Synthesis of polypropionate subunits from cyclopropanes

Tetrahedron 61 (2005) 7632–7653

*

Magali Defosseux, Nicolas Blanchard, Christophe Meyer and Janine Cossy

´

Laboratoire de Chimie Organique, associe au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France

Received 29 March 2005; revised 26 May 2005; accepted 31 May 2005

Available online 22 June 2005

Abstract—The oxymercuration–reductive demercuration of several cyclopropanealkanol or their derivatives bearing adjacent stereocenters

has been investigated in order to synthesize polypropionate subunits. The crucial importance of the ester protecting group for the remote

oxygenated moieties on the mechanism and the stereochemical outcome of these reactions has been rationalized.

1. Introduction

Polypropionate subunits are present in a great number of

biological active natural products such as antibiotics,

antitumors, antifungals, antiparasitics or immuno-

modulators.¹The importance of these natural products

together with their structural and stereochemical complexity

has led to the development of several ingenious method-

Scheme 1. Reagents and conditions: (a) Hg(OCOCF₃)₂, CH₂Cl₂then NaCl

(XZCl) or KBr (XZBr); (b) reductive demercuration.

ologies to provide access to these structures.²A widespread

strategy involves the disconnection of polypropionate

cyclopropanemethanols of type₀A bear₀ing a remote oxy-

chains into shorter subunits bearing an alternance of methyl

and hydroxyl groups and to combine these fragments by

using coupling reactions.³In conjunction with our interest

concerning the development of methods for polypropionate

synthesis,⁴the generation of such subunits from cyclo-

propanealkanols bearing adjacent stereocenters has been

investigated. Indeed, several cyclopropanealkanols of type

A were reported to undergo highly regio- and stereo-

selective oxymercurations when treated with mercuric

triﬂuoroacetate.^5–9This reaction involves an electrophilic

ring-opening of the cyclopropanealkanols of type A at the

most electron-rich carbon–carbon bond with concomittant

anti nucleophilic attack of the triﬂuoroacetate counter-anion

(or any other added more powerful nucleophile). After

hydrolysis in the presence of halide ions and subsequent

reductive demercuration of the intermediate organo-

mercuric halides of type B, 1,3-diols of type C were

elaborated (Scheme 1).^5–7

genated moiety (RZCH₂CH₂OR with R ZH or Sit-BuPh₂).

However, the reaction proceeded in modest yield if an ester

protecting group (RZCH₂CH₂OAc) was chosen for the

remote hydroxyl group, presumably due to an internal

participation of the ester moiety, although, this had only

been suggested and not further investigated.⁵

Since, the cyclopropane could be regarded as an equivalent

of a methyl-hydroxyl array, whose relative conﬁguration is

controlled by the initial stereogenic centers of the three-

membered ring, the oxymercuration of cyclopropane-

methanol derivatives of types D, E and F bearing one to

three adjacent stereocenters and remote hydroxyl groups

protected as esters (PZAc or Piv) was envisaged with the

aim of obtaining stereotriads, stereotetrads and stereo-

pentads, respectively.^9,10On the other hand, the oxymer-

curation–reductive demercuration of the secondary

cyclopropanealkanols derivatives of type G and H bearing

adjacent stereocenters on both sides of the three-membered

ring could also provide an access to stereotetrads and

stereopentads by a similar process (Scheme 2).

It is noteworthy that, a complex mixture of products was

obtained when oxymercurations were applied to some

The preparation of racemic cyclopropanealkanols of type

D–H was ﬁrst considered in order to probe their conversion

to polypropionate subunits by an oxymercuration–reductive

demercuration sequence.

Keywords: Cyclopropanes; Diastereoselectivity; Ring opening; Electro-

philic additions; Mercury.

*

Corresponding author. Tel.: C33 1 40 79 44 29; fax: C33 1 40 79 46 60;

e-mail: janine.cossy@espci.fr

doi:10.1016/j.tet.2005.05.099

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7633

Scheme 3. Reagents and conditions: (a) BH₃$THF, THF, K30 8C to rt,

then NaOH, H₂O₂; (b) PivCl, Et₃N and/or DMAP, Et₂O or CH₂Cl₂;

(c) n-Bu₄NF, THF.

Scheme 2.

2. Preparation of cyclopropanealkanols of type D–H

Previous investigations from our laboratory were devoted to

the development of efﬁcient synthetic routes to cyclo-

propanemethanols bearing adjacent stereocenters. In this

context, cis-1,2-disubstituted alkenylcyclopropanes were

reported to undergo highly diastereoselective electrophilic

additions, whereas the corresponding trans isomers reacted

in an almost stereorandom fashion.^11,12Thus, when

isopropenylcyclopropanes 1 and 2 were hydroborated with

BH₃$THF followed by a standard alkaline oxidative work-

up (NaOH/H₂O₂), a 50/50 diastereomeric mixture of the

corresponding primary alcohols 3a,b (88%) and 4a,b (64%),

respectively, was obtained.¹¹The diastereomers were easily

separated by ﬂash chromatography and, by standard

protecting group manipulations, compounds 3a and 3b

were converted into cyclopropanemethanols 5a (90%) and

5b (78%), respectively, whereas compounds 4a and 4b were

converted into the corresponding benzyl ethers 6a (96%)

and 6b (93%) (Scheme 3).

Scheme 4. Reagents and conditions: (a) BH₃$THF, THF, K30 8C to rt, then

NaOH, H₂O₂; (b) PivCl, DMAP, CH₂Cl₂; (c) n-Bu₄NF, THF.

adjacent stereocenter anti to the cyclopropane, the

isopropenylcyclopropane 8 was ﬁrst subjected to an allylic

oxidation with SeO₂in the presence of tert-butyl-

hydroperoxide (TBHP).¹⁴Reduction of the crude reaction

mixture with sodium borohydride in the presence of

cerium(III) chloride afforded the allylic alcohol 9 (84%).¹⁵

By analogy with the hydroboration of 8, the hydrogenation

of the cis-disubstituted isopropenylcyclopropane 9 was

anticipated to involve an addition to the less hindered face

of the carbon–carbon double bond in the gauche confor-

mation,^12,13which would then stereoselectively lead to

compound 4d having the methyl group anti to the

cyclopropane. Indeed, the reduction of 9 with diimide

turned out to proceed with high diastereoselectivity (drZ4c/

4dZ8/92) and the resulting primary alcohol 4d (74%) was

subsequently converted to the pivalate ester 6d (87%)

(Scheme 5).

By contrast, the cis-isopropenylcyclopropanes 7 and 8, were

hydroborated with high diastereoselectivity (drO96/4) to

afford, respectively, the primary alcohols 3c (91%) and 4c

(82%), having the methyl group syn to the adjacent

cyclopropane.¹¹This result was explained by the attack of

the organoborane on the less hindered face of the double

bond in the more stable and possibly reactive gauche

conformation.^12,13Compounds 3c and 4c were then

converted to the cyclopropanemethanol 5c (91%) or to the

benzyl ether 6c (90%) (Scheme 4).

Having synthesized all the possible diastereomeric cyclo-

propanemethanols of type D 5a–5d and their corresponding

benzyl ethers 6a–6d, the preparation of cyclopropanes of

type E and F, bearing two or three stereocenters adjacent to

the three-membered ring, was achieved.

In order to have access to a cis-disubstituted cyclo-

propanemethanol derivative with the methyl group on the

The primary alcohols 4a and 4c were oxidized

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M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

diastereoselectivity by using 9-BBN-H followed by a

standard oxidative work-up to afford diol 14 (drZ90/10,

97%),¹⁸which was ﬁnally, converted to the diacetate 15

(82%), a substrate of type F (Scheme 7).

Scheme 5. Reagents and conditions: (a) SeO₂, t-BuOOH, CH₂Cl₂;

(b) NaBH₄, CeCl₃$7H₂O, MeOH, 0 8C; (c) KO₂C–N]N–CO₂K, AcOH,

EtOH, 45 8C; (d) PivCl, Et₃N, cat. DMAP, Et₂O.

(cat. n-PrNRuO₄(TPAP), NMO, CH₂Cl₂/MeCN)¹⁶to the

corresponding sensitive aldehydes 10a and 10c, which were

not puriﬁed but directly treated with ethylmagnesium

bromide in THF, to afford diastereomeric mixtures of the

corresponding secondary alcohols 11a/11⁰a (drZ77/23) and

11c/11⁰c (drZ85/15). The major diastereomers 11a (32%)

and 11c (51%) could be separated after puriﬁcation by ﬂash

chromatography and their relative conﬁgurations were

initially attributed on the basis of the Felkin–Anh model

for nucleophilic additions to carbonyl compounds.¹⁷This

assignment was later conﬁrmed after the oxymercuration to

polypropionate subunits. The secondary alcohols 11a and

11c were transformed into the acetates 12a (92%) and 12c

(91%), respectively. They constitute two examples of

cyclopropanes of type E (Scheme 6).

Scheme 7. Reagents and conditions: (a) cat. TPAP, NMO, CH₂Cl₂/MeCN,

0 8C to rt; (b) isopropenylMgBr, THF, K30 8C; (c) 9-BBN-H, THF,

K30 8C to rt; (d) Ac₂O, cat. DMAP, Et₂O.

Next, the synthesis of the secondary cyclopropanealkanols

of type G and H was realized. The cyclopropanemethanol

5c was oxidized with PCC¹⁹to the corresponding

cyclopropanecarboxaldehyde 16 (94%). This aldehyde 16

was treated with ethylmagnesium bromide to afford a

diastereomeric mixture of the secondary cyclopropane-

propanols 17 and 17⁰(60/40 ratio, 52%), which were readily

separated by ﬂash chromatography. It is known that the

bisected conformers of cyclopropylcarbonyl derivatives are

more stable than other conformers and that they are also

envisaged to be the reactive conformers in models for

nucleophilic additions to this class of compounds.²⁰For

cyclopropanecarboxaldehydes, the s-trans conformation is

only slightly preferred, whereas for cyclopropylketones the

s-cis conformation is markedly more stable.²⁰Moreover,

nucleophilic addition to the s-trans confomer follows the

anti-Felkin–Anh addition mode with respect to the carbonyl

adjacent stereocenter, whereas addition to the s-cis

conformer implies a Felkin–Anh mode.¹⁷In agreement

Scheme 6. Reagents and conditions: (a) cat. TPAP, NMO, CH₂Cl₂/MeCN,

0 8C to rt; (b) EtMgBr, THF, K30 8C and separation by ﬂash

chromatography; (c) Ac₂O, cat. DMAP, Et₂O.

One single cyclopropane of type F bearing three adjacent

stereocenters was synthesized from compound 4c, which

was oxidized to aldehyde 10c and addition of iso-

propenylmagnesium bromide gave a diastereomeric mixture

of alcohols 13 and 13⁰(drZ85/15). The major diastereomer

13 (43%) was separated and hydroborated with high

˚

Scheme 8. Reagents and conditions: (a) PCC, 4 A molecular sieves,

CH₂Cl₂; (b) EtMgBr, THF, K30 8C; (c) NaBH₄, MeOH, 0 8C.

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7635

type H was derived from substrate 4c. This compound was

protected as a tert-butyldiphenylsilylether 19 (89%) and

subsequent debenzylation afforded the cyclopropane-

methanol 20 (86%). The latter compound was subjected to

a three step sequence involving an oxidation with PCC, a

Wittig oleﬁnation and subsequent reduction of the a,b-

unsaturated ester with DIBAL-H, leading to the allylic

alcohol 21 (60% overall yield). Based on previous

investigations, hydroboration of cis-1,2-disubstituted

alkenylcyclopropane 21 (bearing a trisubstituted double

bond) with thexylborane proceeded with high diastereo-

selectivity (drZ12/1) giving a mixture of diols 22 and 22⁰,

which were separated by ﬂash chromatography and isolated

in 71 and 6% yields, respectively.^11bA third minor ring-

opened by-product, whose structure was assigned as 22⁰⁰,

was also isolated in 6% yield.^11bThe major diastereomer 22

was then desilylated to generate the triol 23 (76%) and the

primary alcohol moieties were protected as pivalates to

afford the secondary cyclopropanealkanol 24 (63%) of type

H (Scheme 9).

Scheme 9. Reagents and conditions: (a) TBSCl, imidazole, DMF; (b) H₂,

˚

cat. Pd/C, EtOH; (c) PCC, 4 A molecular sieves, CH₂Cl₂; (d) Ph₃P]

CHCO₂Me, toluene, reﬂux; (e) DIBAL-H, CH₂Cl₂, K78 8C; (f) T-hexBH₂,

THF, K30 8C to rt then NaOH, H₂O₂; (g) n-Bu₄NF, THF; (h) PivCl, Et₃N,

cat. DMAP, CH₂Cl₂.

Thirteen racemic cyclopropanealkanol derivatives of type

D–H were synthesized during the ﬁrst part of this study and

are reported in Table 1. Their oxymercuration–reductive

demercuration was then investigated with the aim of

obtaining stereotriads, stereotetrads and stereopentads.

with these results, the addition of ethylmagnesium bromide

to cyclopropanecarboxaldehyde 16 occurred with a low

degree of diastereoselectivity and provided a 60/40 mixture

of the secondary cyclopropanealkanols 17 and 17⁰(52%),

which were separated by ﬂash chromatography. Alterna-

tively, ketone 18 resulting from the oxidation of 17 was

reduced with NaBH₄in MeOH into the secondary

cyclopropylpropanol 17⁰with a higher diastereoselectivity

of 88/12 (Scheme 8).^17,20

3. Oxymercuration of cyclopropanes of type D–F

3.1. Oxymercuration of cyclopropanemethanols 5a–c

When the cyclopropanemethanols 5a–c were subjected to

an oxymercuration with mercuric triﬂuoroacetate (2 equiv)

in CH₂Cl₂, a rapid reaction occurred and after treatment

Finally, one example of secondary cyclopropanealkanol of

Table 1. Structure of cyclopropanealkanols of type D–H

Type of structure

Cyclopropanes

5a RZH

6a RZBn

5c RZH

6c RZBn

D

5b RZH

6b RZBn

6d RZBn

E

12a

12c

F

15

17⁰

24

G

17

H

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Table 2. Oxymercuration of cyclopropanemethanols 5a–c

26a (96%)

25a (60%)

5a

26⁰a (92%)

25⁰a/25⁰⁰aZ80/20 (20%)

26b/26⁰bZ95/5 (80%)

5b

26b (88%)

25c (60%)

5c

26⁰⁰b/26⁰bZ75/25 (70%)

25⁰c/25⁰⁰cZ75/25 (17%)

with an aqueous solution of KBr, the organomercuric

bromides of type I were formed. These compounds have

been characterized in the case of substrates 5a and 5c,

otherwise they were directly subjected to a reductive

demercuration by using n-Bu₃SnH and a catalytic amount

of AIBN in THF,²¹to generate the stereotriads of type J.

The results are shown in Table 2.

crude reaction mixture. After careful puriﬁcation by ﬂash

chromatography, 25a was isolated in 60% yield together with

an inseparable mixture of 25⁰a and 25⁰⁰a (ratio 80/20, 20%

yield). The reductive demercuration of 25a afforded the

symmetrical stereotriad 26⁰a, whereas both compounds 25⁰a

and 25⁰⁰a (80/20 mixture) were converted in a similar fashion

into the same stereotriad 26⁰a (92%) (racemic series).²²

The oxymercuration of 5a led to two major organomercuric

bromides 25a and 25⁰a and a third minor one 25⁰⁰a, which was

barely detected by analysis of the H NMR spectrum of the

The fact that compounds 26a and 26⁰a were reduced by LiAlH₄

to the same known anti,anti-triol 27,²³indicated that they only

differ by the positioning of the pivaloyl ester group and that the

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M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7637

a dioxycarbenium ion intermediate of the type 30a.

Hydrolysis of this intermediate is expected to generate the

corresponding regioisomeric organomercuric bromides 25a

and 25⁰a. In order to explain the formation of the minor

organomeruric bromide 25⁰⁰a, the intermediacy of a bicyclic

orthoester 31a could also be envisaged,²⁴and its subsequent

hydrolysis would generate a mixture of the three regio-

isomeric organomercuric bromides 25a, 25⁰a and 25⁰⁰a.

Apparently, products that would have resulted from an

oxymercuration proceeding with retention of conﬁguration

(hydrolysis products of intermediate 32a) were not observed

(Scheme 11).

Scheme 10. Conﬁgurational assignment of compounds 26a, 26a⁰and 26b.

organomercuric bromides 25a, 25⁰a and 25⁰⁰a all share the

same relative anti,anti relative conﬁguration (Scheme 10).

In the case of cyclopropanemethanol 5b, the oxymercura-

tion led to a regioisomeric mixture of organomercuric

bromides, which was directly subjected to reductive

demercuration. A regioisomeric mixture of two stereotriads

26b and 26⁰b (95/5 ratio) was obtained in 80% overall yield

and in this case the third regioisomeric product 26⁰⁰b was not

detected. The relative conﬁguration of 26b was assigned

unambiguously after reduction with LiAlH₄to the known

syn,anti-triol 28²³(Scheme 10), whereas the relative

conﬁguration of 26⁰b was later conﬁrmed by a chemical

correlation.²²Finally, in the case of cyclopropanemethanol

5c, the oxymercuration led to three organomercuric

bromides 25c, 25⁰c and 25⁰⁰c. The major one was isolated

in 60% yield, whereas an inseparable mixture of 25⁰c and

25⁰⁰c (75/25 ratio) was isolated in 17% yield. The reductive

demercuration of 25c afforded the previously characterized

stereotriad 26b (88%), whereas the mixture of 25⁰c and 25⁰⁰c

(75/25 ratio) was converted to the stereotriads 26⁰⁰b and

26⁰b (75/25 ratio), respectively, (70% combined yield).

From the results of this study, it appeared that the

cyclopropanes 5a–c of type D, with remote oxygenated

functional groups protected as pivalates can undergo highly

diastereoselective oxymercuration, which proceed with

inversion of conﬁguration at the stereocenter bearing the

newly introduced oxygenated moiety (at C3). In sharp

contrast, cyclopropanemethanols 29c and 29d having a

remote oxygenated moiety protected as a 4-methoxy-benzyl

ether, failed to be oxymercurated under the same conditions

despite extended reaction times (Fig. 1).

Scheme 11. Oxymercuration of cyclopropanemethanol 5a.

Although, the possibility of synthesizing stereotriads from

cyclopropanemethanols of type D was demonstrated,

regioisomeric products were obtained from compounds

5a–c. In order to generate stereotriads having the two

primary alcohol functions differentiated, the oxymercura-

tion–reductive demercuration of cyclopropanemethanol

derivatives 6a–d having one hydroxyl group protected as

a benzyl ether and the remote hydroxyl group protected as

an ester (pivalate) was investigated. Indeed, previous

literature results as well as the absence of reactivity of the

cyclopropanemethanols 29c and 29d (Fig. 1) suggested that

benzyl ethers, as protecting groups, should be compatible

with the oxymercuration conditions.^6,8a

Figure 1. Structure of cyclopropanemethanols 29c and 29d.

