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 esters in at least one step [26].

SchemeScheme 1.1. JuliaJulia olefination. olefination. Scheme 1. Julia olefination. This variant of the Julia reaction has been used in the synthesis of E-alkene dipeptide This variant of the Julia reaction has been used in the synthesis of E-alkene dipeptide isosteres [41,42], isosteresThis [41,42],variant but of itsthe wider Julia scopereaction and hasgeneral been app usedlicability in the is stillsynthesis unexplored. of E-alkene In this paper,dipeptide we but its wider scope and general applicability is still unexplored. In this paper, we demonstrate that the isosteresdemonstrate [41,42], that but the its α wider-aminoester scope Juliaand generalolefination app licabilityis a conv isenient still unexplored. method for In the this synthesis paper, we of α-aminoester Julia olefination is a convenient method for the synthesis of terminal and disubstituted demonstrateterminal and thatdisubstituted the α-aminoester allylamines Julia (Scheme olefination 2). is a convenient method for the synthesis of allylaminesterminal and (Scheme disubstituted2). allylamines (Scheme 2).

Scheme 2. Julia olefination of chiral α-amino esters. Scheme 2. Julia olefination of chiral α-amino esters. Scheme 2. Julia olefination of chiral α-amino esters. 2. Results and Discussion 2. Results and Discussion

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MoleculesMolecules 20162016,, 2121,, 805805 33 ofof 1515 2. Results and Discussion TheThe synthesissynthesis startsstarts withwith thethe reactionreaction betweenbetween NN-Boc-Boc aminoamino estersesters 11 andand lithiatedlithiated The synthesis starts with the reaction between N-Boc amino esters 1 and lithiated phenylmethylsulfonephenylmethylsulfone 2a2a,, givinggiving thethe correspondingcorresponding ketosulfonesketosulfones 33.. TheThe experimentalexperimental conditionsconditions forfor phenylmethylsulfone 2a, giving the corresponding ketosulfones 3. The experimental conditions thisthis keykey stepstep werewere initiallyinitially optimized,optimized, withwith respectrespect toto yieldsyields andand eeee,, usingusing NN-Boc-Boc alaninealanine methylmethyl esterester for this key step were initially optimized, with respect to yields and ee, using N-Boc alanine methyl 1a1a asas thethe substratesubstrate (Table(Table 1)1) [43].[43]. ester 1a as the substrate (Table1)[43]. TableTable 1.1. OptimizedOptimized synthesissynthesis ofof ketosulfoneketosulfone 3a3a.. Table 1. Optimized synthesis of ketosulfone 3a.

Entry 2a (equiv.) Base (equiv.) T (°C) Yield aa % ee a,ba,b % EntryEntry 2a (equiv.) 2a (equiv.) Base Base (equiv.) (equiv.) T (°C) T (˝C) Yield Yield a%% eeeea,b %% 11 11 nn-BuLi-BuLi (2)(2) −−7878 5555 <70<70 1 1 n-BuLi (2) ´78 55 <70 22 211 1 nn-BuLi-BuLin-BuLi (2)(2) (2) −−3030´ 30 6666 66 <70<70<70 33 311 1 nn-BuLi-BuLin-BuLi (3)(3) (3) −−7878´ 78 868686 <70<70<70 44 422 2 nn-BuLi-BuLin-BuLi (4)(4) (4) −−7878´ 78 898989 65 65 65 ´ 55 522 2 nn-BuLi-BuLin-BuLi (4)(4) (4) −−3030 30 4242 42 <70<70<70 6 2 n-BuLi/TMEDA (4) ´78 -- 6 2 n-BuLi/TMEDA (4) −78 - - 6 72 2n-BuLi/TMEDA KHMDS (4) −78´ 78 - -- - 77 822 2 KHMDS KHMDS NaH −−7878´ 78 ------88 922 2 NaH NaHn-BuLi (4) −−7878´ 78 89-- c 95 - -c a By addition99 of 1a to lithiated22 2a; b ee determinednn-BuLi-BuLi after(4)(4) conversion to−−7878 the allylamine89896a ;cc c By the reverse9595 cc addition a of a suspension of lithiated 2a to 1a. b c a ByBy additionaddition ofof 1a1a toto lithiatedlithiated 2a2a;; b eeee determineddetermined afterafter conversionconversion toto thethe allylamineallylamine 6a6a;; c ByBy thethe reversereverse additionaddition ofof aa suspensionsuspension ofof lithiatedlithiated 2a2a toto 1a1a.. Addition of 1a to one equivalent of lithiated phenylmethylsulfone 2a, even in the presence of two Addition of 1a to one equivalent of lithiated phenylmethylsulfone 2a, even in the presence of equivalentsAddition of ofn-BuLi 1a to as one originally equivalent suggested of lithiated by Lygo phenylmethylsulfone [42,44], resulted in a2a partial, even conversionin the presence into theof two equivalents of n-BuLi as originally suggested by Lygo [42,44], resulted in a partial conversion twoketosulfone equivalents3a (Table of n-BuLi1, Entries as originally 1 and 2). suggested The low yieldsby Lygo are [4 likely2,44], dueresulted to the in presence a partial of conversion ionizable into the ketosulfone 3a (Table 1, Entries 1 and 2). The low yields are likely due to the presence of intoprotons, the ketosulfone both in the starting3a (Table amino 1, Entries ester 1 (NHBoc) and 2). The and low in the yields ketosulfone are likely product due to (methylene) the presence that of ionizable protons, both in the starting amino ester (NHBoc) and in the ketosulfone product ionizablecan exchange protons, with lithiatedboth in 2athe. Thestarting yield amin improvedo ester when (NHBoc) an excess and ofin BuLi the andketosulfone2a was employed product (methylene) that can exchange with lithiated 2a. The yield improved when an excess of BuLi and 2a (methylene)(Entries 3 and that 4); can under exchange these conditions, with lithiated however, 2a. The the yield enantiomeric improved purity when ofan the excess ketosulfone of BuLi and3a was 2a was employed (Entries 3 and 4); under these conditions, however, the enantiomeric purity of the wasmodest. employed The use (Entries of TMEDA 3 and in 4); association under these with condit butyllithiumions, however, [45] (Entry the 6)enantiomeric and of other purity base systems of the ketosulfone 3a was modest. The use of TMEDA in association with butyllithium [45] (Entry 6) and of ketosulfone(Entries 7, 8) 3a was was not modest. successful. The use The of best TMEDA results in wereassociation eventually with obtainedbutyllithium with [45] two (Entry equivalents 6) and of of other base systems (Entries 7, 8) was not successful. The best results were eventually obtained with othersulfone base and systems four equivalents (Entries 7, of 8) butyl was lithiumnot successful. [46,47],with The thebest resulting results were yellow eventually suspension obtained added towith the two equivalents of sulfone and four equivalents of butyl lithium [46,47], with the resulting yellow twoamino equivalents ester 1a, at of´ sulfone78 ˝C under and four argon. equivalents In this case, of completebutyl lithium conversion [46,47], into with the the ketosulfone resulting yellow3a was suspension added to the amino ester 1a, at −78 °C under argon. In this case, complete conversion into suspensionachieved, which added was to isolatedthe amino in excellentester 1a, at yield −78 and°C under enantiomeric argon. In purity this case, (Entry complete 9). It has conversion been suggested into the ketosulfone 3a was achieved, which was isolated in excellent yield and enantiomeric purity thethat, ketosulfone under similar 3a conditions,was achieved, the dilithiated which was sulfone isolated8 is formedin excellent and isyield the reactive and enantiomeric nucleophile [purity46,47]. (Entry 9). It has been suggested that, under similar conditions, the dilithiated sulfone 8 is formed and (EntryIt seems 9). moreIt has likely, been suggested however, thatthat, theunder monolithiated similar conditions, species the9 is dilithiated formed following sulfone 8 H/Li is formed exchange and is the reactive nucleophile [46,47]. It seems more likely, however, that the monolithiated species 9 is iswith the thereactive protected nucleophile aminoester [46,47]. (Scheme It seems3) and more is thelikely, actual however, nucleophile. that the A monolithiated second equivalent species of 98 isis formed following H/Li exchange with the protected aminoester (Scheme 3) and is the actual formedthen required following for aH/Li further exchange H/Li exchange with the giving protec theted dilithiated aminoester product (Scheme12, in3) agreementand is the with actual the nucleophile. A second equivalent of 8 is then required for a further H/Li exchange giving the nucleophile.observed stoichiometry. A second equivalent of 8 is then required for a further H/Li exchange giving the dilithiateddilithiated productproduct 1212,, inin agreementagreement withwith thethe observedobserved stoichiometry.stoichiometry.

Scheme 3. SchemeScheme 3.3. ReactionsReactions ofof mono-mono- andand bis-lithiatedbis-lithiated sulfones.sulfones.

TheThe optimizedoptimized reactionreaction conditionsconditions werewere were thenthen then appliedapplied applied toto to thethe the NNN-Boc-amino-Boc-amino-Boc-amino estersesters esters 1b1b1b–––fff (Table(Table(Table 2),22),), givinggiving thethe correspondingcorresponding ketosulfones ketosulfones 33 inin good good to to excellent excellent yields yields and and eeee,, withwith thethe onlyonly exceptionexception ofof thethe protectedprotected tyrosinetyrosine methylmethyl esterester 1f1f;; repeatedrepeated attemptsattempts underunder severalseveral reactionreaction conditionsconditions invariablyinvariably ledled toto aa significantsignificant lossloss inin enantiomericenantiomeric puritypurity forfor thisthis compound.compound. WithWith L-prolineL-proline methylmethyl

Molecules 2016, 21, 805 4 of 14

Moleculesthe protected 2016, 21 tyrosine, 805 methyl ester 1f; repeated attempts under several reaction conditions invariably4 of 15 led to a significant loss in enantiomeric purity for this compound. With L-proline methyl ester 1g ester(Entry 1g 7), (Entry where 7), no where ionizable no ionizable protons are protons present, are the present, best optical the best purity, optical albeit purity, at the albeit expenses at the of expenses of a lower yield, was obtained by using two equivalents of PhSO2Me and BuLi with respect a lower yield, was obtained by using two equivalents of PhSO2Me and BuLi with respect to the toaminoester, the aminoester, whereas whereas racemization racemization was observed was obse byrved employing by employing the usual the conditions. usual conditions. This further This furtherconfirms confirms that the reactivethat the nucleophile reactive innucleophile the reaction in with the the reaction amino esterswith isthe the monolithiatedamino esters speciesis the monolithiated species PhSO2CH2Li, as suggested above (Scheme 3). PhSO2CH2Li, as suggested above (Scheme3).

a Table 2. Reactions between amino esters 1 and lithiated sulfones 2 a..

