Angewandte
Communications
Chemie
eoinversion at C3; (2) mechanistically, the oxa-Michael
addition reaction of 5 could proceed not only in a 6-endo-
trig manner (via attack at C7) to give dihydropyran-4-one 6
but also in a 5-exo-trig manner (via attack at C6) to give
dihydrofuran-3-one 7; and (3) in either case, the absolute
configuration at C7 of 6 or at C6 of 7 remains to be
determined. Intrigued by these ambiguities, we set about to
synthesize this unique natural product with the goal of
unveiling its true structure and facilitating a comprehensive
investigation of its biological activity.
Herein, we report that we have achieved a biomimetic
synthesis of sarocladione in only two or seven steps from
ergosterol, an inexpensive, commercially available sterol. The
synthesis was enabled by the development of a novel
[8]
ruthenium-catalyzed endoperoxide fragmentation reaction,
which transformed the A/B/C tricyclic ring system of the
classical steroids into 14-membered macrocyclic diketones by
cleavage of two CÀC bonds. Moreover, the synthesis allowed
us to unambiguously determine that the structure of sarocla-
dione is in fact not 1 but 2 (Figure 1A), as indicated by X-ray
crystallographic analysis.
The key reaction in the biosynthesis of sarocladione is the
endoperoxide fragmentation, which is not without precedent
in synthetic chemistry. However, most of the reported
methods suffer from a narrow substrate scope and low
yields and are therefore of limited utility (Figure 2A). In
1
979, Coughlin and Salomon reported the thermal decom-
position of 2,3-dioxabicyclo[2.2.2]octane to give succinalde-
[9]
hyde and ethylene. Shortly thereafter, the groups of Noyori
and Balci reported catalytic decomposition reactions of
saturated bicyclic endoperoxides with catalysis by Pd-
[
10]
[11]
(
PPh ) , RuCl (PPh ) , or CoTPP (tetraphenylporphyr-
3 4 2 3 3
[
12]
ine).
In the 1980s, Mihailovi c´ reported the thermal
fragmentation of steroidal 5a,8a-peroxides in refluxing
[13]
diglyme to afford diketone products in low yields. More
recently, Higuchi and colleagues studied fragmentation of 2,3-
dioxabicyclo[2.2.1]heptane with catalysis by iron porphyrin to
[14]
generate malondialdehyde and ethylene as products.
Despite this progress, a general method for endoperoxide
fragmentation remains elusive, and we decided to explore this
transformation in the context of the synthesis of sarocladione.
Inspired by the work of Noyori and Balci, we planned to
search for a suitable catalyst for this fragmentation. After
extensive experimentation, we found that heating a solution
of endoperoxide 8 and 5 mol% [RuCl (CO) )] in toluene
Figure 2. A) Precedents for endoperoxide fragmentation and new
developments and B) optimization of reaction conditions.
proceeded via a radical mechanism (see Supporting Informa-
tion for a detailed discussion of the plausible mechanism).
2
3
2
[15]
produced desired macrocyclic diketone 9 in 71% yield
(
(
Figure 2B, entry 1), after in situ removal of the triethylsilyl
TES) ether protecting group for ease of purification.
Furthermore, no reaction occurred when the catalyst was
changed to CoTPP (entry 7), and the use of various other
ruthenium catalysts also resulted in little conversion
(entries 8–15). Lastly, we compared the efficiency of our
optimal conditions with previously reported conditions for
this fragmentation. Specifically, we found that refluxing 8 in
Notably, subjecting the C3-OH derivative of 8 to the standard
conditions furnished 9 directly, albeit in a lower yield (40%).
Reaction of 8 at 1208C in the microwave also gave 9, albeit in
a slightly lower yield over a longer time (4 h, entry 2). When
conventional heating was used instead of microwave heating,
the yield dropped to 61% (entries 3 and 4). Control experi-
ments showed that most of the starting material was
recovered in the absence of [RuCl (CO) )] (entry 5) and
[
13a]
diglyme for 9 h (Mihailovi c´ ꢀs conditions)
afforded 10 in
only 28% yield (entry 16); and no reaction occurred when 8
was treated with RuCl (PPh ) in DCM at 508C (Noyoriꢀs
2
3 3
[
11]
conditions, entry 17).
2
3
2
that adding 1.0 equiv of TEMPO ((2,2,6,6-tetramethylpiper-
idin-1-yl)oxyl) to the reaction mixture dramatically reduced
the conversion (entry 6), indicating that the reaction probably
With the standard conditions in hand, we briefly explored
the substrate scope of the endoperoxide fragmentation
(Table 1). Steroidal endoperoxides 11a–f derived from cho-
Angew. Chem. Int. Ed. 2021, 60, 11222 –11226
ꢀ 2021 Wiley-VCH GmbH