1-azabicyclo[2.2.2]octan-8-ol (3-Quinuclidinol; Quinuclidin-3-ol) [CAS 1619-34-7; InChIKey IV

Query Query

Results

Date

27 reactions in Reaxys

2016-04-25 15h:26m:09s (EST)

27 reactions in Reaxys

2016-04-25 16h:09m:59s (EST)

HO

1. Query N

Search as: As drawn 2. Query

(1. Query) AND NOT itemno in (1,2,3)

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

1/11

2016-04-25 16:14:13

N T-4

OH

T-4 T-4 H

HCl OH

N

Rx-ID: 23677723 View in Reaxys 1/27 Yield

Conditions & References

99 %

21.21A :(R)-3-Quinuclidinol hydrochloride (20 g, 12.2 mmol; Aldrich) was treated with aq. NaOH (20percent, 50 mL) at ambient temperature for 10 min, then extracted with CHCl3/i-PrOH (10:1, 3.x.200 mL). The extracts were combined, washed with brine (50 mL) and dried over MgSO4. After removal of the drying agents by filtration, the filtrate was concentrated under reduced pressure to afford the title compound as white solid (15.5 g, 122 mmol, 99percent yield). 1H NMR (300 MHz, methanol-d4) δ 3.88-3.82 (1H, m), 3.10 (1H, ddd, J=14, 8, 2 Hz), 2.95-2.50 (5H, m), 2.05-1.90 (1H, m), 1.85-1.76 (2H, m), 1.60-1.52 (1H, m), 1.50-1.36 (1H, m). MS (DCl/NH3): m/z 128 (M+1)+.

With sodium hydroxide in water, Time= 0.166667h, T= 20 °C Patent; Schrimpf, Michael R.; Sippy, Kevin B.; Ji, Jianguo; Li, Tao; Frost, Jennifer M.; Briggs, Clark A.; Bunnelle, William H.; US2005/234031; (2005); (A1) English View in Reaxys

T-4

O

OH

T-4

N

N

Rx-ID: 38894014 View in Reaxys 2/27 Yield

Conditions & References

Ca. 73 %

Preparative scale fermentation : Preparative scale fermentation : The fermentation was carried out using twenty flasks containing 50 mL of 24 h well grown culture of M. piriformis in modified Czapek dox medium. 100 mg of 3-quinuclidinone (I) in the powder form was added to the fermentation media and incubated at 30 °C on a rotary shaker at 200 rpm. After twelve days of incubation, contents of the flasks were pooled and filtered. pH of the broth was adjusted to 6.0 using 1 N HCl and subjected to purification using Amberlite IR-120 resin. In the scale up experiment transformation was carried out into single flask (2.8 L) under identical fermentation conditions.

Stage 1:, Time= 288h, T= 30 °C , Microbiological reaction, Industrial scale Stage 2: With hydrogenchloride in water, pH= 6, Industrial scale Stage 3:, Industrial scale, Time, enantioselective reaction Kolet, Swati P.; Jadhav, Dipesh D.; Priyadarshini, Balaraman; Swarge, Bhagyashree N.; Thulasiram, Hirekodathakallu V.; Tetrahedron Letters; vol. 55; nb. 43; (2014); p. 5911 - 5914 View in Reaxys

–O

HO

Na + N

N

Rx-ID: 22969267 View in Reaxys 3/27 Yield

Conditions & References R.Riv :Riv) (S)-Cyclohexyl-hydroxy-thiophen-2-yl-acetic acid (R)-(l-aza-bicyclo[2.2.2]oct-3-yl) ester;:To a stirred, cooled (1O0C) suspension comprising sodium hydride (24.6 g, of a 60percent dispersion in oil, 0.614 mol) in DMF (450 ml) is added portionwise R-3-quinuclidinol (52.1 g, 0.409 mol) over 40 minutes and the resulting mixture is allowed to stir at 100C for 90 minutes. In the meantime, a second reaction vessel comprising (S)-cyclohexyl-hydroxythiophen-2-yl- acetic acid (98.4 g, 0.409 mol) in DMF (450 ml) is cooled to 100C and treated portionwise with CDI (73.0 g, 0.45 mol) over 30 minutes. After stirring at 100C for 90 minutes, this mixture is added dropwise to the cooled (100C ) suspension of the sodium salt of R-3- quinucliodinol. After stirring at 1O0C for 1 hour, water (1 litre) is added dropwise over 30 minutes ensuring the temperature remains below 15°C. The resulting slurry is stirred at 100C for 30 minutes and then filtered, washed with water (2 x 150 ml) and then dried in vacuo over phosphorus pentoxide to afford the titled compound.

