The Synthetic Routes of (16α)-21-(Acetyloxy)-17-hydroxy-16-methylpregna-1,4,9(11)-triene-3,20-dione

The Synthetic Routes of (16α)-21-(Acetyloxy)-17-hydroxy-16-methylpregna-1,4,9(11)-triene-3,20-dione: A Comprehensive Review

In the world of chemical synthesis, the creation of new and complex molecules is a constant challenge.
The synthesis of (16α)-21-(acetyloxy)-17-hydroxy-16-methylpregna-1,4,9(11)-triene-3,20-dione, also known as calcipotriol, is a prime example of this challenge.
Calcipotriol is a synthetic derivative of vitamin D3, and it has been shown to have potent anti-inflammatory and anti-skin cancer activities.
As a result, calcipotriol has found widespread use in the treatment of a variety of skin conditions, including psoriasis and cancer.

The synthesis of calcipotriol has been the subject of extensive research, with many different synthetic routes being proposed and developed over the years.
In this article, we will provide a comprehensive review of the most commonly used synthetic routes for the synthesis of calcipotriol, and discuss the advantages and disadvantages of each route.

1. The classic route: The classic route for the synthesis of calcipotriol involves a sequence of five steps, starting with the synthesis of 16α-hydroxy-17-methylpregna-1,4-diene-3,20-dione (compound 1) (Figure 1).
   This compound is then converted into 17-hydroxy-16-methylpregna-1,4-diene-3,20-dione (compound 2) through a series of chemical reactions.
   The next step involves the formation of the acetyloxy group, which is introduced onto the 16α-position of the steroid nucleus.
   Finally, the last step involves the installation of the 21-epi-group onto the 20-dione ring.
   

This classic route is well-established, and has been used extensively in the synthesis of calcipotriol.
However, it has some drawbacks, including the use of hazardous reagents, such as diazo compounds, and the need for several synthetic steps.

2. The Sharpless epoxidation method: The Sharpless epoxidation method involves the use of a phosphine oxide, such as dimethyl sulfide, as a catalyst to epoxidize the 16α-hydroxy group of compound 1 (Figure 2).
   This method is highly regioselective, and has been used as a key step in the synthesis of calcipotriol.
   

3. The total synthesis of lipid A: The total synthesis of lipid A, a complex lipid molecule found in the outer membrane of gram-negative bacteria, has been used as a synthetic route to calcipotriol.
   This route involves the synthesis of several key intermediate metabolites, including the synthesis of the 16α-hydroxy group, which is introduced onto the steroid nucleus (Figure 3).
   

4. The Knoevenagel condensation: The Knoevenagel condensation involves the use of a carbonyl compound, such as aldehyde, in the presence of a strong base, such as sodium hydroxide, to form a new carbon-carbon bond (Figure 4).
   This reaction has been used as a key step in the synthesis of calcipotriol, allowing the formation of the 16α-hydroxy group on the steroid nucleus.
   

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