A Total Synthesis of (–)-Nardoaristolone B

Article abstract of DOI:10.1002/ejoc.201600538

A stereoselective total synthesis of (–)-Nardoaristolone B, a nor-aristolane sesquiterpenoid natural product with an unusual 3/5/6 tricyclic ring system is described. The highlights of the present work includes use of (+)-(R)-Pulegone as a chiral-pool sta

Full text of DOI:10.1002/ejoc.201600538

DOI: 10.1002/ejoc.201600538
Full Paper
Natural Product Synthesis
A Total Synthesis of (–)-Nardoaristolone B
Rohini S. Ople,[a,b] Kishor L. Handore,[a,b] Nidhi S. Kamat,[a] and D. Srinivasa Reddy*[a,b]
Abstract: A stereoselective total synthesis of (–)-Nardoaristol- and stereoselective cyclopropanation. In addition, a new ana-
one B, a nor-aristolane sesquiterpenoid natural product with an
unusual 3/5/6 tricyclic ring system is described. The highlights
of the present work includes use of (+)-(R)-Pulegone as a chiral-
pool starting material, ring-closing metathesis, allylic oxidation
logue of Nardoaristolone B (minor product from the final step)
was isolated in pure form and fully characterized with the help
of single-crystal X-ray analysis.
Introduction
reported in the literature like Lindenene (2)[6] and Chloranthal-
actone A (3),[7] having a similar 3/5/6 structural core as Nardoar-
Sesquiterpenoids are a class of terpenoids that consist of three
isoprene units followed by biochemical modifications such as
oxidation or rearrangement. Isolation of such a sesquiterpenoid
natural product, Nardoaristolone B (1), was reported in 2013 by
Yao and co-workers from the underground parts of the Nardos-
tachys chinensis plant.[1a] The investigation of this particular
plant suggests that it is a source of a series of natural products
such as aristolane,[1b] nardosinane,[1c–1e] guaiane types,[1f,1g]
lignans,[1h] sesquiterpenoids, debilon,[1i] and kanshone A.[1d]
The roots and rhizomes of Nardostachys chinensis Batalin (Valeri-
anaceae family) have been used as stomachic and sedative
agents[2a] in Chinese traditional medicine for centuries.[2b] In
addition, it exhibits antimalarial, antinociceptive,[1g] and cyto-
toxic activities[1i] and also helps to enhance the nerve growth
factor.[2c] The natural product Nardoaristolone B isolated from
the same species exhibits a protective activity on the injury of
neonatal rat cardiomyocytes in a dose-dependent manner and
is believed to be biogenetically derived from Kanshone C (4).[1a]
This compound is also expected to have many interesting bio-
logical activities such as 5′-adenosine monophosphate acti-
vated protein kinase (AMPK) activation, insect repellent, and
insecticidal activities due to its structural resemblance to that
of Nootkatone (5).[2d–2h] In fact, in our hands, compound 1 in
recemic form showed excellent mosquito-repellent activity
against the Aedes mosquito, which is the vector for Dengue
fever and the Zika virus.[3] Isolation of the closely related ses-
quiterpene (–)-Aristolone (6)[4] was reported in 1955 from the
roots of Aristochia debilis, and its several syntheses were re-
ported in the literature.[5] There are a few more natural products
Figure 1. Structures of selected natural products.
[a] Division of Organic Chemistry, CSIR – National Chemical Laboratory,
Dr. Homi Bhabha Road, Pune 411008, India
E-mail: ds.reddy@ncl.res.in
http://academic.ncl.res.in/ds.reddy/research
[b] Academy of Scientific and Innovative Research (AcSIR),
New Delhi 110020, India
E-mail: ds.reddy@ncl.res.in
http://academic.ncl.res.in/ds.reddy/research
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600538.
Figure 2. Previous and present synthetic approaches.
