Carboxylic acid derivatives, activation

Activated Adds Chern. Soc. Rev. 1983, 12, 129 Angew. Chern. fnt. Ed. Engl. 1978, 17, 569. RC02F4 "activated acid" carboxylic acid derivative (ester, amide, etc.)... 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

Rates of debromination of bromonitro-thiophenes and -selenophenes with sodium thio-phenoxide and sodium selenophenoxide have been studied. Selenophene compounds were about four times more reactive than the corresponding thiophene derivatives. The rate ratio was not significantly different whether attack was occurring at the a- or /3-position. As in benzenoid chemistry, numerous nucleophilic displacement reactions are found to be copper catalyzed. Illustrative of these reactions is the displacement of bromide from 3-bromothiophene-2-carboxylic acid and 3-bromothiophene-4-carboxylic acid by active methylene compounds (e.g. AcCH2C02Et) in the presence of copper and sodium ethoxide (Scheme 77) (75JCS(P1)1390). 

The cinnamyl ester can be prepared from an activated carboxylic acid derivative and cinnamyl alcohol it is cleaved under nearly neutral conditions [Hg(OAc)2, MeOH, 23°, 2-4 h KSCN, H2O, 23°, 12-16 h, 90% yield]. 

The cinnamyl ester can be prepared from an activated carboxylic acid derivative and cinnamyl alcohol or by transesterification with cinnamyl alcohol in the presence of the H-Beta Zeolite (toluene, reflux, 8 h, 59-96% yield). It is cleaved under nearly neutral conditions [Hg(OAc)2, MeOH, 23°, 2-A h KSCN, H2O, 23°, 12-16 h, 90% yield]or by treatment with Sulfated-Sn02, toluene, anisole, reflux. The latter conditions also cleave crotyl and prenyl esters. 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

Carboxylic acid derivatives of heterocycles have proved a source of compounds that show the same allergic mediator release inhibiting activity as sodium cromoglycate. A number of these agents have been taken to the clinic for trial as antiallergic agents. 

The discovery of the utility of the bis-chromone carboxylic acid derivative cromolyn sodium in the treatment of asthma and related allergies has led to an intensive, and thus far not very fruitful, effort to discover analogues which would show oral activity in contrast to the lead which must be administered by inhalation. Preparation of a typical analogue, proxicromil (63), starts with the O-allylated phenol 57. Claisen rearrangement leads to the corresponding C-allylated product 58. 

As noted in the preceding section, one of the most general methods of synthesis of esters is by reaction of alcohols with an acyl chloride or other activated carboxylic acid derivative. Section 3.2.5 dealt with two other important methods, namely, reactions with diazoalkanes and reactions of carboxylate salts with alkyl halides or sulfonate esters. There is also the acid-catalyzed reaction of carboxylic acids with alcohols, which is called the Fischer esterification. 

The best yields are obtained when the ketene has an electronegative substituent, such as halogen. Simple ketenes are not very stable and must usually be generated in situ. The most common method for generating ketenes for synthesis is by dehydrohalo-genation of acyl chlorides. This is usually done with an amine such as triethylamine.167 Other activated carboxylic acid derivatives, such as acyloxypyridinium ions, have also been used as ketene precursors.168 Ketene itself and certain alkyl derivatives can be generated by pyrolysis of carboxylic anhydrides.169... 

Use of the relatively small cyclopropane ring drastically reduces the potential for deleterious steric bulk effects and adds only a relatively small lipophilic increment to the partition coefficient of the drug. One of the clever elements of the rolicyprine synthesis itself is the reaction of d,l tranylcypromine (67) with L-5-pyrrolidone-2-carboxylic acid (derived from glutamic acid) to form a highly crystalline diastereomeric salt, thereby effecting resolution. Addition of dicyclohexylcarbodiimide activates the carboxyl group to nucleophilic attack by the primary amine thus forming the amide rolicyprine (68). 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

Further activities in research into 6-amino-7-oxotetrahydro-177,577-pyrazolo[l,2- ]pyrazole-l-carboxylic acid derivatives 677 exhibiting inhibition of penicillin-binding protein have been reported <1997JHC1323>. 

