aldolization)

Tetrahedron: Asymmetry 21 (2010) 2361–2366

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Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy

Cyclosulfamide as a chiral auxiliary: application to efficient asymmetric synthesis (alkylation/aldolization) Fabien Fécourt a, Gérald Lopez a, Arie Van Der Lee b, Jean Martinez a, Georges Dewynter a,⇑ a Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Universités Montpellier 1 et 2, Bâtiment Chimie (17), Université Montpellier 2, Place E. Bataillon, 34095 Montpellier Cedex 5, France b Institut Européen des Membranes (IEM), UMR 5635 CNRS-Université Montpellier 2, Case Courrier 047, Place E. Bataillon, 34095 Montpellier Cedex 5, France

a r t i c l e

i n f o

Article history: Received 14 September 2010 Accepted 16 September 2010 Available online 18 October 2010

a b s t r a c t The chiral cyclosulfamide (S)-2-benzyl-4-isopropyl-1,2,5-thiadiazolidine 1,1-dioxide was designed as a chimera of Evans and Oppolzer chiral auxiliaries. The N-propionyl derivative appeared to be very powerful for the stereocontrolled synthesis of chiral building blocks through asymmetric aldolization and alkylation reactions. Ó 2010 Elsevier Ltd. All rights reserved.

1. Introduction The introduction of chirality via the use of chiral auxiliaries has been demonstrated as an effectual means for preparing chiral compounds.1 In particular, the importance of Evans0 1,3-oxazolidin-2-ones 12 and Oppolzer0 s chiral sultams 23 for asymmetric carbon–carbon bond formation has been well documented. Ahn et al. previously investigated titanium-mediated aldol reactions using the C2 symmetric cyclosulfamide chiral auxiliary 3 in order to prepare syn dialdols with high stereoselection (>95:5).4 However, the difficult dialdol cleavage of this bis-reactive chiral auxiliary appeared to be the weak point of this well-thought strategy. Herein we report a simple access to cyclosulfamides as chiral auxiliaries through the synthesis of (S)-2-benzyl-4-isopropyl1,2,5-thiadiazolidine-1,1-dioxide 7.5 The applications to asymmetric aldol and alkylation reactions as well as the auxiliary recovery process are also discussed. 2. Results and discussion 2.1. Preparation of (S)-2-benzyl-4-isopropyl-1,2,5-thiadiazolidine 1,1-dioxide 7 and N-acyl compound 8 Our synthetic strategy involves five steps as shown in Scheme 1. Inexpensive L-valine was first reduced with LiAlH4 into L-valinol 4, which was subsequently derivatized with N,N-dimethylsulfonyl chloride to give the valinol-sulfonamide 5. Then, an APTS-mediated conversion of the free hydroxyl function into the corresponding leaving group afforded the sulfamoyl-aziridine 6 under basic ⇑ Corresponding author. Tel.: +33 467 144 819. E-mail address: [email protected] (G. Dewynter). 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.09.001

Me2NSO2Cl, Et3N

LAH COOH

THF

H2N

HN H2N

CH2Cl2

OH

OH O

S

O

N

4

5

p-TsCl KOH THF

O

EtCOCl, Et3N N

N

THF

HN

N

O O

S O O

8

7

S

BnNH2 N

DMSO O

S

O

N 6

Scheme 1.

conditions. Subsequent heating of 6 with 5 equiv of benzylamine in DMSO as previously described6 gave the desired chiral sulfonamide auxiliary 7 in 44% overall yield from L-valine. Starting from 7, the corresponding N-propionyl compound 8 was then easily obtained in high yield using propionyl chloride under basic conditions (see Fig. 1).4 2.2. Diastereocontrolled aldolization The titanium enolate of 8 was generated by reaction with 1.2 equiv of TiCl4 in CH2Cl2 at 78 °C for 30 min followed by addition of 1.2 equiv of N-diisopropylethylamine at the same

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R

Ph

HN

O

HN

HN O S

O

O O 3

2

HN

NH S

O

1

Ph

N S Figure 2. Molecular structure of compound 9a; thermal ellipsoids are drawn at the 75% probability level.

O O 7 Figure 1.

temperature and then stirring the resulting brown solution for 30 min.7,8 The enolate thus generated was then trapped with iso-butyraldehyde at 78 °C for 4 h and progressively warmed to 0 °C overnight (Scheme 2). Analysis of the crude product mixture by 1H and 13C NMR indicated the presence of only one diastereoisomeric product 9a (dr >99%). After silica gel chromatography purification, the syn versus anti stereochemistry of the aldol product was assigned on the basis of 1H NMR coupling constants. The measured value for the aldol fragment0 s vicinal protons was found to be Jsyn 3 Hz, which was completely in accordance with previously reported values for syn aldols.2 The absolute configuration of 2,3-syn adduct 9a was then unambiguously established through an X-ray crystallographic analysis (Fig. 2),9a corresponding with the stereostructures previously described in oxazolidinone and sultam series.9b The reaction of 8 was then investigated with a variety of aldehydes, including aromatic, cyclic, and aliphatic ones, using the same conditions as described above. The results are summarized in Table 1. All aldol products were then easily hydrolyzed with LiOH at 0 °C in THF/H2O to afford the corresponding carboxylic acids 10a–d as well as the recovered auxiliary 7 without any loss of the stereochemical integrity (Table 1). The enantiomeric purity of the b-hydroxyacids and their absolute configurations were confirmed by their specific rotations, which were in complete agreement with those previously reported. 2.3. Stereocontrolled alkylation The first attempts of alkylation (Scheme 3) were carried out by using NaHMDS as a base and benzyl bromide or allyl bromide as

