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Part I. Asymmetric synthesis of 2,6-diaminopimelic acids (DAP) and γ-D(L)-glutamyl-L-meso-diaminopimelic acid dipeptide. Part II. Total synthesis of TAN-1057 and analogues




Yuan, Chenguang, author
Williams, Robert M., advisor

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Part I. An asymmetric and stereochemically unambiguous construction of diaminopimelic acid and related system using the chiral, non-racemic diphenyl oxazinones glycinate templates has been developed. The preparations of (R,R)-DAP, (S,S)-DAP, (S,S)-2,7-diaminosuberic acid, and mono-N-protected (S,R)-DAP are described. The synthesis of γ-D(L)-glutamyl-L-meso-diaminopimelic acid dipeptide, a subunit of both FK-156 and FK-565, is also described. The availability of both optical antipodes of the glycinate templates renders this chemistry adaptable to prepare all possible diastereoisomers of substances based on the DAP skeleton in optically pure form.
Part II. The first total synthesis of anti-MRSA dipeptides TAN-1057 A~D has been achieved. A new efficient method for preparation of amidinoureas has been developed and successfully applied to the total synthesis of TAN-1057. More importantly, this concise total synthesis paves the way for access to analogues that are not available from natural sources. Eight new analogues of TAN-1057 were designed, synthesized and assayed against MRSA. A new synthetic analogue 102 (CY-1800) showed very similar activity to that of TAN-1057. Other analogues prepared showed weak or no activity against Staphylococcus aureus up to 1 mg/mL. The success on discovery of a new potent anti-MRSA analogue proved the usefulness of this highly flexible strategy for the development of better analogues than the natural ones for the potential use as antibiotics.


1997 Spring.
Includes bibliographical references.

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Amino acids -- Analysis
Peptides -- Analysis
Asymmetric synthesis


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