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Synthesis 2016; 48(16): 2553-2571
DOI: 10.1055/s-0035-1561650
short review
© Georg Thieme Verlag Stuttgart · New York

A Decade of Advance in the Asymmetric Vinylogous Mannich Reaction

María Sánchez Roselló*
a   Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain
b   Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain   Email: maria.sanchez-rosello@uv.es   Email: santos.fustero@uv.es
,
Carlos del Pozo
a   Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain
,
Santos Fustero*
a   Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain
b   Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain   Email: maria.sanchez-rosello@uv.es   Email: santos.fustero@uv.es
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Further Information

Publication History

Received: 19 April 2016

Accepted: 25 April 2016

Publication Date:
21 June 2016 (online)

 
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Abstract

When the principle of vinylogy is applied to imines as electrophiles, the so-called vinylogous Mannich reaction (VMR), γ-aminocarbonyl (such as butenolides) and β-aminocarbonyl compounds are generated in a very efficient manner. The asymmetric version of this vinylogous Mannich reaction gives access to highly functionalized chiral synthons, which are suitable for further transformations. The versatility of this methodology is exemplified with the synthesis of several alkaloids and natural products.

1 Introduction

2 Asymmetric Vinylogous Mannich Reactions (VMR) with 2-Silyl­oxyfurans and 2-Silyloxypyrroles

3 Asymmetric VMR with Acyclic Silyl Dienolates and Silyl Dienol Ketene Acetals

4 Asymmetric VMR with γ-Butenolides and γ-Butyrolactams

5 Asymmetric VMR with α,α-Dicyanoolefins

6 Miscellaneous Donors in Asymmetric VMR

7 Application of the VMR to Natural Product Synthesis

8 Conclusions


#

Key words

vinylogous - Mannich reaction - asymmetric synthesis - γ-aminocarbonyl compounds - dienolates
1

Introduction

One of the most important goals for organic chemists in the last few decades has been the development of new stereoselective methods for the synthesis of optically pure molecules that bear diversity in their structures. This search has been driven in part by the growing demand for chiral drugs due, in turn, to the increased control of the enantiopurity of drug candidates. In this context, the asymmetric Mannich reaction is a powerful, straightforward carbon–carbon bond-forming process leading to the synthesis of β-amino carbonyl compounds.[1] Its vinylogous counterpart, the vinylogous Mannich reaction (VMR), involves the γ-addition of dienolate equivalents to imines and provides access to optically active δ-amino-α,β-unsaturated carbonyl derivatives.[2] [3] These are valuable structural motifs in biologically active compounds as well as highly functionalized intermediates for the synthesis of nitrogen-containing compounds such as alkaloids.[4] In comparison with the related vinylogous aldol reaction,[5] the development of asymmetric vinylogous Mannich procedures, in particular enantioselective variants, has progressed to a much lesser extent, despite the versatility of this transformation. Nevertheless, it has attracted increasing interest in recent years, not only from the methodological point of view, but also because of its applicability in the synthesis of alkaloids and other related natural products.

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Santos Fustero(left) was born in Aínsa, Spain, in 1949. He studied chemistry at the University of Zaragoza, where he obtained his Licenciatura (equivalent to a B.Sc. degree) in 1972. He received his Ph.D. in organic chemistry in 1975 from the same University, working in the field of heterocyclic chemistry under the supervision of Professor J. Barluenga­ and Professor V. Gotor. He spent two years as a postdoctoral research associate at Professor H. Lehmkuhl’s laboratory at Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr, Germany, researching organometallic chemistry. In 1983, he became Associate Professor at the University of Oviedo, Spain, and in 1990, he was promoted to Full Professor in Organic Chemistry at the University of Valencia. In 2005, he became research group leader at Centro de Investigación ‘Príncipe Felipe’ (CIPF) in Valencia. His research interests include organofluorine and medicinal chemistry, fluorous synthesis, organocatalysis and new reaction methodologies.
María Sánchez-Roselló (center) was born in Valencia, Spain, in 1977. She studied pharmacy and received her Ph.D. in 2005 from the University of Valencia under the supervision of Professor Santos Fustero, working in the field of organofluorine chemistry and focusing on the synthesis of α- and β-amino acids through the olefin metathesis reaction. She spent two years as a postdoctoral researcher in the laboratories of Professor Scott J. Miller at Boston College and Yale University, USA, working on peptide-based asymmetric catalysis. She then joined Professor Fustero’s group with a Juan de la Cierva research contract and currently she is an assistant professor in organic chemistry at the University of Valencia. Her scientific interests include asymmetric organocatalysis and organofluorine chemistry.
Carlos del Pozo (right) was born in Palacios del Sil, León (Spain), in 1965. He studied chemistry at the University of Oviedo, where he obtained his B.Sc. in 1988. He received his Ph.D. in organic chemistry in 1995, performed under the supervision of Professor J. Barluenga, working in the field of heterocyclic chemistry. He then carried out postdoctoral studies for 27 months at the University of Colorado at Boulder (USA) under the supervision of Professor Gary A. Molander, working on samarium iodide chemistry. He subsequently joined the group of Dr. Francisco Javier González at the University of Oviedo until the end of 2001, focusing on beta-lactam chemistry and protease inhibitor synthesis. In 2005, after working for three years in the pharmaceutical industry (total synthesis of natural products with antitumor activity), he joined the group of Professor Santos Fustero at the University of Valencia­, where he currently holds an associate professor position. His research interests are organofluorine chemistry, natural product synthesis and organocatalysis.

In a broad sense, vinylogous Mannich-type reactions can be categorized into direct addition processes, in which the vinylogous nucleophiles are generated in situ, or indirect protocols, mostly built upon preformed silyl dienolates (Mukaiyama-type additions). Both methodologies can engage either cyclic or acyclic donors with a variety of imines or iminium salts as the acceptor component.

In this review, we present an overview of the major contributions reported in the literature over the last decade (from 2006 to 2015) in the field of the asymmetric vinylogous Mannich reaction (VMR), emphasizing those involving catalytic methodological approaches. The review has been organized with a focus on the nature of the different pronucleophiles employed, namely 2-silyloxyfurans and 2-silyl­oxypyrroles, acyclic silyl dienolates, α,α-dicyanoolefins, and γ-butenolides and butyrolactams (sections 2–5). A section regarding the application of the reaction in the synthesis of natural products is also included (section 7). Several reviews covering vinylogous nucleophile addition reactions have been published to date, two of them specifically focused on the VMR although dating from 2001 and 2002. More recent advances in metal-catalyzed asymmetric Mannich­ reactions were also reviewed in 2013.[6] However, we consider the enantioselective VMR relevant enough to be treated now as a separate topic, together with its application in target-oriented synthesis of complex molecules.


# 2

Asymmetric Vinylogous Mannich Reactions­ (VMR) with 2-Silyloxyfurans and 2-Silyloxypyrroles

Asymmetric aldol-, Mannich-, and Michael-type addition reactions involving siloxy carbon nucleophiles, as well as their conjugate versions employing vinylogous silyl dienolates, have become exceptionally useful methods for chemo­-, stereo- and regioselective carbon–carbon bond formations since Mukaiyama’s seminal report in 1977.[7]

One of the main challenges in the development of the asymmetric VMR, i.e., the γ-addition of dienolate equivalents to imines, lies in the combination of both high γ-regio­selectivity and enantioselectivity in the generation of new stereogenic centers. In order to address these issues, the use of 2-silyloxyfurans became an attractive strategy due to the electronically more favorable γ-carbon addition of these aromatic heterocycles in comparison to the reaction through the α carbon.[8] Moreover, this strategy enables the synthesis of versatile γ-butenolide scaffolds, often found in many natural products, and which are also valuable building blocks in organic synthesis endeavors.

