Synthesis of isocaryophyllene by titanium-induced keto ester cyclization.

Tetrahedron Letters,Vol.24,No.l8,pn Printed in C-reat Britain

SYNTHESIS

0040-4039/83/181885-04$03.00/C 01983 Pergamon Press Ltd.

lR85-1888,1383

OF ISOCARYOPHYLLENE

BY TITANIUM-INDUCED

and Dennis D. Miller

John E. MC Murry"

Department

KETO ESTER CYCLIZATION.

of Chemistry,

Cornell University,

Baker Laboratory

Ithaca, NY

14853

Abstract: A total synthesis of d,l isocaryophyllene is reported that employs the titanium-induced cyclization of a keto ester as the key step in forming the cyclononenone ring. The synthesis requires four steps starting from ethyl geranylacetate, and the key cyclization occurs in 38% yield. We have recently undergo reagent

discovered

an intramolecular 1

.

The method

to be of great value

W-i&,

We now wish to report nine-membered-ring

coupling

of cycloalkanone reaction

natural

isolated

double-bond

stereochemistry.

8 C-OEt

1. TiC1-JLiA1H4

J

2. H$+

four through

fourteen,

titanium

and promises

product,

>

of this new method

isocaryophyllene

from oil of cloves2,

differs

Both compounds

(1).

to the synthesis Isocaryophyllene,

from its isomer,

have been previously

\ -9

1

in which keto esters

with a low-valent

synthesis.

the application

hydrocarbon

synthesis

on treatment

works well on all ring sizes studied, in organic

8 R-C c

a new method

dicarbonyl

of the a sesquiterpene

caryophyllene

, only in

synthesized3.

\ -9.)

Isocar.yoohyllene

2 -*

lF85

Caryophyllene

1886

We began this work with the intention the intramolecular should

titanium-induced

it be successful,

unusual

carbocyclic

involved

would represent

ring system.

attempted

alkylations

of synthesizing

coupling

caryophyllene

an extraordinarily

Although

using,

of keto ester 2 to cyclononenone

our initial

as our key step,

6.

This coupling,

direct and simple approach

attempts

of 3,3_dimethylcyclobutanone,

at preparing

to this

keto ester 2

we soon found that 5 could be

synthesized

in two simple steps according to the route shown in the Scheme. Thus, cycloaddition 4. of dichloroketene with ethyl geranylacetate5 (3) led in 75% yield to the unstable dichlorocyclobutanone The cycloaddition

4, which was dechlorinated

proved

bond of ethyl geranylacetate; The cyclization

no isomeric

titanium

reagent

suspension

of Tic13

(728 mg, 4.72 mmol)

for 5 rain at room temperature,

slurry was refluxed

cyclobutanone

was prepared

by adding LiA1H4

triethylamine

mixture

addition

of 5 mL methanol

The filtrate

the formation

with brine, dried

on neutral

cm-l; 'H NMR (CDC13)

alumina

had occurred prepared

of natural

phosphorane

in DMSO solution 7 spectroscopic comparison . How does double-bond itself

cyclizations that occurs believe

diluted

titanium

product

and the

reagent.

titanium

3 h period of reflux.

with 10 mL ether,

filtered

through

quenched

Purification

occur?

of diketones,

Treatment

by IR (neat> 1695

that the isomerization

occurring

strain of the E double here is unique

experiment

studies

of the

step is a pinacol-type titanium

particles

reaction 8

.

Thus, we

reaction

and the double

bond is rigidly

held in close

when

the two ends of the keto ester molecule

by isomerization.

strained

that

double-bond

to come close enough to bond and deoxygenate

bond is relieved to the highly

mechanistic

sample by

the cyclization

Evidently,

of the metal.

but are unable

with an authentic

during

proximity

particle

sample of 1,

by analogy with our work on the related bond-forming

particle

to the surface

identical

on the surface of insoluble

is most likely

isomerization

with an authentic

and does not undergo

out detailed

we assume

that the carbon-carbon manner

215.6,

of z with methylenetriphenyl-

We have shown in a control

conditions

we have not carried

by

lead to 6, which could be converted

to find that double-bond

was identical

then gave isocaryophyllene,

keto ester cyclization,

slurry The

a small pad of Florisil.

