d ring synthon

Tetrahedron Letters,Vol.29,No.41,pp Printed in Great Britain

SEQUENTIAL

CLAISEN-ENE

APPROACH

TO CARBOCYCLIZATION:

A NEW ENTRY TO A STEROID

Kazuhiko Department

Summary:

of Chemical

A new

sequential involving

and

facile

combination

The

bond

intramolecular

propargyl (es

entry

ether This

lL2

synthesis

ene

of a steroid

now describe be easily is whether

in this

derived the

we have

1 can create observation

ring

the

Claisen-ene

Claisen

group

the

is described

been

Its

Scheme

can

ene

as one ene

is that

Thus,

be achieved

152,

which

relies

ene

reaction

of efficient

cyclization

Japan

on the

our

the

requisite

an intriguing

in tandem

to the

strategy ene

problem

for

fashion

methodology basic

tools

of the crotyl

diastereoselective

cyclization

1 illustrates

key feature

rearrangement.

emerging

in a highly this

Tokyo

as the enophile.

the thermal

that

center

Nakai* Meguro-ku,

intramolecular

reported

synthon.3

sequence4

synthon

with

has currently

us to apply

communication.

via

ring

rearrangement

a quarternary

prompted

C/D

C/D

and Takeshi

of Technology,

methoxycarbonyl

reaction

Recently

Institute

to a steroid

with

C/D RING SYNTHON

Ko'ichi Mikami,

Tokyo

of the Claisen

an acetylenic

carbocyclization.'

Takahashi,

Technology,

0040-4039/88 $3.00 + .oo Pergamon Press plc

5277-5280,1988

which

substrate in this

we 4 can

strategy

or not.

&J’“-- #OzCH3 (1)

Scheme

1 CO2CH3 ene

3 HO

,& CH3O2C

3

5277

5278

The

requisite

alcohol

a straightforward salt

85 under high

substrate

3 in 84%

THF:

R-TsOH,

Thus,

standard

condition

the

extremely

3 (Claisen

manner.

stereoselectivity yield

substrate)

7 was

[D-BuLi,

standard

prepared

to the

'Cl

9 was

three-step

from

Wittig

THF. -78 Enyne

(>98% L).6

by the

was

subjected

the protected

reaction

to afford

then

using

76% yield

converted

operation

7 in

phosphonium

of enyne

to the

[D-Bu4NF,

acetoin

the

9 with

Claisen

THF; D-BuLi/ClC02CH3,

CH30H].

THPO MeSdPh3';

2

3'

With

a

large

a-propenyl

methyl

spontaneously product yield

5.

We found

and with

Claisen On

low

that

occurrence

basis

[Hg(OAc)2.

the the

at a lower

the

out

ene

yield

follows.

of the

relatively

selectivity.

CH3

ketal

next

occur

hope

rearrangement

that

the

Claisen

the desired

in tandem

4).7g8

:

[lo0

This

yield the

with product

cyclization

to give

low

involving

'C.

[pTsOH,

moiety

1 day]

more

in 4a

= 8

on the

is apparently

:

5 only may

in 29%

be attributed

carbonyl

reaction the

group

after

Claisen

of

by ketalization ketal

4a was

gave

product rise

protection

rearrangement [HOCH2CH20H,

then

subjected

to

in an increased

5a

to the

desired

methyl

2).7

in diastereoselectivity

ketone

A (endo)

favorable

R. depending

The

of 5a

increase to the

ene

Thus,

the cyclization

acetone]

states

the

followed

yield.

(trans/cis

relative

4a

out

isolated.

90 h] to give

transition

and

carried

once

is the significant

is sterically

between bulky

170 'C.

ketal

Of the two possible

repulsion

the

to yield

reactions

in 71% overall

4a

Deprotection

interest

cyclization

we

stereoselectivity

the trans-configuration steric the

ketal

[toluene,

enhanced

Of particular the ene

did = 6

of ene

product

temperature

to afford

cyclization

5 with

type

of the Claisen

(86%) as expected.

ketone

sequence

the Claisen

with

reaction

(trans/cis

observation,

was

benzene]

2 days],

ene

Claisen-ene

attempted

4.'

of these

group

carried

first

170 'C,

of the other

of the carbonyl

pTsOH.

we

intramolecular

stereoselectivity

product

the

of 3 in hand,

ether

undergoes

to concurrent the

quantity

Me3Si

4. which

and

because bulkiness

8 (exe)," the of

responsible

observed

is readily the

latter R.

former

could

Thus,

explicable

to

the

presence

for the enhanced

as

leading

suffer

the

in

trans-

of

4

5279

r trans

Finally, ring

the

synthon

6 via

intramolecular [SiO2, 6'*

in 32%

In summary,

the

have

ity along

acyclic

Acknowledqment: Scientist

This

from

REFERENCES

the

AND

1. Reviews:

be noted

outlined

(CH3)2S]

to the

this

for

the

steroid

further

steroid

followed

chromatographic furnished

that

is useful

array. l3

was

Ministry

cyclization

facile

entry

here, although form

is well

Further

along

in part

Education,

made

starting

C/D

by the

purification pure

C/D

trans-isomer

ring

construction

methodology,

to the

synthon

6

of A/B

ring

line

and

Culture,

ring

active

specific

is under

by Grand-in-Aid

combined C/D

form, could

optically

to attain

this

Science

steroid

in racemic with

established

work

supported

of

the ene

and

active

concerned

work

that

a unique

of the optically

rearrangement the

It should which

converted

Column

stereomixture

demonstrated

provides

transformation

Claisen

pyridine.

benzene].

