Catalytic asymmetric total syntheses of (+)-α-cuparenone, (+)-cuparene and (+)-herbertene

Article abstract of DOI:10.1016/j.tetlet.2020.152169

A general catalytic asymmetric route to either enantiomers of sesquiterpenes, cuparenes (1–2) and herbertenes (8–9) is disclosed from commercially available 3-methyl cyclopenten-2-one. Following a catalytic enantioselective addition of arylboronic acids to enone 15, compounds 14a-b with all carbon quaternary stereocenters are synthesized in up to 90percent ee in the presence of Pd(II)-PyOx (pyridine oxazoline). Compounds 14a-b are used as precursors for the asymmetric total syntheses of (+)-cuparene (1a) (35percent overall yield in 3 steps), α-(+)-cuparenone (1b) (56percent overall yield in 2 steps), and (+)-herbertene (8a) (34percent overall yield in 3 steps).

Full text of DOI:10.1016/j.tetlet.2020.152169

Journal Pre-proofs
Catalytic Asymmetric Total Syntheses of (+)-α-Cuparenone, (+)-Cuparene
and (+)-Herbertene
Kundan Shaw, Sovan Niyogi, Rhituparna Nandi, Vishnumaya Bisai
PII:
S0040-4039(20)30629-8
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152169
TETL 152169
To appear in:
Tetrahedron Letters
Received Date:
Accepted Date:
4 June 2020
22 June 2020
Please cite this article as: Shaw, K., Niyogi, S., Nandi, R., Bisai, V., Catalytic Asymmetric Total Syntheses of
(+)-α-Cuparenone, (+)-Cuparene and (+)-Herbertene, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/
j.tetlet.2020.152169
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Catalytic Asymmetric Total Syntheses of (+)--Cuparenone, (+)-Cuparene and ()-
Herbertene
Kundan Shaw, Sovan Niyogi, Rhituparna Nandi, and Vishnumaya Bisai*
O
Me
O
Me
N
O
Me
Me
N
1b
(+)--cuparenone (
)
O
L1
)
PyOx (
t-Bu
CH3
)
15
(
Me
Pd(TFA)2, (CH2Cl)2
60 °C, 12 h
+
Me
Me
B(OH)2
16a-b
Me
Me
Me
Me
up to 95%
up to 90% ee
1a
p-Me, cuparene (
)
(
)
14a-b
(
)
8a
m-Me, herbertene (
)

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Catalytic Asymmetric Total Syntheses of (+)--Cuparenone, (+)-Cuparene and ()-
Herbertene
Kundan Shaw,a Sovan Niyogi,a Rhituparna Nandi,a and Vishnumaya Bisai*a,b,
c
aDepartment of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhauri, Bhopal - 462 066, Madhya Pradesh, India
bDepartment of Chemistry, Indian Institute of Science Education and Research Berhampur, Ganjam, Berhampur – 760 010, Odisha, India
cDepartment of Chemistry, Indian Institute of Science Education and Research Tirupati, Mangalam, Tirupati – 517 507, Andhra Pradesh, India
Address for correspondence: vishnumayabisai@gmail.com
This work is dedicated to Professor Amit Basak, IIT Kharagpur
ARTICLE INFO
ABSTRACT
A general catalytic asymmetric route to either enantiomers of sesquiterpenes,
cuparenes (1-2) and herbertenes (8-9) is disclosed from commercially available 3-methyl
cyclopenten-2-one. Following a catalytic enantioselective addition of arylboronic acids to
enone 15, compounds 14a-b with all carbon quaternary stereocenters are synthesized in up
to 90% ee in the presence of Pd(II)-PyOx (pyridine oxazoline). Compounds 14a-b are used
as precursors for the asymmetric total syntheses of (+)-cuparene (1a) (35% overall yield in
3 steps), -(+)-cuparenone (1b) (56% overall yield in 2 steps), and (+)-herbertene (8a)
(34% overall yield in 3 steps).
