Download PDF
Synlett 2008(16): 2443-2446  
DOI: 10.1055/s-2008-1078273
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereocontrolled Synthesis of the Tetracyclic Core Framework of (-)-Lemonomycin

Peter Siengalewicz, Lothar Brecker, Johann Mulzer*
Institute of Organic Chemistry, University of Vienna, Währingerstraße 38, 1090 Vienna, Austria
Fax: +43(1)42779521; e-Mail: johann.mulzer@univie.ac.at;
Further Information

Publication History

Received 4 June 2008
Publication Date:
22 August 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

In a convergent approach, an advanced intermediate (2) in a projected total synthesis of the alkaloid (-)-lemonomycin (1) was prepared from readily available starting materials. The key transformations were a Pictet-Spengler cyclization, a Strecker-type amino alkylation, and an N-acyliminium cyclization.

Key words

lemonomycin - antitumor antibiotic - tetrahydroisoquinoline - acyliminium cyclization - Pictet-Spengler reaction

    References and Notes

  • 1 For a recent review of tetrahydroisoquinoline alkaloids, see: Scott JD. Williams RM. Chem. Rev.  2002,  102:  16-69  
    Google Scholar
  • 2 Whaley HA. Patterson EL. Dann M. Shay AJ. Porter JN. Antimicrob. Agents Chemother.  1964,  8:  83 
    Google Scholar
  • 3 He H. Shen B. Carter GT. Tetrahedron Lett.  2000,  41:  2067 
    CrossrefGoogle Scholar
  • 4a Magnus P. Matthews KS. J. Am. Chem. Soc.  2005,  127:  12476 
    Google Scholar
  • 4b Rikimaru K. Mori K. Kan T. Fukuyama T. Chem. Commun.  2005,  394 
    Google Scholar
  • 4c Couturier C. Schlama T. Zhu J. Synlett  2006,  1691 
    Google Scholar
  • 4d Vincent G. Chen Y. Lane JW. Williams RM. Heterocycles  2007,  72:  385 
    Google Scholar
  • 5 Ashley ER. Cruz EG. Stoltz BM. J. Am. Chem. Soc.  2003,  125:  15000 
    CrossrefGoogle Scholar
  • 6 Rush J. Bertozzi CR. Org. Lett.  2006,  8:  131 
    CrossrefGoogle Scholar
  • 9 For a recent review of the Pictet-Spengler reaction, see: Youn SW. Org. Prep. Proc. Int.  2006,  38:  505 
    Google Scholar
  • 10 Kwon S. Myers AG. J. Am. Chem. Soc.  2005,  127:  16796 
    CrossrefGoogle Scholar
  • 11a

    The (E)-(5-bromopent-2-enyl)trimethylsilane side chain employed in the enantioselective Myers’ alkylation reaction was prepared by cross-metathesis between allyl-TMS and allyl bromide.

  • 11b Myers AG. Kung DW. Zhong B. Movassaghi M. Kwon S. J. Am. Chem. Soc.  1999,  121:  8401 
    Google Scholar
  • 11c Myers AG. Schnider P. Kwon S. Kung DW. J. Org. Chem.  1999,  64:  3322 
    Google Scholar
  • 13 Dess DB. Martin JC. J. Am. Chem. Soc.  1991,  113:  7277 
    CrossrefGoogle Scholar
7

Preparation of aryl bromide 6 was performed via a five-step sequence from 2,6-dimethoxytoluene according to a method developed recently by us.

8

No cyclization product was obtained performing the Pictet-Spengler reaction with the corresponding benzyl-protected phenol.

12

Using the unprotected phenol in this reaction sequence led to the undesired formation of the quinone system upon treatment with Dess-Martin periodinane.

14

The atom connectivities of all key intermediates were proven by through-bond correlation NMR techniques. In particular the structure of the rigid tetracyclic core in compound 2 was in full agreement with the NOEs and all ¹H-¹H coupling constants.

