Biomimetic investigations from reactive lysine-derived C5 units: one step synthesis of complex polycyclic alkaloids from the Nitraria genus

Article abstract of DOI:10.1016/j.tet.2005.12.069

A single biomimetic cascade sequence featuring intermolecular followed by intramolecular cyclizations allowed the biomimetic synthesis of nitraramine and the formation of an interesting original cage-like structure from simple C₅ lysine-derived metabolites. In the course of the study, the structure and spectral data of 1-epinitraramine were also revisited.

Full text of DOI:10.1016/j.tet.2005.12.069

Tetrahedron 62 (2006) 5248–5253
Biomimetic investigations from reactive lysine-derived C5 units:
one step synthesis of complex polycyclic alkaloids from the
Nitraria genus
*
Edmond Gravel, Erwan Poupon and Reynald Hocquemiller
´
Laboratoire de Pharmacognosie associe au CNRS, UMR 8076 (BioCIS), Centre d’Etudes Pharmaceutiques,
´
Universite Paris-Sud 11, 5 rue Jean-Baptiste Clement, 92296 Chatenay-Malabry, France
´
´
ˆ
Received 29 September 2005; revised 26 December 2005; accepted 29 December 2005
Available online 12 April 2006
Abstract—A single biomimetic cascade sequence featuring intermolecular followed by intramolecular cyclizations allowed the biomimetic
synthesis of nitraramine and the formation of an interesting original cage-like structure from simple C5 lysine-derived metabolites. In the
course of the study, the structure and spectral data of 1-epinitraramine were also revisited.
Ó 2006 Elsevier Ltd. All rights reserved.
tripiperidine alkaloids
indole alkaloids
1. Introduction
1.1. The Nitraria genus
N
iv
iii
N
N
N
H
Plants from the Nitraria genus (Zygophyllaceae) are bushes
that can grow up to 2 m high. They have fleshy leaves, little
white flowers (with five petals and 15 stamens), and their
fruits have three pyramidal chambers. Well adapted to arid
climate, species of Nitraria are found in desert regions of
south-east Europe (Nitraria komarovii, Nitraria sibirica)
and middle-east (Nitraria schoberi) but also in Australia
(Nitraria billardieri) and Africa, in northern and occidental
parts of the Sahara desert, and in Mauritania (Nitraria tri-
dendata or Nitraria retusa).
N
Schoberine
H
Nitrarine
N
O
5
simple
spiro alkaloids
complex
spiro alkaloids
common biosynthetic
intermediate
OH
N
O
N
R
i
ii
H
H
N
R=H: Isonitramine
R=CH3: Sibirine
1.2. Nitraria alkaloids
Nitraramine 1
Isolated from aerial parts of the plants, alkaloids of the Nitra-
ria genus are classically classified into three major groups
(Fig. 1):1 tripiperidine alkaloids (e.g., schoberine), indole
alkaloids (e.g., nitrarine), and the group of spiro alkaloids.
The latter can be divided in two sub-groups: simple spiro
alkaloids (e.g., sibirine) and complex spiro alkaloids (e.g.,
nitraramine 1, 1-epinitraramine 2).
Figure 1. Central biosynthetic role of intermediate 5.
thetic origin. In fact, a particularly primitive lysine-based
metabolism can account for the biogenesis of these alkal-
oids. Moreover, the fact that numerous Nitraria alkaloids
are present as chiral but as racemic forms in nature strongly
suggests a minimum enzymatic intervention, at least for the
key diversity-generating cyclizations.2
These piperidine alkaloids from Nitraria species constitute
a singular class of natural compounds both in terms of chem-
ical diversity (e.g., many 3-spiropiperidines) and biosyn-
1.3. Biosynthesis
The biosynthesis of many of these compounds can be ex-
plained by the assembly of simple C5 units derived from
L-lysine, such as2-piperideine3 and glutaraldehyde 6 (Scheme
1). The formation of an endocyclic enamine 3 from lysine is
a known step in the biosynthesis of many alkaloids such as
Keywords: Nitraria; Nitraramine; Biosynthesis; Biomimetic synthesis;
Polycyclic alkaloids; Epinitraramine; Structure reassignment.
