. To

a solution of thiol 22 (550 mg, 2.41 mmol) in CH₂Cl₂(10 cm³)

was added triethylsilane (1.15 cm³, 7.2 mmol) and boron

triﬂuoride–diethyl ether (0.90 cm³, 7.2 mmol) at 0 ЊC. The reac-

tion mixture was stirred at RT for 16 h, after which it was

quenched by the addition of saturated ammonium chloride

solution. The separated aqueous layer was extracted with

CH₂Cl₂(3×) and the combined organics were washed with

brine, dried (MgSO₄), concentrated under reduced pressure and

puriﬁed by ﬂash column chromatography (ethyl acetate–petrol

10 : 90) to aﬀord 7 (330 mg, 52% over three steps) as a colour-

less oil; [α]²_D²= Ϫ83.3 (c 1.08 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ12953,

2885, 2712, 1479 and 1458; δ_H(250 MHz; CDCl₃) 0.82 (3H, s,

CH₃), 0.93 (3H, s, CH₃), 1.01–1.19 (2H, m, 2CH), 1.39 (3H, s,

CH₃), 1.60 (1H, dt, J 12.5 and 3.7, CH), 1.69–1.81 (1H, m, CH),

1.89 (1H, d, J 4.8, CH), 2.57–2.78 (2H, m, CH₂S), 3.07 (1H, d,

J 7.0, CHS), 3.36 (1H, d, J 7.0, CHO), 3.54 (1H, ddd, J 10.6, 6.9

and 4.0, CHHO) and 3.86 (1H, ddd, J 10.6, 8.8 and 8.4,

CHHO); δ_C(63 MHz; CDCl₃) 12.2, 21.4, 21.7, 24.2, 26.0, 37.6,

48.0, 48.9, 51.0, 55.9, 62.5 and 80.9; m/z (CI) 213 ([M ϩ H]^ϩ,

100%) and 102 (60) (Found: M^ϩ, 212.1239. C₁₂H₂₀OS requires

M^ϩ, 212.1234).

7,7-Dimethyl-1-mercaptomethyl-5Ј-methoxyspiro[bicyclo[2.2.1]-

heptane-2,2Ј-oxolane] 11

Cerium chloride heptahydrate (9.3 g, 25 mmol) was ﬁnely

ground and heated under reduced pressure (0.5 mmHg) at 140

ЊC for 2 h. While the ﬂask was still hot, argon gas was intro-

duced. The ﬂask was then cooled in an ice bath and THF (80

cm³) was introduced. The resulting suspension was submitted

to sonication for 1 h at RT before being cooled at Ϫ78 ЊC. 3,3-

Dimethoxypropylmagnesium bromide¹⁰(25 mmol) was added

dropwise to the cooled mixture. After stirring for 1 h at Ϫ78 ЊC

the ketone 10 (1.53 g, 8.3 mmol) in THF (10 cm³) was added

dropwise and the reaction mixture was allowed to warm to RT

overnight. The reaction was quenched with brine and the aque-

ous layer was acidiﬁed with 2 M HCl until complete dissolution

of the salts and then extracted with ethyl acetate. The combined

extracts were washed with brine, dried over MgSO₄and the

solvents were evaporated under reduced pressure. Puriﬁcation

of the residue by ﬂash column chromatography (petroleum

ether–Et₂O 50 : 50) gave 11 (1.7 g, 80%, 70 : 30 mixture of

diastereoisomers) as a pale yellow oil; ν_max(ﬁlm)/cm^Ϫ12984,

2936, 2827, 2562, 1482, 1463 and 1440; δ_H(250 MHz; CDCl₃)

0.91 (3H, s, CH₃), 1.05 (3H, s, CH₃), 1.32 (1H, d, J 13.0, SH),

1.58–1.90 (8H, m), 2.02 (1H, dt, J 3.0 and 12.0), 2.40 (1H, dd,

J 10.0 and 14.0, CHHS), 2.71–2.84 (1H, m), 3.01 (1H, dd, J 8.0

and 14.0, CHHS), 3.35 (3H, s, OCH₃) and 4.94–4.96 (1H, m,

OCHO); δ_C(63 MHz; CDCl₃) 20.7, 21.1, 22.6, 26.4, 27.8, 31.7,

34.6, 45.9, 48.9, 50.4, 53.9, 54.4, 93.6 and 104.7.

(1S,2R,4R)-1-Mercaptomethyl-7,7-dimethyl-2-(3,3-dimethyl-

prop-2-enyl)bicyclo[2.2.1]heptan-2-ol 12

A mixture of lithium (230 mg, 32.6 mmol) and naphthalene

(4.18 g, 32.6 mmol) in THF (40 cm³) was stirred at RT for 4 h,

after which 3,3-dimethylprop-2-enyl phenyl sulﬁde (2.9 g, 16.3

mmol) was added at 0 ЊC. The resulting red solution was stirred

at 0 ЊC for 1 h and then added to a mixture of cerium trichloride

(6.08 g, 16.3 mmol) [prepared by drying cerium trichloride

heptahydrate (6.08 g, 16.3 mmol) under reduced pressure (0.5

mmHg) at 150 ЊC for 2.5 h before suspending in THF (50 cm³)

and sonicating for 1 h followed by stirring at RT for 1 h] at Ϫ78

ЊC. The resulting brown solution was stirred at Ϫ78 ЊC for 1 h

and then ketone 10 (1.0 g, 5.43 mmol) was added portionwise

over 10 min. The reaction mixture was stirred at RT for 16 h,

after which it was quenched by the addition of HCl solution

(2 M). The separated aqueous layer was extracted with petrol-

eum ether (3×) and the combined extracts were dried (MgSO₄),

concentrated under reduced pressure and puriﬁed by ﬂash

column chromatography (ethyl acetate–petrol 3 : 97) to aﬀord

12 (790 mg, 50%) as a colourless oil together with ketone 10

(50%); ν_max(ﬁlm)/cm^Ϫ13535, 2930 and 1667; δ_H(250 MHz;

CDCl₃) 0.90 (3H, s, CH₃), 1.09 (3H, s, CH₃), 1.26–1.36 (1H, dd,

(1R,8S)-1,11,11-Trimethyl-3-thiatricyclo[6.2.1.0^2,7]undec-2(7)-

ene 8

To a solution of a 7 : 3 exo–endo mixture of allylcamphor 23

(440 mg, 2.3 mmol) in benzene (15 cm³) was added AIBN (20

mg, 0.12 mmol) and thioacetic acid (0.65 cm³, 9.2 mmol). The

reaction mixture was heated at reﬂux for 1 h and then quenched

by the addition of sodium hydroxide solution (10% w/v). The

solution was extracted with ether (3×), dried (MgSO₄) and

concentrated under reduced pressure to aﬀord the crude thio-

acetate 24, which was immediately dissolved in degassed

methanol (10 cm³). At 0 ЊC, lithium hydroxide hydrate (210 mg,

4.6 mmol) was added and the mixture stirred for 20 min before

quenching by the addition of saturated ammonium chloride

solution. The mixture was diluted with ether (50 cm³), acidiﬁed

to pH 1 with a 1 M HCl solution and extracted with ether (3×).

The combined organics extracts were washed with brine, dried

(MgSO₄) and concentrated under reduced pressure to aﬀord

the crude thiol 25, which was immediately dissolved in CH₂Cl₂

2614

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

View Article Online

J 8.9 and 7.0), 1.36–2.20 (9H, m), 1.69 (3H, s, CH₃), 1.77 (3H, s,

CH₃), 2.59 (1H, dd, J 13.4 and 7.0), 3.01 (1H, dd, J 13.4 and

8.9), 3.12 (1H, dd, J 13.4 and 9.8) and 5.15–5.45 (1H, m);

δ_C(63 MHz; CDCl₃) 18.5, 21.4, 21.5, 23.0, 26.2, 26.7, 26.9, 39.3,

45.7, 46.8, 50.7, 55.0, 80.1, 119.6 and 137.8.

separated aqueous layer extracted with ethyl acetate (3×). The

combined extracts were dried (MgSO₄) and concentrated under

reduced pressure to aﬀord 16 (65 mg, 84%) as a colourless oil;

[α]²_D⁰= ϩ9.3 (c 2.68 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ13462, 2956, 2161

and 842; δ_H(250 MHz; CDCl₃) 0.08–0.21 (9H, m, Si(CH₃)₃),

0.77–1.29 (3H, m), 0.90 (3H, s, CH₃), 1.60 (3H, s, CH₃), 1.49–

1.83 (4H, m), 2.12–2.42 (2H, m), 2.53 (1H, dd, J 13.0 and 7.5,

CHHS) and 3.01 (1H, dd, J 13.0 and 7.0, CHHS); δ_C(63 MHz;

CDCl₃) Ϫ0.2, 20.8, 21.6, 23.4, 26.5, 29.4, 45.8, 49.5, 49.7, 56.3,

89.9, 111.3 and quaternary not visible; m/z (EI) 282 (M^ϩ, 46%),

233 (27), 108 (52) and 73 (100) (Found: M^ϩ, 282.1472.

C₁₅H₂₆OSSi requires M^ϩ, 282.1474).

(1S,4S,6R,8R)-11,11-Dimethyl-4-(1-methylethyl)-3-thiatricyclo-

[6.2.1.0^1,6]undecan-6-ol 13

A mixture of thiol 12 (460 mg, 1.8 mmol) and AIBN (30 mg,

0.18 mmol) in benzene (17 cm³) was heated at reﬂux for 24 h.

The solution was concentrated under reduced pressure and

the residue puriﬁed by ﬂash column chromatography (ethyl

acetate–petrol 10 : 90) to aﬀord 13 (257 mg, 56%) as a colour-

less oil; δ_H(250 MHz; CDCl₃) 0.90 (3H, s, CH₃), 1.10 (3H, s,

CH₃), 0.80–2.20 (18H, m), 3.15 (1H, br s) and 3.22 (1H, br s); δ_C

(63 MHz; CDCl₃) 19.9, 20.1, 21.2, 22.6, 26.6, 27.5, 30.7, 32.6,

38.9, 44.3, 45.6, 47.1, 48.3, 50.9 and 78.5.

(1R,3R,4S)-3-(Ethenyloxy)-1,7,7-trimethylbicyclo[2.2.1]heptan-

2-one 20

To a solution of phenanthroline (100 mg, 0.56 mmol) in CH₂Cl₂

(20 cm³) was added palladium acetate (120 mg, 0.54 mmol).

