A Boron Activating Effect Enables Cobalt-Catalyzed Asymmetric Hydrogenation of Sterically Hindered Alkenes.

Unsymmetric 1,1-diboryl alkenes bearing one -[BPin] (BPin = pinacolatoboryl) and one -[BDan] (BDan = 1,8-diaminonaphthalatoboryl) substituent each were hydrogenated in high yield and enantioselectivity using C1-symmetric pyridine(diimine) (PDI) cobalt complexes. High activities and stereoselectivities were observed with an array of 2-alkyl-, 2-aryl-, and 2-boryl-substituted 1,1-diboryl alkenes, giving rise to enantioenriched diborylalkane building blocks. Systematic study of substrate substituent effects identified competing steric and electronic demands in the key activating role of the boron substituents, whereby sterically unencumbered boronates such as -[BDan], -[BCat] (BCat = catecholatoboryl), and -[Beg] (Beg = ethylene glycolatoboryl) promote the hydrogenation of trisubstituted alkenes by enabling irreversible α-boron-directed insertion pathways to achieve otherwise challenging hydrogenations of trisubstituted alkenes. Deuterium-labeling studies with 1,1-diboryl alkenes support an insertion pathway generating a chiral intermediate with two different boron substituents and cobalt bound to the same carbon.

Asymmetric Synthesis of the Tricyclooctane Core of Trachylobane Natural Products and Related Terpenoids.

Enantioselective synthesis of a highly versatile building block en route to trachylobanes and related terpenoids is presented. The synthesis features diastereoselective Diels-Alder cycloaddition reaction, a cyclopropanation/homoquadricyclane rearrangement cascade, and palladium-catalyzed C-H acetoxylation. The targeted tricyclooctane was obtained in 20% yield over 8 steps and in 95% ee. The ketone and alcohol functional groups serve as handles for further elaboration.

Iridium-Catalyzed Enantioselective Allylic Substitution with Aqueous Solutions of Nucleophiles.

The iridium-catalyzed asymmetric allylic substitution under biphasic conditions is reported. This approach allows the use of various unstable and/or volatile nucleophiles including hydrazines, methylamine, t-butyl hydroperoxide, N-hydroxylamine, α-chloroacetaldehyde and glutaraldehyde. This transformation provides rapid access to a broad range of products from simple starting materials in good yields and up to >99% ee and 20:1 d.r. Additionally, these products can be elaborated efficiently into a diverse set of cyclic and acyclic compounds, bearing up to four stereocenters.

Total Synthesis of (-)-Mitrephorone A.

The first synthesis of (-)-mitrephorone A is disclosed along with discussion and study of synthetic strategies. The natural product includes a highly congested hexacyclic ent-trachylobane diterpenoid framework featuring a rare, embedded oxetane. The synthetic analysis presented dissects a number of approaches for the synthesis of the central oxetane, including carbonyl-olefin photocycloadditions, Prins-type cyclizations, and oxidative ring closures. In the successful route, three [4 + 2] cycloadditions enable rapid construction of all carbocycles. A novel late-stage oxidative cyclization of a hydroxy diosphenol with Koser's reagent furnishes the pivotal oxetane moiety.

Stereoselective Synthesis of Piperidines by Iridium-Catalyzed Cyclocondensation.

An iridium-catalyzed cyclocondensation of amino alcohols and aldehydes is reported. Intramolecular allylic substitution by an enamine intermediate and subsequent in situ reduction furnishes 3,4-disubstituted piperidines with high enantiospecificity and good diastereoselectivity. The modular approach and the broad functional group tolerance provide access to diverse piperidine derivatives, which were further functionalized to give a versatile set of products.

Stereodivergence in Asymmetric Catalysis.

This Perspective presents an overview of catalytic enantioselective transformations that allow convenient access to all stereoisomers of a given product with multiple stereogenic centers. Particular focus is placed on discussion of the concept of stereodivergent dual catalysis and its application in target-oriented synthesis. The potential of this concept in the development of new transformations as well as implications for achieving stereochemical diversity in library design and diversity-oriented synthesis are also discussed.

Study of Intermediates in Iridium-(Phosphoramidite,Olefin)-Catalyzed Enantioselective Allylic Substitution.

Experimental mechanistic studies of iridium-catalyzed, enantioselective allylic substitution enabled by (phosphoramidite,olefin) ligands are reported. (η2-Allylic alcohol)iridium(I) and (η3-allyl)iridium(III) complexes were synthesized and characterized by NMR spectroscopy as well as X-ray crystallography. The substrate complexes are catalytically and kinetically competent to be intermediates in allylic substitutions of branched, racemic allylic alcohols with various nucleophiles. In addition, we have identified an off-cycle pathway involving reversible binding of molecular oxygen to iridium, which contributes to the air tolerance of the catalyst system.

Cobalt-Catalyzed 1,1-Diboration of Terminal Alkynes: Scope, Mechanism, and Synthetic Applications.

