Ozonolysis, cyclizations

The ozonolysis/cyclization of the corresponding alcohol 290 to give the less-oxidized 10-deoxoartemisinin 108 has been accomplished, but only in a suprisingly low yield (Equation 37) <1996JME4149>. 

The early Escherunoser-Stork results indicated, that stereoselective cyclizations may be achieved, if monocyclic olefins with 1,5-polyene side chains are used as substrates in acid treatment. This assumption has now been justified by many syntheses of polycyclic systems. A typical example synthesis is given with the last reaction. The cyclization of a trideca-3,7-dien-11-ynyl cyclopentenol leads in 70% yield to a 17-acetyl A-norsteroid with correct stereochemistry at all ring junctions. Ozonolysis of ring A and aldol condensation gave dl-progesterone (M.B. Gravestock, 1978 see p. 279f.). 

The final step can involve introduction of the amino group or of the carbonyl group. o-Nitrobenzyl aldehydes and ketones are useful intermediates which undergo cyclization and aromatization upon reduction. The carbonyl group can also be introduced by oxidation of alcohols or alkenes or by ozonolysis. There are also examples of preparing indoles from o-aminophcnyl-acetonitriles by partial reduction of the cyano group. 

The pyrazole ring is resistant to oxidation and reduction. Only ozonolysis, electrolytic oxidations, or strong base can cause ring fission. On photolysis, pyrazoles undergo an unusual rearrangement to yield imidazoles via cleavage of the N —N2 bond, followed by cyclization of the radical iatermediate to azirine (27). 

Scheme 7.11. Domino ozonolysis/aldol cyclization of unsaturated ketonitriles.

The strategy employed in studies aiming at the synthesis of the spiro segment of halichlorine (see also Section 12.01.11.4) involved a ring expansion in indolizidine 264. The double bond of this compound was cleaved by ozonolysis yielding compound 265, which was cyclized to quinolizidine derivative 266 in the presence of base (Scheme 56) <2004TL2879>. 

Several lupin alkaloids have been derived from the unsaturated quinalozidine 433, that was obtained in the treatment of amine 431 with ortho-quinone 432. This quinone behaves as a model of topaquinone, the cofactor of copper-containing amine oxidases. The cyclization step involved a nucleophilic attack of the piperidine nitrogen of 431 onto a side-chain aldehyde function that is unmasked by the oxidative deamination. Quinolizine 433, when treated with dehydropiperidine, gave the oxime ether 434 that, on ozonolysis followed by reduction, afforded sparteine 10, presumably via the bis(iminium) system 435 (Scheme 102) <1996JOC5581>. 

Treatment of 122 with (R,R)-tartrate crotyl-boronate (E.R.R)-W 1 provides the alcohol corresponding to 123 with 96% stereoselectivity. Benzylation of this alcohol yields 123 with 64% overall yield. The crude aldehyde intermediate obtained by ozonolysis of 123 is again treated with (Z,R,R)-111 (the second Roush reaction), and a 94 5 1 mixture of three diastereoisomers is produced, from which 124 can be isolated with 73% yield. A routine procedure completes the synthesis of compound 120, as shown in Scheme 3-44. Heating a toluene solution of 120 in a sealed tube at 145°C under argon for 7 hours provides the cyclization product 127. Subsequent debromination, deacylation, and Barton deoxygenation accomplishes the stereoselective synthesis of 121 (Scheme 3-44). 

The ozonolysis of cyclobutene derivatives in the preparation of 1,4-diketones was also applied to the total synthesis of eyclopentanoid antibiotics 161 162k The oxidative cleavage of (470) by ozone and reductive work-up yielded the diketone (471) in 73 % yield. Diketone (471) underwent intramolecular aldol cyclization to give the key intermediate (472), which was used to synthesize ( )-xanthocidin161,162), (+)-epi-xanthocidin 162), ( )-p-isoxanthocidin161,162) as well as ( )-desdihydroxy-4,5-didehydroxanthocidin162). 

Using an identical process, the pipecolic acid derivative (112) was converted into a bicyclic amide derivative as shown in Scheme 36. In this case, the methoxylated amide proved to be unstable in the crude electrolysis reaction and was taken directly into the cyclization-ozonolysis sequence. A 74% yield of the bicyclic ketone was obtained over three steps. Compound (114) was converted into A58365B demonstrating that the anodic oxidation reaction allowed for rapid access to both natural products. 

The syntheses of (-l-)-mww,a ri,m -dicyclohexano-18-crown-6, i+)-trans-cyclohexano-15-crown-5, and (-l-)-r wis-cyclohexano-18-crown-6 (115) ftom (-l-)-mi/w-cyclohexane-l,2-diol (Figure 15) have been described. They involve base-promoted cyclizations with the appropriate ditosylates after chain extension of the chiral diol using the allylation-ozonolysis-reduction procedure. 

Capnellane is the generic name applied to a group of sesquiterpene alcohols and the hydrocarbon isolated from the soft coral Capnella imbricata A < >-Capnellene (667), the presumed biosynthetic precursor of the capnellenols, was first synthesized in 1981 by Stevens and Paquette Their synthetic plan called for the construction of bicyclic ketone 668 and its appropriate annulation. The latter event was achieved by application of the Rupe rearrangement to 668, conjugate addition of a vinyl group to 669, ozonolysis, and cyclization (Scheme LXVIII). Hydrogenation and olefination completed the sequence. 

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