Synthesis of homoallylic oxygenated α-methylene-γ-butyrolactones: a model for preparing biologically active natural lactones

Article abstract of DOI:10.1016/j.tetlet.2008.07.099

In this Letter we describe a 12% overall yield synthesis of a model for homoallylic oxygenated α-methylene-γ-butyrolactones with relative stereochemistry defined by selective hydrogenation with Rh/Al₂O₃. The synthesis was realized in 9 steps involving simple reactions.

Full text of DOI:10.1016/j.tetlet.2008.07.099

Tetrahedron Letters 49 (2008) 5770–5772
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of homoallylic oxygenated a-methylene-c-butyrolactones:
a model for preparing biologically active natural lactones
*
Daiane Cristina Sass, Kleber Thiago de Oliveira, Mauricio Gomes Constantino
Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida dos Bandeirantes,
3900, 14040-901 Ribeirão Preto—SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter we describe a 12% overall yield synthesis of a model for homoallylic oxygenated a-methyl-
Received 18 June 2008
Revised 17 July 2008
Accepted 19 July 2008
Available online 24 July 2008
ene-
The synthesis was realized in 9 steps involving simple reactions.
Ó 2008 Elsevier Ltd. All rights reserved.
c-butyrolactones with relative stereochemistry defined by selective hydrogenation with Rh/Al2O3.
Keywords:
Synthesis
Natural products
a-Methylene-c-butyrolactones
The group of organic functions described as ‘
a
-methylene-
c
-
shown in Figure 1; as we are presently investigating, it can also be
modified to give different relative configurations.
butyrolactone’, which occurs in many terpenic natural products,
has been recognized as responsible for a large number of biological
activities due to their ability to accept Michael addition of nucleo-
philic enzymes to the conjugated system.1 As a consequence, an
expressive number of original papers and reviews about synthesis
of these lactonic moieties have been produced in the last decades.2
There is, however, a particular case that has not received as
H
O
O
OH
H
O
O
O
H
H
O
much attention as it deserves: the homoallylic oxygenated
a-
O
H
methylene- -butyrolactones. Occurring in many natural products,
c
O
H
as shown by examples in Figure 1, this group brings some charac-
teristic challenges to the synthetic work, which is the subject of
this Letter.3
O
3
H
Our synthetic strategy is based on the short retrosynthetic anal-
ysis shown in Scheme 1.
1
O
The two oxygenated functions symmetrically distributed on
each side of the isopropenylic acidic substituent could come from
a b-diketone system, which could also be used to introduce the
acidic substituent in the system through the easily formed enolate.
The regiochemistry of the lactone formation and the relative ste-
reochemistry of the three stereogenic centers are the main problems
in this type of synthesis.4 There are no simple solutions because the
natural diversity is large: we can find examples of natural lactones
for virtually all possible combinations of regio- and stereoisomers.
The method described here, summarized in Scheme 2, can produce
the lactones with the relative stereochemistry of the examples
O
O
H
O
O
O
H
H
O
O
O
H
O
OH
OH
OH
2
4
Figure 1. Examples of natural homoallylic oxygenated
actones: 8
12-olide (1),3 eriolangin (2),4 helenalin (3),5
oxy)-4 -hydroxy-9-oxo-5bH-eudesm-1Z,11(13)-dien-6b,12-olide (4).
a
-methylene-
c
-butyrol-
a
-(20S,30S-epoxy-20-methylbutyryloxy)-9-oxogermacra-4E,1(10)E-dien-6b,
* Corresponding author. Tel.: +55 16 3602 3747; fax: +55 16 3602 4838.
E-mail address: mgconsta@usp.br (M. G. Constantino).
8a
-(20R,30R-epoxy-20-methylbutyryl-
a
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.099

