Asymmetric Access to α-Substituted Functional Aspartic Acid Derivatives by a [3+2] Strategy...

Job/Unit: O31739 /KAP1 Date: 31-03-14 17:09:22 Pages: 10

FULL PAPER

DOI: 10.1002/ejoc.201301739

Asymmetric Access to α-Substituted Functional Aspartic Acid Derivatives by a[3+2] Strategy Employing a Chiral Dienophile

Kawther Ben Ayed,[a,b] Anne Beauchard,[a] Jean-François Poisson,[c] Sandrine Py,[c]

Mathieu Y. Laurent,[a] Arnaud Martel,[a] Houcine Ammar,[b] Souhir Abid,[b] andGilles Dujardin*[a]

Keywords: Asymmetric synthesis / Cycloaddition / Amino acids / Heterocycles

Enantiopure vinyl ethers of Stericol® underwent diastereo-selective thermal 1,3 dipolar cycloadditions with N-benzyl,N-benzhydryl, and N-PMB aspartate ester nitrones. Chemo-selective N-debenzylation of the resulting cycloadducts af-forded diastereomerically and enantiomerically pure crystal-

Introduction

Despite numerous studies, the asymmetric synthesis of α-tertiary amines[1] and α,α-disubstituted α-amino acids(DAAs)[2] still remains a challenge. These classes of com-pounds have attracted growing interest due to their greatpotential in the synthesis of biologically active molecules.In addition to their ability to induce helix conformationsignificantly when present in peptides,[3] their major appli-cations are the inclusion of DAAs in peptidomimetics[4] andtheir use in inhibitor design[5] or as building blocks for thesynthesis of natural products. Moreover, a particularlyinteresting feature of this class of amino acids is the chemi-cal, enzymatic, and stereochemical stabilities conferred bythe quaternary C-center. Among compounds of this class,α-substituted aspartic acid derivatives of type 1 (Figure 1)display a very rich functionality that makes them of par-ticular interest for synthesis, especially when the α-substitu-ent possesses an orthogonal functionality allowing subse-quent chemoselective transformations. For instance, a di-ester of type 2 (Pg = CO2Me), obtained from (S)-trypto-phan by stereoselective transformation and final degrad-ative oxidation, was fruitfully employed by Crich et al. asa precursor of (R)-α-methyl aspartic acid.[6] Therefore, thedevelopment of new methods allowing selective access to α-

[a] LUNAM Université du Maine, IMMM (MSO) UMR 6283CNRS,72085 Le Mans, FranceE-mail: [email protected]://immm.univ-lemans.fr

[b] Université de SFax, Laboratoire de Chimie Appliquée HCGP,Sfax, Tunisie

[c] Département de Chimie Moléculaire (SERCO) UMR 5250,ICMG FR-2607, CNRS-Université Joseph Fourier,BP 53, 38041 Grenoble Cedex 09, FranceSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201301739.

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line NH-isoxazolidine, the absolute configuration of whichwas established by X-ray crystallography. N-Protection andN–O cleavage of this isoxazolidine gave enantioenrichedquaternary aspartate derivatives bearing functionalized sidechains.

substituted aspartic acid derivatives such as 2–4 (Figure 1)is highly valuable.

Figure 1. Asymmetric synthesis of α-substituted aspartate esters:the nitrone route.

We described in 2010[7] a route to racemic disubstitutedaspartic derivatives 3b (R�� = tBu, Pg = COCF3) and 4a(Pg = Ac) through a strategy based on the selective func-tional group manipulation of quaternary-center-containingisoxazolidines 5 (R�� = tBu, Pg� = Bn), obtained by 1,3-dipolar cycloaddition involving “aspartic” ketonitrones 6and vinyl ethers.[8] Therefore, an attractive objective was toachieve an efficient enantioselective version of this syntheticsequence, based on a key [3+2] cycloaddition that wouldbe asymmetrically controlled by the use either of a chiralauxiliary borne by one cycloreactant or of an enantioselec-tive catalytic pathway. We report here the preparation of theenantioenriched acid (R)-2b (Pg = COCF3) through facialand exo-selective [3+2] cycloaddition of nitrones of type 6with chiral vinyl ethers as dipolarophiles.

Results and Discussion

For this study, in addition to the already described N-benzyl aspartic nitrone 6a (Figure 1, Pg� = Bn),[8] we alsoemployed the N-benzhydryl and N-p-methoxybenzyl as-partic nitrones 6b and 6c, conveniently prepared by ad-dition of the corresponding hydroxylamines to dimethyl


G. Dujardin et al.FULL PAPERacetylenedicarboxylate (DMAD) (Scheme 1).[9] The twonew aspartic nitrones were tested in order to evaluate alter-native procedures for the N-deprotection of the isoxazolid-ine ring after the [3+2] cycloaddition. The hydroxylamineprecursors of 6b and 6c were obtained as oxalate salts, eachin three steps from the corresponding amine.[10] Nitrone6d[7] was also used in this study to measure the influence ofthe C-substitution on the diastereocontrol of the cycload-dition. The pure E geometry of the crystalline nitrone 6b(m.p. 97–98 °C) was established by X-ray crystallography(Figure 2). Importantly, in view of the analogies displayedin the NMR spectroscopic data, this also confirms the as-signment of pure E geometry to 6a and to the other N-benzyl nitrones described previously.[7]

Scheme 1. Preparation of nitrones 6b and 6c.

Figure 2. X-ray structure of nitrone 6b.

In our previous report, thermal 1,3-dipolar cycload-ditions (1,3-DCs) between nitrone 6a and vinyl ethers de-rived from (–)-menthol, d-(–)-pantolactone, and (R)-methylmandelate were found to proceed in high yields but withlow diastereoselectivities.[8] This study was extended to chi-ral benzyl vinyl ethers 7a,[11] originating from (R)-1-phen-ylethanol, and 7b, derived from (R)- or (S)-1-(2,4,6-triiso-propylphenyl)ethanol[12] (Stericol®). For the preparation ofO-vinyl ethers 7b, the previously employed two-step methodinvolving the formation of a dichlorovinyl ether[13] (Table 1,Entry 1) was compared with direct O-vinylation procedures.Whereas Ishii’s method[14] employing an IrI catalyst(Table 1, Entry 2) gave disappointing results in our hands,methods employing AuI/AgI[15] or PdII[16] catalysis (Table 1,Entries 3 and 4) were found to improve the yield. The gold-catalyzed method proved particularly efficient, producingvinyl ether 7b in a high state of purity.

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Table 1. Synthesis of O-vinyl-substituted Stericol® derivative 7b.

