Allyl p lactams

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Allylic phosphonate esters react with imines, in the presence of a palladium catalyst, to give P-lactams. " Alkynyl reagents such as BuC=CO Li react with imines to form P-lactams. 

Treatment of the 1,2-oxazines 52 with carbon monoxide at 1000 psi in the presence of cobalt carbonyl brings about insertion of carbon monoxide to form the 1,3-oxazepines S3 <96TL2713>. A convenient route to P-lactams fused to oxepines is made available by alkene metathesis. Thus reaction of 4-acetoxyazetidin-2-one with ally alcohol in the presence of zinc acetate, followed by iV-allylation of the nitrogen affords the derivative 54 which cyclises by RCM to form the oxazepinone 55 <96CC2231>. The same communication describes a similar synthesis of 1,3-dioxepines. 

Indium mediated allylation of 4-acetoxy-2-azetidinones gave the products 57 in high yield <99SL447> and similar reactions with azetidin-2,3-diones gave 3-substituted 3-hydroxy-P-lactams 58 <98H97>. 

Scheme 47 Synthesis of spiro-P-lactams using 3-allyl-3-benzylthio-fS-lactams...

The carbonylative [2+2] cycloaddition was performed also on chiral imines with allyl halides affording p-lactams with good stereoselectivity [160]. 

The Bayhs-Hillman reaction of optically pure azetidine-2,3-diones [235, 236] with methyl vinyl ketone in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) in acetonitrile at -20°C for 1 h have been reported to give functionalized allylic alcohols, having the p-lactam scaffold, in good yields (80%) and complete diastereoselectivity [237]. In terms of achieving good yields with a reasonable rate of reaction, 50 mol% of DABCO seemed to be the catalyst amount of choice for this reaction. No significant solvent effect was observed in the overall yield (Scheme 108). 

R2 PMP, Bn, Allyl,CH2CCH, CH2C02Me Scheme 56 Dihydroxylated y-lactams from P-lactams... 

Here again are fairly good prospects for the industrial use of this method in the area of the area of fine chemicals. For example, Torii et al. (Otsuka Patents 90 92>) have used electrochemical allyl halogenation for the synthesis of intermediates for P-lactam antibiotics. 

A valuable part of the [2,3]-sigmatropic rearrangement of ammonium ylides is the fact that stereochemical information can be transferred. For example, Kaiser and co-workers stereoselectively alkylated the C-6 position of penicillin using the nitrogen ylide 46 derived from lactam 45.28 Quatemization of 45 with allyl bromide followed by ylide generation using sodium hydride effected the [2,3]-rearrangement. This resulted in the exclusive formation of P-lactam 47 in 75% yield. 

A similar approach was used by the Alcaide group [183] in the synthesis of tricyclic P-lactams 6/1-391 from 6/1-390 (Scheme 6/1.99). In this domino process the primarily obtained JT-allyl-Pd-complex reacts with the N-nudeophile of the urethane moiety to form a C-N-bond and a vinyl halide. The final step is then an intramolecular Heck-type reaction of the vinyl halide with the alkyne moiety and re-... 

Alkylation of hydrazine with a, 3-unsaturated carbonyl derivatives or carbonyl derivatives with a leaving group in the p-position provides pyrazole derivatives. For example, treatment of the tosylate (77), obtained from L-serine, with anhydrous hydrazine gives racemic pyrazolidinone (78). It appears that py-razolidinone (78) or one of the intermediates suffers base-catalyzed racemization (equation 32). Starting from P-lactam (79) seven-membered cyclic hydrazine (80) has been formed by ring closure in an unusually high (84%) yield (equation 33). Reaction of ( ir-allyl)palladium complex (81) with dimethyl-hydrazine produces exocyclic diene (82) in a modest (29%) yield, but this is still more efficient than the reaction of 2,3-bis(chloromethyl)butadiene (83) with dimethylhydrazine (equation 34). ... 

BINAP was first introduced by Noyori [80]. It has been particularly explored for reduction with ruthenium catalysts. BINAP is an atropisomeric ligand because rotation aroimd the central C-C bond is blocked. Accordingly BINAP exists in two enantiomers. Complexes of Ru(II) with BINAP are extremely powerful catalysts for enantioselective hydrogenations of prochiral a,p- and P,Y-unsaturated carboxylic acids, enamides, allylic and homoallylic alcohols, imines etc. [83]. In many cases, the hydrogenation is quantitative with enantiomeric excesses of over 95%. A wide variety of vitamins, terpenes, P-lactam antibiotics, etc. are accessible by the use of catalysts containing the BINAP stereogenic element. An example for 3-oxo carboxylic esters is shown in reaction (1) of Fig. 6.32. 

The allyl group was used to protect the nitrogen in a P-lactam synthesis, hut was removed in a four-step sequence. ... 

A large number of P-lactams have been prepared by this method (equations 56-61). (Tycload-ditions of CSI with 1,5-hexadiene, allyl iodide and vinyl acetate yield azetidinones which have been used as starting materials in the synthesis of carbapenems and penems. In some cases the cycloaddition must be conducted at low temperature to avoid open-chain products (equations 61 and 62). 

A related approach was used for the synthesis of an interesting tricyclic p-lactam <05HCA1387>. However, only the allylic ether starting material, shown below, was able to undergo the subsequent ring-closing step. 

D-Glyceraldehyde acetonide (118) has also been used for the synthesis of other (3-lactams (Scheme 14). It was converted into the Schiff base 129, followed by reaction with potassium azidoacetate, cyanuric chloride and triethylamine to give the p-lactam 130 as a single c/s-isomer in 55% yield. The reaction of 130 with methoxyacetyl chloride in the presence of triethylamine afforded the cw-p-lactam 131. Similarly, c/ -p-lactams 131-135 were also prepared as single isomers in comparable yields. Acid hydrolysis of 130 afforded 136, which underwent oxidation of the diol side chain and then removal of the p-methoxybenzyl group with CAN to afford 137. The allyl derivative 135 was oxidized to... 

The acetoxy group was hydrolyzed using hydrazine to give (46). Nucleophilic substitution of the fluorine atom produced the tricyclic p lactam (47). A diastereoselective aza-Diels-Alder reaction was used in a synthesis of (—)-lasubine (I). Tin tetrachloride-mediated reaction of complex (48) with Danishefsky s diene afford 2,3-dihydro-4-pyridone (49) as a single diastereomer (Scheme 86). Chiral benzaldehyde imines can be allylated with high diastereoselectivity to give optically active homoallylic amines (Scheme 87). 

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