Synthesis of (5r*,6r*)-6-(3-(tertbutyldimethylsilyloxy)prop-1-ynyl)-5- hydroxypiperidin-2-one - Dau Xuan Duc

Journal of Science and Technology 55 (2) (2017) 202-208 DOI: 10.15625/0866-708X/55/2/8728 SYNTHESIS OF (5R*,6R*)-6-(3-(TERT- BUTYLDIMETHYLSILYLOXY)PROP-1-YNYL)-5- HYDROXYPIPERIDIN-2-ONE Dau Xuan Duc*, Vo Cong Dung Faculty of Chemistry, Vinh University, 182 Le Duan Street, Vinh city, Nghe An *Email: xuanduc80@gmail.com Received: 24 September 2016; Accepted for publication: 28 December 2016 ABSTRACT The synthesis of racemic (5R*,6R*)-6-(3-(tert-Butyldimethylsilyloxy)prop-1-ynyl)-5- hydroxypiperidin-2-one was accomplished in 10.3 % overall yield over 7 steps. The key steps involved a Sonogashira coupling reaction to make an ene-yne ester and an azidolysis reaction of an epoxide ester to form a γ-lactone. Keywords: piperidinone, azide, Stemona alkaloids, epoxidation. 1. INTRODUCTION The Stemona alkaloids represent a unique class of natural products exclusively isolated from the monocotyledonous family Stemonaceae, mainly distributed in South East Asia [1]. Structurally the alkaloids are characterised by the presence of either a pyrrolo[1,2-a]azepine or a pyrido[1,2-a]azepine core structure [2]. The dried roots from these species, known as 'Bai Bu' in Chinese traditional medicine, 'Bach Bo' in Vietnam and 'Non Tai Yak' or 'Pong Mot Ngam' in Thailand, are used to suppress coughing, and are claimed to have antituberculosis, antibacterial, antifungal and antihelmintic properties [3]. Although the total syntheses of many pyrrolo[1,2- a]azepine Stemona alkaloids have been reported [3], none of them involves the synthesis of a member of the stemocurtisine group possessing a pyrido[1,2-a]azepine core. The cis-5,6- disubstituted- piperidinones are necessary synthon for the synthesis of Stemocurtisine alkaloids. In this paper, we report our synthesis of (5R*,6R*)-6-(3-(tert-Butyldimethylsilyloxy)prop-1- ynyl)-5-hydroxypiperidin-2-one in our study on the synthesis of stemocurtisine. Figure 1. Core structure of the Stemona alkaloids. Synthesis of (5R*,6R*)-6-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl) 203 2. EXPERIMENTAL SECTION AND SUPPORTING DATA All reactions were monitored by thin-layer chromatography (TLC) using silica gel (Merck, 60–120 mesh). Column chromatography was performed using Meck silica gel (40-63 µm) packed by the slurry method, under a positive pressure of air. 1H and 13C NMR spectra were recorded on a Varian Inova NMR Spectrometer (1H NMR running at 500 MHz and 13C NMR running at 125 MHz) instrument. CDCl3 was used as the NMR solvent unless otherwise stated. Low-resolution mass spectra were obtained on a Shimadu GC spectrometer (EI) or Water LCZ single quadropole (ESI). High resolution spectra were obtained on a VG Autospec mass spectrometer (EI) or Waters QTOF (ESI). Infrared spectra were obtained as neat samples on a Smart Omni-Sampler Avator ESP Nicolet-Brand. The melting points were recorded on a Gallenhamp MF-370 carpillary tube, melting point apparatus and are uncorrected. The values are expressed in degree Celcius (ºC). Uncertanties in the quoted values are ± 2 ºC. (Z)-Methyl 7-(trimethylsilyl)hept-4-en-6-ynoate (4): Compound 4 was prepared following the procedure described in reference [4]. 