Enantio‐ and Diastereoselective Hydrogenation of Farnesol and O‐Protected Derivatives: Stereocontrol by Changing the CC Bond Configuration

Abstract

We recently reported a class of chiral iridium catalysts derived from pyridylphosphine ligands 1, which for the first time have allowed highly selective asymmetric hydrogenation of unfunctionalized trialkyl-substituted C=C bonds.[1, 2] Unlike rhodium or ruthenium diphosphine complexes, these catalysts do not require any special coordinating group next to the C = C bond. Enantiofacial selection by the catalysts in this case results from discrimination between the H atom and a sterically more demanding alkyl group at the monosubstituted olefinic C atom. Consequently, cis and trans olefins are converted into products of opposite configuration.[1] Thus, the sense of asymmetric induction can be controlled by proper choice of the double bond geometry. In this way, two or more stereogenic centers can be introduced with the desired relative and absolute configuration by hydrogenation of a di-or polyene.[3]Herein we report the asymmetric hydrogenation of farnesol and O-protected derivatives to demonstrate the potential of this strategy. This class of substrates was chosen because efficient routes to all four cis/trans isomers were available, [5] and we were interested in comparing the reactivity of the two trialkyl-substituted C=C bonds with the allylic alcohol unit in its free and protected form. Furthermore, hexahydrofarnesol, which can be readily prepared by this route in any of the four possible stereoisomeric forms, [6] is an important building block for the syntheses of vitamins E and K [7] or related antioxidants, [8] and insect pheromones. [9] It also has an important function as a constituent of ether lipids in archea [10] and was identified as a precursor of many terpenoid compounds in plants [11] and geological sediments.[12]

Asymmetric Hydrogenation of Olefins Using Chiral Crabtree-type Catalysts: Scope and Limitations

“…79c This later finding was further exploited to hydrogenate all four stereoisomers of farnesol (Section 2.1.2, Scheme 12b). 132 For terminal allylic alcohols, the Ir-catalyzed asymmetric hydrogenation has achieved ee's up to 88% in the hydrogenation of S126 using phosphinite-oxazoline 19a (Figure 4) ligand (Table 7, entry 32). 67 Introducing a phosphite moiety in the ligand design is advantageous, achieving enantioselectivities up to 95% in the reduction of S127 (Table 7, entry 33).…”

Asymmetric Synthesis and Biological Activity of nor‐α‐Tocopherol, a New Vitamin E Analogue

“…For the synthesis of the key intermediate 16 two building blocks were required: 1) the Grignard reagent 17, [14] available from (3R,7R)-hexahydrofarnesol 18, [15] and 2) the allyl epoxide 19, which was accessible from commercially available (R)-epichlorohydrin. [16] The reaction between 17 and 19, catalyzed by lithium cuprate, [17][18] gave the alcohol 16 in 80 % yield and 97 % de (diastereomeric excess), determined on the corresponding p-nitrobenzoate.…”

Recent Progress in Iridium-Catalyzed Enantioselective Hydrogenation: Tetrasubstituted Olefins and Polyenes

“…Indeed, all four stereoisomers of farnesol were formed with high enantioand diastereoselectivity using the same catalyst Ir-12 (Scheme 4). [19] Alternatively, a stepwise approach starting from only one geometrical isomer may be taken. Since unfunctionalized C=C bonds do not react with Ru-diphosphine catalysts, the C=C bond of the allylic alcohol moiety of farnesol can be reduced selectively without affecting the trialkyl substituted C=C bonds.…”

“…Subsequent hydrogenation of the remaining two C=C bonds with a suitable iridium-catalyst then gives the desired hexahydrofarnesol with high stereoselectivity (Scheme 5). [19] Because the Ru and Ir catalysts are available in both enantiomeric forms, each of the four stereoisomers can be obtained from ( E,E)-farnesol using the proper combination of ( R ) or ( S ) catalysts.…”