Synthesis of medium-ring lactones via tandem methylenation/Claisen rearrangement of cyclic carbonates

TETRAHEDRON

Pergamon

Tetrahedron 58 92002) 1943±1971

Synthesis of medium-ring lactones via tandem methylenation/

Claisen rearrangement of cyclic carbonates

Edward A. Anderson,^aJames E. P. Davidson,^aJustin R. Harrison,^aPaul T. O'Sullivan,^a

Jonathan W. Burton,^a,pIan Collins^band Andrew B. Holmes^a,p

^aDepartment of Chemistry, University of Cambridge, Lens®eld Road, Cambridge CB2 1EW, UK

^bMerck, Sharp and Dohme, Neurosciences Research Centre, Terlings Park, Eastwick Road, Harlow CM20 2QR, UK

Received 9 October 2001; accepted 29 October 2001

AbstractÐThe conversion of vinyl-substituted 6- and 7-membered cyclic carbonates into 8- and 9-membered medium-ring lactones has

been achieved in good yield using dimethyltitanocene in toluene at re¯ux. The reaction proceeds by initial formation of a ketene acetal which

undergoes subsequent in situ Claisen rearrangement to provide the corresponding lactones. The preparation of the cyclic carbonates is carried

out under basic conditions and hence this methodology complements our existing selenium-based methodology for the synthesis of medium-

ring lactones. q 2002 Published by Elsevier Science Ltd.

1. Introduction

of the selenoacetal 9precursor to the selenoxide 1) from a

1,3- or a 1,4-diol requires acidic conditions 9PPTS, re¯uxing

toluene). This can be a problem in cases where the allylic

hydroxyl group of the diol is prone to b-elimination.

Exposure of 5 to our standard reaction conditions 9phenyl-

selanylacetaldehyde diethylacetal, PPTS, toluene, re¯ux)

provided the selenoacetal 6 in low yield 946%) as well as

varying amounts of the a-b-unsaturated aldehyde 7

9Scheme 2).

Medium-ring oxacycles form the core of many biologically

and structurally interesting natural products such as the

brevetoxins,^1,2obtusenyne^3,4and 91)-laurencin⁵and an

ef®cient route towards these systems is a desirable aim. In

recent years we have developed an approach towards

medium-ring oxacycles via the ring-expansion Claisen

rearrangement of a vinyl-substituted ketene acetal 3,

generated in situ from the thermal elimination of benzene-

selenenic acid 2 from the corresponding selenoxides 1

9Scheme 1).^6±8

A further limitation of the selenium route to medium-ring

lactones is that benzeneselenenic acid 2, the product of

selenoxide elimination, has been shown to disproportionate

to benzeneseleninic acid and diphenyl diselenide under the

reaction conditions.¹⁰The latter may be able to act as a

reducing agent, converting the selenoxide 9ketene acetal

precursor) back into the selenoacetal 9Scheme 3).

Whilst this methodology provides ef®cient access to

medium-ring lactones 4 9which can be readily converted

into medium-ring ethers)⁵several limitations became

evident during the course of our investigations into the

total synthesis of octalactins A and B.⁹In addition to the

toxicity associated with selenium reagents,¹⁰the formation

The disproportionation of benzeneselenenic acid 2 can be

Scheme 1.

Keywords: medium-ring; lactone; Claisen rearrangement; carbonate; dimethyltitanocene.

Corresponding authors. Tel.: 144-1223-336-404; fax: 144-1223-336-362; e-mail: jwb1004@cus.cam.ac.uk; abh1@cus.cam.ac.uk

p

0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.

PII: S0040-4020902)00049-2

1944

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

Scheme 2. 9i) PhSeCH₂9OEt)₂, PPTS, toluene re¯ux.

recovery of large amounts of the selenide. Finally,

selenoxide elimination towards oxygen and subsequent

Claisen rearrangement require high temperatures 9sealed

tube, up to 1858C). These conditions and the need for high

dilution 9which also reduces the amount of disproportiona-

tion leading to recovered selenide) could make large scale

preparations more troublesome. Here we report the syn-

thesis of a series of 8- and 9-membered lactones via the

methylenation of cyclic carbonates derived from allylic

1,3- and 1,4-diols using dimethyltitanocene,^12±14and the

subsequent in situ Claisen rearrangement of the presumed

ketene acetal intermediates. Some of this work has been

reported in a preliminary communication.¹⁵

Scheme 3.

2. Preparation of the 1,4-diols

suppressed by the use of non-nucleophilic bases and the

addition of a nucleophilic silyl ketene acetal as a selenium

scavenger.¹¹Even under these optimal conditions, oxygen

transfer from the selenoxide to produce the selenoacetal can

still be a signi®cant side reaction which may lead to the

Preparation of the allylic 1,4-diols 9a±c could be achieved

in three steps from 2-deoxy-d-ribose 9Scheme 4, Table 1).

Treatment of the lactols 8 91:1 mixture of diastereomers

derived from 2-deoxy-d-ribose according to our previously

Scheme 4. ConditionsÐsee Table 1.

Table 1. Addition of vinyl Grignard reagents to the lactols 8, 19 or benzaldehyde

Entry

Compound

R¹

R²

R³

Conditions^a

Yield 9%)

d.r. 95R)/95S)

1

9a

9b

13

9c

21

H

TMS

H

Me

H

Me

H

THF, 2 h

75

77

73

53

78

1:1

Nd

±

1:1.65

±

2

THF, 2.2 h

Ether, 30 min

Ether, 4 h^c

THF, 1.5 h

3^b

4

5

a

All reactions conducted at 08C.

Reaction with benzaldehyde.

Grignard reagent prepared at 408Cfrom TMS-propyne, i-BuMgBr and Cp₂TiMe₂910 mol%) in ether.

b

c

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1945

Scheme 5. 9i) i-BuMgBr, Cp₂TiCl₂910 mol%), ether, re¯ux, 6 h; 9ii) PhCHO, 08C.

reported route)¹⁶with vinylmagnesium bromide provided

the diols 95R)-9a and 95S)-9a as a 1:1 mixture of separable

diastereomers 9Table 1, entry 1, 75%). Similarly, reaction of

the Grignard reagent derived from cis-1-bromoprop-1-ene¹⁷

with the lactols 8 provided the diols 95R)-9b and 95S)-9b in

77% yield, again as a mixture of separable diastereomers

9Table 1, entry 2). The stereochemistry of the diols was

vinyl anion using hydrozirconation^21±23or hydroalumi-

nation²⁴resulted in decomposition upon addition of the

organometallic reagent to the lactols 8. In the light of the

failure of these routes, further investigation of the hydro-

titanation/magnesiation strategy was carried out. The effect

of the reaction temperature on the regioselectivity of hydro-

titanation proved crucial, and preparation of the Grignard

reagent 11 at 408C9ether, re¯ux, 6 h) followed by addition

to benzaldehyde at 08Cprovided the corresponding addition

product 13 as a single regioisomer in good yield 973%,

Table 1, entry 3, Scheme 5).

1

assigned on the basis of H NMR nOe experiments on the

corresponding carbonates 9vide infra).

In an effort to extend the range of functionality introduced

into the lactone target, the trisubstituted vinyl derivative 9c

was also prepared. Use of the titanocene dichloride cata-

lysed alkyne hydromagnesiation methodology developed

by Sato^18±20allowed the preparation of what was presumed

to be 9Z)-1-trimethylsilyl-prop-1-enyl-1-magnesium bromide

11 from 1-trimethylsilyl-1-propyne 10. Initial attempts to

form this vinyl Grignard reagent 11 were conducted at

08Cor room temperature. Under these conditions a complex

91:1:1:1) mixture of isomeric products was obtained corre-

sponding to the addition of a 1:1 mixture of 9Z)-1-trimethyl-

silyl-prop-1-enyl-1-magnesium bromide 11 and 9E)-1-

trimethylsilyl-prop-1-enyl-2-magnesium bromide 12 to the

lactols 8, from which only the diol 95S)-9c could be isolated,

in pure form 911% yield). Alternative routes to the desired

Repetition of this experiment using the lactols 8 as the

electrophilic substrates led to the formation of a 1.65:1

mixture of the separable diastereomers 95S)-9c and

95R)-9c, in 53% overall yield 9Table 1, entry 4, Scheme

4), with no detection of the undesired isomers arising

from addition of 9E)-1-trimethylsilyl-prop-1-enyl-2-mag-

nesium bromide 12 to the lactols 8.

Our continued efforts towards the synthesis of the halo-

genated marine natural product obtusenyne⁴required the

synthesis of a chlorinated 9-membered lactone which was

made from 2-deoxy-d-ribose as outlined below. Thus

exposure of 2-deoxy-d-ribose to acidic methanol followed

Scheme 6. 9i) HCl, MeOH, ether, rt, 0.5 h; 9ii) TBDPSCl, pyridine, RT, 18 h; 9iii) Me₂N¹vCCl₂Cl², pyridine, CH₂Cl₂; 9iv) SiO₂.

1946

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

Scheme 7. 9i) BCl₃´SMe₂, ether, 10 min then THF, NaHCO₃9aq) 1 h; 9ii) vinylmagnesium bromide, THF 08C.

by the addition of pyridine and TBDPSCl provided the silyl-

ated methyl glycosides 15a and 15b in good yield as a 1.2:1

mixture of a- and b-anomers 9Scheme 6).

of the lactols 19 indicated that they were in equilibrium with

the open-chain aldehyde 19a.

Addition of vinylmagnesium bromide to the lactols 19

provided the corresponding allylic alcohols 21 as white

crystalline solids in good yield 9Table 1, entry 5); the

relative stereochemistry at C-5 of the diols 21 has not

been established.

Chlorination of the separated anomers 15 was achieved

according to a modi®ed literature procedure.²⁵Exposure

of 15 to phosgene iminium chloride and pyridine in

dichloromethane provided the chlorinated furanosides 16a

and 16b. These reactions also produced the corresponding

dihydrofurans 17a and 17b which arise from a competing

elimination reaction. The dihydrofurans are both acid

sensitive and readily lose methanol to form the furan 18²⁶

on ¯ash chromatography on silica gel; puri®cation of the

dihydrofurans 17 can be achieved by column chroma-

tography on silica gel made basic with triethylamine. The

methyl glycosides 16 were readily deprotected on exposure

to boron trichloride-methyl sul®de complex which provided

the corresponding lactols 19 in good yield 9Scheme 7); this

reaction also produced a small quantity of the a-b-unsatu-

rated aldehyde 20 which arises from elimination of HCl

from the open-chain aldehyde 19a. The ¹H NMR spectrum

3. Preparation of the 7-membered carbonates

Our initial approach towards the carbonate Claisen rear-

rangement precursors was based on the work of Burk and

Roof, who reported the synthesis of cyclic carbonates

derived from 1,2- and 1,3-diols on treatment with tri-

phosgene and pyridine.²⁷Exposure of the diol 95R)-9a to

0.5 equiv. of triphosgene and 6 equiv. of pyridine in

dichloromethane at 2788Cprovided the carbonate 22

as the sole product in 65% yield, together with 15% of

recovered starting material 9Scheme 8).

Scheme 8. 9i) Triphosgene 90.5 equiv.), py 96 equiv.), CH₂Cl₂, 2788C, 105 min; 9ii) as 9i) reaction time 15 min.

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1947

Scheme 9. Possible mechanism for formation of the carbonate 23 and the THF 24.

In contrast, reaction of the diol 95S)-9a under the same

conditions led to the isolation of two productsÐthe desired

carbonate 23 969%), a small amount of the tetrahydrofuran

derivative 24 96%), and 17% recovered starting material

9Scheme 8). The stereochemistry at C-7 of the carbonate

23 [C-5 of the diol 95S)-9a] was assigned on the basis of

¹H NMR nOe experiments. Reciprocal nOes were observed

between H-7 and H-5 in the carbonate 23 indicating that

these two protons were on the same face of the molecule

and that the carbonate 23 and the diol 95S)-9a had the 9S)

con®guration at C-7 and C-5, respectively. By inference the

stereochemistry at C-7 of the carbonate 22 and C-5 of the

diol 95R)-9a has the opposite 9R)-con®guration.

studies. Mutual nOe enhancements were observed between

H-7 and H-4 9carbonate numbering, Scheme 10); by infer-

ence the stereochemistry of the carbonate 26 and the diol

95R)-9b is as shown. Similarly, the stereochemistry of the

tetrahydrofuran 29 arising from the diol 95S)-9b could be

assigned from mutual nOe enhancements observed between

H-2 and H-5 9tetrahydrofuran numbering) and, by inference,

the stereochemistry at C-5 of the tetrahydrofuran 27 is 9S).

These stereochemical assignments indicate that tetrahydro-

furan formation is occurring in a stereospeci®c manner via

an S_N2-like mechanism with inversion of con®guration at

C-5 9diol numbering).

The low isolated yields of the carbonates 26 and 28 may be a

consequence of the acid sensitivity of the carbonates to

puri®cation by ¯ash chromatography 9which may be

reduced by the use of a basic solvent system) or an increased

tendency of the diols 9b to form tetrahydrofuran by-

products under the reaction conditions. It is likely that the

activation energy for the S_N2 reaction which leads to the

tetrahydrofurans 27 and 29 is lower in energy than the corre-

sponding transition state for the formation of 24 due to the

greater electron releasing power of a 2-propenyl group

compared with a vinyl group²⁸and hence the tetrahydro-

furans 27 and 29 form more readily than the tetrahydrofuran

24. Whilst the use of pyridine is probably necessary to

promote carbonate formation through pyridine-assisted acti-

vation of the triphosgene, the pyridinium hydrochloride

formed in situ may also be suf®ciently acidic 9pK_a5.23) to

protonate the carbonate product to some extent, leading to

eventual tetrahydrofuran formation by the mechanism

discussed earlier. This hypothesis was tested by the addition

of triethylamine 9pK_a10.75) into the reaction mixture. The

use of 6 equiv. each of pyridine and triethylamine 9Table 2,

entry 3), followed by chromatography in the presence of

triethylamine, led to suppression of tetrahydrofuran forma-

tion from the reaction of the diol 95S)-9b, and the desired

carbonate 28 was formed in 77% yield. It was subsequently

The formation of the tetrahydrofuran by-product 24 can be

rationalised by the initial acylation at the less hindered

alcohol with the formation of an intermediate such as 25

[Scheme 9, shown for the diol 95S)-9a], which has a choice

of two ring-closing pathways; 7-exo-trig cyclisation leads to

the desired carbonate 23, whereas 5-exo-tet ring closure 9via

an S_N2 type pathway) provides the tetrahydrofuran by-

product 24 with inversion of con®guration at the reacting

centre.

The stereochemistry of the furan 24 was assigned by

comparison with the stereochemistry of the furan 29 9vide

infra) implying that the reaction occurred by an S_N2-like

mechanism. Tetrahydrofuran formation may also be pos-

sible if nucleophilic ring-opening of the carbonate occurs

to provide 25. This process may be catalysed by pyridinium

hydrochloride generated under the reaction conditions or

may occur during puri®cation. The intermediate 25 could

subsequently cyclise to the undesired tetrahydrofuran

product 24 or indeed may revert to the diol starting material.

The promising yields of the desired carbonates 22 and 23

prompted us to attempt carbonate formation from the

methyl-substituted allylic diols 95R)-9b and 95S)-9b. In

the event, treatment of the diols 9b with triphosgene and

pyridine led to the predominant formation of the tetrahydro-

furans 27 and 29 9Scheme 10, Table 2, entries 1 and 2) as

well as some of the desired carbonates 26 and 28. The

stereochemistry of the carbonate 26 [and hence that of the

precursor diol 95R)-9b] was determined from ¹H NMR nOe

Ê

found that the inclusion of powdered 4 A molecular sieves

into the reaction mixture further increased consumption of

starting material and improved the isolated yields of the

carbonates 26 and 28 9Table 2, entries 4 and 5), although

the diol 95S)-9b still showed some tendency towards for-

mation of the tetrahydrofuran 29 compared with the diol

1948

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

Scheme 10. 9i) Triphosgene 90.5 equiv.), see Table 2.

Table 2. Preparation of the carbonates 26 and 28 from the diols 95R)- and 95S)-9b

Entry

Diol

Py 9equiv.)

Et₃N 9equiv.)

Conditions

Carbonate 9yield, %)

THF 9yield, %)

1

2

3

4

95R)-9b

95S)-9b

95R)-9b

6.2

6

±

6

2788C, 20 min^a

2788C, 20 min^b

26 933)

28 94)

28 977)

26 999)

27 957)

29 978)

29 9trace)

27 9trace)

Ê

6

4 A MS, 15 min

at 2788Cthen

10 min!rt^c

Ê

4 A MS, 15 min

5

6

7

95S)-9b

95R)-9b

95S)-9b

6

±

28 981)

29 912)

at 2788Cthen

10 min!rt^c

6^d

26/27, 1:1.5^e

28/29, 1:2.5^e

26/27, 1:1.5^e

28/29, 1:2.5^e

Ê

4 A MS, 15 min

at 2788Cthen

10 min!rt

Ê

4 A MS, 15 min

at 2788Cthen

10 min!rt

a

Puri®cation by ¯ash chromatography 9on silica; hexane/ether, 10:1).

Puri®cation by ¯ash chromatography 9on silica; hexane/ether, 4:112% Et₃N).

Puri®cation by ¯ash chromatography 9on silica; hexane/ether, 4:115% Et₃N).

DMAP used instead of pyridine.

b

c

d

e

1

Ratios determined by H NMR; yield not determined.

95R)-9b. Replacement of pyridine with the more nucleo-

philic DMAP 9Table 2, entries 6 and 7) led to a greater

proportion of tetrahydrofuran formation from both diols.

trated the need to maintain the reaction temperature at

2788Cduring carbonate formation.

Conversion of the diol 95S)-9c into the corresponding

carbonate 30, the potential Claisen rearrangement precursor

to a tetrasubstituted lactone, could also be accomplished.

Gratifyingly, treatment of the diol 95S)-9c with triphosgene

The effect of reaction temperature on the ratio of carbonate

and tetrahydrofuran products was also investigated. Carbo-

nate formation from the diol 95S)-9b was studied at a range

of temperatures from 2708Cto ambient temperature. An

increased proportion of the tetrahydrofuran 29 was

produced at higher temperatures 9Table 3); this result illus-

Ê

in the presence of 4 A molecular sieves, triethylamine and

pyridine in dichloromethane at 2788C, according to our

optimised procedure, led to the formation of the desired

carbonate 30 and a small amount of what was presumed

to be the tetrahydrofuran 31 in a 10.8:1 ratio 999% yield,

Scheme 11). The stereochemistry of the carbonate 30 [and

hence the diol 95S)-9c] was again assigned through ¹H NMR

nOe experiments; mutual nOe enhancements were observed

between H-5 and H-7 in 30, indicating these two protons to

Table 3. Formation of the carbonate 28 and the tetrahydrofuran 29 from the

diol 95S)-9b

Entry

Temperature

98C)

Product ratio^a,b

9carbonate 28/THF 29)

1

be on the same face of the carbonate ring. H NMR nOes

1

2

3

4

5

270

245

225

0

9:1

5.1:1

1:1

0.35:1

from H-7 to the TMS group and the vinyl proton 9but not to

the vinyl methyl group) suggested the geometry of the ole®n

to be 9Z) as expected.

25

Treatment of the diols 21 under our optimised conditions for

carbonate formation, provided the corresponding carbonates

32 in moderate to good yields 950 and 77%, respectively;

a

Conditions: Pyridine 96 equiv.), triethylamine 96 equiv.), CH₂Cl₂,

15±30 min.

b

1

Determined by H NMR.

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1949

Ê

Scheme 11. 9i) Triphosgene 90.5 equiv.), py 96 equiv.), triethylamine 96 equiv.), 4 A MS, CH₂Cl₂, 2788C, 25 min, 99% 930/31, 10.8:1).

Ê

Scheme 12. 9i) Triphosgene, pyridine, triethylamine, 4 A MS, CH₂Cl₂.

Scheme 12). The carbonates were very unstable on storage

and hence full characterisation was not possible.

for several months in the freezer with no loss of activity.²⁹

Treatment of the diastereomeric carbonates 22 and 23 with

dimethyltitanocene afforded the 9-membered lactone 35 in

76 and 49%, yields, respectively 9Scheme 13); the lactone

35 was formed in 85% yield using the alternative selenium

based methodology.¹⁶

4. Conversion of the 7-membered carbonates to

9-membered lactones

The overall success of this transformation was encouraging

and our attention was turned to the more heavily substituted

vinyl carbonates 26, 28, 30 and the chloro-substituted vinyl

carbonate 32. Exposure of the carbonate 26 to 1.25 equiv. of

dimethyltitanocene in toluene at re¯ux led to the formation

With a range of 7-membered cyclic carbonates in hand,

methylenation to the presumed ketene acetal intermediates

and subsequent in situ Claisen rearrangement was investi-

gated. Dimethyltitanocene was conveniently prepared

according to the reported procedure and could be stored

Scheme 13. 9i) Cp₂TiMe₂91.25 equiv.), toluene, re¯ux, dark, 2 h.

Scheme 14. 9i) Cp₂TiMe₂91.25 equiv.), toluene, re¯ux, 0.5 h, dark.

1950

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

Figure 1. Lowest energy conformations for the constrained ketene acetal 37-TMS ®ltered by the H-7±C-7±C-8±H-8 torsion angle: 9a) 0^908 and

9b) 180^908. The oxygen lone pairs and TMS groups have been removed for clarity. Constrained bonds are indicated. Molecular modelling was carried

out with in vacuo simulation.

of a single less polar compound by thin layer chroma-

tography 9TLC) 9Scheme 14). Analysis of the puri®ed

product revealed that a 1:1 mixture of atropisomeric

lactones 36b and 36c had been produced in 65% yield, as

evidenced by the presence of two distinct methyl peaks in

the ¹H NMR spectrum [d_H9CDCl₃, 500 MHz) 1.13 9d, 3H,

J7.0 Hz), 1.18 9d, 3H, J7.0 Hz)].

mation of each set is illustrated 9Fig. 1). Boltzmann distri-

butions were calculated for each ®ltered set 9at 384 K, with

a global minimum of 211.866 kJ mol²¹, corresponding to a

boat transition state), which predicted a transition state ratio

of 1191:1, boat/chair. The large preference for a boat-like

transition state predicted by molecular modelling [leading to

an 9E)-ole®n, 36b] can be rationalised by examination of the

two transition state structures 9Fig. 1). The cis-propenyl

methyl group clearly leads to large unfavourable trans-

annular interactions in the chair-like transition state [leading

to a 9Z)-ole®n, 36a] which are relieved in the alternative

boat conformation, where the methyl group adopts an exo-

orientation relative to the 7-membered ring.

In an effort to identify and rationalise this mixture of

products, a Monte Carlo conformational search³⁰using the

MM2 force®eld³¹implemented in Macromodel^wversion

5.5³²was carried out for the analogous TMS-protected

presumed ketene acetal intermediate 37-TMS. The inter-

atomic distance between C-2⁰and C-7⁰⁰9forming bond)

Ê

was constrained at 2.3 A, whilst the C-7±O-1 9breaking

The experimentally observed ratio of 9E)-alkene isomers

91:1) does not seem to be supported by the molecular model-

ling calculations which would predict the formation of

solely the lactone 36b containing an 9E)-ole®n. One pos-

sible explanation for the formation of two atropisomeric

lactones 36b and 36c is that the initially formed lactone

36b undergoes rotation around the C-4±C-5 and C-6±C-7

bonds 9atropisomerisation) under the reaction conditions to

provide the lactone 36c. The 1:1 ratio of 36b/36c would

therefore correspond to the thermodynamic ratio 9Scheme

14). A Monte Carlo conformational search³⁰using the

²

Ê

bond) was set at 1.8 A, in a crude transition state model.

