Asymmetric synthesis Noyori reduction

After extensive developmental studies, [35] the final crucial element in our most recent synthesis of epothilone B involves an asymmetric catalytic reduction of the C3 ketone of 67 proceeding via a modified Noyori procedure (Scheme 2.8, 67—>68). In the event, Noyori reduction of ketone 67 afforded the desired diol 68 with excellent diasteresdectivity (>95 5). The ability to successftdly control the desired C3 stereochemistry of the late stage intermediate 68 permitted us to introduce the Cl-C7 fragment into the synthesis as an achiral building block. 

Two asymmetric synthesis approaches to chiral cyclopentenone derivatives can be envisaged. The first, reduced to practice by Noyori (43), involved reduction of cyclopentene-l,4-dione with lithium aluminum hydride chirally modified with binaphthol to give R-4-hydroxycyclopent-2-en-l-one in 94% e.e. Alternatively, manganese dioxide oxidation of allylic alcohol [40] (Fig. 7), in analogy to the cis isomer (54), would be expected to give the same enone. 

For a general overview of the reduction of imines, see the following (a) Morrison, J.D. (1983) Asymmetric Synthesis, vol. 2, Academic, New York (b) Noyori, R. (1994) Asymmetric Catalysis in Organie Synthesis, John WUey Sons, New York (c) Ojima, I. (2000) Catalytic Asymmetric Synthesis, 2nd edn, John WUey Sons, New York ... 

These furfliryl alcohols can be produced in either enantiomeric form via asymmetric catalysis. Our preferred method for the asymmetric synthesis of these fiiran alcohols 4.2 is by the highly enantioselective Noyori reduction of achiral acylfurans 4.1 (Scheme 4). Alternatively fiirfurly alcohols like 4.4 can be prepared by the Sharpless asymmetric dihydroxylation of vinylfuran 4.3. Key to this later approach was the recognition that vinylfuran 4.3 could be made by a Petersen olefination reaction. 

An important aspect of this approach is the ease with which fiiran alcohols can be prepared in enantiomerically pure form from achiral furans (e.g., 7 and 8). There are many asymmetric approaches to prepare furan alcohols. The two most prevalent approaches are (i) the Noyori reduction ofacylfurans (8 to 12) and (ii) the Sharpless dihydroxylation of vinyUurans (7 to 12) (Scheme 1.4) [17]. Both routes are readily adapted to 100 g scale synthesis and use readily available reagents. While the Sharpless route is most amenable to the synthesis of hexoses with a C-6 hydroxy group, the Noyori route distinguishes itself in its flexibility to virtually any substitution at the C-6 position. Herein, we review the development of the Achmatowicz approach to the de novo synthesis of carbohydrates, with apphcation to oligosaccharide assembly and medicinal chemistry studies. 

A range of highly reactive Ru"-BINAP complexes 222 were shown to be effective in significantly expanding the substrate scope in ketone reductions to include aromatic and unsaturated cyclic and acyclic ketones lacking any additional polar functionality as shown in Figure 2.9 [115-118, 141, 142]. An example that demonstrates the powerful use of the mixed Ru-complex 231 is found in Noyori s asymmetric synthesis of the antidepressant (R)-fluoxetine (186, Scheme 2.28) [142]. 

Noyori s synthesis of menthol by Rh+-catalysed [1,3]H shifts Corey s CBS Reduction of Ketones A synthesis of the H1 blocker cetirizine Part II - Asymmetric Formation of C-C Bonds Organic Catalysis... 

Synthesis of left-hand segment began with 7-benzyloxyindole 197. A Vilsmeier-Haack formylation followed by condensation afforded nitroalkene 198. Reduction, acylation with succinic anhydride, and subsequent Bischler-Napieralski cyclization provided dihydro-p-carboline 199. Noyori asymmetric reduction of 199, further treatment with A-iodosuccinimide, followed by activation with silver triflate in the presence of dimethoxy-N,N-diallylaniline furnished the desired coupling product 200. Subsequent saponification and cyclization via a ketene intermediate gave the rearrangement precursor 201. Oxidative skeletal rearrangement initiated by m-CPBA followed by removal of the Fmoc group and conversion of the aniline to the hydrazine furnished Fischer indole precursor 202 (Scheme 35). 

Take the millions of lives saved by the synthesis of indinavir, for example. This drug would not have been possible had not the Sharpless and Jacobsen asymmetric epoxidations, the catalytic asymmetric reduction, and the stereoselective enolate alkylation, along with many of the methods tried but not used in the final synthesis, been invented and developed by organic chemists in academic and industrial research laboratories. Some of the more famous names involved, like Sharpless, Jacobsen, and Noyori, invented new methods, while others modified and optimized those methods, and still others applied the methods to new types of molecules. Yet all built on the work of other chemists. 

Chapter 8 The Nobel Prize-winning asymmetric reduction work by Noyori and Knowles is discussed, together with its implications for enantioselective drug synthesis. 

The aldehyde 218 possessing 2,6-frans-tetrahydropyran, was synthesized as shown in Scheme 48. /3-Keto ester 220 was reduced by Noyori hydrogenation [97] to give 6-hydroxy ester 221 in 94% ee, which was converted into iodide 222. Asymmetric alkylation using Myers chiral auxiliary [98] with 222, followed by acid treatment, furnished 5-lactone 223 with high stereoselectivity. Reductive acetylation, axial allylation by the Hosomi-Sakurai reaction, and ozonolysis completed the synthesis of 218. 

Prize in Chemistry. (The other half of the 2001 prize was awarded to W. Knowles and R. Noyori for their development of catalytic asymmetric reduction reactions see Section 7.14A.) The following reaction, involved in an enantioselective synthesis of the side chain of the anticancer drug paclitaxel (Taxol), serves to illustrate Sharpless s catalytic asymmetric dihydroxylation. The example utilizes a catalytic amount of K20s02(0H)4, an OSO4 equivalent, a chiral amine ligand to induce enan-tioselectivity, and NMO as the stoichiometric co-oxidant. The product is obtained in 99% enantiomeric excess (ee) ... 

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