Total Synthesis of Beshanzuenone D and Its Epimers and Abiespiroside A

Article abstract of DOI:10.1021/acs.orglett.0c03157

A unified and protecting-group-free six-step total synthesis of bisabolane-type sesquiterpenoid beshanzuenone D and its stereoisomers and abiespiroside A using S-(+)-carvone as a common chiral-pool building block is disclosed. This synthetic route feature

Full text of DOI:10.1021/acs.orglett.0c03157

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Letter
Total Synthesis of Beshanzuenone D and Its Epimers and
Abiespiroside A
Balasaheb R. Borade, Ruchi Dixit, and Ravindar Kontham*
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ABSTRACT: A unified and protecting-group-free six-step total synthesis of bisabolane-type sesquiterpenoid beshanzuenone D and
its stereoisomers and abiespiroside A using S-(+)-carvone as a common chiral-pool building block is disclosed. This synthetic route
features chemoselective allylic chlorination of carvone, Au(I)-catalyzed cycloisomerization induced construction of furan from
homopropargylic diol, substrate-controlled selective hydroxylation using Davis-oxaziridine, and dye-sensitized photo-oxidation
1
(
through O ) of hydroxyalkyl tethered furan to access oxaspirolactone as key transformations. A comprehensive set of NMR data
2
along with DFT calculations, ECD spectra, and optical rotation measurements of the synthesized beshanzuenone D and its epimers
were obtained to confirm absolute configurations.
esquiterpenoids are a class of immensely diverse natural
products emerged from 15-carbon precursors, and they
their biological profile and found to significantly inhibit PTP1B
(a key target for type-II diabetes and obesity therapy) with
IC50 values of 16.6 and 10.6 μg/mL, respectively. The
structural similarity and identical stereochemical features reveal
the close biogenetic relationship between sesquiterpenoids 1,
S
continue to play a remarkable role in synthetic organic
chemistry, medicinal chemistry, and drug discovery owing to
their broad range of biological activities and diverse structural
1
features. These C-15 sesquiterpenes undergo regio- and
2
, and 3 (Figure 1).
stereoselective oxygenation with the aid of P450s (cytochrome
P450 monooxygenases), widely present in bacteria, fungi, and
plants, and generate diverse natural products with a wide range
Recently, in 2018, the Dai, Adibekian, and Zhang research
6
groups disclosed an elegant synthetic approach for abiespiro-
2
of biological profile. Inspired by traditional Chinese medicinal
applications of plants, in 2010, Zhang and co-workers reported
the isolation of abiespiroside A (1), an unprecedented
oxaspirolactone sesquiterpenoid possessing a 6/6/5 ring
system from Abies delavayi Franch., trees in the highlands
(
3300−4000 m high) of the northwest of the Yunnan and
southeast of the Tibet provinces of China. They also disclosed
its inhibitory properties against LPS-induced NO production
in RAW264.7 macrophages, an important therapeutic effect for
Figure 1. Chemical structures of abiespiroside A (1), beshanzuenone
C (2), and beshanzuenone D (3)
3
numerous inflammatory diseases.
Later, in 2016, Hu’s research group disclosed the isolation of
beshanzuenone C (2) and beshanzuenone D (3) (oxidized
aglycons of abiespiroside A (1)) from the shed trunk barks of
the plant Abies beshanzuensis, which is regarded as one of the
Received: September 19, 2020
1
2 critically endangered plant species in the world by the
Species Survival Communication (SSC) of the International
Union for Conservation of Natural Resources (IUCN) since
4
,5
1
987; further, natural products 2 and 3 were assessed for
©
XXXX American Chemical Society
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A
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side A, beshanzueone C and D, and structurally close
congeners using their in-house developed Pd-catalyzed hydro-
carbonylative lactonization to install the 6/6 fused bicyclic
lactone 6 from diol 5 (prepared from S-(+)-carvone (4)) and
the Dreiding−Schmidt reaction employing bromo-ester 7 to
construct the 6/5-oxaspirolactone moiety, followed by
substrates 9 or 10). Next, the furan intermediate 9 or 10
possessing a methylene or methyl substituent at C7,
4
respectively (beshanzuenone D numbering), would be
prepared from propargylic diol 11 through Au-catalyzed
dehydrative cycloisomerization. Propargylic diol 11 could
readily be synthesized from chiral-pool building block S-
(+)-carvone (4) and known alkyne-diol 12 utilizing an
interesting classical sequence of reactions (Scheme 2).
