C O M M U N I C A T I O N
Asymmetric synthesis of the central tryptophan residue of
stephanotic acid†
David J. Bentley and Christopher J. Moody*
Department of Chemistry, University of Exeter, Exeter, UK EX4 4QD.
E-mail: c.j.moody@ex.ac.uk
Received 28th September 2004, Accepted 18th October 2004
First published as an Advance Article on the web 3rd November 2004
The C-6 substituted tryptophan di- and tri-peptides 5 and 6,
representing the tryptophan core of stephanotic acid, have
been synthesized, the key steps being the formation of the
phosphono-di- and tri-peptides 8 and 10 by a highly chemo-
selective rhodium(II) catalyzed carbene N-H insertion re-
action, their subsequent Horner–Wadsworth–Emmons re-
actions with N-Boc-6-bromoindole-3-carboxaldehyde, and
the rhodium(I) catalyzed asymmetric hydrogenation of the
resulting dehydro di- and tri-peptides.
we have recently shown that such phosphonoglycines can
be readily accessed by dirhodium(II) catalyzed reactions of
7
diazophosphonates. Thus N-Boc-valinamide 7 was treated with
8
trimethyl diazophosphonoacetate in the presence of dirhodium
tetraoctanoate in boiling chloroform; this resulted in chemose-
lective N-H insertion of the (presumed) intermediate rhodium
carbene into the amide NH to give the phosphono-dipeptide
8 in 64% yield. Likewise the dipeptide amide, Boc-Ile-Val-
NH 9, also reacted with the diazophosphonate to give the
2
phosphono-tripeptide 10 albeit in 40% yield. Although the
yield of the tripeptide 10 was modest, there was no evidence
for products formed by reaction of the rhodium carbene at
any other sites in the dipeptide amide 9. The phosphono-
tripeptide 10 could also be obtained from dipeptide 8 by TFA
cleavage of the Boc-group followed by coupling to Boc-Ile-OH
using bromotri(pyrrolidino)phosphonium hexafluorophosphate
Natural products of the moroidin family, many of which are
potent inhibitors of tubulin polymerization, are characterized
by the presence of a highly modified tryptophan within a macro-
cyclic peptide array. Thus moroidin itself, 1, originally isolated
from the leaves of the Australian rain forest bush Laportea
moroides, and the structure determined by a combination of
molecular modelling and detailed NMR experiments by the
ꢀ
R
(
PyBroP ) (Scheme 1). Phosphonopeptides 8 and 10 were
1
obtained as mixtures of epimers at the new stereocentre and
were used without further purification.
Williams group in Cambridge, contains the unusual direct
linkages of the tryptophan C-2 and C-6 to the imidazole N-1 of
histidine and the b-carbon of a leucine residue respectively. More
recently moroidin has been re-isolated from the seeds of Celosia
argentea, along with the closely related celogentins, for example
celogentin A 2, which share a similar structural motif based
2
on the same tryptophan core, whereas the simplest member
of this family of cyclic peptides, stephanotic acid 3, isolated
3
from Stephanotis floribunda, lacks the right-hand histidine-
containing ring of moroidin and has a leucine to isoleucine
substitution.
Despite their fascinating structures, these cyclic peptides
have attracted little attention from synthetic chemists, although
over a decade ago we developed a route to simple N-(2-
4
indolyl)imidazoles, and subsequently we have used this method-
5
ology to prepare the right-hand macrocycle of moroidin. More
recently Castle and Srikanth have reported an asymmetric
synthesis of the central core 4 of moroidin/celogentins using
Cook’s versatile tryptophan synthesis in which the indole is
formed by the Larock methodology, but replacing the original
alkylation of a Sch o¨ llkopf auxiliary with a phase transfer
6
catalyzed alkylation using Park et al.’s chiral catalyst. We
now report an alternative route to the tryptophan core 5/6
of stephanotic acid using rhodium(II) catalyzed carbene N-H
insertion chemistry in conjunction with rhodium(I) catalyzed
asymmetric hydrogenation of dehydro di- and tri-peptides.
In order to generate the modified tryptophan stereocentre
by asymmetric hydrogenation, an appropriate alkene (dehy-
droamino acid) was required. In general, simple dehydroamino
acids are prepared by Horner–Wadsworth–Emmons reactions
of a phosphonoglycine such as the commercially available N-
benzyloxycarbonyl-a-phosphonoglycine trimethyl ester. How-
ever, we preferred to use a more complex phosphonoglycine
that already incorporates one or more additional amino acids
residues, thus making the synthesis more convergent, and
†
Electronic supplementary information (ESI) available. Experimental
procedures for compounds 5–13; HPLC data for compounds 5 and 6.
See http://www.rsc.org/suppdata/ob/b4/b414996c/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 4 5 – 3 5 4 7
3 5 4 5