Chiral pool synthesis

Dutton reported on the synthesis of an e-caprolactam analog of an anthelmintic cyclic peptide. The a-hydroxy-e-caprolactam 44 was generated in an ex chiral pool synthesis staring from malic acid. The a-hydroxy carboxylic acid unit was protected as a dioxolanone in 43. The protective group served simultaneously as the reactive function during cyclization lactam 44 formation succeeded by ring opening of the dioxolanone 43 by the nucleophilic attack of the amino function, Eq. (8) [14]. 

The enantioselective ex-chiral-pool synthesis of the enantiomer of the natural (-i-)-dolasta-l(15),7,9-trien-14-ol (ent-122) was achieved by Mehta and coworkers in 1987 (Scheme 24) [85, 86]. From the hydroazulene 136, the synthesis proceeded analogous to the synthesis of Pattenden (Scheme 20) and provided the dolastane ent-122 as a mixture with the non-natural dolas-tanes 153 and 154. However, in contrast to Pattenden s work, Mehta and... 

In the case of diastereomeric mixtures of chiral hydroperoxides, standard chromatography on achiral phase can be employed to separate the diastereomers. As one example for the preparation of optically pure hydroperoxides via this method, the ex-chiral pool synthesis of the pinane hydroperoxides 11 is presented by Hamann and coworkers . From (15 )-cw-pinane [(15 )-cw-10], two optically active pinane-2-hydroperoxides cA-lla and trans-llb were obtained by autoxidation according to Scheme 17. Autoxidation of (IR)-c -pinane [(17 )-cw-10] led to the formation of the two enantiomers ent-lla and ent-llh. The ratio of cis to trans products was 4/1. The diastereomers could be separated by flash chromatography to give optically pure compounds. 

Synthetic transformation of an enantiomerically pure compound into the target compound without a step causing racemization. If the starting material is a readily accessible natural product the term ex-chiral-pool synthesis, which was introduced by Seebach and Kalinowski3, is used (see Section A.2). 

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. 

Although these definitions are vague, it appears that partial synthesis is restricted to those modifications which do not change the basic chemical structure, whereas ex-chiral-pool synthesis generally leads to a new type of compound. For instance, the introduction of new substituents into a steroid nucleus is partial synthesis , whereas the conversion of D-glucose into the pheromone e.vo-brevicomin is ex-chiral-pool synthesis . 

Another contentious issue is how far the term ex-chiral-pool synthesis should be extended. Some researchers use it for any synthesis starting from an optically active natural product. However, in the original meaning, ex-chiral-pool synthesis is defined in the sense that only stereo-unambiguous operations must be performed on the substrate. Thus, all diastereoselec-tive processes (as discussed in Section 2.3.2.) are excluded. 

In its strictest definition ex-chiral-pool synthesis" requires that... 

To demonstrate the problems associated with ex-chiral-pool syntheses, some typical examples are given in this section. Three start with n-glucose, which is by far the most popular substrate in ex-chiral-pool synthesis, and illustrate the key transformations, in the first example, D-glu-cose is transformed into the mannosidase inhibitor iV-acetyl-4-deoxymannosamine by 4-deoxygenation and a SN2 displacement reaction of nitrogen introducing an amino function in place of a 2-hydroxy function 5. 

The potential of regioselective epoxide opening is shown in the ex-chiral-pool synthesis of thromboxane B2 from levoglucosan via epoxide opening as the key step. 

Therefore, (S)-3-hydroxy-2-methylpropanoic acid (1) is preferred over the structurally similar citronellol derivatives which have more, but often superfluous, carbon atoms and which are optically impure (ee values of 80%). Application of ent-2 in ex-chiral-pool synthesis is demonstrated in the preparation of ac-tocopherol (vitamin E)14. 

Reviews on Ex-Chiral-Pool Synthesis A Vasel-la. Mod. Synth. Methods 1980. 1. 

Ex-chiral-pool synthesis is seldomly applied, one case being the production of ascorbic acid (4) from D-glucose according to Reichstein2. 

Correction of a CD-based erroneous configurational assignment of (+)-cryptosporin (see Section 4.3.4.1.1., p432) through a chiral-pool synthesis commencing from L-fucosal184. 

There are many problems associated with carrying out asymmetric synthesis at scale. Many asymmetric transformations reported in the literature use the technique of low temperature to allow differentiation of the two possible diastereoisomeric reaction pathways. In some cases, the temperature requirements to see good asymmetric induction can be as low as -100°C. To obtain this temperature in a reactor is costly in terms of cooling and also presents problems associated with materials of construction and the removal of heat associated with the exotherm of the reaction itself. It is comforting to see that many asymmetric catalytic reactions do not require the use of low temperature. However, the small number of robust reactions often leads development chemists to resort to a few tried and tested approaches, namely chiral pool synthesis, use of a chiral auxiliary, or resolution. In addition, the scope and limitations associated with the use of a chiral catalyst often result in a less than optimal sequence either because the catalyst does not work well on the necessary substrate or the preparation of that substrate is long and costly. Thus, the availability of a number of different approaches helps to minimize these problems (Chapter 2). 

Valsartan (22) is an orally active, angiotensin II antagonist that is marketed under the name Diovan by Novartis for hypertension. Novartis has also developed a combination therapy, valsartan plus hydrochlorothiazide, for the second-line therapy of hypertension. The synthesis is straightforward from a stereochemical viewpoint because a chiral pool synthesis is used. The stereogenic center is derived from L-valine (Scheme 31.17).220 223... 

Most asymmetric syntheses require rather more than one or two steps from chiral pool constituents. Male bark beetles of the genus Ips produce a pheromone that is a mixture of several enantiomerically pure compounds. One is a simple diene alcohol (S)-(-)-ipsenol. Japanese chemists in the 1970s noted the similarity of part of the structure of ipsenol (in black) to the widely available amino acid (S)-leucine and decided to exploit this in a chiral pool synthesis, using the stereogenic centre (green ring) of leucine to provide the stereogenic centre of ipsenol. 

The obvious approach for chiral synthesis would be to find a chiral starting material, such as a natural amino acid, carbohydrates, carboxylic acids or terpene. The major source of these chiral starting materials sometimes called chirons is nature itself. The synthesis of a complex enantiopure chemical compound from a readily available enantiopure substance such as natural amino acids is known as chiral pool synthesis. For example, chiral lithium amides 1.39 that are used for several types of enantioselective asymmetric syntheses can be prepared in both enantiomeric forms starting from the corresponding optically active amino acids, and these are often available commercially. 

However, chiral pool synthesis is restricted by the number of possible starting enantiomeric pure compounds and requires a stoichiometric amount of the starting material, which may be scarce and expensive. 

A simple heterocyclic acid needed for an anti-HIV drug A chiral pool synthesis from aspartic acid Choosing a new reaction to solve the stereochemistry problem Making the new reaction asymmetric Part III - Grandisol and Some Bicyclo[3.2.0]Heptan-2-Ols A bicyclic insect attractant used in agriculture Chiral Pool Syntheses from Other Terpenes An attempt from linalool... 

A chiral pool synthesis of lactacystin from glucose... 

A chiral pool synthesis from aspartic acid... 

Though (25,47 )-4-hydroxy pipecolic acid 17 is a natural product it cannot be obtained in sufficient quantity from nature. A chiral pool synthesis from aspartic acid 19 is known involving... 

In 1992 Yoda et al. reported an ex-chiral pool synthesis of butyrolactones starting from Z-malic acid (16) [44] and applied their methodology to the... 

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