Total synthesis of the proposed structure of Anti-TMV active tabasesquiterpene A

Article abstract of DOI:10.1016/j.tet.2021.132282

The proposed structure of Tabasesquiterpene A, an illudalane type of sesquiterpene has been synthesized in twelve steps from 2-methoxy-4-methylbenzaldehyde in 40% overall yield. Triflic acid mediated intramolecular Freidel-Crafts acylation allows to develop the critical indanone moiety, a key intermediate of this synthesis. A careful ortho-selective formylation and subsequent Knoevenagel condensation to incorporate three carbon side chain, followed by reduction, formation of tricyclic lactone and DIBAL-H supported reduction of lactone to target were other key transformation involved. The NMR spectroscopic data of the synthetic sample differ from those of natural tabasesquiterpene A.

Full text of DOI:10.1016/j.tet.2021.132282

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of the proposed structure of Anti-TMV active
tabasesquiterpene A
Anusueya Kumari, Muthiah Suresh, Raj Bahadur Singh*
Department of Chemistry, Central University of Jharkhand, Cheri-Manatu, Kamre, Ranchi, 835 222, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The proposed structure of Tabasesquiterpene A, an illudalane type of sesquiterpene has been synthesized
in twelve steps from 2-methoxy-4-methylbenzaldehyde in 40% overall yield. Triflic acid mediated
intramolecular Freidel-Crafts acylation allows to develop the critical indanone moiety, a key intermediate
of this synthesis. A careful ortho-selective formylation and subsequent Knoevenagel condensation to
incorporate three carbon side chain, followed by reduction, formation of tricyclic lactone and DIBAL-H
supported reduction of lactone to target were other key transformation involved. The NMR spectro-
scopic data of the synthetic sample differ from those of natural tabasesquiterpene A.
© 2021 Elsevier Ltd. All rights reserved.
Received 1 April 2021
Received in revised form
31 May 2021
Accepted 3 June 2021
Available online xxx
Keywords:
Knoevenagel condensation
Lactone tabasesquiterpene A
Triflic acid
1. Introduction
and propyl chain regioselectively would be a challenging part
associated with this synthesis. In the last two decades, remarkable
Nicotiana tabacum of the genus Nicotiana, native to the tropical
Americas is a commercial crop of tobacco [1]. Apart from a stimu-
lating agent, the herbs of N. tabacum have been used as an insec-
ticide, anesthetic, diaphoretic, sedative, and emetic agent in
Chinese folk medicine [2e4]. This herbaceous plant constitutes of
diverse molecular scaffolds with remarkable biological activities,
including anti-HIV-1, anti-TMV, and cytotoxicity [5]. In 2015, Shang
et al. isolated a new sesquiterpene tabasesquiterpene A 1 (Fig. 1)
with unprecedented structure from Nicotiana tabacum [6]. The ar-
chitecture of 1 is similar to illudalane sesquiterpene, which is
commonly found in fungi and ferns [7,8]. Unlikely, tabasesqui-
terpene A 1 has a gem-dimethylated indane core with hydroxy
propyl side chain, whereas the illudalanes comprise of hydroxy
ethyl side chain. Additionally, 1 exhibited potential anti-TMV ac-
tivity with good inhibition rates. Shang et al. proposed the structure
of 1 based on an extensive spectroscopic studies such as UV, HRMS,
1D NMR and 2D NMR (1He1H COSY, HMBC). Apart from the bio-
logical activity, the polysubstituted benzene core represents taba-
sesquiterpene A 1 as a synthetic target for studies. In addition, the
interesting part of 1 is a methyl group at C-6, hydroxypropyl side
chain at C-5 of gem-dimethylated indane core. Generating this
indane core from aromatic compound with poor directing groups
works have been reported in the synthesis of illudalane sesquiter-
penes [9]. In our ongoing endeavour to synthesize new biologically
active natural products, we herein discuss our effort to synthesize
target 1.
2. Results and discussion
Retrosynthetic plan for synthesis of 1 is briefly outlined in
Scheme 1. After careful evaluation of the structural features, we
envisaged that the final compound could be obtained from the
tricyclic lactone 2 by DIBAL-H mediated reduction. The precursor 2
could be easily developed from the intermediate 3 via ortho-for-
mylation, methylation, Knoevenagel condensation followed hy-
drogenation and demethylation. Phenolic indane 3 could be
accessible from the indanone 4 by the sequence of methylation,
reduction of ketone to alkane followed by deprotection. The syn-
thesis of challenging indanone 4 was imagined from readily avail-
able aldehyde 5 via Knoevenagel condensation, reduction of C]C
bond and acid mediated intramolecular cyclization.
