ReviewReview EnzymaticEnzymatic KineticKinetic ResolutionResolution ofof 2-Piperidineethanol2-Piperidineethanol forfor thethe EnantioselectiveEnantioselective TargetedTargeted andand DiversityDiversity OrientedOriented SynthesisSynthesis ††

DarioDario PerdicchiaPerdicchia *,*, MichaelMichael S.S. Christodoulou,Christodoulou, GaiaGaia Fumagalli,Fumagalli, FrancescoFrancescoCalogero, Calogero, CristinaCristina MarucciMarucci andand DanieleDaniele PassarellaPassarella **

Received:Received: 22 NovemberNovember 2015;2015; Accepted:Accepted: 1515 DecemberDecember 2015;2015; Published:Published: 242015 December 2015 AcademicAcademic Editor:Editor: VladimírVladimír KˇrenKřen

DipartimentoDipartimento didi Chimica,Chimica, UniversitaUniversita deglidegli StudiStudi didi Milano,Milano,Via Via Golgi Golgi 19, 19, 20133 20133 Milano, Milano, Italy; Italy; [email protected]@gmail.com (M.S.C.);(M.S.C.); [email protected]@unimi.it (G.F.);(G.F.); [email protected]@gmail.com (F.C.);(F.C.); [email protected]@unimi.it (C.M.)(C.M.) ** Correspondences:Correspondences: [email protected] [email protected] (D (D.Pe.);.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 This paper paper is is dedicated dedicated to to the the memory memory of of Brun Brunoo Danieli, Danieli, Professor Professor of of Organic Organic Chemistry, Chemistry, UniversitàUniversità degli degli Studi Studi di di Milano, Milano, 20122 20122 Milano, Milano, Italy. Italy.

Abstract:Abstract: 2-Piperidineethanol2-Piperidineethanol ((11)) andand itsits correspondingcorresponding NN-protected-protected aldehydealdehyde ((22)) werewere usedused forfor thethe synthesissynthesis ofof severalseveral natural natural and and synthetic synthetic compounds. compounds. The The existence existence of of a stereocentera stereocenter at positionat position 2 of 2 theof the piperidine piperidine skeleton skeleton and and the presencethe presence of an of easily-functionalized an easily-functionalized group, group, such such as the as alcohol, the alcohol, set 1 asset a 1 valuable as a valuable starting starting material material for enantioselective for enantioselective synthesis. synthesis. Herein, areHerein, presented are presented both synthetic both andsynthetic enzymatic and enzymatic methods for methods the resolution for the ofresolution the racemic of the1, asracemic well as 1 an, as overview well as an of synthesizedoverview of naturalsynthesized products natural starting products from st thearting enantiopure from the 1enantiopure. 1.

Keywords:Keywords: 2-piperidineethanol;2-piperidineethanol; piperidinepiperidine alkaloids;alkaloids; enzymaticenzymatic resolution;resolution; alkaloidalkaloid synthesissynthesis

1.1. Introduction Introduction 2-Piperidineethanol2-Piperidineethanol ((11)) (Figure(Figure1 1)) is is a a chiral chiral piperidine piperidine derivative derivative bearing bearing two two functional functional group group suitablesuitable forfor diversifieddiversified elaborationselaborations ofof thethe molecule.molecule.

N OH N O H Pg 1 2 FigureFigure 1.1. Structure ofof 2-piperidineethanol2-piperidineethanol ((11)) andand thethe correspondingcorresponding NN-protected-protected aldehydealdehyde ((22).).

WithWith moremore thanthan 10,00010,000 moleculesmolecules listedlisted inin SciFinder,SciFinder, containcontain thethe substructuresubstructure ofof 2-piperidineethanol2-piperidineethanol keeping keeping the the stereocentre stereocentre in positi in positionon 2 of piperidine, 2 of piperidine, its potentiality its potentiality is self-evident is self-evidentas a valuable as chiral a valuable starting chiral material starting in organic material synthesis. in organic In synthesis. racemic form, In racemic it is a form,quite itcheap is a quitecompound cheap compoundsince it is since synthesized, it is synthesized, on an onindu an industrialstrial scale, scale, by bycatalytic catalytic hydrogenation hydrogenation ofof 2-(2-hydroxyethyl)pyridine2-(2-hydroxyethyl)pyridine [1[1];]; on on the the contrary, contrary the, enantiopurethe enantiopure form isform expensive is expensive and less available.and less available.N-protected aldehyde (2), easily obtained by controlled oxidation of the parent alcohol, is the derivativeN-protected of 2-piperidineethanol aldehyde (2), easily usually obtained used to by a greatcontrolled extent oxidation in synthesis. of the parent alcohol, is the derivative of 2-piperidineethanol usually used to a great extent in synthesis.

Int.Int. J.J. Mol.Mol. Sci.Sci. 20162016,, 1717,, 17;0017; doi:10.3390/ijms17010017 doi:10.3390/ijms17010017 www.mdpi.com/journal/ijmswww.mdpi.com/journal/ijms Int. J. Mol. Sci. 2016, 17, 17 2 of 15

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). Int. J. Mol. Sci. 2016, 17, 17 3 of 15

Int. J. Mol. Sci. 2016, 17, 0017 3 of 15 Enantiopure 2-Piperidineethanol by Enzymatic Kinetic Resolutions EnantiopureInt. J. Mol. Sci. 20162-Piperidineethanol, 17, 0017 by Enzymatic Kinetic Resolutions 3 of 15 EnzymaticInt. J. Mol. Sci. kinetic 2016, 17, 0017 resolutions of racemates have been widely exploited in the past3 of years15 for the preparationEnantiopureEnzymatic 2-Piperidineethanol of enantiopurekinetic resolutions compoundsby Enzymatic of racemates Kinetic [29 –have31 Resolutions]. be Despiteen widely the exploited breakthroughs in the past achieved years for throughthe Enantiopure 2-Piperidineethanol by Enzymatic Kinetic Resolutions the abilitypreparation of enzymes of enantiopure to selectively compounds react with[29–31]. only De onespite of the the breakthroughs enantiomers achieved from a racemicthrough mixture,the Enzymatic kinetic resolutions of racemates have been widely exploited in the past years for the thereability are only ofEnzymatic enzymes few examples kinetic to selectively resolutions reported react of for racemates with the resolutiononly have one be ofen ofthe widely1, enantiomers each exploited one related infrom the apast to racemic the years reactivity formixture, the at the therepreparationpreparation are only of few ofenantiopure enantiopure examples compoundsreported compounds for [29–31].the[29–31]. resolution Despite of the the1, each breakthroughsbreakthroughs one related achieved toachieved the reactivity through through theat the hydroxyl group. It was a difficult task, due to the fact that the molecule is a conformationally flexible hydroxylabilityability of group.ofenzymes enzymes It was to to selectively a selectively difficult task,react react due withwith to onlyonlythe fa onect that ofof thethe enantiomersmoleculeenantiomers is afrom conformationallyfrom a aracemic racemic mixture, mixture, flexible and primary alcohol located two carbons away from the molecule stereocenter. An early reference andtherethere primary are are only only alcohol few few examples examples located reportedtwo reported carbons for for thetheaway resolutionresolution from the ofof molecule 11, ,each each one one stereocenter. related related to to the theAn reactivity reactivityearly reference at theat the approachedapproachedhydroxylhydroxyl the group. group. resolutionthe resolution It Itwas was a of adifficult difficultof several several task, task, racemic racemic due due toto piperidine piperidi the fact nethat derivatives derivatives thethe molecule molecule [32] [is 32is awith ]aconformationally withconformationally either either a stereocenter a stereocenter flexible flexible in in positionpositionandand 2primary or primary 3,2 or exploiting 3,alcohol alcoholexploiting located thelocated the hydrolysis two hydrolysistwo carbons carbons of anof awayaway an ester ester from group group thethe molecule bymolecule by pig pig liver liverstereocenter. stereocenter. esterase esterase An (EC(EC An early 3.1.1.1).3.1.1.1).early reference reference With With 11 two strategiestwoapproachedapproached strategies were tested the werethe resolution resolution (Scheme tested (Schemof of1 several) several bye the 1) racemic racemicby synthesis the synthesis piperidipiperidi of estersne of derivativesderivatives esters3 and 3 and4 [32] :[32] 4 :with with either either a stereocentera stereocenter in in positionposition 2 or2 or3, 3,exploiting exploiting the the hydrolysis hydrolysis ofof anan ester group byby pig pig liver liver es esteraseterase (EC (EC 3.1.1.1). 3.1.1.1). With With 1 1 twotwo strategies strategies were were tested tested (Schem (Schemee 1) 1) by by thethe synthesissynthesis ofof estersesters 3 3 and and 4 :4 :

