Chiral forms

Biological systems depend on specific detailed recognition of molecules that distinguish between chiral forms. The translation machinery for protein synthesis has evolved to utilize only one of the chiral forms of amino acids, the L-form. All amino acids that occur in proteins therefore have the L-form. There is, however, no obvious reason why the L-form was chosen during evolution and not the D-form... 

Forskolin is an activator of the enzyme adenylate cyclase which has therapeutic utility. Outlined below are stereocontrolled routes to racemic and natural chiral forms of forskolin derived by multistrategic retrosynthedc analysis. 

A new generation coordination catalysts are metallocenes. The chiral form of metallocene produces isotactic polypropylene, whereas the achiral form produces atactic polypropylene. As the ligands rotate, the catalyst produces alternating blocks of isotactic and atactic polymer much like a miniature sewing machine which switches back and forth between two different kinds of stitches. 

Cyclic dithioketals and acetals represent another important class of sulfur containing chiral auxiliaries, which are available in chiral form by biooxidation. Biotransformations were performed on a preparative scale using whole-cells (wild type and recombinant) and isolated enzyme. Again, enantiocomplementary oxidation of unsubstituted dithianes (linear and cyclic, R = H) was observed when using and CPMOcomo (Scheme 9.28) [211,212]. Oxygenation of functionalized substrates (R = substituted alkyl) with gave preferably trans... 

The second report from La Jolla attempts to cast some light on the question of the homochirality of biomolecules (see Sect. 9.4). Put simply, the question is why only one of the two possible chiral forms is always found in some important classes of biomolecules. 

Structure of the chiral poly-Schiff base [14] has been studied by NMR spectroscopy.29 It was shown that poly-Schiff bases have an interesting feature their chiral forms can be self-assembled into nanometer-size fibrous architecture, while their racemic analogues did not show any self-assembling properties. 

The main result of three papers respectively by Holland and Miller [91] and by Chau and Geil [96,97] is that the polymorph which results in crystallization at or close to r.t. of solutions of iPBl depends on the maximum temperature reached by the solutions (TMs), or, more precisely, on the temperature at which the solution has been equilibrated last, irrespective of the polymorph of the initial crystals. For example if samples of any of the three crystal forms are dissolved at concentrations of 0.01-0.03% in amyl acetate (clearing point 65 °C) and brought to Tms of 90 °C, kept there for 3 to 48 hours (ts) and then crystallized at temperatures (Tx) between 24 and 50 °C, then 100% form I crystals are obtained. With the same procedure but using a Tms of 120 °C, 100% of the chiral form III crystallizes. For shorter values... 

Amino acids are the building blocks of protein. Except for glycine, all amino acids come into two different chiral forms, laevorotatory (L) and dextrorotatory (D) these forms are called enantiomers. In living organisms, the amino acids in protein are almost exclusively... 

L and the D/L ratio approaches zero. After the death of the living organism, proteins start to spontaneously break down. An inter-conversion of the amino acids occurs from one chiral form (L) to a mixture of D- and L- forms following protein degradation this process is called amino acid racemisation. The extent of racemisation is measured by the ratio of D/L isomers and increases as a function of time and temperature. The longer the racemisation process continues the closer to 1 the ratio between the D- and L-forms becomes. If the D/L ratio is <1 it may be possible to use it to estimate age. The D/L ratio of aspartic acid and isoleucine are the most widely used for this dating technique [104]. Dates have been obtained as old as 200 000 years. However, it has been used mainly to date samples in the 5000 100 000 year range. Recent studies [ 105] mention an estimation of the method accuracy to be around 20%. 

The structure of carbon nanotubes depends upon the orientation of the hexagons in the cylinder with respect to the tubule axis. The limiting orientations are zigzag and arm chair forms, Fig. 8B. In between there are a number of chiral forms in which the carbon hexagons are oriented along a screw axis, Fig. 8B. The formal topology of these nanotube structures has been described [89]. Carbon nanotubes have attracted a lot of interest because they are essentially onedimensional periodic structures with electronic properties (metallic or semiconducting) that depend upon their diameter and chirality [90,91]. (Note. After this section was written a book devoted to carbon nanotubes has been published [92], see also [58].)... 

The structure of this compound is very close to 148 the chiral form Z)2. 

As shown in Scheme 8-11, nucleophilic entry from the a-face (24a) may be hindered by the sterically bulky substituent R2 on the oxazoline moiety therefore entry from the / -face 24/ predominates. Free rotation of the magnesium methoxy bromide may be responsible for the sense of the axial chirality formed in the biaryl product. If the azaenolate intermediate 25 is re-aromatized with a 2 -methoxy substituent complexed to Mg, (iS )-biphenyl product is obtained. Upon re-aromatization of azaenolate 25B, (R)-product is obtained. 

