Concise asymmetric total syntheses of (?)-nuciferol, (?)-nuciferal, and (?)-dihydrocurcumene via Rh(I)-catalyzed boronic acid addition

Article abstract of DOI:10.1016/j.tetlet.2020.152790

A general catalytic asymmetric total synthesis of aromatic bisabolane sesquiterpenes, (?)-nuciferol (ent-1c), (?)-nuciferal (ent-1d), and (?)-dihydrocurcumene (ent-1h) have been achieved in 5–6 steps in high chemical yields from commercially available (E)

Full text of DOI:10.1016/j.tetlet.2020.152790

Tetrahedron Letters 65 (2021) 152790
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise asymmetric total syntheses of (À)-nuciferol, (À)-nuciferal, and
(À)-dihydrocurcumene via Rh(I)-catalyzed boronic acid addition
Souvik Pal a, Arindam Khatua a, Mrinal K. Das a,1, 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 462 066, Andhra Pradesh, India
c Department of Chemistry, Indian Institute of Science Education and Research Berhampur, Berhampur 462 066, Odisha, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A general catalytic asymmetric total synthesis of aromatic bisabolane sesquiterpenes, (À)-nuciferol (ent-
1c), (À)-nuciferal (ent-1d), and (À)-dihydrocurcumene (ent-1h) have been achieved in 5–6 steps in high
chemical yields from commercially available (E)-ethylcrotonate. A key catalytic enantioselective boronic
acid addition onto (E)-crotonate in the presence of Rh(I)-(S)-BINAP afforded enantioenriched product
with benzylic stereogenic center in 93% yield with up to >99% ee.
Received 28 November 2020
Revised 13 December 2020
Accepted 15 December 2020
Available online 6 January 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
(E)-Crotonate
p-Tolylboronic acid
Rh(I)-catalyzed
Catalytic asymmetric
Bisabolane sesquiterpenes
Among various sesquiterpenoids, naturally occurring aromatic
bisabolanes are components of many plant essential oils that pos-
sess a benzylic stereogenic centers. [1]. In particular, oxidized aro-
matic bisabolanes (Fig. 1) are attracting increasing attention
because of their valuable biological activities [2]. As per a recent
report, the volatile oil from P. dasyrachis containing oxidized bis-
abolanes such as (+)-ar-turmerone (1e) and (+)-dihydro-ar-tur-
and antitumor activities] [5a] and (À)-curcuphenol (ent-1b) [iso-
lated from gorgonian corals Pseudopterogorgia rigida and shows
antibacterial activity] [5b] are isolated from Nature. In addition,
aromatic bisabolane with a fully saturated carbon skeleton such
as (+)-dihydrocurcumene (1h) has also been isolated from various
sources [6].
Aromatic monocyclic bisabolenes with oxidized side chains
could be the advanced intermediate for the synthesis of bicyclic
sesquiterpenes with a trans double bond such as parvifoline (2a)
[7a] and parvifoline isovalerate (2b) (Fig. 1) [7b]. In addition, iso-
merized parvifolines with a double bond at the benzylic position
such as isoparvifoline (3a) [8a] and isoparvifolinone (3b) [8b] are
also secondary metabolites that are isolated from various species
(Fig. 1). From a structural viewpoint it could be hypothesized that
these secondary metabolites 2–3 could be accessed from an
intramolecular Friedel-Crafts alkylation of (Z)-isomer of nuciferol
(1d). Therefore, asymmetric strategies to enantioenriched bis-
abolanes having oxidized side chain such as (+)-nuciferol (1c)
and (+)-nuciferal (1d) would be an important problem to be tested.
Although, there are many reports on racemic approaches to these
congeners [9], however, a catalytic asymmetric approach would
be very much welcome to these targets having oxidized side
chains, given their interesting biological profiles [4,10].
merone
(1g)
exhibit
inhibitory
activities
against
acetylcholinesterase (AChE) [2]. Since the inhibition of AChE may
be one of the most realistic approaches to the symptomatic treat-
ment of Alzheimer’s diseases (AD), therefore, these oxidized bis-
abolanes have garnered interests from the synthetic community
[2]. On the other hand, oxidized aromatic bisabolanes isolated from
the rhizomes of Curcuma longa L. (Zingiberaceae) are popular her-
bal medicines worldwide and are considered to be the anticancer
constituents of turmeric [3]. (+)-Nuciferol (1c) [4] and (+)-nuciferal
(1d) [1], possess side chains that are more highly oxidized than
those present in (+)-a-curcumene (1a). Interestingly, both enan-
tiomers of curcuphenol, namely (+)-curcuphenol (1b) [isolated
from marine sponges Didiscus flavus and shows potent antifungal
⇑
Corresponding author at: The AB Research Group, Department of Chemistry,
Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road,
Bhopal 462 066, India.
We envisioned that (À)-nuciferol (ent-1c) and (À)-nuciferal
(ent-1d) could be accessed from a reduction of
a,b-unsaturated
E-mail address: vishnumayabisai@gmail.com (V. Bisai).
Current address: Department of Chemistry, Karimpur Pannadevi College, Univer-
1
ester 4, which in turn could be synthesized from aldehyde
sity of Kalyani, Nadia 741 152, West Bengal, India.
https://doi.org/10.1016/j.tetlet.2020.152790
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

