Enantioselective Nazarov Cyclizations Catalyzed by an Axial Chiral C6 F5 -Substituted Boron Lewis Acid.

A chiral variant of B(C6 F5 )3 with a 3,3'-disubstituted binaphthyl backbone is shown to catalyze Nazarov cyclizations with high levels of enantio- and diastereocontrol. The parent B(C6 F5 )3 also promotes these ring closures efficiently. This electrocyclization is another example of the still small family of C-C bond formations mediated by B(C6 F5 )3 as the catalyst.

Direct Observation of Intermediates Involved in the Interruption of the Bischler-Napieralski Reaction.

The first mechanistic investigation of electrophilic amide activation of α,α-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, (1)H, (13)C, and (19)F NMR in our interrupted Bischler-Napieralski-based synthetic strategy to the aspidosperma alkaloids, including a complex tetracyclic diiminium ion, is discussed. The reactivity of a wide range of pyridines with trifluoromethanesulfonic anhydride was systematically examined, and characteristic IR absorption bands for the corresponding N-trifluoromethanesulfonylated pyridinium trifluoromethanesulfonates were assigned. The reversible formation of diiminium ether intermediates was studied, providing insight into divergent mechanistic pathways as a function of the steric environment of the amide substrate and stoichiometry of reagents. Importantly, when considering base additives during electrophilic amide activation, more hindered α-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation.

Concise and enantioselective total synthesis of (-)-mehranine, (-)-methylenebismehranine, and related Aspidosperma alkaloids.

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (-)-mehranine and (+)-(6S,7S)-dihydroxy-N-methylaspidospermidine. A late-stage dimerization of (-)-mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (-)-methylenebismehranine.

Experimental analysis of the catalytic cycle of the borane-promoted imine reduction with hydrosilanes: spectroscopic detection of unexpected intermediates and a refined mechanism.

The discovery of intermediates that had not been seen before in imine reduction involving borane-mediated Si-H bond activation provided new insight into the mechanism, eventually leading to a refined catalytic cycle that also bears relevance to asymmetric variants. The catalysis proceeds through an ion pair composed of a silyliminium ion and a borohydride that subsequently reacts to yield an N-silylated amine and the borane catalyst. The latter step is enantioselectivity-determining when using a chiral borane. It was now found that there are additional intermediates that profoundly influence the outcome of such enantioselective transformations. Significant amounts of the corresponding free amine and N-silylated enamine are present in equimolar ratio during the catalysis. The free amine emerges from a borohydride reduction of an iminium ion (protonated imine) that is, in turn, generated in the enamine formation step. The unexpected alternative pathway adds another enantioselectivity-determining hydride transfer to reactions employing chiral boranes. The experiments were done with an axially chiral borane that was introduced by us a few years ago, and the refined mechanistic picture helps to understand previously observed inconsistencies in the level of enantioinduction in reductions catalyzed by this borane. Our findings are general because the archetypical electron-deficient borane B(C6F5)3 shows the same reaction pattern. This must have been overlooked in the past because B(C6F5)3 is substantially more reactive than our chiral borane with just one C6F5 group. Reactions with B(C6F5)3 must be performed at low catalyst loading to allow for detection of these fundamental intermediates by NMR spectroscopy.

Illuminating the mechanism of the borane-catalyzed hydrosilylation of imines with both an axially chiral borane and silane.

The reduction of C=O groups with silanes catalyzed by electron-deficient boranes follows a counterintuitive mechanism in which the Si-H bond is activated by the boron Lewis acid prior to nucleophilic attack of the carbonyl oxygen atom at the silicon atom. The borohydride thus formed is the actual reductant. These steps were elucidated by using a silicon-stereogenic silane, but applying the same technique to the related reduction of C=N groups was inconclusive due to racemization of the silicon atom. The present investigation now proves by the deliberate combination of our axially chiral borane catalyst and axially chiral silane reagents (in both enantiomeric forms) that the mechanisms of these hydrosilylations are essentially identical. Unmistakable stereochemical outcomes for the borane/silane pairs show that both participate in the enantioselectivity-determining hydride-transfer step. These experiments became possible after the discovery that our axially chiral C(6)F(5)-substituted borane induces appreciable levels of enantioinduction in the imine hydrosilylation.

An axially chiral, electron-deficient borane: synthesis, coordination chemistry, Lewis acidity, and reactivity.

An axially chiral dihydroborepine with a binaphthyl backbone and a C(6)F(5) substituent at the boron atom was prepared by transmetalation from the corresponding tin precursor. This novel motif was structurally characterized by X-ray diffraction analysis as its THF and its PhCN Lewis acid/base complex. (1)H NMR measurements at variable temperatures of the former adduct revealed a remarkable dynamic behavior in solution. Several more Lewis pairs with oxygen, nitrogen, carbon, and phosphorus σ-donors were synthesized and analyzed by multinuclear NMR spectroscopy. The determination of the borane's Lewis acidity with the Gutmann-Beckett method attests its substantial Lewis acidity [85% with Et(3) PO as well as 74% with Ph(3) PO relative to the parent B(C(6)F(5))(3)]. Representative examples of Si-H bond activation (carbonyl reduction and dehydrogenative Si-O coupling) are included, demonstrating the chemical stability and the synthetic potential of the new chiral boron-based Lewis acid.

Asymmetric Si-O coupling of alcohols.

Stereoselective Si-O couplings are auspicious processes for the synthesis of both chiral alcohols and chiral silanes. Attractive facets of this theme are currently enjoying a renaissance, and the several significant contributions are summarised in this Emerging Area.