Total synthesis of (+)-epiquinamide from d-mannitol

Article abstract of DOI:10.1016/j.tetlet.2008.11.115

The total synthesis of (+)-epiquinamide, a novel quinolizidine alkaloid isolated from the Ecuadoran poison frog, Epipedobates tricolor is described. The key step includes a ring-closing metathesis reaction to construct both the six member rings. d-Mannito

Full text of DOI:10.1016/j.tetlet.2008.11.115

Tetrahedron Letters 50 (2009) 1177–1179
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Total synthesis of (+)-epiquinamide from D-mannitol
*
Subhash Ghosh , J. Shashidhar
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 of (+)-epiquinamide, a novel quinolizidine alkaloid isolated from the Ecuadoran poi-
Received 15 October 2008
Revised 21 November 2008
Accepted 28 November 2008
Available online 3 December 2008
son frog, Epipedobates tricolor is described. The key step includes a ring-closing metathesis reaction to
construct both the six member rings.
D-Mannitol was used as a chiral pool material.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Epiquinamide
Ring-closing metathesis
D-Mannitol
Ecuadoran frog skin is an important source of interesting bio-
1st generation catalyst in CH2Cl2 at 50 °C for 6 h and gave six-
membered lactum 9.6,8 At this stage, we thought that both deb-
enzylation and reduction of the double bond could be carried
out under hydrogenation conditions. But when compound 9
was hydrogenated under atmospheric pressure using hydrogen
balloons and Pd–C as a catalyst in methanol, it afforded 10
exclusively. Finally, the N-benzyl group was removed under Li/
liq. NH3 conditions9 to get compound 5. N-Allylation of 5 with
NaH and allyl-bromide in DMF afforded compound 11, which
was converted to bis-olefinic compound 13 in five steps. Aceto-
nide deprotection followed by routine protecting-group manipu-
lations afforded primary alcohol 12. Oxidation of the primary
alcohol with DMP10 followed by Wittig olefination with stable
ylide Ph3P@CHCOOEt in CH2Cl2 at room temperature furnished
bis-olefinic compound 13. Herein, it is worth mentioning that
the Wittig reaction with Ph3P@CH2 under different conditions
failed. Now the stage was set for the crucial ring-closing metath-
esis reaction for the construction of the second ring. Accordingly,
compound 13 was treated with 10 mol % of Grubbs’1st genera-
tion catalyst in CH2Cl2 for 24 h to give 1411 in 71% yield. Reduc-
tion of the double bond followed by TBS deprotection12 afforded
logically-active alkaloids.1 In 2003, Daly et al. isolated novel quin-
olizidine alkaloids epiquinamide (1)2 along with known alkaloids
epibatadine (2)3 from the methanolic skin extracts of an Ecuadoran
frog, Epipedobates tricolor (Fig. 1). The structure of the compound
was disclosed to be 1 on the basis of detailed spectral data (MS,
IR and NMR) analysis and recently the absolute stereochemistry
was determined by Rutjes et al. via chiral GC.4a Daly et al.2 evalu-
ated the bioactivity of the molecule on the basis of membrane-po-
tential fluorescence and it was found to be b2 selective. But due to
the low abundance of the molecule, they could not do further bio-
logical studies with epiquinamide. Thus, low availability and po-
tential biological activity make this molecule an attractive target
for synthetic organic chemists.4 As part of our continuing interest
in stereoselective syntheses of natural products from the chiral
pool5, we report herein, an approach for the total synthesis of
epiquinamide (1) starting from the cheap and easily-available
starting material, D-mannitol.
Retrosynthetically (Scheme 1), epiquinamide could be obtained
from alcohol 3, which in turn could be obtained from bis-alkene 4
via ring-closing metathesis.6 Again bis-alkene 4 could be obtained
by means of N-allylation of 5, which could be synthesized through
ring-closing metathesis of bis-alkene 6 which in turn, could be syn-
thesized from known compound 7.7
O
The synthesis of bis-olefinic compound 6 (Scheme 2) com-
menced from 7, which was prepared from D-mannitol according
NH
Cl
to the reported procedure.7 N-Acylation with 3-butenoic acid
using isobutylchloroformate and NMM in THF afforded com-
pound 6 which underwent ring-closing metathesis with Grubbs’
H
N
H
N
N
(+)-Epiquinamide (1)
Epibatadine (2)
* Corresponding author. Fax: +91 40 27193108.
E-mail address: subhashbolorg3@yahoo.com (S. Ghosh).
Figure 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.115

