M. Adamczyk, R. E. Reddy / Tetrahedron: Asymmetry 9 (1998) 3919–3921
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the stereoselectivity. A six-membered chair like transition state mechanism was proposed for the addition
of sodium enolate of methyl acetate to mono-sulfinimines by Davis et al.4a Therefore, by analogy, the
stereochemistry of the major bis-sulfinamide diastereomers 4a–c was assigned to be (SS,R;SS,R) which
were obtained from (S,S)-sulfinimines 3a–c.
The (SS,R;SS,R)-bis-sulfinamides 4a–c were hydrolyzed using trifluoroacetic acid in methanol at 0°C
for 4 h followed by HPLC purification12 to afford the pure (R,R)-bis-β-amino esters (5a–c) in 82–93%
yield as bis-TFA salts in >97% ee.13 The enantiomeric purity of (R,R)-bis-β-amino esters (5a–c) was
determined by converting them to the corresponding bis-β-Mosher’s amides by treatment with (S)-
(+)-MTP-Cl (3.0 equiv.) and triethylamine (10.0 equiv.) in methylene chloride at room temperature
for 3 h, followed by preparative reverse phase HPLC purification in 75–95% yield.14,15 Similarly,
the (S,S)-(+)-bis-β-amino ester (5b) was also prepared in good yield and optical purity (>97% ee)
from (R,R)-(+)-bis-sulfinimine (3b) (Table 1, entry 3) via enolate addition and subsequent hydrolysis
with trifluoroacetic acid.15 In summary, a stereoselective synthesis of enantiopure bis-β-amino acids
(5a–c), valuable building blocks for the preparation of conformationally enriched peptide mimetics, was
described from chiral bis-sulfinimines (3a–c) in two steps.
References
1. For reviews see (a) Drey, C. N. C. In Chemistry and Biochemistry of Amino Acids; Barret, G. C., Ed.; Chapmann and
Hall: New York, 1985. (b) Spatola, A. F. In Chemistry and Biochemistry of Amino Acids and Proteins; Weinstein, B., Ed.;
Marcel Dekker: New York, 1983. (c) Cole, D. C. Tetrahedron 1994, 50, 9517. (d) Cardillo, G.; Tomasini, C. Chem. Soc.
Rev. 1996, 25, 117. (e) Enantioselective Synthesis of β-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
2. (a) Hruby, V. J.; Bonner, G. G. In Methods in Molecular Biology, Vol. 35: Peptide Synthesis Protocols; Pennington, M. W.;
Dunn, B. M., Eds; Humana Press: New Jersey, 1994, p. 201. (b) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1994, 116,
1054.
3. Seebach, D.; Matthews, J. L. J. Chem. Soc., Chem. Commun. 1997, 2015.
4. Davis, F. A.; Reddy, R. T.; Reddy, R. E. J. Org. Chem. 1992, 57, 6337. (b) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M. J.
Org. Chem. 1995, 60, 7037.
5. (a) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Portonovo, P. S. Tetrahedron Lett. 1993, 34, 6229. (b) Davis, F. A.; Reddy,
R. E.; Szewczyk, J. M.; Reddy, G. V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org.
Chem. 1997, 62, 2555.
6. The bis-sulfinimine 3a was purified by silica gel column chromatography (30% ethyl acetate in hexanes) and 3b–c were
purified by crystallization (twice) from ethyl acetate.
1
7. All new compounds were characterized by H, 13C NMR, mass spectrometry and HPLC and the yield referred to the
spectroscopically homogeneous materials.
20
8. Selected data for bis-sulfinimines (3): (S,S)-(+)-3a: mp 124–126°C, [α]D +82.6 (c 0.64, CHCl3); (S,S)-(−)-3b: mp
20
20
147–149°C, [α]D −143.8 (c 0.92, CHCl3); (R,R)-(+)-3b: mp 149–151°C, [α]D −147.1 (c 0.85, CHCl3); (S,S)-(+)-
3c: mp 155–157°C, [α]D20 +154.6 (c 1.12, CHCl3).
20
9. Selected data for the major sulfinamide diastereomer (4): (SS,R;SS,R)-(+)-4a: mp 47–49°C, [α]D +129.08 (c 0.82,
20
20
CHCl3); (SS,R;SS,R)-(+)-4b: mp 50–54°C, [α]D +122.24 (c 0.67, CHCl3); (RS,S;RS,S)-(−)-4b: mp 49–53°C, [α]D
20
−114.22 (c 0.64, CHCl3); (SS,R;SS,R)-(+)-4c: mp 78–82°C, [α]D +49.16 (c 0.48, CHCl3).
20
10. Selected data for the minor sulfinamide diastereomer (4): (SS,R;SS,S)-(+)-4a: yield: 20%, mp 45–47°C, [α]D +50.32 (c
20
0.62, CHCl3); (SS,R;SS,S)-(+)-4b: yield: 21%, mp 50–54°C, [α]D +39.84 (c 0.63, CHCl3); (RS,S;RS,R)-(−)-4b: yield:
20
20%, mp 52–55°C, [α]D −39.57 (c 0.47, CHCl3); (SS,R;SS,S)-(−)- 4c: yield: 13%, [α]D20 +41.52 (c 0.46, CHCl3).
11. The minor sulfinamide diastereomer (SS,R;SS,S)-4 is identical to the minor (SS,S;SS,R)-4 isomer.
12. Preparative reverse phase (RP) HPLC was performed on a Waters, C18 µBondpak, (40×100 mm), using MeCN:0.1%
aqueous trifluoroacetic acid 10:90 45 ml min−1 at 254 nm.
13. Hydrolysis of the minor diastereomer of (SS,R;SS,S)-4a–c using trifluoroacetic acid in methanol gave the corresponding
meso-bis-β-amino esters (5a–c) as bis-TFA salts in 75–91% yield with no optical rotation.
14. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
15. Preparative reverse phase HPLC was performed on a Waters C18, Symmetry column (40×100 mm) using MeCN:H2O
(40:60) 40 ml min−1 at 254 nm.