An enantiospecific synthesis of the spiroketal portion of avermectin B1a

Tetrahedron Letters,Vol.29,No.Z4,pp Printed in Great Britain

AN ENANTIOSPECIFIC

SYNTHESIS

0040-4039/88 $3.00 + .OO Perqamon Press plc

2923-2926,1988

OF THE SPIROKETAL

PORTION

Christina M. J. Fox, Roger N. Hiner, Ulhas Warrier, Department

SUMMARY:

of Chemistry,

The acetonide

laevoglucosan,

reacted

silyloxy-l-heptyne,

Oregon

with the cerium

prepared

from

The potent

anthelmintic

numerous

directed

toward

mycins

avermectin convergence

of the three

subunits

moiety

synthesis

activity

of these Streptomyces achievements,

associated

metabolites

including

in a recent

with the avermectins'

formula

Letter4

the spiroketal

total

construction

(1).

milbe-

synthesis

of

and

A route to the

and we now describe

component

has

The endeavors

and the companion

a recent

Bla envisions

in its trisected

of 2, representing

from

that was converted

from synthesis.'

of avermectin

identified

prepared

Bla.

contributions

of 1 was reported

U.S.A.

an

(C-16 to C-28) of

Bla.'

A structural

element

mycins

is a set-butyl

C-26.

This feature,

of 1, suggested with a crotyl coupled

diverse

Our plan for the synthesis

enantiospecific

97331,

to give a carbinol

of avermectin

and antiparasitic

in some noteworthy

hexahydrobenzofuran

avermectin

segment

de novo synthesis

Ala.3

Oregon,

of (3S,4R,5S)-3,5-dimethyl-4-t-butyldimethyl

(2S)-2-methylbutanol,

and exceptionally

has resulted

derivative

Bla

and James D. White*

Corvallis,

of (3S,SS)-5,6-dihydroxy-3-p-methoxybenzyloxyhexana~,

in four steps to the spiroketal

elicited

State University,

OF AVERMECTIN

cornnon to certain

substituent together

an approach

anion

species

at C-25.

avermectins

with the additional in which alkylation

to give an alkyne

to a glucose-derived

aldehyde

that distinguishes

In consequence,

a stereogenic

five stereogenic

centers

of (2S)-2-methylbutanal incorporating

them from milbecarbon

HO

1

(R -

ohne

L-oleandrosyl-L-oleandrosyl)

2923

This could then be

carbinol

to 2.6

H 1 OH

of the spiroketal

(3) would be effected

C-22 to C-28.

(C-16 to C-21) and the resulting

is present at

2

transformed

2924

The aldehyde

3 was obtained

(2'S)-2-methyl-1-butanol reagent

prepared

with no loss of optical

and was reacted

purity'

with crotyl bromide

in situ from chromium(II1)

chloride

by Swern oxidationa

in the presence

and lithium aluminum

of

of a chromium(I1)

hydride.g

: : HO-

i

ii_++

OHCF

‘d,i

3

4 \

iii,iv

* 6

Scheme 1. Reagents and condihs: THF. 25’C;

ik t-BuMezSioSOZCF,,

I, (COCI),, DMSO. EhN. -6OT (62%); ii, MI,, LiAIH,, then CH,CH-CHCH,B~, iv, 4, CH,CI,-MeOH, then ~e,s,

2,6-lutidine, CH,CI,, O’C (66%);

-76°C (92%); v. CBr,. PPh,, Zn dust, CH,CI,. 25°C (63%); vi, n-BuLi (2 equiv), THF, -76OC to 2s°C, 2 h (66%).

Diastereomeric

alcohols

which the desired after

protection

alcohol

A&

0

4 was separated

to the substituted

(TBDMS) ether,

heptyne

respectively,

in 53% yield. was ozonized

9 via dibromo

v 0

OAC

_L+

0”

in the ratio 61:30:9

chromatographically

as its t-butyldimethylsilyl

latter was converted

7

4, 5, and 6 were produced

olefin

This substance,

to aldehyde

8 (Scheme

7.

