Alcohols MacMillan catalyst

The direct nucleophilic substitution of alcohols represents a valuable methodology for the preparation of a variety of derivatives, since water is the only byproduct of the transformation. In this context, Cozzi et al. have reported very recently an organocatalytic alkylation of aldehydes proceeding through an SNl-type reaction of alcohols. This very simple method to effect the enantioselective direct alkylation of a wide range of aldehydes with unfunctionalised alcohols was catalysed by MacMillan catalyst and provided good to high yields and enantioselectivities of up to 90% ee, as shown in Scheme 5.5. 

Notably, proline was unique for this transformation, as all the other chiral secondary amines tested failed to promote the reaction. Another weU-estabUshed organo-catalyst (4), invented by MacMillan [27], and unable to form secondary interactions with electrophiles Uke proUne, was used in the addition of aldehydes to indolyl and other carbocations derived from alcohols. The formation of stable carbenium ions from alcohols and their compatibihly with water, generated by the organocatalytic cycle (formation of enamines from the corresponding carbonyl derivatives), was estabUshed by Cozzi in a S l nucleophilic substitution of alcohols in the presence of water [28]. The enamine formed in situ by the MacMillan catalyst approaches the carbocation from the less hindered side and the hindrance of the incipient carboca-tion controls the stereoselectivity of the reaction (Scheme 26.2) [29]. 

Not only alcohols can be used with the MacMillan catalyst-isolated and stable carbenium ions are also suitable partners for the reaction [30], Tropylium tetrafluor-oborate is commercially available, and it is a stable carbenium ion that can be used in this type of reaction without any precautions. However, other carbenium ions are less stable and are difficult to generate they can be obtained using the conditions described by Mayr in his papers as unstable soUds. Although the appH-cation of an Sul-type reaction with alcohols seems to be Umited to the use of the MacMillan catalyst, the Hayashi-Jorgensen catalyst is also suitable for this transformation [31]. 

Minfiensine, a secoiridoid indole alkaloid, was isolated from the African plant Strychnos minfiensis by Massiot and co-workers in 1989. The unique structure feature of the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9//-carbazole has received much attention for the synthetic efforts and has culminated in several elegant total syntheses. For example. Overman et al. reported on the first and second total synthesis of (-l-)-minfiensine. " In addition, Qin et al. revealed a synthesis of ( )-minfiensine in 2008. Recently, MacMillan and co-workers reported on a nine-step enantiose-lective total synthesis of (-l-)-minfiensine via the key step reaction of organocatalytic Diels-Alder cyclization and amine heterocyclization cascade (Scheme 21.32). For the key step reaction in their approach, reaction of 2-vinylindole 139 and 3 equivalents of propynal in the presence of secondary amine catalyst 140 followed by the addition of NaBH4, stereoselective afforded the tricyclic alcohol 142 via a iminium activated endo-selectiye Diels-Alder cycloaddition and a 5-exo amine heterocy cliz ation. 

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