A concise review on the s tereoselective synthesis of chiral α -bisamides using stereoselective Ugi-type reaction

To ensure a sustainable development, the “ twelve principles of green chemistry ” have been proposed for the field of synthetic organic chemistry. The stereoselective Ugi reaction is one of the most widely used reactions with high atom economy to prepare chiral α -bisamides and this reaction satisfies many of the green chemistry principles. The recent achievements in this reaction include one pot synthetic methodology, aqueous phase transformations and solvent free transformations even at ambient conditions. This review summarizes the progress recorded in this field over the past 20 years


Introduction
The Ugi reaction involves a one-pot condensation of four components, an aldehyde or a ketone, an isocyanide, an amine, and a carboxylic acid to furnish α-bisamides. 1,2In addition to three new bonds (two C-N bonds and one C-C bond) a new stereogenic center may be generated in this reaction by using a prochiral ketone / aldehyde having enantiotopic / diastereotopic faces.As one stereocenter can be generated, the search for its stereoselective version has become a much-desired goal among synthetic organic chemists.However, achieving the control of chirality in this reaction is still an extremely difficult task.This reaction can be carried out using one pot synthetic methodology and hence unnecessary derivatization steps such as protecting or deprotecting reactions can be avoided.To prevent waste or to maximize atom economy, these kinds of multicomponent reactions are to be encouraged not only in academic laboratories but also in industry.The recent developments in this field include the usage of aqueous phase transformations and solvent free transformations at ambient conditions.It offers high atom economy and low-cost production to access complex heterocycles within a short period of time using simple procedures.The control of stereochemical outcome is still a long-standing challenge.In case of its asymmetric version, the genesis of chirality is achieved by using chiral non-racemic compounds.In the past few years, stereoselective approaches have been realized by employing chiral catalysts, chiral substrates or chiral auxiliaries to obtain optically pure asymmetric chiral Ugi products.A wide range of natural products and pharmacologically relevant α-bisamides can be synthesized directly by using asymmetric version of the Ugi reaction.Some examples are as follows:

Chiral amino acid derivatives as substrate
In 2002, Dyker 3 and his group reported the synthesis of novel chiral ligands from amino acids by employing the Ugi reaction (Scheme 1).The amino acid L-valine 2 on condensation with pyridine-2-aldehyde 3 and tert-butyl isocyanide 4 in anhydrous methanol at room temperature afforded the Ugi product 1,1ʹ-iminodicarboxylic acid derivative 5 in good yield and excellent diastereoselectivity.It is one of the first examples of an asymmetric Ugi reaction based on chiral amino acid as substrate.Ugi products can be further used as efficient ligands for enantioselective transition metal catalysis.

Scheme 3
Plausible mechanism β-Lactam ring generation starts through the formation of Schiff base intermediate 10a.The next step includes nucleophilic addition of isocyanide on to the intermediate 10a, followed by generation of product 9a and 9b.The approach of the isocyanide from the Si face is sterically hindered by existing dimethylmethylene bridge of 10a resulting a minor product 9b.Steric interactions are absent for Re face mediated nucleophilic addition process and hence it proceeds preferentially resulting the major product 9a (Scheme 4).

Scheme 6 Mechanism
A plausible mechanism for this protocol (Scheme 7) proceeds via intermediate 15a.Formyltryptophan 13 and amine react to give an iminium ion which then gets protonated intramolecularly by carboxylic acid to generate pseudocyclic intermediate 15a.In the next step, carboxylate can then attack from the Re face giving a transition state 15f in which the substituent on nitrogen is in pseudoequatorial position where unfavorable allylic strain with indole N-H is absent.Substitution by isocyanide leads to inversion of configuration giving an intermediate 15h which then rearranges to 15i followed by acyl transfer to give trans isomer as major product.Alternatively, carboxylate can attack 15a from the Si face giving an unfavorable transition state 15b.Attack of isocyanide and acyl transfer in later steps results in cis isomer as minor product.
In 2012, Banfi 8 and his co-workers reported an asymmetric Ugi reaction of oxanorbornene β-amino acid derivative 16 leading to a bicyclic peptidomimetics 17a-c with moderate to high yield and diastereo selectivities (Scheme 8).The generality and postulated mechanism for this reaction has been described.

