The synthesis of the 2,3-difluorobutan-1,4-diol diastereomers

Transcription

1 Supporting Information The synthesis of the,3-difluorobutan-,4-diol diastereomers for Robert Szpera, Nadia Kovalenko, Kalaiselvi Natarajan, Nina Paillard and Bruno Linclau* Address: Chemistry, University of Southampton, ighfield, Southampton S7 BJ, United Kingdom Bruno Linclau - bruno.linclau@soton.ac.uk * Corresponding author Experimental part and NMR spectra S

2 Table of Contents Experimental Section... S5. The synthesis of anti-5... S5.. (±)-syn-,4-bis(benzyloxy)-3-fluorobutan--ol ((±)-syn-3)... S5.. anti-,4-bis(benzyloxy)-,3-difluorobutane (anti-4)... S6..3,-Dimethyl-,3-dioxep-5-ene (6) []:... S6..4 4,4-Dimethyl-3,5,8-trioxabicyclo[5..]octane (7) [3]:... S7..5 syn--luoro-3,4--isopropylidene butane-,3,4-triol ((±)-9):... S (,-Difluoroethyl)-,-dimethyl-,3-dioxolane ((±)-):... S8..7 (±)-6-luoro-,-dimethyl-,3-dioxepan-5-ol ((±)-8):... S9..8 Deoxofluorination of (±)-8... S. Synthesis of (±)-syn-5... S.. (E)-But--ene-,4-diol (trans-) [7]:... S.. (E)-,4-Dibenzyloxybut--ene (trans-4) [7]:... S..3 (±)-trans-,-bis((benzyloxy)methyl)oxirane ((±)-trans-) [7]:... S3..4 (±)-Anti-,4-bis(benzyloxy)-3-fluorobutan--ol ((±)-anti-3):... S (±)-Syn-,4-bis(benzyloxy)-,3-difluorobutane ((±)-syn-4):... S (±)-Syn-,3-difluorobutane-,4-diol ((±)-syn-5):... S5.3 References... S5 Copies of Spectra... S6. syn-,4-bis(benzyloxy)-3-fluorobutan--ol ((±)-syn-3)... S6.. NMR (4 Mz, CDCl 3 )... S6.. 3 C NMR ( Mz, CDCl 3 )... S C DEPT-35 NMR 3 C NMR ( Mz, CDCl 3 )... S NMR (376 Mz, CDCl 3 )... S9..5 Diastereoselectivity of the epoxide opening... S.,-Dimethyl-,3-dioxep-5-ene (6)... S.. NMR (4 Mz, CDCl 3 )... S S

3 .. 3 C NMR ( Mz, CDCl 3 )... S3.3 4,4-Dimethyl-3,5,8-trioxabicyclo[5..]octane (7)... S4.3. NMR (4 Mz, CDCl 3 )... S C NMR ( Mz, CDCl 3 )... S5.4 syn--luoro-3,4--isopropylidene butane-,3,4-triol ((±)-9)... S6.4. NMR (4 Mz, CDCl 3 )... S6.4. {} NMR (5 Mz, CDCl 3 )(D exchange experiment)... S7.4.3 { 9 }{} NMR (5 Mz, CDCl 3 )(D exchange experiment)... S NMR of ±9 (47 Mz, CDCl 3 )... S C NMR ( Mz, CDCl 3 )... S3.5 4-(,-Difluoroethyl)-,-dimethyl-,3-dioxolane ((±)-)... S3.5. NMR (5 Mz, CDCl 3 )... S3.5. { 9 } NMR (5 Mz, CDCl 3 )... S NMR (47 Mz, CDCl 3 )... S { } (47 Mz, CDCl 3 )... S C NMR ( Mz, CDCl 3 )... S DEPT-35 ( Mz, CDCl 3 )... S luoro-,-dimethyl-,3-dioxepan-5-ol ((±)-8)... S37.6. NMR (4 Mz, CDCl 3 )... S C NMR ( Mz, CDCl 3 )... S NMR (376 Mz, CDCl 3 )... S39.7 Sulfonate byproduct (±)-... S4.7. NMR (4 Mz, CDCl 3 )... S C NMR ( Mz, CDCl 3 )... S NMR (376 Mz, CDCl 3 )... S4.8 meso-5,6-difluoro-,-dimethyl-,3-dioxepane (meso-)... S43.8. NMR (4 Mz, CDCl 3 )... S NMR (376 Mz, CDCl 3 )... S C NMR ( Mz, CDCl 3 )... S45 S3

