A unified approach to sesquiterpenes sharing trimethyl(p-tolyl) cyclopentanes: Formal total synthesis of (±)-laurokamurene B

Article abstract of DOI:10.1016/j.tetlet.2019.05.032

A unified approach to the sesquiterpenoids sharing common trimethyl(p-tolyl) cyclopentane skeleton has been disclosed via a key Stork-Danheiser sequence on a cyclopentane based vinylogous ester with aryl Grignard reagent followed by α-methylation strategy

Full text of DOI:10.1016/j.tetlet.2019.05.032

Accepted Manuscript
A Unified Approach to Sesquiterpenes Sharing Trimethyl(p-tolyl) Cyclopen-
tanes: Formal Total Synthesis of (±)-Laurokamurene B
Mrinal K. Das, Bidyut K. Dinda, Vishnumaya Bisai
PII:
S0040-4039(19)30478-2
https://doi.org/10.1016/j.tetlet.2019.05.032
TETL 50804
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 February 2019
14 May 2019
17 May 2019
Please cite this article as: Das, M.K., Dinda, B.K., Bisai, V., A Unified Approach to Sesquiterpenes Sharing
Trimethyl(p-tolyl) Cyclopentanes: Formal Total Synthesis of (±)-Laurokamurene B, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.05.032
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Leave this area blank for abstract info.
A Unified Approach to Sesquiterpenes Sharing Trimethyl(p-tolyl) Cyclopentanes:
Formal Total Synthesis of (±)-Laurokamurene B
Mrinal K. Das, Bidyut K. Dinda, and Vishnumaya Bisai*

1
Tetrahedron Letters
A Unified Approach to Sesquiterpenes Sharing Trimethyl(p-tolyl) Cyclopentanes:
Formal Total Synthesis of (±)-Laurokamurene B
Mrinal K. Das,§ Bidyut K. Dinda,§ and Vishnumaya Bisai*
Department of Chemistry, Indian Institute of Science Education and Research Berhampur, Berhampur - 462 066, Odisha, India
Contact: +91-755-6692374, Fax: +91-755-6692392. Address for correspondence: vishnumayabisai@gmail.com
§Both authors contributed equally to this work.
ARTICLE INFO
ABSTRACT
A unified approach to the sesquiterpenoids sharing common trimethyl(p-tolyl)
cyclopentane skeleton has been disclosed via a key Stork-Danheiser sequence on a
cyclopentane based vinylogous ester with aryl Grignard reagent followed by -methylation
strategy. The strategy is eventually applied to the concise formal total synthesis of (±)-
laurokamurene B (1b) in only 5 steps with 45.4% overall yield.
Article history:
Received
Received in revised form
Accepted
Available online
2012 Elsevier Ltd. All rights reserved.
Keywords:
Vinylogous esters, Stork-Danheiser Sequence,
-alkylations, laurokamurene B
Red algae of the genus Laurencia Lamouroux are well-known for
their ability to biosynthesize a large variety of structurally unusual
secondary metabolites having brominated and non-brominated
sesquiterpenes.1 The genus Laurencia is particularly distributed
widely in tropical and subtropical areas.1 More than 1100 different
metabolites with sesquiterepene (C-15 unit), diterpenes (C-20 unit),
and triperpenes (30 unit) have been characterized from
approximately 80 species of this genus till date.
During their investigations on the isolation of biologically active
compounds from Chinese marine organisms, Mao and Guo isolated
two new aromatic sesquiterpenes laurokamurenes A and B (1a-b)
from genus Laurencia in 2006.2a Recently, in 2014, Mao and co-
workers have isolated laurokamurenes C and D (1c-d) from the red
alga Laurencia okamurai Yamada, together with six other known
sesquiterpenes.2b The structures of these secondary metabolites,
including relative configuration, were elucidated by detailed analysis
of spectroscopic data (2D NMR experiments), and by comparison
with data for related known compounds. Although, elaborate study
of the biological profile of majority of these sesquiterpenes are yet to
be undertaken, preliminary findings revealed that laurokamurene B
(1b) displays antifungal and cytotoxic activities.2b-d
Structurally, laurokamurenes (1a-d) are closely related to other
sesquiterpenoids, such as cuparenes (2a-b), deconins (3a-c)3, and
aplysins (4-5) with same total numbers of carbons present in them in
Figure 1: Selected sesquiterpene based secondary metabolites,
laurokamurenes A-D (1a-d), cuparenes (2a-b), deconins (3a-c) and
aplysins (4-5).
a
rearranged structural scaffold (Figure 1). Particularly, in
laurokamurenes (1a-d), three methyl groups are situated at 2,2,3-
fashion in 1-arylcyclopentane ring. In contrast, cuparanes (2a-b)
share three methyl groups at 1,2,2-fashion, whereas in lauranes (1a-
d) they follow 1,2,3-fashion.4a Among various sesquiterpenes
isolated till date, laurokamurenes (1a-b) are the first members with
three methyl groups in the aliphatic ring arranged in a 2,2,3 fashion.
Biogenetically, they are synthesized from intermediate carbocation
6d (Scheme 1) via the rearrangement of methyl group (1,2-shift of
methyl group) to establish a 3˚ carbocation intermediates such as 7a
(for lauranes e.g. debromoaplysin 4b) and 8a (e.g. laurokamurenes

