3.4- Disubstituted azetidinones

The acetonide 151 is available from a 4-substituted azetidinone in three steps and is converted into the 3,4-disubstituted azetidinone 152 by the action of pyridine chlorochromate in the presence of a catalytic amount of Jones reagent. The disubstituted /3-lactam is a suitable starting material for the synthesis of trinems <1996TL2467>. 

Stereocontrolled access to bicyclic /3-lactams has been achieved by application of the Heck reaction to bromoalk-enes. Cyclization of the 3,4-disubstituted azetidinone 287 (R = H) was achieved using palladium(n) acetate, triphe-nylphosphine, and potassium carbonate in DMF but two products 288 (R = H) and 289 were obtained in 21% and 27% yield, respectively. When the allyloxy group had a methoxycarbonyl substituent in 287 (R = G02Me) only one product 288 (R = C02Me) was produced in 47% yield <2005JOC2713>. 

Cyclization of 1,4- and 3,4-disubstituted azetidinones are commonly used routes to /3-lactams and have been discussed (Sections 2.04.9.3 and 2.04.9.4), but cyclization of 1,3-disubstituted azetidinones is very unusual and one example can be included here. The /3-lactam 358, carrying an N-terminal dipeptide chain, reacts with the penta-fluorophenyl (Pfp) activated ester to give the cyclic peptide 359 containing a /3-lactam moiety in 93% yield <2004EJO4379>. 

A tandem one-pot elimination-intramolecular Diels-Alder reaction occurs when the mesylate of 4-homoallylic azetidinone having a orc-alkene or alkyne substituent is heated in a sealed tube in the presence of an equimolecular quantity of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The method has been used to produce derivatives of oxace-pham. In a similar way, the 3,4-disubstituted azetidinone mesylate 473 afforded an 88% yield of 474. The method can be further elaborated through the introduction of a novel [3,3]-sigmatropic rearrangement of a-allenic mesylates thus, 475 yielded 476 on thermolysis C1999TL1015, 2000JOC3310, 2005EJ098>. 

An alternative route to chiral p-lactams was provided by reactions of electron-deficient isocyanates with chiral nucleophilic alkenes such as vinyl ethers or vinyl acetates. Chlorosulfonyl isocyanate (CSI), a commonly used reactive isocyanate [34], undergoes stereospecific 5-yn-addition to alkenes. The chlorosulfonyl group can subsequently be reductively removed from the nitrogen atom. It has been shown that reactions between CSI and (Z)- and ( )-alkenyl ethers stereoselectively give cA-3,4-disubstituted azetidinones from (Z)-olefins and tmns-3,4-... 

All the bicyclic /3-lactams included in this section have a bridgehead nitrogen atom and are formed from 1,4-disubstituted azetidinones, so this section can be considered as an extension of Section 2.04.9.3. In addition, the Wittig reaction has been extensively employed in the preparation of tricyclic and tetracyclic /3-lactams and its use is referred to in Section 2.04.11. The main use of the reaction to form bicyclic compounds has been to produce 2-substituted carbapen-2-ems. 

Extension of the Phosphorane Route. Ample evidence of the versatihty of the phosphorane synthesis strategy is provided by the proliferation of penems that followed. Nucleophilic displacement of the acetate function of the acetoxy-azetidinone (51, R = OCOCH ) [28562-53-0] (86) provided azetidinones where R = SCOCH, SCSSC2H, and SCSOC2H, which on elaboration gave the penems (52, R = CH ) (87), (52, R = SC2H ) (88), (52, R = 0C2H ) (89). Similar treatment of 3-substituted (or disubstituted) acetoxyazetidinones allowed the synthesis of a number of 2-substituted- 6-alkyl-and 6,6-dialkylpenems (90). 

JPR269>. 1,3,5-TriaIIyl-hexahydro-l,3,5-triazine has been used in the preparation of a C-4 unsubstituted azetidinone which is the starting material for the synthesis of penems and cephams <00S289>. A novel method for the preparation of AfW-disubstituted-Af"-nitroguanidines via 2-nitroimino-hexahydro-1,3,5-triazine derivatives has been studied <00TL7187>. 

In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition [15-21] to gene activation [22], Systems containing one carbon atom common to two rings, spirocyclic compounds, represent an important structural organization. Spirocyclic p-lactams (Fig. 3) behave as p-tum mimetics [23-26] as well as enzyme inhibitors [27, 28], they are precursors of a,a-disubstituted p-amino acids [29-32], and the spiranic p-lactam moiety is present in chartellines and chartelamides [33-38], a family of marine natural products. Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C have been described [38],... 

The photochemical reaction of alkoxychromium(0)carbene complexes and ferrocene mono- and disubstituted imines have been reported to form 2-azetidinones having one or two ferrocene moieties in good yields [136]. The chromium(0) carbene complex reacted smoothly with ferrocene imines that allowed to place ferrocene substituents at the N-l, and the C-4, or simultaneously at the N-l and the C-4 positions of the (3-lactam ring, with cis stereoselectivity (Scheme 71). 

In 2001, 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinones have been reported to be prepared by base-assisted intramolecular alkylation of /V-benzvI -/V-chloroacetyl amino acid derivatives [180]. /V-benzyl or /V--methoxvbenzvI) amino acid derivatives in THF, treated with propylene oxide and chloroacetyl chloride afforded the /V-chloroacetyl amino acid derivatives. The treatment of the latter in CH3CN with CS2CO3 (or NaH) produced the intramolecular cyclization of 4,4-disubstituted (3-lactams, (Scheme 81). 

RCM reactions have been little used with 3,4-disubstituted azetidines or azetidinones, in contrast to their enthusiastic use with the corresponding 1,4-disubstituted compounds (see Section 2.04.9.3). However, the 3,4-disubstituted /3-lactam 290 has been converted to the bicyclic /3-lactam 291 in 93% yield with >95% de by the action of the ruthenium carbene (Equation 31) <2003T3253>. 

An azetidinone carrying vicinal alkene and alkyne groups, one of which may be an N-substituent, on the four-membered ring may be cyclized in the presence of a trisubstituted tin hydride at elevated temperature (Scheme 9) <1999JOC5377, 2003JOC3106>. In this way, the 1,4-disubstituted /3-lactams 303 were converted into the fused bicyclics 304 in moderate yield. 

Pauson-Khand cyclization of vic-enyne derivatives of /3-lactams gave good yields of fused tricyclic compounds. The 1,4-disubstituted 2-azetidinone 391 and cobalt octacarbonyl gave the alkyne-cobalt carbonyl complex, which on thermolysis gave the tricycle 392 in 95% yield (Equation 54). When the complexes of 393 with cobalt octacarbonyl were treated with TMANO, a lower yield (65%) of 394 was obtained (Equation 55). A single diastereoisomer was formed in each case <1996TL6901>. 

Carbodiimides are also used in the enantioselective synthesis of 3-substituted 4-(alkoxy-carbonyl)-2-azetidinones from malic acid. DCC is used in the the synthesis of nocardicin Penam, 4-thiazabicyclo[3.2.0]heptan-7-one, and 2,3-disubstituted derivatives utilize EDCCl in the cyclization steps. ... 

Barton, D H R, Gateau-Oleska, A, Anaya-Mateos, J, Cleophax, J, Gero, S D, Chiaroni, A, Riche, C, Asymmetric synthesis of 1,3,4-trisubstituted and 3,4-disubstituted 2-azetidinones strategy based on use of D-glucosamines as a chiral auxiliary in the Staudinger reaction, J. Chem. Soc. Perkin. Trans. 1, 3211-3212, 1990. 

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