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Tetrahedron 68 (2012) 10218e10229

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Tetrahedron

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A [3þ3] cyclization strategy for asymmetric synthesis of alkyl substitutedpiperidine-2-ones using 1,2-cyclic sulfamidates: a formal synthesisof (S)-coniine from L-norvaline

Abdullah Karanfil, Berrin Balta, Mustafa Eskici *

Department of Chemistry, Faculty of Arts and Science, Celal Bayar University, 45016 Mansa, Turkey

a r t i c l e i n f o

Article history:Received 19 June 2012Received in revised form 29 August 2012Accepted 17 September 2012Available online 23 September 2012

Keywords:Cyclic sulfamidatesLithium triethylorthopropiolateCyclizationPiperidines

* Corresponding author. Tel.: þ90 2362412151; faaddress: mustafa.eskici@cbu.edu.tr (M. Eskici).

0040-4020/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2012.09.081

a b s t r a c t

Regioselective ring-opening reactions of a set of representative 1,2-cyclic sulfamidates with lithiumtriethylorthopropiolate proceeded efficiently to deliver the corresponding d-amino-a,b-unsaturated es-ters after acidic hydrolysis. Hydrogenation of the unsaturated esters and subsequent thermal cyclizationafforded the related alkyl substituted piperidine-2-ones. This approach represents a novel [3þ3] cycli-zation strategy for the asymmetric synthesis of alkyl substituted piperidin-2-ones. Efficiency of the cy-clization process is illustrated by a formal asymmetric synthesis of (S)-coniine from L-norvaline.

� 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Activation of the hydroxyl group of readily available, oftenenantiopure, 1,2- and 1,3-aminoalcohols for nucleophilic displace-ment through formation of cyclic sulfamidates provides an effectivealternative to the reactivity profile of activated aziridines andazetidines, respectively.1 Additionally there exist several advan-tages in favor of the chemistry of cyclic sulfamidates.2 With cyclicsulfamidates nucleophilic attack occurs regioselectively at the ox-ygen bearing carbon, and attack at the CdN bond is not generallyobserved. There is also no specific requirement for the presence andsubsequent removal of a strictly activating protecting group on thenitrogen atom. Thus, the use of cyclic sulfamidates allows flexibilityconcerning the protecting group employed, and a range of pro-tecting groups including Ts, Bn, Cbz, and Boc can be used witha very little effect on nucleophilic cleavage.3,4 Moving from 3- to 4-ring systems, azetidines could lack the required reactivity to beused as electrophiles.5 In the case of cyclic sulfamidates, on goingfrom five- to six-membered ring systems, a useful level of reactivityis attainable as the reactivity of 1,2-cyclic sulfamidates is not largelyderived from the ring strain. Besides, cyclic sulfamidates with de-fined stereochemistry at the CdO bond are generally accepted toundergo nucleophilic displacement with a clean inversion of

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stereochemistry. These beneficial features make cyclic sulfamidatessynthetically potent electrophilic synthons for the synthesis of N-containing compounds, and the reaction of cyclic sulfamidates witha wide range of nucleophiles including, nitrogen,6 oxygen,7 sulfur,8

phosphorus,9 and halogene-based10 nucleophiles has been re-ported in the literature.11

Of particular interest is the ring-opening reaction with carbon-based nucleophiles that enable the synthesis of functionalizedamines. In this context, the reactivity of cyclic sulfamidates towardsynthetically more versatile carbon-based nucleophiles other thancyanide has been less widely exploited in synthesis. Over the lastdecade, Gallagher and co-workers12 and others13 have shown thatcyclic sulfamidates could exhibit a high level of reactivity towardstabilized carbon nucleophiles. Nucleophilic cleavage of a series of1,2 and 1,3-cyclic sulfamidates by structurally functionalized andstabilized-enolates followed by thermal lactamization of the sub-stitution products constituted [3þ2] and [4þ2] cyclization strate-gies to the syntheses of a-functionalized pyrrolidone andpiperidone systems, respectively.12 Application of this sulfamidate-based chemistry in the syntheses of a number of piperidine con-taining natural products as well as industrially important mole-cules, (�)-aphanorphine,12c,f (þ)-laccarin, and antidepressant(�)-paroxetine12a largely contributes to the establishment of cyclicsulfamidates as synthetically versatile emerging building blocks insynthesis.

We have recently reported a synthetically useful level of re-activity of cyclic sulfamidates toward acetylides (Scheme 1).14 Ring-

Scheme 1. Nucleophilic substitution of cyclic sulfamidates with acetylides.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229 10219

opening reactions of a structurally diverse set of 1,2- and 1,3-cyclicsulfamidates 1 with a range of lithium acetylides 2 proceededsmoothly in a regioselective fashion to form N-sulfate in-termediates 3. Acidic hydrolysis afforded the alkynylated amines 4in yields ranging from 29% to 98%. The acetylenic displacement ofsulfamidates 1 provided an alternative route for the synthesis ofalkynylated amines.15 Primary carbon-centered 1,2-cyclic sulfami-dates were found to be particularly effective in the alkylation re-action furnishing the related b-alkynylated amines in excellentyields.

The high reactivity of 1,2-cyclic sulfamidates toward acetylidesprompted us to explore the formation of a piperidine skeleton fromthe b-alkynylated amines through lactamization upon hydrogena-tion, once the acetylide possesses a pendant ester functionality. Inthis communication, we disclose the results of the efficient sub-stitution of a structurally diverse set of 1,2-cyclic sulfamidates bylithium triethylorthopropiolate to give d-amino-a,b-unsaturatedesters after acidic hydrolysis that upon hydrogenation thermallycyclize to the alkyl substituted piperidine lactams, in which[NeCeC] fragment from the 1,2-cyclic sulfamidate and [CeCeC]fragment from the propiolate anion are combined to form the pi-peridine ring system. This approach represents a novel [3þ3] an-nulation strategy for the asymmetric synthesis of the substitutedpiperidin-2-ones. The efficiency of the cyclization process has been

Scheme 2. Synthesis of 1,2-c

illustrated by a formal synthesis of the hemlock alkaloid (S)-coniinefrom L-norvaline.

2. Results and discussion

2.1. Synthesis of cyclic sulfamidates

Although a number of elegant technologies have been de-veloped over the last decade for the synthesis of cyclic sulfamidatesutilizing precursors other than aminoalcohols,16 the most directroutes to relatively simple cyclic sulfamidates, as in the case of thepresent work, involve the use of aminoalcohols and a two-stepcyclization approach (thionyl chloride and Ru-mediated oxida-tion). A structurally representative set of 1,2-cyclic sulfamidates7aeg was prepared from aminoalcohols using the two-step cycli-zation procedure in order to examine briefly their structural effecton the alkylation by triethylorthopropiolate (Scheme 2). The benzylgroup was used for N-protection due to the ease of installation andsubsequent removal by hydrogenation, as well as the stability un-der basic conditions. Primary carbon-centered sulfamidates 7aedwere prepared in enantiomerically pure form. Among the second-ary carbon-centered 1,2-cyclic sulfamidates, ephedrine-derived 7eand lactic acid-derived 7f were optically pure, 7g was synthesizedin racemic form for convenience.11c The use of 7g is considered to

yclic sulfamidates 7aeg.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e1022910220

be a test of the triethylorthopropiolate anion for the eliminationpathway, as the potential of the sulfamidate 7g toward eliminationis already reported.11c

L-Phenylalanine, alanine and valinewere esterified using thionylchloride and then converted into the benzamide derivatives 5aecwith benzoylchloride (Scheme 2). Global reduction with LiAlH4gave the aminoalcohols 6aec in high yields. Cyclization of theaminoalcohols 6aec to 1,2-cyclic sulfamidates 7aec was achievedby the standard two-step cyclization protocol. In the synthesis ofalaninol cyclic sulfamidate 7b, exposure of the intermediate sulfa-midite to the oxidation conditions longer than 10e15 min led toextensive decomposition on a large scale preparation, therefore theduration of the oxidation step kept short to obtain a high yield of7b. Prolinol cyclic sulfamidate 7d was prepared directly from thereaction of L-prolinol with sulfuryl chloride at �78 �C in DCM ina single operation.11i Ephedrine-derived 7e and elimination-sensitive 7g sulfamidates were prepared according to literature.11c

(S)-Ethyl lactate 8 was converted into the benzylamide derivative9 via an amidation reaction,17 which was reduced to the desiredaminoalcohol 10with LiAlH4.18 The two-step sulfamidate formationsequence produced lactic acid-derived sulfamidate 7f in 71% yieldunder unoptimized conditions. In this way, multigram quantities ofsulfamidates 7aeg were readily available for ring-openingreactions.

