Angewandte
Communications
Chemie
Scheme 5. Derivatization of the oxyarylation products.
Scheme 7. Energy profile for the generation of transient b-ketoester 3i
(see H’) in the presence of water. Free enthalpies DGDMF and
enthalpies DHDMF are given with respect to association complex D’
(=D+H2O). Distances are given in ꢃ.
affording ketene acetal G’, which is followed by exergonic
water-assisted tautomerization (TSG’-H’) to generate ketoester
H’ (= 3i and H2O). Alternatively, an initial [1,5] sigmatropic
rearrangement of dihydrofuran E’ (TSE’-F’) followed by water-
mediated proton transfer/rearomatization (TSF’-G’) also leads
to G’. In light of the small energy difference between the two
processes (TSE’-G’ vs. TSE’-F’: DDG° < 1.0 kcalmolꢀ1), both
pathways should be operative. Finally, hydrolysis and sub-
sequent decarboxylation of b-ketoester 3i give rise to ketone
4i.[21]
Selected compounds were tested for inhibition of the
human 11b-hydroxylase CYP11B1 and its isozyme CYP11B2
(aldosterone synthase, 93% sequence homology). Four com-
pounds, namely 4b, 4e, 4n, and 4o, showed strong inhibition
of both enzymes, with 4o also displaying two-digit nanomolar
inhibitory activity like metyrapone (Table 2).
Scheme 6. Energy profile for the formation of key cyclopropane D
through a [3,5] rearrangement of the formal (3+2) cycloaddition
product C. The free enthalpies DGDMF and enthalpies DHDMF are given
with respect to association complex A. Distances are given in ꢃ.
ꢀ46.4 kcalmolꢀ1) under the reaction conditions, with the final
step being irreversible (C!D). Interestingly, the (3+2)
cycloaddition event proceeds via discrete vinyl anion B,[18]
with the final concerted [3,5] rearrangement (TSC-D) being
symmetry-allowed owing to the participation of the orthog-
onal oxygen lone pair.
The reaction pathway from D to b-ketoester 3i is depicted
in Scheme 7. The oxyarylation process was found to proceed
more efficiently in the presence of both water and DMF (see
Table 1), strongly suggesting that water may (re)actively
participate in the reaction pathway leading to transient
b-ketoester 3. In accordance with this observation, we
evaluated mechanistic scenarios in the absence and presence
of explicit solvent molecules. Our computational data indeed
suggest that water facilitates the formation of b-ketoester 3i
by acting as a proton shuttle (see TSF’-G’/TSE’-G’, Scheme 7).[19]
Furthermore, the anticipated[14] direct cyclopropane opening/
rearomatization sequence was found to be kinetically disfa-
vored by DDG = 4.9 kcalmolꢀ1 over yet another pseudoper-
icyclic [3,5] rearrangement, which leads to dihydrofuran E’ in
the presence of water (Scheme 7). The preference of cyclo-
propane D’ to undergo a [3,5] rearrangement (TSD’-E’) can also
be deduced from an analysis of its LUMO.[20] This step
(TSD’-E’) is rate-determining (DG° = 30.3 kcalmolꢀ1).
Clearly, small electron-donating groups in the meta and
para position to the heme-binding pyridyl nitrogen atom are
important structural requirements for inhibition. Bulky
moieties or substituents ortho to the pyridyl nitrogen atom
lead to less active or inactive compounds. These compounds
are good starting points for structural optimization to
enhance CYP11B1 inhibition and the selectivity towards
CYP11B2, in particular, as this enzyme must not be inhibited
with similar potency to avoid side effects in the treatment of
Cushingꢀs syndrome.
In summary, we have developed a metal-free oxyarylation
of alkynes with pyridine N-oxides, providing the correspond-
ing meta-substituted pyridines in moderate to good yields
with high regioselectivities. Metyrapone analogues were thus
readily synthesized. Furthermore, computational studies have
revealed that the oxyarylation proceeds through an unex-
pected elaborate rearrangement cascade involving rather
unusual [3,5] pseudopericyclic reactions. The process devel-
oped herein resulted in a series of hit compounds as good
Once formed, dihydrofuran E’ can undergo a water-
mediated proton transfer/rearomatization sequence (TSE’-G’
)
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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