molecules Article ArticleSynthesis of Chiral, Enantiopure Allylic Amines by Synthesisthe Julia Olefination of Chiral, Enantiopure of α-Amino AllylicEsters Amines by the Julia Olefination of α-Amino Esters Fabio Benedetti *, Federico Berti, Lidia Fanfoni, Michele Garbo, Giorgia Regini and FabioFulvia Benedetti Felluga * *, Federico Berti, Lidia Fanfoni, Michele Garbo, Giorgia Regini and Fulvia Felluga * Department of Chemical and Pharmaceutical Sciences, University of Trieste, via Giorgieri 1. 34127 Trieste, DepartmentItaly; [email protected] of Chemical (F.B.); and [email protected] Pharmaceutical Sciences, (L.F.); University [email protected] of Trieste, via Giorgieri (M.G.); 1. 34127 Trieste, Italy; [email protected]@phd.units.it (F.B.); [email protected] (G.R.) (L.F.); [email protected] (M.G.); [email protected]* Correspondence: [email protected] (G.R.) (F.B.); [email protected] (F.F.); Tel.: +39-040-5583919 (F.B.); * Correspondence:+39-040-5583924 (F.F.) [email protected] (F.B.); [email protected] (F.F.); Tel.: +39-040-5583919 (F.B.); +39-040-5583924 (F.F.) Academic Editors: Carlo Siciliano and Constantinos M. Athanassopoulos AcademicReceived: 24 Editors: May 2016; Carlo Accepted: Siciliano and14 Ju Constantinosne 2016; Published: M. Athanassopoulos 20 June 2016 Received: 24 May 2016; Accepted: 14 June 2016; Published: 21 June 2016 Abstract: The four-step conversion of a series of N-Boc-protected L-amino acid methyl esters into Abstract: The four-step conversion of a series of N-Boc-protected L-amino acid methyl esters into enantiopure N-Boc allylamines by a modified Julia olefination is described. Key steps include the enantiopure N-Boc allylamines by a modified Julia olefination is described. Key steps include the reaction of a lithiated phenylalkylsulfone with amino esters, giving chiral β-ketosulfones, and the reaction of a lithiated phenylalkylsulfone with amino esters, giving chiral β-ketosulfones, and the reductive elimination of related α-acetoxysulfones. The overall transformation takes place under reductive elimination of related α-acetoxysulfones. The overall transformation takes place under mild conditions, with good yields, and without loss of stereochemical integrity, being in this mild conditions, with good yields, and without loss of stereochemical integrity, being in this respect respect superior to the conventional Julia reaction of α-amino aldehydes. superior to the conventional Julia reaction of α-amino aldehydes. Keywords: chiral pool; allylamines; amino acids; sulfones; acylation Keywords: chiral pool; allylamines; amino acids; sulfones; acylation 1. Introduction 1. Introduction Allylic amines (allylamines) are compounds of significant synthetic and biological interest [1– Allylic amines (allylamines) are compounds of significant synthetic and biological interest [1–3]. 3]. The allylamine fragment is present in natural products [4–6] and other biologically-active The allylamine fragment is present in natural products [4–6] and other biologically-active compounds [7–9], including drugs for the treatment of mycosis (terbinafine, naftifine) [10], compounds [7–9], including drugs for the treatment of mycosis (terbinafine, naftifine) [10], depression depression (zimelidine) [11], motion sickness (cinnarizine) [12], migraine and epilepsy (flunarizine) (zimelidine) [11], motion sickness (cinnarizine) [12], migraine and epilepsy (flunarizine) [13] (Figure1). [13] (Figure 1). Figure 1. Bioactive compounds based on the allylamine structure. On the other hand, the characteristic bifunctionalbifunctional unit can undergo a wide range of chemical transformations, thus thus making making allylamines allylamines versatile versatile building building blocks blocks in organic in organic synthesis synthesis [1]. Chiral [1]. Chiralallylamines, allylamines, in particular, in particular, are valuable are valuable intermediates intermediates for forthe thesynthesis synthesis of ofa avariety variety of of chiral, enantiomerically-pure bioactive compounds [[14–17].14–17]. Considerable efforteffort has has been been devoted devoted to the to asymmetric the asymmetric synthesis synthesis of α-chiral of α allylamines,-chiral allylamines, resulting inresulting the development in the development of several approaches,of several approaches, among which among the transition which the metal-catalyzed transition metal-catalyzed asymmetric allylicasymmetric amination allylic has amination been extensively has been documentedextensively documented [18–20]. Other [18–20]. methods Other include methods the asymmetricinclude the vinylationasymmetric of vinylation imines [21 of], imines the Overman [21], the rearrangement Overman rearrangement of allylic imidates of allylic [22 ],imidates the asymmetric [22], the