2.2. Substitution with 1,2-cyclic sulfamidates and cyclizationstudies

Initially, we tried to generate the propiolate anion from thereaction of n-BuLi on methylpropiolate directly in THF,19 and reactit with phenylalaninol sulfamidate 7a to obtain d-amino-a,b-un-saturated methylester. These efforts produced no success in ourhands; the sulfamidate remained unreacted in the mixture. Thisfailure may be attributable to the instability of the propiolateanion in solution through the inclination of the acetylenic moietyand alkyl carboxylate group to react with each other.20 Accord-ingly attention moved to known triethylorthopropiolate as a syn-thetically more stable propiolate anion precursor. Thustriethylorthopropiolate 11 was prepared from triethylorthopro-pionate using double brominationeelimination reactions.21 Ac-tion of n-BuLi on triethylorthopropiolate in THF at �10 �C readilygenerated lithium triethylorthopropiolate 12.22 Ring-opening ofsulfamidate 7a with 12 proceeded smoothly to form the in-termediate N-sulfate 13a (Scheme 3). Hydrolysis of 13a with 5 MHCl solution not only cleaved the N-sulfate but also led to con-current hydrolysis orthoester to the corresponding ethylester14a.21b Neutralization of the reaction mixture with aqueous sat-urated NaHCO3 solution followed by chromatographic purificationfurnished N-benzyl-d-amino-a,b-unsaturated ethylester 14a in89% yield. A slight excess (2 equiv) of the nucleophilic component12 was required for the complete consumption of 7a. The amino

Scheme 3. Reaction of phenylalaninol 1,2-cyclic su

ester 14awas found to be not sufficiently stable; decomposition toa varying extent on storage was observed, and therefore wasrapidly subjected to hydrogenation to effect both saturation anddebenzylation. A brief scanning of palladium catalysts (Pd(OH)/Cand Pd/C) and solvents (MeOH and THF) revealed that a combi-nation of Pd(OH)/C and Pd/C in THF were effective hydrogenationconditions for saturation and debenzylation.23 Exposure of 14a toatmospheric hydrogenation conditions led to desired saturationand deprotection forming amino ester 15a. Premature lactam-ization was observed during hydrogenation (TLC). In order todrive lactamization to completion, the crude reaction mixture wasfiltered through a pad of Celite�, followed by removal of volatilesunder reduced pressure, and the residue dissolved in toluene wasrefluxed for 6 h. Chromatographic purification affordedphenylalanine-derived lactam 16a (½a�30D �55.3 (c 1, CHCl3)) in 87%yield over two steps.

Using a similar set of reaction conditions, the results of nu-cleophilic cleavage of the representative set of 1,2-cyclic sulfa-midates 7aeg with 12 and thermal cyclization of thesubstitution products 14aef, to the corresponding lactams 16aefare shown in Table 1. With the exception of prolinol 7d, primarycarbon-centered 1,2-cyclic sulfamidates 7aec were particularlysuitable in the alkylation reaction with 12 delivering the relatedd-amino-a,b-unsaturated ester 14aec in high yields followingacidicebasic work-up. Cyclization of the amino esters 14aec wasequally efficient also, leading to the synthesis of the desiredlactams 16aec. Ring-opening of prolinol sulfamidate 7d oc-curred readily under similar conditions, but we were unable tohydrolyze the resulting intermediate using the standard 5 M HClconditions. Attempted hydrolysis of the intermediate undervarious acidic conditions (concentrated HCl, 20% and 50% H2SO4)failed to yield any success; heating usually resulted in degra-dation of the intermediate.

The steric and/or electronic tolerance of the 1,2-cyclic sulfami-dates toward 12 were examined with 7eeg. Sterically demandingephedrine-derived sulfamidate 7e was completely unreactive with12 under the standard conditions. We previously observed thatinclusion of HMPA in the reaction mixture was found to enhanceboth the reaction rates and yields significantly.14 In an attempt toovercome the lack of reactivity of 7e for 12, the same reaction run inthe presence of 10% HMPA by volume at either �10 �C or �78 �Cgave a complex mixture. The reaction of sterically less demandinglactic acid-derived 7f with 12 proceeded slowly without HMPA(substitution product 14fwas obtained in a 30% yield); a significantamount of the sulfamidate 7f remained unreacted in the reactionmixture (TLC). With the use of HMPA, the reaction seemed to bemore rapid and efficient; the corresponding amino ester 14f wasobtained in a good yield (76%). On exposure of the eliminationsensitive sulfamidate 7g to the propiolate 12, a smooth reactionproceeded to form an intermediate (all sulfamidate 7g consumedby TLC). Acidic hydrolysis of the intermediate produced N-benzyl

lfamidate 7a with triethylorthopropiolate 12.

Table 1Reactions of lithium triethylorthopropiolate 12 with various 1,2-cyclic sulfamidates 7aeg

Entry 1,2-Cylic sulfamidates Substitution products 14 (yield)a Lactams 16 (yield)a

1

2

3

4 dsee text d

5 dcomplex mixture d

6

7 d

a Yield of isolated product after chromatographic purification.b Reactions performed at �78 �C (see text).c Reaction run in THF with the addition of 10% HMPA by volume.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229 10221

cinnamylamine 17 as the major product by TLC analysis. Duringchromatographic purification, significant decomposition of 17 wasobserved causing to the isolation of 17 in a much reduced yield35%.24 Efforts to achieve any observable degree of substitution byrunning the reaction�78 �Cwith or without HMPA did not produceany success. These results suggest that sulfamidate 7g is not suit-able for the present cyclization strategy.

The critical issue of the alkylation with 1,2-cyclic sulfamidatesdescribed in this study that requires clarification is the SN2 natureof the displacement with 7f. Attempts to derivatize N-benzyl-d-amino-a,b-unsaturated ethylester 14f with (þ)-MTPA into thecorresponding Mosher amide was unsuccessful due to de-composition.25 Instead lactam 16f was converted to the piperidinehydrochloride salt 18, which was derivatized into the correspond-ing Mosher amide 19 (Scheme 4). Observation of a pair of tworotamers (approximately 2:1 ratio) of 19 by analysis of the 1H NMRspectroscopic data26 and the specific rotation (½a�23D �82.5 (c 1,CHCl3)) of the known lactam 16f in close agreement with the

literature value (½a�30D �89 (c 0.96, EtOH))27 indicate clean inversionof the stereochemistry during the alkylation of 7f with 12.

Utilizing the high reactivity of the stereoelectronically suitable1,2-cyclic sulfamidates toward lithium triethylorthopropiolate,this novel and equally efficient [3þ3] cyclization strategy enablesthe transformation of a-aminoacids into the corresponding pi-peridine lactams in a concise manner, and in this sense is com-parable favorably with the existing strategy.28 It is alsoappropriate to note here that the present [3þ3] annulation ap-proach for the synthesis of the piperidine skeleton complementsto the [4þ2] cyclization strategy developed by Gallagher,12 whichrelies upon the reactivity of 1,3-cyclic sulfamidates towardstabilized-enolates. More readily availability of the precursorvicinal aminoalcohols in optically pure form coupled with sig-nificantly higher reactivity of the corresponding 1,2-cyclic sulfa-midates could largely contribute to the wider syntheticapplication of the [3þ3] cyclization strategy for the asymmetricsynthesis of substituted 2-piperidones.

