An enantioselective approach to synthesis of advanced chiral templates for the construction of indolic and indolizidinic alkaloids

Article abstract of DOI:10.3987/COM-09-11690

A new approach for the syntheses of chiral indolic and indolizidinic templates is presented. They were obtained in three steps starting from a chiral primary amino-vinylsilane. The key step was the N-acyliminium π-cyclization, leading diastereoselectively

Full text of DOI:10.3987/COM-09-11690

HETEROCYCLES, Vol. 78, No. 9, 2009
2193
HETEROCYCLES, Vol. 78, No. 9, 2009, pp. 2193 - 2199. © The Japan Institute of Heterocyclic Chemistry
Received, 26th February, 2009, Accepted, 14th May, 2009, Published online, 14th May, 2009.
DOI: 10.3987/COM-09-11690
AN ENANTIOSELECTIVE APPROACH TO SYNTHESIS OF
ADVANCED CHIRAL TEMPLATES FOR THE CONSTRUCTION OF
INDOLIC AND INDOLIZIDINIC ALKALOIDS
Radouane Affani,a Sébastien Comesse,a Adam Daïch,a Louis Hamon,b and
Catherine Kadouri-Puchotb
a
URCOM, EA 3221, CNRS-INC3M FR3038, UFR-ST, University of Le Havre,
BP 540, 25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
b University of Pierre & Marie Curie-Paris VI, Laboratory of Organic Chemistry,
IPCM-UMR7201, 4 place Jussieu, case courrier 47, F-75005 Paris, France
E.mail: adam.daich@univ-lehavre.fr; and/or cathy.kadouri-puchot@upmc.fr
Abstract – A new approach for the syntheses of chiral indolic and indolizidinic
templates is presented. They were obtained in three steps starting from a chiral
primary amino-vinylsilane. The key step was the N-acyliminium -cyclization,
leading diastereoselectively to the formation of the six membered ring templates.
Indolizidines or their unsaturated analogues are among of the most important structural motifs found
abundantly in nature. Their sources are extremely divers varying from marine and terrestrial materials to
organisms, such as plants, bacteria, fungi, vertebrates and invertebrates.1 For example, alkaloids 1,2
(Scheme 1) are well-known for their ability to function as excellent inhibitors of biologically important
pathways. These include the binding and processing of glycoproteins, potent glycosidase inhibitory
activities,2 activity against AIDS virus HIV and some carcinogenic cells as well as against other
important pathologies.3 In addition, gephyrotoxins such as 3a-d show significant biological activities as
exemplified by the ability of many of them to act as non-competitive blockers of neuromuscular
transmission by interacting with nAChRS (nicotinic acetylcholine receptors) of the CNS.4
Scheme 1. Representative Natural products containing indolizidine unit.
H
OH
OH
HO
HO
H
H
N
R1 = n-Pr, R2 = H : (3a) indolizidine 167B
R1 = H, R2 = CH2OH : (3b) tashiromine
R1 = CO2Et, R2 = n-Bu : (3c) mymicarin 237A
R1 = n-Pr, R2 = n-Bu : (3d) gephyrotoxin 223AB
OH
OH
HO
N
N
R2
R1
2: swainsonine
1: castanospermine
3

