Jacobsen Epoxidation Synthesis

Jacobsen epoxidation turned out to be the best large-scale method for preparing the cis-amino-indanol for the synthesis of Crixivan, This process is very much the cornerstone of the whole synthesis. During the development of the first laboratory route into a route usable on a very large scale, many methods were tried and the final choice fell on this relatively new type of asymmetric epoxidation. The Sharpless asymmetric epoxidation works only for allylic alcohols (Chapter 45) and so is no good here. The Sharpless asymmetric dihydroxylation works less well on ris-alkenes than on trans-alkenes, The Jacobsen epoxidation works best on cis-alkenes. The catalyst is the Mn(III) complex easily made from a chiral diamine and an aromatic salicylaldehyde (a 2-hydroxybenzaldehyde). 

The synthesis of the tetrasubstituted dihydroquinoline portion of siomycin Di, which belongs to the thiostrepton family of peptide antibiotics, was achieved in the laboratory of K. Hashimoto. The Jacobsen epoxidation was utilized to introduce the epoxide enantioselectively at the C7-C8 position. The olefin was treated with 5 mol% of Jacobsen s manganese(lll)-salen complex (R =f-Bu) and 4% aqueous NaOCI solution in dichloromethane. To enhance the catalyst turnover, 50 mol% of 4-phenylpyridine-A/-oxide was added to the reaction mixture. The desired epoxide was obtained in 43% yield and with 91% ee. 

The catalytic asymmetric synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine was developed by J. Lee et al. using an intramolecular epoxide opening 5-exo-tet) followed by ring expansion. The acyclic c/s-epoxide substrate was prepared in good yield and in greater than 94% ee by the Jacobsen epoxidation from the corresponding (Z)-alkene. ... 

J.E. Lynch and co-workers reported the asymmetric total synthesis of the PDE IV inhibitor CDP840 in which they utilized the Jacobsen epoxidation to introduce the only stereocenter of the target. The triaryl (Z)-olefin substrate was epoxidized with significantly higher enantiomeric excess than the triaryl ( )-olefin. This finding was interpreted with Jacobsen s skewed side-on approach model. 

These may seem strange molecules to have a place in the new chiral pool but they were made on a vast scale by Merck in the synthesis of their HIV protease inhibitor crixivan (Indinavir). They both come from Jacobsen epoxidation of indene 283 (chapter 25) the anti-compound 285 by opening the epoxide 284 at the benzylic centre with azide ion.51... 

Perhaps the most famous Jacobsen epoxidation is that of indene 206 used in the synthesis of the amino-indanol45 209. The anti-AIDS drug Crixivan incorporates 209 which is also a cheap chiral auxiliary in its own right. 

Other improvements include the development of more sterically hindered ligands46 and changes in oxidant to mCPBA and NMO to give efficient asymmetric synthesis of monosubstituted epoxides.47 The asymmetric epoxidation of dimethylchromenes such as 216, a previously problematic task, is easy with Jacobsen epoxidation and these epoxides such as 217 have been used to make calcium channel antagonists 218. 

Catalytic reactions look like the best bet for the future of asymmetric synthesis. In the next chapter you will see how C- H and C-C bonds can also be made by catalytic asymmetric reactions. The only limitation at the moment is the relatively small number of reactions that have been developed. Some of those you have met in this chapter - Sharpless AE and AD and Jacobsen epoxidation - are among the best. 

There are all sorts of problems with epoxidation by micro-organisms and in general laboratory chemists prefer to use the Sharpless or Jacobsen epoxidations described in chapter 25. The co-hydroxylase from Pseudomonas oleovorans does epoxidise aryl ethers of allylic alcohols with good selectivity and one product has been used in the synthesis of the (5-blocker metropolol.29 However the organism requires gaseous hydrocarbons as carbon sources and the epoxide products poison it. 

In summary, the broad application of the Shi epoxidation in the total synthesis of natural products and in drug discovery is a good indication that the reaction will receive more attention and find extended use in the future. Together with the Sharpless epoxidation and the Jacobsen epoxidation, Shi epoxidation has been considered one of the three major catalytic enantioselective epoxidations useful for the synthesis of ehiral epoxides. 

Reactions where catalytic asymmetric induction has been achieved include the Sharpless epoxidation (a) Morrison, J. D., Asymmetric Synthesis (Finn, M. G. and Sharpless, K. B., eds.). Academic Press New York, 1985, Vol. 5, Chap. 8. (b) Morrison, J. D., Asymmetric Synthesis (Rossiter, B. E., ed.) Academic Press New York, 1985 Vol. 5, Chap. 7 the Jacobsen epoxidation (c) Zhang, W. Loebach, J. 

