Abstract
Due to their intrinsic rigidity, three‐dimensionality and structural novelty, spirocyclic molecules have become increasingly sought‐after moieties in drug discovery. Herein, we report a strain‐release driven synthesis of azetidine‐containing spirocycles by harnessing the inherent ring strain of the azabicyclo[1.1.0]butane (ABB) fragment. Novel ABB‐ketone precursors bearing silyl‐protected alcohols were synthesized in a single step and shown to engage in electrophile‐induced spirocyclization‐desilylation reactions. Primary, secondary and tertiary silyl ethers were effectively transformed into a library of new spiro‐azetidines, with a range of substituents and ring sizes. In addition, the products are generated with synthetically useful ketone and protected‐amine functional groups, which provides the potential for further elaboration and for this chemistry to be utilized in the rapid assembly of medicinally relevant compounds.
Highlights
Due to their intrinsic rigidity, three-dimensionality and structural novelty, spirocyclic molecules have become increasingly sought-after moieties in drug discovery
Typically through alkylation,[7] cycloaddition,[8] metal-catalyzed cyclization onto alkenes or alkynes,[9] or ring-closing metathesis reactions.[10]. Another limitation is the difficulty in forming highly functionalized spiro-azetidines that would be amenable to additional structural diversification. Such fragments would represent highly valuable building blocks that could facilitate the application of spiro-azetidines in medicinal chemistry programs.[11]
We recently reported that lithiation of ABB to give azabicyclobutyllithium (ABB-Li, 1) effectively converts the bridgehead carbon into a strong nucleophile, providing a highly strained carbenoid species that was applied to the synthesis of 1,3-substituted azetidine boronic esters (Figure 1 b,ii).[15]
Summary
Due to their intrinsic rigidity, three-dimensionality and structural novelty, spirocyclic molecules have become increasingly sought-after moieties in drug discovery. With a range of silyl ether-containing ABB-ketones in hand, we subsequently investigated the proposed spirocyclization reaction.
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