A Unified Approach toward trans- Hydrindane Sesterterpenoids

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1 Supporting Information for A Unified Approach toward trans- Hydrindane Sesterterpenoids Daniel T. Hog, Peter Mayer, and Dirk Trauner* Fakultät für Chemie und Pharmazie, Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstraße 5 13, München, Germany Dirk.Trauner@cup.uni-muenchen.de

2 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S1 Table of Contents 1 General Working Methods....S2 2 X-Ray Crystallographic Data.. S5 2.1 (3a'S,7a'S)-7a'-methylhexahydrospiro[[1,3]dioxolane-2,5'-inden]-1'(6'H)-one (10).. S5 2.2 (3a'R,7a'S)-7a'-methyl-3a',4',7',7a'-tetrahydrospiro[[1,3]dioxolane-2,5'-inden]- 1'(6'H)-one (11)....S6 2.3 (3'R,3a'R,7a'S)-7a'-methyl-3'-(prop-1-en-2-yl)hexahydrospiro[[1,3]dioxolane-2,5'- inden]-1'(6'h)-one (12)....S8 2.4 (3'R,3a'R,7a'S)-3'-isopropyl-7a'-methylhexahydrospiro[[1,3]dioxolane-2,5'-inden-] 1'(6'H)-one (13) S9 2.5 (3'S,3a'R,7a'S)-3'-isopropyl-7a'-methylhexahydrospiro[[1,3]dioxolane-2,5'-inden]- 1'(6'H)-one (14) S (2S,3S,3aR,7aR)-2-((tert-butyldimethylsilyl)oxy)-3-isopropyl-7a-methylhexahydro-1H-inden-5(6H)-one (20). S (3R,3aR,7aS)-3-isopropyl-7a-methylhexahydro-1H-inden-5(6H)-one (24) S H and 13 C NMR Spectra.. S16 4 References.....S33

3 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S2 1 General Working Methods All reactions were magnetically stirred and carried out under a positive pressure of inert-gas (N 2 or argon) utilitzing standard Schlenk-technique. Glassware was dried in an oven at 120 C and repeatedly at 650 C in vacuo prior to use. Liquid reagents and solvents were added by syringes or oven-dried stainless steel canulas through rubber septa. Solids were added under inert gas counter flow or were dissolved in appropriate solvents. Low temperature-reactions were carried out in a Dewar vessel filled with a cooling agent: acetone/dry ice ( 78 C), acetonitrile/liquid N 2 ( 40 C), NaCl/ice ( 20 C) or H 2 O/ice (0 C). Reaction temperatures above room temperature were conducted in a heated oil bath. Solvents and reagents Tetrahydrofuran (THF) and diethyl ether (Et 2 O) were distilled under N 2 atmosphere from Na/benzophenone as drying reagent prior to use. Triethylamine (Et 3 N), diisopropylamine (DIPA) and Hünig s base (DIPEA) were distilled under N 2 atmosphere from CaH 2 as drying agent prior to use. Further dry solvents such as dichloromethane (CH 2 Cl 2 ), N,N-dimethylformamide (DMF), acetonitrile (MeCN), acetone, methanol (MeOH), benzene and toluene were purchased from commercial suppliers and used as received. Solvents for extraction, crystallization and flash column chromatography were purchased in technical grade and distilled under reduced pressure prior to use. Eder-Sauer-Wiechert- Hajos-Parrish ketone (7) S1 and trans-hydrindane (8) S2 were prepared as described previously. (S)-Alpine-Boramine TM was purchased and stored in a glove-box. All other reagents and solvents were purchased from chemical suppliers and were used as received. Chromatography Reactions and chromatography fractions were monitored by qualitative thin-layer chromatography (TLC) on silica gel F 254 TLC plates from Merck KGaA. Analytes on the glass plates were visualized by irradiation with UV-light and/or by immersion of the TLC plate in an appropriate staining solution followed by heating with a hot-air gun (350 C). The following staining solutions were applied: p-anisaldehyde staining solution (3.7 ml p-anisaldehyde, 5.0 ml concentrated aqueous H 2 SO 4, 1.5 ml glacial AcOH, 135 ml EtOH). Hanessian s staining solution (CAM, 5.0 g, Ce(SO 4 ) 2, 25 g (NH 4 ) 6 Mo 7 O 24 4H 2 O, 50 ml concentrated aqueous H 2 SO 4, 450 ml H 2 O). KMnO 4 staining solution, (3.0 g KMnO 4, 20 g K 2 CO 3, 5.0 ml aqueous 5% NaOH, 300 ml H 2 O). Brady s staining solution (12 g 2,4-dinitrophenylhydrazine, 60 ml concentrated aqueous H 2 SO 4, 200 ml EtOH, 80 ml H 2 O).

