Selective Enzymatic Oxidation of Silanes to Silanols

Article abstract of DOI:10.1002/anie.202002861

Compared to the biological world's rich chemistry for functionalizing carbon, enzymatic transformations of the heavier homologue silicon are rare. We report that a wild-type cytochrome P450 monooxygenase (P450_BM3 from Bacillus megaterium, CYP102A1) has promiscuous activity for oxidation of hydrosilanes to give silanols. Directed evolution was applied to enhance this non-native activity and create a highly efficient catalyst for selective silane oxidation under mild conditions with oxygen as the terminal oxidant. The evolved enzyme leaves C?H bonds present in the silane substrates untouched, and this biotransformation does not lead to disiloxane formation, a common problem in silanol syntheses. Computational studies reveal that catalysis proceeds through hydrogen atom abstraction followed by radical rebound, as observed in the native C?H hydroxylation mechanism of the P450 enzyme. This enzymatic silane oxidation extends nature's impressive catalytic repertoire.

Full text of DOI:10.1002/anie.202002861

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Accepted Article
Title: Selective Enzymatic Oxidation of Silanes to Silanols
Authors: Susanne Bähr, Sabine Brinkmann-Chen, Marc Garcia-Borràs,
John M. Roberts, Dimitris E. Katsoulis, Kendall N. Houk, and
Frances H. Arnold
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202002861
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Selective Enzymatic Oxidation of Silanes to Silanols
Susanne Bähr,[a] Sabine Brinkmann-Chen,[a] Marc Garcia-Borràs,[b,e] John M. Roberts,[c] Dimitris E.
Katsoulis,[d] Kendall N. Houk[b] and Frances H. Arnold*[a]
Abstract: Compared to the biological world’s rich chemistry for
functionalizing carbon, enzymatic transformations of the heavier
homologue silicon are rare. We report that a wild-type cytochrome
P450 monooxygenase (P450BM3 from Bacillus megaterium,
CYP102A1) has promiscuous activity for oxidation of hydrosilanes to
make silanols. Directed evolution enhanced this non-native activity
and created a highly efficient catalyst for selective silane oxidation
under mild conditions with oxygen as terminal oxidant. The evolved
enzyme leaves C–H bonds present in the silane substrates untouched,
and this biotransformation does not lead to disiloxane formation, a
common problem in silanol syntheses. Computational studies reveal
that catalysis proceeds through hydrogen atom abstraction followed
by radical rebound, as observed in the P450’s native C–H
hydroxylation mechanism. Enzymatic silane oxidation now extends
Nature’s impressive catalytic repertoire.
Silanols are widely used[1] to build silicone polymers[2], which are
Scheme 1. Synthesis of silanols (top) and native vs. evolved activity of P450s
(bottom).
found in an enormous number of modern lifestyle products.
Silanols are also synthetic intermediates in organic synthesis[3],
catalysts,[4] and serve as functionally interesting isosteres for
bioactive molecules.[5] The selective and mild synthesis of silanols
In most cases, these are hydrolytic processes, i.e. water is the
has received substantial attention and remains of high interest.[1]
oxidant, and stoichiometric amounts of dihydrogen are released
Protocols that start from functionalized precursors such as
(Scheme 1, top, a). This process is also exothermic, which
chlorosilanes[6] or use strong oxidants[7] in combination with
presents a safety issue when dihydrogen is evolved. Furthermore,
hydrosilanes often result in disiloxane formation, lead to other side
contamination with disiloxane is often unavoidable, as the silanol
reactions, or generate waste products in substantial amounts.
product can react with the activated hydrosilane instead of water.