The mixture was stirred at RT for 20 min after which exo-

hydroxy camphor 19 (1.8 g, 10.71 mmol) and ethyl vinyl ether

(100 cm³) were added. Following stirring for 6 days at RT the

solution was concentrated under reduced pressure and the

residue puriﬁed by ﬂash column chromatography (ethyl

acetate–petrol 10 : 90) to aﬀord 20 (820 mg, 40%) as a colour-

less oil and alcohol 19 (1.0 g, 55%); δ_H(250 MHz; CDCl₃) 0.93

(6H, s, CH₃), 0.95 (3H, s, CH₃), 1.32–1.52 (2H, m, 2CH), 1.63–

1.73 (1H, m, CH), 2.02–2.08 (1H, m, CH), 2.21 (1H, d, J 4.8,

(1S,4S,8R)-11,11-Dimethyl-4-(1-methylethyl)-3-thiatricyclo-

[6.2.1.0^1,6]undec-5-ene 14

A solution of oxalyl chloride (0.45 cm³, 5.25 mmol) and sulﬁde

13 (257 mg, 1.01 mmol) in benzene (3 cm³) was stirred at RT for

5 h, after which it was concentrated under reduced pressure and

the residue puriﬁed by ﬂash column chromatography (ethyl

acetate–petrol 10 : 90) to aﬀord 14 (193 mg, 81%) as a colour-

less oil; [α]²_D⁰= Ϫ36.0 (c 1.0 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ12955,

2872, 1686 and 1387; δ_H(250 MHz; CDCl₃) 0.76 (3H, s, CH₃),

0.91 (3H, s, CH₃), 0.98 (3H, d, J 7.5, CH₃), 1.01 (3H, d, J 7.5,

CH₃), 1.13–1.29 (2H, m), 1.50–1.96 (6H, m), 2.40 (1H, d, J 12.8,

CHHS), 2.76 (1H, d, J 12.8, CHHS), 3.30–3.40 (1H, m) and

5.30–5.33 (1H, m); δ_C(63 MHz; CDCl₃) 18.5, 19.0, 19.6, 19.7,

27.4, 28.7, 32.5, 32.9, 36.4, 44.1, 46.6, 47.7, 49.5, 118.1 and

147.2.

CH), 3.81 (1H, s, CHO), 4.05 (1H, dd, J 14.0 and 6.6, ᎐CH),

᎐

4.25 (1H, dd, J 14.0 and 2.0, ᎐CH) and 6.50 (1H, dd, J 14.0 and

᎐

6.6, ᎐CHO).

᎐

(5R)-2,2,5-Trimethyl-1,4-oxathiane 28a

To a solution of sulﬁde 38a (1.65 g, 6.06 mmol) in THF (24

cm³) at 0 ЊC was added dropwise lithium triethylborohydride

(24 cm³, 24 mmol, 1 M solution in THF). The solution was

stirred at 30 ЊC for 24 h after which it was then poured portion-

wise into cold 2 M HCl. The aqueous layer was extracted with

ether (3 × 50 cm³). The combined organic extracts were washed

with saturated sodium bicarbonate solution (50 cm³) and brine

(50 cm³), dried (MgSO₄), concentrated under reduced pressure

and puriﬁed by ﬂash column chromatography (ether–petrol 10 :

90) to aﬀord 28a (530 mg, 60%) as a yellow oil; [α]²_D²= ϩ3.6

(c 0.55 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ12975, 2928, 2869, 1453, 1381

and 1364; δ_H(250 MHz; CDCl₃) 1.13 (3H, d, J 7.0, CH₃CH),

1.39 (3H, s, CH₃C), 1.48 (3H, s, CH₃C), 2.40 (1H, d, J 13.0,

CHHS), 2.80–3.00 (2H, m, CHS and CHHS), 3.57 (1H, dd,

J 12.0 and 10.0, CHHO) and 3.92 (1H, dd, J 12.0 and 3.0,

CHHO); δ_C(63 MHz; CDCl₃) 16.4, 22.1, 29.2, 34.1, 37.4,

68.5 and 69.1; m/z (CI) 147 (M^ϩ, 100%), 88 (34), 71 (15), 63 (31)

and 58 (28) (Found: [M ϩ H]^ϩ, 147.0846. C₇H₁₅OS requires

[M ϩ H]^ϩ, 147.0844).

(1R,4R,6S,8R)-11,11-Dimethyl-4-(1-methylethyl)-3ꢀ⁴-thiatri-

cyclo[6.2.1.0^1,6]undecan-3-one 15

To a solution of sulﬁde 4 (51 mg, 0.21 mmol) in CH₂Cl₂(0.5 cm³)

at 0 ЊC was added a solution of MCPBA (44 mg, 0.26 mmol) in

CH₂Cl₂. After 1 h the mixture was diluted with CH₂Cl₂(10 cm³)

and washed with sodium bicarbonate solution (10 cm³) and

brine (10 cm³). The organic extract was dried (MgSO₄) and

concentrated under reduced pressure to aﬀord 15 (50 mg, 92%)

as a crude solid which was recrystallised (ether–hexane) to

obtain X-ray quality crystals; δ_H(250 MHz; CDCl₃) 0.78–2.14

(9H, m, 9CH), 0.87 (3H, s, CH₃), 1.04 (6H, d, J 4.0, 2CH₃), 1.06

(3H, s, CH₃), 2.23 (1H, sextet, J 6.5, CH), 2.49–2.58 (2H, m,

2CH), 2.80 (1H, d, J 13.0, CHH) and 2.91 (1H, d, J 13.0,

CHH); δ_C(63 MHz; CDCl₃) 18.1, 20.5, 20.6, 20.7, 27.3, 27.4,

27.7, 36.7, 38.4, 39.0, 44.6, 46.7, 48.3, 48.8 and 68.4.

Crystal structure of 15. Crystal data for C₁₅H₂₆OS; M =

254.42. Crystallises from n-hexane as colourless blocks; crystal

dimensions 0.14 × 0.14 × 0.10 mm³. Orthorhombic, a =

7.5509(7), b = 7.9475(8), c = 23.423(2) Å, U = 1405.6(2) Å³,

Z = 4, D_c= 1.202 Mg m^Ϫ3, space group P2₁2₁2₁(D⁴₂, no. 19), Mo-

Kα radiation (λ = 0.71073 Å), µ(Mo-Kα) = 0.214 mm^Ϫ1, F(000)

= 560. CCDC reference number 168552. See http://ww w .rsc.org/

suppdata/p1/b1/b105416n/ for crystallographic ﬁles in .cif or

other electronic format.

(5R)-2,2-Dimethyl-5-(1-methylethyl)-1,4-oxathiane 28b

To a cooled (0 ЊC) solution of lithium aluminium hydride (380

mg, 10 mmol) in THF (25 cm³) was added dropwise a solution

of sulﬁde 38b (2.0 g, 6.7 mmol) in THF (5 cm³). At the end of

the addition, the ice bath was removed and the mixture was

stirred for 15 h. The mixture was then cooled to 0 ЊC and dilute

HCl solution was added. The aqueous layer was extracted with

ether (3 × 25 cm³). The combined organic extracts were washed

with brine (20 cm³), dried (MgSO₄), concentrated under

reduced pressure and puriﬁed by ﬂash column chromatography

(ether–petrol 2 : 98) to aﬀord 28b (0.67 g, 64% based on

recovered starting material) as a yellow oil; ν_max(ﬁlm)/cm^Ϫ1

3005, 2963, 2930, 2873, 1464 and 1371; δ_H(250 MHz; CDCl₃)

0.96 (3H, d, J 6.0, CH₃CH), 0.98 (3H, d, J 6.0, CH₃CH), 1.25

(3H, s, CH₃C), 1.35 (3H, s, CH₃C), 1.67–1.80 (1H, m, CH₃CH),

2.35 (1H, d, J 13.0, CHHS), 2.55 (1H, ddd, J 10.0, 6.0 and 3.0,

CHS), 2.71 (1H, d, J 13.0, CHHS), 3.71 (1H, dd, J 12.0 and

(1S,2S,4R)-1-Mercaptomethyl-7,7-dimethyl-2-(trimethyl-

silanylethynyl)bicyclo[2.2.1]heptan-2-ol 16

Trimethylsilylacetylene (0.15 cm³, 1.1 mmol) was added drop-

wise to a solution of n-butyllithium (0.32 cm³, 0.8 mmol, 2.5 M

in hexanes) at Ϫ78 ЊC in THF (0.5 cm³). After 30 min a solution

of ketone 10 (50 mg, 0.27 mmol) in THF (0.5 cm³) was added to

the reaction mixture which was then stirred for 3 h at Ϫ78 ЊC.

The reaction was quenched by the addition of brine and the

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

2615

View Article Online

10.0, CHHO) and 3.86 (1H, dd, J 12.0 and 3.0, CHHO); δ_C(63

MHz; CDCl₃) 20.1, 20.2, 22.1, 29.2, 29.4, 37.5, 46.7, 65.5 and

69.4; m/z (EI) 174 (M^ϩ, 57%), 149 (17), 116 (49), 101 (18), 69

(100), 59 (35) and 55 (55) (Found: M^ϩ, 174.1070. C₉H₁₈OS

requires M^ϩ, 174.1078).

27.1, 29.5, 40.8, 69.3, 69.6 and 98.6; m/z (EI) 202 (M^ϩ, 24%),

144 (53), 101 (100), 74 (91) (Found: M^ϩ, 202.1026. C₁₀H₁₈O₂S

requires M^ϩ, 202.1028).

(4aS,6R,8aS)-8a-Methyl-6-(1-methylethyl)perhydro-1,4-benz-

oxathiine 30

(4aS,8aS)-2,2-Dimethylperhydrothiopyrano[3,2-d][1,3]dioxine

To a mixture of sodium hydride (160 mg, 4.0 mmol, 60%

dispersion in oil) in DMF (7 cm³) at 0 ЊC was added mercapto-

acetaldehyde diethyl acetal 46 (550 mg, 3.67 mmol). (1R,4S)-

trans-Limonene oxide 45 (0.4 cm³, 2.4 mmol) was added to the

mixture which was then stirred at RT for 18 h. Hydrochloric

acid solution (5 cm³, 2 M) was added to the solution and the

separated aqueous layer was extracted with ether (3 × 20 cm³).

The combined organic extracts were washed with sodium

hydroxide solution (10 cm³, 10% w/v) and brine (10 cm³), dried

(MgSO₄) and concentrated under reduced pressure. The residue

was immediately dissolved in ether (30 cm³) and at 0 ЊC boron

triﬂuoride–diethyl ether (0.9 cm³, 7.2 mmol) was added. After

stirring at RT for 3 h, the mixture was quenched by the addition

of saturated ammonium chloride solution (10 cm³) and the

separated aqueous layer was extracted with ether (3 × 20 cm³).