4 .9 anti-,3-difluorobutane-,4-diol (anti-5)... S46.9. NMR (4 Mz, CDCl 3 )... S NMR (376 Mz, CDCl 3 )... S47. (E)-But--ene-,4-diol (trans-)... S48.. NMR (4 Mz, CDCl 3 )... S C NMR ( Mz, CDCl 3 )... S49. (E)-,4-Dibenzyloxybut--ene (trans-4)... S5.. NMR (4 Mz, CDCl 3 )... S5.. 3 C NMR ( Mz, CDCl 3 )... S5. trans-,-bis((benzyloxy)methyl)oxirane ((±)-trans-)... S5.. NMR (4 Mz, CDCl 3 )... S5.. 3 C NMR ( Mz, CDCl 3 )... S53.3 anti-,4-bis(benzyloxy)-3-fluorobutan--ol ((±)-anti-3)... S54.3. NMR (5 Mz, CDCl 3 )... S C NMR ( Mz, CDCl 3 )... S NMR (376 Mz, CDCl 3 )... S Diastereoselectivity of the epoxide opening... S58.4 syn-,4-bis(benzyloxy)-,3-difluorobutane ((±)-syn-4)... S6.4. NMR (5 Mz, CDCl 3 )... S C NMR ( Mz, CDCl 3 )... S NMR (376 Mz, CDCl 3 )... S6.4.4 Diastereoselectivity of the DAST reaction... S64.5 syn-,3-difluorobutane-,4-diol ((±)-syn-5)... S66.5. { 9 } NMR (5 Mz, CDCl 3 )... S C NMR ( Mz, CDCl 3 )... S NMR (376 Mz, CDCl 3 )... S68 S4

5 Experimental section. The synthesis of anti-5.. (±)-syn-,4-bis(benzyloxy)-3-fluorobutan--ol ((±)-syn-3) Et 3 N 3 or Bn Bn TBA/K cis- 6 3 (±)-syn a) pening with Et 3 N 3: A mixture of epoxide cis- (4.5 g, 86. mmol) and Et 3 N 3 (37.5 ml, 3 mmol) were heated at 3 C under argon for 6 h. The reaction mixture was diluted with ice cold water (3 ml), and then quenched with NaC 3 solution (3 ml). The mixture was extracted with Et, then the combined extracts were dried over MgS 4 and concentrated in vacuo to afford the crude product as a dark brown oil (6. g, 99%). b) pening with TBA/K : TBA 3 (5.3 g, 6.6 mmol) and K (.7 g,. mmol) were added sequentially to cis- (3.4 g,. mmol) and the resulting mixture was heated at 5 C for h. The reaction mixture was allowed to cool to rt and was diluted with Et and quenched with sat. NaC 3. The organic phase was separated and the aqueous phase was extracted with Et. The combined organic phases were dried over MgS 4 and filtered to give a brown oil. The crude was purified by column chromatography (% ethyl acetate/petroleum ether) to give (±)-syn-3 as a pale yellow oil (.5 g, 75%). NMR (4 Mz, CDCl 3 ) δ -7.8 (, m, Ar), 4.73 (, ddt, J = 47., 5.5, 3.4 z, -3), (4, m, -5 and -6), 4.4 (, dm, J =.3 z, -), 3.8 (, ddd, J = 3.,.4, 3.7 z, -4 or -4 ), (, ddd, J = 4.3,.4, 5.4 z, -4 or -4 ), 3.63 (, ddd, J = 9.8, 5.3,. z, - or - ), (, ddd, J = 9.8, 6.4,. z, - or - ),.6 (, dd, J = 4.7,.7 z) ppm; 3 C NMR ( Mz, CDCl 3 ), δ 37.7 (C Ar ), 37.5 (C Ar ), 8.4 (C Ar ), 7.8 (C Ar ), 7.7 (C Ar ), 9.6 (d, J = 76. z, C-3), 73.7 (C-5 or C-6), 73.5 (C-5 or C-6), 7. (d, J = 5. z, C-), 7. (d, J = 9.8 z, C-), 69.6 (d, J =.7 z, C-4) ppm; 9 NMR (376 Mz, CDCl 3 ) δ -4.4 (, dq, J = 46.8, 3. z, -3) ppm. Data matches literature []. S5

