Organocatalytic Transfer Hydrogenation and Hydrosilylation Reactions

Abstract

The reduction of different carbon–carbon or carbon–heteroatom double bonds is a powerful tool that generates in many cases new stereogenic centers. In the last decade, the organocatalytic version of these transformations has attracted more attention, and remarkable progress has been made in this way. Organocatalysts such as chiral Brønsted acids, thioureas, chiral secondary amines or Lewis bases have been successfully used for this purpose. In this context, this chapter will cover pioneering and seminal examples using Hantzsch dihydropyridines 1 and trichlorosilane 2 as reducing agents. More recent examples will be also cited in order to cover as much as possible the complete research in this field.

1 Introduction

The reduction of different carbon–carbon or carbon–heteroatom double bonds is an important transformation that generates in many cases new stereogenic centers. Particularly, the asymmetric reduction of prochiral ketimines represents one of the most important methods and straightforward procedures for preparing chiral amines. This approach is one of the key reactions and powerful tools in synthetic organic chemistry, which provides precious building blocks for natural products, pharmaceutical, and other fine chemical industries [1]. Until the last decade, available chemical catalysts for the enantioselective reduction of these substrates were mostly limited to chiral transition metal complexes, which often required elevated pressures and/or the use of additional additives to afford high yields and ee values (for reviews, see [2–10]). However, with the increasing interest during the last years in the development of the organocatalysis field [11–13], the organocatalytic version of these transformations has attracted more attention, and remarkable progress has been made in this way (For selected reviews on organocatalytic transfer hydrogenations, see [14–20]). The organocatalytic transfer hydrogenation is carried out by four fundamentally different approaches (Fig. 1): (1) reduction with Hantzsch dihydropyridines 1, mainly catalyzed by chiral Brønsted acids, which activate the electrophilic substrates (for reviews, see: [21–26]); (2) hydrosilylation with trichlorosilane 2, catalyzed through chiral Lewis-bases, which, in contrast, activate the nucleophilic hydride source [27–30]; and more recently, (3) transfer hydrogenation using benzothiazolines 3 as the reducing agent (Benzothiazoline 3 was firstly introduced by Akiyama’s group for asymmetric transfer hydrogenation reactions: [31, 32]; [33]) and (4) hydrogen activation by frustrated Lewis pair 4 [34].

Fig. 1

Model reducing agents

Interestingly, 1a–c and 2 are commercially available, while 1d–e must be synthesized. Trichlorosilane 2 is cheaper than the other reagents and 1a is the most expensive one. Trichlorosilane 2 has shown a great spectrum of reactivity, as the reader will find in the second part of this chapter.

Although this field has been extensively reported, only pioneering and seminal examples using Hantzsch dihydropyridines 1 and trichlorosilane 2, as reducing agents, will be disclosed in this chapter. More recent examples will be also cited in order to cover as much as possible the complete research in this field.

2 Hantzsch Esters as Hydride Source

Inspired by Nature, and trying to reproduce the enzymatic reductions using NAD(P)H as cofactor in living organisms, many research groups have focused part of their investigation on the development of new environmentally friendly and successful reducing agents trying to simulate its reactivity. That is the case of Hantzsch esters 1 as a hydride source [35, 36], which were initially synthesized following a multicomponent approach as an interesting synthetic example of 1,4-dihydropyridines. Although, it was only in the last decade when Hantzsch esters 1 became a key piece in the reduction processes using organocatalysts, the first reported example of transfer hydrogenation using this hydride source without metals is dated from 1989 ([37], for earlier examples on the transfer hydrogenation of imines with Hantzsch esters 1: [38–40]). In the next pages, the pioneering enantioselective examples using Hantzsch dihydropyridines 1 in organocatalysis, and the most recent advances in this subarea of research will be briefly covered.

2.1 Chiral Phosphoric Acid Catalyzed Transfer Hydrogenation

The reduction of imines is potentially useful for the synthesis of enantiomerically pure amines, since chiral amines appear in numerous interesting compounds in nature, and they have also a remarkable use as ligands in metal catalysis or as chiral organocatalysts. However, until 2001, this approach had been mainly explored using metal catalysts [2–10].

The first enantioselective Brønsted acid-catalyzed transfer hydrogenation of ketimines using Hantzsch ester 1b was reported by Rueping’s [41] (Scheme 1) and, independently, by List’s groups (Scheme 2) [42] affording excellent results in terms of enantioselectivity and reactivity and, in both cases, using chiral phosphoric acid derivatives 6 and 9. Interestingly, in the latter case, the authors significantly improved the results employing 20-fold reduction in the catalyst loading.

