Multigram Synthesis of 3,3-Spiro-α-prolines.

A series of novel spirocyclic α-proline building blocks with a spiro conjunction in position 3 of the pyrrolidine ring was prepared to employ two convenient and practical synthetic approaches. Both alternative routes utilize simple and readily available starting materials─cyclic ketones and esters─and comprise 6 and 7 steps, respectively. The methodologies feature distinct advantages, using routine organic chemistry transformations, and are suitable for producing multigram amounts of the target prolines.

4-Azaspiro[2.3]hexane, an Overlooked Piperidine Isostere: Multigram Synthesis and Physicochemical and Structural Evaluation.

An expedient approach to the synthesis of 4-azaspiro[2.3]hexane derivatives is described. The synthetic scheme consists of Tebbe olefination of -Boc-protected 2-azetidinone (including the first use of the deuterated Petasis reagent CpTi(CD) in the building block preparation) and cyclopropanation of the resulting intermediate.

Stellane at the Forefront: Derivatization and Reactivity Studies of a Promising Saturated Bioisostere of -Substituted Benzenes.

This work highlights stellane's cage stability and derivatization opportunities. A diverse range of building blocks were synthesized using modern synthesis protocols to demonstrate stellane's reactivity and chemical tolerance across different reaction systems, proving its promise as a bioisosteric scaffold. It can be utilized in scaffold-based molecular design and is superior in terms of topological precision compared to existing isosteres, as well as monosubstituted benzene mimetics, holding the potential to become a robust platform for future medicinal chemistry studies.

Toward a Chemical Constructor: A Lego-Like Approach for Formal α-Alkylation of Cyclic Ketones.

A conceptual strategy for a formal α-alkylation of α-methylene ketones was developed. Diverse 1° and 2° alkyl substituents were generated in the α-position of various ketones via synthesis of enaminone (step 1) and treatment with organomagnesium (step 2) with subsequent catalytic hydrogenation (step 3, 1° alkyl) or organocopper reagents (step 4, 2° alkyl). Tolerance toward ester, Boc-protected amine, and α-fluoro-substituted ketone moieties was demonstrated.