Synthesis of epothilone D with the forced application of oxycyclopropane intermediates

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 11, pp. 1653−1674. © Pleiades Publishing, Ltd., 2011.

Original Russian Text © A.L. Hurski, O.G. Kulinkovich, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 11, pp. 1623−1642

Dedicated to Academician O.M. Nefedov on occasion of his 80th anniversary

Synthesis of Epothilone D with the Forced Application

of Oxycyclopropane Intermediates

A. L. Hurski and O. G. Kulinkovich

Belorussian State University, Minsk, 220030 Belarus’, e-mail: o.kulinkovich@gmail.com

Received July 18, 2011

Abstract—The total synthesis of epothilone D with six-fold application in the intermediate stages of successive

cyclopropanation – opening or cleavage of the three-membered ring was performed. These transformations underlie

the new stereoselective method developed for coupling fragments С⁷–С¹²and С¹³–С²¹in the target molecule.

DOI: 10.1134/S1070428011110029

The cleavage of the three-membered ring of cyclo-

propane compounds is widely used in the organic syn-

thesis [1]. They proceed under mild conditions and with

the high selectivity due to the internal strain in the ring

and the presence of substituents capable of stabilizing

the reactive intermediates or providing for the reaction

course by a concerted mechanism.Asigniﬁcant synthetic

potential is inherent in particular to hydroxy-substituted

cyclopropanes for they are capable to convert under mild

conditions into carbonyl compounds, esters, allyl alco-

hols, allyl halides, and some other compounds [2]. Many

hydroxycyclopropanes are readily available, in particular,

by their preparation through the reaction of carboxylic ac-

ids esters with alkoxytitanacyclopropane reagents [3–5].

The latter can be generated directly from titanium(IV)

alkoxides and the corresponding Grignard reagents [3,

5] иor by the ligand exchange at the titanium(II) atom [4,

5]. Some cyclopropanol derivatives we have successfully

used in the synthesis of natural bioactive compounds [6].

Yet the disadvantage inherent to the reactions

based on the formation of cyclic intermediates with

their subsequent cleavage is the two-stage character.

This drawback is especially important at the repeated

application of this tactics. To this end we carried out

a multistage synthesis of compound with a complex

structure with the forced use of hydroxycyclopropane

intermediates, and the overall characteristics of this

process efﬁciency were compared with those for the

previously published approaches. We chose epothilone

D (I) as the target compound for due to the practical

importance of this compound the total schemes of its

synthesis were recently developed in several leading

laboratories [7–19].

To obtain epothilone D (I) [20] we used the popular

macrolactonization strategy [21]. The designing of the

carbon skeleton of the acyclic precursor was carried out

by the diastereoselective aldol addition of lithium enolate

of ketone II to aldehyde III (Scheme 1).

Scheme 1.

12

13

15

S

12

21

6

S

1

3

13

8

7

HO

5

+

N

8

16

O

17

N

16

O

1

17

7

5

3

O

6

OTBS

Macrolactonization

Aldol condensation

O

OH

O

C

cyclopropanol protection

II

I

III

of carboxy group

1653

HURSKI, KULINKOVICH

1654

To obtain the epothilone fragment С¹–С⁶(II) ester

Z-trisubstituted alkenes by the cationic cyclopropyl-allyl

rearrangement of Е-cyclopropyl sulfonates [26]. First

ester was obtained of unsaturated carboxylic acid XIV

suitable for the subsequent stereoselective transformation

of the ester function into a three-substituted alkene frag-

ment by the cyclopropanation reaction with an appropriate

alkoxytitanacyclopropane reagent (see below) followed

by the disrotatory cyclopropyl-allyl rearrangement [26,

27] (Scheme 3). It was suggested to convert the isopro-

penyl group into the corresponding α-methyl-substituted

aldehyde by the hydration of the multiple bond through

a stage of its chiral hydroborination [17].

IV [22] was converted into cyclopropanol V whose

magnesium alcoholate was acylated with pivaloyl

chloride (Scheme 2). On removing the acetal protection

from the formed compound VI aldehyde VII was brought

into the reaction with ketene acetal VIII [23] in the

presence of a chiral oxazaboralidinone catalyst IX [24].

The product Xb of the silylation of the hydroxy group in

hydroxyester Xa was further involved into the titanium-

catalyzed reaction with ethylmagnesium bromide at low

temperature. Under these conditions a regioselective

cyclopropanation occurred of the sterically more

accessible phenylcarboxylate moiety, and the obtained

cyclopropanol XI was further converted in 1,3-dioxolane

XII by treating with 2,2-dimethoxypropane in the

presence of pyridinium p-toluenesulfonate. The removal

of the pivaloyl protection in compound XII effected by

lithium aluminum hydride gave cyclopropanol XIII

converted into the ethylketone fragment С¹–С⁶(II) by

treating with KОН in methanol [25].

Compound XIV was obtained from available

lactone XV [28], and the lactone moiety was subjected

to regioselective cyclopropanation [3] into ester of

dihydroxyacid XVI. After the mesylation of the hydroxy

groups obtained compound XVII was treated with

magnesium bromide in ethyl ether cleanly leading both

to the cationic cyclopropyl-allyl rearrangement of the

cyclopropyl sulfonate fragment [27, 29] and to the

replacement of the secondary mesyl group by the bromine

atom. Obtained dibromide XVIII was further transformed

into compound XIV by the reductive dehalogenation with

The building up of fragment C⁷–C²¹(III) of more

complex structure was based on the application of the

method we had previously developed for the synthesis of

Scheme 2.

OEt OR¹

OEt

IV

EtMgBr, 50% Ti(OPr-i)₄

82%

CO₂Et

EtO

V, R¹= H

EtMgBr,

PivCl, 99%

VI, R¹= Piv

O

OTMS

OPh

O

,

N

PivO

OR²

BH

PivO

O

Ts

IX

TsOH, H₂O

90%

VIII

CO₂Ph

58%, 96% ee

Xa

Xb

Me₃SiCl,

Et₃N

R²= H (a), SiMe₃(b).

VII

MeO

OMe

,

OTMS

R³O

O

PivO

EtMgBr, Ti(OPr-i)₄, ^_30°C

74%

OH

.

Py HOTs

KOH

II

78%

99%

in 2 stages

XII, R³= Piv

XIII, R³= H

XI

LiAlH₄

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF EPOTHILONE D WITH THE FORCED APPLICATION

1655

Scheme 3.

EtMgBr,

OR

Ti(OPr-i)₄

RO

CO₂Pr-i

O

CO₂Pr-i

O

78%

XVI, R = H

XVII, R = Ms

XV

MsCl,

Et₃N

Mg, BrCH₂CH₂Br

Zn, AcOH

60%

CO₂Pr-i

98%

for 2 stages

Br

XVIII

XIV

zinc in acetic acid.

ated, and by the treatment of the product obtained with

magnesium bromide in ethyl ether it was converted into

a mixture of primary and secondary allyl bromides XXV

and XXVI in the ratio 78 : 22, and the three-substituted

double bond in the primary bromide XXV formed with

a high diastereoselectivity (E–Z, 99 : 1). By treating bro-

mides XXV and XXVI with lithium aluminum hydride

we succeeded to perform the reductive debromination of

the primary bromomethyl group. The subsequent treat-

ment of the reaction mixture with potassium acetate in

DMF provided the conversion of the unreacted secondary

bromide XXVI into the corresponding acetate that was

easily isolated by column chromatography from the target

diene XXVII [26] obtained in 48% yield with respect to

ester XIV.

TheestergroupofcompoundXIV wasfurthersubjected

to the cyclopropanation by the alkoxytitanacyclopropane

reagent generated from functionalized terminal oleﬁn

XIX through the ligand substitution at the titanium(II)

atom (Scheme 4) [4]. Compound XIX was synthesized

proceeding from optically pure (R)-methyl-2,3-О-

isopropylideneglycerate (XX) obtained from D-mannitol.

Glycerate XX along the scheme we had lately described

[30] was converted in 40% yield in oxirane XXI. The

treatment of oxirane XXI with vinylmagnesium bromide

in the presence of a copper catalyst [31] followed by the

removal of the mesylate moiety by treating with excess

ethylmagnesium bromide furnished in a good yield diol

XXII that was converted into dioxolane XIX.

After the hydrolysis of acetonide XXVII and the

successive treatment of the obtained diol with pivaloyl

chloride and mesyl chloride we obtained substituted

cyclopropyl sulfonate XXVIII that was in a plausible

yield converted into allyl bromide XXIX by the action

of magnesium bromide [27, 29] in toluene at 100°С in

the presence of diisopropylethylamine (Scheme 6). The

attempts to convert cyclopropyl sulfonate XXVIII into

The hydroxycyclopropanation of the terminal double

bond in compound XIX with ester XIV in the presence

of butylmagnesium bromide and titanium(IV) isopropox-

ide proceeding through the stage of the ligand exchange

in the intermediate 2-butyltitanacyclopropane reagent

[Ti(II) – 1-butene complex XXIII] [4] resulted in cis-

1,2-disubstituted cyclopropanol XXIV as a mixture of

diastereomers (Scheme 5). Compound XXIV was mesyl-

Scheme 4.

O

OMs

O

OMe

D-mannitol

40%

5 stages

O

XX

XXI

,

MgBr

(1) CuCN

(2) Excess of

EtMgBr

2,2-Domethoxy-

O

.

propane, Py HOTs

OH

O

79%

84%

XIX

XXII

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

HURSKI, KULINKOVICH

1656

Scheme 5.

Ti(OPr-i)₂

OR

Ti(OPr-i)₂

XIV

XXIII

^_C₂H₅CH CH₂

67%

XIX

O

XXIVa

XXIVb

MsCl,

Et₃N

R = H (а), Ms (b).

Br

(1) LiAlH₄

(2) AcOK

Br

Mg, BrCH₂CH₂Br

98%

+

73%

O

XXVI, 22%

XXVII

XXV, 78%

Scheme 6.

.

(1) Py HOTs, MeOH

Mg, BrCH₂CH₂Br,

(i-Pr)₂NEt

(2) PivCl, Py, DMAP,

then MsCl

XXVII

Br

62%

69%

OR²

R¹O

XXVIIIa, XXVIIIb

OPiv

XXIX

R¹= R²= H (a); R¹= Piv, R²= Ms (b).

S

t-BuOK

73%

N

BrMg

N

XXX

OR³

XXXIIа, XXXIIb

R³= H (a), TBS (b).

OPiv

OPic

CuI, THF

XXXI

72%

(1) TBSCl, ImH

(2) (^_)-Ipc₂BH, NaBO₃

S

N

70%

OTBS

XXXIII

TBS is t-BuMe₂Si, Ipc is isopinocamphenyl.

OH

the target product in the absence of sterically hindered

base resulted in the chromatographically unseparable

mixtures of low polar compounds.

complications. The substrate conversion was not com-

plete, and the yields of the reaction product (42–57%)

were irreproducible. We established that the decrease in

the yield was due to the concurrent S_N2′ substitution of

the pivaloyloxy group in the expected triene XXXI. This

side process of allyl substitution was successfully avoided

The coupling of bromide XXIX with thiazolylmag-

nesium bromide XXX under the conditions previously

developed by our research team [32] also occurred with

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF EPOTHILONE D WITH THE FORCED APPLICATION

1657

(Scheme 8) containing a Е-trisubstituted double bond

by replacement the ethyl ether as solvent by THF.

conjugated with the thiazole moiety.

The double bond in compound XXXI was transferred

from the β-position with respect to the thiazole ring into

the position conjugated with the latter by treating with

potassium tert-butylate by the previously developed

procedure [32]. Simultaneously the pivaloyl protection

was removed, and alcohol XXXII formed with a high

diastereoselectivity. The hydroxy group in the latter was

protected with tert-butyldimethylsilyl chloride, and the

obtained silyl ether was brought into the hydroborination–

oxidation reaction. In contrast to [17] the hydration of the

multiple bond proceeded here with low stereoselectivity

giving a mixture of diastereomers in the ratio 60 : 40 with

target alcohol XXXIII prevailing.

Synthesis of compound XXXIV was started with

biscyclopropanol XXXVI prepared from diethyl adipate

[33] which was converted in 63% yield into pivaloate

XXXVII whose unprotected cyclopropanol moiety

was subjected to oxidative cleavage with phenyliodoso

diacetate in acetic acid [34]. As a result a mixture of acid

XXXVIII, its anhydride and mixed anhydride with acetic

acid formed. The dilution of the reaction mixture with aque-

ous THF and the subsequent short boiling led to the hydro-

lysis of anhydrides and to the high yield of acid XXXVIII

that was further methylated by Evans method through the

conversion into acid chloride, entered into the condensa-

tion with oxazolidinone XXXIX, and the obtained product

was alkylated with methyl iodide. By treating compound

XL with lithium borohydride the primary alcohol was

obtained, and the pivaloyl protection was removed with

lithium aluminum hydride. The cleavage of the obtained

cyclopropanol XLI into the corresponding methyl ester

by the action of phenyliodoso diacetate in methanol [34]

and protecting the primary hydroxy group with the use

of tetrahydropyranyl protection afforded ester XXXIV in

30% yield with respect to diethyl adipate.

Thus in the described approach to the synthesis of

fragment С⁷–С²¹(XXXIII) the use of the cyclopropanol

intermediates made it possible to build up both trisub-

stituted oleﬁn moieties with a high isomeric purity. Yet

the low diastereoselectivity of the hydroborination and

the multistage manipulations with the functionalized

diene XXVII resulted in the low overall yield of alcohol

XXXIII from ester XX (1.2% in 18 stages). This result

prompted us to ﬁnd an alternative approach to the prepa-

ration of fragment С⁷–С²¹(III), based on the coupling of

ester XXXIV (Scheme 7) with the build up at С⁸methyl

branching and the derivative of homoallyl alcohol XXXV

In the preparation of the sililated homoallyl alcohol

XXXV as well as in the synthesis of the fragment С¹³–С¹⁷

Scheme 7.

OH

PivCl, Py, DMAP

63%

OH

OPiv

XXXVII

XXXVI

O

PhI(OAc)₂, AcOH,

then H₂O, THF, boiling

93%

NaHMDS, MeI

82%

R¹

N

O

OPiv

Bn

XL

O

XXXVIIIа

(1) LiBH₄

(2) LiAlH₄

LiN

SOCl₂,

R¹= OH (а), 4-benzyl-2-оxooxazolidine-3-yl (b).

O

Bn

80%

XXXVIIIb

XXXIX

(1) PhI(OAc)₂, MeOH;

(2) DHP, Py HOTs

.

O

OR³

OH

86%

OR²

OMe

XLIа, XLIb

R²= Piv (a), H (b).

XXXIVа, XXXIVb

R³= H (а), ТНР (b).

HDMS is hexamethyldisilazide

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

HURSKI, KULINKOVICH

1658

Scheme 8.

OH

OTBS

OAc

TBSCl, ImH

92%

N

S

XXI

Br

64%

for 3 stages

68%

for 3 stages

S

XLII

XLIII

XXXV

(XIX) was used oxirane XXI. The latter in the overall

yield 40% in 6 stages was converted into silyl ether

XXXV through intermediate bromide XLII and alcohol

XLIII [30].

tained cyclopropanol and the subsequent reaction of the

arising mixture of diastereomeric mesylates with magne-

sium bromide furnished bromides XLV and XLVI in the

ratio 87 : 13. By treating the obtained mixture with lithium

aluminum hydride primary bromide XLV was reduced

into alkene XLVII, and after converting the unreacted

bromide XLVI into the corresponding acetate the column

chromatography gave the protected diol XLVII [26]. On

deprotecting the primary hydroxy group and Swern oxida-

tion of the arising alcohol XXXIII we obtained aldehyde

III in a high yield.

