Asymmetric Catalysis Mediated by Synthetic Peptides, Version 2.0: Expansion of Scope and Mechanisms

Abstract

Low molecular weight synthetic peptides have been demonstrated to be effective catalysts for an increasingly wide array of asymmetric transformations. In many cases, these peptide-based catalysts have enabled novel multifunctional substrate activation modes and unprecedented selectivity manifolds. These features, along with their ease of preparation, modular and tunable structures, and often biomimetic attributes make peptides well-suited as chiral catalysts and of broad interest. Many examples of peptide-catalyzed asymmetric reactions have appeared in the literature since the last survey of this broad field in Chemical Reviews (Chem. Rev. 2007, 107, 5759-5812). The overarching goal of this new Review is to provide a comprehensive account of the numerous advances in the field. As a corollary to this goal, we survey the many different types of catalytic reactions, ranging from acylation to C-C bond formation, in which peptides have been successfully employed. In so doing, we devote significant discussion to the structural and mechanistic aspects of these reactions that are perhaps specific to peptide-based catalysts and their interactions with substrates and/or reagents.

Figure 1.

(a) Juliá–Colonna epoxidation. (b) Synthesis of polypeptides by polymerization with N-carboxyanhydrides. (c) Analysis of reaction mechanism and intermediates. (d) Proposed model for stereoselectivity.

Figure 2.

(a) Synthesis of imidazolium-containing poly(Leu) catalyst. (b) Epoxidation reactions.

Figure 3.

(a) Epoxidations of enals mediated by Pro-containing peptides with both β-turn and α-helix design elements. (b) Epoxidations of enones mediated by free N-terminal arene-containing residues.^,

Figure 4.

Juliá–Colonna epoxidations mediated by poly(Leu) peptide immobilized on hydrotalcite.

Figure 5.

(a) Stapling of short peptides in order to stabilize helical conformations. (b) Epoxidations utilizing stapled and unstapled peptides.

Figure 6.

(a) Epoxidation with peptide containing helical forming cyclic residues. (b) Crystal structure of peptide 2.10c. Adapted with permission from ref. . Copyright 2010 American Chemical Society.

Figure 7.

Juliá–Colonna epoxidations mediated by cyclic dipeptides.

Figure 8.

(a) Cartoon depicting the synthesis of a polypeptide with a rotaxane-based molecular machine. (b) Synthesis of a poly(Leu) peptide with a rotaxane-based molecular machine. (c & d) The degree of polymerization (DP) with and without the molecular machine approach. (e) Epoxidations mediated by the rotaxane-based poly(Leu) catalysts. Adapted with permission from ref. . Copyright 2017 Nature Publishing Group.

Figure 9.

(a) Polymerization of amino acids mediated by the protease papain utilizing mechanosynthesis. (b) Cartoon representation of simple ball milling. (c) Water is beneficial for many lipophilic amino acids, indicating that a hydrophobic effect could be operative. (d) Epoxidations with mechanosynthesized peptides.

Figure 10.

(a) Juliá–Colonna epoxidations in pure water. (b) Mechanistic model centered on a hydrophobic cavity formed from the Leu sidechains of the α-helix. Adapted with permission from ref. . Copyright 2017 Royal Society of Chemistry.

Figure 11.

(a) Putative catalytic cycle for the generation of electrophilic aspartyl peracid species. (b) Epoxidation of 2.21 with aspartyl peracid-based peptides. (c) Functional analysis of catalyst 2.23 through synthesis of peptidomimetic analogues. (d) Hypothesized transition state for enantioselective epoxidations.^,

Figure 12.

(a) The prediction of peptide sequences that are matched to perform selective chemistry on new substrates remains challenging. (b) Split-and-pool one-bead-one-catalyst library synthesis, screening, and identification.

Figure 13.

(a) The epoxidation of farnesol 2.27 could provide up to six epoxide products, posing challenges in site-selectivity and enantioselectivity. (b) Biased libraries for selective 2,3-epoxidation revealed hit catalyst 2.34b. (c) Peptide 2.34b can function as a highly selective catalyst in the epoxidation of numerous allylic olefins. (d) Evolution of a 6,7-selective farnesol epoxidation catalyst.^, Ternary plots show the positional selectivity, with 6,7-selective catalysts toward the top. Reproduced with permission from ref. . Copyright 2014 American Chemical Society.

Figure 14.

(a) NMR and computational structural analysis of peptide 2.34b. Adapted with permission from ref. . Copyright 2014 Royal Society of Chemistry. (b) NMR-constrained computational structural analysis of peptide 2.37b. Reproduced with permission from ref. . Copyright 2014 American Chemical Society. (c) Proposed model for the 2,3-selective epoxidation of farnesol with 2.34b. (d) Proposed model for the 6,7-selective epoxidation of farnesol with 2.37b.

Figure 15.

(a) Enantioselective peptide-based oxidations of achiral indole 2.38. (b) Diastereo- and site-selective oxidations of indole 2.41 with peptides.

Figure 16.

(a) Initial retrosynthesis of 2.43 proceeded through a key, diastereoselective indole oxidation of 2.45. (b) Catalyst 2.52 overturned the inherent substrate-derived selectivity and provided 2.46, syn to the acetamide motif. (c) Rearrangement of 2.45 provided pseudoindoxyl 2.53, instead of the desired spirooxindole 2.43.

Figure 17.

(a) Dioxirane-based epoxidation catalysts. (b) Epoxidation of 2.56 with trifluoromethyl ketone-containing peptide catalysts.^,

Figure 18.

(a) The mechanism of Baeyer–Villiger (BV) oxidation: nucleophilic addition of the peracid species followed by 1,2-migration of an adjacent C–C bond. (b) A conserved, peptide-based aspartyl peracid catalyst could function as both a nucleophile in BV oxidations and as an electrophile in epoxidations.

Figure 19.

(a) BV oxidations with monomeric Asp catalyst. (b) BV oxidations with perfluorinated benzoic acid. (c) Mechanism of BV oxidation, with key off-cycle intermediate inhibiting higher conversions.

Figure 20.

Mechanistic analysis of kinetic resolution of 2.64 via BV oxidation. In this case, rotation of the peracid dihedral results in the formation of regioisomeric products.