Direct catalytic hydrosilane oxidation is an attractive alternative,
Some catalysts can also catalyze silanol self-condensation to
and several methods have been developed, most of which rely on
yield disiloxanes. A limited number of protocols use other oxidants
precious metals;[8] base-metal catalysts[9] or metal-free
like oxygen or hydrogen peroxide together with base metals[9d–g]
transformations[10] are rare.
or even metal-free, though very basic, conditions (Scheme 1, top,
b).[10] Few reported selective syntheses of silanols employ
[a]
[b]
Dr. S. Bähr, Dr. S. Brinkmann-Chen, Prof. F. H. Arnold
Division of Chemistry and Chemical Engineering
California Institute of Technology
1200 East California Blvd, Pasadena, CA 91125 (USA)
E-mail: frances@cheme.caltech.edu
Dr. M. Garcia-Borràs, Prof. K. N. Houk
Department of Chemistry and Biochemistry
University of California
environmentally friendly catalysts, proceed under mild reaction
conditions, and avoid competing side reactions.[1] We
hypothesized that a biocatalytic protocol employing nature’s
versatile oxidation catalysts could be a valuable complement to
existing synthetic methods.
Los Angeles, CA 90095 (USA)
Dr. J. M. Roberts,
Dow Core R&D
633 Washington Street, Midland, MI 48674 (USA)
Dr. D.E. Katsoulis
Even though silicon is the second most abundant element in the
Earth’s crust, the silicon chemistry of the biological world is very
limited. Diatoms, for example, can incorporate ortho-silicic acid as
stabilizing units in skeletons and materials; this process is usually
based on the hydrolysis or alcoholysis of Si–O bonds.[15,16] Also,
biocatalytic approaches for the formation of silicon polymers and
small molecules are limited to the formation of Si–OR bonds
through condensation reactions.[16] Although enzymatic
manipulations of functional groups in the neighborhood of or
remote to the silicon in various organosilicon compounds have
been reported,[17] the direct biocatalytic functionalization of silicon
[c]
[d]
[e]
Dow Silicones Corporation
2200 Salzburg Rd, Auburn, MI 48611 (USA)
Present address: Dr. M. Garcia-Borràs
Institut de Química Computacional i Catàlisi (IQCC)
Departament de Química, Universitat de Girona
Girona, Spain
Supporting Information for this article is given via a link at the end of the
document.
centers remained unknown until this group engineered
a
cytochrome c in 2016 to catalyze carbene insertion into Si–H
bonds in vitro and in vivo.[18] Biocatalytic oxidation of silanes to
silanols is unknown.[19]
1
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Figure 1. Activity of P450BM3 variants in whole cells (green) or lysate (blue) over the course of directed evolution and under optimized conditions (red), given as total
turnover number for silanol production. See the Supporting Information for experimental details. B) Structure of wild-type cytochrome P450BM3 (PDB: 1JPZ)[22]
showing bound heme cofactor. Amino acid residues mutated during evolution are highlighted in orange (A = alanine, F = phenylalanine, L = leucine; NADPH =
nicotinamide adenine dinucleotide phosphate).
The ubiquitous cytochrome P450 enzymes catalyze a range of
oxidative reactions using atmospheric oxygen as terminal
oxidant.[11,12] These transformations typically proceed via a
reactive, high-valent iron-oxene intermediate (Compound I,
Scheme 1, bottom),[13] which undergoes, for example,
hydroxylations or epoxidations with C–H or C=C bonds.[14] We
envisioned that we could use the natural promiscuity of P450s and
repurpose a native enzyme for the efficient and selective oxidation
of hydrosilanes using directed evolution.
discover potential beneficial epistatic interactions between these
sites. Screening identified only a single beneficial mutation,
A328L, which further increased the yield of silanol 2a to 8.5% (850
TTN) using 2nd-generation variant P450SiOx2. A further round of
double site-saturation mutagenesis at residues L181 and A184[25]
led to the discovery of mutations L181D and A184H in P450SiOx3
,
which improved the TTN to 1,200.
We also compared the performance of wild-type P450BM3 and the
final variant P450SiOx3 in E. coli lysate, which requires the addition
of the cofactor NADPH in stoichiometric amounts (Figure 1A, blue
bars). Turnover numbers were generally higher in lysate than in
whole cells, which we ascribe to the absence of a diffusion barrier
for the substrate and product through the cell wall and the limited
availability of NADPH in whole cells. The final variant P450SiOx3
proved superior in lysate as well, with 3,620 TTN (36% yield of
2a) compared to 1740 (17% yield) for wild-type P450BM3. We next
investigated the effect of changing various conditions on the
production of 2a (Figure 1A, red bars; see Supporting Information).