Scheme 1

Reduction of imines using phosphoric acid 6 as catalyst

Scheme 2

Reduction of imines using Brønsted acid 9 as catalyst

Based on previous studies where the imines were reduced with Hantzsch dihydropyridines in the presence of achiral Lewis [43] or Brønsted acid catalysts, [44] joined to the capacity of phosphoric acids to activate imines (for reviews about chiral phosphoric acid catalysis, see: [45–58]), the authors proposed a reasonable catalytic cycle to explain the course of the reaction (Scheme 3) [41]. A first protonation of the ketimine with the chiral Brønsted acid catalyst would initiate the cycle. The resulting chiral iminium ion pair A would react with the Hantzsch ester 1b giving an enantiomerically enriched amine product and the protonated pyridine salt B (Scheme 3). The catalyst is finally recovered and the byproduct 11 is obtained in the last step. Later, other research groups also supported this mechanism (for mechanistic studies of this reaction, see: [59–61]).

Scheme 3

Proposed catalytic cycle for the reduction of ketimines

Since these seminal organocatalytic reports, other groups have used the same strategy for the reduction of different interesting imine derivatives such as MacMillan [62] [It is important to remark that as declared by the authors, the complete details of MacMillan’s group concerning reductive amination were first published via oral presentation in August 2005 in presentations in Germany, Wales, Japan, and the USA prior to submission of their manuscript on this field (October 23rd, 2005) (see Ref. [21], You [63, 64], and Antilla [65]).

Because of the importance of chiral nitrogen on heterocycles constituting the structural core of many natural alkaloids and synthetic drugs, a great extension of this protocol has been performed during the last decade mainly by Rueping’s group, affording different and valuable chiral heterocyclic products. In the next pages some pivotal examples reported by this research group will be disclosed and commented on.

Thus, Rueping and co-workers used their abovementioned methodology for the interesting activation of quinolines 12 by catalytic protonation and subsequent transfer hydrogenation, which involved a 1,4-hydride addition, isomerization, and final 1,2-hydride addition to generate the desired 1,2,3,4-tetrahydroquinolines 14 in a cascade process (Scheme 4) [66]. These compounds have proven to be interesting synthetic scaffolds in the preparation of pharmaceuticals and agrochemicals [67]. In this context, and having developed a general and enantioselective protocol, the authors demonstrated the applicability of this new methodology to the synthesis of biologically active tetrahydroquinoline alkaloids: galipinine 15a [68, 69], cuspareine 15b, [69, 70], and angustureine 15c [69] (Scheme 4) (for a report on the achiral transfer hydrogenation of differently substituted quinolines, see also [71]) (for similar methodologies as an extension of this approach, see: [72–78]; for transfer hydrogenation of 1,2-dihydroquinolines, see: [79]).

Scheme 4

Syntheses of biologically active tetrahydroquinoline alkaloids 15

Biologically active tetrahydroquinoline alkaloids 15 were prepared by simple N-methylation of intermediates 14 to lead the desired natural products in good overall yields and high enantioselectivities (for examples of dual catalysis, see: [80, 81], for more recent examples, see: [82–84]).

To explain the obtained products, the authors hypothesized that the first step should be the protonation of the quinoline 12 through the phosphoric acid catalyst 13 to generate the iminium ion A (Scheme 5). Transfer of a first hydride from the dihydropyridine 1b would generate the enamine intermediate 16 and pyridinium salt B, which would regenerate the acid catalyst 13 and release pyridine 11. The enamine 16 would interact with another molecule of Brønsted acid 13 to produce iminium C, which would receive the attack of a second molecule of hydride giving rise to the desired tetrahydroquinoline 14. Subsequent proton transfer would recycle again the Brønsted catalyst 13 and would generate a second equivalent of pyridine 11 (Scheme 5).

Scheme 5

Mechanism for the cascade transfer hydrogenation of quinolines 12

The reduction of quinolines was applied to the asymmetric preparation of the anti-bacterial agent (R)-flumequine 18 [85, 86], starting from quinoline 12a and generating the key tetrahydroquinoline intermediate 14a for the total synthesis and using 17 as catalyst (Scheme 6) [87].

Scheme 6

Synthesis of (R)-flumequine 18

Gong and co-workers developed the first step-economical synthesis of the previously described process. The approach involves a Friedländer condensation [88, 89] followed by a transfer hydrogenation catalyzed by a combination of an achiral Lewis acid and a chiral Brønsted acid. This affords the direct conversion of 2-aminobenzaldehyde derivatives 19 and ketones 23 into highly optically active 1,2,3,4-tetrahydroquinoline derivatives 22 and 24, with enolizable dicarbonyl compounds 20 (Scheme 7) [90].

Scheme 7

Step-economical syntheses of tetrahydroquinolines 22 and 24

The Lewis acid (LA) is believed to only participate in the catalyzed Friedländer condensation, while the chiral phosphoric acid (B*-H) could participate in the first condensation to give 25 and in the asymmetric transfer hydrogenation of A (Scheme 8). The success of this approach relies in the compatibility and synergic effect of both catalysts, the Lewis acid, and the chiral Brønsted acid.

