Synthesis and biological evaluation of 12-, 13-, 14-membered macrolides and open chain 2,6-trans-disubstituted dihydropyran analogues for aspergillides

Article abstract of DOI:10.1016/j.tetlet.2018.05.056

Stereoselective synthesis of twenty (three 12-, five 13- and twelve 14-membered) macrolides and seventeen functionalized 2,6-trans-disubstituted dihydropyran derivatives have been achieved. The key reactions include an Achmatowicz rearrangement, Ferrier-type alkynylation, Yamaguchi macrolactonization and Lindlar's hydrogenation. Biological screening of the synthesised compounds showed moderate activity against human cancer cell-lines.

Full text of DOI:10.1016/j.tetlet.2018.05.056

Accepted Manuscript
Synthesis and biological evaluation of 12-, 13-, 14-membered macrolides and
open chain 2,6-trans-disubstituted dihydropyran analogues for aspergillides
Srihari Pabbaraja, Naresh Gantasala, Sridhar Ydhyam, Hari Krishna Namballa,
Subhashini Gundeboina, Mallikharjuna R. Lambu, Sanjeev Meena, Dipak Datta
PII:
S0040-4039(18)30669-5
https://doi.org/10.1016/j.tetlet.2018.05.056
TETL 50003
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 March 2018
18 May 2018
19 May 2018
Please cite this article as: Pabbaraja, S., Gantasala, N., Ydhyam, S., Krishna Namballa, H., Gundeboina, S., Lambu,
M.R., Meena, S., Datta, D., Synthesis and biological evaluation of 12-, 13-, 14-membered macrolides and open
chain 2,6-trans-disubstituted dihydropyran analogues for aspergillides, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.05.056
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Graphical Abstract
Synthesis and biological evaluation of 12-, 13-, 14-
membered macrolides and open chain 2,6-trans-
disubstituted dihydropyran analogues for aspergillides
Leave this area blank for abstract info.
Srihari Pabbaraja, Naresh Gantasala, Sridhar Ydhyam, Hari Krishna Namballa, Subhashini Gundeboina, Mallikharjuna R
Lambu, Sanjeev Meena, Dipak Datta

Bioorganic & Medicinal Chemistry Letters
jo u r n a l h o m e p a g e : w w w . e ls e v i e r . c o m
Synthesis and biological evaluation of 12-, 13-, 14-membered macrolides and
open chain 2,6-trans-disubstituted dihydropyran analogues for aspergillides
Srihari Pabbaraja,* a,b Naresh Gantasala,a,b Sridhar Ydhyam,a Hari Krishna Namballa,a Subhashini
Gundeboina,a Mallikharjuna R Lambu,a Sanjeev Meena,c Dipak Dattab,c
a Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India,
b Academy of Scientific and innovative Research (AcSIR), Anusandhan Bhawan, 2-Rafi Marg, NewDelhi 110001, India.
c Biochemistry Division, Council of Scientific & Industrial Research (CSIR), Central Drug Research Institute (CDRI), Lucknow, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Stereoselective synthesis of twenty (three 12-, five 13- and twelve 14-membered)
macrolides and seventeen functionalized 2,6-trans-disubstituted dihydropyran derivatives
have been achieved. The key reactions include an Achmatowicz rearrangement, Ferrier-
type alkynylation, Yamaguchi macrolactonization and Lindlar’s hydrogenation. Biological
screening of the synthesised compounds showed moderate activity against human cancer
cell-lines and no significant activity were observed towards the antifungal, antibacterial
and anti-inflammatory cell-lines.
Keywords:
Aspergillides
Macrolides
Cancer
2009 Elsevier Ltd. All rights reserved.
Ferrier
Achmatowicz
Many a times, the chiral centers play a crucial role in
biological properties.7 Despite one isomer is biologically potent,
Marine natural products have attracted extensive interest from
chemists and pharmacologists due to their structural architecture
and potent biological properties providing lead compounds for
the discovery of new drugs.1 The use of isolated MNPs as
scaffold(s) for modification can be a reasonable approach for
drug discovery and development. Despite many limitations
associated with MNPs, the total synthesis, semisynthetic
modification, SAR-based modification, occasionally even a
single atom alteration, may lead to the discovery of a novel drug.2
there is always a chance that the other isomer/diastereomer may
show improved potency or cause side effects. This feature has
necessitated the synthetic community for stereoselective
synthesis and also their other isomers towards exploring the
biological properties. We have recently accomplished the total
synthesis4h, 4n, 5a and analogue synthesis of aspergillide C and in
continuation, as a project mode, we became interested in the
synthesis of the several other analogues of aspergillides to
evaluate their biological activity.
Aspergillides A, B and C (Figure 1) (three, novel, bicyclic,
14-membered macrolides with 2,6-cis or trans-fused di- or
tetrahydropyan rings) are novel secondary metabolites, isolated
from the marine-derived fungus Aspergillus ostianus strain
01F313 in bromine-modified 1/2PD culture medium.3
Interestingly, these compounds show cytotoxicity against mouse
lymphocytic leukemia cells (L1210) with LD50 values of 2.1,
71.0, and 2.0 μg/mL respectively. The unusual structural
architecture and impressive biological properties have gained
significant attention from synthetic chemists with respect to their
total synthesis4,5 and have inspired medicinal chemists to
synthesize diverse analogues in search for better potential
molecule(s).6
Figure 1: Structures of aspergillides A–C.
We describe herein the synthesis of 12-, 13-, and 14-
membered macrolides along with the 2,6-trans disubstituted
functionalized pyran derivatives for aspergillides (Figure 2). All
the synthesized analogues were screened for anticancer,
antifungal, antibacterial and anti-inflammatory activities and the
results pertaining to the screening are also discussed.
_________
*Corresponding author. Tel.:+91-402-719-1815; fax: +91-402-716-0512; e-mail: srihari@iict.res.in

