Stereoselective Mannich Reactions in the Synthesis of Enantiopure Piperidine Alkaloids and Derivatives
Graphical Abstract
An overview of recent syntheses of enantiopure pharmaceutically relevant piperidines using Mannich reactions is presented. The asymmetric induction has been classified in three conceptual approaches using the chiral pool, chiral auxilliaries and asymmetric catalysis.
Abstract
Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six-membered nitrogen-containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool-based (internal asymmetric induction), (2) chiral auxiliary-based (relayed asymmetric induction) and (3) asymmetric catalysis-based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products.
1 Introduction
Alkaloids are natural products with typically one or more ring structures containing at least one basic nitrogen atom as the most common feature. These low-molecular weight structures are mostly derived from amino acids and are found mainly in plants. Approximately 20 % of all plant species accumulate alkaloids as secondary metabolites, which have greater structural and biosynthetic diversity compared to other secondary metabolites, as over 20,000 different alkaloids have been described.1, 2
Aside from poisonous effects, alkaloid-containing plants and animals have been used in the preparation of stimulants, sedatives, narcotics, insecticides, aphrodisiacs and medicines since ancient times.1 In addition, alkaloid-containing plants have been and still are part of our regular diet. Alkaloids can be present in a modern Western diet as constituents of, for example, vegetables or tea because of food processing, as food contaminants or as food flavorings.3 Piperidine alkaloids constitute a particular class of alkaloids and are characterized by a substituted six-membered nitrogen heterocycle. As an example, piperidine alkaloids are responsible for the toxicity of the poisonous plant hemlock (C. maculatum), which produces eight known piperidine alkaloids (Figure 1). Two of them, γ-coniceine and coniine, are usually present as the major constituents and account for most of the biological activity.4, 5
Piperidine alkaloids produced by C. maculatum.
The biological activities of piperidine alkaloids have sprouted research on these natural products. Rather low quantities of alkaloids are produced in plants and thus synthesis of naturally occurring alkaloids and their derivatives remains a relevant target for drug discovery.2 As early as in 1886, Ladenburg reported the synthesis of racemic coniine, which is considered the first complete synthesis of an alkaloid. It was achieved by reacting 2-methylpyridine with acetaldehyde and reducing the resulting 2-(prop-1-enyl)pyridine with sodium.6 Since then, numerous reports have been published on the synthesis of piperidine alkaloids, supporting the relevance of alkaloid synthesis until today. The presence of multiple chirality centers in piperidine alkaloids renders the stereoselective synthesis of such compounds a continuous challenge. Throughout the years, researchers have developed a myriad of methods to stereoselectively synthesize enantiopure piperidine derivatives.7, 8 In this review, we focus on approaches in which a Mannich reaction has been employed as the key step to synthesize piperidine alkaloids and derivatives in an enantio- and/or diastereoselective manner.9
The Mannich reaction was named after Carl Mannich, who was the first to recognize the importance of the aminoalkylation of carbon acids in the early 20th century. Over time, the Mannich reaction has been developed into one of the most important carbon–carbon bond-forming reactions in organic chemistry. The classic Mannich reaction involves reaction of an amine, formaldehyde and a carbon acid such as a carbonyl compound, an aliphatic nitro compound or an imine to form the corresponding β-amino ketone (Scheme 1).10
Mannich reaction with an enolizable ketone as the carbon acid component.
In a series of equilibrium reactions, the amine 15 reacts with formaldehyde to form the corresponding iminium ion in tiny amounts. The electrophilic iminium ion is attacked by the enol tautomer of the carbonyl compound 16, resulting in the formation of β-amino-carbonyl compound 17. Diastereo- or enantioselective formation of the β-amino-carbonyl product is a challenge when utilizing the Mannich reaction in the synthesis of complex and chiral piperidines.11
The attractive C−C bond forming characteristic of the Mannich reaction has led researchers to improve the reaction. For example, preformed electrophiles such as imines or iminium salts can be used, or preformed nucleophiles including enolates, enol ethers and enamines have been developed and of both reaction partners stereodirecting variants are known. These stereodirecting variants of the Mannich reaction provide a distinctly simpler entry into β-amino-carbonyl compounds and also provide opportunities to induce asymmetry in the reaction.11
In the synthesis of substituted piperidines, researchers have utilized methods to induce stereoselectivity in the Mannich reaction that can be divided into three separate groups.12, 13 The first method is by internal asymmetric induction (chiral pool approach). This method relies on a chirality center being part of the reactant to favor another stereogenic center by promoting a certain transition state over another. Relayed asymmetric induction (chiral auxiliary approach) is another method to employ a stereoselective Mannich reaction and consists of installing a chiral group prior to the Mannich reaction to influence the stereochemical outcome. This chiral auxiliary moiety is then removed in a separate step after the reaction has taken place. The last method of inducing asymmetry in the Mannich reaction is by external asymmetric induction (asymmetric catalysis) where the asymmetry is introduced in the transition state through the use of chiral catalysts or ligands. The interaction with the substrates can occur via either covalent or non-covalent interactions. We describe herein known different procedures that have been used to induce asymmetry in the Mannich reaction in the synthesis of piperidine alkaloids and derivatives. We categorize these procedures by the method used to influence the stereochemical outcome of the reaction.
2 Asymmetric induction by chiral starting material
Internal asymmetric induction relies on the use of chiral starting materials, whose intrinsic asymmetric information influences the stereoisomerism of the new stereogenic unit. In this case, the stereogenic unit present in the starting material is the decisive factor that causes a preference for one transition state over another because of a lower activation energy. With internal asymmetric induction, the original stereounit is an integral part of the final product and this requires careful selection of starting materials in the planning stages of the synthesis. Troin et al. used this chiral pool approach to synthesize various enantiopure piperidines (Scheme 2).14
Reagents: (a) MgSO4, CH2Cl2, Δ, 1–3 h, then TsOH, PhMe, 70 °C, 3 h, 60–96 %, 93 : 7→20 : 1 dr; R1=(E)-non-2-enyl, 2,4-nonadienyl, Ph, 4-MeOC6H4, 4-BrC6H4, 4-NO2C6H4, pyridin-2-yl.
The approach utilized by the Troin's group consisted of a reaction between an aldehyde (18) and enantiopure amine (S)-19.15 After formation of the iminium ion, a cyclization step furnished piperidine 22. The 2,6-cis-diastereomer was formed predominantly, which was explained by the apparent 1,3-diaxial strain present in 20 and therefore this transition state is less favorable than transition state 21. Various natural piperidine alkaloids have been synthesized using this approach, for example, isosolenopsins A–C (25 a–c), pipecolic acid derivative 25 d, (+)-dihydropinidine 25 e and alkaloid (+)-241D (26) as shown in Scheme 3.16 Alkaloids 25 a–c are found mainly in the venom of fire ants from the genera Solenopsis and possess antibacterial, antifungal, phytotoxic and insecticidal properties.17 Pipecolic acid and its derivatives (e.g. 25 d) are natural non-proteinogenic α-amino acids, which often display potent biological activities.18 (+)-Dihydropinidine (25 e) is an alkaloid isolated from the Mexican bean beetle Epilachna varivestis and plays a role in its defense mechanism.19 The piperidine alkaloid (+)-241D (26), isolated from methanolic skin extracts of the poison frog Dendrobates speciosus, shows bioactivity as a potent non-competitive blocker of acetylcholine and ganglionic nicotinic receptor channels.20-23 Alkaloids 25 a–e were obtained by first applying the Mannich protocol explained in Scheme 2 followed by conversion of the protected piperidinones 24 into the corresponding dithiolanes, which were then desulfurized using Raney nickel at elevated temperatures and treatment of the corresponding piperidines with HCl gave the isosolenopsins A–C (25 a–c), pipecolic acid derivative 25 d and (+)-dihydropinidine 25 e.
Reagents: (a) MgSO4, CH2Cl2, Δ, 1–3 h; TsOH, PhMe, 70 °C, 3 h, 70–90 %, 9 : 1→20 : 1 dr. (b) (CH2SH)2, BF3 ⋅ OEt2 (c) Raney Ni, Δ (d) HCl (e) 6 % HCl, Me2CO (f) NaBH4, 92 : 8 dr. 25 a: R1=n-C11H23; 25 b: R1=n-C13H27, 25 c: R1=n-C15H31, 25 d: R1=CO2Et, 25 e: R1=Pr.
Alkaloid 26 was generated from 24 by first performing a deprotection under acidic conditions to furnish the corresponding piperidinone, followed by a stereoselective reduction of the ketone using NaBH4 to obtain alkaloid (+)-241D (26) in a 92 : 8 diastereomeric ratio.
In a later publication, they described the diastereoselective synthesis of higher substituted piperidines from the more substituted amines 27 and 31 (Scheme 4).24
Reagents: (a) MgSO4, CH2Cl2, Δ, 1–3 h; TsOH, PhMe, 70 °C, 3 h, 46–49 % (b) 6 % HCl, Me2CO (c) L-Selectride, >20 : 1 dr.
