The Use of Optically Active Starting Materials

The Use of Optically Active Starting Materials.—This is arguably the most satisfying strategy to adopt in synthesizing optically active compounds, and a number of examples have already been given in this chapter. Others noted have been the synthesis of (-)-(15,7S)-exo-brevicomin (30) from ( + )-(2i ,3i )-diethyl tartrate by Meyer, a synthesis which may be compared to and contrasted with a short photochemical route to racemic exo-brevicomin (30) by Chaquin et al. The ( + )-and (—)-forms of camphor have often been used as optically active starting materials 

The Use of Optically Active Starting Materials.—It has been gratifying to see that, in the year under review, carbohydrates have been used several times as readily available, optically active starting materials. The attributes of carbohydrates in this sphere have been discussed by Fraser Reid and by Hanessian, the latter in relation to macrolide antibiotics. Fraser Reid, in a separate paper, gives details of the synthesis of either enantiomer of frontalin (34) from methyl-a-o-gluco-pyranoside. Coincidentally, the identical idea and achievement have been described 

Fraser Reid, Abstracts of Papers, Amer. Cbem. Soc., Centenary Meeting CARB 33, 1976. S. Hanessian and G. Rancourt, in ref. 65, CARB 32, 1976. 

Ohrui and S. Emoto, Agric. and Biot. Chem. (Japan), 1976, 40, 2261. 

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For excellent discussions of the use of optically active starting materials in synthesis, see (a) Hanes-sian, S. The Total Synthesis of Natural Products. The Chiron Approach, Pergamon Press New York, 1983 (b) Scott, J.W. In Asymmetric Synthesis, Morrison, J.D. Scott, J. W., Eds., Academic Press San Diego, 1984, Vol. 4, p. 1. 

The inclusion of the allyl moiety in an appropriate ring system led to the formation of a new, chiral quaternary carbon center (3.13.), By the use of optically active starting material, Mori and co-workers were able to control the stereochemistry of the new chiral centre (N.B. the chirality of the first centre was also set by a palladium catalysed reaction, the Tsuji-Trost allylation).17... 

Racemic material Is available In bulk and Is used for mating disruption In control programs. It costs about 400 per kilogram In large quantities. The (+) enantiomer Is much more expensive, and a number of syntheses have been described that entail the use of optically active starting materials or Intermediates (6-10). The superiority of the (+) enantiomer over racemic disparlure to attract males Into traps has stimulated efforts to devise more convenient and economical syntheses. 

The organic synthesis section (Chapter 30) has been expanded to include more examples of multistage syntheses, including the use of optically active starting materials and chiral catalysts. 

The second broad type of asymmetric syntheses are enantioselective processes which give rise to one of the enantiomers of a pair in excess. Enantioselective syntheses can only be achieved by the participation of optically active starting materials, reagents, or catalysts in the reaction process. There are several ways in which an enantioselective synthesis can be achieved. In principle, the ideal method is to use a single enantiomer of an available chiral substance as a catalyst. The advantage is that, theoretically, an optically active catalyst can generate an unlimited amount of product. A second possible choice is the use of an optically active... 

When planning the synthesis of an optically active product, the easiest approach is to use an optically active starting material from the chirality pool. For many decades this was in fact the only source of enantiomeri-cally pure catalysts or auxiliaries, a situation which has now changed due to recent successes by organic chemists in the design and synthesis of new... 

In most of the prior syntheses, optically active starting materials were used to synthesize isocarbacyclin (4) and different analogs. Many of these synthetic routes involve either annulation of a five-membered ring onto an optically active cyclopentane derivative (8-11 Fig. 4) that is commercially available or using a starting material that already has a bicyclo[3.3.0]octane skeleton (12 and 13 Fig. 4). An issue that Umited these approaches is how to selectively introduce the endocyclic double bond. 

Pubhcations have described the use of HFPO to prepare acyl fluorides (53), fluoroketones (54), fluorinated heterocycles (55), as well as serving as a source of difluorocarbene for the synthesis of numerous cycHc and acycHc compounds (56). The isomerization of HFPO to hexafluoroacetone by hydrogen fluoride has been used as part of a one-pot synthesis of bisphenol AF (57). HFPO has been used as the starting material for the preparation of optically active perfluorinated acids (58). The nmr spectmm of HFPO is given in Reference 59. The molecular stmcture of HFPO has been deterrnined by gas-phase electron diffraction (13). 

All sixteen of the racemic carba-sugars predicted are known, as well as fifteen of the enantiomers. The most accessible starting-material for the synthesis of racemic carba-sugars is the Diels-Alder adduct of furan and acrylic acid, namely, e i o7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylicacid (29). Furthermore, adduct 29 is readily resolved into the antipodes, (—)-29 and (+)-29, by use of optically active a-methylbenzylamine as the resolution agent. The antipodes were used for the synthesis of enantiomeric carba-sugars by reactions analogous to those adopted in the preparation of the racemates. 

