Approach to Merosesquiterpenes via Lewis Acid Catalyzed Nazarov-Type Cyclization: Total Synthesis of Akaol A

Article abstract of DOI:10.1021/acs.orglett.6b00446

A Lewis acid catalyzed Nazarov-type cyclization of arylvinylcarbinol has been developed for the asymmetric synthesis of carbotetracyclic core of merosesquiterpenes. The reaction works only in the presence of 2 mol % of Sn(OTf)₂ and Bi(OTf)₃ in dichloroethane under elevated temperature. The methodology offers the synthesis of a variety of enantioenriched arylvinylcarbinols from commercially available (3aR)-sclareolide 9 in six steps with an eventual concise total synthesis of marine sesquiterpene quinol, akaol A (1a).

Full text of DOI:10.1021/acs.orglett.6b00446

Letter
pubs.acs.org/OrgLett
Approach to Merosesquiterpenes via Lewis Acid Catalyzed Nazarov-
Type Cyclization: Total Synthesis of Akaol A
Badrinath N. Kakde, Nivesh Kumar, Pradip Kumar Mondal, and Alakesh Bisai*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhopal, Madhya Pradesh
462 066, India
S
* Supporting Information
ABSTRACT: A Lewis acid catalyzed Nazarov-type cyclization of arylvinylcarbinol has been developed for the asymmetric
synthesis of carbotetracyclic core of merosesquiterpenes. The reaction works only in the presence of 2 mol % of Sn(OTf)2 and
Bi(OTf)3 in dichloroethane under elevated temperature. The methodology offers the synthesis of a variety of enantioenriched
arylvinylcarbinols from commercially available (3aR)-sclareolide 9 in six steps with an eventual concise total synthesis of marine
sesquiterpene quinol, akaol A (1a).
erosesquiterpenes are natural products of mixed
biosynthetic origin (arising from polyketide-terpenoid)
cochinchinensis.8 These novel C-24 nortriterpenoids exhibit
significant cell protecting activity against H2O2-induced PC12
cell damage.8 Recently, in 2012, the same group isolated two
more new C-24 nortriterpenoids walsucochinoids A (1j) and B
(1k) from Walsura cochinchinensis.9 Even though the
bioactivities of this family of compounds have yet to be
examined comprehensively, preliminary studies have revealed
that pelorol (1c) is an activator of the Src homology 2 domain
containing inositol 5-phosphatase (SHIP),10 whereas dasyscy-
phin B (1e) shows potent cytotoxic activities in several human
cell lines6a and dasyscyphin D (1f) and E (1g) exhibit
antifungal properties.7
M
containing a sesquiterpene unit joined to a phenolic (or
sometimes as quinone moiety).1 Compounds bearing a bicyclic
terpene (especially drimane) moiety are the most important
group of this family, owing to their wide variety of structural
types and potent biological activities.2 Among various
merosesquiterpenes,3 pelorol (1c) (Figure 1) was isolated
Despite the significant biological activities and the intriguing
tetracyclic structure of these natural products, only a few
syntheses have been reported in the literature. Prominent
examples include Andersen’s elegant approach of pelorol (1c)
starting from (+)-sclareolide 9 (Scheme 1) via a key
intramolecular Friedel−Crafts alkylation to create the cyclo-
pentane C ring11,12 total synthesis of dasyscyphin D (1f) by
She13 featuring a key PtCl2-catalyzed pentannulation reaction
and acid-catalyzed Robinson annulations,13 a Diels−Alder
approach by Alvarez-Manzaneda for first enantiospecific
synthesis of akaol A (1a) from commercial (−)-sclareol,14
and dasyscyphin B (1e) starting from commercial abietic acid.15
In 2014, She et al. carried out the first asymmetric synthesis of
walsucochin B (1i)16 through a cationic polyolefin cyclization
initiated by chiral epoxide.
