Total synthesis of dl -elemol

Tetrahedron Letters No.22, p,'u 1779-1782,

Pergamon Press.

1969,

Printed

in Great Britain.

TOTAL SYNTHESIS OF $-ELEMOL E. J. Corey and Emil A. Broger Department

of Chemistry,

Harvard University, ly69;

(Received in USA 27 lkr& Elemol

is a crystalline

this substance

is an indirect

note outlines

a direct

acteristic

sesquiterpenic preparation

synthesis

1,2-divinylcyclohexane

Cambridge,

received in UK for publication 9 April 1969) alcohol

of structure

from (-)a-santonin

of g-1

(4) which involves

closure

which has recently

8-,

allylic

formed

of d-

Although it

intermediate, direct

a novel method for the construction

process

of elemol

and c&-l,

carbocyclic

has previously

via e,

the effect of structure

to humulene synthesis

rings (5-7).

2-divinylcyclohexanes

The intermediate

trans-1,

(ratio 2

5-cyclodecadiene.

on the course

Of special

of the char-

relevance

(11-membered

ring formatio@

additional

required

to the appli-

S-decadiene

was trans-

: 1) by reaction with nickel carbonyl was not an

of trans-1,2-divinylcyclohexane

by a

This fact together with previous

of the nickel carbonyl

of the -trans, trans-cyclodecadiene

(I), and this provided

This

(3).

been used to effect ring

was the finding that l, lO-dibromo-2,

could not be made between the formation

and formation

could lead to a synthesis elemol

with nickel carbonyl

shown in the case of the -cis product that cis, trans-1,5-cyclodecadiene

a distinction

tions regarding application

was

dibromides

and 11- to 18-membered to the synthesis

(7).

been described

of

unit.

cation of this reaction into a mixture

synthesis

II

of acyclic

to form 6-,

The only recorded

I (1, 2).

I

The reaction

02138

Massachusetts

cyclization,

(6), made it seem possible

II, a probable

precursor

observa-

including the that this approach

of elemol

(8), as well as

incentive for this study.

for the cyclization

reaction,

1779

the dibromide

VIId, was synthesized

as

No . 22

I

mpoT III

dOOCH, IV

Va, U = Cl, V = CHQCOZ Vb, U = g-TolCOz,

V = CH3C02

Via,

Vc, U = o-TolC02,

V = OH

VIb, U=OH,

Vd, U = o-TolC02,

V = Br

VIc,

U = g-TolC02,

w = OTHP

W=OTHP

U=W=OTHP

COOCHQ COOCHQ

Vna,

W = OTHP,

VIIb, W=OTHP, VIIc,

X = CHO

VIII

X=H

W = OH, X = H

VIId, W = Br, X = H

\ P Ma,

:Rl

k2

R1 = COOCH3. R2 = H

Ixb, R1 = H, R2 = COOCH3

COOCHQ X

No.22

1781

The trans iodide III, prepared

follows. in acetone, 20

from the corresponding

was allowed to react with sodio dimethyl malonate

bromide

(6) by treatment with sodium iodide

in tetrahydrofuran--dimethylformamide

: 1) for 48 hr. at 40” (after an initial period of 1 hr. at 25”) to give IV (9, 10) in 85% yield.

the sodio derivative tuted malonic

of IV by a similar

ester Via (9, 10).

The bromide

butene (Va) (11) by the sequence: ethanol at 80” for 15 hr., 25” to form Vc,

the o-disubstituted afforded

malonic

hr. produced

Vd (9) was prepared

equiv.

tribromide

of sodium methoxide

(2 equiv. ) in

sodium hydroxide

in ether at 0”.

hydroxide

Treatment

in methanol--toluene

ether VIc (9)

(1

: 3) at -70” for 8

to produce VIIb (79% from VIc) (9)

at 100” under nitrogen for 0.5 hr.

mono ester VIIb was subjected

to acid hydrolysis

this was converted

ester VIId (9) (90% from VIIb) by reaction

of

acid catalyst.

hydride in pentane--toluene

without purification

at

in methanol at 25” for 10 hr.

into the bis-tetrahydropyranyl

in dioxane at 25” with a small amount of ptoluenesulfonic

the aldehyde VIIa which was deformylated

to dibromo

o-toluate

of phosphorus

of diisobutylaluminum

of

from 1-chloro-2-methyl-4-acetoxy-2-

of aqueous ethanolic

of potassium

Alkylation

(85% yield) the o-disubsti-

using 1 equiv.

ester VIb (9) which was transformed

of VIc with 2 equiv.

by heating with 0.2 equiv.

Vd afforded

to Vb using benzyltrimethylammonium

ester Via with 1.3 equiv.

of dihydropyran

Treatment

using the bromide

acetyl cleavage

with 0.5 molar

the hydroxy malonic

using 1.5 equiv.

conversion

selective

and reaction

procedure

Q.

to form the corresponding

dihydroxy

ester VIIc (i),

with phosphorus

The

and

tribromide

in ether

at -5”. Slow addition (over 14 hr.) carbonyl

in N-methylpyrrolidone

isomeric

cyciization

0.08,

products

by tic analysis

ether,

1

at 47-50” under an atmosphere

of Ilf 0.45,

: 3 petroleum ether--ether,

Gf 0.08,

32% yield) consisted

orientation

of carboxyl

methylmagnesium m. p. 37 -38”.

bromide

preparatively 0.23, and 3

Reaction

afforded, n. m. r.

to 7 equiv.

of carbon monoxide

ether--ether

by column chromatography

and 0.08 were eluted respectively

Rf 0.45,

(3

of 0.23,

: 1) as’eluant.

of the mixture by 1

using the same

: 1 petroleum ether--

: 5 : 1 petroleum ether--ether--benzene.

