review article

Published online: 19 February 2010 | doi: 10.1038/nchem.539

organocatalytic cascade reactions as a new tool in total synthesis

christoph Grondal1*, matthieu Jeanty2 and dieter enders2*
The total synthesis of natural products and biologically active compounds, such as pharmaceuticals and agrochemicals, has reached an extraordinary level of sophistication. We are, however, still far away from the ‘ideal synthesis’ and the state of the art is still frequently hampered by lengthy protecting-group strategies and costly purification procedures derived from the stepby-step protocols. In recent years several new criteria have been brought forward to solve these problems and to improve total synthesis: atom, step and redox economy or protecting-group-free synthesis. Over the past decade the research area of organocatalysis has rapidly grown to become a third pillar of asymmetric catalysis standing next to metal and biocatalysis, thus paving the way for a new and powerful strategy that can help to address these issues — organocatalytic cascade reactions. In this Review we present the first applications of such asymmetric organocascade reactions to the total synthesis of natural products.

he complexity and structural diversity of natural products have fascinated organic chemists for a very long time. The development of new types of chemical reactions over the past few decades has enabled synthetic chemists to assemble almost every discovered natural product. A main driving force for these huge synthetic efforts is clearly the important biological activities of natural products, which are not only of enormous interest for the pharmaceutical and agrochemical industry, but also have a long-lasting impact on natural sciences and the wealth and welfare of our society 1. A historical retrospect on the progress of the total synthesis of natural products2,3 reveals that most of the synthetic approaches share two main features: the so-called stop-and-go approach4, and the implementation of orthogonal protecting-group strategies. Both single-step and protecting-group operations have increased significantly the number of chemical steps and waste, while simultaneously decreasing the synthetic efficiency. Nevertheless, organic synthesis is a relatively young discipline of the natural sciences compared with nature, which has been optimizing its biosynthetic machinery over billions of years of evolution. The blueprints of biosynthesis are based on some key elements, namely cascade reaction sequences and the avoidance of protecting-group strategies, which, when put together, have a tremendous impact on the efficiency of biosynthesis5–7. In addition, all natural products are built up via a relatively small number of basic biosynthetic pathways that employ simple key building blocks. Their complexity and diversity are achieved by the myriads of different possible combinations of these key building blocks and by their further enzymatic transformations. Current developments in the field of total synthesis indicate that chemists have adopted the fundamental principles of biosynthesis, namely cascade reactions8–10, protecting-group-free synthesis11, redox economic12, atom economic13, step economic14 and biomimetic synthesis15,16 as strategic key elements for their synthetic approaches17. In this Review we want to draw the readers’ attention to the field of organocascade reactions, which have an important role in the efficient and rapid generation of complex architectures. One of the big advantages of such domino reactions over classical synthesis is that at least two reactions are carried out in a single operation under the same reaction conditions18. Furthermore, this
1

avoids time-consuming, costly protecting-group manipulations as well as the isolation of reaction intermediates. In this way molecular complexity is achieved quickly, often accompanied by high levels of stereoselectivity. A major topic of current research is the exploration of catalysed cascade reactions by employing a single catalyst capable of promoting each single step. Organocatalysts are particularly favourable when used in catalytic cascade reactions because they allow distinct modes of activation, which can often be easily combined19,20. Furthermore, organocatalysts are tolerant of numerous functional groups and can be employed under mild reaction conditions. This enables a single organocatalyst to be used in a broad variety of possible cascade reactions. Therefore, these small organic molecules, such as the natural amino acid proline, are often considered as small artificial enzymes. It is thus unsurprising that the field of asymmetric organocatalytic cascade reactions has attracted much attention, and a lot of powerful new reaction cascades for the rapid construction of molecular complexity, starting from simple key precursors, have been explored in recent years. In this Review we would like to highlight not only the first applications of organocatalytic cascade reactions in total synthesis, but also give the reader an impression of how powerful this concept is and how it can help to simplify the synthesis of complex natural products and biological active compounds.

conceptual insights

The use of LUMO-lowering iminium ion activation and HOMOraising enamine activation has been studied intensively in synthetic organic chemistry over the past 10 years. Recent advances in catalyst development have demonstrated that it is possible to efficiently control the iminium ion geometry in the stereoselective formation of carbon–carbon and carbon–heteroatom bonds. Likewise, enamine activation has gained significant attention for controlling the absolute configuration in the α-functionalization of aldehydes and ketones by a variety of electrophilic reagents. These two powerful methodologies contributed significantly to the success of the rapidly developing area of asymmetric organocatalysis21–27. The combinations of iminium and enamine activation in a single operation of an organocatalysed cascade reaction constitute a second milestone in the area of amine-catalysis. Initiated by these first contributions,

