A phosphine-catalyzed [3+2] cycloaddition strategy leading to the first total synthesis of (-)-hinesol

In one step, the skeleton of cis-spirovetivanes was constructed with high stereoselectivity by the phosphine-catalyzed [3+2] cycloaddition reaction of tert-butyl 2,3-butadienoate or 2-butynoate with 3-methyl-2-methylenecyclohexanone (5). This method was exemplified by the first highly efficient total synthesis of natural product (-)-hinesol, which is an active ingredient of cerebral circulation and metabolism improvers.     

An expedient phosphine-catalyzed [4 + 2] annulation: synthesis of highly functionalized tetrahydropyridines

Ethyl 2-methyl-2,3-butadienoate acts as a 1,4-dipole synthon and undergoes [4 + 2] annulation with N-tosylimines in the presence of an organic phosphine catalyst. The resulting adducts, ethyl 6-substituted-1-(4-tosyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylates, are formed in excellent yields with complete regioselectivity. Mechanistic reasoning for this new annulation has led to an expansion of the reaction scope by employing ethyl 2-(substituted-methyl)-2,3-butadienoates to give ethyl 2,6-cis-disubstituted-1-(4-tosyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylates with high diastereoselectivities.     

Abnormal aza-Baylis-Hillman reaction of N-tosylated imines with ethyl 2,3-butadienoate and penta-3,4-dien-2-one

[reaction: see text] The attempted aza-Baylis-Hillman reaction of N-tosylated imines with ethyl 2,3-butadienoate or penta-3,4-dien-2-one gave azetidine derivatives in the presence of DABCO. In the case of the aza-Baylis-Hillman reaction of N-tosylated imines with ethyl 2,3-butandieonate catalyzed by DMAP, novel dihydropyridine derivatives were formed.     

Phosphine-catalyzed tandem reaction of allenoates with nitroalkenes

A P(p-FC(6)H(4))(3)-catalyzed tandem reaction between ethyl 2,3-butadienoate and nitroalkenes has been developed, which involves a [3 + 2] cycloaddition and a subsequent umpolung addition. The asymmetric version of this tandem reaction has also been investigated by using chiral phosphanes.     

DABCO-catalyzed reaction of allenic esters and ketones with salicyl N-tosylimines: synthesis of highly functionalized chromenes

[reaction: see text] DABCO-catalyzed reactions of salicyl N-tosylimines with ethyl 2,3-butadienoate and penta-3,4-dien-2-one proceed smoothly at room temperature in dichloromethane to give the corresponding chromenes in good to excellent yields.     

DABCO and Bu(3)P catalyzed [4 + 2] and [3 + 2] cycloadditions of 3-acyl-2H-chromen-ones and ethyl 2,3-butadienoate

DABCO-catalyzed [4 + 2] and Bu(3)P-catalyzed [3 + 2] cycloadditions between 3-acyl-2H-chromen-ones and ethyl 2,3-butadienoate were developed for the synthesis of dihydropyran-fused and cyclopenten-fused chromen-2-ones with high regio- and stereo-selectivities, respectively. The synthetic procedures have the advantages of mild reaction conditions, convenient handling and good atom economy as well as a wide substrate scope, which make this method useful for the synthesis of potentially biologically active dihydropyran-fused and cyclopenten-fused chromen-2-ones derivatives. Possible reaction mechanisms have also been proposed on the basis of previous literature and our investigation.     

Aza-Baylis-Hillman reactions of N-tosylated aldimines with activated allenes and alkynes in the presence of various Lewis base promoters

[reaction: see text] The attempted aza-Baylis-Hillman reactions of N-tosylated aldimines with ethyl 2,3-butadienoate, ethyl penta-2,3-dienoate, penta-3,4-dien-2-one, methyl propiolate, and but-3-yn-2-one have been systematically investigated in the presence of various nitrogen or phosphine Lewis base promoters. We found that a series of nitrogen-containing heterocyclic compounds, as "abnormal" aza-Baylis-Hillman reaction products, can be formed in the presence of an appropriate Lewis base promoter. The Lewis base and solvent effects in these reactions have been discussed along with the corresponding plausible mechanism.     