Although compound XXXV contained an al-

lyl alcohol moiety highly reactive with respect to

alkoxytitanacyclopropane intermediates [35] we still

succeeded in the choice of conditions for the regioselec-

tive hydroxycyclopropanation of the terminal double

bond. The reaction was carried out in THF in the pres-

ence of four-fold excess of cyclopentylmagnesium

chloride [36] and of equimolar amount of titanium(IV)

isopropoxide giving as a result cyclopropanol XLIV

as the mixture of diastereomers (1:1.4) with excellent

(Е)-diastereoselectivity and with the yield of 95% with

respect to alkene (Scheme 9). The mesylation of the ob-

The building of the carbon skeleton of the epothilone

D molecule was performed by the syn-selective addition

of the lithium enolate of ethyl ketone II to aldehyde III [9,

12]. On removing the acetonide protection in the formed

hydroxyketone XLVIII by the action of 80% formic acid

Scheme 9.

OR

MgCl, Ti(OPr-i)₄

S

XXXIV + XXXV

66% from XXXIV

95% from XXXV

THPO

N

OTBS

XLIVа, XLIVb

R = H (а), Ms (b).

Br

(1) MsCl, Et₃N

(2) Mg, BrCH₂CH₂Br

Br

S

THPO

+

N

THPO

98%

N

OTBS

XLVI, 13%

XLV, 87%,

E/Z > 99 : 1

S

(1) LiAlH₄

(2) AcOK

N

R

OTBS

60%

.

XLVII, R = CH₂OTHP

XXXVIII

III

i-PrOH, Py HOTs, 94%

(COCl)₂, DMSO, Et₃N, 92%

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF EPOTHILONE D WITH THE FORCED APPLICATION

1659

Scheme 10.

S

HO

HCO₂H

77%

LDA

80%

HO

N

II + III

N

OTBS

O

OH

XLIX

XLVIII

(1) TBSOTf, 2,6-lutidine

(2) AcOH, H₂O, THF

(3) Bu₄NF

S

PhI(OAc)₂, H₂O

91%

TBSO

HO

N

60%

OH

CO₂H

OTBS

CO₂H

O

OH

L

LI

2,4,6-Cl₃C₆H₂COCl,

CF₃CO₂H

DMAP

Et₃N,

I

LII

in ethyl ether at room temperature the cyclopropanol frag-

ment of triol XLIX was converted into a carboxy group

by treating with phenyliodoso diacetate in aqueous THF

(Scheme 10) [34]. By the standard transformations of the

protecting groups obtained acid L was transformed into

hydroxyacid LI which was subjected to macrolactoniza-

tion by Yamaguci method [9, 37], and on removing the

silyl protections we obtained epothilone D (I).

cyclopropanols preparation and the reactions of the cleav-

age of the three-membered ring of hydroxycyclopropane

intermediates, and also the low price of the corresponding

reagents and catalysts. The latter statement was quantita-

tively illustrated by the estimation from the catalog data

[38] the average price of the molar amounts of reagents

and the corresponding proportional quantities of catalysts.

In the previously published syntheses of epothilone D it

equaled 37 × 10³€ ·mol^–1, whereas in this work it was

11×10³€ ·mol^–1. The latter value had the smallest abso-

lute magnitude, and calculated per 1% of epothilone D

(I) yield this approach was in the ﬁrst ﬁve “proﬁtable”

procedures [9, 10, 12, 15].

To estimate the advantages and drawbacks of the above

described “cyclopropanol” approach to the synthesis of

epothilone D we compared the overall yields and the

number of stages in the longest linear successions of

syntheses carried out by the other research teams [8–19].

Besides we calculated, when possible, the total number

of the preparative stages.

In conclusion, it should be stated that we performed

the total synthesis of epothilone D (I) with the six-fold

application of the reactions of opening and fragmenta-

tion of the three-membered ring of the intermediate

hydroxycyclopropane compounds for building up (Z)-

С¹²–С¹³and (E)-С¹⁶–С¹⁷trisubstituted double bonds,

ethylketone fragment, and also for the protection of

carboxy and ester groups. Although each of these syn-

thetic operations required carrying out successive reac-

tions of the formation and the cleavage of the ring of the

hydroxycyclopropane intermediates the advantage of

the developed cyclopropanol procedure consisted in the

simplicity of the experiment, the multifunctional latent-

ness of the hydroxycyclopropane moiety, and relatively

The yields of epothilone D (I) in the synthesis we

developed in the longest linear successions of 23 stages

proceeding from diethyl adipate and 24 stages, from

(R)-methyl 2,3-О-isopropylidene glycerate (XX) were 2

and 1.6% respectively. It is close to the average number

of stages (22) and overall yield (2.3%) in the previously

described approaches. The overall number of stages

(44) of the synthesis of epothilone D (I) carried out in

this study was as expected considerably larger than the

average number (31) in the known syntheses. Yet as the

advantages of the used approach should be mentioned the

experimental simplicity of performing the reactions of

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

HURSKI, KULINKOVICH

1660

saturated NaHCO₃solution. The organic layer was sepa-

low cost of the used reagents.

rated, the products were extracted from the water layer

into Et₂O. The combined organic solutions were washed

with brine and dried with MgSO₄. The solvents were dis-

tilled off under a reduced pressure, the residue was chro-

matographed on silica gel (eluent petroleum ether–ethyl

acetate). Yield 7.38 g (99%). IR spectrum, ν, cm^–1: 3096

(СН of cyclopropane), 1740 (CO₂). ¹H NMR spectrum,

δ, ppm: 0.76–0.79 m (2H, СН of cyclopropane), 0.84 s

[6H, С(СН₃)₂], 0.93–0.96 m (2H, СН pf cyclopropane),

1.15 s [9H, С(СН₃)₃], 1.22 t (6H, СН₂СН₃, J 6.9 Hz),

3.58 d.q (2H, СН₂СН₃, J₁9.0, J₂6.9 Hz), 3.80 d.q (2H,

СН₂СН₃, J₁9.0, J₂6.9 Hz), 4.36 s [1H, CH(OEt)₂].

¹³C NMR spectrum, δ, ppm: 9.2 (2CН₂), 15.4 (2СН₃),

19.4 (2СН₃), 27.1 (3СН₃) 38.9 (С), 43.0 (С), 64.0 (С),

66.0 (2СН₂), 107.9 (СН), 177.4 (С). Found, %: C 67.12;

H 10.58. C₁₆H₃₀O₄. Calculated, %: С 67.10; H 10.56.

EXPERIMENTAL

¹H and ¹³С NMR spectra of compounds solutions in

deuterochloroform were registered on a spectrometer

BrukerAC 400 at operating frequencies 400 and 100 MHz

respectively. IR spectra were recorded on a spectropho-

tometer Bruker Vertex 70 from solutions in tetrachloro-

methane. Melting points were measured in capillaries on

an instrument Apotec. The chromatographic isolation of

individual substances was carried out on columns packed

with silica gel (70–230 mesh). All solvents before use

were dried by common methods and distilled.

1-(1,1-Diethoxy-2-methylpropan-2-yl)cyclo-

propanol (V). To a solution of 8.62 g (39.5 mmol) of

ester IV and 5.9 ml (19.8 mmol) of Ti(OPr-i)₄in 40 ml

of THF at room temperature was added dropwise within

2 h a solution of ethylmagnesium bromide obtained

from 4.74 g (198 mmol) of magnesium and 14.8 ml

(198 mmol) of ethyl bromide in 130 ml of THF. The

reaction mixture was stirred for 30 min, the solvent was

distilled off under a reduced pressure, the residue was dis-

solved in 100 ml of CH₂Cl₂, cooled with ice, and treated

with 24 ml of saturated NH₄Cl solution. The precipitate

was ﬁltered off, washed with CH₂Cl₂, the ﬁltrate was

washed with saturated NaHCO₃solution and dried with

MgSO₄. The solvents were distilled off under a reduced

pressure, the residue was chromatographed on silica

gel (eluent petroleum ether–ethyl acetate). Yield 6.52 g

(82%). IR spectrum, ν, cm^–1: 3517 (ОН), 3094 (СН of

cyclopropane). ¹H NMR spectrum, δ, ppm: 0.52–0.61 m

(4H, СН of cyclopropane), 0.87 s [6Н, С(СН₃)₂], 1.23 t

(6Н, СН₂СН₃, J 7.0 Hz), 3.58 d.q (2H, СН₂СН₃, J₁9.0,

J₂7.0 Hz), 3.88 d.q (2H, СН₂СН₃, J₁9.0, J₂7.0 Hz),

3.96 br.s (1Н, ОН), 4.29 s [1Н, CH(OEt)₂]. ¹³C NMR

spectrum, δ, ppm: 9.2 (2СН₂), 15.4 (2СН₃), 19.9 (2СН₃),

41.6 (С), 59.6 (С), 66.3 (2СН₂), 111.4 (СН). Found, %:

C 65.22; H 10.90. C₁₁H₂₂O₃. Calculated, %: С 65.31;

H 10.96.

1-(2-Methyl-1-oxopropan-2-yl)cyclopropyl

pivaloate (VII). To a solution of 7.38 g (25.8 mmol) of

acetal VI in 90 ml of 90% aqueous acetone was added

0.1 g of p-toluenesulfonic acid. The reaction mixture was

maintained for 3 h (TLC monitoring), acetone was dis-

tilled off under a reduced pressure, the residue was treated

with saturated NaHCO₃solution, and the water phase

was extracted with Et₂O. The combined organic solutions

were washed with brine and dried with MgSO₄. The sol-

vents were distilled off under a reduced pressure, the resi-

due was chromatographed on silica gel (eluent petroleum

ether–ethyl acetate). Yield 4.93 g (90%). IR spectrum,

ν, cm^–1: 3103 (СН of cyclopropane), 1742 (C=O), 1740

(C=O).

¹H NMR spectrum, δ, ppm: 0.83–0.86 m (2H,

СН of cyclopropane), 1.00 с [6H, С(СН₃)₂], 1.01–1.04 m

(2H, СН of cyclopropane), 1.11 с [9H, С(СН₃)₃], 9.64 s

(1H, CHO). ¹³C NMR spectrum, δ, ppm: 8.3 (2СН₂), 19.0

(2СН₃), 26.8 (3СН₃), 38.6 (С), 48.1 (С), 61.7 (С), 178.3

(С), 202.6 (СН). Found, %: C 67.75; H 9.48. C₁₂H₂₀O₃.

Calculated, %: С67.89; H 9.50.

(3S)-Phenyl 3-hydroxy-4-methyl-4-[1-(pivaloyloxy)-

cyclopropyl]pentanoate (Xа). To a solution of 2.91 g

(10.7 mmol) of N-tosyl-L-valine in 85 ml of CH₂Cl₂was

added at stirring within 20 min 10.9 ml (10.7 mmol) of

0.98 M borane solution in THF. The reaction mixture

was stirred for 30 min more and it was cooled to –80°С.

On cooling to the reaction mixture was added dropwise

in succession 1.8 g (8.49 mmol) of aldehyde VII and

3.48 g (16.7 mmol) of ketene acetal VIII. The solution

was warmed to –50°С, stirred for 6 h, treated with 40 ml

of phosphate buffer solution, and then warmed to room

1-(1,1-Diethoxy-2-methylpropan-2-yl)cyclopropyl

pivaloate (VI). To a solution of 5.30 g (26.2 mmol) of

cyclopropanol V in 25 ml of THF was added at stirring

and cooling with ice within 3 min 14.7 ml (27.0 mmol)

of 1.85 M solution of ethylmagnesium bromide in Et₂O.

After 15 min to the reaction mixture at room temperature

was added 3.5 ml (28.4 mmol) of pivaloyl chloride, the

solution was stirred for 12 h, cooled, and treated with

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF EPOTHILONE D WITH THE FORCED APPLICATION

1661

of cyclopropane), 0.97–1.08 m (2H, CH of cyclopropane),

1.09 s [3H, C(CH₃)₂], 1.17 s [9H, C(CH₃)₃], 2.60 d.d

(1H, CH₂, J₁16.4, J₂9.5 Hz), 3.35 d.d (1H, СН₂, J₁16.4,

J₂1.5 Hz), 4.28 d.d (1H, СHOTMS, J₁9.5, J₂1.5 Hz),

7.12–7.14 m (2H, C₆H₅O), 7.20–7.23 m (1H, C₆H₅O),

7.36–7.40 m (2H, C₆H₅O). ¹³C NMR spectrum, δ, ppm:

0.6 (3CH₃), 8.8 (CH₂), 11.3 (CH₂), 17.2 (CH₃), 24.4

(CH₃), 27.1 (3CH₃), 39.0 (СН₂, С), 42.1 (С), 64.0 (С),

73.9 (СН), 121.6 (2СН), 125.6 (СН), 129.3 (2СН), 150.9

(С), 171.3 (С), 177.5 (С). Found, %: C 65.77; H 8.70.

C₂₃H₃₆O₅Si. Calculated, %: С 65.68; H 8.63.

temperature. The organic layer was separated, the water

layer was extracted with CH₂Cl₂. The combined organic

solutions were washed with brine and dried with MgSO₄.

The solvents were distilled off under a reduced pressure,

the residue was dissolved in hexane, and the solution ob-

tained was kept at room temperature for 1 h. The precipi-

tate was ﬁltered off, washed with hexane, the ﬁltrate was

evaporated, the residue was subjected to chromatography

on silica gel (eluent petroleum ether–ethyl acetate). We

obtained 0.41g (23%) of initial aldehyde VII and 1.33 g

(45%, with respect to the reacted aldehyde VII 58%) of

compound X, [α]_D+31° (c 6.2, CHCl₃). IR spectrum, ν,

cm^–1: 3611 (ОН), 3492 (ОН), 3102 (СН of cyclopropane),

1-[(3S)-4-(1-Hydroxycyclopropyl)-2-methyl-3-

(trimethylsiloxy)but-2-yl]cyclopropyl pivaloate (XI).

To a solution of 1.52 g (3.62 mmol) of compound Xb

and 2.2 ml (7.40 mmol) of Ti(OPr-i)₄in 36 ml of Et₂O

at –35°С was added within 2 h while stirring 11 ml

(22 mmol) of 2 M ethylmagnesium bromide solution.

The reaction mixture was treated with 2.6 ml of H₂О,

the precipitate was ﬁltered off, washed with EtOAc, the

ﬁltrate was evaporated, the residue was chromatographed

on silica gel (eluent petroleum ether–ethyl acetate). We

obtained 0.23 g (15%) of initial ester Xb and 0.81 g (63%,

with respect to reacted ester Xb 74%) of compound XI.

[α]_D–18° (c 2.0, CHCl₃). IR spectrum, ν, cm^–1: 3542

(ОН), 3081 (СН of cyclopropane), 1723 (СО₂). ¹H NMR

spectrum, δ, ppm: 0.15 s [9H, Si(CH₃)₃], 0.29–0.34 m

(1H, СН of cyclopropane), 0.50–0.67 m (3H, СН of

cyclopropane), 0.58 s [3H, C(CH₃)₂], 0.70–1.06 m (4H,

СН of cyclopropane), 1.10 s [3H, C(CH₃)₂], 1.12 s

[9H, C(CH₃)₃], 1.45 d.d (1H, CH₂, J₁14.3, J₂10.2 Hz),

2.44 d.d (1H, CH₂, J₁14.3, J₂1.5 Hz), 2.90 br.s (1H, ОН),

3.96 d.d (1H, СНOTMS, J₁10.2, J₂1.5 Hz). ¹³C NMR

spectrum, δ, ppm: 1.2 (3СН₃), 8.5 (СН₂), 11.7 (СН₂),

12.2 (СН₂), 14.1 (СН₂), 16.5 (СН₃), 25.6 (СН₃), 27.0

(3СН₃), 39.0 (С), 40.1 (СН₂), 42.1 (С), 53.8 (С), 65.0

(С), 75.7(СН), 178.5 (С). Found, %: C 64.17; H 10.17.

C₁₉H₃₆O₄Si. Calculated, %: С 64.00; H 10.18.

