Synthesis of Variously Functionalized Azabicycloalkane Scaffolds by Domino. Metathesis Reactions

Transcription

1 Supporting Information Synthesis of Variously Functionalized Azabicycloalkane Scaffolds by Domino Metathesis Reactions Massimo Serra*, Elena Giulia Peviani, Eric Bernardi, and Lino Colombo* Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 12, Pavia, Italy Table of Contents S3 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 7 S4 S5 S6 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 9a Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 9b Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 10a S7 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 3 S8 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 11 S9 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 12 S10 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 13 S11 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 14 S12 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 15 S13 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 16 S14 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 17 S15 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 20 S16 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 22 S17 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 23 S18 S19 Copies of 1 H NMR (400 MHz), spectra for compounds 24a and 24b Copies of 3 C NMR and DEPT 135 spectra for compounds 24a and 24b

2 S20 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 26 S21 S22 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 27a Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 27b S23 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 28 S24 S26 1 H NMR (400 MHz), 13 C NMR, DEPT 135, 2D-COSY and 2D-NOESY spectra for compound 29a 1 H NMR (400 MHz), 13 C NMR, DEPT 135, 2D-COSY and 2D-NOESY spectra for compound 29b S28 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for compound 30 S29 Copies of 1 H NMR (500 MHz), 13 C NMR, DEPT 135, 2D-COSY, HSQC-DEPT, and 2D-NOESY spectra of compound 31 S32 Computational studies (part 1) S35 Computational studies (part 2) S38 Synthesis of 4-allyl-4-benzyloxazolidine-2,5-dione (side product I) S39 S40 S41 Copies of 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra for side product I Synthesis and copy of 1 H NMR (400 MHz) spectra of 2-benzyl-2- (((benzyloxy)carbonyl)amino)pent-4-enoic anhydride (side product II) References S2

3 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 7 S3

4 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 9a S4

5 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 9b S5

6 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 10a S6

7 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 3 S7

8 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 11 S8

9 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 12 S9

10 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 13 S10

11 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 14 S11

12 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 15 S12

13 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 16 S13

14 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 17 S14

15 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 20 S15

16 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 22 S16

17 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 23 S17

18 1 H NMR (400 MHz) spectra of compound 24a 1 H NMR (400 MHz) spectra of compound 24b S18

19 13 C NMR and DEPT 135 spectra of compound 24 (mixture of diastereoisomers) S19

20 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 26 S20

21 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 27a S21

22 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 27b S22

23 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 28 S23

24 1 H NMR (400 MHz), 13 C NMR, DEPT 135, 2D-COSY and 2D-NOESY spectra of compound 29a S24

25 NOEs of H 7 with H 2 and H 3 are diagnostic for the (R) absolute configuration of the C3 quaternary stereocenter. S25

26 1 H NMR (400 MHz), 13 C NMR, DEPT 135, 2D-COSY and 2D-NOESY spectra of compound 29b S26

27 S27

28 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of compound 30 S28

29 1 H NMR (500 MHz), 13 C NMR, DEPT 135, 2D-COSY, HSQC-DEPT, and 2D-NOESY spectra of compound 31 S29

30 S30

31 2D-NOESY spectrum overlapped with 2D-COSY spectrum (green) of compound 31. The red lines highlight the presence of an NOE peak between H 6 and H 7, which, in contrast are not correlated by a COSY peak. S31

