Tetrols, synthesis

The synthesis of halcinonide is summarized in Figure 1, starting with 16a-hydroxy-9a-fluorohydrocortisone (A1 -pregnene-9a-fluoro-llg,16a,17a,21-tetrol-3,20-dione dihydrotriamcinolone, I), which is available commercially.10-13 This tetrahydroxy steroid is slurried in acetone, and then 70% perchloric acid is added slowly. The acetonide, II (9a-fluoro-llg, 16a, 17, 21-tetrahydroxypregn-4-ene-3, 20-dione, cyclic 16,17-acetal with acetone dihydrotriamcinolone-acetonide) precipitates spontaneously from solution. Mesyl chloride is added to the acetonide in pyridine to give the 21-mesylate derivative (dihydrotriamcinolone acetonide-21-mesylate, III). Compound III is dissolved in dimethylformamide, lithium chloride is added and the mixture is refluxed to produce halcinonide (IV), which is recrystallized from a solution of ft-propanol in water. 

Mikami, M. Shinkai, S. Synthesis of helical polymers by polycondensation of diboronic acid and chiral tetrols. Chem. Lett. 1995, 603-604. 

A CM-dihydroxylation involved in the synthesis of fl//o-inositol was the conversion of lL-l,2,3,4-di-0-iX(9propylidenecyclohex-5-ene-l,2/3,4-tetrol (1) to lD-l,2 5,6-di-O-ixopropyli-dene-fl/to-inositol (2) by RuCyaq. Na(IO )/CH3CN or EtOAc-CH CN (Eig. 3.3) [168]. Directions were given for both small- and a large-scale oxidations. 

This second approach70 was based on the nitromethane synthesis,71 and involved, as the key intermediate, l-C-nitro-l-hexene-D-n6o-3,4,5,6-tetrol tetraacetate (66), previously reported by Sowden and Fischer.77 In re-studying their conversion of D-ribose (64) into the hexenetetrol (66), it was possible70 to secure 2,3,4,5,6-penta-O-acetyl-l-deoxy-l-nitro-D- altritol (65) as crystalline material. When (65) was subjected to the Schmidt-... 

Huisgen and co-workers486,490 have described a useful synthesis of N-substituted pyrroles (41) from mesoionic oxazolones (39) via the intermediates 40, which were not isolated. A variety of acetylenic esters (phenylpropiolic, propiolic, tetrolic, and DMAD) were used. The kinetics of these reactions have been studied.491 The addition of carbon... 

The addition of DMAD to 2-aminothiazole (25) gave 26, whereas propiolic ester gave 27, 28 and 29, all derived by Michael-type additions.549 Dunwell and Evans550,551 have also added acetylenic esters to 2-amino- (and 2-amino-4-methyl)thiazole and obtained 26 and 27 from DMAD and EP, and similar compounds from tetrolic and phenyl-propiolic esters. By independent synthesis, these compounds were shown not to have the isomeric structures derived by initial addition to the exocyclic nitrogen. 

Ley and co-workers reported the total synthesis of (+)-aspicilin using 2,3-butane diacetal protected butane tetrols <01CJC1668> and Danishefsky and Gaul published the synthesis of the 14-membered macrolide core of migrastatin <02TL9039> (Scheme 72). 

A crucial step in this synthesis is the selective oxidation of the tetrols 22 and 23 but the application of a very interesting method, published by J. Fried and J. C. Sih66) with platinium in aqueous acetone in the presence of sodium bicarbonate gave 24 and 25, respectively, in 50% yield. The absolute configuration of the products 24 and 25 were carefully determined by chemical and physical methods. 

Bis(2,3-dihydroxypropyl)aminc (1 g. 6.1 mmol) was stirred with TFAA (10 mL) in a 100-mL round-bottomed flask for 1 h. TPA and unreacted TFAA were removed in a rotary evaporator. The residue was dissolved in CHjClj. washed with aq NaHCOj, dried (MgSOj.), filtered, and evaporated. In small-scale synthesis (100 mg tetrol) TFA and TFAA were removed directly with a stream of at 50 C without extraction yield 95-97%. 

When applied to penta-1,4-diene, the Sharpless asymmetric dihydroxylation forms a 1 1 mixmre of (25,45)- and (25,4/ )-penta-l,2,4,5-tetrols 478 and 479, which can be converted to diepoxides 480 and 481, respectively [214] (Scheme 13.110). A stereo- and enantioselective synthesis of 480 is possible starting from l,5-dichloropenta-2,4-dione applying Noyori s asymmetric hydrogenation [215]. 

Hvdroxvlation pathway An alternative explanation for the bile acid synthetic defect in CTX has been proposed by Oftebro and colleagues which starts via 26-hydroxylation of 5P-cholestane-3a,7a,12a-triol (IX, Fig. lOa and 10b). In this pathway the mitochondrial fraction of both human and rat liver contains a 26-hydroxylase enzyme (63) which can convert 5P-cholestane-3a,7a,12a-triol (IX ) to 5P-cholestane-3a,7a,12a,26-tetrol (XI) (Fig. 10a and 10b ). This tetrol is oxidized to 3a,7a,12a-trihydroxy-5P-cholestan-26-oic acid (THCA, XII) by liver cytosol (2,64). Further hydroxylation at C-24 forms varanic acid (XIV) and its side chain is shortened with oxidation at C-24 to yield cholic acid (X,Fig. 10 a). These investigators demonstrated diminished mitochondrial 26-hydroxylation of 5p-cholestane-3a,7a,12a-triol and 5P-cholestane-3a,7a-diol, possible precursors for cholic acid and chenodeoxycholec acid in CTX liver. As a consequence, neither 26-hydroxylated intermediates can be formed so that total primary bile acid synthesis would be diminished. Accordingly, the accumulation of 5P-cholestane-3a,7a,12a,25-tetrol arises from 25-hydroxylation of 5P-cholestane-3a,7a,12a-triol by the alternative microsomal 25-hydroxylation mechanism. 

In summary, these studies demonstrated that in CTX the impaired synthesis of bile acids is due to a defect in the biosynthetic pathway involving the oxidation of the cholesterol side-chain. As a consequence of the inefficient side-chain oxidation, increased 23, 24 and 25-hydroxylation of bile acid precursors occurs with the consequent marked increase in bile alcohol glucuronides secretions in bile, urine, plasma and feces (free bile alcohols). These compounds were isolated, synthesized and fully characterized by various spectroscopic methods. In addition, their absolute stereochemistiy determined by Lanthanide-Induced Circular Dichroism (CD) and Sharpless Asymmetric Dihydroxylation studies. Further studies demonstrated that (CTX) patients transform cholesterol into bile acids predominantly via the 25-hydroxylation pathway. This pathway involves the 25-hydroxylation of 5P-cholestane-3a,7a, 12a-triol to give 5P-cholestane-5P-cholestane-3a,7a,12a,25- tetrol followed by stereospecific 24S-hydroxylation to yield 5P-cholestane-3a,7a,12a,24S,25-pentol which in turn was converted to cholic acid. 

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