A Saghatelian | Search PubMed

PubMed2001

Total synthesis of the calphostins: application of fischer carbene complexes and thermodynamic control of atropisomers.

The total syntheses of the potent protein kinase C inhibitors calphostins A, B, C, and D as well as a variety of structural analogues are reported. An aminobenzannulation reaction of an enantiopure chromium Fischer carbene complex is utilized to prepare a pentasubstituted naphthylamine. After optimization of side-chain substituents, conversion of the naphthylamine to an o-naphthoquinone was followed by biomimetic oxidative dimerization using trifluoroacetic acid and air yielding a 1:2 P/M mixture of atropisomeric perylenequinones. Thermal equilibration to a 3:1 P:M atropisomeric ratio and separation of the perylenequinones followed by side chain desymmetrization and functionalization led to the total synthesis of enantio- and diastereomerically pure calphostin C in only twelve steps from commercially available starting materials. In addition, calphostins A, B, D, and several structural analogues were prepared to evaluate biological activities.

Hydrocarbons↗

PubMed2001

A chiroselective peptide replicator.

The origin of homochirality in living systems is often attributed to the generation of enantiomeric differences in a pool of chiral prebiotic molecules, but none of the possible physiochemical processes considered can produce the significant imbalance required if homochiral biopolymers are to result from simple coupling of suitable precursor molecules. This implies a central role either for additional processes that can selectively amplify an initially minute enantiomeric difference in the starting material, or for a nonenzymatic process by which biopolymers undergo chiroselective molecular replication. Given that molecular self-replication and the capacity for selection are necessary conditions for the emergence of life, chiroselective replication of biopolymers seems a particularly attractive process for explaining homochirality in nature. Here we report that a 32-residue peptide replicator, designed according to our earlier principles, is capable of efficiently amplifying homochiral products from a racemic mixture of peptide fragments through a chiroselective autocatalytic cycle. The chiroselective amplification process discriminates between structures possessing even single stereochemical mutations within otherwise homochiral sequences. Moreover, the system exhibits a dynamic stereochemical 'editing' function; in contrast to the previously observed error correction, it makes use of heterochiral sequences that arise through uncatalysed background reactions to catalyse the production of the homochiral product. These results support the idea that self-replicating polypeptides could have played a key role in the origin of homochirality on Earth.

Amino Acid Sequence↗