15

Synthesis of Tetrahydroisoquinoline 3: Acetic acid (5 µL, 0.078 mmol) and powdered 4 Å molecular sieves were sequentially added to a solution of amino phenol 10 (75 mg, 0.16 mmol) in CH2Cl2 (2 mL). The resulting solution was degassed by three freeze-pump-thaw cycles. A solution of benzyloxy acetaldehyde 5 (25 µL, 0.171 mmol, 95%) in CH2Cl2 (1 mL) was slowly added via a syringe pump to the degassed solution over a period of 8.5 h. After stirring for 20 h at r.t., including the time of the addition, the reaction suspension was filtered through Whatman No. 5 filter paper to remove the molecular sieves. Sat. aq NaHCO3 solution (40 mL) was added to the filtrate and the resulting biphasic solution was extracted with CH2Cl2 (4 × 50 mL). The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (CH2Cl2-MeOH, 99:1, then 98:2, then 9:1) to afford tetrahydroisoquinoline 3 as pale yellow foam (77 mg, 81% after recovery of the unreacted starting material); R f 0.51 (CH2Cl2-MeOH, 20:1); [α]D ²0 +57.5 (c = 2.35, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 7.28-7.34 (m, 5 H), 5.08 (d, J = 2.2 Hz, 1 H), 4.60 (dd, J = 12.2, 13.2 Hz, 2 H), 4.42 (t, J = 5.9 Hz, 1 H), 3.85 (dd, J = 3.8, 5.4 Hz, 2 H), 3.81 (s, 3 H), 3.72 (s, 3 H), 3.61 (d, J = 4.3 Hz, 1 H), 3.24 (m, 2 H), 2.26 (s, 3 H), 0.92 (t, J = 7.9 Hz, 6 H), 0.88 (s, 9 H), 0.56 (dd, J = 4.2, 7.9 Hz, 9 H), 0.20 (s, 3 H), 0.00 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 150.5, 145.8, 142.5, 138.0, 128.3, 127.7, 127.6, 125.1, 122.5, 121.4, 73.9, 73.1, 63.7, 61.8, 61.3, 60.5, 59.4, 49.3, 25.9, 18.0, 9.7, 6.7, 4.3, 4.3,
-4.5, -5.1. HRMS (180 ˚C, 70 eV): m/z calcd for C33H56O6NSi2: 618.3634; found: 618.3624.
Synthesis of 12: Tetrahydroisoquinoline 3 (78 mg, 0.127 mmol) and cyanohydrin 11 (55 mg, 0.127 mmol) were dissolved in anhyd 2,2,2-trifluoroethanol (800 µL). The reaction mixture was allowed to stir at r.t. for 24 h. The solvent was evaporated and the crude residue was purified by flash column chromatography (hexanes-EtOAc, 7:1) to afford a 1.6:1 mixture of two diastereomers of 12 (29 mg, 23% less polar diastereomer, 46 mg, 35% more polar diastereomer; 75 mg, 58%, combined yield). R f 0.69, 0.66 (hexanes-EtOAc, 2:1); [α]D ²0 +34.8 (c = 0.65, CHCl3). ¹H NMR (400 MHz, CDCl3; major diastereomer): δ = 7.77 (m, 2 H), 7.61 (m, 2 H), 7.41 (m, 2 H), 7.27-7.34 (m, 5 H + 2 H), 6.07 (m, 1 H), 5.43-5.59 (m, 1 H), 5.35 (m, 1 H), 5.20 (m, 1 H), 4.49-4.61 (m, 2 H), 4.30-4.46 (m, 2 H + 1 H), 4.24 (m, 1 H + 1 H), 4.08 (m, 1 H), 3.97 (m, 1 H), 3.81 (m, 3 H), 3.71 (m, 1 H), 3.70 (m, 3 H), 3.42 (m, 1 H), 2.93 (t, J = 10.6 Hz, 1 H), 2.55 (m, 1 H), 2.24 (s, 3 H), 2.21 (m, 1 H), 1.65 (m, 1 H), 1.37 (m, 1 H), 0.92 (m, 9 H), 0.85 (s, 9 H), 0.60 (m, 6 H), 0.18 (s, 3 H), -0.02 (m, 9 H), -0.08 (s, 3 H). ¹³C NMR (100 MHz, CDCl3, two sets of signals corresponding to two rotamers, * denotes the minor rotamer): δ = 157.7*, 155.6, 150.0, 146.1, 146.1*, 144.2*, 144.1, 143.9, 143.8*, 141.7, 141.6*, 141.3*, 141.2, 138.0, 137.9*, 131.7, 130.6, 128.4, 128.4*, 128.8*, 128.8, 127.7*, 127.7, 127.6*, 127.6, 127.0, 127.0*, 125.3, 125.2*, 123.6, 123.1, 123.1*, 122.1, 121.2*, 121.1, 120.7, 120.5*, 120.0*, 119.9, 76.9, 73.1, 73.1*, 67.1, 63.4*, 62.9, 62.1*, 61.6*, 61.4, 60.7, 60.3*, 60.1, 57.6, 57.2*, 53.2, 53.1*, 50.0*, 49.6, 47.2, 34.0, 26.0, 25.7*, 23.1, 18.7*, 18.0, 9.7, 6.8, 4.3, -1.9, -2.0, -4.9, -5.1. HRMS (100 ˚C, 70 eV): m/z calcd for C58H83O8N3Si3Na: 1056.5386; found: 1056.5402.
