1 Introduction

Carbohydrates are naturally occurring complex chiral molecules that have significant biological significance. They have been used in the laboratory setting as chirons for the transformation into multiple functionalities such as aldehydes, acids, amines, and isocyanides as well as employed in reaction settings such as multicomponent reactions. In recent years, there has been a marked increase in utilizing carbohydrates as key components in multicomponent coupling reactions such as the Ugi, and Passerini reactions to name a few [1, 2]. In the aforementioned reactions, sugars were used as the isocyanide and amine components for understanding diastereoselective roles in the key carbon–carbon bond forming reaction. However, over a period of time the use of carbohydrates in such multicomponent reactions has diminished. In the later sections of this chapter, we attempt to discuss the role of carbohydrates in multicomponent reactions as both isocyanide and amine functionalities.

An isocyanide, also known as an isonitrile or carbylamine is an organic compound characterized by the functional group R–N≡C. It is the isomer of closely related cyanide (R–C≡N), thus the prefix iso. Electronically, isocyanides are similar to carbon monoxide and therefore have been used to substitute carbon monoxide in organometallic transformations. Akin to carbon monoxide, the isocyanides are represented by two resonance structures, one with a triple bond between nitrogen and carbon and the other with a double bond (Fig. 1).

Fig. 1
figure 1

General representation of the isocyanide and carbon monoxide

Full size image

Isocyanides are adaptable functional groups having a divalent carbon which acts as a proton acceptor (Brønsted base). Very few compounds belong to this class of proton acceptors. Isocyanides are also stable to basic conditions but under highly acidic conditions, they tend to hydrolyze or polymerize. Some suspect that they may even undergo radical formations depending on reaction conditions [3,4,5,6].

The first reported synthesis of an isocyanide was serendipitously discovered in 1859 by Lieke [7] when the synthesis of allyl cyanide was attempted but instead an isocyanide was characterized. The first naturally occurring isocyanide, Xanthocillin, discovered by Rothe in 1950, was later used as an antibiotic (Fig. 2).

Fig. 2
figure 2

First isolated naturally occurring isocyanide 3 and early attempts at isocyanide synthesis. (X = Halogen)

Full size image

Ever since the development of synthetic routes for isocyanides established circa 1867 by Gautier and Hoffman [8, 9], there have been many reports describing further developments, not just in terms of different synthetic routes but also for obtaining varied isocyanides which have been used in the synthesis of biologically important scaffolds. The synthetic importance and utility of isocyanides rocketed following their use in multicomponent reactions (MCRs). MCRs involve the use of three or more different compounds as starting materials, which can react to give a product comprising the majority of atoms from the starting materials, making them atom economical reactions. Even though there has been an exponential increase in isocyanide published manuscripts over the past 15–20 years, there is a need for novel isocyanides that can be used in the synthesis of various natural products via well-known transformations. Isocyanides are used to introduce new functionality in the molecule, which is overshadowed by utilizing harsh reaction conditions to hydrolyze the amide bond formed. This creates complications in highly functionalized compounds and a major drawback for extended uses. To overcome this challenge a new class of isocyanides, now termed “Convertible Isocyanides” (CICs), have been developed. The name convertible is justified by the role it plays in the MCRs and the post-modifications of the products obtained. The labile amide can be easily removed in a single step and be “converted” into a variety of other moieties with augmented diastereoselectivity. These are, at times, referred to as “Universal Isocyanides”.

2 Convertible Isocyanides (CICs)

CICs are isocyanides consisting of a moiety that allows for selective cleavage of the terminal amide; for example in an Ugi post-condensation product. They are widely used in MCRs like the Passerini reaction. The concept of CICs was first introduced by Armstrong in the year 1996. There has been a considerable increase in efforts for the development of CICs and some of the famous CICs are shown in Fig. 3.

Fig. 3
figure 3

Some of the more well-known convertible isocyanides

Full size image

Despite the fact that isocyanides 13 and 18 do not have the appearance of CICs, recent reports prove that they can be used as such [10, 11]. Recently, Orru and co-workers have reported on the use of 2-bromo-6-isocyanopyrudine 14 as a universal CIC for MCRs to synthesize some biologically important compounds [12].

