Azetidi nones

Various nucleophilic attacks at C(3) and C(4) of -lactams have been employed to introduce desired functionalities. Nucleophilic displacement of a halogen at C(3) by nucleophiles, for example, potassium phthalimide, has been performed (93JCS(Pl)2357). The a-azidation of l-hydroxy-2-azetidi-nones, for example (37), with arenesulfonyl azides in the presence of triethylamine affords 3-azido-2-azetidinones (38) via Otosylation and SN2 -type of displacement of the tosyloxy group (92JA2741, 93JA548, 93BMC2429). 

Keywords 1,3-azadiene, microwave irradiation, /V-/crf-butyldimethylsilyl azetidi-none... 

Heterocyclic rearrangement. Suitable heterocycles can rearrange to 2-azetidi-nones. 

The addition of lithium bis(methylenecyclopropyl)cuprates to acetoxy azetidi-nones has been reported to give methylenecyclopropyl azetidinones (Fig. 4) which could be further converted into various /V-functionalized (3-lactams [249]. 

Optically pure c/.v-2-azetidi none-tethered dienes have been reported to undergo intermolecular Diels-Alder reaction with a variety of symmetric and unsymmetric dienophiles [257] providing a synthetic entry to various types of racemic and homochiral 1,3,4-trisubstituted 2-azetidinones (I, Fig. 7). 

The Diels-Alder cycloaddition reaction of both cis- and trans-dienyl-2-azetidi-nones with unsymmetrical dienophiles in the presence of Lewis acid catalysts has been reported to give in regio-, stereo-, and remarkably high 7i-facial selectivity novel l,3,4-trisubstituted-2-azetidinone derivatives in good yields (I and II, Fig. 26), [306],... 

The most significant biological and pharmacological applications of the 2-azetidi-nones are reported in this paragraph, highlighting the SAR studies applied for the design of new and more efficient molecules. 

As early as 1977 Pracejus et al. investigated alkaloid-catalyzed addition of thiols to a-phthalimido acrylates, methylene azlactones, and nitroolefins [56a]. In the former approach, protected cysteine derivatives were obtained with up to 54% ee. Mukaiyama and Yamashita found that addition of thiophenol to diisopropyl mal-eate in the presence of cinchonine (10 mol%) proceeds in 95% yield and that the product, (S)-phenylthiosuccinate, was formed with 81% ee [56b]. The latter Michael adduct was used as starting material for preparation of (R)-(+)-3,4-epoxy-1-butanol. In the course of an asymmetric total synthesis of (+)-thienamycin Ike-gami et al. studied the substitution of the phenylsulfonyl substituent in the azetidi-none 69 by thiophenol in the presence of cinchonidine (Scheme 4.34) [56c]. This substitution probably proceeds via the azetinone 70. In this reaction the phenyl-thioazetidinone 71 was obtained in 96% yield and 54% ee. Upon crystallization, the optically pure substitution product 71 was obtained from the mother liquor... 

The 2 + 2-cycloaddition of chlorosulfonyl isocyanate with chiral alkoxyallenes, derived from ethylidene and benzylidene L-erythritol and D-threitol, produces azetidi-nones that are readily converted into the corresponding tricyclic cephams. NMR and CD spectroscopy were used to assign the absolute configurations of the azetidinones... 

Treatment of 5-arylimino-4-chloro-l,2,3-dithiazoles 56 with in situ-generated (chloro)phenylketene gave azetidi-none-l,2,3-dithiazoles 137 in high to moderate yields through [2+2] cycloaddition to the N=C-Ar imine bond (Scheme 23) <2001CC1412>. 

The unusual 4/6/4 system has been obtained by an intramolecular [2+2] cycloaddition reaction of 2-azetidi-none-tethered enallenols by thermolysis in toluene solution at 220 °C in a sealed tube (Equation 69) <2006CEJ1539>. 

Phenyl isocyanate adds to enamines derived from isobutyraldehyde to yield azetidi-nones (equation 8)25,26. 

AZEnDINONE-4,4-DIMETHYL-l-SULFO-NYL CHLORIDE AND 2-AZETIDI-NONE-4,4-DniETHYL, 46, SI 2-Azetidinones, preparation of, 46, S6 e-Azidobiphenyls, decomposition to ni-trenes and cydization to carba-zoles, 46,88... 

When 4-phenylsulfonyl-2-azetidinone (11) is allowed to react with thiophenol in the presence of cinchonidine, the azetinone formed in situ undergoes thiol addition and 4-phenylthio-2-azetidi-none (13) is obtained in 96% yield with 54% optical purity. Recrystallization of this product, [a]D + 55.0, from benzene/cyclohexane allows the pure enantiomer, [a]D +105.1 (CIICI3) to be isolated from the mother liquor9. 

The discovery of ezetimibe, cholesterol-formation inhibitor, substituted azetidi-none 04JMC1. 

Perez-Faginas P, Alkorta I, Garcia-Lopez MT, Gonzalez-Muniz R (2008) From theoretical calculations to the enantioselective synthesis of a 1,3,4-trisubstituted Gly-derived 2-azetidi-none. Tetrahedron Lett 49 215-218... 

The pitfalls that can accompany the development of the amorphous form of a drug substance were shown for the capsule formulation of (3i ,4.Sy)-l,4-bis(4-methoxy-phenyl)-3-(3-phenylpropyl)-2-azetidi-none [17]. A variety of spectroscopic techniques were used to study the amorphous-to-crystalline phase transition, and it was determined that problems encountered with dissolution rates could be related to the amount of crystalline material generated in the formulation. 

Reports of simple ring-fluorinated tetrazoles appear to be limited. In one example, 1-benzyl-5-fluorotetrazole 166 was prepared by the action of KF on the corresponding chloro derivative. This was used to prepare a series of A-(tetrazol-5-yl) azetidi-nones 167 by reaction with A-unsubstituted p-lactams (Fig. 3.97). 

Similar transamidation leading to the enlargement of the four-membered ring has been reported by Banfi et al. [32]. hi that case, the amino function in 17 was introduced to the end of the 4-allyloxy substituent of the azetidi-none 16 by a sequence of reactions involving hydroxylation, introduction of an azide, and its reduction (Scheme 5) [32]. 

Finally, propargylic carbonates bearing pendant amines give rise to allenyl azetidi-nones. In many cases, however, isomerization of the allene moiety to an alkyne is a side reaction (Scheme 50). ... 

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