Rhodium‐Catalyzed Enantioselective Hydrogenation of (<i>E</i>)‐Enol Acetate Acids

Arena, Giada; Barreca, Giuseppe; Carcone, Luca; Cini, Elena; Marras, Giovanni; Nedden, Hans Günter; Rasparini, Marcello; Roseblade, Stephen J.; Russo, A. Peter; Taddei, Maurizio; Zanotti‐Gerosa, Antonio

doi:10.1002/adsc.201200934

Cited by 19 publications

(12 citation statements)

References 36 publications

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“…This approach was used to provide an intermediate to the renin inhibitor aliskiren, used to treat hypertension (eq 8). 26 A recent example showing progress made in hydrogenation of acyclic trisubstituted olefins without traditional coordinating groups is shown in eq 9. 27 Chiral (α-chloroalkyl)boronic esters can be obtained via iridium-catalyzed asymmetric reduction of the corresponding 1-chloro-1-alkenylboronic esters (eq 10).…”

Section: Carbon-carbon Bond Reductionsmentioning

confidence: 99%

Hydrogen

Wilt

Collier

2016

Encyclopedia of Reagents for Organic Synthesis

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Section: Carbon-carbon Bond Reductionsmentioning

confidence: 99%

Hydrogen

Wilt

Collier

2016

Encyclopedia of Reagents for Organic Synthesis

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“…Following our interest in optimizing the synthesis of API for important medicines, [14][15][16] we tried to design a new approach to Ozanimod 1 based on catalytic introduction of the stereogenic center, reduction of unrequired steps and limited use of protective groups and dangerous solvents.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis of Ozanimod, the Active Pharmaceutical Ingredient of a New Drug for Multiple Sclerosis

Cianferotti

Barreca²,

Bollabathini

et al. 2021

Eur J Org Chem

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This paper is dedicated to Professor Franco Cozzi on his 70th Birthday. We report here a short enantioselective synthesis of Ozanimod, a potent modulator of the enzyme Sphingosine-1-phosphate receptor (S1P R), recently approved by FDA and EMA for the treatment of relapsing-remitting multiple sclerosis. Amongst different synthetic approaches explored, we achieved the best result introducing the stereogenic centre in the last step through imine asymmetric transfer hydrogenation (ATH) using Wills' catalysts. Besides the reduced numbers of enantiomeric purity controls required, this process culminates in an exceptionally high enantioselective reductive amination obtained with commercially available tethered Ru catalysts. Starting from commercially available 4-cyano-indanone, enantiomerically pure Ozanimod was obtained in 5 steps in 62 % overall yield and 99 % ee.

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“…Nevertheless, the inclusion of a substituent in β position of the vinyl fragment introduces fundamental reactivity aspects to study. First, in comparison with widely studied disubstituted substrates, increase in olefin substitution should be accompanied by a reduced catalyst activity, further to the relatively low reactivity of enol esters . Second, the enantioselectivity of the hydrogenation may critically be dependent on the olefin configuration, which can limit severely the usefulness of this approach as enol esters are often obtained as E / Z mixtures and their separation is usually cumbersome.…”

Section: Introductionmentioning

confidence: 99%

Broad Scope Synthesis of Ester Precursors of Nonfunctionalized Chiral Alcohols Based on the Asymmetric Hydrogenation of α,β-Dialkyl-, α,β-Diaryl-, and α-Alkyl-β-aryl-vinyl Esters

et al. 2017

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The catalytic asymmetric hydrogenation of trisubstituted enol esters using Rh catalysts bearing chiral phosphine-phosphite ligands (P-OP) has been studied. Substrates covered comprise α,β-dialkyl, α-alkyl-β-aryl, and α,β-diarylvinyl esters, the corresponding hydrogenation products being suitable precursors to prepare synthetically relevant chiral nonfunctionalized alcohols. A comparison of reactivity indicates that it decreases in the order: α,β-dialkyl > α-alkyl-β-aryl > α,β-diaryl. Based on the highly modular structure of P-OP ligands employed, catalyst screening identified highly enantioselective catalysts for α,β-dialkyl (95-99% ee) and nearly all of α-alkyl-β-aryl substrates (92-98% ee), with the exception of α-cyclohexyl-β-phenylvinyl acetate which exhibited a low enantioselectivity (47% ee). Finally, α,β-diarylvinyl substrates showed somewhat lower enantioselectivities (79-92% ee). In addition, some of the catalysts provided a high enantioselectivity in the hydrogenation of E/Z mixtures (ca. Z/E = 75:25) of α,β-dialkylvinyl substrates, while a dramatic decrease on enantioselectivity was observed in the case of α-methyl-β-anisylvinyl acetate (Z/E = 58:42). Complementary deuteration reactions are in accord with a highly enantioselective hydrogenation for both olefin isomers in the case of α,β-dialkylvinyl esters. In contrast, deuteration shows a complex behavior for α-methyl-β-anisylvinyl acetate derived from the participation of the E isomer in the reaction.

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Rhodium‐Catalyzed Enantioselective Hydrogenation of (E)‐Enol Acetate Acids

Cited by 19 publications

References 36 publications

Hydrogen

Hydrogen

Enantioselective Synthesis of Ozanimod, the Active Pharmaceutical Ingredient of a New Drug for Multiple Sclerosis

Broad Scope Synthesis of Ester Precursors of Nonfunctionalized Chiral Alcohols Based on the Asymmetric Hydrogenation of α,β-Dialkyl-, α,β-Diaryl-, and α-Alkyl-β-aryl-vinyl Esters

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