N O

electrophiles to afford 11a and 11b, respectively, with high diastereoselectivity (>99%) whereas the yields were modest (Table 2, entries 1 and 3) after elimination of the starting materials by flash chromatography. In order to improve these results, LiHMDS was used as a base; this allowed us to obtain the a-alkylated products 11a and 11b with higher yields (entries 2 and 4). The use of allyl iodide as an electrophile instead of allyl-bromide afforded 11b with a maximum yield of 78% (entry 4). An immediate 1H and/or 13C NMR analysis of the crude products 11a and 11b indicated the presence of only one diastereoisomer in each case (dr >99%). The absolute configuration of the new asymmetric center was assigned after removal of the chiral auxiliary by lithium hydroxide hydrolysis as for the aldolization reactions. The chiral cyclosulfamide auxiliary 7 was recovered quantitatively in this hydrolysis reaction and it could be easily recycled. The absolute stereochemistry of 12b was assigned as (S) by comparison of the known specific rotations for (S)-2-methylpent-4-enoic acid10 and (R)-2-methylpent-4-enoic acid.10b,11 Similarly we assumed an (S)-configuration for 12a.10b,11 3. Mechanism The results presented above indicate a transition state involving a metal-chelated Z-enolate (Fig. 3) within which, similar to the Oppolzer0 s sultams, the cyclosulfamide may exhibit an sp3 acylated nitrogen. However, in contrast to an Si-face approach Oppolzer model, using the homosteric 1-(R)-(+) camphorsultame 2, our results seem to indicate a C(a)-Re-face approach. In fact, the enolization probably induces a quasi 90° rotation of the enolate plan, placing it perpendicular to the average cyclosulfamide plan. This new organization confers a gain of stability and rigidity to the transition state through the pseudo-chair ring involving both the

1. TiCl4, DIPEA -78°C, CH2Cl2

N S O O

2. RCHO, -78°C (4 hrs) to 0°C overnight

8

R N HO

N S O O

O

9a: R=iPr 9b: R=Ph 9c: R=nPr 9d: R=cHex

LiOH THF/H2O

HN

N S O O

R

OH OH

Scheme 2.

O

10a: R=iPr 10b: R=Ph 10c: R=nPr 10d: R=cHex

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F. Fécourt et al. / Tetrahedron: Asymmetry 21 (2010) 2361–2366 Table 1

a b c

Entry

Aldehyde

dra

% Yieldb

Product

1 2 3 4

iPr-CHO Ph-CHO nPr-CHO cHex-CHO

>99:1 >99:1 >99:1 >99:1

93% 88% 92% 87%

9a 9b 9c 9d

% Yield of recovery 7c 96% 98% 95% 93%

% Yieldc

Product

95% 96% 94% 93%

10a 10b 10c 10d

Diastereoisomeric ratios were determined by 1H and 13C NMR. Isolated adducts yields after silica gel chromatography. Crude yields after auxiliary cleavage.

1.Base, -78°C, THF N

N

2. RX -78°C (4 hrs) to 0°C

S O

R

N O

O

O

N S

O O 11a: R= Bn 11b: R= Allyl

8 LiOH THF/H2O HN

N S

O O 7

OH

R

12a: R= Bn 12b: R= Allyl

O Scheme 3.

Table 2

a b c

Entry

RX

Base

dra

% Yieldb

Product

1 2 3 4 5

Bn-Br Bn-Br Allyl-Br Allyl-Br Allyl-I

NaHMDS LiHMDS NaHMDS LiHMDS LiHMDS

>99:1 >99:1 >99:1 >99:1 >99:1

30% 58% 48% 60% 78%

11a 11a 11b 11b 11b

% Yield of recovery 7c 96% 97% 98% 97% 98%

% Yieldc

Product

95% 91% 94% 92% 96%

12a 12a 12b 12b 12b

Diastereoisomeric ratios were determined by 1H and 13C NMR. Isolated adducts yields after silica gel chromatography. Crude yields after auxiliary cleavage.

Re face of enolate

Si face of enolate

R H Me R

Me

(S)

N H O

O S

O Cl Cl

O

N

O S

N Bn

Ti Cl

Bn

Ti Cl

(S)

N O

Cl

O pro S

Cl

O pro S

disfavoured state

favoured state Figure 3.

chelated metal and the Pro-S sulfone oxygen. During the aldol reactions, the observation of our syn-aldol products suggests a chlorotitanium enolate proceeding through a Zimmerman–Traxler transition state,12 within which both the aldehyde and the

cyclosulfamide are coordinated to titanium. This approach can be realized only by the most polar and the less hindranced Re-face. In fact, this face is more accessible than the Si-face due to the isopropyl group (as in Evans oxazolidinones). In brief, these

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Si face of enolate

(S)

N

Me R E O

O S

N Bn

Metal O

favoured state Figure 4.

