Progesterone Johnson

Johnson s classic synthesis of progesterone (1) commences with the reaction of 2-methacrolein (22) with the Grignard reagent derived from l-bromo-3-pentyne to give ally lie alcohol 20 (see Scheme 3a). It is inconsequential that 20 is produced in racemic form because treatment of 20 with triethyl orthoacetate and a catalytic amount of propionic acid at 138 °C furnishes 18 in an overall yield of 55 % through a process that sacrifices the stereogenic center created in the carbonyl addition reaction. In the presence of propionic acid, allylic alcohol 20 and triethyl orthoacetate combine to give... 

Vinyl cations no doubt will be involved in more synthetic reactions and schemes, as already demonstrated by the elegant synthesis of progesterone by Johnson and co-workers (85). 

Knowledge regarding biosyntheses has induced several biomimetic approaches towards steroids, the first examples being described by van Tamelen [10] and Corey [11]. A more efficient process was developed by Johnson [12] who, to synthesize progesterone 0-10 used an acid-catalyzed polycyclization of the tertiary allylic alcohol 0-7 in the presence of ethylene carbonate, which led to 0-9 via 0-8 (Scheme 0.3). The cyclopentene moiety in 0-9 is then transformed into the cyclohexanone moiety in progesterone (0-10). 

Lukert BP, Johnson BE, Robinson RG. Estrogen and progesterone replacement therapy reduces glucocorticoid-induced bone loss. J Bone Miner Res 1992 7(9) 1063-9. 

Nature often provides excellent suggestions about how to synthesize a compound. After the pathway for the biosynthesis of steroids by cationic cyclization of polyenes was determined, Professor William S. Johnson and coworkers at Stanford University used a very similar reaction to synthesize progesterone. The last part of this synthesis is outlined in the following equations. Alcohol A was prepared in 12 steps with an overall yield of 10%. It was then cyclized to form the steroid ring system. 

The following reaction sequence was used to prepare the starting material for Johnson s synthesis of progesterone described in the Focus On box Syntheses That Mimic Nature. ... 

Here is one of Johnson s best examples which leads eventually to a biomimetic synthesis of the human hormone progesterone. The cydization occurs just on treatment of the tertiary alcohol with acid. 

The synthesis of the female sex hormone progesterone by W. S. Johnson and co-workers at Stanford University is considered one of the classics in total synthesis. The last six-membered ring needed in the steroid skeleton was prepared by a two-step sequence using an intramolecular aldol reaction, as shown in Figure 24.5. 

This cyclization has obvious applications to the synthesis of steroids and indeed Johnson et al. applied this reaction to a synthesis of dZ-progcsterone. The key step in the synthesis involves the cyclization of (3) to give (4). This reaction was carried out with trifluoroacetic acid as above, but ethylene carbonate was added to the reaction to trap the vinyl cation. After cyclization potassium carbonate was added to hydrolyze the enol complex. In this way (3) was converted into (4) in 71 % yield. The tetracyclic ketone (4) was converted into progesterone (6) by ozonization followed by intramolecular aldol condensation. Nole that (4) is a 5 1 mixture of the 17/7- and 17a-epimeric ketones. The mixture was converted into (6) and then separated by fractional crystallization. 

Allan GF, Lombardi E, Haynes-Johnson D, Palmer S, Kiddoe M, Kraft P, Campen C, Rybczynski P, Combs DW, Phillips A. Induction of a novel conformation in the progesterone receptor by ZK299 involves a defined region of the carboxyl-terminal tail. Mol. Endocrinol. 1996 10 1206-1213. 

In summary, the stereochemical course of cation-7t cyclizations is determined by stereoelectronic and conformational effects. Concerted cation-Ti cyclizations usually involve a stereospecific trans-addition (axial attack) of the carbocation to the double bond. This is exemplified by Johnson s biomimetic synthesis ( )-progesterone, which possesses a trans, anti, trans-fused ring system." - ... 

BIO. Bonomi, P., Gale, M., and von Roenn, J., Anderson, K., Johnson, P., Wolter, J., and Economou, S., Quantitative estrogen and progesterone receptor levels related to progression-free interval in advanced breast cancer patients treated with megestrol acetate or tamoxifen. Semin. Oncol. 15(2), 26-33 (1988). 

Mobbs, B. G., and Johnson, 1. E., Use of an enzymeimmunoassay (EIA) for quantitation of cytosolic and nuclear estrogen receptor and correlation with progesterone receptor in human breast cancer. J. Steroid Biochem. 28, 653-662 (1987). 

Johnson, W.S. et al. 1977, Asymmetric total synthesis of 1 la-hydroxy progesterone via a biomimetic polyene cyclization , Journal of the American Chemical Society, 99, 8341-3. 

E.F. Johnson (1988). Selective inactivation by 21-chlorinated steroids of rabbit liver and adrenal microsomal cytochromes P-450 involved in progesterone hydroxylation. Arch. Biochem. Biophys. 264,462 71. 

The synthesis of lanosterol (140) from epoxide 139 has an Lfo, =+4. The key multiple ring-closure step 141+142- [143] in Johnson s synthesis of progesterone has also an Lfoj =+4 (Lfor for [143]- 144 would depend on the by-products). Next, we see the three steps 145+146- 147- [148]- 149 in Vollhardts synthesis of estrone with Lfor is +3, -1, +2 respectively for the overall transformatiom L r =+3-l+2=+4. The next two transformations, ISO- 151 in Nicolaou s biomimetic synthesis of endiandric acid A, and Negishi s palladium-catalyzed tetracyclization 152- 153 are also characterized by Lfor =+4. Trost s one-step polyclization... 

A pioneering step in synthetic poiyene cyciisation for the preparation of steroids was the synthesis of racemic progesterone in a few stages and with excel-ient yields by Wiiiiam S. Johnson (1913-1995) in 1971. [8] The first diastereo-selective polyene cyciisation, starting from an enantio-merically pure epoxide, originates from Elias J. Corey cf. section 3.7.5 - Polyene cyclisations). [9]... 

In Problem 7.28, we saw this step in Johnson s synthesis of the steroid hormone progesterone. 

In Problem 7.28, we saw this two-step sequence in Johnson s synthesis of the steroid hormone progesterone. Propose a structural formula for the intermediate formed in Step 3 and a mechanism for its conversion in Step 4 to progesterone. 

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