Synthesis of the C1-C15 fragment of palmerolide A via protecting group dependent RCM reaction

Article abstract of DOI:10.1016/j.tetlet.2013.04.069

The steric effect of protecting groups on the outcome of the ring-closing metathesis reaction has been studied for the construction of key 13-membered macrolactone. The protocol has been successfully utilized for the synthesis of C1-C15 fragment of palmerolide A in a highly convergent and concise manner.

Full text of DOI:10.1016/j.tetlet.2013.04.069

Accepted Manuscript
Synthesis of the C1-C15 fragment of palmerolide A via protecting group de‐
pendent RCM reaction
Bighnansu Jena, Debendra K. Mohapatra
PII:
S0040-4039(13)00664-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.04.069
TETL 42837
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 February 2013
15 April 2013
17 April 2013
Please cite this article as: Jena, B., Mohapatra, D.K., Synthesis of the C1-C15 fragment of palmerolide A via
protecting group dependent RCM reaction, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.04.069
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Graphical Abstract
Synthesis of the C1-C15 fragment of palmerolide A
via protecting group dependent RCM reaction
Leave this area blank for abstract info.
Bighnansu Jena, and Debendra K. Mohapatra*

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
Synthesis of the C1-C15 fragment of palmerolide A via
protecting group dependent RCM reaction
Bighnansu Jena, and Debendra K. Mohapatra*
Natural Products Chemistry Division,CSIR- Indian Insititute of Chemical Technology, Hyderabad-500007, India
Abstract— The steric effect of protecting groups on the outcome of the ring-closing metathesis reaction has been studied for the
construction of key 13-membered macrolactone. The protocol has been successfully utilized for the synthesis of C1-C15 fragment of
palmerolide A in a highly convergent and concise manner.
© 20133 Elsevier Science. All rights reserved
Natural products synthesis has stimulated incredible
advance in the development, testing, and demonstration of
methods and strategies for the complex arrangements of
functionality and stereochemistry in the target molecule. To
date numerous complex natural products and their simpler
synthetic derivatives are used as pharmaceutical agents.1
Ongoing efforts to identify new natural products with
extraordinary properties, Baker and co-workers isolated
palmerolide A (Figure 1), a complex polyunsaturated
macrolide with an impressive molecular architecture and
biological profile, from the circumpolar marine tunicate
Synoicum adareanum, which is commonly found in the
shallow waters around Anvers Island on the Antarctic
peninsula. This marine natural product found to exhibit
excellent antitumor activity against a number of cell lines
in the 60 cell panel of the National Cancer Institute (NCI).2
Specifically, it exhibits potent cytotoxicity against the
stereochemistry of the natural product.4a Subsequently
Nicolaou4b-d, and Hall4e also reported the total synthesis of
palmerolide A. Formal total syntheses5 and approaches to
various fragments6 were also reported. Notable approach
for construction of the 1,4-alkenol C7-C11 fragment
include an intramolecular Wittig reaction followed by
reduction and a Claisen-Ireland rearrangement of an
alkenyl boronate.4e Considering all these synthetic reports,
we envisioned a distinct retrosynthesis of fragment 3
(Scheme 1) that would take advantage of protecting group
dependent ring-closing metathesis reaction developed in
our group.
melanoma cell lines UACC-62 (LC50
= 18 nM).
Palmerolide A appears to act on melanoma cells through
inhibition of vacuolar ATPase with an IC50 of 2 nM.3 The
remarkable 103 in vitro selectivity index for the melanoma
cells over other most sensitive cell lines tested prompted
further biological evaluation of the compound. The
impressive biological properties of palmerolide A, along
with its extremely limited supply and for further structure-
activity studies, prompted us to undertake its chemical
synthesis. Several groups have reported on the synthesis of
palmerolide A.4 An elegant study by De Brabander’s group
Figure 1. Structures of originally proposed (1) and revised (1a)
palmerolide A
disclosed the first total synthesis of 1 and revised the
———
Key words: Natural products, palmerolide A, cytotoxic, Sharpless dihydroxylation, Heck coupling, ring-closing metathesis reaction.
*Corresponding author. Tel.: +91-40-27193128; fax: +91-40-27160512; e-mail: mohapatra@iict.res.in

