Deprotonative metalation of substituted aromatics using mixed lithium-cobalt combinations

International audienceThe deprotonation of anisole was attempted using different homo- and heteroleptic TMP/Bu mixed lithium-cobalt combinations. Using iodine to intercept the metalated anisole, an optimization of the reaction conditions showed that in THF at room temperature 2 equiv of base were required to suppress the formation of the corresponding 2,2'-dimer. The origin of the dimer was not identified, but its formation was favored with allyl bromide as electrophile. The metalated anisole was efficiently trapped using iodine, anisaldehyde, and chlorodiphenylphosphine, and moderately employing benzophenone, and benzoyl chloride. 1,2-, 1,3- and 1,4-dimethoxybenzene were similarly converted regioselectively to the corresponding iodides. It was observed that 2-methoxy- and 2,6-dimethoxypyridine were more prone to dimerization than the corresponding benzenes when treated similarly. Involving ethyl benzoate in the metalation-iodination sequence showed the method was not suitable to functionalize substrates bearing reactive functions

Deprotonative metallation of ferrocenes using mixed lithium-zinc and lithium-cadmium combinations.

International audienceA mixed lithium-cadmium amide and a combination of lithium and zinc amides were reacted with a range of ferrocenes; deprotonative mono- or dimetallation in general occurred chemoselectively at room temperature, as evidenced by subsequent quenching with iodine

Synthesis of both enantiomers of ferrocene[1,2-c]1H-quinolin-2-one by diastereoselective deproto-zincation of sugar-derived ferrocene esters

This research has also been performed as part of the Indo-French "Joint Laboratory for Sustainable Chemistry at Interfaces". The calculations were performed by using the RIKEN Integrated Cluster of Clusters (RICC) facility.International audienceDiastereoselective deproto-metallation of several sugar-derived ferrocene esters using lithium-zinc bases was studied. While bis[(R)-1-phenylethyl]amino as ligand afforded the diacetone-D-glucose-based (SP)-2-iodoferrocene ester in 91% de after iodination, the RP was synthesized from α-D-glucofuranose using 2,2,6,6-tetramethylpiperidino as ligand. Both (RP)- and (SP)-ferrocene[1,2-c]1H-quinolin-2-one were reached by subsequent cyclizing coupling, albeit their racemization was noted

Diastereoselective deprotonative metalation of chiral ferrocene derived acetals and esters using mixed lithium-cadmium and lithium-zinc combinations

International audienceIn situ bimetal combinations, and notably those prepared from MCl2(radical dotTMEDA) (M=Zn, Cd; TMEDA=N,N,N′,N′-tetramethylethylenediamine) and Li(TMP) (3 or 4 equiv, TMP=2,2,6,6-tetramethylpiperidino), were screened for their ability to diastereoselectively deprotonate ferrocenes bearing a chiral group. The ferrocene carboxylate generated from diacetone-d-glucose afforded the corresponding 2-iodo derivative in 74% yield with 90% de (SP diastereoisomer) using the base generated from CdCl2 and Li(TMP) (3 equiv), and in 85% yield with 91% de (SP diastereoisomer) through a double asymmetric induction using a chiral lithium-zinc base generated from ZnCl2*TMEDA and lithium (R)-bis(1-phenylethyl)amide (4 equiv). In contrast, using a combination prepared from ZnCl2 and Li(TMP) (4 equiv) with the ferrocene carboxylate obtained from 6-(tert-butoxycarbonylamino)-6-deoxy-3-O-methyl-1,2-O-isopropylidene-α-d-glucofuranose led to the RP-iodo derivative in 57% yield after separation. Suzuki coupling was performed satisfactorily on the isolated SP and RP diastereoisomer iodoesters

A Versatile and Stereocontrolled Total Synthesis of Dihydroxylated Docosatrienes Containing a Conjugated E,E,Z-Triene.

International audienceA versatile strategy featuring a Colvin rearrangement, hydrozirconation, a Sonogashira cross-coupling reaction and a Z-selective Wittig olefination, was successfully developed for the construction of a conjugated E,E,Z-triene subunit, flanked on both sides by two Z-allylic hydroxyl groups. This chemical pattern is found in many endogenous lipid metabolites such as maresin 1 (MaR1), neuroprotectin D1 (NPD1), and its aspirin triggered-isomer AT-NPD1, which not only counter-regulate inflammation but also actively orchestrate (at nanomolar doses) the resolution and termination program of acute inflammation while promoting wound healing, return to homeostasis and neuroprotection. Unlike previous approaches, the advantages of the present strategy are obvious, as it allows us to modify the nonpolar tail, the carboxylated head or both ends of the molecule without repeating the whole synthetic sequence (about 26-34 steps according to the literature). Thus, the first total syntheses of NPD1 methyl ester epimer (which can also be considered as an enantiomer of AT-NPD1) and its n-3 docosapentaenoic acid derived analogue were achieved from a highly functionalized and late advanced pivotal intermediate. This innovative route may be easily adapted to gain access to other dihydroxylated metabolites and analogues of polyunsaturated fatty acids containing a conjugated E,E,Z-triene subunit. Different epimers/diastereoisomers may be obtained by purchasing the suitable optically pure (S)- and/or (R)-1,2,4-butanetriol(s) as a chiral pool for both stereogenic centers

