Anti aldehyde formation

In 1998, Wakatsuki et al. reported the first anti-Markonikov hydration of 1-alkynes to aldehydes by an Ru(II)/phosphine catalyst. Heating 1-alkynes in the presence of a catalytic amount of [RuCljlCgHs) (phosphine)] phosphine = PPh2(QF5) or P(3-C6H4S03Na)3 in 2-propanol at 60-100°C leads to predominantly anti-Markovnikov addition of water and yields aldehydes with only a small amount of methyl ketones (Eq. 6.47) [95]. They proposed the attack of water on an intermediate ruthenium vinylidene complex. The C-C bond cleavage or decarbonylation is expected to occur as a side reaction together with the main reaction leading to aldehyde formation. Indeed, olefins with one carbon atom less were always detected in the reaction mixtures (Scheme 6-21). 

The hydrative cyclization involves the formation of a ruthenium vinylidene, an anti-Markovnikov addition of vater, and cyclization ofan acylmetal species onto the alkene. Although the cyclization may occur through a hydroacylation [32] (path A) or Michael addition [33] (path B), the requirement for an electron- vithdra ving substituent on the alkene and lack of aldehyde formation indicate the latter path vay to be the more likely mechanism. Notably, acylruthenium complex under vent no decarbonylation in this instance. 

As the size of the allylmetal reagent increases, 1,2-induction plays an increasingly important role. This is illustrated in Eqs. (11.10) and (11.11), where the ( -silyloxyallyl)stannane 113 gives high levels of stereoselectivity for the Felkin dia-stereomer 141 with the 2,3-anti aldehyde 135, but poor diastereoselectivity for the Felkin diastereomer 143 with the 2,3-syn aldehyde 138 (ratio = 59 32 9) [93]. Note that in this case the Felkin isomer 143 predominates vs the preferential formation of the anti-Felkin isomer in Eq. (11.9), thus highlighting the role of the steric demands of the reagent in determining the overall reaction stereoselectivity. 

The 3(S)-hydroxybutanoate 141 obtained by bakers yeast reduction of ethyl acetoacetate was the starting material providing the required chirality at C37 (Scheme 18). Stereoselective alkylation, hydroxy group protection, and aldehyde formation at C35 gave the anti-product 142. Aldol condensation with vinylbor-... 

The diastereomeric ratios realized with several P-oxy aldehydes in three solvent systems including water are compiled in Table III. Adherence to a chelation-controlled pathway in this series translates into anti adduct formation. Good correlation with the a-alkoxy aldehydes is noted. For the P-hydroxy derivative, the pronounced facial selectivity suggests that structural rigidification once again occurs prior to nucleophilic attack (Scheme 1). 

Addition of n-BuLi to 2 regenerated the enolate. There were two issues in the addition of that enolate to the aldehyde 7 syn vs. anti stereocontrol, and control of the configuration of the newly formed ternary center on the ring relative to the abeady-estahUshed quaternary center. Inclusion of Et,B in the reaction mixture assured anti aldol formation, hut there was... 

Ghosh and co-workers have recently used the indanyl-derived auxiliary 69 (Table 1.9) in titanium enolate condensations with a range of aldehydes [34], Of the four possible diastereomers, only the anti 71 and syn TL were produced (the alternative anti and syn diastereomers were not detected by 1H or 13C NMR). The use of monodentate aliphatic aldehydes resulted in the formation of anti diastereomers... 

Enhanced anti selectivity is observed in reactions of lithiated 4.5-dihydrooxazoles bearing an additional substituent which facilitates the formation of rigid azaenolates by internal chelation of lithium13. Thus, reaction of 2-ethyl-4,5-dihydro-4,4-dimethyloxazole (10) with 2-methylpropanal gives a 56 44 mixture of adducts while (R)-2-ethyl-4,5-dihydro-4-(methoxymethyl)-oxazolc (12) reacts with the same aldehyde to yield a 90 10 mixture of adducts 1313. 

A variety of such ternary catalytic systems has been developed for diastereoselective carbon-carbon bond formations (Table). A Cp-substituted vanadium catalyst is superior to the unsubstituted one,3 whereas a reduced species generated from VOCl3 and a co-reductant is an excellent catalyst for the reductive coupling of aromatic aldehydes.4 A trinuclear complex derived from Cp2TiCl2 and MgBr2 is similarly effective for /-selective pinacol coupling.5 The observed /-selectivity may be explained by minimization of steric effects through anti-orientation of the bulky substituents in the intermediate. 

