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Summer Research Fellowship Programme of India's Science Academies

Approaches to analgesics, eptazocine

Nishi Singh

Dr. Harisingh Gour University (DHSGSU), Saugor, MP 470003, India

Prof. Alakesh Bisai

Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, MP 462066, India

Abstract

Eptazocine (l-1,4-Dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine) is a narcotic-antagonist analgesic with a homobenzomorphan structure and belongs to the opiate family with some other representatives containing benzylic quaternary carbon centres like morphine and pentazocine, which is naturally found in a number of plants and animals. It has been clinically demonstrated that eptazocine is suitable for managing cancer-related pain and post-operative pain, because it has little ability to induce respiratory depression and physical tolerance. The major challenge in this synthesis of this compound (−)-eptazocine is the installation of all-carbon quaternary centre. We are working on the synthetic approaches to (−)-eptazocine via catalytic enantioselective decarboxylative allylation of allyl carbonate to access the advanced intermediate. In this regard, α-tetralone was reacted with methylmagnesium bromide followed by dehydration to afford tetralin compound over 2 steps. The latter under hydroboration-oxidation furnished alcohol in mixture of diastereomers, which was further oxidized under Swern oxidation to afford β-tetralone. Next, a reaction of β-tetralone with allyl chloroformate in the presence of triethylamine and catalytic amount of DMAP furnished allylenolcarbonate. Currently, we are actively working on the catalytic enantioselective version of this decarboxylative allylation of allylenolcarbonate. Finally, with β-tetralone with an all-carbon quaternary center.

Keywords: eptazocine, decarboxylative allylation, all-carbon quaternary centre, α-tetralone, β-tetralone

INTRODUCTION

Natural Products have been proved to be a continued and eminent source of various bioactive compounds. A natural product is a chemical organic substance which is produced by the living organisms found in nature by the pathways of primary and secondary metabolism. It can be synthesized by using various methodologies and total syntheses which are responsible for the development in the field of organic chemistry by providing challenging synthetic targets.

Natural products have an important role in the discovery of analgesic drugs along with the determining of the complex mechanisms involved in pain transmission and pain relief and still hold great potential for the discovery of novel agents for treatment of pain disorders and potentially drug addictions with exciting pharmacological profiles (i.e. no side effects, no addictive potential).

So, herein, we are specifically interested to deal with a natural molecule named Eptazocine which is an analgesic drug and very widely used in medicinal field.

SYNTHETIC APPROACHES

Eptazocine

Eptazocine (1) belongs to the opiate family with some other representatives containing benzylic quaternary carbon centres like morphine and pentazocine, which is naturally found in a number of plants and animals. Eptazocine (l-1,4-Dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine) was developed as a narcotic-antagonist analgesic first synthesised by Shiotani et al. in 1976, with a homobenzomorphan structure.

Eptazocine (1) mainly interacts with opioid receptors. It has been clinically demonstrated that eptazocine is suitable for managing cancer-related pain and post-operative pain, because it has little ability to induce respiratory depression and physical tolerance. The analgesic effect of eptazocine is equal to or more potent than that of pentazocine when systematically administered to mice or rats or humans.

figure1.JPG
    (-)-Eptazocine (1).

    Eptazocine(1) produces side-effects similar to those associated with the morphine-like analgesics, and as with these analgesics the effects are exaggerated in ambulatory patients. Unlike the narcotic antagonist nalorphine, eptazocine produces only occasional subjective psychotomimetic effects at usual therapeutic doses.

    The major challenge in this synthesis of this compound (-)-eptazocine(1)is the installation of all-carbon quaternary centre. Herein, we are reporting synthetic approaches to (-)-eptazocine via catalytic enantioselective decarboxylative allylation of allyl carbonate to access the advanced intermediate.

    Retrosynthetic Analysis

    Development of expeditious strategies for total syntheses of architecturally complex natural products is always challenging and come at the fore front of organic synthesis. As a part of an ongoing program in finding efficient strategies for total syntheses of architecturally complex natural products, we became intrigued by the biological profile of eptazocine(1). We are particularly interested in the development of the methodology for the efficient synthesis of this core via decarboxylative allylation of allyl carbonate. The proposed strategy of synthesis of a common intermediate 2 required for eptazocine is shown in Scheme 1. It was envisioned that eptazocine can be obtained from intermediate 2 via an intramolecular Mannich cyclization. Further intermediate 2 can be achieved from aldehyde precursor 3 via imine formation followed by Eschenmoser’s salt, which in turn could be synthesized from 4.

    figure2.JPG
      Scheme 1: Retrosynthetic analysis of (-)-eptazocine (1).

      We hypothesized that intermediate 4 can be obtained through a catalytic asymmetric Pd(0)-catalyzed decarboxylative allylation of allyl carbonate 5. This allyl carbonate can be achieved from β-tetralone 6, which can be obtained from α-tetralone via methyl Grignard addition followed by successive reduction/oxidation steps.

