Principles and Applications of Asymmetric Synthesis
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1.6 EXAMPLES OF SOME COMPLICATED COMPOUNDS |
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that two groups, led by K. C. Nicolaou in the Scripps Research Institute and by Robert Holton at Florida State University, had independently completed the total synthesis of TaxolTM. At present, the nucleus of TaxolTM can be obtained from the needles of the tree, and the C-13 side chain can be prepared on large scale.94
Several novel natural products with an intriguing system containing the cisendiyne moiety have attracted considerable attention from chemists in recent years. Several derivatives with this characteristic skeleton have now been isolated: neocarzinostatin,96 esperamicin,97 calicheamicin gI1,98 and dynemicin A1.99 The high antitumor activity of these compounds is based on an elegant
60 INTRODUCTION
Figure 1±32. Ring-closure reaction of endiyne anticancer antibiotics.
initiation of the ring-closure reaction illustrated in Figure 1±32. The resulting aromatic di-radical reacts with a nucleotide unit of DNA to cause chain cleavage and thus cause the antitumor activity of the compounds.100
The following compounds contain a great number of chiral centers that must be built up in asymmetric synthesis. They exemplify the signi®cance of asymmetric synthesis.
. Esperamicin A1101:
. Kedarcidin, a new chromoprotein antitumor antibiotic102:
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. Calicheamicin gI1103:
. Rapamycin,104 an antiproliferative agent:
FK-506 was isolated105 from Streptomyces trukubaensis, possessing a unique 21-membered macrolide, in particular an unusual a,b-diketoamide hemiketo system. It shows immunosuppressive activity superior to that of cyclosporin in the inhibition of delayed hypersensitivity response in a variety of allograft transplantation and autoimmunity models.
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62 INTRODUCTION
1.7 SOME COMMON DEFINITIONS IN ASYMMETRIC SYNTHESIS AND STEREOCHEMISTRY
In this chapter a number of common terms in the ®eld of stereochemistry have been introduced. These terms appear repeatedly throughout this book. Therefore, it is essential that we establish common de®nitions for these frequently used terms.
Asymmetric and dissymmetric compounds
Asymmetric: Lack of symmetry. Some asymmetric molecules may exist not only as enantiomers; they can exist as diastereomers as well.
Dissymmetric: Compounds lacking an alternating axis of symmetry and usually existing as enantiomers. Some people prefer this to the term asymmetric.
d/ l and d/l
d or l: Absolute con®gurations assigned to a molecule through experimental chemical correlation with the con®guration of d- or l- glyceraldehyde; often applied to amino acids and sugars, although (R) and (S) are preferred.
d or l: Dextrorotatory or levorotatory according to the experimentally determined rotation of the plane of monochromatic plane-polarized light to the right or left.
Diastereomer or diastereoisomer and enantiomer
Stereoisomer: Molecules consisting of the same types and same number of atoms with the same connections but di¨erent con®gurations.
Diastereoisomer: Stereoisomers with two or more chiral centers and where the molecules are not mirror images of one another, for example, d- erythrose and d-threose; often contracted to diastereomer.
Enantiomer: Two stereoisomers that are nonsuperimposable mirror images of each other.
Enantiomer excess
Enantiomer excess (ee): Percentage by which one enantiomer is in excess over the other in a mixture of the two, ee 1 j…E1 ÿ E2†=…E1 ‡ E2†j 100%.
Optical activity, optical isomer, and optical purity
Optical activity: Experimentally observed rotation of the plane of monochromatic plane-polarized light to the observer's right or left. Optical activity can be observed with a polarimeter.
Optical isomer: Synonym for enantiomer, now disfavored, because most enantiomers lack optical activity at some wavelengths of light.
Optical purity: The optical purity of a sample is expressed as the magnitudes of its optical rotation as a percentage of that of its pure enantiomer (which has maximum rotation).
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Racemic, meso, and racemization
Racemic: Compounds existing as a racemate, or a 50±50 mixture of two enantiomers; also denoted as dl or …G†. Racemates are also called racemic mixtures.
Meso compounds: Compounds whose molecules not only have two or more centers of dissymmetry but also have plane(s) of symmetry. They do not exist as enantiomers, for example, meso-tartaric acid:
Racemization: The process of converting one enantiomer to a 50±50 mixture of the two.
Scalemic: Compounds existing as a mixture of two enantiomers in which one is in excess. The term was coined in recognition of the fact that most syntheses or resolutions do not yield 100% of one enantiomer.
Prochirality: Refers to the existence of stereoheterotopic ligands or faces in a molecule that, upon appropriate replacement of one such ligand or addition to one such face in an achiral precursor, gives rise to chiral products.
Pro-R and Pro-S: Refer to heterotopic ligands present in the system. It is arbitrarily assumed that the ligand to be introduced has the highest priority, and replacement of a given ligand by this newly introduced ligand creates a new chiral center. If the newly created chiral center has the (R)- con®guration, that ligand is referred to as pro-R; while pro-S refers to the ligand replacement that creates an (S)-con®guration. For example, as shown in Figure 1±33, HA in ethanol is pro-R and HB in the molecule is pro-S.
Figure 1±33. Prochiral ligands.
64 INTRODUCTION
Re and Si: Labels used in stereochemical descriptions of heterotopic faces. If the CIP priority of the three ligands a, b, and c is assigned as a > b > c, the face that is oriented clockwise toward the viewer is called Re, while the face with a counterclockwise orientation of a ! b ! c is called Si, as shown in Figure 1±34:
Figure 1±34. Prochiral faces.
Syn/anti and Erythro/threo
Syn/anti: Pre®xes that describe the relative positions of substituents with respect to the de®ned plane of a ring: syn for the same side and anti for the opposite side (Fig. 1±35).
Figure 1±35. Syn/anti and Erythro/threo.
Erythro/threo: Terms derived from carbohydrate nomenclature used to describe the relative con®guration at adjacent stereocenters. Erythro refers to a con®guration with identical or similar substituents on the same side of the vertical chain in Fischer projection. Conversely, a threo isomer has these substituents on opposite sides. These terms came from the nomenclature of two carbohydrate compounds, threose and erythrose (see Fig. 1±35).
This chapter has provided a general introduction to stereochemistry, the nomenclature for chiral systems, the determination of enantiomer composition and the determination of absolute con®guration. As the focus of this volume is asymmetric synthesis, the coming chapters provide details of the asymmetric syntheses of di¨erent chiral molecules.
1.8 REFERENCES 65
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