2.1 Methyl Isocyanides

Methyl isocyanides (MICs), can be considered a class of CICs where the substituent is present on the methyl group. Some of the better known MICs are p-tolylsulfonylmethyl isocyanide (TosMIC), diphenylmethyl isocyanide (DPMIC), benzotriazol-1-yl-methyl isocyanide (BetMIC), and methyl 2-isocyanoacetate (MICAc). Although the aforementioned MICs have been used as CICs in MCRs, the role of methyl isocyanide (MIC) alone as a CIC in an Ugi4-CR was only just first explored and reported by Andreana and co-workers [13] in 2016. The general outline for the reaction using MIC is given in Scheme 1. The required compound 24, was obtained by mixing benzaldehyde 22, methyl isocyanide 20, propionic acid 21, and isopropyl amine 23 in methanol at room temperature for 24 h (Scheme 1). Then the dipeptide 24 was reduced to give compound 25 under Bechamp-type reduction conditions. Under microwave reactor conditions, the desired cyclized product 26 was readily obtained. Apart from the role as a CICs, MIC has also been used by the same group as a key component in the one-pot synthesis of diketopiperazine-based natural product Thaxtomin A (±)-syn (TA); well known for herbicidal activity [14]. First, the required starting materials 4-nitroindolylacetaldehyde 27, methyl amine 28, 3-hydroxyphenylpyruvic acid 29 and compound 20 were reacted in methanol followed by epimerization and cyclization under basic conditions using KOH at 70 °C to afford Thaxtomin A (±-syn-30) and the corresponding anti-diastereomer in a 4:1 ratio (Scheme 2).

Scheme 1
scheme 1

Synthesis of 3-substituted indolinones

Full size image
Scheme 2
scheme 2

Synthesis of (±)-Thaxtomin A

Full size image

3 Asymmetric Control of Isocyanide-Based Multicomponent Reactions

Isocyanides have gained a lot of interest among the organic chemists in view of its importance in the various reactions used to generate a library of compounds and natural products via diversity-oriented synthesis (DOS). This is attributed to the generation of new chiral centers implicit in various multicomponent reactions like Passerini, Ugi to name a few. Admitting the fact, that the isocyanide is just one of the components in the MCR, the outcome of the reaction can be controlled by the types of isocyanides used along with the use of chiral catalysts as seen in some of the cases discussed hereafter.

3.1 Diastereoselective Additions

Although isocyanides have been widely used in the MCRs for the synthesis of various scaffolds including natural products and biologically active compounds, there has been a concern lurking over the stereoselectivity of the reactions involving isocyanides. Although there have been stereoselective reactions developed for a myriad of multicomponent coupling reactions, the isocyanide-based reactions seem to be a little more challenging and to date only the asymmetric Passerini reaction has been achieved.

Zhu and co-workers [15] reported the stereoselective synthesis of pyrrolo-pyridine via the formation of the oxanorbornene heterocyclic intermediate 35, followed by the Diels–Alder reaction to give the desired product 36. Isocyanide 31, ester 32, and aldehyde 33 were dissolved in methanol and stirred for 2 h at room temperature followed by the addition of triflouroacetic acid (TFA) at −78 °C and stirred for 20 min which afforded the pyrrolo-pyridine moiety 36 in 80% yield (Scheme 3). Intermediate 35 was obtained in high diastereoselectivity of >90% de with an excellent yield of 92%.

Scheme 3
scheme 3

Synthesis of pyrrolo-pyridine derivatives

Full size image

Furthermore, Kazmeier et al. [16, 17] reported the use of an enantiomerically pure isocyanide 38 to form oxazoline, ligands (40a and 40b) which were used in stereoselective additions of Et2Zn to various aldehydes. Due to the instability of the oxazolines, they designed an alternate two-step synthesis of thiazoline ligands (42a and 42b). In both the cases, an excellent stereoselectivity of >92% ee was obtained. The oxazoline ligand 40b was synthesized in one step followed by the addition of Et2Zn to benzaldehyde to yield 43 in 100% yield with a 94% ee. The thiazoline ligand 42b was synthesized in a two-step process followed by the addition of Et2Zn to benzaldehyde to yield 43 in 100% yield with a 92% ee (Scheme 4).

