Review Review

Enzymatic Enzymatic Kinetic Kinetic Resolution Resolution of of 2-Piperidineethanol 2-Piperidineethanol for the the Enantioselective Enantioselective Targeted Targetedand andDiversity Diversity for Oriented Synthesis Synthesis †† Oriented Dario Perdicchia Perdicchia *,*, Michael MichaelS. S.Christodoulou, Christodoulou,Gaia GaiaFumagalli, Fumagalli,Francesco FrancescoCalogero, Calogero, Dario Cristina Marucci and Daniele Passarella * Cristina Marucci and Daniele Passarella * Received: 22 November November 2015; 2015; Accepted: Accepted: 15 15 December December 2015; 2015; Published: Published: 24 2015 Received: December 2015 AcademicEditor: Editor: Vladimír VladimírKˇ Křen Academic ren Dipartimentodi diChimica, Chimica,Universita Universitadegli degliStudi Studidi diMilano, Milano,Via ViaGolgi Golgi19, 19,20133 20133Milano, Milano,Italy; Italy; Dipartimento [email protected] (M.S.C.); (M.S.C.); [email protected] [email protected] (G.F.); (G.F.);[email protected] [email protected](F.C.); (F.C.); [email protected] [email protected] (C.M.) (C.M.) [email protected] ** Correspondences: Correspondences:[email protected] [email protected](D.Pe.); (D.Pe.);[email protected] [email protected](D.Pa.); (D.Pa.); Tel.: Tel.:+39-02-5031-4155 +39-02-5031-4155(D.Pe.); (D.Pe.);+39-02-5031-4081 +39-02-5031-4081(D.Pa.); (D.Pa.); Fax: Fax:+39-02-5031-4139 +39-02-5031-4139(D.Pe.); (D.Pe.);+39-02-5031-4078 +39-02-5031-4078(D.Pa.) (D.Pa.) †† This Thispaper paperisisdedicated dedicatedtotothe thememory memoryofofBruno BrunoDanieli, Danieli,Professor Professorof ofOrganic OrganicChemistry, Chemistry, Università Universitàdegli degliStudi Studidi diMilano, Milano,20122 20122Milano, Milano,Italy. Italy.

Abstract: Abstract: 2-Piperidineethanol 2-Piperidineethanol (1) (1) and and its its corresponding corresponding N-protected N-protected aldehyde aldehyde (2) (2) were were used used for for the the synthesis of several natural and synthetic compounds. The existence of a stereocenter at position 2 synthesis of several natural and synthetic compounds. The existence of a stereocenter at positionof2 the piperidine skeleton andand the presence of anofeasily-functionalized group, such such as theasalcohol, set 1 of the piperidine skeleton the presence an easily-functionalized group, the alcohol, as startingstarting materialmaterial for enantioselective synthesis.synthesis. Herein, are presented both synthetic seta 1valuable as a valuable for enantioselective Herein, are presented both and enzymatic methods for the resolution the racemic 1, as well as1,anasoverview of synthesized synthetic and enzymatic methods for the of resolution of the racemic well as an overview of natural products starting fromstarting the enantiopure synthesized natural products from the 1. enantiopure 1. Keywords: Keywords: 2-piperidineethanol; 2-piperidineethanol; piperidine piperidine alkaloids; alkaloids; enzymatic enzymaticresolution; resolution;alkaloid alkaloidsynthesis synthesis

1. Introduction 1. Introduction 2-Piperidineethanol 2-Piperidineethanol (1) (1) (Figure (Figure 1) 1) is is aa chiral chiral piperidine piperidine derivative derivative bearing bearing two two functional functional group group suitable for diversified elaborations of the molecule. suitable for diversified elaborations of the molecule.

N H 1

OH

N Pg

O

2

Figure 1. 1. Structure Structure of of 2-piperidineethanol 2-piperidineethanol (1) (1) and and the the corresponding correspondingN-protected N-protectedaldehyde aldehyde(2). (2). Figure

With With more more than than 10,000 10,000 molecules molecules listed listed in in SciFinder, SciFinder, contain contain the the substructure substructure of of 2-piperidineethanol keeping stereocentre in position 2 of piperidine, its potentiality is 2-piperidineethanol keeping thethe stereocentre in position 2 of piperidine, its potentiality is self-evident self-evident as chiral a valuable chiral starting materialsynthesis. in organicInsynthesis. In racemic is a as a valuable starting material in organic racemic form, it is aform, quite itcheap quite cheap compound it is synthesized, an industrial scale, catalytic hydrogenation hydrogenation of compound since it issince synthesized, on anonindustrial scale, by bycatalytic of 2-(2-hydroxyethyl)pyridine thethe contrary, the enantiopure form isform expensive and less available. 2-(2-hydroxyethyl)pyridine[1]; [1];onon contrary, the enantiopure is expensive and less N-protected aldehyde (2), easily obtained by controlled oxidation of the parent alcohol, is the available. derivative of 2-piperidineethanol usually used toby a great extentoxidation in synthesis. N-protected aldehyde (2), easily obtained controlled of the parent alcohol, is the derivative of 2-piperidineethanol usually used to a great extent in synthesis. Int. J.J. Mol. Mol. Sci. Sci. 2016, 2016, 17, 17, 17; 0017; doi:10.3390/ijms17010017 Int. doi:10.3390/ijms17010017

www.mdpi.com/journal/ijms www.mdpi.com/journal/ijms

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The racemic compound is clearly related to the main exploitations but in the last decades there was a growing utilization of the enantiopure form, mostly concerning the synthesis of new leads in medicinal chemistry and the total synthesis of natural compounds. Per se, it is utilized in the industrial plants for CO2 capture [2]; as racemic starting compound was used in the synthesis of the catalysts for Ziegler–Natta polymerization [3]. It is used as scaffold for the synthesis of insect and mite repellents [4] as Icaridin (trade name Saltidin) [5]; tert-butyl carbamate (N-Boc) protected 2-piperidineethanol was patented as anthelminthic agents for humans and animals [6]. In medicinal chemistry, several leads were synthesized from racemic 1; it is worth citing the synthesis of a new orexin receptor antagonist [7], of a new class of non-opiate antinociceptive agents [8], of (aryloxyalkyl)piperidines as calcium channel antagonists [9] and of sulfonamide derivatives as 5-HT7 receptor (5-hydroxytryptamine receptor 7) antagonists [10]. In some cases, a further improvement of activity was granted with the proper enantiomer, for example, the synthesis of aminoindane compounds as sodium channel inhibitors and TRPV1 receptor (transient receptor potential cation channel subfamily V member 1) activator for the treatment of pain [11], of a novel non-xanthine adenosine A1 receptor antagonist [12], of dermal anesthetic agents [13], of gonadotropin-releasing hormone antagonists [14], of a new inhibitor of cyclin-dependent kinases [15], of non-peptide quinolone GnRH (gonadotropin-releasing hormone) receptor antagonists [16] and of selective thrombin inhibitors [17]. Nature is the prime developer of compounds with a piperidine backbone with many structurally-interesting alkaloids; the wide range of biological activities in this family of natural products make them ideal targets for total synthesis. A selection of synthesis of alkaloids starting from enantiopure 1 is displayed at the end of this review. 2. Enantiopure 2-Piperidineethanol: Resolution versus Synthesis Some research groups took into account the enantioselective synthesis of 1 or aldehyde 2; an early strategy was established on intermolecular nitrone cycloadditions to chiral allyl ethers [18,19] obtaining benzyl carbamate (N-Cbz) 2. Asymmetric allylation was the next synthetic tool using a chiral auxiliary [20,21]; a synthetic sequence involving a Maruoka asymmetric allylation with a chiral catalyst [22] was successful in obtaining N-Boc 2. Recently, a straightforward organocatalyzed intramolecular aza-Michael reaction accomplished the synthesis of either N-Boc or N-Cbz 2 in high enantiomeric excess (e.e.) [23,24]. To obviate to the numerous synthetic steps necessary in the synthesis of 1 from scratch was also taken advantage of the homologation of the commercially-available N-(Boc)-S-pipecolic acid by carboxyl reduction, modified Swern oxidation, Wittig olefination, and enol ether acidic hydrolysis [25]. Resolution of the racemic mixture certainly provides practical benefits, considering the low price and good availability of 1, although suffers from the disadvantage that only half of the starting material is transformed into the desired product. Resolution can then offer the most cost efficient route to the enantiomerically pure chiral synthon. Indeed, it was the first method used to obtain the enantiopure isomer by careful recrystallization of the diasteroisomeric D-10-camphorsulfonate salt from ethanol-ether [26]. This method generally provided the alcohol in low yield, since there was a strong tendency for the racemic salt to separate, rather than the diastereoisomeric forms and numerous sequential recrystallizations were required to achieve enantiomeric excess of 95%. The procedure was subjected at slight modifications as it was repeated by several research groups and, although with some drawbacks, was used for the production of 12 kg of (R)-(´)-2-piperidineethanol [12]. Recently, the pushing necessity for a better resolving agent, brought about the development of two patents that utilized either N-sulphonyl pyroglutamic acid [27] or N-acetyl-L-leucine [28]: a single crystallization of the corresponding diastereoisomeric salt with 1, was enough to achieve high enantiomeric excess (86% and 95%, respectively) and higher with the second crystallization (99% and 98%, respectively).

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Int. J. Mol. Sci. 2016, 17, 0017 Enantiopure 2-Piperidineethanol by Enzymatic Kinetic Resolutions

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Enantiopure 2-Piperidineethanol by Enzymatic Kinetic Resolutions

Int. J. Mol. Sci.kinetic 2016, 17, 0017 3 of years 15 Enzymatic resolutions of racemates have been widely exploited in the past for Enzymatic kinetic resolutions of racemates have been widely exploited in the past years for the the preparation of enantiopure compounds [29–31]. Despite the breakthroughs achieved through Enantiopure 2-Piperidineethanol by Enzymatic Kinetic Resolutions Enantiopure 2-Piperidineethanol by Enzymatic Kinetic Resolutions preparation of enantiopure compounds [29–31]. Despite breakthroughs through mixture, the the ability of enzymes to selectively react with only one ofthe the enantiomersachieved from a racemic Enzymatic kinetic resolutions of have been widely exploitedin inthe the past years for Enzymatic kinetic resolutions ofracemates racemates have been widely exploited past years for thethe ability of enzymes to selectively react with only one of the enantiomers from a racemic mixture, therepreparation are only few examples reported for the resolution ofthe 1, each one related to the through reactivity enantiopure Despite breakthroughs achieved theat the preparation of enantiopure compounds [29–31]. Despite breakthroughs through the there are onlyoffew examples compounds reported for [29–31]. the resolution ofthe 1, each one relatedachieved to the reactivity at the hydroxyl group. It was a difficult task, due to the fact that the molecule is a conformationally flexible ability of group. enzymes totoselectively react with onethat of the the enantiomers enantiomers froma aracemic racemic mixture, ability of enzymes reactdue with only one of mixture, hydroxyl It was aselectively difficult task, to only the fact the molecule is afrom conformationally flexible and primary alcohol located two carbons from the molecule stereocenter. An early there areare only few examples for the resolution ofmolecule 1,each eachone one relatedtotothe the reactivity atreference the there only few examples reported foraway the resolution of 1, related reactivity at the and primary alcohol located reported two carbons away from the stereocenter. An early reference approached the resolution of several racemic piperidine derivatives [32] with either a stereocenter hydroxyl group. It was a difficult task, due to the fact that the molecule is a conformationally flexible hydroxyl group. It was a difficult task, due to the that the molecule is a conformationally flexible approached the resolution of several racemic piperidine derivatives [32] with either a stereocenter in in andand alcohol located two from the molecule molecule stereocenter. An early reference alcohol located twocarbons carbons away the stereocenter. early reference position 2primary orprimary 3, exploiting the hydrolysis of an ester group by esterase (EC 3.1.1.1). With11 two position 2 or 3, exploiting the hydrolysis ofaway an ester group bypig pigliver liver esteraseAn (EC 3.1.1.1). With approached the resolution of several racemic piperidine derivatives [32] with either a stereocenter in in approached the resolution of several racemic piperidine derivatives [32] with either a stereocenter strategies were tested 1) by the synthesis of esters 3 and 4: 4: two strategies were(Scheme tested (Scheme 1) by the synthesis of esters 3 and

position 2 or exploitingthe thehydrolysis hydrolysis of of an an ester group 3.1.1.1). With 1 1 position 2 or 3, 3, exploiting group by bypig pigliver liveresterase esterase(EC (EC 3.1.1.1). With strategies were tested(Scheme (Scheme1) 1)by bythe the synthesis synthesis of twotwo strategies were tested of esters esters33and and4:4:

