Aldehydes aldol reaction, chelation control

Under either the catalytic (eq 1) or the stoichiometric conditions (eq 2), the reagent undergoes addition to chiral aldehydes with complete reagent control , i.e. the stereochemistry of the aldol reaction is totally controlled by the chiral catalyst regardless of the inherent diastereofacial preference of the chiral aldehydes (eq 4). Titanium(IV) chloride and tm(TV) chloride mediate the addition of the title reagent to chiral a-alkoxy aldehydes and -alkoxy aldehydes with complete chelation control (eq 5), whereas the corresponding silyl ketene acetal is unselective. 4... 

LA represents Lewis acid in the catalyst, and M represents Bren sled base. In Scheme 8-49, Bronsted base functionality in the hetero-bimetalic chiral catalyst I can deprotonate a ketone to produce the corresponding enolate II, while at the same time the Lewis acid functionality activates an aldehyde to give intermediate III. Intramolecular aldol reaction then proceeds in a chelation-controlled manner to give //-keto metal alkoxide IV. Proton exchange between the metal alkoxide moiety and an aromatic hydroxy proton or an a-proton of a ketone leads to the production of an optically active aldol product and the regeneration of the catalyst I, thus finishing the catalytic cycle. 

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. 

This dual behaviour must allow control of the configuration at the a carbon atom in an aldol reaction, provided that one can control whether or not the metal is chelated at the time the aldol condensation occurs. Thornton and Nerz-Stormes [35] reported an approach to this problem by using titanium enolates to obtain "non-Evans" 5jn-aldols. On the other hand, Heathcock and his associated found that aldehydes react with chelated boron enolates 100b to afford the anh-aldols 102 or the "non-Evans" i yn-aldols 103 depending upon the reaction conditions (Scheme 9.32). 

The design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

On the other hand, chelation-controlled aldol reactions usually provide the awh -Cram aldol. This has been early illustrated by Heathcock and coworkers76 who reported that the proportion of the exclusive syn condensation products B and C (>98%) of the bulky enolate A (Scheme 116) was completely reversed when a chelating group was present on the aldehyde backbone (although the chelating ability of the f-butyl dimethylsilyloxy group is questionable566). 

The orientation of the enolate and aldehyde in the transition state of the aldol reaction, open transition state vs. the ordered, chelate-controlled transition state... 

The Eu-catalyst Eu(dppm)3 provides a remarkable level of chemoselectivity but is only effective for the Mukaiyama-aldol reaction of aldehydes with several ketene silyl acetals (KSA) (Table 2-3) [55]. When ketones and aldehydes are treated, respectively, with KSA and ketone-derived silyl enol ethers, no reaction results. The rate enhancement by chelation control (entry 4, Table 2-3) is intriguing. This is a feature common to other Lewis acids such as TiC [56] or LiC104 [57],... 

A similar aluminum cation was also available in the Mukaiyama-aldol reaction. It is worth noting that the t-butyldimethylsilyloxy (TBSO) group, which otherwise is unable to make chelation complex with neutral bidentate Lewis acids, is under chelation control with excess Me2AlCl or MeAlfJh. [12]. Aldehyde and ketone carbonyls are capable of participating in the chelation-controlled aldol reaction to give anti-6 with high diastereoselectivity (Scheme 6.4). 

The utility of BF3-OEt2, a monodentate Lewis acid, for acyclic stereocontrol in the Mukaiyama aldol reaction has been demonstrated by Evans et al. (Scheme 10.3) [27, 28]. The BF3-OEt2-mediated reaction of silyl enol ethers (SEE, ketone silyl enolates) with a-unsubstituted, /falkoxy aldehydes affords good 1,3-anti induction in the absence of internal aldehyde chelation. The 1,3-asymmetric induction can be reasonably explained by consideration of energetically favorable conformation 5 minimizing internal electrostatic and steric repulsion between the aldehyde carbonyl moiety and the /i-substituents. In the reaction with anti-substituted a-methyl-/ -alkoxy aldehydes, the additional stereocontrol (Felkin control) imparted by the a-substituent achieves uniformly high levels of 1,3-anti-diastereofacial selectivity. 

Aluminum has exceedingly high affinity toward fluorine, as is evident from the bond strengtlis in several metal-fluorine diatomic molecules Al-F, 663.6 6.3 Li-F, 577 21 Ti-F, 569 34 Si-F, 552.7 2.1 Sn-F, 466.5 13 and Mg-F, 461.9 5.0 kJ mol [33]. This characteristic feature can be used for chelation-controlled aldol reaction of fluorinated aldehydes with KSA. Thus, in the presence of a stoichiometric amount of MesAl, 2-fluorobenzaldehyde reacts smoothly with KSA 10 to give aldol 11 with high anti selectivity. Other Lewis acids and non-fluorinated aldehydes lead to less stereoselectivity (Scheme 10.6) [34]. 

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. 

Aldol and related reactions may also be chelation-controlled. Boron enolates of N-acyloxazolidinones 19 are chelated in the ground state. Their reactions with aldehydes will necessitate the coordination of the aldehyde with the boron atom at transition state, so that the initial bidentate chelate will be broken (Figure 1.26). However, the titanium atom of related titanium enolates can accommodate hexa-coordination so that the initial titanium chelate 20 does not need to be disrupted. In each case, the aldol reaction leads to different syn stereoisomers (Figure L26) via transition models 21 and 22. 

In order to reverse the diastereoselectivity in the aldol reaction, the Lewis acid-catalyzed silyl enol ether addition (73) (Mukaiyama aldol reaction) was examined. Since the Mukaiyama aldol reaction is assumed to be proceeded via an acyclic transition state, a chelation controled aldol reaction of the a-alkoxy aldehyde should be possible (74). In the presence of TiCU, the silyl enol ether derived from 14 was reacted with aldehyde 13, followed by desilylation to afford the desired anti-Felkin product 122a as a single adduct (Scheme 21). Based on precedents for chelation-controlled Mukaiyama aldol reaction (74), the exceptional high selectivity in this reaction would be accounted for by chelation of TiCl4 with the C23-methoxy group of the aldehyde 13 (eq. 13). On the other hand, when the lithium enolate derived from 14 was treated with the aldehyde 13, followed by desilylation, it gave a 1 4 ratio of the two epimers in favour of the undesired (22S)-aldol product... 

Keck et al. have used the lactone annulation procedure developed in their laboratory to install the lactone moiety by reaction of the lithium enolate of methylacetate with a (3-acetoxy aldehyde [108]. The other key steps include a diastereoselective Lewis acid mediated (Z)-crotylstannane aldehyde addition, a highly selective Lewis acid promoted Mukaiyama aldol reaction and an arari-selective Sml2 reduction of a p-hydroxyketone. The preparation of the C8-C15 fragment of (-)-pironetin started with the chelation-controlled addition of (Z)-crotyl tri-n-butylstannane to the (3-benzyloxy-aldehyde 153 in the presence of TiCU [109] to give the... 

As a result of a chelation-controlled aldol reaction exclusive formation of compound 43 tvith the desired 6(R),7(S),8(R)-triad tvas observed. The structure has been confirmed by X-ray analysis after transformation to a crystalline six-membered lactone. In their macro-lactonizsation strategy to synthesize epothiione B Nicolaou et al. used the same ketone 41 in an aldol reaction vith aldehyde 19. The diastereoselectivity in the aldol addition vas only moderate, giving a ratio of 3 1 in favor of the natural epothiione configuration [33]. 

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