Intramolecular cyclization modifications

Another successhil strategy for derivatization of erythromycin employed modification of functional groups involved in intramolecular cyclizations. The C-9 ketone, C-6 hydroxyl group, C-8 proton, and/or C-ll,12-diol of erythromycin were converted into functional groups which participate poorly, if at all, in intramolecular cyclizations. Some derivatives which have been extensively evaluated in preclinical and clinical trials exhibit such desirable properties as better stabiUty under acidic conditions, greater oral bioavadabihty, and higher and more prolonged concentrations of antibiotic in semm and tissues. 

A modification of the K-R reaction was introduced by Mozingo. This method involved reacting an o-hydroxyacetophenone with an ester in the presence of metallic sodium to form a 1,3-diketone. Treatment of the diketone with an acid then delivered the chromone via an intramolecular cyclization reaction. This method was applied to the preparation of 2-ethylchromone (21). 0-hydroxyarylketone 22 was allowed to react with ethyl propionate (23) in the presence of sodium metal.The resulting sodium enolate was then quenched with acetic acid to deliver the 1,3-diketone 24. Upon heating 24 in glacial acetic acid and hydrochloric acid, 2-ethylchromone (21) was delivered in 70-75% overall yield. 

Synthetic endeavours have continued in the diterpenoid series. The cyclization of geranylgeranic acid chloride to derivatives of cembrene, and their conversion into cembrene itself, have been described. Some further extensions of the route to macrocyclic diterpenoids based on the intramolecular cyclization of epoxysulphides and the subsequent modification of the macrocylic product have been described. ... 

Methylene chromans can be prepared by a palladium-catalyzed intramolecular cyclization of 2-iodophenyl alkynyl ethers 455. Simple modifications to the reaction conditions lead to either (E)- or (Z)-4-methylene chromans (Scheme 103) <2001TL2657>. 2-Iodophenyl alkynyl acetals are also viable substrates for this reaction <2005JOG489>. Addition of tris(2,6-diphenylbenzyl)tin hydride (TDTH) to a triethylborane-mediated intramolecular cyclization of 2-iodophenyl alkynyl ethers ensures complete (A)-selectivity is observed in the resulting 4-methylene chroman <2001AGE411>. 

On the contrary, in a slight modification of this route, a reductive intramolecular cyclization has been carried out which showed low 1,3-asymmetric induction. Thus, treatment of ketone 11 with excess sodium borohydride in dioxane at 20 C gives a 71 29 cisjtrans) diastereomeric mixture in 82% yield91. 

The Nef reaction often represents the key transformation in a reaction sequence in which it is involved. The synthesis of simple aliphatic ketones or aldehydes is probably not the most useful application of the Nef reaction. More important is the access to dicarbonyl compounds for intramolecular cyclization reactions leading to a large variety of carbocycles or heterocycles. However, the method can be capricious and success depends on the structure of the substrate. In order to overcome synthetic drawbacks, several roundabout methods have been devised for application to peculiar polyfunctionalized molecules. The number of modifications of the Nef reaction which can be carried out under a wide variety of conditions clearly reveals that no procedure is of general application. The scope and limitations of the different modifications will be discussed considering the structure of desired carbonyl derivative. 

Intramolecular cyclization of 1 forms an azetidine ring, resulting in the formation of a biosynthetically significant postulated intermediate (29). Oxidation of this intermediate leads to okaramines Q (18) and E (6). Subsequent modification of 18 leads to okaramine B (2) and okaramine... 

The intramolecular cyclization of J-iminoacetylenes to pyrazino[l,2-a]indoles described by Abbiati [67] is a new example of modification of selectivity. When 1-propargyl indoles 79 were treated in a sealed tube at 100 °C with 2 m ammonia in methanol, the corresponding pyrazino indoles 80 and 81 were obtained in good yields. Differences between the relative ratio of 80 and 81 were related to ... 

Another synthetic strategy for partially or completely inhibiting intramolecular cyclization of erythromycin to hemiketal (8) and spiroketal (9) is modification of the functional groups that participate in the cyclization reactions. These groups include the C-9 ketone, C-6 hydroxyl, and C-8 proton in addition to the 11,12-diol discussed above. These approaches have led to a variety of semi-synthetic derivatives of erythromycin, some of which have been recently approved by regulatory agencies or are in late stages of clinical trials [12-17],... 