All these observations clearly demonstrate the fundamental

role exerted by the remote ester functionality during the

mercuration of cyclopropanemethanols 5a–c. As illustrated

in the case of the cyclopropanemethanol 5a, a reasonable

scenario would involve an anchimerically assisted oxymer-

curation by the carbonyl group of the ester moiety,¹⁰

proceeding with inversion of conﬁguration and leading to

3.2. Oxymercuration of the cyclopropane derivatives

6a–d protected as benzyl ethers

Thus, the benzyl-protected cyclopropanemethanols 6a–d

were subjected to a three-step sequence involving oxymer-

curation with mercuric triﬂuoroacetate and subsequent

work-up with a saturated aqueous solution of KBr, reductive

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Table 3. Synthesis of stereotetrads and stereopentads

Substrates Products

demercuration with n-Bu₃SnH and deprotection of the

regioisomeric mixtures of pivalates with LiAlH₄in THF.

Although, LiAlH₄itself could have initiated the reductive

demercuration,²¹cleaner reactions were observed by using

this two-step reduction procedure. Under these conditions,

the known four diastereomeric stereotriads 33a–d were,

respectively, obtained from 6a–d in 38–68% overall yields

and with high diastereoselectivity (drR95/5). Their relative

conﬁgurations were conﬁrmed unambiguously by compari-

son with literature data,²⁵conﬁrming that these anchi-

merically assisted oxymercurations proceed, as anticipated,

with inversion of conﬁguration (Scheme 12).

12a

36a

12c

36c

37

Scheme 12. Reagents and conditions: (a) Hg(OCOCF₃)₂, CH₂Cl₂then satd

aq. KBr; (b) n-Bu₃SnH, cat. AIBN, THF; (c) LiAlH₄, THF, 0 8C to rt.

15

The synthesis of stereotetrads and stereopentads from the

structurally related cycloropanemethanols of type E and F

having primary alcohols protected as benzyl ethers and the

remote oxygenated moieties protected as acetates was also

investigated. The corresponding substrates 12a, 12c and 15

were subjected to the same three-step sequence (oxymer-

curation, reductive demercuration, reduction) and the results

are listed in Table 3.

38

Reagents and conditions: (a) Hg(OCOCF₃)₂, CH₂Cl₂then satd aq. KBr;

(b) n-Bu₃SnH, cat. AIBN, THF/toluene, rt then 60 8C; (c) LiAlH₄, THF;

(d) 2,2-dimethoxypropane, cat. CSA, acetone; (e) PivCl, cat. DMAP, Et₃N,

CH₂Cl₂.

benzyl group enables the differentiation of the two primary

alcohol functionalities.

In the case of 12a, the regioisomeric mixture of acetates 34a

and 34⁰a (65%) was not fully characterized but reduced to

produce the diol 35a as a single diastereomer (80%). The

relative conﬁguration of this diol was determined after

conversion to the acetonide 36a by ¹³C NMR.²⁶In the case

of 12c, the regioisomeric acetates resulting from the

oxymercuration–reductive demercuration sequence, 34c

and 34⁰c (75/25 ratio, 43% combined yield) could be

separated by ﬂash chromatography. Both compounds were

reduced to the same diol 35c, whose relative conﬁguration

was determined after conversion to the acetonide 36c

(91%).²⁶Similarly, cyclopropane 15 afforded the triol 37

(25%) after oxymercuration–reductive demercuration and

subsequent reduction with LiAlH₄. The triol 37²⁷was

converted to 38 (64%) by esteriﬁcation of the primary

alcohol as a pivalate and formation of an acetonide, which

served to conﬁrm the conﬁgurational assignment.²⁶In all

these anchimerically assisted oxymercurations leading to

stereotriads and stereopentads, an inversion of conﬁguration

was always observed at the newly introduced oxygenated

moiety. Therefore, a pathway similar to the one described in

Scheme 11 is likely to operate and the presence of the

The formation of stereotetrads and stereopentads from the

cyclopropanealkanols G and H was next studied.

4. Oxymercuration of the secondary cyclopropane-

alkanols of type G–H

The oxymercuration–reductive demercuration of the two

epimeric cyclopropanealkanols 17 and 17⁰; was ﬁrst

investigated in order to study the inﬂuence of the relative

conﬁguration of the secondary alcohol on the outcome of

the reaction. When 17⁰was subjected to the oxymercura-

tion–reductive demercuration sequence, a complex mixture

of products was formed. In sharp contrast, 17 underwent a

faster and cleaner oxymercuration and after reductive

demercuration two major regioisomeric diols 39 and 39⁰

were formed (73/27 ratio) and, respectively, isolated in 44%

and 18% yields. A third minor component (!2%) whose

structure was tentatively assigned to 39⁰⁰was also isolated.

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7639

The structure of 39 and 39⁰was determined by NMR and the

presence of a 1,3-diol moiety was supported by the fact that

both compounds could be converted to the acetonides 40

and 40⁰. Furthermore, examination of the ¹³C NMR

spectrum of 40 enabled the assignment of its relative

conﬁguration²⁶and conﬁrmed that the oxymercuration had

occurred with inversion of conﬁguration at the stereocenter

bearing the newly introduced oxygenated moiety

(Scheme 13).

Scheme 14. Oxymercuration of secondary cyclopropanealkanols 17 and

17⁰.

cyclopropanealkanol 24 of type H met this stereochemical

requirement, this compound was subjected to the oxymer-

curation–reductive demercuration under the standard con-

ditions. In this case, a regioisomeric mixture of three diols

43, 44 and 45 (45/15/40 ratio) was obtained in an excellent

combined yield (88%). Due to its symmetrical character, the

structure of 45 was readily assigned. Among 43 and 44, only

the latter could be converted to the acetonide 46, thereby

establishing the presence of a 1,3-diol moiety in this

Scheme 13. Reagents and conditions: (a) Hg(OCOCF₃)₂, CH₂Cl₂then satd

aq. KBr; (b) n-Bu₃SnH, cat. AIBN, THF/toluene, rt then 60 8C; (c) 2,2-

dimethoxypropane, cat. CSA, acetone.

Although, the precise reason for the difference of reactivity

between the diastereomeric cyclopropanealkanols 17 and

17⁰has not been fully elucidated, it might be due to the fact

that the reactive conformer K in the oxymercuration of 17⁰

is destabilized by a severe 1,3-interaction (cyclopropylic

strain, similar to A^1,3strain),^28,29thereby slowing down the

intramolecularly assisted oxymercuration. This would alter

the usual regioselectivity of electrophilic ring-opening of

cyclopropanealkanols with mercury salts^5–7and lead to

competing side reactions causing the formation of a

complex mixture of products.

By contrast, such a 1,3-interaction is absent in conformer L

arising from 17 and an anchimerically assisted oxymercura-

tion by the carbonyl group of the ester would lead to a

dioxycarbenium ion intermediate of the type 41. As

previously mentioned, this species could be in equilibrium

with a bicyclic orthoester²⁴42. Upon hydrolysis of the

reaction mixture and subsequent reductive demercuration, a

regioisomeric mixture of diols 39, 39⁰and 39⁰⁰is expected to

be produced (Scheme 14).

Therefore, it appeared that the formation of polypropionate

subunits from secondary cyclopropanealkanols was only

possible for substrates having a hydroxyl group syn to

the adjacent cyclopropane. Since, the secondary

Scheme 15. Reagents and conditions: (a) Hg(OCOCF₃)₂, CH₂Cl₂, rt then

satd aq. KBr; (b) n-Bu₃SnH, cat. AIBN, THF/toluene, rt then 60 8C; (c) 2,2-

dimethoxypropane, cat. CSA, acetone; (d) PivCl, cat. DMAP, Et₃N, Et₂O.

7640

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

compound. Moreover, monoesteriﬁcation of a mixture of 43

and 44 by treatment with PivCl led to a single compound 47

(93%) due to the formation of a diastereomer of similar

relative conﬁguration (racemic series). These results

demonstrated once again that 43, 44 and 45 only differ by

the positioning of one pivalate group and that the

oxymercuration has involved, like in all cases investigated,

an inversion of conﬁguration. Moreover, the further remote

second pivalate moiety in cyclopropylcarbinol 24 has not

interfered in the oxymercuration reaction (Scheme 15).

used as received. TLC was performed on Merck 60F₂₅₄

silica gel plates visualized either with a UV lamp (254 nm),

or by using solutions of p-anisaldehyde/H₂SO₄/AcOH in

EtOH or KMnO₄/K₂CO₃in water followed by heating.

Flash chromatography was performed with SDS 60 silica

gel (230–400 mesh).

6.2. Preparation of cyclopropanes of type D

6.2.1. (2R*)-2-[(1S*,2S*)-2-(Hydroxymethyl)cyclo-

propyl]propyl 2,2-dimethylpropanoate 5a. To a solution

of 3a^10,11(500 mg, 1.36 mmol) in Et₂O (10 mL) at rt, were

successively added Et₃N (265 mL, 1.90 mmol, 1.4 equiv),

DMAP (33 mg, 0.27 mol, 0.2 equiv) and PivCl (236 mL,

1.90 mmol, 1.4 equiv). After 12 h, the reaction was

quenched by addition of a saturated aqueous NaHCO₃

solution and the resulting mixture was extracted with Et₂O.

The combined extracts were washed with a 1 M aqueous

HCl solution, brine, dried over MgSO₄, ﬁltered and

concentrated under reduced pressure. The residual oil was

dissolved in THF (5 mL) and to the resulting solution at

0 8C, was added n-Bu₄NF (2.0 mL, 1 M in THF, 2.0 mmol).

After 3 h at rt, the reaction mixture was hydrolyzed with a

saturated aqueous NH₄Cl solution and extracted with Et₂O.

The combined extracts were dried over MgSO₄, ﬁltered and

concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography (cyclohexane–EtOAc: 90/

10–75/25) to afford 261 mg (90%) of 5a as a colorless oil;

5. Conclusion

We have reported a full account of our studies concerning

the synthesis of polypropionate-type subunits from cyclo-

propanes bearing adjacents stereocenters using an oxymer-

curation–reductive demercuration sequence. The presence

of a suitably located ester protecting group for the hydroxyl

group at the b-position was found to be crucial due to a

favorable anchimeric assistance in the oxymercuration

process. Although, the use of mercury salts restricts the

interest of these reactions to academic research activities,

the results presented in this account should encourage the

search for alternative mediators to effect these transform-

ations, as the cyclopropane could be regarded as a useful

synthetic equivalent of a methyl-hydroxyl array. Moreover,

the stereoelectronic properties of the three-membered ring

can be used to control the conﬁgurations of adjacent

stereocenters as illustrated by stereoselective electrophilic

additions to alkenylcyclopropanes or nucleophilic additions

to cyclopropylcarbonyl derivatives.

1

IR 3450, 1725, 1285, 1165, 1035 cm^K1; H NMR d 4.09

(dd, JZ10.7, 5.9 Hz, 1H), 3.91 (dd, JZ10.7, 6.7 Hz, 1H),

3.49 (dd, JZ11.2, 6.9 Hz, 1H), 3.42 (dd, JZ11.2, 7.1 Hz,

1H), 2.31 (br s, 1H, OH), 1.20 (m, 1H), 1.20 (s, 9H), 1.02 (d,

JZ6.8 Hz, 3H), 0.91 (m, 1H), 0.53–0.41 (m, 3H); ¹³C NMR

d 178.7 (s), 68.8 (t), 66.6 (t), 38.7 (s), 37.6 (d), 27.0 (q, 3C),

21.0 (d), 20.4 (d), 16.4 (q), 8.3 (t); MS-EI m/z (relative

intensity) 197 (MKOH^C, 2), 183 (MKCH₂OH^C, 2), 112

(MKt-BuCO₂H^C, 13), 97 (14), 95 (15), 85 (19), 81 (16), 79

(18), 69 (18), 68 (18), 57 (100), 55 (17).

6. Experimental

6.1. General procedures

Infrared (IR) spectra were recorded on a Perkin–Elmer 298,

wavenumbers are indicated in cm^K1. ¹H NMR spectra were

recorded on a Bruker AC 300 at 300 MHz in CDCl₃(unless

otherwise speciﬁed) and data are reported as follows:

chemical shift in ppm from tetramethylsilane as an internal

standard, multiplicity (sZsinglet, dZdoublet, tZtriplet,

qZquartet, mZmultiplet or overlap of non-equivalent

resonances), integration. ¹³C NMR spectra were recorded

on a Bruker AC 300 at 75 MHz in CDCl₃and data are

reported as follows: chemical shift in ppm from tetra-

methylsilane with the solvent as an internal indicator

(CDCl₃d 77.0 ppm), multiplicity with respect to proton

(deduced from DEPT experiments, sZquaternary C, dZ

CH, tZCH₂, qZCH₃). Mass spectra with electronic impact

(MS-EI) were recorded from a Hewlett-Packard tandem

5890A GC (12 m capillary column)-5971 MS (70 eV). Mass

spectra with chemical ionization (MS-CI^C) or FAB and

high resolution mass spectra (HRMS) were performed by

the Centre de Spectrochimie Organique de l’Ecole Normale

6.2.2.

(2S*)-2-[(1S*,2S*)-2-(Hydroxymethyl)cyclo-

propyl]propyl 2,2-dimethylpropanoate 5b. This com-

pound was synthesized from 3b^10,11(500 mg, 1.36 mmol),

following the procedure described for the preparation of 5a

from 3a. Puriﬁcation by ﬂash chromatography (cyclo-

hexane–EtOAc: 90/10–75/25) afforded 227 mg (78%) of 5b

as a colorless oil; IR 3400, 1720, 1290, 1165, 1030 cm^K1

;

¹H NMR d 4.10 (dd, JZ10.7, 5.9 Hz, 1H), 3.90 (dd, JZ

10.7, 6.7 Hz, 1H), 3.48 (dd, JZ11.2, 6.9 Hz, 1H), 3.42 (dd,

JZ11.2, 7.1 Hz, 1H), 2.30 (br s, 1H, OH), 1.28–1.14 (m,

2H), 1.21 (s, 9H), 1.02 (d, JZ6.8 Hz, 3H), 0.53–0.41 (m,

3H); ¹³C NMR d 178.6 (s), 69.0 (t), 66.8 (t), 38.8 (s), 37.0

(d), 27.2 (q, 3C), 20.8 (d), 19.5 (d), 16.6 (q), 9.3 (t); MS-EI

m/z (relative intensity) 197 (MKOH^C, 7), 183 (MK

CH₂OH^C, 4), 112 (MKt-BuCO₂H^C, 14), 97 (19), 95

(19), 85 (20), 81 (15), 79 (20), 69 (16), 68 (18), 57 (100), 55

(18).

´

Superieure Ulm (Paris). Elemental analyses were performed

6.2.3. (2R*)-2-[(1S*,2R*)-2-(Hydroxymethyl)cyclo-

propyl]propyl 2,2-dimethylpropanoate 5c. This com-

pound was prepared from 3c^10,11(1.28 g, 3.47 mmol)

following the procedure described for the preparation of

5a from 3a. Puriﬁcation by ﬂash chromatography (pentane–

Et₂O: 60/40–50/50) afforded 676 mg (91%) of 5c as a

´

by the Centre Regional de Microanalyses (Universite Pierre

et Marie Curie, Paris VI). THF and diethyl ether were

distilled from sodium/benzophenone. CH₂Cl₂, CH₃CN,

toluene, Et₃N, DMF were distilled from CaH₂. Other

reagents were obtained from commercial suppliers and

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7641

1

colorless oil; IR 3420, 1725, 1290, 1160, 1035 cm^K1; H

NMR d 4.28 (dd, JZ10.8, 4.0 Hz, 1H), 3.78 (dd, JZ10.8,

8.3 Hz, 1H), 3.76 (m, 1H), 3.46 (m, 1H), 2.81 (br s, 1H,

OH), 1.36 (m, 1H), 1.18 (m, 1H), 1.16 (s, 9H), 1.04 (d, JZ

6.7 Hz, 3H), 0.72–0.58 (m, 2H), K0.06 (m, 1H); ¹³C NMR

d 179.1 (s), 69.7 (t), 62.7 (t), 38.8 (s), 32.6 (d), 27.1 (q, 3C),

19.7 (d), 18.8 (d), 17.9 (q), 7.6 (t); MS-EI m/z (relative

intensity) 197 (MKOH^C, 3), 183 (MKCH₂OH^C, 3), 112

(MKt-BuCO₂H^C, 14), 97 (17), 95 (17), 85 (21), 81 (16), 79

(20), 69 (18), 68 (16), 57 (100), 55 (16).

5H), 4.50 (s, 2H), 4.07 (dd, JZ10.8, 5.5 Hz, 1H), 3.95 (dd,

JZ10.8, 6.8 Hz, 1H), 3.45 (dd, JZ10.1, 6.1 Hz, 1H), 3.16

(dd, JZ10.1, 7.5 Hz, 1H), 1.19 (m, 1H), 1.19 (s, 9H), 0.98

(d, JZ6.6 Hz, 3H), 0.98 (m, 1H), 0.54–0.36 (m, 3H); ¹³C

NMR d 178.4 (s), 138.5 (s), 128.3 (d, 2C), 127.5 (d, 2C),

127.4 (d), 73.7 (t), 72.4 (t), 69.1 (t), 38.7 (s), 37.2 (d), 27.2

(q, 3C), 20.5 (d), 17.5 (d), 16.5 (q), 8.9 (t); MS-EI m/z

(relative intensity) 213 (MKCH₂Ph^C, 1), 96 (22), 95 (17),

92 (12), 91 (100), 81 (16), 57 (37). Anal. Calcd for

C₁₉H₂₈O₃: C, 74.96; H, 9.27. Found: C, 74.81; H, 9.37.

6.2.6. (2S*)-2-{(1S*,2S*)-2-[(Benzyloxy)methyl]cyclo-

propyl}propyl 2,2-dimethylpropanoate 6b. This com-

pound was synthesized from 4b (100 mg, 0.44 mmol)

following the procedure described for the preparation of

6a from 4a. Puriﬁcation by ﬂash chromatography (cyclo-

hexane–EtOAc: 95/5) afforded 129 mg (93%) of 6b as a

6.2.4. (2R*)-2-{(1R*,2S*)-2-[(Benzyloxy)methyl]cyclo-

propyl}propan-1-ol 4a and (2S*)-2-{(1R*,2S*)-2-

[(benzyloxy)methyl]cyclopropyl}propan-1-ol 4b.^10,11To

a solution of 2 (340 mg, 1.68 mmol) in THF (5 mL) at

K30 8C, was added BH₃$THF (1.7 mL, 1 M in THF,

1.7 mmol, 1.0 equiv) and the reaction mixture was allowed

to warm to rt for 1 h. After 1 h, a 6 M aqueous solution of

NaOH (5 mL) and a 30% aqueous H₂O₂solution (5 mL)

were successively added dropwise at 0 8C. After 3 h at rt, the

resulting mixture was extracted with Et₂O and the combined

extracts were washed with brine, dried over MgSO₄, ﬁltered

and concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography (cyclohexane–EtOAc:

80/20) to afford 144 mg (39%) of 4a and 92 mg (25%) of 4b

as colorless oils.

