Carboxylic acids precursors

By screening 53 Rhodococcus and Pseudomonas strains, an NHase-amidase biocatalyst system was identified for the production of the 2,2-dimethylcyclopropane carboxylic acid precursor of the dehydropeptidase inhibitor Cilastatin, which is used to prolong the antibacterial effect of Imipenem. A systematic study of the most selective of these strains, Rhodococcus erythropolis ATCC25 544, revealed that maximal product formation occurs at pH 8.0 but that ee decreased above pH 7.0. In addition, significant enantioselectivity decreases were observed above 20 °C. A survey of organic solvent effects identified methanol (10% v/v) as the... 

Scheme 8.4 Potential carboxylic acid precursors to pregabaiin.

Introduction of the carboxylic acid precursor group [2,3]-Wittig—Still rearrangement... 

The dibromobutene 149 could be monosubstituted using 2-lithio-l,3-dithiane as a carboxylic acid precursor, followed by substitution of the remaining bromide with sodium azide as the amine precursor (Scheme 32). The azide was reduce under Staudinger conditions and acy-lated. After separation of the EIZ isomers, further functional group transformations gave the dimethyl-substituted Gly-Gly alkene isostere 152J123 ... 

The Buszek (—)-octalactin A synthesis is notable for its useage of the Corey-Nicolaou thiopyridyl ester7 protocol for saturated eight-mem-bered lactone construction. Prior to this synthesis, no eight-membered lactone ring had ever been prepared in high yield from the cyclisation of a saturated hydroxy carboxylic acid precursor. This reaction therefore broke important new ground in the arena of complex natural product synthesis. 

The free radical substitution reactions, other than phenylation, of pyridine and its derivatives have received but scant attention. Alkylation of pyridine itself has been studied briefly, the alkyl radicals being generated either by the thermolysis of diacyl peroxides or of lead tetraacetate in acetic acid, or by electrolysis of the carboxylic acid precursor (for summary, see Norman and Radda369). Most of the available results are summarized in Table XIV. These figures on isomer ratios are not very reliable since the analyses were carried out by... 

Early feeding studies established that monensin A is biosynthesized from a classical polyketide pathway and is derived from five acetate, seven propionate, and one butyrate (for monensin B, an additional propionate unit replaces the butyrate) (7). Four of the nine oxygen atoms are derived from molecular oxygen, with the remaining five deriving from the corresponding carboxylic acid precursors (Fig. 2a). Based on these initial... 

The described two-step procedure is uncomplicated and can be carried out in 1 day to give in good yield a product that does not require any further purification. This procedure has been used for the preparation of 3-methyl-, 9-methyl-, and 6-methoxy-l,2,3,4-tetrahydro-j3-carboline and has been modified to obtain 9-phenyl-l,2,3,4-tetrahydro-j3-carboline. The method is generally applicable to the preparation of other 1-unsubstituted tetrahydro-/3-carbolines providing the 1-carboxylic acid precursor is not insoluble in the hot acid used to effect decarboxylation. 

During the total synthesis of phomazarin, D.L. Boger and co-workers closed the B ring of the natural product with a Friedel-Crafts acylation reaction." This key step provided the fully functionalized phomazarin skeleton. The carboxylic acid precursor was exposed to trifluoroacetic anhydride at 50 °C for 72h. The initial product was a C5 trifluoroacetate, which was subsequently hydrolyzed in the presence of air, which oxidized the phenol to the corresponding B-ring quinone. 

Carboxylate anions can be generated in situ from their carboxylic acid precursors and subsequently alkylated [Eq. (48)] [82]. 

Prepare an alcohol from each carboxylic acid precursor given, using any condition and/or reagent necessary. 

Potassium permanganate periodate Ethylene derivatives as carboxylic acid precursors... 

Plausible biosynthetic relationships between the various pre-anthra-quinones discussed above and some of the anthraquinones of Section 3.5.1 are depicted in Scheme 60. Atrochrysone (321) may be considered as the biogenetic precursor of all of the anthraquinones of the emodin family (598). Thus, if water is lost from atrochrysone, emo-din anthrone (335) is produced which could then lead by oxidation to emodin (288). The hypothetical p-keto carboxylic acid precursor (334) to atrochrysone could provide the link between the acidic and the neutral fungal anthraquinones since dehydration followed by oxida-... 

As a rule, alkenes do not react with 78-80 unless there is another reagent present—specifically, a transition metal. This reaction will not be discussed further. In sharp contrast, peroxycarboxylic acids such as 81 react directly with alkenes. Peroxycarboxylic acids 81 are named by adding the term peroxy to the name of the carboxylic acid (see Chapter 5, Section 5.9.3 and Chapter 16, Section 16.4). Using the common names, the peroxy analog of formic acid is peroxyformic acid (82), and others include peroxyacetic acid (83), peroxytrifiuo-roacetic acid (84), peroxybenzoic acid (85), and me a-chloroperoxybenzoic acid (abbreviated mCPBA, 86). Peroxycarboxylic acid 85 is a derivative of the aromatic carboxylic acid benzoic acid (PhCOOH), and the carboxylic acid precursor to 86 is clearly another aromatic carboxylic acid. (The nomenclature and structural features of benzoic acid and other aromatic carboxylic acid derivatives will be discussed in detail in Chapter 21, Section 21.2.) The salient feature of peroxyacids 82-86 is the presence of the electrophihc oxygen atom mentioned previously, which will react with an alkene. 

