Enantio- and Regioselective Iridium-Catalyzed Allylic Hydroxylation

Gärtner, Martin; Mader, Steffen; Seehafer, Kai; Helmchen, Günter

doi:10.1021/ja109953v

Cited by 110 publications

(32 citation statements)

References 26 publications

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“…Direct allylic hydroxylation yielding highly valuable allylic alcohols has been recognised for a while as one of the most oxyfunctionalizations [1]. Allylic alcohols can further be exploited for the synthesis of pharmaceutical intermediates, agrochemicals and natural products [2–4].…”

Section: Introductionmentioning

confidence: 99%

Selective allylic hydroxylation of acyclic terpenoids by CYP154E1 from Thermobifida fusca YX

Bogazkaya¹,

Bühler²,

Kriening³

et al. 2014

Beilstein J. Org. Chem.

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SummaryAllylic alcohols are valuable precursors in the synthesis of pharmaceutical intermediates, agrochemicals and natural products. Regioselective oxidation of parental alkenes is a challenging task for chemical catalysts and requires several steps including protection and deprotection. Many cytochrome P450 enzymes are known to catalyse selective allylic hydroxylation under mild conditions. Here, we describe CYP154E1 from Thermobifida fusca YX that enables this type of oxidation. Several acyclic terpenoids were tested as possible substrates for CYP154E1, and the regio- and chemoselectivity of their oxidation was investigated. Using a previously established bioinformatics approach we identified position 286 in the active site of CYP154E1 which is putatively involved in substrate binding and thereby might have an effect on enzyme selectivity. To tune regio- and chemoselectivity of the enzyme three mutants at position 286 were constructed and used for substrate oxidation. All formed products were analysed with GC–MS and identified using chemically synthesised authentic samples and known compounds as references. Best regioselectivity towards geraniol and nerol was observed with the wild type enzyme mainly leading to 8-hydroxy derivatives (8-hydroxygeraniol or 8-hydroxynerol) with high selectivity (100% and 96% respectively). Highest selectivities during the oxidation of geranylacetone and nerylacetone were observed with the following variants: V286F led mainly to 7-hydroxygeranylacetone (60% of the total product) and V286A produced predominantly 12-hydroxynerylacetone (75% of total product). Thus, CYP154E1 and its mutants expand the tool-box for allylic hydroxylation in synthetic chemistry.

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Section: Introductionmentioning

confidence: 99%

Selective allylic hydroxylation of acyclic terpenoids by CYP154E1 from Thermobifida fusca YX

Bogazkaya¹,

Bühler²,

Kriening³

et al. 2014

Beilstein J. Org. Chem.

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“…[9] Herein, we describe the direct synthesis of chiral allylic alcohols by the regio-and enantioselective allylic substitution using water as the nucleophile. [10] Previously, we reported the enantioselective allylic substitution of 1,3-disubstituted allylic carbonates with amine and carbon nucleophiles catalyzed by planar-chiral cyclopentadienyl ruthenium (Cp'Ru) complexes (1; see Table 1). [11] This system was successfully extended to the regio-and enantioselective allylic substitution of monosubstituted allylic halides with oxygen and carbon nucleophiles.…”

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confidence: 99%

“…[15] To the best of our knowledge, this is a rare example of an allylic substitution that uses water as the nucleophile to give the chiral allylic alcohol in good yield and high enantioselectivity. [10] The scope of the present allylic hydroxylation is summarized in Table 2. The reactions of cinnamyl chloride derivatives, which possess various substituents, selectively produced the corresponding branched allylic alcohols 3 in good yields with high enantioselectivities (Table 2, entries 1-5), although substrates with electron-withdrawing groups required longer reaction times for complete conversion.…”

mentioning

confidence: 99%

Ruthenium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution with Water: Direct Synthesis of Chiral Allylic Alcohols

Kanbayashi¹,

Onitsuka²

2011

Angew Chem Int Ed

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Enantioselective allylic substitution catalyzed by transitionmetal complexes is an important process in organic synthesis.[1] For many years, mainly palladium complexes that contain chiral ligands have been employed as efficient catalysts in these reactions. Recent studies have demonstrated that chiral catalysts based on other transition metals show different regioselectivity in the synthesis of branched allylic products via monosubstituted p-allyl intermediates. [2] Although a variety of carbon and nitrogen nucleophiles can be used in those reactions, applicable oxygen nucleophiles are still limited to phenols and alcohols, which produce allylic ethers.[3] Thus, enantioenriched branched allylic alcohols, which serve as useful chiral building blocks, are often synthesized by other processes, such as the hydrogenation of a,b-unsaturated ketones, [4] the nucleophilic addition of vinylmetal reagents to aldehydes and ketones, [5] and the kinetic resolution of racemic allylic alcohols.[6] Recently, new ways to access these compounds have been developed, and they involve allylic substitution by a two-step conversion involving allylic esters and silyl ethers (Scheme 1; OPG = ester or silyl ether). [7,8] In the reaction of allylic chlorides with boronic acids in the presence of a ruthenium catalyst, the allylic alcohols were synthesized but high regio-and enantioselectivities were not achieved.[9] Herein, we describe the direct synthesis of chiral allylic alcohols by the regio-and enantioselective allylic substitution using water as the nucleophile.[10]Previously, we reported the enantioselective allylic substitution of 1,3-disubstituted allylic carbonates with amine and carbon nucleophiles catalyzed by planar-chiral cyclopentadienyl ruthenium (Cp'Ru) complexes (1; see Table 1). [11] This system was successfully extended to the regio-and enantioselective allylic substitution of monosubstituted allylic halides with oxygen and carbon nucleophiles. [12] From those studies, we found that Cp'Ru catalysts showed characteristic reactivity towards the less reactive nucleophiles. Thus, we started an examination of the enantioselective allylic substitution with water using Cp'Ru catalysts.Treatment of cinnamyl chloride (2 a) with water in the presence of 1 mol % of the Cp'Ru complex (S)-1 a resulted in the selective formation of the branched allylic alcohol (3 a; see equation in Table 1). After optimization of the reaction conditions, we found that the reaction in a mixture of THF/ water (8:1) at 25 8C with sodium hydrogen carbonate (1.2 equiv), produced 3 a after 4 hours in 99 % yield with 81 % ee.[13] Notably, the linear allylic alcohol was not formed at all. To improve the enantioselectivity, we examined the effect of the aryl groups on the phosphine ligand of the Cp'Ru catalyst (Table 1). Replacement of the phenyl groups with 3,5-dimethylphenyl and 4-methoxy-3,5-dimethylphenyl groups led to an increase in enantioselectivity to 88 % ee and 90 % ee, respectively (Table 1, entries 2 and 3). Complexes 1 d and 1 e, which have 3,...

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“…An iridium-catalyzed asymmetric S N 2′ displacement of 2-ethylenecarbonates procures chiral sec. allyl alcohols 29 , while a homogeneous ruthenium-catalyzed conversion of sec. alcohols with ammonia affords the corresponding prim.…”

Section: Trends and Developments In Synthetic Organic Chemistry 2011mentioning

confidence: 99%

Title Pages

2011

Theilheimer's Synthetic Methods of Organic Chemistry

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Enantio- and Regioselective Iridium-Catalyzed Allylic Hydroxylation

Cited by 110 publications

References 26 publications

Selective allylic hydroxylation of acyclic terpenoids by CYP154E1 from Thermobifida fusca YX

Selective allylic hydroxylation of acyclic terpenoids by CYP154E1 from Thermobifida fusca YX

Ruthenium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution with Water: Direct Synthesis of Chiral Allylic Alcohols

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