A protecting-group-free synthesis of arbusculone, andirolactone, pinnatolide, ipomolactone, cyclocapitelline and isocyclocapitelline

Article abstract of DOI:10.1016/j.tetlet.2018.10.024

A general approach for a collective synthesis of natural products containing substituted THF ring is described. In this paper, Arbusculone, a small molecule natural product accomplished using a short route, is used as the key intermediate to achieve the total synthesis of Andirolactone, Pinnatolide, Ipomolactone, Cyclocapitelline, Isocyclocapitelline and their two isomers in less than ten steps. The present effort highlights protecting-group-free total syntheses and the shortest route to access these natural products from commercially available cheap starting materials.

Full text of DOI:10.1016/j.tetlet.2018.10.024

Accepted Manuscript
A protecting-group-free synthesis of arbusculone, andirolactone, pinnatolide,
ipomolactone, cyclocapitelline and isocyclocapitelline
Srinivas Gajula, Madasu Madhu, Suresh Kumar Chintakrinda, J.S. Yadav,
Debendra K. Mohapatra
PII:
S0040-4039(18)31231-0
https://doi.org/10.1016/j.tetlet.2018.10.024
TETL 50334
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 September 2018
12 October 2018
13 October 2018
Please cite this article as: Gajula, S., Madhu, M., Chintakrinda, S.K., Yadav, J.S., Mohapatra, D.K., A protecting-
group-free synthesis of arbusculone, andirolactone, pinnatolide, ipomolactone, cyclocapitelline and
isocyclocapitelline, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.10.024
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Graphical Abstract
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A protecting-group-free synthesis of arbusculone,
Leave this area blank for abstract info.
andirolactone, pinnatolide, ipomolactone,
cyclocapitelline and isocyclocapitelline
Srinivas Gajula, Madasu Madhu, Suresh Kumar Chintakrinda, J. S. Yadav and Debendra K. Mohapatra*
O
O
O
O
O
O
O
O
5
H
H
HO
HO
4
2a
2
O
H
(+)-Ipomolactone
cis-Linalooloxide trans-Linalooloxide
(+)-Pinnatolide
O
1
cis-Arbusculone
N
N
O
H
O
O
O
1a
O
H
OH
NH
H
trans-Arbusculone
NH
OH
7
6
O
3
(+)-Cyclocapitelline
(-)-Isocyclocapitelline
Andirolactone
Tetrahedron Letters
journal homepage: www.elsevier.com
A protecting-group-free synthesis of arbusculone, andirolactone,
pinnatolide, ipomolactone, cyclocapitelline and isocyclocapitelline
Srinivas Gajula, Madasu Madhu, Suresh Kumar Chintakrinda, J. S. Yadav and Debendra K. Mohapatra*
aOrganic Synthesis and Process Chemistry Division, CSIR-Indian Insititute of Chemical Technology, Hyderabad-500007, India
bAcademy of Scientific and Innovative Research (AcSIR), Mathura Road, New Delhi-110 025, India
cSchool of Science, Indrashil University, Kadi, Gujarat-382740, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A general approach for a collective synthesis of natural products containing substituted THF
ring is described. In this paper, Arbusculone, a small molecule natural product accomplished
using a short route, is used as the key intermediate to achieve the total synthesis of
Andirolactone, Pinnatolide, Ipomolactone, Cyclocapitelline, Isocyclocapitelline and their two
isomers in less than ten steps. The present effort highlights protecting-group-free total syntheses
and the shortest route to access these natural products from commercially available cheap
starting materials.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Natural products
Epoxidation reaction
Wittig reaction,
Pinnick oxidation,
Pictet-Spengler reaction.
Nature has gifted us countless numbers of natural products with complex and fascinating structures with interesting biological
properties. [1] Among them, THF-containing natural products belong to one relatively small but interesting category of natural products
exhibiting an array of important bioactivities. [2] Due to their intriguing biological activities and potential candidates as
pharmaceuticals, THF-containing natural products have been the target of a large number of research groups. [3] Among them, cis- and
trans-Arbusculone were isolated for the first time from the essential oil of A. herba-alba growing wild in Tunsia. [4] Similarly,
Andirolactone, a spirocyclic butenolide natural terpenoid isolated in 1987 from tar wood of the Cedrus libanottea, which is a needle leaf
tree that grows in Southern Turkey and Libanon. [5] Other related natural products like Pinnatolide and Ipomolactone are isolated from
A. pinnata in 1991 by Bohman et al. [6] Cyclocapitelline and Isocyclocapitelline are isolated from rubiaceae family and are available in
minute quantities from natural sources. [7] Because of the interesting structural features and potent biological activities of these natural
products, many groups [8] have reported different synthetic approaches for these natural products. As the biological activity of THF-
containing natural products rely on its stereochemistry, considerable efforts have been expended on the stereoselective synthesis of
tetrahydrofuran ring systems. [9] Current synthetic strategies mostly rely on lengthy synthetic routes to access THF rings and on chiral
building blocks with a number of protecting group and functional group manipulations.
In continuation of our interest in the synthesis of THF and substituted THF containing natural products, [10] we report

