On the stereochemistry of the Pictet-Spengler reaction

Tetrahedron Letters,Vo1.28,No.43,pp 5181-5184,1987 Printed in Great Britain

0040-4039187 $3.00 + .oo Pergamon Journals Ltd.

ON THE STEREOCHEMISTRY OF THE PICTET-SPENGLER REACTION

Patrick D Bailey Department of Chemistry, University of York, Heslington, York YOl 5DD, U.K. Summary. A pathway for the Pictet-Spengler reaction is proposed herein, which is consistent with all of the known mechanistic and sterochemical observations concerning the formation of tetrahydro-B-carbolines by this method. tetrahydro-B-carboline

The

alkaloids,

indole continues

to

be

is a

central feature of many

the

the Pictet-Spengler reaction (Scheme 1) most widely used method of synthesising the

tricyclic

crucial

enantiospecific stereochemical ever. 2

An demonstrated

ring-system.l With emphasis now resting on the synthesis of natural products, the importance of control in the Pictet-Spengler reaction is greater than

indication

of

the

ease

of stereochemical

control was

in

the previous paper, .in which it was shown that low temperatures induce cis selectivity in the formation of

reaction simple single

moiety

and

1,3_disubstituted tetrahydro-9-carbolines.3 Nevertheless, no mechanism has been proposed which is consistent with all of the

known stereochemical features of the Pictet-Spengler reaction.

fJ-JflR~ (1)

RCHo’H+-

R’ Scheme 1

There reaction of

which

However,

is

now

overwhelming

evidence

that

the

Pictet-Spengler

the stereochemistry

proceeds through a spiro-intermediate,4 is presumably retained during the subsequent migration step. recent isotopic labelling experiments suggest that the

The formation of such spiroindolenines is both rapid and reversible.5 sequence outlined in Scheme 2 is consistent, therefore, with the known mechanistic features of the reaction: moreover, this pathway

5181

5182

offers

the first

concerning

full explanation

the formation

for the stereochemical

of tetrahydro-f+carbolines

Scheme Thus,

with

an

starting aldehyde

cation

(3a/b), relationship. 6 place

with

ring,

giving

from

the

Nucleophilic

rise

stereochemistry

presumably

which

the C=N group

below

intermediates

or

groups this

on

above

(4a) or

respect

to

the nucleophile

and the developing

the E-iminium

display

iminium the plane

ion

a can

trans take

of the indole

(4b) respectively;'

is governed

Deslongchamps, a who noted that such additions

(11, condensation

mainly

generates

attack

either

derivative

bulkiest

to spiroindolenines

of these

2

the &-tryptophan

R-CHO in

observations

by this method.

the

by the observations

can take place lone pair

trans with

of electrons.

of

5183

BY

invoking

involves

a

the

"late"

single

cis-1,3-disubstituted favoured

by

this

because

is

preferred

tetrahydro-

conditions

the

(4b);

(obviously)

in

slightly

via the thermodynamically precisely

Moreover, the

the

if the indole

observed

reduction

due to an increase

For

would

formation

of

(4a)

stereochemistry be

all-cis;

the

formed: oroducts. small

then

in

(4b). paper.3

(i.e. R1 # H), again

(i.e.

the E-iminium

effectively

then

be expected,

R3 = CH2Ph),

cation

prohibited

(4b) would

of the L,3-substituents if the aldehyde

However, amounts

(3a/b),

of the Z-iminium

but

because

Spiro-intermediate

of spiroindolenine

yield

the

predominate

the previous

tryptophan

via

be

significant

the would

thus lead to in the final

side-chain cation

(R)

would

be

either

accountina

&

stereo-selectivity temperatures,

substituted

of

proceed

relationship

could

pyrrolidine

strain."

B-carbolines.12

therebv

the -cis or trans 1,3-disubstituted for the reduced trans selectivity with

aldehydes.13.

