J. Andersen, E. B. Pedersen

1.25% HCIIROH

705

8OoC

Anomalously Coupled Nucleosides, I1

Reaction of 3-[N6-(4-Chlorophenyl)-2-methyl-9-adenyl]-2,3-dideoxy-~-threo- pentopyranose with Alcohols and Anilines Jesper Andersen and Erik B. Pedersen"

Department of Chemistry, Odense University, Campusvej 55, DK-5230 Odense M, Denmark

Received March 16, 1987

3- [ N"-(4-C hlorp henyt)-l-met hyl-9-adenyl]-2.3-dideoxy-~-lbreo- pcntopyranosc (1) has been converted into the alkyl 3-[P-(4- clila rop henyl)-2-me thyI-9-adenyl]-2,3-dideoxy-o-rhreo-pento~y- raiiosides 2 and into thc N-aryl-3-~N6~4-chlorophenyl)-2-methyl- ~)-adc:nyl]-2.3-dideoxy-~-fhreo-pcntopyranosylamines 4. Thc compounds 2 wcre isolated as mixtures of CL and p anorners whc- reas pure u momers 3 could be ohiained after prolonged reaction I II11L'S.

Recently, we have reported the direct preparation of 3- (N6-aryl-2-methyl-9-adenyl)-2,3-dideoxy-~-threo-pentopyra- noses by the condensation of 2-deoxy-~-ribose with an ap- propiate adenine derivative in a phosphorus reagent com- posed of tributylammonium salts of trimetaphosphoric acid, pyrophosphoric acid, and phosporic acid in chloroform'). Previous to our synthesis, 2,3-dideoxy-3-(9-purinyl)-~-pen- topyranoses were reported only in connection with unsuc- cessful attempts of synthesizing 2'-deoxynucleosides from 2- deoxy-D-ribose and adenine or hypoxanthine under pre- biotic c o n d i t i o n ~ ~ ~ ~ ) . Although 3-(9-adenyl)-2,3-dideoxy-~- pentopyranose can be prepared under simple biotic condi- tions it has not yet been reported as a natural product, but this may happen when its spectroscopic properties and its chemistry is better explored than today. It is known that its stability towards acid and base is reversed when it is com- pared to adenosine*). The aim of the present work was there- fore to investigate whether its alkyl glycosides and its gly- cosylamines could be prepared in normal manner under acidic and alkaline conditions, respectively. For this purpose 1 was selected because this adenyl-D-pentopyranose deriv- ative was the one which we could prepare in higher yields.

By a modification of the Fischer m e t h ~ d " ~ , ~ ) 1 was heated with 1.25% (mol procent) alcoholic hydrogen chloride at 80°C until 1 had disappeared on TLC (Table 1). The re- sulting alkyl glycoside hydrochloride was neutralized by a saturated solution of ammonia in methanol to give an ano- meric mixture of alkyl 3-[@-(4-chlorophenyl)-2-methyl-9- adenyl]-2,3-didesoxy-~-threo-pentopyranosides 2. Exten- sion of the reaction time to 3 days gave mainly the ct anomer 3 which was isolated in a state of purity after recrystalliza- tion. The phenomenon that an axial polar group, in this case an alkoxy group, on the anomeric C-1 in the carbo-

Ungewiihnlicb vcrkniipfte Nucleoside. 11''. - Reaktion von 3[W- ( 4 - C h l o r p h e p y I ) - Z m e t b y I - 9 9 d w y l ~ - ~ i d ~ o x y - o - r ~ c ~ ~ n l o - pyranm mit Akobolen und Aniliaen

3-[ ~-(4-Chlo~henyl)-2-methyl-9-adeny1~-23-didesolry-o-r Iirro- pentopyranose (1) wurde in die Alkyl-3-[N6-(4-chlorphenyl)-2-mc- thyl-9-adenyi]-2,3didesoxy-~-thrco-pentopyranoside 2 und die N-Ar y l-3-[ Nb-(4-chlorphenyll-Z-rne t hyI-9-adenyl]-2.3-didesoxy- ~-~hreo-pentopyranosylaine 4 umgewanddt. Die Verbindungen 2 wurden als cr/P-Anomcren-Gemischc isolicrt, bei vcrlangertol Reaktionweiten wurden jcdoch reine a-Anomcre 3 crhaltcn.