1

1763 (СO₂), 1720 (СO₂). H NMR spectrum, δ, ppm:

0.54–0.62 m (1H, CH of cyclopropane), 0.73–0.79 m (1H,

CH of cyclopropane), 0.76 s [3H, C(CH₃)₂], 1.07 s [3H,

C(CH₃)₂], 1.07–1.13 m (1H, CH of cyclopropane), 1.18 s

[9H, C(CH₃)₃], 1.22–1.30 m (1H, CH of cyclopropane),

2.64–2.74 m (2H, CH₂), 3.99 d.t (1H, CHOH, J₁9.0,

J₂3.6 Hz), 4.40 d (1H, OH, J 3.6 Hz), 7.08–7.11 m (2H,

C₆H₅O), 7.19–7.23 m (1H, C₆H₅O), 7.35–7.39 m (2H,

C₆H₅O). ¹³C NMR spectrum, δ, ppm: 7.3 (CH₂), 11.7

(CH₂), 16.9 (CH₃), 22.4 (CH₃), 27.0 (3CH₃), 37.2 (CH₂),

39.0 (C), 41.1 (C), 64.8 (C), 71.8 (CH), 121.6 (2CH),

125.7 (CH), 129.3 (2CH), 150.8 (C), 171.2 (C), 180.4

(C). Found, %: C 68.69; H 8.16. C₂₀H₂₈O₅. Calculated,

%: С68.94; H 8.10. The enantiomeric purity of alcohol

X (96% ее) was determined by Mosher procedure [39]

by integrating the signals of protons of СНОMTРА

group at δ 5.83 and 5.85 ppm (main isomer) in the

¹Н NMR spectrum with its ester of (S)-α-methoxy-α-

triﬂuoromethylphenylacetic acid (MTPA).

Phenyl 4-methyl-4-[(1S)-1-(pivaloyloxy)cyclo-

propyl]-3-(trimethylsiloxy)pentanoate (Xb). To

a solution of 0.59 g (1.70 mmol) of alcohol Xa and 0.5 ml

(3.6 mmol) of Et₃N in 6 ml of THF at cooling with ice

while stirring was added dropwise 0.33 ml (2.6 mmol) of

trimethylchlorosilane. The reaction mixture was warmed

to the room temperature, left overnight, and treated with

saturated aqueous solution of NaHCO₃. The organic layer

was separated, the water layer was extracted with Et₂O.

The combined organic solutions were washed with brine

and dried with MgSO₄. The solvents were distilled off un-

der a reduced pressure, the residue was chromatographed

on silica gel (eluent petroleum ether–ethyl acetate). Yield

0.63 g (88%), [α]_D–35° (c 2.0, CHCl₃). IR spectrum,

ν, cm^–1: 3101 (CH of cyclopropane), 1761 (СО₂),

1-[2-{(7S)-5,5-Dimethyl-4,6-dioxaspiro[2.5]-oct-

7-yl}propan-2-yl]cyclopropyl pivaloate (XII). To

a solution of 0.56 g (1.56 mmol) of compound XI in 8 ml

of anhydrous acetone was added 0.76 ml (6.16 mmol) of

2,2-dimethoxypropane and 50 mg of pyridinium tosylate

(Py·HOTs). The reaction mixture was left overnight,

the solvents were distilled off, the residue was chroma-

tographed on silica gel (eluent petroleum ether–ethyl

acetate). Yield 0.50 g (99%), [α]_D8° (c 2.5, CHCl₃).

IR spectrum, ν , cm^–1: 3065 (CH of cyclopropane),

1

1736 (Piv). H NMR spectrum, δ, ppm: 0.35–0.41 m

1740 (СО₂). H NMR spectrum, δ, ppm: 0.12 s [9H,

(1H, CH of cyclopropane), 0.60–0.87 m (6H, CH of

Si(CH₃)₃], 0.70 s [3H, C(CH₃)₂], 0.79–0.90 m (2H, CH

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

HURSKI, KULINKOVICH

1662

prepared from 11.14 g (464 mmol) of magnesium and

34.6 ml (470 mmol) of ethyl bromide in 300 ml of THF.

The solvent was distilled off at a reduced pressure, the

residue was dissolved in 200 ml of СН₂Cl₂, the solution

was cooled and treated 56 ml of saturated NH₄Cl solution.

The precipitate was ﬁltered off, washed with acetone,

the ﬁltrate was evaporated. The residue was dissolved in

a mixture of petroleum ether and, 1 : 1, the solution was

ﬁltered through a bed of silica gel,the ﬁltrate was evapo-

rated. Yield 18.28 g (78%), [α]_D–3° (c 10, CHCl₃). IR

spectrum, ν, cm^–1: 3601 (ОН), 3474 (ОН), 3087 (СН of

cyclopropane), 1728 (СО₂). ¹H NMR spectrum, δ, ppm:

0.44 m (2H, СН of cyclopropane), 0.75 m (2H, СН of

cyclopropane), 1.27 d [3H, OCH(CH₃)₂, J 6.1 Hz], 1.28 d

[3H, OCH(CH₃)₂, J 6.1 Hz], 1.69 m (2H, CH₂С), 1.85 m

(1H, CH₂СНОН), 2.09 m (1H, CH₂СНОН), 2.98 br.s (1H,

ОН), 3.33 br.s (1H, ОН), 4.21–4.25 m (1H, СНОН), 5.09

septet [1H, OCH(CH₃)₂, J 6.1 Hz]. ¹³C NMR spectrum,

δ, ppm: 13.7 (2СН₂), 21.7 (СН₃), 21.8 (СН₃), 31.0 (СН₂),

34.2 (СН₂), 55.1 (С), 69.6 (СН), 70.4 (СН), 174.6 (С).

Found, %: C 59.57; H 8.89. C₁₀H₁₈O₄. Calculated, %:

С 59.39; H 8.97.

cyclopropane), 0.66 s [3H, C(CH₃)₂], 0.87–0.96 m (1H,

CH of cyclopropane), 0.99 s [3H, C(CH₃)₂], 1.14 s [9H,

C(CH₃)₃], 1.25 d.d (1H, CH₂, J₁12.8, J₂2.3 Hz), 1.32 s

[3H, O₂C(CH₃)₂], 1.46 s [3H, O₂C(CH₃)₂], 2.06 t (1H,

CH₂, J 12.5 Hz), 3.97 d.d (1H, CHO, J₁11.8, J₂2.3 Hz).

¹³C NMR spectrum, δ, ppm: 8.0 (CH₂), 10.0 (CH₂), 10.1

(CH₂), 14.2 (CH₂), 17.9 (CH₃), 21.1 (CH₃), 22.3 (CH₃),

27.0 (3 CH₃), 29.9 (CH₃), 32.4 (CH₂), 38.9 (C), 40.4

(C), 53.9 (C), 63.7 (C), 72.5 (CH), 99.9 (C), 177.4 (C).

Found, %: C 70.12; H 10.02. C₁₉H₃₂O₄. Calculated, %:

С 70.33; H 9.94.

2-{(7S)-5,5-Dimethyl-4,6-dioxaspiro[2.5]oct-7-yl}-

2-methylpentan-3-one (II). To a dispersion of 0.05 g

(1.32 mmol) of LiAlH₄in 3 ml of Et₂O at cooling with

ice while stirring was added dropwise asolution of 0.4 g

(1.24 mmol) of pivaloate XII in 1 ml of Et₂O. The reac-

tion mixture was warmed to room temperature and 1 h

later it was treated with 0.2 ml of H₂O at cooling with ice.

The precipitate was ﬁltered off, washed with Et₂O, the

ﬁltrate was evaporated. The obtained crude cyclopropanol

XIII was dissolved in 5 ml of 5% methanol solution of

KOH and boiled for 4 h. The solvent was distilled off,

to the residue H₂O and Et₂O were added. The organic

layer was separated, the products from the water layer

were extracted into Et₂O. The combined organic solu-

tions were washed with brine and dried with MgSO₄.

The solvents were distilled off under a reduced pressure,

the residue was chromatographed on silica gel (eluent

petroleum ether–ethyl acetate). Yield 0.233 g (78%).

[α]_D+29° (c 3.6, CHCl₃). IR spectrum, ν, cm^–1: 3080

Isopropyl 2-(methylsulfonyloxy)-4-[1-(methyl-

sulfonyloxy)cyclopropyl]butanoate (XVII). To

a solution of 18.28 g (90 mmol) of diol XVI and 52 ml

(374 mmol) of Et₃N in 300 ml of Et₂O at cooling with

ice water was added within 20 min at stirring 21 ml

(271 mmol) of mesyl chloride. The reaction mixture was

warmed to room temperature, stirred for 30 min, and

treated with solution of NaHCO₃. The organic layer was

separated, the water layer was extracted with Et₂O. The

combined organic solutions were washed with brine and

dried with MgSO₄. The solvents were distilled off under

a reduced pressure. Yield 32.43 g (100%), mp 51–52°С,

[α]_D–10° (c 7.9, CHCl₃). IR spectrum, ν, cm^–1: 3070

(СН of cyclopropane), 1731 (СО₂), 1359 (SO₂), 1175

1

(CH₂of cyclopropane), 1664 (C=O). H NMR spec-

trum, δ, ppm: 0.32–0.37 m (1H, CH of cyclopropane),

0.54–0.59 m (1H, CH of cyclopropane), 0.66–0.71 m

(1H, CH of cyclopropane), 0.78–0.83 m (1H, CH of

cyclopropane), 0.79 d.d (1H, CH₂, J₁12.8, J₂2.3 Hz),

0.98 t (3H, CH₂CH₃, J 7.2 Hz), 1.04 s [3H, C(CH₃)₂],

1.12 s [3H, C(CH₃)₂], 1.28 s [3H, О₂С(СН₃)₂], 1.45 s

[3H, О₂С(СН₃)₂], 2.04 t (1H, СН₂, J 12.3 Hz), 2.51 q

(2H, CH₂CH₃, J 7.2 Hz), 4.18 d.d (1H, СНО, J₁11.8,

J₂2.3 Hz). ¹³C NMR spectrum, δ, ppm: 7.8 (CH₃), 9.9

(CH₂), 14.4 (CH₂), 19.1 (CH₃), 20.9 (CH₃), 21.0 (CH₃),

29.6 (CH₃), 31.5 (CH₂), 31.6 (CH₂), 50.3 (C), 53.6 (C),

73.3 (CH), 100.0 (C), 215.4 (C). Found, %: C 69.88;

H 9.99. C₁₄H₂₄O₃. Calculated, %: С 69.96; H 10.07.

1

(SO₂). H NMR spectrum, δ, ppm: 0.76 m (2H, CH of

cyclopropane), 1.29 m (2H, CH of cyclopropane), 1.30 d

[6H, OCH(CH₃)₂, J 6.4 Hz], 1.94 m (1H, CH₂), 2.02 m

(1H, CH₂), 2.18 m (1H, CH₂), 2.26 m (1H, CH₂), 3.00 s

(3H, SO₂CH₃), 3.16 s (3H, SO₂CH₃), 5.08 d.d (1H,

CHOMs, J₁7.8, J₂4.1 Hz), 5.10 septet [1H, OCH(CH₃)₂,

J 6.4 Hz]. ¹³C NMR spectrum, δ, ppm: 11.8 (CH₂), 12.1

(CH₂), 21.5 (CH₃), 21.6 (CH₃), 28.3 (CH₂), 31.3 (CH₂),

39.1 (CH₃), 39.6 (CH₃), 65.4 (C), 70.3 (CH), 77.1 (CH),

168.2 (C). Found, %: C 40.35; H 6.19. C₁₂H₂₂O₈S₂.

Calculated, %: С 40.21; H 6.19.

Isopropyl 2-hydroxy-4-(1-hydroxycyclopropyl)

butanoate (XVI). To a solution of 20 g (116 mmol)

of lactone XV and 34 ml (116 mmol) of Ti(OPr-i)₄in

120 ml of THF within 2 h was added at stirring at room

temperature a solution of ethylmagnesium bromide

Isopropyl 2-bromo-5-(bromomethyl)hex-5-enoate

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF EPOTHILONE D WITH THE FORCED APPLICATION

1663

(XVIII). To a solution of magnesium bromide prepared

from 6.5 g (272 mmol) of magnesium and 26 ml

(300 mmol) of 1,2-dibromoethane in 270 ml of Et₂O was

added in one portion a solution of 32.43 g (90 mmol)

of dimesylate XVII in 200 ml of CHCl₃. The reaction

mixture was boiled for 2 h (TLC monitoring), cooled with

ice water, and treated with 200 ml of Н₂O. The organic

layer was separated, the water layer was extracted with

Et₂O. The combined organic solutions were washed

with brine and dried with MgSO₄. The solvents were

distilled off under a reduced pressure. Yield 28.93 g

(98%), [α]_D+17° (c 10, CHCl₃). IR spectrum, ν, cm^–1:

silica gel (eluent petroleum ether–ethyl acetate). Yield

3.30 g (79%). [α]_D–8° (c 2.7, CHCl₃). IR spectrum, ν,

1

cm^–1: 3083 (СН of cyclopropane). H NMR spectrum,

δ, ppm: 0.57 m (1H, СН of cyclopropane), 0.75 m (1H,

СН of cyclopropane), 0.86 m (1H, СН of cyclopropane),

0.97 m (1H, СН of cyclopropane), 1.46 s (3H, CH₃),

1.48 s (3H, CH₃), 2.14 m (1H, CH₂), 2.30 m (1H, CH₂),

4.13 d.d (1H, CHO, J₁7.7, J₂4.6 Hz), 5.12 m (2H,

CH=CH₂), 5.84 m (1H, CH=CH₂). ¹³С NMR spectrum, δ,

ppm: 6.2 (CH₂), 8.7 (CH₂), 26.0 (CH₃), 27.1 (CH₃), 37.4

(CH₂), 64.0 (C), 77.5 (CH), 108.0 (C), 117.2 (CH₂), 134.1

(CH). Found, %: C 71.17; H 9.51. C₁₀H₁₆O₂. Calculated,

%: С 71.39; H 9.59.

1

1738 (СО₂). H NMR spectrum, δ, ppm: 1.28 d [6H,

OCH(CH₃)₂, J 6.4 Hz], 2.16 m (1H, CH₂), 2.28 m (2H,

CH₂), 2.42 m (1H, CH₂), 3.96 s (2H, CH₂Br), 4.18 d.d

(1H, CHBr, J₁7.8, J₂6.5 Hz), 5.02 s (1H, С=CH₂), 5.07

septet [1H, OCH(CH₃)₂, J 6.4 Hz], 5.24 s (1H, С=CH₂).

¹³C NMR spectrum, δ, ppm: 21.3 (CH₃), 21.5 (CH₃), 30.9

(CH₂), 32.5 (CH₂), 36.1 (CH₂), 45.5 (CH), 69.7(CH),

116.3 (CH), 143.3 (C), 169.0 (C). Found, %: C 36.85;

H 5.03. C₁₀H₁₆Br₂O₂. Calculated, %: С 36.61; H 4.92.

1-[(1S)-1-Hydroxybut-3-enyl]cyclopropanol

(XXII). To a suspension of 10 mg (0.11 mmol) of СuCN

in 5.6 ml of THF cooled to–15°С was added at stirring

5.6 ml (4.5 mmol) of 0.8 M solution of vinylmagnesium

bromide in THF. After 5 min to the reaction mixture

was added dropwise a solution of 0.21 g (1.12 mmol)

of oxirane XXI in 1 ml of THF. The solution was stirred

for 45 min, warmed to room temperature, and 2.2 ml

(3.3 mmol) of 1.5 M solution of ethylmagnesium bromide

was added. The reaction mixture was left overnight and

treated with 20 ml of a mixture of saturated solutions of

NH₄Cl and NH₄OH, 1 : 1. The water layer was separated,

the reaction products were extracted into t-BuOMe. The

combined organic solutions were dried with MgSO₄, the

solvent was distilled off under a reduced pressure, the resi-

due was chromatographed on silica gel (eluent petroleum

ether–ethyl acetate). Yield 0.12 g (84%), mp 58–59°С,

[α]_D+1° (c 2.7, CHCl₃). IR spectrum, ν, cm^–1: 3587 (ОН),

3481 (ОН), 3082 (СН of cyclopropane). ¹H NMR spec-

trum, δ, ppm: 0.59 m (2H, СН of cyclopropane), 0.86 m

(2H, СН of cyclopropane), 1.97 br.s (1H, ОН), 2.47 m

(3H, СН₂, ОН), 3.20 d.d (1H, СНОН, J₁8.4, J₂4.6 Hz),

5.19 m (2H, СН=СН₂), 5.92 m (1H, СН=СН₂). ¹³С NMR

spectrum, δ, ppm: 11.1 (СН₂), 12.7 (СН₂), 37.9 (СН₂),

57.8 (С), 76.2 (СН), 117.6 (СН₂), 135.0 (СН). Found, %:

C 65.45; H 9.48. C₇H₁₂O₂. Calculated, %: С 65.60; H 9.44.