The combined organic extracts were dried (MgSO₄), concen-

trated under reduced pressure and puriﬁed by ﬂash column

chromatography (ethyl acetate–petrol 5 : 95) to aﬀord 47 (410

mg, 80% over two steps) as a colourless oil [δ_H(250 MHz;

CDCl₃) 1.32 (3H, s, CH₃), 1.32–1.64 (3H, m, 3CH), 1.70–1.77

(4H, m, CH₃and CH), 2.07–2.15 (2H, m, 2CH), 2.38 (1H, m,

CH), 3.15 (1H, dd, J 13.3 and 3.5, CHS), 4.86–4.98 (3H, m,

29a

To a solution of diol 41 (260 mg, 1.76 mmol) in CH₂Cl₂(4.4

cm³) at RT was added 2,2-dimethoxypropane (0.86 cm³, 7.03

mmol) and PPTS (44 mg, 0.18 mmol). The mixture was stirred

for 48 h, after which time it was diluted with CH₂Cl₂(10 cm³),

washed with saturated sodium bicarbonate solution (5 cm³),

dried (MgSO₄), concentrated under reduced pressure and

puriﬁed by ﬂash column chromatography (ethyl acetate–petrol

10 : 90) to aﬀord 29a (285 mg, 86%) as a white solid, mp 76–78

ЊC; [α]²_D³= Ϫ76.9 (c 0.52 in CHCl₃); ν_max(Nujol)/cm^Ϫ12923–

2853; δ_H(250 MHz; CDCl₃) 1.40 (3H, s, CH₃), 1.43 (3H, s,

CH₃), 1.51 (1H, m, CHH), 1.57–1.68 (1H, m, CHH), 1.82–1.95

(2H, m, CH₂), 2.45–2.56 (1H, m, CHHS), 2.66 (1H, m, CHHS),

2.87 (1H, br s, CH), 3.60 (1H, dd, J 13.0 and 1.0, CHHO), 4.07–

4.13 (1H, m, CHS) and 4.17 (1H, dd, J 13.0 and 3.0, CHHO); δ_C

(63 MHz; CDCl₃) 19.3, 20.2, 28.3, 29.6, 31.5, 39.1, 63.9, 64.1

and 98.9; m/z (EI) 188 (M^ϩ, 65%) and 130 (100) (Found: M^ϩ,

188.0872. C₉H₁₆O₂S requires M^ϩ, 188.0871).

(4aR,8aS)-4,4-Dimethylperhydrothiopyrano[3,2-d][1,3]dioxine

29b

vinyl CH and ᎐CHS) and 6.42 (1H, d, J 6.5, ᎐CHO); m/z (EI)

᎐

2

To a solution of diol 42 (261 mg, 1.52 mmol) in CH₂Cl₂(5 cm³)

at RT was added dimethoxymethane (0.5 cm³, 5.6 mmol) and

PPTS (43 mg, 0.17 mmol). The mixture was stirred at RT for

48 h, after which further dimethoxymethane (0.5 cm³, 5.6 mmol)

was added. Following stirring for a further 48 h, dimeth-

oxymethane (0.5 cm³, 5.6 mmol) was added and the mixture

stirred for another 48 h. The reaction mixture was washed with

saturated sodium bicarbonate solution (5 cm³) and brine (10

cm³). The aqueous layer was extracted with CH₂Cl₂(3 × 10 cm³)

and the combined organic extracts dried (MgSO₄), concen-

trated under reduced pressure and puriﬁed by ﬂash column

chromatography (CH₂Cl₂) to aﬀord 29b (84 mg, 29%) as ﬁne

white needles; [α]²_D⁰= Ϫ67.1 (c 1.44 in CH₂Cl₂); ν_max(Nujol)/

cm^Ϫ12924, 2853 and 1377; δ_H(250 MHz; CDCl₃) 1.27 (3H, s,

CH₃), 1.40 (3H, s, CH₃), 1.41–1.54 (1H, m, CH), 1.62–1.74 (1H,

m, CH), 1.83–2.02 (1H, m, CH), 2.04–2.16 (1H, m, CH), 2.55–

2.65 (2H, m, CH₂), 2.80 (1H, s, CHS), 4.10–4.18 (1H, br m,

CHO) and 5.0 (2H, s, CH₂); δ_C(63 MHz; CDCl₃) 20.4, 22.8,

27.7, 28.0, 31.7, 47.7, 68.4, 73.8 and 88.2; m/z (EI) 188 (M^ϩ,

39%) and 100 (100) (Found: M^ϩ, 188.0870. C₉H₁₆O₂S requires

M^ϩ, 188.0710).

210 (M^ϩ, 100%) (Found: M^ϩ, 210.1078. C₁₂H₁₈OS requires M^ϩ,

210.1078)]. Diene 47 was dissolved in ethanol (50 cm³) and

palladium sulﬁde, 5% wt on carbon (100 mg) was added.

The mixture was hydrogenated (H₂balloon pressure) at RT for

18 h, then ﬁltered through Celite, concentrated under reduced

pressure and puriﬁed by ﬂash column chromatography (ethyl

acetate–petrol 5 : 95) to aﬀord 30 (330 mg, 80%) as a colourless

oil; [α]²_D²= ϩ3.6 (c 0.55 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ12936, 2868,

1459, 1370 and 1298; δ_H(250 MHz; CDCl₃) 0.89 (6H, d, J 6.6,

(CH₃)₂), 1.16–1.94 (11H, m, CH and CH₃), 2.35 (1H, dt, J 13.4

and 2.0, CHS), 3.02–3.07 (2H, m, CH₂S), 3.78–3.82 (1H, m,

CHO) and 4.01 (1H, dt, J 12.3 and 2.3, CHO); δ_C(63 MHz;

CDCl₃) 14.7, 21.3, 21.5, 25.2, 26.2, 30.3, 31.1, 34.7, 40.9, 44.9,

61.2 and 74.8; m/z (CI) 215 ([M ϩ H]^ϩ, 100%), 143 (99), 136

(35) and 129 (45) (Found: M^ϩ, 214.1391. C₁₂H₂₂OS requires

M^ϩ, 214.1387).

(4aS,7R,8aR)-4a-Methyl-7-(1-methylethyl)perhydro-1,4-benz-

oxathiine 31

A mixture of sulﬁde 54 (62 mg, 0.30 mmol) and palladium

sulﬁde, 5% wt on carbon (124 mg) in methanol (4 cm³) was

hydrogenated at 20 atm at RT for 24 h. The mixture was ﬁltered

through Celite, concentrated under reduced pressure and

puriﬁed by ﬂash column chromatography (ethyl acetate–petrol

1 : 99) to aﬀord 31 (38 mg, 60%) as a colourless oil; [α]¹_D⁸= ϩ14.3

(c 0.14 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ12955, 2871, 1451 and 1369;

δ_H(250 MHz; CDCl₃) 0.90 (3H, d, J 1.5, CH₃), 0.93 (3H, d,

J 1.5, CH₃), 1.12–1.57 (9H, m, CH₃, CH₂and CH), 1.66–1.71

(1H, m, CH), 2.32 (1H, d, J 12.0, CH), 2.41 (1H, d, J 12.0, CH),

3.12–3.24 (1H, m, CH), 3.46 (1H, dd, J 12.0 and 4.0, CH), 3.70–

3.77 (1H, m, CH) and 3.92 (1H, dt, J 12.0 and 2.5, CH); δ_C(63

MHz; CDCl₃) 19.9, 20.0, 24.8, 24.9, 28.4, 28.5, 32.5, 39.1, 42.3,

43.8, 58.8 and 79.3; m/z (EI) 214 (M^ϩ, 43%), 58 (100) (Found:

M^ϩ, 214.1397. C₁₂H₂₂OS requires M^ϩ, 214.1391).

(4aS,8aS)-2,2,4a-Trimethylperhydrothiopyrano[3,2-d][1,3]-

dioxine 29c

To a solution of diol 44 (675 mg, 4.17 mmol) in CH₂Cl₂(10 cm³)

at RT was added 2,2-dimethoxypropane (2.5 cm³, 20.8 mmol)

and PPTS (157 mg, 63 mmol). The mixture was stirred for 72 h,

after which time the reaction mixture was diluted with CH₂Cl₂

(15 cm³), washed with saturated sodium bicarbonate solution

(10 cm³), dried (MgSO₄), concentrated under reduced pressure

and puriﬁed by ﬂash column chromatography (ethyl acetate–

petrol 5 : 95) to aﬀord 29c (305 mg, 36%) as a clear glassy

solid, together with 344 mg of a mixture of 29c and the minor

diastereomer and 38 mg of pure minor diastereomer; [α]²_D³

=

Ϫ8.3 (c 0.72 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ12923–2853; δ_H(250

MHz; CDCl₃) 1.27 (3H, s, CH₃), 1.44 (3H, s, CH₃), 1.51 (3H, s,

CH₃), 1.61–1.81 (3H, m, CH₂and CHH), 1.86–2.08 (1H, m,

CHH), 2.49 (1H, td, CHHS), 2.83 (1H, dt, J 13.0 and 2.4,

CHHS), 3.41 (1H, d, J 12.5, CHHO) and 3.72–3.77 (2H, m,

CHHO and CH); δ_C(63 MHz; CDCl₃) 19.0, 20.0, 22.2, 25.4,

(1R,5R)-4,4,5-Trimethyl-6,8-dioxa-3-thiabicyclo[3.2.1]octane

32

To a mixture of thiol 56 (350 mg, 3.3 mmol) and PTSA (35 mg,

0.18 mmol) in o-xylene (15 cm³) heated at reﬂux with a Dean–

2616

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

View Article Online

Stark trap was added 3-hydroxy-3-methylbutan-2-one (0.35

cm³, 3.3 mmol). The mixture was reﬂuxed for 5 h, after which

time, at 20 ЊC, sodium carbonate (150 mg) was added and the

mixture stirred for a further 1 h. The solution was ﬁltered, con-

centrated under reduced pressure and puriﬁed by ﬂash column

chromatography (CH₂Cl₂) to aﬀord 32 (130 mg, 25%) as a white

solid, mp 128–129 ЊC; [α]²_D⁵= Ϫ94.1 (c 1.02 in CHCl₃) (Found:

C, 55.2; H, 8.3; S, 18.2. C₈H₁₄O₂S requires C, 55.2; H, 8.1; S,

18.4%); δ_H(250 MHz; CDCl₃) 1.20 (3H, s, CH₃), 1.40 (3H, s,

CH₃), 1.55 (3H, s, CH₃), 2.22 (1H, dd, J 13.5 and 2.5, CHHS),

3.33–3.40 (1H, m, CHHS), 3.97–4.03 (1H, m, CHHO), 4.27

(1H, d, J 6.5, CHHO) and 4.69–4.75 (1H, m, CHO);

δ_C(63 MHz; CDCl₃) 19.8, 25.6, 26.9, 30.6, 69.2, 74.7 and two

quaternary carbons not apparent in J modulation experiment

(JMOD) spectrum; m/z (EI) 174 (M^ϩ, 37%), 74 (100).

atography (ether–petrol 20 : 80) to aﬀord 38a (390 mg, 80%)

as a yellow oil and as a 1 : 1 mixture of diastereoisomers;

ν_max(ﬁlm)/cm^Ϫ12960, 2926, 2864 and 1451; δ_H(250 MHz;

CDCl₃) 1.14 (3H, d, J 7, CH₃CH), 1.49 (3H, s, CH₃), 2.51

(1H, d, J 13.5, CHHS), 2.74–2.89 (1H, m, CH₃CHS), 2.87 (1H,

d, J 13.5, CHHS), 3.27 (1H, d, J 10.0, CHHI), 3.37 (1H, d,

J 10.0, CHHI), 3.54 (1H, dd, J 12.0 and 9.5, CHHO) and

3.83 (1H, dd, J 12.0 and 3.0, CHHO); δ_C(63 MHz; CDCl₃)

16.1, 17.3, 21.3, 33.8, 34.3, 68.9 and 69.0; m/z (EI) 272

(M^ϩ, 57%), 185 (12), 145 (27), 103 (68), 87 (77), 59 (83) and

55 (100) (Found: M^ϩ, 271.9732. C₇H₁₃IOS requires M^ϩ,

271.9732).