* Corresponding author. Tel.: +33 1 46 83 55 86; fax: +33 1 46 83 53 99;
e-mail: erwan.poupon@cep.u-psud.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.069

E. Gravel et al. / Tetrahedron 62 (2006) 5248–5253
5249
H
N
H
N
N
H
N
H
N
H2N
O
3
L-lysine
- H2O
decarboxylation
H
oxidative deamination
3
4
reactive precursors
N
O
O
O
- H2O
retro-Michael
oxidative deamination
oxidative deamination
6
5
Scheme 1. Different possibilities for the biosynthesis of intermediate 5.
those of the Lupinus genus. Dimerization of 2-piperideine 3
into tetrahydroanabasine 4 followed by opening and oxida-
tion could lead to an intermediate 5,1,3 but the attack of
a 2-piperideine unit on a molecule of glutaraldehyde fol-
lowed by a dehydration step could also be a potential path
for the formation of this pivotal key precursor (Scheme 1)
that spiro, indole, and tripiperidine alkaloids share. Com-
pound 5 can then be reduced and undergo a spirocyclization
process, leading to the formation of simple spiro alkaloids
(Fig. 1, i). It can also react with an additional molecule of
2-piperideine, either through C-alkylation, in which case it
will afford the required intermediates for the formation of
complex spiro alkaloids (Fig. 1, ii), or through N-alkylation
and in that case eventually leads to the formation of tripiperi-
dine alkaloids (Fig. 1, iii). Finally, intermediate 5 can react
with a molecule of tryptamine via a Pictet–Spengler reaction
to afford indole alkaloids such as nitrarine (Fig. 1, iv).
a series of virtually equilibrated reactions essentially con-
sisting of imine/enamine tautomerism, Michael/retro-
Michael, Mannich/retro-Mannich reactions, and hydrations/
dehydrations. In the last step, following a ring inversion,
a nucleophilic attack of the hydroxyl group, and a last aza-
Mannich reaction onto the remaining iminium system af-
forded 1. In this context, the formation of 1-epinitraramine,
which was assigned the structure 2,6 in conjunction with 1,
has been explained by a likely attack on the Si-face or the
Re-face of the iminium, during the aminal formation to
produce 1 and 2, respectively (Scheme 2).
In this paper we discuss a full account of the assembly of 1
from simple precursors7 as well as the absence of formation
of 2, which states the high stereoselectivity of the reaction
cascade. Other molecules formed during the ‘dynamic com-
binatorial process’ have also been characterized and are
presented herein.
One of the products derived from 5 is nitraramine 1,4 a small
but complex intricate structure, isolated from Nitraria scho-
beri.5 From 5, the formation of 1 can be explained through
2. Chemistry
2.1. Biomimetic total synthesis of nitraramine 1
H
N
3
H
N
H
In connection with their biosynthetic hypothesis, Koomen
and Wanner targeted the plausible achiral intermediate 7
by a stepwise approach in their pioneering beautiful synthe-
sis of 1 (7 steps,w0.5% yield).5 On the basis of the proposed
biosynthetic pathway and considering the different possibil-
ities for the formation of intermediate 5 discussed above, we
reasoned that it should be possible to access directly the
nitraramine 1 from much simpler precursors than the ones
chosen by Koomen and Wanner (Scheme 3). A reaction be-
tween 2 equiv of 2-piperideine 3 and 1 equiv of glutaralde-
hyde 6 should logically lead to the assembly of 1, as no
oxidation or reduction step is required for starting the reac-
tion from these precursors.
