RESUMEN

The [5-6-7] azatricyclic ABC core, found in several Daphniphyllum alkaloids, has been synthesized through a novel route involving ring expansion of a perhydroindolone to afford the AC ring system and a radical B ring closure as key steps. The level of functionalization of the reported octahydro-1,7-ethanocyclohepta[b]pyrroles suggests that they can serve as valuable building blocks in this alkaloid field. Also reported is the first synthesis of homomorphans by the ring enlargement of 2-azabicyclo[3.3.1]nonanes.

RESUMEN

The use of isocyanides as acceptor groups in metal-hydride hydrogen atom transfer (MHAT) coupling reactions with nonactivated alkenes to form heterocycles is described. Monosubstituted alkenes couple and cyclize directly, whereas more substituted alkenes proceed via a two-step, one-pot procedure involving MHAT reductive cyclization followed by a MHAT Minisci coupling upon the addition of acid. To highlight the utility of the methodology, a diverse variety of substituted heterocycles such as phenanthridines, indoles, and isoquinolines were prepared.

RESUMEN

From an (R)-(+)-pulegone-derived building block that incorporates the stereo-defined tertiary carbon bearing a methyl group, as found in the targeted sesquiterpenoid, a four-step synthesis of (-)-4-epi-presilphiperfolan-8-α-ol was achieved. The key processes involved are a ring-closing metathesis leading to a bridged alkene-tethered ketone and its subsequent FeIII -mediated metal-hydride atom transfer (MHAT) transannular cyclization. This synthetic method, implying an irreversible addition of a carbon-centered radical upon a ketone by means of a hydrogen atom transfer upon the alkoxy radical intermediate, was also applied in the synthesis of trans-fused hydrindanols structurally related to botrydial compounds.

RESUMEN

A Diels-Alder reaction leading to 4-nitrophenylcyclohexanones followed by a newly developed base-mediated reductive cyclization of the resulting ketone tethered to the nitrobenzene moiety gives access to the hexahydro-2,6-methano-1-benzazocine ring system present in several biologically interesting natural products such as aspernomine. The scope of the reaction was explored with eight substituted nitrobenzenes, obtaining yields of up to 87%. The highest cytotoxicity was observed in benzazocine 4h, bearing an enone moiety, which was active against eight cancer cell lines.

Asunto(s)

RESUMEN

A synthetic approach to a functionalized ABC-tricyclic framework of calyciphilline A-type alkaloids, a building block toward this class of alkaloids, is reported. The key synthetic steps involve a radical cyclization to form the hydroindole system and piperidine ring closure through a stereocontrolled aldol cyclization. The resulting alcohol allows the methyl group to be installed in the bowl-shaped azatricyclic structure; this crucial reaction takes place with configuration retention. The synthesis of azatricyclic compound I constitutes a formal synthesis of himalensine A.

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RESUMEN

The 5-endo-trig radical cyclization of N-benzyl-N-[(2-substituted)cycloalkenyl] trichloroacetamides (tetrasubstituted enamides) using Bu3SnH and AIBN is a reliable synthetic procedure giving access to 3a-methyl- and 3a-methoxycarbonyl enelactams. The substrate-controlled diastereoselective enolate alkylation of these enelactams resulted in the synthesis of a set of 3-substituted derivatives that upon reduction furnished polyfunctionalized cis-octahydroindoles. The latter building blocks, which embody three consecutive stereocenters at C-3, C-3a, and C-7a, were also synthesized through an initial reductive radical cyclization using (carbo-substituted)dichloroacetamides.

RESUMEN

The intermolecular reductive radical coupling of aldehydes with nonactivated alkenes, employing metal hydride atom transfer (MHAT) catalysis with a combination of FeII and FeIII salts, is described. This constitutes the first use of aldehydes as viable acceptor groups in MHAT reactions. The insights gained in this study led to the reexamination of the previously reported intramolecular version of the reaction, and the addition of FeII salts allowed the development of a more efficient second-generation approach.

RESUMEN

Iron-catalyzed hydrogen atom transfer-mediated intermolecular C-C coupling reactions between alkenes and tosylhydrazones, followed by in situ cleavage of the tosylhydrazine intermediates using Et3N, are described. The process involves a new strategic bond disconnection resulting in the reductive alkylation of nonactivated alkenes. The reaction is operationally simple, proceeds under mild conditions, and has a wide substrate scope.

RESUMEN

An azapentacyclic compound with the daphenylline ACDEF ring framework was synthesized from a benzo[e]indole intermediate efficiently obtained by a 5-endo-trig radical cyclization of a bicyclic trichloroenamide. Stereocontrolled processes were used to generate the three stereogenic methine carbons in the pyrrolidine C ring including the all-carbon quaternary stereocenter at C5. Ring closure to build both seven- and five-membered rings was achieved by Friedel-Crafts reactions.

