Oxidative coupling.

Tetrahedron Letters, V01.27, Printed

in

Great

No.2,

pp

127-130,

1986

oo40-4039/86 $3.00 + .OO 01986 Pergamon Press Ltd.

Britain

OXIDATIVE COUPLING.

II. THE TOTAL SYNTHESIS OF ENTEROLACTONE J. L. Belletire*, 5. L. Fremont Department of Chemistry University of Cincinnati Cincinnati, Ohio 45221

Abstract: Oxidative coupling of 3-methoxyhydrocinnamic the key step in an efficient synthesis of enterolactone.

In 1980 investigators and enterodiol

2, both

reported secreted

occurring

lignans

to be found

production

(3) and the significant

(1) the isolation by the

normal

of two unusual

flora

biological

activity

urinary

of intestinal

The intriguing

in humans.

acid dianion

with molecular

metabolites.

bacteria

(2), are

endocrine-coupled

pattern

of enterolactone

(4) have generated

iodine

forms

Enterolactone the first

I

naturally

of enterolactone intense

interest

in

this compound. Kirk -et al. recently properties of enterolactone.

published

Among several

Groen !7), Snieckus @J, and Pelter

analysis

reported

syntheses

of the

crystallographic

of enterolactone

(9).

ch-,,,@ 0

(5) a detailed

0.5 equiv.

HQ

I,

;

w 4

127

and are those

spectroscopic by Kirk &I,

128

In our initial

examination

of carboxylic

hydrocinnamic

acid dianion

3 produces

(11) suggested

the possible

utility

overall

skeletal

synthetic

and substitution

obstacles

stereochemistry

(control

m-methoxycinnamic

yield 99%) to provide

Conditions

generation

alkylations addition

involving

and then 5.0 hrs. Oxidative

coupling

of dianion

of 6 is achieved

the dianion

on a rotary

The organic mixture

reveals

a 63% isolated

can be recovered

procedure

is particularly

3-12 mmoles of 5. In spite of a narrow

product

is a mixture

4.5:1 isomer

ratio.

convenient.

Comparable

of stereoisomers. By analogy

that

occurs

upon

were detrimental.

pale yellow solution

NaHS03

in ~a.

Although

is

yields

the

85%

of 7 are obtained

of the lH nmr in the methoxy

acetic

anhydride

isomer

Simple

mother

liquors

recrystallization

point range (172.5-173.5’C),

(IO), the predominant

yield.

direct

and

with EtOAc.

the remaining

chromatography),

results

solution

by back-extraction

7 is formed

percentage

of model

to -6O’C and then adding

with saturated

followed

yield of 7.

melting

Examination

to earlier

10%

12N HCI and CHC13 are added to the

is washed

via flash

employing

a series

solutions,

The resulting

evaporator,

phase

reaction affords

(H2 (1 atm),

through

solution (-0.15M)

of the

7 (which

of the

at -78’C to O°C over 2.5 hrs.

colored

iodine in THF (-0.4U).

NMR analysis

additional

and adjustment

hydrogenation

by stirring

which led to intensely

The aqueous base layer is acidified

contain

The

The remaining

Maximum dianion concentration

with 2N KOH. crude

smooth

followed

then extracted

from CH30H

product

skeleton

to lignans.

sequence.

6 were explored

of CH3I.

by cooling

of molecular

and the layers are partitioned.

recrYstalliZatiOn

lignan carbon

approach

that

5 (m.p. 43.5~45’C).

intermediate

of 1.0 equivalent

at RT for 12 hrs., the THF is removed

residue,

the basic

synthetic

a lactonic

acid undergoes

of LDA in THF at -78’C

0.5 equivalents

(IO), it was noted

to such a dimerization

to afford

crystalline

at O’C. Higher temperatures,

over 2.0 minutes stirred

the addition

of 5 to 2.0 equivalents

coupling

ring) are easily solved.

Pd(C), EtOAc; distilled

for optimal

in a general

in 1 is well-suited level

oxidative

That 4 possesses

coupling

of the oxidation

available

dianion

4 in 77% yield.

of oxidative

pattern

about the lactone

Commercially

acid

over

a range

the recrystallized

region

indicates

is tentatively

a ~a.

assigned

as

8 forms

in

threo. Upon

treatment

quantitative the crude

yield. acetic

of 7 with Careful

anhydride

reflux for an additional is added

BH3’SVe2

workup affords solvent,

purification

reaction

48 hrs.

after

chromatographed

is carefully

10, which,

of 11 is accomplished

syrup (chromatographed

prolonged

EtOAc-ligroine

ether

anhydride

with excess

(12).

CH30H

In practice

and then held at

to acid ester 9. To a solution of 9 in Et20 Acidification

0’ for 3 hrs.!. pumping

11, a viscous,

of 7 is a flash chromatography

of Lt.

with BBr3 (1.9 equivalents;

hrs., then O°C for 4.0 hrs.; R.T. for 3.75 hrs.). After

treated

upon overnight

dimethyl

for 48 hrs.,

is a single stereoisomer

to remove

colorless

and the usual

the last traces

of

oil. The only required

The overall

yield

from 7 to

11 is 89%.

Demethylation colorless

reflux

in smooth conversion

into lactone

recrystallization

at

this material

-2O’C for 30 minutes;

derivative

transformed

that

mixture

This results

(8.0 equivalents;

hydroxymethyl

is smoothly

excess

13C nmr reveals

trituration

yield from 11 to 1: 90%).

with ligroine,

or CH2C12-CH30H

tone is undepressed

Upon workup,

while our spectral

spontaneous

Initially,

crystallization

gives dense rhombs. data are in complete

A mixed accord

CH2C12; -78’C

spectroscopically crystallization does occur. melting

to -4O’C over 1.25

pure

1 is isolated

of 1 is difficult Recrystallization

point with authentic

with published

values.

as a (13). from

enterolac-

129

-/ \WC

OOH

Me

1 is easily

Since enterolactone total synthesis

the scope of this approach

commencing

and high resolution Further

converted

into enterodio12

(6,7,8), this work also constitutes

a formal

of enterodiol.

To explore sequence

13

12

11

with commercially

m/e are consistent

applications

we have carried available

with hinokinin

of this oxidative

coupling

out preliminary

experiments

12 and leading to material

whose

involving a similar 1 13 C nmr, ir, H nmr,

13 (14). technique

to more complex

lignan natural

products

are

underway. Acknowledgements We would like to thank the Lalor Foundation, the URC of the University spectroscopy CHE-8102974

studies

of Cincinnati

were performed

on instruments

and PCM-82199 12, respectively.

supplied us with authentic

samples

the Eppley Foundation,

for their generous

purchased

The authors

of enterolactone.

financial

support.

through

the Research

Corporation,

High resolution

National

Science

also thank Drs. Snieckus

and

nmr and mass

Foundation

grants

and Groen for having

130

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(a) Stitch,

S. R.; Toumba,

J. K.; Groen,

and Notes

M. B.; Funke,

Nature (London) 1980, 287, 738. (b) Setchell, K.D.Q.,; -H.; Kirk, D. N.; Axelson, M. -Ibid. 1980, 287, 740. 2.

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This problem

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was also noticed

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