Asymmetric alkylation of aldehydes

Pritchett et al.119 found that Ti(OPr )4 did not react with the bis(sulfon-amide) ligand itself, so they postulated that a chiral ligand initially reacted with the diethylzinc and was subsequently transferred to the titanium in the next step. Based on this assumption, they presented an improved procedure for the asymmetric alkylation of aldehyde to overcome the poor solubility of the li-... 

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

The formation of aldehyde enolates is complicated by the disposition of aldehydes to undergo aldol condensation. Therefore, there are very few examples of direct asymmetric alkylations of aldehydes. 

Asymmetric alkylation of aldehydes is possible via enamines or azaenolates of imine derivatives (see Section D. 1.1.1.4.). Alkylation is also possible via enol ethers or esters (see Section 1.1.1.3.1.2.), although the use of these methods for asymmetric synthesis has not yet been explored. 

Asymmetric Alkylation of Aldehydes Catalyzed by Chiral Lewis Bases... 

Asymmetric Alkylation of Aldehydes using Polymer and Dendritic Catalysts... 

A Et2Zn-(5, S)-linked-BINOL (21) complex has been found suitable for chemos-elective enolate formation from a hydroxy ketone in the presence of isomerizable aliphatic iV-diphenylphosphinoylimines.103 The reaction proceeded smoothly and /9- alkyl-yS-amino-a-hydroxy ketones were obtained in good yield and high enantioselectivity (up to 99% ee). A titanium complex derived from 3-(3,5-diphenylphenyl)-BINOL (22) has exhibited an enhanced catalytic activity in the asymmetric alkylation of aldehydes, allowing the reduction of the catalyst amount to less than 1 mol% without deterioration in enantioselectivity.104... 

The asymmetric alkylation of aldehydes by dialkylzinc reagents is one of the most intensively studied catalytic reactions [60-62]. Following the initial discoveries of Oguni and colleagues, including the recognition that a single... 

Asymmetric alkylation of aldehydes. Aldimines derived from the S-( - )-amine and propionaldehyde undergo alkylation (LD A, 1 equiv. of MgBt2) in a stereoselective manner (equation 1). 

Nonracemic Ti-BINOLate (BINOL = l,l -bi-2-naplilli()l) and Ti-TADDOLate (TADDOL = a,a,a, a -tetraaryl-2,2-dimethyl-l,3-dioxolan-4,5-dimethanol) complexes are also effechve chiral catalysts for the asymmetric alkylation of aldehydes [9-11]. Seebach developed polystyrene beads with dendritically embedded BINOL [9] or TADDOL derivatives 11 [10, 11]. As the chiral ligand is located in the core of the dendritic polymer, less steric congeshon around the catalyhc center was achieved after the treatment with Ti(OiPr)4. This polymer-supported TiTADDOLate 14 was then used for the ZnEt2 addition to benzaldehyde. Chiral 1-phenylpropanol was obtained in quantitahve yield with 96% ee (Scheme 3.3), while the polymeric catalyst could be recycled many times. 

Diorganozinc reagents have a monopoly as alkylation reagents in catalytic asymmetric alkylations of aldehydes. But a few catalytic asymmetric alkylations were reported by the use of alkynylborane and trialkylaluminum species. 

The ultimate goal of using an external, chiral Hgand in a chemical reaction is the potential for a catalytic, asymmetric synthetic transformation, [ 1 a, lb, 1 c]. Thus, the substoichiometric, asymmetric alkylation of aldehydes with organozinc reagents represents a major accompHshment [la, 15a, 15b, 15c, 15d], whereas a similar catalytic process for azomethine derivatives has only recently been achieved. 

Scheme 3.21. Asymmetric alkylations of aldehydes and ketones with SAMP hydrazones.

From a meticulous analysis, Roush and VanNieuwenhze developed novel sugar-based chiral reagent 10 for the asymmetric alkylation of aldehydes. Catalyst 10 was designed in the expectation that significant diaster-eofacial bias would be exerted as a consequence of the conformational... 

Alkylation of lithiated hydrazones forms the basis of an efficient method for the asymmetric alkylation of aldehydes and ketones, using the optically active hydrazines (5)-l-amino-2-(methoxymethyl)pyrroUdine (SAMP) 59 and its enantiomer (RAMP) as chiral auxiliaries. Deprotonation of the optically active hydra-zones, alkylation and removal of the chiral auxiliary under mild conditions (ozonol-ysis or acid hydrolysis of the A-methyl salt) gives the alkylated aldehyde or ketone with, generally, greater than 95% optical purity. This procedure has been exploited in the asymmetric synthesis of several natural products. Thus, (S)-4-methyl-3-heptanone, the principal alarm pheromone of the leaf-cutting ant Am texana, was prepared from 3-pentanone in very high optical purity as shown in Scheme 1.74. 

An alternate approach to the asymmetric alkylation of aldehydes with dialkylzinc compounds uses chiral nonracemic titanium-based Lewis add catalysts. This has been primarily achieved using complexes prepared from stoichiometric amounts of Ti(0 Pr)4 and enantiomerically enriched ligands. A variety of BINOL deriva-... 

The utilization of organogallium as an alkylation reagent for asymmetric alkylation of aldehydes has been realized by using titanium complex as a chiral Lewis acid catalyst. The titanium catalyst was obtained by the reaction of TiCU with a salan [N,N-bis(o-hydroxybenzyl)-l,2-diaminoethane] type ligand. Moderate to good chemical yields were obtained with up to 84% ee [53] (Scheme 14.8). 

The hydrazine SAMP, derived from (S)-proline, and its enantiomer RAMP were developed by EndersO ] for the asymmetric alkylation of aldehydes and ketones, and are commercially available, though expensive. The chiral auxiliary may be removed either by quatemisation with methyl iodide followed by hydrolysis, or by ozonolysis. 

Nicewicz DA, MacMillan DWC (2008) Merging photraedox catalysis with organocatalysis the direct asymmetric alkylation of aldehydes. Science 322 77-80... 

SCHEME 2.25 Ender s protocol for the asymmetric [alkylation of aldehydes and ketones]. 

In contrast with carboxyl-derived enolates, few general, highly stereoselective methods for the asymmetric alkylation of aldehyde and ketone enolates are available [15, 20]. Some of the key problems associated with these are widely appreciated. The aldehyde and ketone counterparts are more weakly nucleophilic than carboxamide-derived enolates. In addition, the ease with which the products undergo epimerization under relatively mild acidic or alkaline conditions can provide a practical limit to the isolation of pure adducts. 

---