Figure 2: Structures of proposed aspergillide-based 12-,13-and 14-membered macrolides and 2,6-trans-disubstituted pyran derivatives.
We envisaged that the target macrolides related to (–)-
aspergillides could be prepared from the corresponding seco
acids 38, 39 and 40 by lactonization, removal of the protective
group (Pg / TBS), and alkylation of hydroxyl group at C-7. All
the three seco acids 38, 39 and 40 could be synthesized from a
common intermediate 41 through sequential reactions, that is,
Ferrier type alkynylation, a chemoselective conjugate reduction
of the α,β-unsaturated ketone to a allyl alcohol and protection of
hydroxyl group (Pg). Compound 41 can be obtained from
furfural through addition of lithium enolate of ethyl acetate and
Achmatowicz oxidative rearrangement.8 Alkyne fragment 43 can
be obtained from (S)-propylene oxide and TMS-acetylene
through an epoxide ring opening reaction and hydroxyl
protection. Fragment 44 could be synthesized by the
trimethylsilylation (on terminal alkyne) and hydroxyl protection
(O-Benzoylation) of 4-pentyn-1-ol and fragment 45 can be
accessed from homopropargyl alcohol through an alkyne Zipper
isomerisation reaction, which in turn can be obtained from
commercially available (S)-propylene oxide and 1-butyne (see
Figure 3) by a ring opening reaction.
Figure 3: Retrosynthesis
heteromers, i.e., pyrenone lactal 50 and an enantio-pure furfuryl
alcohol 51 (Scheme 1). The required alkyne fragment 43 was
obtained by the (S)-propylene oxide which was exposed to the
lithium acetylide of TMS-acetylene (52) in the presence of
hexamethylphosphoramide (HMPA) to give homopropargyl
alcohol 53 followed by benzoylation of hydroxyl group.
Compound 44 could be accessed in two steps from commercially
available 4-pentyn-1-ol masked by treating it with TMSCl in the
presence of n-BuLi and further protection of alcohol with
benzoyl chloride (see Scheme 2).
Scheme 1: Synthesis of pyranone lactal 50.
Our synthesis began with an addition reaction of enolate 48
generated from ethyl acetate, to furfuraldehyde (42) to provide
the racemic secondary furfuryl alcohol 49. Racemate 49 was
kinetically resolved under Sharpless conditions9 into two