Scheme 8

Proposed mechanism

Rueping’s group pioneered the first example of a catalyzed enantioselective reduction of pyridines giving rise to direct access to enantiomerically pure piperidines 26 (Fig. 2) [91].

Fig. 2

Scope of reduction of pyridines

The applicability of this new method was demonstrated in the formal synthesis of diepi-pumiliotoxin C 31 from the pumiliotoxin family (Scheme 9) [91]. Hence, the reduction of pyridine 29a, which can be readily prepared according to Bohlmann and Rahtz’s procedure starting from 27 and 28 [92, 93], gives the corresponding (S)-2-propylhexahydroquinolinone 30a as a key intermediate for the subsequent transformation (Scheme 9) [94].

Scheme 9

Formal synthesis of diepi-pumiliotoxin C 31

A plausible mechanism of the reduction was also proposed to explain the final products. Thus, in the first step, the pyridines 29 would be activated through catalytic protonation by the phosphoric acid catalyst 21, resulting in the formation of a chiral ion pair A (Scheme 10). A subsequent hydride transfer from the Hantzsch ester 1b would afford adduct B, which would be transformed into the iminium ion C through an isomerization. A second hydride transfer would render the desired product 26 or 30, and 21 would be regenerated (Scheme 10).

Scheme 10

Proposed mechanism giving rise to piperidines 26 and 30

The same research group developed a similar protocol for the reduction of benzoxazines 32, benzothiazines 33, and benzoxazinones 34 as key examples of heterocyclic compounds (Fig. 3) [95].

Fig. 3

Model heteroaromatic compounds reduced

With the increasing interest experienced by enantioselective domino reactions as powerful tools for the direct construction of enantioenriched complex targets starting from simple and readily available precursors, many investigations have been developed in this area of research, where the organocatalysis has gained an important position [96–98].

In this context, Rueping’s group envisioned the asymmetric organocatalytic multiple-reaction cascade version of the abovementioned process in which a six-step sequence was catalyzed by the chiral Brønsted acid catalyst 21 providing direct access to a broad scope of valuable tetrahydropyridines 26 and azadecalinones 35 with high enantioselectivities (Scheme 11) [99].

Scheme 11

Synthesis of tetrahydropyridines 26 and azadecalinones 35

An interesting mechanism was suggested by the authors to explain the final products obtained through this methodology, where the chiral Brønsted acid catalyst 21 would participate in the six reaction steps proposed (Scheme 12).

Scheme 12

Proposed mechanism for the cascade reaction

Other interesting examples of catalytic transfer hydrogenation have been also described for the transformation of quinoxaline and quinoxalinones into the corresponding 2-tetrahydroquinoxalines 36 (Fig. 4) and 3-dihydroquinoxalinones 37 (Fig. 5) [100], with a structural core which exhibits remarkable biological properties [101–104].

Fig. 4

Scope of the reaction for the generation of 2-tetrahydroquinoxalines 36

Fig. 5

Scope of the reaction for the generation of 3-dihydroquinoxalinones 37

Interestingly, Shi, Tu, and co-workers developed the tandem version of the abovementioned protocol comprising a cyclization/transfer hydrogenation strategy leading to enantioenriched tetrahydroquinoxalines 36 and dihydroquinoxalinones 37 from readily accessible materials with excellent results in terms of reactivity and enantioselectivity (Scheme 13) [105].

Scheme 13

Tandem approach for the preparation of 36 and 37

In order to explain the stereochemical outcome observed in this process, the authors proposed a plausible reaction pathway and transition state on the basis of their experimental results and previously reported calculations on transfer hydrogenation of imines [59–61] (Scheme 14). In this mechanism, the phosphoric acid catalyst 21 would act in a bifunctional mode, and the attack of the hydride in the TS justifies the absolute (R)-configuration observed in final products 36 and 37.

Scheme 14

Plausible reaction pathway and transition state

Rueping and co-workers have recently developed a highly enantioselective synthesis of differently substituted tetrahydroquinolines 40 via a first photocyclization of substituted 2-aminochalcones 38 and subsequent Brønsted acid catalyzed asymmetric reduction of the in situ generated quinoline 39, to give final products in moderate to high yields and with excellent enantioselectivities (Scheme 15) [106, 107].