The synthesis started with the one-pot reaction of amines 27 and 31 with aldehyde 23 f to generate masked piperidinones 28 and 32, respectively, as a mixture of diastereoisomers. The 2,6-cis-substitution was always achieved as expected for the Mannich reaction. The ketone was then generated under acidic conditions to give piperidinones 29 and 33. In both cases, only one epimer was isolated after the deprotection. Data obtained from 1H NMR confirmed a pseudo-equatorial position of the three substituents. Finally, a diastereoselective reduction of ketones 29 and 33 with L-selectride created the fourth stereocenter in a >95 : 5 diastereomeric ratio to furnish the tetrasubstituted piperidines 30 and 34, respectively.
The successful synthesis of a trifluoromethyl derivative of the enantiopure amine 38 opened up new possibilities for the synthesis of biologically active piperidines bearing a trifluoromethyl group.25 The incorporation of fluorine atoms into organic molecules is often of major importance for their activity and has resulted in an increasing number of fluorine-containing drugs on the market.26 With the same approach, the Troin's group used amine 35 to synthesize several trifluoromethyl pipecolic acid derivatives as well as a trifluoromethyl γ-amino acid (Scheme 5).25, 27
Reagents: (a) MgSO4, CH2Cl2, Δ, 1–3 h; TsOH, PhMe, 70 °C, 3 h, 65–68 %, 85 : 15–93 : 7 dr (b) (CH2SH)2, BF3 ⋅ OEt2 (c) Raney Ni, Δ (d) NaOH, Δ; HCl; Dowex (e) CAN (f) NaBH4. 36: R1=CO2Et for 38, 39 and 40; R1=CH2CH2CO2Et for 42.
After the Mannich reaction to give spiro compound 36, the pipecolic acid derivative 38 was synthesized by first forming a dithioacetal of protected piperidinone 36 which, upon treatment with Raney nickel, furnished piperidine 37. Then, hydrolysis of amino ester 37 gave pipecolic acid derivative 38. For the synthesis of α-amino acids 39 and 40, the acetal of 36 was removed with CAN to generate the corresponding piperidinone, which was then diastereoselectively reduced with NaBH4 and hydrolyzed to pipecolic acid derivative 40. Alternatively, CAN deprotection and ester hydrolysis gave amino acid 39.
Troin et al. also synthesized the trifluoromethyl γ-amino acid 42 starting from enantiopure amine 35.27 After the intramolecular Mannich cyclization, the protected piperidinone 36 was converted into dithiolane 41, which upon hydrogenolysis with Raney nickel furnished the cyclic γ-amino ester. Finally, hydrolysis of the amino ester followed by purification on a Dowex® resin gave the targeted γ-amino acid 42.
In 2008, Hynes and co-workers employed a Mannich/lactamization sequence to formally synthesize (−)-paroxetine (49, Scheme 6).28 Paroxetine has been marketed as antidepressant and in 2003 its sales amounted to almost $5 billion worldwide.29, 30 The first step in the synthesis of 49 was the conversion of aldehyde 43 into nitro olefin 44 using standard Henry condensation conditions. Next, an enantioselective Michael addition of dimethyl malonate to nitro olefin 44 furnished Michael adduct 45 in 92 % ee. This was then subjected to a Mannich/lactamization with formaldehyde and benzylamine generating δ-lactam 47 as a single diastereoisomer in 68 % yield.
Reagents: (a) MeNO2, NH4OAc, Δ (b) CH2(CO2Me)2, Soós's catalyst31 (c) HCHO, BnNH2, MeOH, Δ, 16 h, 68 %, >99 % ee, >99 : 1 dr (d) Bu3SnH, AIBN (e) LiBH4
The mechanism of the nitro-Mannich lactamization has not been elucidated, but Jakubec and co-workers gave a possible explanation for the high diastereocontrol in the nitro-Mannich lactamization.32 Presumably, both diastereoisomers of 46 undergo an irreversible lactamization step. The thermodynamically most stable product could then be formed by a post-cyclization epimerization at the stereogenic carbon bearing the nitro group. Then, the nitro group of 47 was reduced with tributyltin hydride in the presence of AIBN, and the ester was reduced with LiBH4 furnishing piperidinone 48, constituting a formal synthesis of (−)-paroxetine (49).33
The Tanaka group utilized D-ribose-derived hemiacetal 50 as a starting point for creating hydroxylated piperidines in enantiopure form (Scheme 7).34 Reaction of hemiacetal 50 with benzylamine led via the corresponding imine, followed by displacement of the tosylate to the cyclic iminium ion 51, which could be trapped in a diastereoselective manner (dr>20 : 1) with various methyl ketone derivatives giving rise to products 52 a–e in high yields. Subsequent hydrogenolysis of 52 a, followed by hydrolysis of the acetal gave also rise to the deprotected polyhydroxylated piperidine 53.
Reagents: (a) BnNH2, CH2Cl2, 3 h, then (b) MeC(O)R, 8–10 h, or (c) ArC(O)CH2CH=CH2, 3 h. 52 a: R=Me, 90 %; 52 b: R=Et, 80 %; 52 c: R=i-Pr, 86 %; 52 d: R=cyclopropyl, 90 %; 52 e: R=CH(OMe)2, 86 %; 54 a: Ar=4-MeOC6H4, 80 %; 54 b: Ar=1-naphthyl, 76 %; 54 c: Ar=4-ClC6H4, 70 %; 54 d: Ar=4-FC6H4, 68 %; 54 e: Ar=4-MeC6H4, 72 %; (d) Pd/C, H2, MeOH; (e) HCl, THF. 83 % (two steps, obtained as HCl-salt)
Alternatively, the intermediate iminium ions 51 could be reacted with aryl allyl ketones to give the corresponding allylic products 54 a–e in good yields and again excellent diastereoselectivity. More recently, also modifications of this approach to synthesize different types of piperidines were published.35
3 Asymmetric induction by chiral auxiliary
Relayed asymmetric induction is another option to control the stereochemical outcome of the Mannich reaction. With relayed asymmetric induction, chiral information is incorporated into the molecule at a suitable stage prior the stereoselective reaction. The installed chiral auxiliary then directs the stereochemical outcome of the reaction resulting in the preferred formation of a single diastereoisomer. After the reaction, the so-called chiral auxiliary is removed from the product resulting in a single enantiomer.13 This method requires two additional synthetic operations compared to external asymmetric induction: one to incorporate the auxiliary and another one to remove it.
Davis and co-workers synthesized (+)-241D (26) performing a Mannich reaction with a chiral auxiliary (Scheme 8).36 The synthesis of this naturally occurring alkaloid began with the reaction of sulfinamide 55 with (2E,4Z)-deca-2,4-dienal (56) to prepare sulfinyl inime 57. Treatment of sulfinyl inime 57 with the sodium enolate of methyl acetate yielded δ-amino β-keto ester 58 as a single diastereoisomer with the N-sulfinyl group acting as the stereodirecting group.
Reagents: (a) Ti(OEt)4 (b) methyl acetoacetate, NaHMDS, THF, −78 °C, 1 h; 57, −78 °C, 2 h, 75 %, >99 : 1 dr (c) TFA (d) acetaldehyde, AcOH, CH2Cl2, 23 °C, 1 h, 75 %, >99 : 1 dr (e) H2, Pd/C (f) LiOH, Δ (g) NaBH4, >99 : 1 dr.
The chiral auxiliary was removed with TFA to furnish the corresponding trifluoroacetate salt. The crude product was then subjected to an intramolecular Mannich reaction via addition of acetaldehyde to furnish piperidinone 60 as a single isomer. The nearly exclusive formation of the 2,6-cis-disubstituted piperidinone 60 is consistent with the more favorable transition state 59. Hydrogenation of piperidinone 55 removed the alkenes and generated piperidinone 61. The obtained piperidinone was then hydrolyzed to the acid with lithium hydroxide, decarboxylated and stereoselectively reduced with sodium borohydride to furnish (+)-241D (26).
In a later publication, Davis et al. applied the same methodology to a formal synthesis of the alkaloid (−)-nupharamine (75) (Scheme 9).37 The piperidine (−)-nupharamine is a member of a large family of sesquiterpenoid and triterpenoid alkaloids having piperidine, indolizidine and quinolizidine ring systems known as Nuphar alkaloids. These alkaloids are isolated from aquatic plants of the genus Nuphar and several members of this family have shown antibiotic and antifungal activity.38
Reagents: (a) EtCOMe, KHMDS, Et2O, −78 °C, 1 h; 63, −78 °C, 30 min, 84 %, >99 : 1 dr (b) TFA (c) Ethyl (E)-4-oxo-2-butenoate, MgSO4 (d) TsOH, PhH, 60 °C, 4 h, 74 %, >99 : 1 dr (e) (CH2SH)2, BF3 ⋅ OEt2 (f) Raney Ni.