1

colorless oil; IR 3060, 1730, 1285, 1165, 1100 cm^K1; H

NMR d 7.35–7.25 (m, 5H), 4.56 (d, JZ12.0 Hz, 1H), 4.49

(d, JZ12.0 Hz, 1H), 4.07 (dd, JZ10.8, 5.5 Hz, 1H), 3.90

(dd, JZ10.8, 6.8 Hz, 1H), 3.38 (dd, JZ10.3, 6.6 Hz, 1H),

3.27 (dd, JZ10.3, 7.0 Hz, 1H), 1.21 (m, 1H), 1.20 (s, 9H),

1.04 (d, JZ6.6 Hz, 3H), 0.93 (m, 1H), 0.52–0.39 (m, 3H);

¹³C NMR d 178.5 (s), 138.6 (s), 128.3 (d, 2C), 127.5 (d, 2C),

127.4 (d), 74.0 (t), 72.4 (t), 69.0 (t), 38.8 (s), 37.3 (d), 27.2

(q, 3C), 20.8 (d), 16.8 (q), 16.7 (d), 9.8 (t); MS-EI m/z

(relative intensity) 304 (M^C, 1), 247 (MKt-Bu^C, 1), 197

(15), 96 (11), 95 (21), 92 (13), 91 (100), 57 (37). Anal. Calcd

for C₁₉H₂₈O₃: C, 74.96; H, 9.27. Found: C, 74.82; H, 9.42.

Compound (4a). R_f0.42 (cyclohexane–EtOAc: 50/50); IR

1

3430, 1095, 1070, 1030 cm^K1; H NMR d 7.38–7.23 (m,

5H), 4.55 (d, JZ12.2 Hz, 1H), 4.47 (d, JZ12.2 Hz, 1H),

3.73 (dd, JZ9.5, 5.3 Hz, 1H), 3.62–3.46 (m, 2H), 3.25 (br s,

1H, OH), 2.86 (dd apparent t, JZ9.5 Hz, 1H), 1.14–0.94 (m,

3H), 0.90 (d, JZ6.4 Hz, 3H), 0.40–0.28 (m, 2H); ¹³C NMR

d 138.1 (s), 128.3 (d, 2C), 127.5 (d), 127.4 (d, 2C), 74.3 (t),

72.7 (t), 69.1 (t), 40.0 (d), 21.7 (d), 18.1 (d), 16.4 (q), 7.1 (t);

MS-EI m/z (relative intensity) 161 (MKCH₃CHCH₂OH^C,

4), 108 (11), 107 (13), 92 (15), 91 (100), 82 (10).

6.2.7. (2R*)-2-{(1R*,2R*)-2-[(Benzyloxy)methyl]cyclo-

propyl}propan-1-ol 4c. To a solution of 8 (5.68 g,

28.1 mmol) in THF (300 mL) at K30 8C, was added

BH₃$THF complex (32 mL, 1 M in THF, 32 mmol,

1.1 equiv) and the reaction mixture was allowed to warm

to rt for 1 h. After 2 h, a 3 M aqueous NaOH solution

(70 mL) and a 30% aqueous H₂O₂solution (70 mL) were

successively added dropwise at 0 8C. After 3 h at rt, the

aqueous phase was extracted with Et₂O, the combined

extracts were washed with brine, dried over MgSO₄, ﬁltered

and concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography (petroleum ether–EtOAc

gradient: 90/10–70/30) to afford 5.04 g (82%) of 4c as a

colorless oil; IR 3420, 3060, 1090, 1070 cm^K1; ¹H NMR d

7.40–7.24 (m, 5H), 4.51 (s, 2H), 3.80 (br s, 1H, OH), 3.80

(dd, JZ10.4, 5.1 Hz, 1H), 3.57 (dd, JZ10.4, 4.5 Hz, 1H),

3.43 (dd apparent t, JZ10.0 Hz, 1H), 3.11 (dd apparent t,

JZ10.0 Hz, 1H), 1.34–1.18 (m, 2H), 0.96 (d, JZ6.8 Hz,

3H), 0.73–0.59 (m, 2H), K0.11 (m, 1H); ¹³C NMR d 137.4

(s), 128.3 (d, 2C), 127.8 (d, 2C), 127.7 (d), 72.9 (t), 70.4 (t),

68.8 (t), 35.1 (d), 21.1 (d), 17.7 (q), 16.2 (d), 6.3 (t); MS-EI

m/z (relative intensity) 143 (MKPh^C, 2), 108 (9), 107 (11),

92 (15), 91 (100), 82 (9), 81 (10), 67 (10), 55 (9). Anal.

Calcd for C₁₄H₂₀O₂: C, 76.33; H, 9.15. Found: C, 76.14; H,

9.37.

Compound (4b). R_f0.22 (cyclohexane–EtOAc: 50/50); IR

3400, 3080, 1090, 1070, 1030 cm^K1; ¹H NMR d 7.40–7.24

(m, 5H), 4.55 (d, JZ12.1 Hz, 1H), 4.50 (d, JZ12.1 Hz,

1H), 3.54 (d, JZ5.9 Hz, 2H), 3.40 (dd, JZ10.0, 6.6 Hz,

1H), 3.24 (dd, JZ10.0, 7.4 Hz, 1H), 2.16 (br s, 1H, OH),

1.24 (m, 1H), 0.93 (m, 1H), 0.92 (d, JZ6.8 Hz, 3H), 0.55–

0.49 (m, 2H), 0.42 (m, 1H); ¹³C NMR d 138.4 (s), 128.3 (d,

2C), 127.5 (d, 2C), 127.4 (d), 74.2 (t), 72.4 (t), 68.3 (t), 38.6

(d), 20.3 (d), 15.4 (q), 15.3 (d), 9.0 (t); MS-EI m/z (relative

intensity) 161 (MKCH₃CHCH₂OH^C, 3), 108 (12), 92 (15),

91 (100), 82 (10).

6.2.5. (2R*)-2-{(1S*,2S*)-2-[(Benzyloxy)methyl]cyclo-

propyl}propyl 2,2-dimethylpropanoate 6a. To a solution

of 4a (460 mg, 2.09 mmol) and DMAP (383 mg,

3.13 mmol, 1.5 equiv) in CH₂Cl₂(10 mL) at rt, was added

PivCl (310 mL, 2.50 mmol, 1.2 equiv). After 2 h, the

reaction was quenched with MeOH (1 mL). After 20 min,

a saturated aqueous NaHCO₃solution was added and the

resulting mixture was extracted with Et₂O. The combined

extracts were dried over MgSO₄, ﬁltered and concentrated

under reduced pressure. The residue was puriﬁed by ﬂash

chromatography (cyclohexane–EtOAc: 95/5) to afford

614 mg (96%) of 6a as a colorless oil; IR 3060, 1725,

6.2.8. (2R*)-2-{(1S*,2R*)-2-[(Benzyloxy)methyl]cyclo-

propyl}propyl 2,2-dimethylpropanoate 6c. This com-

pound was synthesized from 4c (140 mg, 0.636 mmol)

following the procedure described for the preparation of 6a

from 4a. Puriﬁcation by ﬂash chromatography (cyclo-

hexane–EtOAc: 95/5) afforded 172 mg (90%) of 6c as a

colorless oil; IR 3060, 1725, 1285, 1165 cm^K1; ¹H NMR d

1

1480, 1290, 1160, 1095 cm^K1; H NMR d 7.36–7.23 (m,

7642

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7.26–7.15 (m, 5H), 4.47 (d, JZ11.8 Hz, 1H), 4.42 (d, JZ

11.8 Hz, 1H), 4.17 (dd, JZ10.6, 4.1 Hz, 1H), 3.82 (dd, JZ

10.6, 8.1 Hz, 1H), 3.45 (dd, JZ10.1, 6.9 Hz, 1H), 3.39 (dd,

JZ10.1, 7.9 Hz, 1H), 1.31 (m, 1H), 1.17 (s, 9H), 1.13 (m,

1H), 0.97 (d, JZ6.7 Hz, 3H), 0.77–0.64 (m, 2H), K0.04 (m,

1H); ¹³C NMR d 178.4 (s), 138.4 (s), 128.3 (d, 2C), 127.8 (d,

2C), 127.5 (d), 72.8 (t), 70.5 (t), 69.1 (t), 38.8 (s), 32.8 (d),

27.2 (q, 3C), 19.7 (d), 17.6 (q), 16.1 (d), 8.3 (t); MS-EI m/z

(relative intensity) 219 (MKt-BuCO^C, 1), 213 (MK

CH₂Ph^C, 1), 96 (25), 95 (16), 92 (12), 91 (100), 81 (19),

57 (40). Anal. Calcd for C₁₉H₂₈O₃: C, 74.96; H, 9.27.

Found: C, 74.81; H, 9.39.

oil; IR 3380, 3060, 1090, 1070, 1020, 750, 740, 700 cm^K1

;

¹H NMR d 7.37–7.27 (m, 5H), 4.57 (d, JZ11.9 Hz, 1H),

4.51 (d, JZ11.9 Hz, 1H), 3.64 (dd, JZ10.7, 5.7 Hz, 1H),

3.53 (dd, JZ10.3, 6.6 Hz, 1H), 3.52 (dd, JZ10.7, 6.2 Hz,

1H), 3.44 (dd, JZ10.3, 8.0 Hz, 1H), 1.77 (br s, 1H, OH),

1.27–1.14 (m, 2H), 1.08 (d, JZ6.3 Hz, 3H), 0.81–0.62 (m,

2H), 0.13 (m, 1H); ¹³C NMR d 138.4 (s), 128.3 (d, 2C),

127.7 (d, 2C), 127.5 (d), 72.8 (t), 70.3 (t), 68.9 (t), 35.9 (d),

19.7 (d), 17.3 (q), 14.0 (d), 8.5 (t); MS (CI^C, CH₄) m/z

(relative intensity) 221 (MCH^C, 17), 123 (37), 113 (51), 95

(100), 91 (100). Anal. Calcd for C₁₄H₂₀O₂: C, 76.33; H,

9.15. Found: C, 76.03; H, 9.46.

6.2.11. (2S*)-2-{(1S*,2R*)-2-[(Benzyloxy)methyl]cyclo-

propyl}propyl 2,2-dimethylpropanoate 6d. This com-

pound was synthesized from 4d (50 mg, 0.23 mmol)

following the procedure described for the preparation of

6c from 4c. Puriﬁcation by ﬂash chromatography

(petroleum ether–EtOAc: 95/5) gave 59 mg (87%) of 6d

6.2.9. 2-{(1S*,2R*)-2-[(Benzyloxy)methyl]cyclopropyl)}

prop-2-en-1-ol 9. To a solution of SeO₂(28 mg,

0.25 mmol, 0.5 equiv) in CH₂Cl₂(10 mL) at 0 8C, was

added t-BuOOH (370 mL, ca. 5.5 M in decane, 2.04 mmol,

4.0 equiv). After 30 min, a solution of 8 (103 mg,

0.509 mmol) in CH₂Cl₂(5 mL) was added dropwise and

the reaction mixture was allowed to warm to rt. After 7 h,

the reaction mixture was hydrolyzed with a 1 M aqueous

NaOH solution and extracted with CH₂Cl₂. The combined

extracts were washed with brine, dried over MgSO₄, ﬁltered

and concentrated under reduced pressure. The residue was

dissolved in MeOH (5 mL) and to the resulting solution at

0 8C, were successively added CeCl₃$7H₂O (190 mg,

0.509 mmol, 1.0 equiv) and NaBH₄(38 mg, 1.0 mmol,

2.0 equiv). After 20 min, the reaction mixture was poured

into a saturated aqueous NH₄Cl solution and extracted with

Et₂O. The combined extracts were washed with brine, dried

over MgSO₄, ﬁltered and concentrated under reduced

pressure. The residue was puriﬁed by ﬂash chromatography

(petroleum ether–EtOAc: 80/20–70/30) to afford 93 mg

(84%) of 9 as a colorless oil; IR 3400, 3060, 1645, 1060,

as a colorless oil; IR 3070, 1730, 1290, 1165, 1090 cm^K1

;

¹H NMR d 7.35–7.25 (m, 5H), 4.56 (d, JZ12.0 Hz, 1H),

4.49 (d, JZ12.0 Hz, 1H), 4.09 (dd, JZ10.7, 5.5 Hz, 1H),

3.91 (dd, JZ10.7, 7.0 Hz, 1H), 3.54 (dd, JZ10.3, 6.3 Hz,

1H), 3.40 (dd, JZ10.3, 8.1 Hz, 1H), 1.42–1.14 (m, 2H),

1.20 (s, 9H), 1.09 (d, JZ6.6 Hz, 3H), 0.78–0.64 (m, 2H),

0.10 (m, 1H); ¹³C NMR d 178.5 (s), 138.4 (s), 128.3 (d, 2C),

127.6 (d, 2C), 127.5 (d), 72.8 (t), 70.2 (t), 69.6 (t), 38.7 (s),

33.1 (d), 27.2 (q, 3C), 19.8 (d), 17.6 (q), 14.6 (d), 8.7 (t);

MS-EI m/z (relative intensity) 304 (M^C, 1), 247 (MKt-

Bu^C, 1), 197 (20), 95 (23), 92 (13), 91 (100), 57 (38). Anal.

Calcd for C₁₉H₂₈O₃: C, 74.96; H, 9.27. Found: C, 74.79; H,

9.39.

6.3. Preparation of cyclopropanemethanols of type E

1

1030, 905, 740, 700 cm^K1; H NMR d 7.30–7.16 (m, 5H),

4.93 (br s, 1H), 4.56 (br s, 1H), 4.41 (d, JZ11.9 Hz, 1H),

4.34 (d, JZ11.9 Hz, 1H), 4.10 (br s, 2H), 3.60 (dd, JZ10.0,

4.5 Hz, 1H), 3.50 (br s, 1H, OH), 2.89 (dd, apparent t, JZ

10.0 Hz, 1H), 1.54 (m, 1H), 1.40 (m, 1H), 0.71 (m, 1H), 0.45

(m, 1H); ¹³C NMR d 145.6 (s), 137.3 (s), 128.3 (d, 2C),

127.9 (d, 2C), 127.7 (d), 110.7 (t), 72.9 (t), 68.6 (t), 67.5 (t),

18.9 (d), 17.4 (d), 5.1 (t); MS (CI^C, CH₄) m/z (relative

intensity) 219 (MCH^C, 50), 201 (15), 183 (45), 171 (16),

129 (17), 111 (40), 93 (82), 91 (100); HRMS (CI^C, CH₄)

Calcd for C₁₄H₁₉O₂(MCH^C): 219.1385. Found: 219.1381.

6.3.1. (2R*,3S*)-2-{(1S*,2S*)-2-[(Benzyloxy)methyl]-

cyclopropyl}pentan-3-ol 11a and (2R*,3R*)-2-{(1S*,

2S₀*)-2-[(benzyloxy)methyl]cyclopropyl}pentan-3-ol

11 a. To a solution of 4a (1.00 g, 4.55 mmol) in CH₂Cl₂–

MeCN (9/1, 10 mL) at 0 8C, were successively added NMO

˚

(799 mg, 6.82 mmol, 1.5 equiv), 4 A powdered molecular

sieves (2.3 g) and TPAP (102 mg, 0.290 mmol, 0.06 equiv).

After 3 h at rt the reaction mixture was concentrated under

reduced pressure and the residue was ﬁltered through silica

gel (CH₂Cl₂–EtOAc: 50/50). The ﬁltrate was evaporated

under reduced pressure and the crude aldehyde 10a was

dissolved in Et₂O (1 mL). The resulting solution was added

to a solution of EtMgBr (3.0 mL, 3 M in Et₂O, 9.0 mmol,

2.0 equiv) in Et₂O (10 mL) at K50 8C. After 1 h at K50 8C,

the reaction mixture was warmed to rt, poured into a

saturated aqueous NH₄Cl solution and extracted with Et₂O.

The combined extracts were dried over MgSO₄, ﬁltered and

concentrated under reduced pressure. The crude material

6.2.10. (2S*)-2-{(1R*,2R*)-2-[(Benzyloxy)methyl]cyclo-

propyl}propan-1-ol 4d. A solution of AcOH (7.5 g,

0.12 mol) in EtOH (20 mL) was added over 8 h, via a

syringe pump, to a solution of 9 (86 mg, 0.39 mmol) and

potassium azodicarboxylate (2!24 g added at 4 h intervall,

0.24 mol) in EtOH (60 mL) at 45 8C. After a further 1 h at

40 8C, the reaction mixture was cooled to rt and ﬁltered

through Celite. The ﬁltrate was evaporated under reduced

pressure and the solid residue was triturated in Et₂O

(300 mL). The resulting mixture was stirred overnight at

rt, ﬁltered through Celite and the insoluble material was

thoroughly washed with Et₂O. The ﬁltrate was evaporated

under reduced pressure and the crude material was analyzed

by ¹H NMR and GC–MS, which indicated the formation of

a diastereomeric mixture of 4c and 4d (8/92 ratio).

Puriﬁcation by ﬂash chromatography (cyclohexane–

EtOAc: 75/25) afforded 64 mg (74%) of 4d as a colorless

1

was analyzed by H NMR and GC–MS, which indicated a

77/23 ratio of the two diastereomers 11a and 11⁰a. After

puriﬁcation by ﬂash chromatography (petroleum ether–

EtOAc gradient: 95/5–80/20), 92 mg (8%) of 11⁰a (minor

diastereomer) and 358 mg (32%) of 11a (major dia-

stereomer) were obtained as colorless oils.

Compound (11⁰a). IR 3430, 1065, 1025, 965, 735, 700 cm^K1

;

¹H NMR d 7.42–7.27 (m, 5H), 4.60 (d, JZ12.5 Hz, 1H),

4.53 (d, JZ12.5 Hz, 1H), 3.78 (dd, JZ9.4, 5.1 Hz, 1H),

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7643

3.53 (br s, 1H, OH), 3.46 (td, JZ8.1, 2.9 Hz, 1H), 2.83 (dd,

apparent t, JZ9.4 Hz, 1H), 1.71 (m, 1H), 1.42 (m, 1H), 1.17

(m, 1H), 1.01 (t, JZ7.4 Hz, 3H), 0.96 (d, JZ6.6 Hz, 3H),

0.80 (m, 1H), 0.49–0.28 (m, 3H); ¹³C NMR d 138.2 (s),

128.3 (d, 2C), 127.5 (d, 3C), 78.5 (d), 74.2 (t), 72.7 (t), 43.4

(d), 26.7 (t), 22.1 (d), 19.4 (d), 16.7 (q), 9.8 (q), 7.2 (t); MS-

EI m/z (relative intensity) 189 (MKEtCHOH^C, 0.5), 108

(19), 92 (12), 91 (100), 82 (25), 67 (18).

76.9 (d), 72.9 (t), 70.5 (t), 38.1 (d), 26.0 (t), 18.6 (d), 16.6

(d), 16.4 (q), 11.1 (q), 7.2 (t); MS-EI m/z (relative intensity)

219 (MKC₂H^C₅, 0.3), 108 (19), 92 (13), 91 (100), 82 (26),

81 (11), 67 (19).

6.3.4. (1R*,2R*)-2-{(1S*,2R*)-[(Benzyloxy)methyl]-

cyclopropyl}-1-ethylpropyl acetate 12c. This compound

was synthesized from 11c (116 mg, 0.468 mmol) following

the procedure described for the preparation of 12a from 11a.