      Forward Synthesis

      As per our hypothesis, allylenolcarbonate 5 was synthesized from β-tetralone (6). In this regard, α-tetralone (7) was reacted with methylmagnesium bromide followed by dehydration to afford tetralin compound 8 (Scheme 2) in 73% isolated yields over 2 steps. The latter under hydroboration-oxidation furnished alcohol 9 in mixture of diastereomers (78% yield), which was further oxidized under Swern oxidation to afford β-tetralone (6) in 82% yield. Next, a reaction of β-tetralone (6) with allyl chloroformate in the presence of triethylamine and catalytic amount of DMAP furnished allylenolcarbonate 5.

      figure3.JPG
        Scheme 2: Synthesis of allylenolcarbonate (5) from α-tetralone (7).

        Interestingly allylenolcarbonate (5) has the potential to be used for the formation of a π-allyl complex when treated with catalytic Pd(0). In this way, one can not only generates an electrophile in-situ, but also produce enolate of β-tetralone. Therefore, a Pd(0)-catalysed generation of Pd(II)-π-allyl complex would lead to the formation of a C-C bond forming reactions under soft-soft combination (enolate would quickly form a carbanion equivalent), would lead to the synthesis of compound 4 (Scheme 1).

        figure4.JPG
          Scheme 3:Synthesis of 4 via decarboxylative allylation of allylenolcarbonate (5).

          Therefore, allylenolcarbonate (5) in hand our effort was thereafter to elaborate this intermediate to the all-carbon quaternary stereogenic center under Pd(0)-catalysis. Initially, we attempted a racemic methodology using catalytic amount of Pd(0)(PPh3)4 and the result is summarized in Scheme 3. As can be seen, we found that synthesis of 4 can be done using 5 mol% of Pd(0)(PPh3)4-catalyzed decarboxylative allylation of allylenolcarbonate (5).

          figure5.JPG
            Scheme 4: Proposed forward synthesis of eptazocine (1)

            Currently, we are actively working on the catalytic enantioselective version of this decarboxylative allylation of allylenolcarbonate (5). Finally, with β-tetralone (4) with an all-carbon quaternary center, we would like to follow a strategy as shown in Scheme 4.

            INSTRUMENTS AND TECHNIQUES USED

            • Chromatography (TLC, Column)
            • Distillation (Simple, Vacuum)
            • Drying of Solvent
            • Spectroscopic techniques ( NMR)
            • Rotary evaporator
            • HPLC

            RESULTS AND DISCUSSION

            We have undertaken a concise asymmetric route to the analgesics, eptazocine (1). Towards this direction, we have synthesized a key intermediate sharing an all-carbon quaternary center via the development of Pd(0)-catalyzed decarboxylative allylation of allylenolcarbonate (5). Further efforts towards asymmetric total synthesis of (-)-eptazocine (1) is currently under active investigations.

            Synthesis of (−)-Eptazocine

            Step 1

            fig1_1.PNG
              Synthesis of 7-methoxy-4-methyl-1,2-dihydronaphthalene

              Procedure: Took a cleaned and dried 50ml RB Flask and starting material 6-methoxytetralone (510 mg, 1 eq.) in the THF solvent and cooled up to -78°C then MeMgBr (2 ml, 2.1 eq.) was added dropwise. After complete addition, the reaction mixture was stirred at room temperature for over night. Then the reaction mixture was cooled to 0°C and 60 ml water was added followed by addition of 4N HCl and stirred it at room temperature for 1hr. Then organic layer was extracted by ethyl acetate, then purified the compound with column chromatography.

              Step 2

              fig2_1.PNG
                Synthesis of 6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthen-2-ol

                Procedure: In a clean and dried RB flask, olefin compound (60 mg, 1 eq.) was dissolved in THF solvent then a solution of Borane Reagent (0.64 ml, 0.36 eq.) in anhydrous THF was cooled at 0°C and added dropwise, the reaction mixture was stirred at r.t. until full consumption then reaction mixture cooled upto 0°C followed by slow addition of 30% H2O2 (23 mg, 2eq.) and 3N NaOH (0.17μl, 1.5eq.), the reaction mixture was stirred at ambient temperature upto the completion of reaction then diluted it with water and stirred for 30 minutes and extracted the organic layer with diethylether and washed with brine solution and then dried it with sodium sulphate, workup done by ethylacetate then, purified the compound by column chromatography.

