Threo products

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

The premier example of this process in an ylide transformation designed for [2,3]-sigmatropic rearrangement is reported in Eq. 15 [107]. The threo product 47 is dominant with the use of the chiral Rh2(MEOX)4 catalysts but is the minor product with Rh2(OAc)4. That this process occurs through the metal-stabilized ylide rather than a chiral free ylide was shown from asymmetric induction using allyl iodide and ethyl diazoacetate [107]. Somewhat lower enantioselectivities have been observed in other systems [108]. 

As a strategy for the construction of cyclic ethers, the radical cyclization of jS-alkoxyacrylates was used for the preparation of czs-2,5-disubstituted tetrahy-drofurans and cis-2,6-disubstituted tetrahydropyrans. An example is given with S-alkoxymethacrylate 38 as precursor of the optically active benzyl ether of (+)-methyl nonactate, exclusively formed as the threo product (Reaction 44). ° ... 

Support for the suggestion that Fig. 13.6 involves a change in actual reaction pathway is provided by acetolysis of the threo diastereoisomer (31) of the brosylate. Acetolysis leads to two different distinguishable, diastereoisomers whose relative proportion will depend on how much of the total reaction proceeds by external nucleophilic attack via the SN2 pathway (erythro product, 32), and how much by internal nucleophilic attack via a cyclic phenonium ion intermediate (threo product, 33) ... 

Treating boron reagent 45a with an oxazoline compound gives the azaeno-late 52. Subsequent aldol reaction of 52 with aldehyde yields mainly threo-product (anti-53) with good selectivities (Scheme 3-18).38... 

Enolate Ligand Ri Base" Enolate Ratio Z-.E Erythro-Threo Product Ratio"... 

Aldehyde Ligand Rs Metal Solvent [atr( C)] Erythro-Threo Product Ratio Ref. 

Entry Substrate Enolate Ratio Z E Erythro-Threo Product Ratio Yield (%, Zr case) Ref. 

Diastereoselectivity in the aldol and the conjugate additions of 2 -hydroxy-1,T-binaphthyl ester enolates with a variety of carbonyl electrophiles has also been explored the tendency of the ester enolates, generated by BuLi, to react with aldehydes to give threo products preferentially with high diastereoselectivity has been interpreted in terms of an acyclic transition state of chelated lithium enolate involving the aldehyde carbonyl and the 2 -hydroxy group. 

The addition of (TMS)3SiH to prochiral diethyl methyl fumarate (5) gave both diastereoisomers with preferential formation of the threo isomer (Reaction 5.7) [25]. This suggests that the intermediate adduct 6 adopts a preferred conformation due to the allylic strain effect, in which the silyl moiety shields one face of the prochiral radical center, favouring hydrogen transfer to the opposite face, and therefore the threo product is predominantly formed. 

The reactions proceeded efficiently under mild conditions in short time. The silyl enol ethers reacted with the activated acetals or aldehydes at -78 °C to give predominant erythro- or threo-products [136, 137] respectively. In the same manner, the aldol reaction of thioacetals, catalyzed by an equimolar amount of catalyst, resulted in <-ketosulfides [139] with high diastereoselectivity. In the course of this investigation, the interaction of silyl enol ethers with a,]3-unsaturated ketones, promoted by the trityl perchlorate, was shown to proceed regioselec-tively through 1,2- [141] or 1,4-addition [138]. The application of the trityl salt as a Lewis acid catalyst was spread to the synthesis of ]3-aminoesters [142] from the ketene silyl acetals and imines resulting in high stereoselective outcome. 

The carbonylation of both cis- and trans-2-butene in methanol in the presence of a palladium catalyst and copper (II) has demonstrated the stereochemistry of this oxymetallation of simple monoolefins (19). In the initial stages of the reaction, stereospecific trans methoxypallada-tion is observed, yielding exclusively the threo- and erythro-/3-methoxy esters, respectively (Table I). In the later stages of the reaction ds-trans isomerization of both butenes becomes increasingly important such that trans methoxypalladation to the cis-trans mixtures yield both erythro and threo products. The rate of methoxypalladation of ds-2-butene is approximately three times faster than that of the trans isomer. 

Lewis acid-catalyzed stereoselective addition of crotylsilanes to chiral 74 has been studied in detail111,112. The presence of the chiral auxiliary at C2 (e.g. p-tolylsulfinyl or menthoxy carbonyl group) induces the diastereofacially selective addition of cyclopentenones with crotylsilanes. Thus, ( )-crotylsilane favors the erythro product, whilst (Z)-isomer favors the threo product. High enantioselectivity is observed in both reactions (equation 48). In a similar manner, conjugated addition of allylsilane to 75 proceeds with high efficiency (equation 49)113. Interestingly, the yield and enantiomeric excess of the product is dependent on the amount of TiCL used and the best selectivity... 

The addition of CH2(OMe)2 to styrenes 251-254 gives PhCH(0Me)CH2CH20Me in 96% yield from 252, whereas 252 mostly polymerizes. Addition to 253 is 1.9 slower and affords an equimolar mixture of erythro- and threo-products, whereas the d.v-isonier 254 is inert. The reactivities may reflect steric hindrance to planarity in the methylstyrenes, and correspond to the MNDO-calculated heats of formation of the methylstyrene conformers388. 

Discrimination can readily be observed between the two possible modes of attack on a carbonium ion (195 196 and 195 197 when the nucleophile is part of the substrate. In such cases, the phenomenon of neighboring group participation is observed (for a review, see ref. 69). For example, solvolysis of the erythro-tosylate isomer 202 in acetic acid gave largely the erythro-acetate isomer 204 vi a the chiral bridged ion 203, whereas the threo isomer 205 yielded a racemic mixture of threo products 207A and 207B via the achiral intermediate 206 (70). 

Some of these reactions are stereoselective and may be rationalized with simple models The reaction of benzaldehyde and a silylcarbanion gives the threo-product if the silyl group is small. This implies that in the transition state, the two sterically demanding groups are anti. As the silyl group becomes more sterically demanding than trimethylsilyl, the selectivity shifts towards the erythro-isomer. 

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