A,O-Acetals

Physiol Properties of Amino Carba-hexopyranose Penta-A/, O- Acetates... 

In reactions of chiral aldehydes, TiIV compounds work well as both activators and chelation control agents, a- or A-oxygcnated chiral aldehydes react with allylsilanes to afford chiral homoallylic alcohols with high selectivity (Scheme 22).85 These chiral alcohols are useful synthetic units for the synthesis of highly functionalized chiral compounds. Cyclic chiral 0,0- and A/O-acetals react with allylsilanes in the same way.86,87 Allenylsilanes have also been reported as allylation agents. 

The [4+2] cycloaddition of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene A, O-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives <06S1513>. 

Using the same principle as that described for l,3-dioxolan-4-ones, it is possible to a-alkylate 2-amino acids without racemization76,78. An A. O-acetal is formed from an (7 )-amino acid 1, e.g., with trimethylacetaldehyde (R2 = -Bu) the l,3-oxazolidin-5-ones 2 and 3 are furnished with a defined diastereoselectivity, which is the first stage in the process of self-reproduction of chirality 82. Formation of the enolate 4 from 2 and attack of an electrophile in the second step gives the product 6 with retention of configuration in the a-position, and 7 with inversion of configuration, again with a defined diastereoselectivity. Hydrolysis yields the a-alkylated amino acids 10 and 11. 

Co(III)] complexes. For example, the coupling of 3-halocholestanes (333) and Michael acceptors affords epimeric mixtures of the 3-homologated steroids (334). The electrochemical nucleophilic acylation of a, 3-unsaturated aldehydes, a,3-unsaturated ketones and a,(3-unsaturated nitriles with acyl anhydrides affords adducts (335) in moderate yields.226a-b Similarly, the reduction of N-methyloxazolinium salts (336) affords die A, O-acetal intermediates (337) which are readily hydrolyzed (Scheme 102).226c... 

Myers and coworkers40 41 have shown evidence for a pseudorotational mechanism in the reaction of the O-silyl ketene A,O-acetal 17 with aromatic aldehydes (equation 8). 

Napieralski cyclization by heating with POCl3 in xylene followed by methanolic workup and saponification of the acetate groups. After selective tosylation of the hydroxyl group at C-2 on 551 usingp-toluenesulfonyl chloride in pyridine, base-induced elimination with DBU in DMSO and hydrolysis of the A, O-acetal with 50% aqueous acetic acid then produced ( )-haemanthidine (382) (2/5). 

Seebach, D., Charczuk, R., Berber, C., Renaud, P, Bener, H and Schneider, H. (1989) Electrochemical decarboxylation of L-threonine and oligopeptide derivatives with formation of A-acyl-A, O-acetals preparation of oligopeptides with amide or phosphonate C-terminus. Helv. Chim. Acta 72,401 125. 

A study of ketene A, O-acetals has shown that such compounds derived from lactam acetals may be used in the preparation of larger heterocyclic systems via reaction with a 1,3-dipolar species, the initial cycloadducts stabilizing their structures by aromatization. Pyrrolo[2,3-i/]-l,2,3-triazole derivatives, however, do not undergo such elimination reactions and stable cycloadducts may be obtained. Thus, the lactam acetals (133) give the ketene A,0-acetals (134), which on reaction with p-nitrophenyl azide yield substituted pyrrolo[2,3-d]-l,2,3-triazole derivatives (135) <86CB359l>. 

Diels-Alder cycloaddition reactions with tetrazines provide a useful approach to the preparation of pyrrolo[2,3-d]pyridazines. Thus, the lactam acetal (97), which is in equilibrium with the cyclic ketene A,O-acetal (98), reacts with tetrazines (99) to give the partially reduced product (100) <86CB3600>. The methylthio analogue of the acetal (97) also reacts similarly with tetrazines (Scheme 7) <87JHC545>. 