Scheme 1. Synthesis of 2-piperidineethanol derivatives derivatives suitable forfor hydrolysis by pig liverliver esterase. Scheme 1. Synthesis of 2-piperidineethanol suitable hydrolysis by pig esterase. iPr:Scheme isopropyl. 1. Synthesis of 2-piperidineethanol derivatives suitable for hydrolysis by pig liver esterase. iPr: isopropyl. Scheme 1. Synthesis of 2-piperidineethanol derivatives suitable for hydrolysis by pig liver esterase. iPr: isopropyl.

iPr: isopropyl. subjected pig esterase liver esterase hydrolysis pH to the avoid the possibility of TheyThey werewere subjected to pigtoliver hydrolysis at pHat7.0 to 7.0 avoid possibility of competing Theychemical were subjected to pig liver esterase hydrolysis pH 7.0 avoid the possibility of competing hydrolysis or epimerization under theathigher pHtoconditions; reactions were chemical They hydrolysis or epimerization under the higher pH conditions; reactions were stopped were subjected to pigor liver esterase hydrolysis at pH pH 7.02 conditions; to avoid the possibility of after competing chemical hydrolysis epimerization under the were stopped after 50% conversion: results are reassumed in higher Scheme showing areactions generally low 50% conversion: results are reassumed in Scheme 2 showing a generally low enantioselectivity competing hydrolysis epimerization under the higher pH conditions; reactionslow were with stopped chemical after 50% conversion: results are (5). reassumed in Scheme 2 showing a generally enantioselectivity with up to 24%ore.e. for acid up tostopped 24% e.e.after for acid 50%(5). conversion: are (5). reassumed in Scheme 2 showing a generally low enantioselectivity with up to 24%results e.e. for acid enantioselectivity with up to 24% e.e. for acid (5).

Scheme 2. Enzymatic kinetic resolutions of racemic 3 and 4. PLE: pig liver esterase; e.e.: enantiomeric excess.

Scheme 2. Enzymatic kinetic resolutions of racemic 3 and 4. PLE: pig liver esterase; e.e.: enantiomeric excess. Scheme 2. Enzymatic kinetic resolutions of racemic 3 and 4. PLE: pig liver esterase; e.e.: enantiomeric excess. Scheme 2.1994, Enzymatic kinetic resolutions of racemic 3 and 4. PLE: pig liver esterase; e.e.: enantiomeric excess. a first example exploitation of the the porcine pancreas lipase (PPL) for the resolution of of In In 1994, a first example ofofexploitation of porcine pancreas lipase (PPL) for the resolution 9-fluorenylmethylcarbamate carbamate(N-Fmoc) (N-Fmoc) 2-piperidineethanol 2-piperidineethanol (7) was reported inina aJapanese patent 9-fluorenylmethyl (7) was reported Japanese patent In 1994, a first example of of exploitation of the porcine pancreaslipase lipase (PPL) for the resolution of In vinyl 1994, a firstwas example exploitation of the and porcine pancreas (PPL) for the resolution of [33]: acetate was usedas asthe theacylating acylatingagent agent and diisopropyl ether (Scheme 3) 3) (in(in thethe [33]: vinyl acetate used diisopropyl etherasassolvent solvent (Scheme 9-fluorenylmethyl carbamate (N-Fmoc) 2-piperidineethanol (7) was reported in a Japanese patent [33]: English abstract are notindicated indicated thee.e. e.e.2-piperidineethanol of both both the the enantioenriched and 9-fluorenylmethyl carbamate (N-Fmoc) (7) was88reported English abstract are not the of enantioenriched and7).7). in a Japanese patent vinyl[33]: acetate used theasacylating agent and diisopropyl assolvent solvent (Scheme 3)the (in the vinylwas acetate wasasused the acylating agent and diisopropyl ether ether as (Scheme 3) (in English abstract are are notnot indicated the enantioenriched 8 and English abstract indicated thee.e. e.e.ofofboth both the the enantioenriched 8 and 7). 7).

Scheme 3. Enzymatic kinetic resolutions of racemic 7. PPL: porcine pancreas lipase. Fmoc:

Scheme 3. Enzymatic kinetic resolutions of racemic 7. PPL: porcine pancreas lipase. Fmoc: 9-fluorenylmethyl carbamate. 9-fluorenylmethyl carbamate. Scheme 3. Enzymatic kinetic resolutions of racemic 7. PPL: porcine pancreas lipase. Fmoc: Scheme 3. Enzymatic kinetic resolutions of racemic 7. PPL: porcine pancreas lipase. Fmoc: 9-fluorenylmethyl carbamate.

9-fluorenylmethyl carbamate.

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Finally, a comprehensive study on the acylation of the residual Finally, inin2003, 2003, a comprehensive study onenantioselective the enantioselective acylation of the primary residual Int. J. Mol. Sci. 2016, 17, 0017 4 of 15 alcohol (Scheme 4) by lipases was successfully realized [34]. A first screening of over 20 different primary alcohol (Scheme 4) by lipases was successfully realized [34]. A first screening of over 20 ˝ lipase preparations was performed at 45 C; anatorganic (methyl tert-butyl ether) was selected different lipase preparations was performed 45 °C; solvent an organic solvent (methyl tert-butyl ether) Finally, in 2003, a comprehensive study on the enantioselective acylation of the residual as solvent asasit solvent is well-known that the enzymatic performances (activity (activity and selectivity) can be was selected as it is well-known that the enzymatic performances and selectivity) primary alcohol (Scheme 4) by lipases was successfully realized [34]. A first screening of over 20 enhanced greatly using organic solvents as a reaction medium, rather than their natural aqueous can be enhanced usingwas organic solvents reaction rathertert-butyl than their natural different lipasegreatly preparations performed at 45as°C;a an organicmedium, solvent (methyl ether) environments [35]; the protective groups of amino group tested were Boc, Cbz, and Fmoc. aqueous environments [35]; the protective groups of amino group tested were Boc, Cbz, and Fmoc. was selected as solvent as it is well-known that the enzymatic performances (activity and selectivity) can be enhanced greatly using organic solvents as a reaction medium, rather than their natural aqueous environments [35]; the protective groups of amino group tested were Boc, Cbz, and Fmoc.

Scheme 4. 4. Enzymatic Enzymatic enantioselective enantioselective acylation acylation of of racemic racemic 9. 9. Pg: Pg: protecting protecting group. group. Scheme Scheme 4. Enzymatic enantioselective acylation of racemic 9. Pg: protecting group.

This preliminary preliminaryscreening screeningunderlined underlined that reaction enantioselectivities were generally This that reaction enantioselectivities were generally quitequite low. low. The crude porcine pancreatic preparation possessed an opposite enantioselectivity compared to preliminary screening underlined that reaction enantioselectivities were generally quiteto all The crudeThis porcine pancreatic preparation possessed an opposite enantioselectivity compared low.other The crude porcine preparation possessed an opposite enantioselectivity compared to all other the lipases andpancreatic Lipase more enzyme selective enzyme the “(R)-lipases”. the lipases and Lipase PS wasPS the was morethe selective among the among “(R)-lipases”. Comparing all the other lipases and Lipase PS was the more selective enzyme among the “(R)-lipases”. Comparing the three protective groups, N-Boc derivative was a slightly better substrate. A the three protective groups, N-Boc derivative was a slightly better substrate. A new screening new was Comparing the three to protective groups, N-Boc derivative was asolvents slightly better substrate. A of new screening directed out the effect of for different for the reaction N-Boc directed towas pointing out the pointing effect of different solvents the reaction of N-Boc derivative catalyzed screening was directed to pointing out the effect of different solvents for the reaction of N-Boc derivative catalyzed Lipasewas PS and PPL: hexane was a for slightly better while solvent for the former while by Lipase PS and PPL:byhexane a slightly better solvent the former methyl tert-butyl ether derivative catalyzed by Lipase PS and PPL: hexane was a slightly better solvent for the former while methyl tert-butyl ether remained the solvent of choice for the latter. remained the solventether of choice for the methyl tert-butyl remained the latter. solvent of choice for the latter. Finally, an optimized protocol was designed based onon onthe theobserved observed complementary Finally, an optimized protocol based the observed complementary Finally, an optimized protocol was was designed designed based complementary enantioselectivity of the two enzymes (Scheme 5). The racemic mixture 9 was acetylated under the enantioselectivity of the two (Scheme5).5).TheThe racemic mixture was acetylated under enantioselectivity of the twoenzymes enzymes (Scheme racemic mixture 9 was9acetylated under the best condition for Lipase PS; after that enzyme is filtered and reagent removed, the crude mixture bestcondition condition for for Lipase Lipase PS; and reagent removed, the crude mixture the best PS; after afterthat thatenzyme enzymeis isfiltered filtered and reagent removed, the crude mixture was butanoylated butanoylated the PPL the best for thisenzyme. enzyme. In way, the low was butanoylated by the PPLunder under the condition best condition condition for this Inway, thisthis way, theselectivity low was byby the PPL under the best for this enzyme. In this the low of the two lipases was enhanced. The final mixture, composed by by enantioenriched acetate selectivity the two lipases was enhanced. final mixture, composed enantioenriched acetate of theselectivity two of lipases was enhanced. The finalThe mixture, composed by enantioenriched acetate (R)-10, (R)-10, butanoate (S)-11 and the unreacted almost racemic 9, was easily purified by flash (R)-10, butanoate (S)-11 and the unreacted almost racemic 9, was easily purified by flash butanoate (S)-11 and the unreacted almost racemic 9, was easily purified by flash chromatography. chromatography. Hydrolysis of the two esters was followed by a second step of acetylation on the chromatography. Hydrolysis of the two esters was followed by a secondonstep acetylation on the Hydrolysis of the two esters was followed by a second step of acetylation the of two enantioenriched two enantioenriched alcohols by the two lipases; after hydrolysis, both alcohols with high e.e. were two enantioenriched alcohols by the two lipases; after hydrolysis, both alcohols with high e.e. were alcohols by the two lipases; after hydrolysis, both alcohols with high e.e. were obtained. obtained. obtained.

