Nozaki protocol

The Nozaki protocol, - which is an organoaluminum-ate mediated 1,4-addition followed by a 1,2-addition of the resulting enolate, may be considered a 1-acylethenyl anion equivalent, which does fall within the scope of this review. This process may be conducted in either an intramolecular sense or an intermolecular sense. In general, the protocol is compatible with a wide array of functionality however, the intermolecular process requires an aldehyde, whereas the intramolecular case may be terminated by either an aldehyde or a ketone. 

Scheme 9 outlines the synthesis of a prostanoid intermediate (99) that relies on an intermolecular Nozaki process. It is important to note that unlike the intramolecular case described above, the intermolecular version of this protocol requires an aldehyde as the electrophilic trap however, it is interesting to note that there have been no reports of the addition of Lewis acid activated ketones (presumably, as a preformed complex which would be added via cannula at low temperature) to the preformed aluminum enolate. Finally, in this example, the conversion of enone (96) to adduct (98) is promoted by the less reactive dimethylaluminum phenyl thiolate and not the corresponding ate complex. 

The total synthesis of the marine toxin polycavemoside A was achieved by J.D. White and co-workers. In order to couple the central pyran moiety in a Nozaki-Hiyama-Kishi reaction, the aldehyde side chain had to be first homologated to the corresponding terminal alkyne and subsequently transformed into a vinyl bromide. The aldehyde substrate was treated under the Ohira-Bestmann protocol, and the desired alkyne product was obtained in high yield. 

The Nozaki-Hiyama-Kishi (NHK) reaction involves the mild addition of chro-mium(II) organometallics to aldehydes to give homoallylic alcohols in a regio- and stereo-controlled fashion.111 A very significant achievement in the chromium organometallic chemistry was accomplished by Fiirstner who developed a catalytic version of the NHK reaction based on the coupled use of the redox Mn(0)/Cr(III) couple and trimethylsilyl chloride (TMSC1).[21 Moreover, the integration of the Fiirstner protocol with the addition of the Jacobsen s Salen /V,/V -bis(3,5-di-f-butylsalicylidene)-l,2-cyclohexanediamine] and triethylamine allowed Cozzi, Umani-Ronchi, et al. to develop a catalytic enantioselective route to homoallylic alcohols.[3]... 

Vinyl heteroaromatic compounds can be likewise converted into chiral aldehydes. Nozaki and coworkers [33] showed that vinylthiophenes react with high regio- and enantioselectivity to the desired branched aldehydes in the presence of a Rh catalyst bearing a slightly modified (7 ,5)-BINAPHOS ligand (Scheme 4.63). The protocol was used for the synthesis of (S)-tiaprofenic acid. The drug component was obtained in 84% ee upon oxidation of the formed aldehyde with sodium chlorite. 

Barrett applied this procedure to the synthesis of sucrose (Scheme 5) [7]. 2,3,4,6-Tetra-O-benzyl-D-glucopyranose was converted into the a-glucopyranosyl ester 25 with excellent selectivity. In this case the methylenation using Tebbe reagent was unsuccessful. However, the Nozaki-Takai protocol gave the desired vinyl ether. After desilylation, the cyclization reaction gave only the P-fructofuranosyl derivative 26 when the reaction was performed in the presence of silica. 

Scheme 5. Reagents i) TiCU, TMEDA, Zn, CH2Br2, THE (Nozaki-Takai protocol), 68% ii) TBAF on silica, THE, then tBuOK, I2, THE, 25 °C, 65% iii) TEMPO, BusSnH, benzene, Av, 80% iv) Na, NHj, THE then AC2O, pyridine, 90% v) MeONa, MeOH, 96%.

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