Scheme 15

Photocyclization-asymmetric reduction of 38

The same research group applied the above methodology for the synthesis of valuable 4H-chromenes 43 in good yields and with excellent enantioselectivities. The approach consists of a dual light and Brønsted acid mediated isomerization–cyclization reaction starting from enones 41 to yield 2H-chromen-2-ol intermediates A. The subsequent Brønsted acid catalyzed elimination of water leads to an unprecedented intermediary chiral ion pair between a benzopyrylium ion and a chiral phosphate anion B. The following transfer hydrogenation exclusively occurs in the 4-position, providing the desired enantioenriched 4H-chromenes 43 (Scheme 16) [108].

Scheme 16

First asymmetric Brønsted acid catalyzed hydrogenation of benzopyrylium ion B

Recently, a pioneering organocatalytic asymmetric reduction strategy for the synthesis of chiral 1,1-diarylethanes 46 with high efficiency and enantioselectivity was reported by Zhu, Lin, Sun, and co-workers (Scheme 17) [109].

Scheme 17

Enantioselective synthesis of 1,1-diarylethanes 46

A plausible reaction mechanism is hypothesized by the authors. The electron-rich styrene substrate 44 would be protonated by phosphoric acid catalysts 45 to generate the tertiary carbocation intermediate A. The neutral resonance structure B, activated by B*-H would receive the subsequent hydride addition giving the observed products 46 and regenerating the chiral acid catalyst 45 (Scheme 18).

Scheme 18

Plausible reaction mechanism

To support the reaction mechanism and to better understand the role of each species, the authors performed B3LYP-D3 density functional theory (DFT) calculations. Interestingly, the method was applied to a broad spectrum of substrates, and a lead compound with impressive inhibitory activity against a number of cancer cell lines was also identified.

2.2 Aminocatalysis Promoted Transfer Hydrogenation

Another great area of research in organocatalysis that has experienced an incredible growth has been aminocatalysis. Proof of this progress is the huge number of works focused on this field (for selected reviews concerning the aminocatalysis field, see: [110–129]). Among all of them, pivotal contributions related to transfer hydrogenations have been also developed in this area. Although less explored than the phosphoric acid catalyzed examples, these pivotal works will be recovered in the next examples.

In 2004, List and co-workers [130] pioneered only one chiral example of a novel iminium catalytic conjugate reduction of α,β-unsaturated aldehyde 47a (Scheme 19a). In 2005, and independently, List’s (Scheme 19b) [131] and MacMillan’s groups (Scheme 19c) (as reported by the authors in Ref. [21], the complete details of their studies into transfer hydrogenation were first published via oral presentation on March 1st, 2003, at the Eli Lilly Young Award symposium, Indianapolis. Their work was further communicated in >15 presentations in Europe, USA, Australia, and Asia prior to submission of their manuscript (October 10th, 2004) [132]) reported two more extensive protocols for the enantioselective conjugate reduction of α,β-unsaturated aldehydes 47 and 51 using chiral imidazolinone catalysts 50 and 52.

Scheme 19

Pioneering examples of conjugated reduction of α,β-unsaturated aldehydes

List’s group proposed a reasonable mechanism to explain the observed absolute configuration in their final products 49. The process would firstly proceed by formation of iminium ion 54, which could isomerize quickly via dienamine 55 (Scheme 20). The authors assume that the rate determining step would be the hydride transfer from 1a to iminium (E)-54 via the transition state A, which would occur faster than (Z)-54 [k(E) > k(Z)] and, as a result, the enantiomer R would be predominantly formed (Scheme 20) [131].

Scheme 20

Mechanistic hypothesis of the organocatalytic asymmetric transfer hydrogenation

Later, the first enantioselective organocatalytic transfer hydrogenation involving cyclic enones was reported by MacMillan and co-workers following an operationally simple and rapid protocol that allowed access to chiral β-substituted cycloalkenones 58 with very good yields and high enantioselectivities (Scheme 21) [133] (for an application of this methodology by the same research group, see: [134]).

Scheme 21

Scope of the organocatalytic enone hydrogenation

In order to explain the sense of the asymmetric induction observed in final products 58, the authors proposed a plausible attack of the hydride based on the selective engagement of the Hantzsch ester reductant 1c over the Si face of the cis-iminium isomer A (Scheme 22).

Scheme 22

Enantioselective hydride addition mechanism

Interestingly, in this work the authors compared the efficiency of esters 1b, 1c and 1d, in order to observe a possible structural effect of them over the enantioselectivity and the reactivity of this process. In fact, a significant impact on both aspects was found with a plausible correlation on the size of the ester functionality at the 3,5-dihydropyridine site (1b: Et, 96 % conversion, 74 % ee; 1d: i-Pr, 78 % conversion, 78 % ee and 1c: t-Bu, 86 % conversion, 91 % ee). The enantiocontrol results were explained in terms of electronic factors between the hydrogen substituents at the 4-position and the nitrogen lone-pair. The boat conformation found for 1c would facilitate the overlap between one H (4-position) in an axial orientation with the nitrogen lone-pair in the ground state. In contrast, the 1b ring is found in a planarized form wherein poor π-orbital overlap between the analogous C–H bond and nitrogen renders a less reactive hydride reagent. This hypothesis is consistent with not only an increase in enantiocontrol when using the more bulky tert-butyl Hantzsch ester 1c but also improved reaction rate and efficiency [21, 133].

