Limits...
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

DFT calculations of two transition states TS-I and II in enantioselective Steglich rearrangement of 9a with 1g.Geometries of transition states TS-I and II from 9a with 1g were fully optimized by calculation using the B3LYP (Becke's three-parameter hybrid method using the Lee-Yang-Parr correlation functional) DFT with the 6-31G(d) basis set. Harmonic vibrational frequencies were computed for all stationary points to characterize them as saddle points.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4835565&req=5

f8: DFT calculations of two transition states TS-I and II in enantioselective Steglich rearrangement of 9a with 1g.Geometries of transition states TS-I and II from 9a with 1g were fully optimized by calculation using the B3LYP (Becke's three-parameter hybrid method using the Lee-Yang-Parr correlation functional) DFT with the 6-31G(d) basis set. Harmonic vibrational frequencies were computed for all stationary points to characterize them as saddle points.

Mentions: To gain further insight regarding the role of the chiral catalyst's tertiary hydroxyl groups, density functional theory (DFT) calculations were performed at the B3LYP/6-31G(d) level, with 9a as the substrate and compound 1g as the catalyst, which represent simplified catalyst of 1j. These investigations point to two critical attractive interactions, which directly involve the tertiary alcohol moiety, between the chiral catalyst and tight ion-pair intermediate. In the lowest energy transition state TS-I (Fig. 8 and Supplementary Table 7), which consistent with the experimental observations leads to the observed major enantiomer, there appears to be an H-bonding between the enolate oxygen of the ion pair and the catalyst's hydroxy unit; it is likely that the conformational rigidity imposed by the presence of the two aryl unit on the same carbon, forces the hydroxyl unit to be properly positioned to associate with the negatively charged oxygen. Additionally, there appears to be an additional electrostatic attraction4546 between the enolate and an ortho hydrogen of one of the aforementioned aryl units at the C3 site of the chiral catalyst. The second lowest mode of addition, as indicated by DFT calculations, is transition state II (Fig. 8 and Supplementary Table 8). While there appears to be similar electrostatic attractive forces operative here as well, II seems to suffer from a significant steric repulsion between the substrates phenoxy unit and the backbone of the catalyst's biaryl moiety. Nevertheless, DFT calculations indicate that there is in all likelihood steric repulsion between phenyl unit and the tertiary hydroxyl fragment that is involved in attractive interactions with the enolate group (see transition state (TS)-I, Fig. 8); this is supported by the findings that a catalyst with meta-(3,5)-substituted aryl groups give lower enantioselectivities in the reaction of 9a (cf. 1l or 1m in Fig. 4). Further, as indicated by the transformation that afforded 10m (Fig. 5) involving a more diminutive N-Me group, while less enantioselective than when a benzoate group is present (9a), there is still appreciable enantiofacial differentiation observed (98:2 er versus 87:13 er for 10a and 10m, respectively). This suggests that other, non-steric, factors are at play here as well. Towards this end, second order perturbation theory analysis in NBO at the M062X/6-31g** level indicates that C–H/enolate attraction might be notably stronger in the favoured TS-I (Supplementary Table 8).


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)

DFT calculations of two transition states TS-I and II in enantioselective Steglich rearrangement of 9a with 1g.Geometries of transition states TS-I and II from 9a with 1g were fully optimized by calculation using the B3LYP (Becke's three-parameter hybrid method using the Lee-Yang-Parr correlation functional) DFT with the 6-31G(d) basis set. Harmonic vibrational frequencies were computed for all stationary points to characterize them as saddle points.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: DFT calculations of two transition states TS-I and II in enantioselective Steglich rearrangement of 9a with 1g.Geometries of transition states TS-I and II from 9a with 1g were fully optimized by calculation using the B3LYP (Becke's three-parameter hybrid method using the Lee-Yang-Parr correlation functional) DFT with the 6-31G(d) basis set. Harmonic vibrational frequencies were computed for all stationary points to characterize them as saddle points.
Mentions: To gain further insight regarding the role of the chiral catalyst's tertiary hydroxyl groups, density functional theory (DFT) calculations were performed at the B3LYP/6-31G(d) level, with 9a as the substrate and compound 1g as the catalyst, which represent simplified catalyst of 1j. These investigations point to two critical attractive interactions, which directly involve the tertiary alcohol moiety, between the chiral catalyst and tight ion-pair intermediate. In the lowest energy transition state TS-I (Fig. 8 and Supplementary Table 7), which consistent with the experimental observations leads to the observed major enantiomer, there appears to be an H-bonding between the enolate oxygen of the ion pair and the catalyst's hydroxy unit; it is likely that the conformational rigidity imposed by the presence of the two aryl unit on the same carbon, forces the hydroxyl unit to be properly positioned to associate with the negatively charged oxygen. Additionally, there appears to be an additional electrostatic attraction4546 between the enolate and an ortho hydrogen of one of the aforementioned aryl units at the C3 site of the chiral catalyst. The second lowest mode of addition, as indicated by DFT calculations, is transition state II (Fig. 8 and Supplementary Table 8). While there appears to be similar electrostatic attractive forces operative here as well, II seems to suffer from a significant steric repulsion between the substrates phenoxy unit and the backbone of the catalyst's biaryl moiety. Nevertheless, DFT calculations indicate that there is in all likelihood steric repulsion between phenyl unit and the tertiary hydroxyl fragment that is involved in attractive interactions with the enolate group (see transition state (TS)-I, Fig. 8); this is supported by the findings that a catalyst with meta-(3,5)-substituted aryl groups give lower enantioselectivities in the reaction of 9a (cf. 1l or 1m in Fig. 4). Further, as indicated by the transformation that afforded 10m (Fig. 5) involving a more diminutive N-Me group, while less enantioselective than when a benzoate group is present (9a), there is still appreciable enantiofacial differentiation observed (98:2 er versus 87:13 er for 10a and 10m, respectively). This suggests that other, non-steric, factors are at play here as well. Towards this end, second order perturbation theory analysis in NBO at the M062X/6-31g** level indicates that C–H/enolate attraction might be notably stronger in the favoured TS-I (Supplementary Table 8).

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