Scheme 4. Conversion of lactam 16f into Mosher amide derivative 19.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e1022910222

2.3. Asymmetric synthesis of (S)-coniine from L-norvaline

We wished to demonstrate the effective implementation of the1,2-cyclic sulfamidate mediated annulation strategy on a synthesisof biologically active molecules containing an alkyl substituted pi-peridine unit. The piperidine alkaloid (S)-coniine 27 [(S)-2-propylpiperidine] was targeted. There are many routes availablefor the synthesis of (S)-coniine as this simple alkaloid has fre-quently provided a sound platform to rigorously test a new asym-metric methodology.29 Our approach for the synthesis of (S)-coniine 27 from L-norvaline 20 is shown in Scheme 5 and involvesa regioselective ring-opening of norvalinol 1,2-cyclic sulfamidate23 with 12 and thermal cyclization of d-amino-a,b-unsaturatedester 25 after saturation and debenzylation to form the piperidinenucleus. Using the similar reagents and conditions for the synthesisof 1,2-cyclic sulfamidates, L-norvaline 20 was converted into thebenzamide derivative 21, which was reduced to the precursornorvalinol 22. Preparation of the sulfamidate 23 was highly effi-cient using the two-step cyclization procedure. Nucleophiliccleavage of 23 with 12 proceeded smoothly to form the in-termediate 24, which was hydrolyzed to d-amino-a,b-unsaturatedester 25 in a high yield. Palladium catalyzed hydrogenation andsubsequent thermal cyclization afforded 6-n-propylpiperidin-2-one 26 in 86% yield. Reduction of the carbonyl group with LiAlH4

readily generated (S)-coniine 27. Because of the volatility and tox-icity, as well as for ease of comparison, (S)-coniine 27 was con-verted to the known N-Boc coniine 28 (½a�30D þ32.6 (c 1, CHCl3))whose specific rotation is in a close agreement with the literaturevalue (½a�20D þ33.5 (c 1, CHCl3)).29k Efficiency of the [3þ3] cyclizationstrategy has been illustrated by a formal asymmetric synthesis of(S)-coniine from L-norvaline 20 in 46% overall yield.

Scheme 5. Asymmetric syn

2.4. Substitution studies with 1,3-cyclic sulfamidate 31

We were also interested in the reactivity of 1,3-cyclic sulfami-dates in the alkylation reaction with 12. Methyl substituted 31 asthe only studied 1,3-cyclic sulfamidate was prepared from N-ben-zyl-1,3-aminoalcohol 30, available from ethyl crotonate 29(Scheme 6).11c Using the standard two-step sulfamidate formationprotocol, conversion of aminoalcohol 30 into 31 was low yielding(less than 30%). Close monitoring of the reactions showed that theformation of the intermediate cyclic sulfamidite was efficient. It isthe oxidation step of the sulfamidite to the sulfamidate responsiblefor the observation of the low yield; extensive decomposition wasbelieved to take place during oxidation. Changing the oxidationconditions to the biphasic solvent system (CHCl3/MeCN/H2O),routinely used for the synthesis of cyclic sulfates as a closely relatedclass of electrophiles, significantly improved the yield of the oxi-dation step to 73%. It appears that performing oxidation using thebiphasic solvent system could be milder conditions for sensitivesubstrates.

Cyclic sulfamidate 31 exhibited considerably lower reactivitytoward 12 as compared with alanine-derived 7b (Scheme 6).Without HMPA sulfamidate 31 failed to react with 12 even overa longer reaction time (48 h). The use of HMPA led to an useful levelof reactivity, and the corresponding reaction of 31 with 12 gener-ated N-sulfate intermediate 32. Acid-prompted hydrolysis of 32was anticipated to cleave the N-sulfate along with concurrent hy-drolysis of the orthoester to the ethylester 33. After neutralizationof the reaction mixture, chromatographic purification affordedalkylidine pyrrolidine compound 34 in 80% yield. Facile formationof 34 during the work-up conditions could be rationalized on theconjugate addition of the amino group onto the activated triple

thesis of (S)-coniine 27.

Scheme 6. Synthesis and reactivity of 1,3-cyclic sulfamidate 31 toward acetylide 12.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229 10223

bond to form spontaneously the energetically favorable five-membered pyrrolidine ring system. The stereochemistry of 34 wasdetermined by NOE NMR correlation between the benzylic and thealkene protons, which is consistent with literature observations.12d

3. Conclusions

In conclusion, we have developed an efficient [3þ3] cyclizationstrategy for asymmetric synthesis of alkyl substituted piperidin-2-ones using readily available 1,2-cyclic sulfamidates. Efficiency ofthis novel cyclization process has been illustrated by a formalasymmetric synthesis of (S)-coniine from L-norvaline. Extension ofthis chemistry to more complicated 1,2-cyclic sulfamidates, andapplication to synthesis of N-heterocycles containing alkylsubstituted piperidine units are currently underway and will bereported elsewhere.

4. Experimental

4.1. General

Melting points were determined on an Electrothermal 9200apparatus and are uncorrected. IR spectra were recorded on a Per-kineElmer Spectrum BX spectrometer as thin films on NaCl platesor Nujol. 1H and 13C NMR spectra were recorded in CDCl3 ona Varian AS 400 MHz NMR spectrometer with TMS as an internalstandard (Ege University, Izmir, Turkey). Chemical shifts areexpressed in d (parts per million) units downfield from TMS. Cou-pling constants (J) are quoted to the nearest 0.5 Hz. Mass Spectraand Elemental analysis were taken from TUBITAK Marmara Re-search Centre (MAM), Gebze, Istanbul, Turkey and University ofToulouse, France. Optical rotations were measured with RudolphResearch Analytical Autopol I Automatic Polarimeter. THF and etherwere freshly distilled from LiAlH4 before use. TLC was performedusing aluminum plates coated with silica gel (254 nm) and use ofthe basic permanganate dying system. Flash column chromatog-raphy was carried out using silica gel (0.063e0.2 mm). Removal ofsolvents in vacuo was achieved using a IKA rotary evaporator atroom temperature unless otherwise stated. Yields refer to isolatedmaterial, homogeneous by TLC and NMR spectroscopy, unlessotherwise stated.

4.2. Synthesis of 1,2-cyclic sulfamidates 7aeg

1,2-Cyclic sulfamidates 7aeg were prepared according to theliterature protocols. Synthetic procedures for cyclic sulfamidates7aec are given below as general procedures. Synthesis of ephed-rine sulfamidate 7e, elimination sensitive sulfamidate 7g and

prolinol sulfamidate 7d are available in the literature.11c,i Synthesisof the lactate derived sulfamidate 7f is presented separately.

4.2.1. General procedure for synthesis of ethyl 2-benzamidoalka-noates. To a stirred suspension and/or solution of a L-amino acid(100 mmol) in anhydrous ethanol (150 mL) cooled in an ice bathwas added dropwise thionyl chloride (190 mmol). The reactionmixture was then refluxed for 4 h. On heating the solid hydro-chloride salt gradually became solubilized to produce a clear so-lution. After cooling, volatiles were removed in vacuo to give thecorresponding solid ethylester hydrochloride salt. This salt wasused in the benzoylation step directly without further purification.To a stirred solution of the hydrochloride salt and triethylamine(230 mmol) in DCM (250 mL) cooled in an ice-bath was addeddropwise a solution of benzoylchloride (112mmol) in DCM (50mL).After stirring for 4 h, water (300 mL) was added to the resultingmixture. The separated organic phase was sequentially washedwith 2 M HCl (200 mL), saturated NaHCO3 solution (200 mL), thenbrine (200 mL), dried (Na2SO4) and concentrated under reducedpressure. Purification of the crude product by recrystallization fromDCMehexane afforded the colorless benzamide derivative crystals.