Bringing together the concept of aminocatalysis and the activation mode of chiral phosphoric acids, List and co-workers introduced the concept of asymmetric counter anion directed catalysis (ACDC) and they applied this idea to the asymmetric reduction of enals 47 (Scheme 23) [135]. The catalytic species is formed by an achiral ammonium ion 60 and a chiral phosphate anion 59 derived from 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate 9 (TRIP).

Scheme 23

ACDC approach applied to the reduction of enals 47

All reduced β,β-disubstituted enals 49 were obtained in good yields (up to 90 %) and excellent enantioselectivities (up to 99 % ee). Moreover, the methodology was applied to the interesting reduction of citral 61 into the (R)-citronellal 62 and to the asymmetric reduction of farnesal 63, in all cases with excellent enantioselectivies and high yields (Scheme 24).

Scheme 24

Catalytic asymmetric transfer hydrogenation of citral 61 and farnesal 63

Remarkably, the same final enantiomer was obtained in the products even starting from Z enals, which is in agreement with a stereoconvergent catalytic system and a rapid E–Z equilibration, as detected by NMR spectroscopic studies. The mechanism is believed to occur via an iminium ion intermediate since salts of tertiary amines seem to be ineffective.

An extension of this work was reported by the same research group for the asymmetric conjugate reduction of α,β-unsaturated ketones 65, affording final reduced products 67 with high yields and good to excellent enantioselectivities (Scheme 25) [136].

Scheme 25

Asymmetric reduction of ketones 65

More recently, Lear and co-workers applied this new concept as a key synthetic step in the high yielding route leading to the (−)-platensimycin core ([137], for further studies in this field, see also: [138–140]).

2.3 Thiourea-Catalyzed Transfer Hydrogenation

Another big family of organocatalysts that has been successfully used in hydrogen transfer, although less explored, is the chiral thiourea organocatalysts (for pivotal reviews concerning chiral thioureas, see: [141–154] and for the pioneering use of non-chiral thioureas in a transfer-hydrogenation reaction, see: [155]). In this context, List and co-workers reported the first example of conjugate reduction of nitroolefins 68 mediated by thiourea organocatalyst 69 (Scheme 26) ([156], for the non-enantioselective version of this reaction, see: [157]).

Scheme 26

Thiourea promoted asymmetric transfer hydrogenation

As disclosed, the process was suitable for a broad substrate scope, leading to final products 70 with high yields and enantioselectivities for diverse β-alkylsubstituted nitrostyrenes 68.

The reaction could proceed via a hydrogen-bonding interaction between the NH of the thiourea moiety and the nitro group and further enantioselective attack of the hydride from the Hantzsch ester 1c.

An extension of this work was reported by the same research group using β-nitroacrylates 71 and the same thiourea organocatalyst 69 with the main aim of preparing the corresponding saturated β-nitroesters 72 in high yields and enantioselectivities, which can be easily converted into β²-amino acids via hydrogenation (Scheme 27) ([158], for other developed methods of asymmetric transfer hydrogenation of nitroolefins using thioureas, see: [159, 160]).

Scheme 27

Asymmetric reduction of β-nitroacrylates

The same approach was used by Benaglia’s group for the enantioselective organocatalytic reduction of β-trifluoromethyl nitroalkenes 73, with the aim of achieving chiral β-trifluoromethyl amines 75 (Scheme 28) [161]. The authors also performed the organocatalyzed reduction of α-substituted-β-trifluoromethyl nitroalkenes, although with poorer results. The stereochemical result of the reaction and the behavior of thiourea catalyst 74 were discussed based on computational studies and DFT transition-state analysis.

Scheme 28

Organocatalyzed reduction of fluorinated nitroolefins 73

Simultaneously, although independently, Bernardi, Fochi and co-workers developed an extraordinary additional example of highly enantioselective transfer hydrogenation using β-trifluoromethyl nitroalkenes to give easy access to optically active β-trifluoromethyl amines with excellent results [162].

3 Trichlorosilane-Mediated Stereoselective Reduction of C=X Bonds

In the last decade, great progress has been made in the development of highly enantioselective Lewis basic organocatalysts for the reactions of trichlorosilyl derivatives as the reducing agents. The 2 is activated by the base moiety of the catalyst to generate an hexacoordinate hydridosilicate (for the activation of trichlorosilyl reagents by Lewis bases, see also: [163, 164]). Here is reported the successful application on the enantioselective reduction of prochiral ketimines, ketones and C=C bond using trichlorosilane 2 as an effective hydride source.

