Perspectives On The Use Of Stereochemically Pure Drugs

13. FDA Perspective on the Development of New Stereoisomeric Drugs: Chemistry, Manufacturing, and Control Issues 365 Wilson H. De Camp

14. Stereochemical^ Pure Drugs: An Overview 375 Fakhreddin Jamali

15. Stereoisomeric Drugs in Therapeutics: Clinical Perspectives 385 Darrell R. Abernethy and Habil S. Andrawis

16. Development of Stereoisomeric Drugs: An Industrial Perspective 399 Mitchell N. Cayen

Index 411

Contributors

Darreil R. Ab erne thy, Ph.D., M.D. Professor of Medicine and Director, Program in Clinical Pharmacology, Brown University School of Medicine, Providence, Rhode Island

Nabil S. Andrawis, Ph.D., M.D. Research Associate, Program in Clinical Pharmacology, Brown University School of Medicine, Providence, Rhode Island

Mitchell N. Cayen, Ph.D. Senior Director, Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenil-worth, New Jersey

C. Edgar Cook, Ph.D. Research Triangle Institute, Research Triangle Park, North Carolina

Wilson H. De Camp, Ph.D. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland

Dennis E. Drayer, Ph.D.* Cornell University Medical College, New York, New York

Joseph Gal, Ph.D. Professor, Department of Medicine, Division of Clinical Pharmacology, University of Colorado School of Medicine, Denver, Colorado

Kathleen M. Giacomini, Ph.D. Professor, Department of Pharmacy, University of California, San Francisco, San Francisco, California

Fakhreddin Jamali, Ph.D. Professor, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada

Wilfried A. König, Ph.D. Professor, Institute für Organische Chemie, Unviersität Hamburg, Hamburg, Germany

Present affiliation;

'Group Leader, Bioanalytical Development, American Cyanamid Company, Pearl River, New York

James A. Longstreth, Ph.D. Director of Pharmacokinetics, Corporate Drug Development, Corporate Medical & Scientific Affairs, G. D. Searle & Co., Skokie, Illinois

Alice A. Marcotte Food and Drug Administration, Washington, D.C.

Terence A. G. Noctor, Ph.D.* Department of Oncology, McGill University, Montreal, Quebec, Canada

Ronda }. Ott, Ph.D. Postdoctoral Fellow, Department of Pharmacy, University of California, San Francisco, San Francisco, California

John W. Scott, Ph.D. Director, Vitamins Research and Development, Hoffmann-La Roche, Inc., Nutley, New Jersey

David I. Stirling, Ph.D. Vice President, New Technology, Celgene Corporation, Warren, New Jersey

Johan M. te Koppele, Ph.D. TNO-Institute of Aging and Vascular Research, Leiden, The Netherlands

Nico P. E. Vermeulen, Ph.D. Division of Molecular Toxicology, Department of Pharmacochemistry, Free University, Amsterdam, The Netherlands

Irving W. Wainer, Ph.D. Pharmacokinetics Division, Department of Oncology, McGill University and Montreal General Hospital, Montreal, Quebec, Canada

Present affiliation;.

"School of Health Sciences, University of Sunderland, Sunderland, England

Drug Stereochemistry

This Page Intentionally Left Blank

The Early History of Stereochemistry

From the Discovery of Molecular Asymmetry and the First Resolution of a Racemate by Pasteur to the Asymmetrical Chiral Carbon of van't Hoff and Le Bel

Dennis E. Drayer* Cornell University Medical College, New York, New York

The first half of the nineteenth century was the great age of geometrical optics. Several French scientists studied diffraction, interference, and polarization of light. In particular, linear polarization of light and rotation of the plane of polarization very quickly attracted attention because of the possible relationship between these phenomena and the structure of matter. Optical activity, the ability of a substance to rotate the plane of polarization of light, was discovered in 1815 at the College de France by the physicist Jean-Baptiste Biot. In 1848 at the Ecole Normale in Paris, Louis Pasteur (Fig. 1) made a set of observations that led him a few years later to make this proposal, which is the foundation of stereochemistry: Optical activity of organic solutions is determined by molecular asymmetry, which produces nonsuperimposable mirror-image structures. A logical extension of this idea occurred in 1874 when a theory of organic structure in three dimensions was advanced independently and almost simultaneously by Jacobus Henricus van't Hoff (Fig, 2) in Holland, and Joseph Achille Le Bel (Fig, 3) in France. By this time it was known from the work of Kekule in 1858 that carbon is tetravalent (links up with four other groups or

'Present affiliation-, American Cyanamid Company, Pearl River, New York,

FlGURE 2 van't Hoff. [From Zeitschrift Für Physikalische Chemie, 31 (1899).]

atoms), van't Hoff and Le Bel proposed that the four valances of the carbon atom were not planar, but directed into three-dimensional space, van't Hoff specifically proposed that the spatial arrangement was tetrahedral. A compound containing a carbon substituted with four different groups, which van't Hoff defined as an asymmetric carbon (asymtnetrisch koolstof-atoom), would therefore be capable of existing in two distinctly different nonsuperimposabie forms. The asymmetric carbon atom, they proposed, was the cause of molecular asymmetry and therefore optical activity.

