Synthesis of Novel Angular Spirocyclic Azetidines

Abstract

The syntheses of a variety of novel angular azaspiro[3.3]heptanes are reported. gem-Difluoro and gem-dimethyl variants of the angular 1,6-diazaspiro[3.3]heptane module were prepared in high yields using efficient sequences. Additionally, a practical one-pot synthesis of 5-oxo-2-azaspiro[3.3]heptanes and subsequent conversions into functionalized derivatives are described. The methods reported are amenable to the synthesis of these building blocks for drug discovery as members of a library or individually on a preparative scale.

Accelerating fragment-based library generation by coupling high-performance photoreactors with benchtop analysis

“…Simple azetidines partook the reaction to give 2a-c while azaspiro [3,3]heptane analogues were unreactive. The higher reactivity of azaspiro [3,4]octane example 3d highlights the distinct reactivity of azaspiro [3,3]heptanes. On one hand, a rationalization of this observation could be traced back to the first step of the catalytic cycle.…”

“…Reduction of the nickel(II) pre-catalyst to nickel(0) is believed to occur by β-hydride elimination on a sacrificial amount of amine [10]. The strained character of azaspiro [3,3]heptane might prevent this event. On the other hand, pyramidalization at nitrogen is much more important in azetidines [16][17][18].…”

“…Heterocyclic sp 2 -sp 3 fragments are sought-after in fragmentbased libraries, as they offer improved pharmacokinetic properties over more classical, "flat" scaffolds [1]. Specifically, bicyclo-and spiroalkanes are sp 3 -rich (more 3D-like), conformationally-restricted and strained building blocks that are underrepresented in screening collections. These are of high value to medicinal chemists to provide defined exit vectors and facilitate rational lead evolution [2][3][4][5][6][7].…”

“…Specifically, bicyclo-and spiroalkanes are sp 3 -rich (more 3D-like), conformationally-restricted and strained building blocks that are underrepresented in screening collections. These are of high value to medicinal chemists to provide defined exit vectors and facilitate rational lead evolution [2][3][4][5][6][7]. Thus, we were interested in developing reliable synthetic methods and technologies to apply metal-catalyzed cross-coupling reactions to such scaffolds, which often exhibit different reactivity from unstrained substrates [8].…”

General One‐Pot Reductive gem‐Bis‐Alkylation of Tertiary Lactams/Amides: Rapid Construction of 1‐Azaspirocycles and Formal Total Synthesis of (±)‐Cephalotaxine

“…The power of this method is demonstrated by a concise formal total synthesis of racemic cephalotaxine. It is worth mentioning that this method has found applications in the synthesis of azacycles35 and alkaloid FR901483 ( 1 ) 18b…”