Atropselective syntheses of (−) and (+) rugulotrosin A utilizing point-to-axial chirality transfer

Journal name:
Nature Chemistry
Volume:
7,
Pages:
234–240
Year published:
DOI:
doi:10.1038/nchem.2173
Received
Accepted
Published online

Abstract

Chiral, dimeric natural products containing complex structures and interesting biological properties have inspired chemists and biologists for decades. A seven-step total synthesis of the axially chiral, dimeric tetrahydroxanthone natural product ​rugulotrosin A is described. The synthesis employs a one-pot Suzuki coupling/dimerization to generate the requisite 2,2′-biaryl linkage. Highly selective point-to-axial chirality transfer was achieved using palladium catalysis with achiral phosphine ligands. Single X-ray crystal diffraction data were obtained to confirm both the atropisomeric configuration and absolute stereochemistry of ​rugulotrosin A. Computational studies are described to rationalize the atropselectivity observed in the key dimerization step. Comparison of the crude fungal extract with synthetic ​rugulotrosin A and its atropisomer verified that nature generates a single atropisomer of the natural product.

At a glance

Figures

  1. Axially chiral, dimeric tetrahydroxanthone natural products and point-to-axial chirality transfer strategy.
    Figure 1: Axially chiral, dimeric tetrahydroxanthone natural products and point-to-axial chirality transfer strategy.

    a, Structures of the dimeric tetrahydroxanthone natural products secalonic acids B and D. b, Structures of representative axially chiral tetrahydroxanthone natural products. c, Select literature examples of remote point-to-axial chirality transfer. d, Strategy for the synthesis of ​rugulotrosin A.

  2. Scalable syntheses of enantiopure tetrahydroxanthone monomers.
    Figure 2: Scalable syntheses of enantiopure tetrahydroxanthone monomers.

    Key steps involve siloxyfuran addition to a benzopyrylium species (12 to (±)-13) followed by kinetic acylative resolution of (±)-17 using the Birman catalyst.

  3. One-pot Suzuki dimerization of chiral tetrahydroxanthone monomers (+)-18.
    Figure 3: One-pot Suzuki dimerization of chiral tetrahydroxanthone monomers (+)-18.

    Optimal conditions shown using ​Pd(OAc)2 and ​SPhos as achiral ligand.

  4. Syntheses of (−) and (+)-rugulotrosin A and atrop-rugulotrosin A.
    Figure 4: Syntheses of (−) and (+)-rugulotrosin A and atrop-rugulotrosin A.

    a, Synthesis of ent-rugulotrosin A. b, Synthesis of ​rugulotrosin A and comparison rotation data with natural sample. c, Synthesis of atrop-rugulotrosin A. d, Synthesis of ent-atrop-rugulotrosin A. e, Comparison between the natural extract and synthetic rugulotrosins. HPLC-DAD (210 nm) (Zorbax C18 column, gradient elution H2O/​MeCN plus 0.05% ​HCO2H) analysis of 21-day Penicillium nov. sp. (MST-F8741) cultures extracted with (i) ​MeCN or (ii) ​MeOH, compared against (iii) natural (+)-1, (iv) synthetic (+)-1, (v) (-)-23 and (vi) a mixture of (+)-1, (-)-1, (-)-23 and (+)-23. mAU, milli absorption units.

  5. Computational studies for atropselective Suzuki dimerization.
    Figure 5: Computational studies for atropselective Suzuki dimerization.

    Conformational analysis was optimized at the B3LYP/LanL2DZ level of theory. Dihedral angles were measured by C1, C2, C2′ and C1′ and are shown in green. a, Conformers leading to (-)-19. b, Conformers leading to 20.