Alkyne fragment 45 was synthesized in four steps with an overall
yield of 74.8%. Thus, (S)-propylene oxide was exposed to the
lithium acetylide of 1-butyne (47) in the presence of HMPA to
give homopropargyl alcohol 56. The internal alkyne of 56 was
isomerized to terminal alkyne through a Zipper isomerisation10
by using Li-tBuOK in the presence of 1,3-diaminopropane. The
resulting alkynol was appropriately masked by treating it with
TMSCl and Ac2O to afford 45 (see Scheme 2). This sequence
required single column purification in the final step.
Towards proceeding further, the anomeric hydroxyl
functionality in adduct 50 was activated to the corresponding
acetate 41 and subjected to Ferrier-type alkynylation11,4n with
alkyne 43 to get the setereoslective single diastereomer 58 with
good yield. Luche’s reduction12 of 58 afforded the -selective
alcohol compound 59 as a major diastereomer which was easily
separable through column chromatography. Silyl protection of 59
provided silyl ether 60 which underwent basic hydrolysis to yield
the corresponding seco acid 38. Yamaguchi lactonization13 of 38
gave the protected 12-membered macrolide 61 with good yield.
Desilylation with TBAF in THF gave 4, which upon oxidation
under Dess-Martin Periodinane14 condition furnished the
macrolide 5. Conjugate reduction of -keto ester 5 with
LiAlH4/CuI in HMPA/THF4h afforded the 62 with 90% yield.
The carbonyl functionality was reduced with S-CBS catalyst to
afford the secondary alcohol 6 in good yield (see Scheme 3)
along with 6a.
Scheme 2: Synthesis of alkyne compounds 43, 44 and 45.
Scheme 3: Synthesis of 12-membered macrolides

Scheme 4: Synthesis of 13-membered macrolides
Based on our proposal for the synthesis of 13-membered
macrolides, we treated the pyrenone acetate 41 with alkyne 44
under Ferrier rearrangement11,4n conditions in the presence of
SnCl4 to afford the single diastereomer 62 with good yield.
Simultaneously, enone reduction following Luche’s protocol(62
to 63),12 silyl protection (63 to 64) and basic hydrolysis of ester
and benzoate 64 afforded the corresponding seco acid 39.
Yamaguchi lactonization13 of 39 provided protected 13-
membered macrolide 65. Desilylation of 65 using TBAF gave 7.
Independent methylation and benzylation of macrolide 7 afforded
the corresponding methyl and benzyl ethers 8 and 9 respectively
in good yields. Partial hydrogenation of 7 and 9 using Lindlar’s
catalyst15 provided Z-selective 13-membered macrolides 10 and
11 (see scheme 4) respectively. The synthesized 12-,13-
membered macrolides were investigated for cancer properties by
screening them on human cancer cell lines and were found to
show minimum inhibitions(see Table 1).
Scheme 5: Synthesis of 14-membered macrolides
With not much impressive activity from 12- and 13-membered
ring analogues, we further focused to synthesize 14-membered
macrolides using suitable coupling alkyne partner following
similar strategy. Thus, pyrenone acetate 41 was subjected to

