Mg-promoted facile and selective intramolecular cyclization of aromatic δ-ketoesters

Treatment of various types of aromatic δ-ketoesters 2, 7, and 9 with Mg-turnings for Grignard reaction at −5 to 0 °C in N,N-dimethylformamide (DMF) containing trimethylsilyl chloride (TMSCl) brought about selective and reductive intramolecular cyclization to give the corresponding α-aryl-α-hydroxycyclopentanones 5, 8, and 10, respectively, in moderate to good yields. Similar reductive intramolecular cyclization of aromatic δ-ketodiesters 14, followed by acidic hydrolysis and decarboxylation easily gave the corresponding 2-aryl-2-cyclopenten-1-ones 15. The present facile coupling may be initiated through electron transfer from Mg metal to the aromatic carbonyl groups of 2, 7, 9, and 14 to generate the corresponding radical anions, followed by their intramolecular nucleophilic attack to the ester groups to give the corresponding five-membered ring compounds 5, 8, 10, and 15, respectively.     

A new protecting group ‘3,5-O-sulfinyl’ for xylo-nucleosides. A simple and efficient synthesis of 3-amino-3-deoxyadenosine (a puromycin intermediate), 2,2-anhydro-pyrimidine nucleosides and 2,3-anhydro-adenosine

We developed a new protecting group, the cyclic sulfite for the protection of the 3^′,5^′-dihydroxy group of nucleosides. Seven cyclic sulfites, 4a-c, 5a-b, and 6a-b were prepared in high yields from the corresponding xylo-uridines 1 and 2, and xylo-adenosines 3 with thionyl chloride, respectively. Synthesis of the puromycin intermediate 8 was carried out by deprotection of the sulfite moiety through an intramolecular cyclization of the 2^′-α-carbamate 7.     

Preparation and reactions of 3-phosphinyl-1-aza-1,3-butadienes. Synthesis of phosphorylated pyridine and pyrazole derivatives

3-Phosphinyl 1-aza-1,3-butadienes 2 are obtained by aldol condensation between hydrazonoalkyl phosphine oxides and N,N-dimethylformamide dimethyl acetal. Transamination reaction of these azadienes with amines yields functionalized 1-aza-1,3-butadienes 3. Cycloaddition processes of these azadienes 2a with electron-poor dienophiles to give phosphorylated pyridine derivatives 9 and 15 are also reported, while intramolecular cyclization reaction of heterodiene 2b affords phosphorylated pyrazole 17.     

An efficient synthesis of benzofurans and their application in the preparation of natural products of the genus Calea

The intramolecular cyclization of the β-substituted olefins methyl 2-aryloxy-3-dimethylaminopropenoates 3a-3f catalyzed by Lewis acids leads to a short and novel synthesis of benzofurans 2a-2f. When the olefins 4-dimethylamino-3-aryloxy-3-buten-2-ones 4a-4f were used, the cyclization process was faster and provided the corresponding substituted 2-acetylbenzofurans 1a-1f. Among the latter, naturally occurring compounds calebertin (1a), caleprunin A (1b), and caleprunin B (1c) were prepared in good overall yields. These benzofurans were also obtained by direct treatment under MW irradiation of the precursors 1-aryloxypropan-2-ones 7a-7c with DMFDMA, followed by addition of the catalyst, resulting in a route that was one step shorter.     

Asymmetric synthesis of (+)-1-deoxynojirimycin and (+)-castanospermine

Asymmetric total syntheses of (+)-1-deoxynojirimycin (1) and (+)-castanospermine (2) are described. Starting from diene 3, the required absolute stereochemistry is introduced by an asymmetric hydroxylation followed by epoxidation. An intramolecular cyclization of amine 17 gives access to the corresponding tetrasubstituted piperidine 18, which is a precursor to compounds 1 and 2. (+)-Deoxynojirimicyn (1) was obtained in 36% yield over 11 steps from diene 3, while (+)-castanospermine (2) was achieved in 13% after 19 steps from the same starting material.     

Studies toward the total synthesis of (+)-gelsemine and synthesis of spirocyclopentaneoxindole through intramolecular Michael cyclization

During the approach to the total synthesis of (+)-gelsemine, two novel spirocyclopentaneoxindole compounds 2 and 3 were obtained. Starting from compound 9, spirocyclopentaneoxindole 3 was efficiently and unexpectedly obtained through a Boc migration-intramolecular Michael cyclization cascade procedure. This intramolecular Michael addition strategy allows conveniently access to complex spirooxindole and spirocyclopentaneoxindole derivatives.     

