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Enantioselective acyl transfer catalysis by a combination of common catalytic motifs and electrostatic interactions.

Mandai H, Fujii K, Yasuhara H, Abe K, Mitsudo K, Korenaga T, Suga S - Nat Commun (2016)

Bottom Line: Catalysts that can promote acyl transfer processes are important to enantioselective synthesis and their development has received significant attention in recent years.Despite noteworthy advances, discovery of small-molecule catalysts that are robust, efficient, recyclable and promote reactions with high enantioselectivity can be easily and cost-effectively prepared in significant quantities (that is, >10 g) has remained elusive.As little as 0.5 mol% of a member of the new catalyst class is sufficient to generate acyl-substituted all-carbon quaternary stereogenic centres in quantitative yield and in up to 98:2 enantiomeric ratio (er) in 5 h.

View Article: PubMed Central - PubMed

Affiliation: Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.

ABSTRACT
Catalysts that can promote acyl transfer processes are important to enantioselective synthesis and their development has received significant attention in recent years. Despite noteworthy advances, discovery of small-molecule catalysts that are robust, efficient, recyclable and promote reactions with high enantioselectivity can be easily and cost-effectively prepared in significant quantities (that is, >10 g) has remained elusive. Here, we demonstrate that by attaching a binaphthyl moiety, appropriately modified to establish H-bonding interactions within the key intermediates in the catalytic cycle, and a 4-aminopyridyl unit, exceptionally efficient organic molecules can be prepared that facilitate enantioselective acyl transfer reactions. As little as 0.5 mol% of a member of the new catalyst class is sufficient to generate acyl-substituted all-carbon quaternary stereogenic centres in quantitative yield and in up to 98:2 enantiomeric ratio (er) in 5 h. Kinetic resolution or desymmetrization of 1,2-diol can be performed with high efficiency and enantioselectivity as well.

No MeSH data available.


Related in: MedlinePlus

Nucleophilic catalyst in acylation reaction.(a) The proposed and generally accepted catalytic cycle for acyl transfer reactions in the presence of acid anhydride promoted by DMAP; this general scheme was used as the framework for the catalyst development studies described in this report. The anionic component within the loose ion-pair intermediate (ii) is believed to serve as a general base, playing a critical role in determining the rate of the overall processes. (b−e) General strategies, and their specific attributes, of the previously employed strategies involving structural alteration of DMAP-containing molecules to generate enantioselective acyl transfer catalysts. B, base; R1, R2, FG, various functional groups.
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f1: Nucleophilic catalyst in acylation reaction.(a) The proposed and generally accepted catalytic cycle for acyl transfer reactions in the presence of acid anhydride promoted by DMAP; this general scheme was used as the framework for the catalyst development studies described in this report. The anionic component within the loose ion-pair intermediate (ii) is believed to serve as a general base, playing a critical role in determining the rate of the overall processes. (b−e) General strategies, and their specific attributes, of the previously employed strategies involving structural alteration of DMAP-containing molecules to generate enantioselective acyl transfer catalysts. B, base; R1, R2, FG, various functional groups.

