SYNTHESIS OF FUSED T-LACTAM-THIAZOLIDINES RELATED TO PENICILLIN
Aug. 20, 1952
4093
Anal. Calcd. for C16HzzOaNsBr:C, 52.18; H , 6.02. (19.5 g.) and methyl iodide (8 8.) in dry ether (200 ml.) and dry benzene (70 ml.) was added dropwise t o magnesium (5 Found: C, 51.94; H , 5.95. S-Bromo-S-methoxy-4a-rnethyl-l,2,3,4,4a,Q, 10,loa-octa- g.). When the addition was complete the reaction mixture hydrophenanthrene (X). A.-A solution of ketone VI (57 was refluxed for an hour t o complete the formation of the 9.) in ether (100 ml.) was added dropwise t o a cold solution Grignard reagent. The reaction k s k was cooled in an icebath and dry cadmium chloride (15 8.) was added. The of methylmagnesium iodide prepared from magnesium (6.1 mixture was stirred and heated for 15 minutes and then 150 g.), methyl iodide (40 g.) and dry ether (300 ml.). After standing overnight the reaction mixture was treated with ml. of ether was distilled off and replaced by dry benzene. ammonium chloride solution and the ether layer was sepa- A solution of 8-carbomethoxypropionyl chloride (14 8.) in rated, washed with water and concentrated. The crude dry benzene (20 ml.) was added quickly and the reaction alcohol VI1 (60 9.) was dissolved in benzene (40 ml.) and mixture stirred and refluxed for an hour. After standing for cyclized with sulfuric acid (600 ml.) and water (126 ml.) as a day a t room temperature the contents of the flask was poured into a mixture of ice and hydrochloric acid and the in the preparation of VIII. The crude cyclized product crystallized when seeded and stirred with a small amount of product extracted with ether. The residue remaining after absolute ethanol. The first crystals were obtained when a evaporation of the ether was boiled for 8 hours with a solusmall sample purified by evaporative distillation was al- tion of potassium hydroxide (10 g.) in water (60 ml.) and lowed to stand for six months. Thzre was obtained 45 g. ethanol (300 ml.). The ethanol was distilled off and water (78%) of X which melted a t 85-89 After recrystalliza- and ether were added to the residue. The ether layer was concentrated and after distillation 6.3 g. of I X and 1.9 g. of tion from ethyl acetate the pure product melted a t 93-94'. Anal. Calcd. for Cl6HtlOBr: C, 62.14; H , 6.85; Br, X were recovered. By acidification of the water layer there was obtained 8.8 g. (42%) of acid which solidified after seed25.84. Found: C, 62.24; H , 6.93; Br, 25.82. ing (first crystals were obtained after purification by B .-A solution of 5-methoxy-4a-methyl-1,2,3,4,4a,9,10,10a- chromatography silicic acid). The product was reoctahydrophenanthrene (IX) (230 mg.) in carbon tetra- crystallized from on ligroin, m.p. 120-121.5" (yield 6.2 g , ) . chloride (10 ml.) was treated with a solution of bromine (160 An additional amount (1.1 9.) of less pure material, m.p. mg.) in carbon tetrachloride (3.2 ml.) a t 0'. The reaction 117-120°, was recovered from the mother liquors. mixture was washed with water and the carbon tetrachloride Anal. Calcd. for C ~ O H M OC,~ :72.70; H, 7.90. Found: evaporated. The residue crystallized on standing and was C, 72.94; H, 7.92. recrystallized from ethyl acetate. The melting points of .Dehydrogenation of 1X.-The bromine atom was removed this product and the mixture with the product from part A from X (0.5 g.) by shaking with hydrogen and nickel in were 92-93.5'. ,%a-( 5-Methoxy-4a-methyl-I ,2,3,4,4a,Q,lO,loa-octahy- alkaline solution. The crude product was heated with drophenanthroy1)-propionic Acid (XI) .-A cold solution of palladium-on-charcoal (0.1 9.) for 6 hours at 270-300" and aluminum chloride (6 9.) and succinic anhydride (2.2 g.) in for one hour a t 320". Some crystalline product sublimed nitrobenzene (80 ml.) was added t o a solution of IX (4.5 g.) out of the reaction mixture. The crude dehydrogenated in nitrobenzene (70 ml.) and the mixture allowed to stand product was converted to the picrate which after recrystalliin the refrigerator for 72 hours. The reaction mixture was zation melted at 185-187' and was identical with an autreated with dilute hydrochloric acid and ether. The ether thentic sample of 4-methoxyphenanthrerie picrate.' The layer was separated and the acidic products extracted with trinitrobenzene adduct prepared as previously described' dilute potassium hydroxide solution. Acidification of the melted a t 206-208". Some cleavage of the methoxyl group alkaline extract produced 5.6 g. (87%) of crude crystalline occurred during this dehydrogenation since phenanthrene, acid. The product (4.9 g.) melted a t 151.5-153' after m.p. 95-97', was isolated by concentrating the filtrates purification by recrystallization from methanol. .4nal. Calcd. for C ~ O H P ~C, O ~72.70; : H, 7.90. Found: after separating 4-methoxyphenanthrene picrate and treating the residual mixture of picric acid and phenanthrene C, 72.53; H , 8.01. picrate with ammonia and ether. D-S-( 5-Methoxy-4a-methyl-l,2,3,4,4a,9,10, loa-octahyNEW JERSEY drophenanthroy1)-propionic Acid (XII).-A solution of X NEW BRUNSWICK,