6 .. anti-,4-bis(benzyloxy)-,3-difluorobutane (anti-4) 6 3 (±)-syn DAST, py (7%) 3 anti-4 To a solution of fluorohydrin (±)-syn-3 (.6 g, 34.8 mmol) in dry toluene (5 ml) under argon, DAST (6. ml, 47 mmol) was added dropwise. After complete addition, the mixture was stirred at room temperature for 5 min, and then pyridine (7.3 ml, 9 mmol) was added. The reaction mixture was heated at 7 C for 6 h behind a blast shield, and was then poured into ice cold NaC 3 solution ( ml). The mixture was extracted with Et (3 ml), and the combined extracts were washed with NaC 3 solution (3 ml), brine (3 ml), dried over MgS 4, and concentrated in vacuo to afford a dark oil. Purification by flash chromatography ( 8% ethyl acetate in petrol) afforded the desired product as a yellow crystalline solid (7.57 g, 7%). NMR (4Mz, CDCl 3 ): δ 7.9 (, m, Ar-), 4.95 (, m, -), 4.6 (4, s, -3), (4, m, -) ppm. 3 C NMR ( Mz, CDCl 3 ): δ 37.6 (C Ar ), 8.4 (C Ar ), 7.8 (C Ar ), 7.7 (C Ar ), 89.5 (C, dd, J = 77.5, 8.6 z, C-), 73.6 (C, C-3), 68. (C, m, C-) ppm. 9 NMR (377 Mz, CDCl 3 ): δ -99. (, m, C). Data matches literature []...3,-Dimethyl-,3-dioxep-5-ene (6) []: cis-,-dmp, p-tsa R.T., 3 h (7%) To a solution of cis-but--ene-,4-diol (, 9.3 ml, 3 mmol) in DCM, p-tsa (.8 g, 6. mmol) was added under argon at room temperature followed by,-dimethoxypropane (7.9 ml, 7 mmol). The reaction mixture was allowed to stir for 3 h. After the completion of the reaction, the reaction mixture was quenched with sat. NaC 3 solution (5 ml) and extracted with DCM ( 5 ml). The combined organic layers were washed with brine (5 ml), dried over MgS 4 and the solvent was very slowly removed in vacuo to yield 6 as colourless oil (.5 g, 7%). The crude product was directly taken to the next step without purification. R f =.5 (EtAc/hexane %); NMR (4 Mz, S6

7 CDCl 3 ) δ 5.66 (, t, J =.6 z, -), 4.5 (4,, J =.6 z, -),.43 (6, s, -4) ppm; 3 C NMR ( Mz, CDCl 3 ): δ 9.5 (C, C-),. (C, C-3), 6.4 (C, C-), 4. (C, C-4) ppm. Data matches literature [3]...4 4,4-Dimethyl-3,5,8-trioxabicyclo[5..]octane (7) [3]: 6 m-cpba, Na P 4 DCM, R.T., 8 h (85%) To a solution of 6 (. g, 78 mmol) in DCM (4 ml) m-cpba (7. g, 56 mmol) and finely powdered Na P 4 (.7 g, 9 mmol) were added under argon. The reaction mixture was stirred at room temperature for 8 h, and was then chilled to C. The precipitate was removed by filtration through Celite, and the filtrate was washed sequentially with sat. NaC 3 (5 ml), sat. Na S 3 (5 ml), and then brine. The organic phase was then dried over MgS 4 and concentrated in vacuo. The crude product was purified by column chromatography (EtAc/hexane 5% to 3%) to afford 7 as a pale yellow oil (9.6 g, 85%). R f =. (EtAc/hexane %); NMR (4 Mz, CDCl 3 ): δ 4.6- (4, m, - and - ), (, m, -),.38 (3, s, -4 or -5),.3 (3, s, -4 or -5) ppm; 3 C NMR ( Mz, CDCl 3 ): δ. (C, C-3), 6. (C, C-), 56.4 (C, C-), 4.7 (C, C-4 or C-5), 3.4 (C, C-4 or C-5) ppm; Data matches literature [4]...5 syn--luoro-3,4--isopropylidene butane-,3,4-triol ((±)-9): Et 3 N (6%) (±)-9 Epoxide 7 (. g, 6.9 mmol) and neat Et 3 N 3 (3.4 ml,.8 mmol) were added to a flask under argon and heated at 6 C for 4 h. The reaction mixture was slowly added to ice cold sat. NaC 3. The aqueous phase was extracted with Et, and the combined organic phases were washed with saturated aqueous NaC 3 solution, brine, dried over anhydrous MgS 4, and concentrated in vacuo at room temperature to S7

