Chapter Nine - Recent Advances of 1,3-Dipolar Cycloaddition Chemistry for Alkaloid Synthesisa

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Abstract

The synthesis of heterocyclic compounds has attracted significant attention for decades. Among the various heterocycles isolated from nature, alkaloidal natural products have received significant attention due to their diverse bioactivity. As highlighted in this minireview, a growing area of interest in organic synthesis involves the use of substituted 1,3-dipoles for the preparation of different alkaloidal natural products. Cascade reactions proceeding by an intramolecular 1,3-dipolar cycloaddition chemistry are of particular interest to the synthetic organic community because of the increase in molecular complexity involved and the high isolated yields. The synthesis of numerous alkaloids has been elegantly accomplished in recent years using an assortment of synthetic dipole intermediates.

Introduction

1,3-Dipolar cycloaddition reactions are among the most powerful methods in organic synthesis (2003MI). A particularly attractive feature is their ability to rapidly increase molecular complexity and lead to a high degree of functionality. These unique reactions were extensively studied by the Huisgen group starting in the early 1960s (1963AGE565, 1984MI1), and their rate and regioselectivity can be understood through FMO analysis (1984MI407). [3+2]-Cycloadditions are also extremely useful for the synthesis of natural products, pharmaceutical agents, and other biologically important structures employing rather simple starting materials. In addition, dipolar cycloadditions using chiral substrates for asymmetric synthesis have been extensively explored since the 1990s (2014MI175). Because several reviews and related articles have recently been published dealing with the synthetic aspects of dipolar cycloaddition chemistry (2007T12247, 2013MI133) for the preparation of natural products, this review chapter is intended to provide a selective rather than an exhaustive survey of the most useful 1,3-dipoles for alkaloid synthesis over the past several years.

Section snippets

Carbonyl Ylides

The creation of carbonyl ylide dipoles from the reaction of α-diazo compounds with ketones in the presence of Rh(II) catalysts (Scheme 1) (1998MI1, 1986CR919, 1994CR1091, 1991CR263, 1992T5385, 1996CR223, 2013MI133) has significantly broadened their applicability for natural product synthesis (1997JOC1317, 1993JOC7635, 1994TL9185). The ease of the generating the dipole, the rapid accumulation of polyfunctionality in a relatively small molecular framework, the high stereochemical control of the

Mesoionic Systems

Mesoionic oxazolium ylides (isomünchnones) correspond to the cyclic equivalent of a carbonyl ylide embedded in a heteroaromatic ring, and these reactive intermediates readily undergo 1,3-dipolar cycloaddition with suitable dipolarophiles. Isomünchnones are readily obtained through the transition metal–catalyzed cyclization of a suitable α-diazoimide precursor (1994S123). The starting diazoimides are easily constructed by acetoacylation (1985JOC1663) or malonylacylation (1982CPB1315) of the

Azides

Azides are very versatile and valuable synthetic intermediates, known for their wide variety of applications, and have been employed for the synthesis of a number of important heterocyclic compounds. Azides also represent a prominent class of 1,3-dipoles, and their cycloaddition to multiple π-bonds is an old and widely used reaction (1988CR297). The dipolar cycloaddition of an azide to an alkene furnishes a triazoline derivative (2003MI623). Azide-alkene cycloadducts can extrude nitrogen at

Azomethine Ylides

Several methods have been used to generate azomethine ylides for use in dipolar cycloaddition chemistry (1984MI1). A particularly common method is the condensation of N-alkyl amino acid derivatives with aldehydes followed by decarboxylation to afford the 1,3-dipole. The Coldham group employed this method in their strategy for the synthesis of a variety of alkaloids. In a formal synthesis of deethylibophylidine, for example, heating a toluene solution of aldehyde 135 and N-allyl glycine (136) at

Azomethine Imines

Although a few examples of dipole methodology directed toward various classes of natural products have been reported using azomethine imine cycloadditions, there are far fewer natural products synthesized using these reaction partners than azomethine ylides. The Overman group deployed this type of dipolar cycloaddition in the syntheses of (+)-Nanakakurines A and B (195a,b), respectively (Scheme 40). One of the most challenging problems encountered in this synthesis was fashioning the piperidine

Nitrones

1,3-Dipolar cycloaddition of nitrones (1984MI1) continues to play an important role in alkaloid synthesis. For example, Dhavale and coworkers used carbohydrate-derived nitrones for the synthesis of polyhydroxylated indolizidines and perhydro-azaazulene alkaloids. Thus, the d-glucose-derived nitrone 223 was reacted with allyl alcohol in refluxing acetone for 48 min, and this was followed by exposure of the resulting mixture of cycloadducts to p-TsCl and pyridine which afforded a mixture of 224ad

Nitrile Oxides

The nitrile oxide class of 1,3-dipoles are readily accessible from aldoximes or nitroalkanes by simple procedures, and they undergo smooth 1,3-dipolar cycloaddition reactions with a variety of dipolarophiles (2002MI361). In particular, they form synthetically useful isoxazoles and dihydroisoxazoles with alkynes and alkenes, respectively. Especially important are cycloadditions with monosubstituted alkenes since these reactions are regioselective, normally affording dihydroisoxazoles with

Asymmetric Reactions of 1,3-Dipoles

While the application of various dipolar cycloadditions to the synthesis of natural products has generated significant attention, the development of catalytic asymmetric methods has also proved fruitful. Diazoalkane cycloadditions, for example, have garnered a lot of interest. The Matsuoka lab demonstrated that titanium BINOL-ate complexes promote an enantioselective cycloaddition of diazoacetates to acrolein derivatives with modest yield but good to excellent enantioselectivities. For example,

Concluding Remarks

The application of the dipolar cycloaddition of 1,3-dipoles for the synthesis of alkaloids as described in this report spans a broad spectrum of organic chemistry. The regio- and stereoselectivity of the 3+2-cycloaddition reaction is now well established, making it an attractive strategic disconnection for synthetic design of various alkaloids. As is the case in all new areas of research, future investigations of the chemistry of these dipolar cycloadditions for natural product synthesis will

Acknowledgment

AP is particularly grateful to the National Science Foundation (grant CHE-1057350) for generous financial support as well the Camille and Henry Dreyfus Foundation for a Senior Scientist award.

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    Dedicated with respect and affection to the memory of Professor Alan Roy Katritzky, University of Florida, Gainesville (August 18, 1928–February 10, 2014).

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