Scheme 5. Optimized protocol. (a) AcOCH=CH2, hexane, 20 °C, 190 min (45%); (b) PrCOOCH=CH2,

Scheme 5. Optimized protocol. (a) AcOCH=CH2 , hexane, 20 ˝ C, 190 min (45%); (b) PrCOOCH=CH2 , MTBE, 20 °C, 11.5 h (30%), flash chromatography (AcOEt-hexane 1:9); (c) CH3OH, Na2CO3; and (d) MTBE, 20 ˝ C, 11.5 h (30%), flash chromatography (AcOEt-hexane 1:9); (c) CH3 OH, Na2 CO3 ; and 46 h (48%). PPL: porcine pancreas lipase; PS: Lipase PS; Pr: propyl; Ac: AcOCH=CH2, MTBE, 20 °C, (d) AcOCH=CH 20 ˝ C,(a) 46 AcOCH=CH h (48%). PPL: porcine 20 pancreas PS: Lipase PS; Pr: propyl; 2 , MTBE, Scheme 5. Optimized protocol. 2, hexane, °C, 190lipase; min (45%); (b) PrCOOCH=CH 2, acetyl; Boc: tert-butyl carbamate. Ac: acetyl; Boc:11.5 tert-butyl carbamate. MTBE, 20 °C, h (30%), flash chromatography (AcOEt-hexane 1:9); (c) CH3OH, Na2CO3; and (d)

AcOCH=CH2, MTBE, 20 °C, 46 h (48%). PPL: porcine pancreas lipase; PS: Lipase PS; Pr: propyl; Ac: acetyl; Boc: tert-butyl carbamate.

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3. An Overview of the Synthetic Strategies in the Synthesis of Alkaloids Starting from Either Enantiopure 1 or 2 Int. J. Mol. Sci. 2016, 17, 0017 5 of 15

3. An Overview of the Synthetic Strategies in the Synthesis of Alkaloids Starting from Either Enantiopure 1 or 2 of suitable methods for accessing both enantiomers of 1 opened the path to the The development 3. An Overview of the Synthetic Strategies in the Synthesis of Alkaloids Starting from Either total synthesis of a wide range of natural compounds withboth highenantiomers interest in of medicinal The development of suitable methods for accessing 1 openedchemistry; the path toin an Enantiopure 1 or 2 early the stage, some of these syntheses were performed starting with racemic 1. total synthesis of a wide range of natural compounds with high interest in medicinal chemistry; The development suitable methods for performed accessing enantiomers of 1 1. opened path to in an early stage, some of of these starting with racemic As previously mentioned, 2 issyntheses the mainwere derivative ofboth 2-piperidineethanol used inthe total synthesis the total synthesis of a wide range of natural compounds with high interest in medicinal chemistry; previously center mentioned, 2 isC-2 theposition main derivative 2-piperidineethanol used in total synthesis where theAs stereogenic at the would of readily encode the remaining stereochemical in an early stage, somecenter of these syntheses were performed starting withthe racemic 1. stereochemical where the stereogenic at the C-2 position would readily encode remaining information into the final target. It is usually synthesized by Swern oxidation, but some troubles As previously mentioned, 2 isItthe main derivative of 2-piperidineethanol usedbut in total synthesis information intoofthe target. is the usually Swern oxidation, some troublesat the affectwhere the recovery thefinal product and scalesynthesized up of readily the by reaction. Anremaining enzymatic approach the stereogenic center at the C-2 position would encode the stereochemical affect the recovery of the product and the scale up of the reaction. An enzymatic approach at the oxidation reaction (R)-9 realized by exploiting laccases [36],oxidation, either from pubescens information intoofthe finalwas target. It is usually synthesized by[36], Swern but Trametes some troubles oxidation reaction of (R)-9 was realized by exploiting laccases either from Trametes pubescens or or from Myceliophtora TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) as a mediator, affect the recovery termophyla, of the product and the scale up of the reaction. An enzymatic the and from Myceliophtora termophyla, TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) as aapproach mediator,at and oxidation reaction of the (R)-9 realized byoxidant exploiting laccases [36], either from Trametes pubescens or molecular oxygen of the air air aswas thethe primary 6). molecular oxygen of as primary oxidant (Scheme (Scheme 6). from Myceliophtora termophyla, TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) as a mediator, and molecular oxygen of the air as the primary oxidant (Scheme 6).

Scheme 6. Oxidation reaction mediated by laccase. TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy.

Scheme 6. Oxidation reaction mediated by laccase. TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy. Scheme 6. Oxidation reaction laccase. TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy. 3.1. Enantioselective Synthesis of themediated Alkaloid by (+)-Aloperine

3.1. Enantioselective Synthesis of the Alkaloid (+)-Aloperine

Aloperine (12)Synthesis (Scheme of 7)the is aAlkaloid member of a small family of C15 alkaloids that is extracted from 3.1. Enantioselective (+)-Aloperine

Aloperine (12) (Scheme 7) isalopecuroides, a membera of a small family of C15and alkaloids thatlater is extracted the seeds and leaves of Sophora shrub that grows in China Russia, and from Aloperine (12) (Scheme 7) is a member of a small family of C 15 alkaloids that is extracted from and from Leptorhabdos the seeds and leavesBenth. of Sophora alopecuroides, a activity shrub that growsbetween in Chinacardiovascular, and Russia, parviflor Its pharmacological spreads seeds and leavesparviflor of Sophora alopecuroides, a shrub that grows China and Russia, andcardiovascular, later later the from Leptorhabdos Benth. Itsfeatures pharmacological activity spreads between anti-inflammatory, and anti-allergic producing an in intense synthetic interest in from this Leptorhabdos parviflor Benth. Its pharmacological activity spreads between cardiovascular, molecule. In 2002, a synthesis of racemic 12 was realized an [37]; the synthetic strategy (Scheme 7) relied anti-inflammatory, and anti-allergic features producing intense synthetic interest in this molecule. anti-inflammatory, and anti-allergic features producing an step intense synthetic interest ina this on an efficient intermolecular reaction crucial where derivative 15 7) was keyon an In 2002, a synthesis of racemic 12Diels-Alder was realized [37];asthe synthetic strategy (Scheme relied molecule. In 2002, a synthesis of racemic 12 was realized [37]; the synthetic strategy (Scheme 7) relied building block for theDiels-Alder synthesis of the N-acylaminodiene 14. where derivative 15 was a key building efficient intermolecular reaction as crucial step on an efficient intermolecular Diels-Alder reaction as crucial step where derivative 15 was a key blockbuilding for the synthesis of synthesis the N-acylaminodiene 14. block for the of the N-acylaminodiene 14.

Scheme 7. Retrosynthetic analysis of the synthesis of aloperine. Scheme Retrosynthetic analysis of synthesis ofof aloperine. In 2004, the corresponding enantioselective variant [36] was performed starting from (R)-9 for Scheme 7. 7. Retrosynthetic analysis ofthe the synthesis aloperine. the synthesis of (R)-17 (Scheme 8); two consecutive enzymatic oxidations mediated by laccase were Inboth 2004, thesynthesis corresponding enantioselective variant [36]was wasperformed performed starting starting from set2004, for of aldehyde (R)-2 andvariant ketone (R)-17. In thethe corresponding enantioselective [36] from(R)-9 (R)-9for for the the synthesis of (R)-17 (Scheme 8); two consecutive enzymatic oxidations mediated by laccase were synthesis of (R)-17 (Scheme 8); two consecutive enzymatic oxidations mediated by laccase were set for set for both the synthesis of aldehyde (R)-2 and ketone (R)-17.

both the synthesis of aldehyde (R)-2 and ketone (R)-17.

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Scheme fluoride. TMS: TMS: trimethylsilyl. trimethylsilyl. Scheme8.8.Synthesis Synthesisof ofintermediate intermediate(R)-17. (R)-17. TBAF: TBAF: tetrabutylammonium tetrabutylammonium fluoride. Scheme 8. Synthesis of intermediate (R)-17. TBAF: tetrabutylammonium fluoride. TMS: trimethylsilyl.

3.2. 3.2. Enantioselective Enantioselective Synthesis Synthesis of of the the Alkaloid Alkaloid Boehmeriasin Boehmeriasin A A 3.2. Enantioselective Synthesis of the Alkaloid Boehmeriasin A

Boehmeriasin is aa phenanthroquinolizidine phenanthroquinolizidine alkaloid alkaloid extracted extracted from from Boehmeria Boehmeria siamensis siamensis Boehmeriasin A A (22) (22) is Boehmeriasin A (22)cytotoxic is a phenanthroquinolizidine alkaloid extracted from Boehmeria siamensis Craib. It possesses a strong activity, more potent than taxol, against 12 cell lines from six Craib. It possesses a strong cytotoxic activity, more potent than taxol, against 12 cell lines from six panels Craib. It possesses a strong cytotoxic activity, more potent than taxol, against 12 cell lines from six panels cancer including breast, kidney, prostate, colon, cancer, and leukemia, with of cancerofincluding breast, kidney, prostate, colon, lung cancer, andlung leukemia, with topoisomerases and panels of cancer including breast, kidney, prostate, colon, lung cancer, and leukemia, with topoisomerases and SIRT2 as involved targets. Recently, the synthesis of enantiopure 22 [38] was SIRT2topoisomerases as involved targets. Recently, the synthesis of enantiopure 22 [38] was accomplished starting and SIRT2 as involved targets. Recently, the synthesis of enantiopure 22 [38] was accomplished from aldehyde (S)-2 (Scheme 9). from aldehydestarting (S)-2 (Scheme 9). accomplished starting from aldehyde (S)-2 (Scheme 9).

Scheme 9. Synthesis of the alkaloid boehmeriasin A. (a) (4-methoxyphenyl)magnesium bromide; (b)

Scheme 9. Synthesis of the alkaloid boehmeriasin A. (a) (4-methoxyphenyl)magnesium bromide; DMP; (c) TMSCl, MeOH; (d) 2-bromo-4,5-dimethoxyphenylacetic acid, DIPEA, 1-(Bis(dimethylamino) (b) DMP;9.(c)Synthesis TMSCl, MeOH; (d) 2-bromo-4,5-dimethoxyphenylacetic acid, DIPEA, 1-(Bis(dimethylamino) Scheme of the alkaloid boehmeriasin A. hexafluorophosphate (a) (4-methoxyphenyl)magnesium bromide; methylene)-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxid (HATU); (e) KOH, EtOH; (b) methylene)-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxid hexafluorophosphate (HATU); (e) KOH, EtOH; DMP; (c) TMSCl, MeOH; (d) 2-bromo-4,5-dimethoxyphenylacetic acid, DIPEA, 1-(Bis(dimethylamino) (f) Pd(OAc)2, K2CO3, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)-2-amine; and (g) LiAlH4. 1 -(diphenylphosphino)-N,N1 -dimethyl-(1,11 -biphenyl)-2-amine; and (g) LiAlH . (f) Pd(OAc) , K CO , 2 2 2 3 4 methylene)-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxid hexafluorophosphate (HATU); (e) KOH, EtOH;

The synthetic begins with the Grignard addition to the enantiopure and aldehyde (S)-2 2, K2CO3sequence , 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)-2-amine; (g) LiAlH 4. (f) Pd(OAc) The synthetic sequence begins with the Grignard addition to the enantiopure aldehyde followed by oxidation with DMP (Dess-Martin periodinane), deprotection of the Boc group, N-acylation (S)-2 followed by oxidation with DMP (Dess-Martin periodinane), deprotection the Boc group, N-acylation of the amine, intramolecular aldol-type condensation, and palladium-catalyzed intramolecular The synthetic sequence begins with the Grignard addition to the of enantiopure aldehyde (S)-2 of the amine, intramolecular condensation, palladium-catalyzed intramolecular coupling and reduction of thealdol-type amide. followed by oxidation with DMP (Dess-Martin periodinane),and deprotection of the Boc group, N-acylation Recently, a quite of similar synthetic strategy [39] was used for the synthesis of sulfonamide analogues coupling and reduction the amide. of the amine, intramolecular aldol-type condensation, and palladium-catalyzed intramolecular of 22 as potent and orally active antitumor agents. [39] was used for the synthesis of sulfonamide Recently, a quite similar synthetic strategy

coupling and reduction of the amide. analogues of 22 as potent and orally active antitumor Recently, a quite similar synthetic strategy [39] wasagents. used for the synthesis of sulfonamide analogues of 22 as potent and orally active antitumor agents.

