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Home , Isoquinoline, Sodium methoxide

May, 1944 COMMUNICATIONSTO THE EDITOR 849

THE TOTAL SYNTHESIS OF QUININE* (m. p. 165.2-165.8' [dec.]; Anal. Calcd. for Sir: CiiHisQNt: C, 58.40; H, 8.02; N, 12.39; CH&, Quinine preparations have been known adused nil. Found: C, 58.13; H, 7.45; N, 12.39; for centuries in the treatment of malaria. The CH& nil). The free dl-homomeroquinene (m. p. pure crystalhe was isolated in 1820, and 219-220' [dec.]) obtained on cleavage of the the extensive degradative researches of the last uramido group was converted by esterification century culminated in the proposal of the correct and benzoylation to N-benzoylhomomeroquinene structure in 1908, but the complexity of the mole- ethyl . Condensation of the latter with cule has placed hitherto insurmountable difficul- ethyl quininate, following the general methods ties in the way of the total synthesis of the drug. elaborated by Rabe [Ber., 51, 1360 (1918); iW., We wish to record the first total synthesis of qui- 52, 1842 (1919)], working with related natural nine. materials [qf. Pr0"tenik and Prelog, H&. Chim. 7-Hydroxyisoquinoline was converted through Acta, 26, 1965 (1943)], gave dl-quinotoxine. The its 8-piperidinomethyl derivative (m. p. 81.5- racemic alkaloid was resolved through its salts 82.5'; Anal. Calcd. for CUHlsONz: C, 74.36; with dibenzoyl-d-tartaric . The pure syn- H, 7.49; N, 11.57. Found: C, 73.79; H, 7.65; thetic d-quinotoxine dibemoyld-tartrate had N, 11.86) into 7-hydroxy-8-methylisoquinoline m. p. 185.5-186°, and showed no depression in (m. p. 232.0-233.5'; Anal. Calcd. for CloHaON: on admixture with a sample of C, 75.44; H, 5.70; N, 8.80. Found: C, 74.96; authentic material prepared from natural quino- H, 5.51; N, 8.94). Hydrogenation over platinum toxine. The synthetic d-quinotoxjne regenerated oxide to 7-hydroxy-8-meth 1-1,2,3,4-tetrahy&o- from the was a very pale yellow viscous oil, isoquinoline (m. p. 246-250 a:, Anal. Calcd. for [LY]D +43'. COXnWSiOII Of d-quinotoxine to qui- CIOHuON: C, 73.59; H, 8.03; N, 8.58. Found: nine was first effected over twenty-five years ago C, 73.41; H, 8.26; N, 8.63), and acetylation by Rabe [Ber., 51, 466 (1918)], working with gave N-acetylSI7-hydroxy-&methyl- 1 , 2 ,3,4- tetra- natural materials, during the course of his elegant hydroisoquinoline (m. p. 191-198'; Anal. Calcd. work which resulted in the determination of the for C~H1102N: C, 70.22; H, 7.35. Found: C, correct structures of the cinchona . 70.54; H, 7.20). Further hydrogenation ovef RESEARCHLABORATORY, POLAROID &RPoRATION Raney nickel led to a mixture of stereoisomeric N- CONVERSEMEMORIAL LABORATORY acetyl-7-hydroxy-8-methyldecah ydroisoquinolines HARVARDUNIVERSITY R. B. WOODWARD (Anal. Calcd. for C12Hz102N: C, 68.20; H, CAMBRIDGE38, MASS. W. E. DOERING 10.02; N, 6.63. Found: C, 68.06; H, 9.75. RECEIVEDAPRIL 11,1944 Pure cis-isomer, m. p. 126.0-128.0'. Anal. Found: C, 68.34; H, 9.58; N, 6.59) which was oxidized directly to the corresponding N-acetyl- THIOPHANE DERIVATIVES 7-keto-8-methyldecahydroisoquinolines. From sir: the latter, the pttre cis-N-acetyl-7-keto-8-methyl- The appearance of reports by Karrer, Schmid decahydtoisoquinoline (cis refers to the mode of and Kehrer [HeZv. Chim. Acta, 27, 116, 124, 127, locking of the rings) was isolated as the crystalline 142 (1944), Received April 3, 19441 on thiophane donohydrate (m. p. 80.5-82.5' ; Ad. Calcd. for derivatives prompts us to record our experiments CBH~~O~N.H~O:C, 63.40; HI 9.32; N, 6.16. in that field. Found: C, 63.34; H, 8.85; N, 6.40) and converted The dimethyl ester of &mercaptopropionic acid by ethyl nitrite and to N-acetyl- S-acetic acid, obtained by addition of methyl 1O-oximinodihydrohomomeroquinene ethyl ester thioglycolate to methyl acrylate in the presence (two polymorphic forms-labile, m. p. 96-98'; of piperidine, was cyclized in two ways. With stable, m. p. 108.5-109.0°; Anal. Calcd. for sodium in toluene at llOo, the main C14HuOdNs: C, 59.14; H, 8.51; N, 9.85. Found : product was 4-carbomethoxy-3-ketothiophane C, 59.39; H, 8.24; N, 10.02). Reduction of the Im. p. 37-38', b. p. 128.5-129.5' [20 mm.]. oximino-ester to the corresponding amine (char- Ad. Calcd. for CSHSOSS: C, 45.1; H, 5.0; S, acterized as the free 10-aminodihydrohomomero- 20.0. Found: C, 44.3; H, 5.2; S, 19.8). This quinene dihydrate, m. p. 186.5-188'; Anal. substance gave a permanent red-violet coloration Calcd. for CloH2002Nz.2HzO: C, 51.20; H, 10.24; with ferric chloride, and from it a semicurbam N, 11.86. Found: C, 50.83; H, 9.90; N, 12.04), (m. p. 189.5-190.0°. Ad. Calcd. for complete methylation by methyl iodide and C.rHuOsN&: C,38.7; H, 5.1; N, 19.3. Found: potassium carbonate, followed by alkali treatment C, 39.2; H, 4.7; N, 19.1), a rnonobenzylk€ene of the resulting quaternary salt (Ad. Calcd. for derivative (m. p. 158-159'. Ad. Calcd. for C1,HsaOsN21:C, 46.45; H, 7.55; N, 6.35. Found: CIIIH~O&:C, 62.9; H, 4.8. Found: C, 62.7; C, 46.67; H, 7.14; N, 6.18) gave dl-homomero- H, 5.2) and a monofurfurylkkne derivative (m. p. quinene, isolated as the N-uramido derivative 157-158'. Ad. Calcd. for CUHI~O~S:C, 55.5; 4.2. Found: C, 55.6; H, 4.6) were ob- (1) This work was undertaken as a reseorcb project of Polaroid H, Corporation by the senior author,instructor in chemistry at Harvnrd tained. When the initial condensation was car- University and chemical consultant to Polaroid Corporation. ried out at room temperature in with sodium