Small Change, Big Impact: Reversal of Diastereoselection in Cuprate Conjugate Additions to α,β-Unsaturated Lactams and Identification of a Competing Mechanism

A seemingly minor change to a reactant is shown to cause a change in reaction mechanisms. Conjugate addition of organocopper reagents to bicyclic α,β-unsaturated lactams derived from pyroglutaminol is determined by the nature of the aminal group. Aminals derived from aldehydes give anti addition; those from ketones give syn addition. Divergence in diastereoselection occurs because the substrates react by different mechanisms, ultimately due to a small but significant difference in pyramidalization of the aminal nitrogen

Lithium Enolates Derived from Pyroglutaminol: Mechanism and Stereoselectivity of an Azaaldol Addition

A lithium enolate derived from an acetonide-protected pyroglutaminol undergoes a highly selective azaaldol addition with (<i>E</i>)-<i>N</i>-phenyl-1-[2-(trifluoromethyl)­phenyl]­methanimine. The selectivity is sensitive to tetrahydrofuran (THF) concentration, temperature, and the presence of excess lithium diisopropylamide base. Rate studies show that the observable tetrasolvated dimeric enolate undergoes reversible deaggregation, with the reaction proceeding via a disolvated-monomer-based transition structure. Limited stereochemical erosion stems from the intervention of a trisolvated-monomer-based pathway, which is suppressed at low THF concentrations and elevated temperature. Endofacial selectivity observed with excess lithium diisopropylamide (LDA) is traced to an intermediate dianion formed by subsequent lithiation of the monomeric azaaldol adduct, which is characterized as both a dilithio form and a trilithio dianion–LDA mixed aggregate

Synthesis of Chiral Azabicycles from Pyroglutaminols

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular S_N2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery

Aminocarbonylation of Aryl Tosylates to Carboxamides

The palladium - catalyzed aminocarbonylation of aryl tosylates with amines is reported. Suitable conditions were identified by high throughput reaction screening and then further optimized. The substrate scope of the reaction with respect to the aryl tosylate component and the amine component are reported. Competitive aminolysis of the aryl tosylates to afford the amine toluenesulfonamides and the phenol was not observed

Synthesis of Chiral Azabicycles from Pyroglutaminols

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular S_N2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery

Reversal of Diastereoselection in the Conjugate Addition of Cuprates to Unsaturated Lactams

We report that the stereochemical outcome of the conjugate addition of organocopper reagents to bicyclic α,β-unsaturated lactams derived from pyroglutaminol is determined by the nature of the aminal group. Bicyclic α,β-unsaturated lactams in which the aminal is derived from a ketone have been found to afford products of <i>syn</i> conjugate addition. By contrast, bicyclic α,β-unsaturated lactams in which the aminal is derived from an aldehyde afford products of <i>anti</i> conjugate addition. These remarkably different results obtained from very similar starting materials are unexpected

Synthesis of Chiral Azabicycles from Pyroglutaminols

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular S_N2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery

Synthesis of Chiral Azabicycles from Pyroglutaminols

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular S_N2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery

Lithium Enolates Derived from Pyroglutaminol: Aggregation, Solvation, and Atropisomerism

Lithium enolates derived from protected pyroglutaminols were characterized by using ⁶Li, ¹³C, and ¹⁹F NMR spectroscopies in conjunction with the method of continuous variations. Mixtures of tetrasolvated dimers and tetrasolvated tetramers in different proportions depend on the steric demands of the hemiaminal protecting group, tetrahydrofuran concentration, and the presence or absence of an α-fluoro moiety. The high steric demands of the substituted bicyclo[3.3.0] ring system promote dimers to an unusual extent and allow solvents and atropisomers in cubic tetramers to be observed in the slow-exchange limit. Pyridine used as a ⁶Li chemical shift reagent proved useful in assigning solvation numbers

Synthesis of a <i>cis</i> 2,5-Disubstituted Morpholine by De-epimerization: Application to the Multigram Scale Synthesis of a Mineralocorticoid Antagonist

A convergent route to multigram quantities of a mineralocorticoid antagonist <b>3</b> is described. Starting from (<i>R</i>)-phenylglycinol, the synthesis of <i>cis</i> 2,5-morpholine <b>2</b> is accomplished utilizing a de-epimerization to install the second stereogenic center. The multigram synthesis of <b>3</b> was completed through a sequence of an S_NAr reaction, Dakin oxidation, alkylation, and cyclization to provide a crystalline solid