Bayer CropScience AG, Alfred-Nobel-Str. 50, 40789 Monheim am Rhein, Germany. 2Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany. *e-mail: enders@rwth-aachen.de; christoph.grondal@bayercropscience.com.
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review article
further attempts in the field of cascade reactions have been able to explore various ways of combining enamine and iminium catalysis. This concept is limited not only to simple tandem processes, but also to triple-cascade extensions and, since very recently, impressive quadruple-cascades have also been elaborated28–30. The number of reactions for each activation mode and the exponential increase of combinations for double, triple and quadruple processes pave the way to various new reaction combinations and new and rapid entries for the synthesis of complex and valuable synthetic building blocks (Fig. 1). Nowadays, organocatalytic cascade reactions are not limited to amine catalysis. Significant contributions have also been made in the field of hydrogen-bonding and Brønsted-acid catalysis (counter-ion catalysis). Hydrogen-bonding catalysis with small chiral organic molecules has emerged as a powerful research area in the field of asymmetric organocatalysis. These catalysts activate the substrates by forming a hydrogen-bond (LUMO-lowering) and are able to promote several C–C and C–heteroatom bond-forming reactions. A prominent class among the hydrogen-bonding catalysts are the thioureas, which have already found application in cascade reactions. Chiral Brønsted acids activate the substrates by protonation of a suitable C=X bond (X: O, NR, CR2) thereby lead to a chiral counter-ion31,32. In this manner, the LUMO energy is lowered and a nucleophilic addition to the C=X bond is now possible. Phosphoric acids are a very famous class of chiral Brønsted acids and have also found widespread application in the field of organocatalytic cascade reactions. Very recently, NHC-catalysis33 has also been applied to cascade sequences34–36 N-heterocyclic carbenes (NHCs) are capable of activating carbonyl groups through ‘umpolung’37 to undergo nucleophilic acylation reactions. The combination of such nucleophilic
Catalysts Activation modes

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acylations with standard modes of activation will be of particular interest in the future. These organocatalysed cascade processes represent a powerful and novel way of approaching bond disconnections. However, their application to natural product synthesis remains a big challenge and represents a valuable benchmark for these new synthetic methods. The application of organocatalysed cascade reactions in natural product synthesis was impressively demonstrated for the first time by Terashima and co-workers in 1998 when the field of organocatalysis was just in its infancy 38. They used an asymmetric cascade reaction as the key process for their concise synthesis of (−)-huperzine A (1), a natural product isolated from the club moss Huperzia serrata and belonging to the class of sesquiterpene alkaloids. This compound shows interesting biological activities, for example, potent reversible acetylcholinesterase inhibitor activities, and is currently being tested in clinical trials as a promising drug for the treatment of Alzheimer’s disease39. Therefore 1 is the target of many synthetic approaches (Fig. 2). (−)-Huperzine A contains a challenging bridged tricyclic core, which was obtained via a simple Michael/aldol cascade reaction sequence between β-keto ester 2 and methacrolein. The organocatalyst (−)-cinchonidine acts as a base by deprotonating the β-keto ester 2 and forming a chiral ion pair. The secondary alcohol function of the catalyst simultaneously activates a methacrolein molecule by forming a distinct hydrogen bond and incorporating it into the ionic complex. The Michael reaction, as the first step of the cascade sequence, is thus initiated, followed by an intramolecular aldol condensation. The tricyclic core 4 of (−)-huperzine A was formed with an overall yield of 60% and 64% enantiomeric
Established combinations* Simple† Triple Quadruple

historical background

Typical reaction steps

N H O N N H

Enamine activation of aldehydes and ketones (HOMO raising)

EN

Aldol reaction α-Functionalization Michael reaction Mannich reaction

IM

EN

EN

IM

EN

IM

EN

IM

EN

IM

IM

IM

IM

EN

EN

IM

EN

EN

Iminium activation of α,β-unsaturated aldehydes (LUMO lowering)

IM

Michael reaction Diels–Alder reaction Friedel–Crafts reaction

EN

IM

EN

EN

H N S

H N

Hydrogen bonding (LUMO lowering)

H Do

Michael reaction Henry reaction Mannich reaction Strecker reaction

H Do H Do

O O

O OH

Protonation (LUMO lowering) (counterion catalysis)

H+

Reduction Mannich reaction Friedel–Crafts reaction Michael reaction

H+

H+

H+

H+

H+

EN

H+

N N

Umpolung Breslow intermediate

NHC

Nucleophilic acylation Benzoin reaction Stetter reaction

IM

NHC

Figure 1 | Organocatalysed cascade reactions. Summary of the different combinations of organocatalytic activation modes so far described. *Only the organocatalysed bond-formation steps are taken into account. †Simple (double, tandem) is the simplest case of a cascade reaction (two steps).
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NaTuRe chemIsTRy doi: 10.1038/nchem.539

N HO CO2Me 2 DCM, 10 d, −10 °C 45% OMe (−)-Cinchonidine CHO
H Do H Do

review article
N OMe AcONa, AcOH 120 °C, 24 h 77% O CO2Me 4 64% e.e. N OMe 5 steps NH2 1 (−)-Huperzine A H N O

HO

CO2Me 3

H H N N OH (−)-Cinchonidine N O

N H O H O

O N OMe

MeO

Intermediate ionic complex

Figure 2 | First application of an organocatalysed cascade reaction in total synthesis. Preparation of the sesquiterpene (−)-huperzine A by means of an organocatalysed Michael/aldol cascade reaction sequence. DCM, dichloromethane; AcONa, sodium acetate; AcOH, acetic acid.

excess (e.e.). By employing this key cascade sequence, the completion of the total synthesis starting from 4 could be achieved in only five further steps.

