M. E. García-Rubiñoa,
M. C. Núñez-Carreteroa,
D. Choquesillo-Lazarteb,
J. M. García-Ruizb,
Yolanda Madridc and
J. M. Campos*a
aDepartamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, 18071 Granada, Spain. E-mail: jmcampos@ugr.es; Fax: +34 958 243845; Tel: +34 958 243850
bLaboratorio de Estudios Cristalográficos, IACT, CSIC-Universidad de Granada, Avda. de las Palmeras 4, 18100 Armilla, Granada, Spain
cCentro de Instrumentación Científica, Universidad de Granada, Edificio Mecenas, Campus Universitario de Fuente Nueva, 18071 Granada, Spain
First published on 13th May 2014
A novel and efficient synthetic method has been developed for the preparation of alkylated aminopurines (N,N-dimethyl-, 2-chloro-N-methyl-, and N-methyladenines) with achiral and chiral 3,4-dihydro-2H-1,5-benzoxathiepin-3-ol by the Mitsunobu reaction under microwave-assisted conditions. This reaction reveals a complete inversion of the stereogenic centre of the secondary alcohol giving an alkylated purine linked to a homochiral six-membered ring. Fifty novel purine derivatives have been prepared. Alkylation sites have been determined by 2D NMR techniques and for three compounds have been confirmed by X-ray crystallography. The N-9/N-3 regioselectivity can be justified by the electronic effects of the substituents at positions 2 and 6 of the purine.
The essential biological functions of N-substituted adenine compounds have naturally led to extensive interest in the synthesis of a wide variety of alkylated purine systems as potential analogues or antagonists of naturally occurring adenine derivatives.7 Direct alkylation of adenine, of its simple derivatives, and of its metal salts is the dominant synthetic route to N-substituted adenines, largely because of the convenience and simplicity of such reactions.
There are reports dealing with the alkylation reaction of adenine under the Mitsunobu conditions.8–11 Continuing our studies on multident heterocyclic nucleophiles, we examined the alkylation of adenine using a variety of alkylating agents.12,13 The wide variety of alkylation conditions involved in the literature reports makes it difficult to discern what influence the structural features of the alkylating agent has on the alkylation site. To overcome this problem we have used a typical and standardized alkylation condition to study the reaction of several substituted adenines with racemic 3,4-dihydro-2H-1,5-benzoxathiepin-3-ol, and its two enantiomers through the Mitsunobu reaction under microwave conditions. We have described a series of eleven 2- and 6-substituted (RS)-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purine derivatives (1–11) (Fig. 1), by applying a standard Mitsunobu protocol that led to a six-membered ring contraction from (RS)-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol via an episulfonium intermediate.14
Fig. 1 2- and 6-substituted (RS)-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purine derivatives obtained by the Mitsunobu reaction. |
We wish to report herein the reactivity of the racemic and enantiomers of 3,4-dihydro-2H-1,5-benzoxathiepin-3-ol (12) and several adenines, such as N,N-dimethyladenine, 2-chloro-N-methyladenine, and N-methyladenine. The results will be interpreted in terms of multident nucleophile reactivity and SN2 transition state structures for the alkylation reactions. These concepts should allow more confident prediction of the effects that variations in structural features and conditions will have on the alkylation pattern of adenine derivatives during the varied syntheses of alkylated purines.
Scheme 1 Reagents and conditions: (a) (R)-epichlorohydrin, pyridine, MW, 140 °C, 10 min, DMF; (b) NaOH, H2O, 100 °C, 24 h. |
Scheme 2 Reagents and conditions: (a) (S)-epichlorohydrin, pyridine, MW, 140 °C, 10 min, DMF; (b) without isolating (R)-14, NaOH, DMF, 100 °C, 24 h. |
When 2-mercaptophenol is reacted with (R)-epichlorohydrin, (S)-14 is obtained (90%) with an ee = 99.9% with complete inversion of the stereocentre of its oxirane moiety.16 This implies a complete regioselective process as a consequence of the nucleophilic attack of the sulfanyl anion at the less hindered face of the oxirane moiety of (R)-epichlorohydrin, thus resulting in (S)-14 with an excellent ee. After removing DMF in vacuo and purification by flash column chromatography of the reaction crude, heating (S)-14 with NaOH in H2O at 100 °C gives the cyclization products, (S)-12 (62% yield, ee = 95.3%) and the six-membered primary alcohol (R)-13 (24% yield, ee = 98.5%) (Scheme 1).