Entry Conditions Yield7b [%]

1 1) KH, ClHCCCl2; 2) nBuLi; H2, Pd/BaSO4 632 IrCl(cod)2, Na2CO3, toluene, 100 °C, 24 h[14] 423 AuClPPh3, AgOAc, ethyl vinyl ether, 50 °C, 70

20 h[15]

4 Pd(OAc)2, DDP, butyl vinyl ether, NEt3, 9375 °C, 24 h[16]

The nitrones 6a–d and chiral dipolarophiles 7a and 7bwere then subjected to thermal 1,3-DC cycloaddition condi-tions (toluene, 125 °C, 48 h, Table 2). With N-benzylnitrone 6a, cycloadditions occurred in high yields with vinylether 7a in a 86:14 trans selectivity (Table 2, Entry 1), lowerthan that previously obtained with ethyl vinyl ether (92:8).[8]

Replacing vinyl ether 7a, originating from 1-phenylethanol(Table 2, Entry 1), with vinyl ether 7b, derived from Ste-ricol,® allowed for a noticeable increase in the facial selec-tivity, from 75:25 up to 90:10 (Table 2, Entries 2–3), as wellas a slight increase in trans selectivity (90:10). As expected,similar selectivities were observed when N-PMB nitrone 6cwas employed (Table 2, Entry 5). The reaction between thebulkier N-DPM nitrone 6b and 7b (Table 2, Entry 4) pro-vided slightly better trans diastereocontrol (95:5 instead of90:10) but with a simultaneous decrease in facial control(81:19 instead of 90:10). Suppressing the ester functionalityon the side chain of the nitrone (Entry 6, with alanine-based nitrone 6d,[7] vs. Entry 2, with aspartic-based nitrone6a) had a negative influence on both yield and diastereo-selectivities. For adducts 5a–e, isolation of the major transdiastereomers as pure products by simple chromatographyon silica gel was found to be impossible. However the(2�R,5S,3R) configuration could later be assigned to themajor isomer of 5b obtained from O-vinyl-substituted Ste-ricol® derivative (R)-7b (Table 2, Entry 2), after correlationdeduced from further transformations (vide infra).

To obtain the targeted DAA derivatives 2–4 from ad-ducts of type 5, the sequence involving N-debenzylation andsubsequent N-acylation prior to the removal of the chiralauxiliary was investigated. Chemoselective N-debenzylationby Pd/C-catalyzed hydrogenolysis in methanol with formicacid as hydrogen source[17] was planned, although applica-tion of these conditions to adducts 5b–e was challenging,due to the known sensitivity of the Stericol ethers in acidicmedium.[18] However, to our delight, applying these condi-tions to the crude cycloadduct 5b led to the desired N-de-benzylated isoxazolidine 8 as the major product (Scheme 2).In addition, the major isomer of (+)-8 could be obtained asa white solid (m.p. 182 °C) with a very high diastereomericpurity after silica gel chromatography and recrystallization,


α-Substituted Functional Aspartic Acid Derivatives

Table 2. 1,3-DC reactions involving chiral benzyl enol ethers 7.[a]

Entry Nitrone Chiral Adduct Yield trans: drvinyl 5 [%][b] cis [d] (trans)[d]

ether

1 6a (R)-7a 5a � 95/88 86:14 75:252 6a (R)-7b 5b � 95/–[c] 90:10 90:103 6a (S)-7b ent-5b � 95/–[c] 90:10 90:104 6b (S)-7b ent-5c � 95/83 95:5 81:195 6c (R)-7b 5d –/40 88:12 88:126 6d (S)-7b ent-5e –/62 85:15 72:28

[a] 1.0 equiv. of 6 and 7, 1 mL of toluene mmol–1. Only the majordiastereoisomer is depicted. [b] Conversion into adduct from crudeproduct/yield of adduct after silica gel chromatography. [c] Nochromatographic purification. [d] Determined by 1H NMR analy-sis.

in 50% overall yield (two steps) from starting compounds6a and (R)-7b. Applying the same procedure to the crudeN-benzhydryl adduct 5c again led mainly to the desiredproduct (+)-8 (Scheme 2). However, in this case the hydroly-sis of the acetal moiety during hydrogenolysis proved to besignificantly more important (Stericol was isolated from thereaction mixture in 35 % yield) than in the N-benzyl series(20%). N-Deprotected product (+)-8 was obtained after sil-ica gel chromatography in 45% overall yield from startingcompounds 6b and (R)-7b (dr: 98:2). The moderate yieldsobtained for the N-deprotection of adducts 5b and 5c to

Scheme 2. Synthesis of (+)-8.

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afford the isoxazolidinone 8 are clearly the consequence ofthe sensitivity of the Stericol ether moiety under the acidicconditions used. This prompted us to investigate the exten-sion of the sequence to the N-PMB nitrone 6c (Table 2, En-try 5), because it was expected that 6c would allow accessto 8 from an adduct that could be N-deprotected undernon-acidic conditions. Unfortunately, all attempts to re-move the PMB group from isoxazolidine 5e under oxidativeconditions (DDQ, CAN, NBS) led to oxidative degradationof the isoxazolidine ring.

Isoxazolidines (+)-8 and (–)-(8) could thus be obtained inhigh diastereopurity by starting from (R)- or (S)-Stericol®

(equally available) via the cycloadducts 5b (or 5c) and ent-5b, respectively. The high levels of enantiopurity of 8 wereunambiguously established by chiral HPLC [�98 % ee, de-termined on (–)-8]. The relative configuration (2�R,5S,3R)of the diastereomerically pure isoxazolidine (+)-8 could beestablished by X-ray crystallography (Figure 3). The sameconfiguration thus assigned to the major isomer of the ad-duct 5b is consistent with an exo approach from the Si faceof the E nitrone, as depicted in Figure 4.

Figure 3. X-ray structure of (+)-8.

Pure isoxazolidine (–)-(8) was next subjected to N-acetyl-ation, leading to 9 in quantitative yields (Scheme 3). Allattempts to obtain the amidoaldehyde 4a directly from 9 bytreatment with Mo(CO)6 or SmI2

[7] failed. Removal of thechiral auxiliary could be achieved by acidic cleavage (TFA,CH2Cl2), leading to the 5-hydroxyisoxazolidine 10 as a mix-ture of C-5 epimers in 81% yield for the two steps and in30% overall yield from (S)-Stericol® (five steps). Oxidation


G. Dujardin et al.FULL PAPER

Figure 4. Favored approach in the formation of 5b.

of hydroxyisoxazoline 10 under Pinnick conditions[19]

failed, but treatment with TPAP/NMO led to the isoxazol-idinone (–)-11, a direct precursor of the α-substituted as-partic acid (S)-2a, in 41 % unoptimized yield.

Scheme 3. Synthesis of α-substituted aspartic derivatives (S)-2a, 10,and 11.

In a previous report we had also disclosed another origi-nal route to acids of type 2, based on the nonclassical SmI2-mediated ring-opening reaction of an isoxazolidine systemwith trifluoroacetyl N-protection.[7] Therefore, we were veryinterested in applying this unusual pathway to an enantio-pure substrate with the aim of delivering an analogue of(S)-2a with a more labile N-protecting group (Scheme 4).N-Trifluoroacetylation of (–)-8 proceeded in excellent yield.Subsequent treatment of (–)-12 with Mo(CO)6 led only todegradation products, but treatment with SmI2 in THFpleasingly afforded (–)-3a in good yield. Final acid-medi-ated removal of the chiral auxiliary by treatment of ester(–)-3a with TFA led to the pure N-trifluoroacetyl aminoacid (–)-2b in 95 % yield.


Scheme 4. Synthesis of α-substituted aspartic derivatives (S)-2b.