4.2.1.1. (S)-Ethyl 2-benzamido-3-phenylpropanoate 5a.

Mp 102e103 �C (DCM/hexane), lit.11c 102 �C (DCM/petrol ether);½a�30D þ98.5 (c 1.06, CHCl3), lit.31 ½a�30D þ108.6 (c 0.76, CHCl3); TLC, Rf0.56 [(EtOAc/hexane) 1:2]; IR (Nujol): 3366 (NH), 1748 (C]O, es-ter), 1641 (C]O, amide); 1H NMR (400 MHz, CDCl3) d 1.27 (3H, t,J¼7.0), 3.23 (1H, dd, J¼5.5 and 13.5), 3.29 (1H, dd, J¼5.5 and 13.5),4.21 (2H, q, J¼7.0), 5.07 (1H, dt, J¼5.5 and 7.5), 6.65 (1H, d, br, J¼7.0),7.15e7.17 (2H, m, AreH), 7.22e7.31 (3H, m, AreH), 7.39e7.43 (2H,m, AreH), 7.47e7.51 (1H, m, AreH), 7.71e7.74 (2H, m, AreH).

4.2.1.2. (S)-Ethyl 2-benzamidopropanoate 5b.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e1022910224

Mp 98e99 �C (DCM/hexane), lit.32a 95 �C (Ether/petrol ether);½a�30D þ37.5 (c 1, CHCl3), lit.32b ½a�19D þ33.4 (c 1, CHCl3); TLC, Rf 0.42[(EtOAc/hexane) 1:2]; IR (Nujol): 3344 (NH), 1742 (C]O, ester),1641 (C]O, amide); 1H NMR (400 MHz, CDCl3) d 1.28 (3H, t, J¼7.0),1.50 (3H, d, J¼7.0), 4.22 (2H, q, J¼7.0), 4.76 (1H, quintet, J¼7.0), 6.86(1H, d, br, J¼6), 7.38e7.42 (2H, m, AreH), 7.45e7.49 (1H, m, AreH),7.78e7.80 (2H, m, AreH).

4.2.1.3. (S)-Ethyl 2-benzamido-3-methylbutanoate 5c.

Mp 76e78 �C (DCM/hexane), lit.33 77.5e78 �C; ½a�30D þ40.2 (c 1,CHCl3); TLC, Rf 0.59 [(EtOAc/hexane) 1:2]; IR (Nujol): 3333 (NH),1731 (C]O, ester), 1639 (C]O, amide); 1H NMR (400 MHz, CDCl3)d 0.98 (3H, d, J¼7.0), 1.00 (3H, d, J¼7.0), 1.29 (3H, td, J¼0.5 and 7.0),2.23e2.31 (1H, m), 4.16e4.29 (2H, m), 4.76 (1H, dd, J¼5.0 and 9.0),6.67 (1H, d, br, J¼8), 7.40e7.51 (3H, m, AreH), 7.78e7.81 (2H, mAreH).

4.2.2. General procedure for synthesis of 1,2-cyclic sulfamidates 7aec

4.2.2.1. General procedure for the reduction of benzamide de-rivatives 5aec and synthesis of 1,2-cyclic sulfamidates 7aec. Toa stirred suspension of LiAlH4 (321 mmol) in dry THF (500 mL)cooled in an ice-bath was added dropwise a solution of the 2-benzamidoalkanoate (178 mmol) in dry THF (100 mL). Theresulting mixture was then refluxed for 4 h. After cooling in anice-bath, excess LiAlH4 was quenched with sequential additionof water (30 mL), 10% NaOH solution (30 mL), and water(20 mL). The reaction mixture was stirred at room temperaturefor 2 h for hydrolysis and the aluminum residues were removedby filtration. It was observed that the crude aminoalcoholproduct stuck to the aluminum residues on large scale prepa-rations, and several washings with ether were not sufficient totake all aminoalcohols into solutions. Therefore washings wererepeated until TLC showed no further aminoalcohols remainedin the residues. Combined organics were dried (Na2SO4) andconcentrated in vacuo to give the crude product. Aminoalcohols6a,b were obtained as pale yellow solids, while 6c as a paleyellow viscous oil. These crude aminoalcohols were used in thenext step directly without further purification orcharacterization.

To a stirred solution of the aminoalcohol (87.8 mmol), imidazole(370 mmol), and triethylamine (200 mmol) in DCM (750 mL)cooled in an ice-bath was added dropwise a solution of thionylchloride (99 mmol) in DCM (50 mL). The resulting mixture wasstirred until TLC indicated complete conversion of the amino-alcohol into the intermediate sulfamidite and then quenched by theaddition of water (400 mL). The aqueous phase was separated andextracted with DCM (2�250 mL). Combined organics were washedwith water (200 mL) and then brine (200 mL), dried (Na2SO4) andconcentrated in vacuo to give the crude product. Colored basicimpurities were removed by passing through a small pad of silicagel. The intermediate sulfamidites were used directly in the oxi-dation step.

To a stirred cooled (0 �C) solution of the intermediate sulfa-midite (47.8 mmol) in MeCN (400 mL) was added RuCl3 (70 mg),followed by NaIO4 (72.76 mmol) and then water (300 mL). Thereaction mixture was stirred for 15 min to 5 h depending on the

substrate involved. Close monitoring of the reaction mixture wasnecessary in order to perform efficient oxidation without de-composition. The reaction mixture was diluted with ether(500 mL) and phases were separated. The aqueous phase wasextracted with ether (2�500 mL). Combined organic phaseswere washed with NaHCO3 solution (300 mL), then brine(300 mL), dried (MgSO4) concentrated in vacuo to give the crudesulfamidate product. Colored ruthenium impurities were re-moved by passing through a small pad of silica gel. Solid sulfa-midates were further purified by recrystallization from DCM/hexane to give colorless crystals 7a,b. Valine derived sulfamidate7c is a pale yellow viscous oil, which is solidified on storage inthe fridge.

4.2.2.1.1. (S)-3,4-Dibenzyl-1,2,3-oxathiazolidine 2,2-dioxide 7a.

Mp 65e66 �C (DCM/hexane), lit.11c 64 �C (DCM/petrol ether);½a�30D �36.5 (c 1, CHCl3), lit.11c ½a�20D �34 (c 0.76, CHCl3); TLC, Rf 0.33[(EtOAc/hexane) 1:4]; IR (Nujol): 1376 and 1174 (SO2); 1H NMR(400 MHz, CDCl3) d 2.72 (1H, dd, J¼9.5 and 13.5), 3.00 (1H,dd, J¼5.0and 13.5), 3.71e3.78 (1H, m), 4.21 (1H, dd, J¼5.0 and 8.5),4.28e4.34 (3H, m), 7.01 (2H, d, J¼7.0, AreH), 7.23e7.37 (8H, m,AreH); 13C NMR (100 MHz, CDCl3) d 38.66, 51.00, 60.28, 70.65,127.58, 128.69, 129.09 (overlapping two peaks), 129.20, 129.29,134.84, 135.45.

4.2.2.1.2. (S)-3-Benzyl-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide7b.

Mp 67e68 �C (DCM/hexane), lit.10a 64.5e66 �C (DCM/heptane);½a�30D þ21.7 (c 1, CHCl3), lit.10a ½a�30D þ25 (c 0.8, MeOH); TLC, Rf: 0.39[(EtOAc/hexane) 1:2]; IR (Nujol): 1334 and 1186 (SO2); 1H NMR(400 MHz, CDCl3) d 1.19 (3H, d, J¼6.5), 3.69e3.77 (1H, m), 4.10 (1H,dd, J¼7.0 and 8.5), 4.20 (1H, d, J¼15.0), 4.38 (1H, d, J¼15.0), 4.55(1H, dd, J¼6.5 and J¼8.5), 7.29e7.42 (5H, m, Ar-H): 13C NMR(100MHz, CDCl3) d 17.43, 49.84, 55.52, 72.51,128.48, 128.80,128.95,135.08.

