Steroids Synthesis, total

The steroidal total synthesis intermediate (18) contains an aromatic ring of the type found in 5-methoxytetralin, a compound which undergoes Birch reduction slowly. As a consequence, compound (18) is reduced with... 

An example is the preparation of 18-trideuterio 5a-steroids bearing a side chain at C-17. Labeling of this position with three deuteriums was accomplished by utilizing the Johnson procedure for steroid total synthesis. This synthesis involves, in part, introduction of the 18-angular methyl group by methylation of the D-homo-17a-keto-17-furfurylidene intermediate (243). By substituting d3-methyl iodide in this step, the C/D cis- and ra/J5-18,18,18-d3 labeled ketones [(244) and (245)] are obtained. Conversion of the C/D tra 5-methylation product (245) into 18,18,18-d3-d /-3)8-hydroxy-5a-androstan-17-one (246) provides an intermediate which can be converted into a wide variety of C-18 labeled compounds of high (98%) isotopic... 

The scheme used to prepare the direct 8-aza-analogue 21 of estrone bears at least formal similarity to the Torgov-Smith steroid total synthesis sequence. Acylation of the phenethylamine 9 with acryloyl chloride gives amide 16. Michael addition of dimethylamine followed by Bischler-Napieralski cyclodehydration gives the dihydroisoquinoline, 17. 

Microbial reduction of prochiral cyclopentane- and cyclohexane-1,3-diones was extensively studied during the 1960 s in connection with steroid total synthesis. Kieslich, Djerassi, and their coworkers reported the reduction of 2,2-dimethylcyclohexane-l,3-dione with Kloeokera magna ATCC 20109, and obtained (S)-3-hydroxy-2,2-dimethylcyclohexanone. We found that the reduction of the 1,3-diketone can also be effected with conventional baker s yeast, and secured the hydroxy ketone of 98-99% ee as determined by an HPLC analysis of the corresponding (S)-a-methoxy-a-trifluoromethylphenylacetate (MTPA ester).(S)-3-Hydroxy-2,2-dimethy1cyc1ohexanone has been proved to be a versatile chiral non-racemic building block in terpene synthesis as shown in Figure 1. 

The fact that the above reactions allow isolation of 4-hydroxyesters, which are often unstable and lactonize quickly, is a merit of the homoenolate chemistry. Mesylation of the hydroxy group followed by appropriate operations provides stereocontrolled routes to y-lactones and cyclopropane carboxylates [19]. Through application of such methodology steroid total synthesis has been achieved (Section 7). 

Several applications in total syntheses exemplify the value of this methodology 11-oxoequiienin methyl ether (101 Scheme 38),105 107 (+)-a-cuparenone,109 (-)-podorhizon,112 (-)-methyl jasmonate (102 Scheme 39),114 (+)-estrone methyl ether,116 and the so called (+)-A-factor (103 Scheme 40)117 were all prepared in high enantiomeric purity. Other applications constitute preparations of 2-alkylchro-man-4-ones,118 and of 3-vinylcyclopentanones, highly valuable intermediates for steroid total synthesis.106,107... 

I7(x-Methyl-17 -hydroxy-estra-4,9,l l-trien-3-one (Methyltrienolone, N-99). In the course of a steroid total synthesis [293] this compound (Methyltrienolone, N-99) was prepared it was reported [55] to possess 6000% of the androgenic (ventral prostate index), 7500% of the androgenic (seminal vesicles index), and 12,000% of the anabolic (levator ani index) activity of methyltestosterone. Later the anabolic activity was reported [74] to be 30,000% of that of methyltestosterone. As measured by multiple parameters methyltrienolone turned out to be the most hepatotoxic steroid, causing biochemical symptoms of intrahepatic cholestasis [75]. It was also reported [74] to reduce the excretion of 17-ketosteroids and 17-hydroxycorticosteroids and to cause enhancement of the blood coagulation factors V, VII, and X. It also increases the prothrombin content of the plasma [74]. 