(5R)-2-(Iodomethyl)-2-methyl-5-(1-methylethyl)-1,4-oxathiane

38b

To a stirred solution of 35b (2.46 g, 14.1 mmol) in acetonitrile

(160 cm³) was added anhydrous sodium carbonate (15 g, 141

mmol) and iodine (18 g, 70.7 mmol). The mixture was stirred in

the dark at RT for 8 h, diluted with ether (100 cm³) and then

treated with an aqueous solution of Na₂SO₃(10% w/v). The

organic layer was washed with brine (50 cm³), dried (MgSO₄)

and puriﬁed by ﬂash column chromatography (ether–petrol

20 : 80) to aﬀord 38b (2.3 g, 55%) as a yellow oil and as a 1 : 1

mixture of diastereoisomers; ν_max(ﬁlm)/cm^Ϫ12959, 2931, 2871,

1463 and 1360; δ_H(250 MHz; CDCl₃, mixture of diastereo-

isomers) 0.95–1.01 (12H, m, 2(CH₃)₂CH), 1.32 and 1.46 (6H,

2s, 2CH₃), 1.64–1.83 (2H, m, 2(CH₃)₂CH), 2.42–2.93 (6H, m,

2CH₂S and 2CHS) and 3.24–3.94 (8H, m, 2CH₂I and 2CH₂O);

δ_C(63 MHz; CDCl₃, mixture of diastereomers denoted as

unmarked and *) 13.0, 17.4*, 20.0, 20.1, 20.2*, 20.3*, 21.5,

27.8*, 29.0, 29.4*, 34.2, 34.3*, 46.4, 46.5*, 65.9, 66.1*, 69.0 and

69.4*; m/z (CI, NH₃) 301 ([M ϩ H]^ϩ, 100%), 283 (5), 173 (55),

117 (20) and 69 (17) (Found: [M ϩ H]^ϩ, 301.0119. C₉H₁₇IOS

requires [M ϩ H]^ϩ, 301.0123).

(2R)-2-[(2-Methylprop-2-enyl)thio]propan-1-ol 35a

To a mixture of (2R)-2-mercaptopropanol 34a (670 mg, 7.23

mmol) and sodium methoxide (429 mg, 7.95 mmol) in meth-

anol (14 cm³) at 0 ЊC was added methallyl bromide (976 mg,

7.23 mmol). The solution was stirred at 0 ЊC for 1 h and at RT

for 3 h, after which it was concentrated under reduced pressure.

The residue was suction ﬁltered (with ether washings). The

organic ﬁltrate was washed with brine (10 cm³), dried (MgSO₄),

concentrated under reduced pressure and puriﬁed by ﬂash

column chromatography (ether–petrol 20 : 80) to aﬀord 35a

(760 mg, 72%) as a pale yellow oil; [α]²_D²= Ϫ5.3 (c 1.13 in

CHCl₃); ν_max(ﬁlm)/cm^Ϫ13384, 3077, 2970, 2928, 2870 and 1648;

δ_H(250 MHz; CDCl₃) 1.24 (3H, d, J 7, CH₃CH), 1.81 (3H, s,

CH C᎐CH ), 2.15 (1H, br s, OH), 2.75–2.88 (1H, m, CHS), 3.07

᎐

3

2

(1H, dd, J 14.0 and 1.0, CHHS), 3.18 (1H, dd, J 14.0 and 1.0,

CHHS), 3.47 (1H, dd, J 11.0 and 6.0, CHHO), 3.59 (1H,

dd, J 11.0 and 5.0, CHHO) and 4.81–4.84 (2H, m, C᎐CH );

δ_C(63 MHz; CDCl₃) 17.9, 20.7, 38.1, 42.4, 65.4, 113.6 and

141.6; m/z (EI) 146 (M^ϩ, 100%), 115 (78), 81 (33), 59 (42)

and 55 (84) (Found: M^ϩ, 146.0758. C₇H₁₄OS requires M^ϩ,

146.0765).

᎐

2

Ethyl (2R,3S)-3-hydroxytetrahydro-2H-thiopyran-2-carboxylate

40

A conical ﬂask containing tap water (200 cm³) was kept in a

water bath at 30 ЊC for 1 h, after which Baker’s yeast (25 g) was

added and the mixture kept at the same temperature for 40 min.

β-Ketoester 39 (1.0 g, 5.3 mmol) was added (with ethanol

washing, 1 cm³) and this mixture was kept at 30 ЊC for 66 h. The

reaction mixture was ﬁltered under vacuum through Hyﬂo

supercel (with water washing, 50 cm³). The aqueous ﬁltrate was

extracted with ether (3 × 250 cm³). The combined organic

extracts were dried (MgSO₄) and concentrated under reduced

pressure. Puriﬁcation by ﬂash column chromatography (ethyl

acetate–petrol 10 : 90) aﬀorded 40 (669 mg, 66%) as a light

beige amorphous solid. Recrystallisation from ether–hexane at

Ϫ20 ЊC gave clear needles; [α]²_D²Ϫ64.5 (c 1.07 in CHCl₃) (Found:

C, 50.4; H, 7.3; S, 16.7. C₈H₁₄O₃S requires C, 50.5; H, 7.4; S,

16.9%); ν_max(Nujol)/cm^Ϫ13330 and 1719; δ_H(250 MHz; CDCl₃)

1.29 (3H, t, J 7.0, OCH₂CH₃), 1.65–1.88 (2H, m, CH₂), 1.97–

2.10 (2H, m, CH₂), 2.44–2.90 (3H, m, CH₂S and OH), 3.68 (1H,

d, J 3.0, CH), 4.15–4.22 (1H, m, CH) and 4.23 (2H, q, J 7.0,

OCH₂CH₃); δ_C(63 MHz; CDCl₃) 14.1, 24.3, 26.6, 31.2, 47.8,

61.5, 67.1 and 170.9; m/z (EI) 190 (M^ϩ, 90%), 144 (86), 117 (78)

and 71 (100).

(2R)-3-Methyl-2-[(2-methylprop-2-enyl)thio]butan-1-ol 35b

To a mixture of (2R)-3-methyl-2-mercaptobutanol 34b (2.9

g, 24.1 mmol) and sodium methoxide (1.43 g, 26.5 mmol) in

methanol (48 cm³) at 0 ЊC was added methallyl bromide (3.25 g,

24.1 mmol). The solution was stirred at 0 ЊC for 1 h and at RT

for 3 h, after which it was concentrated under reduced pressure.

The residue was suction ﬁltered (with ether washings). The

organic ﬁltrate was washed with brine (10 cm³), dried (MgSO₄),

concentrated under reduced pressure and puriﬁed by ﬂash

column chromatography (ether–petrol 20 : 80) to aﬀord 35b (2.7

g, 64%) as a pale yellow oil; ν_max(ﬁlm)/cm^Ϫ13385, 3077, 2960,

2873, 1648 and 1457; δ_H(250 MHz; CDCl₃) 0.94–1.00 (6H, m,

(CH ) CH), 1.82 (3H, s, CH C᎐CH ), 1.85–2.00 (1H, m,

᎐

3

2

3

2

(CH₃)₂CH), 2.18 (1H, br s, OH), 2.48–2.55 (1H, m, CHS), 3.06

(1H, dd, J 13.0 and 1.0, CHHS), 3.16 (1H, dd, J 13.0 and 1.0,

CHHS), 3.53 (1H, dd, J 11.0 and 7.0, CHHO), 3.68 (1H, dd,

J 11.0 and 5.0, CHHO) and 4.80–4.84 (2H, m, C᎐CH ); δ (63

᎐

2

C

MHz; CDCl₃) 19.5, 20.4, 20.6, 29.6, 39.5, 55.4, 62.6, 113.8 and

141.5; m/z (CI) 175 ([M ϩ H]^ϩ, 100%), 157 (6), 143 (20), 109 (6),

87 (18) and 55 (10) (Found: [M ϩ H]^ϩ, 175.1158. C₉H₁₉OS

requires [M ϩ H]^ϩ, 175.1157).

Crystal structure of 40. Crystal data for C₈H₁₄O₃S; M =

190.25. Crystallises from n-hexane as colourless blocks;

crystal dimensions 0.42 × 0.31 × 0.14 mm³. Orthorhombic,

a = 5.2525(19), b = 10.029(4), c = 17.826(7) Å, U = 939.0(6) Å³,

Z = 4, D_C= 1.346 Mg m^Ϫ3, space group P2₁2₁2₁(D⁴₂, no. 19),

(5R)-2-(Iodomethyl)-2,5-dimethyl-1,4-oxathiane 38a

To a solution of sulﬁde 35a (260 mg, 1.78 mmol) in carbon

tetrachloride (10 cm³) and water (10 cm³) was added anhydrous

sodium bicarbonate (600 mg, 7.13 mmol) followed by iodine

(910 mg, 3.57 mmol). The resulting mixture was stirred at RT

for 4 h then diluted with CH₂Cl₂(20 cm³) and treated with

saturated Na₂SO₃. The organic layer was washed with brine (10

cm³), dried (MgSO₄) and puriﬁed by ﬂash column chrom-

Mo-Kα radiation (λ = 0.71073 Å), µ(Mo-Kα) = 0.311 mm^Ϫ1

,

F(000) = 408. CCDC reference number 1685533. See http://

www.rsc.org/suppdata/p1/b1/b105416n/ for crystallographic

ﬁles in .cif or other electronic format.