Easy access to 4-nitrothiochroman S,S-dioxides via ring-enlargement from 3-nitrobenzo[b]thiophene

The (E)-2-aryl-1-[2-(methylthio)phenyl]-1-nitroethylenes 5 can easily be oxidized to the relevant sulfones 6 and effectively subjected to cyclization via an intramolecular Michael addition after metallation with lithium bis(trimethylsilyl)amide in THF. After quenching with ammonium chloride the 3-aryl-4-nitrothiochroman S,S-dioxides 2 are obtained as diastereomeric mixtures in good to excellent yields. Both yields and stereochemistry of the ring-closure step appear to be influenced by steric effects of the 3-aryl moiety. As sulfides 5 derive from an initial ring opening of 3-nitrobenzo[b]thiophene (1), the overall 1 to 2 process can be considered as an effective 5 to 6 ring enlargement of the sulfur heterocycle. A conformational ¹H NMR and molecular-mechanics investigation on the isolated diastereomeric 2 has also been accomplished.     

Metal iodide mediated ring expansion of cyclopropanecarboxylic thioesters with imines

Metal iodide mediated three-component reactions of cyclopropanecarboxylic thioesters 1, aldehydes, and amines were developed. The initial products, pyrrolidines 2 were obtained in 39-73% yields, which could further be converted to lactams 4, via sequential reactions of a retro-aza-Michael addition and an intramolecular cyclization. This methodology provided facile access to analogs of both pyrrolidines 2 and lactams 4.     

One-pot synthesis of malononitriles by free radical reactions of ylidenemalononitrile with Et3B and iodoalkane in a water-ether biphase medium

The one-pot synthesis of malononitrile derivatives 4, 6, and 7 in moderate to high yields by the reaction of ylidenemalononitriles 3, prepared in situ from carbonyl compounds 1 and malononitrile 2 in the presence of ammonium acetate in aqueous solution at 50-60 °C, with Et₃B or RI 5/Et₃B in a water-diethyl ether biphase medium under an atmosphere of room temperature is reported. The reaction of Et₃B with adamantyl iodides 8 and 10 under similar conditions gave 9 and 11 in high yields, respectively. However, low yields of the monoalkylated combined with dialkylated malonates 14 were obtained when benzaldehyde 1a was condensed with dimethylmalonate 12 followed by parallel free radical treatment in benzene solution.     

A new approach to fused furan ring systems and benzofurans: Intramolecular cyclization reactions of unsaturated acyloxy sulfone derivatives

Unsaturated acyloxy sulfones 3 undergo intramolecular cyclization upon deprotonation with LHMDS in THF. Dehydration and double bond isomerization of the products upon exposure to acid, gave the fused ring furans, 4, in good yields. This strategy could be readily adapted to prepare substituted benzofurans 12 from the cyclization reactions of acyloxy sulfones 11 prepared from phenols. Finally, this approach could be successfully modified to access dihydropyrans and benzopyrans.     

A novel synthesis of 2-arylhydrazono-6-amino-4-arylbenzene-1,3-dicarbonitriles and their conversion into phthalazines

Compounds 1a-d react with benzylidenemalononitrile 2 to yield dihydroaminopyridazines 3a-d and, in contrast, compounds 1e,f react with 2 under the same conditions to yield aminobenzenedicarbonitriles 8e,f compound 8e underwent intramolecular cyclization to phthalazine 9e. Compound 10e reacted with 2a to yield 11e.     

A convenient and efficient route for the synthesis of amidecrownophanes via 1:1 macrocyclization of di(acid chloride) with diamine derivatives

Four amidecrownophanes 3a-d, including three new compounds 3a, 3c and 3d, were readily prepared through amidation of dicarbonyl dichloride with diamine derivatives without using high-dilution or template conditions and then the tandem Claisen rearrangement. At the macrocyclization step the intramolecular hydrogen bonding of the intermediate might play an important role to give high yields of 1:1 macrocycles.     

