Synthesis of a Family of Spirocyclic Scaffolds: Building Blocks for the Exploration of Chemical Space

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• 作者：Sarvesh Kumar ; Paul D. Thornton ; Thomas O. Painter ; Prashi Jain ; Jared Downard ; Justin T. Douglas ; Conrad Santini
• 刊名：The Journal of Organic Chemistry
• 出版年：2013
• 出版时间：July 5, 2013
• 年：2013
• 卷：78
• 期：13
• 页码：6529-6539
• 全文大小：451K
• 年卷期：v.78,no.13(July 5, 2013)
• ISSN：1520-6904

文摘

This report describes the preparation of a series of 17 novel racemic spirocyclic scaffolds that are intended for the creation of compound libraries by parallel synthesis for biological screening. Each scaffold features two points of orthogonal diversification. The scaffolds are related to each other in four ways: (1) through stepwise changes in the size of the nitrogen-bearing ring; (2) through the oxidation state of the carbon-centered point of diversification; (3) through the relative stereochemical orientation of the two diversification sites in those members that are stereogenic; and (4) through the provision of both saturated and unsaturated versions of the furan ring in the scaffold series derived from 3-piperidone. The scaffolds provide incremental changes in the relative orientation of the diversity components that would be introduced onto them. The scaffolds feature high sp³ carbon content which is essential for the three-dimensional exploration of chemical space. This characteristic is particularly evident in those members of this family that bear two stereocenters, i.e., the two series derived from 3-piperidone and 3-pyrrolidinone. In the series derived from 3-piperidone we were able to 鈥渟plit the difference鈥?between the two diastereomers by preparation of their corresponding unsaturated version.