amine-catalysed cascade reactions

The area of amine-catalysed cascade reactions is clearly dominated by secondary amines due to the versatility of possible combinations of enamine (EN) and iminium (IM) activation40–42. Among them, the IM–EN combination has turned out to be very powerful. In 2005 several contributions were made by the groups of Jørgensen43, List 44 and MacMillan45. Today, numerous examples of this combination can be found in the literature19. Hence it is not surprising that simple IM–EN sequences have already been utilized in total synthesis (Fig. 3). The first example comprises a cascade oxa-Michael/aldol condensation reaction for the rapid construction of different tetrahydroxanthones. These intermediates are key building blocks for the synthesis of diversonol or blennolide C, natural products belonging to the large class of mycotoxins found in many different fungi. Their biological activity ranges from antibiotic to antibacterial46. Starting from the salicylaldehyde derivative 5 and the cyclohexenone rac-6, Bräse and colleagues developed an elegant imidazol-catalysed oxa-Michael/aldol cascade sequence to build up the tetrahydroxanthenone core 7 (Fig. 3a). Afterwards, only a few transformations were necessary to afford rac-diversonol 8 (ref. 47), a potent metabolite isolated from the fungus Penicillium diversum, or to accomplish the total synthesis of blennolide C (9)48. Although one new stereogenic centre is formed during the cascade reaction, this stereochemical information is eventually erased later in the synthesis. Therefore, stereocontrol was not required and the use of an achiral base catalyst such as imidazol was sufficient. Later on, the same research group demonstrated that, to access (−)-diversonol, enantiomerically pure 6 could be also employed in this reaction without the loss of any enantiomeric excess49. The mechanism of this oxa-Michael/aldol condensation reaction was studied in detail, and it was shown that tertiary amines (for example, 1,4-diazabicyclo[2.2.2]octane; DABCO) can promote this reaction as well50. Although this example does not constitute an IM–EN sequence, it opened the way for related organocatalysed hetero-/aldol cascade reactions involving a secondary amine catalyst which promotes IM and EN activation modes. Camptothecin (13), a pentacyclic alkaloid, isolated from the bark and stem of Camptotheca acuminate, and first synthesized by Stork and Schultz51 in 1971, is a powerful inhibitor of the DNA enzyme topoisomerase I and has therefore attracted considerable attention from the academic community and the pharmaceutical industry 52. Because of its very promising anticancer activity,
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several highly potent derivatives of camptothecin were synthesized, and some of them have already been launched as effective cancer drugs (topotecan, irinotecan). Both topotecan (Hycamtin) and irinotecan (Camptosar) are semisynthetic drugs derived from 13, which has to be isolated from Camptotheca acuminate. Although numerous research groups have elaborated different total syntheses of camptothecin and its derivatives, none of them are attractive enough from an industrial point of view. To achieve a more practical and efficient total synthesis, the Yao research group employed a piperidine-catalysed cascade reaction followed by oxidation to assemble the cyclic A and B core of 13 (Fig. 3b)53,54. Their approach was based on inexpensive starting materials, namely the orthoaminobenzaldehyde and the simple α,β-unsaturated aldehyde 10. In this IM–EN sequence, piperidine first activates 10 by iminium ion formation, which subsequently undergoes a conjugate addition with ortho-aminobenzaldehyde. The enamine intermediate resulting from this addition promotes an intramolecular aldol condensation and the subsequent formation of 11, which is then oxidized by MnO2 into the key precursor 12. This simple cascade-oxidation sequence proceeds in 75% overall yield. A very similar IM–EN cascade sequence was used for the formal synthesis of martinelline by Hamada and co-workers55 (Fig. 3c). Martinelline 20 and martinellic acid 19 were isolated from the roots of Martinella iquitosensis. These pyrroloquinoline alkaloids act as non-peptidic bradykinin receptor agonists and are characterized by an unusually fused pyrrolidino-tetrahydroquinoline core56. The Hamada approach employed an asymmetric aza-Michael/aldol cascade reaction to form the dihydroquinoline 17. A series of different amine catalysts as well as solvents were screened in order to improve the yield and the enantioselectivity. Best results were found with the catalyst/solvent combination of the triethylsilyl-protected diphenylprolinol 16 in acetonitrile at –20 °C, which gave 17 in almost quantitative yield and 99% e.e. Besides the famous IM–EN cascade sequence, many successful reactions were achieved by simply changing the order of activation. The EN–IM cascade sequence also paves the way for a rapid access to molecular complexity as well. This sequence can already be found in some natural product total syntheses, like the synthesis of ent-dihydrocorynantheol, α-tocopherol or 4-dihydroxydiversonol (Fig. 4). In a first example, Itoh and co-workers established a prolinecatalysed Mannich/Michael cascade reaction for the total synthesis of ent-dihydrocorynantheol (24) (Fig. 4a)57. Dihydrocorynantheol is a member of the corynantheines, archetypal indole alkaloids exhibiting interesting antiparasitic, antiviral or analgetic activities. Dihydrocorynantheol was first isolated in 1967 from the bark of Aspidosperma marcgravianum and has since been an interesting
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a
OMe CHO OH 5 rac-6 O OH
HN N

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OMe O 9 steps O 7 8 steps O MeO 2 C OH 9 Blennolide C H OMe O OH OH

Dioxane/H2O, 7 d, ultrasonic activation 61%

OH OH O OH

OH rac-8 rac-Diversonol

O H3C

CHO NH2 OAc 10

CHO

NH

CHO MnO2, DCM N H rac-11 OAc 75% over 2 steps N 12

CHO

IM EN
DCM, PhCO2H RT

12 steps

B N

C N D

OAc

13 Camptothecin

E O OH O

c
MeO2C CHO NHTs 14 NHBoc

CHO

N H

Ph Ph OTES

16 MeO2C N 17 Ts CHO NHBoc 99% e.e. 10 steps MeO2C

HN 3HCl N H 18 NH2

IM EN
15 CH3CN, −20 °C, 1 d Quant.

