Tandem aldol coupling

In the context of the development of enzymatic methods for the synthesis of higher-carbon sugars we recently developed a new strategy by which dodeca-2,11-diuloses — formally derived from ketohexoses by C-coupling tail to tail — become accessible with deliberately addressable substitution patterns by the twofold aldolase-catalyzed chain elongation ( tandem aldolization) of simple, readily available dialdehydes [207]. The choice of furanoid (179) or pyranoid (180) nature of the products can be determined by a suitable placement of hydroxyl substituents in the allylic (181) or homoallylic ( 182) positions of a corresponding cycloolefinic precursor. 

Recently, the rapid preparation of carbohydrates has been facilitated by a synthetic route based on aldol coupling of three aldehydes used for the de novo production of polyol differentiated hexoses in only two chemical steps. The dimerization of alpha-oxyaldehydes, catalyzed by L-proline, is followed by a tandem Mukaiyama aldol addition-cyclization step catalyzed by a Lewis acid. Differentially protected glucose, allose, and mannose stereoisomers can each be selected, in high yield [46]. Microwave irradiation is becoming an increasingly popular method of carbohydrate synthesis and has been the subject of a recent review [47]. 

A synthesis of the -lactone of (2Z,5 S, 7iS, 9R,l lR)-tetrahydroxyhexacos-2- enoic acid (589), a natural product isolated from the aerial parts of Eupatorium pilosum, employs a strategically similar approach of coupling two chiral aldehyde pieces via a tandem aldol reaction (Scheme 85) [146]. Aldehyde 584 is prepared from 303 in 4 steps (1 -Ci4H29MgBr/CuI 2 DHP, CSA 3 BU4NF 4 PCC) in 73% overall yield. 

The first asymmetric procedure consists of the addition of R2Zn to a mixture of aldehyde and enone in the presence of the chiral copper catalyst (Scheme 7.14) [38, 52]. For instance, the tandem addition of Me2Zn and propanal to 2-cyclohexenone in the presence of 1.2 mol% chiral catalyst (S, R, R)-1S gave, after oxidation of the alcohol 51, the diketone 52 in 81% yield and with an ee of 97%. The formation of erythro and threo isomers is due to poor stereocontrol in the aldol step. A variety of trans-2,3-disubstituted cyclohexanones are obtained in this regioselective and enantioselective three-component organozinc reagent coupling. 

Diastereoselective /3-lactone formation was also carried out by a tandem Mukaiyama aldol lactonization between an aldehyde 132 and a thiopyridyl ketene acetal 133 (Equation 46) <2005CCL1448>. This reaction gave the /3-lactone 134 as a 10 1 (transacts) mixture of diastereoisomers and the major isomer was converted into (-)-tetrahydrolipstatin by silyl deptotection followed by a Mitsunobu coupling to form the ester. 

Kobayashi S, Akiyama R, Moriwaki M, Three-component or four-component coupling reactions leading to 6-lactams, Facile synthesis of y-acyl-6-lactams from silyl enolates, a, /l-unsaturated thioesters, and imines or amines and aldehydes via tandem Michael-imino aldol reactions, Tetrahedron Lett., 38 4819—4822, 1997. 

Both tandem spiro-frameworks 50/51 bear a certain resemblance to trisaccharides. Generally, in the aldol adducts from 3-hydroxyaldehydes the respective pyranose conformations are induced by the preference of the hydroxy functions generated during C-C coupling for an equatorial position. Therefore, the opposite absolute configurations induced by the aldolases consequently force a change of relative orientation of the sugar chairs with respect to the bicyclic... 

A mixture of THF and DMPU has been used as a solvent for Sml2 in various reactions such as cyclization of alkynyl halides [90,91], tandem iodo-enone cy-clization/samarium enolate aldol reaction [92], coupling of (3-silylacrylic esters [93], deprotection of arenesulfonamides [94] and pyridine-2-sulfonamides [95], radical ring-opening reactions of cyclopropyl ketones and the trapping of the resulting samarium(III) enolates by a variety of electrophiles [96] (Scheme 41). 

Furthermore, three-component coupling tandem Michael-aldol reactions were achieved by trapping the aluminium enolate intermediate with an aldehyde (Scheme 19.16a). Initiated by the asymmetric Michael addition of malonic esters to cyclic enones, several natural products were synthesised... 

Based on the concept of tandem reaction, a series of synthetic routes have been developed, including an intramolecular Aldol/Oxa-Michael/Aldol/Lactonization synthetic strategy (see Fig. 1.17). The retrosynthetic analysis indicated that the synthesis starts from compound 1.7.21, which first undergoes an intramolecular Aldol reaction then immediately intramolecular Oxa-Michael reaction to form the tricyclic system. Finally through the intermolecular Aldol reaction and intramolecular esterification reaction, the tetracyclic skeleton of Maoecrystal V can be constructed. And 1.7.21 can be provided by the relatively simple materials 1.7.22 and 1.7.23 through Suzuki cross-coupling reaction. 

The synthetic utility of the Mukaiyama aldol reaction is broadened when coupled with other reactions in a tandem fashion. Romo and coworkers developed a highly diastereoselective tandem Mukaiyama aldol-lactonization... 

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