12
Vol. 77
B. R. BAKER,R. E. SCHAUB,J. P. JOSEPH AND J. H. WILLIAMS
Methyl 2,5-Di-O-acetyl-3-acetamido-3-deoxy-Lu-D crystallized by the addition of 10 cc. of heptane, followed by Recrystalli- furanoside (=a).-A mixture of 3.0 g. of XVIa, 3.4 g. of chilling; yield 2.6 g. (58%), m.p. 105-107'. zation of a similar preparation from the same solvents gave anhydrous sodium acetate and 36 cc. of methyl cellosolve white crystals, m.p. 107-108', [ a l t a D +S6' (3% in CHCL). containing 5% water was refluxed for 21 hours. The cooled Anal. Calcd. for ClsHloNOs.'/aHpO: C, 56.6; H , 6.34; mixture was filtered from sodium methanesulfonate (1.4 g.), then evaporated to dryness in vacuo. The residue was X, 4.40; HpO, 2.83. Found: C, 56.6; H , 6.66; N, 4.54; heated on the steam-bath with 30 cc. of reagent pyridine and H20, 3.93 (Fischer). 30 cc. of acetic anhydride for 1hour. Dilution with 150 cc. of Methyl 2-O-Mesyl-5-O-benzoyl-3-acetamido-3-deoxy-~iced water gave a clear solution which was extracted with n-arabinofuranoside (XVIIIa).-To a solution of 2.6 g. of XVa in 26 cc. of reagent pyridine was added 1.3 cc. of meth- three 50-cc. portions of chloroform. The combined extracts, anesulfonyl chloride with cooling. After 43 hours in a dried with magnesium sulfate and clarified with Norit, were evaporated to dryness in vacuo. The residue, tuice stoppered flask, the mixture was diluted with 3 volumes of water and extracted with chloroform. The combined ex- dissolved in 20 cc. of toluene and evaporated in vacuo to remove pyridine, readily solidified; yield 2.25 g. (94%), m.p. tracts, washed with aqueous sodium bicarbonate and dried In a larger run the yield was 11.8 g. (98%), m.p. with magnesium sulfate, were evaporated to dryness in 85-87'. 85-87'. Recrystallization of a pilot run (360 mg. (go%), vacuo leaving 3.0 g. (92%) of product as a colorless gum m.p. 85-87') from 1: 1 benzene-heptane gave white crystals, which could not be crystallized. ~ (2% in CHCL). m.p. 9C-9l0, [ a ] Z ai-135' Anal. Calcd. for CleHzlNOsS: Iv, 3.62. Found: N, Anal. Calcd. for C I ~ H I ~NO C,~ 49.8; : H , 6.62; N,4.85. 3.33. Found: C,49.5; H , 6.80; N,5.07. Methyl 2,5-Di-O-mesyl-3-acetarnido-3-deoxy-a-~-arabinoMethyl 2,5-Di-O-acetyl-3-acetarnido-3-deoxy-fl-~-ribofurfuranoside (XVIa).-To a solution of 15 g. of XIVa in 254 anoside (XXb).-From 10 g. of XVIb as doescribed for XXa cc. of reagent pyridine was added 15 cc. of methanesulfonyl Recrystallizachloride in portions with ice-cooling a t such a rate that the was obtained 7.5 g. (947&), m.p. 92-93 tion from benzene-heptane gave white crystals, m.p. 98-99', temperature was 10-20'. After 48 hours in a stoppered [ a l r 4$34.6' ~ (2% in CHCla). Bask, just sufficient water to dissolve the pyridine hydroAnal. Calcd. for C ~ Z H ~ ~ N C,O49.8; ~ : H, 6.62; S , 4.82. chloride was added. The solution was concentrated to Found: C, 49.7; H,6.56; N,4.69. about one-third in vacuo (bath 50'). Upon dilution with 200 cc. of water crystals began t o separate. After 2 hours 3-Amino-3-deoxy-~-riboseHydrochloride (XIX).