RESUMEN

Analysis of 13C NMR spectroscopic data of the phlegmarine subset of Lycopodium alkaloids revealed spectral patterns that allowed the stereochemical arrangement of the four stereogenic carbons in the decahydroquinoline core to be established. A relatively simple predictive set of chemical shift combinations is reported, providing a tool for the challenging stereochemical assignment of phlegmarine-type alkaloids. Based on the chemical shifts in their NMR spectroscopic profiles, the alkaloids huperzine K and huperzine M, formally reported as cis derivatives, were structurally reassigned as trans-decahydroquinolines. The NMR spectroscopic data for huperzine M were identical to those reported for lycoposerramine Y and, hence, also implied the configurational reassignment of the latter. The revised structures of the above alkaloids were confirmed by enantioselective total synthesis. Additionally, the synthesis of (-)-serralongamine A via a common intermediate precursor is reported.

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RESUMEN

A straightforward synthetic entry to functionalized hydrindane compounds based on a rapid assembly of the core nucleus by a Danheiser cycloaddition is reported. Valuable bicyclic building blocks containing the fused five and six-membered carbocyclic ring system can be achieved in only four steps from a simple acyclic ß-keto ester.

RESUMEN

A cyanoborohydride-promoted radical cyclization methodology has been developed to access α-chlorolactams in a simple and efficient way using NaBH3 CN and trichloroacetamides easily available from allylic and homoallylic secondary amines. This methodology allowed the synthesis of a library of α-chlorolactams (mono- and bicyclic), which were tested for herbicidal activity, trans-3-chloro-4-methyl-1-(3-trifluoromethyl)phenyl-2-pyrrolidinone being the most active.

RESUMEN

An unprecedented C-C coupling reaction between alkenes and ketones by hydrogen-atom transfer, using Fe(acac)3 and PhSiH3 in EtOH, is described. This mild protocol features high site selectivity and allows the construction of sterically congested structures containing tertiary alcohols and quaternary centers. The overall process introduces a novel strategic bond disconnection for ring-closing reactions.

RESUMEN

A tetracyclic compound with the ABCD ring framework of calyciphylline A-type alkaloids was synthesized from a cis-3a-methyloctahydroindole triggered by a 5-endo radical cyclization. The synthesis required two additional ring-forming steps: the construction of a seven-membered ring by aldol cyclization and the azabicyclic fragment by a radical ring closure of a trichloroacetamide-tethered enol acetate followed by a diastereoselective α-methylation of the lactam group.

RESUMEN

Radical cyclization of dichloroacetamide-tethered ketones using pyrrolidine, AIBN and TTMSS under microwave activation gave 2-azabicyclo[3.3.1]nonan-3,6-diones. In a five-minute one-pot process, after the generation of an enamine, intramolecular addition of a carbamoylchloromethyl radical, and oxidation of the α-aminoalkyl radical intermediate, the resulting iminium salt evolved to the corresponding enamine and, after a workup, to the alkylated ketone.

RESUMEN

A straightforward, two-step asymmetric synthesis of octahydroindoles has been developed on the basis of two complementary strategies: (i) an organocatalyzed Michael reaction followed by a tandem Robinson-aza-Michael double cyclization catalyzed by PS-BEMP, and (ii) a diastereoselective cyclization, which formally constitutes a remote 1,6 asymmetric induction mediated by PS-BEMP. This allowed the construction of complex octahydroindoles with up to four stereocenters, excellent enantioselectivities (up to 95% ee), and complete diastereoselective control in a single-pot operation. DFT calculations were performed to understand the origin of this effect.

RESUMEN

A revised structure for the Lycopodium alkaloid huperzine N is proposed and confirmed by synthesis. The key synthetic steps involve an epimerization of a cis-5-oxodecahydroquinoline to the corresponding trans isomer and a coupling, followed by a diastereoselective hydrogenation using Wilkinson's catalyst to incorporate the pyridylmethyl moiety. This route allowed the alkaloid serralongamine A to be synthesized for the first time, and two additional steps led to the revised structure of huperzine N, both products bearing an unusual decahydroquinoline stereostructure.

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RESUMEN

A unified strategy for the synthesis of the cis-phlegmarine group of alkaloids is presented, leading to the first synthesis of serratezomine E (1) as well as the putative structure of huperzine N (2). A contrasteric hydrogenation method was developed based on the use of Wilkinson's catalyst, which allowed the facial selectivity of standard hydrogenation to be completely overturned. Calculations were performed to determine the mechanism, and structures for huperzines M and N are reassigned.

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RESUMEN

An unexpected C-C bond cleavage was observed in trichloroacetamide-tethered ketones under amine treatment and exploited to develop a new synthesis of normophans from 4-amidocyclohexanones. The reaction involves an unprecedented intramolecular haloform-type reaction of trichloroacetamides promoted by enamines (generated in situ from ketones) as counter-reagents. The methodology was applied to the synthesis of compounds embodying the 6-azabicyclo[3.2.1]octane framework.

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RESUMEN

Synthesis of the tetracyclic cores of madangamines D-F was achieved, featuring a reductive radical process from an ethoxycarbonyldichloroacetamide to build the morphan nucleus, a Mitsunobu-type aminocyclization toward the common diazatricyclic intermediate, and ring-closing metathesis reactions for the macrocyclization step leading to the 13- to 15-membered rings.

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