2
Tetrahedron Letters
As part of our ongoing research program on the synthesis
of biologically active natural and unnatural products using
protecting group dependent ring-closing metathesis
approach,7 we became interested in the synthesis of C1-
C15 fragment of palmerolide A.
Pinnick conditions,14 gave caboxylic acid 6 in 87% yield
over two steps.
According to our retrosynthetic analysis of palmerolide
A (1a) shown in Scheme 1, macrolactone core 2 could be
constructed through esterification of 3 and 4, followed by
intramolecular Heck coupling.8 Fragment 3 could be
obtained from the 13-membered macrolactone 5, which in
turn could be prepared from 6 and 7 via coupling, followed
by ring-closing metathesis reaction of the resulting diene
compound.9
Scheme 2. Reagents and conditions: (a) (i) I2, PPh3, imidazole,
o
THF, 0 C, 10 min, 92%; (ii) Activated Zn, NaI, EtOH, reflux, 2
h, 89%; (b) PMB-Br, NaH, THF, 0 oC, 4 h, 91%; (c) TBAF, THF,
rt, 4 h, 94%; (d) (i) IBX, DMSO, THF, rt, 3 h, 91%; (ii) NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O, rt, 2 h, 92%.
The synthesis of alcohol fragment 7 commenced with
commercially available 1,4-butane diol. Following a
literature protocol,15 α,β-unsaturated ester 14 was obtained.
Sharpless asymmetric dihydroxylation16 with AD-mix-α
(89% yield with 98% ee) followed by protection of
resulting 1,2-diol with 2,2-dimethoxypropane in presence
Scheme 1: Retrosynthetic analysis of palmerolide A
The synthesis of acid fragment 6 began with 1,5-pentane
diol 8, which was converted to epoxy alcohol 910 in 90%
yield and with 97% ee through its corresponding allylic
alcohol by treating with (+)-diethyl tartrate in presence of
Ti(OiPr) and tBuOOH under Katsuki-Sharpless11
conditions. The primary alcohol group of
9 was
transformed into its corresponding iodo derivative with I2
in presence of Ph3P and imidazole. The reductive opening
of the epoxide ring of the iodo compound with Zn in
refluxing ethanol12 afforded secondary allylic alcohol 10 in
82% yield over two steps (Scheme 2), which was protected
as its p-methoxybenzyl ether with PMBBr in presence of
NaH. Silylether deprotection of 11 with 1M solution of
tetrabutylammonium fluoride (TBAF) in THF provided 12
in 94% yield. The primary alcohol 12 was then oxidized
with 2-iodoxybenzoic acid (IBX)13 to furnish the
corresponding aldehyde. Further oxidation14 of the
intermediate aldehyde with NaClO2 in the presence of
NaH2PO4 and 2-methyl-2-butene as a scavenger, under
Scheme 3. Reagents and conditions: (a) AD-mix-α, MeSO2NH2,
K2CO3, K3Fe(CN)6, t-BuOH:H2O (2:1), OSO4, 24 h, 0 C, 89%;
o
(b) 2,2-DMP, CH2Cl2, CSA, rt, 3 h, 92%; (c) (i) DIBAL-H,
CH2Cl2, 0 oC, 30 min; (ii) DMP, CH2Cl2, rt, 2 h; (iii) (PPh3-
o
o
CH3)+Br- , NaHMDS, THF, −78 C to 0 C, 4 h, 70% yield over
o
three steps; (d) AcOH:H2O (3:2), 50 C, 3 h, 87%; (e) PMBBr,
NaH, THF, 0 oC, 4 h, 91%; (f) MOMCl, i-Pr2EtN, rt, 2 h, 85%; (g)
TBAF, THF, rt, 4 h, 95%.
of catalytic amount of camphorsulfonic acid (CSA) gave
the acetonide 16 in 92% yield. Reduction of the ester group
of 16 with diisobutylaluminium hydride (DIBAL-H) in