32 Computational studies (part 1) In order to further confirm the absolute configuration at C6 stereocenter, we carried out computational studies on the minimum energy conformations of 31(6R) and 31(6S) (Figure S1). Each diastereoisomer of compound 31 was subjected to a Monte Carlo/Energy Minimization (MC/EM) conformational search [2] by molecular mechanics methods within the framework of the Schrodinger MacroModel version 10.2 [3], using OPLS_2005 force field [5], and the implicit CHCl 3 GB/SA solvation model [6]. The torsional space of each molecule was randomly varied with the usage-directed Monte Carlo conformational search of Chang, Guida, and Still [2]. A ringclosure bond was defined in the seven-membered ring of the 7,5-fused bicyclic lactam. Ester and amide bonds were constrained to their most stable conformations. For each search, starting structures were generated and minimized until the gradient was less than 0.05 kj/åmol using the truncated Newton-Raphson method [7]. Duplicate conformations and those with energy greater than 3 kcal/mol above the global minimum were discarded. 877 conformations were found for 31 (6R) diastereoisomer and 1465 conformations were found for the 31 (6S) diastereoisomer. In order to better evaluate the magnitude of the coupling constants (J) between H7 and its adjacent protons protons H6 and H8, we acquired 1H-NMR spectra of 31 at 80 C ( K) and applied the same temperature for the calculation of the Boltzmann population. The Coupling constants of interest were derived from the sum of the weighted constants of every conformation with respect to the Boltzmann population. As highlighted in table S1, the experimental data for compound 31 were in accordance with those calculated for compound 31 (6R), which was characterized by a little 1.4 Hz coupling constant between H 6 and H 7, probably not detectable by our 2D-COSY experiments (Figure S2). In contrast, compound 31 (6S) was characterized by a large coupling constant (10 Hz), which should have been well visible in the 2D-COSY spectrum. Moreover, acquiring the 1H-NMR spectra of 31 at 90 C, the broad signal of H 7 turned out to be a broad triplet with coupling constants comparable with those calculated for 31 (6S) (Figure S3). S32

33 Figure S1. Diastereoisomers 31 (6R) and 31 (6S) Table S1. Cmpd Force Field n. of conf. J 7-6 J 7-8 J (6R) OPLS_ (6S) OPLS_ Figure S2. COSY correlations of H 7 S33

34 Figure S3. 1H-NMR (300 MHz, dmso-d 6 ) at 80 C of compound 31 S34

35 Computational studies (part 2) Each compound was subjected to a Monte Carlo/Energy Minimization (MC/EM) conformational search [1] by molecular mechanics methods within the framework of the Schrodinger MacroModel version 10.8 [2], using two different force fields, OPLS3 [3] and OPLS_2005 [4], and the implicit water GB/SA solvation model [5]. The torsional space of each molecule was randomly varied with the usage-directed Monte Carlo conformational search of Chang, Guida, and Still [1]. A ringclosure bond was defined in the seven-membered ring of the 7,5-fused bicyclic lactam. Ester and amide bonds were constrained to their most stable conformations. For each search, starting structures were generated and minimized until the gradient was less than 0.05 kj/åmol using the truncated Newton-Raphson method [6]. Duplicate conformations and those with energy greater than 5 kcal/mol above the global minimum were discarded. According to the previously reported conformational analysis of azabicycloalkane amino acids [8], the reverse-turn inducing properties of the new functionalized bicyclic scaffolds 32a and 32b (Figure S4) were assessed by computing and analyzing different geometrical parameters of the minimum energy conformations (Table S2): the Cα i -Cα i+3 distance (dα) between capping groups on the N- and C-termini [7], the Φ and ψ backbone torsion angles in residues i+1 and i+2 [8], the virtual torsion angle β (C i -Cα i+1 -Cα i+2 -N i+3 ) [9], and parameters indicative of hydrogen bonding (distance between the carbonyl oxygen and the amide hydrogen atom, and directional requirements). Computing the percentage of conformations for which the aforementioned parameters assume typical turn values quantitatively assessed the turn propensity. A summary of the reverse-turn mimetic properties of the calculated structures is reported in Table S2. The lowest energy conformers of 33, 32a and 32b are shown in Figure S5 Figure S4. Bicyclic dipeptide mimics used in modeling studies. S35

36 Figure S5. Superposition of minimum energy conformer of 33 (yellow) with 32a, and 32b (green). Superposition of minimum energy conformer of 33 (yellow) with 32a (green) Superposition of minimum energy conformer of 33 (yellow) with 32b (green) S36