Conclusions

We report here the first example of high facial selectivityinduced by a chiral vinyl ether as a dipolarophile in [3+2]cycloaddition reactions involving nitrones as dipoles andproceeding through an exo approach of the dipolarophile.This result was achieved thanks to the fixed E geometry ofthe α-carboxy ketonitrones and to the strong ability of theStericol chiral auxiliary to induce facial recognition. It al-lowed the preparations of the enantiopure highly functionalα,α-disubstituted amino ester 2b and of valuable cyclic de-rivatives. The crystalline isoxazolidine 8 acts as a pivotalintermediate to access different α,α-disubstituted aminoacid derivatives in enantiopure and diastereopure forms. Inaddition, N-acyl-5-hydroxyisoxazolidine 10 is a maskedform of a stable N-protected β-aminoaldehyde.[19] To thebest of our knowledge, no N-acyl-5-hydroxyisoxazolidinebearing a quaternary center has been reported to date, de-spite their great synthetic potential as α,α-disubstituted α-amino acid precursors.

Experimental Section(E)-N-(1,4-Dimethoxy-1,4-dioxobut-2-ylidene)diphenylmethan-amine Oxide (6b): A solution of dimethyl acetylenedicarboxylate(0.21 g, 1.49 mmol) in methanol (5 mL) was added dropwise at 0 °Cto a suspension of 1-phenylbenzylhydroxylamine dioxalate salt



(0.5 g, 1.49 mmol) and NaOAc·3H2O (0.3 g, 2.23 mmol) in meth-anol (5 mL). After stirring at room temp. for 20 h, the resultingmixture was concentrated. The residue was dissolved in CH2Cl2(20 mL), washed twice with water, dried with MgSO4, and filtered,and the solvents were evaporated. Purification of this material bycolumn chromatography on silica gel (cyclohexane/AcOEt 9:1) af-forded nitrone 6b (0.38 g, 75 %), Rf = 0.45 (cyclohexane/AcOEt70:30), as a white powder (m.p. 97–98 °C). 1H NMR (400 MHz,CDCl3): δ = 8.30 (s, 1 H), 7.31–7.36 (m, 10 H), 3.84 (s, 3 H), 3.79(s, 2 H), 3.68 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =168.5, 162.0, 137.0, 135.6, 129.0, 128.4, 128.3, 77.2, 52.9, 52.2,34.8 ppm. IR (neat): ν̃ = 3021, 2949, 2930, 1732, 1702, 1510, 1434,1313, 1187, 1118 cm–1. HRMS (CI+, NH3): calcd. for C19H20NO5

[M + H]+ 342.1341; found 342.1336.

1,4-Dimethoxy-N-[(4-methoxyphenyl)methyl]-1,4-dioxobutanimineOxide (6c): A solution of dimethyl acetylenedicarboxylate (1.42 g,10 mmol) in methanol (15 mL) was added dropwise at 0 °C to asuspension of 1-phenylbenzylhydroxylamine dioxalate salt (2.29 g,10 mmol) and NaOAc·3 H2O (2.44 g, 30 mmol) in methanol(15 mL). After the end of the addition (1 h 30), the resulting mix-ture was concentrated. The residue was dissolved in CH2Cl2

(20 mL), washed three times with water, dried with MgSO4, andfiltered, and the solvents were evaporated. Purification of this ma-terial by column chromatography on silica gel (cyclohexane/AcOEt9:1) afforded nitrone 6c (1.37 g, 50%). Rf = 0.15 (cyclohexane/Ac-OEt 70:30, UV). 1H NMR (400 MHz, CDCl3): δ = 7.44 (d, J =8.0 Hz, 2 H), 6.87 (d, J = 8.0 Hz, 2 H), 5.72 (s, 2 H), 3.84 (s, 3 H),3.80 (s, 3 H), 3.75 (s, 2 H), 3.67 (s, 3 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 168.5, 161.9, 159.9, 134.3, 130.5, 125.9, 113.9, 67.1,55.3, 52.9, 52.2, 34.4 ppm. IR (neat): ν̃ = 1740, 1612, 1033 cm–1.HRMS (CI+, NH3): calcd. for C14H17NO6 296.1134; found296.1139.

(R)- and (S)-O-Vinyl-1-(2,4,6-triisopropylphenyl)ethanol (7b)

Method (a): An argon-flushed flask was charged with potassiumhydride (30% suspension in mineral oil, 14.3 g, 107 mmol). Themineral oil was removed by washing with pentane (3 portions ofca. 10 mL), and anhydrous THF (60 mL) was then added. A solu-tion of (S)-1-(2,4,6-triisopropylphenyl)ethanol (Stericol®) (12.0 g,48.3 mmol) in anhydrous THF (40 mL) was added dropwise at0 °C. The mixture was stirred at room temperature for 2 h, cooledto –50 °C, and treated dropwise with a solution of trichloroethylene(4.8 mL, 53 mmol) in anhydrous THF (20 mL). The reaction mix-ture was allowed to warm to 0 °C and stirred until TLC (eluentpentane) showed complete disappearance of starting material. Themixture was then carefully treated with methanol (6 mL) and water(12 mL). The crude product was extracted with pentane in the us-ual way, and the combined extracts were washed with water, driedwith Na2SO4, and concentrated under vacuum at 0 °C. The residuewas purified by flash chromatography on silica gel (pretreated withtriethylamine 2.5%, v/v, eluent pentane) to afford the dichloroenolether (13.0 g, 79%) as a white solid: m.p. 38–41 °C. [α]D20 = –16.2 (c= 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.05 (s, 2 H),6.00 (q, J = 6.9 Hz, 1 H), 5.60 (s, 1 H), 3.75–3.15 (br. s, 2 H), 2.90(sept, J = 6.9 Hz, 1 H), 1.70 (d, J = 6.9 Hz, 3 H), 1.35–1.20 (m, 18H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.5, 142.9, 131.2,122.1, 98.3, 76.4, 34.1, 29.4, 24.7, 24.5, 23.9, 20.3 ppm. IR (film):ν̃ = 3086, 1623, 1609, 1078, 1040 cm–1. MS (EI+): m/z = 343 and341 [M]+, 248, 231 (100). C19H28Cl2O: C 66.47, H 8.22; found C66.63, H 8.36.

nBuLi (2.5 m in hexanes, 12.8 mL, 32.1 mmol) was added dropwiseat –78 °C to a solution of the dichloroenol ether (5.0 g, 14.6 mmol)


in anhydrous THF (55 mL). The solution was allowed to warm to–40 °C and stirred for 10 min, and then saturated aqueousNaHCO3 (6 mL) and water (6 mL) were added. The solution wasallowed to warm to 0 °C. Pyridine (30 mL) was then added, andthe mixture was hydrogenated (1 atm) over palladium (10% w/w onBaSO4, 960 mg) at room temperature until IR showed no startingmaterial remaining (triple bond, ca. 2260 cm–1, 1.5 h). The reactionmixture was filtered through Celite®, and water was added. Theproduct was extracted with Et2O, and the combined organic layerswere successively washed with CuSO4(aq), water, and brine, driedwith anhydrous Na2SO4 and filtered, and the filtrate was concen-trated under vacuum. The residue was purified by flash chromatog-raphy on silica gel (pretreated with Et3N, 2.5%, v/v, eluent pentane,100%) to afford vinyl ether (S)-7b (3.2 g, 81%) as a colorless oil.

Method (b) – From (R)- or (S)-Stericol® by Use of [IrClcod]2: (Chlo-rocycloocta-1,5-diene)iridium ([IrClcod]2, 0.01 mmol), sodiumcarbonate (6 mmol), Stericol (10 mmol), and vinyl acetate(20 mmol) in toluene (10 mL) were placed in a 100 mL flaskequipped with a condenser. The reaction mixture was maintainedat 100 °C with magnetic stirring and under argon for 24 h. Afterthe mixture had cooled to room temperature, diethyl ether (2 mL)was added. The mixture was then filtered through silica and con-centrated in vacuo to furnish the crude vinyl ether as a colorlessoil.

