Total synthesis of antifungal gamahonolide A

Article abstract of DOI:10.1016/j.tetlet.2014.04.026

The first stereoselective total synthesis of gamahonolide A (1) has been accomplished using aminoxylation, Keck allylation, and ring-closing metathesis (RCM) reactions as key steps.

Full text of DOI:10.1016/j.tetlet.2014.04.026

Tetrahedron Letters 55 (2014) 3227–3228
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of antifungal gamahonolide A
⇑
Gowravaram Sabitha , K. Purushotham Reddy, S. Purushotham Reddy, J. S. Yadav
Natural Products Chemistry 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:
Received 17 February 2014
Revised 8 April 2014
Accepted 8 April 2014
Available online 18 April 2014
The first stereoselective total synthesis of gamahonolide A (1) has been accomplished using aminoxyla-
tion, Keck allylation, and ring-closing metathesis (RCM) reactions as key steps.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aminoxylation
Keck allylation
Ring-closing metathesis
Natural product
Antifungal
6-Substituted a,b-unsaturated d-lactone moiety containing nat-
O
ural products attracted the attention of synthetic chemists due to
their interesting structure and potential biological activities. The
activities include antiviral, antifungal, antibacterial, growth inhib-
itory, antitumor, and antileukemic.1,2 Gamahonolide A3 (1) is a
d-lactone, isolated from stromata of phytopathogenic fungus,
Epichloe typhina on Phleum pratense. E. typhina causes choke
disease to the pasture grass, timothy, P. pratense. Gamahonolide
structure was determined by spectroscopic methods and the abso-
lute configuration by its ORD spectrum and 1H NMR shift differ-
ence between the diastereomeric pair of its O-methylmandelates.
To the best of our knowledge, the synthesis of gamahonolide A
(1) has not been reported to date. In continuation of our program
OH
O
Gamahonolide A
Figure 1. Structure of Gamahonolide A.
O
OTBDPS
OTBDPS
O
1
OH
on the total synthesis of bioactive
a,b-unsaturated d-lactone con-
2
3
taining natural products,4 herein we report the first total synthesis
of gamahonolide A (1) (Fig. 1) by a simple synthetic strategy.
Retrosynthetic analysis of 1 is outlined in Scheme 1. Ring-
closing metathesis reaction and removal of the functional group
in compound 2 would provide the target molecule, whereas, RCM
precursor 2 could be made available from 3 by oxidation followed
by Keck allylation and acryloylation. This in turn could be made
OH
1,8-octanediol
HO
OPMB
4
Scheme 1. Retrosynthetic analysis.
from octane-1,8-diol via compound 4 by adopting a-aminoxylation
reaction as a key step.
nitroso benzene and 40 mol % of D-proline in CHCl3, followed by
To begin the synthesis, octane-1,8-diol was selectively mono-
protected as its PMB ether 5 and the remaining hydroxyl group
was oxidized to the corresponding aldehyde. The aldehyde without
rapid reduction with sodium borohydride to furnish the unstable
anilinoxy compound which was further treated with Zn in acetic
acid at room temperature to cleave the OAN bond providing the
diol 4 with high enantioselectivity (98.6% ee)6 (Scheme 2). This
resulting 1,2-diol 4 on treatment with TsCl, and Et3N in the pres-
ence of dibutyltin oxide was monosilylated which on further
reduction with LAH in THF provided terminal methyl compound
isolation was subjected to the MacMillan
a
-hydroxylation5 using
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
http://dx.doi.org/10.1016/j.tetlet.2014.04.026
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3228
G. Sabitha et al. / Tetrahedron Letters 55 (2014) 3227–3228
a
ONHPh
b
ONHPh
HO
OH
6
HO
OPMB
6
HO
OHC
OPMB
5
OPMB
5
1,8-octanediol
5
4a
4b
OR
OTBDPS
OH
c
e
f
HO
OPMB
OH
OPMB
5
5
5
4
3
6: R = H
d
7
: R = TBDPS
O
O
O
OTBDPS OH
g
h
i
OTBDPS
3
O
OTBDPS
3
1
3
2
9
8
Scheme 2. Reagents and conditions: (a) NaH, PMB-Br THF, 0 °C–rt, 80%; (b) (i) IBX, DMSO, CH2Cl2, 3 h; (ii) PhNO, D-proline, CHCl3, 0 °C, 2 h then NaBH4, EtOH, 0 °C, 2 h then
AcOH, Zn, rt, 12 h, 55% for 3 steps; (c) (i) TsCl, Et3N, dibutyltin oxide (cat), dry CH2Cl2, 0 °C to rt, 12 h; (ii) LiAlH4, THF, reflux, 3 h, 85% (for 2 steps); (d) TBDPSCl, imidazole,
CH2Cl2, 0 °C, 3 h, 95%; (e) DDQ, CH2Cl2:H2O (9:1), 0 °C, 2 h, 90%; (f) (i) IBX, DMSO, CH2Cl2, 3 h; (ii) (S)-BINOL, 4 Å MS, Ti(Oi-Pr)4, Allyl-tributylstannane, CH2Cl2, À78 °C to
À20 °C, 24 h, 83% (for 2 steps); (g) acryloyl chloride, NaH, THF, 0 °C, 87%; (h) Grubbs’ 2nd generation catalyst (G-II, 10 mol %), CH2Cl2, reflux, 1 h, 72%; (i) TBAF, THF, 0 °C–rt,
85%.