Figure 21.

(a) On-bead screening of Asp-containing peptide catalysts for the BV oxidation of 2.66. (b) Solution-phase screening of hit Asp peptides for the BV oxidation of 2.64a. (c) Selected substrate scope entries highlights the general tendency of 2.68c to reverse the inherent migratory aptitude.

Figure 22.

(a) Ground state structure of 2.68c. (b) Structure of 2.68c with an equimolar amount of (R,S)-2.64e Adapted with permission from ref. . Copyright 2016 American Chemical Society.

Figure 23.

(a) Asp-containing peptide catalysts for BV oxidation and epoxidation. (b) Dual substrate trans-2.69, containing both a 3-amidocyclohexanone motif for BV oxidation and an allylic alcohol for epoxidation. While achiral catalysts provide limited selectivity, catalysts 2.68c and 2.34b facilitated their matched reactivities. (c) Model for selective BV oxidation with ent-2.68c. (d) Model for selective epoxidation with 2.34b.

Figure 24.

(a) On-bead peptide library screening for the BV oxidation of 2.74 revealing two peptides that give opposite senses of asymmetric induction. (b) Coordination of chiral, ring opened products to zinc(II) pyridyl complexes for analysis of absolute stereochemistry and enantioselectivity by CD.

Figure 25.

Putative mechanism of BV oxidation with CPAs, which activate the ketone and Criegee intermediate via outer-sphere interactions.

Figure 26.

(a) Phosphopeptides as catalysts for the BV oxidation of cyclobutanones 2.80 with aqueous H₂O₂. A key Dap(Ac) residue at the i+3 position facilitates noncovalent interactions with the substrate. (c) Reversal in the sense of asymmetric induction upon switching from an ortho- (2.80) to a meta-directing group (2.84).

Figure 27.

(a) Flavin-embedded peptides as oxidation catalysts, with a specifically designed secondary point of contact at the i+3 position for further intra- and intermolecular interactions. (b) Proposed mechanistic cycle for flavin-based oxidations. (c) Flavin catalyzed sulfide oxidation. (d) Flavin catalyzed BV oxidation. (e) Competition experiment revealed that flavin-based peptides are more matched to facilitate BV oxidation than sulfide oxidation.

Figure 28.

Asymmetric reactions mediated by aspartyl peracid-based peptides: epoxidations, BV oxidations, and most recently, N-oxidations of pyridines.

Figure 29.

(a) Desymmetrization of bis(pyridine) 2.91a to the corresponding mono-N-oxide 2.92a catalyzed by Asp-containing peptide 2.95. (b) Optimal conditions and selected substrates for the 2.95-catalyzed desymmetrizing N-oxidation. (c) Enantioselective synthesis of loratadine derivative 2.91c, which freely interconverts between two helically chiral conformations and is locked upon 2.94-catalyzed N-oxidation. (d) Desymmetrizing N-oxidation of varenicline catalyzed by 2.94. (e) The N-oxidized bis(pyridine)s could be further functionalized with retention of enantiopurity.

Figure 30.

(a) Incorporation of a TEMPO catalyst into a helix-forming peptoid sequence. (b) Examination of peptoid-based catalysts in oxidative kinetic resolutions of secondary alcohols.

Figure 31.

(a) Pro-mediated α-oxidation of aldehydes with TEMPO. (b) Combination of peptide-based catalyst and enzymatic oxidant.^–

Figure 32.

Development of a resin-bound, Pro-based peptide catalyst for the α-amination of aldehydes.

Figure 33.

Development of a flow process, featuring solid-supported proline-containing peptides, for α-amination of aldehydes.

Figure 34.

(a) Reduction of enals 3.1 with HEH using proline-containing peptide catalysts. Catalysts required a β-turn motif to achieve high selectivity, as well as a hydrophobic poly(Leu) chain to give high conversion. (b) Selected substrate scope entries.^,

Figure 35.

Enantio- and regioselective reduction of α,β,γ,δ-unsaturated aldehyde 3.4 with Pro-containing catalysts.

Figure 36.

(a) Kinetic resolution of enal-containing ferrocene complexes with Pro-based peptide catalysts. (b) Desymmetrization of bis(enal) containing ferrocene complexes.^,

Figure 37.

(a) Two complementary classes of chiral phosphoric acid (CPA) catalysts: BINOL-derived (3.15) and peptide-based (3.16) CPAs. (b) The transfer hydrogenation of 8-aminoquinolines with pThr-based catalysts.

Figure 38.

(a) Reduction of bis(quinoline) 3.19 with both BINOL-derived CPA ent-3.15 and peptide-based CPA 3.16. (b) Overview of this process when both catalysts are added together. Catalyst ent-3.15 is matched for the first reduction, while catalyst 3.16 is matched for the second.

Figure 39.

(a) Two π-methylhistidine (Pmh)-containing peptides previously found to mediate asymmetric acylations (3.23) and phosphorylations (3.24), respectively. (b) One-pot acylation and phosphorylation of 3.25 and 3.26 by both Pmh catalysts, synthesizing their respective, desired products with high fidelity and stereoselectivity.

Figure 40.

(a) Reductive amination of 3-amidocyclohexanones 3.30. (b) Kinetic analysis and proposed transition state of the reaction.

Figure 41.

(a) Desymmetrization of myo-inositol derivative 4.1 using Pmh-containing peptides 4.3 or 4.4 to provide each enantiomer of monophosphate 4.2 with high levels of enantioselectivity.^, (b) This strategy was employed in the total synthesis of PI5P-DiC8 4.5.

Figure 42.

Two diastereomers of di-myo-inositol-1,1′-phosphate (DIP; 4.6).

Figure 43.

Examination of catalysts for the selective synthesis of both l,l- and l,d-di-myo-inositol-1,1′-phosphate derivatives 4.8.

Figure 44.

Mechanism of (a) Pmh-based catalysis of P(V) transfer vs. (b) Atz-containing peptide catalysis of P(III) transfer.

Figure 45.