Mentions: N,N-4-dimethylaminopyridine (DMAP) has long been recognized as a uniquely effective and broadly applicable nucleophilic catalyst for a number of important reactions in organic chemistry1. One set of transformations for which DMAP is commonly utilized is the acylation of hydroxyl group in the presence of acid anhydride. The commonly accepted mechanism for this class of reactions, which supported by experimental as well as computational findings, is presented in Fig. 1a (refs 2, 3). The nucleophilic is believed to react first with the acylating agent i to generate N-acylpyridinium salt intermediate ii, which is likely subjected to nucleophilic attack by the alcohol substrate (R2OH) via intermediate iii. A critical feature of this general class of catalytic processes is that the acetate anion that resides within complex ii serves as a Brønsted base to enhance the reactivity of the otherwise relatively mildly nucleophilic hydroxyl unit. Ester product iv and pyridinium salt v are thus formed, and the latter is then neutralized by the stoichiometric base (B; typically Et3N) to re-generate the nucleophilic catalyst. The efficiency with which N-acylpyridinium ion ii is generated4, the Lewis basicity of the counteranion unit as well as the degree to which it remains associated with the positively charged acylating agent (versus loose ion pair) are critical to the facility of the overall transformation5. A number of strategies have been adopted to modulate the effectiveness of acyl transfer agents for which DMAP serves as the parent compound. Among these is the utilization of electronic factors to extend the lifetime of the N-acylpyridinium salt, or by manipulation of conformational effects to enhance electron donation by the amino substituent; there are also instances where a combination of the aforementioned approaches has been adopted (for example, 4-pyrrolidinopyridine (PPY) or 9-azajulolidine)6. A variety of chiral variants, employed for kinetic resolution of alcohol or enantioselective acyl transfer processes, have also been introduced78. Such investigations, which have led to the development of various enantiomerically pure promoter molecules that are based on DMAP or PPY scaffolds, as originally put forth by the notable advances reported by Vedejs9 and Fu10, may be classified in four major categories (Fig. 1b–e). One strategy entailed the use of N-acylpyridinium salt with a chiral substituent at the pyridyl ring's C2 position; however, this structural alteration proved to be detrimental to reaction efficiency, requiring the use of stoichiometric amounts of the catalyst (Fig. 1b)9. A similar approach but involving the C3 site of the heterocyclic ring, has been extensively examined111213141516171819. Nonetheless, reactivity levels were again generally reduced, probably as a result of hampering of proper electron donation by the amino substituent, which raises the energy of the critical pyridinium ion intermediates (cf. ii, Fig. 1a)2021. The issue of diminished catalyst efficiency applies to DMAP or PPY derivatives that carry a ring that connects the C2 and C3 carbons of the pyridyl ring (Fig. 1d)22. In most cases, diminished stability of the key ion-pair intermediate because of steric repulsion between substituents and 4-amino moiety and/or N-acetyl group was a complication21. An exception was the ferrocene-based catalysts developed by Fu et al.2324; comparatively high catalyst activity and enantioselectivity was observed in a number of different applications. Obtaining this set of chiral catalysts in the enantiomerically pure form, however, requires costly resolution procedures25. The efficiency and considerable longevity of N-acylpyridinium ion has been attributed to the exceptional electron-donating ability of transition metal framework; what's more, the cyclopentadienyl moiety attached to pyridyl ring is sufficiently small to prevent unfavourable interaction with the N-acetyl and/or the N-dimethyl- and pyrrolidino groups21. Chiral amino derivatives have been positioned at the pyridyl group's C4 site as well (Fig. 1e)26272829, but these distally positioned moieties did not generate high degrees of stereochemical differentiation for a wide variety of substrates and, for electronic reasons already mentioned (cf. Fig. 1c), this came at the cost of significant diminution in efficiency. Thus, relatively large substituents are required to construct chiral environment to achieve high enantioselectivity. Another notable concept (dual catalysis/anion-binding approach), which is not classified into aforementioned categories (Fig. 1b–e), was also very effective for enantioselective acyl transfer reactions303132333435363738.


Enantioselective acyl transfer catalysis by a combination of common catalytic motifs and electrostatic interactions.

Mandai H, Fujii K, Yasuhara H, Abe K, Mitsudo K, Korenaga T, Suga S - Nat Commun (2016)

Nucleophilic catalyst in acylation reaction.(a) The proposed and generally accepted catalytic cycle for acyl transfer reactions in the presence of acid anhydride promoted by DMAP; this general scheme was used as the framework for the catalyst development studies described in this report. The anionic component within the loose ion-pair intermediate (ii) is believed to serve as a general base, playing a critical role in determining the rate of the overall processes. (b−e) General strategies, and their specific attributes, of the previously employed strategies involving structural alteration of DMAP-containing molecules to generate enantioselective acyl transfer catalysts. B, base; R1, R2, FG, various functional groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835565&req=5

