180
S. D. Shnyder and C. W. Wright
Fig. 3 Biosynthesis of 1;
adapted from [5]
10 (anthranilic acid)
H2N
8 (indoxyl)
N
H
O
O
OH
+
imine formation
N
H
NH
O
OH
11
N
H
NH
O
SCoA
12
HSCoA
intramolecular
cyclization
N
H
13
N
O
N
H
14 (quindolinone)
HN
O
SAM
N
H
15 (cryptolepine-11-one)
N
O
N
H
16 (quindoline)
N
NADPH reduction
and dehydration
SAM
N
1 (cryptolepine)
N
N-methylation
phosphate, (6), leads to indole (7), the precursor of indoxyl (8) and isatin (9), from
which anthranilic acid (10) is derived (Fig. 2).
Condensation of 8 and 10 gives rise to 3-anthraniloyl indole (11) that may be
converted to its thioester 12 by co-enzyme A followed by cyclization to form 13,
which isomerizes to quinolinone 14 (Fig. 3). Reduction of 14 by NADPH followed
by dehydration yields quindoline (16), and selective SAM-type N-methylation of the
quinoline nitrogen then results in the formation of 1. N-Methylation of 14 may also
take place, leading to cryptolepine-11-one, (15), of interest as a constituent of C.
sanguinolenta and as a probable human metabolite of 1, as discussed in Section 9.
The biosynthesis of neocryptolepine (2) and isocryptolepine (3) may arise from the
reaction of anthranilic acid 10 with oxindole or 3-formylindole, respectively [5]. A
number of indoloquinoline alkaloid syntheses are to some extent biomimetic.
3 Synthesis of Cryptolepine and Analogs
For reviews of earlier synthesis routes to 1, see [1] and [6]. In most schemes, the
precursor, quindoline (16) is synthesized and then methylated to give 1. Some more
recent methods have employed “domino” or “tandem” processes involving two or