Catalytic Enantioselective [4+2] Cycloadditions of Salicylaldehyde Acetals with Enol Ethers.

A readily accessible conjugate-base-stabilized carboxylic acid (CBSCA) catalyst facilitates highly enantioselective [4+2] cycloaddition reactions of salicylaldehyde-derived acetals and cyclic enol ethers, resulting in the formation of polycyclic chromanes with oxygenation in the 2- and 4-positions. Stereochemically more complex products can be obtained from racemic enol ethers. Spirocyclic products are also accessible.

Approaches to Construction of the Medium-Sized Ring Structure in Zetekitoxin AB by Ring-Closing Metathesis.

Zetekitoxin AB (ZTX), a member of the saxitoxin (STX) family isolated from the Panamanian golden frog Atelopus zeteki, shows extremely potent NaV-inhibitory activity. Here, we investigate the synthesis of 12-membered ring structure with the C11 tertiary hydroxyl group in ZTX by means of the Mislow-Evans rearrangement reaction and subsequent ring-closing metathesis reaction. Although this approach did not provide access to the 12-membered macrocycle, we obtained a new STX analog with an 18-membered macrolactam structure as a synthetic mimic of ZTX.

Guanidinium Hypoiodite-Catalyzed Intramolecular Oxidative Coupling Reaction of Oxindoles with ß-Dicarbonyls.

Spiro[indoline-3,4'-piperidine] is a fundamental motif present in various biologically active compounds. Here, we report an intramolecular oxidative coupling reaction of oxindoles with ß-dicarbonyls in the presence of a guanidinium hypoiodite catalyst, providing spiro-coupling products in moderate to excellent yields. Furthermore, a chiral hypoiodite catalyst derived from the chiral guanidinium organocatalyst is effective for the challenging asymmetric carbon-carbon bond-forming reaction, affording optically active spiro[indoline-3,4'-piperidines].

Nontoxic Enantiomeric Reference Materials for Saxitoxins.

Saxitoxin (STX) is a potent neurotoxin that is biosynthesized by toxic dinoflagellates and accumulated in shellfish via the food chain. STX and its various analogues are now monitored in shellfish by the hygiene authorities in many countries with instrumental analytical methods, which require calibration with standards. Unfortunately, STX is registered as a chemical warfare agent in Schedule 1 of the Chemical Weapons Convention, and this has made it difficult to import calibration standards into some countries. We aimed to avoid violation of the Chemical Weapons Convention and facilitate analyses by preparing calibration standards based on unnatural nontoxic antipodal STXs (ent-STXs) with the same physicochemical properties as natural STXs. Our findings demonstrate that the nontoxic ent-STXs can be safely utilized as alternative reference materials of STXs in the routine monitoring program by the local authorities and consequently can lead to reduced usage of STX.

Enantioselective Total Synthesis of Cepharatines via Bioinspired Ring Reconstruction.

We describe enantioselective total syntheses of cepharatines A-D, members of the hasubanan alkaloid family, which feature an unusual tetracyclic skeleton including an azabicyclo[3.3.1]nonane motif. A key reaction is a regio-divergent oxidative phenolic coupling reaction that affords the tricyclic core structure of hasubanan with different substitution patterns on the A-ring, including the all-carbon quaternary stereogenic center at C13, in a single step. The characteristic tetracyclic azabicyclo[3.3.1]nonane motif was constructed by means of a bioinspired cascade reaction involving the retro-aza-Michael reaction/hemiaminal formation.

Stereodivergent Synthesis of 1,3-Dienes via Protodeboronation of Homoallenylboronic Esters.

Vinylboronic esters and allylboronic esters are well known to afford olefins by protodeboronation, and therefore homoallenylboronic esters should be similarly available as precursors for 1,3-dienes, but this strategy has not been well explored due to the limited availability of homoallenylboronic esters. Here, we describe a versatile synthesis of homoallenylboronic esters via lithiation-borylation and subsequent 1,2-rearrangement. The resulting homoallenylboronic esters were successfully converted into Z- and E-1,3-dienes by protodeboronation using Bu4NF and B(C6F5)3/PhOH, respectively.

Synthesis of Deuterium-Labeled Vitamin D Metabolites as Internal Standards for LC-MS Analysis.

Blood levels of the vitamin D3 (D3) metabolites 25-hydroxyvitamin D3 (25(OH)D3), 24R,25-dihydroxyvitamin D3, and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) are recognized indicators for the diagnosis of bone metabolism-related diseases, D3 deficiency-related diseases, and hypercalcemia, and are generally measured by liquid-chromatography tandem mass spectrometry (LC-MS/MS) using an isotope dilution method. However, other D3 metabolites, such as 20-hydroxyvitamin D3 and lactone D3, also show interesting biological activities and stable isotope-labeled derivatives are required for LC-MS/MS analysis of their concentrations in serum. Here, we describe a versatile synthesis of deuterium-labeled D3 metabolites using A-ring synthons containing three deuterium atoms. Deuterium-labeled 25(OH)D3 (2), 25(OH)D3-23,26-lactone (6), and 1,25(OH)2D3-23,26-lactone (7) were synthesized, and successfully applied as internal standards for the measurement of these compounds in pooled human serum. This is the first quantification of 1,25(OH)2D3-23,26-lactone (7) in human serum.

