Total synthesis of the sesquiterpene (±)β-cuparenone: use of three-carbon annulation in synthesis

TOTAL SYNTHESIS

OF THE SESQUITERPENE

THREE-CARBON Michael Department

Abstract: x_~xxxx_

A total

the three-carbon

synthesis

annulation

The cyclopentane diverse method

compounds

We now wish

target of several nary centers theses

have been described,

very simple 4.

approach

This process

must begin with

the adduct 2, which would under all conditions

tried

and limitations

and disadvantages

of

including

published

three-carbon method

such

a new annulation.

and to report

pankhi,"

the Diels-Alder

S-cuparenone

its

synthetic

reaction

challenge. system

annulation

To date

five total syn-

in a different

way. 4

of the tetrasubstituted

of the diene 3 with

into 1 by the usual four-step

3 and 2 to > 200°C

quarter-

in a sealed

A olefin

the olefin _4 to afford

procedure.

However,

tube for several

days)

1) Reduce 2) Oxidize Me

3) Hydrolyze Ar

Me

2

-1 has been the

is no doubt due to the two contiguous

the three-carbon

(e.g., heating

termed

of this annulation

forms the cyclopentane

then be transformed

products,

We have recently

a process

of "mayur

ring, a reasonable

involve

occurring

1.

This interest

each of which

to -1 would

and terpenes.

oil of the wood

in the cyclopentanone

CA. 90024

the advantages

naturally

from olefins,

of (')a-cuparenone

efforts.

highlights

in numerous

prostaglandins,

the advantages

synthetic

which

Los Angeles,

is described.

is found

from the essential

IN SYNTHESIS

of California,

of cyclopentanones

use in the total synthesis Isolated3

process,

USE OF

and C. David Radcliffe

of B-cuparenone,

as steroids,

to describe

*1

University

ring system

for the formation

ANNULATION+

E. Jung

of Chemistry,

(?)&CUPARENONE:

4) Decarboxylate

1

4

Ar = e-tolyl

Ar = p-tolyl

4597

the initial

Diels-Alder

react-ion could not be forced

use of diene 3, namely

that unactivated

with 3 in cycloaddition To further mediates

reactions,

test the reactivity

for the synthesis

Refluxing

a solution

gave,after 58-9°C)

workup

of 3 with

of 2 and catalytic

-6n furnished

chloro

alcohol

-7n was accomplished

afford

the dechlorinated

same sequence action

of 2 with p-tolyllithium

iously,

9

Oxidation

formed

after chromatography

the dimethyl

ketal blocks

of the olefln

with aqueous

7.8% overall

able from 3 via 10 steps

sp2 (120"). corresponding

-13 and E,6

rate of hydrolysis

to steric

steric

with

ketone.

of the tetrato

by any of several

75% for PCC oxidation). 8

solution

pre-

results. by treatment

is presumably

11. The production

of (+)B-cuparenone

at 25°C for

As observed

followed

This compound

Re-

yields.

at -78°C)

(mp 126-127"C).6

permanganate

The

since

of 12 in

the conversion

of

yield.]'

Thus 1 is avail

of ketal hydrolysis

in these systems

in 56% overall

yield. steric

acceleration

very resistant

in high yield

to acidic

hydrolysis,

of C-7 from sp3

8n and _rO, which

(for lo). We ascribe the exo-methyl

group which

is eliminated

presumably

(idealized

angle

namely,

this greatly

group experiences as the ketal

due to the

of 109.5")

are hydrolyzed

under very mild conditions,

or overnight

acceleration , namely

the syn-methoxy

Basic hydrolysis

face so that only endo addition

in four steps

the hybridization

HCl and Et20 at 25°C for 2 h (for 8&

to the symmetrical

of &

and n-butyllithium

of the intermediate

(Scheme).

(Li, NH3, EtOH, -78°C)7

(e.g.,

inter-

-6x (oil) and -6n (mp

Reduction

Oxidation

in 42X yield.

this is not the case for ketals

ketones,

interactlon

10

adducts

-6x to the ketone 9 in comparable

the total synthesis

are generally

in changing

However,

of 78%,6

from the exe

enone -12

a very interesting

ketals

involved

yield

prepare

under N2 for 3-4 weeks

for the endo series.

conditions

the

if at all

5 was conducted.

