1401067-00-2|(S)-4-Isopropyl-3-(5,5,5-trifluoropentanoyl)oxazolidin-2-one| Ambeed

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Quality Control of [ 1401067-00-2 ] Purity: 95% SDS Specification

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Product Details of [ 1401067-00-2 ]

CAS No. :	1401067-00-2
Formula :	C₁₁H₁₆F₃NO₃
M.W :	267.24
SMILES Code :	O=C1OC[C@@H](N1C(CCCC(F)(F)F)=O)C(C)C
MDL No. :	MFCD30829163
InChI Key :	PDGUBGGKVSFZAA-MRVPVSSYSA-N
Pubchem ID :	68315009

Safety of [ 1401067-00-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501

Application In Synthesis of [ 1401067-00-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1401067-00-2 ]

[ 1401067-00-2 ] Synthesis Path-Downstream 1~35

1
[ 1401067-00-2 ]
[ 1401067-01-3 ]
[ 1401067-02-4 ]

References: [1]Patent: US2012/245151,2012,A1 .

2
[ 1401067-00-2 ]
C₁₁H₁₅F₃NO₃^(1-)*Li⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With lithium chloride; lithium diisopropyl amide; In tetrahydrofuran; hexane; toluene; at -78 - 0℃; for 0.333333h;	Preparation 1D (2R,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate To a cold (-78 C.), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol), then warmed to 0 C. to give a 0.5M solution of LDA. A separate vessel was charged with Preparation 1B (2.45 g, 9.17 mmol), the material was azeotroped twice with benzene (the RotoVap air inlet was fitted with nitrogen inlet to completely exclude humidity) then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to -78 C., was added LDA solution (21.0 mL, 10.5 mmol) and stirred at -78 C. for 10 min, warmed to 0 C. for 10 min then recooled to -78 C. To a separate reaction vessel containing Preparation 1A (3.41 g, 16.07 mmol), also azeotroped twice with benzene, was added toluene (15.3 mL), cooled to -78 C. and LDA (37.0 mL, 18.5 mmol) was added, the resulting solution was stirred at -78 for 25 min. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate, stirred at -78 C. for an additional 5 min at which time the septum was removed and solid powdered bis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reaction vessel and the septum replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40 C.) with rapid swirling with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 min, was poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2*). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP SiO2 120 g). Concentration of appropriate fractions provided Preparation 1C (2.87 g, 66%) as pale yellow viscous oil. 1H NMR showed the product was a 1.6:1 mixture of diastereoisomers 1C:1D as determined by the integration of the multiplets at 2.74 & 2.84 ppm: 1H NMR (400 MHz, CDCl3) δ ppm 4.43-4.54 (2H, m), 4.23-4.35 (5H, m), 4.01 (1H, ddd, J=9.54, 6.27, 3.51 Hz), 2.84 (1H, ddd, J=9.41, 7.28, 3.64 Hz), 2.74 (1H, ddd, J=10.29, 6.27, 4.02 Hz), 2.37-2.48 (2H, m, J=10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3H, m), 1.92-2.20 (8H, m), 1.64-1.91 (5H, m), 1.47 (18H, s), 0.88-0.98 (12H, m).

References: [1]Patent: US2012/245151,2012,A1 .Location in patent: Page/Page column 24-25.

3
[ 1186202-35-6 ]
[ 17016-83-0 ]
[ 1401067-00-2 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 1B (4S)-4-(Propan-2-yl)-3-(5,5,5-trifluoropentanoyl)-1,3-oxazolidin-2-one To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min and the solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at -78 C. was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 min. The reaction mixture was warmed to 0 C., and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, and then extracted with EtOAc (2*). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP SiO2 120 g). Concentration of appropriate fractions provided Preparation 1B (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 4.44 (1H, dt, J=8.31, 3.53 Hz), 4.30 (1H, t, J=8.69 Hz), 4.23 (1H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2H, m), 2.32-2.44 (1H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2H, m), 1.88-2.00 (2H, m), 0.93 (3H, d, J=7.05 Hz), 0.88 (3H, d, J=6.80 Hz).
7.39 g		To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min and the solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (45)-4-(propan-2-yl)-l,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at -78 C was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 min. The reaction mixture was warmed to 0 C, and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4C1, and then extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60%> solvent A/B=hexanes/EtOAc, REDISEP Si02 120g). Concentration of appropriate fractions provided Intermediate S-IH (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDC13) δ ppm 4.44 (1 H, dt, J=8.31, 3.53 Hz), 4.30 (1 H, t, J=8.69 Hz), 4.23 (1 H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz).

References: [1]Patent: US2012/245151,2012,A1 .Location in patent: Page/Page column 24.
[2]Patent: WO2014/47390,2014,A1 .Location in patent: Paragraph 00160; 00161; 00164; 00165.
[3]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 523 - 527.

4
[ 407-62-5 ]
[ 1401067-00-2 ]

References: [1]Patent: US2012/245151,2012,A1 .
[2]Patent: WO2014/47390,2014,A1 .
[3]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 523 - 527.

