Synthesis of 5‐ and 8‐Deoxytetrodotoxin

Tetrodotoxin, a toxic principle of puffer fish intoxication, is one of the most famous marine natural products owing to its complex structure and potent biological activity, which leads to fatal poisoning. Continuous synthetic studies on tetrodotoxin and its analogues to elucidate biologically interesting issues associated with tetrodotoxin have led to the development of versatile routes for a variety of tetrodotoxin derivatives. With the aim of investigating the structure–activity relationship of tetrodotoxin with voltage‐gated sodium channels, this study describes the first total syntheses of 5‐deoxytetrodotoxin, a natural analogue of tetrodotoxin, and 8‐deoxytetrodotoxin, an unnatural analogue, from a newly designed, versatile intermediate in an efficient manner. An estimation of the biological activities of these compounds reveals the importance of the hydroxy groups at the C‐5 and C‐8 positions on the inhibition of voltage‐gated sodium channels.     

Synthesis of 3‐Butadienyl‐1‐tosylpyrroles

A pathway for the formation of 3‐butadienyl‐1‐tosylpyrroles from 3‐acyl derivatives via secondary and tertiary 3‐hydroxyalkyl‐1‐tosylpyrroles has been developed. The dehydration of the alcohols intermediates is the crucial step: conditions for high chemo‐ and diastereocontrol are described.     

Synthesis of 5‐substituted 2‐(2,4‐dihydroxyphenyl)‐1,3,4‐thiadiazoles

One‐stage synthesis of 5‐substituted (alkyl, aryl, heteroaryl, arylalkyl, heteroalkyl, alkoxy‐, aryloxy)‐2‐(2,4‐dihydroxyphenyl)‐1,3,4‐thiadiazoles is described. The compounds were prepared by the reaction of sulfinyl‐bis(2,4‐dihydroxythiobenzoyl) (STB) with hydrazides or carbazates. The structure of new compounds was assigned by ir, nmr and ms data.     

Synthesis of 2‐phosphoro‐1,2‐thiazetidine 1,1‐dioxide

The reactions of phosphorochloridites 5a–c with an equimolar amount of 1,2‐thiazetidine 1,1‐dioxide (2) or L(−)‐3‐carboethoxy‐1,2‐thiazetidine 1,1‐dioxide (7) in the presence of triethylamine, affords the N‐phosphitylated β‐sultams 6a–b and L(−)‐8a,c. Their oxidation by addition of oxygen, sulfur, or selenium results in formation of stable organophosphorus β‐sultams 10a–b, L(−)‐11a,c, 12a, 13a, L(−)‐14c, and L(−)‐15c. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 61–67, 1999     

Synthesis of 3‐aroyl‐4‐(3‐chromonyl)‐2‐pyrazolines

New 3‐aroyl‐4‐(3‐chromonyl)‐2‐pyrazolines have been synthesized by the reaction of 3‐(3‐aryl‐3‐oxo‐propenyl)chromen‐4‐ones and diazomethane. Some of these 2‐pyrazolines have also been N‐acylated with a mixture of anhydrous pyridine and acetic anhydride or propionic anhydride. Structures of all new compounds have been elucidated by elemental analyses, mass spectrometry, ir and nmr spectroscopic measurements.     

Synthesis of 3‐Ω‐aminohydantoins

Several 3‐Ω‐amino monosubstituted hydantoins have been obtained in the reaction of isocyanate of glycine ethyl ester with the appropriate aliphatic or aromatic diamine. It was found, that the 3‐(aminoaryl) monosubstituted hydantoins may be diazotized and their diazonium salts may be coupled and hydrolysed without changes in the hydantoin ring.     

TiCl3‐Mediated Synthesis of 2,3,3‐Trisubstituted Indolenines: Total Synthesis of (+)‐1,2‐Dehydroaspidospermidine, (+)‐Condyfoline,and (−)‐Tubifoline

2,3,3‐Trisubstituted indolenine constitutes an integral part of many biologically important monoterpene indole alkaloids. We report herein an unprecedented access to this skeleton by a TiCl₃‐mediated reductive cyclization of tetrasubstituted alkenes bearing a 2‐nitrophenyl substituent. The proof of concept is demonstrated firstly by accomplishing a concise total synthesis of (+)‐1,2‐dehydroaspidospermidine featuring a late‐stage application of this key transformation. A sequence of reduction of nitroarene to nitrosoarene followed by 6π‐electron‐5‐atom electrocyclization and a 1,2‐alkyl shift of the resulting nitrone intermediate was proposed to account for the reaction outcome. A subsequent total synthesis of (+)‐condyfoline not only illustrates the generality of the reaction, but also provides a mechanistic insight into the nature of the 1,2‐alkyl shift. The exclusive formation of (+)‐condyfoline indicates that the 1,2‐alkyl migration follows a concerted Wagner–Meerwein pathway, rather than a stepwise retro‐Mannich/Mannich reaction sequence. Conditions for almost quantitative conversion of (+)‐condyfoline to (?)‐tubifoline by way of a retro‐Mannich/1,3‐prototropy/transannular cyclization cascade are also documented.     