Peptide 4.15-catalyzed P(III) group transfer to myo-inositol derivative 4.11 followed by kinetic resolution of 4.13 and subsequent deprotection to afford highly enantioenriched d-myo-inositol-4-phosphate 4.14 on gram scale. Conditions: (a) NH₃, Na, −78 °C; (b) DOWEX 50WX8-500, C₆H₁₁NH₂.

Figure 46.

Comparison between Pmh-peptide catalyzed sulfonylation and phosphorylation.

Figure 47.

Peptide 4.21-catalyzed kinetic resolution of (thio)formamides (±)-4.19.

Figure 48.

Derivatization of thioformamide 4.20b.

Figure 49.

Peptide-catalyzed remote desymmetrization of bis(phenol) 4.23, noting the correlation between the observed enantioselectivity and the steric demand of the substituent R.

Figure 50.

Kinetic resolution of trans-cycloalkane-1,2-diols 4.26 with tetrapeptide 4.28.

Figure 51.

Model for the enantioselective acylation of trans-cycloalkane-1,2-diols 4.26 in the chiral “pocket” of acylated peptide 4.28. Hydrogens are omitted for clarity. Adapted with permission from ref. . Copyright 2011 Wiley.

Figure 52.

Lowest-energy computed complexes between acylated-peptide 4.28 and trans-(1R,2R)-4.26b (Complex I, left) and cis-(1R,2S)-4.29a (Complex II, right). Computations were performed at the B3LYP/6-31G*//ONIOM2(B3LYP/6-31*:PM3) level of theory.

Figure 53.

Two lowest-energy transition states for acyl transfer from 4.28 to trans-diol 4.26b leading to each enantiomer of 4.27b. Only select hydrogens are shown for clarity. Lighter gray and darker colored shadings, respectively, represent the lower (PM3) and higher (B3LYP) layers in the ONIOM2 partitioning. Adapted with permission from ref. . Copyright 2009 American Chemical Society.

Figure 54.

Desymmetrization of meso, cis-Diols 4.29 using peptide 4.28.

Figure 55.

Peptide 4.28-catalyzed acyl transfer followed by in situ oxidation to produce configurationally stable 4.31a.

Figure 56.

(a) Peptidic multicatalyst 4.32 designed from the sequence of lead catalyst 4.28 for asymmetric acyl-transfer. (b) An overlay (molecular force-field analysis) of both acylated-peptides is shown below. Adapted with permission from ref. . Copyright 2011 Wiley.

Figure 57.

Concurrent tandem desymmetrization/oxidation of meso-diols 4.29 using multicatalyst 4.32 as compared to a two-step approach with peptide 4.28.

Figure 58.

Acylation of trans-cyclohexane-1,2-diol 4.26b peptide 4.28–catalyzed Steglich esterification.

Figure 59.

Kinetic resolution of (±)-4.26b via oxidative esterification of aldehydes.

Figure 60.

Kinetic resolution of trans-diols (4.26) using various alcohols as acyl synthons with peptidic multicatalyst 4.32.

Figure 61.

Peptide salt 4.34-catalyzed epoxide opening to trans-1,2-diols 4.26 and subsequent kinetic resolution via acylation.

Figure 62.

Epoxidation, ring-opening, and subsequent acylation mediated by peptide 4.35 and hydrazine bisulfate leading to enantioenriched mono-acylated diol 4.27b and trans-diol 4.26b from alkene 4.34.

Figure 63.

Catalytic cycle for the epoxidation of cyclohexene (4.34) with multicatalyst 4.35.

Figure 64.

Activation of Pmh- and β-Asp residues in multicatalyst 4.35 for acylation of (±)-4.26.

Figure 65.

Kinetic resolution of (±)-4.36 with various β-hairpin-biased tetrapeptides 4.38.

Figure 66.

General reaction mechanism for the acylation of (±)-4.36 catalyzed by peptide 4.38a.

Figure 67.

Lowest-energy transition states for the three interaction modes of intermediate I with (1R, 2R)-4.36.

Figure 68.

Lowest-energy transition states of (a) TS 4.4 with (1R, 2R)-4.36 and (b) (1S, 2S)-4.36. Adapted with permission from ref. . Copyright 2016 American Chemical Society.

Figure 69.

Proposed mechanism of the peptide 4.41-catalyzed Dakin–West reaction of (±)-4.39.

Figure 70.

B3LYP-D3 (BJ)/6–31+G(d,p) optimized structures representing the lowest-energy complex of protonated peptide 4.41 with enolate V. Key noncovalent interactions are highlighted. Reproduced with permission from ref. . Copyright 2016 Wiley.

Figure 71.

Synthesis of diastereomerically pure DMAP derivatives 4.43 via a one-pot, Ugi multicomponent reaction.

Figure 72.

Enantioselective Steglich rearrangement of various O-acylated oxindole derivatives 4.44 using catalysts 4.43a or 4.43b.

Figure 73.

Schematic models of the energetically favorable transition states leading to (S)- and (R)-4.45b.

Figure 74.

(a) Synthesis of chiral, C₂-symmetric PPY catalysts 4.46 for (b) the asymmetric desymmetrization of meso-diol 4.29.

Figure 75.

Two possible models for the transition state assembly in the asymmetric acylation of 4.29a catalyzed by 4.46h.

Figure 76.

The kinetic resolution of racemic sec-alcohol 4.47a catalyzed by PPY-containing peptides 4.49.

Figure 77.

Lowest-energy conformers of (a) 4.50a and (b) 4.50d. Adapted with permission from ref. . Copyright 2016 Royal Society of Chemistry.

Figure 78.

Kinetic resolution of various racemic sec-alcohols 4.47 catalyzed by peptide 4.49d.

Figure 79.

Asymmetric hydrocyanation of benzaldehyde 5.1a to cyanohydrin 5.2a catalyzed by diketopiperazine 5.3 originally reported by Inoue and co-workers.^, Three limiting models for asymmetric induction (A, B, & C) have been proposed.

Figure 80.

Computed structures of TS1 and D1 led to the transition state models TS2 and TS3, which provide a basis for stereoselectivity in the 5.3-catalyzed hydrocyanation of benzaldehyde 5.1a. B3LYP/6-31G* geometries and energies reported. Adapted in part with permission from reference . Copyright 2009 American Chemical Society.

