John F. Bower

Diene Hydroacylation from the Alcohol or Aldehyde Oxidation Level via Ruthenium-Catalyzed C−C Bond-Forming Transfer Hydrogenation: Synthesis of β,γ-Unsaturated Ketones

Under the conditions of ruthenium-catalyzed transfer hydrogenation, isoprene couples to benzylic and aliphatic alcohols 1a-g to deliver beta,gamma-unsaturated ketones 3a-g in good to excellent isolated yields. Under identical conditions, aldehydes 2a-g couple to isoprene to provide an identical set of beta,gamma-unsaturated ketones 3a-g in good to excellent isolated yields. As demonstrated by the coupling of butadiene, myrcene, and 1,2-dimethylbutadiene to representative alcohols 1b, 1c, and 1e, diverse acyclic dienes participate in transfer hydrogenative coupling to form beta,gamma-unsaturated ketones. In all cases, complete branch regioselectivity is observed, and, with the exception of adduct 3j, isomerization to the conjugated enone is not detected. Thus, formal intermolecular diene hydroacylation is achieved from the alcohol or aldehyde oxidation level. In earlier studies employing a related ruthenium catalyst, acyclic dienes were coupled to carbonyl partners from the alcohol or aldehyde oxidation level to furnish branched homoallylic alcohols. Thus, under transfer hydrogenative coupling conditions, all oxidation levels of substrate (alcohol or aldehyde) and product (homoallyl alcohol or beta,gamma-unsaturated ketone) are accessible.

Ruthenium-Catalyzed C−C Bond Forming Transfer Hydrogenation: Carbonyl Allylation from the Alcohol or Aldehyde Oxidation Level Employing Acyclic 1,3-Dienes as Surrogates to Preformed Allyl Metal Reagents

Under the conditions of ruthenium-catalyzed transfer hydrogenation, commercially available acyclic 1,3-dienes, butadiene, isoprene, and 2,3-dimethylbutadiene, couple to benzylic alcohols 1a-6a to furnish products of carbonyl crotylation 1b-6b, carbonyl isoprenylation 1c-6c, and carbonyl reverse 2-methyl prenylation 1d-6d. Under related transfer hydrogenation conditions employing isopropanol as terminal reductant, isoprene couples to aldehydes 7a-9a to furnish identical products of carbonyl isoprenylation 1c-3c. Thus, carbonyl allylation is achieved from the alcohol or the aldehyde oxidation level in the absence of preformed allyl metal reagents. Coupling to aliphatic alcohols (isoprene to 1-nonanol, 65% isolated yield) and allylic alcohols (isoprene to geraniol, 75% isolated yield) also is demonstrated. Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the reactant alcohol or sacrificial alcohol (i-PrOH).

Recent Methodologies That Exploit C–C Single-Bond Cleavage of Strained Ring Systems by Transition Metal Complexes

In this review, synthetic and mechanistic aspects of key methodologies that exploit C-C single-bond cleavage of strained ring systems are highlighted. The focus is on transition-metal-catalyzed processes that are triggered by C-C bond activation and β-carbon elimination, with the review concentrating on developments from mid-2009 to mid-2016.

Iridium Catalyzed C-C Coupling via Transfer Hydrogenation: Carbonyl Addition from the Alcohol or Aldehyde Oxidation Level Employing 1,3-Cyclohexadiene

Under hydrogen autotransfer conditions employing a catalyst derived from [Ir(cod)Cl]2 and BIPHEP, 1,3-cyclohexadiene (CHD) couples to benzylic alcohols 1a-9a to furnish carbonyl addition products 1c-9c, which appear as single diastereomers with variable quantities of regioisomeric adducts 1d-9d. Under related transfer hydrogenation conditions employing isopropanol as terminal reductant, identical carbonyl adducts 1c-9c are obtained from the aldehyde oxidation level. Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the reactant alcohol or sacrificial alcohol (i-PrOH).

N-Heterocycle construction via cyclic sulfamidates. Applications in synthesis

When combined with an appropriate nucleophilic component, 1,2- and 1,3-cyclic sulfamidates function as versatile precursors to a range of substituted and enantiopure heterocyclic classes. Functionalised enolates provide a direct entry to C-3 functionalised lactams, as exemplified by total syntheses of (-)-aphanorphine, (+)-laccarin and (-)-paroxetine. Heteroatom nucleophiles, such as thiol esters, amino esters and bromo phenols, provide concise access to a range of enantiomerically pure thiomorpholine, piperazine and benzofused heterocyclic scaffolds. The latter methodology enables a facile synthesis of the antibacteriocidal agent levofloxacin.

An expedient route to substituted furans via olefin cross-metathesis

The olefin cross-metathesis (CM) reaction is used extensively in organic chemistry and represents a powerful method for the selective synthesis of differentially substituted alkene products. Surprisingly, efforts to integrate this remarkable process into strategies for aromatic and heteroaromatic construction have not been reported. Such structures represent key elements of the majority of small molecule drug compounds; methods for the controlled preparation of highly substituted derivatives are essential to medicinal chemistry. Here we show that the olefin CM reaction, in combination with an acid cocatalyst or subsequent Heck arylation, provides a concise and flexible entry to 2,5-di- or 2,3,5-tri-substituted furans. These cascade processes portend further opportunities for the regiocontrolled preparation of other highly substituted aromatic and heteroaromatic classes.

Branch-selective, iridium-catalyzed hydroarylation of monosubstituted alkenes via a cooperative destabilization strategy

Highly branch-selective, carbonyl-directed hydroarylations of monosubstituted alkenes are described. The chemistry relies upon a cationic Ir(I) catalyst modified with an electron deficient, wide bite angle bisphosphine ligand. This work provides a regioisomeric alternative to the Murai hydroarylation protocol.

Heteroaromatic Synthesis via Olefin Cross-Metathesis: Entry to Polysubstituted Pyridines

The olefin cross-metathesis reaction provides a rapid and efficient method for the synthesis of α,β-unsaturated 1,5-dicarbonyl derivatives which then serve as effective precursors to mono-tetrasubstituted pyridines. Manipulation of the key 1,5-dicarbonyl intermediate allows access to pyridines with a wide range of substitution patterns. An extension of this methodology facilitates the preparation of pyridines embedded within macrocycles, as exemplified by an efficient synthesis of (R)-(+)-muscopyridine. High levels of regiocontrol, short reaction sequences, and facile substituent variation are all notable aspects of this methodology.

Directing Group Enhanced Carbonylative Ring Expansions of Amino-Substituted Cyclopropanes: Rhodium-Catalyzed Multicomponent Synthesis of N-Heterobicyclic Enones

Aminocyclopropanes equipped with suitable N-directing groups undergo efficient and regioselective Rh-catalyzed carbonylative C-C bond activation. Trapping of the resultant metallacycles with tethered alkynes provides an atom-economic entry to diverse N-heterobicyclic enones. These studies provide a blueprint for myriad N-heterocyclic methodologies.

Substituted pyrroles via olefin cross-metathesis

Olefin cross-metathesis (CM) provides a short and convenient entry to diverse trans-γ-aminoenones. When exposed to either acid or Heck arylation conditions, these intermediates are converted to mono-, di-, or trisubstituted pyrroles. The value of this chemistry is demonstrated by its application to the tetrasubstituted pyrrole subunit of Atorvastatin.