As outlined in Scheme 2, the synthesis of 1 started with the
ortho-formylation of commercially available phenol 6 by treatment
with MgCl2, Et3N, (HCHO)n in dry acetonitrile to give the aldehyde 7
in 72% yield [10]. The phenolic group in 7 was protected with MeI,
K2CO3 in DMF to give the desired aldehyde 5 in 92% yield [11],
which was subjected to Knoevenagel condensation with malonic
acid to deliver the cinnamic acid 8 in 93% yield [12] (see Scheme 2).
* Corresponding author.
E-mail address: raj.singh@cuj.ac.in (R.B. Singh).
https://doi.org/10.1016/j.tet.2021.132282
0040-4020/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: A. Kumari, M. Suresh and R.B. Singh, Total synthesis of the proposed structure of Anti-TMV active tabasesquiterpene A,
Tetrahedron, https://doi.org/10.1016/j.tet.2021.132282

A. Kumari, M. Suresh and R.B. Singh
Tetrahedron xxx (xxxx) xxx
TfOH Scheme 3.
Delighted with a large quantity of 4 in hand, we next evaluated
its modification to the desired intermediate indane 3. Methylation
of 4 with NaH and MeI in THF provided the gem-dimethylated
indanone 11 in 92% yield [21]. Reduction of indanone 11 with ZnI2
and NaCNBH3 in DCE gave the indane derivative 12 in 96% yield
[22], which upon demethylation with BBr3 in DCM furnished
indane 3 in 93% yield [23]. Once the indane core was generated, we
thought that o-formylation followed by Knoevenagel condensation
will regioselcetively incorporate the three carbon side chain
Scheme 4.
Fig. 1. Structure of tabasesquiterpene A
In turn, compound 3 was readily converted to aldehyde 13 in
81% yield. However, subsequent Knoevenagel condensation of 13 to
coumarin 14 not proceeded well and most of the aldehyde remains
unreacted. Alternatively, protecting the phenolic group followed by
condensation of 15 with malonic acid developed 16 in good yield.
Next, reduction of 16 followed by demethylation of 17 with BBr3
generated the precursor 2 in 95% yield Scheme 5. Finally, the DIBAL-
H mediated reduction successfully furnished the target 1 in 95%
yield [24]. This twelve-step sequence from known aldehyde 5
helped to achieve the proposed tabasesquiterpene A 1 in an overall
40% yield. At the end, we carefully compared the experimental data
of the synthetic molecule 1 (1H and 13C NMR recorded in C5D5N as
well as CDCl3) with those reported for the natural molecule 1 in
Scheme 1. Retrosynthetic analysis for Tabasesquiterpene A.
Scheme 2. Synthesis of indanone derivative 10. Reagents and conditions: i. Et3N, MgCl2, (HCHO)n, dry CH3CN, 70 ꢀC, 8 h, 72%; ii. K2CO3, MeI, dry DMF, rt, 6 h, 92%; iii. Malonic acid,
pyridine, piperidine (cat.), reflux, 8 h, 93%; iv. NieAl alloy, 10% aq. NaOH, 12 h, rt, 96%; v. PPA, 110 ꢀC, 12 h, 12%.
Reduction of the olefinic bond in 8 with NieAl alloy gave
hydrocinnamic acid 9 in 96% yield [13], which was readily con-
verted to indanone 10. However, the polyphosphoric acid (PPA)
mediated cyclization [14] gave drastically low yields (12%) than
expected. Changing the reaction parameter did not improve the
yield of 10, which is probably due to an unfavourable electronic
effect on the aromatic ring in 9. At this stage, proceeding with a
small quantity of indanone will affect the further conversion and
overall yield, which will be unattractive. Since this indanone de-
rivative has already been used in many natural product syntheses
[9s, 15], we intended to prepare it in high yield using other possible
alternative reagents. At the outset, the Friedel-Crafts acylation of 9
with various protic acid as well as Lewis acids was extensively
studied. Efforts to obtain 10 with methanesulfonic acid [16], Eaton's
reagent [17], a mixture of trifluoroacetic acid and its anhydride at
110 ꢀC were not fruitful. Similarly, reaction of 9 with Sc(OTf)3 [18],
or AlCl3 did not yield the desired indanone [19]. In all these at-
tempts, we either recovered the starting material or the complex
mixture obtained. Ultimately, the cyclised product was realised by
the reaction of 9 with TfOH [20]. Attempt with 2 equivalents of
TfOH at 110 ꢀC for 6 h under neat condition compound 9 gave 52% of
10 and 37% of 4 which are compatible to further transformation.
