Aldehydes, 3-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. 

Results of the asymmetric 2-propenylborations of several chiral a- and /i-alkoxy aldehydes are presented in Table 11 74a-82 84. These data show that diisopinocampheyl(2-propenyl)borane A and l,3-bis(4-methylphenylsulfonyl)-4,5-diphenyl-2-propenyl-l,3,2-diazaborolidine C exhibit excellent diastereoselectivity in reactions with chiral aldehydes. These results are in complete agreement with the enantioselectivity of these reagents in reactions with achiral aldehydes (Section 1.3.3.3.3.1.4.). In contrast, however, the enantioselectivity of reactions of the tartrate 2-propenylboronate B (and to a lesser extent the tartrate (/i)-2-butenylhoronate)53b is highly... 

Table 11. Double Asymmetric Reactions of Chiral 1- and fl-Alkoxy Aldehydes...

The stereoselectivity of aldol addition is also affected by chelation.81 a- and P-Alkoxy aldehydes can react through chelated structures with Li+ and other Lewis acids that can accommodate two donor groups. 

The potential for coordination depends on the oxy substituents.82 Alkoxy substituents are usually chelated, whereas highly hindered silyloxy groups usually do not chelate. Trimethylsiloxy groups are intermediate in chelating ability. The extent of chelation also depends on the Lewis acid. Studies with a-alkoxy and (3-alkoxy aldehydes with lithium enolates found only modest diastereoselectivity.83... 

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... 

Systematic studies of the reactions of tartrate allyl-boronates with a series of chiral and achiral alkoxy-substituted aldehydes show that conformationally unrestricted a- and /f-alkoxy aldehyde substrates have a significant negative impact on the stereoselectivity of asymmetric allyl-boration. In contrast, con-... 

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... 

Therefore, a more complex homologative cycle was set up involving the addition of 25a to alkoxy aldehydes and the inversion of the hydroxyl group. By this reaction sequence, the aldehyde 26 was converted into the two tetroses 30 and 34 and four pentoses 35, 37,... 

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