With sodium hydride in N,N-dimethyl-formamide, Time= 2.16667h, T= 10 °C

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

2/11

2016-04-25 16:14:13

Patent; NOVARTIS AG; NOVARTIS PHARMA GMBH; WO2006/48225; (2006); (A1) English View in Reaxys 1 : Method (a) Example 1 Preparation of [BUTYTPHENYLCARBAMIC] acid [(3R)-1-AZABICYCLOL2.] 2. [2] OCT-3-YI] ester. Method (a) Example 1 Preparation of [BUTYTPHENYLCARBAMIC] acid [(3R)-1-AZABICYCLOL2.] 2. [2] OCT-3-YI] ester. Method (a); Example 1; Preparation of [BUTYTPHENYLCARBAMIC] acid [(3R)-1-AZABICYCLOL2.] 2. [2] OCT-3-YI] ester. Method (a) Example 1 Preparation of [BUTYTPH 0.65 g (28.50 [MMOL)] of sodium was added to 70 mi of dry toluene. The suspension was refluxed with vigorous stirring. When all the sodium was melted, 3.60 g (28.30 [MMOL)] of [(3R)-3-HYDROXY-1-AZABICYCLO] [2.2. [2]] octane was added and stirring continued [FOR 2 HOURS,] by which time all the sodium had reacted to form the alcoholate. 6.00 g (28.30 [MMOL)] of Phenylbutylcarbamoyl chloride (intermediate [1-1)] dissolved in 30 mi [OF TOLUENE] was then slowly added. The mixture was refluxed for one hour, and then the reaction was stirred overnight at room temperature. The suspension was filtered and the filtrate evaporated. Ether-was added to the residue and stirred for 10 min. The suspension was filtered and the, filtrate concentrated in vacuo to obtain 7.18 g of brown oil. This product was purified by column chromatography (silica gel, [CHLOROFORM/ETHANOL/AMMONIA] 140: 8: 1) to yield [1.] 78 g (5.89 [MMOL)] (22percent) of a pure product, structure confirmed [BYAPOS;H-NMR.] 1H-NMR (300 MHz, CDCI3) : [6] 0,9 (m, 3H), 1,3 (m, 4H), 1,5 (m, 4H), 1,9 (s, 1H), 2,7 (m, 5H), 3,2 (m, [1H),] 3,7 (m, 2H), 4,7 (m, [1H),] 7,2-7, 4 (m, 5H) ; MS [[M+1] + :] 303.

With sodium in toluene, Time= 2h, Heating / reflux Patent; ALMIRALL PRODESFARMA S.A.; WO2004/840; (2003); (A2) English View in Reaxys 49 :Example 49 Preparation of sodium salt of (R)-3-quinuclidinolTo a cooled solution of freshly prepared sodium methoxide (2.1 g), (R)-3- quinuclidinol (5 g) was added under N2 atmosphere. It was stirred at 5-30 0C for 30 to-60 min. Distilled out the solvent at reduced pressure. To the semi-solid mass dry toluene was added and subsequently distilled out. Again dry toluene was added and distilled out to obtain the solid salt. The solid salt was stirred with diisopropyl ether at 25-30 oC for20 -30 min. It was filtered and washed with diisopropyl ether. White solid powder was obtained (Wt. - 5.8 g).

With sodium methylate, T= 5 - 30 °C , Inert atmosphere Patent; CADILA HEALTHCARE LIMITED; WO2009/87664; (2009); (A1) English View in Reaxys To a solution of Sodium (R)-quinuclidin-3-ol (3.61g, 24.lmmol), previously formed reflux-ing sodium with (R)-quinuclidin-3-ol at 125°C for 4 hours, in 1 OmL of toluene was added 4-bromo-2-isocyanatobiphenyl (6.63g, 21.lmmol). The mixture was stirred 2 hours at 120°C. The solvent was removed under reduced pressure and the crude was partitioned between ethyl acetate and hydrogen chloride 2N. The aqueous phase was neutralized and extracted with chloroform twice. The organic phase was dried, filtered and evaporated, giving the title compound as a solid (4.7g, 48percent), which was used in the next step without further purification.LRMS (mlz): 402;403 (M+1/M+2)+ With sodium, Time= 4h, T= 125 °C Patent; ALMIRALL, S.A.; SOLE FEU, Laia; CARRANCO MORUNO, Ines; AIGUADE BOSCH, Jose; PUIG DURAN, Carlos; FONQUERNA POU, Silvia; WO2014/95920; (2014); (A1) English View in Reaxys -1 F (v4)