(39 mg) in 38% yield;

of 5 would

the keto ester is bound to the titanium

observed

After

found 206.1666.

caryophyllene6.

isomerization

in a heterogeneous

to a titanium

of the low-valent

we were surprised

is stable to reaction

Although

isomerization. titanium-induced

(DME) under argon.

and concentrated.

Thus, our product

cyclization.

by degradation

caryophyllene

206.1671;

that the cyclization

by Wittig reaction,

during

A slurry of the

6 1.00 (s, 6 H), 1.70 (d, 3 H), 5.20 (m, 1 H); 13C NMR (CDC13)

we had assumed

into caryophyllene

(MgS04),

gave the cyclized

136.7, 124.0; MS calcd for C14H220, Although

manner:

(97 mg, 2.5 mmol) to a stirred

by an additional

and vacuum

and 5 mL water,

acid. double

were detected.

(0.35 mL, 2.5 mmol) was added,

was then cooled to ice temperature,

was washed

chromatography

in acetic

for the terminal

in 18 mL DME was slowly added to the refluxing

over a 16.5 h period via syringe pump, followed reaction

products

in the following

in 32 mL dimethoxyethane

for 1.5 h to complete

Keto ester 2 (127 mg, 0.50 mmol)

with zinc-copper

and stereoselective

of keto ester 2 was accomplished

low-valent

stirring

by treatment

to be both regioselective

caryophyllene

That the double-bond ring system

bind

until the

isomerization

is attested

to by the

1887

fact that we have never before observed 8 titanium-induced couplings . In summary,

we have demonstrated

used in the synthesis synthesis

such an isomerization

how our new method

of macrocarbocyclic

natural

in all our prior work with

of cycloalkanone

products.

preparation

We are continuing

can be

our work on the

of other such molecules.

Acknowledgment:

We wish to thank the donors of the Petroleum

Chemical

for their support

Society

of this work through

-A>

COOEt

Research

5

Cl

0

Cl

2

Fund of the American

grant No. 11879-ACl.

’

EtOOC

-4

b %

\ +cJ 0

Scheme.

Synthesis

z.

\

POC13, Zn-Cu, ether,

LiA1H4,

6

\ -YJ

-1

of Isocaryophyllene

(a) C13COC1, (c) TiC13,

d

0

75%;

Et3N, then H30t, 38%;

(b) Zn-Cu, HOAc, 61%; (d) Ph3P=CH2,

DMSO, 55%.

1888

References

1. 2.

J. E. Mc Murry

and D. D. Miller,

For a discussion

of early studies

D. H. R. Barton,

"The Terpenes,"

J. Am. Chem. Sot., in press, on caryophyllene

and isocaryophyllene,

Vol. III, Cambridge

University

see: J. Simonsen

Press, Cambridge,

and

England,

1952, pp. 39-75. 3.

Isocaryophyllene b) A. Kumar,

a) M. Bertrand

syntheses:

and J. -L. Gras, Tetrahedron,

A. Singh, and D. Devprabhakara,

D. Devprabhakara,

Synthesis,

461 (1976).

Tetrahedron

Caryophyllene

Lett.,

30,

793 (1974);

2177 (1976); c) A. Kumar and

synthesis:

E. J. Corey, R. B. Mitra,

and H. Uda, J. Am. Chem. Sot., 86, 485 (1964). 4.

L. R. Krepski

and A. Hassner,

5.

I. Kuwajima

6.

R. Kaiser

7.

The synthetic

and natural

spectroscopy,

and capillary

8.

We have previously

and Y. Doi, Tetrahedron

and D. Lamparsky,

dicarbonyl

coupling

isocaryophyllenes

reactions

evidence

in USA

28

1803 (1976).

were identical

by ir, 300 MHz nmr, mass

on a fused silica column

in support

occur on the surface of titanium

January

by other workers:

1983)

(180,000

plates),

of our belief that titanium-induced

K. L. Kees, and L. R. Krepski,

J. Org. Chem., ft_z,248 (1982).

(Received

1163 (1972).

gas chromatography

support has been presented

H. Geise,

Lett.,

Helv. Chim. Acta, 2,

presented

MC Murry, M. P. Fleming, Further

J. Org. Chem., 43, 2879 (1978).

particles.

J. Org. Chem., 2,

R. Dams, M. Malinowski,

See:

J. E.

2655 (1977). I. Westdorp,

and