5
[ 1049037-18-4 ]
[ 1401067-00-2 ]
[ 1401067-01-3 ]
[ 1401067-02-4 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate S-1I: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate, and Intermediate S-1J: (2R,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate To a cold (-78 C.), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under a nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol). The mixture was then warmed to 0 C. to give a 0.5M solution of LDA. A separate vessel was charged with Intermediate S-1H (2.45 g, 9.17 mmol). The material was azeotroped twice with benzene (the RotoVap air inlet was fitted with a nitrogen inlet to completely exclude humidity), and then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to -78 C., was added the LDA solution (21.0 mL, 10.5 mmol) and the mixture was stirred at -78 C. for 10 min, then warmed to 0 C. for 10 min., and then cooled to -78 C. To a separate reaction vessel containing Intermediate S-1G (3.41 g, 16.07 mmol), also azeotroped twice with benzene, was added toluene (15.3 mL), cooled to -78 C. and LDA (37.0 mL, 18.5 mmol) was added. The resulting solution was stirred at -78 C. for 25 min. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate and stirred at -78 C. for an additional 5 min, at which time the septum was removed and solid powdered bis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reaction vessel and the septum was replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40 C.) with rapid swirling and with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 min, was then poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2*). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP SiO2 120 g). Concentration of the appropriate fractions provided a mixture of Intermediate S-1I and Intermediate S-1J (2.87 g, 66%) as a pale yellow viscous oil. 1H NMR showed the product was a 1.6:1 mixture of diastereomers S-1I:S-1J as determined by the integration of the multiplets at 2.74 and 2.84 ppm: 1H NMR (400 MHz, CDCl3) δ ppm 4.43-4.54 (2H, m), 4.23-4.35 (5H, m), 4.01 (1H, ddd, J=9.54, 6.27, 3.51 Hz), 2.84 (1H, ddd, J=9.41, 7.28, 3.64Hz), 2.74 (1H, ddd, J=10.29, 6.27, 4.02Hz), 2.37-2.48 (2H, m, J=10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3H, m), 1.92-2.20 (8H, m), 1.64-1.91 (5H, m), 1.47 (18H, s), 0.88-0.98 (12H, m).
		To a cold (-78 C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol)in THF (59 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexane) (I4.7mL, 36.8 mmol), then warmed to 0 octo give a 0.5M solution ofLDA. A separate vesselwas charged with Intermediate S-IB (2.45 g, 9.17 mmol), the material was azeotropedtwice with benzene (the RotoVap air inlet was fitted with nitrogen inlet to completelyIS exclude humidity) then toluene (I5.3 mL) was added. This solution was added to a flaskcontaining dry lithium chloride (I.96 g, 46.2 mmol). To the resultant mixture, cooled to-78 C, was added LDA solution (21.0 mL, I0.5 mmol) and stirred at -78 oc for IO min,warmed to 0 oc for I 0 min then recooled to -78 C. To a separate reaction vesselcontaining Intermediate S-IA (3.4I g, I6.07 mmol), also azeotroped twice with benzene,20 was added toluene (I5.3 mL), cooled to -78 C. Next, LDA (37.0 mL, I8.5 mmol) wasadded and the resulting solution was stirred at -78 oc for 25 min. At this time the enolatederived from the ester was transferred via cannula into the solution of the oxazolidinoneenolate, stirred at -78 oc for an additional 5 min. The septum was removed and solidpowdered bis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the25 reaction vessel and the septum replaced. The vessel was immediately removed from thecold bath and immersed into a warm water bath ( 40 C) with rapid swirling with aconcomitant color change from the initial turquoise to brown. The reaction mixture wasstirred for 20 min, was poured into 5% aqueous NH40H (360 mL) and extracted withEtOAc (2x). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by flashchromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solventA/B=hexanes/EtOAc, REDISEP Si02 I20g). Concentration of appropriate fractionsprovided a mixture oflntermediates S-IC and S-ID (2.87 g, 66%) as pale yellow viscous5 oil. 1 H NMR showed the product was a I. 6: I mixture of diastereomers S-IC: S-ID asdetermined by the integration ofthe multiplets at 2.74 and 2.84 ppm: 1H NMR (400 MHz,CDCb) 8 ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.0I (I H, ddd, J=9.54, 6.27, 3.5IHz), 2.84 (I H, ddd, J=9.4I, 7.28, 3.64 Hz), 2.74 (I H, ddd, J=I0.29, 6.27, 4.02 Hz),2.37-2.48 (2 H, m, J=I0.38, 6.98, 6.98, 3.5I, 3.5I Hz), 2.20-2.37 (3 H, m), 1.92-2.20 (8IO H, m), 1.64-1.9I (5 H, m), I.47 (I8 H, s), 0.88-0.98 (I2 H, m).
		Preparation A-i C: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3 -((S)-4-isopropyl-2-oxooxazolidine-3 -carbonyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoate,[00144j To a cold (-78 C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol)in THF (59 mL) under a nitrogen atmosphere was added n-BuLi (2.5M in hexane) (i4.7mL, 36.8 mmol), and then the mixture was warmed to 0 c to give a 0.5M solution ofLDA. A separate vessel was charged with Preparation A-iB (2.45 g, 9.i7 mmol), thematerial was azeotroped twice with benzene (the RotoVap air inlet was fitted withnitrogen inlet to completely exclude humidity), and then toluene (i5.3 mL) was added.This solution was added to a flask containing dry lithium chloride (i .96 g, 46.2 mmol).To the resultant mixture, cooled to -78 c, was added the above LDA solution (2i.O mL,iO.5 mmol) and the mixture was stirred at -78 c for iO mm, warmed to 0 c for iO mmand then cooled to -78 c. To a separate reaction vessel containing Preparation A-iA(3.4i g, i6.07 mmol), also azeotroped twice with benzene, was added toluene (i5.3 mL).The mixture was cooled to -78 c and LDA (37.0 mL, i8.5 mmol) was added, and theresulting solution was stirred at -78 c for 25 mm. At this time, the enolate derived fromthe ester was transferred via cannula into the solution of the oxazolidinone enolate andstirred at -78 c for an additional 5 mm. The septum was removed and solid powderedbis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reactionvessel and the septum replaced. The vessel was immediately removed from the cold bathand immersed into a warm water bath (40 C) with rapid swirling with a concomitantcolor change from the initial turquoise to brown. The reaction mixture was stirred for 20mm, was poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2x). Thecombined organics were washed with brine, dried (Na2SO4), filtered and concentratedunder reduced pressure. The residue was purified by flash chromatography (Teledyneisco combiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP Si02 i2Og).concentration of appropriate fractions provided Preparation A-it (2.87 g, 66%) as a paleyellow viscous oil. ‘H NMR showed the product was a i .6: i mixture of diastereoisomersic:iD as determined by the integration of the multiplets at 2.74 and 2.84 ppm: ‘H NMR(400 MHz, cDcl3) ö ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.Oi (i H, ddd, J9.54,6.27, 3.51 Hz), 2.84 (1 H, ddd, J9.41, 7.28, 3.64 Hz), 2.74 (1 H, ddd, J=i0.29, 6.27,4.02 Hz), 2.37-2.48 (2 H, m, J10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3 H, m),1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m).

