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Asymmetric Domino Reactions
By Hélène Pellissier
The Royal Society of Chemistry
Copyright © 2013 The Royal Society of ChemistryAll rights reserved.
ISBN: 978-1-84973-710-4
CHAPTER 1
Asymmetric Domino Reactions Based on the Use of Chiral Substrates
1.1 Introduction
Of the methods available for preparing chiral compounds, asymmetric synthesis from chiral substrates still attracts a lot of attention. Indeed, it remains the method most commonly employed in total synthesis of optically active compounds, playing an important role in medicine and materials as well as natural products, in spite of the explosive growth of organocatalysis in the last decade, and its application in the synthesis of a number of chiral products. The last six years have witnessed an explosive growth in the field of asymmetric domino reactions starting from chiral substrates and auxiliaries, with an impressive number of novel methodologies and applications in total synthesis. The goal of this chapter is to cover the recent efforts of the chemical community in the development of novel domino reactions of chiral substrates, including chiral auxiliaries and their wide applications in total synthesis, published since the beginning of 2006. This field was most recently reviewed in 2006 by Tietze in a book, and by this author in a review, covering the literature until the beginning of 2006. The domino reactions are catalogued on the basis of the reaction types involved in the first synthetic step(s). They have been selected according to Tietze's definition, qualifying a domino reaction as a reaction involving two or more bond-forming transformations which take place under the same reaction conditions, without adding additional reagents and catalysts, and in which the subsequent reactions are a consequence of the functionality formed by bond formation or fragmentation in the previous step. In order to facilitate presentation, the chapter is divided into two principal sections, dealing successively with one- and two-component domino reactions, and multicomponent domino reactions. The first section, describing the asymmetric one- and two-component domino reactions, is subdivided into eight sections which successively deal with domino reactions with an anionic primary step, domino reactions based on cationic sequences, domino reactions initiated by a pericyclic primary step, domino reactions based on carbene sequences, palladium-catalysed domino reactions, ruthenium-catalysed domino reactions, gold-catalysed domino reactions, and finally miscellaneous domino reactions. The second section of the chapter, describing the asymmetric multicomponent reactions, defined as domino reactions involving at least three substrates and forming products that contain significant portions of all reactants, ideally all atoms, is subdivided into 10 paragraphs, dealing successively with multicomponent reactions initiated by the Michael addition, multicomponent reactions based on the Hantzsch reaction, multicomponent reactions based on the Ugi reaction, multicomponent reactions based on the Strecker reaction, multicomponent reactions based on the Mannich reaction, multicomponent reactions initiated by an allylation reaction, multicomponent reactions based on the Passerini reaction, multicomponent reactions based on the Biginelli reaction, multicomponent reactions based on the Petasis reaction, and finally miscellaneous multicomponent reactions.
1.2 One and Two-Component Domino Reactions
1.2.1 Anionic Primary Step
1.2.1.1 Domino Reactions Initiated by the Michael Reaction
The nucleophilic 1,4-addition of stabilised carbon nucleophiles to electron-poor olefins, generally α,β-unsaturated carbonyl compounds, is known as the Michael addition, although it was first reported by Komnenos in 1883. Michael-type reactions can be considered as one of the most powerful and reliable tools for the stereocontrolled formation of carbon–carbon and carbon-heteroatom bonds, as has been demonstrated by the huge number of examples in which it has been applied as a key strategic transformation in total synthesis. As a consequence, in recent years, many different versions of this important transformation have been reported, using a wide variety of nucleophiles and conjugate acceptors. In particular, the Michael-Michael domino reaction is a powerful tool in forging ring systems common to many natural products. A number of asymmetric double Michael reactions have been reported in the last few years, often applied to the total synthesis of important products. As an example, Garrido et al. have developed an expeditious asymmetric synthesis of a precursor of natural product (-)-pumiliotoxin C, based on an asymmetric domino aza-Michael-Michael reaction. This process was initiated by a highly diastereoselective Michael addition of a chiral lithium amide to nona-2,7-diendioic diester, followed by a 6-exo-trig cyclisation of the thus formed enolate. As shown in Scheme 1.1, the expected chiral cyclohexane domino product was achieved in 80% yield as a single diastereomer which bore three contiguous stereocentres. This chiral product was subsequently converted into the required chiral precursor of (-)-pumiliotoxin C through a three-step sequence, involving successively a Cope elimination, a selective hydrolysis of the less steric demanding ester, and an efficient Barton decarboxylation.
Later, Scheerer et al. described the first asymmetric synthesis of the naturally occurring neoclerodane diterpene salvinorin A, which is a potent k opioid receptor agonist, the only non-alkaloid psychoactive substance, and the most potent natural hallucinogen. The key step of the synthesis was a transannular double Michael reaction cascade of chiral bisenone macrocycle promoted by tetra-n-butylammonium fluoride (TBAF). The corresponding tricycle was obtained in quantitative yield as a single diastereomer, as shown in Scheme 1.2. The process delivered two quaternary methyl stereocentres at C5 and C9 in a 1,3-diaxial alignment from the corresponding β,β-disubstituted enones, moieties commonly known to possess poor reactivity toward conjugate addition. Scheme 1.2 provides a rationale for the observed stereoselectivity in the domino reaction. Conformational analysis of the starting bisenone macrocycle suggested that the three stereocentres, in pseudo-equatorial positions, mutually reinforced the diastereoselectivity. This analysis also suggested that enolisation favoured the Z-enolate. The final enantiopure tricycle was further converted into expected salvinorin A through seven supplementary steps in 41% overall yield.