Scheme 1. Synthesis of 2-piperidineethanol derivatives suitable for hydrolysis by pig liver esterase. Scheme 1. Synthesis of 2-piperidineethanol derivatives suitable for hydrolysis by pig liveresterase. i iPr:Scheme isopropyl. 1. Synthesis of 2-piperidineethanol derivatives suitable for hydrolysis by pig liver esterase. Pr: isopropyl.Scheme 1. Synthesis of 2-piperidineethanol derivatives suitable for hydrolysis by pig liver esterase. iPr: isopropyl. TheyTheyiPr: were isopropyl. were subjected subjected to pig to liverpig esteraseliver esterase hydrolysis hydrolysis at pH at 7.0 pH to 7.0 avoid to theavoid possibility the possibility of competing of chemicalcompeting hydrolysisThey chemical were or subjected epimerizationhydrolysis to pigor epimerizationliver under esterase the higher hydrunderolysis pHthe atconditions;higher pH 7.0 pH to conditions; reactionsavoid the werepossibilityreactions stopped wereof after stoppedcompetingThey after were chemical 50% subjected conversion: hydrolysis to pig orresults liver epimerization esteraseare reassumed hydr underolysis thein higheratScheme pH pH7.0 2 conditions;toshowing avoid theareactions generally possibility were low of 50% conversion: results are reassumed in Scheme2 showing a generally low enantioselectivity with enantioselectivitycompetingstopped chemicalafter 50% with hydrolysis conversion: up to 24% or e.e.results epimerization for acidare (reassumed5). under thein Schemehigher pH2 showing conditions; a generally reactions low were up tostopped 24%enantioselectivity e.e. after for acid50% (with5conversion:). up to 24% results e.e. for acidare (reassumed5). in Scheme 2 showing a generally low 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. SchemeScheme 2. EnzymaticEnzymatic kinetic kinetic resolutions resolutions of racemic of 3 racemicand 4. PLE:3 pigand liver4. esterase; PLE: pige.e.: enantiomeric liver esterase; excess. e.e.: enantiomeric excess. SchemeIn In1994, 2. 1994, Enzymatic a firsta first example kineticexample resolutions of of exploitation exploitation of racemic ofof thethe 3 andporcine 4. PLE: pancreaspancreas pig liver lipase lipase esterase; (PPL) (PPL) e.e.: for forenantiomeric the the resolution resolution excess. of of 9-fluorenylmethyl carbamate (N-Fmoc) 2-piperidineethanol (7) was reported in a Japanese patent In9-fluorenylmethyl 1994, a first example carbamate of exploitation (N-Fmoc) 2-piperi of thedineethanol porcine pancreas (7) was lipasereported (PPL) in a forJapanese the resolution patent of [33]:In vinyl1994, acetatea first examplewas used of as exploitationthe acylating ofagent the andporcine diisopropyl pancreas ether lipase as solvent (PPL) for(Scheme the resolution 3) (in the of 9-fluorenylmethyl[33]: vinyl acetate carbamate was used ( Nas-Fmoc) the acylating 2-piperidineethanol agent and diisopropyl (7) was ether reported as solvent in a (Scheme Japanese 3) patent(in the [33]: English9-fluorenylmethylEnglish abstract abstract are arecarbamate not not indicated indicated (N-Fmoc) th thee e.e. e.e. 2-piperi of of bothbothdineethanol the enantioenriched (7) was 8 8reported and and 7 ).7 ). in a Japanese patent vinyl[33]: acetate vinyl was acetate used was as used the as acylating the acylating agent agent and and diisopropyl diisopropyl etherether as as solvent solvent (Scheme (Scheme 3) (in3) the (in the EnglishEnglish abstract abstract are are not not indicated indicated the th e.e.e e.e. of of both both thethe enantioenriched 8 and8 and 7). 7).

Scheme 3. Enzymatic kinetic resolutions of racemic 7. PPL: porcine pancreas lipase. Fmoc: Scheme9-fluorenylmethyl 3. Enzymatic carbamate. kinetic resolutions of racemic 7. PPL: porcine pancreas lipase. Fmoc: 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.