Isopropyl 5-methylhex-5-enoate (XIV). To a

solution of 28.93 g (88 mmol) of dibromide XVIII in

150 ml of acetic acid at cooling with water and vigorous

stirring was added within 10 min by portions 24 g (375

mmol) of zinc powder. The reaction mixture was stirred

for 30 min, diluted with 500 ml of Н₂O, the reaction

products were extracted into petroleum ether. The com-

bined organic solutions were washed with brine and dried

with MgSO₄. The solvents were distilled off, the residue

was distilled under a reduced pressure [bp 88–92°С

(30 mm Hg)]. Yield 9.05 g (60%). IR spectrum, ν, cm^–1:

1

1732 (СО₂). H NMR spectrum, δ, ppm: 1.22 d [6H,

OCH(CH₃)₂, J 6.4 Hz], 1.71 s (3H, ССН₃), 1.75 quintet

(2H, СН₂СН₂СН₂, J 7.5 Hz), 2.03 t (2H, СН₂С=СН₂,

J 7.5 Hz), 2.26 t (2H, СН₂СО₂, J 7.5 Hz), 4.68 s (1H,

С=СН₂), 4.72 s (1H, С=СН₂), 5.00 septet (1H, С=СН₂,

J 6.4 Hz). ¹³С NMR spectrum, δ, ppm: 21.8 (2СН₃), 22.1

(СН₃), 22.8 (СН₂), 34.0 (СН₂), 37.0 (СН₂), 67.4 (СН),

110.6 (СН₂), 144.8 (С), 173.2 (С). Found, %: C 70.60;

H 10.62. C₁₀H₁₈O₂. Calculated, %: С 70.55; H 10.66.

(1E)-2-[{(7S)-5,5-Dimethyl-4,6-dioxaspiro[2.4]-

hept-7-yl}methyl]-1-[4-methylpent-4-enyl]cyclo-pro-

panol (XXIVа). To a solution of 800 mg (4.76 mmol) of

compound XIX, 890 mg (5.24 mmol) of ester XIV, and

1.351 g (4.76 mmol) of Ti(OPr-i)₄in a mixture of 8 ml of

Et₂O and 4 ml of benzene was added at stirring at room

temperature within 40 min 15 ml (23.8 mmol) of 1.6 M

solution of butylmagnesium bromide in Et₂O. The reac-

tion mixture was stirred for 10 min, cooled with ice water,

and treated with 2.9 ml of saturated NH₄Cl solution. The

(7S)-7-Аллил-5,5-dиmethyl-4,6-dioxaspiro-[2.4]

heptane (XIX). To a solution of 3.17 g (24.8 mmol) of

diol XXII and 9.1 ml (74 mmol) of 2,2-dimethoxypropane

in anhydrous acetone was added 0.3 g of Py·HOTs. The

reaction mixture was maintained at room temperature for

12 h (TLC monitoring). The solvent was distilled off under

a reduced pressure, the residue was chromatographed on

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

HURSKI, KULINKOVICH

1664

С=СН₂). ¹³С NMR spectrum, δ, ppm: 5.9 (СН₂), 6.1

(СН₂), 9.0 (СН₂), 9.5 (СН₂), 17.7 (СН₂), 17.9 (СН₂),

20.7 (СН₃), 20.8 (СН₃), 22.3 (СН₃), 23.4 (СН₂), 26.0

(СН₃), 27.3 (СН₃), 31.6 (СН₂), 31.9 (СН₂), 32.1 (СН₂),

32.6 (СН₂), 37.3 (СН₂), 39.8 (СН₃), 64.0 (С), 63.9 (С),

69.6 (С), 70.0 (С), 77.6 (СН), 77.9 (СН), 108.1 (С), 108.2

(С), 110.3 (СН₂), 145.2 (С). Found, %: C 60.12; H 8.45.

C₁₈H₃₀O₅S. Calculated, %: С 60.31; H 8.43.

precipitate was ﬁltered off, washed with EtOAc, the ﬁl-

trate was evaporated under a reduced pressure, the residue

was chromatographed on silica gel (eluent petroleum

ether–ethyl acetate). Yield 893 mg (67%, isomers mix-

ture, 3:1). IR spectrum, ν, cm^–1: 3606 (OH), 3075 (СН

1

of cyclopropane). H NMR spectrum, δ, ppm: 0.08 t

(0.75H, СН of cyclopropane, J 6.0 Hz), 0.19 t (0.25H,

СН of cyclopropane, J 6.1 Hz), 0.52–0.59 m (1H, СН of

cyclopropane), 0.61–0.67 m (1H, СН of cyclopropane),

0.81–0.99 m (4Н, СН of cyclopropane), 1.13–1.21 m (1Н,

СН₂), 1.30–1.41 m (1Н, СН₂), 1.46 s [6Н, О₂С(СН₃)₂],

1.56–1.71 m (3Н, СН₂), 1.72 s (3H, ССН₃), 1.76–1.83 m

(1Н, СН₂), 1.85 br.s (1Н, ОН), 2.03–2.09 m (2H, СН₂),

4.07 d.d (0.75H, СНО, J₁9.0, J₂3.8 Hz), 4.10 d.d (0.25H,

СНО, J₁7.8, J₂5.2 Hz), 4.69 ы (1H, С=СН₂), 4.71 s

(1H, С=СН₂). ¹³С NMR spectrum, δ, ppm: 6.1 (СН₂),

8.7 (СН₂), 19.2 (СН₂), 19.5 (СН₂), 21.7 (СН₃), 22.2

(СН₃), 22.3 (СН₃), 23.6 (СН₂), 23.7 (СН₂), 26.0 (СН₃),

27.2 (СН₃), 29.6 (СН₂), 32.8 (СН₂), 33.0 (СН₂), 33.6

(СН₂), 33.9 (СН₂), 37.7 (СН₂), 57.9 (С), 58.2 (С), 63.9

(С), 64.0 (С), 78.2 (СН), 78.3 (СН), 107.9 (С), 108.0

(С), 109.9 (СН₂), 145.6 (С). Found, %: C 72.97; H 9.94.

C₁₇H₂₈O₃. Calculated, %: С 72.82; H 10.06.

(7S)-7-[(2E)-3-(Bromomethyl)-7-methylocta-2,7-

dienyl]-5,5-dimethyl-4,6-dioxaspiro[2.4]heptane

(XXV) and (7S)-7-(2-bromo-7-methyl-3-methyleneoct-

7-enyl)-5,5-dimethyl-4,6-dioxaspiro[2.4]heptane

(XXVI). To a solution of MgBr₂obtained from 0.14 g

(5.8 mmol) of magnesium and 1.14 g (6.09 mmol) of

1,2-dibromoethane in 6 ml of Et₂O while stirring at room

temperature was added within 2 min a solution of 1.04 g

(2.9 mmol) cyclopropanol sulfonate XXIV obtained

as described above in 6 ml of Et₂O. After 15 min the

reaction mixture was cooled with ice water and treated

with Н₂O. The water layer was separated, the reaction

products were extracted into Et₂O. The combined or-

ganic solutions were dried with MgSO₄, the solvent was

distilled off under a reduced pressure, the residue was

chromatographed on silica gel (eluent petroleum ether–

ethyl acetate). Yield 0.85 g (86%). Mixture of isomers

XXV–XXVI, 78 : 22. IR spectrum, ν, cm^–1: 3072 (CH

(1E)-2-[{(7S)-5,5-Dimethyl-4,6-dioxaspiro[2.4]-

hept-7-yl}methyl]-1-[4-methylpent-4-enyl]cyclo-

propyl methanesulfonate (XXIVb). To a solution of

215 mg (0.77 mmol) of cyclopropanol XXIV and 0.21 ml

(1.5 mmol) of Et₃N in 5 ml of Et₂O cooled to 0°С was

added at stirring 0.08 ml (1.00 mmol) of methanesulfo-

nyl chloride, the reaction mixture waswarmed to room

temperature and after 30 min it was treated with saturated

solution of NaHCO₃. The organic layer was separated,

the water layer was extracted with Et₂O. The combined

organic solutions were washed with brine and dried with

MgSO₄. The solvent was distilled off under a reduced

pressure, the residue was chromatographed on silica gel

(eluent petroleum ether–ethyl acetate). Yield 270 mg

(98%, isomers mixture, 3:1). IR spectrum, ν, cm^–1: 3083

(СН of cyclopropane), 1350 (SO₂), 1172 (SO₂). ¹H NMR

spectrum, δ, ppm: 0.34 t (0.75H, СН of cyclopropane,

J 6.9 Hz), 0.43 t (0.25H, СН of cyclopropane, J 6.9 Hz),

0.52–0.68 m (2H, СН of cyclopropane), 0.80–1.02 m (3H,

СН of cyclopropane), 1.37 d.d (1H, СН of cyclopropane,

J₁10.8, J₂6.9 Hz), 1.44 s [0.75H, О₂С(СН₃)₂], 1.45 s [3H,

О₂С(СН₃)₂], 1.46 s [2.25H, О₂С(СН₃)₂], 1.49–1.96 m

(6H, СН₂), 1.71 s (3H, ССН₃), 2.05–2.10 m (2H, СН₂),

2.97 s (2.25H, SO₂CH₃), 2.98 s (0.75H, SO₂CH₃),

4.09 d.d (0.75H, CНО, J₁8.2, J₂3.8 Hz), 4.17 d.d (0.25H,

СНО, J₁8.7, J₂3.3 Hz), 4.67 s (1H, С=СН₂), 4.71 s (1H,

1

of cyclopropane). H NMR spectrum of compound

XXV, δ, ppm: 0.53–0.59 m (1H, СН of cyclopropane),

0.64–0.71 m (1H, СН of cyclopropane), 0.85–0.91 m

(1H, СН of cyclopropane), 0.93–1.00 m (1H, СН of

cyclopropane), 1.44 s [3H, О₂С(СН₃)₂], 1.45 s [3H,

О₂С(СН₃)₂], 1.53–1.61 m (2H, СН₂СН₂СН₂), 1.71 с (3H,

ССН₃), 2.01–2.04 m (2Н, СН₂), 2.16–2.22 m (4Н, СН₂),

4.04 d (2H, СН₂Br, J2.6Hz), 4.06 d.d (1H, CHO, J₁7.2,

J₂4.6 Hz), 4.67 s (1H, C=CН₂), 4.72 s (1H, C=CН₂),

5.67 t (1H, С=СНСН₂, J 7.0 Hz). Found, %: C 59.48;

H 7.89. C₁₇H₂₇BrO₂. Calculated, %: С 59.48; H 7.93.

(7S)-7-[(2Z)-3,7-Dimethylocta-2,7-dienyl]-5,5-

dimethyl-4,6-dioxaspiro[2.4]heptane (XXVII). To

a dispersion of 63 mg (1.66 mmol) of LiAlH₄in 6 ml of

Et₂O at room temperature while stirring was added within

3 min a solution of 569 mg (1.66 mmol) of a mixture of

bromides XXV and XXVI in 2 ml of Et₂O. After 30 min

the reaction mxture was cooled with ice water and treated

with 0.18 ml of Н₂O. The precipitate was ﬁltered off and

washed with Et₂O, the ﬁltrate was dried with MgSO₄and

evaporated. The residue was dissolved in 6 ml of DMF,

98 mg (1.0 mmol) of potassium acetate and 7 mg (0.03

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF EPOTHILONE D WITH THE FORCED APPLICATION

1665

cyclopropyl]nona-3,8-dienyl pivaloate (XXVIIIb). To

a solution of 1.083 g (4.83 mmol) of diol XXVIIIa and

0.12 g (0.98 mmol) of dimethylaminopyridine in 10 ml of

pyridine cooled to –20°С was added 0.71 ml (5.8 mmol)

of pivaloyl chloride. The reaction mixture was kept at

5°С for 3 h, and 0.75 ml (9.66 mmol) of methanesulfonyl

chloride was added, and the reaction mixture was left

overnight at the same temperature and afterwards was

treated with 30 ml of Н₂O. The reaction products were

extracted into Et₂O, the combined organic solutions were

washed with brine and dried with MgSO₄. The solvents

were distilled off under a reduced pressure, the residue

was chromatographed on silica gel (eluent petroleum

ether–ethyl acetate). Yield 1.67 g (89%), [α]_D–5° (c 3.26,

СHCl₃). IR spectrum, ν, cm^–1: 1726 (СO₂), 1363 (SO₂),

mmol) of triethylbenzylammonium chloride were added.

The dispersion was stirred for 14 h and treated with Н₂O.

The reaction products were extracted into Et₂O, the

combined organic solutions were washed with brine and

dried with MgSO₄. The solvent was distilled off under a

reduced pressure, the residue was chromatographed on

silica gel (eluent petroleum ether–ethyl acetate). Yield

319 mg (73%), [α]_D–6° (c 3.67, MeOH). IR spectrum, ν,

cm^–1: 3076 (CH of cyclopropane). ¹H NMR spectrum, δ,

ppm: 0.53 d.d.d (1H, CH of cyclopropane, J₁10.8, J₂7.2,

J₃5.6 Hz), 0.71 d.t (1H, CH of cyclopropane, J₁10.8,

J₂6.4 Hz), 0.82 d.d.d (1H, CH of cyclopropane, J₁11.3,

J₂7.2, J₃6.4 Hz), 0.95 d.d.d (1H, CH of cyclopropane,

J₁11.3, J₂6.4, J₃5.6 Hz), 1.45 s [3H, О₂С(СН₃)₂], 1.46 s

[3H, О₂С(СН₃)₂], 1.51 m (2H, СН₂СН₂СН₂), 1.70 s (3H,

ССН₃), 1.71 s (3H, ССН₃), 1.98–2.11 m (5H, СН₂),

2.24 d.t (1H, СН₂, J₁14.3, J₂6.9 Hz), 4.06 d.d (1H,

СНО, J₁7.5, J₂4.9 Hz), 4.68 s (1H, С=СН₂), 4.71 s (1H,

С=СН₂), 5.16 t (1H, С=СНСН₂, J6.7 Hz). ¹³С NMR

spectrum, δ, ppm: 6.3 (СН₂), 8.7 (СН₂), 22.4 (СН₃), 23.4

(СН₃), 25.7 (СН₂), 26.0 (СН₃), 27.2 (СН₃), 31.5 (СН₂),

31.6 (СН₂), 37.6 (СН₂), 64.1 (С), 78.3 (СН), 107.9 (С),

109.8 (СН₂), 120.1 (СН), 137.7 (С), 145.8 (С). Found,

%: C 77.09; H 10.61. C₁₇H₂₈O₂. Calculated, %: С 77.22;

H 10.67.

1

1177 (SO₂). H NMR spectrum, δ, ppm: 0.84 m (1H,

CH of cyclopropane), 1.08 m (1H, CH of cyclopropane),

1.15–1.24 m (2H, CH of cyclopropane), 1.21 s [9H,

С(СН₃)₃], 1.52 m (2H, СН₂СН₂СН₂), 1.67 s (3H, ССН₃),

1.72 s (3H, ССН₃), 1.93–2.11 m (4H, СН₂), 2.45 t (2H,

CH₂СНО, J 7.2 Hz), 3.06 s (3H, SO₂CH₃), 4.68 s (1H,

C=CH₂), 4.71 s (1H, C=CH₂), 4.80 d.d (1H, CHOPiv,

J₁7.4, J₂6.7 Hz), 5.09 t (1H, C=CHCH₂, J 7.2 Hz).