Tetrahedron Letters
3
CH2Cl2 at −78 oC led to the corresponding primary alcohol,
which on oxidation with Dess-Martin periodinane in
CH2Cl2 and subsequent one carbon homologation with
PPh3=CH2 gave alkene 17 in 70% yield over three steps
(Scheme 3). The isopropylidene group was removed upon
treatment with AcOH-H2O at room temperature to afford
diol 18 in 87% yield.17 The allylic hydroxyl group in 18
was selectively masked as its PMB ether with p-
methoxybenzyl bromide (PMBBr) in presence of NaH in
91% yield with 5-7% bis-PMB protected product.18 The
homoallylic alcohol 19 was protected as its MOM ether 20
with methoxymethyl chloride (MOMCl) and N,N-
diisopropylethylamine (DIPEA) in CH2Cl2. Subsequent
silylether deprotection, using 1M solution of TBAF in THF
at room temperature, afforded the desired alcohol fragment
7 in 95% yield.
(21b), di-tert-butyldimethylsilyl (diTBS) (21c) failed to
produce the desired macrolactone with complete recovery
of the starting material. To our surprise, tri-MOM diene
ester (21d) was converted to the corresponding lactone in
70% yield with 20% starting material recovery in 12 h
(entry 5d). By increasing the duration of heating from 12 h
to 36 h, the starting material was completely consumed and
the 13-membered lactone obtained in 78% yield (entry 5e)
(Table 1). Subsequently, when diol diene ester 21f was
treated with Grubbs’ 2nd generation catalyst under high
dilution conditions, required 13-membered macrolactone
(entry 5f) was formed in 82% yield with complete E-
selectivity (J = 15.9 Hz) and there was no detectable
amount of Z-configured macrolactone. We imagined that it
could be due to forbearance of Grubbs’ catalyst with
activated nucleophile in the form of free allylic alcohol
group.
Having synthesized 6 and 7, we proceeded further with
their coupling and the ring closing metathesis reaction. The
coupling of acid 6 and alcohol 7 was initially attempted
under Yamaguchi conditions19 which afforded the ester in
low yield with the mixed anhydride as the byproduct.
Similarly, coupling in the presence of dicyclohexyl
carbodiimide (DCC)20 and 4-dimethylaminopyridine
(DMAP) gave an inseparable mixture of insoluble
dicyclohexyl urea along with the product. Notably, when
the coupling reaction carried out in presence of EDCI21 and
DMAP in CH2Cl2, the desired diene ester 21 was obtained
in 86% yield, which set the stage for crucial ring-closing
metathesis reaction (Scheme 4). Unfortunately, refluxing
the diene ester with Grubbs' 2nd generation catalyst in
CH2Cl2 under high dilution conditions failed to furnish the
desired product leading to complete recovery of the starting
material. We envisaged that steric congestion due to bulky
PMB-protecting group around the reacting centers might
act as a temporary constraint, preventing the participation
of Grubbs' catalyst to disallow the macrolactone formation.
Table 1 Protecting group dependent RCM for 13-membered lactone
Sl.
No.
PG
PG1
PG2
Duration
(in hour)
RCM
(Yield
%)
Starting
Material
Recover
y (%)
5a
5b
5c
5d
5e
5f
PMB
Bn
PMB
Bn
MOM
MOM
MOM
24
24
24
12
36
12
0
0
100
100
100
20
TBS
TBS
0
MOM MOM MOM
MOM MOM MOM
70
78
82
0
H
H
MOM
Keeping in mind for the future formal total synthesis of
palmerolide A, protecting groups in the fragments 6 and 7
were manipulated few steps before esterification, which
was achieved based on our previous approach. Compound
10 was treated with MOMCl in presence of DIPEA in
CH2Cl2 to give the MOM-ether 22 in 91% yield (Scheme
5). By employment the same reaction sequence of Scheme
2 involving TBAF-induced silyl deprotection, oxidation
with IBX and further oxidation under Pinnick conditions,
the MOM-ether 23 was then converted to the desired
carboxylic acid 6b in 89% yield over two steps.
Scheme 5 Reagents and conditions: (a) MOMCl, i-Pr2Et N, 2 h,
rt, 91%; (b) TBAF, THF, rt, 4 h, 93%; (c) (i) IBX, DMSO, THF,
rt, 3 h; (ii) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O,
rt, 2 h, 81% (over two steps).
Scheme 4 Reagents and conditions: (a) EDCI, DMAP, CH2Cl2, 0
oC to rt, 10 h, 86%; (b) Grubbs' 2nd generation catalyst,
CH2Cl2, reflux, no reaction.
At this juncture, we thought of investigating the above
reaction with a set of ring-closing metathesis precursors by
only changing the protecting group of allylic alcohol.
During the process, precursors bearing dibenzyl (diBn)
The allylic hydroxyl group in 18 was selectively masked as
its MOM ether 24 with MOMCl and DIPEA in CH2Cl2 at 0
oC. The hydroxyl group of 24 was then protected as its

