Stereoselective Synthesis of the Core Structures of Pyrrocidines and Wortmannines through the Excited-State Nazarov Reactions

Article abstract of DOI:10.1021/acs.orglett.1c00643

The reaction conditions and scope of the excited-state Nazarov reaction of dicyclicvinyl ketones were studied. The stereochemistry of this electrocyclization is consistent with the mechanism of the pericyclic reaction and Woodward-Hoffmann rule. UV-light-promoted excited-state Nazarov reactions gave hydrofluorenones bearing a syn-cis configuration via a disrotatory cyclization. The core tricyclic hydrofluorenones of pyrrocidines and wortmannines were constructed via the excited-state Nazarov reactions, which demonstrated their synthetic potential in complex natural product total synthesis.

Full text of DOI:10.1021/acs.orglett.1c00643

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Letter
Stereoselective Synthesis of the Core Structures of Pyrrocidines and
Wortmannines through the Excited-State Nazarov Reactions
Dongsheng Xue,§ Yonglei Que,§ Hao Shao, Haibing He, Xiaoli Zhao,* and Shuanhu Gao*
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ABSTRACT: The reaction conditions and scope of the excited-
state Nazarov reaction of dicyclicvinyl ketones were studied. The
stereochemistry of this electrocyclization is consistent with the
mechanism of the pericyclic reaction and Woodward−Hoffmann
rule. UV-light-promoted excited-state Nazarov reactions gave
hydrofluorenones bearing a syn−cis configuration via a disrotatory
cyclization. The core tricyclic hydrofluorenones of pyrrocidines
and wortmannines were constructed via the excited-state Nazarov
reactions, which demonstrated their synthetic potential in complex natural product total synthesis.
wortmannines (Figure 1B).2 Wortmannines A (1), B (2), and
C (3) were isolated from the zeistic culture of Talaromyces
wortmannii LGT-4 by Yang and co-workers in 2016.3 Recently,
structural analogues, such as wortmannines B1(4) and B3 (5),
were discovered from the genus Niesslia (TTI-0426) by Gloer
and co-workers.4
Moreover, the unprecedented trans−anti−trans decahydro-
1H-fluoren-9-ol (II) (Figure 1A) comprises the core skeleton
of a family of complex molecules, isolated from different fungal
sources in the past decades.5 GKK1032 A1 (6) was among the
first member that was isolated from Penicillium sp. GKK1032 in
2001.6a,b Hirsutellones A−E were discovered from the insect
pathogenic fungus Hirsutella nivea BCC 2594 by Isaka and co-
workers in 2005.6c The structure and configuration of
hirsutellone B (7) were determined by X-ray crystallographic
analysis. Specifically, the trans−syn−cis decahydro-1H-fluoren-
9-ol (III) framework was also found in pyrrocidine A (8),
which was isolated from the fungus Cylindrocarpon sp. LL-
Cyan426 by He and co-workers in 2002.6d,7
luorenones, hydrofluorenones, and hydrofluorenols are
Fcomprised by a 6,5,6-fused tricyclic skeleton, which widely
exists in polycyclic natural products.1 The diverse stereo-
chemistry and various substituted groups on the ring junctions
result in their major structural differences and synthetic
challenges (Figure 1A). For instance, the core cis-decahydro-
9H-fluoren-9-one (I) was found in a small group of steroid
Structural analyses of these natural molecules reveals that
the stereoselective constructions of the 6,5,6-fused tricyclic
cores (I, II, and III), containing up to five contiguous
stereogenic centers including one all-carbon quaternary center,
represent a great synthetic challenge. Considerable attention
has been attracted by these complex natural polyketides from
the synthetic community because of their challenging
structures as well as potential biological activities. In 2009,
Received: February 23, 2021
Published: March 24, 2021
Figure 1. (A) Fluorenones and fluorenols. (B) Structures of
polycyclic natural products bearing decahydro-1H-fluoren-9-ol cores
and decahydro-9H-fluoren-9-one cores.
https://doi.org/10.1021/acs.orglett.1c00643
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2736−2741
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Nicolaou and co-workers disclosed an elegant strategy for the
first total synthesis of hirsutellone B (7), and the decahydro-
1H-fluoren-9-ol skeleton was built through a cascade epoxide
opening Diels−Alder reaction.8 Synthetic studies, reported by
the groups of Uchiro,9 Sorensen,10 Liu,11 Nay,12 and others,13
toward this family of natural molecules mainly relied on the
intramolecular Diels−Alder reaction to build the required B−
C rings, which was inspired by the biosynthetic pathway of
these natural polyketides.5 However, the total synthesis of
wortmannines has not been disclosed to date.
