DOI: 10.1002/chem.201500185

Communication

& Total Synthesis

Isostrychnine Synthesis Mediated by Hypervalent Iodine Reagent Guillaume Jacquemot, Gatan Maertens, and Sylvain Canesi*[a] Abstract: Althought there are several reported synthetic routes to strychnine, one of the most widely recognized alkaloids, we report an unexplored route with an oxidative dearomatizing process mediated by hypervalent iodine as the key step. The new syntheses of isostrychnine and strychnine have been achieved from an readily available phenol in nine and ten steps. In addition to the key step, these syntheses involve an aza Michael-ether-enol tandem transformation, two heck type cyclizations, a reductive isomerization, and a double reductive amination in cascade leading to the alkaloid main core.

Figure 1. Strychnine 1 and the related alkaloids, isostrychnine 2 and icajine 3.

thesis of isostrychnine involving an aromatic dearomatization, a Heck-type cyclization, an unprecedented aza-Michael-enol ether tandem process, a reductive isomerization, and a double reductive amination. The target was achieved following the remarkable Heck protocol reported by Rawal,[5d] Figure 2.

Strychnine is generally isolated from the seeds of the trees Strychnos ignatii Bergius and Strychnos nux-vomica.[1] Its toxicity makes it one of the most widely recognized alkaloids by both chemists and the general population, and the poisonous effect of nuts containing strychnine has been employed in several famous murders and legends down the ages.[2] The compound was first isolated by Pelletier and Caventou in 1818,[3] and the total synthesis of this alkaloid by Woodward and coworkers in 1954[4] is considered to be the first complex total synthesis achieved in organic chemistry. The fact that no other strychnine syntheses were reported for almost 40 years demonstrates the advanced nature of this group’s efforts. In the 1990s, several elegant total and formal syntheses appeared in the literature. This alkaloid has been a wonderful source of inspiration that has spurred the development of numerous advances in organic synthesis and has figured prominently in the training of many chemists.[5] A very interesting review by Overman and Cannon outlines the main strategies and accomplishments related to strychnine synthesis.[6] Strychnine 1 belongs to the strychnos alkaloids, a large family of bioactive natural products also including isostrychnine 2 and icajine 3,[7] Figure 1. Despite the fact that several strychnine syntheses have been reported, our interest in oxidative dearomatizing processes[8] mediated by hypervalent iodine reagents led us to consider an unexplored route to this target. We developed a concise syn-

Figure 2. Strychnine retrosynthesis.

The synthesis begins with the available phenol 4. This compound reacts with the aluminum salt[9] of iodoaniline to produce the amide 6 (88 %). The oxidative dearomatization process[10] developed by Kita and coworkers[11] is used to generate the dienone core 7 (54 %). The desired compound is accompanied by a small amount of spirolactam[12] side product resulting from direct nitrogen attack. At this stage, a new method involving an aza-Michael process provoked by a siliconium Lewis acid is employed to generate the bicyclic enol ether 8 (86 %) as a mixture of atropoisomers. The transformation pobably proceeds through imino ether formation followed by activation of the enone moiety with tert-butyldimethylsilyltriflate (TBSOTf), enabling nitrogen attack through a Michael pathway

[a] Dr. G. Jacquemot, G. Maertens, Prof. S. Canesi Dpartement de chimie, Universit du Qubec  Montral Laboratoire de Mthodologie et Synthse de Produits Naturels C.P. 8888, Succ. Centre-Ville, Montral, H3C 3P8, Qubec (Canada) Fax: (+ 1) 514-987-4054 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500185. Chem. Eur. J. 2015, 21, 1 – 4

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Communication to produce the desired enol ether 8. It should be stressed that compound 7 is a prochiral dienone system, and an asymmetric aza-Michael process[13] using this species could lead to enantioselective synthesis of strychnine and its congeners. Unfortunately, in our hands all asymmetric 1,4-addition attempts failed, Scheme 1.

Scheme 3. Pentacyclic core formation.

their noteworthy synthesis.[16] A Heck transformation performed on 1, followed by treatment with HCl, leads to the hexacyclic system isostrychnine 2 (71 %). Conversion of isostrychnine to strychnine under basic conditions is well-known in the literature,[17] and proceeds through an initial double bond isomerization followed by an oxa-Michael addition, Scheme 4.

Scheme 1. Formation of aromatic subunit.

Compound 8 is the required intermediate to produce the tetracyclic core of strychnine 1. The enol ether moiety generated during the previous tandem process may be employed in a further carbopalladation (such as a Heck-type cyclization) to produce 9 (73 %). The first quaternary carbon center is generated at this step by allylation under basic conditions. Regiochemical control exerted by the bowl shape of the molecule results in formation of 10 (79 %). A subsequent Lemieux-Johnson transformation[14] yields aldehyde 11 (88 %), Scheme 2.

Scheme 4. Elaboration of main core of strychnine.

In summary, a new synthesis of isostrychnine and a formal synthesis of strychnine were accomplished in nine and ten steps from a readily available and inexpensive phenol. These syntheses employ several transformations, including an oxidative dearomatization mediated by a hypervalent iodine reagent, a new aza-Michael-enol ether tandem process, a Hecktype cyclization, and a reductive isomerization. The main strategy focused on hypervalent iodine chemistry as an effective tool in the total synthesis of complex natural products.

Scheme 2. Tetracycle formation.

Application of a remarkable reductive isomerization process developed by Wipf and coworkers to compound 11 produces the key adduct 12 (63 %). This reaction is promoted by zinc in acetic acid[15] and enables placement of the double bond in a strategic location for elaboration of the desired hexacyclic system. At this stage, a double reductive amination with the known amine[5d] 13 is performed on 12, yielding the desired substituted pentacyclic core 14 as well as its epimer 15 (60 %) in a 1:1 ratio, Scheme 3. Using this strategy, a concise synthesis of the main pentacyclic core of strychnine has been achieved in only eight steps from the readily available phenol 4. The final steps of the synthesis were previously described by Rawal and coworkers in &

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Acknowledgements We are very grateful to the Natural Sciences and Engineering Research Council of Canada (NSERC), the Canada Foundation for Innovation (CFI), the provincial government of Quebec (FQRNT and CCVC) for their precious financial support in this research.

Keywords: aromatic ring umpolung · hypervalent iodine · natural products · oxidation · total synthesis 2

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Received: January 15, 2015 Published online on && &&, 0000

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COMMUNICATION & Total Synthesis G. Jacquemot, G. Maertens, S. Canesi* && – && Isostrychnine Synthesis Mediated by Hypervalent Iodine Reagent

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Chem. Eur. J. 2015, 21, 1 – 4

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Novel synthesis of strychnine: New syntheses of isostrychnine and strychnine have been achieved from available 3-(4-hydroxyphenyl)-propionic acid methyl ester in nine and ten steps. These syntheses involve an oxidative dearomatization process mediated by

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a hypervalent iodine reagent, an aza Michael-ether-enol tandem transformation, two heck type cyclizations, a reductive isomerization, and a double reductive amination in cascade leading to the alkaloid main core.

 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Isostrychnine synthesis mediated by hypervalent iodine reagent.

Althought there are several reported synthetic routes to strychnine, one of the most widely recognized alkaloids, we report an unexplored route with a...
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