C O M M U N I C A T I O N S
Figure 1. Pre-transition-state assembly for the reaction of 2, 4, and S-5
leading to S-6.
Although there have been several studies of enantioselective
Michael reactions of silyl ketene acetals catalyzed by chiral Lewis
acids,7,10 the cases reported herein represent the first examples of
such reactions with R,â-cycloalkenones, as far as we are aware.
The enantioselective methodology described herein is illustrated
by the application to the synthesis of R-3, a key intermediate for
the enantioselective synthesis of caryophyllene, and also to the
synthesis of the chiral bridged-ring product R-9. Further research
on new applications is in progress.
acetal 4, 0.2 equiv of catalyst S-5, 0.25 equiv of Ph3PO, and 1.5
equiv of DIPP in toluene at -20 °C for 24 h produced the Michael
adduct 17 in 87% yield and 90% ee. This reaction was also
regioselective and followed the selection rules for [2+4] cycload-
dition reactions of 1,4-dienes to 1,4-benzoquinones that have been
described elsewhere.2d Effectively, the regiochemistry follows from
the pathway involving favored coordination of catalyst S-5 to the
sterically less-screened carbonyl oxygen at C(4) of the quinone 16.
Supporting Information Available: Experimental procedures for
the reactions described herein and characterization data (13 pp). This
References
(1) (a) Corey, E. J.; Mitra, R. B.; Uda, H. J. Am. Chem. Soc. 1963, 85, 362-
363. (b) Corey, E. J.; Mitra, R. B.; Uda, H. J. Am. Chem. Soc. 1964, 86,
485-492. (c) Corey, E. J.; Bass, J, D.; Le Mahieu, R. E.; Mitra, R. B. J.
Am. Chem. Soc. 1964, 86, 5570-5583.
(2) (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002,
124, 9992. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125,
6388. (d) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 4800. (e) Hu, Q.-Y.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 13708. For selected examples of enantioselective, intramolecular
Diels-Alder reactions, see: (f) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org.
Lett. 2003, 5, 3979. (g) Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc.
2006, 128, 740-742. (h) Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006,
128, 1346-1352.
(3) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384-5387.
(4) The reaction was considerably slower at -78 °C, but the enantioselectivity
was the same. Distinctly lower enantioselectivity was observed in the
absence of Ph3PO or in CH2Cl2 as solvent.
We also examined the reactions of the silyl tert-butylthio ketene
acetal 18 with the acyclic R,â-enones 19 and 20 as compared to
the cyclic R,â-enones discussed above. Under the standard condi-
tions (0.2 equiv S-5, 0.25 equiv of Ph3PO, 3 equiv of DIPP), with
a reaction time of 24 h, the Michael adducts 21 (94% yield, 90%
ee) and 22 (99% yield, 84% ee) resulted. The chiral Michael
(5) The absolute configuration of the product using the catalyst S-5 was shown
to be S-6 by application of the octant rule and also by comparison of
optical rotation with S-6 that had been made by a different method and
correlated with a known standard. See Chordia, M. D.; Harman, W. D. J.
Am. Chem. Soc. 2000, 122, 2725-2736.
products 21 and 22 had previously been described and the absolute
configurations had been determined by correlation with the corre-
sponding methyl esters.7 Thus, the absolute configurations of 21
and 22 obtained using catalyst S-5 followed from comparison by
chiral-phase HPLC analysis with reported data.7
(6) The use of Me2CdC(OEt) (OTMS) instead of Me2CdC(OMe) (OTMS)
(4) in this and the other Michael reactions described herein led to the
same yields and ee’s of the corresponding ethyl esters of the Michael
products.
(7) Harada, T.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A. Org.
Lett. 2001, 3, 2101-2103. The rates of the various Michael additions to
R,â-enones (including 2-cyclohexenone) are accelerated by DIPP.
(8) The absolute configurations of the Michael adducts 11-15 were assigned
by analogy with the proven stereochemical course for the formation of
R-6 and S-6 from 2 and 4. Enantioselectivities of all the enantioselective
Michael reactions of R,â-enones reported herein were determined by HPLC
analysis using a Chiral Technologies Chiralpak IA, OD-H, OJ, or AD
analytical column with hexane-2-propanol (99:1) for elution.
(9) In the reaction leading to the Michael adduct 15, best results were obtained
by slow addition (syringe drive over 3-4 h) of a solution in toluene of
DIPP and 2-cyclohexenone to the other reactants at -20 °C in toluene.
(10) (a) Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T. Chem. Lett.
1994, 97-100. (b) Bernardi, A.; Colombo, G.; Scolastico, C. Tetrahedron
Lett. 1996, 37, 8921-8924. (c) Bernardi, A.; Karamfilova, K.; Sanguinetti,
S.; Scolastico, C. Tetrahedron 1997, 53, 13009-13026. (d) Kitajima, H.;
Ito, K.; Katsuki, T. Tetrahedron 1997, 17015-17028. (e) Nishikori, H.;
Ito, K.; Katsuki, T. Tetrahedron: Asymmetry 1998, 9, 1165-1170. (f)
Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.; Tedrow, J.
S. J. Am. Chem. Soc. 2000, 122, 9134-9142.
The absolute stereochemical course of the enantioselective
Michael addition of 2-cyclohexenone (2) and 1-methoxy-2-methyl-
1-(trimethylsilyloxy)propene (4) in the presence of the catalyst S-5
can be rationalized by the pre-transition-state assembly, shown in
Figure 1. The mode of complexation of the R,â-enones 2 is the
same that has previously been shown to be reliably predictive of
the absolute configuration of Diels-Alder products from R,â-
enones, R,â-unsaturated esters and lactones, and 1,4-benzoquinones
with 1,3-dienes under catalysis by S-5. Because of shielding the
rear face of the R,â-enones, as depicted in Figure 1, attack by the
silyl ketene acetal 4 on the re face of C(â) of the coordinated R,â-
enones (i.e, the front face in Figure 1). A parallel analysis
successfully predicts the absolute configurations of the products
21 and 22.
JA063332Y
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