¹³С NMR spectrum, δ, ppm: 10.8 (CH₂), 11.6 (CH₂), 22.4

(CH₃), 23.4 (CH₃), 25.7 (CH₂), 27.1 (3CH₃), 29.5 (CH₂),

31.4 (CH₂), 37.5 (CH₂), 38.9 (C), 39.7 (CH₃), 66.7 (C),

75.5 (CH), 109.9 (CH₂), 119.1 (CH), 138.5 (C), 145.7

(C), 177.9 (C). Found, %: C 62.30; H 8.88. C₂₀H₃₄O₅S.

Calculated, %: С 62.14; H 8.87.

1-[(1S,3Z)-1-Hydroxy-4,8-dimethylnona-3,8-

dienyl]cyclopropanol (XXVIIIа). To a solution of 1.63 g

(6.20 mmol) of acetonide XVII in 30 ml of MеОН was

added 0.16 g of Py·HOTs. The reaction mixture was main-

tained for 3 days at room temperature (TLC monitoring),

the solvent was distilled off under a reduced pressure,

the residue was chromatographed on silica gel (eluent

petroleum ether–ethyl acetate). Yield 1.08 g (78%),

mp 55–56°С, [α]_D–5° (c 7.8, СHCl₃). IR spectrum, ν,

(3S,5Z)-2-(Bromomethyl)-6,10-dimethylundeca-

1,5,10-trien-3-yl pivaloate (XXIX). To a solution of

MgBr₂obtained from 0.28 g (11.68 mmol) of magne-

sium and 1.1 ml (12.8 mmol) of 1,2-dibromoethane in

10 ml of Et₂O was added 1.13 g (8.76 mmol) of diiso-

propylethylamine and a solution of 1.13 g (2.92 mmol)

of mesylate XXVIIIb in 40 ml of toluene. The reaction

mixture was stirred at 100°С for 2 h distilling off Et₂O

(TLC monitoring) and then treated with Н₂O. The or-

ganic layer was separated, the reaction products were

extracted into Et₂O, the combined organic solutions were

washed with brine and dried with MgSO₄. The solvents

were evaporated, the residue was chromatographed on

silica gel (eluent petroleum ether–ethyl acetate). Yield

633 mg (62%), [α]_D–2° (c 6.31, СHCl₃). IR spectrum,

1

cm^–1: 3586 (ОН), 3466 (ОН). H NMR spectrum, δ,

ppm: 0.57 m (СН of cyclopropane, 2H), 0.84 m (СН

of cyclopropane, 2H), 1.53 quintet (2H, СН₂СН₂СН₂,

J 7.8 Hz), 1.72 s (3H, ССН₃), 1.74 s (3H, ССН₃), 1.93 br.s

(1H, ОН), 1.98–2.13 m (4H, СН₂), 2.32 m (1H, СН₂),

2.49 m (2H, CH₂СНО, ОН), 3.12 d.d (1H, СНОН, J₁8.9,

J₂4.4 Hz), 4.68 s (1H, С=СН₂), 4.71 s (1H, С=СН₂),

5.23 t (1H, С=СНСН₂, J 7.2 Hz). ¹³С NMR spectrum,

δ, ppm: 10.9 (СН₂), 12.8 (СН₂), 22.4 (СН₃), 23.5 (СН₃),

25.9 (СН₂), 31.5 (СН₂), 31.8 (СН₂), 37.6 (СН₂), 58.0 (С),

76.8 (СН), 109.9 (СН₂), 120.7 (СН), 139.0 (С), 145.7 (С).

Found, %: C 74.89; H 10.86. C₁₄H₂₄O₂. Calculated, %:

С 74.95; H 10.78.

1

ν, cm^–1: 1730 (СO₂). H NMR spectrum, δ, ppm: 1.20

s [9H, С(СН₃)₃], 1.51 m (2H, CH₂CH₂CH₂), 1.68 d

(3H, CCH₃, J 1.0 Hz), 1.72 s (3H, CCH₃), 1.95–2.09 m

(4H, CH₂), 2.47 t (2H, CH₂СНО, J 6.9 Hz), 3.97 d (1H,

(1S,3Z)-4,8-Dimethyl-1-[1-(methylsulfonyloxy)

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HURSKI, KULINKOVICH

1666

(3S,1E,5Z)-2,6,10-Trimethyl-1-(2-methylthiazol-

4-yl)undeca-1,5,10-trien-3-ol (XXXIIа). A solution

of 0.63 g (1.69 mmol) of compound XXXI in 20 ml (5

mmol) of 0.25 M solution t-BuOK in t-BuOН was boiled

for 1 h. To the reaction mixture was added 0.06 ml of Н₂О,

and the boiling was continued for 1 h more. The solvent

was distilled off at a reduced pressure, to the residue wa-

ter was added, and the reaction products were extracted

into Et₂O, the combined organic solutions were washed

with brine and dried with MgSO₄. The solvents were

evaporated, the residue was chromatographed on silica

gel (eluent petroleum ether–ethyl acetate). Yield 367 mg

(73%), [α]_D–5° (c 6.30, СHCl₃). IR spectrum, ν, cm^–1:

CH₂Br, J 10.5 Hz), 4.01 d (1H, CH₂Br, J 10.5 Hz), 4.67 s

(1H, CH₃C=CH₂), 4.71 s (1H, CH₃C=CH₂), 5.09 t (1H,

C=CHCH₂, J 6.9 Hz), 5.26 s (1H, CH₂BrC=CH₂), 5.30 t

(1H, CHOPiv, J 6.9 Hz), 5.34 s (1H, CH₂BrC=CH₂).

¹³С NMR spectrum, δ, ppm: 22.4 (CH₃), 23.4 (CH₃),

25.9 (CH₂), 27.1 (3CH₃), 31.6 (CH₂), 32.4 (CH₂), 32.5

(CH₂), 37.6 (CH₂), 38.8 (C), 73.8 (CH), 109.9 (CH₂),

117.1 (CH₂), 119.4 (CH), 138.4 (C), 144.2 (С), 145.7

(С), 177.4 (С). Found, %: C 61.20; H 8.42. C₁₉H₃₁BrO₂.

Calculated, %: С 61.45; H 8.41.

(3S,5Z)-6,10-Dimethyl-2-[(2-methylthiazol-4-yl)-

methyl]undeca-1,5,10-trien-3-yl pivaloate (XXXI).

To a solution of 0.84 g (4.72 mmol) of 2-methyl-4-

bromothiazole in 3 ml of Et₂O cooled to –78°С was

added at stirring within 5 min 2.7 ml (3.78 mmol) of

1.4 M butyllithium solution in hexane. After 3 h the

reaction mixture was warmed to –60°С and to it was

quickly added a solution of MgBr₂obtained from 0.21 g

(8.75 mmol) of magnesium and 0.49 ml (5.68 mmol) of

1,2-dibromoethane in 5.6 ml of Et₂O. The reaction mix-

ture was warmed to the room temperature, it was stirred

for 15 min, diluted with 22 ml of THF, and cooled to 0°С.

To the obtained solution of methylthiazolylmagnesium

bromide (XXX) 158 mg (0.83 mmol) of CuI was added

and a solution of 0.49 g (1.38 mmol) of bromide XXIX

in 2 ml of THF. After 5 min the mixture was treated with

20 ml of saturated NH₄Cl solution. The water layer was

separated, the reaction products were extracted into Et₂O,

the combined organic solutions were washed with brine

and dried with MgSO₄. The solvents were distilled off un-

der a reduced pressure, the residue was chromatographed

on silica gel (eluent petroleum ether–ethyl acetate). Yield

0.37 g (72%), [α]_D–2° (c 6.3, СHCl₃). IR spectrum, ν,

1

3621 (OH). H NMR spectrum, δ, ppm: 1.49–1.57 m

(2H, CH₂CH₂CH₂), 1.71 s (3H, CCH₃), 1.72 d (3H,

CCH₃, J 1.0 Hz), 1.97–2.08 m (5H, CH₂, OH), 2.04 d

(3H, CH₃С=СНCN, J 1.0 Hz), 2.34 t (2H, CH₂CHOH,

J 6.9 Hz), 2.70 s (3H, CH₃CNS), 4.14 t (1H, СНОН,

J 6.5 Hz), 4.67 с (1H, С=СН₂), 4.70 с (1H, С=СН₂), 5.17 t

(1H, С=СНСН₂, J 7.3 Hz), 6.56 s (1H, С=СНCN), 6.94

s (1H, СНS). ¹³С NMR spectrum, δ, ppm: 14.3 (СН₃),

19.1 (СН₃), 22.3 (СН₃), 23.5 (СН₃), 25.9 (СН₂), 31.6

(СН₂), 34.0 (СН₂), 37.6 (СН₂), 77.2 (СН), 109.8 (СН₂),

115.3 (СН), 118.8 (СН), 120.4 (СН), 138.8 (С), 141.8

(С), 145.7 (С), 152.8 (С), 164.5 (СН). Found, %: C 70.99;

H 9.00. C₁₈H₂₇NOS. Calculated, %: С70.77; H 8.91. The

enantiomeric purity of alcohol XXXII (>99% ее) was

determined by Mosher procedure [39] by integrating the

signals of protons of СНОMTРА group at δ 5.83 and

5.85 ppm (main isomer) in the ¹Н NMR spectrum of its

ester with (S)-α-methoxy-α-triﬂuoromethylphenylacetic

acid (MTPA).

4-[(3S,1E,5Z)-3-(tert-Butyldimethylsiloxy)-2,6,10-

trimethylundeca-1,5,10-trienyl]-2-methylthiazole

(XXXIIb). To a solution of 324 mg (1.13 mmol) of

alcohol XXXIIa and 115 mg (1.69 mmol) of imidazole

in 2.3 ml of DMF at 0°С was added 220 mg (1.46 mmol)

tert-butyldimethylchlorosilane. The reaction mixture

was kept at 5°С for 12 h and was treated with Н₂О. The

reaction products were extracted into Et₂O, the combined

organic solutions were washed with brine and dried with

MgSO₄. The solvents were distilled off under a reduced

pressure, the residue was chromatographed on silica gel

(eluent petroleum ether–ethyl acetate). Yield 410 mg

1

cm^–1: 1729 (СО₂). H NMR spectrum, δ, ppm: 1.16 s

[9H, С(СН₃)₃], 1.44–1.53 m (2H, CH₂CH₂CH₂), 1.65 s

(3H, CCH₃), 1.70 s (3H, CCH₃), 1.89–2.04 m (4H, СН₂),

2.31–2.39 m (2H, СH₂СНО), 2.67 s (3H, CH₃СNS),

3.52 s (2H, СН₂CN), 4.66 s (1H, CH₃C=CH₂), 4.69 s

(1H, CH₃C=CH₂), 4.92 s (1H, NCCH₂C=CH₂), 5.05 t

(1H, C=CHCH₂, J 6.7 Hz), 5.15 s (1H, NCCH₂C=CH₂),

5.20 d.d (1H, CHOPiv, J₁7.2, J₂5.9 Hz), 6.83 s (1H,

CHCS). ¹³С NMR spectrum, δ, ppm: 19.1 (CH₃), 22.4

(CH₃), 23.3 (CH₃), 25.8 (CH₂), 27.1 (3CH₃), 31.8 (CH₂),

32.0 (CH₂), 34.9 (CH₂), 37.6 (CH₂), 38.8 (C), 75.4 (CH),

109.8 (CH₂), 113.6 (CH₂), 114.1 (CH), 119.9 (CH), 137.8

(C), 145.2 (C), 145.7 (C), 153.8 (C), 165.4 (C), 177.5 (C).

Found, %: C 71.09; H 9.12. C₂₃H₃₅NO₂S. Calculated, %:

С70.91; H 9.06.

1

(90%), [α]_D+9° (c 3.4, СHCl₃). H NMR spectrum, δ,

ppm: 0.00 s (3H, SiCH₃), 0.04 s (3H, SiCH₃), 0.88 s [9H,

SiC(CH₃)₃], 1.45–1.54 m (2H, CH₂CH₂CH₂), 1.67 d (3H,

CCH₃, J 0.8 Hz), 1.71 s (3H, CCH₃), 1.94–2.06 m (4H,

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF EPOTHILONE D WITH THE FORCED APPLICATION

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CH₂), 1.99 s (3H, CCH₃), 2.18–2.31 m (2H, CH₂СНОSi),

2.71 s (3H, CH₃CNS), 4.08 t (1H, СHOSi, J 6.4 Hz),

4.66 s (1H, С=СН₂), 4.69 s (1H, С=СН₂), 5.14 t (1H,

С=СНСН₂, J 6.9 Hz), 6.45 s (1H, С=СНCN), 6.92 s

(1H, СНS). ¹³С NMR spectrum, δ, ppm: –5.0 (СН₃), –4.7

(СН₃), 13.9 (СН₃), 18.2 (С), 19.2 (СН₃), 22.4 (СН₃), 23.4

(СН₃), 25.8 (3СН₃), 26.0 (СН₂), 31.6 (СН₂), 36.3 (СН₂),

37.7 (СН₂), 79.0 (СН), 109.7 (СН₂), 114.9 (СН), 118.7

(СН), 121.7 (СН), 136.6 (С), 142.5 (С), 145.9 (С), 153.3

(С), 164.3 (С). Found, %: C 68.55; H 9.80. C₂₄H₄₁NOSSi.

Calculated, %: С68.68; H 9.85.

H 9.95. C₂₄H₄₃NO₂SSi. Calculated, %: С65.85; H 9.90.

The spectral characteristics of the compound obtained

were consistent with the published data [12, 15]. The

diastereomeric purity (dе 20%) of alcohol XXXIІІ was

determined by Mosher procedure [39] by the integration

of the proton signals of СН₂ОMTРА group at δ 4.05

and 4.23 ppm (main isomer) and 4.12, 4.16 ppm (minor

isomer) in the ¹Н NMR spectrum of its ester with (S)-α-

methoxy-α-triﬂuoromethylphenylacetic acid.

Methyl (5S)-6-hydroxy-5-methylhexanoate

(XXXIVа). To a solution of 0.58 g (3.69 mmol) of diol

XLIb in 5 ml of MeOH was added by portions at stirring

within 10 min 1.19 g (3.69 mmol) of PhI(OAc)₂. After

30 min the solvent was distilled off under a reduced

pressure, the residue was chromatographed on silica

gel (eluent petroleum ether–ethyl acetate). Yield 0.52 g

(87%), [α]_D–11° (c 2.2, CHCl₃). IR spectrum, ν, cm^–1:

3640 (ОН), 3534 (ОН), 1742 (СО₂). ¹H NMR spectrum,

δ, ppm: 0.91 d.d (3H, СНСН₃, J₁6.7, J₂0.8 Hz), 1.09–

1.19 m (1H, СН₂), 1.38–1.47 m (1H, СН₂), 1.54–1.75 m

(3H, СН₂, СН), 2.31 t (2H, СН₂СО₂Mе, J 7.3 Hz),

2.31 br.s (1H, ОН), 3.44 d.d.d (1H, СН₂ОН, J₁10.8,

J₂6.4, J₃1.0 Hz), 3.49 d.d.d (1H, СН₂ОН, J₁10.8, J₂6.1,

J₃1.0 Hz), 3.66 s (3H, СО₂Mе). ¹³С NMR spectrum, δ,

ppm: 16.4 (CH₃), 22.2 (CH₂), 32.5 (CH₂), 34.2 (CH₂),

35.4 (CH), 51.5 (CH₃), 67.9 (CH₂), 174.2 (C). Found,

%: C 60.13; H 10.02. C₈H₁₆O₃. Calculated, %: С 59.97;

H 10.07.

