Subscribe to RSS
DOI: 10.1055/s-2003-40322
Total Synthesis of the Coccinellid Alkaloid (±)-Adalinine Utilizing a Nitrenium Ion Cyclization
Publication History
Publication Date:
30 June 2003 (online)
![](https://www.thieme-connect.de/media/synlett/200309/lookinside/thumbnails/10.1055-s-2003-40322-1.jpg)
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.
Key words
adalinine - piperidine alkaloid - nitrenium ions - dearomatization - polyvalent iodine
- 1
Abramovitch RA.Jeyaraman R. In Azides and Nitrenes: Reactivity and UtilityScriven EFV. Academic Press; Orlando, FL: 1984. p.297-357 - Recent notable exceptions include:
-
2a
Itoh N.Sakamoto T.Miyazawa E.Kikugawa Y. J. Org. Chem. 2002, 67: 7424 -
2b
Romero AG.Darlington WH.McMillan MW. J. Org. Chem. 1997, 62: 6582 -
2c
de Sousa JDF.Rodrigues JAR.Abramovitch RA. J. Am. Chem. Soc. 1994, 116: 9745 -
2d
Dalidowicz P.Swenton JS. J. Org. Chem. 1993, 58: 4802 -
2e
Vedejs E.Sam H. Tetrahedron Lett. 1992, 33: 3261 -
2f
Rudchenko VF.Ignatov SM.Kostyanovsky RG. J. Chem. Soc., Chem. Commun. 1990, 261 -
2g
Kikugawa Y.Kawase M. Chem. Lett. 1990, 581 - 3 See, for example:
Abramovitch RA.Ye XC. J. Org. Chem. 1999, 64: 5904 - For reviews of the chemistry of N-alkoxy-N-acylnitrenium ions, see:
-
4a
Kikugawa Y. Rev. Heteroatom Chem. 1996, 15: 263 -
4b
Glover SA. Tetrahedron 1998, 54: 7229 -
5a
Wardrop DJ.Basak A. Org. Lett. 2001, 3: 1053 -
5b
Wardrop DJ.Zhang W. Org. Lett. 2001, 3: 2353 -
5c
Wardrop DJ.Burge MS.Whang Z.Ortíz JA. Tetrahedron Lett. 2003, 43: 2587 -
6a
Attygalle AB.Morgan ED. Chem. Soc. Rev. 1984, 13: 245 -
6b
Numata A.Ibuka T. In The Alkaloids Vol. 37:Brossi A. Academic Press; New York: 1987. p.193 -
6c
Pinder AR. Nat. Prod. Rep. 1992, 9: 491 ; and preceeding articles in this series - 7
Lognay G.Hemptinne JL.Chan FY.Gaspar CH.Marlier M.Braekman JC.Daloze D.Pasteels JM. J. Nat. Prod. 1996, 59: 510 - 8
Laurent P.Lebrun B.Braekman JC.Daloze D.Pasteels JM. Tetrahedron 2001, 57: 3403 -
9a
Hill RK.Renbaum LA. Tetrahedron 1982, 38: 1959 -
9b
King AG.Meinwald J. Chem. Rev. 1996, 96: 1105 - Previous syntheses of 5:
-
10a
Broeders F.Braekman JC.Daloze D. Bull. Soc. Chim. Belg. 1997, 106: 377 -
10b
Yamazaki N.Ito T.Kibayashi C. Synlett 1999, 37 -
10c
Yamazaki N.Ito T.Kibayashi C. Tetrahedron Lett. 1999, 40: 739 -
10d
Honda T.Kimura M. Org. Lett. 2000, 2: 3925 - 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 - 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 - 14
Braun NA.Ousmer M.Bray JD.Bouchu D.Peters K.Peters EM.Ciufolini MA. J. Org. Chem. 2000, 65: 4397 -
15a
Okazoe T.Takai K.Utimoto K. J. Am. Chem. Soc. 1987, 109: 951 -
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 - 16
Cicchi S.Goti A.Brandi A.Guarna A.Sarlo FD. Tetrahedron Lett. 1990, 31: 3351
References
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.
Rf = 0.35 (EtOAc). FT-IR(film):
νmax = 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; Rf = 0.23 (EtOAc); FT-IR(film): νmax = 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.