		To a cold (-78 C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol), then warmed to 0 C to give a 0.5 M solution of LDA. A separate vessel was charged with Intermediate S-1H (2.45 g, 9.17 mmol), the material was azeotroped twice with benzene (the RotoVap air inlet was fitted with nitrogen inlet to completely exclude humidity), and then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to -78 C, was added LDA solution (21.0 mL, 10.5 mmol) and stirred at -78 C for 10 min, warmed to 0 C for 10 min, and then recooled to -78 C. To a separate reaction vessel containing Intermediate S-IG (3.41 g, 16.07 mmol), also azeotroped twice with benzene, was added toluene (15.3 mL), cooled to -78 C and LDA (37.0 mL, 18.5 mmol) was added. The resulting solution was stirred at -78 C for 25 min. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate, stirred at -78 C for an additional 5 min at which time the septum was removed and solid powdered bis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reaction vessel and the septum replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40 C) with rapid swirling with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 min, was poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP Si02 120g). Concentration of appropriate fractions provided a mixture of S-1I and S-1J (2.87 g, 66%) as pale yellow viscous oil. 1H NMRshowed the product was a 1.6: 1 mixture of diastereomers S-1LS-1J as determined by the integration of the multiplets at 2.74 and 2.84 ppm: 1H NMR (400 MHz, CDC13) δ ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.01 (1 H, ddd, J=9.54, 6.27, 3.51 Hz), 2.84 (1 H, ddd, J=9.41, 7.28, 3.64 Hz), 2.74 (1 H, ddd, J=10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m, J=10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3 H, m), 1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m).
		Intermediate S-i I: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3 -((S)-4-isopropyl-2- oxooxazolidine-3 -carbonyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoate, and Intermediate S-i J: (2R,3R)-tert-Butyl 6,6,6-trifluoro-3 -((S)-4-isopropyl-2- oxooxazolidine-3 -carbonyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoate[00147j To a cold (-78 C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol). The reaction mixture was warmed to 0 C to give a 0.5M solution of LDA. A separate vessel was charged with Intermediate S-1H (2.45 g, 9.17 mmol), the material was azeotroped twice with benzene (the RotoVap air inlet was fitted withnitrogen inlet to completely exclude humidity) then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to -78 C, was added LDA solution (21.0 mL, 10.5 mmol) and stirred at -78 C for 10 mm, warmed to 0 C for 10 mm then recooled to -78 C. To a separate reaction vessel containing Intermediate S-1G (3.41 g, 16.07 mmol), alsoazeotroped twice with benzene, was added toluene (15.3 mL), cooled to -78 C and LDA (37.0 mL, 18.5 mmol) was added, the resulting solution was stirred at -78 C for 25 mm. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate, stirred at -78 C for an additional 5 mm at which time the septum was removed and solid powdered bis(2-ethylhexanoyloxy)copper (9.02g, 25.8 mmol) was rapidly added to the reaction vessel and the septum replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40 C) with rapid swirling with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 mm, was poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2x). The combined organics werewashed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP Si02 120g). Concentration of appropriate fractions provided a mixture of Intermediates S-lI and S-1J (2.87 g, 66%) aspale yellow viscous oil. ‘H NMR showed the product was a 1.6:1 mixture ofdiastereomers S-i I: S-i J as determined by the integration of the multiplets at 2.74 and2.84 ppm: ‘H NMR (400 MHz, CDC13) ö ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m),4.01 (1 H, ddd, J9.54, 6.27, 3.51 Hz), 2.84 (1 H, ddd, J9.41, 7.28, 3.64 Hz), 2.74 (1 H,ddd, J10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m, J10.38, 6.98, 6.98, 3.51, 3.51 Hz),2.20-2.37 (3 H, m), 1.92-2.20 (8 H, m), 1.64-1.9 1 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12H, m).
		A 0.5 M solution of LDA was prepared by the addition of a solutionof 2.5 M n-BuLi in hexanes (14.7 mL, 36.8 mmol) to a cold(-78 C) solution of diisopropylamine (5.3 mL, 37.2 mmol) inTHF (59 mL) under N2. The solution was stirred at 0 C for 15min. A solution of <strong>[1401067-00-2](S)-4-isopropyl-3-(5,5,5-trifluoropentanoyl)oxazolidin-2-one</strong> (2.45 g, 9.2 mmol) in toluene (15.3 mL)was added with stirring to dry LiCl (1.96 g, 46.2 mmol). Themixture was cooled to -78 C, and the freshly prepared 0.5 Msolution of LDA (21.0 mL, 10.5 mmol) was added. The reactionmixture was stirred at -78 C for 10 min, at 0 C for 10 min, andcooled to -78 C. Meanwhile, the freshly prepared 0.5 M solutionof LDA (37.0 mL, 18.5 mmol) was added to a cold (-78 C)solution of tert-butyl 5,5,5-trifluoropentanoate (3.41 g, 16.1mmol) in toluene (15.3 mL). After 25 min of stirring at -78 C, this reaction mixture was transferred via cannula into the cold(-78 C) LiCl/enolate solution. After an additional 5 min of stirringat -78 C, solid powdered bis(2-ethylhexanoyloxy)copper(9.02 g, 25.8 mmol) was rapidly added to the reaction vesselthrough a funnel, and the flask was rapidly recapped with aseptum. The vessel was immediately removed from the coldbath and immersed into a warm (40 C) water bath with rapidswirling. The reaction mixture changed from the initial turquoiseto a dark green then to a brown color. After 20 min ofstirring, the reaction mixture was poured into 5% aq NH4OH(360 mL) and extracted with EtOAc (2 × 150 mL). The combinedorganic layer was washed with brine, dried (Na2SO4), filtered,and concentrated under reduced pressure. The residue waspurified by flash chromatography (Teledyne ISCO CombiFlashRf, 0-60% EtOAc in hexanes, RediSep silica gel, 120 g). Concentrationof appropriate fractions provided the product tert-butyl(2S,3R)-6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate (2.87 g, 66%) as apale yellow oil. 1H NMR indicated that the product was a 1.6:1mixture of diastereomers, as determined by integration of themultiplets at 2.74 and 2.84 ppm. 1H NMR (400 MHz, CDCl3): δ =4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.01 (1 H, ddd, J = 9.54,6.27, 3.51 Hz), 2.84 (1 H, ddd, J = 9.41, 7.28, 3.64 Hz), 2.74 (1 H,ddd, J = 10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m), 2.20-2.37 (3 H,m), 1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m).

