Total synthesis of (+)-ar -macrocarpene

Article abstract of DOI:10.1039/c9ob01373c

This report features the first catalytic asymmetric total synthesis of a sesquiterpene, (+)-ar-macrocarpene (1), in 7 steps with 42.1% overall yields from commercially available inexpensive 5,5-dimethylcyclohexane 1,3-dione. This strategy relies on a key [3,3]-sigmatropic rearrangement effecting reductive transposition through allylic diazene rearrangement (ADR) in a single step from intermediate allylic alcohol (+)-12 under the Mitsunobu reaction conditions with o-nitrobenzenesulfonyl hydrazide (o-NBSH). Enantioselective reduction of α-bromo vinylogous ester 16 under the Corey-Bakshi-Shibata reduction conditions forges the required stereocenter in the allylic alcohol (+)-12 in a highly enantioenriched manner (95% ee).

Full text of DOI:10.1039/c9ob01373c

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DOI: 10.1039/C9OB01373C
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Total Synthesis of (+)-ar-Macrocarpene†
Arindam Khatua,a Sovan Niyogi,a and Vishnumaya Bisai*a,b,c
Received 00th January 20xx,
Accepted 00th January 20xx
This report features first catalytic asymmetric total synthesis of sesquiterpene, (+)-ar-macrocarpene (1) in 7
steps in 42.1% overall yields from commercially available inexpensive 5,5-dimethylcyclohexane 1,3-dione. The
strategy relies on a key [3,3]-sigmatropic rearrangement effecting reductive transposition through allylic diazene
rearrangement (ADR) in a single step from intermediate allylic alcohol (+)-12 under Mitsunobu reaction condition
with o-nitrobenzenesulfonyl hydrazide (o-NBSH). Enantioselective reduction of -bromo vinylogous ester 16 under
Corey-Bakshi-Shibata reduction condition forges the required stereocenter in the allylic alcohol (+)-12 in highly
enantioenriched manner (95% ee).
DOI: 10.1039/x0xx00000x
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correlation with the related natural products in the literature.
Other structurally correlated sesquiterpenoids, include
laurokamurene B (
) and debromoaplysin (10) having same total numbers of
6 7), cuparenic acid (8
),2 cuparane ( )3, aplysin
Introduction
(9
carbons i.e they are structural isomers with rearranged
Owing to their wide-ranging bioactivity profiles and many
uncommon structural features, total synthesis endeavors toward
sesquiterpenoids holds considerable synthetic challenge. Towards
this, we found Macrocarpenes (1-3) are naturally occurring irregular
structural scaffolds (Figure 1). Apart from this, majapolene B
(4
),4 a brominated sesquiterpene, was originally isolated from
Laurencia majuscula. Reisolation of majapolene B (
Laurencia sp. (Teluk Juara, Malaysia), along with the isolation of
the previously unreported acetylmajapolene B ( ), led to the
4) from
sesquiterpenes possessing
a 3,3,4’-trimethyl-1,1’-(bicyclohexyl)
5
skeleton to be compelling synthetic targets (Figure 1). From
structural perspective, macrocarpenes bear only three terminal
carbons and the presence of the fourth terminal carbon might be
incorporated during the biogenesis of the dimethylcyclohexane ring.
These sesquiterpenoids were identified in foliage of Cupressus
macrocarpa by Cool in 2005 in widely varying amount.1
determination of the absolute configuration of both
compounds by vibrational circular dichroism (VCD).
Results and Discussion
Despite its limited natural range (only on Point Lobos and
Cypress Point, Monterey Co., California), Cupressus macrocarpa
Hartw. ex Gord. (Monterey cypress) is one of the most widely
planted conifers in the state. The minor component of N-hexane
Structurally, macrocarpenes (1-3) share a common 3,3,4’-trimethyl-
1,1’-(bicyclohexyl) skeleton. However, the three methyl groups are
situated on the 1-arylcyclopentane ring in 2,2,3-fashion,5 1,2,2-
fashion,6 and 1,2,3-fashion.7 in laurokamurene B (6), cuparanes (7-8)
and lauranes [such as aplysin (9) and debromoaplysin (10)]
respectively. Among various sesquiterpenes isolated till date, ar-
macrocarpene 1 is the first member having arylcyclohexane skeleton
(Figure 1).
extract of this species contains ar-macrocarpene
The absolute configuration of ar-macrocarpene
1
1
(Figure 1).
has been
assigned tentatively, on the basis of the optical rotation and
aDepartment of Chemistry, IISER Bhopal, Bhopal Bypass Road, Bhauri, Bhopal
- 462 066, Madhya Pradesh, INDIA.
bDepartment of Chemistry, IISER Berhampur, Transit Campus (Govt. ITI
Building), Engg. School Junction, Berhampur, Odisha – 760 010, INDIA.
bDepartment of Chemistry, IISER Tirupati, Rami Reddy Nagar, Karkambadi
Road, Mangalam, Tirupati – 517 507, INDIA.