Ferrier-type alkynylation with silylated alkyne 45 in the presence
of SnCl4 to give alkyne 66 in 85% yield as a single diastereomer.
Conjugated enone 66 was reduced under Luche’s condition to
afford -face selective hydroxyl compound 67 as a major
diastereomer along with minor diastereomer 67a (dr: 9:1). Silyl
protection of 67 with TBSOTf in the presence of lutidine
afforded 68, which was subjected to basic hydrolysis to furnish
seco acid 40 in excellent yield. Compound 40 was subjected to
Yamaguchi lactonization conditions to give the compound 69
which upon desilyation with TBAF furnished analogue macrolide
12. To make further analogues, we opted to mask the hydroxy
group with different moieties. Towards this, benzylation,
acetylation and propargylation of compound 12 under basic
conditions afforded the corresponding macrolides 13, 14 and 15.
Hydrogenation of compounds 13-15 under Lindlar’s condition
furnished the Z-selective macrolides 16-19 respectively (see
scheme 5).
Despite the synthesized cyclic analogues did not show
promising results, interestingly, the open chain compounds 36
and 37 showed better cancer properties than the corresponding
macrolide molecules. Based on these results, we now focused our
attention to the synthesis of trans-di-substituted dihydropyran
derivatives.5a Alkynes (75, 76 & 77) were synthesised following
Mitsunobu conditions17 by treatment of alcohol 74 with N-
hydroxy phthalimide, phthalimide and phenol (Scheme 7).
In order to synthesize the trans-selective 14-membered
macrolides, compound 68 was stereoselectively hydrogenated
using Trost’s protocol,16 wherein alkyne was trans hydrosilylated
by treatment with triethoxysilane in the presence of
[Cp*Ru(MeCN)3]PF6 followed by protodesilylation with
HF/pyridine to yield trans olefin 70 exclusively. Basic hydrolysis
of 70 afforded the seco acid 71, which was subjected to
lactonization under Yamaguchi conditions to afford the
compound 72 with the yield of 70%. Desilylation by using TBAF
afforded 20 with 93% yield. Benzylation, methylation and
propargylation of hydroxyl group under NaH conditions afforded
the corresponding macrolides 21-23, with excellent yields (see
scheme 6). After the synthesis of 14-membered macrolides (12-
23), all the macrolides along with the two key intermediates (36
and 37) were submitted for the biological screening.
Scheme 7: Synthesis Alkyne derivatives
Treatment of Tri-O-acetyl-D-galactal (78) with alkyne 75
under Ferrier rearrangement conditions in the presence of SnCl4
afforded the single diastereomer 24 with good yield. Similarly,
compounds 25 and 26 were synthesised by using alkynes 76 and
77 under Ferrier rearrangement conditions with good yields.
Deacetylation of compounds 24, 25 and 26 using
NaOMe/MeOH18 afforded corresponding dihydroxy compounds
27, 28 and 29 respectively. Partial reduction of alkyne moiety in
the compounds 24-29 using Lindlar’s catalyst provided the
respective cis-olefinated compounds 30-35 with good yield and
excellent selectivities (Scheme 8).
The tri-O-acetyl-D-galactal was also treated with 79 under
Ferrier rearrangement conditions in the presence of SnCl4 to
afford the single diastereomer 80 with good yield. Compound 80
was stereoselectively reduced using Trost’s protocol to yield
trans olefin 81 in 84% yield. Deacetylation using acetyl chloride
in methanol, followed by desilylation using TBSCl afforded 82 in
90% yield. Selective primary desilylation of 82 provided alcohol
36 which was converted to cyanide 37 5b through triflate (Scheme
9).
Scheme 6: Synthesis of trans-selective 14-membered macrolides

Scheme 8: Synthesis of 2,6-tran-di substituted pyran derivatives
All the synthesised compound have been tested against the
available five human cancer cell lines like HeLa, MCF-7, DLD-
1, A549 and SKOV3 by using SRB (sulforhodamine B) assay
(Table 1).19 During initial screening, the samples showing equal
to or more than 80% growth inhibition of cancer cells at 10 µM
were considered as ‘Hits’ and further screened at 2-fold serial
dilutions against human cancer cell lines to calculate their half
maximal inhibitory concentration (IC50) value.
Among the synthesised compounds one of the open chain
analogue compound 365b showed the potential activity with a
maximum 94.38%, and 67.39% growth inhibition in DLD-1, and
MCF-7. Based of these screening result, further secondary
screening (five dose range from 0.625 µM to 10 µM conc.) were
performed to determine the IC50 value of the most active
compound. The estimated IC50 values of compound 36 as 6.62
(SW48), 6.28 (MDAMB 468), 7.17 (BT-549), 8.08 (LOVO),
7.53 (DLD-1) and 7.92 (SKBR3) were obtained (Table 2).
Scheme 9: Synthesis of open chain aspergillide derivatives
Biology:
Table 1: The % Inhibition of compounds in five human cancer cell line as follow.
Serial No.
Compounds
HeLa
-15.19
-30.22
-18.27
-11.57
-25.67
2.37
MCF-7
-1.72
2.47
DLD-1
-2.37
14.07
3.2
A549
-5.5
SKOV3
6.05
1
2
3
4
5
6
4
5
6
7
8
9
-3.39
-5.35
-2.13
-6.43
1.1
-4.16
5.65
-0.92
-3.12
-8.51
9.62
3.84
0.49
5.41
-14.98
1.6
7.25