Scheme 4
scheme 4

Synthesis of oxazolines and thiazolines and their application in the addition of Et2Zn to benzaldehydes

Full size image

3.2 Enantioselective Additions

Denmark and Fan reported the synthesis of α-hydroxyl amides and esters via the use of the concept of Lewis base activation of Lewis acids which employs the use of SiCl4 and a chiral bisphosphoramide (R,R)-catalyst [18, 19]. The reaction was carried out using various aldehydes 39, 44a–e and isocyanide 18 in the presence of SiCl4 and 5 mol% of the catalyst to give intermediates 46a–f. It was determined that the intermediates could give two different products based on the workup route selected (Scheme 5). Under saturated aqueous NaHCO3 workup conditions, α-hydroxyl amides 47a–f were obtained in good to excellent yields of 76–92% with 82–99% ee. Under conditions where methanol and saturated aqueous NaHCO3 workup conditions, it gives rise to α-hydroxyl esters 48a–f in good to excellent yields of 70–92% with 80–98% ee (Table 1).

Scheme 5
scheme 5

Enantioselective addition of isocyanides to aldehydes using catalyst

Full size image
Table 1 Reaction profile of Lewis base activation of Lewis acids
Full size table

4 Stereoselectivity of Passerini Reactions

4.1 Diastereoselective Passerini Reactions

In recent times, there have been very few reports on the diastereoselective Passerini reaction. Berlozecki and co-workers have reported on Passerini reactions wherein they used N α protected amino acids, cyclic ketones, and isocyanides [20]. They achieved exceptional diastereoselectivity which they attribute to the protecting groups used to protect the amine group of the amino acids. L-phenylalanine (Scheme 6) with Boc- or phthaloyl and trityl protected amine 49 gave a selectivity of 99% de with yields of 86, 84, and 66% respectively (Table 2). Whereas the D-valine (Scheme 7) with Boc- and phthaloyl protected amine 53 gave a selectivity of 85–96% de with the yields of 79 and 74% respectively (Table 3). Albeit high yields and diastereoselectivity was achieved, this approach had a drawback; ketones other than cyclohexanone were not tested for the transformation. They were later tested by Simila and Martin [21].

Scheme 6
scheme 6

Diastereoselective P-3CRs of L-phenylalanines

Full size image
Table 2 Reaction profile of P-3CRs of L-phenylalanines
Full size table
Scheme 7
scheme 7

Diastereoselective P-3CRs of D-valines

Full size image
Table 3 Reaction profile of P-3CRs of D-valines
Full size table

4.2 Enantioselective Passerini Reactions

Over the years many enantioselective Passerini reactions have been reported, but only a few of them have resulted in good enatioselectivity [22,23,24,25]. A recent report by Szymanski imposes the utilization of wheat germ lipase enzyme to resolve the Passerini product by hydrolysis of the racemic mixture (desymmetrization) [26]. Although two different products were obtained, the selectivity was excellent giving 58 ( R ) in 70% ee and 59 in 99% ee.

The α-hydroxyl amide 59 was then converted into the corresponding amino acid by six additional steps. First, compound 59 was mesylated, followed by nucleophilic substitution of azide and hydrogenation using Pd/C in methanol afforded the amide 60 (Scheme 8). This was later subjected to hydrolysis under acidic and basic conditions followed by hydrogenation using Pd/C in methanol to yield the amino acid [27] in 71% with an excellent enatioselectivity (98% ee).