______________
*Corresponding author. Tel.: +91-40-27193128; fax: +91-40-27160512; e-mail: mohapatra@iict.res.in
herein, a scalable and protecting-group-free stereoselective syntheses of a series of THF-containing natural products starting from a key
intermediate cis-Arbusculone and trans-Arbusculone, both are natural products itself. According to the retrosynthetic analysis for the
synthesis of natural products depicted in Figure 1, we hypothesized that cis-Arbusculone (1) could be an ideal
N
O
H
NH
OH
6
(-)-Isocyclocapitelline
O
Figure 1. Structures of natural products.
H
HO
2
O
cis-Linalooloxide
iOntermediate, from which the requisite natural products such as Andirolactone, Pinnatolide, Ipomolactone, and Isocycloca- pitelline
O
O
H
could be obtained. ArbuscuOlone (1) was in turn could be prepared from key allylic alcohol building block which could be obtained from
4
1
O
(+)-Pinnatolide
commercially available (R)-Linalool (8).
cis-Arbusculone
O
O
Our synthesis began with theOreadily available (R)-Linalool (8) as the starting material. The major challenge in our synthesis is the
5
H
O
preparation of cis–Arbusculone. To achieve this, (w+)e-Ipionmitoilaalcltyonoepted for Sharpless asymmetric epoxidation reaction for the synthesis of
1a
common intermediate 1. trans-Arbusculone
O
Accordingly, (R)-Linalool (8) on treatment wiHth2OaSeO in CH Cl followed by reduction of the resultant aldehyde with NaBH
2
2
2
4
HO
O
3
N
furnished allyl alcohol 9 in 68% yield over ttrwanos-Lsitneaploso.loTxihdee asymmetric epoxidation of allyl alcohol 9 under Sharpless asymmetric
epoxiAdnadtiiroonlacrteoancetion conditions was not successful and it might be due to the presence of free tertiary alcohol in compound 9 and in our
O
H
hands only 40% starting material consumed at −20 °C over a period of 7 days to obtain 10 and 11 as a mixture in 4:1 ratio. As per our
NH
OH
knowledge, till now asymmetric7Sharpless epoxidation on this substrate is not reported and as we were looking for the synthesis of cis-
(+)-Cyclocapitelline
Arbusculone (1) and trans-Arbusculone (1a), alternatively, we carried out the epoxidation using m-CPBA which furnished compound
10 and 11 with almost 1:1 ratio in 89% combined
OH
OH
OH
O
a
b
OH
10
8
+
9
OH
OH
O
OH
11
d
d
O
O
H
H
H
O
HO
HO
1
+
2
c
O
O
H
O
1a
2a
1 1a
( / = 1:1)
Scheme 1. Synthesis of key intermediate arbusculone (1/1a). Reagents and conditions: a) SeO2, CH2Cl2, 0 °C to rt, 6 h, NaBH4, 68%; b)
m-CPBA, CH2Cl2, 0 °C to rt, 2 h, 89%; c) NaIO4 on silica, CH2Cl2, 0 °C, 2 h, 87%; d) MeMgBr, Et2O, 0 °C, 30 min, 85% (2) and 84%
(2a).
yield. Both the isomers were separated and treated with sodium metaperiodate to afford a mixture of cis- and trans-THF rings 1 and 1a
from 10 and 11, respectively. These THFs were easily separated by silica gel column chromatography and the stereochemistry was
assigned by key NOE correlations (see Supporting Information).
After successful synthesis of cis-Arbusculone (1), we focused our attention on the total synthesis of other four related natural products
and their isomers. Toward this effort, the Arbusculone (1) in the present synthesis is suitable for the generation of other related natural
products, as it possesses functionalities with orthogonal reactivities. Accordingly, treatment of compound 1 with methyl magnesium
bromide in diethyl ether at 0 °C afforded the required alcohol compound 2 in 85% yield. For the synthesis of alcohol compound 2a,
compound 1a was treated with methyl magnesium bromide, under same reaction conditions as reported for the preparation compound 2
(Scheme 1), to afford 2a in 84% yield.
Towards the synthesis of Andirolactone (3), we identified compound 3a as an ideal late-stage intermediate because it enabled the
incorporation of the tertiary alcohol functionality retaining the double bond geometry of vinyl group through a 2,3-Wittig
rearrangement. [11] The in situ formation of ketone 3a under cis-Wittig reaction conditions furnished Andirolactone (3) in 44% yield
over two steps. The spectral data of Andirolactone (3) matched with those reported for the natural and synthetic material. [8d] This
approach highlights a protecting group free total synthesis and the shortest route to access Andirolactone (3).