Scheme 9
In 2012, Turner 9 and his co-workers reported a stereoselective Ugi reaction of carboxylate salt of amino acids 19 and 21, aromatic aldehyde, and isocyanides in presence of catalytic amount of titanium (IV) chloride for synthesis of peptide mimics 20 and 22 (Scheme 10).A nonchelated model (Scheme 11) has been proposed to explain mechanism of this reaction.

Scheme 12
A new efficient enantioselective and diastereoselective synthesis of N-acyl-2,5-disubstituted pyrrolidine 26a and 26b through a multicomponent Ugi reaction has been described by Banfi 11 and co-workers in 2008, using pyrrolines 25 as cyclic imine, 2-isocyano-2-methylpropyl methyl carbonate and 2-phenylacetic acid (Scheme 13).Pyrrolidines can be further used as substrate for synthesis of many bicyclic derivatives.

Scheme 13
A new catalytic Ugi-type condensation of α-isocyanoacetamide 27 and chiral cyclic imine 28 has been developed by Chen 12 and his co-workers in 2012 where a combination of phenyl phosphilic acid and trifluoroethanol was used as catalytic system to promote the aforementioned reaction.Under mild conditions, the reaction of 27 and 28 proceeded quickly to give 3-oxazolyl-morpholin or piperazine-2-one derivatives 29ab in excellent yield and good diastereoselectivity (Scheme 14).

Mechanism
The stereochemical outcome can be explained in terms of two different structures of ion pair as intermediate in Joullié-Ugi three component reactions (Scheme 16).In non-polar solvent like toluene, imine 30 gets protonated by carboxylic acid to form a contact-oriented ion pair 32a, which is stabilized by coulombic forces prominent in non-polar solvents.This results in an SN2-type transition state 32b in which positive charge is stabilized by carboxylate ion giving cis isomer as major product.However, in polar solvents like HFIP, a solventseparated ion pair 32d also exist along with contact-oriented ion pair 32a.Therefore, when isocyanide reacts with the former, isocyanide attacks iminium ion from opposite side of bulky siloxy group forming an SN1-type transition state 32e where positive charge is not stabilized by carboxylate ion, thus it affords the trans isomer and on reaction with 32a it results in cis isomer as in non-polar solvent.
In 2017, Zarezin 14 and his group reported a diastereoselective azido-Ugi reaction employing 2-(tertbutyl)pyrrolidine 33, isobutyraldehyde, benzyl isonitrile and trimethylsilyl azide as substrates in an alcoholic solvent.This protocol provides a short and efficient route for synthesis of tetrazole derivatives 34 with high control of diastereoselectivity (d.r. up to 100:0) and excellent yield (≤ 98%).Tetrazoles are of interest due to their broad applicability in medicinal chemistry (Scheme 17) 15 .Zhu 16 and his co-workers developed a new asymmetric three-component Ugi reaction of cyclic ketoimines 35 with isocyanides and carboxylic acids to afford novel morpholin-2-one-3-carboxamide 36a-c in the year 2010 (Scheme 18).Cyclic imines show great potential for stereoinduction of new chiral center in the desired Ugi products.Morpholin-2-one-3-carboxamide is important in medicinal and pharmaceutical chemistry 17 .

Scheme 18. Synthesis of 5-substituted morpholin-2-one-3-carboxamide derivatives from ketoimines
The absolute configuration of the major diastereomer was determined through a NOESY experiment.In 2010, Znabet 18 and his group developed an efficient combination of desymmetrization of meso-pyrrolidines using monoamine oxidase (MAO-N) as biocatalyst with Ugi multicomponent reaction for stereoselective synthesis of 3,4-substituted prolyl peptides which are important in medicinal chemistry (Scheme 19).

