Short and efficient total synthesis of fraxinellone limonoids using the stereoselective Oshima-Utimoto reaction

Article abstract of DOI:10.1021/ol0522687

(Chemical Equation Presented) The catalytic diastereoselective Oshima-Utimoto reaction was employed for the construction of fraxinellone and related members of this limonoid family of natural products. After formation of the five-membered lactone, a stereoselective aldol reaction and olefin metathesis established the bicyclic ring system in the natural products.

Full text of DOI:10.1021/ol0522687

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5465-5468
Short and Efficient Total Synthesis of
Fraxinellone Limonoids Using the
Stereoselective Oshima−Utimoto
Reaction
Ste´phane Trudeau and James P. Morken*
Department of Chemistry, The UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
morken@unc.edu
Received September 19, 2005
ABSTRACT
The catalytic diastereoselective Oshima−Utimoto reaction was employed for the construction of fraxinellone and related members of this
limonoid family of natural products. After formation of the five-membered lactone, a stereoselective aldol reaction and olefin metathesis
established the bicyclic ring system in the natural products.
Fraxinellone 1 and isofraxinellone 2 are the simplest
examples of degraded limonoids and have been isolated from
Rutaceae (Dictamnus albus,1 Dictamnus dasycarpus,2 and
Fagaropsis glabra3) and Meliaceae (Melia azedarach4) plants
(Scheme 1). While these compounds are known for their
as an opportunity to examine the utility of the Pd-catalyzed
Oshima-Utimoto reaction for the assembly of sterically
encumbered lactone targets.8 This transformation brings about
the coupling of simple vinyl ethers and allylic alcohols to
afford cyclic five-membered acetals. Recently, we found that
(2) (a) Zhao, W.; Wolfender, J.-L.; Hostettmann, K.; Xu, R.; Qin, G.
Phytochemistry 1998, 47, 7. (b) Liu, Z. L.; Xu, Y. J.; Wu, J.; Goh, S. H.;
Ho, S. H. J. Agric. Food Chem. 2002, 50, 1447.
Scheme 1
(3) Blaise, A. J.; Winternitz, F. Phytochemistry 1985, 24, 2379.
(4) (a) Nakatani, M.; Huang, R. C.; Okamura, H.; Iwagawa, T.; Tadera,
K. Phytochemistry 1998, 49, 1773. (b) D’Ambrosio, M.; Guerriero, A.
Phytochemistry 2002, 60, 419.
(5) Okamura, H.; Yamauchi, K.; Miyawaki, K.; Iwagawa, T.; Nakatani,
M. Tetrahedron Lett. 1997, 38, 263 and references cited therein.
(6) (a) Yu, S. M.; Ko, F. N.; Su, M. J.; Wu, T. S.; Wang, M. L.; Huang,
T. F.; Teng, C. M. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1992, 345,
349. (b) Wu, T.-S.; Wang, M.-L.; Shyur, H.-J.; Leu, Y.-L.; Chan, Y.-Y.;
Teng, C.-M.; Kuo, S.-C. Chin. Pharm. J. 1994, 46, 447.
ichthyotoxic and insect antifeedant activities,5 fraxinellone
was also shown to have antiplatelet-aggregation and vascular
relaxing activities,6 whereas isofraxinellone has demonstrated
antimutagenic activity.7 We viewed these natural products
(7) Miyazawa, M.; Shimamura, H.; Nakamura, S. I.; Kameoka, H. J.
Agric. Food Chem. 1995, 43, 1428.
(8) (a) Fugami, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1987,
28, 809. (b) Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn.
1989, 62, 2050. For a related processes, see: (c) Hafner, W.; Prigge, H.;
Smidt, J. Liebigs Ann. Chem. 1966, 109. (d) Larock, R. C.; Lee, N. H. J.
Am. Chem. Soc. 1991, 113, 7815. (e) Larock, R. C.; Stinn, D. E. Tetrahedron
Lett. 1989, 30, 2767. (f) Kraus, G. A.; Thurston, J. J. Am. Chem. Soc. 1989,
111, 9203.
(1) (a) Thomas, H. Ber. Dtsch. Pharm. Ges. 1923, 33, 568. (b) Thomas,
H.; Dambergis, C. Arch. Pharm. Chem. 1930, 268, 39.
10.1021/ol0522687 CCC: $30.25
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this transformation can be accomplished in an efficient
catalytic and stereoselective fashion with acyclic substrates,
and that it can provide a useful tool for the synthesis of
interesting natural products, such as (-)-11R,13-dihydrox-
anthatin.9,10 To further probe the utility of this reaction, we
have begun to focus our attention on the synthesis of more
challenging targets such as those that bear quaternary centers
and considered fraxinellone 1 and isofraxinellone 2, as well
as 9R- and 9â-hydroxyfraxinellone (3 and 4)4b and fraxinel-
lonone 52a,4a (Figure 1).