Method (c) – From (R)- or (S)-Stericol® by Use of Au/Ag: Ethylvinyl ether (7.4 mL, 10 equiv.) was added under argon to a screwcap tube containing AuClPPh3 (69 mg, 2 mol-%) and AgOAc(23 mg, 2 mol-%). The mixture was stirred at room temp. for10 min. After addition of (R)- or (S)-Stericol® (1.75 g, 10 mmol),the mixture was stirred at 50 °C for 16 h, then allowed to cool toroom temp., diluted with AcOEt (20 mL), and filtered through ce-lite. The solvent was removed under vacuum. Purification by col-umn chromatography on silica gel (pentane/diethyl ether 95:5), Rf

= 0.75 (pentane/diethyl ether 80:20), afforded the vinyl ether (R)-(+)- or (S)-(–)-7b (1.46 g, 70 %) as a transparent oil, as well as start-ing alcohol in a second fraction.

Method (d) – From (R)- or (S)-Stericol® by Use of Pd(OAc)2: Palla-dium acetate (30.3 mg, 0.135 mmol) and 4,7-diphenylphenanthrol-ine (44.8 mg, 0.135 mmol) were dissolved in butyl vinyl ether(27.5 g, 101.8 mmol). After the addition of (R)- or (S)-Stericol(672 mg, 2.7 mmol) and triethylamine (0.8 mL, 0.2 mmol), the mix-ture was stirred at 75 °C for 24 h, then allowed to cooled to roomtemperature, and filtered through activated charcoal. The solventwas removed under vacuum. Purification by column chromatog-raphy on silica gel (pentane/diethyl ether 95:5), Rf = 0.28 (pentane/diethyl ether 95:5), afforded the vinyl ether (R)-(+)- or (S)-(–)-7b(0.68 g, 93%) as a transparent oil. For (R)-(+)-7b: [α]D20 = +22.2 (c= 1.16, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.00 (s, 2 H),6.27 (dd, J = 14, 6.5 Hz, 1 H), 5.45 (q, J = 6.8 Hz, 1 H), 4.28 (dd,J = 14, 1.4 Hz, 1 H), 3.92 (dd, J = 6.5, 1.4 Hz, 1 H), 3.60–3.36 (m,2 H), 2.90–2.80 (m, 1 H), 1.62 (d, J = 6.8 Hz, 3 H), 1.30–1.20 (m,18 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.0, 146.7, 134.9,121.0, 87.5, 73.1, 33.0, 27.9, 23.6, 23.5, 22.9, 21.4 ppm. IR (NaCl):ν̃ = 2961, 2932, 2869, 1633, 1608, 1460, 1383, 1191, 1079 cm–1. For(S)-(–)-7b: [α]D20 = –22.7 (c = 1.15, CHCl3). All attempts to deter-mine ee by chiral GC or HPLC failed, due to our inability to sepa-rate the enantiomers from the racemic vinyl ether (�)-(7b), what-ever the chromatographic conditions used.

General Procedure for Cycloaddition Between Nitrones 6 and Di-polarophiles 7: A dipolarophile 7 was added under argon to a sealed


G. Dujardin et al.FULL PAPERtube containing toluene and a nitrone 6. The mixture was stirredat 125 °C for 48 h and then allowed to cool to room temp. Thereaction mixture was then concentrated under vacuum to removetoluene.

Methyl (3R,5S)-2-Benzyl-3-(2-methoxy-2-oxoethyl)-5-[(R)-1-phenyl-ethoxy]isoxazolidine-3-carboxylate (5a): This compound was pre-pared from 6a (40 mg, 0.15 mmol) and (R)-7a (44.4 mg, 0.34 mmol)in toluene (0.5 mL); purification by flash chromatography (cyclo-hexane/AcOEt 85:15) afforded the title compound as a colorless oil(51 mg, 88 %). R f = 0.15 (cyclohexane/AcOEt 90:10). Dia-stereomeric ratio: 64.5:21.5:10:4. Major adduct: 1H NMR(400 MHz, CDCl3): δ = 7.44–7.19 (m, 10 H), 5.04 (dd, J = 6.3,2.8 Hz, 1 H), 4.60 (q, J = 6.5 Hz, 1 H), 4.08 (d, J = 14.8 Hz, 1 H),3.74 (s, 3 H), 3.67 (s, 3 H), 3.66 (m, 1 H), 3.29 (dd, J = 13.6, 6.4 Hz,1 H), 3.14 (d, J = 16.7 Hz, 1 H), 2.81 (d, J = 16.7 Hz, 1 H), 2.28(dd, J = 13.6, 2.8 Hz, 1 H), 1.36 (d, J = 6.5 Hz, 3 H) ppm. 13CNMR (100 MHz, CDCl3): δ = 170.9, 170.8, 143.2, 137.7, 128.5–126.3, 98.4, 74.9, 70.4, 55.5, 52.2, 51.9, 45.9, 39.6, 24.2 ppm. Somecharacteristic NMR signals of the minor trans adduct: 1H NMR(400 MHz, CDCl3): δ = 5.42 (dd, J = 6.3, 2.9 Hz, 1 H), 4.67 (q, J

= 6.4 Hz, 1 H), 3.97 (d, J = 14.5 Hz, 1 H), 3.80 (s, 3 H), 3.66 (s, 3H), 3.56 (d, J = 14.6 Hz, 1 H), 3.41 (dd, J = 13.6, 6.4 Hz, 1 H),3.08 (d, J = 16.7 Hz, 1 H), 2.74 (d, J = 16.7 Hz, 1 H), 2.30 (dd, J

= 13.6, 3 Hz, 1 H), 1.39 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR(100 MHz, CDCl3): δ = 171.3, 169.9, 143.5, 137.4, 125.4, 99, 74.7,70.5, 55.8, 52.8, 46.2, 39.5, 21.1 ppm. Some characteristic NMRsignals of the minor cis I adduct: 1H NMR (400 MHz, CDCl3): δ= 4.96 (dd, J = 6.5, 3.5 Hz, 1 H), 4.34 (d, J = 14 Hz, 1 H), 3.69 (s,3 H), 3.63 (s, 3 H), 2.75 (d, J = 16.2 Hz, 1 H), 2.60 (dd, J = 14.2,6.5 Hz, 1 H), 1.50 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 137.8, 75.2, 25.2 ppm. Some characteristic NMR sig-nals of the minor cis II adduct: 1H NMR (400 MHz, CDCl3): δ =5.35 (dd, J = 6.6, 3.6 Hz, 1 H), 4.16 (d, J = 14 Hz, 1 H) ppm. IR(NaCl): ν̃ = 2956, 2923, 2851, 1729, 1643, 1454, 1204 cm–1. HRMS(CI+, NH3): calcd. for C23H27NO6 [M + H]+ 414.1917; found414.1913.

