Organic Syntheses, Vol. 75, 19
Checked by Martha Huntington, Edward G. Corley, Andrew S. Thompson, and Ichiro Shinkai.
1. Procedure
2. Notes
3. A
large (7 cm long, 4 cm diameter) football-shaped magnetic stirring bar was required to ensure efficient mixing of the heterogeneous mixture.
4.
Potassium hydride, 35% by weight in mineral oil, was purchased from Aldrich Chemical Company, Inc., and washed with dry
pentane prior to use.
Note that potassium hydride is a pyrophoric solid and must be handled with extreme care.
5.
Methyl iodide was purchased from Aldrich Chemical Company, Inc., and used as received.
6. Anhydrous, powdered
sodium sulfate, purchased from Aldrich Chemical Company, Inc., was used as received.
7. Analytical data for
2 are as follows:
[α]D25 −49.4° (
benzene,
c 6.3); IR (CHCl
3) cm
−1: 3380 (w), 3040 (w), 3000 (w), 2900 (m), 2240 (m), 1580 (m), 1460 (m), 1200 (m), 1120 (s), 905 (s), 700 (s);
1H NMR (500 MHz, CDCl
3) δ: 1.75 (br s, 2 H), 3.39 (t, 1 H, J = 9.1), 3.41 (s, 3 H), 3.53 (dd, 1 H, J = 9.3, 3.9), 4.21 (dd, 1 H, J = 8.7, 3.9), 7.30 (m, 1 H), 7.35 (t, 2 H, J = 7.3), 7.40 (dd, 2 H, J = 8.7, 1.6);
13C NMR (125 MHz, CDCl
3) δ: 55.4, 58.8, 78.9, 126.7, 127.3 (2 C), 128.3, 142.6 (2 C); high resolution mass spectrum (CI, CH
4) m/z 152.1069 [(M+H)
+; calcd for C
9H
14NO: 152.1075].
8.
Isovaleraldehyde was purchased from Aldrich Chemical Company, Inc., and distilled at atmospheric pressure before use.
9.
Toluene was distilled from
sodium spheres at atmospheric pressure under an
argon atmosphere. The checkers report that
reagent grade toluene stored over 4 Å molecular sieves proved satisfactory.
10. An oven-dried,
250-mL, conical flask is charged with freshly distilled
diethyl phosphite (29.3 g, 212.1 mmol) (Note
20) and dry
THF (110 mL) under an
argon atmosphere. The solution is cooled to 0°C (ice bath) and treated dropwise over 20 min with a solution of
butyllithium (1.6 M in hexane; 63.0 mL, 100.8 mmol) (Note
21). After an additional 0.5 hr the mixture is warmed to room temperature and used immediately.
11.
Reagent-grade ethyl acetate and hexanes were purchased from commercial sources and distilled before use.
12.
EM Science Silica Gel 60 (230-400 mesh ASTM) was purchased from Bodman Industries (Aston, PA). The checkers recommend
36 g of silica gel/1 g of crude product.
13. Analytical data for
4 are as follows:
[α]D25 −118.4° (CHCl
3,
c 2.07); IR (CHCl
3) cm
−1: 3340 (br, w), 2985 (s), 2960 (s), 2940 (s), 1460 (m), 1390 (w), 1370 (w), 1230 (s), 1050 (s), 1030 (s), 970 (s), 700 (m);
1H NMR (500 MHz, CDCl
3) δ: 0.51 (d, 3 H, J = 6.5), 0.88 (d, 3 H, J = 6.8), 1.37 (m, 6 H, J = 7.0), 1.41 (q, 2 H, J = 7.6), 1.95 (m, 1 H), 2.12 (br s, 1 H), 2.69 (ddd, 1 H, J
HP = 9.1, J
HH = 7.9, 6.7), 3.38 (t, 1 H, J = 3.9), 3.40 (s, 3 H), 3.46 (t, 1 H, J = 9.6), 4.09-4.19 (m, 4 H), 4.54 (dt, 1 H, J = 9.4, 3.9), 7.27 (m, 1 H), 7.30 (t, 2 H, J = 7.6), 7.40 (d, 2 H, J = 7.2);
13C NMR (125 MHz, CDCl
3) δ: 16.5 (d, J
CP = 6), 16.6, 20.7 (d, J
CP = 6), 23.6 (d, J
CP = 5), 23.7, 40.5 (d, J
CP = 7), 49.4, 58.4, 59.5 (d, J
CP = 138), 61.4 (d, J
CP = 7), 61.8, 77.7, 127.6 (d, J
CP = 7), 128.2 (2 C), 128.3, 140.3 (2 C); high resolution mass spectrum (CI, CH
4) m/z 358.2132 [(M+H)
+; calcd for C
18H
33NO
4P: 358.2147]. Anal. Calcd for C
18H
32NO
4P: C, 60.49; H, 9.02; N, 3.92. Found: C, 60.70; H, 9.21; N, 3.80.