Enantioselective Total Synthesis of (+)-Stephadiamine through Bioinspired Aza-Benzilic Acid Type Rearrangement.

We report the first enantioselective total syntheses of the hasubanan alkaloid (-)-metaphanine and the norhasubanan alkaloid (+)-stephadiamine. Key features of these syntheses include diastereoselective oxidative phenolic coupling reaction and subsequent regioselective intramolecular aza-Michael reaction, which efficiently construct the hasubanan skeleton with the all-carbon quaternary stereogenic center at C13. Based on our hypothesis regarding the biosynthetic pathway of (+)-stephadiamine, we found that (-)-metaphanine is easily converted to (+)-stephadiamine via aza-benzilic acid type rearrangement reaction.

Modular Design of Chiral Conjugate-Base-Stabilized Carboxylic Acids: Catalytic Enantioselective [4 + 2] Cycloadditions of Acetals.

Readily available 1,2-amino alcohols provide the framework for a new generation of chiral carboxylic acid catalysts that rival the acidity of the widely used chiral phosphoric acid catalyst (S)-TRIP. Covalently linked thiourea sites stabilize the carboxylate conjugate bases of these catalysts via anion-binding, an interaction that is largely responsible for the low pKa values. The utility of the new catalysts is illustrated in the context of challenging [4 + 2] cycloadditions of salicylaldehyde-derived acetals with homoallylic and bishomoallylic alcohols, providing polycyclic chromanes in a highly enantioselective fashion.

Synthesis of C12-Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage-Gated Sodium Channels.

A novel series of C12-keto-type saxitoxin (STX) derivatives bearing an unusual nonhydrated form of the ketone at C12 has been synthesized, and their NaV -inhibitory activity has been evaluated in a cell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX (3 a) showed potent inhibitory activity against neuroblastoma Neuro 2A in both cell-based and electrophysiological analyses, with EC50 and IC50 values of 8.5 and 30.7 nm, respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of NaV 1.5, with an IC50 value of 94.1 nm. Derivatives 3 a-d and 3 f showed low recovery rates from NaV 1.2 subtype (ca 45-79 %) compared to natural dcSTX (2), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-keto derivatives with NaV in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp1717 .

Synthesis of Hydrocarbazole Derivatives by Oxidative Dearomative Cyclization of Diarylamines Using a Hypervalent Iodine Reagent.

Hydrocarbazole derivatives bearing a quaternary stereogenic center at C4a were synthesized by means of intramolecular oxidative dearomatization of diarylamines using hypervalent iodine in moderate to good yields. The hydrocarbazole bearing a cyclohexadienone moiety was further converted into the tetracyclic skeletons of Aspidosperma and akuammiline-type alkaloids via regioselective aza-Michael reaction at C4 and at C9a, respectively.

Enantioselective Epoxidation of 2,3-Disubstituted Naphthoquinones by a Side Chain Truncated Guanidine-Urea Bifunctional Organocatalyst.

An organocatalytic enantioselective epoxidation of 2,3-disubstituted naphthoquinones with tert-butyl hydroperoxide as an oxidant was developed using a guanidine-urea bifunctional catalyst lacking C2 symmetry, which was designed based upon the insights obtained from the DFT calculation model for our previous C2 symmetric catalyst. The present organocatalytic reaction provides access to a variety of optically active naphthoquinone epoxides bearing aryl and methyl substituents at C2 and C3 in high yields with high enantioselectivities (up to 97:3 er).

Highly Acidic Conjugate-Base-Stabilized Carboxylic Acids Catalyze Enantioselective oxa-Pictet-Spengler Reactions with Ketals.

Acyclic ketone-derived oxocarbenium ions are involved as intermediates in numerous reactions that provide valuable products, however, they have thus far eluded efforts aimed at asymmetric catalysis. We report that a readily accessible chiral carboxylic acid catalyst exerts control over asymmetric cyclizations of acyclic ketone-derived trisubstituted oxocarbenium ions, thereby providing access to highly enantioenriched dihydropyran products containing a tetrasubstituted stereogenic center. The high acidity of the carboxylic acid catalyst, which exceeds that of the well-known chiral phosphoric acid catalyst TRIP, is largely derived from stabilization of the carboxylate conjugate base through intramolecular anion-binding to a thiourea site.

