Diastereoselective synthesis hydroformylation

SCHEME 14.20. Diastereoselective synthesis of 1-p-methylcarbapenem via asymmetric hydroformylation of 4-vinyl-P-lactam. 

Since the discovery and development of highly efficient Rh catalysts with chiral diphosphites and phosphine-phosphites in the 1990s, the enantioselectivity of asymmetric hydroformylation has reached the equivalent level to that of asymmetric hydrogenation for several substrates. Nevertheless, there still exist substrates that require even further development of more efficient chiral ligands, catalyst systems, and reaction conditions. Diastereoselective hydroformylation is expected to find many applications in the total synthesis of complex natural products as well as the syntheses of biologically active compounds of medicinal and agrochemical interests in the near future. Advances in asymmetric hydrocarboxylation has been much slower than that of asymmetric hydroformylation in spite of its high potential in the syntheses of fine chemicals. 

Aldehyde 11a, produced by diastereoselective hydroformylation (R=Me Scheme 5.4), has been employed in the synthesis of polyketide fragment 40, a key building block for the synthesis of bafilomycin Ai (Scheme 5.16) [21]. 

Diastereoselective hydroformylation for synthesis of natural products and pharmaceuticals 458... 

Scheme 7 Synthesis of 72, a synthetic intermediate for Bafilomycin Ai 71, using the diastereoselective hydroformylation.

Diastereoselective hydroformylation will find many applications in the total synthesis of complex natural products as well as the syntheses of biologically active compounds of medicinal and agrochemical interests in the near future. The diastereoselectivity of such reactions can be improved by the use of a matched-pair combination of a chiral ligand and chirality in the substrate. 

An example is the rhodium catalyzed hydroformylation reaction, which is an industrially important homogenous catalytic process [3]. In contrast, it is amazing that such an important transition-metal catalyzed C/C bond-forming process has been employed only rarely in organic synthesis [4]. Part of the reason stems from the difficulty in controlling stereoselectivity. Even though some recently developed chiral rhodium catalysts allow for enantio- and diastereoselective hydroformylation of certain specific classes of alkenes [5, 6], only little is known about the diastereoselective hydroformylation of acyclic olefins [7, 8]. 

Stereoselective hydroformylation will also be more and more appHed to the total synthesis of complex high molecular weight compounds, e.g., natural products. In this respect, diastereoselectivity will be further investigated because substrate olefins for such a purpose often possess one or more chiral centers. Hydroformylation with a chiral catalyst should be widely employed for this purpose because the diastereoselectivity can be improved by a matched combination of a chiral ligand and a chiral substrate. 

Although iminium cations are usually formed from a secondary amine and an aldehyde, other masked species can also be used in synthesis. Recently, Alper and co-workers reported the synthesis of hexahydropyrrolo[2,l,-6]oxazoles by the Rh-catalyzed hydroformylation of an oxazolidine heterocycle 164 (Scheme 76) with linear selective ligand Xanthphos. This reaction proceeds diastereoselectively through a unique and imexpected silica-mediated (Lewis Acid) hydroformylation-deformylation pathway (139). 

Liu and Jacobsen used the diastereoselective hydroformylation of an exocyclic 1,3-butadiene moiety as a key step in the total synthesis of the antifungal agent (+)-ambruticin (Scheme 4.57) [15]. 

Scheme 4.56 Diastereoselective hydroformylation of a functionalized chiral cyclopentene tetrol derivative for the total synthesis of the pseudo-fructose 2,6-diphosphate.

The double hydroformylation strategy developed by Airiau et al. in their approach to the synthesis of (+)-lupinine ent-926) (c Scheme 132 Section 4.6.3) was also successfully appHed to their synthesis of (+)-epiquinamide (2104) (Scheme 276). This route commenced with Cbz-protected L-methionine (2184), aUylation of which via the Weinreb amide (—)-2185 produced ketone (+)-2186. Reduction of the ketone was accomplished with hthium tri(ferf-butoxy)aluminum hydride to afford alcohol (-)-2187 in excellent yield (94%) and a diastereoselectivity of greater than 98%. The sulfide, having served to disguise the second alkene, was then removed by oxidation to the sulfoxide followed by thermal elimination. The relative configuration of the product (—)-2188 was confirmed... 

---