-H> a t O " , the mixture was filtered and the product washed with drolysis of 330 mg. of XXa in 7 cc. of 1% and 0.1 cc. of conwater; yield 22.1 g. (84%), m.p. 122-124'. Recrystalli- centrated hydrochloric acid for 19 hours as described for zation of a similar preparation from absolute alcohol gave methyl 2,4-di-0-acetyl-3-acetamido-3-deoxy-a-~-ribopy~ white crystals, m.p. 125-126', [a]"D +104O (2% in pyr.). ranosidel gave 120 mg. (57%) of product, m.p. 150-151 Anal. Calcd. for Cld3l9NOe&: C, 33.2; H , 5.30; N, dec. Recrystallization from 0.2 cc. of water by addition of 0.3 cc. of concentrated hydrochloric acid afforded white 3.88. Found: C 3 3 . 6 ; H , 5.36; N,3.93. crystals, m.p. 159" dec., which had an infrared spectrum Methyl 2,5-Di-O-mesyl-J-acetamido-3-deoxy-fl-~-arabinofuranoside (XVIb). -Mesylation of 14.8 g. of XIVb as identical with authentic XIX.2 Similarly hydrolysis of 330 mg. of XXb gave 150 mg. described for XVIa gave 21.7 g. (84%) of product, m.p. 165-166". Recrystallization from alcohol afforded white (71%) of crude XIX, m.p. 147' dec. Recrystallization afforded white crystals, m.p. 159" dec., identical with crystals, m.p. 169-170', [a]*'D -88' (2% in pyridine). Anal. Calcd. for C10H19N0&: C, 33.2; H, 5.30; N, authentic S I X . 2 PEARL RIVER,SEW PORK 3.88. Found: C,33.5; H,5.48; N,3.89.
.
[CONTRIBUTION FROM
THE
CHEMICAL AND BIOLOGICAL RESEARCH SECTIOS, LEDERLE LABORATORIES DIVISION,AMERICAN CYANAMID COMPANY]
Puromycin. Synthetic Studies. IX. Total Synthesis BY B. R. BAKER,^ ROBERTE. SCHAUB, JOSEPH P.
JOSEPH AND JAMES
H. WILLIAMS
RECEIVED JULY 19, 1954 The conversion of methyl 3-amino-3-deoxy-u-ribofuranoside triacetate to 1-0-acety1-2,5-di-0-benzoy1-3-acetamido-3deoxy-D-ribofuranoside is described. Condensation of the titanium chloride complex of l-chloro-2,5-di-O-benzoyl-3-acetamido-3-deoxy-~-ribofuranoside with chloromercury 2-methylmercapto-6-dimethylaminopurinefollowed by desulfuriza(VII) identical tion and 0-debenzoylation afforded 6-dimethylamino-9-(3'-acetamino-3'-deoxy-~-~-r~bofuranosyl)-purine with that obtained from puromycin. Since VI1 previously has been converted t o puromycin (XI), a total synthesis of the antibiotic has been completed starting with D-xylose.
The synthesis of methyl 3-amino-3-deoxy-~ribofuranoside triacetate (111) from D-xylose has been described in the previous paper of this series.2 The conversion of this compound to the nucleoside, 6-dimethylamino-9-(3 '-acetamido-3'- deoxy -/3- D-ribofuranosyl) -purine (VII) is now presented. Since VI1 has been converted to puromycin (XI) via the aminonucleoside (X),a this sequence completes the ( 1 ) Papers VIT, VI11 and IX of this series were presented at the Sixth Summer Seminar in Natural Products at the University of New Brunswick, Canada, during the week of August 17, 1954, and at the A.C.S. Meeting in New York, September, 1954. (2) B . R. Baker, R . E. Schauh and J. H. Williams, THISJOURNAL, 77, 7 (1955), paper VI11 of this series. (3) B. R . Baker, J. P. Joseph a n d J. H. Williams, i b i d . , 77, 1 (lS55), paper VI1 of this series.