Methyl (3R,5S)-2-Benzyl-3-(2-methoxy-2-oxoethyl)-5-[(R)-1-(2,4,6-triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate (5b): Adduct5b was obtained from 6a (795 mg, 3 mmol) and (R)-(+)-7b (822 mg,3 mmol) in toluene (5 mL); the crude adduct was used in the nextstep without further purification. Diastereomeric ratio: 81:9:8:2.Major adduct: 1H NMR (400 MHz, CDCl3): δ = 7.52–6.87 (m, 7H), 5.13 (q, J = 7 Hz, 1 H), 4.96 (dd, J = 6.1, 2.2 Hz, 1 H), 4.07(d, J = 14.5 Hz, 1 H), 3.84–3.75 (m, 2 H), 3.75 (s, 3 H), 3.69 (s, 3H), 3.62 (d, J = 14.4 Hz, 1 H), 3.27 (dd, J = 13.5, 6.3 Hz, 1 H, 1H), 3.16 (d, J = 16.8 Hz, 1 H), 2.85 (d, J = 16.9 Hz, 1 H), 2.83 (m,1 H), 2.23 (dd, J = 13.5, 2.4 Hz, 1 H), 1.44 (d, J = 7 Hz, 3 H),1.31–1.01 (m, 18 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.0,170.9, 147.4, 138, 132.5, 128.4–127, 123.1, 120.5, 97.9, 70.2, 55.7,52.1, 51.9, 46, 39.8, 34.0, 31.0, 29.7, 24.4–23.9, 22.8, 21.2 ppm.Some characteristic NMR signals of the minor trans adduct: 1HNMR (400 MHz, CDCl3): δ = 5.48 (dd, J = 6.3, 3.1 Hz, 1 H), 5.18(q, J = 6.6 Hz, 1 H), 4.34 (d, J = 14 Hz, 1 H), 3.80 (s, 3 H), 3.67(s, 3 H), 3.42 (dd, J = 13.5, 6.3 Hz, 1 H), 3.14 (d, J = 16.1 Hz, 1H), 3.01 (d, J = 16.8 Hz, 1 H), 2.60 (d, J = 16.9 Hz, 1 H), 1.47 (d,J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 129.0,125.3, 69.5, 52.7, 23.9 ppm. Some characteristic NMR signals ofthe minor cis I adduct: 1H NMR (400 MHz, CDCl3): δ = 4.91 (dd,J = 6.5, 3.2 Hz, 1 H), 4.05 (d, J = 13.7 Hz, 1 H), 3.83 (s, 3 H), 3.67(s, 3 H), 2.54 (dd, J = 13.8, 7.1 Hz, 1 H), 2.24 (d, J = 13.6 Hz, 1 H),1.48 (d, J = 6.9 Hz, 3 H) ppm. Some characteristic NMR signals ofthe minor cis II adduct: 1H NMR (400 MHz, CDCl3): δ = 5.40 (dd,


J = 6.2, 3.7 Hz, 1 H) ppm. IR (NaCl): ν̃ = 2959, 2869, 1743, 1607,1572, 1497, 1456, 1437, 1361, 1241, 1208, 1099, 1079, 1008, 969,942, 733, 698 cm–1. HRMS (CI+, NH3): calcd. for C32H46NO6 [M+ H]+ 540.3325; found 540.3344.

Methyl (3S,5R)-2-Benzyl-3-(2-methoxy-2-oxoethyl)-5-[(S)-1-(2,4,6-triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate (ent-5b): Thisadduct was obtained by the same procedure as used for 5b, startingfrom (S)-(–)-7b.

Methyl (3S,5R)-2-Benzhydryl-3-(2-methoxy-2-oxoethyl)-5-[(S)-1-(2,4,6-triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate (ent-5c): This compound was prepared from 6b (51 mg, 0.15 mmol) and(S)-(–)-7b (86 mg, 0.31 mmol) in toluene (0.5 mL); purification byflash chromatography (cyclohexane/Et2O 85:15) afforded the titlecompound as a colorless oil (72 mg, 83%). Rf = 0.55 (cyclohexane/Et2O 80:20). Diastereomeric ratio: 77:18:5:0. Major adduct 1HNMR: (400 MHz, CDCl3): δ = 7.58–6.82 (m, 12 H), 5.13 (q, J =6.9 Hz, 1 H), 4.91 (s, 1 H), 4.83 (dd, J = 6.4, 2.6 Hz, 1 H), 3.88–3.78 (m, 1 H), 3.60 (s, 3 H), 3.53 (s, 3 H), 3.24 (dd, J = 13.5, 6.4 Hz,1 H), 2.87–2.76 (m, 1 H), 2.55 (d, J = 16.7 Hz, 1 H), 2.52–2.44 (m,1 H), 2.37 (d, J = 16.8 Hz, 1 H), 2.25 (dd, J = 13.5, 2.6 Hz, 1 H),1.61 (d, J = 6.9 Hz, 3 H), 1.33–0.80 (m, 18 H) ppm. 13C NMR(100 MHz, CDCl3): δ = 171.0, 170.8, 147.5, 143.2, 140.5, 132.1,128.6, 128.2, 127.9, 127.3, 126.7, 123, 120.5, 96.4, 70.7, 51.9, 51.8,47.1, 40.9, 30.1–28.3, 23.9, 24.8–24.1, 23.8 ppm. Some characteris-tic NMR signals of the minor trans adduct: 1H NMR (400 MHz,CDCl3): δ = 5.40 (dd, J = 6.5, 3.2 Hz, 1 H), 5.13 (q, J = 6.9 Hz, 1H), 4.86 (s, 1 H), 3.58 (s, 3 H), 3.54 (s, 3 H), 3.37 (dd, J = 13.5,6.5 Hz, 1 H), 2.32 (dd, J = 13.5, 3.2 Hz, 1 H), 1.46 (d, J = 6.8 Hz,3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.8, 169.7, 148.6,147.6, 146.9, 141.6, 140.9, 134.9, 99.1, 71.1, 52.1, 51.6, 47.4, 40.6,34.1, 22.5 ppm. Some characteristic NMR signals of the minor cis Iadduct: 1H NMR (400 MHz, CDCl3): δ = 5.53 (q, J = 6.8 Hz, 1H), 5.33 (s, 1 H), 4.78 (dd, J = 6.5, 3.3 Hz, 1 H), 4.65 (q, J =5.2 Hz, 1 H), 2.49 (d, J = 6.6, Hz, 1 H), 3.65 (s, 3 H), 1.50 (d, J =6.9 Hz, 1 H) ppm. IR (NaCl): ν̃ = 2958, 2924, 2851, 1741, 1607,1493, 1455, 1437, 1361, 1205, 1166, 1100, 1079, 997, 972, 742,705 cm–1. HRMS (CI+, NH3): calcd. for C38H49NO6 [M + H]+

616.3639; found 616.3638.

