Formal Total Syntheses of (+)- and (–)-ar-Macrocarpene via Rh(I)-BINAP Catalyzed Conjugate Addition

Article abstract of DOI:10.1002/ejoc.202000100

Catalytic asymmetric formal total syntheses of both antipodes of sesquiterpene, (+)-ar-macrocarpene (1) and (–)-ar-macrocarpene (ent-1) has been achieved from 5,5-dimethyl-(3-p-tolyl)cyclohexanone 12. Enantioenriched compound 12 was obtained in excellent

Full text of DOI:10.1002/ejoc.202000100

A Journal of
Accepted Article
Title: Formal Total Syntheses of (+)- and (−)-ar-Macrocarpene via
Rh(I)-BINAP Catalyzed Conjugate Addition
Authors: Arindam Khatua, Souvik Pal, and Vishnumaya Bisai
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10.1002/ejoc.202000100
European Journal of Organic Chemistry
COMMUNICATION
Formal Total Syntheses of (+)- and (−)-ar-Macrocarpene via Rh(I)-
BINAP Catalyzed Conjugate Addition
Arindam Khatua,a Souvik Pal,a and Vishnumaya Bisai*a,b,c§
these sesquiterpenoids are structural isomers with rearranged
Abstract: Catalytic asymmetric formal total syntheses of both
antipodes of sesquiterpene, (+)-ar-macrocarpene (1) and (−)-
ar-macrocarpene (ent-1) has been achieved from 5,5-dimethyl-(3-
p-tolyl)cyclohexanone 12. Enantioenriched compound 12 was
structural scaffolds as shown in Figure 1. In addition
brominated sesquiterpenoid, majapolene B (3),8 was originally
isolated from Laurencia majuscula.
accessed
in 96% ee with excellent yield from catalytic
Structurally, macrocarpene (1) shares a common 3,3,4’-
trimethyl-1,1’-(bicyclohexyl) skeleton,2 whereas, the three
methyl groups are situated on the 1-arylcyclopentane ring in
2,2,3-fashion in laurokamurenes (4b) (Figure 1).4 There are
sesquiterepenoids, where three methyl groups are situated in
1,2,3-fashion, such as isolaurene (6),5 isolauraldehyde (5b),5c
and 12-hydroxy isolaurene (5c).5c The same is true for other
tricyclic sesquiterpenoids, such as aplysin (7a),7 and
debromoaplysin (7b).7 Further, three methyl groups are found
in 1,2,2-fashion in case of cuparane (6a),6 and cuparenic acid
(6b).6 With regard to its biogenetic connection, ar-
macrocarpene 1 seems to be possibly originated from
bisabolyl cation (10c) via the intermediacy of congener Z--
macrocarpene (2) and other hypothetical intermediates 10d
and 10e (Scheme 1).
enantioselective p-tolylboronic acid addition onto 5,5-dimethyl
cyclohexen-2-one 13 using Rh(I)-(S)-BINAP (L7). Further, ent-12
was achieved in 96% ee by using Rh(I)-(R)-BINAP (ent-L7).
Introduction
Recently, there is global interest in the synthesis of
sesquiterpenoids owing to their volatile and combustible
properties which make them ideal candidate for terpene-
based renewable biofuels.1 ar-Macrocarpene (1) and (Z)--
macrocarpene (2) are belonging to one such group of naturally
occurring irregular aromatic sesquiterpenes (Figure 1), which
were identified in foliage of Cupressus macrocarpa by Cool in
2005 in widely varying amounts.2
In spite of 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. N-Hexane extract of
this species contains ar-macrocarpene
1 as a minor
component (Figure 1).2 Other structurally correlated
sesquiterpenoids, include ar-tenuifolene (4a),3 laurokamurene
B (4b),4 isolaurene (5a),5 isolauraldehyde (5b),5c 12-hydroxy
isolaurene (5c),5c cuparane (6a),6 cuparenic acid (6b),6
aplysin (7a),7 and debromoaplysin (7b).7 Biogenetically,
[a] Mr. Arindam Khatua, Mr. Souvik Pal, and Dr. Vishnumaya Bisai
Department of Chemistry
Indian Institute of Science Education and Research Bhopal
Bhopal Bypass Road, Bhauri
Bhopal – 462 066
Madhya Pradesh, India
E-mail: vishnumayabisai@gmail.com
[b] Dr. Vishnumaya Bisai
Department of Chemistry
Indian Institute of Science Education and Research Tirupati
Transit Campus
Mangalam, Karkambadi Road
Tirupati – 517 507
Andhra Pradesh, India
Figure 1: ar-Macrocarpene (1) and structurally related naturally
occurring sesquiterpenes.