19 Martinellic acid: R = H NH N H RO2C N H H N H N NH N 20 Martinelline : R = H2N

H N NH

Figure 3 | application of Im–eN sequences in total synthesis. a, A simple oxa-Michael/aldol cascade reaction for the synthesis of rac-diversonol and blennolide C. b, Application of an IM–EN cascade sequence for the synthesis of camptothecin. c, Formal synthesis of martinelline using an IM–EN cascade reaction. rac, racemic; Ac, acetyl; RT, room temperature; quant., quantitative; Ts, p-toluenesulfonyl; Boc, tert-butoxycarbonyl; TES, triethylsilyl.

target for total synthesis. The Itoh approach starts directly with the cascade reaction beween 3-ethyl-3-buten-2-one (22) and the dihydro-β-carboline 21, which is obtained from commercially available dihydro-β-carboline by simple tosylation. This sequence is catalysed by 30 mol% of (S)-proline and affords the tetracyclic intermediate 23 in 85% yield. The two new stereocentres are formed with 99% enantiomeric excess and almost complete diastereomeric control. This elegant cyclization approach enabled Itoh et al. to accomplish the total synthesis of ent-dihydrocorynantheol in only five steps, starting from commercially available dihydro-β-carboline. By simply using (R)-proline, the naturally occurring dihydrocorynantheol was made available by this strategy as well. Usually, the use of 2-hydroxy, 2-amino or 2-thiobenzaldehydes and α,β-unsaturated aldehydes in amine-catalysed cascade reaction follows a typical IM–EN activation sequence58, in which the catalyst first activates the α,β-unsaturated aldehyde by iminium ion formation, and then secondly it participates in the enamine activation process. However, under special conditions, another catalytic pathway can be implemented. Recently, Jørgensen and colleagues reported the γ-functionalization of α,β-unsaturated aldehydes using chiral secondary amines via an atypical dienamine activation59. The
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correct choice of catalyst, acidic additive and solvent allowed the formation of a dienamine from the primarily formed iminium ion. It was shown that the nucleophilicity of the γ-position of such dienamines could be exploited for the functionalization of this position. Most interestingly these γ-functionalizations proceed with high enantioselectivity, too. The concept of dienamine formation was used by Woggon and co-workers in an aldol/oxa-Michael cascade reaction (Fig. 4b)60. This EN–IM sequence, involving the salicylic aldehyde 25 and the α,βunsaturated aldehyde 26, permits a very rapid and efficient synthesis of α-tocopherol, the most biologically significant member of the vitamin E family. Catalyst 27 activates phytal 26 by forming a dienamine, which subsequently undergoes an intermolecular aldol reaction with aldehyde 25. The adjacent phenol function can now attack the newly formed iminium ion by an oxa-Michael reaction to build up tricyclic hemiaminal 28. This cascade reaction proceeds with 97% diastereomeric excess and 58% yield. The synthesis of the desired α-tocopherol (29) can be achieved after only four steps from the cascade product 28. The same approach was adopted by Bräse et al. for the formal synthesis of 4-dehydroxydiversonol 33, which belongs to a family of compounds produced by the fungal species Penicillium diversum
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NaTuRe chemIsTRy doi: 10.1038/nchem.539

a
N N Ts 21
N H CO2H

review article
N N H Ts O 99% e.e. 3 steps N H H OH N

EN IM
22 DMSO, RT, 7 d 85% 23

24

ent-Dihydrocorynantheol

b
MeO CHO OH 25

N H

Ar Ar OTES

27 MeO O 28 97% d.e. (determined after oxidation of ketal into lactone) 4 steps O OH
OHC R R R' N H N O OH N R

Ar = 3,5-(CF3)2Ph

OHC

EN IM
Toluene, 72 h, RT 58%

26 HO O 29
Ar

R' O

OH OH R' OH N R

α-Tocopherol

OMe CHO OH 30 31 CHO

N H

Ar OTMS

Ar = 3,5-(CF3)2Ph

OMe

O O

OH

OH 4 steps

OH OH

EN IM
79% 32 87% e.e.

O 33 4-Dehydroxydiversonol

Figure 4 | application of eN–Im sequences in total synthesis. a, Mannich/Michael cascade reaction used in the synthesis of ent-dihydrocorynantheol. b, The use of an unusual EN–IM cascade activation for the synthesis of α-tocopherol. c, Synthesis of 4-dehydroxydiversonol via an EN–IM cascade reaction. DMSO, dimethylsulfoxide; d.e, diastereomeric excess; TMS, trimethylsilyl.

