Synthesis by ozonolysis

Scheme 10. Centrally modified p-pentaketones 57 and 60 synthesis by ozonolysis 57,54,56) and cycUzation behavior 54,56).

Alkenes are cleaved to carbonyl compounds by ozonolysis This reaction IS useful both for synthesis (preparation of aldehydes ketones or car boxyhc acids) and analysis When applied to analysis the carbonyl com pounds are isolated and identified allowing the substituents attached to the double bond to be deduced... 

Until the second half of the twentieth century, the structure of a substance—a newly discovered natural product, for example—was determined using information obtained from chemical reactions. This information included the identification of functional groups by chemical tests, along with the results of experiments in which the substance was broken down into smaller, more readily identifiable fragments. Typical of this approach is the demonstration of the presence of a double bond in an alkene by catalytic hydrogenation and subsequent determination of its location by ozonolysis. After-considering all the available chemical evidence, the chemist proposed a candidate structure (or structures) consistent with the observations. Proof of structure was provided either by converting the substance to some already known compound or by an independent synthesis. 

A stereospecific total synthesis of polyoxin C and related nucleosides is reported, in which thereacdon of l-Cphenylthioi-l-nitroalkenes v/ith nucleophiles and siibseqiientozono lysis are key reacdons Addidonof potassium trimethylsilanoate to l-Cphenylthioi-nitroalkenes derived from D-ribose followed by ozonolysis gives the cr-hydroxy thioester, which is formed v/ith excellent diastereoselecdvity fScheme 4 5 This conformadon meets the stereo-electronic requirements for andperiplanar addition of the nucleophile with the result of high 5-fS stereochemical bias in the reacdons... 

Ebdon and coworkers22 "232 have reported telechelic synthesis by a process that involves copolymerizing butadiene or acetylene derivatives to form polymers with internal unsaturation. Ozonolysis of these polymers yields di-end functional polymers. The a,o>dicarboxy1ic acid telechelic was prepared from poly(S-s tot-B) (Scheme 7.19). Precautions were necessary to stop degradation of the PS chains during ozonolysis. 28 The presence of pendant carboxylic acid groups, formed by ozonolysis of 1,2-diene units, was not reported. 

The synthesis shown in Scheme 13.66 starts with the Sharpless asymmetric epoxidation product of geraniol. The epoxide was opened with inversion of configuration by NaBHjCN-BFj. The double bond was cleaved by ozonolysis and converted to the corresponding primary bromide. The terminal alkyne was introduced by alkylation of... 

Thus, an alkene can be considered as a masked ketone that can be unmasked by ozonolysis. This is illustrated by the synthesis of N-acetylneuraminic acid via the ozonolysis of the precursor acrylic acid in THF/aqueous media (Eq. 3.22). The use of aqueous media facilitated the solubility of the polyhydroxyacids.92... 

In 1991, Whitesides etal. reported the first application of aqueous medium Barbier-Grignard reaction to carbohydrate synthesis through the use of tin in an aqueous/organic solvent mixture (Eq. 8.48).106 These adducts were converted to higher carbon aldoses by ozonolysis of the deprotected polyols followed by suitable derivatization. The reaction showed a higher diastereoselectivity when there was a hydroxyl group present at C-2. However, no reaction was observed under the reaction conditions when there was an /V-acctyl group present at the C-2 position. 

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>. 

Deprotection of N-2 by ozonolysis furnishes triazoles 1225 (Scheme 202) <2003JA7786>. Finding that 1,3-dipolar cycloaddition of alkynes 1222 to trimethylsilyl azide, carried out in DMF/MeOH in the presence of Cul as a catalyst, leads directly to products 1225 with much higher yields provides a significant progress to the synthesis of N-unsubstituted 1,2,3-triazoles <2004EJO3789>. 

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). 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

The synthesis of the non-racemic cyclopentanone (+)-93 is outlined in Scheme 15. Starting with 2-methyl-cyclopent-2-enone (90), sequential cuprate addition and enolate alkylation afforded the racemic cyclopentanone rac-92 as a single diastereomer. The double bond was cleaved by ozonolysis, the resulting aldehyde chemoselectively reduced in the presence of the keto function and the primary hydroxyl function was subsequently protected as a silyl ether to provide racemic rac-93. This sequence has been applied fre-... 

Lactol 128 has been converted into a variety of racemic C-nucleosides. The unstable aldehyde 130 was prepared from 128 by way of oxazolidine 129. Lactone 131 was also derived from 128 and used as starting material in the synthesis of racemic C-nucleosides. Adducts 77 + 77 were transformed into epoxide 132. Opening of the epoxide, followed by ozonolysis and reduction allowed one to... 

A synthesis of a dimethyl derivative of 501 has also recently been announced by Hirao, et al. Following conversion of 513 to its dimesylate, Lewis acid-catalyzed rearrangement gave dienedione 514 as the major product. Heating of the disemi-carbazone of 514 with powdered KOH furnished the diolefin which was transformed into 515 by ozonolysis. When the ditosylhydrazone of 515 was heated with potassium... 

SCHEME 13. Synthesis of a-alkoxy hydroxy hydroperoxides by ozonolysis, OMe OOH... 

Sha et al. (45) reported an intramolecular cycloaddition of an alkyl azide with an enone in an approach to a cephalotaxine analogue (Scheme 9.45). Treatment of the bromide 205 with NaN3 in refluxing methanol enabled the isolation of compounds 213 and 214 in 24 and 63% yields, respectively. The azide intermediate 206 underwent 1,3-dipolar cycloaddition to produce the unstable triazoline 207. On thermolysis of 207 coupled with rearrangement and extrusion of nitrogen, compounds 213 and 214 were formed. The lactam 214 was subsequently converted to the tert-butoxycarbonyl (t-Boc)-protected sprrocyclic amine 215. The exocyclic double bond in compound 215 was cleaved by ozonolysis to give the spirocyclic ketone 216, which was used for the synthesis of the cephalotaxine analogue 217. 

In continuation of our efforts to explore the utility of the SAMP/RAMP hydra-zone methodology, we developed the first asymmetric synthesis of a-phosphino ketones via formation of a carbon-phosphorus bond in the a-position to the carbonyl group [70]. The key step of this asymmetric C—P bond formation is the electrophilic phosphinylation of the ketone SAMP hydrazone 87, giving rise to the borane-adduct of the phosphino hydrazone 88 with excellent diastereoselectiv-ity (de = 95-98%). Since these phosphane-borane adducts are stable with respect to oxidation, the chemoselective cleavage of the chiral auxiliary by ozonolysis leading to the a-phosphino ketones (R)-89 could be accomplished with virtually no racemization. Using RAMP as a chiral auxiliary, the synthesis of the enantiomer (S)-89 was possible (Scheme 1.1.25). 

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