John Little Thompson Pic
Figure 3 Le Be!. [From Snelders (18).]

The purpose of this chapter is to describe the observations and reasoning that led Pasteur, van't Hoff, and Le Bel to make these epochal discoveries. In several instances the protagonists will speak for themselves. More detailed accounts of their work are presented in Weyei (1), Partington (2), and Riddell and Robinson (3). Also, the three methods discovered by Pasteur to resolve for the first time an optically inactive racemate into its optically active components (enantiomers) will be discussed. To truly appreciate the contributions of these three chemists, one should remember that during their time even the existence of atoms and molecules was questioned openly by many scientists, and to ascribe shape to what seemed like metaphysical concepts was too much for many of their contemporaries to accept.

Ordinary tartaric acid has been known since the eighteenth century and is a by-product of alcoholic fermentation obtained in great quantities from the tartar deposited in the barrels. This acid has been especially important in medicine and dyeing. Paratartaric acid (also called racemic acid), discovered in certain industrial processes in the Alsace region of France, came to the attention of chemists only in the 1820s, when Gay-Lussac established that it possessed the same chemical composition as ordinary tartaric acid. Because of their importance for the emerging concept of isomerism, the two acids thereafter attracted considerable notice. On January 20 and February 3, 1860, Pasteur gave lectures before the Council of the Société Chimique of Paris describing the principal results of his research {done from 1848-1850} on tartaric acid and paratartaric acid, from which evolved his proposals on the molecular asymmetry of organic products. The excerpts below are taken, with permission, from an English translation made by the Alembic Club (4). An English translation is also found in Pasteur (5). Additional insight is found in Mauskopf (6). The headings and interspersed comments below are mine. To better understand what follows, ordinary tartaric acid is now called dextro-tartaric acid and paratartaric acid is the racemate, d,/-tartaric acid,

I. HEMIHEDRAL CRYSTAL STRUCTURE

Pasteur begins his first lecture by discussing the precedents that led up to his research and then defines hemihedral crystals. These are cubical crystals with four little facets inclined at the same angle to the adjacent surfaces and arranged alternately so the same edge of the cube does not contain two facets (Fig. 4). Under these conditions, no point or plane of symmetry exists in the cube,

II. MOLECULAR ASYMMETRY AND OPTICAL ACTIVITY

Pasteur now describes the research that led to his conclusion about the causal relationship between molecular asymmetry and optical activity.

When 1 began to devote myself to special work, I sought to strengthen myself in the knowledge of crystals, foreseeing the help that I should draw from this in my chemical researches. It seemed to me to be the simplest

course, to take, as a guide, some rather extensive work on the crystalline forms; to repeat all the measurements, and to compare my determinations with those of the author. In 1841, M. de la Provostaye, whose accuracy is well known, had published a beautiful piece of work on the crystalline forms of tartaric and paratartaric acids and their salts. I made a study of this memoir. I crystallized tartaric acid and its salts, and investigated the forms of the crystals. But, as the work proceeded, I noticed that a very interesting fact had escaped the learned physicist. All the tartrates which I examined gave undoubted evidence of hemihedral faces.

This peculiarity in the forms of the tartrates was not very obvious. This will be readily conceived, seeing that it had not been observed before. But when, in a species, its presence was doubtful, I always succeeded in making it manifest by repeating the crystallisation and slightly modifying the conditions.

The German chemist Eilhard Mitscherlich published a note in 1844 in the Reports of the Academy of Science on the subject of the tartrate and paratartrate of sodium and ammonia. The importance of this note is now acknowledged by Pasteur,

I must first place before you a very remarkable note by Mitscherlich which was communicated to the Arademie des Sciettces by Biot. It was as follows:— "The double paratartrate and the double tartrate of soda and ammonia have the same chemical composition, the same crystalline form with the same angies, the same specific weight, the same double refraction, and consequently the same inclination in their optical axes. When dissolved in water their refraction is the same. But the dissolved tartrate deviates the plane of polarisation, while the paratartrate is indifferent, as has been found by M. Biot for the whole series of those two kinds of salts. Yet," adds Mitscherlich, "here the nature and the number of the atoms, their arrangement and distances, are the same in the two substances compared."