All structures corresponding to unique energy minima were

then ®ltered by the torsion angle H-7±C-7±C-7⁰±H-7⁰into

two sets, with angles 0^90 and 180^908. These ®ltered sets

correspond to chair- and boat-like Claisen rearrangement

transition states, respectively; the lowest energy confor-

²

The bond-making and bond-breaking distances were taken from an ab

initio calculation 93-21G and 3-21G^p) of the transition state for the

Claisen rearrangement of a simple vinyl-substituted ketene acetal.

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1951

Figure 2. Lowest energy conformations for the atropisomers 36b-TMS and 36c-TMS and calculated and experimental ratios for 36b-TMS, 36c-TMS, 36b and

36c. Molecular modelling was carried out with in vacuo simulation.

MM2 force®eld³¹in Macromodel^wversion 5.5³²was carried

out for the TMS-substituted 9E)-ole®n lactone isomer

36b-TMS. The resultant set of unique energy minima

were ®ltered by the H-4±C-4±C-5±H-5 torsion angle into

two sets, with angles 0^90 and 180^908, corresponding to

the two atropisomers 36b and 36c, respectively 9Fig. 2).

the initially formed trans-9-membered lactone underwent

atropisomerism on prolonged heating in toluene.

The diastereomeric carbonate 28 was also subjected to

methylenation/Claisen rearrangement conditions 9Scheme

15). A complex mixture of products was obtained in 52%

1

yield; a H NMR COSY experiment enabled identi®cation

of four separate lactone products. In addition, each lactone

The Boltzmann distributions calculated for each set

predicted a thermodynamic ratio of 1:1.79, 36b-TMS/

36c-TMS at 298 K 91:1.73 at 384 K). Although this calcu-

lation does not make any prediction with regard to the

activation energy for atropisomerisation, the theoretical

ratio of atropisomers is in reasonable agreement with the

experimentally observed distribution of isomeric lactone

products 936b/36c, 1:1), formed from equilibration of the

initially formed atropisomer 36b. The formation of atropiso-

meric 9-membered lactones following ring-expansion

Claisen rearrangement of a ketene acetal has been reported

by Pearson.³³In this study a mixture of cis- and trans-9-

membered lactones was observed and it was shown that

1

gave rise to at least one distinct peak in the H NMR

spectrum, unobscured by other lactone signals 9as assigned

through COSY analysis). Due to the complete connectivity

1

of the H spin systems, it was realised that this complex

mixture of inseparable products could be conveniently

analysed through a series of 1-D TOCSY experiments.^34±36

Irradiation of each of the distinct signals would lead to

enhancements only at those protons within the same spin

1

system; in other words, the H NMR spectrum of each

isomer would be resolved. After this study was complete

the concept of analysing complex mixtures using 1-D

TOCSY experiments was independently published by

Scheme 15. 9i) Cp₂TiMe₂91.35 equiv.), toluene, re¯ux, 0.5 h, dark.

1952

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

Figure 3. Observed 1H NOESY crosspeaks for the lactone 36d and calculated global minimum for the lactone 36d-TMS. The oxygen lone pairs and TMS

protecting groups have been removed for clarity. Distances were measured on the computer using Macromodel^w. Molecular modelling was carried out with in

vacuo simulation.

Sharman.³⁷Examination of the resultant TOCSY spectra

showed that the products could be assigned as 36a, 36d,

36e, 36f and 29 in a ratio of 2.0:3.1:7.7:3.7:1.0 9determined

36d-TMS. The global minimum conformation provided

strong support for the proposed structure; the calculated

interatomic distances were in good agreement with the

observed NOESY crosspeaks 9Fig. 3).

1

through integration of the H NMR spectrum).

The geometry of the ole®n in the unsaturated lactones 36a

and 36d was assigned as 9Z) on the basis of the coupling

constant analysis [36a, d_H9CDCl₃, 500 MHz) 4.79±4.89

9m, 1H, H-6), 5.01 9apparent ddm, 1H, H-5, J11.0,

7.5 Hz); 36d, d_H9CDCl₃, 500 MHz) 5.35 9t, 1H, H-5,

J10.5 Hz), 5.71 9td, 1H, H-6, J10.5, 5.5 Hz)]. A 2-D

NOESY experiment on 36d 9prepared by RhCl₃mediated

isomerisation of a 1:1 mixture of 36b,c) allowed assignment

of the stereochemistry at C-4 as 9S), and thus by inference

The unexpected formation of the isomer 36a could be

rationalised by close examination of the carbonate starting

material which revealed a small amount of the trans-

propenyl substituted carbonate 38. The origin of this

impurity was traced to the commercially purchased pro-

penyl bromide 9Aldrich stated purity, 97%) used for

preparation of the corresponding Grignard reagent for

coupling with the lactols 8.

1

the stereochemistry at C-4 of 36a as 9R). In the H NMR

NOESY spectrum of 36d strong cross peaks were observed

between H-3 and H-5, H-4 and H-7, H-9 and H-6. A Monte

Carlo conformational search³⁰using the MM2 force®eld³¹

in Marcomodel^wversion 5.5³²was conducted for the lactone

Figure 4. Lowest energy conformations for the atropisomers 36e-TMS and 36f-TMS and calculated and experimetental ratios for 36e-TMS, 36f-TMS, 36e

and 36f. Molecular modelling was carried out with in vacuo simulation.

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1953

Scheme 16. 9i) Cp₂TiMe₂91.15 equiv.), toluene, re¯ux, 0.5 h, dark.

Similarly, the double bond geometry of the atropisomeric

lactones 36e and 36f were assigned 9E) on the basis of

coupling constant analysis; [36e, d_H9CDCl₃, 500 MHz)

5.26 9ddd, 1H, H-6, J16.5, 11.7, 3.2 Hz), 5.48 91H, ddd,

J16.5, 7, 1 Hz); 36f, d_H9CDCl₃, 500 MHz) 5.05 9dd, 1H,

H-5, J16.5, 9.5 Hz), 5.43 9ddd, 1H, H-6, J16.5,

8.8, 6.5 Hz)]. Assignment of the stereochemistry of the

atropisomers 36e and 36f was made on the basis of the

molecular modelling prediction of the product distributions.

A Monte Carlo conformational search³⁰using the MM2

force®eld³¹in Macromodel^wversion 5.5³²was carried out

for the analogous TMS-protected presumed ketene acetal

intermediate 39-TMS. The interatomic distance between

C-2⁰and C-7⁰⁰9forming bond) was again constrained at

theoretical ratios had been obtained. As before, a Monte

Carlo conformational search³⁰using the MM2 force®eld³¹

in Macromodel^wversion 5.5³²was carried out for the TMS-

substituted E-ole®n lactone isomer 36e-TMS. Again, the

resultant set of unique energy minima was ®ltered by the

H-4±C-4±C-5±H-5 torsion angle into two sets, with angles

0^90 and 180^908, corresponding to the two atropisomers

36e and 36f, respectively 9Fig. 4). The Boltzmann distri-

butions calculated for each set predicted a thermodynamic

ratio of 2.68:1, 36e-TMS/36f-TMS at 298 K 92.25:1 at

384 K). These ratios compared well with the experimentally

observed ratio of 2.08:1 between the lactones assigned as

36e and 36f. The small amount of the tetrahydrofuran by-

product 29 observed in the product mixture may have

arisen from degradation of any remaining carbonate starting

material during reaction or puri®cation.

Ê

2.3 A, whilst the C-7±O-1 9breaking bond) was set at 1.8 A.

Attention was turned to the TMS-substituted propenyl

carbonate 30. The trans-stereochemistry of the methyl

group relative to the carbonate ring in this compound was

not expected to lead to the problematic mixture of products

observed for the cis-propenyl derivatives 26 and 28, as the

proposed chair-like transition state for the Claisen rear-

rangement 9with the methyl group in a pseudo-equatorial

position) ought not lead to unfavourable transannular inter-

actions in this instance. In the event, exposure of the car-

bonate 30 to dimethyltitanocene afforded solely the lactone

40 as a single isomer, in a satisfactory 51% yield 9Scheme

16).

The structures corresponding to unique energy minima were

then ®ltered by the torsion angle H-7±C-7±C-7⁰±H-7⁰into

two sets, with angles 0^90 and 180^908. Boltzmann distri-

butions were calculated for each ®ltered set 9at 384 K, with

a global minimum of 20.83847 kJ mol²¹, corresponding to

a boat transition state), leading to a predicted transition state

ratio 9and corresponding E/Z, 36e/36d, lactone ole®n ratio)

of 97:1 9boat/chair). Although this ratio is rather more in

favour of the E-ole®n isomer 36e,f than the observed values

93.1:1), qualitative agreement between the experimental and

The stereochemistry of the lactone 40 was assigned through

a H NMR NOESY experiment. Strong crosspeaks were

1

observed between H-4 and H-7a, and between H-7a and

H-9, all of which are proposed to be on the lower face of the

lactone ring 9as drawn). A strong enhancement was also

seen between H-6 and the TMS group, con®rming the

stereochemistry of the double bond to be cis with respect

to the lactone ring. A Monte Carlo conformational search³⁰

using the MM2 force®eld³¹in Macromodel^wversion 5.5³²

was carried out for the lactone 40-TMS. The global mini-

mum conformation provided strong support for the assigned

structure as the calculated interatomic distances were in

good agreement with the observed NOESY crosspeaks

9Fig. 5).

The ®nal 7-membered carbonates to be studied in this series

were the chlorinated compounds 32. On exposure to

dimethyltitanocene in toluene at re¯ux the separated carbo-

nates 32 provided the 9-membered lactone 41 in 55 and 63%

yields 9Scheme 17). This transformation indicates that it is

possible to use reducible functional groups 9i.e. alkyl

halides) in the presence of dimethyltitanocene. Furthermore,

when the formation of the lactone 41 was attempted from

Figure 5. Observed 1H NOESY crosspeaks for the lactone 40 and calcu-

lated global minimum for the lactone 40-TMS. The oxygen lone pairs and

TMS protecting groups have been removed for clarity. Distances were

measured on the computer using Macromodel^w. Molecular modelling

was carried out with in vacuo simulation.

1954

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

the carbonate/Claisen rearrangement methodology to a

range of 8-membered lactones was also investigated.

5. Preparation of the 1,3-diols

The synthesis of a range of representative 1,3-diols 9for

subsequent conversion to 8-membered lactones)⁸was

readily achieved using the boron-mediated aldol method-

Scheme 17. 9i) Cp₂TiMe₂, toluene, re¯ux.

ology developed by Paterson.^38±40

A 91)-Ipc-boron

mediated aldol reaction between the enolate derived from

the ketone 42 [readily prepared in three steps from 9R)-91)-

methyl-3-hydroxy-2-methylpropionate]³⁹and a range of

commercially available acyclic aldehydes 46±48 and the

cyclohexenyl-substituted 92)-perillaldehyde 49 provided

the syn-hydroxyketone products 52a±d in 80±95% yields

as single diastereomers as judged by ¹H NMR 9Scheme 18,

Table 4).

the corresponding selenoxide using our standard Claisen

rearrangement conditions 9toluene, DBU, re¯ux, 18 h) the

lactone 41 was isolated in very poor yield and was of a low

purity.

The effect of the substitution pattern of the carbonates

subjected to the methylenation/Claisen rearrangement reac-

tion clearly has a strong in¯uence on the product distribu-

tions in the case of 9-membered lactones. The application of

The absolute con®guration of the product 52a was

Scheme 18. 9i) 91)-Ipc₂BCl, Et₃N, ether, 08C, 2 h; 9ii) 92)-Ipc₂BOTf, i-Pr₂NEt₂, C HCl₂, 258C, 3 h; 9iii) Cy₂BCl, Et₃N, ether, 2788C, 3 h; 9iv) RCHO

2

946±50), ether, 2788C; 9v) H₂O₂, pH 7 buffer, MeOH, rt, 1 h; 9vi) Me₄NBH9OAc)₃, MeCN, AcOH, see Table 4; 9vii) carbonyldiimidazole, toluene, re¯ux;

Ê

9viii) triphosgene, py, Et₃N, 4 A MS, CH₂Cl₂, 2788C.

Table 4. Preparation of the hydroxyketones 52a±g, the diols 55a±g and the carbonates 56a±g

Ketone

P

R¹

R²

R³

Hydroxyketone

Yield Yield

52a±h 9%) 55a±g 9%)

t 9h) T 98C)

Yield

56a±g 9%)

t 9h)

42

Bn

H

Me

H

Me

H

52a

52b

52c

81^a

95^a

91

18

240

235

66,^b45^c,d

77^c

48, 0.25

0.5

25, 1.0

a

±

66^e

32,^b46^c

a

42

Bn

H

52d

±

51^e

18

235

28^b

24

43

44

Bn

TBDMS

H

Me

Me 52e C-4-9S)^f

Me 52f C-4-9R)^f

Me 52g C-4-9R)^f

90^g

72^h

73^h

72

77

18

48

72

235

230

100^b

91^b

20

23

20

78^b

a

Conditions: Scheme 18 9i), 9iv), 9v).

Conditions: Scheme 18 9vii).

Conditions: Scheme 18 9viii).

33% Recovered 55a.

b

c

d

e

f

Yield over 2 steps.

The con®gurations at C-4 in 52e±g only apply to the hydroxyketones 52e±g and not to the diols 55e±g or the carbonates 56e±g.

Conditions: Scheme 18 9ii), 9iv), 9v).

Conditions: Scheme 18 9iii), 9iv), 9v).

g

h

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1955

methodology from the ethyl ketone 44 and aldehyde 50, for

comparison of the effect of the protecting group on the

Claisen rearrangement.

Anti-reduction of the hydroxyketones 52a±g was achieved

on treatment with tetramethylammonium triacetoxyboro-

hydride⁴²at 2358Cfor at least 18 h 9Scheme 18, Table 4);

moderate to good yields of the corresponding anti-diols

55a±g were obtained with excellent diastereoselectivity

Scheme 19. 9i) 9R)- or 9S)-MTPA, DCC, DMAP, CH₂Cl₂, rt.

established by 500 MHz ¹H NMR analysis following

conversion of the free hydroxy group to the 9R)-91)- and

9S)-92)-phenylmethoxy9tri¯uoromethyl) acetate 9MTPA)

53 derivatives according to the method of Kawisawa

9Scheme 19; see Section 9).⁴¹

9generally single diastereomers by H NMR). Conversion

1

of these diols to the desired 6-membered cyclic carbonate

derivatives 56a±g proved less problematic than the 7-mem-

bered cases. Either the triphosgene or carbonyldiimidazole

9CDI) methodology could be used to effect this trans-

formation 9Table 4).

The aldols 52a and 52b were readily puri®ed by ¯ash

chromatography, however, 52c and 52d could not be

completely separated from isopinocampheol 9an oxidative

side product) and were used in partially puri®ed form.

6. Conversion of the 6-membered carbonates to

8-membered lactones

In a similar manner, the ethyl ketone 43 9prepared in by an

analogous route to the methyl ketone 42) could be combined

with methacrolein 50 using a boron-mediated aldol reaction.

Formation of the 9Z)-enolate of the ketone 43 using 92)-di-

isopinocampheylboron tri¯ate followed by addition of

methacrolein 50 afforded the syn-aldol product 52e in

90% yield 9Scheme 11, Table 4), containing an 9S)-methyl

substituent on the carbon backbone.⁴⁰In contrast, the

9E)-enolate of the ethyl ketone 43 was formed on treatment

with dicyclohexylboron chloride, which provided the anti-

aldol product 52f, containing an 9R)-methyl group, after

reaction with the aldehyde 50.⁴⁰The analogous TBDMS

protected hydroxyketone 52g was prepared using identical

With a range of carbonate substrates in hand, the tandem

methylenation/Claisen rearrangements were carried out

9Scheme 20, Table 5). Treatment of the carbonates 56a±g

with dimethyltitanocene in toluene at re¯ux provided the

8-membered lactone Claisen rearrangement products

1

58a±g as single diastereomers 9by H NMR analysis) in

reasonable to good yields. Carbonates with a greater degree

of substitution around the Claisen rearrangement skeleton

956c and 56d) were both more dif®cult to synthesise, and

required longer reaction times with lower overall yields for

the Claisen rearrangement step. The nature of the side-chain

protecting group 956f, Bn; and 56g, TBDMS) did not seem

to greatly affect the overall yield of the Claisen rearrange-

ment. Gratifyingly, the overall yield for the two-step pro-

cedure 9carbonate formation then Claisen rearrangement)

was found to be comparable, and in several cases superior,

to the alternative selenium route to the same lactones.⁸

7. Discussion

The synthesis of both 8- and 9-membered lactones from 6-

and 7-membered carbonates has been achieved in moderate

to good yields. The ring-expansion reaction proceeds via

initial methylenation of the carbonate with dimethyltitano-

cene followed by in situ Claisen rearrangement of the

derived ketene acetals which provides the corresponding

medium-ring lactones. If the rate of the methylenation of

the carbonates is faster than the rate of the Claisen rear-

rangement of the corresponding ketene-acetals, then the

Scheme 20. 9i) Cp₂TiMe₂, toluene, re¯ux, dark; PBn 956a±f); P

TBDMS 956g).

Table 5. Preparation of the 8-membered lactones 58a±g

Carbonate

R¹

R²

R³

Yield 58a±g 9%)

t 9h)

56a

56b

56c

H

Me

H

Me

H

52

34

3.5

2.5

4.5

56d

H

25

24

56e

56f

56g

H

Me

48; C-7-9S)

63; C-7-9R)

67; C-7-9R)

3.0

16

20

1956

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

ketene-acetal will build up as an intermediate and most of

the dimethyltitanocene reagent will be consumed before the

conversion of the ketene-acetals into the corresponding

medium-ring lactones. However, if the Claisen rearrange-

ment of the ketene-acetals is rapid compared with methyl-

enation of the carbonate, then the lactone products will be

formed in the presence of dimethyltitanocene and so may be

subject to methylenation. In many of the reactions extra

dimethyltitanocene was added to the reaction mixture

when TLCanalysis indicated that the reaction had not

gone to completion. In these cases the lactones were still

isolated as the major component from the reaction mixture

thus indicating that methylenation of a carbonate carbonyl

group is faster than methylenation of a medium ring lactone

carbonyl group. The reason for the selective methylenation

of a carbonate in the presence of a lactone is unclear.⁴³

NOESY spectra were typically acquired with 640 slices in

F₁and 2048 points in F using a mixing time 9t_m) of 1.6 s

9acquisition time typically 8 h).

¹³CNMR spectra were recorded on Bruker DPX-250

962.5 MHz), AM-400 9100 MHz), WM-400 9100 MHz)

and WM-200 950 MHz) spectrometers in the solvent indi-

cated and with proton decoupling. Chemical shifts are

quoted relative to tetramethylsilane 9d0 ppm). The

attached proton tests 9APT) and DEPT-135 experiments

were used to assign signals in particular cases.

Infrared spectra were recorded on a Perkin±Elmer 1600 FT

IR spectrophotometer. The sample was prepared as a thin

liquid ®lm, a KBr disc or as a solution in the solvent indi-

cated. Calibration was relative to polystyrene at 1603 cm²¹

.

Mass Spectra were carried out at the EPSRCMass Spec-

trometry Service Centre, University of Swansea or at the

Cambridge University Chemical Laboratory. In Swansea,

Electron Impact 9EI) and Chemical Ionisation 9CI) low-reso-

lution spectra were carried out on a VG model 12-253 under

ACE conditions. Accurate mass measurements for EI and CI

were performed on a 1VG ZAB-E instrument. In Cambridge

EI and CI, low resolution and accurate mass, spectra were

performed on a KRATOS MS-890. Electrospray spectra

were determined with an ES Bruker FTICR. All CI measure-

ments were performed with NH₃as the carrier gas.

8. Conclusion

An alternative ring-expansion route to 8- and 9-membered

lactones by tandem methylenation/Claisen rearrangement,

which avoids the problems associated with toxic selenium

reagents, has been developed. Comparable, and in certain

cases superior, yields to the selenium route were obtained

for the lactonisation processes. The formation of the chloro-

lactone 41 was achieved in good yield utilising this carbo-

nate methodology but was formed in very poor yield using

our selenium based methodology. The formation of the

carbonates occurs under basic conditions and hence comple-

ments our alternative selenoacetal methodology in which

the key selenoacetal is synthesised under acidic conditions.

We can now prepare both acid and base sensitive medium-

ring lactones 9and precursors) using these complementary

methodologies.

Optical rotations were measured using a Perkin±Elmer 241

polarimeter, in a cell of 1 dm path length. The concentration

9c) is expressed in g/100 mL 9equivalent to g/0.1 dm³).

T

Speci®c rotations denoted as [a]_D, imply units of

dm²g²¹9Ttemperature 98C)).

Microanalyses were carried out by the staff of the

Cambridge University Chemical Laboratory Microana-

lytical Department.

The chemistry reported above should enable the synthesis of

a range of previously inaccessible medium-ring oxacyclic

natural products.

Melting points 9mp) were determined using a Ko¯er block

or a BuÈchi 510 melting point apparatus and are uncorrected.

9. Experimental

9.1. General

Analytical TLCwas carried out on Merck pre-coated 0.25 mm

thick plates of Kieselgel 60 F₂₅₄. Preparative layer chroma-

tography was carried out on 1 mm thick plates 918 cm£

20 cm) of Merck Kieselgel PF₂₅₄. Flash chromatography

was carried out using Merck Kieselgel 60 9230±400 mesh).

¹H NMR spectra were recorded on Bruker DPX-250 9250

MHz), WM-400 9400 MHz), AM-400 9400 MHz), DRX-

500 9500 MHz) and DRX-800 9800 MHz) spectrometers.

Chemical shifts are quoted in ppm relative to tetramethyl-

silane 9d0 ppm) and referenced to the solvent residual. For

convenience, the following abbreviations are used: s, singlet;

d, doublet; t, triplet; q, quartet; qn, quintet; m, multiplet;

dd, doublet of doublets; etc. Where useful, the FID was

zero-®lled 9128 K) and sine-bell shifted 9SSB30) prior

to Fourier Transformation in order to provide baseline

resolved multiplets and, as a result, easily identi®able and

measurable coupling constants.

Non-aqueous reactions were carried out under an atmos-

phere of dry argon unless indicated to the contrary.

Dry THF was distilled from potassium in a recycling still

using benzophenone ketyl as indicator. Other dry solvents

were puri®ed by standard techniques.⁴⁴

Ether refers to diethyl ether. Light petroleum refers to the

fraction boiling between 40 and 608C. Brine refers to a

saturated solution of sodium chloride in water.

All two-dimensional 92D) spectra were recorded on a

Bruker DRX-500 spectrometer, ®tted with gradient coils.

Double Quantum Filtered 9DQF) and magnitude COSY

spectra were typically acquired with 256 slices in F₁and

2048 points in F₂9acquisition time approximately 20 min).

9.1.1.

.2R,3R,5R)-2,5-Dihydroxy-1,3-bis-[tert-butyldi-

phenylsilyloxy]-hept-6-ene .5R)-9a and .2R,3R,5S)-2,5-

dihydroxy-1,3-bis[tert-butyldiphenylsilyloxy]-hept-6-ene

.5S)-9b. The lactols 8¹⁶were dissolved in benzene, the

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1957

resulting solution was heated at re¯ux for 2 h under Dean±

Stark conditions and the solvent was then removed in vacuo.

