Synthetic study of (−)-lasubine II via sequential cyclization process

A new synthetic pathway to lythraceae alkaloid lasubine II has been developed. In this approach, we designed a sequential cyclization pathway for the formation of quinolizidine ring. For the preparation of the requisite precursor, a known chiral β-amino ester has been used as a starting intermediate. Upon deprotection of Cbz group on nitrogen, endo-type Michael addition and the following S_N2 reaction were assumed to proceed to provide (−)-2-epi lasubine II.     

Synthesis of (±)‐Lasubine II Using N‐Methoxyamines

The synthesis of (±)‐lasubine II has been achieved through a three‐component allylation capitalizing on the unique properties of N‐methoxyamines. This reaction enabled the installation of all the carbon atoms of lasubine II in a single operation. The N‐methoxy group was efficiently used for the subsequent nitrone formation. A single‐step cyclization of isoxazolidines or N‐methoxyamines to form functionalized piperidine rings was also developed.     

Studies on the synthesis of the lasubine alkaloids

Formal syntheses of lasubine II and subcosine II have been completed by the synthesis of epi-lasubine II. The synthesis involves diastereoselective allylation of a methoxy isoxazolidine and a tandem hydrogenation process leading stereoselectively to a trisubstituted piperidine.     

Synthetic applications of sulfur-substituted indolizidines and quinolizidines

Starting from the sulfur-substituted indolizidines and quinolizidines, a few useful synthetic transformations have been developed and the synthesis of some natural products including indolizidine 209D, epimyrtine, lasubine II, 8a-epi-dendroprimine, and 5-epi-cermizine C has been accomplished.     

Enantioselective synthesis of (−)-lasubine II

A highly enantioselective synthesis of lythraceae alkaloid lasubine II has been achieved using organo-catalyzed Mannich reaction, Maruoka allylation, and aza-Michael addition as the key steps.     

Enantioselective rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and terminal alkynes: application to the total synthesis of (+)-lasubine II

The use of TADDOL-based phosphoramidite ligands on rhodium allows for the incorporation of terminal alkynes in the [2+2+2] cycloaddition with alkenyl isocyanates. Terminal aliphatic alkynes provide bicyclic lactams, while the use of aryl alkynes provides complementary access to vinylogous amides. Product selectivity seems to be governed by a combination of electronics and sterics, with smaller and/or more electron-deficient substituents favoring lactam formation. The use of homologous alkenyl isocyanates leads to an expedient asymmetric total synthesis of the alkaloid lasubine II.     

Pd(II)/Brønsted acid catalyzed enantioselective allylic C-H activation for the synthesis of spirocyclic rings

A Pd(II)/Br?nsted acid catalyzed migratory ring expansion for the synthesis of indene derivatives possessing a stereogenic spirocyclic carbon center was developed. This transformation is believed to mechanistically proceed via enantioselective allylic C-H activation with concomitant semipinacol ring expansion to the nascent π-allylpalladium species. Enantioselectivities as high as 98% ee were attainable.     

Synthesis of new alkyl- alkenyloxy- and hydroxy-substituted diaza-crown compounds

New diaza-crown compounds with the macro ring nitrogen atoms situated in the 1, 4-, 1, 7- and 1, 10-positions have been prepared. All of the new macrocycles contain alkyl groups on the nitrogen atoms and a functional group substituent in the form of either an allyloxymethyl, allyloxy or hydroxy group on one of the macro ring carbon atoms. A 1, 4-diaza-crown attached to silica gel removes Hg(II) ions from an aqueous mixture of Hg(II), Cd(II) and Zn(II) ions.     

Synthesis of a potential bifunctional mimic of transaminases.

As a potential bifunctional mimic of transaminases 3,7-dimethyl-10-[3-(4- aminomethyl-5-hydroxy-6-methyl-3-pyridyl)propyl]-3,7,10- triazatricyclo[3.3.3.0(1,5)] undecane (I) has been synthesized by attaching 3,7-dimethyl-3,7,10-triazatricyclo [3.3.3.0(1,5)]undecane (II) to a pyridoxamine nucleus via an all-carbon chain. The chain length between the pyridine ring and II is restricted to three atom units so that the possibility for II to act bifunctionally during the transamination is maximized. In its protonated form, the nitrogen closest to the pyridine ring cannot deliver the proton intramolecularly to the alpha-carbon of the developing amino acid. To make the synthetic route generally applicable, introduction of the side-arm base is arranged at a later stage of the synthesis so that different di- or poly-amines can easily be used in place of II to prepare other target molecules that might possess bifunctional catalytic activity. This arrangement also greatly reduces the polarity and water-solubility of the intermediates and the purification of these compounds thus becomes much easier. The method of introducing the amino functionality at the C-4 methylene group described herein provides an alternative to that currently in use (reduction of oximes).     

