1 aldehyde protection acids

Synthesis of the remaining half of the molecule starts with the formation of the monomethyl ether (9) from orcinol (8). The carbon atom that is to serve as the bridge is introduced as an aldehyde by formylation with zinc cyanide and hydrochloric acid (10). The phenol is then protected as the acetate. Successive oxidation and treatment with thionyl chloride affords the protected acid chloride (11). Acylation of the free phenol group in 7 by means of 11 affords the ester, 12. The ester is then rearranged by an ortho-Fries reaction (catalyzed by either titanium... 

In general, the methods for protection and deprotection of carboxylic acids and esters are not as convenient as for alcohols, aldehydes, and ketones. It is therefore common to carry potential carboxylic acids through synthetic schemes in the form of protected primary alcohols or aldehydes. The carboxylic acid can then be formed at a late stage in the synthesis by an appropriate oxidation. This strategy allows one to utilize the wider variety of alcohol and aldehyde protective groups indirectly for carboxylic acid protection. 

Na-Protected a-amino aldehydes 4 are mainly obtained from their corresponding a-amino acid derivatives. Generally the synthetic route proceeds via acid halides, esters, or active amides of a-amino acids that are then reduced. The reduction of N -protected acid halides and esters is often accompanied by some overreduction to the respective alcohols. However, reduction of active amides is apparently free from overreduction. The different procedures described in this review are listed in Table 3. 

The formation of aldehydes widrout a change in oxidation level is not a common synthetic approach because most compounds that can be hydrolyzed to aldehydes widrout change in die oxidation level are formed from aldehydes in the first place. Thus acetals can be hydrolyzed rapidly to aldehydes by acidic water, but drey are normally prepared from aldehydes. As such this is a very common protection strategy for aldehydes wherein they are first converted to an acetal and later hydrolyzed back to the aldehyde when the time is right. 

As with aldehydes, production of ketones by nonredox processes is not a common synthetic approach. Ketone derivatives having the same oxidation level are usually produced from ketones themselves. Several examples of enol and acetal ketone derivatives are shown below. All are prepared from ketones, all can be readily hydrolyzed back to the ketone in the presence of acidic water, and, with the exception of vinyl acetates, all are very stable to strong bases and nucleophiles. Acetals are often used as ketone (and aldehyde) protecting groups while enol derivatives are versatile synthetic intermediates. 

Chiral pyrrolidine derivatives, proline, and amino acid-derived imidazolidinones mediate the asymmetric epoxidation of ,/i-unsalurated aldehydes. Protected a,a-diphenyl-2-prolinol catalyses the asymmetric formation of 2-epoxyaldehydes, with hydrogen peroxide or sodium percarbonate as the oxygen sources, with 81-95% conversion with up to 96 4 dr and 98% ee.204... 

Ladlow and coworkers recently developed an acid-labile fluorous benz-aldehyde protecting group 43 to facilitate the parallel synthesis of sulfonamides 44 (Scheme 25) [56]. The Suzuki coupling reaction was conducted under microwave irradiation. All the intermediates and the final products were purified by F-SPE. 

It has been mentioned in earlier Sections that certain electron deficient heterocyclic carboxylic acids and esters can be reduced electrochemically to aldehydes under acidic conditions, the aldehydes being protected from overreduction by geminal diol formation. This method is also applicable to the corresponding amides, allowing, for example, the conversion of amide (29) into aldehyde (30) in 93% yield. ... 

The alkylation of protected cyanohydrin anions constitutes an excellent method for ketone synthesis. Generally the anions are generated from aliphatic or aromatic aldehyde protected cyanohyd with LDA under nitrogen at -78 C. The addition of an alkyl halide produces the protected ketone cyanohydrin. The carbonyl group is then liberated by successive treatment with dilute acid and dilute aqueous base. This method is applicable for the synthesis of buflomedil. ... 

Optically active dialkyl tartrates and (2i ,4/ )-pentane-2,4-diol were used as homochiral protecting groups in a, 6-unsaturated acetals 51 and 52 which were subjected to Simmons-Smith reaction with diethylzinc and diiodomethane to give cyclopropyl derivatives with a de of > 69% (Table 1). The acetal group was readily converted to the aldehyde by acidic hydrolysis or to the acid by ozonolysis. 