[c] Dr. Vishnumaya Bisai
Department of Chemical Sciences
Indian Institute of Science Education and Research Berhampur
Transit Campus
Engg. School Junction (Govt. ITI Building)
Berhampur – 760 010
A plausible biogenetic connection between naturally occurring
sesquiterpenes is shown in Scheme 1. Biosynthetically,
bisabolyl cation (10c) can be obtained from a farnesyl
pyrophosphate (FPP) 10a with a C-15 unit via its isomeric
rearranged scaffold nerolidyl pyrophosphate 10b having C-15
unit (Scheme 1).9 Whereas, other sesquiterpenes having a
cyclopentane frame-work are supposed to be synthesized
Odisha, India
§This work is dedicated to Professor Subrata Ghosh, IACS Kolkata
on the occasion of his 70th birthday.
1
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10.1002/ejoc.202000100
European Journal of Organic Chemistry
COMMUNICATION
from intermediate secondary carbocation 11a (Scheme 1) via
the rearrangement of methyl group (1,2-shift of methyl group)
to establish a 3˚ carbocation intermediates such as 11b (for
isolaurene 6). It is obvious to think that, the cyclopentane
based 2˚ carbocation 11a could be generated from a bisabolyl
cation intermediate (10c) via a C-C bond forming reaction
(Scheme 1). On the other hand, the hypothetical triene
intermediate 10d could have arisen from an elimination of 3˚
carbocation intermediate 10c. Further, it has been
hypothesized that 3˚ carbocation intermediate 10e possibly
responsible for the synthesis of ar-Macrocarpene (1) via
naturally occurring (Z)--Macrocarpene (1).
intermediate for asymmetric synthesis (+)-ar-macrocarpene
(1) via a Wolf-Kishner reduction,12,14 which in turn could be
accessed from a catalytic enantioselective (p-tolyl)boronic
acid addition onto 5,5-dimethyl cyclohexen-2-one 13 (Scheme
2).13
Scheme 2: Retrosynthetic analysis of (+)-ar-macrocarpene (1).
For our synthesis, precursor 5,5-dimethyl cyclohexen-2-one
13 was synthesized from a well known Stork-Danheiser
sequence of vinylogous ester.12a, 12c Initially, we carried out the
optimization reaction using 1 equivalent of 1312c with 2
equivalent of p-tolylboronic acid in the presence of 5 mol%
[Rh(COD)2]BF4 in combination with 10 mol% of (S)-tBu-PHOX
L1 in tetrahydrofuran and water (10:1 mixture).13 This reaction
led to the formation of the expected product 12 in 90% isolated
yield, however, with only 6% ee (entry 1). Therefore, we tested
a number of phosphine based ligands such as tBu-PHOX (L2),
Trost’s DACH ligand L3, and (R,R)-DUPHOS (L4),
phosphoramidite L5 to enrich enantioselectivity in product
(Table 1). However, these reactions afforded only up to 34%
ee with good yields (entries 1-5, table 1).
Table 1. Optimization of conjugate addition of 5,5-dimethyl
cyclohexen-2-one 13.
Scheme 1: A plausible biogenetic connections between different
sesquiterpenes.