hydroxyalkylation reactions provide only syn ‘Non-Evans’ compounds via a diastereofacial/heteroprochiral approach between the enolate and the carbonyl group. For the alkylation reactions, the same mechanism predicts a Re-face attack (Fig. 4). This approach, after cleavage, generated only acids with the same configuration as the stereogenic center of the cyclosulfamide auxiliary. 4. Conclusions In conclusion, we have efficiently synthesized (S)-2-benzyl-4isopropyl-1,2,5-thiadiazolidine-1,1-dioxide 7 as a chimera of Evans and Oppolzer chiral auxiliaries. Herein an N-propionyl derivative 8 of this asymmetric cyclosulfamide appeared to be very powerful for the diastereocontrolled synthesis of chiral building blocks through asymmetric aldolization and alkylation reactions. Moreover, the efficient workup after the hydrolysis reaction allowed a quantitative recovery of the chiral auxiliary. We are currently investigating the synthesis of new substituted cyclosulfamides as well as a polymer-supported version of the asymmetric synthesis presented in this paper. 5. Experimental section 5.1. General All solvents were dried and freshly distilled prior to use. All reactions were realized in a flame-dried, argon purged roundbottomed flask. TLC was performed with Merck-Kieselgel 60 F254 plates, and spots were visualized with UV light and/or by staining with phosphomolybdic acid solution followed by heating. Flash chromatography was performed on Merck-Kieselgel (60–40 mesh). Melting points were recorded on Buchi 510 melting apparatus. Optical rotations were measured with a 1 cm cell on a Perkin Elmer Polarimeter at 20 °C with a sodium lamp (589 nm). High Resolution Mass Spectra (HRMS) were obtained on JEOL JMSSX-102 high resolution magnetic sector mass spectrometer. 1H NMR and 13C were recorded with Bruker 200 MHz and Bruker Advance 300 MHz, respectively. 5.2. X-ray crystal structure determination of compound 9a X-ray data were collected on an Oxford-Diffraction Gemini-S diffractometer using graphite monochromated Mo-radiation. The crystal structure was solved with the ab initio charge flipping program SUPERFLIP13 and refined using non-linear least-squares implemented in CRYSTALS.14 Molecular graphics used Vesta.15 The Flack parameter determined using the data collected with Mo-radiation was 0.19(7) and the Hooft parameter 0.18(4). The Hooft analysis resulted in a chance that the correct hand was assigned in the two-hypothesis model of an enantiopure material

and in the three-hypothesis of either a correct hand, a 50%/50% racemic mixture or a wrong hand of in both cases 100%.16 Because of the rather high standard deviation on both the Flack and the Hooft parameters data were recollected with Cu radiation which resulted in a Flack parameter of 0.06(1) and a Hooft parameter of 0.03(1) and a 100% chance of correct assignment of the hand for both the two and three hypotheses. 