Int. J. Mol. Sci. 2016, 17, 17 4 of 15 Int. J. Mol. Sci. 2016, 17, 0017 4 of 15

Finally, inin 2003, 2003, a comprehensivea comprehensive study study on the on enantioselective the enantioselective acylation acylation of the residualof the primaryresidual alcoholprimaryInt. J. (Scheme alcoholMol. Sci. 2016 4(Scheme),by 17, 0017 lipases 4) by was lipases successfully was successful realizedly [ realized34]. A first [34]. screening A first screening of over 20 of4 differentof over 15 20 ˝ lipasedifferent preparations lipase preparations was performed was performe at 45 C;d an at organic 45 °C; solventan organic (methyl solventtert-butyl (methyl ether) tert-butyl was selected ether) Finally, in 2003, a comprehensive study on the enantioselective acylation of the residual as solvent as it is well-known that the enzymatic performances (activity and selectivity) can be was selectedprimary asalcohol solvent (Scheme as it is4) well-known by lipases was that successful the enzymaticly realized performances [34]. A first (activityscreening and of over selectivity) 20 enhanced greatly using organic solvents as a reaction medium, rather than their natural aqueous can bedifferent enhanced lipase greatly preparations using was organic performe solventsd at 45 as °C; a anreaction organic medium, solvent (methyl rather tert than-butyl their ether) natural environmentsaqueouswas environmentsselected [35 as]; thesolvent protective[35]; as theit is protectivewell-known groups of groups aminothat the of groupenzymatic amino tested group performances were tested Boc, were(activity Cbz, Boc, and and Fmoc.Cbz, selectivity) and Fmoc. 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. Enzymatic enantioselective acylation of racemic 99.. Pg:Pg: protecting group. Scheme 4. Enzymatic enantioselective acylation of racemic 9. Pg: protecting group. This preliminarypreliminary screeningscreening underlined underlined that that reaction reaction enantioselectivities enantioselectivities were were generally generally quite quite low. Thelow.crude The crudeThis porcine preliminary porcine pancreatic pancreatic screening preparation preparationunderlined possessed that posses reac ansedtion opposite an enantioselectivities opposite enantioselectivity enantioselectivity were generally compared compared quiteto allto theall otherthelow. other lipasesThe crude lipases and porcine Lipaseand pancreatic Lipase PS was PS preparation the was more the selective posses moresed enzymeselective an opposite among enzyme enantioselectivity the among “(R)-lipases”. the compared “( ComparingR)-lipases”. to theComparing threeall the protective otherthe three lipases groups, protective andN Lipase-Boc groups, derivative PS was N-Boc the was morederivative a slightly selective was better enzyme a slight substrate. amongly better Athe new substrate.“(R screening)-lipases”. A new was Comparing the three protective groups, N-Boc derivative was a slightly better substrate. A new directedscreening to was pointing directed out theto pointing effect of differentout the solventseffect of fordifferent the reaction solvents of N for-Boc the derivative reaction catalyzedof N-Boc screening was directed to pointing out the effect of different solvents for the reaction of N-Boc byderivative Lipase PS catalyzed and PPL: by hexane Lipase was PS and a slightly PPL: hexane better solvent was a forslightly the former better whilesolvent methyl for thetert former-butyl while 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. remainedmethyl the tert solvent-butyl ether of choice remained for the the latter.solvent of choice for the latter. Finally, an optimized protocol was designed based on the observed complementary Finally,Finally, an an optimized optimized protocol protocol waswas designeddesigned based based on on the the observed observed complementary complementary enantioselectivityenantioselectivity of of the theof the two two two enzy enzymes enzymesmes (Scheme (Scheme 5).5). The The racemicracemic racemic mixture mixture mixture 9 was9 was 9acetylatedwas acetylated acetylated under under the under the thebest best conditionbest condition condition for forforLipase LipaseLipase PS; PS; after after after that that that enzyme enzyme enzyme is isfiltered filtered and and and reagent reagent reagent removed, removed, removed, the thecrude the crude crude mixture mixture waswas butanoylatedwasbutanoylated butanoylated by by the bythe PPL the PPL underPPL under under the bestthe the conditionbestbest condition forition this forfor enzyme.this this enzyme. enzyme. In this In way, Inthis this theway, lowway, the selectivity lowthe low ofselectivity theselectivity two of lipases the of thetwo was two lipasesenhanced. lipases was was enhanced. enhanced. The final The The mixture, final mixture,mixture, composed composed composed by enantioenriched by byenantioenriched enantioenriched acetate acetate acetate (R )-10, butanoate(R)-10(R, )-butanoate10, ( Sbutanoate)-11 and (S the)-(11S)- unreacted11and and the the almost unreactedunreacted racemic almostalmost9, was racemicracemic easily 9 , purified 9,was was easily byeasily flashpurified purified chromatography. by flashby flash chromatography. Hydrolysis of the two esters was followed by a second step of acetylation on the Hydrolysischromatography. of the twoHydrolysis esters was of the followed two esters by a secondwas followed step of acetylationby a second on step the of two acetylation enantioenriched on the two enantioenriched alcohols by the two lipases; after hydrolysis, both alcohols with high e.e. were alcoholstwo enantioenriched by the two lipases; alcohols after by hydrolysis,the two lipases; both alcoholsafter hydrolysis, with high both e.e. alcohols were obtained. with high e.e. were 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) CH3OH, Na2CO 3; and AcOCH=CH2, MTBE, 20 °C, 46 h (48%). PPL: porcine pancreas lipase; PS: Lipase PS; Pr: propyl; Ac: (d) AcOCH=CH , MTBE, 20 ˝C, 46 h (48%). PPL: porcine pancreas lipase; PS: Lipase PS; Pr: propyl; Schemeacetyl; 5. OptimizedBoc: tert2 -butyl protocol. carbamate. (a) AcOCH=CH2, hexane, 20 °C, 190 min (45%); (b) PrCOOCH=CH2, Ac:MTBE, acetyl; 20 °C, Boc: 11.5tert -butylh (30%), carbamate. 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.

Int. J. Mol. Sci. 2016, 17, 17 5 of 15

3. AnInt. Overview J. Mol. Sci. 2016 of, 17 the, 0017 Synthetic Strategies in the Synthesis of Alkaloids Starting from Either5 of 15 Enantiopure 1 or 2 Int.3. An J. Mol. Overview Sci. 2016, 17 of, 0017 the Synthetic Strategies in the Synthesis of Alkaloids Starting from Either5 of 15 TheEnantiopure development 1 or 2 of suitable methods for accessing both enantiomers of 1 opened the path to the 3. An Overview of the Synthetic Strategies in the Synthesis of Alkaloids Starting from Either total synthesis of a wide range of natural compounds with high interest in medicinal chemistry; in an EnantiopureThe development 1 or 2 of suitable methods for accessing both enantiomers of 1 opened the path to earlythe stage, total some synthesis of these of a syntheseswide range wereof natural performed compounds starting with with high racemicinterest in1. medicinal chemistry; Asin an previouslyThe early development stage, mentioned, some of thesesuitable2 is syntheses the methods main were derivativefor performedaccessing of both 2-piperidineethanolstarting enantiomers with racemic of 1 1opened used. in the total path synthesis to the total synthesis of a wide range of natural compounds with high interest in medicinal chemistry; where theAs stereogenic previously centermentioned, at the 2 is C-2 theposition main derivative would of readily 2-piperi encodedineethanol the remaining used in total stereochemical synthesis in an early stage, some of these syntheses were performed starting with racemic 1. informationwhere the into stereogenic the final center target. at the It isC-2 usually position synthesized would readily by encode Swern the oxidation, remaining butstereochemical some troubles As previously mentioned, 2 is the main derivative of 2-piperidineethanol used in total synthesis affectinformation the recovery into of the the final product target.and It is theusually scale synthesized up of the by reaction. Swern oxidation, An enzymatic but some approach troubles at the whereaffect thethe recoverystereogenic of centerthe product at the andC-2 positionthe scale would up of readilythe reaction. encode An the enzymatic remaining approach stereochemical at the oxidation reaction of (R)-9 was realized by exploiting laccases [36], either from Trametes pubescens informationoxidation reaction into the of (finalR)-9 target.was realized It is usually by exploiting synthesized laccases by [36],Swern either oxidation, from Trametes but some pubescens troubles or or from Myceliophtora termophyla, TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) as a mediator, and affectfrom Myceliophtorathe recovery oftermophyla the product, TEMPO and the (2,2,6,6-tetrame scale up of thethyl-1-piperidinyloxy) reaction. An enzymatic as aapproach mediator, at andthe molecularoxidationmolecular oxygen reaction oxygen of the of the( airR)- air9 as was as the the realized primary primary by oxidant exploitingoxidant (Scheme laccases 6).6). [36], either from Trametes pubescens or 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. 3.1. EnantioselectiveScheme 6. Oxidation Synthesi reactions of the mediated Alkaloid by(+)-Aloperine laccase. TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy. 3.1. Enantioselective Synthesis of the Alkaloid (+)-Aloperine 3.1. EnantioselectiveAloperine (12) Synthesi (Schemes of7) the is aAlkaloi memberd (+)-Aloperine of a small family of C15 alkaloids that is extracted from Aloperinethe seeds and (12 leaves) (Scheme of Sophora7) is alopecuroides a member, a of shrub a small that grows family in ofChina C 15 andalkaloids Russia, and that later is extractedfrom fromLeptorhabdos theAloperine seeds andparviflor (12 leaves) (Scheme Benth. of Sophora7) isIts a memberpharmacological alopecuroides of a small, a activityfamily shrub of that spreadsC15 growsalkaloids between in that China is cardiovascular,extracted and Russia, from and laterthe fromanti-inflammatory, seedsLeptorhabdos and leaves parviflorandof Sophora anti-allergic Benth. alopecuroidesIts features pharmacological, a shrub producing that grows activityan inintense China spreads syntheticand Russia, between interest and cardiovascular, later in fromthis anti-inflammatory,Leptorhabdosmolecule. In 2002,parviflor and a synthesis anti-allergic Benth. of Itsracemic featurespharmacological 12 was producing realized activity an[37]; intense the spreadssynthe synthetictic betweenstrategy interest (Schemecardiovascular, in this 7) relied molecule. anti-inflammatory, and anti-allergic features producing an intense synthetic interest in this In 2002,on an a synthesisefficient intermolecular of racemic 12 Diels-Alderwas realized reaction [37]; as the crucial synthetic step where strategy derivative (Scheme 157 )was relied a key on an molecule. In 2002, a synthesis of racemic 12 was realized [37]; the synthetic strategy (Scheme 7) relied efficientbuilding intermolecular block for the Diels-Alder synthesis of the reaction N-acylaminodiene as crucial step 14. where derivative 15 was a key building on an efficient intermolecular Diels-Alder reaction as crucial step where derivative 15 was a key blockbuilding for the synthesisblock for the of synthesis the N-acylaminodiene of the N-acylaminodiene14. 14.