4
Tetrahedron Letters
PMB ether 25 with PMBBr in presence of NaH in 91%
yield. Removal of silyl group was achieved with 1M
solution of TBAF in THF at room temperature in 94% yield
to complete the synthesis of alcohol fragment (Scheme 6).
was not so much apparent as reported for the most cases of
5- and 6-membered lactones, gratifyingly, the 13-
membered macrolactone 27 was transformed into the
corresponding lactol 28 with DIBAL-H in CH2Cl2 at −78
oC. Subsequent two carbon homologation afforded α,β-
unsaturated ester 29 as the only product in 77% yield over
two steps (Scheme 7). Finally, oxidation of the primary
alcohol group with Dess-Martin periodinane followed by
one carbon homologation with PPh3=CH2 in THF yielded
the required C1-C15 fragment 3 of palmerolide A.
In summary, we have studied the steric effect of protecting
groups on the outcome of the ring-closing metathesis
reaction for the construction of 13-membered
macrolactone. The two fragments bearing alcohol and
carboxylic acid functionality, respectively, were
synthesized from commercially available cheaper starting
materials in a concise manner following well-established
chemistry. Coupling of the two fragments followed by ring-
closing metathesis reaction led to the synthesis of C1-C15
fragment of palmerolide A. Application of the above
protocol towards the formal total synthesis of palmerolide
A and its derivatives with various ring size is underway and
will be reported in due course.
Scheme 6 Reagents and conditions : (a) MOMCl, i-Pr2EtN, 2 h, 0
o
oC, 85% (b) PMB-Br, NaH, THF, 0 C, 6 h, 91%; (c) TBAF,
THF, rt, 3 h, 94%.
The required di-MOM protected diene ester 26 was
synthesized following the earlier strategy described in
Scheme 4, which sets the stage for crucial RCM reaction.
The 13-membered macrolactone formation proceeded
smoothly with Grubbs 2nd generation catalyst under
refluxing conditions to afford 27 in 75% yield with
exclusive formation of E-isomer. Although the next step
Acknowledgments
BJ thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, India, for the financial assistance in the
form of fellowship. DKM thanks the Council of Scientific
and Industrial Research (CSIR), New Delhi, India, for a
research grant (INSA Young Scientist Award Scheme).
References
1. Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311-
335 and references therein.
2. (a) Diyabalanage, T.; Amsler, C. D.; McClintock, J. B.;
Baker, B. J. J. Am. Chem. Soc. 2006, 128, 5630-5631; (b)
Leber, M. D.; Baker, B. J. Tetrahedron Lett. 2007, 48,
8009-8010.
3. Xie, X. –S.; Padron-Perez , D.; Liao, X.; Wang, J.; Roth,
M. G.; De Brabander, J. K. J. Biol. Chem. 2004, 279,
19755-19763.
4. (a) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J.
Am. Chem. Soc. 2007, 129, 6386-6387; (b) Nicolaou, K.
C.; Guduru, R.; Sun, Y. P.; Banerji, B.; Chen, D. Y. K.
Angew. Chem. Int. Ed. 2007, 46, 5896-5900; (c) Nicolaou,
K. C.; Sun, Y. P.; Guduru, R.; Chen, D. Y. K. J. Am. Chem.
Soc. 2008, 130, 3633-3644; (d) Nicolaou, K. C.; Leung, Y.
C. G.; Dethe, D. H.; Guduru, R.; Sun, Y. P.; Lim, C. S.;
Chen, D. Y. K. J. Am. Chem. Soc. 2008, 130, 10019-
10023; (e) Penner, M.; Rauniyar, V.; Kasper, L. T.; Hall,
D. G. J. Am. Chem. Soc. 2009, 131, 14216-14217.
5. (a) Prasad, K. R.; A. B. Pawar, Org. Lett. 2011, 13, 4252–
4255; (b) Pawar, A. B.; Prasad, K. R. Chem. Eur. J. 2012,
18, 15202-15206; (c) Pujari, S. A.; Gowrisankar, P.;
Kaliappan, K. P. Chem. Asia. J. 2011, 6, 3137-3151; (d)
Gowrisankar, P.; Pujari, S. A.; Kaliappan, K. P. Chem. Eur.
Scheme 7 Reagents and Conditions: (a) EDCI, DMAP, CH2Cl2, 0
oC to rt.,10 h, 84%; (b) Grubbs' 2nd generation catalyst, CH2Cl2,
o
reflux, 32 h, 75%; (c) DIBAL-H, CH2Cl2, −78 C, 15 min; (d)
Ph3P=CHCO2Et, benzene, reflux, 2 h, 77% over two steps; (e) (i)
DMP, CH2Cl2, NaHCO3, 0 oC to rt, 2 h; (ii) (PPh3-CH3)+Br-,
nBuLi, THF, −78 oC to 0 oC, 3 h, 78% over two steps.

