內皮素受體拮抗劑:抗高血壓化合物及其與受體作用之研究-(子計畫一)─抗高血壓藥物合成之研究

1

行政院國家科學委員會專題研究計畫成果報告

八十七年度抗高血壓藥物合成之研究

The Synthesis of Potential Anti-Hyper tensive Dr ugs

計畫編號：NSC 87-2113-M-002-023

執行期限：86 年 8 月 1 日至 87 年 7 月 31 日

主持人：蔡蘊明 國立臺灣大學化學系

A conformationally rigid analog of SB209670 (1), a potent endothelin receptor antagonist, was prepared featuring a key step involving Stille coupling.

Keywor ds: SB209670, Stille coupling, receptor antagonist 二、緣由與目的

Endothelin-1 (ET-1), a 21 amino acid peptide, isolated from endothelial cells exhibits profound endogenous vasoconstriction and mitogenic activities.1 _{Intensive efforts were put}

on the search for the endothelin receptor antagonists.2 _{Recently, based partly on the}

molecular modeling of ET-1, SmithKline Beecham Pharmaceuticals reported the finding of (1 S,2R,3S)-3-[2-(carboxymethoxy)-4-methoxyphenyl]-1-[3,4-(methylenedioxy)phenyl]-5-(prop-1-yloxy)indan-2-carboxylic acid (1; SB 209670) as a highly potent antagonist,3

selective for the endothelin receptors. The SB researchers used the 1- and 3-aryl groups to mimic the aromatic side chains of Tyr-13, Phe-14 of ET-1. Electron-donating substituents on these two phenyl moieties were designed to have better binding affinity with the receptors. The 2-carboxylic group was considered to function as the Asp-18 of ET-1. The carboxylic acid side chain on the 3-aryl group was designed to mimic the C-terminal carboxyl of the peptide. The propyloxy group was introduced only for the convenience of the synthesis. Removal of this group basically had no effect on the biological activities.

2 Scheme 1 O OMe PrO CO2H O O O OMe PrO CO2Me O O Br 2 1 SnBu3 O OMe PrO COOH O O COOH SB209670 3

Based on the SB findings, we wish to synthesize acid 2 as the conformationally rigid analog of 1 in order to understand more about the role of the 1- and 3-aryl groups in 1. Retrosynthetically, we planned to employ a Stille coupling4 _{of stannane 3 to construct a}

methyleneoxy bridge connecting the two flanking aromatic rings on the indane skeleton.

三、 研究報告內容

Our synthesis of the cyclic ether 2 was realized as shown in Scheme 2. The preparation of ester 10 followed the same strategy as reported by Elliott et al. The Knoevenagel

coupling of β-ketoester 43 _{with the known bromoaldehyde 5}5 _{gave enone 6 in 80% yield as a}

mixture of E/Z-isomers. Cyclization of enone 6 in TFA gave the β-ketoester 7 (97%) as a mixture of cis- and trans-isomers which was oxidized with DDQ to give indenone 8 (58%). Coupling of 8 with the Grignard reagent 9 prepared from the corresponding bromide3,6 _gave

the alcohol 10. Interestingly, alcohol 10 exists as a separable 3:1 mixture of two conformers presumably due to the hindered rotation of the bromo containing 3-aryl group. The

relationship of the two isomers was confirmed by heating the minor isomer of 10 in benzene at 80 o_{C for 2 h to give back a mixture of the two conformers.}

Attempted catalytic hydrogenation (H2, Pd/C, EtOAc/EtOH) of alcohol 10 was not successful

even at 80 o_{C. The sluggishness of this reaction was probably due to the steric hindrance}

imposed by the 2-bromo-4,5-methylenedioxyphenyl group. Without the bromo group in alcohol 10, the catalytic hydrogenation can be accomplished at room temperature.3 _{To solve}

this problem, we switched to the use of triethylsilane in TFA at 60 o_{C. Under this condition}

we were able to isolate the cis-lactone 11 in 40% yield. The MOM protecting group was removed during the initial 5 min period of the reaction. Treatment of the lactone 11 with potassium carbonate in methanol at room temperature gave the ester 13 in 68% yield. That the ester 13 is the all cis-isomer was confirmed by NOE experiments. Irradiation of H(2) resulted in 8% and 8% enhancement of the 1_{H NMR signals of H(1) and H(3), respectively.}

3

lactone 12 was treated with one equivalent of sodium methoxide in methanol under refluxing temperature, the lactone ring opening was accompanied with epimerization at C(2) to give the all trans-isomer in 70% yield. While the 1_{H NMR signals of H(2) in ester 13 and lactone 11}

appeared at δ 4.1, the corresponding signal in ester 12 appeared at δ 3.2. This chemical shift difference also indicated the difference of stereochemistry at C(2) between esters 12 and 13.

