Catalytic enantioselective total synthesis of (?)-ar-Tenuifolene

Article abstract of DOI:10.1016/j.tetlet.2020.151850

First catalytic asymmetric total synthesis of aromatic sesquiterpene, (?)-ar-teunifolene (1) is featured (3 steps, 75% overall yields) from commercially available 3-methyl cyclohex-2-enone 16. The enantioenriched 3,3-disubstituted cyclohexanone 11 is obtained from Pd(II)-catalyzed enantioselective (p-tolyl)boronic acid addition to 3-methyl cyclohex-2-enone 16 in 90% ee, which is found to be the key intermediate. A diastereoselective methyllithium addition of this enantioenriched product followed by dehydration completes straightforward access to (?)-ar-teunifolene (1).

Full text of DOI:10.1016/j.tetlet.2020.151850

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic enantioselective total synthesis of (À)-ar-Tenuifolene
Kundan Shaw a, Sovan Niyogi a, 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 Berhampur, Ganjam, Berhampur 760 010, Odisha, India
c Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Mangalam, Tirupati 517 507, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
First catalytic asymmetric total synthesis of aromatic sesquiterpene, (À)-ar-teunifolene (1) is featured (3
steps, 75% overall yields) from commercially available 3-methyl cyclohex-2-enone 16. The enantioen-
riched 3,3-disubstituted cyclohexanone 11 is obtained from Pd(II)-catalyzed enantioselective (p-tolyl)
boronic acid addition to 3-methyl cyclohex-2-enone 16 in 90% ee, which is found to be the key interme-
diate. A diastereoselective methyllithium addition of this enantioenriched product followed by dehydra-
tion completes straightforward access to (À)-ar-teunifolene (1).
Received 6 January 2020
Revised 11 March 2020
Accepted 14 March 2020
Available online xxxx
This paper is dedicated in memory of Late
Professor Asima Chatterjee
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Pd(II)-catalysis
Boronic acid addition
Sesquiterpenoids
ar-Teunifolene
Owing to their volatile and combustible properties, which make
them ideal candidate for terpene-based renewable biofuels, a huge
global interest in the synthesis of aromatic sesquiterpene has been
featured in the literature [1]. ar-Tenuifolene (1) includes one such
group of naturally occurring irregular aromatic sesquiterpenes
possessing an all-carbon quaternary stereogenic center at the
pseudobenzylic position. In 2004, two rearranged sesquiterpenes
such as ar-tenuifolene (1) and tenuifolene (2) were isolated by
König and co-workers from the essential oil of the east African san-
dalwood Osyris tenuifolia [2]. The chemical structure of these
sesquiterpenoids was investigated by exhaustive spectroscopic
methods.
There are other cyclohexane based naturally occurring
sesquiterpenoids isolated from various sources such as ar-macro-
carpene (3) [3], brominated metabolites such as majapolene B
(4a), acetyl majapolene B (4b) [4]. Importantly, arylcyclohexanes
sharing an all-carbon quaternary stereogenic center is found to
be common structural features of a number of sesquiterpenoids,
such as heliol (5a) [5], and chlorinated structures 5c-d [6].
Other structurally rearranged aromatic sesquiterpenoids
include laurokamurene B (6a) [7], isolaurene (6b) [8], cuparane
(7a) [9], and cuparenic acid (7b) [10]. These sesquiterpenoids are
having same total numbers of carbons i.e they are structural iso-
mers with rearranged structural scaffolds (Fig. 1).
Biogenetically, ar-tenuifolene 1 seems to be possibly originated
from bisabolyl cation (8c) via the intermediacy of congener tenui-
folene (2) and other hypothetical intermediates 9a and 9b
(Scheme 1) [6b]. Bisabolyl cation (8c) can be originated from
farnesyl pyrophosphate (FPP) 8a (sharing a C-15 unit) via a CAC
bond forming reaction, which in turn could be accessed from
nerolidyl pyrophosphate 8b (an isomer of 8a having a C-15 unit)
(Scheme 1). Whereas, other sesquiterpenes having
a
cyclopentane skeleton are supposed to be originated from
intermediate carbocation 10b (Scheme 1) via the rearrangement
of methyl group (1,2-shift of methyl group) to establish a 3°
carbocation intermediates such as 10a (for cuparane 7a) [9] and
10b [for lauranes e.g. isolaurene 6b] [8]. Cyclopentane based 2°
carbocation 10a could be generated from a bisabolyl cation inter-
mediate (8c) via a CAC bond formation (Scheme 1).
