C O M M U N I C A T I O N S
temperature, affording the product in quantitative yield with a
diastereomeric ratio of 14/1.16 The reaction could be performed
using 1 mol % of the Cu catalyst (24 h), but the diastereoselectivity
diminished to 5.6/1 (entry 10). Further, we confirmed that no
epimerization of the tertiary chiral center occurred during this
allylation reaction.
contributions during the initial stage. Financial support was provided
by a Grant-in-Aid for Young Scientists (S) and Scientific Research
(S) from JSPS. R.M. and Y.S. thank JSPS for the research
fellowships.
Supporting Information Available: Experimental procedures,
characterization of the products, ESI-MS studies of the Y-catalyst
composition, and a proposed catalytic cycle of CuF-catalyzed allylation
of 3. Complete ref 2a was also included. This material is available
Having established the catalytic asymmetric route to enantio-
merically pure key intermediate 2, the remaining tasks included
converting the allyl group to a dimethylaminoethyl group and the
protected quinolinone moiety to a brominated methoxyquinoline
(Scheme 3). After cleaving the N-methoxymethyl (MOM) group,
ozonolysis followed by reductive treatment produced diol 16.
Regioselective bromination of 16 with NBS proceeded in 83% yield
in the presence of buffering NaOAc. The use of DMF as a solvent
was critical in this conversion. Selective O-methylation of 17 was
problematic because the substrate contained undesired competitive
nucleophilic sites. Although most of the attempted combinations
of bases and methylating reagents produced undesired N-methylated
products, a combination of Ag2CO3 and MeI17 selectively produced
the desired O-methylation product. In this case, however, overm-
ethylation occurred at the primary alcohol oxygen atom. This side
reaction was effectively suppressed by adding a dummy substrate,
EtOH, to the reaction mixture. Thus, the desired product 18 was
obtained in 63% yield. Finally, O-tosylation followed by substitution
with Me2NH afforded R207910 (1). The spectroscopic data of
synthetic 1 were consistent with the reported data in all aspects,3,18
References
(1) (a) Thayer, A. Chem. Eng. News 2007, 85, 21. (b) Janin, Y. L. Bioorg.
Med. Chem. 2007, 15, 2479. (c) Gutierrez-Lugo, M.-T.; Bewley, C. A.
J. Med. Chem. 2008, 51, 2606.
(2) (a) Andries, K.; et al. Science 2005, 307, 223. (b) Koul, A.; Dengouga, N.;
Vergauwen, K.; Molenberghs, B.; Vranckx, L.; Willebrords, R.; Ristic, Z.;
Lill, H.; Dorange, I.; Guillemont, J.; Bald, D.; Andries, K. Nat. Chem.
Biol. 2007, 3, 323.
(3) (a) van Gestel, J. F. E.; Guillemont, J. E. G.; Venet, M. G.; Poignet, H. J. J.;
Decrane, L. F. B.; Odds, F. C. U.S. Patent 2005/0148581. (b) The overall
yield of this reported route was less than 1%.
(4) Wang, J.-J.; Hu, W.-P. J. Org. Chem. 1999, 64, 5725.
(5) (a) Hoyos, P.; Sansottera, G.; Fernandez, M.; Molinari, F.; Sinisterra, J. V.;
Alcantara, A. R. Tetrahedron 2008, 64, 7929. (b) Niu, M.; Fu, H.; Jiang,
Y.; Zhao, Y. Synthesis 2008, 2879.
(6) (a) See Supporting Information (SI). (b) Only a single set of 1H and 13C
NMR signals was observed for 4 at room temperature, possibly due to
rapid E/Z isomerization of the double bond.
(7) Inoue, S.; Takaya, H.; Tani, K.; Otsuka, S.; Sato, T.; Noyori, R. J. Am.
Chem. Soc. 1990, 112, 4897.
(8) Morita, M.; Drouin, L.; Motoki, R.; Kimura, Y.; Fujimori, I.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3858.
including the optical rotation ([R]26 ) -168.0 (c ) 0.3, DMF),
D
ref.: [R]20 ) -166.98 (c ) 0.5, DMF)3).