N
N
N
N
3
HO
a
- H2O
N
b
b
O
achiral precursor 7
5
a
H
N
N
N
spiro-
cyclization
spiro-
cyclization
N
O
OH
OH
NH
N
N
ring inversion
OH
H
12
17
H
N
N
N
15 N
H
H
3
N
O
O
H
+
O
1
N
H
EtOH, reflux, 3 h (2–3%)
Water, reflux, 3 h (0.5–1%)
6
H
7
N
N
Si face
Re face
3
N
O
O
1-Epinitraramine 2
Nitraramine 1
Nitraramine 1
6
Scheme 3. Biomimetic synthesis of 1.
O
N
O
N
N
H
From this observation, we decided to develop a one-step syn-
thesis of this particular original molecule, by reacting com-
mercial glutaraldehyde with 2 equiv of 2-piperideine formed
N
H
Scheme 2. Proposed biogenetic pathway to nitraramine 1.

5250
E. Gravel et al. / Tetrahedron 62 (2006) 5248–5253
in situ from its crystalline trimeric form, which was simply
obtained from piperidine8 treated with N-chloro-succini-
mide and sodium methanoate.
Thus, we were able to characterize two molecules formed in
significant proportions during the reaction process: stable
trimer 8 (15–20%) and the much more complex and original
molecule 9 (8–10%).
To carry out the reaction in a polar solvent that could be eas-
ily removed under reduced pressure, we figured that ethanol
was the most convenient solvent. The mixture was stirred
under reflux to allow a better dissociation of the trimer into
2-piperideine 3 but also to provide the energy required for
the ring inversion step of the biomimetic cascade sequence.
After 3 h of reaction, the crude reaction mixture showed
a complex TLC profile.
Trimer 8 is a known product that we expected in the reaction
mixture and it was easily identified by comparison of the ob-
tained spectral data with that of prior literature data (1H NMR
and 13C NMR spectra).8 The formation of this compound can
be easily explained by the reaction of one 2-piperideine 3 unit
on a molecule of tetrahydroanabasine 4 (which is itself ob-
tained from two 2-piperideine units), as shown in Scheme 4.
By mixing the reactive precursors without any control on the
reaction outcome to select specific associations, we knew
that we would obtain many different products amongst
which we would have to identify and isolate the desired alka-
loid. To guide our search for nitraramine within the mixture,
we had limited but relatively precise information at our dis-
H
N
N
N
N
H
N
N
N
3
4
unstable trimer
1
posal consisting mainly in 13C and H NMR data. Despite
certain differences, all 1H NMR spectra displayed a singlet
at 3.5 ppm, attributed to the aminal H-1, which permitted
the identification of the product and enabled the exact loca-
tion of 1 to be determined on TLC (CH2Cl2/MeOH 9:1,
Rf ¼0.35).
H
HN
N
N
N
N
N
stable trimer 8
Scheme 4. Proposed formation path for trimer 8.
Relying on what had been previously published in litera-
ture,5 we at first opted for purification on silica gel column
eluted with methylene chloride/methanol 95:5. Even though
silica gel made it possible to refine the crude mixture by pro-
viding, after several columns, fractions enriched with nitrar-
amine 1, it appeared virtually impossible to obtain the latter
totally free of impurities. We therefore decided to change the
solid phase to basic alumina and to use an elution gradient.
After different tries, optimal conditions were defined and it
turned out that pure nitraramine 1 could be obtained by
two consecutive basic alumina columns eluted with a gradi-
ent of methylene chloride/methanol from 99:1 to 96:4. This
method provided pure 1 as colorless crystals in 2–3% yield.
Moreover, it was observed that when a solution of trimeric 3
in ether was left at room temperature, the rearrangement
took place, resulting in the formation of 8, and that within
48 h all the material was converted.
For the structural determination of compound 9 the process
was more complicated, especially because of numerous H
1
NMR signals, which were overlapping one another in the
CH2 region (1–2 ppm), making exploitation of the informa-
tion impossible.
