A Novel Approach to Erythrinan Alkaloids by Utilizing Substituted Biphenyl as Building Block

Abstract

Aryl ortho-quinone monoacetal 6 possessing a carbamate group on the side chain was synthesized from the appropriate biphenyl precursor via selective oxidation of one of the aromatic rings. Under Lewis acidic conditions, the carbamate group underwent internal attack at the quinone acetal moiety to give the spiro tricycle 9 corresponding to the A-, C-, and D-rings of erythrinan ­alkaloids, from which O-methylerysodienone was synthesized via the B ring formation in an efficient manner.

erythrinan alkaloid - biphenyl compound - spirocyclization - ortho-quinone acetal - O-methylerysodienone

References

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2 Throughout this work, the commonly accepted erythrinan numbering is used. See: Boekelheide V. Prelog V. In Progress in Organic Chemistry   Vol. 3:  Cook JW. Butterworths Scientific; London: 1955.  Chap. 5. see also ref. 1

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5d Hamura T. Morita M. Matsumoto T. Suzuki K. Tetrahedron Lett.  2003,  44:  167 

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7

All new compounds were fully characterized by ¹H and ¹³C NMR, IR and combustion analysis. Data for the selected compounds follow. Compound 5: Colorless needles (hexane), mp 99.5-100.0 °C. ¹H NMR (CDCl₃): δ = 7.48 (d, 2 H, J = 7.4 Hz), 7.39 (dd, 2 H, J ₁ = J ₂ = 7.4 Hz), 7.32 (dd, 1 H, J ₁ = J ₂ = 7.4 Hz), 6.90 (s, 1 H), 6.79 (s, 1 H), 6.66 (s, 1 H), 6.63 (s, 1 H), 5.17 (s, 2 H), 4.39 (br s, 1 H), 3.92 (s, 3 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 3.61-3.50 (m, 2 H), 3.26-3.09 (m, 2 H), 2.59-2.40 (m, 4 H), 1.40 (s, 9 H), 0.95 (s, 21 H). ¹³C NMR (CDCl₃): δ = 155.7, 148.1, 147.5, 147.1, 146.9, 137.1, 133.5, 132.9, 129.0, 128.9, 128.5, 127.8, 127.4, 115.7, 113.7, 113.2, 112.1, 79.1, 71.0, 64.0, 56.1, 55.9, 55.8, 41.4, 36.6, 33.0, 28.3, 17.9, 11.8. IR (KBr): 3330, 2940, 2865, 1700, 1685, 1510, 1465, 1250, 1160, 1115 cm^-1. Anal. Calcd for C₄₀H₅₉NO₇Si: C, 69.23; H, 8.57; N, 2.02. Found: C, 69.39; H, 8.87; N, 1.93. Compound 6: ¹H NMR (CDCl₃): δ = 6.77 (s, 1 H), 6.62 (s, 1 H), 6.21 (s, 1 H), 6.05 (s, 1 H), 4.59 (br, 1 H), 3.91 (s, 3 H), 3.85 (s, 3 H), 3.68-3.58 (m, 2 H), 3.41 (s, 3 H), 3.40 (s, 3 H), 3.40-3.19 (m, 2 H), 2.71 (ddd, 1 H, J ₁ = J ₂ = 6.4 Hz, J ₃ = 12.8 Hz), 2.50 (ddd, 1 H, J ₁ = J ₂ = 6.4 Hz, J ₃ = 12.8 Hz), 2.27 (ddd, 1 H, J ₁ = J ₂ = 7.2 Hz, J ₃ = 14.5 Hz), 2.19 (ddd, 1H, J ₁ = J ₂ = 7.2 Hz, J ₃ = 14.5 Hz), 1.42 (s, 9 H), 0.97 (s, 21 H). ¹³C NMR (CDCl₃): δ = 193.9, 155.7, 152.6, 148.8, 147.4, 139.7, 133.4, 129.3, 129.0, 124.3, 112.2, 112.1, 91.1, 79.3, 61.1, 55.9, 55.8, 49.9, 49.8, 41.3, 37.3, 33.4, 28.4, 17.9, 11.8. IR (NaCl): 3380, 2940, 2870, 1710, 1680, 1515, 1465, 1365, 1250, 1230, 1170, 1100, 755 cm^-1. Anal. Calcd for C₃₄H₅₅NO₈Si: C, 64.42; H, 8.75; N, 2.21. Found: C, 64.24; H, 8.98; N, 2.01. Compound 9: ¹H NMR (CDCl₃): δ = 6.61 (s, 1 H), 6.45 (s, 1 H), 6.19 (s, 1 H), 5.79 (s, 1 H), 4.34 (ddd, 1 H, J ₁ = J ₂ = 4.1 Hz, J ₃ = 12.9 Hz), 3.86 (s, 3 H), 3.70-3.63 (m, 1 H), 3.67 (s, 3 H), 3.65 (s, 3 H), 3.47 (ddd, 1 H, J ₁ = 6.2 Hz, J ₂ = 8.5 Hz, J ₃ = 10.9 Hz), 3.36 (ddd, 1 H, J ₁ = 5.8 Hz, J ₂ = 8.7 Hz, J ₃ = 10.9 Hz), 3.01 (ddd, 1 H, J ₁ = 4.1 Hz, J ₂ = 10.9 Hz, J ₃ = 15.3 Hz), 2.80 (ddd, 1 H, J ₁ = 3.1 Hz, J ₂ = 4.1 Hz, J ₃ = 15.3 Hz), 2.40 (ddd, 1 H, J ₁ = 5.8 Hz, J ₂ = 8.5 Hz, J ₃ = 11.6 Hz), 2.08 (ddd, 1 H, J ₁ = 6.2 Hz, J ₂ = 8.7 Hz, J ₃ = 11.6 Hz), 1.35 (s, 9 H), 0.96 (s, 21 H). ¹³C NMR (CDCl₃): δ = 181.7, 165.8, 155.0, 149.7, 148.5, 147.9, 128.5, 123.9, 123.5, 118.3, 111.2, 109.7, 81.6, 63.9, 61.3, 55.9, 55.8, 55.0, 40.2, 34.0, 29.2, 28.1, 17.8, 11.7. IR (NaCl): 2940, 2865, 1695, 1670, 1645, 1620, 1515, 1465, 1365, 1260, 1220, 1160, 1090, 755 cm^-1. Anal. Calcd for C₃₃H₅₁NO₇Si: C, 65.86; H, 8.54; N, 2.33. Found: C, 65.59; H, 8.58; N, 2.05. Compound 12: Pale yellow needles (CHCl₃), mp 157.5-158.0 °C. ¹H NMR (CDCl₃): δ = 6.57 (s, 1 H), 6.38 (s, 1 H), 6.31 (s, 1 H), 5.99 (s, 1 H), 3.85 (s, 3 H), 3.70 (s, 3 H), 3.62 (s, 3 H), 3.53 (ddd, 1 H, J ₁ = 5.7 Hz, J ₂ = 12.3 Hz, J ₃ = 14.4 Hz), 3.32 (ddd, 1 H, J ₁ = J ₂ = 7.0 Hz, J ₃ = 14.4 Hz), 3.31-3.14 (m, 3 H), 2.71-2.59 (m, 2 H), 2.54 (dd, 1 H, J ₁ = 5.7 Hz, J ₂ = 17.3 Hz). ¹³C NMR (CDCl₃):
δ = 181.7, 167.3, 149.7, 148.5, 148.0, 125.9, 124.1, 122.4, 115.7, 112.1, 108.3, 64.8, 55.83, 55.82, 55.0, 47.0, 40.9, 27.9, 20.2. IR (KBr): 2940, 2845, 1675, 1655, 1620, 1510, 1465, 1250, 1210, 1175, 1105, 1010 cm^-1. Anal. Calcd for C₁₉H₂₁NO₄: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.41; H, 6.76; N, 4.04.

