Concise and Efficient Syntheses of preq 1 base, Q base, and (ent)-q Base

Transcription

1 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry Concise and Efficient Syntheses of preq 1 base, Q base, and (ent)-q Base Supporting Information ans-dieter Gerber and Gerhard Klebe* Institut für Pharmazeutische Chemie, Fachbereich Pharmazie der Philipps-Universität Marburg, Marbacher Weg 6, Marburg, Germany Concise schematic overview (Schemes S1 and S2) and brief discussion of previously reported procedures for the synthesis of preq 1 and Q base S1 MR-Spectra 1 -MR (DMS-d 6 ) 1 S6 1 -MR (CD 3 D) 1 S7 13 C-MR (DMS-d 6 ) 1 S8 13 C-MR (D 2 /CD 3 D) 1 S9 1 -MR (CD 3 D) 2 S10 1 -MR (D 2 ) 2 S11 13 C-MR (CD 3 D) 2 S12 1 -MR (CD 3 D) 3 S13 1 -MR (D 2 ) 3 S14 13 C-MR (CD 3 D) 3 S15 13 C-MR (D 2 /CD 3 D) 3 S16 1 -MR (DMS-d 6 ) 6 S17 13 C-MR (DMS-d 6 ) 6 S18 1 -MR (DMS-d 6 ) 7 S19 13 C-MR (DMS-d 6 ) 7 S20 1 -MR (DMS-d 6 ) 8 S21 13 C-MR (DMS-d 6 ) 8 S22 1 -MR (DMS-d 6 ) 9 S23 13 C-MR (DMS-d 6 ) 9 S24 1 -MR (CDCl 3 ) 10b S25 S1

2 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 1 -MR (CDCl 3 ) 11a S26 13 C-MR (CDCl 3 ) 11a S27 1 -MR (CDCl 3 ) 11b S28 13 C-MR (CDCl 3 ) 11b S29 1 -MR (CDCl 3 ) 12a S30 13 C-MR (CDCl 3 ) 12a S31 1 -MR (CDCl 3 ) 12b S32 13 C-MR (CDCl 3 ) 12b S33 1 -MR (CDCl 3 ) 13a S34 13 C-MR (CDCl 3 ) 13a S35 1 -MR (CDCl 3 ) 13b S36 13 C-MR (CDCl 3 ) 13b S37 1 -MR (CD 3 D) 14a (Cl) S38 13 C-MR (CD 3 D) 14a (Cl) S39 1 -MR (CD 3 D) 14a (base) S40 1 -MR (DMS-d 6 ) 14b (Cl) S41 1 -MR (CD 3 D) 14b (Cl) S42 13 C-MR (CD 3 D) 14b (Cl) S43 1 -MR (CD 3 D) 14b (base) S44 1 -MR (CDCl 3 ) 15 S45 1 -MR (CDCl 3 ) 16 S46 1 -MR (CD 3 D) 17 S47 1 -MR (CD 3 D) 17 S48 S2

3 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry verview and brief discussion of the most recently published procedures for preq 1 by Carell et al.: 1 The two most recent procedures suggested to access the modified guanine analogue preq 1 base were reported by Carell et al. in 2005, both starting from pyrimidine 4 (Scheme S1). 1 The first one (Route A), being a short and seemingly straightforward five-step synthesis, involves intermediate formation of preq 0 base from pyrimidine 4 and 2-chloro-3-oxopropanenitrile, followed by a subsequent hydrogenation step to yield preq 1 base. owever, this approach only yields 6.6 % of the desired nucleobase. The second route represents a higher-yielding, yet synthetically slightly more elaborate six-step sequence rendering preq 1 base in 25 % overall yield. After an intermediate phthalimide deprotection step with hydrazine, the resulting product mixture is reprotected by treatment with (Boc) 2 in DMF to enable separation of the product from the simultaneously formed side-products (mainly Phthalhydrazide) by flash chromatography yielding 31 % of Boc-protected preq 1 base. Final deprotection gives rise to the desired nucleobase 1. Me + Cl C Cl Route A Route B + + C 5 steps, 6.6 % overall steps, 25 % overall 2 2 preq 1 base, Scheme S1: Retrosynthetic approaches of most recent preq 1 syntheses by Carell et al. 1 verview and brief discussion of all hitherto published synthetic approaches for Q base: The first synthesis was reported by Goto et al. 2 in This rather lengthy and time-consuming route finally rendered Q base in 19 steps applying a reductive amination with cyclopentenylamin 19 as key step. In 1988, Akimoto et al. 3 published a shorter, apparently more straightforward synthetic approach. The crucial step of their strategy is based on a regioselective Mannich reaction at the pyrrolo moiety of the previously prepared octanoyl-protected heterocyclic core 20 to introduce a dibenzylated aminomethyl side chain at position 5 of the heterocycle. The resulting intermediate 21 finally allows implementation of the required side chain moiety of queuine by an amine exchange reaction utilizing excessive amounts of the above-mentioned amine 19. Although the regioselectivity of the Mannich reaction (ratio of 5- versus 6-position substitution = 14.2 : 1) is quite high, the obtained product still might contain low amounts of the unwanted 6-substituted isomer. In addition, the synthesis of the required substrate 19 for the following amine exchange is rather challenging and, moreover, has to be applied in large excess (five-fold) in order to achieve a reasonable yield. In 2000, Grubb et al. 4 described an alternative route utilizing a different disconnection approach. erein, the key reaction is the ring closure via a cyclic condensation to install the pyrrolopyrimidine core of the nucleobase S3

