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18.13.1.1.12 Method 12: Addition of Guanidine to Aldehydes, Ketones, and Esters To Give Cyclic Guanidinium Salts

DOI: 10.1055/sos-SD-018-01264

Berlinck, R. G. S.; Kossuga, M. H.; Nascimento, A. M.Science of Synthesis, (2005181107.

The reaction of guanidines with simple ketones was unknown until the early 1980s, when Snider first reported the synthesis of (±)-ptilocaulin with the addition of guanidine to an α,β-unsaturated ketone as the last synthetic step.[‌163‌,‌164‌] In precedent, the reactions between monosubstituted guanidines with β-diketones to give substituted pyrimidin-2-amines,[‌165‌‌169‌] and of guanidine with dimethyl 3-oxopentanedioate to give methyl 2-(2-amino-6-hydroxypyrimidin-4-yl)acetate, were known.[‌170‌,‌171‌] The addition reaction of a guanidine to a saturated ketone was firstly reported as the last step in the synthesis of ()-ptilocaulin.[‌172‌] In developing a synthesis of ptilomycalin A,[‌69‌] 3-phenyl-1,2,4a,5,6,7-hexahydropyrrolo[1,2-c]pyrimidin-1-amine hydrochloride was prepared from N,N-bis(tert-butoxycarbonyl)-protected 2-(2-oxo-2-phenylethyl)pyrrolidine-1-carboximidamide in quantitative yield. In the last step of a synthesis of crambescidin 359 (63),[‌173‌] the bis(tert-butoxycarbonyl)-protected guanidino diketone 62 is reacted with camphorsulfonic acid, to give the desired natural product after counterion exchange (Scheme 31). In an additional example of this method, a 1,3-bis(tert-butoxycarbonyl)-protected guanidine methyl ketal, as a masked aldehyde, is used as a precursor in the synthesis of 8,11-dideoxytetrodotoxin and 4,9-anhydro-8,11-dideoxytetrodotoxin.[‌174‌] A very similar approach is used within the synthesis of 11-deoxytetrodotoxin and anhydroepi-11-deoxytetrodotoxin,[‌45‌] and in the synthesis of tetrodotoxin.[‌175‌] Guanidines also react with β-diesters to give cyclic guanidines.[‌176‌] A very interesting variation of this latter reaction, developed as an alternative of the tethered Biginelli condensation, is the condensation of a 1,1-disubstituted guanidine with a β-oxo ester.[‌177‌] It has been found that when a 2-morpholinopyrrolidine-derived guanidinium 64 reacts with benzyl 3-oxobutanoate under Knoevenagel conditions, the only stereoisomer of the product 65 obtained is trans (Scheme 32).[‌178‌] However, the stereochemistry of this reaction can be reversed using a 4-methoxy-2,3,6-trimethylbenzenesulfonyl-protected guanidine, giving predominately the cis-isomer.[‌178‌] Overman's group explored the tethered Biginelli reaction between substituted guanidines and β-oxo esters in the preparation of a variety of polycyclic guanidines.[‌179‌‌184‌] Complex polycyclic guanidine alkaloids such as ptilomycalin A, crambescidin 657, neofolitispates 2, crambescidin 800,[‌180‌] 13,14,15-isocrambescidin 800, 13,14,15-isocrambescidin 657,[‌181‌] ()-dehydrobatzelladine C,[‌182‌] as well as a variety of batzelladine analogues,[‌183‌,‌184‌] have been synthesized by the tethered Biginelli condensation between 1,1-disubstituted guanidines and β-oxo esters.[‌177‌]

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