10.1002/anie.201802176
Angewandte Chemie International Edition
COMMUNICATION
We have recently shown that SorbC can indeed be utilized for the
fast and stereoselective total synthesis of bisorbicillinoids
resulting from dimerization of 2, e.g., leading to 3 and 4, or from
Diels-Alder reaction of unreacted 1 with 2, e.g., facilitating the first
total synthesis of sorbiquinol.[3] The enzyme also accepted
structural analogs of 1 as substrates, allowing for the synthesis of
unnatural bisorbicillinoid derivatives.[3] The catalytic activity of
SorbC towards a larger set of substrates was recently evaluated
by Narayan and coworkers, also including the monooxygenases
TropB from stipitatonic acid biosynthesis[9] and AzaH from
azaphilone biosynthesis[10] offering different site- and
stereoselectivity. This work nicely showcases the broad synthetic
potential of these biocatalysts for oxidative dearomatization of -
acylated or -formylated phenols.[11]
The oxidative dearomatization of 10 by SorbC did not only
conclude the first synthesis of the natural product 13, but also
promised direct access to the structurally challenging
bisvertinolone (14), as this natural product likely results from a
biosynthetic Michael-Addition / ketalization sequence of 2 with
13.[16] As our previous work only permitted the fusion of
sorbicillinol (2) with itself or sorbicillin (1),[3] a method for the
extraction of 2 from the enzymatic transformation followed by a
controlled reaction setup for further functionalization was required
to pave the way for the chemo-enzymatic synthesis of further
diversified sorbicillinoids such as 14. Given the increased stability
of 2 in polar solvents, such as H2O or DMF, the use of significant
amounts of DMF as co-solvent in the aqueous enzymatic
transformations followed by its extraction from the aqueous phase
with CH2Cl2 and the fast removal of only the CH2Cl2 under
reduced pressure was thought to give access to semi-purified 2
in DMF solution for further functionalization chemistry. While the
formation of the dimeric bisorbicillinol (3) and other minor products
resulting from the inherently high reactivity of 2 towards
dimerization can not entirely be prevented during this work-up
procedure, this strategy indeed enables the controlled reaction of
2 with alternative building blocks. This facilitated the first total
synthesis of bisvertinolone (14) in 20 % isolated yield by treatment
of the DMF solution of 2 with oxosorbicillinol (13) and pyridine,
promoting a highly selective Michael-Addition / ketalization
sequence (Scheme 2).
Following our interest in utilizing SorbC for the total synthesis of
functionalized sorbicillinoid natural products that do not solely
derive from the reaction of 2 with 1 or 2, we tested the catalytic
activity of SorbC towards a set of further monomeric sorbicillin
derivatives 8-10 with different substitution pattern at the aromatic
ring system. These substrates were prepared by AlCl3-promoted
Friedel-Crafts acylation of the corresponding phenols with sorbic
acid chloride (see Supporting Information). Interestingly, the
natural product demethylsorbicillin (8)[12] was selectively oxidized
to triol 11 in 23 % yield,[13] while compound 9, in which one methyl
group is moved from C-5 to C-6 relative to sorbicillin (1), is
oxidized to the corresponding para quinone 12 in 29 % yield
(Scheme 1), a compound know as natural product sorrentanone
from Penicillium chrysogenum.[14] When the hexa-substituted
phloroglucinol 10 was used as a substrate, conversion to the
natural product oxosorbicillinol (13)[12] was achieved in 21% yield
(er = 95:5, see Supporting Information). In contrast to the highly
reactive sorbicillinol (2), all oxidation products 11-13 from these
transformations are stable compounds. Exemplarily for the
production of 12 we furthermore investigated in situ NADH co-
factor regeneration using glucose dehydrogenase Gdh.[15] This
facilitated the reduction of the amount of NADH from approx. 1.2
equivalents to 0.2 equivalents without affecting product yields
(see Supporting Information).
The extension of this methodology to the synthesis of various
other sorbicillinoids, derived by Diels-Alder reaction of 2 with
different dienophiles, was subsequently evaluated. An interesting
set of target compounds were the two reported ether derivatives
sorbivineton[8a] and rezishanone C.[17] However, as recently
shown by synthetic work by Yan et al.,[18] the structures of these
compounds are indeed identical and correspond to 17. This
product was obtainable within our work by addition of
ethylvinylether (15) to 2 in DMF solution to give 17 in 29% yield
(Scheme 2). While the above-mentioned synthesis of the
unnatural ent-17 by Yan et al. required > 20 individual synthetic
steps,[18] our biocatalytic approach delivered 17 in a single step
from sorbicillin (1), with the latter being accessibly in a simple
additional three-step synthetic sequence.[3] Rezishanone B
(18)[17b] was likewise accessible in 32% yield following this
approach by using n-butyl vinyl ether (16) as the dienophile. As
an alternative to the use of DMF and its extraction with CH2Cl2,
the application of acetone as the co-solvent during the enzymatic
synthesis of 2 with subsequent CH2Cl2 extraction followed by the
direct addition of the desired dienophile to the combined organic
phases and slow evaporation of the solvent was also feasible for
non-volatile enes. Using 4-ethenyl-2-methoxyphenol (19) as the
reaction partner for 2 thereby facilitated the first total synthesis of
the anti-viral sorbicatechol A (5)[6] in 30% yield. Interestingly, while
the NMR data of synthetic 5 perfectly matched the data reported
for isolated 5, optical rotation values were in disagreement,
including opposite signs. This discrepancy was resolved by
comparison of the CD spectra, revealing a perfect match of
synthetic with isolated 5 (see Supporting Information). As the
optical rotations of unnatural analogs of 5 with variations in the
aromatic portion (see below) were in a similar range, an incorrect
value reported for 5 in the original isolation paper is likely.
Scheme 1. Oxidation of sorbicillin analogs 8-10 to give triol 11 and the natural
products sorrentanone (12) and oxosorbicllinol (13), respectively. a: phosphate
buffer (50 mM, pH = 8.0), SorbC, NADH, room temperature; acetone was used
as co-solvent (cs) for solubilisation of substrates 8-10.
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Sib, Anna
