Natural products steroids

In recent years, oxyfunctionalization of various natural products (steroids, alkaloids) under superacidic conditions have also been explored. In addition, Nafion resins in combination with various oxidizing agents have also been used in the oxygenations. 

Keywords Alkaloids Microwave irradiation Natural products Steroids ... 

Natural products (steroids, sugars, alkaloids, prostaglandins, etc.) usually have conventional, though arbitrary, layouts and orientations. 

Many stereoselective reactions have been most thoroughly studied with steroid examples because the rigidity of the steroid nucleus prevents conformational changes and because enormous experience with analytical procedures has been gathered with this particular class of natural products (J. Fried, 1972). The name steroids (stereos (gr.) = solid, rigid) has indeed been selected very well, if one considers stereochemical problems. We shall now briefly point to some other interesting, more steroid-specific reactions. 

Compounds of class (iii) are either totally synthetic (a few steroids) or derivatives of natural products isolated from plants or microorganisms. They are discussed within the indicated sections. We will briefly describe published syntheses of the most common compounds... 

Steroids are another class of natural products with multiple chirality centers One such compound is cholic acid which can be obtained from bile Its structural formula IS given m Figure 7 12 Cholic acid has 11 chirality centers and so a total (including cholic acid) of 2" or 2048 stereoisomers have this constitution Of these 2048 stereoiso mers how many are diastereomers of cholic acid s Remember Diastereomers are stereoisomers that are not enantiomers and any object can have only one mirror image Therefore of the 2048 stereoisomers one is cholic acid one is its enantiomer and the other 2046 are diastereomers of cholic acid Only a small fraction of these compounds are known and (+) cholic acid is the only one ever isolated from natural sources... 

Isotope incorporation experiments have demonstrated the essential correctness of the scheme presented m this and preceding sections for terpene biosynthesis Considerable effort has been expended toward its detailed elaboration because of the common biosyn thetic origin of terpenes and another class of acetate derived natural products the steroids... 

Experimental procedures have been described in which the desired reactions have been carried out either by whole microbial cells or by enzymes (1—3). These involve carbohydrates (qv) (4,5) steroids (qv), sterols, and bile acids (6—11) nonsteroid cycHc compounds (12) ahcycHc and alkane hydroxylations (13—16) alkaloids (7,17,18) various pharmaceuticals (qv) (19—21), including antibiotics (19—24) and miscellaneous natural products (25—27). Reviews of the microbial oxidation of aUphatic and aromatic hydrocarbons (qv) (28), monoterpenes (29,30), pesticides (qv) (31,32), lignin (qv) (33,34), flavors and fragrances (35), and other organic molecules (8,12,36,37) have been pubflshed (see Enzyp applications, industrial Enzyt s in organic synthesis Elavors AND spices). 

The Joint lUPAC/IUBMB Commission has pubHshed many recommendations dealing with the nomenclature of natural products (72), steroids... 

Generally, the most powerful method for stmctural elucidation of steroids is nuclear magnetic resonance (nmr) spectroscopy. There are several classical reviews on the one-dimensional (1-D) proton H-nmr spectroscopy of steroids (267). C-nmr, a technique used to observe individual carbons, is used for stmcture elucidation of steroids. In addition, C-nmr is used for biosynthesis experiments with C-enriched precursors (268). The availability of higher magnetic field instmments coupled with the arrival of 1-D and two-dimensional (2-D) techniques such as DEPT, COSY, NOESY, 2-D J-resolved, HOHAHA, etc, have provided powerful new tools for the stmctural elucidation of complex natural products including steroids (269). 

N. Ikekawa, in H. Danielsson and. Sjovah, eds.. Steroids andBile Acids, Elsevier Science Pubhshers BV, Amsterdam, the Nethedands, 1985, pp. 199—230 C. Djerassi, in P. Krogsgaard-Larsen, S. Brogger Christensen, and H. Kofod, eds., Alfred Benpon Symposium 20 Natural Products and Drug Development, Munksgaard, Copenhagen, Denmark, 1984, pp. 164—176 N. W. Withers, in P. J. Scheuer, ed.. Marine Natural Products, Vol. V, Academic Press, Inc., New York, 1983, pp. 87—130 C. Djerassi, Pure Appl Chem. 53, 873 (1981). 