f1: Nucleophilic catalyst in acylation reaction.(a) The proposed and generally accepted catalytic cycle for acyl transfer reactions in the presence of acid anhydride promoted by DMAP; this general scheme was used as the framework for the catalyst development studies described in this report. The anionic component within the loose ion-pair intermediate (ii) is believed to serve as a general base, playing a critical role in determining the rate of the overall processes. (b−e) General strategies, and their specific attributes, of the previously employed strategies involving structural alteration of DMAP-containing molecules to generate enantioselective acyl transfer catalysts. B, base; R1, R2, FG, various functional groups.
Mentions: N,N-4-dimethylaminopyridine (DMAP) has long been recognized as a uniquely effective and broadly applicable nucleophilic catalyst for a number of important reactions in organic chemistry1. One set of transformations for which DMAP is commonly utilized is the acylation of hydroxyl group in the presence of acid anhydride. The commonly accepted mechanism for this class of reactions, which supported by experimental as well as computational findings, is presented in Fig. 1a (refs 2, 3). The nucleophilic is believed to react first with the acylating agent i to generate N-acylpyridinium salt intermediate ii, which is likely subjected to nucleophilic attack by the alcohol substrate (R2OH) via intermediate iii. A critical feature of this general class of catalytic processes is that the acetate anion that resides within complex ii serves as a Brønsted base to enhance the reactivity of the otherwise relatively mildly nucleophilic hydroxyl unit. Ester product iv and pyridinium salt v are thus formed, and the latter is then neutralized by the stoichiometric base (B; typically Et3N) to re-generate the nucleophilic catalyst. The efficiency with which N-acylpyridinium ion ii is generated4, the Lewis basicity of the counteranion unit as well as the degree to which it remains associated with the positively charged acylating agent (versus loose ion pair) are critical to the facility of the overall transformation5. A number of strategies have been adopted to modulate the effectiveness of acyl transfer agents for which DMAP serves as the parent compound. Among these is the utilization of electronic factors to extend the lifetime of the N-acylpyridinium salt, or by manipulation of conformational effects to enhance electron donation by the amino substituent; there are also instances where a combination of the aforementioned approaches has been adopted (for example, 4-pyrrolidinopyridine (PPY) or 9-azajulolidine)6. A variety of chiral variants, employed for kinetic resolution of alcohol or enantioselective acyl transfer processes, have also been introduced78. Such investigations, which have led to the development of various enantiomerically pure promoter molecules that are based on DMAP or PPY scaffolds, as originally put forth by the notable advances reported by Vedejs9 and Fu10, may be classified in four major categories (Fig. 1b–e). One strategy entailed the use of N-acylpyridinium salt with a chiral substituent at the pyridyl ring's C2 position; however, this structural alteration proved to be detrimental to reaction efficiency, requiring the use of stoichiometric amounts of the catalyst (Fig. 1b)9. A similar approach but involving the C3 site of the heterocyclic ring, has been extensively examined111213141516171819. Nonetheless, reactivity levels were again generally reduced, probably as a result of hampering of proper electron donation by the amino substituent, which raises the energy of the critical pyridinium ion intermediates (cf. ii, Fig. 1a)2021. The issue of diminished catalyst efficiency applies to DMAP or PPY derivatives that carry a ring that connects the C2 and C3 carbons of the pyridyl ring (Fig. 1d)22. In most cases, diminished stability of the key ion-pair intermediate because of steric repulsion between substituents and 4-amino moiety and/or N-acetyl group was a complication21. An exception was the ferrocene-based catalysts developed by Fu et al.2324; comparatively high catalyst activity and enantioselectivity was observed in a number of different applications. Obtaining this set of chiral catalysts in the enantiomerically pure form, however, requires costly resolution procedures25. The efficiency and considerable longevity of N-acylpyridinium ion has been attributed to the exceptional electron-donating ability of transition metal framework; what's more, the cyclopentadienyl moiety attached to pyridyl ring is sufficiently small to prevent unfavourable interaction with the N-acetyl and/or the N-dimethyl- and pyrrolidino groups21. Chiral amino derivatives have been positioned at the pyridyl group's C4 site as well (Fig. 1e)26272829, but these distally positioned moieties did not generate high degrees of stereochemical differentiation for a wide variety of substrates and, for electronic reasons already mentioned (cf. Fig. 1c), this came at the cost of significant diminution in efficiency. Thus, relatively large substituents are required to construct chiral environment to achieve high enantioselectivity. Another notable concept (dual catalysis/anion-binding approach), which is not classified into aforementioned categories (Fig. 1b–e), was also very effective for enantioselective acyl transfer reactions303132333435363738.

Bottom Line: Catalysts that can promote acyl transfer processes are important to enantioselective synthesis and their development has received significant attention in recent years.Despite noteworthy advances, discovery of small-molecule catalysts that are robust, efficient, recyclable and promote reactions with high enantioselectivity can be easily and cost-effectively prepared in significant quantities (that is, >10 g) has remained elusive.As little as 0.5 mol% of a member of the new catalyst class is sufficient to generate acyl-substituted all-carbon quaternary stereogenic centres in quantitative yield and in up to 98:2 enantiomeric ratio (er) in 5 h.

View Article: PubMed Central - PubMed

Affiliation: Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.

ABSTRACT
Catalysts that can promote acyl transfer processes are important to enantioselective synthesis and their development has received significant attention in recent years. Despite noteworthy advances, discovery of small-molecule catalysts that are robust, efficient, recyclable and promote reactions with high enantioselectivity can be easily and cost-effectively prepared in significant quantities (that is, >10 g) has remained elusive. Here, we demonstrate that by attaching a binaphthyl moiety, appropriately modified to establish H-bonding interactions within the key intermediates in the catalytic cycle, and a 4-aminopyridyl unit, exceptionally efficient organic molecules can be prepared that facilitate enantioselective acyl transfer reactions. As little as 0.5 mol% of a member of the new catalyst class is sufficient to generate acyl-substituted all-carbon quaternary stereogenic centres in quantitative yield and in up to 98:2 enantiomeric ratio (er) in 5 h. Kinetic resolution or desymmetrization of 1,2-diol can be performed with high efficiency and enantioselectivity as well.

No MeSH data available.


Related in: MedlinePlus