In 2008, the first and long-awaited total synthesis of the natural cardioactive glycosylated steroid ouabain was developed by Deslongchamps et al. on the basis of a polyanionic cyclisation strategy, providing a tricyclic domino intermediate which is depicted in Scheme 1.3. This intermediate arose from an asymmetric domino Michael–Michael reaction occurring between a chiral cyclohexenone and a chiral Nazarov substrate in the presence of Cs2CO3. This key tricyclic domino product was obtained in 85% yield and subsequently submitted to decarboxylation to give the corresponding key tricyclic product as a single diastereomer in 92% yield. Finally, this polyfunctionalised tricyclic compound was converted into the expected ouabain.
On the other hand, Kataoka et al. have previously investigated the reaction of a chiral 3-cinnamoyloxazolidine-2-thione with aromatic aldehydes in the presence of BF3 · Et2O. The reaction evolved through an asymmetric domino thia-Michael–aldol process, providing diastereoselectively the corresponding tricyclic products, which incorporated a bridgehead carbon bound to four heteroatoms. These products were produced as mixtures of two diastereomers with moderate to high diastereoselectivities of up to 90% diastereomeric excess (de), as shown in Scheme 1.4. It must be noted that this process generated four stereocentres. The chiral domino products achieved in good to high yields could be further transformed into the corresponding enantiopure propane-1,3-diols bearing three contiguous stereocentres through acid hydrolysis, allowing the chiral auxiliaries to be recovered. These structurally rare compounds were presumably formed along the reaction pathways shown in Scheme 1.4. BF3 · Et2O coordinated with the carbonyl oxygen of the N-cinnamoylthio-carbamate, allowing the enone moiety to be activated. The intramolecular Michael addition of the thione group to the enone moiety proceeded via intermediate 1, and afforded the boron enolate-iminium salt 2. An aldol reaction between the boron enolate moiety and aldehyde yielded the aldol product 3, which intramolecularly cyclised to afford the final tricyclic products.
In 2009, Davies et al. demonstrated that the condensation of a chiral lithium (R)-N-(α-methylbenzyl)amide to a range of benzylidene imines provided the corresponding almost diastereo- and enantiopure domino aza-Michael–cyclisation products in good to excellent yields, as shown in Scheme 1.5. This process opened a novel and powerful access to enantiopure 2-aryl-4-aminotetrahydroquinoline-3-carboxylic acid derivatives bearing three contiguous stereogenic centres with general diastereo- and enantioselectivities of >98% de and >98% enantiomeric excess (ee), respectively. In addition to being readily applicable to the preparation of libraries of chiral 4-aminotetrahydroquinolines for biological screening, this approach has been shown to be useful in the preparation of corresponding chiral diamino esters through simple hydrogenolysis of the domino products, which occurred without compromising the ddiastereo- an enantiopurity.
In 2006, a novel asymmetric domino Michael–Dieckmann cyclisation reaction was employed by Groth et al. as key step in a total synthesis of naturally occurring fungitoxic (-)-chokol A. As shown in Scheme 1.6, the condensation of a higher-order cuprate derived from the corresponding vinyl bromide to a chiral α,β-unsaturated ester derived from (-)-phenylmenthol provided, after a Michael addition followed by a Dieckmann cyclisation, the corresponding cyclic β-keto ester in 93% yield, combined with an excellent diastereoselectivity of > 98% de. This chiral product was further converted into the expected (-)-chokol A through a five-step sequence, with an overall yield of 29%.
In the course of developing a novel synthesis of natural and biologically active himbacine, McCarthy et al. have found that a domino Michael-Dieckmann reaction of an enantioenriched α,β-unsaturated furanone (ee = 70%) with a racemic diester led to the corresponding tricyclic product, which constituted a key intermediate for the proposed synthesis (Scheme 1.7). In fact, the process generated the domino product as a mixture of three diastereomers, among which the major one was separated by chromatography with 46% yield. This enantiopure tricyclic product constituted a useful intermediate for a short enantioselective synthesis of himbacine and derivatives.
In 2011, another asymmetric domino Michael-Dieckmann reaction was demonstrated by Avenoza et al. to be an efficient entry to both enantiomers of α-(hydroxymethyl)glutamic acid. As shown in Scheme 1.8, the reaction of methyl acrylate with an L-serine-derived bicyclic (3S,7R, 7aS)-N,O-acetal provided, through a sequence of a Michael addition followed by a Dieckmann reaction promoted by the participation of the cyclic carbamate group, the corresponding domino product as a 39:61 mixture of (3S,6R,7aS)-and (3S,6S, 7aS)-diastereomers. This mixture was further submitted to 6N HCl aqueous solution under reflux to achieve the (S)-enantiomer of α-(hydroxy-methyl)glutamic acid. In the same way as that described for the synthesis of this (S)-enantiomer, the authors have achieved the corresponding (R)-enantiomer of α-(hydroxymethyl)glutamic acid starting from the corresponding bicyclic (3R,7R,7aS)-N,O-acetal derived from D-serine, as shown in Scheme 1.8.