Synthetic community takes this array as a remarkable opportu-
nity for chemical study in the hopes of developing new methods
that might access members of these structurally related natural
products from a common linear phenolic system in a selective
fashion. Although (À)-ar-teunifolene (1) and (À)-teunifolene (2)
were isolated way back in 2004, there are only two racemic
approaches of these sesquiterpenoids are featured till date to the
best of our knowledge. The first synthesis was reported by Srikr-
ishna and Baire in 2005 [11a], and next one by Ávila-Zárraga and
Vázquez-Sánchez recently in 2015 [11b]. Therefore, there is an
⇑
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.
E-mail address: vishnumayabisai@gmail.com (V. Bisai).
https://doi.org/10.1016/j.tetlet.2020.151850
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: K. Shaw, S. Niyogi and V. Bisai, Catalytic enantioselective total synthesis of (À)-ar-Tenuifolene, Tetrahedron Letters, https://doi.
org/10.1016/j.tetlet.2020.151850

2
K. Shaw et al. / Tetrahedron Letters xxx (xxxx) xxx
Me
hexanone 11 could be easily synthesize by a Ni(II)-catalyzed Me3-
Me
Me
Al addition onto of 3-(p-tolyl)-2-cyclohexenone 12 (Scheme 2)
[13,8b]. Further, 3-(p-tolyl-2-cyclohexenone 12 could be accessed
from a Stork-Danheiser sequence [14] of vinylogous ester 13 with
arylmagnesium halides. Further, a concise catalytic asymmetric
synthesis of (À)-ar-tenuifolene (1) can be accomplished via a key
Pd(II)-catalyzed p-tolylboronic acid addition onto 3-methyl-2-
cyclohexenone following Stoltz’s methodology [12].
With above hypothesis, we have carried out reaction of cyclo-
hexane 1,3-dione with isobutylalcohol in the presence of catalytic
p-toluenesulphonic acid to access vinylogous ester 13 in 95% yield.
We then established the reaction condition for Stork-Danheiser
sequence on vinylogous ester [14] with various arylmetal reagents
(Table 1). A variety of aryl magnesium bromide nucleophiles were
reacted under the Stork-Danheiser sequence of the vinylogous
ester 13 in THF at 0 °C followed by treatment of dilute HCl. Since
a tolyl group is present in the natural product ar-tenuifolene (1),
we selected o-tolyl, m-tolyl, and p-tolylmagnesium bromides for
the Stork-Danheiser sequence in addition to phenylmagnesium
bromide. These reactions resulted in the synthesis of a wide range
of 3-aryl-cyclohexen-2-ones such as 12a-d in 89–93% yields
(Scheme 3).
Me
Me
Me
Me
H
Me Me
2
1
tenuifolene ( )
ar-tenuifolene ( )
3
ar-macrocarpene ( )
Me
OR
Me
Me
H
O
OH
Br
O
OH Me
Me
Me Me
Me
5b
intermediate (
)
5a
heliol (
)
4a
R = H, majapolene B (
R = Ac, acetyl-majapolene B (
)
4b
)
Me
HO
Cl
Me
Cl
HO
Me
Me
5c
Me
Me
5d
)
(
(
)
Me
Me
Since, ar-tenuifolene (1) and tenuifolene (2) are having an
all-carbon quaternary center at the pseudobenzylic position,
conjugate addition of a methyl group onto 3-(p-tolyl) cyclohexen-
2-one 12d was investigated. In this regard, we have explored
transition-metal catalyzed process utilizing few organometallic
sources of methyl group in tetrahydrofuran at 0 °C–25 °C and the
results are summarized in Table 1. Unfortunately, it was observed
that a well-known 1,4-addition using Me2CuLi was unsuccessful
(entry 1), which may suggest that the formation of quaternary
center needs special condition. Also, use of methyl magnesium bro-
mide or trimethylaluminum didn’t give satisfactory results (entries
2–3). We, therefore, thought of exploring Ni(II)-catalyzed conju-
gate addition of methyl group with various methyl nucleophiles
(entries 4–8). It was also observed that, when methyllithium,
methyl magnesium bromide, and trimethyl aluminum were used
in the presence of 10 mol% of Ni(acac)2Cl2, these conditions could
afford product 12d in 19–34% yields of 3-(p-tolyl)-3-methyl cyclo-
hexanone 11 (entries 4–6). A reaction of trimethyl aluminum in the
presence of 10 mol% of Ni(acac)2Cl2 could afford 41% yield in
diethylether at room temperature (entry 7). This probably hinted
that the reaction requires elevated temperature. Later, it was found
that this reaction was quite facile at elevated temperature. In fact, a
reaction of trimethyl aluminum in the presence of 10 mol% of Ni
(acac)2Cl2 at refluxed tetrahydrofuran, as used by Cossy [15] for
their synthesis of b-cuparenone, afforded 3-(p-tolyl)-3-methyl
cyclohexanone 11 in 91% yield (entries 8–9).
