Aldol substrate-controlled

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

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. 

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 linear synthesis of the title compound started from an enantiopure building block with one stereogenic center. The other six stereogenic centers were introduced by two reagent-controlled Evans aldol reactions, an unselective 1,3-dipolar cycloaddition with subsequent separation of the diastereomers, and a substrate-controlled epoxidation step. 

This is the most common form of substrate control in asymmetric aldol reactions. In general, Ti-facial discrimination arises from the n-stereocenter of the enolate component however, there are many cases where a / -oxygen substituent plays an important role. 

The second total synthesis of swinholide A was completed by the Nicolaou group [51] and featured a titanium-mediated syn aldol reaction, followed by Tishchenko reduction, to control the C21-C24 stereocenters (Scheme 9-30). The small bias for anri-Felkin addition of the (Z)-titanium enolate derived from ketone 89 to aldehyde 90 presumably arises from the preference for (Z)-enolates to afford anti-Felkin products upon addition to a-chiral aldehydes [52], i.e. substrate control from the aldehyde component. 

Evans synthesis of bryostatin 2 (113) also relied upon asymmetric aldol reactions for the introduction of most of the 11 stereocenters [58], At different points, the synthesis used control from an auxiliary, a chiral Lewis acid, chiral ligands on the enolate metal and substrate control from a chiral aldehyde. Indeed, this represents the current state of the art in the aldol construction of complex polyketide natural products. 

In the previous synthesis, two asymmetric aldol reactions using dienyl silyl ethers were described, one using a chiral Lewis acid for stereoinduction while the other used substrate control from a chiral aldehyde. This can be compared with the use of chiral dienolate 131 in the synthesis of a Ci-Cie fragment of the bryo-statins (Scheme 9-41) [59J. Here, the menthyl-derived auxiliary is covalently attached to the enolate, and again an excellent level of asymmetric induction was achieved on addition to aldehyde 132 to give adduct 133. 

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... 

Our synthesis of the C1-C7 fragment 227 of oleandolide started with a substrate-controlled tin-mediated aldol reaction of a-chiral ketone (5)-18 which afforded syn adduct 52 with 93% ds. This same transformation could also be achieved using reagent control with (Ipc)2BOTf, albeit with lower selectivity (90% ds). In a key step, treatment of the aldol adduct 52 with (-i-)-(Ipc)2BH led to controlled reduction of the C3 carbonyl together with stereoselective hydrobora-tion of the C -Cv olefin, affording the desired triol 228 with 90% ds. 

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. 

Catalyst-controlled stereoselectivity is observed for fhe 59-catalyzed aldol reaction of (S)-2-benzyloxypropanal the sense of diastereoselectivity depends on the absolute configuration of the catalyst (Scheme 10.53) [149]. The level of stereoselectivity with (R)-59 is, however, lower than fhat wifh (,S)-59. Thus, a slight influence of substrate control is observed. The stereochemical outcome can be rationalized in terms of steric repulsion between the methyl and TMS groups in fhe cyclic transition structure leading to anti adducts. 

Remote control by substrate-controlled induction 1,4 -Syn induction in the aldol reaction... 

Paterson s synthetic strategy is based on the coupling of three fragments of similar stereochemical and functional group complexity the C1-C6, C9-C16 and C17-C24 subunits. The absolute stereochemistry of these fragments was established via substrate-controlled, boron-mediated aldol reactions of chiral ethylketones. 

An important strategy for achieving substrate control is the use of chiral auxiliaries, which are structures incorporated into reactants for the purpose of influencing the stereochemistry. Two of the most widely used systems are oxazolidinones " derived from amino acids and sultams derived from camphorsulfonic acid. These groups are most often used as carboxylic acid amides. They can control facial stereoselectivity in reactions such as enolate alkylation, aldol addition, and Diels-Alder cycloadditions, among others. The substituents on the chiral auxiliary determine the preferred direction of approach. 

Aldol reactions. Aldol products are obtained in good yields from reaction of ketones with glyoxylic acid monohydrate with assistance of ultrasound irradiation. Substrate-control (by 1,3- + 1,5-asynmietric induction) of the aldol reaction involving y-amino-a-ketoesters under solvent-free conditions is very effective.- With lithium dicyclohexylamide and InCl, the reaction of esters with aldehydes furnishes P-hydroxy esters, and that of a-bromo esters affords a,p-epoxy esters." These are typical Reformatsky and Darzens reaction products, respectively. 

If a chiral catalyst is used to promote the aldol reaction, the determination of stereoselectivity is shifted from substrate control to catalyst control (see Scheme 98). Consequently, when either ( S)-2- er -butyldimethylsilyloxypropanal (689) or its enantiomer (R)-2-tert-butyldimethylsilyloxypropanal (741) is reacted with 738 in the presence of tin(II) triflate and... 

The ability of L-Pro to promote aldol and Mannich reactions has also been exploited with chiral starting materials wherein L-Pro is not controlling the stereochemical outcome of the product, but rather substrate control is operative. The efficiency of the procedure prevents the use of other similar catalysts for these transformations. As an illustration, aldol and Mannich reactions have been employed to prepare carbapenem derivatives with potential value for the preparation of new antibacterial agents (Scheme 2.11). 

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