(Fig. 4c)61. The synthesis of 33 was achieved after only four steps, starting from tricyclic intermediate 32, which was obtained from the salicylaldehyde derivate 30 and enal 31. Although IM–EN and EN–IM activations are the most common nowadays, new possibilities for combining EN-activation and IM-activation already exist. One of these new combinations was independently published by Hong and colleagues62. They demonstrated the use of dienamine catalysis in a new type of cascade reaction: the self-condensation of α,β-unsaturated aldehydes. This new reactivity is possible if one molecule of the enal is activated through iminium ion formation 40 and, simultaneously, a second enal molecule is activated through dienamine formation 41. Thus, the iminium species is electrophilic at the β-position and the dienamine species is nucleophilic at the γ-position. This leads to a C–C bond formation between 40 and 41, followed by an intramolecular aldol reaction of 42 (Fig. 5a). From an organocatalytic point of view, this formal [3+3]-cycloaddition illustrates a simple EN/ IM–EN cascade reaction. The cyclohexene carbaldehyde 34 was used as a precursor for the synthesis of (−)-cubebaol (36), and compound 35 constitutes an intermediate in the synthesis of (−)-isopulgeol (37). Furthermore, derivative 38, obtained from 35, was described as an intermediate in the synthesis of the lycopodium alkaloid magellanine (39). Later on, Hong and colleagues reported that, unlike crotonaldehyde, other aldehydes react under similar conditions via a formal [4+2] cycloaddition to produce diene products (Fig. 5b). The general activation mode is an EN/IM–EN/IM cascade reaction in which the cyclization step proceeds via a Mannich reaction rather than an aldol cyclization. This strategy was used to achieve the total synthesis of (+)-palitantin (45), a polyketide metabolite isolated
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from the Penicillium palitans and Penicillium brefeldianum, having antifungal and antibiotic activity and showing HIV-1 integrase inhibition63. The EN/IM–EN/IM cascade sequence involving aldehyde 43 affords cyclohexadiene carbaldehyde 44 with a yield of 70% and 95% e.e. This diene is then converted into (+)-palitantin after nine steps. Over the past decade MacMillan and colleagues introduced the imidazolidinone-type organocatalysts, which can be also applied in a wide range of organocatalytic cascade reactions64. One of the first applications of this strategy in total synthesis culminated in the total synthesis of flustramine65. In the meantime, the same group advanced this strategy to easily access more complex molecules like (+)-minfiensine (53; Fig. 5c)66. This unique natural product belongs to the Strychnos alkaloids and was isolated about 20 years ago from the African plant Strychnos minfiensis 67. Not only because of its complex structure, but also because of its very interesting and potential biological activity, (+)-minfiensine became an interesting target for total synthesis. The MacMillan approach starts with the preparation of the simple indole precursor 50 in only three steps. Then, the organocatalytic cascade reaction was applied in a newly developed [4+2]-cyclization reaction cascade. First, catalyst 51 forms an iminium ion with propynal to undergo the [4+2]-cyclization with the diene portion of 50 to form intermediate 52. This cycloaddition reaction proceeds with high stereocontrol and endoselectivity, which, as explained by the authors, is due to the rigid conformation of the iminium ion. Then, the counter-acid of the catalyst isomerizes intermediate 54 to iminium ion 55 to initiate the second exo-cyclization towards aldehyde 56. Finally, the reaction is quenched with sodium borohydride to afford alcohol 52 as a single diastereomer. An 87% yield and 96% e.e. are reached for this key
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a
CHO
N H CO2H

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CHO OH CHO OH H O O N

EN IM EN
DMF, −10 °C, 16 h 73% HO OH HO OH 37 (−)-Isopulegol hydrate AcO OH 38 39 H H O Ratio 47:53 34 (95% e.e.) N Me H H OH Magellanine 40 H 35 (80% e.e.) N H O

HO2C H

O H

N 34 or 35 CHO 42

(S)-adduct 41 Me

36 (−)-Cubebaol

Transition state

b
AcO 43

CHO

N H

CO2H

OH AcO AcO 44 H H N 48 OAc O O Mannich reaction CHO 95% e.e. 45 9 steps HO O OH (+)-Palitantin O N

EN IM EN IM
CH3CN, −20 °C, 8 h 70% H

O N H AcO 46 H AcO

O O N N H AcO 47

O O

OH O2 C N 44 49

O H

EN IM

EN IM
AcO

AcO

NHBoc SMe N 50 PMB Cycloaddition NHBoc R N R SMe

O TBA Napht

N N H

OH NBoc 5 steps N H N 53

OH O Ar N PMB

51
O

−40 °C, Et2O, NaBH4, CeCl3, MeOH 24 h, 87% NHBoc TBA N PMB N

SMe N 52 PMB 96% e.e. R R SMe Azacyclization 56

N Me tBu MeS N

(+)-Minfiensine reduction O NBoc SMe N PMB

BocHN Transition state and enantiocontrol of the cycloaddition

54

N PMB

55

Figure 5 | alternative eN and Im combinations in total synthesis. a, Enantioselective organocatalysed formal [3+3]-cycloaddition of α,β-unsaturated aldehydes for the synthesis of cyclohexene carbaldehydes. b, Synthesis of (+)-palitantin via dienamine activation. c, Synthesis of (+)-minfiensine catalysed by an imidazolidinone-acid system. DMF, N,N-dimethylformamide; PMB, p-methoxybenzyl; Napht, 1-naphthyl; TBA, tribromoacetic acid; tBu, tert-butyl.

cascade cyclization. The endgame of the total synthesis comprises five more steps, which enabled the authors to achieve a nine-step enantioselective total synthesis of (+)-minfiensine.