Use of DMF as a solvent for the oxidation of l-o1efins has been reported by Clement and Selwitz. The method requires only a catalytic amount of PdCl2 and gives satisfactory yields under mild conditions. A small amount of olefin migration product is the only noticeable contaminant in the cases reported. The procedure can be applied satisfactorily to various 1-olefins with other functional groups. This useful synthetic method for the preparation of methyl ketones has been applied extensively in the syntheses of natural products such as steroids,macrolides, dihydrojasmone, and muscone. " A comprehensive review article on the palladium-catalyzed oxidation of olefins has... 

Numerous examples of intramolecular Diels-Alder reactions have been repor-ted especially from application in the synthesis of natural products, where stereoselectivity is of particular importance e.g. syntheses of steroids. " ... 

Drugs of particularly complex structure are often prepared commercially by partial synthesis from some abundant, structurally related, natural product obtained from plants. The majority i)f steroid drugs are in fact prepared in just this way. Prostaglandins are unique in that no prostanoid compounds have yet been found in plants, a perhaps surprising finding in view of the wide distribution of essential fatty acids in plant materials. 

Although all the main classes of steroids have now been attained by total synthesis, most drugs are in fact, as noted above, prepared by partial synthesis from natural products that contain the steroid nucleus. The bulk of the world s supply of steroid starting material is derived by differing chemical routes from only two species of plants the Mexican yam, a species of... 

Again, the answer should be fairly obvious. The potential therapeutic value of the steroid hormones makes these of tremendous commercial value. The commercial market for these is of the order of hundreds of millions of dollars per year. There is no comparable market for sterols and bile salts. We are faced with the interesting situation, therefore, that sterols are relatively abundant in natural sources but of relatively low commercial value, whilst steroids occur naturally at very low concentrations but are of great commercial value. Although there are tremendous variations amongst different products, steroids with desirable properties command market prices that are (ten to one thousand fold) greater than their sterol counterparts. 

The enzymatic transformation of natural products is by for file most attractive option. In this approach, it can be envisaged that sterols, which are relatively abundant, may be selectively modified to produce desired products. Hie diversity of enzyme activities, their reaction specificity, regiospecificity and stereospedfidty are all features which could contribute to carrying out the desired changes. This does not mean, however, that transformations using enzyme systems are simple. Nevertheless, biotransformations have become of vital importance in the production of steroids. 

Since its discovery two decades ago, the reversible interconversion of allylic sulfenates to sulfoxides has become one of the best known [2,3]-sigmatropic rearrangements. Certainly this is not only because of the considerable mechanistic and stereochemical interest involved, but also because of its remarkable synthetic utility as a key reaction in the stereospecific total synthesis of a variety of natural products such as steroids, prostaglandins, leukotrienes, etc. 

Successful applications of these stereocontrolled conjugate additions have led to asymmetric syntheses of several natural products such as (+ )-cuparenone (39) which involves formation of a quaternary carbon center81, (- )-/ -vetivone (40)8° and steroidal equilenin 4182 the wavy lines in these structures indicate that C—C bond formed stereoselectively under the influence of a temporarily-attached stereogenic sulfoxide auxiliary group. 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

Two illustrations that show the power of this reaction for the preparation of strained cycloalkenes are the contractions of 102 to the propellane 103 , an application that has been reviewed , and of 104 to the bicyclo[2.1.1]hexene 105 . The utility of the Ramberg-Backlund rearrangement in the preparation of various natural products such as steroids , terpenoids and pheromones has been demonstrated. In addition to the synthetic applications mentioned in the previous subsection, several selected examples taken from the recent literature are given in equations 66-69. These examples further demonstrate the potential of this method for alkene synthesis in general. 

Polyene cyclizations are of substantial value in the synthesis of polycyclic terpene natural products. These syntheses resemble the processes by which the polycyclic compounds are assembled in nature. The most dramatic example of biosynthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, an enzyme not only to induces the cationic cyclization but also holds the substrate in a conformation corresponding to stereochemistry of the polycyclic product.17 In this case, the cyclization is terminated by a series of rearrangements. 

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