steps for a total synthesis of the antibiotic from D-xylose. 0-Deacetylation of crystalline methyl 3-amino3-deoxy-P-~-ribofuranoside triacetate (IIIb) with methanolic sodium methoxide gave, in quantitative yield, I I b as a glass which afforded 6&72y0 of a crystalline dibenzoate I b when treated with benzoyl chloride in pyridine a t 3". A study of acid hydrolysis conditions for cleavage of the glycosidic linkage revealed that the optimum conditions were 3 : 10 concentrated hydrochloric acid :acetic acid a t 50' for 25 minutes. 2,5-Di-O-benzoyl-3-acetamido3-deoxy-D-ribose (IV), m.p. 1 5 4 O , was obtained in 52y0 yield. Similarly, IV was prepared from triacemethyl 3-arnino-3-deoxy-a-~-ribofuranoside
TOTAL SYNTHESIS OF PUROMYCIN
Jan. 5 , 1955
13
bicarbonate treatment for work-up. Davoll, Lythgoe and Todde have circumvented this difficulty cH,oar with D-ribofuranose tetraacetate by use of ethereal hydrogen chloride, then simple removal of the excess solvent and reagent by evaporation in vacuo. This type of procedure, unfortunately, was unsucNHk OAc cessful with l-0-acetyl-2,5-di-O-benzoyl-3-acetamI II m ido-3-deoxy-~-ribofuranoside (V) due to the rapid HClformation of an ether-insoluble hydrochloride salt of the weakly basic amide group which stopped further reaction. Pacsu' has observed that D-glucopyranose pentaacetate will react with titanium tetrachloride in chloroform to give a titanium complex of l-chloroi D-glucopyranose tetraacetate. Cold water washN Me ings break the complex and remove the titanium salts leaving the chloro sugar, which can be isolated in good yield, in the chloroform layer. When titanium tetrachloride reacted with V, the time NHAc 082 of contact with cold water necessary to decompose m Ix the titanium complex VI was sufficient to hydrolyze the chloro sugar back to IV. At this point i t was realized that perhaps the titanium complex VI could be treated directly with chloromercury 2-methylmercapto-6-dimethylaminopurine8 t o give the nucleoside IX. When the condensation was NH OH run in boiling ethylene dichloride for 18 hours, a o=&FHCH,Q OCH, crude nucleoside was isolated as a gum. The ultraNHZ OH ", violet analysis of the gum showed the yield of I X X XI to be 94ojO. It is probable that the titanium is tate (IIIa) in 23% over-all yield, although the di- transferred t o the purine as the insoluble chlorobenzoate I a did not crystallize. The over-all yield mercury salt of the purine rapidly dissolves on was more than doubled when crude I a was cleaved addition of VI, then another precipitate separates. with 30Yc hydrogen bromide in acetic acid,4 form- If the reaction mixture is worked up a t this point no appreciable nucleoside IX is formed. ing 2,5-di-O-benzoyl-3-acetamido-3-deoxy-~-~boRaney nickel desulfurizationlO of X afforded VI11 furanosyl bromide. Hydrolysis with aqueous acetone-silver carbonate formed crystalline IV in 58% as a glass in 54y0 yield (determined by ultraviolet over-all yield from IIIa. Similar over-all yields of analysis). Removal of the 0-benzoyl groups by alcoholysis in methanolic sodium methoxide gave 6IV from IIIb were obtained by this process. This same key intermediate, IV, also can be ob- dimethylamino-9-(3'-acetamido-3'-deoxy -8 -D-ribotained from puromycin (XI) eria the aminonucleo- furanosy1)-purine (VII), m.p. 188', in 41% yield. side X and its N-acetyl derivative VII. Benzoyla- This material, as well as its 0-diacetate, were identition of VI1 in pyridine gave the 2',5'-di-O-benzoate cal in all respects with the natural VI1 and its 0VI11 in quantitative yield as an analytically pure diacetate obtained from puromycin. Thus a total glass. Hydrolysis with the refluxing two-phase synthesis of puromycin from D-XylOSe has been system, 2 N hydrochloric acid-ethylene dichloride, completed since VI1 has been previously converted gave a maximum yield of IV of 41y0after 4 hours. to puromycin. The identity of the 3-acetamido-3-deoxy-2,5-di-O- Acknowledgment.