8 afford a yellow oil which was purified by column chromatography ( 5% acetone in DCM) to afford (±)-9 as a colourless oil (.7 g, 6%). IR (neat): v max (cm - ) 344 (br), 988 (w), 36 (w), 373 (m), 5 (m), 56. NMR (4 Mz, CDCl 3 ): δ 4.5 (, ddt, J = 48., 5.6, 3.8 z, -), 4.3 (, dtd, J =., 6.8, 4.3 z, -3), 4. (, ddd, J = 8.4, 6.9,.4 z, -4 or 4 ), (, dd, J = 8.4, 6.8 z, -4 or 4 ), 3.86 (, m, - and -. This multiplet simplifies to: 3.87 (, dd, J =.7, 5.5 z), and (, dd, J =.6 and 3.7 z) upon 9 and decoupling, spectra taken on 5 Mz),.4 (, dd, J = 7., 5.6 z, ),.45 (3, s, -6 or -7),.39 (3, s, -6 or -7) ppm; 3 C NMR ( Mz, CDCl 3 ): δ. (C, C-5), 9. (C, d, J = 77.5 z C-), 74.9 (C, d, J = 9.8 z, C-3), 64.9 (C, d, J = 5.9 z, C-4), 6.5 (C, d, J =.7, C-), 6. (C, C-6 or C-7), 5.4 (C, C-6 or C-7) ppm; 9 NMR (47 Mz, CDCl 3 ): δ -.3 (, m, -) ppm. These data qualitatively match literature data (all signals were described as multiplet, and no J-values described in 3 C spectrum) [5] (,-Difluoroethyl)-,-dimethyl-,3-dioxolane ((±)-): DAST, pyridine (4%) (±)-9 (±)- To a solution of (±)-9 (. g,.8 mmol) in dry toluene (4 ml) under argon, DAST (.6 ml,.97 mmol) was added dropwise. The solution was stirred for 5 minutes, and then dry pyridine (.3 ml, mmol) was added. The reaction mixture was stirred for 7 h at room temperature, and then further DAST (.3 ml,.98 mmol) was added. Stirring was continued for 3 more hours, and then the reaction mixture was quenched by pouring into sat. NaC 3 solution (7 ml). The mixture was extracted with Et (3 7 ml), and the combined organic layers were washed with sat. NaC 3 ( ml), brine ( ml), dried over MgS 4, and concentrated in vacuo at rt to afford a crude yellow oil (. g). The crude was purified by column chromatography ( 3% Et in pentane) to afford (±)- as a clear oil (.9 g, 4%). IR (neat): v max (cm - ) 99 (w) (939 (w) 895 (w) 457 (w) 373 (m) 8 (m) 7 (s). NMR (5 Mz, CDCl 3 ): δ (3, m, -, -, -), 4.3 (, dtd, J =.5, 6.7, 4. z, -3, simplifies to td, J = 6.6, 3.9 z upon fluorine decoupling), 4. (, dddd, J = 8.5, 6.9,.4,.8 z, -4 or -4, simplifies to dd, J = 8.6, 6.8 z upon fluorine decoupling), (, dd, J = 8.5, 6.6 z, -4 or -4 ),.44 (3, q appears as br d, J =.6 z, -6 or -7),.38 (3, q, J =.6 z, -6 or -7) ppm. 3 C NMR ( Mz, CDCl 3 ): δ.3 (C, C-5), 9. (C, dd, J = 8., 9. z, C-), S8

9 8. (C, dd, J = 7.4, 4. z, C-), 73.8 (C, dd, J =.5, 7.3 z, C-3), 64.7 (C, d, J = 5.9 z, C-4), 6. (C, C-6 or 7), 5.3 (C, C-6 or 7) ppm. { } 9 NMR (47 Mz, CDCl 3 ): δ -3. (, d, J = 4.7 z, -), -3.3 (, d, J = 5. z, -) ppm. MS (ESI +, MeCN): 67. (M+) (±)-6-luoro-,-dimethyl-,3-dioxepan-5-ol ((±)-8): Reaction with Bu 4 N 3 /K : To the mixture of 7 (.8 g,.5 mmol) and Bu 4 N 3 (.56 g,.873 mmol), K (. g,.5 mmol) was added at rt under argon. The reaction mixture was allowed to stir for hours at 5 C. After completion of the reaction, the reaction mixture was quenched with sat. NaC 3 ( ml) and extracted with DCM ( ml). Then the organic layer was washed with brine, dried over anhydrous MgS 4 and concentrated in vacuo. The crude obtained was purified by column chromatography (acetone/dcm % to 4%) to afford fluorohydrin (±)-8 as colourless oil (. g, 56%). Reaction with TBA/K : TBA 3 (5.6 g, 49.6 mmol) and K (4.6 g, 58.3 mmol) were added sequentially to 7 (4. g, 9. mmol) under argon and the resulting mixture was heated at 5 C for h. The dark brown mixture was then cooled to room temperature, diluted with Et ( ml) and water ( ml) and slowly quenched with sat. NaC 3 ( ml). The aqueous layer was extracted with Et ( ml) and the combined organic layers were washed with brine, dried over MgS 4 and filtered through silica plug to remove the brown colour. The solvent was removed in vacuo and the crude was purified by column chromatography (5% acetone/dcm) to give fluorohydrin (±)-8 as pale yellow oil (3. g, 64%). R f =.55 (acetone/dcm %); NMR (4 Mz, CDCl 3 ) δ 4.4 (, dm, J = 44. z, -5), (, ddd, J =.7,.,.5 z, -), (3, m, -4, -4 and -), (, ddd, J =.7, 4.5,. z, - ),.6 (, d, J = 8. z, ),.38 (3, s, -6 or -7),.36 (3, s, -6 or -7) ppm; 3 C NMR ( Mz, CDCl 3 ) δ.8 (C-3), 9.7 (d, J = 76. z, C-5), 7. (d, J = 8.6 z, C-), 6.3 (C-), 59.3 (d, J =.5 z, C-4), 4.9 (C-6 or C-7), 3.9 (C-6 or C-7) ppm; 9 NMR (376 Mz, CDCl 3 ) δ (m, ) ppm. RMS (ESI + ) (M+Na) + calcd: 87.74, found Data matches literature [6]. Bu 4 N 3, K (56%) or TBA, K (64%) 7 (±) S9