To a stirred solution of the lactols 8 9dried as above, 13.81 g,

22.6 mmol) in THF 9100 mL) at 08Cwas slowly added a

solution of vinylmagnesium bromide 952 mL of a 1.0 M

solution in THF, 52 mmol). After addition was complete

stirring was continued for 2 h at 08Cwhereupon the reaction

was quenched by careful addition of a saturated aqueous

solution of ammonium chloride 920 mL) followed by

water 920 mL). The mixture was extracted with ether

94£100 mL), the combined organic extracts were washed

with brine 9100 mL) and dried 9MgSO₄). The solvent was

removed in vacuo and puri®cation by ¯ash chromatography

9hexane/ether, 2:1) provided the diols 9a as a 1:1 mixture of

a colourless oil and a slowly crystallising white solid

910.81 g, 75%). The diastereomeric diols 9a could be sepa-

rated by ¯ash chromatography 9hexane/ether, 4:1) for the

purposes of characterisation.

provided a mixture of the diols 95S)-9b and 95R)-9b

9308 mg, 0.470 mmol, 33%) as a clear and colourless oil

and a slow-crystallising white solid 9Found: C, 73.5; H,

8.0; C₄₀H₅₂O₄Si₂requires C, 73.6; H, 8.0%). Further elution

of the column provided the diol 95R)-9b [315 mg,

0.482 mmol, 34%, containing a trace amount of the diol

95S)-9b]. Further puri®cation by preparative TLC9hexane/

ether, 1:1) provided the analytically pure diols.

The diol 95S)-9b was isolated as a clear and colourless oil;

20

R_F0.20 9hexane/ether, 1:1); [a]_D25.6 9c 1.43 in CHCl₃);

n_max9CHCl₃) 3586 cm²¹; d_H9CDCl₃, 500 MHz) 1.00 [s,

9H, C9CH₃)₃], 1.02 [s, 9H, C9CH₃)₃], 1.49 9dd, 3H, H-8,

J6.9, 1.7 Hz), 1.68±1.72 9m, 2H, H-4), 2.26 9br s, 1H,

OH), 2.66 9br s, 1H, OH), 3.42 9dd, 1H, H-1, J10.2,

8.1 Hz), 3.73 9dd, 1H, H-1, J10.2, 5.0 Hz), 3.89 9dt, 1H,

H-2, J8.1, 5.0 Hz), 3.96 9q, 1H, H-3, J5.0 Hz), 4.50±

4.56 9m, 1H, H-5), 5.26 9ddq, 1H, H-6, J10.9, 8.4,

1.7 Hz), 5.40 9dqd, 1H, H-7, J10.9, 6.9, 1.0 Hz), 7.27±

7.46 9m, 12H, ArH), 7.55±7.65 9m, 8H, ArH); d_C9CDCl₃,

62.5 MHz) 13.1, 19.1, 19.4, 26.8, 27.0, 40.4, 64.3, 65.4,

72.4, 74.6, 125.3, 127.8, 129.8, 133.2, 133.3, 133.5, 135.5,

135.9, 136.0; MS 9ES¹) m/z: 675.3320 [9M1H)¹.

C₄₀H₅₂O₄Si₂requires 675.3302].

25

Data for 95R)-9a: R_F0.23 9hexane/ether, 2:1); [a]_D15.5

9c 1.87 in CHCl₃); n_max9CHCl₃) 3415 cm²¹; d_H9CDCl₃,

250 MHz) 0.98 [s, 9H, C9CH₃)₃], 1.02 [s, 9H, C9CH₃)₃],

1.69±1.75 9m, 2H, H-4), 2.85±3.30 9br d, 2H, OH), 3.48

9dd, 1H, H-1, J10, 7 Hz), 3.71 9dd, 1H, H-1, J10, 5 Hz),

3.84±4.02 9m, 2H, H-2, H-3), 4.43 9br q, 1H, H-5, J

5.5 Hz), 4.97 9dt, 1H, H-7_cis, J10, 1.5 Hz), 5.10 9dt, 1H,

H-7_trans, J17, 1.5 Hz), 5.62 9ddd, 1H, H-6, J17, 10,

5.5 Hz), 7.25±7.47 9m, 12H, ArH); MS 9CI, NH₃) m/z:

639.333 [9M1H)¹. C₃₉H₅₁O₄Si₂requires 639.3326], 639

91%), 274 9100). Found: C, 73.5; H, 7.9; C₃₉H₅₀O₄Si₂

requires C, 73.3, H, 7.9%.

The diol 95S)-9a was isolated as a clear and colourless oil

which slowly solidi®ed to a white micro-crystalline solid;

20

mp 91±1008C; R_F0.15 9hexane/ether, 1:1); [a]_D120.5

9c 0.92 in CHCl₃); n_max9CHCl₃) 3564, 3412 cm²¹; d_H

9CDCl₃, 500 MHz) 0.98 [s, 9H, C9CH₃)₃], 1.02 [s, 9H,

C9CH₃)₃], 1.59 9dd, 3H, H-8, J6.9, 1.7 Hz), 1.66 9ddd,

1H, H-4, J14.9, 6.1, 2.8 Hz), 1.80 91H, H-4, ddd, J

14.9, 9.0, 3.6 Hz), 3.05 9br s, 2H, OH), 3.46 9dd, 1H, H-1,

J10.3, 7.6 Hz), 3.67 9dd, 1H, H-1, J10.3, 5.3 Hz), 3.88

9dt, 1H, H-2, J7.6, 5.3 Hz), 4.03±3.97 9m, 1H, H-3), 4.82

9td, 1H, H-5, J9.0, 2.5 Hz), 5.33 9ddq, 1H, H-6, J10.9,

8.8, 1.7 Hz), 5.45 9dqd, 1H, H-7, J10.9, 6.9, 0.9 Hz),

7.28±7.44 9m, 12H, ArH), 7.52±7.65 9m, 8H, ArH); d_C

9CDCl₃, 62.5 MHz) 13.2 9C-8), 19.3, 19.1, 26.8, 27.0,

40.3, 62.9, 65.1, 71.8, 74.4, 125.5, 127.6, 127.7, 129.8,

133.3, 133.5, 135.5, 135.9; MS 9ES¹) m/z: 675.3345

[9M1H)¹. C₄₀H₅₂O₄Si₂requires 675.3302].

25

Data for 95S)-9a: R_F0.27 9hexane/ether, 2:1); [a]_D17.5

9c 0.65 in CHCl₃); d_H9CDCl₃, 250 MHz) 0.97 [s, 9H,

C9CH₃)₃], 1.03 [s, 9H, C9CH₃)₃], 1.58±1.70 9m, 1H, H-4),

1.78 9ddd, 1H, H-4, J15, 5.9, 2.4 Hz), 2.52 9br d, 1H, OH),

2.69 9br s, 1H, OH), 3.43 9dd, 1H, H-1, J10, 8 Hz), 3.75

9dd, 1H, H-1, J10, 4 Hz), 3.82±3.91 9br m, 1H), 3.95 9q,

1H, J4.5 Hz), 4.03±4.14 9br m, 1H, H-5), 4.96 9dt, 1H, H-

7_cis, J10, 1.5 Hz), 5.07 9dt, 1H, H-7_trans, J17, 1.5 Hz),

5.66 9ddd, 1H, H-6, J17, 10, 5.5 Hz), 7.28±7.48 9m,

12H, ArH); MS 9CI, NH₃) m/z: 639.334 [9M1H)¹.

C₃₉H₅₁O₄Si₂requires 639.3326], 639 91%), 274 9100).

Found: C, 73.5; H, 7.9; C₃₉H₅₀O₄Si₂requires C, 73.3, H,

7.9%.

9.1.3. .Z)-.R,S)-1-Phenyl-2-trimethylsilylbut-2-en-1-ol 13.

To a stirred solution of titanocene dichloride 975 mg,

0.3 mmol) in ether 93 mL) at re¯ux was added a solution

of isobutylmagnesium bromide 91.5 mL of a 2.0 M solution

in ether, 3 mmol). The solution was heated at re¯ux for

30 min, then 1-9trimethylsilyl)-1-propyne 9443 mL, 336

mg, 3 mmol) was added. The mixture was stirred at 408C

for 6 h, and then cooled to 08C. Benzaldehyde 9203 mL,

211 mg, 2 mmol) was added and the reaction was stirred

for 30 min. The reaction was quenched at 08Cby the

addition of a saturated aqueous solution of ammonium

chloride 910 mL). The layers were separated, and the

aqueous phase was extracted with ether 93£15 mL). The

combined organic extracts were washed with brine

915 mL), dried 9MgSO₄) and concentrated. Puri®cation by

¯ash chromatography 9hexane/EtOAc, 9:1) provided the

alcohol 13 9320 mg, 1.45 mmol, 73%) as a colourless oil;

R_F0.4 9hexane/EtOAc, 9:1); n_max9CDCl₃) 3604 cm²¹; d_H

9CDCl₃, 250 MHz) 0.05 [s, 9H, 9CH₃)₃Si], 1.85 9m, 1H,

OH), 1.91 9dd, 3H, CH₃, J0.7, 7.0 Hz), 5.29 9m, 1H,

9.1.2.

.Z)-.2R,3S,5S)-1,3-Bis-.tert-butyldiphenylsilyl-

oxy)-oct-6-ene-2,5-diol .5S)-9b and .Z)-.2R,3S,5R)-1,3-

bis-.tert-butyldiphenylsilyloxy)-oct-6-ene-2,5-diol .5R)-

9b. cis-Propenylmagnesium bromide¹⁷94.4 mL of

a

0.75 M solution in THF, 3.25 mmol) was added over

5 min to a stirred solution of the lactols 8 in THF 910 mL)

at 08C. After 2 h 10 min, the reaction mixture was allowed

to warm to ambient temperature over 20 min. The reaction

was quenched by careful addition of a saturated aqueous

solution of ammonium chloride 91 mL) followed by water

95 mL), and the layers were then separated. The aqueous

phase was extracted with ether 92£15 mL), the organic

extracts were combined, washed with brine 915 mL) and

dried 9MgSO₄). Puri®cation by ¯ash chromatography

9hexane/ether, 2:1) provided the diol 95S)-9b 9127 mg,

0.194 mmol, 14%, containing a trace amount of the lactols

8) as a clear and colourless oil. Further elution of the column

1958

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

H-1), 6.40 9qd, 1H, H-3, J1.2, 7.0 Hz), 7.23±7.34 9m, 5H,

ArH); d_C9CDCl₃, 62.5 MHz) 0.3, 17.5, 78.8, 126.9, 127.2,

128.1, 138.2, 142.4, 143.3.

resulting solution was stirred for 0.5 h whereupon pyridine

957 mL) was added. The solvent was removed in vacuo

9high vacuum rotary evaporator) and the residue was co-

evaporated with pyridine 950 mL). The residue was dried

under high vacuum for 0.5 h and then pyridine 923 mL)

and tert-butylchlorodiphenylsilane 95.86 mL, 6.19 g,

22.5 mmol) were added. The resulting solution was stirred

for 18 h and then the solvent was removed in vacuo. To the

residue was added water 9100 mL) and ethyl acetate

9100 mL). The organic layer was separated and the aqueous

layer was extracted with ethyl acetate 92£100 mL). The

organic extracts were washed with saturated aqueous

copper9II) sulfate 92£50 mL) and dried 9MgSO₄). Puri®-

cation by ¯ash chromatography 9hexane/ether, 7:3) pro-

vided the title compounds as clear and colourless oils.

9.1.4. .Z)-.2R,3S,5S)-1,3-Bis-.tert-butyldiphenylsilyloxy)-

6-trimethylsilyl-oct-6-ene-2,5-diol .5S)-9c and .Z)-.2R,

3S,5R)-1,3-bis-.tert-butyldiphenylsilyloxy)-6-trimethyl-

silyl-oct-6-ene-2,5-diol .5R)-9c. To a stirred solution of

titanocene dichloride 975 mg, 0.3 mmol) in ether 93 mL) at

re¯ux was added a solution of isobutylmagnesium bromide

91.5 mL of a 2.0 M solution in ether, 3.0 mmol). The solu-

tion was heated at re¯ux for 30 min then 1-9trimethylsilyl)-

1-propyne 9443 mL, 336 mg, 3 mmol) was added. The

mixture was stirred at 408Cfor 6 h, and then cooled to

08C. A solution of the lactols 8 9650 mg, 1.07 mmol) in

ether 92 mL) was added. The reaction was stirred for 16 h

at 08C, then quenched by the addition of a saturated aqueous

solution of ammonium chloride 910 mL). The layers were

separated, and the aqueous phase was extracted with ether

92£15 mL). The combined organic extracts were washed

with brine 915 mL) and dried 9MgSO₄), and then they

15a-less polar anomer 93.65 g, 9.46 mmol, 42%); R_F0.2

19

9hexane/ether, 1:1);[a]_D167.3 9c 1.48 in methanol);

d_H9CDCl₃, 250 MHz) 1.05 [s, 9H, 9CH₃)₃CSi], 2.01 9bd,

H-4, 1H, J13.5 Hz), 2.26±2.31 9m, 1H, H-4), 2.81 9bd, 1H,

OH, J10.7 Hz), 3.38 9s, 3H, CH₃O), 3.61 9dd, 1H,

CHHOSi, J10.9, 4.9 Hz), 3.76 9dd, 1H, CHHOSi, J

10.9, 3.6 Hz), 4.16 9m, 1H, H-3), 4.30 9bdd, 1H, H-3,

J10.1, 5.6 Hz), 5.11 9bd, 1H, H-5, J4.5 Hz), 7.34±7.47

9m, 6H, ArH), 7.62±7.71 9m, 4H, ArH); d_C9CDCl₃,

100 MHz) 19.2, 26.8, 41.1, 54.8, 64.4, 73.3, 87.7, 105.6,

127.7, 127.7, 129.7, 129.8, 133.1, 133.2, 135.6, 135.6;

MS 9CI, NH₃) m/z: 404.2249 [9M1NH₄)¹. C₂₂H₃₄NO₄Si

requires 404.2257], 404 915%), 98 9100). Found: C, 68.4;

H, 7.9; C₂₂H₃₀O₄Si; requires C, 68.36; H, 7.82%

1

were concentrated. H NMR analysis of the crude product

showed a 13:5 mixture of isomers 95S)-9c and 95R)-9c.

Puri®cation by ¯ash chromatography 9hexane/ether, 9:1)

yielded the diastereomer 95S)-9c 9237 mg, 33%) as a colour-

28

less oil; R_F0.25 9hexane/ether, 9:1); [a]_D21.2 9c 2.34 in

CHCl₃); n_max9CDCl₃) 3584 cm²¹; d_H9CDCl₃, 400 MHz)

0.09 [s, 9H, 9CH₃)₃Si], 0.99 [s, 9H, 9CH₃)₃C], 1.01 [s, 9H,

9CH₃)₃C], 1.57±1.65 9m, 1H, H-4), 1.73 9d, 3H, H-8, J

7.0 Hz), 1.76±1.81 9m, 1H, H-4), 2.37 9br s, 1H, OH), 2.68

9br s, 1H, OH), 3.37 9dd, 1H, H-1, J10.1, 8.1 Hz), 3.70 9dd,

1H, H-1, J10.1, 4.5 Hz), 3.85±3.98 9m, 2H, H-2, H-3),

4.24 9br d, 1H, H-5, J10.0 Hz), 6.18 9qd, 1H, H-7, J

7.0, 0.8 Hz), 7.26±7.44 9m, 8H, ArH), 7.54±7.63 9m, 8H,

ArH); d_C9CDCl₃, 100 MHz) 0.6, 17.4, 19.1, 19.4, 26.8,

27.0, 41.2, 65.4, 72.9, 73.0, 74.6, 127.6, 127.7, 127.7,

129.7, 129.8, 133.1, 133.1, 133.3, 133.4, 134.8, 135.5,

135.8, 135.9, 136.0, 143.5; MS 9CI, NH₃) m/z: 725.410

[9M2OH1NH₄)¹. C₄₃H₆₃NO₃Si₃requires 725.4116], 725

95%), 373 9100).

15b-less polar anomer 93.07 g, 7.94 mmol, 36%); R_F0.1

19

9hexane/ether, 1:1); [a]_D229.3 9c 1.88 in methanol);

d_H9CDCl₃, 250 MHz) 1.08 [s, 9H, 9CH₃)₃CSi], 1.80 9bd,

1H, OH, J4.1 Hz), 2.00±2.12 9m, 1H, H-4), 2.21 9ddd, 1H,

H-4, J13.3, 6.9, 1.9 Hz), 3.27 9s, 3H, CH₃O), 3.66 9dd, 1H,

CHHOSi, J10.1, 7.5 Hz), 3.82 9dd, 1H, CHHOSi, J10.1,

4.8 Hz), 3.94 9dt, 1H, H-3, J7.5, 4.8 Hz), 4.57±4.47 9m,

1H, H-2), 5.05 9dd, 1H, H-5, J5.1, 1.9 Hz), 7.34±7.46 9m,

6H, ArH), 7.65±7.72 9m, 4H, ArH); d_C9CDCl₃, 100 MHz)

19.2, 26.8, 41.0, 55.0, 65.4, 73.3, 85.7, 105.0, 127.8, 129.8,

133.2, 135.5; MS 9CI, NH₃) m/z: 404.2264 [9M1NH₄)¹.

C₂₂H₃₄NO₄Si requires 404.2257], 404 925%), 372 9100).

Found: C, 68.4; H, 7.9; C₂₂H₃₀O₄Si; requires C, 68.36; H,

7.82%.

Further elution of the column provided the diastereomer

95R)-9c 9142 mg, 20%) as a colourless oil; R_F0.15

9hexane/ether, 9:1); n_max9CDCl₃) 3550 cm²¹; d_H9CDCl₃,

400 MHz) 0.13 [s, 9H, 9CH₃)₃Si], 0.98 [s, 9H, 9CH₃)₃C],

1.02 [s, 9H, 9CH₃)₃C], 1.60±1.66 9m, 1H, H-4), 1.72 9d,

3H, H-8, J7.0 Hz), 1.80±1.87 9m, 1H, H-4), 2.82 9br s,

1H, OH), 2.95 9br s, 1H, OH), 3.44±3.49 9m, 1H, H-1), 3.64

9dd, 1H, H-1, J10.3, 5.4 Hz), 3.82±4.06 9m, 2H, H-2,

H-3), 4.46 9br d, 1H, H-5, J8.3 Hz), 6.11 9q, 1H, H-7,

J7.0 Hz), 7.26±7.43 9m, 8H, ArH), 7.53±7.66 9m, 8H,

ArH); d_C9CDCl₃, 100 MHz) 0.9, 17.4, 19.1, 19.4, 26.8,

27.1, 39.9, 65.1, 72.5, 74.2, 74.3, 127.6, 127.7, 127.7,

129.7, 129.7, 129.7, 129.8, 133.1, 133.2, 133.6, 135.5,

135.9, 136.0, 137.0, 143.5.

9.1.6. 2.R),3.R),5.S)-2-tert-Butyldiphenylsilyloxymethyl-

3-chloro-5-methoxy-tetrahydofuran 16a and 2.R),5.S)-

2-tert-butyldimethylsilyloxymethyl-5-methoxy-2,5-di-

hydro-furan 17a. A Schlenk tube was charged with

9dichloromethylene)dimethyl-ammonium chloride 91.22 g,

7.5 mmol) and was vacuum purged with argon 93 times).

Dichloromethane 940 mL) and pyridine 90.9 mL, 880 mg,

11.1 mmol) were added. The reaction mixture was cooled

to 08Cand the furanoside 15a 9861 mg, 2.23 mmol) was

added via cannula as a solution in dichloromethane 96 mL,

2£2 mL rinse). The reaction mixture was allowed to come

to ambient temperature, stirred for 1 h and then quenched by

the addition of saturated aqueous NaHCO₃950 mL). The

organic layer was separated and the aqueous layer was

extracted with dichloromethane 93£30 mL). The organic

layers were washed with saturated aqueous copper9II)

sulfate 950 mL) and dried 9MgSO₄). Puri®cation by ¯ash

9.1.5. 2.R),3.R),5.S)-2-tert-Butyldiphenylsilyloxymethyl-

3-hydroxy-5-methoxy-tetrahydrofuran 15a and 2.R),3.R),

5.R)-2-tert-butyldiphenylsilyloxymethyl-3-hydroxy-5-

methoxy-tetrahydrofuran 15b. To a stirring solution of

2-deoxy-d-ribose 14 93.0 g, 22.4 mmol) in methanol

9115 mL) was added a solution of hydrogen chloride

98.08 mL of a 1 M solution in ether, 8.08 mmol) and the

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1959

chromatography 9hexane/ether/triethylamine, 200:10:1)

provided the chlorofuranoside 16a as a clear and colourless

oil 9555 mg, 1.37 mmol, 62%); R_F0.4 9hexane/ether, 3:1);

16b as a clear and colourless oil 9275 mg, 0.68 mmol,

18

48%); R_F0.3 9hexane/ether, 3:1); [a]_D258.3 9c 0.695

in CHCl₃); d_H9CDCl₃, 250 MHz) 1.08 [s, 9H, 9CH₃)₃CSi],

2.36 9dt, 1H, H-4, J14.7, 1.8 Hz), 2.59 9dt, 1H, H-4, J

14.7, 6.3 Hz), 3.40 9s, 3H, CH₃O), 3.95 9dd, 1H, CHHOSi,

J10.4, 6.1 Hz), 4.03 9dd, 1H, CHHOSi, J10.4, 6.2 Hz),

4.24 9dt, 1H, H-2, J6.1, 4.6 Hz), 4.51 9ddd, 1H, H-2, J

6.6, 4.6, 2.0 Hz), 5.08 9dd, 1H, H-3, J6.0, 2.6 Hz), 7.33±

7.46 94H, m, ArH), 7.74±7.69 96H, m, ArH); d_C9CDCl₃,

62.5 MHz) 19.3, 26.8, 42.8, 55.7, 57.2, 64.2, 82.6, 104.8,

127.7, 129.7, 129.7, 133.4, 133.6, 135.6, 135.6; MS 9CI,

NH₃) m/z: 422.1919 [9M1NH₄)¹. C₂₂H₃₃ClNO₃Si requires

422.1918], 422 9100%), 405 [9M1H)¹, 1].

18

[a]_D240.5 9c 0.385 in CHCl₃); d_H9CDCl₃, 250 MHz)

1.08 [s, 9H, 9CH₃)₃CSi], 2.38 9ddd, 1H, H-4, J14.7, 6.0,

4.2 Hz), 2.57 9ddd, 1H, H-4, J14.7, 5.3, 2.0 Hz), 3.40 9s,

3H, CH₃O), 3.93 9dd, 1H, CHHOSi, J13.2, 10.3 Hz), 3.98

9dd, 1H, CHHOSi, J13.2, 8.3 Hz), 4.23±4.24 9m, 1H, H-

3), 4.54±4.62 9m, 1H, H-2), 5.23 9dd, 1H, H-5, J5.3,

4.2 Hz), 7.35±7.50 94H, m, ArH), 7.65±7.77 96H, m,

ArH); d_C9CDCl₃, 62.5 MHz) 19.3, 26.8, 27.0, 44.2, 55.6,

59.7, 63.2, 80.4, 104.3, 127.7, 129.7, 133.4, 133.5, 135.6,

135.6, 135.9, 136.0; MS 9CI, NH₃) m/z: 422.1919 [9M1

NH₄)¹. C₂₂H₃₃ClNO₃Si requires 422.1918], 422 [9M1

NH₄)¹, 100%], 405 [9M1H)¹, 1]. Found: C, 65.41; H,

7.27; C₂₂H₂₉ClO₃Si requires C, 65.24; H, 7.22%.

If puri®cation of the dihydrofurans 17 was carried out by

silica gel chromatography in the absence of triethylamine

then the furan 18 was isolated instead of the respective

dihydrofurans.

Further elution of the column provided dihydrofuran 17a as

a clear and colourless oil 9300 mg, 0.81 mmol, 36%); R_F0.3

9hexane/ether, 3:1); [a]_D270.9 9c 1.075 in CHCl₃); d_H

9.1.8. tert-Butyl-.furan-2-ylmethoxy)-diphenyl-silane 18.²⁶

d_H9CDCl₃, 250 MHz) 1.07 [s, 9H, 9CH₃)₃Si], 4.66 9s, 2H,

CH₂O), 6.15 91H, d, J3.2 Hz), 6.30±6.32 9m, 1H), 7.35±

7.50 9m, 7H, ArH, furan), 7.67±7.75 9m, 4H, ArH); d_C

9CDCl₃, 62.5 MHz) 19.3, 26.8, 58.9, 107.3, 110.1, 127.7,

129.7, 133.4, 135.6, 142.0, 154.1.