One application in liquid chromatography which does alter the separation process is the use of a specific series of derivatives to enable the separation of chiral (optical isomers) forms of alcohols, amines and amino acids using reverse-phase separation. FLEC is available in the two chiral forms (+)-l-(9-fluorenyl) ethyl chloroformate and (—)-l-(9-fluorenyl) ethyl chlorofor-mate (Figure 3.12). Reaction of two stereoisomers of a test compound (e.g. T+ and T—) with a single isomer of the derivatizing reagent (e.g. R+) will result in the formation of two types of product, T+R+ and T—R+. It is possible to separate these two compounds by reverse-phase chromatography. 

Another mechanism of chiral amplification that extends over an even larger scale has been reported by Huck et al. [119] The molecule 12-(9 H-thioxantbene-9 -yli-dene-12H-benzo[a]xanthene (Fig. 11.6), which has no chiral center, nevertheless exists, like the helicenes, in two chiral forms defined by their enantiomeric configurations. Consistent with the discussion in Section 11.2.3, a small net handedness (ca. 0.7 %) could be induced in racemic solutions of this molecule by use of ultraviolet CPL. However, introducing 20 wt% of this molecule, which contained a 1.5% chiral excess of one roto-enantiomer, into a nematic phase of liquid crystals produced macroscopic (100 pm) regions of a chiral cholesteric liquid crystal phase. The... 

Fig. 11.6 Conversion of one enantiomer to the other by CPL. The molecule 12-(9 H-thioxan-thene-9 -ylidene)-l 2H-benzo[a]xanthene exists in one of two chiral forms that can be intercon-...

Scheme 21 Syntheses of racemic and chiral forms of the lactol pheromone of Biprorulus bibax [111]...

A stereoselective intramolecular aldol reaction of thiazolidinecarboxylate (39) proceeds with retention of configuration to give fused heterocycles (40a,b separable) and (41), the product of a retroaldol-acylation reaction. The selectivity is suggested to be directed by self-induced axial chirality, in which the enolate generated in the reaction has a stereochemical memory, being generated in an axially chiral form (42). The retroaldol step also exemplifies a stereoretentive protonation of an enolate. 

Some chiral compounds exhibit a different crystal structure for each pure enantiomer and their mixture the difference can be used to distinguish them. Again, the use of cascading libraries allows pure compounds to be distinguished from compounds contaminated with relatively small amounts of the other chiral forms. 

Hoveyda et al. reported a novel method for synthesizing of chromene 71 by ROM-RCM of cycloalkene 70 bearing the phenyl ether at the 3-position [Eq. (6.48)]." ° The yield is improved when the reaction is carried out under ethylene gas. In the case of cyclopentene 70a (n = 0) or cyclohexene 70b (n = 1), the yield is poor because the starting cycloalkene is in a state of equihbrium with the product and a thermodynamic product should be formed under these reaction conditions. They obtained enantiomeric ally pure cycloheptene derivative (5)-70e using zirconium-catalyzed kinetic resolution of 70e developed by their group, and chromene 71c was synthesized as a chiral form via ROM-RCM using lb [Eq. (6.49)] ... 

Spent 2,2,6,6-tetramethyl-l-oxopiperidinium can be regenerated directly at a platinum anode in aqueous acetonitrile and aldehyde products do not undergo further oxidation to the carboxylic acid [37]. Either of the two racemic quinolyl-l-oxyls 4 functions better as catalyst for the oxidation of primaiy and secondary al-kanols, but the chiral forms do not achieve selective oxidation of one enantiomer of... 

It may also be the case that the pharmacodynamic effect of a drug is exerted by both the parent compound and its metabolite(s), which implies that both should be included in the PK-PD model. Also, a drug may exist in two chiral forms with different kinetic and dynamic characteristics. 

Figure 3.8 The two enantiomers of a-aminoacids. Here we follow the classic nomenclature of l- and D-aminoacids for indicating the two chiral forms. In terms of the S, R nomenclature, L-aminoacids correspond to the S absolute configuration -except for cystein, which is R.

The dibasic side chain at position 7 can be alternatively provided by a substituted amino alkyl pyrrolidine. Preparation of that diamine in chiral form starts with the extension of the ester function in pyrrolidone (46-1) by aldol condensation with ethyl acetate (46-2). Acid hydrolysis of the (3-ketoester leads to the free acid that then decarboxylates to form an acetyl group (46-3). The carbonyl group is next converted to an amine by sequential reaction with hydroxylamine to form the oxime, followed by catalytic hydrogenation. The desired isomer (46-4) is then separated... 

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