Until recently, the preparation of the bicyclic ene-diones (47a,b), which are important intermediates in steroid total synthesis, has led only to racemic mixtures This deficiency has now been met as follows. Michael addition of the vinyl ketone (44) to the cyclic diketones (45a) and (45b) afforded the triketo-intermediates (46a) and (46b) in high yield, each containing a prochiral centre. Optically active amines and amino-acids were used as chiral reagents to... 

Mikami, K., Takahashi, K., Nakai, T. Asymmetric tandem Claisen-ene strategy for steroid total synthesis an efficient access to (+)-9(11)-dehydroestrone methyl ether. J. Am. Chem. Soc. 1990, 112, 4035-4037. 

This highly reactive compound is made by B. F. Goodrich Chemical Co. by reaction of ketene with formaldehyde. Many reactions and uses are described by Gresham, Jansen, et al. Barkley et at. employed the reagent in one phase of a steroid total synthesis, namely for a Michael addition to the unsaturated system of... 

Triethylamine was used by a Ciba-Basel group in different ways in two successive steps of a steroid total synthesis. Alkylation of the 1,3-diketone (2) with the halide (1) was accomplished by reaction in t-butanol under catalysis by triethylamine. Intramolecular aldolization of (3) with elimination of water to close ring C required... 

Another reaction for which I rilon B is a particularly satisfactory catalyst is cyanoethylation. In the steroid total synthesis by the Woodward group, Triton B-catalyzed cyanoethylation initiated construction of ring A. 

Because of their biological importance and widespread medical and industrial utilities, estrogens and related hormones are among the earliest targets in steroid total synthesis. Major efforts in the synthesis of these aromatic steroids were to set the correct chirality in the C,D rings since the A,B rings are mostly achiral. 

Olefin cyclization. W. S. Johnson and co-workers1 developed a new approach to steroid total synthesis, based upon discovery of a remarkable biogenetic-like cyclization applied in a first instance,2 to the tetraenol (10), prepared in a sequence starting with condensation of the dienic tosylate (1) with the lithium salt of 4-... 

For an application of this method in the steroid total synthesis by a tandem Claisen rearrangement-ene reaction see ref 523. 

Microbial reduction of prochiral cyclopentane- and cyclohexane-1,3-diones was extensively studied during the 1960 s in connection with steroid total synthesis. Klesllch, Djerassl, and their coworkers reported the reduction of 2,2-dimethylcyclohexane-l,3-dione with Kloeakera magna ATCC 20109, and obtained (S)-3-hydroxy-2,2-dimethylcydohexanone. We found that the... 

M.B.Groen and F.j.Zeelen, Steroid Total Synthesis, Reel.Tray. Chim.Pays-Bas, 1986, 105, 465. 

As an example of a steroid total synthesis, the industrial procedure used to make norgestrel, the gestagen used in many contraceptives, is sketched here. Its basis is the Torgov reaction, a variation of the Robinson annelation, which mns essentially neutral media. The carbanion of 1,3-dioxo compounds adds to allylic alcohols, e.g., 2-ethylcyclopentanol-1,3-dione, under weakly basic conditions. Both the dione and the styrene double bond are stable under these conditions. Regio- and stereoselective microbial reduction of one of the keto groups, acid-... 

The design of suitable protecting groups for C—H bonds is intimately associated with the major advances in steroid total synthesis announced by Barton, Johnson, Jones, Robinson, Woodward and others during the period 1943-63. With some exceptions, the problems relate to protection of selected C—H... 

Polyolefin Cyclization Route to Steroid Total Synthesis... 

The application of nonenzymic biogenetic-like olefinic cyclizations for the stereospecific construction of polycyclic systems, developed by W. S. Johnson and his school, represents an exciting new approach to steroid total synthesis. The synthesis of progesterone, outlined below, is based on the finding that an appositely placed acetylenic bond participates in polyolefinic cyclizations directly to produce the C/D trans-fused hydrindane system... 

---