Corresponding author: vishnumayabisai@gmail.com
§both authors contributed equally to this work.
This work is dedicated respectfully to Professor Vinod K. Singh, IIT Kanpur
on the occasion of his 60th birthday.
Electronic Supplementary Information (ESI) available: Experimental
procedures,
characterization
data,
NMR
spectra.
See
DOI: 10.1039/x0xx00000x
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single step. This sequence involves a Mitsunobu reaction with o-
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nitrobenzenesulfonyl hydrazide (o-NBSH) asDdOeIs:c1r0ib.1e0d39b/yC9MOyBe0r1s3a73nCd
co-workers.10 Allylic alcohol 12 could be generated through catalytic
asymmetric reduction of carbonyl functionality in 5,5-Dimethyl 3-aryl
2-cyclohexenone 13a under CBS reduction condition.9 Compound
13a could be easily accessed from a Stork-Danheiser sequence11 of
vinylogous ester 14 with p-tolyllithium/p-tolylmagnesium halide.
Scheme 2. Synthesis of vinylogous ester 14.
With above hypothesis, we have carried out reaction of 5,5-
dimethylcyclohexane 1,3-dione with iso-butylalcohol in the presence
of catalytic p-toluenesulphonic acid to form vinylogous ester 14
(Scheme 2). We then established the reaction condition for Stork-
Danheiser sequence on vinylogous ester with various arylmetal
reagents (Table 1). Following a quick optimization, it was found that
enone 13b could be accessed in 94% yield, when phenylmagnesium
Figure 1: Selected naturally occurring sesquiterpenes,
macrocarpenes (1-3), majapolene B (4-5), laurokamurene B (6),
cuparanes (7-8), and aplysins (9-10).
bromide (entries 5-8) was used as
a nucleophile. In fact,
phenylmagnesium bromide is a good nucleophile as compared to
phenyllithium (entries 1-4) in terms of efficiency of the process
(Table 1).
Since its isolation more than a decade, till date just a single racemic
approach of ar-macrocarpene 1 is featured in the literature by
Srikrishna and co-workers in 2007.8 The report demonstrates the first
total synthesis of (±)-ar-macrocarpene 1a starting from 3-
methylcyclohexenone in four steps. Therefore, there is an urgent
need for asymmetric synthesis of ar-macrocarpene 1a sharing 3,3-
dimethyl 1-arylcyclohexane (Figure 1). Herein, we report the details
of first total syntheses of naturally occurring (+)-ar-macrocarpene 1a
via catalytic asymmetric enone reduction of ketone functionality
under CBS reduction9 followed by a key reductive transposition of
enantioenriched allylic alcohol under Myers condition.10
Table 1. Optimization of Stork-Danheiser sequence of 14.
S.
No.
nucleophi temp.
le
Time
(1st
temp.
(2nd
Time
(2nd
yield
(1st step)
step)
step)
step)
1.
2.
3.
4.
5.
6.
7.
8.
PhLi
PhLi
PhLi
PhLi
PhMgBr
PhMgBr
PhMgBr
PhMgBr
-78 °C
-40 °C
-20 °C
0 °C
-78 °C
-40 °C
-20 °C
0 °C
7 h
6 h
6 h
4 h
8 h
5 h
5 h
5 h
0 °C - rt 2 h
0 °C - rt 2 h
0 °C - rt 2 h
0 °C - rt 1 h
0 °C - rt 2 h
0 °C - rt 2 h
0 °C - rt 1 h
0 °C - rt 1 h
76%
62%
69%
72%
83%
85%
82%
90%
aReactions were carried out on a 1 mmol of 14 under argon atmosphere.
bIsolated yields after column chromatography.
Scheme 1: Retrosynthetic analysis of (+)-ar-macrocarpene (1a).
