Catalytic asymmetric synthesis of spirooxindoles by a mannich-type reaction of isothiocyanato oxindoles

Easy access: a strontium/Schiff base complex as catalyst for the title reaction provided straightforward access to enantiomerically enriched spiro[imidazolidine-4,3'-oxindole] compounds, as well as a spiro[imidazoline-4,3'-oxindole] through a two-step conversion from the Mannich adduct.     

A unique approach to the concise synthesis of highly optically active spirooxazolines and the discovery of a more potent oxindole-type phytoalexin analogue

Drug-lead synthesis through rapid construction of chiral molecular complexity around the biologically relevant framework using a highly efficient strategy is a key goal of organic synthesis. Molecules bearing a spirooxindole-type framework exhibit important bioactivities. Herein, we present a highly efficient and convenient strategy that allows rapid construction of unique optically active spiro[oxazoline-3,3'-oxindole]s through the organocatalyzed asymmetric synthesis of spirocyclic thiocarbamates via an aldol reaction. Preliminary biological evaluation of several of the spirooxazolines using a model of acute neuroinflammation revealed promising antipyretic activity and provided an opportunity to discover new antipyretic agents.     

Scaffold-inspired enantioselective synthesis of biologically important spiro[pyrrolidin-3,2'-oxindoles] with structural diversity through catalytic isatin-derived 1,3-dipolar cycloadditions

Catalytic asymmetric construction of the biologically important spiro[pyrrolidin-3,2'-oxindole] scaffold with contiguous quaternary stereogenic centers in excellent stereoselectivities (up to >99:1 d.r., 98% ee) has been established by using an organocatalytic 1,3-dipolar cycloaddition of isatin-based azomethine ylides. This protocol represents the first example of catalytic asymmetric 1,3-dipolar cycloadditions involving azomethine ylides generated in situ from unsymmetrical cyclic ketones. In addition, theoretical calculations were performed on the transition state of the reaction to understand the stereochemistry. Preliminary bioassays with these spiro[pyrrolidin-3,2'-oxindole] revealed that several compounds showed moderate cytotoxicity to SW116 cells.     

First total synthesis of (+/-)-strychnofoline via a highly selective ring-expansion reaction

An efficient synthesis of the antitumor alkaloid (+/-)-strychnofoline is documented. Key to the development of the highly convergent strategy delineated is the coupling of a cyclic imine with spiro[cyclopropan-1,3'-oxindole], which takes place in a highly diastereoselective manner. The ability to conduct annulation reactions of spirocyclopropyloxindoles with functionalized cyclic imines provides new avenues for the preparation of this important class of biologically active structures.     

Synthesis of (+/-)-strychnofoline via a highly convergent selective annulation reaction

Studies aimed at preparing (+/-)-strychnofoline by total synthesis are detailed. The route described makes use of a recently developed MgI(2)-mediated ring-expansion reaction of spiro[cyclopropan-1,3'-oxindole] with a cyclic disubstituted aldimine. The ring-expansion product was formed as a single diastereoisomer in 55 % yield, possessing the same stereochemical pattern found in strychnofoline. In addition, our synthetic effort has led to the development of new reaction methodology to access 3,4-disubstituted cyclic aldimines.     

Total synthesis of (+/-)-gleenol and (+/-)-axenol via a functionalized spiro[4.5]decane

Total synthesis of the biologically important axane sesquiterpenes, gleenol (1) and axenol (2), was accomplished through a readily available spiro[4.5]decane. The key features of the synthesis of 1 and 2 include Claisen rearrangement to afford the multi-functionalized spiro[4.5]decane 4 as a single diastereomer in excellent yield, installation of the C7 isopropyl group via ketene dithioacetal instead of direct alkylation and a diastereoselective reduction of ketone under the Birch conditions.     

A novel bornane synthesis by an old idea

Aiming at a synthesis of spiro[2.4]hepta-4,6-dienes with a carbon substituent at C-4, we investigated solvolysis reactions of the thiatricycle 2, obtained from spiro[2.4]hepta-4,6-diene (1) and thiophosgene by [4 + 2] cycloaddition. With methanol or ethanol a mixture of the esters 7 and 8 was formed. Desulfurization of the thionoesters 8 gave methyl and ethyl spiro[2.4]hepta-4,6-diene-4-carboxylate (10a,b). The corresponding alcohol (11) was prepared from 10b by LiAlH(4) reduction. Ethenetetracarbonitrile combined with the 4-substituted spiro[2.4]hepta-4,6-dienes to give the [4 + 2] cycloadducts 12a-c. Diels-Alder reaction between 11 and 2-chloroacrylonitrile afforded the spiro(bicyclo[2.2.1]hept-5-ene-7,1'-cyclopropane) derivative 14a that was transformed in three steps to rac-10-hydroxycamphor (17). This synthesis of a bornane derivative opens opportunity for variations and thus may find further applications.     

Formal synthesis of erythrodiene and spirojatamol via rhodium-catalysed Claisen rearrangement/hydroacylation

A novel procedure allows the synthesis of spiro[4.5]decane-1,6-dione 1, a key intermediate in the total synthesis of erythrodiene and spirojatamol. The key step is a combination of Claisen rearrangement of allyl vinyl ethers followed by an intramolecular hydroacylation catalysed by RhCl(cod)(dppe).     

Concise,asymmetric total synthesis of spirotryprostatin A

[structure: see text] The structurally intriguing cell-cycle inhibitor spirotryprostatin A has been synthesized utilizing an azomethine ylide dipolar cycloaddition reaction as the key step. This pentacyclic alkaloid contains a prenylated tryptophan-derived oxindole moiety that has been created in a regiocontrolled and stereocontrolled manner in a single step.     