4 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S3 Flash column chromatography (FCC) was performed on Geduran Si60 (40 63 μm) silica gel from Merck KGaA. All fractions containing a desired substrate were combined and solvents were removed under reduced pressure followed by drying in high vacuo (10 2 mbar). NMR spectroscopy NMR spectra were measured using spectrometers operating at 300 MHz, 400 MHz and 600 MHz for proton nuclei (75 MHz, 100 MHz, 150 MHz for carbon nuclei). The 1 H NMR shifts are reported in ppm related to the residual shift of TMS. 1 H NMR shifts were calibrated to residual solvent resonances: CDCl 3 (7.26 ppm), CD 2 Cl 2 (5.32 ppm). 13 C NMR shifts were calibrated to the center of the multiplet signal of the residual solvent resonance: CDCl 3 (77.16 ppm), CD 2 Cl 2 (54.00 ppm). 1 H NMR spectroscopic data are reported as follows: Chemical shift in ppm (multiplicity, coupling constants J, integration intensity). The multiplicities are abbreviated with s (singlet), brs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and m C (centrosymmetric multiplet). In case of combined multiplicities, the multiplicity with the larger coupling constant is stated first. Except for multiplets, the chemical shift of all signals, as well for centrosymmetric multiplets, is reported as the center of the resonance range. Additionally to 1 H and 13 C NMR measurements, 2D NMR techniques as homonuclear correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond coherence (HMBC) were used to assign signals. For further elucidation of 3D stuctures of the analytes, nuclear Overhauser enhancement spectroscopy (NOESY) was conducted. Coupling constants J are reported in Hz. Mass spectrometry Mass spectra were recorded in high-resolution utilizing the following methods (mass type analyzer in brackets): EI (sector field mass spectrometer) and FAB (sector field mass spectrometer). Only the characteristic molecule fragments or molecule ion peaks are indicated for each analyte. The method used is reported at the relevant section of the experimental part. IR spectroscopy For measuring of IR spectra, substances were dissolved in CH 2 Cl 2 and directly applied on the ATR unit. The measured wave numbers are reported in cm 1. Melting points Melting points were measured on a melting point apparatus and are uncorrected.

5 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S4 Optical rotation Optical rotation values were recorded on a polarimeter. The specific rotation is calculated as follows: [ ] α ϑ λ = [ α ] 100 c d Thereby, the wave length λ is reported in nm and the measuring temperature ϕ in C. α resembles the recorded optical rotation at the apparatus, c the concentration of the analyte in 10 mg/ml and d the length of the cuvette in dm. Thus, the specific rotation is given in 10 1 deg cm 2 g 1. Usage of the sodium D line (λ = 589 nm) is indicated by D instead of the wavelength in nm. The respective concentration as well as the solvent is denoted in the analytical part of the experimental description.

6 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S5 2 X-Ray Crystallographic Data The data collections were performed at 173 K using MoKα-radiation (λ = Å, graphite monochromator). The CrysAlisPro software (version ) S3 was applied for the integration, scaling and multi-scan absorption correction of the data. The structures were solved by direct methods with SIR97 S4 and refined by least-squares methods against F2 with SHELXL-97. S5 All non-hydrogen atoms were refined anisotropically. The hydrogen atoms were placed in ideal geometry riding on their parent atoms. Further details are summarized in the tables S1 S7 at the different sections. S6 2.1 (3a'S,7a'S)-7a'-methylhexahydrospiro[[1,3]dioxolane-2,5'-inden]-1'(6'H)-one (10) Crystals suitable for X-ray analysis were obtained by re-crystallization from n-pentane. Table S1. Crystallographic data for ketone 10. net formula C 12 H 18 O 3 M r /g mol crystal size/mm T/K 173(2) radiation MoKα crystal system orthorhombic space group P a/å (5) b/å (5) c/å (7) α/ 90 β/ 90 γ/ 90 V/Å (10) Z 4 calc. density/g cm (12) μ/mm absorption correction 'multi-scan' transmission factor range refls. measured 8113 R int mean σ(i)/i θ range observed refls x, y (weighting scheme) , 0 hydrogen refinement constr Flack parameter 3.1(15) refls in refinement 1301 parameters 137 restraints 0