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Int. J. Mol. Sci. 2016, 17, 0017 3.3. Enantioselective Synthesis of the Alkaloid Dumetorine

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3.3. Enantioselective of the Alkaloid Dumetorine Dumetorine (28) Synthesis is an alkaloid with piperidine structural unit that is extracted from the tubers of Dioscorea dumetorum Pax and usedstructural in folk unit medicine and arrow Dumetorine (28) is an alkaloid with piperidine that is extracted frompoisons. the tubers The enantioselective few keyand synthetic steps (Scheme 10) starting from of Dioscorea synthesis dumetorum [40] Pax was and established used in folk on medicine arrow poisons. The enantioselective synthesis [40] was established on few key synthetic stepswas (Scheme 10) starting from the enantiopure the enantiopure aldehyde (S)-2. The second stereocenter achieved by an asymmetric allylboration aldehyde (S)-2. The second stereocenter was achieved by an asymmetric allylboration reaction with 23 reaction with β-allyl-diisopinocamphenylborane, obtaining exclusively the required compound β-allyl-diisopinocamphenylborane, obtaining exclusively the required compound 23 ring (diastereoisomeric excess (de) > 95%). After acylation with acryloyl chloride, the dihydropyran (diastereoisomeric excess (de) > 95%). After acylation with acryloyl chloride, the dihydropyran ring was synthesized by ring-closing metathesis reaction with the second generation Grubbs catalyst. was synthesized by ring-closing metathesis reaction with the second generation Grubbs catalyst. Unfortunately, the removal of the Boc group with TFA (trifluoroacetic acid) involved the formation of Unfortunately, the removal of the Boc group with TFA (trifluoroacetic acid) involved the formation the byproduct 26, as the main component of the reaction mixture, and the desired free amine 27 in of the byproduct 26, as the main component of the reaction mixture, and the desired free amine 27 in smallsmall amounts (10%). Finally, N-methylation outby byreductive reductive amination amounts (10%). Finally, N-methylationwas was carried carried out amination withwith CH2CH O in2 O in the presence of NaBH to to give the (+)-28. 3 CN the presence of NaBH 3CN give thetarget targetnatural natural (+)-28.

Scheme 10. Enantioselective synthesis of the alkaloid dumetorine. (a) CH2=CHCH3CH2MgBr,

Scheme 10. Enantioselective synthesis of the alkaloid dumetorine. (a) CH2 =CHCH3 CH2 MgBr, (+)-β-methoxydiisopinocamphenylborane; (b) CH2=CHCOCl; (c) Grubb’s II catalyst; (d) TFA (+)-β-methoxydiisopinocamphenylborane; (b) CH2 =CHCOCl; (c) Grubb’s II catalyst; (d) TFA (trifluoroacetic acid); and (e) CH2O, NaBH3CN. (trifluoroacetic acid); and (e) CH2 O, NaBH3 CN.

Recently, for the improvement of the synthesis, a sequence of five separate synthetic steps, was

Recently, the improvement of thewith synthesis, a sequence of five separate performed for by flow chemistry technology the advantages of minimal workup and synthetic purificationsteps, was [41]. performed flow containing chemistryappropriate technology with the reagents advantages of minimal workup Packed by columns immobilized or scavenger materials were and purification [41].starting Packedcompound columns containing appropriatealcohol immobilized reagents or scavenger used. The was the enantiopure (S)-9 that was converted intomaterials the were corresponding used. The starting compound enantiopure alcoholthe (S)-9 that stream was converted aldehyde (S)-2 was by the continuously cycling flow through into a the polymer-supported 2-iodoxybenzamide pre-packed column. In the second step, the insertion of the corresponding aldehyde (S)-2 by continuously cycling the flow stream through a polymer-supported allyl group was pre-packed realized by reaction thesecond Grignard reagent 2-methyl-allylmagnesium 2-iodoxybenzamide column.with In the step, the insertion of the allyl groupbromide; was realized the two diastereoisomers, formed almost in 1:1 ratio, were purified on a silica gel cartridge to give by reaction with the Grignard reagent 2-methyl-allylmagnesium bromide; the two diastereoisomers, the desired diastereoisomer 23. After acylation with acryloyl chloride, the ring-closing metathesis formed almost in 1:1 ratio, were purified on a silica gel cartridge to give the desired diastereoisomer reaction was realized by a new PEG (polyethylene glycol)-supported Hoveyda catalyst working in 23. After acylation with acryloyl chloride, the ring-closing metathesis reaction was realized by a homogeneous conditions ensured by the solubility of the catalyst in CH2Cl2, maintaining the new PEG (polyethylene glycol)-supported Hoveyda catalyst workingand in homogeneous conditions possibility of simple catalyst recovery by solvent-promoted precipitation filtration. The inherent ensured by the solubility of the catalyst in CH Cl , maintaining the possibility of simple catalyst 2 2 instability of amine 27 was the main drawback of the early synthetic sequence (Scheme 10) since recovery by solvent-promoted precipitation and filtration. The inherent instability of amine 27 Michael addition of the secondary amine to the α,β-unsaturated lactone ring caused the formationwas of the byproduct 26 and reduced the yield of finalMichael reductive amination (39%). A mainthe drawback of the earlysignificantly synthetic sequence (Scheme 10)the since addition of the secondary breakthrough was established by converting directly Boc protected 25 in 26 final product 28 aminedefinitive to the α,β-unsaturated lactone ring caused the formation of the byproduct and significantly through an Eschweiler–Clarke reaction with formaldehyde in the presence of formic acid at high by reduced the yield of the final reductive amination (39%). A definitive breakthrough was established temperature: flash heating with a rapid warming to 140 °C gave a clean product with a yield of 92%. with converting directly Boc protected 25 in final product 28 through an Eschweiler–Clarke reaction formaldehyde in the presence of formic acid at high temperature: flash heating with a rapid warming to 140 ˝ C gave a clean product with a yield of 92%.

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3.4.structure Enantioselective Synthesis of the Alkaloids Sedamine, Allosedamine, Sedridines andofEthylnorlobelols The of several alkaloids are easily recognized as derivatives the reaction of 2 with The structure of reagent. severalofalkaloids are easily recognized as derivatives of and the Ethylnorlobelols reaction of 2 with an appropriate Grignard Indeed, starting from the enantiopure (S)-2, two diastereoisomeric 3.4. Enantioselective Synthesis the Alkaloids Sedamine, Allosedamine, Sedridines an appropriate Grignard reagent. Indeed, starting from the enantiopure (S)-2, two diastereoisomeric alcohols 29 and 30 were (Scheme 11). Their Boc groups were easily methyl The structure of generated several alkaloids are easily recognized as derivatives of theconverted reaction ofinto 2 with alcohols 29 and 30with wereLiAlH generated (Scheme 11). Their Boc groups were easily converted into methyl groups by reduction [34] affording, for R = Ph, respectively, (´)-sedamine (31) 4 an appropriate Grignard reagent. Indeed, starting from the enantiopure (S)-2, two diastereoisomeric and groups by reduction with LiAlH4 [34] affording, for R = Ph, respectively, (−)-sedamine (31) and (´)-allosedamine (32); alternatively, was synthesized from 29, were through flow chemistry technology, alcohols 29 and 30(32); were generated31 (Scheme 11). Their Boc groups easily converted into methyl (−)-allosedamine alternatively, 31 was synthesized from 29, through flow chemistry technology, reduction with LiAlH 4 [34] affording, forEschweiler–Clarke R = Ph, respectively, (−)-sedamine by thegroups protocol developed for for thethe previously Eschweiler–Clarke reaction by the by protocol developed previouslyoutlined outlined reaction [41].[41]. (31) and

(−)-allosedamine (32); alternatively, 31 was synthesized from 29, through flow chemistry technology, by the protocol developed for the previously outlined Eschweiler–Clarke reaction [41].

Scheme 11. Enantioselective synthesis of the alkaloids sedamine, allosedamine, sedridines, and ethylnorlobelols.

Scheme 11. Enantioselective synthesis of the alkaloids sedamine, allosedamine, sedridines, and ethylnorlobelols. On the other hand, removing the Boc group from 29 and 30 afforded respectively Scheme 11. Enantioselective of the alkaloids sedridines, and ethylnorlobelols. (−)-allosedridine (33) andsynthesis (+)-sedridine (34), sedamine, for R = allosedamine, Me, (−)-2′-epi-ethylnorlobelol (35) and On the other hand, (36), removing Boc group from 29 and 30 afforded respectively (´)-allosedridine (+)-ethylnorlobelol for R =the Et [42]. On the other(34), hand, the1 -epi-ethylnorlobelol Boc group from 29(35) and afforded respectively (33) and (+)-sedridine for Rremoving = Me, (´)-2 and30(+)-ethylnorlobelol (36), for (−)-allosedridine (33) and (+)-sedridine (34), for R = Me, (−)-2′-epi-ethylnorlobelol (35) and R = Et 3.5. [42].Synthesis of the Enantiopure Alkaloids Coniine and Epidihydropinidine (+)-ethylnorlobelol (36), for R = Et [42]. Coniine (38) is the major alkaloid extracted from Conium maculatum (poison hemlock) and 3.5. Synthesis of the Enantiopure Alkaloids Coniine and Epidihydropinidine responsible for its toxicity. It was synthesized from the enantiopure (S)-2 (Scheme 12) by elongating 3.5. Synthesis of the Enantiopure Alkaloids Coniine and Epidihydropinidine the chain at the 2-position the piperidine ring through a Wittigmaculatum reaction, hydrogenation of the and Coniine (38) is the majorofalkaloid extracted from Conium (poison hemlock) Coniine (38) the major alkaloid extracted double bound andisremoval of the Boc group [42]. from Conium maculatum (poison hemlock) and responsible for its toxicity. It was synthesized from the enantiopure (S)-2 (Scheme 12) by elongating the responsible for its toxicity. It was synthesized from the enantiopure (S)-2 (Scheme 12) by elongating chain at the 2-position of the piperidine ring through a Wittig reaction, hydrogenation of the double the chain at the 2-position of the piperidine ring through a Wittig reaction, hydrogenation of the bound and removal of removal the Boc of group [42]. double bound and the Boc group [42].