HO

F N

B F F HO H+ N

Rx-ID: 36459914 View in Reaxys 4/27 Yield 98 %

Conditions & References 4.2 Typical procedure for one-pot preparation of alkyl-substituted ammonium BF4 − and PF6 − salts using toluene as the solvent [3p][PF6] (Table 1, entry 16) General procedure: To a 25-mL round-bottomed flask containing ammonium hexafluorophosphate (1.63g, 10mmol) was added toluene (10mL) followed by hexamethyleneimine (0.99g, 10mmol). The mixture was magnetically stirred and refluxed for 1h. The mixture was cooled to room temperature and further cooled in an ice-water bath. The precipitated product was collected by vacuum filtration, washed with toluene (3× 5mL) and air dried

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

3/11

2016-04-25 16:14:13

With NH4BF4 in toluene, Time= 1h, Reflux Saba, Shahrokh; Hernandez, Renee; Choy, Christine Chin; Carta, Kristine; Bennett, Yaasmin; Bondi, Steven; Kolaj, Sebastian; Bennett, Caitlin; Journal of Fluorine Chemistry; vol. 153; (2013); p. 168 - 171 View in Reaxys

OH F

HO

F

N

N

F P– F

F F

H+

Rx-ID: 36459915 View in Reaxys 5/27 Yield

Conditions & References

97 %

4.2 Typical procedure for one-pot preparation of alkyl-substituted ammonium BF4 − and PF6 − salts using toluene as the solvent [3p][PF6] (Table 1, entry 16) General procedure: To a 25-mL round-bottomed flask containing ammonium hexafluorophosphate (1.63g, 10mmol) was added toluene (10mL) followed by hexamethyleneimine (0.99g, 10mmol). The mixture was magnetically stirred and refluxed for 1h. The mixture was cooled to room temperature and further cooled in an ice-water bath. The precipitated product was collected by vacuum filtration, washed with toluene (3× 5mL) and air dried With NH4PF6 in toluene, Time= 1h, Reflux Saba, Shahrokh; Hernandez, Renee; Choy, Christine Chin; Carta, Kristine; Bennett, Yaasmin; Bondi, Steven; Kolaj, Sebastian; Bennett, Caitlin; Journal of Fluorine Chemistry; vol. 153; (2013); p. 168 - 171 View in Reaxys

O

OH

T-4

N

N

Rx-ID: 28531496 View in Reaxys 6/27 Yield

Conditions & References

82 %

With C43H54Br2N2P2Ru, potassium tert-butylate, hydrogen in ethanol, Time= 4h, T= 30 - 45 °C , p= 11400.8Torr , Inert atmosphere, Autoclave, Large scale reaction, optical yield given as percent ee Arai, Noriyoshi; Kurono, Nobuhito; Ohkuma, Takeshi; Tsutsumi, Kunihiko; Katayama, Takeaki; Utsumi, Noriyuki; Murata, Kunihiko; Organic Process Research and Development; vol. 13; nb. 3; (2009); p. 625 - 628 View in Reaxys

O

OH

O O

H

H

O

HO

O

O

OH O

HO

H

O

O

HO O

OH

H N

N

O

O

O

Rx-ID: 37568953 View in Reaxys 7/27 Yield 83 %

Conditions & References Preparation of (R)-3-Quinuclidinol (2a) A mixture of dibenzoyl-D(+)-tartaric acid monohydrate (150.0 g, 0.4 mol), methanol(300 ml) and 3-quinuclidinol (100.0 g, 0.79 mol) was stirred for 30 min and then heatedto 60–65C and maintained at reflux for 3 h. The suspension containing the precipitatedsolid was cooled to 0–5C and stirred for 1 h. The (R)-3-quinuclidinol dibenzoyl-D(+)tartrate salt was collected and washed with 100 ml of chilled methanol to yield 130.0 gof a white crystalline solid. It was dissolved in methanol (600 ml) at 55–60C and stirredfor 30 min. The clear solution was cooled to 0–5C and stirred for 1 h. The resultingsolid was collected, washed with chilled methanol (100 ml), dried under vacuum to affordpure (R)-3-quinuclidinol dibenzoyl-D(+)-tartrate salt (100.0 g, 83percent) as a white solid, mp.174–178C, [α]D25= +550 (c = 2, MeOH).The salt was dissolved in water (100 ml) and ethyl acetate was then added (250 ml),and the

