Stereoselective total synthesis and cytotoxic evaluation of C-9 epimers of herbarumin-II and its C-2 epimer

Article abstract of DOI:10.1016/j.tetlet.2015.06.011

The total synthesis and cytotoxic evaluation of C-9 epimers of herbarumin-II and its C-2 epimer are described for the first time. The key transformations of the synthesis include Wittig olefination, MacMillan α-hydroxylation, Pinnick oxidation, Yamaguchi esterification, and intramolecular ring closing metathesis.

Full text of DOI:10.1016/j.tetlet.2015.06.011

Tetrahedron Letters 56 (2015) 4631–4633
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective total synthesis and cytotoxic evaluation
of C-9 epimers of herbarumin-II and its C-2 epimer q
Lingaiah Maram a, C. Ganesh Kumar b, Y. Poornachandra b, Biswanath Das a,
⇑
a Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis and cytotoxic evaluation of C-9 epimers of herbarumin-II and its C-2 epimer are
described for the first time. The key transformations of the synthesis include Wittig olefination,
Received 13 May 2015
Revised 2 June 2015
Accepted 3 June 2015
Available online 12 June 2015
MacMillan
a
-hydroxylation, Pinnick oxidation, Yamaguchi esterification, and intramolecular ring closing
metathesis.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Nonenolides
Cytotoxic activity
MacMillan a-hydroxylation
Pinnick oxidation
Ring closing metathesis
Nonenolides (10-membered macrolides), an important class of
natural products with interesting structural features, have been
found to exhibit important biological properties such as anticancer,
antifungal, antibacterial and antiviral activities.1 They have
attracted much attention to chemists and biologists in recent
years.2 Herbarumin-II (1), a phytotoxic nonenolide was isolated
in 2000 from the fungus Phoma herbarum (Sphaeropsidaceae).3
The compound contains three hydroxyl groups (all are of b-config-
uration) at C-2, C-7, and C-8 positions, a trans-substituted double
bond and an appended a n-propyl unit at C-9 position. The lactone
showed a high phytotoxic effect on seedling growth. In 2007,
herbarumin-II (1) and its C-2 epimer (2) were isolated along with
a hexaketide from the leaf lesions of Pendulous Yucca (Yucca
recurvifolia).4 The nonenolide (2) contains the hydroxyl group at
respectively (Scheme 1). The required dienes 3 and 3a can be
obtained from the alcohol fragment 4 and the acid fragments 5
(for 3) and 5a (for 3a). The alcohol 4 can in turn, be prepared from
D (À) ribose and acids 5 and 5a from hex-5-ene-1-ol.
The present synthesis was initiated by protecting D (À) ribose
on treatment with acetone in the presence of concentrated H2SO4
(cat.) to give the lactol 67 which by reacting with Ph3PCH3Br and
KtOBu, gave the diol 7 (Scheme 2).8 Selective TBS protection of
the primary alcohol in diol 7 with TBS-Cl produced the TBS ether
8. The free secondary hydroxyl group in 8 was mesylated with
MsCl in the presence of N-methyl imidazole followed by TBS
deprotection with TBAF and subsequent DBU treatment to afford
the epoxide 9.9 The epoxide ring of 9 was then opened with Mg
and EtBr using CuI to afford the desired alcohol 4.
C-2 position with
a
-configuration.
Synthesis of the required acid fragments 5 and 5a was started
from hex-5-en-1-ol. The hex-5-en-1-ol was oxidized with
SO3Py10 in CH2Cl2/DMSO (3:1) to afford the corresponding alde-
The synthesis of both the compounds 1 and 2 has been accom-
plished.5 However, the present work is the first report of the syn-
thesis of their C-9 epimers (1a and 2a) (Fig. 1). Compounds 1a
and 2a bear a n-propyl unit with b-configuration at C-9 position.