However, we obtained 4 in high yield (89%) with 4 equivalents of
C5D5N (Supporting information of this reported article helps to
realize that the 1H and 13C NMR spectrum of natural tabasesqui-
terpene A were recorded in solvent C5D5N, not in CD3OD or CD3Cl)
[6]. Although the spectroscopic data of synthetic compound 1
strongly support the proposed structure, we found a significant
difference in the position of the chemical shift with the natural
compound 1 (See table in SI for more details). In particular, the CH2
on the three-carbon side chain H-10, H-11, and H-12 appeared at
2.64 (t, J ¼ 7.8, 2H), 1.83 (m, 2H), and 3.54 (t, J ¼ 6.5, 2H) respec-
tively, for naturally isolated 1 while for the same observed at 3.13 (t,
J ¼ 7.8 Hz, 2H), 2.14 (m, 2H), 3.95 (t, J ¼ 6.3 Hz, 2H) in C5D5N and
2.79 (t, J ¼ 7 Hz, 2H), 1.83 (m, 2H), 3.64 (t, J ¼ 6 Hz, 2H) in CDCl3 for
synthetic 1. However, we observed a large deviation mainly for C-1
Scheme 3. Synthesis of indanone 4. Reagent and condition: i. 2 eq. TfOH, 110 ꢀC, 8 h, 9
52%, 4 37% and 4 eq. TfOH, 110 ꢀC, 8 h, 4 89%.
2

A. Kumari, M. Suresh and R.B. Singh
Tetrahedron xxx (xxxx) xxx
Scheme 4. Synthesis of intermediate 14. Reagents and conditions: i. NaH, MeI, dry THF, rt, 8 h, 92%; ii. ZnI2, NaCNBH3, dry DCE, reflux, 8 h, 96%; iii. BBr3, dry DCM, 0 ꢀC-rt, 3 h, 93%;
iv. Et3N, MgCl2, (HCHO)n, CH3CN, 70 ꢀC, 8 h, 81%; v. ii. malonic acid, pyridine, piperidine, reflux, 8 h.
Scheme 5. Synthesis of target 1. i. K2CO3, MeI, dry DMF, rt, 96%; ii. malonic acid, pyridine, piperidine, reflux, 8 h, 89%; iii. NieAl alloy, 10% NaOH solution, 8 h, 98%; iv. BBr3, dry DCM,
0
ꢀC-rt, 8 h, 95%; v. DIBAL-H, THF, rt, 95%.
and C-3 in the 13C NMR spectrum. Initially, we believed that the
position of the three carbon side chain greatly alters the 1H
chemical shift. To support this hypothesis, we examined the spec-
troscopic data of various 2-(3-hydroxypropyl) phenol derivatives
[25]. The results suggests that the eOH in the hydroxypropyl side
chain at ortho-position of phenol exerts a strong intramolecular
hydrogen bonding with the phenolic eOH, resulting in a deviation
in the chemical shift of the terminal as well as the benzylic CH2.
Finally, HMBC correlation (Fig. 35, Supporting information) of H-11
lactone formation and DIBAL-H reduction were the other key
transformations. While our spectroscopic data strongly supported
the proposed structure of 1, they did not fully agree with the natural
1.
4. Experimental section
4.1. General experimental procedures
to C-10 (
C-4 ( 151.2), C-6 (
chain connected through the C-5. The correlation of H-15 to C-6 (
135.8), C-5 ( 122.6) and C-7 ( 118.9) indicated that C-15 ( 19.6) is
connected with C-6. Furthermore, strong correlation among H-1 to
C-8 ( 142.8), C-7 ( 118.9), C-9 ( 126.8) and H-3 to C-9 ( 126.8), C-
4 ( 151.2), and C-7 ( 118.9) suggested that the cyclopentane ring is
fused with C-9 and C-8. All these comparisons, HMBC correlation
and C-7 peak at 118.9 in DEPT spectra (Fig. 34, supporting infor-
mation) strongly support that the synthetic molecule and the
proposed structure of tabasesquiterpene A are identical.