Methyl (3R,5S)-2-(4-Methoxybenzyl)-3-(2-methoxy-2-oxoethyl)-5-[(R)-1-(2,4,6-triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate(5d): This compound was prepared from 6c (112.4 mg, 0.38 mmol)and (R)-(+)-7b (104.5 mg, 0.38 mmol) in toluene (3.5 mL); purifica-tion by flash chromatography (cyclohexane/AcOEt 90:10), Rf =0.21 (cyclohexane/AcOEt 80:20), afforded the title compound(87.3 mg, 40%). Diastereomeric ratio: 77:11:10:2. Major adduct 1HNMR: (400 MHz, CDCl3): δ = 7.33 (d, J = 8.6 Hz, 2 H), 7.05–6.95(m, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 5.13 (q, J = 6.8 Hz, 1 H), 4.96(dd, J = 2.5, 6.4 Hz, 1 H), 3.99 (d, J = 14.2 Hz, 1 H), 3.90–3.70(m, 1 H), 3.82 (s, 3 H), 3.74 (s, 3 H), 3.68 (s, 3 H), 3.57 (d, J =14.2 Hz, 1 H), 3.25 (dd, J = 6.4, 13.7 Hz, 1 H), 3.15 (d, J = 16.6 Hz,1 H), 2.83 (d, J = 16.6 Hz, 1 H), 2.83 (m, 2 H), 2.21 (dd, J = 2.4,13.7 Hz, 1 H), 1.44 (d, J = 6.8 Hz, 3 H), 1.22 (d, J = 7.1 Hz, 6 H),1.0–1.2 (m, 12 H) ppm. Characteristic NMR signals of the minoradducts (H-5 proton); minor trans adduct: 5.40 (dd, J = 4.2, 6.6 Hz,1 H); major cis adduct: 4.91 (dd, 1 H, J = 3.2, 6.4 Hz); minor cis

adduct: 5.49 (dd, J = 3.2, 6.3 Hz, 1 H). 13C NMR (100 MHz,CDCl3): δ = 171.1, 170.9, 158.7, 147.4, 132.5, 130.1, 129.4, 123.0,120.5, 113.4, 97.2, 70.2, 69.4, 55.3, 52.1, 51.9, 46.0, 39.8, 34.0, 28.9,28.4, 24.5, 24.1, 23.9, 22.9 ppm. IR (NaCl): ν̃ = 1739, 1616,1078 cm–1. HRMS (CI+, NH3): calcd. for C33H47NO7 [M + H]+

570.3431; found 570.3406.



Methyl (3S,5R)-2-Benzyl-3-methyl-5-[(S)-1-(2,4,6-triisopropylphen-yl)ethoxy]isoxazolidine-3-carboxylate (ent-5e): This compound wasprepared from 6d (80.7 mg, 0.39 mmol) and (S)-(–)-7b (107 mg,0.39 mmol) in toluene (0.5 mL); purification by flash chromatog-raphy (cyclohexane/AcOEt 95:5) afforded the title compound as acolorless oil (116 mg, 62%). Rf = 0.53 (cyclohexane/AcOEt 80:20).Diastereomeric ratio: 61:24:9:5. Major adduct: 1H NMR(400 MHz, CDCl3): δ = 7.49–7.22 (m, 5 H), 7.13–6.88 (m, 2 H),5.18 (q, J = 6.7 Hz, 1 H), 4.96 (dd, J = 6.2, 3.0 Hz, 1 H, 1 H), 4.19(d, J = 14.5 Hz, 1 H), 3.86 (d, J = 14.3 Hz, 1 H), 3.71 (s, 3 H),3.05 (dd, J = 13.2, 6.3 Hz, 1 H), 2.95–2.78 (m, 3 H), 2.16 (dd, J =13.1, 3.1 Hz, 1 H), 1.51 (s, 3 H), 1.47 (d, J = 6.9 Hz, 3 H), 1.27–0.92 (m, 18 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.1,147.4, 138.6, 132.7, 128.5, 128.2, 128.0, 127.9, 126.8, 123.1, 120.5,99.1, 70.0, 55.9, 52, 46.7, 34, 29.2, 28.9, 28.4, 26.9, 24.8, 24.5, 24.1,23.9, 22.9, 20.1 ppm. Some characteristic NMR signals of theminor trans adduct: 1H NMR (400 MHz, CDCl3): δ = 4.88 (dd, J

= 6.2, 2.8 Hz, 1 H), 4.24 (d, J = 14 Hz, 1 H), 3.76 (s, 3 H), 2.31(dd, J = 13.3, 6.3 Hz, 1 H), 1.47 (d, J = 6.9 Hz, 3 H), 1.39 (s, 3H) ppm. 13C NMR (100 MHz CDCl3): δ = 172.7, 172.5, 132.5,126.4, 97.8, 69.4, 55.7, 52.4, 47.3, 34.1, 22.7, 19.9 ppm. Some char-acteristic NMR signals of the minor cis I adduct: 1H NMR(400 MHz, CDCl3): δ = 5.45 (dd, J = 6.2, 3.6 Hz, 1 H), 3.98 (d, J

= 14.7 Hz, 1 H), 3.55 (s, 3 H), 3.14 (dd, J = 13.1, 6.3 Hz, 1 H),1.40 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 100.0, 71.5,38.0 ppm. Some characteristic NMR signals of the minor cis II ad-duct: 1H NMR (400 MHz, CDCl3): δ = 5.38 (dd, J = 6.2, 3.4 Hz,1 H), 4.06 (d, J = 14.4 Hz, 1 H), 2.45 (dd, J = 13.3, 6.3 Hz, 1H) ppm. IR (NaCl): ν̃ = 2960, 2930, 2869, 1731, 1645, 1607, 1456,1279, 1205, 1140, 1123, 1077, 980, 878, 731, 697 cm–1. HRMS(Cl+NH3): calcd. for C30H44NO4 [M + H]+ 482.3270; found482.3236.

Methyl (3R,5S)-3-(2-Methoxy-2-oxoethyl)-5-[(R)-1-(2,4,6-triiso-propylphenyl)ethoxy]isoxazolidine-3-carboxylate [(+)-8] and Methyl(3R,5S)-3-(2-Methoxy-2-oxoethyl)-5-[(S)-1-(2,4,6-triisopropylphen-yl)ethoxy]isoxazolidine-3-carboxylate [(–)-8]: Formic acid (8.6 mL)was added dropwise under argon to a stirred solution of adduct 5b(or ent-5b, 1.691 g, 3.13 mol) in MeOH (13 mL) and Pd/C (10%,644.6 mg). After 16 h of stirring at room temp., the reaction mix-ture was diluted with AcOEt (10 mL) and filtered through celite.The filtrate was concentrated under reduced pressure. Recrystalli-zation of the compound from pentane/AcOEt (2:1) afforded thetitle compound (+)-8 [or (–)-8] as a white solid (466 mg, 50%, m.p.181.5–182.5 °C). 1H NMR (400 MHz, CDCl3): δ = 7.03–7.95 (m,2 H), 6.40–6.25 (m, 1 H), 5.38 (q, J = 6.7 Hz, 1 H), 5.11 (d, J =5 Hz, 1 H), 3.80–3.70 (m, 1 H), 3.74 (s, 3 H), 3.72 (s, 3 H), 3.15 (d,J = 15.9 Hz, 1 H), 3.25–3.10 (m, 1 H), 2.93–2.81 (m, 3 H), 2.11 (d,J = 13.5 Hz, 1 H), 1.56 (d, J = 6.9 Hz, 3 H), 1.25–1.15 (m, 18H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.0, 131.8, 123,120.6, 102.1, 69.7, 53.0, 52, 45.2, 39.7, 34, 28.4, 29.5, 24.7, 23.9,22.9 ppm. IR (neat): ν̃ = 3200, 1732, 1069 cm–1. HRMS (FD):calcd. for C25H39NO6 [M]+ 449.2777; found 449.2840. For (–)-(8):[α]D20 = –153.4 (c = 0.55, CHCl3). Chiral HPLC: ee � 98%[Phenomenex Lux Cellulose (2.5 μm), 250�4.6, isooctane/iPrOH95:5, 1 mLmin–1, 210 nm].