Puriﬁcation by ﬂash chromatography (petroleum ether–

EtOAc: 90/10) afforded 121 mg (89%) of 12c as a colorless

oil; IR 3050, 1735, 1240, 1090, 1075, 1025, 1015, 955, 740,

Compound (11a). IR 3420, 3060, 1090, 1060, 1025, 970,

950, 735, 700 cm^K1; ¹H NMR d 7.34–7.22 (m, 5H), 4.53 (d,

JZ12.1 Hz, 1H), 4.46 (d, JZ12.1 Hz, 1H), 3.55 (dd, JZ

9.9, 5.9 Hz, 1H), 3.45 (m, 1H), 3.03 (dd, JZ9.9, 8.5 Hz,

1H), 2.63 (br s, 1H, OH), 1.59–1.37 (m, 2H), 1.06–0.81 (m,

2H), 0.94 (t, JZ7.4 Hz, 3H), 0.93 (d, JZ5.5 Hz, 3H), 0.56

(m, 1H), 0.44–0.31 (m, 2H); ¹³C NMR d 138.2 (s), 128.2 (d,

2C), 127.4 (d), 127.3 (d, 2C), 76.7 (d), 74.2 (t), 72.5 (t), 42.4

(d), 26.3 (t), 20.7 (d), 17.8 (d), 14.2 (q), 10.6 (q), 8.9 (t); MS

(CI^C, CH₄) m/z (relative intensity) 249 (MCH^C, 40), 141

(57), 123 (100), 107 (22), 91 (100), 83 (33); HRMS (CI^C,

CH₄) Calcd for C₁₆H₂₅O₂(MCH^C): 249.1855. Found:

249.1854.

700 cm^K^{1 1}H NMR d 7.40–7.27 (m, 5H), 4.91 (ddd,

;

apparent td, JZ6.9, 3.8 Hz, 1H), 4.57 (d, JZ12.0 Hz, 1H),

4.52 (d, JZ12.0 Hz, 1H), 3.65 (dd, JZ10.1, 6.6 Hz, 1H),

3.33 (dd, JZ10.1, 8.1 Hz, 1H), 2.05 (s, 3H), 1.62–1.52 (m,

2H), 1.28–1.16 (m, 2H), 1.01 (d, JZ6.6 Hz, 3H), 0.83 (t,

JZ7.5 Hz, 3H), 0.85–0.74 (m, 2H), 0.05 (m, 1H); ¹³C NMR

d 170.9 (s), 138.5 (s), 128.3 (d, 2C), 127.7 (d, 2C), 127.5 (d),

78.9 (d), 72.7 (t), 70.7 (t), 35.8 (d), 24.8 (t), 21.1 (q), 20.1

(d), 16.5 (d), 15.1 (q), 10.3 (q), 8.9 (t); MS-EI m/z (relative

intensity) 261 (MKC₂H^C₅, 0.1), 230 (MKCH₃CO₂H^C,

0.5), 124 (11), 95 (13), 92 (11), 91 (100), 81 (12).

6.3.2. (1R*,2R*)-2-{(1S*,2S*)-2-[(Benzyloxy)methyl]-

cyclopropyl}-1-ethylpropyl acetate 12a. To a solution of

11a (224 mg, 0.902 mmol) and DMAP (57 mg, 0.47 mmol,

0.5 equiv) in Et₂O (5 mL) at rt, was added Ac₂O (200 mL,

2.13 mmol, 2.4 equiv). After 12 h at rt, the reaction was

quenched by addition of MeOH (2 mL) at 0 8C and the

reaction mixture was hydrolyzed with a saturated aqueous

NaHCO₃solution. The aqueous layer was extracted with

Et₂O and the combined extracts were dried over MgSO₄,

ﬁltered and concentrated under reduced pressure. The

residue was puriﬁed by ﬂash chromatography (petroleum

ether–EtOAc: 90/10) to afford 240 mg (92%) of 12a as a

colorless oil; IR 3060, 1730, 1240, 1095, 1070, 1020, 955,

6.3.5. (3S*,4R*)-4-{(1S*,2R*)-2-[(Benzyloxy)methyl]-

cyclopropyl}-2-methylpent-1-en-3-ol 13. To a solution of

4c (970 mg, 4.41 mmol) in CH₂Cl₂/MeCN (9/1, 10 mL) at

0 8C, were successively added NMO (825 mg, 7.04 mmol,

˚

1.5 equiv), 4 A powdered molecular sieves (2.3 g) and

TPAP (93 mg, 0.26 mmol, 0.06 equiv). After 3 h at rt the

reaction mixture was concentrated under reduced pressure

and the residue was ﬁltered through silica gel (CH₂Cl₂–

EtOAc: 50/50). The ﬁltrate was evaporated under reduced

pressure and the crude aldehyde 10c was dissolved in THF

(2 mL). The resulting solution was added to a solution of

isopropenylmagnesium bromide (18 mL, 0.5 M in THF,

9.0 mmol, 2.0 equiv) in THF (10 mL) at K30 8C. After 1 h

at K30 8C, the reaction mixture was poured into a saturated

aqueous NH₄Cl solution and extracted with Et₂O. The

combined extracts were dried over MgSO₄, ﬁltered and

concentrated under reduced pressure. The crude material

was analyzed by ¹H NMR which indicated a 85/15 ratio of

the two diastereomers 13 and 13⁰. Puriﬁcation by ﬂash

chromatography (petroleum ether–EtOAc: 90/10–80/20)

afforded 490 mg (43%) of 13 as a pale yellow oil; IR

3420, 3060, 1645, 1115, 1085, 1070, 1025, 900, 750, 735,

1

735, 700 cm^K1; H NMR d 7.40–7.21 (m, 5H), 4.86 (ddd

apparent dt, JZ8.5, 4.8 Hz, 1H), 4.50 (s, 2H), 3.46 (dd, JZ

10.0, 6.0 Hz, 1H), 3.16 (dd, JZ10.0, 7.4 Hz, 1H), 2.02 (s,

3H), 1.81–1.54 (m, 2H), 1.13–0.92 (m, 2H), 0.93 (d, JZ

6.6 Hz, 3H), 0.86 (t, JZ7.4 Hz, 3H), 0.52–0.39 (m, 2H),

0.35 (m, 1H); ¹³C NMR d 170.6 (s), 138.5 (s), 128.1 (d, 2C),

127.3 (d, 2C), 127.2 (d), 78.9 (d), 73.7 (t), 72.3 (t), 40.5 (d),

24.3 (t), 20.8 (q), 20.3 (d), 18.2 (d), 14.7 (q), 9.9 (q), 8.9 (t);

MS (CI^C, CH₄) m/z (relative intensity) 291 (MCH^C, 27),

183 (100), 123 (82), 91 (41); HRMS (CI^C, CH₄) Calcd for

C₁₈H₂₇O₃(MCH^C): 291.1960. Found: 291.1959.

1

700 cm^K1; H NMR d 7.36–7.27 (m, 5H), 4.95 (br s, 1H),

4.90 (q, JZ1.5 Hz, 1H), 4.57 (d, JZ11.9 Hz, 1H), 4.51 (d,

JZ11.9 Hz, 1H), 4.21 (m, 1H), 3.71 (dd, JZ9.9, 5.5 Hz,

1H), 3.32 (dd, apparent t, JZ9.9 Hz, 1H), 2.79 (d, JZ

6.3 Hz, 1H, OH), 1.69 (br s, 3H), 1.42–1.20 (m, 2H), 0.95

(m, 1H), 0.95 (d, JZ7.0 Hz, 3H), 0.78 (m, 1H), K0.04 (m,

1H); ¹³C NMR d 146.4 (s), 138.0 (s), 128.4 (d, 2C), 127.8 (d,

2C), 127.7 (d), 110.2 (t), 77.9 (d), 72.9 (t), 70.6 (t), 36.8 (d),

19.9 (q), 19.8 (d), 16.6 (d), 14.8 (q), 8.1 (t); MS (CI^C, CH₄)

m/z (relative intensity) 261 (MCH^C, 60), 243 (30), 161

(61), 153 (70), 135 (65), 107 (42), 91 (100), 71 (42); HRMS

(CI^C, CH₄) Calcd for C₁₇H₂₅O₂(MCH^C): 261.1855.

Found: 261.1853.

6.3.3. (2R*,3R*)-2-{(1S*,2R*)-2-[(Benzyloxy)methyl]

cyclopropyl}pentan-3-ol 11c. Following the procedure

described for the preparation of 11a from 6a, compound

6c (489 mg, 2.2 mmol) was converted to a 85/15 dia-

stereomeric mixture of alcohols 11c and 11⁰c. Puriﬁcation

by ﬂash chromatography (petroleum ether–EtOAc gradient:

90/10–80/20) afforded 279 mg (51%) of 11c as a colorless

oil; IR 3420, 1090, 1070, 1025, 975, 950, 750, 735,

1

700 cm^K1; H NMR d 7.38–7.27 (m, 5H), 4.56 (d, JZ

12.1 Hz, 1H), 4.50 (d, JZ12.1 Hz, 1H), 3.72 (dd, JZ10.0,

5.3 Hz, 1H), 3.50 (m, 1H), 3.22 (dd, apparent t, JZ10.0 Hz,

1H), 3.07 (br d, JZ6.6 Hz, 1H, OH), 1.56–1.38 (m, 2H),

1.37–1.18 (m, 2H), 1.00 (t, JZ7.4 Hz, 3H), 0.99 (d, JZ

7.0 Hz, 3H), 0.86 (m, 1H), 0.73 (m, 1H), K0.11 (m, 1H);

¹³C NMR d 137.8 (s), 128.4 (d, 2C), 127.9 (d, 2C), 127.7 (d),

6.3.6. (2R*,3S*,4R*)-4-{(1S*,2R*)-2-[(Benzyloxy)-

methyl]cyclopropyl}-2-methylpentane-1,3-diol 14. To a

solution of 9-BBN-H (5 mL, 0.5 M in THF, 2.5 mmol,

7644

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

2.7 equiv) at K30 8C, was added a solution of 13 (242 mg,

0.929 mmol) in THF (2 mL). The reaction mixture was

warmed to rt and after 2 h, a 3 M aqueous NaOH solution

(2.2 mL) and a 30% aqueous H₂O₂solution (2.2 mL) were

successively added at 0 8C. After 2 h at rt, the resulting

mixture was diluted with water and extracted with EtOAc.

The combined extracts were dried over MgSO₄, ﬁltered and

concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography (petroleum ether–EtOAc

gradient: 70/30–40/60) to afford 251 mg (97%) of 14 as a

colorless oil and a 9/1 mixture of diastereomers; IR 3370,

3060, 1370, 1110, 1085, 1070, 1025, 1010, 980, 750, 740,

700 cm^K1; Only the major diastereomer could be accurately

described; ¹H NMR d 7.36–7.27 (m, 5H), 4.53 (d, JZ

11.8 Hz, 1H), 4.48 (d, JZ11.8 Hz, 1H), 3.72–3.48 (m, 5H),

3.29 (dd, apparent t, JZ9.4 Hz, 1H), 1.87–1.15 (m, 4H),

1.00 (d, JZ7.0 Hz, 3H), 1.06–0.95 (m, 1H), 0.80 (m, 1H),

0.70 (d, JZ6.8 Hz, 3H), K0.02 (m, 1H); ¹³C NMR d 138.0

(s), 128.4 (d, 2C), 127.8 (d, 2C), 127.7 (d), 79.8 (d), 72.9 (t),

70.6 (t), 68.7 (t), 37.3 (d), 35.6 (d), 20.0 (d), 16.3 (d), 13.6

(q), 13.0 (q), 8.4 (t); MS-EI m/z (relative intensity) 219

(MKHOCH₂CH(CH₃)^C, 2), 108 (23), 107 (11), 92 (12), 91

(100), 82 (26), 81 (11), 67 (19).

ﬁltered through silica gel (Et₂O). The ﬁltrate was

evaporated under reduced pressure to give 630 mg (94%)

of the crude aldehyde 16 as a pale yellow oil, which was

dissolved in THF (10 mL). To the resulting solution at 0 8C,

was added EtMgBr (1.5 mL, 3 M in Et₂O, 4.5 mmol,

1.5 equiv), and after 30 min, the reaction mixture was

poured into a saturated aqueous NH₄Cl solution and

extracted with Et₂O. The combined extracts were dried

over MgSO₄, ﬁltered and concentrated under reduced

1

pressure. The crude material was analyzed by H NMR

which indicated a 60/40 ratio of the two diastereomers 17

and 17⁰. Puriﬁcation by ﬂash chromatography (pentane–

Et₂O gradient: 80/20–50/50) afforded 130 mg (18%) of 17⁰

and 240 mg (34%) of 17 as colorless oils.

Compound (17⁰). R_f0.32 (pentane–Et₂O: 70/30); IR 3480,

1

3060, 1730, 1290, 1165, 1035, 990, 970, 775 cm^K1; H

NMR d 4.45 (dd, JZ11.0, 4.0 Hz, 1H), 3.90 (dd, JZ11.0,

8.3 Hz, 1H), 3.22 (br s, 1H, OH), 3.12 (m, 1H), 1.71–1.60

(m, 2H), 1.45 (m, 1H), 1.28–1.19 (m, 1H), 1.21 (s, 9H), 1.08

(d, JZ6.6 Hz, 3H), 1.00 (t, JZ7.4 Hz, 3H), 0.73 (m, 1H),

0.58 (m, 1H), K0.06 (m, 1H); ¹³C NMR d 179.1 (s), 73.6

(d), 70.0 (t), 38.8 (s), 32.6 (d), 30.7 (t), 27.1 (q, 3C), 23.4 (d),

19.2 (d), 18.1 (q), 10.2 (q), 7.9 (t); MS-EI m/z (relative

intensity) 225 (MKOH^C, 1), 213 (MKC₂H₅^C, 5), 140 (MK

t-BuCO₂H^C, 8), 111 (43), 103 (11), 93 (28), 85 (30), 82

(14), 81 (18), 69 (29), 67 (15), 57 (100), 55 (18).

6.3.7. (2R*,3S*,4R*)-3-Acetoxy-4-{(1S*,2R*)-2-[(benzyl-

oxy)methyl]cyclopropyl}-2-methylpentyl acetate 15. To a

solution of 14 (240 mg, 0.863 mmol) in Et₂O (10 mL) at

0 8C, were successively added DMAP (101 mg,

0.827 mmol, 1.0 equiv) and Ac₂O (400 mL, 4.26 mmol,

5.0 equiv). After 2 h at rt, the reaction was quenched by

dropwise addition of MeOH (4 mL) at 0 8C and the resulting

mixture was hydrolyzed with a saturated aqueous NaHCO₃

solution. The aqueous layer was extracted with EtOAc and

the combined extracts were dried over MgSO₄, ﬁltered and

concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography (petroleum ether–EtOAc:

80/20) to afford 255 mg (82%) of 15 as a colorless oil; IR

Compound (17). R_f0.18 (pentane–Et₂O: 70/30); IR 3450,

3070, 1730, 1290, 1165, 1035, 990, 965, 855, 775 cm^K1; ¹H

NMR d 4.18 (dd, JZ10.7, 3.7 Hz, 1H), 3.79 (dd, JZ10.7,

8.5 Hz, 1H), 3.35 (ddd apparent td, JZ7.8, 3.7 Hz, 1H),

2.00 (br s, 1H, OH), 1.73 (m, 1H), 1.67–1.46 (m, 2H), 1.21

(s, 9H), 1.01–0.93 (m, 1H), 1.07 (d, JZ6.6 Hz, 3H), 1.03 (t,

JZ7.4 Hz, 3H), 0.76–0.67 (m, 2H), 0.21 (m, 1H); ¹³C NMR

d 178.6 (s), 72.3 (d), 69.0 (t), 38.8 (s), 32.8 (d), 31.3 (t), 27.2

(q, 3C), 23.4 (d), 20.4 (d), 18.0 (q), 10.0 (q), 7.1 (t); MS-EI

m/z (relative intensity) 225 (MKOH^C, 1), 213 (MKC₂H₅^C,

5), 140 (MKt-BuCO₂H^C, 7), (111 (41), 103 (12), 93 (28),

85 (29), 81 (18), 69 (29), 67 (15), 57 (100), 55 (18).

1

1740, 1235, 1070, 1020, 735, 700 cm^K1; H NMR d 7.43–

7.25 (m, 5H), 5.09 (dd, JZ9.6, 2.6 Hz, 1H), 4.61 (d, JZ

12.0 Hz, 1H), 4.55 (d, JZ12.0 Hz, 1H), 3.97 (dd, JZ11.0,

4.0 Hz, 1H), 3.91 (dd, JZ11.0, 6.3 Hz, 1H), 3.64 (dd, JZ

10.3, 7.4 Hz, 1H), 3.50 (dd, JZ10.3, 7.0 Hz, 1H), 2.09 (s,

3H), 2.05 (m, 1H), 2.00 (s, 3H), 1.39 (m, 1H), 1.24 (m, 1H),

1.03 (d, JZ6.6 Hz, 3H), 0.89 (d, JZ7.0 Hz, 3H), 0.84–0.68

(m, 2H), 0.10 (m, 1H); ¹³C NMR d 170.8 (s), 170.2 (s),

138.4 (s), 128.1 (d, 2C), 127.4 (d, 2C), 127.2 (d), 77.0 (d),

72.3 (t), 70.2 (t), 66.0 (t), 34.4 (d), 34.1 (d), 20.7 (q), 20.6

(q), 20.3 (d), 16.1 (d), 13.9 (q), 13.3 (q), 9.0 (t); MS (CI^C,

CH₄) m/z (relative intensity) 363 (MCH^C, 10), 255 (100),

195 (50), 153 (28), 135 (70), 107 (14), 91 (24); HRMS

(CI^C, CH₄) Calcd for C₂₁H₃₁O₆(MCH^C): 363.2171.

Found: 363.2167.

6.4.2. Epimerization of 17 to 17⁰by an oxidation-

stereoselective reduction sequence. To a solution of 17

(50 mg, 0.21 mmol) in CH₂Cl₂(5 mL) at rt, were added

˚

powdered 4 A molecular sieves (200 mg) and PCC (90 mg,

0.42 mmol, 2 equiv). After 2 h, the reaction mixture was

diluted with Et₂O (50 mL) and ﬁltered through silica gel

(Et₂O). The ﬁltrate was evaporated and the crude

cyclopropylketone 18 was dissolved in MeOH (4 mL). To

the resulting solution at 0 8C, was added portionwise NaBH₄

(40 mg, 1.0 mmol, 5 equiv). After 1 h at rt, the reaction

mixture was hydrolyzed with a saturated aqueous NH₄Cl

solution and extracted with Et₂O. The combined extracts

were dried over MgSO₄, ﬁltered and concentrated under

6.4. Preparation of cyclopropanealkanols of type G and H

1

reduced pressure. The crude material was analyzed by H

NMR and GC–MS which indicated a 12/88 ratio of the two

diastereomers 17 and 17⁰. Puriﬁcation by ﬂash chromato-

graphy (petroleum ether–EtOAc: 90/10, 80/20) afforded

36 mg (72%) of 17⁰as a colorless oil.

