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Biosci. Biotech. Biochem., 59 (9), 1801-1803, 1995

Short Communication

A New Reaction of Adenine with a 1,4-Anhydrorihitol Having a Vicinal cis-Oriented Azide and O-Tosylate: Formation of a Novel Aziridinoadenine Isonucleoside

Hiroshi OHRUI,t Toshiaki WAGA, Akihiro VENO, Manabu OKAMOTO, Hiroko HORIE, Hiroshi MEGURO, and Chizuko KABUTO* Department of Biological Chemistry, Faculty of Agriculture, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981, Japan * Department of Chemistry, Faculty of Science, Tohoku University, Aramaki, Sendai 980, Japan Received April 19, 1995

Adenine reacted with 1,4-anhydro-3-azido-5-0-benzoyl-3-deoxy-2-0-p-toluenesulfon-yl-D-ribitol (4) to unexpectedly give aziri­dinoadenines (6 and 7), whose structures were determined by X-ray crystallography.

There has recently been considerable interest in regio­isomeric nucleosides, in which the heterocyclic base is at­tached to the C-2 or the C-3 position of the sugar moiety, as potent anti-HIV agents. 1- 5) As a part of our study in this field,3) we have commenced the synthesis of iso­nucleosides having an a-azide group at C-3 of 1,4-anhydro-D-pentitol, according to general structure A in Fig. I, by condensing of 4 with heterocyclic bases. In this paper, we describe a novel reaction of 4 with adenine. Compound 4 was prepared from 16) by Scheme 1, and it will be noteworthy that the azide group is compatible under triethysilane reduction conditions. The reaction of 4 with adenine in DMF at 115°C in the presence of K2C03 and 18-crown-6, the same conditions that have been used to prepare the corresponding 3-deoxy, 3-a-hydroxyl, and 3-a-hydroxymethyl adenine isonucleosides,2,3) gave three syrupy products 5, [aJo + 68.0° (c 0.56, MeOH), 6, [aJo + 65.1 0 (c = 0.89, CHC13), and 7, [aJo + 73.3 (c = 0.69, CHCI3) in 10%, 16%, and 15% yields, respectively. The structure of 5 was determined to be expected 2-p-(9-adenyl)-1,4-anhydro-3-azido-5-0-benzoyl-2,3-dideoxY-D-arabinitoI

on the basis of its HRMS, IR, IH-NMR, and UV data. Compounds 6 and 7, which did not show an N 3 (2100 cm - 1) absorption in their IR data, had the same elemental composition (C17H16N603 by HRMS) and almost the same 1 H -NMR data, but differed only in their UV data, indicating they were 9- (259 nm) and 7- (273 nm) positional isomers of substituted adenine, respectively. In the IH-NMR spectrum of 6 (Fig. 2), one of the C-l methylene protons appeared as a sharp doublet, and the other did as a slightly broadening doublet to suggest the absence of a proton in their vicinal positions. Therefore, the structure of 6 was tentatively assigned to be B (Fig. 1). In structure B, all the

BzO

A

N H

B

Fig. 1. Structures of the Target 3-ilC-Azide Isonucleosides and Tentatively Assigned B.

Bz0'q a BZo'q b BZOp c BZO~ ---.... OMe ---.... ---.... R

o Na 0+ Na OH Na OH Na OTs

2 3 4: R=H 4': R=D

NH2

~N~N ~ BzO'fJJ..N~

Scheme 1. Reagents and Conditions.

Na

5: R=H (10%) 5': R=D

+

e

6 + 7 16% 15%

8

a) Dowex 50w x 8, MeOH, 90°C; b) BSA, TMSOTf, Et3SH, r.t.; c) TsCI, py, r.t.; d) adenine, K2C03, 18-crown-6, DMF, 115°C; e) p-BrBzCI, py, O°c.

t To whom correspondence should be addressed.

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1802 H. OHRUI et al.

H-5' H-4 H-5

I H-1

. !

H-1

H-2

(H-3) NH

Fig. 2. 270 MHz lH-NMR spectrum of 6 in CDC1 3.

Br

Fig. 3. Structure of 8 by an X-ray Study .

..

6

Scheme 2. Plausible Mechanism for the Formation of 6 from 4.

lH-NMR signals could be reasonably interpreted, for example, broadening of one of the H -1 protons was due to W-type long-range coupling with H-3, and no coupling between H-3 and H-4 was due to their trans stereochemistry on the tetrahydrofuran ring. However, the mechanism for

deriving B from 4 was not clear at all. In order to obtain more insight into the reaction mechanism, the reaction of deuterated 4' with adenine under the same conditions was investigated. Compound 4' gave de ute rated 5' and non­deuterated 6 and 7. These results show that the deute-

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Formation of Novel Aziridinoadenine Isonucleosides 1803

rium of 4' was eliminated during the formation of 6 and 7. Thus, structure B for 6 was proved to be wrong. An X-ray crystallographic study on p-bromobenzoyl derivative 8, mp 184°C, [aJo 273° (c 0.22, CHCI3), revealed the structure of 8 to be the one shown in Fig. 3. Therefore, 6 was definitively determined to be 3-a-(9-adenyl)-1,4-anhydro-5-0-benzoyl-2,3-dideoxy-2,3-epiimino-o-Iyxitol, and 7 to be its 7-adenyl analog. A plausible mechanism for the formation of 6 from 4 is illustrated in Scheme 2. The very small coupling between vicinal cis H-l' and H-2 can be explained by the effects of the electron-withdrawing CI-Ol and C2-N2 bonds antiparallel to the C2-H2 and CI-Hl' bonds, respectively. 7) A study on the scope and limitation of the new reaction is being made and the syntheses of other aziridine isonucleosides by this reaction

are under investigation.

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(1978). 2) V. Nair and Z. M. Nucsca, J. Arn. Chern. Soc., 114, 7951-7953

(1992). 3) H. Ohrui, T. Waga, and H. Meguro, Biosci. Biotech. Biochern., 57,

1040-1041 (1993). 4) Z. M. Nuesca and V. Nair, Tetrahedron Lett., 35,2485-2489 (1994). 5) K. Sujino and H. Sugimura, J. Chern. Soc., Chern. Cornrnun., 1994,

2541. 6) A. K. M. Anisuzzaman and R. Whistler,l. Org. Chern., 37,3187-3189

(1972). 7) D. H. Williams and I. Fleming, in "Spectroscopic Methods in Organic

Chemistry," 3rd Ed., McGraw-Hill, U.K., 1980, pp. 101-102.