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Although a vast amount of work towards these bicyclic alkaloids in both chiral and racemic syntheses has
been appeared in the literature, the challenges of a plethora of the innovative strategies developed and
used for this purpose rest the introduction of chirality and several functional groups to the indolizidine
scaffold. The latter fact is often problematic and consequently leads to the use of multistep sequences.
In light of the limitations encountered during these investigations and taking into account the interesting
biological profiles and potential of these structures as valuable candidates for new therapeutic agents, the
demand for direct and straightforward methods has become increasingly clear. In this context, the design
of simple aza-bicyclic templates capable of driving by simple additional manipulations to structural
diversity and complexity including subgroups of these alkaloids is of high interest in organic synthesis.5
Scheme 2. Retrosynthetic pathway leading to the advanced chiral indolizidine templates 4A,B.
oxidation
TMS
TMS
OR2
Michael addition
bis-hydroxylation
oxidation
H
H
8
oxidation
reduction
1
7
reduction
8a
bis-hydroxylation
2
N
6
N
N
H2N
4
5
3
alkylation via C=S
alkyl
aryl
arylalkyl
R1
4A,B
O
R1
reduction
R1
O
O
R1
4A,B
5
6
Our objective herein was directed towards the enantioselective synthesis of the aza-bicyclic systems 4A,B
(Scheme 2). The latter, equipped with appropriates functionalities, could tolerate numerous and known
synthetic manipulations6 to provide a large number of polyhydroxylated indoizidine alkaloids,
gephyrotoxins and corresponding benzoindolizidines with different degrees of unsaturations.
Accordingly, the N-acyliminium ions chemistry using enantiopure amino-vinylsilane7 and imide as
starting materials would appear to provide an ideal solution of this dilemma. Retrosynthetically, we
envisioned that we could establish the R/S stereochemistry at C8a-position selectively through -cationic
cyclization of precursor 5, which can be prepared easily in a two step-sequence from amine 6 (Scheme 2).
We focused in the first place our study on the synthesis of the phtalimide derivative 4A (Schemes 2, 3).
Indeed, we anticipated that our approach would be less problematic using an aromatic ring in place of the
double bond on the five membered ring system (phtalimide compared to maleimide). The primary amine
6 was converted in two steps, condensation with phtalic anhydride followed by the reduction of the
resulting imide with LiEt3BH, to the hydroxylactam 5Aa in 74% overall yield. This one was isolated in a
one to one ratio of the two diastereoisomers, implying no stereocontrol from the stereocenter presents on
the side chain. The cyclization was first performed in the presence of two equivalents of BF3.OEt2 as
Lewis acid and led to the tricyclic system 4A in 70% yield. Recently, an efficient method using bismuth
(III) triflate as a Lewis acid catalyst was reported by some of us to generate the formation of
N-acyliminium species.8 In order to use easier and cleaner conditions, we applied this new experimental
procedure to the acetoxylactam 5Ab obtained from the corresponding imide by a simple one-pot

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2195
reduction/acetylation methodology in 67% yield.9 As a matter of fact, when we performed this catalytic
acid-mediated -cationic cyclization with Bi(OTf)3 (1 mol%), we were pleased to isolate compound 4A in
similar yield than with BF3.OEt2 (69% instead of 70%).10 This result shows that the use of 1 mol% of
Bi(OTf)3 is as efficient as the use of a stoechiometric amount of BF3.OEt2 (200 mol%). In addition the
catalytic sequence can be applied with success to cyclizations involving vinylsilane moiety providing
6-membered ring possessing an unsaturation. In both cases, only one diastereoisomer was formed during
the cyclization process thanks to the phenyl substituent presents on the side chain.11 A syn relationship
between the angular H of the newly formed stereogenic center and the phenyl substituent was firstly
deduced from previously published works.12,13
Scheme 3. Synthesis of the benzoindolizidine template 4A and its reduction and epimerization reactions.
H
OR
N
NH2
i,ii or iii
Ph
vi
N
N
TMS
Ph
Ph
Ph
O
O
TMS
O
7
vii
4A
vii
5Aa: R = H (with ii)
5Ab: R = Ac (with iii)
6
iv or v
H
H
H
N
N
N
Ph
Ph
Ph
O
O
O
4A
8
9
Key: (i) phtalic anhydride (1 equiv), Et3N (cat.), toluene, Dean-Stark apparatus, 24 h, 92%; (ii) LiEt3BH (1.4 equiv), CH2Cl2, -
78 °C, 10 min, 80%; (iii) LiEt3BH (1.4 equiv), CH2Cl2, - 78 °C, 10 min, then Ac2O (1.4 equiv), - 78 °C, 2 h, 67%; (iv)
BF3.OEt2 (2 equiv), CH2Cl2, rt, 8 h, 70%; (v) Bi(OTf)3 (0.01 equiv), CH3CN, rt, 8 h, 69%; (vi) MeONa (1.2 equiv), MeOH, 30
min, 84%; (vii) Pd on carbon (0.1 equiv), H2 (1 atm), EtOH, rt, 24 h, 63% for 8 and 69% for 9.
With the aim to confirm the stereochemistry of the newly created stereocenter and to study the possibility
of epimerization of this one in order to reach the trans relationship presents in gephyrotoxins (Scheme 1,
3a,c,d) we investigated the migration of the double bond and its reduction. Treated in basic conditions
(MeONa in MeOH), compound 4A gave the conjugate more stable isomer 7 in 84% yield. The
hydrogenation process was applied on both 4A and 7 and provided the reduced products 8 and 9 in 63%
and 69%, respectively, as two diastereoisomers, epimers at the carbon of the ring junction (Scheme 3).
The total diastereoselectivity observed during the reduction of 7 can be explained by the steric hindrance
of the phenyl substituent, involving the approach by the hydrogen on the more reachable face and
implying the formation of the trans diastereomer. Thus, we obtained the same relative stereochemistry
than the one in gephyrotoxins and that result confirmed, by comparison, the cis relationship in product 8.
Encouraged by these results, we turned our attention to the maleimide derivative in view to synthesis our
main target, the bicyclic system 4B (Scheme 4). So, condensation of amine 6 onto maleic anhydride led to
the imide 5Ba in 88% yield. The selective 1,2 reduction of the C=O bond versus the 1,4 was found to be
troublesome, only the treatment by the couple NaBH4/CeCl3 in methanol produced the desired