Scheme 2 shows the different stereochemical behaviour when the experimental workup was modified using (S)-epichlorohydrin. Although pathway (a) is exactly the same as that shown in Scheme 1, compound (R)-14 is not isolated and NaOH and more DMF are added (instead of water) and the resulting solution is heated at 100 °C for 24 h. After removing DMF and subsequent flash chromatography, (R)-12 (62%, ee = 74.7%) and (S)-13 (24%, ee = 77.3%) are obtained.
The interpretation for the formation of (R)-12 [and for (S)-13 would be very similar] with a marked erosion of its optical purity in relation to the method outlined in Scheme 2 could be rationalized in Scheme 3. The formation of (R)-14 follows the same pattern for (S)-14. As (S)-14 was obtained with a high yield (90%), we decided neither to purify nor isolate (R)-14; although the reaction workup was reduced, the ee worsened due to the presence of HCl in the reaction medium.17 Accordingly, (R)-14 follows two different pathways, i.e., a preferential SN2 process [presumably with an excellent ee, see Scheme 1 with (R)-epichlorohydrin], and a SN1 process with concomitant racemization. Finally, cyclization of pure (R)-14 [route (a) of Scheme 3] and (S)-14 with NaOH at 100 °C leads to (R)-12 and (S)-12, respectively, the enantiomer (R)-12 being produced mainly through pathway (b) and to a lesser extent via pathway (a), whilst (S)-12 is formed only through pathway (a) (Scheme 3).
Due to fact that the syntheses of (R)-14 and (S)-14 are carried out under the same conditions, the racemization process is not produced at this stage [confirmed by isolation of (S)-14] and hence, racemization takes place in the following cyclization step, which differs in both enantiomers (Scheme 3).
Scheme 4 Preparation of the (RS)-(3-alkylated-N,N-dimethyl)adenine [(RS)-17] and (RS)-(9-alkylated-N,N-dimethyl)adenine [(RS)-18]. |
When (S)-12 (ee = 95.3%) is the starting reactant, the products obtained are (R)-17 (38%) and (R)-18 (5%), both of them with excellent optical purities (ee = 96.9% and ee = 94.2%, respectively) (Scheme 5).
When (R)-12 (ee = 74.7%) is the starting reactant, (S)-17 (34%, ee = 76%) and (S)-18 (5%, ee = 73.7%) are obtained (Scheme 6).
The structure of 3-substituted-6-N,N-dimethyladenine is conditioned by the importance of the dipolar iminium form (20) to the possible resonance hybrid [19 ↔ 20 ↔ 21] (Scheme 7), as suggested by non-equivalent N-Me2 signals in the 1H NMR spectrum of 17 and is substantiated by its X-ray analysis. This is consistent with the electron-releasing nature of the dimethylamino group: σp = −0.83,18 or −0.82.19 Although the electronic influence of the NMe2 group on N-1 and N-3 of the purine nucleus is basically the same (its mesomeric electron-releasing effect is much more important than its inductive electron-withdrawing one), the lack of alkylation of N,N-dimethyladenine at its N-1 site could be attributed to the steric hindrance caused by the dimethylamino group. On the other hand, its steric influence also avoids the alkylation at the N-7 position of the adenine-derived compound.
Scheme 7 Resonance hybrid 20 can explain the alkylation at the N-3 atom of the purine moiety, as suggested by non-equivalent –NMe2 signals in the 1H NMR spectrum of (RS)-17. |
The structure of (RS)-17 has been determined by 1H, 13C NMR, HMBC (Fig. 2), HSQC and moreover by X-ray crystallography. HMBC gives 2-bond and 3-bond information, i.e., which of the 1H are 2-bonds or 3-bonds away from a particular 13C. HSQC gives 1-bond information, i.e., which 1H is attached to which 13C. The combination of 1H NMR and 1H-13C HSQC spectra is very powerful, and often allows the complete assignment of all protons in a molecule. In the HMBC experiment to three bonds, the following two correlations are important: (a) the first one between the exocyclic methylene group and the quaternary carbon C-4 of the purine (common carbon atom that is correlated through three bonds to CH-2 and CH-8) of 17; and the second one: (b) between the exocyclic methylene group and CH-2 (which is correlated to C-6) of the purine ring. This correlation proves unequivocally that the linkage between the six-membered moiety and the purine base takes place through N-3 in (RS)-17 (Fig. 2).