A number of reports has been directed toward the synthesis
of natural sesquiterpenoids. In fact, soon after the isolation of
ar-macrocarpene (1) in 2005, the first synthesis (racemic
approach) of this secondary metabolite was featured by
Srikrishna and co-workers in 2007.11 However, there was no
report of asymmetric total synthesis ar-macrocarpene (1) until
very recently our report on the catalytic asymmetric synthesis
via a key late-stage allylic diazene rearrangement (ADR)
strategy (7 steps from commercially available 5,5-
dimethylcyclohexane 1,3-dione),12a catalytic asymmetric enone
reduction using Corey-Bakshi-Shibata catalyst as key steps (6
steps from commercially available 4,4-dimethylcyclohex-2-
enone),12b and Pd(II)-catalyzed asymmetric conjugate
addition of arylboronic acid onto (4 steps from commercially
available dimidone).12c In spite of these approaches, there is
still an urgent need for concise asymmetric synthesis of ar-
macrocarpene 1 (Figure 1). Herein, we report a formal
catalytic enantioselective total synthesis of (+)-ar-
macrocarpene (1) via a key enantioselective Rh(I)-catalyzed
arylboronic
acid
addition
onto
5,5-dimethyl
2-
cyclohexenone.13
Results and Discussion
S.
N
o.
Rh(I)-cat.
solvent
temp.
Time
yieldb
eec
Retrosynthetically, we imagined that enantioenriched 3-
arylcyclohexanone 12 may serve as an advanced
2
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10.1002/ejoc.202000100
European Journal of Organic Chemistry
COMMUNICATION
1.
2.
3.
4.
5.
6.
7.
8.
5 mol% Rh(I)
& 10 mol% L1
5 mol% Rh(I)
& 10 mol% L2
5 mol% Rh(I)
& 10 mol% L3
5 mol% Rh(I)
& 10 mol% L4
5 mol% Rh(I)
& 10 mol% L5
5 mol% Rh(I)
& 6 mol% L6
5 mol% Rh(I)
& 10 mol% L7
5 mol% Rh(I)
& 10 mol% L6
5 mol% Rh(I)
& 10 mol% L7
3 mol% Rh(I)
& 6 mol% L6
3 mol% Rh(I)
& 6 mol% L7
THF:H2O
(10:1)
THF:H2O
(10:1)
(THF:H2O
(10:1)
THF:H2O
(10:1)
THF:H2O
(10:1)
THF:H2O
(10:1)
THF:H2O
(10:1)
dioxane:H
2O (10:1)
dioxane:H
2O (10:1)
dioxane:H
2O (10:1)
dioxane:H
2O (10:1)
70 ºC
70 ºC
70 ºC
29 h
27 h
30 h
29 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
90%
87%
85%
79%
93%
91%
95%
90%
89%
92%
94%
12%d
21%d
33%d
-21%d
34%d
89%e
90%d
91%d
93%d
93%e
96%e
100
ºC
70 ºC
70 ºC
70 ºC
100
ºC
100
ºC
100
ºC
100
ºC
9.
10
.
11
.
aReactions were carried out on a 1 mmol of 13 with 2 mmol of (p-
b
tolyl)boronic acid in organic solvent and water (10:1 ratio). Isolated
yields after column chromatography. cee’s were determined by using
chiralpak OD-H column. dsubstrate to catalyst ratio = 20:1. esubstrate
to catalyst ratio = 33:1.
Next, we carried out exhaustive optimization studies using
axially chiral C2-symmetric bisphone ligands such as (S)-
SEGPHOS (L6), and (S)-BINAP (L7). To our delight, it was
found that corresponding product 3-(p-tolyl)-5,5-dimethyl
cyclohexanone 12 was obtained in 91% yield with 89% ee, in
dioxane:H2O (10:1) at 70 C in the presence of 5 mol%
[Rh(COD)2]BF4 and 6 mol% of (S)-SEGPHOS (L6) ligand
(entry 6, Table 1). Under similar conditions (S)-BINAP (L7)
afforded cyclohexanone 12 in 90% ee (entry 7, Table 1).
aReactions were carried out on a 1 mmol of 13 with 2 mmol of
arylboronic acid in dioxane and water (10:1 ratio) in the presence of 3
mol% of [Rh(COD)2]BF4 in combination with 6 mol% (S)-BINAP. bee’s
were determined by using chiralpak OD-H column. cIsolated yields
after column chromatography.