2
Tetrahedron Letters
1a-d). Cyclopentane based 2˚ carbocation 6d can be generated
cuparene 2a. Compound 11 could be accessed from a Stork-
Danheiser sequence9 of vinylogous ester 12 with p-tolyllithium/p-
tolylmagnesium halide.
from a bisabolyl cation intermediate (6c) via a C-C bond formation,
which in turn can be obtained from a farnesyl pyrophosphate 6a (C-
15 unit) via a nerolidyl pyurophosphate 6b (C-15 unit) (Scheme 1).
Scheme 2: Unified retrosynthetic analysis of laurokamurenes B (1a)
and cuparene (2a).
Assuming above hypothesis, we have carried out reaction of
cyclopentane 1,3-dione 13 with iso-butylalcohol in the presence of
catalytic p-toluenesulphonic acid to form vinylogous ester 14 (90%
yield). -Methylation of vinylogous ester 14 was carried out in the
presence of LDA with methyl iodide at -78 ºC (Scheme 3). It was
observed that a sequential -methylation of 14 afforded gem-
dimethyl vinylogous ester 12 in 75% yield. However, a two-step
protocol of -methylation of 14 following monomethylated
intermediate 15 afforded 12 in 87% overall yield over 2 steps
(Scheme 3).
Scheme 1: Biogenetic connections between laurokamurenes (1b),
cuparene (2-3), and laurane (4-5).
Owing to their diverse biological profiles and uncommon structural
features, cuparane (2a-b) and laurane (3-5) based sesquiterpenoids
have gained extensive attention from the synthetic community all
over the world leading to numerous efficient synthetic approaches.1a
Although laurokamurenes were isolated more than a decade, only a
few synthesis of laurokamurene B 1a are reported till date. In 2007,5a
Srikrishna and co-workers have reported the first total synthesis of
(±)-laurokamurene
B 1a from isobutyric acid employing a
combination of an Ireland–Claisen rearrangement and RCM
reactions establishing the structure of the marine natural product
(22% overall yields over 11 steps). In 2008,6 the same group has
reported first asymmetric synthesis of (+)-laurokamurene B 1a from
commercially available -campholenaldehyde7 in 31.2% overall
yields over 7 steps (this strategy is essentially a semisynthesis
Scheme 3. Synthesis of vinylogous ester 12.
With gem-dimethyl vinylogous ester 12 in hand, our effort was
thereafter to establish the reaction condition for the Stork-Danheiser
sequence on the vinylogous ester 14 with arylmetal reagent (Table
1). Initially, we began our studies by carrying out a Stork-Danheiser
sequence on the vinylogous ester 14 by subjecting it with
phenylmagnesium bromide in THF at different temperature followed
by treatment of dilute HCl. Following exhaustive optimization, it
was found that phenylmagnesium bromide (entries 5-8) was a good
nucleophile as compared to phenyllithium (entries 1-4) in terms of
chemical yields (Table 1).
starting from
Subsequently, in 2009, Lecornué and co-workers have disclosed a
total synthesis of (±)-laurokamurene 1a from 2-
methylcyclopentenone (39.7% overall yields over
steps).5b
a
naturally occurring secondary metabolite).
B
7
Recently, in 2017, Echavarren and co-workers have reported total
synthesis of (±)-laurokamurene B 1a via an elegant Au(I)-catalyzed
[3+2]-cycloaddition
reaction
between
an
allene
and
styrylcycloheptatriene.5c
Table 1. Optimization of Stork-Danheiser sequence of 11.
Despite these reports, there is urgency for a straightforward and
efficient unified approach for sesquiterpene natural products sharing
a common arylcyclopentane skeleton (shown in Figure 1). Herein,
we report a concise total synthesis of (±)-laurokamurene B 1a via a
key Stork-Danheiser sequence of vinylogous ester
9 with
arylmagnesium halide followed by -alkylation strategy.
Retrosynthetically, it was envisioned that, 4,4-dimethyl 3-aryl
cyclopenten-2-one (such as 11 in Scheme 2) could serve as a
potential intermediate for unified synthesis of laurokamurene B (1a)
and cuparene (2a) sesquiterpenoids (Scheme 2). -Methylation of
cyclopenten-2-one 11 with methyl iodide would afford (±)-10.8
Deoxygenation of compound 9 could afford laurokamurene B 1b. On
the other hand, a methylcuprate addition onto 3-aryl cyclopenten-2-
one (11) followed by the reduction of carbonyl group would provide
S.
nucleoph temp.
Time
(1st step)
4 h
2 h
2 h
2 h
4 h
2 h
temp.
Time
yield
No. ile
(1st step)
-78 ºC
-40 ºC
-20 ºC
0 ºC
(2nd step) (2nd step)
1.
2.
3.
4.
5.
6.
PhLi
PhLi
PhLi
PhLi
0 ºC - rt
0 ºC - rt
0 ºC - rt
0 ºC - rt
0 ºC - rt
0 ºC - rt
8 h
9 h
9 h
9 h
8 h
9 h
63%
69%
68%
74%
90%
94%
PhMgBr
PhMgBr
-78 ºC
-40 ºC