14

9CDCl₃, 250 MHz) 1.06 [s, 9H, 9CH₃)₃CSi], 3.39 9s, 3H,

CH₃O) 3.68 9dd, 1H, CHHOSi, J10.3, 5.6 Hz), 3.81 9dd,

1H, CHHOSi, J10.3, 4.5 Hz), 5.00±4.99 9m, 1H), 5.80 9d,

1H, J4.3 Hz), 5.85 9bd, 1H, J6 Hz), 6.25 9d, 1H, J

6 Hz), 7.35±7.47 9m, 6H, ArH), 7.66±7.69 9m, 4H, ArH),

d_C9CDCl₃, 62.5 MHz) 19.3, 26.8, 53.8, 66.1, 86.0, 109.4,

127.1, 127.7, 129.7, 133.9, 135.6; MS 9CI, NH₃) m/z: 386

[9M1NH₄)¹, 100%], 369 [9M1H)¹, 20]. Found: C, 71.73;

H, 7.64; C₂₂H₂₈O₃Si requires C, 71.70; H, 7.66%.

9.1.9. 5.R,S),3.R),2.R)-2-tert-Butyldiphenylsilyloxymethyl-

4-chloro-2-hydroxy-tetrahydrofuran 19. The furanosides

were isolated as a mixture of diastereomers 19 in equi-

librium with the open-chain form 19a.

9.1.7. 2.R),3.R),5.R)-2-tert-Butyldiphenylsilyloxymethyl-

3-chloro-2-methoxy-tetrahydofuran 16b and 2.R),5.R)-

2-tert-butyldimethylsilyloxymethyl-5-methoxy-2,5-di-

hydro-furan 17b. A Schlenk tube was charged with

9dichloroemethylene)dimethyl-ammonium chloride 9784 g,

4.8 mmol) and was vacuum purged with argon 93 times).

Dichloromethane 925 mL) and pyridine 90.57 mL, 562 mg,

11.1 mmol) were added. The reaction mixture was cooled to

08Cand the furanoside 15b 9548 mg, 1.42 mmol) was added

via cannula as a solution in dichloromethane 94 mL,

2£1 mL rinse). The reaction mixture was allowed to come

to ambient temperature, stirred for 1 h and then quenched by

the addition of saturated aqueous NaHCO₃920 mL). The

organic layer was separated and the aqueous layer was

extracted with dichloromethane 93£30 mL). The organic

layers were washed with saturated aqueous copper9II)

sulfate 950 mL) and dried 9MgSO₄). Puri®cation by ¯ash

chromatography 9hexane/ether/triethylamine, 200:10:1)

provided the dihydrofuran 17b as a clear and colourless

oil 993 mg, 0.25 mmol, 18%); R_F0.4 9hexane/ether, 3:1);

To a stirring solution of the chlorofuranoside 16a 9555 mg,

1.37 mmol) in ether 920 mL) was added boron trichloride±

methyl sul®de complex 91.37 mL of a 2.0 M solution in

dichloromethane, 2.74 mmol). The resulting solution was

stirred for 10 min and then quenched by the addition of

saturated aqueous sodium carbonate solution 920 mL)

followed rapidly by the addition of THF 910 mL). The

resulting biphasic mixture was stirred vigorously for 1 h.

The phases were separated and the aqueous phase was

extracted with ether 92£30 mL). The organic phases were

washed with brine 950 mL) and dried 9MgSO₄). Puri®cation

by ¯ash chromatography 9hexane/ether, 2:1!1:1) provided

the title compounds as a clear and colourless oil 9365 mg,

0.94 mmol, 68%); n_max9CDCl₃) 3506 cm²¹; d_H9CDCl₃,

250 MHz) 1.09 [s, 9H, 9CH₃)₃C, major furanoside], 1.11

[s, 9H, 9CH₃)₃C, minor furanoside], 2.54±2.59 9m, 1H,

major furanoside), 2.33±2.43 9m), 2.60±2.66 9m, 1H,

minor furanoside), 3.02 9dd, J6.7, 1.3 Hz), 3.47±3.56

9m), 3.90 9dd, 1H, CHHOSi, major furanoside, J10.5,

6.2 Hz), 3.96 9dd, 1H, CHHOSi, major furanoside, J

10.5, 5.5 Hz), 4.02 9d, 2H, CH₂OSi, minor furanoside,

J5.6 Hz), 4.14±4.20 9m, 1H, minor furanoside), 4.57

9ddd, 1H, minor furanoside, J6.0, 4.2, 2.3 Hz), 4.60±

4.65 9m, 1H, major furanoside), 4.69 9m, 1H, open chain),

5.49 9dd, H-2, minor furanoside, 1H, J9.6, 5.5 Hz), 5.77

9brm, 1H, H-2, major furanoside), 7.51±7.37 9m, 6H, ArH,

all compounds), 7.66±7.77 9m, 4H, ArH, all compounds), 9.79

9bs, 1H, CHO); d_C9CDCl₃, 62.5 MHz) 19.2, 26.9, 26.9, 44.0,

44.8, 58.2, 59.8, 63.8, 80.7, 82.5, 97.9, 98.8, 127.7, 127.8,

127.9, 129.8, 129.9, 133.3, 133.4, 135.6, 135.7; MS 9CI,

NH₃) m/z: 408.1761 [9M1NH₄)¹. C₂₁H₃₁ClNO₃Si requires

408.1762], 408 930%), 390 [9M1NH₄-H₂O)¹, 15], 274 9100).

15

[a]_D288.2 9c 0.27 in CHCl₃); d_H9CDCl₃, 250 MHz)

1.07 [s, 9H, 9CH₃)₃CSi], 3.36 9s, 3H, CH₃O) 3.66 9dd, 1H,

CHHOSi, J10.1, 6.2 Hz), 3.80 9dd, 1H, CHHOSi, J10.1,

5.8 Hz), 4.86±4.78 9m, 1H, H-2), 5.73 9q, 1H, H-5, J

1.2 Hz), 5.84 9ddd, 1H, J6.0, 2.1, 1.1 Hz), 6.26 9dt, 1H,

J6.0, 1.3 Hz), 7.33±7.46 9m, 6H, ArH), 7.64±7.73 9m, 4H,

ArH); d_C9CDCl₃, 62.5 MHz) 19.2, 26.8, 54.5, 67.3, 86.0,

109.4, 127.2, 127.7, 129.7, 133.6, 135.6, 135.6; MS 9CI,

NH₃) m/z: 386.2152 [9M1NH₄)¹. C₂₂H₃₃ClNO₃Si requires

386.2151], 386 9100%), 369 [9M1H)¹, 17]. Found: C,

71.76; H, 7.67; C₂₂H₂₈O₃Si requires C, 71.70; H, 7.66.

Further elution of the column provided chlorofuranoside

1960

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

The lactols 19 were prepared in a similar manner in 44%

yield starting from the b-glycoside 16b

organic phase was separated. The aqueous phase was

extracted with dichloromethane 93£5 mL), then the organic

extracts were combined. The organic extracts were washed

with 1 M hydrochloric acid 95 mL), a saturated aqueous

solution of sodium bicarbonate 910 mL), brine 910 mL),

were dried 9Na₂SO₄) and concentrated. Puri®cation by

¯ash chromatography 9hexane/ether, 3:1) provided the

carbonate 22 934.0 mg, 0.051 mmol, 65%) as a clear and

9.1.10.

3.R),5.R),6.R)-7-tert-Butyldiphenylsilyloxy-5-

chloro-3,6-dihydroxy-hept-1-ene .3R)-21 and 3.S),5.R),

6.R)-7-tert-butyldiphenylsilyloxy-5-chloro-3,6-dihydroxy-

hept-1-ene.3S)-21. To a stirring solution of the lactols 19

9365 mg, 0.94 mmol), previously dried by azeotropic distil-

lation with toluene 92£5 mL), in THF 915 mL) at 08Cwas

added vinylmagnesium bromide 92.15 mL, of a 1.0 M solu-

tion in THF, 2.15 mmol) and the resulting solution was

stirred for 1.5 h before being quenched by the addition of

saturated aqueous ammonium chloride 925 mL) and ether

925 mL). The aqueous phase was separated and extracted

with ether 92£25 mL). The organic phases were washed

with brine 925 mL) and dried 9MgSO₄). Puri®cation by

¯ash chromatography 9ether/hexane, 2:1) provided the title

compounds 21 as white crystalline solids.

21

colourless oil; R_F0.37 9hexane/ether, 2:1); [a]_D20.26

9c 1.55 in CHCl₃); n_max9CHCl₃) 1748 cm²¹; d_H9CDCl₃,

500 MHz) 0.97 [s, 9H, C9CH₃)₃], 1.05 [s, 9H, C9CH₃)₃],

1.74±1.83 9m, 1H, H-6), 1.89 9ddd, 1H, H-6, J15.5,

10.6, 3.0 Hz), 3.74 9dd, 1H, CHHOSi, J11.0, 5.5 Hz),

3.80 9dd, 1H, CHHOSi, J11.0, 5.5 Hz), 4.16±4.18 9m,

1H, H-5), 4.42 9q, 1H, H-4, J5 Hz), 5.18 9dd, 1H,

CHvCHH_cis, J10.6, 0.9 Hz,), 5.26 9dd, 1H, H-7, J

10.6, 6.0 Hz), 5.32 9d, 1H, CHvCHH_trans, J17.0 Hz),

5.73 9ddd, 1H, CHvCH₂, J17.0, 10.6, 5.9 Hz), 7.30±

7.45 9m, 12H, ArH), 7.55±7.63 9m, 8H, ArH); d_C9CDCl₃,

62.5 MHz) 19.1, 19.2, 26.7, 26.9, 37.7, 62.3, 67.2, 76.5,

83.1, 116.9, 127.8, 127.9, 127.9, 129.8, 129.8, 130.1,

132.7, 132.7, 133.0, 135.5, 135.7, 135.7, 152.1; MS 9FIB)

m/z: 9FIB) 665.31250 [9M1H)¹. C₄₀H₄₉O₅Si₂requires

665.31183].

Less polar diastereomer 21-LP: 9122 mg, 0.29 mmol, 31%);

mp 60±628C9hexane/ether); R_F0.3 9hexane/ether, 1:1);

18

[a]_D13.6 9c 1.35 in CHCl₃); n_max9CDCl₃) 3606, 3564

cm²¹; d_H9CDCl₃, 250 MHz) 1.10 [s, 9H, 9CH₃)₃CSi], 1.82±

2.00 9m, 2H), 2.09 9ddd, 1H, J14.6, 10.4, 2.8 Hz), 2.48

9bd, 1H, OH), 3.74±3.95 9m, 3H), 4.53 9bdt, 1H, J10.0,

3.0 Hz), 5.14 9d, 1H, H-1_cis, J10.4 Hz), 5.30 9d, 1H,

H-1_trans, J17.2 Hz), 5.92 9ddd, 1H, H-2, J17.2, 10.4,

5.7 Hz), 7.35±7.50 9m, 6H, ArH), 7.63±7.76 9m, 4H,

ArH); d_C9CDCl₃, 62.5 MHz) 19.2, 26.9, 42.0, 60.9,

65.0, 69.7, 74.2, 114.8, 127.8, 133.0, 133.1, 135.6, 135.6,

140.6; MS 9CI, NH₃) m/z: 436.2073 [9M1NH₄)¹.

C₂₃H₃₅ClNO₃Si requires 436.2075], 436 9100%), 420

[9M1H)¹, 3]; Found: C, 65.9; H, 7.5; C₂₃H₃₁ClO₃Si

requires C, 65.93; H, 7.46%.

Further elution of the column provided the starting diol

95R)-9a as a clear and colourless oil 97.7 mg, 0.012 mmol,

15%).

9.1.12.

.4R,5S,7S)-5-tert-Butyldiphenylsilyloxy-4-tert-

butyldiphenylsilyloxymethyl-7-vinyl[1,3]dioxepan-2-one

23 and .2R,3S,5R)-3-tert-butyldiphenylsilyl-2-tert-butyl-

diphenylsilyloxymethyl-5-vinyl-tetrahydrofuran 24. A

solution of triphosgene 930.4 mg, 0.102 mmol) in dichloro-

methane 91 mL) was added via cannula over 5 min to a

stirred solution of the diol 95S)-9a¹⁶9130.8 mg, 0.205

mmol) and anhydrous pyridine 9100 mL, 98 mg, 1.23

mmol) in dichloromethane 99 mL) at 2788C. After 15 min

at 2788Cthe reaction was quenched by addition of a satu-

rated aqueous solution of ammonium chloride 95 mL)

followed by water 92 mL). The mixture was allowed to

warm to 58Cand the organic phase was separated. The

aqueous phase was extracted with dichloromethane

93£15 mL), then the organic extracts were combined,

washed with brine 930 mL), dried 9MgSO₄) and concen-

trated. Puri®cation by ¯ash chromatography 9hexane/ether,

10:1!2:1) provided the tetrahydrofuran 24 as a clear and

More polar diastereomer 21-MP: 9183 mg, 0.44 mmol); mp

18

74±758C9hexane); R_F0.2 9hexane/ether); [a]_D22.13 9c

0.89 in CHCl₃); n_max9CDCl₃) 3603 cm²¹; d_H9CDCl₃,

250 MHz) 1.09 [s, 9H, 9CH₃)₃CSi], 2.22±2.03 9m, 2H),

2.67 9br, 1H, OH), 2.97 9d, 1H, OH, J6.4 Hz), 3.74 9dd,

1H, CHHOSi, J10.0, 7.0 Hz), 3.79 9dd, 1H, CHHOSi,

J10.0, 5.6 Hz), 3.85±3.96 9m, 1H), 4.36±4.51 9m, 2H),

5.19 9d, H-1_cis, J10.3 Hz), 5.33 9d, 1H, H-1_trans, J

17.2 Hz), 5.87 9ddd, 1H, H-2, J17.2, 10.3, 6.5 Hz),

7.37±7.50 9m, 6H, ArH), 7.64±7.78 9m, 4H, ArH); d_C

9CDCl₃, 62.5 MHz) 19.3, 26.9, 42.1, 60.7, 64.7, 70.3,

73.4, 116.1, 127.8, 127.9, 133.0, 133.1, 135.5, 135.6,

139.7; MS 9CI, NH₃) m/z: 436.2071 [9M1NH₄)¹.

C₂₃H₃₅ClNO₃Si requires 436.2075], 436 9100%), 420

[9M1H)¹, 20]; Found: C, 65.9; H, 7.5; C₂₃H₃₁ClO₃Si

requires C, 65.93; H, 7.46%.

19

colourless oil; R_F0.59 9hexane/ether, 2:1); [a]_D140.3 9c

0.30 in CHCl₃); n_max9CHCl₃) 3072, 3011, 2932, 2859,

1589 cm²¹; d_H9CDCl₃, 250 MHz) 0.93 [s, 9H, C9CH₃)₃],

1.08 [s, 9H, C9CH₃)₃], 1.64 9ddd, 1H, H-4, J12.7, 10.8 Hz,

J5.2 Hz), 1.94 9dd, 1H, H-4, J12.7, 5.5 Hz), 3.29 9dd,

1H, CHHOSi, J10.9, 3.7 Hz), 3.39 9dd, 1H, CHHOSi,

J10.9, 4.3 Hz), 3.99±4.06 9m, 1H, H-3), 4.48 9d, 1H,

H-2, J4.9 Hz), 4.62±4.75 9m, 1H, H-5), 5.10 9br d, 1H,

9.1.11.

.4R,5S,7R)-5-tert-Butyldiphenylsilyloxy-4-tert-

butyldiphenylsilyloxymethyl-7-vinyl-[1,3]-dioxepan-2-

one 22. A solution of triphosgene 911.7 mg, 0.039 mmol) in

dichloromethane 91 mL) was added via cannula over 5 min

to a stirred solution of the diol 95R)-9a¹⁶950.0 mg, 0.078

mmol) and anhydrous pyridine 938 mL, 37 mg, 0.47 mmol)

in dichloromethane 94 mL) at 2788C. After 1 h 45 min at

2788Cthe reaction was quenched by addition of a saturated

solution of aqueous ammonium chloride 95 mL) and water

92 mL), followed by the addition of further dichloromethane

92 mL). The mixture was allowed to warm to 158Cand the

CHvCHH_cis, J10.3 Hz), 5.30 9br d, 1H, CHvCHH_trans

,

J17.2 Hz), 5.82 9ddd, 1H, CHvCH₂, J17.2, 10.3,

6.8 Hz), 7.24±7.44 9m, 12H, ArH), 7.48±7.68 9m, 8H,

ArH); d_C9CDCl₃, 62.5 MHz) 19.1, 26.7, 27.0, 42.1, 64.4,

75.7, 79.9, 88.0, 116.0, 127.6, 127.7, 129.5, 129.7, 133.3,

133.3, 133.8, 134.0, 134.8, 135.6, 135.6, 135.8, 138.6; MS

9CI, NH₃) m/z 638.349 [9M1NH₄)¹. C₃₉H₅₂NO₃Si₂requires

638.3485], 638 915%), 109 9100).

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1961

25

Further elution of the column provided the carbonate 23

993.4 mg, 0.140 mmol, 69%) as a clear and colourless oil;

R_F0.39 9hexane/ether, 2:1); [a]_D14.6 9c 0.68 in CHCl₃);

n_max9CDCl₃) 1743 cm²¹; d_H9CDCl₃, 500 MHz) 0.93

[9H, s, C9CH₃)₃], 1.03 [9H, s, C9CH₃)₃], 1.70 9dd, 3H,

CHvCHCH₃, J3.6, 0.9 Hz,), 1.70±1.75 9m, 1H, H-6),

1.95 9ddd, 1H, H-6, J7.9, 5.4, 1.5 Hz), 3.68 9dd, 1H,

CHHOSi, J5.6, 2.7 Hz), 3.75 9dd, 1H, CHHOSi, J5.6,

2.7 Hz), 4.12±4.15 9m, 1H, H-5), 4.39 9q, 1H, J2.7 Hz,

H-4), 5.39±5.45 9m, 1H, H-7), 5.59±5.66 9m, 2H,

CHvCH), 7.31±7.37 9m, 8H, ArH), 7.39±7.46 9m, 4H,

ArH), 7.52±7.65 9m, 8H, ArH); d_C9CDCl₃, 62.5 MHz)

13.3, 19.1, 19.2, 26.7, 26.9, 38.3, 62.3, 67.5, 72.1, 83.2,

127.7, 127.8, 127.9, 127.9, 128.0, 128.5, 129.8, 129.8,

130.1, 132.6, 132.9, 135.5, 135.6, 135.7, 135.7, 152.6; MS

9CI, NH₃) m/z: 696.3540 [9M1NH₄)¹. C₄₁H₅₄NO₅Si₂

requires 696.3540].

18

R_F0.40 9hexane/ether, 2:1); [a]_D112.2 9c 1.88 in

CHCl₃); n_max9CHCl₃) 1762 cm²¹; d_H9CDCl₃, 500 MHz)

0.99 [9H, s, C9CH₃)₃], 1.08 [9H, s, C9CH₃)₃], 1.76±1.84

9m, 1H, H-6), 1.89 9ddd, 1H, H-6, J14.7, 4.9, 2.1 Hz),

3.85 9dd, 1H, CHHOSi, J11.3, 5.9 Hz), 4.04 9td, 1H,

H-5, J8.7, 4.9 Hz), 4.12 9dd, 1H, CHHOSi, J11.3,

2.9 Hz), 4.24 9ddd, 1H, H-4, J8.7, 5.9, 2.9 Hz), 4.51±

4.55 9m, 1H, H-7), 5.10±5.16 9m, 2H, CHvCH₂), 5.71

9ddd, 1H, CHvCH₂, J17.2, 10.6, 5.6 Hz), 7.30±7.46 9m,

12H, ArH), 7.60±7.63 9m, 4H, ArH), 7.72±7.68 9m, 4H,

ArH); d_C9CDCl₃, 62.5 MHz) 19.2, 19.3, 26.9, 40.9, 63.3,

69.0, 77.2, 85.2, 116.9, 127.7, 127.9, 129.7, 129.8, 130.0,

130.1, 132.5, 133.2, 133.4, 135.1, 135.8, 153.0; MS 9CI,

NH₃) m/z 682.338 [9M1NH₄)¹. C₄₀H₅₂NO₅Si₂requires

682.3382], 682 92%), 638 913), 467 926), 411 923), 349

978), 323 940), 316 969), 309 9100), 295 951), 289 957)

and 287 9100). Found: C, 72.3; H, 7.4; C₄₀H₄₈O₅Si₂requires:

C, 72.3; H, 7.3%.

9.2.2. .4R,5S,7S)-5-tert-Butyldiphenylsilyloxy-4-tert-butyl-

diphenylsilyloxymethyl-7-[.Z)-prop-1-enyl][1,3]dioxepan-

2-one 28 and .2R,3S,5R)-3-tert-butyldiphenylsilyl-2-tert-

butyldiphenylsilyloxymethyl-5-[.Z)-prop-1-enyl]-tetra-

hydrofuran 29. Triphosgene 97.1 mg, 24 mmol) was added

to a solution of the diol 95S)-9b 931.4 mg, 0.048 mmol),

pyridine 923 mL, 22 mg, 0.28 mmol), triethylamine

9.2. Representative procedure for the formation of the

carbonates 26, 28 and 30

Ê

940 mL, 29 mg, 0.29 mmol) and powdered 4 A molecular

sieves 9spatula tip) according to the standard procedure.

Puri®cation by ¯ash chromatography 9hexane/ether/triethyl-

amine, 80:20:5) provided the carbonate 28 933.2 mg,

0.049 mmol, 99%) containing a trace of the THF 29.

9.2.1.

.4R,5S,7R)-5-tert-Butyldiphenylsilyloxy-4-tert-

butyldiphenylsilyloxymethyl-7-[.Z)-prop-1-enyl][1,3]-

dioxepan-2-one 26and .2 R,3S,5S)-3-tert-butyldiphenyl-

silyl-2-tert-butyldiphenylsilyloxymethyl-5-[.Z)-prop-1-

enyl]-tetrahydrofuran 27. A solution of triphosgene

97.3 mg, 0.025 mmol) in dichloromethane 90.6 mL) was

added over 10 min to a stirred solution of the diol 95R)-9b

932.1 mg, 0.049 mmol), pyridine 924 mL, 0.29 mmol),

triethylamine 940 mL, 30 mg, 0.29 mmol) and powdered

The THF 28 was isolated from a number of experiments as

a clear and colourless oil; R_F0.60 9hexane/ether, 2:1);

20

[a]_D17.4 9c 0.35 in CHCl₃); n_max9CHCl₃) 2931,

2859 cm²¹; d_H9CDCl₃, 500 MHz) 0.97 [s, 9H, C9CH₃)₃],

1.12 [s, 9H, C9CH₃)₃], 1.55±1.65 9m, 1H, H-4), 1.76 9dd,

3H, CHvCHCH₃, J7.0, 1.7 Hz), 1.92 9dd, 1H, H-4,

J12.7, 4.9 Hz), 3.37 9dd, 1H, CHHOSi, J10.9, 3.7 Hz),

3.42 9dd, 1H, CHHOSi, J10.9, 4.6 Hz), 4.05±4.07 9m, 1H,

H-2), 4.54 9d, 1H, J5.0 Hz, H-3), 5.08±5.15 9m, 1H, H-5),

5.38±5.43 9m, 1H, CHvCHCH₃), 5.57±5.65 9m, 1H,

CHvCHCH₃), 7.31±7.44 9m, 12H, ArH), 7.55±7.57 9m,

2H, ArH), 7.60±7.62 9m, 2H, ArH), 7.66±7.70 9m, 4H,

ArH); d_C9CDCl₃, 62.5 MHz) 13.4, 19.2, 26.8, 27.0, 42.1,

64.5, 74.1, 76.1, 87.8, 127.1, 127.6, 127.7, 127.7, 129.5,

129.6, 129.7, 131.1, 133.4, 133.9, 134.1, 135.6, 135.6,

135.8; MS 9CI, NH₃) m/z: 652.3640 [9M1NH₄)¹.

