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Grahamine an Unusual Tropane Alkaloid from Schizanthus grahamii.

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analysis. C.49.20(56.10); H, 7.93 (8.05); N, 11.07 (12.92); Pd, 2.5 (4.10); CI,
1.51% (2.76%). The values in parentheses were calculated from the composition corresponding to complete conversion of the reacting comonomers. The
reaction mixture after standing for 30 min was easily separated via cannulation
from the catalyst, which was then washed with methanol.
Received: June 30, 1989;
revised: December 28, 1989 [Z3416IE]
German version: Angew. Chem. 102 (1990) 404
[I] G. Parshall: Homogeneous Catalysis, Wiley, New York 1980.
[2] C. U. Pittmann, Jr., C. E. Carraher, Appl. Polym. Proc. A m . Chem. Soc.
Symp. O.A. Batlista. Appl. Polym. Sci. 1987, Plenum, New York 1988.
[3] F. R. Hartley: Supported Metal Complexes, Reidel, Dordrecht 1985.
141 FT-IR: V(cm-') = 2271,2256 (m, s, cis-Pd(CNR),). 1717 (s, C=O), 1614
(w. C = C ) . 'H NMR (90 MHz, CDCI,, TMS intern): 6 = 6.51-5.81
(CH,=CH-), 4.33 (t, CH,O), 4.1-3.9 (m, CH,N). 2.4-2.1 (m, -CH,-).
M.p 69-71°C.
[ 5 ] B. Corain, M. Zecca, F. 0. Sam. S. Lora, G. Palma, A. C. Veronese,
Makromol. Chem., Rapid. Commun. 10 (1990) 697.
[6] L. Malatesta, F.Bonati: lsocanide Complexes ofMetals, Wiley, New York
1969. p. 158.
[7] M. Carenza, S. Lora, G . Palma, E. Boccu, R. Largajolli, F. M. Veronese.
Radial. Ph.ys. Chem. 31 (1988) 657.
[8] U. Casellato. B. Corain, M. Zecca, R. A. Michelin, M. Mozzon, R. Graziani. Inorg. Chim. Acfa. 156 (1989) 165.
[9] B. Corain, M. Zecca, S. Rancan, G. Palma, S. Lora, J. Mol. Catal55 (1990)
209.
[lo] B. Corain, M. Zecca, R. A. Michelin, M. Mozzon in U. Schubert (Ed.):
Advances in Metal-Carbene Chemistry, Kluwer, Dordrecht 1989, p. 75
I l l ] E. Singleton, H. Oosthuizen, Adv. Organornet. Chem. 22 (1984) 209.
Grahamine, an Unusual Tropane Alkaloid
from Schizanthus grahamii**
By RudoCf Hartmann, Aurelio San-Martin, Orlando Munloz,
and Eberhard Breitmaier *
Alkaloids with cyclobutane partial structure are rare. A
CAS on-line search resulted in bis(2-methoxycarbonyltropyl) a-truxillate from leaves of the coca plant, Erythroxyfum coca,[11 and santiaguine, the diamide formed from truxillic acid and 1,2,3,4-tetrahydr0-5-(2-piperidyl)pyridine.~'~In
Schizanthus grahamii, we have now found a further tropane
alkaloid containing a 2-methyl-4-phenylcyclobutane-I
,2,3tricarboxylic triester as central partial structure.
Schizanthus grahamii (Gill) belongs to the Solanaceae or
nightshade family and to the Salpiglossideae branch native
to Chile. The plant grows up to 60cm high and possesses
doubly pinnatifid leaves and large, butterfly-like, purplepink blossoms.[31Several tropane alkaloids have been isolated from the plant, including hygrolinhydroxytropane esters
and schizanthine, in which two 3a-(6P-hydroxytropane) esters of angelic acid are linked as a mesaconic diester.l4,
Using previously described methods,"] we isolated an extract from the dried and pulverized aboveground parts of the
plant and subjected it to countercurrent distribution (dichloromethane and McIlvaine buffer, pH = 5.4). Column chromatography of the first nine fractions (alumina 60/E, petroleum ether (40 -60 "C): ethyl acetate = 4: 5 ) gave, besides the
[*I
Prof. Dr. E. Breitmaier, Dr. R. Hartmann
lnstitut fur Organische Chemie der Universitat
Gerhard-Domagk-Strasse l . , D-5300 Bonn (FRG)
Prof. Dr. A. San-Martin, Dr. 0. Mufioz
Faculty of Science, Department of Chemistry
University of Chile, Santiago (Chile)
['*I This work was supported by the Ministerium fur Wissenschaft und
Forschungdes Landes Nordrhein-Westfalen. We thank Dr. C. J. Wolffand
M . Murtter (Bruker, Rheinstetten) for allowing US to use a ~ O O - M H Z
NMR spectrometer.
