Chemical Science
Edge Article
mutation toward enhancing the catalytic activity of the hemo-
protein (Fig. 1). Given its location in the active site (Fig. 2), this
substitution is expected to expand the distal cavity above the
heme, thereby better accommodating the aryl/alkyl group of the
thiol substrate aer attack to the electrophilic carbene moiety
References
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2
group (R group, Scheme 3). Consistent with this hypothesis,
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8b
N–H insertion, in which a mechanism similar to that of
18
Scheme 3 could be operative, but not for Mb-catalyzed cyclo-
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1
i
olen to the heme-bound carbenoid. Finally, it is worth
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1i
reactions, a Hammett analysis of the relative rates of S–H
insertion for different para-substituted thiophenol derivatives
(
i.e., 11–13, 15) versus thiophenol did not yield a linear corre-
+
lation for the corresponding plot of log(k /k ) against s (or s )
X
H
(
Fig. S4†). While multiple factors could contribute to this
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phenomenon, these results remain consistent with the mech-
anistic scenario outlined above. Indeed, according to it, the aryl
ring of these substrates is expected to come in close proximity to
residues within the distal pocket of the protein. As such, both
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Conclusions
Myoglobin has represented an attractive scaffold for biocatalyst
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19
development. This work demonstrates that engineered Mb
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insertion reactions, providing the rst example of a biocatalyst
capable of supporting this valuable transformation. These
Mb-based catalysts were found to offer high catalytic activity
(
1100–5400 TON) across a wide range of aryl and alkyl
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mercaptan substrates as well as across different a-diazo esters
as carbene precursors. Their potential utility for synthetic
applications is further supported by proof-of-principle demon-
strations of their ability to catalyze asymmetric S–H insertions
and of the scalability of these reactions. Initial insights into the
mechanism of this reaction were gleaned through the present
studies, which can provide a basis for further optimization of
the activity and selectivity of these biocatalysts. Finally, the
ability of these hemoproteins to catalyze the [2,3]-sigmatropic
rearrangement of allyl sulphides (36 / 38) is another notable
nding of this work and the scope of this transformation is
currently under investigation in our laboratory.
Acknowledgements
2014, 22, 5697; (e) R. Singh, J. N. Kolev and P. A. Sutera,
This work was supported by the U.S. National Institute of Health
grant GM098628. MS instrumentation was supported by the
U.S. NSF grant CHE-0946653.
ACS Catal., 2015, 5, 1685–1691.
Chem. Sci.
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