Chiral Synthetic Units

Production of some C3 and C4 chirals such as EP, CPD, GLD, propanediol, 4-chloro-3-hydroxybutyrate is also being carried out or has been reported by other means such as chiral metal catalysts [2], reduction using microorganisms [3] or enzymatic resolution of suitable derivatives [4], A comparison of these methods can be found in [1]. 

In this section, we describe the problems for the industrial production of our C3 chiral units and our solutions to these problems. Chiral DCP and CPD are produced from racemic DCP and CPD by microbial resolution, chiral EP from chiral DCP, and chiral GLD from chiral CPD by the microbial resolution via synthetic conversion, respectively. 

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The study and development of microbial methods for the industrial-scale production of C3 and C4 chiral synthetic units such as 2,3-dichloro-l-propanol (DCP), epichloro-hydrin (EP), 3-chloro-l,2-propanediol (CPD), glycidol (GLD), 4-chloro-3-hydroxy-butyrate (CHB), 3-hydroxy-y-butyrolactone (HL) is described. The following points are emphasized overall strategy screening, isolation, and cultivation of bacteria control of fermentation reactions and transfer from lab- to production-scale. 

These chiral synthetic units have the following characteristics. 

Scale-up of the Production of C3 Chiral Synthetic Units 5.2.4.1 Fed-Batch Fermentation and Control... 

C4 chiral synthetic units are also important for the syntheses of pharmaceuticals and their intermediates. For example, optically active 4-chloro-3-hydroxybutyrate (CHB) and 4-chloro-3-hydroxybutyronitrile (BN) are key compounds as C4 chiral building blocks for the syntheses of L-carnitine [16], l-GABOB [17], / -hydroxybuty-ric acid, 3-hydroxy-y-butyrolactone, and 4-hydroxy-2-pyrrolidone. Recently, CHB has been reported as being used for synthesizing an intermediate for HMG-CoA reductase inhibitor for hyperlipidemia (Fig. 11) [18]. 

In reactions of chiral aldehydes, TiIV compounds work well as both activators and chelation control agents, a- or A-oxygcnated chiral aldehydes react with allylsilanes to afford chiral homoallylic alcohols with high selectivity (Scheme 22).85 These chiral alcohols are useful synthetic units for the synthesis of highly functionalized chiral compounds. Cyclic chiral 0,0- and A/O-acetals react with allylsilanes in the same way.86,87 Allenylsilanes have also been reported as allylation agents. 

In synthetic efforts toward the DNA reactive alkaloid naphthyridinomycin (164), Gamer and Ho (41) reported a series of studies into the constmction of the diazobicyclo[3.2.1]octane section. Constmction of the five-membered ring, by the photolytic conversion of an aziridine to an azomethine ylide and subsequent alkene 1,3-dipolar cycloaddition, was deemed the best synthetic tactic. Initial studies with menthol- and isonorborneol- tethered chiral dipolarophiles gave no facial selectivity in the adducts formed (42). However, utilizing Oppolzer s sultam as the chiral controlling unit led to a dramatic improvement. Treatment of ylide precursor 165 with the chiral dipolarophile 166 under photochemical conditions led to formation of the desired cycloadducts (Scheme 3.47). The reaction proceeded with an exo/endo ratio of only 2.4 1 however, the facial selectivity was good at >25 1 in favor of the desired re products. The products derived from si attack of the ylide... 

The synthetic method has several useful features beyond high stereoselectivity. A chiral CHX unit (X = Cl, Br) is inserted into the carbon-boron bond of a boronic ester, and the resulting chain-extended a-halo boronic ester is treated with a nucleophile Y- to displace the halide and form a chiral a-substituted boronic ester1-3. 

The chiral C5 synthetic block 45, the synthetic unit of dolicol, is prepared in the reaction sequence (42 - 45) in which the electrooxidative oxyselenation and the EGA catalysis are effectively employed Karahanaenone 51, an aroma constituent... 

Crown ethers have given impressive enantioselectivites in Michael additions (Chart 10.2). Purely synthetic chiral crowns are of limited use on large scale based on cost although, in general, the crowns are less susceptible to catalyst degradation and, therefore, have higher catalyst turnover numbers than the chiral quaternary ammonium salts. Of interest are crowns with symmetry, aza-crowns, and those with sugars or other chiral-pool units as sources of chirality (Charts 2 and 4). 

The efficiency and low relative environmental impact of the asymmetric chiral synthetic route to armodafinil (Scheme 7) is a significant process chemistry achievement by the Cephalon/Novasep team.34 It offers several advantages over the isomeric resolution processes The process begins with low-cost achiral raw materials and overall is a true catalytic process. Throughout the four-step process, only two intermediates are isolated, which not only saves operating costs and time but also simplifies the unit operation. From a process viewpoint, intermediates 25 and 10 are both liquids, and are therefore not ideal for purification. Thus, the formation of 25 and 10 must be carried out with sufficient control over purity to avoid additional purification steps. In this case, it appears that the process is sufficiently robust to use the intermediates on an as is basis and still produce the key intermediate 11 as a pure solid compound. In addition, the armodafinil isolated from the asymmetric oxidation is typically > 99% chemical purity and > 99.5% chiral purity, meeting the specification in every way for the API. 

Dimeric sapphyrins 5.138 and 5.139, containing chiral bridging units have also been synthesized. These were obtained by treating the activated form of the sapphyrin mono-acid 5.109 with a chiral diamine (i.e., 5.135 or 5.136 Figure 5.6.3). This afforded the corresponding sapphyrin dimers 5.138 and 5.139 in yields as high as 60% (Schemes 5.6.8 and 5.6.9). The cyclic sapphyrin dimer 5.140 was also prepared from the chiral diamine 5.137 and bis-acid sapphyrin 5.109. However, in this latter instance a stepwise synthetic approach was required. It involved reacting two equiva-... 

The synthesis of chiral dendrimers by using commercially available chiral core units is another attractive field of research in dendrimer chemistry. As Newkome et al.26 and Seebach et al.27 have shown, this is an efficient method for preparing such molecules. We tried to transfer our synthetic strategy, developed for oligoamines, to accommodate chiral core units. The commercially available enantiomers of 1,2-diphenyl-l,2-diaminoethane (74a and 74b) looked like optimal precursors for chiral dendrimers (Scheme 21). 

Fig. 1 Chiral C3 synthetic units microbial resolution of (R)- and (S)-DCP, (R)- and (S)-CPD and the corresponding epoxides.

Fig. 2 Concept for study and development of chiral C3 and C4 synthetic units.

A large number of chiral crowns have been prepared by numerous groups. The reader is directed to the tables at the end of this chapter to obtain an overview of these structures. It would not be useful to try to recount the synthetic approaches used in the preparation of all of these compounds we have chosen rather to subdivide this mass of compounds into three principal groups. The groups are (1) Cram s chiral binaphthyl systems (2) chiral crowns based on the tartaric acid unit and (3) crowns incorporating sugar subunits. These are discussed in turn, below. 

Chlorothricolide, the aglycon of the chlorothricin antibiotic, is a complex molecule containing an octahydronaphthalene unit. Roush and Sciotti [121] recently reported the total enantioselective synthesis of chlorothricolide. The multiple Diels-Alder reaction between poliene 130 and chiral dienophile (R)-131 was the key step in the synthetic process (Scheme 2.50). The interaction... 

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