A unified, RCM anchored approach to spiro[4.5]decane-based sesquiterpenoids: Collective synthesis of (±)-α & β-vetispirenes, (±)-β-vetivone, (±)-agarospirol and (±)-hinesol

Article abstract of DOI:10.1016/j.tetlet.2019.05.011

Collective syntheses of five spiro[4.5]decane framework bearing sesquiterpenoids, namely, α & β-vetispirenes, β-vetivone, agarospirol and hinesol as well as formal synthesis of axenol and gleenol from a readily available precursor cyclohexanone-β-ketoester via the intermediacy of a versatile intermediate (2,10-dimethylspiro[4.5]dec-1-en-6-one) have been accomplished in a concise manner.

Full text of DOI:10.1016/j.tetlet.2019.05.011

Accepted Manuscript
A unified, RCM anchored approach to spiro[4.5]decane-based sesquiterpenoids:
Collective synthesis of (±)-α & β -Vetispirenes, (±)-β-Vetivone, (±)-Agaro-
spirol and (±)-Hinesol
Sudhakar Athe, Subhash Ghosh, Goverdhan Mehta
PII:
S0040-4039(19)30441-1
https://doi.org/10.1016/j.tetlet.2019.05.011
TETL 50783
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
1 April 2019
7 May 2019
Please cite this article as: Athe, S., Ghosh, S., Mehta, G., A unified, RCM anchored approach to spiro[4.5]decane-
based sesquiterpenoids: Collective synthesis of (±)-α & β -Vetispirenes, (±)-β-Vetivone, (±)-Agarospirol and (±)-
Hinesol, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.05.011
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A unified, RCM anchored approach to spiro[4.5]decane-based sesquiterpenoids:
Collective synthesis of (-  -Vetispirenes, (--Vetivone, (-Agarospirol and (-
Hinesol
Sudhakar Athe,a Subhash Ghoshb* and Goverdhan Mehtaa*
aSchool of Chemistry, University of Hyderabad, Hyderabad 500046, India
bOrganic Synthesis & Process Chemistry, CSIR-IICT, Hyderabad 500007, India
agmehta43@gmail.com; bsubhash@iict.res.in;
Abstract: Collective syntheses of five spiro[4.5]decane framework bearing sesquiterpenoids,
namely,  & β-vetispirenes, β-vetivone, agarospirol and hinesol as well as formal synthesis
axenol and gleenol from a readily available precursor cyclohexanone-β-ketoester via the
intermediacy of a versatile intermediate (2,10-dimethylspiro[4.5]dec-1-en-6-one) have been
accomplished in a concise manner.
Keywords: Spiro[4.5]-dacane, vetivene sesquiterpenes, total synthesis, RCM-reaction.
Introduction:
Structural and functional diversity in their myriad forms is the hallmark of natural products
landscape and the wide ranging bioactivity displayed by many of them can be largely traced
to these distinctive attributes. Among natural products, terpenoids in general and C15-
sesquiterpenoids in particular are notable for the richness of their diverse carbocylic
frameworks which are forged through the multiple modes of cyclizations of its acyclic
biogenetic precursor like farnesyl pyrophosphate (FPP). These enzymatic C+-- type
cyclizations proceed with remarkable facility and specificity to generate complex and diverse
concatenated ring architecture, embellished with quaternary centers, variegated
stereochemical patterns and functionalities.1 At times, the biogenetic cyclization cascades
enroute are intercepted by cationic 1,2-rearrangements (Wagner-Meerwein) to further
augment the structural and functional diversity encountered among sesquiterpenoids. The
resulting sesquiterpenoid natural product frameworks mostly embody fused or bridged
carbocyclic ring system of various sizes (3-12) with occasional occurrence of the less
encountered spiro-fused ring system. 2
One of the earliest example of a spiro-fused natural product is of sesquiterpenoid β-
vetivone 1, isolated by Pfau and Plattner 3 in 1939 from the roots of Vetiveria zizanioides but
its structure incorporating a spiro[4.5]decane system was settled only in 1968 through the
total synthesis efforts of the Marshall group.4 The decades of 1960 and 70’s witnessed a spurt