The all

rz

would

trans

this

A

were

"chair"

Spiro-intermediate

noted

the

(3a) = (3b)e

might

of this 1,2,3_trisubstituted

observed

small,

less

in cis selectivity lo would

rearrangement

tetrahydrowere

nitrogen

derivatives

again

piperidine

[(4a)+

higher

preferred

observation

in Al,2

Nu-benzyl

reaction

be able to adopt

tetrahydro-B-carboline

This

is

whilst at

be

low temperature):

trana-1,3-disubstituted

shown

trans-1,3-disubstituted

would

equilibrium

therefore,

be

(R3 = H) would

(e.g.

the resulting

initial the

(5a)

control

substituents

positions

favour

Spiro-intermediate would

B-carboline

kinetic

ring

However,

would

(4b)I

of

the

equatorial

structure.

assumption that the migration step state, 9 formation of the protonated

transition

the

known

Pictet-Spengler

reaction.

stereochemical

REFERENCES

in Scheme

mechanistic

and

control

therefore,

2 is consistent,

features

stereochemical

Application

of key tetrahydro-I%carbolines

preparation precise

outlined

pathway

of

of

these

is already

in the synthesis

ideas leading

of indole

with of the the

to

to more

alkaloids.

AND NOTES

1 a) G. Massiot b) T. Suzuki,

and T. Mulamba,

J. Chem.

Sot.,

Chem.

E. Sato,

K. Unno,

and T. Kametani,

S. Sato,

E. Goto,

and K. Ogasawara,

Commun.,

Heterocycles,

1984,

715;

1985, 2,

835 and 839: c) s. Takano, Commun.,

1986,

156.

J. Chem.

Sot.,

Chem.

5184

2

a)

b)

D.M.

Massiot

G.

and T. Mulamba,

Harrison

and R.B.

c) M. Nakagawa, M.

Taniguchi,

H. Fukushima, and T. Hino,

d) M. Nakagawa, Lett., e) P.D.

Bailey,

Commun.,

1985,

3

M. Hongu,

S.P. Hollinshead,

F. Ungemach

5

P.D. Bailey,

6

Inversion/rotation

and J.M.

Cook,

J. Chem.

J. Org.

Inversion

to give

then

(see Note

Res.,

J. Hammond,

F. Ungemach, Cook,

11

F. Johnson,

12

F. Ungemach,

13

46,

Sot.,

McLay,

Tetrahedron

Chem.

Lett.,

1987,

of the imine

1978, 2, 1089.

202.

is expected

(see M. Pankratz

and

1985, -50, 4553, and references therein), still be governed by the thermodynamic imines.

at nitrogen

could If this

must

be retained: factors

then

readily

take place

intermediate the

if it re-equilibrates

should

regain

to the

the imine -E/Z ratio

Tetrahedron,

J. Amer.

Chem.

D. Soerens, J. Amer. Chem.

Sot.,

1955, 11,

R. Weber,

Chem.

Rev.,

1975, -31, 2463.

Sot.,

M. DiPierro,

M. DiPierro,

1980,

1968, E,

334.

102,

0. Campos,

375.

R. Weber,

and E. Winterfeldt,

in UK 21 August

1987)

P. Mokry,

6976.

and J.M.

Cook,

J. Org.

164.

P. Flecker

(Received

J. Chem.

6).

9

1981,

1986, -27, 3235. and T. Hino, Tetrahedron

Chem.,

thermodynamic

P. Deslongchamps,

and J.M.

and N.R.

the tetrahydro-f3-carboline,

8

10

Lett.,

of the spiroindolenine.

1,3-stereochemistry imine,

1147;

T. Kawate,

Heterocycles,

of stereochemistry

formation

proceeds

1983,

paper.

but the -E/Z ratio would stability of the isomeric

after

M. Hongu,

and Z. Dauter,

S.P. Hollinshead,

4

7

Commun.,

1986, 27, 521; S. Kodato, T. Une,

6217:

preceding

R.F. Childs,

T. Kawate,

Chem.

Lett.,

1507.

P.D. Bailey,

1987, 28,

Sot.,

Tetrahedron

Tetrahedron

S. Kodato,

1986, 27,

J. Chem.

Sharma,

Tetrahedron,

1984, 40, 4853.

Chem.,