Lactams, preparation from

The electrophilic fluorination of chiral bicyclic lactams (prepared from the epimers of pyroglutamic acid) by means of A-fluoro sulfonimide (NFSI) yields l- and d-4, 4-difluoroglutamic acids and 4,4-difluoroglutamines (Figure 5.21). They have also been prepared with a good ee starting from ethyl (/ )-bromodifluoroalaninate. ... 

Several syntheses of carbon-14 labeled taxols have been reported. N-3 -[Carbonyl- " C]-taxol 11.1.1 was prepared by coupling a [carbo-nyl- C]-A -benzoyl- 5-lactam with 7-(triethylsilyl)baccatin III (378), while the same group prepared [3 - " C]-taxol 11.1.2 by using a / -lactam prepared from carbonyl- " C-benzaldehyde (379). [3 - " C]-Docetaxel 11.1.3 was prepared by attachment of a labeled cinnamoyl side chain to 7,10-ditroc-10-deacetylbaccatin III, followed by hydroxyamination of the side chain (380). A slightly different approach was used to prepare [2, 3 - " C2]taxol, in that the required doubly labeled /3-lactam synthon was prepared using a doubly labeled Oppolzer s bromoacylbomanesul-tam intermediate (381). 7-([carbonyl- C]-acetyl)taxol was prepared by simple acylation of 2 -(triethylsilyl)taxol with [carbonyl--acetic anhydride and deprotection (382). The taxol analog PNU-105298 (4.1.3.12) was also prepared in both deuterium and carbon-14 labeled forms in both cases the label was placed on the side chain (383). 

Chiral P-lactams prepared from a 6-imino-D-galactose derivative have been used as synthons for 6-epz-lincosamine. ... 

The cyclic carbonate of benzoin (4,5-diphenyl-l,3-dioxol-2-one, prepared from benzoin and phosgene) blocks both hydrogen atoms of primary amines after dehydration acid stable, easily crystallizable Sheehan oxazolinones are formed, which are also called Ox derivatives. The amine is quantitatively deblocked by catalytic hydrogenation in the presence of 1 equiv. of aqueous acid (J.C Sheehan, 1972, 1973 M.J. Miller, 1983). An intelligent application to syntheses of acid labile -lactams is given in the previous section (p. 161). 

Pharmaceuticals. -Hydroxybenzaldehyde is often a convenient intermediate in the manufacture of pharmaceuticals (qv). For example, 2-(p-hydroxyphenyl)glycine can be prepared in a two-step synthesis starting with -hydroxybenzaldehyde (86). This amino acid is an important commercial intermediate in the preparation of the semisynthetic penicillin, amoxicillin (see ANTIBIOTICS, P-LACTAMs). Many cephalosporin-type antibiotics can be made by this route as well (87). The antiemetic trimethobenzamide [138-56-7] is convenientiy prepared from -hydroxybenzaldehyde (88) (see Gastrointestinal agents). 

Then in a series of chemical transformations the diamine or lactam can be prepared from brassyUc acid (177,178). The diamine is formed as described above for the 12-carbon diamine, ie, diacid —> diamide —> dinitrile —> diamine. The lactam is made from the dinitrile as follows. 

Cephalosporin 5-oxides and penicillin 5-oxides (221) can be converted into isothiazol-3-ones (222) by the action of bases. These reactions proceed via an intermediate azetidinonesulfenic acid (223 Scheme 37) (77SST(4)339). Attempts to prepare /3-lactam compounds from isothiazoles have, as yet, been unsuccessful (81X2181). 

A third approach to 3-amino-/3-lactams is by Curtius rearrangement of the corresponding acyl azides. These are readily prepared from r-butyl carbazides, available via photochemical ring contraction of 3-diazopyrrolidine-2,4-diones in the presence of f-butyl carbazate (c/. Section 5.09.3.3.2). Thus treatment of (201) with trifluoroacetic acid followed by diazotiz-ation gives the acyl azide (202) which, in thermolysis in benzene and subsequent interception of the resulting isocyanate with r-butanol, yields the protected 3-amino-/3-lactam (203) (73JCS(P1)2907). 

Where the material is denoted by a single number, viz nylon 6 and nylon 11, preparation from either an co-amino acid or a lactam is indicated. The polymer nylon 66/6.10 (60 40) indicates a copolymer using 60 parts of nylon 6.6 salt with 40 parts of nylon 6.10 salt. 

