Aldehydes, reduction with DIBAL

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

The key intermediate in the total synthesis of furaquinocin was obtained in good yield by a reductive Heck reaction that proceeded with a sterically hindered base pentamethylpiperidine (PMP) <02JA11616>. A new hypothesis for the major skeletal rearrangement (anthraquinone —> xanthone —> coumarin) that occurs in the complex biosynthesis of aflatoxin Bi was proposed. To test this hypothesis, an intermediate 11-hydroxy-O-methylstergmatocystin (HOMST) was synthesized as shown below. The key transformation in this synthesis involved the treatment of an ester-aldehyde with Pr3SiOTf, which smoothly produced a mixed acetal. Direct reduction with DIBAL-H led to the aldehyde. The desired product was eventually obtained via several steps as shown <02JA5294>. 

Af-Acyl-5,5-dimethyloxazolidin-2-one 228 can be considered as a latent aldehyde equivalent. Its reduction with DIBAL-H afforded the corresponding I -hydroxy-alkyloxazolidinone 229 as the sole product. The product can react under the Wadsworth-Homer-Emmons protocol to afford the a-p unsaturated ester 232 or the free aldehyde 231 could be isolated after hydrolysis <030B2001>. This methodology was also employed in the asymmetric synthesis of a-alkyl and p-alkyl aldehydes <03OB2886>. 

There are several ways to cleave the auxiliary from the product 7. Typical reactions include reduction with complex hydrides such as LiBH4 to obtain the alcohol 18 or transamination to the Weinreb amide and subsequent reduction with DIBAL to give the aldehyde 19 that would have been obtained from direct aldol reaction. ... 

The coupling partner (104) for the aldehyde 86 was synthesized as shown in Scheme 22. Starting with lactone 101 [53], a reduction with DIBAL-H to afford the lactol and extension of the carbon framework furnished compound 102. In six steps, the researchers were able to... 

Recent developments extend the asymmetric P-lactone formation to dichloroaldehydes 183 with formation of the ketene 163 by elimination on acetyl chloride rather than from a ketene generator. A mixture of the aldehyde 183, Hunig s base and 2 mol % quinidine 169 is treated with acetyl chloride to give the p-lactones 184 in good yield (40-85%) and excellent ee. Reduction with DIBAL gives the diol 185 with the two chlorine atoms intact.42... 

The diversity associated with silyl protecting groups as well as the chemical conditions available for their removal makes them attractive alternatives to benzyl protection of the hydroxy groups of either D- or L-tartaric acid derivatives. O-isopropylidene-L-threitol (37) is mono-protected with er -butyldimethylsilyl chloride to furnish 266, which is converted in three steps to the nitrile 267. Reduction with DIBAL and Wittig olefination followed by desilylation with fluoride and Swern oxidation of the resulting alcohol provides aldehyde 268, which reacts with methyl 10-(triphenylphosphorane)-9-oxo-decanoate (269) to afford enone 270. Reduction of 270 with subsequent preparative TLC and acetal hydrolysis furnishes (9R)-271 and (9 S)-272, both interesting unsaturated trihydroxy Cig fatty acid metabolites isolated from vegetables [91] (Scheme 62). 

The synthetic utility of (i )-enoate 392 is illustrated in the stereoselective synthesis of the bengamide E derivative 399 (Scheme 88). Silyl protection of 392, reduction with DIBAL, and Sharpless epoxidation of the resulting allylic alcohol furnishes epoxy alcohol 396 as a 95 5 anti syn mixture. Conversion of the primary hydroxyl group of 396 to an iodide under neutral conditions followed by a metallation-elimination and subsequent in situ methylation provides the ether 397. Ozonolysis, desilylation with aqueous acetic acid, and a Dess-Martin oxidation supplies the a,jS-dialkoxy aldehyde 398. This, utilizing stannane Se addition, is then converted to 399 [135]. 

Treatment of readily available arylacetonitriles with KHMDS and subsequent alkylation with a.iu-dibromo or dichloroalkanes produces cycloalkyl adducts in good yields and short reaction time (eq 37). In this process, the nitrile moiety serves as a masked aldehyde, which could be revealed upon reduction with DIBAL-H. 

Nitrile 13 was readily converted to aldehyde 16, via reduction with DIBAL, which was treated with 1,3-propanedithiol gave the dithiane 17 (Scheme 8). The carbanion of 17 afforded the first reagent that can give entrance to an all C-unimolecular micelle. Due to the bulky environment of this dithiane, it was rationalized that a cleaner procedure would utilize a carbanion with less steric congestion. Thus, when aldehyde 16 is reduced with sodium borohydride, alcohol 18 was isolated in excellent yield alternatively, nitrile 13 can be hydrolyzed... 

The silyloxy aldehyde 1 was prepared from the ester 9 by reduction with Dibal. Felkin-controlled 1,2-addition of the allyl stannane 2 established the relative configuration of the secondary alcohol of 3, that was then used to control the relative configuration of the new alcohol in 10. Addition of the crotyl horane 12 to the derived aldehyde 11 also proceeded with high diastereocontrol. 