1 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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istolone B (Figure 1). Due to its potential biological activity, aldol reaction, converting the OH group into an OMs group,
along with the unusual 3/5/6 tricyclic structural features, com- and elimination using MsCl/triethylamine reaction conditions
pound 1 has already attracted the attention of a few research to give compound 9 in 60 % yield.[10] This reaction sequence
groups including our own. The first total synthesis of Nardoaris- proceeded with complete diastereoselectivity, efficiently in-
tolone B in racemic form was reported from our group in stalled the vinyl group, and no olefin isomerization to the con-
2014.[8] The key features of this synthesis are a Diels–Alder/ jugated enone was observed. Grignard reaction of allyl magne-
Wittig/ring closing metathesis (RCM) reaction sequence, double sium bromide with enone 9 furnished the tertiary alcohol 12 in
allylic oxidation, followed by stereoselective cyclopropanation.
Later, Echavarren's group documented an interesting enan-
tioselective total synthesis of (–)-Nardoaristolone B using a
highly selective copper(I)-catalyzed conjugate addition/enolate
trapping sequence and a gold(I)-catalyzed oxidative cycliza-
tion[9] (Figure 2). Here we describe a stereoselective total syn-
thesis of (–)-Nardoaristolone B using a chiral-pool approach
starting from commercially available (+)-(R)-Pulegone.
66 % yield.[12] Although we observed excellent diastereoselect-
ivity, we did not attempt to establish the stereochemistry of the
new center as it would be destroyed in the next step. The terti-
ary alcohol 12 was then oxidized with PCC to afford compound
8 in 72 % yield with the desired transposition.[12] Compound
8 on ring closing metathesis using Grubbs' second-generation
catalyst resulted in hydrindane derivative 13 in 83 % yield. The
next major task was to introduce the oxygen functionality on
the five-membered ring; we tested a few conditions to achieve
the desired allylic oxidation product. When we tried the allylic
oxidation of 13 using PDC/tBuOOH[8a] and NaClO2/tBuOOH[8b]
conditions, we could not isolate clean compound 7 and always
obtained a mixture of compounds, which are probably resulting
from the isomerization of the double bond. However, after a
few attempts, the allylic oxidation of compound 13 was suc-
cessful with a combination of Mn(OAc)3·2H2O/tBuOOH[13] re-
sulting in the desired dienone 7 in 60 % yield.[8c] Compound 7
was previously synthesized in racemic form in our group, and
Results and Discussion
We envisioned the target molecule 1 by a stereoselective cyclo-
propanation of dienone 7 as planned in our racemic synthesis.
The dienone 7 could be prepared from trienone 8 by RCM fol-
lowed by allylic oxidation. A sequence of introducing allyl
groups followed by oxidative transposition on compound 9
would afford 8, which in turn could be constructed using
known methods from a commercially available starting material
(+)-(R)-Pulegone (Scheme 1).
Scheme 1. Retrosynthetic analysis of (–)-Nardoaristolone B.
Our synthetic route commenced with the preparation of the
known intermediate 9[10a] by applying literature procedures
starting from (+)-(R)-Pulegone.[10,11] The reaction of (+)-(R)-
Pulegone with LDA and MeI at –78 °C followed by retro-aldol
reaction in 20 % HCl under reflux conditions for 3 d gave 2,3-
dimethylcyclohexanone (10) in 88 % yield as a mixture of dia-
stereomers.[11] 2,3-Dimethylcyclohexanone (10) on TMS enolate
formation followed by a bromination/elimination sequence
gave 2,3-dimethyl-2-cyclohexenone (11) with 68 % yield over
two steps. The quaternary stereocenter was then installed by
insertion of a vinyl group at the α-position of 2,3-dimethyl-2-
cyclohexenone (11) with phenylselenoacetaldehyde using an
Scheme 2. Total synthesis of (–)-Nardoaristolone B.
