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

<A NAME="RU09707ST-1">1</A> For a review of the earlier work on haplophytine, see: Saxton JE. Alkaloids  1965,  8:  673 

<A NAME="RU09707ST-2A">2a</A> Rogers EF. Snyder HR. Fischer RF. J. Am. Chem. Soc.  1952,  74:  1987 

<A NAME="RU09707ST-2B">2b</A> Snyder HR. Fischer RF. Walker JF. Els HE. Nussberger GA. J. Am. Chem. Soc.  1954,  76:  2819 

<A NAME="RU09707ST-2C">2c</A> Snyder HR. Fischer RF. Walker JF. Els HE. Nussberger GA. J. Am. Chem. Soc.  1954,  76:  4601 

<A NAME="RU09707ST-2D">2d</A> Synder HR. Strohmayer HF. Mooney RA. J. Am. Chem. Soc.  1958,  80:  3708 

<A NAME="RU09707ST-3">3</A> 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 

<A NAME="RU09707ST-4">4</A> Cheng P.-T. Nyburg SC. MacLachlan FN. Yates P. Can. J. Chem.  1976,  54:  726 

<A NAME="RU09707ST-5A">5a</A> Cava MP. Talapatra SK. Nomura K. Weisbach JA. Douglas B. Shoop EC. Chem. Ind. (London)  1963,  1242 

<A NAME="RU09707ST-5B">5b</A> Cava MP. Talapatra SK. Yates P. Rosenberger M. Szabo AG. Douglas B. Raffauf RF. Shoop EC. Weisbach JA. Chem. Ind. (London)  1963,  1875 

<A NAME="RU09707ST-5C">5c</A> 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:

<A NAME="RU09707ST-6A">6a</A> Yates P. Schwartz DA. Can. J. Chem.  1983,  61:  509 

<A NAME="RU09707ST-6B">6b</A> Schwartz DA. Yates P. Can. J. Chem.  1983,  61:  1126 

<A NAME="RU09707ST-6C">6c</A> Rege PD. Tian Y. Corey EJ. Org. Lett.  2006,  8:  3117 

<A NAME="RU09707ST-7">7</A> For a similar approach of this work, see: Nicolaou KC. Majumder U. Roche SP. Chen DYK. Angew. Chem. Int. Ed.  2007,  46:  4715 

<A NAME="RU09707ST-8">8</A> He F. Bo Y. Altom JD. Corey EJ. J. Am. Chem. Soc.  1999,  121:  6771 

<A NAME="RU09707ST-9A">9a</A> Sumi S. Matsumoto K. Tokuyama H. Fukuyama T. Org. Lett.  2003,  5:  1891 

<A NAME="RU09707ST-9B">9b</A> Sumi S. Matsumoto K. Tokuyama H. Fukuyama T. Tetrahedron  2003,  59:  8571 

<A NAME="RU09707ST-10">10</A> Mejia-Oneto JM. Padwa A. Org. Lett.  2006,  8:  3275 

<A NAME="RU09707ST-11">11</A> Marino JP. Cao GF. Tetrahedron Lett.  2006,  47:  7711 

<A NAME="RU09707ST-12A">12a</A> Matsumoto K. PhD Dissertation   University of Tokyo; Japan: 2006. 

<A NAME="RU09707ST-12B">12b</A>

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.

<A NAME="RU09707ST-13">13</A> 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 

<A NAME="RU09707ST-14">14</A> Shimizu M. Ishikawa M. Komoda Y. Matsubara Y. Nakajima T. Chem. Pharm. Bull.  1982,  30:  4529 

<A NAME="RU09707ST-15A">15a</A> Kan T. Fukuyama T. J. Synth. Org. Chem., Jpn.  2001,  59:  779 

<A NAME="RU09707ST-15B">15b</A> Kurosawa W. Kan T. Fukuyama T. Org. Synth.  2002,  79:  186 

<A NAME="RU09707ST-15C">15c</A> Kan T. Fukuyama T. Chem. Commun.  2004,  353 

<A NAME="RU09707ST-16">16</A>

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.

<A NAME="RU09707ST-17">17</A>

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.

<A NAME="RU09707ST-18">18</A>

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.