Asymmetric synthesis of (-)-adaline

Article abstract of DOI:10.1021/ol0200807

(Matrix presented) (-)-adaline An enantioselective total synthesis of (-)-adaline has been achieved starting from a chiral 6,6-disubstituted piperidone derivative previously prepared by diastereoselective allylation of a chiral tricyclic N-acyl-N,O-acetal

Full text of DOI:10.1021/ol0200807

ORGANIC
LETTERS
2002
Vol. 4, No. 15
2469-2472
Asymmetric Synthesis of (−)-Adaline
Toshimasa Itoh, Naoki Yamazaki, and Chihiro Kibayashi*
School of Pharmacy, Tokyo UniVersity of Pharmacy and Life Science,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
kibayasi@ps.toyaku.ac.jp
Received April 18, 2002
ABSTRACT
An enantioselective total synthesis of (−)-adaline has been achieved starting from a chiral 6,6-disubstituted piperidone derivative previously
prepared by diastereoselective allylation of a chiral tricyclic N-acyl-N,O-acetal. The key steps include lithium ion-activated SN2-type alkynylation
of the tricyclic N,O-acetal leading to exclusive formation of the (6S)-ethynylpiperidine and ring-closing olefin metathesis of the (2R,6S)-cis-
2,6-dialkenylpiperidine for constructing the bridged azabicyclononane.
We previously reported TiCl4-mediated asymmetric allylation
employing tricyclic N-acyl-N,O-acetals, in which enantio-
meric 2-(1-aminoethyl)phenol (3) has been proven useful as
a chiral auxiliary.1 In connection with this investigation, most
recently we have developed a convenient practical asym-
metric synthesis of 3 via nucleophilic addition of methyl-
lithium to a chiral oxime ether.2 We have also demonstrated
that this asymmetric allylation protocol is efficiently ap-
plicable to the total synthesis of various alkaloids,1 and the
first enantioselective synthesis of a new coccinellid alkaloid
(-)-adalinine (1)3,4 was achieved on the basis of a diaste-
reoselective addition of allylsilane to an in situ generated
as shown in Scheme 1.1a We envisioned compound 7 utilized
as the key synthetic intermediate in this scheme could be
Scheme 1
N-acyliminium ion 6 to form the (R)-allylated piperidone 7
(1) (a) Yamazaki, N.; Ito, T.; Kibayashi, C. Tetrahedron Lett. 1999, 40,
739-742. (b) Yamazaki, N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2, 465-
467. (c) Yamazaki, N.; Dokoshi, W.; Kibayashi, C. Org. Lett. 2001, 3, 193-
196.
10.1021/ol0200807 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/29/2002

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
2470

pane 16. However, attempts to induce the reaction using
Grubbs catalyst 2016 failed, leading to recovery of the starting
material. This failure is most probably due to diequatorial
arrangement of the 2,6-dialkenyl substituents in 15 in a chair
form as indicated by the NOESY correlation (Figure 3),
Figure 2. Selected NOE correlation for 12.
nitrogen bond to furnish a transient trienone 13, which can
be immediately aromatized in the presence of water to the
hydroxyphenol 14 with complete racemization.12
For ring-closing metathesis (RCM),14 the enyne 12 was
transformed to the cis-2,6-dialkenylpiperidine 15 by hydro-
genation of the alkynyl moiety using Lindlar catalyst
(Scheme 3). Since free bases are claimed to be ineffective
Figure 3. Selected NOE correlation for 15.
which is inadequately disposed for the requisite ring closing
to 16. Indeed, it has been shown that RCM requires the
substrate conformation constraining the olefins in close
proximity.17 We thus envisaged as a substrate for the RCM
the use of the N-acyl derivative of 14, wherein the 2,6-
dialkenyl substituents would prefer the diaxial orientation
required for the ring closure to avoid unfavorable A(1,3)
strain18 between the vinyl group at C6 and the N-acyl group.
Thus, the hydrochloride salt of 12 was treated with tri-
methylorthoformate to give the formamide 17, which was
converted to the cis-2,6-dialkenylformamide 18 by Lindlar-
catalyzed partial hydrogenation. The NOESY data revealed
that 18 preferentially exists in the expected conformation
18a having the diaxial disposition of the dialkenyl substit-
uents. The RCM reaction applied to 18 smoothly proceeded
with Grubbs catalyst 20 (25 mol %) in benzene at 50 °C for
6 h to give the ∆3-homotropane 19 in high yield (90%).19
When the second-generation Grubbs catalyst 2120 (15 mol
%) was employed, the reaction proceeded more efficiently
and was completed in 40 min affording 19 in almost
quantitative yield.
Scheme 3a
a Key: (a) Lindlar catalyst, H2, MeOH; (b) HCl/MeOH; (c)
Grubbs catalyst 20 (0.25 equiv), benzene, 50 °C; (d) HCl/MeOH,
then HC(OMe)3, TsOH; (e) Grubbs catalyst 21 (0.15 equiv),
benzene, 50 °C.
for RCM mediated by Grubbs ruthenium catalyst due to
poisoning of the catalyst by the amine functionality,15 15
was converted to the hydrochloride salt and the RCM
reaction was applied to the construction of the ∆3-homotro-
The resulting homotropane 19 was subjected to dihy-
droxylation with OsO4-NMO to form the diol 22 as the only
product (97%) owing to an exclusive convex approach of
(13) For a review on the reactions and synthetic application of bicyclic
lactams containing N,O-acetals, see: Romo, D.; Meyers, A. I. Tetrahedron
1991, 47, 9503-9569.
(14) For reviews, see: (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc.
Chem. Res. 1995, 28, 446-552. (b) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413-4450.
(15) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856-9857. (b) Suzuki, H.; Yamazaki, N.; Kibayashi, C.
Tetrahedron Lett. 2001, 42, 3013-3015.
(16) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
Org. Lett., Vol. 4, No. 15, 2002
2471

