Bishomoallyl alcohols

Compound 16, the projected precursor of 15, could conceivably be assembled from bishomoallylic alcohol 17 via a pathway that features the oxidative functionalization of the A20,21 double bond with participation by the C-17 secondary hydroxyl. Compound 17 is an attractive retrosynthetic precursor for compound 16 because the A20-21 double bond, which could permit the introduction of the adjacent C-20 and C-21 stereocenters in 16, provides a convenient opportunity for significant molecular simplification. Thus, retrosynthetic cleavage of the A20 21 double bond in 17 furnishes compounds 18 and 19 as potential building blocks. The convergent union of the latter two compounds through a Wittig reaction would be expected to afford 17 stereoselectively. 

For the formation of substituted THF rings (Route a, Scheme 8.1), Kishi developed a procedure based on the hydroxy-directed epoxidation of a y-alkenol [10]. Epoxidation of bishomoallylic alcohol 3 by TBHP/VO(acac)2 by this approach, followed by treatment of the intermediate epoxide 4 with acetic acid, gave the TH F derivative 5 of isolasalocid A (a 5-exo cydization Scheme 8.2) [11]. Further epoxidation of 5 (a y-alkenol) under the same conditions, followed by acetylation, afforded epoxide 6. For the synthesis of the natural product, the configuration of epoxide 6 had to be inverted before the second cydization reaction. Epoxide 6 was consequently hydrolyzed under acid conditions to the corresponding diol and was then selectively... 

The compatibility of Et3B with a hydroxy group is demonstrated by the reaction with cyclic hemiacetals (n = 1 or 2). Here again the reaction proceeds smoothly without using any extra amount of Et3B and provides co-hydroxy bishomoallyl alcohols 44 with an excellent 1,3-asymmetric induction (Eq. 13). 

In Morimoto s total synthesis of (-t-)-eurylene and (+)-14-deacetyleurylene, the pivotal steps are the construction of trans- and cw-tetrahydrofuran rings via a hydroxy-directed syn oxidative cyclization of acyclic bishomoallylic alcohols promoted by Re(VII) and Cr(VI) oxides, respectively. As depicted below, the trans-THF is achieved by treatment of the triol with the oxorhenium(VII) complex, and the cis-THF is constructed by the use of PCC <00AG(E)4082>. 

In these reactions, the major diastereomer is formed by the addition of hydrogen syn to the hydroxyl group in the substrate. The cationic iridium catalyst [Ir(PCy3)(py)(nbd)]+ is very effective in hydroxy-directive hydrogenation of cyclic alcohols to afford high diastereoselectivity, even in the case of bishomoallyl alcohols (Table 21.4, entries 10-13) [5, 34, 35]. An intermediary dihydride species is not observed in the case of rhodium complexes, but iridium dihydride species are observed and the interaction of the hydroxyl unit of an unsaturated alcohol with iridium is detected spectrometrically through the presence of diastereotopic hydrides using NMR spectroscopy [21]. 

Alkylation of the C-l carbonyl group of 223 with homoallyllithium reagent in benzene produces the desired bishomoallylic -alcohol at high yield with perfect diastereoselectivity. Deprotection of the TBS group results in the for-... 

Allylic and cis-homoallylic alcohols are epoxidized readily, but frans-homoallylic and bishomoallylic alcohols react slowly, if at all. The stereoselectivity in the epoxidation of acyclic allylic alcohols is the same as and is comparable to that observed with r-BuOOH/VO(acac)2. The stereoselectivity in epoxidation of acyclic homoallylic alcohols is also the same but lower than that obtained with t-BuOOH/ VO(acac)2. Epoxidation of cyclic allylic alcohols proceeds more slowly and in lower yield than that of acyclic allylic alcohols. 

Bishomoallyl alcohols, via allyindium reagents, 9, 703 Bis(hydrostannation), in tin-carbon bond formation, 3, 814 Bis(imidazolyl) ligands, chromium complexes, 5, 359 Bis(imido) systems, with chromium(VI), as models, 5, 377 Bis(imido)tungsten complexes, synthesis, 5, 749 Bis(imido)uranium(VI) complexes, synthesis, 4, 216-217 Bis(imino)carbenes, with Zr(IV), 4, 798 Bis(iminooxazolidine) complexes, biaryl-bridged, with Zr(IV) and Hf(IV), 4, 811-812... 