Scheme 12. Synthesis of the alkaloid (−)-coniine.

Scheme 12. Synthesis of the alkaloid (−)-coniine.

Scheme 12. Synthesis of the alkaloid (´)-coniine.

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Closely related to coniine is the alkaloid epidihydropinidine (43) that shared the same synthetic Closely related to is alkaloid epidihydropinidine (43) that the same synthetic related to coniine coniine is the the alkaloid epidihydropinidine that shared shared same stepsClosely for the building of the propyl group [40]. The key (43) synthetic step the was thesynthetic Beak’s steps for the building of the propyl group [40]. The key synthetic step was the Beak’s N-Boc-piperidine steps for the building of the propylmethodology group [40]. for The synthetic ofstep was thegroup Beak’s N-Boc-piperidine α-lithiation/alkylation thekey introduction the methyl at α-lithiation/alkylation methodology for methodology the introduction of the methyl group at the C-6 position; N-Boc-piperidine α-lithiation/alkylation for the introduction of the methyl group at the C-6 position; TBDMS protection of the hydroxyl group of (R)-9 was important in order to keep TBDMS protection of the hydroxyl group of (R)-9 was important in order to keep the C-2 chain at the C-2 C-6 chain position; of the hydroxyl group 13). of (R)-9 importantand in order to keep the at a TBDMS distanceprotection from the reactive center (Scheme Afterwas deprotection Dess–Martin athe distance from the reactivefrom center (Scheme 13). After deprotection and Dess–Martin oxidation to C-2 chain at a distance the reactive center (Scheme 13). After deprotection and Dess–Martin oxidation to aldehyde 42, the synthesis proceeded alike Scheme 12. aldehyde the synthesis proceeded alike Schemealike 12. Scheme 12. oxidation 42, to aldehyde 42, the synthesis proceeded

Scheme 13. Enantioselective synthesis of the alkaloid (−)-epidihydropinidine. (a) imidazole, Scheme 13. 13. Enantioselective of the N,N,N′,N′-Tetramethylethylenediamine alkaloid (´)-epidihydropinidine. (−)-epidihydropinidine. (a) (a) imidazole, imidazole, Scheme Enantioselective synthesis of (b) the alkaloid tert-butyldimethylsilyl chloride synthesis (TBDMSCl); (TMEDA), tert-butyldimethylsilyl chloride (TBDMSCl); (b) N,N,N′,N′-Tetramethylethylenediamine (TMEDA), 1 1 tert-butyldimethylsilyl chloride (b) N,N,N -Tetramethylethylenediamine (TMEDA), 4; (c)(TBDMSCl); Na2CO3, MeOH; and (d),N Dess-Martin reagent. sec-BuLi, Et2O, −78 °C, MeSO ˝ C,MeSO −78 °C, 4; (c) Na2CO3, MeOH; and (d) Dess-Martin reagent. sec-BuLi, Et Et2O, sec-BuLi, O, ´78 MeSO ; (c) Na CO , MeOH; and (d) Dess-Martin reagent. 2 4 2 3

3.6. Enantioselective Synthesis of Polycyclic Piperidine Derivatives 3.6. Enantioselective Enantioselective Synthesis Synthesis of of Polycyclic Polycyclic Piperidine Piperidine Derivatives Derivatives 3.6. The changeover of the aldehyde group of 2 into the carbon–carbon double bond of 37 allowed a The changeover of exploiting the group bond The of the aldehyde aldehyde group of of 22 into into the the carbon–carbon double bond of3737allowed alloweda switch ofchangeover reactivity by reactions affecting thecarbon–carbon alkene group double [43] such as of intramolecular switch of reactivity by exploiting reactions affecting the alkene group [43] such as intramolecular aHeck switchreactions, of reactivity by exploiting reactions affecting alkene group [43] such 1,3-dipolar cycloadditions, ring the closing metathesis andas intramolecular intramolecular Heck reactions, 1,3-dipolar cycloadditions, ring closing metathesis and intramolecular Heck reactions, 1,3-dipolar cycloadditions, ring closing metathesis and intramolecular chloroamination chloroamination reactions, reaching an increased molecular complexity. Indeed, bicyclic derivative chloroamination reactions, reaching an increased molecular complexity. Indeed, bicyclic derivative reactions, reaching increased molecular complexity. Indeed, bicyclic derivative 45 was by 45 was obtained byanreaction of urea 44 using Pd(CH3CN) 2Cl2 as a catalyst and CuCl 2 asobtained an oxidant 45 was obtained by reaction of urea 44 using Pd(CH 3 CN) 2 Cl 2 as a catalyst and CuCl 2 as an oxidant reaction of urea 44 using Pd(CH CN) Cl as a catalyst and CuCl as an oxidant (Scheme 14). 3 2 2 2 (Scheme 14). (Scheme 14).

Scheme 14. 14. Enantioselective synthesis of of bicyclic bicyclic derivative derivative 45. 45. Scheme Enantioselective synthesis Scheme 14. Enantioselective synthesis of bicyclic derivative 45.

Combining more morereactions reactionstogether together in order to modifying the carbon–carbon bond Combining in order to modifying the carbon–carbon doubledouble bond before Combining more reactions together in order to modifying the carbon–carbon double bond before the 1,3-dipolar cycloaddition, allowed the stereoselective synthesis of fused tricyclic derivatives the 1,3-dipolar cycloaddition, allowed the stereoselective synthesis of fused tricyclic derivatives with before the 1,3-dipolar cycloaddition, allowed the stereoselective synthesis of fused tricyclic derivatives with up to three stereogenic centers. Then, aryl derivative 46 was subjected to an intramolecular up to three stereogenic centers. Then, aryl derivative 46 was subjected to an intramolecular Heck with up to three stereogenic centers.the Then, arylalkene derivative 46 was 1,3-dipolar subjected tocycloaddition, an intramolecular Heck reaction (Scheme 15) obtaining bicyclic 47 that, reaction (Scheme 15) obtaining the bicyclic alkene 47 that, afterafter 1,3-dipolar cycloaddition, gavegave the Heck reaction (Scheme 15) obtaining the bicyclic alkene 47 that, after 1,3-dipolar cycloaddition, gave the tricyclic spiro derivative as mixture of two diastereoisomers. tricyclic spiro derivative 48 as48mixture of two diastereoisomers. the tricyclic spiro derivative 48 as mixture of two diastereoisomers.

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Scheme ofderivative derivative Scheme15. 15.Synthesis Synthesis of 48.48. Scheme 15. Synthesis of derivative 48. Scheme 15. Synthesis of derivative 48.

Likewise, derivative was subjectedto toring-closing ring-closing metathesis (Scheme 16) 16) by aby Grubbs catalyst Likewise, derivative 49 49 was subjected metathesis (Scheme a Grubbs catalyst Likewise, derivative 49 was subjected to ring-closing metathesis (Scheme 16) by a Grubbs catalyst of second generation obtaining the bicyclicto unsaturated 5050 that after 1,3-dipolar cycloaddition Likewise, derivative 49 was subjected ring-closingamide metathesis (Scheme 16) by a Grubbs catalyst of second generation obtaining the bicyclic unsaturated amide that after 1,3-dipolar cycloaddition of second generation obtaining the bicyclic unsaturated amide5050that that after 1,3-dipolar cycloaddition gave the tricyclic derivative single diastereoisomer. second generation obtaining the bicyclic unsaturated amide after 1,3-dipolar cycloaddition gaveof the tricyclic derivative 5151 asas single diastereoisomer. gave gave the tricyclic derivative 51 as single diastereoisomer. the tricyclic derivative 51 as single diastereoisomer.

Scheme 16. Synthesis of derivative 51. Scheme16. 16.Synthesis Synthesis of 51.51. Scheme ofderivative derivative

Scheme 16. Synthesis of derivative 51. 4. A General Overview of the Structures of Alkaloids Synthesized from both 1 or 2 4. A General Overview of the Structures of Alkaloids Synthesized from both 1 or 2 Further examplesof ofthe natural compounds synthesized starting fromfrom bothboth enantiopure 4. A Overview Structures of Synthesized 11 or 4. AGeneral General Overview of the Structures of Alkaloids Alkaloids Synthesized from both or 22 1 or 2 are shortly exemplified in this subsection; the substructure derived from 1 isboth pointed out in red. Further examples of natural compounds synthesized starting from enantiopure 1 or 2 are Further starting from both out in red. 1 or 2 are Further examples in of this natural compounds synthesized shortly exemplified subsection; the substructure derived from 1 is pointed enantiopure shortly exemplified in this this subsection; subsection; the substructure substructure derived from11isisand pointed outin inred. red. shortly in the derived from pointed out 4.1.exemplified Enantioselective Synthesis of the Alkaloids (−)-Oncinotine, (−)-Isooncinotine, (−)-Stellettamide B 4.1. Enantioselective Synthesis of the Alkaloids (−)-Oncinotine, (−)-Isooncinotine, and (−)-Stellettamide B (−)-Oncinotine (52) and (−)-isooncinotine (53) (Figure 2) are a group of isomeric polyamine 4.1. (´)-Isooncinotine,and and(−)-Stellettamide (´)-StellettamideBB 4.1. Enantioselective Synthesis of the the Alkaloids Alkaloids (´)-Oncinotine, (−)-Oncinotine, (−)-Isooncinotine, alkaloids which are characterized by macrocyclic lactams containing biogenetic base spermidine; (−)-Oncinotine (52) and (−)-isooncinotine (53) (Figure 2) are athe group of isomeric polyamine (´)-Oncinotine (52) and (´)-isooncinotine (53) (Figure 2) are arethe isomeric polyamine they are isolated from the stem bark of Oncinotis nitida (Apocynaceae). 52 was of synthesized in 1996 alkaloids which are characterized by macrocyclic lactams containing biogenetic base spermidine; (−)-Oncinotine (52) and (−)-isooncinotine (53) (Figure 2) a group isomeric polyamine [19] starting from N-Cbz 2 instead. 53 was synthesized in 2007 [44] from 1. Stellettamide B (54) they are isolated from the stem bark of Oncinotis nitida (Apocynaceae). 52 was synthesized in 1996 alkaloids which are characterized by macrocyclic lactams containing the biogenetic base spermidine; alkaloids (Figure 2) is extracted from a marine sponge of the genus Stelletta and showed antifungal and [19] starting from N-Cbz 2 instead. 53 was synthesized in 2007 [44] from 1. Stellettamide B (54) they bark of of Oncinotis nitida (Apocynaceae). 52 was synthesized in 1996 [19] they are areisolated isolatedfrom fromthe thestem stem bark Oncinotis nitida (Apocynaceae). 52 was synthesized in 1996 cytotoxic activity; itinstead. wasfrom synthesized in 2001 [20]of from 1.genus (Figure 2)N-Cbz is extracted awas marine sponge the Stelletta and showed antifungal and 2) is starting from 2 53 synthesized in 2007 [44] from 1. Stellettamide B (54) (Figure [19] starting from N-Cbz 2 instead. 53 was synthesized in 2007 [44] from 1. Stellettamide B (54) cytotoxic activity; it was synthesized in 2001 [20] from 1.

extracted a marinefrom sponge of the genus Stelletta showed antifungal and cytotoxic activity; (Figure 2)from is extracted a marine sponge of theand genus Stelletta and showed antifungal and it was synthesized 2001synthesized [20] from 1.in 2001 [20] from 1. cytotoxic activity; itinwas

Figure 2. Structures of the alkaloids (−)-oncinotine, (−)-isooncinotine, and (−)-stellettamide B. Figure 2. Structures of the alkaloids (−)-oncinotine, (−)-isooncinotine, and (−)-stellettamide B.