7
-32.55
5.67
-6.71
-3
-1.06
0.12
-6.14
-3
-8.43
-10.83
4.84
10
8
11
9
-27.49
2.87
-21.94
-14.91
-12.03
-11.36
-9.34
21.32
-15.03
22.92
23.26
28.29
24.56
20.09
7.3
-7.16
3.25
-0.94
11.81
-1.01
-1.44
0.91
12
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
3.78
13
-19.92
49.1
5.51
13.3
14
19.31
-2.75
-1.16
-1.67
0.69
3.17
15
-15.64
19.85
-21.81
24.74
18.12
27.74
3.03
9.11
16
-29.07
-2.58
-5.14
-27.74
6.99
-13.31
3.8
17
18
-19.16
-44.84
-20.2
-10.6
-60.78
7
19
-1.67
0.69
20
21
-1.67
-2.36
15.25
19.62
-6.02
-6.15
-5
-2.57
-28.92
1.84
22
2.93
23
-6.44
6.26
24
1.23
2.5
19.62
15.71
0.37
25
7.22
0.57
1.68
26
-0.54
7.9
-6.19
-0.7
0.72
27
10.14
6.96
6.64
28
4.51
13.07
3.3
-9.31
14.13
12.14
23
9.3
29
11.67
12.92
13.45
-4.97
13.75
-7.9
-8.07
1.48
15.13
17.82
12.87
4.86
30
12.8
31
12.34
-15.77
-10.26
-8.9
-6.75
-12.54
-0.66
3.43
32
15.17
5.63
33
8.86
34
9.75
10.98
-18.54
23.24
60.15
35
31.65
22
67.49
42.83
76.71
94.38
80.15
75.32
59.89
40.32
73.58
36
37
84.33
Doxorubicin
Table 2: Further secondary screening (IC50 value calculation from 5 serial dilutions 0.625µM to 10µM conc.) for compound 36.
IC50 value with SE in µM conc.
Compound
36
MCF-7
8.12 ± 0.29
2.64 ± .81
SK-BR-3
7.83 ± 0.30
0.98 ± 0.67
BT-549
MDA MB 468
5.89 ± 0.43
0.7 ± 0.38
DLD-1
7.4 ± 0.16
2.11 ± 0.93
LOVO
SW 48
7.04 ± 0.14
1.25 ± 0.79
7.38 ± 0.30
1.12 ± 0.46
6.3 ± 0.38
1.13 ± 0.63
Doxorubicin
In addition, all the key compounds were also evaluated for anti-
fungal, anti-bacterial, and inhibition of LPS induced TNF-
production. However, no significant activity was observed at 10
g/mL concentration.
Investigations are currently underway to identify better potent
molecule which is suitable for in-vivo testing in animal model.
Acknowledgements
PS acknowledge MoES and CSIR, New Delhi for funding the project
under budget head GAP-390 (MoES-2/DS/6/2007 PC-IV dated 15th
October, 2012). YS, NHK and GS acknowledge CSIR, GN
acknowledges UGC, LMR acknowledges SERB (PDF/2016/003599)
New Delhi for financial assistance.
Conclusions
The synthesis of thirty seven compounds including the cyclic
(three 12-, five 13- and twelve 14-membered) and seventeen
functionalized 2,6-trans-disubstituted dihydropyran derivatives
has been accomplished. The compound 36 showed potential
anticancer activity in DLD-1 and MCF-7 human cancer cell lines.
% Inhibition and further IC50 value calculation among different
human cancer cell lines indicate that the compound 36 showed
most effective against panel of breast and colon cancer cell lines.
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Supplementary Material
Selected spectra and experimental details are available as
Supplementary material.

Graphical Abstract
Synthesis and biological evaluation of 12-, 13-, 14-
membered macrolides and open chain 2,6-trans-
disubstituted dihydropyran analogues for aspergillides
Leave this area blank for abstract info.
Srihari Pabbaraja, Naresh Gantasala, Sridhar Ydhyam, Hari Krishna Namballa, Subhashini Gundeboina, Mallikharjuna R
Lambu, Sanjeev Meena, Dipak Datta


Synthesis of several analogue compounds for
aspergillides was accomplished.


Twenty macrolides have been synthesized.
Seventeen open-chain 2,6-trans-disubstituted
dihydropyran derivatives synthesized.
One compound was found to display anticancer
properties.