The product was slightly less polar than compound 8 and its
IR spectrum showed the absence of N–H bonds. Mass spec-
troscopy (ESI-MS) gave a quasi-molecular ion peak [M+H]+
at m/z 248 and a unique fragment ion peak at m/z 165.
At first sight this yield may seem rather deceiving but one
needs to consider that it is the global yield of a total synthesis
in the course of which five new bonds (including three
carbon–carbon bonds) and six chiral centers (including
one spiro-carbon) were formed in a single vessel. Starting
material is inexpensive and experimental procedure is very
simple, permitting the whole synthesis to be carried out in
less than a day.
The 13C NMR spectrum showed the presence of five CH and
10 CH2 that constituted a mass of 205 to which three nitrogen
atoms had to be added to get the right molecular weight and
give the molecular formula C15H25N3, requiring five degrees
of unsaturation. Given the absence of ethylenic signals, it
was obvious that these came from the presence of cycles.
In ideal biomimetic conditions the reaction should be con-
ductible in water; the same condensation protocol was there-
fore tried in boiling water (citrate buffer 4%) and the resulting
TLC profile of the crude reaction mixture was similar to the
one obtained in ethanol. After purification, pure nitraramine
1 was obtained but in lower yield (0.5–1%), probably due to
an important loss of material in water during workup.
The analysis of the COSY spectrum turned out not to be as
informative as it should have been. Most signals were over-
lapping one another between 1 and 2 ppm and it was impos-
sible to determine any sequence between CH2. Nevertheless,
it was possible to identify the most substituents of tertiary
carbons, thanks to the correlation signals on the HSQC spec-
trum, and three segments were determined. Considering the
number of nitrogen atoms and the different couplings ob-
2.2. Other molecules formed during the process
1
served on the H NMR spectra, we were able to assemble
these fragments in a bicyclic system, as shown in Figure 2.
Given the yield of just a few percents, one can rightfully
wonder how all the residual material has reacted. Even
though it was not our priority to do so, we decided to investi-
gate the reaction products other than the expected alkaloid 1.
Relative configuration of carbons 20 and 300 was given by the
coupling constant that existed between the 1H NMR signals

E. Gravel et al. / Tetrahedron 62 (2006) 5248–5253
5251
10 which is rearranged by a hydride transfer to yield mole-
cule 11.9 The attack of the imine by the free secondary amine
followed by the reduction of the iminium completes the
synthesis of compound 9.
4''
3'
2'
4''
N
N
2
2''
N
N
2' N
3'
6'
3
3''
6'
5'
3''
=
+
+
2
N
5'
3
N
N
N
2''
N
Figure 2. Construction of the central bicyclic system of molecule 9.
4
N
H
H
H
N
N
H
N
NH
N
N
N
4
10
H
N
N
N
N
9
N
HN
N
H
11
Scheme 6. Possible formation mechanism proposed for molecule 9.
Our structural hypothesis is strengthened by the fact that the
molecule could result from the association of two units of
tetrahydroanabasine 4, which also contributes to the forma-
tion of compound 8 found in large quantity in the mixture.
This observation led us to think that the low yield for the for-
mation of 1 was probably widely due to the formation of
a large amount of 4.
Figure 3. Selected NOESY correlations for molecule 9.
(J¼11.5 Hz) and the difference between carbons 2 and 60
was made by an analysis of the NOESY spectrum (see
Fig. 3). The central bicyclic structure was confirmed by
the HMBC correlations (the most significant ones are shown
on Fig. 4).
2.3. Revision of the previously reported 1-epinitrar-
amine 2
5
6
It appeared clearly, when comparing compiled NMR data,10
that relatively important variations existed in chemical shifts
observed for the same product. We simply could not find two
totally superimposable spectra. Various hypotheses were
considered to explain the phenomena until the NMR analysis
of a diluted solution of nitraramine 1 gave us a spectrum
equivalent to the one attributed by Quirion and colleagues
to 1-epinitraramine 2, in their 1995 article.6
4
3
2''
3''
N
N
4''
6''
5''
2
N
N
N
2'
3'
N
6'
4'
5'
9
1H
13C
Figure 4. Selected HMBC correlations for molecule 9.