D. C. Sass et al. / Tetrahedron Letters 49 (2008) 5770–5772
5771
OH
O
OH
OH
O
CO2R
O
O
Scheme 1. Retrosynthetic analysis.
O
O
O
a
b
CO2Me
CO2Me
85%
78%
O
OH
OAc
5
6
7
OH
OH
6
5
c
d
e
Figure 2. A stable conformation of compound 9.
CO2Me
CO2Me
OAc
1
2
3
81%
73%
81%
4
OAc
chair by over 2 kcal/mol. The calculated (Boltzmann averaged con-
sidering all found conformations) coupling constants for H6 were
10.9, 10.3, and 4.7 Hz, which are in good agreement with the
experimental values of 10.2, 10.2, and 4.1 Hz.
The transformation of 9 into the lactone 11 was accomplished
through two simple steps: protection of the alcohol function as
methoxymethyl ether10 followed by basic hydrolysis of the ester
functions.11 Finally, the methylene group was introduced in the
lactone ring by the sequence developed by Danishefsky et al.12
using Eschenmoser’s salt.
8
9
OMOM
MOMO
H
f
g, h
60%, 85%
CO2Me
O
85%
O
OAc
H
10
11
MOMO
OH
H
H
H
This 12% overall yield synthesis represents a versatile approach
i
to the preparation of homoallylic oxygenated
a-methylene-c-
O
O
butyrolactones with clearly defined relative stereochemistry.
91%
O
O
H
Acknowledgments
12
13
Scheme 2. Summary of the synthetic steps. Reagents and conditions: (a) MeONa,
BrCH2CO2Me; (b) Ac2O/Pyr, DMAP; (c) NaBH4, CeCl3.7H2O; (d) H2/5% Rh on
alumina; (e) MOMCl, CH2Cl2; (f) K2CO3, MeOH; (g) LDA/Me2N+ = CH2Iꢀ, THF;
(h) (1) MeI/MeOH; (2) K2CO3; (i) PTSA/MeOH.
The authors thank the Fundação de Amparo à Pesquisa do Esta-
do de São Paulo (FAPESP), the Conselho Nacional de Desenvolvi-
mento Científico
e Tecnológico (CNPq), the Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and the
Financiadora de Estudos e Projetos (FINEP) for financial support.
We thank also Professor Norberto Peporine Lopes for the mass
spectra.
In the first step, the enolate of 1,3-cyclohexanedione was used
to make a simple nucleophilic substitution on methyl bromo-
acetate.6 Direct reduction of 6 could not be easily effected with
NaBH4, but the corresponding enol acetate 7 gave good yield of
the reduced material 8 when treated with NaBH4/CeCl3.7
The hydrogenation of 8 is the step that defines the relative
stereochemistry of the three substituents of the cyclohexane ring.
The use of Pd catalysts gave large amounts of hydrogenolysis prod-
ucts, but Rh/Al2O3 at 6 atm/room temperature gave good results.8
As expected, the addition of the two hydrogen atoms occurred in
a cis manner, from the same face of the OH group, thus resulting
in product 9.
The relative stereochemistry of product 9 could be determined
by NMR analysis. By carefully comparing 1H, 13C, DEPT-135,
gHMQC, and gHMBC data we can unequivocally assign the 1H
NMR signals to H6, H1, and H2. From the signal of H6, a double
triplet with two Jaa (10.2 Hz) values, we can conclude that both
H6 and H1 are in axial positions. The signal of H2, on the other
hand, has only small values of J, showing that H2 must be
equatorial.
Supplementary data
Supplementary data (experimental section, 1H and 13C NMR
spectra, including 2D spectra) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.07.099.
References and notes
1. (a) Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J. Synthesis 1986, 157; (b)
Hoffman, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94; (c) Huldrlik,
P. F.; Chou, D. T. W.; Stephenson, M. A. J. Org. Chem. 1982, 47, 2987; (d) Grieco,
P. A.; Marinovic, N.; Miyashita, M. J. Org. Chem. 1975, 40, 1670; (e) Grieco, P. A.
Synthesis 1975, 67.
2. (a) Schall, A.; Reiser, O. Eur. J. Org. Chem. 2008, 73, 3935–3937; (b) Hajra, S.; Giri,
A. K. J. Org. Chem. 2008, 73, 3935; (c) Donner, C. D. Tetrahedron Lett. 2007, 48,
8888; (d) Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2007, 18, 2479;
(e) López, I.; Rodríguez, S.; Izquierdo, J.; González, F. V. J. Org. Chem. 2007, 72,
6614; (f) Ziegler, F. G.; Marino, A. F.; Petroff, O. A. C.; Studt, W. L. Tetrahedron
Lett. 1974, 23, 2035; (g) Marshall, J. A.; Cohen, N. J. Org. Chem. 1965, 30,
3475.
3. (a) Wagner, S.; Hofmann, A.; Siedle, B.; Terfloth, L.; Merfort, I.; Gasteiger, J. J.
Med. Chem. 2006, 49, 2241–2252; (b) Lindenmeyer, M. T.; Hrenn, A.; Kern, C.;
Castro, V.; Murillo, R.; Müller, S.; Laufer, S.; Schulte-Mönting, J.; Siedle, B.;
Merfort, I. Bioorg. Med. Chem. 2006, 14, 2487–2497; (c) Müller, S.; Murilo, R.;
Confirming these conclusions, a conformational search carried
on with molecular mechanics programs9 has shown that the ring
conformation depicted in Figure 2 is more stable than the other

