Biomimetic Total Syntheses of Callistrilones A, B, and D

Article abstract of DOI:10.1021/acs.orglett.7b03815

A biomimetic total syntheses of antibacterial natural products (±)-callistrilones A, B, and D, the first triketone-phloroglucinol-monoterpene hybrids with an unprecedented [1]benzofuro[2,3-a]xanthene and [1]benzofuro[3,2-b]xanthene pentacyclic ring system

Full text of DOI:10.1021/acs.orglett.7b03815

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Biomimetic Total Syntheses of Callistrilones A, B, and D
Dattatraya H. Dethe,* Balu D. Dherange,‡ and Saikat Das‡
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: A biomimetic total syntheses of antibacterial natural products ( )-callistrilones A, B, and D, the first triketone−
phloroglucinol−monoterpene hybrids with an unprecedented [1]benzofuro[2,3-a]xanthene and [1]benzofuro[3,2-b]xanthene
pentacyclic ring system along with the postulated biosynthetic intermediate, isolated from the leaves of Callistemon rigidus, were
achieved. The total synthesis features highly regio- and diastereoselective catalytic Friedel−Crafts alkylation, palladium-catalyzed
Wacker-type oxidative cyclization, Michael addition, and late-stage diastereoselective epoxide formation from the extremely
hindered β face as key steps.
relieving problems of the urinary tract. Australian natives use
hloroglucinols containing natural products have been a
Pgreat source of inspiration for synthetic organic chemists bottlebrush flowers as a natural energy drink. Callistrilones A
and B represent a new carbon skeleton with unprecedented
[1]benzofuro[2,3-a]xanthene and [1]benzofuro[3,2-b]-
xanthene pentacyclic ring systems composed of three kinds of
building blocks combined via two different coupling partners to
form dihydrofuran (ring D) and pyran (ring B) rings. The
structures of 1−3 were elucidated by spectral analysis, X-ray
diffraction, and electronic circular dichroism (ECD) calcu-
lations. The crude methanol extract of the fresh leaves of C.
rigidus also indicated the presence of 1−3 (analyzed by HPLC−
HRESIMS), confirming the natural occurrence of these
compounds. While our manuscript was being prepared,
Cheng et al. reported the isolation of callistrilones C (4), D
(5), and E (6) and the catalytic asymmetric total syntheses of
callistrilones A (1), C (4), D (5), and E (6).4 Herein, we report
biomimetic total syntheses of callistrilones A (1), B (2), and D
(5) and the postulated biosynthetic intermediate 3.
over a long period of time. Because of their complex structural
features and diverse biological effects, natural products of this
class have become attractive targets for organic chemists.1
Recently, Shaheen and co-workers2 isolated a phloroglucinol
adduct containing unprecedented carbon skeletons with two
kinds of building blocks from Myrtus communis, a new inhibitor
of reactive oxygen species (ROS). In 2016, Ye and co-workers
isolated the first triketone−phloroglucinol−monoterpene hy-
brids callistrilones A (1) and B (2) along with the postulated
biosynthetic intermediate 3 (Figure 1) from the plant
Callistemon rigidus,3 popularly known as bottlebrush because
of its cylindrical brushlike flowers resembling a traditional
bottle brush. The bottlebrush plant is used as a diuretic and for
Ye and co-workers postulated that callistrilones A (1) and B
(2) might be biosynthetically derived from intermediate 8 and
3, respectively (Scheme 1).3 The intermediates 3 and 8 were
assumed to be obtained by the radical addition of
isobutyrylphloroglucinol (9) across phellandrene (10) and
further intramolecular cyclization between phenolic 2-OH and
the carbocation of 11. Based on the biosynthetic pathway, we
proposed retrosynthetic analysis for callistrilones A (1), B (2),
and D (5) and the biosynthetic intermediate 3 as depicted in
Scheme 2. It was envisioned that callistrilone A (1) could be
obtained from 13-epi-callistrilone D (12) by stereoselective
epoxidation of the isolated double bond. 13-epi-Callistrilone D
Figure 1. Structures of callistrilones A (1) and B (2) and the
biosynthetic intermediate 3.
Received: December 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03815
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 1. Biosynthetic Pathway for 1−3 Proposed by Ye
and Co-workers
Scheme 3. Attempted Coupling of Phloroglucinol Derivative
17 and Phellandrene (10)
SI for preparation) on treatment with 10 mol % of BF3·OEt2
led to the formation of a diastereomeric mixture of 16 and 20
in a 6:1 ratio with 88% yield. As expected, compounds 16 and
20 showed zero optical rotation, since dihydrocarveol (19) on
treatment with Lewis acid generates the symmetrical allylic
carbocation 21; and the attack of electron-rich arene on
symmetrical intermediate 21 is possible from both sides
(Scheme 4).