Scheme 7. Retrosynthetic analysis of the synthesis of aloperine. In 2004, the correspondingSchemeScheme 7. 7.Retrosynthetic Retrosynthetic enantioselective analysisanalysis variant of of the the [36] synthesis synthesis was performed of ofaloperine. aloperine. starting from (R)-9 for the synthesis of (R)-17 (Scheme 8); two consecutive enzymatic oxidations mediated by laccase were Inset 2004, forIn both2004, the the correspondingthe synthesis corresponding of aldehyde enantioselective enantioselective (R)-2 and variantketone variant ( [R 36[36])-17] was .was performed performed starting from from (R (R)-)-9 9forfor the the synthesis of (R)-17 (Scheme 8); two consecutive enzymatic oxidations mediated by laccase were synthesis of (R)-17 (Scheme8); 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.

Int. J. Mol. Sci. 2016, 17, 17 6 of 15 Int. J. Mol. Sci. 2016, 17, 0017 6 of 15

Int. J. Mol. Sci. 2016, 17, 0017 6 of 15

SchemeScheme 8. 8. SynthesisSynthesis of of intermediate intermediate ( (RR)-17.)-17. TBAF: TBAF: tetrabutylammonium tetrabutylammonium fluoride.fluoride. TMS:TMS: trimethylsilyl.trimethylsilyl. Scheme 8. Synthesis of intermediate (R)-17. TBAF: tetrabutylammonium fluoride. TMS: trimethylsilyl. 3.2. Enantioselective Enantioselective Synthesis of the Alkaloid Boehmeriasin A 3.2. Enantioselective Synthesis of the Alkaloid Boehmeriasin A Boehmeriasin A ( 22) is a phenanthroquinolizidinephenanthroquinolizidine alkaloid extracted from Boehmeria siamensis Craib. ItIt possessespossessesBoehmeriasin aa strong strong A (22 cytotoxic )cytotoxic is a phenanthroquinolizidine activity, activity, more more potent potent thanalkaloid than taxol, extractedtaxol, against against from 12 cell Boehmeria 12 lines cell fromlines siamensis six from panels six Craib. It possesses a strong cytotoxic activity, more potent than taxol, against 12 cell lines from six panelsof cancer of including cancer including breast, kidney, breast, prostate, kidney, colon, pros lungtate, cancer, colon, and lung leukemia, cancer, with and topoisomerases leukemia, with 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 involvedtargets. and SIRT2 Recently, as involved the synthesis targets. Recently, of enantiopure the synthesis22 [38 of] enantiopure was accomplished 22 [38] was starting accomplished starting from aldehyde (S)-2 (Scheme 9). fromaccomplished aldehyde (S)- starting2 (Scheme from9 ).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; (c) TMSCl, MeOH; (d) 2-bromo-4,5-dimethoxyphenylacetic acid, DIPEA, 1-(Bis(dimethylamino) Schememethylene)-1H-1,2,3-triazolo(4,5-b)pyridinium 9. Synthesis of the alkaloid boehmeriasin 3-oxid A. hexafluorophosphate(a) (4-methoxyphenyl)magnesium (HATU); (e) KOH, bromide; EtOH; (b) methylene)-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxid hexafluorophosphate (HATU); (e) KOH, EtOH; DMP;( f()c Pd(OAc)) TMSCl,2, KMeOH;2CO3, 2 ′(-(diphenylphosphino)-d) 2-bromo-4,5-dimethoxyphenylaceticN,N′-dimethyl-(1,1′-biphenyl)-2-amine; acid, DIPEA, 1-(Bis(dimethylamino) and (g) LiAlH4. 1 1 1 methylene)-1H-1,2,3-triazolo(4,5-b)pyridinium(f) Pd(OAc)2,K2CO3, 2 -(diphenylphosphino)-N 3-oxid,N -dimethyl-(1,1 hexafluorophosphate-biphenyl)-2-amine; (HATU); and (e) (KOH,g) LiAlH EtOH;4.

(f) Pd(OAc)The synthetic2, K2CO 3sequence, 2′-(diphenylphosphino)- begins with theN Grigna,N′-dimethyl-(1,1rd addition′-biphenyl)-2-amine; to the enantiopure andaldehyde (g) LiAlH (S)-42. Thefollowed synthetic by oxidation sequence with DMP begins (Dess-Martin with the Grignardperiodinane), addition deprotection to the of the enantiopure Boc group, N aldehyde-acylation (S)-2 followedTheof the bysynthetic amine, oxidation intramolecularsequence with DMP begins (Dess-Martinaldol-type with the condensation, periodinane),Grignard addition and deprotection palladium-catalyzed to the ofenantiopure the Boc group,intramolecular aldehydeN-acylation (S)-2 followedof thecoupling amine, by oxidation and intramolecular reduction with DMPof the aldol-type amide.(Dess-Martin condensation, periodinane), anddeprotection palladium-catalyzed of the Boc group, intramolecular N-acylation ofcoupling the amine,Recently, and reduction intramolecular a quite ofsimilar the amide.syntheticaldol-type strategy condensation, [39] was used andfor the palladium-catalyzed synthesis of sulfonamide intramolecular analogues of 22 as potent and orally active antitumor agents. couplingRecently, and reduction a quite similarof the amide. synthetic strategy [39] was used for the synthesis of sulfonamide analoguesRecently, of 22 a quiteas potent similar and synthetic orally active strategy antitumor [39] was agents.used for the synthesis of sulfonamide analogues of 22 as potent and orally active antitumor agents.

Int. J. Mol. Sci. 2016, 17, 17 7 of 15

3.3. EnantioselectiveInt. J. Mol. Sci. 2016, Synthesis17, 0017 of the Alkaloid Dumetorine 7 of 15 Dumetorine3.3. Enantioselective (28) Synthesi is ans alkaloidof the Alkaloid with Dumetorine piperidine structural unit that is extracted from the tubersDumetorine of Dioscorea (28) is dumetorum an alkaloid Paxwith andpiperidine used structural in folk unit medicine that is extracted and arrow from poisons. the tubers The enantioselectiveof Dioscorea synthesisdumetorum [Pax40] wasand establishedused in folk onmedicine few key and synthetic arrow poisons. steps (Scheme The enantioselective 10) starting from the enantiopuresynthesis [40] aldehyde was established (S)-2. The on few second key syntheti stereocenterc steps was (Scheme achieved 10) starti by anng asymmetricfrom the enantiopure allylboration reactionaldehyde with β(S-allyl-diisopinocamphenylborane,)-2. The second stereocenter was achieved obtaining by an asymmetric exclusively allylboration the required reaction compound with 23 (diastereoisomericβ-allyl-diisopinocamphenylborane, excess (de) > 95%). Afterobtainin acylationg exclusively with acryloyl the chloride,required thecompound dihydropyran 23 ring was synthesized(diastereoisomeric by ring-closing excess (de) > 95%). metathesis After acylatio reactionn with with acryloyl the second chloride, generation the dihydropyran Grubbs ring 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 small amounts (10%). Finally, N-methylation was carried out by reductive amination with CH O in small amounts (10%). Finally, N-methylation was carried out by reductive amination with CH2O in2 the presencethe presence of NaBH of NaBH3CN3CN to to give give the the target target naturalnatural (+)- 2828. .

