Abstract(Z)-Trisubstituted allylic alcohols are widespread structural motifs in natural products and biologically active compounds but are difficult to directly prepare. Introduced herein is a general one-pot multicomponent coupling method for the synthesis of (Z)-α,α,β-trisubstituted allylic alcohols. (Z)-Trisubstituted vinylzinc reagents are formed in situ by initial hydroboration of 1-bromo-1-alkynes. Addition of dialkylzinc reagents induces a 1,2-metallate rearrangement that is followed by a boron-to-zinc transmetallation. The resulting vinylzinc reagents add to a variety of prochiral aldehydes to produce racemic (Z)-trisubstituted allylic alcohols. When enantioenriched aldehyde substrates are employed (Z)-trisubstituted allylic alcohols are isolated with high dr (>20:1 in many cases). For example, vinylation of enantioenriched benzyl protected α-and β-hydroxy propanal derivatives furnished the expected anti-Felkin addition products via chelation control. Surprisingly, silyl protected α-hydroxy aldehydes also afford anti-Felkin addition products. A protocol for the catalytic asymmetric addition of (Z)-trisubstituted vinylzinc reagents to prochiral aldehydes with a (−)-MIB-based catalyst has also been developed. Several additives were investigated as inhibitors of the Lewis acidic alkylzinc halide byproducts, which promote the background reaction to form the racemate. α-Ethyl and α-cyclohexyl (Z)-trisubstituted allylic alcohols can now be synthesized with excellent levels of enantioselectivity in the presence of diamine inhibitors.
Furans and pyrroles are important synthons in chemical synthesis and are commonly found in natural products, pharmaceutical agents, and materials. Introduced herein are three methods to prepare 2-substituted 3-furfurals starting from 3-furfural, 3-bromofuran, and 3-vinylfurans. Addition of a variety of organolithium, Grignard, and organozinc reagents (M-R) to 3-furfural provides 3-furyl alcohols in high yields. Treatment of these intermediates with NBS initiates a novel oxidative rearrangement that results in the installation of the R group in the 2 position of the 2-substituted 3-furfurals. Likewise, metalation of 3-bromofuran with n-BuLi and addition to benzaldehyde provides a furyl alcohol that is converted to 2-phenyl 3-furfural upon oxidative rearrangement. Enantioenriched disubstituted furans can be prepared starting with the Sharpless asymmetric dihydroxylation of 3-vinylfurans. The resulting enantioenriched diols undergo the oxidative rearrangement to furnish enantioenriched 2-substituted 3-furfurals with excellent transfer of asymmetry. This later method has been applied to the enantioselective preparation of an intermediate in Honda's synthesis of the natural product (-)-canadensolide. Mechanistic studies involving deuterium-labeled furyl alcohol suggest that the oxidative rearrangement proceeds through an unsaturated 1,4-dialdehyde intermediate. The alcohol then cyclizes onto an aldehyde, resulting in the elimination of water and rearomatization. On the basis of this proposed mechanism, we found that 3-furyl imines undergo the addition of organometallic reagents to provide furyl sulfonamides. Under the oxidative rearrangement conditions, 2-substituted 3-formyl pyrroles are formed, providing a novel route to these heterocycles. In contrast to the metalation of heterocycles, which often lead to mixtures of regioisomeric products, these new oxidative rearrangements of furyl alcohols and furyl sulfonamides generate only one regioisomer in each case.
2008
Furan derivatives R 0060Addition/Oxidative Rearrangement of 3-Furfurals and 3-Furyl Imines: New Approaches to Substituted Furans and Pyrroles. -Chiral disubstituted furans are prepared by oxidative rearrangement of dihydroxy precursors such as (XVII), obtained by Sharpless asymmetric dihydroxylation of 3-vinylfurans.The method is applied to the enantioselective preparation of intermediate (XIX) in Honda's synthesis of the natural product (-)-canadensolide. -(KELLY, A. R.; KERRIGAN, M. H.; WALSH*, P. J.; J.
Multicomponent reactions O 0359One-Pot Multicomponent Coupling Methods for the Synthesis of Diastereo-and Enantioenriched (Z)-Trisubstituted Allylic Alcohols. -The ability to access (Z)-trisubstituted vinylzinc reagents with near perfect control of the double-bond geometry and their propensity to add to chiral aldehydes with high enantio-and diastereoselectivity render this method valuable in the synthesis of diverse (Z)-trisubstituted allylic alcohols that are otherwise difficult to prepare. A protocol for the catalytic asymmetric addition of (Z)-trisubstituted vinylzinc reagents to prochiral aldehydes using Nugent's enantioenriched amino alcohol, MIB, as catalyst is also developed. -(KERRIGAN, M. H.; JEON, S.-J.; CHEN, Y. K.; SALVI, L.; CARROLL, P. J.; WALSH*, P. J.; J. Am. Chem. Soc. 131 (2009) 24, 8434-8445; Dep. Chem., Univ. Pa., Philadelphia, PA 19104, USA; Eng.) -Bartels 45-052
2008 Furan derivatives R 0060 Addition/Oxidative Rearrangement of 3-Furfurals and 3-Furyl Imines: New Approaches to Substituted Furans and Pyrroles. -The procedure enables the selective preparation of diverse 2-substituted 3-furals and 2-substituted 3-formyl pyrroles.The heterocycles are formed without contamination by other isomers (to be continued). -(KELLY, A. R.; KERRIGAN, M. H.; WALSH*, P. J.; J.
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