5772
D. C. Sass et al. / Tetrahedron Letters 49 (2008) 5770–5772
Castro, V.; Brecht, V.; Merfort, I. J. Nat. Prod. 2004, 67, 622–630; (d) Bohlmanng,
F.; Scmeda-Hirschimanjn, G.; Jakupovic, J.; Castro, V.; Ciccio, J. F.; Calvo, G.
Schwichtenberg, L.; Schröder, J.-M. M.; Harder, J. J. Invest. Dermatol. 2006,
126, 121–127.
J. Nat. Prod. 1984, 47, 663–672.
6. Stetter, H. Angew. Chem. 1955, 67, 769.
4. (a) Merten, J.; Hennig, A.; Schwab, P.; Fröhlich, R.; Tokalov, S. V.; Gutzeit, H. O.;
Metz, P. Eur. J. Org. Chem. 2006, 5, 1144–1161; (b) Merten, J.; Fröhlich, R.; Metz,
P. Angew. Chem., Int. Ed. 2004, 43, 5991–5994; (c) Metz, P.; Seng, D.; Plietker, B.
Tetrahedron Lett. 1996, 37, 3841; (d) Wakamatsu, T.; Miyachi, N.; Ozaki, F.;
Shibasaki, M.; Ban, Y. Tetrahedron Lett. 1988, 29, 3829; (e) Kupchan, S. M.;
Baxter, L. R.; Chiang, C. K.; Gilmore, C. J.; Bryan, R. F. J. Chem. Soc., Chem.
Commun. 1973, 842–843.
5. (a) Wagner, S.; Arce, R.; Murillo, R.; Terfloth, L.; Gasteiger, J.; Merfort, I. J. Med.
Chem. 2008, 51, 1324–1332; (b) Krutzik, P. O.; Crane, J. M.; Clutter, M. R.; Nolan,
G. P. Nat. Chem. Biol. 2008, 4, 132–142; (c) Scotti, M. T.; Fernandes, M. B.;
Ferreira, M. J. P.; Emerenciano, V. P. Bioorg. Med. Chem. 2007, 15, 2927–2934;
(d) Boulanger, D.; Brouillette, E.; Jaspar, F.; Malouin, F.; Mainil, J.; Bureau, F.;
Lekeux, P. Vet. Microbiol. 2007, 119, 330–338; (e) Supornsilchai, V.; Soeder, O.;
Svechnikov, K. Reprod. Toxicol. 2006, 22, 631–635; (f) Wehkamp, K.;
7. (a) Marchand, A. P.; LaRoe, W. D.; Sharma, G. V. M.; Suri, S. C.; Reddy, D. S. J. Org.
Chem. 1986, 51, 1622; (b) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103,
5454; (c) Constantino, M. G.; Matias, L. G. O.; da Silva, G. V. J.; Heleno, V. C. G.
Synth. Commun. 1997, 27, 4285.
8. Johnson, F.; Starkovsky, N. A.; Paton, A. C.; Carlson, A. A. J. Am. Chem. Soc. 1966,
88, 149.
9. PCMODEL, version 7.0, Serena Software, PO Box 3076, Bloomington, IN 474-
23076; GMMX, version 1.5, Serena Software, PO Box 3076, Bloomington, IN
474-23076.
10. Minato, H.; Horibe, I. Chem. Commun. 1965, 531.
11. Hanzlik, R. P.; Grieder, A.; Büchi, G. Org. Synth. 1988, 6, 560.
12. (a) Danishefsky, S.; Kitara, T.; Mckee, R.; Schuda, P. F. J. Am. Chem. Soc. 1976, 98,
6715; (b) Roberts, J. L.; Borromeo, P. S.; Poulter, C. D. Tetrahedron Lett. 1977, 19,
1621.