sis devised by the U.S.S.R.'s Dr. S. N. Ananchenko and Dr. I. V. Torgov, Institute of Organic Chemistry, Moscow. By using 2-ethylcyclopentane-l,3dione, Dr. Smith and his group have prepared ( ± ) -13-ethyl-3-methoxygona-l,3,5(10),8,14-pentaen-17-one. The compound is the intermediate used to make the clinically promising anabolic and progestational compounds. The intermediate is first hydrogenated to saturate the D ring, then ethynylated at C-17 (alpha substitution) and hydrogenated again. The 17a:-ethyl intermediate is further reduced stereospecifically with lithium in aniline and ammonia. Ring A with the 3-methoxy group is then reduced by a Birch reduction. Subsequent acid hydrolysis gives the anabolic agent. The sequence to the progestational agent is similar, except that the ethynyl group is retained at C-17a. Scale-up of the synthesis is well under way at the firm's facilities in West Chester, Pa. It has been carried out in 200-gallon vessels to provide quantities of both materials required for clinical trials. Additionally, the general synthesis makes feasible a commercial total synthesis of estrone and therapeutic agents derived from this hormone.
New Route Eases Syntheses of Carbo-tert-Butoxy Derivatives A simple synthesis of tert-bxxtyl carbazate has been worked out by Dr. Louis A. Carpino of the University of Massachusetts, Amherst [/. Org. Chem., 28, 1909 (1963)]. The new route opens the door to a host of carbo-terf-butoxy derivatives on a kilogram scale. Carbo-ferf-butoxy groups have been found to be very good protective groups, especially in peptide chemistry and in the synthesis of highly sensitive organic nitrogen compounds. The methods required for removing carbo-fcrf-butoxy groups are milder and faster (for example, trifluoroacetic acid or hydrogen chloride in nitromethane, both at room temperature) than those required for functions such as carbobenzoxy, phthaloyl, and tosyl. Also, the cleavage by-products are gaseous; work-up of the desired products is easier. However, the use of the caxbo-tertbutoxy group as a protective function 34
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hasn't developed as rapidly as expected, Dr. Carpino says. In 1957, the Massachusetts worker proposed its use in peptide synthesis. Independently, Frank C. McKay and Dr. Noel F. Albertson of the Sterling-Winthrop Research Institute, Rensselaer, N.Y., did some of the first experiments with the carbo-tert-butoxy group with peptides. Dr. George W. Anderson and Anne C. McGregor of American Cyanamid's Lederle laboratories at Pearl River, N.Y., also developed the use of carbo-tert-butoxy groups in peptide synthesis and found a practical reagent— tert-butyl p-nitrophenyl carbonate—for making terf-butyloxycarbonyl derivatives. The recent total synthesis of /^-corticotropin (ACTH) by Dr. Robert Schwyzer and P. Sieber of Ciba, Ltd., Basel, Switzerland, represented the first extensive practical use of these groups as masking functions in peptide chemistry (C&EN, Aug. 5, page 4 4 ) . The most generally useful carbote/t-butoxylating agent prepared so far is tert-butyl azidoformate, Dr. Carpino says. tert-Butyl p-nitrophenyl carbonate and tert-butyl cyanoformate have also been used. Dr. Carpino's synthesis of tot-butyl carbazate begins with methyl chlorothiolformate (which is now commercially available). Treatment of this compound with tert-butyl alcohol gives the S-methyl thiol ester, which yields tert-butyl carbazate on treatment with hvdrazine:
Treatment of the carbazate with nitrous acid gives tert-butyl azidoformate [ N 3 C O O C ( C H 3 ) 3 ] . ' Dr. Carpino and his co-workers have also recently developed a new route to the cyanoformate from tertbutyl oximinoacetate. In the process, they discovered a new general synthesis of alkyl glyoxylates. In other work, these chemists have also found a synthetic route to tert-butyl iminodicarboxylate, an intermediate which promises to allow bis protection by the carbo-tert-butoxy group. The carbo-tert-butoxy function also seems to have application in organic syntheses. For example, O-acyl and O-sulfonylhydroxylamines —difficult or impossible to obtain in other ways—are readily available through carbo-terf-butoxy protection.