References: [1]Patent: US2014/87992,2014,A1 .Location in patent: Paragraph 0287-0288.
[2]Patent: WO2014/47369,2014,A1 .Location in patent: Paragraph 00135.
[3]Patent: WO2014/47391,2014,A1 .Location in patent: Paragraph 00144.
[4]Patent: WO2014/47390,2014,A1 .Location in patent: Paragraph 00161; 00162.
[5]Patent: WO2014/47393,2014,A1 .Location in patent: Paragraph 00147.
[6]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 523 - 527.
[7]Synlett,2016,vol. 27,p. 2254 - 2258.

6
[ 1049037-18-4 ]
[ 1401067-00-2 ]
[ 1401067-03-5 ]
[ 1401067-04-6 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate S-1: (2R,3S)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid, and Intermediate S-1E: (2R,3R)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid [0289] [0290] To a cool (0 C.), stirred solution of Intermediate S-1I and Intermediate S-1J (4.54 g, 9.51 mmol) in THF (140 mL) and water (42 mL) were sequentially added hydrogen peroxide (30% in water) (10.3 g, 91 mmol) and LiOH (685.3 mg, 28.6 mmol). The mixture was stirred for 1 hr. At this time the reaction vessel was removed from the cold bath and then stirred for 1.5 hr. To the reaction mixture were added saturated NaHCO3 (45 mL) and saturated Na2SO3 (15 mL), and then the mixture was partially concentrated under reduced pressure. The resulting crude solution was extracted with DCM (3×). The aqueous phase was acidified to pH1-2 with 1N HCl, extracted with DCM (3×) and then EtOAc (1×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide a mixture of Intermediates S-1 and S-1E (3.00 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 2.76-2.84 (1H, m, diastereomer 2), 2.64-2.76 (3H, m), 2.04-2.35 (8H, m), 1.88-2.00 (4H, m), 1.71-1.83 (4H, m), 1.48 (9H, s, diastereomer 1), 1.46 (9H, s, diastereomer 2); 1H NMR showed a 1.7:1 mixture of S-1E:S-1F by integration of the peaks for the t-butyl groups.

References: [1]Patent: US2014/87992,2014,A1 .Location in patent: Paragraph 0287-0290.

7
[ 407-62-5 ]
[ 17016-83-0 ]
[ 1401067-00-2 ]

