LINOXEPIN SPECTRAL DATA

Weinstabl, H., Suhartono, M., Qureshi, Z. and Lautens, M. (2013), Total Synthesis of (+)-Linoxepin by Utilizing the Catellani Reaction . Angew. Chem. Int. Ed., 52: 5305–5308. doi: 10.1002/anie.201302327

1. ^†
   We gratefully thank the NSERC, Merck Frosst, and Merck for an Industrial Research Chair. We also thank the University of Toronto for support of our program, Dr. Alan Lough (Chemistry Department, University of Toronto) for single-crystal X-ray structure analysis. H.W. thanks the Austrian Science Fund (FWF): J3250-N19 for an Erwin Schroedinger postdoctoral fellowship and M.S. thanks the DFG for a postdoctoral fellowship. We would like to thank Pierre Thesmar and Patrick Lui for their contributions.

Total Synthesis of (+)-Linoxepin by Utilizing the Catellani Reaction^†

1. Dr. Harald Weinstabl, 
2. Dr. Marcel Suhartono, 
3. Zafar Qureshi, 
4. Prof. Dr. Mark Lautens^*

Article first published online: 16 APR 2013

DOI: 10.1002/anie.201302327

http://onlinelibrary.wiley.com/doi/10.1002/anie.201302327/full

Lignans are a diverse class of plant-derived natural products belonging to the phytooestrogen family. They have long been used as herbal remedies for pain, rheumatoid arthritis, and warts. However, more recently, lignans exhibiting immunosuppressive activity, tumor growth inhibition, and anti-fungal properties have been used in disease therapy, such as the anticancer agent etoposide.2

In 2007, Schmidt and co-workers isolated a lignan from the aerial parts of Linum perenne L. (Linaceae) with a previously undescribed carbon skeleton, which they named linoxepin (1). This caffeic acid dimer exhibits an oxidation-prone dihydronaphthalene core, a tetrasubstituted double bond embedded within a highly strained ring system, and a dibenzo–dihydrooxepine moiety, which is unique within this class of molecules. These interesting structural characteristics and their associated challenges make (+)-linoxepin (1) an interesting synthetic target.

Angewandte Chemie International Edition

Volume 52, Issue 20, pages 5305–5308, May 10, 201
3

IR spectra were obtained using a Perkin-Elmer Spectrum 1000 FT-IR spectrometer as neat films or as solutions (CHCl3 or CH2Cl2) on a NaCl plate. Data is presented as frequency of absorption (cm–1).  1H and 13C NMR spectra were recorded at 23 °C in CDCl3 or DMSO-d6 with a Bruker Avance 400 spectrometer or a Varian Mercury 400 spectrometer. Recorded shifts for protons are reported in parts per million (δ scale) and are referenced to residual proton signals in the NMR solvent (CHCl3: δ = 7.26, DMSO-d6: δ = 2.50). Chemical shifts for carbon resonances are reported in parts per million (δ scale) and are referenced to the carbon resonances of the solvent (CDCl3: δ = 77.0, DMSO-d6:  39.43). Data are represented as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet,

(+)-linoxepin (1) or (R)-6-methoxy-9a,10-dihydro-4H-[1,3]dioxolo[4',5':3,4]benzo[1,2-e]furo[3',4':6,7]naphtho[1,8-bc]oxepin-12(9H)-one 

1H NMR (500 MHz, CDCl3): δ = 6.87 (d, J = 8.0 Hz, 1H), 6.84 (dd, J = 8.2, 1.2 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.04 – 6.02 (m, 2H), 5.39 (dd, J = 12.6, 1 Hz, 1H), 5.14 (d, J = 12.5 Hz, 1H), 4.68 (t, J = 8.9 Hz, 1H), 4.03 (t, J = 8.7 Hz, 1H), 3.85 (s, 3H), 3.36 – 3.16 (m, 1H), 2.99 (dd, J = 14.7, 5.7 Hz, 1H), 2.66 (td, J = 14.8, 1.3 Hz, 1H);  

13C NMR (125 MHz, CDCl3): δ = 168.83, 149.43, 149.04, 148.52, 145.68, 144.79, 129.43, 128.15, 124.35, 124.14, 122.22, 119.82, 116.50, 111.83, 108.12, 101.85, 70.00, 64.66, 56.18, 36.84, 34.46;  

IR (neat) νmax = 2900, 1748, 1661, 1572, 1481, 1464, 1436, 1300, 1277, 1264, 1244, 1199, 1183, 1102, 1032, 1013, 913, 760  

HRMS (DART) [M+H]+ m/z = 365.10195 calcd. for C21H17O6: 365.10251.  

Melting point: decomp. 228 °C  

Optical rotation: [α]D20: + 90.0 (c = 0.25, CHCl3). 

Weinstabl H, Suhartono M, Qureshi Z, Lautens M * University of Toronto, Canada 

Total Synthesis of (+)-Linoxepin by Utilizing the Catellani Reaction.

Angew. Chem. Int. Ed. 2013;
52: 5305-5308

Lautens and co-workers report the synthesis of linoxepin, a lignin isolated from Linum perennne L.(Linaceae). The elegant strategy relies on the Catellani reaction, in which a strained olefin (norbornene) is used to couple an iodoarene, an alkyl halide, and a terminal olefin using palladium catalysis. This is the first application of the Catellani reaction in the synthesis of a natural product and underscores the power of processes that form multiple bonds in a single step. In this context, it is worth highlighting the recent synthesis of linoxepin by Tietze and co-workers (Angew. Chem. Int. Ed. 2013, 52, 3191), which relies on a different palladium-catalyzed domino reaction.

Alkylation of phenol A with benzyl iodide B gave Catellani precursor C in 94% yield. The norbornene-mediated domino process involving aryl iodide C, enantiopure alkyl iodide D and acrylate E delivered key intermediate F in 89% yield. Oxidative cleavage of the olefin followed by TiCl4-promoted aldol condensation furnished G, which in the presence of catalytic amounts of a palladium catalyst underwent a Mizoroki–Heck reaction to give (+)-linoxepin in 76% yield.