Isoureas cyclic

Cyanogen bromide can be used to activate hydroxyl groups on particles to create reactive cyanate esters, which then can be coupled to amine-containing ligands to form an isourea bond (Figure 14.17). CNBr activation also can produce cyclic imidocarbonate groups, which are less reactive than the cyanate ester, but can form imidocarbonate bonds. The exact reactive species formed by the reaction is dependent on the structure of the hydroxylic support being activated (Kohn and Wilchek, 1982). 

Poor nucleophiles react with acyl isoureas B so slowly that the latter start to decompose. In some sense they acylate themselves. The N atom designated with the positional number 3 intramolecularly substitutes the O-bound leaving group that is attached to the carboxyl carbon Cl. A four-membered cyclic tetrahedral intermediate is formed. When the Cl -Ol bond in this intermediate opens up, the N-acyl urea E is produced. Because compound E is an amide derivative it is no longer an acylating agent (cf. Section 6.2). 

The amino alcohols d-50 and l-50 were converted into d-408 and l-408 via coupling with isothiocyanate 7 to give the thiourea d-405 (93%), which was similarly converted into the cyclic isourea d-406 100%) (Scheme 53).98 Conventional O-debenzylation afforded the trehazolin analogue d-407 (96%), which was further characterized as the octa-iV,O-acetyl derivative d-408. Likewise, the diastereoisomer l-407 was synthesized in 91% overall yield by similar reaction sequence, starting from the l-405 (97%) obtained from isothiocyanate 7 and aminotetrol l-50. 

C. Uchida, H. Kimura, and S. Ogawa, Potent glycosidase inhibitors, IV-phenyl cyclic isourea derivatives of 5-amino- and 5-amino-l-C-(hydroxymethyl)-cyclopentane-l,2,3,4-tetraols, Bioorg. Med. Chem. Lett., 4 (1994) 2643-2648. 

Cyclic hydroxyimides 482 react with carbodiimides to form the expected isourea derivative, which undergoes further reaction with the starting material to give the isolated aminoacid derivative 483. 

The iodocyclization of acyclic unsaturated isoureas containing (S )-phenylethylamine as the chiral auxiliary gave chiral cyclic isoureas, which are masked 1,2-diamines. Starting from (S)-phenyl-ethylamine, the corresponding cyanamide was easily obtained, which was then converted, after allylation, to the corresponding isourea. The iodocyclization of the isourea derived from (S)-phenylethylamine afforded an equimolar diastereomeric mixture of 4,5-dihydroimidazoles 4 in 90% yield, which were easily separated by chromatography167. 

Recently, Pinter and co-workers313 have reported the use of cyclic thiocarbamates as precursors of cyclic isoureas by sequential -p-chlorobenzy-... 

Abstract The high synthetic versatiUty exhibited by the isothiocyanato motif has allowed its use as a building block in the preparation of a plethora of derivatives. When present in carbohydrates, the strong electrophilicity shown by isothiocyanates, together with the possibility of undergoing cycloaddition reactions has made it possible to access a broad spectrum of heterocyclic compounds, of either synthetic or pharmaceutical interest. Among them, noteworthy are 1,3-oxazolidine- and l,3-oxazinane-2-thiones (cyclic thiocarbamates), 2-amino-2-oxazolines (cyclic isoureas), 2-amino-2-thiazolines (cyclic isothioureas), nucleosides, and spironucleosides. 

In this work, we will describe the use of sugar-derived isothiocyanates in the stereocontrolled synthesis of heterocychc derivatives, such as 1,3-oxazohdine- and l,3-oxazinane-2-thiones (5- and 6-membered cyclic thiocar-bamates, respectively), 2-amino-2-oxazolines (5-membered cyclic isoureas), nucleosides, spiroglycosides and spironucleosides, and compounds that are simultaneously pseudo-C- and N-nucleosides. 

Fernandez-Bolanos JG, Lopez 0, Maya I (2003) Synthesis of O-unprotected sugar isothiocyanates and their transformation into thioureas and cyclic isoureas. In Pan-dalai S (ed) Recent Developments in Carhohydrate Research, Transworld Research Network, Trivandrum, India, p 81... 

Refluxing the 1,2-cyclic isourea 45 in pyridine caused elimination of water, affording the corresponding 2,3-unsaturated derivative. ... 

The original Pfittner-Moffatt procedure for alcohol oxidation by activated dimethyl sulfoxide utilized dicyclohexylcarbodiimide (DCC) and a source of protons such as polyphosphoric acid or pyridinium tri-fluoroacetate. The use of strong acids such as the common mineral acids must be avoided since, although acidic conditions are initially required, the reaction must readily become basic in the later stages of the process. Mechanistically it is reasonable to suggest that the activation follows the pattern whereby initial attack of the nucleophilic sulfinyl oxygen of dimethyl sulfoxide, with the protonated carbodiimide, forms a sulfonium isourea. This is followed by displacement of dicyclohexylurea by the alcohol to form an alkoxysulfonium salt. Base treatment of this salt forms an ylide, which collapses via the proven cyclic mechanism to the carbonyl compound and dimethyl sulfide (Scheme 4). 

The synthesis of the (1- ) linked "trehazoloid" drivative 70 as an analogue of the potent o,a-tFehalase inhibitor trehazolin, using a similar method of forming the cyclic isourea as described above, has been described. ... 

The popularity of use of cyanogen bromide-activated agarose for the immobilization of enzymes, affinants, etc. has continued but further work on the mechanism of activity of the matrix has suggested that the derivative is an isourea rather than the heretofore assumed cyclic imidocarbonate. Since other references have claimed to have proved the existence of the cyclic imidocarbonate ring, the use of the term agarose cyclic imidocarbonate has been retained in this volume but readers should familiarize themselves with the underlying chemistry. - ... 

Cyclic imidocarbonate derivatives of agarose continue to be used extensively for the immobilization of biologically active macromolecules and for affinity chromatography. The reaction of a cyclic imidocarbonate group with a protein presumably occurs by nucleophilic attack of an amino-group on the trans-imidocarbonate ring (1) to give either an isourea, or an iST-substituted imidocarbonate, or an JV-substituted carbonate (see Vol. 7, p. 511). Recent references... 

Problems have arisen in using agarose cyclic imidocarbonate for immobilization purposes, since material with high insulin-specific activity was released from an insulin-agarose derivative (an -substituted isourea) in the presence of bovine serum albumin, presumably by the type of reaction shown in Scheme 8. ... 

Uchida and co-workers have further exemplified their synthesis (cf. Vol.28, p.233) of cyclic isoureas, e.g. S a-carbatrehazolin 39, by condensing glycosyl isothiocyanates with the cyclitolamine trehazoline, and cyclizing the resulting thiourea adducts (with HgO) for further details see Chapter 19. cis-Fused 1,2-oxazolidine-2-thiones such as 40 were the exclusive products from reactions of 1,2-O-sulfinyl-a-D-gluco-furanose or -pyranose derivatives (i.e. 1,2-cyclic sulfites) with sodium thiocyanate. ... 

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