Regiocontrolled synthesis of bicyclo[3.2.1]octane derivatives by cuprate addition and intramolecular acylation

Tetrahedron Letters Vol. 21, pp 3929 - 3932 @Pergamon Press Ltd. 1980. Printed in Great Britain

REGIOCONTROLLED

SYNTHESIS

OF BICYCLO[3.2.ijOCTANE

ADDITION

AND

INTRAMOLECULAR

by Anthony University

Summary:

Chemical

Copper-catalysed

cyclohexenones mediate

During

Laboratory,

reaction

of another

with suitable

functionalised

cyclohexenone

(2), reaaily

(1)' by the steps cuprate

derived

-40°C),

reaction of

with saturated

below.2

of the Grignard

was conducted became

(60% at 80% conversion).

conjugate

iour has been observed

attack occurs

the reaction,

We chose as a suitable

the major

higher

product

a smaller

temperature

product,

addition,

with

of (4) follows preferentially

the

towards

amount

reaction

ester group.

When this the

(n.m.r.) structure

(4)

of the enolate,

Although

this behav-

or ketones, 5 so far as we

of this type of acylation.

at the less hindered

aphidi-

of a faster

(-20 to -23'C)

from the known mode of cuprate

3929

by quenching

as a single stereoisomer

for halides 4 and aldehydes

(21, in

(3)3 (40-5036 at

data were in accord with

examples

(-35 to

(4-5 equiv.) with the enone

as part of a model study

Spectroscopic

the

At low temperatures

bromide.

together with

at slightly

complex

reagent

silica gel, 10% EtOAc-C 6H 6; 15-X1%).

are aware there are no recorded stereochemistry

to study

from the cyclohexadiene-Fe(CO)3

this new compound, 2 the result of intramolecular

formed during

(4) and (6).

of the 4,4-disubstituted

gave the alkylation

syntheses,

(t.l.c.,

of the inter-

(25 mol %, THF, 4-5 h), followed

which was required

component

CB2 1EW

bromide with

acylation

we required

reagents,

reagent

cuprous bromide aqueous NH4C1,

latter compound

for

investigation

obtained

indicated

colane and stemodinane

reaction

intramolecular

from 4-butenylmagnesium

90% conversion),

running

Road, Cambridge,

of 4-butenylmagnesium

cuprate

CUPRATE

ACYLATION

to give Bicyclo[3.2.1] oc t ane derivatives

the course

BY

J Pearson

Lensfield

(2) and (5) occurs witb

enolate

the presence

DERIVATIVES

The

addition

where

face of the cyclohexenone. 6

Me0

(6)

(5) Reagents: (i) (ii)

NaFlH4, DhnE-MeOH, 80%. CH30CH2C1,

(i-Pr)2NEt,

(iii)

Me3N0,

CBH6,

(iv)

Oxalic

acid, MeOH-H20,

(v)

reflux,

CHZ:CH{CH,&Mg3r,

CH2C12,

reflux.

100%.

93%.

CuBr,

70%. T'HF, temperature

as in text.

The simpler

enone

also examined conditions

(5), which was available Subjection

in this reaction.

(C4H,MgBr,

from our earlier of this compound

CuBr, THF, -28 to -12'C,

to similar

(6).

observation

The

of

(4.5 Hz) for angular proton H, establishes that the structural

a doublet

integrity of the enolate intermediate the coupling

equatorial

is maintained

is that expected

during this reaction.

for either

the axial/equatorial

protons

(3.6-4.8 Hz}' which have the alternative our

Consequently,

assignment

for cuprate

This reaction ring system

constant

in (6), or

protons

derivatives

precedent

was

3.5 h) gave as the major

product (60%) the bicyclol3.2.1] octane derivative

However,

studies,7

is tentative

additions.

and is based on the literature

6

related

in natural products

in helminthosporal

stereochemistry.

in view of the widespread

is interesting

the equatorial/

to gibberellic

occurence

of this

acid and helminthos-

poral.

This work is supported

Acknowledgements: Research

financially

by the Science

Council.

References and Notes 1.

A.J. Pearson,

E. Mincione,

M. Chandler

and P.R. Raithby,

J.C.S. Perkin

I,

in press. 2.

All new compounds

were obtained

tical and spectroscopic Compound

(2): m.p.

as racemates

and gave satisfactory

analy-

data, as follows:

48-49OC;

urnax (CHC13) 1728, 1673 cm-l; G(CDC13)

7.27 (lH, dd, J 11, 2.5 Hz), 5.75 (lH, d, J 11 Hz), 4.55 (ZH, ABq, J 7 Hz, CX2OMe),

3.73 (3H, s), 3,6 (lH, m), 3.32 (3H, s), 2.6-1.1

(12 H), 1.21 (3H, s). requires:

Found: C 6'5.91, H 8.34; C17H2605

C 65.78, H a.4#&.

(4): m.p. 7%79Oc; 6(CDC13)

M 310.

urnax (Ccl,) 3080, 1745, 1715, 1645, 920 cm-l;

5.7 (lH, m), 5.05 (U-I, d, br, J 8 Hz), 4.88 (lH, s, br),

4.63

(2H,

3.0-1.1

(18 H),

334.2144.

3.

Approx.

cn?;

(3H,

oil,

v max

5.7

3.21

{lH,

s, br),

Me).

M

206.1297,

mixtylre

of

(lH,

dd,

s).

M

C 72.02,

&(CDC13)

(IH,

2:l

3.53

1.07

Found:

colow-less

(6): 920

s, Cg20),

(CC141

C13H1802

m),

4.5

3082, 5.03

(3H,

(lH,

1720,

H 9.04%.

1645,

6 Hz),

d, br,

(10 H),

s),

requires

C 71.82,

1757,

2.5-1.1

requires

3.30

C20H3004

Requires

Hz),

stereoisomers.

6 Hz),

334.2111,

H 9.12.

(lH, d,

J 11,

1.19

997, 4.85 (3H,

s,

206.1298.

Further

details

will be published

elsewhere. 4.

R.S.

Ratney

and J. English,

G.H. Pesner, Brunelle,

Jr., J. Org. Chem.,

J.J. Sterling,

J. Am. Chem.

C.E.

Sot.,

1960,

Whitten,

1974, 97,

25,

2213;

C.M. Lentz

and D.J.

107, and references

cited

therein. 5.

F. NBf, R. Decoreant

6.

G-H. Posner,

7.

A.3. Pearson,

8.

P. de Mayo,

and W. Thommen,

Helv.

Org. Reactions', 1972, l9, J.C.S. Perkin

E.Y. Spencer

E.J. Corey

I, 1979,

(Received in UK 26 July IWO)

1, and references

1975, 58, cited

1808.

therein.

1255.

and R.W. White,

and S. Noze,

Chim. Acta.,

Can, J. Chern., 1963, 4l,

J. Am. Chem.

Sot.,

1965, 87,

5728.

2996;