Indoles asymmetric hydrogenation

M., Humphrey, G.R. et al. on the long term factory process for the production of a prostaglandin D2 receptor antagonist - unprecedented asymmetric hydrogenation of an indole Fxo-Cyclic Trisubstituted a,(i-Unsaturated Acid. 

Much like the enol systems discussed in Sect. 6.1, enamines are predictably difficult substrates for most iridium asymmetric hydrogenation catalysts. Both substrate and product contain basic functionahties which may act as inhibitors to the catalyst. Extended aromatic enamines such as indoles may be even more difficult substrates for asymmetric hydrogenation with an additional energetic barrier to overcome. Initial reports by Andersson indicated a very difficult reaction indeed (Table 14) [75]. Higher enantioselectivities were later reported by Baeza and Pfaltz (Table 14) [76]. 

In the heterocyclic series several heteroarylalanines have been obtained by asymmetric hydrogenation using chiral homogeneous catalysts. For example, replacement of the phenyl ring by furan, thiophene, selenophene, pyridine, or indole yields fiirylalanines, thienyManines, 2- and 3-selenienyManines,... 

Kuwano, R. and Kashiwahara, M. Ruthenium-catalyzed Asymmetric Hydrogenation of N-Boc-Indoles. Org. Lett. 2006, 8, 2653-2655. 

CATALYTIC ASYMMETRIC HYDROGENATION OF 3-METHYL-A-(E-TOLUENESULFONYL)INDOLE... 

Table 2.5 Asymmetric hydrogenation of indoles using (S,S)-(I ,I )-PhTRAP-rhodium complex as catalyst...

Asymmetric hydrogenation of alkenes is efficiently catalysed by rhodium complexes with chiral diphosphite and diphosphoramidite ligands derived from BINOL or diphenylprolinol. Choice of a proper achiral backbone is crucial.341 Highly enantioselective hydrogenation of A-protected indoles was successfully achieved by use of the rhodium catalyst generated in situ from [Rh(nbd)2]SbF6 (nbd = norborna-2,5-diene)... 

The asymmetric hydrogenations of N acetyl, N carbamate, and N sufonyl indoles are asymmetric hydrogenations of enamides. not imines, and will therefore not be covered here. For reports of this reaction, see (a) Kuwano, R. and Kashiwabara. M., (2006) Org. Lett., 8,... 

Asymmetric Hydrogenation of Indoles 325 Table 10.12 Asymmetric hydrogenation of N tosylindoles (24a 24f). 

This method was successfully applied to the total synthesis of chiral indoline alkaloid 2Sh, which is Wierenga s synthetic intermediate for the left hand segment of the antitumor agent ( + ) CC 1065. As shown in Scheme 10.28, the asymmetric hydrogenation of N methanesulfonyl indole (24g) to the corresponding indoline (25g) with 93% ee was the key step. 

Scheme 10.29 Asymmetric hydrogenation of 3 substituted and 2,3 disubstituted indole...

Based on the above results, asymmetric hydrogenation of indoles provides a... 

Scheme 10.31 Pathway of asymmetric hydrogenation of indoles (34a 34i) by Kuwano.

Dixneuf, Bruneau and coworkers have reported an interesting reduction of the unsaturated acyl oxazolidinone (2.90). The reduction works with high yield and asymmetric induction, and the product (2.91) is effectively propionic acid with a chiral auxiliary attached. The chiral auxiliary was then used to induce asymmetry in a subsequent step. 2,3-Substituted N-Boc indoles imdergo hydrogenation to... 

Chiral indolines represent useful building blocks in pharmaceuticals, herbicides and insecticides. Asymmetric hydrogenation of unprotected indoles with molecular hydrogen represents the most straightforward and atom-economy method to produce these compounds.Although the asymmetric (up to 98% ee) hydrogenation of N-protected or N-Ts indoles with is known since 2000 (R. Kuwano, Kyushu... 

Kuwano, R. Kashiwabara, M. Sato, K. Ito, T. Kaneda, K. Ito, Y. Catalytic asymmetric hydrogenation of indoles using a rhodium complex with a chiral bisphosphine ligand PhTRAP. Tetrahedron Asymmetry 2006,17,521-535. 

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