At that point, there were still six residual CH2 to assign in
order to complete the last three cycles of the structure. Keep-
ing in mind the reagents and preferring six-membered rings,
we realized that only one structure could be considered.
Configurations of the peripheral cycles were determined
After a closer study of the spectra obtained during our ex-
periments, we realized that a relation existed between the
concentration of 1 and the corresponding NMR signals (re-
garding chemical shifts as well as signal shape/multiplicity).
We therefore decided to carry out an NMR study on samples
of different nitraramine concentrations. The results clearly
demonstrated that the compound previously described as 1-
epinitraramine 2 was in fact diluted nitraramine 1 in CDCl3
(Fig. 5 shows the most significantly variable area of the spec-
trum, under different concentration conditions). As a matter
of fact, the observed spectrum for a solution of about
6 mg mLꢀ1 is equivalent to the one attributed to 1-epinitrar-
amine,6 and the spectrum observed for about 24 mg mLꢀ1
equivalent to the one attributed to nitraramine by Quirion
and colleagues.6
1
on the basis of the observation of the H NMR signals
(i.e., multiplicities and coupling constants).
Moreover, the obtained structure could explain the observed
fragment ion peak at m/z 165 on the ESI-MS mass spectrum,
through a mechanism shown in Scheme 5.
H
N
N
NH
+
N
N
N
The phenomena still needed an explanation and we came to
think that it could come from the influence of acid traces,
found in CDCl3, on the protonation state of the molecule
(the most variable signals were the ones attributed to protons
that are close to nitrogen atoms). To confirm the hypothesis
we decided to collect the contents of all NMR tubes that gave
‘epinitraramine-like’ spectra and made a single batch that
m/z 248
Scheme 5. Proposed fragmentation mechanism.
m/z 165
A plausible hypothesis for the formation of compound 9
from piperideine-derived units is shown in Scheme 6. Two
tetrahydroanabasine units react to give rise to compound

5252
E. Gravel et al. / Tetrahedron 62 (2006) 5248–5253
only in restricted areas) and with the previous total synthesis.
H-1
Enough material has been prepared for needed biological
screening of this intriguing complex small molecule. Fur-
thermore, total synthesis unexpectedly led to a structural re-
assignment of 1-epinitraramine 2.11 Finally, the chemistry of
simple C5 lysine-type molecules12 presented in this paper of-
fers further opportunities toward biomimetic synthesis13 and
molecular self-assembly of complex natural product-like
skeletons,14 as illustrated by the formation of compound 9.
H-3ax
H-15eq
H-15ax
H-3eq
24 mg.mL−1
12 mg.mL−1
8 mg.mL−1
6 mg.mL−1
4 mg.mL−1
4. Experimental
3 mg.mL−1
2 mg.mL−1
4.1. Synthesis of 3 from piperidine
5
4
6
3''
ppm (t1)
3.50
3.00
2
N 2''
N
3
4''
5''
N
N
2'
Figure 5. Concentration influence on chemical shifts of 1 (400 MHz,
25 ꢁC).
6'
6''
3
3
5'
3'
4'
we treated with K2CO3. The dried product was then dis-
solved in CDCl3 (that had previously been filtered on basic
alumina to remove traces of acid), and an NMR analysis
was performed. The obtained spectrum was the one corre-
sponding to what had been reported by Koomen and Wanner
as 1. The product was then sequentially diluted with CDCl3
(previously filtered on basic alumina) until no product could
be detected by NMR analysis and all observable spectra
were identical to the one obtained with concentrated nitrar-
amine.
