Angewandte
Communications
Chemie
Biocatalysis
Myoglobin-Catalyzed Olefination of Aldehydes
Vikas Tyagi and Rudi Fasan*
Abstract: The olefination of aldehydes constitutes a most
valuable and widely adopted strategy for constructing carbon–
carbon double bonds in organic chemistry. While various
synthetic methods have been made available for this purpose,
no biocatalysts are known to mediate this transformation.
Reported herein is that engineered myoglobin variants can
catalyze the olefination of aldehydes in the presence of a-
diazoesters with high catalytic efficiency (up to 4,900 turn-
overs) and excellent E diastereoselectivity (92–99.9% de). This
transformation could be applied to the olefination of a variety
of substituted benzaldehydes and heteroaromatic aldehydes,
also in combination with different alkyl a-diazoacetate
reagents. This work provides a first example of biocatalytic
aldehyde olefination and extends the spectrum of synthetically
valuable chemical transformations accessible using metallo-
protein-based catalysts.
We and others have recently reported the ability of heme-
[
7]
dependent metalloproteins such as cytochrome P450s and
[
8]
myoglobin to engage diazo-containing reagents in carbene-
transfer reactions. In particular, we recently discovered that
engineered variants of myoglobin can provide particularly
[8a]
efficient catalysts for olefin cyclopropanation, carbene NH
[8b]
[8c]
insertion,
and carbene SH insertion reactions
in the
presence of a-diazo ester reagents. Our mechanistic studies
supported the intermediacy of an electrophilic heme/carbene
[8a]
complex which reacts with a nucleophilic olefin, amine, or
mercaptan to yield the carbene insertion adduct. These
studies also showed the possibility to generate a transient
sulfonium ylide intermediate upon attack of a thiol substrate
[8c]
to the myoglobin-bound carbenoid species. Building upon
these findings and inspired by pioneering studies conducted
[4j,l]
by Woo and co-workers with metalloporphyrins,
we
hypothesized that an analogous process could be exploited
in the presence of tertiary phosphine nucleophiles to yield
a myoglobin-bound phosphonium ylide. We further envi-
sioned the latter could react with an aldehyde to yield an
olefin through a Wittig reaction, with the active site of the
protein potentially furnishing an asymmetric environment to
influence the stereoselectivity of the reaction. Herein, we
report that engineered variants of myoglobin can mediate
aldehyde olefination reactions across a range of aldehydes
and a-diazoacetates with high catalytic activity and E selec-
tivity. This transformation proceeds in buffer and at room
temperature, thus providing an extremely mild biocatalytic
route for the olefination of aryl and benzylic aldehydes.
Guided by the hypothesis outlined above, we began our
studies by testing the ability of wild-type sperm whale
myoglobin to promote the conversion of benzaldehyde (1a)
and ethyl a-diazo acetate (EDA; 2a) to ethyl cinnamate (3a)
[
1]
T
he Wittig reaction represents one of the most valuable
and broadly adopted routes for the construction of olefinic
[2]
bonds during the synthesis of organic molecules. Classically,
this method involves the reaction between carbonyl com-
pounds and phosphonium ylides, which are prepared by
[3]
deprotonation of the corresponding phosphonium salts.
Because of the basic conditions required for the latter
process, there has been a significant interest toward develop-
ing alternative methods to enable the olefination of aldehydes
under milder, neutral reaction conditions. In this regard, the
transition metal catalyzed transformation of carbonyls in the
presence of diazo compounds and tertiary phosphines has
provided a particularly attractive strategy because of the
[4]
ready accessibility of these reagents. Over recent years,
a number of organometallic catalysts including Mo, Re,
[4a]
[4b–d]
[
4e]
[4f]
[4g,h]
[4i]
[4j–o]
Rh, Ir, Ru,
Cu, and Fe
complexes, have proven
useful in this transformation, yielding E-configured olefins
with modest to good catalytic activity (typically, 50-300
turnovers) and moderate to high E selectivity (typically, 70–
in the presence of triphenylphosphine (PPh ). To our delight,
3
we observed formation of the desired product 3a with good
diastereoselectivity (76% de for E isomer), albeit with only
modest activity [31 turnovers (TON); Table 1, entry 3]. Both
reducing (Na S O ) and oxygen-free conditions were found to
9
8% de). In contrast to the important progress made in the
development of synthetic catalysts for aldehyde olefination,
2
2
4
[5]
no natural enzyme or artificial biocatalysts has been
reported to promote this valuable transformation. An alde-
hyde olefination biocatayst would thus represent a valuable
addition to the toolbox of currently available enzymes for
be required for the observed Mb-dependent aldehyde olefi-
nation activity, indicating that the ferrous form of the
hemoprotein is involved in the activation of the diazo
compound. Additional experiments showed that hemin can
also promote this transformation, but with reduced catalytic
efficiency (22 TON) and lower diastereoselectivity (65% de)
as compared to Mb (Table 1, entry 1). In addition, the hemin
reaction is much less chemoselective, yielding larger amounts
of the carbene dimerization byproducts, diethyl fumarate, and
diethyl maleate (TON(3a)/TON(4a): 0.4 vs. 2.8 with Mb,
Table 1). In an effort to improve the efficiency and selectivity
of the Mb-mediated olefination reaction, a variety of trialkyl
[
6]
asymmetric synthesis .
[
*] Dr. V. Tyagi, Prof. Dr. R. Fasan
Department of Chemistry, University of Rochester
1
20 Trustee Road, Rochester, NY 14627 (USA)
E-mail: fasan@chem.rochester.edu
phosphines [e.g., PEt , P(tBu) , P(nBu) ] as well as heavier
3
3
3
congeners of PPh (i.e., AsPh , SbPh , and BiPh ) were tested
3
3
3
3
2512
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 2512 –2516