-The authors wish to thank benzoyl-D-ribose (IV) prepared by both methods W. McEwen and J. Poletto for large-scale prepaserves as an additional chemical proof that the ration of some of the intermediates, L. Brancone aminonucleoside X and puromycin XI have the D- and staff for the microanalyses and W. Fulmor ribose moiety attached to the purine in the fura- and staff for the rotations and spectra. nose form.5 Acetylation of IV with acetic anhyExperimental dride in pyridine a t 100" gave a quantitative yield Methyl 2,5-Di-0-benzoyl-3-acetamido-3-deoxy-p-~-riboof acetate V as a mixture of CY- and 8-forms from furanoside (a).-To a solution of 5.1 g. of crude IIIb2in 100 which one anomer, probably the 8-form, could be cc. of methanol was added 1.8 cc. of 1 N methanolic sodium crystallized. methoxide. After being refluxed for 30 minutes, the solution The standard method for preparing a 1-haloaceto was evaporated to dryness in vacuo leaving a glass. The sugar, namely, hydrogen chloride or bromide in (6) J. Davoll, B . Lpthgoe and A. R. Todd, J . Chcm. SOC.,967 (1948). acetic acid, is not suitable for the preparation of (7) E.Pacsu, Bcr., 61, 1508 (1928). (8) B. R.Baker, J. P. Joseph, R . E. Schaub and J. H. Williams, J . haloacylated sugar furanoses because of their great . Chem., l B , 1780 (1954),paper I V of this series. ease of hydrolysis during the cold aqueous sodium O m(9) The use of titanium complexes of chlorofuranose sugars for the a Series, d-Configurrrtion
b Scriee, b-Configurntion
(4) H.G.Fletcher, THIS JOURNAL. 76, 2624 (1953),has used this procedure to convert methyl 2,3,6-tri-O-benzoyl-n-ribofiiranoside to 2,3,6-tri-O-benzoyl-~-ribose. (5) C.W. W a l k , P. W. Fryth, B. L. Hutchings and J . H . Williams, N. Y. Meeting-in-miniature, Feb., 1954.
synthesis of nucleosides does not appear tu be general and is probably limited to 2- and 3-aminopentufuranose derivatives as will be reported in future papers. (10) R. Mozingo, D. E. Wolf, S. A . Harris and K. Folkers, THIS JOURNAL, 66, 1013 (1943).
14
I3. R. BAKER,R. E. SCHAUB, J. P.
JOSEPH AND
J. H. WILLIAMS
VOl. 77
residue was dissolved in 50 cc. of reagent pyridine and (?).-A solution of 6.0 g. of VI11 (prepared from purotreated dropwise with shaking and ice-cooling with 5.1 cc. mycin) in 60 cc. of ethylene dichloride and 60 cc. of 2 N hyof benzoyl chloride a t such a rate that the temperature was drochloric acid was refluxed for 4 hours. The separated 5-7". After 68 hours a t 3' in a stoppered flask, the mix- aqueous layer was extracted with ethylene dichloride. The ture was diluted with 200 cc. of water and extracted with combined organic solutions were further processed as in three 50-cc. portions of chloroform. The combined ex- preparation A; yield 1.8 g. (41%), m.p. and mixed m.p. A reflux period of 2 hours tracts, washed with aqueous sodium bicarbonate, dried with with preparation A, 150-152'. magnesium sulfate and clarified with Norit, were evaporated gave a 310/, yield whereas increase in reflux time to 19 hours to dryness in wucuo. Crystallization of the residue (8.2 g.) gave 24% yield. Hydrolysis procedure A gave only 18% from 14 cc. of benzene by the addition of hepta;e t o turbid- yield. l-U-Acetyl-2,5-di-U-benzoyl-3-acetamido-3-deoxy-a( and In other ity gave 4.7 g. (64%) of product, m.p. 139-141 runs the yields were 64-7270. Recrystallization from the p)-D-ribofuranoside (V).