Strategic Application of Synthon Disconnection Approach in the Synthesis Planning of a Bioactive Natural Product ‘Withasomnine’

Chittaranjan Bhanja¹*, Satyaban Jena²

¹Department of Chemistry, Dinakrushna College, Jaleswar, Balasore-756084 Odisha India

²Department of Chemistry, Utkal University, Bhubaneswar-751004, Odisha India.

*Corresponding Author E-mail: bhanjac@gmail.com

ABSTRACT:

Chemical synthesis of bioactive compounds from natural sources is a part and parcel of drug discovery and development process. Developing new synthetic strategies and methods towards such compounds is therefore an attractive option for obtaining larger quantities of the natural product without putting strain on the natural resources. Designing synthetic routes for convergent and viable synthesis from readily available materials is very fundamental to natural product synthesis. In this paper, we endeavor to profile some synthesis schemes for a natural pyrazole alkaloid ‘Withasomnine’ in a novel way basing on Synthon Disconnection Approach.

KEYWORDS: Bioactive, natural product, synthesis, Synthon disconnection approach, withasomnine.

1. INTRODUCTION:

Organic synthesis had its genesis in the study of naturally occurring substances, and this remains a constant source of information and intellectual challenge since its inception. Developing new synthetic strategies and methods towards such compounds is therefore an attractive option for obtaining larger quantities of the natural product without putting strain on the natural resource. But the complex structural features of natural products always need multi-step synthesis and require careful plans with respect to sequence of steps from starting materials to the final product for achieving their total syntheses. The design of synthetic methodologies for convergent and efficient synthesis is very fundamental to natural product synthesis. The details as to how the synthetic chemists formulate the sequence of steps are not always published. Among synthetic chemists, retrosynthetic analysis / synthon disconnection approach^1-3 developed

by Noble Laureate Prof. E.J. Corey of Harvard University, has emerged as the most popular approach for designing chemical synthesis. This strategy systematically simplifies the target molecule by repeated bond disconnections in retrosynthetic direction, leading to progressively smaller precursors until recognized starting material emerges.

‘Withasomnine’ is a natural pyrazole alkaloid, first isolated in 1966 from the roots of a medicinal plant Withania somnifera Dun (Solanaceae) which is widely distributed in India and Africa⁴ . It is commonly known as Ashwagandha in Sanskrit or Indian ginseng and is used as folk medicine in India. This alkaloid and its analogues possess the unique 5, 6-dihydro-4(H)-pyrrolo [1, 2-b] pyrazole framework (Fig-1) ^{5, 6} and are used in several indigenous drug preparations for maintaining health as well as treatment of several disease conditions. Withasomnine exhibits central nervous and circulatory system depressions, mild analgesic activity, and TBL₄, cyclooxygenase-1 (COX-1), and COX-2 inhibitory activities ^{7, 8}.

Figure-1

Although few synthetic methodologies for Withasomnine have been well cited in the literature, they are often impractical for large –scale synthesis. Alternative synthetic routs and improvement in its existing processes are constantly required in pharmaceutical industries for its commercial success. In continuation with our interests in the synthesis designing of natural products and pharmaceuticals, we, herein, propose a good number of synthesis schemes for Withasomnine keeping a bird’s eye view on the works published in journals ^9-14. Our synthetic approach is based on synthon disconnection approach /retrosynthetic analysis and the utilization of readily available building blocks while designing synthetic routes for achieving its total synthesis. It is an innovative work that has not been reported earlier. The choice of this molecule for synthesis planning is obvious as synthesis provides an alternative to nature for rarely found bioactive compounds. Again, Withasomnine is the most representative of pyrazole scaffold natural product and becomes a challenging lead compound, for the synthesis of analogues that could also be promising candidates for CNS depressant and analgesic activity.

2. MATERIALS AND METHODS:

The structure and information regarding Withasomnine as a natural Central Nerves System depressant and analgesic has been collected from different books ^4-8. The proposed synthesis planning are then exploited in a novel way from the result of retrosynthetic analysis of natural product structure using the basic principle outlined in the pioneering works of Prof. E.J. Corey. The terms, abbreviations and symbols used during synthesis planning are synonymous to that represented in books ^15-20. The analysis–synthesis schemes being theoretical propositions, obviously the synthesis have not been executed in the laboratory. Most of the retrosynthesis schemes have been derived taking in to account the synthesis earlier done for its preparation as found from different literatures. The actual laboratory execution requires the cross examination of a considerable number of factors such as reagents, reactions, order of events, economical viability, environmental benign, saftyness, short time and scalable synthesis.

Sonogoshira coupling of 4-pentyn-1-ol 31 with iodobenzene 30 forms 4-phenylbut-3-yn-1-ol 29. TBDMS protection of the alcohol provides the alkyne 28. Titanium-catalyzed 3-component coupling of aniline 26, alkyne 28, and t-Bu-isonitrile 27 followed by treatment with hydrazines 24 provides pyrazole 23 in a one-pot procedure. Bromination of alcohol forms 22 Intramolecular cyclisation of 22 with NaOEt/EtOH forms the Withasomnine (TM) (Scheme-4)

4. CONCLUSION:

The synthesis of natural products is a challenging task owing to complexity of their structure. The power of synthon disconnection approach/ retrosynthetic analysis has been evidenced in designing their synthesis in logical manner. The approach is expected to provide an ideal platform for the design, execution and development of new synthetic methodology or improvement in existing methodologies. It is a paper exercise; a full analysis of this type will provide many routes for synthesizing the target molecule. As a consequence of this approach, we have proposed a good number of analysis-synthesis schemes for a bioactive natural product Withasomnine. Scalable synthetic routes for extremely scare natural products, pharmaceuticals and useful compounds not available in adequate quantities from natural resources can be best provide by this approach. Through Synthon disconnection approach and with the validation of new synthetic reactions and reagents developed within the academic community, it is now time to rethink the synthesis of other bioactive natural products for the improvement of the existing process for their commercial success.

5. ACKNOWLEDGMENTS:

The author CB deeply acknowledges UGC, ERO, Kolkata, India for providing financial support as Minor Research Project Grant. The author also thanks the authorities of IIT Kharagpur, CU, Hyderabad, IMMT Bhubaneswar and NCL, Pune for permission to collect information from books and journals from their library.

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