in the identification of many more spiro-sesquiterpenoids, mostly from essential oils, among
which agarospirol 2, 5a axenol 3, 5b acorone 4, 5c,d spirolaurenone 5 5e and β-chamigrene 6 5f
based either on bicylo[4.5]decane or bicylo[5.5]undecane framework, respectively, are
prototypical. In the following decades, spirocyclic terpenoids continued to be unraveled in
increasing numbers from sources other than essential oils that included fungi and marine flora
and fauna. It may also be recalled that spirocyclic framework has also been encountered
5g
5h
among higher terpenes and cyanthiwigin AC 7
and vannusal A 8
exemplify these
findings, Figure 1. Concurrently, unraveling of many new spiro-fused naturally occurring
constructs among sesquiterpenoids drew considerable attention of synthetic chemists towards
their total synthesis and although the initial flurry dating back to the 60’s and 70’s has
subsided somewhat, they are still a potent test bed for exploring new synthetic tactics.
OH
O
HO
O
O
1)
-Vetivone (
2)
Agarospirol (
3)
Axenol (
4)
Acorone (
OH
OH
Br
O
OAc
OH
H
H
H
H
O
O
OAc
6)
-Chamigrene ( CyanthiwiginAC (
7)
5)
8)
Spirolauenone (
Vannusal A (
Figure 1. Representative examples of spirocyclic-terpenoids.
Reports that many of the spiro[4.5]decane sesquiterpenoids exhibit biological activities that
range from anti-malarial and antifouling to termiticidal to antihelmintic on one hand 6 and the
increasing use of essential oils rich in these fragrant constituents 7a in ‘aroma therapy’ and
cosmetic industry 7b on the other, has further sustained the interest of the synthetic organic
chemistry community in their total synthesis. 8
Many approaches have been successfully developed for the synthesis of spiro[4.5]decane
sesquiterpenoids with particular attention given to installation of the quaternary carbon at the
spiro center with attendant regio- and stereocontrol.2f A recent review, covering a broader
mandate, documents some of the attainments towards the synthesis of spiro[4.5]decane

sesquiterpenoids.2g As part of our long standing interest in terpenoid natural products, we
were drawn to the synthesis of spiro[4.5]decane group of sesquiterpenoids. Herein, we report
a flexible general approach to spiro[4.5]decane based spirocyclic sesquiterpenoids. In this
effort, RCM has been employed as a key reaction to assemble a versatile spirocyclic
intermediate in a concise manner, which in turn was elaborated to several sesquiterpenoid
natural products like β-vetivone 1,3  & β-vetispirenes 9 & 10, 9 agarospirol 2 5a and hinesol
1110 constituting their racemic total syntheses.11 In addition, formal synthesis of axenol 3 and
gleenol 12 are also reported.8d, 11n-s
Results and Discussion:
In our approach to spiro[4.5]decane based spirocyclic sesquiterpenoids, we identified
bicyclic ketone 13, bearing requisite stereochemical disposition at C5 and C10 stereogenic
centers and desired functionality in both the five- and six membered rings as the common
starting material for the synthesis of this class of sesquiterpenoids. Bicycle 13 has been
previously reported8d and deployed for accessing spiro[4.5]decane sesquiterpenoids but in a
demanding multi-step synthesis.8c-d, 11b Our first task therefore was to devise an alternate and
efficient route to the pivotal building block 13. This was conveniently accomplished from
readily available keto-ester 1412 in less than half the number of steps compared to the
previous synthesis8d with a RCM reaction serving as the key operation, Scheme 1. Alkylation
of 14 with commercial 4-iodo-2-methylbut-1-ene was expectedly stereoselective to furnish
15. This was a simple yet critical step as it set-up C5 quaternary center and fixed the relative
stereochemistry of what will become the C5 and C10 stereogenic centers in all the targeted
natural products. The ester group in 15 was elaborated to a vinyl group through routine
manipulations and the resulting 16 was now poised for the projected RCM reaction. Exposure
of 16 to Grubb’s II catalyst smoothly delivered the desired spiro[4.5]decanone 13 in decent
yield.13 The analytical data were in good agreement with the values reported in the
literature.8d For further evolution of 13 towards the targeted natural products, it was deemed
appropriate to protect the carbonyl group in it and this was accomplished quite uneventfully
to deliver the ketal 17, Scheme 1.