-A solution of 2.5 g. of IV in 5 cc. of reagent pyridine and 5 cc. of acetic anhydride was heated same solvents gave white crystals, m.p. 139-141', [a]"D on the steam-bath for 1 hour, then diluted with 25 cc. of iced +83" (1.5'%in CHC18). Anal. Calcd. for CZZH~~NO?: C, 64.0; H , 5.57; N, 3.39. water and extracted with one 25 cc. and two 15-cc. portions of chloroform. The combined extracts, dried with magneFound: C,63.9; H,5.57; N,3.52. sium sulfate, were evaporated t o dryness i n vacuo leavirig Similarly from 29.1 g. of I I I a was obtained 47.4 g. (114%) 2.7 g. (987,) of a slightly gummy solid, m.p. 127-131 . of crude methyl 2,5-di-U-benzoyl-3-acetamido-3-deoxy-cuRecrystallization from 8 cc. of ethyl acetate by addition of D-ribofuranoside (Ia) as a glass which could not be crystal- 8 cc. of heptane and followed by standing a t room temperalized. overnight gave 1.5 g. (54%) of one anomer, m.p. 1496-Dimethylamino-9-( 2 ',5 '-di-0-benzoyl-3 '-acetamido-3 '- ture 151'. Recrystallization from the same solvent afforded deoxy-p-D-ribofuranosy1)-purine (VIII) from Puromycin.To a solution of 11.2 g. of VIIS in 100 cc. of reagent pyridine white crystals, m.p. 152-154", [ c Y ] * ~ DfG3" (1.5% in pyriwas added 9.6 cc. of benzoyl chloride with ice-cooling a t dine). Anal. Calcd. for C&123X08: C, 62.6; H, 5.21; S , 3.18. such a rate that the temperature was 7-9' (7 minutes). After 17 hours a t room temperature in a stoppered flask, Found: C, 62.2; H, 5.31; N, 3.46. The filtrate from the 1.5 g. gave on evaporation 1.1 g. the mixture was poured into 400 cc. of iced water and ex(40%) of a gum which could not be crystallized and had tracted with three 100-cc. portions of methylene chloride. [cuIz4~ t84' (2% in p-yridine). The combined extracts were washed with aqueous sodium 2-Methylmercapto-6-dethylamino-9-( 2 ',5'-di-0-benbicarbonate, dried with magnesium sulfate and evaporated to dryness in vacuo leaving 18.3 g. (101%) of a glass which zoyl-3'-acetamido-3 '-deoxy-p-D-ribofuranosyl )-purine (IX). -To a solution of 990 mg. of V (a,p-mixture, m.p. 127could not be crystallized, but was nearly pure. 131') in 8.5 cc. of ethylene dichloride was added a solution Anal. Calcd. for C28Hz8N606: C , 61.8; H , 5.18; N, 15.4. of 0.30 cc. of titanium tetrachloride in 4.4 cc. of ethylene diFound: C,62.0; H,5.34; N, 14.7. chloride. A yellow precipitate separated which quickly 2,5-Di-0-benzoyl-3-acetamido-3-deoxy-~-ribose (IV). (A). redissolved. After being refluxed for 1 hour, the yellowish-To a solution of 5.0 g. of Ib in 50 cc. of acetic acid was brown solution mas added to a stirred mixture of 1.25 g. of added 15 cc. of concentrated hydrochloric acid. The solu- chloromercury 2-rnethylmer~apto-6-dimethylaminopurine,~ tion was stirred in a 50" bath for 25 minutes, then diluted 1.35 g. of Celite and 90 cc. of ethylene dichloride which had with 175 cc. of ice-water. The gum which separated was been dried previously by distilling off 20 cc. of solvent. The collected by extraction with 75 cc., then two 50-cc. portions chloromercury purine rapidly dissolved and in a few minutes of chloroform. Washed with aqueous sodium bicarbouate a different precipitate separated. The mixture was reand dried with magnesium sulfate, the combined extracts fluxed and stirred for 18 hours, then treated with 45 cc. of were evaporated to dryness in vacuo. Crystallization of the water and stirred without heating for 15 minutes. The residue (3.6 g.) from 10 cc. of ethyl acetate by the addition mixture was filtered and the solids washed with hot chloroof heptane to turbidity followed by standing a t room tem- form. The separated organic layer from the combined perature overnight gave 2.5 g. (52%) of product, m.p. 144filtrate and washings was evaporated in vacuo leaving a 147'. Several recrystallizations of a similar preparation glass. This was dissolved in 25 cc. of chloroform and from the same solvents gave white crystals, m.p. 153-154", washed with 25 cc. of 30% aqueous potassium iodide, then [cY]~~ + lDO 8 ' (2% in pyridine). The cornpouiid gave a posi- water. Dried with magnesium sulfate and clarified with tive Benedict test in dilute alcohol. Norit, the chloroform solution was evaporated to dryness Anal. Calcd. for C ~ I H ~ I N OC, ? : 63.1; H , 5.26; N, 3.51; in vacuo leaving 1.33 g. (100%) of a glass which had Lax hleO, 0.0. Found: C, 63.2; H , 5.89; N, 3.41; MeO, 0.0. 