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
cuparane, herbertene, conjugate addition,
boronic acid, Pd(II)-PYOX
2012 Elsevier Ltd. All rights reserved.
and B (10-11) from the liverwort Mastigophora diclados8a and
Naturally occurring secondary metabolites cuparenes (1-7) (Figures
1) and herbertenes (8-11) (Figure 2) are sesquiterpenes with a
cyclopentanoid backbone.1 They possess vicinal all-carbon
quaternary centers, including at least one stereogenic quaternary
center situated at the pseudobenzylic position.2 Although no
biological activities are reported for (R)-(+)-cuparene (1a), isolated
in 1958 by Erdtman et. al., 1 secondary metabolites (S)--cuparenone
(1b) and (S)--cuparenone (1c) from the essential oil of leaves from
Thujaorientallis (commonly known as ‘Morpankhi’ tree) are
biologically significant. Isolated by Dev and Chetty in 1964,3a these
compounds are used to treat fungal infections, cancer, coughs,
hemorrhages, excessive menstruation, bronchitics, asthma, and
arthritic pains.
aquaticenols (5) from the liverwort Lejeunea aquatica.8b These novel
sesquiterpenoid biaryls, were co-isolated with their monomeric
phenolic precursors, such as herbertenediol (9b) and 1,2-
cuparenediol (2b). Importantly, mastigophorene A (10) exhibits
nerve growth and network formation acceleration activities.8a
O
X
OH
X
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
1a
X = H, H; cuparene (
)
X = H, 2-cuparenol (2a)
X = OH, 1,2-cuparenediol (
1c
-cuparenone (
)
1b
X = O; -cuparenone (
)
2b
)
Subsequently, the (R)-enantiomer of both -cuparenone (ent-1b) and
-cuparenone (ent-1c) were also isolated from the liverworts Mania
fragrans by Benesova et. al.3b Later, in 1997, two new cuparene-type
sesquiterpenoids, aquaticenol (5) and 1,4-cuparenediol were isolated
from the Japanese liverwort Lejeuneaaquatica, along with 2-
cuparenol (2a), 1,2-cuparenediol (2b) and other congeners.4 Further,
in 2015, Stadler and co-workers reported the isolation of deconins A
(6), and B (7) as conjugates of -cuparenone (1c) or cuparenic acid
(3) with mevalonic acid from cultures of a basidiomycete from
Northern Thailand, which represents a new species of the genus
Deconica.4 The crude extracts from submerged cultures of Deconica
sp. 471 showed antimicrobial activities against Gram-positive
bacteria, i.e., Bacillus subtilis and Staphylococcus aureus.5
HO
HO
Me
Me
OH
Me
OH
O
Me
OH
Me
Me
Me
Me
Me
3
Me
cuparenic acid ( )
Me
O
5
(S)-(-)-aquaticenol ( )
OH
Me
O
OH
O
X
Me
Me
AcO
tochuinyl acetate ( )
Me
6
X = H, H; deconin A ( )
X = O; deconin B ( )
Me
4
7
Me
Me
On the other hand, (R)-()-herbertene (8a) was isolated in 1981 by
Matsuo and co-workers.6 A number of dimeric herbertenes were
isolated with biaryl structural scaffolds,7 such as mastigophorenes A
Figure 1: Cuparene (1a), -cuparenone (1b), -cuparenone (1c), 2-
cuparenol (2a), 1,2-cuparene diol (2b), and cuparenic acid (3).

2
Scheme 1: Retrosynthetic analysis of cuparenes (1a-b), and herbertene
(8a).
In spite of its compact size, the perimeter of these sesquiterpenes
contains vicinal all-carbon quaternary centers those are part of a
cyclopentane ring, thus posing a respectable synthetic challenge.
Few congeners of this class of sesquiterpenoid, such as tochuinyl
acetate (4, Figure 1) and herbertinolide (12, Figure 2) possess two
contiguous all-carbon quaternary stereogenic centers.
