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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.

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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) Selected 1H–1H ROESY correlationsfound in 1 at 25 °C and truncated peptide 7 at −20 °C. (B) Two structural ensembles fromthe 20 CNS-generated structures of 1 computed using 25°C ROESY data. (C) One structure chosen from the 20 structuresshown with side chains.
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fig3: (A) Selected 1H–1H ROESY correlationsfound in 1 at 25 °C and truncated peptide 7 at −20 °C. (B) Two structural ensembles fromthe 20 CNS-generated structures of 1 computed using 25°C ROESY data. (C) One structure chosen from the 20 structuresshown with side chains.

Mentions: While the NH-Asn signals shift back upfield inthe spectra of pentamer 7 and hexamer 1 (relativeto 8), the observed Boc-NH shifts appearfurther downfield for both. Indeed, the spectra of the longer peptidesare difficult to interpret given the broadening of some peaks at thislow temperature. Nonetheless, 2D 1H–1H rotating-frame nuclear Overhauser effect spectroscopy (ROESY) datacorroborate the interpretation of a β-turn (Figure 3A). The spectra suggest a through-space correlationbetween the β-protons of the i Asp and i + 3 Asn(Trt) in spectra of 1 and 7 acquired at 25 and −20 °C, respectively. Additionally,these data suggest that the Hα-d-Pro is close to theamide protons of both the i + 2 Thr(Bn) and i + 3 Asn(Trt). Notably, many of the correlations foundin 1 at 25 °C are also found in truncated peptide 7 at −20 °C, indicating that the room-temperaturedata for 1 are likely relevant.


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

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

(A) Selected 1H–1H ROESY correlationsfound in 1 at 25 °C and truncated peptide 7 at −20 °C. (B) Two structural ensembles fromthe 20 CNS-generated structures of 1 computed using 25°C ROESY data. (C) One structure chosen from the 20 structuresshown with side chains.
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Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4333582&req=5

fig3: (A) Selected 1H–1H ROESY correlationsfound in 1 at 25 °C and truncated peptide 7 at −20 °C. (B) Two structural ensembles fromthe 20 CNS-generated structures of 1 computed using 25°C ROESY data. (C) One structure chosen from the 20 structuresshown with side chains.
Mentions: While the NH-Asn signals shift back upfield inthe spectra of pentamer 7 and hexamer 1 (relativeto 8), the observed Boc-NH shifts appearfurther downfield for both. Indeed, the spectra of the longer peptidesare difficult to interpret given the broadening of some peaks at thislow temperature. Nonetheless, 2D 1H–1H rotating-frame nuclear Overhauser effect spectroscopy (ROESY) datacorroborate the interpretation of a β-turn (Figure 3A). The spectra suggest a through-space correlationbetween the β-protons of the i Asp and i + 3 Asn(Trt) in spectra of 1 and 7 acquired at 25 and −20 °C, respectively. Additionally,these data suggest that the Hα-d-Pro is close to theamide protons of both the i + 2 Thr(Bn) and i + 3 Asn(Trt). Notably, many of the correlations foundin 1 at 25 °C are also found in truncated peptide 7 at −20 °C, indicating that the room-temperaturedata for 1 are likely relevant.

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.

Show MeSH