Figure 81.

Computed structures of TS4 and TS5. B3LYP/6–31* geometries and energies reported. Adapted in part with permission from reference . Copyright 2009 American Chemical Society.

Figure 82.

Optimization of the asymmetric cyanosilylation of benzaldehydes catalyzed by resin-bound helical polypeptides 5.5.

Figure 83.

Scope of the 5.5-catalyzed asymmetric cyanosilylation of benzaldehydes 5.1.

Figure 84.

Optimization of a dipeptide-based ligand for the asymmetric addition of dimethylzinc to benzaldehyde 5.8a.

Figure 85.

Scope of the 5.10a-catalyzed, asymmetric organozinc addition to benzaldehydes 5.8.

Figure 86.

Development and optimization of a resin-bound, bifunctional peptide catalyst for the hydrolysis of formylphenyl esters 5.11.

Figure 87.

Preliminary results for a hydrolytic kinetic resolution.

Figure 88.

Peptide-catalyzed, alcoholytic ring-opening DKR of oxazol-5(4H)-ones 5.20.

Figure 89.

Diketopiperazine-catalyzed, alcoholytic ring-opening DKR of oxazolone 5.20a.

Figure 90.

Optimization of a β-turn biased peptide catalyst for the methanolytic ring-opening DKR of oxazol-5(4H)-one 5.20a.

Figure 91.

Sequence truncation study showing the effect of each residue on the reactivity and selectivity in the methanolytic DKR of 5.20a under the conditions described in Figure 90.

Figure 92.

Scope of the methanolytic DKR of oxazolones 5.20 catalyzed by 5.23k.

Figure 93.

Stereochemical model for the 5.23k-catalyzed methanolysis of (S)-5.20a.

Figure 94.

Thiourea-derived peptide catalysts for the asymmetric ring-opening of meso-stilbene oxides.

Figure 95.

Asymmetric ring-opening of stilbene oxides 5.28 with piperazine 5.29 catalyzed by thiourea-functionalized peptide 5.31a.

Figure 96.

Effect of catalyst epimerization and the observation of enantiodivergence.

Figure 97:

Inspirations for the design of amine-based peptide catalysts.

Figure 98:

Aldol reaction catalyzed by aldo-keto reductase mimics.

Figure 99:

Peptide catalysts for the asymmetric aldol reaction between 4-nitrobenzaldehyde and acetone: (a) Enzyme/protein-inspired or geometrically constrained peptide catalysts; (b) Solid-supported catalysts; and (c) various di/tri-peptide catalysts.

Figure 100:

Peptide catalysts for the asymmetric aldol reaction between 4-nitrobenzaldehyde and cyclohexanone: (a) Enzyme/protein-inspired or geometrically constrained peptide catalysts; (b) Solid-supported catalysts; (c) Various di/tri-peptide catalysts.

Figure 101:

Peptide catalysts for the asymmetric aldol reaction between electron-rich benzaldehydes and (a) acetone and (b) cyclohexanone.

Figure 102:

(a) Dehydrative kinetic resolution of hydroxy ketones (b) Proposed catalytic cycle.

Figure 103:

Peptide catalysts for the asymmetric aldol reaction between (a) cyclohexanecarboxaldehyde and acetone, (b) iso-butyraldehyde and acetone, and (c) iso-butyraldehyde and cyclohexanone.

Figure 104:

One-pot tandem aldol reaction using solid-supported acid and base catalysts showcasing the reusability of the catalysts.

Figure 105:

One-pot, tandem oxidation/aldol reaction using resin-supported catalysts that may be reused up to eight times.

Figure 106:

Kinetic resolution of ansa cyclophanes by aldol and retro-aldol reactions.

Figure 107:

Peptide-catalyzed asymmetric aldol reactions using various ketone acceptors.

Figure 108:

Potential future directions for catalytic direct aldol reactions.

Figure 109:

Divergence in site-selective, asymmetric aldol reactions catalyzed by short peptides.^,

Figure 110:

Substrate-influenced site-selectivity in asymmetric aldol reaction.

Figure 111:

Divergence of diastereoselectivity in peptide-catalyzed, asymmetric aldol reactions.^,

Figure 112:

Aldol reaction between cyclohexanone and 4-nitrobenzaldehyde showcasing a reversal in enantioselectivity with 6.46 in different solvents.

Figure 113:

CD spectra of 6.59 in methanol (blue), 10% H₂O in methanol (red), 50% H₂O in methanol (green), and water (orange). Reproduced with permission from ref. . Copyright 2011 Thieme.

Figure 114:

Aldol reactions catalyzed by di- and tripeptides that provide enantiodivergent outcomes.

Figure 115.

Pro-catalyzed 1,2-addition reaction (i.e., aldol) compared to a peptide-catalyzed 1,4-addition reactions.

Figure 116.

Lowest-energy conformations of (a) H-Pro-OH and (b) H-Pro-Pro-Asp-NH₂ (7.4) calculated using MacroModel 8.0. (c) Peptide-catalyzed conjugate addition of aldehydes 7.1 into nitroolefins 7.2, which is proposed to proceed through an enamine intermediate and is assisted by judicious placement of a protic sidechain. Reproduced in part from with permission from ref. . Copyright 2008 Wiley.

Figure 117.

Conjugate addition of aldehydes 7.1 into nitroolefins 7.8 lacking substitution at the β-position.

Figure 118

Optimization of the C-terminal residue of tripeptides in the asymmetric conjugate addition of aldehydes into nitroolefins.

Figure 119.

(a) Conjugate additions between n-butanal 7.11 and nitrostyrene 7.12 under different conditions. Under the “dry” conditions, anhydrous reagents and solvents were used in contrast to the standard conditions. (b) Initial rates vs. concentration of 7.11 under various conditions in the conjugate addition of 7.11 to 7.12 (green = standard conditions, red = anhydrous conditions, and blue = 10 mol% excess of water). (c) Influence of water on rates of product formation. Reproduced in part from with permission from ref. . Copyright 2010 American Chemical Society.

Figure 120.

Strategy for verifying an enamine mechanism by employing an ESI-MS study of the reverse-reaction using mass-labeled quasi-enantiomeric conjugate addition products.