mixture of 3-siloxy alcohol 23 and 4-siloxy alcohol 24 with
10:1 chemoselectivity in a total yield of 98%. Conversion
of 23 into 25 was accomplished by the Barton-McCombie
radical-induced deoxygenation procedure.21 Thus, 23 was
converted to the methyl xanthate (CS2, NaI, MeI), which
was treated with AIBN and Bu3SnH in refluxing benzene to
give 25 in 82% yield. Removal of the TBDMS and formyl
protecting groups in 25 was performed by treatment with
TBAF in wet THF and Li-ethylenediamine complex,22
respectively, to furnish the amino alcohol (dihydroadaline)
26, which underwent PCC oxidation to provide (-)-adaline
(2), [R]28 -11.4 (c 0.7, CHCl3) [lit.5 [R]20 -11 (c 2,
Scheme 4a
D
D
CHCl3)]. Spectral data (1H NMR, 13C NMR, and MS) of
the synthetic material were identical to those reported8b for
the natural adaline.
In conclusion, we have demonstrated the utility of 2-(1-
aminoethyl)phenol as a chiral auxiliary on the highly
diastereoselective SN2-type alkynylation of the tricyclic N,O-
acetal leading to exclusive formation of the (6S)-ethynylpi-
peridine. Using this reaction as well as ring-closing olefin
metathesis for constructing the bridged azabicyclononane,
the enantioselective total synthesis of (-)-adaline has been
achieved.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
adaline. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0200807
(17) (a) Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.;
Smith, D. W., Jr.; Schulz, G. R.; Wagener, K. B. J. Am. Chem. Soc. 1992,
114, 10978-10980. (b) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R.
H. J. Am. Chem. Soc. 1995, 117, 2108-2109. (c) Marsella, M. J.; Maynard,
H. D.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1101-1103.
(18) For reviews, see: (a) Johnson, F. Chem. ReV. 1968, 68, 375-413.
(b) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1860.
(19) After completion of our own work, a similar RCM approach to
bridged azabicyclic structures was reported by Martin et al.; see: Neipp,
C. E.; Martin, S. F. Tetrahedron Lett. 2002, 43, 1779-1782.
(20) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
a Key: (a) OsO4, NMO, MeCN-H2O; (b) TBDMSOTf, Et3N,
CH2Cl2; (c) CS2, NaH, MeI, THF; (d) AIBN, Bu3SnH, benzene,
reflux; (e) TBAF, THF; (f) Li‚H2NCH2CH2NH2; (g) PCC, CH2Cl2.
the oxidant (Scheme 4). The configuration of the C3 and
C4 stereogenic centers newly generated by the dihydroxy-
lation was assigned on the basis of the coupling constants
(21) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
1
(22) (a) Hallsworth, A. S.; Henbest, H. B. J. Chem. Soc. 1957, 4604-
4608. (b) Brown, H. C.; Ikegami, S.; Kawakami, J. H. J. Org. Chem. 1970,
35, 3243-3245. (c) Mueller, R. H.; Thompson, M. E.; DiPardo, R. M. J.
Org. Chem. 1984, 49, 2217-2231.
observed for the vicinal protons in the H NMR spectra of
compound 23 (see below). Regioselective protection of 22
was achieved with TBDMSOTf and Et3N to give a separable
2472
Org. Lett., Vol. 4, No. 15, 2002