10 ..8 Deoxofluorination of (±)-8 - with Pyluor, which gives 6-fluoro-5-(-pyridylsulfonyl)-,-dimethyl-,3-dioxepan-5-ol ((±)-): Pyluor, DBU N 5 S (44%) 8 6 (±)-8 9 (±)- To a solution of fluorohydrin (±)-8 (. g,. mmol) in toluene (. ml), Pyluor (. g,.34 mmol) and DBU (.9 g,.44 mmol) were added and stirred at room temperature for 7 h. The reaction mixture was cooled to C and quenched with sat. NaC 3 followed by extraction with Et. The organic layer was washed with brine and concentrated in vacuo. Column chromatography was performed (pentane/et 5 4%) to give the sulfonate (±)- (.9 g, 44%). IR (neat): v max (cm - ) 94 (m), 58 (w), 454 (w), 49 (w), 37 (s), 778 (s); NMR (4 Mz, CDCl 3 ) δ (, ddd, J = 4.7,.6,.9 z, -), 8.6 (, dt, J = 7.8,. z, -4), 7.97 (, td, J = 7.7,.7 z, - 3), 7.59 (, ddd, J = 7.6, 4.7,. z, -), 5. (, dtdd, J = 3., 4.9,.5,.6 z, -7 or -7'), 4.6 (, dtdd, J = 44., 6.,.3,.7 z, - ), 4. (, dt, J = 3.3,.7 z, -7 or -7 ), - (3, m, -6, - and - ),.33 (6, x s, -9 and -) ppm; 3 C NMR ( Mz, CDCl 3 ) δ 54.9 (C-5), 5.3 (C-), 38. (C-3), 7.8 (C-), 3. (C-4),. (C-8), 89.8 (d, J = 78.3 z, C-), 8.9 (d, J = 9.4 z, C-7), 59. (m, C-6 and C-), 4. (C-9 or C-), 4. (C-9 or C-); 9 NMR (376 Mz, CDCl 3 ) δ 93.7 (, ddd J = 44., 4.3, 8.7 z, -) ppm. RMS (ESI +, Me) (M+Na) + calcd: 38.65, found S

11 - with DAST, including deprotection, to give anti-,3-difluorobutane-,4-diol (anti-5): ±8 DAST meso- Cl, Et (3%) anti-5 To solution of fluorohydrin (±)-8 (.9 g, 7.5 mmol) in toluene (3 ml), DAST (.5 ml, 9.43 mmol) was added dropwise and the mixture was stirred for 5 min at rt. Pyridine (.47 ml, 8.3 mmol) was added and the mixture was heated at 6 C for 3 h behind a blast shield. The reaction mixture was cooled to rt and M Cl in Et (6.3 ml, 3.63 mmol) was added carefully and stirred at rt for h. Et was removed in vacuo and column chromatography was performed directly (3-5% acetone/petroleum ether) to give diol anti-5 as an off-white solid (.76 g, 3%). NMR (4 Mz, acetone-d 6 ) δ 4.7 (, m, -), 4.9 (, t, J = 5.8 z, ), 3.8 (4, m, -) ppm; 9 NMR (376 Mz, acetone-d 6 ) δ -.4 (m, -) ppm. RMS (ESI+): (M+Na) + Calcd , ound Data matches literature []. An analytical sample of meso- was isolated: NMR (4 Mz, CDCl 3 ) δ 4.7 (, m, -), 4.5 (, m, - or -'), 3.66 (, m, - or -'),.39 (3, s, -4 or -5),.33 (3, s, -4 or -5) ppm; 3 C NMR ( Mz, CDCl 3 ) δ.9 (C-3), 88.3 (app dd, J = 83.4, 7.6 z, C-), 58. (m, C-), 4.7 (C-4 or C-5), 4. (C-4 or C-5) ppm; 9 NMR (376 Mz, CDCl 3 ) δ -8.5 (m, -) ppm.. Synthesis of (±)-syn-5.. (E)-But--ene-,4-diol (trans-) [7]: LiAl 4 (79 %) 3 trans- S