5.3. Preparation of N0 -[(S)-2-hydroxy-1-isopropyl-ethyl]-N,Ndimethylsulfonamide 5 To a solution of L-valinol (97 mmol) in anhydrous THF (100 mL) were added Et3N (30 mL, 213 mmol, 2.2 equiv) and N,N-dimethylsulfamoyl chloride (12.4 mL, 116 mmol, 1.2 equiv). The solution was stirred overnight at room temperature. The reaction was quenched with water. The organic layer was extracted with ethyl acetate, dried over MgSO4, and concentrated. The crude product was purified by flash chromatography (CH2Cl2, CH2Cl2/EtOAc: 6/4) to give N0 -[(S)-2-hydroxy-1-isopropylethyl]-N,N-dimethyl-sulfonamide 5 as a yellow oil (Yield: 88%). 1H NMR (300 MHz, CDCl3) d: 0.97 (d, J = 6.8 Hz, 3H); 0.99 (d, J = 6.8 Hz, 3H); 1.85–1.97 (m, 1H); 2.82 (s, 6H, NMe2); 3.07–3.16 (m, 1H); 3.67 (dd, J = 5.6, 11.5 Hz, 1H); 3.77 (dd, J = 3.8, 11.5 Hz, 1H) 13C NMR (75 MHz, CDCl3) d: 18.9 (CH3); 19.2 (CH3); 29, 7 (CH); 38.2 (CH3); 61.5 (CH); 62.9 (CH2). ½a20 D ¼ 35 (c 1.0, CHCl3). HRMS (Q-Tof) m/z [M+H]+ calcd for C7H19N2O3S 211.1116, found 211.1121. 5.4. Preparation of (S)-2-isopropyl-N,N-dimethyl-aziridine-1sulfonamide 6 To a solution of 5 (19.02 mmol) in anhydrous THF (100 mL) were added TsCl (4.35 g, 22.83 mmol, 1.2 equiv) and, at 0 °C, freshly and finely broiled KOH (5.34 g, 95 mmol, 5 equiv). The resulting mixture was stirred for 45 min at room temperature, filtered and washed with Et2O. The filtrate was concentrated and the crude oil was purified by flash chromatography (Cyclohexane/ CH2Cl2: 1/1 to CH2Cl2) to give N,N-dimethylaziridine-1-sulfonamide 6 as a yellow liquid (Yield: 82%). 1H NMR (300 MHz, CDCl3) d: 0.98 (d, J = 6.8 Hz, 3H); 1.05 (d, J = 6.7 Hz, 3H); 1.46–1.57 (m, 1H); 2.08 (d, 1H); 2.38–2.44 (m, 1H); 2.48 (d, J = 6.9 Hz, 1H); 2.92 (s, 6H, NMe2) 13C NMR (300 MHz, CDCl3) d: 18.9 (CH3); 19.7 (CH3); 30.1 (CH); 32.5 (CH2); 38.4 (CH3); 44.4 (CH). ½a20 D ¼ þ52:7 (c 1.1, CHCl3). HRMS (Q-Tof) m/z [M+H]+ calcd for C7H17N2O2S 193.1011, found 193.1013. 5.5. Preparation of (4S)-2-benzyl-4-isopropyl-1,2,5-thiadiazolidine 1,1-dioxide 7 Compound 7 was prepared from the procedure described by Hannam et al.6 Isolated product purified by flash chromatography: cyclohexane/CH2Cl2 1/1 to CH2Cl2 to yield 7 in 68% as a white solid. Mp = 78 °C. 1H NMR (300 MHz, CDCl3) d: 0.78 (d, J = 6.7 Hz, 3H); 0.91 (d, J = 6.6 Hz, 3H); 1.62–1.73 (m, 1H); 2.85 (dd, J = 8.8 Hz, 1H); 3.22 (dd, J = 7.23 Hz, 1H); 3.29–3.39 (m, 1H); 3.90 (d, J = 13.8 Hz, 1H); 4.25 (d, J = 13.8 Hz, 1H); 4.35 (d, J = 7.2 Hz, 1H); 7.22–7.29 (m, 5H). 13C NMR (75 MHz, CDCl3) d: 17.9 (CH3); 19.1 (CH3); 32.4 (CH); 50.4 (CH2); 51.7 (CH2); 58.5 (CH); 128.1 (CH); 128.6 (CH); 128.8 (CH); 135.2 (Cq). ½a20 D ¼ 36 (c 1.0, CHCl3). HRMS (Q-Tof) m/z [M+H]+ calcd for C12H19N2O2S 255.1167, found 255.1160. 5.6. Preparation of (3S)-5-benzyl-3-isopropyl-2-propanoyl1,2,5-thiadiazolidine 1,1-dioxide 8 To a solution of cyclosulfamide 7 (200 mg, 0.786 mmol) in anhydrous dichloromethane (10 mL) were added successively at

