First Enantioselective Synthesis
of a Hydroxyindolizidine Alkaloid from the Ant Myrmicaria
melanogaster

Naoki Toyooka; Dejun Zhou; Hideo Nemoto; Yasuhiro Tezuka; Shigetoshi Kadota; Tappey H. Jones; H. Martin Garraffo; Thomas F. Spande; John W. Daly

doi:10.1055/s-2008-1078502

LETTER

First Enantioselective Synthesis of a Hydroxyindolizidine Alkaloid from the Ant Myrmicaria melanogaster

Naoki Toyooka*^a, Dejun Zhou^a, Hideo Nemoto^a, Yasuhiro Tezuka^b, Shigetoshi Kadota^b, Tappey H. Jones^c, H. Martin Garraffo^d, Thomas F. Spande^d, John W. Daly^d
^a Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
Fax: +81(76)4344656; e-Mail: toyooka@pha.u-toyama.ac.jp;
^b Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
^c Department of Chemistry, Virginia Military Institute, Lexington, Virginia 24450, USA
^d Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA

Abstract

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Abstract

The first enantioselective synthesis of the recently reported ant alkaloid 1 has been achieved starting from commercially available lactam 3 in seven steps and 25% overall yield. The proposed structure of the natural product was confirmed by comparison with synthetic 1 and its absolute configuration established as 3S,5R,8S,9S.

Key words

hydroxyindolizidine - venoms of ant - Myrmicaria melanogaster - chelation control - new ant alkaloid

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References

References and Notes

1a Daly JW. Spande TF. Garraffo HM. J. Nat. Prod. 2005, 68: 1556

1b Daly JW. Garraffo HM. Spande TF. In Alkaloids: Chemical and Biological Perspectives Vol. 13: Pelletier SW. Pergamon Press; New York: 1999. p.1-161

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2d Schroder F. Sinnwell V. Baumann H. Kaib M. Francke W. Angew. Chem., Int. Ed. Engl. 1997, 36: 77

3a Toyooka N. Kobayashi S. Zhou D. Tsuneki H. Wada T. Sakai H. Nemoto H. Sasaoka T. Garraffo HM. Spande TF. Daly JW. Bioorg. Med. Chem. Lett. 2007, 17: 5872

3b Kobayashi S. Toyooka N. Zhou D. Tsuneki H. Wada T. Sasaoka T. Sakai H. Nemoto H. Garraffo HM. Spande TF. Daly JW. Beilstein J. Org. Chem. 2007, 3: 30

3c Tsuneki H. You Y. Toyooka N. Kagawa S. Kobayashi S. Sasaoka T. Nemoto H. Kimura I. Dani JA. Mol. Pharmacol. 2004, 66: 1061

4a Michael JP. Beilstein J. Org. Chem. 2007, 3: 27

4b Michael JP. Nat. Prod. Rep. 2007, 24: 191

5 Jones TH. Voegtle HL. Miras HM. Weatherford RG. Spande TF. Garraffo HM. Daly JW. Davidson DW. Snelling RR. J. Nat. Prod. 2007, 70: 160

6a Toyooka N. Tsuneki H. Kobayashi S. Zhou D. Kawasaki M. Kimura I. Sasaoka T. Nemoto H. Curr. Chem. Biol. 2007, 1: 97

6b Toyooka N. Tsuneki H. Nemoto H. Yuki Gosei Kagaku Kyokaishi 2006, 64: 49

6c Toyooka N. Nemoto H. New Methods for the Asymmetric Synthesis of Nitrogen Heterocycles Vicario JL. Research Signpost; India: 2005. p.149-163

6d Toyooka N. Nemoto H. Recent Research Developments in Organic Chemistry Vol. 6: Pandalai SG. Transworld Research Network; Trivandrum India: 2002. p.611-624