Scheme 10. Enantioselective synthesis of the alkaloid dumetorine. (a) CH2=CHCH3CH2MgBr, Scheme 10. Enantioselective synthesis of the alkaloid dumetorine. (a) CH2=CHCH3CH2MgBr, (+)-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) CH2O, NaBH3CN. Recently, for the improvement of the synthesis, a sequence of five separate synthetic steps, was Recently,performed forby flow the improvementchemistry technology of the with synthesis, the advantages a sequence of minimal of five workup separate and syntheticpurification steps, was[41]. performed Packed bycolumns flow containing chemistry appropriate technology immobilized with the reagents advantages or scavenger of minimal materials workup were and purificationused. The [41 ].starting Packed compound columns containingwas the enantiopure appropriate alcohol immobilized (S)-9 that reagents was converted or scavenger into materials the werecorresponding used. The starting aldehyde compound (S)-2 wasby thecontinuously enantiopure cycling alcohol the (S )-flow9 that stream was converted through intoa the correspondingpolymer-supported aldehyde 2-iodoxybenzamide (S)-2 by continuously pre-packed cycling column. the flow In the stream second through step, the a polymer-supported insertion of the 2-iodoxybenzamideallyl group was pre-packedrealized by reaction column. with In the the second Grignard step, reagent the insertion 2-methyl-a ofllylmagnesium the allyl group bromide; was realized by reactionthe two with diastereoisomers, the Grignard formed reagent almost 2-methyl-allylmagnesium in 1:1 ratio, were purified bromide; on a silica the gel two cartridge diastereoisomers, to give 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 PEGpossibility (polyethylene of simple catalyst glycol)-supported recovery by solvent-promoted Hoveyda catalyst precipitation working and in homogeneousfiltration. The inherent conditions ensuredinstability by the of solubility amine 27 ofwas the the catalyst main drawback in CH2 Clof2 the, maintaining early synthetic the sequence possibility (Scheme of simple 10) since catalyst recoveryMichael by solvent-promoted addition of the secondary precipitation amine to and the filtration.α,β-unsaturated The inherent lactone ring instability caused ofthe amine formation27 was of the mainthe drawback byproduct of the26 and early significantly synthetic sequencereduced the (Scheme yield of10 the) since final Michael reductive addition amination of the(39%). secondary A aminedefinitive to the α ,breakthroughβ-unsaturated was lactone established ring causedby converting the formation directly Boc of theprotected byproduct 25 in 26finaland product significantly 28 reducedthrough the yield an Eschweiler–Clarke of the final reductive reaction amination with formaldehyde (39%). A definitive in the presence breakthrough of formic was acid established at high by convertingtemperature: directly flash Boc heating protected with 25a rapidin final warming product to 14028 °Cthrough gave a anclean Eschweiler–Clarke product with a yield reaction of 92%. with 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%.

Int. J. Mol. Sci. 2016, 17, 17 8 of 15

Int. J. Mol. Sci. 2016, 17, 0017 8 of 15 3.4. Enantioselective Synthesis of the Alkaloids Sedamine, Allosedamine, Sedridines and Ethylnorlobelols Int. J. Mol. Sci. 2016, 17, 0017 8 of 15 The3.4. structure Enantioselective of several Synthesis alkaloids of the Alkaloids are easily Sedamine, recognized Allosedamin ase, derivatives Sedridines and of Ethylnorlobelols the reaction of 2 with an appropriate3.4. EnantioselectiveThe structure Grignard Synthesisof reagent.several of alkaloids the Indeed, Alkaloids are starting easilySedamine, recognized from Allosedamin the enantiopureas derivativese, Sedridines (ofS )- andthe2, Ethylnorlobelols tworeaction diastereoisomeric of 2 with an appropriate Grignard reagent. Indeed, starting from the enantiopure (S)-2, two diastereoisomeric alcohols 29Theand structure30 were of generatedseveral alkaloids (Scheme are easily11). Their recognized Boc groups as derivatives were easily of the converted reaction of into 2 with methyl alcohols 29 and 30 were generated (Scheme 11). Their Boc groups were easily converted into methyl groupsan appropriate by reduction Grignard with LiAlHreagent.4 [Indeed,34] affording, starting from for Rthe = enantiopure Ph, respectively, (S)-2, two (´ diastereoisomeric)-sedamine (31) and groups by reduction with LiAlH4 [34] affording, for R = Ph, respectively, (−)-sedamine (31) and (´)-allosedamine (32); alternatively, 31 was synthesized from 29, through flow chemistry technology, alcohols(−)-allosedamine 29 and 30 ( were32); alternatively, generated (Scheme 31 was synthesized 11). Their Boc from groups 29, through were easily flow chemistry converted technology, into methyl by thegroupsby protocol the byprotocol reduction developed developed with for forLiAlH the the previously 4previously [34] affording, outlined outlined for Eschweiler–Clarke R = Ph, respectively, reaction reaction (−)-sedamine [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)-allosedridine 11. Enantioselective (33) and synthesis (+)-sedridine of the alkaloids (34), sedamifor R ne,= allosedamine,Me, (−)-2′-epi-ethylnorlobelol sedridines, and ethylnorlobelols. (35) and On(+)-ethylnorlobelol the other hand, ( removing36), for R = theEt [42]. Boc group from 29 and 30 afforded respectively (´)-allosedridine (33) and (+)-sedridineOn the other (34 hand,), for Rremoving = Me, (´ )-2the1 -epi-ethylnorlobelolBoc group from 29 ( 35and) and 30 (+)-ethylnorlobelol afforded respectively (36 ), for R = Et(−3.5. [)-allosedridine42 ].Synthesis of the(33 Enantiopure) and (+)-sedridine Alkaloids Coniine (34), andfor Epidihydropinidine R = Me, (−)-2 ′-epi-ethylnorlobelol (35) and (+)-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 Coniinethe chain (38 at) the is the2-position major of alkaloid the piperidine extracted ring through from Conium a Wittig maculatumreaction, hydrogenation(poison hemlock) of the and responsibledoubleConiine for bound its ( toxicity.38 and) is removal the It major was of synthesizedthe alkaloid Boc group extracted from [42]. the from enantiopure Conium maculatum (S)-2 (Scheme (poison 12 )hemlock) by elongating and 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 bounddouble and removalbound and of removal the Boc of group the Boc [42 group]. [42].

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

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

Int. J. Mol. Sci. 2016, 17, 17 9 of 15 Int. J. Mol. Sci. 2016, 17, 0017 9 of 15 Int. J. Mol. Sci. 2016, 17, 0017 9 of 15 Closely related to coniine is the alkaloid epidihydropinidine (43) that shared the same synthetic Closely related to coniine is the alkaloid epidihydropinidine (43) that shared the same synthetic stepsClosely for the related building to coniine of the is thepropyl alkaloid group epidihydropinidine [40]. The key (43synthetic) that shared step thewas same the synthetic Beak’s steps for the building of the propyl group [40]. The key synthetic step was the Beak’s N-Boc-piperidine Nsteps-Boc-piperidine for the building α-lithiation/alkylation of the propyl methodology group [40]. forThe the key introduction synthetic ofstep the methylwas the group Beak’s at α-lithiation/alkylation methodology for the introduction of the methyl group at the C-6 position; theN-Boc-piperidine C-6 position; TBDMS α-lithiation/alkylation protection of the methodology hydroxyl group for the of (introductionR)-9 was important of the methylin order group to keep at TBDMS protection of the hydroxyl group of (R)-9 was important in order to keep the C-2 chain at thethe C-2C-6 chainposition; at a TBDMSdistance protection from the reactive of the hydroxyl center (Scheme group 13).of ( RAfter)-9 was deprotection important and in order Dess–Martin to keep a distance from the reactive center (Scheme 13). After deprotection and Dess–Martin oxidation to oxidationthe C-2 chain to aldehyde at a distance 42, the from synthesis the reactive proceeded center alike (Scheme Scheme 13). 12.After deprotection and Dess–Martin aldehydeoxidation 42to, aldehyde the synthesis 42, the proceeded synthesis alike proceeded Scheme alike 12. Scheme 12.