Theoretical Study of Mechanism and Regioselectivity of 1,3-dipolar Cycloaddition of N-[methyl]-C-[5-nitro-2-furyl] Nitrilimine with Dimethyl 7-oxabicyclo[2,2,1]hepta-2,5-diene-2,3-dicarboxylate

The mechanism and regioselectivity of 1,3-dipolar cycloaddition of N-[methyl]-C-[5-nitro-2-furyl] nitrilimine with dimethyl 7-oxabicyclo[2,2,1]hepta-2,5-diene-2,3-dicarboxylate were investigated using activation energy calculations and density functional theory-based re-activity indexes. The reaction proceeds by an asynchronous concerted mechanism. The calculations are performed at the B3LYP/6-31G(d) level of theory and the obtained results are in agreement with experimental outcome.     

Nucleophilic phosphine-catalyzed [3+2] cycloaddition of allenes with N-(thio)phosphoryl imines and acidic methanolysis of adducts N-(thio)phosphoryl 3-pyrrolines: a facile synthesis of free amine 3-pyrrolines

In this report, the dipolarophile imines with easily removable activating group O,O-diethyl(thio)phosphoryl have been investigated in the nucleophilic phosphine-catalyzed [3+2] cycloaddition reaction of electron-deficient allenes. Under the catalysis of a tertiary phosphine, N-(thio)phosphorylimines readily undergo the [3+2] cycloaddition reaction with ethyl 2,3-butadienoate or ethyl 2,3-pentadienoate, affording the corresponding N-(thio)phosphoryl 3-pyrrolines in moderate to high yields with good diastereoselectivity. Removal of the (thio)phosphoryl group from the adducts has been successfully achieved via the acidic methanolysis of the P-N bond, giving the free amine 3-pyrrolines in fair to good yields without severe aromatization. Thus, a facile synthesis of N-unsubstituted 3-pyrrolines is established from the phosphine-catalyzed [3+2] cycloaddition reaction of allenes with imines.     

Intermolecular [2+2] photocycloaddition of chalcones with 2,3-dimethyl-1,3-butadiene under neat reaction conditions

The intermolecular [2 + 2] photocycloaddition of chalcones with 2,3-dimethyl-1,3-butadiene under visible-light irradiation for the synthesis of cyclobutane derivatives has been developed. Without using any photosensitizer, metallic catalyst and solvent, the reaction proceeded with high regioselectivity and moderate to high stereoselectivity. Mild reaction conditions and no additives make the reaction easy to operate. Control experiments and density functional theory (DFT) computations demonstrated that the reaction takes place via visible-light activation of chalcones, which is different from the previously reported [2 + 2] cycloaddition of chalcones.     

A novel multicomponent reaction involving isoquinoline,allenoate and activated ketone

The reaction of isoquinoline and allenoate with activated ketone resulted in a novel three component reaction, affording [1,3]oxazino[2,3-a]isoquinoline derivatives in moderate yields along with moderate diastereoselectivities via 1,4-dipolar cycloaddition. It was also found that when isatins were used as substrates, the regioselectivity of cycloadducts was different from those using ethyl trifluoropyruvate as substrate.     

Total Synthesis of (+)-okaramine J featuring an exceptionally facile N-reverse-prenyl to C-prenyl aza-Claisen rearrangement

[reaction: see text] The convergent total synthesis of (+)-okaramine J was achieved in a longest linear sequence of 12 steps from l-tryptophan tert-butyl ester. A key reaction was the acid-catalyzed room-temperature aza-Claisen rearrangement of a N-reverse-prenylated hexahydro[2,3-b]pyrroloindole to a C-prenylated derivative.     

Highly regioselective ring opening of quinolinic[2,3]anhydrides under mild conditions

We report a study of the influence of Lewis acids upon the regioselectivity of ring opening of quinolinic[2,3]anhydrides to provide 2-(isopropoxycarbonyl)-nicotinic acids. In the presence of stoichiometric amounts of indium trifluoromethanesulfonate or lanthanum trifluoromethanesulfonate, the desired 2-position ester was generated with greater than 95:5 regioselectivity. This methodology was also applied to 6-methyl-[2,3]-quinoline to provide similar results.     

