HETEROCYCLES

Communication | Special issue | Vol. 82, No. 1, 2010, pp. 313-318
Received, 24th June, 2010, Accepted, 21st July, 2010, Published online, 22nd July, 2010.
DOI: 10.3987/COM-10-S(E)67

■ An Enantioselective Synthesis of the Resorcylic Acid Lactone L-783,277 via Addition of an Acetylide Anion to a Tethered Weinreb Amide

Andrew Lin, Anthony C. Willis, and Martin G. Banwell*

Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia

Abstract

Abstract – Treatment of the terminal acetylene 12, readily obtained from the previously reported acid 10, with LiHMDS resulted in a novel macrocyclization reaction to give the cycloalkyne 13. Subjection of compound 13 to hydrogenation under Lindlar-type conditions afforded the Z-configured enone 14 that could be converted into the resorcylic acid lactone 4 upon treatment with BCl3 in CH2Cl2 at –78°C.

Radicicol (1),1 zearalenone (2)2 and hypothemycin (3)3 are iconic and long-known members of a rather large group of 14-membered and benzannulated macrolides isolated from various fungal sources and known collectively as the resorcylic acid lactones (RALs).4 RALs display a significant range of biological properties, including a capacity for potent and selective inhibition of kinases.4 As a result considerable effort has been devoted to the study of these compounds, including the development of syntheses,5 and much of this has been reviewed recently.4 In 1999 a group at Merck reported on the isolation, structural elucidation and biological evaluation of the isomeric RALs L-783,277 (4) and L-783,290 (5) both of which were obtained from a Phoma spp. (ATCC 74403) by bioassay guided fractionation using a kinase screen.6 Compound 4, a so-called cis-enone RAL,7 is a potent and irreversible inhibitor of mitogen-activated protein kinase (MAPK) (IC50 = 4 nM) while its trans-isomer 5 is much less active (IC50 = 300 nM) against the same enzyme.6

Recently, we reported the first total synthesis of L-783,290 (5) using an enzymatically-derived and enantiomerically pure cis-1,2-dihydrocatechol as starting material for the assembly of the south-eastern quadrant of the target.8 The other key features of our synthesis were the use of a Heck reaction to establish the C6 to C1' linkage and a ring-closing metathesis (RCM) to form the trans-enone unit. Based on some of our earlier studies on the synthesis of certain non-benzannulated macrolides,9 we attempted to effect the photo-isomerization of L-783,290 (5) to the more biologically active system 4. However, all of our efforts to do so failed. Accordingly, we sought other ways to adapt our earlier work so as to establish a total synthesis of compound 4, something that has only been achieved previously by the groups of Altmann5i and Winssinger.5m Herein we report a new total synthesis of L-783,277 (4) wherein the macrolide ring is established through the addition of an acetylide anion to a tethered Weinreb amide, a novel ring-forming process that does not appear to have been exploited previously in the synthesis of RALs.
The reaction sequence leading from the previously reported and readily available building blocks 6 and 7 to target 4 is shown in Scheme 1. Thus, as we have described recently,8 compounds 6 and 7 are coupled under Heck conditions to give compound 8 as an 8:1 mixture of E- and Z-isomers in 56% combined yield. Oxidation of aldehyde 8 to the corresponding acid 9 was readily achieved in 75% yield using Pinnick’s procedure10 and the latter compound was then subjected to standard hydrogenation conditions so as to afford the previously reported8 and saturated acid 10. Reaction of compound 10 with the enantiomerically pure homopropargyl alcohol (R)-(–)-11, which was readily obtained through enzymatic resolution of the commercially available racemate,11 then gave the ester 12 in 70% yield.

In the pivotal step of the reaction sequence, compound 12 was treated with LiHMDS in THF at –35 to 18 °C for 0.25 h and by such means the cyclic alkyne 13 was formed in ca. 45% yield. Presumably, this conversion involves deprotonation of the terminal alkyne unit within substrate 12 and intramolecular addition of the resulting acetylide anion to the pendant Weinreb amide. While all the spectral data derived from compound 13 were completely consistent with the assigned structure final confirmation of this was secured through a single-crystal X-ray analysis.12 The derived ORTEP is shown in Figure 1.

The completion of the synthesis of target 4 involved Lindlar-type hydrogenation of alkyne 13 in the presence of pyridine and 5% Pd on lead-poisoned CaCO3. The resulting cis-enone 14 (80%) was immediately treated with BCl3 in CH2Cl2 at –78 °C for 0.5 h and L-783,277 (4) was thereby obtained in 50% yield. This was accompanied by ca. 12% of the corresponding trans-isomer from which it could be separated by semi-preparative HPLC. Reversing the order of the last two steps of the reaction sequence lead to a less favorable outcome. In particular, while BCl3-mediated deprotection of compound 13 afforded the desired compound, Lindlar-type hydrogenation of this intermediate gave an inseparable mixture of compound 4, isomer 5 and the corresponding saturated material resulting from complete reduction of the alkyne unit. The 13C and 1H NMR spectral data derived from the synthetic sample of compound 4 obtained by the route shown in Scheme 1 were in complete accord with the assigned structure13 and matched those reported6 for the natural product.
The longest linear sequence associated with the synthesis of L-783,277 described here is 16 steps from commercially available material. The Altmann synthesis is just one step longer while the Winssinger route comprises some twenty steps. The kinase inhibiting effects of compounds 4 and 5 as well as various congeners available using the chemical sequences described above will be reported in due course.

ACKNOWLEDGEMENTS
We thank the Australian Research Council and the Institute of Advanced Studies for generous financial support.

References

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12. Single-crystal X-ray analysis of compound 13: C23H28O7, M = 416.47, T = 200 K, orthorhombic, space group P212121, Z = 4, a = 8.6558(1), b = 8.9051(2), c = 28.2982(5) Å, V = 2181.25(7) Å3, Dx = 1.268 g cm–3, 2937 unique data (2θmax = 55.8°), R = 0.038 [for 2429 reflections with I > 2.0σ(I)]; Rw = 0.081 (all data), S = 1.01. Atomic coordinates, bond lengths and angles, and displacement parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC-781986). These data can be obtained free-of-charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
13. Selected spectral data derived from compound 4: [α]D = –15.3 (c 0.15, CHCl3); 1H NMR (800 MHz, CD2Cl2) δ 12.21 (s, 1H), 6.46 (ddd, J = 11.2, 3.2 and 0.8 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.32 (td, J = 11.2 and 2.4 Hz 1H), 5.48 (m, 1H), 4.57 (d, J = 2.4 Hz, 1H), 3.87 (m, 1H), 3.86 (s, 3H), 3.41 (m, 1H), 3.03 (m, 1H), 2.62 (dm, J = 17.6 Hz, 1H), 2.55 (m, 1H), 1.79 (m, 1H), 1.59 (m, 2H), 1.23 (m, 1H), 1.49 (d, J = 5.6 Hz, 3H) (signals due to aliphatic hydroxyl groups not observed); 13C NMR (200 MHz, CD2Cl2) δ 200.4, 172.2, 167.0, 164.8, 148.0, 146.7, 126.7, 109.7, 104.9, 99.4, 81.6, 74.0, 73.6, 55.9, 37.6, 37.0, 33.5, 29.4, 21.2; IR νmax 3315, 2921, 2850, 1727, 1683, 1648, 1615, 1568, 1461, 1420, 1379, 1350, 1313, 1291, 1252, 1220, 1203, 1053, 1038, 1016, 902, 870, 838, 795, 748, 712 cm–1; HRMS Found: (M + Na)+, 387.1418. C19H24O7 requires (M + Na)+, 387.1420.