Similar to the synthesis of (+)-241D (26), the first step of the synthesis of nupharamine (70) was the asymmetric Mannich reaction between sulfinyl imine 63 and ethyl methyl ketone to furnish amino ketone 64 as a single diastereoisomer. The chiral auxiliary was then removed under acidic conditions followed by reaction with ethyl (E)-4-oxo-2-butanoate to generate imine 66. The crude imine was then treated with TsOH at elevated temperatures to give the trisubstituted piperidinone 67 as a single isomer in 74 % yield via the intramolecular Mannich reaction. After formation of thioacetal 68, hydrogenation with Raney nickel furnished piperidine 69, which is a known intermediate in the synthesis of (−)-nupharamine (70).38
In 1989, Kunz and Pfrengle reported the first use of a chiral auxiliary in the synthesis of piperidines involving an asymmetric Mannich reaction.39, 40 The auxiliary of choice was 2,3,4,6-tetra-O-pivaloyl-β-D-galactosylamine (71) and was used in the synthesis of the naturally occurring piperidine alkaloids (S)-coniine and (−)-anabasine. Interestingly, in a later publication it was reported by the same group that X-ray analysis revealed that their synthesized coniine had the (R)-configuration and a negative optical rotation instead of the previously reported (S)-configuration, thus should be called (−)-coniine.41 As a result, they revised the proposed mechanism and also expanded the scope of the research. Using the carbohydrate-based auxiliary, Kunz and co-workers successfully synthesized the 2,6-disubstituted piperidine (−)-dihydropinidine (ent-25 e) as well (Scheme 10).
Reagents: (a) SiO2, 4 Å MS (b) Danishefsky's diene (1.25 equiv.), ZnCl2 ⋅ OEt2 (1.1 equiv), THF, −20 °C, 24–48 h, 96 %, 38 : 1 dr (c) 1. MeLi, CuI, TMSCl; 2. TBAF (d) 1. (CH2SH)2, BF3 ⋅ OEt2; 2. H2, Raney Ni (e) HCl (aq), MeOH.
The first step of the synthesis was the condensation of chiral auxiliary 71 with butanal (72) to generate aldimine 73. The piperidine structural motif was then formed with a Mannich reaction/conjugate addition (MR/CA) sequence with Danishefsky's diene and zinc chloride, which plays a decisive role in the reaction. This Lewis acid increases the electrophilicity of the imine and coordinates both the imine nitrogen and the carbonyl oxygen of the 2-pivaloyl group of the carbohydrate auxiliary thereby effectively shielding the Re-face of the imine (see 74). Nucleophilic attack then occurs preferentially from the less hindered Si-face generating intermediate 75. Subsequent cyclization gave piperidinone 76 with excellent diastereoselectivity. The 2,6-disubsituted piperidinone 77 was then synthesized by a 1,4-addition reaction with an in situ generated Gilman reagent in combination with trimethylsilyl chloride (TMSCl), followed by removal of the silyl ether using TBAF to afford piperidinone 77 in high diastereomeric ratio (>91 : 9). The ketone was then reduced to give the N-galactosyl dihydropinidine 78. Treatment with hydrogen chloride in aqueous methanol resulted in cleavage of the N-glycosidic bond liberating (−)-dihydropinidine ent-25 e in enantiomerically pure form. The carbohydrate auxiliary was recollected almost quantitatively after extraction of the reaction mixture with diethyl ether.
This MR/CA sequence has been a focus of the Kunz group dedicating several papers to this method. Herein they described the synthesis of a variety of piperidines ranging from monosubstituted piperidine alkaloids to 2,6-disubstituted 5-bromopiperidin-4-ones showing the versatility of this approach (Scheme 11).
Reagents: (a) L-Selectride, PhNTf2 (b) Pyrimidin-5-ylboronic acid, Pd(PPh3)2Cl2, Cs2CO3 (aq) (c) HCl (aq), MeOH (d) L-Selectride (e) 1. (CH2SH)2, BF3 ⋅ OEt2; 2. H2, Raney Ni, (f) NBS (g) MeCu ⋅ BF3, 8 : 1 dr.
The products of the MR/CA sequence, piperidinones 79 a–b, can undergo several transformations. The Kunz group synthesized tetrahydropyridine 82, which is considered an interesting pharmacophore.42 After the MR/CA sequence, conjugate hydride addition to piperidinone 79 with L-selectride was carried out and the resulting enolate was trapped with N-phenyltriflimide to give enol triflate 80, which underwent efficient Suzuki–Miyaura cross-coupling to yield tricyclic product 81. The 2,4-disubstituted tetrahydropyridine 82 was finally liberated under acidic hydrolysis conditions.
In 1989 and again in 1997, Kunz et al. synthesized the aforementioned (−)-anabasine [(−)-85] and (−)-coniine (−)-7 by first reducing the corresponding enones (79 a with R2=3-pyridinyl for 85 and 79 b with R2=propyl for (−)-7) with L-selectride to afford piperidinones 83 and 86, respectively.39-41 Then, complete reduction of the ketone gave the 2-substituted piperidines 84 and 87, and finally, removal of the auxiliary under acidic conditions provided the piperidine alkaloids (−)-anabasine [(−)-85] and (−)-coniine, (−)-7.
In addition, dihydropyridinone 79 b was converted into bromopiperidinone 89. This route started with bromination using NBS yielding bromodihydropyridinone 88 in 48 % yield. Conjugate addition of organocopper complex MeCu ⋅ BF3 provided 2,3,6-trisubstituted piperidinone 89 in high diastereoselectivity (8 : 1 (C2 epimer):0 (C3 epimer):0 (C2+C3 epimers)) with the product shown as the major diastereoisomer.
A feature of this methodology is that it offers the possibility to synthesize both enantiomeric series of chiral piperidines by varying the carbohydrate auxiliary. In 2004, Kunz et al. used D-arabinosylamine 89 to form the opposite enantiomer (Scheme 12).43 Even though arabinosylamine 89 is a D-sugar, it is almost the mirror image of D-galactosylamine 71 and as such D-arabinosylamine can be regarded as its pseudo-enantiomer.
Reagents: (a) RCHO, SiO2, 4 Å MS (b) Danishefsky's diene, ZnCl2 ⋅ OEt2, THF, −20 °C, 48 h. 79 a–d: 95 : 5 to 97 : 3 dr, 58 to 96 %. 95 a–e: 86 : 14 to 99 : 1 dr, 73 to 96 %.
The opposite enantiotopic sides are effectively shielded by the C2 pivaloyl group in aldimines derived from these glycosylamines. Whereas the Re-face of galactosylimine 91 is blocked, it is readily accessible in arabinosylimine 92 resulting in the formation of the pseudo-enantiomers 79 and 95.
Analogous to the formation of N-galactopyranosylimines 91, N-arabinosylimines 92 were formed via the reaction of glycosylamine 90 with aliphatic aldehydes in the presence of molecular sieves or with aromatic aldehydes under acid catalysis. The formed aldimines 92 reacted with Danishefsky's diene in a MR/CA sequence promoted by zinc chloride to give dihydropyridinones 95 in 73–96 % yield and a diastereoselectivity typically around a 90 : 10 ratio.
Similar to N-galactosyl dihydropyridinones 79, the N-arabinosyl variants, 95 (Scheme 12), represents a versatile precursor for the synthesis of variously substituted nitrogen heterocycles. Illustrating this versatility, the group of Kunz achieved a regio- and stereoselective preparation of several piperidines, including 2,3-, 2,5- and 2,6-disubstituted nitrogen heterocycles (Scheme 13).43, 44
Reagents: (a) L-Selectride, Comins's reagent (b) H2, Pd/C, Li2CO3 (c) HCl (aq), MeOH (d) Me2CuLi, TMSCl, 88 %, 91 : 9 dr (e) 1. (CH2SH)2, BF3 ⋅ OEt2; 2. H2, Raney Ni (f) NIS (g) 4-(MeO)C6H4B(OH)2, Pd(PPh3)2Cl2, Cs2CO3 (aq) (h) 1. LiHMDS; 2. MeI, >95 : 5 dr.
A successful example has been the employment of this reaction strategy in the synthesis of (+)-coniine ((+)-7, Scheme 13), a well-known piperidine alkaloid that is highly toxic and leads to central respiratory paralysis. In this synthesis, the MR/CA product 95 a was reduced with L-selectride and the intermediate enolate was subsequently trapped as triflates 96. Hydrogenation of the enol triflate gave 2-propylpiperidine 97 and removal of the carbohydrate auxiliary yielded the alkaloid coniine ((+)-7).44 The synthesis of the N-heterocycle dihydropinidine 25 e followed a different pathway: A conjugate addition of an in situ generated Gilman reagent to dihydropyridinone 97 a was carried out with the help of TMSCl, followed by treatment with TBAF to provide piperidinone 98 in a 91 : 9 diastereomeric ratio. The ketone of piperidinone derivative 98 was reduced as described before (Scheme 10) to give piperidine 99. Finally, 25 e was liberated from the auxiliary under acidic conditions.