4.2.2.1.3. (S)-3-Benzyl-4-isopropyl-1,2,3-oxathiazolidine 2,2-di-oxide 7c.13c

Pale yellow viscous oil; ½a�30D �35.4 (c 1, CHCl3); TLC, Rf 0.33[(EtOAc/hexane) 1:4]; IR (film): 1348 and 1186 (SO2); 1H NMR(400 MHz, CDCl3) d 0.85 (3H, d, J¼7.0), 0.89 (3H, d, J¼7.0), 1.83e1.93(1H, m), 3.43 (1H, dt, J¼5.5 and 7.0), 4.22e4.28 (2H, m), 4.39e4.44(2H, m), 7.30e7.42 (5H, m, AreH); 13C NMR (100 MHz, CDCl3)d 16.11, 18.35, 29.77, 52.26, 64.74, 67.30, 128.53, 128.94, 129.10,135.10.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229 10225

4.2.2.2. Synthesis of 1,2-cyclic sulfamidate 7f.4.2.2.2.1. (S)-N-Benzyl-2-hydroxypropanamide 9.

A mixture of (S)-ethyl lactate (20.9 g, 177 mmol) and benzyl-amine (59.5 g, 556 mmol) was refluxed overnight. The reactionmixturewas dissolved in DCM (250mL), washed with 5MHCl untilTLC showed that all benzylamine was removed, then brine(200 mL), dried (Na2SO4) and concentrated in vacuo. Purification ofthe crude product by flash column chromatography eluting((EtOAc/hexane) 1:1 to 1:0 gradient) afforded the title compound asa pale yellow oil (23.50 g, 74%); ½a�30D �6.5 (c 1, CHCl3), lit.34½a�30D�6.8 (c 6.9, CHCl3); TLC, Rf 0.58 [EtOAc]; 1H NMR (400 MHz, CDCl3)d 1.42 (3H, d, J¼7), 3.47 (1H, s, br), 4.24 (1H, q, J¼7), 4.42 (2H, d,J¼6), 7.01 (1H, s, br), 7.23e7.34 (5H, m, AreH).

4.2.2.2.2. (S)-3-Benzyl-5-methyl-1,2,3-oxathiazolidine 2,2-dioxide 7f.

Using the general reduction procedure with LiAlH4, benzyla-mide 9 (14.93 g, 83 mmol) was reduced to the aminoalcohol 10(10.46 g, 76%) as a pale yellow viscous oil. The crude aminoalcoholwas used in the next step directly.

Using the general sulfamidate formation procedure, the ami-noalcohol 10 (14.95 g, 90.47 mmol) was converted into the lactatederived sulfamidate 7f (14.6 g, 71%) as a pale yellow oil (It is worthmentioning that duration of the oxidation step was kept short(5e10 min) in order to avoid decomposition). ½a�20D �15.2 (c 1,CHCl3); TLC, Rf 0.44 [(EtOAc/hexane) 1:3]; IR (film): 1605, 1344 and1185 (SO2); 1H NMR (400 MHz, CDCl3) d 1.50 (3H, d, J¼6.4), 3.04(1H, dd, J¼8.0 and 9.5), 3.42 (1H, dd, J¼6.0 and 9.5), 4.11 (1H, d,J¼14), 4.32 (1H, d, J¼14), 4.83e4.92 (1H, m), 7.31e7.40 (5H, m, Ar-H); 13C NMR (100 MHz, CDCl3) d 19.56, 51.47, 53.98, 77.51, 128.67,128.85, 129.10, 134.70; MS (MALDI-ToF) m/z: [MþNa]þ found250.0537, C10H13NNaO3S requires 250.0514.

4.3. Synthesis of alkyl substituted piperidin-2-ones

4.3.1. Synthesis of (S)-ethyl 5-(benzylamino)-alky-2-ynoates

4.3.1.1. General procedure for ring-opening reactions of 1,2-cyclicsulfamidates 7aeh with lithium triethylorthopropiolate. To a stirredsolution of triethylorthopropiolate (1.35 g, 7.85 mmol, 2 equiv) infreshly distilled THF (20 mL) cooled to �10 �C (salt-ice bath) underargon atmosphere was added n-butyllithium (5.2 mL, 8.3 mmol,15% solution in hexane), and the solution was stirred at this tem-perature for 1 h. A solution of a cyclic sulfamidate (1.2 g,3.93 mmol) in dry THF (2e3 mL) was then added to the acetylidesolution via a syringe. After stirring at �10 �C for 5e6 h, theresulting mixture was allowed to warm up to room temperaturegradually with stirring for 24 h. The reaction mixture was thentreated with 4 mL 5 M HCl solution to hydrolyze the N-sulfateintermediate for 2-3 h before neutralization with saturatedNaHCO3 solution. Extraction with ether (2�100 mL) and dryingover anhydrous Na2SO4 followed by evaporation of volatiles invacuo gave the crude product. Purification by flash column chro-matography eluting with the ((EtOAc/hexane) 1:8 to 1:3 gradient)solvent system (containing 0.5% triethylamine) afforded ethyl 5-

(benzylamino)-alky-2-ynoate 14aef as a pale yellow oil. The un-saturated amino esters 14aef were found to be prone to de-composition during column chromatography and/or storage.Amino ester 14b and lactate-derived 14f were particularly sensi-tive to decomposition; analytical pure samples of 14b and 14fcould not be obtained. Thus analytical and spectroscopic data of14aef should be treated with caution. The unsaturated amino es-ters 14aef were swiftly subjected to hydrogenation conditions totransform them into stable lactam derivatives 16aef.

Also, using the same stoichiometry as above, the reactionwas carried out in freshly distilled THF (20 mL) containing HMPA(1 mL) cooled at�10 �C (ice-salt bath) or at�78 �C (dry ice-acetonebath).

4.3.1.1.1. (S)-Ethyl 5-(benzylamino)-6-phenylhex-2-ynoate 14a.

½a�31D �6.4 (c 1.95, CHCl3); TLC, Rf 0.53 [(EtOAc/hexane) 1:3]; IR(film): 3481, 3338 (NH), 2337 (C^C), 1706 (C]O ester); 1H NMR(400 MHz, CDCl3) d 1.32 (3H, t, J¼7.0), 2.40e2.51 (2H, m), 2.83(1H, dd, J¼7.0 and 13.5), 2.88 (1H, dd, J¼7.0 and 13.5), 3.02e3.08(1H, m), 3.77 (1H, d, J¼13.5), 3.86 (1H, d, J¼13.5), 4.23 (2H, q,J¼7.0), 7.16e7.31 (10H, m, AreH); 13C NMR (100 MHz, CDCl3)14.27, 23.73, 40.61, 51.27, 56.74, 62.07, 75.52, 85.59, 126.76,127.24, 128.22, 128.64, 128.77, 129.53, 138.41, 140.08, 153.84; MS(ESI-ToF) m/z: [MþH]þ found 322.1809, C21H24NO2 requires322.1807.

4.3.1.1.2. (S)-Ethyl 5-(benzylamino)hex-2-ynoate 14b.

½a�31D �14.8 (c 1.65, CHCl3); TLC, Rf 0.6 [(EtOAc/hexane) 1:3];IR (film): 3394, 3327(NH), 2235 (C^C), 1709 (C]O ester); 1HNMR (400 MHz, CDCl3) d 1.21 (3H, d, J¼6.5), 1.30 (3H, td, J¼1.0and 7.0), 2.47 (1H, d, J¼3.0), 2.48 (1H, d, J¼3.0), 2.94e3.01 (1H,m), 3.80 (2H, s), 4.21 (2H, q, J¼7.0), 7.20e7.33 (5H, m, AreH);13C NMR (100 MHz, CDCl3) 14.26, 20.69, 26.53, 51.07, 51.29,62.06, 75.10, 85.76, 127.29, 128.28, 128.68, 140.28, 153.86; MS(ESI-ToF) m/z: [MþNa]þ found 268.1325, C15H19NNaO2 requires268.1313.