Scheme 2. Retrosynthetic Analysis for Callistrilones A (1), B
(2), and D (5) and the Biosynthetic Intermediate 3
Scheme 4. Friedel−Crafts Reaction between Phloroglucinol
Derivative 14 and Dihydrocarveol (16)
The next task was regioselective Wacker-type oxidative
cyclization, for which various palladium catalysts and oxidants
were screened (Table 1). Among the catalysts screened, 10 mol
Table 1. Optimization Table for Palladium Catalyzed
Wacker-Type Oxidative Cyclization
a
entry
catalyst
PdCl2
oxidant
solvent
temp (°C) yield (%)
(12) and callistrilones D (5) and B (2) could be accessed from
compounds 6, 7, and 13, respectively, by acid-mediated
intramolecular cyclization, while compounds 6, 7, and 13
could be prepared by base-mediated Michael addition of
tricyclic intermediate 8 and 3 across isobutylidenesyncarpic acid
(14). It should be possible to synthesize compounds 8 and 3
from 15 and 16 by Wacker-type oxidative cyclization. As
postulated by Ye and co-workers, it was thought that alkenes 15
and 16 could be accessed via Friedel−Crafts alkylation of
phloroglucinol derivatives 9 and 17 with phellandrene (10).
Our explorations to test this overall hypothesis began with
the reaction of phloroglucinol derivative 17 and phellandrene
10 in the presence of 10 mol % of BF3·OEt2 in toluene or
CH2Cl2 did not generate the expected C-1 coupling product
16; instead, formation of C-4 coupling product 18 was
observed (Scheme 3). It was thought that, instead of using
phellandrene (10), dihydrocarveol (19) could generate
carbocation at C-1 under acidic conditions and would lead to
the formation of the desired product 16. To our delight,
phloroglucinol derivative 17 and dihydrocarveol (19) (see the
1
2
3
4
5
6
7
8
O2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
reflux
rt
17
7
PdCl2
O2
Pd(TFA)2
PdBr2
O2
reflux
reflux
reflux
rt
21
19
28
17
52
86
AgOAc
O2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOAc
MnO
MnO
reflux
rt
a
Isolated yields.
% Pd(OAc)2 and 3 equiv MnO in acetonitrile at room
temperature gave the best yield of 86% for tricyclic compound
3. The spectral data (1H, 13C, IR, HRMS) were in complete
agreement with those of natural 3. The stereochemistry of 3
was unambiguously established by single-crystal X-ray analysis.
Although there are literature reports on oxidative cyclizations
using palladium catalyst,5 this is one rare example where the
transformation is carried out at ambient temperature.
B
DOI: 10.1021/acs.orglett.7b03815
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Organic Letters
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Next, we focused our attention on the total synthesis of
callistrilone B (2). Alas, tricyclic compound 3, when subjected
to Michael addition with isobutylidenesyncarpic acid (14) (see
the SI for preparation) using NaH6 in THF or DMF, resulted
in the decomposition of the starting material 3, with no trace
amount of product formation. Due to strong intramolecular
hydrogen bonding, deprotonation of phenolic OH (chelated
with carbonyl oxygen) of compound 3 proved to be
problematic. Hence it was thought that compound 16, which
contains two phenolic OH groups, might react with
isobutylidenesyncarpic acid (14). As expected, compound 16
when treated with NaH6 followed by addition of isobutylide-
nesyncarpic acid (14), led to the formation of inseparable 1:1
diastereomeric mixture of Michael adducts 22 and 23, which on
further treatment with Pd(OAc)2 and MnO in acetonitrile
resulted in the formation of oxidative cyclized products 13 and
24 in 76% yield over two steps (Scheme 5). Independent
Scheme 6. Synthesis of Pentacyclic 13-epi-Callistrilone D
(12) and Callistrilone D (5)
Scheme 5. Completion of Total Synthesis of
( )-Callistrilone B (2)
THF, furnished an inseparable diastereomeric mixture of
callistrilone E (6) and 13-epi-callistrilone E (7), which on
further treatment with p-TSA in 1,2-dichloromethane under
reflux conditions afforded compounds 13-epi-callistrilone D
(12) and callistrilone D (5) in a 3:1 ratio with 78% yield for
two steps. The stereochemistry of compounds 12 and 5 was
unambiguously established by single-crystal X-ray analysis.
