Toward Efficient and Stereoselective Aromatic and Dearomative Cope Rearrangements: Experimental and Theoretical Investigations of α-Allyl-α'-Aromatic γ-Lactone Derivatives.

The aromatic Cope rearrangement is an elusive transformation that has been the subject of a limited number of investigations compared to those seemingly close analogues, namely the Cope and aromatic Claisen rearrangement. Herein we report our investigations inspired by moderate success observed in the course of pioneering works. By careful experimental and theoretical investigations, we demonstrate that key substitutions on 1,5-hexadiene scaffold allow fruitful transformations. Especially, efficient functionalisation of the heteroaromatic rings results from the aromatic Cope rearrangement, while highly stereoselective interrupted aromatic Cope rearrangements highlight the formation of chiral compounds through a dearomative process.

cis-Dihydroxylated α-Trifluoromethylated N,O-Acetal from l-Tartaric Acid: Synthesis of Tetrasubstituted Stereocenter via Diastereoselective Pictet-Spengler Cyclization of N-Acyliminium Ions.

The synthesis of cyclic, chiral α-trifluoromethylated N,O-acetals having a protected cis-diol moiety has been readily achieved in two steps from a known bis-Weinreb amide derived from l-tartaric acid. The reaction of O-acetyl analogues of these N,O-acetals with triflic acid in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at 0 °C generated in situ the corresponding electrophilic α-trifluoromethyl N-acyliminium ions that undergo Pictet-Spengler-type cyclizations. After only 10 min of reaction, the original enantiopure aza-tricyclic scaffolds bearing a trifluoromethyl substituent at the bridgehead position were obtained with diastereoselectivities ranging from 75:25 to 97:3.

Diastereoselective Ritter-like Reaction on Cyclic Trifluoromethylated N,O-Acetals Derived from l-Tartaric Acid.

Despite the presence of the highly electron-withdrawing fluorinated substituent, cyclic α-trifluoromethylated N-acyliminium ions were successfully generated from fluorinated O-acetyl-N,O-acetal l-tartaric acid derivatives. The addition of nitriles on these intermediates occurred with high to excellent syn diastereoselectivity and led, in most cases, to oxazolines and amides as single diastereomers. The diastereoselectivity of the addition and the nature of the reaction product depend on the substituents on the hydroxyl groups of the tartaric acid scaffold. This methodology gave access to enantiopure, highly functionalized 5-(trifluoromethyl)pyrrolidin-2-one derivatives, bearing the fluorinated substituent on a tetrasubstituted carbon.

α-Trifluoromethylated tertiary homoallylic amines: diastereoselective synthesis and conversion into ß-aminoesters, γ- and δ-aminoalcohols, azetidines and pyrrolidines.

The diastereoselective addition of allyl zinc and allylindium derivatives to α-trifluoromethyl N-tert-butanesulfinyl hemiaminals, bench stable precursors of aryl and alkyl trifluoromethyl ketimines, allows the synthesis of homoallylic amines containing a tetrasubstituted carbon stereocentre bearing a trifluoromethyl group with good diastereoselectivities (up to dr > 99 : 1). This approach was also suitable for accessing chiral homoallylic amines bearing two contiguous stereocenters. The synthetic usefulness of N-tert-butanesulfinyl homoallylamines was illustrated by preparing various trifluoromethylated nitrogen containing bifunctional synthons (aminoesters, aminoalcohols) and small azaheterocycles (azetidines, pyrrolidines).

Enantiopure trifluoromethylated ß(3,3)-amino acids: synthesis by asymmetric Reformatsky reaction with stable analogues of trifluoromethyl N-tert-butanesulfinylketoimines and incorporation into α/ß-peptides.

Addition of a Reformatsky reagent to α-aryl(alkyl) α-trifluoromethyl N-tert-butanesulfinyl hemiaminals, bench-stable surrogates of trifluoromethyl ketoimines, provided ß-alkyl(aryl) ß-trifluoromethyl ß-amino acids derivatives in good yields and high diastereoselectivities. The N-tert-butanesulfinyl ß(3,3)-amino esters were further utilized as versatile intermediates for the elaboration of heterodi- and -tripeptides.

