Expeditious Enantioselective Biomimetic Synthesis of the Nitrarta Alkaloids (+)-Isonitramine and (-)-Sibirine

Full text of DOI:10.1002/(SICI)1521-3773(19980202)37:1/2<104::AID-ANIE104>3.0.CO;2-K

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According to this biogenetic hypothesis, the crucial step is
the reduction of the conjugated iminium system of C to a
simple enamine. We reasoned that a stereocontrolled Michael
addition of a convenient nucleophile to B should a) create a
new stereogenic center which would further control the
spirocyclization and b) allow elimination of the nucleophile
by reductive cleavage.
Expeditious Enantioselective Biomimetic
Synthesis of the Nitraria Alkaloids
(‡)-Isonitramine and ( )-Sibirine
David François, Marie-Christine Lallemand,
Mohamed Selkti, Alain Tomas, Nicole Kunesch,* and
Henri-Philippe Husson*
We chose sodium p-toluenesulfinate as the nucleophile in
the expectation that 1,4-addition to the a,b-unsaturated
oxazolidine system of D would generate the desired enamine.
Whereas the 1,4-addition of phenylsulfinate ion to a,b-
unsaturated ketones is well documented, there are few
examples of reaction with iminium salts. As far as conjugated
iminium ions are concerned, we observed the only known case
for a rearrangement in which a 1,4-addition occurred.[5]
The first step of our synthetic sequence was accomplished
by condensation of (R)-( )-phenylglycinol and glutaralde-
hyde (2.5 equiv) followed by addition of sodium p-toluene-
sulfinate. This resulted in the formation of the spirocompound
3 (51% yield) as the major diastereomer, which was isolated
by simple crystallization (Scheme 2) and characterized by X-
ray structure analysis.[6]
Isonitramine 1 (Scheme 2) is a representative member of
the Nitraria alkaloid family, for which considerable structural
variety is encountered but in which a piperidine ring is an
essential feature. We achieved the enantioselective syntheses
of the spiropiperidine alkaloids (‡)- and ( )-isonitramine,[1]
and a number of other racemic[2] and asymmetric syntheses[3]
have appeared. Some require numerous steps and have low
overall yields. In a continuation of our work on the use of
glutaraldehyde for constructing piperidine alkaloids,[4] we
report here the most straightforward syntheses of natural
sibirine ( )-2 as well as isonitramines (‡)-1 and ( )-1 from
commercially available starting materials.
Despite the important achievements of Koomen et al.[2] in
biomimetic approaches to synthesizing Nitraria alkaloids, some
desirable objectives have not yet been attained. In particular,
generation of a nonracemic chiral biogenetic intermediate
with a suitable oxidation level remains an unsolved problem.
We previously showed[1] that the condensation of (R)-( )-
phenylglycinol with excess glutaraldehyde gives a tetracyclic
compound containing the spiropiperidine skeleton of Nitraria
alkaloids. However, six and eight additional steps are
necessary to transform this precursor into ( )- and (‡)-
isonitramine, respectively. Such a reaction might form the
basis of a biomimetic approach to synthesizing the title
alkaloids. Since the first step of the reaction between (R)-( )-
phenylglycinol and glutaraldehyde is the formation of the
enantiopure intermediate A (Scheme 1), we imagined that
condensation of a second molecule of glutaraldehyde would
afford aldehyde B, a chiral derivative of the piperideinoalde-
hyde C postulated by Koomen as a key intermediate in the
biosynthesis of Nitraria alkaloids.[2]
O
N
Ph
a
OH
Ph
R
NH2
O
(R)-(–)-phenylglycinol
b
3, R =TolSO2
d,c
HO
N
HO
Ph
N
H3C
R
OH
5
4, R = TolSO2
c
e
HO
HO
N
N
H3C
H
2
1
Scheme 2. a) Aqueous glutaraldehyde (2.5 equiv), pH 3.5, NaSO2Tol
(2.2 equiv), ZnBr2, 3 h (51%); b) W-2 Raney Ni, MeOH (reflux), 2 h
(91%); c) Na(Hg), anhydrous MeOH, anhydrous Na2HPO4, 24 h, 208C
(95%); d) LiAlH4, Et2O (82%); e) H2/Pd(OH)2/C 20%, MeOH, 24 h
(85%).
