Phosphothreonine (pThr)-Based Multifunctional Peptide Catalysis for Asymmetric Baeyer-Villiger Oxidations of Cyclobutanones

Abstract

Biologically inspired phosphothreonine (pThr)-embedded peptides that function as chiral Brønsted acid catalysts for enantioselective Baeyer-Villiger oxidations (BV) of cyclobutanones with aqueous H₂O₂ are reported herein. Complementary to traditional BINOL-derived chiral phosphoric acids (CPAs), the functional diversity of the peptidic scaffold provides the opportunity for multiple points of contact with substrates via hydrogen bonding, and the ease of peptide synthesis facilitates rapid diversification of the catalyst structure, such that numerous unique peptide-based CPA catalysts have been prepared. Utilizing a hypothesis-driven design, we identified a pThr-based catalyst that contains an N-acylated diaminopropionic acid (Dap) residue, which achieves high enantioselectivity with catalyst loadings as low as 0.5 mol%. The power of peptide-based multi-site binding is further exemplified through reversal in the absolute stereochemical outcome upon repositioning of the substrate-directing group (ortho- to meta). Modifications to the i+3 residue (^LDap to ^LPhe) lead to an observed enantiodivergence without inversion of any stereogenic center on the peptide catalyst, due to noncovalent interactions. Structure-selectivity and ¹H-¹H-ROESY studies revealed that the proposed hydrogen bonding interactions are essential for high levels of enantioinduction. The ability for the phosphopeptides to operate as multifunctional oxidation catalysts expands the scope of pThr catalysts and provides a framework for the future selective diversification of more complex substrates, including natural products.

Keywords: Baeyer–Villiger; asymmetric catalysis; chiral phosphoric acid; peptides; phosphothreonine.

Figure 1.

(a) Phosphorylation event as a post-translational modification. (b) BINOL-derived chiral phosphoric acids. (c) Peptide-mediated transfer hydrogenation of 8-aminoquinolines using pThr as a catalytic residue. (d) Ding and co-workers’ pioneering Brønsted acid catalyzed Baeyer–Villiger oxidation of 3-substituted cyclobutanones. (e) Proposed mechanism for the CPA catalyzed BV reaction utilizing H₂O₂ as the oxidant.

Figure 2.

Comparison of X-ray crystal structures of pThr- and Dmaa-embedded peptides. (a) X-ray structure of P4. Two 1,4-dioxane solvent molecules omitted for clarity (see SI for details). (b) X-ray structure of 7. Two distinct packing polymorphs were observed in the unit cell (7a, 7b), only one is shown for clarity (See SI for details). (c) Catalytically active residues (pThr and Dmaa) embedded in i position of conserved peptide sequence.

Figure 3.

(a) General reaction scheme for BV oxidation with peptide catalyst and (b) structure–selectivity study with P41 and Phe analog (P42). Reaction conditions: Cyclobutanone 4 (0.05 mmol, 1.0 equiv), catalyst (2.5 mol%), and H₂O₂ (30% w/w aq. 1.5 equiv) at −15 °C with [4c] = 0.05 M CHCl₃. Yield was determined by ¹H NMR analysis of the crude reaction mixture using an internal standard (1,3,5-trimethoxybenzene). Enantiomeric ratios were by CSP-HPLC analysis. Reported results are the average of two trials. The absolute configuration of products 5m–r were assigned in analogy to 5e and 5f. The absolute configuration of 5a was assigned as (R)-(−)-5a by comparison of the measured optical rotation to literature values.

Figure 4.

Divergences in enantioselectivity in meta- and para-N-aryl carbamate without inversion of a catalyst stereogenic center.^{a,b a} Conditions: Cyclobutanone 4 (0.05 mmol, 1.0 equiv), H₂O₂ (30% w/w aq. 1.5 equiv), catalyst (2.5 mol%) at −15 °C with [4] = 0.05 M CHCl₃. ^b Yield was determined by ¹H NMR analysis of the crude reaction mixture using an internal standard (1,3,5-trimethoxybenzene), and enantiomeric ratios determined by CSP-HPLC analysis. Reported results are the average of two trials. ^c Absolute configuration of 5t assigned in analogy to 5s.

Figure 5.

(a) ¹H–¹H ROESY NMR of peptide catalysts P41 and P42 show both unique and conserved interresidue nOe correlations (800 MHz, 5.0 mM in CDCl₃ at 25 °C). (b) ¹H NMR solvent titration curve of DMSO-d₆ to identify solvent exposed and hydrogen bonded amides for peptides P41 and P42 (5.0 mM concentration in CDCl₃ (referenced to 7.26 ppm) at 25 °C).

Figure 6.

(a) Speculative transition structures showing putative substrate-catalyst hydrogen bonding interactions with an antiperiplanar orientation of the peroxyl group in the Criegee intermediate, which is consistent with the absolute configuration of the product. (b) Speculative transition structures for the switching in stereoselection in substrate 4s, which is meta-substituted.

Scheme 1.

Syn/anti Criegee intermediates.

Scheme 2.

Preliminary pThr-catalyzed Baeyer–Villiger oxidation of 4a–b.

Scheme 3.

Baeyer–Villiger oxidation of carbamate 4c.

Scheme 4.

Observed reversal in absolute stereochemistry in the BV of meta-4s.