Figure 121.

(a) Strategy for conducting reactions with tripeptide catalysts suspended on resin. (b) Performance of the proposed strategy in the asymmetric conjugate addition of aldehyde 7.11 into nitroolefin 7.12. Reproduced in part from with permission from ref. . Copyright 2011 Wiley.

Figure 122.

Application of tripeptide catalysts with added alkyl chains (e.g., 7.18 & 7.19) to promote micelle formation in asymmetric conjugate addition reactions under aqueous conditions.

Figure 123.

(a) Conjugate addition of aldehydes 7.1 to nitroolefins 7.20 bearing both α- and β-substitution catalyzed by peptides 7.22 and 7.23. (b) Influence of catalysts on the distribution of diastereomers 7.21a–d in the conjugate addition of aldehyde 7.11 into nitroolefin 7.20a bearing both α- and β-substitution. Both peptide catalysts 7.22 and 7.23 substantially alter the intrinsic diastereomeric preference.

Figure 124.

Optimization of tripeptides for the conjugate addition of aldehydes 7.1 into sterically hindered β,β-disubstituted nitroolefins 7.24 to generate an all-carbon quaternary stereogenic center.

Figure 125.

Conjugate addition of acetophenone into dicyanoolefins catalyzed by a tripeptide 7.10 containing a secondary amine.

Figure 126.

(a) Optimization of tripeptide-based catalysts for the asymmetric conjugate addition of aldehydes 7.31 into maleimide 7.32. (b) Low-yielding conjugate addition into N-phenyl protected maleimide.

Figure 127.

(a) Crystal structures of three optimized catalysts for conjugate addition reactions with various olefin acceptors. (b) Overlay of the three crystal structures for 7.7 (green), 7.27 (orange), and 7.35 (yellow) with H-atoms and TFA counterion removed for clarity. (c) The n→π* interactions suggested by the distance between the carbonyl O and the adjacent carbonyl C, as well as the approximation of the Bürgi–Dunitz angle. Reproduced in part with permission from ref. . Copyright 2011 Wiley.

Figure 128.

(a) Influence of ring size on the trans/cis ratio for the amide bond of the central Pro residue and its relation to enantioselectivity in the conjugate addition reactions. (b) K_t/c values for catalyst 7.10 and its enamine form 7.10-En in different solvents.

Figure 129.

Effects of substitution on the ring pucker of the i+1 Pro residue and its influence on enantioinduction in the asymmetric conjugate additions of aldehydes 7.11 into nitroolefins 7.12.

Figure 130.

(a) K_trans/cis values for 7.41 and 7.42 in various solvents. (b) Computed Boltzmann-averaged dipole moments of trans and cis conformers for compounds 7.34 and 7.35. (c) Solvent influence on trans/cis ratios of peptide 7.7 and its effect of enantioselectivity. Ratios were determined by NMR analysis in DMSO-d₆ and a 9:1 mixture of CDCl₃:CD₃OD. Reproduced in part from with permission from ref. . Copyright 2015. Royal Society of Chemistry.

Figure 131.

(a) Selected NOE, ³J_H,H coupling, and ³J_C,H coupling interactions for catalyst 7.10. (b) Variations in NOE interactions between 7.10 and 7.10-En. (c) Overlay of lowest energy DFT structures 7.10 (blue) and 7.10-En (green) (d) Overlay of four calculated structures within 2 kcal/mol of lowest energy structure of 7.10-En. Reproduced in part from with permission from ref. . Copyright 2018 American Chemical Society.

Figure 132.

Proposed catalytic cycle for the peptide-catalyzed, asymmetric conjugate addition of aldehydes to nitroolefins considering all previous mechanistic studies.

Figure 133.

(a) Strategy for the synthesis of diverse peptide catalysts scaffolds via a four-component Ugi reaction. (b) Asymmetric conjugate addition of aldehyde 7.47 into nitroolefin 7.2 catalyzed by peptide 7.49. (c) Diversity oriented approach pursued by Paixao and co-workers to develop catalysts for asymmetric conjugate addition reactions and a comparison of the number of low energy conformations of peptides 7.50 and 7.51. Reproduced in part from with permission from ref. . Copyright 2013 American Chemical Society.

Figure 134.

Asymmetric conjugate addition of aldehydes 7.1 to nitroolefins 7.2 catalyzed by tripeptides bearing a bifunctional phosphonic acid moiety at the C-terminal residue.

Figure 135.

Asymmetric conjugate addition of aldehydes 7.1 into nitroolefins 7.2 catalyzed by H-Pro-Phe-OH under aqueous conditions.

Figure 136.

Asymmetric conjugate addition of aldehydes into nitroolefins catalyzed by bifunctional diketopiperazine.

Figure 137.

(a) Peptide-catalyzed asymmetric Friedel–Crafts-type addition of indole 7.62 into unsaturated aldehydes 7.62 in aqueous media. (b) One-pot sequential Friedel-crafts-type alkylation and oxidation catalyzed by 7.64f and laccase.

Figure 138.

(a) Catalyst and solvent optimization for the conjugate addition of nitromethane (7.67) to unsaturated aldehyde 7.66a. (b) Asymmetric conjugate addition of nitromethane 7.67 into β,β-disubstituted α,β-unsaturated aldehydes 7.66 catalyzed by peptide 7.69 in aqueous media.

Figure 139.

Asymmetric conjugate addition of nitromethane (7.67) into α,β-unsaturated ketones 7.70 catalyzed by peptides containing unprotected N-termini.

Figure 140.

Asymmetric conjugate addition of 2-naphthalenethiol 7.78 into α,β,δ,γ-unsaturated aldehydes 7.77.

Figure 141.

(a) Kinetic resolution of metallocene complexes via peptide 7.83-catalyzed conjugate addition of nitromethane into α,β-unsaturated aldehydes 7.81. (b) Kinetic resolution of paracyclophane derivatives 7.84 via peptide 7.86-catalyzed conjugate addition.

Figure 142.

Asymmetric conjugate addition of boronic acids 7.88 into γ-hydroxy-α,β-unsaturated aldehydes 7.87.

Figure 143.

