Core Of Alkaloids Research Articles

Application of Cross-Conjugated Heteroaromatic Betaines to the Synthesis of the Schizozygane Alkaloid (±)-Strempeliopine

An efficient stereocontrolled route to the isoschizozygane alkaloid core has been developed utilizing an intramolecular 1,4-dipolar cycloaddition of a cross-conjugated heteroaromatic betaine. The resulting cycloadduct undergoes loss of COS, and further reduction delivers a 5a-azaacenaphthylene intermediate that was transformed into the isoschizozygane skeleton upon treatment with acid. A variation of this tactic was then employed for a synthesis of the hexacyclic framework of the shizozygane alkaloid (+/-)-strempeliopine. The key step of the synthesis corresponds to an intramolecular 1,4-dipolar cycloaddition of a heteroaromatic betaine across a tethered 4-((2-nitrophenyl)but-3-enyl) side chain. Catalytic reduction of the nitro group followed by reaction with NBS resulted in the formation of the required pentacyclic indoline framework of the target alkaloid. Closure of the final ring of the shizozygane skeleton was carried using an oxidative cyclization.

Efficient Access to the Core of the Strychnos, Aspidosperma and Iboga Alkaloids. A Short Synthesis of Norfluorocurarine

An efficient anionic bicyclization of tryptamine-derived Zincke aldehydes forms the basis for a three-step route to the tetracyclic ABCE core of many Strychnos, Aspidosperma, and Iboga alkaloids. This powerful reaction is showcased in a five-step synthesis of the Strychnos alkaloid norfluorocurarine from tryptamine and pyridine.

Bifunctional Cinchona Sulfonamides in Asymmetric Michael Reaction

A novel bifunctional catalyst 1, which uses the cinchona alkaloid core as the ­stereocontrolling element and an N-sulfonamide moiety for single hydrogen-bonding catalysis, was employed in an enantioselective Michael addition. This quaternary carbon-forming reaction afforded the products in excellent yields and enantioselectivities, though diastereoselectivity was generally moderate. The catalyst is thought to activate both the nucleophile and the electrophile by hydrogen bonding with the quinuclidine nitrogen and the N-sulfonamide group, respectively.

Synthesis of Diazatricyclic Core of Madangamines from cis-Perhydroisoquinolines

Synthesis of the tricyclic core of madangamine alkaloids has been achieved in a 10-step sequence starting from a 4-(aminomethyl)anisole derivative. A Birch reduction and acylation with cyanoacetic acid followed by an intramolecular Michael process renders a polyfunctionalized cis-perhydroisoquinoline. A diastereoselective allylation and reduction of amide, nitrile, and ketone groups leads to a bicyclic alcohol, which undergoes aminocyclization through the nosyl derivative to the diazatricyclic ring.

A unified synthetic strategy toward oroidin-derived alkaloids premised on a biosynthetic proposal

Details of the evolution of a synthetic strategy toward the spirocyclic chlorocyclopentane core of oroidin-derived alkaloids, including the axinellamines and potentially adaptable to palau'amine, are described. A proposed refinement of the Kinnel–Scheuer biosynthetic proposal for palau'amine is posited. Studies undertaken to improve the regioselectivity and efficiency of a key Diels–Alder reaction utilizing a novel protecting group strategy, microwave chemistry, and other strategies are described. Further insights regarding the suitability of different protecting groups during the epoxidation/chlorination/ring contraction sequence are disclosed. Several interesting by-products from this reaction sequence are reported. These studies have led to a unified synthetic strategy to the axinellamines and palau'amine.

Synthesis of the heterocyclic core of martinelline and martinellic acid

A Povarov reaction, between an aromatic imine derived from cinnamaldehyde and a cyclic enamide, was employed to rapidly construct the tricyclic core of the alkaloids martinelline and martinellic acid. The cycloaddition was completely regioselective though the exo/ endo selectivity was poor. The diastereoisomers were readily separated by flash chromatography and the relative stereochemistry of the exo-isomer confirmed by single crystal X-ray crystallography. This intermediate was converted to the central core of the aforementioned alkaloids in five additional synthetic operations.

An Approach to the Isoschizozygane Alkaloid Core Using a 1,4-Dipolar Cycloaddition of a Cross-Conjugated Heteroaromatic Betaine

[reaction: see text] A new strategy for the synthesis of the isoschizozygane alkaloid core has been developed that is based on a 1,4-dipolar cycloaddition reaction of a cross-conjugated heteroaromatic betaine. The resulting cycloadduct undergoes loss of COS, and further reduction delivers a 5a-aza-acenaphthylene intermediate that was transformed into the isoschizozygane skeleton upon treatment with acid.