of each Isomer

of the alcohol x

and dehydration

in 4.3% overall

We have also observed

ring strain

metal

with a buffered

out by Maldonado4c

acetate

in > 95% yield.6

from p-bromotoluene

addition

from 3 completes

-12 into 1 has been carried

Norborn-Z-en-7-one

only

-7n (mp 139-41°C)

a 92% yield

the desired

decarboxylation

yield

in detail

used to convert

was accomplished

acid to produce

by double

The conversion

-8n in a purlfied

(formed

and to thereby

the two stereoisomerlc

under dissolving

were also

olefins

in excess 5 as solvent

PCC) gave the ketone 2 in good yield

of reactions

1 hr furnished

(Prep HPLC),

the alcohol

alcohol

Collins,

(Jones,

hydroquinone

with

5

hindrance.

substituted

problem

react very sluggishly

of 2 with isobutenyl

out but will be described

of the acetate

methods

highly

of 3% and 358, respectively.6

ketone 9 was carried

olefins

due to steric

of 1, the reaction

and chromatography

in yields

tetrasubstituted

presumably

This is a general

to occur.

to

to the two-phase accelerated

a very large

is hydrolyzed

to

0.5N

5

3

6x -

3%

35%

-6n

SCHEME

Acknowledgment: _____I _V_____Z their generous chased with

We thank support

-8n

X = H. Y = OH

-13

lo

x = OH, Y = Ar

14

the National

Cancer

of our synthetic

funds provided

by a major

Institute

program.

instrument

and the National

The Bruker grant

WP-200

from NSF.

Science

Foundation

MHz NMR spectrometer

for

was pun

t

There

is still

be correct

a discrepancy

in the spelling

from Latin roots meaning

since both are derived

and annelation

from anellus.

common

dictionaries.

English

We prefer

1.

Camille

and Henry

Foundation,

Dreyfus

3.

G. L. Chetty

4.

a) P. T. Lansbury

5.

cantly

and F. R

diminished

in this regard

6.

7.

by causing

from annulus

appears

in most

of the Alfred

P. Sloan

J.C.S.

99, 5508 (1977).

__

Chem.

Cornm., 619

Syn.

Inhibits

this

the Diels-Alder

reaction

studies

are currently

b) P. Leriverend,

(1969);

&

Rao, J. Chem. Sot. Perkin

Trans.

Cotnnun., 6, 11 (1976); e) L. A. J. Org. Chem.,

intermolecular

as part of the same molecule.

_45, 3017 (1980).

cycloaddition

to he intramolecular,

Some success in progress.

can be signifii.e., by having

has been already

achfeved

M. E. Jung and L. Light,

un-

results. exhibited

with their

structure.

resolution

mass spectra.

alkali

metals

spectral

In addition,

could

technique

gives

of the doubly the alkali planation

significantly

desmethyl

metal

to account

9.

M. E. Jung and J. P. Hudspeth,

Il.

We thank

R. Ramage,

Tetrahedron

and R. A

Dr. Maldonado

shown to he identical

elemental

as rapidly

than the normal

workup.

by the production

of the chloro

compound

analyses

This

or high

in this case.

as possible reduction

of a bright

in ammonia.

accord

We

since

this

(and that

green

light as

We have no ex-

for this chemiluminescence.

E, J. Corey and J. W. Suggs.

W. Parker,

IR, MS) in complete

gave the best results

up this reduction

is accompanied

to the solution

l3 C NMR,

gave correct

but lithium

higher yields

8.

IO.

(200 MHz 'H NMR,

all compounds

to work

analogue')

is added

data

be employed

have found that it is preferable

(Ftecelved

to

73 (1964).

and L. A. Maldonado,

greatly

and further

All new compounds

Other

Fellow

D. S. Dime, and T. R. Bailey,

which

the diene and olefin

published

this spelling

c) R. B. Mare and G. 5. Krishna

d) A. Casares

hindrance

Lett.,

Hilfiker,

Fr., 3498 (1973);

W. E. Fristad,

The steric

1978-83;

J. Am. Chem. SOC.,

and S. Dev, Tetrahedron

1806 (1973);

Paquette,

annulation

appear

1979-81

M. E. Jung and J. P. Hudspeth,

r,

"ring,"

would

AND NOTES

Teacher-Scholar,

2.

Sot. Chim.

since

annulation

REFERENCES

Bath variations

of this term.

Raphael,

to -12 (NMR, IR). 1980)

2647

J. Am. Chem. Sot.,

for generously

In USA 22 July

Lett.,

100, ___

J. Chem. Sot.,

providing

(1975). 4309

(1978).

1558

(1962).

an authentic

sample

of the enone,

which

was