2784
Z. Chen, T. Ye
LETTER
proline (28) in good yield.20 Using similar transformations
we then converted pyrrolidine 25 to the required target
(2S,3R)-3-hydroxy-3-methylproline (19, Scheme 6).
Deprotection of the benzoyl ester in 25 by DIBAL-H
reduction as before and subsequent oxidation yielded the
corresponding acid. Without further purification, the
crude product was treated with trifluoroacetic acid in
dichloromethane to give the fully deprotected amino acid.
Purification by chromatography on reverse-phase silica
gel provided (2S,3R)-3-hydroxy-3-methylproline in 56%
yield over three steps. However, in order to obtain suffi-
cient material for the total synthesis project, some optimi-
zation of the reaction conditions was carried out. To our
delight, we have found that the yield for the conversion of
compound 25 into the final amino acid 19 can be in-
creased up to 80% by employing a modified oxidation
procedure (RuO2, NaIO4).21 The synthetic (2S,3R)-3-hy-
(4) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277. (b) Stevenson, P. J.; Treacy, A. B.; Nieuwenhuyzen,
M. J. Chem. Soc., Perkin Trans. 2 1997, 589.
(5) (a) Whisler, M. C.; Vaillancourt, L.; Beak, P. Org. Lett.
2000, 2, 2655. (b) Pippel, D. J.; Weisenburger, G. A.;
Faibish, N. C.; Beak, P. J. Am. Chem. Soc. 2001, 123, 4919.
(c) Whisler, M. C.; Beak, P. J. Org. Chem. 2003, 68, 1207.
(6) Procedure for the Synthesis of Enamine 10.
(–)-Sparteine (773 mg, 3.3 mmol) and n-BuLi (2.1 mL, 1.6
M in hexane) in toluene (20 mL) were cooled to –78 °C
under nitrogen and pre-cooled 9 (0.784 g, 2.35 mmol) in
toluene (15 mL) was added. The bright yellow mixture was
stirred for 45 min and Et2AlCl (3.5 mL, 1 M in hexane) was
added, and the color faded to pale yellow. After 1 h,
propionaldehyde (1.5 mL, 20.8 mmol) was added and the
mixture was stirred for 12 h at this temperature. Then,
MeOH (20 mL) was added and the reaction warmed to r.t.
After warming to r.t., HCl (20 mL, 1 M) was added and the
mixture extracted with EtOAc (2 × 50 mL). The organic
extracts were washed with brine (20 mL), dried (Na2SO4),
concentrated and purified by flash chromatography.
(7) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.
A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.;
Wang, Z. M.; Xu, D. Q.; Zhang, X. L. J. Org. Chem. 1992,
57, 2768.
1
droxy-3-methylproline (19) showed H NMR and 13C
NMR data, together with optical rotation data, that were
identical to those recorded for the natural sample.22 The
overall yield for the synthesis of (2S,3R)-3-hydroxy-3-
methylproline (19) from N-Boc-L-threonine is 43%.
(8) Compound 17: 1H NMR (300 MHz, CDCl3): d = 0.72 (3 H,
d, J = 6.8 Hz), 0.73 (3 H, q, J = 6.8 Hz, 8.2 Hz), 0.80 (3 H, t,
J = 7.4 Hz), 0.93 (2 H, m), 1.10 (1 H, m), 1.11 (1 H, m), 1.17
(1 H, m), 1.22 (1 H, m), 1.24 (3 H, t, J = 7.1 Hz), 1.32 (1 H,
m), 1.35 (1 H, m), 1.50 (3 H, s), 1.52 (1 H, m), 1.63 (1 H, m),
1.69 (1 H, m), 1.85 (1 H, m), 3.40 (1 H, m), 3.56 (1 H, d,
J = 2.5 Hz), 3.61 (1 H, s), 4.19 (2 H, q, J = 7.1 Hz). 13C NMR
(75 MHz, CDCl3): d = 173.59, 96.78, 79.40, 75.68, 61.83,
38.25, 35.82, 31.04, 31.02, 28.47, 25.16, 24.64, 19.14,
18.64, 14.23, 11.60, 8.81. [a]D20 +20.4 (c 0.6, CHCl3).
HRMS: m/z calcd for C6H11NO3 [M – H2O]: 298.2144;
found: 298.2151.
(9) (a) Wagner, I.; Musso, H. Angew. Chem., Int. Ed. Engl.
1983, 22, 816. (b) Williams, R. W. Synthesis of Optically
Active a-Amino Acids; Pergamon Press: New York, 1989.
(c) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (d)Davies,
J. S. Amino Acids, Peptides and Proteins, Vol. 1-31; Royal
Society of Chemistry: Cambridge, 1968-2000.
In summary, the synthesis of the acyl side-chain and sub-
stituted proline fragments of polyoxypeptin A have been
conveniently completed in a stereoselective manner.
Work is ongoing towards the completion of polyoxy-
peptin A, and this will be reported in due course.
Acknowledgment
We thank the support from the Area of Excellence Scheme (esta-
blished under the University Grants Committee of the Hong Kong
Special Administrative Region), The University of Hong Kong and
Hong Kong Polytechnic University.
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Synlett 2005, No. 18, 2781–2785 © Thieme Stuttgart · New York