Synthesis of a Greek tobacco lactonic natural product and its analogues

Article abstract of DOI:10.1016/j.tetlet.2012.05.151

A total synthesis of a Greek tobacco lactonic natural product and three of its analogues has been achieved using a commercially available starting material and our furan approach to oxacyclic systems, the proven scope of which is thus broadened.

Full text of DOI:10.1016/j.tetlet.2012.05.151

Tetrahedron Letters 53 (2012) 4293–4295
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Synthesis of a Greek tobacco lactonic natural product and its analogues
⇑
⇑
Andrea Zúñiga, Gonzalo Pazos, Pedro Besada , Yagamare Fall
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Vigo, 36200 Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A total synthesis of a Greek tobacco lactonic natural product and three of its analogues has been achieved
using a commercially available starting material and our furan approach to oxacyclic systems, the proven
scope of which is thus broadened.
Received 20 March 2012
Revised 23 May 2012
Accepted 30 May 2012
Available online 8 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Greek tobacco
Natural products
Total synthesis
Lactones
Wahlberg and co-workers isolated in 1993,1 13 lactones from
an extract of sun-cured leaves of Greek tobacco. Nine of these lac-
tones were new natural products, some of them are depicted in
Figure 1.
The bicyclic lactone (3aR,5R,7aR)-7a-methyl-5-(prop-1-en-2-
yl)hexahydro-2H-furo[3,2-b]pyran-2-one (1) was isolated in race-
mic form due to the fact that its proposed biogenesis is not an
enantioselective process. Clark et al.2 published in 2007 the first to-
tal synthesis of 1, completed its characterization and confirmed its
relative stereochemistry.
As outlined in Scheme 1, we anticipated that lactone 1 could be
synthesized using a methodology we developed in our laboratories
and which we coined the furan approach to oxacyclic systems.3
Accordingly, 4-hydroxybutenolide (9) was prepared as shown
in Scheme 2.
Commercially available ester 8 was easily transformed into
aldehyde 11 in two steps (85% overall) or in one step using DI-
BAL-H (75% yield). Metalation of vinyl bromide 12 and addition
to aldehyde 11 afforded alcohol 13 (70%) which was protected as
tert-butyldiphenylsilylether, giving 14 in 99% yield. Furan 14 was
subjected to singlet oxygen oxidation3f affording hydroxybuteno-
lide 9 in 77% yield.
O
O
O
O
O
H
O
O
O
1
2
3
O
O
O
O
O
O
O
O
O
6
O
7
4
5
With hydroxybutenolide 9 in hand, our next goal was to intro-
duce an angular methyl group, which was achieved by addition of
Figure 1. Structures of some of the new natural products isolated by Wahlberg and
co-workers from sun-cured Greek tobacco leaves.
O
O
O
O
O
O
O
OEt
OH
9
H
8
OTBDPS
1
Scheme 1. Retrosynthetic analysis of lactone 1.
⇑
Corresponding authors. Fax: +34 986 81 22 62 (Y.F.).
E-mail addresses: pbesada@uvigo.es (P. Besada), yagamare@uvigo.es (Y. Fall).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.151

4294
A. Zúñiga et al. / Tetrahedron Letters 53 (2012) 4293–4295
i
OH
O
O
O
10
8
OEt
ii
iii
v
iv
O
O
O
O
OTBDPS
14
OH
13
H
11
Br
12
vi
O
O
OH
OTBDPS
9
Scheme 2. Reagents and conditions: (i) LiAlH4, Et2O, rt (96%); (ii) TEMPO, BAIB, CH2Cl2 (89%); (iii) DIBAL-H, CH2Cl2, ꢀ78 °C (75%); (iv) 12, tBuLi, THF, ꢀ78 °C (70%); (v)
TBDPSCl, Imid, DMAP, DMF, rt (99%); (vi) O2, MeOH, Rose Bengal, DIPEA, h
m ꢀ78 °C (77%).
OCH3
O
OCH3
O
i
O
O
O
O
O
O
OH
O
Me
O
OTBDPS
H
H
OTBDPS
O
9
H
H
15
5.51%
x
4.28%
19
20
O
O
ii
Figure 3. NOE correlations for lactones 19 and 20.
O
+
O
O
H
16
H
1
Reaction of c-lactone 15 with TBAF at room temperature afforded
Scheme 3. Reagents and conditions: (i) (i-PrO)3TiCl, MeLi, ꢀ78 °C to rt (63%); (ii)
TBAF, THF, rt [1 (51%) and 16 (30%)].
target compound 15 in 51% yield, together with 30% of diastereo-
isomeric lactone 16.6 The NMR data of lactone 1 were in close
agreement with those reported by Clark et al.2
The relative stereochemistries of 1 and 16 were established by
NOE experiments (Fig. 2).
3.32%
CH3
2.43%
CH3
Having synthesized lactone 1 and its diastereoisomer 16, we
decided to use our furan approach to oxacyclic systems,3 for the
synthesis of 19 and 20, two new analogues of 1 (Scheme 4).
Accordingly, alcohol 13 was protected as tert-butyldimethylsil-
ylether, giving 17 in 99% yield. Furan 17 was subjected to singlet
oxygen oxidation3i affording methoxybutenolide 18 in 81% yield.
Reaction of butenolide 18 with TBAF at room temperature afforded
lactones 197 and 208 in 53% and 24% yields, respectively.
The relative stereochemistries of 19 and 20 were established by
NOE experiments (Fig. 3).
O
O
7a
7a
O
3a
O
5
3a
O
O
H
3.30%
H
H
H
1.59%
1.83%
3.57%
16
1
Figure 2. NOE correlations for lactones 1 and 16.
(i-PrO)3TiCH3 to 9, following Miles’s procedure.4 In our case, how-
ever, the best yields for 15 were obtained when the organotitani-
um reagent was generated in situ (Scheme 3). Use of lithium or
Grignard reagents afforded very poor yields of compound 15.
In conclusion, using our furan approach we have synthesized
bicyclic lactone (3aR,5R,7aR)-7a-methyl-5-(prop-1-en-2-yl)hexa-
hydro-2H-furo[3,2-b]pyran-2-one (1) and its three new analogues
16, 19, and 20 which were fully characterized.
ii
O
i
O
O
O
OMe
OTBS
OTBS
17
OH
13
18
OCH3
O
OCH3
O
iii
O
O
O
O
H
H
19
20
Scheme 4. Reagents and conditions: (i) TBSCl, imidazole, DMAP, DMF (99%); (ii) (a) O2, h
m, Rose Bengal, MeOH; (b) Ac2O, Py, DMAP (81%); (iii) TBAF, THF, rt [19 (53%) and 20
(24%)].