In 2007, Nagasaka et al. reported the first domino Michael addition-Mannich-type reaction using a TiCl4 –tetra-n-butylammonium iodide (TBAI) system and occurring intramolecularly between α,β-unsaturated carbonyl compounds which bore an Evans oxazolidinone as a chiral auxiliary and in situ generated N-acyliminium ion intermediates. The intramolecular cyclisation of the chelated iodo titanium enolate intermediates, arising from the Michael addition, afforded the corresponding chiral indolizidines bearing three stereogenic centres in moderate to good diastereoselectivities of up to 80% de, as shown in Scheme 1.9. In this study, the use of mixed solvents, such as AcOEt and CH2Cl2, was shown to be the most effective.
In 2011, Qin et al. reported a novel domino Michael–Mannich–Mannich reaction of a tryptamine derivative with a chiral amidinobenzodiene, which was generated in situ from the corresponding isatin-derived chloride. Surprisingly, the process led, in the presence of two equivalents of AgBF4, to a 3 :1 diaste-reomeric mixture of complex products possessing a polycyclic skeleton of 2,3,4,5-diindolinohexahydropyrrole in 76% yield. The authors assumed that the formation of these products was explained through a three-step cascade reaction beginning with the attack of indole on the benzodiene, which gave the corresponding indolinium 4 (Scheme 1.10). This intermediate 4 was susceptible to addition of its imidate group to afford the corresponding iminium intermediate 5. A final Mannich addition of the amide group in 5 to the iminium moiety provided the final products. The stereochemistry of the chiral formed products was established by X-ray crystal-structural analysis.
In another context, the Michael reaction has also been combined with intramolecular alkylation reaction. As an example, the synthesis of a pheromone was achieved by Reddy et al. on the basis of a domino Michael–intramolecular alkylation reaction of a chiral α,β-unsaturated ester derived from (R)-pantolactone with Me2CuLi. Indeed, the resulting enolate arising from the Michael addition of this cuprate to the α,β-unsaturated ester subsequently cyclised to furnish the corresponding chiral cyclopentane derivative as a single diastereomer in 94% yield, as shown in Scheme 1.11. This product was further converted into the expected sex pheromone depicted in the same scheme.
In 2010, another type of asymmetric domino Michael–intramolecular alkylation reaction was developed by Pathak et al. to achieve a range of chiral six-membered heterocycles and carbocycles bearing three contiguous stereocentres. In this case, the domino reaction occurred between a chiral vinyl sulfone derived from ribose and NaS, which provided the corresponding enantiopure cyclic sulfide in 72% yield, as shown in Scheme 1.12. This highly efficient methodology was applied to a series of other nucleophiles, such as primary amines and dialkyl malonates, leading to the corresponding piperidine derivatives and cyclohexane derivatives, respectively. Remarkably, in all cases of the substrates studied, the products were produced in good to high yields and as single diastereomers. Furthermore, the scope of the reaction was applied to malonitrile as nucleophile, yielding the corresponding enantiopure carbocycle in 68% yield, as shown in Scheme 1.12. The synthetic utility of many of these chiral products was demonstrated by converting the sulfonylated piperidine derivatives into functionalised olefinic piperidines, for example.
In 2012, Csaky et al. developed a nice route to enantiopure poly-functionalised tetrahydropyrans based on an asymmetric domino Michael-acetal ring-opening reaction promoted by trifluoroacetic anhydride. This sequence consisted in the metal-free conjugate addition of boronic acids to chiral acetals performed in the presence of 3 equivalents of trifluoroacetic anhydride, providing the corresponding tetrahydropyrans in good to high yields and high to excellent diastereoselectivities of up to >96% de. A mechanism accounting for the diastereoselective formation of these products is depicted in Scheme 1.13. Reaction of trifluoroacetic anhydride with boronic acid could give a mono- or a diacylboronate intermediate 6, in which the Lewis acidity of the boron atom was enhanced with respect to boronic acid. Coordination of this species with the γ-oxygen of acetal led to intermediate 7. The subsequent intramolecular delivery of the R1 group was facilitated by the lone pair on the δ-oxygen, providing intermediate 8. Intramolecular ring-closure accounted for the formation of the final products. The stereochemistry has been found to depend on both the substrate and reagent structures. Indeed, a highly selective trans relative disposition between R1 and OH groups in the final products was found, which was consistent with a substrate-controlled chelated syn Michael addition step, as depicted on intermediate 7. The final cyclisation could be envisioned by an approach of the enolate to the sp2 carbon of the electrophilic moiety in a chairlike transition state 9. The pseudoequatorial disposition of the substituents minimised the steric interaction between R and benzyl groups in the final tetrahydropyrans.
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