LETTER
Valuable Precursors to Enantiomerically Pure C- and N-Protected a-Alkyl Prolines
A. J. Med. Chem. 1991, 34, 1777. (d) Juvvadi, P.; Dooley,
35
prolines 1, are valuable compounds for further synthetic
elaboration or biological evaluation. For example the N-
formyl function of prolines 5 is a protecting group that can
be cleaved under more mild acidic conditions than other
amides.13 In addition the products 5 may have chemotac-
tic activity, since N-formyl peptides are potent chemotac-
tic agents.14
D. J.; Humblet, C. C.; Lu, G. H.; Lunney, E. A.; Panek, R. L.;
Skeean, R.; Marshall, G. R. Int. J. Peptide Prot. Res 1992, 40,
163. (e) Genin, M. J.; Johnson, R., L. J. Am. Chem. Soc. 1992,
114, 8778. (f) Andres, C. J.; Macdonald, T. L.; Ocain, T. D.;
Longhi, D. J. Org. Chem. 1993, 58, 6609. (g) Bisang, C.;
Weber, C.; Inglis, J.; Schiffer, C. A.; van Gunsteren, W. F.;
Jelesarov, I.; Bosshard, H. R.; Robinson, J. A. J. Am. Chem.
Soc. 1995, 117, 7904. (h) Beausoleil, E.; Lubell, W. D. J. Am.
Chem. Soc. 1996, 118, 12902.
Alternatively oxazolidinones 4 could be directly convert-
ed to free amino acids through hydrolysis. For instance
(R)-2-(2-propenyl)proline (1a) was obtained in high yield
after stirring 4a in 6 N HCl at room temperature.15 The op-
tical rotation of this material was essentially identical to
that for the same product obtained by Seebach’s proce-
dure.6c Since a-alkyl prolines6c,g, 7, 9 particularly proline
analog 1a5c,d,g,h,6b,c,e are popular precursors for peptidomi-
metics, our procedure should find utility in preparation of
compounds of medicinal interest.
(7) (a) Isono, N.; Mori, M. J. Org. Chem. 1995, 60, 115. (b) Wil-
liams, R. M.; Glinka, T.; Kwast, E. J. Am. Chem. Soc. 1988,
110, 5927.
(8) Overberger, C. G.; Jon, Y. S. Biopolymers 1977, 15, 1413.
(9) Lubec, G.; Labudova, O.; Seebach, D.; Beck, A.; Hoeger, H.;
Hermon, M.; Weninger, M. Life Sci. 1995, 57, 2245.
(10) (a) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am.
Chem. Soc. 1983, 105, 5390. (b) Shatzmiller, S.; Dulithzki, B.
Z.; Bahar, E. Liebigs Ann. Chem. 1991, 375. (c) Schollkopf,
U.; Hinrichs, R.; Lonsky, R. Angew. Chem. 1987, 99, 237.
(d) Williams, R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113,
9276. (e) Beck, A. K.; Blank, S.; Job, K.; Seebach, D. E.;
Sommerfeld, T. Org. Synth. 1992, 72, 62.
(11) Seebach, D; Sting, A. R.; Hoffmann, M. Angew. Chem. 1996,
35, 2708.
(12) (a) Orsini, F.; Pelizzoni, F.; Forte, M.; Sisti, M.; Bombieri, G.;
Benetollo, F. J. Heterocyclic Chem. 1989, 26, 837. See also
(b) Polonski, T. Tetrahedron 1985, 41, 603.
The methyl ester hydrochloride 6 could be directly ob-
tained from oxazolidinone 4a in good yield by refluxing
the oxazolidinone in acidic anhydrous methanol for one
hour.15 Importantly the latter reaction gives no character-
izable products in the case of the corresponding 4-prope-
nyl-2-t-butyloxazolidinone analog.10
In conclusion 4-alkyl-2-trichloromethyloxazolidinones 4
are readily available compounds that offer access to vari-
ous a-substituted proline derivatives in enantiomerically
pure form. We are currently exploring the chemistry of
chloral with other amino acids and will report these results
in due course.
(13) Bodanszky, M. Principles of Peptide Synthesis Springer-Ver-
lag: New York; 1984. For a summary of uses of N-formyl ami-
no acids see Duczek, W; Deutsch, J.; Vieth, S.; Niclas, H.-J.
Synthesis 1996, 37.
(14) Bommakanti, R. K.; Dratz, E. A.; Siemsen, D. W.; Jesaitis, A.
J. Biochemistry 1995, 34, 6720.
(15) General Procedure for Reaction of the Enolate of 3b with
Electrophiles. An ice cold solution of LDA (1.5 equiv) in
THF was added dropwise to a solution of oxazolidinone 2 (1.0
equiv) in THF at -78 °C. After 30 min, the electrophile was ad-
ded, and the temperature was allowed to warm to -30 °C over
a period of 2 h. The resulting mixture was partitioned between
chloroform and water. The aqueous layer was extracted with
another volume of chloroform. The combined organic layers
were dried over MgSO4, filtered and evaporated under redu-
ced pressure to afford a crude product that was purified by cry-
stallization.
Acknowledgement
Financial support from the Robert Welch Foundation is gratefully
acknowledged.
References
(1) Creighton, T. E. Proteins: Structures and Molecular Proper-
ties Freeman: New York; 1993, pp 225.
(2R, 4R)-4-(2-Propenyl)-2-trichloromethyloxazolidin-5-
one (4a) Allyl bromide (51.1 g, 422.1 mmol) and 34.4 g
(140.7 mmol) of 3a gave product 4a (23.6 g, 69%) as a solid:
mp 20-24 oC; [a]25D= +44.6° (c 2.0, CHCl3); 1H NMR
(CDCl3): d 5.83 (m, 1H), 5.19 (s, 1H), 5.17 (d, J = 5.5 Hz, 1H),
4.96 (s, 1H), 3.16 (m, 2H), 2.54 (d, J = 9.6 Hz, 2H), 2.00-1.50
(m, 4H); 13C NMR (CDCl3): d 175.9, 131.9, 119.8, 102.0,
100.5, 71.1, 58.1, 41.5, 35.1, 25.1. Anal. Calcd for
C10H12NO2Cl3: C, 42.18; H, 4.22; N, 4.92. Found: C, 42.55; H,
4.28; N, 4.72.
(2R, 4R)-4-Methyl-2-trichloromethyloxazolidin-5-one (4b)
Methyl iodide (11.5 g, 81.0 mmol) and 6.6 g (27.0 mmol) of
3a gave product 4b (4.0 g, 58%) as yellow needles: mp 57-60
°C; [a]25D= +6.5° (c 1.0, CHCl3); 1H NMR (CDCl3): d 4.98
(s, 1H), 3.40 (m, 1H), 3.20 (m, 1H), 2.22 (m, 1H), 1.95 (m,
1H), 1.89-1.70 (m, 2H), 1.52 (s, 3H); 13C NMR (CDCl3): d
176.9, 147.0, 102.5, 100.7, 58.1, 39.0, 25.7, 25.2. Anal. Calcd
for C8H10NO2Cl3: C, 37.14; H, 3.87; N, 5.42. Found: C, 37.27;
H, 3.86; N, 5.19.
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(2R, 4R)-4-Benzyl-2-trichloromethyloxazolidin-5-one (4c)
Benzyl bromide (4.2 g, 24.5 mmol) and 2.0 g (8.18 mmol) of
3a gave product 4c (1.4 g, 51%) as yellow crystals: mp 72-77
Synlett 1999, No. 1, 33–36 ISSN 0936-5214 © Thieme Stuttgart · New York