Synthesis of 3‐Ω‐amino‐2‐thiohydantoins

In the reaction of ethyl isothiocyanatoacetate with diamines, followed by cyclization of the intermediate product, 3‐monosubstituted thiohydantoins have been obtained. It was found that the reaction course depends on the purity of the isothiocyanate used and also, in the case of dialkylaminoamines, the self‐cyclization occurs. Besides the dialkylamino derivatives of 3‐monosubstituted 2‐thiohydantoins also new monoalkylamino, amino and heterocyclic derivatives were synthesized. The aryldiazonium derivative of 3‐monosubstituted 2‐thiohydantoin yielded both respective phenol derivative after hydrolysis and the product of coupling with 2‐naphthol.     

Synthesis of 1‐Methyl‐6,10‐diphenylheptalene Derivatives

The reduction of heptalene diester 1 with diisobutylaluminium hydride (DIBAH) in THF gave a mixture of heptalene‐1,2‐dimethanol 2a and its double‐bond‐shift (DBS) isomer 2b (Scheme 3). Both products can be isolated by column chromatography on silica gel. The subsequent chlorination of 2a or 2b with PCl₅ in CH₂Cl₂ led to a mixture of 1,2‐bis(chloromethyl)heptalene 3a and its DBS isomer 3b . After a prolonged chromatographic separation, both products 3a and 3b were obtained in pure form. They crystallized smoothly from hexane/Et₂O 7 : 1 at low temperature, and their structures were determined by X‐ray crystal‐structure analysis (Figs. 1 and 2). The nucleophilic exchange of the Cl substituents of 3a or 3b by diphenylphosphino groups was easily achieved with excess of (diphenylphospino)lithium (=lithium diphenylphosphanide) in THF at 0° (Scheme 4). However, the purification of 4a / 4b was very difficult since these bis‐phosphines decomposed on column chromatography on silica gel and were converted mostly by oxidation by air to bis(phosphine oxides) 5a and 5b . Both 5a and 5b were also obtained in pure form by reaction of 3a or 3b with (diphenylphosphinyl)lithium (=lithium oxidodiphenylphospanide) in THF, followed by column chromatography on silica gel with Et₂O. Carboxaldehydes 7a and 7b were synthesized by a disproportionation reaction of the dimethanol mixture 2a / 2b with catalytic amounts of TsOH. The subsequent decarbonylation of both carboxaldehydes with tris(triphenylphosphine)rhodium(1+) chloride yielded heptalene 8 in a quantitative yield. The reaction of a thermal‐equilibrium mixture 3a / 3b with the borane adduct of (diphenylphosphino)lithium in THF at 0° gave 6a and 6b in yields of 5 and 15%, respectively (Scheme 4). However, heating 6a or 6b in the presence of 1,4‐diazabicyclo[2.2.2]octane (DABCO) in toluene, generated both bis‐phosphine 4a and its DBS isomer 4b which could not be separated. The attempt at a conversion of 3a or 3b into bis‐phosphines 4a or 4b by treatment with t‐BuLi and Ph₂PCl also failed completely. Thus, we returned to investigate the antipodes of the dimethanols 2a, 2b , and of 8 that can be separated on an HPLC Chiralcel‐OD column. The CD spectra of optically pure (M)‐ and (P)‐configurated heptalenes 2a, 2b , and 8 were measured (Figs. 4, 5, and 9).     

Synthesis of 7‐chloro‐9‐trifluoromethyl‐/7‐fluorophenothiazines

Synthesis of 7‐chloro‐9‐trifluoromethyl‐/7‐fluorophenothiazines is reported by Smiles rearrangement of 5‐chloro‐3‐trifluoromethyl‐/5‐fluoro‐2‐formamido‐2′‐nitrodiphenyl sulfides. The later were obtained by the formylation of 2‐amino‐5‐chloro‐7‐trifluoromethyl‐/5‐fluoro‐2′‐nitrodiphenyl sulfides, which were prepared by the condensation of 2‐amino‐5‐fluoro‐/5‐chloro‐3‐trifluoromethyl benzenethiols with o‐halonitrobenzenes. 1‐Nitrophenothiazines have also been synthesized by the condensation of 2‐aminobenzenethiols with o‐halonitrobenzenes, involving Smiles rearrangement in situ. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:81–86, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20235