N
Ph
Ph
H
O
N
GA
N
O
The outcome of this highly efficient reaction suggests that 3
is the most thermodynamically stable compound resulting
from a series of equilibration reactions. The possible control
elements include a) diastereoselective 1,4-nucleophilic addi-
tion of TolSO2 to the a,b-unsaturated oxazolidine system of
D[7] and b) addition of the substituted enamine goup of E to
the aldehyde group via a chairlike transition state in which the
sulfone and the developing secondary alcohol are in a
diequatorial arrangement, which provides stereocontrolled
spiroaldolization.
H
OH
O
A
B
C
Ph
Ph
H+
N
3
O
N
O
OH
H
H
O
TolSO2
TolSO2
D
E
Scheme 1. Mechanism for the formation of spirocompound 3.
[*] Dr. N. Kunesch, Prof. H.-P. Husson, D. François, Dr. M.-C. Lallemand
Finally, natural sibirine ( )-2 was obtained in a two-step
procedure from 3 by hydrogenolysis/alkylation with Raney
nickel in MeOH[8] followed by sulfone elimination (yield
86%).[9] The synthesis of isonitramine ( )-1 required reduc-
tion with LiAlH4, sulfone elimination, and hydrogenolysis of
the chiral N substituent (yield for three steps from 3 66%).[10]
Natural isonitramine (‡)-1 could be obtained starting from
Â
URA 1310 associee au CNRS
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Faculte des Sciences Pharmaceutiques et Biologiques
Universite Rene-Descartes
Â
Â
4, Avenue de l'Observatoire, F-75270 Paris Cedex 06 (France)
Fax: Int. code ‡ (33)1-43291403
e-mail: husson@pharmacie.univ-paris5.fr
Dr. M. Selkti, Prof. A. Tomas
Laboratoire de Biocristallographie, Universite Rene-Descartes
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104
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Angew. Chem. Int. Ed. 1998, 37, No. 1/2

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[1] J.-C. Quirion, D. S. Grierson, J. Royer, H.-P. Husson, Tetrahedron Lett.
1988, 29, 3311 ± 3314.
[2] M. J. Wanner, G.-J. Koomen in Studies in Natural Products Chemistry:
Stereoselectivity in Synthesis and Biosynthesis of Lupine and Nitraria
Alkaloids, Vol. 14 (Ed.: Atta-ur-Rahman), Elsevier, Amsterdam,
1994, pp. 731 ± 768, and references therein.
[3] a) D. Kim, W. J. Choi, J. Y. Hong, I. Y. Park, Y. B. Kim, Tetrahedron
Lett. 1996, 37, 1433 ± 1434; b) T. Yamane, K. Ogasawara, Synlett 1996,
925 ± 926; c) M. Keppens, N. De Kimpe, J. Org. Chem. 1995, 60, 3916 ±
3918, and references therein; d) B. Westermann, H. G. Scharmann, I.
Kortmann, Tetrahedron: Asymmetry 1993, 4, 2119 ± 2122; e) T.
Imanishi, T. Kurumada, N. Maezaki, K. Sugiyama, C. Iwata, J. Chem.
Soc. Chem. Commun. 1991, 1409 ± 1411; f) P. J. McCloskey, A. G.
Schultz, Heterocycles 1987, 25, 437 ± 447.
[4] a) C. Yue, I. Gauthier, J. Royer, H.-P. Husson, J. Org. Chem. 1996, 61,
4949 ± 4954; b) H.-P. Husson, J. Royer in Advances in the Use of
Synthons in Organic Chemistry: Chemistry of Potential and Reversed
Iminium Systems, Vol. 2 (Ed.: A. Dondoni), JAI Press, Greenwich, CT,
USA, 1995, pp. 1 ± 68.
enantiomeric (S)-(‡)-phenylglycinol. These results show the
crucial role of the chiral phenylglycinol, which serves not only
for the transfer of chirality but also for the stabilization of the
intermediate iminium.
The nitramine alkaloids (derivatives of 2-azaspiro[5.5]un-
decan-7-ol) are structurally analogous to the neurotoxic
histrionicotoxin alkaloids,[11] compounds which have a 1-
azaspiro[5.5]undecan-8-ol skeleton with unsaturated lipophil-
ic side chains. The introduction of such essential side chains on
the nitramine skeleton is therefore of particular interest.
