Journal article
Scope of stereoselective Mn-mediated radical addition to chiral hydrazones and application in a formal synthesis of quinine
Journal of organic chemistry, Vol.77(7), pp.3159-3180
04/06/2012
DOI: 10.1021/jo2026349
PMID: 22329534
Abstract
Stereocontrolled Mn-mediated addition of alkyl iodides to chiral N-acylhydrazones enables strategic C-C bond constructions at the stereogenic centers of chiral amines. Applying this strategy to quinine suggested complementary synthetic approaches to construct C-C bonds attached at the nitrogen-bearing stereogenic center using multifunctional alkyl iodides 6a-d as radical precursors, or using multifunctional chiral N-acylhydrazones 26a-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-C 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.
Details
- Title: Subtitle
- Scope of stereoselective Mn-mediated radical addition to chiral hydrazones and application in a formal synthesis of quinine
- Creators
- Gregory K Friestad - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA. gregory-friestad@uiowa.eduAn JiJonas BaltrusaitisChandra Sekhar KorapalaJun Qin
- Resource Type
- Journal article
- Publication Details
- Journal of organic chemistry, Vol.77(7), pp.3159-3180
- DOI
- 10.1021/jo2026349
- PMID
- 22329534
- NLM abbreviation
- J Org Chem
- ISSN
- 0022-3263
- eISSN
- 1520-6904
- Publisher
- United States
- Grant note
- R01 GM067187 / NIGMS NIH HHS R01-GM67187 / NIGMS NIH HHS
- Language
- English
- Date published
- 04/06/2012
- Academic Unit
- Chemistry
- Record Identifier
- 9983985990402771
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