1178
S. Ghosh, J. Shashidhar / Tetrahedron Letters 50 (2009) 1177–1179
NHAc
H
OH
OTBS
H
O
H
H
O
HN
N
N
N
4
O
3
O
O
5
Epiquinamide (1)
O
O
H
H
O
O
D-Mannitol
BnN
6
NHBn
8
7
O
O
Scheme 1. Retrosynthetic analysis of 1.
O
H
O
H
H
O
i
O
ref. 7
ii
O
D-mannitol
BnN
BnN
9
8
7
6
NHBn
O
O
O
O
H
O
H
O
H
O
O
v
iv
vi
HN
iii
N
BnN
5
O
11
10
O
O
OTBS
H
OTBS
H
OTBS
H
EtOOC
HO
viii
vii
ix, x
N
N
N
13
14
O
12
O
O
OH
NHAc
H
N3
H
H
N
xii
xi
N
N
3
O
1)
(+)-Epiquinamide (
15
O
Scheme 2. Reagents and conditions: (i) 3-butenoic acid, isobutylchloroformate, NMM, THF, 0 °C to rt, 8 h, 87%; (ii) 5 mol % Grubbs’ 1st generation catalyst, CH2Cl2, 50 °C, 5 h,
92%; (iii) H2, Pd–C, MeOH, rt, 0.5 h, 90%; (iv) Li, liq. NH3, THF, ꢀ78 °C, 1 h, 64%; (v) NaH, ally bromide, DMF, 0 °C to rt, 2 h, 83%; (vi) (a) CSA, MeOH, rt, 4 h, 77%; (b) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 °C, 0.5 h, 96%; (c) HF–Py, THF, rt, 14 h, 86%; (vii) (a) DMP, CH2Cl2, 0 °C to rt, 1.5 h; (b) Ph3P@CHCOOEt, CH2Cl2, rt, 1 h, 84% over two steps; (viii) 10 mol %
Grubbs’ 1st generation catalyst, CH2Cl2, 50 °C, 24 h, 71%; (ix) Pd–C, H2, MeOH, 0.5 h, 90%; (x) TBAF, THF, rt, 7 h, 89%; (xi) (a) Ms–Cl, Et3N, CH2Cl2, 0.5 h; (b) NaN3, DMF, 100 °C,
24 h, 50% over two steps; (xii) (a) LiAlH4, THF, reflux, 24 h; (b) Ac2O, 1 N NaOH, dioxane, 2 h, 79% over two steps.
secondary alcohol 3. Compound 3 was converted to 15 in two
steps; mesylation followed by mesyl displacement with NaN3
gave 15. Finally 15 was converted to epiquinamide (1) according
to the reported procedures.4a,e,f The spectral data of compounds
1513 and 114 are in full agreement with the literature data.4f
In conclusion, we have achieved the stereoselective total syn-
thesis of epiquinamide from the commercially available, cheap
Acknowledgements
One of usis thankfulto U.G.C, New Delhi, for a researchfellowship
(J.S.). We are also thankful to Dr. T. K. Chakraborty, Dr. A. C. Kunwar
and the Director, IICT, for their support and encouragement.
References and notes
starting material D-mannitol, with an overall yield of 4.6% from
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compound 7, using ring-closing metathesis as a key step. The func-
tionalization of ring-closing metathesis products could provide a
large number of analogues of this molecule. Work is going on in
that direction, and will be reported in due course.

