Organic Letters
Letter
(6) (a) Ramachandran, P. V.; Chanda, P. B.; Otoo, B. Tetrahedron
Lett. 2014, 55, 1289. (b) Ramachandran, P. V.; Otoo, B.; Chanda, P. B.
Tetrahedron Lett. 2015, 56, 3019.
(7) TMSOTf-mediated aldol reactions of acetic acid, propionic acid,
and butyric acid were also reported: Downey, C. W.; Johnson, M. W.;
Lawrence, D. H.; Fleisher, A. S.; Tracy, K. J. J. Org. Chem. 2010, 75,
5351.
(8) Borinic acid catalyzed direct aldol reactions of pyruvic acids
containing highly acidic α-protons were reported: Lee, D.; Newman, S.
G.; Taylor, M. S. Org. Lett. 2009, 11, 5486.
In summary, we developed the first carboxylic acid selective
aldol reaction mediated by boron compounds. The introduc-
tion of electron-withdrawing N-sulfonyl amino acid ligands on
the boron atom enhanced the Lewis acidity of the boron atom,
thereby facilitating carboxylic acid selective enolate formation,
even in the presence of other carbonyl groups such as ketones,
esters, amides, or aliphatic aldehydes. Moreover, the high
functional group tolerance of the reaction was applicable to
late-stage diversification of drugs and drug-like molecules.
Further exploration of catalytic asymmetric aldol reactions of
carboxylic acids and elucidation of the reaction mechanism are
ongoing in our laboratory.
(9) Morita, Y.; Yamamoto, T.; Nagai, H.; Shimizu, Y.; Kanai, M. J.
Am. Chem. Soc. 2015, 137, 7075.
(10) For selected examples of catalytic electrophilic activation of
carboxylic acids with boron compounds, see: (a) Furuta, K.; Miwa, Y.;
Iwanaga, K.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 6254.
(b) Maki, T.; Ishihara, K.; Yamamoto, H. Tetrahedron 2007, 63, 8645.
(c) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed.
2008, 47, 2876. (d) Zheng, H.; McDonald, R.; Hall, D. G. Chem. - Eur.
J. 2010, 16, 5454. (e) Azuma, T.; Murata, A.; Kobayashi, Y.; Inokuma,
T.; Takemoto, Y. Org. Lett. 2014, 16, 4256. (f) Ishihara, K.; Lu, Y.
Chem. Sci. 2016, 7, 1276.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
Experimental procedure, mechanistic study, character-
(11) For the investigation of other boron compounds and bases, see
1
ization data, and copies of H, and 13C NMR spectra
(12) Brown, H. C.; Stocky, T. P. J. Am. Chem. Soc. 1977, 99, 8218.
(13) For selected examples of the combined use of amino acid
derived ligands and BH3, see: (a) Kiyooka, S.; Kaneko, Y.; Komura,
M.; Matsuo, H.; Nakano, M. J. Org. Chem. 1991, 56, 2276. (b) Yeung,
Y.-Y.; Corey, E. J. Org. Lett. 2008, 10, 3877.
(14) The observed positive ligand effects of Ts-L-Val can be partly
explained by enhanced acidity of the α-protons of the carboxylic acid
after covalent bond formation with the ligand-chelated boron
promoter. The pKa values of the α-proton of the following
acyloxyboranes were calculated by the Jaguar v8.5 pKa module
AUTHOR INFORMATION
Corresponding Authors
■
Author Contributions
§H.N. and Y.M. contributed equally.
(Schrodinger, LLC, New York, NY, 2013), suggesting that the
̈
Notes
substituent of the ligand’s nitrogen atom markedly affects acidity of the
α-proton.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT (M.K.) and
a Grant-in-Aid for Scientific Research (C) from the JSPS (Y.S.).
(16) Steric hindrance of the amino acid-derived ligands prevented the
ligands from being reduced by BH3·SMe2. When Ts-L-Ala and Ts-L-
Phe were mixed with propionic acid and BH3·SMe2 in a 1:2:1 ratio, the
corresponding alcohols derived from the ligands were detected in 51%
and 14% yield, respectively. In contrast, no reduction was observed
when Ts-L-Val was mixed with propionic acid and BH3·SMe2.
(17) For the reaction between aromatic aldehyde 1a and 2a, the
optimized conditions for the aliphatic aldehydes were inferior to the
conditions of Table 1, entry 17: using L2, 3aa was obtained in 73%
yield with a syn/anti ratio of 1.4/1.
We thank Dr. Daisuke Yoshidome (Schrodinger, LLC) for
helpful suggestions about pKa calculation.
̈
REFERENCES
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