Problem 1. Salvia Species Growing in Turkey: Isolation and Total Synthesis of Abietane Diterpenoids

The genus Salvia, named after a Latin word, salvare (“healer”), has a variety of species with important medicinal activities. They have been used for the treatment of colds, flu, and menstrual disorders in most regions of the world since ancient times. In Turkish folk medicine, Salvia L. species have also been used as a carminative, diuretic, hemostatic, spasmolitic, and stomachic, and in the treatment of mouth and throat irritations due to their antibacterial and wound healing properties. The genus Salvia includes over 900 species across the world, 58 of which are endemic in Turkey.

Female Turkish scientists Ulubelen & Topçu with co-workers have studied Anatolian Salvia plants growing in Turkey, and isolated and characterized more than 320 natural products, most of which are terpenoids, while one third are new diterpenoids.

In one of their studies on Salvia multicaulis Vahl., Ulubelen & Topçu isolated four new aromatic abietane norditerpenoids (1–4), which showed strong antituberculous activity. In addition to the antibacterial and antifungal activities of the isolated diterpenoids, the plant extracts also showed antioxidant, antiinflammatory, and cholinesterase inhibitory activities. S. multicaulis has folkloric use in Anatolia, such as an appetizer, for wound healing, against scorpion stings, and in the treatment of respiratory and urinary infections and diabetes.

Later, a research group in Turkey developed a synthetic route to obtain derivatives of natural products 1–4. This problem covers the synthesis of related compounds. The following reaction schemes illustrate the total synthesis of diterpenoids 1 and 5.

1.1. Draw the structure of the products A–M, without any stereochemical detail. Hint: In second step (�� →��), combination of lithium bromide and cerium(IV) ammonium nitrate (CAN) is used as a brominating reagent. Compound C is a benzaldehyde derivative and used in the synthesis step of compound M.

1.2. During the cyclization of H to I-1, another isomeric compound, I-2, with the formula C18H20O, is also formed. Draw the structure of I-2.

1.3. The following reaction scheme is related to the synthesis of 6, a desmethyl derivative of the diterpenoids 1 and 2. Draw the structures of products N–Y, without any stereochemical detail. Hint: Compounds R, S and T exhibit acidic character. The transformation of compound V to W includes Robinson annulation and a possible deformylation reaction steps.

1.4. During the transformation of compound V to W (Robinson annulation step), the use of a precursor of the α,β-unsaturated ketone, such as a β-chloroketone or N,N,N,-trialkyl-3oxobutan-1-aminium halide (as used in the reaction scheme), can be more favorable. Explain.

1.5. Draw possible tautomeric forms of compound V.

1.6. Compound Y can be also obtained via ring-closing (electrocyclization) of the compound Z. Draw structure of Z.

1.7. For the transformation of X to Y, which of the following reagents can also be used? (Ignore SN2' type reactions).

☐ i) PBr3/pyridine; ii) n-Bu3SnH/AIBN ☐ i) PBr3/pyridine; ii) Na/t-BuOH ☐ i) MnO2; ii) DDQ ☐ i) TsCl/pyridine; ii) LiAlH4 ☐ i) TsCl/pyridine; ii) DBU

Solution:

1.1.

1.2.

1.3.

1.4. The use of a precursor of the α,β-unsaturated ketone, such as a β-chloroketone or N,N,Ntrialkyl-3-oxobutan-1-aminium halide, can reduce the steady-state concentration of enone and decrease the possible side reactions of precursors such as self-condensation or polymerization reactions.

1.5.

1.6.

1.7.

☐ i) PBr3/pyridine; ii) n-Bu3SnH/AIBN ☐ i) PBr3/pyridine; ii) Na/t-BuOH ☐ i) MnO2; ii) DDQ ☐ i) TsCl/pyridine; ii) LiAlH4 ☒ i) TsCl/pyridine; ii) DBU