In this context, the first report regarding a VMR with 2-silyloxyfurans by Martin and Lopez[9] was enhanced by Hoveyda­ and Snapper in 2006.[10] These authors reported a practical and general protocol for the Ag-catalyzed enan­tioselective VMR of aryl-substituted aldimines 1 and 2-trimethylsilyloxyfurans 2a,b, to yield anti-γ-butenolide derivatives 4 in very good isolated yields. These reactions proceeded with complete diastereocontrol and high enantioselectivity in the presence of commercially available silver acetate­ and easily accessible amino acid based chiral phosphines 3, either with electron-rich or electron-poor aldimines. It should be noted that the use of 3-methylsilyloxyfuran (2c) (R1 = H, R2 = Me) led to the opposite syn diastereoisomer as the major reaction product after careful optimization of the reaction conditions (–60 °C, 10–15 mol% of AgOAc and phosphine ligand 3) (Scheme [1]). In addition, this protocol was performed on gram scale with almost the same efficiency and enantioselectivity.

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Scheme 1 Asymmetric Ag-catalyzed VMR of aryl-substituted aldimines 1 and 2-trimethylsilyloxyfurans 2

Two years later, the same authors reported a similar protocol for the three-component Ag-catalyzed enantioselective VMR of alkyl-substituted aldimines. They found that the use of an N-protecting group bearing an o-thiomethyl and a p-methoxy substituent (amine 5) was highly beneficial to achieve the excellent stereoselectivity results found in the butenolides 6 (Scheme [2]). Again, a reversal in diastereoselectivity was observed when employing the α-methyl-substituted furan 2c. In addition, reactions with enantiomerically enriched (S)- and (R)-2-phenylpropanal afforded the corresponding diastereoisomeric products in high stereoselectivity, thus demonstrating that this Ag-catalyzed enantioselective VMR was subjected to catalyst control.[11]

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Scheme 2 Three-component Ag-catalyzed VMR with alkyl-substituted aldimines

The extension of the reaction to more challenging keto­imine substrates was accomplished next.[12] Specifically, α-ketoimine esters 7 were found to perform efficiently in the asymmetric VMR with 2-TMS-silyloxyfuran 2a giving rise to the γ-butenolide products 8 bearing an N-substituted quaternary stereogenic center (Scheme [3]). The N-aryl moiety incorporating a p-nitro unit was crucial in order to obtain high levels of efficiency, diastereo- and enantioselectivity. It was also beneficial for its removal and the subsequent conversion of the vinylogous Mannich products into unprotected α-quaternary amino esters in high yields. When an o-bromo-substituted arylimine was employed, the syn diastereoisomer was the major product, albeit in poor enantioselectivity (32% ee).

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Scheme 3 Asymmetric Ag-catalyzed VMR of α-ketoimine esters 7 and 2-trimethylsilyloxyfuran (2a)

More recently, Hoveyda and co-workers showed that the same Ag-based chiral complexes catalyzed enantioselective VMRs involving 2-silyloxypyrrole 9 as the nucleo­philic component. Additions to aryl- and alkynyl-substituted aldimines 10 took place in good yields, furnishing compounds 11 bearing two contiguous N-substituted stereogenic centers with exceptional site- (γ- vs α-addition), dia­stereo- and enantioselectivity (Scheme [4]).[13]

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Scheme 4 Asymmetric Ag-catalyzed VMR of aryl- and alkynyl-substituted aldimines 10 and N-Boc TMS-silyloxypyrrole 9

Finally, the same authors reported the first example of an asymmetric VMR with 5-methyl-substituted silyloxyfuran 12, resulting in the formation of butenolides 14 bearing an O-substituted quaternary stereogenic center (Scheme [5]).[13] Addition to different aldimines 13 proceeded with high diastereo- and enantioselectivity although variable amounts of α-addition products were detected, probably due to the lower nucleophilicity and accessibility of the γ site.

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Scheme 5 Addition of 5-methyl-substituted silyloxyfuran 12 to aryl- and alkynyl-substituted aldimines 13

In 2008, Carretero and co-workers reported an efficient metal-catalyzed asymmetric procedure to carry out the VMR on N-(2-thienyl)sulfonylimines 15.[14] Both cyclic and acyclic silyl dienol ethers were used in this protocol catalyzed by copper(I) complexes of Fesulphos ligands 16. Reactions with 2-trimethylsilyloxyfuran (2a) proceeded at –40 °C in the presence of AgClO4 to deliver chiral γ-aminoalkyl-substituted butenolides 17 in excellent yields, and dia­stereo- and enantiocontrol (Scheme [6]). Moreover, the 2-thienylsulfonyl group can be easily removed (with Mg in MeOH) and the butenolide moiety transformed into the 5-hydroxy-2-piperidone (+)-18.

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Scheme 6 Asymmetric VMR of 2a and aldimines 15 catalyzed by copper(I)–Fesulphos complex 16

A new catalytic system for the asymmetric VMR of aldimines with 2-trimethylsilyloxyfuran (2a) was described in 2009 by Shi and co-workers. It involved the use of silver acetate and axially chiral phosphine–Schiff-base-type ligands 3, which allowed the synthesis of the expected δ-amino-butenolide products 21 in up to 91% yield and 81% ee.[15] Subsequently, the authors improved these results by using phosphine–oxazoline ligand 20, and 2,2,2-trifluoroethanol as an additive. After an extensive optimization of the reaction conditions, the anti-configured VMR adducts were obtained in up to 95% yield and 99% ee (Scheme [7], eq 1).[16]

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Scheme 7 Asymmetric VMRs of 2a and aldimines 19 and 22 catalyzed by Ag(I)-chiral phosphine–oxazoline ligand 20

The extension of this protocol to fluorinated aldimines was studied next,[17] aimed at the synthesis of chiral fluorine-containing γ-butenolide derivatives.[18] Shi and co-workers found that fluorinated aldimines 22 containing an (S)-1-phenylethyl auxiliary reacted with silyloxyfuran 2a to yield the corresponding VMR products 23 in high yields, enantiomeric excesses and diastereoselectivities. The optimized reaction conditions involved the use of AgOAc (10 mol%), EtOH (1.8 equiv), and the axially chiral phosphine–oxazoline ligand 20b (11 mol%), in THF at –78 °C (Scheme [7], eq 2).[19] The same protocol was also successfully applied to N-Boc aldimines.[20]

The Hoveyda–Snapper amino acid derived silver(I) catalysts were employed by Curti, Casiraghi and Zanardi in 2011 to carry out an asymmetric vinylogous addition of pyrrole-based silyl dienolates to a series of N-aryl ald­imines, thus affording δ-aminopyrrolinones in high yields and anti diastereoselectivities.[21] Subsequently, the same authors published an improved asymmetric vinylogous Mannich protocol that was particularly useful for aldimines derived from alkyl- and α-alkoxyalkyl-substituted aldehydes 25.[22] Through this optimized three-component procedure, α,β-unsaturated δ-amino-γ-butyrolactams 26 were obtained with virtually complete γ-site and anti-selectivity (Scheme [8]).

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Scheme 8 Three-component asymmetric Ag-catalyzed VMR with N-Cbz TMS-silyloxypyrrole 24

Products 26 were in turn converted into valuable enantiomerically pure 1,2-diamino compounds, which are common building blocks in organic synthesis, and are found in many natural products and also in several drugs with a variety of biological activities. Notably, a chemo- and diastereoselective oxa-Michael annulation took place to yield an unprecedented fused furopyrrolone heterocycle 27, an aza-analogue derivative related to the natural product (+)-goniofufurone (Scheme [9]).