Methyl (3R,5S)-2-Acetyl-3-(2-methoxy-2-oxoethyl)-5-[(R)-1-(2,4,6-triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate [(+)-9] andMethyl (3R,5S)-2-Acetyl-3-(2-methoxy-2-oxoethyl)-5-[(S)-1-(2,4,6-triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate [(–)-9]: Asolution of (+)-8 [or (–)-8, 200 mg, 0.44 mmol] in Ac2O (0.8 mL)was stirred at room temp. for 16 h, and the reaction mixture wasthen concentrated under reduced pressure to afford (+)-9 [or (–)-9,


respectively] as a yellow oil (240 mg, �95%) that was used in thenext step without further purification. 1H NMR (400 MHz,CDCl3): δ = 7.05–6.97 (m, 2 H), 5.42 (q, J = 6.9 Hz, 1 H), 5.17 (d,J = 4.8 Hz, 1 H), 3.73 (s, 3 H), 3.71 (s, 3 H), 3.80–3.65 (m, 1 H),3.65 (d, J = 16.1 Hz, 1 H), 3.25–3.12 (m, 1 H), 3.1 (d, J = 13.5 Hz,1 H), 2.98 (d, J = 16.1 Hz, 1 H), 2.90–2.74 (m, 2 H), 2.16 (s, 3 H),1.58 (d, J = 6.9 Hz, 3 H), 1.28–1.08 (m, 18 H) ppm. 13C NMR(100 MHz, CDCl3): δ = 170.9, 170.7, 167.5, 148.3, 131.0, 123.5,120.8, 99.2, 70.7, 65.2, 53.0, 51.7, 45.1, 44.5, 38.0, 34.0, 29.7, 29.3,26.9, 26.4, 24.3, 23.9, 22.9, 21.5, 20.7 ppm. IR (NaCl): ν̃ = 2988,2939, 2869, 1642, 1466, 1443, 1374, 1273, 1208, 1104, 1059, 987,858, 766, 696 cm–1. HRMS (Cl+NH3CH4): calcd. for C27H42NO7

[M + H]+ 492.2961; found 492.2947. For (+)-9: [α]D25 = +63.2 (c =0.275, CH2Cl2).

Methyl (3S)-2-Acetyl-5-hydroxy-3-(2-methoxy-2-oxoethyl)isoxazol-idine-3-carboxylate (10): Isoxazolidine (–)-9 (0.127 g 0.26 mmol)was dissolved in dichloromethane (6 mL). Trifluoroacetic acid(350 μL, 0.52 g, 4.6 mmol) was added, and the mixture was stirredovernight. Water (1 mL) was added. After a few minutes, the mix-ture was diluted with dichloromethane and treated with a saturatedsolution of NaHCO3. The aqueous phase was extracted twice withdichloromethane. The organic phase was then dried with MgSO4

and concentrated under reduced pressure to give a residue that waspurified by chromatography on silica gel (cyclohexane/AcOEt 9:1,then pure AcOEt) to give 10 (54.5 mg, 0.21 mmol, 81 %) as a color-less oil. Rf 0.19 (cyclohexane/AcOEt 9:1, vanillin detection). 1HNMR (CDCl3, 400 MHz): two anomers (α/β) in a 60:40 ratio: δ =6.28 (d, J = 10.8 Hz, 1 Hβ), 6.14 (d, J = 12 Hz, 1 Hα), 5.55–5.47(m, 1 H), 3.85 (s, 3 Hα), 3.77 (s, 3 Hβ), 3.73 (s, 3 Hβ), 3.71 (d, J =17.8 Hz, 1 Hβ), 3.70 (s, 3 Hα), 3.42 (d, J = 16.6 Hz, 1 Hα), 3.27(d, J = 17.8 Hz, 1 Hβ), 2.95 (dd, J = 6.1, 14.2 Hz, 1 Hβ), 2.84–2.80 (m, 2 Hα), 2.76 (d, J = 12.7 Hz, 1 Hβ), 2.72 (d, J = 16.6 Hz,1 Hα), 2.16 (s, 3 Hβ), 2.14 (s, 3 Hα) ppm. 13C NMR (CDCl3,100 MHz): Major anomer: δ = 174.0, 170.2, 169.4, 97.8, 64.4, 54.0,51.9, 47.6, 39.1, 21.2 ppm; minor anomer: 172.5, 171.2, 170.7, 96.2,64.9, 53.3, 52.5, 47.3, 37.2, 22.0 ppm. IR (NaCl): ν̃ = 3371, 2956,1741, 1632, 1438, 1357, 1261, 1204, 1109, 906 cm–1. HRMS (DCI,NH3, CH4): calcd. for C10H16NO7 262.0927 [M + H]+; found262.0931.

Methyl (3R)-2-Acetyl-3-(2-methoxy-2-oxoethyl)-5-oxoisoxazolidine-3-carboxylate [(–)-11]: N-Acetyl-5-OH-isoxazolidine 10 (0.011 g,0.04 mmol) was dissolved in anhydrous dichloromethane (1 mL)over molecular sieves (4 Å). NMO (0.0133 g, 0.11 mmol) and TPAP(2.2 mg, 6.3 μmol, 0.15 equiv.) were added, and the mixture wasstirred at room temperature for 90 min. The mixture was then fil-tered through a plug of silica gel. The crude product obtained fromwashing of this plug of silica with AcOEt was purified bychromatography on silica gel (cyclohexane/AcOEt 8:2, then pureAcOEt) to give a colorless oil (4.5 mg, 0.017 mmol, 41 %). Rf

0.10 (cyclohexane/AcOEt 8:2, vanillin detection). [α]D20 = –48.0 (c =0.09, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 3.80 (s, 3 H), 3.73(s, 3 H), 3.58 (d, J = 18.3 Hz, 1 H), 3.33 (d, J = 17.1 Hz, 1 H),3.29 (d, J = 18.1 Hz, 1 H), 3.25 (d, J = 17.1 Hz, 1 H), 2.20 (s, 3H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 170.8, 169.9, 169.1,167.7, 66.8, 53.7, 52.2, 39.4, 38.1, 21.7 ppm. IR (NaCl): ν̃ = 3009,2957, 2852, 1820, 1794, 1689, 1439, 1408, 1370, 1279, 1177, 1083,1051, 1009, 883, 737 cm–1. HRMS (DCI, NH3CH4): calcd. forC10H14NO7 [M + H]+ 260.0770; found 260.0770.

