Nakada's synthesis of digitoxigenin

Digitoxin and digoxin make up the drug digitalis, which is used as a cardiac drug to treat cardiac congestion and cardiac arrythmias. The mechanism within the heart involves increasing intracellular Na⁺ and Ca²⁺ while decreasing intracellular K⁺. The increased Ca²⁺ promotes muscle contraction and cardiac contractile force. Digitalis has also been reported to exhibit anti-cancer activity.

Cardiac drug structure

A glycoside consists of part sugar and part nonsugar. The sugar portion is called the glycone and the nonsugar portion is called the aglycone, or genin. Digitoxigenin is the aglycone of digitoxin.

Retrosynthetic Analysis

The synthesis of digitoxigenin was developed by Honma and Nakada. A retrosynthetic analysis was performed and the final product was broken down into two major retrosynthetic pieces, shown below (pieces A and B).

Synthesis of Part A

1. Ethylene ketal formation (protecting group), addition of TBS protecting group
2. Conversion of an alkene to an alcohol and protection of the alcohol with TBDPSCl, ketal hydrolyzed to ketone with base
3. Wolff–Kishner reduction, Conversion to -I, Suzuki coupling reaction, removal of protecting groups TBDPSO and TBSO
4. Protection of the primary alcohol with a TBS protecting group, Oxidation of the secondary alcohol to a ketone
5. Removal of the TBS protecting group, Conversion of the alcohol to a bromine
6. Formation of a ketal from the ketone and final step of product A.

Synthesis of Part B

1. The first step is a catalytic asymmetric intramolecular cyclopropanation
2. The cyclopropane ring is opened and the phenylthio group/phenylsulfonyl group removed.
3. The starting material is first reduced with L-selectride to form the correct stereoisomer. The hydroxyl is then protected with a TBDPS protecting group.
4. Allylic oxidation is performed using a reagent reported by Ochiai to form retrosynthetic piece B.

Convergent Steps

1. Cuprate with lithium produces a single diastereomer
2. Ethylene ketal removed under acidic conditions
3. Intramolecular aldol reaction
4. Deoxygenation in four steps, TBDPS protecting group removed

References

• Honma, Masahiro and Nakada, Masahisa. Tet. Letters 48(2007) 1541-1544. doi:10.1016/j.tetlet.2007.01.024
• Desai, Umesh. www.people.vcu.edu/~urdesai/car.htm, accessed 16 April 2008.
• Haux, J. Medical Hypotheses (1999) 53(6), 543-54. doi:10.1054/mehy.1999.0985