d
21.1), C-12 (
d 60.9), C-5 (d 122.6) and H-10 to C-5 (d 122.6),
Reagents were obtained from commercial sources and used
without further purifications. All reactions were performed in oven
dried glassware under anhydrous condition and used freshly
distilled solvents, whereas NieAl alloy mediated reduction per-
formed in water. All reactions were monitored by thin layer chro-
matography, which was performed on 0.25 mm silica gel-coated
aluminum sheets (F-254, Merck) and visualized using UV light
and spraying with a KMnO4 solution. Column chromatography was
performed using silica gel (100e200 mesh) with hexane and ethyl
acetate as eluent. 1H NMR spectra,13C NMR, HMBC and DEPT spectra
recorded in CDCl3, C5D5N on a 300, 400 and 500 MHz Bruker-
AVANCE spectrometers with TMS as internal standard. High-
resolution electrospray ionization mass spectra (HRMS-ESI) were
obtained with an Agilent 6520 Q-TOF instrument using chloroform
solutions.
d
d
135.8) strongly indicated that three carbon side
d
d
d
d
d
d
d
d
d
d
3. Conclusion
The first total synthesis of the proposed structure of 1 have been
successfully achieved from the commercially available starting
material m-cresol in fourteen steps with 26.5% overall yield. Two
non-consecutive Knoevenagel condensations are serviceable for
the generation of three carbon chains in the initial and final stages.
Triflic acid mediated Friedel-Crafts acylation enabled us to achieve
the key intermediate indanone in good quantity, which is very
difficult to produce with other known methods. Also, MgCl2 and
(HCHO)n supported regioselective formylation, BBr3 supported
4.1.1. 2-Hydroxy-4-methylbenzaldehyde (7)
A mixture of m-cresol 6 (20 g, 185.1 mmol) and MgCl2 (54.3 g,
572 mmol) was taken in a 500 mL round bottom flask. Triethyl-
amine (72.7 mL, 518.5 mmol) followed by dry CH3CN (150 mL) was
added to the mixture and stirred for 5 min. Paraformaldehyde
(20 g) was added to the mixture and heated at 70 ꢀC for 12 h. After
completion, the reaction mixture was acidified with dil. HCl
3

A. Kumari, M. Suresh and R.B. Singh
Tetrahedron xxx (xxxx) xxx
solution and extracted with ethyl acetate. The combined mixture
was dried over anhydrous Na2SO4. The solvent was removed under
vacuum at 40 ꢀC to get the crude aldehyde (this aldehyde is slightly
volatile). The crude residue was purified by column chromatog-
raphy using hexane as eluent and concentrated to afford 7 (18 g,
72%) as a colourless crystalline solid. 1H NMR (500 MHz, CDCl3)
anhydrous condition for 12 h. The reaction was monitored by TLC.
The mixture was poured on crushed ice and extracted with ethyl
acetate. Organic layer was washed twice with excess of sat. NaHCO3
solution followed by distilled water and dried over anhydrous
Na2SO4. The concentrated residue was purified by column chro-
matography using a mixture of hexane and ethyl acetate (9.5:0.5) to
obtain 10 (12%) as light brown liquid.
d
11.06 (s, 1H), 9.84 (s, 1H), 7.44 (d, J ¼ 10 Hz, 1H), 6.84 (d, J ¼ 10 Hz,
1H), 6.81 (s, 1H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3)
161.8, 148.9, 133.6, 121.2, 118.7, 117.7, 22.2.
d
195.9,
1H NMR (300 MHz, CDCl3)
d 7.15 (s, 1H), 6.85 (s, 1H), 3.89 (s, 3H),
2.98 (t, J ¼ 5.7 Hz, 2H), 2.66 (t, J ¼ 5.7 Hz, 2H), 2.40 (s, 3H); 13C NMR
(75 MHz, CDCl3)
36.6, 22.4, 21.7.
d 207.5, 156.9, 141.7, 139.3, 138.8, 116.3, 115.4, 55.6,
4.1.2. 2-Methoxy-4-methylbenzaldehyde (5)
An anhydrous K2CO3 (32.5 g, 235.2 mmol) was added to the
solution of 7 (16 g, 117.6 mmol) in 100 mL dry DMF and the het-
erogeneous mixture was stirred for 10 min. Iodomethane (15.18 mL,
235.2 mmol) was added dropwise to the mixture and stirred at
room temperature for 6 h. After completion, cold distilled water
was added and extracted with ethyl acetate. Organic layer was
washed with brine, dried on anhydrous Na2SO4 and concentrated.