Scheme 8
scheme 8

Enzymatic resolution of the racemic Passerini product

Full size image

Similar to the Lewis base catalyzed Passerini reaction, Lewis acid catalyzed Passerini reactions were initially described by Domling [22] and Schreiber groups (2004) [28] using titanium- and copper-based catalysts respectively. However in each case, when these approaches were used, the drawback was lower enantioselectivity when non-chelating agents were employed. This was further explored by Zhu and co-workers (2008) using aluminum-based catalysts [29]. Several catalysts and reaction conditions were optimized which showed that the use of salen-aluminum catalyst could render good enantioselectivities. The reactions were carried out by mixing the aldehyde, carboxylic acid, and the isocyanide in toluene at −40 °C and stirring for 48 h (Scheme 9). The reaction yields were moderate to good (59–70%) affording the amide 65a–i with moderate to excellent enatioselectivity of 63–99% ee (Table 4). Screening a set of diversified reagents revealed that the enatioselectivity is greatly dependent on the structures of the aldehydes and isocyanides. It was determined that the carboxylic acid also played a minor role in selectivity. The S-selectivity of the product is favored by the attack of the isocyanide on the Re-face of the aldehyde.

Scheme 9
scheme 9

Salen-aluminum catalyzed enantioselective P-3CR

Full size image
Table 4 Reaction profile of Lewis acid catalyzed Passerini reaction
Full size table

Zhu and co-workers further modified the catalyst and replaced the carboxylic acid with the hydrazoic acid 67 which gave a cyclic product following a 1,5-dipolar cyclization (Scheme 10) instead of the acylation as observed in the previous case [24]. The products were achieved in high yields of 76–95% with excellent enatioselectivity up to 95% ee (Table 5). But this approach is also limited due to the fact that it is more suitable for aliphatic aldehydes and very few aromatic aldehydes.

Scheme 10
scheme 10

Enantioselective synthesis of tetrazoles via P-3CR and the proposed mechanism

Full size image
Table 5 Reaction profile of synthesis of tetrazoles via P-3CR
Full size table

A very recent report by Bin Tan’s group has shown that the use of phosphoric acid based catalysts could actually enhance the enantioselectivity of Passerini reactions and could be applied to wide range of aldehydes and carboxylic acids. They have optimized the reaction conditions by screening a wide range of catalysts [30] and selecting the catalyst with the best results (CP6) followed by its use to further explore the reaction profile. Moderate to excellent yields of 45–99% with enantioselectivity of 84–99% ee were observed (Fig. 4).

Fig. 4
figure 4

Phosphoric acid catalyzed asymmetric Passerini reaction

Full size image

5 Stereoselective Ugi Reaction

Successful attempts at the diastereoselectivity and enatioselectivity of the Passerini reaction encouraged the organic chemists’ community to look for ways to access similar success in Ugi reactions. List and co-workers [31] demonstrated the lack of enatioselectivity in Ugi reactions. Recent reports by Zhu and co-workers have given a ray of hope when they reported the enantioselective Ugi reaction [32, 33].

In the past few years, efforts from various research groups have shown that the diastereoselective outcome of the Ugi reaction has been fruitful. Kobayashi and co-workers [34, 35] demonstrated the synthesis of Omuralide, a proteasome inhibitor. The synthesis involved the use of beta-hydroxy gamma-keto acid. The starting materials {protected β-hydroxyγ-keto acid intermediate (I), isocyanide 15 and amine 71} underwent the Ugi four center three-component reaction (Ugi-4C-3CR) to afford anti-72 predominantly with a yield of 78% with the formation of single diastereomer (Scheme 11). This compound 72 further was used to complete the synthesis of Omuralide 74.

Scheme 11
scheme 11

Synthesis of Omuralide 74 via Ugi reaction

Full size image

Use of chiral isocyanides was reported by Nenjadenko and co-workers to achieve diastereoselectivity for the Ugi MCRs. They have used the 4-methyl-2,6,7-trioxabicyclo[2.2.2]octyl derivatives or the chiral oxabicyclooctyl (OBO)esters 78a–e (previously synthesized by them) to study the role of chiral isocyanide in the stereoselectivity [36]. The OBO esters played a key role in controlling the racemization. The general reaction module for this reaction is, stirring a mixture of amine, aldehyde or ketone, carboxylic acid, and the OBO esters of the isocyanide in methanol at room temperature. They observed the retention of configuration of the Ugi products 80a–k (Scheme 12). To further investigate the reaction profile they used the esters 79a–e, surprisingly racemization at the chiral center on the isocyanide was observed. This observation suggests that the OBO plays an important role to prevent the racemization.