Kunz and co-workers also synthesized 2,5-disubstituted piperidinone 101 (Scheme 13). The derivatization of product 95 a started with an electrophilic substitution reaction using N-iodosuccinimide to furnish α-iodo ketone 100. This vinyl iodide was functionalized with a 4-methoxyphenyl group via a Suzuki reaction with Pd(PPh3)Cl2 as the catalyst, Cs2CO3 and 4-methoxyphenylboronic acid to afford 2,5-disubstituted piperidinone 101 in moderate yield (40 %) without optimization. The synthesis of trans-2,3-disubstituted piperidinones was also possible, but then with product 95 d as shown by Kunz et al. in the synthesis of piperidinone 102. Dihydropyridinone 95 d was deprotonated at the C3 position by LiHMDS and was subsequently treated with methyl iodide to generate trans-2,3-disubstituted piperidin-4-one 102 with excellent diastereoselectivity (>95 : 5). The diastereoselectivity can be explained by the fact that after deprotonation of 95 d, a 6π-electron system is formed resulting in additional flattening of the ring, which results in the formation of trans-2,3-disubstituted piperidin-4-one 102.44
In 1992, Waldmann and Braun reported the synthesis of dihydropyridinones 106 by employing a different auxiliary. The overall strategy was similar to Kunz's method and consisted of the same tandem MR/CA sequence with Danishefsky's diene, this time using amino acid esters as the stereodifferentiating group (Scheme 14).45
Reagents: (a) EtAlCl2, CH2Cl2, −78→−20 °C, 1 h, 80 %, 94 : 6 dr (b) NaOH, MeOH (c) (PhO)2P(O)N3 (d) 40 °C (e) BnOH (f) H2, Pd/C (g) Cbz-Cl (h) L-Selectride (i) 1. (CH2SH)2, BF3 ⋅ OEt2; 2. Raney Ni, 80 °C.
Aldimine 103 was formed after treating amino acid L-isoleucine with butanal. In a tandem Mannich/Michael sequence, imine 103 and Danishefsky's diene were converted into dihydropyridinone 106 with the aid of Lewis acid EtAlCl2. The dihydropyridinone was obtained in 80 % yield with a 94 : 6 diastereomeric ratio. To explain the stereochemical outcome of this reaction, Waldmann and Braun proposed that first the Lewis acid coordinates to the imine nitrogen causing the amino acid ester to adopt a conformation in which the α-C−CO2Me bond is oriented perpendicular to the CN double bond, resulting in a parallel arrangement and thus an overlap of the respective σ* and π* orbitals (104). The attack of the diene should then preferably occur from the Re-side giving piperidinone 106. The Mannich/Michael product 106 was then used as a starting point in the synthesis of (S)-coniine ((+)-7; Scheme 13). In this synthesis, Waldmann and Braun utilized a self-developed strategy for the removal of the auxiliary with a Curtius rearrangement as the key step.
To achieve the desired degradation, methyl ester 106 was first converted into carboxylic acid 107 under basic conditions. The free piperidinone 111 was generated from carboxylic acid 107 in a one-pot procedure. Treatment of the resulting carboxylic acid with diphenoxyphosphoryl azide resulted in the formation of acyl azide 108, which underwent a Curtius rearrangement to furnish isocyanate 109. This rearranged product was trapped with benzyl alcohol to form carbamate 110. The removal of the auxiliary was completed by hydrogenation to give piperidinone 111 in 80 % yield from amino ester 106. Enaminone 111 was Cbz-protected to furnish carbamate 112 and then chemoselectively reduced using L-selectride to ketone 113. Conversion into the thioacetal and treatment with Raney nickel at elevated temperature resulted in desulfurization and Cbz removal to yield alkaloid (+)-coniine ((+)-7).
In 1999, the group of Casiraghi developed a synthesis of hydroxy lactam 123 (Scheme 15).46 At the time, compound 123 was a potential candidate of an emerging progeny of HIV-protease inhibitors. These inhibitors exhibited potency in the micromolar inhibitory concentration range.47
Reagents: (a) TBSOTf (60 mol %), CH2Cl2, −80 °C, 3 h, 83 %, 9 : 1 dr (b) 1. H2, Pd/C; 2. DBU (c) 1. TBSCl; 2. Boc2O (d) LiHMDS, BnBr (e) 1. AcOH (aq); 2. NaIO4 (aq) (f) 1. [Ph3PBn]Br, NaHMDS; 2. H2, Pd/C (g) 1. NaH, BnBr; 2. HCl.
In the strategy employed by Casiraghi and co-workers, the asymmetry in the Mannich reaction was incorporated by reacting the Lewis acid catalyst with a chiral substrate. The vinylogous Mannich reaction between silyl ether 114 and chiral aldimine 115 was catalyzed by TBSOTf and generated butenolide 117 in a 90 : 10 diastereomeric ratio. The stereochemical outcome can be explained by favorable stereoelectronic interactions when the Re-face of the dienolate attacks the Si-face of the imine (116), which then leads to anti-product 117. The attack of the nucleophile to the Si-face of imine 115 is preferred because of the presence of the stereogenic center making the Si-face more accessible. Furanone 117 was hydrogenated and then underwent a ring expansion under basic conditions to provide piperidinone 118. After protection, piperidinone 119 was diastereoselectively benzylated at the C3 position to afford compound 120. The next step involved removal of the acetonide to yield a diol intermediate, which was subjected to periodate oxidative fission to produce aldehyde 121. A Wittig olefination followed by hydrogenation afforded compound 122, which was then N-benzylated. Acidic removal of the TBS protecting group completed the synthesis of 5-hydroxypiperidinone 123.
In 2011, Ruan et al. developed methodology that employed a vinylogous Mannich reaction in the synthesis of 5,6-disubstituted piperidin-2-ones. The generated piperidin-2-one 128 is a known intermediate in the synthesis of deoxoprosophylline (129), which is a member of a family of trisubstituted piperidine alkaloids showing anesthetic, analgesic, antibiotic, and CNS stimulating biological properties, and hence of considerable pharmacological interest (Scheme 16).48
Reagents: (a) TMSOTf, CH2Cl2, −78 °C, 1 h, 80 %, 3 : 1 dr. (b) H2, Pd/C, (c) HCl, MeOH; K2CO3, MeOH.
The methodology by Ruan and co-workers featured Ellman's sulfinyl imine 124 as the auxiliary.49 Aldimine 124 was reacted with furan 114 as the vinylogous nucleophile in the presence of a Lewis acid, providing separable diastereoisomers of Mannich product 126 in a 75 : 25 ratio at the former furan carbon. Ruan and co-workers hypothesized that because only one equivalent of the Lewis acid was required for the reaction. As a result, the Si-face of the imine is sterically shielded by the Lewis acid leading to attack of the vinylogous nucleophile from the Re-face. The attack of the nucleophile is thought to take place via the favored transition state 125 (Scheme 16) to form the anti-adduct as the major diastereoisomer. The obtained furanone 126 was then hydrogenated with H2 and Pd/C to generate lactone 127. Cleavage of the sulfinyl group under acidic conditions, followed by a base-promoted cyclization with K2CO3 produced hydroxy piperidinone 128, which had been converted into bioactive deoxoprosophylline 129 before.48
In 2011, Yang et al. reported a practical approach to carry out stereoselective vinylogous Mannich reactions with acyclic dienolates to give functionalized piperidine targets, which was successfully employed in the synthesis of anabasine (85; Scheme 17).50 The reaction sequence started with the condensation of 1-(1-naphthyl)ethan-1-amine 132 with aldehyde 131 in the presence of 4 Å molecular sieves in one pot. The in situ generated imine was then treated with silyl ketene acetal 130 in the presence of Sn(OTf)2 to give product 133 in a 90 : 10 diastereomeric ratio. The steric hindrance of the substrate appeared to be critical for the stereoselectivity. Higher diastereoselectivities were obtained with sterically more demanding aldehydes. Hydrogenation of α,β-unsaturated ester 133 followed by transfer hydrogenation with formic acid in methanol was done in the presence of palladium on carbon to cleave off the chiral auxiliary to generate a mixture of compounds 134 and 135. Refluxing the mixture in toluene afforded lactam 135 as a single product. Finally, reduction of piperidinone 135 with lithium aluminum hydride yielded anabasine (85).
Reagents: (a) 4 Å MS, CH2Cl2, 23 °C, 30 min; 135, Sn(OTf)2, −78 °C, 8 h, −30 °C, 17 h, 90 : 10 dr (b) H2, Pd/C (c) Pd/C, HCO2H, MeOH (d) PhMe, (e) LiAlH4.
Yang used a similar strategy to synthesize two natural piperidine alkaloids, such as (+)-241D (26) and isosolenopsin A (25 a) (Scheme 18). With this approach, Yang was able to synthesize the natural alkaloids in only two steps. Isosolenopsin A was isolated from the venom of the fire ant solenopsis and was found to display a variety of interesting bioactivities including antibiotic, antifungal and anti-HIV.51, 52 The vinylogous Mannich reaction started out similar to the previous method with a condensation reaction between aldehyde 23 f or 137 and chiral auxiliary 138 forming the corresponding imine. The in situ generated imine was then reacted with enol ether 136 in the presence of Sn(OTf)2 yielding both the linear and cyclized products. This crude mixture was treated with a catalytic amount of acetic acid to afford dihydropyridinones 139 and 140. Using this approach, a variety of functionalized aldehydes were tolerated and the products were obtained in moderate to good yield (53–75 %) with excellent diastereoselectivities because only single isomers were observed and isolated from the reaction mixtures. The obtained dihydropyridinones 139 and 140 were then converted into piperidine alkaloids 26 and 25 a in a single step using different reduction conditions (Scheme 18).