40-180 min I 3days

2

2h

R

n-C4Hy 3a iso-C4Hy 3b sec-C4Hy 3h

~

n-C8H17

R

CZH, n-C3H7 n-C4Hy

hydrate moiety is more stable than the corresponding equa- torial group, is known as the anomeric effect 'I.

Liebigs Ann. Chem. 1987, 705 -708 0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1987 0170-2041/87/0808 -0705 $ 02.50/0

706 J. Andersen, E. B. Pedersen

4 R

4 1 a b c d e

R 1 3-Br 3-CI 4-CI 3,4-CI2 4-C02Et

2-Deoxy-~-ribose has been treated with arylamines in either ethanol or hydrous ethanol and ammonium chloride to give the corresponding N-aryl-2-deoxy-~-erythro- pent~sylamine~,~). The 2-deoxy-~-ribose derivative 1 was too insoluble in ethanol to be condensed with arylamines in this way. But the condensation of 1 with arylamines substituted with electron-withdrawing groups was carried out by heat- ing with ammonium chloride in hydrous solutions of eth- ylene glycol for 1-4 days at 70- 100°C (Scheme 2) to give N-aryl-3-[N6-(4-chlorophenyl)-2-methyl-9-adenyl]-2,3-di- deoxy-D-threo-pentopyranosylamines 4 in 36 - 59% yields. When the stronger base, aniline, was used as the arylamine we observed cleavage of the bond between the carbohydrate moiety and the purine ring in agreement with earlier re- ported alkaline lability of 2,3-dideoxy-3-(9-purinyl)-~- pentopyranoses’). Furthermore, in most cases we found that 4 was too unstable to be recrystallized which resulted in epimerization in the deoxypyranose ring to give an approx- imate one to one molar ratio of a and p anomers. 4e was isolated as pure a anomer.

From the above experiments we draw the conclusion that compounds of type 1 under acidic conditions behave like ordinary sugars whereas they are stable under extreme weak alkaline conditions, only.

The structures of the compounds prepared were con- firmed by MS, ‘H NMR, including 500-MHz spectra”) of 2b, 3a, and 4c and I3C NMR measurements along with reference data of 1 I). The 13C chemical shift values of 4 were assigned according to carbon numbering given in Scheme 2.

Experimental Alkyl3-[N6- (4-Chlorophenyl) -2-meihy1-9-adenyl]-2,3-dideoxy-o-

threo-pentopyranosides 2 and 3 b -c. - General Procedure: 1 (3.00 g, 0.008 mol) and 0.008 mol hydrogen chloride as an 1.25% (mol percent) alkoholic hydrogen chloride solution were mixed at room temp. The mixture was heated with stirring on an oil bath at 80°C for the reaction time given in Table 1. The alcohol was evaporated in vacuum, and the resulting hydrochloride was neutralized by stir- ring it in 200 ml of a saturated solution of ammonia in methanol for 1 h. The solution was evaporated to dryness, and the crude product was washed with water, and recrystallized (Table 1).

Ethyl 3-[N6-(4-Chlorophenyl)-2-mefhyl-9-ndenylj-2,3-dideoxy-cc-o- threo-petopyranoside (3a): The same procedure as in the general

was followed, except that absol. ethanol (15 ml) was added to the 1.25% ethanolic hydrogen chloride solution.