Running the reaction for 48 h at 37 °C substantially increased the
yield, now delivering silanol 2a with 2,400 TTN and also indicating
that the protein retains activity over this time. Furthermore, the
yield of 2a was almost as high at a lower catalyst loading (0.1 µM
protein concentration), resulting in remarkably high TTNs of
19,100. Even though these conditions show the potential of
variant P450SiOx3, the yield of 2a obtained in this setup is not
synthetically useful. Increasing the protein concentration to 8.1–
9.0 µM and lowering the substrate concentration to 5.0 mM, we
were able to achieve the transformation of 1a to 2a in quantitative
yield as determined by GC analysis (76% isolated yield after 72 h
at 37 °C; Scheme 2). Similarly, ethyl-substituted silanol 2b was
formed in high yield. The conversion of vinylsilane 1c to silanol 2c
was lower, but chemoselectivity was good, and epoxidation of the
double bond was not observed.[26] Both 2b and 2c are silicon-
stereogenic, but as we expect configurational lability on the silicon
center of acyclic silanols under aqueous, slightly basic conditions,
we did not attempt to monitor enantioselectivity.[27]
We chose cytochrome P450BM3 (CYP102A1) from the soil
bacterium Bacillus megaterium[12] to investigate Si–H oxidation
activity. This self-sufficient monooxygenase is a 118-kDa enzyme
with its NADPH-dependent reductase domain fused to the C-
terminus of the heme domain; it has served as a robust scaffold
for directed evolution of hydroxylation activity in previous work.[20]
We tested the ability of wild-type P450BM3 to oxidize
dimethylphenylsilane (1a) in Escherichia coli (E. coli) cells under
aerobic conditions (Figure 1A). The enzyme delivered product 2a
with 210 TTN in 2.1% yield at 1.0 µM protein concentration. A
negligible amount of 2a was observed in control reactions under
anaerobic conditions and otherwise identical setup, indicating that
oxygen serves as the oxidant (see Supporting Information). We
then used directed evolution by sequential rounds of saturation
mutagenesis at selected amino acid residues to increase the
enzyme’s activity for hydrosilane oxidation. Mutations at a number
of amino acid residues in P450BM3 are known to affect oxidation
activity.[20] We chose F87 as a first target for directed evolution
due to its close proximity to the heme cofactor (Figure 1B).[21]
A
single site-saturation mutagenesis (NNK) library was screened in
whole E. coli cells, from which we identified improved variant
P450SiOx1 (containing mutation F87G) with a 1.5-fold improvement
in both yield and TTN of product 2a (Figure 1A). Subsequently,
we targeted residues T327 and A328 with double site-saturation
mutagenesis using the 22-codon trick.[23] These residues are
close to the iron cofactor in the distal heme-binding pocket, and
mutations at these positions have influenced performance and
selectivity in previous engineering studies.[24] A double site-
saturation mutagenesis strategy was chosen in an attempt to
2
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subsequently undergoes a barrierless process (TS2) where
hydroxyl rebound occurs to yield the final silanol product 2a. The
hydrogen atom abstraction corresponds to the rate-limiting step
of the overall reaction (ΔG‡ = 18.1 kcal·mol–1). We also explored
the possibility of silyl cation formation, which might be formed
through electron transfer (ET) from the silyl radical to the
porphyrin–Fe–OH species (Figure 2C). This step was found to be
thermodynamically unfavorable (ΔG = 10.2 kcal·mol–1 for 1a); in
contrast, the OH rebound step is barrierless (see Figure S1),
hence silyl cation formation is unlikely. We found similar energy
barriers for the rate-limiting hydrogen atom abstraction when
using benzyldimethylsilane (1d, ΔG‡ = 19.6 kcal·mol–1) or a
simple siloxane (HMe2Si–O–SiMe2H, ΔG‡ = 17.7 kcal·mol–1) as
substrate. This is expected, since C–Si bonds are longer than C–
C bonds, and orbital overlap and resonance stabilization by
phenyl of the radical intermediate at the silicon center is less
effective (see Figure S5).[29] Thus, Si–H-bond strengths are less
prone to vary substantially with the substitution pattern.[28] We
concluded that the limitations we observe in the substrate scope
are related to potential issues with binding the substrate in a
catalytically competent pose and steric effects, which the
truncated DFT model does not account for, and not to intrinsic Si–
H-bond strengths or electronic effects.
