Stereodivergent Synthesis of Alkaloid (±)-223A and (±)-6-epi-223A via Rh-Catalyzed Hydroformylation Double Cyclization.

A stereodivergent approach toward total syntheses of Dendrobatid alkaloids 223A and 6-epi-223A is described. The approach features a concise construction of an indolizidine skeleton by Rh-catalyzed domino hydroformylation double cyclization and sequential stereocontrolled transformations such as reductive alkylation or anti-selective α-alkylation of the 5-oxoindolizidine. These stereoselective reactions afford the desired stereochemistry in the targets.

Diastereocontrolled Formal Syntheses of (±)-Lepadiformines A, B, and C and the Divergent Synthesis of 2-epi-Lepadiformine C through Unexpected Double Consecutive Epimerizations.

We describe here the diastereocontrolled formal racemic syntheses of tricyclic marine alkaloids, lepadiformines A, B, and C as well as their C2 epimers, featuring divergent and stereoselective syntheses of the N-acetyl-8a-cyanodecahydroquinoline frameworks and the base-mediated intramolecular cyclization to establish the spiral quaternary center of the tricyclic framework from sterically well-defined α-aminonitrile 2. The approach allows us to accomplish the tricyclic core structure efficiently from readily available starting materials through simple operations. An unexpected pair of consecutive epimerizations at two contiguous stereocenters is observed on the basis of single-crystal X-ray analyses of the intermediates and derivatives. The findings have been successfully applied to the total synthesis of 2-epi-lepadiformine C. The epimerization mechanism has been elucidated through a series of deuterium-labelling-controlled experiments.

Synthesis of (±)-Aphanorphine Using Rh-Catalyzed Cyclohydrocarbonylation.

A facile formal synthesis to aphanorphine and its analogue is described, featuring Rh-catalyzed cyclohydrocarbonylation of 2-aminodihydronaphthalene to the bridged benzazepine core. Subsequent introduction of the methyl group and functional group transformation complete the synthesis of aphanorphine and its analogue over eight steps.

Total Synthesis of (±)-20-epi-Kopsiyunnanine K: A Domino and Stereocontrolled Approach.

A one-pot route to a novel azepane-fused tetrahydro-ß-carboline framework from tryptyl-4-pentenamide derivatives has been developed, featuring the Rh-catalyzed hydroformylation double cyclization. Subsequent alkylation in the tetracyclic system proceeded stereoselectively to form a quaternary carbon. The synthesis of (±)-20-epi-kopsiyunnanine K was accomplished through the strategy.

Syntheses of (-)-pelletierine and (-)-homopipecolic acid.

Enantiomeric syntheses of (-)-homopipecolic acid and (-)-pelletierine have been achieved by chiral resolution of tropanol followed by Baeyer-Villiger oxidation. The methodology provides a practical route for the synthesis of optically pure piperidines.

Total Synthesis of (±)-Fasicularin through Double Consecutive Epimerizations.

The total synthesis of tricyclic marine alkaloid fasicularin (1b) has been accomplished from a novel sterically well-defined α-aminonitrile 7, featuring a novel double consecutive epimerization process and Ir-catalyzed reductive functionalization of a tertiary γ-lactam. The required configuration is obtained through the thermodynamically stereoselectively driven isomerization of a readily available 8a-cyanodecahydroquinoline framework. The strategy allows us to achieve the tricyclic core structures efficiently from affordable starting materials through simple operations.

Facile syntheses of enantiopure 3-hydroxypiperidine derivatives and 3-hydroxypipecolic acids.

Facile syntheses of enantiopure trans- and cis-3-hydroxypiperidine derivatives and 3-hydroxypipecolic acids are reported, featuring Rh-catalyzed cyclohydrocarbonylation through common intermediates. A diaxial conformation in a 2,3-disubstituted N-Boc-piperidinyl structure is revealed by an X-ray crystallographic analysis.

Rh-Catalyzed Hydroformylation-Initiated Bicyclization: Construction of Azabicyclic Systems.

