Photorearrangement of [8]-2,6-Pyridinophane N-Oxide.

Reaction pathways operative when pyridinophane N-oxides are photoirradiated have been studied using time course analyses and careful isolation of photolabile intermediates with support from DFT calculations. Based on the data and the isolation of two previously unknown heterocyclophanes, we outline a unified mechanistic scheme that explains competing processes under varying photochemical conditions.

General Access to Concave-Substituted cis-Dioxabicyclo[3.3.0]octanones: Enantioselective Total Syntheses of Macfarlandin C and Dendrillolide A.

The evolution of a strategy to access the family of rearranged spongian diterpenoids harboring a concave-substituted cis-2,8-dioxabicyclo[3.3.0]octan-3-one fragment is described. The approach involves late-stage fragment coupling of a tertiary-carbon radical and an electron-deficient double bond to form vicinal quaternary and tertiary stereocenters with high fidelity. A stereoselective Mukaiyama hydration is the key step in the subsequent elaboration of the cis-2,8-dioxabicyclo[3.3.0]octan-3-one moiety. This strategy was utilized in enantioselective total syntheses of (-)-macfarlandin C and (+)-dendrillolide A. An efficient construction of enantiopure tetramethyloctahydronaphthalenes was developed during the construction of (-)-macfarlandin C.

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave-Substituted cis-Dioxabicyclo[3.3.0]octanone Fragment.

The enantioselective total synthesis of the rearranged spongian diterpenoid (-)-macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the cis-2,8-dioxabicyclo[3.3.0]octan-3-one moiety. The strategy involves a late-stage fragment coupling between a tertiary carbon radical and an electrophilic butenolide resulting in the stereoselective formation of vicinal quaternary and tertiary stereocenters. A stereoselective Mukaiyama hydration that orients a pendant carboxymethyl side chain cis to the bulky octahydronapthalene substituent was pivotal in fashioning the challenging concave-substituted cis-dioxabicyclo[3.3.0]octanone fragment.

Anomalous Chromophore Disruption Enables an Eight-Step Synthesis and Stereochemical Reassignment of (+)-Marineosin A.

An eight-step asymmetric synthesis of (+)-marineosin A is described. The route proceeds by condensing fragments of reversed polarity relative to conventional prodiginine constructions. The resultant unstable chromophore is disrupted by a unique cycloisomerization promoted at a tailored manganese surface. This provides a premarineosin and subsequently marineosin A in a particularly concise manner. A pyridinophane N-oxide photorearrangement in flow and structural isomers of premarineosin are discussed, as is the reassignment of marineosin stereochemistry. The route gives access to the natural product as well as diastereomers, congeners and analogs that are currently inaccessible by other means.

Exploring the Boundaries of "Practical": De Novo Syntheses of Complex Natural Product-Based Drug Candidates.

This review examines the state of the art in synthesis as it relates to the building of complex architectures on scales sufficient to drive human drug trials. We focus on the relatively few instances in which a natural-product-based development candidate has been manufactured de novo, rather than semisynthetically. This summary provides a view of the strengths and weaknesses of current technologies, provides perspective on what one might consider a practical contribution, and hints at directions the field might take in the future.

Lewis Acid Activation of Fragment-Coupling Reactions of Tertiary Carbon Radicals Promoted by Visible-Light Irradiation of EDA Complexes.

The addition of tertiary carbon radicals generated from N-(acyloxy)phthalimide esters to cyclic α,ß-unsaturated ketones and lactones is markedly enhanced by the addition of substoichiometric amounts of a Ln(OTf)3. The reaction is accomplished by irradiation with visible light in the absence of a photosensitizer and is suggested to proceed by excitation of a ternary electron donor-acceptor complex between the NHPI ester, Hantzsch ester, and a Ln(OTf)3.

Constructing Saturated Guanidinum Heterocycles by Cycloaddition of N-Amidinyliminium Ions with Indoles.

We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of N-amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of N-amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of N-acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.