Oxetanes ring synthesis

A 10-20%-soln. of the startg. m. (mixture of cis- and rrawj-isomers) in diphenyl-methane heated at 280-300° in a Pyrex ampoule methyl 3-methyl-2-butenoate. Y 90%.-In combination with photochemical oxetane ring synthesis from ethylene derivs. and oxo compds. (s. Synth. Meth. 19, 764), ethylene deriv.-oxo compd. interconversion may be achieved. F. e. s. G. Jones II, S. B. Schwartz, and M. T. Marton, Chem. Commun. 1973, 374. 

The synthesis of S. J. Danishefsky s group is outlined in Scheme 13.55. The starting material is a protected derivative of the Wieland-Miescher ketone. The oxetane ring is formed early in this synthesis. An epoxide is formed using dimethylsulfonium methylide (Step A-3) and opened to an allylic alcohol in Step A-4. The double bond... 

A. Roy, B. Achari, and S. B. Mandal, An easy access to spiroannulated glyco-oxetane, -thietane and -azetane rings Synthesis of spironucleosides, Tetrahedron Lett., 47 (2006) 3875—3879. 

The synthesis of an alditol having a 4-membered (oxetane) ring was first reported by Ustyuzhanin and coworkers,50 who prepared 1,3-anhydro-5,6-di-0-methyl-2,4-0-methylene-D-glucitol by saponification of the 1-p-toluenesulfonate of the corresponding derivative of D-... 

Uryu and coworkers also reported the first synthesis of a nonhydro-lyzable polysaccharide by cationic, ring-opening polymerization of an oxetane ring. The monomer was 3,5-anhydro-l,2-0-isopropylidene-a-D-xylofuranose, and it formed a polymer of molecular weight of 10,000-11,000. Spectral and optical data indicated regular polymerization to a (3— 5)-linked polymer of 1,2-O-isopropylidene-a-D-xylofuranose.14... 

Ring Synthesis Classified by Number of Ring Atoms 2.05.9.1 Oxetane Synthesis by Single C-0 Bond Formation... 

The photo-cycloaddition of ethylene to 3-alkoxy chromones such as 315 has been applied to the synthesis of marine sesquiterpene filiformin and congeners (Scheme 43) <1996JOC4391>. Tandem [2+2] 7i-photo-cycloaddi-tion and y-hydrogen abstraction provided tetracyclic intermediate 316 which was converted to terpene 317 by subsequent oxetane ring reduction and acid-catalyzed rearrangement. 

After these pioneering works, several reviews cover the enormous number of papers published in this field [3-7]. The synthesis of oxetanes can have a great importance in the development of compounds with relevant biological properties oxetane ring is present in the skeleton of taxol (1), an important drug used in the treatment of ovarian cancer [8] in merrilactone A (2), a new sesquiterpene dilactone with neurotrophic activity [9] and in several antiviral oxetanes, such as 3, 4, and 5, which have been described in literature (Scheme 3.2) [10-12],... 

The intramolecular nudeophilic substitution reaction - for example, the William-son-type reaction - represents one of the important methods for preparing oxetane ring structures, and have been widely applied to the synthesis of oxetanes (Scheme 7.1) [10]. Unfortunately, side reactions - which indude fragmentation from the intermediary alkoxide anion or elimination from the intermediary carboca-tion - often decrease the chemical yields of oxetane formation. 

A recent synthesis of the tricyclic secoiridoid ( )-sarracenin (98) relied on the Patemo-Biichi addition of acetaldehyde and cyclopentadiene as the initial step. Irradiation of cyclopentadiene and acetaldehyde provided a 5 1 mixture of bicyclic oxetanes (97) and (96) in 5-10% yield. Treatment of the crude photolysate with CSA and methanol followed by tosylation of the cmde product gave (99), which represents the toluenesulfonate ester derived from the major oxetane (97). The tosylate was displaced by the anion prepared from dimethyl 3-styrenylmalonate to afford the substituted malonate (100) in 84% yield (Scheme 10). Attempts to effect ring opening of the oxetane mixture were unsuccessful. Decarboxylation and demethylation gave the alcohol (102) which was subjected to ozonolysis and reductive work-up to afford ( )-sarracenin in 60% yield. The oxetane-based synthesis is noteworthy due to its brevity and use of a biosynthetically postulated trialdehyde equivalent. 

The first synthesis of d4T was accomplished in 1966 by Horwitz from l-(2-deoxy-3,5-epoxy-/3-D-r/2reo-pentosyl)thymine abstraction of a proton from the 2 -position by potassium butoxide in DMSO resulted in an opening of the oxetane ring and formation of d4T. Other syntheses were based on the elimination of sulfoxide or the selenoxide moiety placed at the C-2 position in the nucleoside, which was prepared from cheap lactone 6 (O Scheme 7) [6]. 

During the early stages of the total synthesis of (+)-gelsemine, S.J. Danishefsky et al. wanted to install a key oxetane ring on a bicyclic ketone intermediate. The Eschenmoser methenylation was chosen to prepare the required bicyclic a-methylene ketone which was later converted to the oxetane in a few steps. 

The first total synthesis of the cytotoxic agent (+)-euplotin A was completed by the research team of R.L. Funk. The key step of the synthetic effort was the intramolecular hetero DIels-Alder cycloadditlon of a 3-acyl oxadiene (generated from 5-acyl-4H-1,3-dioxins via thermal retrocycloaddition) with a substituted dihydrofuran to afford the tricyclic skeleton of the natural product. The correct relative stereochemistry of the required dihydrofuran substrate was established using the Paterno-Buchi reaction between ethyl glyoxylate and furan. Subsequently, the oxetane ring was opened stereoselectively under Lewis acid catalysis. 

The total synthesis of (+)-merrilactone A was accomplished by S.J. Danishefsky and co-workers. The last step of the sequence was an acid-induced homo-Payne rearrangement. The tetracyclic homoallylic alcohol precursor was first epoxidized using mCPBA. The epoxidation was expected to occur from the same face as the C7 hydroxyl group, but due to the congested nature of the C1-C2 double bond at its 3-face, the epoxide was formed predominantly on the a-face. The epoxide substrate then was exposed to p-toluenesulfonic acid at room temperature to afford the desired oxetane ring of the natural product. 

Oxetanes rarely occur in nature. The diterpene alcohol taxol (paclitaxel ) was isolated in 1971 from the bark of the pacific yew tree (Taxus brevifolia) native to the northwest USA, and its structure elucidated. The compound, which is now marketed, contains an oxetane ring and displays a strong antitumour and antileukaemia activity. Its total synthesis has been achieved [5]. 

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