Synthesis of a novel Boc-protected cyclopropane-modified proline analogue

An Enantioselective Approach to 4-Substituted Proline Scaffolds: Synthesis of (S)-5-(tert-Butoxy carbonyl)-5-azaspiro[2.4]heptane-6-carboxylic Acid

“…Subsequently, we proposed the preparation of amino acid 1. Direct cyclopropanation using the classical Simmons-Smith reaction (ZnEt 2 , CH 2 I 2 ) of 12, 6 or 5 led to complex mixtures with significant amounts of deprotected products, probably due to the necessary acidic media [14]. Better results were achieved by addition of dibromocarbene species to the double bond followed by debromination.…”

“…(S)-5-(tert-butoxycarbonyl)-5-azaspiro [2.4]heptane-6-carboxylic acid (1). [14] Melting point: 94-5 A sample of 1 [32] was transformed into their benzyl ester derivative: A mixture of 1 (100 mg, 0.41 mmol) and Cs 2 CO 3 (135 mg, 0.41 mmol) was stirred under nitrogen in anhydrous DMF (1 mL) at rt. Benzyl bromide (49 µL, 0.41 mmol) was added and the mixture was stirred overnight at rt.…”

“…The spirocyclic structure of Ledipasvir is always synthesized enantiomerically pure, either by resolution of the racemic mixture [5,[9][10][11][12] or from enantiopure natural amino acid derivatives: pyroglutamic acid (4) [5,13] or 4-hydroxyproline (3) [5,[14][15][16] (see Scheme 1) [17,18]. Nevertheless, an enantioselective and catalytic approach to 4-substituted proline scaffold is still lacking.…”

Recent developments in the utility of saturated azaheterocycles in peptidomimetics

“…Spirocyclic proline 49 can be synthesized from 4-hydroxyproline in three steps by a known literature procedure. 94 Peptidomimetic 51 was then synthesized from 50 in four steps that involved Boc deprotection followed by peptide coupling then a second round of deprotection and formation of the acyloxime. 93 Docking studies of the analogue of compound 51 to the active site of human HsPDF showed that the spiro cyclopropyl moiety fits better in the hydrophobic pocket made up of loop structure consisting of residues Glu112 to Phe120.…”

Successive Nucleophilic and Electrophilic Allylation for the Catalytic Enantioselective Synthesis of 2,4-Disubstituted Pyrrolidines

“…The synthesis of carboxamide 7d from compound 5d demonstrates facile removal of the o-nosyl protecting group and corroborates the anticipated inversion of stereochemistry in the Mitsunobu cyclization. 15 4-Methylenepyrrolidine 5h is readily converted to the spirocyclopropane 6h, 16 which embodies a structural motif evident in an FDA-approved drug for the treatment of hepatitis C. 17 Finally, oxidative cleavage 18 of 4-methylenepyrrolidine 5h followed by exposure of the resulting ketone 7h to Deoxy-Fluor 19 delivers the gem-difluoride 8h.…”