8a Miyaura N. Yanagi T. Suzuki A. Synth. Commun.  1981,  11:  513 

8b Watanabe T. Miyaura N. Suzuki A. Synlett  1992,  207 

8c For a review, see: Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 

9

Boronic acid 2 was prepared from isovanillin in six steps [(1) BnBr, NaOH aq, Bu₄NHSO₄, CH₂Cl₂ (73%); (2) Ph₃P=CH₂, THF (98%); (3) (sia)₂BH, THF, then H₂O₂, NaOH aq (97%); (i-Pr)₃SiCl, imidazole, DMF (quant); (5) NBS, DMF (84%); (6) BuLi, THF, -78 °C, then B(i-PrO)₃, -78 °C to 0 °C, then 2 M HCl aq (75%)].

10 For a review on synthetic use of ortho-quinone monoacetals, see: Quideau S. Pouységu L. Org. Prep. Proced. Int.  1999,  31:  617 

11a Tamura Y. Yakura T. Haruta J. Kita Y. J. Org. Chem.  1987,  52:  3927 

11b Lewis N. Wallbank P. Synthesis  1987,  1103 

11c For reviews on phenolic oxidation with hypervalent iodine reagents, see: Pelter A. Ward RS. Tetrahedron  2001,  57:  273 

11d Moriarty RM. Prakash O. Org. React.  2001,  57:  327 

12

Compound 7 was synthesized from aryl bromide i and boronic acid ii in three steps [(1) 10 mol% Pd(PPh₃)₄, Ba(OH)₂, DME, H₂O, reflux; (2) H₂, 10% Pd/C, MeOH; (3) (AcO)₂IPh, MeOH] in 37% overall yield (Figure [2] ).

13

Experimental Procedure as Follows: To a mixture of powdered molecular sieves 4 Å (40 mg) and BF₃·OEt₂ (2.6 mg, 18 µmol) in CH₂Cl₂ (0.5 mL) was added 6 (49.2 mg, 0.0776 mmol) in CH₂Cl₂ (1.5 mL) at -20 °C. After 40 min, the reaction was quenched with sat. aq NaHCO₃ and the mixture was extracted with EtOAc (× 3). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by PTLC (hexane/EtOAc = 6:4) to give 9 (39.3 mg, 84%) as a colorless oil.

14

Cu(OTf)₂, Sc(OTf)₃, and Yb(OTf)₃, though worked satisfactorily, did not exceed BF₃·OEt₂ in the yield of 9.

15 Sakaitani M. Ohfune Y. J. Org. Chem.  1990,  55:  870 ; and references cited therein

16 Yasui Y. Suzuki K. Matsumoto T. Synlett  2004,  DOI