Enantioselective alkynylation

Keywords Copper acetylides, secondary phosphine-boranes, 1,10-phenanthroline, oxygen atmosphere, toluene, room temperature, oxidative P-alkynylation, enantioselective alkynylphosphine-boranes... 

The addition of lithium acetylides can also be carried out enantioselectively in the presence of 22-24 ]vjucieophiiic addition of the unsubstituted lithium acetylide led to the alkynyl alcohol with lower enantioselectivity than the addition ofsilyl-substituted acetylides. The trimethylsilyl substituted acetylides gave the best results. 

In addition, the most efficient mem-ligand depicted above was successfully applied, in 2006, to the alkynylation of ketones. Thus, Liu et al. showed that this ligand was able to catalyse the enantioselective addition of phenylacetylene to various ketones, using Cu(OTf)2 as the starting base in toluene. The results were excellent and homogeneous not only for substituted aryl alkyl ketones, but also for aliphatic methyl ketones (Scheme 4.6). 

Furthermore, variation of the achiral adduct for formation of alkoxy zinc such as 63 (shown in Scheme 1.23) had a profound influence on the enantioselectivity of the alkynylation reaction the results are summarized in Table 1.9. 

An enantioselective synthesis of 2-alkylidene-l,4-dioxanes is based on the Pd-catalysed heteroannulation of alkynyl carbonates to benzene-1,2-diol in the presence of chiral diphosphine ligands (Scheme 63) . 

Nakamura et al.141 reported a closely related reaction, that is, the enantioselective addition of allylzinc reagent to alkynyl ketones catalyzed by a bisox-azoline catalyst 137. High ee values were obtained in most cases (Scheme 2-55). 

The Lewis acid catalyst 53 is now referred to as the Narasaka catalyst. This catalyst can be generated in situ from the reaction of dichlorodiisopropoxy-titanium and a diol chiral ligand derived from tartaric acid. This compound can also catalyze [2+2] cycloaddition reactions with high enantioselectivity. For example, as depicted in Scheme 5-20, in the reaction of alkenes bearing al-kylthio groups (ketene dithioacetals, alkenyl sulfides, and alkynyl sulfides) with electron-deficient olefins, the corresponding cyclobutane or methylenecyclobu-tene derivatives can be obtained in high enantiomeric excess.18... 

A different approach towards titanium-mediated allene synthesis was used by Hayashi et al. [55], who recently reported rhodium-catalyzed enantioselective 1,6-addition reactions of aryltitanate reagents to 3-alkynyl-2-cycloalkenones 180 (Scheme 2.57). In the presence of chlorotrimethylsilane and (R)-segphos as chiral ligand, alle-nic silyl enol ethers 181 were obtained with good to excellent enantioselectivities and these can be converted further into allenic enol esters or triflates. In contrast to the corresponding copper-mediated 1,6-addition reactions (Section 2.2.2), these transformations probably proceed via alkenylrhodium species (formed by insertion of the C-C triple bond into a rhodium-aryl bond) and subsequent isomerization towards the thermodynamically more stable oxa-jt-allylrhodium intermediates [55],... 

Scheme 2.57 Rhodium-catalyzed enantioselective 1,6-addition of aryltitanium reagents to 3-alkynyl-2-cycloalkenones 180 (ee values referto the corresponding allenic enol pivalates).

Carreira and co-workers developed a highly efficient enantioselective addition of terminal alkynes to aldehydes giving propargyl alcohols by the mediation of zinc tri-flate and N-methylephedrine [17]. This reaction serves as a convenient and powerful synthetic route to a wide variety of enantioenriched allenes via propargyl alcohols. Dieter and Yu applied this alkynylation to the asymmetric synthesis of allenes (Scheme 4.12) [18]. Reaction of phenylacetylene with isobutyraldehyde afforded the propargyl alcohol in 80% yield with 99% ee, which was mesylated to 49 in quantitative yield. Reaction of 49 with the cyanocuprate 50 afforded the desired allene 51 with 83% ee. 

Introduction of a trimethylsilyl group at the terminal alkynyl position of the foregoing chiral mesylates reverses the regiochemistry of the addition reactions (Table 9.35) [50]. In these systems, the allenyl adducts are strongly favored in additions that are highly diastereo- and enantioselective. 

A lnBr3/(R)-BlNOL system was also successfully used in the enantioselective alkynylation of both aliphatic and aromatic aldehydes (Scheme 5.10). This reaction has the following advantages (1) the broad scope of substrates and (2)... 

Enantioselective addition of alkynyl groups to aldehydes and ketones afford enantioen-riched alkynyl alcohols62. Early approaches to the catalytic enantioselective addition of dialkynylzincs and alkynylalkylzincs to aldehydes employed catalytic amounts of chiral amino alcohol63 and amino pyridine64. Stoichiometric enantioselective addition of alkynylzinc halide is reported using the lithium alkoxide of IV-methylephedrine65. 

Chiral Zn(salen) catalyzed enantioselective alkynylation of ketones has been examined by Cozzi82 and by Saito and Katsuki83. Camphorsulfonamide/Cu(OTf)284, Ti(0-i-Pr)4/BINOL85 and Et3Al/cinchona alkaloid86 systems have also been reported. Chiral / -amino alcohols work as chiral catalysts without an additional Lewis acid component87. 

Meanwhile, Carreira and coworkers introduced enantioselective addition of a terminal alkyne to an aldehyde in the presence of Zn(OTf)2, Et3N and IV-methylephedrine 41 (equation 22)88. The amounts of Zn(OTf)2 and Et3N were later reduced to a catalytic amount88b. This catalytic system has been employed by another group89 and the enantioselective alkynylation of a-ketoesters has been examined90. 

As another approach, Carreira and coworkers reported the alkynylation of a nitrone using a terminal alkyne and catalytic amounts of Zn(OTf)2 and amine135. In the presence of a chiral ligand, the reaction proceeds enantioselectively to give hydroxyamine with . 

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