Tetrahedron Letters
J. 2010, 16, 5858-5862; (e) Jägel, J.; Maier, M. E.
5
R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450; (j)
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-
388.
Synthesis 2009, 2881-2892.
6. (a) Lisboa, P. M.; Jeong-Im, H. J.; Jones, D. M.; Dudley,
G. B. Synlett 2012, 1493-1496; (b) Jones, D. M.; Dudley,
G. B. Synlett 2010, 223-226; (c) Leber, M. D.; Baker, B. J.
Tetrahedron 2010, 66, 1557-1562; (d) Prasad, K. R.;
Pawar, A. B. Synlett 2010, 1093-1095; (e) Kaliappan, K.
P.; Gowrisankar, P. Synlett 2007, 1537-1540; (f) Cantagrel,
G.; Meyer, C.; Cossy, J. Synlett 2007, 2983-2986; (g)
Chandrasekhar, S.; Vijeender, K.; Chandrasekhar, G.;
Reddy, C. R. Tetrahedron: Asymmetry 2007, 18, 2473-
2478; (h) Jägel, J.; Scmauder, A.; Binanzer, M.; Maier, M.
E. Tetrahedron 2007, 63, 13006-13017.
7. (a) Mohapatra, D. K.; Pattanayak, M. R.; Das, P. P.;
Pradhan, T. R.; Yadav, J. S. Org. Biomol. Chem. 2011, 9,
5630-5632; (b) Mohapatra, D. K.; Reddy, D. P.; Dash, U.;
Yadav, J. S. Tetrahedron Lett. 2011, 52, 151-154; (c)
Mohapatra, D. K.; Sahoo, G.; Ramesh, D. K.; Rao, J. S.;
Sastry, G. N. Tetrahedron Lett. 2009, 50, 56365639; (d)
Mohapatra, D. K.; Dash, U.; Naidu, P. R.; Yadav, J. S.
Tetrahedron Lett. 2009, 50, 2129-2131; (e) Mohapatra, D.
K.; Ramesh, D. K.; Giardello, M. A.; Chorghade, M. S.;
Gurjar, M. K.; Grubbs, R. H. Tetrahedron Lett. 2007, 48,
2621-2625.
10. Ruiz, J. M.; Afonso, M. M.; Palenzuela, J. A. Molecules
2007, 12, 194-204.
11. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974-5976.
12. Reddy, L. V. R.; Sagar, R.; Shaw, A. K. Tetrahedron Lett.
2006, 47, 1753-1756.
13. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
8019-8022.
14. (a) Balkrishna, S. B.; Childers, Jr., W. E.; Pinnick, H. W.
Tetrahderon 1981, 37, 2091-2096; (b) Dalcanale, E.;
Montanari, F. J. Org. Chem. 1986, 51, 567-569.
15. Nacro, K.; Baltas, M.; Gorrichon, L. Tetrahedron 1999, 55,
14013-14030.
16. Kolb, H. C.; VanNiewenzie, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483-2547.
17. Yang, J.-H.; Liu, J.; Hsung, R. P. Org. Lett. 2008, 10,
2525-2528.
18. Seepersaud, M.; Al-bed, Y. Tetrahedron Lett. 2000, 41,
7801-7803.
19. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993.
20. (a) Williams, A.; Ibrahim, I. T. Chem. Rev. 1981, 81, 589–
636; (b) Mikolajczyk, M.; Kielbasin´ ski, P. Tetrahedron
1981, 37, 233–284; (c) Neises, B.; Steglich, W. Angew.
Chem. Int. Ed. Engl. 1978, 17, 522–524.
8. (a) Negishi, E.-I. Bull. Chem. Soc. Jpn. 2007, 80, 233-257;
(b) Link, J. T. Org. React. 2002, 60, 157-534; (c) Bhatt, U.;
Chirstmann, M.; Quitschalle, M.; Cluas, E.; Kalesse, M. J.
Org. Chem. 2001, 66, 1885-1893.
9. (a) Gradillas, A.; Pérez-Castells, J. Angew. Chem. Int. Ed.
2006, 45, 6086-6101; (b) Deiters, A.; Martin, S. F. Chem.
Rev. 2004, 104, 2199-2238; (c) Grubbs, R. H. Tetrahedron
2004, 60, 7117-7140; (d) Prunet, J. Angew. Chem. Int. Ed.
2003, 42, 2826-2830; (e) Love, J. A. In Handbook of
Metathesis; Grubbs, R. H. Ed.; Wiley-VCH: Weinheim,
Germany, 2003; pp 296-322; (f) Trnka, T. M.; Grubbs, R.
H. Acc. Chem. Res. 2001, 34, 18-29; (g) Fürstner, A.
Angew. Chem. Int. Ed. 2000, 39, 3012-3043; (h) Maier, M.
E. Angew. Chem. Int. Ed. 2000, 39, 2073-2077; (i) Grubbs,
21. (a) Nozaki S.; Muramatsu, I. Bull. Chem. Soc. Jpn. 1982,
55, 2165-2168; (b) Sheehan, J. C.; Preston, J.;
Cruickshank, P. A. J. Am. Chem. Soc. 1965, 87, 2492-
2493.