Angru Chem. In1 Ed. Engl 29 (1990) No. 4
known schizanthine, the new compound grahamine as an
oily, but pure, fairly stable substance [01]:g0~
= + 6.21"
(c = 0.0016 M in CHCI,), R, = 0,1125 (thin layer chromatography, neutral alumina, CHCI,)] .
Fast atom bombardment (FAB) mass spectrometry gave a
molecular mass of 871 for grahamine. The best-resolved
NMR spectrum in the proton region was obtained in hexadeuteriobenzene as solvent.[61The 'H-broadband-decoupled
3C-NMR spectrum contains 46 signals, two of which, displaying double intensity, belong to a monosubstituted benzene ring, so that 48 C atoms may be assumed. The DEPT
subspectra reveal seven methyl (C7H2'), nine aliphatic methylene (C9H18),twenty-two methine (CzZHz2),and ten quaternary C atoms (Cl,,). The sum of these CH, fragments,
C,,H,, , corresponds to a molecular mass of 637, a difference of 234 from the actual molecular mass of 871. The
typical shifts (6 = 40.5,41.1, 41.2), splittings (quartets), and
CH coupling constants ( ' J = 134-140 Hz) of N-methyl
groups indicate the presence of three nitrogen atoms. If their
molecular mass of 42 is subtracted from the above difference,
the resulting mass (192) corresponds exactly to twelve oxygen atoms. The empirical formula thereby obtained,
C,,H,,N,O,, ,respresents twenty double-bond equivalents.
Further structure elucidation was accomplished by oneand two-dimensional NMR methods (400- and 600- MHz
'H NMR; 100- and 150-MHz 13CNMR; Scheme 1). All 38
'&
33'40
4
CH,-groups
HA
C
127.2 0
164.7
5.15166 3 i
69.2
/'"1<5,6
H8
'::%2CH3
35
46 . 1
40 2
2
1 ... 20
6 150 1.00
1.9
2
40
0
3.37
66. 9
33.7 1.90 2.15
3 5 . 4 2.30 2 . 3 3
35.9 1.47 1.98
N
I
41.2
2.46CH3
B
2. 91
69:i9
35.4
82. 6
5.65
\
85:99
60. 8
36.0
34.4
5.79<
67.2
3 28
0
/-
/N
41.1
2 . 24CH3
CH,-groups
HA
C
HB
1.13 1 . 7 9
2 03 2 . 4 9
1 53 1 . 8 6
34.9
96.6
33.6
/
F
o
H5.87
21.4
l. 95%
Scheme 1. Partial structures A-F of grahamine (1). "C- and 'H-NMR chemical shifts, the latter in italics.
CH, fragments of the molecule can be assigned in the C,H
COSY contour diagram. All 61 H atoms of the molecule are
bonded to carbons, so that no OH Or NH groups are present'
The cross signals of an H,H COSY diagram reveal three
3,6-dihydroxytropane rings, A, B, and C, as well as a methyl-
VCH Verlagsgesellsehaff mbH. 0-6940 Wemheim, 1990
0570-Ocl33i90ja4~4-03858 02 5010
385
cyclobutane partial structure, which was identified from the
typical CH coupling constants ('J = 140-145 Hz) in the
coupled 13C-NMR spectrum. In the C,H COLOC diagram,
the connectivity of all six carboxyl C atoms (6 = 164.7174.7) is clearly revealed by the two- and three-bond coupling constants 'JCH
and 3JcH,respectively. Accordingly,
tropane rings A and B are linked as mesaconic diester D.
Further cross signals in the C,H COLOC diagram show that
a 2-methyl-4-phenylcyclobutane-1,2,3-tricarboxylic
ester E
is present, whereby the carboxylic acid function on C 1 forms
an ester linkage with the third 3,6-dihydroxytropane C at its
3-hydroxyl group. Furthermore, the C,H COLOC diagram
reveals an angelic ester partial structure F, which is linked to
tropane ring C through the 6-hydroxyl group. Combination
of all partial structures gives the constitution of grahamine
(l),which accounts for the twenty double-bond equivalents.
The relative configuration of the 0-acyl groups on the
tropane rings may be derived from the HH coupling constants. All signals of protons in a 3-position are split into a
doublet of doublets (3JHH
= 4-5 Hz) owing to coupling with
the pseudo-axial protons 2-H and 4-H (interplanar angle ca.
60"). Signal broadening occurs as a result of unresolved HH
coupling to the pseudo-equatorial protons in 2- and 4-positions (interplanar angle ca. 90°). Accordingly, the 3-H protons are pseudo-equatorial and the 3-0-acyl groups pseudoaxial. The signals of the 6-H protons are each a doublet of
doublets with 3JHH
= 7.8-8.8 Hz to 7-H,,,, and 3.5-3.8 Hz
to 7-H,,,. Further couplings with 5-H are again unresolved
(interplanar angle nearly 90"); examination of the interplanar angle between the protons 5-H and 6-H in a Dreiding
model reveals that only 6-H in endo position allows an interplanar angle to 5-H of about 90". Thus, the 6-0-acyl groups
are exo.