Figure2.2.Structures Structuresofofthe thealkaloids alkaloids(´)-oncinotine, (−)-oncinotine,(´)-isooncinotine, (−)-isooncinotine, and (−)-stellettamide B. Figure and (´)-stellettamide B.

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The azabicyclic of quinolizidine is a relevant structural subunit present in 11 numerous Int. J. Mol. Sci. 2016, 17,skeleton 0017 of 15 4.2. Enantioselective Alkaloids (+)-Vertine and (+)-Lythrine The azabicyclicSynthesis skeletonofofthe quinolizidine is a relevant structural subunit present in numerous alkaloids and can be built starting from 1. (+)-Vertine (55) and (+)-lythrine (56) are examples of this alkaloids and can beSynthesis built starting from 1. (+)-Vertine (55)(+)-Lythrine and (+)-lythrine (56)present are examples of this The azabicyclic skeleton is a relevant structural subunit in numerous 4.2. Enantioselective ofofthequinolizidine Alkaloids and class class of natural compounds (Figure 3); they (+)-Vertine are extracted from Decodon verticillatus and displayed a of natural compounds (Figurefrom 3); they are extracted Decodon verticillatus and displayed a alkaloids and can be built starting 1. (+)-Vertine (55)from and (+)-lythrine (56) are examples of this widewide range of biological activities, such as anti-inflammatory, sedative, and antispasmodic actions; The azabicyclic skeleton of quinolizidine is a relevant structural subunit present in numerous range of biological activities, as anti-inflammatory, and antispasmodic actions;a class of natural compounds (Figuresuch 3); they are extracted fromsedative, Decodon verticillatus and displayed alkaloids andrealized can be built starting from 1. (+)-Vertine (55) and (+)-lythrine (56) are examples of this recently, was realized their total synthesis starting from 1 [45]. recently, was their total synthesis starting from 1 [45]. wide range of biological activities, such as anti-inflammatory, sedative, and antispasmodic actions; class of natural compounds (Figure 3); they are extracted from Decodon verticillatus and displayed a recently, was realized their total synthesis starting from 1 [45]. wide range of biological activities, such as anti-inflammatory, sedative, and antispasmodic actions; recently, was realized their total synthesis starting from 1 [45].

Figure 3. Structures of the alkaloids (+)-vertine and (+)-lythrine.

Figure 3. Structures of the alkaloids (+)-vertine and (+)-lythrine. Figure 3. Structures of the alkaloids (+)-vertine and (+)-lythrine.

4.3. Enantioselective Synthesis of the Alkaloids (+)-Myrtine, (−)-Lupinine, and (+)-Epiepiquinamide

4.3. Enantioselective Synthesis of the Alkaloids (+)-Myrtine, (´)-Lupinine, and (+)-Epiepiquinamide Figure 3. Structures of the alkaloids (+)-vertine and (+)-lythrine.

4.3. Enantioselective Synthesis of from the Alkaloids (+)-Myrtine, (+)-Epiepiquinamide (+)-Myrtine (57), isolated Vaccinium myrtillus,(−)-Lupinine, (−)-lupinineand (58), isolated from the yellow

(+)-Myrtine (57), isolated from Vaccinium myrtillus, (´)-lupinine (58), frompoison the yellow lupin seeds (Lupinus luteus), asfrom well as (+)-epiepiquinamide (59), isolated in isolated 2003 from (+)-Myrtine (57), isolated Vaccinium myrtillus,(−)-Lupinine, (−)-lupinine (58), isolated from the the yellow 4.3. Enantioselective Synthesis of the Alkaloids (+)-Myrtine, and (+)-Epiepiquinamide lupinfrog seeds (Lupinus luteus), as well as (+)-epiepiquinamide (59), isolated in 2003 from the poison frog tricolor, shareasa well quiteascomparable structure, although they in originate from different lupinEpipedobates seeds (Lupinus luteus), (+)-epiepiquinamide (59), isolated 2003 from the poison (+)-Myrtine (57), isolated from Vaccinium myrtillus, (−)-lupinine (58), isolated from the yellow Epipedobates tricolor, share a quite comparable structure, although they originate from different natural natural sources (Figure Theyawere 2011 from N-Boc 2 they [46]. originate from different frog Epipedobates tricolor,4).share quitesynthesized comparableinstructure, although lupin seeds 4). (Lupinus were luteus),synthesized as well as (+)-epiepiquinamide (59),[46]. isolated in 2003 from the poison sources (Figure in 2011 from N-Boc natural sources They (Figure 4). They were synthesized in 2011 from 2 N-Boc 2 [46]. frog Epipedobates tricolor, share a quite comparable structure, although they originate from different natural sources (Figure 4). They were synthesized in 2011 from N-Boc 2 [46].

Figure 4. Structures of the alkaloids (+)-myrtine, (−)-lupinine, and (+)-epiepiquinamide. Figure 4. Structures of the alkaloids (+)-myrtine, (−)-lupinine, and (+)-epiepiquinamide.

Figure 4. Structures of of the and (+)-epiepiquinamide. 4.4. Enantioselective Synthesis thealkaloids Alkaloids(+)-myrtine, (−)-Cermizine(´)-lupinine, C, (−)-Senepodine G and (+)-Cermizine D Figure 4. Structures of the alkaloids (+)-myrtine, (−)-lupinine, and (+)-epiepiquinamide. 4.4. Enantioselective Synthesis of the Alkaloids (−)-Cermizine C, (−)-Senepodine G and (+)-Cermizine D

From the family of lycopodium alkaloids are worth mention (−)-Cermizine C (60) andD 4.4. Enantioselective Synthesis of the Alkaloids (´)-Cermizine C, to (´)-Senepodine G and (+)-Cermizine (+)-cermizine (62),Synthesis both isolated fromalkaloids the(−)-Cermizine club moss Lycopodium cernuum the related alkaloid From theD family of lycopodium are worth to mention (−)-Cermizine C (60) 4.4. Enantioselective of the Alkaloids C, (−)-Senepodine G and and (+)-Cermizine D and

From the family ofboth lycopodium alkaloids worth to mention C (60) and (−)-senepodine (61) from the clubfrom moss Lycopodium (Figure 5); the(´)-Cermizine second latter displaced (+)-cermizine DG(62), isolated the club are mosschinense Lycopodium cernuum and the related alkaloid From the family of lycopodium alkaloids are cells. worth to mention (−)-Cermizine Creduction (60) and modest cytotoxicity against murin lymphoma L1210 60 was synthesized from 61 by (+)-cermizine D (62), both isolated from the club moss Lycopodium cernuum and the related alkaloid (−)-senepodine G (61) from the club moss Lycopodium chinense (Figure 5); the second latter displaced (+)-cermizine Dwhile (62), both isolated from the club moss Lycopodium cernuumstarting and thefrom related alkaloid with NaBH 4 , the synthesis of the latter was accomplished 1 [47,48]. (´)-senepodine G (61) from themurin club lymphoma moss Lycopodium chinense (Figure 5); thefrom second latter displaced modest cytotoxicity against L1210 cells. 60 was synthesized 61 by reduction (−)-senepodine Gsynthesis (61) fromofthe moss the Lycopodium chinense 5); intermediate the second latter displaced Enantioselective 62 club exploited of N-Boc 260 as(Figure common to61 access two with NaBH4, while the murin synthesis of the use latter was starting from from 1by[47,48]. modest cytotoxicity against lymphoma L1210 cells.accomplished was synthesized reduction modest cytotoxicity against murin lymphoma L1210 cells. 60 was synthesized from 61 by reduction of the three piperidine rings [49]. Enantioselective synthesis of 62 of N-Boc 2 asstarting commonfrom intermediate access two with NaBH the synthesis of exploited the latterthe wasuse accomplished 1 [47,48].toEnantioselective 4 , while with NaBH 4, while the synthesis of the latter was accomplished starting from 1 [47,48]. of the three piperidine rings [49]. synthesis of 62 exploited theofuse of N-Bocthe2 use as common to access to two of the Enantioselective synthesis 62 exploited of N-Boc 2intermediate as common intermediate access twothree piperidine rings [49]. of the three piperidine rings [49].

Figure 5. Structures of the alkaloids (−)-cermizine C, (−)-senepodine G, and (+)-cermizine D. Figure 5. Structures of the alkaloids (−)-cermizine C, (−)-senepodine G, and (+)-cermizine D. Figure 5. Structures of the alkaloids (−)-cermizine C, (−)-senepodine G, and (+)-cermizine D.

Figure 5. Structures of the alkaloids (´)-cermizine C, (´)-senepodine G, and (+)-cermizine D.

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Enantioselective Synthesis of the Alkaloids Psylloborine A and Isopsylloborine A The4.5. complex dimers psylloborine A (63) and isopsylloborine A (64) (Figure 6) belong to coccinellid Int. J. Mol. Sci. 2016, 17, 0017 12 of 15 The complex dimers secreted psylloborine (63) and isopsylloborine A (64) (Figure 6) belong to family of alkaloids, materials by Anumerous species of ladybugs as defensive compounds Int. J. Mol. Sci. 2016, 17, 0017 12 of 15 4.5. Enantioselective Synthesis of the Alkaloids Psylloborine A and as Isopsylloborine coccinellid family alkaloids, materials by numerous ofAladybugs defensive when provoked. In theof synthesis, N-Boc 9secreted was identified a species common startingaspoint for the two compounds when provoked. In the synthesis, N-Boc 9 was identified as a common starting point for The complex dimers psylloborine A Psylloborine (63) and isopsylloborine A synthetic (64) 6) belong to tricyclic4.5. intermediate ofSynthesis the dimerization reaction [50]; the allowed the Enantioselective of the Alkaloids Amoreover, and Isopsylloborine A (Figurestrategy the two tricyclic intermediate of the dimerization reaction [50]; moreover, the synthetic strategy coccinellid family of alkaloids, materials secreted byclass numerous species of ladybugs as defensive total syntheses of eight monomeric members of these of alkaloids. The the complex dimers psylloborine A (63)members and isopsylloborine (64) (Figure 6) belong to allowed total syntheses of eight monomeric of these class A of alkaloids. compounds when provoked. In the synthesis, N-Boc 9 was identified as a common starting point for coccinellid family of alkaloids, materials secreted by numerous species of ladybugs as defensive the two tricyclic intermediate of the dimerization reaction [50]; moreover, the synthetic strategy compounds when provoked. In the synthesis, N-Boc 9 was identified as a common starting point for allowed the total syntheses of eight monomeric members of these class of alkaloids. the two tricyclic intermediate of the dimerization reaction [50]; moreover, the synthetic strategy allowed the total syntheses of eight monomeric members of these class of alkaloids.

Figure 6. Structures of the alkaloids psylloborine A and isopsylloborine A.

Figure 6. Structures of the alkaloids psylloborine A and isopsylloborine A. 4.6. Enantioselective Synthesis of the Alkaloids Tetraponerines T3, T4, T7, and T8

Figure 6. of Structures of the alkaloids psylloborine and isopsylloborine 4.6. Enantioselective Synthesis the Alkaloids Tetraponerines T3,A T4, T7, and T8 A.