3.1 Reduction of Ketimines

3.1.1 N-Formylpyrrolidine Derivatives

In a pioneering work, Matsumura and co-workers presented a new finding where trichlorosilane 2 activated with N-formylpyrrolidine derivatives 77 was an effective catalyst for the reduction of imines 76. Reducing agent 2 showed much higher selectivity towards the imino group rather than the carbonyl group, because the carbonyl moiety in the catalysts was not reactive against the reduction (Scheme 29) [165]. Later, Tsogoeva’s group demonstrated the use of pyrrolidine 78 as a suitable catalyst for ketimines reduction, although only for one example and using HMPA as additive [166]. More recently, Lewis base 79 was successfully employed for the hydrosilylation of α-imino esters as direct precursors of α-amino acids ([167], for the use of additional picolinoyl catalyst derivatives, see also: [168–172]).

Scheme 29

Reduction of imines with N-formylpyrrolidine-based catalysts

The role of the carbonyl groups in the catalysts seemed to be responsible for the silicium activation (for other pyrrolidine derivatives, see: [173–175]). In order to explain the sense of the stereoselectivity in final products, Matsumura’s group suggested that the reduction predominantly proceeded through a transition state A rather than the most hindered transition state B, justifying the major enantiomer observed (Fig. 6). This mechanistic proposal was an early hypothesis, which was later modified by other authors on the basis of more experimental results (see below).

Fig. 6

Mechanism of hydrosilylation of imines

3.1.2 l-Valine-Derived N-methyl Formamides

Malkov, Kočovský, and co-workers have developed different l-valine-based Lewis basic catalysts such as 81 [176, 177], for the efficient asymmetric reduction of ketimines 76 with trichlorosilane 2, or catalyst 82 [178] with a fluorous tag, which allows an easy isolation of the product and can be used in the next cycles, while preserving high enantioselectivity in the process. Sigamide catalyst 83 [179, 180] and Lewis base 84 [181] were employed in a low amount (5 mol%) affording final chiral amines 80 with high enantioselectivity (Scheme 30) [182]. Interestingly, 83 was used for the enantioselective preparation of vicinal α-chloroamines and the subsequent synthesis of chiral 1,2-diaryl aziridines. In these developed approaches the same absolute enantiomer was observed in the processes.

Scheme 30

Pioneering examples of l-valine-based Lewis basic catalysts

From these studies, the authors suggested different important conclusions: (1) the structure–reactivity studies showed that the product configuration seems to be controlled by the nature of the side chain of the catalyst scaffold, and the electronic properties of the substituents in the phenyl ring on the Lewis base. Interestingly, catalysts of the same absolute configuration may induce the formation of the opposite enantiomers of the product; (2) hydrogen bonding and arene–arene interactions between the catalyst and the imine appear to be crucial for the success of determining the enantiofacial selectivity; (3) the activation of trichlorosilane seems to be in agreement with a bidentate coordination with both carbonyl groups of the amide moiety in the catalyst, as previously invoked (Fig. 7) [176]. It is remarkable that the mode of activation in this case differs from that proposed previously by Matsumura’s group in Fig. 6 [165].

Fig. 7

Mechanism of hydrosilylation of imines

3.1.3 l-Pipecolinic Acid Derived N-Formamides

Sun and co-workers developed a novel Lewis basic organocatalyst 86 (Scheme 31), easily synthesized from commercially available l-pipecolinic acid. The catalyst 86 promoted the reduction of N-aryl ketimines 85 with HSiCl₃ 2 in high yield and excellent ee values under mild conditions with an unprecedented spectrum of substrates [183]. The same group also found that the l-pipecolinic acid derived N-formamide 87 was a highly effective Lewis basic organocatalyst for the same reaction [184].

Scheme 31

Model L-pipecolinic acid derived N-formamide catalysts 86–88

On the basis of the experimental results, the methoxy group on C2′ has proven to be critical for the high efficiency of catalyst 87 in the reduction of the imines. A hexacoordinate silicon transition structure was proposed to justify the experimental observations. In a more extended mechanistic study N-funtionalized pipecolinamides 88 were proposed as an example of efficient catalyst after several variations in the C2 and the N-protected group ([185], for more recent l-pipecolinic basic organocatalysts for hydrosilylation of imines, see: [186, 187]).

3.1.4 Piperazine Lewis base Organocatalyst

Sun and co-workers envisioned that the piperidinyl ring on the abovementioned catalysts could be replaced by a piperazinyl backbone, considering that the additional secondary amino group on the 4-position (N4) should provide a suitable site to introduce structural variations and thus accurately to modify the catalytic properties. In this context, a new catalyst 91 was designed (Scheme 32) [188, 189], which promoted the unprecedented reduction of the relatively bulky ketimines 90, becoming a complementary structure to the existing catalytic systems. The reductions of both N-aryl acyclic methyl ketimines and non-methyl ketimines 90 were catalyzed for a broad spectrum of substrates affording the desired chiral amines 92 in high yields and with high ee values.

