Stereodivergence allylation

A stereodivergent approach to 2,5-disubstituted dihydrofurans that makes use of a stereoselective Ir-catalyzed allylic etherification of Cu-alkoxides followed by an RCM has been reported by Hartwig and Shu (Scheme 39). Due to the catalyst-controlled stereoselectivity in the allylic etherification step, both the cis- and the /ra r-epimer are made accessible depending on which enantiomer of the phosphoramidite ligand is employed <2004AGE4794>. 

Addition of y-disubstituted allylic phosphates to RCHO Both (E)- and (Z)-ally lie halides add to RCHO when catalyzed by CrCl2 to form nnri-homoallylic alcohols. Similar stereoselectivity obtains in additions of (E)- and (Z)-allylic phosphates. In this case addition of Lil and use of DMPU as solvent are usually required for satisfactory yields. In contrast, addition of y-disubstituted phosphates to aldehydes is both stereoselective and stereodivergent (equations I and II). 

Stereodivergent pathways relative to other allylic systems (e.g. allylic acetates) have been found in the reactions of cyclic allylic sulfides or ethers of benzothiazole with organocopper reagents. In this case the Sn2 process occurs with syn stereochemistry (eq 5) and is due to the anchimeric coordination of the organometallic reagent with the heterocyclic moiety. This has been utilized for regio- and stereocontroUed access to branched-chain sugars. 

As shown in Scheme 14.9a,b, an efficient protocol for the stereoselective synthesis of 1,3-syn and -anti tetrahydropyrimidinones (syn- and anti- 2) could be developed [13]. The modular procedure is based on a stereodivergent cycliza-tion of readily available urea-type substrates 41 by intramolecular allylic substitution. The cychzation proceeds with excellent yield (up to 99%) and selectivity (up to dr > 20 1), purely based on substrate control. The product pyrimidines 42 can be readily transformed into the corresponding free syn- and anti-amines 43. Furthermore, also a novel domino sequence for the rapid assembly of 1,3-syn-substituted oxazines 46 could be realized [14]. Mechanistically, the one-pot procedure is based on a three-step sequential process involving a hemi-aminalization... 

Py and coworkers presented also a convenient route to 2,2-disubstituted piperidines. This strategy involved a highly selective, stereodivergent nucleophilic addition of vinylmagnesium bromide to L-sorbose-derived nitrone 174 which provided hydrojg lamines 175 and 176 (Scheme 36). Crude products were reduced and the resulting amines 177 and 179 were separated by chromatography. Subsequently, JV-allyl-substituted piperidines 178 and 180 were obtained, and transformed into a series of bicyclic derivatives, for example 182 and 183. 

A concise, stereodivergent synthesis of ( )-cyclophellitol (380) and its unnatural diastereomer (17 , 15 )-cyclophelli-tol (379) starting from the furan/acrylic acid cycloadduct 375 was reported recently [136]. The key intermediate was the protected diol 377. For P = benzyl, the epoxidation with mCPBA is controlled by the free allylic hydroxyl group and led, after debenzylation, to (l/ , 15 )-cyclophellitol (379) (Scheme 13.81). A protection (TBSOTf)/debenzyla-tion sequence converted cyclohexenol 377 (P = PMB) into the silyl-protected diol 378. Selective epoxidation of this diol... 

Knochel et al. have shown that, in contrast to y-monosubstituted allylic halides that add in a stereoconvergent fashion to an aldehyde in the presence of C1C2, y-disubstituted allylic phosphates or chlorides and a (3, y-disubstituted allylic phosphate react in a stereodivergent fashion.It is suggested that this difference in behavior may be the result of a very slow isomerization of the intermediate y-disubstituted allylic chromium(III) species compared with the addition of the aldehyde. 

Nowotny S, Tucker CE, Jubert C, Knochel P. Chromium (Il)-mediated stereodivergent additions of allylic phosphates and halides to aldehydes. J. Org. Chem. 1995 60 2762-2772. 

As is apparent from the preceding discussion, a full understanding of the observed diastereoselectivity in dihydroxylation reactions of acyclic allylic alcohols remains elusive. Thus, the use of any one model is insufficient, and a careful analysis of the steric and electronic particulars of a given substrate must be conducted. Nevertheless, an impressive number of diastereoselec-tive dihydroxylations of acyclic olefins in complex molecule synthesis attest to the central role of this transformation [42, 43], Selected examples of stereodivergent dihydroxylations reported by Danishefsky are showcased in Schemes 9.36 and 9.37 [201]. Dihydroxylation of ( )- and (Z)-unsaturated esters 287 and 290, respectively, thus proceeded with excellent diastereoselectivity. Danishefsky has proposed a transition state model based on the ground state conformations of the starting materials as determined by X-ray analysis. The dihydroxylations were thus postulated to occur from the sterically less hindered faces of the olefins, as depicted in 288 and 291. Diol 292 was subsequently converted into N-acetylneuraminic acid (293). 

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