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

2617

View Article Online

(2S,3S)-2-(Hydroxymethyl)tetrahydro-2H-thiopyran-3-ol 41

portionwise. The mixture was warmed to RT and then reﬂuxed

for 18 h. At 0 ЊC, iced water (9 cm³), dilute HCl (9 cm³, 3% v/v),

potassium sodium tartrate (2 g) and ethyl acetate (30 cm³) were

sequentially added. The mixture was stirred rapidly for 10 min,

extracted with ethyl acetate (3 × 40 cm³). The combined organic

extracts were dried (MgSO₄), concentrated under reduced

pressure and puriﬁed by ﬂash column chromatography (ethyl

acetate–petrol 50 : 50) to aﬀord 44 (738 mg, 77%) as a white

To a solution of ester 40 (500 mg, 2.63 mmol) in ether (8 cm³) at

0 ЊC was added lithium aluminium hydride (500 mg, 13.2

mmol). The mixture was warmed to RT and then reﬂuxed for 18

h. At 0 ЊC, iced water (4 cm³), dilute HCl solution (4 cm³, 3%

v/v), potassium sodium tartrate (2 g) and ethyl acetate (20 cm³)

were sequentially added. The mixture was stirred rapidly for

10 min, extracted with ethyl acetate (3 × 20 cm³). The combined

organic extracts were dried (MgSO₄), concentrated under

reduced pressure and puriﬁed by ﬂash column chromatography

(ethyl acetate–petrol 50 : 50) to aﬀord 41 (295 mg, 76%) as a

white solid; [α]²_D²= Ϫ51.8 (c 1.1 in CHCl₃) (Found: C, 48.4; H,

8.3; S, 21.9. C₆H₁₂O₂S requires C, 48.6; H, 8.2; S, 21.6%); ν_max

(Nujol)/cm^Ϫ13394 and 3318; δ_H(250 MHz; CDCl₃) 1.52–1.66

(1H, m, CHH), 1.78–2.06 (3H, m, CHH and CH₂), 2.48 (1H,

dd, J 6.5 and 5.0, CH₂OH), 2.55–2.59 (2H, m, CH₂S), 2.90 (1H,

d, J 9.0, CHOH), 3.11 (1H, dt, J 6.5 and 2.0, CHS), 3.74–3.93

(2H, m, CH₂OH) and 4.10–4.16 (1H, m, CHOH); δ_C(63 MHz;

CDCl₃) 22.9, 27.2, 32.1, 48.6, 63.1 and 66.7; m/z (EI) 148 (M^ϩ,

88%), 130 (88), 117 (87), 87 (100).

solid and as an inseparable mixture of diastereomers; [α]²_D³

=

Ϫ36.7 (c 0.98 in CHCl₃); ν_max(Nujol)/cm^Ϫ13333; δ_H(250 MHz;

CDCl₃) 1.42 (3H, s, CH₃), 1.60–1.91 (3H, m, CH₂and CHH),

2.02–2.11 (1H, m, CHH), 2.26 (2H, br s, 2OH), 2.46–2.68 (2H,

m, CH₂S), 3.71 (1H, d, J 11.0, CHH), 3.84 (1H, dd, J 9.0 and

3.0, CH) and 3.97 (1H, d, J 11.0, CHH); δ_C(63 MHz; CDCl₃)

22.4, 25.3, 26.3, 30.0, 46.9, 66.4 and 75.6; m/z (EI) 162 (M^ϩ,

34%), 131 (100) (Found: M^ϩ, 162.0707. C₇H₁₄O₂S requires M^ϩ,

162.0715).

(2S,5R)-2-Methyl-5-(1-methylethenyl)-2-[(phenylmethyl)thio]-

cyclohexan-1-one 50

To a solution of silyl enol ether 49 (3.66 g, 16.35 mmol) in THF

(33 cm³) at 0 ЊC was added methyllithium (10.3 cm³, 16.35

mmol, 1.58 M in ether) dropwise. The solution was stirred at

0 ЊC for 1 h and was then added via cannula to a solution of

benzylthiotosylate (5.0 g, 17.99 mmol) and HMPA (8.5 cm³,

49.05 mmol) in THF (33 cm³) at Ϫ78 ЊC. The mixture was

stirred at this temperature for 3.5 h, after which saturated

ammonium chloride solution (10 cm³) was added to the

solution and the separated aqueous layer extracted with ether

(3 × 50 cm³). The combined organic extracts were dried

(MgSO₄), concentrated under reduced pressure and puriﬁed by

ﬂash column chromatography (ethyl acetate–petrol 2.5 : 97.5) to

aﬀord 50 (3.75 g, 84%) as a colourless oil and an inseparable

(2R,3S)-2-(1-Hydroxy-1-methylethyl)tetrahydro-2H-thiopyran-

3-ol 42

To a solution of ester 40 (405 mg, 2.13 mmol) in ether (25 cm³)

at 0 ЊC was added methylmagnesium bromide (4 cm³, 12 mmol,

3 M in ether). The mixture was warmed to RT and stirred for

18 h. At 0 ЊC, saturated ammonium chloride solution (10 cm³)

was added to the solution and the separated aqueous layer

extracted with ether (3 × 20 cm³). The combined organic

extracts were dried (MgSO₄), concentrated under reduced

pressure and puriﬁed by ﬂash column chromatography (ethyl

acetate–petrol 30 : 70) to aﬀord 42 (280 mg, 75%) as a white

solid, mp 78–80 ЊC; [α]²_D⁸= Ϫ25.5 (c 0.98 in CH₂Cl₂); ν_max

(Nujol)/cm^Ϫ13224; δ_H(250 MHz; CDCl₃) 1.32 (3H, s, CH₃),

1.37 (3H, s, CH₃), 1.39–1.51 (1H, m, CHH), 1.69–2.03 (3H, m,

CHH and CH₂), 2.55–2.70 (4H, m, CH₂and OH), 2.87 (1H, d,

J 1.0, CH) and 4.30–4.36 (1H, m, CH); δ_C(63 MHz; CDCl₃)

20.8, 28.3, 28.6, 29.0, 33.7, 57.9, 64.6 and 73.0; m/z (EI) 176

(M^ϩ, 12%), 158 (34), 100 (100), 85 (44) and 58 (56) (Found: M^ϩ,

176.0867. C₈H₁₆O₂S requires M^ϩ, 176.0871).

mixture of diastereomers (ratio of 4 : 1 in favour of 50); [α]¹_D⁸

=

ϩ167.3 (c 0.55 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ12929, 1698 and 1452;

δ_H(250 MHz; CDCl₃, major diastereomer) 1.29 (3H, s, CH₃),

1.57 (3H, s, CH₃), 1.58–2.16 (6H, m, CH and CH₂), 2.95–3.07

(1H, m, CH), 3.25 (1H, d_AB, J 12.0, CHHS), 3.54 (1H, d_AB

,

J 12.0, CHHS), 4.49–4.74 (2H, m, CH ᎐) and 7.04–7.17 (5H, m,

᎐

2

CH); δ_C(63 MHz; CDCl₃) 20.4, 23.6, 26.4, 33.4, 39.3, 41.6,

46.3, 54.0, 109.9, 127.2, 128.6, 129.1, 137.1 and 147.3; m/z (EI)

274 (M^ϩ, 31%), 152 (100), 109 (73), 91 (67) (Found: M^ϩ,

274.1404. C₁₇H₂₂OS requires M^ϩ, 274.1391).

Ethyl (2R,3S)-3-hydroxy-2-methyltetrahydro-2H-thiopyran-2-

carboxylate 43

(1R,2S,5R)-2-Methyl-5-(1-methylethenyl)-2-[(phenylmethyl)-

thio]cyclohexan-1-ol 51

To a solution of freshly prepared lithium diisopropylamide

(19.16 mmol) in THF (7 cm³) at Ϫ50 ЊC was added a solution of

ester 40 (1.5 g, 7.90 mmol) in THF (9 cm³). The mixture was

slowly warmed to Ϫ15 ЊC and methyl iodide (0.64 cm³, 10.26

mmol) in HMPA (5.9 cm³) was added. The mixture was stirred

at Ϫ15 ЊC for 1.5 h. Saturated ammonium chloride solution

(15 cm³) was added to the solution and the separated aqueous

layer extracted with ether (3 × 30 cm³). The combined organic

extracts were dried (MgSO₄), concentrated under reduced

pressure and puriﬁed by ﬂash column chromatography (ethyl

acetate–petrol 10 : 90) to aﬀord 43 (1.31 g, 81%) as a colourless

oil and an inseparable mixture of diastereomers (ratio of 6 : 1

in favour of 43); [α]²_D³= Ϫ55.9 (c 0.93 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ1

3449, 2931 and 1720; δ_H(250 MHz; CDCl₃) 1.29 (3H, t, J 7.0,

OCH₂CH₃), 1.55 (3H, s, CH₃), 1.63–2.11 (4H, m, 2CH₂), 2.36–

2.44 (1H, m, CHHS), 2.53–2.65 (1H, m, CHHS), 2.76 (1H, br s,

OH), 3.65 (1H, m, CH) and 4.22 (2H, q, J 7.0, OCH₂CH₃);

δ_C(63 MHz; CDCl₃) 14.1, 23.2, 27.0, 27.2, 31.0, 51.4, 61.5, 75.0

and 174.0; m/z (EI) 204 (M^ϩ, 65%), 158 (100), 131 (78) and 71

(100) (Found: M^ϩ, 204.0822. C₉H₁₆O₃S requires M^ϩ, 204.0820).

To a solution of ketone 50 (6.0 g, 21.9 mmol) in CH₂Cl₂(100

cm³) at Ϫ78 ЊC was added DIBAL-H (32.8 cm³, 32.8 mmol,

1 M in hexane). The solution was stirred at this temperature for

2 h, after which methanol (5 cm³), water (20 cm³) and potas-

sium sodium tartrate (1.5 g) were sequentially added. The

mixture was stirred rapidly for 10 min, extracted with ether (3 ×

100 cm³). The combined organic extracts were dried (MgSO₄),

concentrated under reduced pressure and puriﬁed by ﬂash

column chromatography (ethyl acetate–petrol 5 : 95 to 20 : 80)

to aﬀord 51 (4.05 g, 67%) as a white solid; [α]¹_D⁸= ϩ32.6 (c 0.46

in CHCl₃); ν_max(ﬁlm)/cm^Ϫ13347, 2928, 2362 and 1450; δ_H(250

MHz; CDCl₃) 1.32–1.94 (7H, m, CH and CH₂), 1.43 (3H, s,

CH₃), 1.64 (3H, s, CH₃), 3.30 (1H, m, CHOH), 3.69 (1H, d_AB

,

J 12.0, CHHS), 3.76 (1H, d_AB, J 12.0, CHHS), 4.60–4.65 (2H,

m, CH₂) and 7.16–7.31 (5H, m, CH); δ_C(63 MHz; CDCl₃) 20.9,

26.7, 27.0, 32.6, 36.4, 38.2, 44.2, 53.6, 78.1, 109.0, 127.1, 128.6,

129.1, 138.5 and 148.8; m/z (EI) 276 (M^ϩ, 25%), 185 (100)

(Found: M^ϩ, 276.1559. C₁₇H₂₄OS requires M^ϩ, 276.1548).

(2S,3S)-2-(Hydroxymethyl)-2-methyltetrahydro-2H-thiopyran-

3-ol 44

(1R,2S,5R)-2-(2,2-Diethoxyethylthio)-2-methyl-5-(1-methyl-

ethenyl)cyclohexan-1-ol 53

To a solution of ester 43 (1.2 g, 5.9 mmol) in ether (18 cm³) at

0 ЊC was added lithium aluminium hydride (1.2 g, 29.4 mmol)

Ammonia (105 cm³) was condensed into a three-necked ﬂask at

Ϫ78 ЊC. Sodium pieces (1.71 g, 74.1 mmol) were added to the

2618

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

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mixture, which was then stirred for 30 min. A solution of sulﬁde

51 (3.9 g, 14.1 mmol) in THF (47 cm³) was added to the

mixture, which was kept at Ϫ78 ЊC for 50 min. Methanol

(25 cm³) and saturated ammonium chloride solution (50 cm³)

were added to the solution, which was warmed to RT for 2 h.