Modification of the C-9 ketone has been successfully accomplished in several ways. Conversion of the ketone to simple oximes was known to diminish intramolecular cyclization, but this transformation also reduced antibiotic activity. In order to increase antimicrobial activity, an expanded series of oximes was synthesized by 0-alkylation of the oxime of erythromycin with alkyl halides and base in aprotic solvents [29]. From evaluation of this series, roxithromycin, the 9-[0-(2-methoxyethoxy)methyl]oxime (see Fig. 4), was selected as the derivative with the best therapeutic index [29]. Roxithromycin has now been introduced in France as a new antibiotic. 

The cyclic 11,12-carbonate of erythromycin represents a previously recognized method for stabilization of erythromycin by maintaining an equilibrium between the 6-hydroxy-9-keto and 6,9-hemiketal forms [44]. A new direction within this approach was recently reported with a series of cyclic 11,12-carbamate derivatives of erythromycin and clarithromycin (see Fig. 5), prepared by a general sequence of 10,11-dehydration, 12-0-carbamoylation, and intramolecular cyclization [45, 46]. Other structural modifications within this part of the erythromycin molecule include 10,11-anhydroerythromycin, previously synthesized from the cyclic 11,12-carbonate [47],... 

For peptides containing Trp and/or Met, which have side-chains susceptible to oxidation in the presence of excess KsFeiCNIe, Mlslcke and Hruby (90) proposed a modification of the above procedure add simultaneously the peptide solution and the oxidant solution (same concentrations as above), very slowly and at the same rate, to a reaction flask. This modification allows for peptide and ferricyanide to be at the equimolar highly-dilute concentration believed to allow for optimal intramolecular cyclization without side reactions. 

Esterification.—Another way to improve the sometimes unsatisfactory N,N-dicyclohexylcarbodi-imide esterification method is to add catalytic quantities of toluene-p-sulphonic acid to the reaction mixture (c/. 3, 149). Esters can be obtained very rapidly and generally in high yields by reactions between 2-substituted 1,3-benzoxathiolium salts and alcohols (Scheme 30). One drawback could be the rather acidic conditions employed in the second step. A neat modification of the mixed-anhydride esterification method requires no added acid or base in the final step but uses an intramolecular cyclization as the driving... 

In recent years, silicon-containing derivatives of proline have attracted considerable attention of chemists. The replacing proline by these unnatural amino acids, which are more stable towards proteolytic degradation, may increase the bioavailability of the structurally similar peptides without a modification of their conformational and biological properties (104). Currently, the Schdllkopf method is the only proven approach for the synthesis of silaproline cycle (105). Hydropyrazine is hydrolyzed under mild conditions to yield hydrochloride of 3-[(iodomethyl) (dimethyl) silyl] alanine methyl ester. The reaction of the latter with amine affords a product of the intramolecular cyclization of the 4,4-dimethyl-4-sila-proline methyl ester and its interaction with (t-Boc)20 gives rise to the corresponding N-t-Boc-silaproline methyl ester 133 (Scheme 24.17). 

Reaction with Di- and Polyols. Although intermolecular dehydration between two molecules of alcohols to afford acyclic ethers usually does not occur with the DEAD-TPP system, intramolecular cyclization of diols to produce three to seven-membered ethers is a common and high yielding reaction. Contrary to an early report, 1,3-propanediol does not form oxetane. Oxetanes can be formed, however, using the trimethyl phosphite modification of the Mitsunobu reaction. The reaction of (5)-1,2-propanediol and ( )-l,4-pentanediol with DEAD and TPP affords the corresponding cyclic ethers with 80-87% retention of stereochemistry at the chiral carbon, while (5)-phenyl-1,2-ethanediol affords racemic styrene oxide. In contrast to the reaction of the same 1,2-diols with benzoic acid (eq 4), oxyphos-phonium salts (25a) and (25b) have been postulated as key intermediates in the present reaction (eq 20). ... 

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