Yield	Reaction Conditions	Operation in experiment
86%		Intermediate S-1H: (4S)-4-(Propan-2-yl)-3-(5,5,5-trifluoropentanoyl)-1,3-oxazolidin-2-one [0285] 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min. The solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at -78 C. was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride, dissolved in THF (20 mL), was added via cannula over 15 min. The reaction mixture was warmed to 0 C., and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, and the mixture was extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP SiO2 120 g). Concentration of the appropriate fractions provided Intermediate S-1H (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 4.44 (1H, dt, J=8.31, 3.53Hz), 4.30 (1H, t, J=8.69 Hz), 4.23 (1H, dd, J=9.06, 3.02Hz), 2.98-3.08 (2H, m), 2.32-2.44 (1H, m, J=13.91, 7.02, 7.02, 4.03Hz), 2.13-2.25 (2H, m), 1.88-2.00 (2H, m), 0.93 (3H, d, J=7.05 Hz), 0.88 (3H, d, J=6.80 Hz).
86%		To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) inDCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol)dropwise over 5 min and the solution was stirred until all bubbling subsided. Thereaction mixture was concentrated under reduced pressure to give pale yellow oil. To aseparate flask charged with a solution of ( 48)-4-(propan-2-yl)-I ,3-oxazolidin-2-one ( 4.I820 g, 32.4 mmol) in THF (IOO mL) at -78 oc was added n-BuLi (2.5M in hexane, 13.0 mL,32.5 mmol) dropwise via syringe over 5 min. After stirring for IO min, the above acidchloride dissolved in THF (20 mL) was added via cannula over I5 min. The reactionmixture was warmed to 0 C, and was allowed to warm to room temperature as the bathwarmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, and25 then extracted with EtOAc (2x). The combined organics were washed with brine, dried(Na2S04), filtered and concentrated under reduced pressure. The crude material waspurified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solventA/B=hexanes/EtOAc, REDISEP Si02 I20g). Concentration of appropriate fractionsprovided Intermediate S-IB (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCh) 8 ppm 4.44 (I H, dt, J=8.3I, 3.53 Hz), 4.30 (I H, t, J=8.69 Hz), 4.23 (I H, dd, J=9.06,3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (I H, m, J=13.9I, 7.02, 7.02, 4.03 Hz), 2.13-2.25(2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz).
86%		[00141] To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) inDCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol)dropwise over 5 min. The solution was stirred until all bubbling subsided. The reactionmixture was concentrated under reduced pressure to give a pale yellow oil. To a separateflask, charged with a solution of ( 48)-4-(propan-2-yl)-1 ,3-oxazolidin-2-one ( 4.18 g, 32.420 mmol) in THF (100 mL) at -78 oc was added n-BuLi (13.0 mL, 32.5 mmol, 2.5M inhexane) dropwise via syringe over 5 min. After stirring for 1 0 min, the above acidchloride, dissolved in THF (20 mL ), was added via cannula over 15 min. The reactionmixture was warmed to 0 oc and was allowed to warm to room temperature as the bathwarmed and stirred overnight. To the reaction mixture was then added saturated NH4Cl,25 and it was then extracted with EtOAc (2x). The combined organics were washed withbrine, dried (Na2S04), filtered and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography (hexanes/EtOAc) to provideIntermediate S-1G (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCh) 8 4.44 (1H, dt, J=8.31, 3.53 Hz), 4.30 (1 H, t, J=8.69 Hz), 4.23 (1 H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz).

86%		Preparation A-i B: (4S)-4-(Propan-2-yl)-3 -(5,5,5 -trifluoropentanoyl)- 1,3 -oxazolidin-2- one [00143j To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 mm and the solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)- 1 ,3-oxazolidin-2-one (4.18g, 32.4 mmol) in THF (100 mL) at -78 C was added n-BuLi (2.5M in hexane) (13.0 mL,32.5 mmol) dropwise via syringe over 5 mm. After stirring for 10 mm, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 mm. The reaction mixture was warmed to 0 C, and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4C1, andthe mixture was then extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP Si02 120g). Concentration of appropriate fractions provided Preparation A-lB (7.39 g, 86%) as a colorless oil: ‘HNMR (400 MHz, CDC13) ö ppm 4.44 (1 H, dt, J8.31, 3.53 Hz), 4.30 (1 H, t, J8.69 Hz),4.23 (1 H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02,7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz).
86%		Intermediate S-i H: (4S)-4-(Propan-2-yl)-3 -(5,5,5 -trifluoropentanoyl)- 1,3 -oxazolidin-2- one[00146j To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 mm and the solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)- 1 ,3-oxazolidin-2-one (4.18g, 32.4 mmol) in THF (100 mL) at -78 C was added n-BuLi (2.5M in hexane) (13.0 mL,32.5 mmol) dropwise via syringe over 5 mm. After stirring for 10 mm, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 mm. The reaction mixture was warmed to 0 C, and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4C1, andthen extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP Si02 1 20g). Concentration of appropriate fractions provided Intermediate S-1H (7.39 g, 86%) as a colorless oil: ‘H NMR (400 MHz, CDC13)o ppm 4.44 (1 H, dt, J=8.31, 3.53 Hz), 4.30 (1 H, t, J=8.69 Hz), 4.23 (1 H, dd, J9.06,3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25(2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J6.80 Hz).
86%		To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) inDCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol)dropwise over 5 min. The solution was stirred until all bubbling subsided. The reaction5 mixture was concentrated under reduced pressure to give a pale yellow oil. To a separateflask charged with a solution of ( 48)-4-(propan-2-yl)-1 ,3-oxazolidin-2-one ( 4.18 g, 32.4mmol) in THF (100 mL) at -78 oc was added n-BuLi (13.0 mL, 32.5 mmol, 2.5M inhexane) dropwise via syringe over 5 min. After stirring for 1 0 min, the above acidchloride dissolved in THF (20 mL) was added via cannula over 15 min. The reaction10 mixture was warmed to 0 C, and was allowed to warm to room temperature as the bathwarmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, andthen extracted with EtOAc (2x). The combined organics were washed with brine, dried(Na2S04), filtered and concentrated under reduced pressure. The crude material waspurified by silica gel chromatography (hexanes/EtOAc) to provide Intermediate S IA15 (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCh) 8 4.44 (1 H, dt, J=8.31, 3.53Hz), 4.30 (1 H, t, J=8.69 Hz), 4.23 (1 H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93(3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz).

References: [1]Patent: US2014/87992,2014,A1 .Location in patent: Paragraph 0285-0286.
[2]Patent: WO2014/47369,2014,A1 .Location in patent: Paragraph 00134.
[3]Patent: WO2014/47397,2014,A1 .Location in patent: Paragraph 00141.
[4]Patent: WO2014/47391,2014,A1 .Location in patent: Paragraph 00143.
[5]Patent: WO2014/47393,2014,A1 .Location in patent: Paragraph 00146.
[6]Patent: WO2014/47374,2014,A1 .Location in patent: Paragraph 00240.