EntryEntry Aminoester Aminoester Sulfone Sulfone R R2 2 ProductProduct Yield% Yield% 11 AlaAla (1a) (1a) 2a2a HH 3a 3a 89 89 22 Val (Val1b) (1b) 2a2a HH 3b 3b 84 84 3 Leu (1c) 2a H 3c 89 43 Ile (Leu1d) (1c) 2a2a HH 3c 3d 89 86 54 Phe (Ile1e )(1d) 2a2a HH 3d 3e 86 94 6 Tyr (1f) b 2a H 3f 80 75 ProPhe (1g) (1e) 2a2a HH 3e 3g 94 60 c d 86 PheTyr (1e) (1f) b 2b2a HMe 3f 3h 80 77 9 Pro (1g) 2b Me 3i 80 c,e c a 7 Pro (1g) 2a H 3g 60 b Reactions were carried out with 2 equivalents of bis-lithiated sulfone (PhSO2CLi2R); Protected as O-TBDMS c d d (see Scheme2); With 28 equivalents Phe of (1e mono-lithiated) 2b PhSOMe2CHRLi;3h 3:277 mixture of diastereoisomers; e 55:45 mixture of diastereoisomers. 9 Pro (1g) 2b Me 3i 80 c,e

a Reactions were carried out with 2 equivalents of bis-lithiated sulfone (PhSO2CLi2R); b Protected as Finally, the same conditions were applied to the reaction of amino esters 1e and 1g with O-TBDMS (see Scheme 2); c With 2 equivalents of mono-lithiated PhSO2CHRLi; d 3:2 mixture of phenylethylsulfone 2b (Table2, Entries 8 and 9), giving the corresponding ketosulfones 3h and diastereoisomers; e 55:45 mixture of diastereoisomers. 3i, as mixtures of diastereoisomers, in excellent yield. The ketosulfones 3a–g thus obtained were reduced with NaBH (Scheme2), giving quantitatively Finally, the same conditions were applied to the reaction 4of amino esters 1e and 1g with the α-hydroxysulfones 4a–g as mixtures of syn (S,S) and anti (S,R) diastereoisomers in ratios from phenylethylsulfone 2b (Table 2, Entries 8 and 9), giving the corresponding ketosulfones 3h and 3i, as approximately 10:1 for branched Compounds 4b–d (Val, Leu, Ile) to 3:1 for compounds having linear mixtures of diastereoisomers, in excellent yield. side chains 4a,e,f (Ala, Phe, Tyr) to 1.5:1 for 4g (Pro), in agreement with previous findings [48]. The ketosulfones 3a–g thus obtained were reduced with NaBH4 (Scheme 2), giving No attempts were made to optimize the stereoselectivity, as the newly-formed stereogenic center is quantitatively the α-hydroxysulfones 4a–g as mixtures of syn (S,S) and anti (S,R) diastereoisomers in lost in the final step of the synthesis. Not surprisingly, complex mixtures containing all four possible ratios from approximately 10:1 for branched Compounds 4b–d (Val, Leu, Ile) to 3:1 for compounds diastereoisomers were obtained in the reduction of ketosulfones 3h and 3i. having linear side chains 4a,e,f (Ala, Phe, Tyr) to 1.5:1 for 4g (Pro), in agreement with previous Conversion of hydroxysulfones 4 into the allylamines 6 follows the standard protocol of the Julia findings [48]. No attempts were made to optimize the stereoselectivity, as the newly-formed reaction. Thus, the alcohols 4 were acetylated with acetic anhydride and DMAP, and the corresponding stereogenic center is lost in the final step of the synthesis. Not surprisingly, complex mixtures acetoxysulfones 5 were converted to the target aminoalkenes 6 in the final reductive elimination, containing all four possible diastereoisomers were obtained in the reduction of ketosulfones 3h and promoted by sodium amalgam [36] or in situ generated magnesium amalgam [38] (Scheme2, Table3). 3i. The two methods were shown to proceed with comparable yields and ee, except for 5f: in this case, Conversion of hydroxysulfones 4 into the allylamines 6 follows the standard protocol of the sodium amalgam caused the deprotection of the phenol group, leading directly to the allylamine 6f1, Julia reaction. Thus, the alcohols 4 were acetylated with acetic anhydride and DMAP, and the while the O-protected product 6f was smoothly obtained with magnesium amalgam. corresponding acetoxysulfones 5 were converted to the target aminoalkenes 6 in the final reductive elimination, promoted by sodium amalgam [36] or in situ generated magnesium amalgam [38] (Scheme 2, Table 3). The two methods were shown to proceed with comparable yields and ee, except for 5f: in this case, sodium amalgam caused the deprotection of the phenol group, leading directly to the allylamine 6f′, while the O-protected product 6f was smoothly obtained with magnesium amalgam.

Molecules 2016, 21, 805 5 of 14

Molecules 2016, 21, 805 Molecules 2016, 21, 805 5 of 15 5 of 15 Molecules 2016, 21, 805 Molecules 2016, 21, 805 5 of 15 5 of 15 Molecules 2016,, 2121,, 805805 Molecules 2016, 21, 805 Table 3. Synthesis of allylamines 6. 5 of 15 5 of 15 Table 3. Synthesis of allylaminesTable 3. Synthesis 6. of allylamines 6. Table 3. Synthesis of allylaminesTable 3. Synthesis 6. of allylamines 6. a Table 3.b SynthesisSynthesis c ofof allylaminesallylaminesTable 3. Synthesis 6.. of allylamines 6. a b c AllylamineAllylamine Method MethodAllylamine a Yield bYield % Methodee c % a Yieldee Allylamine b % ee c % AllylamineMethodAllylamine a Yield b %Method ee Method c % a YieldYield b % ee %c % ee % Allylamine MethodAllylamine a Yield b % Methodee c % a YieldAllylamine b % ee c % MethodAllylamine a Yield b %Method ee c % a Yield b % ee c % Allylamine MethodAllylamine aa YieldYield b % Methodee cc %% a Yield% Allylamine b % ee c % MethodAllylamine aa YieldYield b %Method ee cc %% a Yield b % ee c %

6a A6a (1h) 68 (60) A 95(1h) 6f 68 (60) 95 6f A d,e (2h) 65 (52) A d,e 80 (2h) e 65 (52) 80 e 6a A (1h) 68 (60) 95 6f d,e A d,e (2h)e 65 (52) 80 e 6a A6a (1h) 68 (60) A 95(1h) 6f 68 (60) 95 6f A d,e (2h) 65 (52) A d,e 80 (2h) ee 65 (52) 80 e 6a 6a A6a (1h)A (1h) 68 (60) 68A (60) 95(1h) 6f 6895 (60) 6f 95 6f A (2h)(2h) 65 65 (52)(52) A d,e 80 80A (2h) d (2h) 65 (52)65 (52) 80 e 80 e

6b A6b (2h) 60 (50) A >99 (2h) 6f′ 60 (50) >99 6f′ B d (4h) 71 (57) B d ND (4h) 71 (57) ND 6b A6b (2h) 60 (50) A >99 (2h) 6f′ 60 (50) >99 6f′ B d (4h) 71 (57) B d ND (4h) 71 (57) ND 6b A6b (2h) 60 (50) A >99 (2h) 6f′ 60 (50) >991 6f′ B d (4h) 71 (57) B d ND (4h)d 71 (57) ND 6b 6b A6b (2h)A (2h) 60 (50) 60A (50) >99 (2h) 6f′ >99 60 (50) 6f >99 6f′ B (4h) 71 (57) B NDB (4h) (4h) 71 (57)71 (57) ND ND

6c A6c (2h) 67 (62) A >99 (2h) 6g 67 (62) >99 6g B (2h) 84 (50) B >99(2h) 84 (50) >99 6c 6c A6c (2h) A (2h) 67 (62) 67A (62) >99 (2h) 6g >99 67 (62) 6g >99 6g B (2h) 84 (50) B >99(2h)B (2h) 84 (50) 84 (50) >99 >99 6c A6c (2h) 67 (62) A >99 (2h) 6g 67 (62) >99 6g B (2h) 84 (50) B >99 (2h) 84 (50) >99

6d A6d (3h) 69 (59) A >99 (3h) 6h 69 (59) >99 6h B (4h) 71 f (55) B ND(4h) 71 f (55) f ND 6d 6d A6d (3h)A (3h) 69 (59) 69A (59) >99 (3h) 6h >99 69 (59) 6h >99 6h B (4h) 71 f (55) B ND(4h)B (4h) 71 f (55)71 (55)ND ND 6d A6d (3h) 69 (59) A >99 (3h) 6h 69 (59) >99 6h B (4h) 71 ff (55) B ND(4h) 71 f (55) ND 6d A6d (3h) 69 (59) A >99 (3h) 6h 69 (59) >99 6h B (4h) 71 (55) B ND(4h) 71 (55) ND