Organocatalyzed Asymmetric Allylic Alkylation Enables Synthesis of Chiral γ-Lactones Bearing Vicinal Tertiary and Quaternary Stereocenters.

The synthesis of enantioenriched α-aryl-α'-allyl-γ-butyrolactones bearing vicinal tertiary and quaternary stereocenters through organocatalyzed asymmetric allylic alkylation is reported. The process demonstrated that weakly stabilized enolates derived from α-aryl-γ-butyrolactones can undergo regio-, diastereo-, and enantioselective allylation using the proper activation of Morita-Baylis-Hillman (MBH) carbonates.

The role of the counterion and of silicon chelation in the selective mono(trifluoromethylation) of tartaric acid derived 1,4-diketones.

The addition of trifluoromethyl(trimethyl)silane (TFMTMS) to tartaric acid derived aromatic 1,4-diketones was reported to be highly stereoselective but also chemoselective towards a monoaddition product. This chemoselectivity remained unexplained. Complementary experiments and monitoring of the reaction by electrospray ionization mass spectrometry (ESI-MS) show that: i) the countercation (tetrabutylammonium (TBA(+)) or Cs(+)) associated to the initiator and the charged intermediates in the chain reaction plays a crucial role and ii) in the case of a tetrabutylammonium salt initiator, the second addition on the preformed monoadduct does occur but the resulting bis(trifluoromethyl)carbinolate is unable to evolve through the chain-transfer process and it exhibits an intramolecular Si-O interaction.

Enantiomerically pure 2-aryl(alkyl)-2-trifluoromethylaziridines: synthesis and ring opening with selected O- and N-nucleophiles.

We report herein the synthesis of enantiomerically pure 2-phenyl- and 2-ethyl-2-trifluoromethylaziridines by Mitsunobu-type cyclisation of the corresponding N-protected amino alcohols, and our results regarding their ring opening with selected nucleophiles. Under basic conditions, N-tosyl aziridines have been regioselectively opened at the less hindered carbon. Under acidic conditions, the regioselectivity of the attack depends on the nature of the substituent at C-2 and on the nitrogen protecting group.

Organocatalytic enantioselective allylic alkylation of α-aryl γ-lactones: an approach to densely functionalized quaternary stereocentres.

The asymmetric allylic alkylation (AAA) of α-aryl γ-lactones involving the activation of Morita-Baylis-Hillman (MBH) carbonates by an original chiral Lewis base is reported. A wide range of γ-lactones bearing a quaternary stereocentre was thus obtained in both high yields and high enantiomeric ratios. The direct alkylation by MBH alcohol using in situ activation has been also established. Additionally synthetically useful functional transformations of groups surrounding the quaternary stereocentre have been performed.

Enantiopure quaternary alpha-trifluoromethyl-alpha-alkoxyaldehydes from L-tartaric acid derived ketoamides.

The diastereoselective nucleophilic trifluoromethylation of a range of ketoamides derived from L-tartaric acid has been studied. TMSCF3 in the presence of a catalytic amount of K2CO3 in DMF has been identified as the conditions leading to the highest diastereoselectivities. A sequential one-pot reaction trifluoromethylation-etherification of the trifluoromethylcarbinol has been developed. Only one further one-pot reaction, ketal hydrolysis-oxidative cleavage, led to the final alpha-trifluoromethylated alpha-alkoxyaldehydes. This procedure was applied to the preparation of a series of enantiopure aryl, heteroaryl, and alkyl alpha-trifluoromethyl-alpha-alkoxyaldehydes.

New three-step domino reaction, "thiophilic addition-beta-elimination of fluoride-[3,3] sigmatropic rearrangement": Synthesis of alpha-allylic and alpha,alpha-bis(allylic) alpha-trifluoromethyl dithioesters.