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Scheme 9 Elaboration of Mannich product 26a into hexahydrofuro[3,2-b]pyrrolone 27

As indicated before, the first example of a catalytic enantioselective VMR of ketimines was reported by Hoveyda, Snapper and co-workers (see Scheme [3]), employing activated ketimines derived from keto esters.[12] However, a more challenging reaction on imines 28 derived from unactivated ketones was accomplished by Nakamura and co-workers using chiral catalysts 29 derived from cinchona alkaloids and Cu species in the presence of trimethylsilyl alcohol (TMSOH) as an additive.[23] Once the reaction conditions had been optimized, a series of aromatic ketimines 28 bearing either electron-donating or electron-withdrawing groups as well as ketimines derived from dialkyl ketones reacted with silyloxyfuran derivatives 2 to give optically active δ-amino-δ,δ-disubstituted α,β-unsaturated carbonyl compounds 30 in high yields and excellent stereoselectivities (Scheme [10]).

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Scheme 10 Asymmetric VMR of ketimines 28 catalyzed by cinchona alkaloid amide 29/Cu(OAc)2

In 2013, Xu and co-workers developed a new family of axially chiral monophosphines 31 as ligands for the silver-catalyzed asymmetric VMR of 2-trimethylsilyloxyfuran (2a) with aromatic aldimines 19. This procedure led to γ-butenolide derivatives 32 in very good yields, moderate to good enantioselectivities and excellent diastereoselectivities under mild conditions (Scheme [11]).[24]

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Scheme 11 Asymmetric VMR of 2a and aldimines 19 catalyzed by Ag(I)–chiral phosphine ligand 31

Organocatalyzed asymmetric vinylogous Mannich-type reactions have also been reported in recent years. For instance, Akiyama investigated a chiral Brønsted acid catalyzed approach to the enantioselective synthesis of γ-butenolide derivatives by means of an asymmetric VMR. To this end, a chiral BINOL-derived phosphoric acid 34 bearing iodine groups at the 6 and 6′ positions was developed. Both aromatic and aliphatic aldimines 33 reacted with 2-trimethylsilyloxyfuran (2a) to give preferentially the anti isomers of the corresponding butenolides 35 in high yields, diastereo- and enantioselectivities (Scheme [12]).[25]

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Scheme 12 Asymmetric VMR of 2a and aldimines 33 catalyzed by iodine­-substituted chiral phosphoric acid 34

Auxiliary-driven approaches to developing asymmetric versions of the VMR have also been reported. The first example of a chiral-auxiliary-mediated asymmetric VMR was reported in 2011 by Miao and Chen. It involved the reaction of aldimines 36 with 2-trimethylsilyloxyfuran (2a) using O-pivaloylated d-galactosylamine as a chiral template.[26] High yields and moderate to good diastereomeric excesses of N-galactosyl α-amino-2(5H)-furanone derivatives 37 were achieved using ZnCl2·Et2O as the promoter in Et2O at –78 °C. In a final stage, the carbohydrate template was easily detached under acidic conditions providing rapid access to γ-butenolide derivatives 38 (Scheme [13]).

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Scheme 13 VMR of N-(2,3,4,6-tetra-O-pivaloylated d-galactosyl)ald­imines 36 with 2a

A second example of an asymmetric VMR induced by a chiral auxiliary was also reported in 2011. Taking advantage of Ellman’s N-tert-butanesulfinimine chemistry, Huang and co-workers disclosed the nucleophilic addition of 2-(tert-butyldimethylsilyloxy)furan (40) to chiral imines 39 for the synthesis of 5-aminoalkylbutenolides 41.[27] The optimum conditions for the VMR involved the treatment of a solution of the furan and the imine partners in dichloromethane in the presence of TMSOTf at –78 °C for one hour. In this manner, a series of butenolides 41 was obtained as a mixture of two separable diastereoisomers in good yields and anti dia­stereoselectivity (Scheme [14]). The applicability of this methodology was illustrated by the synthesis of functionalized lactones 42 as well as 6-substituted trans-5-hydroxy­piperidin-2-ones 43, which are highly functionalized heterocycles susceptible to transformation into many bioactive compounds.

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Scheme 14 VMR of tert-butylsulfinylimines 39 with silyloxyfuran 40

During a study aimed at the asymmetric synthesis of pandamarilactonine alkaloids, an unexpected syn-diastereoselective (95:5 dr) VMR between 3-methyl-2-(tert-butyldimethylsilyloxy)furan and Ellman (RS )-N-tert-butanesulfinimine was observed (see Scheme [53]).[28] A similar strategy was recently developed by Liu taking advantage of 2-chlorotetrafluoroethanesulfinamide (CTFSA) as the chiral auxiliary.[29] Thus, the γ-addition of TBS-silyloxyfuran 40 to imines 44 derived from (S)-CTFSA took place regioselectively in DMSO at room temperature to give syn addition products 45 with high diastereoselectivity (up to 98:2 dr) (Scheme [15]). Alternatively, the anti products were obtained as the major isomers when the reactions were performed at –78 °C in the presence of tetrabutylammonium fluoride (TBAF). Removal of the chiral auxiliary without epimerization and further elaboration of the products into piperidone derivatives showed the synthetic potential of this methodology.

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Scheme 15 (S)-CFTSA-induced asymmetric VMR of aldimines 44 with TBS-silyloxyfuran 40

In 2014, Singh and co-workers reported a practical and direct approach to obtain chiral 3-substituted 3-amino­oxindoles, which are found in many structurally complex natural products. This method entailed a highly diastereoselective nucleophilic addition of various 2-silyloxyfurans 2 to isatin-derived N-tert-butanesulfinyl ketimines 46 promoted by a Lewis acid such as trimethylsilyl triflate (TMSOTf­).[30] This asymmetric VMR allowed the synthesis of highly enantiomerically enriched 3-butenolide-substituted 3-aminooxindoles 47 bearing two contiguous stereocenters and a variety of substituents at different positions on the aromatic oxindole ring. Remarkably, reactions with sterically hindered 5-substituted 2-trimethylsilyloxyfurans yielded chiral adducts bearing two adjacent quaternary centers with excellent selectivity (up to 99:1 dr) (Scheme [16]). The versatility of the developed methodology was demonstrated by 1,4-addition of nucleophiles to the butenolide moiety.

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Scheme 16 Diastereoselective VMR of N-tert-butanesulfinyl ketimines 46 and silyloxyfurans 2

Finally in this section, Tamura and co-workers described a diastereoselective addition of 2-trimethylsilyloxyfuran (2a) to chiral nitrones 48 derived from l-gulose as an N-chiral auxiliary, in the presence of a catalytic amount of TMSOTf­.[31] The resulting adducts were further treated with TBAF to afford bicyclic products 49 in good yields (Scheme [17]). One of these bicyclic products was elaborated to afford a key synthetic intermediate for polyoxin C and the natural product dysiherbaine.

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Scheme 17 Stereoselective VMR of 2a with l-gulose-derived chiral nitrones 48

# 3

Asymmetric VMR with Acyclic Silyl Dienolates and Silyl Dienol Ketene Acetals

Open-chain butadiene-based silyl dienol ethers and silyl dienol ketene acetals have been also employed as donors in Mukaiyama-type protocols, though to a lesser extent than the corresponding reactions with cyclic dienolates. It is known that acyclic dienolates derived from α,β-unsaturated carbonyl compounds may lead to mixtures of α- and γ-addition products, thus imposing regioselectivity issues to these processes. To the best of our knowledge, four types of catalytic systems have been successfully developed for the asymmetric addition of acyclic silyl dienolates to imines.

The first catalytic enantioselective VMR employing acyclic silyl dienol ethers as truly vinylogous enolate equivalents was described by Schneider in 2008. The addition of ester-derived silyl dienolates 52 to imines using a BINOL-based phosphoric acid catalyst took place with complete γ-site regiocontrol and high asymmetric induction to give δ-amino-α,β-unsaturated esters. The initial optimized conditions entailed the use of a phosphoric acid with bulky 3,3′-bismesityl substituents in the BINOL backbone in a 1:1:1 mixture of THF/tert-butanol/2-methyl-2-butanol as the solvent. Under these conditions, a variety of aromatic and heteroaromatic aldimines were converted into the corresponding vinylogous Mannich products 54 in good yields and enantioselectivities­ of up to 92% ee.[32] In order to further increase the enantioselectivity as well as the scope of the process, additional BINOL-based phosphoric acids were investigated. Derivative 53 bearing tert-butyl groups at the para positions increased significantly the previously obtained enantioselectivities (Scheme [18]).[33] The authors also found γ-substituted silyl dienolates 52 to be suitable substrates for this VMR, thus furnishing products with two new stereocenters with good diastereo- and enantiocontrol.