Selective methodologies for the synthesis of biologically active piperidinic compounds

The synthesis of optically active substituted piperidines has been achieved by using four different methodologies. The first one is an intramolecular nucleophilic displacement of activated alcohol moieties that was used to build up the piperidine ring of (-)-prosophylline and (-)-slaframine, and the second one is a ring-closing metathesis of unsaturated amines which was employed in the synthesis of (+)-sedamine and 4a,5-dihydrostreptazoline. The third methodology is the alpha-functionalization of N-Boc piperidines which was particularly useful in the synthesis of argatroban, and the fourth one is a ring expansion of prolinols to 3-chloropiperidines or 3-hydroxypiperidines which was utilized to synthesize (-)-paroxetine, (-)-pseudoconhydrine, the piperidine ring of (-)-velbanamine and (+)-zamifenacin.     

Efficient route to 2H-1,3-oxazines through ring expansion of isoxazoles by rhodium carbenoids

Studies related to the total synthesis of elisabethin C led to the discovery of a rhodium-catalyzed cascade sequence involving isoxazole ring expansion and a [4+3] cycloaddition. The scope of the isoxazole ring expansion was explored, resulting in the synthesis of a range of 2H-1,3-oxazines in 47-96% yield.     

Synthesis,characterization and H<Subscript>2</Subscript> adsorption performances of polymeric Co(II) and Ni(II) complexes of pyrazine-2,3-dicarboxylic acid and 1-vinylimidazole

We studied the synthesis and characterization of polymeric coordination complexes of Co(II) and Ni(II) ions with pyrazine-2,3-dicarboxylic acid and 1-vinylimidazole. The e lemental analysis, infrared spectroscopy, powder X-ray diffraction, magnetic susceptibility, thermal analysis and X-ray single crystal techniques were used in the characterization. The X-ray single crystal analysis suggests that the pyrazine-2,3-dicarboxylato ligand acts as a bridging ligand through the oxygen atoms of the carboxylate groups and the nitrogen atoms on the pyrazine ring. The 1-vinylimidazole ligand behaves as a monodentate ligand via the ring nitrogen atom. Further, the H₂ adsorption studies were carried out at 75 K for various increasing pressures and the highest H₂ adsorption performances for Co(II) and Ni(II) complexes were estimated as 2.66 and 2.99 wt% at 87 bar. The theoretical calculations using the crystal data were also performed to determine the voids in the structure of Co(II) complex.     

Enantiodivergent synthetic entry to the quinolizidine alkaloid lasubine II

Intramolecular cycloaddition of the syn- and the anti-nitrone 9 and 13 leads stereoselectively to the azabicyclic compounds 10 and 14 which may provide access to both enantiomers of the quinolizidine alkaloid lasubine II.     

Synthesis of N-Vinyl-1,2,3-triazole Derivatives

Nitro-substituted N-vinyl-1,2,3-triazole derivatives were synthesized by the vinyl exchange reaction. The process was promoted by the catalytic system mercury(II) acetate-trifluoroacetic acid. This system is universal, and it can be used in the synthesis of vinylazoles having two, three, and four nitrogen atoms in the ring. in the ring.     

Asymmetric synthesis of 4-deoxyverrucarol via two types of ring expansion reactions

Asymmetric synthesis of a trichothecane analogue, 4-deoxyverrucarol (2), was carried out through two types of ring expansion reactions. First, synthesis of the racemate of 2 was investigated. Thus, 1-[1-(tert-butyldimethylsiloxy)-ethyl]-1-methoxycarbonyl-2-hexen-4-on e (10), prepared by Diels-Alder reaction, was converted into the cyclopropylidene 15. The cyclobutanone (+/-)-18 was obtained from 15 via dihydroxylation, followed by successive treatments with SO(2)Cl(2) in the presence of imidazole and Florisil. After transformation of (+/-)-18 into the vinylcyclobutanol (+/-)-19, the second ring expansion reaction was performed with Pd(OAc)(2) to provide the cyclopentanone (+/-)-20. The product was converted into the racemate of 4-deoxyverrucarol (2) through the cyclohexenone (+/-)-22, but the diastereoselectivity during the introduction of the double bond was unsatisfactory. The selectivity was improved in the case of the asymmetric synthesis. The optically active cyclobutanone (+)-18 was prepared via AD reaction of 15 with 73% ee. After the transformation of (+)-18 into the cyclohexanone (-)-30 through the palladium-mediated ring expansion reaction, (-)-30 was subjected to the diastereoselective deprotonation reaction using the chiral amide. The key synthetic intermediate (-)-25 of 4-deoxyverrucarol (2) was synthesized in an optically pure form by taking advantage of a kind of kinetic resolution that occurred during the deprotonation step.     