The three-step domino reaction, "thiophilic addition of an organomagnesium reagent onto dithioester-beta-elimination of fluoride-[3,3] sigmatropic rearrangement", provides the product of formal regiospecific substitution of a fluorine atom by an allyl group. This mild and versatile methodology was applied to the synthesis of various alpha-allylic and alpha,alpha-bis(allylic) alpha-trifluoromethyl dithioesters.

Decarboxylative Claisen rearrangement reactions of allylic tosylmalonate esters.

[reaction: see text] Two different combinations of silylating agent and base are used for one-pot [3,3]-sigmatropic rearrangement-decarboxylation reactions of tosylmalonic mono(allylic) esters under mild conditions, providing the products of formal regiospecific allylation of methyl tosylacetate at the more substituted allylic terminus.

Synthesis of new artemisinin-derived dimers by self-cross-metathesis reaction.

[reaction: see text] New artemisinin-derived dimers, fluorinated or not, have been prepared by a self-cross metathesis reaction in the presence of first- or second-generation ruthenium catalysts without degradation of the endoperoxide bridge and with a good E/Z selectivity (up to 100:0).

Orally active antimalarials: hydrolytically stable derivatives of 10-trifluoromethyl anhydrodihydroartemisinin.

New fluoroartemisinin derivatives containing polar or water-soluble functionalities at C-16 (11a-j, 12a-g) were synthesized using the key intermediate 16-bromo-10-trifluoromethyl anhydrodihydroartemisinin 10. The substitution reaction from 10 was more selective than that from the nonfluorinated parent bromide; the allylic bromide 10 underwent no allylic rearrangement and provided only nucleophilic substitution products in high yields with N-, O-, and C-nucleophiles. Among them, amines 11a-c appeared to be highly in vivo efficient antimalarials on mice infected with Plasmodium berghei, more than the reference sodium artesunate 1d. In particular, the most effective piperazinoethanol derivative 11b cured all mice after oral treatment at a dose lower than 10 mg/kg. Further pharmacokinetic studies showed that the bioavailability in rats following oral administration was 25 times greater for 11b than for artemether 1b.

First synthesis of 10 alpha-(trifluoromethyl)deoxoartemisinin.

[reaction: see text] A novel, nonacetal (trifluoromethyl)deoxoartemisinin was prepared with good stereoselectivity. This compound was obtained by debromination of the 10 alpha-CF3-10-bromodeoxoartemisinin in the presence of tributyltin hydride at reflux in toluene without alteration of the endoperoxide bridge. It presented a reasonable antimalarial activity.

Asymmetric decarboxylative Claisen rearrangement reactions of sulfoximine-substituted allylic tosylacetic esters.

Allylic acetate esters containing a variety of N-arylsulfonyl sulfoximines on the acetyl residue have been prepared and submitted to the decarboxylative Claisen rearrangement reaction. Rearranged products were isolated in generally good yields, and diastereoselectivities up to 82:18 have been obtained. The N-(2,4,6-triisopropylphenylsulfonyl)-S-phenyl sulfoximine moiety gave the best selectivity. The stereochemistry of the major isomer was established by X-ray crystallography. A model to explain the stereochemical course of the rearrangement is proposed.

Anhydrodihydroartemisinin and its 10-trifluoromethyl analogue: access to novel d-ring-contracted artemisinin trifluoromethyl ketones.

The preparation of the 10-trifluoromethyl hydroartemisinin, followed by dehydration, afforded the trifluoromethyl analogue 2 of anhydrodihydroartemisinin 1. The reactivity of these two glycals of artemisinin were compared in epoxidation and halogenation reactions. Iodination of glycal 1 in water and the further rearrangement of the produced iodo hemiacetal provided the new D-ring-contracted aldehyde 8alpha, where the methyl at C-9 is beta. Epoxidation of 10-trifluoromethyl anhydrodihydroartemisinin 2 stereoselectively provided the beta-epoxy ether 11 in high yield. When treated with hexafluoro-2-propanol or trifluoroethanol, 11 readily underwent a rearrangement yielding to the D-ring-contracted trifluoromethyl ketone 9alpha with retention of configuration at C-9.