Although decarboxylation reaction seems to be a simple one-carbon removing reaction, it is demonstrated that this reaction is a unique and useful reaction in the preparation of optically active carboxylic acids. If the starting material is a racemic carboxylic acid, the optically active compound can be obtained via symmetrization by chemical carboxylation followed by asymmetrization via enzymatic reaction. Accordingly, the whole process can be said as chemicoenzymatic deracemization (Fig. 24). 

The third approach is the main topic of this volume. According to the definition given above it involves enantiomerically pure starting materials which at some point must be provided by resolution or ex-chiral-pool synthesis. It is more or less equivalent to the term asymmetric synthesis defined by Marckwald in 19047 as follows Asymmetric syntheses are those reactions which produce optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with the exclusion of all analytical processes . In today s language, this would mean that asymmetric syntheses are those reactions, or sequences of reactions, which produce chiral nonracemic substances from achiral compounds with the intermediate use of chiral nonracemic materials, but excluding a separation operation. 

Around 70% of the pharmaceuticals on the market are chiral, and approximately one third of these are chiral amines [1], This represents a substantial number of achve drug substances that are typically manufactured at a scale of 1-100 l y . The three main manufacturing processes used to introduce these homochiral centers are from optically active starting materials (the so-called Chiral Pool approach), by asymmetric synthesis and by resolution. The last technique is widely practiced but results in waste of the undesired enantiomer. This chapter deals with developments in asymmetric transformations, that is to say methods for augmenting the yield of amine resolution processes to theory 100%, resulting in an alternative to asymmetric synthesis and a practical Green Chemistry solution to the synthesis of optically active amines. Figure 13.1 shows different approaches to the asymmetric transformation that will be discussed in the chapter. 

All the examples so far have been homonuclear. Complexes (14) provide examples of hetero-nuclear di- -OH cations, with M = Cu, Mn, Co, Ni or Zn, in solution.73 NiI+/Al3+ dimers with di- -OH have been characterized in the solid state, and may well also exist in solution.74 Although cocrystallization of cobalt and chromium hydroxo complexes normally gives the statistically expected mixture of Co2, Cr2 and CoCr di-/i-OH species (difficult to separate), if optically active starting materials are used a very high yield of the mixed dinuclear species [(en)2Cr(jt-OH)2Co(en)2]4+ can be obtained. 

By analogy, die formation of diastereomers is observed for additions to other trigonal systems, such as olefins, which have a chiral center elsewhere in the molecule. In these cases, if optically active starting materials are used, then the diastereomers will be optically active. If racemic starting materials are employed, the diastereomeric mixture will be optically inactive. In either case it is common to find different amounts of the two diastereomers. 

The catalytic enantioselective addition of aromatic C - H bonds to alkenes would provide a simple and attractive method for the formation of optically active aryl substituted compounds from easily available starting materials. The first catalytic, highly enantioselective Michael addition of indoles was reported by Jorgensen and coworkers. The reactions used a,fl-unsaturated a-ketoesters and alkylidene malonates as Michael acceptors catalyzed by the chiral bisoxazoline (BOX)-metal(II) complexes as described in Scheme 27 [98,99]. 

Enantiomeric Mannich bases may be obtained either by using optically active starting materials or by optical resolution of racemic derivatives. In the former case, the reactants are mostly provided by natural products, such as components of essential oils (e.g., camphor ), hormones, nucleic acids, employed as substrates, or a-amino acids - mainly used as amine reagents, etc. A list of optically active reactants reported in the literature is summarized in Table 12. 

The selectivity of the epoxidation, in conjunction with the availability of optically active terpenes from natural sources, has resulted in the application of terpene epoxides as starting materials for the synthesis of several natural products. Both enantiomers of carvone, (10) and (ent-l0), have been used for the synthesis of methyl trans- and c/.v-chrysanthemates 15 and ent-15. i+Hsy Carvone (10) was converted into hydrochlorinated compound 13 and the methylated derivative 11, which were selectively epoxidized with alkaline hydrogen peroxide, and further converted into methyl trum-chrysanthcmate 15. The same route led from (— )-(/ )-carvone ent-10) to m-chrysanthemate ent-1543 ent-13 was converted to ( + )-a-3,4-epoxycaran-2-one 1644. 

We highlight here a few studies in which the synthesis of chiral molecules has been achieved through the use of organic crystals in the hopes that this will prove a useful incentive and review. The reported studies fall into two natural categories. In the one case one starts with racemic mixtures or optically inactive compounds, crystallize these materials into chiral crystals and finally by subsequent reactions, trap this chirality in the final chemical products. In the second category one forms host-guest inclusion compounds in which the host is already an optically resolved compound. This in turn leads to the formation of optically active guest molecules. 

Montmorillonite KIO effects regioselective cyclopentylation (68% ori/zo-selectivity) of phenol using cyclopentanol (equation 16). The latter serves as starting material for the preparation of optically active S )-penbutolol, an antihypertensive drug. 

It should be pointed out that Scheme 3.33 depicts the reaction of optically active compounds, but the data of references 34 and 67 were obtained using racemic 5-HPETE as starting material. 

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