12 To a suspension of LiAl 4 (5.9 g, mmol) in T (35 ml) at C under argon, was added a solution of 3 (. g, 6.6 mmol) in T ( ml). The resulting mixture was stirred at room temperature for 36 h. The reaction mixture was then cooled to C, and the excess LiAl 4 was quenched via sequential addition of (6 ml), 3 M aqueous Na (6 ml) and finally more (6 ml). MgS 4 was added, and stirring was continued at room temperature for a further 3 min. The reaction mixture was filtered through celite, and the solid was washed with ethyl acetate (4 ml). The filtrate was concentrated in vacuo to afford a crude colourless oil (9.484 g). Purification via column chromatography (5 % EtAc in hexane) afforded trans- as a colourless oil (8.8 g, 79%). IR (neat): v max 38 (br), 93 (m), 854 (m), 656 (w), 47 (m), 8 (s), 97 (s) cm -. NMR (4Mz, CDCl 3 ): δ 5.89 (, t, J =.5 z, C), 4.7 (4, s, C ),.93 (, br s, ) ppm. 3 C NMR ( Mz, CDCl 3 ): δ 3.5 (C, C), 6.8 (C, C ) ppm. Data matches literature [7]... (E)-,4-Dibenzyloxybut--ene (trans-4) [7]: trans- Na, T; BnBr (93%) trans-4 Na (6% in dispersion oil; g,.4 mmol) was added to a flask under argon and the mineral oil was removed by washing with hexane (3 3 ml). A solution of trans- (8.8 g, 9.5 mmol) in T (3 ml) was added to the Na at C under argon, and the resulting mixture was stirred at reflux for 3.5 h. The reaction mixture was allowed to cool, benzyl bromide (6.33 ml,.4 mmol) was added, and stirring was continued at reflux for a further 3.5 h. The mixture was then cooled to room temperature and quenched with water (44 ml). The phases were separated and the aqueous was extracted with Et ( 44 ml). The combined organic phases were washed sequentially with saturated aqueous N4Cl (44 ml), water (44 ml), and brine (44 ml), then dried over MgS4, and concentrated to afford a straw coloured crude oil ( g). The crude was purified by column chromatography ( % EtAc in petroleum ether) to afford trans-4 as a pale yellow oil (.976 g, 93%). IR (neat): v max 39 (w), 85 (m), 496 (m), (s), 696 (s) cm -. NMR (4Mz, CDCl 3 ): δ 7.3 (, m, Ar-), 5.9 (, m, CC ), (4, s, C Bn), 4.9 (4, m, C C) ppm. 3 C NMR ( Mz, CDCl 3 ): δ 38. (C Ar ), 9.5 (C, CC ), 8.3 (C Ar ), 7.7 (C Ar ), 7.6 (C Ar ), 7. (C, C Bn), 7. (C, C C) ppm. Data matches literature [7]. S

13 ..3 (±)-trans-,-bis((benzyloxy)methyl)oxirane ((±)-trans-) [7]: Bn m-cpba Bn (74%) trans-4 (±)-trans- m-cpba ( 77, 9.5 g, 4.4 mmol) was added portionwise to a solution of trans-4 (9.39 g, 35. mmol) in DCM ( ml) at C. The resulting mixture was allowed to warm to room temperature and stirred for 6 hours. The mixture was cooled to C and the precipitate removed by filtration though celite, and the solid was washed with ice cold DCM ( ml). The filtrate was washed with NaC 3 solution ( ml), Na S 4 solution ( ml), and finally brine ( ml). The organic phase was then dried over MgS 4 and concentrated in vacuo to afford the epoxide (±)-trans- as a yellow oil (7.3 g, 74%), which can be used directly in the next step. Purification by column chromatography ( 5% EtAc in petroleum ether) is possible. An experiment starting from.976 g of trans-4 thus afforded 6.67 g of trans- as a pale yellow oil (67%). IR (neat): v max 33 (w), 857 (m), 453 (m), 873 (m), 734 (s), 696 (s) cm -. NMR (4 Mz, CDCl 3 ): δ 7.9 (, m, Ar-) 4.6 (, d, J.9 z, CPh), (, d, J =.9 z, CPh), (, dd, J =.6,.7 z, CC), 3.5 (, dd, J =.6, 5.3 z, CC), 3.3 (, m, CC ) ppm. 3 C NMR ( Mz, CDCl 3 ): δ 37.8 (C Ar ), 8.4 (C Ar ), 7.7 (C Ar ), 73.3 (C, C Ph), 69.8 (C, CC ), 54.4 (C, CC ) ppm. Data matches literature [7]...4 (±)-anti-,4-bis(benzyloxy)-3-fluorobutan--ol ((±)-anti-3): Et 3 N.3 Bn Bn (86%) (±)-trans- (±)-anti-3 Et 3 N 3 (7. ml, 4 mmol) was added to a flask containing the crude epoxide (9. g, 3.7 mmol), and the mixture was heated at C for 6 h. The mixture was then diluted with water ( ml) and poured into ice-cold NaC 3 solution. The aqueous was extracted with Et (3 5 ml), and the combined extracts were washed with NaC 3 solution (5 ml), brine (5 ml), then dried over MgS 4 and concentrated in vacuo to afford the anti-fluorohydrin (±)-anti-3 as a dark oil (8.7 g, 9 %), which was used directly in the next step. Purification by column S3