6.4.1. (2R*)-2-[(1R*,2R*)-2-((1R*)-1-Hydroxypropyl)-

cyclopropyl]propyl 2,2-dimethylpropanoate 17 and

(2R*)-2-[(1R*,2R*)-2-((1S*)-1-hydroxypropyl)cyclo-

propyl]propyl 2,2-dimethylpropanoate 17⁰. To a solution

of 5c (670 mg, 3.12 mmol) in CH₂Cl₂(30 mL) at rt, were

successively added powdered 4 A molecular sieves (2.7 g)

and PCC (1.35 g, 6.25 mmol, 2 equiv). After 1 h, the

reaction mixture was diluted with Et₂O (200 mL) and

˚

6.4.3. ((2R*)-2-{(1S*,2R*)-2-[(Benzyloxy)methyl]cyclo-

propyl})propoxy-tert-butyldiphenylsilane 19. To a

solution of 4c (1.87 g, 8.50 mmol) and imidazole (1.41 g,

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7645

20.7 mmol, 2.4 equiv) in DMF (8 mL) was added TBDPSCl

(2.70 mL, 10.4 mmol, 1.2 equiv). After 1 h at rt, the reaction

mixture was hydrolyzed with a saturated aqueous NH₄Cl

solution and extracted with a petroleum ether–CH₂Cl₂(90/

10) mixture. The combined extracts were washed with

brine, dried over MgSO₄, ﬁltered and concentrated under

reduced pressure. The residue was puriﬁed by ﬂash

chromatography (petroleum ether–EtOAc: 95/5) to afford

3.47 g (89%) of 19 as a colorless oil; IR 3060, 1590, 1110,

1080, 820, 740, 710, 700, 690, 610 cm^K1; ¹H NMR d 7.75–

7.69 (m, 4H), 7.48–7.35 (m, 6H), 7.34–7.25 (m, 5H), 4.43

(d, JZ12.1 Hz, 1H), 4.38 (d, JZ12.1 Hz, 1H), 3.79 (dd, JZ

9.7, 4.2 Hz, 1H), 3.57 (dd, JZ9.7, 7.2 Hz, 1H), 3.43 (dd,

JZ10.3, 7.0 Hz, 1H), 3.31 (dd, JZ10.3, 7.5 Hz, 1H), 1.28

(m, 1H), 1.17 (d, JZ6.3 Hz, 3H), 1.11 (m, 1H), 1.10 (s, 9H),

0.82–0.69 (m, 2H), 0.05 (m, 1H); ¹³C NMR d 138.6 (s),

135.6 (d, 4C), 134.2 (s), 134.0 (s), 129.5 (d, 2C), 128.3 (d,

2C), 127.6 (d, 2C), 127.5 (d, 4C), 127.3 (d), 72.6 (t), 70.7 (t),

68.8 (t), 36.1 (d), 26.9 (q, 3C), 19.7 (d), 19.3 (s), 17.8 (q),

16.1 (d), 8.6 (t); MS-EI m/z (relative intensity) 401 (MKt-

Bu^C, 2), 319 (20), 290 (14), 289 (52), 259 (31), 233 (40),

211 (28), 205 (29), 199 (32), 183 (35), 167 (23), 139 (23),

135 (20), 95 (27), 91 (100); HRMS (CI^C, CH₄) Calcd for

C₃₀H₃₉O₂Si (MCH^C): 459.2719. Found: 459.2721.

reaction mixture was cooled to rt, evaporated under reduced

pressure and the residue was triturated in pentane. The

insoluble triphenylphosphine oxide was removed by

ﬁltration through Celite (pentane) and the ﬁltrate was

evaporated under reduced pressure. The crude resulting a,b-

unsaturated ester (2.38 g, 5.28 mmol) was dissolved in

CH₂Cl₂(70 mL), and to the resulting solution at K70 8C,

was added DIBAL-H (15.0 mL, 1 M in hexanes, 15.0 mmol,

2.8 equiv). After 3 h, the reaction mixture was poured into a

saturated aqueous solution of Rochelle salt (200 mL). After

3 h stirring, the resulting mixture was extracted with Et₂O

and the combined extracts were dried over MgSO₄, ﬁltered

and concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography (petroleum ether–EtOAc:

83/17) to afford 1.35 g (60% from 20, 3 steps) of 21 as a

colorless oil; R_f0.30 (petroleum ether–EtOAc: 80/20); IR

3340, 3060, 1110, 1075, 820, 765, 740, 710, 700, 690 cm^K1

;

¹H NMR d 7.69–7.64 (m, 4H), 7.48–7.33 (m, 6H), 4.99 (dq,

JZ9.4, 1.5 Hz, 1H), 3.83 (d, JZ5.9 Hz, 2H), 3.62 (dd, JZ

9.6, 4.1 Hz, 1H), 3.42 (dd, JZ9.6, 7.7 Hz, 1H), 1.64 (d, JZ

1.5 Hz, 3H), 1.48 (m, 1H), 1.29 (m, 1H), 1.18 (d, JZ6.3 Hz,

3H), 1.04 (s, 9H), 0.98–0.87 (m, 2H), 0.81 (m, 1H), 0.17 (m,

1H); ¹³C NMR d 135.6 (d, 2C), 135.5 (d, 2C), 135.4 (s),

134.2 (s), 134.0 (s), 129.5 (d, 2C), 127.5 (d, 4C), 126.2 (d),

69.0 (t), 68.2 (t), 36.6 (d), 26.8 (q, 3C), 21.9 (d), 19.3 (s),

17.6 (q), 14.9 (d), 13.9 (q), 12.6 (t); MS-EI m/z (relative

intensity) 351 (MKt-Bu^C, 1), 229 (10), 200 (19), 199 (100),

197 (14), 181 (12), 135 (40), 107 (12), 93 (17); HRMS

(CI^C, NH₃) Calcd for C₂₆H₄₀NO₂Si (MCNH^C₄): 426.2828.

Found: 426.2814.

6.4.4. {(1R*,2S*)-2-[(1R*)-2-(tert-Butyldiphenylsilyl)-

oxy-1-methylethyl]cyclopropyl}methanol 20. To a

solution of 19 (1.80 g, 3.91 mmol) in EtOH (60 mL) was

added Pd/C (250 mg, 5% Pd, 0.117 mmol, 0.03 equiv) and

the resulting mixture was stirred under an atmosphere of H₂.

After 24 h, the reaction mixture was diluted with CH₂Cl₂

and ﬁltered through Celite. The ﬁltrate was concentrated

under reduced pressure and the residue was puriﬁed by ﬂash

chromatography (petroleum ether–EtOAc: 85/15) to afford

2.21 g (86%) of 20 as a white solid; mpZ74 8C; IR 3580,

3410, 3060, 3020, 1590, 1110, 1040, 825, 740, 705,

6.4.6. Hydroboration of 21. To a solution of T-hexylborane

[prepared from BH₃$THF (2.2 mL, 1 M in THF, 2.2 mmol,

2.6 equiv) and 2,3-dimethylbut-2-ene (2.2 mL, 1 M in THF,

2.2 mmol, 2.6 equiv), 2 h stirring at 0 8C] at K40 8C, was

added a solution of 21 (350 mg, 0.856 mmol) in THF

(3 mL). The reaction mixture was gradually warmed to rt

over 3 h. After 18 h, the reaction mixture was cooled to 0 8C

and a 3 M aqueous NaOH solution (2 mL) and a 30%

aqueous H₂O₂solution (2 mL) were successively added.

After 3 h at rt, the resulting mixture was extracted with Et₂O

and the combined extracts were washed with brine, dried

over MgSO₄, ﬁltered and concentrated under reduced

pressure. The residue was puriﬁed by ﬂash chromatography

(petroleum ether–EtOAc gradient: 75/25–40/60) to afford

21 mg (6%) of 22⁰, 258 mg (71%) of 22 and 20 mg (6%) of

22⁰⁰as colorless oils.

1

690 cm^K1; H NMR d 7.74–7.70 (m, 4H), 7.49–7.38 (m,

6H), 3.83 (m, 1H), 3.60 (dd, JZ10.0, 5.1 Hz, 1H), 3.43 (dd,

JZ10.0, 8.3 Hz, 1H), 3.31–3.21 (m, 2H), 1.46 (m, 1H), 1.30

(m, 1H), 1.09 (s, 9H), 0.93 (d, JZ7.0 Hz, 3H), 0.72–0.59

(m, 2H), K0.06 (m, 1H); ¹³C NMR d 135.7 (d, 2C), 135.6

(d, 2C), 133.1 (s), 133.0 (s), 129.7 (d, 2C), 127.7 (d, 4C),

70.7 (t), 63.1 (t), 34.5 (d), 26.8 (q, 3C), 20.8 (d), 19.4 (d),

19.1 (s), 17.8 (q), 7.0 (t); MS-EI m/z (relative intensity) 311

(MKt-Bu^C, 1), 229 (21), 200 (20), 199 (100), 181 (10), 139

(8), 95 (28); HRMS (CI^C, CH₄) Calcd for C₂₃H₃₃O₂Si (MC

H^C): 369.2250. Found: 369.2248.

6.4.5. 3-{(1R*,2S*)-2-[(1R*)-2-(tert-Butyldiphenylsilyl)-

oxy-1-methylethyl]cyclopropyl}-2-methylprop-2-en-1-ol

21. To a solution of 20 (2.03 g, 5.51 mmol) in CH₂Cl₂

6.4.7. (1R*,2S*)-1-{(1R*,2R*)-2-[(1R*)-2-(tert-Butyl-

diphenyl-silyl)oxy-1-methylethyl]cyclopropyl}-2-methyl-

propan-1,3-diol 22⁰. R_f0.54 (petroleum ether–EtOAc: 50/

50); IR 3380, 3060, 1115, 1035, 820, 805, 740, 705 cm^K1

;

˚

(100 mL) at rt, were successively added powdered 4 A

molecular sieves (4.8 g) and PCC (2.55 g, 11.8 mmol,

2.1 equiv). After 4 h, the reaction mixture was diluted

with Et₂O and ﬁltered through silica gel (Et₂O). The ﬁltrate

was evaporated under reduced pressure, and the crude

aldehyde was dissolved in toluene (50 mL). To the resulting

solution was added (carboethoxyethylidene)triphenyl-

phosphorane (3.12 g, 8.59 mmol, 1.5 equiv) and the

reaction mixture was heated at reﬂux. After 12 h, an

additional quantity of (carboethoxyethylidene)triphenyl-

phosphorane (2.14 g, 5.90 mmol, 1.1 equiv) was added

and the reaction mixture was heated at reﬂux. After 2 h, the

¹H NMR d 7.73–7.68 (m, 4H), 7.49–7.37 (m, 6H), 5.18 (br s,

1H, OH), 3.95 (br s, 1H, OH), 3.68–3.61 (m, 2H), 3.66 (dd,

JZ9.9, 4.0 Hz, 1H), 3.33 (dd, apparent t, JZ9.9 Hz, 1H),

3.09 (dd, JZ9.9, 7.9 Hz, 1H), 1.97 (m, 1H), 1.58 (m, 1H),

1.22 (m, 1H), 1.08 (s, 9H), 0.95 (d, JZ7.0 Hz, 3H), 0.83 (d,

JZ7.0 Hz, 3H), 0.79 (m, 1H), 0.58 (m, 1H), 0.04 (m, 1H);

¹³C NMR d 135.7 (d, 2C), 135.6 (d, 2C), 132.5 (s), 132.4 (s),

129.9 (d, 2C), 127.8 (d, 2C), 127.7 (d, 2C), 79.1 (d), 71.3 (t),

68.9 (t), 41.4 (d), 34.2 (d), 26.8 (q, 3C), 23.8 (d), 20.3 (d),

19.0 (s), 17.8 (q), 14.0 (q), 8.4 (t); MS (CI^C, CH₄) m/z

(relative intensity) 427 (MCH^C, 94), 409 (39), 391 (30),

7646

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

331 (100), 269 (25), 133 (30); HRMS (CI^C, CH₄) Calcd for

(84 mL, 0.68 mmol, 2.1 equiv). After 2.5 h at 0 8C, the

reaction mixture was hydrolyzed with a saturated aqueous

NaHCO₃solution and extracted with CH₂Cl₂. The

combined extracts were dried over MgSO₄, ﬁltered and

concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography (petroleum ether–EtOAc

gradient: 90/10–80/20) to afford 72 mg (63%) of 24 as a

colorless oil; IR 3500, 1730, 1285, 1160, 1030, 985,

770 cm^K1; ¹H NMR d 4.26 (dd, JZ10.9, 5.2 Hz, 1H), 4.26–

4.16 (m, 1H), 4.19 (dd, JZ10.9, 6.4 Hz, 1H), 3.76 (dd, JZ

10.7, 8.5 Hz, 1H), 3.52 (dd, apparent t, JZ5.5 Hz, 1H), 2.22

(br s, 1H, OH), 2.00 (m, 1H), 1.61 (m, 1H), 1.21 (s, 9H),

1.20 (s, 9H), 1.10 (d, JZ7.0 Hz, 3H), 1.07 (d, JZ7.0 Hz,

3H), 1.12–0.90 (m, 1H), 0.77–0.64 (m, 2H), 0.33 (m, 1H);

¹³C NMR d 178.7 (s, 2C), 71.4 (d), 69.0 (t), 66.0 (t), 40.1 (d),

38.8 (s, 2C), 32.3 (d), 27.2 (q, 6C), 21.3 (d), 20.3 (d), 18.1

(q), 14.5 (q), 6.3 (t); MS (CI^C, CH₄) m/z (relative intensity)

357 (MCH^C, 5), 340 (33), 339 (MCH^CKH₂O, 100), 255

(11), 237 (14), 153 (10), 135 (16); HRMS (CI^C, CH₄) Calcd

for C₂₀H₃₇O₅(MCH^C): 357.2641. Found: 357.2646.

C₂₆H₃₉O₃Si (MCH^C): 427.2668. Found: 427.2667.

6.4.8. (1S*,2R*)-1-{(1R*,2R*)-2-[(1R*)-2-(tert-Butyl-

diphenyl-silyl)oxy-1-methylethyl]cyclopropyl}-2-methyl-

propan-1,3-diol 22. R_f0.37 (petroleum ether–/EtOAc: 50/

50); IR 3350, 3070, 1590, 1110, 1075, 1030, 970, 825, 770,

1

740, 705, 690 cm^K1; H NMR d 7.72–7.67 (m, 4H), 7.50–

7.37 (m, 6H), 3.78 (dd, JZ10.8, 3.1 Hz, 1H), 3.63 (dd, JZ

9.9, 5.5 Hz, 1H), 3.51 (dd, JZ9.9, 6.4 Hz, 1H), 3.50 (dd,

JZ11.9, 6.4 Hz, 1H), 3.38 (dd, apparent t, JZ6.4 Hz, 1H),

3.20 (br s, 1H, OH), 2.84 (br s, 1H, OH), 1.68 (m, 1H), 1.54

(m, 1H), 1.10–1.00 (m, 1H), 1.12 (d, JZ6.6 Hz, 3H), 1.09

(s, 9H), 0.86 (d, JZ7.0 Hz, 3H), 0.83–0.67 (m, 2H), 0.22

(m, 1H); ¹³C NMR d 135.6 (d, 2C), 135.5 (d, 2C), 133.6 (s),

133.5 (s), 129.6 (d, 2C), 127.6 (d, 4C), 75.9 (d), 69.0 (t),

66.7 (t), 40.8 (d), 35.3 (d), 26.8 (q, 3C), 22.7 (d), 21.5 (d),

19.2 (s), 18.2 (q), 14.3 (q), 6.2 (t); MS (CI^C, CH₄) m/z

(relative intensity) 427 (MCH^C, 62), 409 (100), 391 (17),

331 (48), 160 (14), 139 (14); HRMS (CI^C, CH₄) Calcd for

C₂₆H₃₉O₃Si (MCH^C): 427.2668. Found: 427.2667.

6.5. Oxymercuration–reductive demercuration of

cyclopropanemethanols of type D

6.4.9. (E)-(2S*,5R*)-2-[(1R*)-2-(tert-Butyldiphenylsilyl)

oxy-1-methylethyl]-5-methylhex-3-en-1,6-diol 22⁰⁰. R_f

0.24 (petroleum ether–EtOAc: 50/50); IR 3350, 3060,

6.5.1. Oxymercuration of 5a: representative procedure.

To a degassed solution of 5a (400 mg, 1.87 mmol) in

CH₂Cl₂(15 mL) [argon bubbling, 15 min] at rt, was added

Hg(OCOCF₃)₂(1.59 g, 3.74 mmol, 2 equiv). After 1 h with

exclusion of light [reaction ﬂask wrapped with an aluminum

foil], the reaction mixture was hydrolyzed with a saturated

aqueous KBr solution and extracted with CH₂Cl₂. The

combined extracts were dried over MgSO₄, ﬁltered and

concentrated under reduced pressure. The crude material

was puriﬁed by ﬂash chromatography (cyclohexane–EtOAc

gradient: 40/60–60/40) to afford 191 mg (20%) of a mixture

of 25⁰a and 25⁰⁰a (80/20 ratio) and 562 mg (60%) of 25a, as

colorless foams.

1

1110, 1085, 1030, 820, 740, 705 cm^K1; H NMR d 7.70–

7.65 (m, 4H), 7.48–7.37 (m, 6H), 5.42 (dd, JZ15.4, 6.8 Hz,

1H), 5.33 (dd, JZ15.4, 7.9 Hz, 1H), 3.71 (dd, JZ10.7,

5.2 Hz, 1H), 3.61 (dd, JZ10.3, 5.9 Hz, 1H), 3.53–3.46 (m,

2H), 3.44 (dd, JZ10.3, 5.5 Hz, 1H), 3.35 (dd, JZ10.7,

7.2 Hz, 1H), 2.36–2.23 (m, 2H), 1.79 (m, 1H), 1.71–1.49

(2H, OH), 1.07 (s, 9H), 0.98 (d, JZ6.6 Hz, 3H), 0.93 (d, JZ

6.6 Hz, 3H); ¹³C NMR d 136.2 (d), 135.6 (d, 2C), 135.5 (d,

2C), 133.5 (s, 2C), 130.4 (d), 129.7 (d, 2C), 127.7 (d, 4C),

67.2 (t), 66.9 (t), 64.0 (t), 48.6 (d), 39.5 (d), 37.1 (d), 26.9 (q,

3C), 19.2 (s), 16.4 (q), 15.1 (q); MS (CI^C, CH₄) m/z

(relative intensity) 427 (MCH^C, 100), 409 (40), 369 (12),

349 (28), 331 (23); HRMS (CI^C, CH₄) Calcd for

C₂₆H₃₉O₃Si (MCH^C): 427.2669. Found 427.2670.