Stereoselective Synthesis of Four Calcitriol Lactone Diastereomers at C23 and C25.

(23 S,25 R)-Calcitriol lactone is a major metabolite of vitamin D3, but its synthesis has been far less well investigated than that of 1α,25(OH)2 vitamin D3, the active form of vitamin D3, even though the lactone is present at a significant level in serum. This paper describes stereoselective syntheses of natural calcitriol lactone and its diastereomers at C23 and C25. This work features (i) the diastereoselective Reformatsky-type crotylation of aldehyde 25 in the presence of chiral ligand L2 to construct the stereochemistry at C23 and (ii) the diastereoselective epoxidation of homoallylic-allylic alcohol 31 to control the stereochemistry at C25. These key reactions allowed us to synthesize CD-ring synthon 30 with all four stereoisomers, and these were further converted into calcitriol lactones 3a-3d by reaction with ene-yne-type A-rings 33 in the presence of a palladium (0) catalyst.

Synthetic Approaches to Zetekitoxin AB, a Potent Voltage-Gated Sodium Channel Inhibitor.

Voltage-gated sodium channels (NaVs) are membrane proteins that are involved in the generation and propagation of action potentials in neurons. Recently, the structure of a complex made of a tetrodotoxin-sensitive (TTX-s) NaV subtype with saxitoxin (STX), a shellfish toxin, was determined. STX potently inhibits TTX-s NaV, and is used as a biological tool to investigate the function of NaVs. More than 50 analogs of STX have been isolated from nature. Among them, zetekitoxin AB (ZTX) has a distinctive chemical structure, and is the most potent inhibitor of NaVs, including tetrodotoxin-resistant (TTX-r) NaV. Despite intensive synthetic studies, total synthesis of ZTX has not yet been achieved. Here, we review recent efforts directed toward the total synthesis of ZTX, including syntheses of 11-saxitoxinethanoic acid (SEA), which is considered a useful synthetic model for ZTX, since it contains a key carbon-carbon bond at the C11 position.

Synthesis of 2,6,7-Trisubstituted Prenylated indole.

Prenylated indole alkaloids bearing more than one prenyl or reverse-prenyl group show various biological activities. Among them, synthesis of trisubstituted-type prenylated indoles have not been well explored because of the difficulty in regioselective introduction of multiple prenyl and reverse-prenyl groups due to steric hindrance problems. Herein, we describe a synthesis of 2,6,7-trisubstituted prenylated indole using aza-Claisen rearrangement under mild conditions to introduce a prenyl group at C7 in the presence of the prenyl group at C6.

Total Synthesis of (+)-Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration.

The enantioselective total synthesis of (+)-gracilamine (1) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza-Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza-Friedel-Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)-gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.

Total Synthesis of Rishirilide†B by Organocatalytic Oxidative Kinetic Resolution: Revision of Absolute Configuration of (+)-Rishirilide†B.

Described herein is the enantioselective syntheses of (+)- and (-)-rishirilide B from the corresponding optically active ß-substituted tetralones, which were obtained by oxidative kinetic resolution based on α-hydroxylation in the presence of a chiral guanidine-bisurea bifunctional organocatalyst. Benzylic oxidation of the tetralones at C1 followed by regioselective isomerization of the oxabenzonorbornadiene structure led to rishirilide B. Our findings lead to the revision of the previously proposed (2R,3R,4R) absolute configuration of (+)-rishirilide B to (2S,3S,4S).

Asymmetric α-amination of ß-keto esters using a guanidine-bisurea bifunctional organocatalyst.

An asymmetric α-amination of ß-keto esters with azodicarboxylate in the presence of a guanidine-bisurea bifunctional organocatalyst was investigated. The α-amination products were obtained in up to 99% yield with up to 94% ee.

Origin of stereocontrol in guanidine-bisurea bifunctional organocatalyst that promotes α-hydroxylation of tetralone-derived ß-ketoesters: asymmetric synthesis of ß- and γ-substituted tetralone derivatives via organocatalytic oxidative kinetic resolution.

The mechanism of asymmetric α-hydroxylation of tetralone-derived ß-ketoesters with guanidine-bisurea bifunctional organocatalyst in the presence of cumene hydroperoxide (CHP) was examined by means of DFT calculations to understand the origin of the stereocontrol in the reaction. The identified transition-state model was utilized to design an enantioselective synthesis of ß- or γ-substituted tetralones by catalytic oxidative kinetic resolution reaction of tetralone-derived ß-ketoesters. This kinetic resolution reaction proceeded with high selectivity, and selectivity factors (s value) of up to 99 were obtained. The potential utility of this oxidative kinetic resolution method for synthesis of natural products was confirmed by applying it to achieve an enantioselective synthesis of (+)-linoxepin (13) from ß-substituted tetralone rac-7 in only six steps.