Formal synthesis of Pellasoren – A

Article abstract of DOI:10.1016/j.tetlet.2018.09.035

A convergent and highly stereoselective formal synthesis of Pellasoren – A is described. The salient features of the synthesis are the utilization of enzymatic desymmetrization, Crimmin's non-Evans syn aldol, Lindlar's and Wittig reaction.

Full text of DOI:10.1016/j.tetlet.2018.09.035

Accepted Manuscript
Formal synthesis of Pellasoren - A
Katta Muralikrishna, Gavireddy Chaithanya kumar, Vavilapalli Satyanarayana,
R. Sudheer Kumar, Jhillu singh Yadav
PII:
S0040-4039(18)31125-0
https://doi.org/10.1016/j.tetlet.2018.09.035
TETL 50274
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
3 July 2018
10 September 2018
13 September 2018
Please cite this article as: Muralikrishna, K., kumar, G.C., Satyanarayana, V., Sudheer Kumar, R., Yadav, J.s.,
Formal synthesis of Pellasoren - A, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.09.035
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Formal synthesis of Pellasoren-A
Katta Muralikrishna,a Gavireddy Chaithanya kumar,a Vavilapalli Satyanarayana,a R Sudheer Kumar,a Jhillu
singh Yadav*a,b

Tetrahedron Letters
1
Tetrahedron Letters
journal homepage: www.elsevier.com
Formal synthesis of Pellasoren - A
Katta Muralikrishna,a Gavireddy Chaithanya kumar,a Vavilapalli Satyanarayana,a Sudheer Kumar R,a Jhillu singh
Yadav*a,b
aCentre for Semiochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, Email: yadavpub@gmail.com; Fax: 91-40-27160512.
bSchool of Science, Indrashil University, Kadi, Mehsana, Email ID : jsyadav@indrashiluniversity.edu.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convergent and highly stereoselctive formal synthesis of Pellasoren – A is
described. The salient features of the synthesis are the utilization of enzymatic
desymmetrization, Crimmin’s non-Evans syn aldol, Lindlar’s and Wittig reaction.
Available online
Keywords:
Pellasoren- A, enzymatic desymmetrization,
cytotoxicity, Lindlar’s reduction, Wittig
reaction, Crimmin’s non-Evans syn aldol
and anticancer activity.
2009 Elsevier Ltd. All rights reserved.
The wide varieties of efficient secondary metabolites are
produced by Myxobacteria, and the genus Sorangium is
commonly characterized as proficient source for new,
biologically active natural products.1 In 2012, Pellasoren – A
(1) and B (2) are secondary metabolites, were isolated from S.
cellulosum So ce35 by Christine Jahn, both display anticancer
activity, in particular Pellasoren – A (1) exhibits cytotoxicity
against HCT-116 human colon cancer cells at a concentration
of 155 nm (IC50), emphasizing the importance of the linear an
all-(E) configuration. Furthermore, both pellasorens show a
strong effect on lysosomes. In structural of view in interesting
structural features of Pellasoren A (1) and B (2) are isobaric
compounds having the same constitution, some changes in the
double bond system at C10–C11 which can be rationalized by
photochemical isomerization of E/Z isomers, respectively.2
synthesis of pellasoren – A (1) by Cross Metathesis via
synthesis of stereoselective bromination of the E,E-
vinylketene silyl N,O acetal a chiral auxiliary and applied to
introduction of heteroatom at γ -position of α, β - unsaturated
imide.3 We herein present a facile and general method for the
stereoselective formal synthesis of Pellasoren - A (1) using
enzymatic desymmetrization and a Crimmins “non-Evans”
syn aldol reaction to generate the four of the five stereogenic
centres with good diastereoselectivity.
Christine Jahn et al reported the discovery, complete structure
elucidation in year 2012 and first total synthesis of pellasoren
- A (1) through coupling of two key fragments by E-selective
Wittig olefination. Recently Shinji Sekiya et al disclosed total

