Protecting-Group-Free Total Syntheses of (±)-Norascyronones A and B

Article abstract of DOI:10.1021/acs.orglett.0c00212

Protecting-group-free total syntheses of natural products norascyronone A and norascyronone B were accomplished in eight steps from the commercially available starting material 1-bromo-4-methoxy-2-methylbenzene. The key step was a Mn/Cu-mediated oxidative

Full text of DOI:10.1021/acs.orglett.0c00212

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Letter
Protecting-Group-Free Total Syntheses of ( )-Norascyronones A
and B
Tingting Cao,∥ Lei Zhu,∥ Yu Lan,* Jun Huang,* and Zhen Yang*
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ABSTRACT: Protecting-group-free total syntheses of natural products
norascyronone A and norascyronone B were accomplished in eight steps
from the commercially available starting material 1-bromo-4-methoxy-2-
methylbenzene. The key step was a Mn/Cu-mediated oxidative cascade
annulation reaction that formed the tetracyclic core of the target molecules
bearing vicinal bridge-head all-carbon quaternary chiral centers. Our
investigation indicated that the C5 stereogenic center of norascyronone C
plays a critical role in the proposed biomimetic oxidative reaction for B-ring
formation.
orascyronones A (2) and B (3) (Figure 1) were recently
isolated from Hypericum ascyron. Both compounds
against the SK-BR-3 cell line (IC50 values of 4.3 and 7.8 μM,
respectively).1
N
In the biosynthetic pathway proposed when these
compounds were isolated,1 2 and 3 are postulated to be
derived from norascyronone C (4) via an oxidative 1,3-
dicarbonyl radical-initiated cascade cyclization through inter-
mediates A−D (Figure 1). Compound 4 undergoes an
oxidative 5-exo-trig radical cyclization to afford radical B
through intermediate A. Further cyclization of B at C16 of the
phenyl ring yields resonance-stabilized radical C (path a),
which undergoes further oxidation to carbonium ion D and
then aromatization via proton loss to give 2. From a chemistry
perspective, intermediate B, bearing a stable tertiary radical,
might also undergo further oxidation to form stabilized
carbocation E, as proposed by George and Lee,2 which
might trigger an intramolecular Friedel−Crafts reaction to
form carbonium ion D, followed by aromatization to give 2.
Among various oxidative transformations of enolized
carbonyl moieties mediated by metal ions (such as Mn(III),
Cu(II), Fe(III), and Ce(IV)),3 Mn(III)-based oxidative radical
cyclizations of carbonyl compounds with unactivated olefins4
have attracted much interest because they allow unconven-
tional and efficient access to a range of molecules5 that cannot
be easily synthesized using other methods.
As part of our continuing interest in the development of
diastereoselective syntheses of complex natural products
bearing vicinal bridged all-carbon quaternary chiral centers,6
we were intrigued by the possibility of constructing the
Figure 1. Proposed synthetic transformations.
contain a congested 6/6/5/6 polycyclic core bearing five
stereogenic centers, two of which are all-carbon quaternary
carbons (C1 and C8).1 Their absolute configurations have
been determined from X-ray diffraction data for 2 and
experimental and calculated electronic circular dichroism
spectra of 3. Biologically, both compounds show cytotoxicities
Received: January 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00212
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
tetracyclic cores of 2 and 3 through the proposed biomimetic
pathway, taking into account that the diastereoselective
formation of the vicinal all-carbon quaternary chiral centers
at C1 and C8 might be difficult owing to their steric effect.7
Inspired by the application of a Mn(III)-mediated oxidative
radical cyclization in the total syntheses of yezo’otogirins A and
C by the groups of George2b and Lee,5i we decided to use this
oxidative radical reaction as a key step for the formation of the
tetracyclic cores of 2 and 3. Herein, we report the development
of a protecting-group-free approach to the diastereoselective
total syntheses of 2 and 3, including the serendipitous finding
that the stereochemistry of C5 plays a critical role in the
proposed oxidative cyclization owing to its steric effect in the
aromatization step for B-ring formation. The developed
chemistry allowed us to achieve the total syntheses of 2 and
3 for the first time.
afforded an aryllithium species, which was then reacted with
prenyl bromide to give 6 in 95% yield. To install the enone
motif in 7, compound 6 was subjected to a Birch reduction (Li
in NH3 at −78 °C),9 and the resultant methyl vinyl ether was
then hydrolyzed with HCl to afford 7 in 70% yield.