An Efficient and Enantioselective Approach to the Azaspirocyclic Core of Alkaloids: Formal Synthesis of Halichlorine and Pinnaic Acid

A novel, highly stereoselective synthesis of an azaspirocyclic core, which contains four stereogenic carbons consistent with structures of natural halichlorine and pinnaic acid, is presented. Lipase PS-catalyzed selective acylation, asymmetric methylation on the alpha-methylene of the bicyclic lactone, and an asymmetric Michael addition of the tertiary nitro cyclopentane were concisely used to conquer the challenging problem of successfully constructing the C9 quarternary carbon center with complete stereocontrol. The spiropiperidine ring was formed by reduction of the delta-nitroketone, intramolecular condensation, and then highly stereoselective reduction of the cyclic nitrone with NaBH(4). This spirocyclic core is a key intermediate in Danishefsky's synthesis of pinnaic acid and halichlorine.

Radical amination with sulfonyl azides: a powerful method for the formation of C-N bonds.

A novel reaction for the introduction of an azide moiety by means of a mild radical process is currently under development. Sulfonyl azides are suitable azidating agents for nucleophilic radicals, such as secondary and tertiary alkyl radicals. More electrophilic radicals, such as enolate radicals, do not react with sulfonyl azides. This feature allowed the development of efficient intra- and intermolecular carboazidations of olefins. Due to the versatility of the azido group, this reaction has an important synthetic potential, as already demonstrated by the preparation of the core of several alkaloids, particularly those containing an amino-substituted quaternary carbon center, such as FR901483.

An approach toward azacycles using photochemical and radical cyclizations of N-alkenyl substituted 5-thioxopyrrolidin-2-ones.

The photochemical reactions of a series of cyclic N-alkenyl-substituted thioimides have been examined. Irradiation of N-3-methylbut-3-enyl-5-thioxo-pyrrolidin-2-one (16) results in intramolecular [2 + 2] cycloaddition to give the highly strained thietane 17, whose structure was confirmed on the basis of its X-ray analysis. Treatment of cycloadduct 17 with dimethyl(methylthio)sulfonium tetrafluoroborate gave 2,5,6,7-tetrahydropyrrolizin-3-one (20) in good yield. Further reduction of 20 with Raney-Ni afforded 5,5-dimethylhexahydro-pyrrolizin-1-one (21). This sequence of reactions demonstrates the facility with which the 2 + 2 photoadduct can be converted into the pyrrolizidine alkaloid core skeleton. The photochemistry of the closely related N-butenyl thioxopyrrolidin-one (22) proceeded in a slightly different fashion and produced 7-mercaptomethyl tetrahydropyrrolizin-3-one (24) in 68% yield. In contrast to the above results, irradiation of the thioxaphthalimido system containing an N-cycloalkenyl group in the side chain gave rise to products derived by gamma-hydrogen abstraction from the n-pi triplet excited state. The photobehavior of the related N-3-alkenyl pyrrolidine-2,5-dithione system (62) was also studied and found to give products derived from both a 2 + 2 cycloaddition (63) and hydrogen atom transfer (64). Finally, the reaction of several N-alkenyl substituted thioimides (71-73) with tributylstannane in the presence of AIBN gave cyclized products derived from transient radical intermediates.

Synthesis of the dipyrrolopyrazinone core of dibromophakellstatin and related marine alkaloids

The dipyrrolopyrazinone (ABC) core of the phakelline-type pyrrole–imidazole alkaloids from marine sponges was synthesized starting from l-prolinol and 2-trichloroacetylated pyrroles. On oxidation of the condensation product with IBX, immediate cyclization occurs. It was found that the presence of a bromine substituent in the 8-position of the resulting tricyclic N, O-hemiacetal exclusively favors the cis relative configuration at the stereogenic centers C10 and C10a. Via an intermediate tertiary N-acyliminium ion, the pyrazinone core was dihydroxylated by treatment with m-CPBA in the presence of water. The simultaneous functionalization of the C10 and C10a positions is an important step towards the synthesis of the cytotoxic natural product dibromophakellstatin

Synthesis of the heterocyclic core of the alkaloids martinelline and martinellic acid

The tricyclic core of martinelline and martinellic acid was rapidly assembled utilising an imino Diels–Alder reaction of an imine derived from cinnamaldehyde with a cyclic enamide. The cycloaddition was completely regioselective though the exo– endo selectivity was poor. These diastereoisomers were readily separated by flash chromatography and the relative stereochemistry of the exo-isomer confirmed by single crystal X-ray crystallography. This intermediate was converted to the central core of the aforementioned alkaloids in five additional synthetic operations.