2
The chiral auxiliary was cleaved from aldol adduct 12 by
treating with sodium borohydride in THF: H2O (2:1) to
furnish diol 13 with a considerably good yield.8 The 1, 3-diol
group of 13 was protected with p-methoxy benzyl dimethyl
acetal and catalytic amount of CSA in CH2Cl2 to afford the
acetal compound 14 in 94% yield.9 The regioselectively PMB
acetal 14 was reduced by using DIBAL-H in CH2Cl2 at – 40
oC to afford the compound 15 in 92 % yield.10 The primary
alcohol in 15 (TsCl, TEA, 92%) was converted to its tosyl
derivative 16 (Scheme 3).
Our retrosynthetic plan of Pellasoren – A (1) is disclosed in
Scheme 1. The target molecule 1 was divided into two
fragments i.e, lactone fragment 3 and amide fragment 4,
which could be combined by cross metathesis. A key
objective for preparing lactone fragment 3 would be obtained
from a compound 5, which could be constructed by means of
Crimmin’s non-Evans syn aldol reaction with chiral auxiliary
10 and aldehyde 9, which in turn to be achived from meso-
4,6-Dimethylcyclohexane-1,3-dione 7. Amide fragment 4
would be synthesized by coupling of carboxylic acid and
amine along with the tetraene geometry in a concise manner;
amine might be derived from 8.
Results and Discussion:
Our synthesis began with a known precursor meso-4,6-
Dimethylcyclohexane-1,3-dione 7 by the application of the
enzymatic desmmetrization to the known diol to produce
monoacetate 9 the diol commenced from compound 7
according to a literature procedure.4 Monoacetate 9 was
protected as silyl ether using TBSCl and imidazole in CH2Cl2
and then treated with CH3ONa in methanol to furnish the
desired primary alcohol 6 in 96% yield over two steps.5
(Scheme 2)
The tosyl derivative 16 was treatment with 5 equiv of lithium
acetylide in dimethyl sulfoxide (DMSO) to furnish
corresponding alkyne 5 in 72% yield.11 The PMB and TBS
groups in compound
5
were deprotected with
CeCl3:7H2O/NaI to furnish diol 17 in 94% yield.12 The diol 17
was converted to compound 18 by the oxidation using
bis(acetoxy)iodobenzene (BIAB) in the presence of catalytic
amounts of tetramethyl-1-piperidinyloxyl (TEMPO) in
CH2Cl2 with good yield.13 A partial reduction of alkyne
functionality in compound 18 was generated using Lindlar’s
catalyst in the presence of quinoline under hydrogen
atmosphere to give corresponding partially hydrogenated
lactone 3 in 95 % yield (Scheme 4).
At this stage primary alcohol in 6 was then oxidized to the
corresponding aldehyde 11 under Swern conditions6 with a
considerably good yield. The aldehyde 11 was subjected to
TiCl4 mediated Crimmin’s non-Evans syn aldol reaction7 with
Crimmin’s chiral auxiliary 10 using DIPEA to produce the
non-Evans syn aldol adduct 12 with dr >95:5 (Scheme 2).
The amide fragment 4 was synthesized starting from Boc-
protected amino alcohol 8. The Boc-protected amino alcohol
8 converted to required alcohol 19 prepared according to a
previously reported procedure.2 The compound 19 was
oxidized with IBX in DMSO to afford corresponding
aldehyde. The aldehyde which was submitted to a one carbon
extension by means of Wittig reaction with Ph3CH3I and
Potassium tert-butoxide as base to provide corresponding
olefine 4 in 66% yield 14 (Scheme 5).
The Formal Synthesis of Pellasoren – A (1)
The compounds 3 and 4 are key advanced intermediates for
the total synthesis of Pellasoren – A (1). Thus, we have