The mixture was extracted with ether (3 × 100 cm³), dried

(MgSO₄) and concentrated under reduced pressure to aﬀord 52

(1.93 g) as a white solid, which was used immediately in the

next step. A mixture of hydroxythiol 52 (1.93 g, 10.38 mmol),

bromoacetaldehyde diethyl acetal (1.7 cm³, 11.41 mmol) and

powdered potassium hydroxide (1.42 g, 25.42 mmol) in 95%

ethanol (19 cm³) was heated at reﬂux for 16 h. The solvent was

removed under reduced pressure and the residue puriﬁed by

ﬂash column chromatography (ethyl acetate–petrol 5 : 95) to

aﬀord 53 (1.65 g, 39% over two steps) as an oil; [α]¹_D⁸= ϩ38.1

(c 0.21 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ13439, 2975, 2931 and 1645;

δ_H(250 MHz; CDCl₃) 1.22 (3H, t, J 7.0, OCH₂CH₃), 1.26 (3H,

t, J 7.0, OCH₂CH₃), 1.46–1.55 (4H, m, CH and CH₃), 1.73 (3H,

s, CH₃), 1.78–2.00 (4H, m, CH₂), 2.76 (1H, dd, J 14.0 and 4.5,

CHHS), 3.00 (1H, dd, J 14.0 and 7.0, CHHS), 3.08 (1H, d,

J 10.5, OH), 3.35 (1H, dt, J 10.5 and 5.0, CHOH), 3.50–3.82

(4H, m, OCH₂CH₃), 4.61 (1H, dd, J 7.0 and 4.0, CH(OEt)₂) and

4.68–4.74 (2H, m, CH₂); δ_C(63 MHz; CDCl₃) 15.1, 15.3, 20.8,

26.7, 27.2, 31.1, 36.5, 39.3, 44.5, 52.7, 61.0, 63.2, 78.1, 102.7,

108.8 and 149.0; m/z (CI) 303 ([M ϩ H]^ϩ, 19%), 257 (56), 211

(100), 135 (56) (Found: M^ϩ, 302.1921. C₁₆H₃₀O₃S requires M^ϩ,

302.1916).

(2R,6R)-6-(Hydroxymethyl)tetrahydro-2H-pyran-2-ylmethanol

62

To a ﬂask containing liquid ammonia (25 cm³) at Ϫ78 ЊC was

added sodium metal (250 mg, 11 mmol) portionwise. Sulﬁde 76

(251 mg, 0.7 mmol) in THF (4 cm³) was added dropwise and the

reaction was allowed to stir at Ϫ78 ЊC for 1.5 h. The reaction

was then quenched by the addition of absolute ethanol (20 cm³)

and diluted with ether (20 cm³) before allowing the reaction to

warm to RT and the ammonia to subsequently evaporate. The

aqueous layer was extracted with ether (3 × 20 cm³). The com-

bined extracts were washed with brine (10 cm³), dried (MgSO₄),

concentrated under reduced pressure and puriﬁed by ﬂash

column chromatography (ethyl acetate–petrol 50 : 50) to aﬀord

62 (64 mg, 54%) as a white solid, mp 58–59 ЊC; [α]²_D^5.5= Ϫ112.8

(c 0.47 in CHCl₃); ν_max(KBr disc)/cm^Ϫ13331, 2940 and 2870;

δ_H(250 MHz; CDCl₃) 1.50–1.64 (2H, m, CH₂), 1.65 (2H, m,

CH₂), 1.85–2.00 (2H, br m, CH₂), 2.70 (2H, s, 2OH), 2.90–3.05

(2H, br m, CH₂) and 3.60–3.65 (4H, m, 2CH₂OH); δ_C(63 MHz;

CDCl₃) 20.9, 29.0, 41.1 and 64.4; m/z (EI) 162 (M^ϩ, 23%), 131

(100), 113 (60), 79 (53), 67 (28) (Found: M^ϩ, 162.0707.

C₇H₁₄O₂S requires M^ϩ, 162.0714).

(2R,6R)-2,6-Dimethyl-4-(phenylsulfonyl)tetrahydro-2H-

thiopyran 63

A mixture of lithium sulﬁde (180 mg, 3.93 mmol) in DMF (3

cm³) was heated at reﬂux for 15 min, before being cooled to RT.

Dimesylate 79 (285 mg, 0.67 mmol) was added and the mixture

was stirred for 50 h, after which water (15 cm³) was added. The

mixture was extracted with ether (3 × 10 cm³), dried (MgSO₄),

concentrated under reduced pressure and puriﬁed by ﬂash

column chromatography (ethyl acetate–petrol 50 : 50) to aﬀord

(4aS,7R,8aR)-4a-Methyl-7-(1-methylethenyl)-4a,5,6,7,8,8a-

hexahydro-1,4-benzoxathiine 54

To a solution of sulﬁde 53 (500 mg, 1.66 mmol) in ether (8 cm³)

at 0 ЊC was added BF₃ؒOEt₂(0.42 cm³, 3.3 mmol). After 1.5 h

BF₃ؒOEt₂(0.42 cm³, 3.3 mmol) was added and the solution

stirred for a further 2 h. Further BF₃ؒOEt₂(0.42 cm³, 3.3 mmol)

was added, after which the solution was warmed to RT and

stirred for 18 h. The mixture was quenched with water (5 cm³),

extracted with ether (3 × 10 cm³), dried (MgSO₄), concentrated

under reduced pressure and puriﬁed by ﬂash column chrom-

atography (hexane) to aﬀord 54 (171 mg, 50%) as a colourless

oil; [α]¹_D⁸= ϩ328.0 (c 0.25 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ12918, 2860,

1610 and 1449; δ_H(250 MHz; CDCl₃) 1.44 (3H, s, CH₃), 1.49–

2.11 (7H, m, CH and CH₂), 1.74 (3H, s, CH₃), 3.72 (1H, dd,

J 11.0 and 4.0, CHO), 4.70–4.78 (2H, m, CH₂), 4.99 (1H, d,

J 6.5, CHS) and 6.47 (1H, d, J 6.5, CHO); δ_C(63 MHz; CDCl₃)

20.7, 26.5, 28.6, 33.7, 37.8, 43.1, 44.5, 78.0, 91.3, 109.3, 135.8

and 148.5; m/z (EI) 210 (M^ϩ, 73%), 93 (100), 68 (70) (Found:

M^ϩ, 210.1088. C₁₂H₁₈OS requires M^ϩ, 210.1078).

63 (145 mg, 81%) as clear crystals, mp 106.5–108 ЊC; [α]²_D⁵

=

ϩ36.9 (c 1.6 in CHCl₃); ν_max(Nujol)/cm^Ϫ12923, 1305 and 1284

(Found: C, 57.8; H, 6.7; S, 23.7. C₁₃H₁₈O₂S₂requires C, 57.6; H,

6.5; S, 23.8%); δ_H(250 MHz; CDCl₃) 1.24 (3H, d, J 7.0, CH₃),

1.34 (3H, d, J 6.5, CH₃), 1.19–1.35 (1H, m, CHH), 1.81 (1H, dt,

J 13.0 and 4.5, CHH), 2.16 (1H, m, CHH), 2.34 (1H, m, CHH),

2.94 (1H, m, CHSO₂Ph), 3.14 (2H, m, 2CHCH₃), 7.52 (2H, m,

CH), 7.63 (1H, m, CH) and 7.79 (2H, m, CH); δ_C(63 MHz;

CDCl₃) 20.8, 21.2, 31.3, 32.2, 34.1, 35.7, 59.5, 129.2, 129.2,

133.9 and 136.3; m/z (EI) 270 (M^ϩ, 43%), 128 (100) and 113

(75).

(2R)-1-{2-[(2R)-2-Hydroxy-3-methoxypropyl]-1,3-dithian-2-yl}-

3-methoxypropan-2-ol 68

To a solution of dithiane 66 (1.06 g, 4.5 mmol) and HMPA

(4 cm³) in THF (30 cm³) at Ϫ78 ЊC was added dropwise tert-

butyllithium (4.5 cm³, 6.8 mmol, 1.5 M in pentane). (S)-

Glycidyl methyl ether 67 (1.0 g, 11.3 mmol) was then added

and the solution warmed to Ϫ40 ЊC and stirred for 1.5 h.

The mixture was quenched with saturated ammonium chloride

solution (10 cm³), extracted with ether (3 × 30 cm³), dried

(MgSO₄) and concentrated under reduced pressure to aﬀord

a crude product which was immediately dissolved in THF

(10 cm³). Excess TBAF (1 M solution in THF) was added at

0 ЊC and the mixture was stirred at RT for 30 min. The mixture

was quenched with saturated ammonium chloride solution

(5 cm³), extracted with ether (3 × 15 cm³), dried (MgSO₄),

concentrated under reduced pressure and puriﬁed by ﬂash

column chromatography (EtOAc–petrol 60 : 40) to aﬀord 68

(850 mg, 63% over two steps) as a colourless oil; [α]²_D⁵= ϩ20.6

(c 0.97 in CHCl₃); δ_H(250 MHz; CDCl₃) 1.91–2.00 (2H, m,

CH₂), 2.14–2.31 (4H, m, 2CH₂), 2.72–2.83 (4H, m, 2CH₂S),

3.32 (4H, d, J 5.5, 2CH₂OCH₃), 3.38 (6H, s, 2OCH₃), 3.66

(2H, br s, 2OH) and 4.13–4.23 (2H, m, 2CHOH); m/z (CI)

297 ([M ϩ H]^ϩ, 100%), 279 (45), 223 (65) and 207 (55)

(Found: [M ϩ H]^ϩ, 297.1197. C₁₂H₂₄O₄S₂requires [M ϩ H]^ϩ,

297.1194).

(2S,6S)-2,6-Bis[(methyloxy)methyl]tetrahydro-2H-thiopyran 61

To a solution of diol 69 (130 mg, 0.68 mmol) and triethylamine

(0.28 cm³, 2.0 mmol) in CH₂Cl₂(10 cm³) at Ϫ15 ЊC was added

methanesulfonyl chloride (0.13 cm³, 1.70 mmol). After 1 h, the

mixture was quenched with saturated sodium bicarbonate

solution (5 cm³), extracted with CH₂Cl₂(3 × 10 cm³), dried

(MgSO₄) and concentrated under reduced pressure to aﬀord the

crude mesylate which was immediately dissolved in DMSO

(5 cm³). Lithium sulﬁde (40 mg, 0.81 mmol) was added and the

mixture was then stirred at 50 ЊC for 24 h. The mixture was

quenched with sodium bicarbonate solution (5 cm³), extracted

with petroleum ether (3 × 10 cm³), dried (MgSO₄), concentrated

under reduced pressure and puriﬁed by ﬂash column chrom-

atography (ether–petrol 20 : 80) to aﬀord 61 (21 mg, 43% over

two steps) as a colourless oil; [α]²_D²= ϩ90.0 (c 0.70 in CHCl₃);

δ_H(250 MHz; CDCl₃) 1.54–1.66 (2H, m, 2CH), 1.83–1.94 (2H,

m, 2CH), 3.05 (2H, m, 2CHS), 3.34 (6H, s, 2OCH₃) and 3.40–

3.55 (4H, m, 2CH₂O); δ_C(63 MHz; CDCl₃) 20.2, 28.9, 37.8, 58.8

and 75.1; m/z (CI) 191 ([M ϩ H]^ϩ, 100%), 159 (45), 145 (30),

113 (55) (Found: [M ϩ H]^ϩ, 191.1106. C₉H₁₉O₂S requires

[M ϩ H]^ϩ, 191.1106).

