Recent Literature Presentation

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1 ecent Literature Presentation H 2 PhC 2 H 2 10 kbar 2 (n = ca. 16) TPGS-750-M n rg. Lett. 2011, DI: /ol201275h J. rg. Chem. 2011, 76, Christopher D. Thomas Group eting July 11, 2011

2 Effect of High Pressure on the rganocatalytic Asymmetric Michael eaction: Highly Enantioselective Synthesis of gamma-itroketones with Quaternary Stereogenic Centers organocatalyst (1-5 mol %) = Alk, Ar 2 PESSUE (10 kbar) % yield 96-99% ee H 2 PhC 2 H organocatalyst Piotr Kwaitkowski,* Krsysztof Dudzinski, and Dawid Lyzwa rg. Lett. 2011, 1,

3 Dr. Piotr Kwiatkowski University of Warsaw University Logo Chemistry Building Famous Main Gates University was founded in 1816 is ranked as best Polish university. Late 190 s university was occupied by azis until Currently the faculty is divided into teaching divisions and research laboratories. - Inorganic and Analytical - Physical -rganic -Technology -Theoretical Chemistry and Crystallography -Physics and adiochemistry - Dydactics of Chemistry

4 High-Pressure Techniques in rganic Synthesis C 2 heat or 15.8 kbar 7.5 h C 2 heat = 0% yield pressure = 5% yield C heat or 8.4 kbar 1 h C heat = % yield pressure = 90% yield Dauben, W. G.; Kozikowski, A. P. J. Am. Chem. Soc. 1974, 96,

5 High-Pressure Techniques in rganic Synthesis catalyst pressure ee config C 2 + Ph (0.2 M) 5 mol % cat. C 2 H H H H 0.1 MPa 900 MPa 0.1 MPa 900 MPa S S S S Sera, A.; Takagi, K.; Katayama, H.; Yamada, H. J. rg. Chem. 1988, 5, CH Br + H 2 0 mol % L-Proline DMS, 28 h H H + + Br Br Br 200 MPa, -20 ºC 57%, 95% ee 11%, 78% ee 0% 0.1 MPa, 2 ºC 25%, 88% ee 10%, 74% ee 12% Hayashi, Y.; Tsuobi, W.; Shoji, M.; Suzuki,. J. Am. Chem. Soc. 200, 125,

6 eaction Setup Vessel was a direct, single-stage liquid piston-cylinder (LV/0/16) with a hydraulic press (U101) from Unipress (Warsaw, Poland). Experiments were run in Teflon ampules (0.5, 1.0, 2.0,.0, 5.0 and 10 ml) with hexane as a transmission medium. Up to 12 parallel reactions can be run in 0.5 ml ampules.

7 Model eaction 5 mol % cat. Ph Ph Ph H 2 H 2 2 (2 eq.) Ph, 20 h 2 H 2 H 2 H2 1a 1b 1c entry cat. 1a 1b 1c 1d 1e 1f 1f 1f 1f 1i additive BzH BzH one one 1 bar yield <1% 2% 6% 9% <1% 1% % <2% 1% <0.1% yield 11% 55% 55% 70% 55% 78% 75% 80% 6% 6% 10 kbar conv 2% 60% 95% 77% 99% 91% 99% 96% 89% 4% ee 4% (S) 98% () 75% () 82% (S) 7% (S) 96% () 98% () 98% () 85% () 92% () Ph H 2 1d Hn-Pr H 2 Ph H 2 1e H H S H 2 1f = H 1g = 1h F C CF 1i Enantioselectivity maintained at a high rate across a range of pressures, however yield is significantly affected. ptimized conditions: 8-10 kbar, 2 mol % of cat. 1f with -4 mol % BzH: 87% yield, 98% ee ().

8 Model eaction 5 mol % cat. 2 (2 eq.) Ph, 20 h 2 1 bar 10 kbar entry cat. additive yield yield conv ee a 1b 1c 1d 1e 1f 1f 1f 1f 1i BzH BzH one one <1% 2% 6% 9% <1% 1% % <2% 1% <0.1% 11% 55% 55% 70% 55% 78% 75% 80% 6% 6% 2% 60% 95% 77% 99% 91% 99% 96% 89% 4% 4% (S) 98% () 75% () 82% (S) 7% (S) 96% () 98% () 98% () 85% () 92% () Enantioselectivity maintained at a high rate across a range of pressures, however yield is significantly affected. ptimized conditions: 8-10 kbar, 2 mol % of cat. 1f with -4 mol % BzH: 87% yield, 98% ee ().

