6592
VOl. 77
BERNHARD WITKOPAND RICHARD K. HILL
[CONTRIBUTION FROM THE NATIONAL INSTITUTE
OF ARTHRITISAND
METABOLIC DISEASES, NATIONAL INSTITUTES O F HEALTH]
The Synthesis of 2-Carboxydeoxyeserolines oia p-Methyl-$-tryptophan] BY BERNHARD WITKOPWITH RICHARD K. HILL^ RECEIVED MAY19, 1955 On refluxing in glacial acetic acid 4-acetamino-4,4-dicarbethoxy-2-methylbutyraldehyde phenylhydrazone ( I ) underwent both Fischer and internal cyclization to yield, via a derivative of @-methyl-+tryptophan( I I ) , a deoxyeseroline derivative 111. 2-Carboxybisnordeoxyeseroline ( I X ) was obtained, vie IV, 17,VI, VI1 and 17111, by controlled saponification and decarboxylation reactions. The stereochemical and phylogenetic implications are discussed.
The fact that in animal metabolism3 tryptophan is oxidized to 5-hydroxytryptophan4J which then undergoes decarboxylation to 5-hydroxytryptamine (serotonin) raises the question whether a similar sequence of reactions may not be operative in the plant for the synthesis of 5-hydroxyindole alkaloids. The recent isolation of 5-hydroxytryptophan from the culture medium of Chromobacterium violaceum6 points to the possibility of such a pathway in plants. To put this view to a test, e . g . , in the eseCH?
HsCHNCO
I/ ' + 7 , 7 ,
0
- CO? --. -- - +
9
'\d\< ' \/ ~-/~~\COOH CHj
S\II
CH,
HSCHh'C=O I
SVIII
CH3 CH?
rine series, it would be necessary to have a t hand 2-carboxyeserine (XVII), formed via 5-hydroxytryptophan, as a substrate for a decarboxylase possibly occurring in plant tissue or extracts of Physostigma
venenosum leading to eserine (XVIII). This paper describes an approach to 2-carboxydeoxyeserolines (Chart I). 4-Acetamino-4,4-dicarbethoxy-2-methylbutyraldehyde phenylhydrazone (1)' on refluxing with glacial acetic acid would be expected to give the indolenine 11, Le., a derivative of an acetylated pmethyl-+tryptophan. The acetyl group a t N b was expected to prevent internal addition of -HNb- to the reactive indolenine double bond.8 The reaction product, however, had a dihydroindole spectrum (A,, (log E) : 300 (3.42), 244 (3.85)) and was the cyclized deoxyeseroline 111, which could be acetylated further to IV. In order to simplify the subsequent hydrolysis and removal of carbethoxy and acetyl groups Kissman explored the addition of dibenzyl carbobenzyloxyaminomalonate and formaminomalonateQ to a-methylacrolein. Compared with the facile addition of the anion of diethyl acetaminomalonate to amethylacrolein the reactions with the less reactive or sterically more hindered benzyl esters were difficult and either led to self-condensation of the aldehyde or to low yields. The formyl analog of I, i.e., Ia, was prepared. The action of hot alcoholic or aqueous acid or base on the diester I11 led to darkening and decomposition. After storage in the cold with 2070 etha-
r
1
CH3
A
I , R = CHa; 153' Ia, R = G ; 92-94.5'
CH
l
-
Ba(OH)*at 120°
IS,K1 = Kq = H ; R( = COOH; 216-219' V I I , R = E t ; OD" S,R1 = RP = R3 = H ; deoxyeseroline; 72-73"'* VIII, R = H ; 108" Ac; R3 = H;142-143"* XI, RI = Rz
I., R VI, R
= =
K , 16s: H ; 111
_____.-
( 1 ) Presented In part a t the Fourth National Medicinal Chemistry Symposium of the American Chemical Society at Syracuse, N. Y.. June 17-14, 1954; cf. Abstracts, p. 77. (2) Department of Chemistry, Princeton University. (3) Cf. V. Erspamer, Rcnd. sci.favmilalio, 1, 5 (1954) ( 4 ) A. Ek a n d B. Witkop, THIS JOURNAL, 76, 5579 (1954). (6) S.lidenfriend, C . T. Clark and E. Titus, i b i d . , 75, 501 ( 1 9 3 3 ) . P , !I9 I ( G ) C . h I i t n i n n . 11, Wri.;sl,acli ond S lI