S. Pal, A. Khatua, M.K. Das et al.
Tetrahedron Letters 65 (2021) 152790
Fig. 1. Naturally occurring monocyclic bisabolene sesquiterpenes.
Scheme 1. Retrosynthetic analysis of (À)-nuciferol (ent-1c) and (À)-nuciferal (ent-
1d).
5 following an obvious approach (Scheme 1). Compound 5 could be
prepared from aldehyde 6 via one carbon elongation via Wittig ole-
fination. We thought of exploring p-tolylbenzene boronic acid
addition onto (E)-crotonates to install benzylic stereocenter
required for these natural products.
As per our hypothesis, we carried out Miyura’s Rh(I)-catalyzed
asymmetric arylboronic acid addition onto (E)-ethylcrotonate 9a
in refluxing dioxane and water mixture (dioxane: water = 10:1)
in the presence of a number of ligands shown in Fig. 2. For our tar-
gets we have chosen p-tolylboronic acid for the synthesis of
required aldehyde 6 (Scheme 1) [11].
Initially, we tested Rh(I)-catalyzed p-tolylboronic acid addition
in the presence of 2 mol% Rh(I) and 4 mol% of a number of phosphi-
nes (L1-L3 and L5-L6) and oxazoline based ligands (L4). The best
enantioselectivity was observed with 2 mol% Rh(I)-(S)-BINAP (L5)
catalyst, which afforded product in 67% yield with 95% ee (entry
5). Under this condition, 2 mol% Rh(I)-(S)-SEGPHOS (L6) afforded
7a in 91% ee (entry 6) (Table 1).
Fig. 2. Ligand screened in p-tolylboronic acid addition onto ethylcrotonate 9a.
Since Rh(I)-(S)-BINAP (L5) catalyst was found to be superior
over Rh(I)-(S)-SEGPHOS (L6) catalyst in terms of enantioselectivity,
the metal complex of L5 was utilized for further studies. In order to
have optimum chemical yields, number of inorganic bases such as
potassium carbonate, sodium bicarbonate, sodium carbonate,
cesium carbonate were added as additives (entries 7–14) [12]. Fur-
ther few other solvents were tested as well. Gratifyingly, the enan-
tioselectivity of compound 7a could be increased to >99% ee when
2 mol% Rh(I)-(S)-BINAP (L5) was employed in combination with 1
equivalent of sodium bicarbonate refluxing dioxane and water
mixture (entry 8). It is worthwhile to mention that 1 mol% Rh(I)
and 3 mol% of (S)-BINAP (L5) afforded product in 95% ee in 24 h
(87% yield, entry 14). Further, p-tolylboronic acid addition onto
(E)-benzylcrotonate 9b afforded 7b in 94% ee. Enantioselectivities
of esters 7a and 7b were determined by converting these to corre-
sponding primary alcohol 10 using lithium aluminum hydride
reduction in tetrahydrofuran at room temperature (Scheme 2).
With a perfect enantioselectivity of ethyl ester 7a in hand, this
was further elaborated to the secondary metabolites, (+)-nuciferol
(1c) and (+)-nuciferal (1d) (Scheme 3). In this regard, compound 7a
was reduced with DIBAL-H to furnish aldehyde 6 in 74% yield. The
absolute configuration of the product from enantioselective p-
tolylboronic acid addition onto (E)-crotonate was determined by
comparing their specific rotation with the literature data [13].
However, this reaction was always associated with 15–20% yield
of primary alcohol 10. Alternatively, a 2-step protocol comprising
lithium aluminum hydride reduction of 7a followed oxidation by
Dess-Martin Periodinane (DMP) produce aldehyde 6 in 89% yield
over 2 steps. Next, homologation of aldehyde 6 was carried out
with methoxymethyl Wittig reagent followed by hydrolysis of in-
situ prepared methylvinyl ether 11, which afforded aldehyde 5 in
68% yield (Scheme 3).
Next, aldehyde 5 was reacted with a stabilized Wittig reagent
12 in refluxing toluene to furnish
a,b-unsaturated ester 4 in 96%
yield (Scheme 3). Compound 4 is considered to be a common inter-
mediate for the total syntheses of various members of bisabolane
sesquiterpenoids. Later, a lithium aluminum hydride reduction of
4 in tetrahydrofuran at room temperature completed the total syn-
thesis of unnatural (À)-nuciferol (ent-1c) in 91% yield. Allylic alco-
hol functionality of ent-1c was oxidized with pyridinium
chlorochromate (PCC) to complete the total synthesis of unnatural
(À)-nuciferal (ent-1d).
2