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

4/11

2016-04-25 16:14:13

mixture was stirred for 10 min. It was then treated with conc. HCl (42 ml) to adjustthe pH to 1–2 and stirred for 1 h at 25–30C. The aqueous and organic layers were separatedand then the organic layer was saved to recover dibenzoylD(+)-tartaric acid. The aqueouslayer was treated with aqueous NaOH (23.0 g in 50 ml of water) to adjust the pH 12– 13and extracted with chloroform (4 × 200 ml). The combined chloroform extracts were driedover sodium sulfate and the solvent was evaporated completely under vacuum below 50Cto give a white solid (40.0 g). It was treated with mixture of methanol (10 ml) and acetone(90 ml) and stirred at 55–60C for 30 min. The suspension containing the solid was cooledto 0–5C and stirred for 1 h. The product was collected, washed with chilled acetone (30ml)to yield 38.0 g (91percent) of a white crystalline solid, mp. 221–224C., lit.9 220–222C. [α]D25=−43.6 (c = 3, 1N HCl)., lit.9 [α]D25=−43.8 (c = 3, 1N HCl). 99.9percent chiral purity byHPLC. IR (cm−1): 3400, 3095, 2940, 1445, 1340; 1HNMR: δ 1.25–2.0 (5H, m), 2.50–2.90(5H, m), 3.05 (1H, m), 3.75 (1H, m, CH-OH); MS (ESI): m/z 128 (M +H). in methanol, Time= 3h, Reflux, Resolution of racemate Chavakula, Ramadas; Mutyala, Narayana Rao; Chennupati, Srinivasa Rao; Organic Preparations and Procedures International; vol. 45; nb. 6; (2013); p. 507 - 509 View in Reaxys

OH

O

O

HO

OH

HO OH

H

H

OH

O

OH

HO OH

N

O

Rx-ID: 23311262 View in Reaxys 8/27 Yield

Conditions & References

28 %

13.C : (3S)-1-azabicyclo[2.2.2]oct-3-yl benzoate (D)-tartrate The filtrates was concentrated to give 3-quinuclidinol benzoate (15.25 g, 66 mmol) It was then treated with (D)-tartaric acid (Aldrich, 97percent ee, 9.9 g, 66 mmol,) in EtOH (80percent, 190 ml) at room temperature for 3 days according to the procedure of Example 1A. The title product was obtained (7.0 g, yield, 28percent, 92.3percent ee). in ethanol Patent; Ji, Jianguo; Li, Tao; US2005/137184; (2005); (A1) English View in Reaxys

H

O

H

HO

N

H N

HO

O N

HO

N

O

Rx-ID: 25196046 View in Reaxys 9/27 Yield

Conditions & References 4 : Quinuclidinol methylcarbamate EXAMPLE 4 Quinuclidinol methylcarbamate To 0.05 moles of 3-quinuclidinol dissolved in 100 ml of dry toluene was added to 0.07 moles of methylisocyanate and the mixture was refluxed for 8 hours.

After removal of the solvent in vacuo, the mixture was taken up to 50 ml of H2 O and extracted twice with H2 O. After removal by CHCl3, the yellow oily liquid was distilled in vacuo at 5 mm Hg and 130° C. The yield was An infrared analysis of quinuclidinol methylcarbamate yielded the following bands: 2985, 1730, 1530, 1265 cm-1.