Scheme 2. Substrate scope of P450SiOx3. GC yields are given as average of
triplicate runs (see the Supporting Information for further details). a Isolated yield
after 72 h at 37 °C in parentheses. b No conversion to the silanol observed.
Silanol 2d was obtained in good yield as well, again showing that
a certain degree of steric flexibility close to the silicon center is
accepted. Conversely, steric congestion of the aromatic ring
limited reactivity: whereas a methyl group at the para-position of
the aryl substituent in 2e was still tolerated, increasing the steric
bulk thwarted the reaction so that isopropyl-substituted 2f was not
formed. C–H oxidation in the benzylic positions did not occur for
1d and 1e.[28] The performance of the catalyst on electronically
similar hydrosilanes 1g and 1h again indicates a certain size
limitation. The smaller thiophenyl substituent was accepted and
2g was obtained in 64% yield; we did not observe the formation
of 2h. Methyldiphenylsilane (1i) as well as aliphatic hydrosilanes
1j and 1k reacted selectively to the corresponding silanols 2i–k,
albeit with lower yields. Notably, siloxane 1l was oxidized to 2l,
even though uncatalyzed background hydrolysis occurred in
significant amounts (see Supporting Information). It is worth
noting that, if moderate or low yields of the silanols were obtained,
they are a consequence of incomplete conversion of the starting
hydrosilane. Products of competing C–H or C=C oxidation were
not observed, nor was the formation of disiloxanes.
Figure 2. A) Computed mechanism for FeIV–oxene-catalyzed oxidation of 1a to
2a. B) DFT-optimized, lowest energy and rate-determining H atom abstraction,
transition state TS1 and radical intermediate INT1 (quartet electronic state). The
spin density localized at the Si atom (ꢀspin(Si)) in INT1 is shown. C) The
endergonic (ΔG = 10.2 kcal·mol–1) electron transfer for the silyl cation formation
pathway reinforces the conclusion that the radical oxidation pathway is the most
plausible. Key distances are given in Å and angles in degrees.
Overall, the Si–H-oxidation mechanism described here is similar
to the mechanism for native P450-catalyzed C–H oxidation,[12]
and it involves the same FeIV-oxene catalytic intermediate and
sequence of hydrogen atom abstraction and rebound. The high
chemoselectivity observed for Si–H oxidations over C–H can be
directly attributed to the lower bond dissociation energy (BDE) of
the Si–H bond as compared to the sterically accessible C–H
bonds from the Si–Me groups (see Figure S5). This DFT study
confirms that the P450 enzyme can adapt its native mechanism
to oxidize hydrosilanes, and it also explains the absence of
disiloxane side products which would require the activation of the
hydrosilane to invite attack of the silanol.
To explain this selectivity, we investigated the mechanism of the
P450-catalyzed Si–H oxidation in further detail using density
functional theory (DFT) calculations of a truncated computational
model (Figure 2A, see Supporting Information for computational
details). This model consists of an iron–porphyrin pyrrole core and
methanethiol as axial ligand, mimicking the heme cofactor bond
to a cysteine in the enzyme active site. The calculations indicate
that the oxidation of dimethylphenylsilane (1a) proceeds through
a transition state (TS1, Figure 2A–B) in which hydrogen atom
transfer (HAT) from the hydrosilane to an FeIV-oxene intermediate
generates a silyl radical (INT1, Figures 2A–B). This intermediate
3
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(S), 1997, 400–401; d) M. Yu, H. Jing, X. Liu, X. Fu, Organometallics
2015, 34, 5754–5758 (both Rh); e) Y. Kikukawa, Y. Kuroda, K.
Yamaguchi, N. Mizuno, Angew. Chem. 2012, 124, 2484–2487; Angew.