4 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry employing 2,6-diaminopyrimidine-4-one (4) and α-bromoaldehyde intermediate 22, prior to this derived via cyclopentenol 10 starting from D-(-)-ribose, and the fully protected 3-aminopropanol precursor 23. D-(-)-ribose D-(-)-ribose Mitsunobu 26 Staudinger red. + s 23 TBS 2 10 Trt 25 1.) silylation 2.) reduction C + 19 red. amin. 2 Q base 2 cycl. condens. s Br Mitsunobu Showalter et al. 5 amine displacem. red. amin. 22 Grubb et al C 7 21 Bn Bn equiv Bn regiosel. Mannich 5- vers. 6-subst. Goto et al C Akimoto et al. 3 Scheme S2: Retrosynthetic approach and key steps of previously reported syntheses of Q base In total, this sequence requires 14 steps in a convergent approach applying several protection strategies to finally yield Q base (2) in an overall yield of 1.6 % from D-(-)-ribose. In 2010, Showalter et al. 5 reported a significantly shorter strategy using the biochemical preq 1 precursor preq 0 base (24), available in two preceding steps from heterocycle 4, 6 as starting material. Reductive amination of the trityl-protected formyl deazaguanine derivative 25, obtained from preq 0 base 24, with cyclopentenylamine 19, furnishes, after a S4

5 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry final deprotection step, queuine (2) as monohydrochloride in 36 % over four steps from 24. Cyclopentenylamine 19 is accessible via the corresponding cyclopentenylazide 26 by a modified four-step protocol of Carell et al. 7 in 14.5 % overall yield. owever, a necessary requirement of this synthesis is the implementation of an intermediate silylation step with 24 thus gaining sufficient solubility of the heterocyclic intermediate for the successive nitrile reduction with DIBAL- to form the trityl-protected derivative 25 at lower temperatures. 1. F. Klepper, K. Polborn and T. Carell, elv. Chim. Acta, 2005, 88, T. Kondo, T. hgi and T. Goto, Chem. Lett., 1983, 12, Akimoto, E. Imamiya, T. itaka,. omura and S. ishimura, J. Chem. Soc., Perkin Trans. 1, 1988, C. J. Barnett and L. M. Grubb, Tetrahedron, 2000, 56, A. F. Brooks, G. A. Garcia and. D.. Showalter, Tetrahedron Lett., 2010, 51, M. T. Migawa, J. M. inkley, G. C. oops and L. B. Townsend, Synth. Commun., 1996, 26, F. Klepper, E.-M. Jahn, V. ickmann and T. Carell, Angew. Chem. Int. Ed., 2007, 46, S5

6 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5-(aminomethyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (1, DMS-d 6 ) (Millions) *2 Cl * X : parts per Million : S6

7 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5-(aminomethyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (1, CD 3 D) 2 (Millions) *2 Cl * X : parts per Million : 1 S7

8 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5-(aminomethyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (1, DMS-d 6 ) *2 Cl * 2 (Thousands) X : parts per Million : 13C S8

9 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5-(aminomethyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (1, D 2 /CD 3 D) *2 Cl * X : parts per Million : 13C S9

10 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(1S,4S,5R)-4,5-dihydroxycyclopent-2-en-1-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (2, CD3D) (R) *2 Cl * 2 X : parts per Million : 1 S10