Scheme 21
In 2012, Znabet 19 and his group developed an efficient combination of MAO-N-catalyzed desymmetrization of cyclic meso-amines with Ugi-Smiles multicomponent reaction to synthesize chiral N-aryl proline amides (Scheme 22).

Scheme 24
In 2013, Rijsel 21 and his group reported an Ugi reaction involving chiral pyrroline 46 formed from Staudinger-aza-Wittig reaction of a D-pentose-derived 4-azido aldehyde 45 leading to pyrrolidine derivative 47 in moderate yield and high diastereoselectivities favoring the cis isomer (Scheme 25).

Scheme 25
In 2019, van der Heijden 22 and his co-workers reported a highly diastereoselective Ugi reaction of Δ 1piperideines, various isocyanides and carboxylic acids for the synthesis of pipecolic amides 49a-b (Scheme 26).

Mechanism
The observed diastereoselectivity can be explained by Fürst-Plattner rules.Δ 1 -piperideine on protonation by carboxylic acid affords an iminium ion having half chair conformation 50a where alkyl substituent occupies a pseudo-equatorial position.In the next step, since equatorial attack of isocyanide gives an unfavorable twistboat conformation, so it attacks from top face (axial attack) giving a more favorable chair conformation 50b.As a result, trans-pipecolic amide 49 is formed exclusively (Scheme 27).

Mechanism
Imine 51 gets protonated by carboxylic acid to give iminium ion 53a.From computational studies it was found that isocyanide prefers to attack from more favorable Si face resulting intermediate 53b followed by reaction with acid to give more stable intermediate 53c which then rearranges to final product 52 as major diastereomers.

Scheme 29
In 2011, Banfi 24 and his co-workers reported Ugi reaction of 2-substituted dihydrobenzoxazepines 54 leading to synthesis of tetrahydrobenzoxazepine derivative 55a-c using methanol as solvent at room temperature (Scheme 30).It is the first example of asymmetric Ugi reaction involving seven membered cyclic imines.

Mechanism
The observed diastereoselectivity can be explained by the fact that, equatorial attack of isocyanide leads to an intermediate 56b which is unfavorable due to peri-interactions so that the trans isomer is obtained as a minor product.In contrast, axial attack of isocyanide gives cis isomer as major product.

Scheme 31 2.3 Chiral amine as substrates
In 1988, Kunz 25 and his group reported a stereoselective synthesis of N-galactosyl-amino acid amide derivative 58a-c via Ugi reaction of β-D-galactopyranosylamines 57, aldehydes and isocyanides in presence of catalytic amount Lewis acid (Scheme 32).The reaction proceeded smoothly to give product with satisfactory yields and high diastereoselectivity.

Scheme 32
In 2002, Ross 26 and his group reported a stereoselective Ugi reaction of 1-amino-5-desoxy-5-thio-2,3,4-Oisobutanoyl-β-D-xylopyranose 59 to furnish various peptide derivatives (Scheme 33).Excellent yields, stereoselectivities and easy removal of chiral auxiliary after the Ugi reaction are the merits of this protocol.However, the versatility of this reaction in terms of the substrate scope has not been explored by the authors.

Scheme 33
In 2016, Basso 27 and his co-workers reported Ugi reaction employing β-amino alcohol 65 as a chiral template to access complex heterocycles 63 in presence of Lewis acid catalysts (Scheme 34).Products with three adjacent stereogenic centers were obtained in high yield and stereoselectivities.The diversity of this reaction has been explored by varying amino alcohols, aldehyde, acid, isocyanide and conditions.

Scheme 34
Surajit Haldar 28 and his group reported a metal free stereoselective synthesis of α-tetrazolyl pyrrolidines via an azido-Ugi reaction in 2013 (Scheme 35).Structurally diverse chiral amines and isocyanides were employed to afford the desired skeleton with good yield and up to >99% ee.Enantioenriched prolinol 66 upon reaction with various isocyanides under standard conditions furnished tetrazole derivatives 67a-c (Scheme 36).Pyrrolidine 68 was treated with isocyanoethyl benzene 69 in presence of fluorenimine to give enantioenriched tetrazole 70a and 70b which then subjected to standard hydrogenolysis to obtain (S)-2tetrazolyl pyrrolidine 70c and (R)-2-tetrazolyl pyrrolidine respectively 70d (Scheme 37).