Fig. 2 Representation of the HMBC interactions (with double-tipped arrows) observed between the exocyclic methylene group and the purine atoms, when the linkage is N-3 in compound (RS)-17. |
When the same reaction is carried out between (RS)-12, (R)-12, (S)-12 and N,N-dimethyladenine, the 3-substitution on N,N-dimethyladenine is still preferred, and is accompanied by the formation of the corresponding 9-substituted-N,N-dimethyladenine (RS)-18, (S)-18 and (R)-18. Miyaki and Shimizu20 found that, after chromatographic separation of the reaction products, the benzylation of N,N-dimethyladenine with PhCH2OH in THF gave the N-3 and N-9-regioisomers.
The structure of (RS)-18 has been determined by 1H, 13C NMR, HMBC and HSQC (Fig. 3). In the HMBC experiment to three bonds the following two correlations are important: (a) the first one between the exocyclic methylene group and the quaternary carbon C-4 of the purine (common carbon atom that is correlated through three bonds to CH-2 and CH-8) of (RS)-18 and the second one: (b) between the exocyclic methylene group and CH-8 (which is the CH group that is not correlated with C-6) of the purine ring. This correlation proves unequivocally that the linkage between the six-membered moiety and the purine base takes place through N-9 in (RS)-18 (Fig. 3).
Fig. 3 Representation of the HMBC interactions (with double-tipped arrows) observed between the exocyclic methylene group and the purine atoms, when the linkage is N-9 in compound (RS)-18. |
The methylamino moiety is an electron-releasing group with a σp similar to that of the dimethylamino moiety {σp (MeHN) = −0.76;21 σp (Me2N) = −0.83,18 or 0.82 (ref. 19)} and then favours the nucleophilicity of the N-3 atom of purine. However the presence of an electron-withdrawing atom such as chlorine {σI (Cl) = 0.47 (ref. 27)} neutralizes the effect of the methylamino group and consequently the alkylation site moves to the N-9 atom of 2-chloro-N-methyladenine, i.e., going from 17 and 18 to 22, there is a shift of σ-electron-density from the six- to the five-membered ring of purine. Moreover, no exocyclic N-alkylation takes place due to its relatively weak nucleophilic character.
The structure of (RS)-22 has been determined by 1H, 13C NMR, HMBC and by X-ray in (R)-22 (Schemes 8–10). The HMBC experiment to three bonds proves unequivocally that the linkage between the six-membered moiety and the purine base does not take place through N-3 because the exocyclic methylene group is correlated with CH-8 of the purine, and accordingly the linkage could be through N-9 or N-7 (Fig. 4). It was finally determined by (R)-22 X-ray crystal structure because in the HMBC experiment it was impossible to differentiate between C-4 and C-5 of the purine.
Fig. 4 Representation of the HMBC interactions (with double-tipped arrows) observed between the exocyclic methylene group and the purine atoms of (RS)-22 when the linkage is through N-9. |
The stereochemistry of (S)-22 shows the complete inversion of the stereogenic alcohol center. This result is consistent with a SN2 mechanism and strongly enhances the application of the reported method as a general approach for the stereospecific synthesis of alkylated purines.
Scheme 11 Preparation of (RS)-(N-3-alkylated-N-methyl)adenine [(RS)-23] and (RS)-(N-9-alkylated-N-methyl)adenine [(RS)-24]. |
Scheme 12 Preparation of (S)-(N-3-alkylated-N-methyl)adenine [(S)-23] and (S)-(N-9-alkylated-N-methyl)adenine [(S)-24]. |
Scheme 13 Preparation of (R)-(N-3-alkylated-N-methyl)adenine [(R)-23] and (R)-N-9-alkylated-N-methyl)adenine [(R)-24]. |
In the HMBC experiment to three bonds, the two following correlations are important: (a) the first one between the exocyclic methylene group and the quaternary carbon C-4 of the purine (common carbon atom which is correlated to CH-2 and CH-8) of (RS)-23; and the second one: (b) between the exocyclic methylene group and CH-2 (which is the group that is not correlated with C-6) of the purine ring. This correlation proves unequivocally that the linkage between the six-membered moiety and the purine base takes place through N-3 in (RS)-23 (Fig. 5).