Scheme 12
scheme 12

Diastereoselective Ugi-4CR using chiral OBO esters

Full size image

Along the same lines of using the chiral isocyanides, Sureshbabu and co-workers [37] attempted the utilization of the N β-Fmoc amino alkyl isocyanides, which were previously synthesized by the same group. They employed those isocyanides for the synthesis of a series of β-lactam peptidemimics via Ugi 4C-3CR (Scheme 13). The reactions were conducted using the isocyanides 84a–h, aldehydes and methyl ester of the aspartic acid 87 to give the peptidomimics 88a–h in moderate to good yields (53–78%) with excellent diastereoselectivity {de between 85 and 100% (Table 6)}.

Scheme 13
scheme 13

Synthesis of β-lactams using chiral amino alkyl isocyanides

Full size image
Table 6 Reaction profile for the synthesis of β-lactams 88a–h
Full size table

The high selectivity can be attributed to the formation of the 7-membered oxazeoinone intermediate [38]. Furthermore, the Fmoc group on the final product can be deprotected and be used in other reactions to synthesize various complex natural products.

A collaborative work between Orru and van der Eycken [39] accomplished a new level of diastereoselectivity. They utilized an aldehyde-carboxylic acid derivative of biphenyl 89, amine (71) and the isocyanide (18) for the microwave assisted Ugi 4C-3CR (Scheme 14). The reaction gave a dibenzo[c,e]azepinone derivative as a single diastereomer with an excellent yield of 82%. The reaction proceeds through the formation of iminium ion which is attacked by the isonitrile to form nitrilium ion followed by the intramolecular acylation to give the intermediate IV. This intermediate upon Mumm rearrangement forms the (R a , S) isomer of the product 90.

Scheme 14
scheme 14

Microwave assisted Ugi-4C-3CR and the proposed mechanism

Full size image

After all the years of hard work put in by various research groups to achieve the enantioselectivity for the Ugi reactions, the initial breakthrough was provided by Zhu’s group in 2012, wherein they used chiral phosphoric acids (CPAs) as catalysts for the one-pot four-component Ugi type reaction [32]. The reactions were conducted by adding the first three components (aldehyde, amine and isocyanide) in dichloromethane and stirring for 24 h at −35 °C followed by addition of the fourth component (unsaturated acid chloride) and base and refluxing the mixture for 5 h in toluene. The process gave the desired single diastereomer in yields ranging from 41 to 94% with the enantioselectivity of 81–94% ee.

Following up on this work they further explored the role of the CPAs in achieving excellent enatioselectivity for Ugi reactions [33]. There were two different approaches that they followed in order to achieve the desired product. In the first approach, they followed a two-component version wherein they reacted the preformed furan (from carboxaldehyde and amine) and the isocyanide followed by the addition of the catalyst (CP–NO 2 ). Second approach was mixing all the components in a single pot followed by addition of the catalyst (CP–NO 2 ). In both the cases excellent yields (74–98%) and enantioselectivities (82–97% ee) were obtained (Fig. 5).

Fig. 5
figure 5

Chiral phosphoric acid catalyzed enantioselective Ugi reaction

Full size image

6 Carbohydrates as Chiral Auxiliaries

There have been efforts in improving the stereoselectivity in the Ugi 4CRs to synthesize the substituted amino acids. Horst Kunz and co-workers have reported the use of carbohydrates as chiral auxiliaries keeping other constituents achiral [1, 2]. The α-D and L-amino acids can be achieved by simply switching the amines between the galactosamine and the arabinosylamine respectively.

When the galactosamine 91 was reacted with isocyanide 18 and formic acid 94, variety of aldehydes in the presence of ZnCl2 and tetrahydrofuran at lower temperatures, N-galactosyl amino acid amide derivative 95a–i were obtained in excellent yields ranging from 80 to 93% and high enantioselectivity (only one chiral center) of 91–94% (Table 7). The derivatives were further processed for the cleavage of the N-glycosidic bond following a two-step acidic hydrolysis (Scheme 15) giving the galactose template 96 and the desired free α-D-amino acids 98a–i in quantitative yields [1].

