Lactones, olefinic, reduction

Another popular olefination-reduction sequence starts with commercially available ketone 122, transformed into olefin 123 using a Wittig or Wittig-Horner reaction [103] (illustrated in Scheme 11.32). Reduction of the double bond proceeds with high stereocontrol to yield the alio derivative 124. The cis arrangement at C2-C3 allowed formation of lactone 125 and the synthesis of avenaciolide 126 [104,105]. 

Scheme 3 Olefin (29) prepared from dienone (26) by standard organic reactions was converted to bromohydrin derivative (30), which on subjection to photolysis and dehydrohalogenation yielded ketal (32), whose conversion to a,P unsaturated ketone (34) was accomplished by hydrolysis, bromination and dehydrobromination respectively. The cyanation of (34) followed by hydrolysis and esterification produced ester (35), which on Clemmensen reduction and oxidation afforded lactone (37). Reduction of (37) followed by oxidation and esterification gave ketoester (38), which was converted to (39).

Enzyme-catalyzed hydrogenations have a long history as an alternative for stereoselective olefin reduction [12, 72). Selected illustrative examples of enzymatic olefin reductions are depicted below. In an elegant series of studies by scientists at Hoffmann-La Roche, it was found that baker s yeast effects the reduction of unsaturated ester 96 (Scheme 8.10) [73]. Unsaturated alcohol 99 was selectively transformed into lactone 100 by use of the fungus Geotrichum candidum. The optically pure substituted lactones, 98 and 100, were subsequently utilized in a synthesis of a-tocopherol (vitamin E 101) [74]. 

With the co side chain at C-12 in place, we are now in a position to address the elaboration of the side chain appended to C-8 and the completion of the syntheses. Treatment of lactone 19 with di-isobutylaluminum hydride (Dibal-H) accomplishes partial reduction of the C-6 lactone carbonyl and provides lactol 4. Wittig condensation8 of 4 with nonstabilized phosphorous ylide 5 proceeds smoothly and stereoselectively to give intermediate 20, the bistetra-hydropyranyl ether of ( )-1, in a yield of -80% from 18. The convergent coupling of compounds 4 and 5 is attended by the completely selective formation of the desired cis C5-C6 olefin. 

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

The synthesis in Scheme 13.21 starts with a lactone that is available in enantiomer-ically pure form. It was first subjected to an enolate alkylation that was stereocontrolled by the convex shape of the cis ring junction (Step A). A stereospecific Pd-mediated allylic substitution followed by LiAlH4 reduction generated the first key intermediate (Step B). This compound was oxidized with NaI04, converted to the methyl ester, and subjected to a base-catalyzed conjugation. After oxidation of the primary alcohol to an aldehyde, a Wittig-Horner olefination completed the side chain. 

Very simple synthesis of a-substituted y-methyl-y-lactones is also possible by olefination using nitroalkanes followed by reduction, as shown in Eq. 7.128.174... 

Diastereoselective intermolecular nitrile oxide—olefin cycloaddition has been used in an enantioselective synthesis of the C(7)-C(24) segment 433 of the 24-membered natural lactone, macrolactin A 434 (471, 472). Two (carbonyl)iron moieties are instrumental for the stereoselective preparation of the C(8)-C(ii) E,Z-diene and the C(i5) and C(24) sp3 stereocenters. Also it is important to note that the (carbonyl)iron complexation serves to protect the C(8)-C(ii) and C(i6)-C(i9) diene groups during the reductive hydrolysis of an isoxazoline ring. 

White et al. developed a stereospecific synthesis of Z-olefins, including isotretinoin [84]. Thus, isotretinoin was obtained by a Reformatsky reaction of p-cyclocitral with the C5 bromoester, followed by DIBAL-H lactone reduction, lactol ring opening, selective olefin bond formation with ethyl 4-diethoxyphosphoryl-3-methyl-2-butenoate and further saponification, Fig. (46). 

Reductive cleavage of the lactone in methyldecinine (9) followed by formic acid dehydration afforded the olefin (29). 

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