Synthesis of 3‐Azabicyclo[3.2.0]heptane‐Derived Building Blocks via [3+2] Cycloaddition

Abstract

An efficient approach to synthesis of various substituted 3‐azabicyclo[3.2.0]heptane‐derived building blocks based on [3+2] cycloaddition of cyclobut‐1‐eneraboxylic acid ester and in situ generated azomethine ylide was developed and applied on multigram scale. The utility of 1,3‐disubstituted 3‐azabicyclo[3.2.0]heptane scaffold was demonstrated by additional structural analysis using exit vector plot (EVP) tool, and tested in parallel synthesis of compound library.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[466][467][468] One more retrosynthetic disconnection of the 3-azabicyclo [3.2.0]heptane core relied on the [3 + 2] cycloaddition of cyclobutene derivatives and azomethine ylides, used for the construction of 1,3-disubstituted derivatives (Scheme 60). [459] A copper-catalyzed asymmetric version of this transformation leading to polysubstituted 3-azabicyclo[3.2.0]heptanes was also reported. [469] Scheme 55.…”

“…[458] Recently, structural analysis of 1,3-and 3,6-disubstituted 3azabicyclo[3.2.0]heptanes based on exit vector plots (EVP) was used to compare these scaffolds with 1,3-and 1,4-disubstituted piperidines and to provide a rationale for such isosteric replacements (Figure 10). [342,459,460] A general approach to the synthesis of 3-azabicyclo[3.2.0] heptanes relies on the intramolecular photochemical [2 + 2] cycloaddition of properly functionalized dienes (Scheme 58).…”

Fluoroalkyl‐Containing 1,2‐Disubstituted Cyclobutanes: Advanced Building Blocks for Medicinal Chemistry

“…All the compounds shown in Figure 1 demonstrate the 1,3‐substitution pattern of the fluorinated cyclobutane fragment; this is partially related to their more or less satisfactory synthetic accessibility. The known approaches to install the fluoroalkyl group onto the cyclobutane ring relied on deoxofluorination [30–33] or decarboxylative trifluoromethylation [34] of carboxylic acids, the addition of the Ruppert‐Prakash reagent or its CHF 2 ‐substituted analog to C=O and C=N bonds, [35,36] fluoride‐mediated nucleophilic substitution, [37] metal‐catalyzed C( sp 3 )−Br [38] and C( sp 3 )−H [39] trifluoromethylation, direct side‐chain C(sp 3 )−H fluorination, [40] rearrangement of fluoroalkyl‐substituted cyclopro panes, [41–43] difluoromethylation of cyclobutene with CHF 2 I, [44] and other methods. Meanwhile, the corresponding 1,2‐disubstituted fluorinated counterparts have been largely underrepresented in the literature to date [39,41,44] .…”

Heteroaliphatic Dimethylphosphine Oxide Building Blocks: Synthesis and Physico‐Chemical Properties

“…In particular, straightforward preparation of dimethyl(pyrrolidin-3yl)phosphine oxide (6), an isomer of the product 2 a bearing no additional substituents, relied on the construction of the pyrrolidine ring by 1,3-dipolar cycloaddition of azomethyne ylides that demonstrated very good efficiency in our previous works. [41][42][43][44] For this purpose, a robust and scalable approach to the synthesis of dimethyl(vinyl)phosphine oxide (7) was developed, which included treatment of vinyl bromide with the parent dimethylphosphine oxide in the presence of Pd(PPh 3 ) 4 and Et 3 N in MeCN (68 % yield) (Scheme 3).…”