The cyclization of the five-atom component O-acylated amidoximes 204 leads to 1,2,4-oxadiazoles via C-N bond formation as shown in Scheme 30. The requisite O-acylated amidoximes 204 are accessed via the reaction of an amidoxime with an activated carboxylic acid or a carboxylic acid derivative. Often the O-acylated amidoxime 204 is not isolated and the cyclization is either spontaneous or occurs in a one-pot process, and these approaches are dealt with in Section 5.04.9.1.2 as syntheses from a one-atom component and a four-atom component. In this section, only those methods in which the O-acylated amidoxime 204 is isolated and cyclized in a separate step are dealt with. 

Optically active 3-arylisoxazoline-5-carboxylic acid derivatives 403 or 404 have been, prepared by the reaction of (S)- or (/ )-3-acryloyl-4-benzyl-5,5-dimethyloxazolidin-2-one (405 or 406) with nitrile oxides, obtained from benzo-hydroximoyl chloride and its substituted derivatives in the presence of a catalytic amount of metal salt, for example, Yb(OTf)3 (445). This procedure improves the diastereoselectivity of compounds 403 or 404, which are industrially useful as intermediates for various drugs and agrochemicals. It also enables the amount... 

Namely, allyl alcohol is successively treated with diethylzinc, (R,R) dipropyl tartrate, and 4-methoxybenzohydroximinoyl chloride (163) to afford the enantiomeric isoxazoline alcohol 166, which under the Jones oxidation conditions affords the corresponding carboxylic acid derivative (167). Treatment of compound 167 with hydroxylamine-O-triflate followed by tri-fluoroacetic acid gives rise to the desired enantiomeric 165 in high excess enantiomeric yield. The synthesis of other isosteric analogues of 165 was reported in the same paper. None of the isosteric analogues exhibits LpxC inhibitory and antibacterial activities [103]. 

The asymmetric synthesis of / -branched carboxylic acid derivatives was accomplished by conjugate addition of mixed organoaluminum reagents to optically active Arabinose-derived c -unsaturated A-acyloxazolidinones (Scheme 47). Efficient stereocontrol was achieved using different optically active bicyclic oxazolidinones, yielding (.R)- or ( -configured / -branched carboxylic acid derivatives.136a... 

Homogeneous Hydrogenation of Aldehydes, Ketones, Imines and Carboxylic Acid Derivatives Chemoselectivity and Catalytic Activity 413... 

The development of diversification linkers allows introduction of an additional element of diversity. Upon completion of the synthesis sequence, the linker is activated facilitating nucleophilic release of the library members from support In the ideal case, as implemented with the acylsulfonamide linker (Scheme 4a), the activated linker is sufficiently reactive that limiting amounts of nucleophile may be added to provide pure product after resin filtration.181 Diversification linkers have been developed for the preparation of carboxylic acid derivatives (Scheme 4a), amines (Scheme 4b),191 aromatic (Scheme 4c) and even heteroaromatic compounds (Scheme 4d).1101... 

Attack on Unsaturated Carbon. The annual addition of phosphites to every variety of activated double bond continues. These include nitro-alkenes,9 a/S-unsaturated carboxylic acid derivatives,10 maleimides,11 fulvenes,12 and pyridinium salts.13 The reaction of diethyl phosphite with keten 0,N-, S,N, and Al,AT-acetals has been used to prepare the enamine phosphonates (19).14... 

GatCAB amidotransferase.This natural product mimics the charged 3 -terminus of aa-tRNA and has been used as a tool for the study of protein biosynthesis. The parent compound 22 is a very weak inhibitor of AdT. The amino acid chain is related to tyrosine and differs from the glutamic and aspartic side chains transformed in the kinase or the transamidase steps. Replacement of the methoxyphenyl moiety of puromycin by carboxylic acid derivatives (23-26) improved the ability to inhibit this AdT. Stable analogues of the transition state in the last step of the transamidation process (27-29) where the carbonyl to be attacked by NH3 is replaced by tetrahedral sulfur or phosphorus atom with a methyl group mimicking ammonia exhibited the highest activity. 

The next step is an unusual approach to making an ester via an Sn2 reaction. We usually make esters by the reaction of alcohols with activated carboxylic acid derivatives like acyl chlorides, or anhydrides as we have just seen. We do not particularly want to have to convert the carboxylic acid (X) into a more reactive... 

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