7 Brenneman JB. Machauer R. Martin SF. Tetrahedron 2004, 60: 7301

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9

Spectral Data of 1
IR (neat): 3482, 2956, 2872, 1513, 1457, 1378, 1234, 1130, 1054, 970, 826 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 0.90 (3 H, t, J = 7.2 Hz), 0.91 (3 H, t, J = 7.2 Hz), 1.17-1.49 (11 H, br m), 1.53-1.62 (4 H, m), 1.68-1.86 (3 H, m), 2.25 (1 H, t-like, J = 9.8 Hz), 2.40 (1 H, m), 2.75 (1 H, t-like, J = 8.5 Hz), 3.03 (1 H, d, J = 10.3 Hz), 3.74 (1 H, d, J = 9.8 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 14.27 (q), 14.50 (q), 19.16 (t), 22.98 (t), 25.92 (t), 26.67 (t), 28.75 (t), 28.98 (t), 32.18 (t), 37.83 (t), 39.43 (t), 60.43 (d), 64.07 (d), 65.45 (d), 70.06 (d). MS: m/z (%) = 239 [M⁺], 196 (100). HRMS: m/z calcd for C₁₅H₂₉ON: 239.2103; found: 239.2121. [α]_D ^²6 -48.92 (c 0.62, CHCl₃).

10

Spectral Data of 9
Mp 39-40 ˚C. IR (KBr): 3343, 2955, 2933, 2859, 2784, 1466, 1378, 1259, 1207, 1194, 1158, 1123, 1062, 1019 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 0.89 (3 H, t, J = 7.3 Hz), 0.91 (3 H, t, J = 7.3 Hz), 1.18-1.36 (8 H, m), 1.42 (1 H, m), 1.45-1.64 (4 H, m), 1.80-1.84 (2 H, m), 1.92-2.08 (3 H, m), 2.15 (1 H, br), 2.66 (1 H, t-like, J = 8.5 Hz), 3.43 (1 H, br). ^¹³C NMR (75 MHz, CDCl₃): δ = 14.24 (q), 14.53 (q), 19.55 (t), 22.88 (t), 27.91 (t), 29.22 (t), 29.68 (t), 30.87 (t), 34.08 (t), 37.51 (t), 39.37 (t), 62.10 (d), 63.75 (d), 72.87 (d), 73.05 (d). MS: m/z (%) = 239 [M⁺], 182 (100). HRMS: m/z calcd for C₁₅H₂₉ON: 239.2103; found: 239.2127; [α]_D ^²6 -53.55 (c 1.05, CHCl₃).

11

For proof of identity of (-)-1 with the natural ant alkaloid (10a, see ref. 5), a Shimadzu QP-2010 GC/MS equipped with an RTX-5 column (30 m × 0.25 mm i.d.) was used employing a program of 60 ˚C to 250 ˚C at 10 ˚C/min. Here, both synthetic (-)-1 and natural product 10a coeluted and had identical mass spectra. Synthetic (-)-1 also had a retention time and mass spectrum identical to the first eluting isomer, (±)-1, of the mixture of diastereomers synthesized in a nonstereoselective manner by Jones et al.⁵ For the determination of the absolute configuration of 10a, an HP 5890 GC with flame-ionization detection was used with He carrier gas and a head pressure of 20 psi. This was fitted with a chiral permethylated β-cyclodextrin column (SGE, 30 m × 0.22 mm i.d., 0.25 µm film thickness) operated with a program of 100 ˚C at a rate of 1 ˚C/min. Using these conditions, the Myrmicaria melanogaster ant hydroxyindolizidine 10a and (-)-1 each coeluted with the slightly more slowly eluting enantiomer (156.5 ˚C) of the (±)-1 racemate present in Jones’ synthetic mixture, whereas the (+)-1 enantiomer, from Jones’ synthetic mixture eluted at 156.0 ˚C.

12 Toyooka N. Zhou D. Nemoto H. J. Org Chem. 2008, DOI: 10.1021/jo800593n