Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

Abstract

Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C-C and C-N bonds react with amines to allow for the "any-stage" installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release "cyclopentylation" of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral "cyclopentylation" reagents.

Figure 1

(A) Examples of the utility of strained bonds in organic synthesis. (B) Suite of strain-release reagents for the installation of bioisosteres. (C) Installation of chiral 1,3-disubstituted cyclopentanes via stereospecific strain-release X–H functionalization.

Figure 2

(A) Lead compounds containing the BCP bioisostere. (B) BCP as a phenyl bioisostere and rigidifying linker. (C) Previous syntheses of bicyclo[1.1.1]pentan-1-amine.

Figure 3

(A) Della’s addition of alkyl lithium reagents into [1.1.1]propellane. (B) Addition of amines to 1,3-dehydroadamantane. (C) Attempted addition of Hauser bases to [1.1.1]propellane. (D) Davies’ addition of chiral lithium amides to enones. (E) Development and optimization of the direct amination of [1.1.1]propellane. (F) Process-scale synthesis of bicyclo[1.1.1]pentan-1-amine.

Figure 4

(A) Rationale for the development of a medicinal chemistry version of the “propellerization”. (B) Scope of the direct “propellerization” of amines. ^aConditions: amine substrate (1 equiv). ^bThe HCl salt of the amine starting material was used. ^cConditions: amine substrate (2 equiv). ^dThe extra equivalent of the amine starting material was recovered in ca. 90% yield (see SI for details).

Figure 5

(A) Azetidines in lead compounds. (B) Nagao’s addition of anilines to ABB. (C) Scalable preparation of ABB precursor 87. (D) Development of the reaction of “turbo amides” with ABB.

Figure 6

(A) Screen of the trapping agents for the “azetidinylation” of amines. (B) Scope of the “azetidinylation” of amines.

Figure 7

(A) Cyclobutanes in lead compounds. (B) Gaoni’s addition of benzylamine to sulfone 114. (C) Initial studies for the addition of dibenzylamine and “turbo amide” 43 to sulfone 8a. (D) Scalable synthesis of 8a and designer sulfones 8b–8g.

Figure 8

(A) Design and optimization of a one-pot “cyclobutylation” of amines and anilines. (B) Scope of the “cyclobutylation”. (C) Diversification of strain-release product 122. ^aGeneral procedure A with 8g: one-pot, no purification of intermediates. ^bGeneral procedure B with 8g: intermediates isolated by column chromatography (first yield for strain-release step, second yield for desulfonylation). ^cGeneral procedure C with 8g: one-pot, no purification of intermediates, reduction initiated by sonication. ^dThis compound was also prepared from 4-hydroxy-piperidine (43% over three steps, see SI for details).

Figure 9

(A) Chemoselectivity of bicyclobutylsulfones for Cys side chains over other proteinogenic amino acids. (B) Superior selectivity of reagent 8g over N-ethylmaleimide 147. (C) Optimized conditions and substrate scope of Cys “cyclobutylation.” (D) Temporal control of Cys labeling using electronically distinct bicyclobutylsulfones.

Figure 10

(A) Unified approach to chiral 1,3-disubstituted cyclopentanes. (B) Proof of concept for the stereospecific ring-opening of housane reagent 9 with amine 157. (C) Initial optimization of the stereospecific “cyclopentylation”.

Figure 11

(A) Racemic synthesis of sulfones 9 and 10. (B) Lipase-based synthesis of chiral sulfones 9 and 10. (C) X-ray structures of reagents (+)-9, (−)-9, (+)-10, and (−)-10. (D) Ketoreductase-based asymmetric synthesis of chiral sulfones 9 and 10.

Figure 12

(A) Development of reagent 10 to avoid S_NAr side reactions. (B) Substrate scope of alcohols. (C) Substrate scope of other heteroatoms. (D) Comparison of the reaction of dibenzylamine with 9, 10, and the “parent” housane 160 (Ar = Ph). Notes: ¹Ar = 4-CF₃, reaction run with reagent (+)-10. ²Ar = 4-CF₃, reaction run with reagent (−)-10. ³(−)-10 at ∼97% ee was used in this reaction (complete stereotransfer was observed). ⁴(−)-10 at 98% ee was used in this reaction (complete stereotransfer was observed).

Figure 13

(A) Diversification of strain-release intermediate 182. (B) Strain-release “cyclopentylation” of polypeptide 244 on solid phase.

Figure 14

Synthetic comparisons of stereospecific strain-release “cyclopentylation” vs current state of the art.

Figure 15

(A) C–C bond activation provides a new disconnection for the installation of BCP units. (B) A reference guide for the use of 6–10 in strain-release functionalization.