Chem. Int. Ed. 2012, 51, 2434–2437 (Ag); f) Y. Lee, D. Seomoon, S. Kim,
H. Han, S. Chang, P. H. Lee, J. Org. Chem. 2004, 69, 1741–1743 (Ir); g)
E. A. Ison, R. A. Corbin, M. M. Abu-Omar, J. Am. Chem. Soc. 2005, 127,
11938–11939 (Re).
In summary, we have engineered a fully genetically encoded
catalyst capable of functionalizing silicon-containing compounds
inside and outside cells, expanding our ability to manipulate this
element in living systems. Three rounds of directed evolution
created a highly active variant with four mutations from wild-type
P450BM3. This work demonstrates that P450s are easily evolvable
for unnatural hydrosilanes, although yields are currently limited for
sterically hindered and trialkyl silanols. Furthermore, this
renewable, iron-based biocatalyst shows high selectivity for
forming silanols instead of disiloxanes; it also favors Si–H over
the native C–H and C=C oxidation. This ability to enzymatically
oxidize hydrosilanes in concert with previously identified
biocatalysts for C–Si bond formation[18] could offer access to a
range of useful organosilicon compounds in engineered microbial
systems and open more sustainable paths to producing the
silicon-containing molecules that have become ubiquitous in our
modern world.
[9]
Base metals in hydrolytic processes: a) E. Matarasso-Tchiroukhine, J.
Chem. Soc., Chem. Commun. 1990, 681–682 (Cr, no selectivity for the
silanol); b) U. Schubert, C. Lorenz, Inorg. Chem. 1997, 36, 1258–1259
(Cu, low selectivity for the silanol); c) A. K. Liang Teo, W. Y. Fan, Chem.
Commun. 2014, 50, 7191–7194 (Fe). A Te complex with O2: d) Y. Okada,
M. Oba, A. Arai, K. Tanaka, K. Nishiyama, W. Ando, Inorg. Chem. 2010,
49, 383–385. A Ti zeolite with H2O2: e) W. Adam, H. Garcia, C. M.
Mitchell, C. R. Saha-Möller, O. Weichold, Chem. Commun. 1998, 2609–
2610. A Mn complex with H2O2: f) K. Wang, J. Zhou, Y. Jiang, M. Zhang,
C. Wang, D. Xue, W. Tang, H. Sun, J. Xiao, C. Li, Angew. Chem. 2019,
131, 6446–6450; Angew. Chem. Int. Ed. 2019, 58, 6380–6384. Cu- or
Co-catalysis with O2: g) A. V. Arzumanyan, I. K. Goncharova, R. A.
Novikov, S. A. Milenin, K. L. Boldyrev, P. N. Solyev, Y. V. Tkachev, A. D.
Volodin, A. F. Smol’yakov, A. A. Korlyukov, A. M. Muzafarov, Green
Chem. 2018, 20, 1467–1471. For heterogeneous, hydrolytic Ni-catalysis,
see ref. [8a].
Acknowledgements
[10] Metal-free protocols, both at pH 11: a) D. Limnios, C. G. Kokotos, ACS
Catal. 2013, 3, 2239–2243; b) A. T. Kelly, A. K. Franz, ACS Omega 2019,
4, 6295–6300.
This work was supported by the Dow University Partnership
Initiative (227027AO), the Rothenberg Innovation Initiative (RI2)
Program (F.H.A.), the NIH National Institute for General Medical
[11] P. Manikandan, S. Nagini, Curr. Drug Targets 2018, 19, 38–54.
[12] C. J. C. Whitehouse, S. G. Bell, L.-L. Wong, Chem. Soc. Rev. 2012, 41,
1218–1260.
Sciences
GM-124480
(K.N.H.),
the
Deutsche
Forschungsgemeinschaft (DFG) Postdoctoral Fellowship (BA
6604/1-1 to S.B.), and the Spanish MINECO (JdC-I contract IJCI-
2017-33411 to M.G.-B.). We thank N. W. Goldberg, Dr. S. B. J.
Kan, and A. M. Knight for productive discussions, and Dr. Zhijun
Jia for experimental assistance.