Table 1. Preparation of 2 (anomeric mixtures) and 3 (pure CL an- omers) as well as elementary analyses of 2 and 3

Analysis React. Mol ratioa) Mol. (Mol. mass) C H N No. time CI: p

(% Yield) (M.P.~) [ T I )

2a 60min 1: l CI8HzoC1N5O3 Calcd. 55.46 5.17 17.96 (60) (287-290) (389.84) Found 55.15 5.21 17.72

2b 150min 1:1 C19H22C1NS03 Calcd. 56.51 5.49 17.34 (57) (279-283) (403.87) Found 56.49 5.50 17.18

2c 4 0 m i n l : t C20H24C1NS03 Calcd. 57.48 5.79 16.76 (52) (265-268) (417.89) Found 57.60 5.87 16.31

2d 120min 2.3:1 Cz0H24C1N503 Calcd. 57.48 5.79 16.76 (56) (274-278) (417.89) Found 57.40 5.80 16.44

2e 90min 1.3:1 C2,H2&1NS03 Calcd. 58.40 6.07 16.21 (50) (241-243) (431.92) Found 58.60 6.13 15.76

2f 180min 1.4:1 C21HZ6C1NS03 Calcd. 58.40 6.07 16.21 (47) (258-264) (431.92) Found 58.35 6.06 16.00

2g 105min 5 : l C21Hz6C1N503 Calcd. 58.40 6.07 16.21 (56) (254-258) (431.92) Found 58.33 6.06 16.05

2h 135 min 1.2:1 C2,H34CIN503 Calcd. 61.53 7.02 14.35 (55) 237-249 (488.03) Found 61.09 7.06 14.28

3a 3d - C,9H22C1N503 Calcd. 56.51 5.49 17.34 (53) 306-307 (403.87) Found 56.48 5.50 17.13

3b 3d - Cz0Hz4ClN5O3 Calcd. 57.48 5.79 16.76 (47) 297-298 (417.89) Found 57.74 5.82 16.56

3c 3d - C21HZ6ClNS03 Calcd. 58.40 6.07 16.21 (43) 254-256 (431.92) Found 57.94 6.07 16.15

a) Estimated on basis of the ‘3C-resonance intensities of C-~’(cL) and C-l’(p) from the carbohydrate moiety. - b, 2a-d, 2h and 3a-c were recrystallized from methyl cellosolve and 2e- g from ethanol.

N- Aryl-3-(N6-chlorophenyl) -2-methyl-9-adenyl]-2,3-dideoxy-~- threo-pentopyranosylamines 4. - General Procedure: 1 (1.25 g, 0.0033 rnol), ethylene glycol (30 ml), water (3 ml), ammonium chlo- ride (0.18 g, 0.0033 mol), and the appropriate primary aromatic amine (0.0132 mol) were mixed at room temp. and then heated on an oil bath at 70-100°C with mechanical stirring for 22 h to 4 d. The reaction mixture was allowed to cool to room temp., and the precipitate was filtered off, washed with 20 ml ethylene glycol, 40 ml water, and 40 ml ether and dried. The crude product was worked up as described for each compound. The mol ratios CL: p were es- timated on the basis of the I3C-resonance intensities of C-~’(cL) and c - 1 ’( p). N- (3-Bromophenyl) -3-[W- (4-chlorophenyl)-2-methyl-9-adenyl j- 2,3-dideoxy-~-threo-pentopyvanosylnmine (4a): Obtained from 3- bromoaniline, reaction temp. 70”C, reaction time 22 h. The crude product was dissolved in cold DMSO (25 ml), the solution was filtered, and the product was precipitated by adding water (10 ml). The product was collected and washed with 100 ml water, and 50 ml ether; yield 43%, mol ratio CL: p = 3: 1, m.p. 199°C (dec.). - ‘H NMR ([D,]DMSO): 6 = 3.84-5.27 (m; I/-, 2‘-, 3’-, 4‘-, 5’-H, 2-CH3, OH), 6.76-7.43 (m, a r -H, a r - H , NH), 7.99-8.27 (m, ar- H”, 8-H), 9.87 (s, N6-H). - 13C NMR ([D,]DMSO): 6 = 26.0 (2- CHJ, 33.8 [C-~’(CL)], 35.7 [C-Y(p)], 55.3 [C-~’(CL)], 58.2 [C-3’(p)], 62.1 [C-~’(CL)], 66.3 [C-4’(p)], 67.4 [C-~’(CL)], 67.9 [C-5’(p)], 78.2 [C- ~’(cL)], 81.0 [C-I’(p)], 112.5 (C-6), 115.5 (C-2”’), 118.5 (C-5), 119.7 (C-4”’), 121.8 (C-2”), 122.1 (C-3”’), 125.7 (C-4), 128.1 (C-3”), 130.6 (C-5”’), 139.0 (C-1”), 141.0 (C-8), 148.3 (C-I”’), 150.8 (C-4), 151.3