4.3.1.1.3. (R)-Ethyl 5-(benzylamino)-6-methylhept-2-ynoate 14c.

½a�31D �38.4 (c 0.98, CHCl3); TLC, Rf 0.67 [(EtOAc/hexane) 1:3]; IR(film): 3400 (NH), 2235 (C^C), 1711 (C]O ester); 1H NMR(400MHz, CDCl3) d 0.93 (3H, d, J¼7.0), 0.95 (3H, d, J¼7.0),1.31 (3H, t,J¼7.0), 1.85e1.94 (1H, m), 2.43e2.26 (3H, m), 3.75 (1H, d, J¼13.0),3.89 (1H, d, J¼13.0), 4.22 (2H, q, J¼7.0), 7.22e7.37 (5H, m, AreH);13C NMR (100 MHz, CDCl3) 14.27, 18.70, 19.04, 21.44, 31.10, 51.82,60.95, 62.02, 74.81, 87.93, 127.18, 128.38, 128.57, 140.67, 153.91; MS(ESI-ToF) m/z: [MþNa]þ found 296.1648, C17H23NNaO2 requires296.1626.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e1022910226

4.3.1.1.4. (S)-Ethyl 5-(benzylamino)-4-methylpent-2-ynoate 14f.

Using the general procedure, the reaction of lactate derivedsulfamidate 7f (2 g, 8.81 mmol) with 12 in dry THF (30 mL) con-taining HMPA (1.5 mL) cooled at �10 �C (salt-ice bath) under argonatmosphere afforded (S)-ethyl5-(benzylamino)-4-methylpent-2-ynoate (14f) (1610 mg, 74%) as a pale yellow oil. It is worth notingthat with inclusion of HMPA as a polar cosolvent, the reaction wascomplete less than 2e3 h. ½a�31D �56.2 (c 1.0, CHCl3); TLC, Rf 0.26[(EtOAc/hexane) 1:3]; IR (film): 3394, 3338 (NH), 2238 (C^C), 1708(C]O ester); 1H NMR (400 MHz, CDCl3) d 1.23 (3H, d, J¼7.0), 1.30(3H, t, J¼7.0), 2.66e2.85 (3H, m), 3.82 (2H, d, J¼3.5), 4.21 (2H, q,J¼7.0), 7.22e7.34 (5H, m, AreH); 13C NMR (100MHz, CDCl3) d 14.25,17.74, 27.03, 53.64, 53.83, 62.02, 74.29, 91.65, 127.21, 128.25, 128.62,140.28, 153.93; MS (ESI-ToF) m/z: [MþNa]þ found 268.1324,C15H19NNaO2 requires 268.1313.

4.3.1.1.5. N-Benzyl cinnamylamine17.11c

Using the general procedure, the reaction of the sulfamidate 7g(1.0 g, 6.6 mmol) with 12 in dry THF (20 mL) cooled to �10 �C (salt-ice bath) under argon atmosphere for 48 h afforded N-benzyl cin-namylamine 17 (258 mg, 35%) as a pale yellow oil. TLC, Rf 0.5 1HNMR (400 MHz, CDCl3) d 3.44 (2H, dd, J¼1.0 and 6.5), 3.84 (2H, s),6.31 (1H, dt, J¼6.0 and 16), 6.54 (1H, d, J¼16), 7.19e7.38 (10H, m,AreH).

4.3.2. Synthesis of alky substituted piperidin-2ones 16aef

4.3.2.1. General procedure of cyclization of ethyl 5-(benzylamino)-alky-2-ynoates. To a solution of the ethyl 5-(benzylamino)-alkyl-2-ynoate (3.47 mmol) in THF (25 mL) was added Pd/C (140 mg) andPd(OH)/C (140mg) at room temperature. The resulting solutionwasflushed with argon several times and then hydrogenated for 24 h.The reaction mixture was filtered through Celite� in vacuo to givethe crude product. The resulting products mixture was dissolved intoluene (15 mL) and then refluxed for 4e10 h. After cooling,evaporation of the volatiles in vacuo gave the crude lactam. Puri-fication by flash column chromatography eluting with the ((DCM/acetone) 7:3) solvent system afforded the alkyl substituted lactamas a viscous oil. Analytical pure samples were obtained by re-crystallization from hexane.

4.3.2.1.1. (R)-6-Benzylpiperidin-2-one 16a.35

Mp 141e142 �C (hexane); ½a�30D �55.3 (c 1, CHCl3); TLC, Rf 0.6[(DCM/acetone) 7:3]; IR (Nujol); 3182 (NH), 1658 (C]O amide); 1HNMR (400 MHz, CDCl3) d 1.41e1.51 (1H, m), 1.64e1.76 (1H, m),1.88e2.00 (2H, m), 2.26e2.43 (2H, m), 2.62 (1H, dd, J¼9.0 and 13.5),2.87 (1H, dd, J¼5.0 and 13.0), 3.61 (1H, septet, J¼5.0), 5.65 (1H, s, br),7.16e7.18 (2H, m, ArH), 7.23e7.27 (1H, m, ArH), 7.30e7.34 (2H, m,ArH); 13C NMR (100 MHz, CDCl3) d 19.97, 28.89, 31.64, 43.57, 54.51,

127.17, 129.05, 129.40, 137.06, 172.37. MS (ESI-ToF) m/z: [MþNa]þ

found 212.1092, C12H15NNaO requires 212.1051; Anal. Calcd forC12H15NO: C, 76.16;H, 7.99;N, 7.40%. Found: C, 76.19;H, 8.03; N, 7.45.

4.3.2.1.2. (S)-6-Methylpiperidin-2-one 16b.

Mp 82e84 �C (hexane), lit.29e 79e81 �C; ½a�30D þ32.5 (c 1, CHCl3),lit.29e ½a�25D þ22.7 (c 0.3, CHCl3); TLC, Rf 0.3 [(DCM/acetone) 7:3]; IR(Nujol); 3198 (NH), 1672 (C]O amide); 1H NMR (400 MHz, CDCl3)d 1.20 (3H, dd, J¼1.0 and 6.5), 1.29e1.37 (1H, m), 1.64e1.75 (1H, m),1.85e1.92 (2H, m), 2.22e2.40 (2H, m) 3.47e3.55 (1H, m), 6.88 (1H,s, br); 13C NMR (100 MHz, CDCl3) d 20.03, 22.92, 30.62, 31.20, 48.90,172.29.

4.3.2.1.3. (R)-6-Isopropylpiperidin-2-one 16c.

Mp 79e80 �C (hexane), lit.29e 75e77 �C; ½a�30D þ62.3 (c 1, CHCl3),lit.29e ½a�30D þ68.9 (c 0.4, CHCl3); TLC, Rf 0.45 [(DCM/acetone) 7:3]; IR(Nujol); 3232 (NH), 1667 (C]O amide); 1H NMR (400 MHz, CDCl3)d 0.91e0.95 (6H, m), 1.32e1.43 (1H, m), 1.60e1.73 (2H, m),1.79e1.96 (2H, m), 2.18e2.29 (1H, m), 2.35e2.42 (1H, m), 3.16e3.21(1H, m), 6.17 (1H, s, br); 13C NMR (100 MHz, CDCl3) d 17.92, 18.25,20.24, 24.95, 31.63, 33.00, 58.89, 173.00.

4.3.2.1.4. (S)-5-Methylpiperidin-2-one 16f.