14 chromatography (5 % EtAc in petroleum ether) is possible. An experiment starting from.4 g of (±)-trans- thus afforded 9.6 g of (±)-anti-3 as pale yellow oil (86%). IR (neat): v max 343 (br), 364 (w), 33 (w), 96 (w), 865 (w), 496 (w), 453 (m), 3 (s), 57 (s) cm -. NMR (5 Mz, CDCl 3 ): δ -7.9 (, m, Ar-), (, dddd, J = 47.4, 7.5, 5.,.7 z, C), 4.6 (, m, C Ph), (, s, C Ph), 4.4 (, m, C), (, ddd, J = 5.8,.5,.7 z, CC), (, ddd, J = 7.8,.5, 5. z, CC), (, ddd, J = 9.8, 3.6,.5 z, CC), 3.65 (, ddd, J = 9.7, 5.6,. z, CC),.59 (, d, J = 6. z, ) ppm. 3 C NMR ( Mz, CDCl 3 ): δ (C Ar ), (C Ar ), 8.48 (C Ar ), 8.43 (C Ar ), 7.88 (C Ar ), 7.77 (C Ar ), 7.75 (C Ar ), 7.7 (C Ar ), 9.6 (d, J = 75.3 z, C), 73.6 (C Ph), 73.5 (C Ph), 7. (d, J = 5. z, C C), 69.3 (d, J =.5 z, C C), 69. (d, J 4.9 z, C). 9 NMR (47Mz, CDCl 3 ): δ (, ddddt, J = 47.4, 7.9, 5.7, 8.,. z). RMS (ESI +, MeCN): (M+Na) + Calcd. 37, ound (±)-syn-,4-bis(benzyloxy)-,3-difluorobutane ((±)-syn-4): Bn (±)-anti-3 Bn DAST, pyridine (56%) (±)-syn-4 To a solution of the crude fluorohydrin (±)-anti-3 (5.8 g, 5.9 mmol) in dry toluene (75 ml) under argon, DAST (8.9 ml, 67.4 mmol) was added dropwise, and after complete addition the mixture was stirred at room temperature for 5 min. Pyridine (. ml, 36 mmol) was then added and the reaction mixture was stirred at 7 C for 6 h behind a blast shield. The mixture was then allowed to cool, poured into saturated aqueous NaC3 ( ml), and extracted with Et (3 ml). The combined extracts were washed with NaC3 solution (3 ml), brine (3 ml), dried over MgS4, and concentrated in vacuo to afford a yellow oil (.55 g). The crude product was purified by column chromatography ( 6% EtAc in petroleum ether) to afford the syn-difluoride (±)-syn-4 as a dark oil (8.9 g, 56%). IR (neat): v max 33 (w), 97 (w), 866 (w), 36 (w), 496 (w), 453 (m), 7 (s), 6 (s) cm -. NMR (5 Mz, CDCl 3 ): δ 7.3 (, m, Ar-), 4.84 (, m, C), (, d, J =. z, CPh), (, d, J =. z, CPh), (4, m, C C) 3 C NMR ( Mz, CDCl 3 ): δ 37.5 (CAr), 8.5 (CAr), 7.9 (CAr), 7.8 (CAr), 9.5 (C, dd, J = 79.,.5 z, C), 73.7 (C, C Ph), 68. (C, m, CC ). 9 NMR (47 Mz, CDCl 3 ): δ -3.8 (, m). RMS (ESI+, MeCN): (M+Na) + Calcd , ound S4