The most polar fraction

by CA. 10% of the diastereomer

of the pure ester VIII (9, 12), obtained by preparative

after the usual isolation,

of nickel

led to a mixture

into three components,

gel with petroleum

of the ester VIII contaminated

at C*.

The infrared,

an authentic sample

nitrate on silica

were separated

The products

ester VIId in N-methylpyrrolidone

(total yield 83%) which was resolved

using 20% silver

These three materials adsorbent.

of the dibromo

85% yield of g-elemol

differing

(I) (13) as needles,

, and mass spectra of the synthetic product were identical with those of

(14) of natural elemol.

The cyclization

product from VIId of _Rf 0.23 (27% yield) was identified

Ma and IXb (differing

in orientation

of carboxyl).

Both isomers

as an 8

: 1 mixture of isomers

were obtained pure by preparative

gc (15).

The product from VIId of _Rf 0.45 (11% yield) was identified as the -_ cis, cis or -cis, trans isomer analytical

and spectroscopic

measurements

(9, 16) and the finding that thermolysis The g,

in the vapor phase yielded mainly IXa and IXb. structure periods

should afford VIII upon thermolysis of time and also the n. m. r. spectrum

In summary,

in

gc, with excess

the reaction

(8).

trans formulation

In addition,

the thermal

of X by

at 285” (minimum

temp.)

for X can be ruled out since this stability

of X at 100° for long

(8) argue against the -trans, trans geometry.

of the dibromide

VIId with nickel carbonyl

has afforded

a synthetic

route to

1782

g-elemol

No 22 ”

(I), but not to the isomeric

trans, trans-cyclodecadiene --

II (17).

REFERENCES 1.

See V. Sy’kora,

V. Herout,

and F. germ,

Collect.

Czech.

Chem.

Commun.

2. -

220 (1955) and earlier

papers therein cited. 2.

For absolute

configuration

see (a) T. G. Halsall,

D. W. Theobald,

1029 (1964) and (b) A. D. Wagh, S. K. Paknikar, 3.

L. J. Patil and A. S. Rao,

4.

All synthetic

5.

(a) E. J. Corey and E. Hamanaka,

J. Am.

Semmelhack,

6237 (1966).

6. 7. 8.

IO.

reported

Tetrahedron

Letters

II has been reported

Infrared

and n. m. r. spectra

Chem.

Sot.

This intermediate

agreement

was purified by preparative

centers

layer chromatography

by considerable

V-VII,

were not obtained for these liquids.

11.

W. Oro’shnik

12.

The following (calcd.,

analyses

and R. Mallory,

222.1620)

exhibited

(AEI-MS-9

absorption

n. m. r. spectrum methylene

at 5.75 (CO),

6.08

g,

(4 H, multiplet)

“hedycaryol,”

1229 (1968).

structure.

using silica

for this substance

possessing

Commun.

gel.

Since distillation

and also most of the products

4608 (1950).

C, 75.45;

H, 9.91;

molecular

ion at -m/e

222.1620

The infrared spectrum of VIII (CC14) H* 9.95 and 11.0 ( ,C=CH2), and 11.21 p (:C=CH2).

instrument).

(C=C),

at 4.50-5.02

at 3.62 and 1.01 ppm (3 H each),

ppm, and an olefinic

The

olefinic

methine proton (1 H, ABE quartet)

ppm.

Found for &I-I:

14.

The sample was kindly provided

15.

The following

C, 81.33;

H, 11. 95; molecular by Prof.

0.

infrared

C=CH2); n.m.r.

5.17 (m, 4 H, 2 C=CH2),

absorption absorption

6. W-6.60

Found for X:

C, 75. 99; H, 10.30;

17.

This work was generously

Jeger,

Zurich. C, 75.61;

(CC14) at 5.75

H, 9.97;

molecular

(C=O), 6.08 (C=C),

(q, 1 H, Cg=CH2).

9.95,

Satisfactory

analytical

ion at -m/e 10.92,

ion at -m/e

by the Hoffmann-La

222.1260

(calcd.,

Roche Co.

222.1620

and 11.22 p

3.63 (s, 3 H, CH3), 4.57and spectroscopic

of IXb.

molecular

supported

222.

(CC14) (in ppm) at 1.03 (s, 3 H, CH3),

were also obtained for the diastereomer 16.

ion at -m/e

Found:

data were obtained for Ma.

, 222.1620);

(CH=CH2,

Found:

double focusing

13.

(calcd.

Chem. Sot.

of VIII showed sharp methyl singlets

protons

at 5.50-6.03

J. Am.

decomposition

data were obtained for VIII.

were obtained as racemates.

Chem.

with the assigned

in vacua was accompanied -elemental

Sot.

2647 (1964).

86, 1641 (1964); (b) E. J. Corey and M. F. =

by R. V. H. Jones and M. D. Sutherland, were in excellent

20, -

2273 (1967).

herein which contain asymmetric

Letters

J. Chem.

Tetrahedron

E. J. Corey and E. Hamanaka, J. Am. Chem. Sot. 89, 2758 (1967). = E. J. Corey and E. K. W. Wat, --ibid. 89, 2757 (1967). Since completion of the present study the isolation of a new sesquiterpene, structure

9.

substances

Tetrahedron

and K. B. Walshaw,

and S. C. Bhattacharyya,

222.1260).

data