F. Fécourt et al. / Tetrahedron: Asymmetry 21 (2010) 2361–2366

0 °C triethylamine (133 lL, 0.944 mmol, 1.2 equiv) and propionyl chloride (82 lL, 0.944 mmol, 1.2 equiv). The reaction mixture was stirred overnight at room temperature and then the reaction was quenched by the addition of a saturated solution of ammonium chloride. The organic layer was extracted with dichloromethane, dried over MgSO4, and the solvent was removed under vacuum. The crude oil was purified by flash chromatography (cyclohexane/CH2Cl2: 1/1 to CH2Cl2) to yield 8 (222 mg, 91%) as a white solid. Mp = 60 °C. 1H NMR (300 MHz, CDCl3) d: 0.82 (d, J = 7.0 Hz, 3H); 0.87 (d, J = 6.9 Hz, 3H); 1.22 (t, J = 7.3 Hz, 3H); 2.25–2.36 (m, 1H); 2.78–2.94 (m, 2H); 2.99 (dd, J = 3.2, 9.9 Hz, 1H); 3.14 (dd, J = 7.23, 9.9 Hz, 1H); 3.97 (d, J = 13.6 Hz, 1H); 4.24– 4.29 (m, 1H); 4.38 (d, J = 13.7 Hz, 1H); 734–7.41 (m, 5H). 13C NMR (75 MHz, CDCl3) d: 8.65 (CH3), 16.3 (CH3), 18.4 (CH3), 28.7 (CH2), 29.3 (CH), 44.2 (CH2), 49.9 (CH2), 58.2 (CH), 128.6 (CH), 128.8 (CH), 128.9 (CH), 133.7 (Cq), 171.8 (Cq). ½a20 D ¼ þ17 (c 1.0, CHCl3). HRMS (Q-Tof) m/z [M+H]+ calcd for C15H33N2O3S 311.1429, found 311.1432. 5.7. General procedure for aldol reactions At first, TiCl4 (1 M in CH2Cl2, 773 lL, 0.77 mmol, 1.2 equiv) was added to a solution of 8 (0.64 mmol) in anhydrous CH2Cl2 (10 mL) at 78 °C. After 15 min, diisopropylethylamine (135 lL, 0.77 mmol, 1.2 equiv) was added. After 15 min, the appropriate aldehyde (0.77 mmol, 1.2 equiv) was added and the solution was stirred for 4 h at 78 °C and gradually warmed overnight. Then the reaction was quenched by the addition of a saturated solution of ammonium chloride. The organic layer was extracted with CH2Cl2, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2 to CH2Cl2/EtOAc: 6/4) to give the desired aldol 9a–d. 5.7.1. (20 S,30 R,3S)-5-Benzyl-3-isopropyl-2-(20 ,40 -dimethyl-30 hydroxy)pentanoyl-1,2,5-thiadiazolidine 1,1-dioxide 9a Obtained in 93% yield from compound 8, using the general procedure aldol reaction. 1H NMR (300 MHz, CDCl3) d: 0.61 (d, J = 7.0 Hz, 3H); 0.65 (d, J = 6.9 Hz, 3H); 0.69 (d, J = 6.8 Hz, 3H); 0.83 (d, J = 6.7 Hz, 3H); 1.10 (d, J = 7.0 Hz, 3H); 1.46–1.58 (m, 1H); 1.99–2.10 (m, 1H); 2.79 (dd, J = 3.8, 10.0 Hz, 1H); 2.95 (dd, J = 7.4, 10.0 Hz, 1H); 3.00 (br s, 1H); 3.29 (dq, J = 2.3, 7.0 Hz, 1H); 3.37 (br d, J = 8.6 Hz, 1H); 3.79 (d, J = 13.7 Hz, 1H); 4.04–4.10 (m, 1H); 4.12 (d, J = 13.8 Hz, 1H); 7.10–7.20 (m, 5H). 13C NMR (75 MHz, CDCl3) d: 11.4 (CH3), 16.3 (CH3), 18.2 (CH3), 18.8 (CH3), 19.2 (CH3), 29.2 (CH), 30.5 (CH), 41.0 (CH), 44.1 (CH2), 50.0 (CH2), 57.9 (CH), 75.9 (CH), 128.7 (CH), 128.8 (CH), 129.0 (CH), 133.5 (Cq), 176.6 (Cq). ½a20 D ¼ þ25 (c 1.0, CHCl3). Mp = 49 °C. HRMS (Q-Tof) m/z [M+H]+ calcd for C19H31N2O4S 383.2005, found 383.2008. Crystal data for 9a: Formula = C19H29N2O4S, T = 175 K, Mr = 382.52 g mol1, crystal size = 0.040  0.170  0.430 mm, monoclinic, space group C2, a = 24.9190(16), b = 6.3825(3), c = 14.1290(9) Å, a = 90°, b = 111.453(7)°, c = 90°, V = 2091.5(2) Å3, Z = 4, qcalcd = 1.212 g cm3, l = 0.179 mm1, hmax = 28.877°, experimental resolution 0.74 Å. 4214 reflections measured, 3602 unique, 3107 with I > 2r (I), Rint = 0.020, = 0.0509, refined parameters = 235, R1 (I > 2r (I)) = 0.0320, wR2 (I > 2r (I)) = 0.0456 R1 (all data) = 0.0384, wR2 (all data) = 0.0456, GOF = 1.1223, Dq (min/ max) = 0.29/0.25 e Å3. 5.7.2. (20 S,30 S,3S)-5-Benzyl-3-isopropyl-2-(30 -hydroxy-20 -methyl30 -phenyl)propanoyl-1,2,5-thiadiazolidine 1,1-dioxide 9b Obtained in 88% yield from compound 8, using the general aldol reaction procedure (colorless oil). 1H NMR (300 MHz, C6D6) d: 0.57 (d, J = 7.0 Hz, 3H); 0.76 (d, J = 6.9 Hz, 3H); 1.50 (d, J = 7.0 Hz, 3H); 2.18–2.29 (m, 1H); 2.60 (s, 1H); 2.62 (d, J = 1.3 Hz, 1H); 3.70–