The CH coupling constants of the carboxyl C atoms at
6 = 166.3 (D) and 167.7 (F) reflect the relative configuration
of the two C-C double bonds. A 3JCHcoupling of 15 Hz
between the carboxy signal at 6 = 167.7 and the proton signal at 6 = 5.87 is characteristic of the trans configuration of
the methyl group of angelic ester F. A correspondingly large
coupling with the proton signal at 6 = 6.92 is absent for the
carboxyl signal at 6 = 166.3, which confirms the E configuration of the mesaconic diester partial structure D.
0
D
H
v
0%cH3
F
Since the 3JHH
couplings of the cis and trans protons in
cyclobutane derivatives differ only slightly,['] the relative
configuration of this ring was determined by H,H NOE dif386
c', VCH Verlagsgesellschafi mbH. D-6940 Weinhelm. 1990
ference spectroscopy. Pronounced nuclear Overhauser effects corresponding to a cis relationship are found between
the protons at 6 = 4.45 and 4.96 as well as 4.13 and 2.03
(methyl). Saturation of the resonance at 6 = 2.03 also leads
to an NOE at the N-methyl proton of tropane ring B
(6 = 2.46). Accordingly, the partial structures may be joined
as shown by 1.
Presumably, the plants, which grow at sunny sites, form
the cyclobutane ring from mesaconic diester (left half in 1)
and cinnamic ester (right half) by [2 + 21 cycloaddition.
Received: November 30, 1989 [Z 3660 IE]
German version: Angew. Chem. 102 (1990) 441
CAS Registry number:
grahamine, 24583-56-0.
[l] C . Liebermdnn, Ber. Dtsch. Chem. Ges. 2 f (1888) 2342; ihid. 22 (1889) 672;
W. C. Evans, J Ethnopharmacol. 3 (1981) 265.
[2] I. Ribas, E. Riviera, An. R. Soc. ESP.Fis. Quim. Ser. 8 4 9 (1953) 707.
[3] E. Petersen: Praktisches Garrenlexikon, 3rd ed. Nymphenburger Verldgshandlung, Miinchen 1982.
[4] H. Ripperger, Phyrochemistry 18 (1979) 717; A. San-Martin, J Rovirose, V
Gambaro, M. Castillo, ihid. 19 (1980) 1007.
[5] A. San-Martin, C. Labbe. M. Castillo, Phvtochemistr.v 22 (1983) 1838; ibid.
26 (1987) 819.
[6] R. Hartmann, Dissertation, Universitit Bonn 1989 (detailed description of
the interpretation and documentation of the spectra).
[7] D. J. Pasto, S. H. Yang, J. Am. Chem. Soc. 106 (1984) 152.
Enzyme-Catalyzed Synthesis
of (S)-Cyanohydrins **
By Uwe Niedermeyer and Maria-Regina Kula *
The enzyme-catalyzed addition of hydrogen cyanide to
aldehydes leads to optically active cyanohydrins.['] These
compounds open up a simple route to chiral j3-amino alcohols,[21a-hydroxy acids, and pyrethroid insecticide^.'^] However, obtaining cyanohydrins with high optical purity is fundamentally difficult, since the optical yield of the enzymecatalyzed asymmetric synthesis is decreased by the concomitant nonselective chemical addition of hydrogen cyanide.
This reaction cannot be completely suppressed in most solvent systems.r41The importance of optically active cyanohydrins, on the one hand, and the lack of methods for asymmetric synthesis of cyanohydrins, on the other, prompted
us to investigate in more detail the potential of enzymecatalyzed cyanohydrin formation.
The synthesis of (R)-cyanohydrins is documented by numerous examples. One of the most effective catalysts is an
oxynitrilase (4.1.2.10) from Prunus amygdalus (bitter almond).['. 5 , 61 By contrast, the enzymatic synthesis of ( S ) cyanohydrins has not yet been studied!***] We have now
found that an oxynitrilase from Sorghum bicolor (4.1.2.1 I),
which was described mainly from a botanical viewpoint in
the 1960~,[~"-allows the preparative synthesis of ( S ) cyanohydrins with high optical purity.'']
[*] Prof. Dr. M.-R. Kula. Dr. U. Niedermeyer
lnstitut fur Enzymtechnologie der Universitit Dusseldorf
in der KFA Julich
Postfach 2050. D-5170 Julich (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
[***I Editorial note (March 16, 1990): A communication concerning the enzyme-catalyzed synthesis of (S)-cyanohydrinshas been published in issue
No. 911990 of Tetrahedron Lett: F. Effenberger, B Horsch, S. Forster, T.
Ziegler, Tetrahedron Lett. 31 (1990) 1249 (Received: December 22.1989).
0570-0833I90j0404-0386 3 02.SOj0
Angew. Chem. Inr. Ed. Engl. 29 (1990) No. 4
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