1H NMR (500 MHz, CDCl3) δ 5.94 (dt, J = 10.5, 7.5 Hz, 1H), 5.52 (d, J = 10.5 Hz, 1H), 3.67 (s, 3H), 2.62 (q, J = 7.5 Hz, 2H), 2.43 (t, J = 7.5 Hz, 2H), 0.18 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 173.5, 142.8, 111.0, 101.6, 100.0, 51.9, 33.4, 25.9, 0.3. IR (neat, νmax/cm-1): 2958, 1734, 1507, 1249, 1168, 841. Satisfactory EI or ESI MS data could not be obtained on this compound. Dihydroxylation of alkene 4: The dihydroxylation of 4 was followed procedure described in reference [5] and products were purified by column chromatography to give three compounds 3 ,8 and 9. (R*)-5-((S*)-1-Hydroxy-3-(trimethylsilyl)prop-2-ynyl)dihydrofuran-2(3H)-one (3) White solid. Mp = 92 - 94 ºC 1H NMR (500 MHz, CDCl3) δ 4.32 (m, 2H), 2.52 (m, 2H), 1.94 (m, 1H), 1.84 (m, 1H), 0.18 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 174.9, 103.1, 92.5, 73.7, 66.9, 30.7, 27.6, 0.12. IR (neat, νmax/cm-1): 3402, 2957, 2170, 1757, 1181, 1060, 992, 838. ESIMS m/z 235 [(M+Na)+ 100 %]. HRESIMS calcd. For C10H16O3NaSi, (M+Na)+ 235.0766, found: 235.0757. (R*)-5-((S*)-1-Hydroxyprop-2-ynyl)dihydrofuran-2(3H)-one (8). White solid. Mp = 73 - 74 ºC. 1H NMR (500 MHz, CDCl3) δ 4.61 (m, 2H), 2.70 – 2.59 (m, 1H), 2.51 – 2.42 (m, 1H), 2.49 (s, 1H), 2.39 – 2.24 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 178.3, 81.7, 80.3, 75.5, 63.8, 28.5, 22.0. IR (neat, νmax/cm-1): 3280, 2921, 2312, 2180, 1763, 1184, 1054, 1015, 990, 938. NMR spectroscopic data matched with the published data [6]. (4S*,5R*)-Methyl 4,5-dihydroxy-7-(trimethylsilyl)hept-6-ynoate (9). Colourless oil. 1H NMR (500 MHz, CDCl3) δ 4.32 (d, J = 3.5 Hz, 1H), 3.67 (s, 4H), 2.52 (dd, J = 6.5, 4.5 Hz, 2H), 1.97-1.90 (m, 1H), 1.88-1.80 (m, 1H) 0.16 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 174.9, 103.1, 92.5, 73.7, 66.9, 52.1, 30.7, 27.6, 0.12. IR (neat, νmax/cm-1): 3431, 2960, 2179, 1763, 1249, 1180, 1016, 840, 759. ESIMS m/z 245 [(M+H)+ 100 %]. HRESIMS calcd. for C14H26O3NaSi, (M+Na)+ 267.1029, found: 267.1026. Conversion of 9 to 3: The conversion of 9 to 3 was followed procedure described in reference [7]. ((4-Fluorophenyl)ethynyl)trimethylsilane (10): Similar fashion for preparation of compound 4 was applied to prepare compound 10 from 4- floro- iodobenzene. 1H NMR (500 MHz, CDCl3) δ 7.48 (dd, J = 8.5, 5.5 Hz, 2H), 7.02 (t, J = 8.5 Hz, 2H), 0.28 (s, 9H). Methyl 3-(4-fluorophenyl)propiolate (11): Compound 11 was prepared following the procedure described in reference [8]. 1H NMR (500 MHz, CDCl3) δ 7.56 (dd, J = 8.5, 5.5 Hz, Dau Xuan Duc, Vo Cong Dung 204 2H), 7.05 (t, J = 8.5 Hz, 2H), 3.82 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 164.2 (d, J = 254 Hz), 154.6, 135.5 (d, J = 9 Hz), 116.4 (d, J = 10 Hz), 115.9 (d, J = 4.0 Hz), 85.7, 80.6, 53.1. (Z)-Dimethyl oct-4-en-2-ynedioate (12) Compound 12 was prepared in 63 % yield from compound 4 following similar fashion for compound 10. 1H NMR (500 MHz, CDCl3) δ 6.24 (dt, J = 11.0, 7.5 Hz, 1H), 5.58 (d, J = 11.0 Hz, 1H), 3.76 (s, 3H), 3.66 (s, 3H), 2.65 (q, J = 7.5 Hz, 2H), 2.43 (t, J = 7.5 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 173.0, 154.6, 148.7, 108.2, 85.3, 83.0, 53.0, 52.00, 33.1, 26.4. Satisfactory EI or ESI MS data could not be obtained on this compound. Attempted to prepare 14 from compound 3: Similar fashion for preparation of compound 11 was applied to prepare compound 14 from compound 3. However the desired product 14 was not formed in this reaction, only the undesired product 8 was formed in 93% yield. (Z)-Methyl 8-(tert-butyldimethylsilyloxy)oct-4-en-6-ynoate (19): Compound 19 was prepared in 78 % yield from vilnyl 7 following similar fashion for compound 4: colourless oil 1H NMR (500 MHz, CDCl3) δ 5.90 (dt, J = 10.5, 7.5 Hz, 1H), 5.53 (d, J = 10.5 Hz, 1H), 4.46 (s, 2H), 3.68 (s, 3H), 2.61 (dd, J = 15.0, 7.5 Hz, 2H), 2.42 (t, J = 7.5 Hz, 2H), 0.91 (s, 9H), 0.13 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 173.6, 141.6, 110.6, 93.2, 81.4, 52.6, 52.0, 33.6, 26.2, 25.9, 18.7, -4.8. IR (neat, νmax/cm-1): 2956, 1710, 1168, 1022, 919. ESIMS m/z 305 [(M+Na)+ 100%]. HRESIMS calcd. for C15H26O3SiNa, (M+H)+ 305.1563, found: 305.1544. Methyl 3-((2R*,3S*)-3-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)oxiran-2-yl)propanoate (17) Compound 17 was prepared from compound 19 following the procedure described in reference 10 1H NMR (500 MHz, CDCl3) δ 4.34 (s, 2H), 3.70 (s, 3H), 3.48 (d, J = 4.0 Hz, 1H), 3.14 (ddd, J = 6.5, 5.5, 4.0 Hz, 1H), 2.53 (t, J = 7.5 Hz, 2H), 2.11 – 1.92 (m, 2H), 0.90 (s, 9H), 0.11 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 173.4, 85.0, 79.5, 57.2, 52.1, 52.0, 45.7, 30.7, 26.1, 25.3, 18.6, - 4.9. IR (neat, νmax/cm-1): 2955, 2239, 1767, 1251, 1185, 1041. ESIMS m/z 321 [(M+Na)+ 100 %]. HRESIMS calcd. for C15H26O4SiNa, (M+Na)+ 321.1498, found 321.1488. Azidolysis of epoxide 17: The azidolysis of 17 was followed the procedure described in reference [9] to provide the azide 16 as a colourless oil and the diol 20 as a colourless oil. (R*)-5-((R*)-1-Azido-4-(tert-butyldimethylsilyloxy)but-2-ynyl)dihydrofuran-2(3H)-one (16). Colourless oil. 1H NMR (500 MHz, CDCl3) δ 4.54 (dt, J = 7.0, 6.0 Hz, 1H), 4.41-4.37 (m, 1H), 4.39 (s, 1H), 2.67 (m, 1H), 2.53 (m, 1H), 2.35 (m, 1H), 2.26 – 2.16 (m, 1H), 0.91 (s, 9H), 0.12 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 176.2, 88.9, 79.6, 76.0, 56.0, 51.8, 30.1, 26.0, 23.7, 18.6, -4.89 . IR (neat, νmax/cm-1): 2930, 2857, 2220, 2140, 1774, 1153, 1062, 814, 777. ESIMS m/z 310 [(M+H)+ 100 %]. HRESIMS calcd. for C14H24O3N3Si, (M+H)+ 310.1589, found: 310.1587. (4S*,5S*)-Isopropyl 8-(tert-butyldimethylsilyloxy)-4,5-dihydroxyoct-6-ynoate (20). Colourless oil. 1H NMR (500 MHz, CDCl3) δ 5.06 – 4.95 (m, 1H), 4.34 (s, 2H), 4.20 (d, J = 6.5 Hz, 1H), 3.64 (ddd, J = 9.5, 6.5, 3.0 Hz, 1H), 2.53 – 2.40 (m, 2H), 2.00 (dtd, J = 10.5, 7.5, 3.0 Hz, 1H), 1.79 (qd, J = 14.5, 7.5 Hz, 1H), 1.23 (d, J = 6.0 Hz, 6H), 0.89 (s, 9H), 0.11 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 173.9 , 85.5, 83.1, 74.5 (C4), 68.3, 66.5, 52.0, 31.4, 27.9, 26.1, 22.1, 18.6, -4.8. IR (neat, νmax/cm-1): 3293, 2924, 2313, 1764, 1647, 1398, 1136, 1013. ESIMS m/z 367 [(M+Na)+ 100 %]. HRESIMS calcd. for C17H32O5SiNa, (M+Na)+ 367.1918, found: 367.1917. (R*)-5-((R*)-1-Amino-4-(tert-butyldimethylsilyloxy)but-2-ynyl)dihydrofuran-2(3H)- one (21) Compound 21 was prepared from compound 16 following the procedure described in reference [10]. A mixture of amine 21 and Ph3PO was used in the next step without further Synthesis of (5R*,6R*)-6-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl) 205 purification. 1H NMR (500 MHz, CDCl3) δ 4.46 (dd, J = 7.0, 7.0 Hz, 1H), 4.32 (s, 2H), 3.78 (d, J = 7.0 Hz, 1H), 2.70 – 2.47 (m, 2H), 2.42 – 2.29 (m, 1H), 2.24 – 2.10 (m, 1H), 0.91 (s, 9H), 0.11 (s, 6H). (5R*,6R*)-6-(3-(tert-Butyldimethylsilyloxy)prop-1-ynyl)-5-hydroxypiperidin-2-one (15) To the above mixture of amine 21 and Ph3PO were added MeOH (1 mL) and Et3N (200 µL) and the reaction mixture was heated and stirred at reflux temperature for 14 h. The solvent was removed in vacuo and the residue was purified by column chromatography (9:1, EtOAc/MeOH) to provide the lactam 15 (21 mg, 88 % yield from 16) as a colourless oil. 1H NMR (500 MHz, CDCl3) δ 5.75 (bs, 1H), 4.40 (s, 1H), 4.36 (s, 2H,), 4.12 - 3.07 (m, 1H), 2.66 – 2.57 (m, 1H), 2.38 – 2.29 (m, 1H), 2.19 – 2.10 (m, 1H), 1.93 – 1.85 (m, 1H), 0.91 (s, 9H), 0.12 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 171.0, 86.3, 80.3, 65.4, 51.9, 51.1, 27.1, 26.6, 26.2, 18.6, -4.82 (CH3Si). IR (neat, νmax/cm-1): 3242, 2927, 1638, 1329, 1250, 1195, 1060, 834, 776. ESIMS m/z 284 [(M+H)+ 100 %]. HRESIMS calcd. for C14H26O3NSi, (M+H)+ 284.1682, found: 284.1678. 