Here, we describe the recent progress toward construction of 1-azabicyclic structures using a domino hydroformylation double cyclization strategy of an amide bearing the trisubstituted alkene functionality. The method provides a rapid and atom-economic access to alkaloid structures under mild conditions, especially for quinolizidine and pyrrolidine-fused azepane skeletons with yields up to 82% and good diastereoselectivity. Subsequent oxidative cleavage conditions are developed for the synthesis of Dendrobatid alkaloid epi-epiquinamide.

Application of Rhodium-Catalyzed Cyclohydrocarbonylation to the Syntheses of Enantiopure Homokainoids.

Kainic acid, rigidified (S)-glutamic acid, is a well-known kainite receptor agonist for the excitatory transmission in the central nerve system. Our interest in highly selective kainite ligands, prompted us to design a series of new kainic homologues, "homokainoids", i.e., conformationally rigidified (S)-glutamic acids. For the syntheses of enantiopure novel homokainoids (pipecolinoglutamic acids), we successfully applied cyclohydrocarbonylation (CHC) reaction that has been developed in these laboratories. Efficient total syntheses of enantiopure novel homokainoids from (R)-serine feature the highly diastereoselective conjugate addition and the regioselective CHC process in the key steps.

Construction of Fused Tropone Systems Through Intramolecular Rh(I)-Catalyzed Carbonylative [2+2+2+1] Cycloadditon of Triynes.

"Tropone" is a non-benzenoid aromatic skeleton that can be found in a variety of natural products. This cyclohepta-2,4,6-trien-1-one skeleton appears simple, but there have been no straightforward ways to construct this molecular architecture. It is conceivable that this molecule can be constructed via a higher order cycloaddition of three acetylene units and CO, but such process was not known until we have discovered that the carbonylative [2+2+2+1] cycloaddition of triynes can take place in the presence of a Rh complex catalyst and CO. However, this highly challenging process is naturally accompanied by ordinary [2+2+2] cyclotrimization products, i.e., benzenes, as side products. A mechanistic study led to two competing processes wherein the critical CO insertion occurs either to a rhodacyclopentadiene intermediate (Path A) or a rhodacycloheptatriene intermediate (Path B). The DFT analysis of those two pathways disclosed that the Path A should be the one that yields the carbonylative [2+2+2+1] cycloaddition products, i.e., fused tricyclic tropones. A further substrate design, inspired by colchicine structure, led to the almost exclusive formation of a fused tetracyclic tropone from a triyne bearing 1,2-disubstituted benzene moiety in a single step and excellent yield.

Rhodium-Catalyzed Domino Hydroformylation/Double-Cyclization Reaction of Arylacetylenecarboxamides: Diastereoselectivity Studies and Application in the Synthesis of 1-Azabicyclo[x.y.0]alkanes.

A domino method for the rapid syntheses of 1-azabicyclo[x.y.0]alkane scaffolds, such as indolizidines, quinolizidines, decahydropyridoazepines, and their derivatives, has been developed. This strategy involved a rhodium-catalyzed hydroformylation of allyl-, 3-butenyl-, or homoallyl amides, followed by two spontaneous ring closures under mild conditions. The reaction scope and diastereoselectivity were fully explored by changing the substitution pattern on the amide and by altering the length of the carbon chain. This method was applied to the syntheses of natural alkaloids tashiromine and epilupinine. The clear differences between the reactivities of two isomeric amide substrates, 3-butenamide 1 j and homoallyl amide 1 i, could be attributed to better HOMO-LUMO overlap in the transition states that were derived from butenamides during cyclization. This explanation was supported by DFT calculations.

Nazarov Cyclization Entry to Chiral Bicyclo[5.3.0]decanoid Building Blocks and Its Application to Formal Synthesis of (-)-Englerin A.

A divergent entry to the chiral bicyclo[5.3.0]decane skeletons relevant to sesqui- and higher terpenoids has been achieved. Its usefulness was demonstrated by formal synthesis of a guaiane sesquiterpenoid (-)-englerin A. The key reactions are (i) diastereoselective Nazarov cyclization for stereoselective construction of the bicyclo[5.3.0]decane skeleton, (ii) intramolecular C-H amination for tuning an oxidation state, and (iii) introduction of an alkyl group to a ß-alkoxy ketone with a zinc(II) ate complex.

