The acetate of (Z)-4-chloro-2-methyl-2-buten-1-ol. Stereoselective wittig synthesis of a new hemiterpenoid synthon

Tetrahedron Letters,Vol.23,No.21,pp 2219-2222,1982 Prmted In Great Brltam

THE ACETATE

OF (Z)-4-CHLORO-2-METHYL-2-BUTEN-l-OL SYNTHESIS

E Chemical

l-01, a precursor the preparation

method

Department

of a metabollte

The hemlterpenold

group

Bellora,

of Istltuto

prenyl

(lsopentenyl,

compounds

attack

biotransformation

and A

prenyl)

of medlclnal

Donettl* I-20139 Milan,

of the acetate

synthon

The use of such synthon

substance

present 3,4

Italy

of (Z)-4-chloro-2-methyl-2-buten-

1s described

Interest

WITTIG

SYNTHON

De Angell,

of a prenyl-contalnlng

as well as In synthetic during metabolic

E

for the preparation

of the (Z)-hydroxy

STEREOSELECTIVE

OF A NEW HEMITERPENOID

Cereda, M. Attollnl,

Research

a synthetic

Summary

0040-4039/82/212219-04$03.00/0 01982 Pergamon Press Ltd.

In

1s also Illustrated

I" various

natural

substances

1s well known to undergo

132

oxldatlve

in mammals HO \

5 Recently, containing following

In our studies

a prenyl

on the metabolism

side-chain,

three urinary

of feprazone

metabolltes

(1)

an antllnflammatory

In rat were isolated

having

drug the

structures

1

,"I::="' R' = CH*OH R' = Me

The synthetic challenges

strategy

Without

conslderlng 6

selective

oxldatlon

for a preparation problems

of the terminal

R = CH20H

4

R=R'

=CH20H

of these substances

connected

methyl

3

groups

2219

(2, 2, and 2) Poses

with stereoselectlvlty

for 2 and 3, chemo-

of the prenyl part of the molecule

1s clearly

2220

unpractical Wlttlg

owing to the senslt1vlty

reactlon

compound

for double bond generatIon

of the rather

A synthon

of 1 to oxldlzlng

complex

approach

nucleophlllc

the foreseeable

reactlvlty

The trlsubstltuted

of the suitable

was thought

reasonable

of the anion of the 3,5-pyrazolldlnedlone

of the allyllc

functlonallzed

carbonyl

molecule

by the bond dIssectIon)

character

On the other hand, the use of a

the synthesis

3,5-pyrazolldlnedlone

(represented

the favourable

requires

agents

In view of

nucleus

and of

substltuent

olefln

synthons

(4a-6a) were then envisaged

sultable

tools for our approach R'

R'

(r~ - W2 4a -

R' = Me (E)

5a

R = CH20Ac R = Me

-6a

R= R’ = CH20Ac Preparation

procedure

R' = CH20Ac

for the symmetric

preparation synthons

are obtalned

reported

In the literature

w-c, recently allJllc

by prefrrentla, concerning

of this synthon was therefore

usefulness

R=R’ =CH*OAc

R' = CH20Ac

(3)

Nothlng

A correspondingly

2

1s Instead

simple preparation

In view also of the potential

contalnlng

utlllty

via the corresponding of metabollte

synthesis

of the acetate

key-IntermedIate

2,

of (Z)-4-

and Illustrate

2

Q -

2

)

KN(SlMe

)

THF-HMPA

N(n-Buj2

3 2'

Br@ 7

z

66

-5a

of such

the lsoprene unit

the stereoselectlve

In the preparation

from which the desired

with ethyl chloroformate

the (Z)-synthon

deemed of Interest

respectively,

AcO

Ph3P sN(n-Bu

(Z)

was avallable from the literature' , while a 8 Their synthesis 1s based on the described by us

spllttlng

In this letter, we wish to report

Its synthetic

%

amlnes 4b and E,

In the field of substances

-chloro-2-methyl-2-buten-l-01

5b

R = CH20Ac R = Me

of (E)-conflguratlon

E

of the pre-target

lntermedlates

(Z)

of synthon s

RI = Me (E)

4b

(Z > 99%)

