Communications
(1:1:0.5; 6 mL), and the resulting mixture was stirred at room
temperature for 2 h. 2-Propanol (1 mL) was then added to the
reaction mixture, and the mixture was filtered through a pad of Celite.
The solid mass collected was washed with EtOAc. The filtrate was
then washed with an aqueous NaHCO3 solution (0.5m; 10 mL), and
the aqueous layer was acidified with 1n HCl (pH 2) and then
extracted with EtOAc (2 ꢀ 20 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. Purification of the crude compound by column chromatog-
raphy on silica gel (gradient elution with 25–30% EtOAc in hexane)
yielded pure 2 (92 mg, 78%) as a foamy solid. IR (neat): v = 2931,
1
2857, 1724, 1452, 1272, 1111, 710 cmÀ1; H NMR (400 MHz, CDCl3):
Scheme 4. Stereoselective synthesis of protected cis-(2R,3S)-3-hydroxy-
pipecolic acid 37. Ts=p-toluenesulfonyl.
d = 7.96–7.94 (m, 2H), 7.48–7.47 (m, 1H), 7.37–7.34 (m, 2H), 4.53 (t,
J = 6.2 Hz, 2H), 2.78 ppm (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d = 176.2, 166.3, 133.2, 129.8, 129.7, 128.4, 59.9, 33.7 ppm;
HRMS (ESI): m/z calcd for C10H10O4Na: 217.0473 [M+Na]+; found:
217.0477.
Received: October 22, 2009
Published online: December 28, 2009
Keywords: benzylidene acetals · hydroxy carboxylic acids ·
.
oxidation · regioselectivity · terminal alkenes
[2] a) C. M. Coppola, H. F. Schuster, a-Hydroxy Acids in Enantio-
selective Syntheses, VCH, Weinheim, 1997; b) S. Hanessian, Total
Synthesis of Natural Products: The Chiron Approach, Pergamon,
New York, 1983, chap. 2: c) S. M. Roberts in Comprehensive
Organic Chemistry, Vol. 2 (Eds.: I. O. Sutherland, D. H. Barton,
W. D. Ollis), Pergamon, Oxford, 1979, pp. 743 – 747; d) J. O.
Bunte, A. N. Cuzzupe, A. M. Daly, M. A. Rizzacasa, Angew.
R. M. Hanson, J. M. Klunder, Y. K. Soo, H. Masamune, K. B.
6137; d) K. B. Sharpless, T. R. Verhoeven, Aldrichimica Acta
1979, 12, 63 – 74.
Scheme 5. Plausible mechanism for the direct oxidation of benzylidene
acetals to benzoyloxy carboxylic acids.
a less hindered oxygen atom of the benzylidene acetal is
followed by nucleophilic attack of oxygen atom “a” of the
ruthenium reagent at the benzylic carbon atom. Subsequent
carbon–oxygen bond cleavage would lead to intermediate 1b.
Reductive elimination of intermediate 1b would then lead to
the formation of intermediate 1c, the further oxidation of
which via 1d would furnish the corresponding b-benzoyloxy
carboxylic acid 2.
In conclusion, novel and facile methodology has been
developed for the direct oxidation of benzylidene acetals to
the corresponding a- and b-benzoyloxy carboxylic acids with
the reagent system RuCl3–NaIO4. Salient features of this
methodology are 1) its high stereo- and regioselectivity, 2) the
mild reaction conditions, and 3) the stability of reactive
functional groups, such as TBDPS ether, azide, ester, and
N-Ts groups, under the reaction conditions. This methodology
provides ready access to synthetically useful chiral a-benzoyl-
oxy carboxylic acids from terminal olefins. The synthetic
potential of this methodology was further exemplified by the
stereoselective synthesis of protected biologically active cis-
(2R,3S)-3-hydroxypipecolic acid from d-glucose. We strongly
believe that this reaction will find broad application in
synthetic organic chemistry.
[5] M. P. Bousquet, R. M. Willemot, P. Monsan, E. Boures, J. Mol.
[6] a) D. A. Evans, M. M. Morrissey, R. L. Dorow, J. Am. Chem.
1047 – 1050; f) T. C. Michael, A. E. Kyle, J. D. Katz, Org. Lett.
2000, 2, 2165 – 2167, and references therein; g) B. E. Howard,
therein.
[7] a) T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
´
Synthesis, Wiley, New York, 1999; b) P. J. Kocienski, Protecting
Groups, Georg Thieme, New York, 1994; c) S. Hanessian,
Preparative Carbohydrate Chemistry, Marcel Dekker, New
Experimental Section
Typical procedure: NaIO4 (652 mg, 3.05 mmol) and RuCl3·3H2O
(12.6 mg, 0.061 mmol) were added successively to a stirred solution of
1 (100 mg, 0.61 mmol) in the solvent system CH3CN/CCl4/H2O
106 – 112; b) M.-C. Yan, Y.-N. Chen, H.-T. Wu, C.-C. Lin, C.-T.
806
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 804 –807