Far Away from Flatland. Synthesis and Molecular Structure of Dihetera[3.3.n]propellanes and Trihetera[3.3.n]propellanes: Advanced Analogues of Morpholine/Piperazine

Abstract

An approach to di- and trihetera­[3.3.n]­propellanes (n = 2–4 ), advanced morpholine and piperazine analogues, is developed. The key step of the reaction sequence included a [3 + 2] cycloaddition reaction of unsaturated vicinal dicarboxylic acid derivatives and in situ generated azomethine ylide resulting in the formation of the pyrrolidine ring. One more heteroaliphatic ring (i.e., pyrrolidine or tetrahydrofuran) was annelated by nucleophilic cyclization of the appropriate 1,4-dielectrophilic intermediates. There were 11 examples of the title products obtained in 3–5 steps on a multigram scale with 10–72% overall yields. Additionally, molecular structures of homologous dihetera­[3.3.n]­propellanes, analogues of morpholine, were obtained from X-ray diffraction studies and analyzed using exit vector plots (EVPs). It was shown that the scaffolds obtained are somewhat larger as compared to the parent morpholine and bicyclic 3-oxa-7-azabicyclo[3.3.0]­octane. Moreover, despite very similar chemical structures, they provide a very distinct spatial position of heteroatoms, which is clearly seen from the conformation adopted by a formal eight-membered ring including both N and O atoms (i.e., crown, boat–chair, twist chair–chair, and boat–boat for the oxaza[3.3.2]-, -[3.3.3]-, -[4.3.3]­propellanes, and 3-oxa-7-azabicyclo[3.3.0]­octane, respectively).

Synthesis of Spirocyclic β‐ and γ‐Sultams by One‐Pot Reductive Cyclization of Cyanoalkylsulfonyl Fluorides

“…This is somewhat different from the case of the corresponding spirocyclic derivative 16 (Figure 3): although the pyrrolidine ring also adopts the envelope conformation, it is the spirocyclic carbon atom which outstands from the mean plane formed by other five‐membered ring atoms by 0.575 Å. Exit vector plot (EVP) analysis [67–70] of the corresponding bifunctional scaffolds shows that despite some differences, their overall geometry is similar and corresponds to the truly three‐dimensional relative disposition of the corresponding groups attached to the variation points (Table 5).…”

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).…”

A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D‐Shaped Triquinazine Ring System from Chemical Space

“…Among these, angular triquinane 1 , known as hydrocarbon and as substructure of more complex natural products (see Figure S1 in the Supporting Information), [29–31] stood out as the only chiral ring system with a quaternary center. The other three ring systems, known both as hydrocarbons and as nitrogen containing analogs 2 , [32] 3 , [33] and 4 , [34] were achiral. We selected the angular diaza‐triquinane 8 , here named triquinazine, as our target building block representing a new functionalizable piperazine analog (Figure 1 b).…”