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[CONTRIBUTION FROM
THE
COXVERSE MEMORIAL LABORATORY O F HARVARD ~ X I V E R S I T Y ,A S D LABORATORY O F YALE UNIVERSITY]
THE
STERLIXG CHEMISTRY
Studies on the Mucohalic Acids. 11. The Synthesis of Fused r-lactam-thiazolidines Related to Penicillin1 BYHARRYH. WASSERMAN, FRANK M. PRECOPIO AND TIEN-CHUAN LIU* RECEIVED FEBRUARY 21, 1952 Mucochloric, mucobromic and mucophenoxychloric acids were condensed with dl-penicillamine hydrochloride and its methyl ester to form fused y-lactarn-thiazolidines structurally related to the penicillins. The 2-thiazolidineacrylic acids pictured as intermediates appeared to cyclize to y-lactams either spontaneously or after mild heating.
The condensation of cysteine and penicillamine with aldehydes and ketones to form thiazolidines takes place under a wide variety of conditons.2-4 In the case of the reaction with aldehyde-acids, the
*
M a r y E. Woolley and Skinner Fellow from M t . Holyoke College 1951-1952. (I) I n part, from the doctoral dissertation of H. H. Wasserman, Harvard University, 1948. (2) H. T. Clarke, J. R. Johnson and R. Robinson, Editors, "The Chemistry of Penicillin," Princeton University Press, princeton, N. J . , 1948, p. 921. (3) s. Lieberman, P. Brazeau and L. B. Hariton, THISJOUR~VAL. 70, 3094 ( 1 9 4 8 ) . (4) M. P. Schubert, J (1037); 130, 601 (1030).
Bioi
C.hetth., 114, 311 (193G); 121, 530
initial thiazolidine formation may be followed by interaction of the carboxyl group with the cyclic imino group to produce a fused lactam-thiazolidine. Although p-lactam formation by this utilizing a-aldehydo-acids, has never been observed, y-lactams have been prepared successfully by the use of P-aldehydo-acids. Thus, as reported in the recent monograph on the chemistry of penici11inJ5derivatives of P-formylprOpiOniCacid were condensed with the appropriate a-amino6-mercapto acids to form thiazolidines which readily cyclized to fused-ring y-lactams. Among ( 5 ) Refcrericc 2 , p . 1004
13. H.IY.iSSERM,iN, F. l f . PRECOPIO AND T. LIV
4094
lrol. 74
the compounds prepared by this procedure was the y-lactam of benzylhomopenicilloic acid {I), a homolog of benzylpenicillin.
When mucophenoxychloric acid (IC),was allowed to react with the methyl ester of dl-penicillamine hydrochloride under the same conditions, it was possible to isolate an acidic intermediate as well as the neutral lactam. The acid I11 (R = CHa, X = C1, Y = OC6H5) was characterized by its ready cyclization, through gentle warming, to the y-lactam (VII). The analogous reaction between cysteine hydrochloride or its methyl ester with mucochloric acid 1 The present work describes the reactions of did not take place smoothly. On mixing solutions of the reactants under the conditions described several 0-formylacrylic acids in the mucohalic acid series with dl-penicillamine (11, R = H ) and its above, an immediate yellow coloration appeared , iollowed by gradual darkening of the solution. methyl ester (11, R = CH.3) t o form fused ylactam-thiazolidines (IV, V, VI and VII). These S o crystalline product could be isolated from this lactams are structurally related t o the penicillins, reaction mixture. The infrared absorption spectra of the y-lactamand might provide, through suitable methods of ring thiazolidines (V, VI and VII) (Fig. 1), are in accortl contraction, a synthetic route toward the fused pwith the assigned structures. Each of the products lactam-thiazolidine ring systcni present in the exhibits a broad band in the 5.8-5.83 p region of the p c nicillins. The c o n d e n s a t i o ~shown ~ in the reaction scheme spectrum, corresponding t o a superposition of ester and fused y-lactam carbonyl groups. (It was not I1 OII possible to resolve this band into the two carbonyl \ / coinponents.) Other fused y-lactams have been .CIIO ITS 1--c S-C. ‘C ( CH I ? reported to absorb in the 5.8 p region of the infra0 -+ -r + red,6 as in the case of the y-lactam of benzylhomoy C -, f-y.-c, CH penicilloic acid (I), the methyl ester of which has a ‘COOII H i d \COOK c band at 535 p attributed to the carbonyl present in 11 0 the fused y-lactam ring. 11 la, S = Y = C1 Acknowledgment.-One of the authors (H.H.\V.) Ih, S = Y = Rr acknowledges the very pleasant association with I C , s = el; Y = OC&T, Professor R. B. Woodward at Harvard University during t.hc course of which this work was begun.