The epoxide functional group is often an intermediate in organic synthesis sequences because it can be readily opened by a variety of nucleophiles, leading to complex functionalization that starts with just an alkene. Asymmetric variants of epoxidation are important reactions, with the Sharpless and Jacobsen epoxidations being the most well known. Both these reactions involve metal catalysts. 

Jacobsen epoxidation 23 Jacobsen synthesis (indazole) 245 Japp-Klingemann reaction 143... 

Asymmetric manganese-salen-catalyzed epoxidation of unfunctionalized olefins was reported by Jacobsen et al. [74] in 1990, which allowed the enantioselective epoxidation of unfunctionalized olefins. In particular, the high enantioselectivities obtained for Jacobsen epoxidation on cis-olefins, nicely complement the Sharpless epoxidation and dihydroxylation protocols, which give reduced enantioselectivities for these substrates. The Sharpless and Jacobsen procedures are frequently used asymmetric oxidative reactions in API synthesis. More recently, organocatalytic procedures such as Shi epoxidations [75] were also employed to avoid toxic transition metal catalysts. 

Although Prasad et al. reported an alternative Jacobsen epoxidation approach for the preparation of 162, the SAD procedure was chosen for further scale-up due to the higher overall yield in the synthesis of 163 (43% versus... 

Lynch JE, Choi WB, ChurchiU HRO, Volante RP, Reamer RA, Ball RG. Asymmetric synthesis of CDP840 by Jacobsen epoxidation. An unusual syn selective reduction of an epoxide. J. Org. Chem. 1997 62(26) 9223-9228. 

Researchers at Merck utilised the Jacobsen epoxidation as the key stereodefining step in their synthesis of a variety of substituted piperidines which were screened as neurokinin-1 receptor antagonists (Scheme 14.55). Lee et al, effectively epoxidised cis styrene derivative 141 to prepare the key intermediate (142) in good yield and 94% ee. Utilising 142, the authors prepared piperidine 143, which was further elaborated to the final targets (144 and 145). Formation of 143 proceeds by a 5-exo cyclisation of 142 followed by ring-expansion to furnish the piperidine ring systems. This process... 

The first application of the Jacobsen-Katsuki epoxidation reaction to kinetic resolution of prochiral olefins was nicely displayed in the total synthesis of (+)-teretifolione B by Jacobsen in 1995. 

Jacobsen-Katsuki epoxidation reaction in total synthesis Scheme 1.4.11... 

The asymmetric epoxidation of electron-poor cinnamate ester derivatives was highlighted by Jacobsen in the synthesis of the Taxol side-chain. Asymmetric epoxidation of ethyl cinnamate provided the desired epoxide in 96% ee and in 56% yield. Epoxide ring opening with ammonia followed by saponification and protection provided the Taxol side-chain 46 (Scheme 1.4.12). 

The Best results are obtained with cA-alkenes however, the epoxidation of tri-and tetra-substituted double bonds is also possible. Because of its versatility, the Jacobsen-Katsuki epoxidation is an important method in asymmetric synthesis. 

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

Conjugated dienes can be epoxidized to provide vinylepoxides. Cyclic substrates react with Katsuki s catalyst to give vinylepoxides with high ees and moderate yields [17], whereas Jacobsen s catalyst gives good yields but moderate enantiose-lectivities [18]. Acyclic substrates were found to isomerize upon epoxidation (Z, )-conjugated dienes reacted selectively at the (Z)-alkene to give trans-vinylepoxides (Scheme 9.4a) [19]. This feature was utilized in the formal synthesis of leuko-triene A4 methyl ester (Scheme 9.4b) [19]. 

The past thirty years have witnessed great advances in the selective synthesis of epoxides, and numerous regio-, chemo-, enantio-, and diastereoselective methods have been developed. Discovered in 1980, the Katsuki-Sharpless catalytic asymmetric epoxidation of allylic alcohols, in which a catalyst for the first time demonstrated both high selectivity and substrate promiscuity, was the first practical entry into the world of chiral 2,3-epoxy alcohols [10, 11]. Asymmetric catalysis of the epoxidation of unfunctionalized olefins through the use of Jacobsen s chiral [(sale-i i) Mi iln] [12] or Shi s chiral ketones [13] as oxidants is also well established. Catalytic asymmetric epoxidations have been comprehensively reviewed [14, 15]. 

The hydrolytic kinetic resolution (HKR) of terminal epoxides using Co-salen catalysts provides a convenient route to the synthesis of enantioemiched chiral compounds by selectively converting one enantiomer of the racemic mixture (with a maximum 50% yield and 100% ee) (1-3). The use of water as the nucleophile makes this reaction straightforward to perform at a relatively low cost. The homogeneous Co(III) salen catalyst developed by Jacobsen s group has been shown to provide high... 

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