Chapter 7, Problem 7.28P

The standard procedure for synthesizing a compound is the stepwise progress toward a target molecule by forming individual bonds through single reactions. Typically, the product of each reaction is isolated and purified before the next reaction in the sequence is carried out. One of the ways nature avoids this tedious practice of isolation and purification is by the use of a domino sequence in which each new product is built on a preexisting one in stepwise fashion. A great example of a laboratory domino reaction is William S. Johnson’s elegant synthesis of the female hormone progesterone. Johnson first constructed the polyunsaturated monocyclic 3° alcohol (A) and then, in an acid-induced domino reaction, formed compound B, which he then converted to progesterone.

A remarkable feature of this synthesis is that compound A, which has only one stereo-center, gives compound B, which has five stereocenters, each with the same configuration as those in progesterone. We will return to the chemistry of Step 2 in Section 16.7 and to the chemistry of Steps 3 and 4 in Chapter 19. In this problem, we focus on Step 1.

1. (a) Assume that the domino reaction in Step 1 is initiated by protonation of the 3° alcohol in compound A followed by loss of H₂O to give a 3° carbocation. Show how the series of reactions initiated by the formation of this cation gives compound B.
2. (b) If you have access to a large enough set of molecular models or to a computer modeling program, build a model of progesterone and describe the conformation of each ring. There are two methyl groups and three hydrogen atoms at the set of ring junctions in progesterone. Which of these five groups occupies an equatorial position? Which occupies an axial position?