Liebigs Ann. Chem. 1987, 705 - 708

Anomalously Coupled Nucleosides, I1

(C-6), 160.1 (C-2). - MS: m/z (Yo) = 528 (1.3, M+), 259 (98), 258 (loo). C23H22BrC1N602 . 7/4 H 2 0 . 1/4 DMSO (580.9)

Calcd. C 48.59 H 4.68 N 14.47 Found C 48.50 H 4.36 N 14.63

Table 2. ’H NMR data of 2 and 3a’

‘H NMR ( [D6]DMSO/TMS)

No. 6 values

2a 1.95-2.57(m,2’-H,2-CH3),3.37-4.83(m,OCH3,1’,3’,4’,

5’-H),5.25(d,6Hz,OH),7.39(d,9Hz,Ar-H),8.10(d,9Hz,

Ar-H) ,8.34( s, 8-H( B ) ) ,8.38( s, 8-H(a) ) ,9.85 (s ,N6-H).

2b,3ab) 1.08( t,7.1Hz,CH3(8)) ,1.17(t,7.1Hz,CH3(a)) ,2.00

2c,3b

2d

2e, 3c

2f

2g

2h

(dd,Z’-He(a) ),2.07(ddd,2’-He18)),2.29(td,2’-Ha(B)),

2.47(td,Z’-Ha(a)),2.5O(s,2-CH3),3.23(dd,5’-Ha(8)),

3.41(dq,9.7Hz,7.1Hz,0CH2(a)),3.46(t,5’-Ha~~)),

3.49( dq, 9.7Hz,7.1 Hz ,0CH2(6) ),3.63(dd, 5’-He(a) 1 ,

3.64(dq,9.7Hz,7.1Hz,0CH2(n)).3.75(dq,9.7Hz,7.1Hz,

OCH2(8)),3.89(dd,5’-He(8)),4.08(td,4’-H(E)),

4.13(td,4’-H(o)),~.40(ddd,3’-H(E)),4.58(ddd,3’-H(a)),

4.64(dd,l’-H(8)),4.9l~d,l’-H(a)),7.31(d,8.9Hz,Ar-H~,

7.99(d,8.9Hz,Ar-H),8.25(~,8-H(B)),8.32(~,8-H(o)),

9.78( b, N6-H( a ) ) , Y .79 ( s , N6-H( 8) ) . 0.87(t,6Hz,CH3(6)),0.97(t,6Hz,CH3(a))1.33-2.58

(m,CH2,Z’-H,2-CH3),3.23-5.00(m,1’,3’,4’,5’-H,OCH2),

5.27(d,6Hz,OH),7.40(d,9Hz,Ar-H),8.12(d,9Hz,Ar-H),

8.34(s,8-H(B)) ,8.43(s,8-H(a)) ,9.87(s,N6-H).

1.16(d,6Hz,CH3(o)),1.27(d,6Hz,CH3(8)),1.83-2.59

(m,2’-H,2-CH3),3.15-5.13(m,1’,3’,4’,5’-H,OCH),5.25

(d,GH7,OHj,7.39(d,9Hz,Ar-H),8.12(d,9Hz,Ar-H),8.35

( s ,8-H( 8 ) ,8.42(s, 8 - H ( m ) ) ,9.85(s ,N6-H).

