Enantiodivergent Synthesis of Bis-Spiropyrrolidines via Sequential Interrupted and Completed (3 + 2) Cycloadditions

Abstract

Both (5R)- and (5S)-1,7-diazaspiro[4.4]nonan-6-ones are obtained via a sequence of interrupted and completed stepwise (3 + 2) cycloadditions between azomethine ylides and π-deficient alkenes. The only source of chirality along the whole process is an enantiopure ferrocenyl pyrrolidine catalytic ligand. When the starting imine incorporates two aryl groups or one aryl group with one electron-releasing substituent, the reaction between the azomethine ylide and the alkene stops at the first step, leading to the corresponding Michael adduct. When imines derived from p-methoxybenzaldehyde are used, the corresponding syn-α-amino-γ-nitro ester is obtained with almost complete enantiocontrol. In contrast, imines derived from benzophenone lead to the corresponding anti analogue. From this interrupted (3 + 2) cycloaddition, cis- and trans-α-amino-γ-lactams can be obtained via hydrogenation of the nitro group followed by in situ cyclization. Imines derived from these latter compounds are the precursors of N-metalated azomethine ylides from which up to four new chiral centers can be generated via completed (3 + 2) cycloaddition reactions with full regio- and diastereocontrol. Cis- and trans-γ-lactams lead to opposite bis-spiropyrrolidine enantiomers. Therefore, both enantiomeric series of spiro compounds can be obtained by means of the same catalytic system. The potential of these rigid, densely substituted homochiral compounds in medicinal chemistry is briefly described.

Application of 1,3‐Dipolar Reactions between Azomethine Ylides and Alkenes to the Synthesis of Catalysts and Biologically Active Compounds

“…Alternatively, an additional phenyl group present in imines 31 derived from acetophenone is able to frustrate the cycloaddition but, in this case, only anti ‐γ‐nitro‐α‐amino esters 32 were obtained in the presence of the same chiral ligand NH‐ d ‐EhuPhos 25 (Scheme ). Also in this case, DFT calculations permitted to rationalize these different stereochemical outcomes . It is also noteworthy that, once again, NH‐ d ‐EhuPhos , an unnatural d ‐Proline ester, promoted the formation of l ‐amino esters via these frustrated (3+2) cycloadditions.…”

“…We reasoned that substituents that stabilize positive charges on the iminium moieties of these intermediates could frustrate the completion of the second step of the (3+2) cycloaddition, thus permitting the chemical synthesis of γ‐nitro‐α‐amino esters and their derivatives. In effect, we found that in the presence of 1 equiv. of NH‐ d ‐EhuPhos 25 and at –60 °C, reaction of nitroalkenes with imines 27 derived from 4‐methoxybenzaldehyde permitted to isolate syn ‐γ‐nitro‐α‐amino esters 31 with excellent enantiocontrol (Scheme ).…”

“…In Section 2.1, we have shown that NH‐ d ‐EhuPhos 25 can react with imines 27c – e and 31a – c to yield syn ‐ and anti ‐γ‐nitro‐α‐amino esters 32 by an interrupted stepwise 1,3‐dipolar reaction that stops at the Michael addition step . From these amino esters we generated cis ‐ and trans ‐γ‐lactams 106 after a catalytic hydrogenation/imine formation sequence (Scheme ).…”

“…Some of these spiro‐ l ‐proline lactams showed interesting biological activity . For example, spiro compound 108 with R 1 = R 2 = Ph and EWG‐R 3 = N ‐methyl phthalimido is an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme with IC 50 = 5 µ m .…”

Nitroprolinates as Nucleophiles in Michael‐type Additions and Acylations. Synthesis of Enantiomerically Enriched Fused Amino‐pyrrolidino‐[1,2‐a]pyrazinones and ‐diketopiperazines

“…A series of enantiopure tetrasubstituted nitroprolinate surrogates has been designed as scaffolds for proteasome inhibitors with high medicinal prospects . In addition, the NH−D−EhuPhos ligand 7 has been efficiently employed in the 1,3‐dipolar cycloadditions (1,3‐DC) to yield nitroprolinates and structurally rigid spirocompounds from chiral γ‐lactams . exo ‐ 6 a Series were employed as amino component in the multicomponent amino−aldehyde−dienophile (AAD) reaction affording chiral cyclohex‐2‐enyl amines and in two different multicomponent 1,3‐cycloadditions furnishing pyrrolizidines …”