7 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S6 R(F obs ) R w (F 2 ) S shift/error max max electron density/e Å Flack parameter meaningless. 933 Friedel pairs merged. C10 C7 O3 C8 C12 C6 C9 C1 O1 C5 C4 C2 C11 O2 C3 Figure S1. Crystal structure of ketone (3a'R,7a'S)-7a'-methyl-3a',4',7',7a'-tetrahydrospiro[[1,3]dioxolane-2,5'-inden]- 1'(6'H)-one (11) Crystals suitable for X-ray analysis were obtained by re-crystallization from hexanes. Table S2. Crystallographic data of enone 11. net formula C 12 H 16 O 3 M r /g mol crystal size/mm T/K 173(2) radiation MoKα crystal system monoclinic space group P2 1 a/å (5) b/å (7) c/å (7) α/ 90 β/ (4) γ/ 90 V/Å (7) Z 2 calc. density/g cm (17) μ/mm

8 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S7 absorption correction none refls. measured 3526 R int mean σ(i)/i θ range observed refls. 874 x, y (weighting scheme) , hydrogen refinement constr Flack parameter 1.7(19) refls in refinement 1016 parameters 137 restraints 1 R(F obs ) R w (F 2 ) S shift/error max max electron density/e Å min electron density/e Å Flack parameter meaningless. 845 Friedel pairs merged. Absolute structure deduced from synthesis, C4 C5 C12 O1 C3 C6 O3 C1 C7 C11 O2 C10 C8 C2 C9 Figure S2. Crystal structure of enone 11.

9 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S8 2.3 (3'R,3a'R,7a'S)-7a'-methyl-3'-(prop-1-en-2-yl)hexahydrospiro[[1,3]dioxolane-2,5'- inden]-1'(6'h)-one (12) Crystals suitable for X-ray analysis were grown by slow evaporation of a solution of ketone 12 in pentane at 25 C. Table S3. Crystallographic data of ketone 12. net formula C 15 H 22 O 3 M r /g mol crystal size/mm T/K 173(2) radiation MoKα crystal system monoclinic space group P2 1 a/å (5) b/å (3) c/å (7) α/ 90 β/ (6) γ/ 90 V/Å (6) Z 2 calc. density/g cm (11) μ/mm absorption correction 'multi-scan' transmission factor range refls. measured 4829 R int mean σ(i)/i θ range observed refls x, y (weighting scheme) , 0 hydrogen refinement constr Flack parameter 2.5(13) refls in refinement 1488 parameters 165 restraints 1 R(F obs ) R w (F 2 ) S shift/error max max electron density/e Å Flack parameter meaningless. 741 Friedel pairs merged. Absolute structure deduced from synthesis.

10 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S9 C5 C12 O3 C4 C6 C7 O2 C3 C8 C2 C1 O1 C11 C10 C9 C14 C13 C15 Figure S3. Crystal structure of ketone (3'R,3a'R,7a'S)-3'-isopropyl-7a'-methylhexahydrospiro[[1,3]dioxolane-2,5'- inden]-1'(6'h)-one (13) Crystals suitable for X-ray analysis were grown by slow evaporation of a solution of ketone 13 in Et 2 O/pentane. Table S4. Crystallographic data of ketone 13. net formula C 15 H 24 O 3 M r /g mol crystal size/mm T/K 173(2) radiation MoKα crystal system orthorhombic space group P a/å (4) b/å (5) c/å (14) α/ 90 β/ 90 γ/ 90 V/Å (14) Z 4 calc. density/g cm (12) μ/mm absorption correction 'multi-scan' transmission factor range refls. measured 5778 R int

11 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S10 mean σ(i)/i θ range observed refls x, y (weighting scheme) , 0 hydrogen refinement constr Flack parameter 1.5(14) refls in refinement 1665 parameters 166 restraints 0 R(F obs ) R w (F 2 ) S shift/error max max electron density/e Å Flack Parameter meaningless Friedel pairs merged. Absolute structure derived from synthesis. C10 C7 C8 C9 C1 O1 O2 C2 C15 C6 C5 C4 C3 C14 O3 C11 C13 C12 Figure S4. Crystal structure of ketone 13.

