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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

Enantioselective Steglich-type reactions promoted by catalyst 1j.(a) Initial catalysts screening for the Steglich rearrangement of O-acylated oxindole derivative with C2- or C1-symmetric binaphthyl-based chiral nucleophilic catalyst. The results clearly indicated that tertiary alcohol unit at C3 and C3′ of binaphthyl are essential for achieving high yield and enantioselectivity. (b) The enantioselective reaction can be easily performed in multigram scale without any adverse effect on the efficiency or enantioselectivity of the process. Moreover, the same silica gel chromatography procedure delivers the recovered chiral catalyst in 95% yield.
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f4: Enantioselective Steglich-type reactions promoted by catalyst 1j.(a) Initial catalysts screening for the Steglich rearrangement of O-acylated oxindole derivative with C2- or C1-symmetric binaphthyl-based chiral nucleophilic catalyst. The results clearly indicated that tertiary alcohol unit at C3 and C3′ of binaphthyl are essential for achieving high yield and enantioselectivity. (b) The enantioselective reaction can be easily performed in multigram scale without any adverse effect on the efficiency or enantioselectivity of the process. Moreover, the same silica gel chromatography procedure delivers the recovered chiral catalyst in 95% yield.

Mentions: With a collection of possible catalysts in hand, we chose Steglich rearrangement11519344243 of oxindole derivative 9a (Design option 1, Fig. 2) as the model transformation for identifying the optimal promoter molecule. Reactions were performed using 5 mol % of 1a−p in tetrahydrofuran (THF) (0.1 M) at 0 °C for 12 h (Fig. 4a). Reaction with 4-amino pyridine 1a was efficient but generated nearly racemic product (99% conv., 43:57 enantiomeric ratio (er)). Structurally modified versions 1b−f, which contain methoxy, phenyl, 2-naphthyl, carboxyl ester or amide groups at their C3 and C3′ positions were either equally or less efficient than 1a, and were all ineffective in generating 10a with significant enantioselectivity (no more than 72:28 er). The surprising breakthrough came when we evaluated compounds that contain tertiary alcohols unit within their chiral binaphthyl moiety (1g−m); under otherwise identical conditions, use of these catalysts led to the formation of the all-carbon quaternary stereogenic centre not only with exceptional efficiency (>98% conv.) but also in up to 98:2 er. In sharp contrast, C1-symmetric systems, represented by 1n, 1o and 1p proved to be substantially less effective, and afforded nearly racemic mixture of product. Apparently, C2-symmetric scaffold are essential for the establishment of proper enantiofacial discrimination. Subsequent optimization studies (Supplementary Figs 29–38 and Supplementary Tables 1–5), revealed that THF is indeed the optimal solvent and when the transformation is performed at –20 °C with no more than 0.5 mol % 1j, the reaction proceeds to complete conversion within five hours to afford 10a in 98:2 er. Finally, we find that use of 15 g of substrate 9a under the latter conditions (193 mg of 1j) delivers the desired product in quantitative yield (purification by standard silica gel chromatography) and 98:2 er (Fig. 4b, Supplementary Figs 39 and 40); furthermore, catalyst 1j could be recovered in 95% yield, and used in same reaction (0.1 mmol scale) to afford the desired product 10a in >98% yield with 98:2 er without loss of any catalytic activity (Supplementary Fig. 41 and Supplementary Method).


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)

Enantioselective Steglich-type reactions promoted by catalyst 1j.(a) Initial catalysts screening for the Steglich rearrangement of O-acylated oxindole derivative with C2- or C1-symmetric binaphthyl-based chiral nucleophilic catalyst. The results clearly indicated that tertiary alcohol unit at C3 and C3′ of binaphthyl are essential for achieving high yield and enantioselectivity. (b) The enantioselective reaction can be easily performed in multigram scale without any adverse effect on the efficiency or enantioselectivity of the process. Moreover, the same silica gel chromatography procedure delivers the recovered chiral catalyst in 95% yield.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Enantioselective Steglich-type reactions promoted by catalyst 1j.(a) Initial catalysts screening for the Steglich rearrangement of O-acylated oxindole derivative with C2- or C1-symmetric binaphthyl-based chiral nucleophilic catalyst. The results clearly indicated that tertiary alcohol unit at C3 and C3′ of binaphthyl are essential for achieving high yield and enantioselectivity. (b) The enantioselective reaction can be easily performed in multigram scale without any adverse effect on the efficiency or enantioselectivity of the process. Moreover, the same silica gel chromatography procedure delivers the recovered chiral catalyst in 95% yield.
Mentions: With a collection of possible catalysts in hand, we chose Steglich rearrangement11519344243 of oxindole derivative 9a (Design option 1, Fig. 2) as the model transformation for identifying the optimal promoter molecule. Reactions were performed using 5 mol % of 1a−p in tetrahydrofuran (THF) (0.1 M) at 0 °C for 12 h (Fig. 4a). Reaction with 4-amino pyridine 1a was efficient but generated nearly racemic product (99% conv., 43:57 enantiomeric ratio (er)). Structurally modified versions 1b−f, which contain methoxy, phenyl, 2-naphthyl, carboxyl ester or amide groups at their C3 and C3′ positions were either equally or less efficient than 1a, and were all ineffective in generating 10a with significant enantioselectivity (no more than 72:28 er). The surprising breakthrough came when we evaluated compounds that contain tertiary alcohols unit within their chiral binaphthyl moiety (1g−m); under otherwise identical conditions, use of these catalysts led to the formation of the all-carbon quaternary stereogenic centre not only with exceptional efficiency (>98% conv.) but also in up to 98:2 er. In sharp contrast, C1-symmetric systems, represented by 1n, 1o and 1p proved to be substantially less effective, and afforded nearly racemic mixture of product. Apparently, C2-symmetric scaffold are essential for the establishment of proper enantiofacial discrimination. Subsequent optimization studies (Supplementary Figs 29–38 and Supplementary Tables 1–5), revealed that THF is indeed the optimal solvent and when the transformation is performed at –20 °C with no more than 0.5 mol % 1j, the reaction proceeds to complete conversion within five hours to afford 10a in 98:2 er. Finally, we find that use of 15 g of substrate 9a under the latter conditions (193 mg of 1j) delivers the desired product in quantitative yield (purification by standard silica gel chromatography) and 98:2 er (Fig. 4b, Supplementary Figs 39 and 40); furthermore, catalyst 1j could be recovered in 95% yield, and used in same reaction (0.1 mmol scale) to afford the desired product 10a in >98% yield with 98:2 er without loss of any catalytic activity (Supplementary Fig. 41 and Supplementary Method).

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