Scheme 1 shows our retrosynthetic plan for cuparene (1a), -
cuparenone (1b), and herbertene (8a). We envisioned that 2,2-
dimethyl 3-aryl-3-methylcyclopenten-5-ones (13 and 1b) having
vicinal all-carbon quaternary centers could be advanced
intermediates for a unified approach to sesquiterpenoids 1a-b and 8a
via Wolff-Kishner reduction.14 These compounds could be
synthesized from 3-aryl-3-methylcyclopentanones 14a-b by a highly
regioselective gem-dimethylation. The latter could be achieved via a
key Pd(II)-PyOx catalyzed arylboronic acid (16) addition onto 3-
methylcyclopenten-2-one (15) (Scheme 1) following Stoltz’s
condition.15 In this regard, it is worthwhile to mention that an
elegant PdCl2-Ph-BOX catalyzed aryl boronic acid addition onto 3-
methyl cycloalkanone has been reported by Minnaard et. al. for the
total synthesis of -cuparenone (1b).16a This methodology has nicely
been utilized for catalytic asymmetric total syntheses of several other
congeners16b including an atropselective total synthesis of
mastigophorene A (10).16c
Me
Me
Me
X
Me
Me
Me
X
Me
Me
OH
8a
X = H, herbertene (
)
9a
X = H, -herbertenol (
X = OH, herbertenediol (
)
9b
8b
X = OH, -herbertenol (
)
)
Me Me
Me
Me
Me
Me
O
Me
Me
Me
Me
HO
O
Me
)
OH
HO
OH
10
12
herbertinolide (
mastigophorene A (
)
Since, there were no reports for Pd(II)-PyOx catalyzed addition of p-
tolylboronic acid (16a) onto 3-methylcyclopenten-2-one (15), which
is relevant to our synthetic plan,17 we carried out optimization studies
using 3-methylcyclopenten-2-one (15) with boronic acid 16a (Table
1). The optimization studies of asymmetric boronic acid addition
onto 15 using L1-L2 is shown in Table 1. It was observed that
Pd(II)-PyOx (L1) is found to be superior over Pd(II)-PHOX (L2)
(entries 1-3) and Pd(OCOCF3)2 is better choice as Pd-source than
Pd(OAc)2 (entries 1-4). Among various solvents, dichloroethane was
found to be good choice than dichloromethane, toluene, and
tetrahydrofuran (Table 1). Following exhaustive optimization, it was
Me Me
Me
Me
Me
Me
Me
Me
HO
OH
HO
OH
11
mastigophorene B (
)
Figure 2: Herbertene (8a), -herbetenol (8b) and -herbetenol (9a),
herbertenediol (9b), mastigophorenes
herbertinolide (12).
A (10) and B (11) and
Although, there are a number of elegant total syntheses of racemic
cuparene (1a)9 and herbertene (8a)10 reported in the literature, the
catalytic enantioselective syntheses of these compounds are very
limited.11-12 In fact, the total syntheses of such sesquiterpenoids via
catalytic asymmetric processes are scarcely reported.11a A unified
catalytic asymmetric approach to both of these classes of
sesquiterpenoids would eventually allow access of both their natural
and unnatural synthetic analogues. Herein, we delineate our efforts
towards a unified total synthesis of cuparene (1a), -cuparenone
(1b), and herbertene (8a) from appropriately functionalized common
cyclopentenone intermediate 12. Key to this synthetic strategy is
Stoltz’s elegant Pd(II)-PyOx catalyzed arylboronic acid addition onto
3-methylcyclopenten-2-one13 to install all carbon quaternary
stereocenter in enantioenriched fashion (Scheme 1).
discovered
that
corresponding
product
3-(p-tolyl)-3-
methylcyclopentanone 14a could be obtained in 95% yield with 85%
ee, in dichloroethane at 60 C in the presence of 5 mol% Pd(TFA)2
and 8 mol% of (S)-PyOx (L1) ligand (entry 7, Table 1).
Table 1. Optimization of p-tolylboronic acid (16a) addition onto 3-
methylcyclopentenone 15.a
O
O
N
PPh2 N
L2
N
L1
)
PyOx (
t-Bu
)
t-Bu
PHOX (
O
O
B(OH)2
Me
Me
Pd(TFA)2, (CH2Cl)2
temp, time
+
Me
X
Me
H3C
Me
CH3
Me
up to 95%
Me
Me
Me
13
14a
(
)
15
(
)
16a
(
)
Me
(
)
8a
X = H, herbertene (
)
8b
X = OH, -herbertenol (
)
S.
