The Horner-Wadsworth-Emmons reaction in the synthesis of macrocyclic peptides: The Trp-His-Gly-Arg derived macrocycle of moroidin

Article abstract of DOI:10.1016/S0040-4039(03)01258-9

The Trp-His-Gly-Arg derived macrocycle 4 of moroidin 1 containing the unusual tryptophan C-2 histidine N-1 link has been synthesised in protected form. The key steps are displacement of a 2-chloroindole with a histidine derived nucleophile, a Horner-Wadsw

Full text of DOI:10.1016/S0040-4039(03)01258-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5189–5191
The Horner–Wadsworth–Emmons reaction in the synthesis of
macrocyclic peptides: the Trp-His-Gly-Arg derived
macrocycle of moroidin
Justin R. Harrison and Christopher J. Moody*
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
Received 31 March 2003; revised 13 May 2003; accepted 20 May 2003
Abstract—The Trp-His-Gly-Arg derived macrocycle 4 of moroidin 1 containing the unusual tryptophan C-2 histidine N-1 link has
been synthesised in protected form. The key steps are displacement of a 2-chloroindole with a histidine derived nucleophile, a
Horner–Wadsworth–Emmons reaction followed by asymmetric hydrogenation to establish the tryptophan side chain, and
incorporation of the Gly-Arg dipeptide by peptide coupling. © 2003 Elsevier Science Ltd. All rights reserved.
Moroidin 1 is a bicyclic peptide with potent biological
activity. It was 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
Williams group in Cambridge.1 The bush from which
moroidin is extracted is covered with stinging hairs,
contact with which results in intense pain, and in
extreme cases unconsciousness and death. Although not
as bioactive as the crude plant extract, pure moroidin
does elicit powerful acetylcholine like responses at the
5–10 microgram level. More recently moroidin has been
re-isolated from the seeds of Celosia argentea, its struc-
ture confirmed, and shown to possess potent inhibitory
activity on tubulin assembly.2 The closely related celo-
gentins, for example celogentin A 2, have been isolated
from the same seeds and also shown to have potent
antimitotic effects,3 whilst stephanotic acid 3, isolated
from Stephanotis floribunda,4 is a related but slightly
simpler cyclic peptide lacking the right-hand histidine-
containing ring of moroidin.
The structure of moroidin 1 is characterised by the
presence of a highly modified tryptophan and several
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01258-9

5190
J. R. Harrison, C. J. Moody / Tetrahedron Letters 44 (2003) 5189–5191
amino acids in a double macrocyclic array, and is
unique in the direct linkage of the indole C-2 to the
imidazole N-1 of histidine, although N-linked histidine
residues are known to occur in other macrocyclic pep-
tides such as the theonellamides.5 We now report the
first synthesis of the (protected) Trp-His-Gly-Arg
derived macrocycle 4 of moroidin, the fragment con-
taining the unique indole-imidazole link.
Scheme 1.
The strategy is outlined in Figure 1, and in addition to
two straightforward peptide bond forming reactions,
includes a Horner–Wadsworth–Emmons (HWE) reac-
tion. The macrocycle 4 incorporates the histidine
residue as a protected histidinol to prevent the facile
racemisation which often occurs with histidinyl esters.
The indolic nitrogen is also blocked, which not only
protects the indole nitrogen but also modifies the reac-
tivity of the indole-3-carboxaldehyde 6. The aldehyde
group is a key feature of the strategy for formation of
a key carbonꢀcarbon bond in an intra- or intermolecu-
lar HWE reaction, although only the intermolecular
variant is described herein. Some years ago,6 we devel-
oped a route to simple N-(2-indolyl)imidazoles based
on the facile displacement of chloride from 2-chloroin-
dole-3-carboxaldehydes, a reaction in which the formyl
group plays a key role. Hence a similar displacement of
chloride remained a key feature of our strategy for the
synthesis of the macrocyclic fragment 4 of moroidin
(Fig. 1).
gave the desired coupled product 7 in an optimised
yield of 89%. Subsequent HWE reaction of the alde-
hyde 7 with the protected aminophosphonate 8 in the
presence of DBU8 gave the dehydrotryptophan deriva-
tive 9 in excellent yield. The stereochemistry of the
alkene is assigned on the basis of literature precedent,
Schmidt’s DBU protocol being highly Z-selective.8,9
The stage was now set for the asymmetric hydrogena-
tion of the dehydro amino acid 9, and on the basis of
literature precedent,9,10 the DuPHOS and DIPAMP
ligands were selected, with the (R,R)-DlPAMP rho-
dium(I) catalyst giving better results. This gave the
desired protected amino acid derivative 10 in excellent
yield (Scheme 2). Although this compound was appar-
ently a single diastereomer as evidenced by NMR, this
was not conclusive, HPLC evidence suggesting that the
reduction had proceeded with ca. 70% ee.
The remaining Arg-Gly fragment was then incorpo-
rated into the macrocycle by peptide bond forming
reactions. The Boc-Arg(NO2)-Gly-OH dipeptide 11 was
prepared by conventional methodology from commer-
cially available Boc-Arg(NO2)-OH, and coupled to the
amine derived by cleavage of the N-Boc-protected
indole-imidazole ‘dipeptide’ 10. This gave the protected
The histidinol derivative 5 required for coupling to the
indole 2-position was prepared as shown in Scheme 1.
Thus reaction of histidinol dihydrochloride with an
excess of di-tert-butyl dicarbonate gave the N1,Na-di-
Boc-derivative, treatment of which with aqueous base
cleaved the N1-Boc group to give Na-Boc-histidinol.
Protection of the primary alcohol as its trimethylacetyl
(Piv) ester then gave the required histidinol derivative 5.
The indole 6 was readily prepared by protection of
2-chloroindole-3-carboxaldehyde, itself easily obtained
on a large scale by reaction of oxindole with the
Vilsmeier reagent.7 Reaction of the 2-chloroindole 6
with the imidazolyl sodium salt, prepared by treating 5
with NaHMDS, in N,N-dimethylacetamide (DMA)
Figure 1.
Scheme 2.

J. R. Harrison, C. J. Moody / Tetrahedron Letters 44 (2003) 5189–5191
5191
In summary, we have described the first synthesis of the
unusual macrocyclic peptide fragment of moroidin con-
taining the unique direct link between the tryptophan
indole C-2 and histidine imidazole N-1 residues. Fur-
ther studies are underway.
Acknowledgements
We thank the EPSRC for support of this work, the
EPSRC Mass Spectrometry Centre at Swansea for mass
spectrometric studies, and the EPSRC Chemical Data-
base Service at Daresbury.12
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(Scheme 3). The terminal carboxyl and amino groups
were deprotected sequentially by treatment with
aqueous lithium hydroxide and then HCl in dioxan.
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