Lactam allyl esters

Moving away from ketones to other prochiral nucleophiles has also been an important goal in our group. We choose to explore lactam-derived substrates in part because we envisioned that the products formed would be useful intermediates in the synthesis of various alkaloids and because we would be able to modulate the electronics and sterics of the lactam enolate by attaching different groups at nitrogen with the aim of optimizing the enantioselectivity of the allylic alkylation. In the event, we chose to initially test tosyl-protected lactam allyl ester 29 and Boc-protected lactam aUyl ester 30 with two Pd PHOX catalysts in several solvents (Scheme 18). 

Scheme 19 Screening of reaction conditions in the asymmetric allylic alkylation of lactam allyl esters...

Another method for deallylation of allyl esters is the transfer of the allyl group to reactive nucleophiles. Amines such as morpholine are used[415-417], Potassium salts of higher carboxylic acids are used as an accepter of the allyl group[418]. The method is applied to the protection and deprotection of the acid function in rather unstable /3-lactam 664[419,420]. 

Some examples of photolytic intramolecular [2 + 2] cycloadditions which lead to the formation of lactones and lactams are sketched in Scheme 9.9. The allyl ester and N-monosubstituted amide do not undergo cydization, probably because of the high energy of the required E conformers. Cydization of the homoallyl ester does,... 

The simultaneous deprotection of both an allyl ester and an Aloe group is a popular tactic for liberating an amino and carboxyl function prior to formation of a lactam ring. The strategy is exemplified in Scheme 8.83 en route to a derivative of the ichthyotoxic cyclic lipopeptide Antillatoxin.196... 

As has already been detailed for the allyloxycarbonyl (Aloe) moiety, allyl esters also proved to be very versatile and useful carboxy-protecting groups. They can be easily constructed by azeotropic esterification or nucleophilic displacement on allylic halides. For the cleavage of these esters lithium di-methylcuprate can be used. However, a much milder method is found in the Rh -catalyzed isomerization of the allyl moiety to a propenyl ester which immediately hydrolyzes under the reaction conditions (Scheme 67). Even milder is the Pd°-catalyzed allyl transfer to morpholine as an accepting nucleophile. The removal of allyl ester protection has earlier been used in particular in -lactam anti-... 

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. 

Bicyclic dienic products recently synthesized by this method (Scheme 36) are lactams 144a and b (07T8267) and enamine ester 145 (09CEJ4565). The precursor of the latter substance originates from a four-component synthesis followed by y-allylation. The alternative y-propargylation and subsequent ring-closing enyne metathesis performed under an ethene atmosphere lead to the 8-vinyl derivative of product 145. 

Allylic nitro compounds containing a suitable dipolarophile undergo Diels-Alder cycloaddition to alkenes in the presence of tin(lV) chloride affording cyclic nitronic esters (Scheme 16).26 Nitronic ester (59) could not be isolated but spontaneously cyclized to the 5,5-fiised cyclic product (60), isolated in 68% yield. The nitronic esters (61a) and (61b) were isolated from the Diels-Alder reaction and could be separated. Heating (61a) in refluxing benzene afforded the 5,6-fused dipolar cydization product (62a) in 93% (68% overall) yield (61b) likewise afforded (62b) in 62% (11% overall) yield. Either (62a) or (62b) could be converted to the tricyclic lactam (63) by catalytic hydrogenolysis followed by lactamiza-... 

Solid-supported reagents which have found utility include Nafion-scandium Lewis acid catalyst (allyl additions to aldehydes) [62], HOBt (medium-ring lactamization) [63], EDC (preparation of active esters) [64], and thiazolium hydrotribromide (brominations) [65], A review has also appeared describing the use of supported reagents in separation science, primarily for the selective sequestration of metal ions [66],... 

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