Table 1. Survey of the Catalytic Oshima-Utimoto Reaction
with Alcohol 7a
entry
equiv
oxidant
solvent
temp. (°C)
% 8
1b
2
8
2
2
2
2
2
5
8
4
4
none
neat
25
55
55
55
55
45
45
45
25
25
77
25
25
39
16
42
48
55
60
55
Cu(OAc)2
Cu(OAc)2
BQ
BQ/AcOH
BQ/AcOH
BQ/AcOH
BQ/AcOH
BQ/AcOH
BQ/AcOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
neat
3c
4
5d
6
7
8
9
10e
CH3CN
CH3CN
a Reaction conditions: 10 mol % of Pd(OAc)2, 2.5 equiv of Cu(OAc)2
or 3 equiv of BQ, and 1.1 equiv of AcOH (if any); [7] ) 1.0 M, 16 h of
reaction time; BQ ) benzoquinone. b 100 mol % of Pd(OAc)2 was used.
c 30 mol % of Pd(OAc)2 was used. d [7] ) 0.2 M in CH3CN. e µW ) 300
W, 2 h of reaction time.
Figure 1.
ether instead of n-butyl vinyl ether (Table 1). This strategy
was adopted since we expected that, under acidic conditions
of the Jones oxidation, cleavage of the tert-butyl group might
facilitate oxidation. In an initial experiment, stoichiometric
palladium(II) acetate was employed in neat tert-butyl vinyl
ether at room temperature according to the original conditions
set by Oshima and Utimoto, and acetal 8 was generated in
77% yield (entry 1). Using catalytic palladium (10 or 30 mol
%) and copper(II) acetate as the reoxidant in acetonitrile at
55 °C, low yields of desired product were obtained (entries
2 and 3). When benzoquinone was used as the oxidant, the
yield of product was slightly improved to 39% (entry 3).
Addition of acetic acid was found to be inefficient at first
(entry 4), but lowering the temperature of reaction and raising
the amount of tert-butyl vinyl ether provided a cleaner higher
yielding reaction (entries 6-10). The most efficient reac-
tion was observed with 4 equiv of tert-butyl vinyl ether, 10
mol % of Pd(OAc)2, 3 equiv of benzoquinone, and 1.1 equiv
of acetic acid in acetonitrile at room temperature. Under these
conditions, a 60% yield of desired acetal 8 was obtained
after 16 h with >20:1 stereoinduction at the quaternary center
and with a 2.6:1 ratio of anomers. It is noteworthy that
performing the reaction in a microwave oven at 300 µW
accelerated the reaction, giving acetal 8 in 55% yield after
2 h (entry 10).
While previous total syntheses of fraxinellone11,12 and
isofraxinellone12 involved formation of the lactone moiety
followed by late stage addition of the furan ring, we felt the
Oshima-Utimoto reaction would enable an alternate ret-
rosynthetic analysis. In this sense, we anticipated generating
a key intermediate lactone, with the furan ring already in
place, by executing a catalytic Oshima-Utimoto reaction
followed by Jones oxidation.
Synthesis of fraxinellone 1 and isofraxinellone 2 began
with the preparation of the secondary allylic alcohol 7 by
treatment of (E)-2-bromo-2-butene with t-BuLi in THF at
-78 °C followed by addition of 3-furaldehyde 6 (Scheme
1). Next, the Oshima-Utimoto reaction was examined using
conditions established in our previous report.9 Alcohol 7 was
submitted to 10 mol % of Pd(OAc)2, 2.5 equiv of Cu(OAc)2
as the stoichiometric oxidant, and n-butyl vinyl ether in
acetonitrile at 55 °C for 15 h. Unfortunately, the reaction
was plagued with decomposition of starting material and low
yield of desired product (12%). Furthermore, oxidation of
the newly formed acetal to the lactone with Jones reagent
was also inefficient (20% yield, data not shown).
To improve both the Oshima-Utimoto reaction with
substrate 7 and the subsequent Jones oxidation, we investi-
gated a series of reaction conditions with tert-butyl vinyl
Deprotection and oxidation of tert-butyl acetal 8 with Jones
reagent afforded γ-butyrolactone 9 in good yield (Scheme
2). To prepare for construction of the six-membered ring,
lactone 9 was deprotonated with LDA and the enolate trapped
with 4-penten-2-one (10).13 This aldol reaction furnished
alcohol 11 with complete control of the relative configuration
(9) Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3367.
(10) Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371.
(11) Tokoroyama, T.; Fukuyama, Y.; Kubota, T.; Yokotani, K. J. Chem.
Soc., Perkin Trans. 1 1981, 1557.
(12) Okamura, H.; Yamauchi, K.; Miyawaki, K.; Iwagawa, T.; Nakatani,
M. Tetrahedron Lett. 1997, 38, 263.
5466
Org. Lett., Vol. 7, No. 24, 2005