Total Synthesis of Neuroprotectin D1 Analogues Derived from Omega‑6 Docosapentaenoic Acid (DPA) and Adrenic Acid (AdA) from a Common Pivotal, Late-Stage Intermediate.

International audienceThe first total synthesis of three omega-6 dihydroxylated (E,E,Z)-docosatrienes has been successfully achieved employing a flexible strategy. The key features encompass a Boland semireduction, to create the (E,E,Z)-triene via an (E,E)-ynediene, and a selective deprotection of a tris(tert-butyldimethylsilyl) ether. The main advantage of the present strategy over previous syntheses of noncyclic dihydroxylated PUFA metabolites derived from docosahexaenoic and arachidonic acids comes from the introduction of the polar head chain at the very end of the synthesis from an advanced, pivotal aldehyde. In terms of divergency this enables late-stage modification of the head group

Cobalt mediated C–H bond functionalization: emerging tools for organic synthesis

International audienceno abstrac

Total Synthesis of Neuroprotectin D1 Analogues Derived from Omega‑6 Docosapentaenoic Acid (DPA) and Adrenic Acid (AdA) from a Common Pivotal, Late-Stage Intermediate

The first total synthesis of three omega-6 dihydroxylated (<i>E</i>,<i>E</i>,<i>Z</i>)-docosatrienes has been successfully achieved employing a flexible strategy. The key features encompass a Boland semireduction, to create the (<i>E</i>,<i>E</i>,<i>Z</i>)-triene via an (<i>E</i>,<i>E</i>)-ynediene, and a selective deprotection of a tris­(<i>tert</i>-butyldimethylsilyl) ether. The main advantage of the present strategy over previous syntheses of noncyclic dihydroxylated PUFA metabolites derived from docosahexaenoic and arachidonic acids comes from the introduction of the polar head chain at the very end of the synthesis from an advanced, pivotal aldehyde. In terms of divergency this enables late-stage modification of the head group

Diastereoselective Deprotonative Metalation of Sugar-Derived Ferrocene Esters Using Mixed Lithium-Cadmium Combinations

International audienceThe ability of a mixed lithium-cadmium amide to deproto-metallate diastereoselectively several sugar-derived ferrocene esters was studied. The ferrocenecarboxylates generated from α-D-glucofuranoses gave the best results, as evidenced after subsequent trapping with iodine. Good chemical yields and diastereoselectivities up to 82 % in favor of the SP stereoisomer were obtained. The use of a different chiral group favored the formation of the RP stereoisomer, isolated in 34 % yield and 98 % diastereoselectivity

(Chiral) lithium-(magnesium-)zinc and lithium-cobalt combinations as dual reagents for aromatic deproto-metalation and aryl transfer to aldehydes.

International audienceThe deprotonating ability of mixed lithium-zinc or lithium-magnesium-zinc combinations contg. amido and alkyl ligands in THF were compared using anisole as substrate and iodine to quant. trap the formed arylmetal species. The results showed that the deprotonating ability is hampered if a Grignard reagent is employed to introduce the alkyl ligand, and is reduced when 2,2,6,6-tetramethylpiperidino ligands are replaced by less hindered/basic chiral amido or alkyls. Concerning the interception of the generated lithium-zinc aryl species by aldehydes, the presence of amido ligands leads to side reactions/lower yields, and no clear improvement was obsd. if lithium-magnesium-zinc aryl species are used. Racemic mixts. to very low enantioselectivities were noted when chiral amido ligands were incorporated in the compn. of the bases. Still with enantioselective aryl transfer to aldehyde as purpose, the deprotonating ability of mixed lithium-cobalt combinations contg. amido and alkyl ligands were compared using anisole as substrate and anisaldehyde to trap the formed arylmetal species. As before, the deprotonating ability is reduced when 2,2,6,6-tetramethylpiperidino ligands are replaced by less hindered/basic alkyls or chiral amido. The trapping step using aldehydes being in this case more efficient, even in the presence of amido ligands, the alcs. were obtained in higher yields. With recourse to a lower interception temp., and using only bis[(R)-1-phenylethyl]amino as ligands, 32 and 22% yield, and 69 and 65% ee were obtained using, resp., anisaldehyde and 3,4,5-trimethoxybenzaldehyde to intercept the metalated anisole. [on SciFinder(R)