Compound 12 on epoxidation using m-CPBA resulted in the
formation of 10,11-di-epi-callistrilone A (29) in 42% yield,
where epoxidation took place from undesired α face (Scheme
7). Epoxidation using various other reagents such as DMDO,
treatment of compounds 13 and 24 with p-TSA in toluene
under reflux conditions resulted in the formation of callistrilone
B (2) and 13-epi-callistrilone B (25)7 in 88% and 86% yields,
respectively. The spectral data of synthetic callistrilone B (2)
(1H, 13C, IR and HRMS) were in complete agreement with
those of natural 2.3 The structure of 13-epi-callistrilone B (25)
was further confirmed by single-crystal X-ray analysis.
Scheme 7. Completion of Total Synthesis of Callistrilone A
(1)
After the completion of the synthesis of 3 and callistrilone B
(2), our next target was callistrilone A (1) and D (5).
Isobutyryl phloroglucinol (9) and dihydrocarveol (19) on
treatment with 10 mol % of BF3·OEt2 led to the formation of a
diastereomeric mixture of rotameric compounds 15 and 15a
(only major isomer is shown in Scheme 6) in a 6:1 ratio with
90% yield (see the SI for a detailed discussion). Next,
protection of phenolic OH was considered to avoid the
formation of undesired products during oxidative cyclization.
Taking advantage of hydrogen bonding, the phenolic OH of
compound 15 was regioselectively protected as a TBDPS ether,
followed by acetylation of remaining phenolic OH groups, and
finally, deprotection of the TBDPS group furnished the desired
diacetate compound 28 (Scheme 6). Compound 28 on
Wacker-type oxidative cyclization using Pd(OAc)2 and MnO
followed by the hydrolysis of the acetate groups using LiOH led
to the formation of advanced tricyclic intermediate 8 in 79%
yield for two steps. Tricyclic compound 8, when subjected to
Michael addition with isobutylidenesyncarpic acid (14) in
10
VO(acac)2,8 MnSO4,9 or NO2 resulted in either decom-
position of starting material or formation of α epoxide with low
yield. From the X-ray crystal structure of compound 12, it was
evident that the angle between fused rings D and E is ∼90°,
making the β face extremely hindered and hence epoxidation
under the above conditions proceeded from the least hindered
C
DOI: 10.1021/acs.orglett.7b03815
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α face. Finally, after trying various reagents and conditions to
get β epoxide, we relied on the formation of halohydrin, a case
where C10−C11 double bond in 12 would form α bromonium
ion (from the least hindered face) which, upon diaxial opening
with water, would result in the halohydrin formation. Then,
finally nucleophilic attack of the hydroxy group on halide under
basic conditions would result in the formation of the desired β
epoxide. Unfortunately, compound 12, when subjected to
halohydrin formation using NBS or 1,3-dibromo-5,5- dime-
thylhydantoin,11 resulted in decomposition of starting material.
It was thought that the aromatic ring in compound 12 is highly
electron rich and hence prone to oxidation under above
conditions. Hence, it was decided to protect phenolic OH
group of compound 12 as its acetate. Thus, compound 12 on
treatment with Ac2O and Et3N in the presence of catalytic
amount of DMAP afforded acetate 30 in 91% yield. Compound
30 on treatment with 1,3-dibromo-5,5-dimethylhydantoin
(DBDMH)11 smoothly generated halohydrin product, which
on exposure to KOH resulted in the formation of the desired β
epoxide and concurrent hydrolysis of acetate group to give
callistrilone A (1) in 87% yield over two steps. The spectral
data of synthetic callistrilone A (1) (1H,13C, IR and HRMS)
were in complete agreement with those of natural 1.3
ACKNOWLEDGMENTS
■
We thank Mr. Dinesh De, IIT Kanpur, for his help with the X-
ray analysis. S.D. thanks CSIR, New Delhi, for the award of a
research fellowship.
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In summary, a biomimetic total syntheses of callistrilones
( )-A, B, and D and the postulated biosynthetic intermediate
were achieved in 10, 4, 7, and 2 steps, respectively, with 21, 22,
26, and 65% overall yield using a highly regio- and
diastereoselective Friedel−Crafts alkylation, palladium-cata-
lyzed Wacker-type oxidative cyclization, and stereoselective
epoxide formation from extremely hindered β face as a key
reactions. This method is fairly general to the synthesis of other
natural products of this class as well as their analogues.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03815.
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Accession Codes
(7) Dethe, D. H. Presented at 21st International Conference on
Organic Synthesis, IIT Bombay, Mumbai, India, Dec 11−16, 2016.
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CCDC 1560549 and 1560553−1560555 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ddethe@iitk.ac.in.
ORCID
Dattatraya H. Dethe: 0000-0003-2734-210X
Balu D. Dherange: 0000-0002-4123-5012
Author Contributions
‡B.D.D. and S.D. contributed equally.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b03815
Org. Lett. XXXX, XXX, XXX−XXX