New and efficient synthesis of azabicyclo[4.4.0]alkane amino acids by Rh-catalyzed cyclohydrocarbonylation.

[reaction: see text] Highly efficient syntheses of azabicyclo[4.4.0]alkane amino acids were achieved by Rh-catalyzed cyclohydrocarbonylation of dipeptides bearing a terminal olefin moiety and a heteroatom nucleophile.

Domino Rh-catalyzed hydroformylation-double cyclization of o-amino cinnamyl derivatives: applications to the formal total syntheses of physostigmine and physovenine.

A parallel, versatile and efficient route to synthesis of pyrrolidinoindoline and tetrahydrofuranoindoline alkaloids from cinnamyl derivatives has been developed, featuring a domino Rh-catalyzed hydroformylation-double cyclization sequence. This method can be applied to the syntheses of anti-Alzheimer drugs such as physostigmine and physovenine.

Alkyne-mediated domino hydroformylation/double cyclization: mechanistic insight and synthesis of (±)-tashiromine.

A novel domino reaction, alkyne-mediated domino hydroformylation/double cyclization, has been developed for rapid preparation of indolizidine type alkaloids. DFT calculations were applied for rationales of reactivity and selectivity. A concise synthesis of tashiromine as the application of the methodology is also reported.

Efficient syntheses of crispine A and harmicine by RH-catalyzed cyclohydrocarbonylation.

The first examples of Rh-catalyzed cyclohydrocarbonylation-bicyclization of N-allylic amides of arylacetic acids are reported. This novel carbonylative bicyclization process was successfully applied to the rapid syntheses of crispine A and its analogues (tricyclic indolizidine alkaloids) as well as harmicine (tetracyclic beta-carboline alkaloid).

Highly efficient synthesis of azabicyclo[x.y.0]alkane amino acids and congeners by means of Rh-catalyzed cyclohydrocarbonylation.

A highly efficient method for the synthesis of 1-azabicyclo[x.y.0]alkane amino acid derivatives and their congeners by means of extremely regioselective cyclohydrocarbonylation (CHC) is described. The CHC reactions are catalyzed by Rh-BIPHEPHOS complex under mild conditions. These CHC reaction processes involve (i) an extremely linear-selective hydroformylation of the terminal alkene moiety of a dehydrodipeptide substrate, (ii) intramolecular condensation to form cyclic N-acyliminium key intermediate, and (iii) the second cyclization through intramolecular nucleophilic addition of a heteoatom nucleophile to the cyclic N-acyliminium moiety to afford the corresponding 1-azabicyclo[x.y.0] system. This consecutive double cyclization process proceeds with extremely high diastereoselectivity in most cases. This method has been successfully applied to the syntheses of 1-azabicyclo[4.4.0], -[5.4.0], and -[4.3.0] systems. The mechanisms of the reactions and the rationale for the observed extremely high diastereoselectivity are presented. This Rh-catalyzed CHC process would serve as a highly efficient and versatile method for the syntheses of a variety of conformationally restrained dipeptides, peptidomimetics, alkaloids, and other biologically active natural or unnatural products.

Rhodium-catalyzed cyclohydrocarbonylation approach to the syntheses of enantiopure homokainoids.

Homologues of kainic acid, a naturally occurring potent glutamate receptor agonist, were designed based on a rigidified pipecolinoglutamic acid structure and can be regarded as homokainoids for their potential activities in the central nervous system. These novel homokainoids in an enantiomerically pure form were synthesized from enantiopure (R)- and (S)-Garner's aldehyde, featuring (i) the highly diastereoselective addition of alkenylcuprates to the acrylate intermediates and (ii) the Rh-catalyzed cyclohydrocarbonylation of homoallylic amine intermediates to construct the functionalized piperidine moiety in the key steps. For the introduction of a substituent at the 4- or 5-position of pipecolinoglutamic acid, a few different strategies were used, which successfully led to the formation of enantiopure homokainoids.