Intermediate 3 opens the way to a variety of substitutions
which can be made a) at the carbon atoms adjacent to the
nitrogen of the piperidine ring by selective opening of the
oxazolidine and/or 1,3-oxazine in an iminium ion and b) on
the cyclohexane ring by the sulfone reactivity.
[5] D. S. Grierson, J.-L. Bettiol, I. Buck, H.-P. Husson, M. Rubiralta, A.
Diez, J. Org. Chem. 1992, 57, 6414 ± 6421.
Experimental Section
[6] Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-100690. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK
(fax: int. code ‡ (1223)336-033; e-mail: deposit@ccdc.cam.ac.uk).
[7] a) P. Mangeney, A. Alexakis, J.-F. Normant, Tetrahedron 1984, 40,
1803 ± 1808; b) M. Huche, J. Aubouet, G. Poncelot, J. Berlan,
Tetrahedron Lett. 1983, 24, 585 ± 586.
[8] a) X.-S. He, A. Brossi, J. Heterocyclic Chem. 1991, 28, 1741 ± 1746; b)
W. Meise, Methoden Org. Chem. (Houben-Weyl), 4th ed. 1980-, Vol. 4/
1c, p. 257.
[9] B. M. Trost, H. C. Arndt, P. E. Strege, T. R. Verhoeven, Tetrahedron
Lett. 1976, 3477 ± 3478.
[10] Isonitramine ( )-1 could be obtained in a single step by treating 3 with
Raney nickel at 808C and 25 bar in THF; however, the yield was
modest (20%, not optimized).
[11] J. W. Daly, H. Martin Garraffo, T. F. Spande in The Alkaloids:
Amphibian Alkaloids, Vol. 43 (Ed.: G. A. Cordell), Academic Press,
New York, 1993, pp. 185 ± 288.
All new compounds were characterized by 2D 1H and 13C NMR as well IR
spectra, [a]D values, simple and high-resolution mass spectrometry, or
elemental analysis.
(R)-( )-phenylglycinol (6.9 g, 50 mmol) was added to a solution of citric
acid (24 g) in distilled water (200 mL). The mixture was stirred vigourously
until complete dissolution of the phenylglycinol and then cooled to 0 ± 58C
in an ice/water bath. A 25% aqueous solution of glutaraldehyde (47 mL,
125 mmol) was added dropwise over 30 min, and then sodium p-toluene-
sulfinate (19.6 g, 110 mmol) was added simultaneously with CH2Cl2
(120 mL). The reaction mixture was stirred for 2 h at room temperature.
The aqueous phase was neutralized with 5n aqueous NaOH (80 mL) and
extracted with CH2Cl2 (3 Â 150 mL). The combined organic layers were
concentrated under vacuum, diluted with MeOH (50 mL), and treated with
ZnBr2 (2 g, 8.9 mmol) over 12 h. Evaporation of the solvent gave an oily
crude residue which crystallized from MeOH to give 11.19 g (51%) of 3 in
two crops.
3: M.p. 222 ± 2238C; [a]D 77 (c ˆ 1 in CHCl3); 1H NMR (300 MHz,
CDCl3) d ˆ 1.12 (m, 1H, H-9), 1.50 ± 2.10 (m, 6H, H-5, Hs-8, H-9, Hs-10),
1.95 ± 2.10 (m, 1H, H-5), 2.15 ± 2.35 (m, 2H, Hs-4), 2.44 (s, 3H, CH3 Tol),
3.28 (dd, 1H, J ˆ 13, 4 Hz, H-7), 3.66 (dd, 1H, J ˆ 9.5, 8.5 Hz, H-13), 3.97
(dd, 1H, J ˆ 11.5, 4.5 Hz, H-11), 4.30 (dd, 1H, J ˆ 3.5, 1.5 Hz, H-6), 4.35
(dd, 1H, J ˆ 8.5, 6.5 Hz, H-13), 4.60 (dd, 1H, J ˆ 9.5, 6.5 Hz, H-12), 5.86 (s,
1H, H-2), 7.20 ± 7.45 (m, 7H, Ar Hs), 7.78 (d, 1H, J ˆ 8 Hz, Tol H); 13C
NMR (75.5 MHz, CDCl3) d ˆ 16.4 (C-4), 21.4 (CH3 Tol), 21.4 (C-9), 23.6
(C-10), 27.2 (C-5), 28.2 (C-8), 40.7 (C-3), 62.6 (C-7), 63.2 (C-12), 70.4 (C-
11), 73.0 (C-13), 78.5 (C-6), 91.3 (C-2), 127.3, 128.2, 129.5 (Ar CH), 136.9
(Ar C), 139.9 (Ar C), 144.3 (Ar C).