Analysis by mass spectroscopy yielded the following: 184, 156, 58. in toluene Patent; Abood; Leo G.; US4835162; (1989); (A1) English View in Reaxys

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

5/11

2016-04-25 16:14:13

OH O

O

OH

T-4

O

N

N

Rx-ID: 21437748 View in Reaxys 10/27 Yield

Conditions & References Reaction Steps: 12 1: 86 percent / pyridine / 2 h / 0 °C 2: 89 percent / NaN3 / dimethylformamide / 8 h / 65 °C 3: 1.) H2, 2.) lithium diisopropylamide / 1.) palladium black / 1.) ethanol, 2.) THF, -40 deg C 4: LiAlH4 / tetrahydrofuran 5: aq. NaHCO3 / diethyl ether 6: 1.) TiCl4, 2.) DBU / 1.) CDCl3, -20 deg C, 10 min 7: 1.) O3, 2.) NaBH4 / 1.) methanol, dichloromethane, -65 deg C, 20 min 8: 84 percent / pyridine / -10 °C 9: 84 percent / lutidine / CH2Cl2 / -20 °C 10: H2 / palladium black / ethanol / 2 h / 20 °C 11: ethanol / 6 h / 50 °C 12: aqueous trifluoroacetic acid With pyridine, sodium tetrahydroborate, lithium aluminium tetrahydride, sodium azide, lutidine, hydrogen, titanium tetrachloride, sodium hydrogencarbonate, ozone, 1,8-diazabicyclo[5.4.0]undec-7-ene, trifluoroacetic acid, lithium diisopropyl amide, palladium in tetrahydrofuran, diethyl ether, ethanol, dichloromethane, N,N-dimethyl-formamide Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys

O

O

T-4

OH

N

N OH

OH

Rx-ID: 21438027 View in Reaxys 11/27 Yield

Conditions & References Reaction Steps: 5 1: 84 percent / pyridine / -10 °C 2: 84 percent / lutidine / CH2Cl2 / -20 °C 3: H2 / palladium black / ethanol / 2 h / 20 °C 4: ethanol / 6 h / 50 °C 5: aqueous trifluoroacetic acid With pyridine, lutidine, hydrogen, trifluoroacetic acid, palladium in ethanol, dichloromethane Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys

H HN

O

O

T-4

OH

N

H

Rx-ID: 21447078 View in Reaxys 12/27 Yield

Conditions & References Reaction Steps: 8

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

6/11

2016-04-25 16:14:13

1: aq. NaHCO3 / diethyl ether 2: 1.) TiCl4, 2.) DBU / 1.) CDCl3, -20 deg C, 10 min 3: 1.) O3, 2.) NaBH4 / 1.) methanol, dichloromethane, -65 deg C, 20 min 4: 84 percent / pyridine / -10 °C 5: 84 percent / lutidine / CH2Cl2 / -20 °C 6: H2 / palladium black / ethanol / 2 h / 20 °C 7: ethanol / 6 h / 50 °C 8: aqueous trifluoroacetic acid With pyridine, sodium tetrahydroborate, lutidine, hydrogen, titanium tetrachloride, sodium hydrogencarbonate, ozone, 1,8-diazabicyclo[5.4.0]undec-7-ene, trifluoroacetic acid, palladium in diethyl ether, ethanol, dichloromethane Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys

H HN O

O

O

OH

T-4

N

H

Rx-ID: 21449758 View in Reaxys 13/27 Yield

Conditions & References Reaction Steps: 9 1: LiAlH4 / tetrahydrofuran 2: aq. NaHCO3 / diethyl ether 3: 1.) TiCl4, 2.) DBU / 1.) CDCl3, -20 deg C, 10 min 4: 1.) O3, 2.) NaBH4 / 1.) methanol, dichloromethane, -65 deg C, 20 min 5: 84 percent / pyridine / -10 °C 6: 84 percent / lutidine / CH2Cl2 / -20 °C 7: H2 / palladium black / ethanol / 2 h / 20 °C 8: ethanol / 6 h / 50 °C 9: aqueous trifluoroacetic acid With pyridine, sodium tetrahydroborate, lithium aluminium tetrahydride, lutidine, hydrogen, titanium tetrachloride, sodium hydrogencarbonate, ozone, 1,8-diazabicyclo[5.4.0]undec-7-ene, trifluoroacetic acid, palladium in tetrahydrofuran, diethyl ether, ethanol, dichloromethane Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys

N

N N

O

O

T-4

OH

N O

N

Rx-ID: 21454771 View in Reaxys 14/27 Yield

Conditions & References Reaction Steps: 10 1: 1.) H2, 2.) lithium diisopropylamide / 1.) palladium black / 1.) ethanol, 2.) THF, -40 deg C 2: LiAlH4 / tetrahydrofuran 3: aq. NaHCO3 / diethyl ether 4: 1.) TiCl4, 2.) DBU / 1.) CDCl3, -20 deg C, 10 min 5: 1.) O3, 2.) NaBH4 / 1.) methanol, dichloromethane, -65 deg C, 20 min 6: 84 percent / pyridine / -10 °C 7: 84 percent / lutidine / CH2Cl2 / -20 °C 8: H2 / palladium black / ethanol / 2 h / 20 °C 9: ethanol / 6 h / 50 °C 10: aqueous trifluoroacetic acid

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

7/11

2016-04-25 16:14:13

With pyridine, sodium tetrahydroborate, lithium aluminium tetrahydride, lutidine, hydrogen, titanium tetrachloride, sodium hydrogencarbonate, ozone, 1,8-diazabicyclo[5.4.0]undec-7-ene, trifluoroacetic acid, lithium diisopropyl amide, palladium in tetrahydrofuran, diethyl ether, ethanol, dichloromethane Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys

O O

H N

O

T-4

OH

N

H

Rx-ID: 21454898 View in Reaxys 15/27 Yield

Conditions & References Reaction Steps: 6 1: 1.) O3, 2.) NaBH4 / 1.) methanol, dichloromethane, -65 deg C, 20 min 2: 84 percent / pyridine / -10 °C 3: 84 percent / lutidine / CH2Cl2 / -20 °C 4: H2 / palladium black / ethanol / 2 h / 20 °C 5: ethanol / 6 h / 50 °C 6: aqueous trifluoroacetic acid With pyridine, sodium tetrahydroborate, lutidine, hydrogen, ozone, trifluoroacetic acid, palladium in ethanol, dichloromethane Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys

O O

H N

O

O

T-4

OH

N

H

Rx-ID: 21455962 View in Reaxys 16/27 Yield

Conditions & References Reaction Steps: 7 1: 1.) TiCl4, 2.) DBU / 1.) CDCl3, -20 deg C, 10 min 2: 1.) O3, 2.) NaBH4 / 1.) methanol, dichloromethane, -65 deg C, 20 min 3: 84 percent / pyridine / -10 °C 4: 84 percent / lutidine / CH2Cl2 / -20 °C 5: H2 / palladium black / ethanol / 2 h / 20 °C 6: ethanol / 6 h / 50 °C 7: aqueous trifluoroacetic acid With pyridine, sodium tetrahydroborate, lutidine, hydrogen, titanium tetrachloride, ozone, 1,8-diazabicyclo[5.4.0]undec-7-ene, trifluoroacetic acid, palladium in ethanol, dichloromethane Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys

O O O

S O

O

T-4

OH

N O

N

Rx-ID: 21456794 View in Reaxys 17/27 Yield

Conditions & References Reaction Steps: 11 1: 89 percent / NaN3 / dimethylformamide / 8 h / 65 °C

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

8/11

2016-04-25 16:14:13

2: 1.) H2, 2.) lithium diisopropylamide / 1.) palladium black / 1.) ethanol, 2.) THF, -40 deg C 3: LiAlH4 / tetrahydrofuran 4: aq. NaHCO3 / diethyl ether 5: 1.) TiCl4, 2.) DBU / 1.) CDCl3, -20 deg C, 10 min 6: 1.) O3, 2.) NaBH4 / 1.) methanol, dichloromethane, -65 deg C, 20 min 7: 84 percent / pyridine / -10 °C 8: 84 percent / lutidine / CH2Cl2 / -20 °C 9: H2 / palladium black / ethanol / 2 h / 20 °C 10: ethanol / 6 h / 50 °C 11: aqueous trifluoroacetic acid With pyridine, sodium tetrahydroborate, lithium aluminium tetrahydride, sodium azide, lutidine, hydrogen, titanium tetrachloride, sodium hydrogencarbonate, ozone, 1,8-diazabicyclo[5.4.0]undec-7-ene, trifluoroacetic acid, lithium diisopropyl amide, palladium in tetrahydrofuran, diethyl ether, ethanol, dichloromethane, N,N-dimethyl-formamide Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys

O

O

T-4

N

N

OH

O S

OH

O

O

Rx-ID: 21458495 View in Reaxys 18/27 Yield

Conditions & References Reaction Steps: 4 1: 84 percent / lutidine / CH2Cl2 / -20 °C 2: H2 / palladium black / ethanol / 2 h / 20 °C 3: ethanol / 6 h / 50 °C 4: aqueous trifluoroacetic acid With lutidine, hydrogen, trifluoroacetic acid, palladium in ethanol, dichloromethane Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys

O

O

T-4

N

O

O S

Si

OH

N

O

O

Rx-ID: 21461025 View in Reaxys 19/27 Yield

Conditions & References Reaction Steps: 3 1: H2 / palladium black / ethanol / 2 h / 20 °C 2: ethanol / 6 h / 50 °C 3: aqueous trifluoroacetic acid With hydrogen, trifluoroacetic acid, palladium in ethanol

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

9/11

2016-04-25 16:14:13

Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys O OH

OH O

O

N

O

N

O O

Rx-ID: 38591544 View in Reaxys 20/27 Yield

Conditions & References Reaction Steps: 2 1.1: potassium hydroxide / water / 0.33 h 1.2: |Reflux 2.1: water; ethanol / |Heating With potassium hydroxide in ethanol, water D'Agostino, Simone; Grepioni, Fabrizia; Braga, Dario; Moreschi, Daniele; Fattori, Valeria; Delchiaro, Francesca; Di Motta, Simone; Negri, Fabrizia; CrystEngComm; vol. 15; nb. 48; (2013); p. 10470 - 10480 View in Reaxys

H N

O

O S

Si

T-4

OH

N

O

O

Rx-ID: 21454664 View in Reaxys 21/27 Yield

Conditions & References Reaction Steps: 2 1: ethanol / 6 h / 50 °C 2: aqueous trifluoroacetic acid With trifluoroacetic acid in ethanol Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys O

O Cl

HO

HO

Cl

N

Cl

Cl

N

O

O

Rx-ID: 1515193 View in Reaxys 22/27 Yield

Conditions & References in cyclohexane, ethyl acetate, T= 20 °C Campbell, Michel J. M.; Demetriou, Basil; Jones, Ronald; Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999); (1983); p. 917 - 922 View in Reaxys

O

HO O

O N

O

O

O HO OH

N

OH

O N

Rx-ID: 29040213 View in Reaxys 23/27 Yield

Conditions & References With Bacillus licheniformis subtilisin, water, Time= 16h, T= 20 °C , optical yield given as percent ee

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

10/11

2016-04-25 16:14:13

Brossat, Maude; Moody, Thomas S.; Taylor, Stephen J.C.; Wiffen, Jonathan W.; Tetrahedron Asymmetry; vol.

20; nb. 18; (2009); p. 2112 - 2116 View in Reaxys

O

T-4

T-4

Si

N

OH

N

Rx-ID: 2533857 View in Reaxys 24/27 Yield

Conditions & References With trifluoroacetic acid Fleet; James; Lunn; Tetrahedron Letters; vol. 27; nb. 26; (1986); p. 3053 - 3056 View in Reaxys O

O N

OH

OH

HO

O

N

O

O N

N

OH

O

Rx-ID: 38591547 View in Reaxys 25/27 Yield

Conditions & References in ethanol, water, Heating, Solvent D'Agostino, Simone; Grepioni, Fabrizia; Braga, Dario; Moreschi, Daniele; Fattori, Valeria; Delchiaro, Francesca; Di Motta, Simone; Negri, Fabrizia; CrystEngComm; vol. 15; nb. 48; (2013); p. 10470 - 10480 View in Reaxys O

O

O

N

O

O Cl

O HO

HO

N

HO

O O

N

N

N

N O

O

N

N O

O

Rx-ID: 1515198 View in Reaxys 26/27 Yield

Conditions & References in water, T= 25 °C , Rate constant Gandler, Joseph R.; Setiarahardjo, Irianto U.; Tufon, Chrisanthus; Chen, Chinpan; Journal of Organic Chemistry; vol. 57; nb. 15; (1992); p. 4169 - 4173 View in Reaxys

HO 2H

N

Rx-ID: 6585747 View in Reaxys 27/27 Yield

Conditions & References Aminoketon VI, LiAlD4 Palecek; Collection of Czechoslovak Chemical Communications; vol. 36; (1971); p. 2070 View in Reaxys

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

11/11

2016-04-25 16:14:13