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

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(2R,6R)-1,7-Dimethoxyheptane-2,6-diol 69

being diluted with ether (30 cm³) and ﬁltered through Celite.

The ﬁltrate was washed with brine (3 × 40 cm³), dried (MgSO₄),

concentrated under reduced pressure and puriﬁed by ﬂash

column chromatography (ethyl acetate–petrol 20 : 80) to aﬀord

75 (2.45 g, 88%) as a colourless oil; [α]²_D²= Ϫ6.35 (c 1.89 in

CHCl₃) [lit., [α]_D= ϩ3.9 (c 1.35 in CHCl₃) ent]; ν_max(ﬁlm)/cm^Ϫ1

2924, 2867, 1598 and 1496; δ_H(250 MHz; CDCl₃) 1.10–1.30

(2H, m, CH₂), 1.55–1.70 (4H, m, 2CH₂), 2.40 (6H, s, 2CH₃),

3.35–3.50 (4H, m, 2CH₂), 4.34 (2H, d_AB, J 12.1, 2CHPh), 4.42

(2H, d_AB, J 12.1, 2CHPh), 4.55 (2H, m, 2CH), 7.15–7.35 (14H,

m, Ar) and 7.70–7.80 (2H, m, Ar); δ_C(63 MHz; CDCl₃) 20.0,

21.7, 31.2, 70.6, 73.3, 81.2, 127.7, 127.8, 127.9, 128.4, 128.5,

129.7, 129.8, 134.1, 137.7 and 144.6; m/z (CI) 670 ([M ϩ NH₄]^ϩ,

20%), 498 (100), 408 (53), 280 (52), 190 (51) and 108 (53)

(Found: [M ϩ NH₄]^ϩ, 670.7748. C₃₅H₄₄NO₈S₂requires [M ϩ

NH₄]^ϩ, 670.2508).

To a solution of diol 68 (850 mg, 2.87 mmol) in ethanol (1 cm³)

at RT was added a solution of freshly prepared Raney nickel

(10 cm³). The mixture was stirred for 72 h, after which it was

ﬁltered through Celite, concentrated under reduced pressure

and puriﬁed by ﬂash column chromatography (MeOH–CH₂Cl₂

10 : 90) to aﬀord 69 (150 mg, 27%) as a colourless oil; ν_max

(ﬁlm)/cm^Ϫ13416; δ_H(250 MHz; CDCl₃) 1.35–1.58 (6H, m,

3CH₂), 2.40 (2H, br s, 2OH), 3.22 (2H, dd, J 9.5 and 7.9,

2CHHO), 3.36 (6H, s, 2OCH₃), 3.40 (2H, dd, J 7.9 and 3.0,

2CHHO) and 3.76 (2H, m, 2CHOH); δ_C(63 MHz; CDCl₃)

21.6, 36.4, 59.0, 70.1 and 77.0; m/z (CI) 193 ([M ϩ H]^ϩ, 100%),

175 (20), 129 (55), 97 (15) (Found: [M ϩ H]^ϩ, 193.1441.

C₉H₂₁O₄requires [M ϩ H]^ϩ, 193.1440).

(2S,6S)-1,7-Bis(benzyloxy)-4-(phenylsulfonyl)heptane-2,6-diol

73

(2R,6R)-2,6-Bis[(benzyloxy)methyl]tetrahydro-2H-thiopyran 76

To a solution of sulfone 70 (782 mg, 5.0 mmol) in THF (19 cm³)

and HMPA (1 cm³) at Ϫ78 ЊC was added n-butyllithium (7 cm³,

11.2 mmol, 1.6 M in hexane) dropwise. The resulting orange

solution was stirred at Ϫ78 ЊC for 1 h before the addition of

(R)-(ϩ)-benzyl glycidyl ether 71 (1.66 g, 10 mmol). The reaction

was stirred at Ϫ78 ЊC for 3 h and then at RT for 18 h, after

which it was quenched by the addition of saturated ammonium

chloride solution (10 cm³). The mixture was extracted with

ether (3 × 30 cm³), washed with water (20 cm³) and brine (20

cm³), dried (MgSO₄), concentrated under reduced pressure and

puriﬁed by ﬂash column chromatography (ethyl acetate–petrol

50 : 50) to aﬀord 73 (1.22 g, 50%) as white needles and mono-

A mixture of lithium sulﬁde (1.05 g, 23 mmol) in DMF (6 cm³)

was heated at 70 ЊC for 45 min. Bis(toluene-p-sulfonate) 75

(2.45 g, 3.8 mmol) was subsequently added and the reaction was

maintained at 70 ЊC for 72 h. Following cooling to RT the

mixture was poured into water (40 cm³) and extracted with

ether (3 × 40 cm³). The combined organic extracts were washed

with brine (40 cm³), dried (MgSO₄), concentrated under

reduced pressure and puriﬁed by ﬂash column chromatography

(ethyl acetate–petrol 5 : 95) to aﬀord 76 (558 mg, 43%) as a

colourless oil; [α]²_D⁶= Ϫ19.7 (c 1.5 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ1

3030, 2927, 2856 and 1496; δ_H(250 MHz; CDCl₃) 1.60 (2H, q,

J 5.7, CH₂), 1.65–2.00 (4H, m, 2CH₂), 3.00–3.15 (2H, m, 2CH),

3.55 (2H, d, J 6.0, 2CH), 3.57 (2H, d, J 6.0, 2CH), 4.52 (2H,

d_AB, J 6.0, 2CHPh), 4.56 (2H, d_AB, J 6.0, 2CHPh) and 7.25–7.40

(10H, m, aryl); δ_C(63 MHz; CDCl₃) 20.1, 29.1, 38.0, 72.5, 73.1,

127.7, 127.7, 128.4 and 138.2; m/z (EI) 342 (M^ϩ, 1%), 234 (40),

145 (38) and 91 (100) (Found: M^ϩ, 342.1653. C₂₁H₂₆O₂S

requires M^ϩ, 342.1654).

alkylated 72 (639 mg, 40%), mp 42–44 ЊC (EtOAc); [α]_D^24.5

=

Ϫ21.6 (c 1.16 in CHCl₃); ν_max(KBr disc)/cm^Ϫ13466, 3427,

2930, 2868 and 1448; δ_H(250 MHz; CDCl₃) 1.55–1.75 (2H, m,

CH₂), 1.85 (1H, ddd, J 13.6, 10.4 and 3.1, CH), 2.20 (1H, ddd,

J 15.6, 6.3 and 2.6, CH), 3.05 (1H, br s, OH), 3.15–3.20 (1H, br

d, J 4.0, OH), 3.25–3.50 (4H, m, CH₂), 3.50–3.60 (1H, m, CH),

3.85–4.00 (2H, m, CH₂), 4.50 (4H, s, 2CH₂Ph), 7.20–7.40 (10H,

m, 2PhCH₂O), 7.45–7.60 (2H, m, PhSO₂), 7.60–7.70 (1H, m,

PhSO₂) and 7.80–7.90 (2H, m, PhSO₂); δ_C(63 MHz; CDCl₃)

30.7, 33.0, 58.1, 66.3, 69.3, 73.3, 73.35, 73.8, 73.9, 127.5, 127.6,

127.7, 128.2, 128.3, 128.8, 129.1, 133.6, 137.3, 137.7 and 137.9;

m/z (EI) 484 (M^ϩ, 1%), 287 (50), 113 (28) and 91 (100) (Found:

M^ϩ, 484.1896. C₂₇H₃₂O₆S requires M^ϩ, 484.1920).

(2S,6S)-4-(Phenylsulfonyl)heptane-2,6-diol 78

To a solution of sulfone 70 (1.30 g, 8.32 mmol) in THF (25 cm³)

at 0 ЊC was added n-butyllithium (7.3 cm³, 18.3 mmol, 2.5 M in

hexane) dropwise. The mixture was cooled to Ϫ78 ЊC, HMPA

(2.5 cm³) was added and the solution was stirred for 1 h. Pre-

cooled (Ϫ78 ЊC) (S)-(Ϫ)-propylene oxide (966 mg, 16.6 mmol)

was added to the mixture, which was kept at Ϫ78 ЊC for 2 h,

after which it was warmed slowly to RT and stirred for 72 h.

The mixture was quenched with water (15 cm³), extracted with

ether (3 × 20 cm³), dried (MgSO₄), concentrated under reduced

pressure and puriﬁed by ﬂash column chromatography

(EtOAc–petrol 50 : 50) to aﬀord 78 (1.32 g, 58%) as a colourless

oil and monoalkylated 77 (420 mg); [α]²_D⁵= ϩ41.9 (c 2.6 in

CHCl₃) [lit. [α]_D= ϩ50.0 (c 1.19 in CHCl₃)]; ν_max(ﬁlm)/cm^Ϫ1

3410, 2969, 1709 and 1447; δ_H(250 MHz; CDCl₃) 1.13 (6H, m,

2CH₃), 1.50–1.75 (3H, m, CH₂and CHH), 2.10 (1H, ddd, J 6.5,

4.0 and 2.5, CHH), 3.40 (1H, m, CHSO₂Ph), 3.83 (2H, m,

CHOH), 7.52 (2H, m, CH), 7.61 (1H, m, CH) and 7.84 (2H, m,

CH); δ_C(63 MHz; CDCl₃) 23.2, 23.9, 35.1, 38.0, 59.0, 63.2,

67.8, 128.9, 129.3, 133.8 and 137.2; m/z (CI) 273 ([M ϩ H]^ϩ,

100%) (Found: [M ϩ H]^ϩ, 273.1158. C₁₃H₂₁O₄S requires [M ϩ

H]^ϩ, 273.1161).

(2S,6S)-1,7-Bis(benzyloxy)heptane-2,6-diol 74

To a solution of diol 73 (2.39 g, 4.9 mmol) in methanol (45 cm³)

was added successively anhydrous sodium hydrogen phosphate

(dibasic) (3.18 g) and sodium amalgam (24.1 g, 4%). The

reaction was stirred vigorously for 3 h before it was poured

into water (200 cm³) and the aqueous layer extracted with ether

(4 × 100 cm³). The combined extracts were dried (MgSO₄) and

concentrated under reduced pressure to aﬀord 74 (1.46 g, 86%)

as a colourless oil; [α]²_D²= ϩ3.6 (c 1.93 in CHCl₃) [lit. [α]_D= Ϫ4.8

(c 1.19 in CHCl₃) ent]; ν_max(ﬁlm)/cm^Ϫ13420, 2918, 2861, 1496

and 1453; δ_H(250 MHz; CDCl₃) 1.35–1.55 (6H, m, 3CH₂),

2.35–2.60 (2H, br s, 2OH), 3.30 (2H, dd, J 9.2 and 7.9, 2CH),

3.50 (2H, dd, J 9.3 and 3.2, 2CH), 3.75–3.90 (2H, m, 2CH), 4.55

(4H, s, 2PhCH₂) and 7.25–7.40 (10H, m, 2Ph); δ_C(63 MHz;

CDCl₃) 21.6, 33.0, 70.2, 73.3, 74.7, 127.8, 128.5 and 138.0;

m/z (CI) 362 ([M ϩ NH₄]^ϩ, 71%), 222 (61), 219 (41), 108 (40)

and 106 (100) (Found: [M ϩ H]^ϩ, 345.2081. C₂₁H₂₉O₄requires

[M ϩ H]^ϩ, 345.2066).

