The absolute configuration of natural rotenone is determined at centres 6a and 6' by exhaustive ozonolysis and oxidation. The 5'-centre was extracted from the rotenone degradation product ( -)-dihydrotubaic acid as ( +)-3-hydroxy-4-methylpentanoic acid. Synthesis and resolution gave the (-)-form of the latter, and this was degraded to (-)-2-methylpentan-3-01, which can be related to L-glyceraldehyde by correlations in the literature. The 5'-centre of rotenone has the (R)-configuration. Ozonolysis of the enol acetate of dihydrorotenone, which has the same configuration as rotenone a t positions 6a and 5', gave (-)-D-glyceric acid containing the 6a-centre, whose configuration is therefore (S) .Conformation in the rotenone molecule, which has the stable form of B/C fusion, is considered. Closely related 12a-hydroxy-derivatives are shown to be more stable with a cis-than with a transfusion. Reduction of rotenone and compounds known to have the same B/C fusion as rotenone, [( -J-)-isorotenone, (-)and (A)-dihydrodeguelin] gives crystalline 12hydroxy-compounds which show intramolecular hydrogen bonding. This is adequately explained only when O(,> is the acceptor, a situation possible only with a cis-fusion. Other evidence supports the assignment and it is in agreement with study of the hydrogenation of rotenoid derivatives. It follows that the configuration of rotenone a t 12a is (S), and the complete configuration is (6aS, 12aS, 5'R), as shown in formula (I).STRUCTURAL investigations of the insecticidal compound rotenone, which occurs in members of the Leguminosz, culminated in the proposal (I without stereochemical designation) .l The stereochemical problem could be solved by three determinations of absolute configuration two determinations of absolute and one of relative configuration, or one determination of absolute and two of relative configuration. We have chosen the second course. First, the absolute configuration is determined at 5', and then again at 6a since it would be difficult to relate these centres to each other. Finally, the mode of 1 (a) LaForge and Haller,
The synthesis of a series of novel, potent angiotensin converting enzyme (ACE) inhibitors containing saturated bicyclic amino acids in place of proline is described. Octahydroindole-2-carboxylic acid, octahydroisoindole-1-carboxylic acid, and octahydro-3-oxoisoindole-1-carboxylic acid can replace proline in both sulfhydryl and non-sulfhydryl ACE inhibitors to give compounds equipotent to captopril and enalapril both in vitro and in vivo. Structure-activity relationships are discussed. Compound 11a (CI-907, indolapril) has advanced to clinical evaluation.
A number of peptides and modified peptides were synthesized and studied for their ability to reverse electroconvulsive shock-induced amnesia in rodents. A few of these peptides were selected for secondary evaluation in tests of short-term memory in rats and aged rhesus monkeys. A number of the peptides and modified peptides were active in the amnesia reversal test. In selected secondary tests, however, the chosen compounds failed to show significant activity in enhancing memory. New methods for preparing methyleneamino and methyleneoxy isosteres of peptides are reported. Other modified peptides also included methylenethio, methylenesulfonyl, and ethylene isosteres in place of the normal peptide amide bond.
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