Scalable Synthesis of Biologically Relevant Spirocyclic Pyrrolidines

Abstract

Synthetic approaches toward multigram preparation of spirocyclic α,α-disubstituted pyrrolidines from readily available starting materials are discussed. It was shown that although a number of synthetic methodologies have been known to date, many of the title compounds remain hardly accessible. The most appropriate literature method (which relied on reaction of imines and allyl magnesium halide, followed by bromocyclization) was identified and optimized. It was found that the method is most fruitful for simple non-functionalized substrates. Two novel approaches based on the Sakurai or Petasis reactions of cyclic ketones, followed by hydroboration–oxidation at the allyl moiety thus introduced, were elaborated. The latter method had the largest scope and was beneficial for the substrates containing organosulfur or protected amino functions. For the synthesis of 4-azaspiro[2.4]heptane, an alternative synthetic scheme commencing from tert -butyl cyclopropanecarboxylate (instead of the corresponding ketone) was developed. It was shown that the whole set of the methodologies developed can be used for the synthesis of various spirocyclic α,α-disubstituted pyrrolidines—advanced building blocks of potential importance to medicinal and agrochemistry—at up to a 100 g scale.

Photocatalytic α‐Tertiary Amine Synthesis via C−H Alkylation of Unmasked Primary Amines

“…Although the centre wavelength of 455 nm was sub‐optimal for our purposes, a space‐time yield (STY) of 0.74 mol L −1 h −1 for γ‐amino ester 8 still proved possible, and we were able to isolate 10.1 g of product 17 b from a single 5.3 h run, post‐lactamisation. Notably, this chemistry provides a scalable access to spirocyclic pyrrolidine building blocks for drug discovery that outcompetes the current most practical synthetic routes for process‐scale work (5–7 steps) …”

“…In summary, we have developed the first visible‐light photocatalysed α‐C−H alkylation of primary aliphatic amines with electrophilic alkenes that does not rely on in situ masking of the amino group's intrinsic reactivity. Our dual catalytic approach, which uses azide ion as a HAT catalyst, is amenable to the decagram‐scale preparation of hitherto difficult‐to‐access α‐tertiary amines and aza(spiro)cyclic building blocks . We anticipate that this technology will open up new retrosynthetic strategies for the disconnection of substituted amine derivatives in organic synthesis, and find immediate application in conventional and fragment‐based lead identification programmes.…”

Facile Synthesis of Spirocyclic Lactams via [3+2] and [3+3] Aza‐Annulation Reactions

“…Spirocyclic N-heterocycles are privileged building blocks in drug discovery because of their 3D character [1,2] (escaping from aromatic flatland), conformational restriction, improved physicochemical properties, compared to their monocyclic analogs, and improved metabolic resistance (Scheme 1a). [3][4][5][6][7][8] Common methodologies for assembling spirocyclic scaffolds are mainly relaying on intramolecular S N 2 alkylation [9][10][11][12][13][14][15][16][17][18][19] and Nacylation, [11,20,21] ring closing metathesis [20,[22][23][24] of the appropriate precursors. Additionally, metal-catalyzed [25][26][27][28] and hypervalent iodine mediated [29] dearmoatization reactions, Prins reaction [30][31][32] and cycloaddition reactions [23,[33][34][35] should be mentioned.…”

“…Common methodologies for assembling spirocyclic scaffolds are mainly relaying on intramolecular S N 2 alkylation [9–19] and N‐acylation, [11,20,21] ring closing metathesis [20,22–24] of the appropriate precursors. Additionally, metal‐catalyzed [25–28] and hypervalent iodine mediated [29] dearmoatization reactions, Prins reaction [30–32] and cycloaddition reactions [23,33–35] should be mentioned.…”

Silver‐Catalyzed Diastereoselective Synthesis of Spirocyclic Pyrrolidine‐Lactones by 1,3‐Dipolar Cycloaddition

“…Spirocyclic pyrrolidines are commonly present in natural products (for example 1–3 ) and are considered as advanced building blocks in the discovery of biologically important drugs (molecules 4–6 ) (Figure ). The particular balance in their conformational rigidity and flexibility allow exclusive biological effects in nature .…”