282.5 mp (E 17,000) in methyl cellosolve, corresponding to a When the above reaction time was increased to 1 hour or maximum purity of 94%. The lower peak* was masked by decreased, the yield was lowered. Hydrolysis a t room benzoate adsorption a t 230 mp. Anal. Calcd. for CBI&JNBO~S:C, 59.0; H , 5.12; S , temperature for 30 minutes gave 71% recovery of starting 14.2. Found: C, 58.1; H, 5.50; N, 12.6. material. The use of 48% aqueous hydrobromic acidx e t i c acid mixture a t room temperature, boiling 1 N hydro6-Dimethylamino-9-(2 ',5 '-di-O-benzoyl-3 '-acetamido-d 'chloric acid and chloroform for 2 hours or boiling 0.1 N hy- deoxy-p-D-ribofuranosyl)-purine(VIII) (Synthetic).-A soludrochloric acid in 50% alcohol for two hours gave crude tion of 1.28 g. of the preceding I X in 75 cc. of methyl celloproducts which a t best gave only a poor Benedict test and solve was stirred with 2 spoonsful of desulfurizing Raney from which no IV could be isolated. nickello on the steam-bath for 40 minutes. The hot solu(B).-Hydrolysis of 1.27 g. of crude Ia (obtained in 108% tion was filtered through Celite and the catalyst washed yield) as in procedure A gave 0.255 g: (23% from IIIa) of several times with hot methyl cellosolve. Evaporation of product, m.p. and mixed m.p. 146-149 . the combined filtrate and washings to dryness in vacuo left ( C ) . y T o a solution of 46.6 g. of crude Ia (obtained in 0.705 g. (60%) of a glass which had 27,5 m p (e 16,900) 114% yield) in 93 cc. of methylene chloride was added 233 in methyl cellosolve or a maximum purity of 90%. cc. of 30% hydrogen bromide in acetic acid.4 After 2 hours Anal. Calcd. for C28H~8N606:C, 61.8; H, 5.18; W, the solution was diluted with 116 cc. of methylene chloride 15.5. FoulId: C, 59.4; H , 5.80; N, 12.1. and washed twice with 930-cc. portions of ice-water, then 6-Dimethylamino-Q-(3 '-acetamido-3 '-deoxy-p-D-ribofurexcess aqueous sodium bicarbonate. The methylene chlo- anosy1)-purine (VII) (Synthetic).-A solution of 690 mg. of ride solution was treated successively with 460 cc. of ace- the preceding VI11 in 15 cc. of dry methanol and 0.14 CC. tone, 4.6 cc. of water and 46 g. of silver carbonate. After of 1 N methanolic sodium niethoxide was refluxed for 30 being vigorously stirred for 30 minutes, the solution was minutes, then evaporated to dryness in WQCUO. The residue filtered through Celite, then evaporated t o dryness in vacuo. was dissolved in 3 cc. of hot alcohol and the solution was Crystallization of the residue from 120 cc. of ethyl acetate clarified with Norit. Coolin5 afforded 130 mg. (30%) of white crystals, m.p. 184-186 . Recrystallization from alby addition of 100 cc. of heptane gave 19.1 g. (48% fro? A mixture with VI1 obIIIa) of product in three crops, m.p. between 142 and 150 . cohol raised the m.p. to 187-188'. Retreatment of the residue from the mother liquors with tained from puromyciriJ gave no depression in m.p. and both had identical infrared spectra and specific rotations. hydrogen bromide, then silver carbonate gave an additioual C, 50.0; H , 6.00; N, 25.0. Anal. Calcd. for CI4H2oN~O4: 3.4 g. (total 58%) of product. Acetolysis of Ib gave similar Found: C,49.X; H,5.93; N,25.2. over-all >ields of 1 x 7 froin IIIb.