Methyl (3S,5R)-3-(2-Methoxy-2-oxoethyl)-2-(2,2,2-trifluoroacetyl)-5-[(S)-1-(2,4,6-triisopropylphenyl)ethoxy]isoxazolidine-3-carb-oxylate [(–)-12]: Et3N (0.23 mL) and (CF3CO)2O (0.22 mL,


G. Dujardin et al.FULL PAPER1.4 mmol) were added to a solution of (–)-8 (516 mg, 1.15 mmol)in THF (2.6 mL), and the mixture was stirred overnight at roomtemp. The reaction mixture was quenched with NH4Cl and ex-tracted with EtO2. Organic phases were combined, washed withNaCl, dried with MgSO4, filtered, and concentrated under reducedpressure to afford the title compound (610 mg, 97%) as a yellowoil, which was used in the next step without further purification.[α]D25 = –90.7 (c = 3.08, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ= 7.05–6.98 (m, 2 H), 5.46 (q, J = 6.9 Hz, 1 H), 5.26 (d, J = 5.1 Hz,1 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 3.67 (d, J = 15.8 Hz, 1 H), 3.72–3.60 (m, 1 H), 3.22–3.13 (m, 2 H), 3.05 (d, J = 15.9 Hz, 1 H), 2.91–2.81 (m, 2 H), 1.57 (d, J = 6.9 Hz, 3 H), 1.28–1.12 (m, 18 H) ppm.13C NMR (100 MHz, CDCl3): δ = 170.0, 169.0, 151.8 (q, J =39.8 Hz, 1 C), 148.5, 147.0, 130.3, 123.4, 120.9, 115.6 (q, J =286.8 Hz), 100.2, 70.9, 66.9, 53.5, 52.0, 43.5, 36.7, 34.0, 29.1, 28.4,24.6, 24.3, 24.1, 23.8, 22.4 ppm. 19F NMR (376 MHz, CDCl3): δ =–74.5 ppm. IR (NaCl): ν̃ = 2966, 2871, 1739, 1701, 1608, 1573,1438, 1363, 1230, 1113, 1072, 1019, 920, 881, 778, 735 cm–1.HRMS (Cl+NH3): calcd. for C27H38F3NO7 [M + NH4]+ 563.2944;found 563.2964.

1,2-Dimethyl 3-[(S)-1-(2,4,6-Triisopropylphenyl)ethyl] (R)-2-(2,2,2-Trifluoroacetamido)propane-1,2,3-tricarboxylate [(–)-3a]: A solu-tion of SmI2 in THF (0.1 m, 0.312 mmol, 3.12 mL) was added drop-wise under argon at 0 °C to a solution of N-(trifluoroacetyl)isox-azolidine (–)-12 (170 mg, 0.312 mmol) in THF (1.5 mL). After5 min, TLC showed complete consumption of the starting material.The reaction was quenched by bubbling air through the solutionuntil disappearance of its blue color, and aqueous solutions of satd.NaHCO3 and sodium thiosulfate were then added. The aqueousphase was extracted three times with AcOEt, and the combinedorganic phases were washed with brine, dried with MgSO4, filtered,and concentrated under vacuum. Purification of the residue by sil-ica gel chromatography (pentane/AcOEt 9:1) afforded the ester(–)-3a as a clear oil (102 mg, 60%), Rf 0.3 (pentane/AcOEt 9:1).[α]D25 = –64.7 (c = 1.35, CHCl3). 1H NMR (400 MHz, CDCl3): δ =7.73 (br. s, 1 H), 7.17 (br. s, 2 H), 6.44 (q, J = 6.9 Hz, 1 H), 3.64(s, 3 H), 3.57 (s, 3 H), 3.52 (d, J = 15.5 Hz, 1 H), 3.50 (d, J =15.8 Hz, 1 H), 3.35–3.27 (m, 2 H), 2.85 (d, J = 15.8 Hz, 1 H), 2.82–2.72 (m, 1 H), 2.75 (d, J = 15.5 Hz, 1 H), 1.51 (d, J = 6.9 Hz, 3H), 1.21–1.13 (m, 18 H) ppm. 13C NMR (100 MHz, CDCl3): δ =170.6, 169.2, 168.3, 156.4 (q, J = 37.7 Hz), 148.5, 131.5, 129.1,128.1, 115.4 (q, J = 288.4 Hz), 69.6, 59.8, 53.8, 52.2, 39.8, 39.2,34.2, 29.5, 24.5, 24.3, 24.1, 24.0, 22.1 ppm. 19F NMR (376 MHz,CDCl3): δ = –74.5 ppm. IR (neat): ν̃ = 3379, 2959, 2871, 1736,1608, 1526, 1439, 1211, 1164, 1053 cm–1. HRMS (Cl+NH3): calcd.for C27H39F3NO7 [M + H]+ 546.2600; found 545.2649.

(S)-5-Methoxy-3-(methoxycarbonyl)-5-oxo-3-(2,2,2-trifluoroacet-amido)pentanoic Acid [(S)-(–)-2b]: TFA (0.5 mL) was added slowlyto a stirred solution of (–)-3a (125 mg, 0.22 mmol) in CH2Cl2

(6 mL), and the mixture was stirred overnight and then washedwith saturated NaHCO3 solution (10 mL� 3). The aqueous layerswere combined, acidified to pH = 2 (10% HCl), and extracted withCH2Cl2 (10 mL� 3). The organic layers were combined, dried withMgSO4, and filtered, and the solvent was removed in vacuo to yieldthe acid (S)-(–)-2b as a colorless oil (66 mg, 95%). [α]D25 = –17 (c =0.065, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 9.52–9.40 (m, 1H), 7.78 (s, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 3.64 (d, J = 16.3 Hz,1 H), 3.57 (d, J = 15.7 Hz, 1 H), 3.02 (d, J = 16.3 Hz, 1 H), 2.94(d, J = 15.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173,170.3, 169.0, 156.5 (q, J = 37.9 Hz), 115.2 (q, J = 288.2 Hz), 59.2,54.1, 52.3, 39.1, 38.7 ppm. 19F NMR (376 MHz, CDCl3): δ = –77.3(s) ppm. IR (NaCl): ν̃ = 3460, 1743, 1717, 1637, 1618, 1560, 1440,


1383, 1327, 1224, 1193, 1162, 1008 cm–1. HRMS (Cl+NH3CH4):calcd. for C10H13F3NO7 [M + H]+ 316.0644; found 316.0635.

Supporting Information (see footnote on the first page of this arti-cle): Copies of 1H and 13C NMR spectra of all new compoundsand crystallographic data for compounds 6b and (+)-8, as well asdetermination of the enantiopurity of acid 2a by chiral HPLC.

Acknowledgments

The authors thank the University of Sfax (PhD and Master grantsto K. B. A). Financial support of this study by grants from AgenceNationale de la Recherche (ANR) (grant number BS07-005-01) isgratefully acknowledged. The authors thank Pascale Cividino ofthe University of Grenoble (DCM-CNRS) for the preparation of(R)- and (S)-Stericol and Frédéric Legros (IMMM-CNRS) fortechnical assistance. Patricia Gangnery and Amélie Durand of theUniversity of Le Mans (IMMM-CNRS) are thanked for HRMSand NMR measurements, respectively. The authors thank KarimAdil and Vincent Maisonneuve of the University of Le Mans(IMMM-CNRS) for X-ray analysis. Imen Abid is thanked for herwork on the synthesis and N-deprotection of isoxazolidine 5e.

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Received: November 19, 2013Published Online: �


G. Dujardin et al.FULL PAPER

Quaternary Amino Acids

K. Ben Ayed, A. Beauchard, J.-F. Poisson,S. Py, M. Y. Laurent, A. Martel,H. Ammar, S. Abid,G. Dujardin* ................................... 1–10

Enantiopure isoxazolidine (–)-8 is obtained Such an isoxazolidine is a direct precursorAsymmetric Access to α-Substituted Func-

through the highly diastereoselective [3+2] of a “superaspartic” acid bearing two dif-tional Aspartic Acid Derivatives by a [3+2]

cycloaddition of an aspartate-derived ferentiated side chains.Strategy Employing a Chiral Dienophile

ketonitrone and (S)-Stericol vinyl ether.

Keywords: Asymmetric synthesis / Cycload-dition / Amino acids / Heterocycles


Asymmetric Access to α-Substituted Functional Aspartic Acid Derivatives by a [3+2] Strategy...

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