0.76-1.76(m,CH2CH2CH3),1.98-2.57(m,2’-H,2-CH3),

3.24-4.96(m,1’,3’,4’,5’-H,OCH2),5.23(d,6Hz,OH),7.34

(d,SHz,Ar-H),8.05(d,9Hz,Ar-H),8.30(s,8-H(E)),8.35

( 5 , E-H(~) ),9.79( :, , N~-H) . 0.87(d,6Hz,CH3(E)),0.95(d,6Hz,CH3(a)),1.57-2.58

(m,2’-H,CH,Z-CH3),3.f7-4.93(m,1’,3’,4’,5’-H,OCH2),

5.25(d,6Hz,OH),7.36(d,9Hz,Ar-H),8.07[d,9Hz,Ar-H),

8.32( s, 8-H( E ) ),8.36(s, 8-H(a) ) , 9. el(s,N6-H).

0.74-1.69(m,CH2CIl7,CH3),1.87-2.59(m,2’-H,2-CH3),

3.23-5.09(m,1’,3’,4’,5’-H,OCH),5.24(d,6Hz,OH),

7.38(d,9Hz,Ar-H),B.OS[d,9Hz,Ar-H),8.34(s,8-H(8

8.39( s, 8-H( a ) ) ,9.83 (s , N6-H).

0.86-1.70(m,(CH2)6CH3),1.89-2.55(m,2’-H,2-CH3)

3.07-4.95(m,1’,3’,4’,5’-H,0CH2),5.24(d,5Hz,0H)

7.35(d,9Hz,Ar-H),R.O6(d,9Hz,Ar-H),8.32(s,8-H(B

8.37( s, 8-H( a ) ,9.116(s ,N6-H) .

a’ The spectra of 2 and 3 wcre recorded at 60 MHz with exception of 2b and 3a which were recorded at 500 MHz. - b, 2b, 3a: J[Hz] - a(P):J(1’-H,2’-HC) = 0.0 (2.0), J(1’-H,2’-Ha) = 3.0 (9.4), J(2’-He,2’-H3 = 12.6 (12.5), J(2’-He,3’-H) = 5.1 (4.9, J(2’-Ha,3’- H) = 12.8 (12.5), J(3’-H,4’-H) = 10.3 (9.9), J(4’-H,5’-He) = 5.3 (5.2), J(4-H,5’-Ha) = 10.6 (10.2), J(5’-He,5’-H,) = 11.0 (1 1.4).

Liebigs Ann. Chem. 1987, 705 - 708

707

Table 3. 13C NMR data of 2 and 3”’

Pentose C No. Anomer C-1 c-2 c-3 c-4 c-5 c-1

2a 97.0 34.9 54.2 66.6 62.8 53.9 f 101.1 35.8 56.6 67.1b) 66.6b) 55.7

2b,3a o 95.6 35.0 54.3 66.8 62.8 61.9 6 99.8 36.0 56.7 66.8 66.8 6 3 . 5

2c,3b II 95.8 34.9 54.4 66.8 62.8 68.0 8 100.0 36.0 56.7 66.8 66.8 69.8

2d 93.1 35.3 54.3 67.0 62.9 67.8 B 98.1 3 6 . 6 5 6 . 8 67.0 67.0 69.4

2e.3~ m 95.8 34.9 54.4 66.7 6 2 . 8 66 .1 8 100.0 36.0 56.6 66.7 66.7 67.8

2f 95.9 34.9 54.5 65.7 62.8 73.1 6 100.3 36.0 56.6 56.7 66.7 74.9

2 2 ) (1 95.2 35.3 54.4 66.9 63.0 74.0 - 93.0 35.3 54.4 66.9 6 3 . 0 71.9

B 99.6 36.6 56.7 66.9 66.9 75.6 97.7 36.6 56.7 66 .9 66.9 74.0

2h 95.8 34.9 54.4 66.7 62.8 66.7 B 100.0 36 .0 56.7 66.7 66.7 68.2

None of the shift values for the purine and P-aryl carbon atoms for 2 and 3 deviate more than 0.1 ppm from the following values; purine moiety: 6 = 160.0 (C-2), 151.2 (C-6), 150.7 (C-4), 140.8 (C- 8), 118.3 (C-5), 25.8 (2-CHJ; N6-aryl: 6 = 139.0 (C-l), 128.1 (C-3, C-5), 125.6 (C-4), 121.7 (C-2, C-6). - b, The assignments may be interchanged. - Racemic mixture of 2-butanol gave four isomers.