Synthesis of 13: Acetic anhydride (13 µL, 0.134 mmol) and pyridine (18 µL, 0.223 mmol) were sequentially added to a solution of phenol 12 (46 mg, 0.045 mmol) in CH2Cl2 (0.7 mL) at r.t. After stirring for 16 h, sat. aq NaHCO3 solution (20 mL) was added and the resulting solution was extracted with CH2Cl2 (3 × 25 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (hexanes-EtOAc, 5:1) to furnish acetate 13 (47 g, 98%) as single product. R f 0.69 (hexanes-EtOAc, 2:1); [α]D ²0 -136 (c = 0.10, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 7.6 Hz, 2 H), 7.60 (dd, J = 3.1, 4.3 Hz, 2 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.28-7.35 (m, 2 H + 5 H), 5.42-5.59 (m, 1 H), 5.38 (m, 1 H), 5.02-5.25 (m, 1 H), 4.58 (m, 1 H), 4.27-4.47 (m, 5 H), 4.24 (m, 1 H), 4.09 (m, 1 H), 3.95 (m, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.44 (m, 1 H + 1 H), 2.88 (m, 1 H), 2.49 (m, 1 H), 2.27 (s, 3 H), 2.23 (s, 3 H), 2.21 (m, 1 H), 1.60 (m, 1 H), 1.37 (m, 2 H), 0.93 (t, J = 7.9 Hz, 9 H), 0.87 (s, 9 H), 0.60 (dd, J = 7.9, 7.9 Hz, 6 H), 0.20 (s, 3 H), -0.01 (s, 3 H), -0.02 (s, 3 H), -0.03 (s, 6 H). ¹³C NMR (100 MHz, CDCl3, two sets of signals, * denotes the minor rotamer): δ = 168.4, 168.4*, 155.6, 154.9, 150.8, 144.1*, 143.9, 141.3, 138.3, 138.1*, 136.7, 136.6*, 131.5, 130.5*, 128.3, 128.3*, 127.9, 127.8, 127.6, 127.0, 127.0*, 125.2, 125.2*, 124.6, 124.6*, 124.1, 124.0*, 122.3, 119.9, 77.6, 72.8, 67.0, 62.9, 62.5*, 61.3, 60.6, 60.4, 57.5, 57.0*, 53.8, 53.6*, 50.3*, 49.8, 47.2, 34.0, 26.0, 23.1, 20.5, 20.4*, 18.8*, 18.0, 9.9, 6.8, 4.3, -1.8, -2.0, -4.8, -4.9. HRMS (120 ˚C, 70 eV): m/z calcd for C60H85O9N3Si3Na: 1098.5491; found: 1098.5505.
Synthesis of 14: Compound 13 (86 mg, 0.080 mmol) was dissolved in a mixture of 30% HF-pyridine, (100 µL), pyridine (400 µL) and anhyd THF (2.7 mL). The reaction mixture was stirred at r.t. for 30 min. After total consumption of the starting material the reaction was quenched with buffer solution (pH 7.00, 20 mL) and extracted with CH2Cl2 (2 × 25 mL). The organic extracts were washed with brine (40 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by flash column chromatography (hexanes-EtOAc, 3:1) to furnish primary alcohol 14 (68 mg, 88%) as single product. R f 0.43 (hexanes-EtOAc, 2:1); [α]D ²0 +31.8 (c = 0.65, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 7.5 Hz, 2 H), 7.59 (m, 2 H), 7.40 (m, 2 H), 7.28-7.35 (m, 7 H), 5.49 (m, 1 H), 5.22 (m, 1 H), 5.16 (m, 1 H), 4.55 (m, 2 H), 4.32-4.43 (m, 4 H), 4.24 (t, J = 6.8 Hz, 1 H), 4.00 (m, 1 H), 3.94 (m, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.55 (m, 1 H), 3.46 (m, 1 H), 3.11 (m, 1 H), 2.48 (m, 1 H), 2.27 (s, 3 H), 2.23 (m, 1 H + 3 H), 1.35 (m, 2 H), 0.86 (m, 9 H), 0.20 (s, 3 H), -0.02 (s, 3 H), -0.03 (s, 6 H), -0.05 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 168.5, 156.0, 154.6, 150.9, 143.9, 141.3, 138.3, 136.8, 131.9, 128.4, 127.9, 127.7, 127.4, 127.1, 125.2, 124.7, 124.5, 122.1, 120.2, 119.9, 77.8, 72.9, 67.1, 63.9, 61.7, 61.3, 61.0, 60.6, 58.0, 54.2, 49.4, 47.1, 34.1, 25.9, 23.1, 20.4, 18.0, 9.9, -1.8, -2.0, -4.8, -5.0. HRMS (150 ˚C, 70 eV): m/z calcd for C54H71O9N3Si2Na: 984.4627; found: 984.4600.