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

If there is no other interaction, the reaction proceeds through an acyclic TS and steric factors determine the amount of syn versus anti addition. This is the case with BF3, where the tetracoordinate boron-aldehyde adduct does not offer any free coordination sites for formation of a cyclic TS. Stereoselectivity increases with the steric bulk of the silyl enol ether substituent R1.50... 

Scheme 2.7 gives some examples of the control of stereoselectivity by use of additional Lewis acid and related methods. Entry 1 shows the effect of the use of excess TiCl4. Entry 2 demonstrates the ability of (C2H5)2A1C1 to shift the boron enolate toward formation of the 2,3-anti diastereomer. Entries 3 and 4 compare the use of one versus two equivalents of TiCl4 with an oxazoldine-2-thione auxiliary. There is a nearly complete shift of facial selectivity. Entry 5 shows a subsequent application of this methodology. Entries 6 and 7 show the effect of complexation of the aldehyde... 

The TS proposed for these proline-catalyzed reactions is very similar to that for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however, the aldehyde substituent is directed toward the enamine double bond because of the dominant steric effect of the (V-aryl substituent. This leads to formation of syn isomers, whereas the aldol reaction leads to anti isomers. This is the TS found to be the most stable by B3LYP/6-31G computations.199 The proton transfer is essentially complete at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline carboxy group in the most stable TS. 

Scheme 4.9 gives some examples of the use of boranes in syntheses of alcohols, aldehydes, ketones, amines, and halides. Entry 1 demonstrates both the regioselec-tivity and stereospecificity of hydroboration, resulting in the formation of trans-2-methylcyclohexanol. Entry 2 illustrates the facial selectivity, with the borane adding anti to the endo methyl group. 

In the presence of zinc chloride, stereoselective aldol reactions can be carried out. The aldol reaction with the lithium enolate of /-butyl malonate and various a-alkoxy aldehydes gave anti-l,2-diols in high yields, and 2-trityloxypropanal yielded the syn-l,2-diol under the same conditions.633 Stoichiometric amounts of zinc chloride contribute to the formation of aminoni-tropyridines by direct amination of nitropyridines with methoxyamine under basic conditions.634 Zinc chloride can also be used as a radical initiator.635... 

It has been assumed that formation of the cis-fused product 2-771 in the domino reaction of aldehyde 2-769 is due to a strongly favored exo-Z-syn transition state 2-770. The endo-E-syn structure is prohibited by the rigidity of the acetonide existing in 2-769, whereas the proximity of the same moiety to the benzyloxymethyl substituent at the double bond disfavors the exo-E-anti transition state, which would be responsible for the formation of the trans-fused diastereomer. 

Because anti/syn ratios in the product can be correlated to the E(0)/Z(0) ratio of the involved boron enolate mixture,10b initial experiments were aimed at the preparation of highly E(0)-enriched boron enolate. The E(0)/Z(0) ratio increases with the bulk of the alkanethiol moiety, whereas the formation of Z(O) enolates prevails with (S )-aryl thioates. (E/Z = 7 93 for benzenethiol and 5 95 for 2-naphthalene thiol esters). E(O) reagent can be formed almost exclusively by reaction of (5)-3,3-diethyl-3-pentyl propanethioate 64 with the chiral boron triflate. High reactivity toward aldehydes can be retained in spite of the apparent steric demand (Scheme 3-22).43... 

Hayakawa and Shimizu developed a novel C-C bond-forming reaction by epoxi-dation of methoxyallene 145 with m-chloroperbenzoic acid, which provides a meth-oxyallene oxide intermediate capable of adding to aldehydes. This reaction sequence provides 3-hydroxy-2-methoxy ketones 234 (Scheme 8.59) [133]. The best anti/syn selectivity was obtained by application of a 1 1 mixture of Til4 and Ti(OiPr)4. They also observed the formation of a,/3-unsaturated ketones 236 under comparable reaction conditions when 1-silylated methoxyallene 235 was employed as starting material (Scheme 8.60) [134]. 

Reaction of the transient zinc intermediates with various electrophiles yielded the acetylenic substitution products and only minor amounts of allenes (Table 9.49). Reactions with aldehydes were non-selective, affording mixtures of stereo- and regioisomeric adducts. However, prior addition of ZnCl2 resulted in the formation of the homopropargylic alcohol adducts with high preference for the anti adduct, as would be expected for an allenylzinc chloride intermediate (Table 9.50). 

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