Site Selectivity in Pd-Catalyzed Reactions of α-Diazo-α-(methoxycarbonyl)acetamides: Effects of Catalysts and Substrate Substitution in the Synthesis of Oxindoles and ß-Lactams.

The Pd-catalyzed intramolecular carbene C-H insertion of α-diazo-α-(methoxycarbonyl)acetamides to prepare oxindoles as well as ß-lactams was studied. In order to identify what factors influence the selectivity of the processes, we explored how the reactions are affected by the catalyst type, using two oxidation states of Pd and a variety of ligands. It was found that, in the synthesis of oxindoles, ((IMes)Pd(NQ))2 can be used as an alternative to Pd2(dba)3 to catalyze the carbene CArsp2-H insertion, although it was less versatile. On the other hand, it was demonstrated that the Csp3-H insertion leading to ß-lactams can be effectively promoted by both Pd(0) and Pd(II) catalysts, the latter being most efficient. Insight into the reaction mechanisms involved in these transformations was provided by DFT calculations.

Palladium- and Ruthenium-Catalyzed Intramolecular Carbene CAr -H Functionalization of γ-Amino-α-diazoesters for the Synthesis of Tetrahydroquinolines.

A synthetic method to prepare tetrahydroquinoline-4-carboxylic acid esters has been developed through the transition-metal-catalyzed intramolecular aromatic C-H functionalization of α-diazoesters. Both [{Pd(IMes)(NQ)}2 ] (IMes=1,3-dimesitylimidazol-2-ylidene, NQ=1,4-naphthoquinone) and the first-generation Grubbs catalyst proved effective for this purpose. The ruthenium catalyst was found to be the most versatile, although in a few cases the palladium complex afforded better yields or selectivities. According to DFT calculations, Pd0 - and RuII -catalyzed sp2 -CAr -H functionalization proceeds through different reaction mechanisms. Thus, the Pd0 -catalyzed reaction involves a Pd-mediated 1,6-H migration from the sp2 -CAr -H bond to the carbene carbon atom, followed by a reductive elimination process. In contrast, electrophilic addition of the ruthenacarbene intermediate to the aromatic ring and subsequent 1,2-proton migration are operative in the Grubbs catalyst promoted reaction.

Grubbs catalysts in intramolecular carbene C(sp3)-H insertion reactions from α-diazoesters.

Grubbs catalysts are described as a useful alternative to promote intramolecular carbene C-H insertion from α-diazoesters. Moreover, no competition arises from the possible metathesis reactions on substrates bearing alkene and alkyne moieties. DFT calculations were also carried out to gain insight into the reaction mechanism involved in these transformations.

Palladium-Catalyzed Intramolecular Carbene Insertion into C(sp(3) )-H Bonds.

A palladium-catalyzed carbene insertion into C(sp(3) )-H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd(0) and Pd(II) , is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium-catalyzed C(sp(3) )-C(sp(3) ) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp(3) )-H bond functionalization reaction involves an unprecedented concerted metalation-deprotonation step.

Intramolecular palladium-catalysed enolate arylation of 2- and 3-iodoindole derivatives for the synthesis of ß-carbolines, γ-carbolines, and pyrrolo[3,4-b]indoles.

The palladium-catalysed intramolecular α-arylation of carbonyl compounds with amino-tethered 2- and 3-iodoindoles provides a useful methodology for the synthesis of indolo-b-fused nitrogen heterocycles. A variety of substituted tetrahydro ß- and γ-carbolines, and pyrrolo[3,4-b]indoles, have been prepared by means of this palladium-catalysed annulation process.

3-Indolylacyl radical cyclizations upon pyridines and tetrahydropyridines: access to ergoline-related indole [cd]-fused isoquinolines.

Cyclizations of selenoester-derived 3-indolylacyl radicals, involving the homolytic acylation of pyridines or the addition to double bonds included in tetrahydropyridine rings, have been used to synthesize indole [cd]-fused isoquinolines related to the natural ergoline system.

A straightforward synthetic entry to cleavamine-type indole alkaloids by a ring-closing metathesis-vinyl halide Heck cyclization strategy.

An indole-templated ring-closing metathesis has been used to create the central nine-membered ring of the cleavamine-type alkaloids. A subsequent intramolecular vinyl halide Heck reaction upon the resulting azacyclononene ring completes the assembly of the strained 1-azabicyclo[6.3.1]dodecane framework of the alkaloids. The usefulness of the approach is illustrated with the synthesis of (±)-cleavamine and (±)-dihydrocleavamine.

Total synthesis of the bridged indole alkaloid apparicine.

An indole-templated ring-closing metathesis or a 2-indolylacyl radical cyclization constitute the central steps of two alternative approaches developed to assemble the tricyclic ABC substructure of the indole alkaloid apparicine. From this key intermediate, an intramolecular vinyl halide Heck reaction accomplished the closure of the strained 1-azabicyclo[4.2.2]decane framework of the alkaloid with concomitant incorporation of the exocyclic alkylidene substituents.

The first total synthesis of (+/-)-apparicine.

The first total synthesis of the indole alkaloid apparicine has been developed through a sequence that includes an indole-templated ring-closing metathesis and a vinyl halide Heck cyclization.

A new acyl radical-based route to the 1,5-methanoazocino[4,3-b]indole framework of uleine and Strychnos alkaloids.

C-4 or C-12 ethyl substituted 1,5-methanoazocino[4,3-b]indoles, which constitute the tetracyclic framework of uleine alkaloids as well as the ABDE substructure of the Strychnos alkaloid family, have been synthesized by novel 6-exo and 6-endo cyclizations of selenoester-derived 2-indolylacyl radicals upon 5-ethyl-1,2,3,6- and 3-ethyl-1,2,5,6-tetrahydropyridines, respectively.