recent developments

One of the recent developments in the field of organocatalytic cascade reactions is the extension of this strategy by at least one metal-catalysed cycle. This will certainly open up the way to many completely new cascade reactions and new forms of tackling bond disconnections. However, the challenge of combining metal- and organocatalysis lies on the compatibility of the metal-catalysed and organocatalysed steps. In a seminal contribution, our research group investigated the extension of a triple cascade reaction68 by a Lewis-acid-promoted intramolecular Diels–Alder reaction69,70. In this way, five carbon–carbon bond formations and the generation of eight stereocentres could be stereoselectively controlled in a one-pot operation.
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A more recent example was published by List and Michrowska, who disclosed the total synthesis of (+)-ricciocarpin A, a furanosesquiterpene lactone isolated from the liverwort Ricciocarpos natans (Fig. 6a)71. (+)-Ricciocarpin A possesses potent molluscicidal activity against the water snail Biomphalaria glabrata, a vector of the parasitic disease schistosomiasis72,73. The synthetic approach is based on their recently published reductive Michael-cyclization, a simple IM–EN cascade reaction employing the MacMillan imidazolidinone catalysts 59 (ref. 44). Furthermore, List and Michrowska impressively extended this cascade reaction by a samarium triisopropoxide-promoted epimerization–Evans–Tishchenko reaction sequence. Although this example still remains a simple cascade reaction, List et al. were able to demonstrate that such an organocatalytic cascade reaction can be combined with a Lewis-acid-promoted cascade sequence in a one-pot reaction. The imidazolidinone catalyst 59 first activates the α,β-unsaturated aldehyde by iminium ion formation, which is afterwards reduced by hydride transfer from the
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O

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N N H tBu HCl

a
CHO O O tBuO

O OtBu N H 58

Bn

59

IM EN
Dioxane, 22 °C, 72 h 79%

CHO O

O Sm(OiPr)3, 4 h O 97% e.e. 1:2 d.r. 48% over 2 steps O

57

trans-60

61

(+)-Ricciocarpin A

b
62 CHO

TMSO

Catalyst combination O

Me Me OH 95% e.e. 5:1 d.r.

HO Me 7 steps Me H OH Me Me 65

Ru IM EN
DCM/AcOEt 64%
N Mes Ru Ph PCy3 O

63

OHC H 64

(−)-Aromadendranediol

Mes N Cl Cl

N N H N H

CO2H

Ph

Grubbs II catalyst (1 mol%) 66

Iminium catalyst (20 mol%) 67

Enamine catalyst (30 mol%)

O O RuLx O O O H Ph O O LxRu O Me Me LxRu H O Me A tBu O O RuLx CHO O O O O H Ph tBu N N O H HO2C O N Me O Ph N N O O2C N O H O Me N N H tBu O O O Me H Me O

O O Me O OHC H

62

68

69

N H

CO2H

HO

Me

64
CO2

OH

Cross metathesis
O

CHO tBu

Ph N N

Iminium cycle

Enamine cycle
H Me O O

O Me

OTMS

63

Figure 6 | combination of metal- and organocatalysis in natural product synthesis. a, Synthesis of (+)-ricciocarpin A via a cascade hydride addition/ Michael cyclization. b, Triple cascade sequence providing an important intermediate for the synthesis of (+)-aromadendranediol. Bn, benzyl; d.r., diastereomeric ratio; iPr, isopropyl; AcOEt, ethyl acetate; Mes (mesityl), 2,4,6-trimethylphenyl; Cy, cyclohexyl. Lx, number of ligands; A–, counterion.

Hantzsch-ester 58. A subsequent intramolecular Michael addition follows to form the cascade product 60 in 79% yield and 97% enantiomeric excess. Intermediate 60 is formed predominately as the undesired cis-isomer, which slowly isomerizes to the desired transisomer. The epimerization towards the trans-isomer can be accelerated by adding samarium triisopropoxide to the crude reaction mixture. Fortunately, the samarium reagent also promotes the next step, a diastereoselective Evans–Tishchenko reaction to complete the total synthesis of (+)-ricciocarpin A (61) in only three steps. This elegant approach enabled the authors to synthesize different derivatives of the latter. A biological evaluation revealed that one compound at least four times more bioactive against Biomphalaria glabrata than (+)-ricciocarpin A had been identified. A highlight of this review is presented with the following example, emanating from the MacMillan laboratory. They published for the first time the merger of a transition-metal-catalysed reaction
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with an organocatalytic cascade sequence. This newly developed cycle-specific cross-metathesis-IM–EN triple cascade reaction was employed for a very efficient construction of the (−)-aromadendranediol framework74. (−)-Aromadendranediol is a sesquiterpene natural product, isolated from the marine coral Sinularia mayi as well as from the leaves of the Amazonian tree Xylopia brasiliensis 75,76. Although the biological profile has not yet been fully explored, (−)-aromadendranediol is known to be a constituent of extracts used in Chinese77 and Brazilian76 folk medicine as sedatives, analgesics or to treat lung inflammation. The novelty of this cycle-specific catalysis approach is that each organocatalytic cycle is specifically catalysed by a distinct chiral amine, either the imidazolidinone catalyst 67 or proline (Fig. 6b). Although it is known that imidazolidinones are capable of both iminium ion and enamine activation, they lack the structural features necessary for bifunctional activation present in proline-mediated catalysis. On
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Ar

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O O Ar O P OH 72 1) HCHO, AcOH 2) NaBH4 N H 73a-c R 90–91% e.e. 90–95% N 74a-c R

EtO2C N 70a-c R N H 71

CO2Et

Ar = 9-phenanthryl

H+ H+
Benzene, RT, 12 h 88–95%

N 74a (−)-Angustureine

N 74b (+)-Cuspareine

OMe OMe

N 74c (+)-Galipinine

O O

EtO2C EtO2C N 70a-c R N H 75a-c O O OAr P OAr R N H 71 N H 79a-c O O O ArO 72 P OH ArO P OAr OAr R CO2Et N H

CO2Et 71

N H 73a-c

EtO2C N EtO2C CO2Et N H O O P OAr OAr N H 76a-c R O 72 ArO P OH ArO H

CO2Et

EtO2C N 78

CO2Et

77a-c O

OAr OAr

77a-c

Proposed mechanism for the cascade transfer hydrogenation Ar

b
O EtO2C N 80 N H 71 CO2Et

O O Ar

O P OH 81 O Sequence reported by Hsung et al.82 N H 82 Me H

Ar = anthracenyl

H+ H+
Benzene, 50 °C

69%

89% e.e.

