174 Journal of Medicinal Chemistry, 1971, Vol. 14, S o . 2
New Compounds __
Some Aminoacyl Derivatives of Amino Sugar Nucleosides HERBhRT 4.F R I E D h L i X
Department of Pharmacology, rniversity of Pennsylvania, School of Medicine, Philaclelphza, Pennsylvania 19104 Received August 7 , 1970
It \-cab recently reported' that amino acid3 could be condensed v itli amino sugar nucleosides t o give the corresponding aminoacyl c'.-rivatives. I n the quest for ne\v potential nucleoside antibiotics the L - J ~ ~and S the L-Glu-ylle ester derivatives of 1-(3-amino-3-deos?-8D-glucopyranosy1)uracil n ere prepared. Tlieir y ntheses are given belov
4
I
RO R@
,
a,R=Ac;R=H b,R = A c ; R = Cbo.Nlu-r-hle ester C, R = OH; R = Cbo-L-Glu.r.Me este: d, R = O H ; R=L-Glu-r-Me ester e, R = OH, Ac, Ac , R = di-Cbo-L-Lys f , R = OH, Ac. Ac; R = L-LYS
I
OR
I Cbo = C, H CH-OCO Experimental Section2
1-(3-N-Carbobenzoxy-~-glutamylamido--,-methyl Ester 3Deoxy-2',4',6'-tri-O-acetyl- p-~-glucopyranosyl)uracil(Ib).-l-( 3Ani~no-3-deoxytri-O-acetyl-p-~-glucopyra~~os~~l)~~rac~l~ HC13 (1s. HC1) (1.2 g, 2.9 mmoles) was added to 7 ml of dry CHC1,. S o h took place upon the addition of 0.81 ml (5.8 mmoles) of E t 3 K . A second s o h was prepd containing S-Cbo-L-Glu-r-3Ie ester4 (856 mg, 2.9 mmoles), Et& (0.41 ml, 2.9 mmoles), and
was added t o 15 nil of aiihyd MeOH. Following the addition of 7 mg of arihyd LiOtI the s o h , protect,ed from moisture, was allowed t o stir for 26 hr a t room temp. Li ion was removed by the addit,ioii of a small amt of L)on.ex 50 ( H + ) resin and stirring the slurry for 1 hr. Silica gel tlc (CIICI3-hIeOH, 5 : 1) indicated one major vompoiieiit alorig with a trace of impurity. The compd had an indefinite melting point, yield 320 mg (85:; based on Ib). Anal. (C24HsoS,0,,~I120) C! H, P;. The HrO presumably came from the resin. 1-(3-S-~-Glutamylamido-y-methylEster 3-Deoxy-P-~-glucopyranosy1)uracil (Id).-Compd I Cm-as prepd without the isolation of I b aiid as dissolved in 80yc aq 3IeOK. The sohi p maintained at, ca. 1 by adding IlCl during hydrogenolysis Pd-C). T h e product, a tali-colored compd, was isolat,ed by tioii of the catalyst mid evapn of the supernatant soln. Recrystn from n-PrOH gave a compd in a yield o Ia). The melting point was of no value 60" and coritiiiued ;lowly with rising temp. Silica gel tlc (t-BuOH-MEK-H~O-ITHIOH 4 : 3 : 2 : 1 ) indicated minor impurities qirnilar to those fourid prior to pnrification. Anal. (CisH22?j,01.11C1.CaH;OH.E120)C, P;; H: calcd, 6.43; found, 5.63. 1 -( 3-;L',~~'-Dicarbobenzoxy-~-lysylamido-3-~~?oxydi-O-acetyl8-D-glucopyranosy1)uracil (Ie).-The prodedure followed was qimilar to that for Ib m d ICexcept that S,S'-di-Cbo-L-Lys6 waJ iwed. 1)uriiig the deacetylatioii reaction with LiOH a ppt d veloped which r a s filtered and wmhed well with EtIO; yield 18 (based 011 Ia), rnp 110-125°. Silica gel tlc (CHCI3-NeOH, 5:1 iiidicated :L pure wriipd. 4 n a i . (C3J3~&dh.CHaOH) C, II; N : cnlpd, 8.92: foiuid i3.4:3. The reiults iiidicate that oiily o i i i s ncetate group v-a* removed duriiig the deacetylatioii reaction, the resultant diacetoxy compd beiiig insol. Prolonged reaction times with iiicreased amts ( J f LiOH did not, change the results :iccording to tlr. The position of deacetylatiou remains uncertaiii. 1-( 3-~-Lysylamido-3-deoxydi-O-acetyl-~-~-glucopyranosyl)uracil Dihydrochloride (If).--The procedure followed was similar t,o that for I d except, thar EtOH wa-3 iised for trituration; white solid, yield 67'i (based on IC); nip 196-203". Anal. (CHHUY;0?.2HCI.0.3H.O) C ! €1; ?r: upported by :L grant from the Southeastern Pennsylvaniu Heart Aiw!:ntlon. ~ j )National
CHC13 (8 nil). Both solns were cooled to 0" in an ice bath. X e t h y l chloroformate (0.22 ml, 2.9 mmoles) was added to the second soln, and the mixturewas stirred for 20 min at 0". The wl:i contg the iiucleoside was added to the mixed anhydride, aiid the mixture was stirred for an additional 1.5 mill at 0" followed by overiiight stirring at room temp. The s o h was estd with 0.2 -1HCI, followed by a satd s o h of X a H C 0 8 itiid finally with HA) coiitg a few crystals of NaCl (to discourage emulsion formation!. The CHC13 layer was dried (XgSO,) and evapd in uacuo. Trituration of the residue with cyclohexane-CHC13 (10: 1) yielded t material (450 mg, 2 3 % ) . I t had an indefinite melting point begiiiiiiiig a t 105'. Silica gel tlc (CHCl3-XeOI-T, 5 : l ) indicated one spot with a slight trace of impurity. A n a l . ( C ~ O H ~ S XC, ~O H,I ~X). l-(3-LV-Carbobenzoxy-~-glutamylamido-y-meth~l Ester 3Deoxy-p-o-g1ucopyranosyl)uracil (IC).-Compound I b (460 mg) (1) 11. A . Friedman, I