Compounds

37 compounds View all compounds
  1. Rugulotrosin A
    Compound 1 Rugulotrosin A
  2. Rugulotrosin A
    Compound (+)-1 Rugulotrosin A
  3. ent-Rugulotrosin A
    Compound (-)-1 ent-Rugulotrosin A
  4. Rugulotrosin B
    Compound 2 Rugulotrosin B
  5. Gonytolide E
    Compound 3 Gonytolide E
  6. Gonytolide A
    Compound 4 Gonytolide A
  7. (S)-7-Hydroxy-9-isopropoxy-10-methoxy-3-(2-((triisopropylsilyl)oxy)ethyl)-3,4-dihydro-1H-benzo[g]isochromen-1-one
    Compound 5 (S)-7-Hydroxy-9-isopropoxy-10-methoxy-3-(2-((triisopropylsilyl)oxy)ethyl)-3,4-dihydro-1H-benzo[g]isochromen-1-one
  8. (3S,3'S,6R)-7,7'-Dihydroxy-9,9'-diisopropoxy-10,10'-dimethoxy-3,3'-bis(2-((triisopropylsilyl)oxy)ethyl)-3,3',4,4'-tetrahydro-1H,1'H-[6,6'-bibenzo[g]isochromene]-1,1'-dione
    Compound 6 (3S,3'S,6R)-7,7'-Dihydroxy-9,9'-diisopropoxy-10,10'-dimethoxy-3,3'-bis(2-((triisopropylsilyl)oxy)ethyl)-3,3',4,4'-tetrahydro-1H,1'H-[6,6'-bibenzo[g]isochromene]-1,1'-dione
  9. (4-(Benzyloxy)-5-methoxy-7-(((triisopropylsilyl)oxy)methyl)naphthalen-1-yl)boronic acid
    Compound 7 (4-(Benzyloxy)-5-methoxy-7-(((triisopropylsilyl)oxy)methyl)naphthalen-1-yl)boronic acid
  10. ((1R,3S)-6,8-Bis(benzyloxy)-5-iodo-1-methyl-2-tosyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl 2-naphthoate
    Compound 8 ((1R,3S)-6,8-Bis(benzyloxy)-5-iodo-1-methyl-2-tosyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl 2-naphthoate
  11. ((1R,3S,5R)-6,8-Bis(benzyloxy)-5-(4-(benzyloxy)-5-methoxy-7-(((triisopropylsilyl)oxy)methyl)naphthalen-1-yl)-1-methyl-2-tosyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl 2-naphthoate
    Compound 9 ((1R,3S,5R)-6,8-Bis(benzyloxy)-5-(4-(benzyloxy)-5-methoxy-7-(((triisopropylsilyl)oxy)methyl)naphthalen-1-yl)-1-methyl-2-tosyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl 2-naphthoate
  12. Methyl 5-hydroxy-7-methyl-4-oxo-4H-chromene-2-carboxylate
    Compound 12 Methyl 5-hydroxy-7-methyl-4-oxo-4H-chromene-2-carboxylate
  13. (±)-Methyl (R)-5-hydroxy-7-methyl-4-oxo-2-((R)-5-oxotetrahydrofuran-2-yl)chromane-2-carboxylate
    Compound (±)-13 (±)-Methyl (R)-5-hydroxy-7-methyl-4-oxo-2-((R)-5-oxotetrahydrofuran-2-yl)chromane-2-carboxylate
  14. (±)-Methyl (4R,4aR)-1,4,8-trihydroxy-6-methyl-9-oxo-2,3,4,9-tetrahydro-4aH-xanthene-4a-carboxylate
    Compound (±)-14 (±)-Methyl (4R,4aR)-1,4,8-trihydroxy-6-methyl-9-oxo-2,3,4,9-tetrahydro-4aH-xanthene-4a-carboxylate
  15. (±)-Methyl (4R,4aR)-4,8-dihydroxy-9-methoxy-6-methyl-1-oxo-1,2,3,4-tetrahydro-4aH-xanthene-4a-carboxylate