Figure 1. Selected merosesquinoids 1a−k.
from Dactylospongia elegans in 20004 and akaol A (1a) was
isolated from a Micronesian sponge of the genus Aka in 2003.5
Other merosesquiterpenes, such as dasyscyphins A, B and D, E
(1d,e and 1f,g) were isolated from the ascomycete Dasyscyphus
niveus.6,7 In 2008, Yue and co-workers also isolated two
unprecedented skeletons with C-24 nortriterpenoid structural
motifs, walsucochins A (1h) and B (1i), from Walsura
Recently, our group reported an expeditious approach to the
core structure of taiwaniaquinoids of type 3 through a Lewis
acid catalyzed Nazarov-type cyclization of arylvinylcarbinols of
Received: February 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00446
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Organic Letters
Letter
Scheme 1. Our Approach to Merosesquiterpenoids
Table 1. Selected Optimization of Nazarov-Type Reaction of
6a
Lewis acid
(mol %)
T
time
yield (%) yield (%) of
a,b a,b
no.
1
solvent
CH2Cl2
(°C) (h)
of 7a
12a
c
BF3·OEt2
(5)
25
25
25
25
80
80
80
80
0.5
1
27
60
2
3
4
5
6
7
8
Sn(OTf)2
(5)
CH2Cl2
0
0
94
89
93
08
0
In(OTf)3
(5)
CH2Cl2
1
Bi(OTf)3
(5)
CH2Cl2
1
0
type 2 (Scheme 1).17 This reaction essentially goes through an
intermediate bis-allylic carbocataion 4. Utilizing this strategy,
we demonstrated the first total synthesis of taiwaniaquinol F
(5) (Scheme 1). Using similar arguments, herein we envisioned
that arylvinylcarbinols of type 6 could efficiently be converted
to carbotetracyclic framework such as 7a via a key Nazarov-type
cyclization (Scheme 1). Compound 7a (Scheme 1) once
formed, would provide opportunities to access total syntheses
of various congeners of aforesaid merosesquiterpenoids. We
hypothesized that arylvinylcarbinol 6a would generate allyl
benzyl carbocation species 8a in the presence of Lewis acid,
which would further be stabilized via 8b and 8c. Herein, we
report an efficient route to access the tetracyclic core of
merosesquiterpenes which is further utilized in the total
synthesis of akaol A (1a) and related structures.
In(OTf)3
(2)
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
2
88
d
Sn(OTf)2
(2)
2
92
71
93
c
Cu(OTf)2
(2)
2
18
0
e
Bi(OTf)3
(2)
2
a
Reactions were carried out on 0.25 mmol of (6a) in 3 mL of solvent.
b
c
Isolated yields reported after column chromatography. Determined
d
from 1H NMR of impure materials. Condition A (2 mol % of
Sn(OTf)2). Condition B (2 mol % of Bi(OTf)3).
e
Lewis acids used, only BF3·EtO2 could afford the carbote-
tracyclic core 7a in just 27% along with the formation of 60% of
diene (entries 1−4). It was observed that with 5 mol % of
Sn(OTf)2, In(OTf)3 and Bi(OTf)3 at room temperature, diene
12a was formed exclusively with no traces of carbotetracyclic
core 7a (entries 2−4). Following exhaustive optimization (see
the Supporting Information for details) it was found that 2 mol
% of Sn(OTf)2 and Bi(OTf)3 at elevated temperature afforded
compound 7a as single diastereomer exclusively in 92 and 93%
yields with no traces of diene 12a (entries 5−8). In fact, the
diene 12a could be converted to 7a under standard
conditions.19 This result indicated the intermediacy of
carbocataion species 8a−c in this Nazarov-type cyclization
(Scheme 1).19 On the basis of these optimization studies, it was
decided to carry out further substrate scope using 2 mol % of
Sn(OTf)2 (condition A) and Bi(OTf)2 in refluxing dichloro-
ethane (condition B).
To this end, we synthesized a variety of arylvinylcarbinols of
the type 6 utilizing a highly diastereoselective 1,2-addition of
aryllithium onto a α,β-unsaturated aldehyde 11 (Scheme 2).
Scheme 2. Synthesis of Arylvinylcarbinols 6 from 9
With the standard protocol in hand, we then probed few
arylvinylcarbinols 6b−e to construct carbotetracyclic cores 7b−
e, and the results are shown in Scheme 3. We could isolate
carbotetracycles 7b−d exclusively as single diastereomers in
93−98% yield from arylvinylcarbinols 6b−d. As expected, 2
mol % of Sn(OTf)2 and Bi(OTf)3 at room temperature
exclusively afforded diene12b−d in 92−96% yield (also see,
entries 2−4, Table 1), whereas under optimized conditions A
and B 6e (Scheme 3) also afforded carbotetracycle 7e as a
single diastereomer exclusively in 99% yield with no traces of
diene. The X-ray structure of one of the carbotetracycle 7b
unequivocally proved the formation of expected product
(CCDC no. 1453267).