11 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(1S,4S,5R)-4,5-dihydroxycyclopent-2-en-1-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (2, D2) (R) *2 Cl * X : parts per Million : 1 S11

12 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(1S,4S,5R)-4,5-dihydroxycyclopent-2-en-1-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (2, CD 3 D) (Thousands) (R) *2 Cl * X : parts per Million : 13C S12

13 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(1R,4R,5S)-4,5-dihydroxycyclopent-2-en-1-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (3, CD3D) (R) (R) *2 Cl * 2 X : parts per Million : 1 S13

14 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(1R,4R,5S)-4,5-dihydroxycyclopent-2-en-1-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (3, D2) (R) (R) *2 Cl * X : parts per Million : 1 S14

15 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(1R,4R,5S)-4,5-dihydroxycyclopent-2-en-1-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (3, CD3D) (R) (R) *2 Cl * X : parts per Million : 13C S15

16 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(1R,4R,5S)-4,5-dihydroxycyclopent-2-en-1-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (3, D 2 /CD 3 D) (R) (R) *2 Cl * X : parts per Million : 13C S16

17 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (R,S)-2-(2-ydroxy-3-nitropropyl)-1-isoindole-1,3(2)-dione (6, DMS-d6) (R,S) 2 X : parts per Million : 1 S17

18 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (R,S)-2-(2-ydroxy-3-nitropropyl)-1-isoindole-1,3(2)-dione (6, DMS-d6) (R,S) X : parts per Million : 13C S18

19 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-[(2E)-3-nitroprop-2-en-1-yl]-1-isoindole-1,3(2)-dione (7, DMS-d6) (E) 2 X : parts per Million : 1 S19

20 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-[(2E)-3-nitroprop-2-en-1-yl]-1-isoindole-1,3(2)-dione (7, DMS-d 6 ) (E) (Millions) X : parts per Million : 13C S20

21 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (R,S)-2-[2-(2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-3-nitropropyl]-1-isoindole-1,3(2)-dione hydrate (8, DMS-d6) (Millions) (R,S) 2 2 * X : parts per Million : 1 S21

22 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (R,S)-2-[2-(2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-3-nitropropyl]-1-isoindole-1,3(2)-dione hydrate (8, DMS-d6) 2 (R,S) 2 2 * 2 (Millions) X : parts per Million : 13C S22

23 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-({[(2-Amino-4-oxo-4,7-dihydro-3-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]amino}carbonyl)benzoic acid dihydrate (9, DMS-d6) * X : parts per Million : 1 S23

24 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-({[(2-Amino-4-oxo-4,7-dihydro-3-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]amino}carbonyl)benzoic acid dihydrate (9, DMS-d6) 2 *2 2 (Millions) X : parts per Million : 13C S24

25 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3'aR,4'R,6'aS)-4',6'a-dihydro-3'a-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-ol (10b, CDCl3) (R) (R) X : parts per Million : 1 S25

26 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3aS,4S,6aS)-2,2-dimethyl-2,3a,4,6a-cyclopenta[d][1,3]dioxol-4-yl 4-nitrobenzoate (11a, CDCl3) X : parts per Million : 1 S26

27 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3aS,4S,6aS)-2,2-dimethyl-2,3a,4,6a-cyclopenta[d][1,3]dioxol-4-yl 4-nitrobenzoate (11a, CDCl 3 ) X : parts per Million : 13C S27

28 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3a'S,4'S,6a'S)-4',6a'-dihydro-3a'-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-4'-yl 4-nitro-benzoate (11b, CDCl3) X : parts per Million : 1 S28

29 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3a'S,4'S,6a'S)-4',6a'-dihydro-3a'-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-4'-yl 4-nitro-benzoate (11b, CDCl 3 ) X : parts per Million : 13C S29

30 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3aR,4S,6aS)-2,2-dimethyl-2,3a,4,6a-cyclopenta[d][1,3]dioxol-4-ol (12a, CDCl3) (R) X : parts per Million : 1 S30

31 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3aR,4S,6aS)-2,2-dimethyl-2,3a,4,6a-cyclopenta[d][1,3]dioxol-4-ol (12a, CDCl 3 ) (R) X : parts per Million : 13C S31

32 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3'aR,4'S,6'aS)-4',6'a-dihydro-3'a-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-ol (12b, CDCl3) (R) X : parts per Million : 1 S32