In continuation of our work6 on the construction of naturally
occurring bioactive molecules we have realized that compounds
hyde. Subsequently, MacMillan
a
-aminoxylation11 of the gener-
-proline,
ated aldehyde with nitrosobenzene in the presence of
D
followed by treatment with NaBH4 in MeOH gave the crude ami-
nooxy alcohol. Treatment of aminooxy alcohol with (30 mol %)
CuSO45H2O afforded the chiral diol 10 in 70% overall yield (ee
97%). The primary hydroxyl group of 10 was protected as TBS ether
11 by treatment with TBS-Cl and imidazole and the free hydroxyl
group of 11 was protected as MOM ether 12 by reaction with
MOM-Cl and DIPEA. Compound 12 was then treated with TBAF
to furnish the corresponding primary alcohol 13. This was
1a and 2a can be synthesized from the dienes
3 and 3a,
q
Part 86 in the series, ‘Synthetic studies on natural products’.
⇑
Corresponding author. Tel.: +91 40 2719 1625; fax: +91 40 27193198.
E-mail address: biswanathdas@yahoo.com (B. Das).
http://dx.doi.org/10.1016/j.tetlet.2015.06.011
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

4632
L. Maram et al. / Tetrahedron Letters 56 (2015) 4631–4633
6
9
OH
4
O
HO
HO
b
7
8
5
a
HO
3
OH
HO
HO
D (-) ribose
O
1
O
OH
O
2
HO
12
OH
O
O
O
O
O
10
11
7
6
C-2 epimer of herbarumin-II (2)
Herbarumin-II (1)
O
O
OH
d
c
TBSO
HO
HO
HO
O
O
O
OH
O
HO
OH
O
O
O
8
9
e
OH
C-9 epimer of 1 (1a)
C-9 epimer of 2 (2a)
Figure 1. Structures of nonenolides.
O
O
converted into acid 5 by a two-step sequence; oxidation of 13 with
DMP12 in CH2Cl2 gave the corresponding aldehyde and oxidation
of the aldehyde under Pinnick conditions13 (NaClO2, NaH2PO4,
t-BuOH/H2O/2-methylbut-2-ene) gave the acid 5 in 90% yield over
the two steps (Scheme 3). The required enantiomeric acid fragment
5a was synthesized starting from 5-hexene-1-ol by using
4
Scheme 2. Reagents and conditions: (a) acetone, con. H2SO4 (cat.), 6 h, rt, 96%; (b)
Ph3PCH3Br, NaHMDS, THF, N2, 0 °C–rt, 10 h, 86%; (c) TBS-Cl, imidazole, THF, 0 °C–rt,
2 h, 98%; (d) (i) MsCl, Et3N, N-methyl imidazole, 12 h, (ii) TBAF, THF, 0 °C–rt and
then (iii) DBU, CH2Cl2, 40 °C, 28 h, 96% (for three steps); (e) EtMgBr, CuI, À50 °C to
rt, 94%.
MacMillan
a L-proline as the catalyst, by
-aminoxylation11 with
following the same sequence of the reactions as followed in the
synthesis of the acid fragment (5).
TBSO
HO
HO
HO
HO
c
a
b
After successful achievement of required alcohol 4 and acid
fragments 5 and 5a, the alcohol fragment 4 was coupled with acid
fragments 5 and 5a individually under Yamaguchi esterification
protocol14 to afford the dienes 3 and 3a, respectively (Scheme 4).
The obtained dienes 3 and 3a were successfully utilized to make
10-membered ring systems (macrolides) by treatment with
Grubbs’ second generation catalyst (A)15 to yield the nonenolides
14 and 14a. Finally, deprotection of the acetonide group in 14
and 14a was achieved with 4 N HCl in CH3CN to afford the target
C-9 epimers (1a and 2a) of 1 and 2, respectively.
