Synthesis of new stable analogues of prostacyclin: (±)-6a-oxo-6,9-metrano-15-hydroxyprosta-5,13-dienoic acids

Tetrahedron Letters,Vol.26,No.34,pp 4101-4104,1985 Printed in Great Britain

SYNTHESIS

OF NEW STABLE ANALOGUES

oo40-4039/85 $3.00 + .oo 81985 Perqamon Press Ltd.

OF PROSTACYCLIN:

(+~-6a-OXO-6,9-METHANO-15-HYDROXYPROSTA-5,L3-DTENOIC

C.W. Bird+, H.I. Butler+,

M.P.L.

Caton, E.C.J.

ACIDS

Coffee*,

C.J. Hardy, T.W. Hart and H.J. Mason The Research

Laboratories,

Dagenham, and +Department

of Chemistry,

Campden

The synthesis

Abstract 5,13-dienoic inhibiting

College,

Hill, London W8 7AH, U.K.

is described

acids as stable analogues

Considerable

analogues

Queen Elizabeth

of (fi)-6a-oxo-6,9-methano-L5-hydroxyprosta-

of prostacyclin

with blood platelet

aggregation

activity.

effort has been devoted

prostacyclin.'

group

May & Baker Ltd.,

Essex, RMLO 7XS

to the preparation

We report here the synthesis

in which

the 6,9 ether

to give the stable enone

of chemically

stable analogues

of a new class of biologically

linkage of 11-deoxyprostacyclin

is replaced

by a carbonyl

(15). -

Scheme1

AcO

0

OMe

.cg _ C02H

3

._ Yq 0

AcO

-

-

._ b-

AcO

CO,Me

4

5

4101

of

active

CO,H

4102

The synthesis

commenced with

2-methoxybutadiene3 this

reaction

confirmed

to

was in accord

a reported

concurred

with

our

contrast

to

of

butadienes

other

the

carbonyl

The key

of

to of

in

filter,

reflux

preferred nature

the

than

the

followed

enolisation 5

converted 94%) to

to give

carbonyl

4

100%) of

of

(41 which

the

spectroscopic

(HCl,

function

gave of

and 50.3

predicted

ppm which could 6 values. Selective

permitted

identification

9.5

Hz),

x 2,5

confirmation

H5 3.04 of

successive

of

these

exchange

be assigned decoupling the

(tdd,

at

chemical

J = 7.5

assignments of

to

ring

contraction

is

which

obtained

is

in

had the

analysis.

For

x 2,

of

9.5,

4.0

was provided

turn

the acid

(2), (3)

was

CH2C12, r.t., between

the

off-resonance carbons

at

frequencies

protons

as Hl 2.7 Hz)

ppm.

decoupling

was treated

by the

rather

52.1,

by comparison

(q,7.5

(0.5

by the

resonance

attached

Hz) and 2.54

when (4,

of

determined

purpose

(PCC,

by proton-proton

Hl and H6 by deuterium

to

The relationship

proton

the

in

addition

controlled

C5 and C6 respectively

individual

shifts

formed

in acetic

structure

this

oxidised

g.1.c.

Cl,

and

(2).

(2)

(1 eq)

by preparative

is the

97% yield)

nitrate

MeOH, 72%) and then

was purified

O’C,

contraction

group,

thus

theory,

C5H5N, 95%) and subsequent

ether ring

carbonyl

acid

Et20,

of

also

with

thallic of

of

hydrindanone

encountered

(DIBAL,

(Ac20,

employing

the

ring-fused

the enol

The direction

That

upon Frontier-orbital 2 The latter report

products

Reduction

addition

regiospecificity

and ester groups was established as follows. As expected the 13 C nmr spectrum of (4) contained three doublets for tertiary

decoupled 45.4

ester

the cis

ring-fused

(2)

by a full

the methyl

based

was the oxidative

45%).

junction.

(11 was established

only

by the

The observed

cis-jasmone.

by acetylation

5 min,

synthesis

hr,

of

ring

that

acid

0.5

direction of

into

2-cyclopentenone. (1)

cl_) prepared*

27% yield.

expectations

(1,

and trans

bicyclo[3,3,0]octanecarboxylic hr,

our of

cis

MeOH, 20°C,

step

in

own observations

group (HCl,

with

conversion

the mixture

hydrolysis

the hydrindanone

2-cyclopentenone

with

with

(td, Further

experiments sodium

J =

and

methoxide

in

deuteromethanol. Two routes method, which

proved

was oxidised

[PCC/CH2C12; to yield

(1).

(31,

aldehyde,

which

which

to

(21.

it

permitted

Reduction

of

separation (loo%),

and reduction

acetoxy

of

67%] group

second the

and then to

first

67% yield,

the

sequence,

Cl5 epimers, reduced

with

aldehyde

reaction

“L-Selectride”

was then hydrolysed (11).

