Penicillin derivatives synthesis

Therapeutics. Compounds containing the furan or tetrahydrofuran ring are biologically active and are present in a number of pharmaceutical products. Eurfurjdamine [617-89-0] is an intermediate in the diuretic, furosemide. Tetrahydrofurfurylamine [4795-29-3] may also have pharmaceutical applications. 5-(E)imethyiaininomethyi)furfuryi alcohol [15433-79-17 is an intermediate in the preparation of ranitidine, which is used for treating ulcers. 2-Acet5dfuran [1192-62-7] prepared from acetic anhydride and furan is an intermediate in the synthesis of cefuroxime, a penicillin derivative. 2-Euroic acid is prepared by the oxidation of furfural. Both furoic acid [88-14-2] and furoyl chloride [527-69-5] are used as pharmaceutical intermediates. 

Another synthetic sequence leading to penicillin derivatives is illustrated in Scheme 61 (77MI51102). Note that the cycloaddition of azidoacetyl chloride to the thiazoline affords an azidopenam with the 6-epi configuration. Equilibration leads to a mixture of (81) and (82) in a ratio of 4 1, but repeated recycling allowed the isolation of (82) in 40% yield. A related synthesis was shown in Scheme 26. 

Tbe penicillin derivatives 311, 312 <1982SC85>, and 313 <1983TL201> were converted to 1,4-tbiazines in good yields (Scheme 79). Another synthesis of a 1,4-thiazine from a bicyclic compound has also been reported (Equation 112) <1986J(P1)2187>. 

Semisynthetic heterocycles are also important dmg molecules. These compounds attempt to capture the best of both worlds, being synthetic derivatives of natural products. The use of a natural product in the preliminary stages of the synthesis enables the elimination of numerous costly synthetic steps. The subsequent synthetic modifications enable further fine tuning of the natural product pharmacophore. There are a number of semisynthetic penicillin derivatives available. Similarly, there are also semisynthetic hormone analogs, especially of estrogens and gestagens. 

Acetyl furan [1192-62-7], prepared from acetic anhydride and furan is an intermediate in the synthesis of cefuroxime, a penicillin derivative. 2-Furoic acid is prepared by the oxidation of furfural. Both furoic acid [88-14-2] and furoyl chloride [527-69-5] are used as pharmaceutical intermediates. 

Baldwin and Christie (18) have proposed that the origin of this difference almost certainly derives from a stereoelectronic factor. In 64 and 65, the Cg - S bond is more nearly orthogonal to the B-lactam amide plane than the C — S bons is, with respect to the thiazolidine amide plane (cf. 66). The Cg - S bond is therefore weaker than the CA - S bond and is preferentially cleaved. With tricyclic a-lactam 61, due to the five-membered ring, the C - S bond becomes more nearly orthogonal to the thiazolidine amide plane (cf. 67). As a consequence, the ordering of bond lability is reversed and the C — S bond is cleaved more readily. The stereoelectronically controlled step 61 63 has led to a stereospecific synthesis of a penicillin derivative from a peptide precursor. 

The earliest reports of constrained Ugi adducts derived from bi-functional precursors appeared in the 1960s with the preparation of penicillin derivatives such as 68, involving sequential Asinger and Ugi four-component reactions (Scheme 11.13). As such, the synthesis represents the shortest preparation of a known penicillin derivative [65], The /Mactam ring is formed after isocyanide addition to the cyclic Schiff base, followed by carboxylate nitrilium ion trapping and acyl transfer to give the final penicillin core. In this example, the amine and carboxylic acid inputs may be considered tethered. 

LC Blaszczak, NG Halligan, DE Seitz. Radioiododestannylation convenient synthesis of a stable penicillin derivative for rapid penicillin binding protein (PBP) assay. J Labelled Compd Radiopharmacol 27 401-406, 1989. 

A known p-lactam type antibiotic (for example, benzhydryl 2-p-chloromethyl-2-a-methylpenam-3-a-carboxylate) was used for synthesis of new penicillinic derivatives. 

