Carbocyclic oxetanocin synthesis

Chiral cyclobutanes can be prepared by cycloaddition of alkenes substituted with one or more chiral auxiliary groups. A diastereofacial selectivity of 95% was observed in the diethylalu-minum chloride catalyzed cycloaddition of 1,1-dimethoxyethene (36) with ( — )-dimenlhyl-3-yl fumarate (37).16 The chiral cyclobutane 38 has been used as an intermediate in the synthesis of carbocyclic oxetanocin analogs. 

A total enantioselective synthesis of antiviral carbocyclic oxetanocins 289 and 290 was also completed by the Ichikawa group by utilizing a... 

Asymmetric [2 + 2] cycloaddition reaction affords a practical means of synthesis of optically active cyclobutanes, which can be used as useful intermediates in organic synthesis [138]. Narasaka reported that asymmetric [2 -i- 2] cycloaddition between acryloyl oxazolidinone derivatives and bis(methylthio)ethylene proceeded with high enantios-electivity when catalyzed by TADDOL-derived titanium complex (Sch. 58) [139]. The cyclobutane product was transformed into carbocyclic oxetanocin analogs or (-n)-grand-isol [140]... 

The previously described 7-deazapurine carbocyclic nucleoside synthesis (see Scheme 1) indicated that the most efficient route to 22 would be via reaction of the protected chiral amine 23 with the dimethylacetal of 2-(2-amino-4,6-dichloropyrimidin-S yl)acetaldehyde followed by ring closure, hydrolysis and dqirotection. A review of the literature revealed two enantioselective routes to cyclobutyl derivatives that had been used in the chiral synthesis of carbocyclic oxetanocins and could be employed for preparing a precursor to 23. In one case, however, the initial step involved a [2-i-2]-cycloaddition reaction of not easily obtainable reagents in the presence of a chiral titanium compound as... 

Hsiao, C.-N. et al. Efficient Syntheses of Protected (2S,3S)-2,3-Bis(hydroxy-methyl)cyclobutanone, Key Intermediates for the Synthesis of Chiral Carbocyclic Analogues of Oxetanocin. 4.1 1990 [127]... 

The carbocyclic analogue of the trehalase inhibitor, trehazolin, has been prepared and reported to have potency indistinguishable from the natural product." The synthesis of other antibiotic-related cyclopentane derivatives such as analogues of mannostatin A, allosamidin (and allosamizolin) and a 4-membered carbocyclic thiazole analogue of oxetanocin, are covered in Chapter 19. 

There has been a further report on the synthesis of racemic 2, 3 -dideoxy-2, 3 -methanoadenosine (see Vol. 33, p. 297). 4 -Hydroxymethyl-carbocyclic nucleosides 162 (B = Ade, Thy) have been made as racemates, along with their 3 -epimers, and the compounds 163 (B = Ade, Hx) have been described. References to the carbocyclic analogues of oxanosine and oxetanocin are mentioned in the next section. 

In the area of carbocyclic nucleoside antibiotics, a full account of syntheses of (—)-aristeromycin and (—)-neplanocin A (see Vol. 31, p. 261) was mentioned above. " The known intermediate 174, prepared from D-ribose, has been used for the first synthesis of neplanocin C (175), a minor component of the neplanocin family. The diastereomeric epoxide was also obtained. In efforts to prepare prodrugs, the oxetanocin analogue 176, an antiviral agent (lobucavir), has been selectively aminoacylated with l-valine on either of the hydroxymethyl groups using enzymic methods. A synthesis of the cyclohexenyl nucleoside antibiotic pyralomycin Ic is mentioned in Chapter 18. 

Two groups have reported on the synthesis of the hydroxymethyl-branched carbocyclic systems 184 (B = Ad, Gua), which can be regarded as ring-enlarged oxetanocin analogues or as carbocyclic analogues of important anti-HIV agents. In one approach, the racemic unit 183 was produced by photochemical addition of methanol to the enone,2i4 whilst other workers reported routes to both 184 and its enantiomer. iS... 

The naturally occurring oxetanocin A (18) and synthetic oxetanocin G (19) represent a novel class of nucleosides possessing antiviral propmies. Modification of die unique oxetanosyl-lV-glycoside structural feature of 18 and 19 into the carbocyclic nucleoside framework led to the synthesis of 20 and 21 as racemates and enantiomers, which have shown activity against herpesviruses and HIV.22b,c,24,25 in view of the potent and selective anti-HCMV properties of the l -enantiomer of 21, the synthesis of the R sto eoisomer 22 was undertaken and accomplished. 

C.-N. Hsiao and S.M. Hannick, Efficient synthesis of protected (25,3S)-2,3-bis(hydroxymethyl)cyclobutanone, key intermediates for the synthesis of chiral carbocyclic analogues of oxetanocin, Tetrahedron Lett. 31 6609 (1990) reports the synthesis of the (+)-enantiomer of 26 in a rather lengthy process. 

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