Titanium-catalyzed hydroalumination of conjugated dienes: access to fulvene-derived allylaluminium reagents and their diastereoselective reactions with carbonyl compounds.

The described titanium-catalyzed hydroalumination of conjugated dienes opens up a new way to allylaluminium reagents. The reaction is carried out by using diisobutylaluminium hydride (DIBAL-H) and a catalytic amount of [Cp2TiCl2] (Cp = cyclopentadienyl). When applied to mono- and disubstitued pentafulvenes, this reaction proceeds in a highly endocyclic manner. The formed allylaluminium compounds react regio- and stereoselectively with both aldehydes and ketones to afford homoallylic alcohols that are suitable synthons for functionalized cyclopentanones. An extension of this methodology to simple dienes was also investigated. In the proposed mechanism, the initially formed bimetallic species (Ti/Al) are involved in the two possible catalytic cycles with a direct hydroalumination or/and a hydrotitanation followed by a titanium to aluminium transmetallation.

Trapping the Lewis acid generated transient species from pentafulvene derived diazanorbornenes with ortho-functionalized aryl iodides and aliphatic alcohols.

Herein we describe our efforts on the Lewis acid catalyzed stereoselective ring-opening of pentafulvene derived diazabicyclic olefins using various ortho-functionalized aryl iodides such as 2-iodoanilines, 2-iodophenols and 2-iodobenzene thiols to access trans-1,2 disubstituted alkylidenecyclopentenes. The scope of the reaction was also explored with a range of easily available aromatic and aliphatic alcohols. Furthermore, the palladium catalyzed intramolecular Heck cyclization of trans-1,2 disubstituted alkylidenecyclopentenes would provide an easy approach for the synthesis of highly functionalized spiropentacyclic frameworks consisting of a cyclopentene fused to an indoline/benzothiophene and pyrazolidine.

Asymmetric synthesis of proline-based conformationally constrained tryptophan mimetic.

The synthesis of an optically pure proline-based tryptophan mimetic is described. The strategy involves the in situ generation of an unprecedented allylmetal species containing the indole moiety, and its coupling with a chiral imine. The construction of the 3-substituted proline skeleton is then achieved through a hydrozirconation/iodination sequence applied to the resulting homoallylic amine.

The spirocyclopropyl moiety as a methyl surrogate in the structure of l-fucosidase and l-rhamnosidase inhibitors.

Nitrogen-in-the-ring analogues of l-fucose and l-rhamnose were prepared, which feature a spirocyclopropyl moiety in place of the methyl group of the natural sugar. The synthetic route involved a titanium-mediated aminocyclopropanation of a glycononitrile as the key step. Four new spirocyclopropyl iminosugar analogues were generated, which displayed some activity towards l-fucosidase and l-rhamnosidase.

Diene-titanium complexes as synthetic intermediates for the construction of three- or five-membered carbocycles.

It has been shown that diene-titanium complexes exhibit substrate-dependent 1,2- or 1,4-dicarbanion reactivity. On this basis, 3-cyclopentenylamines and spiro-vinylcyclopropane lactams were easily prepared by using homoallylic Grignard reagents, Ti(O-i-Pr)4, and nitriles or cyanoesters, respectively.

A direct stereoselective approach to trans-2,3-disubstituted piperidines: application in the synthesis of 2-Epi-CP-99,994 and (+)-epilupinine.

A simple synthesis of enantiomerically pure piperidine esters is described, offering a straightforward access to the trans-2,3-disubstituted piperidine skeleton which is present in a broad range of biologically active compounds.

Synthesis of a C-glucosylated cyclopropylamide and evaluation as a glycogen phosphorylase inhibitor.

The synthesis of carbohydrate-based glycogen phosphorylase inhibitors is attractive for potential applications in the treatment of type 2 diabetes. A titanium-mediated synthesis led to a benzoylated C-glucosylated cyclopropylamine intermediate, which underwent a benzoyl migration to afford the corresponding 2-hydroxy-C-glycoside. X-ray crystallographic studies revealed a unit cell composed of four molecules as pairs of dimers connected through two hydrogen bonds. The deprotection of the benzoate esters under Zemplén conditions afforded a glycogen phosphorylase inhibitor candidate displaying weak inhibition toward glycogen phosphorylase (16% at 2.5mM).

Titanium- and Lewis acid-mediated cyclopropanation of imides.

We report a straightforward synthesis of 1-azaspirocyclopropane lactams from imides. Following the described procedure, polycyclic nitrogen heterocycles containing a cyclopropane unit could be obtained from unsaturated imides. [reaction: see text].

Reduction of Cp2ZrCl2 with mischmetall: a new method for generating an efficient "Cp2Zr" equivalent.

