Synthesis of [c]‐Fused Bicyclic Proline Analogues

Abstract

An overview of synthetic methods developed to build [c]‐fused bicyclic proline analogues is presented. The focus is on the preparation of azabicycles that bear a carbocyclic ring fused to the [c] face of the pyrrolidine unit. Attention is paid both to procedures that afford the desired compounds in racemic form and to asymmetric strategies. Procedures are organized according to the size of the carbocycle that is fused to the pyrrolidine moiety. Strategies able to provide multigram quantities of enantiopure compounds that have application in the synthesis of marketed drugs are highlighted.

Organocatalytic Asymmetric Conjugate Additions to Cyclopent‐1‐enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core

“…[a] 25 D =+3( c = 0.633 in CH 2 Cl 2 ); 1 HNMR (CDCl 3 ,4 00 MHz): d = 9.66 (d, J = 1.6 Hz, 1H), 4.43 (dd,J = 12.5,7.0 Hz,1H),4.38 (dd,J = 12.7,7.4 Hz,1H), 3.0 (sext, J = 7.6 Hz, 1H), 2.62 (dq, J q = 7.6, J d = 1.7 Hz, 1H), 2.07-1.39 ppm (m, 6H); 13 CNMR (CDCl 3 ,1 00 MHz): d = 201. 4,78.6,54.8,37.9,30.3,26.6,24.4 ppm;MS (ESI): m/z:180 [M+ +Na + ]. Ethyl 2-((1S,2S)-2-formylcyclopentyl)-2-nitroacetate (7):I nat est tube equipped with am agnetic stirring bar were sequentially added toluene (1.05 mL), as olution of benzoic acid in toluene (100 mL, prepared by using benzoic acid (12.2 mg) in toluene (2 mL), 5 mmol added), as olution of catalyst (R)-Ia in toluene (100 mL, prepared by using (R)-Ia (16.3 mg) in toluene (2 mL), 2.5 mmol added, 0.5 mol %c atalyst loading), ethyl nitroacetate (3) (55 mL, 0.5 mmol) and aldehyde 1 (59 mL, 0.6 mmol).…”

“…1 HNMR (CD 3 OD, 400 MHz): d = 4.22 (d, J = 6.5 Hz, 1H), 3.42 (s, 3H), 3.37 (s, 3H), 2.80 (dd, J = 12.2, 5.3 Hz, 1H), 2.59 (dd, J = 12.4, 6.9 Hz, 1H), 1.90-1.70 (m, 4H), 1.74-1.55 (m, 3H), 1.40-1.30 ppm (m, 1H); 13 CNMR (CD 3 OD, 100 MHz): d = 109. 7, 55.8, 53.2, 47.3, 47.2, 44.6, 32.2, 29.4, 25.6 (3aS,6aR)- 1,3a,4,5,6,pyrrole and (3aS,5aR,8aS,10aR,13aS,15aR)-octadecahydro-1 H, 5 H,10 H-cyclopenta[3,4]pyrrolo [1,2-a]cyclopenta [3,4]pyrrolo [1,2-c]cyclopenta [3,4]pyrrolo [1,2-e] [1,3,5]triazine (12):I nat est tube equipped with am agnetic stirring bar compound 11 (42 mg, 0.24 mmol) was dissolved in 2M HCl (500 mL, 0.96 mmol). The solution was stirred and heated at 70 8Cf or 20 min, then the reaction mixture was allowed to cool to RT.W ater and CH 2 Cl 2 were then added, the phases separated and the aqueous phase was washed with CH 2 Cl 2 (2 2 mL).…”

“…This peptide inhibitor can be assembled by combining the individual amino acids and other simple components by using standard peptidechemistry (Scheme 1). [3] Among the individual constituents of the peptideo f telaprevir, the bicyclic a-aminoacidc ore (i.e., (1 S,3aR,6aS)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid, highlighted in Scheme1)s tands out as being synthetically challenging, [4] especially considering the defined relative and absolutec onfiguration of its three contiguous chiral centres.E arly syntheses of this and relatedb icyclic proline analoguesr elied on lengthy and tortuous routes, [5] mostly involving HPLC separation of the enantiomers. [6] Subsequent approaches, some of which are reported at the top of Scheme2,i nvolved resolutiono faracemate through crystallisation, or chiral auxiliary methodology.I n particular,t he racemic N-protected amino acid for resolution was obtained by deprotonation of an N-protected 3-azabicyclo[3.3.0]octane [7] with sec-o rtert-butyl lithium in the presence of as uitable chelating agent, followed by quenching with carbon dioxide.…”

“…Among the individual constituents of the peptide of telaprevir, the bicyclic α‐amino acid core (i.e., (1 S ,3a R ,6a S )‐octahydro‐cyclopenta[ c ]pyrrole‐1‐carboxylic acid, highlighted in Scheme ) stands out as being synthetically challenging,4 especially considering the defined relative and absolute configuration of its three contiguous chiral centres. Early syntheses of this and related bicyclic proline analogues relied on lengthy and tortuous routes,5 mostly involving HPLC separation of the enantiomers 6.…”