Applications of Iridium-Catalyzed Asymmetric Allylic Substitution Reactions in Target-Oriented Synthesis

Abstract

Metal catalyzed allylic substitution is a cornerstone of organometallic and synthetic chemistry. Enantioselective versions have been developed with catalysts derived from transition metals, most notably molybdenum, nickel, ruthenium, rhodium, iridium, palladium, and copper. The palladium- and the iridium-catalyzed versions have turned out to be particularly versatile in organic synthesis because of the very broad scope of the nucleophile and great functional group compatibility. Assets of the iridium-catalyzed reaction are the formation of branched, chiral products from simple monosubstituted allylic substrates, high degrees of regio- and enantioselectivity, and use of modular, readily available chiral ligands. The possibility to use carbon, nitrogen, oxygen, and sulfur compounds as well as fluoride as nucleophiles allows a wide range of chiral building blocks to be prepared. Our Account begins with the presentation of fundamental reaction schemes and chiral ligands. We will focus our discussion on reactions promoted by phosphoramidite ligands, though numerous chiral ligands have been employed. The subsequent section presents a brief overview of reaction mechanism and experimental conditions. Two versions of the iridium-catalyzed allylic substitution have emerged. In type 1 reactions (introduced in 1997), linear allylic esters are commonly used as substrates under basic reaction conditions. In type 2 reactions (introduced in 2007), environmentally friendly branched allylic alcohols can be reacted under acidic conditions; occasionally, derivatives of allylic alcohols have also been applied. A unique feature of the type 2 reactions is that highly electrophilic allylic intermediates can be brought to reaction with weakly activated alkenes. The subsequent text is ordered according to the strategies followed to transform allylic substitution products to desired targets, most of which are natural products or drugs. Syntheses starting with an intermolecular allylic substitution are discussed first. Some fairly complex targets, for example, the potent nitric oxide inhibitor (-)-nyasol and the drug (-)-protrifenbute, have been synthesized via less than five steps from simple starting materials. Most targets discussed are cyclic compounds. Intermolecular allylic substitution with subsequent ring closing metathesis is a powerful strategy for their synthesis. Highlights are stereodivergent syntheses of Δ-tetrahydrocannabinols (THC), wherein iridium- and organocatalysis are combined (dual catalysis). The combination of allylic alkylation with a Diels-Alder reaction was utilized to synthesize the ketide apiosporic acid and the drug fesoterodine (Toviaz). Sequential allylic amination, hydroboration and Suzuki-Miyaura coupling generates enones suitable for conjugate addition reactions; this strategy was employed in syntheses of a variety of alkaloids, for example, the poison frog alkaloid (+)-cis-195A (pumiliotoxin C). Intramolecular substitutions offer interesting possibilities to build up stereochemical complexity via short sy...

Iridium‐Catalyzed Asymmetric Allylic Aromatization Reaction

“…[7e, 11] Gratifyingly,when Yb(OTf) 3 , In(OTf) 3 ,a nd Fe(OTf) 2 were tested, the reactions worked better,a ffording 3a in 58-70 %y ields.N ext, as eries of solvents were evaluated with Fe(OTf) 2 as the promoter, and DCE was identified as the optimal choice (entries [6][7][8][9]. With an Ir complex derived from [Ir(cod)Cl] 2 (3 mol %) and the Carreira (P,o lefin) ligand (S)-L1 (12 mol %) as the catalyst, and diphenylsulfonimide as the promoter for the electrophile,the reaction proceeded in 1,2-dichloroethane (DCE) and afforded the desired product 3a in 30 %yield (entry 1).…”

“…[7] Notably,i n2 014, the group of Carreira reported highly enantioselective allylic substitution reactions of branch cinnamyl alcohols with 1,1-disubstituted olefins using achiral Ir-(P,olefin) complex. [7] Notably,i n2 014, the group of Carreira reported highly enantioselective allylic substitution reactions of branch cinnamyl alcohols with 1,1-disubstituted olefins using achiral Ir-(P,olefin) complex.…”

Regio‐ and Enantioselective Iridium‐Catalyzed N‐Allylation of Indoles and Related Azoles with Racemic Branched Alkyl‐Substituted Allylic Acetates

“…Iridium-catalyzed allylic amination has emerged as an important method for enantioselective C À N bond formation. [1][2][3][4][5][6][7][8][9] Pursuant to the pioneering work of Takeuchi, [1,2] studies from the laboratories of Helmchen, [3,4] Hartwig, [5,6] Carreira, [7] and You [8,9] have shown that chiral phosphoramidite-modified iridium complexes are especially effective in this regard (Figure 1). Like the parent palladium-catalyzed Tsuji-Trost reactions, [10] the iridium-phosphoramidite-catalyzed allylic alkylations occur via cationic p-allylmetal intermediates.Recently,wefound that p-allyliridium-C,O-benzoates,w hich are wellknown to promote nucleophilic allylation of carbonyl compounds, [11,12] are also effective catalysts for highly regio-and enantioselective electrophilic allylation of amines.…”

Regio‐ and Enantioselective Iridium‐Catalyzed N‐Allylation of Indoles and Related Azoles with Racemic Branched Alkyl‐Substituted Allylic Acetates

“…[1][2][3][4][5][6][7][8][9] Pursuant to the pioneering work of Takeuchi, [1,2] studies from the laboratories of Helmchen, [3,4] Hartwig, [5,6] Carreira, [7] and You [8,9] have shown that chiral phosphoramidite-modified iridium complexes are especially effective in this regard ( Figure 1). [1][2][3][4][5][6][7][8][9] Pursuant to the pioneering work of Takeuchi, [1,2] studies from the laboratories of Helmchen, [3,4] Hartwig, [5,6] Carreira, [7] and You [8,9] have shown that chiral phosphoramidite-modified iridium complexes are especially effective in this regard ( Figure 1).…”