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hydroxylactam 5Bb in 86% yield. When reacted with two equivalents of BF3.OEt2, 5Bb led to the
formation of the expected bicyclic compound 4B but with a low yield of 25% partially explained by the
presence of the allylsilane derivative 10 in 8% yield and other non-characterized side products. The diene
4B was obtained as a single diastereoisomer11 and despite the low yield this result legitimates our strategy.
For its part, the compound 10 was a result and an evidence of the aza-Cope transposition between the
N-acyliminium ions I and J, this last one giving after hydrolysis the debenzylated molecule 10.
Scheme 4. Synthesis of the indolizidine template 4B.
H
TMS
Ph
NH2
TMS
Ph
X
TMS
iii
TMS
H
H
H
i
-cyclization
aza-Cope
N
+
+
N
N
N
NH
O
ii
hydrolysis
O
O
O
O
Ph
TMS
Ph
Ph
5Ba: X = O
5Bb: X = H, OH
and/or
I
J
4B
10
6
Key: (i) maleic anhydride (1 equiv), Et3N (cat.), toluene, Dean-Stark apparatus, 48 h, 88%; (ii) NaBH4 (1 equiv), CeCl3 (1
equiv), MeOH, rt, 8 h, 86%; (iii) BF3.OEt2 (2 equiv), CH2Cl2, rt, 3 h, 25% for 4B and 8% for 10.
A dramatic change in the course of the -cyclizations between 5Aa,b and 5Bb was observed, the first
giving good yields and the second providing poor yields and side reactions. This significant difference is
the direct consequence of the presence or not of an aromatic ring on the pyrrolidine one. In order to get an
idea about these results, we calculated14 the transition state energies between the six possible cationic
species I-N in accordance with the results published earlier on iminium series (Scheme 5).17 The cation
products N or J would be obtained from L or I by the way of M or K common intermediates for both the
aza-Cope process but also the formation of the cyclic systems 4A,B. The passage from M to N is higher
in energy than the one from M to L (1.83 Kcal.mol-1) while the energies between K and J is lower than
the one between K and I (-11.39 Kcal.mol-1). This huge difference in energy could explain the dramatic
change in reactivity. As a consequence, the phtalimidic derivative leading cleanly to the desired tricyclic
product 4A and the maleimidic derivative giving way to the competitive aza-Cope reaction.
Scheme 5. Transition state energies between cationic species I,J,K and L,M,N in Kcal.mol-1.
TMS
H
TMS
H
TMS
+
Ph
+
N
N
N
+
209.59
207.76
Ph
Ph
O
TMS
H
O
O
L
M
N
TMS
TMS
H
+
Ph
N
N
+
N
+
193.90
205.29
Ph
Ph
O
O
O
I
J
K
In conclusion, we have demonstrated that chiral amino-vinylsilane is suitable for the synthesis of
aza-bicyclic templates. The efficiency of the N-acyliminium ions chemistry for the α-amidocyclization