Tetraponerines are a family of alkaloids that Pseudomyrmecine ants of the genus Tetraponera

Figure 6.enemies; Structures of thestructures alkaloids A and 4.6. Enantioselective Synthesis of of thetheir Alkaloids Tetraponerines T3, T4, T7,isopsylloborine and T8ants Tetraponerines are a family alkaloids thatpsylloborine Pseudomyrmecine ofA.the genus Tetraponera segregate against their possess a singular aminal moiety inside a fused tricycle. Theytheir act asenemies; paralyzingtheir venoms since are efficient inhibitors of a range of nAChRs (nicotinic segregate against structures possess a singular aminal moiety inside TetraponerinesSynthesis are a family alkaloids that Pseudomyrmecine ants Tetraponeraa fused 4.6. Enantioselective of the of Alkaloids Tetraponerines T3, T4, T7, tetraponerines and T8 of the genus receptors). Recently, enantioselective synthesis of the T3 (65), T4 (66), tricycle.acetylcholine They act as paralyzing venoms since are efficient inhibitors of a range of nAChRs (nicotinic segregate against their enemies; their structures possess a singular aminal moiety inside a fused T7 (67), and T8 (68) (Figure 7) wasofachieved starting from N-Cbz 2 [51,52]. Their anticancer activity, Tetraponerines are a family alkaloids that Pseudomyrmecine ants of the genus Tetraponera tricycle.receptors). They act as paralyzing since are efficient inhibitors of a tetraponerines range of nAChRs T3 (nicotinic acetylcholine Recently,venoms enantioselective synthesis of the (65), T4 (66), against four different human cell linespossess was examined showing promising cytotoxic segregate against theircarcinoma enemies; their structures a singular aminal amoiety a fused acetylcholine receptors). Recently, enantioselective synthesis of the 2 tetraponerines T3inside (65), T4 (66),activity, T7 (67),activity and T8of(68) (Figure 7) was achieved starting from N-Cbz [51,52]. Their anticancer 67 against breast carcinoma cell lineare MCF-7. tricycle. act(68) as paralyzing venoms since efficient of a range nAChRs (nicotinic T7 (67), They and T8 (Figure 7) was achieved starting from inhibitors N-Cbz 2 [51,52]. Theirofanticancer activity, againstacetylcholine four different carcinoma human cell lines wassynthesis examined a promising cytotoxic receptors). Recently, enantioselective of showing theshowing tetraponerines T3 (65), T4 (66),activity against four different carcinoma human cell lines was examined a promising cytotoxic of 67 against breast carcinoma cell line MCF-7. T7 (67), and T8 (68) (Figure 7) was achieved starting from N-Cbz 2 [51,52]. Their anticancer activity, activity of 67 against breast carcinoma cell line MCF-7.

against four different carcinoma human cell lines was examined showing a promising cytotoxic activity of 67 against breast carcinoma cell line MCF-7.

Figure 7. Structures of the tetraponerines T3, T4, T7, and T8.

4.7. Enantioselective Synthesis of the Alkaloids (+)-Conhydrine and Figure 7. Structures of the tetraponerines T3, T4, T7, and T8. 4-(2-(Piperidin-2-yl)ethoxy)quinoline Derivatives Figure 7. Structures of the tetraponerines T3, T4, T7, and T8. 4.7. Enantioselective of7. the Alkaloids andT3, T4, T7, and(69) Figure Structures of (+)-Conhydrine the tetraponerines T8. (Figure 8) [53], which Other alkaloidsSynthesis that contain the piperidine unit are: (+)-conhydrine

4.7. Enantioselective theseeds Alkaloids (+)-Conhydrine and plant Conium maculatum L. and is 4-(2-(Piperidin-2-yl)ethoxy)quinoline Derivatives was isolated inSynthesis 1856 fromofthe and leaves of the poisonous 4-(2-(Piperidin-2-yl)ethoxy)quinoline Derivatives 4.7. Enantioselective Synthesis of the Alkaloids (+)-Conhydrine and effectively in the treatment of cognitive disorders since it has been shown to display

Other alkaloids that contain the piperidine unit are: (+)-conhydrine (69) (Figure 8) [53], which 4-(2-(Piperidin-2-yl)ethoxy)quinoline Derivatives

memory-enhancing properties; and 4-(2-(piperidin-2-yl)ethoxy)quinoline derivatives (70), as Other piperidine unit are:poisonous (+)-conhydrine (69) (Figure 8) [53], was was alkaloids isolated inthat 1856contain from thethe seeds and leaves of the plant Conium maculatum L. andwhich is selective agonists of somatostatin receptor subtype 2 (Figure 8) [54]. Other alkaloids that contain piperidine unit are: (+)-conhydrine (Figure [53], which in the the seeds treatment ofthecognitive disorders since has (69) been shown8) isolatedeffectively in 1856 from and leaves of the poisonous plant it Conium maculatum L.to anddisplay is effectively was isolated in 1856 from the seeds and4-(2-(piperidin-2-yl)ethoxy)quinoline leaves of the poisonous plant Coniumderivatives maculatum L. andasis memory-enhancing properties; and (70), in the treatment of cognitive disorders since it has been shown to display memory-enhancing properties; effectively in theof somatostatin treatment ofreceptor cognitive disorders since it has been shown to display selective agonists subtype 2 (Figure 8) [54]. and 4-(2-(piperidin-2-yl)ethoxy)quinoline derivatives (70), as selective agonists of somatostatin receptor memory-enhancing properties; and 4-(2-(piperidin-2-yl)ethoxy)quinoline derivatives (70), as subtypeselective 2 (Figure 8) [54]. agonists of somatostatin receptor subtype 2 (Figure 8) [54].

Figure 8. Structure of (+)-conhydrine and general structure of 4-(2-(piperidin-2-yl)ethoxy)quinoline derivatives.

Figure 8. Structure of (+)-conhydrine and general structure of 4-(2-(piperidin-2-yl)ethoxy)quinoline derivatives.

Figure 8. Structure of (+)-conhydrine and general structure of 4-(2-(piperidin-2-yl)ethoxy)quinoline derivatives.

Figure 8. Structure of (+)-conhydrine and general structure of 4-(2-(piperidin-2-yl)ethoxy)quinoline derivatives.

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5. Conclusions The discovery of both synthetic and enzymatic methods for the obtaining of enantiopure 1 opens the way for the use of this compound as a vital starting material for the enantioselective synthesis of natural and synthetic compounds. This review highlights the synthesis of natural alkaloids starting from both enantiopure 2-piperidineethanol and its corresponding derivative N-protected aldehyde 2. Author Contributions: All authors contributed to the development of the overall structure and the writing of the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

References 1. 2. 3.

4. 5. 6.

7. 8.

9. 10. 11.

12. 13.

14.

15.

16.

Freifelder, M.; Robinson, R.M.; Stone, G.R. Hydrogenation of substituted pyridines with rhodium on carbon catalyst. J. Org. Chem. 1962, 27, 284–286. [CrossRef] Paul, S.; Ghoshal, A.K.; Mandal, B. Absorption of carbon dioxide into aqueous solutions of 2-piperidineethanol: kinetics analysis. Ind. Eng. Chem. Res. 2009, 48, 1414–1419. [CrossRef] Zhang, L.; Fang, Y. Cyclic Organosilicon Compounds as Electron Donors in Ziegler-Natta Catalyst Systems for Producing Propylene Polymer Having High Melt-Flowability. PCT Int. Appl. Patent WO 2013063464, 2 May 2013. Krueger, B.W.; Sasse, K.; Hoever, F.P.; Nentwig, G.; Behrenz, W. Preparation of α,ω-Amino Alcohols as Insect and Mite Repellents. Eur. Appl. Patent EP 289842, 9 November 1988. He, H.; Zhao, D.; Zhu, Y. Process for Preparation of Insect Repellent Icaridin. Chinese Patent CN 102167681, 31 August 2011. Harder, A.; von Samson-Himmelstjerna, G.; Kruger, B.W.; Mehlhorn, H.; Schmidt, J. Aminocarbonyloxy Compound Anthelminthic Agents for the Prevention of Parasitic Infections in Humans and Animals. PCT Int. Appl. Patent WO 2002002115, 10 January 2002. Gaillard, P.; Johnson, C.N.; Novelli, R.; Porter, R.A.; Stemp, G.; Thewlis, K.M. Preparation of N-Aroyl Cyclic Amines as Orexin Receptor Antagonists. PCT Int. Appl. Patent WO 2002089800, 14 November 2002. Carson, J.R.; Carmosin, R.J.; Vaught, J.L.; Gardocki, J.F.; Costanzo, M.J.; Raffa, R.B.; Almond, H.R., Jr. 2-Substituted 1-azabicycloalkanes, a new class of non-opiate antinociceptive agents. J. Med. Chem. 1992, 35, 2855–2863. [CrossRef] [PubMed] Brown, T.H.; Copper, D.G. Preparation of (Aryloxyalkyl)piperidines and Analogs as Calcium Channel Antagonists. PCT Int. Appl. Patent WO 9533723, 14 December 1995. Forbes, I.T.; Rahman, S.K. Preparation of Sulfonamide Derivatives as 5-HT7 Receptor Antagonists . PCT Int. Appl. Patent WO 9749695, 31 December 1997. Thompson, S.K.; Priestley, T.; Smith, R.A.; Saha, A.K.; Rudra, S.; Hajra, A.K.; Chatterjee, D.; Behrens, C.H.; He, Y.; Li, H.Y. Aminoindane Compounds as Sodium Channel Inhibitors and TRPV1 Receptor Activator and Their Preparation and Use in the Treatment of Pain. PCT Int. Appl. Patent WO 2012112969, 23 August 2012. Zanka, A.; Uematsu, R.; Morinaga, Y.; Yasuda, H.; Yamazaki, H. Process development of a novel non-xanthine adenosine A1 receptor antagonist. Org. Process. Res. Dev. 1999, 3, 389–393. [CrossRef] Aberg, G.; Chen, J.L. The R-Isomer of 2-[2-(N-(2-Indanyl)-N-phenylamino)ethyl]piperidine and Other Dermal Anesthetic Agents for Inducing Local Anesthesia, Analgesia and Sleep. PCT Int. Appl. Patent WO 2006037047, 6 April 2006. Young, J.R.; Huang, S.X.; Chen, I.; Walsh, T.F.; de Vita, R.J.; Wyvratt, M.J.; Goulet, M.T.; Ren, N.; Lo, J.; Yang, Y.T.; et al. Quinolones as gonadotropin releasing hormone (GnRH) antagonists: Simultaneous optimization of the C(3)-aryl and C(6)-substituents. Bioorg. Med. Chem. Lett. 2000, 10, 1723–1727. [CrossRef] Paruch, K.; Dwyer, M.P.; Alvarez, C.; Brown, C.; Chan, T.Y.; Doll, R.J.; Keertikar, K.; Knutson, C.; McKittrick, B.; Rivera, J.; et al. Discovery of Dinaciclib (SCH 727965): A potent and selective inhibitor of cyclin-dependent kinases. ACS Med. Chem. Lett. 2010, 1, 204–208. [CrossRef] [PubMed] DeVita, R.J.; Goulet, M.T.; Wyvratt, M.J.; Fisher, M.H.; Lo, J.L.; Yang, Y.T.; Cheng, K.; Smith, R.G. Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists. Bioorg. Med. Chem. Lett. 1999, 9, 2621–2624. [CrossRef]

Int. J. Mol. Sci. 2016, 17, 17

17.