Mp 69e70 �C (hexane); ½a�23D �82.5 (c 1, CHCl3), lit.27 ½a�30D�89 (c 0.96, EtOH); TLC, Rf 0.45 [(DCM/acetone) 7:3]; IR (Nujol);3232 (NH), 1667 (C]O amide); 1H NMR (400 MHz, CDCl3) d 1.01(3H, d, J¼6.5), 1.42e1.52 (1H, m), 1.87e1.96 (2H, m), 2.28e2.44(2H, m), 2.91 (1H, t, J¼11.0), 3.32e3.27 (1H, m), 7.18 (1H, s, br);13C NMR (100 MHz, CDCl3) d 18.52, 28.32, 29.20, 30.88, 49.15,172.82.

4.3.2.1.5. Mosher amide derivative (19): (R)-3,3,3-trifluoro-2-methoxy-1-((S)-3-methylpiperidin-1-yl)-2-phenylpropan-1-one.26

To a stirred suspension of LiAlH4 (250 mg, 6.59 mmol) indry ether (20 mL) cooled in an ice-bath was added dropwisea solution of the lactam 16f (340 mg, 3.01 mmol) in dry ether

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229 10227

(2e3 mL). The reaction mixture was then refluxed for 3e4 h.After cooling in an ice-bath, excess LiAlH4 was quenched withsequential addition of water (0.5 mL), 10% NaOH solution(0.5 mL). The reaction mixture was stirred at room temperaturefor 2 h for hydrolysis and the aluminum residues were re-moved by filtration. The filtrate was dried over anhydrousNa2SO4, then anhydrous HCl solution (3e5 mL) in ether wasadded. Evaporation of volatiles in vacuo gave the solid hydro-chloride salt. The crude salt was recrystallization from ether(280 mg, 69%).

To a stirred solution of (þ)-MTPA (83 mg, 0.35 mmol) andDMF (26 mg, 0.35 mmol) in hexane (15 mL) was added dropwiseoxalyl chloride (0.15 mL, 1.68 mmol). The reaction mixture wasstirred at room temperature for 1 h, and then filtered. Evapora-tion of volatiles in vacuo gave the corresponding MTPA-Cl. Toa stirred solution of the hydrochloride salt (40 mg, 0.29 mmol)and DMAP (90 mg, 0.74 mmol) in DCM (3 mL) cooled in an ice-bath was added a solution of the prepared MTPA-Cl solution inDCM (1 mL). The resulting mixture was stirred at room temper-ature overnight and then sequentially washed with 2 M HCl(5 mL), saturated NaHCO3 solution (5 mL), then brine (5 mL), anddried (Na2SO4). Evaporation of volatiles in vacuo and purificationby flash column chromatography eluting with the ((EtOAc/hex-ane) 1:10 to 1:6 gradient) solvent system afforded Mosher lactam19 (48 mg, 55%) as a clear oil and a pair of rotamers (approxi-mately 2:1). TLC, Rf 0.71 [(EtOAc/hexane) 1:4]; 1H NMR (400 MHz,CDCl3) d 0.31e0.42 (1H, m, major), 0.65 (3H, d, J¼7.0, minor), 0.89(3H, d, J¼7.0, major), 0.92e1.08 (H, series of multiplet), 1.34e1.61(H, series of multiplet), 1.71e1.85 (H, series of multiplet), 2.25(1H, dd, J¼11.0 and 12.5, major), 2.54 (1H, td, J¼3.0 and 13.0,minor), 2.74 (1H, ddd, J¼3.0, 12.5 and 13.5, major), 3.67 (3H, q,J¼1.5, major), 3.73 (3H, q, J¼1.5, minor), 3.69e3.74 (H, m, signalsoverlapping with peaks at 3.73 ppm), 3.87 (1H, m, major), 4.54(1H, m, major), 4.60 (1H, m, minor), 7.35e7.39 (H, m, AreH),7.45e7.49 (H, m, AreH), 7.54e7.56 (H, m, AreH); 13C NMR(100 MHz, CDCl3) d 18.98, 19.26, 23.96, 25.35, 27.15, 31.14, 31.69,32.95, 33.11, 43.17, 45.42, 50.04, 52.92, 55.60, 55.63, 56.28, 84.92,85.16, 126.74, 126.92, 128.34, 128.48, 129.29, 129.32, 134.48,163.89, 164.13.

4.4. Asymmetric synthesis of (S)-coniine from L-norvaline

4.4.1. (S)-Ethyl 2-benzamidopentanoate 21.

Using the general procedure, L-norvaline (5 g, 42.7 mmol) wasconverted into (S)-ethyl 2-benzamidopentanoate 21 (9.4 g, 88%)as colorless crystals. Mp 60e61 �C (DCM/hexane), lit.36 58e59 �C;½a�30D þ35.7 (c 1, CHCl3), lit.36 ½a�30D þ15.9 (c 0.0014, EtOH, for R-21); TLC, Rf 0.46 [(EtOAc/hexane) 1:2]; IR (Nujol); 3310 (NH), 1753(C]O, ester), 1641 (C]O, amide); 1H NMR (400 MHz, CDCl3)d 0.96 (3H, t, J¼7.5), 1.31 (3H, t, J¼7.0), 1.34e1.5 (2H, m), 1.70e1.80(1H, m), 1.88e1.97 (1H, m), 4.22 (2H, q, J¼7.0), 4.75e4.80 (1H, m),6.70 (1H, d, br, J¼7.0), 7.38e7.42 (2H, m, AreH), 7.45e7.49 (1H, m,AreH), 7.77e7.79 (2H, m, AreH); 13C NMR (100 MHz, CDCl3)d 13.95, 14.40, 18.83, 35.03, 52.69, 61.66, 127.25, 128.76, 131.84,134.33, 167.20 (C]O, amide), 173.03 (C]O, ester); Anal. Calcdfor C14H19NO3: C, 67.45; H, 7.68; N, 5.62%. Found: C, 67.79; H,7.75; N, 5.66.

4.4.2. (S)-3-Benzyl-4-propyl-1,2,3-oxathiazolidine 2,2-dioxide 23.

Using the general procedure, benzamide derivative 21(9 g, 36.15 mmol) was reduced to the aminoalcohol 22 (6.2 g,88%). The aminoalcohol (6.2 g, 32.1 mmol) was then con-verted into cyclic sulfamidate 23 (7.9 g, 90%) as a pale yellowviscous oil. ½a�30D þ18.0 (c 1, CHCl3); TLC, Rf 0.60 [(EtOAc/hexane) 1:2]; IR (film); 1342 and 1186 (SO2); 1H NMR(400 MHz, CDCl3) d 0.82 (3H, t, J¼7.0), 1.15e1.30 (2H, m),1.42e1.51 (1H, m), 1.58e1.66 (1H, m), 3.57e3.64 (1H, m),4.16e4.22 (2H, m, unresolved signals due to overlapping withsignals at 4.20 ppm), 4.41 (1H, d, J¼15.0), 4.52 (1H, dd, J¼7.0and 9.0), 7.29e7.42 (5H, m AreH); 13C NMR (100 MHz, CDCl3)d 13.95, 17.87, 34.08, 50.94, 59.52, 70.99, 128.48, 128.88,128.93, 135.17; MS (ESI-ToF) m/z: [MþNa]þ found 278.0811,C12H17NNaO3S requires 278.0827.

4.4.3. (S)-Ethyl 5-(benzylamino)oct-2-ynoate 25.

