Rodger F. Henry

Ritonavir: An Extraordinary Example of Conformational Polymorphism

AbstractPurpose. In the summer of 1998, Norvir semi-solid capsules supplies were threatened as a result of a new much less soluble crystal form of ritonavir. This report provides characterization of the two polymorphs and the structures and hydrogen bonding network for each form.nMethods. Ritonavir polymorphism was investigated using solid state spectroscopy and microscopy techniques including solid state NMR, Near Infrared Spectroscopy, powder X-ray Diffraction and Single crystal X-ray. A sensitive seed detection test was developed.nResults. Ritonavir polymorphs were thoroughly characterized and the structures determined. An unusual conformation was found for form II that results in a strong hydrogen bonding network A possible mechanism for heterogeneous nucleation of form II was investigated.nConclusions. Ritonavir was found to exhibit conformational polymorphism with two unique crystal lattices having significantly different solubility properties. Although the polymorph (form II) corresponding to the “cis” conformation is a more stable packing arrangement, nucleation, even in the presence of form II seeds, is energetically unfavored except in highly supersaturated solutions. The coincidence of a highly supersaturated solution and a probable heterogeneous nucleation by a degradation product resulted in the sudden appearance of the more stable form II polymorph.

The chemistry of ascomycin : structure determination and synthesis of pyrazole analogues

Abstract Ascomycin (1) is a close analogue of the immunosuppressant FK-506 (2) which differs slightly in the side chain at position 21 (ethyl vs allyl). Structurally unique ascomycin and FK-506 are the subjects of intense chemical research because of their application in organ transplantation and autoimmune disease. We have been interested in studying the effect of structural modification and conformational change on biological activity. This paper reports the fermentation and structural determination of ascomycin as well as the synthesis and structure confirmation of a series of pyrazole analogues (3 and 4) derived from ascomycin.

Alkylation of tricarbonyl(diene)iron complexes: Model studies for the preparation of protomycinolide IV

Abstract The alkylation of (4,6-heptadien-3-one)- and (methyl 3,5-hexadienoate)Fe(CO) 3 ( 1 and 2 ) were examined (0–42% de and 69–92% de respectively). Optically active (methyl 3,5-hexadienoate)Fe(CO) 3 (−)- 2 was prepared by resolution of the corresponding carboxylic acid complex with α-methylbenzylamine.