Synthesis of Cyclic Guanidine Intermediates of Anatoxin-a(s) in Both Racemic and Enantiomerically Pure Forms

Abstract

The alkyl chain of anatoxin-a(s) (cyclic guanidines), which can be used as an intermediate in the total synthesis of anatoxin-a(s), was synthesized in both racemic and enantiomerically pure forms. These enantiomerically pure cyclic compounds can be used as chiral inductors in some reactions. The two racemic routes disclosed herein have the advantages of high overall yield and mild reaction conditions. Both routes proceed through an intermediate 2,3-diaminoacid - an important synthetic scaffold - with good yields. Furthermore, the N,N-dimethyl-2(tosylimino)imidazolidine-4-carboxamide might be obtained from 2-(tosylimino)imidazolidine-4-carboxylic acid followed by selective reduction of the carbonyl functionality. All synthesized compounds were analyzed by mass spectrometry and [¹] H NMR and ^¹³C NMR spectroscopy.

cyclic guanidines - anatoxin-a(s) - neurotoxin - racemic synthesis - chiral synthesis

References and Notes

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Synthesis of Compound 5 or 8: 2-(Tosylimino)-imidazolidine-4-carboxylic Acid
The 2,3-diamine acid (312 mg, 3 mmol) was dissolved in H₂O (5 mL) and 1 N NaOH (10 mL) was added. S,S-Dimethyl-N-tosyliminoditiohcarbonimidate (0.813 mg, 3 mmol) in EtOH was added. The mixture was refluxed for
15 h. With reduction of original volume in one-third, the product precipitated. ^¹H NMR (300 MHz, CDCl₃): δ = 2.33 (3 H, s), 3.68 (2 H, dd, J ₁ = 7.2 Hz), 4.04 (1 H, dd, J ₁ = 7.8 Hz), 7.21 (2 H, d, J = 8.0 Hz), 7.83 (2 H, d, J = 7.3 Hz) ppm. ^¹³C NMR (300 MHz, CDCl₃): δ = 20.4, 57.3, 61.8, 125.1 (2 C), 127.0 (2 C), 134.2, 143.7, 143.9, 165.9 ppm. ESI-MS:
m/z = 284 [M + H]⁺, 238 [M - COOH]⁺, 155 [SO₂PhCH₃]⁺, 91.2 [PhCH₃]⁺.

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Synthesis of Compound 7: 2-Acetamido-3-amino-propanoic Acid α-Acetamidoacrylic acid (1.5 g) was dissolved in a solution of NH₄OH (37%, 50 mL). This mixture was allowed to stand at 40 ˚C for 72 h. The amine excess was removed for evaporation in vacuum. This compound was used without purification in the next step.

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Synthesis of Compound 8: ( R , S )-2,3-Diaminopropanoic Acid
The compound 6 was hydrolyzed by boiling for 2 h with a solution of 2 N HCl (30 mL). ^¹H NMR (300 MHz, D₂O): δ = 3.04 (1 H, dd, J ₁ = 7.2 Hz), 3.15 (1 H, dd, J ₁ = 7.2 Hz), 3.74 (1 H, dd, J ₁ = 7.2 Hz). Mp 225-227 ˚C.