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Scheme 18 Brønsted acid catalyzed VMR of aldimines and TBS-substituted dienolate 52

The same authors developed a modified and highly useful protocol to carry out this enantioselective VMR of acyclic silyl dienolates and aliphatic aldimines specifically.[34] Furthermore, the reaction was successfully extended to amide-based silyl dienolates. In this manner, the addition of vinylketene silyl N,O-acetals to aromatic imines furnished δ-amino-α,β-unsaturated amides in good yields and enantioselectivities.[35]

As indicated before, the methodology developed by Carretero­ and co-workers was applicable to both cyclic and acyclic silyl dienol ethers 55.[14] Thus, the combination of Cu(I)–Fesulphos catalyst 16 and N-(2-thienyl)sulfonyl­imines 15 gave rise to optically enriched α,β-unsaturated γ-amino carbonyl derivatives 56 in good yields and enan­tioselectivities with complete γ-site regiocontrol (Scheme [19]).

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Scheme 19 Catalytic asymmetric VMR of acyclic silyl dienol ethers 55 and aldimines 19 catalyzed by copper(I)–Fesulphos complex 16

In 2010, Liu and Feng reported a highly efficient asymmetric three-component VMR involving acyclic silyl dienol ether 55a, aldehydes 50 and 2-aminophenol. The success of the reaction relied on the use of a chiral N,N′-dioxide–scandium(III) complex as the catalyst, generated in situ by reaction of Sc(OTf)3 and chiral ligand 57. Under these mild optimized conditions, a variety of aromatic aldehydes reacted to yield the expected δ-amino-α,β-unsaturated esters 58 in excellent yields and enantioselectivities (Scheme [20]).[36] In addition, a gram-scale synthesis of these chiral esters was performed without any loss of reactivity and enantioselectivity, thus demonstrating the robustness of this catalytic system.

More recently, List and co-workers described a general and highly enantioselective approach to the synthesis of δ-amino-β-keto esters and derivatives by means of an organocatalytic asymmetric vinylogous Mukaiyama–Mannich reaction utilizing chiral disulfonimide 61 (DSI) as the catalyst.[37] This methodology engaged the reaction of readily available dioxinone-derived silyloxydienes 60 with a variety of N-Boc-protected aromatic and heteroaromatic imines 59, thus leading to enantiomerically enriched dioxinone derivatives 62 in excellent yields (Scheme [21]). These products were subjected to various transformations to give different enantioenriched building blocks such as δ-amino-β-keto esters, keto thioesters, ketoamides and β-amino ketones, as well as ε-amino-δ,β-diketo esters through a C–C bond-forming reaction with a silyl ketene acetal. Moreover, the developed methodology was further applied in a formal synthesis of (–)-lasubin.

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Scheme 20 Asymmetric three-component VMR catalyzed by a chiral N,N′-dioxide–scandium(III) complex
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Scheme 21 Disulfonimide-catalyzed asymmetric vinylogous Mukaiyama–Mannich reaction

Later on, the same synthetic strategy was employed in a direct asymmetric synthesis of δ-amino-β-keto esters 64 by reaction of Chan diene 63 with N-Boc imines 59 (Scheme [22]).[38]

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Scheme 22 Disulfonimide-catalyzed asymmetric synthesis of δ-amino-β-keto esters 64

Liu, Chen and co-workers described a highly regio- and diastereoselective vinylogous Mannich-type reaction between chiral N-tert-butanesulfinyl imino esters 65 and dioxinone-derived silyl dienolates 60.[39] Interestingly, the choice of the Lewis acid employed as the catalyst allowed the authors to control the α- or γ-regioselectivity, thus achieving the first example of an α-selective Lewis acid catalyzed vinylogous Mannich-type reaction. Hence, AgOTf- and Zn(OTf)2-catalyzed reactions occurred selectively at the γ-position to yield compounds 66 in moderate to good yields, with a reversal of stereoselectivity between them. On the other hand, with AgOCOCF3 or AgOAc, α-adducts 67 were obtained in good yields and excellent diastereoselectivity (Scheme [23]). Finally, the obtained products were transformed into substituted chiral amino acid derivatives.

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Scheme 23 Vinylogous Mannich-type reaction of dioxinone-derived silyl dienolate 60 and N-tert-butanesulfinyl imino esters 65

A second example of a chiral auxiliary controlled stereoselective VMR was reported in 2011.[40] Thus, a three-component diastereoselective reaction involving aldehydes 50, a chiral naphthylamine 68 and silyl ketene acetal 55 gave the corresponding γ-adducts 69 in the presence of Sn(OTf)2 in moderate to good yields and diastereoselectivities (Scheme [24]). This methodology was applied to the synthesis of the tobacco alkaloid (S)-anabasine (see section 7).

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Scheme 24 Asymmetric three-component VMR catalyzed by Sn(OTf)2

# 4

Asymmetric VMR with γ-Butenolides and γ-Butyrolactams

The direct nucleophilic addition of in situ generated dienolates to imines is a highly attractive C–C bond-forming reaction because of its atom economy. In this regard, γ-butenolides and related compounds have been used as valuable carbon pronucleophiles in asymmetric VMRs due to the presence of relatively acidic protons that facilitate the generation of the corresponding dienolates and, also, to the presence of the γ-butenolide skeleton in many natural products.

Pioneering work in this area was carried out by Shibasaki and Matsunaga taking advantage of their bimetallic Schiff base catalysts for the deprotonation of the α-proton in carbonyl donors. These catalytic systems are able to activate simultaneously the pronucleophile and the electrophile species, thus inducing high reactivity and stereoselectivity in diverse catalytic asymmetric C–C bond-forming reactions.[41] These authors reported the first example of a direct catalytic asymmetric vinylogous Mannich addition of γ-butenolide donors 70 to N-diphenylphosphinoyl imines 71 catalyzed by the chiral Lewis acid, La(OTf)3/Me-PyBox (72), in the presence of an amine base (TMEDA) and a Brønsted acid (TfOH), which was found to be important for improving the yield, stereoselectivity and reproducibility of the final products 73 (Scheme [25]).[42]

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Scheme 25 Direct catalytic asymmetric VMR of γ-butenolides 70 and N-diphenylphosphinoyl imines 71

The second report in this area entailed the direct catalytic asymmetric VMR of α,β-unsaturated γ-butyrolactams 74 as donors with N-Boc imines 59 as electrophiles. This challenging reaction was successfully achieved employing homodinuclear Ni2–Schiff base complex 75 derived from BINAM. The optimized conditions, which required the use of DRIERITE (CaSO4) as a desiccant, allowed the reaction of non-isomerizable aryl and heteroaryl imines to give the desired γ-vinylogous Mannich adducts 76 as single isomers in high yields, diastereoselectivity up to 30:1 and 99% ee (Scheme [26]).[43] The authors proposed a bimetallic Lewis acid­/Brønsted base bifunctional mechanism to explain the stereochemical outcome observed in these reactions.

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Scheme 26 Direct catalytic asymmetric VMR of α,β-unsaturated γ-butyrolactam 74 and N-Boc imines 59

In 2011, Feng and co-workers applied their chiral N,N′-dioxide–scandium(III) complex (generated from ligand 57) to the catalytic enantioselective VMR of aldimines 77 with nonactivated natural α-angelica lactone 70b as a useful vinylogous nucleophile.[44] The reaction afforded chiral δ-amino-γ,γ-disubstituted butenolide carbonyl derivatives 78, bearing adjacent quaternary and tertiary stereocenters, in good yields and excellent diastereo- and enantioselectivities (Scheme [27]).

