Asymmetric total syntheses of (–)-ar-turmerone, (–)-dihydro-ar-turmerone, (–)-ar-dehydrocurcumene, and (–)-ar-himachalene via a key allylic oxidative rearrangement

Article abstract of DOI:10.1016/j.tetlet.2021.153105

A Nature inspired strategy to oxidized aromatic bisabolanes has been envision from naturally occurring 2-methyl-6-(4′-methylphenyl)-3-hepten-2-ol (2a). The key methodology utilized in this synthesis is the allylic oxidative rearrangement following a [3,3]-sigmatropic rearrangement (Dauben oxidation) of tertiary allylic alcohol of natural product 2a. The enantioselectivity of 2a has been introduced via a Rh(I)-(S)-BINAP catalyzed p-tolylboronic acid addition onto E-ethylcrotonate. Thus, the total syntheses of (–)-ar-turmerone (1a), (-)-dihydro-ar-turmerone (1b) and (-)-ar-himachalene (3) has been achieved only in 6–7 steps.

Full text of DOI:10.1016/j.tetlet.2021.153105

Tetrahedron Letters xxx (xxxx) xxx
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Asymmetric total syntheses of (–)-ar-turmerone,
(–)-dihydro-ar-turmerone, (–)-ar-dehydrocurcumene, and
(–)-ar-himachalene via a key allylic oxidative rearrangement
Arindam Khatua a, Souvik Pal a, Mrinal K. Das a,d, Vishnumaya Bisai a,b,c,
⇑
a Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhauri, Bhopal 462 066, Madhya Pradesh, India
b Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Mangalam, Tirupati 517 507, Andhra Pradesh, India
c Department of Chemistry, Indian Institute of Science Education and Research Berhampur, Berhampur 760 010, Odisha, India
d Department of Chemistry, Karimpur Pannadevi College, University of Kalyani, West Bengal, INDIA
a r t i c l e i n f o
a b s t r a c t
Article history:
A Nature inspired strategy to oxidized aromatic bisabolanes has been envision from naturally occurring
2-methyl-6-(40-methylphenyl)-3-hepten-2-ol (2a). The key methodology utilized in this synthesis is the
allylic oxidative rearrangement following a [3,3]-sigmatropic rearrangement (Dauben oxidation) of
tertiary allylic alcohol of natural product 2a. The enantioselectivity of 2a has been introduced via a
Rh(I)-(S)-BINAP catalyzed p-tolylboronic acid addition onto E-ethylcrotonate. Thus, the total syntheses
of (–)-ar-turmerone (1a), (-)-dihydro-ar-turmerone (1b) and (-)-ar-himachalene (3) has been achieved
only in 6–7 steps.
Received 27 February 2021
Revised 11 April 2021
Accepted 17 April 2021
Available online xxxx
This work is dedicated respectfully to
Professor Sukh Dev on the occasion of his
98th birthday.
Ó 2021 Published by Elsevier Ltd.
Keywords:
Bisabolane sesquiterpenoids
Oxidative allylic rearrangement
(–)-ar-Turmerone
(–)-Dihydro-ar-turmerone
(–)-ar-Himachalene
Aromatic bisabolanes are a large class of naturally occurring
sesquiterpenoids those are widespread in nature and most of
them are having a stereogenic center at the pseudobenzylic
position [1]. In this regard, bisabolanes having an oxidized
skeleton in their aliphatic side chain drew interests because of
their important biological profiles. As for example, the rhizomes
of Curcuma longa L. (Zingiberaceae) [2a] of turmeric is the
source of many oxidized bisabolanes e.g. (+)-ar-turmerone (1a),
(+)-dihydro-ar-turmerone (1b) etc. (Fig. 1) that are considered
to be the anticancer constituents [2b]. It is interesting to note that
both enantiomers of few bisabolane sesquiterpenes have been
isolated from different species and both are having important
biological activities. As for example, (ꢀ)-curcuphenol (1c) is
produced by terrestrial plants and soft corals [3a] whereas
(+)-curcuphenol (ent-1c) is isolated from marine sponges [3b–c].
Interestingly, (ꢀ)-curcuphenol (1c) has antibiotic activity [3b],
while (+)-curcuphenol (ent-1c) exhibits cytotoxicity against
murine and human tumors and inhibits HK-ATPase [3c].
(ꢀ)-Curcuphenol (1c) differs from (ꢀ)-curcumene (1d) only in
the oxidation pattern in the aromatic ring (Fig. 1) [4a–c].
(+)-Dehydrocurcumene (1e) features
a S-trans 1,3-butadiene
motif in the aliphatic side chain [4d].
In 2003, a novel highly oxygenated bisabolene, 6-hydroxy-2-
methyl-5-(50-hydroxy-10(R),50-dimethyl-hex-30-enyl)-phenol (2b)
has been isolated from the resins of Commiphora kuaa (Burseraceae)
(Fig. 2) [5a]. Fukuda and co-workers have isolated 2-methyl-6-(40-
methylphenyl)-3-hepten-2-ol (2a) from Baccharis dracunculifolia
(Fig. 2) [5b,c]. The bicyclic aromatic sesquiterpene such as ar-hima-
chalene (3) [6] are considered to be the cyclized derivatives of (+)-
ar-turmerone (1a) (Fig. 2).
Although, (E)-tertiary allyl alcohol of types 2a or 2b are isolated,
however, corresponding (Z)-tertiary allyl alcohol of type 2c are not
reported till date. Compound 2c could be potential substrate to
generate a tertiary allylic carbocation intermediate (LUMO) to
react with arene (HOMO) to generate bicyclic structure like ar-
himachalene (3) [6]. Because of their important biological profiles,
a number of asymmetric total syntheses of oxidized bisabolanes
are reported [7].
⇑
Corresponding author at: Department of Chemistry, Indian Institute of Science
Education and Research Bhopal, Bhauri, Bhopal 462 066, Madhya Pradesh, India.
E-mail address: vishnumayabisai@gmail.com (V. Bisai).
https://doi.org/10.1016/j.tetlet.2021.153105
0040-4039/Ó 2021 Published by Elsevier Ltd.
Please cite this article as: A. Khatua, S. Pal, M.K. Das et al., Asymmetric total syntheses of (–)-ar-turmerone, (–)-dihydro-ar-turmerone, (–)-ar-dehydrocur-
cumene, and (–)-ar-himachalene via a key allylic oxidative rearrangement, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153105