No.
1.
Pd(II):L
solvent
temp.
40 ºC
40 ºC
40 ºC
40 ºC
60ºC
time
28 h
24 h
24 h
30 h
18 h
25 h
14 h
18 h
18 h
yield
eec
b
O
Me
2.5 mol%:
6 mol% L1
5 mol%:
6 mol% L1
5 mol%:
6 mol% L2
5 mol%:
6 mol% L1
5 mol%:
8 mol% L1
5 mol%:
6 mol% L1
5 mol%:
8 mol% L1
5 mol%:
12 mol% L1
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
CH2Cl2
60%
72%
67%
55%
94%
65%
95%
94%
90%
78%
80%
58%
72%d
77%
70%
85%
81%
78%
Me
2.
3.
4.
5.
6.
7.
8.
9.
14a
14b
p-Me-Ph (
m-Me-Ph (
)
)
X
OH
Me
Me
Me
O
O
Me
Me
Me
Me
40 ºC
60 ºC
60 ºC
60 ºC
2a
cuparenic acid (
)
1a
X = H, H; cuparene (
X = O; (+)--cuparenone (
)
1b
)
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
Me
Me
O
(HO)2B
+
Me
Me
16a
p-Me-Ph (
m-Me-Ph (
)
5 mol%:
16 mol% L1
14a
p-Me-Ph (
m-Me-Ph (
)
16b
)
15
)
14b
(
)

3
10.
11.
12.
5 mol%:
20 mol% L1
5 mol%:
8 mol% L1
5 mol%:
(CH2Cl)2
PhMe
60 ºC
60 ºC
60 ºC
17 h
24 h
24 h
80%
66%
20%
76%
69%
60%
Another possibility might be the stabilizing interactions arising
from the interaction between Li+ with ortho-C-H bond of arenes
as shown in 17a’-b’ and 20a’-b’. However, since there is no
trace of ortho-methylation of arenes were observed, the later
possibility of interactions between Li+ and ortho-C-H bond may
be ruled out.
THF
8 mol% L1
aReactions were carried out on a 1 mmol of 15 with 2 mmol of aryl boronic
acid in dichloromethane or dichloroethane (DCE). bIsolated yields after
column chromatography. cee’s were determined by HPLC using Chiralpak
AD-H column. dPd(OAc)2 was used as catalyst.
no lithiation observed
O
O
H
OMe
NaHMDS
H
5
O
MeO
2
Li
MeI
14a
14b
(p-Me)
(m-Me)
Me
Me
Me
Under the standard condition, m-tolylboronic acid (16b) addition
onto 3-methylcyclopenten-2-one (15) afforded 3-(m-tolyl)-3-methyl
cyclopentane 2-one 14b in 92% yield with 90% ee (Scheme 2).
Me
Me
O
H
-10 °C
17a
17b
(p-Me)
(m-Me)
18a
18b
(p-Me)
(m-Me)
O
O
Me
15
(
)
Pd(TFA)2, (CH2Cl)2
60 °C, 12 h
O
+
N
O
Me
OMe
O
Me
Me
B(OH)2
Me
14b
Me
MeO
N
L
92%
90% ee
O
NaHMDS
MeI
PyOx ( )
(
)
t-Bu
1b
17
Li
(p-Me)
(m-Me)
16b
(
)
H
Me
Me
Me
Me
-10 °C
O
H
Scheme
2.
m-Tolylboronic
acid
addition
onto
3-
methylcyclopentenone 15.
20a
20b
19a
19b
(p-Me)
(m-Me)
(p-Me)
(m-Me)
O
Me
O
H
Thereafter, we sought to elaborate the enantioenriched 3-aryl-3-
methylcyclopentanones 14a-b to the natural products cuparene (1a)
O
O
Li
Li
H
and herbertene (8a) (Scheme 3). Towards this,
regioselective gem-dimethylation of
a
highly
Me
Me
Me
Me
O
O
3-(aryl)-3-
H
methylcyclopentanones 14a-b was explored using different bases
such as LDA, LiHMDS, KHMDS, and NaHMDS in a solvent
capable of stabilizing metal-enolate (as well as corresponding
carbanion) complex such as dimethoxyethane (DME). The
17a'
17b'
(p-Me)
(m-Me)
20a' (p-Me)
20b'
(m-Me)
optimization of gem-dimethylation was carried out using
3
Figure 3: Plausible transition states 17a-b and 20a-b.