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Scheme 27 Direct catalytic asymmetric VMR of aldimines 77 with nonactivated natural α-angelica lactone 70b

A direct asymmetric VMR of aryl aldimines 79 with 3,4-dihalofuran-2(5H)-one 80 catalyzed by quinine 81 was described in 2012 by Xu, Wang and co-workers. Reactions in m-xylene at –30 °C gave functionalized γ-butenolide derivatives 82 in moderate to good yields (up to 98%) and enan­tioselectivities (up to 95% ee) (Scheme [28]).[45] The synthetic utility of this protocol was exemplified by the synthesis of biologically relevant compounds such as γ-butyrolactones and vicinal amino alcohols from the vinylogous Mannich adducts.

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Scheme 28 Direct asymmetric VMR of aldimines 79 and γ-dihalo­butenolides 80 catalyzed by quinine 81

The first example of a direct catalytic asymmetric VMR of a γ-butenolide pronucleophile and ketimines to produce α-tetrasubstituted amines was developed by Kumagai and Shibasaki. The success of this reaction relied on the use of N-thiophosphinoyl ketimines 83 activated by a soft Lewis acid as the catalyst. At the same time, the dienolate nucleophile was generated through deprotonation of γ-butenolides 70 catalyzed by a hard Brønsted base. The best catalytic system was comprised of the acetonitrile complex [Cu(CH3CN)4]PF6 as the Lewis acid, (R,RP )-TANIAPHOS 84 as the chiral ligand, and Et3N as the Brønsted base. Under these conditions, high diastereo- and enantioselectivities were observed with a range of N-thiophosphinoyl ketimines 83, even with methyl-substituted γ-crotonolactones (Scheme [29]).[46]

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Scheme 29 Direct asymmetric VMR of γ-butenolides 70 and N-thiophosphinoyl ketimines 83

One year later, Wang and co-workers reported an asymmetric VMR of γ-butenolides 80 with N-Boc ketimines 86, derived from isatins, catalyzed by a bifunctional quinidine-derived catalyst 87.[47] Thus, the tertiary amino group of the catalyst activated the γ-butenolides, while the hydroxy group activated the isatin electrophile through hydrogen bonds. Under the optimum reaction conditions, various ketimines 86 with different substituents on the aromatic ring reacted with γ-butenolides 80 to furnish 3-aminooxindoles 88, bearing adjacent quaternary and tertiary stereocenters, in good yields, moderate diastereoselectivities and high enantioselectivities (Scheme [30]).

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Scheme 30 Direct asymmetric VMR of γ-butenolides 80 and N-Boc isatin-derived ketimines 86
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Scheme 31 Direct asymmetric VMR of ketimines 71 with γ-butenolide 70a

A third example of a vinylogous addition of in situ generated dienolates from γ-butenolide 70a to ketimines 71 was recently disclosed by Nakamura and co-workers.[48] The catalytic system employed entailed the combination of cinchona alkaloid amide 89 with Zn(OTf)2 in the presence of triethylamine. A variety of N-phosphinoyl ketimines 71 bearing either electron-donating or electron-withdrawing substituents were subjected to the optimized reaction conditions to give the expected δ-amino-δ,δ-disubstituted α,β-unsaturated carbonyl compounds 90 in high yields, diastereo- and enantioselectivities (Scheme [31]). In addition, both enantiomers of the products could be accessed by using pseudoenantiomeric chiral catalysts.


# 5

Asymmetric VMR with α,α-Dicyanoolefins

Activated alkylidenes have shown interesting reactivity patterns toward the stereoselective generation of C–C bonds as they display a dual reactivity profile, namely α- and γ-functionalization. Among them, α,α-dicyanoalkenes, which have been known for more than a hundred years, inherently act as electron-deficient electrophiles. However, this behavior changed after the pioneering work of Jørgensen[­49] and Deng,[50] who described for the first time the vinylogous donor profile of these substrates.[51]

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Scheme 32 Asymmetric VMR of dicyanoalkenes 91 with α-amido sulfones 92

Jørgensen found that dicyanoalkylidenes 91 could act as nucleophiles in the enantioselective VMR with highly electrophilic N-acyl imines prepared in situ from α-amido sulfones 92. Optimized conditions involved the use of phase-transfer catalysis conditions, with 3 mol% of catalyst 93 and 50% K3PO4 in toluene at –25 °C. Good yields and enantioselectivities of vinylogous products 94 were achieved, with nearly complete control of the diastereoselectivity in all cases, favoring the formation of the anti isomers (Scheme [32]).[52] A wide range of dicyanoalkenes 91 proved to be good partners in the process, while only aromatic and heteroaromatic imine precursors 92 were compatible under the reaction conditions. With enolizable alkyl amido sulfones, mixtures of α- and γ-addition products were formed.

The obtained VMR adducts 94 are valuable synthetic intermediates and they could be utilized for a variety of transformations, considering the dicyanomethylene group as a masked ketone. Hence, compound 94a was converted into β-amino carbonyl derivative 95 by treatment with KMnO4­, with no erosion of the enantioselectivity (Scheme [33]).

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Scheme 33 Derivatization of compound 94a

At the same time, Chen and co-workers found that the enantioselective VMR of dicyanoalkenes 96 could also be performed with N-Boc aldimines 59.[53] To this end, chiral hydrogen donors such as thiourea 97 were employed as organocatalysts. Even with low catalyst loadings (2 mol%), complete diastereo- and enantioselectivity was achieved in most cases, affording trans-dicyano amines 98 in excellent yields (Scheme [34]). Again, the main limitation of this protocol was the use of enolizable aldimines.

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Scheme 34 Asymmetric VMR with dicyanoalkene donors 96 and N-Boc imines 59

Zhou demonstrated that the enantioselective VMR with α,α-dicyanoolefins as donors could also be performed in a metal-catalyzed process. Thus, dicyanoalkenes 91 reacted with aromatic aldimines 59 in the presence of silver acetate and chiral ferrocenyl ligand 99 at low temperature to render the corresponding adducts 100 in good yields and dia­stereoselectivities, although with moderate enantioselectivities (Scheme [35]).[54]

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Scheme 35 Asymmetric VMR with dicyanoalkene donors 91 and N-Boc imines 59

The aforementioned examples share the limitation of the imine type, being only successful with aromatic imines. These problems were overcome by Chen and co-workers, who found that the γ-addition product could be exclusively obtained with N-tosyl aldimines 101.[55] Furthermore, they developed a diastereodivergent approach to access both syn and anti diastereoisomers in the enantioselective VMR. Thus, the reaction of dicyanoalkenes 91 with sulfonyl imines 101 bearing enolizable substituents with the right combination of BINOL and the corresponding cinchona alkaloid (102), led the authors to identify conditions to obtain adducts syn-103 and anti-103 as the major products. On the one hand, with catalysts 102a or 102b, compounds syn-103 were obtained in good yields, moderate diastereomeric excesses and generally good enantiomeric excesses. On the other hand, the use of catalysts 102c and 102d was less efficient, affording anti-103 with moderate diastereo- and enantioselectivities (Scheme [36]).

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Scheme 36 VMR with dicyanoalkanes 91 and tosyl imines 101

# 6

Miscellaneous Donors in Asymmetric VMR

Most examples of vinylogous donors used in VMR were covered in sections 2–5. However, some other types of donors, i.e., different than butenolides, silyloxyfurans and silyl­oxydienes have also been employed to achieve this transformation.

