The metal catalyzed reactions of diazo compounds have been broadly used in organic synthesis. The resulting metal-carbenoid intermediates are capable of undergoing a range of unconventional reactions, and due to their high energy, they are ideal for initiating a cascade sequence leading to rapid the rapid generation of structural complexity. This tutorial review will be give an overview of the most versatile reactions of donor/acceptor carbenoids, an exciting class of intermediates capable of highly selective reactions. This will include cyclopropanation, [4 + 3] cycloaddition, and C–H functionalization methodologies. The application of this chemistry to the synthesis of a range of natural products will be described.
The total synthesis of (−)-5-epi-vibsanin E (2) has been achieved in 18 steps. The synthesis combines the rhodium-catalyzed [4 + 3] cycloaddition between a vinylcarbenoid and a diene to rapidly generate the tricyclic core with an effective end game strategy to introduce the remaining side-chains. The [4 + 3] cycloaddition occurs by a cyclopropanation to form a divinylcyclopropane followed by a Cope rearrangement to form a cycloheptadiene. The quaternary stereogenic center generated in the process can be obtained with high asymmetric induction when the reaction is catalyzed by the chiral dirhodium complex, Rh2(S-PTAD)4.
The reaction of a variety of alpha-aryl-alpha-diazo ketones with activated olefins, catalyzed by the adamantyl glycine-derived dirhodium complex Rh(2)(S-PTAD)(4), generates cyclopropyl ketones with high diastereoselectivity (up to >95:5 dr) and enantioselectivity (up to 98% ee). Intermolecular C-H functionalization of 1,4-cyclohexadiene by means of carbenoid-induced C-H insertion was also possible with this type of carbenoid.
The reaction of 1-aryl-2,2,2-trifluorodiazoethanes with alkenes, catalyzed by the adamantylglycine-derived dirhodium complex Rh2(R-PTAD)4, generates trifluoromethyl-substituted cyclopropanes with high diastereoselectivity (>94%) and enantioselectivity (88->98%).
Nitrile-substituted cyclopropanes are readily synthesized in a stereocontrolled fashion from the intermolecular cyclopropanation between 2-diazo-2-phenylacetonitrile and electron-rich olefins, catalyzed by the chiral dirhodium complex, Rh(2)(S-PTAD)(4).
Vibsanin E (1), a structurally rare complex diterpene, consisting of a compact 3-oxatricyclo[6.3.2.05,10] tridecane core and an unprecedented 3,3-dimethylacroyl enol ester functional group, formulate a considerable synthetic challenge. Williams and Davies failed to independently synthesize this nemesis, however, a ‘two heads are better than one’ approach delivered the first total synthesis of the molecule, since its diamond aniversary isolation.
A triple cascade process was developed for the rapid synthesis of polycyclic benzo-fused dihydrofurans. The first step is a rhodium-catalyzed cyclopropanation of α-aryldiazoketones with alkenes. This is followed by a silver-catalyzed ring expansion to dihydrofurans, which then undergo a gold-catalyzed cyclization to form benzo-fused dihydrofurans.
Sulfonamide heterocycles, specifically 3-acylindoles, undergo a deprotection/alkylation sequence in the presence of an appropriate alcohol when cesium carbonate or potassium carbonate and a phase-transfer catalyst are utilized. The outcome of the onepot protocol was found to be significantly dependent on both the alcohol and sulfonamide heterocycle employed. Strictly anhydrous conditions are not necessary for this protocol.
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