Lawesson's Reagent: Thionation of Natural Compounds

Introduction

Transformation of a carbonyl functional group into thiocarbonyl has been an important interest to synthetic organic chemists for many years. Lawesson's reagent is one of the most widely used agents for such a transformation as well as for the synthesis of wide range of heterocyclic compounds having sulfur atoms. Due to its important applications in synthetic organic chemistry, it has regularly been reviewed. [1]

Application of Lawesson's reagent in Steroids

The steroids are an important class of natural products, exhibiting a spacious variety of biological activities. The introduction of one or more heteroatoms at carbon atoms in steroids can vary their biological activities. Sometimes the addition of other functional groups and heterocyclic rings to steroids can alter their physiological activities. Using Lawesson's reagent to thionate is one of the possible strategy to modify the activity of naturally occurring steroidal skeletons. [2]

Synthesis of Thioanalogues of Neo-tanshinlactone

Neo-tanshinlactone is a steroid-like tetracyclic natural product originally isolated from the traditional Chinese medicine Danshen. It is used for the treatment of breast cancer. Among women, breast cancer is the most common disease. The main source of medicinal leads is in natural products. However, complex structure, multi ring system, and chiral centers have made them difficult to synthesize. For this reason, simplification, modification, and design of analogs is the highly productive tool for the development. A famous example is the simplification of morphine, which led medicines to be used in clinics such as levorphanol and meperidine. F. Bastow et al. synthesized this core structure using Lawesson's reagent. Lawesson's reagent was used to synthesize thioanalogue of naturally occurring neo-tanhinlactone; replacement of oxygen in the lactone carbonyl with sulfur (thiolactone) led to greatly reduce or no antibreast cancer activity. [3]

Preparation of α,β-unsaturated Steroidal Thioketones

Lawesson's reagent can be suitable for preparation of α,β-unsaturated steroidal thioketones as well as different, depending on the solvent, sulfur steroid derivatives. α,β-Unsaturated ketones 1a-e in boiling toluene gave, besides dimer-sulfides 2a-e, the thioketones 3a-e in 11–27% yields. Much higher yields of thioketones were obtained when thionation was carried out in CH2Cl2 (28–70%). In this reaction the dithioketones 4c and 4d were isolated as well. With prolonged reaction times in both solvents and due to the enethiones instability and formation of by-products neither thioketone could be isolated. In toluene, the initially formed unstable enethiones dimerize to give only the corresponding dimer-sulfides 2a-e (30–51%). In CH2Cl2 all unsaturated ketones 1a-egave as a main product the corresponding dimers with 1,2,4-trithiolane ring 5a-e in 11-79% yields, and (4-methoxyphenyl) phosphonotrithioates 6b-e (8–36%) as a result of further reaction of the initially formed thioketones with Lawesson's reagent. [4]

Application of Lawesson's reagent in Terpenoids

Thionation of Betulinines

Triterpenoids are a vital class of natural compounds showing various biological activities. Recently, Jan Sarek et al. determined structure–activity relationship in lupane and 18α-oleanane derivatives (betulinines). Triterpenic derivatives showed antitumor activity. This fact has encouraged them to prepare the newly modified skeleton of betulinines. Thionation is one possible modification that could have some effect on antitumor activity despite lipophilicity that is an inherent feature of thionation. Herein, Jan Sarek and co-workers reported on the reaction of several lupane and 18α-oleanane carbonyl derivatives with Lawesson's reagent to form new sulfur analogs. [3]

Thionation of Sarcophine Using Lawesson's reagent

Sulfur-containing compounds are known to show anticancer properties in natural as well as synthetic products; for example, garlic shows anticancer properties due to organic sulfides. Sulfur-containing compounds also show the detoxification effect which helps the liver to crush carcinogenic substances. In light of these facts, Swant et al. synthesize sulfur-containing derivatives of sarcophine by reacting with Lawesson's reagent. Even if lactone and epoxide rings both are present, Lawesson's reagent can react with lactone as well epoxide, and at higher temperature, the lactone reacts with Lawesson's reagent to produce, while at the low temperature, epoxide reacts with Lawesson's reagent to produce.[3]

References:

[1] Ozturk, T., Ertas, E., & Mert, O. (2007). Use of Lawesson's reagent in organic syntheses. Chemical reviews, 107(11), 5210-5278.

[2] Khatoon, H., & Abdulmalek, E. (2021). A focused review of synthetic applications of Lawesson’s reagent in organic synthesis. Molecules, 26(22), 6937.

[3] Saeed, A., Mehfooz, H., Larik, F. A., Faisal, M., & Channar, P. A. (2017). Applications of Lawesson’s reagent in the synthesis of naturally occurring steroids and terpenoids. Journal of asian natural Products research, 19(11), 1114-1123.

[4] Krsti?, N. M., Bjelakovi?, M. S., Dabovi?, M. M., & Pavlovi?, V. D. (2010). Thionation of some α, β-unsaturated steroidal ketones. Molecules, 15(5), 3462-3477.