6.5.1.1. Organomercuric 25a. IR 3440, 1710, 1280,

1170, 1025 cm^K1; ¹H NMR d 4.71 (dd, JZ6.9, 5.7 Hz, 1H),

3.61 (dd, JZ11.2, 4.6 Hz, 2H), 3.45 (dd, JZ11.2, 5.5 Hz,

1H), 3.38 (dd, JZ11.2, 6.2 Hz, 1H), 2.40 (m, 1H), 1.98 (m,

1H), 1.83 (dd, JZ11.9, 4.4 Hz, 1H), 1.73 (dd, JZ11.9,

7.8 Hz, 1H), 1.17 (s, 9H), 0.95 (d, JZ6.9 Hz, 3H); ¹³C NMR

d 179.6 (s), 77.8 (d), 63.2 (t), 62.4 (t), 41.3 (d), 39.1 (s), 36.5

(d), 32.5 (t), 27.2 (q, 3C), 14.6 (q).

6.4.10. (1R*,2S*)-1-[(1R*,2R*)-2-((1R*)-2-Hydroxy-1-

methylethyl)cyclopropyl]-2-methylpropan-1,3-diol 23.

To a solution of 22 (560 mg, 1.31 mmol) in THF (10 mL)

at 0 8C, was added dropwise a solution of n-Bu₄NF (4.0 mL,

1 M in THF, 4.0 mmol, 3.1 equiv). After 3 h at rt, the

reaction mixture was concentrated under reduced pressure

and the residue was puriﬁed by ﬂash chromatography

(Petroleum ether–EtOAc: 50/50 then EtOAc–MeOH: 90/

10) to afford 188 mg (76%) of 23 as a colorless oil; IR 3300,

6.5.1.2. Organomercuric 25⁰a. IR 3440, 1710, 1290,

1

1165, 1030 cm^K1; H NMR d 4.29 (dd, JZ11.1, 5.3 Hz,

1450, 1025, 965 cm^K1

;

¹H NMR d 3.83 (dd, JZ10.9,

1H), 4.15 (dd, JZ11.1, 4.0 Hz, 1H), 3.96 (dd, JZ11.0.

4.4 Hz, 1H), 3.67 (dd, JZ11.0, 3.4 Hz, 1H), 3.31 (dd, JZ

8.4, 3.7 Hz, 1H), 2.38 (m, 1H), 2.01 (m, 1H), 2.01 (dd, JZ

11.9, 4.5 Hz, 1H), 1.88 (dd, JZ11.9, 5.7 Hz, 1H), 1.22 (s,

9H), 1.00 (d, JZ6.8 Hz, 3H); ¹³C NMR d 179.6 (s), 77.3 (d),

66.5 (t), 63.6 (t), 40.1 (d), 38.9 (s), 36.8 (d), 33.7 (t), 27.2 (q,

3C), 14.3 (q).

3.5 Hz, 1H), 3.70–3.20 (3H, OH), 3.63 (dd, JZ10.9, 6.8 Hz,

1H), 3.62 (dd, apparent t, JZ6.2 Hz, 1H), 3.55 (dd, JZ10.7,

6.6 Hz, 1H), 3.48 (dd, JZ10.7, 6.1 Hz, 1H), 1.85 (m, 1H),

1.52 (m, 1H), 1.04 (m, 1H), 1.02 (d, JZ6.3 Hz, 3H), 0.99 (d,

JZ7.0 Hz, 3H), 0.72–0.59 (m, 2H), 0.22 (m, 1H); ¹³C NMR

d 75.0 (d), 68.2 (t), 66.7 (t), 40.8 (d), 35.1 (d), 21.9 (d), 21.8

(d), 18.1 (q), 14.1 (q), 5.8 (t).

6.5.1.3. Organomercuric 25⁰⁰a. These spectroscopic

data have been tentatively deduced from the spectra of a

mixture of 25⁰a and 25⁰⁰a (80/20 ratio); ¹H NMR d 4.28 (m,

1H), 3.96 (m, 1H), 3.86 (dd, JZ10.6, 3.7 Hz, 1H), 3.62 (m,

1H), 3.50 (m, 1H), 2.65 (m, 1H), 2.15–1.85 (m, 3H), 1.23 (s,

9H), 0.91 (d, JZ6.9 Hz, 3H); ¹³C NMR d 178.9 (s), 79.1 (d),

6.4.11. (2S*,3R*)-3-{(1R*,2R*)-2-[(1R*)-2-(2,2-Dimethyl-

propanoyloxy)-1-methylethyl]cyclopropyl}-3-hydroxy-

2-methylpropyl 2,2-dimethylpropanoate 24. To a solution

of 23 (60 mg, 0.32 mmol) and DMAP (87 mg, 0.71 mmol,

2.2 equiv) in CH₂Cl₂(5 mL) at 0 8C, was added PivCl

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7647

68.4 (t), 65.8 (t), 39.5 (d), 38.8 (s), 37.3 (d), 34.3 (t), 27.0 (q,

3C), 13.4 (q).

1.00 (d, JZ7.0 Hz, 3H), 0.85 (d, JZ7.0 Hz, 3H); ¹³C NMR

d 179.9 (s), 73.4 (d), 64.4 (t), 64.0 (t), 39.2 (s), 36.7 (d), 36.5

(d), 27.2 (q, 3C), 13.6 (q), 9.5 (q).

6.5.2. Reductive demercuration of 25a: representative

procedure. To a degassed solution of 25a (560 mg,

1.10 mmol) in THF (12 mL) [argon bubbling, 15 min] at

rt, were added a catalytic amount of AIBN (2 mg) and

n-Bu₃SnH (590 mL, 2.19 mmol). Mercury began to precipi-

tate almost instantaneously, and after 1 h at rt the reaction

mixture was hydrolyzed with a 20% aqueous KF solution

(3 mL). After 30 min, the reaction mixture was diluted with

EtOAc, ﬁltered through Celite, and the ﬁltrate was extracted

with EtOAc. The combined extracts were dried over

MgSO₄, ﬁltered and concentrated under reduced pressure.

The crude material was puriﬁed by ﬂash chromatography

(cyclohexane–EtOAc: 60/40–40/60) to afford 244 mg

(96%) of 26a as a colorless oil.

6.5.3.2. (2R*,3S*,4R*)-3,5-Dihydroxy-2,4-dimethyl-

pentyl 2,2-dimethylpropanoate 26⁰b. IR 3400, 1730,

1

1710, 1290, 1170, 1030 cm^K1; H NMR d 4.25 (dd, JZ

11.0, 8.5 Hz, 1H), 3.91 (dd, JZ11.0, 5.5 Hz, 1H), 3.78–3.60

(m, 2H), 3.47 (d, JZ9.2, 2.2 Hz, 1H), 2.03–1.73 (m, 2H),

1.22 (s, 9H), 0.91 (d, JZ7.0 Hz, 3H), 0.79 (d, JZ7.0 Hz,

3H); ¹³C NMR d 179.3 (s), 76.4 (d), 68.6 (t), 66.7 (t), 38.8

(s), 36.9 (d), 35.2 (d), 27.2 (q, 3C), 13.4 (q), 8.9 (q).

6.5.4. Oxymercuration–reductive demercuration of

cyclopropylcarbinol 5c. According to the representative

procedure, oxymercuration of 5c (400 mg, 1.87 mmol) and

subsequent puriﬁcation by ﬂash chromatography (cyclo-

hexane–EtOAc: 80/20) afforded 165 mg (17%) of an

inseparable mixture of 25⁰c and 25⁰⁰c (75/25 ratio) and

574 mg (60%) of 25c.

6.5.2.1. (1S*,2R*)-3-Hydroxy-1-((1S*)-2-hydroxy-1-

methylethyl)-2-methylpropyl 2,2-dimethylpropanoate

1

26a. IR 3380, 1710, 1285, 1170, 1030 cm^K1; H NMR d

4.80 (t, JZ6.4 Hz, 1H), 3.62 (dd, JZ11.2, 3.8 Hz, 2H), 3.44

(dd, JZ11.2, 5.8 Hz, 2H), 3.03 (br s, 2H, OH), 2.00 (m, 2H),

1.23 (s, 9H), 1.02 (d, JZ6.9 Hz, 6H); ¹³C NMR d 179.4 (s),

77.4 (d), 63.2 (t, 2C), 39.0 (s), 36.5 (d, 2C), 27.1 (q, 3C),

14.4 (q, 2C); MS-EI m/z (relative intensity) 173 (MK

CH₃CHCH₂OH^C, 4), 147 (5), 133 (MKt-BuCO^C, 9), 103

(61), 95 (16), 89 (20), 85 (37), 82 (12), 71 (14), 69 (18), 57

(100), 55 (11).

6.5.4.1. Organomercuric 25c. ¹H NMR d 4.96 (dd, JZ

8.8, 3.7 Hz, 1H), 3.63 (dd, JZ9.9, 5.1 Hz, 1H), 3.57–3.40

(m, 3HCOH), 2.73 (br s, 1H, OH), 2.46 (m, 1H), 2.00 (m,

1H), 1.97 (dd, JZ11.9, 4.0 Hz, 1H), 1.76 (dd, JZ11.9,

9.0 Hz, 1H), 1.25 (s, 9H), 1.03 (d, JZ7.0 Hz, 3H); ¹³C NMR

d 179.5 (s), 75.4 (d), 65.1 (t), 63.6 (t), 41.3 (d), 39.2 (s), 36.8

(d), 28.7 (t), 27.4 (q, 3C), 14.1 (q).

6.5.4.2. Organomercuric 25⁰c. ¹H NMR d 4.34 (dd, JZ

11.0, 4.8 Hz, 1H), 4.07 (dd, JZ11.0, 4.0 Hz, 1H), 3.87–3.62

(m, 3H), 2.39 (m, 1H), 2.01–1.89 (m, 1H), 1.79–1.58 (m,

2H), 1.22 (s, 9H), 0.95 (d, JZ7.0 Hz, 3H); ¹³C NMR d

179.6 (s), 73.2 (d), 67.4 (t), 66.9 (t), 40.2 (d), 38.9 (s), 36.4

(d), 27.2 (q, 3C), 25.5 (t), 13.8 (q).

6.5.2.2. (2S*,3R*,4R*)-3,5-Dihydroxy-2,4-dimethyl-

pentyl 2,2-dimethylpropanoate 26⁰a. Reductive demer-

curation of a mixture of 25⁰a and 25⁰⁰a (80/20 ratio, 150 mg,

0.294 mmol) with n-Bu₃SnH (150 mL, 0.557 mmol) in the

presence of a catalytic amount of AIBN in THF (4 mL) at rt,

and puriﬁcation by ﬂash chromatography (cyclohexane–

EtOAc: 60/40–40/60) afforded 66 mg (98%) of 26⁰a as a

6.5.4.3. Organomercuric 25⁰⁰c. ¹H NMR d 4.16 (dd, JZ

11.0, 7.3 Hz, 1H), 3.97 (dd, JZ11.0, 6.1 Hz, 1H), 3.87–3.62

(m, 3H), 2.66 (m, 1H), 2.01–1.89 (m, 1H), 1.79–1.58 (m,

2H), 1.22 (s, 9H), 0.83 (d, JZ7.0 Hz, 3H); ¹³C NMR d

179.1 (s), 75.0 (d), 68.4 (t), 67.4 (t), 39.4 (d), 38.8 (s), 36.7

(d), 27.2 (q, 3C), 26.1 (t), 13.2 (q).

1

colorless oil; IR 3400, 1710, 1285, 1165, 1030 cm^K1; H

NMR d 4.22 (dd, JZ11.0, 4.8 Hz, 1H), 4.13 (dd, JZ11.0,

6.2 Hz, 1H), 3.84 (dd, JZ10.8, 3.4 Hz, 1H), 3.61 (dd, JZ

10.8, 6.3 Hz, 1H), 3.50 (br m, 1H, OH), 3.41 (dd apparent t,

JZ6.1 Hz, 1H), 3.10 (br m, 1H, OH), 2.07 (m, 1H), 1.88 (m,

1H), 1.21 (s, 9H), 1.02 (d, JZ7.0 Hz, 3H), 1.00 (d, JZ

7.0 Hz, 3H); ¹³C NMR d 179.0 (s), 79.4 (d), 66.8 (t), 66.0 (t),

38.9 (s), 36.5 (d), 36.0 (d), 27.2 (q, 3C), 14.7 (q), 14.5 (q);

MS-EI m/z (relative intensity) 173 (MKCH₃CHCH₂-

OH^C,16), 103 (100), 89 (42), 85 (57), 82 (10), 71 (22), 57

(84).

According to the representative procedure, reductive

demercuration of 25c (570 mg, 1.12 mmol) and puriﬁcation

by ﬂash chromatography (cyclohexane–EtOAc: 60/40–40/

60) gave 227 mg (88%) of 26b₀as a colorless oil. Similarly,

reductive demercuration of 25 c and 25⁰⁰c (75/25 mixture,

165 mg, 0.324 mmol) afforded, after puriﬁcation by ﬂash

chromatography (cyclohexane–EtOAc: 60/40–40/60),

52 mg (70%) of a mixture of 26⁰⁰b and 26⁰b (75/25 ratio).

6.5.3. Oxymercuration–reductive demercuration of 5b.

Compound 5b (530 mg, 2.47 mmol) was subjected to the

oxymercuration–reductive demercuration representative

procedures. Puriﬁcation by ﬂash chromatography (cyclo-

hexane–EtOAc: 70/30–50/50) afforded 451 mg (80%) of a

regioisomeric mixture of 26b and 26⁰b (95/5 ratio).

6.5.4.4. (2S*,3R*,4S*)-3,5-Dihydroxy-2,4-dimethyl-

pentyl 2,2-dimethylpropanoate 26⁰⁰b. IR 3400, 1730, 1710,

1290, 1170, 1030 cm^K1; ¹H NMRd 4.35(dd, JZ11.0, 5.2 Hz,

1H), 4.09 (dd, JZ11.0, 3.7 Hz, 1H), 3.78–3.60 (m, 2HCOH),

3.56 (dd, JZ9.7, 2.0 Hz, 1H), 3.39 (br s, 1H, OH), 2.03–1.73

(m, 2H), 1.22 (s, 9H), 0.95 (d, JZ7.0 Hz, 3H), 0.91 (d, JZ

7.0 Hz, 3H); ¹³C NMR d 179.4 (s), 74.5 (d), 67.5 (t), 67.0 (t),

38.9 (s), 36.7 (d), 35.7 (d), 27.2 (q, 3C), 13.7 (q), 8.5 (q).

6.5.3.1. (2R*)-3-Hydroxy-1-((1R*)-2-hydroxy-1-

methyl-ethyl)-2-methylpropyl 2,2-dimethylpropanoate

1

26b. IR 3400, 1710, 1285, 1180, 1030 cm^K1; H NMR d

4.99 (dd, JZ9.9, 2.2 Hz, 1H), 3.54 (dd, JZ11.2, 3.5 Hz,

1H), 3.45 (dd, JZ11.2, 5.5 Hz, 1H), 3.44 (dd, JZ11.1,

4.8 Hz, 1H), 3.22 (dd, JZ11.1, 9.4 Hz, 1H), 3.09 (br s, 1H,

OH), 2.65 (br s, 1H, OH), 2.10–1.89 (m, 2H), 1.24 (s, 9H),

6.5.5. Chemical correlation for the attribution of the

relative conﬁguration of compounds 26a, 26⁰a and 26b.

7648

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

6.5.5.1. (2S*,3S*,4R*)-2,4-Dimethylpentane-1,3,5-

IR 3330, 1430, 1110, 1070, 745, 705 cm^K^{1 1}H NMR

;

triol 27.²³To a solution of 26a (147 mg, 0.63 mmol) in

THF (5 mL) at 0 8C, was added LiAlH₄(72 mg, 1.9 mmol,

3.0 equiv). After 40 min at rt, the reaction was quenched by

successive addition of H₂O (0.1 mL), a 15% aqueous NaOH

solution (0.1 mL) and H₂O (0.3 mL). After 3 h stirring at rt,

the reaction mixture was ﬁltered through Celite and the

insoluble salts were thoroughly washed with boiling THF.

The ﬁltrate was concentrated under reduced pressure and the

crude material was puriﬁed by ﬂash chromatography

(CH₂Cl₂–MeOH: 90/10) to afford 81 mg (86%) of 27 as a

waxy white solid. Similarly, compound 26⁰a (54 mg,

0.23 mmol) was reduced with LiAlH₄(26 mg, 0.68 mmol,

3 equiv) to give 22 mg (65%) of 27. Based on literature

results,²³the ¹³C NMR data readily enabled the stereo-

chemical assignment; ¹³C NMR (D₂O) d 79.4 (d), 66.4 (t,

2C), 39.8 (d, 2C), 16.6 (q, 2C).

(C₆D₆) d 7.23–7.05 (m, 5H), 4.17 (s, 2H), 3.83 (br s, 1H,

OH), 3.73–3.63 (m, 3H), 3.28 (dd, JZ9.0, 4.5 Hz, 1H), 3.21

(dd apparent t, JZ9.0, 8.5 Hz, 1H), 2.30 (br s, 1H, OH),

1.84 (m, 1H), 1.51 (m, 1H), 1.00 (d, JZ7.0 Hz, 3H), 0.52 (d,

JZ6.9 Hz, 3H); ¹³C NMR (C₆D₆) d 138.9 (s), 129.3 (d),

128.7 (d, 2C) (overlap with solvent), 128.4 (d, 2C), 79.4 (d),

76.9 (t), 74.1 (t), 68.4 (t), 37.6 (d), 37.0 (d), 13.8 (q), 9.7 (q).

6.5.6.3. (1S*,2S*)-1-[(1R*)-2-(Benzyloxy)-1-methyl-

ethyl]-2-methylpropane-1,3-diol 33c.²⁵This compound

was synthesized from 6c (80 mg, 0.26 mmol) according to

the representative procedure. Puriﬁcation by ﬂash chroma-

tography (cyclohexane–EtOAc: 60/40) afforded 40 mg

(65%) of 33c as a colorless oil; IR 3330, 1430, 1110,

1

1070, 745, 705 cm^K1; H NMR (C₆D₆) d 7.25–7.06 (m,

5H), 4.26 (s, 2H), 3.83 (br s, 1H, OH), 3.70–3.58 (m, 3HC

OH), 3.38 (dd, JZ8.9, 5.8 Hz, 1H), 3.29 (dd, JZ8.9,

4.8 Hz, 1H), 1.84–1.69 (m, 2H), 0.96 (d, JZ7.0 Hz, 3H),

0.58 (d, JZ6.9 Hz, 3H); ¹³C NMR (C₆D₆) d 139.4 (s), 129.2

(d), 128.4–128.0 (d, 2CC2C, overlap with solvent), 79.2 (d),

75.8 (t), 74.1 (t), 69.2 (t), 38.3 (d), 36.4 (d), 14.1 (q), 10.3 (q).

6.5.5.2. (2S*,4S*)-2,4-Dimethylpentane-1,3,5-triol

28.²³Reduction of 26b (68 mg, 0.29 mmol) with LiAlH₄

(22 mg, 0.58 mmol, 2.0 equiv) in THF (5 mL) at 0 8C and

puriﬁcation by ﬂash chromatography (CH₂Cl₂–MeOH: 90/

10) afforded 27 mg (68%) of 28 as waxy white solid; ¹³C

NMR (D₂O) d 75.6 (d), 67.6 (t), 67.2 (t), 40.4 (d), 39.1 (d),

15.7 (q), 11.3 (q).

