Aldol reactions stereoselective substrate-controlled

Tin(IV)-chloride-mediated double aldol reaction of acyclic ketones is rendered stereoselective by a chiral phosphine oxide, (5)-BE JAPO it is proposed that the catalyst controls the first aldol and the substrate controls the second. Another chiral diphosphine oxide, this one based on thiophene, catalyses direct aldols in high delee Chiral a-silyloxy ketones derived from lactate (61) undergo titanium(IV)-mediated aldols giving diastereomerically pure syn-syn adducts (62) in high yield, irrespective of the alkyl groups fianking the silyl or carbonyl. 

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. 

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... 

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. 

The Eu-catalyzed aldol reactions of chiral a-siloxy and a-alkoxy aldehydes with KSA show high levels of diastereocontrol, the sense depending on the nature of the a-substituent (Scheme 10.20) [68]. The stereoselectivity with the a-siloxy aldehyde can be explained by an antiperiplanar transition state merged with Felkin control, whereas reaction of fhe a-alkoxy aldehyde would proceed mainly via a synchnal transition state involving chelation of the substrate and coordination of fhe acetal alkoxy group of KSA. 

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. 

These aldols have all had just one chiral centre in the starting material. Should there be more than one, double diastereomeric induction produces matched and mismatched pairs of substrates and reagents, perfectly illustrated by the Evans aldol method applied to the syn and anti aldol products 205 themselves derived from asymmetric aldol reactions. The extra chiral centre, though carrying just a methyl group, has a big effect on the result. The absolute stereochemistry of the OPMB group is the same in both anti-205 and yvn-205 but the stereoselectivity achieved is very different. The matched case favours Felkin selectivity as well as transition state 201 but, with the mismatched pair, the two are at cross purposes. It is interesting than 1,2-control does not dominate in this case.33... 

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. 

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... 

Transition metal catalyzed aldol reactions are attractive methods due to their high catalytic activity, privileged chelation effects of controlling stereoselectivity, and mild or neutral reaction conditions. Except group 5-7, most of transition metals have been shown as efficient catalyst in homogeneous aldol reactions with variants of substrates. Thus and correspondingly, the catalytic aldol reactions will be emphasized herein with representative transition metal based complexes in group 4 and 8-11. 

The cross-aldol reaction is actively studied with the aim of improved control of the stereoselectivity.58 The use of silyl enol ethers for a condensation with aldehydes constitutes important progress, but catalysis by Lewis acids can be unsatisfactory for acid labile substrates, and the predominant anti stereoselectivity is not always optimal. An attempt was made to solve this problem by running the reaction sonochemically in the presence of alumina, without any solvent.59 products are absent, and the anti-isomer forms predominantly (Eq. 16). 

Enolates or their neutralized equivalents (silyl enol ethers or enol acetates) play a central role in stereoselective reactions [97]. They can be employed in C-C-bond forming reactions, such as alkylations or aldol additions or in C-hetero bond formations, for example, oxygenation. Stereocontrol can be exerted via substrate control by preexisting stereocenters or via chiral auxiliaries, which are temporarily attached to the substrate. 

Whereas the examples above used substrate control for stereoselective transannular aldol or related reactions, reagent control has also been reported for the transannular aldol reactions. One example is synthesis of the musk ordorants (R)-muscone and (R,Z)-5-muscenone by Knopff and co-workers. It involved enantioselective formation of 73 by the transannular aldol condensation of the symmetrical macrocyclic 1,5-diketone 72 using sodium ephedrate for desymmetrization (Scheme 20.19). The reaction was assumed to proceed by a reversible transannular aldol reaction followed by an enantioselective dehydration reaction. 

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