HETEROCYCLES, Vol. 78, No. 9, 2009
2197
was shown to be substrate dependant, giving or not an aza-Cope rearrangement. The templates 4A,B
obtained in three steps from the primary amines should be convenient intermediates for the access to both
polyhydroxylated indolizidines and gephyrotoxins. Works are currently underway in our group in order to
avoid the aza-Cope competitive reaction and to apply this methodology to the synthesis of alkaloids.
ACKNOWLEDGEMENTS
The authors thank the University of Le Havre, France, for the financial support for this research program.
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temperature to a solution of hydroxy lactam 5Aa or 5Ba (0.5 mmol) in CH2Cl2 (5 mL). After one
night of stirring, the reaction was cooled to 0 °C and carefully quenched by addition of a saturated
aqueous solution of NaHCO3 (5 mL). The aqueous layer was extracted with CH2Cl2 (3×5 mL), the
organic layers were combined, dried over MgSO4 and evaporated. The residue was then purified by
chromatography on SiO2 column using AcOEt/cyclohexane as eluenting mixture and provided cycles
4A and 4B in 70% and 25% yields, respectively, for two steps. Protocol (b): Bi(OTf)3 (0.01 equiv)
was added in one portion to a stirred solution of acetoxy lactam 5Ab (197 mg, 0.5 mmol) in MeCN
(2.5 mL). When the reaction was over (monitored by TLC) a saturated aqueous solution with
NaHCO3 was added. The aqueous layer was then extracted with CH2Cl2 (3×5 mL), the organic layers
were combined, dried over MgSO4 and evaporated under vacuo. The residue was than purified by
chromatography on SiO2 column using same eluent as outlined above to provide in 69% yield
compound 4A. This product was isolated as a colorless gummy. (AcOEt/cyclohexane, 30:70). [α]20
D
-88 (c 0.5, CHCl3). 1H NMR (200 MHz, CDCl3): 7.86 (d, J=7.8Hz, 1H), 7.52-7.24 (m, 8H), 5.98 (s,
13
2H), 5.87 (t, J=3.9Hz, 1H), 4.70-4.63 (m, 1H), 2.72 (bs, 2H). C NMR (50 MHz, CDCl3): 167.2,
144.0, 140.0, 132.0, 131.7, 128.7, 128.3, 127.5, 127.3, 125.6, 125.2, 124.0, 122.1, 54.7, 48.6, 27.6.
Data for 4B. This product was isolated as a colorless gummy from hydroxy lactam 5Ba by using
1
Protocol (a). (AcOEt/cyclohexane, 30:70). H NMR (200 MHz, CDCl3): 7.40-7.26 (m, 5H), 7.04
(dd, J=5.4 and 2.3Hz, 1H), 6.17 (dd, J=5.4 and 2.3Hz, 1H), 5.99 (dq, J=10.1 and 2.3Hz, 1H), 5.94
(dd, J=10.2 and 2.3Hz, 1H), 5.68 (t, J=4.8Hz, 1H), 4.42-4.42 (m, 1H), 2.70-2.61 (m, 2H). 13C NMR
(50 MHz, CDCl3): 167.3, 147.3, 140.8, 139.4, 133.9, 134.2, 129.1, 127.9, 122.7, 58.20, 48.79, 28.03.
11. Determined by 1H-NMR analysis on the crude mixture.
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