An Enantioselective Access to an Anthracycline AB Synthon by a ­Desymmetrizing Heck Cyclization

Abstract

A group-selective intramolecular Heck reaction of an acyclic prochiral cyclization precursor provides an entry into the catalytic asymmetric synthesis of the AB bicyclic skeleton of ­anthracyclines. Enantiotopic group selection is strongly influenced by the hydroxylation pattern relative to the triflate moiety of the B ring (47% ee for 3,6-dimethoxy, 76% ee for 3-methoxy, and 92% ee without substitution).

Key words

asymmetric synthesis - catalysis - cyclizations - Heck ­reaction - palladium

References and Notes

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• 22a

  Analytical Data for Trifluoromethanesulfonic Acid ( E , E )-2-[2-Hydroxy-5-phenyl-2-(3-phenyl-2-propenyl)-4-pentenyl]-3,6-dimethoxyphenyl Ester ( 9a).
  IR (CHCl₃): 3627 (w), 3033 (s), 3016 (s), 2976 (m), 2897 (w), 1521 (m), 1492 (m), 1420 (m), 1238 (s), 1225 (s), 1211 (s), 1083 (m), 1047 (m) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.34 (s, 1 H, OH), 2.38 (dd, J = 14.1 Hz, J = 7.3 Hz, 2 H), 2.45 (dd, J = 14.1 Hz, J = 7.3 Hz, 2 H), 3.09 (s, 2 H), 3.80 (s, 3 H), 3.82 (s, 3 H), 6.32 (ddd, J = 15.9 Hz, J = 7.3 Hz, J = 7.3 Hz, 2 H), 6.44 (d, J = 15.9 Hz, 2 H), 6.83 (m, 1 H), 7.12-7.35 (m, 11 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 35.1, 43.9, 56.4, 56.6, 75.8, 110.4, 111.1, 118.8 (q, J = 319 Hz), 122.0, 125.7, 126.2, 127.1, 128.5, 129.1, 133.5, 137.7, 146.0, 152.0 ppm. MS (CI with NH₃): m/z = 580 [M + NH₄]⁺. Anal. Calcd for C₂₉H₂₉F₃O₆S: C, 61.91; H, 5.20; S, 5.70. Found: C, 62.13; H, 5.37; S, 5.58.

• 22b

  Analytical Data for ( E , E )-4-Benzylidene-5,8-dimethoxy-2-(3-phenyl-2-propenyl)-1,2,3,4-tetrahydro-2-naphthol ( 8a).
  [α]_D ²⁰ -10.8 (c 1.09, CHCl₃) for 52% ee. IR (CHCl₃): 3628 (w), 3016 (s), 2977 (m), 2899 (w), 1521 (m), 1477 (m), 1437 (m), 1234 (s), 1216 (s), 1087 (m), 1046 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.87 (s, 1 H, OH), 2.34 (ddd, J = 13.8 Hz, J = 8.1 Hz, J = 1.1 Hz, 1 H), 2.48 (ddd, J = 13.8 Hz, J = 6.9 Hz, J = 1.4 Hz, 1 H), 2.72 (dd, J = 13.0 Hz, J = 0.9 Hz, 1 H), 2.86 (d, J = 13.0 Hz, 1 H), 2.88 (s, 2 H), 3.78 (s, 3 H), 3.80 (s, 3 H), 6.08 (ddd, J = 15.8 Hz, J = 8.1 Hz, J = 6.9 Hz, 1 H), 6.39 (d, J = 15.8 Hz, 1 H), 6.71 (d, J = 8.9 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H), 7.10-7.38 (m, 10 H), 7.76 (s, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 37.3, 39.4, 44.5, 55.8, 56.2, 71.3, 109.0, 109.9, 125.3, 125.7, 125.9, 126.2, 126.5, 127.2, 128.3, 128.5, 129.4, 131.0, 133.5, 134.0, 137.4, 138.5, 151.6, 151.8 ppm. MS (EI): m/z = 412 [M⁺]. HRMS (EI): m/z calcd for C₂₈H₂₈O₃: 412.2044; found: 412.2039.

12

Machotta, A. B.; Sempere-Culler, F.; Straub, B. F.; Oestreich, M. manuscript in preparation.

21

General Procedure for Heck Reaction.
A base-washed and flame-dried sealed tube equipped with a magnetic stir bar is charged with Pd(OAc)₂ (5.0 mol%), (R)-BINAP (7.5 mol%), and K₂CO₃ (4.0 equiv) or TMP (4.0 equiv). Then a solution of triflate 9 and degassed toluene (0.1 M) is subsequently added. The resulting suspension is vigorously stirred at r.t. until the formation of a red homogeneous solution except for the solid base. The tube is sealed and heated at the indicated temperature for 18 h. After cooling to r.t., silica gel is added and the solvent is evaporated under reduced pressure. The crude product 8 on silica gel is subjected to flash column chromatography on silica gel using cyclohexane-tert-butylmethylether solvent mixtures.