A (2h) 68 (64) A >99 (2h) 68 (64) >99 A (2h) 68 (64) A >99 (2h) 68 (64) >99 A (2h) 68 (64) A >99 (2h) 68 (64) >99 6e A (2h) 68 (64) A >99 (2h) 6i 68 (64) >99 B (12h) 65 g (52) ND g 6e 6eA (2h) 68 (64)6i >99 6i B (12h) 65 g (52) B (12h)ND 65 g (52) ND 6e 6e 6i 6i B (12h) 65 (52) B (12h)ND 65 (52) g ND 6e 6e B6e (4h) 71 (67) B >99 (4h) 6i 71 (67) 6i >99 6i B (12h) 65 g (52) B (12h)NDB (12h) 65 g (52) 65 (52)ND ND B (4h) 71 (67) B >99 (4h) 71 (67) >99 a B (4h) 71 (67) B >99 (4h) 71 (67) >99 a Method A: Mg powderB (4h)a (2.5 eq), HgCl 71 (67)2 (0.1 equiv.), >99 EtOH/THF2 (3:1), 25 °C; Method B: 5% Na/Hg (3 Method A: Mg powdera Method (2.5 eq), A: HgCl Mg powder2 (0.1 equiv.), (2.5 eq), EtOH/THF HgCl (0.1 (3:1), equiv.), 25 °C; EtOH/THF Method B: (3:1), 5% Na/Hg 25 °C; Method(3 B: 5% Na/Hg (3 a Method A: Mg powdera Method (2.5 eq), A: HgCl Mg powder2 (0.1 equiv.), (2.5 eq), EtOH/THF HgCl2 (0.1 (3:1), equiv.), 25 °C; EtOH/THF Method B: (3:1), 5% Na/Hg 25 °C; Method(3 B: 5% Na/Hg (3 aa a b c d a equiv.), Method EtOH, A: Mg − powder15 °C;aequiv.), Methodb (2.5Overall eq), EtOH, A: yieldsHgCl Mg − powder1522 from(0.1(0.1 °C; equiv.),equiv.), aminob (2.5Overall eq), EtOH/THFEtOH/THFesters yieldsHgCl 1 2in from(0.1 brackets;(3:1),(3:1), equiv.), amino 2525 °C;°C; c EtOH/THFestersBy MethodMethod chiral 1 in B:B:HRGC; brackets;˝(3:1), 5%5% Na/HgNa/Hg 25 d °C;From c By (3Method(3 chiral B:HRGC; 5% Na/Hg d From (3 Methodequiv.), EtOH, A: Mg −15 powder °C;equiv.), b Overall (2.5 EtOH, eq),yields − HgCl15 from °C;2 aminob (0.1Overall equiv.), esters yields 1 EtOH/THFin from brackets; amino c estersBy (3:1), chiral 1 25in HRGC;brackets;C; Method d Fromc By chiral B: 5% HRGC; Na/Hg d From (3equiv.), equiv.),O-TBDMS EtOH, ˝protected b−15 °C; sulfoneequiv.),O-TBDMS bb Overall 5f; EtOH, e protectedByyields chiral −15 fromfrom °C; HPLC;sulfone aminoaminob Overall f 5f;80:20 estersesters e Byyields mixture chiral1 inin from brackets;brackets; HPLC;of aminoE and f 80:20c c Z estersByBy isomers; chiralchiralmixture 1 in HRGC;HRGC; gbrackets; 85:15 of E and mixtured FromFrom c ZdBy isomers; chiral HRGC;g 85:15 mixtured From EtOH,O-TBDMS´15 protectedC; Overall sulfoneO-TBDMS yields 5f; e protectedBy from chiral amino HPLC;sulfone estersf 5f;80:20 e By mixture1 chiralin brackets; HPLC; of E and f 80:20 ZBy isomers; mixture chiral g 85:15 HRGC;of E and mixture Z isomers;From O-TBDMS g 85:15 mixture protected O-TBDMSof E and Ze protectedisomers. sulfoneO-TBDMSof E and 5f; Z eef protectedisomers.ByBy chiralchiral HPLC;HPLC;sulfone ff 5f;80:2080:20 e By mixturemixture chiral HPLC;ofof E andand f 80:20 Zg isomers;isomers; mixture gg 85:1585:15 of E andmixturemixture Z isomers; g 85:15 mixture sulfoneof E and 5f; Z isomers.By chiral of HPLC; E and Z isomers.80:20mixture of E and Z isomers; 85:15 mixture of E and Z isomers. of E andand Z isomers.isomers. of E and Z isomers. The Julia reaction Theis known Julia reactionto favor is the known formation to favor of thethe Eformation isomer, whenof the leading E isomer, to when leading to The Julia reaction Theis knownJulia reactionto favor is theknown formation to favor of thethe Eformation isomer, whenof the leadingE isomer, to when leading to disubstitutedThe Julia alkenesreactiondisubstituted [36, Theis 37].known Julia Accordingly, alkenes reactionto favor [36, is whenthe 37].known formationAccordingly, substituted to favor of theacetateswhenthe Eformation isomer,isomer,substituted 5h,i were whenwhenof theacetatessubjected leading leadingE isomer, 5h,i toto werewhen subjected leading to disubstituted alkenesdisubstituted [36,37]. Accordingly, alkenes [36, when37]. Accordingly, substituted acetateswhen substituted 5h,i were acetatessubjected 5h,i to were subjected to Thedisubstitutedreductive Julia elimination reaction alkenesdisubstitutedreductive [36,with is37]. known Na(Hg), eliminationAccordingly, alkenesto the favor corresponding[36,with when37]. theNa(Hg), Accordingly, substitutedsubstituted formation theallylamines corresponding acetatesacetateswhen of the 6h,isubstituted 5h,i Ewere allylamines isomer,werewere obtained acetatessubjectedsubjected when 6h,i as 5h,i 4:1weretoto leading were obtained subjected to disubstitutedas 4:1to reductive eliminationreductive with Na(Hg),elimination the withcorresponding Na(Hg), theallylamines corresponding 6h,i were allylamines obtained 6h,i as were4:1 obtained as 4:1 reductivemixtures ofelimination E and Z reductivemixturesisomers, with Na(Hg),asofelimination Edetermined and Zthe isomers, correspondingwith by NMR. asNa(Hg), determined A comp theallylamineslete corresponding by list NMR. of 6h,ithe A allylamines compwerewere allylamineslete obtainedobtained list synthesized of 6h,ithe asas allylamines4:14:1were obtained synthesized as 4:1 alkenesmixtures [36, 37of E]. and Accordingly, Zmixtures isomers, ofas Edetermined whenand Z isomers, substituted by NMR. as determined A comp acetateslete by list NMR. of5h,i the A allylaminescompwerelete subjected list synthesized of the allylamines to reductive synthesized elimination mixturesin this work of E with andand overall Z mixturesin isomers,isomers, this yields work asofas andEdetermined determinedwith and enan overallZ isomers,tiomeric byby yields NMR.NMR. as excess anddetermined AA enancompcompis reportedtiomericletelete by listlist NMR. in ofofexcess Table thethe A allylaminesallylamines compis3. reportedlete list synthesizedinsynthesized of Table the allylamines 3. synthesized in this work with overallin this yields work andwith enan overalltiomeric yields excess and enan is reportedtiomeric in excess Table is3. reported in Table 3. with Na(Hg),inin thisthis workworkthe withwith corresponding overalloverallin this yieldsyields work andand with enanenan allylaminesoveralltiomeric yields excess and6h,i enanis reportedweretiomericobtained in excess Table is3. reported as 4:1 in mixtures Table 3. of E and Z isomers, as 3. Experimental Section3. Experimental Section determined3. Experimental by NMR. Section3. Experimental A complete Section list of the allylamines synthesized in this work with overall yields 3. Experimental Section3. Experimental Section Glassware was thoroughlyGlassware oven-dried was thoroughly for reactions oven-dried using foranhydrou reactionss conditions. using anhydrou THF wass conditions. THF was and enantiomericGlassware was excess thoroughlyGlassware is reported oven-dried was thoroughly in for Table reactions oven-dried3. using foranhydrou reactionss conditions. using anhydrou THF wass conditions. THF was distilledGlassware over sodium wasdistilled thoroughly benzopheGlassware overnone oven-driedsodium was ketyl, thoroughly benzophe under for reargon;actionsnone oven-dried CHketyl, using2Cl under2 and foranhydrou EtOH reargon;actions weres CH conditions. using 2distilledCl2 and anhydrou EtOH overTHF CaH werewass conditions.2 distilled overTHF CaH was2 2 2 2 2 2 2 distilled over sodiumdistilled benzophe overnone sodium ketyl, benzophe under argon;none CHketyl,Cl under and EtOH argon; were1 CH Cldistilled and EtOH over CaHwere distilled over CaH distilledunder argon. over sodiumYieldsdistilledunder referbenzophe argon.to over chromatographicallynone sodiumYields ketyl, referbenzophe under to argon;chromatographically noneand spectroscopically CHketyl,22Cl under22 andand EtOHEtOH argon; and ( were1were H-NMR) spectroscopicallyCH 2 distilleddistilledCl2 and homogeneous EtOH overover CaH( CaHwere1H-NMR)22 distilled homogeneous over CaH2 3. Experimentalunder argon. Yields Sectionunder refer argon.to chromatographically Yields refer to chromatographically and spectroscopically and ( 1H-NMR)spectroscopically homogeneous (1H-NMR) homogeneous undermaterials. argon. Reactions Yieldsundermaterials. wererefer monitoredargon.to chromatographicallyReactions Yields by wereTLCrefer carriemonitoredto chromatographically andd out spectroscopically byon TLCsilica carrie gel platesandd out(11 H-NMR)spectroscopically usingon silica UV homogeneous gel light plates as(1H-NMR) the using UV homogeneous light as the materials. Reactionsmaterials. were monitored Reactions by wereTLC monitoredcarried out byon TLCsilica carrie gel platesd out usingon silica UV gel light plates as the using UV light as the materials.visualizing Reactions agent andmaterials.visualizing were KMnO monitored 4 Reactions asagent the bydevelopingand wereTLC KMnO carriemonitored 4agent. asd theout Silica bydevelopingon TLCsilica gel carrie 60gel (230agent. platesd out−400 Silica usingon mesh) silica gel UV was 60gel light (230 platesused as−400 thefor using mesh) UV was light used as thefor Glasswarevisualizing agent was andvisualizing thoroughlyKMnO4 asagent the anddeveloping oven-dried KMnO 4 agent.as the for Silicadeveloping reactions gel 60 agent.(230− using400 Silica mesh) gel anhydrous was60 (230 used−400 for mesh) conditions. was used for THF was visualizingflash column agent chromatography. andvisualizingflash KMnO column44 as asagentNMR chromatography.thethe developingandspectradeveloping KMnO were 4agent. agent. asrecordedNMR the Silica Silica developingspectra on gelgel a were Varian6060 (230agent.(230 recorded 500−400 Silica MHz mesh) on gel spectrometera wasVarian60 (230 used 500−400 for inMHz mesh) spectrometer was used for in flash column chromatography.flash column NMR chromatography. spectra were NMRrecorded spectra on a were Varian recorded 500 MHz on spectrometera Varian 500 inMHz spectrometer in 1 1 13 13 δ distilledflashCDCl overcolumn3, unless sodium chromatography.otherwiseflashCDCl benzophenone stated, column3, unless atNMR chromatography.500otherwise MHzspectra ( ketyl,1stated,H) were and atrecordedNMR under125.68 500 MHzspectra MHz on argon; ( a(H) 13wereVarianC); and chemical CHrecorded 125.68 5002Cl MHz MHz shifts2 onand spectrometer a( areVarianC); EtOH in chemical ppm 500 were ( inδMHz) shifts spectrometer distilled are in ppm over (inδ) CaH2 CDCl3, unless otherwiseCDCl stated,3, unless at otherwise500 MHz ( stated,1H) and at 125.68 500 MHz MHz (1 H)(13C); and chemical 125.68 MHz shifts ( 13areC); in chemical ppm (δ) shifts are in ppm (δ) δ 111 1 1313 13 13 δ δ CDClwith chloroform33,, unlessunless otherwiseotherwise as theCDClwith reference stated,stated,chloroform3, unless atat ( δ500otherwise500 = as7.26 MHzMHz the for reference(( stated, H)1H-NMR and at 125.68( δ 500and = 7.26 MHz 77.16MHz for ( for(H)1H-NMRC); 13andC-NMR). chemical 125.68 and 77.16CouplingMHz shifts for( areC); 13 constantsC-NMR).in chemical ppm1 ( )CouplingJ shifts are constantsin ppm (δ )J under argon. Yieldswith refer chloroform to chromatographicallyδ as the reference1 (δ = 7.26 forand 1H-NMR13 spectroscopically and 77.16 for 13C-NMR). ( H-NMR) Coupling constants homogeneous J with chloroform as1 thewith reference chloroform13 (δ = as7.26 the for reference 11H-NMR (δ and = 7.26 77.16 for for1H-NMR 1313C-NMR). and 77.16Coupling for 13 C-NMR).constants CouplingJ constants J withare given chloroform in hertz. as 1theHwithare and referencegiven chloroform 13C-NMR in hertz.(δ == resonances as7.267.26 1 theH forforand reference H-NMR 13 C-NMRwere ( assignedδ and = resonances 7.26 77.16 for using for1H-NMR were aC-NMR). combination assigned and 77.16Coupling using offor DEPT, 13 constantsaC-NMR). combination COSY CouplingJ of DEPT, constants COSY J are given in hertz. 1Hare and given 13C-NMR in hertz. resonances 1H and 13 C-NMRwere assigned resonances using were a combination assigned using of DEPT, a combination COSY of DEPT, COSY materials.areand given HSQC Reactions in spectra. hertz. 11 HareandInfrared and were given HSQC 1313C-NMR spectra in monitored spectra. hertz. resonanceswere 1 HInfrared andrecorded by13 C-NMRwere spectra TLC as assigned thin resonanceswere carried film recordedusing or Nujolwereout a combination as assigned onmull thinsilica onfilm NaClusing of or gelDEPT, Nujol platesa combination plates COSYmull on aon using NaCl of DEPT, plates UV COSY lighton a as the and HSQC spectra. andInfrared HSQC spectra spectra. were Infrared recorded spectra as thin were film recorded or Nujol as mull thin onfilm NaCl or Nujol plates mull on aon NaCl plates on a andNicolet HSQC Avatar spectra. FT-IR andNicoletInfrared spectrometer HSQC Avatar spectra spectra. FT-IR(Thermo were Infrared spectrometerrecorded Fisher spectra Scientific,as thin(Thermo were film Waltham,recorded orFisher Nujol Scientific,as MA, mull thin USA). onfilm Waltham,NaCl orMelting Nujol plates MA, pointsmull on USA). aon NaCl Melting plates points on a visualizingNicolet Avatar agent FT-IR andNicolet spectrometer KMnO Avatar4 FT-IR(Thermoas the spectrometer Fisher developing Scientific, (Thermo agent.Waltham, Fisher Scientific,Silica MA, USA). gel Waltham, Melting 60 (230 MA, points´ 400USA). mesh) Melting waspoints used for Nicoletare uncorrected. Avatar FT-IR ElectrosprayNicoletare spectrometer uncorrected. Avatar (ESI) FT-IRmass(Thermo Electrospray spectraspectrometer Fisher we (ESI) Scientific,Scientific,re obtained mass(Thermo spectra Waltham,Waltham, on Fisher a weBruker Scientific,re MA,MA, obtained Daltonics USA).USA). Waltham, on MeltingMelting Esquirea Bruker MA,pointspoints 4000 Daltonics USA). Melting Esquire points 4000 flashare column uncorrected. chromatography. Electrosprayare uncorrected. (ESI) mass Electrospray NMR spectra spectra we(ESI)re obtainedmass were spectra on recorded a weBrukerre obtained Daltonics on a on Varian Esquirea Bruker 4000 500 Daltonics MHz Esquire spectrometer 4000 in arespectrometer uncorrected. (Bruker Electrosprayarespectrometer Corporation, uncorrected. (ESI) (Bruker Billerica,mass Electrospray spectraCorporation, MA, we USA).(ESI)re obtainedBillerica,mass HRMS spectra analyses onMA, a weBrukerUSA).re were obtained HRMSDaltonics carried analyseson out Esquirea Bruker in thewere 4000 ESIDaltonics carried out Esquire in the 4000 ESI spectrometer (Brukerspectrometer Corporation, (Bruker Billerica, Corporation, MA, USA).1 Billerica, HRMS analysesMA, USA). were HRMS carried analyses13 out in werethe ESI carried out in the ESI CDClspectrometermode3, unless on a TOF-MS otherwise (Brukerspectrometermode instrument Corporation, on stated, a TOF-MS (B(Bruker rukerBillerica,Billerica, at 500 instrument Corporation).Corporation, MA,MA, MHz USA).USA). (B ( rukerBillerica,H) Enantiomeric HRMSHRMS and Corporation). analysesanalyses MA, 125.68 USA).excesses werewere MHz EnantiomericHRMS carriedcarriedwere( analyses determined outoutC); excessesinin chemical thethewere ESI ESIby carriedwere shiftsdetermined out in arethe ESI inby ppm (δ) mode on a TOF-MSmode instrument on a TOF-MS (Bruker instrumentCorporation). (Bruker Enantiomeric Corporation). excesses Enantiomeric were determined excesses by were determined by modeChiral onHigh a TOF-MS ResolutionmodeChiral instrument GC onHigh analyses a TOF-MS Resolution(Bruker on γ instrumentCorporation).- or GC β-cyclodextrin analyses (B1 rukerEnantiomeric on γ capillaryCorporation).- or β-cyclodextrin excessescolumns Enantiomeric wereand, capillary fordetermined13 compounds excessescolumns by wereand, fordetermined compounds by with chloroformChiral High Resolution as theChiral GC reference High analyses Resolution on (δ γ=- or GC 7.26 β -cyclodextrinanalyses for H-NMRon γ capillary- or β-cyclodextrin and columns 77.16 and, capillary for for compoundsC-NMR). columns and, Coupling for compounds constants J Chiral3f and High6f only, Resolution by chiralChiral3f and GC high High 6fanalyses only, pressure Resolution by on chiral γliquid- or GC highβ -cyclodextrinchromatography analyses pressure on γliquidcapillary- or on β -cyclodextrinchromatography a Cellulose2columns and, column,capillary foron acompounds with Cellulose2columns a UV and, column, for compounds with a UV are given3f and in6f hertz.only, by 1chiral3fH and and high 6f 13only, pressureC-NMR by chiral liquid resonances high chromatography pressure liquid were on chromatography assigneda Cellulose2 usingcolumn, on a aCellulose2with combination a UV column, with of DEPT, a UV COSY 3fdetector andand 6f operating only,only, byby atchiralchiral3fdetector λ and = 280highhigh 6f operating nm,only, pressurepressure eluting by atchiral liquidliquid λwith = 280high nHex/iPrOHchromatographychromatography nm, pressure eluting liquid9:1. with Opticalonon nHex/iPrOHchromatography aa Cellulose2Cellulose2 rotations 9:1.column,column, were Opticalon measureda withCellulose2with rotations aa UVUV at column, were measured with a UV at detector operating atdetector λ = 280 operating nm, eluting at λwith = 280 nHex/iPrOH nm, eluting 9:1. with Optical nHex/iPrOH rotations 9:1. were Optical measured rotations at were measured at and HSQCdetector25 °C with operating spectra. a Jasco at detector25P-2000 Infraredλ °C== 280280 with polarimeteroperating nm,nm, a spectraelutingelutingJasco at P-2000 (Jasco λwithwith = were280 nHex/iPrOHnHex/iPrOH Inc,polarimeter nm, recordedEaston, eluting 9:1.9:1.MD, (Jascowith OpticalOptical as USA). nHex/iPrOHInc, thin rotations rotationsEaston,Commercial film 9:1.MD, werewere or Optical USA).reagentsNujol measuredmeasured rotations Commercial mulland atat were on reagents measured NaCl platesand at on a 25 °C with a Jasco 25P-2000 °C with polarimeter a Jasco P-2000(Jasco Inc,polarimeter Easton, (JascoMD, USA). Inc, Easton, Commercial MD, USA).reagents Commercial and reagents and 25solvents °C with were a Jascopurchased 25solventsP-2000 °C fromwith polarimeterwere Sigma-Aldricha Jascopurchased P-2000(Jasco from (Milan, Inc,polarimeter Sigma-Aldrich Easton, Italy); MD,(JascoPhSO USA).(Milan, 2MeInc, and Easton,Commercial Italy); PhSO MD,PhSO2Et were USA).reagents2Me preparedand Commercial PhSOand 2Et were reagents prepared and Nicoletsolvents Avatar were FT-IRpurchasedsolvents spectrometer from were Sigma-Aldrich purchased (Thermo from (Milan, Sigma-Aldrich Italy); Fisher PhSO Scientific, (Milan,2Me and Italy); PhSO Waltham, PhSO2Et were2Me preparedand MA, PhSO USA).2Et were prepared Melting points solvents were purchasedsolvents from were Sigma-Aldrich purchased from (Milan, Sigma-Aldrich Italy); PhSO (Milan,22Me and Italy); PhSO PhSO22Et were2Me preparedand PhSO 2Et were prepared are uncorrected. Electrospray (ESI) mass spectra were obtained on a Bruker Daltonics Esquire 4000 spectrometer (Bruker Corporation, Billerica, MA, USA). HRMS analyses were carried out in the ESI mode on a TOF-MS instrument (Bruker Corporation). Enantiomeric excesses were determined by Chiral High Resolution GC analyses on γ- or β-cyclodextrin capillary columns and, for compounds 3f and 6f only, by chiral high pressure liquid chromatography on a Cellulose2 column, with a UV detector operating at λ = 280 nm, eluting with nHex/iPrOH 9:1. Optical rotations were measured at 25 ˝C with a Jasco P-2000 polarimeter (Jasco Inc, Easton, MD, USA). Commercial reagents and solvents were purchased from Sigma-Aldrich (Milan, Italy); PhSO2Me and PhSO2Et were prepared by reaction of sodium phenylsulfinate with the appropriate iodoalkane according to the literature [49]. Molecules 2016, 21, 805 6 of 14

