Tandem oxidative radical decarboxylation-β-iodination of amino acids. Application to the synthesis of chiral 2,3-disubstituted pyrrolidines

Article abstract of DOI:10.1016/S0040-4039(00)00188-X

A mild and efficient procedure for the tandem decarboxylation- halogenation of α-amino acids is reported. The iodine is introduced at previously unfunctionalized positions, in good yields. The methodology has been used for the diastereoselective synthesis of 2,3-disubstituted pyrrolidines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00188-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2495–2498
Tandem oxidative radical decarboxylation-β-iodination of amino
acids. Application to the synthesis of chiral 2,3-disubstituted
pyrrolidines
Alicia Boto, Rosendo Hernández and Ernesto Suárez ∗
Instituto de Productos Naturales y Agrobiología del C.S.I.C., Carretera de La Esperanza 3, 38206 La Laguna, Tenerife, Spain
Received 30 November 1999; revised 11 January 2000; accepted 25 January 2000
Abstract
A mild and efficient procedure for the tandem decarboxylation-halogenation of α-amino acids is reported. The
iodine is introduced at previously unfunctionalized positions, in good yields. The methodology has been used for
the diastereoselective synthesis of 2,3-disubstituted pyrrolidines. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amino acids; radical decarboxylation; halogenation; nitrogen heterocycles; metathesis.
Enantiomerically pure pyrrolidine derivatives are interesting chiral synthons because numerous natural
products possess this type of heterocyclic ring system in their structures.1 Some of these metabolites
isolated from a large variety of natural sources are important therapeutic agents in a number of
pharmaceutical contexts.2 Furthermore, substituted enantiomerically pure pyrrolidines have been used
as chiral auxiliaries.3 All these facts have stimulated efforts from natural product and synthetic chemists
for the isolation and development of the stereocontrolled synthesis of this class of compounds.4
We have recently reported on a new method for the synthesis of N-acyliminium ions by oxidative decar-
boxylation of α-amino acids. The N-acyliminium intermediate can be trapped inter- or intramolecularly
by different nucleophiles.5 In further studies on this subject, we were pleased to find that under certain
conditions this reaction can be transformed into a new tandem process of decarboxylation-β-iodination,
which allows the synthesis of 3-iodinated pyrrolidine and piperidine derivatives (Scheme 1). Thus, when
N-(methyloxycarbonyl)-L-proline 1a (Table 1, entry 1) was treated with (diacetoxyiodo)benzene (DIB)
and iodine in acetonitrile under the conditions shown in Table 1, 3-iodo-2-hydroxypyrrolidine 3a was
obtained in good yields after aqueous work-up, along with the non-iodinated analog 2a.
When the reaction was quenched with dry methanol before work-up, 3-iodo-2-methoxypyrrolidine 4a
was obtained as the major product. Only the 2,3-trans-disubstituted product was isolated, since the bulky
iodine group hinders the approach of the nucleophile from the same face. The reaction also proceeds
∗
Corresponding author. Tel: 34 922 251004; fax: 34 922 260135; e-mail: esuarez@ipna.csic.es (E. Suárez)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00188-X
tetl 16468

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Scheme 1. Oxidative decarboxylation-β-iodination of α-amino acids
Table 1
One-pot decarboxylation-halogenation-nucleophilic additiona
with good yields with other proline carbamates, such as compounds 1b–c (entries 3 and 4), although the
halogenation process requires longer times with the phenyl carbamate group. However, using an amide
derivative, such as 1d, only the non-iodinated product 2d was isolated, even after extended reaction times.
To extend further the scope of the reaction, we have investigated the feasibility of applying this
methodology to the synthesis of 3-iodopiperidine derivatives. The decarboxylation of L-pipecolinic acid
methyl carbamate 1e (Scheme 1) proceeded even in CH2Cl2 (Table 1, entry 5). After quenching with
dry methanol (entry 5) trans-3-iodo-2-methoxypiperidine 4e was obtained in good yield. Interestingly, a
3,3-dihalogenated compound 5e was formed when acetonitrile was used as solvent (entry 6).
A plausible mechanism for this tandem decarboxylation-iodination is outlined in Scheme 2. Each step
of the sequence must proceed in excellent yield to account for the observed overall yields. The first
step involves an equilibrium between the N-acyliminium ion (Ia) formed initially and its enecarbamate
(Ib), which is subsequently halogenated by the excess of iodine present in the medium. The iodinated
N-acyliminium ion (IIa) can then be trapped by nucleophiles (e.g. methanol) to give (III). Alternatively,
(IIa) may equilibrate with (IIb); the iodination of the latter accounts for the formation of 5e. The acid-
catalyzed equilibrium N-acyliminium–enamide has been observed as an important side reaction in N-
acyliminium ion chemistry, leading in most cases to undesired dimeric products.6 The halogenation of
enamides/carbamates has also been described and proven useful in the synthesis of natural products.7
When we applied this methodology to the commercially available trans-4-hydroxy-L-proline deriv-
ative 5, two isomeric monoiodinated compounds 6a (2S,3R,4S) and 6b (2R,3S,4S) were obtained in

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Scheme 2. Proposed mechanism for the formation of iodinated products
moderate overall yield (Scheme 3). Compounds 6a and 6b are interesting chiral synthons from which
3- or 2,3-substituted pyrrolidines can be easily prepared.
Scheme 3. Synthesis of chiral 2,3 disubstituted pyrrolidines. (a) (i) DIB, I2, MeCN, 5 h; (ii) MeOH, TsOH catalytic, 12 h; 53%
6a (2S,3R,4S): 6b (2R,3S,4S) 2:1. (b) allyltributyltin, AIBN cat., PhH, 80°C, 92%. (c) allyltrimethylsilane, BF3·Et2O, CH2Cl2,
0°C, 99%. (d) Grubbs’ catalyst, CH2Cl2, reflux, 95%
To illustrate the synthetic versatility of this methodology we have performed a radical allylation
at C-3 and an ionic allylation at C-2 (Scheme 3), both with excellent yields and stereoselectivity, to
give the diallylated pyrrolidine 7. This compound was transformed via a metathesis reaction8 into
the hexahydroindole derivative 8. The hexa- or octahydroindole ring is present in Amarillidaceae and
Sceletium alkaloids9a and peptides as Aeruginosins.9b The application of the present strategy to the
synthesis of bicyclic alkaloids is underway and will be reported in due course.
Acknowledgements
This work was supported by Investigation Programme PB96-1461 of the Dirección General de
Investigación Científica y Técnica.
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