3
7.
8.
PhMgBr
PhMgBr
-20 ºC
0 ºC
2 h
2 h
0 ºC - rt
0 ºC - rt
9 h
9 h
92%
92%
aReactions were carried out on a 1 mmol of 14 under argon atmosphere.
c
bIsolated yields after column chromatography. 12-23% of starting material
14 was recovered in case to case due to incomplete reaction.
Later, a variety of aryl magnesium bromides were used under
standard condition in THF at 0 ºC followed by treatment of dilute
HCl. This resulted in a smooth reaction of Stork-Danheiser sequence
on the vinylogous ester 14 to provide a variety of 3-aryl-
cyclopenten-2-ones 16a-d in 83-92% yields (Figure 2).
S.
No.
1.
2.
3.
Base (solvent)
temp.
time Yield
(10)
LDA (THF)
-40 ºC
-40 ºC
-40 ºC
-78 ºC
8 h
9 h
6 h
9 h
63%
75%
56%
87%
LiHMDS (THF)
KHMDS (THF)
LiHMDS (THF)
4.
aReactions were carried out on a 0.5 mmol of 11a with 0.6 mmol of MeI at -
78 ˚C under argon atmosphere. bIsolated yields after column chromatography.
With enone (±)-10, we then investigated Luche reduction10 at 0 ˚C,
which afforded allylalcohol (±)-9 in 96% yield as
a sole
diastereoemer.11 Later,
a
concise total synthesis of (±)-
laurokamurene B (1a) was achieved from enone (±)-10 via a known
NaCNBH3 reduction4a in the presence of BF3.OEt2.
aReactions were carried out on a 1 mmol of 14 under argon atmosphere.
bIsolated yields after column chromatography.
Figure 2. Substrate scope of Stork-Danheiser sequence of 14.
Scheme 5. Formal total synthesis of (±)-laurokamurene B (1b).
Since, laurokamurenes (1a-d) and cuparene (2a-b) sesquiterpenoids
possess a gem-dimethyl group in their cyclopentane motifs, the
Stork-Danheiser sequence of vinylogous ester 12 was further
elaborated to furnish products 4,4-dimethyl 3-aryl-cyclopenten-2-
ones 17a-d in 87-91% yields (Scheme 4). Importantly, Stork-
Danheiser sequence on compound 12 with p-tolylmagnesium
bromide was performed in 5g scale to provide 11a in 91% yields.
In conclusion, concise total synthesis of (±)-laurokamurene B
(1b) has been achieved in 5 steps (45.4% overall yields) from
cyclopentane 1,3-dione following a key Stork-Danheiser sequence
followed by -alkylation strategy. We believed that a catalytic
enantioselective under a dynamic kinetic resolution (DKR) would
afford allylalcohol 9 as enantiopure compound. Further investigation
towards this direction as well as application of this strategy for the
synthesis of cuparene (2a) is currently under active investigation.
Acknowledgments
V.B. thanks the Science and Engineering Research Board (SERB),
Department of Science and Technology (DST) for a research grants.
M.K.D. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, for a Senior Research Fellowship (SRF). B.K.D
thanks IISER Berhampur for a postdoctoral fellowship. Facilities
from Department of Chemistry, IISER Bhopal is gratefully
acknowledged.
aReactions were carried out on a 1 mmol of 12 under argon atmosphere.
bIsolated yields after column chromatography.
Supplementary data
Scheme 4. Stork-Danheiser sequence of 12.
Supplementary data associated with this article can be found, in
the online version, at http:.....................
Next, with 4,4-dimethyl 3-(p-toyl)-cyclopenten-2-one 11a in hand, it
was -methylated with methyl iodide (Table 2). It was observed that
-methylation at -40 ˚C afforded desired enone compound 10 in 56-
75% yields (entries 1-3). Following optimization, it was found that
LiHMDS at -78 ºC afforded -methylated compound (±)-10 in 87%
yield (Table 2).
§Current Address:
The AB Research Group, Department of Chemistry, Indian Institute
of Science Education and Research Bhopal, Bhopal Bypass Road,
Bhopal - 462 066, India.
Table 2. -Alkylation of enone 11a.
References and notes:
1. (a) Martin, J. D.; Darias, J. In Marine Natural Products; Scheuer,
P. J., Ed.; Academic Press: New York, 1978; Vol. I, pp 151–161. (b)
Asakawa, Y.; Ludwiczuk, A. J. Nat. Prod. 2018, 81, 641-660.

