A new spiro-annelation procedure: intramolecular decarboxylative alkylation of β-keto-esters

Eilerman, Robert G.; Willis, Brian J.

doi:10.1039/c39810000030

Cited by 19 publications

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“…Michael addition to (−)-dehydrocryptone 17 was initially envisioned using a substituted malonate nucleophile, such as 24 , to construct the decalone core via intermediate 25 (Scheme ). After allylic chlorination, the diester 27 might be used in a Krapcho decarboxylation/alkylation event , to forge the cyclopentane ring. However, over months of experimentation, two major issues with this approach emerged: (1) the propensity for dehydrocryptone to isomerize to the conjugated dienone 26 under Michael conditions and (2) a rapid retro-Michael fragmentation pathway of compounds of type 25 upon attempted closure of the decalin ring system by enolate alkylation.…”

Section: Resultsmentioning

confidence: 99%

An Enantiospecific Synthesis of Isoneoamphilectane Confirms Its Strained Tricyclic Structure

et al. 2023

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We describe a total synthesis of the rare isocyanoterpene natural product isoneoamphilectane and two of its unnatural diastereomers. The significantly strained ring system of the reported natural product�along with a hypothesis about a biosynthetic relationship to related family members�inspired us to consider a potential misassignment in the structure's relative configuration. As a result, we initially targeted two less strained, more accessible, stereoisomers of the reported natural product. When these compounds failed to exhibit spectroscopic data that matched those of isoneoamphilectane, we embarked on a synthesis of the originally proposed strained structure via an approach that hinged on a challenging cis-to-trans decalone epimerization. Ultimately, we implemented a novel cyclic sulfite pinacol-type rearrangement to generate the strained ring system. Additional features of this work include the application of a stereocontrolled Mukaiyama−Michael addition of an acyclic silylketene acetal, an unusual intramolecular alkoxide-mediated regioselective elimination, and an HAT-mediated alkene hydroazidation to forge the C−N bond of the tertiary isonitrile. Throughout this work, our synthetic planning was heavily guided by computational analyses to inform on key issues of stereochemical control.

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Section: Resultsmentioning

confidence: 99%

An Enantiospecific Synthesis of Isoneoamphilectane Confirms Its Strained Tricyclic Structure

et al. 2023

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Lithium Chloride-Hexamethylphosphoric Triamide

Wright

McMills

2001

Encyclopedia of Reagents for Organic Synthesis

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The Krapcho Dealkoxycarbonylation Reaction of Esters with α‐Electron‐Withdrawing Substituents

Krapcho

Ciganek

2013

Organic Reactions

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The Krapcho reaction involves esters with α‐electron‐withdrawing substituents such as malonates, β‐keto esters, and α‐cyano esters, which undergo dealkoxycarbonylation on being heated in polar aprotic solvents (such as DMSO, DMF, or HMPT) in the presence of water, or in polar aprotic solvents with water in the presence of added salts (such as NaCN, NaCl, LiCl, LiI, or MgCl 2 ). This procedure avoids the use of strongly aqueous acidic and alkaline conditions and tolerates many functional and protecting groups. The chapter presents the mechanistic aspects of this procedure, which include reaction parameters such as solvents, salts, other additives, and the use of microwave irradiation. The diastereoselectivity of protonation of the enolate intermediate leading to the dealkoxycarbonylated products is discussed. Trapping of the intermediate enolate by electrophiles other than a proton is illustrated. Potential side reactions and same‐pot subsequent reactions of substrates are discussed along with functional‐group compatibility for halogens and nitrogen, oxygen, sulfur, selenium, and carbon functional groups. Several examples of applications of this methodology for the synthesis of natural products along with experimental conditions and procedures are presented. Closely related methods are discussed in the Comparison with Other Methods section. The tables, which consist of 371 pages, are grouped according to substrate structure. Selective entries for other methods (excluding classical aqueous acidic or basic methods) are included in the tabular survey for comparative purposes.

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A new spiro-annelation procedure: intramolecular decarboxylative alkylation of β-keto-esters

Abstract: A new intramolecular decarboxylative alkylation route to spirocyclic ketones, and its application t o the synthesis of (j-)-p-vetivone and ( f )-P-vetispirene are described.

Cited by 19 publications

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An Enantiospecific Synthesis of Isoneoamphilectane Confirms Its Strained Tricyclic Structure

An Enantiospecific Synthesis of Isoneoamphilectane Confirms Its Strained Tricyclic Structure

Lithium Chloride-Hexamethylphosphoric Triamide

The Krapcho Dealkoxycarbonylation Reaction of Esters with α‐Electron‐Withdrawing Substituents

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