Asymmetric Synthesis of (<i>S,S,S</i>)-2-Aza-bicyclo-[3.3.0]-octane-3-carboxylic Acid Benzyl Ester: Formal Synthesis of Ramipril

Kondaiah, G. C. M.; Vivekanandareddy, M.; Reddy, Lekkala Amarnath; Anurkar, Smita V.; Gurav, V. M.; Ravikumar, Muttineni; Bhattacharya, Apurba; Bandichhor, Rakeshwar

doi:10.1080/00397911003798757

Cited by 12 publications

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“…Representative examples include hexahydrocyclopenta[ b ]pyrrole-6a-carboxylate, which has been used as a building block in the synthesis of peptidomimetics and natural products such as kopsihainanine B and caldaphnidine R . Furthermore, Ramipril, a marketed drug used to treat hypertension, presents a bicycloproline motif in its structure (Figure ).…”

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Catalytic Asymmetric Synthesis of Bicycloprolines by a 1,3-Dipolar Cycloaddition/Intramolecular Alkylation Strategy

et al. 2016

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Esta es la versión de autor del artículo publicado en: This is an author produced version of a paper published in:Journal of Organic Chemistry.DOI: http://dx.doi.org/10.1021/acs.joc.6b01100 Copyright: © 2016 American Chemical SocietyEl acceso a la versión del editor puede requerir la suscripción del recurso Access to the published version may require subscription ABSTRACT: The diastereoselective one-pot synthesis of hexahydrocyclopenta [b]pyrrole derivatives (bicycloprolines) has been 8 achieved by base-mediated reactions of (E)-tert-butyl 6-bromo-2-hexenoate with α-imino esters. The catalytic asymmetric version 9 of this process has been efficiently achieved using the Cu I /(R)-DTBM-Segphos complex as a catalyst following a two-step 1,3-10 dipolar cycloaddition/intramolecular alkylation sequence. 11T he pyrrolidine ring is present in a myriad of natural 12 products and has been broadly used as a chemical core to 13 synthesize molecules with interesting pharmaceutical proper-14 ties. 1 In peptidomimetic chemistry α-quaternary proline 15 analogues have generated special interest due to their ability 16 to restrict the conformation and limit torsional angles of the 17 We began our study by examining the reaction of N-64 benzylidene glycine methyl ester (1a) with (E)-tert-butyl 6-65 bromo-2-hexenoate 17 (2) in the presence of a base such as 66 NaH, conditions previously described for the preparation of α-67 alkylated iminoglycinates. 18 We found that, using NaH in THF, 68 the expected alkylated product was not observed, the bicyclic 69 t1 product 4a being the only product detected ( (7) in the presence of KO t Bu (eq 100 2), showing that the intermolecular alkylation process is not 101 facile. Interestingly, the reaction of (E)-tert-butyl 7-bromo-2-102 heptenoate (8; homologous substrate of the model bromoal-103 kene 2) with the imino ester 1a in the presence of 1.1 equiv of 104 KO t Bu led selectively to the pyrrolidine endo-9, the 105 corresponding azabicycle not being detected by NMR (Scheme 106 3, eq 3). All of these test reactions strongly suggest that the 107 direct synthesis of bicycloprolines 4 by base-promoted reaction 108 of α-imino esters 1 with the 6-bromohexenoate 2 occurs by a 109 starting intermolecular 1,3-dipolar cycloaddition followed by 110 intramolecular alkylation. 111Next, we turned our attention toward the development of the 112 metal-mediated asymmetric version of the reaction in the 113 presence of a catalytic amount of the metal salt, chiral ligand, 114 and base. Taking into account the excellent enantioselectivities 115 described by several research groups, 20 including ours, 16 using 116 the chiral biphenyl DTBM-Segphos ligand, we focused our 117 attention on this ligand under silver-and copper-catalyzed 118 reaction conditions in the presence of a catalytic amount of t2 119 KO t Bu (Table 2). In agreement with the typically highly exo 120 diastereoselective behavior of this very bulky ligand in the 1,3-121 dipolar cycloaddition with α,β-unsaturated esters, 20b,16e the 122 reac...

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