Science of Synthesis

Berlinck, R. G. S.; Kossuga, M. H.; Nascimento, A. M., Science of Synthesis, (2005) 18, 1109.

The use of 2-methylisourea in the synthesis of cyclic guanidines was first introduced by Snider, during the synthesis of polycyclic guanidine alkaloids isolated from the sponge Crambe crambe. Previously, this approach was known for the synthesis of 1,4-dihydropyrimidines.[‌185‌] While the reaction of β-oxo α,β′-unsaturated ester ‌66‌ with guanidine free base gives a tetrahydropyrimidine derivative, reaction with 2-methylisourea provides the corresponding protected urea ‌67‌ in 94% yield. Hydrolysis of the silyl ether protecting group gives ‌68‌, which is converted into a mixture of the mono(benzyloxycarbonyl)-protected bis-guanidines ‌69‌ and ‌70‌ using ammonia and ammonium acetate in tert-butyl alcohol, followed by treatment with aqueous sodium carbonate in methanol (‌Scheme 33‌). Further reaction steps give the major crambescin C homologue.[‌88‌] The same approach is used in the synthesis of the central pentacyclic core of ptilomycalin A by the same authors.[‌89‌] Essentially the same approach is employed in the synthesis of a tricyclic model of ptilomycalin A,[‌173‌] in the total synthesis of crambescins A, B and C2,[‌69‌] and in the synthesis of the tricyclic central core of batzelladines A, B, and batzelladine E.[‌186‌–‌188‌] Interesting variations of this method have been reported, in the synthesis of a tricyclic model of batzelladine A,[‌189‌] and in the synthesis of epicylindrospermopsin.[‌190‌–‌192‌]

‌Meeeee 88‌ Meeeeeeee ee Mee-eeeeeeeeee eeee e β-Mee α,β′-Meeeeeeeeee Meeee eee e Meeeeeeeeeeee[‌88‌]

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8-{[(Meeeeeeee)eeeeeeee][{[(eeeeeeeee)eeeeeeee]eeeee}(eeeee)eeeeee]eeeee}eeeee 8-{8-[eeee-Meeee(eeeeeeee)eeeeee]eeeeee}-8-eeeeeee-8-eeeeeee-8,8-eeeeeeeeeeeeeeeee-8-eeeeeeeeeee (‌88‌):[‌88‌]

M eeeeeeeeee ee ‌88‌ (888 ee, 8.88 eeee), 8-eeeeeeeeeeeee eeeeeee (888 ee, 8.8 eeee), eee MeMMM8 (888 ee, 8.8 eeee) ee MMM (8 eM) eee eeeeeee ee 88°M eee 8 e, eeeeeee eeee M8M (88 eM), eee eeeeeeeee eeee eeeeee/MeMMe (8:8, 8 × 88 eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeeee eeee eeeee (88 eM) eee eeeee (Me8MM8). Meeeeee ee eee eeeeeee eeeee eeeeeee eeeeeeee eeeeeeee ee eeeee eeeeeeeeeeeeee (eeeeee eee, eeeeee/MeMMe 8:8) eeee e eeeeeeeee eee; eeeee: 8.88 e (88%).

8-{[Meeee(eeeee)eeeeee][(eeeeeeeee)eeeeeeee]eeeee}eeeee 8-Meeee-8-(8-eeeeeeeeeeeee)-8-eeeeeee-8,8-eeeeeeeeeeeeeeeee-8-eeeeeeeeeee (‌88‌) Meeeeeeeeeeee eee 8-[({[(Meeeeeeee)eeeeeeee]eeeee}(eeeee)eeeeee)eeeee]eeeee 8-Meeee-8-(8-eeeeeeeeeeeee)-8-eeeeeee-8,8-eeeeeeeeeeeeeeeee-8-eeeeeeeeeee (‌88‌) Meeeeeeeeeeee:[‌88‌]

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References