In 2012, Gong, Luo and co-workers reported a Povarov reaction of 2-hydroxystyrenes 105 with aromatic imines generated in situ in a multicomponent manner. The process involved an initial VMR followed by an intramolecular Friedel–Crafts reaction that gave rise to tetrahydroquinoline scaffolds 107. The process was performed in an organocatalytic approach using chiral BINOL phosphoric acid 106 as the catalyst. Under the optimized conditions, reactions were performed in toluene at room temperature to afford final products 107 with good levels of diastereo- and enantioselectivity (Scheme [37]).[56]

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Scheme 37 Asymmetric organocatalytic Povarov reaction of 2-hydroxy­styrenes 105 with aromatic imines

More recently, Qing reported the use of 3-alkenyl-2-oxindoles 108 as vinylogous Mannich nucleophiles. The corresponding enolate reacted regioselectively through the γ-position with fluorinated sulfinyl aldimines 109 in the presence of Ti(Oi-Pr)4 as the catalyst to render chiral α-alkylidene-δ-amino-δ-fluoroalkyl oxindoles 110 as the final products in good yields and diastereoselectivities (Scheme [38]).[57]


# 7

Application of the VMR to Natural Product Synthesis

VMR is a well-suited methodology for the generation of γ-aminocarbonyl compounds and butenolides, merely depending on the vinylogous nucleophilic reagent employed. These highly functionalized synthons may be converted into a broad array of alkaloids and nitrogen heterocycles, endowing high versatility to the process. In the present section, the use of diastereoselective VMRs in natural product synthesis will be covered.

Waldmann and co-workers took advantage of the functionality introduced by the VMR in the preparation of new phosphatase inhibitors, which may result in a new approach for the treatment of diabetes or cancer. Inspired by the BIOS (biology-oriented synthesis) strategy, that builds on the diversity created by Nature, the authors developed a solid-phase synthesis of yohimbane analogues, which resulted in the identification of new indolo[2,3-a]quinolizidines 114 and 115 as inhibitors of mycobacterium tuberculosis protein tyrosine phosphatase (MptpB).[58]

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Scheme 38 VMR of alkenyl oxindoles 108 with fluorinated sulfinyl imines 109

VMR of tryptophan-derived imines 111 (attached to a solid phase) with disubstituted silyloxydienes 112 catalyzed by ZnCl2, afforded pyridones after ring closure of the VMR adducts. This reaction proceeded with moderate dia­stereoselectivity, the major isomers being compounds 113. The reaction sequence was compatible with aromatic, heterocyclic, and aliphatic imines 111 as well as differently substituted electron-rich silyloxydienes 112, with aromatic imines affording the best yields. By means of cyclization and solid-phase release, compounds 113 were converted into the final tetracyclic structures 114 and 115 (Scheme [39]).

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Scheme 39 Synthesis of phosphatase inhibitors 114 and 115

Martin and co-workers described a stereoselective methodology for the synthesis of galactofuranoside mimics 117.[59] Thus, Cbz-protected glucosamine 116 underwent the formation of the corresponding N-acyliminium ion in the presence of TMSOTf, that reacted in a VMR-type reaction with 2-trimethylsilyloxyfuran (2a). The process afforded two separable diastereoisomeric butenolides 117 in a 73:27 ratio and 52% yield (Scheme [40]). These compounds are of particular interest as synthetic precursors of disaccharide mimics.

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Scheme 40 Synthesis of galactofuranoside mimics 117

In 2005, Figueredo and co-workers employed the VMR as one of the key steps in the synthesis of the alkaloids norsecurinine 121a and securinine 121b.[60] The stereochemistry of the three stereocenters was settled in the reaction of silyloxydiene 119 with pyrrolidone 118a and piperidone 118b as precursors of the corresponding iminium cations. In order to obtain insights into the stereochemical preference of the VMR, the authors performed ab initio calculations using density functional theory. This study predicted that threo adducts would predominate, which was in agreement with the experimental results. Under the optimized conditions, pyrrolidone 118a reacted with furan 119 in the presence of BF3·OEt2 as the catalyst to afford a mixture of butenolide diastereoisomers, the major one being 120a. Allowing the reaction mixture to reach room temperature overnight, the major adduct 120a crystallized from the reaction mixture without any solvent, and it could be separated by filtration in 51% yield. In a final stage, compound 120a was converted into norsecurinine (121a) in three more steps. On the other hand, piperidone 118b reacted with furan 119 at –20 °C in the presence of n-Bu2BOTf to render a mixture of diastereoisomers. After chromatographic separation, the major threo product 120b was transformed into the natural product securinine (121b) (Scheme [41]).

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Scheme 41 Total synthesis of norsecurinine (121a) and securinine (121b)

Three years later, Busqué, de March and co-workers devised an alternative strategy to access the epimer, allosecurinin (126), again based on a VMR as the key transformation.[61] To this end, benzofuranone ketal 122 (readily available from p-benzoquinone) was envisaged as the starting material. Treatment with TIPSOTf in the presence of triethylamine afforded the dienic substrate 123 in almost quantitative yield. Reaction of 123 with the piperidinium ion derived from 124 was accomplished with TIPSOTf as a Lewis acid, rendering condensation product 125 as a 5:1 mixture of diastereoisomers. The major isomer was transformed into the desired natural product 126 in four steps (Scheme [42]).

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Scheme 42 Total synthesis of allosecurinine (126)

Since this methodology encountered several problems, the authors developed an alternative strategy to overcome the instability of some of the intermediates. It involved the use of the natural product menisdauriliden (127) as the starting material of the synthetic sequence. The dienic substrate 128 for the VMR was generated by initial protection of the hydroxy functionality followed by the generation of the silyl enol ether. Reaction with piperidine 124 was now catalyzed by n-Bu2BOTf to render condensation product 129 as a separable 4:1 mixture of diastereoisomers in almost quantitative yield. After chromatographic separation, the major isomer was transformed into the natural product in four steps, improving the final yield to 38% (Scheme [42]).

In 2009, Schneider and co-workers synthesized the tobacco alkaloid (S)-anabasine (132) by means of a catalytic enantioselective VMR, previously developed by them, as the key step.[62] The chiral center of the natural product was assembled by reaction of silyl dienolate 52 and imine 130 using a chiral BINOL-based phosphoric acid as the catalyst. The best results were obtained with phosphoric acid 53 at –50 °C, yielding the desired adduct 131 in 96% yield and 92% ee. Transformation of 131 into the desired product, anabasine (132), was accomplished in three steps with 55% overall yield (Scheme [43]).

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Scheme 43 Total synthesis of anabasine 132 (route 1)

Later on, the same research group applied their organocatalytic approach to the enantioselective VMR to access different indolizidine-type alkaloids.[63] The three-component reaction of p-anisidine, silyl-O,O-acetal 133a and aldehyde 134 in the presence of chiral BINOL-phosphoric acid 135a afforded the corresponding Mannich adduct that was heated in situ in acetic acid to afford lactam 136a in 86% yield and 96% ee. This transformation was performed on 32 mmol scale. Lactam 136a contains the functionalized carbon chain required for the assembly of the bicyclic framework of indolizidine alkaloids. Therefore, 136a was further converted into the alkaloids coniceine (137a), indolizidine 167B (137b) and monomorine (137c). Following the same sequence, the multicomponent reaction, on 17 mmol scale, with silyl-O,O-acetal 133b followed by treatment with acetic acid afforded lactam 136b in 68% yield and 93% ee. This compound was transformed into indolizidine alkaloid 167A (137d) (Scheme [44]).

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Scheme 44 Total synthesis of indolizidine alkaloids 137a–d

In 2011, Yang and co-workers also reported a total synthesis of (S)-anabasine (132) by means of a three-component diastereoselective VMR.[40] Thus, the combination of silyl ketene acetal 55 with nicotinaldehyde (138) and (R)-(+)-1-naphthalen-1-yl-ethylamine (139) in the presence of tin triflate afforded amino ester 140 as an 8:1 mixture of dia­stereoisomers. Removal of the chiral auxiliary and creation of the piperidine ring completed the synthetic sequence to afford the natural product 132 (Scheme [45]).

