Asymmetric synthesis of a model compound for the cyclohexenone core of ambuic acid

Article abstract of DOI:10.1016/j.tetasy.2008.03.023

A model compound for the central core of ambuic acid has been prepared chemoenzymatically from toluene in enantiomerically pure form. An approach to the introduction of the C-9 side chain has also been investigated.

Full text of DOI:10.1016/j.tetasy.2008.03.023

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 893–895
Asymmetric synthesis of a model compound
for the cyclohexenone core of ambuic acid
Maitia Labora, Viviana L. Heguaburu, Enrique M. Pandolfi and Valeria Schapiro*
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de la Repu´blica, CC1157 Montevideo, Uruguay
Received 12 December 2007; revised 14 March 2008; accepted 19 March 2008
Abstract—A model compound for the central core of ambuic acid has been prepared chemoenzymatically from toluene in enantio-
merically pure form. An approach to the introduction of the C-9 side chain has also been investigated.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
construction of a simple, but homochiral model, by means
of an efficient and well-known chemoenzymatic methodol-
ogy12 using a mutant strain of Pseudomonas, Pseudomonas
putida F39/D.13,14
A group of molecules with highly functionalized cyclohexe-
none cores and bearing several stereogenic centers in their
structures have been found in Nature, isolated mainly from
fungal sources.1–5 They exhibit interesting biological prop-
erties such as antibiotic, antimicotic, and antitumoral activ-
ity, among others.6
In the previous work, we have reported the preparation of
polyhydroxylated chiral enones of type I from aromatic
compounds.15 The trihydroxyenone prepared from toluene
(R = CH3, Scheme 1) is a suitable starting material for pre-
paring a chiral model for (+)-ambuic acid, bearing a
methyl group on carbon 5 and lacking the side chains on
carbons 8 and 9 as shown in the retrosynthetic analysis
(Scheme 1). The appropriate starting material for ambuic
acid total synthesis would be an enone of type I obtained
from a microbial metabolite derived from phenylacetalde-
hyde (Scheme 1).
Ambuic acid 1 belongs to this group of molecules (Fig. 1).
It has been isolated from Pestalotiopsis spp. and from one
Monochaetia sp.,7 which are found as endophytic fungi in
several plants;8 it has shown an interesting antifungal activ-
ity toward several species of fungal plant pathogens, thus
suggesting a symbiotic association. Its structure9 consists
of a highly functionalized cyclohexenone bearing three side
chains.
Starting from enone 2, we are able to perform convenient
protection–deprotection steps in order to achieve oxirane
ring closure to give 5. With subsequent inversion of the
configuration of the carbon, which bears the hydroxyl
group, we are able to obtain the desired model molecule
for ambuic acid 7.
18
O
4
15
17
13
11
9
8
5
2
10
7
COOH
1
3
16
14
12
19
O
6
HO
OH
1
Figure 1. Ambuic acid structure and numbering.
2. Results and discussion
Since only a few syntheses of this molecule have been
reported,10,11 it was interesting for us to propose the
According to the synthetic plan shown in Scheme 2, tri-
hydroxyenone 2 was selectively protected on the less hin-
dered secondary hydroxy group by forming a silylether
with bulky dimethylthexylsilyl chloride (THSCl) to give
3.16 Next, the remaining secondary alcohol on 3 was
*
Corresponding author. Tel.: +5982 924 4066; fax: +5982 924 1906;
e-mail: vschapir@fq.edu.uy
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.023

894
M. Labora et al. / Tetrahedron: Asymmetry 19 (2008) 893–895
O
O
O
"C-C"
"C-C"
COOH
COOH
O
O
COOH
O
HO
O
OH
OH
O
HO
OH
Wittig
O
several
steps
ring
Pseudomonas
R
R
R
O
closure
putida F39/D
Mitsunobu
R
R
OH
OH
O
OH
OH
enones type I
OH
OH
model molecule
OH
O
R =
O
for ambuic acid
CH2
2:R = CH3 for the model molecule
Scheme 1. Retrosynthetic analysis of ambuic acid.
H3C
CH3
HO
H3C
O
H3C
CH3
CH3
HO
HO
O
O
OH
OMs
O
O
O
O
O
O
i) e
OH
OH
b
a
c
d
ii) f
OTHS
OTHS
OTHS
OH
OH
2
3
4
5
6
7
g
CH3
HO
CH3
HO
CH3
HO
O
O
O
O
O
O
i
h
O
C5H11
O
I
O
9
10
8
Scheme 2. Preparation of model molecules. Reagents and conditions: (a) THSCl, imidazole, DMF, 0 °C, 98%; (b) MsCl, Et3N, CH2Cl2, 0 °C, 45%; (c)
K2CO3, 18-crown-6, THF, 0 °C, 76%; (d) Py-HF, THF, 0 °C to rt, 64%; (e) PPh3, benzene, rt, then p-nitrobenzoic acid, rt, then DEAD, rt; (f) K2CO3,
MeOH, À20 °C, 22%; (g) DMP, acetone, rt, 95%; (h) I2, DMAP, CH2Cl2, 50 °C, 77%; (i) trans-1-heptenylboronic acid, Pd(PPh3)4, K2CO3, THF–H2O,
reflux, 50%.
mesylated to 4, to provide a good leaving group for the ring
closure to 5.
Table 1. Reagents and conditions for introducing a good leaving group on
carbon 3
Several reagents were assayed for the introduction of the
leaving group on carbon 3 (Table 1).
Entry
1
Reagents and conditions
Products
p-Toluensulfonylchloride,
Py, rt
No reaction in 72 h
Neither triflate nor tosylate could be obtained with satis-
factory yields, but the mesylation of 3 under the conditions
shown in entry 2 was carried out with acceptable results.
2
3
4
CH3SO2Cl, Et3N, CH2Cl2,
0 °C
CH3SO2Cl, Py, CH2Cl2,
0 °C
(CF3SO2)2O, DMAP,
CH2Cl2, 0 °C
4 (45%) + 5 (39%)
4 (13%) + decomposition
products
4 (20%) + 11
The treatment of 4 in basic medium permitted oxirane ring
closure, leading to compound 5 and thus demonstrating
that the proposed methodology is useful for the prepara-
tion of chiral epoxyenones. The following steps consisted
of the deprotection of the silylated hydroxyl group and fur-
ther the inversion of configuration through a Mitsunobu
reaction, leading to the desired model molecule of the cen-
tral core of ambuic acid 7. The Mitsunobu reaction proved
(traces)* + decomposition
products
*
O
O
OTHS
11