    Compound (±)-15 (±)-Methyl (4R,4aR)-4,8-dihydroxy-9-methoxy-6-methyl-1-oxo-1,2,3,4-tetrahydro-4aH-xanthene-4a-carboxylate
  16. (±)-Methyl (4R,4aR)-4,8-dihydroxy-1-methoxy-6-methyl-9-oxo-2,3,4,9-tetrahydro-4aH-xanthene-4a-carboxylate
    Compound (±)-16 (±)-Methyl (4R,4aR)-4,8-dihydroxy-1-methoxy-6-methyl-9-oxo-2,3,4,9-tetrahydro-4aH-xanthene-4a-carboxylate
  17. (±)-Methyl (4R,4aR)-4,8-dihydroxy-7-iodo-1-methoxy-6-methyl-9-oxo-2,3,4,9-tetrahydro-4aH-xanthene-4a-carboxylate
    Compound (±)-17 (±)-Methyl (4R,4aR)-4,8-dihydroxy-7-iodo-1-methoxy-6-methyl-9-oxo-2,3,4,9-tetrahydro-4aH-xanthene-4a-carboxylate
  18. Methyl (4S,4aS)-4,8-dihydroxy-7-iodo-1-methoxy-6-methyl-9-oxo-2,3,4,9-tetrahydro-4aH-xanthene-4a-carboxylate
    Compound (-)-17 Methyl (4S,4aS)-4,8-dihydroxy-7-iodo-1-methoxy-6-methyl-9-oxo-2,3,4,9-tetrahydro-4aH-xanthene-4a-carboxylate
  19. Methyl (4R,4aR)-8-hydroxy-7-iodo-1-methoxy-6-methyl-9-oxo-4-(propionyloxy)-2,3,4,9-tetrahydro-4aH-xanthene-4a-carboxylate
    Compound (+)-18 Methyl (4R,4aR)-8-hydroxy-7-iodo-1-methoxy-6-methyl-9-oxo-4-(propionyloxy)-2,3,4,9-tetrahydro-4aH-xanthene-4a-carboxylate
  20. Dimethyl (2R,5S,5'S,10aS,10'aS)-1,1',5,5'-tetrahydroxy-8,8'-dimethoxy-3,3'-dimethyl-9,9'-dioxo-5,5',6,6',7,7',9,9'-octahydro-10aH,10'aH-[2,2'-bixanthene]-10a,10'a-dicarboxylate
    Compound (-)-19 Dimethyl (2R,5S,5'S,10aS,10'aS)-1,1',5,5'-tetrahydroxy-8,8'-dimethoxy-3,3'-dimethyl-9,9'-dioxo-5,5',6,6',7,7',9,9'-octahydro-10aH,10'aH-[2,2'-bixanthene]-10a,10'a-dicarboxylate
  21. Dimethyl (5S,5'S,10aS,10'aS)-1,1',5,5'-tetrahydroxy-8,8'-dimethoxy-3,3'-dimethyl-9,9'-dioxo-5,5',6,6',7,7',9,9'-octahydro-10aH,10'aH-[2,2'-bixanthene]-10a,10'a-dicarboxylate
    Compound 20 Dimethyl (5S,5'S,10aS,10'aS)-1,1',5,5'-tetrahydroxy-8,8'-dimethoxy-3,3'-dimethyl-9,9'-dioxo-5,5',6,6',7,7',9,9'-octahydro-10aH,10'aH-[2,2'-bixanthene]-10a,10'a-dicarboxylate
  22. Dimethyl (5R,5'R,10aR,10'aR)-1,1'-dihydroxy-8,8'-dimethoxy-3,3'-dimethyl-9,9'-dioxo-5,5'-bis(propionyloxy)-5,5',6,6',7,7',9,9'-octahydro-10aH,10'aH-[2,2'-bixanthene]-10a,10'a-dicarboxylate
    Compound (+)-21 Dimethyl (5R,5'R,10aR,10'aR)-1,1'-dihydroxy-8,8'-dimethoxy-3,3'-dimethyl-9,9'-dioxo-5,5'-bis(propionyloxy)-5,5',6,6',7,7',9,9'-octahydro-10aH,10'aH-[2,2'-bixanthene]-10a,10'a-dicarboxylate
  23. Dimethyl (5S,5'S,10aS,10'aS)-1,1'-dihydroxy-8,8'-dimethoxy-3,3'-dimethyl-9,9'-dioxo-5,5'-bis(propionyloxy)-5,5',6,6',7,7',9,9'-octahydro-10aH,10'aH-[2,2'-bixanthene]-10a,10'a-dicarboxylate
