Stereoselective allylation reduction

In this case an active dendritic Pd°-species could be generated by hydrazine reduction and subsequently used in a DMF/heptane mixture at 75 °C for the stereoselective allylic amination. After completion of the reaction and cooling to room temperature, the catalysts can be recovered by simple phase separation. 

Stereoselective radical reduction or allylation.2 Radical reduction of (1-alkoxy-a-halo esters such as 1 shows marked onri-stereoselectivity with Bu3SnH (AIBN) at 50°, which is markedly improved when conducted under photochemical irradiation at —78°. Similar but even higher stereoselectivity obtains in reduction of the tetrahy-drofuran derivative 2. 

Treatment of the aldehyde 148 with lithium phenylacetylide yielded another versatile intermediate (149), which could be transformed, after stereoselective partial reduction to the corresponding tram allylic alcohol (150), either by simple deprotection to racemic 36 or first by oxidation and then deprotection to the diketone 39. Elimination of water from the ketol 36 gave 8, which could be reduced with diisobutyl aluminum hydride without affecting the double bond to the dienol 48. ... 

BCnight and co-workers approached the synthesis of the unnatural ( + )-enantiomer of lupinine (ent-344) by first resolving racemic 2-(piperidin-2-yl)-ethanol with (+ )-camphorsulfonic acid (357,358). The (i -( + )-enantiomer 362 was then converted into the substituted acetic ester 363, the enolate of which was stereoselectively allylated to give 364 and 365 in isolated yields of 71% and 12%, respectively (Scheme 45). The major isomer 364 was readily hydroborated and cyclized to the bicyclic ester 366, reduction of which completed the first reported synthesis of (+ )-lupinine (ent-344). The optical rotation was measured as +19.5° (c 1, EtOH), which compared favorably with the rotation of natural (- )-lupinine (-21°) recorded under similar conditions (359). It was also hoped that epimeriza-tion of 366 would give the thermodynamically more stable compound 377 in which the ester group is equatorial, after which reduction would provide access to (- )-epilupinine (ent-331). However, the product obtained after these transformations was optically inactive, which indicated that epimerization was accompanied by racemization, probably through base-induced retro-Michael reaction followed by Michael recyclization. 

As an example of a steroid total synthesis, the industrial procedure used to make norgestrel, the gestagen used in many contraceptives, is sketched here. Its basis is the Torgov reaction, a variation of the Robinson annelation, which mns essentially neutral media. The carbanion of 1,3-dioxo compounds adds to allylic alcohols, e.g., 2-ethylcyclopentanol-1,3-dione, under weakly basic conditions. Both the dione and the styrene double bond are stable under these conditions. Regio- and stereoselective microbial reduction of one of the keto groups, acid-... 

The allylic alcohol was subjected to an Eschenmoser-Claisen rearrangement with dimethylacetamide dimethylacetal to introduce the C14 substituent in a stereoselective manner. Reduction of the amide to the corresponding aldehyde with phenyl silane in the presence of Ti(0/Pr)4 was followed by an acid-promoted closure of the C-ring of codeine. In order to prevent N-oxidation, the amine was converted to the corresponding tosylamide, via debenzylation and treatment with tosyl chloride, before the allylic alcohol was introduced by the reaction of the alkene with selenium dioxide (65). The stereochemistry of the C6 hydroxy functionality was corrected by applying the well-known oxidation/reduction protocol [46, 60] before the benzylic double bond was reductively removed under Birch conditions. Codeine (2) was obtained in 17 steps with an overall yield of approximately 0.6%. 

N-halogenosuccinimides and Me2S, esters (206) are converted into allylic halides (207) stereoselectively, while reduction (LiBEtjH) of the derived acetates leads to... 

A Birch reduction of 40, followed by acylation of the amino group in the resulting dihydro derivatives 41 with cyanoacetic acid and subsequent hydrolysis of the enol ether moiety gave cyclohexenones 42. Treatment of 42 with a substoichiometric amount of NaOEt caused the isomerization of the carbon—carbon double bond to give an a,P-enone and the closure of the piperidine B ring by an intramolecular Michael addition, leading to the ds-fused perhydroisoquinoUne derivatives 43 as mixtures of C-9 epi-mers. A stereoselective allylation from the most accessible face of 43... 

Either anti- or jy -allylic 1,2-diols can be obtained from the highly stereoselective (>95%) reduction of protected -hydroxy-enones by simple variation of the protecting group (Scheme 20) when chelation is possible, the anti-diastereomer is favoured, whereas bulky protecting groups lead to the syn possibility. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Solanesol and other prenyl alcohols are important as metabolites in mulberry and tobacco leaves and in the synthesis of isoprenoid quinones. Hence, Sato and collaborators107 have developed a stereoselective synthesis of all-trans-polyprenol alcohols up to C50. Construction of the requisite skeletons was accomplished by the alkylation of a p-toluenesulphonyl-stabilized carbanion, followed by reductive desulphonylation of the resulting allylic sulphonyl group. This was achieved most efficiently by the use of a large excess of lithium metal in ethylamine (equation (43)), although all reaction conditions led to mixtures. The minor product results from double bond rearrangement. 

Applications of peroxide formation are underrepresented in chiral synthetic chemistry, most likely owing to the limited stability of such intermediates. Lipoxygenases, as prototype biocatalysts for such reactions, display rather limited substrate specificity. However, interesting functionalizations at allylic positions of unsaturated fatty acids can be realized in high regio- and stereoselectivity, when the enzymatic oxidation is coupled to a chemical or enzymatic reduction process. While early work focused on derivatives of arachidonic acid chemical modifications to the carboxylate moiety are possible, provided that a sufficiently hydrophilic functionality remained. By means of this strategy, chiral diendiols are accessible after hydroperoxide reduction (Scheme 9.12) [103,104]. 

Chiral tricyclic fused pyrrolidines 29a-c and piperidines 29d-g have been synthesized starting from L-serine, L-threonine, and L-cysteine taking advantage of the INOC strategy (Scheme 4) [19]. L-Serine (23 a) and L-threonine (23 b) were protected as stable oxazolidin-2-ones 24a and 24b, respectively. Analogously, L-cysteine 23 c was converted to thiazolidin-2-one 24 c. Subsequent N-allylation or homoallylation, DIBALH reduction, and oximation afforded the ene-oximes, 27a-g. Conversion of ene-oximes 27a-g to the desired key intermediates, nitrile oxides 28 a-g, provided the isoxazolines 29 a-g. While fused pyrrolidines 29a-c were formed in poor yield (due to dimerization of nitrile oxides) and with moderate stereoselectivity (as a mixture of cis (major) and trans (minor) isomers), corresponding piperidines 29d-g were formed in good yield and excellent stereoselectivity (as exclusively trans isomers, see Table 3). 

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