3. RESULT AND DISCUSSION We first investigated a synthetic route to prepare the piperidinone 1 following the retrosynthetic analysis shown in Scheme 1 starting from 4-pentyn-1-ol. Scheme 1. Retrosynthesis of piperidinone 1. For the synthesis of 4, iodination of 4-pentyn-1-ol with I2/KOH in MeOH led to the iodide 5, which underwent syn-reduction of the alkyne by diimide (NH=NH), prepared in situ from KOOCN=NCOOK and AcOH, to give the (Z)-vinyl iodide 6 in 61 % yield. Jones' oxidation of the primary alcohol 6 gave the corresponding acid, which was converted to the methyl ester 7 by treatment with Me3SiCl in MeOH. Sonogashira coupling [11] of 7 with trimethylsilylacetylene and PdCl2(PPh3)2/CuI provided the novel ene-yne 4 in 81 % yield (Scheme 2). Scheme 2. Synthesis of ene-yne 4. Syn-Dihydroxylation of the alkene 4 with catalytic OsO4, prepared in situ from K2OsO4 and NMO, gave a chromatographically separable mixture of the racemic desired lactone 3, the desilylated lactone 8 and the diol ester 9 [5]. The diol 9 could be converted to the hydroxy- Dau Xuan Duc, Vo Cong Dung 206 lactone 3 in 88 % yield by treatment with TsOH (1.5 equiv) in MeOH at rt for 2 h (Scheme 3) [7]. Scheme 3. Dihydroxylation of 4. The next step in the synthesis was to replace the terminal TMS substituent of 3 with an ester group. Under Kondo’s conditions [8], the methyl ester 11 was obtained in 62 % yield from 10 (Scheme 4 (a)). Then we obtained the diester 12 in 63 % yield from 14 (Scheme 4 (b)). Unfortunately, the desired ester 14 was not formed when we applied the same conditions to 3. Only the undesired alkyne 8 was formed via a proto-desilylation reaction (Scheme 4 (c)). This unsuccessful step prevented us from continueing this pathway to prepare the piperidinone 1. COOMe TMS 1. CsF, DMSO,rt, 3 h CO2 (balloon) COOMe MeOOC 12 63%4 2. MeI, rt, 1 h (b) Scheme 4. Model work and attempts to convert compound 3 to compound 14. We then tried another pathway to prepare the piperidinone 15 following the retrosynthetic analysis outlined in Scheme 5. Scheme 5. Retrosynthesis of the piperidinone 15. Following this synthetic route, Sonogashira coupling of the Z-vinyliodide 7 with the alkyne 18 proceeded smoothly to provide the ene-yne 19 in good yield. Epoxidation of 19 with m- CPBA gave a chromatographically separable mixture of the racemic epoxide 17 and the starting Synthesis of (5R*,6R*)-6-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl) 207 material (14 %). The ring opening of epoxide 17 with azide under Kesselmayer’s conditions [8] gave the desired azide 16 in good yield and the diol i-propyl ester 20 in 19 % yield (Scheme 6). Scheme 6. Synthesis of azide 16. The azide 16 was then converted to amine 21 by treatment with PPh3 in THF for 1 d, followed by reduction with NaBH4 and MeOH. Amine 21 was obtained as a mixture with Ph3PO and used in the next step without purification. This mixture then was heated with Et3N in methanol at reflux temperature for 14 h to form the lactam 15 in 88 % yield from 16 (Scheme 7). Scheme 7. Synthesis of piperidinone 15. 4. 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