(1S,5S)-1-Methyl-5-[(methylsulfonyl)oxy]-3-(phenylsulfonyl)-

hexyl methanesulfonate 79

(2S,6S)-1,7-Bis(benzyloxy)-2,6-bis[( p-tolylsulfonyl)oxy]heptane

75

To a solution of diol 74 (1.46 g, 4.25 mmol) in CH₂Cl₂(20 cm³)

were added successively triethylamine (1.9 cm³, 13.6 mmol),

toluene-p-sulfonyl chloride (2.5 g, 13.1 mmol) and DMAP (132

mg, 1.2 mmol). The reaction was stirred at RT for 18 h before

To a solution of diol 78 (397 mg, 1.46 mmol) in CH₂Cl₂(4 cm³)

at Ϫ10 ЊC were added sequentially triethylamine (0.51 cm³, 3.65

mmol) and methanesulfonyl chloride (0.28 cm³, 3.65 mmol).

The mixture was stirred for 1 h, after which HCl solution (1.5

cm³, 3% v/v) was added. The mixture was extracted with

CH₂Cl₂(3 × 5 cm³), dried (MgSO₄), concentrated under

2620

J. Chem. Soc., Perkin Trans. 1, 2001, 2604–2622

View Article Online

and M. Standen, J. Am. Chem. Soc., 1996, 118, 7004; (d ) V. K.

reduced pressure and puriﬁed by ﬂash column chromatography

(ethyl acetate–petrol 50 : 50) to aﬀord 79 (297 mg, 41%) as a

white solid, mp 127.5–130 ЊC; [α]²_D⁵= ϩ0.4 (c 2.15 in CHCl₃);

ν_max(Nujol)/cm^Ϫ12923 and 1461 (Found: C, 42.1; H, 5.6; S,

22.4. C₁₅H₂₄O₈S₃requires C, 41.8; H, 5.5; S, 22.5%); δ_H(250

MHz; CDCl₃) 1.32 (3H, d, J 6.5, CH₃), 1.38 (3H, d, J 6.5, CH₃),

1.61 (1H, m, CHH), 1.60–1.95 (2H, m, CH₂), 2.28 (1H, m,

CHH), 2.86 (3H, s, CH₃), 3.05 (3H, s, CH₃), 3.47 (1H, m,

CHSO₂Ph), 4.75 (1H, m, CHOMs), 5.23 (1H, m, CHOMs),

7.54 (2H, m, CH), 7.64 (1H, m, CH) and 7.88 (2H, m, CH);

δ_C(63 MHz; CDCl₃) 21.6, 21.8, 35.9, 36.9, 38.2, 38.8, 56.3, 74.9,

76.6, 128.8, 129.4, 134.2 and 137.0; m/z (CI) 446 ([M ϩ NH₄]^ϩ,

59%).

Aggarwal, Synlett, 1998, 329.

6 For use of stoichiometric quantities of chiral sulfonium salts

in asymmetric expoxidation see: (a) N. Furukawa, Y. Sugihara and

H. Fujihara, J. Org. Chem., 1989, 54, 4222; (b) L. Breau, W. W.

Ogilvie and T. Durst, Tetrahedron Lett., 1990, 31, 35; (c) L. Breau

and T. Durst, Tetrahedron: Asymmetry, 1991, 2, 367; (d ) A. Solladié-

Cavallo and A. Adib, Tetrahedron, 1992, 48, 2453; (e) A. Solladié-

Cavallo, A. Adib, M. Schmitt, J. Fischer and A. DeCian,

Tetrahedron: Asymmetry, 1992, 3, 1597; ( f ) A. Solladié-Cavallo and

A. Diep-Vohuule, J. Org. Chem., 1995, 60, 3494; (g) A. Solladié-

Cavallo, A. Diep-Vohuule, V. Sunjic and V. Vinkovic, Tetrahedron:

Asymmetry, 1996, 7, 1783; (h) A. Solladié-Cavallo, M. Roje,

T. Isarno, V. Sunjic and V. Vinkovic, Eur. J. Org. Chem., 2000, 1077;

(i) A.-H. Li, L.-X. Dai, X.-L. Hou, Y.-Z. Huang and F.-W. Li, J. Org.

Chem., 1996, 61, 489; (j) Y.-G. Zhou, X.-L. Hou, L.-X. Dai, L.-J.

Xia and M.-H. Tang, J. Chem. Soc., Perkin Trans. 1, 1999, 77; (k)

K. Julienne, P. Metzner and V. Henryon, J. Chem. Soc., Perkin

Trans. 1, 1999, 731; (l ) K. Julienne and P. Metzner, J. Org. Chem.,

1998, 63, 4532; (m) R. Hayakawa and M. Shimizu, Synlett, 1999, 8,

1328.

7 V. K. Aggarwal, E. Alonso, G. Hynd, K. M. Lydon, M. J. Palmer,

M. Porcelloni and J. R. Studley, Angew. Chem., Int. Ed., 2001, 40,

1430.

8 K.-Y. Ko and K.-I. Kim, Bull. Korean Chem. Soc., 1998, 19, 378.

9 N. Greeves and L. Lyford, Tetrahedron Lett., 1992, 33, 4759;

T. Imamoto, N. Takiyama, K. Nakamura, T. Hatajima and Y.

Kamiya, J. Am. Chem. Soc., 1989, 111, 4392.

10 T. V. Lee and J. R. Porter, Org. Synth., 1995, 72, 189.

11 B. S. Guo, W. Doubleday and T. Cohen, J. Am. Chem. Soc., 1987,

109, 4710.

12 D. H. R. Barton and D. Crich, Tetrahedron Lett., 1985, 26, 757;

D. H. R. Barton and D. Crich, J. Chem. Soc., Perkin Trans. 1, 1986,

1603.

General procedure for the epoxidation of benzaldehyde using

catalytic quantities of sulﬁde

To a 5 cm³round-bottomed ﬂask ﬁtted with a nitrogen balloon

and containing a magnetic stirrer bar were added sequent-

ially sulﬁde (20 mol%), anhydrous acetonitrile (1.0–1.2 cm³),

rhodium() acetate dimer (1.5 mg, 1 mol%, 3.3 × 10^Ϫ3mmol),

benzyltriethylammonium chloride (15 mg, 20 mol%, 0.066

mmol), benzaldehyde (34 µL, 0.33 mmol) and tosylhydrazone

sodium salt 2 (148 mg, 0.50 mmol). The reaction mixture was

stirred vigorously at RT for 10 min, then at the required

temperature for 40 h. Work up consisted of sequential addition

to the reaction mixture of water (0.5 cm³) and ethyl acetate

(0.5 cm³). The separated aqueous layer was extracted with ethyl

acetate (2 × 0.5 cm³) and the combined extracts dried (MgSO₄),

and concentrated under reduced pressure. The crude product

was analysed by ¹H NMR to determine the diastereomeric ratio

and then puriﬁed by ﬂash column chromatography (ether–

hexane 0.5 : 99.5) to aﬀord trans-stilbene oxide as a white solid.

13 T. Fujisawa, M. Nagai, Y. Koike and M. Shimizu, J. Org. Chem.,

1994, 59, 5865.

14 V. K. Aggarwal, J. G. Ford, R. V. H. Jones and R. Fieldhouse,

Tetrahedron: Asymmetry, 1998, 9, 1801.

15 C. Kouklovsky, A. Pouilhes and Y. Langlois, J. Am. Chem. Soc.,

1990, 112, 6672.

16 P. M. Weintraub and C.-H. R. King, J. Org. Chem., 1997, 62,

1560.

Acknowledgements

17 D. N. Kursanov, Z. N. Parnes and N. M. Loim, Synthesis, 1974, 633.

18 J. M. Brown and J. A. Ramsden, Chem. Commun., 1996, 18, 2117;

P. Dubs and R. Stuessi, Helv. Chim. Acta, 1978, 61, 2351; H. C.

Araujo and J. R. Mahajan, Synthesis, 1978, 228.

19 We also tested Eliel’s oxathiane 88 which has been used by Solladié-

Cavallo (ref. 6g) for stoichiometric asymmetric epoxidation under

conventional Corey–Chakovsky conditions, but this sulﬁde was also

unstable to the reaction conditions.

20 (a) H. G. Aurich and J.-L. Ruiz Quintero, Tetrahedron, 1994, 50,

3929; (b) M. J. Kurth, S. H. Tahir and M. M. Olmstead, J. Org.

Chem., 1990, 55, 2286.

21 K. Furuta, Y. Ikeda, N. Meguriya, N. Ikeda and H. Yamamoto,

Bull. Chem. Soc. Jpn., 1984, 57, 2781.

22 B. Figadère, X. Franck and A. Cavé, Tetrahedron Lett., 1997, 38,

1413; A. F. Barrero, J. Altarejos, E. Alvarez-Manzaneda, J. M.

Ramos and S. Salido, Tetrahedron, 1993, 49, 6251.

23 C. M. Rayner, Organosulfur Chemistry. Synthetic Aspects, ed. P. B.

Page, Academic Press, London, 1995, p. 89.

24 R. E. Ireland, D. Häbich and D. W. Norbeck, J. Am. Chem. Soc.,

1985, 107, 3271; M. Hirama, M. Iwashita, Y. Yamazaki and S. Itô,

Tetrahedron Lett., 1984, 25, 4963.

25 Kellogg has obtained the corresponding α-mercapto carboxylic acid

with ee > 98% from (S)-2-bromoisovaleric acid by nucleophilic

substitution with caesium thiobenzoate and subsequent aminolysis;

B. Strijtveen and R. M. Kellogg, J. Org. Chem., 1986, 51, 3664.

26 E. A. Fehnel, J. Am. Chem. Soc., 1952, 74, 1569.

27 D. Seebach, A. K. Beck, R. Imwinkeiried, S. Roggo and

A. Wonnacott, Helv. Chim. Acta, 1987, 70, 954.

We thank EPSRC (DB, MJP, GDF), EU (RA, SJF, PJ), Zeneca

(PB, GDF), Sheﬃeld University (EJ), and Bristol University

(GH) for support. We also thank Professor V. Rawal for a

sample of 60b.

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Synthesis and evaluation of a broad range of chiral sulfides for asymmetric sulfur ylide epoxidation of aldehydes

DOI: 10.1039/b105416n

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