C₄₀H₅₄NO₃Si₂requires 652.3642].

Ê

4 A molecular sieves 9spatula tip) in dichloromethane

90.6 mL) at 2788C. The reaction mixture became pink/

peach coloured, and after 5 min was allowed to warm to

ambient temperature. After 10 min of warming, the reaction

was quenched by the addition of a saturated aqueous solu-

tion of ammonium chloride 91 mL) and water 91 mL). The

layers were separated, and the aqueous phase was extracted

with dichloromethane 92£2 mL). The organic phases were

combined, washed with brine 95 mL), then they were dried

9Na₂SO₄) and concentrated. Puri®cation by ¯ash chroma-

tography 9hexane/ether/triethylamine, 80:20:5) provided

the tetrahydrofuran 27 and the carbonate 26 930.3 mg,

48 mmol, 98%) as a 1:8 mixture.

The carbonate 28 was isolated as a clear and colourless oil

which contained traces of the tetrahydrofuran 29; R_F0.41

The THF 27 was isolated from a number of experiments as a

clear and colourless oil; R_F0.61 9hexane/ether, 2:1); d_H

9CDCl₃, 500 MHz) 0.98 [9H, s, C9CH₃)₃], 1.10 [9H, s,

C9CH₃)₃], 1.64 9dd, 3H, J7.9, 1.7 Hz, CHvCHCH₃),

1.73±1.84 9m, 2H, H-4), 3.44 9dd, CHHOSi, 1H, J11.0,

3.5 Hz), 3.60 9dd, 1H, CHHOSi, J11.0, 3.5 Hz), 4.12 9q,

1H, H-2, J3.5 Hz), 4.59±4.64 9m, 1H, H-3), 4.90 9q, 1H,

H-5, J7.5 Hz), 5.56±5.64 9m, 1H, CHvCH), 5.72±5.77

9m, 1H, CHvCH), 7.30±7.45 9m, 12H, ArH), 7.56±7.58

9m, 2H, ArH), 7.63±7.70 9m, 6H, ArH); d_C9CDCl₃,

62.5 MHz) 13.1, 19.2, 26.8, 27.0, 42.1, 64.7, 74.3, 75.1,

86.5, 126.0, 127.6, 127.7, 127.7, 129.5, 129.7, 132.5,

133.4, 133.8, 133.9, 135.6, 135.8, 135.9; MS 9FIB) m/z:

633.31980 [9M2H)¹. C₄₀H₄₉O₃Si₂requires 633.32202].

20

9hexane/ether, 2:1); [a]_D17.4 9c 0.35 in CHCl₃); n_max

9CHCl₃) 1760 cm²¹; d_H9CDCl₃, 500 MHz) 0.95 [9H, s,

C9CH₃)₃], 1.06 [9 H, s, C9CH₃)₃], 1.38 9dd, 3H,

CHvCHCH₃, J7.0, 1.7 Hz), 1.72 9ddd, 1H, H-6, J

14.7, 4.7, 1.7 Hz), 1.80±1.88 9m, 1H, H-6), 3.84 9dd, 1H,

CHHOSi, J11.3, 6.0 Hz), 4.00 9td, 1H, H-5, J9.0,

4.7 Hz), 4.11 9dd, 1H, CHHOSi, J11.3, 2.9 Hz), 4.20

9ddd, 1H, H-4, J9.0, 6.0, 2.9 Hz), 4.78 9t, 1H, H-7,

J9.3 Hz), 5.36±5.40 9m, 1H, CHvCH), 5.45±5.52 9m,

1H, CHvCH), 7.28±7.44 9m, 12H, ArH), 7.58±7.60 9m,

2H, ArH), 7.66±7.70 9m, 2H, ArH); d_C9CDCl₃,

62.5 MHz) 13.1, 19.2, 19.3, 26.8, 26.8, 41.6, 63.4,

69.0, 73.5, 85.2, 127.7, 127.9, 129.6, 129.7, 130.0, 130.1,

132.3, 133.1, 133.2, 133.3, 135.6, 135.8, 153.4; MS 9ES¹)

The carbonate 26 was isolated as a clear and colourless oil;

1962

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

m/z: 701.30778 [9M1Na)¹. C₄₁H₅₀NaO₅Si₂requires

701.30944].

pyridine 961 mL, 60 mg, 0.76 mmol), triethylamine 90.175

Ê

mL, 127 mg, 126 mmol) and 4 A molecular sieves in

dichloromethane 94 mL) at 2788Cwas added triphosgene

937.6 mg, 126 mmol) as a solution in dichloromethane

92.0 mL) via cannula. The resulting orange reaction mixture

was stirred for 10 min at 2788Cand then for 0.5 h at 0 8C

before being quenched by the addition of saturated aqueous

ammonium chloride 93 mL). The aqueous phase was sepa-

rated and the organic phases was extracted with dichloro-

methane 92£5 mL). The organic phases were washed with

saturated aqueous copper9II) sulfate solution 910 mL) and

dried 9MgSO₄). Puri®cation by ¯ash chromatography

9hexane/ether, 1:1) provided the title compound 32 as a

clear and colourless oil 928 mg, 63 mmol, 50%); R_F0.2

9.2.3.

.4R,5S,7S)-5-tert-Butyldiphenylsilyloxy-4-tert-

butyldiphenylsilyloxymethyl-7-[.Z)-1-trimethylsilyl-prop-

1-enyl]-[1,3]dioxepan-2-one 30. Triphosgene 95.1 mg,

0.017 mmol) was added to a solution of the diol 95S)-9c

924.9 mg, 0.034 mmol), pyridine 918 mL, 17 mg, 0.21

mmol), triethylamine 929 mL, 21 mg, 0.21 mmol) and

Ê

powdered 4 A molecular sieves 9spatula tip) according to

the standard procedure. Puri®cation by ¯ash chroma-

tography 9hexane/ether:triethylamine, 85:15:5) yielded a

mixture of the carbonate 30 925.5 mg, 99%, containing a

small amount of the presumed THF 31, 10.8:1 ratio) as

a clear and colourless oil. Further puri®cation of the mixture

by ¯ash chromatography 9hexane/ether/triethylamine,

90:10:5) provided a pure sample of 30; R_F0.51 9hexane/

18

9ether/hexane, 1:1); [a]_D221.0 9c 1.6 in CHCl₃); n_max

9CDCl₃) 1757 cm²¹; d_H9CDCl₃, 250 MHz) 1.08 [s, 9H,

9CH₃)₃CSi], 2.45 91H, ddd, H-6, J15.5, 9.6, 8.3 Hz),

2.57 9ddd, 1H, H-6, J15.5, 6.3, 2.8 Hz), 3.97 9dd, 1H,

CHHOSi, J11.1, 6.4 Hz), 4.02 9dd, 1H, CHHOSi, J

11.1, 5.9 Hz), 4.51 9ddd, 1H, J9.2, 6.3, 3.0 Hz), 4.61

9ddd, 1H, J6.2, 3.0 Hz), 4.83±4.90 9m, 1H), 5.31 9dt, 1H,

25

ether, 2:1); [a]_D18.5 9c 0.69 in CHCl₃); n_max9CHCl₃)

1756 cm²¹; d_H9CDCl₃, 500 MHz) 20.04 [s, 9H, 9CH₃)₃Si],

0.93 [s, 9H, 9CH₃)₃C], 1.07 [s, 9H, 9CH₃)₃C], 1.70 9dd, 3H,

CHvCHCH₃, J7.1, 0.7 Hz,), 1.72±1.82 9m, 2H, H-6),

3.84±3.89 9m, 1H, CHHOSi), 3.98 9td, 1H, H-5, J9.4,

5.3 Hz), 4.11±4.17 9m, 2H, H-4, CHHOSi), 4.44 9d, 1H,

H-7, J9.5 Hz), 6.18±6.24 9m, 1H, CHvCHCH₃), 7.26±

7.45 9m, 12H, ArH), 7.57±7.61 9m, 4H, ArH), 7.68±7.72

9m, 4H, ArH); d_C9CDCl₃; 62.5 MHz) 20.1, 17.4, 19.2,

19.3, 26.8, 26.8, 43.4, 63.5, 69.0, 80.9, 85.2, 127.6, 127.7,

127.7, 127.9, 129.6, 129.7, 129.9, 130.1, 132.5, 133.3,

133.5, 135.7, 135.8, 137.8, 138.2, 153.6.

CvCHH_cis, J10.5, 1.0 Hz), 5.46 9dt, 1H, CvCHH_trans

,

J17.1, 1.0 Hz), 5.97 9ddd, 1H, CHvCH₂, J17.1, 10.5,

6.1 Hz), 7.38±7.50 9m, 6H, ArH), 7.66±7.71 9m, 4H, ArH);

d_C9CDCl₃, 62.5 MHz) 19.2, 26.8, 39.9, 54.8, 62.1, 79.4,

79.5, 118.4, 127.9, 130.0, 132.5, 132.6, 134.4, 135.6,

135.6, 150.7.

9.3. Representative procedure for tandem methylenation/

Claisen rearrangement of the carbonates 22, 23 and 26

9.2.4. 4.R),5.R)-4-tert-Butyldiphenylsilyloxymethyl-5-

chloro-7-vinyl-[1,3]-dioxepan-2-one 32. To a stirring

solution of the more polar diol 21-MP 930 mg, 70 mmol),

pyridine 933 mL, 33 mg, 0.42 mmol), triethylamine 997 mL,

9.3.1.

.Z)-.8S,9R)-8-tert-Butyldiphenylsilyloxy-9-tert-

butyldiphenylsilyloxymethyl-2,3,4,7,8,9-hexahydro-oxonin-

2-one 35. Preparation from the carbonate 22. Dimethyl-

titanocene 90.12 mL of a 0.24 M solution in toluene,

28 mmol) was added to a stirred solution of carbonate 22

914.5 mg, 22 mmol) in toluene 93 mL). The resulting solu-

tion was heated at re¯ux for 70 min in the absence of

light, after which time, starting material remained. Further

dimethyltitanocene 90.05 mL of a 0.24 M solution in tolu-

ene, 12 mmol) was added. After a further 25 min re¯ux the

reaction mixture was allowed to cool and was evaporated

onto silica. Puri®cation by ¯ash chromatography 9hexane/

ether, 4:1) provided the lactone 35 911.0 mg, 17 mmol, 76%)

as a pale yellow oil identical to previously prepared;

Ê

70 mg, 0.7 mmol) and 4 A molecular sieves in dichloro-

methane 92 mL) at 2788Cwas added triphosgene 920 mg,

70 mmol) as a solution in dichloromethane 90.5 mL, 0.5 mL

rinse) via cannula. The resulting orange reaction mixture

was stirred for 10 min at 2788Cand then for 0.5 h at

ambient temperature before being quenched by the addition

of saturated aqueous ammonium chloride 95 mL) and ether

95 mL). The aqueous phase was separated and the organic

phase was extracted with ether 92£5 mL). The organic

phases were washed with saturated aqueous copper9II)

sulfate solution 910 mL) and dried 9MgSO₄). Puri®cation

by ¯ash chromatography 9hexane/ether, 3:1) provided the

title compound 32 as a clear and colourless oil 924 mg,

25

18

[a]_D28.8 9c 1.77 in CHCl₃); {lit.¹⁶[a]_D210.8 9c

0.87 in MeOH)}; d_H9CDCl₃, 500 MHz) 1.00 [s, 9H, or

9H⁰, C9CH₃)₃], 1.03 [s, 9H, or 9H⁰, C9CH₃)₃], 2.11±2.33

9m, 5H, H-3, H-4, H-7), 2.39±2.45 9m, 1H), 3.74±3.81

9m, 2H, CH₂OSi), 4.13±4.17 9m, 1H, H-8), 4.98±5.01 9m,

1H, H-9), 5.31±5.37 9m, 1H, H-6), 5.46±5.52 9m, 1H, H-5),

7.30±7.43 9m, 12H, ArH), 7.56±7.60 9m, 4H, ArH), 7.63±

7.66 9m, 4H, ArH); m/z: 9CI; NH₃) 663.333 [9M1H)¹.

C₄₁H₅₁O₄Si₂requires 663.3326].

24

54 mmol, 77%); R_F0.8 9ether/hexane, 1:1); [a]_D218.8

9c 0.33 in CHCl₃); n_max9CDCl₃) 1763 cm²¹; d_H9CDCl₃,

400 MHz), 1.06 [s, 9H, 9CH₃)₃CSi], 2.29 91H, ddd, J16,

3.6, 1.0 Hz), 2.36 9ddd, 1H, J16, 3.2, 1.8 Hz), 3.83 9dd,

1H, CHHOSi, J10, 9 Hz), 3.86 9dd, 1H, CHHOSi, J10.0,

6.0 Hz), 4.41 9dd, 1H, J8.0, 6.0 Hz), 4.72 9t, 1H, J

3.5 Hz), 5.10±5.16 9m, 1H), 5.29 9d, 1H, CvCHH_trans

,

J10.2 Hz), 5.44 9d, 1H, CvCHH_transJ16.0 Hz), 5.88

91H, ddd, CHvCH₂, J16.0, 10.2, 5.6 Hz), 7.36±7.50 9m,

6H, ArH), 7.60±7.70 9m, 4H, ArH); d_C9CDCl₃, 62.5 MHz)

19.2, 26.8, 41.8, 55.3, 62.2, 76.3, 79.9, 227.8, 127.9, 127.9,

130.1, 130.1, 132.5, 132.6, 134.5, 135.5, 135.5, 152.3;

Preparation from the carbonate 23. Dimethyltitanocene

90.28 mL of a 0.24 M solution in toluene, 67 mmol) and

the carbonate 23 934.9 mg, 52 mmol) were used according

to the standard procedure; reaction time 2 h at re¯ux.

Puri®cation by PLC9hexane/ether, 2:1) provided the lactone

35 917.0 mg, 26 mmol, 49%) as a clear and colourless oil;

data identical to previous values.

9.2.5. 4.R),5.R)-4-tert-Butyldiphenylsilyloxymethyl-5-

chloro-7-vinyl-[1,3]-dioxepan-2-one 32. To a stirring

solution of the less polar diol 21-LP 953 mg, 0.126 mmol),

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1963

9.3.2. .E)-.4S,8S,9R)-8-tert-Butyldiphenylsilyloxy-9-tert-

butyldiphenylsilyloxymethyl-4-methyl-2,3,4,7,8,9-hexa-

hydro-oxonin-2-one 36b/c. Dimethyltitanocene 90.46 mL

of a 0.24 M solution in toluene, 0.110 mmol) and the car-

bonate 26 960.4 mg, 89 mmol) in toluene 95.5 mL) were

used according to the standard procedure; reaction time

0.5 h at re¯ux. Puri®cation by ¯ash chromatography

9hexane/ether, 20:1) afforded the lactone 36b/c 939.4 mg,

58 mmol, 65%) as a clear and colourless oil 91:1 mixture

of atropisomers); R_F0.58 9hexane/ether, 2:1); n_max9CHCl₃)

1730 cm²¹; d_H9CDCl₃, 500 MHz) 0.95 [s, 9H or 9H⁰,

C9CH₃)₃], 0.97 [s, 9H, or 9H⁰, C 9CH₃)₃], 1.02 [s, 9H, or

9H⁰, C 9CH₃)₃], 1.06 [s, 9H, or 9H⁰, C 9CH₃)₃], 1.13 9d, 3H,

CH₃CH, J6.8 Hz,), 1.18 9d, 3H, CH₃CH, J7.0 Hz), 1.92

9dd, 1H, H-3, J11.0, 2.3 Hz), 1.99±2.20 9m, 3H, H-7,

H-3⁰, H-7⁰), 2.29±2.45 9m, 4H, H-3, H-7, H-7⁰), 2.49±

2.75 9m, 2H, H-4, H-4⁰), 3.56 9dd, 1H, CH⁰H⁰OSi, J

11.1, 7.1 Hz), 3.87 9dd, 1H, CH⁰H⁰OSi, J11.1, 3.4 Hz),

3.94±4.06 9m, 4H, H-8, CHHOSi, CHHOSi, H-8⁰), 4.70±

4.75 9m, 1H, H-9), 4.97±5.07 9m, 3H, H-5, H-6, H-9⁰),

5.53±5.57 9m, 2H, H-5⁰, H-6⁰), 7.27±7.45 9m, 24H, ArH,

ArH⁰), 7.50±7.68 9m, 16H, ArH, ArH⁰); d_C9CDCl₃,

62.5 MHz) 15.1, 19.3, 21.4, 26.8, 26.9, 32.2, 37.4, 42.2,

43.2, 44.2, 64.0, 64.5, 71.3, 73.6, 79.5, 121.5, 127.5,

127.7, 127.8, 129.5, 129.6, 129.6, 129.8, 133.5, 133.7,

133.8, 134.1, 135.7, 135.8, 135.8, 135.9, 136.0, 138.4,

171.8, 172.7; MS 9CI, NH₃) m/z: 677.3480 [9M1H)¹.

C₄₂H₅₃O₄Si₂requires 677.3482].

50 ms 9power56 dB) and had a typical excitation band-

width of 100 Hz. Signals were assigned on the basis of a

COSY experiment run on the mixture. The signals for the

protecting group protons were not seen in the 1-D TOCSY

experiment as they were not part of the spin system which

was irradiated.

Data for 36a: d_H9CDCl₃, 500 MHz; pulsed at d_H4.86) 1.07

9d, 3H, CH₃CH, J7.0 Hz), 1.88 9t, 1H, J11.0 Hz, H-3),

1.89±1.95 9m, 1H, H-7), 2.18±2.28 9m, 2H, H-3, H-7),

2.58±2.66 9m, 1H, H-4), 3.87±3.90 9m, 2H, CH₂OSi),

3.93 9t, 1H, H-8, J9.0 Hz), 4.79±4.89 9m, 1H, H-9), 5.01

9apparent ddm, 1H, J11.0, 7.5 Hz), 5.18±5.24 9m, 1H,

H-6).

Data for 36d: d_H9CDCl₃, 500 MHz; pulsed at d_H5.73) 1.03

9d, 3H, CH₃CH, J7.0 Hz), 1.93 9dd, 1H, H-3, J13.9,

11.2 Hz), 1.96±2.02 9m, 1H, H-7), 2.47±2.54 9m, 1H,

H-7), 2.57 9dd, 1H, H-3, J13.9, 6.5 Hz), 2.98±3.06 9m,

1H, H-4), 3.60 9dd, 1H, CHHOSi, J11.5, 4.3 Hz), 3.64

9dd, 1H, CHHOSi, J11.5, 2.5 Hz), 4.36±4.40 9m, 1H,

H-8), 4.69±4.74 9m, 1H, H-9), 5.35 9t, 1H, H-5 J

10.5 Hz), 5.71 9td, 1H, H-6, J10.5, 5.5 Hz).

Data for 36e: d_H9CDCl₃, 500 MHz; pulsed at d_H4.69) 1.08

9d, 3H, CH₃CH, J7.0 Hz), 1.80 9dd, 1H, H-3, J10.5,

8.5 Hz), 2.04 9q, 1H, H-7, J11.0 Hz), 2.39±2.48 9m, 2H,

H-3, H-7), 2.53±2.60 9m, 1H, H-4), 4.00±4.07 9m, 3H, H-8,

CH₂OSi), 4.67 9dt, 1H, H-9, J9.3, 4.0 Hz), 5.26 9ddd, 1H,

H-6, J16.5, 11.7, 3.2 Hz), 5.48 9ddd, 1H, H-5, J16.5, 7.0,

1.0 Hz).

9.3.3. .Z)-.4R,8S,9R)-8-tert-Butyldiphenylsilyloxy-9-tert-

butyldiphenylsilyloxymethyl-4-methyl-2,3,4,7,8,9-hexa-

hydro-oxonin-2-one 36a, .Z)-.4S,8S,9R)-8-tert-butyldi-

phenylsilyloxy-9-tert-butyldiphenylsilyloxymethyl-4-

methyl-2,3,4,7,8,9-hexahydro-oxonin-2-one 36d and

.E)-.4R,8S,9R)-8-tert-butyldiphenylsilyloxy-9-tert-butyl-

diphenylsilyloxymethyl-4-methyl-2,3,4,7,8,9-hexahydro-

oxonin-2-one 36e/f. Dimethyltitanocene 950 mL of a

0.24 M solution in toluene, 12 mmol) was added to a stirred

solution of the carbonate 28 925.5 mg, 38 mmol) in dry

toluene 95 mL). The solution was heated to re¯ux for

35 min in the absence of light, then it was allowed to cool

to room temperature and diluted with light petroleum

98 mL). After 5 min the solution was ®ltered and concen-

trated. Puri®cation by ¯ash chromatography 9hexane/ether,

15:1) afforded an inseparable 1:2.5:1.2 mixture 9as judged

by ¹H NMR) of the lactones 36d/36e/36f 913.1 mg,

0.019 mmol, 52%) 9containing a small amount of the

lactone 36a, due to small amounts of the corresponding

trans-propenyl substituted carbonate, and the tetrahydro-

furan 29, due to degradation of the remaining carbonate

during puri®cation) as a clear and colourless oi1; d_C

9CDCl₃, 62.5 MHz) 18.3, 19.1, 19.2, 19.3, 19.7, 20.2,

22.5, 26.8, 26.8, 26.9, 27.0, 29.4, 29.7, 31.0, 31.8,

32.0, 35.5, 37.2, 38.3, 42.0, 42.4, 42.6, 45.1, 45.8, 63.5,

63.9, 64.0, 64.5, 71.5, 72.4, 73.8, 76.0, 77.2, 78.3, 79.3,

79.5, 79.8, 80.0, 124.2, 127.5, 127.5, 127.5, 127.7, 127.8,

129.5, 129.5, 129.7, 129.8, 133.2, 133.5, 133.7, 133.7,

134.0, 135.6, 135.7, 135.8, 135.9, 135.9, 139.2, 172.7,

173.2, 173.6, 174.0; m/z: 9FIB) 677.34170 [9M1H)¹.

Data for 36f: d_H9CDCl₃, 500 MHz; pulsed at d_H3.97) 1.06

9d, 3H, CH₃CH, J7.0 Hz), 1.85 9t, 1H, H-3, J11.0 Hz),

2.02±2.08 9m, 1H, H-7), 2.25±2.32 9m, 1H, H-7), 2.36 9dd,

1H, H-3, J11.0, 5.0 Hz), 2.48±2.56 9m, 1H, H-4), 3.62

9dd, 1H, CHHOSi, J11.0, 7.0 Hz), 3.89±3.98 9m, 2H,

H-8, CHHOSi), 4.98 9td, 1H, H-9, J7.0, 3.0 Hz), 5.05

9dd, 1H, H-5, J16.5, 9.5 Hz), 5.43 9ddd, 1H, H-6, J

16.5, 8.8, 6.5 Hz).