This reaction afforded a single diastereomer via a “Re-face”
approach of aryllithium.18 As is evident from the energy-
minimized structure of compound 11, the “Si-face” approach is
not favorable because of steric clash laid by the angular methyl
group with the approaching aryllithium (Scheme 2). Aldehyde
11 can be synthesized from β-hydroxy aldehyde 1011 in the
presence of BF3·OEt2, which in turn could be accessed from
(3aR)-(+)-sclareolide (9) in four steps in 51% overall yield
(Scheme 2).
Next, we examined the Nazarov-type cyclization on the
arylvinylcarbinol 6 in the presence of various Lewis acids in
different solvents to construct the key carbotricyclic structure 7
as proposed. At the outset, we took compound 6a as a model
substrate to optimize the Nazarov-type cyclization in dichloro-
methane at room temperature using 5 mol % of variety of Lewis
acids under open flask conditions (Table 1). Among various
While arylvinylcabinols 6a−e, having an alkyloxy group ortho
to the reaction center, afforded a single diastereomer under
standard conditions (Scheme 3), surprisingly, the reaction of
arylvinylcabinols 6f−h led to the formation of mixture of
diastereomers 7f−h and 13f−h (dr ∼1.2:1) (Scheme 4). It was
B
DOI: 10.1021/acs.orglett.6b00446
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Letter
a
compound 14 in 92% yield as single diastereomer (Scheme 6).
The excellent diastereoselectivity observed was attributed to the
Scheme 3. Nazarov-Type Reaction of Arylvinylcarbinols 6b
Scheme 6. Highly Diastereoselective Hydrogenation of
a
Carbotetracycle 7b
a
X-ray structure of 14 (CCDC no. 1453268).
hydrogenation from the less hindered convex face of 7b, which
is quite clear from the X-ray crystal structure of 7b (Scheme 3).
Further, the X-ray crystal structure of compound 14 (CCDC
no. 1453268) unambiguously proved the formation of the cis-
fused indane ring (Scheme 6).
We applied this methodology in the total synthesis of 9-epi-
pelorol (epi-1c) (Scheme 7). We began with hydrogenation of
Scheme 7. Total Synthesis of Unnatural 9-epi-Pelorol (epi-
1c)
a
X-ray structure of 7b (CCDC no. 1453267).
Scheme 4. Nazarov-Type Reaction of Arylvinylcarbinols 6f−i
carbotetracycle 7e which afforded saturated carbotetracycle 15
in quantitative yield as a single diastereomer.21 This was then
brominated with N-bromosuccinimide (NBS) followed by
treatment with DMF in the presence of n-BuLi to afford
carbotetracyclic aldehyde 16 in 92% yield (76% in overall two
steps). Aldehyde 16 was then oxidized under Pinnick oxidation
to afford carboxylic acid, which was further esterified, without
purification, to obtain 17 in an overall 89% yield in two steps.
Eventually, selective demethylation using BI3 in dry dichloro-
methane at −78 °C afforded 9-epi-pelorol (epi-1c) in 58% yield
(Scheme 7).
Later, we attempted the total synthesis of akalol A (1a) from
13g (Scheme 4). Toward this end, we hydrogenated a mixture
of 7g and 13g in the presence of Pd−C in MeOH under 1 atm
of H2 gas, which afforded chromatographically separable
carbotetracycles 18 and 19, respectively, in 98% yield in 1:1
ratio (Scheme 8).
found that the diastereoselectivity of these reactions very much
depends on the sterics imposed by sp3 carbon (highlighted in
Scheme 4). In fact, benzyl ether protected substrate 6i afforded
diastereomers 7i and 13i in dr up to ∼8.9:1 (Scheme 4).20
Later, in order to check the regioselective issues, if any,
associated with this Nazarov-type cyclization, we further
synthesized arylvinylcarbinols 6j,k (Scheme 5). Arylvinylcabi-
Scheme 5. Nazarov-Type Reaction of Arylvinylcarbinols 6j−
k
Next, 19 was oxidized using PCC to furnish aldehyde 20 in
97%, which was then demethylated with PhSH in the presence
of K2CO3 to afford aldehyde 21 in 83% yield. The later was
then reduced with LiAlH4 in THF followed by a chemoselective
methylation of benzylalcohol with concn HCl in MeOH
completed the total synthesis of akaol A (1a) in 88% yields over
two steps (Scheme 8). Along a similar line, carbotetracycle 18
was converted to the unnatural sesquiterpene quinol 22 via
aldehyde 16 in with similar efficiency (66.5% over four steps
from 18).