6.5.6.4. (1S*,2R*)-1-[(1R*)-2-(Benzyloxy)-1-methyl-

ethyl]-2-methylpropane-1,3-diol 33d.²⁵This compound

was synthesized from 6d (18 mg, 0.059 mmol) according to

the representative procedure. Puriﬁcation by ﬂash chroma-

tography (pentane–Et₂O gradient: 60/40–40/60) afforded

7 mg (47%) of 33d as a colorless oil; R_f0.13 (cyclohexane–

EtOAc: 50/50); IR 3380, 1470, 1090, 1030, 980, 745,

6.5.6. Synthesis of stereotriads 33a–d from the benzyl

ethers 6a–d.

6.5.6.1. (1S*,2S*)-1-[(1S*)-2-(Benzyloxy)-1-methyl-

ethyl]-2-methylpropane-1,3-diol 33a²⁵(representative

procedure) Compound 6a (200 mg, 0.657 mmol) was

oxymercurated with Hg(OCOCF₃)₂(560 mg, 1.31 mmol,

2.0 equiv) in CH₂Cl₂(7 mL) at rt for 1 h. The crude mixture

of organomercuric bromides was subjected to reductive

demercuration with n-Bu₃SnH (210 mL, 0.781 mmol) and a

catalytic amount of AIBN (2 mg) in THF (10 mL) for

30 min at rt. The resulting crude material was dissolved in

THF (5 mL) and LiAlH₄(30 mg, 0.78 mmol) was added at

0 8C. After 2 h at rt, the reaction was quenched by

successive addition of H₂O (0.1 mL), a 15% aqueous

NaOH solution (0.1 mL) and H₂O (0.3 mL) and after 2 h at

rt, the resulting mixture was ﬁltered trough Celite. The

insoluble salts were thoroughly washed with boiling THF

and the ﬁltrate was evaporated under reduced pressure. The

crude material was puriﬁed by ﬂash chromatography

(cyclohexane–EtOAc: 50/50) to afford 59 mg (38%) of

33a as a colorless oil; R_f0.25 (cyclohexane–EtOAc: 50/50);

1

705 cm^K1; H NMR (C₆D₆) d 7.25–7.06 (m, 5H), 4.22 (s,

2H), 3.70 (dd apparent t, JZ5.1 Hz, 1H), 3.38 (d, JZ

5.1 Hz, 2H), 3.23 (dd, JZ9.1, 5.4 Hz, 1H), 3.18 (dd, JZ9.1,

4.8 Hz, 1H), 2.35 (br s, 1H, OH), 1.84 (m, 1H), 1.65 (m,

1H), 1.30 (br s, 1H, OH), 1.07 (d, JZ7.0 Hz, 3H), 0.99 (d,

JZ7.0 Hz, 3H); ¹³C NMR (C₆D₆) d 139.6 (s), 129.2 (d),

128.9 (d, 2C), 128.3 (d, 2C) (overlap with solvent), 76.5 (d),

75.1 (t), 73.9 (t), 67.7 (t), 38.7 (d), 37.4 (d), 13.4 (q), 12.2 (q).

6.6. Oxymercuration of cyclopropanes of type E

6.6.1. (2R*,3R*,4S*,5R*)-1-Benzyloxy-2,4-dimethylhep-

tane-3,5-diol 35a. Compound 12a (114 mg, 0.393 mmol)

was oxymercurated with Hg(OCOCF₃)₂(352 mg,

0.825 mmol, 2.1 equiv) in CH₂Cl₂(4 mL) for 1 h at rt.

The crude mixture of organomercuric bromides was

dissolved in a mixture of THF and toluene (1/1, 6 mL)

and to the resulting degassed solution [argon bubbling,

20 min] was added AIBN (2.3 mg) and n-Bu₃SnH (0.26 mL,

0.97 mmol, 2.5 equiv). After 1 h at rt and 1 h at 55 8C, CCl₄

(1 mL) was added in order to destroy the excess tin hydride.

The reaction mixture was diluted with a mixture of

petroleum ether–CH₂Cl₂(75/25, 20 mL) and the resulting

solution was washed with a 5% aqueous solution of KF (4!

10 mL). The organic extracts were dried over MgSO₄,

ﬁltered and concentrated under reduced pressure. The crude

material was suspended in CH₂Cl₂and the insoluble

material was removed by ﬁltration. The ﬁltrate was

evaporated and the residual oil was puriﬁed by ﬂash

chromatography (petroleum ether–EtOAc gradient: 95/5–

80/20) to afford 79 mg (65%) of a regioisomeric mixture of

34a and 34⁰a (70 mg, 0.023 mmol), which was dissolved in

THF (3 mL). To the resulting solution at 0 8C, was added

1

IR 3370, 1455, 1095, 1070, 1030, 990, 745, 705 cm^K1; H

NMR (C₆D₆) d 7.31–7.05 (m, 5H), 4.20 (s, 2H), 4.07 (d, JZ

4.6 Hz, 1H), 3.78 (m, 1H), 3.63–3.57 (m, 2H), 3.38 (dd, JZ

9.1, 4.8 Hz, 1H), 3.36 (m, 1H), 3.30 (dd, JZ9.1, 5.7 Hz,

1H), 1.84 (m, 1H), 1.72 (m, 1H), 0.88 (d, JZ7.0 Hz, 6H);

¹³C NMR (C₆D₆) d 139.1 (s), 129.3 (d), 128.5 (d, 2C), 128.4

(d, 2C) (overlap with solvent), 82.0 (d), 74.4 (t), 74.1 (t),

67.4 (t), 38.1 (d), 36.8 (d), 15.6 (q), 15.3 (q).

6.5.6.2. (1S*,2R*)-1-[(1S*)-2-(Benzyloxy)-1-methyl-

ethyl]-2-methylpropane-1,3-diol 33b.²⁵This compound

was synthesized from 6b (50 mg, 0.16 mmol) according to

the representative procedure. Puriﬁcation by ﬂash chroma-

tography (cyclohexane–EtOAc: 50/50) afforded 19 mg (50%)

of33b asa colorless oil;R_f0.17(cyclohexane–EtOAc: 50/50);

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7649

LiAlH₄(28 mg, 0.74 mmol, 3.3 equiv) and after 3 h at rt, the

reaction was quenched by successive addition of H₂O

(30 mL), a 15% aqueous NaOH solution (30 mL) and H₂O

(120 mL). After 3 h, the resulting mixture was diluted with

Et₂O and ﬁltered through Celite. The insoluble salts were

thoroughly washed with boiling THF and the ﬁltrate was

evaporated under reduced pressure. The crude material was

puriﬁed by ﬂash chromatography (petroleum ether–Et₂O

gradient: 60/40–50/50) to afford 48 mg (80%) of 35a as a

colorless oil; IR 3350, 1085, 965, 735, 700 cm^K1; ¹H NMR

d 7.39–7.26 (m, 5H), 4.53 (s, 2H), 4.42 (br s, 1H, OH), 3.87

(m, 1H), 3.81 (br s, 1H, OH), 3.66 (dd, JZ9.1, 4.0 Hz, 1H),

3.58 (dd, JZ8.3, 3.5 Hz, 1H), 3.49 (dd, JZ9.1, 8.3 Hz, 1H),

2.17 (m, 1H), 1.72 (m, 1H), 1.57 (m, 1H), 1.39 (m, 1H), 1.02

(d, JZ7.0 Hz, 3H), 0.93 (t, JZ7.4 Hz, 3H), 0.83 (d, JZ

7.0 Hz, 3H); ¹³C NMR d 137.4 (s), 128.5 (d, 2C), 127.9 (d),

127.7 (d, 2C), 82.4 (d), 76.1 (t), 73.6 (t), 72.7 (d), 37.1 (d),

35.7 (d), 27.2 (t), 13.7 (q), 10.9 (q), 10.6 (q); MS (CI^C, CH₄)

m/z (relative intensity) 267 (MCH^C, 100), 249 (15), 231

(13), 157 (12), 141 (28); HRMS (CI^C, CH₄) Calcd for

C₁₆H₂₇O₃(MCH^C): 267.1960. Found: 267.1955.

(8 mg, 0.2 mmol, 2.1 equiv). After 1 h at rt, and usual work-

up, puriﬁcation of the crude material by ﬂash chromato-

graphy (petroleum ether–Et₂O gradient: 70/30–50/50)

afforded 19 mg (73%) of 35c as a colorless oil. Similarly,

reduction of 34⁰c (13 mg, 0.042 mmol) with LiAlH₄and

puriﬁcation by ﬂash chromatography (petroleum ether–

Et₂O gradient: 70/30–50/50) afforded 5 mg (45%) of 35c;

IR 3400, 1095, 1070, 970, 735, 700 cm^K1; ¹H NMR d 7.39–

7.27 (m, 5H), 4.54 (d, JZ12.1 Hz, 1H), 4.49 (d, JZ12.1 Hz,

1H), 3.83 (dd, JZ9.2, 2.6 Hz, 1H), 3.71 (m, 1H), 3.60 (dd,

JZ9.0, 4.0 Hz, 1H), 3.55 (dd, JZ9.0, 4.8 Hz, 1H), 3.33 (br

s, 1H, OH), 2.82 (br s, 1H, OH), 1.93–1.77 (m, 2H), 1.61–

1.38 (m, 2H), 1.01 (d, JZ7.0 Hz, 3H), 0.99 (t, JZ7.4 Hz,

3H), 0.79 (d, JZ7.4 Hz, 3H); ¹³C NMR d 138.0 (s), 128.4

(d, 2C), 127.7 (d), 127.6 (d, 2C), 76.6 (d), 75.7 (t), 75.6 (d),

73.5 (t), 39.4 (d), 35.3 (d), 25.8 (t), 11.8 (q), 11.1 (q), 9.9 (q);

MS (CI^C, CH₄) m/z (relative intensity) 267 (MCH^C, 56),

249 (22), 231 (22), 157 (31), 141 (100), 125 (25), 123 (31),

119 (27); HRMS (CI^C, CH₄) Calcd for C₁₆H₂₇O₃(MC

H^C): 267.1960. Found: 267.1965.

6.6.4. (4R*,5S*,6R*)-4-[(1R*)-2-(Benzyloxy)-1-methyl-

ethyl]-6-ethyl-2,2,5-trimethyl-1,3-dioxane 36a. To a

solution of 35a (20 mg, 0.075 mmol) in a mixture of

acetone (1 mL) and 2,2-dimethoxypropane (1 mL) was

added a catalytic amount of CSA (3 mg). After 6 h at rt, the

reaction mixture was hydrolyzed with a saturated aqueous

NaHCO₃solution and extracted with Et₂O. The combined

extracts were dried over MgSO₄, ﬁltered and concentrated

under reduced pressure to afford 22 mg (96%) of 36a as a

colorless oil; IR 1220, 1180, 1150, 1095, 1020, 990, 880,

735, 700 cm^K1; ¹H NMR d 7.36–7.26 (m, 5H), 4.54 (d, JZ

12.0 Hz, 1H), 4.49 (d, JZ12.0 Hz, 1H), 3.66 (m, 1H), 3.61

(dd, JZ9.2, 4.8 Hz, 1H), 3.37 (dd, JZ9.2, 7.0 Hz, 1H), 3.26

(dd, JZ7.0, 5.3 Hz, 1H), 1.96 (m, 1H), 1.84 (m, 1H), 1.70–

1.33 (m, 2H), 1.32 (s, 3H), 1.31 (s, 3H), 1.04 (d, JZ7.0 Hz,

3H), 0.92 (t, JZ7.4 Hz, 3H), 0.85 (d, JZ7.0 Hz, 3H); ¹³C

NMR d 138.8 (s), 128.3 (d, 2C), 127.5 (d, 2C), 127.4 (d),

100.2 (s), 76.6 (d), 73.1 (t), 72.4 (t), 71.0 (d), 37.8 (d), 36.5

(d), 25.4 (q), 23.6 (t and q, 2C), 14.3 (q), 12.4 (q), 10.5 (q);

MS (CI^C, CH₄) m/z (relative intensity) 307 (MCH^C, 62),

291 (22), 249 (100), 231 (35), 157 (21), 141 (46); HRMS

(CI^C, CH₄) Calcd for C₁₉H₃₁O₃(MCH^C): 307.2273.

Found: 307.2272.

6.6.2. (1R*,2S*,3R*,4S*)-5-Benzyloxy-1-ethyl-3-hydroxy-

2,4-dimethylpentyl acetate 34c and (1R*,2S*,3R*)-1-

[(1S*)-2-benzyloxy-1-methylethyl]-3-hydroxy-2,4-

dimethylpentyl acetate 34⁰c. Compound 12c (107 mg,

0.368 mmol) was subjected to the oxymercuration–reduc-

tive demercuration procedure. ¹H NMR analysis of the

crude material indicated the formation of regioisomeric

mixture of 34c and 34⁰c (75/25 ratio). Puriﬁcation by ﬂash

chromatography (CH₂Cl₂–Et₂O: 97/3–96/4) afforded 33 mg

(29%) of 34c and 16 mg (14%) of 34⁰c as colorless oils.

Major regioisomer (34c). IR 3510, 1710, 1250, 1100, 1020,

1

1015, 955, 885, 740, 700 cm^K1; H NMR d 7.38–7.25 (m,

5H), 5.21 (ddd, JZ9.2, 4.8, 1.7 Hz, 1H), 4.53 (d, JZ

12.1 Hz, 1H), 4.49 (d, JZ12.1 Hz, 1H), 3.56 (dd, JZ9.0,

6.8 Hz, 1H), 3.46 (dd, JZ9.0, 5.7 Hz, 1H), 3.41–3.27 (m,

2H, 1HCOH), 2.09 (s, 3H), 1.96 (m, 1H), 1.79–1.65 (m,

2H), 1.49 (m, 1H), 0.91 (t, JZ7.4 Hz, 3H), 0.89 (d, JZ

7.0 Hz, 3H), 0.81 (d, JZ7.0 Hz, 3H); ¹³C NMR d 172.4 (s),

138.6 (s), 128.3 (d, 2C), 127.5 (d, 3C), 75.7 (d), 74.5 (t),

73.2 (t), 71.5 (d), 39.6 (d), 34.7 (d), 25.4 (t), 21.0 (q), 10.5

(q), 9.2 (q), 8.2 (q); MS-EI m/z (relative intensity) 248 (MK

AcOH^C, 1), 202 (4), 160 (9), 159 (9), 108 (15), 107 (31), 99

(13), 92 (11), 91 (100), 70 (10), 69 (12).

6.6.5. (4R*,5S*,6R*)-4-[(1S*)-2-Benzyloxy-1-methyl-

ethyl]-6-ethyl-2,2,5-trimethyl-1,3-dioxane 36c. Acetonide

formation from 35c (19 mg, 0.071 mmol) provided 20 mg

(91%) of 36c as a colorless oil; IR 1225, 1180, 1150, 1095,

Minor regioisomer (34⁰c). IR 3520, 1715, 1250, 1095, 1020,

1

965, 955, 740, 700 cm^K1; H NMR d 7.38–7.25 (m, 5H),

1

1020, 980, 880, 730, 700 cm^K1; H NMR d 7.36–7.26 (m,

5.08 (dd, JZ10.3, 2.6 Hz, 1H), 4.50 (d, JZ11.8 Hz, 1H),

4.44 (d, JZ11.8 Hz, 1H), 3.34 (m, 1H), 3.27 (d, JZ7.0 Hz,

2H), 2.79 (br d, JZ3.3 Hz, 1H, OH), 2.19 (m, 1H), 2.03 (s,

3H), 1.73–1.53 (m, 2H), 1.32 (m, 1H), 0.93 (t, JZ7.5 Hz,

3H), 0.91 (d, JZ7.0 Hz, 3H), 0.85 (d, JZ7.0 Hz, 3H); ¹³C

NMR d 172.4 (s), 138.2 (s), 128.4 (d, 2C), 127.8 (d, 2C),

127.6 (d), 75.5 (d), 73.3 (t), 72.8 (t), 71.0 (d), 38.6 (d), 34.2

(d), 26.9 (t), 20.8 (q), 11.1 (q), 10.0 (q), 8.4 (q); MS-EI m/z

(relative intensity) 248 (MKAcOH^C, 1), 202 (3), 160 (9), 159

(9), 108 (14), 107 (30), 99 (12), 92 (11), 91 (100), 69 (12).

5H), 4.52 (s, 2H), 3.65 (dt, JZ8.5, 4.8 Hz, 1H), 3.50–3.43

(m, 2H), 3.36 (dd, JZ9.0, 6.1 Hz, 1H), 1.93–1.77 (m, 2H),

1.51–1.22 (m, 2H), 1.31 (s, 6H), 0.95 (d, JZ7.0 Hz, 3H),

0.93 (t, JZ7.4 Hz, 3H), 0.83 (d, JZ6.6 Hz, 3H); ¹³C NMR

d 138.7 (s), 128.3 (d, 2C), 127.6 (d, 2C), 127.4 (d), 100.2 (s),

74.1 (d), 73.1 (t, 2C), 71.2 (d), 36.4 (d), 36.3 (d), 25.0 (q), 23.7

(q), 23.6 (t), 11.8 (q), 11.2 (q), 10.6 (q); MS EI m/z (relative

intensity) 291 (MKMe^C, 6), 248 (MKMe₂C]O^C, 6), 190

(9), 179 (12), 107 (18), 92 (10), 91 (100), 69 (19), 59 (24).

6.6.3. (2S*,3R*,4S*,5R*)-1-Benzyloxy-2,4-dimethyl-hep-

tane-3,5-diol 35c. To a solution of 34c (30 mg,

0.097 mmol) in THF (2 mL) at 0 8C, was added LiAlH₄

6.6.6. (2R*,3R*,4S*,5R*,6S*)-7-Benzyloxy-2,4,6-tri-

methylheptane-1,3,5-triol 37.²⁷Compound 15 (125 mg,

0.345 mmol) was subjected to oxymercuration–reductive

7650

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

demercuration sequence. The intermediate regioisomeric

mixture of acetates (ratio not determined) was reduced with

LiAlH₄(45 mg, 1.2 mmol, 8 equiv) in THF (2 mL) for 2 h at

rt and puriﬁcation by ﬂash chromatography (petroleum

ether–EtOAc: 20/80) gave 25 mg (25% from 15) of 37 as a

colorless oil; IR 3360, 1080, 1025, 970, 735, 700 cm^K1; ¹H

NMR d 7.39–7.25 (m, 5H), 4.51 (s, 2H), 3.94 (dd, JZ9.7,

2.0 Hz, 1H), 3.74 (dd, JZ7.5 and 3.5 Hz, 1H), 3.66 (d, JZ

5.9 Hz, 2H), 3.57 (dd, JZ8.8, 4.0 Hz, 1H), 3.53 (dd, JZ8.8,

4.4 Hz, 1H), 3.60–3.49 (m, 2H, 2OH), 3.29 (br s, 1H, OH),

1.99–1.84 (m, 2H), 1.74 (m, 1H), 1.04 (d, JZ7.0 Hz, 3H),

0.89 (d, JZ7.0 Hz, 3H), 0.71 (d, JZ7.0 Hz, 3H); ¹³C NMR

d 137.9 (s), 128.4 (d, 2C), 127.8 (d), 127.7 (d, 2C), 77.2 (d),

76.8 (d), 75.4 (t), 73.5 (t), 69.5 (t), 37.1 (d), 37.0 (d), 35.6

(d), 13.2 (q), 11.0 (q), 10.2 (q).

