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A concise synthesis of three members of the withasomnine family of natural products is reported. The synthesis features a regioselective sydnone-alkynylboronate cycloaddition followed by Suzuki cross coupling and silyl group removal, and marks the first d

Withasomnine has been prepared by rearrangement of 1-(3-chloropropyl)-cyclopropanol into 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, followed by bromination and [NiCl2(dppp)]-catalyzed phenylation.

A novel synthetic protocol for the synthesis of [1,2-b]-fused bicyclic pyrazoles has been developed using radical cyclisation. The protocol uses cyclisation of pyrazole-1-(ω-alkyl) radicals generated from 1-[ω-(phenylselenyl)alkyl]-pyrazole precursors. The pyrazole natural product, withasomnine (3-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole), and larger ring analogues have been synthesised in good yield using the protocol. A Bu3SnH-mediated oxidative cyclisation mechanism is facilitated by azo or Et3B radical initiators acting as oxidants of the intermediate π-radicals.

The direct 4-alkoxylation of 4-iodo-1H-pyrazoles with alcohols was achieved by a CuIcatalyzed coupling protocol. The optimal reaction conditions employed excess alcohol and potassium t-butoxide (2 equiv) in the presence of CuI (20 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (20 mol%) at 130 °C for 1 h under microwave irradiation. The present method was efficiently applied to the synthesis of withasomnine and its six- and seven-membered cyclic homologs.

A key thioether substituent in readily accessible 2-alkyl-5-(methylthio) tetrazoles enables facile photoinduced denitrogenation and intramolecular nitrile imine 1,3-dipolar cycloaddition to afford a wide range of polycyclic pyrazoline products with excellent diastereoselectivity. The methylthio group red-shifts the UV absorbance of the tetrazole, obviating the requirement in all previous substrate systems for at least one aryl substituent, and can subsequently be converted into a variety of other functionalities. This synthetic platform has been applied to the concise total syntheses of the alkaloid natural products (±)-newbouldine and withasomnine. This journal is the Partner Organisations 2014.

Total synthesis of all three pyrazole-based withasomnine alkaloids and selected examples of their non-natural analogs has been achieved from readily available aldehydes and 4-nitro-1-butanol in three steps. Since 4-nitro-1-butanol in turn is prepared in t

In the paper we indicate the increasing importance of derivatives containing a dihydropyrrolo[1,2-b]pyrazole (DPP) core. We try to show our synthetic approach based on an improved Kulinkovich method as well as our new synthetic pathway. A complex methodology involving the preparation of substituted DPPs focuses on withasomnine and the synthesis of several structurally related compounds. The developed reaction protocols enable the preparation of the mentioned bicyclic system with broadly diverse substitution. Thus, we are able to prepare systems with aliphatic, aromatic, polyaromatic, heteroaromatic, TMS, and even adamantane substitution with known biologically active properties. The reaction protocol, consisting of two multi-step synthetic pathways, includes Sonogashira and Suzuki-Miyaura cross-coupling reactions, allenyl synthon formation, Kulinkovich cyclopropanation, ring transformations, and nonsymmetrical homoallenyl azines cycloadditions. Moreover, we prepared compounds with a resemblance to other bioactive species: fadrozole, nagstatine, an antitumor agent LY2109761 and a mixed lineage kinase 7 inhibitor DHP-2.

The divergent synthesis of natural withasomnines and analogues was achieved from 4-hydroxypyrazoles, which was prepared via alkaline hydrolysis of the Baeyer-Villiger oxidation products from 4-formylpyrazoles. Key steps of this synthesis are regioselective Claisen rearrangement of 4-allyloxypyrazoles and the Suzuki-Miyaura coupling of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl trifluoromethanesulfonate and commercially available arylboronic acids. The Suzuki-Miyaura coupling at the final step of this strategy enabled facile access to natural withasomnines and their analogues. The biological activities of the twelve synthesized compounds against cyclooxygenases-1 and -2 (COX-1 and COX-2) were evaluated.

A base mediated reaction of α-diazo-β-ketosulfone with nitroalkenes affords sulfonylpyrazoles as single regioisomers in excellent yield in a one-pot room temperature reaction. Aryl, heteroaryl, styrenyl, alkyl, hydroxymethyl, and hydrazinyl groups could b

4-Hydroxypyrazoles were synthesized by the alkaline hydrolysis of the Baeyer-Villiger oxidation products of 4-formylpyrazoles. This new synthesis of 4-hydroxypyrazoles was applied to the divergent synthesis of withasomnine alkaloids in a unique strategy, for which the key steps included the regioselective Claisen rearrangement of their 4-O-allyl-4-hydroxy-1H-pyrazoles and a Suzuki coupling of 4-trifluoromethanesulfonyloxy-1H-pyrazoles and arylboronic acids.

The titanium-catalyzed 3-component coupling of an alkyne, isonitrile, and amine can be used to generate tautomers of 1,3-diimines. These diimines produced in situ undergo cyclization with hydrazine and hydrazine derivatives in a one-pot procedure to provi

Alkyl radicals have been cyclised onto pyrroles, imidazoles and pyrazoles, and acyl radicals cyclised onto pyrroles, using Bu3SnH-, (TMS)3SiH- and Bu3GeH-mediated aromatic homolytic substitution for the synthesis of bicyclic N-heterocycles. The reactions yield intermediate π-radicals that lose hydrogen in the?rearomatisation step of the aromatic homolytic substitution. Mechanistic studies of these rearomatisation steps indicate aromatic homolytic substitution in which the initiator or breakdown products from the inhibitor are responsible for the H-abstraction step.

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The pyrazole alkaloid withasomnine 1, has been synthesized by construction of the 1,2-diazabicyclo [3.3.0]octa-2,4-diene system in a single step.

Withasomnine (2), the only bicyclic pyrazole alkaloid found thus far in Nature, has been prepared, in one step, by cyclo-addition of and the strained bicyclic meso-ionic system 1, derived from L-proline.The cyclo-addition also gives the novel, un-natural isomer 3.

Withasomnine (5), a pyrazole alkaloid isolated from Withania somnifera Dun.(Solanaceae), has been synthesized from 4-phenylpyrazole(1), a compound with potential symmetry.