With the general retrosynthetic analysis in hand, we began
our study with the synthesis of furan intermediate 14, which
contains a complete carbon skeleton of target natural products
11,13
10,11
Ru (CO) -mediated exo (Δ ) to endo (Δ ) olefin
3
12
isomerization to deliver advanced intermediate 8 as key steps
Scheme 1). Further, they synthesized and identified an
(
Scheme 1. Previous Synthesis of Abies Sesquiterpenoids
1
and 3 (Scheme 3). Thus, our synthetic efforts were
Scheme 3. Initial Attempt for the Synthesis of Abies
Sesquiterpenoids
analogue as the first covalent and selective SHP2 (Src
homology region 2-containing protein tyrosine phosphatase
(
PTP) 2; a known oncogenic driver) inhibitor, in addition to
potential PTP inhibitory activities, with POLE3 (DNA
polymerase epsilon subunit 3) identified as one of the cellular
targets for these scaffolds with the aid of chemoproteomic
6
studies (Scheme 1). Further to this elegant example of total
synthesis, there is an urgent need to develop concise, facile,
and practical synthetic routes for these natural products to
access in sufficient quantities to carry out comprehensive
pharmacological investigations.
In continuation of our interest in the chemistry of
7
oxaspirolactones and total syntheses of biologically active
8
natural products, we embarked on the synthesis of abiespiro-
side A (1) and beshanzuenone D (3). In a retrosynthetic
analysis (depicted in Scheme 2), we envisioned an approach to
access 1, 3, and its stereoisomers through dye-sensitized photo-
oxidation-mediated oxaspirolactone construction from hy-
droxy-cyclohexenone tethered furan precursor 9 or 10 (here,
the nascent stereochemistry at C7 and C9 of 1 or 3 would be
determined principally by the pre-existing stereocenters on the
commenced from natural chiral-pool building block S-
(
+)-carvone (4), which was subjected to chemoselective allylic
Scheme 2. Retrosynthetic Analysis of Abies
Sesquiterpenoids 1 and 3 and Epimers
chlorination using NaClO and KH PO to give intermediate
1
2
4
9
10
3 in 84% yield. Subsequent Cu(I)-catalyzed coupling of 13
with propargylic diol 12 (prepared from hydroxyacetone 17 in
11
two steps via 18) cleanly furnished diol 11 in 95% yield.
Next, AuCl-catalyzed dehydrative cycloisomerization of alkyne
diol 11 delivered 1,3-disubstituted furan 14 in a good yield of
12
8
3% under open-flask conditions. The next task was to
introduce the α-hydroxyl functionality at the C1 position of
1
3
intermediate 14 in which the Davis-oxaziridine -mediated
hydroxylation was found to be fruitful and furnished 9 in 65%
yield with good diastereoselectivity (dr, 9:1; assigned based on
14
2D NMR and NOE analysis) (Scheme 3).
With a good quantity of furan intermediate 9 in hand, we
have proceeded for the construction of 6/6/5 oxaspirolactone
precursor 15 or 15a (Scheme 3). In view of the sensitivity of
the α-hydroxyl functionality of 9, nearly neutral reaction
B
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conditions of Mitsunobu’s and Vassilikogiannakis’s dye-
sensitized photo-oxidation of furan were chosen for this
endeavor that was known to proceed through [4 + 2]-
cycloaddition of singlet oxygen with furan and intramolecular
opening of the adduct with the hydroxyl functionality followed
Scheme 4. Synthesis of Beshanzuenone D (3) and Its
Isomers (3a, 16, and 16a)
15
by subsequent lactol oxidation steps. Accordingly, hydroxy-
alkyl furan 9 was treated with methylene blue (MB), oxygen
(
balloon pressure), and hv (visible light, 200 W bulb) followed
by Ac O in pyridine to get oxaspirolactone 15 and its C9-
2
epimer 15a in 35 and 28% isolated yield, respectively. We then
7
,14
move forward to the challenging chemoselective Δ
reduction of 15 and 15a precursors; thus, initially 15 was
subjected to hydrogenation using various catalysts (Pd/C,
Pd(OH) /C, and Pt/C) and solvent systems, which resulted in
2
a complex mixture due to nonselective reaction pathways. To
16
our surprise, Wilkinson’s reduction of 15 and 15a using
RhCl(PPh ) and H (50 psi) in benzene at 70 °C showed
3
3
2
great selectivity but delivered undesired stereoisomeric
products 7-epi-beshanzuenone D (16) and 7,9-di-epi-beshan-
zuenone D (16a) in 82 and 80% yield, respectively. This
stereochemical outcome could be due to the steric influenced
convex facial (α-face) attack of the hydrogenation catalytic
14
system onto the 15 or 15a (Scheme 3).