Spiro[4.5]decanes by photoannelation. Total synthesis of (−)-acorenone

An efficient synthesis of the optically active spiro[4.5]decane sesquiterpene acorenone is described. The key carbon-carbon bonds are formed by a (2+2) photochemical cycloaddition between 2,2-dimethyl-3(2H)-furanone and an alkene derived from limonene.     

Domino Pd-catalyzed Heck cyclization and bismuth-catalyzed hydroamination: formal synthesis of elacomine and isoelacomine

The formal synthesis of hemiterpene spirooxindole alkaloids elacomine (1) and isoelacomine (2) is described. Heck reaction of protected iodoanilines with 5,6-dihydro-2H-pyran-2-one or six-membered unsaturated lactams was investigated. The coupling product was readily converted to a carbamoyl chloride with an incorporated diene unit. The spiro(pyrrolidine-3,3'-oxindole) skeleton, which corresponds to the carbon skeleton of 1 and 2, was efficiently constructed from this intermediate by using a domino palladium-catalyzed Heck reaction and bismuth-catalyzed hydroamination. An isolated byproduct of the reaction could also be converted to the spirooxindole skeleton.     

A formal synthesis of (-)-cephalotaxine

An enantioselective formal synthesis of the alkaloid (-)-cephalotaxine has been completed, using an alkylidene carbene 1,5-CH insertion reaction as a key step to construct the spiro[4.4]azanonane core D/E-ring system. A Heck-type cyclization was used to close the tetrahydroazepine C-ring and a selective epoxidation-rearrangement sequence was used to elaborate the E-ring.     

Asymmetric synthesis of chiral spiro bis(isoxazoline) and spiro (isoxazole–isoxazoline) ligands

Asymmetric synthesis of novel chiral ligands, bis(isoxazoline) on a spiro[4.4]nonane scaffold and isoxazole–isoxazoline on a spiro[4.5]decane scaffold, has been achieved by utilizing an enantiomerically pure alcohol as the starting material.     

A biomimetic total synthesis of (-)-spirotryprostatin B and related studies

The prenylated natural products spirotryprostatin A and B derived from the Trp-Pro diketopiperazine also feature an oxidative rearrangement of the indole to form a spirooxindole. Synthetically, formation of the oxindole ring was stereoselectively accomplished by reaction of the appropriate indole precursor with N-bromosuccinimide. For optimum results, the oxidation should be carried out prior to diketopiperazine cyclization. In this manner, we have synthesized the tetrahydro- and dihydro- analogues of spirotryprostatin B in four steps from L-tryptophan methyl ester. The dihydro derivative was then converted to spirotryprostatin B by unsaturation of the pyrrolidine ring to a pyrroline, thus unambiguously confirming the structure of the natural product.     

Grindstone chemistry: one-pot synthesis of spiro[diindenopyridine-indoline]triones and spiro[acenaphthylene-diindenopyridine]triones

A one-pot, pseudo four-component, and simple synthesis of spiro[diindenopyridine-indoline]triones and spiro[acenaphthylene-diindenopyridine]triones via the reaction of 1,3-indandione, aromatic amines and isatins or acenaphthylene-1,2-dione using a ‘Grindstone Chemistry’ method is reported.     

A Clean synthesis of spiro[indoline-3,9'-xanthene]trione derivatives

A simple, clean and efficient method for the synthesis of spiro[indoline-3,9'-xanthene]trione derivatives and spiro[acenaphthene-1,9'-xanthene]-1',2,8'(2'H,5'H)-trione by condensation reaction of dimedone and isatins or acenaphthene in aqueous media is reported.     

A spirobiscalix[4]azacrown: synthesis and complexing properties

The synthesis and complexation properties of a novel type of calix[4]azacrown, in which two cone calix[4]arenes are linked via a spiro C-atom incorporated into polyaminoalkylene chains are presented.     

The synthesis and analgesic properties of new spiroisochromanyl acid derivatives synthesized from natural safrole

We describe in this paper the synthesis of a new spiro[2-carboxycyclopentane-1,1-(6,7-methylene-dioxy)isochroman] and a spiro[2-carboxycyclohexane-1,1-(6,7-methylenedioxy)isochroman] acids 11 and 12 , obtained from natural safrole (7) , isolated from Sassafras oil. These derivatives were obtained in high overall yield using a synthetic route in which was observed brevity and appreciable diastereoselectivity in the intramolecular regioalkylation of the 6-position of the aromatic system of the natural starting material, the key step of the synthetic route representing a variable in the well-known Friedel-Crafts reaction. The new acids, derivatives 11 and 12 , were obtained in ca. 74% and 78% overall yield. They show a good analgesic profile in the pharmacological assay, the test in mice abdominal contortion.     

An efficient synthesis of the 1,6-dioxaspiro[4.4]nonan-2-one motif of the immunosuppressive triterpenoid Phainanoid F

We describe an efficient synthesis of the 1,6-dioxaspiro[4.4]nonan-2-one motif of the immunosuppressive triterpenoid Phainanoid F and its C4 epimer. A furan oxidative spirocyclization for constructing the spiro center was used as the key step. Other important reactions involved Sharpless asymmetric dihydroxylation, Weinreb ketone synthesis and Yamaguchi esterfication. The synthesis was achieved in 11 linear steps with 17.3% overall yield.     

Integral stereocontrolled synthesis of a spiro-norlignan, sequosempervirin A: revision of absolute configuration

A novel synthetic path to sequosempervirin A was established by employing a samarium diiodide promoted intramolecular Barbier-type reaction of the lactonic iodide, in which the key structural feature, a spiro[4.5]decane ring system, could be constructed by controlling the stereochemistry of the hydroxyl group at the 8-position. The absolute configuration of natural sequosempervirin A was revised to be 4S based on this synthesis.