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The methods have been utilized for decades until the recent
for the one-pot synthesis of the target compounds, we decided
past, proving productive and suitable for natural product
syntheses. However, overcoming inconvenient work-up pro-
cedures as well as preventing the use of reagents such as
trimethylaluminium, methyl iodide or hexamethylphosphoric
triamide (HMPA) was the resource-economic goal of the
present endeavor: Inexpensive starting materials 3 should be
converted in a one-pot enantioselective catalytic procedure to
the desired products, thereby drastically reducing the down-
stream processing operations. It was anticipated that a combi-
nation of an amine-based organocatalyst (yielding the inter-
mediate 4 via a Morita–Baylis–Hillman-type[49–51] reaction
sequence) with suitable biocatalysts would provide the target
compounds (Scheme 1D).
to shed some light on the role of the carboxylic acid for the
etherification process.
Mechanistic insights. In order to elucidate the role of
benzoic acid during the newly found etherification protocol,
we first intended to rule out a process of general proton
catalysis. Thus, we tested a series of non-carboxylic Brønsted
acids being added to the one-pot etherification reaction.
Several additives with pKa-values matching or not matching
those of the carboxylic acids did not provide equally good
results under otherwise identical conditions (for details see
Supporting Information).
Next, the benzoate 10 of the corresponding Morita–
Baylis–Hillman product 7 was prepared as a reference com-
pound to evaluate its role in the overall process. Interestingly,
GC–MS analysis revealed that benzoate 10 is indeed also
formed during one-pot ether 4a synthesis (Scheme 3A).
Furthermore, isolated intermediate 7 was not converted
yielding ester 10 under reaction conditions in the absence of
DABCO. The organocatalyst is also essential for the following
etherification: Ether 4a is neither formed in the absence of
the additive nor in the presence of a Brønsted base[56,57] such
as triethylamine (Scheme 3B; see also Supporting Informa-
tion). Alternatively, we considered the involvement of a highly
electrophilic ammonium species 11.[58] Its presence could be
confirmed by high resolution mass spectrometry when treat-
ing ester 10 with DABCO as well as upon converting alcohol 7
in the presence of benzoic acid (Scheme 3C and Supporting
Information).
Results and Discussion
Organocatalytic protocols. Based on our experience with
reductases,[52–54] we were confident that the selective reduc-
tions of enone 4 should be feasible. However, finding
compatible conditions for providing the required intermedi-
ate 4 might prove more difficult: While the one-pot Morita–
Baylis–Hillman etherification sequence was feasible with
primary alcohols,[55] the overall conversion would require
improvement. Furthermore, upon applying the identical
conditions for secondary alcohols, the transformation failed.
As exemplified for 2-hexanol (5a), the corresponding inter-
mediates 6a and 7 were formed as expected, but the
etherification leading to product 4a did not occur upon
heating to 458C (Scheme 2). Instead, side products 8 and 9
were formed indicating the comparable reduced nucleophi-
licity of the secondary alcohol 5a. It was found (and later
further optimized, see Supporting Information) that upon
addition of benzoic acid (BzOH) the desired product 4a could
indeed be obtained for the first time. It is also interesting to
note that the reaction conditions are not very sensitive to the
relative DABCO:BzOH ratio (see Supporting Information).
Before optimizing the reaction conditions as well as extending
the scope and demonstrating the versatility of the approach
From the results obtained, a plausible central role of
DABCO in the reaction mechanism can be deduced as its
involvement in the formation of the key intermediates 10 and
11 could be verified. Furthermore, benzoic acid can be
considered as a non-proton co-catalyst ultimately required for
the formation of the electrophilic intermediate 11, boosting
the formation of ethers also derived from secondary alcohols
5 (Scheme 3D).
Scope. Based on the mechanistic insights, a general
protocol for a one-pot procedure towards enones 4 could be
established after some optimization in detail (see Supporting
Information: In particular, the synthesis of steroid-derived
derivatives 4k–m requires special attention due to low
solubility). The versatility was tested with a series of primary
and secondary alcohols 5 (Scheme 4). It was demonstrated
that not only simple alkyl- and aryl-substituted derivatives
4a–g could be accessed in good to excellent yield, but also
sterically demanding compounds such as 4h–m. Furthermore,
the acceptor 3 is not limited to methyl vinyl ketone (3a, R2 =
Me), but also substituent R2 can be altered as was shown in
the synthesis of ethyl- and aryl ketones 4n + o. Also, primary
alcohols were introduced with a wide range of ethers 4p–4ae
bearing various functional groups that were compatible with
the reaction conditions. Overall, 31 examples with an average
yield of 71% over three steps could be provided from mostly
commercially available materials by the established protocol
in scale with reagent grade purity determined by quantitative
NMR spectroscopy (qNMR) or elemental analysis. It should
be noted that ethers of tertiary alcohols could also be accessed
by evaporating the sacrificial secondary alcohol (e.g. hexa-
Scheme 2. Morita–Baylis–Hillman etherification sequence utilizing
0.05 equiv of DABCO as organocatalyst (added only once when
premixing paraformaldehyde and alcohol 5a before heating the mixture
to 808C; all other components were added subsequently as shown).
The formation of side products 8 and 9 was omitted upon addition of
benzoic acid (BzOH).
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
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