Having obtained the undesired (inverse) stereochemistry at
Scheme 5. Formal Synthesis of Abiespiroside A (1)
the C7-Me group of 16 and 16a, we decided to slightly alter
7,14
the synthetic sequence by the reduction of the Δ
at the
stage of intermediate 14 instead of advanced tricyclic
intermediate 15 and 15a, that could avoid the restricted single
α-facial reduction. Thus, intermediate 14 was reduced using
Wilkinson’s catalyst under identical conditions employed in
Scheme 3, which furnished C7-diastereomers 19 and 19a in
8
2% yield as an inseparable mixture. Subsequent α-
hydroxylation of the mixture using Davis-oxaziridine delivered
diastereomers 10 (36%) and 10a (32%) with complete
substrate controlled stereoselection, which were separated
successfully through conventional silica-gel (SiO ) column
2
chromatography. Next, intermediate 10 was subjected to a
photo-oxidation reaction, which delivered beshanzuenone D
(
3) and 9-epi-beshanzuenone D (3a) in 40 and 30% yield,
respectively, whereas precursor 10a delivered 7-epi-beshanzue-
none D (16) and 7,9-di-epi-beshanzuenone D (16a) in 38 and
2
3% yield, respectively. The predominant formation of spiro-
epimers 3 and 16 (possessing the β-orientation of lactone ring
oxygen) over 3a and 16a could be attributed to the
stabilization of the oxaspirolactone through an anomeric
1
7
effect.
4
,6
Having successfully completed the synthesis of bashanzue-
none D and its epimers (Schemes 3 and 4), we extended our
work to access abiespiroside A (1) (the β-D-glucopyranoside
derivative of beshanzuenone D (3)) using a similar strategy to
literature. Furthermore, the ECD spectral (MeOH) data (c
−
3
= 2.3 × 10 M (MeOH)) of 3 were also in agreement with
that reported in the literature. Interestingly, the ECD spectra
4
of epimer (+)-16 (possessing the β-orientation of lactone
oxygen) show a high degree of similarity with the ECD spectra
of 3, whereas analogues 3a and 16a (having the α-orientation
of lactone oxygen) displayed distinct ECD curves compared to
3 and 16, which clearly demonstrates the relation between the
stereochemistry at the spiro-center (C9) and ECD absorption
6
that reported by Davis et al. The selective carbonyl reduction
of 3 using NaBH in THF at −78 °C gave the hydroxyl
4
intermediate 20 as a single diastereomer. Next, the selective β-
glycosylation of alcohol 20 was performed using NIS, BF3·
Et O, and known thioglycoside donor 22 (prepared from D-
2
1
4
glucose (21) in two steps with 58% isolated yield) to furnish
the tetra-acetylated glycoside 23 in 70% yield. The global
deprotection of acetate groups of 23 using NaOMe in MeOH
delivered abiespiroside A (1) in 85% yield (Scheme 5).
In order to establish the absolute configurations of 3 and its
epimers (3a, 16, and 16a), initially (+)-beshanzuenone D (3)
(Figure 2).
This unambiguous establishment of the structure of
beshanzuenone D (3) and the synthetic sequence followed
and in turn provided the information about the absolute
stereochemistry at C7 of 10, 10a, and 3a (Scheme 4).
Consequently, the second congener obtained from intermedi-
ate 10 was assigned as 9-epi-beshanzuenone D (3a) (Scheme
4). The next crucial task was to establish the stereochemistry
14
1
13
was confirmed through the comparison of H and C NMR,
14
HRMS, and optical rotation data with the reported
C
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phenomenon has been noticed for 16 (H-1 showed a
downfield signal at δ 4.47 ppm (calcd δ 4.56 ppm) due to
the β orientation of ring-C oxygen (entry C, Figure 2)) and
1
6a (H-1 showed an upfield signal at δ 4.22 ppm (calcd δ 4.37
ppm) due to the α orientation of ring-C oxygen (entry D,
Figure 2)). These downfield changes in chemical shifts are due
to the deshielding effect of the nearby electronegative ring-C
14,20
oxygen atom.
