and, although myotropically less active than proctolin itself,
has been shown to exhibit a considerably higher membrane
affinity for receptors in muscle tissue of the locust hindgut,
thus representing an interesting structure for receptor block-
ing studies.10
Scheme 2
Initially, we evaluated two distinct routes potentially
applicable to compounds 2-4. First, synthesis of an ap-
propriately protected precursor peptide containing a â-hy-
droxy-R-amino acid moiety, cyclodehydrative oxazoline
formation, and oxidation to the resulting oxazole (Scheme
1). This approach had the added attraction of also providing
Scheme 1
compounds 2-4, namely, a convergent synthesis via amide
bond formation of appropriately protected oxazole building
blocks.
Many methods have been reported for the synthesis of the
oxazole ring system.16 Many are not compatible with the
functionality present in (protected) amino acids and peptides,
particularly with respect to racemization. For the preparation
of the oxazole fragment found in 2 we initially investigated
the cyclodehydration of a suitably protected dipeptide,
containing a â-hydroxy-R-amino acid moiety, followed by
oxidation of the resulting oxazoline to the corresponding
oxazole. A variety of oxidation reagents were tested for the
transformation of Boc-Pro-ψ[oxazoline]-Thr-OH (8) to the
corresponding oxazole 9. The best result, affording 9 in 43%
yield was obtained using CuBr/Cu(OAc)2/perbenzoic acid
tert-butyl ester (Scheme 3).17 Other reagents such as DBU/
oxazoline-containing proctolin analogues.
Thus, Boc-Arg(Boc)2-Tyr(Bzl)-Leu-Pro-Thr-OBzl (5) was
prepared using standard solution-phase peptide synthesis
(C f N terminus sequential amino acid coupling using
EDCI/HOBt). Applying the pioneering work of Wipf,11 this
protected pentapeptide was treated with the Burgess re-
agent12,13 to afford the oxazoline 6 in 66% yield, following
chromatographic purification (Scheme 2). However, follow-
ing catalytic hydrogenolysis to remove the benzyl ether and
benzyl ester groups, respectively, Boc-Arg(Boc)2-Tyr-Leu-
Pro-allo-Thr-OH was the only product isolated. Allo-threo-
nine has the (S)-configuration at the â-carbon atom. Sub-
sequent removal of the Boc groups using trifluoroacetic acid
afforded the fully deprotected peptide H-Arg-Tyr-Leu-Pro-
allo-Thr-OH (7) as its trifluoroacetic acid salt, in 98% yield
following lyophilization. As far as we are aware, [allo-Thr5]-
proctolin has not been previously reported, and we were able
to confirm its structure by 2D NMR studies. These findings
can be explained by oxazoline formation taking place with
concomitant inversion of configuration at the threonine
â-carbon atom, consistent with literature precedent.14,15
Adventitious moisture was probably responsible for the
hydrolysis of the oxazoline ring, giving rise to the allo-
threonine moiety in the product.
Scheme 3
CCl4/acetonitrile/pyridine,18 CuBr2/DBU/HMTA,19,20 and
DDQ,21,22 gave less satisfactory results. We consistently
Because of the difficulties in manipulating some of the
oxazolines, we decided to pursue an alternative approach to
(16) Vorbru¨ggen, H.; Krolikiewicz, K. Tetrahedron 1993, 49, 9353.
(17) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207.
(18) Videnov, G.; Kaiser, D.; Kempter, C.; Jung, G. Angew. Chem. 1996,
108, 1604.
(19) Barrish, J. C.; Singh, J.; Spergel, S. H.; Han, W.; Kissick, T. P.;
Kronenthal, D. R.; Mueller, R. H. J. Org. Chem. 1993, 58, 4494.
(20) Li, G.; Warner, P. M.; Jebaratnam, D. J. J. Org. Chem. 1996, 61,
778.
(10) King, L. E.; Sevela, V. M.; Loughton, B. G. Insect Biochem. Mol.
Biol. 1995, 25, 293.
(11) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907.
(12) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744.
(13) Burgess, E. M.; Harold, H. R., Jr.; Taylor, E. A. J. Org. Chem.
1973, 38, 26.
(14) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 1575.
(15) Okonya, J. F.; Kolassa, T.; Miller, M. J. J. Org. Chem. 1995, 60,
1932.
(21) McGarvey, G. J.; Wilson, K. J.; Shanholtz, C. E. Tetrahedron Lett.
1992, 33, 2641.
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Org. Lett., Vol. 3, No. 22, 2001