N-Heterocyclic Carbene–Copper-Catalyzed Group-, Site-, and Enantioselective Allylic Substitution with a Readily Accessible Propargyl(pinacolato)boron Reagent: Utility in Stereoselective Synthesis and Mechanistic Attributes

Abstract

The first instances of catalytic allylic substitution reactions involving a propargylic nucleophilic component are presented; reactions are facilitated by 5.0 mol % of a catalyst derived from a chiral N-heterocyclic carbene (NHC) and a copper chloride salt. A silyl-containing propargylic organoboron compound, easily prepared in multigram quantities, serves as the reagent. Aryl- and heteroaryl-substituted disubstituted alkenes within allylic phosphates and those with an alkyl or a silyl group can be used. Functional groups typically sensitive to hard nucleophilic reagents are tolerated, particularly in the additions to disubstituted alkenes. Reactions may be performed on the corresponding trisubstituted alkenes, affording quaternary carbon stereogenic centers. Incorporation of the propargylic group is generally favored (vs allenyl addition; 89:11 to >98:2 selectivity); 1,5-enynes can be isolated in 75-90% yield, 87:13 to >98:2 SN2'/SN2 (branched/linear) selectivity and 83:17-99:1 enantiomeric ratio. Utility is showcased by conversion of the alkynyl group to other useful functional units (e.g., homoallenyl and Z-homoalkenyl iodide), direct access to which by other enantioselective protocols would otherwise entail longer routes. Application to stereoselective synthesis of the acyclic portion of antifungal agent plakinic acid A, containing two remotely positioned stereogenic centers, by sequential use of two different NHC-Cu-catalyzed enantioselective allylic substitution (EAS) reactions further highlights utility. Mechanistic investigations (density functional theory calculations and deuterium labeling) point to a bridging function for an alkali metal cation connecting the sulfonate anion and a substrate's phosphate group to form the branched propargyl addition products as the dominant isomers via Cu(III) π-allyl intermediate complexes.

Catalytic diastereo- and enantioselective additions of versatile allyl groups to N–H ketimines

“…3a). The computational errors for modeling a charged species notwithstanding, we propose a similar steric and electronic environment as suggested formerly vis-à-vis enantioselective allylic substitutions effected by the same catalyst class 27 . The sulfonate group is probably situated in the rear ( I – II ); this would allow for the large 3,5-bis-(2,4,6-( i -Pr) 3 -phenyl)phenyl moiety to obstruct the right side of the complex, and causes the sizeable B(pin) moiety to be situated in the less occupied left/front quadrant in I (Fig.…”

“…These investigations provide the first step towards development of a series of catalytic enantioselective reactions involving N-H ketimines and other types of readily available and versatile carbon-based nucleophiles, protocols that render a range of chiral drug candidates with one or more α-tertiary amine moieties much more accessible. Finally, this study further expands the utility of sulfonate-containing chiral NHC ligands, previously utilized in catalytic enantioselective conjugate additions 48 , allylic substitutions 49 as well as copper-boryl additions to alkenes 50 and allenes 51 and copper–hydride additions to alkenes 52 , to include allyl additions to ketimines.…”

“…Enantioselectivity was considerably higher compared to the closely related N -mesityl-substituted variant ( 7a ; see below for mechanistic analysis). Additionally, while sulfonate-containing NHC–Cu catalysts have been used for enantioselective allylic substitutions 26,27 and conjugate additions 28,29,30 , none emerged as optimal for a 1,2-addition.…”

Catalytic SN2′‐ and Enantioselective Allylic Substitution with a Diborylmethane Reagent and Application in Synthesis

“…[4–6,7] We first found that EAS with only CuCl (no ligand) proceeds to 45% conversion, affording the linear isomer ( 4a ) exclusively (Table 1, entry 1). A chiral ligand would have to bind efficiently to the transition metal and/or the derived Cu complex to promote formation considerably faster than a free Cu complex.…”

An Iridium(I) N‐Heterocyclic Carbene Complex Catalyzes Asymmetric Intramolecular Allylic Amination Reactions

“…[14] As part of our ongoing program towards iridium-catalyzed allylic substitution reactions, [15] we envisaged that chiral NHCs would be promising ligands for iridium and the corresponding Ir/NHC complexes might be efficient catalysts in allylic substitution reactions. Herein, we report the first example of using an iridium(I) N-heterocyclic carbene complex as the catalyst for the highly enantioselective intramolecular allylic amination reaction of indoles and pyrroles.…”