9.3.4. .E)-.4R,8S,9R)-8-tert-Butyldiphenylsilyloxy-9-tert-

butyldiphenylsilyloxymethyl-4-methyl-5-trimethylsilyl-

2,3,4,7,8,9-hexahydro-oxonin-2-one 40. To the carbonate

30 920.6 mg, 27 mmol, 10.8:1 mixture with the tetrahydro-

furan 31) in toluene 95 mL) was added a solution of

dimethyltitanocene 9130 mL of a 50 mg/mL solution in

toluene, 0.031 mmol). The resultant solution was heated at

re¯ux, in the dark, for 30 min. The reaction mixture was

allowed to cool to ambient temperature, and was then

diluted with light petroleum 97 mL). After 5 min, the

resultant suspension was ®ltered through a small plug of

silica and the mixture was concentrated. Puri®cation by

¯ash chromatography 9hexane/ether, 30:1) provided the

lactone 40 910.5 mg, 14 mmol, 51%) as a clear and colour-

25

less oil; R_F0.38 9hexane/ether, 30:1); [a]_D25.7 9c 0.39

in CHCl₃); n_max9CHCl₃) 1721 cm²¹; d_H9CDCl₃, 500 MHz)

20.01 [s, 9H, 9CH₃)₃Si], 0.99 [s, 9H, 9CH₃)₃C], 1.02 [s, 9H,

9CH₃)₃C], 1.23 9d, 3H, CH₃CH, J7.3 Hz), 1.87±1.98 9m,

1H, H-7), 2.02 9t, 1H, H-3, J11.0 Hz), 2.14 9d, 1H, H-3,

J11.0 Hz), 2.33±2.42 9m, 1H, H-7), 2.87±2.95 9m, 1H,

H-4), 3.84 9dd, 1H, CHHOSi, J11.5, 1.9 Hz), 4.00±4.08

9m, 2H, H-8, CHHOSi), 5.10±5.16 9m, 2H, H-6, H-9), 7.28±

1

C₄₂H₅₃O₄Si₂requires 677.34827]. H NMR spectra of the

individual lactones were obtained from standard Bruker 1-D

selective TOCSY experiments,^34±36with a Gaussian selec-

tive pulse 91% truncation). The pulse was for a duration of

1964

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

7.45 9m, 12H, ArH), 7.58±7.62 9m, 4H, ArH), 7.64±7.70

9m, 4H, ArH); d_C9CDCl₃, 62.5 MHz) 1.0, 19.2, 19.3, 22.5,

26.8, 26.8, 35.2, 36.2, 42.6, 62.9, 71.2, 79.7, 127.5, 127.8,

129.5, 129.6, 129.9, 133.0, 133.1, 133.8, 134.0, 135.5,

135.8, 135.9, 138.9, 142.3, 174.5; MS 9CI, NH₃) m/z:

749.388 [9M1H)¹. C₄₅H₆₁O₄Si₃requires 749.3877], 766

[9M1NH₄)¹, 5%], 749 [9M1H)¹, 5], 691 92), 671 92),

274 913), 196 910), 98 955), 90 9100), 78 950). Found: C,

71.2; H, 8.2; C₄₅H₆₀O₄Si₃requires C, 71.22; H, 8.34%.

92£250 mL). The organic extracts were washed with water

950 mL), brine 950 mL), were dried 9MgSO₄) and concen-

trated. Puri®cation by ¯ash chromatography 9hexane/

EtOAc, 17:3!4:1) yielded a mixture of the product 52a

and IpcOH. Further puri®cation by ¯ash chromatography

9hexane/EtOAc, 9:1!17:3) yielded the pure hydroxyketone

52a 91.045 g, 4.21 mmol, 81%) as a colourless oil; R_F0.16

28

9light petroleum/EtOAc, 4:1); [a]_D233.8 9c 2.36 in

CHCl₃); n_max9CDCl₃) 3543, 1707, 1658 cm²¹

; d_H

9CDCl₃, 200 MHz) 1.08 9d, 3H, CH₃, J7.0 Hz), 2.78 9m,

1H, H-4), 2.83 9m, 1H, H-4), 2.91±3.01 9m, 1H, H-2), 3.20

9br s, 1H, OH), 3.52 9dd, 1H, J8.9, 5.1 Hz, H-1), 3.60 9dd,

1H, J8.9, 8.2 Hz, H-1), 4.49 9s, 2H, CH₂Ph), 4.55±4.64

9m, 1H, H-5), 5.12 9dt, 1H, H-7, J10.5, 1.0 Hz), 5.27 9dt,

1H, H-7, J17.0, 1.0 Hz), 5.85 9ddd, 1H, H-6, J17.0, 10.5,

5.0 Hz), 7.25±7.37 9m, 5H, ArH); d_C9CDCl₃, 62.5 MHz)

13.1, 46.9, 48.5, 68.4, 72.1, 73.3, 114.8, 127.7, 127.8, 128.4,

137.8, 139.1, 213.5; MS 9ES¹) m/z 271 [9M1Na)¹, 82%],

249 [9M1H)¹, 40], 231 [9M2H₂O1H)¹, 100]. Found: C,

72.4; H, 8.0; C₁₅H₂₀O₃requires C, 72.6; H, 8.1%.

The reaction mixture also contained what is believed to be

tetrahydrofuran by-products 9¹H NMR analysis).

9.3.5. 8.R),9.R)-tert-Butyldiphenylsilyloxymethyl-8-chloro-

4,7,8,9-tetrahydro-.3H)-oxonin-2-one 41. To a stirred

solution of the carbonate 32 9prepared from 21-MP)

924 mg, 54 mmol) in toluene 94 mL) was added dimethyl-

titanocene 90.17 mL, of a 87 mg/mL solution in toluene,

70 mmol) and the resulting solution was heated under re¯ux

for 2 h. The solvent was removed in vacuo and puri®cation

by ¯ash chromatography 9hexane/dichloromethane, 3:2)

provided the lactone 41 as a clear and colourless oil

9.4.2. .E)-.2R,5S)-1-Benzyloxy-5-hydroxy-2-methyl-oct-

6-en-3-one 52b. 91)-Ipc₂BCl 911.34 g, 35.4 mmol), triethyl-

amine 94.34 mL, 3.15 g, 31.2 mmol), the ketone 42 94.0 g,

20.8 mmol), ether 9240 mL) and crotonaldehyde 47 93.45

mL, 2.92 g, 41.6 mmol) were used according to the standard

procedure. Puri®cation by ¯ash chromatography 9EtOAc/

hexane, 4:1) afforded the hydroxyketone 52b 95.20 g,

19.8 mmol, 95%) as a pale yellow oil; R_F0.24 9hexane/

17

913.5 mg, 29 mmol, 55%); [a]_D261.2 9c 0.94 in

CHCl₃); n_max9CHCl₃) 1742 cm²¹; d_H9CDCl₃, 250 MHz)

1.07 [s, 9H, 9CH₃)₃C)Si], 2.08±2.20 9m, 1H) 2.32 9ddd,

1H, J13.3, 10.9, 4.9 Hz), 2.46±2.61 9m, 2H), 2.72±2.88

9m, 1H), 2.94±3.07 9m, 1H), 3.89±4.01 9m, 2H, CH₂OSi),

4.52 9dd, 1H, H-8, J9.9, 4.3 Hz), 4.90±4.97 9m, 1H, H-9),

5.67 9m, 2H, H-5, H-6), 7.35±7.47 9m, 6H, ArH), 7.66±7.74

9m, 4H, ArH); d_C9CDCl₃, 62.5 MHz) 19.2, 23.7, 26.7, 33.2,

34.1, 60.2, 62.8, 76.1, 127.7, 128.3, 129.7, 129.8, 130.5,

133.1, 135.5, 135.7, 174.3; MS 9CI, NH₃) m/z: 460.2084

[9M1NH₄)¹. C₂₅H₃₅ClO₃NSi requires 460.2084], 460

9100%), 443 [9M1H)¹, 970). Found: C, 67.76; H, 7.06;

C₂₅H₃₁ClO₃Si requires C, 67.77; H, 7.05%.

22

EtOAc, 4:1); [a]_D235.1 9c 1.03 in CHCl₃); n_max

9CHCl₃) 3603, 1705, 1602 cm²¹; d_H9CDCl₃, 250 MHz)

1.07 9d, 3H, CH₃CHCO, J7.0 Hz), 1.68 9ddd, 3H, H-8,

J6.5, 1.5, 1.5 Hz), 2.67±2.71 9m, 2H, H-4), 2.82±2.96

9m, 1H, H-2), 3.03 9d, 1H, J3.5 Hz, OH), 3.49 9dd, 1H,

H-1, J9.0, 5.0 Hz), 3.62 9dd, 1H, H-1, J9.0, 8.0 Hz), 4.48

9s, 2H, CH₂Ph), 4.48±4.59 9m, 1H, H-5), 5.47 9ddq, 1H,

H-6, J15.5, 6.5, 1.5 Hz), 5.68 9dqd, 1H, H-7, J15.5,

6.5, 1.0 Hz), 7.26±7.35 9m, 5H, ArH); d_C9CDCl₃, 62.5

MHz) 13.1, 17.6, 46.9, 48.9, 68.4, 72.1, 73.3, 126.9,

127.6, 127.7, 128.4, 132.0, 137.9, 213.8; MS 9FAB) m/z:

261.1491 [9M2H)¹. C₁₆H₂₁O₃requires 261.1491]. Found:

C, 72.6; H, 8.5; C₁₆H₂₂O₃requires C, 73.3; H 8.5%.

The lactone 41 could be prepared from the carbonate 32,

derived from the diol 21-LP, in 63% yield.

9.4. Representative procedure for the preparation of the

3-hydroxyketones 52a±d

9.4.1. .2R,5S)-1-Benzyloxy-5-hydroxy-2-methyl-hept-6-

en-3-one 52a. To a cooled 908C) solution of 91)-Ipc₂BCl

92.6 g, 8.1 mmol) in dry ether 960 mL) was added Et₃N

91.2 mL, 871 mg, 8.6 mmol) via syringe followed by a solu-

tion of the ketone 42 91.00 g, 5.2 mmol) in ether 910 mL) via

cannula. The white suspension was stirred for 2 h and then

cooled to 2788C. A solution of acrolein 46 90.7 mL,

587 mg, 10.5 mmol) in ether 910 mL) was added dropwise

via syringe. The reaction mixture was stirred at 2788Cuntil

TLCanalysis 9hexane/EtOAc, 4:1) of an aliquot 9quenched

with water, methanol and a 30% aqueous solution of hydro-

gen peroxide, followed by extraction with EtOAc) showed

consumption of the ketone 46. After 2.5 h, the reaction was

quenched with a mixture of methanol 9130 mL), pH 7 buffer

945 mL) and an aqueous solution of hydrogen peroxide

930%, 15 mL). The biphasic system was stirred vigorously

at ambient temperature for at least 1 h. The mixture was

poured into water 9100 mL) and was extracted with

EtOAc/hexane 91:1, 400 mL; emulsions tended to form

if EtOAc was used). The aqueous layer was saturated

with sodium chloride and was extracted with EtOAc

9.4.3. .E)-.2R,5S)-1-Benzyloxy-5-hydroxy-2,6-dimethyl-

oct-6-en-3-one 52c. 91)-Ipc₂BCl 94.0 g, 12.2 mmol), tri-

ethylamine 91.7 mL, 1.23 g, 12.2 mmol), the ketone 42

91.5 g, 7.8 mmol), ether 990 mL) and trans-2-methylbut-2-

enal 48 9tiglic aldehyde; 1.5 mL, 1.31 g, 15 mmol) were

used according to the standard procedure. Puri®cation by

¯ash chromatography 9hexane/EtOAc, 41:9) yielded the

hydroxyketone 52c as a mixture with IpcOH, the bulk of

which was used without further puri®cation. A small portion

was rechromatographed to provide material for characteri-

sation; R_F0.13 9light petroleum/EtOAc, 4:1); [a]_D

18

223.6 9c 2.28 in CHCl₃); n_max9CHCl₃) 3602, 1706,

1652 cm²¹; d_H9CDCl₃, 250 MHz) 1.08 9d, 3H, CH₃CHCO,

J7.5 Hz), 1.59 9d, 3H, H-8, J0.5 Hz,), 1.61 9s, 3H,

CH₃CvCH), 2.77 9s, 1H, H-4), 2.71 9d, 1H, H-4, J

2.5 Hz), 2.93±3.00 9m, 1H, H-2), 3.01 9d, 1H, OH, J

2.0 Hz), 3.50 9dd, 1H, H-1, J9.0, 5.0 Hz), 3.62 9t, 1H,

H-1, J9.0 Hz), 4.48±4.54 9m, 1H, H-5), 4.54 9s, 2H,

CH₂Ph), 5.53 9m, 1H, H-7), 7.25±7.37 9m, 5H, ArH); d_C

9CDCl₃, 62.5 MHz) 11.8, 13.0, 13.1, 46.9, 47.6, 72.2, 72.7,

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1965

73.2, 120.6, 127.6, 127.7, 128.4, 136.2, 137.9, 214.1; MS

9ES¹) m/z: 276.1724 9M¹. C₁₇H₂₄O₃requires 276.1725).

J17 Hz), 5.85 9m, 1H, CH₂vCH), 5.99 9m, 1H,

CHOCO), 7.26±7.49 9m, 10H, ArH).

9.4.7. .2R,4S,5S)-1-Benzyloxy-5-hydroxy-2,4,6-trimethyl-

hept-6-en-3-one 52e.⁴⁰To a stirred solution of 92)-

9Ipc)₂BOTf 9prepared according to the literature pro-

cedure,⁴⁵6.2 mL, 8.1 mmol, ca. 1.3 M in hexane) in

dichloromethane 920 mL) at room temperature was added

dropwise N,N-diisopropylethylamine 93.5 mL, 2.6 g, 20

mmol) and the solution decolourised. This was followed

by the addition of a solution of the ketone 43 91.03 g,

5.01 mmol) in dichloromethane 910 mL, 10 mL rinse) via

cannula. The pale yellow solution was stirred at ambient

temperature for 3 h and then cooled to 08C. A solution of

methacrolein 50 91.3 mL, 1.10 g, 16 mmol) in dichloro-

methane 98 mL) was added dropwise via cannula and the

reaction stirred at 258Cfor 16 h. The reaction mixture was

then partitioned between ether 93£250 mL) and pH 7 buffer

9250 mL) and the combined organic extracts were concen-

trated. The residue was resuspended in methanol 950 mL)

and pH 7 buffer 912 mL) and cooled to 08C. An aqueous

solution of hydrogen peroxide 930%, 25 mL) was added

dropwise and stirring continued at ambient temperature

for 1 h. The mixture was poured into water 9100 mL) and

extracted with dichloromethane 93£100 mL). The combined

organic extracts were washed with a saturated aqueous solu-

tion of sodium bicarbonate 975 mL) and brine 950 mL), then

they were dried 9MgSO₄) and concentrated. Flash chroma-

tography 9dichloromethane/ether, 9:1!light petroleum/

EtOAc, 25:4) gave the product 52e 91.24 g, 4.5 mmol,

90%) as a colourless oil; R_F0.49 9dichloromethane/ether,

9.4.4. .2R,5S)-1-Benzyloxy-5-hydroxy-5-[.4S)-4-isopro-

penyl-cyclohex-1-enyl]-2-methyl-pentan-3-one 52d. 91)-

Ipc₂BCl 92.5 g, 7.8 mmol), triethylamine 91.2 mL, 871 mg,

8.6 mmol), the ketone 42 91.01 g, 5.3 mmol, 60 mL) and

92)-perillaldehyde 49 91.7 mL, 1.64 g, 11 mmol) were

used according to the standard procedure. Puri®cation by

¯ash 15% 9hexane/EtOAc, 17:3) yielded some of the pure

product 52d as a colourless oil and predominantly the

hydroxyketone 52d mixed with IpcOH. This was used

without further puri®cation; R_F0.19 9light petroleum/

21

EtOAc, 4:1); [a]_D251.5 9c 2.33 in CHCl₃); n_max

9CHCl₃) 1716, 1602 cm²¹; d_H9CDCl₃, 250 MHz) 1.08 9d,

3H, CH₃CHCO, J7.0 Hz), 1.41±1.51 9m, 2H, H-5⁰), 1.73

9s, 3H, CH₃CHvCH), 1.79±2.26 95 H, m, H-3⁰, H-4⁰, H-6⁰),

2.78±2.83 9m, 2H, H-4), 2.87±2.11 9m, 1H, H-2), 3.09 9br s,

1H, OH), 3.49 9dd, 1H, H-1, J9.0, 5.0 Hz), 3.62 9dd, 1H,

H-1, J9.0, 8.0 Hz), 4.44±4.49 9m, 1H, H-5), 4.49 9s, 2H,

CH₂Ph), 4.70 9m, 2H, CvCH₂), 5.73 9m, 1H, H-2⁰), 7.17±

7.41 9m, 5H, ArH); d_C9CDCl₃, 100 MHz) 13.0, 20.7, 24.9,

27.3, 30.2, 41.0, 46.8, 47.7, 70.9, 72.0, 73.2, 108.5, 109.2,

121.6, 127.6, 127.7, 128.3, 137.7, 149.6, 214; MS 9CI) m/z:

360.2539 [9M1NH₄)¹. C₂₂H₃₄NO₃requires 360.2539].

9.4.5. .R)-[Methoxy.tri¯uoromethyl)phenyl]-acetic acid,

2.R),5.S)-1-.4-benzyloxy-3-methyl-2-oxobutyl)-allyl ester

.R)-54. A solution of the alcohol 52a 94.0 mg, 16 mmol),

9R)-91)-MTPA 98 mg, 0.03 mmol), DCC 979 mg, 0.4

mmol) and a catalytic quantity of DMAP in dichloro-

methane 91.1 mL) was stirred overnight under nitrogen.

The resultant suspension was ®ltered through a small pad

of Celitee, washed with 2 M hydrochloric acid, saturated

aqueous sodium bicarbonate, dried 9MgSO₄) and concen-

trated. The ester 9R)-54 was puri®ed by passage through a

plug of silica; R_F0.42 9light petroleum/EtOAc, 4:1); n_max

9CDCl₃) 1750, 1719 cm²¹; d_H9CDCl₃, 500 MHz) 1.01 9d,

3H, CH₃CH, J7 Hz), 2.85 9dd, 1H, CHHCHO, J18,

4 Hz), 2.82 9m, 1H, CHCH₃), 3.00 9dd, 1H, CHHCHO,

J18, 9 Hz), 3.45±3.60 9m, 5H, CH₂OBn, CH₃O), 4.44

9d, 1H, CHHPh, J12 Hz), 4.48 9d, 1H, CHHPh, J

12 Hz), 5.24 9d, 1H, CHvCHH_cis, J10.5 Hz), 5.29 9d,

1H, CHvCHH_trans, J17 Hz), 5.75 9m, 1H, CH₂vCH),

5.94 9m, 1H, CHOCO), 7.10±7.72 9m, 10H, ArH).

9:1); [a]_D238.4 9c 2.5 in CHCl₃) {lit.⁴⁰ent-52e

27

20

[a]_D143.6 9c 2.1 in CHCl₃)};n_max9CHCl₃) 3495

9br), 1698 cm²¹; d_H9CDCl₃, 250 MHz) 1.02 9d, 3H,

CH₃CHCH₂O, J7.0 Hz), 1.07 9d, 3H, CH₃CHCOH,

J7.0 Hz), 1.63 9s, 3H, CH₃CHvCH), 2.87 9dq, H-4, 1H,

J7.0, 2.0 Hz), 3.13±3.21 9m, 2H, H-2, OH), 3.48 9dd, 1H,

H-1, J9.0, 5.0 Hz), 3.62 9t, 1H, H-1, J9.0 Hz), 4.42±4.50

9m, 3H, H-5, CH₂Ph), 4.93 9d, 1H, H-7, J1.5 Hz), 5.09

9apparent br s, 1H, H-7), 7.23±7.33 9m, 5H, ArH); d_C

9CDCl₃, 62.5 Hz) 8.3, 13.6, 19.6, 44.7, 48.4, 72.7, 73.2,

73.5, 111.4, 127.7, 127.8, 128.4, 137.5, 143.4, 218.0; MS

9CI, NH₃) m/z: 294.2069 [9M1NH₄)¹. C₁₇H₂₈NO₃requires

294.2069], 294 [9M1NH₄)¹, 15%], 224 9100). Found: C,

74.3; H, 8.8; C₁₇H₂₄O₃requires C, 73.9; H 8.8%.

9.4.6. .S)-[Methoxy.tri¯uoromethyl)phenyl]-acetic acid,

2.R),5.S)-1-.4-benzyloxy-3-methyl-2-oxobutyl)-allyl ester

.S)-54. A solution of the alcohol 52a 94.0 mg, 16 mmol),

9S)-92)-MTPA 941 mg, 0.18 mmol), DCC 98 mg, 40

mmol) and a catalytic quantity of DMAP in dichloro-

methane 91.1 mL) was stirred overnight under nitrogen.

The resultant suspension was ®ltered through a small pad

of Celitee, washed with 2 M hydrochloric acid, saturated

aqueous sodium bicarbonate, dried 9MgSO₄) and concen-

trated. The ester 9S)-54 was puri®ed by passage through a

plug of silica; R_F0.40 9light petroleum/EtOAc, 4:1); n_max

9CDCl₃) 1750, 1720 cm²¹; d_H9CDCl₃, 500 MHz) 0.81 9d,

3H, CH₃CH, J7 Hz), 2.84 9m, 1H, CHHCHO), 2.91 9m,

1H, CHCH₃), 2.110 9dd, 1H, CHHCHO, J18, 9 Hz), 3.40±

3.55 9m, 5H, CH₂OBn, CH₃O), 4.42 9d, 1H, CHHPh, J

12 Hz), 4.46 9d, 1H, CHHPh, J12 Hz), 5.27 9d, 1H,

9.5. Procedure for the preparation of the hydroxy-

ketones 52f and 52g

9.5.1. .2R,4R,5S)-1-Benzyloxy-5-hydroxy-2,4,6-trimethyl-

hept-6-en-3-one 52f.⁴⁰To a stirred solution of Cy₂BCl

9prepared according to the literature procedure,⁴⁵1.4 mL,

1.36 g, 6.5 mmol) in ether 910 mL) at 2788Cwas added

dropwise triethylamine 91.2 mL, 871 mg, 8.6 mmol). This

was followed by addition of the ketone 43 91.10 g,

5.36 mmol) in ether 93 mL, 3 mL rinse) via cannula. A

white precipitate formed, and after 3 h at 2788Cmethacro-

lein 50 90.89 mL, 754 mg, 10.8 mmol) was added dropwise.

The reaction mixture was stirred for 3 h at 2788Cand then

allowed to warm to 2208Cfor 18 h. The solution was par-

titioned between ether 970 mL) and pH 7 buffer solution

970 mL), then extracted with ether 93£70 mL). The com-

bined organic extracts were concentrated. The residue was

CHvCHH_cis, J10.5 Hz), 5.41 9d, 1H, CHvCHH_trans

,

1966

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

resuspended in methanol 925 mL) and pH 7 buffer 95 mL) at

08C. An aqueous solution of hydrogen peroxide 930%,

10 mL) was added dropwise and the mixture was stirred at

room temperature for 2 h. The mixture was then poured into

water 970 mL) and extracted with dichloromethane 94£

70 mL). The combined organic extracts were washed with

a saturated aqueous solution of sodium bicarbonate 950 mL)

and brine 950 mL), then they were dried 9MgSO₄) and

concentrated. Puri®cation by ¯ash chromatography

9dichloromethane/ether, 9:1) provided the hydroxyketone

52f 91.06 g, 3.84 mmol, 72%) as a colourless oil; R_F0.53

was poured over ice, was neutralised with a saturated

aqueous solution of sodium bicarbonate 9100 mL) followed

by portionwise additions of solid sodium bicarbonate, and

was extracted with EtOAc 9350 mL). The aqueous layer was

saturated with solid sodium chloride and was extracted

again with EtOAc 92£350 mL). The combined organic

layers were washed with a saturated aqueous solution of

sodium bicarbonate 9200 mL), brine 9150 mL), were dried

9MgSO₄) and concentrated. Puri®cation by ¯ash chroma-

tography 9ether/hexane, 1:1!1:0) afforded the diol 55a

90.450 g, 1.8 mmol, 91%) as a colourless oil; R_F0.25

21

28

9dichloromethane/ether, 9:1); [a]_D220.9 9c 4.67 in

9hexane/EtOAc); [a]_D213.4 9c 1.55 in CHCl₃); n_max

CHCl₃); n_max9CHCl₃) 3456 9br), 1707, 1649 cm²¹; d_H

9CDCl₃, 250 MHz) 0.98 9d, 3H, CH₃CHCH₂, J7.0 Hz),

1.06 9d, 3H, CH₃CHOH, J7.0 Hz), 1.73 9br s, 3H,

CH₃CHvCH), 2.10 9dq, 1H, H-4, J16.0, 7.0 Hz), 3.05±

3.11 9m, 1H, H-2), 3.45 9dd, 1H, 1-H, J9.0, 5.0 Hz), 3.67

9t, 1H, H-1, J9.0 Hz), 4.20 9dd, 1H, H-5, J9.0, 4.0 Hz),

4.43 9d, 1H, CH₂Ph, J12.0 Hz), 4.54 9d, 1H, CH₂Ph, J

12.0 Hz), 4.91 9q, 1H, CHvCH, J1.5 Hz), 4.94 9br d, 1H,

CHvCH, J1.0 Hz), 7.26±7.34 9m, 5H, ArH); d_C9CDCl₃,

62.5 MHz) 13.4, 13.7, 16.9, 46.2, 49.1, 73.2, 73.4, 78.3,

113.9, 127.6, 127.6, 128.3, 137.8, 144.6, 217.2; MS 9CI)

m/z: 277.1804 [9M1H)¹. C₁₇H₂₅O₃requires 277.1804],

294 [9M1NH₄)¹, 95%], 277 [9M1H)¹, 30], 224 9100).

