Diversity-oriented approach to spirocycles via ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2014.06.049

We have demonstrated a simple and an efficient method for the synthesis of spirocycles starting with inexpensive and commercially available carbonyl compounds. Various spirocycles involving spiropropellane derivative have been assembled via ring-closing m

Full text of DOI:10.1016/j.tetlet.2014.06.049

Tetrahedron Letters 55 (2014) 4492–4495
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diversity-oriented approach to spirocycles via ring-closing
metathesis
⇑
Sambasivarao Kotha , Rashid Ali, Ajay Kumar Chinnam
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, Mumbai 400076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have demonstrated a simple and an efficient method for the synthesis of spirocycles starting with
inexpensive and commercially available carbonyl compounds. Various spirocycles involving spiropropel-
lane derivative have been assembled via ring-closing metathesis with the aid of Grubbs’ first generation
catalyst.
Received 21 May 2014
Revised 10 June 2014
Accepted 11 June 2014
Available online 18 June 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Spirocycles
Carbonyl compounds
Ring-closing metathesis
Propellane derivative
Development of efficient synthetic strategies to spirocycles1
from commercially available starting materials involving environ-
mentally benign processes is worthy of systematic investigation.
To this end, our efforts are directed to design diverse spirocycles
that exhibit a broad range of structural diversities. Spiro moiety
is a core structural element present in various biologically active
substances. Axial chirality as well as a quaternary center2 present
in the spiro systems is responsible for their biological activity.3
Since the last two decades, commercial availability of ruthenium-
based catalysts4 and their tolerance to a variety of functional
groups fueled the growth of olefin metathesis5 and this protocol
has gained much prominence in synthetic organic chemistry.
During the last three decades, synthesis of polyquinanes6 and pro-
pellanes7 has drawn the attention of synthetic organic chemists
due to their structural intricacy along with biological activity.
Some important triquinane structural motifs and various natural
products containing spiro center are shown in Figure 1. Since spi-
rocycles and propellanes have a wide range of applications in
diverse areas, we envisioned a new and simple approach to a
library of spirocycles including spiropropellane derivatives by
employing ring-closing metathesis (RCM) as a key step in a diver-
sity-oriented manner.
H
H
H
H
1(linear triquinane)
2 (angular triquinane)
3 [3.3.3] propellane
H
H
H
O
COOH
5 (isocomene)
6 (retigeranic acid)
4[(+)-arnicenone]
Figure 1. Triquinane structural motifs and natural products containing spiro
center.
O
O
O
O
O
O
O
O
7c
7f
7e
7d
7a
7b
7e
Figure 2. Commercially available carbonyl compounds used in our strategy.
Our strategy to spirocycle synthesis started with the tetra-
allylation of simple and readily available starting materials such
as carbonyl compounds 7a–g (Fig. 2). We started our journey with
the tetra-allylation of cyclobutanone 7a under NaH/allyl bromide
conditions to deliver the compound 8a. Later, it was subjected to
RCM with the aid of Grubbs’ first generation catalyst (G-I) in
CH2Cl2 at room temperature (rt) to furnish the bis-spirocyclic
compound 9a in 73% yield. Further treatment of 9a with Pd/C in
EtOAc under hydrogen atmosphere (1 atm) afforded the saturated
⇑
Corresponding author. Tel./fax: +91 (22) 2572 7152.
E-mail address: srk@chem.iitb.ac.in (S. Kotha).
http://dx.doi.org/10.1016/j.tetlet.2014.06.049
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Kotha et al. / Tetrahedron Letters 55 (2014) 4492–4495
4493
Table 1
List of bis-spirocycles assembled by RCM
O
O
O
O
Entry
Time (h)
Time (h)
Time (h)
10a-g
9a-g
7a-g
8a-g
O
1
2
21%
10
18
73%
90%
12
10
83%
98%
20
15
7a
O
O
67%
52%
7b
7c
3
4
30
82%
—
12
—
89%
—
24
—
O
56a
69
5 days
7d
O
O
5
6
12
12
78
6
8
93
18
20
7e
7f
O
80%
72%
81%
97%
O
7
18
88
10
93%
24
7g
a
Triallylated product.
bis-spirocyclic compound 10a in 83% yield (Table 1, entry 1). Along
similar lines, allylation sequence with cyclopentanone 7b and
cyclohexanone 7c furnished the corresponding tetra-allylated
compounds 8b and 8c in 67% and 52% yields. Later, treatment of
these allyl derivatives 8b and 8c with G-I catalyst followed by
hydrogenation delivered the bis-spirocycles 10b and 10c in 98%
and 89% yields, respectively (Table 1, entries 2 and 3). Surprisingly,
cycloheptanone 7d delivered the tri-allylated compound 8d and
we were unable to obtain the tetra-allylated compound under
NaH/allyl bromide conditions even after 5 days. In addition, we
have also tried various other reaction conditions but we did not
realize the formation of tetra-allylated product. The structure of
tri-allylated compound 8d has been confirmed by 1H and 13C
NMR spectroscopy and further supported by HRMS data. Later,
we have extended this strategy to heteroatom containing bis-spi-
rocyclic and benzofused bis-spirocycles by using RCM as a key
step. To this end, we have chosen tetrahydro-4H-pyran-4-one 7e
for the synthesis of heteroatom containing bis-spirocyclic system.
To expand this strategy to aromatic systems 2-indanone 7f and
b-tetralone 7g have been selected. Allylation of these compounds
7e, 7f, and 7g under NaH/allyl bromide conditions cleanly fur-
nished the tetra-allylated compounds 8e, 8f, and 8g in 69%, 80%,
and 72% yields, respectively. RCM followed by hydrogenation of
these compounds produced the corresponding saturated bis-spiro-
cycles 10e, 10f, and 10g in good to excellent yield (Table 1, entries
5–7 (see Scheme 1)).
Since bicyclo [2.2.2]octane system is very common in several
natural and non-natural products, we have also synthesized a sat-
urated bis-spirobicyclic system 15 by adopting the same strategy
(allylation, RCM and hydrogenation sequence) starting with the
readily available starting material such as hydroquinone
(Scheme 2). The bicyclic diketone 12 was prepared by the literature
procedure.8 In addition, we have also prepared interesting bis-spi-
ropropellane derivative starting with a simple and commercially
available starting materials such as cycloctadiene. In this connec-
tion, the diketone 19 required for the synthesis of bis-spiropropel-
lane was prepared by following the literature method.9 Treatment
of the diketone 19 with NaH/allyl bromide (4 equiv) for 6 h at rt
O
O
O
O
Pd/C, H2
EtOAc
NaH, THF
C3H5Br
G-I, CH2Cl2
rt, 15-24 h
83-98%
rt, 6-12 h
73-90%
rt, 10-30 h
21-80%
7a-g
9a-g
8a-g
10a-g
Scheme 1. General strategy to bis-spirocycles via RCM.

