Scope of Stereoselective Mn-Mediated Radical Addition to Chiral Hydrazones and Application in a Formal Synthesis of Quinine

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• 作者：Gregory K. Friestad ; An Ji ; Jonas Baltrusaitis ; Chandra Sekhar Korapala ; Jun Qin
• 刊名：The Journal of Organic Chemistry
• 出版年：2012
• 出版时间：April 6, 2012
• 年：2012
• 卷：77
• 期：7
• 页码：3159-3180
• 全文大小：813K
• 年卷期：v.77,no.7(April 6, 2012)
• ISSN：1520-6904

文摘

Stereocontrolled Mn-mediated addition of alkyl iodides to chiral N-acylhydrazones enables strategic C鈥揅 bond constructions at the stereogenic centers of chiral amines. Applying this strategy to quinine suggested complementary synthetic approaches to construct C鈥揅 bonds attached at the nitrogen-bearing stereogenic center using multifunctional alkyl iodides 6a鈥?b>d as radical precursors, or using multifunctional chiral N-acylhydrazones 26a鈥?b>d as radical acceptors. These were included among Mn-mediated radical additions of various alkyl iodides to a range of chiral N-acylhydrazone radical acceptors, leading to the discovery that pyridine and alkene functionalities are incompatible. In a revised strategy, these functionalities are avoided during the Mn-mediated radical addition of 6d to chiral N-acylhydrazone 22b, which generated a key C鈥揅 bond with complete stereochemical control at the chiral amine carbon of quinine. Subsequent elaboration included two sequential cyclizations to complete the azabicyclo[2.2.2]octane ring system. Group selectivity between two 2-iodoethyl groups during the second cyclization favored an undesired azabicyclo[3.2.1]octane ring system, an outcome that was found to be consistent with transition state calculations at the B3LYP/6-31G(d) level. Group differentiation at an earlier stage enabled an alternative regioconvergent pathway; this furnished the desired azabicyclo[2.2.2]octane ring system and afforded quincorine (21b), completing a formal synthesis of quinine.