Iridium-Catalyzed Regio- and Enantioselective Alkylation of Unsaturated Carbonyls

Abstract

This thesis, entitled “Iridium-Catalyzed Regio- and Enantioselective Alkylation of Unsaturated Carbonyls” primarily deals with the development of various catalytic regio-, diastereo- and enantioselective allylic and allenylic reactions of various cyclic and acyclic unsaturated carbonyls. In Chapter 1, a systematic development of Ir-catalyzed AAS reaction which emerged as an extremely powerful and versatile method for synthesizing enantioenriched complex molecular architectures from easily available achiral or racemic starting materials, is depicted. In Chapter 2, the first catalytic enantioselective α-allylic alkylation of deconjugated butyrolactams is demonstrated. Compared to the burgeoning list of achiral nucleophiles in Ir-catalyzed asymmetric allylic alkylation reactions, prochiral nucleophiles are considerably less investigated. Our developed reaction is catalyzed by Ir(I)/(phosphoramidite,olefin) complex and utilizes readily accessible branched allylic alcohols as the allylic electrophile in combination with sub-stoichiometric amount of Zn(OTf)2 as the Lewis acid promoter. The resulting α-allyl substituted deconjugated butyrolactams, bearing two vicinal tertiary stereogenic centers, were obtained in moderate to good yield and diastereoselectivity with excellent enantioselectivity. Allyl transposition through Cope rearrangement was shown to proceed stereospecifically and hence the enantiopurity of the resulting γ-allyl substituted conjugated butyrolactam varies with the diastereopurity of the starting material. In Chapter 3, the first asymmetric β C(sp2)–H allylic alkylation of kojic acid and structurally related α-hydroxy α,β unsaturated carbonyl compounds is depicted. The β-position of α,β-unsaturated carbonyls is intrinsically electrophilic. Consequently, β C(sp2)–H allylic alkylation of α,β-unsaturated carbonyls using an electrophilic allyl fragment is challenging due to the inherent polarity mismatch and therefore remains elusive. Our hydroxy-directed allylic alkylation reaction is catalyzed by an in situ generated Ir(I)/(P,olefin) complex and employs Fe(OTf)2 as the Lewis acid co-catalyst to activate easily accessible racemic branched allylic alcohols. The ensuing β-allyl 3-hydroxypyranone derivatives, even equipped with pharmaceutically important structural motifs, are generally obtained in good to excellent yield with outstanding enantioselectivity. The α hydroxy group in the allylic alkylation product is transformed into a phenyl group and the overall process represents the first formal β-C(sp2)–H allylic alkylation of α,β-unsaturated carbonyl compounds. In Chapter 4: Part A, the first catalytic enantioselective (bis)vinylogous allenylic substitution reaction using extended silyl enol ethers as the nucleophile is presented. Remote functionalization (γ- or ε-) of unsaturated carbonyls represents a highly sought-after transformation in organic synthesis. Among various strategies, the use of (bis)vinylogous nucleophiles emerged as a prominent one, especially for unsaturated carbonyl compounds. However, in contrast to the extensively investigated enol silanes, the utilization of their extended counterparts, particularly as bisvinylogous nucleophiles, in enantioselective catalysis has been scarce. With racemic allenylic alcohols as alkylating reagents, these reactions are cooperatively catalyzed by an Ir(I)/(P,olefin) complex and Lewis acidic La(OTf)3, and proceed in an enantioconvergent fashion. Depending on the choice of nucleophile (i.e., silyl dienol and trienol ether), various allenylic unsaturated ketones are generally obtained in a regio- and diastereoselective manner in moderate to high yield with good to excellent enantioselectivity. This strategy has also been extended for bisvinylogous allylic substitution reactions. Catalyzed by a cooperative combination of an Ir(I)/(P,olefin) complex and Zn(OTf)2 as the Lewis acid promoter, these reactions exhibit remarkable regio- and enantioselectivity across most substrates, while utilizing branched allylic alcohols as the allylic electrophile. The results of this investigation are detailed in Chapter 4: Part B. In Chapter 5, the first catalytic enantioselective alkynylogous allylic alkylation for the construction of chiral tri- and tetrasubstituted skipped enallenes bearing two vicinal stereogenic elements (central and axial chirality) is unveiled using alkynyl silyl enol ethers as the nucleophile. Catalyzed by a cooperative combination of an Ir(I)/(P,olefin) complex and Zn(OTf)2, these reactions exhibit remarkable regio-, diastereo- and enantioselectivity across most substrates while utilizing easily accessible racemic branched allylic alcohols as the electrophile. This protocol endows tri- and tetrasubstituted skipped enallenes, bearing δ-stereocenters in moderate to high yield with good to excellent enantioselectivity (up to >99.5:0.5 er). The products are densely functionalized, and the versatility of functional groups was demonstrated through several synthetic elaborations, which resulted in the synthesis of useful building blocks such as a highly substituted enantioenriched furan derivative.