investigated under the 254 nm UV light (entries 1−7, Figure
2A). Most solvents other than dioxane worked, including
We envisioned that the core decahydro-1H-fluoren-9-ol and
decahydro-9H-fluoren-9-one skeletons could be stereospecifi-
cally constructed by means of the Nazarov reaction14,15 of
dicyclicvinyl ketones, wherein the stereochemistry of the
cyclization could be predicted and controlled by the adopted
reaction conditions. These electrocyclizations were consistent
with the mechanism of the pericyclic reaction and Woodward−
Hoffmann rule.16 UV-light-promoted excited-state Nazarov
reactions give the hydrofluorenones bearing a cis−syn
configuration via disrotatory cyclization,17 while the acid-
promoted ground-state Nazarov reactions of the same
substrates produce the tricyclic products with a trans−anti
configuration via conrotatory cyclization. In our previous
studies,18 we have applied the excited-state Nazarov reaction in
the total synthesis of farnesin, a rearranged ent-kaurenoid
(Scheme 1A).18c Herein, we report the detailed reaction
Scheme 1. Synthetic Plan
Figure 2. Reaction conditions of the photo-Nazarov reaction.
Reaction scale (13, 0.1 mmol). (a) All the photoreactions were run
in degassed anhydrous solvent. (b) Conversion, ratio, and yields were
determined by 1H NMR spectroscopic crude analysis using CH2Br2 as
an internal standard, unless noted. (c) Additives (3.0 equiv).
dichloromethane, tetrahydrofuran, acetonitrile, 1,2-dichloro-
ethane, toluene, and ether, among which 1,2-dichloroethane
(DCE) was superior to the others, generating the desired
product 14 in 36% yield (entry 5, Figure 2A). The newly
generated double bond in the corresponding product 14 was
located at the C2C3 position, and its relative stereo-
chemistry matched with the structure obtained in our previous
work.18c We further optimized photolytic conditions by
screening the light sources and additives using 1,2-dichloro-
ethane as the solvent. UV light at λmax = 366 nm gave a better
reaction yield of 52% (entry 9, Figure 2A). While using UV
light at 419 and 575 nm, a longer reaction time was needed,
and it resulted in lower yields (entries 10 and 11, Figure 2A).
Subsequently, acidic additives including Brønsted acids and
Lewis acids were added during photolysis, such as AcOH, LiCl,
FeCl3, TiCl4, and Sc(OTf)3 (entries 12−16, Figure 2A). We
were pleased to find that the addition of LiCl and AcOH
condition screening of the excited-state Nazarov reactions of
dicyclicvinyl ketones and its applications in the formation of
the tricyclic core of pyrrocidine A. As a further synthetic
application, we planned to investigate the practicality of the
photo-Nazarov reaction to build the basic skeleton of
wortmannines using the substrate bearing the acid sensitive
cyclic acetal group, such as dicyclicvinyl ketone 10 (Scheme
1B).19 A convergent approach was planned to couple two
fragments 11 (A−B ring) and 12 (D ring).
We started to optimize the reaction conditions of the photo-
Nazarov reaction by using a simple dicyclicvinyl ketone 13 as a
model substrate. The influence of the solvents was first
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Scheme 2. Construction of the Core Structure of Wortmannines
dramatically improved the reaction yields. When 3.0 equiv of
AcOH was added, the photoreaction occurred smoothly to
give 14 in 93% yield. We reasoned that an interaction between
LiCl or AcOH and the enone group of 13, through a weak
coordination or hydrogen bonding, stabilized the photolytic
intermediates and accelerated the electrocyclization (for the
discussion of the reaction mechanism, see Schemes S1−S3 in
the Supporting Information). These results were consistent
with that of photolysis of 2-furyl vinyl ketones observed by
Coombs and co-workers.20
We then explored the scope of the photo-Nazarov reaction
to examine its generality for the construction of hydro-
fluorenones (Figure 2B). Photolysis of dicyclicvinyl ketones
bearing a hydroxyl group at C-6, methyl group at C-8, and gem-
dimethyl group at C-4 and C-12 generated the desired cyclized
products 14a−14f with four contiguous stereogenic centers in
moderate yields (68−79%) under the optimal conditions.
