Asymmetric synthesis catalytic

Generally enzymes are highly selective, both in terms of the substrates they can act on and the levels of enantioselectivity that can be induced. In many cases enzymes must be modified for a particular substrate. They are usually only stable in aqueous media and are highly sensitive to pH and temperature. A particular enzyme can be 

Organocatalysis can be defined as the acceleration of chemical reactions with a sub-stoichiometric amount of an organic compound which does not contain a metal atom [18]. The first example of an asymmetric organocatalytic reaction was 

Transition metal mediated asymmetric catalysis is a cornerstone of organic chemistry. To emphasise its importance to the field the Nobel Prize in Chemistry was awarded jointly to Knowles and Noyori for their work on chirally catalysed hydrogenation reactions and to Sharpless for his work on chirally catalysed oxidation reactions in 2001 in recognition of their pioneering contributions to the development of transition metal catalysed transformations. The application of these transformations in industrial processes further emphasises their importance [25]. 

A chiral transition metal catalyst generally consists of a metal atom ligated by a chiral organic molecule. This coordination complex can influence the outcome of a reaction by interacting with a substrate. This interaction involves coordination of the substrate to a vacant site on the metal atom. The ligand is covalently bound to the ligand via donor atoms such as P, N, O or S, typically in a bidentate fashion to form the chiral metal complex (Fig. 4.2). The complex can transfer its chiral information to a substrate when it binds to the metal. The nature of the donor atoms and the backbone through which they are linked can have a profound effect on the 

2 General components of a transition metal bidentate Ugand complex [26] 

Until relatively recently, practical access to single enantiomers form pro-chiral precursors was considered possible using only microbiological processes, as described earlier. The scope of such methods is somewhat limited, because biological processes exhibit single-handed specificity. Synthetic chemists, however, have developed a variety of versatile stereoselective reactions which complement biological processes. 

In an idealistic sense, a chemical approach which uses a small amount of a chiral catalyst to produce either enantiomer, cleanly and efficiently from a prochiral precursor, is the preferred method. For such asymmetric catalysis the efficiency of chiral multiplication can be infinite. The use of chiral metal complexes as homogeneous catalysts has become one of the most powerful economically and environmentally sound strategies for the preparation of enantiopure compounds. An excellent comprehensive review of asymmetric catalysis in organic synthesis has recently been published by Noyori [30]. 

No discussion on catalytic asymmetric synthesis would be complete without mention of the Sharpless asymmetric epoxidation of allylic alcohols [34]. This utilises a Ti(IV)-tartrate catalyst and /-butyl hydroperoxide as the oxidant. High enantioselectivity can be achieved using this system for a wide variety of allylic alcohols. Commercial applications, however, are at present limited to relatively small scale production. 

The key steps in this process are catalytic and with a reputed overall chiral multiplication efficiency in excess of 400 000 for the asymmetric step, the environmental impact of this process must be extremely low. 

The foregoing account outlines the various technologies which can be used for industrial synthesis of optically active compounds. It is impossible to state that any single technology is superior to any other on envir- 

---

Catalytic Asymmetric Synthesis, VCH publishers New York, 1993 (d Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley New York, 1994... 

Catalytic asymmetric synthesis with participation and formation of heterocycles (including asymmetric phase transfer reactions and asymmetric reactions with chiral Lewis catalysts) 93MI1. 

See e.g. (a) W. Cahhuthehs, Cycloaddition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry Series Vol. 8 Pergamon Press Elmsford, NY 1990 (b) I. OjiMA, Catalytic Asymmetric Synthesis, VCH Publishers. Inc. New York. 1993 ... 

For his work on chirally catalyzed oxidation reactions, representing a major contribution to the development of catalytic asymmetric synthesis, K. B. Sharpless was awarded the Nobel Prize for chemistry in 2001. ... 

An early success story in the field of catalytic asymmetric synthesis is the Monsanto Process for the commercial synthesis of l-DOPA (4) (see Scheme 1), a rare amino acid that is effective in the treatment of Parkinson s disease.57 The Monsanto Process, the first commercialized catalytic asymmetric synthesis employing a chiral transition metal complex, was introduced by W. S. Knowles and coworkers and has been in operation since 1974. This large-scale process for the synthesis of l-DOPA (4) is based on catalytic asymmetric hydrogenation, and its development can be... 

Scheme 5. The Sumitomo Chemical Company s catalytic asymmetric synthesis of ethyl (+)-(1 S)-2,2-dimethylcyclopropanecarboxylate (18), an intermediate in Merck s commercial synthesis of cilastatin (19).

We now turn to the Takasago Process for the commercial synthesis of (-)-menthol (1),4 one of the most successful industrial applications of catalytic asymmetric synthesis. This exquisite synthesis is based on the BINAP-Rh(i)-catalyzed enantioselecdve isomerization of allylic amines, and has been in operation for the commercial production of (-)-menthol since 1984. 

For some excellent monographs and reviews that deal with catalytic asymmetric synthesis, see (a) Asymmetric Synthesis, Morrison, J. D., Ed., Academic Press New York, 1985, Vol. 5 (b) Bosnich, B. Asymmetric Catalysis, Martinus Nijhoff Dordrecht, 1986 ... 

