Johnson s synthesis of progesterone

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. ... 

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... 

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. 

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... 

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... 

The key trienyol (A), which has also served as an intermediate for the synthesis of progesterone, has been obtained in optically active form and shown to undergo cyclization without racemization to give optically active tetracyclic products, R. L. Markezich, W. E. Willy, B. E. McCarry and W. S. Johnson, J. Amer. Chem. Soc., 95, 4414 (1973) B. E. McCarry, R. L. Markezich and W. S. Johnson, J. Amer. Chem. Soc., 95, 4416 (1973). 

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. 

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." - ... 

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. 

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]... 

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. 

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