The resulted residue was purified by column chromatography using
hexane as an eluent to provide 5 (16.2 g, 92%) as off-white solid. 1H
4.1.6. 4-Hydroxy-6-methyl-2,3-dihydro-1H-inden-1-one (4)
Mixture of compound 9 (1 g, 5 mmol), TfOH (1.8 mL, 20.6 mmol)
was cooled at 0 ꢀC for 10 min, and then heated at 110 ꢀC for 8 h
under anhydrous conditions. The reaction was monitored by TLC
and the mixture was poured on the crushed ice and extracted with
ethyl acetate. Organic layer was washed twice with sat. NaHCO3
solution followed by dried over anhydrous Na2SO4 and concen-
trated. The precipitate was purified by column chromatography
using hexane and ethyl acetate (9:1) as eluent to obtain 4 (0.72 g,
89%) as white solid, mp. 160e162 ꢀC. 1H NMR (300 MHz, CDCl3)
NMR (500 MHz, CDCl3)
d
10.4 (s, 1H), 7.72 (d, J ¼ 8 Hz, 1H), 6.83 (d,
J ¼ 7.5 Hz, 1H), 6.79 (s, 1H), 3.91 (s, 3H), 2.40 (s, 3H); 13C NMR
(125 MHz, CDCl3)
22.3.
d
189.4,161.9, 147.5, 128.5,122.6,121.6,112.2, 55.5,
d
7.18 (s, 1H), 6.88 (s, 1H), 5.67 (broad s, 1H), 3.03 (t, J ¼ 6 Hz, 2H),
2.72 (t, J ¼ 5.7 Hz, 2H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
207.8, 153.3, 139.6, 139.1, 139.1, 121.6, 116.4, 36.7, 22.1, 21.3. HRMS
4.1.3. 3-(2-Methoxy-4-methylphenyl)propenoic acid (8)12b
A mixture of pyridine 200 mL and piperidine 2 mL was taken in
a 500 mL round bottom flask which contains aldehyde 5 (18 g,
120 mmol) and malonic acid (26.70 g, 256 mmol). The mixture was
refluxed for 8 h, and then poured to ice cold water containing
excess of con. HCl. The precipitate was filtered, washed with excess
cold water, dried and recrystallized using methanol to get 8 (22 g,
93%) as a white solid. Mp. 193e195 ꢀC.
(ESIþ) m/z [M þ H]þ calcd for C10H11Oþ2 163.0759; found, 163.0764.
4.1.7. 4-Methoxy-2,2,6-trimethyl-2,3-dihydro-1H-inden-1-one (11)
Compound 4 (2 g, 12.3 mmol) in dry THF (10 mL) was added
dropwise to a stirred heterogeneous solution of NaH (1.18 g,
49 mmol) in dry THF. After 10 min, MeI (1.6 mL, 24.6 mmol) was
added dropwise and stirred further for 6 h. After completion, the
reaction was quenched with crushed ice and extracted with ethyl
acetate. Organic layer was dried over anhydrous Na2SO4 and
concentrated under vacuum. The residue was purified by column
chromatography using hexane as eluent to obtain 11 (2.3 g, 92%) as
light brown liquid.
1H NMR (300 MHz, CDCl3)
d
8.05 (d, J ¼ 16.2 Hz, 1H), 7.41 (d,
J ¼ 7.8 Hz, 1H), 6.79 (d, J ¼ 8.1 Hz, 1H), 6.74 (s, 1H), 6.51 (d,
J ¼ 16.2 Hz, 1H), 3.88 (s, 3H), 2.38 (s, 3H);
1H NMR (300 MHz, DMSO‑d6)
d
7.79 (d, J ¼ 16.2 Hz, 1H), 7.54 (d,
J ¼ 7.8 Hz, 1H), 6.91 (s, 1H), 6.80 (d, J ¼ 8.4 Hz, 1H), 6.44 (d,
1H NMR (400 MHz, CDCl3)
d 7.17 (s, 1H), 6.86 (s, 1H), 3.88 (s, 3H),
J ¼ 16.2 Hz, 1H), 3.85 (s, 3H), 2.33 (s, 3H); 13C NMR (75 MHz,
2.85 (s, 2H), 2.41 (s, 3H), 1.22 (s 6H); 13C NMR (75 MHz, CDCl3)
DMSO‑d6)
d
168.0, 157.7, 142.1, 138.8, 128.3, 121.5, 119.8, 118.0, 112.3,
d 211.8, 156.9, 139.4, 138.6, 137.0, 116.6, 116.1, 55.5, 45.7, 39.4, 25.5,
55.5, 21.4.