Scheme 37
The absolute configurations of products were determined from crystallographic studies.Lindermann 29 and his co-workers developed a convertible isonitrile and applied in asymmetric Ugi reaction in 1999.Both aliphatic and aromatic aldehydes can be tolerated in this reaction leading to optically pure amino acids with noteworthy diastereoselectivity (Scheme 38).

Chiral aldehydes as substrate
The first diastereoselective N-arylative Ugi-Smiles (US-4CR) reaction using a chiral aldehyde 74 to afford N-aryl amides 75 was reported by Radhakrishna 30 and his group in 2014 (Scheme 39).The reaction proceeds smoothly under optimized conditions to give N-aryl amides in moderate to good yield and diastereomeric ratios.

Mechanism
A general mechanism for the formation of β-lactam derivatives has been represented below.aminoacid condenses with aldehyde to afford Schiff's base followed by reaction with isocyanide to give oxazepinone intermediate 78b.In the next step, intramolecular N,O-acyl migration results in synthesis of β-lactam derivatives (Scheme 41).The origin of selectivity in the formation of products 77 a-c is based on the usage of chiral substrates such as chiral amino acid 76 and chiral isocycnides.

Chiral keto acid as substrate
In 2008, Kobayashi 33 and his group investigated the stereoselectivity of Ugi-4C-3CR involving chiral levulinic acid derivatives 79 as starting material.The resulting pyroglutamic acids 80a-c were obtained in good yield and stereoselectivities (Scheme 42).

2.7 Chiral cyclic hemiacetals as substrates
In 2015, de la Torre 34 and his group developed a new strategy for synthesis of cyclic depsipeptide mimics 82a,b employing 4,5-disubstituted 2-hydroxytetrahydropyrans as chiral substrate by means of an Ugi five centered three component reaction (Scheme 43).Products were obtained in good yields and low diastereoselectivities (d.r. up to 1:1:0.5:0.5).

Asymmetric Ugi reactions involving chiral auxiliary
In 2005, Basso 35 and his group reported the application of β-amino acids derivative 83 as a novel chiral auxiliary in Ugi reactions for the preparation of optically pure α-amino acid derivatives 85 in both D-and L-form (Scheme 44).It was suggested that the stereoselectivity is due to the conformation of the cyclic intermediate formed from condensation of 83 and aldehyde followed by attack of isocyanide from the side opposite to the carboxylic oxygen.The origin of selectivity in the formation of products 84a is based on the usage of chiral substrate 83.

Scheme 44
In 2014, Klossowski 36 and his group synthesized a new chiral auxiliary α-(2,4-dimethoxyphenyl)ethylamine 86 from α-phenylethylamine and employed it for preparation of peptidomimetics 87a-b in a stereoselective manner by means of Ugi reaction (Scheme 45).Broad substrate scope and easy removal of auxiliary from product makes this reaction attractive.

Scheme 45
Plausible mechanism of the Ugi reaction Condensation of aldehyde and amine gives an imine, which on protonation by carboxylic acid leads to iminium ion 89.Attack of isocyanide from less hindered side results in intermediate 90 to finally afford the desired product 87 in an intramolecular acyl migration (Mumm rearrangement).

Asymmetric Ugi reactions involving chiral catalysts
In 2011, Riguet 37 reported an enantioselective Friedel-Crafts reaction of indole 91 with 5-hydroxyfuran-2(5H)one using a diphenylprolinol silyl ether as catalyst to afford chiral indoyl oxo-carboxylic acid 92 which was further employed as a chiral synthon in Ugi reaction leading to γ-lactams 93-96 (Scheme 47).This one pot synthetic methodology was developed on the basis of a green chemistry approach consisting of sequential reactions such as enantioselective organocatalytic Friedel-Crafts alkylation reaction of indoles and Ugi 4center 3-component reaction resulting chiral five-membered lactams 93-96 in high yields and enantioselectivities.