37 Table S2 Quantitative characterization of the reverse-turn forming ability of the conformers (MC/EM, OPLS3 and OPLS_2005, H 2 O GB/SA) calculated for dipeptide mimics. Hi+3 Cα i+2 N N CH 3 Cα i+1 O O i+2 i+1 Cα i+3 HN i+1 O C i i dα β(c i -Cα i+1 -Cα i+2 -N i+3 ) CH 3 Cα i Cmpd Force Field Number %dα a % β b %H-bond c %H-bond c of conf. < 7 Å < 60 NH i+3 -CO i+1 γ-turn d NH i+3 -CO i β-turn 33 OPLS a OPLS b OPLS OPLS_ a OPLS_ b OPLS_ a % dα is the percentage of all conformers for which the distance between Cαi and Cαi+3 is < 7 Å. b % β is the percentage of all conformers in which the virtual torsion angle β (absolute value) is < 60. c % H-bond is the percentage of all conformers in which H O distance < 2.5 Å, N H O bond angle > 120, and H O=C angle > 90. d Inverse γ-turn. S37

38 Synthesis of 4-allyl-4-benzyloxazolidine-2,5-dione (side product I) R f = 0.42 (hexane/acoet 60:40); IR (neat, cm -1 ) 3360, 1848, 1792, 1494, 1412, 1328, 1268, 1030; 1 H NMR (CDCl 3, 400 MHz) δ 2.54 (dd, J = 7.3, 14.1 Hz, 1H), 2.71 (dd, J = 7.5, 14.1 Hz, 1H), 2.99 (d, J = 14.0 Hz, 1H), 3.20 (d, J = 14.0 Hz, 1H), 5.26 (dd, J = 1.4, 16.9 Hz, 1H), 5.31 (dd, J = 1.4, 10.4 Hz, 1H), 5.73 (ddt, J = 7.4, 10.4, 17.0 Hz, 1H), 6.72 (m, 1H), (m, 2H), (m, 3H); 13 C{ 1 H} NMR (CDCl 3, 100 MHz) δ 41.4 (t), 42.9 (t), 68.6 (s), (t), 128.4, 129.3, 129.4, 130.4, (s), (s), (s); MS (ESI): m/z = [M + Na] + S38

39 1 H NMR (400 MHz), 13 C NMR and DEPT 135 spectra of side product I S39

40 Synthesis of 2-benzyl-2-(((benzyloxy)carbonyl)amino)pent-4-enoic anhydride (side product II) R f = 0.57 (hexane/acoet 85:15); 1 H NMR (CDCl 3, 400 MHz) δ (m, 4H), 3.05 (d, J = 13.4 Hz, 2H), 3.11 (d, J = 13.4 Hz, 2H), 5.16 (dd, J = 1.6, 10.0 Hz, 2H), 5.20 (dd, J = 1.6, 17.3 Hz, 2H), 5.30 (app s, 4H), 5.68 (ddt, J = 7.3, 10.0, 17.3 Hz, 2H), (m, 4H), (m, 6H), (m, 12H). 1 H NMR (400 MHz) spectra of side product II S40

41 References [1] Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989, 111, [2] MacroModel, version 10.8, Schrödinger, LLC, New York, [3] Harder, E.; Damm,W.; Maple, J.; Wu, C.; Reboul, M.; Xiang, J. Y.; Wang, L.; Lupyan, D.; Dahlgren, M. K.; Knight, J. L.; Kaus, J. W.; Cerutti, D. S.; Krilov, G.; Jorgensen, W. L.; Abel, R.; Friesner, R. A. J. Chem. Theory Comput., 2016, 12 (1), [4] Banks,J. L.; Beard, H. S.; Cao, Y.; Cho, A. E.; Damm, W.; Farid, R.; Felts, A. K.; Halgren, T. A.; Mainz, D. T.; Maple, J. R.; Murphy, R.; Philipp, D. M.; Repasky, M. P.; Zhang, L. Y.; Berne, B. J.; Friesner, R. A.; Gallicchio, E.; Levy, R. M. J. Comp. Chem. 2005, 26, [5] Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J. Am. Chem. Soc. 1990, 112, [6] Ponder, J. W.; Richards, F. M. J. Comput. Chem. 1987, 8, [7] a) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico, C. Eur. J. Org. Chem. 1999, b) Belvisi, L.; Colombo, L.; Manzoni, L.; Potenza, D.; Scolastico, C. Synlett 2004, [8] Rose, G. D.; Gierasch, L. M.; Smith, J. A. Adv. Prot. Chem. 1985, 37, [9] Ball, J. B.; Hughes, R. A.; Alewood, P. F.; Andrews, P. R. Tetrahedron 1993, 49, S41