Examples of Asymmetric Syntheses

1 Hydrogenation of the C=0 Bond Catalyzed by Chiral Organometallic Complexes 

The results indicate that non-systematic variation of the structure of chbal ligands leads to a casual degree of enantioselectivity. This statement is valid for aU enantioselective catalytic processes. Systematic study of chiral catalysts and reaction conditions is required to reach high enantioselectivity. 

Alcohol 17 is a key intermediate in the synthesis of Montelukast, a broadly used drug in the therapy of asthma. The biological aclivily of (/ )-enantiomer is much higher than that of (5)-enanliomer therefore, the direction of enantioselectivity and optical purity of the product are cmcial for the technological feasibility of this synthetic step. For dmgs used in human therapy in the optically pure form, an optical purity of 98-100 % e.e. is required. 

Synthesis of a- and (3-amino acids in the enantiomerically pure form is often completed by asymmetric reduction of the corresponding imino precursors. Since imines are considerably less stable than parent aldehydes and ketones, their asymmetric hydrogenation has been less explored. Here follow two examples. 

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Other interesting examples of asymmetric syntheses involving chiral monoterpenoids include the Claisen reaction between (—)-menthyl phenylacetate and benz-aldehyde (optical purity is confirmed by microcalorimetry), a highly enan-tioselective carbenoid cyclopropanation catalysed by (4), ° and the crossed aldol... 

The last approach to chiral synthesis begins with a chiral precursor whose components will be integrated into the final product, which is the chiral template approach (sec. 10.9). The examples of asymmetric syntheses involving Diels-Alder templates are as varied as the targets. One typical example is by Oppolzer, who reported an asymmetric synthesis of pumiliotoxin C via Diels-Alder cyclization of 303, prepared from (/ )-norvaline, to give 304.248... 

A general view of asymmetric allylation is summarized briefly here, and numerous examples of asymmetric syntheses are cited in individual sections. The asymmetric synthesis is classified into the following types based on how the differentiation or enantio-discriminating events occur ... 

The other recent examples of asymmetric syntheses involving Danishefsky s diene focused on hetero Diels-Alder reactions. Shibasaki and Feng separately reported asymmetric reactions with carbonyl dienophiles. Shibasaki demonstrated successful asymmetric reactions of ketones using a chiral Cu(I)-Walphos catalyst. Feng used a chiral A,iV -dioxide/In(OTf)3 catalyst in asymmetric cycloaddition reactions of aldehydes. Imine dienophiles are also amenable to asymmetric Diels-Alder reactions with Danishefsky s diene. Wulff reported enantioselective reactions using a VAPOL-B(OPh)3 catalyst system, while Snapper and Hoveyda disclosed silver-catalyzed enantioselective aza Diels-Alder reactions. ... 

The selected examples of asymmetric syntheses in this book are not regularly related to the target molecule of retrosynthetic analysis. Chiral target molecules are selected either to demonstrate the practicability of certain asymmetric syntheses in non-catalytic and catalytic mode, on the laboratory and industrial scale, or because of their scientific originality. 

Examples of asymmetric syntheses attempted with optically active polymers as catalysts in heterogeneous systems... 

AT-heterocyclic carbene complexes of Pd(II) or Pd(0) were extensively used in various reactions and several groups have reported syntheses of chiral complexes [5]. However, only a few examples of asymmetric catalysis are... 

Grubbs synthesized molybdenum catalyst 74 and reported the first example of asymmetric induction by kinetic resolution of diene using RCM with complex 74." After 90% conversion of the reaction of diene with 74, an enantiomeric excess (ee) of the recovered staring material 78 showed 84% and an absolute configuration is determined to be 5 ... 

Recent developments regarding the utility of chiral amino acids in asymmetric synthesis of natural products were reported. Examples of such syntheses are the preparation of carbohydrates from (S)-glutamic acid 257), (S)-alanine 258), or (S)-threonine 259), and syntheses of alkaloids 260), terpenes 26I), peptide 262) derivatives, and toxines 263>. 

In conclusion, the aldol reaction with L-proline as an enzyme mimic is a successful example for the concept of using simple organic molecules as chiral catalysts. However, this concept is not limited to selected enzymatic reactions, but opens up a general perspective for the asymmetric design of a multitude of catalytic reactions in the presence of organocatalysts [1, 3]. This has been also demonstrated by very recent publications in the field of asymmetric syntheses with amino acids and peptides as catalysts. In the following paragraphs this will be exemplified by selected excellent contributions. 