8
[ 1401067-00-2 ]
[ 93958-21-5 ]
[ 1581734-66-8 ]
[ 1581734-67-9 ]

Yield	Reaction Conditions	Operation in experiment
		Diisopropylamine (6.64 ml, 46.6 mmol) was dissolved in 71.7 mL ofTHF andcooled to -78 C, then n-BuLi (I8.0 mL, 44.9 mmol, 2.5M in hexane) was addeddropwise over a period of 5 minutes. After 5 minutes, the resulting 0.5 M LDA solution20 was kept at 0 C. In a separate flask, lithium chloride (2.62 g, 61.7 mmol) was driedunder high vacuum with heating and cooled under nitrogen. Intermediate S-IB (3.0 g,II.23 mmol ), azeotroped once with toluene, was transferred with I5. 0 mL toluene to theflask containing LiCl, and cooled to -78 C. To this stirring suspension was added LDA(25.83 mL, I2.9I mmol, l.I5 equiv., 0.5M LDA) dropwise via syringe over 5 min. The25 reaction mixture was stirred at -78 oc for I5 minutes, then at 0 oc for I 0 minutes andcooled to -78 C.[00149] In a separate flask, Intermediate S-2A (3.44 g, 20.2I mmol) was dissolved inI5.0 mL toluene underN2 and cooled to -78 C. To this solution was added LDA (46.48mL, 23.24 mmol, l.I5 equiv., 0.5M LDA) dropwise and stirred at -78 oc for 30 minutes, at which time this solution was added via cannula (fast negative pressure, all addedwithin 30 seconds) to the LiCl/oxazolidone solution at -78 C. After 1 minute followingtransfer, solid bis(2-ethylhexanoyloxy)copper (1 0.80 g, 30.9 mmol) was added at -78 C,and the flask was transferred to 40 oc water bath and swirled vigorously for 15 minutes,5 and quenched over 5% NH40H solution (20 mL saturated NH40H and 100 mL water),and extracted with ethyl acetate (2x100 mL). The pooled organic phases were washedwith brine, dried (Na2S04), filtered, concentrated and purified by silica gelchromatography (hexanes/EtOAc) to afford a mixture ofPreparations S-2B and S-2C(1.58g, 32% yield) as an oil: 1H NMR showed this material to be a 1.5:1 mixture of S-10 2B:S-2C, by integration of the t-Bu peaks: 1H NMR of diastereoisomer mixture(400MHz, CDCh) 8 4.53-4.41 (m, 2H), 4.39-4.19 (m, 5H), 4.10-4.01 (m, 1H), 2.89-2.77(m, 2H), 2.47-2.26 (m, 2H), 2.16-1.72 (m, 8H), 1.47 (s, 9H, t-Bu ofS-2B, integrates forrelative intensity of 1.5), 1.46 (s, 9H, t-Bu of S-2C, integrates for relative intensity of 1 ),0.98-0.86 (m, 16H), 0.78-0.64 (m, 2H), 0.56-0.37 (m, 4H), 0.14-0.01 (m, 4H).
		Diisopropylamine (6.64 ml, 46.6 mmol) was dissolved in 71.7 mL of THF and cooled to -78 C, then n-BuLi (18.0 mL, 44.9 mmol, 2.5M in hexane) was added dropwise over a period of 5 minutes. After 5 minutes, the resulting 0.5 M LDA solution was kept at 0 C. [00168] In a separate flask, lithium chloride (2.62 g, 61.7 mmol) was dried under high vacuum with heating and cooled under nitrogen. Intermediate SI A (3.0 g, 11.23 mmol), azeotroped once with toluene, was transferred with 15.0 mL toluene to the flaskcontaining LiCl, and cooled to -78 C. To this stirring suspension was added LDA (25.83 mL, 12.91 mmol, 1.15 equiv., 0.5M LDA) dropwise via syringe over 5 min. The reaction mixture was stirred at -78 C for 15 minutes, then at 0 C for 10 minutes and cooled to -78 C. [00169] In a separate flask, Intermediate S2B (3.44 g, 20.21 mmol) was dissolved in 15.0 mL toluene under N2 and cooled to -78 C. To this solution was added LDA (46.48 mL, 23.24 mmol, 1.15 equiv., 0.5M LDA) dropwise and stirred at -78 C for 30 minutes, at which time this solution was added via cannula (fast negative pressure, all added within 30 seconds) to the LiCl/oxazolidone solution at -78 C. After 1 minute following transfer, solid bis(2-ethylhexanoyloxy)copper (10.80 g, 30.9 mmol) was added at -78 C, and the flask was transferred to 40 C water bath and swirled vigorously for 15 minutes, and quenched over 5% NH4OH solution (20 mL saturated NH4OH and 100 mL water), and extracted with ethyl acetate (2x100 mL). The pooled organic phases were washed with brine, dried (Na2S04), filtered, concentrated and purified by silica gel chromatography (hexanes/EtOAc) to afford a mixture of Intermediate SIC and Intermediate SID (1.58g, 32% yield) as an oil: 1H NMR showed this material to be a 1.5:1 mixture of S1C:S1D, by integration of the t-Bu peaks: 1H NMR of diastereoisomer mixture (400MHz, CDC13) δ 4.53-4.41 (m, 2H), 4.39-4.19 (m, 5H), 4.10-4.01 (m, 1H), 2.89-2.77 (m, 2H), 2.47-2.26 (m, 2H), 2.16-1.72 (m, 8H), 1.47 (s, 9H, t-Bu of I1C, integrates for relative intensity of 1.5), 1.46 (s, 9H, t-Bu of I1D, integrates for relative intensity of 1), 0.98-0.86 (m, 16H), 0.78-0.64 (m, 2H), 0.56-0.37 (m, 4H), 0.14-0.01 (m, 4H).
		Diisopropylamine (6.64 ml, 46.6 mmol) was dissolved in 71.7 mL ofTHF andcooled to -78 C, then n-BuLi (I8.0 mL, 44.9 mmol, 2.5M in hexane) was addedI5 dropwise over a period of 5 minutes. After 5 minutes, the resulting 0.5 M LDA solutionwas kept at 0 C. In a separate flask, lithium chloride (2.62 g, 61.7 mmol) was dried under highvacuum with heating and cooled under nitrogen. Intermediate SIA (3.0 g, I1.23 mmol),azeotroped once with toluene, was transferred with I5.0 mL toluene to the flask20 containing LiCl, and cooled to -78 C. To this stirring suspension was added LDA (25.83mL, I2.9I mmol, l.I5 equiv., 0.5M LDA) dropwise via syringe over 5 min. The reactionmixture was stirred at -78 oc for I5 minutes, then at 0 oc for I 0 minutes and cooled to -78oc. In a separate flask, Intermediate SIB (3.44 g, 20.2I mmol) was dissolved in25 I5.0 mL toluene underN2 and cooled to -78 C. To this solution was added LDA (46.48mL, 23.24 mmol, l.I5 equiv., 0.5M LDA) dropwise and stirred at -78 oc for 30 minutes,at which time this solution was added via cannula (fast negative pressure, all addedwithin 30 seconds) to the LiCl/oxazolidone solution at -78 C. After I minute followingtransfer, solid bis(2-ethylhexanoyloxy)copper (I 0.80 g, 30.9 mmol) was added at -78 C, and the flask was transferred to 40 oc water bath and swirled vigorously for I5 minutes,and quenched over 5% NH40H solution (20 mL saturated NH40H and IOO mL water),and extracted with ethyl acetate (2xiOO mL). The pooled organic phases were washedwith brine, dried (Na2S04), filtered, concentrated and purified by silica gel5 chromatography (hexanes/EtOAc) to afford a mixture of Intermediate SIC andIntermediate SID (1.58g, 32% yield) as an oil. 1H NMR showed this material to be aI.5:I mixture ofSIC:SID, by integration of the t-Bu peaks: 1H NMR of diastereoisomermixture (400MHz, CDCh) 8 4.53-4.4I (m, 2H), 4.39-4.19 (m, 5H), 4.I0-4.0I (m, IH),2.89-2.77 (m, 2H), 2.47-2.26 (m, 2H), 2.16-1.72 (m, 8H), I.47 (s, 9H, t-Bu of SIC,I 0 integrates for relative intensity of I.5), I.46 (s, 9H, t-Bu of SID, integrates for relativeintensity of I), 0.98-0.86 (m, I6H), 0.78-0.64 (m, 2H), 0.56-0.37 (m, 4H), 0.14-0.0I (m,4H).