Scheme 13. Enantioselective synthesis of the alkaloid (−)-epidihydropinidine. (a) imidazole, SchemetertScheme-butyldimethylsilyl 13.13. Enantioselective chloride synthesis (TBDMSCl); of ( thetheb) N alkaloidalkaloid,N,N′,N′ -Tetramethylethylenediamine (´(−)-epidihydropinidine.)-epidihydropinidine. (a) imidazole,(TMEDA),imidazole, tert-butyldimethylsilyl chloride (TBDMSCl); (b) N,N,N1 ′,N1 ′-Tetramethylethylenediamine (TMEDA), tertsec-BuLi,-butyldimethylsilyl Et2O, −78 °C, MeSO chloride4; (c) (TBDMSCl);Na2CO3, MeOH; (b) N and,N, N(d),N Dess-Martin-Tetramethylethylenediamine reagent. (TMEDA), sec-BuLi, Et2O, −78 °C,˝ MeSO4; (c) Na2CO3, MeOH; and (d) Dess-Martin reagent. sec-BuLi, Et2O, ´78 C, MeSO4;(c) Na2CO3, MeOH; and (d) Dess-Martin reagent. 3.6. Enantioselective Synthesis of Polycyclic Piperidine Derivatives 3.6.3.6. Enantioselective SynthesisSynthesis ofof PolycyclicPolycyclic PiperidinePiperidine DerivativesDerivatives The changeover of the aldehyde group of 2 into the carbon–carbon double bond of 37 allowed a switchTheThe of changeover changeoverreactivity by of exploitingthe aldehyde reactions group group ofaffect of 22 intointoing the thethe carbon–carbon carbon–carbonalkene group double[43] double such bond bond as ofintramolecular of 3737 allowedallowed a aHeckswitch switch ofreactions, of reactivity reactivity 1,3-dipolar by by exploiting exploiting cycloadditions, reactions reactions affect affecting ringing the theclosing alkene alkene group metathesis [[43]43] suchsuchand asas intramolecularintramolecular HeckchloroaminationHeck reactions,reactions, 1,3-dipolar reactions, 1,3-dipolar cycloadditions,reaching cycloadditions, an increased ring closing molecularring metathesis closing complexity. andmetathesis intramolecular Indeed, and bicyclic chloroaminationintramolecular derivative chloroamination reactions, reaching an increased molecular complexity. Indeed, bicyclic derivative reactions,45 was obtained reaching by an reaction increased of urea molecular 44 using complexity. Pd(CH3CN) Indeed,2Cl2 as bicyclic a catalyst derivative and CuCl45 was2 as obtained an oxidant by 45 was obtained by reaction of urea 44 using Pd(CH3CN)2Cl2 as a catalyst and CuCl2 as an oxidant reaction(Scheme of14). urea 44 using Pd(CH3CN)2Cl2 as a catalyst and CuCl2 as an oxidant (Scheme 14). (Scheme 14).

Scheme 14. Enantioselective synthesissynthesis of bicyclic derivative 45.. Scheme 14. Enantioselective synthesis of bicyclic derivative 45. Combining moremore reactions reactions together together in orderin order to modifyingto modifying the carbon–carbonthe carbon–carbon double double bond beforebond Combining more reactions together in order to modifying the carbon–carbon double bond thebefore 1,3-dipolar the 1,3-dipolar cycloaddition, cycloaddition, allowed allowed the stereoselective the stereoselective synthesis synthesis of fused of fused tricyclic tricyclic derivatives derivatives with before the 1,3-dipolar cycloaddition, allowed the stereoselective synthesis of fused tricyclic derivatives upwith to up three to three stereogenic stereogenic centers. centers. Then, Then, aryl derivativearyl derivative46 was 46 subjected was subjected to an intramolecularto an intramolecular Heck with up to three stereogenic centers. Then, aryl derivative 46 was subjected to an intramolecular reactionHeck reaction (Scheme (Scheme 15) obtaining 15) obtaining the bicyclic the bicyclic alkene alkene47 that, 47 that, after after 1,3-dipolar 1,3-dipolar cycloaddition, cycloaddition, gave gave the Heck reaction (Scheme 15) obtaining the bicyclic alkene 47 that, after 1,3-dipolar cycloaddition, gave tricyclicthe tricyclic spiro spiro derivative derivative48 as 48 mixture as mixture of two of two diastereoisomers. diastereoisomers. the tricyclic spiro derivative 48 as mixture of two diastereoisomers.

Int.Int. J.J. Mol.Mol. Sci. 2016, 17, 0017 17 1010 of of 15 15 Int. J. Mol. Sci. 2016, 17, 0017 10 of 15 Int. J. Mol. Sci. 2016, 17, 0017 10 of 15

SchemeScheme 15. 15. Synthesis Synthesis ofof derivative derivative 48 48. . Scheme 15. Synthesis of derivative 48. Scheme 15. Synthesis of derivative 48. Likewise,Likewise, derivative derivative 49 49was was subjected subjected to to ring-closingring-closing metathesis metathesis (Scheme (Scheme 16) 16)by aby Grubbs a Grubbs catalyst catalyst Likewise, derivative 49 was subjected to ring-closing metathesis (Scheme 16) by a Grubbs catalyst of secondof secondLikewise, generation generation derivative obtaining obtaining 49 was the the subjected bicyclic bicyclic tounsaturated unsaturated ring-closing amide amidemetathesis 50 50 that that (Scheme after after 1,3-dipolar 16) 1,3-dipolar by a Grubbs cycloaddition cycloaddition catalyst of second generation obtaining the bicyclic unsaturated amide 50 that after 1,3-dipolar cycloaddition gave ofgavethe second tricyclic the tricyclic generation derivative derivative obtaining 51 51 as asthe single single bicyclic diastereoisomer. diastereoisomer. unsaturated amide 50 that after 1,3-dipolar cycloaddition gavegave the tricyclic the tricyclic derivative derivative51 51as as single single diastereoisomer. diastereoisomer.

