Ethers, vinyl ozonolysis

Further examination of the extracts of A. cannabina revealed axisonitrile-4 (7), axisothiocyanate-4 (8) and axamide-4 (9) [33], A vinylic isonitrile function was supported by H NMR signals at <51.67 and 1.89, which were assigned to the two isopropylidene methyls of 7. Difficulty in isolating the natural product 9 was circumvented, when isonitrile 7 was transformed to 9, mp 81-84 °C, by acetic acid in anhydrous ether. The absolute configurations of both axanes 1 and 7 and their analogs were later established [31] by studies including X-ray diffraction of the p-bromoaniline derivative of 2 and by CD data of ( + )-10-methyldecalone-l obtained from ozonolysis of the reduction (Na/NH3) product of 1 [1]. 

Being aware of the fact that a hetero-substituted carbon-carbon double bond is convertible into a carbonyl group, one can use a-hetero-substituted lithio-alkenes 2 as nucleophilic acylation reagents 142 and 143, which display the umpoled d reactivity, provided that the carbanionic character is effective. Depending on the hetero-snbstitnent X, the conversion of the vinyl moiety into a carbonyl gronp can be effected either by hydrolysis or by ozonolysis. The former procednre has been applied preferentially in the case of lithiated vinyl ethers, whereas the latter has been nsed in particnlar for cleavage of the double bond in such products that result from the reaction of hthiated vinyl bromides with electrophiles (Scheme 17). 

Carbonyl oxides (191), generated in situ by ozonolysis of vinyl ethers readily add across the CN double bond of imines (192) to give 1,2,4-dioxazolidines (193) (Equation (18)) <88CC1550>. Alkyl substituted CN double bonds are more reactive than phenyl substituted ones. Ketones are far less reactive than imines. 

The preparation of (128) (Scheme 34) highlights the use of the trifluoromethyl group to increase the dipolarophilicity of a ketone. This activating effect of electron withdrawing groups is also taken advantage of in the preparation of 3-carbonyl substituted 1,2,4-trioxolanes (131) via the ozonolysis of a vinyl ethers in the presence of a 1,2-dicarbonyl compound (Scheme 36) <9iJOC659l>. 

Antimalarial activity is also shown by 13,43-tetraoxanes and these compounds have been synthesised by the acid-catalysed dimerisation of ozonides <99JMC2604>. Ozonolysis of vinyl ethers and cyclocondensation of the derived bis(hydroperoxides) with carbonyl... 

In the case of carbonyl oxides 127, generated by ozonolysis of vinyl ethers 126, the addition to a number of thioketones affords thioozonides 128 in moderate yields461 (equation 134), although sometimes oxidation to sulfines was observed. 

Hydrolysis of cyclic orthoesters Ozonolysis of tetrahydropyranyl ethers Cleavage of vinyl orthoesters... 

Carbonyl O-oxides 144, generated in situ by the ozonolysis of vinyl ethers at low temperature (—70 °C), readily undergo [3+2] cycloaddition with imines 145 added to the reaction mixture to afford the corresponding 1,2,4-dioxazolidines 15-18 in 14-97% isolated yields (Scheme 41) <1994J(P1)2449, 1995J(P1)41>. The repetition of these reactions in MeOH results in the quantitative recovery of the initial imines 145. The steric bulk of the a-substituents did not appear to diminish the imines 145 reactivity, because the isolated yields of 1,2,4-dioxazolidines... 

The study was continued with diastereoisomeric vinyl ethers. The ( )-isomer afforded on ozonolysis at —70 °C in ether a ry -carbonyl oxide, and with or without trifluoroacetophenone only the intramolecular ozonide 167, while the (Z)-isomer led to an anti-carbonyl oxide and to co-ozonolysis in the presence of trifluoroacetophenone, because the tf //-carbonyl oxide cannot adopt a suitable conformation for the intramolecular ozonide formation (Scheme 56) < 1996JOC5953, 1998JOC5617>. 

Ozonolysis of the cyclic vinyl ethers 71 (n = 2, 3 or 4) in the presence of M-benzylidene-benzylamine affords the dioxazoles 73 by dipolar cycloaddition to transient carbonyl oxides 72. The dioxazoles fragment to mixtures of phenylcycloalkenes, benzaldehyde and N-formyl-benzylamine by the action of silica gel (94JCS2449). Carbonyl oxides 75 (E = C02Me), generated by thermolysis of the peroxides 74, add to phenyl isocyanate to yield 1,2,4-dioxa-zolidin-3-ones 76 (94JCS3295). 

Synthesis and Reaction of 2-(Acyloxy) and 2-(Benzoyloxy) vinyl ethers of (R)-(-)-DCP. 2-(Acyloxy)vinyl ethers (13) of DCP have been prepared (eq 7). Allylation of 1 followed by ozonolysis with a zinc/acetic acid reductive work-up affords the corresponding chiral aldehyde. Heating this aldehyde with the appropriate anhydride and sodium salt of the carboxylic acid gives the desired 2-(acyloxy)vinyl ethers. 

A typical example of an application of ozonolysis in synthesis is the cleavage of the alkene unit in 351 to give aldehyde 352, with loss of formaldehyde, a part of Smith s synthesis of (+)-thiazinotrienomycin In this case, the reductive workup used triphenylphosphine. Ozonolysis of 353 gave aldehyde 354, an intermediate in Corey s synthesis of the Cecropia Moth Juvenile hormone, via a reductive workup with DMS. Note that the electron rich vinyl ether moiety reacted in preference to the simple alkene moiety. The ozonolysis product of the methyl vinyl ether was a methyl ester. This method is particularly useful for the preparation of protected acids. In general, electron rich alkenes are oxidized faster than electron-poor alkenes. 

Similar methodologies have been used to synthesize 1,2,4,5-tetroxanes. Ozonolysis of vinyl ethers 203 efficiently produces the intermediate carbonyl oxide, which dimerizes to the tetroxane (Scheme 36) <2002RMC113>. 

An elegant synthesis of unsymmetrical tetroxanes 238 involves ozonolysis of vinyl ethers 239 in the presence of hydrogen peroxide in diethyl ether. This procedure afforded the 1,1-bishydroperoxides 240, which on subsequent trimethylsilylation with A, 0- A(trimethylsilyl)acetamide (BSA) gave 241. TMSOTf-catalyzed cyclocondensation of 241 with carbonyl compounds afforded tetroxanes 238 (method A, Scheme 45 Table 4) <1999J(P1)1867>. 

Trioxazines. Condensation of carbonyl oxides (from ozonolysis of vinyl ethers or 0-methyl oximes) with nitrones (Scheme 35). 

A section on cardenolides would not be complete without mentioning the total synthesis of (+)-digitoxinin by Stork and his co-workers. Protected Wieland-Miescher ketone 66 was converted into compound 67 via formation of the trimethylsilyl enol ether ozonolysis of the enol ether gave a mixture of hydroxyketones, which was reduced to the corresponding diol and then cleaved with sodium periodate to yield dialdehyde intermediate 67. Compound 67 was then elaborated into Diels-Alder precursor 68 in two steps. After completion of the Diels-Alder reaction, four additional steps led to the preparation of intermediate 69, which was ideally set up for a vinyl radical cyclization. Key intermediate 70 was then elegantly converted into (+)-digitoxinin (71). 

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