N- (3-Chlorophenyl)-3-[N6- (4-chlorophenylj-2-methyl-9-adenyl]- 2,3-dideoxy-~-threo-pentopyranosylamine (4b): Obtained from 3- chloroaniline, reaction temp. 70°C, reaction time 4 d. The crude product was purified with DMSO and water as described for com- pound 4a; yield 59%, mol ratio u: b = 20: 1, m.p. 184°C (dec.). - ‘H NMR [([D,]DMSO): 6 = 1.84-5.29 (m, 1’-, 2- , 3’-, 4‘-, 5’-H, 2-CH3, OH), 6.61 -7.44 (m, ar-H”, ar-H”’, NH), 7.99-8.26 (m, ar- H”, 8-H), 9.86 (s, N6-H). - I3C NMR ([D,]DMSO): 6 = 26.0 (2- CH3), 33.8 [C-~’(U)], 35.3 [C-2’(p)], 55.3 [C-3’(a)], 58.2 [C-S’(p)], 62.1 [C-~’(C()], 66.2 [C-4’(b)], 67.4 [C-4(a), C-S’(P)], 78.2 [C-l’(a)], 80.9 [C-I’(p)], 112.1, 112.6 (C-2”’, C-6”’), 116.8 (C-4”’), 118.5 (C-5), 121.7 (C-2”), 125.7 (C-4”), 128.1 (C-3”), 130.3 (C-5”’), 133.4 (C-3”’), 139.0 (C-1”), 141.0 (C-8), 148.2 (C-l”’), 150.8 (C-4), 151.3 (C-6), 160.1 (C-2). - MS: m/z (%) = 484 (2.2) [M’], 259 (loo), 258 (87), 31 (32). C23H22CI2N602 ’ 3 H2O . 1/2 DMSO (578.5)

Calcd. C 49.83 H 5.40 N 14.53 Found C 49.59 H 4.95 N 14.67

N- (4-Chloropheny1)-3-(P- (4-chlorophenyl)-2-methyl-9-adenyl]- 2,3-dideoxy-~-threo-pentopyranosylamine (4c): Obtained from 4- chloroaniline, reaction temp. 70”C, reaction time 3 d. The crude product was recrystallized from 96% ethanol; yield 57%, mol ratio a : 0 = 1 : 1.5, m.p. 205°C (dec.). - ‘H NMR ([D6]DMSO): 6 = 2.09 [dd, 2’-He(a)], 2.16 [ddd, 2’-He(P)], 2.51 [td, 2’-Ha(B)], 2.52, 2.53 [2-CH3(a), 2-CH,(P)], 2.81 [dt, 2’-Ha(a)], 3.36 [dd, 5’-H,(P)], 3.43 [t, 5’-Ha(a)l, 3.53 [dd, 5’-He(a)], 3.85 [dd, 5’-He(p)], 4.12 [td, 4’-H(a)], 4.20 [td, 4-H(P)], 4.48 [ddd, 3’-H(P)], 4.78 [ddd, 3’-H(a)], 4.84 [td, l’-H(P)], 5.16 [t, l’-H(ct)], 6.67 [d, 9.0 Hz, ar-H”’(P)], 6.73 [d, NH(P)], 6.79 [d, J = 9.0 Hz, ar-H’”(~)], 6.91 [d, NH(a)], 7.10 [d, J = 9.0 Hz, ar-H”’(b)], 7.13 [d, J = 9.0 Hz, ar-H”‘(a)], 7.32 (d, J = 9.0 Hz, ar-H”), 7.99 (d, J = 9.0 Hz, ar-H”), 8.21 [s, 8-H(a)], 8.24 [s, S-H(P)], 9.81 (s, N6-H); J [Hz] - a (0): J(1’-H,2’-He) = 0.0 (1.8), J(1’-H,NH) =z 5.0 (9.0), J(1‘-H,2’-Ha) = 5.0 (9.0), J(2’-He,2’- H,) = 13.0 (12.2), J(2’-He,3’-H) = 4.6 (4.5), J(2’-Ha,3’-H) = 13.0 (12.5), J(3’-H,4’-H) = 10.8 (10.2), J(4’-H,5’-He) = 5.3 (5.2), 44’- H,5’-Ha) = 10.8 (10.2), J(5’-H,,5’-Ha) = 11.1 (10.5). - I3C NMR