Reagents: (a) 4 Å MS, CH2Cl2, 23 °C, 10 min; 136, Sn(OTf)2, −78 °C, 8 h; 0 °C, 17 h (b) AcOH (c) H2, Pd/C, MeOH (d) H2, Pd/C, AcOH, MeOH.
When 139 was dissolved in MeOH in the presence of palladium on carbon, cleavage of the chiral benzyl group and saturation of the double bond and ketone occurred to give cis-4-hydroxy piperidine 26 diastereospecifically as the major product, accompanied by the corresponding dehydroxylated product as the minor product (10 : 1). These conditions were applied to synthesize 241D (26) from the vinylogous Mannich product 139 in a good yield of 72 %.
Alternatively, when hydrogenation was performed on 140 at 2.8 bar hydrogen pressure in a mixture of methanol and acetic acid (1 : 1), the major product was deoxygenated cis-2,6-dialkylated piperidine 25 a accompanied by the corresponding 4-hydroxypiperidine as the minor product (5 : 1). These conditions were used to generate isosolenopsin A 25 a from dihydropyridinone 140 in a moderate yield of 45 %.
Vicario and co-workers reported in 2013 the use of an asymmetric Mannich reaction as the key step in the synthesis of 2,3-disubstituted piperidines and fully substituted piperidin-2-ones. The asymmetry was induced by employing (+)-(S,S)-pseudoephedrine as the chiral auxiliary (Scheme 19).53
Reagents: (a) LDA, LiCl, THF, −78 °C, 1 h; 141, 0 °C, 2 h, 86 %, >99 : 1 dr (b) H2SO4 (aq) (c) BH3 ⋅ SMe2 (d) HCHO; NaBH4, TFA (e) IBX (f) Ph3P=CHCO2Et (g) H2, PtO2 (h) CAN, H2SO4 (concd); NaOH (i) LiAlH4 (j) EtCHBrCO2H, DCC, DMAP (k) BuLi, LiCl, 92 : 8 dr.
The synthesis commenced with the Mannich reaction between (+)-(S,S)-pseudoephedrine propionamide 142 and N-PMP aldimine 141. Propionamide 142 was first enolized using LDA in the presence of LiCl after which imine 141 was added to give adduct 144 in a yield of 86 % as a single anti diastereoisomer. The selective formation of the anti-Mannich product is in agreement with the previously proposed mechanism.54 The Mannich product arises from attack of the Z-enolate from the less-hindered Si-face in an open staggered conformation. This conformation remains rigid with the aid of a bridging solvent or diisopropylamine (from LDA) molecules. In the pseudo-chair-like transition state (143), the PMP-substituent of the imine lies in a pseudo-axial position to allow the only available electron pair at the imine nitrogen to coordinate with the lithium atom.55 As the aldimine is in an E-configuration, the phenyl substituent would also be in a pseudo-axial position in the cyclic transition state and would therefore afford the diastereoisomer of the relative anti configuration. Acid hydrolysis of β-amino amide 144 led to removal of the auxiliary and afforded carboxylic acid 145. A borane-mediated reduction of the acid led to the formation of γ-amino alcohol 146 without epimerization. Next, N-methylation was carried out to prevent oxidation of the secondary amino group The N-methylated product 147 was then oxidized with IBX to obtain β-amino aldehyde 148. A Wittig olefination was carried out on aldehyde 148 with commercially available Ph3P=CHCO2Et to yield the corresponding conjugated α,β-unsaturated ester 149 as a single E-diastereoisomer. This ester was then converted into either a 2,3-disubstituted piperidine or a fully substituted piperidin-2-one (Scheme 19).
The conversion of α,β-unsaturated ester 149 to piperidine 152 started with the hydrogenation of 149 in the presence of PtO2 to afford saturated ester 150. Next, the 4-methoxyphenyl group was removed under oxidative conditions and directly delivered piperidinone 151 after an intramolecular amide formation, which took place in situ after basification. Finally, 2,3-disubstituted piperidine 152 was obtained after reduction with LiAlH4 in an overall yield of 25 % over nine steps starting from propanamide 142.
To synthesize the fully substituted piperidin-2-one 155, the PMP-group was first cleaved from α,β-unsaturated ester 149 under oxidative conditions with CAN. The obtained secondary amine 153 was then acylated with 2-bromobutanoic acid to yield α-bromo amide 154. Treating this compound with butyllithium facilitated an intramolecular Michael addition and furnished the desired piperidinone 155 as a 92 : 8 mixture of C3 diastereoisomers.
The auxiliary-based asymmetric Mannich reaction has been a main focus of Troin's group. Their first efforts utilized a chiral iron dienal complex to induce enantioselectivity.56, 57
This method has been used to synthesize the secondary metabolite SS 20846 A (164 a, Scheme 19) and the 2,3,4-trisubstituted piperidine alkaloid (+)-dienomycin C (164 b, Scheme 20). Metabolite 164 a is an intermediate in the biosynthesis of the potent antimicrobial agent streptazolin isolated from a Streptomyces strain.58 (+)-Dienomycin C (164 b) is an alkaloid isolated from a Streptomyces strain and shows moderate antibiotic activity against Myobacteria.59, 60
Reagents: (a) MgSO4, CH2Cl2, Δ, 3 h; TsOH, CH2Cl2, 70 °C, 4 h, 54–68 %, 86 : 14 to 90 : 10 dr (b) FmocCl, DIPEA (c) TFA (aq) (d) Piperidine (e) L-Selectride (f) TMANO, Me2CO, Δ.
In the approach by Troin et al., the Fe(CO)3 unit of 156 a and 156 b served as a protecting and directing group for the formation of the C2 stereocenter in the piperidine skeleton. Amine 157 a was reacted with chiral complex 156 a followed by acidic treatment to furnish the corresponding piperidine 159 a with 68 % yield and 90 : 10 diastereomeric ratio.61 To rationalize the stereochemical outcome, Troin and co-workers hypothesized that in an acidic medium, the more stable s-trans complex 158 a and 158 b are predominantly present over the s-cis complex leading to attack of the enol ether to the s-trans complex. This cyclization of the enol ether to the iminium ion occurs anti to the bulky Fe(CO)3 group giving the pseudo anti product 159 a and 159 b with the newly created C2 center having absolute (S)-configuration.62 Piperidine 159 a was then treated with FmocCl in the presence of Hünig's base to yield N-Fmoc protected piperidine 160 a. Treatment of 160 a with aqueous TFA to give 161 a, followed by piperidine furnished deprotected piperidinone 162 a, which was then stereoselectively reduced with L-selectride at low temperature to give the expected axial piperidinol 163 a in a 90 : 10 diastereomeric ratio. Finally, decomplexation of the piperidin-2-ol with trimethylamine N-oxide (TMANO) afforded the alkaloid SS 20846 A (164 a).
Next to the synthesis of 164 a from 156 a and 157 a, this reaction sequence was also used to construct alkaloid 164 b from 156 b and 157 b (Scheme 20). Thus (see above), reaction of amine 157 b with chiral complex 156 b followed by acid gave piperidine 159 b with 54 % yield and 86 : 14 diastereomeric ratio. Then, 159 b was Fmoc-protected to give N-protected piperidine 160 b, after which ketone deprotection of 160 b to give 161 b and subsequent Fmoc removal gave piperidinone 162 b. Stereoselective reduction gave axial piperidinol 163 b with 90 : 10 dr and finally decomplexation gave alkaloid (+)-dienomycin C (164 b).
Although the use of the iron complex as the auxiliary permits the asymmetric construction of diverse polysubstituted piperidines, this method does not allow the stereoselective elaboration of a 2,6-disubstitution pattern by the same pathway. To overcome this limitation, Troin et al. altered the methodology and utilized internal asymmetric induction to induce stereoselectivity in the Mannich reaction (see above, Scheme 2).
4 Asymmetric induction by asymmetric catalysis
4.1 Asymmetric induction by covalent interactions
The stereochemical outcome of the Mannich reaction can be controlled by external means, such as a chiral catalyst or ligand. The enantio- or diastereoselectivity arises from the influence of the catalyst on the transition state preferring the formation of one stereoisomer. The catalyst can act on the transition state either by covalent or non-covalent interactions. In the case of covalent interactions, the catalyst reacts with one of the starting materials to form a chiral intermediate that determines the stereochemical outcome. During this process, the catalyst is not consumed and thus the reaction can be carried out using a substoichiometric amount of the reagent. In particular enantioselective organocatalytic Mannich reactions recently received much retention as a result of the Nobel Prize that was awarded to MacMillan and List, for their seminal work in developing enantioselective organocatalytic reactions.63
In the synthesis of (+)-pelletierine (167) by Monaco et al., several organocatalysts were tested for their abilities to induce enantioselectivity and activate the carbon acid through the formation of a chiral enamine (Scheme 21).64 The piperidine alkaloid (+)-pelletierine was first isolated by Charles Tanret in 1878 from the bark of the pomegranate tree (Punica granatum L., Lythraceae).65
Reagents: (a) NCS; 85 % KOH in EtOH (b) L-Proline (20 mol %), PhCN, −20 °C, 168 h, 82 %, 95 % ee.