9CHCl₃) 3608, 3450 cm²¹; d_H9CDCl₃, 250 MHz) 0.86 9d,

3H, CH₃, J7.0 Hz), 1.69±1.75 9m, 2H, H-4), 1.88±2.04

9m, 1H, H-6), 3.48 9dd, 1H, H-7, J9.0, 8.0 Hz), 3.64 9dd,

1H, H-7, J9.0, 4.0 Hz), 3.00±3.70 9br s, 2H, 2£OH), 3.87

9dt, 1H, H-5, J7.5, 4.0 Hz), 4.44±4.53 9m, 1H, H-3), 4.53

9s, 2H, CH₂Ph), 5.12 9dt, 1H, H-1_cis, J10.5, 2.0 Hz), 5.30

9dt, 1H, H-1_trans, J17.0, 2.0 Hz), 5.93 9ddd, 1H, H-2, J

17.0, 10.5, 5.0 Hz), 7.25±7.40 9m, 5H, ArH); d_C9CDCl₃,

100 MHz) 13.6, 36.2, 39.9, 70.1, 73.4, 74.0, 75.3, 113.9,

127.6, 127.8, 128.4, 137.5, 140.9; MS 9CI) m/z: 251.1647

[9M1H)¹. C₁₅H₂₃O₃requires 251.1647].

9.6.2. .E)-.4S,6S,7R)-8-Benzyloxy-7-methyl-oct-2-ene-

4,6-diol 55b. Me₄NBH9OAc)₃93.5 g, 13 mmol), acetic

acid 97 mL), acetonitrile 920 mL) and the hydroxyketone

52b 90.874 g, 3.34 mmol) were used according to the

standard procedure at 2358Cfor 18 h. Puri®cation by

¯ash chromatography 9hexane/EtOAc, 4:1) afforded the

diol 55b 90.798 g, 3.02 mmol, 91%) as a colourless oil; R_F

9.5.2. .2R,4R,5S)-1-tert-Butyldimethylsilyloxy-5-hydroxy-

2,4,6-trimethyl-hept-6-en-3-one 52g.⁴⁰Cy₂BCl 95.9 mL,

5.72 g, 27.1 mmol), triethylamine 94.9 mL, 3.56 g, 35.2

mmol), the ketone 43 95.0 g, 21.7 mmol) ether 945 mL)

and methacrolein 50 95.0 g, 21.7 mmol) were used accord-

ing to the standard procedure. Puri®cation by ¯ash chroma-

tography 9hexane/ether, 17:3) provided the hydroxyketone

52g 94.84 g, 15.9 mmol, 73%) as a colourless oil; R_F0.17

18

0.32 9light petroleum/EtOAc, 1:1); [a]_D212.4 9c 2.7 in

CHCl₃); n_max9CHCl₃) 3606, 3456 cm²¹; d_H9CDCl₃,

250 MHz) 0.86 9d, 3H, CH₃CHOH, J7.0 Hz), 1.69 9d,

3H, H-1, J6.0 Hz), 1.87±2.04 9m, 1H, H-7), 3.20 9br s,

1H, OH), 3.48 9dd, 1H, H-8, J9.0, 8.0 Hz), 3.61 9dd, 1H,

H-8, J9.0, 4.5 Hz), 3.85 9dd, 1H, H-6, J13.0, 6.0 Hz),

3.97 9br s, 1H, OH), 4.40 9dd, 1H, H-4, J11.5, 6.0 Hz),

4.52 9s, 2H, CH₂Ph), 5.55 9ddq, 1H, H-3, J15.0, 7.0,

1.5 Hz), 5.69 9dqd, 1H, H-4, J15.0, 6.0, 1.0 Hz), 7.22±

7.39 9m, 5H, ArH); d_C9CDCl₃, 62.5 MHz) 13.6, 17.7,

38.2, 40.2, 70.0, 73.5, 74.1, 75.5, 125.8, 127.7, 127.8,

128.5, 134.0, 137.6; MS 9CI) m/z: 265.1804 [9M1H)¹.

C₁₆H₂₅O₃requires 265.1804].

21

9hexane/ether, 17:3); [a]_D225.5 9c 4.6 in CHCl₃); n_max

9CHCl₃) 3606, 3435 9br), 1706, 1649 cm²¹; d_H9CDCl₃,

400 MHz) 0.03 [2£s, 6H, 9CH₃)₂Si], 0.86 [d, 9H, 9CH₃)₃C,

J0.9 Hz], 0.97±1.01 9m, 6H, CH₃CH₂, CH₃CHOH), 1.73

9s, 3H, CH₃CHvCH), 2.61 9d, 1H, J3.5 Hz, OH), 2.86±

2.95 9m, 2H, H-2, H-4), 3.58 9dd, 1H, H-1, J9.1, 4.4 Hz),

3.80 9t, 1H, H-1, J9.1 Hz), 4.18 9dd, 1H, H-5, J8.3,

3.5 Hz), 4.90 9d, 1H, CHvCH, J1.2 Hz), 4.94 9br s, 1H,

CHvCH, J1.0 Hz); d_C9CDCl₃, 100 MHz) 25.6, 12.9,

13.6, 18.3, 25.8, 48.8, 48.8, 65.4, 78.3, 113.8, 144.7,

217.6; MS 9EI) m/z: 301.2193 [9M1H)¹. C₁₆H₃₃O₃Si

requires 301.2199].

9.6.3.

.E)-.4S,6S,7R)-8-Benzyloxy-2,7-dimethyl-oct-2-

ene-4,6-diol 55c. Me₄NBH9OAc)₃95.8 g, 22 mmol), acetic

acid 915 mL), acetonitrile 980 mL) and the crude hydroxy-

ketone 52c 97.1 mmol) were used according to the standard

procedure at 2358Cfor 18 h. Puri®cation by ¯ash chroma-

tography 9hexane/EtOAc, 4:1) afforded the diol55c 91.30 g,

4.65 mmol, 66% over two steps) as a colourless oil; R_F0.1

9.6. Representative procedure for the preparation of the

diols 55a±g

9.6.1. .3S,5S,6R)-7-Benzyloxy-6-methyl-hept-1-ene-3,5-

diol 55a. To a stirred suspension of Me₄NBH9OAc)₃

91.8 g, 6.8 mmol) in acetonitrile 925 mL) at ambient

temperature was added acetic acid 96.5 mL). The colourless

solution was cooled to 2408Cand a solution of the hydroxy-

ketone 52a 90.488 g, 1.17 mmol) in acetonitrile 95 mL,

5 mL rinse) was added via cannula. The mixture was stirred

at 2408Cfor 18 h and then allowed to warm to 2208Cfor

2 h after which time consumption of the starting material

was complete. The reaction was quenched with a saturated

aqueous solution of potassium sodium tartrate 928 mL), then

was allowed to warm to ambient temperature and was

stirred for 30 min. A white precipitate formed. The mixture

18

9hexane/EtOAc, 10:3); [a]_D215.7 9c 2.52 in CHCl₃);

n_max9CHCl₃) 3608, 3450 cm²¹; d_H9CDCl₃, 250 MHz)

0.86 9d, 3H, CH₃CHCH₂, J7.0 Hz), 1.58±1.68 9m, 7H,

CH₃CvCH, H-1, H-5), 1.80 9ddd, 1H, H-5, J14.0, 18.5,

3.0 Hz), 1.94±2.03 9m, 1H, H-7), 3.49 9dd, 1H, H-8, J9.0,

8.0 Hz), 3.63 9dd, 1H, H-8, J9.0, 4.0 Hz), 3.80 9dt, 1H,

H-6, J8.0, 3.0 Hz), 4.32 9dd, 1H, H-4, J8.5, 3.0 Hz), 4.53

9s, 2H, CH₂Ph), 5.57 9m, 1H, H-2), 7.29±7.39 9m, 5H, ArH);

d_C9CDCl₃, 62.5 MHz) 13.0, 13.8, 21.1, 38.1, 38.6, 73.5,

74.0, 74.0, 75.2, 119.0, 127.7, 127.8, 128.5, 137.7, 138.0;

MS 9FAB) m/z: 279.1941 [9M1H)¹. C₁₇H₂₇O₃requires

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1967

279.1960), 279 [9M1H)¹, 15%], 261 [9M2H₂O1H)¹, 20],

243 9100).

9CDCl₃, 62.5 MHz) 10.1, 13.0, 18.8, 35.5, 35.8, 73.5, 76.1,

76.6, 79.3, 111.5, 127.6, 127.8, 128.4, 137.5, 146.0; MS 9CI)

m/z: 279.1960 [9M1H)¹. C₁₇H₂₇O₃requires 279.1960], 279

9100%). Found: C, 73.6; H, 9.3; C₁₇H₂₆O₃requires: C, 73.4;

H, 9.4%.

9.6.4. .1S,3S,4R)-5-Benzyloxy-1-[.4S)-4-isopropenylcyclo-

hex-1-enyl]-4-methyl-pentane-1,3-diol 55d. Me₄NBH

9OAc)₃95.6 g, 21 mmol), acetic acid 911 mL), acetonitrile

960 mL) and the crude ketone 52d 94.6 mmol) were used

according to the standard procedure at 2358Cfor 18 h.

Puri®cation by ¯ash chromatography 9hexane/EtOAc, 4:1)

afforded the diol 55d 90.810 g, 2.35 mmol, 51% over two

steps) as a colourless oil; R_F0.18 9light petroleum/EtOAc,

9.6.7. .3S,4S,5R,6R)-7-tert-Butyldimethylsilyloxy-2,4,6-

trimethyl-hept-1-ene-3,5-diol

55g.

Me₄NBH9OAc)₃

96.92 g, 26.3 mmol), acetic acid 920 mL), acetonitrile

9100 mL) and the ketone 52g 91.94 g, 6.37 mmol) were

used according to the standard procedure at 2508Cfor

30 min then at 2308Cfor 48 h. Additional Me ₄NBH9OAc)₃

93.25 g, 12.4 mmol) was added and the mixture stirred for a

further 24 h. Following the usual work-up, puri®cation by

¯ash chromatography 9hexane/ether, 7:3!3:2) afforded the

diol 55g 91.51 g, 4.92 mmol, 77%) as a colourless oil; R_F

18

10:3); [a]_D268.8 9c 1.96 in CHCl₃); n_max9CHCl₃) 3606,

3462, 1643 cm²¹; d_H9CDCl₃, 250 MHz) 0.87 9d, 3H,

CH₃CH, J7.0 Hz), 1.74 9s, 3H, CH₃CvCH₂), 1.40±2.20

9m, 10 H, H-2, H-4, H-3⁰, H-4⁰, H-5⁰, H-6⁰), 3.48 9dd, 1H,

H-5, J9.0, 8.0 Hz), 3.63 9dd, 1H, H-5, J9.0, 4.0 Hz), 3.82

9dt, 1H, H-3, J8.0, 3.5 Hz), 3.98 9br s, 1H, OH), 4.3 9m,

1H, H-1), 4.53 9s, 2H, CH₂Ph), 4.72 9br s, 2H, CvCH₂),

5.80 9m, 1H, H-2⁰), 7.22±7.39 9m, 5H, ArH); d_C9CDCl₃,

100 MHz) 13.7, 20.7, 25.6, 27.5, 30.4, 38.0, 38.1, 41.4, 72.8,

73.5, 74.4, 75.5, 108.5, 120.7, 127.7, 128.5, 127.9, 137.5,

139.2, 150.0; MS 9FAB) m/z: 345.2430 [9M1H)¹. C₂₂H₃₃O₃

requires 345.2430], 345 [9M1H)¹], 309 [9M22H₂O1H)¹,

70], 154 9100).

22

0.29 9hexane/ether, 1:1); [a]_D218.6 9c 2.4 in CHCl₃);

n

_max9CHCl₃) 3609, 3438 cm²¹; d_H9CDCl₃, 400 MHz) 0.07

[s, 6H, 9CH₃)₂Si], 0.69 9d, 3H, CH₃CHCH₂, J6.9 Hz), 0.89

[s, 9H, 9CH₃)₃C], 1.01 9d, 3H, CH₃CHCHOH, J7.0 Hz),

1.69 9s, 3H, CH₃CvCH), 1.71±1.87 9m, 2H, H-4, H-6),

3.44 9d, 1H, OH, J6.0 Hz), 3.58 9t, 1H, H-7, J9.9 Hz),

3.72 9dd, 1H, H-7, J9.9, 4.3 Hz), 3.80 9td, 1H, H-5, J9.4,

1.5 Hz), 4.04 9d, 1H, H-3, J6.0 Hz), 4.32 9s, 1H, OH), 4.93

9s, 1H, H-1), 5.10 9br s, 1H, H-1); d_C9CDCl₃, 100 MHz)

25.6, 10.1, 12.6, 18.1, 18.7, 25.9, 35.8, 37.2, 69.9, 76.4,

79.3, 111.5, 146.4; MS 9EI) m/z: 303.2350 [9M1H)¹.

C₁₆H₃₅O₃Si requires 303.2355].

9.6.5. .3S,4R,5R,6R)-7-Benzyloxy-2,4,6-trimethyl-hept-

1-ene-3,5-diol 55e.⁴⁶Me₄NBH9OAc)₃91.2 g, 4.6 mmol),

acetic acid 96 mL), acetonitrile 918 mL) and the hydroxy-

ketone 52e 90.312 g, 1.13 mmol) were used according to the

standard procedure at 2358Cfor 18 h. Puri®cation by ¯ash

chromatography 9hexane/EtOAc, 7:3) afforded the diol 55e

90.226, 0.81 mmol, 72%) as a translucent low-melting solid;

mp 30±328C; R_F0.28 9light petroleum/EtOAc, 10:3);

9.7. Representative procedures for the preparation of

the cyclic carbonates

9.7.1.

.4S,6S)-4-[.1R)-2-Benzyloxy-1-methyl-ethyl]-6-

25

[a]_D213.1 9c 3.8 in CHCl₃); n_max9CHCl₃) 3607,

vinyl-[1,3]dioxan-2-one 56a. Preparation using carbonyl-

diimidazole. A solution of the diol 55a 926.8 mg,

0.107 mmol) and carbonyldiimidazole 920.5 mg, 0.126

mmol) in toluene 92 mL) was heated under re¯ux for 48 h.

Further carbonyldiimidazole 92£10 mg) was added after 23

and 28 h, after which time no starting material remained.

The reaction mixture was poured into water 95 mL) and

extracted with ether 93£10 mL). The combined organic

phases were washed with water 92£5 mL) and brine

95 mL), then they were dried 9Na₂SO₄) and concentrated.

Puri®cation by ¯ash chromatography 9light petroleum/

EtOAc, 7:3!1:0) gave the carbonate 56a 919.5 mg,

0.071 mmol, 66%) as a colourless oil; R_F0.34 9hexane/

3434, 1652 cm²¹; d_H9CDCl₃, 250 MHz) 0.88 9d, 3H,

CH₃CHCH₂O, J7.0 Hz), 0.95 9d, 3H, CH₃CHOH, J

7.0 Hz), 1.67 9s, 3H, CH₃CvCH), 1.83±1.86 9m, 1H,

H-6), 2.28±2.27 9m, 1H, H-4), 3.52 9t, 1H, H-7, J

9.0 Hz), 3.60±3.70 9m, 1H, H-7), 3.93 9s, 1H, H-5), 4.44

9d, 1H, H-3, J2.0 Hz), 4.54 9s, 2H, CH₂Ph), 4.92 9d, 1H,

H-1, J1.0 Hz), 5.11 9br s, 1H, H-1), 7.26±7.40 9m, 5H,

ArH); d_C9CDCl₃, 62.5 MHz) 10.4, 13.7, 19.9, 35.7, 35.9,

73.3, 73.7, 76.1, 81.7, 110.2, 127.7, 128.0, 128.6, 137.4,

145.2; MS 9CI) m/z: 279.1960 [9M1H)¹. C₁₇H₂₇O₃requires

279.1960], 279 [9M1H)¹, 65%], 106 9100).

25

9.6.6. .3S,4S,5R,6R)-7-Benzyloxy-2,4,6-trimethyl-hept-1-

ene-3,5-diol 55f.⁴⁶Me₄NBH9OAc)₃91.02 g, 3.88 mmol),

acetic acid 95 mL), acetonitrile 915 mL) and the ketone

52f 90.261 g, 0.944 mmol) were used according to the

standard procedure at 2308Cfor 18 h. Puri®cation by

¯ash chromatography 9hexane/EtOAc, 25:8) afforded the

diol 55f 90.226 g, 0.81 mmol, 72%) as a colourless oil; R_F

EtOAc, 1:1); [a]_D156.0 9c 1.8 in CHCl₃); n_max

9CHCl₃) 1745 cm²¹; d_H9CDCl₃, 360 MHz) 1.01 9d, 3H,

CH₃, J7.0 Hz), 1.94 9dt, 1H, H-5, J14.0, 3.0 Hz),

2.10±2.42 9m, 2H, H-1⁰, H-5), 3.43±3.56 9m, 2H, H-2⁰),

4.42±4.57 9m, 3H, CH₂Ph, H-4), 5.04±5.07 9m, 1H, H-6),

5.36±5.43 9m, 2H, CH₂vCH), 5.85 9ddd, 1H, CH₂vCH,

J17.0, 11.0, 4.0 Hz), 7.24±7.37 9m, 5H, ArH); d_C9CDCl₃,

62.5 MHz) 12.5, 27.9, 37.6, 70.7, 73.2, 76.8, 112.6, 118.1,

127.6, 127.7, 128.4, 134.4, 138.2, 148.9; MS 9CI) m/z:

277.1440 [9M1H)¹. C₁₆H₂₁O₄requires 277.1440].

23

0.28 9light petroleum/EtOAc, 10:3); [a]_D234.9 9c 5.45

in CHCl₃); n_max9CHCl₃) 3604, 3452, 1650 cm²¹; d_H

9CDCl₃, 500 MHz) 0.75 9d, 3H, CH₃CHCH₂O, J7.0 Hz),

1.02 9d, 3H, CH₃CHCHOH, J7.0 Hz), 1.69 9s, 3H,

CH₃CvCH), 1.80 9qn, 1H, H-4, J7.0 Hz), 1.97±2.04

9m, 1H, H-6), 3.51 9t, 1H, H-7, J9.0 Hz), 3.57 9dd, 1H,

H-7, J9.0, 4.0 Hz), 3.79 9d, 2H, H-5, J9.0 Hz), 4.04±

4.05 9m, 2H, H-3, OH), 4.50 9d, 1H, CH₂Ph, J12.0 Hz),

4.54 9d, 1H, CH₂Ph, J12.0 Hz), 4.95 9d, 1H, H-1, J

1.0 Hz), 5.12 9br s, 1H, 1-H), 7.25±7.36 9m, 5H, ArH); d_C

Preparation using triphosgene. To a solution of diol 55a

937.6 mg, 0.15 mmol) in dichloromethane 90.75 mL) at

2788Cwas added dry pyridine 90.075 mL, 73 mg,

0.93 mmol). A solution of triphosgene 923 mg, 0.77

mmol) in dichloromethane 90.75 mL) was added dropwise

via cannula. The mixture was stirred at 2788Cfor 15 min

1968

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

and then quenched with a saturated aqueous solution of

ammonium chloride 910 mL) before removing the cooling

bath. The mixture was poured into ether 920 mL) and water

910 mL) and the organic phase separated. The organic layer

was washed sequentially with saturated aqueous solutions of

copper9II) sulphate 910 mL), sodium bicarbonate 910 mL)

and brine 910 mL). The organic phase was dried 9MgSO₄)

and concentrated. Puri®cation by ¯ash chromatography

9light petroleum/EtOAc, 4:1!0:1) gave the carbonate 56a

918.5 mg, 0.067 mmol, 45%, data identical to previous

values) and the starting diol 55a 912.2 mg, 0.049 mmol, 33%).

according to the standard procedure at re¯ux for 24 h.

Further carbonyldiimidazole was added after 16 h

919.6 mg) and 23 h 911.7 mg). Puri®cation by ¯ash chroma-

tography 9dichloromethane/ether, 19:1) gave the carbonate

56d 99.6 mg, 26 mmol, 28%) as a colourless oil; R_F0.58

27

9dichloromethane/ether, 9:1); [a]_D216.7 9c 2.5 in

CHCl₃); n_max9CHCl₃)1739 cm²¹; d_H9CDCl₃, 250 MHz)

1.00 9d, 3H, CH₃CHCH₂, J7.0 Hz), 1.25±2.41 9m, 13H,

H-5, H-1⁰, H-3⁰⁰, H-4⁰⁰, H-5⁰⁰, H-6⁰⁰, CH₃CvCH₂), 3.45±

3.59 9m, 2H, H-2⁰), 4.41±4.56 9m, 2H, CH₂Ph), 4.72 9dt,

1H, H-6, J9, 2.5 Hz), 4.86 9br s, 1H, H-4), 5.29 9s, 2H,

CH₂vC), 5.77±5.84 9m, 1H, H-2⁰), 7.18±7.38 9m, 5H,

ArH); d_C9CDCl₃, 100 MHz) 12.3, 20.7, 25.3, 25.7, 27.0,

30.2, 37.2, 40.0, 70.7, 73.3, 78.7, 109.0, 124.1, 127.6, 127.7,

128.4, 132.9, 138.0, 149.1; MS 9CI) m/z: 388.2488

[9M1NH₄)¹. C₂₃H₃₄NO₄requires 388.2488], 388 915%),

196 9100).

9.7.2. .4S,6S)-4-[.1R)-2-Benzyloxy-1-methyl-ethyl]-6-

[.E)-propenyl]-[1,3]dioxan-2-one 56b. The diol 55b

Ê

93.35 g, 12.65 mmol), 4 A molecular sieves 9spatula tip),

pyridine 96.14 mL, 6.0 g, 75.9 mmol), triethylamine

910.59 mL, 7.7 mL, 75.9 mmol), dichloromethane 975 mL)

and triphosgene 91.88 g, 6.33 mmol) were used according to

the standard procedure at 2788Cfor 30 min. Following

work-up, the concentrate was passed through a silica plug

9light petroleum/EtOAc, 3:1) to remove pyridine and then

reconcentrated. Puri®cation by ¯ash chromatography 9light

petroleum/EtOAc, 3:1) yielded the carbonate 56b as a pale

yellow oil 92.81 g, 9.68 mmol, 77%); R_F0.14 9light

9.7.5. .4S,5R,6R)-6-[.1R)-2-Benzyloxy-1-methyl-ethyl]-

5-methyl-4-isopropenyl-[1,3]dioxan-2-one 56e. The diol

55e 938.5 mg, 0.138 mmol), toluene 93 mL) and carbonyl-

diimidazole 926.7 mg, 0.165 mmol) were used according to

the standard procedure at re¯ux for 23 h. Further carbonyl-

diimidazole 92£13 mg) was added after 6.75 and 21.25 h.

