DIBAL Ester reduction

The DIBAL reduction of esters to aldehydes in the presence of phosphonate anions appears to solve problems of overreduction to alcohol and provides a good general method of 2-carbon homologation... 

Hydroboration and oxidation of 160 yields an alcohol that is subsequently oxidized with PDC to give ketone compound 161. Enolization and triflation converts this compound to enol triflate 162, which can be further converted to x,/i-unsaturated ester 163 upon palladium-mediated carbonylation methox-ylation. The desired alcohol 164 can then be readily prepared from 163 via DIBAL reduction. Scheme 7 50 shows these conversions. 

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

With the fully functionalized heterocyclic core completed, synthetic attention next focused on introduction of the 3,5-dihydroxyheptanoic acid side-chain. This required initial conversion of the ethyl ester of 35 to the corresponding aldehyde through a two-step reduction/oxidation sequence. In that event, a low-temperature DIBAL reduction of 35 provided primary alcohol 36, which was then oxidized to aldehyde 37 with TRAP. Subsequent installation of the carbon backbone of the side-chain was accomplished using a Wittig olefination reaction with stabilized phosphonium ylide 38 resulting in exclusive formation of the desired -olefin 39. The synthesis of phosphonium ylide 38 will be examined in Scheme 12.5 (Konoike and Araki, 1994). 

Preparation of the Aldehyde 2 The absolute configuration of the iriene aldehyde 2 was set by Noyori hydrogenation of ethyl butyrylacetate S. Silylation and Dibal reduction then gave the aldehyde 6. Reduction of the homologated ester gave the alcohol, which was oxidized to the desired aldehyde 7 by the Swem procedure. Condensation of 7 with the Wollenberg stannyl diene followed by deprotection then gave the unstable aldehyde 2. 

Fig. 17.61. Mechanism of the DIBAL reduction of carboxylic esters to aldehydes and further...

There is one type of ester -> alcohol reduction for which one employs DIBAL (in a polar solvent) rather than LiAlH4 (in ether of THF). This reduction is the reduction of a,/)-unsaturated esters to allyl alcohols (example in Figure 17.63). The reaction of this kind of substrate with LiAlH4 sometimes results in a partial reduction of the C=C double bond to a C—C single bond in addition to the desired transformation —C(=Q)OR —> —CH2OH. 

Fig. 17.63. DIBAL reduction of an a,/3-unsaturated ester to an allylic alcohol. (See Figure 11.6 for a preparation of the substrate.)...

The latter reaction was further described by Koizumi et al. [86b] with slightly different results (lower facial selectivity for the exo-approach), in connection with the enantiodivergent synthesis of fused bycyclo [2,2,1] heptane lactones 91 (see Scheme 47). The key step of this transformation was the regioselective DIBAL reduction of only one of the two ester groups in the adducts, followed by... 

Fig. 14.53. Mechanism of the DIBAL reduction of carboxylic esters to aldehydes and further to alcohols. In nonpolar solvents the reaction stops with the formation of the tetrahedral intermediate A. During aqueous workup, A is converted into the aldehyde via the hemiacetal. In polar solvents, however, the tetrahedral intermediate A quickly decomposes forming the aldehyde via complex B. In the latter situation the aldehyde successfully competes with unreacted ester for the remaining DIBAL. The aldehyde is reduced preferentially, since the aldehyde is the stronger electrophile, and it is converted into the alcohol.

The intramolecular allylboration of an aldehyde function leads selectively to cir-disubstituted cyclic ethers. It has been shown that both the reactive aldehyde and the allylboronate moiety can be initially generated in situ in a masked form and then liberated simultaneously by hydrolysis of the precursor functions <1997JA7499>. This methodology was successfully applied to the one-pot synthesis of the oxocene 82, a precursor of (-l-)-laurencin (Scheme 13). A DIBAL reduction of the Weinreb amide 80, metalation with r f-butyllithium, borylation with the pinacol borate ester, and, finally, liberation of both the aldehyde and the allylboronate function by aqueous pH 7 buffer solution generated the reactive 81, which cyclized in 38% overall yield to the oxocene 82. Only the all-cis-diastereomer is formed, which means that the cyclization proceeds under high asymmetric induction from the resident stereogenic center present in 80. 

Racemic hydroxy ester 225 was converted, via a Sharpless kinetic resolution, to the enantiomerically pure epoxide 226. This epoxide was then converted to the diol "/-lactone by intramolecular attack of the ester, assisted by nucleophilic dealkylation with iodide ion. Deprotonation and methylation anti to the alkoxide followed by acetonide formation afforded 227 in 56% yield. Dibal reduction, protection of the resulting aldehyde as the terminal olefin, silylation of the tertiary alcohol, and liberation of the aldehyde via ozonolysis provided a 45% yield of the C-9 to C-15 fragment 228. 

The first synthesis of vermiculine by Corey, outlined in Scheme 4.14, employed an isopropenyl group as a protected version of the acetone sidechain. Aldehyde 57, the Dibal reduction product of readily available dimethyl 2,2-dimethoxyglutarate, was condensed with dimethallyl cadmium and the resulting alcohol silylated to produce 58 (70%). Reduction of ester 58 to the aldehyde followed by two-carbon homologation afforded a 94% yield of a,P unsaturated ester 59. Hydrolysis of 59 to the to the acid and conversion to the 2-thiopyridyl ester (77%) set the stage for double lactonization. This transformation was accomplished by thermolysis of a diluted solution of the thioester, affording a 30% yield of the diasteromeric diolides 60a and 60b (1 1). The former was then converted by oxidation into the synthetic 56 and the latter into the meso isomer 61, both in 70% yield. 

The open-chain tautomers 24b and 25 of precursor incipient imidazolidine and perhydropyrimidine derivatives, which bear a six carbon transferable fragment, on acid-catalyzed reactions with tryptamine formed the diester 85. A similar reaction of 24a leads to quantitative formation of 86 and the reaction of 25 with tryptamine is appreciably faster than that of 24b. Sodium cyanoborohydride/acetic acid reduction of 85 was accompanied by intramolecular aminolysis to form piperidone 87. Its Bischler-Napieralski cyclization followed by borohydride reduction gave cis- and trara-isomers of indoloquinolizine ester 88, which on hydrolysis to acid and subsequent methylene lactam rearrangement gave methylene lactam 89. Its DIBAL reduction gave 18- or-deplancheine 84a (88T6187). 

The synthesis of the spirocyclic core [70-77] is obviously the most difficult task, the biomimetic approach being the most frequent way of preparing it. The strategy is based on the hipervalent iodine-mediated oxidative hydroxylation of a tyrosinal derivative followed by a cis-bisepoxidation. The shortest way [75] involved the introduction of the side chain as an amide of tyrosine ethyl ester. Aranorosin was obtained after DIBAL reduction to the aldehyde, oxidation to the dienone with phenyliodosyl bis(trifluoroacetate) (PIFA) and final epoxidation (Scheme 24). 

DIBAL reduction of the ester to the allylic alcohol and oxidation to the aldehyde delivered citreoviral 103 eventually. 

The homologation of esters via a DIBAL reduction and phosphonate extension sequence is a commonly desired transformation. The DIBAL reduction to give an aldehyde suitable for homologation is often plagued by over-reaction problems,so that a reduction-reoxidation procedure is often required. These... 

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