33 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3'aR,4'S,6'aS)-4',6'a-dihydro-3'a-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-ol (12b, CDCl 3 ) (R) X : parts per Million : 13C S33

34 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3aS,4R,6aS)-4-bromo-2,2-dimethyl-2,3a,4,6a-cyclopenta[d][1,3]dioxole (13a, CDCl3) (Millions) Br (R) 0.28 X : parts per Million : 1 S34

35 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3aS,4R,6aS)-4-bromo-2,2-dimethyl-2,3a,4,6a-cyclopenta[d][1,3]dioxole (13a, CDCl 3 ) Br (R) (Millions) X : parts per Million : 13C Filename = C:\Dokumente und Einstellu X_Acq_Duration = [s] X_Pulse = 4.6[us] S35

36 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3aS,4R,6aS)-4-bromo-4,6a-dihydro-3a-spiro[cyclohexane-1,2-cyclopenta[d][1,3]dioxole (13b, CDCl3) Br (R) X : parts per Million : 1 S36

37 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3aS,4R,6aS)-4-bromo-4,6a-dihydro-3a-spiro[cyclohexane-1,2-cyclopenta[d][1,3]dioxole (13b, CDCl 3 ) Br (R) X : parts per Million : 13C S37

38 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(3a R,4 S,6a S)-2,2-dimethyl-4,6a -dihydro-3a -cyclopenta[d][1,3]dioxol-4-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3- d]pyrimidin-4-one hydrochloride (14a, CD3D) (R) * Cl X : parts per Million : 1 S38

39 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(3a R,4 S,6a S)-2,2-dimethyl-4,6a -dihydro-3a -cyclopenta[d][1,3]dioxol-4-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3- d]pyrimidin-4-one hydrochloride (14a, CD3D) 2 (R) * Cl (Thousands) X : parts per Million : 13C S39

40 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(3a R,4 S,6a S)-2,2-dimethyl-4,6a -dihydro-3a -cyclopenta[d][1,3]dioxol-4-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3- d]pyrimidin-4-one (14a, CD3D) (R) X : parts per Million : 1 S40

41 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 5-({[(3'aR, 4'S,6'aS)-4',6'a-dihydro-3'a-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-yl]amino}methyl)-2-amino-3,4,7pyrrolo[2,3-d]pyrimidin-4-one hydrochloride (14b, CD3D) (R) * Cl X : parts per Million : 1 S41

42 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 5-({[(3'aR, 4'S,6'aS)-4',6'a-dihydro-3'a-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-yl]amino}methyl)-2-amino-3,4,7pyrrolo[2,3-d]pyrimidin-4-one hydrochloride (14b, DMS-d6) (R) * Cl X : parts per Million : 1 S42

43 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 5-({[(3'aR, 4'S,6'aS)-4',6'a-dihydro-3'a-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-yl]amino}methyl)-2-amino-3,4,7pyrrolo[2,3-d]pyrimidin-4-one hydrochloride (14b, CD 3 D) (R) * Cl X : parts per Million : 13C S43

44 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 5-({[(3'aR, 4'S,6'aS)-4',6'a-dihydro-3'a-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-yl]amino}methyl)-2-amino-3,4,7pyrrolo[2,3-d]pyrimidin-4-one (14b, CD3D) (R) X : parts per Million : 1 S44

45 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3aS,4R,6aR)-2,2-dimethyl-2,3a,4,6a-cyclopenta[d][1,3]dioxol-4-ol (15, CDCl3) (R) (R) X : parts per Million : 1 S45

46 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry (3aR,4S,6aR)-4-bromo-2,2-dimethyl-2,3a,4,6a-cyclopenta[d][1,3]dioxole (16, CDCl3) (Millions) Br (R) (R) X : parts per Million : 1 S46

47 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(3a S,4 R,6a R)-2,2-dimethyl-4,6a -dihydro-3a -cyclopenta[d][1,3]dioxol-4-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3- d]pyrimidin-4-one hydrochloride (17, CD3D) (R) (Millions) (R) * Cl X : parts per Million : 1 S47

48 Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry 2-Amino-5({[(3a S,4 R,6a R)-2,2-dimethyl-4,6a -dihydro-3a -cyclopenta[d][1,3]dioxol-4-yl]amino}methyl)-3,7-dihydro-4-pyrrolo[2,3- d]pyrimidin-4-one hydrochloride (17, CD 3 D) (R) (R) * Cl X : parts per Million : 13C S48