The Bicyclo[3.2.0]heptan-endo-2-ol and Bicyclo[3.2.0]hept-3-en-6-one Approaches in the Synthesis of Grandisol:  The Evolution of an Idea and Efforts to Improve Versatility and Practicality

Abstract

In this paper we will disclose a chemistry story that started with a single molecule, the monoterpene grandisol, used in protecting cotton crops from an important pest, Anthonomus grandis Boheman. Initially, efforts were aimed at giving ever more practicality, versatility, and efficiency to a synthetic scheme that was centered on the key role of the 2,5-dimethylbicyclo[3.2.0]heptan-endo-2-ol, available from intermolecular photocyclization and methylation or, better and more conveniently, by an intramolecular copper(I)-catalyzed photobicyclization of the 3,6-dimethylhepta-1,6-dien-3-ol. We have developed an enantiospecific synthesis of both enantiomers of grandisol although some drawbacks would preclude scale up and commercialisation. The major limits of this original single-target synthetic scheme are pointed out along with the changed landscape resulting from recent developments in the fields of bioorganic chemistry and entomology. These changes prompted the elaboration of a new strategy focused on the conception and the development of a practical and efficient preparation bicyclo[3.2.0]hept-2-en-6-ones. The “bicyclo[3.2.0]hept-2-en-6-one approach” stems from a very convenient and general preparation, without photochemical steps, of bicyclo[3.2.0]hept-2-en-6-ones. These compounds proved to be amenable to selective manipulations to prepare not only grandisol but also other important molecules such as lineatin, filifolone, and raikovenal in multitarget and versatile synthetic schemes. Moreover, through resolution of the bicyclo[3.2.0]hept-2-en-6-ones, the procedures can be used to produce enantiomerically pure products. The bismethylation of the carbon atom adiacent to the carbonyl group as well as the conversion into the corresponding unsaturated bicyclic lactones are two important reactions that amplify the potential utility of bicyclo[3.2.0]hept-2-en-6-ones. Their peculiar reactivity, ascribed to the fact that the carbonyl group and the carbon−carbon double bond are attached to the same bridge-head carbon atom, has been demonstrated by the high chemio-, regio-, and stereoselectivity of the NBS-induced lactonization.

Recent Advances in the Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition Reactions

“…Oxygen substituents and, in particular, a hydroxy group can be positioned axially because this position facilitates additional binding to copper. 89 In the context of a synthetic approach to pseudolaric acid, Paquette and Pettigrew examined the [2 + 2] photocycloaddition of substrates rac - 19 and rac - 20 , which were submitted to the Cu(I)-catalyzed photocycloaddition as a mixture of diastereoisomers ( Scheme 8 ). 90 The resulting product mixture revealed that diastereoisomeric products rac - 23 were formed via a copper complex rac - 21 , in which the methyl group is equatorially and the hydroxy group is axially positioned.…”

Photochemische Reaktionen als Schlüsselschritte in der Naturstoffsynthese

“…Die Synthese der in Abbildung 8 gezeigten Hydroazulensesquiterpene (+)-Aphanamol I (264) und II (265) wurde so über eine [2+2]-Photocycloaddition/Fragmentierung möglich. [340] Die Radikalfragmentierung von Verbindungen des Typs III wurde von Lange et al erfolgreich in Naturstoffsynthesen eingesetzt.…”

A New Stereoselective Synthesis of (±)-Grandisol Based on the Remote Alkylation Protocol

“…Diazotization of 3a with the safe and very convenient 2‐azido‐1‐ethylpyridinium tetrafluoroborate18 (generated in situ) afforded the expected α‐diazo‐β‐ketosulfone 3b as an oil, in practically quantitative yield. Reflux of a dichloromethane solution of the crude diazo compound 3b with a catalytic amount of rhodium acetate led to a smooth intramolecular carbenoid cyclization,19 to afford crystalline 1‐methyl‐4‐(phenylsulfonyl)bicyclo[3.2.0]heptan‐3‐one ( 4 )20 in 79% overall yield from 3a (Scheme ).…”