S. V. Narina, A. Sudalai / Tetrahedron Letters 47 (2006) 6799–6802
6801
of the crude product with 30% CuSO4 yielded chiral diol
References and notes
25
78 in 86% yield; ½aꢁD ꢀ4.0 (c 1.1, CHCl3). The regioselec-
tive intramolecular cyclization9 of diol 7 using sodium
hydride in THF at 0 °C furnished the desired oxazolidi-
none 8 in 96% yield and 99% ee (determined by 1H
NMR analysis of its Mosher’s ester). The physical and
spectroscopic data of 8 were in complete agreement with
the reported values.2e Oxazolidinone 8 was then con-
verted into the corresponding azide 9 in two steps with
92% overall yield. Finally, the azide function was
reduced with H2 using Pd/C to furnish the crude amine,
1. (a) Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed.
2003, 42, 2010; (b) Bobkova, E. V.; Yan, Y. P.; Jordan, D.
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278, 9802; (c) Aoki, H.; Ke, L. Z.; Poppe, S. M.; Poel, T.
J.; Weaver, E. A.; Gadwood, R. C.; Thomas, R. C.;
Shinabarger, D. L.; Ganoza, M. C. Antimicrob. Agents
Chemother. 2002, 46, 1080; (d) Halle, E.; Majcher-
Peszynska, J.; Drewelow, B. Chemother. J. 2002, 11, 1;
(e) Ford, C. W.; Zurenko, G. E.; Barbachyn, M. R. Curr.
Drug Targets 2001, 1, 181; (f) Brickner, S. J. Curr. Pharm.
Des. 1996, 2, 175; (g) Park, C. H.; Brittelli, D. R.; Wang,
C. L. J.; Marsh, F. D.; Gregory, W. A.; Wuonola, M. A.;
McRipley, R. J.; Eberly, V. S.; Siee, A. M.; Forbes, M. J.
Med. Chem. 1992, 35, 1156; (h) Gregory, W. A.; Brittelli,
D. R.; Wang, C. L. J.; Wuonola, M. A.; McRipley, R. J.;
Eustice, D. C.; Eberly, V. S.; Bartholomew, P. T.; Slee, A.
M.; Forbes, M. J. Med. Chem. 1989, 32, 1673.
2. (a) Madhusudhan, G.; Reddy, G. O.; Ramanatham, J.;
Dubey, P. K. Indian J. Chem. B 2005, 44, 1236; (b)
Mallesham, B.; Rajesh, B. M.; Reddy, P. R.; Srinivas, D.;
Trehan, S. Org. Lett. 2003, 5, 963; (c) Perrault, W. R.;
Pearlman, B. A.; Godrej, D. B.; Jeganathan, A.; Yama-
gata, K.; Chen, J. J.; Lu, C. V.; Herrinton, P. M.;
Gadwood, R. C.; Chan, L.; Lyster, M. A.; Maloney, M.
T.; Moeslein, J. A.; Greene, M. L.; Barbachyn, M. R. Org.
Proc. Res. Dev. 2003, 7, 533; (d) Lohray, B. B.; Baskaran,
S.; Rao, B. S.; Reddy, B. Y.; Rao, N. Tetrahedron Lett.
1999, 40, 4855; (e) Brickner, S. J.; Hutchinson, D. K.;
Barbachyn, M. R.; Manninen, P. R.; Ulanowicz, D. A.;
Garmon, S. A.; Grega, K. C.; Hendges, S. K.; Toops, D. S.;
Ford, C. W.; Zurenko, G. E. J. Med. Chem. 1996, 39, 673.
3. (a) List, B.; Seayad, J. Org. Biomol. Chem. 2005, 3, 719; (b)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138; (c) Houk, K. N.; List, B. Acc. Chem. Res. 2004, 37,
487; (d) List, B.; Bolm, C. Adv. Synth. Catal. 2004, 346, 9;
(e) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001,
40, 3726.
which was converted (Ac2O, py) to linezolid 12e {mp
25
181–182.5 °C; ½aꢁD ꢀ9 (c 1, CHCl3); lit.2e mp 181.5–
25
182.5 °C; ½aꢁD ꢀ9 (c 1, CHCl3)} in 92% yield and 99%
ee (Scheme 1).
A similar strategy was extended to the asymmetric
synthesis of eperezolid 2 (Scheme 2). Protection of the
secondary amine group of 102e with Cbz–Cl gave 11 in
quantitative yield. Reduction of the nitro group in 11
(NaBH4, cobalt chloride, MeOH, 60 °C)10 produced
arylamine 12, which was transformed to alcohol 14 in
79% overall yield (vide supra). Swern oxidation of
alcohol 14 gave aldehyde 15, which was subjected to
D-proline catalyzed asymmetric a-aminooxylation with
nitrosobenzene followed by reduction to furnish chiral
25
diol 1611 in 82% yield (two steps) ½aꢁD ꢀ3.2 (c 1, CHCl3).