2 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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the spectral data was matching. Finally, the gem-dimethylcyclo- it as a novel analogue of the natural product Nardoaristolone B.
propyl group was installed[14] on compound 7 by treatment of The assigned exo stereochemistry of the cyclopropane ring in
isopropyldiphenylsulfonium tetrafluoroborate[15] with tBuLi compound 14 was confirmed unambiguously by its single-
in THF at –78 °C to –30 °C to furnish the target compound crystal X-ray analysis (Figure 3). Although our synthesis is not
(–)-Nardoaristolone B (1) in 35 % yield and compound 14 with the best one and inferior to Echavarren's synthesis, our route
an exo-cyclopropyl ring in 13 % yield (Scheme 2).[8c] To improve can be an alternative to prepare the target and related com-
the yield in the final steps, we attempted a few other condi- pounds using chiral-pool starting materials.
tions, but the results were inferior. The three different condi-
tions tried for the cyclopropanation are captured in Scheme 3.
Conclusions
We have achieved a stereoselective total synthesis of natural
product (–)-Nardoaristolone B from the commercially available
monoterpene (+)-(R)-Pulegone. Having access to enantiopure
natural product (–)-Nardoaristolone B and its analogue com-
pound 14, it is now possible to evaluate their biological activi-
ties.
Experimental Section
General: All reactions were carried out in oven-dried glassware un-
der a positive pressure of argon or nitrogen, unless otherwise men-
tioned, with magnetic stirring. Air-sensitive reagents and solutions
were transferred by syringe or cannula and were introduced to the
apparatus through rubber septa. All reagents, starting materials,
and solvents were obtained from commercial suppliers and used as
Scheme 3. Optimization conditions for the cyclopropanation.
1
All the spectral data (IR, H NMR, 13C NMR and HRMS) were
such without further purification. Reactions were monitored by thin
found to be identical to those of the earlier reports, and the
layer chromatography (TLC) with 0.25 mm pre-coated silica gel
optical rotation of synthetic Nardoaristolone B was measured
plates (60 F254). Visualization was accomplished with either UV light
at [α]2D6 = –7.8 (c = 0.5, CH3OH) with the reported value being
or by immersion in an ethanolic solution of phosphomolybdic acid
at [α]2D6 = –7.4 (c = 0.5, CH3OH).[1,8c,9] Since we had racemic
(PMA), para-anisaldehyde, 2,4-dinitrophenylhydrazine (2,4-DNP),
Nardoaristolone B in hand from a previous synthesis, we were
and KMnO4 solution followed by heating with a heat gun for ca.
also able to determine the enantiomeric purity of synthesized
(–)-Nardoaristolone B using chiral HPLC,[16] and it was found to
15 s. Column chromatography was performed on silica gel (100–200
or 230–400 mesh size). Deuterated solvents for NMR spectroscopic
be > 99 %. Thus, we have accomplished the stereoselective and analyses were used as received. All 1H NMR and 13C NMR spectra
were obtained using a 200 MHz, 400 MHz, or 500 MHz spectrome-
ter. Coupling constants are given in Hertz. All chemical shifts are
quoted in ppm, using the residual solvent peak as a reference stan-
dard. The following abbreviations are used to explain the multiplici-
ties: s = singlet, d = doublet, dd = doublet of doublets, td = triplet
of doublets, dq = doublet of quartets, ddt = doublet of doublets of
triplets, m = multiplet. HRMS (ESI) data were recordedwith an ORBI-
TRAP mass analyser (Q Exactive). Mass spectra were measured with
ESI ionization using an MSQ LCMS mass spectrometer. Infrared (IR)
spectra were recorded with an FT-IR spectrometer as a thin film.