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Scheme 45 Total synthesis of anabasine 132 (route 2)

Huang and co-workers took advantage of a diastereoselective VMR for the creation of the tricyclic structure of the stemona alkaloid, 9-epi-sessilifoliamide J (144).[64] The piperidine core was synthesized through the reaction of bicyclic N,O-acetal 141 with 2-methylsilyloxyfuran 142, giving optimum results with TMSOTf as a Lewis acid. VMR adduct 143 was introduced into the synthetic sequence as a diastereoisomeric mixture, allowing the authors to obtain, in four steps, the complex natural product 144 (Scheme [46]).

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Scheme 46 Total synthesis of 9-epi-sessilifoliamide J (144)

Gademann reported the synthesis of the complex natural products virosaine A (148) and bubbialidine (149) introducing the initial stereochemistry by means of a diastereoselective VMR.[65] The silyloxydiene precursor 128 was generated from silyl-protected aquilegiolide 145 (prepared by known methodologies) and the VMR was achieved with aminol 146 and TIPSOTf as a Lewis acid. Among the four possible diastereoisomers, only two were formed in 90% yield in a 1:1 diastereoisomeric ratio. After chromatographic separation, isomer 147 was transformed, in several steps, into the natural products 148 and 149 (Scheme [47]).

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Scheme 47 Total synthesis of virosaine A (148) and bubbialidine (149)

Huang and co-workers used the potential of the diastereoselective VMR to carry out an asymmetric synthesis of piperidine alkaloids.[66] After some optimization work, the authors found that sulfinylimines 150 reacted with 2-(tert-butyldimethylsilyloxy)furan (40) in the presence of Sm(OTf)3 in dichloromethane at room temperature, to give butenolide 151 as a 6:1 mixture of diastereoisomers. With this substrate in hand, the piperidine alkaloids deoxoprosophylline (152), deoxyallonojirimycin (153) and 3-epi-fagomine (154) were synthesized efficiently (Scheme [48]).

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Scheme 48 Total synthesis of piperidine alkaloids 152–154

One of the problems associated with the treatment of seasonal flu epidemics is the emergence of drug-resistant mutant strains. In the context of target-oriented synthesis, Sartori, Zanardi and co-workers developed a synthesis platform that provided access to several epimers, at positions C4 and C5, of oseltamivir phosphate (159).[67] This stereodivergent synthetic methodology was achieved by means of a diastereoselective VMR. Glyceraldehyde acetonide 155, 2-methoxyaniline (156) and silyloxypyrrole 157 were heated either neat or in water under ultrasonic irradiation to render a mixture of separable condensation products 158a–c in excellent overall yield (95–96%). Each individual diastereoisomer was converted into the final epimers of oseltamivir phosphate 159 (Scheme [49]).

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Scheme 49 Synthesis of oseltamivir phosphate analogues

Martin and co-workers disclosed the first total synthesis of the complex alkaloids citrinadins A and B (164a,b).[68] The strategy featured a highly diastereoselective VMR which set the first chiral center, while the remaining stereocenters of the pentacyclic core were substrate-controlled. Additionally, the synthesis led the authors to revise the initially wrongly assigned stereochemistry of the natural products.

Zinc dienolate 161, which was generated in situ from ester 160, was added to chiral pyridinium salt 162 to afford, in a highly diastereoselective manner, the pyridine derivative 163. The created chirality was exploited to generate the rest of the stereocenters of the pentacyclic core in a linear sequence, accessing citrinadins A and B (164a,b) in 20 and 21 steps, respectively (Scheme [50]).

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Scheme 50 Total synthesis of citrinadins A and B (164a,b)

Yang also took advantage of the ability of the VMR to generate versatile building blocks for the synthesis of chiral multisubstituted piperidines and quinolizidines.[69] Inspired by the biosyntheses of piperidines and quinolizidines, employing l-lysine as the starting material, Yang envisioned that a similar process could be accomplished by a VMR. It was found that 1,3-bis-trimethylsilyl enol ether 166, as a vinylogous nucleophilic reagent, reacted with aldehydes 165 and chiral amine 167 in a multicomponent process in the presence of tin triflate, to render the condensation products 168 together with variable amounts of cyclized products 169. Treatment of the crude mixture with acetic acid promoted cyclization to give piperidones 169 in moderate yields and excellent diastereoselectivities, since in all cases single isomers were observed and isolated from the reaction mixtures. The method was showcased by concise approaches to the piperidine alkaloids 241D (170), isosolenopsin A (171) and the quinolizidine alkaloid epimyrtine (172) (Scheme [51]).

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Scheme 51 Total synthesis of alkaloids 170–172

The skeleton of 8b-azaacenaphthylene, present in alkaloids such as crepidine and alkaloid 205B, is a tricyclic ring system rarely encountered in Nature. Recently, Delair and co-workers reported the utility of a diastereoselective VMR as one of the key transformations to access highly functionalized 8b-azaacenaphthylene scaffold 175.[70] When aminal 173 was treated with 2-trimethylsilyloxyfuran (2a) in the presence of BF3·OEt2 as the Lewis acid at low temperature, a 2.7:1 separable mixture of the diastereoisomers of butenolide 174 was obtained in almost quantitative yield. After chromatographic separation, which rendered 72% of the desired diastereoisomer, compound 174 was converted in eight steps into the tricyclic derivative 175. This synthetic effort was aimed at the synthesis of closely related alkaloid 205B (Scheme [52]).

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Scheme 52 Total synthesis of tricyclic derivative 175

Finally, Ye, Huang and co-workers developed a protecting-group-free asymmetric synthesis of the alkaloid pandamarilactonine A (178).[28] This total synthesis was a challenging task due to the configurational instability of pyrrolidin-2-yl-butenolide-containing alkaloids. The authors found that VMR of Ellman sulfinylimine 176 with 3-methyl-2-(tert-butyldimethylsilyloxy)furan (142) took place at –78 °C in the presence of a catalytic amount of TMSOTf to render the syn adduct 177 in high yield and diastereoselectivity. An interesting switch of selectivity was observed in this process, since anti selection had usually been observed for VMRs employing sulfinylimines. The total synthesis of the alkaloid pandamarilactonine A (178) was accomplished from 177 in three steps with a 58% overall yield (Scheme [53]).

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Scheme 53 Total synthesis of pandamarilactonine A (178)

# 8

Conclusions

This short review clearly illustrates that the asymmetric VMR constitutes an excellent tool for the synthesis of highly functionalized γ-aminocarbonyl (and β-aminocarbonyl) compounds, which in turn can be converted into different alkaloids and natural products. The main improvements, in the last decade, rely mostly on the extension of this methodology to the more challenging ketimines and imino esters as electrophiles. Various enantioselective methodologies have been devised in this area, allowing the generation of the corresponding quaternary stereocenters in a very efficient manner. Probably, the main limitation of this reaction is related to the types of nucleophilic donors, being restricted, in most cases, to butenolides, silyloxyfurans (pyrroles) and silyloxydienes. In our opinion, more work should be done in this context to adapt this methodology into a more versatile synthetic tool for organic chemists.


#
#

Acknowledgment

We thank the Spanish Ministerio de Ciencia e Innovación (CTQ2013-43310-P) and Generalitat Valenciana (GV/PrometeoII/2014/073) for their generous financial support.