Molecules 2016, 21, 805; doi:10.3390/molecules21060805 www.mdpi.com/journal/molecules Molecules 2016, 21, 805; doi:10.3390/molecules21060805 www.mdpi.com/journal/molecules Molecules 2016, 21, 805 2 of 14 Molecules 2016, 21, 805 2 of 15 Molecules 2016, 21, 805 2 of 15 hydrogenation of dienamines [23], the transition metal-catalyzed asymmetric allylic C-H amination [24] asymmetric hydrogenation of dienamines [23], the transition metal-catalyzed asymmetric allylic andasymmetric the nitroso-ene hydrogenation reaction[ 25of]. dienamines [23], the transition metal-catalyzed asymmetric allylic C-HIn amination spite of recent [24] and advances the nitroso-ene in asymmetric reaction synthesis, [25]. the olefination of α-amino aldehydes from C-H aminationIn spite of [24]recent and advances the nitroso-ene in asymmetric reaction synthesis, [25]. the olefination of α-amino aldehydes from the chiral pool is still an attractive alternative, as the starting materials can be obtained from the the chiralIn spite pool of recentis still advances an attractive in asy alternative,mmetric synthesis, as the starting the olefination materials of can α-amino be obtained aldehydes from from the corresponding α-amino acids by several routes [26–28]. The synthesis of chiral allylamines by the thecorresponding chiral pool αis-amino still an acids attractive by several alternative, routes as[26–28]. the starting The synthesis materials of can chiral be obtainedallylamines from by thethe Wittig [29–31], Julia [32–34] and Peterson [35] olefination of α-amino aldehydes has been reported, correspondingWittig [29–31], αJulia-amino [32–34] acids and by Petersonseveral routes [35] olefination [26–28]. Th ofe αsynthesis-amino aldehydes of chiral allylamineshas been reported, by the but these approaches are often limited by the chemical and configurational instability of α-amino Wittigbut these [29–31], approaches Julia [32–34] are andoften Peterson limited [35] by olefination the chemical of α-amino and configurationalaldehydes has beeninstability reported, of aldehydesbutα-amino these [aldehydes27 approaches]. [27]. are often limited by the chemical and configurational instability of α-aminoInIn the the aldehydes classical classical Julia[27]. Julia reaction reaction [36[36,37],37] (Scheme(Scheme1 1)),, aa lithiatedlithiated aryl alkyl sulfone sulfone is is added added to to an an aldehydealdehydeIn the to to give classical give the the corresponding Juliacorresponding reaction [36,37]α α-hydroxysulfone-hydroxysulfone (Scheme 1), Aa lithiated(pathway aryl aa).). This,alkyl This, in insulfone turn, turn, is is converted convertedadded to into an into thealdehydethe target target alkene to alkene give by theby in incorresponding situ situ acetylation acetylation α and-hydroxysulfone and treatment treatment of of A the the(pathway resulting resulting a).α αThis,-acetoxysulfone-acetoxysulfone in turn, is converted withwith sodiumsodium into or the target alkene by in situ acetylation and treatment of the resulting α-acetoxysulfone with sodium magnesiumor magnesium amalgam amalgam [38] [38] or SmI or SmI2 [392 ].[39]. The The same sameα-hydroxysulfone α-hydroxysulfone A, A, however, however, can can be be obtained obtained in twoorin steps magnesiumtwo bysteps the by acylationamalgam the acylation [38] of the or lithiatedofSmI the2 [39]. lithiated phenylalkylsulfone The same phenylalkylsulfone α-hydroxysulfone with an with ester, A, anhowever, followed ester, followedcan by be the obtained reductionby the ofin thereduction two corresponding steps of theby correspondingtheα acylation-ketosulfone ofα-ketosulfone the (Scheme lithiated1, (Scheme pathway phenylalkylsulfone 1, bpathway). Chiral b allylamines).with Chiral an allylamines ester, may followed thus may be thusby obtained the be startingreductionobtained from startingof readily-available the corresponding from readily-availableα α-amino-ketosulfone esters α-amino (Scheme that areesters 1, chemically pathway that are bchemically and). Chiral configurationally allylamines and configurationally may more thus stable be obtained starting from readily-available α-amino esters that are chemically and configurationally thanmoreα-amino stable aldehydesthan α-amino [40]; aldehydes furthermore, [40]; the furthermore, additional the step additional of pathway stepb is of not pathway a limitation, b is not as a the more stable than α-amino aldehydes [40]; furthermore, the additional step of pathway b is not a latterlimitation, compounds as the are latter generally compounds prepared are generally from the prepared corresponding from the esters corresponding in at leastone esters step in [at26 least]. limitation,one step [26]. as the latter compounds are generally prepared from the corresponding