18. 19. 20. 21. 22.

23.

24.

25. 26. 27. 28.

29. 30. 31. 32.

33. 34.

35. 36.

37. 38.

14 of 15

Danilewicz, J.C.; Abel, S.M.; Brown, A.D.; Fish, P.V.; Hawkeswood, E.; Holland, S.J.; James, K.; McElroy, A.B.; Overington, J.; Powling, M.J.; et al. Design of selective thrombin inhibitors based on the (R)-Phe-Pro-Arg sequence. J. Med. Chem. 2002, 45, 2432–2453. [CrossRef] [PubMed] Ito, M.; Maeda, M.; Kibayashi, C. Diastereofacial selectivity in intermolecular nitrone cycloadditions to chiral allyl ethers. Application to chiral synthesis of coniine. Tetrahedron Lett. 1992, 33, 3765–3768. Ina, H.; Ito, M.; Kibayashi, C. Enantioselective Total synthesis of the macrocyclic spermidine alkaloid (´)-Oncinotine. J. Org. Chem. 1996, 61, 1023–1029. [CrossRef] Yamazaki, N.; Dokoshi, W.; Kibayashi, C. Total synthesis of (´)-stellettamide b and determination of its absolute stereochemistry. Org. Lett. 2001, 3, 193–196. [CrossRef] [PubMed] Bosque, I.; Gonzalez-Gomez, J.C.; Guijarro, A.; Foubelo, F.; Yus, M. Concise total synthesis and stereochemical analysis of Tetraponerines T3 and T4. J. Org. Chem. 2012, 77, 10340–10346. [CrossRef] [PubMed] Satyalakshmi, G.; Suneel, K.; Shinde, D.B.; Das, B. Stereoselective total synthesis of the piperidine alkaloids, (+)-coniine, (+)-pseudoconhydrine, and (+)-sedamine through a common intermediate. Tetrahedron Asymmetry 2011, 22, 1000–1005. [CrossRef] Fustero, S.; Jimenez, D.; Moscardo, J.; Catalan, S.; del Pozo, C. Enantioselective organocatalytic intramolecular aza-michael reaction: A concise synthesis of (+)-Sedamine, (+)-Allosedamine, and (+)-Coniine. Org. Lett. 2007, 9, 5283–5286. [CrossRef] [PubMed] Carlson, E.C.; Rathbone, L.K.; Yang, H.; Collett, N.D.; Carter, R.G. Improved protocol for asymmetric, intramolecular heteroatom michael addition using organocatalysis: Enantioselective syntheses of homoproline, pelletierine, and homopipecolic acid. J. Org. Chem. 2008, 73, 5155–5158. [CrossRef] [PubMed] Singh, R.; Panda, G. L-Proline derived nitrogenous steroidal systems: An asymmetric approach to 14-aza steroids. RSC Adv. 2013, 3, 19533–19544. [CrossRef] Toy, M.S.; Price, C.C. D- and L-Polyconidine. J. Am. Chem. Soc. 1960, 82, 2613–2616. [CrossRef] Callens, R.; Gire, R.; Pousset, C. Use of Enantiopure N-Sulfonylpyroglutamic Acids as Resolving Agents for Amines and Amino Alcohols. PCT Int. Appl. Patent WO 2009080708, 2 July 2009. Chen, F.X.; Tamarez, M.M.; Xie, J. Process for Resolving (S)-2-Piperidin-2-ylethanol from a Mixture of Isomers Using N-Acetyl-L-leucine or N-Acetyl-L-methionine. PCT Int. Appl. Patent WO 2008021509, 21 February 2008. Koeller, K.M.; Wong, C.H. Enzymes for chemical synthesis. Nature 2001, 409, 232–240. [CrossRef] [PubMed] Carrea, G.; Riva, S. Properties and synthetic applications of enzymes in organic solvents. Angew. Chem. Int. Ed. 2000, 39, 2226–2254. [CrossRef] Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A. The biocatalytic approach to the preparation of enantiomerically pure chiral building blocks. Chem. Rev. 1992, 92, 1071–1140. [CrossRef] Toone, E.J.; Jones, J.B. Enzymes in organic synthesis. 40. Evaluation of the enantioselectivity of the pig liver esterase-catalyzed hydrolyses of racemic piperidine carboxylic acid esters. Can. J. Chem. 1987, 65, 2722–2726. [CrossRef] Eguchi, T.; Mochida, K. Manufacture of Optically Active Piperidines with Lipase. Japanese Patent JP 06014798, 25 January 1994. Angoli, M.; Barilli, A.; Lesma, G.; Passarella, D.; Riva, S.; Silvani, A.; Danieli, B. Remote stereocenter discrimination in the enzymatic resolution of piperidine-2-ethanol. short enantioselective synthesis of sedamine and allosedamine. J. Org. Chem. 2003, 68, 9525–9527. [CrossRef] [PubMed] Klibanov, A.M. Improving enzymes by using them in organic solvents. Nature 2001, 409, 241–246. [CrossRef] [PubMed] Barilli, A.; Belinghieri, F.; Passarella, D.; Lesma, G.; Riva, S.; Silvani, A.; Danieli, B. Enzyme assisted enantioselective synthesis of the alkaloid (+)-aloperine. Tetrahedron Asymmetry 2004, 15, 2921–2925. [CrossRef] Passarella, D.; Angoli, M.; Giardini, A.; Lesma, G.; Silvani, A.; Danieli, B. Concise total synthesis of (˘)-aloperine and 6-epi-aloperine. Org. Lett. 2002, 4, 2925–2928. [CrossRef] [PubMed] Christodoulou, M.S.; Calogero, F.; Baumann, M.; Garcia-Argaez, A.N.; Pieraccini, S.; Sironi, M.; Dapiaggi, F.; Bucci, R.; Broggini, G.; Gazzola, S.; et al. Boehmeriasin A as new lead compound for the inhibition of topoisomerases and SIRT2. Eur. J. Med. Chem. 2015, 92, 766–775. [CrossRef] [PubMed]

Int. J. Mol. Sci. 2016, 17, 17

39.

40.

41. 42.

43.

44. 45. 46.

47. 48.

49. 50. 51. 52.

53. 54.

15 of 15

Kwon, Y.; Song, J.; Lee, H.; Kim, E.-Y.; Lee, K.; Lee, S.K.; Kim, S. Design, synthesis, and biological activity of sulfonamide analogues of Antofine and Cryptopleurine as potent and orally active antitumor agents. J. Med. Chem. 2015, 58, 7749–7762. [CrossRef] [PubMed] Passarella, D.; Riva, S.; Grieco, G.; Cavallo, F.; Checa, B.; Arioli, F.; Riva, E.; Comi, D.; Danieli, B. Enantiopure N-Boc piperidine-2-ethanol for the synthesis of (+)- and (´)-dumetorine, and (+)- and (´)-epidihydropinidine. Tetrahedron Asymmetry 2009, 20, 192–197. [CrossRef] Riva, E.; Rencurosi, A.; Gagliardi, S.; Passarella, D.; Martinelli, M. Synthesis of (+)-Dumetorine and Congeners by Using Flow Chemistry Technologies. Chem. Eur. J. 2011, 17, 6221–6226. [CrossRef] [PubMed] Passarella, D.; Barilli, A.; Belinghieri, F.; Fassi, P.; Riva, S.; Sacchetti, A.; Silvani, A.; Danieli, B. Short enantioselective synthesis of sedridines, ethylnorlobelols and coniine via reagent-based differentiation. Tetrahedron Asymmetry 2005, 16, 2225–2229. [CrossRef] Borsini, E.; Broggini, G.; Colombo, F.; Khansaa, M.; Fasana, A.; Galli, S.; Passarella, D.; Riva, E.; Riva, S. Enantiopure 2-piperidylacetaldehyde as a useful building block in the diversity-oriented synthesis of polycyclic piperidine derivatives. Tetrahedron Asymmetry 2011, 22, 264–269. [CrossRef] Cheng, H.Y.; Hou, D.R. Efficient, asymmetric synthesis of (´)-isooncinotine. Tetrahedron 2007, 63, 3000–3005. [CrossRef] Chausset-Boissarie, L.; Arvai, R.; Cumming, G.R.; Guenee, L.; Kundig, E.P. Asymmetric synthesis of (+)-vertine and (+)-lythrine. Org. Biomol. Chem. 2012, 10, 6473–6479. [CrossRef] [PubMed] Fustero, S.; Moscardo, J.; Sanchez-Rosello, M.; Flores, S.; Guerola, M.; del Pozo, C. Organocatalytic enantioselective synthesis of quinolizidine alkaloids (+)-myrtine, (´)-lupinine, and (+)-epiepiquinamide. Tetrahedron 2011, 67, 7412–7417. [CrossRef] Snider, B.B.; Grabowski, J.F. Total synthesis of (´)-Senepodine G and (´)-Cermizine C. J. Org. Chem. 2007, 72, 1039–1042. [CrossRef] [PubMed] Veerasamy, N.; Carlson, E.C.; Collett, N.D.; Saha, M.; Carter, R.G. Enantioselective approach to quinolizidines: Total synthesis of Cermizine D and formal syntheses of Senepodine G and Cermizine C. J. Org. Chem. 2013, 78, 4779–4800. [CrossRef] [PubMed] Veerasamy, N.; Carlson, E.C.; Carter, R.G. Expedient enantioselective synthesis of Cermizine D. Org. Lett. 2012, 14, 1596–1599. [CrossRef] [PubMed] Sherwood, T.C.; Trotta, A.H.; Snyder, S.A. A Strategy for complex dimer formation when biomimicry fails: Total synthesis of ten coccinellid alkaloids. J. Am. Chem. Soc. 2014, 136, 9743–9753. [CrossRef] [PubMed] Bosque, I.; Gonzalez-Gomez, J.C.; Loza, M.I.; Brea, J. Natural tetraponerines: A general synthesis and antiproliferative activity. J. Org. Chem. 2014, 79, 3982–3991. [CrossRef] [PubMed] Airiau, E.; Girard, N.; Pizzeti, M.; Salvadori, J.; Taddei, M.; André, M. Hydroformylation of alkenylamines. Concise approaches toward piperidines, quinolizidines, and related alkaloids. J. Org. Chem. 2010, 75, 8670–8673. [CrossRef] [PubMed] Shaikh, T.M.; Sudalai, A. Enantioselective synthesis of (+)-α-Conhydrine and (–)-Sedamine by L -Proline-Catalysed α-Aminooxylation. Eur. J. Org. Chem. 2010, 3437–3444. [CrossRef] Wolkenberg, S.E.; Zhao, Z.; Thut, C.; Maxwell, J.W.; McDonald, T.P.; Kinose, F.; Reilly, M.; Lindsley, C.W.; Hartman, G.D. Design, synthesis, and evaluation of novel 3,6-diaryl-4-aminoalkoxyquinolines as selective agonists of somatostatin receptor subtype 2. J. Med. Chem. 2011, 54, 2351–2358. [CrossRef] [PubMed] © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).