Scheme 48
In 2018, Zhang 39 and his group reported an asymmetric four component Ugi reaction catalyzed by chiral phosphoric acid derivatives (R)-101 and (R)-102 leading to optically pure α-acylaminoamides from achiral building blocks (Scheme 49).α-Acylaminoamides were obtained in excellent yield (up to 96%) and enantiomeric excess (up to 99%).Non-covalent interactions such as intermolecular hydrogen bonding restricts the approach of the isocyanide to only one enatiotopic face of the iminium ion.

Mechanism
From Density Functional Theory calculations and control experiments, the mechanism of this reaction has been proposed as presented below (Scheme 50).At first, phosphoric acid and carboxylic acid form a relatively stable heterodimer 104a which then co-ordinates with imine formed from aldehyde and amine to generate a heterotrimer 104b.In the next step, nucleophilic attack of isocyanide results in a nitrilium intermediate 104c followed by attack of carboxylate to nitrilium carbon to give imidate intermediate 104d.Phosphoric acid promotes Mumm rearrangement to afford final product α-acylaminoamide 103 accompanied by regeneration of catalyst.The α-addition of isocyanide to imine is the enantio-determining step.

Mechanism
A possible reaction mechanism (Scheme 52) for formation of heterocycle 107 has been shown below.At first aldehyde and amine condenses to give imine which gets protonated by chiral phosphoric acid 105 to give iminium ion 108a followed by nucleophilic attack of isocyanide to the Si-face of iminium ion leads to nitrilium intermediate 108b.Then, deprotonation of α-proton by phosphate and simultaneous attack of resulting enolate oxygen to nitrilium carbon affords oxazole 108c with regeneration of catalyst 105.In the next step, addition of acyl chloride and triethylamine, followed by acylation of secondary amine results in 108d which then undergoes an intramolecular Diels-Alder reaction to furnish epoxy-tetrahydropyrrolo [3,4-b]pyridine-5ones 107.

Scheme 52
In 2009, Yue 41  In 2016, Zhang 42 and his group reported an enantioselective Ugi three component reaction between 2formylbenzoic acid 114, anilines, and isocyanides in presence of a binol derived chiral phosphoric acid 113 acting as catalyst to give structurally diverse heterocycles 115a-d with excellent yield and enantiomeric excess (Scheme 55).

Mechanism
A plausible mechanism (Scheme 56) for the enantioselective synthesis of 3-oxoisoindoline-1-carboxamides 115 via Ugi reaction has been elucidated as depicted below.Condensation of formyl benzoic acid 114 with amine affords iminium salt 116a.In the next step, nucleophilic addition of isocyanide carbon to iminium ion results in formation of nitrilium intermediate and is trapped by carboxylate to give 116c.Mumm rearrangement of 116c via bridged intermediate 116d affords isoindolinone115.However, 116c can undergo isomerization to give isocoumarin116e.Now, there are two possibilities for accounting observed enantioselectivity: a) Mumm rearrangement (step b) is faster than the imine-enamine isomerization (step c/d; kb >>kc, kd).In this case, the C-C bond-forming step (step a) leading to 116b would determine the absolute configuration of the final adduct; b) imine-enamine isomerization (step c/d) is much faster than the Mumm rearrangement (step b; kc, kd>>kb).In this case, the DKR (Dynamic Kinetic Resolution) of 116e would be responsible for the observed enantioselectivity.Control experiments and mechanistic studies indicate that observed enantioselectivity results from a DKR of the primary Ugi adduct rather than from the C-C bondforming process.

Scheme 56
In 2014, Zhao 43 and his group investigated the catalytic property of various BOROX catalysts bearing functional groups of different electronic properties and found 117 to provide optimum selectivity.In presence of catalytic amount of this R-BOROX catalyst 117, the Ugi three component reaction of aldehyde 118, amine 119 and isocyanide 120 leads to synthesis of enantio-enriched α-amino amide 121a-c in good yields (Scheme 57).