equivalents of base, 0.6 equivalent of hexamethyl phosphoramide
(HMPA), and 6 equivalents of methyl iodide (Scheme 3). Following
a quick optimization, we were pleased to find that a highly
regioselective gem-dimethylated products 1b and 13 were obtained
in 59% and 56% yields, respectively, when sequential methylation
was carried out using LiHMDS (3 equiv.), HMPA (0.6 equiv.) and
methyl iodide (6 equiv.).18, 16a
Thus, our effort culminated a 2 steps stereoselective total synthesis
of -cuparenone (1b) in 56% overall yield for the first time, to the
best of our knowledge (Scheme 3). Later, Wolff-Kishner reductions14
of (+)--cuparenone (1b) and compound 13 completed the total
synthesis of (+)-cuparene (1a) (35% yields over 3 steps from enone
15), and (+)-herbertene (8a) (34% yields over 3 steps from enone
15), clearly indicating greater efficiencies of our approach.
The preference of gem-dimethylation at C-2 position of 14a-b rather
than at C-5 position clearly indicates that the corresponding lithiated
carbanions 17a-b and 20a-b are probably stabilized by the favorable
interactions shown in Figure 3. It is most likely that, in the presence
of corresponding carbanion of Li-enolate of 14a-b, Li+ might interact
with the arene substrate through a favorable Li+ ion-p interactions to
promote highly regioselective gem-dimethylation.19
O
O
NBS, CH3CN,
25 C, 20 h
NaIO4, DMF
110 C, 8 h
Me
Me
Me
Me
Me
1b
Me
21
77%
Me
66%
Br
(
)
(
)
LiHMDS, HMPA
MeI, DME
-10 C - rt, 5 h
O
O
O
1b
R = p-Me, ( ), 59%
Me
Me
O
(+)--cuparenone
13
R = m-Me, ( ), 56%
Me2C=CHMe, KH2PO4
NaClO2, tBuOH, THF,
H2O, 25 C, 2 h
Me
Me
56-59%
R
Me
Me
Me
Me
R
Me
Me
22
14a
14b
R = p-Me, (
R = m-Me, (
)
)
O
NH2-NH2.2HCl, KOH
hydrazine hydrate
diethylene glycol
120 °C, 5 h
70%
3a
(
)
63-66%
O
(
)
HO
oxo cuparenic acid
Me
Me
Scheme 4. Synthesis of oxo cuparenic acid (3a).
Me
Further synthetic elaboration was shown by synthesizing oxo
cuparenic acid (3a) from (+)--cuparenone (1b), which is the
advanced intermediate for cuparenic acid (3) and ent-deconin A
(ent-6) (Figure 1). Towards this end, benzylic bromination of
1b using N-bromo succinimide (NBS) in acetonitrile at room
temperature afforded benzyl bromide 21 in 77% yield (Scheme
4). Compound 21 upon treatment with NaIO4 in N,N-
R
1a
R = p-Me, (+)-cuparene ( ), 63%
8a
R = m-Me, (+)-herbertene ( ), 66%
Scheme 3. Total syntheses of (+)--cuparenone (1b), (+)-cuparene
(1a) and (+)-herbertene (8a).

4
Srikrishma, A.; Satanarayana, G.; Prasad, K. R. Synth. Commun., 2007,
dimethylformamide under elevated temperature afforded
benzaldehyde 22 in 66% yield. Next, Pinnick oxidation of
benzaldehyde 22 with NaClO2 in the presence of excess 2-
methyl 2-butene at room temperature furnished oxo cuparenic
acid (3a) in 70% yield.
37, 1511. (c) Secci, F.; Frongia, A.; Ollivier, J.; Piras, P. P. Synthesis,
2007, 7, 999. (d) Cohen, T.; Kreethadumrongdat, T.; Liu, X.; Kulkarni,
V. J. Am. Chem. Soc., 2001, 123, 3478. (e) Bailey, W. F.; Khanolkar, A.
D. Tetrahedron, 1991, 47, 7727. (f) Krief, A.; Barbeau, P. Synlett, 1990,
511.