Chemical nomenclature was generated using ChemBioDraw-
Ultra 13.0. HPLC analysis was performed with a Shimadzu Class-VP
SP5 instrument with Shimadzu SPD-10-AVP UV detector. Melting
points of solids were measured with a Büchi B-545 melting-point
apparatus.
protecting-group-free total synthesis of (–)-Nardoaristolone B
(1) in eleven steps and 3 % overall yield. We have also isolated
a minor product (14) from the same reaction and characterized
(1R,5R,6S)-1-Allyl-5,6-dimethyl-6-vinylcyclohex-2-en-1-ol (12):
To a solution of compound 9 (1.6 g, 10.65 mmol) in dry diethyl
ether (60 mL) was added allyl magnesium bromide (1
M solution in
diethyl ether, 21.3 mL, 21.31 mmol) dropwise at 0 °C, and the mix-
ture was stirred for 15 min. The reaction was then quenched with
saturated aqueous NH4Cl (15 mL) and the mixture extracted with
diethyl ether (2 × 30 mL). The combined organic layers were
washed with water (20 mL) and brine (20 mL), dried with anhydrous
Na2SO4, and concentrated in vacuo. Purification by flash chromatog-
raphy on silica gel (diethyl ether/petroleum ether, 1:9) afforded enol
12 (1.35 g, 66 %) as light yellow oil. [α]2D9 = –18.05 (c = 1.8, CHCl3).
Figure 3. Crystal structure of compound 14.
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1
IR (film): νmax = 3074, 1636, 1217 cm–1. H NMR (200 MHz, CDCl3): A 1.9
M
solution of tBuLi in pentane (0.45 mL, 0.852 mmol) was
˜
δ = 6.04–5.76 (m, 2 H), 5.70–5.61 (m, 1 H), 5.52–5.45 (m, 1 H), 5.23
added dropwise to a suspension of isopropyldiphenylsulfonium
(dd, J = 10.8, 1.64 Hz, 1 H), 5.19–5.10 (m, 2 H), 5.07–5.00 (m, 1 H), tetrafluoroborate (296 mg, 0.937 mmol) in THF (4 mL) at –78 °C.
2.37 (ddd, J = 13.6, 9.6, 7.6 Hz, 2 H), 2.18–1.98 (m, 2 H), 1.80–1.69 After 30 min, 7 (50 mg, 0.284 mmol) was added as a solution in THF
(m, 1 H), 0.97 (s, 3 H), 0.82 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (2 mL) at –78 °C. The resulting mixture was maintained at –30 °C
(100 MHz, CDCl3): δ = 143.6, 134.9, 132.3, 126.5, 117.9, 115.4, 76.1,
for 15 min, quenched with saturated aqueous NH4Cl (2 mL), and
warmed to room temperature. The reaction mixture was then ex-
tracted with ethyl acetate (3 × 5 mL). The combined organic layers
were washed with water (5 mL) and brine (5 mL), dried with anhy-
drous Na2SO4, filtered, and concentrated in vacuo. Purification by
column chromatography (silica gel 100–200, ethyl acetate/petro-
leum ether, 1.5:8.5) afforded (–)-Nardoaristolone B (1) (21 mg, 35 %)
and 14 (12 mg, 13 %) as yellow solid. The ee of (–)-Nardoaristol-
one B (1) was determined by chiral HPLC as 99.52 %. [α]2D6 = –7.8
46.7, 44.9, 33.5, 31.7, 16.7, 10.6 ppm. HRMS (ESI): calcd. for C13H19
O
[M – H]– 191.1430, found 191.1428.