Scheme 32

Reduction of imines using piperazine Lewis base derivative 91

Unfortunately, other N-substituted phenyl ketimines 93a–e afforded lower ee values compared with 90. The N-benzyl ketimine 93e was also proven to be an unsuitable substrate using 91 as catalyst. The authors found that the arene sulfonyl group on N4 and the 2-carboxamide groups were crucial for the high enantioselectivity of the process and the efficiency of the catalytic system.

3.1.5 S-Chiral Sulfinamide Derivatives

Although stereogenic sulfur centers had been used as the source of chiral auxiliaries and ligands [190–195], organocatalysts incorporating chirality solely through the sulfur atom had been almost overlooked in the literature before the development of this subarea of research. In this context, Sun’s group developed the first highly effective example of sulfinamide organocatalyst 95 to promote the asymmetric hydrosilylation of ketimines with 2 in high yield and enantioselectivity (Scheme 33) [196]. Having in mind the idea that two molecules of monosulfinamide catalyst could participate in the mechanism of the reaction (Fig. 8), the same authors designed bissulfinamide 96 [197] incorporating two sulfinamide units, which efficiently promoted the asymmetric reduction of N-aryl ketimines in high yields and improved enantioselectivities (Scheme 33). Compound 96 resulted to be a better catalyst than the former monosulfinamide 95.

Scheme 33

Example of efficient sulfinamide organocatalysts 95–97

Fig. 8

Mode of action of monosulfinamide organocatalysts

The same group developed a new Lewis base organocatalyst 97, which included stereogenic atoms represented by a sulfinamide group and a α-amino acid framework bearing Lewis basic carboxamide functionality, both for the activation of HSiCl₃ 2. Excellent enantioselectivities and high yields for a wide range of aromatic N-alkyl ketimines were achieved (Scheme 33) ([198], for more recent examples belonging to the same research group, see also: [199, 200]).

3.1.6 Supported Lewis Base Organocatalysts

With the increasing interest in developing catalysts able to be easily separated from the final product, many efforts have been devoted to the preparation of immobilized structures (for reviews on polymer-supported organocatalysts, see: [201–204], for a more recent example, see also: [205]). In this field, Kočovský’s group has also reported interesting Lewis base supported catalysts for the efficient asymmetric hydrosilylation of ketimines with silane 2. The first reported example was an N-methylvaline-derived Lewis basic formamide anchored to a polymeric support with a varying spacer 100. This protocol represented a considerable simplified procedure to isolate the catalyst from the crude of the reaction, which is not a trivial task, for instance on a large scale protocol (Scheme 34). The polymer-supported catalyst was reused at least five times without any loss of activity [206].

Scheme 34

Application of polymer-supported organocatalyst 100

The same research group designed a soluble catalyst 102 with the main aim of avoiding the problems associated with the heterogeneous systems, and related to the common supported catalysts [207]. The main advantage of this system is the inverted solubility pattern that this catalyst exhibits, since it is soluble in non-polar solvents and insoluble in polar media (Fig. 9). This feature simplified the recovery (up to 99 %) and re-use of the catalyst at least five times without loss of activity, improving the results obtained with catalyst 100 (for the preparation of other immobilized catalysts easily recoverable, see: [208]).

Fig. 9

Soluble supported catalyst 102

In order to enable the isolation procedure of the organocatalysts, Kočovský’s group also reported an alternative approach using a dendron-anchored organocatalyst 103 to efficiently reduce the imines with trichlorosilane 2 [209]. The isolation procedure of the catalyst from the crude was substantially simplified, since most of the catalyst (≥90 %) could be recovered by precipitation and centrifugation (Fig. 10).

Fig. 10

Dendron-anchored organocatalyst 103

3.2 Reduction of Ketones

Although the reduction of imines has been widely explored, as described above, the reduction of carbonyl groups has been less studied until now. Specifically, the reduction of ketones is more limited due to the low reactivity shown by these compounds. In this field, the pioneering works using trichlorosilane as reducing agent and a chiral Lewis base were reported by Matsumura and co-workers in 1999, affording low to moderate enantioselectivities (for the seminal enantioselective work using Lewis base to reduce carbonyl groups, see: [210], for pioneering works using chiral lithium salts, see: [211–213]). More recently and independently, Malkov, Kočovský, and co-workers [214] and Matsumura’s group [215], reported isoquinolinyloxazoline 105 and N-formylpyrrolidine 106, respectively, as new catalysts to significantly improve the enantioselectivity of the process in comparison with the pioneering work (Scheme 35).