Tetrahedron Lett. 2009, 50, 6298–6302; (d) Sabitha, G.; Rao, A. S.; Yadav, J. S.
Tetrahedron: Asymmetry 2011, 22, 866–871; (e) Sabitha, G.; Reddy, S. S. S.; Yadav,
J. S. Tetrahedron Lett. 2010, 51, 6259–6261; (f) Sabitha, G.; Reddy, S. S. S.; Yadav,
J. S. Tetrahedron Lett. 2011, 52, 2407–2409; (g) Sabitha, G.; Shankaraiah, K.;
Yadav, J. S. Eur. J. Org. Chem. 2013, 4870–4878.
6. The secondary alcohol silylated using TBDPSCl and imidazole to
silyl ether 7 followed by removal of the PMB group resulted in 3.
IBX oxidation of alcohol provided aldehyde which was allylated
following Keck’s protocol7 to give homoallyl alcohol 8 with high
diastereoselectivity (83%, 98% de).8
Acrylation of 8 was achieved by treatment with acryloyl chlo-
ride and NaH in THF to obtain diene 2 in 87% yield. Ring-closing
metathesis9 of 2 proceeded well with 10 mol % of Grubbs-II to pro-
duce lactone 9 in 72% yield. Finally, desilylation with TBAF in THF
afforded the target gamahonolide A (1) in 85% yield. This com-
pound is identical in all respects to the reported natural product
including NMR, optical rotation.
5. (a) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696–3697;
(b) Varseev, G. N.; Maier, M. E. Org. Lett. 2007, 9, 1461–1464; (c) Brown, S. P.;
Brochu, M. P.; Sinz, C. J.; MacMillian, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808–
10809; For other reports on proline catalyzed oxidation of aldehydes, see: (d)
Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247–4250; (e) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293–8296.
6. The enantiomeric excess was determined by chiral HPLC column: (CHIRAL PAK OD-
H: 250 Â 4.6 mm, 5
l) mobile phase: 10% IPA in Hexane, flow rate: 1 mL/min,
detection: 210 nm, retention time: 13.054 min, 98.6% ee.
7. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467.
8. The diastereomeric excess of the product was determined using a Shimadzu
high-performance liquid-chromatography (HPLC) system equipped with a chiral
HPLC column and a UV detector at an absorbance of 210 nm. Atlantis C18,
In conclusion, we have accomplished the first total synthesis of
gamahonolide A by a simple strategy involving
a-aminoxylation,
4.6 Â 150 MM, 5
l) (column) and a solvent system of 90% acetonitrile in water
at a flow rate of 1.0 ml/min were used. tR: 6.7 and 9.9 min.
Keck allylation, and ring closing-metathesis as the key steps.
9. For a recent review on ring-closing metathesis reactions, see: (a) Frustner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012–3043; (b) Trnka, T.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18–29; (c) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed.
2003, 42, 1900–1923; (d) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243–
251; (e) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 8168–8179; (f) Reddy, M. V. R.; Rearick, J. P.; Hock, N.;
Ramachandran, P. V. Org. Lett. 2001, 3, 19–20; (g) Ramachandran, P. V.; Liu,
H.; Reddy, M. V. R.; Brown, H. C. Org. Lett. 2003, 5, 3755–3757
Acknowledgements
The authors, K.P. thanks CSIR and S.P. thanks UGC New Delhi,
INDIA, for the financial support.
