ct-Amino acid isoxazolidides have been developed as educís for the preparation of optically pure a'-amino-,ß-ynones. The -amino acids were first N-protected as their ethoxycarbonyl, tert-butoxycarbonyl, or phenylsulfonyl derivatives. The isoxazolidides then were formed by the simple, high yield acylation of isoxazolidine by in situ generated -amino acid isobutyl carbonic anhydrides. Individual isoxazolidides of L-a-N-substituted alanine, phenylalanine, and methionine, when treated with lithium acetylide, lithium (trimethylsilyl)acetylide, or 1-hexynyllithium, gave high yields of the corresponding optically pure a,(¡-acetylenic ketones.

The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H- imidazole (2), is a highly potent, selective alpha 2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of alpha 2A-adrenoceptor-mediated human platelet aggregation and agonists on alpha 1- and alpha 2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (alpha 2A-subtype) and guinea pig ileum (alpha 1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on alpha 2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on alpha 2A- (human platelets), alpha 1- (guinea pig ileum), or alpha 2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater alpha 2/alpha 1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both alpha 1- and alpha 2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in alpha 2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of alpha 2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent alpha 2-adrenoceptor activity and high alpha 2/alpha 1-selectivity within the 4-substituted imidazole class.

Two fractions were collected, centered at times tA = 45.5 min and tB = 51.8 min, corresponding to isomers A and B, respectively. These fractions were lyophilized to obtain diastereomer A (100 mg) as an amorphous glass and diasteromer B (33 mg) as a white powder. Isomer A has been tentatively assigned the S configuration (26) at C-8 and isomer B and the R configuration (4). These assignments have been made on the relative inhibitory activities22 against adenosine deaminase of A and B. Isomer A (amorphous glass): fe'(HPLC)23 = 3.14; [apD -29.4°(c 2.18, H20); UV Xmax [methanol] 277 nm (log10 e 3.90), [pH 1] 260 (3.78), [pH 11] 276 (3.96). Isomer B: mp 210 °C, dec; fc'(HPLC)23 = 3.71; [a]23D-79.70 (c 1.33, H20); UV Xmax [methanol] 278 nm (log10 c 3.88), [pH 1] 260 (3.88), [pH 11] 277 (4.05). For NMR data, see Table III. For 13C NMR data see Table II.Acknowledgment. This investigation was supported by Grant CA-28381, by the National Cancer Institute, DREW, and in part by the Filariasis Working Group of the World Bak/UNDP/WHO Special Program for Research and Training in Tropical Diseases (I.D. 800134 and 840398).

Two approaches to prepare 2,4-dimethoxypyrrolo [3,2-d]pyrimidine (1) are described. 2,4-Dimethoxy-6methyl-5-nitropyrimidine (2) was converted to 6-(cyanomethyI)-2,4-dimethoxy-5-nitropyrimidine (6) in two steps. Subsequent catalytic hydrogenation of 6 produced 1. In a second approach, 2 was formylated, giving rise to 6-[2-(dimethylamino)vinyl]-2,4-dimethoxy-5-nitropyrimidine (7). Hydrogenation of 7 resulted in the formation of 1. Reduction of 2 provided 5-amino-2,4-dimethoxy-6-methylpyrimidine (10). Reaction of compound 10 with triethyl orthoformate produced 2,4-dimethoxy-5-[(ethoxymethylene)amino]-6-methylpyrimidine (11). Reaction of 11 with lithium diisopropylamide gave 2,4-dimethoxy-5-isocyano-6-methylpyrimidine ( 12).The first synthetic pyrrolo [3,2-d]pyrimidine to demon-strate2 biological activity was 4-aminopyrrolo[3,2-d]pyrimidine.More recently, 4-amino-7-C-(l-/3-D-ribofuranosyl)pyrrolo[3,2-d]pyrimidine (9-deazaadenosine) has demonstrated3 significant in vitro and in vivo antitumor activity3'4 5and has renewed interest in this ring system. Approaches toward the synthesis of compounds in this ring system have been made by (1) constructing a pyrimidine ring onto an appropriately substituted aminopyrrole3'6,7 or pyrrole dicarboxylate,6 7891011(2) the chemical transformation of a bicyclic heterocycle to produce a pyrrolo[3,2-d]pyrimidine,8,9 and (3) annulation of a pyrrole ring onto an appropriately substituted pyrimidine.10,11 As part of a study in the area of C-nucleosides, we have been interested in the conversion of pyrimidines into model pyrrolo[3,2-d]pyrimidines which are unsubstituted in the 6-and 7-positions. The synthesis10,12 of such unsubstituted pyrrolo-[3,2-d]pyrimidines has only been accomplished by the pyrolytic (300 °C, copper powder) decarboxylation of the corresponding 6-carboxypyrrolo[3,2-d]pyrimidine. We now report13 two procedures by which a readily available 5nitropyrimidine is converted under mild conditions into a 6,7-unsubstituted pyrrolo[3,2-d]pyrimidine. Results and DiscussionWe elected to prepare 2,4-dimethoxypyrrolo[3,2-d]pyrimidine (l)as the target compound since subsequent hydrolysis of the methoxy groups should provide a compound amenable to elaboration into a variety of 2-and 4-substituted pyrrolo [3,2-d]pyrimidines.12 To accomplish the(1) This study was supported by funds from the National Institutes of Health and the American Cancer Society (Grant CH-133).(2)

No abstract