Synthèse de l'hydroxichloroquine

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one.

methylation, was converted into the trans product followed by crystallization from acetone-wate IV, m.p. 202–204°, C, 78.9; H, 8.33, in 69% yield. containing an equivalent of pyridine, led to 750 Alkaline peroxide oxidation transformed IV into V of D-a-phenoxymethylpenicilloic acid hydrate (IV) (R = H) which was converted with diazomethane C18H20N20.S.H20; m.p. 129° dec. Found: into the ester V (R = CH), and cyclized with 49.61; H, 5.77; N, 6.94; 025D + 94° (c, 1 i potassium t-butoxide in benzene. The resulting methanol) ). Identity with a sample prepared b keto ester was decarbomethoxylated with hydro- saponification of natural penicillin V5 was estab chloric and acetic acid to give the dl-ketone VI, lished by comparison of m.p., infrared spectr m.p. 158.5-161.5°. The infrared spectrum of this (KBr), optical rotation and mixed m.p. material was indistinguishable from that of Treatment with N,N-dicyclohexylcarbodiimid authentic 38-hydroxy-9,11-dehydroandrostane-17- in dioxane-water (20 min. at 25°) cyclized IV as th

monopotassium salt in 10-12% yield. By partitio (8) At this stage the 3-hydroxyl group was protected as the tetra

between methyl isobutyl ketone and pH 5.5 phos hydropyranyl ether (cf. ref. 3).

phate buffer (two funnels) the totally syntheti (9) C. W. Shoppee, J. Chem. Soc., 1134 (1946).

crystalline potassium salt of penicillin V was iso DEPARTMENT OF CHEMISTRY

lated. The natural and synthetic potassium salt UNIVERSITY OF WISCONSIN

WILLIAM S. JOHNSON were shown to be identical by microbiological as MADISON, WISCONSIN

DUFF S. ALLEN, JR. say,6 optical rotation (synthetic, Q25D + 223 RECEIVED FEBRUARY 1, 1957

(c, 0.2 in water); natural, q2D + 223° (c, 0.2 in

water); reported," a?'D + 223° (c, 1 in water) ), in THE TOTAL SYNTHESIS OF PENICILLIN V frared spectra (KBr), m.p. 263° dec. (reported, Sir:

256-260° uncorr.), undepressed upon admixture. The ability of aliphatic carbodiimides to form amide bonds in aqueous solution directly from the

1) CHOCH COCI

HCI H2NCH-CH C(CH3)2 amine and carboxyl components under verv mild

(2) HCI conditions suggested the use of these reagents for co KH-CHCOH (3) CHỌN the cyclization of a pencilloic acid to a penicillin. We have prepared by total synthesis in good over

OC(CH) all yield the penicilloic acid corresponding to peni

II, D-a cillin V (phenoxymethylpenicillin). By use of N N'dicyclohexylcarbodiimide cyclization was effected

C,H,OCH,CONHCH-CH (CH3)2 rapidly at room temperature, thereby completing the first rational synthesis of a natural penicillin.?

Có VH-CHCOH Condensation of D-penicillamine with t-butyl

(1) KOH (one equiv.) phthalimidomalonaldehydate afforded the t-butyl

(2) C&H1N-C-=NCH11 D-2-4-carboxy-5,5-dimethyl-a-phthalimido-2-thiazolidineacetate (I), C20H12N206S, m.p. 161o dec.

S (Found: C, 57.45; H, 6.06; N, 6.83; c250 + 54° (c,1 in acetic acid)] as described for the cor

CH,OCH,CONHCH--CH (CH3)2 responding DL-c acid.3,4 The Q, or natural,

co_ CHCO configuration of the more soluble (ethanol-water)

penicillin V potassium I was established chemically by relationship to

(potassium phenoxymethylpenicillinate) natural dimethyl D-a-benzylpenicilloate. The less soluble D-y-isomer may be isomerized in high yield

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