In conclusion, a unified total synthesis of (+)-cuparene (1a), (+)--
cuparenone (1b) and (+)-herbertene (8a) has been demonstrated in
only 2-3 steps in high chemical yields from commercially available
3-methylcyclopenten-2-one (15). The Stoltz methodology of Pd(II)-
PyOx (L1) catalyzed aryl boronic acids (16a-b) addition onto 3-
methylcyclopenten-2-one (15) worked well for our synthetically
relevant substrates. Further application of this strategy to asymmetric
total syntheses of structurally complex sesquiterpenoids is currently
under active investigation in our laboratory and will be reported in
due course.
10. Selected reports on the synthesis of (±)-herbertene, see: (a) Bernard,
A. M.; Frongia, A.; Secci, F.; Piras, P. P. Chem. Commun., 2005, 3853.
(b) Gupta, P. D.; Pal, A.; Roy, A.; Mukherjee, D. Tetrahedron Lett.,
2000, 41, 7563. (c) Ho, T.-L. J. Chem. Soc., Perkin. Trans. 1, 1999,
2479. (d) Mandelt, K.; Fitjer, L. Synthesis, 1998, 1523.
11. Asymmetric total syntheses of cuparenes, see: (a) Kumar, R.; Halder,
J.; Nanda, S. Tetrahedron, 2017, 73, 809. (b) Graninger, R. S.; Patel, A.
Chem. Commun., 2003, 1072. (c) Nayek, A.; Drew, M. G. B.; Ghosh, S.
Tetrahedron, 2003, 59, 5175. (d) Aavual, B. R.; Cui, Q.; Mash, A.
Tetrahedron: Asymmetry, 2000, 11, 4681. (e) Fuganti, C.; Serra, S. J.
Org. Chem., 1999, 64, 8728. (f) Ichiba, T.; Higa, T. J. Org. Chem., 1986,
51, 3364.
Acknowledgments
12. Asymmetric total syntheses of herbertenes, see: (a) Nayek, A.;
Ghosh, S. Tetrahedron Lett., 2002, 43, 1313. (b) Abad, A.; Agullo, C.;
Cunat, A. C.; Perni, R. H. J. Org. Chem., 1999, 64, 1741. (c) Tori, M.;
Miyako, T.; Sono, M. Tetrahedron: Asymmetry, 1997, 8, 2731. (d)
Takano, S.; Moriya, M.; Ogassawara, K. Tetrahedron Lett., 1992, 33,
329.
V.B. thanks the SERB, DST for a research grant [CS-021/2014].
Facilities from Department of Chemistry, IISER Bhopal, IISER
Tirupati and IISER Berhampur is gratefully acknowledged. S.N. and
R.N. thank the CSIR and Inspire Scheme, respectively, for Junior
Research Fellowships (JRFs).
13. (a) Kikushima, K.; Holder, J. C.; Gatti, M.; Stoltz, B. M. J. Am.
Chem. Soc., 2011, 133, 6902. For related catalytic asymmetric boronic
acid addition, see; (b) Morisaki, Y.; Imoto, H.; Hirano, K.; Hayashi, T.;
Chujo, Y. J. Org. Chem., 2011, 76, 1795.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http:.....................
14. Wolff-Kishner reduction: (a) Campbell, W. P.; Todd, D. J. Am.
Chem. Soc., 1942, 64, 928. (b) Furrow, M. E.; Myers, A. G. J. Am.
Chem. Soc., 2004, 126, 5436. (c) Dai, X.-J.; Li, C.-J. J. Am. Chem.
Soc., 2016, 138, 5344.
§Current Address:
The AB Research Group, Department of Chemistry, Indian Institute
of Science Education and Research Bhopal, Bhopal Bypass Road,
Bhopal - 462 066, India.
15. Holder, J. C.; Zou, L.; Marziale, A. N.; Liu, P.; Lan, Y.; Gatti, M.;
Kikushima, K.; Houk, K. N.; Stoltz, B. M. J. Am. Chem. Soc., 2013, 135,
14996.
