Total Synthesis of the Coccinellid Alkaloid (±)-Adalinine Utilizing a Nitrenium Ion Cyclization

 

 Buy Article Permissions and Reprints All articles of this category

Abstract

The total synthesis of (±)-adalinine, a piperidine alkaloid from the European two-spotted ladybird Adalia bipunctata, is reported. Central to this undertaking are (i) the use of an N-alkoxy-N-acylnitrenium ion-induced spirocyclization to rapidly access the 6,6′-disubstituted piperidinone ring of the natural product and (ii) exploitation of the cyclohexa-2,5-dienone system generated in this process as a latent 1,6-ketoaldehyde.

References

• 1 Abramovitch RA. Jeyaraman R. In Azides and Nitrenes: Reactivity and Utility   Scriven EFV. Academic Press; Orlando, FL: 1984.  p.297-357  
  Google Scholar
• Recent notable exceptions include:
• 2a Itoh N. Sakamoto T. Miyazawa E. Kikugawa Y. J. Org. Chem.  2002,  67:  7424 
  CrossrefGoogle Scholar
• 2b Romero AG. Darlington WH. McMillan MW. J. Org. Chem.  1997,  62:  6582 
  CrossrefGoogle Scholar
• 2c de Sousa JDF. Rodrigues JAR. Abramovitch RA. J. Am. Chem. Soc.  1994,  116:  9745 
  CrossrefGoogle Scholar
• 2d Dalidowicz P. Swenton JS. J. Org. Chem.  1993,  58:  4802 
  CrossrefGoogle Scholar
• 2e Vedejs E. Sam H. Tetrahedron Lett.  1992,  33:  3261 
  CrossrefGoogle Scholar
• 2f Rudchenko VF. Ignatov SM. Kostyanovsky RG. J. Chem. Soc., Chem. Commun.  1990,  261 
  CrossrefGoogle Scholar
• 2g Kikugawa Y. Kawase M. Chem. Lett.  1990,  581 
  CrossrefGoogle Scholar
• 3 See, for example: Abramovitch RA. Ye XC. J. Org. Chem.  1999,  64:  5904 
  Google Scholar
• For reviews of the chemistry of N-alkoxy-N-acylnitrenium ions, see:
• 4a Kikugawa Y. Rev. Heteroatom Chem.  1996,  15:  263 
  CrossrefGoogle Scholar
• 4b Glover SA. Tetrahedron  1998,  54:  7229 
  CrossrefGoogle Scholar
• 5a Wardrop DJ. Basak A. Org. Lett.  2001,  3:  1053 
  Google Scholar
• 5b Wardrop DJ. Zhang W. Org. Lett.  2001,  3:  2353 
  Google Scholar
• 5c Wardrop DJ. Burge MS. Whang Z. Ortíz JA. Tetrahedron Lett.  2003,  43:  2587 
  Google Scholar
• 6a Attygalle AB. Morgan ED. Chem. Soc. Rev.  1984,  13:  245 
  CrossrefGoogle Scholar
• 6b Numata A. Ibuka T. In The Alkaloids   Vol. 37:  Brossi A. Academic Press; New York: 1987.  p.193 
  CrossrefGoogle Scholar
• 6c Pinder AR. Nat. Prod. Rep.  1992,  9:  491 ; and preceeding articles in this series
  CrossrefGoogle Scholar
• 7 Lognay G. Hemptinne JL. Chan FY. Gaspar CH. Marlier M. Braekman JC. Daloze D. Pasteels JM. J. Nat. Prod.  1996,  59:  510 
  CrossrefGoogle Scholar
• 8 Laurent P. Lebrun B. Braekman JC. Daloze D. Pasteels JM. Tetrahedron  2001,  57:  3403 
  CrossrefGoogle Scholar
• 9a Hill RK. Renbaum LA. Tetrahedron  1982,  38:  1959 
  CrossrefPubMedGoogle Scholar
• 9b King AG. Meinwald J. Chem. Rev.  1996,  96:  1105 
  CrossrefPubMedGoogle Scholar
• Previous syntheses of 5:
• 10a Broeders F. Braekman JC. Daloze D. Bull. Soc. Chim. Belg.  1997,  106:  377 
  CrossrefGoogle Scholar
• 10b Yamazaki N. Ito T. Kibayashi C. Synlett  1999,  37 
  CrossrefGoogle Scholar
• 10c Yamazaki N. Ito T. Kibayashi C. Tetrahedron Lett.  1999,  40:  739 
  CrossrefGoogle Scholar
• 10d Honda T. Kimura M. Org. Lett.  2000,  2:  3925 
  CrossrefGoogle Scholar
• 11 Compound 10 is readily available in two steps and in 78% overall yield from 2-methylanisole: Zubaidha PK. Chavan SP. Racherla US. Ayyangar NR. Tetrahedron  1991,  47:  5759 
  CrossrefGoogle Scholar
• 13 For a recent review of phenol oxidation, see: Moriarty RM. Prakash O. In Organic Reactions   Vol. 57:  Overman LE. Wiley; New York: 2001.  p.327 
  Google Scholar
• 14 Braun NA. Ousmer M. Bray JD. Bouchu D. Peters K. Peters EM. Ciufolini MA. J. Org. Chem.  2000,  65:  4397 
  CrossrefPubMedGoogle Scholar
• 15a Okazoe T. Takai K. Utimoto K. J. Am. Chem. Soc.  1987,  109:  951 
  CrossrefGoogle Scholar
• 15b For an isolated example of the selective Takai ethylidenation of a ketoaldehyde, see: Meng D. Tan Q. Danishefsky SJ. Angew. Chem. Int. Ed.  1999,  38:  3197 
  CrossrefGoogle Scholar
• 16 Cicchi S. Goti A. Brandi A. Guarna A. Sarlo FD. Tetrahedron Lett.  1990,  31:  3351 
  CrossrefGoogle Scholar