Methylation of enone 7, by treating with lithium diisopropyl-
amine (LDA) followed by methyl iodide, gave compound 8 as
a single diastereomer in 85% yield.2b,5i
To achieve the diastereoselective synthesis of diketone 10,
we adopted a domino Michael/aldol condensation reaction
strategy developed by Shibasaki,10 George,2b and Lee.5i
Accordingly, Cu-catalyzed conjugate addition of (4-methyl-
pent-3-en-1-yl)magnesium bromide to enone 8 at −20 °C for
20 min, an in situ trapping of the resulting magnesium enolate
by benzaldehyde at −78 °C, afforded hydroxy ketone 9 as a
pair of diastereomers at the newly generated C10 chiral center.
Further oxidation of the hydroxyl group at C10 via Dess−
Martin oxidation gave diketone 10 as a single diastereomer in
70% yield over two steps. The stereochemistry of substituents
at C1, C5, C7, and C8 on the cyclohexanone ring of 10 was
Our syntheses of 2 and 3 began with the diastereoselective
preparation of key intermediate 4 in a protecting-group-free
manner (Scheme 1). Accordingly, the exposure of commer-
Scheme 1. Diastereoselective Synthesis of Diketones 4 and
10
1
assigned based on the 2D H NMR spectrum (see SI for
details).
To prepare key intermediate 4, a toluene solution of 10 was
treated with 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) at
reflux for 48 h, affording 4 as the more thermally stable
product in 44% yield. The stereochemistry of 10 was assigned
unambiguously by 2D NMR analysis (see SI for details).
With diketone 4 in hand, our investigation then concen-
trated on the proposed biomimetic cyclization of diketone 4
for the formation of the tetracyclic core in 2 and 3. Initially, we
used Mn(OAc)3/Cu(OAc)2 as oxidant3a to perform the
proposed biomimetic oxidative annulation of diketone 44 in
EtOH as solvent. Unfortunately, only a trace amount of desired
product 2 was observed after conducting the reaction at 80 °C
for 48 h, with the majority of starting material diketone 4
decomposed under these conditions (Table 1, entry 1). To
evaluate the solvent effect on the annulation outcome, the
above reaction was conducted in various solvents, including
acetic acid,11 2,2,2-trifluoroethanol,12 and DMF.2b,13 However,
no desired product 2 was obtained, and significant amounts of
starting material decomposition were observed (entries 2−4).
Furthermore, replacing Mn(OAc)3/CuOAc2 with Mn(OAc)3
cially available aryl bromide 5 to n-BuLi in the presence of
tetramethylethylenediamine (TMEDA)8 in THF at −78 °C
Table 1. Profile of the Oxidative Cascade Reaction of Diketone 4
a
yield (%)
entry
oxidant
equiv
solvent
temp (°C)
time (h)
4
11
2
b
1
2
3
4
5
6
7
8
Mn(OAc)3·2H2O; Cu(OAc)2·H2O
Mn(OAc)3·2H2O; Cu(OAc)2·H2O
Mn(OAc)3·2H2O; Cu(OAc)2·H2O
Mn(OAc)3·2H2O; Cu(OAc)2·H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O; Yb(OTf)3·H2O
CAN
FeCl3
(MnIII/CuII = 2/1)
(MnIII/CuII = 2/1)
(MnIII/CuII = 2/1)
(MnIII/CuII = 2/1)
(2)
(MnIII/YbIII = 2.2/1)
(2)
EtOH
80
80
80
130
80
80
48
16
16
16
16
16
12
12
30
25
trace
b
AcOH
10
c
c
CF3CH2OH
c
DMF
b
AcOH
34
8
CF3CH2OH
c
MeCN
70
70
c
(2)
MeCN
a
b
c
Isolated yield. Starting material partially decomposed. Starting material decomposed.