Scheme 16. Synthesis of derivative 51. Scheme 16. Synthesis of derivative 51. Scheme 16.16. Synthesis of derivative 5151.. 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 4.4. A A General GeneralFurther Overview Overview examples of of of the thenatural Structures Structures compounds of of Alkaloids Alkaloids synthesized Synthesized Synthesized starting from from from both both bothenantiopure 1 1 or or 2 2 1 or 2 are shortlyFurther exemplified examples in thisof natural subsection; compounds the substructure synthesized derived starting from from 1 is both pointed enantiopure out in red. 1 or 2 are FurtherFurthershortly exemplified examples in of this natural subsection; compounds the substructure synthesizedsynthesized derived starting from from 1 is pointed both enantiopureout in red. 1 or 2 are shortlyshortly4.1. exemplifiedexemplified Enantioselective inin thisSyntthis hesissubsection;subsection; of the Alkaloids thethe substructuresubstructure (−)-Oncinotine, derivedderived (−)-Isooncinotine, fromfrom1 1is is and pointedpointed (−)-Stellettamide outoutin inred. red. 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 4.1.4.1. Enantioselective SynthesisSynthesis of thethe AlkaloidsAlkaloids ((´−)-Oncinotine,)-Oncinotine, ( (−´)-Isooncinotine,)-Isooncinotine, and and (− (´)-Stellettamide)-Stellettamide B B alkaloids(−)-Oncinotine which are characterized(52) and (−)-isooncinotine by macrocyclic (53 lactams) (Figure containing 2) are a the group biogenetic of isomeric base spermidine; polyamine ((alkaloidsthey´−)-Oncinotine)-Oncinotine are isolated which are (from (5252 characterized)) and andthe stem( −´)-isooncinotine)-isooncinotine bark by macrocyclic of Oncinotis (53 ( 53lactams nitida) )(Figure (Figure (Apocynaceae). containing 22)) areare the aa group groupbiogenetic52 was of ofsynthesized isomeric baseisomeric spermidine; polyamine inpolyamine 1996 alkaloidsalkaloidsthey[19] starting whichare isolated arefrom characterized from N-Cbz the 2stem instead. bybark macrocyclic 53of Oncinotiswas synthesized lactamsnitida (Apocynaceae). in containing 2007 [44] thefrom 52 biogeneticwas 1. Stellettamidesynthesized base spermidine; in B 1996(54) theythey are[19](Figureare isolatedisolatedstarting 2) is fromfrom extractedfrom theN the-Cbz stem fromstem 2 barkinstead. abark marine of ofOncinotis53 Oncinotis spongewas synthesized nitidaof nitida the(Apocynaceae). genus (Apocynaceae). in 2007 Stelletta [44] andfrom52 was 52showed 1 .was synthesizedStellettamide synthesized antifungal inB 1996(and 54in) 1996 [19] cytotoxic activity; it was synthesized in 2001 [20] from 1. starting[19] starting(Figure from 2) Nfrom -Cbzis extracted N2-Cbzinstead. from2 instead.53 a wasmarine synthesized53 wassponge synthesized of in the 2007 genus [ 44in] fromStelletta2007 1[44]. Stellettamideand from showed 1. Stellettamide antifungal B (54) (Figure and B 2 ()54 is) cytotoxic activity; it was synthesized in 2001 [20] from 1. extracted(Figure 2) from is extracted a marine from sponge a marine of the genus spongeStelletta of theand genus showed Stelletta antifungal and showed and cytotoxic antifungal activity; and itcytotoxic was synthesized activity; it in was 2001 synthesized [20] from 1 .in 2001 [20] from 1.

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

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

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Int. J. Mol. Sci. 2016, 17, 0017 11 of 15

4.2. EnantioselectiveInt. J. Mol. Sci. 2016, Synthesis17, 0017 of the Alkaloids (+)-Vertine and (+)-Lythrine 11 of 15 4.2. Enantioselective Synthesis of the Alkaloids (+)-Vertine and (+)-Lythrine TheInt. J. Mol. azabicyclic Sci. 2016, 17 skeleton, 0017 of quinolizidine is a relevant structural subunit present in11 numerous of 15 4.2. EnantioselectiveThe azabicyclic Synthesis skeleton of of the quinolizidine Alkaloids (+)-Vertin is a relevante and (+)-Lythrine 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 be built starting from 1. (+)-Vertine (55) and (+)-lythrine (56) are examples of this class4.2. of naturalEnantioselectiveThe azabicyclic compounds Synthesis skeleton (Figure of of the quinolizidine 3Alkaloids); they are(+)-Vertin is extracted a relevante and (+)-Lythrine from structuralDecodon subunit verticillatus present inand numerous displayed a classalkaloids of natural and can compounds be built starting (Figure from 3); they 1. (+)-Vertine are extracted (55 )from and (+)-lythrineDecodon verticillatus (56) are examplesand displayed of this a wide rangeThe of azabicyclic biological skeleton activities, of quinolizidine such as anti-inflammatory, is a relevant structural sedative, subunit and present antispasmodic in numerous actions; wideclass ofrange natural of biological compounds activities, (Figure such 3); they as anti are-inflammatory, extracted from sedative, Decodon verticillatusand antispasmodic and displayed actions; a alkaloids and can be built starting from 1. (+)-Vertine (551) and (+)-lythrine (56) are examples of this recently,recently,wide was range was realized of realized biological their their totalactivities, total synthesis synthesis such as starting starting anti-inflammatory, fromfrom 1 [45].[45]. 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(+)-Myrtine (57 Synthesis), isolated of fromthe Alkaloids Vaccinium (+)-Myrtine, myrtillus ,( −()-Lupinine,−)-lupinine and (58 (+)-Epiepiquinamide), isolated from the yellow (+)-Myrtine (57), isolated from Vaccinium myrtillus,(´)-lupinine (58), isolated from the yellow lupin4.3. Enantioselective(+)-Myrtine seeds (Lupinus (57 Synthesis), luteusisolated), ofas fromthe well Alkaloids Vacciniumas (+)-epiepiquinamide (+)-Myrtine, myrtillus (, −()-Lupinine,−)-lupinine (59), isolated and (58 (+)-Epiepiquinamide), isolatedin 2003 fromfrom thethe poisonyellow lupin seeds (Lupinus luteus), as well as (+)-epiepiquinamide (59), isolated in 2003 from the poison frog froglupin Epipedobates seeds (Lupinus tricolor luteus, share), as a wellquite as comparable (+)-epiepiquinamide structure, although(59), isolated they inoriginate 2003 from from the different poison (+)-Myrtine (57), isolated from Vaccinium myrtillus, (−)-lupinine (58), isolated from the yellow Epipedobatesnaturalfrog Epipedobates sources tricolor ,(Figure sharetricolor a4)., quiteshare They comparablea were quite synthesized comparable structure, in structure, 2011 although from although N-Boc they 2 they originate[46]. originate from from different different natural lupin seeds (Lupinus luteus), as well as (+)-epiepiquinamide (59), isolated in 2003 from the poison sourcesnatural (Figure sources4). They (Figure were 4). They synthesized were synthesized in 2011 from in 2011N -Bocfrom 2N-Boc[46]. 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. 4.4. EnantioselectiveFigure 4. Structures Synthesis of of the the alkaloids Alkaloids (+)-myrtine, (−)-Cermizine (´ C,)-lupinine, (−)-Senepodine and (+)-G andepi epiquinamide.(+)-Cermizine D 4.4. EnantioselectiveFigure 4. SyntStructureshesis of of the the Alkaloids alkaloids ((+)-myrtine,−)-Cermizine (− )-lupinine,C, (−)-Senepodine and (+)- epiG epiquinamide.and (+)-Cermizine D 4.4. EnantioselectiveFrom the family Synthesis of lycopodium of the Alkaloids alkaloids (´)-Cermizine are worth C, to (´ )-Senepodinemention (−)-Cermizine G and (+)-Cermizine C (60) and D (+)-cermizine4.4. EnantioselectiveFrom the D family(62 ),Synt both ofhesis lycopodiumisolated of the Alkaloidsfrom alkaloids the ( −club)-Cermizine mossare worth Lycopodium C, ( −to)-Senepodine mention cernuum (G− )-Cermizineand (+)-Cermizinethe related C (alkaloid60 D) and From((+)-cermizine−)-senepodine the family D G ( 62(61), of )both from lycopodium isolated the club from moss alkaloids the Lycopodium club aremoss chinense worth Lycopodium to(Figure mention cernuum 5); the (and ´seco)-Cermizine thend relatedlatter displaced alkaloid C (60) and From the family of lycopodium alkaloids are worth to mention (−)-Cermizine C (60) and (+)-cermizinemodest(−)-senepodine cytotoxicity D (62 G), ( both61 against) from isolated themurin club from lymphoma moss the Lycopodium club L1210 moss cells. chinenseLycopodium 60 was (Figure synthesized cernuum 5); the seco fromandnd the 61latter by related reductiondisplaced alkaloid (+)-cermizine D (62), both isolated from the club moss Lycopodium cernuum and the related alkaloid (´)-senepodinewithmodest NaBH cytotoxicity G4, (while61) fromagainst the thesynthesis murin club lymphoma moss of Lycopodiumthe latteL1210r cells.was chinense 60accomplished was(Figure synthesized5 );starting the from second from 61 by latter 1reduction [47,48]. displaced (−)-senepodine G (61) from the club moss Lycopodium chinense (Figure 5); the second latter displaced modestEnantioselectivewith cytotoxicity NaBH4, while synthesis against the murinofsynthesis 62 exploited lymphoma of the use L1210latte ofr Nwas cells.-Boc accomplished260 aswas common synthesized intermediatestarting fromfrom to61 access1by [47,48]. reduction two ofmodest the three cytotoxicity piperidine against rings murin[49]. lymphoma L1210 cells. 60 was synthesized from 61 by reduction with NaBHEnantioselective4, while the synthesis synthesis of 62 of exploited the latter the was use accomplished of N-Boc 2 as starting common from intermediate1 [47,48]. to Enantioselective access two with NaBH4, while the synthesis of the latter was accomplished starting from 1 [47,48]. of the three piperidine rings [49]. synthesisEnantioselective of 62 exploited synthesis the of use62 exploited of N-Boc the2 useas commonof N-Boc 2 intermediateas common intermediate to access to two access ofthe twothree piperidineof the three rings piperidine [49]. 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.