4494
S. Kotha et al. / Tetrahedron Letters 55 (2014) 4492–4495
OH
G-I
CH2Cl2
O
O
O
NaH, THF
3 Steps
O
Pd/C, H2
C3H5Br, 18 h
rt, 66%
ref. 8
O
rt, 8 h
82%
EtOAc, rt
20 h, 97%
O
O
O
OH
13
12
14
11
15
Scheme 2. Synthesis of bis-spirobicyclic system 15 via RCM.
O
O
O
G-I, CH2Cl2
rt, 24 h, 87%
Pd/C, H2
EtOAc, rt
12 h, 96%
20
NaH, THF
O
O
O
22
21
6 h, 58%
C3H5Br, rt
OAc
OH
O
Pb(OAc)4
20% KOH, MeOH
PCC, CH2Cl2
rt, 8 h, 94%
AcOH, PdCl2
rt, 4 days
rt, 34 h, 58%
(2 steps yield)
AcO
HO
O
19
16
18
17
reflux
24 h, 61%
NaH, THF
C3H5Br
O
O
O
Pd/C, H2
EtOAc, rt
G-I, CH2Cl2
rt, 24 h, 93%
32 h, 96%
O
O
O
24
25
23
Scheme 3. Synthesis of bis-spiropropellane via RCM.
delivered the tetra-allylated compound 20 (58%) (Scheme 3). On
the other hand, the same diketone 19 with NaH/allyl bromide
(excess) for 38 h at rt furnished the hexa-allylated compound 23
(50%) along with tetra-allylated compound 20 (19%) yield. In addi-
tion, the diketone 19 on treatment with NaH/allyl bromide (excess)
in refluxing THF delivered the hexa-allylated compound 23 in 61%
yield (Scheme 3). When the compounds 20 and 23 were subjected
to RCM with the aid of G-I catalyst, we obtained the bis-spiro com-
pound 21 and bis-spiropropellane 24 in 87% and 93% yields,
respectively. Further treatment of these unsaturated systems with
Pd/C in EtOAc under hydrogen atmosphere (1 atm) furnished the
saturated compounds 22 and 25 in 96% yield each (Scheme 3).
In summary, we have developed a simple and useful methodol-
ogy for the synthesis of spirocycles in a diversity-oriented man-
ner10 starting with monocyclic ketones and bicyclic diones.
Generally, creation of a spiro center is considered to be a difficult
task in preparative organic chemistry. Here, we have used readily
available starting materials and operationally simple proce-
dure11–13 to generate a library of intricate spirocycles in good to
excellent yields.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.06.
049.

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