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Experimental lineage and functional analysis of a remotely directed peptide epoxidation catalyst.

Lichtor PA, Miller SJ - J. Am. Chem. Soc. (2014)

Bottom Line: We examined the selectivity of truncated analogues to find that a trimer is sufficient to furnish the remote selectivity.Both 1D and 2D (1)H NMR studies were used to determine possible catalyst conformations, culminating in proposed models showing possible interactions of farnesol with a protected Thr side chain and backbone NH.The models were used to rationalize the selectivity of a modified catalyst (17) for the 6,7-position relative to an ether moiety in two related substrates.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Yale University , P.O. Box 208107, New Haven, Connecticut 06520, United States.

ABSTRACT
We describe mechanistic investigations of a catalyst (1) that leads to selective epoxidation of farnesol at the 6,7-position, remote from the hydroxyl directing group. The experimental lineage of peptide 1 and a number of resin-bound peptide analogues were examined to reveal the importance of four N-terminal residues. We examined the selectivity of truncated analogues to find that a trimer is sufficient to furnish the remote selectivity. Both 1D and 2D (1)H NMR studies were used to determine possible catalyst conformations, culminating in proposed models showing possible interactions of farnesol with a protected Thr side chain and backbone NH. The models were used to rationalize the selectivity of a modified catalyst (17) for the 6,7-position relative to an ether moiety in two related substrates.

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(A–C) Ternaryplots showing an overlay of peptide selectivitiesfrom successive generations of 6,7-selective peptides, where eachaxis represents the fraction of the total monoepoxide: (A) the firstlibrary demonstrating 6,7-selectivity (first generation, red); (B)the first biased library for 6,7-selectivity (second generation, green);(C) second biased library (third generation, blue). Points that arehigher (further away from the triangle base) are more 6,7-selective.The highlighted generation from each plot is in the solid color inthe foreground atop the other library generations in the background.Solid markers indicate peptides that were sequenced. (D) List of aportion of sequenced peptides from each library generation (shownwith solid markers in A–C). Residues shown in blue indicatewere picked from the pool of variable residues from their particularlibrary. (E) Selectivity with amino acids at the i + 2 position, which can be compared to the library with i + 2 Thr(Bn) directly to the left (C, third generation,blue). Product ratios were measured by GC. In all of the on-bead screeningstudies, the formation of diepoxides was intentionally limited throughthe use of 0.3 equiv of DIC, resulting in analysis of low-conversionreaction mixtures.
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fig1: (A–C) Ternaryplots showing an overlay of peptide selectivitiesfrom successive generations of 6,7-selective peptides, where eachaxis represents the fraction of the total monoepoxide: (A) the firstlibrary demonstrating 6,7-selectivity (first generation, red); (B)the first biased library for 6,7-selectivity (second generation, green);(C) second biased library (third generation, blue). Points that arehigher (further away from the triangle base) are more 6,7-selective.The highlighted generation from each plot is in the solid color inthe foreground atop the other library generations in the background.Solid markers indicate peptides that were sequenced. (D) List of aportion of sequenced peptides from each library generation (shownwith solid markers in A–C). Residues shown in blue indicatewere picked from the pool of variable residues from their particularlibrary. (E) Selectivity with amino acids at the i + 2 position, which can be compared to the library with i + 2 Thr(Bn) directly to the left (C, third generation,blue). Product ratios were measured by GC. In all of the on-bead screeningstudies, the formation of diepoxides was intentionally limited throughthe use of 0.3 equiv of DIC, resulting in analysis of low-conversionreaction mixtures.

Mentions: A limited understandingof the importance of the residues within peptide 1 wasinitially derived from studies of the libraries leading to the discoveryof 1. The observation of a peptide that exhibited a modicumof selectivity for the 6,7-position of 2 (relative tothe 2,3- or 10,11-positions) was unexpected. In fact, the libraryfrom which this initial 6,7-selective “hit” derivedwas generated in order to study 2,3-selectivity. This library hadbeen designed such that two internal residues had been omitted fromthe original hexameric sequences.7 This shortened library of tetramerswas biased to contain a choice of d-amino acids adjacentto the catalytic N-terminal aspartic acid residue and two additionalC-terminal variable residues. The first peptide that was found toexhibit the alternate 6,7-selectivity, Boc-Asp-d-Pro-Thr(Bn)-Leu(Boc = tert-butoxycarbonyl, Bn = benzyl), exhibitedonly modest selectivity (4:5:6 = 1.3:1.5:1.0, point shown in Figure 1A).10 A subsequent library biased toward this initialhit was immediately prepared.7


Experimental lineage and functional analysis of a remotely directed peptide epoxidation catalyst.