(2S,6Z,9S,10E)-9-(tert-Butyldimethylsiloxy)-2,6,10-

trimethyl-11-(2-methylthiazol-4-yl)-undeca-6,10-dien-

1-ol(XXXIII). Toasolutionofdiisopinocamphenylborane

prepared from 0.39 ml (2.46 mmol) of (+)-α-pinene and

0.12 ml (1.12 mmol) of complex BH₃DMS in 3.5 ml THF

cooled to 0°С was slowly added at stirring a solution of

0.41 g (1.02 mmol) of unsaturated silyl ether obtained by

the above described procedure in 1ml of THF. The reac-

tion mixture was warmed to room temperature, stirred

for 30 min, 1.1 ml (3.3 mmol) of 3 M of LiOH solution

and 0.47 g (3.3 mmol) of NaBO₃were added, and the

mixture was stirred for another 2 h. The water layer was

separated, the reaction products were extracted into Et₂O,

the combined organic solutions were washed with brine

and dried with MgSO₄. The solvents were distilled off un-

der a reduced pressure, the residue was chromatographed

on silica gel (eluent petroleum ether–ethyl acetate).

Yield of initial alkene 125 mg (30%), yield of alcohol

XXXIII 235 mg (55%, 78% with respect to the reacted

alkene), isomers mixture, 3:2, [α]_D+1° (c 2.03, СHCl₃).

IR spectrum, ν, cm^–1: 3640 (ОН), 3370 (ОН). ¹H NMR

spectrum, δ, ppm: 0.00 s (3H, SiCH₃), 0.04 s (3H, SiCH₃),

0.88 s [9H, SiC(CH₃)₃], 0.91 d.d (3H, СНСН₃, J₁6.4,

J₂1.0 Hz), 1.03–1.14 m (1H, СН₂), 1.30–1.48 m (3H,

СН₂), 1.56–1.63 m (1H, СН), 1.66 с (3H, ССН₃), 1.84 br.s

(1Н, ОН), 1.93–2.04 m (2H, СН₂), 1.98 s (3H, ССН₃),

2.18–2.30 m (2H, СН₂), 2.70 s (3H, СН₃С=N), 3.40 d.d

(1H, СН₂ОН, J₁10.5, J₂6.5 Hz), 3.49 d.d (1H, СН₂ОН,

J₁10.5, J₂6.0 Hz), 4.08 t (1H, CHOSi, J 6.4 Hz), 5.15 t

(1H, C=CHCH₂, J 7.0 Hz), 6.45 с (1H, Н¹¹), 6.92 s (1H,

СНS). ¹³С NMR spectrum, δ, ppm: –5.0 (CH₃), –4.7

(CH₃), 13.9 (CH₃), 16.6 (CH₃), 18.2 (C), 19.1 (CH₃),

23.4 (CH₃), 25.3 (CH₂), 25.4 (CH₂), 25.8 (3CH₃), 32.1

(CH₂), 32.2 (CH₂), 33.1 (CH₂), 35.4 (CH₂), 35.7 (CH₃),

35.8 (CH₃), 68.1 (CH₂), 79.1 (СН), 79.2 (СН), 114.8

(СН), 118.6 (СН), 121.61 (СН), 121.64 (СН), 136.7

(С), 142.7 (С), 153.1 (С), 164.4 (С). Found, %: C 65.66;

Methyl (5S)-5-methyl-6-(tetrahydro-2H-pyran-

2-yloxy)hexanoate (XXXIVb). To a solution of 0.5 g

(3.13 mmol) of ester XXXIVа and 0.37 ml (4 mmol)

of dihydropyran in 5 ml of CH₂Cl₂was added 50 mg of

Py·HOTs. The reaction mixture was maintained at room

temperature for 20 h and treated with a saturated solution

of NaHCO₃. The organic layer was separated, the reac-

tion products were extracted into CH₂Cl₂, the combined

organic solutions were dried with MgSO₄. The solvents

were distilled off under a reduced pressure, the residue

was chromatographed on silica gel (eluent petroleum

ether–ethyl acetate). Yield 0.76 g (99%), mixture of

diastereomers, 1:1, [α]_D–10° (c 2.0, CHCl₃). IR spectrum,

ν, cm^–1: 1742 (CO₂). ¹H NMR spectrum, δ, ppm: 0.88 d

(1.5H, СНСН₃, J 5.6 Hz), 0.90 d (1.5H, СНСН₃,

J 5.6 Hz), 1.06–1.20 m (2H, СН₂), 1.35–1.81 m (9H, СН₂,

СН), 2.27 t (2H, СН₂СО₂Mе, J 7.3 Hz), 3.12 d.d (0.5H,

СH₂OTHP, J₁9.5, J₁6.4 Hz), 3.18 d.d (0.5H, СH₂OTHP,

J₁9.5, J₂6.1 Hz), 3.43–3.50 m (1.5H, СH₂OTHP, CH₂O

of tetrahydropyran), 3.55 d.d (0.5H, СH₂OTHP, J₁9.5,

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

HURSKI, KULINKOVICH

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J₂6.4 Hz), 3.62 s (3H, СО₂Mе), 3.78–3.84 m (1H,

CH₂O of tetrahydropyran), 4.51–4.53 m (1H, CHO₂

of tetrahydropyran). ¹³С NMR spectrum, δ, ppm: 16.8

(СН₃), 16.9 (СН₃), 19.4 (СН₂), 19.5 (СН₂), 22.4 (СН₂),

25.4 (СН₂), 30.6 (СН₂), 33.1 (СН), 34.2 (СН₂), 51.3

(СН₃), 62.0 (СН₂), 62.1 (СН₂), 72.6 (СН₂), 72.7 (СН₂),

98.8 (СН), 98.9 (СН), 174.0 (С). Found, %: C 63.68;

H 10.00. C₁₃H₂₄O₂. Calculated, %: С 63.91; H 9.90.

dried with MgSO₄, evaporated at a reduced pressure,

the residue was chromatographed on silica gel (eluent

petroleum ether–ethyl acetate). Yield 8.96 g (93%). IR

spectrum, ν, cm^–1: 3095 (ОН), 1739 (СО₂), 1712 (CO₂H).

¹H NMR spectrum, δ, ppm: 0.61–0.64 m (2H, СН of

cyclopropane), 0.75–0.78 m (2H, СН of cyclopropane),

1.13 s [9H, С(СН₃)₃], 1.40–1.48 m (2H, CH₂), 1.61–

1.69 m (2H, CH₂), 1.73–1.77 m (2H, CH₂), 2.34 t (2H,

CH₂CO₂H, J 7.4 Hz), 10.13 br.s (1H, CO₂H). ¹³С, δ, ppm:

11.7 (2СН₂), 24.3 (СН₂), 25.3 (СН₂), 26.9 (3СН₃), 33.8

(СН₂), 34.0 (СН₂), 38.6 (С), 59.1 (С), 178.4 (С), 179.7

(С). Found, %: C 64.21; H 9.13. C₁₃H₂₂O₄. Calculated,

%: С 64.44; H 9.15.

1-[4-(1-Hydroxycyclopropyl)butyl]cyclopro-

pyl pivaloate (XXXVII). To a solution of 13.01 g

(77 mmol) of diol XXXVI [33] and 1.87 g (15 mmol) of

dimethylaminopyridine in 77 ml of pyridine at 0°C while

stirring was added within 10 min 11.4 ml (92.4 mmol) of

pivaloyl chloride. The reaction mixture was left overnight

at 5°С, then it was treated with 200 ml of Н₂O, the prod-

ucts were extracted into Et₂O. The extract was washed

with brine and dried with MgSO₄. The solvents were

distilled off under a reduced pressure, the residue was

dissolved in the mixture of 50 ml of benzene and 50 ml

of petroleum ether, then the solution was cooled to 5°C

and left overnight. The initial crystalline diol XXXVI

[1.8 g (14%)] was ﬁltered off, the ﬁltrate was evaporated,

the residue was subjected to chromatography on silica

gel (eluent petroleum ether–ethyl acetate). Yield 10.5 g

(54%, 63% with respect to reacted diol XXXVI). IR

spectrum, ν, cm^–1: 3604 (ОН), 3525 (ОН), 3089 (СН of

cyclopropane), 1738 (СО₂). ¹H NMR spectrum, δ, ppm:

0.38–0.42 m (2H, СН of cyclopropane), 0.60–0.64 m

(2H, СН of cyclopropane), 0.69–0.72 m (2H, СН of

cyclopropane), 0.74–0.77 m (2H, СН of cyclopropane),

1.13 d [9H, С(СН₃)₃, J0.8 Hz], 1.43–1.47 m (2H, CH₂),

1.51–1.54 m (4H, CH₂), 1.73–1.76 m (2H, CH₂), 2.7 br.s

(1H, ОН). ¹³С NMR spectrum, δ, ppm: 11.7 (2СН₂), 13.4

(2СН₂), 25.6 (СН₂), 25.8 (СН₂), 27.0 (3СН₃), 34.3 (СН₂),

38.2 (СН₂), 38.6 (С), 55.5 (С), 59.4 (С), 178.4 (С).

Found, %: C 70.66; H 10.22. C₁₅H₂₆O₃. Calculated, %:

С 70.83; H 10.30.

1-{5-[(4S)-4-Benzyl-2-oxooxazolidin-3-yl]-5-

oxapentyl}cyclopropyl pivaloate (XXXVIIIb). To a

solution of 3 g (12.3 mmol) of acid XXXVIIIа in 9 ml

of CCl₄was added 3 ml (41.3 mmol) of SOCl₂, the reac-

tion mixture was boiled for 3 h. The solvent and excess

reagent were distilled off under a reduced pressure to

obtain the acid chloride that was further used without

additional puriﬁcation.

To a solution of 2.18 g (12.3 mmol) of (4S)-4-benzyl-

oxazolidin-2-one in 37 ml of THFcooled to –78°С, was

added within 5 min at stirring 7.7 ml (12.3 mmol) of 1.6 M

butyllithium solution in hexane. After 5 min to the ob-

tained lithium derivative XXXIX was added at the same

temperature while stirring the chloride obtained from

acid XXXVIIIа. After 30 min the solution was warmed

to room temperature and treated with 10 ml of saturated

NH₄Cl solution. The solvent was distilled off under

a reduced pressure, the products were extracted from the

water layer with СН₂Cl₂. The combined organic extracts

were dried with MgSO₄, evaporated at a reduced pressure,

the residue was chromatographed on silica gel (eluent

petroleum ether–ethyl acetate). Yield 4.39 g (89% in

2 stages), [α]_D+28° (c 1.8, CHCl₃). IR spectrum, ν, cm^–1:

3075 (СН of cyclopropane), 1786 (СО oxazolidinone),

5-[1-(Pivaloyloxy)cyclopropyl]pentanoic acid

(XXXVIIIа). To a solution of 10.00 g (39.4 mmol) of

compound XXXVII in 50 ml of acetic acid at cooling

with cold water while stirring was added by portions

within 20 min 12.68 g (39.4 mmol) of phenyliodoso

diacetate. After 10 min the reaction mixture was diluted

with 50 ml of H₂O and 100 ml of THF, and the solution

obtained was boiled for 1 h. The solvents were distilled

off under a reduced pressure, 50 ml of H₂O was added to

the residue, the products were extracted into Et₂O. The

combined organic extracts were washed with brine and

1

1732 (СО₂), 1704 (СОN). H NMR spectrum, δ, ppm:

0.64–0.67 m (2H, СН of cyclopropane), 0.77–0.80 m

(2H, СН of cyclopropane), 1.15 s [9H, С(СН₃)₃], 1.40–

1.53 m (2H, СН₂), 1.68–1.77 m (2H, СН₂), 1.78–1.82

m (2H, СН₂), 2.75 d.d (1H, СН₂О, J₁13.3, J₂9.5 Hz),

2.85–3.01 m (2H,СН₂СОN), 3.28 d.d (1H, СН₂О, J₁13.3,

J₂2.8 Hz), 4.15–4.22 m (2Н, СH₂Ph), 4.63–4.69 m (1H,

CHN), 7.19–7.35 m (5H, C₆H₅). ¹³

С NMR spectrum, δ,

ppm: 11.7 (2CH₂), 24.0 (CH₂), 25.4 (CH₂), 27.0 (3CH₃),

34.0 (CH₂), 35.5 (CH₂), 37.9 (CH₂), 38.6 (C), 55.1

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF EPOTHILONE D WITH THE FORCED APPLICATION

1669

spectrum, ν, cm^–1: 3641 (ОН), 3076 (ОН), 1739 (СО₂).

¹H NMR spectrum, δ, ppm: 0.59–0.62 m (2H, СН of

cyclopropane), 0.73–0.76 m (2H, СН of cyclopropane),

0.88 d (3H, CHCH₃, J 6.9 Hz), 1.07–1.11 m (1H, СН₂),

1.12 с [9H, С(СН₃)₃], 1.30–1.47 m (3H, СН₂), 1.54–1.61

m (1H, CH), 1.64–1.77 m (2H, СН₂), 1.80 br.s (1H, ОН),

3.37 d.d (1H, СН₂ОН, J₁10.5, J₂6.7 Hz), 3.46 d.d (1H,

СН₂ОН, J₁10.5, J₂5.9 Hz). ¹³С NMR spectrum, δ, ppm:

11.70 (СН₂), 11.71 (СН₂), 16.4 (СН₃), 23.1 (СН₂), 26.9

(3 СН₃), 32.8 (СН₂), 34.4 (СН₂), 35.6 (СН), 38.6 (С),

59.3 (С), 68.1 (СН₂), 178.4 (С). Found, %: C 69.55;

H 10.75. C₁₄H₂₆O₃. Calculated, %: С 69.38; H 10.81.

The enantiomeric purity (ее 88%) of alcohol obtained

was estimated by Mosher method [39] by the integration

of the proton signals of СН₂ОMTРА group at δ 4.06 and

4.22 ppm (main isomer), and δ 4.12, 4.15 ppm (minor

isomer) in the ¹Н NMR spectrum of its ester with (S)-α-

methoxy-α-triﬂuoromethylphenylacetic acid.

(СН), 59.2 (С), 66.1 (CH₂), 127.3 (СН), 128.9 (2СН),

129.4 (2СН), 135.2 (С), 153.4 (С), 173.0 (С), 178.3 (С).

Found, %: C 68.66; H 7.63. C₂₃H₃₁NO₅. Calculated, %:

С 68.80; H 7.78.

1-{(4S)-5-[(4S)-4-Benzyl-2-oxooxazolidin-3-yl]-4-

methyl-5-oxapentyl}cyclopropyl pivaloate (XL). To

a solution of 3.36 g (8.34 mmol) of compound XXXVIIIb

in 30 ml of THF at –78°С while stirring was added within

10 min 14 ml (9.17 mmol) of 0.65 M sodium hexameth-

yldisilazide solution in THF. After 30 min to the reaction

mixture at stirring and the same temperature was added

1.56 ml (25.02 mmol) of MeI. The reaction mixture was

stirred for 3 h at –78°С, treated with 10 ml of saturated

NH₄Cl solution, and warmed to room temperature. The

reaction products were extracted into Et₂O, the combined

organic solutions were washed with brine and dried with

MgSO₄. The solvent was distilled off under a reduced

pressure, the residue was chromatographed on silica

gel (eluent petroleum ether–ethyl acetate). Yield 3.21 g

(92%), [α]_D+50° (c 1.9, CHCl₃). IR spectrum, ν, cm^–1:

3090 (СН of cyclopropane), 1787 (СО oxazolidinone),

1-[(4S)-5-Hydroxy-4-methylpentyl]cyclopropanol

(XLIb). To a dispersion of 0.16 g (4.1 mmol) of LiAlH₄

in 8 ml of Et₂O at 0°С while stirring was added within

10 min a solution of 1 g (4.1 mmol) of pivaloate XLIа

in 8 ml of Et₂O. After 30 min the reaction mixture was

treated with 0.8 ml of Н₂O. The precipitate was ﬁltered

off, washed with EtOAc, the ﬁltrate was evaporated, the

residue was subjected to chromatography on silica gel

(eluent petroleum ether–ethyl acetate). Yield 583 mg

(90%), [α]_D–15° (c 2.0, CHCl₃). IR spectrum, ν, cm^–1:

3640 (ОН), 3350 (ОН), 3086 (СН₂of cyclopropane).

