Synthesis of alkaloids from amino acids via N-acyliminium ions generated by one-pot radical decarboxylation-oxidation

Article abstract of DOI:10.1016/S0040-4039(00)00306-3

A one-pot methodology for the synthesis of α-substituted nitrogen heterocycles from commercial amino acids has been developed. Good stereoselectivity can be achieved with chiral substituted rings. This procedure has been applied to the synthesis of piperidine, pyrrolidine and indolizidinone alkaloids. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00306-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2899–2902
Synthesis of alkaloids from amino acids via N-acyliminium ions
generated by one-pot radical decarboxylation–oxidation
Alicia Boto, Rosendo Hernández ∗ and Ernesto Suárez
Instituto de Productos Naturales y Agrobiología del C.S.I.C., Avda. Astrofísico F. Sánchez, 3, CP: 38206 La Laguna, Tenerife,
Spain
Received 6 January 2000; accepted 12 February 2000
Abstract
A one-pot methodology for the synthesis of α-substituted nitrogen heterocycles from commercial amino acids
has been developed. Good stereoselectivity can be achieved with chiral substituted rings. This procedure has been
applied to the synthesis of piperidine, pyrrolidine and indolizidinone alkaloids. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: radical decarboxylation; N-acyliminium ion; alkaloids; nitrogen heterocycles; indolizidinone.
The synthetic utility of N-acyliminium ions is widely recognized, and their trapping by carbon
nucleophiles has been used in the synthesis of many biologically active products.1 Accordingly, several
methodologies have been developed to generate these ions, such as acid treatment of N,O-acetals or
aminals;1 treatment of imines with acyl chlorides;1,2 or electrochemical oxidation of amino or amido
derivatives.1,3 In addition to these, we have recently reported on a mild and operationally simple method
based on the tandem radical decarboxylation–oxidation of commercial amino acids.4 On treatment with
(diacetoxyiodo)benzene (DIB) and iodine, an N-acyliminium intermediate (I) (Scheme 1) was generated,
and trapped in situ with oxygen (path a) or nitrogen (path b) nucleophiles to give (II) or (III), respectively.
The reaction proceeded at room temperature with high yields and was applied to the synthesis of azasugar
analogues.
We assumed that the use of carbon nucleophiles would broaden the scope of this reaction. The
feasibility of this approach and its application to the synthesis of alkaloids are reported herein.
We decided to explore nucleophiles which would be compatible with most common functional groups
on the substrate. Allylsilanes and silyl enol ethers seemed ideal for this purpose. Initially, the proline
derivative 1a (Scheme 2) was treated with the system (diacetoxyiodo)benzene (DIB) and iodine to
generate the acyliminium intermediate,4 and after 3 h the reaction was cooled at 0°C and quenched
with allyltrimethylsilane (Table 1, entry 1). Disappointingly, in this first attempt the desired allylation
∗
Corresponding author. Tel: 34 922 251004; fax: 34 922 260135; e-mail: rhernandez@ipna.csic.es (R. Hernández)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00306-3
tetl 16586

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Scheme 1. N-Acyliminium intermediate trapping by oxygen or nitrogen nucleophiles
product 2b was not obtained, but rather hydroxypyrrolidine 2a.4 However, the problem was solved by
adding boron trifluoride–etherate to the reaction mixture (entry 2), yielding the allylproline derivative 2b
in excellent yield after purification by chromatography. The role of the Lewis acid may be double: (a) to
regenerate the N-acyliminium ion in the event of trapping by nucleophiles (e.g. acetate) in the reaction
mixture3c,5 and (b) to coordinate the carbonyl group on the substrate, increasing the electronic deficiency
of the acyliminium intermediate.
Scheme 2. One-pot radical decarboxylation–oxidation addition of allyltrimethylsilane
Table 1
Decarboxylation–oxidation-N-acyliminium trapping with allyltrimethylsilanea

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To study the stereoselectivity of the reaction, 4-(trimethylacetyloxy)-L-proline derivative 1b was
treated under the previous conditions (entry 3), giving 78% of the (2S,4R) diastereomer 3a, versus 13%
of the 2R epimer 3b (91% overall yield, d.r. 6:1). It is noteworthy that the major diastereomer has the
cis-configuration, opposite to that present in the starting material.6 Thus, our one-pot methodology is
complementary to the elaboration of the allyl substituent from the carboxylic group of the amino acid,
which would give 3b.
The reaction also works well with six-membered rings. Thus, the decarboxylation–allylation
of N-methyloxycarbonyl pipecolinic acid (4) (Scheme 2), afforded (±)-N-methyloxycarbonyl-
2-allylpiperidine (5a) (Table 1, entry 4), which could be quantitatively reduced to (±)-N-
methyloxycarbonyl coniine (5b). (±)-Coniine is the active principle of hemlock poison.7
We next applied this methodology to the synthesis of alkaloids with the indolizidine skeleton, many of
which have potent biological activity, as inhibitors of glycosidases and as immunoregulatory agents.8 The
synthesis of these alkaloids and analogues is necessary for structure–activity relationship (SAR) studies.
Two approaches to the indolizidinone system are shown in Scheme 3.
Scheme 3. (i) DIB (2 equiv.), I2 (0.5 equiv.), CH2Cl2, 3 h, then 2-(trimethylsilyloxy)furan (5 equiv.), BF3·Et2O (1.5 equiv.),
0°C to rt, threo 7:erythro 6:1, 66%; (ii) Pd(OH)2, H2, MeOH, 12 h, 99%; (iii) DIB (2 equiv.), I2 (0.5 equiv.), CH2Cl2, 3 h; then
BF3·Et2O (1.5 equiv.), isopropenyl acetate (5 equiv.), 0°C to rt, 4 h, 58%; (iv) tBuOK, tBuOH, reflux, 12 h, 98%
Thus, treatment of the acyliminium ion obtained from N-benzyloxycarbonyl-L-proline 6 with 2-
(trimethylsilyloxy)furan9 yielded the 2-pyrrolidinyl-2(5H)-furanone 7 and its erythro diastereomer in a
6:1 ratio and 66% yield.10 The reduction of the double bond, the removal of the benzyl carbamate group
and the cyclization were accomplished in one step, in quantitative yield, by hydrogenation catalyzed by
palladium hydroxide in methanol, affording the hydroxyindolizidinone 8. This constitutes an improved
procedure with respect to previous syntheses.11 The functionalization of the furanone ring prior to
hydrogenolysis would broaden the range of available derivatives.
In a second and new approach, proline amide 9 (Scheme 3) was treated with DIB-I2, followed by
isopropenyl acetate and BF3·OEt2, yielding the (±)-norhygrine derivative 10 in good yield. Treatment
of 10 with base afforded the 6,7-disubstituted indolizidinone 11 in excellent yield. Other substituents can
be introduced in the bicyclic system by using derivatized prolines as substrates, and/or by varying the
amido and ketone chains, offering a versatile route to other analogues. Further work on the synthesis of
indolizidine alkaloids is underway and will be reported in due course.

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Acknowledgements
This work was supported by Investigation Programme PB96-1461 of the Dirección General de
Investigación Científica y Técnica.
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