Catalytic Ring Expansion of Cyclic Hemiaminals for the Synthesis of Medium‐Ring Lactams

A mild and efficient intermolecular ring‐expansion approach was developed for the synthesis of medium‐ring lactams by using siloxy alkynes. Key to success is the suitable combination of a superior catalyst and an exceptional nitrogen‐protecting group. Control experiments indicated that the reaction is remarkably selective toward the desired lactam formation, even with many possible non‐productive pathways.     

Synthesis and stereochemical determination of complestatin A and B (neuroprotectin A and B)

Recently, we reported the first total synthesis of chloropeptin II (1, complestatin), the more strained and challenging of the two naturally occurring chloropeptins. Central to the design of the approach and by virtue of a single-step, acid-catalyzed ring expansion rearrangement of chloropeptin II to chloropeptin I, the route also provided a total synthesis of chloropeptin I. Herein, we report a complementary and divergent oxidation of chloropeptin II (1, complestatin) to either complestatin A (2, neuroprotectin A) or complestatin B (3, neuroprotectin B), providing the first synthesis of the natural products and establishing their remaining stereochemical assignments. Key to the approach to complestatin A (2, neuroprotectin A) was the development of two different single-step indole oxidations (HCl-DMSO and NBS, THF-H(2)O) that avoid the rearrangement of chloropeptin II (1) to chloropeptin I (4), providing the 2-oxindole 2 in superb yields (93% and 82%). With a mechanistic understanding of features that impact the latter oxidation and an appreciation of the intrinsic reactivity of the chloropeptin II indole, its modification (NCS, THF-H(2)O; Cs(2)CO(3), DMF-H(2)O) provided a two-step, single-pot oxidation of chloropeptin II (1) to afford directly the 3-hydroxy-2-oxindole complestatin B (3, neuroprotectin B). Extensive studies conducted on the fully functionalized synthetic DEF ring system of chloropeptin II were key to the unambiguous assignment of the stereochemistry as well as the exploration and subsequent development of the mild oxidation conditions used in the synthesis of complestatin A and B.     

Enantiocontrolled Total Synthesis of (−)‐Mersicarpine

A racemic synthesis of mersicarpine ( 1 ) was achieved by the Mizoroki–Heck reaction and a DIBALH‐mediated reductive ring‐expansion reaction. Based on a first‐generation synthesis, a second‐generation enantiocontrolled total synthesis of (?)‐mersicarpine ( 1 ) was achieved by an 8‐pot/11‐step sequence in 21 % overall yield from commercially available 2‐ethylcyclohexanone. Subjection of a ketoester, which was prepared by an asymmetric Michael addition (according to the protocol by d’Angelo and Desmaële), and phenylhydrazine to modified Fischer indole conditions provided a six‐membered tricyclic indole. Benzylic oxidation and subsequent oxime formation provided a ketoxime, which was treated with diisobutylaluminum hydride (DIBALH) to construct the characteristic azepinoindole skeleton in good yield. In the DIBALH‐mediated reductive ring‐expansion reaction, gradually increasing the reaction temperature and in situ‐protection of the nitrogen in an oxygen‐sensitive azepinoindole with a benzyloxycarbonyl (Cbz) group were crucial for the high‐yielding process. With these methodologies, the short‐step and efficient synthesis of (?)‐mersicarpine was accomplished. Several synthetic efforts are also described.     

A Reaction of Triazoles with Thioesters to Produce β‐Sulfanyl Enamides by Insertion of an Enamine Moiety into the Sulfur–Carbonyl Bond

N‐Sulfonyl‐1,2,3‐triazoles react with thioesters in the presence of a rhodium(II) catalyst to produce β‐sulfanyl enamides in a stereoselective manner. The reaction proceeds through generation of an α‐imino rhodium carbene complex, nucleophilic addition of the sulfur atom of a thioester onto the carbenoid carbon atom, and subsequent intramolecular migration of the acyl group from the sulfur atom to the imino nitrogen atom. The method is successfully applied to a ring‐expansion reaction of thiolactones, thus leading to the formation of sulfur‐containing lactams.     

Total synthesis and biological evaluation of (-)-9-deoxy-englerin A

An effective total synthesis of (-)-9-deoxy-englerin (4), an analogue of the natural guaiane sesquiterpene englerin A (1), has been achieved. The synthesis features a transannular epoxide opening to construct the 5,7-fused ring system followed by transannular ether formation with mercury(II) trifluoroacetate.