708 J. Andersen, E. B. Pedersen

([D6]DMSO): 6 = 26.0(2-CH,), 33.9 [C-~’(U)], 35.7 [C-T(p)], 55.4 (C-3’(~)],58.4 [C-3’(p)], 62.0 [C-~’(CL)], 66.3 [C-4’(@)], 67.5 [C-~(CL)], 67.9 [C-5’(p)], 78.4 [C-l’(a)], 81.3 [C-l’(p)], 114.8 (C-2), 118.5 (C-5), 120.7 (C-4), 121.7 (C-2”), 125.7 (C-4) , 128.1 (C-3”), 128.5 (C-3”’), 139.0 (C-I”), 141.1 (C-8), 145.3 [C-~”‘(U)], 145.5 [C-l”‘(P)], 150.6 [C-~(U)], 150.8 [C-4@)], 151.3 (C-6), 160.1 (C-2). - M S m/z (%) = 484 (1.9) [M’], 259 (31), 258 (24), 31 (100).

Calcd. C 56.39 H 4.63 N 17.16 Found C 56.42 H 4.57 N 16.87

Cz~HzzCI2N602 ‘ 1/4 H2O (489.9)

3-[N6- (4-Chlorophenyl)-2-methyl-Y-adenyl]-2,3-dideoxy-N- (3,4- dichlorophenylj-n-threo-pentopyranosylamine (4d): Obtained from 3,4-dichloroanihne, reaction temp. 70”C, reaction time 4 d. The crude product was purified with DMSO and water as described for compound 4a; yield 36%, mol ratio a:p = 1:3.4, m.p. 172°C (dec.). - ‘H NMR ([D6]DMSO): 6 = 1.84-5.24 (m, 1’-, 2’-, 3’-, 4’-,5’-H, CH3), 6.65 - 7.42 (m, ar-H”, ar-H”’, NH), 7.99 - 8.30 (m, ar- H”, 8-H), 9.88 (s, N6-H). - 13C NMR ([D6]DMSO): 6 = 26.0 (2- CH,), 33.9 [C-2’(~r)], 35.5 [C-2’(p)], 55.2 [C-~’(CL)], 58.2 [C-3’(p)], 62.2 [C-S’(a)], 66.3 [C-4(p)], 67.4 [C-4(a)], 67.8 [C-S’(p)], 78.1 [C- l’(~)], 80.9 [C-l’(p)], 113.8, 114.3 (C-6”’, C-2”’), 118.2 (C-5), 121.8 (C-2), 125.7 (C-4 ) , 128.1 (C-3”), 130.5 (C-S”’), 131.1 (C-3’7, 139.0 (C-1”), 141.2 (C-8), 146.2 (C-l”’), 150.6 (C-4), 151.3 (C-6), 160.1 (C- 2); C - 4 was not observed. - MS: m/z (%) = 518 (3.8) [M’], 259 (loo), 258 (86).

C ~ ~ H ~ ~ C I ~ N S O ~ . 3/2 HZO .1/4 DMSO (566.4) Calcd. C 49.84 H 4.54 N 14.84 Found C 49.99 H 4.23 N 15.06

OH), 6.46-8.37 (m, ar-H”’, ar-H”, 8-H, NH), 9.86 (s, N6-H). - 13C NMR ([D,]DMSO): 6 = 14.3 (CH,), 26.0 (2-CH3), 33.6 (C-2’), 55.3 (C-3’), 59.7 (OCH2), 62.3 (C-53, 67.3 (C-4), 77.8 (C-l’), 112.6 (C-2), 118.3 (C-4) , 118.6 (C-5), 121.7 (C-2”), 125.7 (C-4), 128.1 (C- 3”), 130.6 (C-3”’), 139.0 (C-I”), 141.0 (C-8), 150.8 (C-4, C-l”’), 151.3 (C-6), 160.1 (C-2), 165.7 (C=O). - MS: m/z (%) = 522 (24) [M’], 259 (loo), 258 (79, 31 (62).

C26H27ClN604 ‘ I/2 DMSO (562.1) Calcd. C 57.70 H 5.38 N 14.95 Found C 57.48 H 5.37 N 15.20

CAS Registry Numbers

la: 104091-26-1 / 18: 104091-36-3 / 2aa: 108319-92-2 / 2ap: 108319-93-3 / 2ba: 108319-94-4 / 2bp: 108319-95-5 / 2ca: 108319- 96-6 / 2cp: 108319-37-7 / 2da: 108319-98-8 / 2dp: 108319-99-9 / 2ea: 108320-00-9 / 2ep: 108320-01-0 / 2fa: 108320-02-1 / 2fS: 108320-03-2 / 2ga (R isomer): 108320-04-3 / 2ga (S isomer): 108320-16-7 / 2gp (R isomer): 108320-05-4 / 2gp (S isomer): 108320-17-8 / 2ha: 108320-06-5 / 2bp: 108320-07-6 / 4aa: 108320- 08-7 / 4ap: 108320-09-8 / 4ba: 108320-10-1 / 4ca: 108320-11-2 / 4cp: 108320-12-3 / 4da: 108320-13-4 / 4dp: 108320-14-5 / 4ea: 108320-15-6 / 3-bromoaniline: 591-19-5 / 3-chloroaniline: 108- 42-9 / 4-chloroaniline: 106-47-8 / ethyl 4-aminobenzoate: 94-09-7

’) Part I: J. Andersen, E. B. Pedersen, Liebigs Ann. Chem. 1986,

2, J. A. Carbon, J. Am. Chem. Soc. 86 (1964) 720. 3, G. L. Nelsestuen, Biochemistry 18 (1979) 2843. 4, E. Fischer, Ber. Dtsch. Chem. Ges. 26 (1893) 2400. 5 , E. Fischer. Ber. Dtsch. Chem. Ges. 28 (1895) 1145.

1837.

Ethyl 4- (3-[N6-(I-Chlorophenyl)-2-methyl-y-adenyl]-2,3-dideoxy- cr-D-threo-pentopyranosylaminolbenzoate (4e): Obtained from ethyl 4-aminobenzoate, reaction temp. loo”C, reaction time 41 h. The crude material was dissolved in cold DMSO (25 ml). The solution was filtered, and the product was precipitated by adding methanol (50 ml). The product was collected and washed with methanol; yield 50%, m.p. 227°C (dec.). - ‘H NMR ([DdDMSO): 6 = 1.33 (4 J = 7 Hz, CH,), 1.90-5.40 (m, It- , 2’-, 3’-, 4 - , 5’-H, 2-CH3, OCH2,

6, R. E. Deriaz, w. G. Overend, M. Stacey, L. F. Wiggins, J. Chem.

7 ) S, J. ~ ~ ~ ; ~ l , A ~ ~ ~ . J , them, 21 (1968) 2737, *) R. E. Deriaz, W. G. Overend, M. Stacey, E. G. Teece, L. F.

Wiggins, J . Chem. Soc. 1949, 1879. 9, C. Yoshikumi, F. Hirose, Y. Ohmura, T. Fujii, M. Ikuzawa, M.

Ohhara, K. Matsunaga, T. Ando, Ger. OSfen. 3,038,327 (April 23, 1981) [Chem. ~ b ~ ~ ~ , g5 (1981) 49421 p ~ ,

lo) Klaus Bock, The Technical University of Denmark, is greatly acknowledged for recording NMR spectra.

[48/871

Soc. 1949 2836.

Liebigs Ann. Chem. 1987, 705 - 708