Scheme 2
Figure 2. X-ray structure of 15.
in a 1:1 ratio of fraxinellone 1 and isofraxinellone 2 in a
combined yield of 79%. This difference in product distribu-
tion can be explained by the fact that the proton R to the
lactone carbonyl in compound 15 is antiperiplanar with re-
spect to the departing oxygen atom and can easily participate
in dehydration to afford fraxinellone 1. The methylene
protons vicinal to the alcohol can also participate and afford
isofraxinellone 2. In contrast, the R-hydrogen in compound
14 is likely orthogonal to the alcohol, and elimination occurs
to provide exclusively isofraxinellone 2 by loss of a
methylene proton. Finally, migration of the double bond in
isofraxinellone can be performed with DBU in benzene to
give fraxinellone 1 in 88% yield.
To access natural products 3-5, isofraxinellone 2 was
treated with m-CPBA in dichloromethane. In this reaction,
the electron-rich trisubstituted alkene reacts with the peracid
faster than the furan ring to produce a 1:1.6 mixture of
epoxides 16 and 17 in 65% yield (Scheme 4).15 While the
epoxidation reaction proceeded with poor stereocontrol, both
at the R-carbon but little control of the newly formed hy-
droxyl stereocenter. While the relative stereochemistry at the
newly formed tertiary alcohol was not controlled, both dia-
stereomers could be separated following ring-closing meta-
thesis with Grubbs’ 2nd generation catalyst to provide tri-
cycles 12 and 13 in 95% yield. Additionally, both diaster-
eomers ultimately converge upon the natural product (vide
infra).
Tricycles 12 and 13 were hydrogenated with 5% palladium
on carbon to provide alcohols 14 and 15 in 84 and 91% yield,
respectively (Scheme 3). The structure and relative config-
Scheme 3
Scheme 4
uration of alcohol 15 was confirmed by single-crystal X-ray
crystallography (Figure 2).14 It is noteworthy that tricycle
12 required 100 psi of hydrogen pressure to perform
hydrogenation of the double bond versus 1 atm for compound
13. Completion of the synthesis was accomplished by
dehydration of tertiary alcohol with thionyl chloride in
pyridine. Alcohol 14 provided exclusively isofraxinellone 2
in 89% yield upon dehydration, while alcohol 15 afforded
Org. Lett., Vol. 7, No. 24, 2005
5467

9R-hydroxyfraxinellone (3) and 9â-hydroxyfraxinellone (4)
could be isolated after DBU-induced epoxide opening.
Compounds 16 and 17 yielded 3 in 91% yield and 4 in 86%
yield, respectively. Fraxinellonone 5 was synthesized by
oxidation with TPAP/NMO of either hydroxyfraxinellone 3
or 4 in 86 and 96% yield, respectively.
reaction in order to improve yield and ease of utilization,
notably by performing the reaction with milder conditions
at room temperature. Current efforts in our laboratories are
now directed at the synthesis of other natural product targets.
Developments regarding these efforts will be reported in due
time.
In summary, we have elaborated an efficient route for the
synthesis of members of the family of fraxinellone using the
catalytic diastereoselective Oshima-Utimoto reaction as the
key step. We also surveyed a set of conditions for this key
Acknowledgment. This work was supported by the NIH
(GM 64451). J.P.M. is a fellow of the Alfred P. Sloan
foundation. The authors thank Dr. Peter White of the UNC
X-ray analysis facility for assistance with crystallography.
Supporting Information Available: Characterization
data, spectra, and experimental procedures (31 pages). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Schmieder-van de Vondervoort, L.; Bouttemy, S.; Padro´n, J. M.;
Le Bras, J.; Muzart, J.; Alsters, P. L. Synlett 2002, 243.
(14) CCDC 283893 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(15) Similar selectivity in alkenyl furans has been noted: Tanis, S. P.;
Herrinton, P. M. J. Org. Chem. 1983, 48, 4572.
OL0522687
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Org. Lett., Vol. 7, No. 24, 2005