Me
Me
R
)
Me
Me
isolaurene (6b)
Me
Me
Me
Me Me
7a
R = H, cuparane (
7b
6a
laurokamurene B (
)
R = OH, (
)
Fig. 1. ar-Tenuifolene (1) and selected naturally occurring sesquiterpenes.
Me
Me
Me
Me
Me
Me
Me
Me
OPP
Me
Me
Me
Me
OPP
8b
nerolidyl pyrophosphate (
)
)
8a
farnesyl pyrophosphate (
)
8c
bisabolyl cation (
+H-
isomerization
Me
Me
Me
Me
Me
Me
Me
[O]
Me
Me
cuparane (
Me
10a
(
)
7a
)
1,2-CH3 shift
9a
(
)
Me
+H-
Me
Me
Me
Me
Me
[O]
+H-
[O]
Me
Me
Me
10b
6b
)
isolaurene (
Me
(
)
Me
(
Next, with 3-(p-tolyl)-3-methyl cyclohexanone 11 in hand our
effort was thereafter to complete the synthesis of ( )-ar-tenuifo-
lene (1) (Scheme 4). Towards this end, we have reacted compound
Me
Me
Me
Me
+H-
[O]
9b
)
[O]
Me
2
tenuifolene ( )
1
ar-tenuifolene ( )
O
Me
O
Me
Me
Me
Scheme 1. Biogenetic connections between ar-tenuifolene (1) and different
Me
sesquiterpenes.
11
(
)
12
(
)
Me
p-TolMgBr
Me
Me
urgent need for asymmetric synthesis of ar-teunifolene (1) sharing
an all carbon quaternary stereogenic center at the benzylic center
(Fig. 1). Herein, we report a 3 steps catalytic enantioselective total
synthesis of (À)-ar-tenuifolene (1) via a key Pd(II)-catalyzed
p-tolylboronic acid addition onto 3-methyl-2-cyclohexenone [12].
Retrosynthetically, we imagined that enantioenriched 3-aryl-3-
methyl cyclohexanone 11 may serve as advanced intermediate for
asymmetric synthesis (À)-ar-tenuifolene (1) via methyllithium
addition followed by dehydration (Scheme 2). Substituted cyclo-
Me
1
ar-tenuifolene ( )
Me
Me
O
O
Me
13
(
)
Me
Scheme 2. Retrosynthetic analysis of (À)-ar-teunifolene (1).
Please cite this article as: K. Shaw, S. Niyogi and V. Bisai, Catalytic enantioselective total synthesis of (À)-ar-Tenuifolene, Tetrahedron Letters, https://doi.
org/10.1016/j.tetlet.2020.151850

K. Shaw et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 1
Optimization of conjugate addition of 3-(p-tolyl) cyclohex-2-enone 12d.a,b
O
O
solvent, temp.
up to 91%
+
'Me'
nucleophile
Me
Me
12d
(
)
11
( )-(
)
Me
S. No.
Reagent
T-M catalyst
solvent
Temp.
Time
Yield
1.
2.
3.
4.
5.
6.
7.
8.
9.