This note of Mitscherlich's attracted my attention forcibly at the time of publication. I was then a pupil in the Ecole Normale, reflecting in my leisure moments on these elegant investigations of the molecular constitution of substances, and having reached, as I thought at least, a thorough comprehension of the principles generally accepted by physicists and chemists. The above note disturbed al! my ideas. What precision in every detail! Did two substances exist which had been more fully studied and more carefully compared as regards their properties? But how, in the existing condition of the science, could one conceive of two substances so closely alike without being identical? Mitscherlich himself tells us what was, to his mind, the consequence of this similarity:

The nature, the number, the arrangement, and the distance of the atoms are the same. If this is the case what becomes of the definition of chemical species, so rigorous, so remarkable for the time at which it appeared, given by Chevreul in 1823? In compound bodies a species is a collection of individuals identical in the nature, the proportion, and the arrangement of their elements.

In short, Mitscherlich's note remained in my mind as a difficulty of the first order in our mode of regarding material substances.

You will now understand why, being preoccupied, for the reasons already given, with a possible relation between the hemihedry of the tartrates and their rotative property, Mitscherlich's note of 1844 should recur to my memory, 1 thought at once that Mitscherlich was mistaken on one point. He had not observed that his double tartrate was hemihedral while his paratartrate was not. If this is so, the results in his note are no longer estraordinary; and further, I should have, in this, the best test of my preconceived idea as to the inter-relation of hemihedry and the rotatory phenomenon.

I hastened therefore to re-investigate the crystalline form of Mitscherlich's two salts. I found, as a matter of fact, that the tartrate was hemihedral, like all the other tartrates which I had previously studied, but, strange to say, the paratrate was hemihedral also. Only, the hemihedral faces which in the tartrate were all turned the same way were in the paratartrate inclined sometimes to the right and sometimes to the left. In spite of the unexpected character of this result, I continued to follow up my idea. 1 carefully separated the crystals which were hemihedral to the right from those hemihedral to the left, and examined their solutions separately in the polarising apparatus. I then saw with no less surprise than pleasure that the crystals hemihedral to the right deviated the plane of polarisation to the right, and that those hemihedral to the left deviated it to the left (here Fig, 5); and when I took an equal weight of each of the two kinds of crystals, the mixed solution was indifferent towards the light in consequence of the neutralisation of the two equal and opposite individual deviations.

Thus, I start with paratartaric acid; I obtain in the usual way the double paratartrate of soda and ammonia; and the solution of this deposit, after some days, crystals all possessing exactly the same angles and the same aspect. To such a degree in this case that Mitscherlich, the celebrated crystallographer, in spite of the most minute and severe study possible, was not able to recognise the smallest difference. And yet the molecular arrangement in one set is entirely different from that in the other. The rotatory power proves this, as does also the mode of asymmetry of the crystals. The two kinds of crystals are isomorphous, and isomorphous with the corresponding tartrate. But the isomorphism presents itself with a hitherto unobserved peculiarity; it is the isomorphism of an asymmetric crystal with its mirror image. This comparison expresses the fact very exactly. Indeed, if, in a crystal of each kind, imagine the hemihedral facets produced till they meet, I obtain two symmetrical tetrahedra, inverse, and which cannot be superposed, in spite of the perfect identity of all their respective parts. From this I was justified in concluding that, by crystallisation of the double paratartrate of soda and ammonia, I had separated two symmetrically isomorphous atomic groups, which are intimately united in paratartaric acid. Nothing is easier to show than that these two species of crystals represent two distinct salts from which two different acids can be extracted.

The announcement of the above facts naturally placed me in communication with Biot, who was not without doubts regarding their accuracy. Being charged with giving an account of them to the Academy, he made me come to him and repeat before his eyes the decisive experiment. He handed over to me some paratartaric acid which he had himself previously studied with particular care, and which he had found to be perfectly indifferent to polarised light, I prepared the double salt in his presence, with soda and ammonia which he had likewise desired to provide. The liquid was set aside for slow evaporation in one of his rooms. When it had furnished about 30 to 40 grams of crystals, he asked me to call at the College de France in order to collect them and isolate them before him, by recognition of their crystallography character, the right and the left crystals, requesting me to state once more whether I really affirmed that the crystals which I should place at his right would deviate to the right, and the others to the left. This done, he told me that he would undertake the rest. He prepared the solutions with carefully measured quantities, and when ready to examine them in the polarising apparatus, he once more invited me to come into his room. He first placed in the apparatus the more interesting solution, that which ought to deviate to the left. Without even making a measurement, he saw by the appearance of the tints of the two images, ordinary and extraordinary, in the analyser, that there was a strong deviation to the left. Then, very visibly affected, the illustrious old man took me by the arm and said:

"My dear child, I have loved science so much throughout my life that this makes my heart throb."