Total synthesis of valeriananoids A, B, and C via autocatalytic diastereoselective domino Michael reaction

Natural enantiomers of unique tricyclic sesquiterpenoids, valeriananoids A-C 1-3, have been synthesized starting from bicyclo[2.2.2]octane-2,5-dione derivative 11, which was obtained by diastereoselective catalytic domino Michael reaction of oxophorone 5 with 8-phenylmenthyl acrylate 10 by LDA or silica-gel-base (NMAP-Li). The tricyclic ring was closed selectively by intramolecular 6-endo-trig mode cyclization of the ketyl radical, which was generated from keto-allylether 25 by either lithium or sodium naphthalenide.     

Laboratory and practical synthesis of Suvorexant,a selective dual orexin receptor antagonist

The development of a laboratory and practical synthesis of Suvorexant 1, using intramolecular Mitsunobu cyclization reaction of intermediate 5 as the key reaction, has been reported. Compound 5 was obtained from known chiral ester 2 in three steps, and the key cyclization proceeded smoothly to provide the core seven-membered ring compound 6, which was transformed into 1 by an additional four-step sequence. The procedure described here needs no chiral-HPLC separation, no classical resolution, and no unique enzyme reactions, and offers an alternative practical synthesis of 1.     

A new approach to cyclic hydroxamic acids: Intramolecular cyclization of N-benzyloxy carbamates with carbon nucleophiles

N-Alkyl-N-benzyloxy carbamates, 2, undergo facile intramolecular cyclization with a variety of carbon nucleophiles to give functionalized five- and six-membered protected cyclic hydroxamic acids, 3, in good to excellent yields. This method can be extended to prepare seven-membered cyclic hydroxamic acids in moderate yields. The sulfone intermediates 3 from this study can be alkylated while the corresponding phosphonates have been shown to undergo HWE reaction. The α,β-unsaturated synthon, 8, prepared by thermal elimination of sulfoxide 3m, undergoes Michael addition with secondary amines. The usefulness of this approach to prepare polydentate chelators has been demonstrated by the synthesis of bis cyclic hydroxamic acids 12, 14, and 15.     

Dipyrone approach toward the synthesis of the cytotoxic natural product auripyrone A

An approach to the synthesis of the cytotoxic natural product auripyrone A 1 via the cyclization of an alcohol onto a γ-pyrone in 3 is described. The bis(pyrone) alcohol 3 was prepared efficiently from the advanced aldolate 4 via silyl ether cleavage, oxidation, pyrone formation, and PMB ether removal. Instead of providing auripyrone A 1, the attempted cyclization of 3 gave the product of 1,5-acyl migration 8. Model studies show this to be a general process; therefore, cyclization of an alcohol on such a hindered γ-pyrone under normal conditions is very difficult.     

Platinum-catalyzed consecutive C-N bond formation-[1,3] shift of carbamoyl and ester groups

The reaction of ortho-alkynylphenylureas 1 having a carbamoyl group attached to the nitrogen atom proceeded in the presence of catalytic amounts of PtI₄, affording corresponding indole-3-carbamides 2 in moderate to high yields. In addition, the platinum-catalyzed cyclization of ortho-alkynylphenyl carbamates 3 afforded corresponding indole-3-carboxylates 4 in good yields. The present reaction proceeds through the intramolecular addition of carbon-nitrogen bonds to triple bonds, the so-called carboamination.     

tert-BuOK-mediated carbanion-yne intramolecular cyclization: synthesis of 2-substituted 3-benzylbenzofurans

A mild, efficient, and regioselective carbanion-yne intramolecular cyclization mediated by t-BuOK for the synthesis of 2-substituted 3-benzylbenzofurans is developed. It was started from o-iodophenol (1), based on O-alkylation, and the Sonogashira reaction in sequence to produce 2-(2-phenylethynylphenoxy)-1-arylalkanones (5). An intramolecular carbanion-yne 5-exo-dig cyclization reaction of 5, which was mediated by t-BuOK, yielded title benzofurans in good yields.     

Synthesis of the ABC and IJ ring fragments of yessotoxin

Synthesis of a 6/6/6 tricyclic ether system (3) corresponding to the ABC ring fragment of yessotoxin (1) has been achieved via coupling of a triflate and a 2-lithiofuran followed by intramolecular hetero-Michael addition. The IJ ring fragment (4) of 1 was readily synthesized via successive Sharpless epoxidation and 6-endo cyclization of the resulting vinyl epoxide.     

A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.