(9) Enone 4 gradually converted to 3, even in the absence of any catalyst at
room temperature, indicating that 3 is thermodynamically more stable than
4.
(10) Racemic 3 was produced from 4 in 33% yield in the presence of 2 mol %
of Bu4NCl (in the absence of an asymmetric catalyst) at -50 °C for 60 h.
(11) It was confirmed that no racemization of 3 occurred during the reaction
time course under the optimized conditions.
D
Scheme 3. Completion of the Synthesisa
(12) (a) The peak corresponding to the ternary complex was not observed in
the presence of Bu4NCl. Instead, binary complex 11 was the predominant
species. Nonetheless, we assume that the ternary complex is the actual
catalyst based on the fact that enantioselectivity was significantly increased
in the presence of MEPO. (b) ESI-MS provided valid structural information
for the related rare earth metal catalysts. For example, see: Kato, N.; Mita,
T.; Kanai, M.; Therrien, B.; Kawano, M.; Yamaguchi, K.; Danjo, H.; Sei,
Y.; Sato, A.; Furusho, S.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128,
6768.
(13) (a) Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 8910. (b) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 6536. (c) Wada, R.; Shibuguchi,
T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2006, 128, 7687.
(14) (a) Gulliner, D. J.; Levason, W.; Webster, M. Inorg. Chim. Acta 1981, 52,
153. (b) The constitutional crystalline solvent EtOH was essential for the
promotion of this reaction.
a Reagents and conditions: (a) B-bromobenzodioxaborole, CH2Cl2, 83%.
(b) O3, MeOH/H2O; NaBH4, 74%. (c) NBS, NaOAc, DMF, 83%. (d) MeI,
Ag2CO3, EtOH, CH3CN, 63%. (e) TsCl, DMAP, py, 90%. (f) Me2NH, DMF,
H2O, 62%.
(15) Attempts to improve the diastereoselectivity through chiral ligand control
were not successful. In the presence of chiral bisphosphines, unexpected
R-C-Ccarbonyl bond cleavage subsequent to the allyl addition to the ketone
occurred.
In conclusion, we achieved the first asymmetric synthesis of
R207910 by developing two key catalytic transformations: a
catalytic enantioselective proton migration reaction of 4 to 3 using
a bimetallic Y-complex and a CuF-catalyzed diastereoselective
allylation of ketone 3 to 2. This synthesis includes 12 of the longest
linear steps from commercially available materials6a with an overall
yield of 5%. Further improvement of the synthetic efficiency and
elucidation of the mechanism of the two key catalytic reactions
are currently ongoing.
(16) (a) Preliminary studies using 11B and 19F NMR suggested that ZnFCl and
Bu4PBF3Cl might be generated from the additives. A ZnFCl species would
have higher Lewis acidity than ZnCl2, which might be beneficial for the
improvement of the diastereoselectivity by favorably forming chelate 15.
(b) For a proposed catalytic cycle of this allyboration including possible
roles of additives, see SI.
(17) For examples of O-methylation of quinolinone derivatives using Ag2CO3
as a base, see: (a) Morel, A. F.; Larghi, E. L.; Selvero, M. M. Synlett 2005,
2755. (b) Bodendiek, S. B.; Mahieux, C.; Ha¨nsel, W.; Wulff, H. Eur. J. Med.
Chem. 2009, 44, 1838.
(18) (a) Gaurrand, S.; Desjardins, S.; Meyer, C.; Bonnet, P.; Argoullon, J.-M.;
Oulyadi, H.; Guillemont, J. Chem. Biol. Drug Des. 2006, 68, 77. (b) Petit,
S.; Coquerel, G.; Meyer, C.; Guillemont, J. J. Mol. Struct. 2007, 837, 252.
Acknowledgment. We acknowledge Drs. Reiko Wada, Nobu-
hisa Fukuda, Masataka Morita, and Rolf Roesmann for their
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