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M. Mantel et al. / Tetrahedron xxx (2018) 1e9
2.2.3. Application
As already mentioned in the introduction, the potential appli-
cability of the products 4/5 provided by the presented methods is
multifarious. While utilizations in polymer science should also be
feasible, one selected example for the synthesis of
intermediate applied in total synthesis shall be given:
a key-
The set of building blocks 9 has a long history in the construc-
tion of complex natural products, often polyketides, and their de-
rivatives. Beginning in the late 1980's, especially Paterson and co-
workers as well as White and co-workers have coined the very
efficient preparation of ketones 9 starting from enantiomerically
pure propionates 10 with few losses over a three step reaction
sequence including benzylation, Weinreb amide formation or hy-
drolysis and methylation.80 Ever since, the value of this flexible
synthetic procedure has been honoured extensively by various
applications also in the more recent past.63,69,71
We herein present the utilization of 3-(benzyloxymethyl)but-3-
en-2-one (5a) obtained via the one-pot-etherification: The product
5a was subjected to an asymmetric hydrogenation reaction using
conditions known for very similar substrates.20,82 To our delight,
the ene reductase YqjM83 of the Old Yellow Enzyme family enabled
the stereoselective reduction of the double-bond on a gram scale in
good yields of 78%. Inherent to this method, the ketone function-
ality and the benzyl protection group remained intact. Starting
from rather inexpensive methyl vinyl ketone (3a), enantiomerically
pure building block 9a could be prepared on a gram-scale in two
reactions with fair overall yields of 48% (Scheme 5). In comparison
to the established methods for the preparation of ketone 9a, not
only a short, but also very efficient route could be presented.
Namely, the high atom economy of both steps using extremely
inexpensive bulk chemicals, low catalyst loadings and sustainable,
yet highly selective biocatalysts make the shown approach worth
being pursued on both, an economic and a synthetic level.
Scheme 6. Overview established MBH and MBH-one-pot etherification methodology
and application in building block synthesis.
MBH-type reactions could be achieved in short reaction times.
While doing so, low loadings (5 mol%) of the inexpensive organo-
catalyst DABCO (1) proved to be sufficient. Upon a slightly varied
setup, yields for aromatic vinyl ketones 3c-d were even found to be
further more increased. The original setup could then be used for an
in situ etherification, if intended. Simple heating after completion of
the MBH reaction allowed an easy to regulate access to ethers 5,
without the need of any other pre-activation of either coupling
partner. Therefore, low loadings of the bulk chemical DABCO (1)
could be used in total three-times as a catalyst within one process,
while no additional solvents, but small amounts of an alcohol were
used, which represents a stabilizer, a catalyst and a reagent
simultaneously during the course of the reaction. Practically, a va-
riety of ethers 5a-o could be generated in fair to good yields and up
to a multi-gram scale. Over two steps under mild conditions, a
valuable tolerance to the nature of each of the coupling partners
could be shown. As the provided molecules bear great potential for
polymer science as well as for total synthesis, we were finally able
to show an alternative access to commonly utilized building blocks
9 with our method. Not only does the demonstrated route provide
product 9a in good yields with excellent stereoselectivity in only
two steps from a vinyl ketone 3 (Scheme 6), it also keeps costs at a
minimum due to the high atom economy simultaneously utilizing
inexpensive compounds.
4. Experimental
4.1. General information
All starting materials were purchased from commercial sources
(for purities see supplementary information) and were used
directly without any further purification unless indicated. THF and
diethyl ether for synthesis were used directly from a MB SPS-800
(M BRAUN). Diethyl ether, ethyl acetate, petroleum ether and n-
pentane for chromatography were obtained in technical grades and
distilled prior to use.
Thin layer chromatography (TLC) was performed on silica gel
POLY-GRAM® SIL G/UV254 plates and was visualized with UV light
(254/366 nm UV-lamp) and/or a potassium permanganate stain
[1.5 g potassium permanganate, 10 g potassium carbonate, 1.25 mL
Scheme 5. Application of the MBH-one-pot etherification in the efficient synthesis of
sodium hydroxide solution (10
u-%), 200 mL H2O]. Due to the
chiral building blocks (glu: glucose).53,55,69,81
.
volatility of some of the compounds examined, reaction control
was performed by GC-MS (Thermo Elektron MAT 95, Helium). TLC
is a viable option for the very same purpose where volatility of the
substances does not prohibit this technique. Column chromatog-
raphy was performed in cylindrical glass columns packed with
silica gel (0.040e0.063 mm, 230e400 mesh) purchased from
Macherey-Nagel. Unless further indicated, removal of solvents
described as ‘removed under reduced pressure’ was performed
using rotary evaporators.
3. Conclusion
In the presented work we were able to establish a convenient
and efficient method synthesizing a-hydroxymethylated vinyl ke-
tones 4 and their subsequent one-pot etherification, if desired
(Scheme 6).
For the first time, good to very good yields for the conversion of
aliphatic and aromatic vinyl ketones 3a-d with formaldehyde (2) in
For specifications regarding the collection of analytical data see
supplementary information.
Please cite this article in press as: Mantel M, et al., Simple organocatalysts in multi-step reactions: An efficient one-pot Morita-Baylis-Hillman-
type -hydroxymethylation of vinyl ketones followed by the convenient, temperature-controlled one-pot etherification using alcohols,
a
Mantel, Marvin