Preparation of Lithium Oligosiloxane
Aluminates and Acid Strength of Hydroxy
Groups in a Molecular Aluminum
Oligosiloxane
4: M.p. 211 ± 2138C (MeOH); [a]D
3
(c ˆ 1 in CHCl3); 1H NMR
Michael Veith,* Maria Jarczyk, and Volker Huch
(300 MHz, CDCl3) d ˆ 1.1 ± 1.2 (m, 1H), 1.3 ± 2.0 (m, 8H), 2.0-2.2 (m,
4H), 2.30 (s, 3H, N-Me), 2.42 (s, 3H, CH3 Tol), 2.5 ± 2.9 (br m, 2H), 3.5 ± 3.7
(m, 2H), 7.32 (d, 1H, J ˆ 8 Hz, H Tol), 7.72 (d, 1H, J ˆ 8 Hz, H Tol); 13C
NMR (75.5 MHz, CDCl3) d ˆ 21.4 (CH3 Tol), 21.7 (CH2), 22.3 (CH2), 23.2
(CH2), 28.8 (CH2), 43.0 (C-3), 46.0 (N-Me), 55.3 (C-6), 65.4 (C-2), 68.6 (C-
7), 81.9 (C-11), 128.1 (CH Tol), 129.6 (CH Tol), 137.2 (C Tol), 144.3 (C Tol).
5: [a]D 17 (c ˆ 1 in CHCl3); 1H NMR (300 MHz, CDCl3) d ˆ 0.7 ± 1.0 (m,
2H), 1.0 ± 1.8 (m, 8H), 1.85 (d, 1H, J ˆ 11 hz, H-2), 2.0 ± 2.1 (m, 2H), 2.25
(td, 1H, J ˆ 10, 3 Hz, H-6), 2.67 (d, 1H, J ˆ 11 Hz, H-2), 2.8 ± 2.9 (m, 1H),
3.5 ± 3.6 (m, 2H), 3.80 (dd, 1H, J ˆ 11, 6 Hz), 4.08 (dd, 1H, J ˆ 11, 8 Hz),
7.0 ± 7.4 (m, 5H); 13C NMR (75.5 MHz, CDCl3) d ˆ 20.3 (CH2), 22.8 (CH2),
23.8 (CH2), 28.1 (CH2), 29.5 (CH2), 35.9 (C-3), 51.8 (C-6), 62.1 (C-2), 62.7
(C-13), 71.0 (C-12), 79.0 (C-11), 127.8 (Ar CH), 128.4 (Ar CH), 128.6 (Ar
CH), 147.5 (Ar C).
Dedicated to Professor Manfred Weidenbruch
on the occasion of his 60th birthday
As we recently reported, the molecular aluminum oligo-
siloxane 1, which contains four aluminum atoms that are
connected through OH bridges to form a ring, can be readily
prepared in a one-step synthesis.[1] We observed that the
hydrogen atoms of the OH groups are available for coordi-
nation with Lewis bases. Compound 1 can therefore be
isolated as an adduct with three molecules of diethyl ether (a
fourth is incorporated within the crystal lattice and does not
Received: July 25, 1997 [Z10731IE]
German version: Angew. Chem. 1998, 110, 112 ± 114
[*] Prof. Dr. M. Veith, M. Jarczyk, Dr. V. Huch
Institut für Anorganische Chemie der Universität
Postfach 151150, D-66041 Saarbrücken (Germany)
Fax: Int. code ‡ (681)302-3995
Keywords: alkaloids ´ asymmetric synthesis ´ biomimetic
synthesis ´ natural products ´ spiro compounds
e-mail: veith@rz.uni-sb.de
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