The first highly stereocontrolled total synthesis of a natural penicillin was reported 2 years later by Baldwin et al. <1976JA3045>. In this case, the methodology relies on the formation of the fi-lactam ring before the thiazolidine ring closure, via the sulfenic acid intermediate 97 (Rz = OH), which gives electrophilic attack on the double bond to produce a penam sulfoxide 98 (see Section 2.03.5.3) (Scheme 52). A similar route has been developed independently by Kishi for the total synthesis of 6cr-methoxy penicillin derivatives <1975JA5008>. 

Miscellaiieoiis Additions.—Aoyama and his co-workershave reported the synthesis of p-lactams (115) by photocyclization of the methacrylamides (116). Photocyclization of the azetidinones (117) affording the penicillin derivatives (118) has been the subject of a patent application. ... 

The halogen-magnesium exchange of a-halo carbonyl compounds has been reported to afford magnesium enolates which react with aldehydes to yield aldol products [107, 108]. The application of this reaction to the synthesis of penicillin derivatives has been reported (Scheme 3.94) [109-111]. 

Woodward s Phosphorane Route. The first penem synthesis, shown in Figure 2, utilized an intramolecular Wittig reaction to form the [2,3] double bond of the thiazoline ring (84). Reductive acylation of the penicillin derived disulfide (44) gave the thioester (45). Ozonolysis of the latter provided the oxalimide (46) which on mild methanolysis gave the azetidinone (47). Well established methods were applied to convert (47) to the phosphorane (48) which underwent thermal cydization to the penem ester (49). Catalytic hydrogenation gave the penem acid [64370-39-4] (50) which was shown to possess antibacterial activity in spite of its rather limited stability. 

Acid-induced reactions of silicon-containing unsaturated compounds with A -acyliminium intermediates have proven particularly useful. Allylsilanes lead to the corresponding allyl-substituted products. This reaction proceeds well even for -lactams (equation 49). 5.86 j, g penicillin-derived 4-acetoxyazet-idinone (91) reacts with excess allylsilane in refluxing dichloroethane, catalyzed by TMSOTf, to produce as the sole product trans compound (92). A -Acyliminium ions generated from cyclic ureas and carbamates (93) likewise yield allylated products with virtually complete trans stereoselectivity (equation SO). Allylstannanes react under somewhat milder conditions than allylsilanes, requiring only a catalytic amount of BFsZ EtjO at room temperature for a 3-lactam system (equation 51). This allylstannane procedure was applied to cyclic carbamate systems for the stereoselective synthesis of several isomers of statine. Thus, ethoxycarbamate (94) reacts with methallyltributylstannane in excellent yield and dia-stereoselectivity (equation 52). ... 

An interesting synthesis of tiazofurin is that in which the penicillinate derivative 573 was condensed with the 2,5-anhydro-D-allonoyl chloride 507... 

Penicillin Formation by Penicillium Chrysogenum. The first reactions of the penicillin biosynthetic pathway are identical to the ones in A. chrysogenum (Figure 1.1-1). IPN, however, is not epimerized to penicillin N instead it is converted to 6-aminopenicillanic acid (6-APA) by removal of the L-a-aminoadipic acid side chain, which is substituted by a hydrophobic acyl group. Both steps are catalyzed by the same enzyme, the acyl coenzyme A IPN acyltransferase (IAT). The enzymatic activity of lAT is believed to be the result of the processing of a 40-kD monomeric precursor into a dimeric form consisting of two subunits with MWs of 11 and 29 kD. Due to the broad substrate specifity of lAT, various penicillin derivatives are synthesized naturally by attachment of different acyl-CoA derivatives to the 6-APA-core. For industrial purposes, to facilitate extraction by organic solvents, synthesis usually is directed to the less hydrophilic penicillin V or penicillin G. This is by addition of phenoxyacetic acid or phenylacetic acid, respectively, as precursors to the culture broth. 

A large number of 1-oxa-l-dethiacephalosporins have been prepared from a readily available penicillin-derived azetidinone. The central feature of the synthesis is the use of an intramolecular Wittig reaction, as shown in Scheme 140, to form the dihydro-oxazine ring. ... 

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