A variety of aryl magnesium bromide nucleophiles were the
subjected to the Stork-Danheiser sequence on the vinylogous ester
14 in THF at 0 °C followed by treatment of dilute HCl. This resulted in
the synthesis of wide range of 3-aryl-cyclopenten-2-ones 13a-i in 86-
92% yields without event (Figure 2).11c
In devising
a retrosynthetic strategy for accessing the ar-
macrocarpene 1, we simplified our target to enantioenriched 5,5-
dimethyl 3-arylcyclohexene 11, which could serve as a platform to
the asymmetric synthesis of ar-macrocarpene 1a via late stage
hydrogenation (Scheme 1). We envisioned the conversion of allylic
alcohol 12 to compound 11 via
a key [3,3]-sigmatropic
rearrangement effecting reductive transposition of double bond in a
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DOI: 10.1039/C9OB01373C
Scheme 4. Catalytic enantioselective reduction of enone 13a.
aReactions were carried out on a 1 mmol of 14 under argon atmosphere.
bIsolated yields after column chromatography.
Starting from vinylogous ester 16, compound 17 was synthesized in
91% yield following a Stork-Danheiser sequence. Fortuitously, as per
our expectation, a catalytic enantioselective reduction of 5,5-
Dimethyl 3-(p-tolyl)-2-bromo cyclohexenone 17 with CBS reagent,
afforded the allylic alcohol (+)-18 in 93% yield with excellent
enantioselectivity i.e. 95% ee (Scheme 5). Further allylic alcohol (R)-
12 was synthesized via a reductive cleavage of bromo group in the
presence of n-tributyltin hydride and 10 mol% azo-bis-
isobutyronitrile (AIBN) as radical initiator, without compromising
enantiopurity (94% ee).
Figure 2. Substrate scope of Stork-Danheiser sequence of 13.
With 5,5-Dimethyl 3-(p-tolyl)-2-cyclohexenone 13a in significant
quantity, next step was its hydrogenation to form 3-arylketone 15 in
quantitative yield (Scheme 3). In fact, a concise total synthesis of
racemic (±)-ar-macrocarpene (1a) was achieved from ketone 15 via
a modified Wolff-Kishner reduction in 82% yield (67.9% yield over 4
steps from commercially available 5,5-dimethylcyclohexane 1,3-
dione).12 Further synthetic elaboration of 5,5-Dimethyl 3-aryl 2-
cyclohexenone 13a was done under Luche condition,13 which
afforded allylic alcohol (±)-12 in 91% yield (Scheme 4).
Scheme 3. Total synthesis of (±)-ar-macrocarpene (1).
Next, we turned our attention for asymmetric total synthesis of (+)-
1. Towards this direction, unfortunately, Corey-Bakshi-Shibata
reduction of enone 13a with borane using 10 mol% (S)-CBS reagent
at -78 C for 16 h furnished the product only in 65% ee in favor of (R)-
12 (Scheme 4), thus implying the presence of sterics at the -position
of carbonyl might be essential to achieve excellent
enantioselectivity.14 Thus, we thought of installing an easily
removable bromo group at the -position of enone 13a i.e. 17
(Scheme 5) to test if that helps in securing enantioenriched allylic
alcohol.
Scheme 5. Catalytic enantioselective reduction of sterically crowded
2-bromoenone 16.
Next, we sought to demonstrate the feasibility of reductive
transposition through allyllylic diazene rearrangement (ADR) on
compound (R)-12 (94% ee) under Mitsunobu condition using o-
nitrophenylsulfonyl hydrazide (Myer’s protocol).13 The procedure
involves first formation of corresponding stereo inverted
sulfonylhydrazine 19 which on gentle extrusion of O-
nitrobenzenesulfinic acid in the presence of methanol leads to
concomitant formation of
a
diazene intermediates 20a-20b.
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Intermediate 20b slowly loses N2 gas (through spontaneous retro-
ene reaction) to furnish the deoxygenated product cyclohexene (+)-
11 in 65% yield via a reductive transposition following a [3,3]-
sigmatropic rearrangement (Scheme 6). Finally, hydrogenation of
cyclohexene (+)-11 completed the synthesis of (+)-ar-macrocarpene
(1) in quantitative yield.
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2. (a) T. G. Köllner, C. Schnee, S. Li, A. Svatoš, B. Schneider, J. Gershenzon,
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J. Degenhardt, J. Bio. Chem. 2008, 30, 20779–20788. (b) B. M. Fraga, Nat.
Prod. Rep. 2006, 23, 943-972.
3. (a) Y. Asakawa, A. Ludwiczuk, J. Nat. Prod. 2018, 81, 641-660. (b) K. L.
McPhail, M. T. Davies-Coleman, J. Starmer, J. Nat. Prod. 2001, 64, 1183-
1190 and references cited.
4. (a) Isolation of majapolene B (2a): K. L. Erickson, J. A. Beutler, G. N.