M. Labora et al. / Tetrahedron: Asymmetry 19 (2008) 893–895
895
3. Li, C.; Lobkovsky, E.; Porco, J. J. Am. Chem. Soc. 2000, 122,
10484.
4. Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582–
1583.
troublesome, although it could be optimized by the addi-
tion of p-nitrobenzoic acid before DEAD with acceptable
yield (Scheme 2).
5. Block, O.; Klein, G.; Altenbach, H.-J.; Brauer, D. J. J. Org.
Chem. 2000, 65, 716–721.
6. Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev.
2004, 104, 2857–2899.
7. Li, J. Y.; Harper, J. K.; Grant, D. M.; Tombe, B. O.; Bashyal,
B.; Hess, W. M.; Strobel, G. A. Phytochemistry 2001, 56,
463–468.
We also investigated the introduction of a heptenyl side
chain corresponding to carbon 9 of the ambuic acid, on
acetonide 8, as shown in Scheme 2. This was successfully
achieved by a-iodination17 and further Suzuki coupling18
with trans-1-heptenylboronic acid19 in 39% overall yield.
8. Strobel, G. A. Microb. Infect. 2003, 5, 533–544.
9. Harper, J. K.; Barich, D. H.; Hu, J. Z.; Strobel, G. A.; Grant,
D. M. J. Org. Chem. 2003, 68, 4609–4614.
10. Li, C.; Johnson, R. P.; Porco, J. J. Am. Chem. Soc. 2003, 125,
5095.
All the compounds were purified by column chromato-
graphy, their optical rotations were determined and they
were fully characterized by spectroscopic methods.
11. Metha, G.; Chandra Pan, S. Tetrahedron Lett. 2005, 46,
3045–3048.
3. Conclusion
12. Hudlicky, T.; Gonzalez, D.; Gibson, D. T. Aldrichim. Acta
1999, 32, 35.
13. Gibson, D. T.; Koch, J.; Kallio, R. Biochemistry 1968, 7,
2653–2662.
14. Gibson, D. T.; Hensley, M.; Yoshiota, H.; Mabry, T. J.
Biochemistry 1970, 9, 1626–1630.
15. Schapiro, V.; Cavalli, G.; Seoane, G. A.; Faccio, M.;
Mombru, A. W. Tetrahedron: Asymmetry 2002, 13, 2453–
2459.
16. Hudlicky, T.; Boros, C. H.; Boros, E. E. Synthesis 1992, 174–
178.
17. Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.;
Shibasaki, H. J. Am. Chem. Soc. 2002, 124, 14546–14547.
18. Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94,
4370–4371.
We have developed a chemoenzymatic synthetic methodol-
ogy for the synthesis of chiral epoxy enones, thus obtaining
a valuable chiral model molecule for ambuic acid. We have
also demonstrated the introduction of alkene side chains by
means of Suzuki C–C coupling on this highly functional-
ized core. We are currently investigating the total synthesis
of ambuic acid using sulphonylcarbanion chemistry for the
introduction of the hydroxymethylene group on carbon
8.20 We are also attempting the synthesis of other natural
epoxyenones6 such as bromoxone and parasitenone.
References
19. Urdaneta, N.; Ruiz, J.; Zapata, A. J. J. Organomet. Chem.
1994, 464, C33–C34.
20. Pandofi, E.; Comas, H. Synthesis 2004, 15, 2493–2498.
1. Hu, Y.; Li, C.; Kulkarni, A. B.; Strobel, G.; Lobkovsky, E.;
Torczynsky, R. M.; Porco, J. A. Org. Lett. 2001, 3, 1649.
2. Johnson, C. R.; Miller, M. J. Org. Chem. 1995, 60, 6674.