21.7; HRMS (ESIþ) m/z [M þ H]þ calcd for C13H17O2þ 205.1229;
found, 205.1229.
4.1.4. 3-(2-Methoxy-4-methylphenyl)propanoic acid (9)
Cinnamic acid 8 (16 g, 81.6 mmol) was taken in 1000 mL beaker,
and 10% NaOH (48 g in 480 mL distilled water) solution was added.
NieAl alloy (22 g) was added portion wise to the reaction mixture
over 30 min period and stirred for 8 h. The completion of the re-
action was monitored by TLC, and the mixture was filtered using
the Celite bedded sintered funnel. The filtrate was acidified by
pouring to ice cold water with excess of concentrated HCl, and
extracted with ethyl acetate. The solvent was dried over anhydrous
Na2SO4, and concentrated under vacuum and purified by column
chromatography using mixture of hexane and ethyl acetate (8:2) as
an eluent to obtain 9 (15.5 g, 96%) as colourless crystalline solid.
Mp. 80e82 ꢀC.
4.1.8. 4-Methoxy-2,2,6-trimethyl-2,3-dihydro-1H-indene (12)
Mixture of compound 11 (2 g, 9.80 mmol), ZnI2 (4.69 g,
14.7 mmol) and NaCNBH3 (4.62 g, 73.5 mmol) in dry DCE (30 mL)
was refluxed for 8 h. The reaction was monitored by TLC. Then
mixture of saturated NH4Cl and concentrated HCl was added to the
heterogeneous reaction mixture at 0 ꢀC, and extracted with ethyl
acetate. The combined organic layer was dried over anhydrous
Na2SO4 and concentrated under reduced vacuum. The resulted
residue was purified by column chromatography using hexane as
eluent to obtain 12 (1.8 g, 96%) as colourless thin liquid.
1H NMR (400 MHz, CDCl3)
2.68 (s, 2H), 2.64 (s, 2H), 2.32 (s, 3H), 1.14 (s, 6H); 13C NMR (75 MHz,
d 6.62 (s, 1H), 6.48 (s, 1H), 3.79 (s, 3H),
1H NMR (400 MHz, CDCl3)
d
7.03 (d, J ¼ 7.2 Hz, 1H), 6.69 (d,
CDCl3) d 156.2, 145.6, 137.6, 127.9, 118.1, 109.1, 55.3, 48.2, 44.2, 40.1,
J ¼ 7.6 Hz, 1H), 6.66 (s, 1H), 3.80 (s, 3H), 2.90 (t, J ¼ 8 Hz, 2H), 2.64 (t,
29.4, 21.9. HRMS (ESIþ) m/z [M þ H]þ calcd for C13H19Oþ 191.1436;
J ¼ 8 Hz, 2H), 2.33 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
180.0, 157.6,
found, 191.1432.
137.8, 129.9, 125.9, 125.7, 121.2, 111.5, 55.3, 34.3, 25.8, 21.7. HRMS
(ESIþ) m/z [M þ H]þ calcd for C11H15Oþ3 195.1021; found, 195.1026.
4.1.9. 2,2,6-Trimethyl-2,3-dihydro-1H-inden-4-ol (3)
Boron tribromide (1.53 mL, 16.1 mmol) was added dropwise to
the stirred solution of 12 (1 g, 5.68 mmol) in 10 mL dry DCM at 0 ꢀC.
The mixture was stirred for 30 min at 0 ꢀC and 4 h at room tem-
perature. After completion, saturated NH4Cl solution was added
and extracted with ethyl acetate. The combined organic layer was
4.1.5. 4-Methoxy-6-methyl-2,3-dihydro-1H-inden-1-one (10)
Compound 9 (1 g, 5.2 mmol) was added to a freshly prepared
PPA [P2O5 (3.69 g, 26.2 mmol) and H3PO4 88% (3.7 mL) heated at
95 ꢀC for 1 h] and the mixture was heated at 110 ꢀC under
4

A. Kumari, M. Suresh and R.B. Singh
Tetrahedron xxx (xxxx) xxx
washed twice with sat. Na2S2O4 solution followed distilled water,
then dried over Na2SO4 and concentrated. The residue was purified
by column chromatography using hexane and ethyl acetate (9:1) as
eluent to obtain 3 (0.9 g, 93%) as light yellow gum.
organic layer was washed twice with saturated Na2S2O3 solution,
dried over anhydrous Na2SO4 and evaporated under reduced
pressure. The crude mixture was purified by column chromatog-
raphy using hexane as eluent to obtain the lactone 2 (0.25 g, 95%) as
colourless liquid.