The synthesis of aldehyde 212 started with an Evans alkylation of the known acylated oxazolidinone 215 with allyl iodide 216 to form the corresponding alkylated product 217 as a single diastereoisomer in 81% yield (Scheme 2.88) [118]. Reductive removal of the chiral auxiliary followed by tosylation of the resulting primary alcohol, cyanide substitution, and reduction with DIBAL... 

Aldehyde 123 was then reacted in a stereoselective Homer-Wadsworth-Emmons reaction with the sodium salt of phosphonate 124 to produce enone 125 (Scheme 3.31). Chemo- and stereoselective rednction of enone 125 with zinc borohydride provided secondary alcohol 126 as a 1 1 mixture of C-15 epimers, which could be separated by chromatography. Next, solvolysis of the acetate in 126 with basic methanol was followed by protection of the two alcohols with dihydropyran in the presence of a catalytic amount of para-toluenesulfonic acid. Reduction with DIBAL-H then provided lactol 127. Wittig reaction of 127 with the nonsta-bilized ylide 128 and snbsequent deprotection produced ( )-prostaglandin F (113). 

The latter was converted into corresponding hydroxy ester through transesterification with NaOMe and further converted into iodide 253 (Scheme 29.32). A chemoselec-tive copper-catalyzed alkylation of iodide 253 was performed using /-PrMgCl and catalytic amounts of LiaCuCLj in the presence of A -methyl-2-pyrrolidinone without affecting the ester moiety, and further reduction with DIBAL-H at -90°C furnished aldehyde 254 in good overall yield. Aldehyde 254 was finally converted into (-l-)-vittatalactone 255 via reaction sequence boron aldol... 

Sharpless and Masumune have applied the AE reaction on chiral allylic alcohols to prepare all 8 of the L-hexoses. ° AE reaction on allylic alcohol 52 provides the epoxy alcohol 53 in 92% yield and in >95% ee. Base catalyze Payne rearrangement followed by ring opening with phenyl thiolate provides diol 54. Protection of the diol is followed by oxidation of the sulfide to the sulfoxide via m-CPBA, Pummerer rearrangement to give the gm-acetoxy sulfide intermediate and finally reduction using Dibal to yield the desired aldehyde 56. Homer-Emmons olefination followed by reduction sets up the second substrate for the AE reaction. The AE reaction on optically active 57 is reagent... 

The key intermediate 25 was prepared efficiently from aldehyde 23, obtained by reduction of nitrile 22 with Dibal-H. Treatment of 23 with the lithium salt of frans-diethyl cinnamylphosphonate furnishes compound 24 in 75 % yield and with a 20 1 ratio of E Z olefin stereoisomers. The stage is now set for the final and crucial operations to complete the molecular skeletons of endiandric acids A and B. 

The strategy for the construction of 13 from aldehyde 16 with two units of phosphonate 15 is summarized in Scheme 12. As expected, aldehyde 16 condenses smoothly with the anion derived from 15 to give, as the major product, the corresponding E,E,E-tri-ene ester. Reduction of the latter substance to the corresponding primary alcohol with Dibal-H, followed by oxidation with MnC>2, then furnishes aldehyde 60 in 86 % overall yield. Reiteration of this tactic and a simple deprotection step completes the synthesis of the desired intermediate 13 in good overall yield and with excellent stereoselectivity. 

In order to establish the correct absolute stereochemistry in cyclopentanoid 123 (Scheme 10.11), a chirality transfer strategy was employed with aldehyde 117, obtained from (S)-(-)-limonene (Scheme 10.11). A modified procedure for the conversion of (S)-(-)-limonene to cyclopentene 117 (58 % from limonene) was used [58], and aldehyde 117 was reduced with diisobutylaluminium hydride (DIBAL) (quant.) and alkylated to provide tributylstannane ether 118. This compound underwent a Still-Wittig rearrangement upon treatment with n-butyl lithium (n-BuLi) to yield 119 (75 %, two steps) [59]. The extent to which the chirality transfer was successful was deemed quantitative on the basis of conversion of alcohol 119 to its (+)-(9-methyI mande I ic acid ester and subsequent analysis of optical purity. The ozonolysis (70 %) of 119, protection of the free alcohol as the silyl ether (85 %), and reduction of the ketone with DIBAL (quant.) gave alcohol 120. Elimination of the alcohol in 120 with phosphorus oxychloride-pyridine... 

Treatment of the alcohol 211 with f-butyklimethylsilyl triflate and 2,6-lutidine affords disiloxyester 212 with high yield. Reduction of the ester function of 212 with DIBAL followed by Swern oxidation gives the corresponding aldehyde 213, and subsequent alkylation with MeMgBr and Swern oxidation produce methyl ketone 214 (Scheme 7-70). 

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