A radical approach to asymmetnc iildol synthesis, which is based on the radical addition of a chiral hydroxyalkyl radical equivalent to a tutroalkene, has been reported, as shown in Eq 4 93 The radical precursor is prepared from the corresponding carboxyhc acid by the Barton reaction, which has been used for synthesis of new fi-lactams ... 

Ethoxycarbonyloxyethyl 6-(D-a-azidophenylacetamido)penicillinate (98 g) was prepared from sodium 6-(D-a-azidophenylacetamido]penicillinate (397 g, 1 mol), a-chlorodiethylcar-bonate (458 g, 3 mols) and sodium bicarbonate (504 g, 6 molsl. The product showed strong IR absorption at 2090 cm- and 1 780-1750 cm" showing the presence of azido group and /3-lactam and ester carbonyls. 

Dehydrogenation of the hydrazide derivative 33 with mercuric oxide in the presence of ethylene diamine tetraacetic acid (EDTA) gave 34 and 35 (77AP588). The latter (35) was prepared from a reaction of ester 36 with the appropriate lactam 37 (Scheme 11). 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Diastereoselective alkylation of lactams derived from 7 -(-)-phenylglycinol is an efficient method for the preparation of various substituted piperidines <961(52)7719, 961(52)7727, 961L(37)849>. Ihe asymmetric s mthesis of a series of 2-(l-aminoalkyl)piperidines using (-)-2-cyano-6-phenyloxazolopiperidine has been described <96JOC(61)6700>. 

In the first step, catalyst 64c attacks ketene 66 to form a zwitterionic enolate 71, followed by Mannich-type reaction with imine 76 (Fig. 40). A subsequent intramolecular acylation expels the catalyst under formation of the four-membered ring. Utilizing 10 mol% of 64c, N-Ts substituted (3-lactams 77 were prepared from symmetrically as well as unsymmetrically substituted ketenes 66, mainly, but not exclusively, with nonenolizable imines 76 as reaction partners [96]. Diastereos-electivities ranged from 8 1 to 15 1, yields from 76 to 97%, and enantioselectivities from 81 to 94% ee in the case of aliphatic ketenes 66 or 89 to 98% ee for ketenes bearing an aromatic substituent. Applying complexes 65 or the more bulky and less electron-rich 64b, ee values below 5% were obtained. 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

Triflates prepared from (V-alkoxyearbonyl lactams can be coupled with aryl and alkenylboronic acids.227... 

Macrocyclic lactams making use of the double reaction of bisimidazolides — in this case, prepared from the corresponding dicarboxylic acids by in-situ reaction with C6H5POIm2 - were obtained in acceptable yield considering the unfavorable ring sizes of the products 1-1295... 

A series of N-substituted narceine amides (Section III,D,1) was prepared from 101 under the action of primary amines (100). Acid-catalyzed dehydration transformed these amides to corresponding imides (ene lactams) of the ( )-narceine imide (117) type (100). Similar transformations were performed in the hydrastine series (101). JV-Methylhydrastine (98) when treated with dilute ammonium hydroxide gave hydroxy lactam 127, which was dehydrated to (Z)-fumaridine (113) (5). Sodium borohydride was able to reduce the stilbene double bond in 98 to produce saturated lactone 132 (5). 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

Samarium(II) iodide also allows the reductive coupling of sulfur-substituted aromatic lactams such as 7-166 with carbonyl compounds to afford a-hydroxyalkylated lactams 7-167 with a high anti-selectivity [74]. The substituted lactams can easily be prepared from imides 7-165. The reaction is initiated by a reductive desulfuration with samarium(ll) iodide to give a radical, which can be intercepted by the added aldehyde to give the desired products 7-167. Ketones can be used as the carbonyl moiety instead of aldehydes, with good - albeit slightly lower - yields. 

The same group has developed the enantiospecffic synthesis of a-hydroxy [5-lactams 224 from readily available carbohydrates (Scheme 9.72) [123]. Microwave-assisted chemical reactions have been utilized for the preparation of these 3-hydroxy-2-azetidinones 224 and their subsequent conversion to enantiomeric forms of intermediates for natural products. 

Macrocyclic 14-membered lactams, lactones, and thiolactones 211 have also been prepared from 3-amino-l,2,5-thiadiazole-4-carboxylic acids 210 (Equation 47) <1996CHE975>. 

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