3.1. General Procedure for the Synthesis of α-Ketosulfones 3 1.6 M n-BuLi in hexane (2.5 mL, 4 mmol for 3a–f,h; 1.25 mL, 2 mmol for 3g,i) was slowly added at ´5 ˝C, under Ar, to a solution of sulfone 2 (2.0 mmol) in 1.5 mL dry THF, and the mixture was stirred at ´5 ˝C for 30 min (4 h for reactions with sulfone 2b). The resulting yellow suspension was transferred via a syringe to a three-necked flask, containing a 2.5 M solution of the N-Boc amino ester 1 (1 mmol) in dry THF (1M for 3h,i), at ´78 ˝C, under an Ar atmosphere, with stirring. The mixture was stirred overnight while the temperature was allowed to reach 25 ˝C, and partitioned between 5% aqueous citric acid (water for 3f) and ethyl acetate. The organic phase was extracted with saturated NaHCO3 and brine, dried over Na2SO4 and evaporated to give a solid that was purified by flash chromatography (eluent AcOEt/petroleum ether from 0%–15%).

3.2. Spectroscopic and Analytical Data for α-Ketosulfones 3 (3S)-3-(tert-Butoxycarbonylamino)-1-(phenylsulfonyl)-2-butanone (3a)[42]: 89% from 1a and 2a; white ˝ 25 ´1 1 solid, mp 115–117 C, rαsD ´36 (c 0.8, CHCl3); IR: 3387, 1736, 1700, 1288, 1148 cm ; H-NMR: δ 1.35 (d, J = 7.0 Hz, 3H), 1.44 (s, 9H), 4.24 (d, J = 14.0 Hz, 1H), 4.33 (m, 1H), 4.44 (d, J = 14.0 Hz, 1H), 5.15 (br, 1H), 7.58 (m, 2H), 7.69 (m, 1H), 7.90 (m, 2H) ppm. 13C-NMR: δ 16.1, 28.1, 55.9, 63.2, 80.2, 128.4, 129.3, 134.3, 139.0, 155.3, 198.4 ppm; ESI-MS: m/z 350 [M + Na]+.

(3S)-3-(tert-Butoxycarbonylamino)-4-methyl-1-(phenylsulfonyl)-2-pentanone (3b)[44]: 85% From 1b and 2a; ˝ 25 ´1 1 white solid, mp 85–88 C, rαsD ´34 (c 1, CHCl3); IR: 3372, 1709, 1506, 1323, 1160 cm ; H-NMR: δ 0.80 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H), 1.44 (s, 9H), 2.29 (m, 1H), 4.20 (d, J = 14.5, 1H), 4.25 (dd, J = 4.6, 8.7 Hz, 1H), 4.43 (d, J = 14.5 Hz, 1H), 5.10 (d, J = 8.7 Hz, 1H), 7.57 (m, 2H), 7.67 (m, 1H), 7.93 (m, 2H) ppm; 13C-NMR: δ 17.0, 19.9, 28.4, 28.9, 64.0, 65.2, 80.5, 128.6, 129.4, 134.4, 139.1, 156.0, 197.8 ppm; ESI-MS: m/z 378 [M + Na]+, 394 [M + K]+.

(3S)-3-(tert-Butoxycarbonylamino)-5-methyl-1-(phenylsulfonyl)-2-hexanone (3c): 89% From 1c and 2a; white ˝ 25 ´1 1 solid, mp 76–78 C; rαsD ´43 (c 1.6, CHCl3); IR: 3369, 1708, 1511, 1323, 1159 cm ; H-NMR: δ 0.93 (d, J = 6.1 Hz, 3H), 0.94 (d, J = 6.1 Hz, 3H), 1.37–1.44 (s and, 10H), 1.67 (m, 2H), 4.21 (d, J = 13.9 Hz, 1H), 4.28 (m, 1H), 4.49 (d, J = 13.9 Hz, 1H), 5.06 (d, J = 7.1 Hz, 1H), 7.58 (t, 2H), 7.67 (t, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 2H) ppm; 13C-NMR: δ 21.4, 23.1, 24.8, 28.2, 39.1, 58.9, 63.3, 80.5, 128.4, 129.2, 134.2, 138.9, 155.5, + + 198.6 ppm; ESI-MS: m/z 392 [M + Na] , 408 [M + K] . Anal. Calcd. for C18H27NO5S: C, 58.51; H, 7.37; N, 3.79. Found C, 58.50; H, 7.43; N, 3.86.