.
A NOVEL BREAKDOWN OF
Jan. 5, 1955
The filtrate from the 130 mg. was evaporated to dryness
in vacuo. Acetylation of the residue with acetic anhydride
in pyridine as described for xggave a glass. Crystallization from ethyl acetate afforded 60 mg. (11%)of white crystals, m.p. 185-187’. A mixture with 6-dimethylamino-9-(3’-
[CONTRIBUTION FROM
Puromycin.
THE
THE
PURINE RINGSYSTEM
15
amino-3’-deoxy-,9-~-ribofuranosy~)-purinetriacetate obtained from puromycin’ gave no depression in m.p. and both compounds had the Same infrared spectra.
PEARL RIVER,NEW YORK
CHEMICALAND BIOLOGICAL RESEARCH SECTION,LEDERLELABORATORIES DIVISION,AMERICAN CYANAMID COMPANY]
Synthetic Studies. X.
A Novel Breakdown of the Purine Ring System
BY B. R. BAKERAND
JOSEPH
P.
JOSEPH
RECEIVEDJULY 19, 1954 6-Dimethylamino-9-(5’-methanesulfonyl-3’-amino3’-deoxy-~-~-ribof~anosyl)-purine 2’,3’-carbonate (VI) has been found to quaternerize easily t o V. The latter is very labile t o 0.1 N base at25’, hydrolyzing rapidly to 5’,N4-cyclo-3-(2’,3’-carbonyl3’-amino-3 ’-deoxy-~-~-ribofuranosyl)-4-formam~do~m~dazole-5-( N,N-dimethyl)-carboxamidinemethanesulfonate (IV) which in turn hydrolyzes more slowly to 5’,N4-cyclo-3-(2’,3’-carbonyl-3’-amino-3‘-deoxy-~-~-ribofuranosyl)-4-amino~idazole-5carboxamide (VII). Biological implications are suggested for this sequence.
