Synthetic Studies on Haplophytine: Protective-Group-Controlled Rearrangement

Abstract

The characteristic tetracyclic structure of haplophytine containing a bridged ketone, aminal, and γ-lactam was constructed by oxidative rearrangement of a tetrahydro-β-carboline derivative.

haplophytine - aspidophytine - alkaloids - oxidations - rearrangements

References and Notes

1 For a review of the earlier work on haplophytine, see: Saxton JE. Alkaloids  1965,  8:  673 

2a Rogers EF. Snyder HR. Fischer RF. J. Am. Chem. Soc.  1952,  74:  1987 

2b Snyder HR. Fischer RF. Walker JF. Els HE. Nussberger GA. J. Am. Chem. Soc.  1954,  76:  2819 

2c Snyder HR. Fischer RF. Walker JF. Els HE. Nussberger GA. J. Am. Chem. Soc.  1954,  76:  4601 

2d Synder HR. Strohmayer HF. Mooney RA. J. Am. Chem. Soc.  1958,  80:  3708 

3 Yates P. MacLachlan FN. Rae ID. Rosenberger M. Szabo AG. Willis CR. Cava MP. Behforouz M. Lakshmikantham MV. Zeigler W. J. Am. Chem. Soc.  1973,  95:  7842 

4 Cheng P.-T. Nyburg SC. MacLachlan FN. Yates P. Can. J. Chem.  1976,  54:  726 

5a Cava MP. Talapatra SK. Nomura K. Weisbach JA. Douglas B. Shoop EC. Chem. Ind. (London)  1963,  1242 

5b Cava MP. Talapatra SK. Yates P. Rosenberger M. Szabo AG. Douglas B. Raffauf RF. Shoop EC. Weisbach JA. Chem. Ind. (London)  1963,  1875 

5c Rae ID. Rosenberger M. Szabo AG. Willis CR. Yates P. Zacharias DE. Jeffrey GA. Douglas B. Kirkpatrick JL. Weisbach JA. J. Am. Chem. Soc.  1967,  89:  3061 

For synthetic studies, see:

6a Yates P. Schwartz DA. Can. J. Chem.  1983,  61:  509 

6b Schwartz DA. Yates P. Can. J. Chem.  1983,  61:  1126 

6c Rege PD. Tian Y. Corey EJ. Org. Lett.  2006,  8:  3117 

7 For a similar approach of this work, see: Nicolaou KC. Majumder U. Roche SP. Chen DYK. Angew. Chem. Int. Ed.  2007,  46:  4715 

8 He F. Bo Y. Altom JD. Corey EJ. J. Am. Chem. Soc.  1999,  121:  6771 

9a Sumi S. Matsumoto K. Tokuyama H. Fukuyama T. Org. Lett.  2003,  5:  1891 

9b Sumi S. Matsumoto K. Tokuyama H. Fukuyama T. Tetrahedron  2003,  59:  8571 

10 Mejia-Oneto JM. Padwa A. Org. Lett.  2006,  8:  3275 

11 Marino JP. Cao GF. Tetrahedron Lett.  2006,  47:  7711 

12a Matsumoto K. PhD Dissertation   University of Tokyo; Japan: 2006. 

12b

The preliminary results of this work were communicated in the Pharmaceutical Society of Japan, the 33th Symposium on Progress in Organic Reaction and Syntheses - Applications in the Life Science on November 7-8, 2005 (Book of Abstracts, ISSN 0919-2123). The approach described in this paper and a similar approach reported by K. C. Nicolaou and co-workers (ref. 7) were developed independently.

13 Yates P. MacLachlan FN. Rae ID. Rosenberger M. Szabo AG. Willis CR. Cava MP. Behforouz M. Lakshmikantham MV. Zeigler W. J. Am. Chem. Soc.  1973,  95:  7842 