The

l).l'

0

,,,oR

“* OAC

m

..*’

OAc

OH

ji

c:

::

“,I”,

OR

3 (p) (MPM)

vi

HOGoH

OMPM vii (

13

2SC,H,CH 3 (p)

$ ~ Scheme 2. Reagents and ccnditlons:

from

16.

R-CH,OH

17,

R-CHO

I, ref 9: ii, p-TsCI, pyridine-CHCI,,

OMPM 15

25OC. 50 h (90%); iii, U&Q

(6 equip), THF,

250~

49 h (55%); iv, KH, p-MeoC~H,CH&I, Tf+F. O’C, (60%); V, H,O-THF (l:l), p-TsOH (cat), reflux, 5 h (76%); vi, LiAfH,, THF, 25’C, 3 h, then Me,C(oMe),. camphcrsulfcnic acid (cat),CH,C+ 1 h (56%); VII, (COCI),, DMSO, E&N, CH,CI, -6OOC (62%).

2925

The second

component

required

for 2 was prepared

by a known route from glucose

pentaacetate."

C-4 were excised

by reduction

of ditosylate

that led through

intervening

epoxides

tion of 12 as its p-methoxybenzyl bridge,

yielded

lactol

as its acetonide give aldehyde

with much recovered

alcohol

was readily

forward

sequence

methoxy

acetal

oxidized

derivative

20,

a n.0.e. experiment

However,

19.

(i) acidic

(ii) deprotection

of the alkyne

acetylide

a 67% yield

to ketone

that entailed

isomer, the structure

at C-2 and a process

hydrolysis

was subjected

PrOteC-

of the anhydro

of 15 was selectively

protected

to Swern oxidation

to

of the desired

Elaboration

H-22

alkynyl

which

reagent

carbinol

of 19 was carried removed

of 18

18.

from 9

This

out in a straight-

the acetonide

and led to

of the silyl ether to give diol 21, and (iii) partial

The spiroketal

in which

from 9 gave a poor yield

the less basic alkynylcerium15

methanolysis,

2,

[al0 +

of which was established

tion of the Spiro carbon

derived

to cis olefin 22, followed

(S 1.43) but no enhancement

i

by acidic

upon reduction

heptanol

alkyne.

and afforded

to yield 2 (Scheme 3).6

H-20a

substituents

by 13 ("5:l) respectively.13

(MPM) ether 14, followed

of 17 with the lithium

was more satisfactory

hydrogenation

to 12 accompanied

16 and the resulting

oxygen

17 (Scheme 2).14

Alkylation together

The superfluous

(101, itself acquired

111* with lithium triethylborohydride,

The trio1 obtained

15.

from laevoglucosan

by a final acid-catalyzed

100.6',

was obtained

by a detailed

(S 5.56) was irradiated of either

H-17 or

as a single

IH NMR study.16

resulted

cyclization stereo-

In particular,

in a 5.5% enhancement

of

H-19. This result defines the configura-

unambiguously.

+&k

iii_“r”;“v”” c

9-

MAO

*

vi

HO&

OMPM

22

2 Scheme 3. Reagents and conditions:

i, n-BuLi, THF, -7V’C, then C&I,.

0.5 h, then

1 7 (67%); ii, MnC,, CH,&,

ijig MeOH, camphorsulphonic acid (cat). 1 h (84%); iv, n-Bu,N+ F-, THF, 50’~~. I h (85%); ,,, H,, pd/~asC,, vi, Et&A camphorsulphonic acid, 10 min (83% from 2 1 ).

2 h (75%);

quinoline, MeOH, o,5 h;

2926

We thank the Council

Acknowledgments. Fulbright (grant

grant

(to C.M.J.F.)

for International

and the National

Exchange

Institutes

of Scholars

of Health

for a

for financial

support

A110964).

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