A. Khatua, S. Pal, M.K. Das et al.
Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Naturally occurring aromatic bisabolane sesquiterpenoids.
Fig. 2. Naturally occurring sesquiterpenes with benzylic stereocenter.
Scheme 1. Our hypothesis of ar-turmerone (1a) via oxidative transposition of
allylic alcohol.
There is no report on the synthesis of secondary metabolites 2a
or 2b to the best of our knowledge (Fig. 2). We envisioned that 2-
methyl-6-(40-methylphenyl)-3-hepten-2-ol (2a) could serve as an
advanced intermediate for the total syntheses of several members
of aromatic bisabolanes sharing an oxidized side chain via allylic
oxidative rearrangement (Dauben oxidation) of tertiary allylic
alcohol [8]. Our rationale of the conversion of 2a to ar-turmerone
(1a) and related sesquiterpenes such as dihydro-ar-turmerone
(1b), ar-dehydrocurcumene (3) and ar-himachalene (3) via a key
oxidative allylic rearrangement following [3,3]-sigmatropic rear-
rangement is shown in Scheme 1.
Therefore, our initial target was to ensure the total synthesis of
naturally occurring 2-methyl-6-(40-methylphenyl)-3-hepten-2-ol
(2a). Our retrosynthetic analysis in this regard is shown in
Scheme 2. We argued that 2a could be synthesized from a,b-unsat-
urated ethyl ester 5 via methyl lithium addition. Ester 5 could be
accessed from aldehyde 6 by a reaction with a stabilized Wittig
reagent, which in turn could be accessed from a DIBAL-H reduction
of ethyl ester 7 (Scheme 2).
Recently, our group has reported an expeditious synthesis of
ethyl ester 7 via p-tolylboronic acid addition onto E-crotonate [9]
to access product with benzylic stereogenic center (Scheme 3)
[10]. We have shown a concise total syntheses of aromatic bis-
abolanes, (-)-dihydrocurcumene, (-)-nuciferol and (-)-nuciferal
[9]. We have seen that a Rh(I)-(S)-BINAP (L) could efficiently cat-
alyze p-tolylboronic acid addition onto E-crotonate in the presence
of NaHCO3 as an additive (Scheme 3). Upon completion of the reac-
tion the crude product was purified via usual column chromatog-
raphy and converted to corresponding primary alcohol 10 using
lithium aluminum hydride reduction of 7 in THF at 25 °C. The HPLC
analysis of primary alcohol 10 confirmed > 99% enantiopurity of
product (Scheme 3).
Scheme 2. Retrosynthetic analysis of ar-turmerone (1a).
Thus, we started our synthesis of 2a from ethyl ester 7
(Scheme 4). DIBAL-H reduction of ester 7 furnished aldehyde 6 in
78% yield, which was reacted with a stabilized Wittig to obtain
a
, b -unsaturated ethyl ester 5 in 96% yield. The later was then
2