These observations are in close accordance
with that reported for the structural assignment of
1
8
8b,19
20
ritterazines and hippuristanol
epimers (Figure 2).
These conclusions were further supported by key NOESY
correlations of H-1/H-7 and H-8α/Η-10 in compound 3; H-
1
1
/H-10, H-1/H-7, and H-8β/Η-10 in compound 3a; H-1/Me-
4 and H-8α/Η-10 in compound 16; and H-1/Me-14 and H-
14
Figure 2. ECD (circular dichroism) spectra (MeOH) of (+)-be-
shanzuenone D (3), (+)-3a, (+)-16, and (+)-16a
8β/Η-10 in compound 16a (Figure 3).
In conclusion, an efficient and unified synthesis of
beshanzuenone D and its three epimers has been accomplished
from a chiral pool building block S-(+)-carvone. This
protecting-group-free synthetic route is highly concise with
six linear transformations and an overall yield of 7.82, 5.86,
9.64, and 12.35% obtained for 3, 3a, 16, and 16a, respectively.
Furthermore, formal total synthesis of abiespiroside A was also
accomplished in a total number of nine steps. This synthetic
route would facilitate access to diverse analogues via changing
the readily accessible alkyne diol coupling partner (12), which
in turn generates the library of the furan precursor of the
oxaspirolactone skeleton and could help in SAR studies.
Absolute configurations of beshanzuenone D (3) and its
epimers (3a, 16, and 16a) were established using extensive
NMR data, ECD measurements, and DFT calculations. These
investigations can assist in the determination of absolute
stereochemistry in future isolated natural compounds of this
type. The biological activity evaluation of all of these epimers
and intermediates is under progress, and the results will be
published in due course.
at C9 (the spiro stereocenter) of epimers 3a, 16, and 16a. To
solve this puzzle, low-energy conformations of 3, 3a, 16 and
1
6a, and distances between H-1 and ring-C oxygen were
obtained through DFT calculations, and in silico chemical shift
values for H-1 were further calculated at B3LYP/6-31 level of
theory using the GIAO method, which might provide insight
into the stereochemical orientation of the lactone ring oxygen
(
Figure 3).
When the terminal oxygen of the ring-C is β-configured (in
3), H-1 is in close proximity (2.71 Å) to it and showed δ 4.43
ppm (calcd δ 4.56 ppm) (entry A, Figure 2), whereas, in the
spiro-epimer 3a, ring-C oxygen is in the α-configuration and
away from H-1 (3.99 Å); hence, H-1 showed an upfield signal
at δ 4.08 ppm (calcd δ 4.29 ppm) (entry B, Figure 2). A similar
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03157.
Experimental procedures, spectroscopic data, and copies
of NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Ravindar Kontham − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India; Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad
2
01002, India; orcid.org/0000-0002-5837-2777;
Email: k.ravindar@ncl.res.in, konthamravindar@gmail.com
Authors
Balasaheb R. Borade − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India; Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad
2
01002, India
Ruchi Dixit − Physical and Material Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India; Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad
2
01002, India
Figure 3. Low energy conformations of 3, 3a, 16, and 16a; NOE
interactions; and NMR analysis.
Complete contact information is available at:
D
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https://pubs.acs.org/10.1021/acs.orglett.0c03157
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from CSIR-New Delhi, India (INPROTICS-
Pharma and Agro; HCP0011/No.9/1/CS/CIA/2017-MD), is
gratefully acknowledged. B.R.B. thanks UGC-India for the
award of Senior Research Fellowship (SRF). We thank Dr.
Udaya Kiran Marelli, CSIR-NCL, Pune, for 2D NMR support
and Prof. H. N. Gopi, IISER-Pune, for ECD analyses.
REFERENCES
1) (a) Degenhardt, J.; Ko
■
(
2
̈
llner, T. G.; Gershenzon, J. Phytochemistry
009, 70, 1621−1637. (b) Ludwiczuk, A.; Skalicka-Wozniak, K.;
Georgiev. Pharmacognosy 2017, 233−266. (c) Fraga, B. M. Nat. Prod.
