DIBAL-H reduction

Enantiospecific syntheses of amino derivatives of benzo[ ]quinolizidine and indolo[2,3- ]quinolizidine compounds have also been achieved via A-acyliminium ion cyclization reactions, as an alternative to the more traditional Bischler-Napieralski chemistry (see Section 12.01.9.2.2). One interesting example involves the use of L-pyroglutamic acid as a chiral starting material to construct intermediates 240 via reaction with arylethylamine derivatives. Diisobutylaluminium hydride (DIBAL-H) reduction of the amide function in 240 and subsequent cyclization and further reduction afforded piperidine derivatives 241, which stereoselectively cyclized to benzo[ ]quinolizidine 242 upon treatment with boron trifluoride (Scheme 47) <1999JOC9729>. 

The reaction tolerates ketone, chloride, internal C=C bonds, esters, nitriles, and ether functional groups. Given that the DIBAL-H reduction of acid derivatives often suffers from over-reduction to alcohols, these catalytic procedures are of synthetic value for laboratory-scale syntheses. However, it is likely that the requirement for excess (tBuCO)20 will prevent this reaction from ever being used in commercial production. 

Spino and Frechette reported the synthesis of non-racemic allenic alcohol 168 by a combination of Shi s asymmetric epoxidation of 166 and its organocopper-mediat-ed ring-opening reaction (Scheme 4.43) [74]. Reduction of the ethynyl epoxide 169 with DIBAL-H stereoselectively gave the allenic alcohol 170, which was converted to mimulaxanthin 171 (Scheme 4.44) [75] (cf. Section 18.2.2). The DIBAL-H reduction was also applied in the conversion of 173 to the allene 174, which was a synthetic intermediate for peridinine 175 (Scheme 4.45) [76], The SN2 reduction of ethynyl epoxide 176 with DIBAL-H gave 177 (Scheme 4.46) [77]. 

The diisobutylaluminium hydride (DIBAL-H) reduction of perhydrofuro[2,3- ]py derivatives, 58, is a novel entry to highly functionalized cyclopentanes containing high enantiomeric purity. The reduction targets the acetal group of the furo[2,3-/ ]pyran framework <2001CAR63>. 

In order to replace the chlorine atom by the desired hydroxy functionality, di-isobutylaluminum hydride (DIBAL-H) reduction followed by an acid-catalyzed acetalization with isopropanol in refluxing benzene had to be performed to protect the lactone moiety as an acetal and provided the thermodynamically preferred a-anomer 38 together with 5-8% of the other epimer. The conversion of the... 

The Peterson reaction of the chlorovinyl-complex with ethyl trimethylsilylacetate provided the 11Z isomer preferentially (77%), and the 1 IE isomer as a secondary product (15%). The ester was transformed into the C 8 ketone (PhsSnCfy, BuLi, Et20, 79%). Reaction with (/Pr0)2P(0)CH2CN afforded the 1 lZ-retinonitrile in 73% yield. The complex was removed by CuC (72%) and DIBAL-H reduction led quantitatively to 1 lZ-retinal, Fig. (24). 

In a comparable approach, Valla et al. [73] described the synthesis of 9-methylene analogues of retinol, retinal, retinonitrile and retinoic acid, using the p-methylenealdehyde derived from P-ionone. Homer-Emmons condensation with ethyl 4-(diethoxyphosphoryl)-3-methylbut-2-enoate carbanion afforded the ester in 55% yield, as a mixture of 13E/13Z isomers (50/50). This ethyl 9-methylene-retinoate was saponified with ethanolic NaOH to give the corresponding 9-methylene-retinoic acid in 55% yield (13 /13Z 50/50). The retinol analogue was obtained by DIBAL-H reduction of the ethyl ester (75%, 132T/13Z isomers 65/35). 

In the same way, the anion of ethyl 3-cyano-2-methylprop-2-enyl-phosphonate was reacted with the p-methylenealdehyde to give the 9-methylene-retinonitrile in 50% yield, as a mixture of 13E/13Z isomers (65/35). DIBAL-H reduction of the latter compound provided the related retinal (70%, 13E/13Z 65/35). Alternatively, MnCh oxidation of the... 

Related to this reaction is the acid treatment of the (l-hydFoxymethylcyclohexadiene)tricarbonyliron (45), prepared via DIBAL-H reduction of ester (26) or borane reduction of the corresponding carboxylic acid, which leads to the 1-methylcyclohexadienyliron complex (46 equation 18).11 Using these methods, it is therefore possible to prepare a range of alkyl-substituted dienyl complexes having a defined substitution pattern. 

Ethoxyethyl groups were chosen for the alcohol protection. Other protecting groups were tried but rejected for various reasons. TMS groups were easy to install and survived the subsequent DIBAL-H reduction but were lost in the Wittig reaction. The more stable TBDMS groups were used for initial stereochemical correlation experiments but were difficult to install and to remove. Various carbonates were made but had limited stability in the DIBAL-H reduction. 

The DIBAL-H reduction of 19 proceeds smoothly at -40 °C. Some over reduction occurs but the over reduction product is easily removed in subsequent processing. The formation of intractable gels during the workup was eliminated by quenching with aqueous sodium potassium tartrate at 65 °C. 