MeLi
Cu(I)I
Cu(I)I
Cu(I)I
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
THF
THF
THF
THF
THF
THF
Et2O
THF
THF
0 °C–25 °C
0 °C–25 °C
0 °C–25 °C
0 °C–25 °C
0 °C–25 °C
0 °C–25 °C
25 °C
16 h
16 h
16 h
14 h
12 h
13 h
10 h
12 h
9 h
–
–
MeMgBr
Me3Al
MeLi
MeMgBr
Me3Al
Me3Al
Me3Al
Me3Al
15%
19%
21%
34%
41%
63%
91%
40 °C
70 °C
a
Reactions were carried out on a 0.2 mmol of 12d with 0.4 mmol of organometallic reagent in the presence of 10 mol% of Cu(I)I or Ni(acac)2Cl2 under argon atmosphere.
Isolated yields after column chromatography.
b
HO
O
Me
+
OH
Me
p-TSA, PhH
95%
Me
THF, temp.
then H3O+
O
O
O
+
Me
R
ArMgBr
89-93%
12a-d
(
)
13
(
)
O
O
O
O
Me
)
Me
Me
12d
93% (
)
12a
90% (
)
12b
12c
89% ( )
92% (
aReactions were carried out on a 1 mmol of 13 with 1.5 mmol of aryl magnesium
bromide in THF at 0 °C. bIsolated yields after column chromatography.
Scheme 3. Optimization of Stork-Danheiser sequence of 14. aReactions were carried out on a 1 mmol of 13 with 1.5 mmol of aryl magnesium bromide in THF at 0 °C. bIsolated
yields after column chromatography.
11 with methyllithium at 0 °C, which afforded tertiary alcohol
compound 14 in 94% yield with >10:1 dr. At this stage which
was left was to perform dehydration of compound 14. This was
achieved via an E2 elimination (Saytzev’s elimination) of insitu pre-
pared mesylate of tertiary alcohol. The reaction of methanesulfonyl
chloride in the presence of trimethylamine afforded crude mesy-
late, which was treat with DBU to affect elimination to form endo-
cyclic olefin in 85% yield (Scheme 4). Therefore, our effort
culminated in total synthesis of ( )-ar-tenuifolene (1) in 5 steps
from commercially available cyclohexane 1,3-dione in an overall
yield of 66.9%.
O
Me
OH
MsCl, Et3N, CH2Cl2
0 °C, 30 min
MeLi, THF
0 °C - 25 °C
Me
Me
98%
11
(
)
14
(
)
Me
Me
Me
O
Me
O
Me
OMs
Me
Me
DBU, CH2Cl2
25 °C, 3 h
Me
Me
Me
16
(
)
11
(
)
+
85%
15
Me
(
)
B(OH)2
17
Me
1
ar-tenuifolene ( )
Me
Me
1
( )-ar-tenuifolene ( )
H3C
(
)
Scheme 4. Total synthesis of ( )-ar-tenuifolene (1).
Scheme 5. Retrosynthetic analysis of (+)-ar-teunifolene (1).
Please cite this article as: K. Shaw, S. Niyogi and V. Bisai, Catalytic enantioselective total synthesis of (À)-ar-Tenuifolene, Tetrahedron Letters, https://doi.
org/10.1016/j.tetlet.2020.151850

4
K. Shaw et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 2
Optimization of p-tolylboronic acid addition onto 3-methylcyclopentenone 16.a–c
O
O
B(OH)2
Pd(OCOR)2, (CH2Cl)2
temp, time
+
Me
H3C
Me
up to 91%
up to 90% ee
16
(
)
17
(
)
11
(
)
Me
O
O
O
O
N
N
PPh2
N
PPh2
N
Me
Me
Me
L2
Me
L1
Me
Bu-PHOX (
i
t
Pr-PHOX (
)
)
L3
BOX (
)
O
N
O
O
PPh2
PPh2
P
N
N
Me
Me
Me
t
L5
(S)-BINAP (
)
L4
L6
)
Bu-PyOX (
)
(R)-phosphoramidite (
S. No.
Pd(II):L
Pd(II) cat.
Solvent
Temp.
Time
Yield
ee
1.
2.
3.
4.
5.
6.
7.
8.