In a round bottom flask (1 L), N-chloro-succinimide (65 g,
0.5 mol) was stirred in ether (450 mL) and the suspension
was cooled to 4 C in an ice bath. Piperidine (40 mL,
ꢁ
0.47 mol) was then slowly added. After 2 h under agitation
at room temperature, the mixture was filtered and the filtrate
was washed with water (2ꢂ250 mL), and then dried. After
filtration, three-third of the solvent was removed under re-
duced pressure and sodium methanoate (267 mL of a 2 N so-
lution in methanol) was added carefully. The mixture was
stirred under reflux for 45 min after which water was added
until total dissolution of the formed salt (NaCl). An extrac-
tion with ether was performed and the organic phase was
dried. Afterꢁsolvent evaporation, a thick yellow oil (crystal-
lizing at 4 C) was obtained (27 g, 70%). Compound 3:
yellow crystals; 13C NMR (100 MHz, CDCl3): d 82.1 (C-
Each spectrum on Figure 5 probably reflects a different de-
gree of protonation, showing different average of the two
chemical forms. In fact, according to the 1H NMR chemical
shift time scale, protonated/deprotonated states are consid-
ered in fast exchange giving rise to a weighted averaged
spectrum of extreme values (i.e., d (protonated) and d (free
base)).
1
2), 46.5 (C-6), 29.5 (C-3), 26.3 (C-5), 22.8 ppm (C-4); H
NMR (400 MHz, CDCl3): d 2.86 (3H, m, H-2), 2.55 (3H,
m), 1.65–1.95 (6H, m), 1.25–1.62 (12H, m), 1.18 ppm (3H,
m); Mass (ESI-MS) [M+H]+ 250.
For these reasons, 1-epinitraramine 2, which was only char-
acterized upon NMR analysis by Quirion and colleagues, is
likely to be an experimental artefact. The existence of 1-epi-
nitraramine cannot be totally excluded but if it does exist, it’s
rather surprising that it has never been encountered in plants
containing nitraramine. In terms of chemical assembly, the
cascade involved in the formation of 1 appears therefore to
be highly stereoselective.
4.2. Synthesis of 1 from 3
13
12
11
14
17
15 N
10O 9
H
H
1
6
7
N
8
5
3
4
3. Conclusion
2-Piperideine 3 (in its trimeric form, 5 g, 0.06 mol) was dis-
solved in ethanol (500 mL). Immediately after dissolution,
glutaraldehyde (0.5 equiv, 0.03 mol, 12 mL of 25% aqueous
solution) was added. The mixture was stirred under reflux for
3 h and then concentrated under reduced pressure. Purifica-
tion of the crude mixture was performed on two consecutive
alumina columns (CH2Cl2/MeOH 99:1, 98:2, 97:3, and fi-
nally 96:4) and monitored by TLC on silica gel (CH2Cl2/
MeOH 9:1) to furnish pure nitraramine 1 (165–225 mg, 2–
3%). Compound 1: colorless crystals; Rf¼0.35 (silica gel,
CH2Cl2/MeOH 9:1); IR (film, CHCl3): nmax¼2928, 1635,
The low yield of 1 reflects the multiple biomimetic coupling
possibilities of lysine-derived precursors 3 and 6 but states
for the incontestable spontaneous formation of 1 from funda-
mental C5 units presumably derived from lysine. Bearing in
mind that the poor yield of our synthesis is a significant
drawback, one can add that the easiness and reliability of
the reaction conditions from costless reagents permit the
preparation of pure 1 in a few hour time scale. Therefore,
the described total synthesis of 1 competes largely with
scarce extraction from natural sources (which are present
1066 cmꢀ1 13C NMR (100 MHz, CDCl3 filtered through
;

E. Gravel et al. / Tetrahedron 62 (2006) 5248–5253
5253
activated alumina) d 82.2 (C-17), 75.9 (C-1), 66.5 (C-7), 50.5
(C-15), 45.1 (C-3), 38.8 (C-11), 38.0 (C-12), 32.4 (C-6), 30.4
(C-5), 28.4 (C-8), 25.2 (C-13), 24.1 (C-10), 21.6
(ES) calculated for C15H25N3H+ [M+H]+ 248.2082, found
[M+H]+ 248.2085.