4
Tetrahedron Letters
2. (a) Mao, S.-C.; Guo, Y.-W. J. Nat. Prod. 2006, 69, 1209–1211.
(b) Yu, X.-Q.; He, W.-F.; Liu, D.-Q.; Feng, M.-T.; Fang, Y.; Wang,
B.; Feng, L.-H.; Guo, Y.-W.; Mao, S.-C. Phytochemistry 2014, 103,
162-170. (c) Angawi, R. F.; Alarif W. M.; Hamza, R. I.; Badria, F.
A.; Ayyad, S. -E. N. Helv. Chem. Acta 2014, 97, 1388-1395. (d)
Gribble, G. W. Mar. Drugs 2015, 13, 4044-4136.
3. (a) Mao, S.-C.; Guo, Y.-W. Chin. Tradit. Herb. Drugs 2004, 35,
8–17. (b) Mao, S.-C.; Guo, Y.-W. Zhongguo Tianran Yaowu 2010, 8,
321–325.
4. (a) Deconins are conjugates of cuparenic acid and mevalonic acid
and are isolated in 2015 by Stadler and co-workers. (b) Surup, F.;
Thongbai, B.; Kuhnert, E.; Sudarman, E.; Hyde, K. D.; Stadler, M. J.
Nat. Prod. 2015, 78, 934-938.
5. (a) Srikrishna, A.; Khan, I. A.; Babu, R. R.; Sajjanshetty, A.
Tetrahedron 2007, 63, 12616–12620. (b) Tallineau, J.; Bashiardes,
G.; Coustard, J.-M.; Lecornué, F. Synlett 2009, 2761–2764. (c) Yin,
X.; Mato, M.; Echavarren, A. M. Angew. Chem., Int. Ed. 2017, 56,
14591-14595.
6. Srikrishna, A.; Beeraiah, B.; Babu, R. R. Tetrahedron: Asymmetry
2008, 19, 624-627.
7. Liu, H.-J.; Chan, W. H. Can. J. Chem. 1982, 60, 1081–1091.
8. Reduction of (±)-10 under the Dynamic Kinetic Resolution (DKR)
could led to the formation of enantioenriched core 9. For some of the
important reviews, see: (a) Noyori, R.; Tokunaga, M.; Kitamura, M.
Bull. Chem. Soc. Jpn. 1995, 68, 36-55. (c) Perllissier, H. Tetrahedron
2003, 59, 8291-8327.
9. (a)
J. Org. Chem.
38
(b) Bennett, N. B.; Hong, A. Y.; Harned, A. M.; Stoltz, B. M.
Org. Biomol. Chem. 2012, 10, 56-59.
10. (a) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008,
130, 7222-7223. (b) Bisai, V.; Sarpong, R. Org. Lett. 2010, 12, 2551-
2553.
11. Compound 9 was found to be unstable and decomposes at room
temperature. This is probably because of the sbalization of the allylic
carbocation 17a-e followed by polymerization via a Friedel-Crafts
type alkylations.

14th May, 2019
Prof. Vinod K. Singh
Editor, Tetrahedron Lett.
Professor
Indian Institute of Technology Kanpur
Kanpur – 208 016
Uttar Pradesh, INDIA
Highlights for the publication in Tetrahedron Lett.
Manuscript Title: A Unified Approach to Sesquiterpenes Sharing Trimethyl(p-tolyl) Cyclopentanes:
Formal Total Synthesis of (±)-Laurokamurene B
Authors: Mrinal K. Das, Bidyut K. Dinda, and Vishnumaya Bisai*
Dear Professor Singh,
Please see following highlights for this manuscript:
(a) Approach to sesquiterpenoids with trimethyl(p-tolyl)cyclopentanes is reported.
(b) Stork-Danheiser sequence on vinylogous ester yileds 3-arylcyclopetenone 11a.
(c) -Methylation of enone 11a sets all carbon present in Laurokamurene B (1b).
(d) (±)-Laurokamurene B (1b) is synthesized in 5 steps with 45.4% overall yield.
With best regards,
(Vishnumaya Bisai)