Fig. 5 Representation of the HMBC interactions (with double-tipped arrows) observed between the exocyclic methylene group and the purine atoms, when the linkage is through N-3 in compound (RS)-23. |
The structure of (RS)-24 has been determined by 1H, 13C NMR, HMBC and HSQC. In the HMBC experiment to three bonds the following two correlations are outstanding: (a) the first one between the exocyclic methylene group and the quaternary carbon C-4 of the purine (common carbon atom that is correlated through three bonds to CH-2 and CH-8) of (RS)-24; and the second one: (b) between the exocyclic methylene group and CH-8 (which is the CH group that is not correlated with C-6) of the purine ring. This correlation proves unequivocally that the linkage between the six-membered moiety and the purine base takes place through N-9 in (RS)-24 (Fig. 6).
Fig. 6 Representation of the HMBC interactions (with double-tipped arrows) observed between the exocyclic methylene group and the purine atoms, when the linkage is through N-9 in compound (RS)-24. |
Neither 2,6-diaminopurine nor 6,8-dichloro-2-methylthiopurine, as possible purine bases in the Mitsunobu coupling, produced the desired coupling products with the secondary racemic and homochiral alcohols 12. These results may be due to the poor solubility of the bases.
Chemical shifts (CDCl3) of the carbon atom for the CH-2 group follows the same tendency in N-3 [(RS)-17 and -23] and N-9 [(RS)-18 and -24] isomers. These signals are shifted downfield in N-3 isomers [(RS)-17 and (RS)-23, δ 141.9–145.1 ppm] compared with the corresponding signals in N-9 isomers [(RS)-18 and -24, δ 152.8–152.4 ppm].
Chemical shift (CDCl3) of the carbon atom for CH-8 is shifted up-field in N-9 isomers [(RS)-18 and (RS)-24, δ 152.7–148.2 ppm] compared with the corresponding signals in N-3 isomers [(RS)-17 and -23, δ 139.5–140.7 ppm].
(R)-13: ee = 98.5%, [α]25D + 38.1 (c 1.0 in CH2Cl2); HPLC analysis: hexane–CH2Cl2 = 65/35, flow rate 1.0 mL min−1, λ = 250 nm, tR (S)-13 = 14.682 min, tR (R)-13 = 15.890 min.
(R)-12: ee = 74.7%, [α]25D + 28.3 (c 1.0 in CH2Cl2); HPLC analysis: hexane–CH2Cl2 = 65/35, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-12 = 9.854 min, tR (S)-12 = 11.114 min.
(S)-13: ee = 77.3%, [α]25D −33.2 (c 1.0 in CH2Cl2); HPLC analysis: hexane–CH2Cl2 = 65/35, flow rate 1.0 mL min−1, λ = 250 nm, tR (S)-13 = 14.899, tR (R)-13 = 16.249 min.
(RS)-N,N-Dimethyl-3-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-3H-adenine [(RS)-17]: white solid (57 mg, 32%), mp 152–154 °C. 1H NMR: δH (500 MHz, CDCl3) 3.35 (3H, br s, CH3), 3.92 (3H, br s, CH3), 4.18 (1H, m, CH-3), 4.27 (1H, d, Jgem = 12.0 Hz, J1,2 = 1.7 Hz, CH-2), 4.37 (1H, dd, Jgem = 12.0 Hz, J1,2 = 2.9 Hz, CH-2), 4.42 (1H, dd, Jgem = 13.7 Hz, J1,2 = 8.4 Hz, 1H-exocyclic), 4.65 (1H, dd, Jgem = 13.7 Hz, J1,2 = 6.9 Hz, 1H-exocyclic), 6.89 (2H, m, CH-aromatics), 7.03 (2H, m, CH-aromatics), 7.87 (1H, s, H2-purine), 7.96 (1H, s, H8-purine). 13C NMR: δC (125 MHz, CDCl3) 36.99 (CH-3), 38.23 (CH3), 39.95 (CH3), 51.77 (CH2-exocyclic), 66.14 (CH2-2), 115.92 (C-4a), 122.02 (C-5-purine), 118.91 (CH-aromatics), 122.74, 126.38, 128.15, 141.92 (CH-2-purine), 150.11 (C-4-purine), 151.27 (C-8a), 152.74 (CH-8-purine), 153.85 (C-6-purine). HR LSIMS m/z calcd for C16H17N5OS [M + H]+ 328.1232, found 328.1238.