14. The minor (R,S) diastereomer is present in the crude reaction mixture to the extent of approximately 0.9% as determined by capillary gas-liquid chromatographic analysis performed on a Hewlett-Packard 5790A gas chromatograph equipped with a Hewlett-Packard 3390A integrator and HP-1 methylsilicone gum column (25 m × 0.2 mm × 0.33 μm film thickness). The checkers found that HPLC analysis (Zorbax SB-Phenyl column 25 cm × 4.6 mm, 40:60
MeCN/0.1% aqueous
phosphoric acid, 1.5 mL/min, 250 nm detection) provided satisfactory resolution of the R,R- and R,S-diastereomers. The minor diastereomer is hardly discernible by
1H NMR (500 MHz) after purification by flash chromatography.
15.
Palladium hydroxide on carbon (moist, Pd content 20%, dry weight basis, moisture content ≤50%) was purchased from Aldrich Chemical Company, Inc., and used as received.
16. The checkers found the use of a Parr shaker (2 PSIG
hydrogen, 16 hr, ambient temperatures) satisfactory for the hydrogenolysis step, and distillation (bp 108°C/2.5 mm, 89.9-91% yield) for purification.
17. The filter pad was prepared by compressing Celite (4 cm) onto a layer of sand (1.5 cm) in a
fritted glass funnel (10-cm diameter).
18. Analytical data for
5 are as follows:
[α]D25 −20.8° (CHCl
3,
c 1.6); IR (CHCl
3) cm
−1: 3690 (br, w), 3000 (s), 2940 (m), 1470 (w), 1390 (m), 1230 (s), 1040 (s), 965 (s), 780 (m) ;
1H NMR (500 MHz, CDCl
3) δ: 0.90 (d, 3 H, J = 6.7), 0.96 (d, 3 H, J = 6.7), 1.34 (td, 6 H, J
HH = 7.0, J
HP = 1.8), 1.50 (m, 2 H), 1.56 (br s, 2 H), 1.91 (m, 1 H, J = 1.4), 3.04 (ddd, 1 H, J
HP = 10.8, J
HH = 10.8, 3.7), 4.16 (m, 4 H);
13C NMR (125 MHz, CDCl
3) δ: 16.5, 21.0, 23.5 (d, 2 C, J
CP = 5), 24.1, 39.9 (d, J
CP = 13), 46.7 (d, J
CP = 148), 62.0 (d, J
CP = 7), 62.1 (d, J
CP = 7); high resolution mass spectrum (CI, CH
4) m/z 224.1419 [(M+H)
+; calcd for C
9H
23NO
3P: 224.1415]. Anal. Calcd for C
9H
22NO
3P: C, 48.42; H, 9.93; N, 6.28. Found: C, 48.60; H, 9.93; N, 6.23.
19. α-Aminophosphonate
5 is obtained in >99% enantiomeric excess as determined by
1H NMR (500 MHz) analysis of the derived S-Mosher amide.
3
20.
Diethyl phosphite, purchased from Aldrich Chemical Company, Inc., was vacuum distilled just prior to use (bp
50-51°C, 2 mm).
21.
Butyllithium, purchased from Aldrich Chemical Company, Inc., was standardized by titration with
diphenylacetic acid.
Butyllithium solutions with concentrations less than 1.5 M may result in drastically reduced diastereomeric excesses and should be avoided.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Several methods have been devised for the preparation of racemic α-aminophosphonates; in 1972 the first optically active example was synthesized.
13 Since then, optically active α-aminophosphonates have been obtained by a variety of methods including resolution, asymmetric phosphite additions to imine double bonds and sugar-based nitrones, condensation of optically active ureas with phosphites and aldehydes, catalytic asymmetric hydrogenation, and 1,3-dipolar cycloadditions. These approaches have been discussed in a comprehensive review by Dhawan and Redmore.
14 More recent protocols involve electrophilic amination of homochiral dioxane acetals,
15 alkylation of homochiral imines derived from
pinanone16 and
ketopinic acid,
17 and alkylation of homochiral, bicyclic phosphonamides.
18
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