Stereochemistry and asymmetric synthesis are topics with which chemists traditionally have been concerned (1 ). In recent years there has been a virtual explosion of literature in the area of asymmetric organic synthesis that has fortuitously paralleled the increased awareness of insect pheromone stereochemistry. Many useful reviews of asymmetric synthesis exist (2, 2> 4, 5, 0 and this paper will only briefly direct the reader s attention to examples of reported syntheses by type that may be of potential general use for pheromone synthesis. It should be clear even to the casual reader that this field is in need of almost annual review and current literature would have to be consulted in the face of an original problem in synthesis. 

Some examples of enantioselective syntheses, carried out in chiral media, have already been given at the end of Section 3.2, which deals with chiral solvents cf. also Table A-2 (Appendix). In general, asymmetric inductions as a result of chiral solvents or chiral cosolvents are disappointingly low [700], The reason for this is that the differential solvation by the chiral solvent of the two enantiomorphic activated complexes which lead to either the (/ )- or (S)-product is not sufficient. That is, the difference in Gibbs energy of activation, AAG = AG — AG -, is not large enough to favour only one of the two enantiomeric products. It should be remembered that a difference of AAG = 10.8 kJ/mol (2.6 kcal/mol) at 20 °C would be sufficient to get an product ratio of 99 1 i.e. an enantiomeric excess ee = 98%). 

Perhaps the simplest of the isoquinoline alkaloids is salsolidine. It has been synthesized by asymmetric alkylation of 6,7-dimethoxytetrahydroisoquinoline using either a formamidine ° or oxazoline chiral auxiliary. Scheme 25 illustrates the recently published Organic Syntheses preparation of salsolidine on a 5 g scale. It is of interest to note that, in this and all subsequent examples of asymmetric alkylation of tetrahydroisoquinolines, formamidines derived from L-valine afford (IS)-tetrahydroisoquinolines, while oxazolines derived from L-valine afford the (lf )-enantiomer. The reason is simply the opposite orienta-... 

The first example of asymmetric cycloaddition involving 1,2-DHPs synthesized from chiral amines (Scheme 15) was reported by Mehmandoust, et al. [100]. Diels-Alder... 

An interesting example of asymmetric induction has been utilized in a new biogenetic-type synthesis of (—)-tetrahydroharman and ( — )-1,2,3,4,6,7,12,12b-octahydroindoIo[2,3-a]quinolizine (6) from L-tryptophan the synthesis of (6) is outlined in Scheme 3. Apparently the Pictet-Spengler closure is stereospecific, and affords the 1,3-cis stereoisomer (6a) removal of the unwanted chiral centre is achieved in good yield and without epimerization at C-1 by NaBH4 reduction of an a-aminonitrile. This synthesis may well find application in other areas. The alkaloid (6) has also been synthesized by a more conventional, non-stereospecific route. ... 

Methyl L-ohvoside (24) is an important compound, because it has been repeatedly used as a key intermediate for synthesis of other deoxypyrano-sides, e.g., L-oleandroside, L-kedarosaminide, L-ristosaminide, and L-daunos-aminide [20]. The examples of its syntheses presented above could be easily multiplied by application of known principles of acychc stereoselection, e.g., asymmetric hydroboration, epoxidation, dihydroxylation, etc. Considering recent advances in enantioselective synthesis based on asymmetric... 

In 1999, Mikami and co-workers reported the first example of asymmetric Fujiwara-Moritani reaction catalyzed by Pd" and sulfonylamino-oxazoline ligand (Scheme 5.12a). A 1 1 complex between the chiral ligand and Pd(OAc)2 could be the active catalyst in this asymmetric Fujiwara-Moritani reaction. This method provides a convenient process to synthesize aromatic C—H bond activation/olefin coupling products but with moderate enantioselectivity. 

As an efficient bifunctional catalyst, proline has been used as a Br0nsted acid in combination with a nucleophilic Lewis base catalyst in the asymmetric BH reaction. Miller and co-workers [119] disclosed that in the L-proline-catalyzed BH reaction of MVK and electron-deficient aldehydes the imidazole-tailed peptide 67 was an efficient co-catalyst. A matched/mismatched phenomenon of two chiral catalysts was observed in this reaction. Furthermore, Zhou and co-workers [120] synthesized various chiral amines and screened them as co-catalysts of L-proline in the BH reaction of MVK and aldehydes, revealing that chiral benzodiazepine 68 and aminoalcohol 69 were efficient catalysts. Interestingly, the intramolecular reaction shown in Scheme 9.34 could be directly catalyzed by L-proline in DMF solvent, while the addition of imidazole resulted in enhancement of the enantioselectivity with opposite configurational product [121]. A similar process was realized in the intramolecular reaction shown in Scheme 9.35 with 70 as co-catalyst of iV-methylimidazole. Moreover, Cordova and co-workers [122] reported in 2007 the first example of asymmetric aza-BH reaction between (3-mono- or disubstituted acroleins and aldimines. By utilizing L-proline as catalyst in combination with... 

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