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3.75 (m, 2H); 4.08–4.20 (m, 3H); 5.57 (br s, 1H); 7.10–7.35 (m, 8H); 7.84 (d, J = 7.6 Hz, 2H). 13C NMR (75 MHz, C6D6) d: 11.8 (CH3), 16.3 (CH3), 18.0 (CH3), 29.4 (CH), 44.1 (CH2), 46.7 (CH), 50.2 (CH2), 58.0 (CH), 72.8 (CH), 126.7 (CH), 127.5 (CH), 128.3 (CH), 128.5 (CH), 128.9 (CH), 129.0 (CH), 134.3 (Cq), 141.9 (Cq), + 176.2 (Cq). ½a20 D ¼ þ20 (c 1.0, CHCl3). HRMS (Q-Tof) m/z [M+H] calcd for C22H29N2O4S 417.1848, found 417.1844. 5.7.3. (20 S,30 R,3S)-5-Benzyl-3-isopropyl-2-(30 -hydroxy-20 methyl)hexanoyl-1,2,5-thiadiazolidine 1,1-dioxide 9c Obtained with 92% from compound 8, using the general aldol reaction procedure (colorless oil). 1H NMR (300 MHz, CDCl3) d: 0.85 (d, J = 7.0 Hz, 3H); 0.90 (d, J = 6.9 Hz, 3H); 0.97 (t, J = 7.0 Hz, 2H); 1.36 (d, J = 7.1 Hz, 3H); 1.35–1.48 (m, 2H); 1.50–1.66 (m, 2H); 2.24–2.34 (m, 1H); 3.03 (dd, J = 3.7, 10.0 Hz, 1H); 3.11 (br d, J = 1.8 Hz, 1H); 3.20 (dd, J = 7.3, 10.0 Hz, 1H); 3.32 (dq, J = 2.5, 7.0 Hz, 1H); 4.01–4.06 (m, 2H); 4.29–4.35 (m, 1H); 4.37 (d, J = 13.6 Hz, 1H); 7.35–7.44 (m, 5H). 13C NMR (75 MHz, CDCl3) d: 11.7 (CH3), 14.0 (CH3), 16.3 (CH3), 18.2 (CH3), 19.1 (CH2), 29.2 (CH), 35.9 (CH2), 43.7 (CH), 44.1 (CH2), 50.0 (CH2), 57.9 (CH), 70.5 (CH), 128.7 (CH), 128.8 (CH), 138.9 (CH), 133.5 (Cq), 176.3 (Cq). + ½a20 calcd for D ¼ þ30 (c 1.0, CHCl3). HRMS (Q-Tof) m/z [M+H] C19H31N2O4S 383.2005, found 383.2006. 5.7.4. (20 S,30 R,3S) 5-Benzyl-3-isopropyl-2-(30 -cyclohexyl-30 -hydroxy-20 -methyl)propanoyl-1,2,5-thiadiazolidine 1,1-dioxide 9d Obtained with 87% from compound 8, using the general aldol reaction procedure (colorless oil). 1H NMR (300 MHz, CDCl3) d: 0.85 (d, J = 7.0 Hz, 3H); 0.89 (d, J = 6.9 Hz, 3H); 0.97–1.08 (m, 2H); 1.41–1.28 (m, 3H); 1.33 (d, J = 7.1 Hz, 3H); 1.39–1.52 (m, 1H); 1.67 (br. d, J = 10.8 Hz, 2H); 1.78 (br d, J = 12.5 Hz, 2H); 2.16 (d, J = 12.9 Hz, 1H); 2.23–2.34 (m, 1H); 3.03 (dd, J = 3.7, 10.0 Hz, 1H); 3.19 (dd, J = 7.3, 10.0 Hz, 1H); 3.53 (dq, J = 1.9, 7.0 Hz, 1H); 3.68 (dd, J = 2.0, 8.7 Hz, 1H); 4.03 (d, J = 13.6 Hz, 1H); 4.28–4.34 (m, 1H); 4.36 (d, J = 13.6 Hz, 1H); 7.34–7.45 (m, 5H). 13C NMR (75 MHz, CDCl3) d: 11.2 (CH3), 16.3 (CH3), 18.2 (CH3), 25.9 (CH2), 26.0 (CH2), 26.4 (CH2), 28.7 (CH2), 29.2 (CH), 29.6 (CH2), 39.8 (CH), 40.4 (CH), 44.1 (CH2), 50.0 (CH2), 57.9 (CH), 74.7 (CH), 128.7 (CH), 128.8 (CH), 129.0 (CH), 133.5 (Cq), 176.8 (Cq). + ½a20 calcd for D ¼ þ31 (c 1.0, CHCl3). HRMS (Q-Tof) m/z [M+H] C22H35N2O4S 423.2318, found 423.2313. 5.8. General procedure for alkylation reactions At first, LiHMDS (387 lL, 0.387 mmol, 1.2 equiv) was added to a solution of 8 (100 mg, 0.322 mmol) in anhydrous THF (7 mL) at 78 °C. After 30 min, the appropriate alkyl halide (0.966 mmol, 3 equiv) was added and the solution was stirred for 4 h at 78 °C and gradually warmed overnight. Then the reaction was quenched by the addition of a saturated solution of ammonium chloride. The organic layer was extracted with CH2Cl2, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (cyclohexane/CH2Cl2 7/3–1/1) to give the desired alkyl product. 5.8.1. (20 S,3S) 5-Benzyl-3-isopropyl-2-(20 -methyl-30 -phenyl)propanoyl-1,2,5-thiadiazolidine 1,1-dioxide 11a Obtained in 58% yield from compound 8, using the general alkylation adduct procedure (colorless oil). 1H NMR (300 MHz, CDCl3) d: 0.52 (d, J = 6.9 Hz, 3H); 0.63 (d, J = 7.0 Hz, 3H); 1.17 (d, J = 6.5 Hz, 3H); 1.89–2.06 (m, 1H); 2.66 (dd, J = 13.3, 7.5 Hz, 1H); 2.84 (dd, J = 9.9, 3.5 Hz, 1H); 2.94–3.12 (m, 2H); 3.39–3.58 (m, 1H); 3.90 (d, J = 13.7, 1H); 4.10–4.21 (m, 1H); 4.27 (d, J = 13.7 Hz; 1H); 6.95–7.46 (m, 10H).13C NMR (75 MHz, CDCl3) d: 15.9 (CH3); 16.7 (CH3); 18.2 (CH3); 29.2 (CH); 41.1 (CH2); 42.0 (CH); 43.7 (CH2); 49.9 (CH2); 58.0 (CH); 126.4 (CH); 128.3 (CH); 128.5 (CH);