N H H di-epi-Pumiliotoxin C 83

Figure 7 | Brønsted-acid-catalysed cascade reactions in natural product synthesis. a, Synthesis of natural tetrahydroquinolines via a double organocatalytic transfer hydrogenation. b, Application of the organocatalytic enantioselective reduction of pyridine to the synthesis of di-epi-pumiliotoxin C.

the other hand, proline is incapable of mediating the iminium activation of enals and enones. Thus, these orthogonal reactivity profiles could be exploited. A blend of 67 and (R)- or (S)-proline turned out to be an orthogonal catalyst system for cis- and trans-selective IM–EN cascade reactions. MacMillan et al. connected their cycle-specific cascade reaction by an upstream cross-metathesis reaction using 1 mol% of Grubbs II catalyst 66 to access the advanced precursor 64 for the
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synthesis of (−)-aromadendranediol. The first catalytic cycle generates the desired α,β-unsaturated aldehyde 68 for the second IM-cycle by a cross-metathesis reaction of ketone 62 and crotonaldehyde. After completion of this reaction, catalyst 67 together with silyloxyfuran 63 were added to the reaction mixture, followed by (S)-proline. First, catalyst 67 activates the newly formed α,β-unsaturated aldehyde 68 by iminium ion formation to undergo a Mukaiyama–Michael reaction
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a
O O 84 H tBuO2C 85 NO2
N H Ph Ph 86 OTMS

review article
STol O tBuO2C 5 NO2 (5R)-88 Not isolated CO2Et TolSH, EtOH, −15 °C, 36 h O tBuO2C 5 NO2 (5S)-89 2 one-pot operations CO2Et

DCM, ClCH2CO2H, RT, 40 min then Cs2CO3, 0 °C, 3 h (EtO)2P(O) CO2Et 87

HO O AcHN NH2 91 (−)-Oseltamivir phosphate (Tamiflu) CO2Et H3PO4 HO AcHN HN HN

OH H O CO2H NH2 O AcHN 92 NH2 90 (−)-Oseltamivir CO2Et

Zanamivir (Relenza)

H O N H

84
H2O

86
O N

O P EtO EtO CO2Et O O tBuO2C

Enamine cycle 93
N H2O

O tBuO2C NO2

87

EtO OEt P O NO2 CO2Et

Horner–Wadsworth– Emmons reaction

CO2Et O tBuO2C NO2

Cs2CO3 [1,4]-addition

95
O

96

88

tBuO2C

NO2

85

tBuO2C NO2

94 NMe2

b
MeO

F3C O O O 97 NO2 Cl N 98 CF3

H N S

H N 99

O O HO

OMe NO2 N 100 Cl 75% e.e. 4 steps HO 101

10 mol%, toluene, 0 °C then KOH, EtOH, 0 °C 85%

NO2 N Cl

3 steps

H N H

Cl

102 (−)-Epibatidine

Figure 8 | applications of organocatalytic cascade reactions in the synthesis of pharmaceuticals. a, One-pot synthesis of Tamiflu employing an organocatalytic key step and a cascade reaction. b, Asymmetric synthesis of (−)-epibatidine via a thiourea-catalysed enantioselective double Michael addition of a γ,δ-unsaturated β-ketoester to a nitroalkene. Tol, tolyl.

with 63. After release of the imidazolidinone catalyst, (S)-proline can now form an enamine with the keto-aldehyde 69 to perform an intramolecular aldol reaction affording 64 in 64% yield. During this triple cascade reaction, four stereocentres are formed with 95% enantioselectivity and a diastereomeric ratio of 5:1. This approach affords access to (−)-aromadendranediol (65) in seven steps from 64 and eight synthetic steps in total.

brønsted-acid-catalysed cascade reactions

Very recently chiral Brønsted acid catalysts have found widespread application in organocatalysis. For instance, the reduction of imines by Hantzsch ester hydride transfer has become a favourite application of this process78,79. In principle, nitrogen-containing heterocycles like pyridines or quinolines bear an embedded α,β-unsaturated imine.
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Rueping and co-workers demonstrated the Brønsted-acid-catalysed transfer hydrogenation of such heterocycles to the corresponding tetrahydroquinolines or tetrahydropyridines80. This double-transfer hydrogenation, also a simple H+–H+ cascade reaction, proceeds with good yields and high enantioselectivities. It is worth mentioning that these Brønsted-acid-catalysed transfer hydrogenations proceed extremely chemoselectively in comparison with standard metalcatalysed transfer hydrogenation. This approach gives access to a variety of highly enantio-enriched heterocycles that can be found in many different alkaloid natural products. This new methodology was used for the synthesis of biologically active tetrahydroquinoline alkaloids such as (–)-angustureine (74a), (+)-cuspareine (74b) and (+)-galipinine (74c) (Fig. 7a)80. Brønsted acid catalyst 72 activates the corresponding quinoline 70 by
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protonating the nitrogen and forming the iminium ion 75. The first hydride transfer from the Hantzsch ester 71 generates the enamine intermediate 76, which can be activated again as an iminium ion and undergo another hydride transfer. Tetrahydroquinolines 73 are obtained with good yields and 90-91% e.e., and the desired alkaloids are finally obtained from 73a-c by N-methylation. A similar approach was also used by the Rueping group to synthesize some decahydroquinolines (Fig. 7b)81. These are very important scaffolds in natural products and, in particular, the main core of the pumiliotoxin family derivatives. Pumiliotoxins are toxins found in the skin of poison dart frogs native to central and south America. These very powerful toxins interfere with the calcium channel affecting muscle contraction and resulting in death. The Brønsted acid catalyst 81 can activate the pyridine 80 as an iminium ion and promote a double-cascade hydrogenation in which the Hantzsch ester 71 has the role of the hydride source. This cascade sequence enables the formation of the decahydroquinolines 82, which can be converted into the di-epi-pumiliotoxin C (83) according to the method developed by Hsung and co-workers82.