B
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14
or Mn(OAc)3/Yb(OTf)3 (entries 5 and 6) or using other
oxidants, such as CAN15 and FeCl3,16 failed to afford the
desired product 2 (entries 7 and 8). The observed extensive
decomposition of diketone 4 led us to speculate that the initial
oxidative step might occur but that the generated radical did
not undergo the proposed cascade reaction to afford the
tetracyclic ring in product 2.
different relative conformations at C5 adjusted this domino
oxidative radical cyclization.
As shown in Figure 2, 1,3-dicarbonyl radical CP1 could be
obtained from norascyronone C through initiation by the
oxidant. Subsequent radical addition to the C−C double bond
via five-membered transition state TS1 afforded tertiary carbon
radical CP2 reversibly. Starting from CP2, an electrophilic
radical addition to the phenyl moiety via transition state TS2
generates intermediate CP3, with subsequent oxidation/
aromatization leading to desired compound 217 (see note in
reference). The calculated results showed that the electrophilic
radical addition was the rate-determining step, with an energy
barrier of 13.7 kcal/mol. This indicated that the process of
initiation of the 1,3-dicarbonyl radical was endergonic, which
would increase the overall activation energy of the annulation
reaction. Meanwhile, we also conducted calculations for 1,3-
dicarbonyl radical CP1-iso from diastereoisomer 10 (black
line). The inverse chirality at C5 resulted in a larger
conformational adjustment of the transition state (TS2-iso)
in the electrophilic radical addition step. Structure analysis
indicated the methylene at C1 presented as an axial bond in
TS2, resulting in strong intramolecular strain (shortest
H(C7)−H(C31) distance of 1.97 Å), while the analogous
strain was absent in TS2-iso due to the methylene being
equatorial. This conformational adjustment led to a 2.0 kcal/
mol decrease in the energy barrier for TS2-iso. The generated
tetracyclic core intermediate CP3-iso was also more stable than
CP3, suggesting that diastereoisomer 10 would exhibit
enhanced reactivity in this oxidative radical cyclization.
To explore this synthetic feasibility, diketone 10 was treated
with Mn(OAc)3/Cu(OAc)2 in AcOH at 80 °C for 16 h. To
our delight, desired annulated product 12 was obtained in 40%
yield as a single diastereoisomer (Table 2, entry 1). In this
reaction, compounds 4 and 11 were also formed in 22% and
13% yields, respectively, which were derived from the
epimerization of 10 at the corresponding C1 and C5 chiral
centers.
Inspection of the 3D structure of 4 (Figure 2) showed that
the methyl group at C5 might have a profound steric effect on
Figure 2. Free energy profiles of the radical cyclization. Red line
represents the reaction of the 1,3-dicarbonyl radical obtained from
norascyronone C. Black line represents the reaction of the 1,3-
dicarbonyl radical obtained from 10.
To improve the yield of 12, we first profiled the solvent
effect on the oxidative annulation outcome (Table 1, entries
2−5), with the best results obtained in EtOH as solvent,
affording 12 in 61% yield (entry 2). Under such reaction
the outcome of the tetracyclic ring formation in product 2. To
better understand this domino reaction, we performed density
functional theory (DFT) calculations to determine whether
Table 2. Oxidative Cyclization for the Synthesis of 12
a
yield (%)
entry
oxidant
equiv
solvent
AcOH
EtOH
MeCN
1,4-dioxane
DMF
AcOH
AcOH/Ac2O
EtOH
temp (°C)
time (h)
4
11
12
1
2
3
4
5
6
7
8
9
Mn(OAc)3·2H2O; Cu(OAc)2·H2O
Mn(OAc)3·2H2O; Cu(OAc)2·H2O
Mn(OAc)3·2H2O; Cu(OAc)2·H2O
Mn(OAc)3·2H2O; Cu(OAc)2·H2O
Mn(OAc)3·2H2O; Cu(OAc)2·H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Cu(OAc)2·H2O
(MnIII/CuII = 2/1)
(MnIII/CuII = 2/1)
(MnIII/CuII = 2/1)
(MnIII/CuII = 2/1)
(MnIII/CuII = 2/1)
MnIII = 2
80
80
80
80
80
80
80
80
80
16
32
32
32
32
16
16
16
16
22
13
40
61
5
27
18
6
25
22
10
18
b
MnIII = 2
MnIII = 2
4
CuII = 2
AcOH
61
14
a
b
Starting material partially decomposed. Starting material decomposed.