General procedure: A 0.5 M solution of LDA was prepared by the addition of a solutionof 2.5 M n-BuLi in hexanes (14.7 mL, 36.8 mmol) to a cold(-78 C) solution of diisopropylamine (5.3 mL, 37.2 mmol) inTHF (59 mL) under N2. The solution was stirred at 0 C for 15min. A solution of <strong>[1401067-00-2](S)-4-isopropyl-3-(5,5,5-trifluoropentanoyl)oxazolidin-2-one</strong> (2.45 g, 9.2 mmol) in toluene (15.3 mL)was added with stirring to dry LiCl (1.96 g, 46.2 mmol). Themixture was cooled to -78 C, and the freshly prepared 0.5 Msolution of LDA (21.0 mL, 10.5 mmol) was added. The reactionmixture was stirred at -78 C for 10 min, at 0 C for 10 min, andcooled to -78 C. Meanwhile, the freshly prepared 0.5 M solutionof LDA (37.0 mL, 18.5 mmol) was added to a cold (-78 C)solution of tert-butyl 5,5,5-trifluoropentanoate (3.41 g, 16.1mmol) in toluene (15.3 mL). After 25 min of stirring at -78 C, this reaction mixture was transferred via cannula into the cold(-78 C) LiCl/enolate solution. After an additional 5 min of stirringat -78 C, solid powdered bis(2-ethylhexanoyloxy)copper(9.02 g, 25.8 mmol) was rapidly added to the reaction vesselthrough a funnel, and the flask was rapidly recapped with aseptum. The vessel was immediately removed from the coldbath and immersed into a warm (40 C) water bath with rapidswirling. The reaction mixture changed from the initial turquoiseto a dark green then to a brown color. After 20 min ofstirring, the reaction mixture was poured into 5% aq NH4OH(360 mL) and extracted with EtOAc (2 × 150 mL). The combinedorganic layer was washed with brine, dried (Na2SO4), filtered,and concentrated under reduced pressure. The residue waspurified by flash chromatography (Teledyne ISCO CombiFlashRf, 0-60% EtOAc in hexanes, RediSep silica gel, 120 g). Concentrationof appropriate fractions provided the product tert-butyl(2S,3R)-6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate (2.87 g, 66%) as apale yellow oil. 1H NMR indicated that the product was a 1.6:1mixture of diastereomers, as determined by integration of themultiplets at 2.74 and 2.84 ppm. 1H NMR (400 MHz, CDCl3): δ =4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.01 (1 H, ddd, J = 9.54,6.27, 3.51 Hz), 2.84 (1 H, ddd, J = 9.41, 7.28, 3.64 Hz), 2.74 (1 H,ddd, J = 10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m), 2.20-2.37 (3 H,m), 1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m).

