Aldehydes asymmetric alkynylation

Zinc catalysts have shown a major increase in their possible applications. Some examples of catalysis using halide complexes, including immobilized catalytic systems, have been discussed in Section 6.8.8. Some areas such as asymmetric alkynylation of aldehydes have been recently reviewed.930... 

Other Systems In contrast to the highly successful alkynylation of imines, copper catalysts failed in the asymmetric alkynylation of aldehydes. On the other hand, the combination of various Uewis acids and chiral amines were studied extensively to... 

Scheme 5.6. Asymmetric alkynylation of iminiums generated from aldehydes and amines.

Zinc-catalysed asymmetric alkynylation of a -unsaturated aldehydes giving high yields and ees has been reported.192 A dinuclear complex is proposed. ... 

Asymmetric alkynyl additions to aldehydes by prior, separate generation of the alkynylides (e.g. dialkylzinc reagents) have recently been reviewed and are a topic of current research [10], They will not be covered in the context of this chapter. Instead, in line with the theme of this book, this chapter will focus on the metala-tion of terminal alkynes by activation of the terminal C-H and the use of the corresponding metal acetylides in aldehyde and ketone addition reactions. 

Trost has exploited the asymmetric alkynylation of an a-unbranched acetaldehyde in an elegant synthesis of the core of the mitomycin analog FR900482 [22]. This is a remarkable example wherein an enolizable aldehyde participates in the addition reaction. It has been suggested that this is critical for the success of these substrates, because the aldehyde undergoes reversible enolization. (Eq. 18). 

The use of polymer-supported oxazolidine derived from (17 ,2iS)-c/s-l-amino-2-indanol for the asymmetric alkynylation of aldehyde has been reported [155]. Three chiral supported-oxazolidines 244 were prepared in two steps from Merrifield resin (2.5 mmol Cl/g) (Scheme 98). 

A simpler preparation of catalytic chiral indium complex based on BINOL ligand were reported by Shibasaki et al. in their asymmetric alkynylation of aldehydes [317]. InBrs was the Lewis acid of choice and the authors proposed a dual role for this bifunctional catalyst, both in activating the alkyne triple bond and the carbonyl moiety. These characteristics, and the inclusion of the chiral BINOL ligand into the In(III) center, had allowed the asymmetric addition of terminal alkynes to aldehydes with just the addition of a mild amine base (Figure 8.150). Positive nonlinear effect was observed with BINOL of varying optical enrichment, and thus the active catalytic species was expected by the authors to be most likely bimetallic in nature. 

SCHEME 12.29. The first example of a chromium-catalyzed asymmetric alkynylation of aldehydes using 1-iodo- and 1-bromoalkynes in the presence of complex 28. 

Boukouvalas and co-workers employed an intramolecular oxycarbonylation of benzyl alcohol 89 in the asymmetric synthesis of (—)-panacene, tetrahydrofuroben-zofuran derivative, which holds the prominent position of being the archetypical member of a family of marine bro-moallenes. ° The synthesis of the panacene building block 89 (Scheme 15.22) starts from the aldehyde 87, which is accessed from commercially available 2-methoxy-6-metyl-benzoic acid. An asymmetric alkynylation of 87 followed by reduction of the triple bond with hydrogen over Lindlar... 

Table 1.6 Asymmetric Diels-Alder reactions of alkynyl aldehydes catalyzed by 8 [lOc]...

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. 

Asymmetric addition to aldehydes. In the presence of 1, lithium trimethylsilyl-acctylide reacts with aliphatic aldehydes to form predominately (R)-alkynyl alcohols. One of these products was converted into optically active 5-octyl-2(5//)-luranonc (2) as shown in equation (I).1... 

When the allylic alcohol needed for asymmetric epoxidation is unavailable from a commercial source, reasonably general synthetic routes have been developed to allylic alcohols of several different substitution patterns. Good methods are available for the preparation of 3-substituted allylic alcohols, whereas synthesis of 2-substituted allylic alcohols is more problematic. The substrates for kinetic resolution, 1-substituted allylic alcohols, frequently can be derived by addition of alkenyl or alkynyl organometallic reagents to aldehydes followed by modification of the resulting product as required. 

We found that chiral 5-pyrimidyl alkanol, 3-quinolyl alkanol and 5-carbamoyl-3-pyridyl alkanol are highly enantioselective asymmetric autocatalysts for the addition of z-Pr2Zn to the corresponding aldehydes, respectively. Among these, 2-alkynyl-5-pyrimidyl alkanol is a highly efficient asymmetric auto-... 

Furthermore, optically active alkynyl alcohols, useful intermediates for the synthesis of several optically active natural products, were obtained by the asymmetric addition of lithium acetylides to aldehyde in the presence of chiral ligand 2a Enhanced enantioselectivity in this reaction depends apparently on the substituent group in the acetylene moiety. As shown in Table 8, use of trialkylsilylacetylides gave the best results Various optically active ethynyl alcohols were obtained by the reaction of lithium trimethylsilylacetylide with aliphatic aldehydes, as summarized in Table 9... 

The enantioselective alkynylation of ketones catalyzed by Zn(salen) complexes has been reported [24]. Polymeric salen ligand 30 was prepared with a polycondensation reaction and subsequently used as a polymeric chiral ligand of Zn. The polymeric Zn(salen) complex (prepared by 30) was then used as a catalyst of asymmetric addihon of phenylacetylene to aldehyde in the presence of 2 equivalents of Et/Zri. Subsequent asymmetric alkynylahon of 31 gave 33 in 96% yield and 72% ee (Scheme 3.9) [25]. 

Practically perfect asymmetric autocatalysts of the (2-alkynyl-5-pyrimidyl)alkanol series have been identified. A /-butylalkynyl residue fulfills the role of proper bulkiness and moderate electron-withdrawing power. Quartz also induces enantioselective addition of (-Pr2Zn to this heterocyclic aldehyde, by virtue of its morphological chirality and acidity, which enable differentiation of the enantiofaces of the aldehyde upon coordination with the oxygen and nitrogen atoms. Chiral sodium chlorate crystals have the same effect. ... 

Alkynylzinc reagents. The direct alkynylation of aldehydes is subject to asymmetric induction in the presence of a chiral base such as (-l-)-Af-methylephedrine. Addition to the C=N bond of A-tosylimines and nitrones by this procedure is also successful. ... 

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