1
(C-4), 15.3 (C-9), 14.6 ppm (C-14); H NMR (400 MHz,
References and notes
CDCl3 filtered through activated alumina) d 4.43 (1H, m,
H-7), 4.06 (1H, d, J¼2 Hz, H-17), 3.36 (1H, s, H-1), 3.10
(2H, m, H-3eq, H-15eq), 2.68 (2H, m, H-15ax, H-3ax), 2.17–
2.13 (1H, m, Jgem¼13.7 Hz, H-5eq), 2.00 (1H, m, H-12),
1.87–1.38 (10H, m), 1.26–1.22 (1H, m, H-10ax), 1.16 (1H,
m, H-11), 1.09–1.00 ppm (2H, m, H-14ax, H-5ax); HRMS
(ES) calculated for C15H24N2OH+ [M+H]+: 249.1967,
found: 249.1969.
1. Wanner, M. J.; Koomen, G.-J. Studies in Natural Products
Chemistry: Stereoselectivity in Synthesis and Biosynthesis of
Lupine and Nitraria Alkaloids; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, USA, 1994; Vol. 14, pp 731–768 and references
cited therein.
2. Wanner, M. J.; Koomen, G.-J. Pure Appl. Chem. 1996, 68,
2051–2056.
3. Franc¸ois, D.; Lallemand, M.-C.; Selkti, M.; Tomas, A.;
Kunesch, N.; Husson, H.-P. Angew. Chem., Int. Ed. 1998, 37,
104–105; Angew. Chem. 1998, 110, 112–114.
4. Tashkodzhaev, B.; Ibragimov, A. A.; Yunusov, S. Y. Khim. Prir.
Soedin. 1985, 692–698; Chem. Nat. Compd. (Engl. Transl.)
1985, 649–655.
4.3. Trimer 8
5
4
6
H
HN
2
N 2'' N
3''
6''
5''
3
N
N
N
6'
5. Wanner, M. J.; Koomen, G.-J. J. Org. Chem. 1995, 60, 5634–
5637.
2'
4''
8
5'
3'
4'
6. Epinitraramine was characterized from Nitraria billardieri, see
Shen, M. Y.; Zuanazzi, J. A.; Kan, C.; Quirion, J.-C.; Husson,
H.-P.; Bick, I. R. C. Nat. Prod. Lett. 1995, 6, 119–125.
7. Gravel, E.; Poupon, E.; Hocquemiller, R. Org. Lett. 2005, 7,
2497–2499.
Compound 8: C15H27N3; waxy yellow solid; Rf¼0.70 (silica
gel, CH2Cl2/MeOH 90:10); IR (film, CHCl3) nmax¼3300,
2935, 1651, 1442 cmꢀ1 13C NMR (100 MHz, CDCl3):
;
d 83.7 (C-2), 81.7 (C-200), 63.9 (C-20), 48.2 (C-6), 47.7 (C-
60), 45.4 (C-600), 43.3 (C-300), 29.4 (C-30), 28.3 (C-3), 27.3
(C-5), 26.1 (C-50), 25.8 (C-500), 25.0 (C-40), 23.1 (C-400),
8. Kessler, H.; Mohrle, H.; Zimmermann, G. J. Org. Chem. 1977,
42, 66–70.
