Biogenesis of Lycopodium alkaloids

TetrahedronLetters 30. 10, pp. 34-37, in Treat 3ritair.

BIOGENESIS

OJ! LYCOPODIUM Harold

Department

1960. ?erqamon Press Ltd. Printed

of Chemistry,

ALKALOIDS1

Conroy

Yale University,

New Haven,

Conn.

(Received4 April 1960)

IN 1356, shortly structure

of the Lycopodium

vriesner, Valenta

the skeleton derivation

1 3

after the brilliant alkaloid

and their coworkers

inherent

elucidation

in I might

to the condensation

annotinine 2

of (I) by

, we considered

that

owe its biogenetic

of two eight-carbon

Contribution number 1612 from the Sterling Laboratory at Yale University.

Chemistry

K. Wiesner, 2. Valenta, W. A. Ayer and C. Bankiewicz, 1019 (19ij6); K. Wiesncr, W. A. Ayer, Chem. and Ind. L. R. Fowler and 2. Valenta, Chem. and Ind. 564 (1957): K. Wicsner, 2. Valenta, W. A. Ayer, L. R. Fowler and 2, 87 (1958); cf. M. J. E. Francis, Tetrahedron Przybylska and F. R. Ahmed, Acta Cryst. 11, 718 (1958).

34

Biogenesisof Lycopodiumalkaloids

No.10 polyacetate part,

straight

for example,

formation

obscurines

6

selagine

, whose

of further

beginning

are all based

with two molecules

acid equivalent

aspects

(II) but for many

course,

while

accounts

the scheme

require

is plausible

experimental

i

shown will

?rmediate

the C-7

dehydration.

’

A speculative

of a 3,5,7-triketo-

details enough,

as well.

Of

it will

scrutiny.

uncertain:

however

A second aldol condensation

the

The common

from aldol condensation

and the C-4' methylene,

o+ooH

and the

upon the framework

serve for illustration.

(III) results

carbonyl

of this 6

not only for the grosser

structural

The order of steps is somewhat sequences

alkaloids

is seen to gain support.

octanoic

nontheless

or in the

, lycopodine 5 , lycodine

formulae

(II), this hypothesis biosynthesis

4

to play a

With the recent

antibiotics3.

of structures

notably

of the type believed

in fatty acid biosynthesis,

of macrolide

elaboration class,

chains

35

followed

between by

links C-8 and C-71

o&OH

III

IV

3 3.3. Zoodward, Anger. Chem. $6, 50 (1957). 4 Z. Valenta, H. Yoshimura, !3.F.Rogers, ?I!. Ternbah and K. Pliesner, TetrahedronLetters No. 10, 26 (1960). 5 D.B- I.hcLeanand J-k. Harrison, In press. -Cf. ref. 4. 5 -;[*r 4. A,Yerand G.G. Iverach, TetrahedronLetters No. 10, 19 (1960).

Biogenesisof Lycopodiumalkaloids

36

as in (IV), and after reduction condensation Completion reduction

of the double bond, Mannich

with an ammonia molecule of both

6-lactam

No.10

joins C-4 and C-5!

rings gives

(V), and further

at (carbons 1, 1: -j, 3: and T/results

in lycopodine

5 (VI) ’ OH

I

04%044) V Similarly, intermediate methylated

VI

formation (VII), where

of the obscurines

the first nitrogen

and the second nitrogen

the site of the C-5 carbonyl. removal

requires

has been

After

has been introduced

lactam closure

of oxygen we have the pyridone

the

and

(VIII) (P-obscurine) 6 ,

H2N

I

Me HOOC&O

R VII, R = Me X,R=H

the corresponding pyridine

dihydropyridone

(lycodine)6.

at

(a-obscurine),

or the

Biogenesisof Lyconodium alkaloids No.10 37 In the case of selagine (IX)4, we proceed from X, but the (C-1/) is lost (decarboxylation of a f%ketoacid) / signs of unsaturation at C-3' and C-7 are still present in

carboxyl

carbon

the final alkaloid.

0 / COOH

0

0

ti o+COOH XI The scheme deviation

for annotinine

(I) represents

from these pathways.

at least prior to the formation C-8 becomes

oxidized

We

suggest

only a minor

that,

in III or

of IV, the methyl

to the level of carboxyl.

carbon

With aldol-

ization at C-8 prohibited, an alternative involves closure / at C-4 , with formation of the cyclobutane ring of XI. Again,

Mannich

adjustment results

condensation

of oxidation

in the naturally

and lactamization

(as in IV-V),

state and, in this case, occurring

alkaloid

(I).

It is a fact that each and every oxygenated of the postulated molecules

either

two 3,5,7-triketo8ctanoic i) takes a direct

the final skeleton an oxygenated

center

position

acid precursor

part in the formation

or ii) can otherwise

or unsaturated

lactonization,

be accounted

of

for as

in one or the other of the

final alkaloids. We wish to thank Professor iYiesner for many stimulating discussions and for the opportunity to read his manuscript in advance of publication.