(4S,5R)-3-Allyl-4,5-dimethyl-4-vinylcyclohex-2-en-1-one (8): To a
magnetically stirred solution of enol 12 (1.35 g, 7.02 mmol) in anhy-
drous CH2Cl2 (80 mL) was added a homogenous mixture of PCC
(7.57 g, 35.12 mmol) and silica gel (7.57 g), and reaction mixture
was stirred at room temperature for 8 h. The reaction mixture was
then filtered through a small pad of silica gel using ethyl acetate
(50 mL) as eluent. Evaporation of the solvent and purification of the
residue on a 100–200 silica gel column (ethyl acetate/petroleum
ether, 1.5:8.5 as eluent) furnished the enone 8 (962 mg, 72 %) as
(c = 0.5, CH OH). M.p. 95–96 °C; IR (film): ν
= 2923, 2852, 2360,
˜
3
max
1713, 1460, 1215 cm–1. H NMR (400 MHz, CDCl3): δ = 6.18 (s, 1 H),
2.41–2.22 (m, 3 H), 1.94 (d, J = 5.5 Hz, 1 H), 1.77 (d, J = 5.5 Hz, 1 H),
1.17 (s, 3 H), 1.12 (s, 3 H), 1.08 (s, 3 H), 1.06 (d, J = 6.8 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 201.6, 200.0, 165.1, 123.5, 44.3, 42.3,
42.2, 40.3, 35.5, 32.1, 28.8, 20.8, 17.8, 15.9 ppm. HRMS (ESI): calcd.
for C14H19O2 [M + H]+ 219.1380, found 219.1379.
1
colorless oil. [α]2D9 = –7.23 (c = 0.65, CHCl3). IR (film): νmax = 2970,
˜
1671, 1416, 1352, 1281 cm–1. 1H NMR (500 MHz, CDCl3): δ = 5.91 (s,
1 H), 5.73 (ddt, J = 16.8, 9.9, 6.8 Hz, 1 H), 5.65 (dd, J = 17.5, 10.7 Hz,
1 H), 5.28 (d, J = 10.7 Hz, 1 H), 5.14–5.10 (m, 2 H), 5.06 (dq, J = 17.2,
1.5 Hz, 1 H), 2.85 (td, J = 6.9, 1.1 Hz, 2 H), 2.43 (dd, J = 17.2, 4.6 Hz,
1 H), 2.24 (dd, J = 17.2, 11.8 Hz,1 H), 2.12–2.08 (m, 1 H), 1.15 (s, 3
H), 0.92 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
199.2, 168.6, 143.1, 134.5, 126.6, 118.3, 115.8, 46.4, 41.8, 38.0, 37.7,
16.0, 15.8 ppm. HRMS (ESI): calcd. for C13H18ONa [M + Na]+
213.1250, found 213.1248.
(1aS,4R,4aR,7aR)-1,1,4,4a-Tetramethyl-1,1a,4,4a-tetrahydro-2H-
cyclopropa[d]indene-2,7(3,H)-dione (14): M.p. 105–107 °C. [α]D26
=
–1.11 (c = 0.125, CH3OH). IR (film): νmax = 2964, 2879, 1692, 1455,
˜
1
1374, 1236, 1181 cm–1. H NMR (400 MHz, CDCl3): δ = 7.66 (d, J =
6.1 Hz, 1 H), 6.23 (d, J = 6.1 Hz, 1 H), 2.22–2.16 (m, 3 H), 1.93–1.87
(m, 1 H), 1.50 (s, 3 H), 1.41 (s, 3 H), 1.29 (s, 3 H), 1.02 (d, J = 6.7 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 206.9, 205.5, 169.2, 131.6,
51.9, 48.3, 46.4, 45.3, 40.1, 36.6, 21.7, 21.3, 17.6, 15.8 ppm. HRMS
(ESI): calcd. for C14H19O2 [M + H]+ 219.1380, found 219.1379.
(7R,7aR)-7,7a-Dimethyl-3,6,7,7a-tetrahydro-5H-inden-5-one
(13): Grubbs' second-generation catalyst (215 mg, 5 mol-%) was
added to a magnetically stirred solution of 8 (962 mg, 5.06 mmol)
in anhydrous CH2Cl2 (80 mL), and the mixture was stirred at room
temperature for 4 h. The reaction mixture was concentrated in
vacuo, and the residue was purified by column chromatography
(silica gel 100–200; ethyl acetate/petroleum ether, 1.2:8.8) to afford
13 (680 mg, 83 %) as colorless oil. [α]2D9 = +10.7 (c = 0.25, CHCl3).