¹H NMR spectrum, δ, ppm: 0.40–0.42 m (2H, СН of

cyclopropane), 0.70–0.72 m (2H, СН of cyclopropane),

0.91 d (3H, СНСН₃, J 6.7 Hz), 1.10–1.21 m (1H, СН₂),

1.41–1.66 m (6H, СН, СН₂), 2.42 br.s (2H, ОН), 3.43 d.d

(1H, СН₂ОН, J₁10.5, J₂6.1 Hz), 3.47 d.d (1H, СН₂ОН,

J₁10.5, J₂6.1 Hz). ¹³С NMR spectrum, δ, ppm: 13.4

(2СН₂), 16.6 (СН₃), 23.2 (СН₂), 32.9 (СН₂), 35.6 (СН),

38.4 (СН₂), 55.4 (С), 67.9 (СН₂). Found, %: C 68.26;

H 11.37. C₉H₁₈O₂. Calculated, %: С68.31; H 11.47.

1

1738 (Piv), 1700 (СОN). H NMR spectrum, δ, ppm:

0.61–0.64 m (2H, СН of cyclopropane), 0.75–0.78 m (2H,

СН of cyclopropane), 1.14 s [9H, С(СН₃)₃], 1.21 d (3H,

CHCH₃, J 6.9 Hz), 1.37–1.50 m (3H, CH₂), 1.72–1.80 m

(3H, CH₂), 2.76 d.d (1H, CH₂O, J₁13.3, J₂9.7 Hz),

3.25 d.d (1H, CH₂O, J₁13.3, J₂2.6 Hz), 3.70 m (1H,

CHCH₃), 4.16 d.d (1H, CH₂Ph, J₁8.9, J₂2.7 Hz), 4.21 d.d

(1H, CH₂Ph, J₁8.9, J₂7.7 Hz), 4.66 m (1H, CHN),

7.21–7.35 m (5H, С₆Н₅). ¹³С NMR spectrum, δ, ppm:

11.7 (CH₂), 11.8 (CH₂), 17.3 (CH₃), 23.5 (CH₂), 27.0

(3CH₃), 33.0 (CH₂), 34.2 (CH₂), 37.6 (CH), 37.8 (CH₂),

38.6 (C), 55.3 (CH), 59.2 (C), 66.0 (CH₂), 127.3 (CH),

128.9 (2CH), 129.4 (2CH), 135.3 (C), 153.0 (C), 177.0

(C), 178.3 (C). Found, %: C 69.15; H 7.88. C₂₄H₃₃NO₅.

Calculated, %: С 69.37; H 8.00.

1-[(4S)-5-Hydroxy-4-methylpentyl]cyclopropyl

pivaloate (XLIа). To a solution of 0.26 g (0.62 mmol) of

compound XL and 0.25 ml (6.2 mmol) of MеОН in 6 ml of

THF at 0°С while stirring was added 0.62 ml (1.24 mmol)

of 2 M solution of LiBH₄in THF. The reaction mixture

was warmed to room temperature and 30 min later it was

treated with 1 M NaOH. The organic layer was separated,

from the water layer the reaction products were extracted

into Et₂O, the combined organic solutions were washed

with brine and dried with MgSO₄. The solvent was dis-

tilled off under a reduced pressure, the residue was chro-

matographed on silica gel (eluent petroleum ether–ethyl

acetate). Yield 0.13 g (89%), [α]_D–13° (c 2.0, CHCl₃). IR

(1E)-2-[(2S,3E)-2-(tert-Butyldimethylsiloxy)-3-

methyl-4-(2-methylthiazol-4-yl)but-3-enyl]-1-[(4S)-

4-methyl-5-tetrahydro-2H-pyran-2-yloxy)pentyl]

cyclopropanol (XLIVа). To a solution of a mixture of

0.5 g (2.05 mmol) of ester XXXIV, 1 g (3.1 mmol) of

alkene XXXV, and 0.61 ml (2.05 mmol) of Ti(OPr-i)₄

in 40 ml of THF was added at stirring within 40 min

4.1 ml (8.2 mmol) of 2 M solution of cyclopentylmag-

nesium chloride. After 10 min the reaction mixture was

treated with 1.1 ml of Н₂О. The precipitate was ﬁltered

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

HURSKI, KULINKOVICH

1670

off, washed with EtOAc, the ﬁltrate was evaporated

under a reduced pressure, the residue was subjected to

chromatography on silica gel (eluent petroleum ether–

ethyl acetate). Yield of unreacted alkene XXXV 0.54 g

(1.67 mmol), yield of cyclopropanol XLIV obtained as

a mixture of diastereomers 0.72 g (66% with respect to

ester XXXIV and 95% with respect to reacted alkene

XXXV). IR spectrum, ν, cm^–1: 3609 (OH), 3468 (OH).

¹H NMR spectrum, δ, ppm: 0.00 s (3H, SiCH₃), 0.06 s

(3H, SiCH₃), 0.06–0.11 m (1H, CH of cyclopropane),

0.78–0.89 m (3.5H, СНСН₃, СН of cyclopropane),

0.88 s [9H, SiC(CH₃)], 0.92 d (1.5H, СНСН₃, J 7.7 Hz),

1.07–1.83 m (15H, СН₂, СН), 1.94 с (3H, ССН₃),

2.52 br.s (1H, ОН), 2.68 s (3H, СН₃СNS), 3.14 d.d (0.5H,

СН₂ОSi, J₁9.2, J₂6.5 Hz), 3.22 d.d (0.5H, СН₂ОTHP,

J₁9.2, J₂5.9 Hz), 3.45–3.53 m (1.5H, СH₂OTHP, CH₂O

of tetrahydropyran), 3.58 d.d (0.5H, СН₂ОTHP, J₁9.2,

J₂6.5 Hz), 3.80–3.85 m (1H, CH₂O of tetrahydropyran),

4.12–4.18 m (1H, CHOTBS), 4.52–4.56 m (1H, CHO₂

of tetrahydropyran), 6.46 s (1H, C=CHCN), 6.90 s (1H,

CHS). Found, %: C 64.66; H 9.44. C₂₉H₅₁NO₄SSi.

Calculated, %: С 64.76; H 9.56.

C₃₀H₅₃NO₆S₂Si. Calculated, %: С 58.50; H 8.67.

4-[(1E,3S,5E,10S)-6-(Bromomethyl)-3-

(tert-butyldimethylsiloxy)-2,10-dimethyl-

11-(tetrahydro-2H-pyran-2-yloxy)undeca-1,5-

dienyl]-2-methylthiazole (XLV) and 4-[(3S,10S,E)-

5-bromo-3-(tert-butyldimethylsiloxy)-2,10-

dimethyl-6-methylene-11-(tetrahydro-2H-pyran-

2-yloxy)undec-1-enyl]-2-methylthiazol (XLVI). Asolu-

tion of 1.5 g (2.44 mmol) of methanesulfonate XLIVb in

5 ml Et₂O was within 2 min added at stirring to a cooled

with cold water solution of MgBr₂prepared from 0.17 g

(7.2 mmol) of magnesium and 0.62 g (7.2 mmol) of

1,2-dibromoethane in 5 ml of Et₂O. The reaction mixture

was warmed to room temperature and 20 min later it was

treated with 7 ml of Н₂О. The organic layer was sepa-

rated, the reaction products were extracted into Et₂O, the

combined organic solutions were dried with MgSO₄. The

solvents were distilled off under a reduced pressure. Yield

1.45 g (99%). The mixture of isomers XLV, XLVI, 87 : 13,

was used in the next stage without puriﬁcation. ¹H NMR

spectrum of bromide XLV, δ, ppm: 0.00 s (3H, SiCH₃),

0.05 s (3H, SiCH₃), 0.88 s [9H, SiC(CH₃)₃], 0.89–0.93 m

(3H, СНСН₃), 1.07–1.18 m (1H, СН₂), 1.37–1.59 m

(7H, СН₂), 1.67–1.85 m (3H, СН₂, СН), 1.99 с (3H,

ССН₃), 2.15–2.22 m (2H, СН₂), 2.24–2.37 m (2H, СН₂),

2.70 s (3H, СН₃CNS), 3.14 d.d (0.5H, CH₂OTHP, J₁9.2,

J₂6.4 Hz), 3.21 d.d (0.5H, CH₂OTHP, J₁9.2, J₂5.9 Hz),

3.47–3.52 m (1.5H, CH₂OTHP, CH₂O of tetrahydropyran),

3.58 d.d (0.5H, CH₂OTHP, J₁9.2, J₂6.4 Hz), 3.82–3.87

m (1H, CH₂O of tetrahydropyran), 3.98 s (2H, СH₂Br),

4.13 t (1H, CHO₂, J 6.4 Hz), 4.54–4.56 m (1H, CHOSi),

5.62 t (1H, C=CHCH₂, J 7.3 Hz), 6.45 s (1H, C=CHCN,

6.93 s (1H, CHS). ¹³С NMR spectrum, δ, ppm: –5.0

(СН₃), –4.7 (СН₃), 13.8 (СН₃), 17.0 (СН₃), 17.1 (СН₃),

18.1 (С), 19.1 (СН₃), 19.5 (СН₂), 25.4 (СН₂), 25.8

(3СН₃), 28.6 (СН₂), 30.6 (СН₂), 33.1 (СН), 33.2 (СН),

33.6 (СН₂), 35.5 (СН₂), 39.3 (СН₂), 62.0 (СН₂), 62.1

(СН₂), 72.8 (СН₂), 72.9 (СН₂), 78.1 (СН), 98.7 (СН),

98.9 (СН), 115.2 (СН), 118.9 (СН), 128.4 (СН), 137.3

(С), 137.4 (С), 141.8 (С), 152.9 (С), 164.3 (С). Found,

%: C 58.20; H 8.38. C₂₉H₅₀BrNO₃SSi. Calculated, %:

С 57.98; H 8.39.

(1E)-2-[(2S,3E)-2-(tert-Butyldimethylsiloxy)-3-

methyl-4-(2-methylthiazol-4-yl)but-3-enyl]-1-[(4S)-

4-methyl-5-(tetrahydro-2H-pyran-2-yloxy)pentyl]

cyclopropyl methanesulfonate (XLIVb). To a solution

of 1.32 g (2.46 mmol) of cyclopropanol XLIV and 0.49 g

(4.85 mmol) of Et₃N in 25 ml of Et₂O cooled to 0°С was

added dropwise at stirring 0.23 ml (2.97 mmol) of meth-

anesulfonyl chloride. The reaction mixture was warmed

to room temperature and treated with 10 ml of saturated

NaHCO₃solution. The water layer was separated, the

reaction products were extracted into Et₂O, the combined

organic solutions were washed with brine and dried with

MgSO₄. The solvents were distilled off under a reduced

pressure. Yield 1.5 g (99%), mixture of diastereomers.

IR spectrum, ν, cm^–1: 1350 (SO₂), 1182 (SO₂). ¹H NMR

spectrum, δ, ppm: 0.00 с (3H, SiCH₃), 0.06 с (3H, SiCH₃),

0.34 t (0.6H, СН of cyclopropane, J 7.0 Hz), 0.39 t

(0.4H, СН of cyclopropane, J 6.4 Hz), 0.84–0.94 m (5H,

СНСН₃, СН of cyclopropane), 0.88 s [9H, SiC(CH₃)₃],

1.03–2.07 m (15H, СН₂, СН), 1.97 s (3H, ССН₃), 2.69

s (3H, СН₃CNS), 2.92 s (3H, Ms), 3.13–3.17 m (0.5H,

CH₂OTHP), 3.19–3.24 m (0.5H, CH₂OTHP), 3.45–

3.53 m (1.5H, CH₂OTHP, CH₂O of tetrahydropyran),

3.55–3.60 m (0.5H, CH₂OTHP), 3.80–3.85 m (1H,

CH₂O of tetrahydropyran), 3.16–3.23 m (1H, CHOSi),

4.53–4.55 m (1H, CHO₂of tetrahydropyran), 6.49 с (1H,

C=CHCN), 6.92 (1H, CHS). Found, %: C 58.71; H 8.59.

4-[(1E,3S,5Z,10S)-3-(tert-Butyldimethylsiloxy)-

2,6,10-trimethyl-11-(tetrahydrо-2H-pyran-2-yloxy)

undeca-1,5-dienyl]-2-methylthiazole (XLVII). To

a dispersion of 10 mg (0.26 mmol) of LiAlH₄in 2 ml of

Et₂O cooled with cold water was added within 2 min at

stirring 154 mg (0.26 mmol) of the mixture of bromides

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF EPOTHILONE D WITH THE FORCED APPLICATION

1671

XLV and XLVI in 0.6 ml of Et₂O. The reaction mixture

was warmed to room temperature, 30 min later it was

cooled with ice and treated with 0.05 ml of Н₂О. The

precipitate was ﬁltered off, washed with Et₂O, the ﬁltrate

was evaporated. The residue was dissolved in DMF, and

to the solution obtained 26 mg (0.26 mmol) of potassium

acetate and 15 mg of triethylbenzylammonium chloride

were added. The reaction mixture was stirred for 14 h at

room temperature, diluted with 5 ml of Н₂О, the reac-

tion products were extracted into Et₂O, the combined

organic solutions were washed with brine and dried with

MgSO₄. The solvents were distilled off under a reduced

pressure, the residue was chromatographed on silica

gel (eluent petroleum ether–ethyl acetate). Yield 81 mg

added dropwise at stirring a solution of 75 mg (0.96

mmol) of dimethyl sulfoxide in 1 ml of СН₂Cl₂. After

20 min to the reaction mixture was added at stirring a

solution of 168 mg (0.4 mmol) of dienol XXXVIII in

1 ml of СН₂Cl₂, and 1 h later 0.3 ml (2.2 mmol) of Et₃N

was added. After that the reaction mixture was warmed

to 0°С and treated with 4 ml of saturated NH₄Cl solution.

The water layer was separated and extracted with Et₂O.

The combined organic solutions were washed with brine

and dried with MgSO₄. The solvents were evaporated,

the residue was chromatographed on silica gel (eluent

petroleum ether–ethyl acetate). Yield 154 mg (92%).

The spectral characteristics of compound obtained were

consistent with those published in [9].

1

(60%), mixture of diastereomers. H NMR spectrum,

(4R,5S,6S,10Z,13S,14E)-13-(tert-Butyldimethyl-

siloxy)-2-{(7S)-5,5-dimethyl-4,6-dioxaspiro[2.5]

oct-7-yl}-5-hydroxy-2,4,6,10,14-pentamethyl-15-

(2-methylthiazol-4-yl)pentadeca-10,14-dien-3-one

(XLVIII). To LDA solution prepared from 91 mg

(0.9 mmol) of diisopropylamine and 0.5 ml (0.9 mmol)

of 1.76 M n-butyllithium solution in 0.5 ml of THF,

cooled to –78°С was added dropwise at stirring and

cooling a solution of 215 mg (0.9 mmol) of ethyl ketone

II in 0.9 ml of THF. After 1 h the reaction mixture was

warmed within 45 min to –40°С, cooled again to –78°С,

diluted with 1 ml of THF and within 1 min along the

ﬂask wall was added a solution of 163 mg (0.37 mmol)

of aldehyde III in 1 ml of THF. After stirring for 5 min

at the same temperature the reaction mixture was treated

with a solution of 0.2 ml of acetic acid in 0.4 ml of THF,

the reaction mixture was warmed to room temperature,

2 ml of water was added, the water layer was separated,

the products were extracted into Et₂O. The combined

organic solutions were washed with brine and dried with

MgSO₄. The solvents were distilled off under a reduced

pressure, the residue was chromatographed on silica gel

(eluent petroleum ether–ethyl acetate). Yield 200 mg

(80%), [α]_D+8° (c 1.8, CHCl₃). IR spectrum, ν, cm^–1:

δ, ppm: 0.00 s (3H, SiCH₃), 0.04 s (3H, SiCH₃), 0.88 s

[9H, SiC(CH₃)₃], 0.90 d (1.5H, CHCH₃, J 6.9 Hz), 0.92 d

(1.5H, CHCH₃, J 6.9 Hz), 1.03–1.86 m (11H, CH₂, CH),

1.66 с (3H, CH₂C=CCH₃), 1.94–2.04 m (2H, CH₂), 1.99 s

(3H, NCCH=CCH₃), 2.19–2.29 m (2H, CH₂), 2.71 s (3H,

СН₃CNS), 3.12 d.d (0.5H, CH₂OTHP, J₁9.5, J₂6.7 Hz),

3.22 d.d (0.5H, CH₂OTHP, J₁9.5, J₂5.9 Hz), 3.47–3.51 m

(1.5H, CH₂OTHP, CH₂O of tetrahydropyran), 3.59 d.d

(0.5H, CH₂OTHP, J₁9.2, J₂6.1 Hz), 3.82–3.88 m (1H,

CH₂O of tetrahydropyran), 4.07 t (1H, CHOSi, J 6.4 Hz),

4.55–4.57 m (1H, CHO₂), 5.12 t (1H, C=CHCH₂,

J 7.1 Hz), 6.45 s (1H, C=CHCN), 6.92 s (1H, CHS).