F \
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Experimental’ I l l
Mucohalic Acids.-The mucochloric, mucobromic mi! niucophenoxychloric acids used in this investigation w-erc prepared according to the methods of Hill and co-workcrs Methyl Ester of dl-Penicillamine Hydrochloride. The methyl ester was prepared by bubbling dry HC1 into ; I solution containing 19 g. of dl-penicillamine hydrochloridc in 150 ml. of dry methanol in an ice-bath for three hours. After storage in the cold overnight, the solution was filtered, refluxed on the steam-bath for two hours, and then evapcirated t o dryness in vacuo. The residue was dissolved in tbutyl alcohol, decolorized with charcoal, and chilled. Clusters of needles gradually separated, m.p. 174-176”. After recrystallization from t-butyl alcohol, 6.2 g. (30%).of ester was obtained, melting 175176”. The melting point previously reported1’ was 1 7 3 - - 1 7 5 O . -(-Lactam of 4-Carboxy-5,5-dimethyl-2-thiazolidine-~, ddichloroacrylic Acid (IV).--4n aqueous solution (10 nil. ) containing one gram of dl-penicillamine hydrochloride buffered with one equivalent of sodium acetate was mixed with 5 nil. of an ethanolic solution of rnucochloric acid (0.91 g. !, niid eiiough ethanol was adtled to tli olve any solid precipit:itiiig. The solutioii ITUS refi-iger et1 overnight, ivhercup011 a straw-coloreci oil scpur:ttecl. This oil was I~-:ISIILY 1 w i t h 5oyb cthaiiol and tlie solid wliich s c y a r ~ t r t l LIS wcrystallized from briizetir. I n this way, 0.8 g. (52L?,) t l i tiny prisms was obtained which melted 153-154’ (dec.). 011standing a t room temperature the lactam slowly tieromposed with the development of it greeu coloration. This acid showed none of the characteristic tests for M free sulfhydryl group (no transient blue coloration with ferric chloride, no deep red-violet coloration with alkaline sodium nitroprusside). liltll.--
0
11. S = C1. Y = C1 V. R = CH.,. X = C1. Y = C1
I\’. R
=
took place it1 cold aqueous ethanolic solution buffered with an equivalent of sodium acetate to form the lactams iri yields of .SO-SO(!”,. In three of the iour cases cited, lactam iormation appeared to take place spontaiieously, and no iiitermecktc thiazolidineacrylic acid was isolated, Thus, the reactioii between niucochloric acid (la), and til1)enicillanii1ieliytlrocliloride readily ?-ieltlrtl a 1110110carboxylic acid C~HUO&SCI~ which showed 1101ie of the characteristic tests for a free sulfhydryl group. Treatment with diazomethane converted tha acid t u u methyl ester which was ideIitica1 with the product derived from the direct condensatiuri of mucochloric acid with the methyl ester of dlpenicillamine hydrochloride. On the basis of these facts the above condensation products were assigned the fused y-lactam-thiazolidinestructures 11‘ a:icl V, .\ siiiiilar reactioil took 1)lace with IiulcoLromic acitl ( I l ) ) , yielding the y-lactain-tliiazolictitic. ~ 1 - 1 ) .