Acknowledgments
We acknowledge the Council of Scientific and Industrial Re-
search (CSIR), New Delhi, for the support through the XII Five
Year Plan (CSC0108: ORIGIN and BSC0124: NCL-IGIB Joint Re-
search Program) and Dr. Rajesh Gonnade and Ms. Ekta Sangtani
of the Center for Materials Characterization (CSIR-NCL, Pune) for
X-ray analysis. R. S. O. and K. L. H. thank CSIR for the award of
research fellowships.
IR (film): νmax = 2929, 2358, 1654, 1454, 1262 cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = 5.90 (d, J = 5.9 Hz, 1 H), 5.83 (s, 1 H), 5.80–
5.79 (m, 1 H), 3.43–3.37 (m, 1 H), 3.09–3.04 (m, 1 H), 2.31–2.27 (m,
2 H), 2.12–2.06 (m, 1 H), 1.05 (s, 3 H), 1.04 (d, J = 6.4 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 199.6, 176.6, 137.8, 126.5, 121.6,
50.9, 42.2, 38.0, 37.8, 17.2, 16.2 ppm. HRMS (ESI): calcd. for C11H15
O
[M + H]+ 163.1117, found 163.1116.
Keywords: Natural products · Total synthesis · Chiral pool ·
Nardoaristolone B · Cyclopropanation
(3aR,4R)-3a,4-Dimethyl-4,5-diydro-1H-indene-1,6(3aH)-dione
(7): To a solution of compound 13 (680 mg, 4.19 mmol) in EtOAc
(60 mL) were added 4 Å molecular sieves (1.36 g) and tBuOOH
(5.0
M in decane, 4.2 mL, 20.9 mmol) at room temperature. The
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(561 mg, 2.09 mmol) was added at room temperature. The resulting
mixture was stirred under nitrogen for 24 h before it was filtered
through Celite, eluted with EtOAc (20 mL), and concentrated in
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solid. [α]2D9 = –22.7 (c = 2.25, CHCl3). M.p. 74–76 °C. IR (film): νmax
=
˜
2926, 2361, 1703, 1650, 1456, 1375, 1217 cm–1. H NMR (400 MHz,
CDCl3): δ = 7.71 (d, J = 6.1 Hz, 1 H), 6.37 (d, J = 6.1 Hz, 1 H), 6.29
(s, 1 H), 2.56–2.48 (m, 2 H), 2.29–2.23 (m, 1 H), 1.24 (s, 3 H), 1.14 (d,
J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 199.7, 195.8,
165.0, 160.4, 133.7, 121.9, 46.6, 42.9, 36.3, 18.5, 15.1 ppm. HRMS
(ESI): calcd. for C11H13O2 [M + H]+ 177.0910, found 177.0909.
1
(1aS,1bR,2R,6aR)-1,1,1b,2-Tetramethyl-1,1a,1b,2,3,6a-hexa-
hydrocyclopropa[a]indene-4,6-dione, (–)-Nardoaristolone B (1):
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254 nm, inject vol.: 5 μL, tR(major) = 8.5–8.6 min, tR(minor) = 12.5–
12.6 min, 99.52 % ee.
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Received: April 29, 2016
Published Online: ■
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Natural Product Synthesis
R. S. Ople, K. L. Handore, N. S. Kamat,
D. Srinivasa Reddy* ............................ 1–6
A Total Synthesis of (–)-Nardoaristol-
one B
A stereoselective total synthesis of (–)- described. Use of (+)-(R)-Pulegone as a
Nardoaristolone B, a nor-aristolane ses- chiral-pool starting material, ring clos-
quiterpenoid natural product with an ing metathesis and stereoselective
unusual 3/5/6 tricyclic ring system is cyclopropanation are the highlights.
DOI: 10.1002/ejoc.201600538
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim