Pentanidium catalyzed enantioselective phase transfer reactions 4

Solvent was removed under reduced pressure and C was obtained by flash chromatography silica gel, hexane-ethyl acetate 3:1, as a white solid, 2.10 g 2 steps, 80% overall yield... Toluene

Chapter 4

Experimental

4.1 General information

4.1.1 General procedures and methods

Experiments involving moisture and/or air sensitive components were performed under a positive pressure of nitrogen in oven-dried glassware equipped with a rubber septum inlet Air sensitive reagents were weighed in a glovebox Dried solvents and liquid reagents were transferred by oven-dried syringes or hypodermic syringe cooled

to ambient temperature in a desiccator Reactions mixtures were stirred in round bottle flasks or 4mL sample vials with Teflon-coated magnetic stirring bars unless otherwise stated Moisture in non-volatile reagents/compounds was removed in high

vacuo by means of an oil pump and subsequent purging with nitrogen Solvents were

removed in vacuo under ~30 mmHg and heated with a water bath using Heidolph or

Büchi rotary evaporator with Eyela A-3S aspirator The condenser was cooled with running water at 0 °C Reactions requiring temperatures −20 °C were stirred in either Thermo Neslab CB-60 with Cryotrol temperature controller or Eyela PSL-1400 with digital temperature controller cryobaths Technical grade isopropanol was used as the bath medium All experiments were monitored by analytical thin layer chromatography (TLC) TLC was performed on pre-coated plates, Merck 60 F254 After elution, plate was visualized under UV illumination at 254 nm for UV active material Further visualization was achieved by staining KMnO4, ceric molybdate, or anisaldehyde solution For those using the aqueous stains, the TLC plates were heated

on a hot plate Columns for flash chromatography (FC) contained silica gel 60 (0.040

mm - 0.063 mm, Merck) Columns were packed as slurry of silica gel in hexane and

equilibrated with the appropriate solvent/solvent mixture prior to use The analyte was loaded neat or as a concentrated solution using the appropriate solvent system The elution was assisted by applying pressure with an air pump

4.1.2 Instrumentations

Proton nuclear magnetic resonance (1H NMR), carbon NMR (13C NMR), phosphorous NMR (31P NMR), and fluorine NMR (19F NMR) spectra were recorded

in CDCl3 otherwise stated. 1H (500 MHz or 300 MHz), 13C (125 MHz or 75 MHz) with complete proton decoupling, 31P (202 MHz) with complete proton decoupling, and 1H Nuclear Overhauser Effect (NOE) NMRs were performed on a 500 MHz Bruker AMX NMR spectrometer 19F NMR (282 MHz) was performed on a 300 MHz

Bruker ACF spectrometer Chemical shifts were reported as δ in units of parts per million (ppm) downfield from tetramethylsilane (δ 0.00), using the residual solvent

signal as an internal standard: CDCl3 (1H NMR: δ 7.26, singlet; 13C NMR: δ 77.0, triplet) Multiplicities were given as: s (singlet), d (doublet), t (triplet), q (quartet),

quintet, m (multiplets), dd (doublet of doublets), dt (doublet of triplets), and br (broad)

Coupling constants (J) were recorded in Hertz (Hz) The number of proton atoms (n) for a given resonance was indicated by nH The number of carbon atoms (n) for a given resonance was indicated by nC High resolution Electrospray Ionization (ESI)

mass spectra were obtained by Chemical and Molecular Analysis Centre (CMAC) of the National University of Singapore MS and HRMS were reported in units of mass

of charge ratio (m/z) Mass samples were dissolved in MeCN (HPLC Grade) unless otherwise stated Melting points were determined on a BÜCHI B-540 melting point

apparatus Enantiomeric excesses were determined by chiral High Performance Liquid Chromatography (HPLC) analysis on Dionex HPLC UltiMate® 3000 series, including a variable wavelength UV/VIS detector VWD-3400 and LPG-3400A pump with manual injection valve Data acquisitions were done using Chromeleon® software HPLC samples were dissolved in HPLC grade isopropanol (IPA) unless otherwise stated

4.1.3 Materials

All commercial reagents were purchased from Sigma-Aldrich, Fluka, Alfa Aesar, Merck, TCI, and Acros of the highest purity grade They were used without further purification unless specified All solvents used, mainly hexane (Hex) and ethyl acetate (EtOAc), were distilled Anhydrous DCM was freshly distilled from CaH2 Anhydrous THF was freshly distilled from Na/benzophenone MeCN and CHCl3 were distilled from CaH2 Anhydrous hexane was purchased from Sigma-Aldrich All compounds synthesized were stored in a −34 °C freezer and light-sensitive compounds were protected with aluminium foil

4.2 Experimental procedures related in the conjugate addition reaction

4.2.1 Synthesis of chiral pentanidium and characterizations

Representative procedure for the synthesis of chiral pentanidium 80a:

Step 1: To a solution of chiral diamine 81 (2.12 g, 10 mmol) and Et3N (4.1 ml, 30 mmol) in CH2Cl2 (25 mL), triphosgene (977 mg, 3.3 mmol, dissolved in 5 mL CH2Cl2) was added in a dropwise manner, keeping the temperature lower than 5 oC all the time After allowing the temperature to rise to room temperature, an additional 4-5 hours of stirring was required to allow the reaction to complete (monitored by TLC) After

diamine 81 was completely consumed, reaction was quenched by water (20 mL) and

extracted using CH2Cl2 3 times (30 mL x 3) The combined organic layer was washed

by brine and dried by Na2SO4 Solvent was removed under reduced pressure Product

82 was pale yellow solid, which can be used in the next step without any further

purification

Step 2: To a suspension of NaH (720 mg, 30 mmol, 3.0 equiv) in THF (15 mL) was

added a solution of 82 (from step 1) in THF (20 mL) After 0.5h, MeI (2.3 mL, 37

mmol, 3.7 equiv) was added in one portion After completion of the reaction (monitored by TLC), the mixture was filtered through a short pad of Celite Solvent was removed under reduced pressure and C was obtained by flash chromatography (silica gel, hexane-ethyl acetate 3:1), as a white solid, 2.10 g (2 steps, 80% overall yield)

Step 3: A 100 mL RBF was charged with a solution of 83 (1.60 g, 6 mmol, 1 equiv)

in toluene (40 mL) with a condenser under N2 atmosphere (COCl)2 (5.2 mL, 60 mmol,

10 equiv) was added via syringe in one portion The mixture was refluxed overnight

until 83 was completely reacted Toluene was removed under reduced pressure and solid 84 (1.93 g) was obtained for the next step without any purification (84 is air and

moisture sensitive, which should be stored under nitrogen atmosphere or vacuum.)

Step 4: Separate half of 84 for the step 5 The other part (960mg) was dissolved in dry

MeCN/MeOH (volume ratio 1:1, 20 mL), NH3 was bubbled into the solution at 0 oC for 0.5 h After the introduction of NH3, the seal tube was sealed and placed in 60 oC oil bath After stirring overnight to complete reaction, pressure was released and water was added (40 mL) The mixture was extracted by CH2Cl2 3 times (20 mL x 3) The combined organic layer was dried by Na2SO4 After removing solvent under reduced

pressure, guanidine 85 was obtained as a brown solid, 801 mg, >99% yield

Step 5: To a solution of 85 (800 mg, 3.06 mmol) and Et3N (0.45 mL, 3.24 mmol) in

MeCN (15 mL) was added a solution of 84 (from step 4, 970 mg, 1.0 equiv) in dry

MeCN (10 mL) was added in a dropwise manner The reaction mixture was stirred until the reaction was completed Reaction was quenched by water (20 mL), and extracted using CH2Cl2 3 times (20 mL x 3) The combined organic layer was dried

by Na2SO4 Solvent was removed under reduced pressure The brown solid obtained was re-crystallized by CH2Cl2/ethyl acetate solvent system Chiral pentanidium

chloride 80a was isolated as a white solid, 820mg, 48% yield

(S, S)-4, 5-Diphenylimidazolidin-2-one (82): white solid; 1

H NMR (300 MHz, CDCl3): δ 7.38-7.34 (m, 6H), 7.27-7.30 (m, 4H), 5.83 (s, 2H), 4.57 (s, 2H) 13C NMR (126 MHz, CDCl3) δ 163.1, 140.2, 128.7, 128.2, 126.4, 65.9, LRMS (ESI) m/z 239.1 (M + H+), HRMS (ESI) m/z 239.1185 ([M + H+]), calc for [C15H14N2O+H+

] 239.1179

(S, S)-1,3-Dimethyl-4,5-diphenylimidazolidin-2-one (83): white solid; 80% yield

for 2 steps; 1H NMR (300 MHz, CDCl3): δ 7.34-7.32 (m, 6H), 7.14-7.11 (m, 4H), 4.07 (s, 2H), 2.69 (s, 6H); 13

C NMR (126 MHz, CDCl3) δ 161.7, 137.9, 128.7, 128.3, 127.2, 70.2, 29.9; LRMS (ESI) m/z 267.1 (M + H+

), HRMS (ESI) m/z 267.1497 ([M + H+]), calc for [C17H18N2O +H+

] 267.1492

(4S, 5S)-1,3-Dimethyl-4,5-diphenylimidazolidin-2-imine (85): brown solid; 99%

yield; 1

H NMR (300 MHz, CDCl3): δ 7.17-7.14 (m, 6H), 6.99-6.97 (m, 4H), 4.48 (b, 1H), 3.87 (s, 2H), 2.52 (s, 6H); 13

C NMR (125.77 MHz, CDCl3): δ 163.3, 137.9, 128.6, 128.2, 127.4, 72.1, 31.4; LRMS (ESI) m/z 266.1 (M + H+

), HRMS (ESI) m/z 266.1664 ([M + H+

]), calc for [C17H19N3 + H+] 266.1652

(S,S)-Tetraphenyl-tetramethyl-pentanidium chloride (80a): white solid, mp

276-278 oC; 48% yield; 1

H NMR (500 MHz, CDCl3): δ 7.35-7.34 (m, 12H), 7.24-7.21 (m, 8H), 4.67 (s, 4H), 2.93 (s, 12H); 13C NMR (126 MHz, CDCl3) δ 159.5, 135.4, 129.3, 129.3, 127.6, 72.6, 32.5; LRMS (ESI) m/z 514.5 ([M-Cl-

])+, HRMS (ESI) m/z 514.2970 ([M-Cl-

])+, calc for [C34H36N5+] 514.2965 [α]29= +171.2 (c 1.18, CHCl3);

For the synthesis of 80b, the following step is required: transformation to thiourea1

1.0 eq 86 and 1.0 eq Lawesson’s reagent were reflux in O-xylene under N2 condition for overnight Full conversion and 90% yield was achieved The following steps are

the same with 80a

(S, S)-Tetraphenyl-tetraethyl-pentanidium chloride (80b): white solid; 1H NMR (500 MHz, CDCl3) δ 7.42-7.40 (m, 12H), 7.17-7.15 (m, 8H), 4.53 (s, 4H), 4.31-4.24 (m, 4H), 3.05-3.03 (m, 4H), 1.16 (t, J=7.5, 12H); 13C NMR (126 MHz, CDCl3) δ

157.1, 136.5, 129.4, 129.4, 127.0, 69.8, 39.0, 11.3; LRMS (ESI) m/z 570.5 ([M-Cl

-])+, HRMS (ESI) m/z 570.3586 ([M-Cl-])+, calc for [C38H44N5+] 570.3591

(S, S)-Tetra-4-methoxy-phenyl-tetraethyl-pentanidium chloride (80c): white solid;

56% yield; 1H NMR (300 MHz, CDCl3) δ 7.19 (d, J=8.7 Hz, 8H), 6.89 (d, J=8.7 Hz, 8H), 4.60 (s, 4H), 3.79 (s, 12H), 2.90 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 160.2, 159.2, 129.0, 127.3, 114.6, 72.2, 55.2, 32.3; LRMS (ESI) m/z 634.5 ([M-Cl-

])+, HRMS (ESI) m/z 634.3403 ([M-Cl-])+, calc for [C38H44N5O4+] 634.3388

Chiral pentanidium salt 80d and 80e were prepared in the following manner:

(S, S)-Tetraphenyl-tetramethyl-pentanidium tetrafluoroborate (80d): white solid;

98% yield; 1H NMR (300 MHz, CDCl3) δ 7.40-7.37 (m, 12H), 7.26-7.22 (m, 8H), 4.62 (s, 4H), 2.91 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 159.5, 135.5, 129.30, 129.2, 127.6, 104.9, 72.7, 32.2; 19F NMR (282 MHz, CDCl3) δ -76.59

(S, S)-Tetraphenyl-tetramethyl-pentanidium hexafluorophosphate (80e): white

solid; 99% yield; 1H NMR (300 MHz, CDCl3) δ 7.43-7.40 (m, 12H), 7.27-7.24 (m, 8H), 4.63 (s, 4H), 2.92 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 159.4, 135.4, 129.4, 129.3, 127.6, 72.7, 32.2; 19F NMR (282 MHz, CDCl3) δ 3.32 (d, 710Hz) 31P NMR (121 MHz, CDCl3) δ -143.6 (tt, J1=709Hz, 1418Hz)

Chiral pentanidium salt 80f is colorless oil, thus flash chromatography was required

for purification step (silica gel, CH2Cl2/MeOH, 50:1)

(S, S)-Dicyclohexyl-tetramethyl-pentanidium chloride (80f): colorless oil; 1H NMR (300 MHz, CDCl3) δ 3.01-2.99 (m, 4H), 2.79 (s, 12H), 2.19-2.10 (m, 8H), 1.93 (d, J = 6.2 Hz, 4H), 1.45-1.42 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 162.7, 66.2, 31.4, 27.8, 23.8; LRMS (ESI) m/z 318.5 ([M-Cl-])+, HRMS (ESI) m/z 318.2659 ([M-Cl-])+, calc for [C18H32N5+] 318.2652

2-(((4S,5S)-1,3-dimethyl-4,5-diphenylimidazolidin-2-ylidene)amino)-1,3-dimethyl -4,5-dihydro-1H-imidazol-3-ium chloride (80g): pale yellow oil; 1H NMR (300 MHz, MeOD) δ 7.42-7.44 (m, 6H), 7.30-7.34 (m, 4H), 4.69 (s, 2H), 3.82-3.67 (m,

4H), 3.04 (s, 6H), 2.74 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 159.6, 158.9, 135.3, 129.2, 127.2, 72.3, 63.9, 47.6, 33.2, 31.7; LRMS (ESI) m/z 326.5 ([M-Cl-])+, HRMS (ESI) m/z 326.2213 ([M-Cl-])+, calc for [C22H28N5+] 326.2267

4.2.2 Procedure synthesis of glycine Schiff base

glycine Schiff base 1 was synthesized as following Scheme, using procedures

modified from existing literature.2

Alternative procedure for the synthesis of glycinate Schiff base 1: 3

Bromo tert-butyl acetate (3 mmol) was first dissolved in acetonitrile (8 mL) and

diphenylmethanimine (3 mmol, 600 mg) added Diisopropylethylamine (175 μL, 3

mmol) was next added and the reaction was refluxed for 12 hours The reaction was subsequently diluted with 50 mL CH2Cl2 and the organic layers washed with water (2x10 mL), brine (10 mL), dried with MgSO4 and solvent removed under reduced

pressure Products 1 were isolated via flash column chromatography (hexane: EA 10:1

with 1% triethylamine) as a bright yellow/orange solid (60-70% yield) After

re-crystallization from hot hexane, white solide 1 was obtained

4.2.3 Syntheses of Starting Materials: 54j, 54k and chalcone derivatives

To a solution of (Benzoylmethylene)triphenylphosphorane (760 mg, 2 mmol, 1.0 equiv) in CH2Cl2 (4 mL) was added 37% formaldehyde (0.81ml, 10 mmol, 5.0 equiv)

in one portion The reaction mixture was stirred at room temperature overnight and extracted by CH2Cl2 (10 mL+10 mL) After drying over MgSO4, the solvent was evaporated to give a crude product, which was purified by flash chromatography

(silica gel, hexane-ethyl acetate 15:1) to yield phenyl vinyl ketone (54k) as a colorless oil, 210 mg, 80% yield 54k is known compound 4

To a cooled (ice bath) solution of the n-butyl magnesium bromide(5.0 mmol, 1.25 equiv, prepared from 5.5 mmol n-butyl bromide and 5.0 mmol of magnesium in 10

mL dry THF), acrolein (4 mol, 1.0 equiv) was added very slowly The reaction mixture was stirred overnight and quenched by saturated NH4Cl solution The organic layer was separated The aqueous layer was extracted with three portions (10 mL) of dithylether The combined organic layer were washed with brine and dried by MgSO4

After removing the solvent under reduced pressure, product was obtained by flash chromatography (silica gel, hexane-ethyl acetate 5:1) Alcohol adduct was dissolved

in CH2Cl2 (10 mL),followd by 1.0 equiv PCC (860 mg，4 mmol) The reaction was stirred for 24 h, then filterd through a short pad of celite After solvent was romoved under reduced pressure, the residue was purified by column chromatography (silica

gel, hexane-diethyl ether 10:1) to yield 4c as colorless oil in 62% yield, 275 mg 54j is

4.2.4 Representative Procedure for Phase Transfer Michael Addition Reactions Catalyzed by Chiral Pentanidium

For enantioselective synthesis of 55b

tert-Butyl glycinate benzophenone Schiff base 1 (17.7 mg, 0.06 mmol, 1.0 equiv), (S, S)-80a (0.66 mg, 0.0012 mmol, 0.02 equiv) and Cs2CO3 (97 mg, 0.2 mmol, 5.0 equiv) were placed in mesitylene (0.6 mL) and stirred at -20 oC for 10 min, then ethyl vinyl

keton 54b (12.8 L, 0.12 mmol, 2.0 equiv) was added by syringe in one portion The reaction mixture was stirred at -20 oC and monitored by TLC After indicated time,

upon complete consumption of 1, the reaction mixture was directly loaded onto a

short silica gel column, followed by gradient elution with hexane/ethyl acetate

(15:1-12:1 ratio) After removing the solvent, product 55b (20.9 mg) was obtained as

colorless oil

(R)-tert-Butyl-2-((diphenylmethylene)amino)-5-oxoheptanoate(55b): colorless oil;

92% yield; 1H NMR (300 MHz, CDCl3) δ 7.67-7.58 (m, 2H), 7.47-7.27 (m, 6H), 7.16

(dd, J = 6.4, 3.1 Hz, 2H), 3.95 (t, J = 6.1 Hz, 1H), 2.59-2.32 (m, 4H), 2.15 (dd, J = 13.6, 7.6 Hz, 2H), 1.43 (s, 9H), 1.01 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 210.8, 170.9, 170.3, 139.4, 136.4, 130.2, 128.5, 127.9, 127.6, 81.0, 64.7, 38.4, 35.8,

), HRMS (ESI) m/z 388.1900 ([M + Na+]), calc for [C23H27NO3+Na+] 388.1883; [α]29= +64.2 (c 1.30, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 92/8, 0.8 mL/min, 210 nm, 23°C), 6.5 (major), 7.2 min,

91% ee

(R)-tert-Butyl-2-((diphenylmethylene)amino)-5-oxononanoate(55j): colorless oil;

97% yield; 1H NMR (500 MHz, CDCl3) δ 7.66-7.60 (m, 2H), 7.47-7.41 (m, 3H),

7.38-7.37 (m, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.19-7.13 (m, 2H), 3.95 (t, J=12.1 Hz,1H), 2.55-2.42 (m, 2H), 2.41-2.33 (m, 2H), 2.14 (dd, J = 13.8, 7.5 Hz, 2H), 1.54-1.47 (m, 2H), 1.43 (s, 9H), 1.27 (dd, J = 15.0, 7.4 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR

(75 MHz, CDCl3) δ 210.6, 171.0, 170.3, 139.4, 136.4, 130.2, 128.7, 128.5, 128.4, 127.9, 127.6, 81.0, 64.7, 42.4, 38.8, 28.0, 27.7, 25.8, 22.2, 13.8; LRMS (ESI) m/z 430.1 (M + Na+

), HRMS (ESI) m/z 430.2364 ([M + Na+]), calc for [C26H33NO3+Na+] 430.2353; [α]29= +43.4 (c 1.62, CHCl3); HPLC analysis: Chiralcel OD-H + Chiralcel

OD-H (Hex/IPA = 95/5, 0.5 mL/min, 230 nm, 23°C), 19.4 (major), 23.6 min, 93% ee

(R)-tert-Butyl-2-((diphenylmethylene)amino)-5-oxo-5-phenylpentanoate(55k):

colorless oil; 50% yield; 1H NMR (300 MHz, CDCl3) δ 7.95-7.93 (m, 2H), 7.65 (d, J

= 7.1 Hz, 2H), 7.56-7.53 (m, 1H), 7.45-7.39 (m, 6H), 7.32 (t, J = 7.3 Hz, 2H), 7.15-7.13 (m, 2H), 4.08 (t, J = 6.0 Hz, 1H), 3.16-3.01 (m, 2H), 2.33 (dd, J = 13.3, 6.9

Hz, 2H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 199.6, 176.1, 171.0, 170.1, 136.8, 132.9, 132.4, 130.3, 130.0, 128.8, 128.5, 128.4, 128.2, 128.1, 128.0, 127.7, 64.7, 34.7, 28.0; LRMS (ESI) m/z 450.1 (M + Na+

), HRMS (ESI) m/z 450.2056 ([M + Na+]), calc for [C28H29NO3 + Na+] 450.2040; [α]29= +19.1 (c 0.5, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 92/8, 0.8 mL/min, 254 nm, 23°C), 6.5 (major), 8.8 min,

88% ee

(R)-1-tert-Butyl-5-ethyl-2-((diphenylmethylene)amino)pentanedioate(55h):

colorless oil; 71% yield; 1H NMR (500 MHz, CDCl3) δ 7.67-7.6 (m, 2H), 7.47-7.41

(m, 3H), 7.40-7.35 (m, 1H), 7.35-7.29 (m, 2H), 7.20-7.14 (m, 2H), 4.05 (q, J = 7.1 Hz,

2H), 3.97 (dd, J = 6.9, 5.7 Hz, 1H), 2.35 (dd, J = 8.6, 6.8 Hz, 2H), 2.33-2.21 (m, 2H), 1.44 (s, 9H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 210.8, 170.9, 170.3, 139.4, 136.4, 130.2, 128.5, 127.9, 127.6, 81.0, 64.7, 38.4, 35.8, 27.8, 7.67; LRMS (ESI) m/z 418.1 (M + Na+), HRMS (ESI) m/z 418.1997 ([M + Na+]), calc for [C24H29NO4 + Na+] 418.1989; [α]29= +75.2 (c 1.38, CHCl3); HPLC analysis: Chiralcel

OD-H (Hex/IPA = 95/5, 0.5 mL/min, 254 nm, 23°C), 9.5 (major), 11.6 min, 97% ee

12.9 (major), 13.8 min, 96% ee

For the enantioselective synthesis of 89a-r

tert-Butyl glycinate benzophenone Schiff base a (17.7 mg, 0.06 mmol, 1.0 equiv), (S, S)-80a (0.66 mg, 0.0012 mmol, 0.02 equiv) and Cs2CO3 (97 mg, 0.2 mmol, 5.0 equiv) were placed in mesitylene (0.6 mL) and stirred at -20 oC for 10 min, followed by

chalcone 26a (15.0 mg, 0.072 mmol, 1.2 equiv) The reaction mixture was stirred at

-20 oC and monitored by TLC After indicated time, upon complete consumption of 1,

the reaction mixture was directly loaded onto a short silica gel column, followed by gradient elution with hexane/ethyl acetate (15:1-12:1 ratio) After removing the

solvent, product 89a (29.6 mg) was obtained as colorless oil

(2R,3S)-tert-Butyl2-((diphenylmethylene)amino)-5-oxo-3,5-diphenylpentanoate(8

9a): colorless oil; 98% yield; 1H NMR (300 MHz, CDCl3) δ 8.00-7.96 (m, 2H),

7.74-7.64 (m, 2H), 7.58-7.27 (m, 9H), 7.22-7.08 (m, 5H), 6.73 (d, J = 6.4 Hz, 2H),

4.27-4.16 (m, 2H), 3.83-3.70 (m, 1H), 3.69-3.57 (m, 1H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.6, 171.0, 170.0, 141.3, 139.3, 137.2, 136.2, 132.7, 130.3, 128.8, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.5, 126.5, 81.2, 70.9, 44.8, 40.0, 27.8; LRMS (ESI) m/z 526.1 (M + Na+), HRMS (ESI) m/z 526.2373 ([M + Na+]), calc for [C34H33NO3 + Na+] 526.2353; [α]29= +58.8 (c 2.48, CHCl3); HPLC analysis: Chiralcel

OD-H (Hex/IPA = 95/5, 0.5 mL/min, 230 nm, 23°C), 10.9 (major), 21.5 min, 92% ee

enylpentanoate (89b): colorless oil; 91% yield; 1H NMR (500 MHz, CDCl3) δ 8.10

(d, J = 8.2 Hz, 1H), 8.05-7.98 (m, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.70-7.60 (m, 3H), 7.56-7.52 (m, 1H), 7.48-7.36 (m, 5H), 7.33 (t, J = 7.4 Hz, 2H), 7.30-7.23 (m, 2H), 7.11 (t, J = 7.4 Hz, 1H), 6.96 (t, J = 7.4 Hz, 2H), 6.27 (s, 2H), 5.20-5.10 (m, 1H), 4.30 (d, J = 3.7 Hz, 1H), 4.11 (dd, J = 17.3, 9.8 Hz, 1H), 3.81 (dd, J = 17.3, 4.2 Hz, 1H),

1.35 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.5, 171.1, 170.3, 139.3, 137.2, 135.8, 133.9, 132.7, 131.7, 130.2, 128.7, 128.5, 128.4, 128.1, 127.9, 127.7, 127.1, 126.9, 125.9, 125.2, 124.8, 123.0, 81.3, 69.2, 39.2, 27.8; LRMS (ESI) m/z 576.1 (M + Na+

), HRMS (ESI) m/z 576.2494 ([M + Na+]), calc for [C38H35NO3 + Na+] 576.2509; [α]29

= +87.8 (c 2.79, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 95/5, 0.5

mL/min, 254 nm, 23°C), 12.1 (major), 14.0 min, 92% ee

(2R,3S)-tert-Butyl-2-((diphenylmethylene)amino)-3-(naphthalen-2-yl)-5-oxo-5-ph

enylpentanoate (89c): colorless oil; 93% yield; 1H NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 5.1, 3.3 Hz, 2H), 7.74-7.54 (m, 5H), 7.60 (s, 1H), 7.55-7.52 (m, 1H),

7.45-7.30 (m, 9H), 7.22-7.19 (m, 2H), 6.64 (d, J = 7.0 Hz, 2H), 4.40-4.37 (m, 1H), 4.29 (d, J = 5.0 Hz, 1H), 3.89 (dd, J = 17.0, 10.2 Hz, 1H), 3.72 (dd, J = 17.0, 3.8 Hz, 1H), 1.31 (s, 9H).; 13C NMR (126 MHz, CDCl3) δ 198.7, 171.2, 170.0, 141.1, 140.6, 139.4, 137.2, 136.3, 132.8, 130.4, 129.0, 128.9, 128.7, 128.5, 128.4, 128.2, 128.2, 128.1, 127.5, 127.0, 127.0, 126.8, 81.4, 70.9, 44.5, 39.9, 27.9; LRMS (ESI) m/z 576.1 (M + Na+), HRMS (ESI) m/z 576.2496 ([M + Na+]), calc for [C38H35NO3 + Na+] 576.2509; [α]29= +44.8 (c 2.74, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/IPA =

95/5, 0.5 mL/min, 210 nm, 23°C), 12.4 (major), 22.7 min, 90% ee

), HRMS (ESI) m/z 602.2664 ([M + Na+]), calc for [C40H37NO3 + Na+] 602.2677; [α]29= +41.0 (c

0.98, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 92/8, 0.8 mL/min, 254 nm,

23°C), 9.4 (major), 13.1 min, 91% ee

nylpentanoate (89e): colorless oil; 89% yield; 1H NMR (500 MHz, CDCl3) δ 7.95 (d,

J = 7.3 Hz, 2H), 7.70-7.66 (m, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.46-7.32 (m, 8H), 7.11

(dd, J = 8.6, 5.5 Hz, 2H), 6.86 (t, J = 8.7 Hz, 2H), 6.77 (d, J = 6.9 Hz, 2H), 4.22-4.09 (m, 2H), 3.69 (dd, J = 16.9, 10.0 Hz, 1H), 3.60 (dd, J = 16.9, 3.7 Hz, 1H), 1.33 (s, 9H);

13C NMR (126 MHz, CDCl3) δ 198.6, 171.3, 169.9, 162.6, 160.6, 139.3, 137.1, 136.2, 132.9, 130.5, 130.1, 130.0, 128.8, 128.5, 128.5, 128.3, 128.2, 128.1, 127.5, 115.0, 114.8, 81.4, 70.9, 44.1, 40.2, 27.9; LRMS (ESI) m/z 544.1 (M + Na+

), HRMS (ESI) m/z 544.2258 ([M + Na+]), calc for [C34H32FNO3+Na+] 544.2258; [α]29= +54.5 (c

1.26, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 95/5, 0.5 mL/min, 254 nm,

23°C), 10.2 (major), 19.9 min, 90% ee

(2R,3S)-tert-Butyl-3-(4-chlorophenyl)-2-((diphenylmethylene)amino)-5-oxo-5-phe

nylpentanoate (89f): colorless oil; 98% yield; 1H NMR (500 MHz, CDCl3) δ 7.99-7.93 (m, 2H), 7.69-7.66 (m, 2H), 7.59-7.51 (m, 1H), 7.46-7.40 (m, 3H),

7.39-7.31 (m, 5H), 7.16-7.12 (m, 2H), 7.11-7.06 (m, 2H), 6.76 (d, J = 6.9 Hz, 2H), 4.18-4.14 (m, 2H), 3.73 (dd, J = 17.1, 9.7 Hz, 1H), 3.61 (dd, J = 17.1, 3.4 Hz, 1H),

1.34 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 198.4, 171.4, 169.8, 140.1, 139.3, 137.1, 136.2, 133.0, 132.3, 130.5, 129.9, 128.8, 128.5, 128.5, 128.3, 128.2, 128.2, 128.1, 127.5, 81.5, 70.7, 44.1, 39.9, 27.9; LRMS (ESI) m/z 560.0 (M + Na+

), HRMS (ESI) m/z 560.1966 ([M + Na+]), calc for [C34H32ClNO3+Na+] 560.1963; HPLC analysis: [α]29= +40.9 (c 2.88, CHCl3); Chiralcel OD-H (Hex/IPA = 95/5, 0.5 mL/min, 230 nm,

23°C), 10.1 (major), 16.9 min, 92% ee

), HRMS (ESI) m/z 604.1262 ([M + Na+]), calc for [C34H32BrNO3 + Na+] 604.1458; [α]29= +36.7 (c 2.73, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 95/5, 0.5 mL/min, 230 nm, 23°C), 10.2 (major),

16.7 min, 92% ee.

ylpentanoate (89h): colorless oil; 91% yield; 1H NMR (500 MHz, CDCl3) δ 8.05 (m, 2H), 7.97-7.95 (m, 2H), 7.68-7.66 (m, 2H), 7.58-7.55 (m, 1H), 7.48-7.31 (m, 10H), 6.75 (d, J = 7.1 Hz, 2H), 4.31-4.27 (m, 1H), 4.20 (d, J = 4.8 Hz, 1H), 3.87 (dd, J = 17.6, 10.5 Hz, 1H), 3.69 (dd, J = 17.6, 3.6 Hz, 1H), 1.36 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 197.9, 171.9, 169.4, 149.6, 146.6, 138.9, 136.7, 135.9, 133.2, 130.7, 129.4, 128.8, 128.6, 128.4, 128.2, 128.1, 127.3, 123.3, 81.9, 69.9, 44.4, 39.5, 27.9; LRMS (ESI) m/z 571.1 (M + Na+), HRMS (ESI) m/z 571.2187 ([M + Na+]), calc for [C34H32N2O5 + Na+] 571.2203; [α]29= +26.1 (c 3.00, CHCl3); HPLC analysis: Chiralcel OD-H (Hex/IPA = 92/8, 0.8 mL/min, 230 nm, 23°C), 8.9 (major), 13.9 min,

94% ee.

(2R,3S)-tert-Butyl-3-(2-chlorophenyl)-2-((diphenylmethylene)amino)-5-oxo-5-phe

nylpentanoate (89i): colorless oil; 93% yield; 1H NMR (500 MHz, CDCl3) δ

8.05-7.98 (m, 2H), 7.69-7.61 (m, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.50-7.42 (m, 2H), 7.42-7.37 (m, 1H), 7.34 (q, J = 7.1 Hz, 3H), 7.29-7.23 (m, 3H), 7.18 (dd, J = 7.3, 2.0

Hz, 1H), 7.09-7.03 (m, 2H), 6.57 (d, J = 6.7 Hz, 2H), 4.73 (dt, J = 10.4, 4.0 Hz, 1H),