9.9, 1.7 Hz, 1H), 3.45 (br s, 1H, OH), 1.91 (m, 1H), 1.67–1.39

(m, 3H), 1.22 (s, 9H), 0.95 (t, JZ7.4 Hz, 3H), 0.91 (d, JZ

7.0 Hz, 3H), 0.90 (d, JZ7.1 Hz, 3H); ¹³C NMR d 179.6 (s),

78.8 (d), 78.0 (d), 66.8 (t), 39.0 (s), 36.8 (d), 36.7 (d), 28.0 (t),

27.2 (q, 3C), 13.7 (q), 10.5 (q), 3.9 (q); MS (CI^C, CH₄) m/z

(relative intensity) 261 (MCH^C, 100), 243 (18), 225 (14), 173

(15), 159 (11), 141 (68), 123 (38); HRMS (CI^C, CH₄) Calcd

for C₁₄H₂₉O₄(MCH^C): 261.2066. Found: 261.2065.

6.7.1.2. (1R*,2R*,3S*,4S*)-1-Ethyl-3,5-dihydroxy-

2,4-dimethylpentyl 2,2-dimethylpropanoate 39⁰. R_f0.17

(petroleum ether–EtOAc: 60/40); IR 3440, 1730, 1290,

1170 cm^K1; ¹H NMR d 4.84 (ddd, JZ7.3, 5.5, 4.8 Hz, 1H),

3.71 (dd, JZ11.0, 4.0 Hz, 1H), 3.67 (dd, JZ11.0, 3.7 Hz,

1H), 3.61 (dd, JZ8.6, 2.8 Hz, 1H), 3.30–3.00 (br m, 2H,

2OH), 1.92–1.75 (m, 2H), 1.73–1.61 (m, 2H), 1.22 (s, 9H),

0.91 (d, JZ7.0 Hz, 3H), 0.88 (t, JZ7.7 Hz, 3H), 0.82 (d,

JZ7.0 Hz, 3H); ¹³C NMR d 179.0 (s), 79.2 (d), 78.1 (d),

68.4 (t), 39.1 (s), 38.7 (d), 37.3 (d), 27.2 (q, 3C), 25.7 (t),

13.9 (q), 9.8 (q), 7.3 (q); MS (CI^C, CH₄) m/z (relative

intensity) 261 (MCH^C, 100), 243 (23), 159 (31), 141 (35),

124 (14), 123 (26); HRMS (CI^C, CH₄) Calcd for C₁₄H₂₉O₄

(MCH^C): 261.2066. Found: 261.2065.

6.6.7.

(2R*,3R*,4R*,5R*,6S*)-7-Benzyloxy-3,5-di-

hydroxy-2,4,6-trimethyl 2,2-dimethylpropanoate 38. To

a solution of the triol 37 (10 mg, 0.034 mmol) in CH₂Cl₂

(1 mL) were successively added at 0 8C, Et₃N (60 mL,

0.43 mmol, 13 equiv) and PivCl (50 mL, 0.40 mmol,

12 equiv). After 12 h at 0 8C, additional quantities of Et₃N

(30 mL, 0.21 mmol, 6 equiv) and PivCl (20 mL, 0.16 mmol,

4.8 equiv) were added. After a further 12 h at 0 8C, the

reaction mixture was evaporated under reduced pressure

and the residual oil was dissolved in a mixture of acetone

(1 mL) and 2,2-dimethoxypropane (1 mL). A catalytic

amount of CSA (2 mg) was added and after 1 h at rt, the

reaction mixture was hydrolyzed with a saturated aqueous

NaHCO₃solution and extracted with ether. The combined

extracts were dried over MgSO₄, ﬁltered and concentrated

under reduced pressure. The residue was puriﬁed by ﬂash

chromatography (petroleum ether–EtOAc: 95/5) to afford

9 mg (64%) of 38 as a colorless oil; IR 1730, 1480, 1280,

1225, 1160, 730, 700 cm^K1; ¹H NMR d 7.35–7.26 (m, 5H),

4.53 (d, JZ12.1 Hz, 1H), 4.48 (d, JZ12.1 Hz, 1H), 4.19

(dd, JZ10.7, 3.3 Hz, 1H), 4.02 (dd, JZ10.7, 5.9 Hz, 1H),

3.55 (dd, JZ10.9, 4.2 Hz, 1H), 3.48–3.41 (m, 2H), 3.35 (dd,

JZ8.8, 5.9 Hz, 1H), 1.97–1.83 (m, 3H), 1.27 (s, 3H), 1.25

(s, 3H), 1.21 (s, 9H), 0.95 (d, JZ7.0 Hz, 3H), 0.90 (d, JZ

7.0 Hz, 3H), 0.87 (d, JZ6.6 Hz, 3H); ¹³C NMR d 178.6 (s),

138.7 (s), 128.3 (d, 2C), 127.6 (d, 2C), 127.5 (d), 100.5 (s),

74.4 (d), 73.1 (t), 72.9 (t), 70.0 (d), 66.3 (t), 38.9 (s), 366.8

(d), 34.8 (d), 33.0 (d), 27.3 (q, 3C), 25.0 (q), 23.4 (q), 12.9

(q), 11.8 (q), 11.3 (q); MS (CI^C, CH₄) m/z (relative

intensity) 421 (MCH^C, 52), 363 (100), 345 (39), 261 (76),

255 (97), 173 (61), 171 (22); HRMS (CI^C, CH₄) Calcd for

C₂₅H₄₁O₅(MCH^C): 421.2954. Found: 421.2959.

6.7.1.3. (2S*)-2-((4S*,5S*,6R*)-6-Ethyl-2,2,5-tri-

methyl-1,3-dioxan-4-yl)propyl 2,2-dimethylpropanoate

40. Acetonide formation from diol 39 (25 mg,

0.096 mmol) provided, after puriﬁcation by ﬂash chroma-

tography (petroleum ether–EtOAc: 95/5), 20 mg (69%) of

40 as a colorless oil; IR 1730, 1285, 1200, 1160, 1020, 975,

865 cm^K1; ¹H NMR d 4.13 (dd, JZ10.7, 3.3 Hz, 1H), 4.07

(dd, JZ10.7, 5.5 Hz, 1H), 3.74 (m, 1H), 3.65 (dd, JZ10.1,

2.0 Hz, 1H), 1.92 (m, 1H), 1.62–1.33 (m, 3H), 1.37 (s, 6H),

1.21 (s, 9H), 0.90 (t, JZ7.4 Hz, 3H), 0.89 (d, JZ7.4 Hz,

3H), 0.83 (d, JZ7.0 Hz, 3H); ¹³C NMR d 178.6 (s), 98.8 (s),

75.1 (d), 73.8 (d), 66.2 (t), 38.9 (s), 34.3 (d), 31.9 (d), 29.9

(q), 27.3 (q, 3C), 25.7 (t), 19.5 (q), 12.2 (q), 9.8 (q), 4.2 (q);

MS-EI m/z (relative intensity) 285 (MKMe^C, 53), 242

(MKMe₂C]O^C, 1), 173 (28), 141 (20), 123 (100), 85 (38),

82 (85), 70 (19), 59 (51), 57 (79), 55 (15); HRMS (CI^C,

CH₄) Calcd for C₁₇H₃₃O₄(MCH^C): 301.2379. Found:

301.2385.

6.7.1.4. (1R*,2S*)-1-Ethyl-2-((4S*,5S*)-2,2,5-tri-

methyl-1,3-dioxan-4-yl)propyl 2,2-dimethylpropanoate

40⁰. Acetonide formation from diol 39⁰(10 mg,

0.038 mmol) provided, after puriﬁcation by ﬂash chroma-

tography (petroleum ether–EtOAc: 94/6), 4 mg (35%) of

40⁰; IR 1730, 1285, 1200, 1170 cm^K1; ¹H NMR d 4.85 (m,

1H), 3.70 (dd, JZ11.4, 5.0 Hz, 1H), 3.61 (dd, JZ10.3,

1.8 Hz, 1H), 3.51 (dd, apparent t, JZ11.4 Hz, 1H), 1.92–

1.79 (m, 2H), 1.73–1.50 (m, 2H), 1.42 (s, 3H), 1.34 (s, 3H),

1.22 (s, 9H), 0.91 (d, JZ7.0 Hz, 3H), 0.86 (t, JZ7.5 Hz,

3H), 0.70 (d, JZ6.6 Hz, 3H); ¹³C NMR d 177.9 (s), 97.9 (s),

77.2 (d), 74.7 (d), 66.3 (t), 38.9 (s), 36.4 (d), 30.6 (d), 29.7

(q), 27.3 (q, 3C), 24.1 (t), 18.8 (q), 12.4 (q), 9.5 (q), 8.8 (q);

MS-EI m/z (relative intensity) 285 (MKMe^C, 46), 242

(MKMe₂C]O^C, 4), 201 (35), 183 (11), 141 (26), 140 (11),

129 (44), 123 (84), 103 (46), 99 (34), 97 (10), 85 (53), 81

(12), 71 (22), 70 (14), 69 (16), 59 (82), 57 (100), 55 (13);

HRMS (CI^C, CH₄) Calcd for C₁₇H₃₃O₄(MCH^C):

301.2379. Found: 301.2379.

6.7. Oxymercuration of cyclopropanes of type G and H

6.7.1. Oxymercuration of cyclopropane 17. Compound 17

(125 mg, 0.516 mmol) was subjected to the oxymercura-

tion–reductive demercuration sequence and, after puriﬁ-

cation by ﬂash chromatography (petroleum ether–EtOAc

gradient: 80/20–0/100), 42 mg (32%) of 39, and 38 mg

(29%) of 39⁰were obtained as colorless oils.

6.7.1.1. (2S*,3S*,4S*,5R*)-3,5-Dihydroxy-2,4-dimethyl-

heptyl 2,2-dimethylpropanoate 39. R_f0.42 (petroleum

ether–EtOAc: 60/40); IR 3440, 1720, 1290, 1170, 970 cm^K1

;

¹H NMR d 4.43 (dd, JZ11.2, 4.5 Hz, 1H), 4.02 (dd, 11.2,

3.7 Hz, 1H), 3.90 (br s, 1H, OH), 3.72 (m, 1H), 3.47 (dd, JZ

M. Defosseux et al. / Tetrahedron 61 (2005) 7632–7653

7651

6.7.2. Oxymercuration of cyclopropane 24. Compound 24

(55 mg, 0.15 mmol) was subjected to the oxymercuration–

reductive demercuration procedures. After puriﬁcation by

ﬂash chromatography (petroleum ether–EtOAc gradient:

80/20–0/100), 21 mg (36%) of 45, 7 mg (12%) of 44 and

23 mg (40%) of 43 were obtained as colorless oils (88%

combined yield from 24).

(t), 39.1 (s), 38.8 (s), 35.3 (d), 34.3 (d), 30.7 (d), 29.7 (q),

27.4 (q, 3C), 27.2 (q, 3C), 18.7 (q), 15.2 (q), 12.2 (q), 8.7

(q); MS (CI^C, CH₄) m/z (relative intensity) 415 (MCH^C,

10), 357 (100), 313 (17), 255 (21), 153 (14); HRMS (CI^C,

CH₄) Calcd for C₂₃H₄₃O₆(MCH^C): 415.3060. Found:

415.3063.

6.7.2.5. (2R*,3R*,4S*,5S*,6S*)-5,7-Bis(2,2-dimethyl-

propanoyloxy)-3-hydroxy-2,4,6-trimethylheptyl 2,2-

dimethylpropanoate 47. To a mixture of 43 (13 mg,

0.035 mmol) and 44 (6 mg, 0.02 mmol) and DMAP

(107 mg, 0.876 mmol, 17 equiv) in CH₂Cl₂(2 mL) at rt,

was added PivCl (80 mL, 0.65 mmol, 13 equiv). After 15 h

at rt, the reaction mixture was hydrolyzed with a saturated

aqueous NH₄Cl solution and extracted with CH₂Cl₂. The

combined extracts were dried over MgSO₄, ﬁltered and

concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography (petroleum ether–EtOAc:

75/25) to afford 21 mg (93%) of 47 as a colorless oil; IR

3500, 1725, 1280, 1155 cm^K1; ¹H NMR d 4.97 (dd, JZ6.1,

5.3 Hz, 1H), 4.29 (dd, JZ11.0, 5.2 Hz, 1H), 4.18–4.09 (m,

2H), 3.88 (dd, JZ11.0, 7.7 Hz, 1H), 3.44 (ddd, JZ8.8, 4.8,

3.0 Hz, 1H), 2.64 (d, JZ4.8 Hz, 1H, OH), 2.20 (m, 1H),

2.04–1.89 (m, 2H), 1.22 (s, 9H), 1.21 (s, 9H), 1.20 (s, 9H),

1.00 (d, JZ6.6 Hz, 3H), 0.95 (d, JZ7.0 Hz, 3H), 0.88 (d,

JZ6.6 Hz, 3H); ¹³C NMR d 179.0 (s), 178.5 (s), 178.4 (s),

77.2 (d), 74.3 (d), 66.7 (t), 65.0 (t), 39.2 (s), 38.9 (s), 38.8

(s), 36.4 (d, 2C), 35.1 (d), 27.3 (q, 6C), 27.2 (q, 3C), 14.8

(q), 14.1 (q), 7.4 (q); MS (CI^C, CH₄) m/z (relative intensity)

459 (MCH^C, 24), 441 (27), 357 (100), 339 (21), 255 (22),

213 (13), 173 (29), 153 (72), 135 (30), 103 (51); HRMS

(CI^C, CH₄) Calcd for C₂₅H₄₇O₇(MCH^C): 459.3322.

Found: 459.3324.

6.7.2.1. (2R*,3R*,5S*,6S*)-7-(2,2-Dimethylpropanoy-

loxy)-3,5-dihydroxy-2,4,6-trimethylheptyl 2,2-dimethyl-

propanoate 45. R_f0.45 (petroleum ether–EtOAc: 70/30);

IR 3420, 1725, 1700, 1285, 1175, 1065, 970 cm^K^{1 1}H

;

NMR d 4.33 (dd, JZ11.1, 5.0 Hz, 2H), 4.03 (dd, JZ11.1,

3.7 Hz, 2H), 3.98 (br s, 2H, 2OH), 3.41 (m, 2H), 1.91 (m,

2H), 1.74 (m, 1H), 1.17 (s, 18H), 0.86 (d, JZ7.0 Hz, 9H);

¹³C NMR d 179.3 (s, 2C), 78.3 (d, 2C), 66.8 (t, 2C), 39.0 (s,

2C), 36.8 (d, 2C), 34.1 (d), 27.2 (q, 6C), 13.7 (q, 2C), 3.8

(q); MS (CI^C, CH₄) m/z (relative intensity) 375 (MCH^C,

81), 357 (52), 339 (12), 273 (28), 255 (22), 173 (55), 153

(100), 135 (41), 103 (53); HRMS (CI^C, CH₄) Calcd for

C₂₀H₃₉O₆(MCH^C): 375.2747. Found: 375.2744.

6.7.2.2. (2R*,3R*,4S*,5S*,6S*)-5-(2,2-Dimethyl-pro-

panoyloxy)-3,7-dihydroxy-2,4,6-trimethylheptyl 2,2-

dimethylpropanoate 44. R_f0.35 (petroleum ether–

EtOAc: 70/30); IR 3420, 1725, 1700, 1285, 1175,

1

970 cm^K1; H NMR d 4.96 (dd, JZ8.1, 4.0 Hz, 1H), 4.27

(dd, JZ11.1, 5.2 Hz, 1H), 4.11 (dd, JZ11.1, 3.9 Hz, 1H),

3.52 (m, 2H), 3.41 (dd, JZ8.1, 3.7 Hz, 1H), 2.41 (br s, 1H,

OH), 2.07–1.86 (m, 3H), 1.63 (br s, 1H, OH), 1.24 (s, 9H),

1.22 (s, 9H), 1.03 (d, JZ7.0 Hz, 3H), 0.96 (d, JZ6.6 Hz,

6H); ¹³C NMR d 179.3 (s), 178.9 (s), 77.4 (d), 75.3 (d), 66.4

(t), 63.8 (t), 39.2 (s), 38.9 (s), 37.5 (d), 36.3 (d), 36.2 (d),

27.3 (q, 3C), 27.2 (q, 3C), 14.3 (q), 14.2 (q), 7.5 (q).

6.7.2.3. (2R*,3R*,4R*,5S*,6S*)-3-(2,2-Dimethyl-pro-

panoyloxy)-5,7-dihydroxy-2,4,6-trimethylheptyl 2,2-

dimethylpropanoate 43. R_f0.18 (petroleum ether–

EtOAc: 70/30); IR 3420, 1725, 1700, 1290, 1175, 1030,

1070, 970 cm^K1; ¹H NMR d 4.85 (dd, JZ7.0, 4.0 Hz, 1H),

4.15 (dd, JZ11.0, 4.0 Hz, 1H), 3.91 (dd, JZ11.0, 7.0 Hz,

1H), 3.68 (m, 2H), 3.60 (dd, JZ8.8, 2.6 Hz, 1H), 3.38–3.15

(m, 2H, OH), 2.20 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.22

(s, 9H), 1.20 (s, 9H), 1.02 (d, JZ6.6 Hz, 3H), 0.89 (d, JZ

7.0 Hz, 3H), 0.84 (d, JZ6.6 Hz, 3H); ¹³C NMR d 179.2 (s),

178.4 (s), 80.0 (d), 77.3 (d), 68.4 (t), 65.0 (t), 39.3 (s), 38.9

(s), 37.4 (d), 37.2 (d), 36.0 (d), 27.2 (q, 6C), 14.6 (q), 13.9

(q), 7.2 (q).

Acknowledgements

M. D. and N. B. thank the MRES for a grant.

References and notes

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New York, 1991. (b) Sankawa, U., Barton, D. H. R.,

Nakanishi, K., Meth-Cohn, O., Eds.; Comprehensive natural

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colorless oil; IR 1725, 1280, 1200, 1150 cm^K1; ¹H NMR d

5.01 (dd, JZ6.8, 4.6 Hz, 1H), 4.33 (dd, JZ11.0, 3.9 Hz,

1H), 3.79–3.67 (m, 2H), 3.70 (dd, JZ11.8, 5.2 Hz, 1H),

3.56 (dd, apparent t, JZ11.2 Hz, 1H), 2.17 (m, 1H), 1.99

(td, JZ6.8, 2.2 Hz, 1H), 1.86 (m, 1H), 1.40 (s, 3H), 1.34 (s,

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(d, JZ6.6 Hz, 3H), 0.75 (d, JZ6.6 Hz, 3H); ¹³C NMR d

178.5 (s), 177.4 (s), 98.1 (s), 77.2 (d), 75.7 (d), 66.2 (t), 65.2

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Article Doi

Synthesis of polypropionate subunits from cyclopropanes

DOI: 10.1016/j.tet.2005.05.099

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