Total synthesis of (+)-chloriolide

Haug, Timm T.; Kirsch, Stefan F.

doi:10.1039/b925644j

“…Kirsh and Haug prepared the chiral allylic alcohol (S)-10 from the readily available trichloroacetimidate in seven steps, which included the Overman allylic esterification. [17] Although our attempt at the direct chlorination of the commercially available methyl sorbate 8 failed, the allylic chloride 9 was prepared in three steps through the corresponding allylic bromide and alcohol, in 43 % yield. The reaction of 9 using (R)-1 b gave the target allylic alcohol (S)-10 in 93 % yield with 91 % ee, and this can be converted into (+)-chloriolide in nine steps.…”

Section: Entrymentioning

confidence: 99%

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

Kanbayashi¹,

Onitsuka²

2011

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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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“…This reaction was successfully applied to the synthesis of a known intermediate enroute to the 12‐membered macrolide (+)‐chloriolide (Scheme ). Kirsh and Haug prepared the chiral allylic alcohol ( S )‐ 10 from the readily available trichloroacetimidate in seven steps, which included the Overman allylic esterification 17. Although our attempt at the direct chlorination of the commercially available methyl sorbate 8 failed, the allylic chloride 9 was prepared in three steps through the corresponding allylic bromide and alcohol, in 43 % yield.…”

Section: Methodsmentioning

confidence: 99%

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

Kanbayashi

¹

,

Onitsuka

²

2011

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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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“…chlamydosporum) in 2006 by Gloer and coworkers. [86] In 2010 the initial total synthesis of (+) chloriolide was achieved in a longest linear sequence of 20 steps in 7% overall yield. [87] Total synthesis of (+)-chloriolide was commenced from easily accessible trichloroacetimidate 35, [88] which afforded primary alcohol 36 in 85% overall yield upon two steps.…”

Section: -Membered Macrolidesmentioning

confidence: 99%

Applications of Wittig Reaction in the Total Synthesis of Natural Macrolides

Heravi

¹

,

Zadsirjan

²

,

Daraie

³

et al. 2020

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The Wittig reaction involves the synthesis of an alkene via the conversion of an aldehyde or ketone with the already generated ylide from a phosphonium salt. Significantly, when this important name reaction is employed the desired alkenes are constructed via a predictable manner, thus resultant particularly are useful in the total synthesis of natural products and synthetic complex organic compounds with definite geometric isomers, exhibiting diverse biological potencies. In this review we try to highlight the applications of the Wittig reaction as an efficient and attractive strategy in the total synthesis of macrolides from 2008 to 2020.

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Total synthesis of (+)-chloriolide

Abstract: The first total synthesis of (+)-chloriolide, a 12-membered macrolide from Chloridium virescens (var. chlamydosporum), was accomplished in a longest linear sequence of 20 steps from commercial materials in 7% overall yield.

Cited by 18 publications

References 41 publications

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

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

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

Applications of Wittig Reaction in the Total Synthesis of Natural Macrolides

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