Modulating the reactivity of functionalized N,S-ketene acetal in MCR: selective synthesis of tetrahydropyridines and thiochromeno[2,3-b]pyridines via DABCO-catalyzed tandem annulation

An efficient and straightforward three-component synthetic protocol was developed to synthesize 1,2,3,4-tetrahydropyridine derivatives or thiochromeno[2,3-b]pyridine derivatives from β-aroylthioacetanilides or β-(2-haloaroyl)thioacetanilides, aldehydes, and aroyl acetonitriles via DABCO-catalyzed tandem [3 + 2 + 1] annulation and S(N)Ar reaction. This synthetic approach has the prominent features of high chemo-, stereo- (or enantio-), and unusual regioselectivity. In the domino processes, at least seven reactive sites were involved, and up to three covalent bonds and one functionalized pyridine ring were generated. This facile and efficient reaction is a quite general for the preparation of tetrahydropyridine derivatives or thiochromeno[2,3-b]pyridine derivatives.     

The first regioselective palladium-catalyzed indolization of 2-bromo- or 2-chloroanilines with internal alkynes: a new approach to 2,3-disubstituted indoles

[reaction: see text] The first practical and economical process for synthesis of 2,3-disubstituted indole compounds has been developed with high regioselectivity by palladium-catalyzed indolization of 2-bromo- or chloroanilines and their derivatives with internal alkynes.     

A new entry to the synthesis of substituted azetidines: [2+2] cycloaddition reaction of four-membered endocyclic enamides to ketenes

The first example of a [2+2] cycloaddition reaction of a four-membered endocyclic enamide (2-azetine) to dichloroketene is described and constitutes a new entry to the synthesis of substituted azetidines. Preliminary studies concerning the Baeyer-Villiger oxidation of the [2+2] cycloadduct revealed an unusual regioselectivity. The synthesis of a new azetidine-3-carboxylic acid derivative from the [2+2] cycloadduct is also presented.     

Metathesis reactions for the synthesis of ring-fused carbazoles

[reactions: see text] The metathesis reaction is used as a key step for the synthesis of the indolo[2,3-a]carbazole core of rebeccamycin 13 and the sulfur analog of furostifoline 21. Using the same methodology for the attempted synthesis of furostifoline, we unexpectedly formed tert-butyl-2a-methyl-1,2,2a,10c-tetrahydro-6H-cyclobuta[c]furo[3,2-a]carbazole-6-carboxylate 26 from the unstable diene, tert-butyl 2-(2-isopropenyl-3-furyl)-3-vinyl-1H-indole-1-carboxylate 25, presumably via a spontaneous pi8 electrocyclization reaction.     

Synthesis of 1,6-dihydropyrrolo[2,3-g]indazoles using Larock indole annulation

The synthesis of 1,6-dihydropyrrolo[2,3-g]indazole derivatives is described. The indolic ring system is constructed via a Larock palladium-catalyzed annulation using terminal and internal alkynes. Additionally, when using internal alkynes for this reaction, we found that a directing effect on regioselectivity was mediated by the ester group of alkyl 3-substituted propiolate derivatives.     

1,2-Bisanionic coupling approach to 2,3-disubstituted cyclopentenols and cyclopentenones

[reaction: see text] We describe a new approach to 2,3-disubstituted cyclopentenols and cyclopentenones through two consecutive regioselective additions of equal or different electrophiles to a cyclopentene bisanionic synthon. Indeed, on exposure to BuLi, 3-bromo-2-iodocyclopent-2-enol O-TBS ether undergoes iodine-lithium permutation with complete regioselectivity. Successive reaction of the monolithium anion with different C(sp(2))- and C(sp(3))-electrophiles affords the corresponding 2-substituted-3-bromocyclopentenol derivative. Subsequent bromo-lithium exchange with t-BuLi, followed by reaction with an equal or different electrophile, affords the desired 2,3-disubstituted cyclopentenol.     

Elaboration of phosphoramidite ligands enabling palladium-catalyzed diastereo- and enantioselective all carbon [4+3] cycloaddition

A palladium-catalyzed diastereo-and enantioselective all carbon [4+3] cycloaddition of trimethylenemethane was developed by employing the elaborate tetrahydroquinoline-derived phosphoramidite ligand. The exclusive regioselectivity was realized by using the aromatization-driven diene indole-2,3-quinodimethanes, affording biologically important cyclohepta[b]indoles with excellent diastereo-, and enantioselectivities(up to 20:1 dr, 99% ee). Furthermore, the more challenging pyrrolidone-3,4-dienes, in the absence of aromatization force, were also compatible inthereaction, providing novel cyclohepta[c]pyrrol-1(2H)-ones with excellent regio-, diastereo-, and enantioselectivities(up to 20:1 rr, 20:1 dr, 99% ee).