Alkyne derivatives lactamization

In addition to alcohols, some other nucleophiles such as amines and carbon nucleophiles can be used to trap the acylpalladium intermediates. The o-viny-lidene-/j-lactam 30 is prepared by the carbonylation of the 4-benzylamino-2-alkynyl methyl carbonate derivative 29[16]. The reaction proceeds using TMPP, a cyclic phosphite, as a ligand. When the amino group is protected as the p-toluenesulfonamide, the reaction proceeds in the presence of potassium carbonate, and the f>-alkynyl-/J-lactam 31 is obtained by the isomerization of the allenyl (vinylidene) group to the less strained alkyne. 

The application of this methodology to suitably functionalized alkynes has allowed a direct and easy synthesis of important heterocyclic compounds starting from readily available substrates. New /1-lactone [100,101] and /3-lactam [102] derivatives were synthesized in good yields from a,a-disubstituted propynyl alcohols and amines, respectively (Eq. 38), through the mechanistic route shown in Scheme 18, path a. The substitution a to the triple bond was a necessary requisite for cychzation to occur, owing to the reactive rotamer effect [301]. 

Cycloaddition of a ketene complex with unsaturated bonds other than alkenes and alkynes is also possible. The ketene 312, formed from 311, adds to imine 313 to give the /1-lactam 314 under sunlight photolysis. The optically active /1-lactam 314 was prepared from the optically active carbene complex 311 with 99% ee, and converted to 315 [95]. Irradiation of carbene complex 316 generates ketene 317, which cyclizes to the o-hydroquinone derivative 318 [96],... 

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>. 

The group of Sieber has used an improved ABPP approach to look again at the targets of certain (3-lactam antibiotics and prepared derivatives 58-61 by attaching an alkyne tag to clinically used parent compounds (Fig. 27). With these probes, they were able to perform in vivo experiments and identify a series of PBPs [102]. 

Figure 25 /3-Lactones and /3-lactams as natural product-derived probes for ABPP. (a) A biomimetic /3-lactone probe library with an alkyne tag and several diversity elements, (b) /3-Lactam probes derived from known antibiotics and synthetic approaches.

Hydroamination. Amides, lactams, carbamates and ureas add to 1-alkynes to give enamide derivatives. The stereoselectivity of this anti-Markovnikov addition is sensitive to phosphine ligands that are present. ... 

N-Alkenylattion Heating a lactam and a l-alkyne with Re2(CO)io in toluene gives the A -alkenyl derivative. 

The tosylate derivative 102 was condensed with alkyne 100 to produce compound 104 (89%), which can be under similar sequence of reactions used above, but with removal of tosyl group with Sm afforded 107, which was cyclized to the lactam 108, whose de-O-methylation gave (+)-narciclasine (9). 

A range of indolo(triazolo)-l,4-diazepine derivatives 104 were obtained by a microwave-heated three-component reaction involving tandem N-alkylation of indole 101 with epichlorohydrin 102, ring-opening of the epoxide with azide 103, and intramolecular azide-alkyne 1,3-dipolar cycloaddition reactions (13BJO401). Fused triazolodiazepinones were obtained via azide-alkyne 1,3-dipolar cycloaddition followed by lactamization (13JHC430). 

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