(R)-N,N-Dimethyl-3-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-3H-adenine [(R)-17] (68 mg, 38%): ee = 96.9%, [α]25D −135.49 (c 1.0 in CH2Cl2); HPLC analysis: hexane–EtOH = 80/20, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-17 = 17.84 min, tR (S)-17 = 23.430 min.
(S)-N,N-Dimethyl-3-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-3H-adenine [(S)-17] (61 mg, 34%): ee = 76%, [α]25D + 104.74 (c 1.0 in CH2Cl2); HPLC analysis: hexane–EtOH = 80/20, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-17 = 18.242 min, tR (S)-17 = 23.055 min.
(RS)-N,N-Dimethyl-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-adenine [(RS)-18]: white solid (9 mg, 5%), mp 170–172 °C. 1H NMR: δH (500 MHz, CDCl3) 3.52 (6H, br s, N(CH3)2), 3.89 (1H, m, CH-3), 4.25 (2H, m, CH2-2), 4.41 (1H, dd, Jgem = 14.2 Hz, J1,2 = 7.7 Hz, 1H-exocyclic), 4.50 (1H, dd, Jgem = 14.2 Hz, J1,2 = 7.7 Hz, 1H-exocyclic), 6.89 (2H, m, CH-aromatics), 7.02 (2H, m, CH-aromatics), 7.71 (1H, s, H8-purine), 8.33 (1H, s, H2-purine). 13C NMR: δC (125 MHz, CDCl3) 29.93 (CH3), 37.72 (CH-3), 45.76 (CH2-exocyclic), 65.91 (CH2-2), 116.25 (C-4a), 118.82 (CH-aromatics), 120.54 (C-5-purine), 122.63, 126.17, 127.96, 139.15 (CH-8-purine), 150.65 (C-4-purine), 151.45 (C-8a), 152.84 (CH-2-purine), 155.25 (C-6-purine). HR LSIMS m/z calcd for C16H17N5OS [M + H]+ 328.1232, found 328.1233.
(R)-N,N-Dimethyl-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-adenine [(R)-18] (9 mg, 5%): ee = 94.2%, [α]25D + 67.1 (c 0.34 in MeOH); HPLC analysis: hexane–EtOH = 80/20, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-18 = 20.053 min, tR (S)-18 = 25.755 min.
(S)-N,N-Dimethyl-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-adenine [(S)-18] (9 mg, 5%): ee = 73.7%, [α]25D −53.3 (c 0.34 in MeOH); HPLC analysis: hexane–EtOH = 80/20, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-18 = 20.050 min, tR (S)-18 = 25.764 min.
(RS)-2-Chloro-N-methyl-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-adenine [(RS)-22]: white solid (86 mg, 45%), mp 117–119 °C. 1H NMR: δH (500 MHz, CDCl3) 3.11 (3H, m, CH3), 3.82 (1H, m, CH-3), 4.23 (1H, ddd, Jgem = 12.0 Hz, J1,2 = 3.0 Hz J1,3 = 1.9 Hz, CH-3), 4.25 (2H, m, CH2-2), 4.37 (1H, dd, Jgem = 14.2 Hz, J1,2 = 8.0 Hz, CH2 exocyclic), 4.47 (1H, dd, Jgem = 14.2 Hz, J1,2 = 7.5 Hz, CH2 exocyclic), 6.88 (2H, m, CH-aromatics), 7.02 (2H, m, CH-aromatics), 7.73 (1H, s, H8-purine). 13C NMR: δC (126 MHz, CDCl3) 27.75 (CH3), 37.53 (CH-3), 45.79 (CH2-exocyclic), 65.70 (CH2-2), 115.72 (C-4a), 118.21 (C-5-purine), 118.74 (CH-aromatics), 122.64, 126.20, 127.84, 140.45 (CH-8-purine), 149.63 (C-4-purine), 151.19 (C-8a), 155.86 (C-6-purine). HR LSIMS m/z calcd for C16H14N5ClOS [M + H]+ 348.0686, found 348.0687.
(R)-2-Chloro-N-methyl-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-adenine [(R)-22] (85 mg, 42%): ee = 99.9%, [α]25D + 33.59 (c 0.65 in DMSO); HPLC analysis: hexane–EtOH = 80/20, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-22 = 13.353 min.
(S)-2-Chloro-N-methyl-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-adenine [(S)-22] (100 mg, 49%): ee = 73.7%, [α]25D −22.8 (c 0.65 in DMSO); HPLC analysis: hexane–EtOH = 80/20, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-22 = 13.352 min, tR (S)-22 = 14.560 min.
