Chiral a-alkoxy

An analogous solvent effect was observed upon treatment of the chiral a-alkoxy aldehyde 11 with 2-lithio-4-methylfuran in the presence of zinc bromide. This highly diastereoselective addition reaction was the key step in a synthesis of the enantiomcrically pure C-10-C-20 fragment of the immunosuppressant KK 506139. 

Charlton121 has recently reported the asymmetric induction in the reaction of dimethyl fumarate and l,3-dihydrobenzo[c]thiophene 2,2-dioxide (198) containing a chiral a-alkoxy group at the 2-position (equation 128). A diastereomeric excess of 2.8 1 of 199 to 200 is achieved by using 198 derived from optically active a-methylbenzyl alcohol. 

Addition of diethyl phosphites to aldo nitrones derived from chiral a-alkoxy (Scheme 2.202) and A-Boc-a-amino (Scheme 2.203) aldehydes can be achieved... 

More recently, lithiated allenes with chiral a-alkoxy groups have been generated and added to aldehydes as well as to a tosylimine with substantial diastereoselec-tivity. 

Related Alkylations of Chiral a-Alkoxy Vinyl-Metal Complexes Chiral a-Alkoxy Vinyl-Iron Complexes... 

SCHEME 8. Schematic representation for the chelate-controlled addition of an organometaUic reagent (M—R) to the carbonyl group of a chiral a-alkoxy carbonyl compound (17). Two diastere-omers 18 with different orientation of R with respect to CH2R can be obtained. The syn diastereomer is obtained when the nucleophihc attack of R takes place on the same face of the plane, defined by the carbonyl group and the R-substituted carbon atom, where CH2R is located in the chelate complex... 

The addition paths of two separated MeMgCl molecules to the carbonyl group of chiral a-alkoxy carbonyl compounds, which are shown in Schemes 8 and 9 and in Figure 11 in Section IV, were traced. However, in these models, one MeMgCl molecule bridges two oxygen atoms and acts merely as a catalyst. Instead, the Schlenck dimer (MeMgCl)2 should be considered for the carbonyl reactant coordination. 

The reversed configuration of these adducts that was mistakenly assigned in our first report (Ref 57a) was timely corrected in a second paper (Ref 57b). For a commentary to this reaction, see A. Zamojski, Stereoselective aminohomologation of chiral a-alkoxy aldehydes via thiazole addition to nitrones. Application to the synthesis of W-acetyl-D-mannosamine, Chemtracts Org. Chem. 6 172 368 (1993). 

Aldol condensation of a-amino silyl ketene acetals (l).10 2-Dibenzylami-noketene trimethylsilyl acetals (1) react with aldehydes premixed with TiCl4 to give a-amino-p-hydroxy carboxylic esters (2) with moderate to high syn-selectivity. Surprisingly, TiCl4-catalyzed reaction of 1 with a chiral a-alkoxy aldehyde proceeds with low asymmetric induction. 

A number of acyl trimethyl silanes chiral at the a- or -carbon atom have been prepared in non-racemic form. Chiral a-alkoxy and a-silyloxy acyl silanes have been generated in very high yields by oxidative rearrangement of enantiomerically pure silyl epoxides, induced by dimethyl sulphoxide and silyl triflates (Scheme 32)112. 

Nucleophilic additions to chiral a-alkoxy and a-amino nitrones have been reviewed, focusing on tuning of Lewis acid catalysts and protecting groups so as to exert stereocontrol in producing hydroxylamines and ultimately useful amino acids, amino alcohols, and nucleoside analogues.96... 

Addition of crotyltri-n-butyltin (5 11, 143) to chiral a-alkoxy aldehydes (6) presents a more complicated situation, since four products are possible. Products 7 and 8 result from chelation-controlled diastereofacial selectivity products 9 and 10 are products of Cram-Felkin control. In the reaction catalyzed by BF, etherate the major products are 7 and 9 in the ratio 67 33. Use of TiCl4 or MgBr, results in formation of only 7 and 8. With the former catalyst the 7/8 ratio is 63 37 with the latter, 92.5 7.5. The almost exclusive formation of 7 is consistent with the known ryn-stereoselectivity in the reaction of 5 with achiral aldehydes. 

Stereoselective additions to chiral a- and -alkoxy aldehydes. Lewis-acid-catalyzed additions of enol silyl ethers to chiral a-alkoxy or (3-alkoxy aldehydes can proceed with high 1,2- and 1,3-asymmetric induction. Moreover, the sense of induction can be controlled by the Lewis acid.1 Thus BF3, which is nonchelating, can induce diastereo-... 

R)- and (S)-f-Butyl-5-methylene-l,3-dioxolan-4-one, a Chiral a-Alkoxy Acrylate. It is also possible to introduce an ex-ocyclic double bond onto the dioxolanone ring, as in compounds (9)-(ll), derived from lactic and malic - acids. These a,3-unsaturated carbonyl derivatives are acceptors for radical additions and undergo cycloadditions with dienes and heterodienes. The Diels-Alder adduct (12) of ent-(9) with cyclopentadiene is formed with exo selectivity (96 4) and serves as aprecursor to norbomenone (13). Cycloadduct (14), obtained from methylenedioxolanone (9) and an open-chain triene, is also the result of an exo addition and is used in tetronolide synthesis. ... 