In the total synthesis of (+)-trienomycins A and F, Smith et al. used an Evans aldol reaction technology to construct a 1,3-diol functional group8 (Scheme 2.1i). Asymmetric aldol reaction of the boron enolate of 14 with methacrolein afforded exclusively the desired xyn-diastereomer (17) in high yield. Silylation, hydrolysis using the lithium hydroperoxide protocol, preparation of Weinreb amide mediated by carbonyldiimidazole (CDI), and DIBAL-H reduction cleanly gave the aldehyde 18. Allylboration via the Brown protocol9 (see Chapter 3) then yielded a 12.5 1 mixture of diastereomers, which was purified to provide the alcohol desired (19) in 88% yield. Desilylation and acetonide formation furnished the diene 20, which contained a C9-C14 subunit of the TBS ether of (+)-trienomycinol. 

Newly added reactions are DIBAL-H reduction of esters, and dialkylcuprate reaction with acid chlorides to produce ketones. 

In recent work Coates, Mason and Shah have successfully achieved the synthesis of gymnomitrol (29Ja).280) Since intramolecular aldol condensation of the aldehyde obtained by hydrolysis of 291 (Scheme 45) was unfavorable, conversion to enol lactone 292 was effected. Dibal-H reduction of 292 resulted directly in aldoli-zation of the intermediate lactol, oxidation of which afforded 293. The latter was converted successfully to keto alcohol 294 by capitalizing on the different steric environments about the carbonyl groups. Sequential dehydration and hydride reduction of 294 gave a 45 55 mixture of exo and endocyclic isomers 295a and295 b which were separated by TLC. 

The DIBAL-H reduction of lactam 175 and subsequent etherification of the resulting A,0-hemiacetal with TMSOTf resulted in 176 (Scheme 35). It was further reacted with a variety of nucleophiles in the presence of Lewis acid to afford corresponding a-substituted azonines 177 in high yields <2002TL3165>. 

In a stereocontrolled route to thromboxane B2, Corey and coworkers used the Eschenmoser rearrangement for the preparation of lactone (91 Scheme 14). The product of the 3,3-sigmatropic shift, amide (90), is directly iodolactonized, thus avoiding often troublesome amide hydrolysis conditions. Another application involving a carbohydrate derivative was demonstrated by Fraser-Reid and coworkers (Scheme 15). Reductive elimination of benzylidene (92), followed by in situ alkylation, Wittig reaction, DIBAL-H reduction and rearrangement, led to amide (94), which was transformed into the corresponding pyranoside diquinane by double radical cyclization. 

The DIBAL-H reduction of an ester to an aldehyde in the synthesis of the marine neurotoxin ciguatoxin CTX3C... 

DIBAL-H is the reducing agent of choice for regioselective reduction of oc,(3-unsat-urated esters to allylic alcohols. Horner-Wadsworth-Emmons olefmation (see Section 8.3b) followed by DIBAL-H reduction provides a tandem synthesis of ( )-allylic alcohols. ... 

Oxymercuration of cyanohydrin 98 was examined as a third option (Scheme 21) [52]. Treatment of this cyanohydrin under Hg(II) trifluoroacetate-mediated brominative conditions afforded tetra-hydropyran 99. Inversion of configuration at C3 by allowing 99 to react with Br2 under photolytic conditions afforded pyran 100. DIBAL-H reduction of the cyano group provided aldehyde 86 in racemic form. This method was later abandoned due to the difficulties in obtaining or synthesizing an enantiomerically pure starting material (98). 

For the preparation of Gly- j/-[CF=CH]-Pro in relation to the study of cyclophilin A inhibitors, Welch and co-workers employed the Peterson reaction of a-fluoro-a-trimethylsilyl acetate (15a,b) with ketone 10. E/Z selectivity was found to be influenced by the ester part of the acetate (see Scheme 10.4) [15]. The reaction of tert-butyl ester 15a gave almost an equal amount of the isomers (lib, E Z= 1 1.1), while moderate E selectivity was observed when trimethylphenyl ester 15b was used (11c, E Z= 6 1). Conversion of ester Z-llb to amino derivative 16 was achieved via the Mitsunobu reaction of phthalimide with the alcohol formed by the DIBAL-H reduction of Z-llb. 

Similarly, in connection with the cytotoxic meroterpenoid sargaol, the phenol 470 was subjected to PhI(OAc)2-promoted oxidation in MeOH, followed by DIBAL-H reduction to afford in 57% overall yield the target molecule 471 similar to sargaol. 

The DIBAL-H reduction of 48 produced a mixture of the alcohol 49 and aldehyde 8. We were unable to halt the reduction completely at the aldehyde stage even by reducing the temperature to -100 °C. Fortunately, oxidation of the mixture proceeded without detriment to the integrity of the aldehyde component. Aldehyde 8 was purified by a tedious chromatography and was a stable compound, though unfortunately not crystalline. Several by-products were isolated (55-57). These are very probably formed from traces of the corresponding side products carried through the synthesis from the previous steps. 

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