References: [1]Patent: WO2014/47369,2014,A1 .Location in patent: Paragraph 00148; 00149.
[2]Patent: WO2014/47390,2014,A1 .Location in patent: Paragraph 00166-00168.
[3]Patent: WO2014/47374,2014,A1 .Location in patent: Paragraph 00242; 00243; 00244.
[4]Synlett,2016,vol. 27,p. 2254 - 2258.

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Yield	Reaction Conditions	Operation in experiment
		[00142] Diisopropylamine (3.01 mL, 21.11 mmol) was dissolved in 28.8 mL ofTHF10 and cooled to -78 C. nBuLi (1.6 Min hexane) (13.10 mL, 20.95 mmol) was addeddropwise over a period of 5 minutes. After 5 minutes, the ~0.5 M LDA solution was keptat 0 C. In a separate flask, lithium chloride (1.221 g, 28.8 mmol) was dried in an ovenovernight, and then under high vacuum while heating with a heat gun and then cooledunder nitrogen. Intermediate S-1G (1.4 g, 5.24 mmol), having been azeotroped once with15 toluene, was transferred (under nitrogen) with toluene (10 mL) to the flask containingLiCl, and then cooled to -78 C. Intermediate S-1F (2.077 g, 9.43 mmol), having beenazeotroped once with toluene, was dissolved in toluene (10 mL) and cooled to -78 C.The solution ofLDA (13.1 mL of a 0.5 M LDA solution) was added dropwise to theLiCl/oxazolidinone (1.4 g, 5.24 mmol) solution at -78 oc over a period of 5 minutes. The20 reaction mixture was stirred at -78 oc for 15 minutes, and then at 0 oc for 10 minutes andthen cooled to -78 C. A solution ofLDA (23.6 mL of a 0.5 M LDA solution) was addeddropwise to the solution oflntermediate S-1F and stirred at -78 oc for 30 minutes. Thissolution was then added via cannula (fast negative pressure, all added within 30 seconds)to the LiCl/oxazolidone solution at -78 C. After 1 minute following the transfer, solid25 bis((2-ethylhexanoyl)oxy)copper (5.50 g, 15.72 mmol), having been dried in an ovenovernight, was added at -78 C, and the flask was transferred to a 40 oc water bath andswirled for 15 minutes. The reaction was quenched with 5% NH40H solution (30 mLsaturated NH40H in 150 mL water), and extracted 2x100 mL with ethyl acetate. The combined extracts were washed with brine, dried and concentrated. The crude mixturewas purified by silica gel chromatography ( 40g column, EtOAc/hexane, 0-35%) to give a1.3:1mixture oflntermediates S-IH and S-II (1.196 g, 47%).
		General procedure: A 0.5 M solution of LDA was prepared by the addition of a solutionof 2.5 M n-BuLi in hexanes (14.7 mL, 36.8 mmol) to a cold(-78 C) solution of diisopropylamine (5.3 mL, 37.2 mmol) inTHF (59 mL) under N2. The solution was stirred at 0 C for 15min. A solution of <strong>[1401067-00-2](S)-4-isopropyl-3-(5,5,5-trifluoropentanoyl)oxazolidin-2-one</strong> (2.45 g, 9.2 mmol) in toluene (15.3 mL)was added with stirring to dry LiCl (1.96 g, 46.2 mmol). Themixture was cooled to -78 C, and the freshly prepared 0.5 Msolution of LDA (21.0 mL, 10.5 mmol) was added. The reactionmixture was stirred at -78 C for 10 min, at 0 C for 10 min, andcooled to -78 C. Meanwhile, the freshly prepared 0.5 M solutionof LDA (37.0 mL, 18.5 mmol) was added to a cold (-78 C)solution of tert-butyl 5,5,5-trifluoropentanoate (3.41 g, 16.1mmol) in toluene (15.3 mL). After 25 min of stirring at -78 C, this reaction mixture was transferred via cannula into the cold(-78 C) LiCl/enolate solution. After an additional 5 min of stirringat -78 C, solid powdered bis(2-ethylhexanoyloxy)copper(9.02 g, 25.8 mmol) was rapidly added to the reaction vesselthrough a funnel, and the flask was rapidly recapped with aseptum. The vessel was immediately removed from the coldbath and immersed into a warm (40 C) water bath with rapidswirling. The reaction mixture changed from the initial turquoiseto a dark green then to a brown color. After 20 min ofstirring, the reaction mixture was poured into 5% aq NH4OH(360 mL) and extracted with EtOAc (2 × 150 mL). The combinedorganic layer was washed with brine, dried (Na2SO4), filtered,and concentrated under reduced pressure. The residue waspurified by flash chromatography (Teledyne ISCO CombiFlashRf, 0-60% EtOAc in hexanes, RediSep silica gel, 120 g). Concentrationof appropriate fractions provided the product tert-butyl(2S,3R)-6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate (2.87 g, 66%) as apale yellow oil. 1H NMR indicated that the product was a 1.6:1mixture of diastereomers, as determined by integration of themultiplets at 2.74 and 2.84 ppm. 1H NMR (400 MHz, CDCl3): δ =4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.01 (1 H, ddd, J = 9.54,6.27, 3.51 Hz), 2.84 (1 H, ddd, J = 9.41, 7.28, 3.64 Hz), 2.74 (1 H,ddd, J = 10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m), 2.20-2.37 (3 H,m), 1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m).

References: [1]Patent: WO2014/47397,2014,A1 .Location in patent: Paragraph 00142.
[2]Synlett,2016,vol. 27,p. 2254 - 2258.

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References: [1]Patent: WO2014/47397,2014,A1 .

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