Indeed there is more here than personal reminiscences. In Biofs case the emotion of the scientific man was mingled with the personal pleasure of seeing his conjectures realized. For more than thirty years Biot had striven in vain to induce chemists to share his conviction that the study of rotatory polarisation offered one of the surest means of gaining a knowledge of the molecular constitution of substances.

Let us return to the two acids furnished by the two sorts of crystals deposited in so unexpected a manner in the crystallisation of the double paratartrate of soda and ammonia. I have already remarked that nothing could be more interesting than the investigation of these acids.

One of them, that which comes from crystals of the double salt herni-hedral to the right, deviates to the right, and is identical with ordinary tartaric acid. The other deviates to the left, like the salt which furnishes it. The deviation of the plane of polarisation produced by these two adds is rigorously the same in absolute value. The right acid follows special laws in its deviation, which no other active substance had exhibited. The left acid exhibits them, in the opposite sense, in the most faithful manner, leaving no suspicion of the slightest difference.

The paratartaric acid is really the combination, equivalent for equivalent, of these two acids, ts proved by the fact that, if somewhat concentrated solutions of equal weights of each of them are mixed, as I shall do before you, their combination takes place with disengagement of heat, and the liquid solidifies immediately on account of the abundant crystallisation of paratar-

FlGURE 5 Paratarate of soda and ammonia formed by an equal mixture of hemihedral crystals of levo-tartrate (on left) and d ex tro-tartrate (on right). The anterior hemihedral facet "h" is on the left side of the observer in the levo-tartrate and on his or her right in the dextro-tartrate. [From Descour (17).]

taric acid, identical with the natural product. (This beautiful experiment called forth applause from the audience.)

Pasteur ends the first lecture with the following summary:

1). When the elementary atoms of organic products are grouped asymmetrically, the crystalline form of the substance manifests this molecular asymmetry in nonsuperposable hemihedry.

The cause of this hemihedry is thus recognised.

2). The existence of this same molecular asymmetry betrays itself, in addition, by the optica! rotative property.

The cause of rotatory polarisation is likewise determined.

3). When the non-superposable molecular asymmetry is realised in opposite senses, as happens in the right and left tartaric acids and all their derivatives, the chemical properties of these identical and inverse substances are rigorously the same.

In the second lecture, Pasteur gives a further discussion of his fundamental idea that optical activity of organic solutions is related to molecular geometry This insight was far ahead of the organic structural theory of the time.

We saw in the last lecture that quartz possesses the two characteristics of asymmetry—hemihedry in form, observed by Hauy, and the rotative phenomenon discovered by Arago! Nevertheless, molecular asymmetry is entirely absent in quartz. To understand this, let us take a further step in the knowledge of the phenomena with which we are dealing. We shall find in it, besides, the explanation of the analogies and differences already pointed out between quartz and natural organic products.

Permit me to illustrate roughly, although with essential accuracy, the structure of quartz and of the natural organic products. Imagine a spiral stair whose steps are cubes, or any other objects with superposable images. Destroy the stair and the asymmetry will have vanished. The asymmetry of the stair was simply the result of the mode of arrangement of the component steps. Such is quartz. The crystal of quartz is the stair complete. It is hemihedral. It acts on polarised light in virtue of this. But let the crystal be dissolved, fused, or have its physical structure destroyed in any way whatever; its asymmetry is suppressed and with it all action on polarised light, as it would be, for example, with a solution of alum, a liquid formed of molecules of cubic structure distributed without order.

Imagine, on the other hand, the same spiral stair to be constructed with irregular tetrahedra for steps. Destroy the stair and the asymmetry will still exist, since it is a question of a collection of tetrahedra. They may occupy any positions whatsoever, yet each of them will nonetheless have an asymmetry of its own. Such are the organic substances in which all the molecules have an asymmetry of their own, betraying itself in the form of the crystal. When the crystal is destroyed by solution, there results a liquid active towards polarised light, because it is formed of molecules, without arrangement, it is true, but each having an asymmetry in the same sense, if not of the same intensity in all directions.

Was this article helpful?

0 0
Natural Treatments For Dandruff

Natural Treatments For Dandruff

Stop Your Scalp From Snowing! Finally... A Real Cure for Dandruff! No medication! No weird cures! No messy creams, smelly solutions or strange diets! Are you sick to death of being sold products that could make the problem worse? Are you sick of the shampoos and conditioners that make your head smell like sulphur? If so then try a permanent revolutionary treatment for dandruff!

Get My Free Ebook


Post a comment