Each of these acid derivatives has a unique system of nomenclature, but all are fundamentally based on the carboxylic acid precursor (the parent acid). Several examples are shown in Table 16.3. Acid chlorides 56 are named by taking... 

The reaction of anhydrides with aqueous acid or aqueous base is essentially identical to that of acid chlorides (replace Cl with O2CR in the mechanism for 1-6 or 8-7), and it also gives the parent acid as the product. Anhydrides are converted to the anion of the carboxylic acid precursors by base hydrolysis. Base hydrolysis of dibutanoic anhydride with aqueous sodium hydroxide leads to two molar equivalents of sodium butanoate similar reaction with butanoic ethanoic anhydride gives one molar equivalent of sodium ethanoate and one molar equivalent of sodium butanoate. 

All esters discussed so far are acyclic molecules (this means they do not contain rings), but there are also cyclic esters, where both the acyl carbon and the alcohol oxygen are constituent members of a ring, as in 88-90. These cyclic esters are called lactones. The common names for structurally simple lactones arise by using the suffix for the open chain carboxylic acid precursor and the word lactone. Compound 88 is y-butyrolactone and 89 is 6-valerolactone, where the name is taken from the common names for the four-carbon acid (butyric acid) and the five-carbon acid (valeric acid). The lUPAC names are based on the cyclic ether, so 88 is 2-oxoolane and 89 is 2-oxooxane. 

Chiral ketene fragments have proven to offer more general utility in the quest for enantioselective Staudinger reactions. In particular, ketenes containing the Evans oxazolidinone have proven to offer high diastereoselectivities in the synthesis of 3-amino-P-lactams. The ease of preparation of the carboxylic acid precursor, the low cost of the auxiliary, and the facile unmasking of the 3-amino group from the auxiliary all... 

Mixed ketene dimers are also obtained by generating haloketenes in the presence of dimethylketene, by mixing of solutions of two different ketenes, and by cogeneration of two different ketenes from the carboxylic acid precursors Bis(trifluoromethyl)ketene does not dimerize thermally, but it reacts with Me2C=C=0 to form cyclobutanone and /3-propiolactone-type dimers ". The cycloaddition always proceeds across the C=C bond in the dimethylketene. In the reaction with ketene and methylketene, only the jS-propiolactone-type mixed dimers are formed. 

By thermal decomposition of the nano 2D MOCP precursors [Pb(2-pyc)(NCS)] and [Pb(3-pyc)(NCS)] (.Hpyc = pyridinecarboxylic acid) at 400°C, nanorods and nanoplates of PbS were obtained (Figure 3.4) [141]. The sizes and shapes of the nanostructures are related to the structure of the coordination polymers. An identical thermal processing on the [Pb(L4)(p3 3-NCS)(H20)] HL4 = lH-l,2,4-triazole-3-carboxylic acid) precursor has led to the formation of a mixture composed from PbS and Pb (S0 )0 nanoparticles [142]. This reveals that the composition or crystal packing of the initial MOCP may lead to different final products. 

Coehlo and coworkers synthesized the carboxylic acid precursor of (+)-efaroxan (118), an 0.2 adrenoreceptor antagonist, which is a treatment for neurodegenerative disease, migraine, and type II diabetes. The synthesis opened with an MBH reaction which afforded key moieties. Thus, 2-fluorobenzaldehyde 120 was converted to the MBH adduct 121 under ultrasound conditions in 90% yield. After acetylation of the hydroxyl group, the acetylated MBH adduct was treated with dimethyl cuprate to furnish the trisubstituted olefin 122 via an Sn2 reaction. The methyl ester of 122 was reduced to the allylic alcohol which then underwent a Sharpless asymmetric oxidation to furnish the epoxide 123. In several steps, the epoxy alcohol 123 was then converted to the carboxylic acid 124. Upon treatment with sodium hydride the a-hydroxy carboxylic acid, 124 cyclized to deliver the hydrobenzofuran 119 in 65% yield and hence the precursor of (+)-efaroxan (118). 

The authors considered microbial P-hydroxylation to be particularly suitable for further refinement. The availability and low cost of carboxylic acid precursors would favor the large-scale use of processes based on this method, but one major disadvantage is that when optically active p-hydroxycarboxylic acids were obtained, only the (5) form was observed. As noted earlier, (/ )-p-hydroxycarboxylic acids exhibit potential as precursors of pharmaceuticals, and this was one of tiie incentives for the development of a robust, general method for the (R) forms of these intermediates. 

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