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. 2010 Apr 12;16(14):4328-36.
doi: 10.1002/chem.200903500.

Total synthesis and configurational assignment of chondramide A

Anke Schmauder  1 , L David Sibley, Martin E Maier
Affiliations

Total synthesis and configurational assignment of chondramide A

Anke Schmauder et al. Chemistry. .

Abstract

The first total synthesis of the cyclodepsipeptide chondramide A (2 b) is described. This depsipeptide is composed of four subunits, namely L-alanine, N-Me-D-tryptophan, 3-amino-2-methoxy-propionic acid (beta-tyrosine derivative), and a 7-hydroxy-alkenoic acid. While the configuration of the stereogenic centers in the 7-hydroxy-alkenoic acid were known, the configuration of the tyrosine derivative required clarification and turned out to be (2S,3R) or (2L,3L), respectively. The synthesis of the 3-amino-2-methoxy-3-arylpropanoic ester 20 b relied on an asymmetric dihydroxylation yielding diol ent-15 a followed by a regioselective Mitsunobu substitution leading to 3-azido-2-hydroxypropanoate 18 b. We could also show that the ester bond in the seco compound 26 b can be fashioned by a Mitsunobu esterification by using hydroxy ester (7S)-7 and the tripeptide acid 25 b. This synthesis should allow for the preparation of various analogues.

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Figures

Figure 1
Figure 1
Structures of jasplakinolide and the chondramides. The atom numbering follows the suggestions from the isolation papers.
Figure 2
Figure 2
Key fragments for the synthesis of chondramide A diastereomers.
Scheme 1
Scheme 1
Summary of the synthesis of hydroxy ester 7.
Scheme 2
Scheme 2
Synthesis of the (2D,3L)-diastereomer 20a via the anti-acetoxy bromo ester 16a.
Scheme 3
Scheme 3
Synthesis of the (2D,3L)-3-amino-2-methoxy acid 20a via an aminohydroxylation reaction.
Scheme 4
Scheme 4
Synthesis of diastereomer 2a which does not correspond to chondramide A from the three building blocks 6, 20a, and 7.
Scheme 5
Scheme 5
Attempted synthesis of amino ester 20b and its incorporation in the cyclodepsipeptide. The obtained product 2c did not correspond to chondramide A.
Scheme 6
Scheme 6
Postulated formation of ent-16a from diol 15b via isomerization of cyclic oxonium ion B to D.
Scheme 7
Scheme 7
Independent synthesis of 3-amino-2-methoxy-tyrosine derivative ent-20b by aminhydroxylation.
Scheme 8
Scheme 8
Synthesis of the anti-diastereomer (2L,3L) 20b via dihydroxylation and substitution of the benzylic hydroxyl group by azide.
Scheme 9
Scheme 9
Synthesis of chondramide A (2b).
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