References and notes:
16. (a) Gottumukkala, A. L.; Matcha, K.; Lutz, M.; de Vries, J. G.;
Minnaard, A. J. Chem. -Eur. J., 2012, 18, 6907. (b) Buter, J.; Moezelaar,
R.; Minnaard, A. J. Org. Biomol. Chem., 2014, 12, 5883. (c) Buter, J.;
Heijnen, D.; Vila, C.; Hornillos, V.; Otten, E.; Giannerini, M.; Minnaard,
A. J.; Feringa B. L. Angew. Chem. Int. Ed., 2016, 55, 3620.
1. (a) Enzell, C.; Erdtman, H. Tetrahedron, 1958, 4, 361. (b) Erdtman,
H.; Thomas, B. R. Acta Chem Scand., 1958, 12, 267.
2. For a general method for the construction of quaternary carbon
stereocentres, see: (a) Hong, A. Y.; Stoltz, B. M. Eur. J. Org. Chem.,
2013, 2745. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci.
U.S.A., 2004, 101, 5363. (c) Christoffers, J.; Baro, A. Angew. Chem., Int.
Ed., 2003, 42, 1688. (d) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed., 1998, 37, 388.
17. This is the first example of p-totylboronic acid addition onto 3-
methylcyclopenten-2-one to get 85% ee.
18. gem-Dimethylation of cyclopentanone 14a afforded 32% and 39% of
product 1b (along with 16-20% of recovery of 14a), when reactions were
carried out using NaHMDS and LDA as bases, respectively. Under the
same condition, KHMDS furnished 52% yield of 1b.
3. (a) Chetty, G. L.; Dev, S. Tetrahedron Lett., 1964, 5, 73. (b)
Benesova, V. Collect Czech. Chem. Commun., 1976, 41, 3812.
4. Toyota, M.; Koyama, H.; Ashakawa, Y. Phytochemistry, 1997, 46,
145.
19. A similar type of metal ion-p-interactions is reported to promote
biaryl-coupling, for reference, see; Sun, C.-L.; Li, H.; Yu, D.-G.; Yu, M.;
Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S. F.; Li, B.-J.; Shi, Z.-J. Nature
Chem., 2010, 2, 1044.
5. Surup, F.; Thongbai, B.; Kuhnert, E.; Dundarman, E.; Hyde, K. D.;
Stadler, M. J. Nat. Prod., 2015, 78, 934.
6. (a) Matsuo, A.; Yuki, S.; Nakayama, M.; Hayashi, S. J. Chem. Soc.,
Chem. Commun., 1981, 16, 864. (b) Fraga, B. M. Nat. Prod. Rep., 2006,
23, 943.
Graphical Abstract
7. Review on dimeric sesquiterpenoids: Zhan, Z. J.; Ying, Y.-M.; Ma, L.-
F.; Shan, W.-G. Nat. Prod. Rep., 2011, 28, 594.
8. (a) Fukuyama, Y.; Asakawa, Y. J. Chem. Soc., Perkin Trans. 1, 1991,
2737. (b) Toyota, M.; Koyama, H.; Asakawa, Y. Phytochemistry, 1997,
46, 145.
9. Selected reports on the synthesis of (±)-cuparene, see: (a) Chavan, S.
P.; Dhawane, A. N.; Kalkote, U. R. Synthesis, 2007, 24, 3827. (b)

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Catalytic Asymmetric Total Syntheses of (+)--Cuparenone, (+)-Cuparene and ()-
Herbertene
Kundan Shaw, Sovan Niyogi, Rhituparna Nandi, and Vishnumaya Bisai*
O
Me
O
Me
N
O
Me
Me
N
1b
(+)--cuparenone (
)
O
L1
)
PyOx (
t-Bu
CH3
)
15
(
Me
Pd(TFA)2, (CH2Cl)2
60 °C, 12 h
+
Me
Me
B(OH)2
16a-b
Me
Me
Me
Me
up to 95%
up to 90% ee
1a
p-Me, cuparene (
)
(
)
14a-b
(
)
8a
m-Me, herbertene (
)