A. Khatua, S. Pal, M.K. Das et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 3. Catalytic asymmetric p-tolyl boronic acid addition onto ethyl crotonate
(9).
Scheme 5. Asymmetric approach to (-)-dihydro-ar-turmerone (1b) and (-)-ar-
himachalene (3).
precursor of (-)-ar-himachalene (3) in one step, our effort culmi-
nated in the formal total synthesis of this sesquiterpene.
Further synthetic exploration of (-)-ar-turmerone (1a) was car-
ried out for the total synthesis of (-)-dehydrocurcumene (ent-1g).
In this regard, Luche reduction [12] of 1a afforded allylic alcohol
12 (Scheme 6). Interestingly, when compound 12 was reacted with
methane sulfonyl chloride in Et3N at 0 °C to room temperature for
30 min, it directly afforded (-)-dehydro-ar-curcumene (1g) with
S-trans structure in 72% yield (Scheme 6).
Scheme 4. Total syntheses of (-)-ar-turmerone (8a).
reacted with MeLi to afford tertiary allylic alcohol 2 (Scheme 4).
Next, as per our hypotheses, oxidative transposition of allylic alco-
hol was conducted with 2.5 equivalent of pyridinium chlorochro-
mate (PCC) (Scheme 4). A quick optimization of this reaction
revealed that dichloromethane is a good solvent to furnish ar-tur-
merone (1a) in 74% yield at 0 °C to room temperature. Other oxi-
dants such as SeO2 and PhI(OAc)2 were found to be inferiors as
compared to PCC for the oxidative transposition of allylic alcohol 2.
With the total synthesis of (-)-ar-turmerone (1a) secure, we
have carried out hydrogenation with catalytic Pd-C under 1 atm.
pressure of hydrogen, which completed the total synthesis of (-)-
dihydro-ar-turmerone (1b) in 99% yield (Scheme 5). Next, we have
attempted the synthesis of (-)-ar-himachalene (3) (Scheme 5).
Towards this, we have carried out electrophilic Michael addi-
tion of aromatic ring under AlCl3-catalyzed Friedel-Crafts condi-
tion. It is worthwhile to mention that Sukhdev et. al. [11] had
reported the synthesis of (-)-oxo-ar-himachalene (11) in car-
bondisulfide (CS2) as solvent, which afforded poor yields (40%)
under tedious reaction condition. We have adopted an alternate
reaction condition in dichloroethane to afford product in improved
yield (65% yield, Scheme 5) with relatively simple work up proce-
dure. Since, oxo-ar-himachalene (11) is already known to be the
Scheme 6. Total synthesis of (-)-dehydro-ar-curcumene (ent-1 g) via vinylogous b -
eliminaion.
3

A. Khatua, S. Pal, M.K. Das et al.
Tetrahedron Letters xxx (xxxx) xxx
The mechanism of this reaction via a vinylogous b -elimination
of mesylate 13 is proposed. However, an alternate mechanisn via
the formation of secondary allylic carbocation 14b and tertiary
allylic carbocation 14a can’t be ruled out because of the
plausible stabilization of 14a via 6 hyperconjugation structures
(Scheme 6).
In conclusion, a Nature inspired strategy for the total syntheses
of bisabolanes having an oxidized skeleton in their aliphatic side
chain has been shown from naturally occurring 2-methyl-6-(40-
methylphenyl)-3-hepten-2-ol (2a). The key methodology utilized
in this synthesis is the allylic oxidative rearrangement (Dauben
oxidation) of tertiary allylic alcohol of natural product 2a. This
strategy afforded (-)-ar-turmerone (1a), (-)-dihydro-ar-turmerone
(1b) and (-)-ar-himachalene (3) only in 6–7 steps in good yields.
Further application of this strategy for asymmetric syntheses of
other secondary metabolites of this class [13] is currently under
active investigation in our laboratory.
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153105.
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