a
b
O
O
H
OH
O
O
3a
O
1
3
Scheme 2. Synthesis of (−)-Andirolactone 3. Reagents and conditions: a) t-BuOK, t-BuOH, 12 h; b) Ethyl 2-[bis(2,2,2-
trifluoroethoxy)phosphoryl]propanoate, n-BuLi, THF, 1 h, 44%, over two steps.
Attention was next focussed on the total synthesis of (+)-Pinnatolide and (+)-Ipomolactone. To the best of our knowledge, Pinnatolide
(5) was prepared by Lutz et al using seven steps. [8g] However, we developed it in a sequence of six steps. Accordingly, hydroboration
of compound 2 followed by Dess-Martin periodinane (DMP) oxidation of the resulting primary alcohol furnished the requisite aldehyde
fragment 13 in 83% yield. Aldehyde 13 was subjected to Grignard reaction to give the diastereomeric mixture (1:1) of alcohols 14 in
80% yield.
b
a
OH
O
O
H
H
H
HO
HO
O
HO
2
12
OH
d
c
O
O
CHO
H
HO
13
14
O
O
e
O
O
O
5
4
(+)-Ipomolactone
(+)-Pinnatolide
Scheme 3. Synthesis of (+)-Pinnatolide (4) and (+)-Ipomolactone (5). Reagents and conditions: a) BH3.DMS, THF, 0 °C to rt, 6 h, 81%;
b) DMP, CH2Cl2, 0 °C to rt, 12 h, 83%; c) C4H7MgBr, 0 °C to rt, 1 h, THF, 80%; d) PCC, CH2Cl2, reflux, 12 h, 60%; e) NiCl2.6H2O,
NaBH4, MeOH, 6 h, 88%.
PCC oxidation [12] of secondary alcohol 14 in refluxing CH2Cl2 followed by isomerization of terminal double bond to internal double
bond furnished directly the (+)-Pinnatolide (4). Finally, α,β-unsaturation in compound 4 was hydrogenated using NiCl2 and sodium
borohydride to form (+)-Ipomolactone (5) in 88% yield. It is noteworthy to mention that the significance of (+)-Pinnatolide (4) to
determine the absolute stereochemistry on C4 carbon of (+)-Ipomolactone (5) was identified by converting Pinnatolide to Ipomolactone.
Having prepared gram quantities of the key intermediate and completed the asymmetric synthesis of two natural products, we diverted
our attention for the synthesis of two more natural products (−)-Isocyclocapitelline and (+)-Cyclocapitelline. Our approach for the
synthesis of (−)-Isocyclocapitelline and (+)-Cyclocapitalline is significantly shorter than the previous stereoselective routes. [8l]
Hartung et al reported the syntheses of cis- and trans-β-carbolines, which are lower homologues of alkaloids (–)-Isocyclocapitelline and
(+)-cyclocapitelline. The key step in their synthesis is the Vanadium-catalyzed oxidation of (R)-Linalool (8) in which epoxidation took
place on both the double bonds, leading to low yield of the required product. Pleasingly, our protocol involves m-CPBA-mediated
oxidation which furnished epoxidation exclusively on allylic double bond resulting in the formation of cis and trans-THF in equal ratios
with good yield. Accordingly, the synthesis commenced from
NH
a
O
N
H
H
H
CHO
HO
O
13
15
H
OH
b
N
N
H
O
H
6
OH
Scheme 4. Synthesis of (−)-Isocyclocapitelline 6. Reagents and conditions: a) Tryptamine, TFA, CH2Cl2, −78 °C, 3 h; b) Pd/C,
Xylenes, reflux, 8 h, 75%, Over two-steps.
aldehyde 13 and was subjected to a Pictet-Spengler [13] reaction with tryptamine under TFA-catalyzed conditions followed by
dehydrogenation using Pd/C in xylene under reflux conditions to afford (−)-Isocyclocapitelline (6) in 75% yield over two steps.