A. Zúñiga et al. / Tetrahedron Letters 53 (2012) 4293–4295
4295
Tetrahedron Lett. 2003, 44, 4467–4469; (j) Margaros, I.; Montagnon, T.; Tofi, M.;
Pavlakos, E.; Vassilikogiannakis, G. Tetrahedron 2006, 62, 5308–5317; (k)
Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc. Chem. Res. 2008, 41, 1001–
1011. and references cited therein.
Acknowledgements
This work was supported financially by the Spanish Ministry of
Foreign Affairs and Cooperation (PCI A/030052/10) and the Xunta
de Galicia (INCITE845B-2010/020 and INCITE08PXIB314255PR).
The work of the NMR and MS divisions of the research support ser-
vices of the University of Vigo (CACTI) is also gratefully acknowl-
edged. Pedro Besada thanks the Xunta de Galicia for an Isidoro
Parga Pondal contract and Andrea Zúñiga, the University of Vigo
for a Ph.D. fellowship.
4. Miles, W. H.; Duca, D. G.; Freedman, J. T.; Goodzeit, E. O.; Hamman, K. B.; Palha
De Sousa, C. A.; Selfridge, B. R. Heterocycl. Commun. 2007, 13, 195–198.
5. Compound 1: colorless oil, Rf: 0.39 (50% EtOAc/hexane); 1H NMR (CDCl3, d): 4.96
(s, 1H, CH2-10), 4.85 (s, 1H, CH2-10), 4.08 (d, J = 4.3 Hz, 1H, CH-3a), 3.73 (d,
J = 9.7 Hz, 1H, CH-5), 2.88 (dd, J = 17.5, 4.3 Hz, 1H, CH2-3), 2.53 (d, J = 17.5 Hz,
1H, CH2-3), 2.30 (m, 1H, CH2-7), 1.72 (s, 3H, CH3-20), 1.65 (m, 2H, CH2-6), 1.31 (s,
13
3H, CH3-7a); C NMR (CDCl3, d): 175.8 (CO), 144.8 (C-20), 111.4 (CH2-10), 81.6
(C-7a), 78.6 (CH-5), 77.5 (CH-3a), 38.2 (CH2-3), 32.3 (CH2-7), 25.2 (CH3-7a), 25.1
(CH2-6), 18.4 (CH3-20); MS (EI) [m/z, (%)]: 197 (100, [M+1]+), 179 (12); HRMS
(EI): 197.11722 calcd for C11H17O3, found 197.11627.
6. Compound 16: colorless oil, Rf: 0.42(50% EtOAc/hexane); 1H NMR (CDCl3, d):
4.96 (m, 2H, CH2-10), 4.19 (m, 1H, CH-5), 4.09 (dd, J = 5.9, 2.4 Hz, 1H, CH-3a),
2.80 (dd, J = 17.9, 5.9 Hz, 1H, CH2-3), 2.60 (d, J = 17.9, 2.4 Hz, 1H, CH2-3), 1.93 (m,
3H, CH2-7, CH2-6), 1.74 (s, 3H, CH3-20), 1.62 (m, 1H, CH2-6), 1.34 (s, 3H, CH3-7a);
13C NMR (CDCl3, d): 175.1 (CO), 143.5 (C-20), 111.4 (CH2-10), 83.5 (C-7a), 73.7
(CH-5), 73.4 (CH-3a), 35.7 (CH2-3), 29.4 (CH2-7), 24.3 (CH3-7a), 22.8 (CH2-6),
19.5 (CH3-20); MS (EI) [m/z, (%)]: 197 (100, [M+1]+), 179 (12); HRMS (EI): calcd
for C11H17O3: 197.11722; found 197.11744.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
05.151.
