Substrate-Controlled Aldol Reactions

Mukai et al.39 used a chiral aryl chromium complex to synthesize the taxol side chain via substrate-controlled aldol reaction (Scheme 7-83). 

An alternative strategy has been used by ourselves in the synthesis of the aply-ronine macrocycle 166, whereby chiral ketones 167 and 168 were used in two substrate-controlled aldol reactions (Scheme 9-49) [67]. Following reduction, this... 

Both these syntheses of oleandolide relied upon substrate-controlled aldol reactions of dipropionate reagents (5)-18 and ent-25. Substrate control is also evident in the way both groups incorporated the exocyclic epoxide with greater than 95% ds. While we chose to use macrocyclic control for this transformation, the Evans synthesis used acyclic stereocontrol and the directing influence of a nearby hydroxyl group. 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

The stereochemistry of the aldol reaction is highly predictable since it is generally controlled by the enzyme and does not depend on the structure or stereochemistry of the substrates. Aldolases generally show a very strict specificity for the donor substrate (the ketone), but tolerate a broad range of acceptor substrates (the aldehyde). Thus, they can be functionally classified on the base of the donor substrate accepted by the enzyme. 

An advantage of these enzymes is that they are stereocomplementary, in that they can synthesize the four possible diastereoisomers of vicinal diols from achiral aldehyde acceptors and DHAP (Scheme 4.2). Although this statement is generally used and accepted, it is not completely true since tagatose-l,6-bisphosphate aldolase (TBPA) from Escherichia coli-the only TBPA that has been investigated in terms of its use in synthesis-does not seems to control the stereochemistry of the aldol reaction when aldehydes different from the natural substrate were used as acceptors [7]. However, this situation could be modified soon since it has been demonstrated that the stereochemical course of TBPA-catalyzed C—C bond formation may be modified by enzyme-directed evolution [8]. 

The aldol reaction between a chiral a-amino aldehyde 16 and an acetate derived enolate 17 creates a new stereogenic center and two possible diastereomers. Several different methods for the synthesis of statine derivatives following an aldol reaction have been reported most of them lead to a mixture of the (35,45)- and (3/ ,45)-diastereomers 18 (Scheme 3), which have to be separated by laborious chromatographic methods.[17 211 Two distinct approaches for stereochemical control have been used substrate control and reagent control. 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

Very recently, Belokon and North have extended the use of square planar metal-salen complexes as asymmetric phase-transfer catalysts to the Darzens condensation. These authors first studied the uncatalyzed addition of amides 43a-c to aldehydes under heterogeneous (solid base in organic solvent) reaction conditions, as shown in Scheme 8.19 [47]. It was found that the relative configuration of the epoxyamides 44a,b could be controlled by choice of the appropriate leaving group within substrate 43a-c, base and solvent. Thus, the use of chloro-amide 43a with sodium hydroxide in DCM gave predominantly or exclusively the trans-epoxide 44a this was consistent with the reaction proceeding via a thermodynamically controlled aldol condensation... 

This reaction is a formal asymmetric aldol addition following a modified Evans protocol. The enolate 26 is formed at 0 °C in the presence of one equivalent of titanium tetrachloride as Lewis acid and two equivalents diisopropylethylamine (Hunig s base) as proton acceptor. Selectively the Z-enolate is formed. The carbon-carbon bond formation takes place under substrate control of the Tvan.v-auxiliary, whose benzyl group shields the, v/-face of the enolate. 

The aldol reaction catalyzed by Ab33F12 is outlined in Scheme 5.65. Regardless of the stereochemistry at C(2) of the aldehyde substrate shown (Scheme 5.65), its antibody catalyzed reaction with acetone resulted in a diastereoselective addition of acetone to the S/ -facc of the aldehyde. The products were formed with similar yields, and thus kinetic resolution was observed. However, the degree of facial stereochemical control of the reaction is surprising, since no stereochemical information was built into the hapten. For the... 

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