(3S,4S)-3-(tert-Butoxycarbonylamino)-4-methyl-1-(phenylsulfonyl)-2-hexanone (3d): 86% from 1d and 2a; ˝ 25 ´1 1 white solid, mp 83–85 C; rαsD –0.2 (c 0.9, CHCl3); IR: 3368, 1708, 1504, 1323, 1156 cm ; H-NMR: δ 0.87 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 1.05 (m, 1H), 1.27 (m, 1H), 1.42 (s, 9H), 1.99 (m, 1H), 4.20 (d, 1H), 4.27 (dd, J = 5.0, 8.7 Hz, 1H), 4.43 (d, J = 14.5 Hz, 1H), 5.08 (d, J = 8.7 Hz, 1H), 7.56 (m, 2H), 7.67 (m, 1H), 7.92 (m, 2H) ppm. 13C-NMR: δ 11.6, 16.1, 24.3, 28.4, 35.7, 64.1, 65.0, 80.5, 128.6, 129.4, + + 134.3, 139.1, 155.9, 197.9 ppm. ESI-MS: m/z 392 [M + Na] , 408 [M + K] . Anal. Calcd. for C18H27NO5S: C, 58.51; H, 7.37; N, 3.79. Found C, 58.42; H, 7.40; N, 3.91.

(3S)-3-(tert-Butoxycarbonylamino)-4-phenyl-1-(phenylsulfonyl)-2-butanone (3e)[44]: 94% from 1e and 2a; ˝ 25 ´1 1 white solid, mp 137–139 C; rαsD –22 (c 1, CHCl3); IR: 3386, 1732, 1691, 1295, 1147 cm ; H-NMR: δ 1.38 (s, 9H), 2.91 (dd, J = 8.5, 14.0 Hz, 1H), 3.16 (dd, J = 5.5, 14.0 Hz, 1H), 4.22 (d, J = 14.0 Hz, 1H), 4.35 (d, J = 14.0 Hz, 1H), 4.47 (m, 1H), 5.12 (d, J = 6.0 Hz, 1H), 7.15 (m, 2H), 7.23–7.31 (m, 3H), 7.56 (m, 2H), 7.67 (m, 1H), 7.86 (m, 2H) ppm; 13C-NMR: δ 28.2, 36.3, 61.4, 63.7, 80.6, 127.1, 128.4, 128.8, 129.3, 134.3, 136.2, 138.8, 155.4, 197.4 ppm; ESI-MS: m/z 426 [M + Na]+, 442 [M + K]+.

(3S)-3-(tert-Butoxycarbonylamino)-4-[4-(tert-butyldimethylsilyloxy)phenyl]-1-(phenylsulfonyl)-2-butanone ˝ 25 (3f): 78% from 1f and 2a; ee 81%; white solid, mp 111–113 C; rαsD ´21(c 1, CHCl3); IR: 3369, 1709, Molecules 2016, 21, 805 7 of 14

1609, 1584, 1511 cm´1; 1H-NMR: δ 0.19 (s, 6H), 0.98 (s, 9H), 1.39 (s, 9H), 2.86 (dd, J = 8.6, 14.6 Hz, 1H), 3.18 (dd, J = 5.7, 14.6 Hz, 1H), 4.17 (d, J = 13.9 Hz, 1H), 4.32 (d, J = 13.9 Hz, 1H), 4.42 (m, 1H), 5.04 (d, J = 6.4 Hz, 1H), 6.77 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H) ppm; 13C NMR: δ ´4.4, 18.2, 25.6, 28.2, 35.7, 61.5, 63.9, 80.6, 120.4, 128.4, 128.5, 129.2, 130.9, 134.2, 138.8, 154.8, 197.6 ppm; ESI-MS: m/z 556.2 [M + Na]+, 572 + [M + K] . Anal. Calcd. for C27H39NO6SSi: C, 60.76; H, 7.37; N, 2.62. Found C, 60.81; H, 7.38; N, 2.55.

1-((2S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinyl)-2-(phenylsulfonyl)-1-ethanone (3g): 60% from 1g and 2a; 25 ´1 1 yellow oil; rαsD ´43.1 (c 1.6, CHCl3); IR: 1698, 1693, 1323, 1157 cm ; H-NMR (mixture of rotamers): δ 1.36 and 1.43 (2s, 9H), 1.85–1.96 (m, 2H), 2.00–2.24 (m, 2H), 3.46 and 3.55 (m, 2H), 4.18–4.42 (m, 3H), 7.58 (m, 2H), 7.67 (m, 1H), 7.94 (m, 2H) ppm; 13C-NMR (Mixture of rotamers): δ 23.9, 24.8, 28.4 and 28.5, 47.0 and 47.2, 62.8 and 64.1, 65.7 and 66.3, 80.6 and 81.1, 128.6, 129.3 and 129.4, 134.2 and 134.4, + 139.3, 153.7 and 155.0, 198.1 and 198.6 ppm; HRMS (ESI) m/z Calcd. for C17H23NNaO5S [M + Na] 376.1195, found 376.1192.

(2S,4S) and (2S,4R)-2-(tert-Butoxycarbonylamino)-1-phenyl-4-(phenylsulfonyl)-3-pentanone (3h): A 3:2 mixture of two diastereoisomers (a and b) was obtained from 1e and 2b in 77% yield; white solid; IR: 3390, 1737, 1700, 1286, 1150 cm´1; 1H-NMR: δ 1.28 and 1.37 (2d, 3H), 1.39 (s, 5.4H), 1.44 (s, 3.6H), 2.85 (dd, J = 9.6, 14.0 Hz, 0.67H), 3.02 (dd, J = 7.8, 13.8 Hz, 0.33H), 3.22 (dd, J = 5.0, 13.8 Hz, 0.33H), 3.33 (dd, J = 5.0, 14.0 Hz, 0.67H), 4.40–4.55 (m, 1H), 4.65–4.75 (m, 1H), 4.97 (d, 0.67H), 5.40 (d, 0.33H), 7.17–7.35 (m, 5H), 7.52–7.77 (m, 5H) ppm; 13C-NMR: δ 12.1 (b), 12.5 (a), 28.0 (a), 28.1 (b), 35.0 (a), 37.7 (b), 61.5 (a), 61.6 (b), 65.9 (b), 66.5 (a), 80.2 (b), 80.7 (a), 126.8 (a), 127.1 (b), 128.3 (b), 128.7, 129.1, 129.2, 129.3, 129.5, 129.6, 129.7, 134.3, 134.5, 135.9, 136.0, 136.3, 137.3, 155.4, 155.7, 200.8, 202.2 ppm; ESI-MS: m/z 440 [M + Na]+, + 456 [M + K] . Anal. Calcd. for C22H27NO5S: C, 63.29; H, 6.52; N, 3.35. Found C, 63.23; H, 6.38; N, 3.38.

(2S) and (2R) 1-((2S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinyl)-2-(phenylsulfonyl)-1-propanone (3i): A 55:45 mixture of two diastereoisomers (a and b) was obtained from 1g and 2b in 80% yield. Yellow oil; IR: ´1 1 ˝ 1700, 1689, 1322, 1157 cm ; H-NMR (d6-DMSO, 80 C): δ 1.30 (d, J = 7.4, 1.65H), 1.34 (d, J = 7.4 Hz, 1.35H), 1.35 (s, 4.95H), 1.41 (s, 4.05H), 1.59–2.25 (m, 4H), 3.28–3.45 (m, 2H), 4.55 (dd, J = 3.0, 8.0 Hz, 0.55H), 4.67 (br, 0.45H), 4.73 (m, 0.45H), 4.85 (br, 0.55H), 7.67 (m, 2H), 7.78 (m, 1H), 7.88 (m, 2H) ppm; 13 ˝ C-NMR (d6-DMSO, 80 C): δ 12.1 (b), 12.3 (a), 22.7 (a and b), 27.6 (a or b), 27.7 (a or b), 46.1 (b), 46.3 (a), 64.3, 64.7, 65.7, 78.8 (a), 79.0 (b), 128.5, 128.6 and 128.8, 133.7 (b), 133.8 (a), 137.0, 153.0, 201.6 ppm; + HRMS (ESI) m/z Calcd. for C18H25NNaO5S [M + Na] 390.1351, found 390.1342.

3.3. General Procedure for the Synthesis of Allylamines 6 from Ketosulfones 3 ˝ NaBH4 (0.04 g, 1 mmol) was added portion-wise, at 0 C, to a solution of ketone 3 (1 mmol) in methanol (5 mL). When the reaction was complete (TLC), the solvent was removed in vacuo; aqueous workup and extraction with ethyl acetate gave the β-hydroxysulfones 4 as mixtures of diastereoisomers, whose ratio was determined by NMR. To the crude mixtures of diastereoisomeric alcohols, in the minimum amount of dry dichloromethane, were added, in the order, 2-dimethylaminopyridine (0.01 mmol), triethylamine (10 mmol) and acetic anhydride (5 mmol), at 0 ˝C with stirring. The reaction mixture was stirred at room temperature until the formation of the product was complete (TLC: AcOEt/petroleum ether 2:8), extracted with 10% aqueous citric acid, saturated NaHCO3 and brine, dried over Na2SO4 and evaporated. If necessary, co-evaporation with toluene was performed to completely remove the excess anhydride. The crude acetates 5 were obtained in quantitative yield and were used in the final step without further purification. Where possible, analytical data are given for the main diastereoisomer obtained in pure form by crystallization (vide infra). Allylamines 6 were finally obtained from β-acetoxysulfones 5 following two methods. Method A: in a Schlenk reactor filled with Ar, Mg powder (2.5 mmol) and HgCl2 (0.1 mmol) were added, in the order, to a 0.2 M solution of sulfone 5 (1mmol, mixture of diastereoisomers) in 3:1 EtOH/THF. The reaction mixture was stirred at Molecules 2016, 21, 805 8 of 14 room temperature monitoring the progress by TLC (petroleum ether/diethyl ether 8:2); 10% aqueous citric acid was added, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by column chromatography using 9:1 petroleum ether/Et2O as the eluent. Method B: in a round-bottomed flask, 5% Na/Hg amalgam (3 mmol of Na) was added, at ´15 ˝C, under an Ar atmosphere, to a stirred 0.5 M solution of sulfone 5 (1 mmol) in anhydrous, degassed ethanol. The reaction mixture was stirred at room temperature monitoring the progress by TLC (petroleum ether/diethyl ether 8:2); water was added, and the workup as above gave the crude allylamines 6.