1H NMR (400 MHz, CDCl3)
d
6.59 (s,1H), 6.44 (s,1H), 2.68 (s, 2H),
2.61 (s, 2H), 2.26 (s, 3H), 1.15 (s, 6H); 13C NMR (75 MHz, CDCl3)
1H NMR (500 MHz, CDCl3)
d
6.82 (s, 1H), 2.92 (t, J ¼ 7 Hz, 2H),
2.78 (t, J ¼ 8 Hz, 2H), 2.76 (s, 2H), 2.72 (s, 2H), 2.28 (s, 3H), 1.17 (s,
6H); 13C NMR (125 MHz, CDCl3)
169.0, 148.7, 144.5, 134.0, 128.4,
d
152.0, 146.1, 138.0, 125.6, 118.3, 113.6, 48.2, 43.3, 40.5, 29.3, 21.4.
HRMS (ESIþ) m/z [M þ H]þ calcd for C12H17Oþ 177.1279; found,
d
177.1272.
122.1, 118.3, 47.8, 43.7, 40.4, 29.1, 28.9, 20.8, 19.2. HRMS (ESIþ) m/z
[M þ H]þ calcd for C15H19Oþ2 231.1385; found, 231.1381.
4.1.10. 4-Hydroxy-2,2,6-trimethyl-2,3-dihydro-1H-indene-5-
carbaldehyde (13)
4.1.15. 5-(3-hydroxypropyl)-2,2,6-trimethyl-2,3-dihydro-1H-inden-
4-ol (tabasesquiterpene A) (1)
Using the abovementioned procedure (4.1.1), reaction of com-
pound 3 (0.08 g, 0.5 mmol) with Et3N (0.18 mL, 1.26 mmol), MgCl2
(0.13 g, 1.4 mmol), and (HCHO)n in dry CH3CN (10 mL) provided 13
(0.08 g, 81%) as a colourless liquid.
DIBAL-H (1 M toluene solution) (1 mL, 1 mmol) was added to a
stirred solution of lactone 2 (0.045 g, 0.2 mmol) in dry toluene
under anhydrous condition. The mixture was stirred at room
temperature for 1 h. The reaction was quenched with dil. HCl,
extracted with diethyl ether. The dried organic layer was concen-
trated under reduced pressure and the residue was purified by
column chromatography using hexane and ethyl acetate (7:3) as
eluent to afford 1 (0.044 g, 95%) as pale yellow solid, mp. 60e62 ꢀC.
1H NMR (300 MHz, CDCl3)
d
12.03 (s, 1H), 10.24 (s, 1H), 6.57 (s,
1H), 2.69 (s, 4H), 2.56 (s, 3H), 1.16 (s, 6H); 13C NMR (75 MHz, CDCl3)
d
195.1, 160.0, 155.6, 141.1, 129.0, 118.9, 117.4, 49.1, 43.3, 40.2, 29.1,
18.4. HRMS (ESIþ) m/z [M þ H]þ calcd for C13H17O2þ 205.1229;
found, 205.1227.
1H NMR (300 MHz, C5D5N)
(t, J ¼ 7.8 Hz, 2H), 2.90 (s, 2H), 2.68 (s, 2H), 2.38 (s, 3H), 2.14 (m, 2H),
1.09 (s, 6H); 13C NMR (75 MHz, C5D5N)
153.0, 142.6, 127.6, 125.9,
d
6.69 (s,1H), 3.95 (t, J ¼ 6.3 Hz, 2H), 3.13
4.1.11. 4-Methoxy-2,2,6-trimethyl-2,3-dihydro-1H-indene-5-
carbaldehyde (15)
d
Using abovementioned procedure (4.1.2), reaction of compound
13 (0.3 g, 1.47 mmol) with anhydrous K2CO3 (0.4 g, 2.94 mmol) in
dry DMF and MeI at room temperature provided 15 (0.31 g, 96%) as
light brown liquid.