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Santos Fustero(left) was born in Aínsa, Spain, in 1949. He studied chemistry at the University of Zaragoza, where he obtained his Licenciatura (equivalent to a B.Sc. degree) in 1972. He received his Ph.D. in organic chemistry in 1975 from the same University, working in the field of heterocyclic chemistry under the supervision of Professor J. Barluenga­ and Professor V. Gotor. He spent two years as a postdoctoral research associate at Professor H. Lehmkuhl’s laboratory at Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr, Germany, researching organometallic chemistry. In 1983, he became Associate Professor at the University of Oviedo, Spain, and in 1990, he was promoted to Full Professor in Organic Chemistry at the University of Valencia. In 2005, he became research group leader at Centro de Investigación ‘Príncipe Felipe’ (CIPF) in Valencia. His research interests include organofluorine and medicinal chemistry, fluorous synthesis, organocatalysis and new reaction methodologies.
María Sánchez-Roselló (center) was born in Valencia, Spain, in 1977. She studied pharmacy and received her Ph.D. in 2005 from the University of Valencia under the supervision of Professor Santos Fustero, working in the field of organofluorine chemistry and focusing on the synthesis of α- and β-amino acids through the olefin metathesis reaction. She spent two years as a postdoctoral researcher in the laboratories of Professor Scott J. Miller at Boston College and Yale University, USA, working on peptide-based asymmetric catalysis. She then joined Professor Fustero’s group with a Juan de la Cierva research contract and currently she is an assistant professor in organic chemistry at the University of Valencia. Her scientific interests include asymmetric organocatalysis and organofluorine chemistry.
Carlos del Pozo (right) was born in Palacios del Sil, León (Spain), in 1965. He studied chemistry at the University of Oviedo, where he obtained his B.Sc. in 1988. He received his Ph.D. in organic chemistry in 1995, performed under the supervision of Professor J. Barluenga, working in the field of heterocyclic chemistry. He then carried out postdoctoral studies for 27 months at the University of Colorado at Boulder (USA) under the supervision of Professor Gary A. Molander, working on samarium iodide chemistry. He subsequently joined the group of Dr. Francisco Javier González at the University of Oviedo until the end of 2001, focusing on beta-lactam chemistry and protease inhibitor synthesis. In 2005, after working for three years in the pharmaceutical industry (total synthesis of natural products with antitumor activity), he joined the group of Professor Santos Fustero at the University of Valencia­, where he currently holds an associate professor position. His research interests are organofluorine chemistry, natural product synthesis and organocatalysis.
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Scheme 1 Asymmetric Ag-catalyzed VMR of aryl-substituted aldimines 1 and 2-trimethylsilyloxyfurans 2
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Scheme 2 Three-component Ag-catalyzed VMR with alkyl-substituted aldimines
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Scheme 3 Asymmetric Ag-catalyzed VMR of α-ketoimine esters 7 and 2-trimethylsilyloxyfuran (2a)
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Scheme 4 Asymmetric Ag-catalyzed VMR of aryl- and alkynyl-substituted aldimines 10 and N-Boc TMS-silyloxypyrrole 9
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Scheme 5 Addition of 5-methyl-substituted silyloxyfuran 12 to aryl- and alkynyl-substituted aldimines 13
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Scheme 6 Asymmetric VMR of 2a and aldimines 15 catalyzed by copper(I)–Fesulphos complex 16
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Scheme 7 Asymmetric VMRs of 2a and aldimines 19 and 22 catalyzed by Ag(I)-chiral phosphine–oxazoline ligand 20
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Scheme 8 Three-component asymmetric Ag-catalyzed VMR with N-Cbz TMS-silyloxypyrrole 24
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Scheme 9 Elaboration of Mannich product 26a into hexahydrofuro[3,2-b]pyrrolone 27
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Scheme 10 Asymmetric VMR of ketimines 28 catalyzed by cinchona alkaloid amide 29/Cu(OAc)2
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Scheme 11 Asymmetric VMR of 2a and aldimines 19 catalyzed by Ag(I)–chiral phosphine ligand 31
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Scheme 12 Asymmetric VMR of 2a and aldimines 33 catalyzed by iodine­-substituted chiral phosphoric acid 34
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Scheme 13 VMR of N-(2,3,4,6-tetra-O-pivaloylated d-galactosyl)ald­imines 36 with 2a
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Scheme 14 VMR of tert-butylsulfinylimines 39 with silyloxyfuran 40
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Scheme 15 (S)-CFTSA-induced asymmetric VMR of aldimines 44 with TBS-silyloxyfuran 40
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Scheme 16 Diastereoselective VMR of N-tert-butanesulfinyl ketimines 46 and silyloxyfurans 2
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Scheme 17 Stereoselective VMR of 2a with l-gulose-derived chiral nitrones 48
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Scheme 18 Brønsted acid catalyzed VMR of aldimines and TBS-substituted dienolate 52
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Scheme 19 Catalytic asymmetric VMR of acyclic silyl dienol ethers 55 and aldimines 19 catalyzed by copper(I)–Fesulphos complex 16
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Scheme 20 Asymmetric three-component VMR catalyzed by a chiral N,N′-dioxide–scandium(III) complex
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Scheme 21 Disulfonimide-catalyzed asymmetric vinylogous Mukaiyama–Mannich reaction
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Scheme 22 Disulfonimide-catalyzed asymmetric synthesis of δ-amino-β-keto esters 64
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Scheme 23 Vinylogous Mannich-type reaction of dioxinone-derived silyl dienolate 60 and N-tert-butanesulfinyl imino esters 65
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Scheme 24 Asymmetric three-component VMR catalyzed by Sn(OTf)2
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Scheme 25 Direct catalytic asymmetric VMR of γ-butenolides 70 and N-diphenylphosphinoyl imines 71
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Scheme 26 Direct catalytic asymmetric VMR of α,β-unsaturated γ-butyrolactam 74 and N-Boc imines 59
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Scheme 27 Direct catalytic asymmetric VMR of aldimines 77 with nonactivated natural α-angelica lactone 70b
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Scheme 28 Direct asymmetric VMR of aldimines 79 and γ-dihalo­butenolides 80 catalyzed by quinine 81
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Scheme 29 Direct asymmetric VMR of γ-butenolides 70 and N-thiophosphinoyl ketimines 83
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Scheme 30 Direct asymmetric VMR of γ-butenolides 80 and N-Boc isatin-derived ketimines 86
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Scheme 31 Direct asymmetric VMR of ketimines 71 with γ-butenolide 70a
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Scheme 32 Asymmetric VMR of dicyanoalkenes 91 with α-amido sulfones 92
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Scheme 33 Derivatization of compound 94a
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Scheme 34 Asymmetric VMR with dicyanoalkene donors 96 and N-Boc imines 59
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Scheme 35 Asymmetric VMR with dicyanoalkene donors 91 and N-Boc imines 59
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Scheme 36 VMR with dicyanoalkanes 91 and tosyl imines 101
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Scheme 37 Asymmetric organocatalytic Povarov reaction of 2-hydroxy­styrenes 105 with aromatic imines
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Scheme 38 VMR of alkenyl oxindoles 108 with fluorinated sulfinyl imines 109
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Scheme 39 Synthesis of phosphatase inhibitors 114 and 115
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Scheme 40 Synthesis of galactofuranoside mimics 117
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Scheme 41 Total synthesis of norsecurinine (121a) and securinine (121b)
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Scheme 42 Total synthesis of allosecurinine (126)
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Scheme 43 Total synthesis of anabasine 132 (route 1)
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Scheme 44 Total synthesis of indolizidine alkaloids 137a–d
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Scheme 45 Total synthesis of anabasine 132 (route 2)
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Scheme 46 Total synthesis of 9-epi-sessilifoliamide J (144)
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Scheme 47 Total synthesis of virosaine A (148) and bubbialidine (149)
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Scheme 48 Total synthesis of piperidine alkaloids 152–154
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Scheme 49 Synthesis of oseltamivir phosphate analogues
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Scheme 50 Total synthesis of citrinadins A and B (164a,b)
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Scheme 51 Total synthesis of alkaloids 170–172
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Scheme 52 Total synthesis of tricyclic derivative 175
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Scheme 53 Total synthesis of pandamarilactonine A (178)