(a) Strategy for the visualization and identification of strongly active catalysts via immobilization of dye molecules to on-bead peptide catalysts. This facilitates rapid screening of peptide catalysts for the conjugate addition of malonate nucleophiles, such as 7.92, into α,β-unsaturated aldehyde like 7.61. (b) Selected enantioselectivity values for high performing catalysts in the reaction of aldehyde 7.61 with dimethyl malonate (7.93). (c) Optimized conditions for asymmetric conjugate addition of 7.99 into enals 7.98 and proposed model for the efficacy of His residues at the 5^th position. (d) Catalysts identified after further screening that demonstrate divergent enantioselectivity in the reaction of 7.61 with 7.93.

Figure 144.

Dipeptide 8.3-catalyzed cyclopropanation of 8.1 to afford 8.2.^,

Figure 145.

Treatment of dipeptide 8.3a with diethylzinc followed by diiodomethane.

Figure 146.

Two potential mechanisms for the dipeptide 8.3a-catalyzed cyclopropanation of 8.1.

Figure 147.

Peptide catalyst optimization for the cyclopropanation of α,β-unsaturated aromatic aldehyde 8.4a.

Figure 148.

Selected substrate scope for the asymmetric cyclopropanation of 8.4 using peptide 8.8e.

Figure 149.

Two potential modes of reactivity in the Lewis base-catalyzed reactions of allenoates 8.9 and imines 8.10.

Figure 150.

Catalyst optimization for the aza-MBH reaction of allenoate 8.9a and imine 8.10.

Figure 151.

Scope of the peptide-catalyzed aza-MBH reaction between allenoates 8.9 and imines 8.10.

Figure 152.

Proposed mechanism for the peptide-catalyzed aza-MBH reaction.

Figure 153.

Optimization of the peptide 8.12-catalyzed coupling of allenoates (±)-8.14 with imines 8.10.

Figure 154.

Selected scope for the peptide 8.12g-catalyzed coupling of allenoates 8.14 and imines 8.10.

Figure 155.

Proposed mechanism for the peptide 8.12g-catalyzed aza-MBH reaction of allenoate 8.14e and imine 8.10j.

Figure 156.

Speculative binding model for the addition reaction between intermediate I and imine 8.10j leading to intermediate II.

Figure 157.

(a) Cys-catalyzed, intramolecular Rauhut–Currier reaction of bis(enone) 8.16 and (b) proposed model for selectivity.^,

Figure 158.

Proposed mechanism for the Cys-catalyzed intramolecular RC reaction.^,

Figure 159.

Optimized transition states for the α-deprotonation step of the E1cB process for (1S, 2R, 3S) and (1R, 2S, 3R) enantiomers of intermediate III including potassium counterion and two explicit water molecules. Distances and angles are denoted in Å and degrees, respectively. Adapted with permission from ref. . Copyright 2013 Wiley.

Figure 160.

Substrate controlled Cys-catalyzed RC ring contraction leading to Sch-642305 (8.21) and epi-Sch-642305 (epi-8.21).

Figure 161.

Catalyst 8.18-controlled enantioselective RC ring contraction of 8.23.

Figure 162.

General strategy and mechanistic proposal for the peptide-catalyzed VCP ring-opening/cycloaddition cascade enabled by cysteine thiyl radicals.

Figure 163.

Initial results establishing proof-of-principle with amide-functionalized VCPs 9.1.

Figure 164.

Peptide optimization for the VCP ring-opening/cycloaddition cascade reaction. Scaffold 9.6 led to significant improvements in enantioselectivity compared to the other archetypal peptides 9.4 and 9.5.

Figure 165.

Modulation of the i+1 Pro γ-substituent led to the identification of lead catalyst 9.6h. Results are presented for the reaction of VCP 9.1c under the conditions described in Figure 164.

Figure 166.

Substrate scope of the 9.6h-catalyzed VCP ring-opening/cycloaddition cascade reaction.

Figure 167.

Proposed model for the 9.6-catalyzed VCP ring opening/cycloaddition cascade reaction.

Figure 168.

General conception of and challenges associated with cyclic deracemization strategies.

Figure 169.

Deracemization of cyclic ureas 9.7 jointly mediated by an Ir(III)-based photocatalyst, a chiral Brønsted base, and a cysteine-containing peptide catalyst.

Figure 170.

Proposed mechanism for the deracemization of urea 9.7. The cysteine containing peptide-based catalyst would mediate the enantioselective HAT step.

Figure 171.

Optimization of the light-driven deracemization of urea 9.7. The enantioselective PT and HAT steps were mediated by chiral BINOL-derived phosphate 9.9 and cysteine-containing tetrapeptides 9.10, respectively.

Figure 172.

Scope of the light-driven deracemization of urea 9.7. Entries marked with an asterisk (*) indicate a 12 h reaction time.

Figure 173.

Dual catalytic strategy for the photochemical [2+2] cycloaddition of enones 9.11 and 9.12 to deliver substituted cyclobutanes 9.13 with high levels of diastereo- and enantioselectivity.

Figure 174.

Optimization of the Lewis acid and chiral ligand led to the identification of peptides 9.18 and 9.19, which provided diastereodivergent results in the [2+2] cycloaddition of 9.11a with 9.12a.

Figure 175.

Scope of the dual catalytic [2+2] photocycloaddition of enones 9.11 and 9.12a using both peptides 9.19 and 9.20.

Figure 176.

DKR of biaryl compounds via atroposelective electrophilic aromatic bromination.

Figure 177.

Tripeptide 10.3-catalyzed atroposelective bromination of biaryls 10.1.

Figure 178.

Racemic control reactions to investigate the elements of peptide 10.3 that are crucial for catalysis.

Figure 179.

Proposed binding and activation model for the 10.3-catalyzed bromination of 10.1a.^,

Figure 180.