a. LAH, Et2O, 0 oC-rt, 2 h
b. (COCl)2, DMSO, CH2Cl2
Et3N, -78 o C, 1 h.
O
O
KOtBu, tBuOH
O
CO2Et
reflux, 12 h, 40%
OEt
c. PPh3CH3I, KOtBu, Et2O
14
I
15
30 min, 42% over three steps
O
O
6
3
2
4
ethylene glycol
O
G-II, CH2Cl2
7
5
1
O
PTSA, benzene
8 h, 98%
reflux, 12 h,78%
8
10
16
9
13
17
Scheme 1. Synthesis of the key spirocyclic building blocks 13 and 17
Bicylic olefinic ketal 17 was now ready for further elaboration to spirocyclic
sesquiterpenoids and -vetispirene 9 was selected as the initial test target. An essential
requirement at this stage was the oxyfunctionalization of the vinylic methyl group in 17 in
order to elaborate it to the required isopropenyl appendage. This was readily accomplished
through selenium dioxide oxidation of 17 to enal 18 in decent yield.14 Grignard addition of
methylmagnesium bromide to 18 and Dess-Martin oxidation of the resulting secondary
alcohol led to the methylketone 19.15 Further addition of methylmagnesium bromide to 19 led
to 20 with the C2-hydroxyisopropyl group in place. Exposure of 20 to camphorsulfonic acid
led to both C6-carbonyl deportation and tertiary hydroxyl group dehydration and smoothly
delivered the dienone 21 in 82% yield, Scheme 2. Lastly, C6 methyl group was installed via
conversion of 21 to its enol-triflate and palladium mediated methyl coupling with
dimethylzinc16 to deliver -vetispirene 9 spectroscopically identical with the natural
product.8c

O
CHO
a. MeMgBr, THF
0 oC, 10 min
SeO2, dioxane
O
O
O
80 oC,12 h
74%
b. DMP, CH2Cl2
0 oC, 1 h, 82%
over twos teps
O
O
O
18
17
19
OH
a. KHMDS, PhN(OTf)2
THF, -78 oC, 1 h
CSA, benzene
MeMgBr, THF
O
O
O
50 oC, 12 h, 82%
over two steps
0 o C, 10 min
94%
b. Me2Zn, Pd(PPh3)4
THF, rt, 10 min, 83%
21
20
9
(±)--Vetispirene
Scheme 2. Synthesis of (±)--Vetispirene 9
Intermediate 20 enroute -vetispirene 9 synthesis was also serviceable for the synthesis of β-
vetispirene 10 and towards that end was first subjected to catalytic hydrogenation followed
by acetylation of the tertiary hydroxyl group to furnish a diastereomeric mixture (70:30) at
C2 of 22a and 22b. While the small stereoselectivity in favor of 22a was understandable in
view of the steric effect exerted by the bystander C10 methyl group, the lack of
stereoselectivity in the present context was of little consequence as the C2 centre was
compromised in the following steps. However, diastereomers 22a and 22b were readily
separable and could be utilized in targeting other related vetivane natural products (vide
infra). Exposure of mixture of diastereomers 22a,b to catalytic iodine (20 mol%)17 served the
dual purpose of acetate elimination and concurrent C6 carbonyl deprotection to furnish 23
with tetrasubstituted regioisomer predominating, contaminated with ~10% of C11-12
exocyclic isomer, Scheme 3. This material was carried forward and Saegusa protocol
involving formation of trimethyslyl enol ether and Pd-mediated catalytic dehydrosilylation
was quite effective in furnishing the requisite enone 24 quite smoothly.18 Further, 1,2-
addition of methylithium to the carbonyl group in enone 24 followed by CSA mediated
dehydration led to β-vetispirene 10 (with ~10% of the exocyclic isomer) in excellent yield.
Our synthetic 10 was spectroscopically identical with the reported data for the natural
product.9b

OAc
OH
a. H2, Pd/C, EtOAc
OAc
3
3
2
2
4
1
I2 (20 mol%)
acetone, rt
4
O
O
rt, 6 h
1
O
5
5
O
O
O
b. Ac2O, pyridine
130 oC, 2 h, 70%
over two steps
20 min, 84%
22a
70:30
20
22b
12
a. MeLi, Et2O, 0 oC
20 min
3
11
1
a. Et3N, TMSOTf
CH2Cl2, rt, 30 min
2
4
O
O
5
6
10
b. CSA, CH2Cl2, 30 min
92% over two steps
b. Pd(OAc)2, DMSO
O2, 80 oC, 24 h
7
9
10
24
23
10
(±)--Vetispirene
76%, over two steps
Scheme 3. Synthesis of (±)-β-Vetispirene 10
The spirocyclic enone 24 was also very well suited for a synthesis of β-vetivone 1, the
seminal vetivane natural product and a transformation towards this end was simply executed
via a two step protocol involving addition of methylithium and PCC-mediated oxidative
transposition, Scheme 4.19 The spectral data for our β-vetivone 1 (with ~10% exocyclic-
isomer) fully matched that reported for the synthetic natural product.11c
12
11
3
2
PCC, CH2Cl2
4
1
9
MeLi, Et2O,
0 oC, 20 min
0oC to rt, 2 h
O
5
6
7
10
HO
8
83% over two steps
24
O
(±)- -vetivone 1