14 Shimizu M. Ishikawa M. Komoda Y. Matsubara Y. Nakajima T. Chem. Pharm. Bull.  1982,  30:  4529 

15a Kan T. Fukuyama T. J. Synth. Org. Chem., Jpn.  2001,  59:  779 

15b Kurosawa W. Kan T. Fukuyama T. Org. Synth.  2002,  79:  186 

15c Kan T. Fukuyama T. Chem. Commun.  2004,  353 

16

Major product 17: mp 220-222 °C (dec.); IR (film): 3419, 3332, 2937, 1732, 1666, 1610, 1516, 1481, 1400, 912, 758 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.28 (d, J = 8.4 Hz, 1 H), 7.20 (t, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 6.98 (t, J = 8.4 Hz, 1 H), 6.87 (d, J = 7.6 Hz, 1 H), 6.38 (d, J = 8.0 Hz, 1 H), 3.59 (s, 3 H), 3.18-3.04 (m, 3 H), 2.84 (s, 6 H), 2.82-2.77 (m, 1 H), 2.69-2.60 (m, 2 H), 2.52-2.44 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 204.8, 169.1, 149.3, 143.0, 141.9, 139.9, 135.2, 127.9, 125.7, 124.4, 123.8, 121.3, 115.7, 104.7, 93.5, 64.0, 59.1, 58.4, 45.6, 42.1, 33.7, 31.3, 30.2. HRMS-FAB: m/z calcd for C₂₃H₂₅N₃O₄ [M + H]⁺: 408.1923; found: 408.1918.

17

Compound 25: IR (film): 2944, 1706, 1681, 1601, 1390, 1336, 1158, 912, 756 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.20 (d, J = 7.2 Hz, 1 H), 7.35-7.24 (m, 13 H), 7.08 (d, J = 8.4 Hz, 1 H), 7.03 (t, J = 8.4 Hz, 1 H), 5.11 (br s, 4 H), 3.65-3.55 (m, 2 H), 3.62 (br s, 3 H), 3.59 (br s, 3 H), 3.44-3.35 (m, 1 H), 3.27-3.20 (m, 1 H), 3.20 (s, 3 H), 2.99 (dt, J = 7.2, 15.6 Hz, 1 H), 2.76 (dd, J = 3.6, 15.6 Hz, 1 H), 2.46 (dt, J = 5.2, 15.6 Hz, 1 H), 1.82 (dt, J = 7.2, 14.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.2, 155.9, 152.6, 150.2, 140.2, 137.1, 136.9, 136.4, 135.9, 133.2, 128.8, 128.7, 128.6, 128.5, 128.1, 124.6, 124.5, 123.2, 122.0, 115.9, 67.7, 67.4, 60.5, 60.1, 49.3, 41.9, 37.9, 33.4, 21.3, 14.5. HRMS-FAB: m/z calcd for C₃₉H₃₇N₃O₇: 659.2632; found: 659.2630.

18

Oxidative Rearrangement
To a solution of 25 (100 mg, 0.152 mmol) in CH₂Cl₂ (1.5 mL) was added NaHCO₃ (38.2 mg, 0.455 mmol) and MCPBA (40.2 mg, 65% purity, 0.152 mmol) at 0 °C under an argon atmosphere. After stirring for 2 h at the same temperature, the reaction mixture was quenched with sat. Na₂SO₃ and stirred for 10 min. Then to the two-phase mixture was added CH₂Cl₂, and the organic layer was separated. The organic layer was washed with sat. NaHCO₃, brine, and dried over Na₂SO₄. Filtration and concentration on a rotary evaporator afforded a crude product. The crude product was purified by flash column chromatography on silica gel (neutral; 30-40% EtOAc in hexane, gradient elution) to give 26 (84.1 mg, 82%). IR (film): 2944, 1709, 1458, 1394, 1316, 1159, 912, 756 cm^-1. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers): δ = 8.29 (d, J = 8.4 Hz, 0.5 H), 8.08 (d, J = 8.0 Hz, 0.5 H), 7.36-6.95 (m, 14 H), 6.80 (dd, J = 7.2, 11.2 Hz, 1 H), 5.15 (br s, 2 H), 5.12 (s, 2 H), 3.83-3.76 (m, 0.5 H), 3.68-3.52 (m, 1.5 H), 3.68 (br s, 1.5 H), 3.61 (br s, 1.5 H), 3.41-3.29 (m, 1 H), 3.25 (s, 3 H), 2.99 (br s, 1 H), 2.88-2.76 (m, 1 H), 2.80 (br s, 3 H), 2.66-2.43 (m, 1.5 H), 2.25-2.05 (m, 1 H), 1.95-1.86 (m, 0.5 H). ¹³C NMR (100 MHz, CDCl₃, doubling due to rotamers): δ = 195.2, 171.9, 168.0, 155.4, 154.6, 149.4, 149.2, 140.2, 136.3, 136.2, 135.3, 135.1, 134.8, 132.8, 130.5, 128.4, 128.3, 128.0, 127.8, 127.2, 125.3, 123.9, 122.9, 122.2, 121.8, 120.8, 120.5, 120.2, 115.7, 81.4, 67.7, 67.6, 66.9, 59.9, 58.1, 56.4, 52.3, 46.1, 40.4, 39.3, 37.4, 36.1, 30.6, 30.3, 30.1, 21.0. HRMS-FAB: m/z calcd for C₃₉H₃₇N₃O₈: 675.2581; found: 675.2578.