Scheme 2 PrO OMe O O O O CHO Br PrO OMe O O Br O O PrO CO2Me O O O Br PrO CO2Me O O O Br OCH3 OMOM MgBr OMOM OMe PrO CO2Me O O Br OH 2 O OMe PrO O O 1 3 i O

Reagents and conditions : (a) AcOH (cat), piperidine (cat), PhH, 80 oC, 6 h; 80%. (b) TFA, rt, 12 h; 97%. (c) DDQ, dioxane, 70 oC, 2.5 h; 58%. (d) THF, 0 oC > rt, 5 h; 70%. (e) Et3SiH, TFA, 60 o_{C, 24 h; 40%. (f) NaOMe, MeOH, reflux, 5 h; 70%. (g) ICH}

2SnBu3, K2CO3, DMF, 70 oC; 75%.

(h) Pd(PPh3)4, AsPh3, Toluene, 100 oC; 80%. (i)NaOH, dioxane, H2O , rt, 12 h; 85%. (j) K2CO3,

MeOH, rt; 68%. Br 14 + 7 OH OMe PrO O O 6 c b 5 Br 4 11 OH OMe PrO O O e 8 10 Br d CO2Me CO2Me a 9 f j 12 ₁₃ 3 2 g _h O OMe PrO CO2Me O O

4

Alkylation of ester 12 with tributyl(iodomethyl)stannane7 in DMF gave the ether 3 in 75% yield. Stille coupling7 with palladium tetrakis(triphenylphosphine) in the presence of triphenylarsine8 afforded the cyclized ether 14 in 80% yield.9 Finally, the saponification of cyclic ether 14 was accomplished with sodium hydroxide in wet dioxane to afford the acid 2 (85%).

四、 參考文獻

1. Yanagisawa, M.; Kurihara, H.; Kimura, S.; Tomobe, Y.; Kobayashi, M.; Mitsui, Y.; Yazaki, Y.; Goto, K.; Masaki, T. Nature 1988, 332, 411–415.

2. (a) Arai, H.; Hori, S.; Aramori, I.; Ohkubo, H.; Nakanishi, S. Nature 1990, 348, 730– 732. (b) Sakurai, T.; Yanagisawa, M.; Takuwa, Y.; Miyazaki, H.; Kimura, S.; Goto, K.; Masaki, T. Nature 1990, 348, 732–735. (c) Cheng, X.-M.; Nikam, S. S.; Doherty, A. M. Current Med. Chem. 1994, 1, 271–312. (d) Doherty, A. M. Drug Develop. Today

1996, 1, 60–70.

3. Elliott, J. D.; Lago, M. A.; Cousins, R. D.; Gao, A.; Leber, J. D.; Erhard, K. F.; Nambi, P.; Elshourbagy, N. A.; Kumar, C.; Lee, J. A.; Bean, J. W.; DeBrosse, C. W.; Eggleston, D. S.; Brooks, D. P.; Feuerstein, G.; Ruffolo, Jr., R. R. ; Weinstock, J.; Gleason, J. G.; Peishoff, C. E.; Ohlstein, E. H. J. Med. Chem. 1994, 37, 1553–1557.

4. For review about Stille coupling, see: Mitchell, T. N. Synthesis 1992, 803–815.

5. (a) Fleming, I.; Noolias, M. J. Chem. Soc. Perkin Trans. I 1979, 829–837. (b) Mervic, M.; Ben-David, Y.; Ghera, E. Tetrahedron Lett. 1981, 22, 5091–5094.

6. de Paulis, T.; Kumar, Y.; Johansson, L.; Ramsby, S.; Florvall, L.; Hall, H.; Angeby-Moller, K.; Ogren, S.-O. J. Med. Chem. 1985, 28, 1263–1269.

7. Seitz, D. E.; Carroll, J. J. ; Clandia, P. C.; Cartaya M., C. P. ; Lee, S.-H.; Zapata, A. Synth. Commun. 1983, 13, 129–134.

8. (a) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W. Tetrahedron Lett.

1992, 33, 919–922. (b) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59, 5905–5911.

9. For related coupling involving a-alkoxystannanes, see: (a) Ye, J.; Bhatt, R. K.; Falck, J. R. J. Am. Chem. Soc. 1994, 116, 1–5. (b) Cardenas, D. J.; Mateo, C.; Echavarren, A. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 2445–2447. (c) Mateo, C.; Cardenas, D. J.; Fernandez-Rivas, C.; Echavarren, A. M. Chem. Eur. J. 1996, 2, 1596–1606.