Supplementary data
Spectral data for selected compounds:
25
Compound 4: [a] D +9.0 (c = 0.5, CHCl3). IR (neat): 3243, 2933, 2855, 1613, 1514,
1249, 1033, 816. 1H NMR (CDCl3, 500 MHz): d 7.26 (d, J = 8.5 Hz, 2H), 6.88 (d,
J = 8.6 Hz, 2H), 4.43 (s, 2H), 3.81 (s, 3H), 3.73–3.62 (m, 2H), 3.45–3.40 (m, 3H),
1.64–1.56 (m, 4H), 1.48–1.30 (m, 6H). 13C NMR (CDCl3, 75 MHz): d 158.7, 130.3,
128.9, 113.4, 72.1, 69.8, 66.3, 54.9, 32.7, 29.3, 29.2, 25.8, 25.6. ESI-MS: m/z 305
Supplementary data (copies of 1H NMR, 13C NMR spectra avail-
able) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2014.04.026.
[M+Na]+. HRMS (ESI): calc. 305.1723 C16H26O4Na, found 305.1719; Compound 8:
25
[
a
]
À0.20 (c = 0.1, CHCl3). IR (neat): 3416, 2930, 2857, 1637, 1108, 703. 1H
D
References and notes
NMR (CDCl3, 500 MHz): d 7.70–7.65 (m, 4H), 7.44–7.34 (m, 6H), 5.87–5.74 (m,
1H), 5.16–5.08 (m, 2H), 3.87–3.79 (m, 1H), 3.64–3.52 (m, 1H), 2.16–2.03 (m, 2H),
1.52–1.15 (m, 10H), 1.07 (d, J = 6.1 Hz, 3H), 1.05 (s, 9H). 13C NMR (CDCl3,
75 MHz): d 135.8, 134.8, 134.5, 129.4, 129.3, 127.4, 127.3, 118.0, 70.4, 69.3, 41.8,
1. (a) Sam, T. W.; Yeu, C. S.; Jodynis-Liebert, J.; Murias, M.; Bloszyk, E. Planta Med.
2000, 66, 199; (b) Murga, J.; Falomoir, E.; Garcia-Fortanet, J.; Carda, M.; Marco, J.
A. Org. Lett. 2002, 4, 3447.
2. (a) Hagen, S. E.; Vara Prasad, J. V. N.; Tait, B. D. Adv. Med. Chem. 2000, 5, 159; (b)
Inayat-Hussain, S. H.; Annuar, B. O.; Din, L. B.; Ali, A. M.; Ross, D. Toxicol. In Vitro
2003, 17, 433; (c) Kikuchi, H.; Sasaki, K.; Sekiya, J.; Maeda, Y.; Amagai, A.;
Kubohara, Y.; Ohsima, Y. Bioorg. Med. Chem. 2004, 12, 3203.
3. Koshino, H.; Yoshihara, T.; Okuno, M.; Sakamura, S.; Tajimi, A.; Shimanuki, T.
BioSci., Biotechnol., Biochem. 1992, 56, 1096–1099.
4. (a) Sabitha, G.; Reddy, C. N.; Raju, A.; Yadav, J. S. Tetrahedron: Asymmetry 2011,
22, 493–498; (b) Sabitha, G.; Reddy, C. N.; Gopal, P.; Yadav, J. S. Tetrahedron Lett.
2010, 51, 5736–5739; (c) Sabitha, G.; Gopal, P.; Reddy, C. N.; Yadav, J. S.
39.2, 36.6, 26.9, 23.1, 21.2. ESI-MS: m/z 447 [M+Na]+. HRMS (ESI): calc. 447.2689
25
C
27H40O2NaSi, found 447.2694 [M+Na]+; Compound 1: [
a
]
À67.5 (c = 0.2,
D
CHCl3). IR (neat): 3449, 2925, 2855, 1713, 1649, 1256, 1093, 769. 1H NMR
(CDCl3, 500 MHz): d 6.91 (ddd, J = 9.7, 5.4, 3.8 Hz, 1H), 6.02 (ddd, J = 10.0, 1.8,
1.5 Hz, 1H), 4.47–4.40 (m, 1H), 3.82 (ddq, J = 6.2, 6.1, 5.9 Hz, 1H), 2.36–2.31 (m,
2H), 1.85–1.75 (m, 1H), 1.73–1.56 (m, 2H), 1.52–1.38 (m, 7H), 1.20 (d, J = 6.2 Hz,
3H). 13C NMR (CDCl3, 125 MHz): d 164.4, 144.9, 121.4, 77.9, 68.0, 39.1, 34.7,
29.4, 29.3, 25.5, 24.8, 23.5. ESI-MS: m/z 235 [M+Na]+. HRMS (ESI): calc.
235.13047 C12H20O3Na, found 235.13106 [M+Na]+.