Novel 7- and 8-endo 2-indolylacyl radical cyclizations: efficient construction of azepino- and azocinoindoles.

Regioselective 7- and 8-endo cyclizations of selenoester derived 2-indolylacyl radicals upon amino tethered alkenes have been used to synthesize azepino[3,2-b]- and azocino[4,3-b]indoles, which are tricyclic subunits present in the indole alkaloids mersicarpine and apparicine, respectively.

SmI(2)-promoted radical addition reactions with N-(2-Indolylacyl)oxazolidinones: synthesis of bisindole compounds.

The treatment of N-acyl oxazolidinones of N-benzyl 2-indolecarboxylic acids varying in the substitution pattern of the indole ring with samarium diiodide at -78 degrees C led to the formation of two indole dimer products. The major product isolated in yields from 55 to 59% represents an unsymmetrical dimer arising from 1,4-addition to the 2-indolecarboxylic acid derivative of a possible ketyl-type radical anion intermediate originating from the reduction of the exocyclic carbonyl group of the N-acyl oxazolidinone. The minor dimer, represented by a symmetrical diketone, was produced in yields ranging from 11 to 23%. Even in the presence of an alpha,beta-unsaturated amide, dimerization was the preferred pathway rather than the formation of a gamma-keto amide. Upon treatment with acid, the unsymmetrical indole dimer cyclized to form a diindolequinone. Finally, the N-acyl oxazolidinones of pyrrole-2-carboxylic acid and 3-indolecarboxylic acid preferred in both cases to undergo C-C bond formation with an acrylamide in the presence of SmI2 rather than dimerization.

Sequential N-acylamide methylenation-enamide ring-closing metathesis: construction of benzo-fused nitrogen heterocycles.

The dimethyltitanocene methylenation of N-acylamides derived from ortho-vinylanilines, ortho-allylaniline, and ortho-vinylbenzylamine provides the corresponding enamides, which upon exposure to the second generation Grubbs ruthenium catalyst give access to indoles, 1,4-dihydroquinolines, and 1,2-dihydroisoquinolines, respectively. This sequential protocol also allows the synthesis of dihydrobenzoazepines, although the ring-closing metathesis (RCM) step is complicated by the alkene isomerization processes. From certain substrates, the direct annulation is observed in the titanium-mediated step, which is likely to occur through an olefin metathesis-intramolecular olefination sequence.

A new radical-based route to calothrixin B.

[structure: see text] A high-yielding totally regioselective intramolecular homolytic acylation of a quinoline ring constitutes the key step in a new synthesis of the pentacyclic indolo[3,2-j]phenanthridine alkaloid calothrixin B.

Regioselective 6-endo cyclizations of 2-indolylacyl radicals: total synthesis of the pyrido[4,3-b]carbazole alkaloid guatambuine.

A regioselective 6-endo reductive cyclization of 2-indolylacyl radicals constitutes the key step of a straightforward synthetic entry to the olivacine skeleton, illustrated by a total synthesis of the tetrahydropyridine alkaloid guatambuine.

Regioselective intramolecular reactions of 2-indolylacyl radicals with pyridines: a direct synthetic entry to ellipticine quinones.

[reaction: see text] 2-Indolylacyl radicals generated from the corresponding selenoesters under hexabutylditin-hnu conditions undergo regioselective intramolecular reaction with unprotonated pyridines to give polycyclic indolylpyridyl ketones. For substrates bearing a (3-pyridyl)methyl moiety connected to the 3-position of the indole ring, the cyclization provides easy access to ellipticine quinones.

Intramolecular reactions of 2-indolylacyl radicals: access to 1,2-fused ring indole derivatives.

The generation of 2-indolylacyl radicals from the corresponding phenyl selenoesters under reductive conditions and their behavior in intramolecular addition reactions to carbon-carbon double bonds located at the indole nitrogen have been studied. [reaction: see text]

Total synthesis of the proposed structures of indole alkaloids lyaline and lyadine.

The harman-1,4-dihydropyridines 1 and 2, which constitute the originally proposed structures for the indole alkaloids lyaline and lyadine, have been synthesized, and their NMR data have been compared with those available for the natural products. Due to the discrepancies in the spectral data, the structures of lyadine and lyaline should be revised.

Chemoselective radical cleavage of Cbz-protected nitrogen compounds.

[reaction: see text] Tributylstannyl radicals promote the deprotection of N-Cbz derivatives of amides and nitrogen-containing heteroaromatic rings. These radical conditions do not affect N-Cbz derivatives of basic amines.

Addition of ester enolates to N-alkyl-2-fluoropyridinium salts: total synthesis of (+/-)-20-deoxycamptothecin and (+)-camptothecin.

Several 4-substituted dihydropyridones or 2-pyridones have been prepared by nucleophilic addition of alpha-(methylsulfanyl)ester enolates to N-alkyl-2-fluoropyridinium salts, followed by acid hydrolysis or oxidation with concomitant hydrolysis, of the intermediate 2-fluoro-1,4-dihydropyridine adducts, respectively. Addition of the enolate derived from isopropyl alpha-(methylsulfanyl)butyrate to N-(quinolylmethyl)-2-fluoropyridinium triflate 21 followed by DDQ treatment gave pyridone 29, from which (+/-)-20-deoxycamptothecin (31), a known precursor of camptothecin, was synthesized by a radical cyclization-desulfurization, with subsequent elaboration of the lactone E ring by chemoselective reduction. A similar sequence starting from the enolate of a chiral 2-hydroxybutyric acid derivative (33) provides access to natural (+)-camptothecin (37).