Puri®cation by ¯ash chromatography 9dichloromethane/

ether, 19:1) gave the carbonate 56e as a colourless oil

942 mg, 0.138 mmol, 100%); R_F0.64 9dichloromethane/

25

petroleum/EtOAc, 5:1); [a]_D164.4 9c 5.52 in CHCl₃);

n_max9CHCl₃) 3019, 1737, 1674 cm²¹

; d_H9CDCl₃,

250 MHz) 1.00 9d, 3H, CH₃CHCH₂, J7.0 Hz), 1.76 9dt,

3H, CH₃CvC, J6.5, 1.5 Hz), 1.90 9dt, 1H, H-5, J14.5,

3.5 Hz), 2.05±2.18 9m, 2H, H-5, H-1⁰), 3.52 9m, 2H, H-2),

4.50 9dd, 2H, CH₂Ph, J17.5, 12.0 Hz), 4.46±4.60 9m, 1H,

H-4), 4.93±5.02 9m, 1H, H-6), 5.52 9ddq, 1H, MeCHvCH,

J15.5, 5.5, 1.5 Hz), 5.82 9ddq, 1H, MeHCvC, J15.5,

6.5, 1.5 Hz), 7.22±7.36 9m, 5H, ArH); d_C9CDCl₃,

62.5 MHz) 12.4, 17.7, 28.3, 37.6, 70.8, 73.2, 76.8, 127.5,

127.5, 127.6, 128.4, 130.3, 138.2, 149.1; MS 9CI) m/z:

308.1855 [9M1NH₄)¹. C₁₇H₂₆O₄N requires 308.1862],

308 984%), 229 9100). Found: C, 70.5; H, 7.66; C₁₇H₂₂O₄

requires C, 70.3; H, 7.64%.

24

ether, 9:1); [a]_D123.3 9c 4.34 in CHCl₃); n_max

9CHCl₃) 1742 cm²¹; d_H9CDCl₃, 250 MHz) 0.99 9d, 3H,

CH₃CHCH₂, J7.0 Hz), 1.06 9d, 3H, CH₃CHCHO, J

7.0 Hz), 1.70 9s, 3H, CH₃CvC), 2.09±2.28 9dq, 1H, H-1⁰,

J7.0, 2.0 Hz), 2.27±2.37 9m, 1H, H-5), 3.56 9dd, 1H, H-2⁰,

J9.0, 3.0 Hz), 3.63 9dd, 1H, H-2⁰, J9.0, 5.0 Hz), 4.20

9dd, 1H, H-6, J8.0, 3.0 Hz), 4.51 9s, 2H, CH₂Ph), 4.79

9br s, 1H, H-4), 5.08 9d, 1H, J1.0 Hz, CHHvCCH₃),

5.18 9br s, 1H, CHHvCH₃), 7.24±7.39 9m, 5H, ArH); d_C

9CDCl₃, 62.5 MHz) 12.0, 14.0, 19.2, 29.2, 37.3, 71.0, 73.4,

79.3, 85.1, 113.3, 127.6, 127.6, 128.4, 138.2, 138.3, 148.9;

MS 9CI) m/z: 305.1753 [9M1H)¹. C₁₈H₂₅O₄requires

305.1753], 322 [9M1NH₄)¹, 100%], 305 920).

9.7.3.

.4S,6S)-6-[.1R)-2-Benzyloxy-1-methyl-ethyl]-4-

[.E)-1-methyl-propenyl]-[1,3]dioxan-2-one 56c. The diol

55c 954.4 mg, 0.195 mmol), toluene 94.2 mL) and carbonyl-

diimidazole 939 mg, 0.24 mmol) were used according to the

standard procedure at re¯ux for 25 h. Further carbonyl-

diimidazole was added after 20 h 940 mg) and 23.5 h

95 mg). Puri®cation by ¯ash chromatography 9dichloro-

methane/ether, 19:1) provided the carbonate 56c 919.2 mg,

63 mmol, 32%) as a colourless oil; R_F0.56 9hexane/ether,

9.7.6. .4S,5S,6R)-6-[.1R)-2-Benzyloxy-1-methyl-ethyl]-5-

methyl-4-isopropenyl-[1,3]dioxan-2-one 56f. The diol 55f

971.9 mg, 0.258 mmol), toluene 95.5 mL) and carbonyl-

diimidazole 951 mg, 0.31 mmol) were used according to

the standard procedure at re¯ux for 20 h. Further carbonyl-

diimidazole 950 mg) was added after 16.5 h. Puri®cation by

¯ash chromatography 9dichloromethane/ether,1:0!19:1)

gave the carbonate 56f as a colourless oil 971.5 mg,

0.24 mmol, 91%); R_F0.62 9light petroleum/ether, 9:1);

21

9:1); [a]_D110.2 9c 1.3 in CHCl₃); n_max9CHCl₃)

1742 cm²¹; d_H9CDCl₃, 250 MHz) 1.00 9d, 3H, CH₃CHCH₂,

J7.0 Hz), 1.62 9dd, 3H, H-3⁰⁰, J11.0, 1.0 Hz), 1.71 9d,

3H, CH₃CvC, J1.0 Hz,), 2.01±2.17 9m, 3H, H-1⁰, H-5),

3.52 9d, 1H, H-2⁰, J5.0 Hz), 4.41±4.85 9m, 3H, CH₂Ph,

H-4), 4.85 9br m, 1H, H-6), 5.53±5.57 9m, 1H, H-2⁰⁰), 7.26±

7.38 9m, 5H, ArH); d_C9CDCl₃, 62.5 MHz) 12.5, 12.7, 13.1,

26.4, 37.4, 70.9, 73.3, 76.9, 79.9, 122.6, 127.6, 127.7, 128.4,

131.4, 138.2, 149.4; MS 9CI) m/z: 322.2018 [9M1NH₄)¹.

C₁₈H₂₈NO₄requires 322.2018], 322 920%).

29

[a]_D161.7 9c 7.38 in CHCl₃); n_max9CHCl₃) 1740

cm²¹; d_H9CDCl₃, 250 MHz) 0.95 9d, 3H, CH₃CHCH₂,

J7.0 Hz), 1.14 9d, 3H, CH₃CHCHO, J7.0 Hz), 1.73 9s,

3H, CH₃CvC), 1.90±2.05 9m, 1H, H-1⁰), 2.15 9dq, 1H, H-5,

J7.0, 1.0 Hz), 3.56 9dd, 1H, H-2⁰, J9.0, 5.0 Hz), 3.60

9dd, H-1⁰, J9.0, 7.0 Hz), 4.31 9dd, 1H, H-6, J10.0,

2.5 Hz), 4.50 9s, 2H, CH₂Ph), 4.62 9br s, 1H, H-4), 5.03 9d,

1H, CHHvCCH₃, J0.5 Hz), 5.11 9d, 1H, CHHvCCH₃,

J0.5 Hz), 7.25±7.33 9m, 5H, ArH); d_C9CDCl₃, 62.5 MHz)

11.0, 12.8, 19.1, 28.2, 35.0, 70.6, 73.2, 77.6, 85.9, 113.5,

127.5, 127.5, 128.3, 138.5, 140.6, 148.5; MS 9CI) m/z:

305.1753 [9M1H)¹. C₁₈H₂₅O₄requires 305.1753], 322

[9M1NH₄)¹, 100%], 305 920).

9.7.4.

.4S,6S)-6-[.1R)-2-Benzyloxy-1-methyl-ethyl)-4-

[.4S)-4-isopropenyl-cyclohex-1-enyl]-[1,3]-dioxan-2-one

56d. The diol 55d 932.5 mg, 94.3 mmol), toluene 93 mL)

and carbonyldiimidazole 918.1 mg, 110 mmol) were used

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

1969

9.7.7. .4S,5S,6R)-6-[.1R)-2-tert-Butyldimethylsilyloxy-1-

methyl-ethyl]-5-methyl-4-isopropenyl-[1,3]dioxan-2-one

56g. The diol 55g 91.45 g, 4.8 mmol), toluene 9100 mL) and

carbonyldiimidazole 90.9 g, 5.52 mmol) were used accord-

ing to the standard procedure at re¯ux for 44 h. Further

carbonyldiimidazole 90.9 g, 5.52 mmol) was added after

20 h. Puri®cation by ¯ash chromatography 9hexane/ether,

4:1) gave the carbonate 56g as white needle-like crystals

91.23 g, 3.74 mmol, 78%); mp 124±1278C; R_F0.27

J7.0 Hz), 1.14 9d, 3H, CH₃CH, J7.0 Hz), 1.94±2.07

9m, 1H, H-1⁰), 2.14±2.25 9m, 1H, H-7), 2.35 9dd, 1H,

H-3, J12.5, 11.0 Hz), 2.60 9dt, 1H, H-7, J17.0,

5.0 Hz), 2.65 9dd, 1H, H-3, J12.5, 5.5 Hz), 2.75±2.90

9m, 1H, H-4), 3.47±3.49 9m, 2H, H-2⁰), 4.49 9s, 2H,

CH₂Ph), 4.70 9dt, 1H, H-8, J9.0, 5.5 Hz), 5.56±5.59 9m,

2H, H-5, H-6), 7.25±7.37 9m, 5H, ArH); d_C9CDCl₃,

62.5 MHz) 14.0, 22.6, 30.2, 30.7, 37.1, 45.3, 71.8, 73.2,

76.0, 152.2, 127.5, 127.6, 128.3, 137.6, 138.6, 175.9; MS

9CI) m/z: 289.1804 [9M1H)¹. C₁₈H₂₅O₃requires 289.1804],

306 [9M1NH₄)¹, 45%], 289 950). Found: C, 74.6; H, 8.4;

C₁₈H₂₄O₃requires C, 75.0; H, 8.4%.

22

9hexane/EtOAc, 3:2); [a]_D145.2 9c 1.89 in CHCl₃);

n_max9CHCl₃) 1739, 1653 cm²¹; d_H9CDCl₃, 400 MHz)

0.02 [s, 6H, 9CH₃)₂Si], 0.85 [s, 9H, 9CH₃)₃C], 0.89 9d, 3H,

CH₃CHCH₂, J6.9 Hz), 1.14 9d, 3H, CH₃CHCHO, J

7.1 Hz), 1.73 9s, 3H, CH₃CvC), 1.77±1.85 9m, 1H, H-1⁰),

2.06±2.13 9m, 1H, H-5), 3.61 9dd, 1H, H-2⁰, J9.8, 2.6 Hz),

3.79 9dd, 1H, H-1⁰, J9.8, 4.4 Hz), 4.34 9dd, 1H, H-6,

J10.3, 2.4 Hz), 4.61 9br s, 1H, H-4), 5.03 9br s, 1H,

CHHvC), 5.10 9br s, 1H, CHHvC); d_C9CDCl₃,

100 MHz) 25.6, 25.5, 11.0, 12.3, 18.2, 19.0, 25.8, 28.1,

36.3, 62.9, 76.9, 85.9, 113.4, 140.8, 148.6; MS 9CI, NH₃)

m/z 329.2155 [9M1H)¹. C₁₇H₃₃O₄Si requires 329.2148],

346 [9M1NH₄)¹, 20%], 329 918), 83 9100). Found: C,

62.2; H, 9.9; C₁₇H₃₂O₄Si requires: C, 62.2; H, 9.8%.

9.8.3. .4R,8S)-8-[.1R)-2-Benzyloxy-1-methyl-ethyl]-4,5-

dimethyl-3,4,7,8-tetrahydrooxocin-2-one 58c. The carbo-

nate 56c 918.6 mg, 61.1 mmol), toluene 92.6 mL) and

dimethyltitanocene 90.32 mL of a 50 mg/mL solution in

toluene, 76 mmol) were used according to the standard

procedure at re¯ux for 4.5 h. Puri®cation by ¯ash chroma-

tography 9light petroleum/ether, 9:1!4:1) afforded the

lactone 58c 96.3 mg, 21 mmol, 34%) as a pale yellow oil;

25

R_F0.16 9hexane/EtOAc, 9:1); [a]_D217.9 9c 0.7 in

CHCl₃); n_max9CHCl₃) 1722 cm²¹); d_H9CDCl₃, 360 MHz)

1.03 9d, 3H, CH₃CH₂O, J7.0 Hz), 1.10 9d, 3H, CH₃CH,

J7.0 Hz), 1.70 9t, 3H, CH₃CvC, J1.5 Hz), 1.94±2.01

9m, 1H, H-1⁰), 2.28 9dt, 1H, H-7, J16.0, 9.0 Hz), 2.48

9dd, 1H, H-3, J14.0, 11.0 Hz), 2.47±2.54 9m, 1H, H-7),

2.94 9dd, 1H, H-3, J14.0, 7.0 Hz), 3.01±3.08 9m, 1H, H-

4), 3.45 9dd, 1H, H-2⁰, J9.0, 4.0 Hz), 3.53 9dd, 1H, H-2⁰,

J9.0, 5.0 Hz), 4.48 9s, 2H, CH₂Ph), 4.73 9dt, 1H, H-8,

J9.0, 5.0 Hz), 5.32 9dd, 1H, H-6, J12.0, 5.0 Hz), 7.25±

7.38 9m, 5H, ArH); d_C9CDCl₃, 100 MHz) 13.6, 18.8, 19.8,

31.0, 32.7, 38.7, 44.6, 71.7, 73.2, 77.6, 120.2, 127.8, 128.4,

138.4, 141.7, 174.4; MS 9CI) m/z: 303.1960 [9M1H)¹.

C₁₉H₂₇O₃requires 303.1960].

9.8. Representative procedure for tandem methylenation/

Claisen rearrangement of the carbonates 56a±g

9.8.1. .8S)-8-[.1R)-2-Benzyloxy-1-methyl-ethyl]-3,4,7,8-

tetrahydrooxocin-2-one 58a. A solution of the carbonate

56a 940.5 mg, 0.147 mmol) and dimethyltitanocene

90.73 mL of a 50 mg/mL solution in toluene, 0.176 mmol)

in toluene 95 mL) was heated at re¯ux in the absence of light

for 3.5 h. The reaction mixture was allowed to cool, and was

then concentrated. Puri®cation by ¯ash chromatography

9light petroleum/EtOAc, 4:1) provided the lactone 58a

920.9 mg, 0.076 mmol, 52%); R_F0.23 9hexane/ether,

27

9.8.4. .4S,9S,10aR)-4-[.1R)-2-Benzyloxy-1-methyl-ethyl]-

9-isopropenyl-1,4,5,7,8,9,10,10a-octahydro-benzo[d]-

oxocin-2-one 58d. The carbonate 56d 915.1 mg,

40.8 mmol), toluene 91.3 mL) and dimethyltitanocene

90.22 mL of a 50 mg/mL solution in toluene, 53 mmol)

were used according to the standard procedure at re¯ux

for 24 h. The reaction mixture was diluted with light petro-

leum until the mixture became cloudy and ®ltered through a

pad of silica. The mixture was then concentrated, and puri-

®cation by ¯ash chromatography 9light petroleum/ether,

9:1!4:1) afforded the lactone 58d 93.8 mg, 10 mmol,

20:3); [a]_D23.9 9c 3.65 in CHCl₃); n_max9CHCl₃)

1740 cm²¹; d_H9CDCl₃, 500 MHz) 1.04 9d, 3H, CH₃CH₂O,

J7.0 Hz), 1.96±2.26 9m, 3H, H-4, H-7, H-1⁰), 2.28±2.36

9ddd, 1H, H-3, J16.0, 11.0, 6.0 Hz), 2.44±2.54 9ddd, 1H,

H-7, J11.0, 4.0, 2.0 Hz), 2.77±2.76 9m, 1H, H-3), 2.78±

2.98 9m, 1H, H-4), 3.37 9dd, 1H, H-2⁰, J9.0, 7.0 Hz), 3.58

9dd, 1H, H-2⁰, J9.0, 5.0 Hz), 4.50 9s, 2H, CH₂Ph), 4.49±

4.59 9m, 1H, H-8), 5.70±5.83 9m, 2H, H-5, H-6), 7.24±7.38

95 H, m, ArH); d_C9CDCl₃, 62.5 MHz) 14.1, 24.3, 31.4, 37.6,

37.9, 72.2, 73.2, 79.9, 127.5, 127.6, 128.3, 128.6, 132.7,

138.6, 177.0; MS 9CI) m/z: 275.1647 [9M1H)¹. C₁₇H₂₃O₃

requires 275.1647]. Further elution of the column gave the

carbonate 56a 92.4 mg, 8.7 mmol, 6%).

25%) as a pale yellow oil; R_F0.29 9hexane/ether, 5:1);

[a]_D131.8 9c 0.4 in CHCl₃); n_max9CHCl₃) 1721 cm²¹

;

27

d_H9CDCl₃, 500 MHz) 1.03 9d, 3H, CH₃CH₂O, J7.0 Hz),

1.39±1.50 9m, 2H, H-4, H-7), 1.69 9s, 3H, CH₃CvC), 1.77

9m, 2H, H-4, H-7), 1.96±2.12 9m, 3H, H-5, H-6, H-1⁰),

2.23±2.37 9m, 2H, H-6, H-9), 2.47±2.56 9m, 2H, H-3,

H-9), 2.66 9dd, 1H, H-3, J12.0, 5.0 Hz), 2.84±2.80 9m,

1H, H-3a), 3.45 9dd, 1H, H-2⁰, J9.0, 6.0 Hz), 3.51 9dd,

1H, H-2⁰, J9.0, 4.0 Hz), 4.49 9s, 2H, CH₂Ph), 4.55

9dt, 1H, H-10, J9.0, 6.0 Hz), 4.67 9br s, 2H, CvCH₂),

5.39 9t, 1H, H-8, J7.0 Hz), 7.26±7.36 9m, 5H, ArH);

d_C9CDCl₃, 62.5 MHz) 14.0, 20.5, 29.8, 29.9, 32.1,

36.0, 37.4, 38.1, 41.6, 43.2, 71.9, 73.2, 76.9, 108.6,

118.2, 127.5, 127.6, 128.3, 138.0, 143.4, 149.4, 175.7;

MS 9CI) m/z: 369.2430 [9M1H)¹. C₂₄H₃₃O₃requires

369.2430].

9.8.2.

.4R,8S)-8-[.1R)-2-Benzyloxy-1-methyl-ethyl]-4-

methyl-3,4,7,8-tetrahydro-oxocin-2-one 58b. The carbo-

nate 56b 90.5 g, 1.72 mmol), toluene 970 mL) and dimethyl-

titanocene 99.3 mL of a 50 mg/mL solution in toluene,

2.23 mmol) were used according to the standard procedure

for 3 h at re¯ux. The crude mixture was passed through a

silica plug 9light petroleum/EtOAc, 3:1) to remove baseline

titanium residues. The ®ltrate was reconcentrated, and puri-

®cation by ¯ash chromatography 9light petroleum/EtOAc,

17:3) provided the lactone 58b as a pale yellow oil 90.255 g,

0.88 mmol, 52%); R_F0.38 9light petroleum/EtOAc, 4:1);

24

[a]_D238.6 9c 1.07 in CHCl₃); n_max9CHCl₃) 1719

cm²¹; d_H9CDCl₃, 250 MHz) 1.05 9d, 3H, CH₃CH₂O,

1970

E. A. Anderson et al. / Tetrahedron 58 12002) 1943±1971

9.8.5. .7S,8S)-8-[.1R)-2-Benzyloxy-1-methyl-ethyl]-5,7-

dimethyl-3,4,7,8-tetrahydrooxocin-2-one 58e. The carbo-

nate 56e 933.3 mg, 0.109 mmol), toluene 94 mL) and

dimethyltitanocene 90.57 mL of a 0.24 M solution in

toluene; 0.14 mmol) were used according to the standard

procedure at re¯ux for 3 h. Puri®cation by ¯ash chroma-

tography 9hexane/ether, 9:1) afforded the lactone 58e

915.8 mg, 0.052 mmol, 48%) as a pale yellow oil; R_F0.33

6.4 Hz), 3.66 9dd, 1H, H-2⁰, J9.7, 3.2 Hz), 4.63 9dd, 1H,

H-8, J9.4, 3.2 Hz), 5.41 9dd, 1H, H-6, J7.4, 0.9 Hz); d_C

9CDCl₃100 MHz) 25.4, 18.3, 26.0, 29.9, 35.4, 36.0, 36.7,

64.9, 80.9, 128.8, 137.5, 176.4; MS 9CI, NH₃) m/z: 327.2381

[9M1H)¹. C₁₈H₃₅O₃Si requires 327.2355], 344 [9M1

NH₄)¹, 2%], 327 940), 195 9100).

25

9light petroleum/ether, 17:3); [a]_D248.1 9c 1.1 in

Acknowledgements

CHCl₃); n_max9CHCl₃) 1737 cm²¹; d_H9CDCl₃, 500 MHz)

0.97 9d, 3H, CH₃CH, J7.0 Hz), 1.09 9d, 3H, CH₃CH₂O,

J7.0 Hz), 1.70 9s, 3H, CH₃CH₂), 1.85±1.89 9ddd, 1H, H-4,

J12.0, 5.0, 2.0 Hz), 2.00±2.24 9m, 1H, H-1⁰), 2.37±2.43

9dtm 1H, H-3, J13.0, 5.0 Hz, 3-H), 2.68±2.83 9ddd, 1H,

H-3, J13.0, 6.0, 2.0), 2.78±2.84 9m, 1H, H-7), 2.91 9dt,

1H, H-4, J12.0, 6.0 Hz), 3.30 9dd, 1H, H-2⁰, J9.0,

8.0 Hz), 3.74 9dd, 1H, J9.0, 6.0 Hz, H-2⁰), 4.27 9dd, 1H,

H-8, J10.0, 2.0 Hz), 4.53 9s, 2H, CH₂Ph), 5.07 9d, 1H, H-6,

J7.0 Hz), 7.26±7.36 9m, 5H, ArH); d_C9CDCl₃, 100 MHz)

16.2, 17.0, 24.1, 29.5, 33.9, 36.5, 36.6, 70.7, 73.1, 87.7,

127.4, 127.5, 128.3, 131.5, 138.0, 138.6, 176.4; MS 9CI)

m/z: 303.1960 [9M1H)¹. C₁₉H₂₇O₃requires 303.1960],

320 [9M1NH₄)¹, 100%], 303 920).

We thank EPSRCfor ®nancial support and provision of the

Swansea Mass Spectrometry Service, the Royal Society for

a University Research Fellowship 9JWB), Merck Sharp and

Dohme for the award of CASE studentships 9to EAA and

JRH), GlaxoWellcome for a studentship 9to JEPD) and the

Cambridge European Trust and the Robert Gardiner

Memorial Fund for ®nancial support 9PTO'S). We thank

Dr K Julienne for the preparation of reagent 12, Dr J. M.

Goodman for advice concerning the molecular modelling

and Dr N. Bampos for developing the ¹H NMR 1-D

TOCSY experiments for the analysis of compound 36.

9.8.6. .7R,8S)-8-[.1R)-2-Benzyloxy-1-methyl-ethyl]-5,7-

dimethyl-3,4,7,8-tetrahydrooxocin-2-one 58f. The carbo-

nate 56f 91.8 g, 5.9 mmol), and dimethyltitanocene

934.0 mL of a 50 mg/mL solution in toluene, 8.26 mmol)

were used according to the standard procedure at re¯ux

for 16 h. Puri®cation by ¯ash chromatography on silica

9hexane/ether, 17:3) afforded the lactone 58f 91.13 g,

3.73 mmol, 63%) as a pale yellow oil; R_F0.28 9light petro-

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Article Doi

Synthesis of medium-ring lactones via tandem methylenation/Claisen rearrangement of cyclic carbonates

DOI: 10.1016/S0040-4020(02)00049-2

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