Mechanism
The proposed mechanism (Scheme 58) for this reaction involves addition of isonitrile 120 to iminium ion 122a to give nitrilium cation 122b which remain as ion pair with BOROX catalyst 123.In the next step exchange of OH group between the nitrilium cation 122b and hemiaminal 122c to refurnish iminium ion 122a accompanied by simultaneous formation of final product 121.

Scheme 58
In 2007, Wang 44 and his group reported an Ugi type reaction of α-isocyanoacetamides 125 and aldehydes catalyzed by a chiral salen-aluminium complex 124 for synthesis of 2-(1-hydroxyalkyl)-5-aminooxazoles 126a-c (Scheme 59).It offers a large substrate scope and structural diversity of product in high yield and low to moderate enantiomeric excess (up to 80%).

Scheme 59
A nickel complex of 130 catalyzed Ugi reaction of cyclic azomethine imines 127 and methyl 2-cyano-2-phenylacetate 128 was reported by List 45 and co-workers in the year 2017 (Scheme 60).This reaction proceeds efficiently to furnish (R)-N-(1-(5-methoxy-4-phenyloxazol-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-4-methylbenzenesulfonamide 129 with high yield and excellent enantiomeric excess.Scheme 60 5. Applications 5.1.Plusbascin A3 (1h) is a potential antimicrobial agent against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE).It has been reported that 1h also inhibits lipid II polymerization.It can be synthesized employing a solvent dependent diastereoselective Ugi reaction.Two peptide derivatives 135 and 138 derived from asymmetric Ugi reaction react to give Plusbacin A3 (1h) 46 (Scheme 61).Scheme 61 5.2.The Ugi reaction can be used for total synthesis of Omuralide 47 (Scheme 62.).It is obtained from natural product lactacystin and is a selective inhibitor of the 20S proteasome present in mammalian and bacterial cells.Proteasome inhibition has been reported to be a novel cancer therapy.Scheme 62 5.3.Ugi adducts can afford the spiro-diketopiperazine scaffold by means of intramolecular aza-Michael reaction.Spiro-diketopiperazines are of interest because of their peptidomimetic properties and are abundant in many natural products such as verruculogen, spirotryprostatin B and brevianamide F 10 (Scheme 63).Scheme 63 5.4.The reaction of oxazole with maleic anhydride leads to synthesis of a novel fused tricyclic framework which contains a morpholinone unit as well as pyrrolopyridine unit 12 (Scheme 64).The pyrrolopyridine, having an analogous structure to the isoindolinones, nicotinamide, etc., is a potential pharmacophore and synthetic intermediate (mechanistic studies were under progress).Scheme 64 5.5.Argatroban which is an effective anticoagulant indicated for prophylaxis or treatment of thrombosis can be synthesized from Ugi product 22 (Scheme 65).Argatroban is an anticoagulant that directly inhibits the thrombin enzyme, which is responsible for the blood clotting in thrombosis.This drug is mainly given to patients suffering from coronary artery disease (CAD) or stroke, when the conventional antithrombotic drug heparin results in heparin-induced thrombocytopenia (HIT) or platelet deficiency.Scheme 65 5.6 Hexahydro-pyrazino isoquinolinone, can be synthesized from Ugi products by means of intramolecular Mitsunobu reaction 23 (Scheme 66).Hexahydro-pyrazino isoquinolinone is a key component in many natural products such as ecteinascidine 743, saframycin and naphthyridinomycin.Scheme 66

Conclusions
In conclusion, this work highlights on various strategies to achieve higher stereoselectivity in Ugi reactions by employing chiral substrates, chiral auxiliaries and chiral catalysts as stereodiscriminating elements.Chiral amino acids and amines provide high yield and stereoselectivity (up to 99%ee or 99%de) whereas in case of chiral isocyanide and acid substrates it is found to be relatively low.This protocol offers efficient and very short routes to diverse complex molecules having bioactive properties.However, a precise mechanism to explain stereoinduction in this reaction is yet to be fully discovered.