(one carbon peak at position 124 is overlapped with solvent peak),
118.9, 62.0, 48.5, 45.7, 40.3, 33.3, 29.4, 23.6, 20.2.1H NMR (500 MHz,
CDCl3)
(s, 2H), 2.65 (s, 2H), 2.27 (s, 3H), 1.83 (m, 2H), 1.16 (s, 6H); 13C NMR
(125 MHz, CDCl3) 151.2, 142.8, 135.8, 126.8, 122.6, 118.9, 60.9, 48.0,
44.0, 40.1, 30.5, 29.2, 21.1,19.6; DEPT (CDCl3,125 MHz) 118.9 (C-H),
d
6.61 (s, 1H), 3.64 (t, J ¼ 6 Hz, 2H), 2.79 (t, J ¼ 7 Hz, 2H), 2.67
1H NMR (300 MHz, CDCl3)
d10.53 (s, 1H), 6.80 (s, 1H), 3.87 (s,
d
3H), 2.80 (s, 2H), 2.70 (s, 2H), 2.55 (s, 3H), 1.17 (s, 6H); 13C NMR
d
(75 MHz, CDCl3) d 192.5, 161.3, 153.1, 140.9, 132.3, 125.4, 123.9, 61.6,
60.9, 48.0, 44.0, 30.5, 21.2 (for five CH2), 29.2, 19.6 (for three CH3)
HRMS (ESIþ) m/z [M þ H]þ calcd for C15H23Oþ2 235.1698; found,
235.1700.
48.3, 44.9, 40.8, 28.9, 21.7. HRMS (ESIþ) m/z [M þ H]þ calcd for
C
14H19Oþ2 219.1385; found, 219.1378.
4.1.12. 3-(4-Methoxy-2,2,6-trimethyl-2,3-dihydro-1H-inden-5-yl)
propenoic acid (16)
Declaration of competing interest
Using abovementioned Knoevenagel condensation procedure
(4.1.3), reaction of compound 15 (0.3 g, 1.38 mmol) with malonic
acid in mixture of pyridine (10 mL) and piperidine (0.25 mL) pro-
vided 16 (0.37 g, 89%) as white solid. Mp. 158e161 ꢀC. 1H NMR
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: Dr. Raj Bahadur Singh reports financial support was
provided by Science and Engineering Research Board, New Delhi,
India.
(300 MHz, CDCl3)
J ¼ 15.9 Hz, 1H), 3.76 (s, 3H), 2.78 (s, 2H), 2.68 (s, 2H), 2.41 (s, 3H),
1.16 (s, 6H); 13C NMR (75 MHz, CDCl3)
173.4, 156.9, 148.6, 142.0,
d
8.00 (d, J ¼ 16.2, 1H), 6.82 (s, 1H), 6.64 (d,
d
Acknowledgements
138.6, 133.0, 123.9, 123.1, 120.6, 59.8, 48.1,45.2, 40.6, 28.9, 21.3.
HRMS (ESIþ) m/z [M þ H]þ calcd for C16H21Oþ3 261.1491; found,
261.1483.
The authors thank the Science and Engineering Research Board
(SERB), New Delhi, India for financial support for the projects EMR/
2017/001292 and SAIF-CDRI Lucknow, India for the instrumenta-
tion facility. A.K. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, India for the Senior Research Fellow-
ship. M.S. thanks the UGC for the Junior Research Fellowship and
Senior Research Fellowship. The authors also thank Mr. Kamakshya
Nath Panda, IIT Bombay, India for helping to get HMBC and DEPT
spectra.
4.1.13. 3-(4-Methoxy-2,2,6-trimethyl-2,3-dihydro-1H-inden-5-yl)
propanoic acid (17)
Using abovementioned NieAl alloy reduction procedure (4.1.4),
reaction of compound 16 (0.2 g, 0.76 mmol) with NieAl alloy
(0.23 g) in aqueous NaOH (0.6 g in 6 mL distilled water) provided 17
(0.196 g, 98%) as colourless solid. Mp.77-79 ꢀC. 1H NMR (300 MHz,
CDCl3)
d
6.74 (s, 1H), 3.79 (s, 3H), 2.95 (t, J ¼ 8.7, 2H), 2.76 (s, 2H),
2.65 (s, 2H), 2.54 (t, J ¼ 8.7 Hz, 2H), 2.29 (s, 3H),1.15 (s, 6H); 13C NMR
Appendix A. Supplementary data
(75 MHz, CDCl3) d179.8, 155.3, 144.2, 135.8, 131.6, 128.4, 122.2, 60.1,
47.7, 45.7, 40.6, 34.5, 29.1, 22.3, 19.7. HRMS (ESIþ) m/z [M þ H]þ
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132282.
calcd for C16H23Oþ3 263.1647; found, 263.1648.
4.1.14. 5,8,8-Trimethyl-3,4,8,9-tetrahydrocyclopenta[h]chromen-
2(7H)-one (2)
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6