Scheme 3. Substrate scope of arylboronic acid addition onto 5,5-
dimethyl cyclohexen-2-one 13.
Further, the optimized condition in hand, two aryl boronic
acids sharing tolyl group were tested and the results are
summarized in Scheme 4. As can be seen, 5,5-dimethyl-3-
(tolyl)cyclohexanones (14a-b) could be synthesized in good
yield (90-95% and excellent enantioselectivities (92-96% ee)
in the presence of 3 mol% [Rh(COD)2]BF4 in combination with
6 mol% of (S)-BINAP (L7) (Scheme 3).
Further, by changing the solvent to dioxane and water (10:1),
6 mol% of (S)-SEGPHOS (L6) and (S)-BINAP (L7) furnished
product 12 in 91% ee (entry 8) and 93% ee (entry 9),
respectively. Noteworthy to observe was that a reaction in the
presence of 3 mol% [Rh(COD)2]BF4 and 6 mol% of (S)-
SEGPHOS (L6), compound 12 was obtained in 92% yield and
93% ee (entry 10). Delightfully, 3 mol% [Rh(COD)2]BF4 in
combination with 6 mol% of L7 afforded required 3-(p-tolyl)-
5,5-dimethyl cyclohexanone 12 in 94% yield with 96% ee
(entry 11).
aReactions were carried out on a 1 mmol of 13 with 2 mmol of
arylboronic acid in dioxane and water (10:1 ratio) in the presence of 3
mol% of [Rh(COD)2]BF4 in combination with 6 mol% (S)-BINAP. bee’s
were determined by using chiralpak OD-H column. cIsolated yields
after column chromatography.
3
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10.1002/ejoc.202000100
European Journal of Organic Chemistry
COMMUNICATION
5. (a) B. M. Fraga, Nat. Prod. Rep., 2008, 25, 1180-1209. (b) X. –L.
Li, T. Kurtán, J.-C. Hu, A. Mándi, J. Li, X.-W. Li, Y.-W. Guo, J. Agric.
Food. Chem. 2017, 65, 1550-1555. (c) W. M. Alarif, S. S. Al-Lihaibi,
S.-E. N. Ayyad, M. A. Abdel-Rhman, F. A. Badria, Eur. J. Med. Chem.
2012, 55, 462-466. (d) S. Niyogi, A. Khatua, V. Bisai, Tetrahedron
Lett. 2019, 60, 150941.
Scheme 4. Catalytic asymmetric (p-tolyl)boronic acid addition
using Rh(I)-(R)-BINAP ligand (ent-L7).
Further in search for the asymmetric synthesis of naturally
occurring sesquiterpenoid, (+)-ar-macrocarpene 1, we have
carried out the asymmetric (p-tolyl)boronic acid addition onto
5,5-dimethyl cyclohexen-2-one 11 using enantiomeric (S)-
BINAP ligand (L7). Importantly, (p-tolyl)boronic acid addition
onto 11 using 3 mol% of [Rh(COD)2]BF4 in combination with 6
mol% of L7 furnished ent-12 in 91% yield with 96% ee
(Scheme 4).
6. (a) R. C. Pandey, S. Dev, Tetrahedron 1968, 24, 3829–3839. (b) K.
L. McPhail, M. T. Davies-Coleman, J. Starmer, J. Nat. Prod. 2001, 64,
1183-1190. (c) Y. Asakawa, A. Ludwiczuk, J. Nat. Prod. 2018, 81,
641-660.
7. (a) R. C. Ronald, M. B. Gewali, B. P. Ronald, J. Org. Chem. 1980,
45, 2224-2229. (b) S. Biswas, A. Ghosh, R. V. Venkateswaran, J. Org.