The synthesis started from piperidine (165), which was converted into imine 166 by N-chlorination and subsequent base-mediated HCl elimination.66 The Mannich reaction was then employed to synthesize (+)-pelletierine (167) in a single step from imine 166 using acetone as the carbon acid. The catalyst of choice in this conversion was L-proline (20 mol %) resulting in a very good yield (82 %) with high enantioselectivity (95 % ee) due to the rigid chair-like transition state 167. Racemization of (+)-pelletierine (167) during the reaction was suppressed to a large extent by using benzonitrile as the solvent despite leading to a longer reaction time. The same approach was adapted by the Evans group, who used enantiopure pelletierine (167) as a starting point for synthesizing other piperidine alkaloids including sedredine (169) and its epimer allosedridine (170).67
A similar approach was pursued by the Snyder group using Mannich-like nitrones as reactive intermediates (Scheme 22).68 Piperidine-derived nitrone 171 was reacted with various methyl ketones (exemplified for acetophenone) in the presence of benzoic acid and chiral catalyst 172 to give the corresponding adduct in good yield and 90 % ee. Diastereoselective reduction of the ketone, followed by TBS protection furnished 174, which in turn was oxidized with IBX to nitrone 175. Subsequent Mannich reaction, followed by reduction of the hydroxylamine and concomitant reductive amination provided the methylated piperidine 176 as a 1 : 1 mixture of cis/trans isomers. Desilylation, followed by Crystallization Induced Diastereomeric Resolution (CIDR) in MeOH led to conversion into the desired cis-product, natural product lobeline (177) in excellent yield.
Reagents: (a) 172 (20 mol %), BzOH (40 mol %), CH2Cl2, 48 h, 70 %, 90 % ee (b) Zn(BH4)2, THF, −78 °C, 4 h (c) TBSOTf, i-Pr2NEt, CH2Cl2, 0.5 h, 67 % over two steps (d) IBX, CH2Cl2, 4 h, 99 % (e) PhC(O)CH2CO2H, CH2Cl2, 22 h (f) Zn, CH2O, AcOH, 4 h, 76 % over two steps, 1 : 1 cis:trans (g) HCl, i-PrOH, 60 °C,12 h (h) CIDR, MeOH, 2 weeks, 90 % over two steps.
Ab enantioselective Mannich reaction with L-proline was also used as the first step in the synthesis of ent-sedridine (183) by Itoh et al. (Scheme 23).69 In 1955, Beyerman and co-workers isolated the alkaloid sedridine from extracts of Sedum acre.70 After testing several conditions, the Mannich reaction was conducted in isopropyl alcohol as alcoholic solvents yielded better results than non-protic polar solvents such as DMSO and DMF. p-Anisidine (178), 5-hydroxypentanal (179) and acetone were used in the Mannich reaction and converted to β-amino ketone 180 with L-proline (30 mol %) as the catalyst. The β-amino ketone was obtained in 76 % yield and 91 % ee. Mannich product 180 was then reduced with LiAlH4, followed by a Mitsunobu reaction to yield piperidine 181 as a mixture of diastereoisomers. Upon subsequent oxidative removal of the PMP group, followed by protection with a Cbz group. Only diastereoisomer 182 was obtained because hydrolysis of the intermediate formed during oxidation of the other diastereoisomer was prevented by intramolecular nucleophilic attack of the hydroxy group on the formed quinonoid intermediate. Lastly, hydrogenation afforded ent-sedridine (183) in 34 % yield over six steps.
Reagents: (a) L-Proline (30 mol %), iPrOH, −10 °C, 185 h, 76 %, 91 % ee. (b) LiAlH4, THF (c) DEAD, PPh3, CH2Cl2 (d) CAN, MeCN, H2O (e) CbzCl, NaOH (aq) (f) H2, Pd(OH)2, MeOH.
Kumar et al. took advantage of the syn-selective nature of proline as a chiral catalyst in the synthesis of functionalized (−)-anabasine (190; Scheme 24).71 The alkaloid (−)-anabasine (85, Scheme 11) is a minor component of tobacco and may contribute to the neuropharmacological effects of tobacco smoke as well to the neuroprotective effect of tobacco smoke in Parkinson's and Alzheimer's diseases.72
Reagents: (a) L-Proline (20 mol %), DMSO, 10 °C, 9 h, 81 % ee, >25 : 1 dr (b) NaBH4, AcOH, H2O, 65 % (c) CAN, MeCN, H2O.
In this procedure, the 2,3-substituted piperidine skeleton was formed by a formal [4+2] annulation via an organocatalytic Mannich-reductive cyclization with the chiral proline-derived enamine inducing the stereoselectivity in the process. In the one-pot synthesis of functionalized (−)-anabasine (190), aqueous glutaraldehyde (184) was used as an in situ 1,4-carbon donor-acceptor precursor and reacted with N-PMP aldimine 185. The reaction was run under optimized conditions with DMSO as solvent at a temperature of 10 °C with 20 mol % of L-proline directly followed by hemiaminal and aldehyde reduction to give the desired product 189 in 65 % yield, 81 % ee and >96 : 4 dr. The proposed mechanism by Kumar et al. commences with the formation of adduct 187 after the syn-Mannich reaction takes place as shown with intermediate 186, followed by cyclization to compound 188, which is then reduced with NaBH4 to yield piperidine 189. The stereochemical outcome was determined by the steric repulsion between the aromatic ring and pyrrolidine moiety in combination with protonation of the imine lone pair by the acid of proline. This leads to Si-face attack to aldimine 185 by the Si-face of the chiral enamine giving rise to syn-Mannich product 187.73 The last step involved deprotection of the PMP group to afford (−)-anabasine functionalized at the 3-position (190).
Han et al. described a similar approach in the synthesis of 2,3-disubstituted tetrahydropyridines 195 (Scheme 25).74 Starting from preformed aldimine 191 and aqueous glutaraldehyde (184), tetrahydropyridine 195 was generated via a cascade reaction involving an enantioselective Mannich reaction followed by cyclization. It was previously demonstrated that the Mannich reaction could tolerate a significant amount of water without compromising the enantiomeric excess of the Mannich product.75 After screening, the reaction was run under the optimized conditions with 20 mol % L-proline in DMSO at room temperature for 3.5 h. Under these conditions, tetrahydro-2H-pyran-2,6-diol was in equilibrium with glutaraldehyde and this dialdehyde formed a chiral enamine after reacting with L-proline as depicted in intermediate 192.
Reagents: (a) L-Proline (20 mol %), DMSO, H2O, 23 °C, 3.5 h, 74 %, 98 % ee, >25 : 1 dr.
The proposed mechanism commences with a syn-selective Mannich reaction forming intermediate 193, after which intramolecular hemiaminal formation generates compound 194. This unstable intermediate is dehydrated under acidic conditions to afford enantiopure tetrahydropyridine 195. The reaction proceeded equally well with both electron-rich and electron-deficient aromatic imines with good to excellent ee albeit that the yield is slightly lower with electron-rich aryl and alkyl derivatives, presumably because of partial imine hydrolysis.
The Mannich reaction in the presence of water was further investigated by Veverková et al.76 Aqueous glutaraldehyde 184 and imine 196 were used as starting materials to generate tetrahydropyridine 198 (Scheme 26).
Reagents: (a) 197 (10 mol %), NaHCO3, DMSO, H2O, 23 °C, 4 h, 56 %, 98 % ee, >95 : 5 dr.
The best results for the Mannich reaction were obtained with imide 197 as the catalyst (10 mol %), DMSO as solvent and NaHCO3 (10 mol %) as an additive with the reaction running at room temperature for 4 h. These conditions afforded enamine 188 in 56 % yield, 98 % ee and >95 : 5 diastereomeric ratio. Catalyst 197 operates in the same fashion as L-proline forming a chiral enamine that directs the Mannich reaction (see intermediates in brackets in Scheme 26). The reaction was also carried out in water without organic solvent and the product was formed with equal ee and de, but the yield did not exceed 20 %.
A paper published by Kumaraswamy et al. described a concise method to synthesize substituted homopipecolic ester derivatives.77 The unique characteristic of this approach is the introduction of three stereogenic centers in a single step using a tandem Mannich-indium promoted allylation sequence (Scheme 27). The first two stereocenters were generated by the syn-Mannich reaction between propanal (199) and imine 200 with D-proline as the catalyst resulting in the formation of aldehyde 201 in 98 % ee and >99 : 1 dr. This reaction was then followed by an indium-promoted allylation with allyl bromide, which generated the third stereocenter affording the reaction product as separable diastereoisomers in a ratio of 66 : 34 syn-anti to syn-syn product. The resulting alcohol 202 was subjected to cross-metathesis using the second-generation Grubbs catalyst and neat methyl acrylate forming α,β-unsaturated ester 203.
