Aldehydes imine protection

A convenient new one-pot procedure for the selective reduction of ketones in the presence of aldehydes (the less usual chemoselectivity) is outlined in Scheme 9. ° The aldehyde is protected as an imine and the ketone is then reduced in situ with a hindred hydride reagent the aldehyde is regenerated on hydrolytic work-up. Conjugated and aromatic aldehydes are protected satisfactorily by this sequence, and moderate discrimination between aliphatic and aromatic aldehydes, with preferential reduction of the aromatic aldehyde, can also be achieved. These authors claim better selectivity than previous methods based on ketalization or hydration of aldehydes with lanthanoid cation catalysts (4,141). 

An interesting extension of this method involves the reaction of Af-silyl oxyketene imines derived from cyanohydrins (Scheme 19) [81]. By judicious selection of the protecting group on the oxygen, highly functionalized (3-hydroxy cyanohydrins can be accessed with high levels of enantio- and diastereoselectivity. These products can then be transformed into a diversity of structural motifs (amines, aldehydes, imines, ketones) important for the synthesis of polyketide and other classes of natural products. In addition, the ethers can be easily converted to enantiomerically enriched unsymmetrical benzoins, thus revealing the synthetic equivalency of A-silyl oxyketene imines as acyl anions (Scheme 19). 

Later, the same group succeeded in achieving a cascade Michael/nitro-Mannich/ acetalization reaction by the combination of covalent enamine catalysis and noncovalent bifunctional base/Br0nsted acid catalysis [32]. The fuUy substituted piperidines with diverse substitution patterns were prepared efficiently starting from simple aliphatic aldehydes, Ts-protected imines, and trani -P-nitro alkenes (Scheme 9.36). This finding effectively incorporated prolinol silyl ether-catalyzed Michael addition of aldehyde 65 to nitroalkene 75 and valine-derived bifunctional thiourea-mediated nitro-Mannich reaction of y-nitro aldehyde 106 to imine 105 in the cascade process, providing a complementary contribution to the well-known single catalyst-promoted triple cascade reactions and two catalyst-promoted reaction cascades. 

Other methods of protecting the aldehyde group include formation of an enol acetate, an enamine, or an imine (174,175). In the enamine route, regeneration of the aldehyde is accompHshed simply by the addition of water. 

In general, imines are too reactive to be used to protect carbonyl groups. In a synthesis of juncusol, however, a bromo- and an iodocyclohexylimine of two identical aromatic aldehydes were coupled by an Ullman coupling reaction modi-fied by Ziegler. The imines were cleaved by acidic hydrolysis (aq. oxalic acid, THF, 20°, 1 h, 95% yield). Imines of aromatic aldehydes have also been prepared... 

A number of imine derivatives have been prepared as amine protective groups, but most of these have not seen extensive use. The most widely used are the ben-zylidene and diphenylmethylene derivatives. The less used derivatives are listed, for completeness, with their references at the end of this section. For the most part, they are prepared from the aldehyde and the amine by water removal cleavage is effected by acid hydrolysis. 

The Borsche modification describes the protection of the aldehyde as an imine ... 

The synthesis of the E-ring intermediate 20 commences with the methyl ester of enantiomerically pure L-serine hydrochloride (22) (see Scheme 9). The primary amino group of 22 can be alkylated in a straightforward manner by treatment with acetaldehyde, followed by reduction of the intermediate imine with sodium borohydride (see 22 —> 51). The primary hydroxyl and secondary amino groups in 51 are affixed to adjacent carbon atoms. By virtue of this close spatial relationship, it seemed reasonable to expect that the simultaneous protection of these two functions in the form of an oxazolidi-none ring could be achieved. Indeed, treatment of 51 with l,l -car-bonyldiimidazole in refluxing acetonitrile, followed by partial reduction of the methoxycarbonyl function with one equivalent of Dibal-H provides oxazolidinone aldehyde 52. 

Parmar et al have developed a method for resolving racemic mixtures of a variety of natural and nonnatural amino acids using the ethyl ester of the amino acid protected at the amino position hy the formation of a Schiff base with an aromatic aldehyde such as /)-chlorobenzaldehyde. Both chymotrypsin and Lip such as porcine Lip gave good yields of the L-amino acid which precipitates out of solution as the amino acid ester released from the imine is cleaved by the hydrolase. 

The chiral cyanohydrins also lead directly to a-hydroxy acids by hydrolysis (sequence B) [69] and to protected a-hydroxy aldehydes by first hydroxyl group protection, followed by reduction of the nitrile and hydrolysis of the intermediate imine (not shown) (sequence C) [114]... 

Aldehydes can also be laterally lithiated if protected as imidazolidines (527) or as imines (528)". With imines, LUMP must be used to prevent nucleophilic addition to C=N (Scheme 207). 

SCHEME 18. Route to enantiomericaUy pure a-hydroxy and a-amino-carbonyl compounds by addition of chiral d synthons 143 to aldehydes and imines. X = H, OH G = protecting group... 

To avoid overoxidation, primary amines (e.g. 128, equation 89) can be converted into Schiff bases with an aromatic aldehyde. Subsequent oxidation of the resultant imines 129 with an excess of peracids produces oxaziridines 130 and/or nitrones 131. Both of them produce hydroxylamines 132 (equation 89) upon hydrolysis in moderate to good overall yields. Yields of hydroxylamines are considerably better if anisaldehyde instead of benzaldehyde is used for the protection . ... 

Alkylation and deprotection of N-protected aminomethylphosphonate esters 6 are shown in Scheme 6. The nitrogen is protected as the imine derived from benzophenone or a benz-aldehyde, and a variety of conditions are used for deprotonation and alkylation (Table 2). The benzaldehyde imine of aminomethylphosphonate can be deprotonated with LDA and alkylated with electrophilic halides (entries 1 and 2). For the best yields, saturated alkyl bromides require an equivalent of HMPA as an additive. 36 Allylic esters can be added to the carbanion with palladium catalysis (entries 3-7). 37,38 For large-scale production, phase-transfer catalysis appears to be effective and inexpensive (entries 8-12). 39,40 ... 

Perhaps the most useful part of the reported synthesis is the facile preparation of (—)-pyrimidoblamic acid (12 Scheme 3). A key to this synthesis is the preparation of the fully substituted pyrimidine 8. This was done by a one-pot inverse electron demand Diels-Alder reaction between the symmetrical triazine 7 and prop-1-ene-1,1-diamine hydrochloride, followed by loss of ammonia, tautomerization, and loss of ethyl cyanoformate through a retro-Diels-Alder reaction. Selective low-temperature reduction of the more electrophilic C2 ester using sodium borohydride afforded 9, the aldehyde derivative of which was condensed with 7V -Boc-protected (3-aminoalaninamide to give the imine 10. Addition of the optically active A-acyloxazolidinone as its stannous Z-enolate provided almost exclusively the desired anti-addition product 11, which was converted into (—)-pyrimidoblamic acid (12). Importantly, this synthesis confirmed Umezawa s assignment of absolute configuration at the benzylic center. 

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