¨
9. Hydride transfers are not uncommon in biomimetic chemistry,
and especially not in imine/enamine chemistry. Examples can
be found in the following articles: (a) Cohen, T.; Onopchenko,
A. J. Org. Chem. 1983, 48, 4531–4537; (b) Heathcock, C. H.
Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 14323–14327; (c)
Jacubowicz, K.; Ben Abdeljelil, K.; Herdemann, M.; Martin,
M.-T.; Gateau-Olesker, A.; Al Mourabit, A.; Marazano, C.;
Das, B. C. J. Org. Chem. 1999, 64, 7381–7387; (d) Jakubowicz,
1
22.9 ppm (C-4); H NMR (400 MHz, CDCl3): d 3.56 (1H,
m, H-6eq), 2.95 (2H, m, H-60eq, H-600eq), 2.42 (3H, m,
H-2, H-20, H-600ax), 1.05–1.72 (19H, m), 0.78 ppm (1H, qd,
Jax–ax¼12.5 Hz, Jax–eq¼5 Hz, H-500ax); Mass (ESI-MS)
[M+H]+ 250.
4.4. Compound 9
´ ´
K.; Wong, Y.-S.; Chiaroni, A.; Benechie, M.; Marazano, C.
J. Org. Chem. 2005, 70, 7780–7783.
5
4
3
6
10. NMR data from Refs. 5 and 6. We thank Professor Dr. Henri-
Philippe Husson for providing us with NMR spectra of 1 and 2.
11. For a recent review article concerning misassigned natural
products, see: Nicolaou, K. C.; Snyder, S. A. Angew. Chem.,
Int. Ed. 2005, 44, 1012–1044.
2''
3''
N
N
6''
5''
2
N
6'
N
N
2'
3'
4''
N
5'
9
4'
12. For recent examples of cascade and multicomponent reactions
involving successive condensations of simple building blocks
to assemble complex structures, see inter alia: (a) Hourcade,
S.; Ferdenzi, A.; Retailleau, P.; Mons, S.; Marazano, C. Eur.
J. Org. Chem. 2005, 1302–1310 and references cited therein;
(b) Amorde, S. M.; Judd, A. S.; Martin, S. F. Org. Lett. 2005,
7, 2031–2033.
13. For a recent review concerning biomimetic synthesis, see inter
alia: de la Torre, M. C.; Sierra, M. A. Angew. Chem., Int. Ed.
2004, 43, 160–181; For a review on biomimetic synthesis of
alkaloids, see, inter alia: Scholz, U.; Winterfeldt, E. Nat.
Prod. Rep. 2000, 17, 349–366.
Compound 9: C15H25N3; yellow wax; Rf¼0.75 (silica gel,
CH2Cl2/MeOH 90:10); IR (film, CHCl3) nmax¼3020,
1215 cmꢀ1 13C NMR (100 MHz, CDCl3): d 83.8 (C-200),
;
83.5 (C-60), 61.5 (C-2), 57.4 (C-20), 56.2 (C-6), 50.2 (C-3),
46.7 (C-600), 35.4 (C-300), 33.0, 31.0, 27.4, 26.4, 25.3, 24.7,
1
20.8 ppm; H NMR (400 MHz, CDCl3): d 3.78 (1H, t/dd,
J¼10 Hz, H-2), 3.69 (1H, sd, J¼2 Hz, H-200), 3.54 (1H,
t, J¼8 Hz, H-6eq), 3.53 (1H, s large, H-60), 3.34 (1H, dd,
J¼14, 6 Hz, H-600eq), 3.10 (1H, td, J¼14, 6 Hz, H-600ax),
2.71 (1H, m, H-6ax), 2.63 (1H, ddd, J¼11, 5 Hz, H-20),
2.51 (1H, ddd, J¼11 Hz, H-3eq), 2.44 (1H, m), 2.05 (1H,
td, J¼11, 2 Hz, H-3ax), 1.68–1.98 (5H, m), 1.60 (1+1H,
ddd, J¼11, 5 Hz, H-300), 1.09–1.55 ppm (7H, m); HRMS
14. For comments on molecular self-construction, see: Sorensen,
E. J. Bioorg. Med. Chem. 2003, 11, 3225–3228.