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therapeutics can also be illustrated by the synthesis of (–)-epibatidine developed by Takemoto and colleagues (Fig. 8b)86. This group developed an organocatalytic one-pot procedure involving an enantioselective double Michael addition. The thiourea 99 catalysed the first Michael addition of the γ,δ-unsaturated β-ketoester to the nitroalkene 98. Then, on addition of some potassium hydroxide, the newly formed nitroalkane cyclized to form the polysubstituted cyclohexene 100 in a high yield and 75% e.e. The total synthesis of (–)-epibatidine (102) was achieved in seven steps from 100. This alkaloid was isolated in the late 1990s from the skin of a poisonous frog living in the Amazon rainforest. The biological activity of this alkaloid was well known, and it was rumoured that native Americans used it to coat the tips of their arrows. Owing to its high toxicity — this alkaloid is some 200 times more potent than morphine — and its lack of selectivity on nicotinic receptors, (–)-epibatidine will never be a candidate for pharmaceutical development. Nevertheless, it is an amazing lead compound and it will certainly open the route for the development of more selective derivatives, for example, Tebanicline. Furthermore, it was found that it is a powerful agonist for the insecticidal nicotinic acetylcholine receptors, analogous to the mode of action of the chloronicotinyl insecticides, for example, Imidacloprid.

organocatalytic cascade reactions for pharmaceuticals

The true acid test for a new synthetic methodology is the successful application to the production on an industrial scale of biologically active compounds such as pharmaceuticals and agrochemicals. With the recent advance of the so called swine flu (H1N1), which can easily spread from human to human, the World Health Organization was forced to rate the new disease as a pandemic and recommended the use of the neuramidase inhibitors Tamiflu and Relenza. Demand for both drugs increased rapidly within a short time, because most countries stockpile these therapeutics to be prepared in the event of a severe outbreak. Although Tamiflu (91) and Relenza (92) look small and not too complex, the difficulty of their preparation is caused by the high density of functional groups (Fig. 8a). The imminent shortage of Tamiflu supply made chemists from all over the world think of new and more efficient syntheses83. Among the various new approaches, Hayashi and colleagues have developed a powerful one-pot reaction for the rapid construction of the Tamiflu core84. The first step of this process is the addition of aldehyde 84 to nitroalkene 85. This Michael addition is catalysed by the diphenylprolinol silyl ether 86 via an EN activation mode and proceeds in almost quantitative yield and excellent enantioselectivity. Intermediate 95 then enters a classical cascade reaction by reacting with vinylphosphonate 87 via a Henry-type Michael addition to form 96, followed by an intramolecular Horner–Wadsworth–Emmons olefination, which assembles the cyclohexene core of 88. Unfortunately, a mixture of (5R)-88 and (5S)-88, in which the undesired 5R isomer predominates, was obtained. Treatment of this mixture with an acid or a base allows only partial conversion of the 5R isomer into the 5S isomer. The authors circumvented this problem by adding thiophenol at the end of the cascade reaction and the resulting sulfa-Michael85 product 89 was generated predominantly as the desired 5S isomer. This sophisticated cascade sequence enabled Hayashi et al. to build up the polyfunctionalized cyclohexene core of Tamiflu in a concise way. The synthesis was completed by employing two further one-pot reaction sequences with a total yield of 57%. The Hayashi Tamiflu synthesis demonstrates the power of asymmetric organocatalysis and cascade reactions and may well allow the flexible synthesis of new derivatives active against Tamiflu-resistant viruses. Although this example does not truly belong to the chapter of organocatalytic cascade reactions, the possibility of combining an organocatalytic reaction with a non-catalytic reaction in a cascade procedure showcases prospective applications of organocatalytic cascade reactions to pharmaceutically relevant targets like Tamiflu. In a similar manner, the powerful combination of organocatalysis and cascade reactions or one-pot processes in the synthesis of
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conclusion

This Review summarizes the initial development of the application of organocatalytic cascade reactions in natural product synthesis and gives a perspective of future industrial applications in drug synthesis. Although this concept is still in its infancy, it is clearly an emerging approach in total synthesis with advantages such as rapid one-pot entries to molecular complexity via atom, step and redox economic protocols. A survey through the literature reveals that the number of publications from 2005 to 2009 has increased year by year and the target molecules have become more complex, with a tendency from simple cascade reactions to triple and even quadruple cascades. With the various recently developed organocatalytic activation modes at hand, including the concept of bifunctional organocatalysts and multicatalytic systems, numerous novel cascade sequences can be envisaged. We hope that this short Review will inspire the synthetic community to continue the search for new organocatalytic cascade reactions and to implement this concept into their future synthetic strategies.
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