Aldehydes, a-alkoxy

Addition of alkynes to a-alkoxy aldehydes is most favorably performed with the corresponding zinc reagents (Table 12)46. As with Grignard reagents, the chelation-controlled addition of zinc alkynes proceeds with higher diastereoselectivity when diethyl ether rather than tetrahydrofuran is used as reaction solvent. 

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. 

The nucleophilic addition of Grignard reagents to a-epoxy ketones 44 proceeds with remarkably high diastereoselectivity70. The chelation-controlled reaction products are obtained in ratios >99 1 when tetrahydrofuran or tetrahydrofuran/hexamethylphosphoric triamide is used as reaction solvent. The increased diastereoselectivity in the presence of hexamethylphos-phoric triamide is unusual as it is known from addition reactions to a-alkoxy aldehydes that co-solvents with chelating ability compete with the substrate for the nucleophile counterion, thus reducing the proportion of the chelation-controlled reaction product (vide infra). 

Whereas the nucleophilic addition of vinylmagnesium bromide to a-alkoxy aldehydes (12, 16) proceeds with a low to moderate chelation-controlled diastereoselectivity, a remarkably high preference for the opposite stereochemical behavior is found with the jS-silyl phosphorus ylide 1477. Due to the electron-donating 4-methoxyphenyl substituents at the phosphorus atom, as well as the /i-methyldiphenylsilyl group, 14 is an excellent vinylation reagent which does not lead to any Wittig olefination products. 

In each instance, the silyl enol ether approaches anti to the methyl substituent on the chelate. This results in a 3,4-syn relationship between the hydroxy and alkoxy groups for a-alkoxy aldehydes and a 3,5-anti relationship for (3-alkoxy aldehydes with the main chain in the extended conformation. 

Heteroatom substituents also introduce polar effects. In the case of a-alkoxy aldehydes the preferred TS appears to be F and G for the E- and Z-enolates, respectively. These differ from the normal Felkin TS for nucleophilic addition. The reactant conformation is believed to be determined by minimization of dipolar repulsion between the alkoxy substituent and the carbonyl group.96 This model predicts higher 3,4-anti ratios for Z-enolates, and this is observed. 

In the presence of zinc chloride, stereoselective aldol reactions can be carried out. The aldol reaction with the lithium enolate of /-butyl malonate and various a-alkoxy aldehydes gave anti-l,2-diols in high yields, and 2-trityloxypropanal yielded the syn-l,2-diol under the same conditions.633 Stoichiometric amounts of zinc chloride contribute to the formation of aminoni-tropyridines by direct amination of nitropyridines with methoxyamine under basic conditions.634 Zinc chloride can also be used as a radical initiator.635... 

Alkynylzinc bromides, BrZnC=CR.6 Unlike magnesium and lithium ace-tylides, these reagents add to an a-alkoxy aldehyde with good to high syn-selectivity. Example ... 

Diastereoface selection has been investigated in the addition of enolates to a-alkoxy aldehydes (93). In the absence of chelation phenomena, transition states A and B (Scheme 19), with the OR substituent aligned perpendicular to the carbonyl a plane (Rl = OR), are considered (Oc-or c-r transition state R2 Nu steric parameters dictate that predoniinant diastereoface selection from A will occur. In the presence of strongly chelating metals, the cyclic transition states C and D can be invoked (85), and the same R2 Nu control element predicts the opposite diastereoface selection via transition state D (98). The aldol diastereoface selection that has been observed for aldehydes 111 and 112 with lithium enolates 99, 100, and 101 (eqs. [81-84]) (93) can generally be rationalized by a consideration of the Felkin transition states A and B (88) illustrated in Scheme 19, where A is preferred on steric grounds. 

SCHEME 20. Debromination of bromoalkenes 146. Synthesis of diols 151, O-protected a-alkoxy aldehydes 152 and Q-.o- -dialkoxyketones 153 G = protecting group... 

SCHEME 22. Stereochemical outcome of the addition of polar organometallic compounds R"M to a-alkoxy aldehydes and ketones (G = protecting group)... 

Grignard reagents show some stereoselectivity in reactions with a-alkoxy aldehydes (threolerythreo = 10 1), but only slight stereoselectivity obtains in reactions with /J-alkoxy aldehydes. On the other hand, fairly high stereoselectivity is observed in the reaction of lithium dialkylcuprates with /5-alkoxy aldehydes, and again formation of the //ireo-product is favored (equation III). s... 

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). 

Stereoselective addition to an a-alkoxy aldehyde.3 The addition of organo-metallic reagents to acrolein dimer 1 can be controlled to a remarkable extent by the metal, evidently as a result of chelation, with R2Zn being more stereoselective than RLi or RMgBr. 

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. 

Figure 8C.9. Transition states of carbonyl-ene and aldol-type reaction of a-alkoxy aldehyde.

Allylic alcohols from sulfones.1 Polish chemists have extended the Julia synthesis of alkenes (11, 474) to a synthesis of allylic alcohols. In the presence of 1 equiv. of BF3 etherate, a-alkoxy aldehydes react with lithiafed sulfones to form adducts that are converted to allylic alcohols on reduction with sodium amalgam. This reaction was developed specifically for a synthesis of prostaglandins from Corey s lactone-aldehyde, but should have wider application. 

However, a reversal of the diastereofacial selectivity may arise when the substrate has, in a or position of the side chain, a group prone to complexation with the Lewis acid. Then, the use of bidentate Lewis acids such as MgBr2, TiCU or ZnC allows the reaction to proceed under a chelation control model, providing preferentially the syn adduct for a 1,4-chelation and the anti adduct for a 1,5-chelation. This was exploited in the stereoselective synthesis of both diastereomers, simply by changing the chelation conditions on the substrate . An impressive amount of work was done with various a-alkoxy aldehydes as a route to carbohydrate chemistry. Similarly, a-amino aldehydes were used as substrates for /3-amino alcohol synthesis . ... 

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. 

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