Ozonolysis with reductive workup

The addition of allylmagnesium bromide to the serinal derivative 38 is syn selective in the presence of (—)-p-methoxydiisopinocampheylborane, giving the erythro derivative 156 (Scheme 13.55). Methylation of the alcoholic moiety of 156, followed by ozonolysis with reductive workup, hydrolysis of the carbamate and acidic treatment forms the methyl glycoside 157 of the E-ring moiety of calicheamicin [61]. A similar approach was proposed by Roush starting from the L-serinal derivative 50 [102]. 

Synthesis of 7 -amino acid-oxazole fragment 68 of calyculins A and B from D-erythronol-actone 58 has been reported by conversion to 59," which was subjected to oxidation reaction to afford the hemiaminal 60 (Scheme 9) Acetylation of 60 furnished 61, which was converted to ketone 62 in 88% yield. Conversion of 62 to a silyl enol ether, ozonolysis with reductive workup and O-methylation of the resultant alcohol 63 furnished 7 -lactam 64. Treatment of 64 with CAN led to 65 (60%), which was reacted with (CHj)2 A1 derivative of 66 to provide 67 (62%), which upon removal of the silyl group provided 68. 

Dimethyl-1-butene will not yield a methyl carbonyl compound upon ozonolysis with reductive workup. Hence, it will subsequently not give a positive iodoform reaction. 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

Dichloro-3.3,3-trifluoropropanal, an intermediate for the production of substituted pyridines, was prepared by ozonolysis of methyl 4,4-dichloro-5,5.5-trifluoro-2-methylpent-2-enoate with reductive workup. ... 

Diethyl P-keto-co-alkenylphosphonates, prepared by y-alkylation of the corresponding diethyl jj-ketophosphonates with allyl or homoallyl bromide, undergo ozonolysis at low temperature in CH2CI2 to give acyclic dicarbonyl phosphonates. Cyclization is accomplished with the aid of TsOH and EtjN as catalysts. Similarly, the diethyl 3-hydroxy-4-formylbutylphosphonate is prepared by allylation of diethyl 2-formylethylphosphonate using allyl bromide and zinc in a protic medium followed by ozonolysis and reductive workup. ... 

In an ozonolysis reaction with reductive workup, carbon-carbon double bonds are cleaved to form carbonyl groups. Hence the structure of A is deduced by rejoining the two carbonyl carbons in 3,7-dimethyl-6-oxo-octanal ... 

Harries ozonolysis of olefins with reductive workup Additive oxidation... 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

Hoye and Richardson have published an ingeneous synthesis of the tricyclic iridoid sarracenin (170) which relied on the Paterno-Buchi cycloaddition between acetaldehyde and cyclopentadiene as the intial step (Scheme 38)79. This reaction provided a 5 1 mixture of adducts 166a and 166b. The major adduct was opened with camphor-10-sulfonic acid (CSA) in methanol and the alcohol was tosylated to give 167. Displacement with malonate 168 and decarboalkoxylation/demethylation steps gave 169. Ozonolysis, reductive workup and acid-catalyzed acetalization then furnished 170. 

The ozonolysis reaction, followed by reductive workup with sulfur dioxide, as described in Part A of the present procedure, illustrates a general method which has been developed for the preparation of acetals. Application of the procedure is illustrated by conversion of the following olefins in alcoholic solution to the corresponding acetals (1) l-chloro-4-(o-nitrophenyl)-2-butene to o-nitrophenylacetaldehyde dimethyl acetal in 84% yield (2) l,4-dibromo-2-butene tobromoacetaldehyde dimethyl acetal in 67% yield (3) 3-butenoic acid to malonaldehydic acid diethyl acetal ethyl ester in 61% yield (4) cyclopentadiene to malonaldehyde bis(diethyl acetal) in 48% yield and (5)... 

The double bond in 7 is cleaved to an aldehyde by ozonolysis (see Chapter 5) and subsequent reductive workup with tnbutylphos-phine Crotylation with reagent 25.15 developed by Brown, produces only a single diastereomer, which is then transformed into benzoate 8 with benzoyl chloride in pyridine. 

The major synthetic problem associated with the synthesis of compounds such as NK-104 is the stereoselective construction of the lactone moiety and its connection to an aromatic or ethylenic core. This has been overcome by Minami and colleagues with the enantioselective synthesis of methyl 6-oxo-3,5-isopropylidenehexanoate (52) by ozonolysis of the ester 53, followed by reductive workup using dimethyl sulfide (Scheme 11,14).54 With the required aldehyde 52 now formed, further reaction could permit the production of NK-104 51 to take place enantioselectively. 

One method for the synthesis of hydroxyalkyl-substituted P-lactams is by the Staudinger reaction, the most frequently used method for the synthesis of P-lactams.86 This method for the preparation of 4-acetoxy- and 4-formyl-substituted P-lactams involves the use of diazoketones prepared from amino acids. These diazoketones are precursors for ketenes, in a diastereoselective, photochemically induced reaction to produce exclusively tram-substituted P-lactams. The use of cinnamaldimines 96, considered as vinylogous benzaldimines, resulted in the formation of styryl-substituted P-lactams. Ozonolysis, followed by reductive workup with dimethyl sulfide, led to the formation of the aldehyde 97, whereas addition of trimethyl orthoformate permitted the production of the dimethyl acetal 98 (Scheme 11.26). 

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. 

Professor Rufus T. Firefly of Fredonia State University wanted to stump his ace chemistry student. Sea Water (C-H2O, alias formaldehyde). The professor asked Sea Water to deduce the structure of menthol, the principal flavoring constituent of peppermint, on the basis of the following data the molecular formula of menthol is C10H20O when heated in the presence of sulfuric acid, a dehydration reaction ensues to form compound A ozonolysis of compound A followed by a reductive workup yields 3,7-dimethyl-6-oxo-octanal menthol also reacts with nitric acid and vanadium oxide, when heated, to form 2-isopropyl-5-methyl-hexanedioic acid. 

When treated with sodium borohydride in i-PrOH, the terminal alcohol was obtained after the substrate was released from the resin via hydrolysis (eq 44). Reductive workup using triphenyl-phosphine yielded the aldehyde product after release from the resin using chlorotrimethylsilane in MeOH/i-PrOH. This removal condition proved very mild and useful as it did not interfere with the aldehyde generated in the reaction. If the ozonolysis was conducted with acetic acid in the medium and was followed by stirring in an oxygen atmosphere overnight, the carboxylic acid can be obtained after release from the resin using the aforementioned TMSCl-mediated removal condition (eq 45). 

Phosphorus-containing compounds provide useful substrates for ozonolysis reactions as well and can provide several products depending on the reaction workup. Several biological uses exist for -amino-a-hydroxy phosphonic acid derivatives and they can be readily prepared by ozonolysis of Al-(ethoxycarbonyl)-/3-amino-Q -methylene phosphonic esters after reductive workup with sodium borohydride (eq 54). When the reaction mixture is treated with sodium hydroxide in MeOH, an anomalous ozonolysis reaction occurs and cleavage of the methylene as well as the carbon-phosphorus bond occurs to yield (V-(ethoxycarbonyl)-a-amino methyl carboxylic esters. 

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