applicable to the synthesis of (-)-adaline (2),4-6 which is
the major defensive alkaloid from the European ladybug,
Adalia bipunctata, and is suggested7 to be biogenetically
related to (-)-adalinine (1) isolated as a minor defensive
alkaloid. In this paper, we describe the enantioselective total
synthesis of (-)-adaline (2)8 starting from the (6S)-piperidone
7 by an SN2-like alkynylation using a tricyclic N,O-acetal
as an extension of the previous N-acyl-N,O-acetal-based
allylation, followed by ring-closing olefin metathesis.
Reductive lactam ring opening of 7 was carried out by
Scheme 2a
9
employing LiH2NBH3 (THF at 40 °C) to give the amino
alcohol 8 in 88% yield (Scheme 2). This compound was
cyclized by a one-pot procedure with TPAP-NMO in
acetonitrile (4A MS, rt, 1 h) that involved oxidation to the
aldehyde 9 followed by dehydrocondensation to afford the
tricyclic N,O-acetal 10 (80% yield) as a single stereoisomer,
where the chiral auxiliary 3 was incorporated. The 5aS
configuration of 10 was confirmed by the NOESY interaction
between 5a-H and the methyl group at C11 as depicted in
Figure 1. Upon treatment of 10 using lithium acetylide
ethylenediamine complex (HCtCLi‚H2NCH2CH2NH2)10 in
THF at 40 °C, the nucleophilic alkynylation11 proceeded with
complete inversion of configuration at the reaction center
and, unexpectedly, with concomitant removal of the 1-(2-
hydroxyphenyl)ethyl function via C-N bond cleavage,
leading to the (6S)-ethynylpiperidine 12 (88%) as a single
diastereomer along with racemic 1-(2-hydroxyphenyl)ethanol
(14) (73%).12 The S absolute stereochemistry at C6 of 12
was determined by the NOESY experiment, which revealed
the equatorial orientation of the C6-ethynyl group, syn to
the C2-allyl group as shown in Figure 2. The exclusive
formation of the (6S)-isomer 12 is a consequence of the
coordination of the lithium ion to the oxygen of the N,O-
acetal, activating the C-O bond for nucleophilic attack of
the lithium acetylide to give the SN2-type ring opening of
the N,O-acetal.13 In the second step, the generated lithium
(2) Yamazaki, N.; Atobe, M.; Kibayashi, C. Tetrahedron Lett. 2001, 42,
5029-5032.
(3) For isolation and structure elucidation, see: Lognay, G.; Hemptinne,
J. L.; Chan, F. Y.; Gaspar, C. H.; Marlier, M.; Braekman, J. C.; Daloze,
D.; Pasteels, J. M. J. Nat. Prod. 1996, 59, 510-511.
(4) For a recent review of the coccinellid alkaloids, see: King, A. G.;
Meinwald, J. Chem. ReV. 1996, 96, 1105-1122.
(5) For the isolation and structural determination of adaline, see: Tursch,
B.; Braekman, J. C.; Daloze, D.; Hootele, C.; Losman, D.; Karlsson, R.;
Pasteels, J. M. Tetrahedron Lett. 1973, 201-202.
a Key: (a) LiH2NBH3, THF, 40 °C; (b) TPAP, NMO, MeCN,
4A MS, rt; (c) HCtCLi‚H2NCH2CH2NH2 (5 equiv), THF, 40 °C.
(6) For the determination of the absolute configuration of natural (-)-
adaline, see: Tursch, B.; Chome, C.; Braekman, J. C.; Daloze, D. Bull.
Soc. Chim. Belg. 1973, 82, 699-703.
phenoxide 11 may form a tight six-membered chelate
complex, facilitating the cleavage of the benzylic carbon-
(7) Laurent, P.; Lebrun, B.; Braekman, J.-C.; Daloze, D.; Pasteels, J. M.
Tetrahedron 2001, 57, 3403-3412.
(8) For the synthesis of (-)-adaline, see: (a) Hill, R. K.; Renbaum, L.
A. Tetrahedron 1982, 38, 1959-1963. (b) Yue, C.; Royer, J.; Husson, H.-
P. J. Org. Chem. 1992, 57, 4211-4214. For the synthesis of (()-adaline,
see: (c) Alder, v. K.; Betzing, H.; Kuth, R.; Dortmann, H.-A. Liebigs Ann.
Chem. 1959, 620, 73-87. (d) Gnecco Medina, D. H.; Grierson, D. S.;
Husson, H.-P. Tetrahedron Lett. 1983, 24, 2099-2102. (e) Go¨ssinger, E.;
Witkop, B. Monatsh. Chem. 1980, 111, 803-811. (f) Davison, E. C.;
Holmes, A. B.; Forbes, I. T. Tetrahedron Lett. 1995, 36, 9047-9050.
(9) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996,
37, 3623-3626.
(10) Beumel, O. F., Jr.; Harris, R. F. J. Org. Chem. 1964, 29, 1872-
1976.
(11) Treatment of 7 with vinylmagnesium bromide or vinyllithium in
THF resulted in no reaction.
(12) Chiral HPLC (Chiralpak AD column) analysis of compound 14
showed two peaks with exactly equal integration for the both enantiomers.
Figure 1. Selected NOESY correlation for 10.
Org. Lett., Vol. 4, No. 15, 2002
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