11
10
TBSO
HO
HO
O
d
e
MOMO
MOMO
MOMO
12
13
5
Scheme 3. Reagents and conditions:(a) (i) SO3Py, CH2Cl2/DMSO (3:1), 0 °C, 1 h and
then (ii) -proline, PhNO, DMSO, 0 °C–rt, 1 h, NaBH4, MeOH, then (30 mol %)
CuSO45H2O (70% for three steps); (b) TBS-Cl, imidazole, THF, 0 °C–rt, 1 h, 96%; (c)
MOM-Cl, CH2Cl2, DIPEA, 0 °C–rt, 3 h, 98%; (d) TBAF, THF, 0 °C–rt, 2 h, 94%; (e) (i)
DMP, CH2Cl2, 0 °C, 1 h then NaClO2, NaH2PO4, t-BuOH/H2O/2-methylbut-2-ene, 0 °C,
2 h (90% for two steps).
The spectral (1H and 13C NMR and MS) properties of the synthe-
sized compounds 1a and 2a are in good agreement with their
structures.16 The structures of the compounds 1a and 2a were also
supported by their 2D-NMR spectra. The NOESY data clearly
showed the correlation between H-8 (d 4.58 (1H, m) for 1a and d
4.40 (1H, m) for 2a) and H-9 (d 4.67 (1H, dd, J = 9.8, 4.5 Hz) for
1a and d 4.73 (1H, m) for 2a) of these two compounds.
D
Cytotoxic activity
The two compounds, C-9 epimers (1a and 2a) were examined
for in vitro cytotoxicity against a panel of four human cancer cell
lines: Neuro-2a (Mouse neuro blastoma cell line), HeLa (Human
cervical cancer cell line), DU145 (Human prostate cancer cell line),
and SKOV3 (Human ovarian cancer cell line). Doxorubicin was
used as the positive control. MTT assay (according to the method
of Mosmann17) was applied to assess the cytotoxic activity of the
N
N
Cl
Ru
Cl
(Cy)3P
Ph
Grubb's catalyst 2nd generation (A)
two compounds. IC50 values (in
lM) are indicated as means SD
HO
HO
O
D (-) ribose
O
OH
OH
O
O
1a : 2R
4
O
O
+
O
OMOM
HO
HO
Hex-5-ene-1-ol
O
HO
O
OMOM
OH
O
3 :
2R
O
3a : 2S
5 : 2R
2a : 2S
5a :
2S
Scheme 1. Retrosynthesis of C-9 epimers 1a and 2a.

L. Maram et al. / Tetrahedron Letters 56 (2015) 4631–4633
4633
O
O
O
a (for 3)
3a
MOMO
HO
O
b (for
)
OH
O
OMOM
)
O
O
3
:
5
)
2R (from
2S (from
5 :
2R
2S
4
3a :
5a
5a :
HO
d
O
O
c
O
O
O
HO
OH
OMOM
O
1a : 2R (from 14)
2a : 2S (from 14a)
14 : 2R (from 3)
14a 3a
: 2S (f rom
)
Scheme 4. Reagents and conditions: (a) 5, 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, THF, rt, 94%; (b) 5a, 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, THF, rt, 90%; (c)
Grubbs’ 2nd generation catalyst, CH2Cl2, 50 °C, 83%; (d) 4N HCl, CH3CN, 0 °C–rt, 8 h, 90%.
4. Seo, C.; Oh, H.; Lee, H. B.; Kim, J. K.; In, S. K.; Ahn, S. C. Bull. Korean Chem. Soc.
1803, 2007, 28.
Table 1
Cytotoxicity of C-9 epimers (1a and 2a) against human cancer cell lines
5. (a) Fürstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, W. C.; Mynott,
R. J. Am. Chem. Soc. 2002, 124, 7061; (b) Diez, E.; Dixon, D. J.; Ley, S. V.; Polara,
A.; Rodriguez, F. Synlett 2003, 1186; (c) Diez, E.; Dixon, D. J.; Ley, S. V.; Polara,
A.; Rodriguez, F. Helv. Chim. Acta 2003, 86, 3717; (d) Krishna, P. D.; Ramana, D.