nols 6j,k afforded products in the form of a diastereomeric
mixture due to approach of the aromatic ring from the p-
position of the OMe group (Scheme 5). We speculate that the
formation of diastereomers may be due to steric bias posed by
the sp3 carbon during the course of the reaction (Scheme 5).20
Next, we were keen to elaborate the Nazarov cyclization
products to synthetically useful intermediates. To this end, we
hydrogenated carbotetracycle 7b in the presence of Pd−C in
MeOH under 1 atm of H2 gas, which afforded tetracyclic
In conclusion, we have developed an efficient Lewis acid
catalyzed Nazarov-type cyclization using only 2 mol % of
Sn(OTf)2 and Bi(OTf)3 under mild conditions. A variety of
C
DOI: 10.1021/acs.orglett.6b00446
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Scheme 8. Total Synthesis of Merosesquiterpene Quinol
Akaol A (1a)
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were synthesized in good to excellent yields. The methodology
provides a concise route to the marine sesquiterpene quinol
akaol A (1a) in six steps from arylvinylcarbinol 6g (32.6%
overall yield) and 12 steps from easily available inexpensive
(3aR)-(+)-sclareolide 9 (8.1% overall yield). We have also
accomplished syntheses of unnatural sesquiterpene quinols 9-
epi-pelorol (epi-1c) and 22 using the aforementioned method-
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of complex merosesquitepenoids is under active investigation.
́
Barranco Perez, I.; Cabrera, E.; Alvarez, E.; Alvarez-Manzaneda, R.
Org. Lett. 2005, 7, 1477. (c) Alvarez-Manzaneda, E. J.; Chahboun, R.;
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́
A.; Alvarez-Manzaneda, R.; Haidour, A.; Ramos, J. M.; Akhaouzan, A.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00446.
■
S
Chem. Commun. 2012, 48, 606.
(15) Akhaouzan, A.; Fernan
́
dez, A.; Mansour, A. I.; Alvarez, E.;
Haidour, A.; Alvarez-Manzaneda, R.; Chahboun, R.; Alvarez-
̈
Experimental procedures and analytical data (1H, 13C
NMR spectra and HRMS) for all new compounds
(PDF)
Manzaneda, E. Org. Biomol. Chem. 2013, 11, 6176.
(16) Xu, S.; Gu, J.; Li, H.; Ma, D.; Xie, X.; She, X. Org. Lett. 2014, 16,
1996.
(17) Kakde, B. N.; Kumari, P.; Bisai, A. J. Org. Chem. 2015, 80, 9889.
(18) Energy minimization (MM2) of α,β-unsaturated aldehyde11
was performed using ChemBio 3D Ultra Version 12.0.
(19) Aryldiene12a can be efficiently converted to carbotetracyclic
core 7a in 90−93% isolated yields, indicating that Lewis acid catalyzed
Nazarov-type cyclization probably goes through an aryl diene of type
12.
X-ray data for 7b (CIF)
X-ray data for 14 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: alakesh@iiserb.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(20) For torquoselectivity in Nazarov-type cyclizations, see:
Financial support from the BRNS, DAE, Government of India
(Sanction No.: 2011/20/37C/12/BRNS/1731) and SERB,
DST, Government of India (Sanction No.: SB/FT/CS-54/
2011) are gratefully acknowledged. B.N.K., N.K., and P.K.M.
thank the CSIR, New Delhi, for Senior Research Fellowships
(SRFs). We sincerely thank the reviewers for their valuable
suggestions to improve the manuscript.
(a) Hutson, G. E.; Turkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc.
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2013, 135, 4988. (b) Denmark, S. E.; Wallace, M. A.; Walker, C. B., Jr.
J. Org. Chem. 1990, 55, 5543.
(21) Among various dissolving metal-mediated reductions attempted,
Na in n-BuOH at elevated temperature afforded 47% yield of 15 from
carbotetracycle7e.
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D
DOI: 10.1021/acs.orglett.6b00446
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