Synthesis of Biologically Important Guanidine-Containing Molecules Using Triflyl-Diurethane Protected Guanidines

Abstract

The guanidine-containing biologically important molecules, guanadrel, guanoxan, guanethidine and smirnovine have been synthesized using the recently developed triflyl-diurethane protected guanidines.Numerous natural and non-natural guanidine-containing compounds have had an significant impact on agricultural and medicinal chemistry. Moreover, many of these novel molecules have shown unprecedented activity ranging from antimicrobial, antiviral, antifungal to neurotoxic making these compounds and their derivatives clear targets for drug design and discovery. 1 With increasing numbers of bioactive molecules containing the guanidine moiety, there is a continuing need for a general and efficient method for their syntheses. We have recently reported the use of N,N'-di-Boc-N"-triflylguanidine (1) and N,N'-di-Cbz-N"-triflylguanidine (2) for the guanidinylation of amines under mild conditions and in high yields. 2 Application of this procedure has now been extended to the facile syntheses of the therapeutic agents, guanadrel (3), 3 guanoxan (4), 4 and guanethidine (5). 5 We have also applied this method to the preparation of the N,N-dialkylated guanidino-alkaloid, smirnovine (6). 6To date, the preparation of compounds 3, 4, and 5 involves either treatment of the appropriate amine with Smethylisothiourea 4-6 or reaction of a tosylate derivative with guanidine. 5 Both methods often require elevated temperatures and extended periods of time in polar solvents, such as H 2 O, methanol, tert-butanol, or DMF for reasons of solubility. The precursor amine 10 of guanadrel (3) was prepared through ketalization of cyclohexanone (7) with diol 8 7 to provide intermediate 9 (Scheme 1). The subsequent removal of the acetyl group of compound 9 using aqueous hydrazine afforded amine 10 in a reasonable overall yield for the two steps. Using either reagent 1 or 2, the guanidinylation step was carried out with a slight excess of amine 10 at room temperature in the presence of Et 3 N. After an aqueous workup, derivatives 11 and 12 were isolated in 95 and 93% yield, respectively. Catalytic hydrogenolysis under parr conditions led to the deprotection of the Cbz groups of compound 11 in quantitative yield to give guanadrel (3) as the free base. Deprotection of the Boc groups of compound 12 was not possible in the presence of the labile ketal (Scheme 1). Scheme 1The precursor amine 13 of guanoxan hydrochloride (15) was prepared following literature procedure. 8 In an analogous process to the guanidinylation of compound 12, excess amine 13 was treated with reagent 1 in the presence of Et 3 N to afford diBoc guanoxan (14) in quantitative yield. After deprotection with SnCl 4 9 followed by crystalDownloaded by: Simon Fraser University Library. Copyrighted material.

Synthesis of 2-Amino-4-pyrimidinones from Resin-Bound Guanidines Prepared Using Bis(allyloxycarbonyl)-Protected Triflylguanidine

“…The encouraging results from Botta et al to prepare heterocyclic structures from resin-bound guanidines prompted us to design novel target structures based on our experience with guanidinylation chemistry − and in the context of solid-phase chemistry. , We also envisioned possibilities of incorporating amino acids into the design of novel heterocyclic compounds…”

Synthetic Routes to Approved Drugs Containing a Spirocycle

“…Upon the displacement of the triflic amide, which is a leaving group in 62, bis-Cbz-protected guanidine 63 was hydrogenated over palladium on charcoal to give guanadrel in quantitative yield as a free base (Scheme 15). Interestingly, the attempted use of Boc protecting groups in lieu of Cbz failed, since the deprotection under acidic conditions led also to the removal of the acid-prone ketal [30]. Scheme 14.…”

Synthetic Routes to Approved Drugs Containing a Spirocycle

“…Upon the displacement of the triflic amide leaving group in 62, bis-Cbz-protected guanidine 63 was hydrogenated over palladium on charcoal to give guanadrel in quantitative yield as a free base (Scheme 15). Interestingly, attempted use of Boc protecting groups in lieu of Cbz failed since the deprotection under acidic conditions led also to the removal of the acid-prone ketal [29]. First synthesized in 1966 and approved for medical use in 1986, this spirocyclic serotonin 5-HT1A receptor agonist is primarily used to treat anxiety disorders [30].…”