The total synthesis of the aminonucleoside, 6- gum insoluble in water and readily soluble in chlorodimethylamino-9-(3‘-amino - 3‘-deoxy-@-D -ribofur- form. However, after standing at room temperaanosy1)-purine (I), from D-xylose’ and its partial ture for several days or, more efficiently, by refluxsynthesis from the antibiotic, puromycinI2 have ing in chloroform for two hours, the gum changed been described recently. Since the aminonucleo- to an isomeric crystalline product, m.p. 283” dec., side I is highly active against the transplanted in 91% yield which was now insoluble in chloroform, adenocarcinoma of the CsH mouse3 as well as but readily soluble in water. The salt-like characTrypanosoma equiperdum4in mice, i t was considered ter of this compound could be explained most readdesirable to prepare some functional analogs of the ily by reaction of the 5’-mesylate with the %nitroaminonucleoside I by replacement of the 5’-hy- gen of the purine ring to form a 3,5‘-cyclonucleodroxyl with other groups (IX) v i a a 5’-mesylate. side V. That the purine ring system had been furAlthough the general method of approach failed, a ther alkylated readily could be seen by the shift in novel breakdown of the pyrimidine portion of the the ultraviolet maximum in water from 275 mp for purine ring system was observed and is the subject an ordinary 9-nucleoside derivative of 6-dimethylaminopurineBsuch as I to 288 mp. of this paper. The conversion of adenosine to its 5’-methylmerClark, Todd and Zussmang have described the capto derivative Via 2‘,3’-isopropylidene-5’-tosyla- formation of a similar quaternary salt when 2’,3‘denosine has been described by Satoh and Makino6 isopropylidene-5‘-tosyladenosine was heated a t as well as Baddiley, Trauth and Weygand.6 A 100’ in acetone or dioxane. Their proposed strucsimilar sequence with the aminonucleoside I was ture was beautifully substantiated by X-ray investigated. Reaction of I with carbobenzoxy crystallographic analysis. Their results also serve chloride and triethylamine in dimethylformamide to explain why only about 2% yield of 5’-methylafforded the carbobenzoxy derivative I1 in 78% mercaptoadenosine can be obtained from the 5‘yield. Ring closure of I1 to the cyclic urethan 111 t o ~ y l a t e . ~The ~ ~ rate of monomolecular quaterniwith elimination of benzyl alcohol proceeded zation is obviously much more rapid than the bismoothly in 93% yield with a catalytic amount of molecular displacement reaction with mercaptide sodium methoxide in dirnethylf~rmamide.~The ion. Since the 6-dimethylaminopurine nucleoside formation of this cyclic urethan I11 was substanti- (VI) appears to quaternerize even more rapidly ated by the hypsochromic shift of the carbonyl ab- than in the adenine series, the use of VI as an insorption of the carbobenzoxy group from 5.87 to termediate in displacement reactions could not 5.62 p in the infrared as would be expected for a five- possibly lead to useful yields of functional analogs membered ring bearing a carbonyl. With the 2‘- of the aminonucleoside IX. The usual routine measurement of the ultraviolet and 3‘-groups now effectively blocked in 111, the remaining 5‘-hydroxyl was mesylated smoothly in absorption spectra a t p H 1, 7 and 14 on the quaterpyridine a t 3’ to give VI in 80% yield as a crude nary salt VI showed an instability a t p H 14. Within five minutes the initial peak a t 230 mp be(1) B. R. Baker, R. E. Schaub, J. P. Joseph and J. H. Williams, gan to shift and in one hour was a t 235 mp. Then a paper I X of this series, TEXIS JOURNAL, 77, 12 (1955). (2) B. R . Baker, J. P. Joseph and J. H . Williams, paper VI1 of this slower shift to 272 mp over 27 hours (Graph 1) series, ibid., 77, 1 (1955). gradually took place, thus indicating a t least two (3) P. Lydick, S.Halladay and J. J . Oleson, to be published. break-down products. The quaternary salt V ab(4) R.I. Hewitt, A. Gumble, W. S. Wallace and J. H. Williams, A m . sorbed at 288 mp a t PH 1 and 7 showing that it J . Trop. Med., in press. (5) K.Satoh and K. Makino, Nature, 167, 238 (1951). could not protonate further which contrasts to an (6) J. Baddiley, 0. Trauth and F. Weygand, ibid., 167, 359 (1951); ordinary nucleoside such as I which will protonate J. Baddiley, J. Chcm. Soc., 1348 (1951); F. Weygand and 0. Trauth, in acid giving a hypsochromic shift of 7-8 mp.8 Chcm. Bcr., 84, 633 (1951). (7) The base-catalyzed condensation of ethanolamine with ethyl carbonate to form 2-orazolidone, which probably proceeds through ethyl N-(8-hydroxyethy1)-carbamate, has been described by A. H. Homeyer, U.S. Patent 2,399,118.
(8) B. R. Baker, R. E. Schauh and J. P. Joseph, paper I1 of this series, J . Ora. Chrm., 19,638 (1954). (9) V. M. Clark, A. R. Todd and S. Zussman, J. Chcm. Soc., 2952
(1951).