[13] J. Rittle, M. T. Green, Science 2014, 330, 933–938.
[14] a) E. M. Isin, F. P. Guengerich, Biochim. Biophys. Acta. 2007, 3, 314–
329; b) P. R. Ortiz de Montellano, Chem. Rev. 2010, 110, 932–948; c) S.
Shaik, S. Cohen, Y. Wang, H. Chen, D. Kumar, W. Thiel, Chem. Rev.
2010, 210, 949–1017.
[15] P. Treguer, D. M. Nelson, A. J. V. Bennekom, D. J. DeMaster, A.
Leynaert, B. Quéguiner, Science 1995, 268, 375–379.
[16] M. B. Frampton, P. M. Zelisko, Chem. Asian J. 2017, 12, 1153–1167.
[17] M. B. Frampton, P. M. Zelisko, Silicon 2009, 1, 147–163.
[18] S. B. J. Kan, R. D. Lewis, K. Chen, F. H. Arnold, Science 2016, 354,
1048–1051.
Keywords: biocatalysis • CYP102A1 • monooxygenation •
silanols • synthetic methods
[1]
a) M. Jeon, J. Han, J. Park, ACS Catal. 2012, 2, 1539–1549; b) V.
Chandrasekhar, R. Boomishankar, S. Nagendran, Chem. Rev. 2004,
104, 5847–5910.
[19] The oxidation of hydrosilanes in rats was reported almost fifty years ago,
but an enzyme responsible for this transformation has never been
identified: R. J. Fessenden, R. A. Hartman, J. Med. Chem. 1970, 13, 52–
54.
[2]
A. Colas, Silicones: Preparation, Properties and Performance; Dow
Corning, Life Sciences, 2005.
[20] S. T. Jung, R. Lauchli, F. H. Arnold, Curr. Opin. Biotech. 2011, 22, 809–
817.
[3]
a) S. E. Denmark, C. S. Regens, Acc. Chem. Res. 2009, 41, 1486–1499;
b) M. Mewald, J. A. Schiffner, M. Oestreich, Angew. Chem. 2012, 124,
1797–1799; Angew. Chem. Int. Ed. 2012, 51, 1763–1765; c) S. E.
Denmark, A. Ambrosi, Org. Process Res. Dev. 2015, 19, 982–994.
Especially silanediols in catalysis: a) K. M. Diemoz, J. E. Hein, S. O.
Wilson, J. C. Fettinger, A. K. Franz, J. Org. Chem. 2017, 82, 6738–6747
and references cited therein. b) A. G. Schafer, J. M. Wieting, T. J. Fisher,
A. E. Mattson, Angew. Chem. 2013, 125, 11531–11534; Angew. Chem.
Int. Ed. 2013, 52, 11321–11324.
[21] H. Li, T. L. Poulos, Biochim. Biophys. Acta 1999, 1441, 141–149.
Whereas F87, A328 and L181 are important for substrate recognition,
A184 plays a role in the thermostability of P450BM3 variants. See Ref. [20].
[22] D. C. Haines, D. R. Tomchick, M. Machius, J. A. Peterson, Biochemistry
2001, 40, 13456–13465.
[4]
[23] S. Kille, C. G. Acevedo-Rocha, L. P. Parra, Z. G. Zhang, D. J. Opperman,
M. T. Reetz, J. P. Acevedo, ACS Synth. Biol. 2013, 2, 83–92.
[24] Examples for the mutation of site A328: a) G. Roiban, M. T. Reetz, Chem.
Comm. 2015, 51, 2208–2224 and cited references. For a recent example,
see: b) H. Zhou, B. Wang, F. Wang, X. Yu, L. Ma, A. Li, M. T. Reetz,
Angew. Chem. 2019, 131, 774–778; Angew. Chem. Int. Ed. 2019, 58,
764–768. See also Ref. [20].
[5]
a) A. K. Franz, S. O. Wilson, J. Med. Chem. 2013, 56, 388–405; b) R.
Ramesh, D. S. Reddy, J. Med. Chem. 2018, 61, 3779–3798.