Int. J. Mol. Sci. 2016, 17, 17 12 of 15

4.5. EnantioselectiveInt. J. Mol. Sci. 2016 Synthesis, 17, 0017 of the Alkaloids Psylloborine A and Isopsylloborine A 12 of 15 4.5. Enantioselective Synthesis of the Alkaloids Psylloborine A and Isopsylloborine A TheInt. complex J. Mol. Sci. 2016 dimers, 17, 0017 psylloborine A (63) and isopsylloborine A (64) (Figure6) belong to12 coccinellidof 15 family of alkaloids,The complex materials dimers secretedpsylloborine by A numerous (63) and isopsylloborine species of ladybugs A (64) (Figure as defensive 6) belong compounds to Int. J. Mol. Sci. 2016, 17, 0017 12 of 15 when provoked.coccinellid4.5. Enantioselective family In the of Synthesis synthesis, alkaloids, of the materialsN Alkal-Bocoids9 secreted wasPsylloborine identified by numerousA and asIsopsylloborine a species common of A ladybugs starting as point defensive for the two compounds when provoked. In the synthesis, N-Boc 9 was identified as a common starting point for tricyclic4.5. intermediate EnantioselectiveThe complex of Synthesisdimers the dimerization psylloborine of the Alkaloids reactionA Psylloborine(63) and [50 ];isopsylloborine A moreover, and Isopsylloborine the A synthetic(64 A) (Figure strategy 6) belong allowed to the the two tricyclic intermediate of the dimerization reaction [50]; moreover, the synthetic strategy coccinellid family of alkaloids, materials secreted by numerous species of ladybugs as defensive total synthesesallowedThe the ofcomplex eighttotal syntheses monomericdimers psylloborineof eight members monome A ( ofric63 )thesemembers and classisopsylloborine of these of alkaloids. class Aof alkaloids.(64) (Figure 6) belong to 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 4.6. Enantioselective SynthesisFigure 6. ofStructures the Alkaloids of the alkaloids Tetraponerines psylloborine T3, A T4,and isopsylloborine T7, and T8 A. Tetraponerines are a family of alkaloids that Pseudomyrmecine ants of the genus Tetraponera Tetraponerinessegregate4.6. Enantioselective against areFigure their Synthesis a family6. enemies; Structures of ofthe th alkaloids Alofeir kaloidsthe structures alkaloids Tetraponerines that psylloborine possess Pseudomyrmecine T3,a singularAT4, and T7, isopsylloborine and aminal T8 ants moiety of A. the inside genus a fusedTetraponera tricycle. They act as paralyzing venoms since are efficient inhibitors of a range of nAChRs (nicotinic segregate againstTetraponerines their enemies; are a family their of alkaloids structures that possessPseudomyrmecine a singular ants aminal of the genus moiety Tetraponera inside a fused 4.6.acetylcholine Enantioselective receptors). Synthesis Recently, of the Al enantioseleckaloids Tetraponerinestive synthesis T3, T4,of theT7, tetraponerinesand T8 T3 (65), T4 (66), tricycle.segregate They act against as paralyzing their enemies; venoms their sincestructures are efficientpossess a inhibitorssingular aminal of a rangemoiety of inside nAChRs a fused (nicotinic T7 (67), and T8 (68) (Figure 7) was achieved starting from N-Cbz 2 [51,52]. Their anticancer activity, acetylcholinetricycle.Tetraponerinesreceptors). They act as paralyzingare Recently, a family venoms enantioselectiveof alkaloids since arethat efficient Pseudomyrmecine synthesis inhibitors of theof antsa tetraponerinesrange of theof nAChRs genus Tetraponera T3(nicotinic (65), T4 (66), against four different carcinoma human cell lines was examined showing a promising cytotoxic segregateacetylcholine against receptors). their enemies; Recently, th enantioseleceir structurestive possess synthesis a singular of the tetraponerines aminal moiety T3 inside (65), T4a fused(66), T7 (67),activity and T8 of ( 6867 )against (Figure breast7) was carcinoma achieved cell line starting MCF-7. from N-Cbz 2 [51,52]. Their anticancer activity, tricycle.T7 (67), Theyand T8 act (68 as) paralyzing(Figure 7) was venoms achieved since starting are efficient from inhibitorsN-Cbz 2 [51,52]. of a range Their of anticancer nAChRs (nicotinic activity, against four different carcinoma human cell lines was examined showing a promising cytotoxic activity acetylcholineagainst four differentreceptors). carcinoma Recently, human enantioselec cell linetives synthesiswas examined of the showing tetraponerines a promising T3 (65 ),cytotoxic T4 (66), of 67 againstT7activity (67), breast andof 67 T8 against carcinoma (68) (Figure breastcell carcinoma7) was line achieved MCF-7. cell line starting MCF-7. from N-Cbz 2 [51,52]. Their anticancer activity, 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)quinolineFigure 7. Structures Derivatives of the tetraponerines T3, T4, T7, and T8. 4.7. EnantioselectiveOther alkaloids Synthesis thatFigure contain of 7. theStructures the Alkaloids pipe ofridine (+)-Conhydrinethe tetraponerines unit are: (+)-conhydrineand T3, T4, T7, and ( 69T8.) (Figure 8) [53], which 4.7. Enantioselectivewas4-(2-(Piperidin-2-yl)ethoxy)quinoline isolated in Synthesis 1856 from of the the seed Alkaloids Derivativess and leaves (+)-Conhydrine of the poisonous and plant Conium maculatum L. and is 4-(2-(Piperidin-2-yl)ethoxy)quinoline4.7.effectively Enantioselective in the Synthesistreatment of the Derivativesof Alkaloids cognitive (+)-Conhydrine disorders andsince 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)quinolinememory-enhancing properties; and Derivatives 4-(2-(piperidin-2-yl)ethoxy)quinoline derivatives (70), as Otherwas alkaloidsisolated in that1856 containfrom the the seed piperidines and leaves unit of the are: poisonous (+)-conhydrine plant Conium (69) (Figuremaculatum8)[ L.53 and], which is was selective agonists of somatostatin receptor subtype 2 (Figure 8) [54]. isolatedeffectively in 1856Other from alkaloidsin thethe seeds thattreatment contain and leavesof the cognitive pipe ofridine the poisonousdi unitsorders are: (+)-conhydrinesince plant itConium has (been maculatum69) (Figure shown 8)L. to[53], and display which is effectively in the treatmentwasmemory-enhancing isolated of cognitivein 1856 fromproperties; disorders the seed and sinces and 4-(2-(piperidin-2-yl)ethoxy)quinoline itleaves has beenof the shown poisonous to display plant Conium memory-enhancing derivatives maculatum L.(70 and), properties;as is effectivelyselective agonists in the of somatostatintreatment of receptor cognitive subtype disorders 2 (Figure since 8) [54]. it has been shown to display 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 agonists8)[54 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.

Int. J. Mol. Sci. 2016, 17, 17 13 of 15

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.

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