¹³С NMR spectrum, δ, ppm: –5.0 (СН₃), –4.7 (СН₃), 13.9

(СН₃), 17.1 (СН₃), 17.2 (СН₃), 18.2 (С), 19.1 (СН₃), 19.4

(СН₂), 19.5 (СН₂), 23.4 (СН₃), 25.3 (СН₂), 25.5 (СН₂),

25.8 (3СН₃), 29.6 (СН₂), 30.7 (СН₂), 32.1 (СН₂), 32.2

(СН₂), 33.3 (СН), 33.4 (СН), 33.6 (СН₂), 35.3 (СН₂),

61.9 (СН₂), 62.0 (СН₂), 72.9 (СН₂), 73.0 (СН₂), 79.0

(СН), 98.7 (СН), 98.9 (СН), 114.9 (СН), 118.6 (СН),

121.4 (СН), 136.8 (С), 142.5 (С), 153.2 (С), 164.2 (С).

Found, %: C 67.00; H 9.83. C₂₉H₅₁NO₃SSi. Calculated,

%: С 66.74; H 9.85.

Dienol (XXXVIII). To a solution of 64 mg

(0.104 mmol) of THP–ether XLVII in 1 ml of i-PrOH was

added 3 mg (0.01 mmol) of Py·HOTs. The solution was

stirred at 65°С for 4 h, the solvent was distilled off under

a reduced pressure, the residue was chromatographed on

silica gel (eluent petroleum ether–ethyl acetate). Yield

of initial ether XLVII 8 mg (13%), yield of alcohol

XXXVIII 37 mg (81%, with respect to reacted ether

XLVII 94%]. The spectral characteristics of compound

obtained were consistent with those published in [12].

1

3510 (ОН), 1685 (С=О). H NMR spectrum, δ, ppm:

–0.02 s (3H, SiCH₃), 0.03 s (3H, SiCH₃), 0.35–0.40 m

(1H, CH of cyclopropane), 0.57–0.62 m (1H, CH of

cyclopropane), 0.70–0.75 m (1H, CH of cyclopropane),

0.76–0.81 m (2H, CH of cyclopropane, CH), 0.81 d

(3H, CHCH₃, J 6.9 Hz), 0.87 s [9H, SiC(CH₃)₃], 1.02 d

(3H, СОСНСН₃, J 6.9 Hz), 1.08 s [3H, С(СН₃)₂],

1.11–1.29 m (2H, СН₂), 1.20 s [3H, С(СН₃)₂], 1.31 s

[3H, О₂С(СН₃)], 1.38–1.60 m (2H, СН₂, СНСН₃),

1.46 s [3H, О₂С(СН₃)], 1.65 s (3H, CH₂CH=ССН₃),

1.73–1.79 m (1H, СН₂), 1.92–2.02 m (2H, CH=ССН₂),

Dienal (III). To a solution of 61 mg (0.48 mmol) of

oxalyl chloride in 2 ml of СН₂Cl₂cooled to –78°С was

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

HURSKI, KULINKOVICH

1672

( 3 S , 6 R , 7 S , 8 S , 1 2 Z , 1 5 S , 1 6 E ) - 1 5 - ( t e r t -

Butyldimethylsiloxy)-3,7-dihydroxy-4,4,6,8,12,16-

hexamethyl-17-(2-methylthiazol-4-yl)-5-

oxaheptadeca-12,16-dienic acid (L). To a solution of

275 mg (0.43 mmol) of cyclopropanol XLIX in a mixture

of 3 ml of THF and 2.5 ml of Н₂О while stirring at room

temperature was added by portions within 10 min 138 mg

(0.43 mmol) of PhI(OAc)₂. After 30 min the solvents

were distilled off under a reduced pressure, the residue

was chromatographed on silica gel (eluent dichlorometh-

ane–methanol). Yield 251 mg (91%), [α]_D–11.6° (c 0.86,

СHCl₃), IR spectrum, ν, cm^–1: 3516 (ОН), 3453 (ОН),

1.97 s (3H, NCCH=ССН₃), 2.04–2.10 m (1H, СН₂),

2.16–2.29 m (2H, C=СНСН₂), 2.70 s (3H, СН₃CNS),

3.29 d.q (1H, СОСНСН₃, J₁6.9, J₂1.2 Hz), 3.35 d (1H,

СНОН, J 9.2 Hz), 3.55 br.s (1H, ОН), 4.06 t (1H, СНОSi,

J 6.4 Hz), 4.19 d.d (1H, СНО, J₁11.8, J₂2.3 Hz), 5.11 t

(1H, С=СНСН₂, J 7.0 Hz), 6.44 s (1H, C=CHCN), 6.91 s

(1H, СНS). ¹³С NMR spectrum, δ, ppm: –4.9 (СН₃), –4.7

(СН₃), 9.4 (СН₃), 10.0 (СН₂), 13.9 (СН₃), 14.5 (СН₂),

15.3 (СН₃), 18.2 (С), 18.7 (СН₃), 19.1 (СН₃), 21.1 (СН₃),

21.4 (СН₃), 23.5 (С), 25.2 (СН₂), 25.8 (3СН₃), 29.7

(СН₃), 31.4 (СН₂), 32.4 (СН₂), 33.0 (СН₂), 35.3 (СН₂),

35.4 (СН), 41.3 (СН), 51.3 (С), 53.5 (С), 74.1 (СН), 74.4

(СН), 79.0 (СН), 100.1 (С), 114.8 (СН), 118.6 (СН),

121.4 (СН), 136.9 (С), 142.6 (С), 153.2 (С), 164.2 (С),

222.7 (С).

1

1719 (СО₂Н), 1679 (СО). H NMR spectrum, δ, ppm:

–0.02 s (3H, SiCH₃), 0.03 s (3H, SiCH₃), 0.83 d (3H,

CHCH₃, J 6.7 Hz), 0.87 s [9H, SiC(CH₃)₃], 1.04 d (3H,

COCHCH₃, J 6.9 Hz), 1.11 s [3H, C(CH₃)₂], 1.07–1.24 m

(2H, CH₂), 1.20 s [3H, C(CH₃)₂], 1.39–1.59 m (2H, CH₂,

CHCH₃), 1.65 s (3H, CH₂CH=ССН₃), 1.65–1.75 m (1H,

CH₂), 1.93 s (3H, NCCH=ССН₃), 2.0–2.05 m (2H, CH₂),

2.16–2.30 m (2H, CH₂), 2.35–2.52 m (2H, CH₂), 2.71 s

(3H, CH₃CNS), 3.26 q (1H, СОСНСН₃, J 6.4 Hz), 3.40 d

(1H, СНСНОН J 9.0 Hz), 4.07 t (1H, СНОSi, J 6.4 Hz),

4.26 d.d (1H, CH₂CHOH, J 9.7, 2.3 Hz), 5.11 t (1H,

C=CHCH₂, J 6.4 Hz), 6.45 с (1H, C=CHCN), 6.92 s

(1H, CHS). ¹³С NMR spectrum, δ, ppm: –5.0 (СН₃), –4.7

(СН₃), 10.1 (СН₃), 13.9 (СН₃), 15.5 (СН₃), 18.2 (С), 18.6

(СН₃), 19.0 (СН₃), 21.1(СН₃), 23.5 (СН₃), 25.0 (СН₂),

25.8 (3СН₃), 32.3 (СН₂), 32.7 (СН₂), 35.2 (СН₂), 35.4

(СН), 36.4 (СН₂), 41.0 (СН), 52.1 (С), 72.2 (СН), 74.6

(СН), 79.0 (СН), 114.6 (СН), 118.2 (СН), 121.4 (СН),

136.9 (С), 143.2 (С), 152.5 (С), 165.2 (С), 176.1 (С),

221.9 (С).

( 2 S , 5 R , 6 S , 7 S , 11 Z , 1 4 S , 1 5 E ) - 1 4 - ( t e r t -

Butyldimethylsiloxy)-2,6-dihydroxy-1-(1-

hydroxycyclopropyl)-3,3,5,7,11,15-hexamethyl-16-

(2-methylthiazol-4-yl)hexadeca-11,15-dien-4-one

(XLIX). Asolution of 136 mg (0.201 mmol) of acetonide

XLVIII in a mixture of 5.5 ml of 80% formic acid and

5.5 ml of Et₂O cooled to 5°С was kept at room tem-

perature over 10 h (TLC monitoring). The solvents were

distilled off under a reduced pressure, the residue was

chromatographed on silica gel (eluent petroleum ether–

ethyl acetate). Yield 98 mg (77%), [α]_D–15° (c 0.98,

СHCl₃). IR spectrum, ν, cm^–1: 3512 (ОН), 1683 (С=О).

¹H NMR spectrum, δ, ppm: –0.02 s (3H, SiCH₃), 0.03 s

(3H, SiCH₃), 0.39–0.50 m (2H, СН of cyclopropane),

0.75–0.83 m (2H, СН of cyclopropane), 0.84 d (3H,

СНСН₃, J 6.7 Hz), 0.87 s [9H, SiC(CH₃)₃], 1.04 d (3H,

COCHCH₃, J 6.7 Hz), 1.08 s [3H, C(CH₃)₂], 1.07–1.31 m

(3H, CH₂), 1.20 s [3H, C(CH₃)₂], 1.40–1.57 m (2H, CH₂,

CHCH₃), 1.65 s (3H, CH₂CH=ССН₃), 1.66–1.76 m (1H,

CH₂), 1.93–2.06 m (3H, CH₂), 1.96 s (3H, NCCH=ССН₃),

2.18–2.28 m (2H, C=CHCH₂), 2.71 s (3H, CH₃CNS),

3.26 d.q (1H, СОСНСН₃, J 6.9, 1.3 Hz), 3.32 br.s (1H,

ОН), 3.38 d (1H, CHCHOH, J 8.7 Hz), 3.78 br.s (1H,

ОН), 3.85 br.s (1H, ОН), 4.07 t (1H, СНОSi, J 6.4 Hz),

4.24 d.d (1H, CCHOH, J₁10.8, J₂1.0 Hz), 5.14 t (1H,

С=СНСН₂, J 6.9 Hz), 6.42 s (1H, С=СНCN), 6.91 s (1H,

CHS). ¹³С NMR spectrum, δ, ppm: –4.9 (СН₃), –4.7

(СН₃), 10.1 (СН₃), 12.4 (СН₂), 13.8 (СН₃), 14.1 (СН₂),

15.5 (СН₃), 18.2 (С), 18.6 (СН₃), 19.0 (СН₃), 21.5 (СН₃),

23.4 (СН₃), 25.1 (СН₂), 25.8 (3СН₃), 32.3 (СН₂), 32.8

(СН₂), 35.3 (СН₂), 35.6 (СН), 38.0 (СН₂), 41.1 (СН),

52.3 (С), 55.8 (С), 74.5 (СН), 76.3 (СН), 79.2 (СН),

114.8 (СН), 118.6 (СН), 121.6 (СН), 136.7 (С), 142.7

(С), 153.1 (С), 164.4 (С), 223.0 (С).

Silylation of dihydroxyacid L. To a solution of

260 mg (0.408 mmol) of acid L and 0.36 ml (3.06 mmol)

of 2,6-lutidine in 6 ml of CH₂Cl₂cooled to 0°С was

added dropwise at stirring 0.42 ml (1.84 mmol) of tert-

butyldimethylsilyl triﬂuoromethanesulfonate. The reac-

tion mixture was kept at 5°С for 4 h and it was treated

with 3 ml of 10% HCl. The water layer was separated,

the reaction products were extracted into CH₂Cl₂, the

combined organic solutions were washed with brine and

dried with MgSO₄. The solvents were evaporated under

a reduced pressure, the residue was dissolved in a mix-

ture of 11 ml of THF, 1.3 ml of acetic acid, and 1.8 ml

of Н₂О, cooled to 5°С, the reaction mixture was kept at

5°С for 3 h, diluted with EtOAc, washed with brine, and

the organic phase was dried with MgSO₄. The solvents

were distilled off under a reduced pressure, the residue

was chromatographed on silica gel (eluent petroleum

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF EPOTHILONE D WITH THE FORCED APPLICATION

1673

ether–ethyl acetate–dichloromethane). Yield 310 mg

(89%). The spectral characteristics of compound obtained

were consistent with those published in [9].

СН₂), 2.06 s (3H, NCСН=ССН₃), 2.24–2.35 m (3H,

СН₂), 2.46 d.d (1H, СН₂, J₁14.3, J₂11.3 Hz), 2.63 d.t

(1H, СН₂, J₁14.8, J₂10.8 Hz), 2.69 s (3H, СН₃CNS),

3.08 br.s (1H, ОН), 3.15 d.q (1H, СОСНСН₃, J₁6.7,

J₂1.5 Hz), 3.64 br.s (1Н, ОН), 3.72 s (1H, СНОН), 4.31 d

(1H, CMе₂СНОН, J 10.2 Hz), 5.14 d.d (1H, СН₂СН=С,

J₁9.7, J₂4.6 Hz), 5.21 d (1H, СНО₂С, J 9.7 Hz), 6.59 s

(1H, NCСН=ССН₃), 6.95 s (1H, СНS). ¹³С NMR spec-

trum, δ, ppm: 13.4 (CH₃), 15.7 (CH₃), 15.8 (CH₃), 17.9

(CH₃), 18.9 (CH₃), 22.8 (CH₃), 22.9 (CH₃), 25.3 (CH₂),

31.5 (CH₂), 31.6 (CH₂), 32.4 (CH₂), 38.3 (CH), 39.6

(CH₂), 41.6 (CH), 53.5 (C), 72.1 (CH), 74.1 (CH), 78.8

(CH), 115.5 (CH), 119.0 (CH), 120.8 (CH), 138.3 (C),

139.1 (C), 151.9 (C), 165.0 (C), 170.3 (C), 220.6 (C).

Heptadecadienic acid LI. To a solution in 0.5 ml of

THF of 92 mg (0.11 mmol) of the tert-butyldimethylsiloxy

derivative of heptadecadienic acid obtained as described

above was added 0.55 ml (5.5 mmol) of 1 M solution of

tetrabutylammonium ﬂuoride in THF. The reaction mixture

was stirred at room temperature for 4 h and it was treated

with 5 ml of saturated NH₄Cl solution. The water layer

was separated, the products were extracted into Et₂O. The

combined organic solutions were washed with brine and

dried with MgSO₄. The solvents were evaporated under

a reduced pressure, the residue was chromatographed on

silica gel (eluent petroleum ether–ethyl acetate–dichlo-

romethane). Yield of initial ether 21 mg (23%), yield of

hydroxyacid LI 42 mg (53%, 69% with respect to reacted

ether). The spectral characteristics of compound obtained

were consistent with those published in [9].

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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

Article Doi

Synthesis of epothilone D with the forced application of oxycyclopropane intermediates

DOI: 10.1134/S1070428011110029

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Article abstract of DOI:10.1134/S1070428011110029

Full text of DOI:10.1134/S1070428011110029

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