Using the general procedure, the reaction of norvalinol sulfa-midate 23 (700 mg, 2.74 mmol) with 12 afforded (S)-ethyl 5-(benzylamino)oct-2-ynoate 25 (660 mg, 92%) as a pale yellow oil.½a�31D �25.5 (c 1.95, CHCl3); TLC, Rf 0.7 [(EtOAc/hexane) 1:3]; IR(film): 3394e3338 (NH), 2235 (C^C), 1711 (C]O ester); 1H NMR(400 MHz, CDCl3) d 0.91 (3H, t, J¼7.0), 1.31 (3H, t, J¼7.0),1.26e1.55 (4H, m), 2.47 (1H, dd, J¼5.0 and 17.0), 2.56 (1H, dd, J¼6and 17.0), 2.79e2.85 (1H, m), 3.75 (1H, d, J¼13.0), 3.81 (1H, d,J¼13.0), 4.22 (2H, q, J¼7.0), 7.22e7.36 (5H, m, Ar-H); 13C NMR(100 MHz, CDCl3) d 14.27, 14.29, 19.32, 24.15, 36.76, 51.16, 55.08,62.04, 75.07, 85.97, 127.22, 128.33, 128.54, 140.48, 153.83. MS (ESI-ToF) m/z: [MþNa]þ found 296.1683, C17H23NNaO2 requires296.1626.

4.4.4. (S)-6-Propylpiperidin-2-one 26.

Using the general procedure, (S)-ethyl 5-(benzylamino)oct-2-ynoate 25 (660 mg) was converted into the lactam 26 (260 mg,87%) as light pale yellow crystals. Mp 57e60 �C (Hexane), lit.29e

58e60 �C; ½a�30D þ23.8 (c 1, CHCl3), lit.29e ½a�25D þ18.1 (c 0.6,CHCl3), TLC, Rf 0.45 [(DCM/acetone) 7:3]; IR (Nujol); 3210 (NH),1667 (C]O, amide); 1H NMR (400 MHz, CDCl3) d 0.90 (3H, t,J¼7.0), 1.26e1.47 (5H, m), 1.58e1.69 (1H, m), 1.81e1.88 (2H, m),2.19e2.38 (2H, m), 3.29e3.35 (1H, m), 6.32 (1H, s, br); 13C NMR(100 MHz, CDCl3) d 14.13, 18.70, 19.98, 28.55, 31.58, 39.26, 53.09,172.68.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e1022910228

4.4.5. (S)-tert-Butyl 2-propylpiperidine-1-carboxylate (28) (N-Bocconiine).

To a stirred suspension of LiAlH4 (500 mg, 166 mmol) in dryether (20 mL) cooled in an ice-bath was added dropwise a solu-tion of the lactam 26 (500 mg, 3.54 mmol) in dry ether (2e3 mL).The reaction mixture was then refluxed for 4 h. After cooling inan ice-bath, excess LiAlH4 was quenched with sequential additionof water (3 mL), 10% NaOH solution (3 mL). The reaction mixturewas stirred at room temperature for 2e3 h for hydrolysis and thealuminum residues were removed by filtration. The filtrate wasdried over anhydrous Na2SO4, then anhydrous HCl solution(3e5 mL) in ether was added dropwise. Evaporation of volatilesin vacuo gave the crude solid hydrochloride salt (550 mg, 97%). Toa solution of the coniine hydrochloride salt (500 mg, 3.16 mmol)in H2O (15 mL) was added solid NaHCO3 (1.86 g, 22.1 mmol), then(Boc)2O (850 mg, 3.9 mmol). After stirring the reaction mixture atroom temperature overnight, %10 NaOH solution (3 mL) wasadded and stirring continued for additional 2 h. The product wasextracted with ether (2�50 mL), then washed brine (2�50 mL)and dried (Na2SO4). Evaporation of volatiles in vacuo and purifi-cation by flash column chromatography eluting with the ((ether/hexane) 1:20) solvent system afforded N-Boc coniine (560 mg,82) as a clear oil. ½a�30D þ32.6 (c 1, CHCl3), lit.29k ½a�25D þ33.5 (c 0.6,CHCl3), TLC, Rf 0.18 [(ether/hexane) 1:20]; 1H NMR (400 MHz,CDCl3) d 0.92 (3H, t, J¼7.0), 1.22e1.41 (4H, m), 1.45 (9H, s),1.51e1.70 (6H, m), 2.71e2.78 (1H, m), 3.96 (1H, d, br, J¼13.0), 4.21(1H, m).

4.5. Synthesis and reactivity of 1,3-cyclic sulfamidate 31

4.5.1. 3-Benzyl-4-methyl-1,2,3-oxathiazinane 2,2-dioxide 31.

1,3-Aminoalcohol 30 was prepared by the reaction of ethylcrotonate with benzylamine.11c Using the standard procedure,aminoalcohol 30 (10.87 g, 60.7 mmol) was transformed into theintermediate sulfamidite (11.5 g, 91%). To a solution of the crudesulfamidite (11.5 g, 55 mmol) in CHCl3 (60 mL) and MeCN (60 mL)cooled in an ice-bath was added sequentially RuCl3 (50 mg),NaIO4 (19.5 g, 90 mmol) and then water (60 mL). The reactionmixture was then stirred for 20e25 min (TLC control) and dilutedwith ether (150 mL), and phases were separated. The aqueousphase was extracted with ether (2�200 mL). Combined organicswere washed with NaHCO3 solution (200 mL), then brine(200 mL), dried (MgSO4), and concentrated in vacuo. Coloredruthenium impurities were removed by passing through a smallpad of silica gel to afford the crude product. Sulfamidate 30 waspurified by recrystallization from ether/hexane to obtain colorlesscrystals (9.1 g, 73%). Mp 60e61 �C (ether/hexane), lit.11c 57 �C(ether/petrol ether); TLC, Rf 031 [(EtOAc/hexane) 1:3]; IR (Nujol);1373 and 1186 (SO2); 1H NMR (400 MHz, CDCl3) d 1.25 (3H, d,J¼7.0), 1.70e1.86 (2H, m), 4.02e4.11 (1H, m), 4.26 (1H, d, J¼16),4.48 (1H, d, J¼16), 4.56e4.67 (2H, m), 7.25e7.38 (5H, m, AreH);13C NMR (100 MHz, CDCl3) d 19.12, 27.39, 49.49, 55.28, 71.20,127.77, 127.84, 128.78, 137.72.

4.5.2. (E)-Ethyl 2-(1-benzyl-5-methylpyrrolidin-2-ylidene)acetate34.

Using the general procedure for the ring-opening studies, thereaction of 1,3-cyclic sulfamidate 30with 12 (1 g, 4.15 mmol) in THF(20 mL) containing HMPA (2 mL) afforded (E)-ethyl 2-(1-benzyl-5-methylpyrrolidin-2-ylidene)acetate 34 (860 mg, 80%) as a paleyellow oil. TLC, Rf 0,67 [(EtOAc/hexane) 1:3]; IR (Nujol); 1682 (C]O,ester), 1594, 1491, 1454 (aromatic); 1H NMR (400MHz, CDCl3) d 1.15(3H, d, J¼6.0), 1.22 (3H, t, J¼7.0), 1.56e1.66 (1H, m), 2.12e2.21 (1H,m), 3.11e3.19 (1H, m), 3.23e3.31 (1H, m), 3.61e3.69 (1H, sextet,J¼6.5), 4.07 (2H, qd, J¼1.0 and 7.0), 4.26 (1H, d, J¼16.5), 4.45 (1H, d,J¼16.5), 4.58 (1H, s, br), 7.16e7.18 (2H, m, AreH), 7.23e7.26 (1H, m,AreH), 7.29e7.33 (2H, m, AreH); dC (100MHz, CDCl3) d 14.91, 19.45,29.83, 31.16, 47.94, 58.44, 59.02, 79.15, 126.99, 127.42, 128.84,136.72, 165.72, 169.76. HRMS m/z: [MþH]þ found 260.1652,C16H22NO2 requires 260.1651.

Acknowledgements

The authors gratefully acknowledge Celal Bayar University forfinancial support through projects (FEF-2006-57 and FEF-2009-101) and Pelin S€OZEN AKTAS for obtaining HRMS.

Supplementary data

These data include1H NMR, 13C NMR and MOL files of the mostimportant compounds described in this article. Supplementarydata associated with this article can be found in the online version,at http://dx.doi.org/10.1016/j.tet.2012.09.081.

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