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.

Short Enantioselective Total Syntheses of trans-Clerodane Diterpenoids: Convergent Fragment Coupling Using a trans-Decalin Tertiary Radical Generated from a Tertiary Alcohol Precursor.

The evolution of a convergent fragment-coupling strategy for the enantioselective total synthesis of trans-clerodane diterpenoids is described. The key bond construction is accomplished by 1,6-addition of a trans-decalin tertiary radical with 4-vinylfuran-2-one. The tertiary radical is optimally generated from the hemioxalate salt of the corresponding tertiary alcohol upon activation by visible light and an Ir(III) photoredox catalyst. The enantioselective total synthesis of trans-clerodane diterpenoid 1 reported here was accomplished in seven steps from 3-methyl-2-cyclohexenone. The synthetic strategy described in this report allows a number of trans-clerodane diterpenoids to be synthesized in enantioselective fashion by synthetic sequences of 10 steps or less. This study illustrates a powerful tactic in organic synthesis in which a structurally complex target structure is disconnected at a quaternary carbon stereocenter to fragments of comparable complexity, which are united in the synthetic pathway by conjugate addition of a nucleophilic tertiary radical to a fragment harboring an electron-deficient C-C double bond.

Constructing quaternary stereogenic centers using tertiary organocuprates and tertiary radicals. Total synthesis of trans-clerodane natural products.

A new concise construction of trans-clerodane diterpenoids is reported in which oxacyclic and trans-hydronaphthalene fragments are coupled, and the critical C9-quaternary carbon stereocenter formed stereoselectively, by 1,6-addition of a tertiary cuprate or a tertiary carbon radical to ß-vinylbutenolide. This strategy is specifically illustrated by total syntheses of (-)-solidagolactone (4), (-)-16-hydroxycleroda-3,13-dien-15,16-olide (5, PL3), and (-)-annonene (6).

Constructing Quaternary Carbons from N-(Acyloxy)phthalimide Precursors of Tertiary Radicals Using Visible-Light Photocatalysis.

Tertiary carbon radicals have notable utility for uniting complex carbon fragments with concomitant formation of new quaternary carbons. This article explores the scope, limitations, and certain mechanistic aspects of Okada's method for forming tertiary carbon radicals from N-(acyloxy)phthalimides by visible-light photocatalysis. Optimized conditions for generating tertiary radicals from N-(acyloxy)phthalimide derivatives of tertiary carboxylic acids by visible-light irradiation in the presence of 1 mol % of commercially available Ru(bpy)3(PF6)2, diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (8), and i-Pr2NEt and their coupling in dichloromethane at room temperature with alkene acceptors were developed. Four representative tertiary N-(acyloxy)phthalimides and 15 alkene radical acceptors were examined. Both reductive couplings with electron-deficient alkenes and radical substitution reactions with allylic and vinylic bromides and chlorides were examined with many such reactions occurring in good yield using only a slight excess (typically 1.5 equiv) of the alkene. In general, the yields of these photocatalytic reactions were higher than the analogous transformations of the corresponding N-phthalimidoyl oxalates. Deuterium labeling and competition experiments reveal that the reductive radical coupling of tertiary N-(acyloxy)phthalimides with electron-deficient alkenes can be terminated by both hydrogen-atom transfer and single-electron reduction followed by protonation, and that this mechanistic duality is controlled by the presence or absence of i-Pr2NEt.

Fragment Coupling and the Construction of Quaternary Carbons Using Tertiary Radicals Generated From tert-Alkyl N-Phthalimidoyl Oxalates By Visible-Light Photocatalysis.

The coupling of tertiary carbon radicals with alkene acceptors is an underdeveloped strategy for uniting complex carbon fragments and forming new quaternary carbons. The scope and limitations of a new approach for generating nucleophilic tertiary radicals from tertiary alcohols and utilizing these intermediates in fragment coupling reactions is described. In this method, the tertiary alcohol is first acylated to give the tert-alkyl N-phthalimidoyl oxalate, which in the presence of visible-light, catalytic Ru(bpy)3(PF6)2, and a reductant fragments to form the corresponding tertiary carbon radical. In addition to reductive coupling with alkenes, substitution reactions of tertiary radicals with allylic and vinylic halides is described. A mechanism for the generation of tertiary carbon radicals from tert-alkyl N-phthalimidoyl oxalates is proposed that is based on earlier pioneering investigations of Okada and Barton. Deuterium labeling and competition experiments reveal that the reductive radical coupling of tert-alkyl N-phthalimidoyl oxalates with electron-deficient alkenes is terminated by hydrogen-atom transfer.

Direct construction of quaternary carbons from tertiary alcohols via photoredox-catalyzed fragmentation of tert-alkyl N-phthalimidoyl oxalates.

A convenient method for the direct construction of quaternary carbons from tertiary alcohols by visible-light photoredox coupling of tert-alkyl N-phthalimidoyl oxalate intermediates with electron-deficient alkenes is reported.

Synthesis and Preclinical Characterization of LY3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator with an Improved Nonclinical Drug-Drug Interaction Risk Profile.

Results from recently completed clinical studies suggest the dopamine D1 receptor positive allosteric modulator (PAM) mevidalen (1) could offer unique value for lewy body dementia (LBD) patients. In nonclinical assessments, 1 was mainly eliminated by CYP3A4-mediated metabolism, therefore at the risk of being a victim of drug-drug interactions (DDI) with CYP3A4 inhibitors and inducers. An effort was initiated to identify a new D1 PAM with an improved DDI risk profile. While attempts to introduce additional metabolic pathways mediated by other CYP isoforms failed to provide molecules with an acceptable profile, we discovered that the relative contribution of CYP-mediated oxidation and UGT-mediated conjugation could be tuned to reduce the CYP3A4-mediated victim DDI risk. We have identified LY3154885 (5), a D1 PAM that possesses similar in vitro and in vivo pharmacologic properties as 1, but is metabolized mainly by UGT, predicting it could potentially offer lower victim DDI risk in clinic.