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128.8 (CH); 128.9 (CH); 129.3 (CH); 133.7 (Cq); 138.6 (Cq); 174.5 + (Cq). ½a20 D ¼ 90 (c 0.3, CHCl3). HRMS (Q-Tof) m/z [M+H] calcd for C22H29N2O3S 401.1899, found 401.1891. 5.8.2. (20 S,3S) 5-Benzyl-3-isopropyl-2-(-20 -methyl)pent-40 -enoyl1,2,5-thiadiazolidine 1,1-dioxide 11b Obtained in 78% yield from compound 8, using the general alkylation adduct procedure (white solid). Mp = 56 °C. 1H NMR (300 MHz, CDCl3) d: 0.74 (d, J = 7.0 Hz, 3H); 0.79 (d, J = 6.9 Hz, 3H); 1.15 (d, J = 6.6 Hz, 3H); 2.09–2.24 (m, 2H); 2.46 (ddd, J = 14.8, 10.6, 6.8 Hz, 1H); 2.91 (dd, J = 10.0, 3.6 Hz, 1H); 3.06 (dd, J = 9.9, 7.4 Hz, 1H); 3.17–3.35 (m, 1H); 3.91 (d, J = 13.7 Hz, 1H); 4.22 (ddd, J = 7.5, 4.8, 3.7 Hz, 1H); 4.28 (d, J = 13.7 Hz, 1H); 4.87– 5.12 (m, 2H); 5.74 (ddt, J = 17.1, 10.1, 7.0 Hz, 1H); 7.24–7.37 (m, 5H).13C NMR (75 MHz, CDCl3) d: 16.2 (CH3); 16.5 (CH3); 18.3 (CH3); 29.2 (CH); 39.3 (CH2); 39.8 (CH); 43.8 (CH2); 50.0 (CH2); 58.1 (CH); 117.4 (CH2); 128.6 (CH); 128.8 (CH); 128.9 (CH); 133.7 (Cq); 134.9 (CH); 174.7 (Cq). ½a20 D ¼ 0:4 (c 0.5, CHCl3). HRMS (Q-Tof) m/z [M+H]+ calcd for C18HéèN2O3S 351.1742, found 351.1739. 5.9. General procedure for cleavage using LiOH hydrolysis The appropriate aldol or alkyl adduct (0.143 mmol) was treated at 0 °C with lithium hydroxidemonohydrate (0.428 mmol, 3 equiv) in a 1:1 mixture of THF/H2O (10 mL). The reaction was stirred overnight at room temperature and then concentrated under reduced pressure. The organic layer was extracted with CH2Cl2 and concentrated to recover quantitatively the homochiral auxiliary. Acidification of the aqueous layer to pH 1 and extraction with EtOAc furnished the desired acid 10a–d or 12a–b. 5.9.1. (2S,3R)-3-Hydroxy-2,4-dimethylpentanoic acid 10a Obtained in 95% yield from compound 9a, using the general hydrolysis cleavage procedure (white solid). NMR (300 MHz, CDCl3) d: 0.82 (d, J = 6.8 Hz, 3H); 0.95 (d, J = 6.6 Hz, 3H); 1.13 (d, J = 7.2 Hz, 3H); 1.57–1.71 (m, 1H); 2.64 (qd, J = 7.1, 3.6 Hz, 1H); 20 3.57 (dd, J = 8.1, 3.6 Hz, 1H). ½a20 D ¼ 8 (c 0.5, CHCl3). ½aD ¼ 9:5 (c 0.4, CH2Cl2) lit.17 5.9.2. (2S,3S)-3-Hydroxy-2-methyl-3-phenylpropanoic acid 10b Obtained in 96% yield from compound 9b, using the general procedure hydrolysis cleavage (white solid). 1H NMR (300 MHz, CDCl3) d: 1.08 (d, J = 7.2 Hz, 3H); 2.77 (qd, J = 7.2, 3.9 Hz, 1H); 5.11 (d, J = 3.9 Hz, 1H); 7.19–7.29 (m, 5H). ½a20 D ¼ 31 (c 1.0 in 18 CHCl3). ½a20 D ¼ 29:3 (c 0.8, CHCl3) lit. 5.9.3. (2S,3R)-3-Hydroxy-2-methylhexanoic acid 10c Obtained in 94% yield from compound 9c, using the general procedure hydrolysis cleavage (colorless oil). 1H NMR (300 MHz, CDCl3) d: 0.88 (t, J = 6.9 Hz, 3H); 1.14 (d, J = 7.2 Hz, 3H); 1.16– 1.57 (m, 5H); 2.53 (qd, J = 7.2, 3.5 Hz, 1H); 3.83–3.96 (m, 1H). ½a20 D ¼ þ12 (c 1.0, CHCl3). 5.9.4. (2S,3R)-3-Cyclohexyl-3-hydroxy-2-methyl-propanoic acid 10d Obtained in 93% yield from compound 9d, using the general procedure hydrolysis cleavage (colorless oil). 1H NMR (300 MHz, CDCl3) d: 0.84–1.69 (m, 13H), 1.12 (d, J = 7.2 Hz, 2H); 2.64