In the in

In the

oxidised

7 to provide

the

(11).

ketal,

with

(a,

HMPTA, -7O”C,

was then

to a Wittig-Homer

(3).

elaboration

hydrolysis to

to

alcohol

(Aldrich),

the ethylene

(100X),

chain

the

by Wittig-Homer

The latter

and the ketal

was silylated,

w-side gave

was oxidised

that

was subjected

NaH, THF,lOO%]S. alcohols

an (3)

and subsequent

the merit

to give

of of

“K-Selectride”

(8)

was converted

100%) which

epimeric

has

THF),

followed

(95%),7

which (4)

[(Me0)2P(0)CH2COR1,

yield

the

attachment

(B2H6,

90%) provided

(loo%),

(PCC,CH2C12,

separable

to

Silylation,

intermediate

“L-Selectride”

for

reduction

(MeO)2P(0)CHNaCOR1,/THF;

(K C03,MeOH,40”C, 1 (R = cyclohexyl), the

suitable

CR1 = pentyl)

(100%)

(60% v/v

gave

AcOH/H20,

the 100%)

to

4103

Scheme2 AcOA

I

AcOA

I

HO_

-

R'

CH,OH 6

7

&iMezBut

8

OH

\

t I

3-

, -

R'

CH,OH 9

13

10

OH COpH

OH

14

OH

R302C

0 R' 6H 15

R*= pH ‘OH

17

R3= Me

16

R2= GH OH

18

R3= H

11

4104

The attachment (LBTMSA., mesylation benzene

the a-side

eq.,

(MeS02C1, r.t.,

(Ac0H:H20:THF 90%) yielded

give

13:7:2,

40”,

81%) and saponification

generally

(17)

EtOAc:Hexane over to

of

since

the

fairly

isomerisation

than prostacyclin

blood,

but

compares

Acknowledgement. is

the

sodium

favourably

isomer

epimers

(2)

is

could

expedited

inhibiting

were

EtOAc:Hexane isomer

be assigned

to

(12)

(eg.

on the basis

by analogy

of

to

chemistry.

a 1:l

mixture

t.1.c.

(Si02,

the E-isomer Z-acid

1:4)

gave

of

the

on storage

(2)

52

(40%

isomerised

as a consequence

of

back

autocatalysis,

by acid.

(2)

is

approximately

collagen

non-prostaglandin

a Science

(lo)

polar

activities,

back

of

MeOH/H20 3:1,

of

gel,

less

corresponding

salt

in

(silica the

presumably

show that

group

(LiOH,

lamp yielded

isomerised

studies

5 eq.,

silyl

by preparative

However , the

by

(D.B.U.,

in prostaglandin

mercury

on standing

with

The award of

gratefully

slowly

ester

pharmacological

active

the

the

ester

condensation

followed

numbering)

whereas

be separated

at 0’).

of the

relationships

could

rapidly of

of

pharmacological

a low pressure

which

27 months

hydrolysis

of of

an aldol

74X),

and elimination

the more polar

The Z-isomer

(14)

Preliminary

to H.I.B.

with

isomers

of

E-acid

of

-7O”,

(prostaglandin

behaviour-property (2)

by means of eq.,

r.t.)

15 R1 = cyclohexyll

and comparison

1:4).11

a period

the

(eg.

The configurations

established

and 5E (13)

Cl5 epimers

as above

polarities

Irradiation

eq.,

When the

Cl5 -isomer

t.1.c.

was effected

60%) to

elaboration the

chain

Me02C(CH213CH0 2.0

70”;

Et N, 1.2 eq., a Successive (21.

16 R1 = cyclohexyl). their

-

1.3

(E).l”

separated, yielded

of

THF, 1.2

induced

inhibitors

and Engineering

aggregation

of

Research

1000 times

platelet

Council

of

less whole

aggregation. CASE studentship

acknowledged. REFERENCES

1. W. Bartmann 2.

Hasegawi

4.

F. Fringuelli,

and G. Beck,

Perfumery

a.

Ltd.,

Chem., --

*.

Kokai -7

1,479,333

. Pat., F. Pizza,

Int.

Pat

2.

&.,

1982,24,751.

53,108,949

(1978).

(1977).

A. Taticchi,

T.D.J.

Halls

and E. Wenkert,

J.&g.Chem.,

1982,47,5056. 5.

A. Romeo and G. Ortar,

6.

J.K.

Whitesell Corey

7.

E.J.

8.

May 8 Baker

9.

Yields

are

and R.S.

Ltd., quoted

All

11.

‘H NMR. (CDC13).

new compounds

(m,

. g., for gave

J.

in

w.

m.,

&.

proton

6 = 5.9

-

6.1

UK 3 May

1985)

=.,

Similar

the

1972 2

6190.

(1977).

NMR spectra of

1977 42 3878.

m.

RL = cyclohexyl.

lH1,

(Received

J.

1,468,830

The resonance

upfield,

1972,28,5337.

Matthews,

and A. Venkateswarlu,

10.

typically

Tetrahedron,

yields

consistent

enone

cm, 1H) to

proton that

of

were with

of the

the

obtained

the

for

assigned

52 isomer

5E isomer

R1 = pentyl.

structures. (17)

(131,

was 6 = 6.5

- 6.6