15 (±)-Syn-,3-difluorobutane-,4-diol ((±)-syn-5): Bn (±)-syn-4 Bn, Pd/C (8%) (±)-syn-5 To a solution of (±)-syn-4 (3. g, 9.83 mmol) in T (45 ml) under argon atmosphere was added Pd/C (5%; 4.8 g,.96 mmol). The flask was evacuated and then placed under hydrogen atmosphere and stirred at room temperature for 6 h. The suspension was filtered through celite, the celite was washed with methanol (5 ml), and the filtrate was concentrated in vacuo to afford a crude yellow crystalline solid (.5 g). The crude was purified by column chromatography (5 5% acetone in petroleum ether) to afford (±)-syn-5 as a white crystalline solid (.993 g, 8%). mp 3 4 C. IR (neat): v max 379 (br), 975 (w), 944 (w), 647 (m), 46 (m), 36 (m) cm -. NMR (5 Mz, acetoned 6 ): δ 4.7 (, m, C), 4.7 (, t, J = 5.9 z, ), - (4, m, C ) ppm. 3 C NMR ( Mz, acetone-d 6 ): δ 93. (C, dd, J = 75.3, 9. z, C), 6.3 (C, dd, J = 8.3, 3.9, C ). 9 NMR (47 Mz, acetone-d 6 ): -5.9 (, m). RMS (ESI-): (M-) + Calcd. 5.47, ound References () Linclau, B.; Leung, L.; Nonnenmacher, J.; Tizzard, G. Beilst. J. rg. Chem., 6, 6. () Elliott, W. J.; ried, J. J. rg. Chem. 976, 4, 469. (3) Al-Dulayymi, A.; Li, X. M.; Neuenschwander, M. elv. Chim. Acta, 83, 633. (4) Mischitz, M.; Kroutil, W.; Wandel, U.; aber, K. Tetrahedron-Asymmetry 995, 6, 6. (5) Bzowska, A.; Kulikowska, E.; Shugar, D.; Chen, B. Y.; Lindborg, B.; Johansson, N. G. Biochem. Pharmacol. 99, 4, 79. (6) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc., 3, 368. (7) achiya, I.; Matsumoto, T.; Inagaki, T.; Takahashi, A.; Shimizu, M. eterocycles, 8, 449. S5

16 S6 Copies of spectra. syn-,4-bis(benzyloxy)-3-fluorobutan--ol ((±)-syn-3).. NMR (4 Mz, CDCl 3 ) -nk7. product M6(dd) M3(s) M4(s) M7(m) M(dtq) M(s) M5(ddt) M4(s) M5(ddt) M(dtq) M(s) M3(s) syn-3

17 S7.. 3 C NMR ( Mz, CDCl 3 ) my4njp...r.esp M5(s) M6(s) M7(s) M8(s) M(s) M(s) M3(s) M4(s) M6(s) M7(s) M8(s) M9(s) M(s) M(s) M6(s) M7(s) M(s) M(s) M5(s) M3(s) syn-3

18 S C DEPT-35 NMR 3 C NMR ( Mz, CDCl 3 ) 9//7 3::7 PM my4njp...r.esp M(s) M(s) M3(s) M4(s) M(s) syn-3

19 S NMR (376 Mz, CDCl 3 ) se47zw7...r.esp M(m) M(dq) M(dq) M(m) syn-3

20 S..5 Diastereoselectivity of the epoxide opening..5. NMR of the cis-epoxide starting material, compared to that of the trans-isomer -np3-trans-epoxide impurity.esp M(m) M5(m) M6(m) M7(m) M4(m) M(m) M3(m) M9(m) esp M(m) M3(dd) M(dd) M4(m) M Bn Bn cis- Bn Bn trans-

21 NMR of the fluorohydrin product syn-3, compared to that of the anti-isomer ja5fgp...r.esp..5 Bn syn-3 Bn fe45njwfp-anti(bn) fluorohydrin.3..r.esp..5 Bn anti-3 Bn S

22 ,-Dimethyl-,3-dioxep-5-ene (6).. NMR (4 Mz, CDCl 3 ) se67rw5-distilled product...r.esp M3(s) M(d).3 M(t) M(d).5. M(t) S

23 C NMR ( Mz, CDCl 3 ) nv54fgp...r.esp 3 M4(s) M(s) M(s) 4 6 M3(s).9.85 M6(s) M5(s) S3

24 S4.3 4,4-Dimethyl-3,5,8-trioxabicyclo[5..]octane (7).3. NMR (4 Mz, CDCl 3 ) KN856-.esp M(s) M3(m) M4(m) M4(m) Chemical Shift (p