Experimental Procedure for Preparation of Dienone 8: To a suspension of phenyliodine(III) bis(trifluoroacetate) (PIFA) (2.290 g, 5.16 mmol) in MeOH (10 mL), at -78 °C, was added a cold (-78 °C) solution of N-methoxyamide 9 (1.020 g, 4.30 mmol) in CH₂Cl₂ (10 mL) via cannula. The reaction mixture was then allowed to warm to 15 °C (internal temperature) over 1.5 h whereupon H₂O (10 mL) was added and the cooling bath removed. After stirring for 10 min, the organic and aqueous phases were separated and the aqueous phase was extracted with CH₂Cl₂ (3 ¥ 20 mL). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure and the residue purified by flash chromatography over silica gel (EtOAc/hexanes, 1:1) to provide 8 (855 mg, 90%) as a colorless oil. Recrystallization from EtOAc/hexanes yielded 8 as white crystals: Mp 97-99 °C. R_f = 0.35 (EtOAc). FT-IR(film):
ν_max = 2933(br), 1674, 1642, 1445, 1376, 1071, 939,
823 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.89 (dd, J = 10.0, 3.2 Hz, 1 H) 6.70-6.68 (m, 1 H), 6.32 (d, J = 10.0 Hz, 1 H), 3.72 (s, 3 H), 2.59 (t, J = 2.6 Hz, 2 H), 2.07-1.99 (m, 2 H), 1.96-1.90 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 185.3, 168.4, 148.6, 143.9, 136.7, 129.9, 64.5, 64.0, 35.8, 33.3, 18.4, 15.9. HRMS-EI calcd for C₁₂H₁₅NO₃Na
[M + Na]⁺: 244.0950. Found: 244.0940. Anal. Calcd for C₁₂H₁₅NO₃: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.21; H, 6.84; N, 6.34.

Data for Synthetic (±)-Adalinine ( 5): Colorless oil; R_f = 0.23 (EtOAc); FT-IR(film): ν_max = 3380, 3206, 2930, 2862, 1712, 1657, 1458, 1402, 1363 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 6.62 (br s, 1 H), 2.70 (d, J = 17.8 Hz, 1 H), 2.64 (d, J = 17.8 Hz, 1 H), 2.33-2.27 (m, 2 H), 2.14 (s, 3 H), 1.83-1.54 (m, 6 H), 1.31-1.21 (m, 6 H), 0.88 (t, J = 7.0 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 207.5, 171.7, 56.4, 51.5, 39.4, 32.1, 32.0, 31.6, 31.4, 24.1, 22.7, 17.4, 14.2. HRMS-EI calcd for C₁₃H₂₃NO₂Na [M + Na]⁺: 248.1610. Found: 248.1616.