Sequential “A-B-C” cross-coupling of 10.4 enables the synthesis of highly functionalized derivatives 10.7. Conditions: (a) 1 equiv aryl MIDA-boronate, 10 mol% Pd(PPh₃)₄, 8 equiv K₃PO₄, THF/H₂O (5:1, 0.1 M), 65 °C, 14 h; (b) 1 equiv benzylamine, 10 mol% Pd(OAc)₂, 20 mol% rac-BINAP, PhMe (0.1 M), 100 °C, 18 h; (c) 1.2 equiv phenol, 10 mol% Pd(OAc)2, 13 mol% t-Bu₂XPhos, 2 equiv K₃PO₄,PhMe (0.3 M), 100 °C, 14 h; (d) 1 equiv NaBH₄, 5 mol% Pd(OAc)₂, 5.5 mol% rac-BINAP, 1.5 equiv TMEDA, THF (0.25 M), 50 °C, 14 h; (e) 1 equiv aryl MIDA-boronate, 10 mol% Pd₂(dba)₃, 10 mol% (S)-BINAP, 8 equiv K₃PO₄, THF/H₂O (4:1, 0.1 M), 65 °C, 14 h; (f) 1 equiv aryl boronic acid, 5 mol% Pd(PPh₃)₄, THF/2 M aq. Na₂CO₃ (2:1, 0.1 M), 100 °C, μw irradiation, 1 h.

Figure 181.

Peptide 10.10-catalyzed, atroposelective bromination of tertiary benzamides 10.8.

Figure 182.

LC/MS studies of reaction mixtures at low conversion under various catalytic conditions.

Figure 183.

Binding and activation of benzamide 10.8a by peptide 10.10.

Figure 184.

(a) Regioselective derivatization of tribromides 10.9 using a cross-coupling/ortho-lithiation sequence. Conditions: (a) 1 equiv phenyl boronic acid, 5 mol% Pd(PPh₃)₄, 8 equiv K₃PO₄, THF/H₂O (5:1, 0.1 M), 50 °C, 20 h; (b) 1.05 equiv NaBH₄, 5 mol% Pd(OAc)₂, 5.5 mol% rac-BINAP, 1.5 equiv TMEDA, THF (0.25 M), 50 °C, 17 h; (c) 1 atm CO, 10 mol% Pd(OAc)₂, 10 mol% Xant-Phos, 10 equiv Et₃N, MeOH (0.05 M), 60 °C, 16 h; (d) 1.1 equiv aniline, 5 mol% Pd₂(dba)₃, 10 mol% Xant-Phos, 2.5 equiv NaOt-Bu, THF (0.25 M), 50 °C, 3.5 h; (e) 1.1 equiv n-BuLi, THF (0.1 M), −78 °C; then 1.2 equiv (i) (MeS)₂, (ii) Ph₂P–Cl, or (iii) Ph₂C=O, 10 min. (b) Implementation of the derivatized product 10.15 as a chiral ligand in enantioselective Tsuji–Trost-type allylation.

Figure 185.

Spontaneous enantioenrichment following 10.10-catalyzed bromination of two-axis substrate 10.18.

Figure 186.

Peptide 10.22-catalyzed bromination of tropolone 10.20. Compared to the corresponding benzamides, amido-tropolones have notably higher rotational barriers.

Figure 187.

Optimization of a peptide-based catalyst for the atroposelective bromination of 3-arylquinazolinone 10.25a, highlighting the effect of the i+2 residue.

Figure 188.

Sequence truncation reveals the structural attributes key for selectivity in the bromination of quinazolinone 10.25a under the conditions described in Figure 187.

Figure 189.

Peptide 10.27q-catalyzed, atroposelective bromination of quinazolinones 10.25.

Figure 190.

A model for binding and activation of quinazolinone 10.25a by peptide 10.27q was proposed on the basis of NMR complexation experiments (10 mM in C₆D₆, 25 °C, 600 MHz), which revealed a number of intermolecular NOEs.

Figure 191.

Regioselective derivatization of tribromides 10.26a using cross-coupling methodologies. Conditions: (a) 1 atm H₂, 10 mass% Pd/C, MeOH (0.02 M), 12 h, 0 °C. (b) 2.0 equiv Ar–B(OH)₂,10 mol% Pd₂(dba)₃, 20 mol% P(t-Bu)(Cy)₂•HBF₄, 4.0 equiv K₃PO₄, THF/H₂O (3:1, 0.1 M), 45 °C, 24 h. (c) 2.0 equiv NHR₂, 10 mol% Pd₂(dba)₃, 20 mol% rac-BINAP, 1.4 equiv NaOt-Bu, PhMe (0.1 M), 80 °C, 18 h.

Figure 192.

Expansion of the catalyst library for the peptide-catalyzed bromination of quinazolinone 10.25a.

Figure 193.

The three conformations of peptide 10.27q observed by X-ray crystallography. The X-ray structure of peptide 10.34a overlays closely with conformer III.

Figure 194.

X-Ray crystal structures of the homologous i+2 variants of sequence 10.34. All but 10.34b adopted the unexpected prehelical conformation, including the most selective quinazolinone bromination catalysts. Enantioselectivity data are for the bromination of quinazolinone 10.25a to tribromide 10.26a under the conditions reported in Figure 192.

Figure 195.

Correlation between enantioselectivity (ee) and catalyst τ_i+2. The homologous catalysts highlighted in Figure 194 are indicated on the plot. Enantioselectivity data are for the bromination of quinazolinone 10.25a to tribromide 10.26a under the conditions reported in Figure 192.

Figure 196.

NOESY correlation diagrams for highly selective catalyst 10.34a and less selective catalyst 10.34b.

Figure 197.

(a) Conformational landscape of peptide 10.27q alone and in the presence of 1.0 equiv of quinazolinone substrates 10.25a and 10.25b. (b) Lowest-energy binding modes showing key intermolecular interactions.

Figure 198.

Multidimensional parameterization data shows that features of both limiting catalyst conformations correlate well with the observed enantioselectivity in the bromination of quinazolinone 10.25a.

Figure 199.

General strategy for the desymmetrizing bromination of diarylmethylamido bis(phenol)s 10.35.

Figure 200.

Results from the peptide-catalyzed desymmetrizing bromination of 10.35a demonstrating the importance of the Dmaa residue for selective catalysis.

Figure 201.

Enantiodivergence between catalysts 10.38 and 10.10 in the bromination of diarylmethylamido bis(phenol)s 10.35.

Figure 202.