5 was CH2C12,

chain. we

synthesis

product

resulting

multifunctionality

rearrangement.

overall

ene

[03,

[CH30Na.

5a .

from

of the

ozonolysis

l] of the

:

yield

as a side

Claisen

selective

= 5

overall

mixture

condensation

the unique

as well

The

the

aldol

hexane/AcOEt

possesses

to the

diastereomeric

for

in our

since of chiral-

laboratory.

Encouragement

Japan

the

be applicable acetoin,

transfer

way

with

synthon.

of Young

(No. 62750792).

NOTES

a) W. Oppolzer

D. F. Taber,

and

V. Snieckus,

"Intramolecular

Angew.

Diels-Alder

Chem.

and Alder

Ene

Int. Ed. Engl., Reactions",

11,

476

(1978);

Springer-Verlag,

b)

Berlin

(1984). 2. K. Mikami. 3. For

K. Takahashi,

leading

Money

and

T. Money,

more

Tetrahedron

4. A similar has

been

E. Ziegler 5. The

Lett..

type

standard has

24, 2,

and

465

1984,

(1983);

2813

F. E. Ziegler

the

sequence

C/D

1986.

288;

ring

M. Iijima,

synthon:

a) T.

b) J. H. Hutchinson.

J. 0. Winkler,

involving

J. J. Mencel. 127 (1984).

prepared

method

Commun..

d) K. Yamamoto,

2374.

of steroid

Stork,

and

salt

that

c)G.

3,

ibid.,

reported

1987,

and

N. A. Saccomano.

Y. Ogimura,

and

J. Tsuji,

(1984).

K. Mikami,

three-step

Lett.,

syntheses

Sot. Chem. 455;

Claisen-ene

8 was

Chem.

on the

J. Chem.

ibid.,

of tandem

reported:

phosphonium

6. Still

S. Piper,

Lett..

T. Nakai,

references

J. H. Hutchinson. and

Tetrahedron

and

recent

[EtMgBr. salt-free

in 38% overall Me3SiCl: Wittig

a simple

Tetrahedron

yield

TsCl, reaction

from

pyridine:

olefin Lett.,

as the enophile 25.

123

4-pentyn-l-01 PPh3.

of an O(-alkoxy

110

(1984);

by the

'Cl.

ketone

in the

F.

5280

presence Still, high

of

HMPA

3. Org.

proceeds

high

z-selectivity

(>98%)

of 9 was

independently

prepared

J. Am. Chem.

was

by

(1980). observed

either

with

by 13C NMR

Kishi's 101,

NMR

[LiAlH4;

isomer

was

stereochemistry

assigned

(200

(70%

isomer

involving

Minor

isomer

J. M. Conia

11. A similar

the

Y.

Cc

11.76

CL:

72.87

CH2N2;

basis

of the

pTsOH,

trans-

acetone]

to the

17 h] did

:6

:

6

1.03

(s, Cti3CO-). 3.69

triggered but

0.86

(s, Ct13CO-), 3.74

(cis-10)

sequence occur,

CDC13)

by the

in a poor

yield

(5. Ctl3-CZ). (s, Cli3CO2-). (s.

Cti3-Cf).

(s,

Ctl3CO2-).

Johnson (16%)

type

rearrange

and with

low

ene reactions

group

as the enophile

P. LePerchec.

state

involving

model

has

la

as the ene component

IO and/or

are conceivable.

Synthesis, been

an enol

proposed

1975.

1.

for

the

intramolecular

ene

reaction

by eq. l.2

'H NMR trans

related

and

transition

depicted

Claisen-ene 'C,

and

trans).

the carbonyl

10. Review:

200

The r-

its E-isomer

K. Akasaka,

on the

(trans-10)

2.17

intramolcular

9. For example,

12. 6:

H+.

[CH3C(OCH3)3,

selectivity

MHz,

Major

10

ment

to trans

2.13 2 H

a similar

a

CO2CH3

RuC13-NaI04;

0

that

W. C.

is established.3c

'H NMR

CH30

found

of HMPA.

65.15

CH302C 3

8. We also

and

however,

3 with

8

S03-pyridinelLiAlH4;

10 whose

compound

T. Fukuyama.

E-isomer

of the major

of 5a

formation

use

alcohol

7.

HO

(ppm)

3

configuration

the

of the

of

19.13 CL:

known

or without

G. Schmidt,

K. P. Durst,

reaction

(1979).

&:

7. The

Wittig

comparison

method:

259

13C

CH302C

C. Streekumar,

present

confirmed

Sot.,

Z-selectivity: In the

Chem.. '45, 4260

configuration

Kishi,

with

1.08

(s, (X3-CZ).

configuration trans

C/D

ring

5.90 (d. J = IO Hz,

of 6 was confirmed synthon

shown

by

COCH=CH).

its

'H NMR

Synthesis", (Received

"Chirality

Transfer

ed. J. D. Morrison,

in Japan

16 July

via

comparison

with

the

COCH=Cli);

closely

below 3d. 'H NMR

13. R. K. Hill,

7.30 (d, J = IO Hz,

Sigmatropic

Academic 1988)

Press

(ppm)

d CH3:

1.11

Ha:

5.94

Hb:

7.33

Rearrangements", Orland.

FL (1984),

in "Asymmetric Vol.

38, p. 503.