Following the same sequence of reactions and conditions as reported in Scheme 4, (+)-Cyclocapitelline (7) was furnished in 73%
yield over two steps starting from aldehyde 13a (Scheme 5).
N
As per
N
O
Scheme 4
H
O
H
CHO
HO
H
7
13a
OH
Scheme 5. Synthesis of (+)-Cyclocapitelline 7.
In summary, the present protocol highlights protecting-group-free total syntheses and the shortest route to access synthesis of five
natural products and two isomers starting from Arbusculone as an ideal intermediate. The key steps involved are Wittig reaction,
Pinnick oxidation, 2,3-Wittig rearrangement and Pictet-Spengler reaction. The present approach demonstrated wide applicability in the
synthesis of various natural products containing THF motif and analogues required for biological activity. Further application of this
method towards the total syntheses of other related complex natural products is in progress.
Acknowledgments
The authors thank Council of Scientific and Industrial Research (CSIR), New Delhi, India, for financial support as part of the XII
Five Year plan programme under the title ORIGIN (CSC-0108; manuscript communication number IICT/Pubs/ 2018/297). G.S. M.M.
and C.H.S.K. thank the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for financial assistance in the form of
fellowship.
Supporting Information
Supplementary data associated with this article can be found, in the online version, at http://dx.doi/xxxxxx.
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Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Highlights
A protecting-group-free synthesis of arbusculone,
Leave this area blank for abstract info.
andirolactone, pinnatolide, ipomolactone,
cyclocapitelline and isocyclocapitelline
Srinivas Gajula, Madasu Madhu, Suresh Kumar Chintakrinda, J. S. Yadav and Debendra K. Mohapatra*
O
O
O
O
O
O
O
O
5
H
H
HO
HO
4
2a
2
O
H
(+)-Ipomolactone
cis-Linalooloxide trans-Linalooloxide
(+)-Pinnatolide
O
1
cis-Arbusculone
N
N
O
H
O
O
O
1a
O
H
OH
NH
H
trans-Arbusculone
NH
OH
7
6
O
3
(+)-Cyclocapitelline
(-)-Isocyclocapitelline
Andirolactone
1. Protecting-group-free total synthesis.
2. Shortest route for the natural products.
3. 2,3-Wittig rearrangement for Andirolactone synthesis in one step.
4. Application of Pictet-Spengler reaction.