Woodward - woodward synthesis the original

[COXTR1HKJ'1.IO~

FROM

THE

ClWhlICAL

KESEARCII

LABORATORY

UF

~'ULAKOIII

COKPOKATION

AYn

'ItiE

COX

VHRSli

x[&MORIAI.

1.ABORATORY

OF

HARVAIID

UNIVERSI

1'Y

1

The

Total

Synthesis

of

Quihine

Rv

11.

B.

WOODWARD

AND

W.

E.

DOERIXG

The c$mination of the structural investigations

on quinine in the proposal of the correct structure

(I)

in ,1908l may be considered the point at which

rational efforts toward total synthesis could

be

4

3

CEI~--CI1--CH

-

CI1

--CH

cri

CI

I

i

9

CU(0H

J--CI

I

S-CI-1

initiated.2 These efforts first took the form

of

an

attack on the synthesis

df

substances containing

the quinoline moiety of the quinine molecule.

First success

was

achieved independently by

Pictet and Misner,% and by Kaufmann and

Pe~er,~~ in

1912

with the synthesis of quininic acid

(11,

R

=

H);

since that time a number

of

other

methods have

been

described for the synthesis of

this

and related quinoline

4-carboxylic

acids.*h

It

was then shown'

that

quininic acid,

in

the form

of its esters, could be condensed with

esters.

of

the type

RCH&OOEt

to produce substances

COOR CO-CHIR

I

CH30Ypf3

I

CHJo\m

iI

111

easily transformable by hydrolysis and decarboxyl-

ation to molecules.of the class

(111),

contain-

ing

various

groupings

attached to the quinoline

ring through

a

carbonyl function.

This

observa-

tion,

not in

itself

of exceptional interest,6 took

on

prime importance

in

consequence of the success

of

a

correlative line of investigation. Pasteur

(1)

Rabe,

Bur.,

41,

62

(1908).

(2)

Earlier attempts had bten made,

notably

that of Perkin,

who

attempted to convert allyl toluidine

to

quinine by oxidation. An

intersting account

of

this

work, which led directly to the establish-

mer

t

of

the coal

tar

color

industry,

and

then&

of the organic chemi-

cal industry,

is

given

by

Pqkin himself

in

the Hofmann Memorial

Lecture,

J.

Chem.

Soc.,

4%

603

(1896).

(3)

(a) Pictet pnd

Mi-,

Ber.,

46,

1800

(1912);

(b)

Kaufmann

and Peyu,

ibid.,

46,

1805

(1912);

(c) Kaufmann.

itid.,

61,

116

(1918);

66,614

(1922);.

(d) Halkkann.

ibid.,

64,

3079,

3090

(1921);

(e) Thielepape,

ibid.,

66,

127

(1922);

71,

387

(1938);

(0

Rabe,

Huntenburg and

Selikin,

ibid.,

64,

2402

(1931);

(g)

Thielepape and

Fulde,

ibid.,

74,

1432

(1939);

(h) Ainley and

King,

Proc.

Roy.

SOC.

(London),

lPIB,

83

(1938).

(4)

Rabe and

Pastwnack,

Ea.,

46,

1032

(1913).

(5)

E.

R.,

certain cempounds

of

this class may he obtained

easily

in 0th- ways, notably by the action

of

Grignard reagents

on

4-

cyanoquinolinea:

cf.

Kaufmadb,

Peyer and Kunkler,

Bcr.,

46,

3090

(1912);

Rabe and Ppsternack,

ibid.,

46,

1026

(1913).

had shown6 in

1853

that the 'ciiiclion:t

:ilkal(~ids,

on

heating with tartaric or sull'uric

a<.i;l.

iverc

transformed into isomeric substaiices,

e.

q

,

ciii-

chotoxine (cinchonicine) and

q

11

i

11

otoxine'

((

I

1

i

I

i

-

cine) from cinchonine and quiniiic, respecti\,cly.

Subsequent investigations by uther workers

rc-

sulted in the verification

of

these ectrly results,y

iii

improvements in the mode

of

effecting the isoineri-

zation,9 and in the successful formulutic

)II

lo

of

quinotoxine

as

(IV,

R

=

OCH3)

and cinchotoxine

as

(IV,

R

=

H).

It

was now apparent th:it thew

CHz-CH-C€I--CIT.-=-CI

I:

I

~

cri,

'

C1I.

co-CH,.

s

11-CH,

I

substances fell into the general category

(111)

and that their synthesis might be effected along

the lines adumbrated in the model experiments

on

ester condensation involving ethyl quininate.

