Stereoselectivities in the Coupling Reaction between Silylated Pyrimidine Bases and 1-Halo-2,3-dideoxyribose (1990)

AbEm ---Coupling reactions between I-chlora-2.3-dideoxyribose and silylated pyrimidines have been examined from the point of stereoselectivity.When the reaction was carried out in chloroform, the selectivity was in the anomeric ratio of a : P =4 : 6.On the other hand, the presence of tertiary amine raises the selectivity to a : P =3 : 7.Nucleaside analogues have been considered as useful materials because of Their biologicd activities.1 Some of them have uses in phannacology.lIn many cases, naturally occuning nucleosides were the stating material for these nucleosides analogue^.^It is, however, rather disadvantageous since the material with a particular nucleic base cannot be obtained preferentially.From this viewpoint, we have been interested in the synthesis of a wide variety of nucleosides staning from other resources.Our attention has mainly focused on the stereoselectivity in the coupling reaction between a nucleic base and a s ~~a r .3In recent years, 2',3'-dideoxynucleosides have received a lot of attention because of their antiviral activities against the HIV, which causes the acquired immune deficiency syndrome (AIDS).~A lot of methods for the preparation of these nucleosides have been reported; deoxygenation of the 3'-hydroxy group of 2'-deoxyn u c ~e o s i d e s , ~ double deoxygenation of vicinal diol of ribonucleosides.6 and the coupling reaction between activated nucleic bases and 2.3-dideoxyn'bose derivatives7 Two types of this coupling reaction have already been reported; Lewis acids catalyzed reaction^'^ and SN2-like reaction of l -b r o m o ~u ~a r .~~In the former case, the stereoselectivities of the reaction were up to a : p =4 : 6.In the latter case, 1-bromosugar was unstable and the reaction resulted in the formation of a mixture of equal amounts of both anomen.I1 has been reported by Hubbard er 01. that the coupling reactions between 1-a-chloro-2-deoxyribose and silylated nucleic bases in chloroform p m e e d with SNZ displacement to give mainly the P -a n ~m e r s .~We have focused our attention on this result, and here we repon the stereoselectivities in the coupling reactions between 1-chlom-2.3-dideoxyriboseand silylated pyrimidine bases. I-Halosuear2.3-Dideoxyribose (1) was prepared as follows (Scheme 1).We used levoglucosenone (2) as a starting materiaL9 This compound is known as the main product from the pyrolysis of cellulose.Compound 3 derived from 2 by hydrogenation was subjected to the Baeyer-Villiger reaction with peracetic acid to give the lactone 4.1°Benmylation of 4 followed by reduction with DIBAL-H gave the sugar (1).2.3-Dideoxyribose (1) was halogenated under the conditions described in ~a b l e . 1 .Two sets of conditions for the preparation of 1-chlorosugar (5a) were adopted as indicated in Table 1.In both cases, however, the anomeric mixtures have almost the same anomeric ratio, 6 : 4, which was determined by l ~-n m r (enmes 1 and 2).It was not possible to determine directly which anomer was the major isomer, but afterwards the anomeric ratio was deduced from the results of the coupling reaction (vide infra).We also prepared 1-bromo-2.3-dideoxyribose(Sb).1-Bromosugar (Sb), which was prepared from 1 and acetyl bromide and after the removal of the lowboiling point materials, exists in a 6 : 4 anomeric mixture in chloroform (entries 3 and 4).It is in the same ratio as @ Pd-C H @ 2) Me2S 3) cat.HCI 0 0 l ' A c O O H ~ MeOH 2: levoglucosenone 3 4 2) DIBAL-H HETEROCYCLES, Vol 31, No.I I , 1990 Table 1.Preparation of I-halosugar (5) and coupling reacdon between 5 and silylated uracil (6)a Enoy X Conditions of h o m e f c ~i e l ~% d ~temse~ectivityd halogenationb ratio of sc ( a + P) ( a : PI 1 C1 HCl (gas)fMgSOq/PhHD h 57 : 43 1 6 43 : 57 2 CI SOCl2 (1.5)lCHC13/5 h 60 : 40 62 42 : 58 3 Br AcBr (1.5)/PhCHg5 h 64 : 36 26 52 : 48 4 Br AcBr (1 .S)ICHC13/5 h 62 : 38 28 51 :49 a) Coupling reactions were carried out under the following conditions; 0.5 mmol scale, sugar : base=l : 2, in 4 ml of chloroform, r w m temperature, overnight.b) The numben in parentheses refer to the equivalent of reagents.C) Determined by 1H-nmr.d) Yields and sterwselectivities were determined by hplc (uv detection.254 nm; compared to uracil as an internal standard) after deprotection by sodium methaxide in methanol.in a solution after the treament of 1-acetylsugar with uimethylsilyl bmmide as reported by Farina and ~e n i ~n i .7 bAs Hubbard er al. have reported, the coupling reaction between I-chlorosugar and silylated uracil (6) in chloroform without catalysts present proceeded completely in an S N ~ mode.8 and 1-chlorosugar (5a) was subjected to these reaction conditions.The m d e coupling product was analyzed by hplc after deprotecdon.The ratio of resulting 2',3'-dideoxyuridine (8) and its anomer was a : P =4 : 6 (enuies 1 and 2).This result indicates that the coupling reaction between 5a and 6 proceeds in an S N ~ manner, and the anamen of l-chloro-2.3-dideoxynbose(5a) exists in chloroform in the ratio of a : P =6 : 4. On the other hand, I-bromosugai (5b) was subjected to the same reaction conditions, but it gave equal amounts of both anomers as was also reported