Aldol and Related Processes

Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan 

Department of Chemistry, University of Chicago, Chicago, Illinois 

5 Aldol Reaction Using Silyl enol Ethers 

Silver in Organic Chemistry Edited by Michael Harmata Copyright 2010 John Wiley Sons, Inc. 

In 1996, Yamamoto and Yanagisawa reported the allylation reaction of aldehydes with allytributyltin in the presence of a chiral silver catalyst.2 They found that the combination of silver and a phosphine ligand accelerates the allylation reaction between aldehydes and allyltributyltin. After this discovery, they screened several chiral phosphine ligands and found that chiral silver-diphosphine catalysts can effect the reaction in an enantioselective fashion (Table 9.1).2 For example, when benz-aldehyde and allyltributyltin were mixed in the presence of 5 mol% of AgOTf and (S)-2,2 -bis(diphenylphosphino)-1,1 -binaphthyl (BINAP), the corresponding homoallyl alcohol was obtained with 96% ee and 88% yield (Table 9.1). Generally, the reaction with aromatic aldehydes afforded the corresponding homoallyl alcohols in excellent 

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Mukaiyama Aldol and Related Processes. The Carreira group has developed an asymmetric catalytic aldol reaction that involves addition of a silyl dienolate to an aldehyde partner in the presence of a chiral catalyst generated in situ from (S)-Tol-BINAP, Cu(OTf)2, and TBAT, e.g., eq... 

This chapter will begin with a discussion of the role of chiral copper(I) and (II) complexes in group-transfer processes with an emphasis on alkene cyclo-propanation and aziridination. This discussion will be followed by a survey of enantioselective variants of the Kharasch-Sosnovsky reaction, an allylic oxidation process. Section II will review the extensive efforts that have been directed toward the development of enantioselective, Cu(I) catalyzed conjugate addition reactions and related processes. The discussion will finish with a survey of the recent advances that have been achieved by the use of cationic, chiral Cu(II) complexes as chiral Lewis acids for the catalysis of cycloaddition, aldol, Michael, and ene reactions. 

Hydrogen bond-promoted asymmetric aldol reactions and related processes represent an emerging facet of asymmetric proton-catalyzed reactions, with the first examples appearing in 2005. Nonetheless, given their importance, these reactions have been the subject of investigation in several laboratories, and numerous advances have already been recorded. The substrate scope of such reactions already encompasses the use of enamines, silyl ketene acetals and vinylogous silyl ketene acetals as nucleophiles, and nitrosobenzene and aldehydes as electrophiles. 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

The aldol reaction and related processes have been of considerable importance in organic synthesis. The control of syn/anti diastereoselectivity, enantioselectivity and chemoselectivity has now reached impressive levels. The use of catalysts is a relatively recent addition to the story of the aldol reaction. One of the most common approaches to the development of a catalytic asymmetric aldol reaction is based on the use of enantiomerically pure Lewis acids in the reaction of silyl enol ethers with aldehydes and ketones (the Mukaiyama reaction) and variants of this process have been developed for the synthesis of both syn and anti aldol adducts. A typical catalytic cycle is represented in Figure 7.1, where aldehyde (7.01) coordinates to the catalytic Lewis acid, which encourages addition of the silyl enol ether (7.02). Release of the Lewis acid affords the aldol product, often as the silyl ether (7.03). 

Enantioselective phase-transfer catalysis (PTC) has been extensively applied for the alkylation, epoxidation, conjugate addition and related process, with the use of chiral ammonium salts being the typical transfer agent [293]. However, the related aldol... 

General reviews include the direct aldol/" aldoi and related processes,the Zimmerman-Traxler TS model used to explain the stereochemistry of the aldoi condensation,catalysis of direct asymmetric aldols by prolinamides versus prolinef/zioamides, " " the catalytic asymmetric aldoi reaction in aqueous media (considering both organometallic and organocatalytic approaches), " the use of BINAP oxide in enantioselective direct aldols,and the use of metal enolates as synthons. " ... 

With simpler, less stabilized, enols and enolates, the same selectivity issues arise in this addition process as we saw for aldol and related reactions—these reactions are related to the aldols, but a double bond simply intervenes as an electron relay. Consider the example shown in Figure 17.68. We have chosen a nucleophile that can enolize readily and an a,p-unsaturated aldehyde that can t enolize. The enal is more electrophilic than the ketone, so self-condensation of the ketone is not... 

The aldol reaction is well established in organic chemistry as a remarkably useful synthetic tool, providing access to p-hydroxycarbonyl compounds and related building blocks. Intensive efforts have raised this classic process to a highly enantioselective transformation employing only catalytic amounts of chiral promoters, as reviewed in the previous section (Chap. 29.1). While some effective applications have been reported, most of the methodologies necessarily involve the preformation of latent enolates 2, such as ketene silyl acetals, using... 

In principle, such processes should also be applicable to bifunctional aldehydes for a two-directional chain elongation in which two equivalents of DHAP nucleophiles would be added sequentially to both the acceptor carbonyls in a fashion that can be classified as a tandem reaction [66,67], without the need for isolation of any intermediates. Depending on the specificity of the enzyme used and on the number and position of hydroxyl functions in the starting material, the isomeric constitution, as well as the absolute and relative stereochemistry should be deliberately addressable. Thus, in a preparatively simple manner, such tandem aldolizations [68] should permit to rapidly construct larger carbohydrate molecules that would rival the carbohydrate core of tunica-mine and related nucleoside antibiotics in structural complexity. 

One of the most successful and widely used methods for diastereoselective aldol addition reactions employs Evans imides 17 and the derived dialkyl boryleno-lates [8J. The 1,2-svn aldol adducts are typically isolated in high diastereoisomeric purity (>250 1 dr) and useful yields. More recent investigations of Ti(IV) and Sn(II) enolates by Evans and others have considerably expanded the scope of the aldol process [9], In 1991, Heathcock documented that diverse stereochemical outcomes could be observed in the aldol process utilizing acyl oxazolidinone imides by variation of the Lewis acid in the reaction mixture [10]. Thus, for example, in contrast to the, l-syn adduct (21) isolated from traditional Evans aldol addition, the presence of excess TiCL yields the complementary non-Evans 1,2-syn aldol diastereomer. This and related observations employing other Lewis acids were suggested to arise from the operation of open transition-state structures wherein a second metal independently activates the aldehyde electrophile. 

The standard aldol reaction involves the addition of an enolate to a ketone or an aldehyde. However, there are related processes and this chapter includes subsections on the isocyanide aldol, nitroaldol and Morita-Baylis-Hillmami reaction. In addition there are reactions involving additions of enolates to the C=N group and a large subsection is devoted to a discussion of the catalytic asynmietric Mamiich reaction. As well as these mechanistically related processes, the carbonyl-ene reaction is also discussed here. Whilst the mechanism of the carbonyl-ene reaction is different from the aldol reaction, the synthetic result is rather similar, and perhaps fits most comfortably into this chapter. 

In a related process, triethylsilane plus SnCLr can expediently convert appropriately protected aldol products to fully protected 1,3-diols. Moreover, the synthesis of iyn-l,3-ethylidene acetals from l-(2-methoxyethoxy)ethyl-protected -hydroxy ketones with SnCLr and EtsSiH can occur with very high levels of diastereocontrol (eq 33). ... 

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