A reagent that will bring about aminomethylation of furans as well as pyrroles is the A-silyl-A,O-acetal 132, used with a Lewis acid, and this also gives primary amines, not available from the classical procedures, e.g., Scheme 61 <2003JOC483>. 

Imino esters derived from benzoyl, nitro and ester-substituted acetonitriles behave as ketene A O-acetals in yielding 1,1-enediamines when reacted with amines29,89,90. For example, cyclic 1,1-enediamines 8 have been prepared by the reaction of imidates 54 and diamines (equation 19)29. 

A concise and efficient synthesis of the potent reverse transcriptase inhibitor Elfavirenz [Scheme 3.130] by the DuPbnt-Merck process development groups entailed the removal of an A O-acetal under basic conditions.252 Oxidation of the N-p-methoxybenzy derivative 130.1 with DDQ at 0 °C generated the NtO-acetal 130.2 in quantitative yield. Treatment of 130,2 with sodium hydroxide in... 

Electrochemical oxidation gives, S,0-acctals199 (e. g. conversion of 11 to 12) and -V,( -acctals200 in high yields. A. O-Acetals or hemiacetals are also synthesized starting from the corresponding pyrimidines201 or pyridinium salts.202... 

Syntheses of indolizidine and diazatricyclic mazangamine alkaloids using cyclic A,O-acetals 03YGK868. 

Reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with 6-methoxy-l,2,3,4-tetrahy-dropyridine gives dimethyl l,2,3,4-tetrahydropyrido[2,3-<5f]pyridazine-5,8-dicarboxylate. Apparently the lactim ether is in tautomeric equilibrium with the corresponding cyclic ketene A,O-acetal, which acts as the dienophile, the final step being the elimination of methanol.73 For a related synthesis, see ref 74. 

Furthermore, mixed ketene A. O-acetals have been generated from ally] /V-phenylimidates by thermal in situ double-bond isomerization250. 

The high selectivity has been attributed to a preferred Z configuration of the ketene A,O-acetal intermediates due to more stcric hindrance in the E-configurated intermediate with bulky A-substituents, especially in the conformation which allows conjugation of the nitrogen lone pair with the 7t-system. 

The results indicate in this case a predominant Z configuration of the vinyl double bond in the ketene A, O-acetal intermediate provided that the reaction proceeds via a chairlike transition state. A change in solvent (THF/HMPA) does not invert the relative configurations of the products. The striking drop in stereoselectivity for the methoxy derivative (R1 = OCH3) has been attributed to a combination of two opposing factors ... 

Scheme 30. Lewis acid-induced nucleophilic alkylation of A O-acetals in the approach by Kibayashi of the tricyclic core...

Reviews Concerning the Synthesis and Reactions of A/.O-Acetals and Their Use in Asymmetric Synthesis 112... 

A/,0-Acetals are extremely sensitive to hydrolysis and therefore seldom used to protect simple amines, but their stability is significantly enhanced if the nitrogen atom is embedded in a functional group wherein the basicity of the nitrogen is diminished by delocalisation as in amides, carbamates and aromatic heterocycles. Our discussion of A O-acetals as N-protecting groups can be divided into... 

A/, O-Acetals afford robust protection for indoles and pyrroles with SEM and BOM ethers being particular favourites. A SEM group has also been used to protect imidazole. They are introduced in much the same way as already discussed for amines and amides in section 8.6.1. Hence treatment of Indolelactam derivative 274.1 with SEMCl and sodium hydride in THF at -15 °C afforded the N,0-acetal 274.2 in >80% yield. s... 

Remote asymmetric induction can be obtained through the use of chiral auxiliaries, such as valine derived oxazolidinones, within the framework of the vinylogous Mukaiyama aldol reaction. During the synthesis of khafrefungin, an antifungal agent, Kobayashi and coworkers reacted the vinylketene silyl A. O-acetal 56 with the aldehyde 57 to yield the a r/-aldol adduct 58 in excellent yield (98%) and high diastereoselectivity (> 20 1). ... 

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