V. J. Org. Chem. 2012, 77, 674; (e) Goswami, D.; Chattopadhyay, A. Tetrahedron:
Asymmetry 2012, 23, 764.
6. (a) Lingaiah, M.; Das, B. Synthesis 2014, 46, 1205; (b) Lingaiah, M.; Das, B.
Synlett 2014, 2327; (c) Reddy, P. R.; Lingaiah, M.; Das, B. Synlett 2014, 0975; (d)
Kumar, J. P. N.; Das, B. Synlett 2014, 0863; (e) Paramesh, J.; Kashannaa, J.;
Ganesh Kumar, C.; Poornachandra, Y.; Das, B. Bioorg. Med. Chem. Lett. 2014, 24,
325; (f) Reddy, P. R.; Das, B. RSC Adv. 2014, 4, 7432; (g) Reddy, C. R.; Das, B.
Tetrahedron Lett. 2014, 55, 67.
7. Moon, H. Y.; Choi, W. J.; Kim, H. O.; Jeong, L. S. Tetrahedron: Asymmetry 2002, 13,
1189.
8. Choi, W. J.; Moon, H. R.; Kim, H. L.; Yoo, B. N.; Lee, J. A.; Shink, D. H.; Jeong, L. S. J.
Org. Chem. 2004, 69, 2634.
9. (a) Srihari, P.; Sathish Reddy, A.; Yadav, J. S.; Yedlapudi, D.; Kalivendi, S. V.
Tetrahedron Lett. 2013, 54, 5616; (b) Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E.
Org. Lett. 2011, 13, 2476.
10. Parikh, J. R.; Doe ring, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
11. (a) Donohoe, T. J.; Lindsay-Scott, P. J.; Parker, J. S.; Callens, C. K. A. Org. Lett.
2010, 12, 1060; (b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2003, 125, 10808; (c) Mangion, I. K.; Macmillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 3696; (d) Varseev, G. N.; Maier, M. E. Org. Lett. 2007, 9,
1461; (e) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003,
44, 8293; (f) Reddy, C. R.; Dilipkumar, U.; Reddy, M. D.; Rao, N. N. Org. Biomol.
Chem. 2013, 11, 3355.
Cell line
IC50 values in lM
Compound (1a)
Compound (2a)
Doxorubicin (control)
Neuro-2a
HeLa
DU145
SKOV3
>100
>100
>100
>100
16.0 0.42
12.3 0.22
15.8 0.28
11.6 0.32
0.6 0.08
0.8 0.09
0.9 0.08
0.7 0.09
of three independent experiments depicted in Table 1. The results
showed that only compound 2a exhibited moderate cytotoxic
activity against all four cancer cell lines. The values observed were
>100 lM for all the tested cell lines in case of compound 1a.
In conclusion, we have developed the stereoselective total syn-
thesis of the C-9 epimers of herbarumin-II and its C-2 epimer. The
synthesis utilized D (À) ribose and hex-5-ene-1-ol as starting
materials and MacMillan
a-hydroxylation, Pinnick oxidation,
Yamaguchi esterification, and intramolecular ring closing metathe-
sis as the key steps. This is the first report of the synthesis of C-9
epimers of herbarumin-II and its C-2 epimer. The cytotoxic activity
of the synthetic compounds 1a and 2a has been evaluated.
12. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 415.
Acknowledgments
13. (a) Balkrishna, S. B.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37,
2091; (b) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567.
14. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1989, 1979, 52.
15. (a) Scholl, M.; Deng, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953; (b)
Mohapatra, D. K.; Prabhakar Reddy, D.; Karhale, D. S.; Yadav, J. S. Synlett 2013,
2679; (c) Giri, A. G.; Mondal, M. A.; Puranik, V. G.; Ramana, C. V. Org. Biomol.