Reagents: (a) 1. D-Proline (10 mol %), MeCN, 0 °C, 24 h, 98 % ee, >99 : 1 dr; 2. In, allyl bromide, H2O, 58 % (2 steps) (b) 1. methyl acrylate, 2nd generation Grubbs catalyst; 2. HCl, THF; 3. NH3 (aq), MeOH.
Finally, piperidine 205 was obtained after exposing unsaturated ester 203 to acidic and then basic conditions. The stereochemical outcome of the conjugate addition can be explained by a 6-exo-trig cyclization, wherein the substituents at positions 2 and 5 are likely to adopt equatorial orientations (configuration 204) leading to diastereoisomer 205.
Diastereoisomers of piperidine 205 have also been synthesized, including the ones that were synthesized with an anti-Mannich reaction. A previously described anti-Mannich strategy by the Melchiorre group was employed using carbamate 206 and propanal in the presence of 20 mol % of catalyst 207 (Scheme 28).78
Reagents: (a) 1. 207 (20 mol %), KF, CHCl3, 30 °C, 96 h; 2. In, allyl bromide, H2O, 58 % (2 steps) (b) 1. Methyl acrylate, 2nd generation Grubbs catalyst; 2. HCl, THF; 3. NH3 (aq), MeOH.
Carbamate 206 eliminated p-toluenesulfinic acid in the presence of an inorganic base to give the carbamate-protected imine, which then participated in a Mannich reaction to yield aldehyde 209. Franzén and co-workers proposed a mechanism for the formation of the anti-Mannich product.79 In the thermodynamically most stable structure of the enamine, one of the aryl groups efficiently blocks the Re-face of the enamine. Therefore, the electrophilic attack must occur from the Si-face giving anti-Mannich product 209. After the indium-promoted allylation reaction, compound 210 was obtained as a diastereomeric mixture of the anti-syn and anti-anti products in a 70 : 30 ratio, which was separated by silica gel chromatography. Compound 210 was then converted into piperidine 212 via α,β-unsaturated ester 211 using the same procedures as for 205.
Another interesting strategy involving the enamine-mediated asymmetric Mannich reaction is the synthesis of iminosugar derivatives as described by the group of Córdova (Scheme 29).80 Iminosugars are an important class of glycosidase inhibitors and are being studied in the treatment of various carbohydrate-mediated diseases, such as diabetes and cancer metastasis.81
Reagents: (a) L-Proline (30 mol %), DMF, 23 °C, 48 h; (EtO)2POCH2CO2Me, DBU, LiBr, 23 °C, 1.5 h, 64 %, 95 % ee, E/Z 4 : 1 dr (b) 1. L-Proline (30 mol %), DMF, 23 °C, 48 h; 2. Ph3P=CHCO2Me, DMF, 23 °C, 56 %, 92 % ee, 4 : 1 Z/E. (c) OsO4 (cat.), NMO, 87 : 13 dr for 218, 90 : 10 dr and 92 % ee for 220 (d) AcOH, MeOH, Δ.
Synthesis of iminosugars usually relies on carbohydrate transformations, but Liao et al. described a de novo approach for their synthesis. This approach creates four new stereocenters in two steps using a tandem one-pot organocatalytic Mannich/Horner–Wadsworth–Emmons sequence and a dihydroxylation with catalytic osmium tetroxide (Scheme 29). The starting materials for the one-pot reaction were aldehyde 213 and p-anisidine (214), with the former participating twice: the aldehyde was transformed into an electrophilic imine and a nucleophilic enamine in the Mannich reaction. Using 30 mol % of L-proline as the catalyst, the syn-Mannich reaction afforded β-amino aldehyde 215, which was then subjected to the Horner–Wadsworth–Emmons reaction to afford α,β-unsaturated ester E-216 in 95 % ee and a 80 : 20 diastereomeric ratio. Using E-216 two new stereocenters were then formed by catalytic dihydroxylation with osmium oxide to yield compound 217 in a 87 : 13 diastereomeric ratio, followed by an acid-catalyzed cyclization to form galactolactam 218.
Iminosugar derivative 219 was synthesized using a similar strategy (Scheme 29). Starting from 213 and 214, a Wittig olefination (instead of the Horner–Wadsworth–Emmons reaction) was used to generate protected vicinal amino alcohol Z-216 in an 80 : 20 Z/E ratio. The next step in the synthesis was cyclization of compound Z-216 to yield dihydropyridinone 219. Finally, a diastereoselective dihydroxylation with osmium tetroxide afforded compound 220 as a single diastereoisomer in 92 % ee.
4.2 Asymmetry by non-covalent interactions
Stereoselectivity during a Mannich reaction can also be achieved by using non-covalent catalysts. Similar to a catalyst forming covalent bonds during the reaction, the asymmetry is induced by the influence of the catalyst on the transition state in the Mannich reaction. Unlike covalently bound catalysts where a chiral intermediate is formed, a non-covalent catalyst influences the transition state by coordinating to one or more reactants in the reaction, thereby favoring the formation of one diastereoisomer and enantiomer over others.
In the synthesis of (−)-anabasine [(−)-85], Giera et al. used an enantiopure BINOL-based phosphoric acid as the catalyst to induce asymmetry in the Mannich reaction.82 The approach employed by Giera and co-workers consisted of four steps to synthesize (−)-anabasine [(−)-85] in 55 % overall yield (Scheme 30). The synthesis started with a vinologous Mannich reaction catalyzed by Brønsted acid 222 in an optimized solvent system consisting of tert-butyl alcohol, 2-methylbutan-2-ol and THF (1 : 1 : 1) with one equivalent of water.83 The use of a coordinating solvent such as THF exhibited a positive effect on the enantioselectivity of the reaction, whereas the use of an alcoholic solvent significantly increased the reaction rate, but also decreased the enantioselectivity. Ultimately, the aforementioned mixture of solvents gave the best results in terms of yield and enantioselectivity. Thus, the vinologous Mannich reaction was performed with silyl dienolate 221 and pyridin-3-yl imine 185 to obtain Mannich product 223 in 96 % yield and 92 % ee. It was proposed that the diaryl groups, which are not coplanar with the naphthyl groups, effectively shield the phosphate moiety leading to efficient asymmetric induction.84 First, protonation of the imine by the phosphoric acid forms chiral contact ion pair 223. Subsequently, silyl dienolate 221 adds to the contact ion pair in the C−C bond-forming process and reacts to Mannich product 224, whereupon chiral phosphoric acid 222 is regenerated.
Reagents: (a) 222 (3 mol %), H2O, THF, tBuOH, 2-methylbutan-2-ol, −50 °C, 60 h, 96 %, 92 % ee (b) [(BDP)CuH], PMHS (c) DIBAL-H (d) Ph3P, DEAD (e) CAN.
The conjugate double bond of compound 224 was then reduced with the Stryker's reagent [(BDP)CuH].85 DIBAL-H reduction of ester 225 delivered the desired piperidine 226 as well as saturated alcohol 227 as a mixture of products. Apparently, most of the in situ formed aldehyde reacted with the secondary amine furnishing a cyclic iminium ion, which was further reduced to yield the piperidine, whereas a minor amount was further reduced to form 227. Compound 227 was also converted into the desired piperidine via a Mitsunobu reaction in good yield. Finally, removal of the PMP-group furnished (−)-anabasine [(−)-85].
In 2010, Wang et al. developed a triple cascade reaction to synthesize fully substituted piperidines 238. This cascade includes as a key step a Mannich reaction in which a bifunctional base–acid catalyst determines the stereochemical outcome. In this cascade process, aldehyde 199, nitro alkene 228 and imine 229 were reacted in the presence of the two organocatalysts 230 and 231 to furnish compound 236 (Scheme 31).86
Reagents: (a) 230 (15 mol %), 231 (15 mol %), PhMe, 12 °C, 28–54 h, 56 %, >99 % ee, >99 : 1 dr (b) 1. Ac2O, pyridine; 2. NiCl2 ⋅ 6H2O, NaBH4, MeOH; (c) TFA.
The group of Wang postulated the following mechanism of the cascade reaction. First, an asymmetric Michael addition takes place between nitro alkene 228 and the enamine formed from aldehyde 199 and catalyst 231. In situ hydrolysis liberates nitro alkane 232 and this is then able to participate in a relay catalytic cycle. Catalyst 230 promotes the Mannich reaction of intermediate 232 with imine 229 and generates the substituted N-tosyl-protected amino aldehyde 235. The piperidine ring is formed in the final step by hemiaminal formation and furnishes compound 236 as a diastereomeric mixture. Both Mannich reactions were highly stereoselective proceeding with >99 % ee and >99 : 1 dr. To illustrate the value of the cascade reaction, Wang and co-workers converted the obtained piperidine 236 into 3-aminopiperidine 238 as 3-amino piperidine alkaloids are found extensively in nature and possess a wide range of biological activities.
