Rigid Dipeptide Mimics: Synthesis of Enantiopure 5- and 7-Benzyl and 5,7-Dibenzyl Indolizidinone Amino Acids via Enolization and Alkylation of δ-Oxo r,ω-Di-[N-(9-(9-phenylfluorenyl))amino]azelate Esters Felix Polyak and William D. Lubell* De ´ partement de chimie, Universite ´ de Montre ´ al C. P. 6128, Succursale Centre Ville, Montre ´ al, Que ´ bec, Canada H3C 3J7 Received April 1, 1998 Azabicyclo[X.Y.0]alkane amino acids are tools for constructing mimics of peptide structure and templates for generating combinatorial libraries for drug discovery. Our methodology for synthesiz- ing these conformationally rigid dipeptides has been elaborated such that alkyl groups can be appended onto the heterocycle to generate mimics of peptide backbone and side-chain structure. Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/ketone alkylation/ reductive amination/lactam cyclization sequence that furnished alkyl-branched azabicyclo[4.3.0]- alkane amino acid. Enantiopure 5-benzyl-, 7-benzyl-, and 5,7-dibenzylindolizidinone amino acids 2-4 were stereoselectively synthesized via efficient reaction sequences featuring the alkylation of di-tert-butyl R,ω-di-[N-(PhF)amino]azelate δ-ketone 5. A variety of alkyl halides were readily added to the enolate of ketone 5 to provide mono- and dialkylated ketones 6 and 7. Hydride additions to 6 and 7, methanesulfonations, and intramolecular S N 2 displacements by the PhF amine gave 5-alkylprolines that were converted by lactam cyclizations into 7- and 5-benzyl-, as well as 5,7- dibenzyl-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylate methyl esters 10, 11, and 14. Epimerization of the alkyl-branched stereocenter via an iminium-enaminium equilibrium proved effective for controlling diastereoselectivity in reductive aminations with 6 and 7 in order to furnish 5-alkylprolines that were similarly converted to 7- benzyl- and 5,7-dibenzylindolizidinone N-(BOC)amino esters 10 and 14. Ester hydrolysis with hydroxide ion and potassium trimethyl- silanolate then gave enantiopure indolizidinone amino acids 2-4. Epimerization at C-9 of benzylindolizidinone amino esters was also used to provide alternative diastereomers of 10, 11, and 14. This practical methodology for introducing side-chain groups onto the heterocycle with regioselective and diastereoselective control is designed to enhance the use of alkyl-branched azabicycloalkane amino acids for the exploration of conformation-activity relationships of various biologically active peptides. Introduction The spatial requirements for protein chemistry and biology may be explored through the employment of azabicyclo[X.Y.0]alkane amino acids as building blocks for the construction of conformationally rigid surrogates of peptide structures. 1,2 These unique dipeptide ana- logues can be used to restrain the backbone geometry and side-chain conformations of the native peptide in order to probe and elucidate structure-activity relationships. 1,2 Furthermore, because these scaffolds possess spatially defined amine and carboxylate handles suitable for functionalization by combinatorial technology, azabicyclo- [X.Y.0]alkane amino acids can also serve as inputs for generating libraries on which different pharmacophores are systematically displayed for studying recognition events in medicinal chemistry. 1,3 Concurrent with increasing applications of these novel tools for studying peptide structure has grown a necessity for practical methodology for the stereocontrolled syn- thesis of azabicyclo[X.Y.0]alkane amino acid. Efficient technology is particularly necessary for appending side chains onto these heterocycle systems in order to gener- ate mimics of both peptide backbone and side-chain properties. Since alkyl-branched azabicycloalkane amino acids have typically been prepared in the course of investigations of specific targets, 1 the current state of the art for their synthesis has usually involved multiple step sequences that provide a single alkyl-substituted frame- work in low overall yield. Because the future investiga- tion of biologically relevant peptides can be advanced through routine employment of alkyl-branched azabicy- cloalkane amino acids, more proficient means are needed for obtaining a series of these dipeptide mimics from common intermediates via efficient reaction sequences. Striving to develop such a versatile process for syn- thesizing azabicyclo[X.Y.0]alkane amino acid, we have introduced a Claisen condensation/reductive amination/ lactam cyclization sequence to stereoselectively furnish these important targets. 4,5 Employment of different N-(9- (9-phenylfluorenyl))aminodicarboxylates (Scheme 1, PhF ) 9-(9-phenylfluorenyl)), such as glutamate, aspartate, and longer aminodicarboxylates, in this scheme is de- signed to provide azabicycloalkane amino acid having a variety of heterocyclic ring sizes. Stereocontrol is at- tained at the ring-fusion and along the peptide backbone (1) For a review, see: Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789. We have adopted the nomenclature and ring system numbering used in this reference in order to maintain clarity and consistency when comparing these different heterocyclic systems. 5937 J. Org. Chem. 1998, 63, 5937-5949 S0022-3263(98)00596-9 CCC: $15.00 © 1998 American Chemical Society Published on Web 08/05/1998