Aug. 20, 1952
SYNTHESlS OF
FUSED7-LACTAM-THIAZOLIDINES RELATED TO PENICILLIN
4095
Anal. Calcd. for C;H,OaNSCle: C, 38.22; H, 3.22; 90 N, 4.96; S, 11.38; neut. equiv., 282. Found: C, 38.52; H , 3.28; N, 5.26; S,11.54; neut. equiv., 279. y-Lactam of 4-Carbomethoxy-5,5-dethyl-2-thiazolidine-a,@-dichloroacrylicAcid (V). ( a ) . - O n e gram of the y-lactam of 4-carboxy-5,5-dimethyl-2-thiazolidine-a,~-dichloroacrylic acid was dissolved in dry ether and ethereal diazomethane was added in slight excess till the yellow color persisted. The ether was allowed to evaporate slowly, 10 whereupon large prisms (1 g.) were obtained, m.p. 99-100". 90 Anal. Calcd. for C1~H1103NSC12: C, 40.55; H, 3.74. Pound: C, 40.63; H, 3.89. & c (b).-A solution of 0.314 g. of rnucochloric acid in 5 ml. 0 of 95% ethanol was added to a soltition containing 0.369 g. vi of penicillamine methyl ester hydrochloride and 0.309 g. .$ of sodium acetate in 10 nil. of water. The oil which formed on cooling gradually solidified. Recrystallization fro? c c ethanol yielded 0.47 g. (85'%) of white crystals m.p. 98-99 @ 10 This sample was shown, by mixed melting point and comparison of infrared spectra, to be identical with the methyl 90 ester prepared by method (a). Anal. Calcd. for CloHllOaNSClz: C, 40.55; H, 3.74; S,4.73. Found: C,40.41; H,3.78; N,4.92. y-Lactam of 4-Carbomethoxy-5,5-dimethyl-2-thiazolidinea,P-dibromoacrylic Acid (VI).-The condensation of mucobromic acid with dl-penicillamine methyl ester hydrochloride was carried out in the same manner as described for the rnucochloric acid addition product above. The dibromo10 lactam ( V I ) m.p. 96-98' WAS recrystallized from a mixture of I , , , , ethanol ant1 w'tter, and then from ethanol alone. On staud3 5 7 9 11 ing the lactam slowly decomposed. The yield was 48%. LVave length, microns. Anal. Calcd. for CloHllOaNSBm: C, 31.19; H, 2.88; S,8.32; N , 3.64. Found: C, 31.40; H , 3.03; S,8.34; K, Fig. 1.-Infrared spectra: (1) y-lactam of 4-carbometh3.70. - a -phenoxy @- chloroacrylic 4 Carbomethox 5,s dimethyl-2-thiazolidine-a-phenoxy- oxy-5,5-dimethyl-2-thiazolidine P-chloroacrylic Acii-( Iu).-&Penicillamine hydrochloride acid (VII); (2) r-lactam of 4-carbomethoxy-5,5-dimethyl-2methyl ester (0.304 g.) was dissolved in 10 ml. of water con- thiazolidine-a, @-dichloroarylicacid (V); (3) r-lactam of 4taining 0.131 g. of sodium acetate, and t o the solution was carbomethoxy- 5,5 dimethyl 2 - thiazolidine - a,@ dibromoadded an equivalent amount (0.341 9.) of mucophenoxychloric acid in 5 ml. of 95% ethanol. Enough alcohol was acrylic acid (VI). All spectra were taken in chloroform added to dissolve the solid which separated. The solution solution (0.1-mm. cell), using a Perkin-Elmer, Model 21 was kept in the cold for 12 hours, whereupon a crystalline instrument. product separated. A second crop of crystals was obtained by adding water to the mother liquor and cooling. The solid product was washed with cold dilute sodium bicarbon- phenoxychloric acid with dl-penicillamine methyl ester hyate, the bicarbonate solution separated from neutral mate- drochloride was recrystallized from ethanol-water. Its rial, and then acidified. From the acid solution there was melting point was 90.592". The free acid (111) was conobtained 0.2 g. of acid, m.p. 95'. This product was char- verted t o the same product (no depression of mixed melting acterized by conversion, through gentle warming, to the y- point) by warming the bicarbonate solution of the acid on the steam-bath, whereupon the crystalline lactam m.p. lactam (VII). 90.5-92' separated. The total yield of crude lactam was Anal. Calcd. for ClaHI806NSC1: C, 51.68; H , 4.84; N, 0.48 g. (90%). 3.76; C1, 9.53. Found: C, 5168; H, 4.92; N, 3.86; C1, Anal. Calcd. for C I ~ H ~ ~ O I N S C C,l : 54.31; H, 4.56; 9.72. N, 3.96; S, 9.06. Found: C, 54.32; H, 4.95; N, 4.15; y-lactam of 4-Carbomethoxy-5,5-dimethyl-2-thiazolidine- S,10.27. a-phenoxy,@-chloroacrylic Acid (VII).-The bicarbonateiiisoluble product derived from thc condensation of muco- NEW HAVEN,CONN. . L
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