Gray, J. H. Cardellina, II, M. R. Boyd, J. Nat. Prod. 1995, 58, 1848. (b)
Majapolene B acetate (2b): J. W. Blunt, B. R. Copp, W.-P. Hu, M. H. G.
Munro, P. T. Northcote, M. R. Prinsep, Nat. Prod. Rep. 2008, 25, 35-94.
5. (a) S.-C. Mao, Y.-W. Guo, J. Nat. Prod. 2006, 69, 1209–1211. (b) X.-Q.
Yu, W.-F. He, D.-Q. Liu, M.-T. Feng, Y. Fang, B. Wang, L.-H. Feng, Y.-W.
Guo, S.-C. Mao, Phytochemistry 2014, 103, 162-170.
6. F. Surup, B. Thongbai, E. Kuhnert, E. Sudarman, K. D. Hyde, M. Stadler,
J. Nat. Prod. 2015, 78, 934-938.
7. (a) B.-G. Wang, J. B. Gloer, N.-Y. Ji, J.-C. Zhao, Chem. Rev. 2013, 113,
3632-3685. (b) B. M. Fraga, Nat. Prod. Rep. 2013, 30, 1226-1264.
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9. (a) Corey, E. J.; Bakshi, R.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551-
5553. (b) Corey, E. J.; Bakshi, R.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am.
Chem. Soc. 1987, 109, 7925-7926. (c) Corey, E. J.; Link, J. O. J. Am. Chem.
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Scheme 6. Total synthesis of (+)-ar-macrocarpene (1).
10. (a) E. J. Corey, G. Wess, Y. B. Xiang, A. K. Singh, J. Am. Chem. Soc. 1987,
109, 4717-4718. (b) A. G. Myers, B. Zheng, J. Am. Chem. Soc. 1996, 118,
4492-4493. (c) A. G. Myers, M. Movassaghi, B. Zheng, J. Am. Chem. Soc.,
1997, 119, 8572-8573.
Conclusions
In conclusion, a concise total synthesis of (+)-ar-macrocarpene (1)
has been achieved (42.1% overall yields over 7 steps) from 11. (a) G. Stork, R. L. Danheiser, J. Org. Chem. 1973, 38, 1775-1776. (b) S.
P. West, A. Bisai, A. D. Lim, R. R. Narayan, R. Sarpong, J. Am. Chem. Soc.
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351–356. (d) B. N. Kakde, S. Bhunia, A. Bisai, Tetrahedron Lett. 2013, 54,
1436-1439.
commercially available inexpensive 5,5-dimethylcyclohexane 1,3-
dione. A key reductive transposition on enantioenriched allylic
alcohol (+)-12 is achieved in single step using Myers protocol to
afford advanced intermediate cyclohexene (+)-11. Enantioenriched
(95% ee) allylic alcohol (+)-12 was prepared via a catalytic
enantioselective CBS reduction of 5,5-Dimethyl 3-(p-tolyl)-2-bromo
cyclohexenone 17. Further application of this strategy for the
synthesis of other sesquiterpenoids is currently under active
investigation in our laboratory.
12. (a) W. P. Campbell, D. Todd, J. Am. Chem. Soc. 1942, 64, 928-935. (b)
M. E. Furrow, A. G. Myers, J. Am. Chem. Soc. 2004, 126, 5436-5445. (c)
X.-J. Dai, C.-J. Li, J. Am. Chem. Soc. 2016, 138, 5433-5440.
13. (a) V. Bisai, R. Sarpong, Org. Lett. 2010, 12, 2551-2553. (b) Das, M. K.;
Dinda, B. K.; Bisai, V. Tetrahedron Lett. 2019, doi.org/10.1016/j.tetlet.
2019.05.032.
Acknowledgements
14. (a) G. Majetich, G. Zou, Org. Lett. 2008, 10, 81-83. (b) N.-W. Jan, H.-J.
Liu, Org. Lett. 2006 8, 151-153.
V.B. thanks the Science and Engineering Research Board (SERB),
Department of Science and Technology (DST) for a research grant
[CS-021/2014]. Facilities from Department of Chemistry, IISER
Bhopal, IISER Berhampur and IISER Tirupati is gratefully
acknowledged.
Notes and references
1. (a) Isolation of macrocarpenes (1a-b): L. G. Cool, Phytochemistry 2005,
66, 249–260. (b) N. Kacem, V. Roumy, N. Duhal, F. Merouane, C. Nuet, P.
Christen, K. Hostettmann, S. Rhouati, Industrial Crops and Products 2016,
90, 87-93.
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