3.4. Spectroscopic and Analytical Data for Alcohols 4, Acetates 5 and Allylamines 6 (3S)-3-(tert-Butoxycarbonylamino)-1-butene (6a)[50]: 68% via alcohol 4a and acetate 5a (Method A). 4a: 3:1 mixture of syn (s) and anti (a) diastereoisomers. Pale yellow oil; IR: 3370, 1693, 1304, 1146 cm´1; 1H-NMR: δ 1.13 (d, J = 8.5 Hz, 2.25H), 1.21 (d, J = 8.5 Hz, 0.75H), 1.40 (s, 9H), 3.21 (m, 1.5H), 3.26 (m, 0.5H), 3.64 (br, 2H), 4.10 (br, 1H), 4.73 (br, 1H), 7.59 (m, 2H), 7.69 (m, 1H), 7.92 (m, 2H) ppm; 13C-NMR: δ 15.4 (s), 18.1 (a), 28.3, 50.1, 59.8 (s), 60.5 (s), 68.5 (s), 68.9 (s), 79.9, 127.3 (s), 127.9 (s), 129.3 (a), 129.4 (s), 133.7 (a), 134.1 (s), 139.1, 155.5 ppm; ESI-MS: m/z 296 [M + Na]+, 368 [M + K]+. 5a: 3:1 mixture of syn (s) and anti (a) diastereoisomers. White solid, mp 110–111 ˝C; IR: 3358, 1742, 1712, 1521 cm´1; 1H-NMR: δ 1.06 (d, J = 7.0 Hz, 0.75H), 1.09 (d, J = 7.0 Hz, 2.25H), 1.40 (s, 6.75H), 1.42 (s, 2.25H), 1.82 (s, 2.25H), 1.95 (s, 0.75H), 3.37 (m, 2H), 3.86 (br, 1H), 4.43 (br, 0.75H), 4.52 (br, 0.25H) 5.21 (br, 0.75H), 5.34 (br, 0.25H), 7.57 (m, 2H), 7.66 (m, 1H), 7.91 (m, 2H) ppm; 13C-NMR: δ 16.3 (s), 18.1 (a), 20.6, 28.3, 48.3 (s) 49.4 (a), 56.7 (s), 57.8 (a), 69.5 (a), 70.2 (s), 80.0, 128.3, 129.3, 133.9, 139.2, 155.1, 169.8 ppm; ESI-MS: + 25 1 m/z 394 [M + Na] . 6a: oil, ee 95% (by GLC); rαsD –6.0 (c 0.45, CHCl3); H-NMR: δ 1.20 (d, J = 8.5 Hz, 3H), 1.44 (s, 9H), 4.22 (br, 1H), 4.45 (br, 1H), 5.10 (m, 2H), 5.81 (m, 1H) ppm; 13C NMR: δ 20.7, 28.4, 48.1, 79.3, 113.6, 140.1, 155.1 ppm; ESI-MS: m/z 194 [M + Na]+.

(3S)-3-(tert-Butoxycarbonylamino)-4-methyl-1-pentene (6b)[51]: 60% via alcohol 4b and acetate 5b (method A). 4b: 10:1 mixture of syn (s) and anti (a) diastereoisomers. Yellow oil; IR: 3368, 1691, 1304, 1146 cm´1; 1H-NMR (syn diastereoisomer): δ 0.87 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 1.40 (s, 9H), 2.18 (m, 1H), 3.23 (m, 1H), 3.32 (m, 1H), 3.48 (m, 1H), 3.56 (d, J = 2.9 Hz, 1H) 4.12 (m, 1H), 4.41 (d, J = 9.7 Hz, 1H), 7.59 (m, 2H), 7.68 (m, 1H), 7.92 (m, 2H) ppm. 13C-NMR ((2S,3S) diastereoisomer): δ 15.7, 20.0, 27.1, 28.3, 58.5, 60.4, 67.4, 80.1, 128.1, 129.7, 134.4, 139.6, 156.7 ppm; + + ˝ 25 ESI-MS: m/z 380 [M + Na] , 396 [M + K] . 5b (syn isomer): white solid, mp: 98–100 C; rαsD ´5 (c 0.6, -1 1 CHCl3); IR: 3365, 1744, 1712, 1523 cm ; H-NMR: δ 0.86 (d, J = 8.5 Hz, 3H), 0.90 (d, J = 8.5 Hz, 3H), 1.41 (s, 9H), 1.62 (m, 1H), 1.75 (s, 3H), 3.33 (d, J = 18.3 Hz, 1H), 3.44 (dd, J = 12.5, 18.3 Hz, 1H), 3.63 (m, 1H), 4.35 (d, J = 13.0 Hz, 1H), 5.29 (m, 1H), 7.57 (m, 2H), 7.66 (m, 1H), 7.90 (m, 2H) ppm; 13C-NMR: δ 17.1, 19.6, 20.6, 28.3, 56.6, 57.3, 68.1, 79.9, 127.4, 128.3, 129.1, 133.9, 139.1, 155.6, 169.7 ppm; ESI-MS: + + 25 m/z 422 [M + Na] , 438 [M + K] . 6b: oil, ee > 99.5% (by GLC); rαsD + 28 (c 0.85, CHCl3), lit. [33] + 25 1 (CHCl3); H-NMR: δ 0.88 (d, J = 7 Hz, 3H), 0.90 (d, J = 7 Hz, 3H), 1.44 (s, 9H), 1.77 (m, 1H), 3.98 (br, 1H), 4.50 (br, 1H), 5.12 (m, 2H), 5.73 (m, 1H) ppm. 13C-NMR: δ 18.2, 18.8, 28.6, 32.4, 58.1, 79.3, 115.2, 137.5, 155.7 ppm; ESI-MS: m/z 222 [M + Na]+, 237 [M + K]+.

(3S)-3-(tert-Butoxycarbonylamino)-5-methyl-1-hexene (6c)[52]: 67% via alcohol 4c and acetate 5c (method A). 4c: 7:1 mixture of syn (s) and anti (a) diastereoisomers. Orange oil; IR: 3368, 1694, 1305, 1146 cm´1; 1H-NMR: δ 0.85 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H), 1.31 (m, 2H), 1.39 (s, 9H), 1.60 (m, 1H), 3.25 (m, 1.76H), 3.27 (m, 0.24H), 3.49 (br, 0.12H), 3.56 (br, 0.88H), 3.74, (br, 0.12H), 3.78 (br, 0.88H), 4.10 (m, 1H), 4.55 (br d, J = 7.3 Hz, 0.88H), 4.72 (br d, J = 9.0 Hz, 0.12H), 7.57 (t, 2H), 7.66 (t, 1H), 7.92 (d, 2H) ppm. 13C-NMR: δ 21.5 (s), 22.0 (a), 23.0 (a), 23.6 (s) 24.6 (s), 24.7 (a), 28.2 (s), 28.3 (a), 38.9 (s), 41.3 (a), 52.6 (a), 52.9 (s), 59.8 (s), 60.3 (a), 67.8 (s), 69.4 (a), 79.6 (s), 79.8 (a), 127.9 (s), 128.0 (a), 129.4 (s), 129.5 (a), 134.0 (a), 134.1 (s), 134.2 (a), 139.2 (a), 139.3 (s), 156.1 ppm. ESI-MS: m/z 394 [M + Na]+, 410 [M + K]+. 5c: 7:1 mixture of syn (s) and anti (a) diastereoisomers. White solid; IR: 3372, 1745, 1707, Molecules 2016, 21, 805 9 of 14

1519 cm-1; 1H-NMR: δ 0.86 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 1.13–1.25 (m, 2H), 1.41 (s, 7.9H) 1.43 (s, 1.1H), 1.60 (m, 1H), 1.78 (s, 2.6H), 1.96 (s, 0.4H), 3.35 (m, 1H) 3.44 (m, 1H), 3.76 (m, 0.13H), 3.89 (br, 0.87H), 4.33 (d, J = 10.0 Hz, 0.9H), 4.45 (d, J = 10.0 Hz, 0.1H), 5.18 (m, 0.9H), 5.37 (dbt, J = 9.4, 2.5 Hz, 0.1H), 7.58 (t, 2H), 7.67 (t, 1H), 7.91 (dd, J = 8.0, 1.5 Hz, 2H) ppm. 13C-NMR: δ 20.6, 21.6 (s), 21.8 (a), 23.1 (a), 23.2 (s), 24.6 (a), 24.7 (s), 28.2 (s), 28.3 (a), 39.5 (s), 41.1 (a), 50.6 (s), 52.0 (a), 56.3 (s), 57.8 (a), 69.1 (a), 70.1 (s), 79.8 (a), 79.9 (s) 128.26 (s), 128.33 (a), 129.27 (s) 129.33 (a), 133.8, 139.3, 155.4, + + 25 169.7 ppm. ESI-MS: m/z 436 [M + Na] , 452 [M + K] . 6c: oil, ee > 99.5% (by GLC); rαsD +3.5 (c 1.0, 1 CHCl3); H-NMR: δ 0.89 (d, J = 6.7 Hz, 3H) 0.90 (d, J = 6.7 Hz, 3H), 1.31 (m, 2H), 1.42 (s, 9H), 1.65 (sept, 1H), 4.12 (br, 1H), 4.62 (br, 1H), 5.03 (d, J = 9.9 Hz, 1H), 5.12 (d, J = 15.8 Hz, 1H), 5.71 (ddd, J = 6.9, 9.9, 15.8 Hz, 1H) ppm; 13C NMR: δ 22.0, 22.7, 24.4, 28.1, 44.7, 51.0, 79.2, 113.9, 139.4, 155.1 ppm. ESI-MS: m/z 236 [M + Na]+.

(3S,4S)-3-(tert-Butoxycarbonylamino)-4-methyl-1-hexene (6d)[53]: 69% via alcohol 4d and acetate 5d (method A). 4d: 94:6 mixture of syn (s) and anti (a) diastereoisomers. Pale yellow oil; IR: 3370, 1693, 1304, 1146 cm´1; 1H-NMR: δ 0.85 (t, 0.18H), 0.90 (d, J = 7.0 Hz, 3H), 0.92 (t, J = 7.0 Hz, 0.82H), 0.99 (m, 1H), 1.39 (s, 9H), 1.54 (m, 1H), 1.85 (m, 1H), 3.27 (m, 2H), 3.50 (m, 1H), 3.58 (br, 1H), 4.18 (m, 1H), 4.40 (d, J = 9.5 Hz, 0.94H), 4.84 (d, J = 10.0 Hz, 0.06H), 7.58 (m, 2H), 7.68 (m, 1H), 7.92 (m, 2H) ppm. 13C-NMR: δ 11.1 (a), 11.8 (s), 15.6 (a), 16.3 (s), 23.1 (s), 25.7 (a), 28.4, 31.0 (a) 34.2 (s), 58.8 (a), 59.0 (s), 60.4 (s), 60.7 (a), 65.2 (s), 67.2 (s), 80.1, 127.5 (a), 128.0 (s), 129.4 (a), 129.6 (s), 133.8 (a), 134.2 (s), 139.6, 156.6 ppm; ESI-MS: m/z 394 [M + Na]+, 410 [M + K]+. 5d: 94:6 Mixture of syn (s) and anti ˝ 25 (a) diastereoisomers. White solid, mp 108–110 C; rαsD ´3.8 (c 1.5, CHCl3); IR: 3367, 1746, 1708, 1518 cm´1; 1H-NMR: δ 0.84 (t, J = 7.2 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H), 1.00 (m, 1H) 1.30 (m, 1H), 1.41 (s, 8.5H), 1.43 (s, 0.5H), 1.50 (m, 1H), 1.73 (s, 2.8H), 1.98 (s, 0.2H), 3.29 (d, J = 15Hz, 1H), 3.43 (dd, J = 9.5, 15.0 Hz, 1H), 3.68 (m, 1H), 4.31 (d, 1H, J = 10.0 Hz, 0.94H), 4.55 (d, J = 10.5 Hz, 0.06H), 5.34 (dt, J = 6.3, 1.2 Hz, 0.94H), 5.55 (dt, J = 9.3, 2.2 Hz, 0.06H), 7.57 (m, 2H), 7.66 (m, 1H), 7.90 (m, 2H) ppm. 13C NMR (syn diastereoisomer): δ 10.8, 15.5, 20.6, 24.2, 27.9, 35.1, 56.3, 56.4, 67.9, 80.0, 128.1, 129.1, 133.6, 139.0, + + 25 155.5, 169.7 ppm; ESI-MS: m/z 436 [M + Na] , 452 [M + K] . 6d: oil, ee > 99.5% (by GLC). rαsD + 32 1 (c 1.0, CHCl3). H NMR: δ 0.85 (d, J = 6.5 Hz, 3H,), 0.89 (t, J = 7.5 Hz, 3H), 1.10 (m, 1H), 1.43 (s, 9H), 1.40–1.53 (m, 2H), 4.05 (br, 1H), 4.54 (br, 1H), 5.12 (m, 2H), 5.70 (m, 1H) ppm; 13C-NMR: δ 11.7, 15.0, 25.3, 28.4, 38.6, 56.9, 78.9, 115.2, 136.8, 155.5 ppm; ESI-MS: m/z 236 [M + Na]+, 252 [M + K]+.

