Chiral auxiliaries hydrogenation

Chips, semiconductor Chiral additives Chiral-AGP Chiral auxiliaries Chiral crown ethers Chiral hydrogenation Chirality... 

This thoroughly revised and updated new edition is a must for every synthetic organic chemist. New material has been added on homogene- ous diastereoselective hydrogenations, enantioselective oxidations, and novel chiral auxiliaries. 

Crystalline, diastereomerieally pure syn-aIdols are also available from chiral A-acylsultams. lhe outcome of the induction can be controlled by appropriate choice of the counterion in the cnolate boron enolates lead, almost exclusively, to one adduct 27 (d.r. >97 3, major adduct/ sum of all other diastereomers) whereas mediation of the addition by lithium or tin leads to the predominant formation of adducts 28. Unfortunately, the latter reaction is plagued by lower induced stereoselectivity (d.r. 66 34 to 88 12, defined as above). In both cases, however, diastereomerieally pure adducts are available by recrystallizing the crude adducts. Esters can be liberated by treatment of the adducts with lithium hydroxide/hydrogen peroxide, whereby the chiral auxiliary reagent can be recovered106. 

An efficient stereoselective Strecker synthesis of phenylglycine has been achieved using the tert-butyl ester tm-leucine as the chiral auxiliary. Its benzaldimine reacts with hydrogen cyanide in hexane at — 23 °C to furnish the ( )-diastereomer with the excellent diastereoselectivity of >98 254. 

Finally, the chiral auxiliary was removed by a Birch reduction or a catalytic hydrogenation. After ring opening several optically active 6-aminohexanoic acids served as linkers in cyclic peptides as /1-turn mimetics (Table 12, Scheme 49) [51c],... 

Among the various strategies [34] used for designing enantioselective heterogeneous catalysts, the modification of metal surfaces by chiral auxiliaries (modifiers) is an attractive concept. However, only two efficient and technically relevant enantioselective processes based on this principle have been reported so far the hydrogenation of functionalized p-ketoesters and 2-alkanons with nickel catalysts modified by tartaric acid [35], and the hydrogenation of a-ketoesters on platinum using cinchona alk oids [36] as chiral modifiers (scheme 1). 

One example of the use of 2D-NMR experiments in conformational analysis is the study of molecular interactions between cinchonidine and acetic acid [26]. These alkaloids are used as chiral auxiliaries in enantioselective hydrogenations, and the enantiomeric excess is dependent on solvent polarity, acetic acid being a good solvent This suggests that protonation and a preferred conformation play a role in achieving high enantioselectivities. With a combination of COSY-experiments, 3J coupling constants and NOESY experiments, it was shown that one conformer is preferred in acidic solutions. 

Before 1968, attempts to perform enantioselective hydrogenations had either used a chiral auxiliary attached to the substrate [1] or a heterogeneous catalyst that was on a chiral support, usually derived from Nature [2]. Since the disclosure of chiral phosphine ligands to bring about enantioselective induction in a hydrogenation, many systems have been developed, as evidenced in this book. The evolution of these transition-metal catalysts has been discussed in a number of reviews [3-12]. 

Chiral amines were always considered important targets for synthetic chemists, and attempts to prepare such compounds enantioselectively date back to quite early times. Selected milestones for the development of enantioselective catalysts for the reduction of C = N functions are listed in Table 34.1. At first, only heterogeneous hydrogenation catalysts such as Pt black, Pd/C or Raney nickel were applied. These were modified with chiral auxiliaries in the hope that some induction - that is, transfer of chirality from the auxiliary to the reactant -might occur. These efforts were undertaken on a purely empirical basis, without any understanding of what might influence the desired selectivity. Only very few substrate types were studied and, not surprisingly, enantioselectivities were... 

The chiral auxiliaries anchored to the substrate, which is subjected to diastereoselective catalysis, is another factor that can control these reactions. These chiral auxiliaries should be easily removed after reduction without damaging the hydrogenated substrate. A representative example in this sense is given by Gallezot and coworkers [268], They used (-)mentoxyacetic acid and various (S)-proline derivates as chiral auxiliaries for the reduction of o-cresol and o-toluic acid on Rh/C. A successful use of proline derivates in asymmetric catalysis has also been reported by Harada and coworkers [269,270], The nature of the solvent only has a slight influence on the d.e. [271],... 

Applications. In the last decade a lot of research has been devoted to the development of catalytic routes to a series of asymmetric carboxylic acids that lack the acetamido ligand as additional functionality. In Figure 4.17 four are listed, which are important as anaesthetics for rheumatic diseases. Their sales in beat many bulk chemicals the turnover of Naproxen (retail) in 1990 was 700 million for 1000 tons. S-Naproxen is now being produced by Syntcx via resolution with a chiral auxiliary. The main patents from Syntex expired in the U.S. in 1993, the reason for a lot of activity to study alternative synthetic routes. Routes leading to an asymmetric centre are o asymmetric hydrogenation of an unsaturated acid, o asymmetric carbohydroxylation of a styrene precursor, o asymmetric hydroformylation of a styrene precursor and oxidation. 

The pyrrolobenzodiazepine-5,11 -diones II have been utilized in asymmetric syntheses of both the cis- and tra i-decahydro-quinoline alkaloids (Schemes 21 and 22). For example, reduction of 100 with 4.4 equiv. of potassium in the presence of 2 equiv. of t-BuOH, followed by protonation of the resulting enolate with NH4CI at —78 °C gave the cA-fused tetra-hydrobenzene derivative 101.Amide-directed hydrogenation of 101 gave the hexahydrobenzene derivative with diastereo-selectivity greater than 99 1. Removal of the chiral auxiliary and adjustment of the oxidation state provided aldehyde 103 which was efficiently converted to the poison frog alkaloid (+)-pumiliotoxin C. 

We have reported one of the shortest total syntheses of epothilone D so far. A large moiety of the 16-membered macrocycle is derived from the easily available isoprenoid nerol. Only four C-C bond formations and three protective groups are required. Only one step requires the use of a (recoverable) chiral auxiliary. The other stereocenters are constructed by catalytic hydrogenation (C8), resolution (C15), and induction (C6, C7). In particular the northern half synthesis is well suited for large-scale preparation because of the combination of cheap reagents and catalytic processes. Using essentially the same method, a number of epothilone D5 analogues were synthesized. 

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