Chem. 2010, 8, 398.
The authors thank the CSIR and UGC, New Delhi, India for finan-
cial assistance. They are also thankful to the NMR, Mass, and IR
divisions of CSIR-IICT for spectral recording.
Supplementary data
16. Spectral data of compounds 1a and 2a:
Compound 1a: IR (KBr): 3523, 3391, 2924, 2863, 1731, 1457, 1211, 1088, 937,
765 cm1; [
a]
D
27: À4.3 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d = 5.58 (1H, dd,
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.06.
011.
J = 16.0, 4.0 Hz), 5.49 (1H, ddd, J = 16.0, 9.0, 2.0 Hz), 4.67 (1H, dd, J = 9.8, 4.5 Hz),
4.58 (1H, m), 4.05–3.95 (2H, m), 2.41 (1H, q, J = 11.3 Hz), 2.27 (1H, m), 2.17 (1H,
m), 1.83 (1H, m), 1.65 (1H, m), 1.41 (1H, m), 1.32–1.21 (2H, m), 0.93 (3H, t,
J = 7.5 Hz); 13C NMR (75 MHz, CDCl3): d = 175.2, 133.4, 126.6, 76.3, 73.3, 71.0,
66.8, 35.4, 29.7, 22.8, 17.8, 14.1; MS (ESI) (m/z): 245 [M+H]+; Anal Calcd. for
References and notes
C
12H20O5: C, 59.00; H, 8.25%. Found: C, 58.91; H, 8.28%; Compound 2a: IR (KBr):
3413, 2926, 2862, 1705, 1278, 1061, 988, 770 cm1; [ 27: +5.4 (c 1.0, MeOH); 1
a
]
H
D
1. (a) Dräger, G.; Kirschning, A.; Thiericke, R.; Zerlin, M. Nat. Prod. Rep. 1996, 13,
365; (b) Sun, P.; Lu, S.; Ree, T. V.; Rohn, K. K.; Li, L.; Zhang, W. Curr. Med. Chem.
2012, 19, 3417; (c) Ferraz, H. M. C.; Bombonato, F. I.; Longo, L. S., Jr Synthesis
2007, 3261; (d) Riatto, V. B.; Pilli, R. A.; Victor, M. M. Tetrahedron 2008, 64,
2279.
2. Sun, P.; Lu, S.; Ree, T. V.; Krohn, K.; Hi, L.; Zhang, W. Curr. Med. Chem. 2012, 19,
3417.
3. (a) Rivero-Cruz, J. F.; Macias, M.; Gerda-Garcia-Rojas, C. M.; Mata, R.
Tetrahedron 2000, 56, 5337; (b) Rivero-Cruz, J. F.; Macias, M.; Gerda-Garcia-
Rojas, C. M.; Mata, R. J. Nat. Prod. 2003, 66, 511.
NMR (500 MHz, CDCl3+DMSO-d6): d = 5.61–5.48 (2H, m), 4.73 (1H, m), 4.68 (1H,
m), 4.40 (1H, m), 3.94 (1H, m), 3.88 (1H, br s), 3.71 (1H, br s), 3.48 (1H, br s), 2.81
(1H, q, J = 11.9 Hz), 2.03 (1H, m), 1.98–1.83 (2H, m), 1.65 (1H, m), 1.40 (1H, m),
1.31–1.23 (2H, m), 0.92 (3H, t, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3+DMSO-d6):
d = 172.2, 133.2, 127.0, 75.1, 73.9, 69.8, 66.1, 35.3, 33.8, 20.5, 18.0, 13.8; MS (ESI)
(m/z): 445 [M+H]+; Anal Calcd. for C12H20O5: C, 59.00; H, 8.25%. Found: C, 58.94;
H, 8.32%.
17. Mosmann, T. J. Immunol. Methods 1983, 65, 55.