5 mol% Pd:8 mol% L1
5 mol% Pd:8 mol% L1
5 mol% Pd:8 mol% L2
5 mol% Pd:8 mol% L2
5 mol% Pd:8 mol% L3
5 mol% Pd:8 mol% L3
5 mol% Pd:8 mol% L4
5 mol% Pd:8 mol% L4
5 mol% Pd:8 mol% L5
5 mol% Pd:8 mol% L5
5 mol% Pd:8 mol% L6
5 mol% Pd:8 mol% L6
Pd(OAc)2
Pd(TFA)2
Pd(OAc)2
Pd(TFA)2
Pd(OAc)2
Pd(TFA)2
Pd(OAc)2
Pd(TFA)2
Pd(OAc)2
Pd(TFA)2
Pd(OAc)2
Pd(TFA)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
28 h
22 h
23 h
25 h
24 h
29 h
26 h
27 h
20 h
24 h
26 h
28 h
60%
68%
78%
81%
63%
79%
82%
91%
76%
75%
69%
72%
09%
12%
19%
24%
11%
12%
89%
90%
28%
29%
17%
21%
9.
10.
11.
12
a
b
c
Reactions were carried out on a 1 mmol of 16 with 2 mmol of (p-tolyl)boronic acid in dichloroethane (DCE).
Isolated yields after column chromatography.
ee’s were determined by HPLC using Chiralpak OJ-H column.
Further, following a similar protocol as shown in Scheme 4, we
have completed catalytic enantioselective total synthesis of (À)-ar-
tenuifolene (1) in 72.8% yield over 3 steps from commercially
available 3-methylcyclohex-2-enone (Scheme 6).
Me
O
80%
over 2 steps
Me
Me
In conclusion, we have developed a concise total synthesis of
( )-ar-tenuifolene (1) in 5 steps in 66.9% overall yields from com-
mercially available cyclohexane 1,3-dione. Further, utilizing Pd
(II)-catalyzed enantioselective (p-tolyl)boronic acid addition to
3-methylcyclohex-2-enone, we have shown first asymmetric
synthesis of naturally occurring (À)-ar-tenuifolene (1) in 3 steps
from 3-methylcyclohex-2-enone in 72.8% overall yield. Further
application of this strategy for the synthesis of related naturally
occurring sesquiterpenoids is currently under active investigation
in our laboratory.
11
(+)-
Me
Me
1
)-ar-tenuifolene ( )
(
Scheme 6. Total synthesis of (À)-ar-tenuifolene (1).
Further, in search for catalytic asymmetric total synthesis of (+)-
ar-tenuifolene (1), we thought of exploring Pd(II)-catalyzed p-
tolylboronic acid addition onto 3-methyl-2-cyclohexenone as
reported by Stoltz and co-workers (Scheme 5) [12]. In this regard,
we have carried our reaction of (p-tolyl)boronic acid (2 equivalent)
addition onto 3-methyl-2-cyclohexenone (1 equivalent) in the
presence of 5 mol% Pd(II) catalysts such as Pd(OAc)2 or Pd(TFA)2
in the presence of a number of enantioenriched ligands such as
Declaration of Competing Interest
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.
t
t
iPr-PHOX (L1), Bu-PHOX (L2), Bn-BOX (L3), Bu-PYOX (L4), BINAP
(L5), carbazole anchored phosphoramidite L6) in dichloroethane
(DCE) and the results are summarized in Table 2.
After a through optimization, it was found that the correspond-
ing product 3-(p-tolyl)-3-methylcyclohexanone 11 could be
obtained in 91% yield with 90% ee, in dichloroethane at 60 °C in
the presence of 5 mol% Pd(TFA)2 and 8 mol% of (S)-tBu-PYOX (L4)
ligand (entry 8, Table 1).
Acknowledgments
V.B. thanks the Science and Engineering Research Board (SERB),
DST for a research grant [CS-021/2014]. S.N. thanks the Council of
Scientific and Industrial Research (CSIR) for a JRF. K.S. thanks IISER
Please cite this article as: K. Shaw, S. Niyogi and V. Bisai, Catalytic enantioselective total synthesis of (À)-ar-Tenuifolene, Tetrahedron Letters, https://doi.
org/10.1016/j.tetlet.2020.151850

K. Shaw et al. / Tetrahedron Letters xxx (xxxx) xxx
5
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Bhopal for a 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.2020.151850.
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Please cite this article as: K. Shaw, S. Niyogi and V. Bisai, Catalytic enantioselective total synthesis of (À)-ar-Tenuifolene, Tetrahedron Letters, https://doi.
org/10.1016/j.tetlet.2020.151850