[reaction: see text] A "Cp(2)Zr" equivalent is generated under mild conditions (THF, room temperature) by reducing Cp(2)ZrCl(2) with cheap and readily available mischmetall (an alloy of Ce, La, Nd, and Pr). Coupling reactions, including those of terminal alkynes, can efficiently be achieved by using this reagent.

Stereoselective synthesis of pyrrolidines from N-allyl oxazolidines via hydrozirconation-cyclization.

[reaction: see text] A new diastereoselective synthesis of pyrrolidines from readily available chiral N-allyl oxazolidines is presented. The construction of the pyrrolidine ring is achieved via a tandem hydrozirconation-stereoselective Lewis acid mediated cyclization sequence.

Titanium-mediated [4 + 1] assembly of 1,3-dienes and nitriles: formation of 3-cyclopentenyl amines and cyclopentenones.

In the presence of Ti(OiPr)4 and iPrMgCl, dienes couple with nitriles to afford the title products in good yields.

A one-pot access to cyclopropanes from allylic ethers via hydrozirconation-deoxygenative ring formation.

A synthetic method for the direct transformation of allylic ether into mono-, di- and trisubstituted cyclopropanes is presented.

Pentafulvene-derived η3-allyltitanocenes as intermediates for the stereoselective functionalization of 5-membered carbocycles.

Allyltitanocene complexes can be generated by reacting pentafulvenes with DIBAL-H and Cp2TiCl2. Their coupling with aldehydes affords homoallylic alcohols in a highly regio- and stereoselective manner. The potential of this method for the stereoselective synthesis of cyclopentane derivatives is illustrated.

Cyclopropyl-tryptamine analogues: synthesis and biological evaluation as 5-HT(6) receptor ligands.

Conformational restrictions: Based on the pharmacophore model for 5-HT(6) receptor ligands (shown), tryptamine analogues bearing a cyclopropyl ring on the α-position of the tryptamine side chain were synthesized and evaluated against 5-HT receptors. N,N-Dimethyl-1-arylsulfonyltryptamine derivatives exhibited promising selectivity for 5-HT(6) over 5-HT(1a) and 5-HT(4) receptors and interesting activity against 5-HT(6) (K(i) =∼0.15 µM; IC(50) =∼0.20 µM).

Palladium/Lewis acid mediated domino reaction of pentafulvene derived diazabicyclic olefins: efficient access to spiropentacyclic motif with an indoline and pyrazolidine fused to cyclopentene.

A palladium/Lewis acid mediated stepwise and one-pot transformation of pentafulvene derived diazabicyclic olefins is described. The reaction offers a facile strategy for the synthesis of novel spiropentacyclic motifs with indoline and pyrazolidine fused to the cyclopentene core.

Reactivity differences between 2,4- and 2,5-disubstituted zirconacyclopentadienes: a highly selective and general approach to 2,4-disubstituted phospholes.

Mixtures of 2,4- and 2,5-disubstituted zirconacyclopentadienes were obtained by the reductive dimerisation of terminal alkynes using the Cp2ZrCl2/lanthanum system. Reactions of dihalophosphines with these mixtures afforded selectively the corresponding 2,4-disubstituted phospholes and 1,4-disubstituted butadienes. A new series of phospholes was characterized by multi-nuclear NMR spectroscopy and X-ray analysis. A possible explanation for the observed selectivity was obtained from X-ray studies and DFT analysis of the intermediate zirconacyclopentadienes.

Switching regioselectivity in the allylation of imines by N-side chain tuning.

A spectacular inversion of α- to γ-regioselectivity in the allylzincation of imines can be achieved by fine-tuning of the N-side chain. This approach allows easy preparation of regioisomeric amines, in racemic as well as enantiopure forms. The usefulness of the method is illustrated by the parallel asymmetric syntheses of 2,3- and 2,5-diphenylpyrrolidines.

Diastereoselective access to nonracemic 2-cis-substituted and 2,6-cis-disubstituted piperidines.

Access to nonracemic amino ketones via a hydrozirconation/transmetalation/acylation sequence applied to Boc-protected 1-aminobut-3-enes is presented. This method was applied to the stereoselective synthesis of cyclic imines (or iminiums) which were diastereoselectively converted into 2-cis-substituted and 2,6-cis-disubstituted piperidines. The potential of this approach in the field of alkaloid synthesis was illustrated by the synthesis of (-)-coniine and (-)-indolizidine 209D. Furthermore, access to indolizidines bearing a quaternary center could also be envisioned through this strategy.

Access to enantiomerically enriched cis-2,3-disubstituted azetidines via diastereoselective hydrozirconation.

An asymmetric variant of the hydrozirconation reaction has been established starting from Boc-protected chiral allylic amines. The resulting diastereoselectively formed N-functionalized organozirconiums can be considered as promising chirons. In this case, they have been transformed into enantiomerically enriched cis-2,3-disubstituted azetidines through a iodination/cyclization sequence.