A cobalt-catalyzed method for the 1,1-diboration of terminal alkynes with bis(pinacolato)diboron (B2Pin2) is described. The reaction proceeds efficiently at 23 °C with excellent 1,1-selectivity and broad functional group tolerance. With the unsymmetrical diboron reagent PinB-BDan (Dan = naphthalene-1,8-diaminato), stereoselective 1,1-diboration provided products with two boron substituents that exhibit differential reactivity. One example prepared by diboration of 1-octyne was crystallized, and its stereochemistry established by X-ray crystallography. The utility and versatility of the 1,1-diborylalkene products was demonstrated in a number of synthetic applications, including a concise synthesis of the epilepsy medication tiagabine. In addition, a synthesis of 1,1,1-triborylalkanes was accomplished through cobalt-catalyzed hydroboration of 1,1-diborylalkenes with HBPin. Deuterium-labeling and stoichiometric experiments support a mechanism involving selective insertion of an alkynylboronate to a Co-B bond of a cobalt boryl complex to form a vinylcobalt intermediate. The latter was isolated and characterized by NMR spectroscopy and X-ray crystallography. A competition experiment established that the reaction involves formation of free alkynylboronate and the two boryl substituents are not necessarily derived from the same diboron source.

Bioisosteric Exchange of Csp3 -Chloro and Methyl Substituents: Synthesis and Initial Biological Studies of Atpenin†A5 Analogues.

Asymmetric synthesis and initial biological studies of two analogues of a naturally occurring chlorinated antifungal agent, atpenin A5, are described. These analogues were selected on the basis of Cl→CH3 or H3 C→Cl exchanges in the side-chain of atpenin A5. The interchange of chloro and methyl substituents led to complex II inhibitors with equal IC50 values. This suggests that Cl↔Me bioisosteric exchange can be realized in aliphatic settings.

Stereodivergent Dual Catalytic α-Allylation of Protected α-Amino- and α-Hydroxyacetaldehydes.

Fully stereodivergent dual-catalytic α-allylation of protected α-amino- and α-hydroxyacetaldehydes is achieved through iridium- and amine-catalyzed substitution of racemic allylic alcohols with chiral enamines generated in situ. The operationally simple method furnishes useful aldehyde building blocks in good yields, more than 99% ee, and with d.r. values greater than 20:1 in some cases. Additionally, the γ,δ-unsaturated products can be further functionalized in a stereodivergent fashion with high selectivity and with preservation of stereochemical integrity at the Cα  position.

Stereodivergent total synthesis of Δ9-tetrahydrocannabinols.

All four stereoisomers of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) were synthesized in concise fashion using stereodivergent dual catalysis. Thus, following identical synthetic sequences and applying identical reaction conditions to the same set of starting materials, selective access to the four stereoisomers of THC was achieved in five steps.

Stereodivergent α-allylation of linear aldehydes with dual iridium and amine catalysis.

We describe the fully stereodivergent, dual catalytic α-allylation of linear aldehydes. The reaction proceeds via direct iridium-catalyzed substitution of racemic allylic alcohols with enamines generated in situ. The use of an Ir(P,olefin) complex and a diarylsilyl prolinol ether as catalysts in the presence of dimethylhydrogen phosphate as the promoter proved to be crucial for achieving high enantio- and diastereoselectivity (>99% ee, up to >20:1 dr). The utility of the method is demonstrated in a concise enantioselective synthesis of the antidepressant (-)-paroxetine.

Enantio- and diastereodivergent dual catalysis: α-allylation of branched aldehydes.

An important challenge in asymmetric synthesis is the development of fully stereodivergent strategies to access the full complement of stereoisomers of products bearing multiple stereocenters. In the ideal case, where four products are possible, applying distinct catalysts to the same set of starting materials under identical conditions would in a single step afford any given stereoisomer. Herein, we describe the realization of this concept in a fully stereodivergent dual-catalytic synthesis of γ,δ-unsaturated aldehydes bearing vicinal quaternary/tertiary stereogenic centers. The reaction is enabled by chiral iridium and amine catalysts, which activate the allylic alcohol and aldehyde substrates, respectively. Each catalyst exerts high local stereocontrol irrespective of the other's inherent preference.

Photocatalytic synthesis of allylic trifluoromethyl substituted styrene derivatives in batch and flow.

A cobalt-catalyzed photochemical synthesis of allylic trifluoromethanes from styrene derivatives using 2,2,2-trifluoroethyl iodide is described. The method complements existing approaches, providing an alternative bond construction strategy to access these compounds. The process may be conducted in continuous mode in a novel photochemical flow reactor, resulting in a notable productivity increase.

Iridium-catalyzed enantioselective polyene cyclization.

A highly enantioselective polycyclization method has been developed using the combination of Lewis acid activation with iridium-catalyzed allylic substitution. This strategy relies on direct use of branched, racemic allylic alcohols and furnishes a diverse and unique set of carbo- and heteropolycyclic ring systems in good yields and ≥99% ee.