A plot of ee vs. catalyst τ_i+2 revealed a linear correlation for the desymmetrizing bromination of 10.35a under the conditions reported in Figure 201.

Figure 203.

Differences in the solution conformations of 10.38 and 10.10 could possibly give rise to inverted binding and activation modes.

Figure 204.

The general strategy for the peptide-catalyzed bromolactonization of pentenoic acid 10.40 to bromolactone 10.41 takes advantage of a bromoiodinane generated in situ to transfer bromenium ion to the olefin.

Figure 205.

Key results from the evaluation of peptide scaffolds 10.42, 10.43, and 10.44 in the bromolactonization of pentenoic acid 10.40.

Figure 206.

Asymmetric Pd-catalyzed allylation of dimethylmalonate with 11.1 using peptide-based phosphine ligands 11.3 and 11.4.

Figure 207.

Application of peptide-based P,S-ligands 11.8 in the Pd-catalyzed allylation of malonate 11.5 with allylic acetate 11.6. Modular peptide synthesis enabled the assessment of many distinct stereochemical arrays.

Figure 208.

(a) Development of a peptide based “SupraPhanePhos” ligand. (b) Catalyst evaluation in the hydrogenation of α,β-unsaturated esters 11.12.

Figure 209.

(a) Asymmetric hydroformylation of styrene 11.14 mediated by heterodimeric β-sheet-like self-assembled Rh complexes. (b) Design of various carbon linked (LC) and nitrogen linked (LN) ligands.

Figure 210.

(a) Influence of peptide H-bonding patterns on the helical chirality of supramolecular phosphine structures. (b) Asymmetric, Rh-catalyzed hydrogenation of dehydroalanine 11.12 to afford 11.13. (c) Optimized ligand scaffolds that have been applied in the hydrogenation of 11.12.^,,

Figure 211.

(a) Design strategy for the encapsulation of achiral catalysts in homochiral, peptide-based Ti-phosphonate assemblies in aqueous environments. (b) Asymmetric hydrogenation of acetophenone 11.31 catalyzed by achiral Ru complexes encapsulated by 11.29 and 11.30. (c) Asymmetric epoxidation/ring-opening of styrenes 11.33 catalyzed an achiral Mn-salen complex encapsulated by 11.29.

Figure 212.

Application of bidentate phosphine ligands 11.36–11.39 derived from gramicidin S in the asymmetric hydrogenation of dehydroalanine 11.12a.^,

Figure 213.

(a) Design of carboxylate-containing peptide ligands for Fe-based catalysts. (b) Asymmetric epoxidation of styrenes 11.40 mediated by Fe-PDP^NMe2 and peptide ligand 11.42. (c) A comparison of enantioselectivity when acetic acid is used compared to peptide 11.42.

Figure 214.

(a) Molmol representation of monomeric bPP and its dimerization driven by hydrophobic interactions. N represents a site for the introduction of a Cu-coordinating residue at the hydrophobic interface between the two monomers. (b) A comparison of ligand sequences and their relative positions in the secondary structure of bPP. (c) Asymmetric Diels-Alder and conjugate addition reactions of enones 11.48 and 11.49 catalyzed by Cu-bPP complexes in water. Reproduced in part from with permission from ref. . Copyright 2009 Wiley.

Figure 215.

Optimization of Cu-coordinating peptides 11.52–11.54 in the asymmetric Diels–Alder reaction of enone 11.48. Ala scan and truncation experiments were used to study the peptides. MOPS = 3-(N-morpholino)propanesulfonic acid buffer.

Figure 216.

Application of peptides 11.53 and 11.54 in (a) asymmetric Diels-Alder reactions and (b) asymmetric Friedel–Crafts-like conjugate addition reactions of enones 11.55.

Figure 217.

(a) Henry reaction of benzaldehyde 11.58 with nitromethane 11.59 used to study the application of peptides derived from the Crt-1 Mets7 motif. (b) The unmodified structure of Crt-1 Mets7 (11.61a) that naturally binds Cu and modified scaffold 11.61b, which is more conformationally rigid.

Figure 218.

(a) Asymmetric Si–H insertion reaction of α-diazoacetates 11.62 with dimethylphenylsilane catalyzed by helical Rh-peptide complexes. (b) A comparison of the performance of monomeric Rh-peptide 11.64a, parallel dimeric complex 11.64b, and anti-parallel dimer 11.64c in the reaction of 11.62 with dimethylphenylsilane. (c) Peptide 11.65 was ultimately identified as the lead catalyst.

Figure 219.

Catalyst 11.65 with appended pyrenes. While the (a) parallel isomer 11.65-Pyr that displays detectable fluorescence, (b) anti-parallel isomer 11.65-Pyr is not able to form an exciplex.

Figure 220.

(a) Synthesis and screening of monomeric catalysts “on-bead” in order the rapidly identify selective sequences. (b) Application of optimized dimeric catalysts 11.68 and 11.69 in the asymmetric cyclopropanation of styrenes with α-diazophenylacetate 11.66, wherein divergent enantioselectivity is observed between the two peptides.

Figure 221.

(a) Disruption of helicity and inactivation of one Rh-site via His coordination to an adjacent axial position on Rh. (b) Optimized peptide 11.70 for cyclopropanation that was identified form on-bead screening of monomeric Rh-peptide complexes. (c) Asymmetric cyclopropanation of olefins 11.71 with α-diazophenylacetates 11.66 catalyzed by resin-supported tripodal Rh-peptide complex 11.70.

Figure 222.

Desymmetrization of diarylmethine 11.73 via Cu-catalyzed C–C, C–O, and C–N cross-coupling reactions.^– Reactivity was enabled by peptide-based ligands containing TMG-Asp residues at the N-terminus, which are proposed to form a 5-membered metallocycle with the Cu(I) catalyst.

Figure 223.

Kinetic resolutions of racemic substrates 11.80 informed a self-consistent model for catalyst–substrate interactions for the transformation depicted in Figure 222.

Figure 224.

(a) Atroposelective cyclodehydration of trifluoroacetamides 11.82 to benzimidazoles 11.83 catalyzed by pThr-containing peptides. (b) Catalyst-controlled diastereoselective cyclodehydration of enantioenriched 11.86.