S. Ghosh, J. Shashidhar / Tetrahedron Letters 50 (2009) 1177–1179
1179
3. (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.; Pannell, L.; Daly,
J. W. J. Am. Chem. Soc. 1992, 114, 3475–3478; (b) Daly, J. W. Cell Mol. Neurobiol.
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(dt, J = 9.8, 3.7 Hz, 1H), 5.75 (ddd, J = 9.8, 4.5, 2.3 Hz, 1H), 5.59 (d, J = 15.8 Hz,
1H), 4.36 (dt, J = 3, 6.8 Hz 1H), 4.20 (d, J = 15.8 Hz, 1H), 4.0 (dd, J = 8.3, 6.8 Hz,
2H), 3.70 (dd, 8.3, 6.8 Hz, 1H), 3.08 (dd, J = 8.3, 3.0 Hz, 2H), 1.42 (s, 3H), 1.32 (s,
3H); 13C NMR (CDCl3, 75 MHz): d 169.1, 136.9, 128.6, 127.7, 127.3, 126.2, 122.1,
109.8, 65.1, 57.8, 47.7, 33.3, 25.8, 25.0; MS (ESIMS): m/z: 288 [M+H]+; HRMS
(ESI) calcd for C17H22NO3 [M+H]+ 288.1594. Found 288.1596.
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ꢀ48.7 (c 0.4, CHCl3); IR (neat): mmax
ꢁ
2940, 2861, 2534, 1639 cmꢀ1;1H NMR (300 MHz, CDCl3): d 5.74–5.63 (m, 2H),
4.72 (dd, J = 18.9, 3.0 Hz, 1H), 4.07 (dd, J = 8.3, 3.7 Hz, 1H), 3.37 (dd, J = 18.9,
2.3 Hz, 1H), 3.21 (dt, J = 9.0, 5.3 Hz, 1H), 2.38 (dd, J = 6.8, 6.0 Hz, 2H), 2.05–1.64
(m, 4H), 0.90 (s, 9H), 0.09 (s, 3H), 0.87 (s, 3H); 13C NMR (CDCl3, 75 MHz): d
169.7, 130.1, 124.3, 68.8, 58.7, 42.1, 32.6, 25.7, 24.5, 17.6, 17.9, ꢀ4.2, ꢀ4.8; MS
(ESIMS): m/z: 282 [M+H]+; HRMS (ESI) calcd for C15H28NO2Si [M+H]+ 282.1884.
Found 282.1881.
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13. Analytical and spectral data of 15: ½a D27
+16.1 (c 0.38, CH2Cl2); IR (neat): mmax
ꢁ
2925, 2884, 2098, 1655 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.81 (m, 1H), 3.63
;
(m, 1H), 3.39 (m, 1H), 2.47–2.22 (m, 3H), 2.16 (m, 1H), 1.93–1.82 (m, 3H), 1.77–
1.71 (m, 2H), 1.68–1.57 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 170.3, 60.7, 58.2,
41.8, 32.7, 28.6, 26.6, 19.5, 19.0; MS (ESIMS): m/z: 195 [M+H]+; HRMS (ESI)
calcd for C9H15N4O [M+H]+: 195.1243. Found 195.1238.
14. Analytical and spectral data of 1: ½a D27
ꢁ
+25 (c 0.1, CHCl3), reported4f +28 (c 0.23,
CHCl3); IR (neat): m ;
7. (a) Badorrey, R.; Cativiela, C.; Diáz-de-villegas, M. D.; Gálvez, J. A. Synthesis
1997, 747–749; (b) Madhan, A.; Rao, B. V. Tetrahedron Lett 2003, 44, 5641–
5643; (c) Badorrey, R.; Cativiela, C.; Dıáz-de-Villegas, M. D.; Roberto Dıéz, R.;
Gálvez, J. A. Eur. J. Org. Chem. 2003, 2268–2275.
max 3354, 2933, 2858, 2356, 1652 cmꢀ1 1H NMR (300 MHz,
CDCl3): d 6.50 (br s, 1H), 3.99 (m, 1H), 2.97–2.75 (m, 2H), 2.02 (s, 3H), 1.91–
1.72 (m, 6H), 1.64–1.44 (m, 5H), 1.37–1.26 (m, 2H); 13C NMR (CDCl3, 150 MHz)
d 169.9, 64.6, 56.7, 56.6, 47.9, 29.5, 28.8, 25.3, 23.9, 23.4, 20.4; MS (ESIMS): m/
z: 197.1 [M+H]+; HRMS (ESI) calcd for C11H21N2O [M+H]+ 197.1653. Found
197.1651.
8. Analytical and spectral data of 9: ½a D27
ꢀ38 (c 0.6, CHCl3); IR (neat): mmax 2984,
ꢁ
2928, 2539, 1643 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.34–7.20 (m, 5H), 5.97
;