It

was

then found that it was possible to effect the

CHzCH-CH-CH=CHz

V

CH2-CH-CH-CH=CH,

I

AH1

1

111

CO-CH--PU'--CH~

(6)

Pasteur,

Comfit.

rend.,

16,

110

(1853).

(7)

The isolation of quinotoxine directly from the mixed alkaloids

of cinchona

bark

was

subsequently

reported [Howard,

J.

Ckcm.

Soc.,

N,61

(1871);

46,

101

(1872)

1,

but it is not entirely clear whether the

substance is

a

bono

fide

natural product,

or

is formed from quinine

during the isolation

processes.

(8)

Hesse,

Ann.,

166,

276

(1873);,178,

244

(1875).

(9)

Von

Miller and Rohde,

Ber.,

48,

1064

(1895);

von

Miller,

(10)

Robe,

Ai%,

$60,

180

(1906);

SW,

366,

377

(1909).

Rohde and Fussenegger.

ibid.,

18,

3228

(1900).

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The Total Synthesis of Quihine

R v 11. B. WOODWARD AND W. E. DOERIXG

The c$mination of the structural investigations

on quinine in the proposal of the correct structure

(I) in ,1908l may be considered the point a t which

rational efforts toward total synthesis could be

initiated.2 These efforts first took the form of an

attack on the synthesis df substances containing

the quinoline moiety of the quinine molecule.

First success was achieved independently by

Pictet and Misner,% and by Kaufmann and

P e ~ e r , ~ ~in 1912 with the synthesis of quininic acid

methods have been^ described for the synthesis of

this and related quinoline 4-carboxylic acids.*h

It was then shown' that quininic acid, in the form

of its esters, could be condensed with esters. of

the type RCH&OOEt to produce substances

COOR CO-CHIR

I

C H 3 0 Y p f 3

I

easily transformable by hydrolysis and decarboxyl-

ation to molecules.of the class (111), contain-

ing various groupings attached to the quinoline

ring through a carbonyl function. This observa-

tion, not in itself of exceptional interest,6 took on

prime importance in consequence of the success

of a correlative line of investigation. Pasteur

Lecture, J. Chem. Soc., 4% 603 (1896).

(London), l P I B , 83 (1938).

had shown6 in 1853 that the 'ciiiclion:t :ilkal(~ids,

on heating with tartaric or sull'uric a<.i;l. iverc

transformed into isomeric substaiices, e. q , ciii-

chotoxine (cinchonicine) and q 11 i 11 otoxine' (( I 1 i I I i -

cine) from cinchonine and quiniiic, respecti,cly.

Subsequent investigations by uther workers rc-

sulted in the verification of these ectrly results,y i i i

improvements in the mode o f effecting the isoineri-

zation,9 and in the successful formulutic ) I I l o of

quinotoxine as (IV, R = OCH3) and cinchotoxine

as (IV, R = H). It was now apparent th:it thew

substances fell into the general category (111)

and that their synthesis might be effected along

the lines adumbrated in the model experiments on

ester condensation involving ethyl quininate.

It was then found that it was possible to effect the

V

CH2-CH-CH-CH=CH,

CO-CH--PU'--CH~

May, I945 THE T o T A L SYNTHESIS OF QUININE 86 1

recopversion, first of cinchotoxine," and later, of

quinotoxine, l 2 into cinchonineand quinine. Quino-

toxine was converted by the action of sodium

hypobromite into N-bromoquinotoxine (V), whid

was cyclized by alkali, with loss of hydrogen

bromide, to give quininone (VI). Reduction of

the ketone (VI) with aluminum powder and eth-

anol in the presence of sodium ethoxide gave a

mixture of^ stereoisomeric alcohols, from which

both quinine (I) and quinidine were isolated.

At this point it seemed likely that by conden-

sation of ethyl quininate with appropriate esters,

substances of the cinchona toxine class could be

prepared, and transformed by the processes de-

scribed above into.the cinchona alkaloids. The

difficulty lay in procuring the apposite .esters,

which contained the skeleton of the quinuclidine

part of the cinchona alkaloid molecule In initial

experiments along this line, Rabe wag able to

demonstrate the validity of the general scheme by

utilizing the ethyl ester of N-benzoylhomocin-

choloipon (VIII), which had been prepared by

K a ~ f m a n n ~ ~by degradation of natural dihydro-

cinchonine. The condensation proceeded

smoothly, and the product, on hydrolysis and

I /CHZCHI