(qd, J = 7.1, 3.3 Hz, 1H); 3.64 (dd, J = 8.4, 3.3 Hz, 1H). ½a20 D ¼ 2 (c 18 1.2, CHCl3). ½a22 D ¼ 4 (c 0.6, CH2Cl2) lit. 5.9.5. (S)-2-Methyl-3-phenylpropanoic acid 12a Obtained in 95% yield from compound 11a, using the general procedure hydrolysis cleavage (colorless oil). 1H NMR (300 MHz, CDCl3) d: 1.17 (d, J = 7.0 Hz, 3H), 2.71 (dd, J = 8.0, 13.5 Hz, 1H), 2.78 (m, 1H), 3.08 (dd, J = 6.5, 13.5 Hz, 2H), 7.20–7.35 (m, 5H). 20 10b ½a20 D ¼ þ25:6 (c 0.5, CHCl3). ½aD ¼ þ26:3 (c 1.0, CHCl3) lit. 5.9.6. (S)-2-Methylpent-4-enoic acid 12b Obtained in 96%yield from compound 11b, using the general procedure hydrolysis cleavage (colorless oil). 1H NMR (300 MHz, CDCl3) d: 1.12 (d, J = 6.9 Hz, 3H); 2.08–2.21 (m, 1H); 2.32–2.43 (m, 1H); 2.43–2.55 (m, 1H); 4.95–5.08 (m, 2H); 5.61–5.78 (m, 20 10a 1H). ½a20 D ¼ þ9:7 (c 0.4, CHCl3). ½aD ¼ þ10:1 (c 1.0, CHCl3) lit. Acknowledgment We thank the CNRS for financial support. References 1. (a) Davies, S. G.; Mortlock, A. A. Tetrahedron: Asymmetry 1991, 2, 1001–1004; (b) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747–5750; (c) Evans, D. A.; Shaw, J. T. Actualité Chimique 2003, 35–38; (d) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1997, 119, 7883–7884; For a very recent review see (e) Geary, L. M.; Hultin, P. G. Tetrahedron: Asymmetry 2009, 20, 131–173. 2. (a) Evans, D. A.; Bartoli, J. A.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–2129; (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. J. Am. Chem. Soc. 1991, 113, 1047–1049; (c) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1–115. 3. (a) Oppolzer, W. Tetrahedron 1987, 43, 1969–2004; (b) Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E. J. Am. Chem. Soc. 1990, 112, 2767–2772; (c) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241–1250. 4. Ahn, K. H.; Yoo, D. J.; Kim, J. S. Tetrahedron Lett. 1992, 33, 6661–6664. 5. (a) Berredjem, M.; Djebbar, H.; Regainia, Z.; Aouf, N.-E.; Winum, J.-Y.; Dewynter, G.; Montero, J-. L. Phosphorous, Sulfur Silicon Relat. Elem. 2003, 174, 694–705; (b) Regainia, Z.; Abdaoui, M.; Aouf, N.-E.; Dewynter, G.; Montero, J.-L. Tetrahedron 2000, 56, 381–387. 6. Hannam, J.; Harrison, T.; Heath, F.; Madin, A.; Merchant, K. Synlett 2006, 833– 836. 7. Evans, D. A.; Urpi, F.; Smers, T. C.; Clark, J.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215–8216. 8. Evans, D. A.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991, 113, 1047–1049. 9. (a) Crystallographic data for 9a has been deposited with the Cambridge Crystallographic Data Center as supplementary publication number CCDC 780191.; (b) Iseki, K.; Oishi, S.; Kobayashi, Y. Tetrahedron 1996, 52, 71–84; (c) Anaya de Parrodi, C.; Clara-Sosa, A.; Perez, L.; Quintero, L.; Maranon, V.; Toscano, R.; Avina, J.; Rojas-Limae, S.; Juaristi, E. Tetrahedron: Asymmetry 2001, 12, 69–77; (d) Garcia-Fortanet, J.; Murga, J.; Carda, M.; Alberto Marco, J. Org. Lett. 2006, 8, 2695–2698; (e) Sofiyev, V.; Navarro, G.; Trauner, D. Org. Lett. 2008, 10, 149–152; (f) Guerlavais, V.; Carroll, P. J.; Joullie, M. M. Tetrahedron: Asymmetry 2002, 13, 675–680; (g) Sedrani, R.; Kallen, J.; Martin Cabrejas, L.-M.; Papageorgiou, C. D.; Senia, F.; Rohrbach, S.; Wagner, D.; Thai, B.; Jutzi Eme, A.M.; France, J.; Oberer, L.; Rihs, G.; Zenke, G.; Wagner, J. J. Am. Chem. Soc. 2003, 125, 3849–3859. 10. (a) Gramatica, P.; Manitto, P.; Monti, D.; Speranza, G. Tetrahedron 1988, 44, 1299–1304; (b) Ueberbacher, B. J.; Griengl, H.; Weber, H. Tetrahedron: Asymmetry 2008, 19, 834–846. 11. Le, T. N.; Nguyen, Q. P. B.; Kim, J. N.; Kim, T. H. Tetrahedron Lett. 2007, 48, 7834– 7837. 12. Zimmerman, H. E.; Traxler, M. D. J. J. Am. Chem. Soc. 1957, 79, 1920–1923. 13. Palatinus, L.; Chapuis, G. J. Appl. Crystallogr. 2007, 40, 786–790. 14. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487. 15. Momma, K.; Izumi, F. J. Appl. Crystallogr. 2008, 41, 653–658. 16. Hooft, R. W. W.; Straver, L. H.; Spek, A. L. J. Appl. Crystallogr. 2008, 41, 96–103. 17. Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H. J. Org. Chem. 1991, 56, 2499–2506. 18. Bonner, M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113, 1299–1308.