Rep. 2006, 23, 943−972.
(
2) Munro, A. W.; Girvan, H. M.; McLean, K. J. Biochim. Biophys.
Acta, Gen. Subj. 2007, 1770, 345−359.
3) Yang, X.-W.; Li, S.-M.; Li, Y.-L.; Xia, J.-H.; Wu, L.; Shen, Y.-H.;
Tian, J.-M.; Wang, N.; Liu, Y.; Zhang, W.-D. Eur. J. Org. Chem. 2010,
010, 6531−6534.
4) Hu, C.-L.; Xiong, J.; Li, J.-Y.; Gao, L.-X.; Wang, W.-X.; Cheng,
K.-J.; Yang, G.-X.; Li, J.; Hu, J.-F. Eur. J. Org. Chem. 2016, 2016,
(
2
(
1
(
(
832−1835.
5) (a) Shao, S.; Jin, Z.; Weng, Y. H. J. Wood Sci. 2008, 54, 81−86.
6) Davis, D. C.; Hoch, D. G.; Wu, L.; Abegg, D.; Martin, B. S.;
Zhang, Z. Y.; Adibekian, A.; Dai, M. J. Am. Chem. Soc. 2018, 140,
7465−17473.
7) (a) Thorat, S. S.; Kontham, R. Org. Biomol. Chem. 2019, 17,
270−7292. (b) Kambale, D. A.; Thorat, S. S.; Pratapure, M. S.;
Gonnade, R. G.; Kontham, R. Chem. Commun. 2017, 53, 6641−6644.
8) (a) Thorat, S. S.; Palange, M. N.; Kontham, R. ACS Omega
018, 3, 7036−7045. (b) Ravindar, K.; Reddy, M. S.; Lindqvist, L.;
Pelletier, J.; Deslongchamps, P. J. Org. Chem. 2011, 76, 1269−1284.
c) Ravindar, K.; Reddy, M. S.; Lindqvist, L.; Pelletier, J.;
Deslongchamps, P. Org. Lett. 2010, 12, 4420−4423.
9) (a) Zhang, W.; Yao, H.; Yu, J.; Zhang, Z.; Tong, R. Angew.
1
(
7
(
2
(
(
Chem., Int. Ed. 2017, 56, 4787−4791. (b) Huang, J.; Yang, J. R.;
Zhang, J.; Yang, J. J. Am. Chem. Soc. 2012, 134, 8806−8809.
(
(
10) Joung, S.; Kim, R.; Lee, H. Y. Org. Lett. 2017, 19, 3903−3906.
11) Paioti, P. H. S.; Abboud, K. A.; Aponick, A. ACS Catal. 2017, 7,
2
(
2
(
133−2138.
12) Aponick, A.; Li, C. Y.; Malinge, J.; Marques, E. F. Org. Lett.
009, 11, 4624−4627.
13) (a) Davis, F. A. Tetrahedron 2018, 74, 3198−3214. (b) Davis,
F. A.; Nadir, U. K.; Kluger, E. W. J. Chem. Soc., Chem. Commun. 1977,
4
(
1, 25−26.
14) See the Supporting Information for details.
(
15) (a) Pavlakos, E.; Georgiou, T.; Tofi, M.; Montagnon, T.;
Vassilikogiannakis, G. Org. Lett. 2009, 11, 4556−4559. (b) Fukuda,
H.; Takeda, M.; Sato, Y.; Mitsunobu, O. Synthesis 1979, 1979, 368−
3
(
70.
16) (a) Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J.
Chem. Soc. A 1966, 1711. (b) Hussey, A. S.; Takeuchi, Y. J. Am. Chem.
Soc. 1969, 91, 672−675.
(
17) (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617−1661.
(
b) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406−
440.
18) Phillips, S. T.; Shair, M. D. J. Am. Chem. Soc. 2007, 129, 6589−
598.
19) Li, W.; Dang, Y.; Liu, J. O.; Yu, B. Chem. - Eur. J. 2009, 15,
0356−10359.
20) Low energy conformations of 3, 3a, 16, and 16a calculated with
DFT at the PBE/TZVP level of theory.
4
(
6
(
1
(
E
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