In an extension of this work, the Shibasaki group developed the novel transformation 48—>51 shown in Scheme 10.25c To rationalize this interesting structural change, it was proposed that oxidative addition of the vinyl triflate moiety in 48 to an asymmetric palladium ) catalyst generated under the indicated conditions affords the 16-electron Pd+ complex 49. Since the weakly bound triflate ligand can easily dissociate from the metal center, a silver salt is not needed. Insertion of the coordinated alkene into the vinyl C-Pd bond then affords a transitory 7t-allylpalladium complex 50 which is captured in a regio- and stereocontrolled fashion by acetate ion to give the optically active bicyclic diene 51 in 80% ee (89% yield). This catalytic asymmetric synthesis by a Heck cyclization/ anion capture process is the first of its kind. 

Of course, the key limitation of the ylide-mediated methods discussed so far is the use of stoichiometric amounts of the chiral reagent. Building on their success with catalytic asymmetric ylide-mediated epoxidation (see Section 1.2.1.2), Aggarwal and co-workers have reported an aza version that provides a highly efficient catalytic asymmetric synthesis of trans-aziridines from imines and diazo compounds or the corresponding tosylhydrazone salts (Scheme 1.43) [68-70]. 

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],... 

Doyle MP (2000) In Ojima I (ed) Catalytic asymmetric synthesis. Wiley-VCH, New York, chap 5... 

Proceedings of the National Academy of Sciences of the United States of America, 101, 5347. (b) Ojima, I. (ed.) (2000) Catalytic Asymmetric Synthesis, 2nd edn, Wiley-VCH Verlag GmbH, New York, (c) Jacobsen, E.N., Pfallz, A. and Yamamoto, H. (eds) (1999) Comprehensive Asymmetric Catalysis, Springer, Berlin, (d) Noyori, R. (1994) Asymmetric Catalysis in Organic Synthesis, John Wiley Sons, Ltd, New York, (e) Drauz, K and Waldmann, H. (eds) (2002) Enzyme Catalysis in Organic Synthesis A Comprehensive Handbook,... 

Ohkuma, T. Kitamaura, M. and Noyori, R. (2000) Asymmetric hydrogenations, in Catalytic Asymmetric Synthesis (ed. I. Ojima), 2nd edn, Wiley-VCH Verlag GmbH, New York. 

Yamano T, Taya N, Kawada M, Huang T, Imamoto T (1999) Tetrahedron Lett 40 2577 Brunner H, Nishiyama H, Itoh K (1993) Asymmetric hydrosilylation. In Ojima I (ed) Catalytic asymmetric synthesis. Wiley-VCH, New York, chap 6 Sawamura M, Kuwano R, Ito Y (1994) Angew Chem, Int Ed Engl 33 111 Kuwano R, Uemura T, Saitoh M, Ito Y (1999) Tetrahedron Lett 40 1327 Hayashi T (1993) Asymmetric allylic substitution and grignard cross-coupling. In Ojima I (ed) Catalytic asymmetric synthesis. WUey-VCH, New York, chap 7-1 Trost BM, Vranken DLV (1996) Chem Rev 96 395 Consiglio G,Waymouth RM (1989) Chem Rev 89 257... 

Ghosh et al. [70] reviewed a few years ago the utihty of C2-symmetric chiral bis(oxazoline)-metal complexes for catalytic asymmetric synthesis, and they reserved an important place for Diels-Alder and related transformations. Bis(oxazoline) copper(II)triflate derivatives have been indeed described by Evans et al. as effective catalysts for the asymmetric Diels-Alder reaction [71]. The bis(oxazoline) Ugand 54 allowed the Diels-Alder transformation of two-point binding N-acylimide dienophiles with good yields, good diastereos-electivities (in favor of the endo diastereoisomer) and excellent ee values (up to 99%) [72]. These substrates represent the standard test for new catalysts development. To widen the use of Lewis acidic chiral Cu(ll) complexes, Evans et al. prepared and tested bis(oxazoHnyl)pyridine (PyBOx, structure 55, Scheme 26) as ligand [73]. 

Anderson CE, Donde Y, Douglas CJ, Overman LE (2005) Catalytic asymmetric synthesis of chiral allylic amines. Evaluation of ferrocenyloxazoline palladacycle catalysts and imidate motifs. J Org Chem 70 648-657... 

Wiskur SL, Fu GC (2005) Catalytic asymmetric synthesis of esters from ketenes. J Am Chem Soc 127 6176-6177... 

Hodous BL, Ruble JC, Fu GC (1999) Enantioselective addition of alcohols to ketenes catalyzed by a planar-chiral azaferrocene catalytic asymmetric synthesis of arylpropionic acids. J Am Chem Soc 121 2637-2638... 

Lee EC, McCauley KM, Fu GC (2007) Catalytic asymmetric synthesis of tertiary alkyl... 

Taggi AE, Hafez AM, Wack H, Young B, Ferraris D, Lectka T (2002) The development of the first catalyzed reaction of ketenes and imines catalytic, asymmetric synthesis of P-lactams. J Am Chem Soc 124 6626-6635... 

Zajac M, Peters R (2009) Catalytic asymmetric synthesis of P-Sultams as precursors for taurine derivatives. Chem Eur J 15 8204-8222... 

---