Subsequent regioselective intramolecular cyclization of
diol 16 (NaH, THF, 0 °C) gave oxazolidinone 17 in
94% yield and 99% ee (determined by 1H NMR analysis
of its Mosher’s ester), which was further converted into
the corresponding azide 18 in two steps, in 94% overall
yield. Reduction of azide 18 to the corresponding amine
was readily achieved with PPh3 in THF–H2O mixture
and the in situ generated amine was acetylated (Ac2O,
py) to give acetamide 19 in excellent yield. Deprotection
of the Cbz group in 19 under catalytic hydrogenolysis
conditions (Pd/C, H2 (1 atm), MeOH–CH2Cl2) provided
piperazine 20, which was acylated (ClCOCH2OBn,
Et3N, CH2Cl2, 0 °C) to give 21 in quantitative yield.
4. For a review of proline-catalyzed asymmetric reactions,
see: List, B. Tetrahedron 2002, 58, 5573.
5. (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M.
Tetrahedron Lett. 2003, 44, 8293; (b) Zhong, G. Angew.
Chem., Int. Ed. 2003, 42, 4247; (c) Hayashi, Y.; Yama-
guchi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed.
2003, 43, 1112; (d) Brown, S. P.; Brochu, M. P.; Sinz, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808;
(e) Cordova, A.; Sunden, H.; Bøgevig, A.; Johansson, M.;
Himo, F. Chem. Eur. J. 2004, 10, 3673.
Finally, debenzylation of 21 (Pd/C, H2 (1 atm), MeOH–
25
CH2Cl2) furnished eperezolid 2 {mp 174–176 °C; ½aꢁD
25
ꢀ21 (c 1, DMSO); lit.2e mp 175–176 °C; ½aꢁD ꢀ21 (c 1,
DMSO)} in 89% yield and 99% ee.
6. Padwa, P.; Austin, D. J.; Price, A. T.; Semones, M. A.;
Doyle, M. P.; Protopopova, M. N.; Winchester, W. R.;
Trans, A. J. Am. Chem. Soc. 1993, 115, 8669.
In conclusion, the enantioselective syntheses of two
antibacterial antibiotics, linezolid 1 and eperezolid 2,
were achieved in 9 and 14 linear steps (56% and 39%
overall yields, respectively). The applicability of the
D-proline catalyzed asymmetric a-aminooxylation of
aldehydes has been demonstrated. The advantages of
our syntheses are the introduction of chirality using a
catalytic amount of D-proline, which is cheap and read-
ily available, and the high enantioselectivity associated
with the process.
7. For reviews of the Swern oxidation, see: (a) Tidwell, T. T.
Synthesis 1990, 857; (b) Tidwell, T. T. Org. React. 1990,
39, 297.
25
8. Spectral data for diol 7: ½aꢁ ꢀ4.0 (c 1.1, CHCl3); 1H
NMR (200 MHz, CDCl3): dD3.08 (t, J = 4.66 Hz, 4H),
3.49–3.61 (m, 2H), 3.65–3.80 (m, 3H), 3.86 (t, J = 4.83 Hz,
4H), 5.13 (s, 2H), 6.83–6.96 (m, 3H), 7.25–7.35 (m, 5H);
13C NMR (50 MHz, CDCl3): d 50.58 (d, J = 3.52 Hz),
52.89, 63.76, 66.70, 67.53, 69.92, 115.49 (d, J = 32.71 Hz),
118.33 (d, J = 3.86 Hz), 123.13 (d, J = 2.92 Hz), 127.38,
127.87, 128.29, 135.97, 138.69 (d, J = 8.95 Hz), 152.33,
156.40, 157.25; IR (CHCl3) mmax: 3433, 3018, 2966, 2862,
2399, 1685, 1514, 1452, 1215, 1117. Elemental analysis:
C21H25FN2O5 requires C, 62.37; H, 6.23; F, 4.70; N, 6.93.
Found: C, 62.30; H, 6.28; F, 4.81; N, 6.85.
Acknowledgements
N.V.S.R. thanks CSIR, New Delhi, for the award of
research fellowships. The authors are thankful to
Dr. B. D. Kulkarni, Head, CEPD, for his support and
encouragement.
9. Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 12, 1915.
10. Satoh, T.; Suzuki, S. Tetrahedron Lett. 1969, 10, 4555.