by auxiliaries,9 chiral oxidizing reagents,10 chiral catalysts,11
chiral phase transfer catalysts, and enzymes12 has also been
reported. Furthermore, it appears in the literature that the
most standard method extensively used in recent years is
the oxidation of oxazolidinone-based chiral amide enolates
with Davis’ oxaziridine.13 Intriguingly, the very attractive
oxidation with molecular oxygen has not yet been developed
for the synthesis of enantiopure compounds by mean of chiral
auxiliaries-based methods. This is probably due to the poor
stability of the intermediate hydroperoxides. To the best of
our knowledge, the only example of a diastereoselective
hydroxylation of a chiral amide enolate in the presence of
molecular oxygen was reported by Adam et al.14 In this
pioneering work, the authors reported the autoxidation of
an amide titanium enolate using (S)-prolinol as chiral
auxiliary. The resulting chiral R-hydroxy amide was obtained
in a rather good yield but with a low diastereoselectivity
(34% de). Provided that the diastereoselectivity of this kind
of reaction could be improved, we believe that the cheap
and environmentally friendly molecular oxygen oxidation
could be a very attractive alternative to onerous or toxic
oxidizing agents. We report herein that fluorinated oxazo-
lidine (Fox) chiral auxiliary presents outstanding perfor-
mances to meet these requirements.
alkylation compound. For example, the benzylation of the
potassium enolate of 1a gave the diastereomerically pure
benzylated amide 2a in 63% isolated yield, the R-hydroxy
amide 3a in 11% yield, and the hydroperoxide 4 in 15%
yield (Scheme 1). Similar oxygenated compounds were also
obtained as very minor products from sodium enolates. We
assumed that these oxygenated compounds were probably
resulting from the enolate oxidation by residual molecular
oxygen dissolved in the solvent. As these compounds were
obtained as single diastereomers, we anticipated that the Fox
chiral auxiliary would be an excellent chiral auxiliary for
the oxygen-mediated oxidation of enolates.
Scheme 1
.
Unexpected Diastereoselective R-Oxidation of
N-Acyloxazolidine 1a
In order to characterize the R-hydroxy amide 3a and to
compare with the diastereoselectivity achieved by a standard
oxidation method, the sodium enolate of 1a was treated with
Vedejs’ reagent (Scheme 2).8b,e Under these conditions, the
R-hydroxy amide 3a was obtained in 49% yield and with
only 62% de. This result shows the superiority of the
molecular oxygen oxidation in term of diastereoselectivity
of the reaction.
We recently reported the highly diastereoselective alky-
lation of fluorinated oxazolidine (Fox) derived amide eno-
lates.15-17 In the course of our studies, while using KHMDS
as base, we were surprised to isolate two oxygenated side
products in addition to the expected diastereomerically pure
(8) (a) Vedejs, E. J. Am. Chem. Soc. 1974, 94, 5944–5946. (b) Mimoun,
H.; Seree de Roche, I.; Sajus, L. Bull. Soc. Chim. Fr. 1969, 1481–1492. (c)
Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43, 188–
196. (d) Vedejs, E.; Martinez, G. R. J. Am. Chem. Soc. 1980, 102, 7994–
7996. (e) Vedejs, E.; Larsen, S. Org. Synth. 1986, 64, 127–137. (f) Marin,
J.; Didierjean, C.; Aubry, A.; Briand, J.-P.; Guichard, G. J. Org. Chem.
2002, 67, 8440–8449.
Scheme 2. Diastereoselective Hydroxylation of
N-Acyloxazolidine 1a with Vedejs’ Reagent
(9) (a) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem.
Soc. 1985, 107, 4346–4348. (b) Davis, F. A.; Vishawakarma, L. C.
Tetrahedron Lett. 1985, 26, 3539–3542. (c) Gamboni, R.; Tamm, C. HelV.
Chim. Acta 1986, 69, 615–620. (d) Enders, D.; Bhushan, V. Tetrahedron
Lett. 1988, 29, 2437–2440.
(10) (a) Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. J.
Org. Chem. 1986, 51, 2402–2404. (b) Davis, F. A.; Haque, M. S. J. Org.
Chem. 1986, 51, 4083–4085. (c) Davis, F. A.; Ulatowski, T. G.; Haque,
M. S. J. Org. Chem. 1987, 52, 5288–5290. (d) Davis, F. A.; Weismiller,
M. C.; Sankar Lal, G.; Chen, B.-C.; Prezslawski, R. M. Tetrahedron Lett.
1989, 30, 1613–1616. (e) Davis, F. A.; Weismiller, M. C.; Murphy, C. K.;
Reddy, R. T.; Chen, B.-C. J. Org. Chem. 1992, 57, 7274–7285.
(11) (a) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488–16489. (b) Brown, S. P.;
Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003,
125, 10808–10809.
As we suspected that residual molecular oxygen should
be the only possible reactant able to oxidize the enolate, we
decided to submit the sodium enolate of 1a to a bubbling
stream of oxygen at -78 °C. To our great delight, the
hydroperoxide 4 was isolated in 85% yield and 97:3 dr after
an aqueous workup (Scheme 3).18 This result clearly
indicates that the hydroperoxide is the product of the reaction
whereas the R-hydroxy compound 3a should result from its
reduction. To this end, the reductions of 4 with a 2 M
aqueous sodium bisulfite solution or a saturated sodium
sulfite aqueous solution were attempted. Unfortunately, under
these conditions, the R-hydroxy amide 3a was only obtained
in low yield and the hydroperoxide 4 mostly decomposed.
(12) Adam, W.; Lazarus, M.; Saha-Moller, C. R.; Schreier, P. Acc. Chem.
Res. 1999, 32, 837–845.
(13) For recent examples, see: (a) Raghavan, S.; Subramanian, S. G.;
Tony, K. A. Tetrahedron Lett. 2008, 49, 1601–1604. (b) Kaliappan, K. P.;
Gowrisankar, P. Synlett 2007, 1537–1540. (c) Monma, S.; Sunazuka, T.;
Nagai, K.; Arai, T.; Shiomi, K.; Matsui, R.; Ohmura, S. Org. Lett. 2006, 8,
5601–5604. (d) Pichlmair, S.; de Lera Ruiz, M.; Vilotijevic, I.; Paquette,
L. A. Tetrahedron 2006, 62, 5791–5802. (e) Gaich, T.; Karig, G.; Martin,
H. J.; Mulzer, J. Eur. J. Org. Chem. 2006, 3372–3394.
(14) Adam, W.; Metz, M.; Prechtl, F.; Renz, M. Synthesis 1994, 563–
566.
(15) Tessier, A.; Pytkowicz, J.; Brigaud, T. Angew. Chem., Int. Ed. 2006,
45, 3677–3681
.
(16) Sini, G.; Tessier, A.; Pytkowicz, J.; Brigaud, T. Chem.sEur. J.
2008, 14, 3363–3370
(17) Tessier, A.; Lahmar, N.; Pytkowicz, J.; Brigaud, T. J. Org. Chem.
2008, 73, 3970–3973
.
(18) The hydroperoxide 4 was conveniently isolated after aqueous
workup, but it decomposed over silica gel.
.
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