Table 7 Reaction profile for Ugi reaction using D-galactosamine auxiliary
Full size table
Scheme 15
scheme 15

Galactose derived chiral auxiliary based asymmetric Ugi reaction

Full size image

When the Ugi reaction was conducted using arabinosylamine as the chiral amine, following similar reaction conditions, the derivatives [2] N-formyl-N-arabinosyl amino acid amides 100a–e were obtained in excellent yields ranging from 85 to 95% and enantioselectivity of >96% respectively as observed in the case of galactosamine (Table 8). The desired L-amino acid derivatives 103a–e and the arabinose template 101 were obtained in quantitative yields via a two-step acidic hydrolysis (Scheme 16).

Table 8 Reaction profile for Ugi reaction using D-arabinosamine auxiliary
Full size table
Scheme 16
scheme 16

Stereoselective synthesis of L-amino acid derivatives via D-arabinose auxiliary

Full size image

Furthermore efforts were put in by Pellicciari’s group [40], synthesizing the glycine derivatives with good to moderate yields and excellent diastereoselectivity (Fig. 6) and Ugi and co-workers [41] used a thiosugar to synthesize the D-leucine derivatives with excellent yields and enantioselectivity (Fig. 7). The selectivity could have been achieved due to the formation of the intermediate which directs the attack of the isocyanide at the imine center.

Fig. 6
figure 6

Pellicciari’s stereoselective synthesis of glycone derivatives

Full size image
Fig. 7
figure 7

Stereoselective synthesis of D-Leucine derivatives using thiosugars as chiral auxiliary

Full size image

Use of sugars as chiral auxiliaries was further explored by Zeigler and co-workers [42] by employing carbohydrate-based isocyanides in the Ugi and Passerini MCRs to synthesize a library of glycopeptides. The reactions were performed using anomeric glucosyl isocyanides 104a, b and protected 2-deoxy-2-isocyano-β-D-glucopyranose 104c with various combinations of aldehydes, carboxylic acids, and amines (Fig. 8). The reactions were characterized by longer reaction time, lower yields and more importantly poor diastereoselectivity with a couple of exceptions as evident from Tables 9 to 10.

Fig. 8
figure 8

Passerini and Ugi reactions of isocyanoglucoses

Full size image
Table 9 Reaction profile for Passerini reaction leading to products 108a-i
Full size table
Table 10 Reaction profile for Ugi reaction leading to products 109a–e
Full size table

The 2-isocyano compound faired well in the Passerini reactions with higher yields and better reaction times. Although the reactions did not result in desired diastereoselectivity, there was room for improvement but unfortunately not many researches have followed this work, and thus far not much work has been done in this area. This approach could be a useful tool for synthesizing complex glycopeptides.

7 Conclusions

This chapter describes the recent developments in the application of isocyanides in the multicomponent reactions (MCR) forming chiral products It also describes the first ever application of methyl isocyanide as a convertible isocyanide, which could be useful in the synthesis of various natural product intermediates via Ugi and Passerini reactions involving the multicomponent transformations. In order to achieve higher stereoselectivity, various catalysts were used giving a sign of importance of catalysis in chemical tranformations en route to the synthesis of natural products of biological significance. The post-modifications of Ugi and Passerini products can give rise to esters, acids, and thioesters.

Recent reports have shown that the high enatioselectivity can be achieved in the Ugi reactions, opening up the avenues to further explore the results that can be implemented in the synthesis of intermediates for complex natural products.

Use of carbohydrates as chiral auxiliaries has revolutionized the utility of the multicomponent reactions owing to their ease of access and further modifications in those reactions. The carbohydrates have been used for the synthesis of various amino acid derivatives and can further be used to synthesize biologically important amino acid based molecules.

We summarize the chapter with an anticipation that this will galvanize the synthetic chemists to focus on further development of applications of isocyanides in various fields of chemistry to synthesize compounds of biological significance and compounds that can make an impact on environment in a positive way.