Bis-heterocycles

Biological and medicinal chemistry of bi-heterocycles and bi-chelates 97CB669. 

The second approach for the synthesis of 2-amino-3-hydroxycarboxylic acids starts with a chiral isothiocyanate which is added, via the tin enolate, to aldehydes. The initially formed adducts are immediately derivatized to the heterocycles, from which. yj 7-2-amino-3-hy-droxycarboxylic acids result after a three-step procedure. The diastereomeric ratios of the intermediate bis-heterocyclic products range from 93 7 to 99 1 (desired isomer/sum of all others)104. 

In general, M—Sb heterocycles either adopt four- or six-membered ring geometries of the type [R2MSbR x (x - 2, 3). The only structurally characterized Al—Bi heterocycle, [Me2AlBi(Tms)2]3 43, also forms a six-membered ring. A1—E heterocycles. The central structural parameters of Al—Sb heterocycles are summarized in Table 9. 

The Al—Bi heterocycle [Me2AlBi(Tms)2]3 43 [78] exhibits almost the same structural parameters as were found in other six-membered heterocycles of the type [R2AlE(Tms)2]3 (E = P, As, Sb). 

Formation of a pyridine ring onto bis-heterocycles is another route to these tricyclic systems. Reaction of 4-amino-2-morpholino-5-(2-morpholinothiazoM-yl)thiazolc 154 with the Vilsmeier reagent proceeds by direct cyclization to the bis-thiazolylpyridine 155 (Equation 36) <1997JHC1291>. 

The imine 217, formed from acetophenone and the 1-aminoimidazole, has been transformed into the enamine 218 which is then cyclized to 219 in trifluoroacetic acid (TFA) (Equation 40) <1995SC3271 >. The diaminoimidazole 220 reacts with ynone 221 to form 222 (Equation 41) <1998CHE1189>. Bromochalcones and chalcone dibromides can also be used in place of the ynone. Similar reactions have been used to prepare the dihydro analogues of 222 <1999CHE1207>. The reaction between 1-aminoimidazoles and 1,3-diketones has been extended to prepare bis-heterocyclic compounds, for example, 223 as ligands for transition metals (Equation 42) <2005EJI4382>. 

The dione 214 upon treatment with hydrazine afforded 215, which was converted into 2,2 -bis(bromomethyl)-3,3 -biquinazoline-4,4 -dione 217 (Scheme 47) via 216. The racemic 1,2,5-triazepine ( )-53 was obtained from 217 by reaction with aqueous ammonia in THF. The enantiomerically pure (—)-53 was formed by refluxing ( )-53 with (+)-CSA (camphorsulfonic acid) <1999CC1991>. It is interesting that this work is the first nonracemic example of a C2-symmetric bis-heterocycle, which is atropisomeric by virtue of retarded rotation around an N-N bond. 

Solid-Phase Synthesis of Bis-Heterocyclic Compounds from Resin-Bound Acylated and Nonacylated Polyamines... 

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

Saturated N-, 0-, and N,0-containing bis-heterocycles in synthesis of polymers 92UK161. 

Also, p-phenylene diisocyanate 74 upon reaction of two equivalents of the imino-phosphorane 75 and subsequent refluxing in p-xylene, affords the bis-heterocycle 76 in 66%yield. ... 

As a result of this first report, a large number of compounds containing an isocyclic or a heterocyclic ring fused tc the steroid skeleton were prepared and tested for androgenic and anabolic activity. Included are steroidal isoxazoles [205], thiazoles [94], pyrroles [206], pyrimidines [207,208], oxazines [209], thiazenone [92], quinoline [107], pyridine [122], and furazane [121], all prepared by the fusion of the heterocyclic ring to ring A. Several bis heterocyclic steroids were also prepared by... 

A characteristic and extremely rare feature of the structure of leucamide A 352 is a mixed 4,2-bis-heterocycle tandem pair formed by the direct connection between the methyloxazole and thiazole residues. Leucamide A 352 closely resembles structures such as tenuecyclamide A 353 and nostocyclamide 354 from Nostoc spp. and dendro-amide A 355 from Stigonema dendroideum. The later showed an interesting multidrug-resistance reversing activity <1995JOC7891, 2001PTC613, 2001JOC3459>. 

C-organostannyl and organosilyl derivatives of (Me2C(pz)2) and (H2C(pz)2) have been reported and characterized spectroscopically by Molloy and co-workers.205 Lithiation and subsequent substitution by R3M takes place at the 5,5 -positions for both bis-heterocycles. 

Dithiocarbamates (171) react with dinucleophiles such as 1,2-phenylenediamines to give bis-heterocyclic compounds (Equation (29)) linked by an amino bridge <82S1066>. 

Reaction of compound 65 with binucleophiles such as hydrazine, phenyl-hydrazine, or hydroxylamine, leads to bis-heterocyclic compounds 66 and 67 (95IZV762) (Scheme 73). 

Bis(thiocarbonyl)hydrazide derivatives of galactaric acid (186,187) have been prepared by reaction of 2,3,4,5-tetra-Oacetyl-D-galactaroyl dichloride (185) with 4-arylthiosemicarbazides335 or S-methyl(benzyl) hy-drazinecarbodithioates336 (Scheme 56). The adducts were subsequently converted into a variety of bis(heterocyclic) compounds including thiadia-zole, triazole, and oxadiazole derivatives. The tetraacetates 186 have been... 

Leucamide A, a bioactive cyclic hexapeptide first isolated from the Australian marine sponge Leucetta microraphis and stmc-turaUy confirmed by total synthesis. It contains an unique mixed 4,2-bis-heterocycle tandem pair consisting of methyloxazole and thiazole subunit showing moderate cytotoxicity toward several tumor cell lines [S. Kehraus et al., J. Org. 

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