Lichtor PA, Miller SJ - J. Am. Chem. Soc. (2014)

(A–C) Ternaryplots showing an overlay of peptide selectivitiesfrom successive generations of 6,7-selective peptides, where eachaxis represents the fraction of the total monoepoxide: (A) the firstlibrary demonstrating 6,7-selectivity (first generation, red); (B)the first biased library for 6,7-selectivity (second generation, green);(C) second biased library (third generation, blue). Points that arehigher (further away from the triangle base) are more 6,7-selective.The highlighted generation from each plot is in the solid color inthe foreground atop the other library generations in the background.Solid markers indicate peptides that were sequenced. (D) List of aportion of sequenced peptides from each library generation (shownwith solid markers in A–C). Residues shown in blue indicatewere picked from the pool of variable residues from their particularlibrary. (E) Selectivity with amino acids at the i + 2 position, which can be compared to the library with i + 2 Thr(Bn) directly to the left (C, third generation,blue). Product ratios were measured by GC. In all of the on-bead screeningstudies, the formation of diepoxides was intentionally limited throughthe use of 0.3 equiv of DIC, resulting in analysis of low-conversionreaction mixtures.
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Related In: Results  -  Collection

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fig1: (A–C) Ternaryplots showing an overlay of peptide selectivitiesfrom successive generations of 6,7-selective peptides, where eachaxis represents the fraction of the total monoepoxide: (A) the firstlibrary demonstrating 6,7-selectivity (first generation, red); (B)the first biased library for 6,7-selectivity (second generation, green);(C) second biased library (third generation, blue). Points that arehigher (further away from the triangle base) are more 6,7-selective.The highlighted generation from each plot is in the solid color inthe foreground atop the other library generations in the background.Solid markers indicate peptides that were sequenced. (D) List of aportion of sequenced peptides from each library generation (shownwith solid markers in A–C). Residues shown in blue indicatewere picked from the pool of variable residues from their particularlibrary. (E) Selectivity with amino acids at the i + 2 position, which can be compared to the library with i + 2 Thr(Bn) directly to the left (C, third generation,blue). Product ratios were measured by GC. In all of the on-bead screeningstudies, the formation of diepoxides was intentionally limited throughthe use of 0.3 equiv of DIC, resulting in analysis of low-conversionreaction mixtures.
Mentions: A limited understandingof the importance of the residues within peptide 1 wasinitially derived from studies of the libraries leading to the discoveryof 1. The observation of a peptide that exhibited a modicumof selectivity for the 6,7-position of 2 (relative tothe 2,3- or 10,11-positions) was unexpected. In fact, the libraryfrom which this initial 6,7-selective “hit” derivedwas generated in order to study 2,3-selectivity. This library hadbeen designed such that two internal residues had been omitted fromthe original hexameric sequences.7 This shortened library of tetramerswas biased to contain a choice of d-amino acids adjacentto the catalytic N-terminal aspartic acid residue and two additionalC-terminal variable residues. The first peptide that was found toexhibit the alternate 6,7-selectivity, Boc-Asp-d-Pro-Thr(Bn)-Leu(Boc = tert-butoxycarbonyl, Bn = benzyl), exhibitedonly modest selectivity (4:5:6 = 1.3:1.5:1.0, point shown in Figure 1A).10 A subsequent library biased toward this initialhit was immediately prepared.7

Bottom Line: We examined the selectivity of truncated analogues to find that a trimer is sufficient to furnish the remote selectivity.Both 1D and 2D (1)H NMR studies were used to determine possible catalyst conformations, culminating in proposed models showing possible interactions of farnesol with a protected Thr side chain and backbone NH.The models were used to rationalize the selectivity of a modified catalyst (17) for the 6,7-position relative to an ether moiety in two related substrates.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Yale University , P.O. Box 208107, New Haven, Connecticut 06520, United States.

ABSTRACT
We describe mechanistic investigations of a catalyst (1) that leads to selective epoxidation of farnesol at the 6,7-position, remote from the hydroxyl directing group. The experimental lineage of peptide 1 and a number of resin-bound peptide analogues were examined to reveal the importance of four N-terminal residues. We examined the selectivity of truncated analogues to find that a trimer is sufficient to furnish the remote selectivity. Both 1D and 2D (1)H NMR studies were used to determine possible catalyst conformations, culminating in proposed models showing possible interactions of farnesol with a protected Thr side chain and backbone NH. The models were used to rationalize the selectivity of a modified catalyst (17) for the 6,7-position relative to an ether moiety in two related substrates.

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