Chelates hydroxy esters

Reduction of a. -epoxy esters to fi-hydroxy esters. Sml2 alone reduces these esters to a mixture of a- and p-hydroxy esters. The reaction rate and yield is increased by addition of HMPT. Addition of a chelating agent, TMEDA or N,N-dimethylaminoethanol (DMAE), results in regioselective reduction to p-hydroxy esters (equation I). The system reduces optically active epoxy esters with complete... 

Magnesium iodide reacts with a,p-epoxy esters to form p-iodo-a-hydroxy esters selectively (200 1). The regioselectivity is attributed to favorable chelation of the iodohydrin. These products are reduced by Bu,SnH to hydroxy esters in 75-95% overall yields with retention of the original configuration at the a-position. 

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. 

When the lithium dianion was prepared in a completely different manner, viz from an a,j -epoxy ester 8 by treatment of the latter with lithium in liquid ammonia and tetrahydrofuran at - 78 C, alkylation experiments (CH3I, — 40 °C) gave the expected a-alkyl- -hydroxy ester 10, but in a ratio of only 4 1 in favor of the anti-isomer and not in the usual 19 1 ratio15. This result could be interpreted as a direct consequence of the participation of an intermolecularly chelated dianionic enolate such as 7 which gains importance because of the use of ammonia as a cosolvent. 

Concellon showed that the reduction of a-halo-p-hydroxy esters and amides, such as 44 and 45, with Sml2 gives a,p-unsaturated esters and amides, 46 and 47, with high stereochemical control.37,38 The diastereoselectivity of the process has been explained by invoking elimination through a six-membered chelate 48 (Scheme 4.34). 

Anti diastereoselectivity gives the optically active (S)-p-hydroxy ester while syn diastereoselectivity leads to the (/ )-P-hydroxy ester, via a chelated six-membered transition state (eq 3). Since the anti intermediate is more stable, the (S)-P-hydroxy ester predominates under thermodynamic conditions (Table 1, entry 1). Higher diastereoselectivity is achieved by changing the counterion from lithium to a more chelating one such as zinc (Table 1, entry 2). On the other hand, in order to obtain diastereoselection under kinetic control, zirconium enolates (prepared by treating the lithium enolate with Dichlorobis(cyclopentadienyl)zirconium) are used, leading to the (/ )-p-hydroxy ester (Table 1, entry 3) in high yield. 

In the stereochemical model of the catalyst-aldehyde chelate complex, the square pyramidal complex 28 [39], the re aldehyde enantioface is shielded by the ligand phenyl group exposing the si enantioface to nucleophilic attack (Fig. 1-9). Since enantioselective formation of (5)-/(-hydroxy esters is observed (si face attack), the absolute stereochemistry of the products is consistent with the proposed coordination model. 

Reduction of epoxy esters was not selective in the presence of methanol or ethanol but gave good yields of [3-hydroxy esters by using N,N-dimethyleth-anolamine (DMEA) [40]. DMEA seems to play the role of a proton source and also acts as a chelator of samarium species, increasing the reduction power of Sml2 and decreasing the Lewis acidity of Sm(III). See Scheme 56 for some examples. 

In contrast to chelation-controlled anionic Claisen rearrangements of /(-hydroxy esters [where chelation control only allows the formation of (i -lithium enolates see p 3420], all four diastereomeric A-crotylic a-hydroxy ketene dithioacetals can be prepared either by deprotona-... 

In contrast to unfunctionalized ketones, Wilkinson-type catalysts are quite effective in the hydrogenation of 2-oxo esters. With in situ catalysts consisting of [Rh(cod)Cl]2 2 and a proline derived chelate phosphane BPPM 3l4, quantitative hydrogenation of 2-oxo esters to (7 )-2-hydroxy esters was achieved. Dry benzene or dry tetrahydrofuran as solvent were superior to alcohols usually used in hydrogenation reactions with Wilkinson-type catalysts. While methyl 2-oxopropanoate was reduced to methyl (R)-2-hydroxypropanoate in only 66% eel5, propyl and 2-methylpropyl 2-oxopropanoate gave the (R)-alcohols with 76% and 71 % ee, respectively (Table 2)15,10. 

Reaction with a-ketoesters. In a regio- and diastereoselective addition reaction, chelation control provides optically active a-hydroxy esters. 

The reaction could be extended to )3-hydroxy esters (Scheme 10-115) [144], In this case, TBAF proved the most effective reagent for providing an almost quantitative conversion to the corresponding alkoxysiladioxanes. Activation of the acetal functionality was best achieved with the superacid [TfOH2B(OTf)4], and trapping with allyltrime-thylsilane provided the anti diol products in excellent yield and stereoselectivity. The outcome is in accord with chelation-controlled intermolecular addition with axial attack of the nucleophile onto the cationic oxonium intermediate. 

Because of chelation, the 20S)/ 22R)-erythro-hydroxy ester 399 (R = H) resulted exclusively from the 3,3-sigmatropic rearrangement of enolate 397, which can be generated from a-alkoxy ester 395. 

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