S. Pal, A. Khatua, M.K. Das et al.
Tetrahedron Letters 65 (2021) 152790
Table 1
Optimization of p-tolylboronic acid addition onto ethylcrotonate 9aa.
S. No.
Rh(I):L (ratio of mol%)
Additive
Solvent
Temp.
Time
Yieldb
eec
1.
2.
3.
4.
5.
6.
7.
8.
2 mol% : 4 mol% L1
2 mol% : 4 mol% L2
2 mol% : 4 mol% L3
2 mol% : 4 mol% L4
2 mol% : 4 mol% L5
2 mol% : 4 mol% L6
2 mol% : 4 mol% L5
2 mol% : 4 mol% L5
2 mol% : 4 mol% L5
2 mol% : 4 mol% L5
2 mol% : 4 mol% L5
2 mol% : 4 mol% L5
1 mol% : 2 mol% L5
1 mol% : 3 mol% L5
none
none
none
none
none
none
K2CO3
NaHCO3
Na2CO3
Cs2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
dioxane : H2O (10:1)
dioxane : H2O (10:1)
dioxane : H2O (10:1)
dioxane : H2O (10:1)
dioxane : H2O (10:1)
dioxane : H2O (10:1)
dioxane : H2O (10:1)
dioxane : H2O (10:1)
dioxane : H2O (10:1)
dioxane : H2O (10:1)
THF : H2O (10:1)
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
70 °C
48 h
48 h
48 h
48 h
48 h
48 h
16 h
16 h
16 h
16 h
28 h
20 h
24 h
24 h
61%
56%
48%
59%
67%
65%
93%
91%
90%
89%
57%
68%
85%
87%
32%
47%
36%
16%
95%
91%
96%
99%
95%
93%
84%
87%
93%
95%
9.
10.
11.
12.
13.
14.
DME : H2O (10:1)
dioxane : H2O (10:1)
dioxane : H2O (10:1)
110 °C
100 °C
100 °C
a
b
c
Reactions were carried out on a 1 mmol of 9a with 2 mmol of arylboronic acid 8 in specified solvent.
Isolated yields of 7a after column chromatography.
ee’s were determined by HPLC using Chiralpak AD-H column.
Scheme 2. p-Tolylboronic acid addition onto benzylcrotonate 9b.
Further synthetic elaborations of homologated aldehyde 6 were
carried out for the synthesis of (À)-curcumene (ent-1a) (Scheme 4).
In this regard, four carbon installation on 6 was made via Grignard
addition to access 12 in 90% yield. When reduction of secondary
allyl alcohol functionality of 12 was carried out with triethylsilane
in the presence of trifluoroacetic acid (TFA), it afforded disubsti-
tuted diene 13 as sole regioisomer in 74% yield (Scheme 4). There
was no trace of trisubstituted olefin as present in (À)-curcumene
(ent-1a). A probable mechanism to account this observation is
shown in Scheme 4. Silane reduction takes place via a more stable
3° allyl alcohol (14a) than a 2° allyl alcohol (14b), thereby affording
13 as sole regioisomer (Scheme 4).
Later, olefin 13 in hand our effort was to complete the synthesis
of aromatic bisabolane with a saturated side chain, (À)-dihy-
drocurcumene (ent-1h) (Scheme 5). Towards this, hydrogenation
using catalytic Pd-C in the presence of 1 atm. pressure of hydrogen
simply completed the total synthesis of (À)-dihydrocurcumene
(ent-1h).
Scheme 3. Total syntheses of (À)-nuciferol (ent-1c) and (À)-nuciferal (ent-1d).
In conclusion, a unified total synthesis of bisabolane sesquiter-
penoids has been shown only in 5–6 steps from commercially
available (E)-crotonate. This synthesis nicely explored the catalytic
enantioselective addition of p-tolylboronic acid onto (E)-crotonate
catalyzed by Rh(I)-(S)-BINAP (L5). Further exploration of aldehyde
6 enabled the total synthesis of (À)-dihydrocurcumene (ent-1h).
Since both enantiomers of BINAP is available, one can synthesize
naturally occurring aromatic bisabolanes, (+)-nuciferol (1c) and
3

S. Pal, A. Khatua, M.K. Das et al.
Tetrahedron Letters 65 (2021) 152790
Acknowledgments
V.B. thanks the Science and Engineering Research Board (SERB)
[CS-021/2014], Department of Science and Technology (DST) for a
research grant. A.K. thanks the INSPIRE, DST, for a Senior Research
Fellowship (SRF). Facilities from Department of Chemistry, IISER
Bhopal is gratefully acknowledged.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152790.
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for catalytic asymmetric syntheses of other congeners is currently
under active investigation in our laboratory.
Declaration of Competing Interest
4977-4981. [a]D20 for ent-6 = +28.5 (c = 1.0, CHCl3).
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
4