    Compound (+)-22 Dimethyl (5S,5'S,10aS,10'aS)-1,1'-dihydroxy-8,8'-dimethoxy-3,3'-dimethyl-9,9'-dioxo-5,5'-bis(propionyloxy)-5,5',6,6',7,7',9,9'-octahydro-10aH,10'aH-[2,2'-bixanthene]-10a,10'a-dicarboxylate
  24. Dimethyl (2R,5R,5'R,10aR,10'aR)-1,1'-dihydroxy-8,8'-dimethoxy-3,3'-dimethyl-9,9'-dioxo-5,5'-bis(propionyloxy)-5,5',6,6',7,7',9,9'-octahydro-10aH,10'aH-[2,2'-bixanthene]-10a,10'a-dicarboxylate
    Compound (-)-22 Dimethyl (2R,5R,5'R,10aR,10'aR)-1,1'-dihydroxy-8,8'-dimethoxy-3,3'-dimethyl-9,9'-dioxo-5,5'-bis(propionyloxy)-5,5',6,6',7,7',9,9'-octahydro-10aH,10'aH-[2,2'-bixanthene]-10a,10'a-dicarboxylate
  25. ent-atrop-Rugulotrosin A
    Compound (+)-23 ent-atrop-Rugulotrosin A
  26. atrop-Rugulotrosin A
    Compound (-)-23 atrop-Rugulotrosin A
  27. SPhos
    Compound L1 SPhos
  28. XPhos
    Compound L2 XPhos
  29. RuPhos
    Compound L3 RuPhos
  30. Dicyclohexyl(2-(2-methoxynaphthalen-1-yl)phenyl)phosphane
    Compound L4 Dicyclohexyl(2-(2-methoxynaphthalen-1-yl)phenyl)phosphane
  31. BI-DIME
    Compound L5 BI-DIME
  32. S-Cy-MOP
    Compound L6 S-Cy-MOP
  33. R-Cy-MOP
    Compound L7 R-Cy-MOP
  34. R-Cy-iPr-MOP
    Compound L8 R-Cy-iPr-MOP
  35. SPhos-Gen 3 pre-catalyst
    Compound C1 SPhos-Gen 3 pre-catalyst
  36. S-Cy-MOP-Gen 3 pre-catalyst
    Compound C2 S-Cy-MOP-Gen 3 pre-catalyst
  37. R-Cy-MOP-Gen 3 pre-catalyst
    Compound C3 R-Cy-MOP-Gen 3 pre-catalyst

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Author information

Affiliations

  1. Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts 02215, USA

    • Tian Qin &
    • John A. Porco Jr
  2. Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, USA

    • Sarah L. Skraba-Joiner &
    • Richard P. Johnson
  3. The University of Queensland, Institute of Molecular Bioscience, 306 Carmody Road, St Lucia, Queensland 4072, Australia

    • Zeinab G. Khalil &
    • Robert J. Capon

Contributions

T.Q. and J.A.P. conceived of the project, designed and carried out the experiments, analysed the data and wrote most of the paper. S.L.S-J. and R.P.J. performed computational studies. Z.G.K. and R.J.C. performed natural extract comparisons and biological studies. All authors discussed the results and commented on the manuscript.

Competing financial interests

The authors declare no competing financial interests.

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Crystallographic information files

  1. Supplementary information (121 KB)

    Crystallographic data for compound (-)-19.

  2. Supplementary information (248 KB)

    Crystallographic data for compound (-)-22.

Additional data