The process scheme (Fig. 12.7-7) starts from the N-protected dipeptide dimer [l-lys-L-homocys]2 disulfide which, after reduction of the S - S bond, is oxidized enzymatically to N-Cbz-L-homo-cys-L-lys-e-aldehyde. Under acidic conditions, the aldehyde group is present as a gem-diol, attacks the a-N and closes the ring to the aminol. After nucleophilic attack of the S - H group, the hydroxyl group acts as a leaving group and affords closure of the 1,3-thiazepine ring. 

Apart from the technical route described to p-apo-8 -carotenal, readily available vitamin A alcohol (Cjo) has served as an intermediate in the form of the phosphonium salt by reaction with the monodiethyl acetal of a Cio dial (ref. 54). The required Cjo monodiethylacetal was obtained (ref.5, p409) by the reaction of the mono aldehyde-protected derivative, the enol ether of methylmalonaldehyde, (C4) with the acetylenic Grignard reagent from trans 3-methyl-2-penten-4-yn-l-ol (C ) followed by acidic dehydration and partial reduction with Lindlar catalyst to give firstly 8-hydroxy-2,6-dimethylocta-2, 4,6-triene-l-al (Cio). Protection of the hydroxyl group by acetylation in pyridine solution with acetyl chloride and formation of the diethyl acetal with ethyl orthoformate followed by hydrolysis of the acetyl group and oxidation afforded the final CIO aldehyde component (D)shown in Scheme 15a. 

A typical example of an application of ozonolysis in synthesis is the cleavage of the alkene unit in 351 to give aldehyde 352, with loss of formaldehyde, a part of Smith s synthesis of (+)-thiazinotrienomycin In this case, the reductive workup used triphenylphosphine. Ozonolysis of 353 gave aldehyde 354, an intermediate in Corey s synthesis of the Cecropia Moth Juvenile hormone, via a reductive workup with DMS. Note that the electron rich vinyl ether moiety reacted in preference to the simple alkene moiety. The ozonolysis product of the methyl vinyl ether was a methyl ester. This method is particularly useful for the preparation of protected acids. In general, electron rich alkenes are oxidized faster than electron-poor alkenes. 

In the key reaction, a [3,3] rearrangement of trifluoroacetimidate 432 provides allylic amine 433 as a single diastereomer. After protecting-group adjustment, ozonolysis of the olefin, and oxidation of the aldehyde to acid, hydrolysis of all the protecting groups under acidic conditions furnishes the desired product [135]. The sole function of the lactic acid, whose carbon skeleton is removed by the ozonolysis, is to ensure the appropriate stereochemistry of the amino group. 

The interesting TBS-protected acid chloride 310, available from monoester 23a by dual silylation of the hydroxyl and ester groups followed by treatment with oxalyl chloride, is an important intermediate in the synthesis of a key fragment (312) of rhisobactin (314), a microbial siderophore (Scheme 42) [92]. Completion of the synthesis of 314 is accomplished by reductive amination of 312 with D-alanine-derived aldehyde 313 followed by hydrolysis of the methyl esters and hydrogenolysis of the Cbz protecting group. 

Conversion of the aldehyde to protected derivatives at the same level of oxidation (such as ketals, oximes, hydrazones) has been long known. A new hydrazone derived from 4-aminothiomorpholine S,S-dioxide has been carefully investigated [134, 138] and some thiazolidine derivatives have been recently evaluated [136]. C-20 thioketals have been recently introduced, which are especially useful as an aldehyde-protecting group when hydrolysis of the acid-labile mycarose is not wanted their synthesis is accomplished by treatment of the aldehyde with diphenyldisulfide and a trialkylphosphine [134, 139]. The aldehyde has also been transformed into ketones with diazoalkanes [134]. 

Precaution Incompat. with strong oxidizing agents Hazardous Decomp. Prods. Aldehydes, org. acids HMIS Health 1, Flammability 0, Reactivity 0 Storage Protect from freezing (material stability may be affected) avoid excessive temps. 

Coupling reactions have also been carried out in a reversal of the imine strategy, by adding a carbanion to an appropriate aldehyde. Thus addition of anion 7.4.21 to acrolein gave racemic adduct 7.4.22 which could be protected, oxidized, and resolved with (+)-ephedrine to give the protected acids 7.4.23 and 7.4.24 (275). 

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