To account for the highly stereoselective formation of the protected syn-β-nitro amine 236, ternary complex 234 consisting of catalyst 230, imine 229 and the azinate of 232 was proposed as a plausible transition state by the group of Takemoto.87 In this transition state, the imine and the azinate are both activated, by coordination to the protons of the thiourea group and to the tertiary ammonium moiety respectively, and syn-β-nitro amine 235 would be obtained diastereoselectively if this transition state is predominantly produced. The generation of ternary complex 234 is possible via two pathways. Complex 234 can be formed by coordination of the nitro alkane to the catalyst followed by deprotonation of the nitroalkane. The nitro alkane is then displaced by the imine and the C−C bond-forming step will take place (not shown). The other pathway (Scheme 31) to complex 234 is that the imine coordinates first to the catalyst and is subsequently activated. Then, the nitro alkane coordinates to the complex and is deprotonated to form complex 234, upon which the C−C bond-forming step will occur.
Xu et al. used a similar thiourea catalyst (240) in a Mannich reaction in the synthesis of (−)-CP-99,994 (244), a selective neurokinin-1 receptor antagonist (Scheme 32).87
Reagents: (a) 240 (10 mol %), CH2Cl2, −20 °C, 72 h, 80 % (b) 1. TFA; 2. K2CO3 (c) 1. KOtBu; 2. AcOH; 3. Zn, AcOH (d) o-Anisaldehyde, Na[BH3CN], AcOH, MeOH.
The Mannich reaction was employed in the first step with nitro alkane 239 and imine 200 as the reactants and although the syn-Mannich product was furnished in 96 % ee and a 86 : 14 diastereomeric ratio, both diastereomers were used in the next step. Removal of the N-Boc group and subsequent treatment of the crude product with aqueous K2CO3 gave the cyclized products 242 as a 90 : 10 mixture of the anti- and syn-isomers. The C3 position of 242 was then successfully epimerized by a kinetically controlled isomerization protocol involving potassium tert-butoxide followed by acetic acid yielding syn-243 as the major product in a 95 : 5 ratio. This labile intermediate was directly reduced with zinc in acetic acid to afford piperidine 243 and subsequently subjected to reductive amination with o-anisaldehyde in the presence of Na[BH3CN] to provide (−)-CP-99,994 (244) as a single product.
A variant of Takemoto's catalyst was utilized in a one-pot cascade reaction to synthesize tetrahydropyridine derivatives as described by the group of Dixon.88, 89 The approach consists of an asymmetric Mannich reaction in the presence of catalyst 246 followed by a gold-catalyzed alkyne hydroamination/alkene isomerization sequence to yield the tetrahydropyridine derivatives 250 (Scheme 33).89 The synthesis started with an asymmetric Mannich reaction of nitro alkyne 245 and N-Boc-protected imine 200 catalyzed by organocatalyst 246 to afford β-nitro amine 247 in a stereoselective fashion. A gold-catalyzed hydroamination was then proposed to cyclize intermediate 246, but a previous study by Belot et al. demonstrated the incompatibility of Au(I) catalysts and bifunctional organocatalysts.90 The addition of a Brønsted acid was necessary to quench the basic nitrogen atom of the bifunctional catalyst prior to the addition of the gold salt. Several Brønsted acids were tested, with sodiumdiphenylphosphate (10 mol %) being most effective in quenching the organocatalyst. The subsequent hydroamination of intermediate 247 was catalyzed by Echavarren's catalyst (via 248) to furnish piperidine 249 after protodeauration.91 Subsequent exo–endo isomerization of the alkene resulted in tetrahydropyridine 250 as the product of the cascade reaction in 66 % yield.
Reagents: (a) 1. 246 (5 mol %), PhMe, −15 °C, 24 h; sodium diphenylphosphate, 23 °C, 30 min; 2. Echavarren's catalyst (5 mol %), 60 °C, 8 h, 66 %, 92 % ee, >98 : 2 dr.
Rutjes and co-workers developed an efficient method to asymmetrically synthesize valuable scaffolds that can be further derivatized into high-value pharmaceutical compounds starting from enantiomerically pure β-amino ketones employing an intramolecular Mannich reaction (Scheme 34).92-94 β-Amino ketone 251 – generated through a proline-catalyzed Mannich reaction – was deprotected with periodic acid under acidic conditions to give HCl salt 252. The free amino ketone was subsequently treated with an aromatic aldehyde, catalytic L-proline, triethylamine and sodium sulfate to give the corresponding piperidinones 256 a–c, which were formed by a diastereoselective intramolecular Mannich reaction. After imine formation of 252 with aromatic aldehyde 253 followed by enamine formation with L-proline, the complex of iminium ion 254 favors the lowest-energy chair-like conformation in which the two aryl groups are in pseudo-equatorial positions. Then the enamine part of 254, formed by L-proline and the ketone, attacks the iminium ion to form piperidinones 255 a–c in 28 to 75 % yield. The cis-stereochemistry of the two bulky aryl groups in the products 255 a–c was confirmed by NOESY and 1H NMR studies. Derivatization of 255 was performed in flow where each piperidinone was reacted with five different isocyanates separately to give a small library consisting of 256aA–E, 256bA–E and 256cA–E in yields from 55 to 99 %. Alternatively, 255 c was reduced with LiBH4 in flow in a diastereoselective manner (10 : 1) to give piperidinol 257 c. Next, the piperidinol was reacted under similar conditions as for the formation of the library of compounds 256 to give 257cA–E in yields ranging from 83–99 %.
Reagents: (a) 1. H5IO6, H2SO4, H2O/MeCN 1 : 1; 2. HCl/EtOAc, 46 % (b) Ar2CHO, L-proline (20 mol %), NEt3, Na2SO4, EtOH, 21 °C, 220 min 256 a: 75 %; 256 b: 38 %; 256 c: 28 % (c) Carried out in flow reactor: R=Et, Pr: isocyanate, tBuOH, 50 °C, 17 min, 83–92 %; R=Ph, 2-ClC6H4, 2,4-FC6H3: isocyanate, 1,2-DCE, 80 °C, 17 min, 55–99 %; (d) Carried out in flow reactor: LiBH4, THF, 3 min, 76 % (e) Carried out in flow reactor: R=Et, Pr, Ph: isocyanate, tBuOH, 50 °C, 17 min, 84–99 %; R=2-ClC6H4, 2,4-F2C6H3: isocyanate, 1,2-DCE, 80 °C, 17 min, 83–99 %.
5 Conclusion
Since the first publications in the early 1990s, there has been a steadily growing number of reports employing an asymmetric Mannich reaction in the synthesis of piperidine structures. The asymmetric induction in the Mannich reaction has been achieved by a range of methods that we have divided into three separate groups: external, relayed and internal asymmetric induction. We have described examples of each method, including the reaction mechanisms and rationalized the stereochemical outcome of the Mannich product to show what strategies can be pursued. Furthermore, we have highlighted examples in which these methods have been applied to synthesize naturally occurring piperidine alkaloids and/or bioactive piperidines. Synthesis and screening of alkaloid derivatives remains relevant for drug discovery as, from a pharmaceutical perspective, alkaloids generally display wide arrays of biological activity and only relatively small quantities of alkaloids can be obtained from plants. Moreover, once the methodology to produce the natural product alkaloids has been established, also the synthesis of focused libraries of close analogues come within reach. We hope that this overview will be useful to inspire new endeavors to further exploit the chemistry and biological applications of piperidine alkaloids.
Conflict of interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
Biographical Information
Stefan van Rootselaar was born in Rotterdam, the Netherlands in 1987. He completed his bachelor and master in Molecular Life Sciences at Radboud University, Nijmegen. After that, he performed his PhD studies in the group of Floris Rutjes on piperidine alkaloid synthesis via organo- and biocatalysis. He is currently a lecturer and researcher in Organic Chemistry at the HAN University of Applied Sciences (Nijmegen).
Biographical Information
Daniel Blanco Ania is a Staff Scientist at Radboud University, where he also obtained his PhD (2009). He studied Chemistry at the Autonomous University of Madrid (MSc, 1996) at the time that he began his independent career as a teacher at Academia Blanco (his own private school of Organic Chemistry; 1994). After his PhD, he did postdoctoral research at Radboud University and at the Spanish National Research Council. In 2019, he was awarded the “Golden Teacher of the Year” award of the Royal Netherlands Chemical Society (KNCV). His research interests include the use of metal- and organocatalysis in organic synthesis, photochemistry, flow chemistry and crop protection.
Biographical Information
Floris Rutjes received his PhD from the University of Amsterdam in 1993 with profs. W.N. Speckamp and H. Hiemstra and conducted postdoctoral research with Prof. K.C. Nicolaou at The Scripps Research Institute, La Jolla, USA. In 1999 he became full professor in organic synthesis at Radboud University, Nijmegen. Awards include the Gold Medal of the Royal Netherlands Chemical Society (KNCV, 2002), the AstraZeneca award for research in organic chemistry (2003), and Most Entrepreneurial Scientist of the Netherlands (2008). He is currently director of the Institute for Molecules and Materials at Radboud University and President of the European Chemical Society (EuChemS).
Biographical Information
Evert Peterse obtained his bachelor's and master's degree in Chemistry at Radboud University, Nijmegen. Afterwards, he received his PhD from the University of Leiden. He is currently a senior scientist at DC4U (Amsterdam, The Netherlands).