12 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S (3'S,3a'R,7a'S)-3'-isopropyl-7a'-methylhexahydrospiro[[1,3]dioxolane-2,5'- inden]-1'(6'h)-one (14) Crystals suitable for X-ray analysis were grown by slow evaporation of a solution of ketone 14 in Et 2 O/pentane. Table S5. Crystallographic data of ketone 14. net formula C 15 H 24 O 3 M r /g mol crystal size/mm T/K 173(2) radiation MoKα crystal system monoclinic space group P2 1 a/å (5) b/å (2) c/å (6) α/ 90 β/ (2) γ/ 90 V/Å (5) Z 2 calc. density/g cm (9) μ/mm absorption correction none refls. measured 4457 R int mean σ(i)/i θ range observed refls x, y (weighting scheme) , hydrogen refinement constr Flack parameter 0.7(12) refls in refinement 2417 parameters 185 restraints 2 R(F obs ) R w (F 2 ) S shift/error max max electron density/e Å min electron density/e Å Flack test results meaningless, no anomalous scatterer in structure. Absolute structure derived from synthesis. C14 and C15 are disordered, split model applied, sof ratio 0.58/0.42.

13 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S12 C8 C10 O1 C7 C1 C9 O2 C6 C2 C141 O3 C5 C4 C3 C11 C151 C12 C13 Figure S5. Crystal structure of ketone 14. Only the main part of the disordered group C14/C15 is shown. 2.6 (2S,3S,3aR,7aR)-2-((tert-butyldimethylsilyl)oxy)-3-isopropyl-7a-methylhexahydro-1H-inden-5(6H)-one (20) Crystals suitable for X-ray analysis were obtained by re-crystallization from MeOH. Table S6. Crystallographic data of ketone 20. net formula C 19 H 36 O 2 Si M r /g mol crystal size/mm T/K 173(2) radiation MoKα crystal system orthorhombic space group P a/å (2) b/å (4) c/å (13) α/ 90 β/ 90 γ/ 90 V/Å (13) Z 4 calc. density/g cm (7) μ/mm absorption correction 'multi-scan'

14 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S13 transmission factor range refls. measured R int mean σ(i)/i θ range observed refls x, y (weighting scheme) , 0 hydrogen refinement constr Flack parameter 0.00(11) refls in refinement 3991 parameters 207 restraints 0 R(F obs ) R w (F 2 ) S shift/error max max electron density/e Å C12 C13 C19 C14 C15 C2 C1 C7 O1 Si1 C3 C6 O2 C11 C10 C9 C8 C16 C18 C5 C4 C17 Figure S6. Crystal structure of ketone 20.

15 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S (3R,3aR,7aS)-3-isopropyl-7a-methylhexahydro-1H-inden-5(6H)-one (24) Crystals suitable for X-ray analysis were grown from a solution of ketone 24 in pentane at 25 C. Table S7. Crystallographic data of ketone 24. net formula C 13 H 22 O M r /g mol crystal size/mm T/K 173(2) radiation MoKα crystal system monoclinic space group P2 1 a/å (10) b/å (11) c/å (2) α/ 90 β/ (10) γ/ 90 V/Å (17) Z 2 calc. density/g cm (3) μ/mm absorption correction none refls. measured 2730 R int mean σ(i)/i θ range observed refls. 715 x, y (weighting scheme) , hydrogen refinement constr Flack parameter 1(5) refls in refinement 974 parameters 130 restraints 1 R(F obs ) R w (F 2 ) S shift/error max max electron density/e Å min electron density/e Å Flack parameter meaningless, 589 Friedel pairs merged. Investigated crystal had poor scattering strength leading to reduced resolution.

16 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S15 C10 C3 C4 C5 C2 C6 C1 C8 C7 C9 O1 C11 C13 C12 Figure S7. Crystal structure of ketone 24.

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34 D. T. Hog et al.: A Unified Approach toward trans-hydrindane Sesterterpenoids Supporting Information S33 4 References S1 Hajos, Z. G.; Parrish, D. R. Org. Synth. 1985, 63, S2 Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.; Portland, L. A.; Sciamanna, W.; Scott, M. A.; Wehrli, P. A. J. Org. Chem. 1975, 40, S3 CrysAlisPro, Oxford Diffraction Ltd., Version (release CrysAlis171.NET). S4 Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, S5 Sheldrick, G. M. Acta Crystallogr. 2008, A64, S6 CCDC (ketone 10), (ketone 12), (ketone 24), (ketone 14), (ketone 20), (enone 11) and (ketone 13) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via

Total Synthesis of Gonytolides C and G, Lachnone C, and. Formal Synthesis of Blennolide C and Diversonol

. This journal is The Royal Society of Chemistry 2014 Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry Total Synthesis of Gonytolides C and G, Lachnone C, and Formal Synthesis