                Step 3

                fig3.PNG
                  Synthesis of 6-methoxy-1-methyl-3,4-dihydronaphthen-2(1H)-one

                  Procedure: In an oven dried 50ml RB Flask, DMSO (92.3 μl, 5 eq.) and DCM was cooled upto -78°C under inert atmosphere then Oxalyl Dichloride (34 μl, 1.5 eq.) (in DCM) was added dropwise and stirred for an hour, then, the Alcohol compound (50 mg, 1 eq.) in DCM solution was added via syringe and stirred it over night at the same temperature, then, Triethylamine (181.44 μl, 5 eq.) added slowly and the reaction was stirred at the same temperature for 10 minutes, then stirred it for 20 minutes at r.t., after the completion of reaction organic layer was extracted with DCM and purified the compound through column chromatography.

                  Step 4

                  fig4_1.PNG
                    Synthesis of allyl (6-methoxy-1-methyl-3,4-dihydronaphthylen-2-yl) carbonate

                    Procedure: Starting compound (110 mg, 1 eq.) was taken in the THF solvent in oven dried 50ml RB flask then Triethylamine (161 μl, 2 eq.) and N,N-dimethylaminopyridine (141 mg, 2 eq.) added at 0oC followed by the addition of Allylchloroformate (74 μl, 1.2 eq.) dropwise and stirred it for 6 hrs, organic layer was extracted by ethylacetate and purified the compound by column chromatography.

                    Step 5

                    fig6.PNG
                      Synthesis of 1-allyl(6-methoxy-1-methyl-3,4-dihydronaphthalen-2(1H)-one

                      Procedure: Starting material (40 mg, 1eq.) was dissolved in THF solvent in a sealed tube, degased it for 10mins. Then, Pd(PPh3)4 (17 mg, 0.1 eq.) was added then stirred it for overnight. After the completion of reaction, organic layer was separated with DCM and purified the desired compound by column chromatography.

                      NMR SPECTRA

                      AB-NS-01-1H.JPG
                        1H-NMR of 7-methoxy-4-methyl-1,2-dihydronaphthalene
                        AB-NS-01-13C.JPG
                          13C-NMR of 7-methoxy-4-methyl-1,2-dihydronaphthalene
                          AB-NS-02B.JPG
                            1H-NMR of 6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthen-2-ol
                            AB-NS-03-1H.JPG
                              1H-NMR of 6-methoxy-1-methyl-3,4-dihydronaphthen-2(1H)-one
                              AB-NS-03-13C.JPG
                                13C-NMR of 6-methoxy-1-methyl-3,4-dihydronaphthen-2(1H)-one
                                AB-NS-04-1H.JPG
                                  1H-NMR of allyl (6-methoxy-1-methyl-3,4-dihydronaphthylen-2-yl) carbonate
                                  AB-NS-04-13C.JPG
                                    13C-NMR of allyl (6-methoxy-1-methyl-3,4-dihydronaphthylen-2-yl) carbonate
                                    AB-NS-05-1H.JPG
                                      1H-NMR of 1-allyl(6-methoxy-1-methyl-3,4-dihydronaphthalen-2(1H)-one

                                      REFERENCES

                                      • Xiaobao Yang, Hongbin Zhai, and Zhong Li, Org. Lett. 2008, 12, 2457-2460.
                                      • Toshiyasu Takemoto, Mikiko Sodeoka, Hiroaki Sasai, and Masakatsu Shibasaki, J. Am. Chem. Soc. 1993, 115, 8477-8478.
                                      • Hwan Jung Lim and T. V. RajanBabu, Org. Lett. 2011, 24, 6596-6599.
                                      • Shunsaku Shiotani, Tadashi Kometani, J. Med. Chem. 1976, 19, 6, 803.
                                      • Yoshiaki Nakao, Shiro Ebata, Akira Yada, Tamejiro Hiyama, Masashi Ikawa, and Sensuke Ogoshi, J. Am. Chem. Soc. 2008, 130, 12874–12875.

                                      ACKNOWLEDGEMENTS

                                      I would like to express my deepest appreciation to all those who provided me the possibility to complete this 2 months of internship and the report. A special gratitude I give to my guide Dr. Alakesh Bisai whose contribution in stimulating suggestions and encouragement, helped me to coordinate my project especially in writing this report.

                                      Furthermore I would also like to acknowledge with much appreciation to the crucial role of my senior labmates, who gave the permission to use all required equipment and the necessary materials to complete the task "Synthetic Approaches to Analgesics, Eptazocine". A special thanks goes to my co-guides Ms. Rhituparna Nandi and Mr. Arindam Khatua who helped me to assemble the parts and gave suggestion about the task. Last but not least, many thanks go to the Indian Academy of Sciences for giving me such a great oppurtinity to work from a very prestigious lab of IISER Bhopal, which gave me confidence to secure my first step in the pursuit of gaining knowledge and continuing my career in the field of Organic Chemistry. I have to appreciate the guidance given by my other lab members who helped me to understand the basics of the lab, equipments and the subject.

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