Dr. Markus Nahrwold Scientific co-worker Room: F2-246 Phone: 0521 106 2145 E-Mail:

β²-Homoalanine (1) represents the only naturally occurring α-monosubstituted β-amino acid (β²-amino acid). This compound serves e.g. as building block of nonribosomal depsipeptides such as cryptophycin-1 (2), topostatin (3) and fusaristatin A (4) and B (5) (see figure 1). Oligomers of synthetic β²-amino acids form distinct secondary structures even at a very short chain length and exhibit structural motifs not observed in conventional peptides or proteins.

Figure 1: Natural products containing β²-homoalanine.

In our work group, a general synthetic route towards enantiomerically pure β²-amino acids D carrying functionalised side chains has been established (see figure 2).^[1] The aminomethylene moiety within the β²-amino acid's backbone is introduced under mild conditions via curtius degradation of α-chiral succinic acid derivatives (C). These are obtained by connecting functionalised carboxylic acids to an Evans' auxiliary (A), followed by diastereoselective α-alkylation using iodoacetic acid esters as electrophiles. The auxiliary A serves both as stereodirecting and as carboxyl protecting group, since its cleaving conditions proved to be orthogonal to commonly used allyl-, benzyl‑, and tert-butyl protective groups.

Figure 2: General synthetic route to functionalised β²-amino acids.^[1]

Cryptophycins are cytotoxic depsipeptides produced as secondary metabolites by the cyanobacteria Nostoc sp. GSV 224 and Nostoc sp. ATCC 53789. Several members of this class of compounds bind to tubulin with high affinity. Especially cryptophycin-1 (2) exhibits high activity against multiple drug resistant tumour cells as well as against solid tumours implanted into mice. In phase II clinical trials, the synthetic cryptophycin-1 analogue cryptophycin-52 showed a considerable disease stabilising effect. Nevertheless, a dose limiting toxicity prevents its application as chemotherapeutic in anticancer therapy. For surveys of cryptophycin synthesis and bioactivity see e.g. ref.^[2,3]

Cryptophycins contain four amino acid and hydroxy acid building blocks (units A–D), among which unit A is the synthetically most challenging one (see figure 3). We succeeded in developing a short and highly efficient synthesis of cryptophycin unit A-precursor 10 containing all four stereogenic centres.^[4] This straightforward access to 10 facilitates comprehensive structure activity relationship (SAR-)studies of cryptophycin analogues.

Figure 3: Retrosynthesis of cryptophycins and total synthesis of unit A-precursor 10.^[4]

^[1] A. Stončius, M. Nahrwold, N. Sewald, Chiral Succinate: A Precursor for Enantiomerically Pure β²-Amino Acids, Synthesis 2005, 1829-1837.

^[2] S. Eißler, A. Stončius, M. Nahrwold, N. Sewald, The Synthesis of Cryptophycins (Review), Synthesis 2006, 3747-3789.

^[3] M. Nahrwold, S. Eifller, N. Sewald, Cryptophycins – Highly cytotoxic depsipeptides. Highlights, challenges, and recent advances, Chim. Oggi–Chem. Today (Suppl. Focus on Peptides) 2008, 26 (4), 13-16. http://www.infonetweb.it/testzone/teknoscienze/schema/index.html?folder=140

^[4] S. Eißler, M. Nahrwold, B. Neumann, H.-G. Stammler, N. Sewald, Short and Efficient Synthesis of Cryptophycin Unit A, Org. Lett. 2007, 9, 817-819.