Tetrahedron Letters
3
J. Am. Chem. Soc. 2005, 127, 13810–13812; (d) Crimmins,
M. T.; Caussanel, F. J. Am.Chem. Soc. 2006, 128, 3128–
3129; (e) Kumar, G. C.; Muralikrishna, K.; Satyanarayana,
V.; Kumar, C.S.; Yadav, J. S. Tetrahedron Lett. 2018, 59,
454-456.
accomplished the formal total synthesis of Pellasoren – A (1)
using enzymatic desymmetrization, a Crimmins “non-Evans”
syn aldol, Lindlar’s and a Wittig olefination (Scheme 6). The
formal synthesis of Pellasoren – A (1) involved 11 steps
starting from compound 8 with a 25% overall yield. Further
efforts towards the completion of the total synthesis of
Pellasoren – A (1) is currently underway.
8. (a) Crimmins, M. T.; McDougall, P. J.; Ellis, J. M. Org.
Lett. 2006, 8, 18, 4079–4082; (b) Crimmins, M. T.; Ellis, J.
M.; Emmitte, K. A.; Haile, P. A.; McDougall, P. J.;
Parrish, J. D.; Zuccarello, J. L. Chem. Eur. J. 2009, 15, 36,
9223–9234; (c) Prasad, N.; Iqbal, J.; Mukkanti, K.; Das, P.
Tetrahedron Lett. 2008, 49, 19, 3185–3188.
9. (a) Gustafsson, T.; Schou, M.; Almqvist, F.; Kihlberg, J. J.
Org. Chem. 2004, 69, 8694–8701; (b) Yadav, J. S.; Reddy,
K. B.; Sabitha, G.; Tetrahrdon. 2008, 64, 1971–1982; (c)
Evans, D. A.; Carter, P. H.; Carreira, E. M.; Andre´ B,
Charette, Prunet, J. A.; Lautens, M. J. Am. Chem. Soc.
1999, 121, 7540–7552; (d) Zhang, F.; Peng, L.; Li, H.;
Ma, A.; Peng, J.; Guo, J.; Yang, D.; Hou, S.; Tu, Y.;
Kitching, W. Angew. Chem. Int. Ed. 2012, 51, 10846–
10850.
Conclusions
In summary, we have successfully completed the efficient
formal synthesis of Pellasoren – A (1). By using a convergent
strategy, we utilized an enzymatic desymmetrization for
10. (a) Tsuchiya, S.; Sunazuka, T.; Hirose, T.; Mori, R.;
Tanaka, T.; Iwatsuki, M.; Ohmura, S.; Org. Lett. 2006, 8,
5577–5580; (b) Gil, A.; Lamariano-Merketegi, J.; Lorente,
A.; Albericio, F.; lvarez, M. Org. Lett. 2016, 18, 4485–
4487; (c) Toshima, H.; Maru, K.; Satio, M.; Ichihara, A.
Tetrahedron Letters. 1999, 40, 939–942; (d) Fujishima, Y.;
Ogura, Y.; Towada, R.; Enomoto, M.; Kuwahara, S.;
Tetrahedron Letters. 2016, 57, 5240–5242; (e) Shiina, I.;
Kikuchi, T.; and Sasaki, A. Org. Lett. 2006, 8, 4955–4958.
enantioselective synthesis of lactone fragment
3 from
enzymatic desymmetrization of meso-diol by using amino
lipase AK. The synthesis involved other important reactions
such as a Crimmins “non-Evans” syn aldol reaction, Lindlar’s
and a Wittig olefination. The synthesis involved 11 steps
starting from compound 8 with a 25% overall yield. One
additional step would be required to complete a total synthesis
of Pellasoren - A.
11. Suh, Y. G.; Jung, J. K.; Seo, S. Y.; Min, K. H.; Shin, D. Y.;
Lee, Y. S.; Kim, S. H.; Park, H. J. J. Org. Chem. 2002, 67,
4127–4137.
Acknowledgements
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1999, 64, 5696–5699.
KMK, G.C.R, VSN, thanks UGC, for the award of fellowship.
JSY thanks CSIR and DST, New Delhi for Bhatnagar and J.
C. Bose Fellowships respectively.
13. Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.;
Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44,
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Supplementary Material
Supplementary data associated with this article can be
found, in the online version at
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4
Highlights of The Pellasoren-A Synthesis
 Formal synthesis of the antitumor
natural product Pellasoren–A was
synthesized.
 Four chiral centers out of five were
created in this synthesis.
 Monoacetate 9 obtained by employing
enzymatic desymmetrization.
 Key steps are Wittig, Lindlar’S and
Crimmin’s non-Evans syn aldol reaction.
 The lactone 3 was achieved in 11 steps
with 25% overall yield.