Chiral compounds Mitsunobu reaction

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

Synthesis of acid 129 starts from the commercially available 6-heptenoic acid (122), which upon reaction with (4S)-benzyloxazolidin-2-one (123) as the chiral auxiliary group yields the intermediate 124, hydroxymethylation of which affords compound 125. Hydrolysis of compound 125 followed by condensation with O-benzylhydroxylamine gives rise to the hydroxamate (126), which is then converted into (Claclam 127 via an intramolecular Mitsunobu reaction. Hydrolysis of the (Claclam 127 affords acid 128, which is subsequently formylated at the benzyloxyamine moiety to give the required intermediate acid (129) in quantitative yield, as depicted in Scheme 26. 

It has been found that the results of this new variant of the Mitsunobu procedure are generally comparable with the results of the traditional Mitsunobu reaction both with respect to the yields and enantiomeric excess (ee) of chiral compounds 26. Thus, products prepared from alcohol 86e using both methods had ee 70% and 72%, and from (Tl-methyl lactate 86i 92% and 99%, respectively. However the new variant of the Mitsunobu procedure has a significant synthetic advantage over the traditional procedure imides 26 can be transformed into primary amines under milder conditions in comparison with the deprotection of /V-alkylphthalimides (see Section 6.03.6.1.3). 

Synthesis of (-I-) calanolide A (Scheme 8-11) was achieved by enzyme catalyzed resolution of the aldol products ( )-53. Compound 7 with acetaldehyde by aldol reaction in the presence of LDA/TiCU stereoselectively produced a mixmre of ( )-53 and ( )-54 (94% yield), the ratio of which was 96 4. ( )-53 was then resolved by lipase AK-catalyzed acylation reaction in the presence of tert-butyl methyl ether and vinyl acetate at 40 °C to obtain 41% yield of (+)-55 and 54% yield of the acetate (—)-56. Mitsunobu cyclization of (+)-55 in the presence of tri-phenylphosphine and dielthyl azodicarboxylate afforded 63% yield of (-l-)-43 with 94% ee as determined by chiral HPLC. Luche reaction on (+)-43 with CeCla 7H2O and triphenyl phosphine oxide and NaBH4 in the presence of ethanol at 30 °C gave the crude product. It was purified by column chromatography on silica gel to give 78% yield of a mixture containing 90% of (+)-calanolide A and 10% (+)-calanohde B, which were further separated by HPLC. 

Amino-l-hydroxyethyl)phosphonic acid occurs in the plasma membrane of Acanthamoeba castellani and the 2R isomer is formed, in that organism, by the hydroxy-lation of (2-aminoethvl)phosphonic acid This biosynthesis step in vitro has been studied by Hammerschmidt" who synthesized various chiral deuterium-labelled derivatives of both compounds using the isotopically labelled 2-benzyloxyethanal in Abramov reactions to obtain, initially, the dimethyl (2-benzyloxy-l-hydroxyethyl)phosphonate (362). This ester was resolved through the diastereoisomeric carbamates 363 the separated carbamates were sequentially de-l-O-protected, silylated at the a-HO group, debenzylat-ed and, by means of the Mitsunobu reaction, converted into dimethyl [2-eizido- -(tert-butyldimethylsilyloxy)ethyl]phosphonates. Subsequently, standard reactions were used to transform the latter into the diastereoisomeric, isotopically labelled (2-amino-1-hydroxy-ethyl)phosphonic acid. 

The encouraging result of the trans-epoxy acylates with the chiral spiro compounds was appUed to the optically active system (Scheme 15). Asymmetric reduction of the enone 31 by Corey s method [72] afforded the allyl alcohol (-)-34 (90% ee). Epoxidation of (-)-34 by the stereoselective Sharpless epoxidation [73] afforded the cts-epoxy alcohol, cfs-(-)-35, as the sole product. The Mitsunobu reaction [74] of czs-(-)-35 with benzoic acid gave the trans-epoxy benzoate, trans- -)-36, (90% ee) in 89% yield. Treatment of trans-(-)-36 with BF3-Et20 afforded the optically active spiro compound (+)-37 in 89% yield with retention of the optical purity (90% ee). This means that the rearrangement occurs stereospecifically. The optically pure epoxy camphanate (-)-38 could be obtained after one recrystallization of the crude (-)-38 (90% de), which was obtained by the Mitsimobu reaction of cfs-(-)-35 with D-camphanic acid. The optically pure spiro compoimd (+)-39 (100% de) was obtained from the optically pure (-)-38 in 89% yield. 

Asymmetric Buchner reactions using chiral auxiliary have also been undertaken. The diazoketo substrate 126 for the chiral tethered Buchner reaction is prepared from optically pure (2/ ,4/f)-2,4-pentanediol in three steps the Mitsunobu reaction with 3,5-dimethylphenol, esterification with diketene, and diazo formation/deacetylation. Treatment of 126 with rhodium(II) acetate results in a quantitative yield of 127 with more than 99% ee. This compound is reduced with lithium aluminium hydride, and the resulting diol 128 undergoes epoxidation and concurrent acetal formation to give 129 as a single diastereomer. Hydrogenation of 129 with Raney nickel proceeds stereoselectively to yield saturated diol 130, which is converted to aldehyde 132 via acid hydrolysis followed by oxidation. Compound 132 is a versatile intermediate for natural product synthesis. 

In another modem application of the Mitsunobu reaction, Blechert et al. used the reaction to prepare chiral diene 150 this compound was ideally set-up for a ring-closing metathesis reaction to prepare an advanced intermediate for the synthesis of (-)-halosaline. ... 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

Addition of an enolate to a chiral aldehyde has also been used. In this interesting approach, addition of the enolate of 7,4.26 (formed in the presence of TiCU and Et3N) to the chiral benzaldehyde 7.4.25 gave the adduct 7.4.27. The chromium was removed from 7.4.27 by treatment with tetrabutylammonium fluoride followed by photolysis, and the azide group was introduced by a Mitsunobu-type reaction to give azide 7.4.28. This compound was then converted to the taxol side chain methyl ester by standard chemistry (276, 277). 

It is interesting to note that the inventors of (/ )-K-13675, in the first reported synthetic approach, targeted the racemic compound 1, and contracted separation of the enantiomers by preparative chiral chromatography to the expert company in this field, Diacel Chemical Indistries Ltd. [37]. Continuing scale-up investigations, the authors succeeded in replacing the Mitsunobu method, in the ether bond-forming reaction, by the technically much more simple use of triflate 21, prepared on a kg scale from (5)-n-butyl-2-hydroxybutanoate 20 (Scheme 3.8) [38]. 

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