C
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conditions, compounds 4 and 11 were not observed. To
demonstrate the synergistic effect of Mn(III) and Cu(II) in
this oxidative annulation, we conducted these reactions in the
presence of Mn(III) and Cu(II) individually. However, no
desired product 12 was observed (Table 2, entries 6−9),
indicating that the combination of Mn(III) and Cu(II) was
essential for this oxidative annulation reaction.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00212.
■
sı
Copies of 1H and 13C NMR spectra for all new
compounds (PDF)
With streamlined access to diketone 12, we next investigated
the total synthesis of 2 and 3.
AUTHOR INFORMATION
Corresponding Authors
■
The synthetic feasibility of the direct conversion of product
12 to 2 was explored. We speculated that 12 could be
converted into 2 by base-mediated epimerization. In the event,
when 2 was treated with DBU in toluene at reflux for 48 h,
norascyronone A (2) was obtained in 30% yield (with 12
recovered in 67% yield) on a 100 mg scale. We later discovered
that 2 could be prepared more effectively by kinetic
protonation of enolate 12a with AcOH at −78 °C, which
afforded 2 in 70% yield. The product was confirmed to be
Yu Lan − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400030, China;
orcid.org/0000-0002-2328-0020; Email: lanyu@
cqu.edu.cn
Jun Huang − State Key Laboratory of Chemical Oncogenomics
and Key Laboratory of Chemical Genomics, Peking University
Shenzhen Graduate School and Shenzhen Bay Laboratory,
Shenzhen 518055, China; Email: junhuang@pku.edu.cn
Zhen Yang − State Key Laboratory of Chemical Oncogenomics
and Key Laboratory of Chemical Genomics, Peking University
Shenzhen Graduate School and Shenzhen Bay Laboratory,
Shenzhen 518055, China; Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education
and Beijing National Laboratory for Molecular Science
(BNLMS), and Peking-Tsinghua Center for Life Sciences,
Peking University, Beijing 100871, China; orcid.org/0000-
0001-8036-934X; Email: zyang@pku.edu.cn
1
norascyronone A (2) by comparison of its H NMR and 13C
NMR spectra with those reported in the literature.4 The high
diastereoselectivity was rationalized by the formation of
chelation complex 12a, in which Li+ is chelated with the
C10 carbonyl group, causing the AcOH to approach from the
Re-face.
We next worked on the total synthesis of 3. Treatment of 12
with LDA (3.0 equiv) at −78 °C gave enolate 12a, which was
then reacted with 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine
(the Davis reagent; 3.0 equiv) to give desired product 3 in 68%
yield as a single diastereomer (Scheme 2). The structure of 3
Authors
1
was confirmed by comparison of its H NMR and 13C NMR
Tingting Cao − State Key Laboratory of Chemical
Oncogenomics and Key Laboratory of Chemical Genomics,
Peking University Shenzhen Graduate School and Shenzhen
Bay Laboratory, Shenzhen 518055, China
Lei Zhu − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400030, China;
orcid.org/0000-0002-7870-8469
spectra with those reported in the literature.4
Scheme 2. Total Syntheses of Norascyronones A (2) and B
(3)
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00212
Author Contributions
∥T.T.C. and L.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Science
Foundation of China (Grant Nos. 21632002, 21702011, and
21871012), Shenzhen Basic Research Program (Grant Nos.
JCYJ20180302150314340 and JCYJ20170818090044432),
and the Scientific and Technological Innovation Project
supported by Qingdao National Laboratory for Marine Science
and Technology (Grant Nos. 2015ASKJ02 and
LMDBKF201802).
In summary, protecting-group-free total syntheses of
( )-norascyronones A (2) and B (3) were achieved for the
first time in eight steps, with overall yields of 17% and 16%,
respectively, from commercially available aryl bromide 5. The
key step was a Mn(III)/Cu(II)-mediated cascade oxidative
cyclization for tetracyclic core formation, in which two new
bonds, two new rings, and two new contiguous stereogenic
centers were constructed in a single step. Notably, the steric
effect of the C5 chiral center on the outcome of the tetracyclic
cyclic ring formation was identified.
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oxidative radical cyclization (see Supporting Information for details).
E
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