Ergiiden, J.-K. Schaumann, E. Phosphoryl functionalized bishomoallyl alcohols by ring opening of epoxides with lithiated allyldiphe-nylphosphane oxide. Synthesis 1996, 707—710. 

Yadav, J. S. Anjaneyulu, S. Ahmed, M. M. Reddy, B. V. S. Indium-mediated regioselective allylation of terminal epoxides a facile synthesis of bishomoallyl alcohols. Tetrahedron Lett. 2001, 42, 2557-2559. 

Even bishomoallylic alcohols with a stereogenic hydroxy-substituted carbon atom can show useful diastereoselectivity in the vanadium-catalyzed epoxidation31,32. 

Corey, E. J., Noe, M. C., Ting, A. Y. Improved Enantioselective Dihydroxylation of Bishomoallylic Alcohol Derivatives Using a Mechanistically Inspired Bis[cinchona] Alkaloid Catalyst. Tetrahedron Lett. 1996, 37, 1735-1738. 

The related (Z)-lithium dialkenylcuprates (147) derived from acetylene itself also react well with epoxides to provide a useful route to (2)-homoallylic alcohols the lack of reactivity with esters allows an easy access to lactones (148) by condensations between epoxy esters and this type of cuprate (Scheme 29). Likewise, the lower homologs (149) and (151), both of which are relatively easy to prepare in optically active forms, can be readily converted into homoallylic and bishomoallylic alcohols (150) and (152) respectively. An ester unit can also be incorporated into the cuprate functions thus, addition of a mixed lithium cuprate, RCuYLi , to ethyl propiolate gives the cuprates (153), which add to epoxides to give unexpectedly the (Z)-crotonates (154). Such isomerization is not uncommon with vinyl carbanions in general, and is obviously a limitation when isomeric mixtures are produced. 

The reactions of allylindium reagents with trifluoroacetaldehyde hydrate or hemiacetal in water (Scheme 8.40) [62], or with aldehyde dimethyl acetals in aqueous THF [63], give the corresponding homoallylic alcohols (Scheme 8.41). Allylindium reacts with terminal epoxides to afford the corresponding bishomoallyl alcohols (Scheme 8.42) [64]. 

Bisdithiocarbonates, 497 Bis(ethylthiolead), 522 Bishomoallylic alcohols, 62 Bismethoxycarbonylcarbene, 159 Bismethoxycarbonylcyclopropanes, 159 Bis-3-methyl-2-butylborane, 41 Bis(o-nitrophenyl) diselenide, 359 Bis(2,4-pentanedionato)nickel, 42 o, a-Bisphenylthiocyclohcptanone, 210 Bis(phenylthio)methane, 126... 

A highly efficient KR of bishomoallylic alcohols has been performed by Loh et al. [114]. Alcohols 199 underwent In(OTf)3-catalysed 3,5-oxonium-ene-type cycliza-tion with steroidal aldehyde 200. Besides the produced oxocyclohexane 201, the unreacted (S)-alcohols 199 were isolated in >99% ee. Among various Lewis acids investigated, In(OTf)3 proved the best. However, as only one enantiomer of the chiral source is readily available, the use of this interesting method has limitations. 

Surprisingly, the same strategy works fine even in the regiodirecting hydroformylation of bishomoallyl alcohols as substrates (Scheme 4.116). Six-membered ring lactols were formed as main products [26]. 

Scheme 4.116 Hydroformylation of bishomoallyl alcohols with the assistance of a reversibly bonded directing group.

With 3-substituted bishomoallyl alcohols, a cis/trans ratio of up to 4 96 was noted because of a particular cyclic transition state with rhodium, where the methylene group adopts the equatorial position (Scheme 4.117). 

Scheme 4.117 Rationalization of the dominant stereochemistry observed in the hydroformylation of substituted bishomoallyl alcohols.

Enantiomerically enriched bishomoallylic alcohols could be readily accessed by reactions of 2-vinyloxiranes with chiral allylating agents based on a-pinene in the presence of a catalytic amount of Sc(OTf)3 [116]. The p,v-unsaturated aldehydes were generated in situ via Lewis acid induced rearrangement (1,2-hydride shift) and subsequently trapping by chiral allylboron compounds. The products were obtained in moderate to high yields with excellent enantioselectivities (Scheme 12.46). 

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