7. Compound 19: colorless oil, Rf: 0.29 (30% EtOAc/hexane); 1H NMR (CDCl3, d):
4.97 (s, 1H, CH2-10), 4.86 (s, 1H, CH2-10), 4.05 (d, J = 4.4 Hz, 1H, CH-3a), 3.79 (d,
J = 10.8 Hz, 1H, CH-5), 3.37 (s, 3H, OCH3), 2.94 (dd, J = 17.2, 4.4 Hz, 1H, CH2-3),
2.58 (m, 1H, CH2-7), 2.45 (d, J = 17.2 Hz, 1H, CH2-3), 1.77 (m, 2H, CH2-7, CH2-6),
1.72 (s, 3H, CH3-20), 1.65 (m, 1H, CH2-6); 13C NMR (CDCl3, d): 176.1 (CO), 144.2
(C-20), 111.7 (CH2-10), 104.4 (C-7a), 78.5 (CH-5), 76.9 (CH-3a), 49.6 (OCH3), 37.1
(CH2-3), 27.6 (CH2-7), 25.9 (CH2-6), 18.5 (CH3-20); MS (EI) [m/z, (%)]: 235 (100,
[M+Na]+), 213 (82, [M+1]+), 201 (42); HRMS (EI): calcd for C11H17O4: 213.11214;
found 213.11177.
References and notes
1. Petterson, T.; Eklund, A.-M.; Wahlberg, I. J. Agric. Food Chem. 1993, 41, 2097–
2103.
2. Clark, J. S.; Hayes, S. T.; Blake, A. J.; Gobbi, L. Tetrahedron Lett. 2007, 48, 2501–
2503.
3. (a) González, M.; Gándara, Z.; Covelo, B.; Gómez, G.; Fall, Y. Tetrahedron Lett.
2011, 52, 5983–5986; (b) Canoa, P.; Gándara, Z.; Pérez, M.; Gago, R.; Gómez, G.;
Fall, Y. Synthesis 2011, 3, 431–436; (c) Álvarez, C.; Pérez, M.; Zúñiga, A.; Gómez,
G.; Fall, Y. Synthesis 2010, 22, 3883–3890; (d) Canoa, P.; Pérez, M.; Covelo, B.;
Gómez, G.; Fall, Y. Tetrahedron Lett. 2007, 48, 3441–3443; (e) García, I.; Gómez,
G.; Teijeira, M.; Terán, C.; Fall, Y. Tetrahedron Lett. 2006, 47, 1333–1335; (f)
Teijeira, M.; Suárez, P. L.; Gómez, G.; Terán, C.; Fall, Y. Tetrahedron Lett. 2005, 46,
5889–5892; (g) Alonso, D.; Pérez, M.; Gómez, G.; Covelo, B.; Fall, Y. Tetrahedron
2005, 61, 2021–2026; (h) Pérez, M.; Canoa, P.; Gómez, G.; Terán, C.; Fall, Y.
Tetrahedron Lett. 2004, 45, 5207–5209; (i) Fall, Y.; Vidal, B.; Alonso, D.; Gómez, G.
8. Compound 20: colorless oil, Rf: 0.24 (30% EtOAc/hexane); 1H NMR (CDCl3, d):
5.04 (s, 1H, CH2-10), 4.97 (s, 1H, CH2-10), 4.05 (m, 1H, CH-5), 3.79 (d, J = 5.1 Hz,
1H, CH-3a), 3.34 (s, 3H, OCH3), 2.90 (dd, J = 17.5, 5.1 Hz, 1H, CH2-3), 2.41 (d,
J = 17.5 Hz, 1H, CH2-3), 2.16 (m, 1H, CH2-7), 2.00 (m, 1H, CH2-7), 1.94 (m, 2H,
13
CH2-6), 1.75 (s, 3H, CH3-20); C NMR (CDCl3, d): 175.9 (CO), 142.4 (C-20), 112.6
(CH2-10), 106.4 (C-7a), 73.9 (CH-5), 71.6 (CH-3a), 49.5 (OCH3), 36.3 (CH2-3), 23.5
(CH2-7), 21.9 (CH2-6), 19.9 (CH3-20); MS (EI) [m/z, (%)]: 235 (77, [M+Na]+), 213
(100, [M+1]+); HRMS (EI): calcd for C11H17O4: 213.11214; found 213.11194.