Scheme 4. Synthesis of (±)-β-vetivone 1
The diastereomers 22a and 22b were eminently suitable for the synthesis of hinesol 11 and
agarospirol 2, two legacy spiro[4.5]decane based sesquiterpenoid targets of total synthesis. In
this regard, major diastereomer 22a was subjected to catalytic iodine (5 mol%) mediated
carbonyl deprotection to 25a and further a two-step protocol involving enol-triflate formation
and Pd-mediated C-C coupling to furnish the methylated olefin 26a, Scheme 5.20 LAH
reduction in 26a delivered the hinesol 11, and was found identical with the natural product.11c

OAc
I2 (5 mol%)
OAc
OAc
a. KHMDS, PhN(OTf)2, THF
-78 oC, 1 h
O
acetone
O
O
0 oC to rt,
b. Pd(PPh3)4, CuTC, Me4Sn
[Ph2PO2] [NBu4], DMF, rt
20 min, 76%
25a
22a
30 min, 78%
26a
OH
LAH, THF
0 oC, 1 h, 80%
11
(±)-Hinesol
Scheme 5. Synthesis of (±)-Hinesol 11
Similarly, the less abundant diastereomer 22b was elaborated to natural product agarospirol 2
via iodine deprotection to 25b, followed by methyl coupling to 26b and deacetylation to
agarospirol 2,8c Scheme 6.
OAc
OAc
a. KHMDS, PhN(OTf)2
THF, -78 oC, 1 h
O
I2 (5 mol%), acetone
O
O
0 oC to rt, 30 min, 78%
b. Pd(PPh3)4, CuTC, Me4Sn
22b
[Ph2PO2] [NBu4], DMF, rt
20 min, 76%
25b
OH
OAc
LAH, THF, 0 oC
1 h, 80%
26b
2
(±)-Agarospirol
Scheme 6. Synthesis of (±)-Agarospirol 2
Lastly, a word about the wider serviceability of the spiro[4.5]decan-6-one 13, made
available through the present studies in fewer, easily implementable steps. The
straightforward access to 13 also constitutes formal synthesis of spiro sesquiterpenoids
8d
axenol 3 and gleenol 12 as depicted in Scheme 7 and reinforcing the versatility of our
approach to this family of natural products.

TiCl4, Bu3N, acetone
CH2Cl2, -78 oC, 1 h then
ref 8d
O
O
R
pyridine, -78 oC to rt
8 h, 86%
13
27
(±)-Axenol 3
OH
R =
=
(±)-Gleenol 12
OH
Scheme 7. Formal synthesis of (±)-Axenol 3 and (±)-Gleenol 12
In short, a concise new approach to spiro[4.5]decane based sesquiterpenoids in which RCM
reaction on a simple, stereoselectively crafted precursor furnishes a versatile intermediate
(2,10-dimethylspiro[4.5]dec-1-en-6-one) has been delineated. This platform intermediate has
been elaborated to several spirocyclic sesquiterpenoid natural products through short,
efficient sequences.
Supplementary data:
Supplementary data associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.xxxxxx
ACKNOWLEDGMENT:
S. A. wishes to thank the University Grants Commission (UGC, India) for the award of Dr.
D. S. Kothari post-doctoral fellowship. GM acknowledges the research support from Dr.
Reddy’s Laboratories (DRL) and award of Dr. Kallam Anji Reddy Chair at the University of
Hyderabad.
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A unified, RCM anchored approach to spiro[4.5]
decane-based sesquiterpenoids: Collective synthesis
of (-β-Vetispirene, (-β-Vetivone, (-Agarospirol
and (-Hinesol
Sudhakar Athe, Subhash Ghosh* and Goverdhan Mehta*
(±)--vetispirene 10
(±)--vetispirene 9
O
(±)--vetivone 1
OH
HO
O
13
(±)-axenol 3
(±)-agarospirol 2
OH
HO
(±)-gleenol 12
(±)-hinesol 11

Highlights
A concise new approach to spiro[4.5]decane based sesquiterpenoids in which RCM reaction
on a simple, stereoselectively crafted precursor furnishes a versatile intermediate (2,10-
dimethylspiro[4.5]dec-1-en-6-one) has been delineated. This platform intermediate has been
elaborated to several spirocyclic sesquiterpenoid natural products namely  & β-
vetispirenes, β-vetivone, agarospirol, hinesol, axenol and gleenol through short, efficient
sequences. The strategy developed here can find many more potential applications in the
synthesis of spirocyclics.