Scheme 35

Enantioselective reduction of ketones 104

In these examples the carbonyl compounds were limited to aromatic ketones. Based on the experimental results, the authors proposed the following TS to explain the enantioinduction observed in their work (Fig. 11) [214].

Fig. 11

Activation proposal

The 2 would be chelated by the catalyst forming an activated hydrosilylating species, while a second molecule of HSiCl₃ would likely activate the ketone by coordination to the oxygen atom. The attack of the hydride would take place from the less hindered Si face. Additionally, the π–π interaction between the heteroaromatic ring of the catalyst and the aromatic ring in the ketone would stabilize the system.

Later, Sun’s group also used their pipecolinic acid derivative 87 for the first efficient reduction of aliphatic and aromatic ketones with silane 2 in moderate to high enantioselectivity [184]. A plausible transition state was proposed in order to explain the results observed, where the catalyst 87 would act as a tridentate activator and would promote the hydrosilylation of ketones through the heptacoordinate silicon structure depicted in Fig. 12.

Fig. 12

Role of pipecolinic acid derivative 87

It is remarkable that the hydrosilylation procedure has been successfully used for the synthesis of important targets. Matsumara and co-workers demonstrated the applicability of their developed method in the preparation of optically active lactone 109 from keto ester 108 in 93 % yield with 97 % ee (Scheme 36) [215]. Lactone 109 is an important building block for the synthesis of a variety of biologically active substances [216–218].

Scheme 36

Synthesis of optically active lactone 109

3.3 Reduction of β-Enamino Esters

In the last decade, increasing efforts have been devoted to the asymmetric preparation of structurally diverse β-amino acids (for selected reviews, see: [219–222]), due to their involvement in the synthesis of peptidomimetics and as valuable building blocks.

In this field of research, enantiomerically enriched β-amino acids could be also obtained through transfer hydrogenation using β-enamino esters ([223], for pioneering works using metals, see: [224, 225]). This approach was initiated by Matsumura and co-workers [173] reporting a single example using catalyst 111 (Scheme 37). Later, the methodology was improved by Zhang’s group with Lewis base catalyst 112 [226] and 113 [227], and also Benaglia and co-workers with catalysts 114 (Scheme 37) [228]. Remarkably, Sun’s group reported an interesting methodology using water as additive and the Lewis base catalyst 115 [229]. The addition of 1 equiv. of water resulted to be crucial for the success of both reactivity and enantioselectivity of the process (Scheme 37). All these approaches were potentially useful for the preparation of enantiomerically enriched β-amino acid derivatives, which in all cases was achieved with good yield and good enantioselectivies [230].

Scheme 37

Reduction of β-enamino esters 110 (for other examples of reduction of enamines, see: [231–233])

Interestingly, in order to extend the applicability of the reduction of β-enamino esters, the protocol developed by Zhang and co-workers using catalyst 113 was successfully applied in the synthesis of the taxol C13 side chain 117 and oxazolidinone 118, which is a potent hypocholesterolemic agent (Schemes 38, 39) [227].

Scheme 38

Enantioselective synthesis of the taxol C13 side chain 117 [234]

Scheme 39

Enantioselective synthesis of oxazolidinone 118 [235]

Malkov, Kočovský, and coworkers also reported the interesting synthesis of β ^2,3-amino acids, in which synthesis is still a challenge, using organocatalyst 83 (Scheme 40) [236]. This approach is based on the fast equilibration between the enamine and imine forms. A subsequent reduction of the equilibrated mixture with HSiCl₃, afforded the corresponding amino esters and amino nitriles with good results.

Scheme 40

Enantioselective synthesis of β³- and β^2,3-amino acid derivatives 119 and 120

AcOH was used in order to maintain the concentration of H⁺ constant. Although the presence of H⁺ also catalyzed the competing nonselective reduction, under the optimized reaction conditions, the use of one equivalent of AcOH provided a good compromise between reactivity and selectivity.

4 Conclusions

A great number of organocatalytic examples of reduction of different C=N, C=O and C=C double bonds affording new stereogenic centers has been illustrated. The organocatalytic transfer hydrogenation has been mainly focused on the pioneering examples using Hantzsch dihydropyridines 1 and trichlorosilane 2 as hydride sources, although other reducing agents have being explored in the last few years. Organocatalysts such as chiral Brønsted acids, thioureas, and chiral secondary amines or Lewis bases have been successfully used in all the reported examples. As reflected in the numerous examples, this field is the focus of great interest. This is proof of the importance that the asymmetric transfer hydrogenation arouses, and the power of this approach to achieve the final target. Certainly, in the near future new hydride sources and novel organocatalysts will be designed to achieve this goal in a greener and more environmentally friendly manner.