2221

When acetoxyacetone' tanned

(0.21 mole) was allowed

from the ,!j-dlalkylamlno phosphonlum

zlde (0 28 mole) under the condltlons allyllc

acetate 2

(51% yield,

described

bp

85-87')

01 Isomer > 99% by vpc, DC 550 column, In comparison substltuent dlstlllatlon

temp

with the corresponding from 2

salt 1

the stereoselectlvely

ob-

(0 3 mole) and potassrum

by Sreekumar

hexamethyldlslla-

et al 11 (10% HMPA/THF),

of high stereolsomerlc

the

purity was obtained

L-i'-

Retention time for 2 (Z-isomer) 1227 set 7 (E-Isomer) 1311 sec._? Spllttlng of the allyllc

s

(1 5 eq) In refluxlng

benzene

from ethyl dl-n-butyl-carbamate

pure Z-synthon

yllde

170°C

by ethyl chloroformate

to effect separation

to react with the unstablllzed 10

bp 15 98-lOlo,

5a /-74% yield, --

for 2 hr gave, after

produced

as a by-product,

vpc analysis

DC 550 column, 7

130°C

temp

Retention

time 565 set

for z,

In comparison

with the corresponding

g

(E-Isomer)

611 set -7 The structure

2k

of these hemlterpenolds

follow

from mlcroanalysls,

lr and nmr spectral

lr (film) 1740 cm -', nmr (CC14) fj 5 42 (t, lH, CH2 = CH), 4 53 (s, 2H, AcOCH2),

2H, CH = CH2-N), CH2-CH2), 5a

2 33 (t, 4H, CH2CH2N),

2 (s, 3H, CH3CO),

1 77 (s, 3H,CH3-C

3 02 (d,

=), 1 13-l 5 (m, 8H,

0 9 (t, 6H, Ci3CH2)

lr (film) 1740 cm -l, nmr (CDC13) b 5 66 (t, lH, CH2 = CH), 4 66 (s, 2H, AcOCH2),

2H, CH = CH2C1),

2.08

(s, 3H, CH3CO),

1 83 (s, 3H, CH 3

conflrmed,ln those

data

addltlon

to vpc InformatIon,

of the corresponding

for the AcOCH2 corresponding

and CH3E-isomer

E-isomer

C = (g)

Double

bond geometry

of the nmr spectral

In particular,

which are downfield

2

exhlblted with respect

(Z) was

data of 2

different

with

relative

shifts

to those of the

b 4.43 and 1.73, respectively

By utllvzzlng the (Z)-synthon to the following

by comparison

(B)'

slnglets,

- C =)

4 15 (d,

2,

the feprazone

metabollte

1 could be synthesized

according

scheme

AcO

C

N/--Ph

,’

Na@

(0

I

j,

NlPh

p,-'Ph

I N\Ph

0

8 -

2 -

2222

Reaction

of 3

with the sodium salt of 1,2-dlphenyl-3,5-dloxopyrazolldlne

dlmethylformamlde

at room temperature

some unreacted

Direct

temperature) -methanol

8

furnished

saponlflcatlon

of this mixture

after acldlflcatlon

(9 1, v/v) 7 the desired

with 5% sodium hydroxide

and chromatography

metabollte

on slllca-gel

2 as a colourless

arom protons), = CHCH2CH),

5 27 (t, lH, CH2 = CH), 4.02

1.73

we wish to express

LImIted,

Donlnl

/-dlchloromethane-

solid /-31% overall nmr (CDC13)

yield, mp

d 7 23 (s, lOH, 2 92 (m, 2H,

(s, 3H, CH3C), 1,56 (brs, lH, OH)

Acknowledgments (TelJin

an aqueous

(2 hr, room

3 48 (t, lH, COCHCO),

(s, 2H, CH20H),

12

of the desired 2 along with

lr (nuJo1) 3400, 3200, 1750, 1720, 1590, 750, and 705 cm -1 ,

1410-7,

Mrs

for 12 hr gave the acetate

(8)

Tokyo, Japan)

our appreclatlon

for the metabolic

to Dr

studies

Y

Hashlmoto

on feprazone.

and Dr

H

Yamaguchl

We are also grateful

to

for nmr spectra.

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