date, no catalytic asymmetric approach toward these eudes-
manes has been developed. Herein, we report an approach9
that incorporates our recent method for the catalytic asym-
metric formation of enantioenriched all-carbon quaternary
stereocenters into a general synthetic strategy for this class
of sesquiterpenoids.
stereocenter,10 and we therefore sought to develop an efficient
and selective means for the preparation of this moiety.
The enantioselective alkylation of ketone enolates is an
area of intense investigation in our laboratory.11 This method
has resulted in the preparation of wide range of carbonyl
compounds with adjacent quaternary stereocenters with high
levels of selectivity and excellent yields, some of which have
proved valuable in synthetic endeavors.12 The application
of R-quaternary ketones such as 8 for the devised strategy
would require a carbonyl transposition (i.e., 8 f 7), and we
therefore chose to exploit the unique properties of vinylogous
esters (i.e., 8 where R2 ) OR) pioneered by Stork and
Danheiser13 for this purpose.
In devising a strategy for accessing the eudesmanes, we
simplified our target to enone 5, which has been utilized in
the preparation of structures such as 4,6d and itself embodies
many features present in various family members (cf. 5 and
1, 2) (Scheme 1). We envisioned that the stereochemistry
Our initial studies for the asymmetric generation of
quaternary stereocenters utilitzing vinylgous ester derivatives
focused on enol carbonates due to preliminary
investigations12c,14 that have demonstrated successes for
similar substrates. Exposure of allyl enol carbonate 9 to
typical reaction conditions consisting of a palladium(0)
catalyst and ligand (S)-1215 in toluene generated vinylogous
ester (+)-13, albeit in variable yield and selectivity (Table
1, entry 1). Unfortunately, the instability of 9 impeded further
Scheme 1. Retrosynthetic Analysis of the Eudesmanes
Table 1. Asymmetric Allylation of Vinylogous Ester
Derivativesa
of the C(7) substituent could arise by means of the diaste-
reoselective hydrogenation of a substituted cyclohexene (i.e.,
6), the stereochemical outcome of which would be controlled
by the C(10) quaternary stereocenter. This cyclohexene could
be obtained from a ring-closing methathesis of triolefin 7,
which would be derived from an appropriately substituted
R-quaternary ketone (i.e., 8). Thus, the key control element
in the design of this synthetic strategy is the C(10) quaternary
entry substrate solvent T (°C) product yieldb (%) eec (%)
(2) Fraga, B. M. Nat. Prod. Rep. 2007, 24, 1350–1381.
1
2
3
4
5
6
7
9
10
10
11
11
11
11
PhMe
PhMe
PhMe
PhMe
PhH
25
50
80
50
50
50
50
13
13
13
14
14
14
14
22-61
19d
86
84-88
79
(3) For the isolation and biological activity of (+)-carissone, see: (a)
Mohr, K.; Schindler, O.; Reichstein, T. HelV. Chim. Acta 1954, 37, 462–
471. (b) Joshi, D. V.; Boyce, S. F. J. Org. Chem. 1957, 22, 95–97. (c)
Achenbach, H.; Waibel, R.; Addae-Mensah, I. Phytochemistry 1985, 24,
2325–2328. (d) Lindsay, E. A.; Berry, Y.; Jamie, J. F.; Bremner, J. B.
Phytochemistry 2000, 55, 403–406.
75
92
92
92
86
61e
88
(4) For the isolation and biological activity of (+)-3-oxocostusic acid,
see: (a) Bohlmann, F.; Jakupovic, J.; Lonitz, M. Chem. Ber. 1977, 110,
301–314. (b) Khanina, M. A.; Kulyyasov, A. T.; Bagryanskaya, I. Y.;
Gatilov, Y. V.; Adekenov, S. M.; Raldugin, V. A. Chem. Nat. Compd. 1998,
34, 145–147. (c) Al-Dabbas, M. M.; Hashinaga, F.; Abdelgaleil, S. A. M.;
Suganuma, T.; Akiyama, K.; Hayashi, H. J. Ethnopharmacol. 2005, 97,
237–240. (d) Mohamed, A. E.-H.; Ahmed, A. A.; Wollenweber, E.; Bohm,
B.; Asakawa, Y. Chem. Pharm. Bull. 2006, 54, 152–155.
THF
dioxane
90
91
a pmdba ) bis(4-methoxybenzylidene)acetone. b Isolated yields.
c Enantiomeric excess determined by chiral HPLC or SFC. d ꢀ-Ketoester
(()-10 was recovered in 69% yield. e ꢀ-Ketoester (()-11 was recovered in
26% yield.
(5) For the isolation and biological activity of R-eudesmol, see: (a)
McQuillin, F. J.; Parrack, J. D. J. Chem. Soc. 1956, 2973–2978. (b) Asakura,
K.; Kanemasa, T.; Minagawa, K.; Kagawa, K.; Ninomiya, M. Brain Res.
1999, 823, 169–176. (c) Toyota, M.; Yonehara, Y.; Horibe, I.; Minagawa,
K.; Asakawa, Y. Phytochemistry 1999, 52, 689–694. (d) Asakura, K.;
Kanemasa, T.; Minagawa, K.; Kagawa, K.; Yagami, T.; Nakajima, M.;
Ninomiya, M. Brain Res. 2000, 873, 94–101.
studies as these results were highly dependent on the
composition of this enol carbonate.16 Given the range of
substrate possibilities for this transformation,11d we next
focused on racemic ꢀ-ketoester (()-10. Surprisingly, this
substrate proved only modestly reactive at 50 °C, producing
ketone (+)-13 in 19% yield and 79% ee (entry 2).17
Increasing the reaction temperature to 80 °C enabled
complete conversion to ketone (+)-13, although with slightly
reduced selectivity (entry 3). As the lack of reactivity seemed
to be a major complication with this substrate, we considered
vinylogous thioesters (i.e., (()-11) for their reported activa-
(6) For syntheses of carissone, see: (a) Pinder, A. R.; Williams, R. A.
J. Chem. Soc. 1963, 2773–2778. (b) Sathe, V. M.; Rao, A. S. Indian
J. Chem. 1971, 9, 95–97. (c) Kutney, J. P.; Singh, A. K. Can. J. Chem.
1982, 60, 1842–1846. (d) Wang, C.-C.; Kuoh, C.-S.; Wu, T.-S. J. Nat. Prod.
1996, 59, 409–411. (e) Aoyama, Y.; Araki, Y.; Konoike, T. Synlett 2001,
9, 1452–1454.
(7) For syntheses of 3-oxocostusic acid, see: (a) Ceccherelli, P.; Curini,
M.; Marcotullio, M. C.; Rosati, O. Tetrahedron Lett. 1990, 31, 3071–3074.
(b) Xiong, Z.; Yang, J.; Li, Y. Tetrahedron: Asymmetry 1996, 7, 2607–
2612.
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