Angewandte
Chemie
Both the exact mass of compound 22 as well as the
fragmentation pattern in the mass spectrum are identical to
those of an authentic sample of anachelin H (1);[13] however,
[1]H. Beiderbeck, K. Taraz, H. Budzikiewicz, A. E. Walsby, Z.
Naturforsch. C 2000, 55, 681 – 687; H. Beiderbeck, Dissertation,
Universität Köln, Germany, 2000.
[2]Y. Itou, S. Okada, M. Murakami, Tetrahedron 2001, 57, 9093 –
9099. This group did not isolate anachelin H (1), but instead two
esters isomeric to 1 of the salicylic acid with C(5)-O and C(7)-O
of the e-amino acid of anachelin.
[3]This amino acid is only to be found in the peptide antibiotic
galantin. Isolation: J. Shoji, R. Sakazaki, Y. Wakisaka, K.
Koizumi, M. Mayama, S. Matsuura, J. Antibiot. 1975, 28, 122 –
125; First synthesis: N. Sakai, Y. Ohfune, J. Am. Chem. Soc. 1992,
114, 998 – 1010.
[4]Compound 2 can be transformed by hydrolysis of the oxazoline
ring into 1 (see [1]). Therefore, we assume that anachelin H is
the more stable compound in the extracellular aquatic environ-
ment of A. cylindrica.
[5]The transformation B!C is analogous to the biosynthesis of
cyclo-DOPA starting from l-DOPA, important intermediates in
the biogenesis of betanidin and the melanins.
[6]Experimental procedures and analytical data of all new com-
pounds are reported in the Supporting Information and can be
sponding author.
1
the H NMR spectra of 1 and 22 display minor differences.
This indicates that compound 22 could be a diastereoisomer
of anachelin H (1). The synthetic route shown here allows for
the preparation of all possible fifteen diastereoisomers of 22
and thus should lead the determination of the absolute and
relative configuration of anachelin H (1).
In addition, our synthesis described herein delivers
intermediates that serve in the further evaluation of our
biogenetic hypothesis. For example, the postulated cascade
B!D in Scheme 1 can be corroborated by biochemical
experiments. While one can assume that in this transforma-
tion C spontaneously reacts to give D, we postulate that an
enzyme in the class of catechol oxidases catalyzes the
oxidation of B to C. Therefore, we decided to test this
hypothesis using an intermediate of our synthesis. We chose
diamine 6 as model substrate, which was transformed in
18 mm phosphate buffer at pH 6.8 with commercially avail-
able tyrosinase (catechol oxidase, EC 1.14.18.1) isolated from
mushrooms (Scheme 5). Interestingly, the formation of the
[7]We did not observe acylation of the aromatic hydroxy groups, as
no corresponding by-products could be isolated.
[8]The Boc group is not stable under the conditions of the borane
reduction.
[9]S. V. Ley, C. A. Meerholz, D. H. R. Barton, Tetrahedron 1981,
37, 213 – 223; for a related application, see J. Clews, C. J.
Cooksey, P. J. Garratt, E. J. Land, C. A. Ramsden P. A. Riley, J.
Chem. Soc. Perkin Trans. 1 2000, 4306 – 4315.
[10]D. W. Brooks, L. D.-L. Lu, S. Masamune, Angew. Chem. 1979,
91, 76 – 78; Angew. Chem. Int. Ed. Engl. 1979, 18, 72 – 74; T. S.
Mansour, C. A. Evans, Synth. Commun. 1990, 20, 773 – 781.
[11]The diastereoisomers were separated by crystallization. The
relative configuration of 13 was assigned after derivatization to
the N,O-acetal using the method of Joulliꢀ: B. D. Harris, M. M.
Joulliꢀ, Tetrahedron 1988, 44, 3489 – 3500.
Scheme 5. Catalytic oxidation of diamine 6 with O2 and catechol
oxidase.
[12]D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc.
1988, 110, 3560 – 3578.
[13]We thank Prof. Dr. H. Budzikiewicz for an authentic sample of
natural anachelin H.
cyclization product 23 could be observed by UV spectroscopy
at 305 nm![14] This biochemical experiment corroborates our
postulated biogenesis and indeed suggests that a catechol
oxidase is likely involved in the biosynthesis of the anachelin
chromophore.
[14]A reference sample of 23 was prepared by chemical oxidation of
6 using dianisyltellurium oxide and characterized: (UV: lmax
=
284 nm, e = 3960mꢀ1 sꢀ1, shoulder at l = 305 nm, e = 850mꢀ1 sꢀ1).
We present in this communication a biomimetic strategy
for the preparation of the peptide alkaloid anachelin featur-
ing a Te-mediated oxidative aza annulation as well as Claisen
condensations under mild conditions as key steps. This route
also delivers substrates, by which our biogenetic hypothesis
can be corroborated. For example, we were able to show that
the enzyme tyrosinase catalyses the cyclization of a key model
substrate of the biogenetic hypothesis. This experiment
suggests that a catechol oxidase could be involved in the
biosynthesis of anachelin. Additional experiments concerning
the biosynthesis, the configuration of anachelin, and the
mechanism of iron acquisition of A. cylindrica are being
pursued in our laboratory and will be reported in due course.
Received: February 3, 2004 [Z53909]
Keywords: alkaloids · biomimetic syntheses · natural products ·
.
peptides · polyketides
Angew. Chem. Int. Ed. 2004, 43, 3327 –3329
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3329