3-Hydroxy-/3-lactams

If a bromomethyl- or vinyl-substituted cyclopropane carbon atom bears a hydroxy group, the homoallyiic rearrangement leads preferentially to cyclobutanone derivatives (J. Sa-laun, 1974). Addition of amines to cydopropanone (N. J. Turro, 1966) yields S-lactams after successive treatment with tert-butyl hypochlorite and silver(I) salts (H.H. Wasserman, 1975). For intramolecular cyclopropane formation see section 1.16. 

ANHBIOHCS - BETA-LACTAMS - PENICILLINS AND OTTiERS] (Vol 3) 2,4,Bis(n-octylthio-6-(4-hydroxy-3,5-di-tert-butylamlino)-l,3,5-tria2ine) [991-84-4]... 

ANTTBIOTTCS - BETA-LACTAMS - BETA-LACTAMASE INHIBITORS] (Vol 3) [2(R)-(2a,3(Z),5a)]-3-(2-Hydroxy-ethylidine)-7-oxo-4-oxa-l-a2abicyclo [3.2.0.]heptane-2-carboxyhc acid... 

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

Huonnations with DAST proceed with high chemoselectivity In general, under very mild reaction conditions usually required for the replacement of hydroxyl groups, other functional groups, including phenolic hydroxyl groups [112], remain intact This provides a method for selective conversion of hydroxy esters [95 97] (Table 6), hydroxy ketones [120, 121], hydroxy lactones [722, 123], hydroxy lactams [124] and hydroxy nitriles [725] into fluoro esters, fluoro ketones, fluoro lactones, fluoro lactams, and fluoro nitnles, respectively (equations 60-63)... 

Ebumamonine was assembled utilizing a Pictet-Spengler cyclization of hydroxy-lactam 52 in the presence of trifluoroacetic acid at low temperature to give a mixture of diastereomers 53 in 95% yield. These compounds were readily separated by chromatography and the a-epimer was further elaborated to give the natural product. 

The hydroxamic acid function in most alicyclic and aromatic compounds is stable to hot dilute acid or alkali, and derivatives cannot undergo normal base-catalyzed Lessen rearrangement. Di Maio and Tardella," however, have shown that some alicyclic hydroxamic acids when treated with polyphosphoric acid (PPA) at 176°-195° undergo loss of CO, CO.2, or H2O, in a series of reactions which must involve earlj fission of the N—0 bond, presumably in a phosphoryl-ated intermediate. Thus, l-hydroxy-2- piperidone(108) gave carbon monoxide, 1-pyrroline (119), and the lactams (120 and 121). The saturated lactam is believed to be derived from disproportionation of the unsaturated lactam. 

The tautomerism of hydroxyindoles (and mercaptoindoles) has been reviewed (79HC1). As was pointed out previously (76AHCS1, p. 243) 2-hydroxyindoles 120 exist as lactams 121 (indolin-2-ones). The same holds for the corresponding A-hydroxy derivatives (1-hydroxyoxindoles) 121 (R = OH) (86AP1084,86JOC1704 90SC2133 94MI4). 

Tlie infrared spectra revealed the dominance of the 2-oxo (153) and 5-0X0 (157) structures (amide or lactam tautomers) over the 2-hydroxy (154) and the 5-hydroxy (192) structures (imidic acid or lactim tautomers)... 

The methylation of 4-hydroxyquinol-2-one (71) is interesting. This compound is both an enol and a lactam it forms 80 of 4-methoxyquinol-2-one (70) and 20% of 2,4-dimethoxyquinoline (73). The dimethoxy compound must be formed from 2-methoxyquinol-4-one (72) because 4-methoxyquinol-2-one (70) does not react with diazomethane. 4-Hydroxy l-methylquinol-2-one (75) yields a mixture of the 4-methoxy analog (74) and 2-methoxy-l-methylquinol-4-one (76) the proportions of the products show kinetic dependence on the concentration of the diazomethane. 

The reactions that accomplished the conversion of intermediate 16 into intermediate 23 have taken place very smoothly. It is worth acknowledging that the //-hydroxy lactam moiety did not, at any stage, participate in any undesirable side reaction processes. The stability of the //-hydroxy lactam substructure in the presence of basic reagents is particularly noteworthy since a destructive retro-aldol cleavage reaction could have conceivably occurred on several occasions. The stability of this potentially labile moiety permits all of the desired transformations leading from 16 to 23 to be conducted without prior protection of the C-8 hydroxyl group. 

All that remains before the final destination is reached is the introduction of the C-l3 oxygen and attachment of the side chain. A simple oxidation of compound 4 with pyridinium chlorochro-mate (PCC) provides the desired A-ring enone in 75 % yield via a regioselective allylic oxidation. Sodium borohydride reduction of the latter compound then leads to the desired 13a-hydroxy compound 2 (83% yield). Sequential treatment of 2 with sodium bis(trimethylsilyl)amide and /(-lactam 3 according to the Ojima-Holton method36 provides taxol bis(triethylsilyl ether) (86 % yield, based on 89% conversion) from which taxol (1) can be liberated, in 80 % yield, by exposure to HF pyridine in THF at room temperature. Thus the total synthesis of (-)-taxol (1) was accomplished. 

The hydroxy lactams 1 are converted into the 2//-2,4-benzodiazepin-l(3//)-ones 3 in refluxing benzene in the presence of p-toluenesulfonic acid. The reaction proceeds by ring opening to the oxo amides 2, followed by dehydration.16,166... 

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