(RS)-N-Methyl-3-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-3H-adenine [(RS)-23]: white solid (77 mg, 45%), mp 199–201 °C. 1H NMR: δH (500 MHz, CDCl3) 3.24 (3H, m, CH3), 4.08 (1H, m, H-3), 4.31 (1H, dd, Jgem = 12.1 Hz, J1,2 = 1.5 Hz, CH2-2), 4.40 (1H, dd, Jgem = 12.11 Hz, J1,2 = 2.8 Hz, CH2-2), 4.49 (1H, dd, Jgem = 13.7 Hz, J1,2 = 8.5 Hz, CH2-exocyclic), 4.72 (1H, dd, Jgem = 13.8 Hz, J1,2 = 6.7 Hz, CH2-exocyclic), 6.90 (2H, m), 7.04 (2H, m), 8.00 (1H, s, H8-purine), 8.07 (1H, s, H2-purine). 13C NMR: δC (126 MHz, CDCl3) 28.32 (CH3), 37.11 (CH-3), 51.81 (CH2-exocyclic), 65.90 (CH2-2), 115.12 (C4a), 117.19 (C-5-purine), 118.96 (CH-aromatics), 122.91, 126.59, 128.10, 145.14 (CH-2-purine), 147.47 (C-4-purine), 148.24 (CH-8-purine), 151.20 (C-8a), 153.86 (C-6-purine). HR (LSIMS) m/z calcd for C15H16N5OS [M + H]+ 314.1076, found 314.1076.
(R)-N-Methyl-3-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-3H-adenine [(R)-23] (80 mg, 47%): ee = 96.1%, [α]25D −61.81 (c 1.0 in MeOH); HPLC analysis: hexane–EtOH = 80/20, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-23 = 14.343 min, tR (S)-23 = 17.190 min.
(S)-N-Methyl-3-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-3H-adenine [(S)-23] (83 mg, 48%): 78.1 ee, [α]25D + 59.43 (c 1.0 in MeOH); HPLC analysis: hexane–EtOH = 80/20, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-23 = 15.004 min, tR (S)-23 = 17.299 min.
(RS)-N-Methyl-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-adenine [(RS)-24]: white solid (77 mg, 45%), mp 168–170 °C. 1H NMR: δH (600 MHz, DMSO-d6) 2.95 (3H, s, CH3), 4.12 (1H, m, H-3), 4.28 (2H, m, CH2-2), 4.40 (1H, dd, Jgem = 14.1 Hz, J1,2 = 8.2 Hz, CH2-exocyclic), 4.56 (1H, dd, Jgem = 14.1 Hz, J1,2 = 6.7 Hz, CH2-exocyclic), 6.90 (2H, m), 7.06 (2H, m), 8.13 (1H, s, H8-purine), 8.23 (1H, s, H2-purine). 13C NMR: δC (150 MHz, DMSO d6) 26.96 (CH3), 37.82 (CH-3), 44.65 (CH2-exocyclic), 65.95 (CH2-2), 116.45 (C4a), 118.99 (C-4-purine), 118.26 (CH-aromatics), 122.10, 125.65, 127.29, 140.77 (CH-8-purine), 148.55 (C-4-purine), 151.07 (C-8a), 152.48 (CH-2-purine), 154.85 (C-6-purine). HR (LSIMS) m/z calcd for C15H16N5OS [M + H]+ 314.1076, found 314.1077.
(R)-N-Methyl-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-adenine [(R)-24] (72 mg, 42%): ee = 99.0%, [α]25D −65.83 (c 1.0 in MeOH); HPLC analysis: hexane–EtOH = 80/20, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-24 = 26.679 min, tR (S)-24 = 29.495 min.
(S)-N-Methyl-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-adenine [(S)-24] (72 mg, 42%): ee = 59.1%, [α]25D + 38.3 (c 1.0 in MeOH); HPLC analysis: hexane–EtOH = 80/20, flow rate 1.0 mL min−1, λ = 250 nm, tR (R)-24 = 26.576 min, tR (S)-24 = 28.695 min.
Footnote |
† Electronic supplementary information (ESI) available: Chromatograms and RMN studies of enantiomers of 12 and 13, and racemates and enantiomers of 17 and 22–24 are provided. CCDC 864711, 864709 and 864710. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra01968g |
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