Coordination Effects Data organized in eight groups in attempt to aid predicting how coordination alters the kinetics of organic reactions The ways in which coordination affects the reactivity of organic compounds have been divided into eight major classes by William A. Connor and Dr. Mark M. Jones of Vanderbilt University, Nashville, Tenn. [I&EC, 55, No. 9,14 ( 1 9 6 3 ) ] . The classification scheme emphasizes the variations in ligand behavior when coordination compounds (usually as intermediates) are formed in reactions. The Vanderbilt chemists believe that they have organized existing data in a way which will make it easier to predict how coordination changes the kinetics of some chemical reactions. There are many examples in which coordination either aids or hinders a desired reaction, but there has been little attempt to organize the data, Mr. Connor and Dr. Jones say. They hope that their system will make it possible to apply the underlying principles to new reactions. Complete understanding and control of reactions, they add, must await a more thorough knowledge of how coordination affects electron density patterns (hence reactivity) of the ligands. Previous classifications of reactions have centered on central metal ions. Dr. A. E. Martell and co-workers, Clark University, Worcester, Mass. [Advan. Catalysis, 9, 319 (1957)], divide reactions into two groups, depending on whether the central metal ion undergoes a permanent change in the course of a reaction. The disadvantage of this system, Mr. Connor and Dr. Jones say, is that it does not have practical use in deciding when coordination offers advantages in carrying out a specific reaction. Dr. M. T. Beck, University of Szeged, Hungary [/. Inorg. Nacl. Chem., 15, 250 ( I 9 6 0 ) ] , has classified
Are Classified
Coordination Affects a Reaction for One of These Reasons
reactions on the basis of catalytic behavior of coordination compounds. According to Dr. Beck, catalytic phenomena occur either with the formation of the complex intermediates themselves, or when subsequent reactions are catalyzed by the complex intermediate.
1 . Ligand and another reactant are brought together more easily for reaction in a mixed complex
Basis. The classes of reactions which the Vanderbilt chemists use are developed on the basis of the manner in which coordination affects the reactivity of the ligand. Most of the examples they use involve the most typical (or classical) type of coordinate bond where the pair of electrons from a donor atom (nitrogen in a pyridine ligand, for example) bonds to a metal ion. Metal cyclopentadienyls, carbonyls, and related types of compounds which involve pi bonding (electrons from the central metal ion occupying available orbitals in the ligand) are used only to illustrate how pi bonding modifies the behavior pattern. Because of the difficulty in predicting charge distribution in such coordination compounds, Mr. Connor and Dr. Jones restrict their classification to compounds having the more simple coordinate bonds. The number of instances where coordination is essential to catalytic activity is large. Some of these, such as the oxo process or the Friedel-Crafts reaction, are of considerable industrial importance. Other reactions take place in living organisms; still others are limited to laboratory use. Coordination effects have practical application in both the suppression of undesirable reactions and in aiding other reactions which occur more readily with coordinated ligands, Mr. Connor and Dr. Jones say. Coordination can frequently accelerate a reaction by providing an easier path for it than is otherwise available. Coordination can also function by providing a favorable thermodynamic system for a reaction, Mr. Connor and Dr. Jones say. In general, when either the reactants or the products (or both) form coordination compounds, the possibility exists for using this phenomenon to increase the yield or the purity of desired products. The number of such examples presently known is but a small fraction of chemical reactions where coordination may be used to advantage, the Vanderbilt chemists believe.
CU2CI2 or pyridine alone does not catalyze the oxidation of aniline to azobenzene. But CU2CI2 in pyridine absorbs one mole of oxygen per mole of CU2CI2 (presumably because of a copperpyridine complex) which accounts for fts catalytic activity
Autoxidation of aromatic amines by atmospheric oxygen
Polarization of the ligand by the positive charge on the central metal ion Catalytic hydrolysis of amino acid esters
3. Ligand stabilized in a form suitable for certain reactions Bromination of ethyl acetoacetate is catalyzed by copper(ll) ion which stabilizes enol form by coordination 4. Coordination masks one or more reactive groups of a molecule so that desired reaction occurs at only a limited number of sites
Sites available for further reaction (with urea, for example)
5. Allows stable chelate to form from two or more reactive species which do not readily react under same condition Preparation of nitroacetic acid
6. Coordination is a prerequisite to the transfer of electrons in oxidation-reduction reactions Examples: Oxidations with Fed 11), phenol oxidation via Cud I), and decomposition of diazoketones 7 . Stereospecificity of coordination utilized 8 . Coordination allows normally unstable ligand to be isolated as a stable complex, or else makes thermodynamics of reaction more favorable Aluminum chloride (acting as a Lewis acid) reacts with an aromatic compound to form a stable complex which then catalyzes a substitution reaction on the aromatic ring
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