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. 2008 Dec 17;130(50):17085-94.
doi: 10.1021/ja806818a.

A surprising mechanistic "switch" in Lewis acid activation: a bifunctional, asymmetric approach to alpha-hydroxy acid derivatives

Ciby J Abraham  1 , Daniel H Paull, Tefsit Bekele, Michael T Scerba, Travis Dudding, Thomas Lectka
Affiliations

A surprising mechanistic "switch" in Lewis acid activation: a bifunctional, asymmetric approach to alpha-hydroxy acid derivatives

Ciby J Abraham et al. J Am Chem Soc. .

Abstract

We report a detailed synthetic and mechanistic study of an unusual bifunctional, sequential hetero-Diels-Alder/ring-opening reaction in which chiral, metal complexed ketene enolates react with o-quinones to afford highly enantioenriched, alpha-hydroxylated carbonyl derivatives in excellent yield. A number of Lewis acids were screened in tandem with cinchona alkaloid derivatives; surprisingly, trans-(Ph(3)P)(2)PdCl(2) was found to afford the most dramatic increase in yield and rate of reaction. A series of Lewis acid binding motifs were explored through molecular modeling, as well as IR, UV, and NMR spectroscopy. Our observations document a fundamental mechanistic "switch", namely the formation of a tandem Lewis base/Lewis acid activated metal enolate in preference to a metal-coordinated quinone species (as observed in other reactions of o-quinone derivatives). This new method was applied to the syntheses of several pharmaceutical targets, each of which was obtained in high yield and enantioselectivity.

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Figures

Figure 1
Figure 1
Lewis acid coordination by o-benzoquinone derivatives.
Figure 2
Figure 2
Computational analysis of putative o-chloranil–metal complexes.
Figure 3
Figure 3
UV-Vis profile of phenylethylketene showing the effects of BQd and trans-(Ph3P)2PdCl2 on the ketene–enolate equilibrium.
Figure 4
Figure 4
Optimized structures (LANL2DZ) of the PdII–enolate complexes.
Figure 5
Figure 5
Calculations of the effect of palladium complexation on enolate isomerization.
Figure 6
Figure 6
Initial plots of product formation vs. time for monofunctional and bifunctional reactions: (A) BQd and trans-(Ph3P)2PdCl2; and (B) BQd.
Figure 7
Figure 7
Calculated transition states for the reaction of o-chloranil with a model enolate in the presence (TS-A and TS-C) and absence (TS-B) of PdII.
Figure 7
Figure 7
Calculated transition states for the reaction of o-chloranil with a model enolate in the presence (TS-A and TS-C) and absence (TS-B) of PdII.
Figure 8
Figure 8
Comparative reaction times of catalytic methanolysis of cycloadduct 5a in the presence of various promoters.
Scheme 1
Scheme 1
Bifunctional Approach to α-Hydroxylated Carbonyl Derivatives
Scheme 2
Scheme 2
Possible Binding Scenarios for Cocatalysts
Scheme 3
Scheme 3
Resonance Tautomerization of Putative Pd(II/IV)-Bound Quinone: Is PdII a Lewis Base to o-Chloranil?
Scheme 4
Scheme 4
Side Reaction of Ejected Triphenylphosphine
Scheme 5
Scheme 5
Mechanistic Scenario to Explain PdII Catalysis
Scheme 6
Scheme 6
Proposed Bifunctional Mechanism for the Palladium(II) Cocatalyzed Reaction
Scheme 7
Scheme 7
Synthesis of α-Hydroxy-γ-lactone 10 and α-Hydroxy-γ-lactam 11
Scheme 8
Scheme 8
Synthesis of the Factor Xa Inhibitor
Scheme 9
Scheme 9
Synthesis of α-Hydroxyl DAPT
See this image and copyright information in PMC

References

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