These structures feature a syn−cis tricyclic framework, which
was confirmed by the X-ray diffraction analysis in our previous
work,18c and it also matched with the required A−B−C ring of
pyrrocidine A (8). Photoinduced electrocyclization of a
substrate with a carbonyl group at the C-4 position afforded
a conjugated enone product 14g in 81% yield. Notably,
substrates bearing two methyl groups at C-7 and C-8 positions
also worked and generated the cyclized products 14h and 14i
with contiguous all-carbon quaternary centers at the bridge-
head. The reaction time increased with increasing the steric
hindrance of the substituted groups on enones and protective
groups on the hydroxyl group at C-6. These results highlight
the capability and synthetic potential of the photo-Nazarov
cyclizations of dicyclicvinyl ketones to build the challenging
hydrofluorenone architectures.
to yield cyclic acetal 18.22 Reaction of the ketone on 18 with
hydrazine afforded hydrazone 19, which was immediately
exposed to iodine in the presence of 1,5-diazabicyclo[4.3.0]-
non-5-ene (DBN) to produce tetra- and trisubstituted vinyl
iodide 20 and 21 as an inseparable mixture.23 After two steps
of deprotection and methylation, the methyl ether 22 was
obtained in 46% over two steps. The bicyclic compound 23
bearing the unsaturated aldehyde was prepared according to a
known procedure24 and coupled with vinyl iodide 22 through a
nucleophilic addition reaction followed by the DMP oxidation.
In order to facilitate the following transformations and
structure determination, we isolated one diastereomer of
dicyclicvinyl ketone 24 bearing a β-OEt group at C-3 to
investigate the photoreaction.
We then turned our attention to study the photo-Nazarov
reaction of 24 to construct the tetracyclic core of
wortmannines with the all-carbon quaternary center at C-10.
We found that the dicyclicvinyl ketone 24, bearing the
sensitive acetal motif, was unstable under the optimized
reaction conditions. Most of the starting material decomposed
when DCE was used as a solvent for the photolysis. After
several trials, we found that the photoreaction occurred to
furnish the cyclized product 26 in low yield (17%) when the
anhydrous and degassed acetonitrile was used. However, the
configuration of the all-carbon quaternary center at C-10 in 26
was opposite to that of the corresponding natural products.
Furthermore, the newly formed C4C5 double bond was
located on the D ring. We speculated that the stereochemistry
of this photo-electrocyclization was controlled by the rigid
trans-fused A−B ring. Then, we prepared bicycle 27, the
enantiomer of 23, which was converted to dicyclicvinyl ketone
28, to verify this hypothesis. Under similar photoreaction
condition, photolysis of 28 generated the cyclized product 29
in 56% yield. The relative configuration of two quaternary
centers at C-10 and C-13 was still opposite which matched
with the results obtained from substrate 24. Interestingly, the
enone group of 29 was consistent with the natural product
wortmannine A (1).
To construct the basic skeleton of wortmannines, we
selected the known β-hydroxyl-ketone 16, generated from L-
(−)-malic acid 15, as the starting material to prepare the D
ring (Scheme 2).21 Substrate 16 was converted to the silyl enol
ether 17 under basic conditions, which was treated by Lewis
acid SnCl4 in the presence of triethyl orthoformate at −78 °C
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Notes
In summary, we investigated the photoinduced Nazarov
reaction of dicyclicvinyl ketones to assemble the syn−cis-fused
tricyclic hydrofluorenones. Three stereogenic centers, includ-
ing contiguous all-carbon quaternary centers, could be
stereospecifically formed through this photo-electrocyclization.
As synthetic applications, the core structures of pyrrocidine A
and wortmannines were constructed. These studies gave us
hints to better understand the reactivity and stereoselectivity of
the photo-Nazarov reaction, which will guide the synthetic
design for the total synthesis of structurally related natural
products.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21971068, 21772044), Program of Shanghai Academic/
Technology Research Leader (18XD1401500), Program of
Shanghai Science and Technology Committee
(18JC1411303), “Shuguang Program (19SG21)”, and “the
Fundamental Research Funds for the Central Universities” for
generous financial support.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00643.
■
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AUTHOR INFORMATION
Corresponding Authors
■
Xiaoli Zhao − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China; orcid.org/0000-0002-4458-6432;
Email: xlzhao@chem.ecnu.edu.cn
Shuanhu Gao − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China; Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, East
China Normal University, Shanghai 200062, China;
orcid.org/0000-0001-6919-4577; Email: shgao@
chem.ecnu.edu.cn
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Authors
Dongsheng Xue − Shanghai Key Laboratory of Green
Chemistry and Chemical Processes, School of Chemistry and
Molecular Engineering, East China Normal University,
Shanghai 200062, China
Yonglei Que − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China
Hao Shao − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China
Haibing He − Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, East
China Normal University, Shanghai 200062, China
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Complete contact information is available at:
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Author Contributions
§D.X. and Y.Q. contributed equally to this work.
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