(3S)-3-(tert-Butoxycarbonylamino)-4-phenyl-1-butene (6e)[54]: 70% via alcohol 4e and acetate 5e (method B). 4e: 3:1 mixture of syn (s) and anti (a) diastereoisomers. White solid, mp 130–131 ˝C; IR: 3370, 1692, 1304, 1146 cm´1; 1H-NMR: δ 1.30 (s, 6.75H), 1.35 (s, 2.25H), 2.78–3.01 (m, 2H), 3.16–3.33 (m, 2H), 3.62–3.92 (multiplets, 2H), 4.07 (br, 0.25H), 4.14 (br, 0.75H), 4.55 (br, 0.75H), 4.93 (d, J = 9.5 Hz, 0.25H), 7.16–7.29 (m, 5H), 7.51 (m, 0.5H), 7.57 (m, 1.5H), 7.64 (m, 0.25H), 7.68 (m, 0.75H), 7.82 (m, 0.5H), 7.89 (m, 1.5H) ppm. 13C NMR: δ 28.1 (s), 28.2 (a), 35.8 (s), 38.3 (a), (55.1 (s), 55.8 (a), detected in HSQC only) 59.8 (s), 60.3 (a), 65.7 (a), 68.1 (s), 79.8 (s) 80.0 (a), 126.5 (s), 126.7 (s), 127.8 (a) 127.9 (s), 128.4 (a), 128.5 (s), 129.2 (s), 129.3 (a), 129.4 (a), 129.5 (s), 134.1 (a), 134.2 (s), 136.9, 139.1, 155.7 ppm; ESI-MS: m/z 428 [M + + ˝ 25 ´1 Na] . 5e (syn isomer): White solid, mp 122–124 C; rαsD ´7 (c 1, CHCl3); IR: 3336, 1732, 1705 cm ; 1H-NMR: δ 1.28 (s, 9H), 1.84 (s, 3H), 2.61 (m, 1H), 2.84 (dd, J = 5.5, 14.0 Hz, 1H), 3.41 (m, 2H), 4.08 (br, 1H), 4.40 (m, 1H), 5.30 (m, 1H), 7.12–7.29 (m, 5H), 7.52–7.57 (m, 2H), 7.66 (m, 1H), 7.81–7.89 (m, 2H) ppm. 13C NMR: δ 20.6, 28.1, 36.8, 53.5, 56.7, 69.7, 80.0, 126.8, 128.2, 128.6, 129.0, 129.3, 133.8, 136.5, 139.3, 155.3, 169.8 ppm; ESI-MS: m/z 470 [M + Na]+, 486 [M + K]+. 6e: white solid, mp 72–74 ˝C; ee > 99.5%. 25 1 rαsD + 15 (c 0.85, CHCl3); H-NMR: α 1.44 (s, 9H), 2.83 (d, J = 6.3 Hz, 2H), 4.47 (br, 2H), 5.08 (m, 2H), 5.80 (m, 1H), 7.17–7.29 (m, 5H) ppm; 13C NMR: δ 28.3, 41.3, 53.3, 79.1, 114.5, 126.2, 128.1, 129.7, 137.1, 137.9, 155.3 ppm; ESI-MS: m/z 270 [M + Na]+.

(3S)-3-(tert-Butoxycarbonylamino)-4-[4-(tert-butyldimethylsilyloxy)phenyl]-1-butene (6f): 76% via alcohol 4f and acetate 5f (method A). 4f: 5:1 mixture of syn (s) and anti (a) diastereoisomers. White solid, mp 107–109 ˝C; IR: 3369, 1693, 1610, 1511, 1256, 1145 cm´1; 1H-NMR: δ 0.17 (s, 7.5H) and 0.18 (s, 1.5H), Molecules 2016, 21, 805 10 of 14

0.97 (s, 5H) and 0.98 (s, 1H), 1.32 (s, 7.5 H) and 1.35 (s, 1.5H), 2.67–2.95 (m, 2H), 3.14–3.35 (m, 2H), 3.56–3.92 (m, 2H), 4.05 (br, 0.17H) and 4.11 (br, 0.83H), 4.51 (br, 0.83H) and 4.89 (d, J = 8.6, 0.17H), 6.71 (d, 0.36H) and 6.75 (d, 1.64H), 7.01 (overlapping d, 2H), 7.61 (m, 2H), 7.67 (m, 1H), 7.83 (d, 0.36H) and 7.90 (d, 1.64H), ppm.13C-NMR: δ ´4.45, 18.2, 25.7, 28.2, 35.0 (s), 37.5 (a), 55.3 (s), 55.9 (a), 59.9 (s), 60.4 (a) 65.7 (a), 68.1 (s), 79.7, 120.0 (a), 120.1 (s), 127.8 (a), 127.9 (s), 129.4, 130.1, 130.4, 134.1, 139.1, 154.4 (s), 155.7 (a) ppm. ESI-MS: m/z 558.2 [M + Na]+, 574.2 [M + K]+. 5f (syn isomer): White solid, mp ˝ 25 ´1 1 159–161 C; rαsD ´6.7 (c 1.5, CHCl3), IR: 3369, 1747, 1705, 1609, 1512 cm ; H-NMR: δ 0.16 (s, 6H), 0.96 (s, 9H), 1.30 (s, 9H) 1.80 (s, 3H), 2.45 (m, 1H), 2.84 (m, 1H), 3.43 (m, 2H), 4.04 (br, 1H), 4.48 (br, 1H), 5.29–5.34 (m, 1H) 6.73 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 7.56 (t, 2H), 7.65 (m, 1H), 7.88 (d, J = 7.5 Hz, 2H) ppm; 13C-NMR: δ ´4.5, 18.2, 20.6, 25.6, 28.1, 35.9, 53.5, 56.6, 69.7, 79.9, 120.1, 128.2, 129.0, 129.3, 129.9, 133.8, 139.3, 154.4, 155.3, 169.8 ppm; ESI-MS: m/z 600 [M + Na]+, 616.2 [M + K]+. ˝ 25 6f: white solid, mp 51–53 C; ee = 80% (by HPLC); rαsD + 1.2 (c 1, CHCl3); IR 2957, 2930, 2858, 1702, 1610, 1510 cm´1; 1H-NMR: δ 0.19 (s, 6H), 0.98 (s, 9H), 1.41 (s, 9H), 2.76 (m, 2H), 4.36 (br, 1H), 4.47 (br, 1H), 5.06 (dt, J = 10.3, 1.2 Hz, 1H), 5.09 (dt, J = 17.4, 1.2 Hz, 1H), 5.78 (ddd, J = 10.3, 17.4, 5.5 Hz, 1H), 6.76 (d, 2H), 7.02 (d, 2H) ppm; 13C-NMR: δ ´4.8, 18.0, 25.7, 28.4, 40.4, 79.0, 114.5, 119.9, 130.0, 130.1, + 130.4, 138.2, 154.2 ppm. ESI-MS: m/z 400 [M + Na] . Anal. Calcd for C21H35NO3Si: C, 66.80; H, 9.34; N, 3.71. Found: C, 66.88; H, 9.26; N, 3.73.

(3S)-3-(tert-Butoxycarbonylamino)-4-[4-(hydroxy)phenyl]-1-butene (6f1): 81% from 5f by method B. White ˝ 26 ´1 1 solid, mp 82–84 C; rαsD +21.5 (c 1.5, CHCl3); IR = 3339, 1683, 1615, 1516 cm ; H-NMR: δ 1.41 (s, 9H), 2.75 (m, 2H), 4.35 (br, 1H), 4.50 (br, 1H), 5.07 (dd, J = 10.3, 1.2 Hz, 1H), 5.10 (dd, J = 17.4, 1.2 Hz, 1H), 5.60 (br, 1H), 5.78 (ddd, J = 17.4, 10.3, 5.5 Hz, 1H), 6.75, (d, 2H), 7.01 (d, 2H) ppm; 13C-NMR: δ 28.4, 40.6, 53.7, 79.7, 114.7, 115.3, 129.0, 130.6, 138.1, 154.6, 155.5 ppm; ESI-MS: m/z 286.1 [M + Na]+, 302 [M + K]+. Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32; O, 18.23; Found: C, 68.41; H, 8.10; N, 5.24.

(2S)-1-(tert-Butoxycarbonyl)-2-vinylpyrrolidine (6g)[35]: 84% via alcohol 4g and acetate 5g (method B). 4g: 3:2 mixture of syn (s) and anti (a) diastereoisomers. Pale yellow oil; IR: 3493, 1687, 1305, 1148 cm´1; 1 ˝ H-NMR (d6-DMSO, 80 C): δ 1.38 (s, 5.4H), 1.39 (s, 3.6H), 1.66–1.92 (m, 2H), 3.08–3.40 (m, 2H), 3.66 (m, 0.6H), 3.80 (m, 0.4H), 4.25 (br, 1H), 4.84 (d, J = 6.0 Hz, 0.4H), 4.91 (d, J = 6.5 Hz, 0.6H), 7.63 (m, 13 ˝ 2H), 7.70 (m, 1H), 7.89 (m, 2H) ppm; C-NMR (d6-DMSO, 80 C): δ 22.9 (a), 24.7 (s), 26.2 (s), 27.6 (a), 27.8 (s), 30.0 (a), 46.2 (s), 46.7 (a), 58.8 (a), 59.8 (s), 60.4 (a), 60.8 (s), 65.6 (s), 66.8 (a), 78.1 (s), 78.3 (a), 126.3 (a), 127.1 (s), 128.6 (s), 128.8 (a), 132.8 (a), 132.9 (s), 140.26 (a), 140.27 (s), 153.5 (s), 153.8 (a) ppm; + + ˝ 25 ESI-MS: m/z 378 [M + Na] , 394 [M + K] . 5g (syn isomer): white solid, mp 140–143 C; rαsD –33.1 (c ´1 1 ˝ 1.25, CHCl3) IR: 1747, 1692, 1520 cm ; H-NMR (d6-DMSO, 80 C): δ 1.38 (s, 9H), 1.67–1.87 (m, 4H), 1.76 (s, 3H), 3.04 (m, 1H), 3.31 (m, 1H), 3.60, 3.65 (part AB of an ABX system, J = 4.1, 7.9, 15.0 Hz, 2H), 3.84 (br, 1H), 5.52 (m, 0.5H), 5.73 (m, 1H), 7.65 (m, 2H), 7.74 (m, 1H), 7.87 (m, 2H) ppm; 13C-NMR ˝ (d6-DMSO, 80 C): δ 19.5, 22.4, 24.7, 27.2, 45.7, 55.6, 58.8, 66.9, 78.0, 127.2, 128.2, 133.0, 139.1, 153.2, + + 25 168.1 ppm; ESI-MS: m/z 378 [M + Na] , 394 [M + K] . 6g: oil, ee > 99.5% (by GLC); rαsD ´15 (c 0.75, 1 CHCl3), lit. [18] ´15.7 (c 0.55, CHCl3]; H-NMR (rotamers): δ 1.43 (s, 9H), 1.69 (m, 1H), 1.77–1.79 (m, 2H), 2.02 (m, 1H), 3.38 (m, 2H), 4.27 (br, 1H), 5.04 (m, 2H), 5.73 (m, 1H) ppm; 13C-NMR (rotamers): δ 22.6 and 23.2, 28.3, 31.4 and 31.8, 46.0 and 46.4, 59.0, 79.0, 113.6, 138.8 and 139.0, 154.8 ppm; ESI-MS: m/z 220 [M + Na ]+.