Application of furanyl carbamate cycloadditions toward the synthesis of hexahydroindolinone alkaloids.

A convenient synthesis of various substituted hexahydroindolinones has been achieved by an intramolecular Diels--Alder cycloaddition reaction (IMDAF) of furanyl carbamates bearing tethered alkenyl groups. The initially formed [4 + 2]-cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation of the resulting zwitterion to give the rearranged ketone. The stereochemical outcome of the IMDAF cycloaddition has the sidearm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. A synthetic route to (+/-)-mesembrane and (+/-)-crinane was accomplished using this methodology. It was possible to carry out a stereoselective reduction of the initially formed hexahydroindolinone ring to produce the cis-3a-aryl-hydroindole skeleton. A related [4 + 2]-cycloaddition/rearrangement sequence was also used for a formal synthesis of the Chinese ornamental orchid (+/-)-dendrobine. The tricyclic alkaloid core was formed stereoselectivity from the thermolysis of N-[(2-methyl-2-cyclopentenyl)methyl]-N-(4-isopropyl-furan-2-yl)carbamic acid tert-butyl ester. Kende's advanced intermediate 33 was prepared in seven additional steps by standard transformations, thereby completing a formal synthesis of (+/-)-dendrobine.

Tandem Radical Cyclizations on Iodoaryl Azides: Synthesis of the Core Tetracycle of Aspidosperma Alkaloids

A new stereoselective approach to the tetracyclic core of Aspidosperma alkaloids is described. Selective attack by tristrimethylsilylsilyl radicals on the aryl carbon−iodine bond of iodoaryl azides was first demonstrated on the simple model 15, thus both extending the recent discoveries of Kim and co-workers on aliphatic C−I bonds and demonstrating that the selectivity can be exploited in cascade radical cyclizations. Extension to the more complex substrate 25 afforded the core ABCE tetracyclic skeleton of the alkaloids in excellent yield and with efficient control of relative stereochemistry.

An Intramolecular Nitrone-Olefin Dipolar Cycloaddition-Based Approach to Total Synthesis of the Cylindricine and Lepadiformine Marine Alkaloids.

A synthetic route to the cylindricine skeleton as well as to the reported structure of the marine alkaloid lepadiformine has been achieved using an intramolecular nitrone/1,3-diene dipolar cycloaddition as the key step. The synthesis began with sequential alkylations of acetone oxime to afford key intermediate oxime 30, which contains all of the carbons necessary to form the tricyclic skeleton of the alkaloids. Nitrone 40, available from oxime 30 by standard transformations, underwent an intramolecular 1,3-dipolar cycloaddition to provide isoxazolidine 43. Related 1,3-dipolar cycloadditions were also explored on two additional nitrone-olefin substrates 41 and 42, which were prepared in a manner similar to that of 40. The tricyclic alkaloid core 52 was formed stereoselectively by a tandem oxidation-Michael addition of amino alcohol 49 derived from isoxazolidine 43. Cleavage of the O-phenyl ether of 52 provided 2-epi-cylindricine C (53). Several unsuccessful attempts were made to convert 52 to cylindricine C by epimerization at C2. Tricyclic ketone 52 was deoxygenated to give amine 59, whose structure and relative stereochemistry were confirmed by single-crystal X-ray analysis of its picrate salt. Removal of the O-phenyl protecting group from 59 provided tricyclic amino alcohol 60 having the putative structure of lepadiformine, but whose NMR data did not correspond to those of the natural product.

Synthetic studies of zoanthamine/norzoanthamine alkaloids: Advanced intermediate for the heterocyclic aminal core

An advanced intermediate for the heterocyclic aminal core of zoanthaminelnorzoanthamine alkaloids was prepared in an enantio and stereoselective manner. Contiguous quaternary chiral centers were selectively constructed utilizing a stereoselective cuprate addition to the readily available (+)-Wieland-Miescher ketone.

Tetrathiafulvalene-mediated stereoselective synthesis of the tetracyclic core of Aspidosperma alkaloids

A novel route to advanced synthetic precursors of Aspidosperma alkaloids is described, utilising radical-polar crossover reactions.