Synthesis of 15: Primary alcohol 14 (53 mg, 0.055 mmol) was dissolved in CH2Cl2 (2 mL) and cooled to 0 ˚C, then Dess-Martin periodinane (67 mg, 0.22 mmol) was added. After stirring at 0 ˚C for 2 h the cooling bath was removed and the reaction mixture was stirred at r.t. for another 30 min. Sat. Na2S2O3 (10 mL) and NaHCO3 solution (10 mL) were added and the mixture was extracted with CH2Cl2 (20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by flash column chromatography (hexanes-EtOAc, 5:1) to furnish an epimeric mixture of the two diastereomeric carbinolamines 15 (47 mg, 89%). R f 0.71 (hexanes-EtOAc, 2:1); [α]D ²0 +6.5 (c = 1.10, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 7.75 (m, 2 H), 7.56 (m, 2 H), 7.28-7.44 (m, 9 H), 5.59 (m, 1 H), 5.37 (m, 1 H), 5.15 (m, 1 H), 4.86-5.05 (m, 1 H), 4.79 (m, 1 H), 4.67 (m, 1 H), 4.35-4.61 (m, 6 H), 4.30, 4.22 (m, 1 H), 3.66-3.76 (m, 6 H), 3.43 (m, 1 H), 3.13 (m, 1 H), 2.38-2.60 (m, 2 H), 2.36, 2.32 (s, 3 H), 2.22 (m, 3 H), 1.60 (m, 2 H), 0.82, 0.79 (s, 9 H), 0.18 (m, 3 H), -0.03 (s, 3 H), -0.06 (s, 6 H),
-0.09 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 170.9, 170.8, 157.3, 157.0, 152.4, 145.6, 145.5, 143.3, 143.3, 140.3, 138.3, 133.0, 129.9, 129.8, 129.4, 129.3, 129.2, 129.2, 129.1, 127.4, 127.1, 126.9, 126.8, 124.8, 123.3, 122.1, 122.0, 118.8, 75.4, 75.3, 73.1, 72.7, 70.1, 69.2, 66.1, 63.4, 63.0, 62.6, 58.8, 57.8, 56.9, 56.8, 49.1, 31.7, 31.3, 27.8, 25.0, 22.4, 20.0, 19.8, 11.8, 11.7, 0.2, 0.1, -3.1. HRMS (110 ˚C, 70 eV): m/z calcd for C54H69O9N3Si2Na: 982.4470; found: 982.4455.
Synthesis of Tetracycle 2: Hemiaminal 15 (24 mg, 0.012 mmol) was treated with a mixture of THF (500 µL) and trifluoroacetic acid (500 µL, 0.0065 mmol) at 0 ˚C. The white foam of the starting material turned pink immediately after addition of the acidic solvent mixture. After stirring for 15 min the starting material had been completely consumed. Upon the removal of the trifluoroacetic acid under reduced pressure, the reaction mixture changed its color from colorless to orange and the crude product was dried under vacuum for another 30 min. The residue was dissolved in CH2Cl2 and the yellow solution was purified by flash column chromatography with gradient elution (hexanes-EtOAc, 9:1, then 3:1) to afford compound 2 (11 mg, 58%). R f 0.50 (hexanes-EtOAc, 2:1); [α]D ²0 -4.4 (c = 0.22, CHCl3). ¹H NMR (600 MHz, CDCl3): δ = 7.77 (d, J = 7.2 Hz, 2 H), 7.60 (m, 2 H), 7.40 (t, J = 7.2 Hz, 2 H), 7.16-7.34 (m, 5 H), 7.07 (m, 2 H), 5.81 (m, 1 H), 5.60 (m, 1 H), 5.52 (m, 1 H), 5.07 (m, 2 H), 4.79 (m, 1 H), 4.78 (dd, J = 2.6, 6.9 Hz, 1 H), 4.61 (m, 1 H), 4.43 (m, 1 H), 4.24 (m, 2 H + 2 H + 1 H), 3.77 (m, 3 H), 3.71 (m, 1 H), 3.70 (s, 3 H), 3.01 (m, 1 H), 2.91 (m, 1 H), 2.54 (m, 1 H), 2.28 (s, 3 H), 2.21 (m, 3 H), 2.00 (m, 1 H), OH not found. ¹³C NMR (125 MHz, CDCl3): δ = 168.8, 150.0, 141.4, 141.3, 140.1, 136.5, 128.4, 127.9, 127.7, 127.2, 127.1, 125.3, 124.9, 122.3, 120.1, 120.0, 118.3, 116.8, 115.0, 90.4, 73.3, 70.5, 62.7, 60.9, 60.8, 54.5, 54.3, 50.8, 31.9, 20.5, 9.6. HRMS (100 ˚C, 70 eV): m/z calcd for C45H45O8N3Na: 778.3104; found: 778.3098.