Checked by Steven S. Henry and Albert I. Meyers.
1. Procedure
2. Notes
1. All glassware is flame dried and cooled under a stream of anhydrous
nitrogen. All reactions are carried out under a positive pressure of
nitrogen except for step D.
3.
tert-Butyl alcohol is distilled prior to use. THF is distilled immediately before use from
sodium benzophenone ketyl.
4. The
ammonia is dried thoroughly over
sodium metal before distillation into the reaction flask. If this step is not performed, a mixture of products may be obtained.
2
5.
Ammonium chloride is introduced as rapidly as possible, but with great care to avoid splashing and violent evaporation of the
ammonia. The coloration of the reaction mixture will change from dark blue to colorless within 5–10 min.
6. As much product as possible is crystallized from the residue obtained from the organic extracts. The mother liquor from the crystallization is chromatographed on a column filled with neutral alumina (available from J. T. Baker Chemical Company, powder, Brockmann Activity Grade 1) using 20 g of alumina per gram of residue (elution with CHCl
3/EtOAc, 1:1). Chromatography removes an impurity that makes crystallization difficult. Material purified by chromatography is also crystallized from
ethyl acetate.
7. TLC analyses were performed on Macherey-Nagel Polygram SIL G UV/254 plates that were stained with a solution of
phosphomolybdic acid in
95% ethanol.
8. Purified
1 has the following spectral data:
1H NMR (300 MHz, CDCl
3) δ: 1.18–1.43 (m, 4 H), 1.69–1.93 (m, 4 H), 1.95–2.08 (m, 2H), 2.19 (dt, 1 H, J = 11.3, 3.3), 2.43–2.53 (m, 1 H), 2.58 (m, 1 H), 3.46–3.69 (m, 3 H), 4.54 (t, 1 H, J = 6.8), 5.95 (s (br), 1 H);
13H NMR (75 MHz, CDCl
3) δ: 22.2, 25.0, 25.6, 27.9, 29.7, 32.4, 48.8, 51.7, 52.5, 56.2, 170.9, 171.2; IR (KBr) cm
−1: 3215, 1678, 1587; chemical ionization mass spectrum, m/z (relative intensity) M
+ + 1 (100). Anal. Calcd for C
12H
18N
2O
2: C, 64.85; H, 8.15. Found: C, 64.74; H, 8.14.
9. The aqueous layer must be strongly alkaline to enable extraction of the amine.
10. The free amine cyclizes to the diamide
1 upon standing.
12. Column chromatography is performed using 30 g of silica per gram of residue and CHCl
3/EtOAc (1:1) as the eluent. The resulting clear solution is concentrated and the product crystallizes slowly upon standing.
13. The N-tosylamino derivative
3 has the following spectral data:
1H NMR (300 MHz, CDCl
3) (

4:1 mixture of rotamers) δ: 1.05–1.27 (m, 2 H), 1.35–1.54 (m, 1 H), 1.59–1.78 (m, 4 H), 1.80–2.34 (m, 5 H), 2.39 (s, 3 H), 2.61 (dt, 1 H, J = 11.5, 3.2), 3.05 (m, 1 H), 3.49 (m, 1 H), 3.71 (s, 0.6 H, minor rotamer), 3.78 (s, 2.4 H, major rotamer), 3.89 (m, 1 H), 4.48 (dd, 0.8 H, J = 8.5, 4.4, major rotamer), 4.53 (d, 0.2 H, J = 8, exchanges with D
2O, minor rotamer), 4.80 (dd, 0.2 H, J = 8.5, 3.0, minor rotamer), 5.41 (d, 0.8 H, J = 2, exchanges with D
2O, major rotamer), 7.25 (d, 2 H, J = 8, overlapping minor and major rotamers), 7.69 (d, 0.4 H, J = 8 minor rotamer), 7.74 (d, 1.6 H, J = 8, major rotamer); IR (KBr) cm
−1: 3260, 1740, 1611, 1417; chemical ionization mass spectrum, m/z (relative intensity) M
+ + 1 (100). Anal. Calcd for C
20H
28N
2O
5S: C, 58.82; H, 6.90. Found: C, 58.92; H, 6.92.
14. The submitters obtained yields of
4 as high as 92% after recrystallization in some runs.
15. The carboxylic acid
4 has the following spectral data:
1H NMR (300 MHz, CDCl
3) δ: 1.08–1.30 (m, 4 H), 1.48 (dd, 1 H, J = 24.5, 11.8), 1.56–1.68 (m, 3 H), 1.88–2.00 (m, 2 H), 2.28 (dt, 1 H, J = 11.1, 3.7), 2.38 (m, 4 H), 3.34 (m, 1 H), 5.27 (d, 1 H, J = 8, exchanges with D
2O), 7.26 (d, 2 H, J = 8), 7.70 (s (br), 1 H, exchanges with D
2O), 7.73 (d, 2 H, J = 8); IR (KBr) cm
−1: 3310, 1674, 1152; chemical ionization mass spectrum, m/z (relative intensity) 298 (M
+ + 1, 30), 280 (100). Anal. Calcd for C
14H
19NO
4S: C, 56.56; H, 6.44. Found: C, 56.60; H, 6.42.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Alkali metal in
ammonia reductions of pyrrolobenzodiazepine-5,11-diones give trans-2-aminocyclohexanecarboxylic acid derivatives (e.g.,
4) in enantiomerically pure form.
2,3 A method for preparation of cis-2-aminocyclohexanecarboxylic acids related to
4 is based on the enantioselective hydrolysis of symmetrical diesters with pig liver esterase.
4 cis-2-Aminocyclohexane derivatives have been used for syntheses of aminocyclitol antibiotics.
4,5 6-Alkyl-cis-2-aminocyclohexanecarboxylic acids can be prepared by alkali metal in
ammonia reduction of
pyrrolobenzodiazepine-5,11-diones followed by olefin hydrogenation; the cis-decahydroquinoline alkaloid (+)-pumiliotoxin C has been prepared by this methodology.
2
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
amine
sodium benzophenone ketyl
pyrrolobenzodiazepine-5,11-diones
6-methylpyrrolobenzodiazepine-5,11-dione
ethanol (64-17-5)
sulfuric acid (7664-93-9)
ammonia (7664-41-7)
ethyl acetate (141-78-6)
methanol (67-56-1)
ammonium chloride (12125-02-9)
chloroform (67-66-3)
sodium bicarbonate (144-55-8)
sodium chloride (7647-14-5)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
sodium (13966-32-0)
ammonium hydroxide (1336-21-6)
potassium (7440-09-7)
dichloromethane (75-09-2)
magnesium sulfate (7487-88-9)
butyllithium (109-72-8)
Tetrahydrofuran (109-99-9)
triethylamine (121-44-8)
tert-butyl alcohol (75-65-0)
phosphomolybdic acid (51429-74-4)
p-Toluenesulfonyl chloride (98-59-9)
(1S,2S)-2-(N-Tosylamino)cyclohexanecarboxylic acid (110456-11-6)
(5aS,9aS,11aS)-Perhydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (110419-86-8)
(S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)dione,
(S)-(+)-2,3-Dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione
(1S,2S)-2-Amino-1-[((2S)-2-carbomethoxypyrrolidinyl)carbonyl]cyclohexane (174624-00-1)
(1S,2S)-2-(N-Tosylamino)-1-[((2S)-2-carbomethoxypyrrolidinyl)carbonyl] cyclohexane (110419-91-5)
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