(4S)-4-(tert-Butoxycarbonylamino)-5-phenyl-1-butene (6h): 8:2 mixture of E and Z isomers, 60% via alcohol 4h and acetate 5h (method B). 4h: mixture of 4 diastereoisomers in approximately 1:1:3:3 ratio. White solid; IR: 3372, 1704, 1297, 1142 cm´1; 1H-NMR: δ [1.03, 1.06, 1.20 (d, 3H)], [1.23, 1.29, 1.31, 1.36 (s, 9H)], 2.75–3.15 (multiplets, 2H, CH2), 3.20–3.30 (m, 1H, CH(CH3)), [3.70, 3.85, 3.98 (multiplets, 1H, CH(NH))], [3.80, 4.06, 4.15 (multiplets, 1H, CH(OH))], [4.38, 4.50 (br, 1H, OH)], [4.85, 4.99, 5.05 (d, 1H, NH)], 7.20–7.30 (m, 5H), 7.53–7.73 (m, 3H), 7.80–7.91 (m, 2H). 13C-NMR: δ [7.1, 11.0, 11.4, 11.7 (CH3CH)], [28.0, 28.17, 28.22, 28.25 (tBu)], [34.2, 36.8, 38.9, 39.8 (CH2)], [52.4, 52.7, 53.0, 54.8 (CHNH)], [60.6, 63.1, 63.4, 63.6 (CHSO2Ph)], [69.1, 69.4, 70.0, 72.3 (CHOH)], [79.4, 79.7, 79.8 (tBu)], [126.4–137.7 Molecules 2016, 21, 805 11 of 14

(CAr)], [155.1, 155.4 (CO)]; ESI-MS: m/z 442 [M + Na]+, 458 [M + K]+. 5h: White solid, mixture of four diastereoisomers. IR: 3369, 1747, 1704, 1513 cm´1. 1H-NMR: δ [1.12, 1.16, 1.24, 1.28 (s, 9H, tBu), [1.17, 1.44 (d, 3H, CH3)], [1.99, 2.02, 2.28, 2.35 (s, 3H, COCH3)], 2.45–2.90 (m, 2H, CH2), 3.38 (m, 1H, CHSO2Ph), 3.90–4.10 (m, 1H, CHNH), [4.64, 4.67, 4.77, 4.82 (m, 1H, NH)], 5.25–5.40 (m, 1H, CHOAc), 7.07–7.90 (m, 5H), 7.45–7.60 (m, 3H), 7.76–7.83 (m, 2H) ppm; 13C-NMR: δ [10.8, 12.0, 13.0, 14.2, 20.9, 21.2, 22.1, 22.8, 27.9, 28.0, 28.3, 28.4 (CH3)], [36.4, 37.6, 39.8, 40.7 (CH2)], [52.3, 52.7, 53.1, 54.6 (CHNH)], [60.2, 60.7, 61.1, 61.3 (CHSO2Ph)], [70.5, 71.7, 71.9, 73.9 (CHOAc)], [79.8, 80.1, 80.5, (tBu)], 126.4–138.2 (CAr), [155.0, 155.4, 155.5 (CO)], [170.0, 170.1, 170.3 (CO)] ppm; ESI-MS: m/z 484 [M + Na]+, 500 [M + K]+. 6h: Pale yellow oil, IR: 3340, 1692, 1390, 1365, 1255 cm´1; 1H-NMR: α 1.40 (s, 7.2H), 1.42 (s, 1.8H), 1.47 (d, J = 7.5 Hz, 0.6H), 1.65 (d, J = 7.4 Hz, 2.4H), 2.65–2.95 (m, 2H), 4.23–4.66 (br, 2H), 5.21 (m, 0.2 H), 5.30 (m, 0.8H), 5.52 (m, 1H), 7.10–7.34 (m, 5H) ppm; 13C-NMR: δ 13.1 (Z), 17.7 (E), 28.36 (Z), 28.37 (E), 42.0, 53.2, 79.3, 126.2, 126.3, 128.17 (E) 128.20 (Z), 129.6 (E), 129.7 (Z), 130.9, 137.7 (E), 137.8 (Z), 155.0 (Z), + 155.1 (E) ppm; HRMS (ESI) m/z Calcd, for C16H23NNaO2 [M + Na] 284.1626, found 284.1628.

1-[(2S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinyl]-1-propene (6i). 85:15 mixture of E and Z isomers, 65% via alcohol 4i and acetate 5i (method B). 4i: mixture of diastereoisomers. Yellow oil; IR: 3420, 1687, 1302, 1148 cm´1; 1H-NMR (major diastereoisomer) δ: 1.37 (d, 3H), 1.44 (s, 9H), 1.70–1.90 (m, 3H), 2.18 (m, 1H), 3.30 (m, 1H), 3.37 (m, 1H), 3.50 (m, 1H), 3.73 (m, 1H), 4.40 (m, 1H), 5.18 (m, 1H), 7.53 (m, 2H), 7.64 (m, 1H), 7.93 (m, 2H) ppm; 13C-NMR (major diastereoisomer) δ: 13.2, 24.3, 27.8, 29.9, 48.1, 60.1, 63.8, 77.4, 80.3, 129.0, 130.1, 134.1, 157.5 ppm; ESI-MS: m/z 392 [M + Na]+, 408 [M + K]+. 5i: yellow oil, mixture of diastereoisomers. IR: 3496, 1744, 1691 cm´1; 1H-NMR (major diastereoisomer): δ 1.40 (br, 12H, CH3), 1.76 (s, 3H, CH3CO), 1.80–2.05 (m, 4H, CH2), 3.07–3.67 (m, 3H, CH2N and CHSO2Ph), 4.2–4.4 (m, 1H, CHN), 5.12 (m, 1H, CHOAc), 7.53 (m, 2H), 7.64 (m, 1H), 7.93 (m, 2H); 13C-NMR (major diastereoisomer): δ 11.9 (CH3), 21.1 (CH3CO), 23.7 (CH2), 28.4 (tBu), 29.4 (CH2), 46.9 (CH2N), 56.9 (CHN), 61.8 (CHSO2Ph), 73.4 (CHOAc), 79.5 (tBu), 128.8, 129.0, 133.5, 139.0, 155.4, 170.2 ppm; ESI-MS: m/z 434 [M + Na]+, 450 [M + K]+. 6i: pale yellow oil, IR: 1695, 1394, 1365, 1252 cm´1; 1H-NMR ˝ (d6-DMSO, 80 C): δ 1.39 (s, 7.65H), 1.40 (s, 1.35H), 1.51 (m, 0.15 H), 1.60–1.65 (m, 0.85H), 1.64 (d, 3H), 1.75 (m, 2H), 1.94 (m, 0.85H), 2.04 (m, 0.15H), 3.20–3.34 (m, 2H), 4.14 (m, 0.85H), 4.48 (m, 0.15H), 13 ˝ 5.30–5.50 (m, 2H); C-NMR (d6-DMSO, 80 C): δ 12.2 (Z), 16.6 (E), 22.3 (Z), 22.8 (E), 27.8 (E,Z), 31.3 (E), 32.0 (Z), 45.5 (E), 45.6 (Z), 53.3 (Z), 57.5 (E), 77.5 (E), 77.6 (Z), 122.3 (Z), 123.6 (E), 131.9 (E), 132.5 (Z), + 153.2 (E,Z). HRMS (ESI) m/z Calcd. for C12H21NNaO2 [M + Na] 234.1470, found 234.1477.

4. Conclusions We have developed a general procedure for the synthesis of α-chiral allylamines from readily available α-amino esters, by a simple modification of the Julia olefination reaction. While retaining all of the advantages of the original Julia reaction, this approach avoids using amino aldehydes as precursors in favor of the more readily-available and chemically and configurationally more stable amino esters. Epimerization at the chiral center, which is a frequent problem in the standard Julia and Wittig olefination of N-protected α-amino aldehydes, is thus prevented, and the desired allylamines are obtained in excellent yield and enantiomeric excess. The approach described here for the synthesis of allylamines is quite general and should provide a useful alternative to the classical Julia reaction whenever the starting aldehyde is unstable or, otherwise, not readily accessible. Moreover, its scope might be further expanded by replacing the phenyl alkyl sulfones of this work with benzotriazolylalkyl sulfones or other heteroarylalkyl sulfones, as in the Julia–Kocienski reaction [55,56], where the intermediate hydroxysulfones directly collapse to alkenes, thus avoiding the final reduction step.

Supplementary Materials: Supplementary materials are available online at http://www.mdpi.com/1420-3049/ 21/6/805/s1. Acknowledgments: This work was supported by MIUR (Ministero dell’Università e Ricerca) (Project PRIN 20109Z2XRJ_11). Lidia Fanfoni is grateful to the University of Trieste for a postdoctoral grant, and Giorgia Regini acknowledges INPS (Istituto Nazionale per la Previdenza Sociale) for a PhD fellowship. Molecules 2016, 21, 805 12 of 14

Author Contributions: Fabio Benedetti, Fulvia Felluga and Federico Berti conceived and designed the experiments. Lidia Fanfoni, Michele Garbo and Giorgia Regini performed the experiments and analyzed the data. Fabio Benedetti and Fulvia Felluga wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations The following abbreviations are used in this manuscript: Boc t-Butoxycarbonyl n-BuLi n-Butyllithium COSY Correlation Spectroscopy DEPT Distortionless Enhancement by Polarization Transfer ee Enantiomeric Excess ESI Electrospray Ionization HRGC High Resolution Gas Chromatography HPLC High Performance Liquid Chromatography HRMS High Resolution Mass Spectrometry HSQC Heteronuclear Single Quantum Coherence Spectroscopy IR Infrared KHMDS Potassium Hexamethyldisilazanide MS Mass Spectrometry NMR Nuclear Magnetic Resonance TBDMS t-Butyldimethylsilyl THF Tetrahydrofuran TLC Thin Layer Chromatography TMEDA Teramethylethylenediamine

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Sample Availability: Samples of the compounds 3a–i, 6a–f are available from the authors.

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