J. A. Cella, J. C. Carpenter, J. Organomet. Chem. 1994, 480, 23–36.
Selected examples: a) P. D. Lickiss, R. Lucas, J. Organomet. Chem.
1995, 521, 229–234 (KMnO4); b) K. Valliant-Saunders, E. Gunn, G. R.
Shelton, D. A. Hrovat, W. T. Borden, J. M. Mayer, Inorg. Chem. 2007, 46,
5212–5219 (OsO4); c) W. Adam, R. Mello, R. Curci, Angew. Chem. 1990,
102, 916–917; Angew. Chem. Int. Ed. Engl. 1990, 29, 890–891
(dioxirans); d) L. H. Sommer, L. A. Ulland, G. A. Parker, J. Am. Chem.
Soc. 1972, 94, 3469–3471 (peracids). See also Ref [1].
[6]
[7]
[25] For the importance of sites 181 and 184, see for example: K. Zhang, B.
M. Shafer, M. D. Denars II, H. A. Stern, R. Fasan, J. Am. Chem. Soc.
2012, 134, 18695–19704.
[26] Double-bond epoxidation was observed for example in a manganese-
catalyzed protocol with H2O2 as oxidant, see Ref. [9f].
[27] a) R. J. P. Corriu, C. Guerin, J. Organomet. Chem. 1980, 198, 231–320;
b) C. Chuit, R. J. P. Corriu, C. Reye, J. C. Young, Chem. Rev. 1993, 93,
1371–1448.
[8]
The use of Pt, Pd, Au, Ag, Ru and Ni as heterogeneous catalysts is
reported. Leading reference: a) G. H. Barnes, Jr., N. E. J. Daughenbaugh,
J. Org. Chem. 1966, 31, 885–887. See also Ref [1]. Hydrolytic,
homogeneous catalysis: b) M. Lee, S. Ko, S. Chang, J. Am. Chem. Soc.
2000, 122, 12011–12012 (Ru); c) M. Shi, K. M. Nicholas, J. Chem. Res.
[28] For a comparison of Si–H and C–H bond strengths, see a) R. Walsh, Acc.
Chem. Res. 1981, 14, 246–252; b) S. J. Blanksby, G. B. Ellison, Acc.
Chem. Res. 2003, 36, 255–263 (BDE of benzylic C–H bonds: 89.8
4
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kcal/mol). Phenyl-substitution weakens the Si–H bond strength by ca. 2
kcal/mol: c) C. Chatgilialoglu, Acc. Chem. Res. 1992, 25, 188–194 (BDE
of Ph3Si–H: 84 kcal/mol, Et3Si–H: 91 kcal/mol). For reviews, see also: d)
B. Tumanskii, M. Karni, Y. Apeloig in Organosilicon Compounds Theory
and Experiment (Synthesis) (Ed.: V. Y. Lee), Elsevier, Academic Press,
2017, pp. 231–294; e) B. Tumanskii, M. Karni, Y. Apeloig in Encyclopedia
of Radicals in Chemistry, Biology and Materials, Vol. 4 (Eds.: C.
Chatgilialoglu, A. Studer), J. Wiley, Chichester, 2012, pp. 2117–2146.
[29] a) W. S. Sheldrick in The Chemistry of Organic Silicon Compounds, Vol.
1 (Eds.: S. Patai, Z. Rapport), Wiley, Chichester, 1989, pp. 227‒303; b)
I. V. Alabugin in Stereoelectronic Effects: A Bridge Between Structure
and Reactivity, Vol.1, John Wiley & Sons, Hoboken, 2016, 1–392.
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10.1002/anie.202002861
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In rerum natura: Wild-type cytochrome P450BM3 catalyzes the oxidation of hydrosilanes to silanols both in vivo and in vitro. Directed
evolution is used to generate an efficient and selective biocatalyst that delivers a broad range of aryl- and alkylsubstituted silanols.
Computational studies reveal a sequence of H atom abstraction and OH rebound as the mechanism, in analogy to the native C–H
hydroxylation activity.
Institute and/or researcher Twitter usernames: @francesarnold
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