Tandem condensation of chiral a-alkoxy aldehydes with the anion of allyl 2-pyridyl sulfoxide and (MeO)3P-promoted desulfurization of the resulting a-adduct provide ( )-alkoxydiols. llie major stereochemical path in their preparation may be accounted for by the Felkin- ih (nonchelation control) model (Scheme 19). ... 

Stereoselective addition of a dithiane anion to chiral 2-metiiyl-3-trimethylsUyl-3-butenal combined with the stereoselective addition of a Grignard reagent to the chiral a-alkoxy ketone affords a practical method for the construction of a, y-dimethyl-a,p-dihydroxy compounds, useful intermediates for the synthesis of erythronolides (Scheme 33). -Hydroxy carboxylic esters were synthesized by the addition of ethyl 1,3-dithiolanyl-2-carboxylate enolate to a chiral aldehyde, followed by desulfurization. ... 

Chiral allylic silanes and chiral aldehydes. This combination of agents provides fascinating opportunities for double asymmetric induction and allows the magnitude of the various controlling features to be expressed. The sense and level of 1,2-asymmetric induction in the Lewis acid-promoted addition of chiral E-2-butenylsilanes to chiral a-alkoxy aldehydes has been examined as well (Scheme 10-18) [37j. 

Aldol reactions of the lithium enolates of chiral a-alkoxy esters have also been studied. Ester (208) reacts with acetone to give diastereomers (209) and (210) in a ratio of 85 15 in THF at -120 C (equation 124) the ratio is only 64 36 in THF at -78 Even higher facial selectivity is obtained with the mesityl analog of (208) the lithium enolate of this ester reacts with acetone in THF at -120 C to give the aldols corresponding to (209) and (210) in a ratio of 94 6. The Seebach and Pearson methods to accomplish this same goal have already been discussed (vide supra, Schemes 6 and 7). 

These tri(alkoxy)titanium enolates, which have low Lewis acidity, are known to react chemoselective-ly with an aldehyde group in the presence of a ketone (equation 4). Other uses described by Reetz et al. include the diastereofacially selective additions of ketone and ester enolates to chiral a-alkoxy aldehydes with nonchelation control. - For example, aldol addition of the tri(isopropoxy)titanium enolate of pro-piophenone to the aldehyde (24) leads to only the two syn diastereomers, with the nonchelation adduct (25) favored (equation 5) i.e. Felkin-Anh selectivity is operating. In the case of aldol addition of t-butyl propionate to the same aldehyde (equation 6), highest stereoselectivity for the isomer (26) is obtained using the tri(diethylamino)titanium enolate. Very high levels of nonchelation stereoselectivity can also be obtained in the aldol addition to chiral a-siloxy or a-benzyloxy ketones if a titanium enolate of low Lewis acidity is employed, as in equation (7). ... 

Chiral a-methyl aldehydes (43) show exceptional diastereofacial preferences in their Lewis acid mediated reactions with enol silanes (equation i6) 2i 25c-26-64 selected data are reported in Table 8. The reason for this selectivity may be due to an approach trajectory of the nucleophile closer to the stereocenter when the carbonyl group is bound to the Lewis acid. Additions to chiral a-alkoxy aldehyde (48) were studied with both nonstereogenic (equation 17 Table 9) and stereogenic enol silanes (equation 18 Table 10). (Stereogenic and nonstereogenic are defined according to Mislow and Siegel.) ... 

TiCU-mediated addition of silyl enol ether (95) to chiral a-amino aldehyde (94) was reported to proceed with good chelation control, albeit in poor yield (equation 28). Effective chelation control was also reported in the TiCU-mediated reactions of chiral a-alkoxy and p-alkoxy acyl cyanides (96) and (97) with silyl enol ether (95 equations 29 and SO). Reaction of acyl cyanide (97) with the ( )-silyl enol ether (93) gave a single stereoisomer as a result of complete chelation control and syn simple stereoselection (equation 31). Additions of silyl enol ethers and silyl ketene acetals to (-)-menthyl phenyl-glyoxylate and pyruvate were reported to proceed with moderate facial selectivity the best result (84 16) is shown in equation (32). ... 

Since the investigations which used ZnCb and BF3-OEt2 as catalysts, other Lewis acids have been shown to catalyze the cyclocondensation reaction. MgBr2, for example, was used by Pearson and Danishefsky to add the power of chelation control to the reaction. When chiral a-alkoxy aldehydes are condensed with dienes under the influence of MgBr2, products derived from an ACF transition state predominate. The chelation of the metal by the a-alkoxy group of the aldehyde forces the aldehyde side chain to occupy the same side of the aldehyde as the metal. The diene, therefore, can attack the aldehyde from the least hindered exo face giving rise to the trans-KC product (Scheme 5). When an aldehyde is used that cannot form a chelate to the metal (such as benzaldehyde) syn (endo) selectivity is observed. 

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