Chem. 1990, 55, 3498-3502.
Since, the total syntheses of (+)-1 and (−)-ent-1 are known
from 12 (Scheme 3) and ent-12 (Scheme 4), our effort
culminated in formal total syntheses of (+)-ar-macrocarpene
(1) and (−)-ar-macrocarpene (ent-1).
8. (a) Isolation of majapolene B (3): K. L. Erickson, J. A. Beutler, G. N.
Gray, J. H. Cardellina, II; M. R. Boyd, J. Nat. Prod., 1995, 58, 1848-
1860. (b) Majapolene B acetate: 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. (c) B.-G. Wang, J. B. Gloer, N.-Y. Ji, J.-C. Zhao, Chem.
Rev. 2013, 113, 3632-3685.
Conclusion
9. (a) B. M. Fraga, Nat. Prod. Rep. 2013, 30, 1226-1264. (b) R. A. Hill,
A. Sutherland, Nat. Prod. Rep. 2017, 34, 1180-1184.
In conclusion, a formal total synthesis of naturally
occurring sesquiterpenoid, (+)-ar-macrocarpene (1) has
been developed from 5,5-dimethylcyclohex-2-enone 13. The
key step of this synthesis is the Rh(I)-catalyzed asymmetric
conjugate addition of p-tolylboronic acid onto 13 in the
presence of (S)-BINAP (up to 96% ee). Further asymmetric
formal total synthesis of unnatural (−)-ar-macrocarpene (ent-
1) has also been achieved with similar efficiency using Rh(I)-
(R)-BINAP (96% ee). Further research to access other
naturally occurring sesquiterpenoids is currently under active
investigation in our laboratory.
11. A. Srikrishna, B. Beeraiah, Synth. Commun. 2007, 37, 2855–2860.
12. For a catalytic asymmetric synthesis, see; (a) A. Khatua, S. Niyogi,
V. Bisai, Org. Biomol. Chem. 2019, 17, 7140-7143. (b) A. Khatua, A.
Roy, V. Bisai, Tetrahedron 2020, 76, 130918. (c) A. Khatua, Shaw,
K.,
V.
Bisai,
Tetrahedron
Lett.
2020,
76,
doi.org/10.1016/j.tetlet.2020.151736.
13. (a) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052-5058. (b) Hayashi, T.; Tokunaga, N.;
Yoshida, K.; Han, J. W. J. Am. Chem. Soc. 2002, 124, 12102-12103.
(c) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem.
Soc. 1999, 121, 11591-11592. (d) C. Nadeau, S. Aly, K. Belyk, J. Am.
Chem. Soc. 2011, 133, 2878-2880. (e) Y. Wang, Y. Liu, D. Zhang, H.
Wei, M. Shi, F. Wang, Angew. Chem., Int. Ed. 2016, 138, 5344-5440
and references cited.
Acknowledgements
V.B. thanks the Science and Engineering Research Board
(SERB), Department of Science and Technology (DST) for a
research grants [CS-021/2014]. Facilities from Department of
Chemistry, IISER Bhopal, IISER Tirupati, and IISER
Berhampur are gratefully acknowledged.
14. Wolff-Kishner reduction: (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, 5344-5440.
Keywords: Conjugate addition, (p-tolyl)boronic acid, Rh(I)-
Catalyzed, Sesquiterpenoid, ar-Macrocarpene
References and Notes
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66, 249–260.
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Phytochemistry 2004, 65, 2045-2049. (b) H. Tesso, W. A. König, Y.
Asakawa, Phytochemistry 2005, 66, 941-949. For synthesis of (±)-ar-
tenuifolene (4), see; (c) A. Srikrishna, B. Baire, Indian J. Chem. 2005,
44B, 1641-1643. (d) A. Vázquez-Sánchez, J. G. Ávila-Zárraga,
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V. Bisai, Tetrahedron Lett. 2019, 60, 2039-2042.
4
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5
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