9 Scope of Asymmetric Michael Addition 2 Bn %, 97% ee 91%, 98% ee both epimers dr ~ 1:1 82%, 97% ee i-pr 81%, 97% ee 2 = C 2 Et 74%, 97% ee = thienyl, 52%, 98% ee = 65%, 80% ee mol % cat mol % additive CH 2 2 (2 eq.) 10 kbar n i-pr 75%, 98% ee 2 2 S 74%, 99% ee 2 74%, 99% ee 2 74%, 99% ee 2 74%, 99% ee X 2 75%, 98% ee X = H 7%, 98% ee X = Br 74%, 96% ee

10 TPGS-750-M: A Second-Generation Amiphile for tal-catalyzed Cross-Couplings in Water at oom Temperature n (n = ca. 16) enables reactions in T Heck, Suzuki-Miyuara, aminations borylations, silylations, egishi-like, olefin metathesis reactions TPGS-750-M Bruce H. Lipshutz, Subir Ghorai, Alexander. Abela, alph Moser, Takashi ishikata, Christophe Duplais and Arkady Krasovskiy (UCSB) icky D. Gaston and obert C. Gadwood (Kalexsyn, Inc.) J. rg. Chem. 2011, 76,

11 Wikipedia: wiki/bruce_h._lipshutz Professor Bruce H. Lipshutz Education and Post-Doctoral Work Bachelors of Science: SUY Binghampton (197) Ph.D: Yale under Harry Wasserman (1977) Post-Doc: Havard under E. J. Corey ( ) Professional Experience Assistant Professor: University of California, Santa Barbara (1979) Professor: University of California, Santa Barbara (1987) Awards (Selected) Alfred P. Sloan Fellowship (1984) Chairman, GC on eactions & Processes (1992) ACS Cope Scholar Award (1997) UCSB Foundation Distinguished Faculty Teaching Award (2002)

12 2011 Green Chemistry Awardee The achievement is a key milestone toward Lipshutz goal of developing chemistry that will allow the synthetic organic community to get organic solvents out of organic reactions, he says. -Stephen K. itter, Chemical and Engineering ews Has been selling his surfactants from Sigma-Aldrich for the last two years (PTS-600).

13 Amiphiphiles for Conducting tal-catalyzed Processes in Water 4 PTS H n (n = ca. 12) I Heck ' X Suzuki- Miyaura Ar rg. Lett. 2008, 10, Br Buchwald- Hartwig 2 Ar rg. Lett. 2008, 10, rg. Lett. 2008, 10, X Sonogashira ' Adv. Synth. Catal. 2009, 51, rg. Lett. 2008, 10, ing-closing tathesis ' Cross- tathesis ' Adv. Synth. Catal. 2008, 50, rg. Lett. 2008, 10,

14 Goals for Second-Generation Amphiphile 4 PTS H n (n = ca. 12) Engineer particle size to accomplish greater rates, higher levels of conversion and yields. More streamlined synthesis of surfactant leading to an improved economic profile. H Cl 4 Cl Et EtAc -15 ºC 4 Cl!-tocopherol 100 g/$65.00 PTS 55% yield overall Lack of egiocontrol PEG-600 (2 eq.) Et, T

15 Second-Generation Ampiphile: TPGS-750 Shorter Less Expensive Linker 15 Mono-methylated poly(ethylene glycol) H Et, Ph 60 ºC, 5 h 99% yield H Higher hydrophilic lipophilic balance of 1 versus 10 to PTS. TPGS-750-M g produced in one sequence early Quantitative Yield Commerically Available PEG-750-M TsH, Ph reflux, 5 h 98% yield

16 Comparison Between TPGS-750-M and Previously Synthesized Surfactants Average Diameter of Surfactants in Water Amphiphile PTS with PEG-600 PTS with PEG-1000 TPGS-1000 TPGS-750-M TPGS-550-M Average Diameter (nm) PTS TPGS-750-M PTS TPGS-750-M Shortening PEG chain leads to larger diameter. Larger nanoparticles accommodate cross-couplings more effectively. TPGS-750-M had the highest percentage of rod-like particles in aqueous media.

17 lefin tathesis eactions un in Water with First and Second-Generation Surfactants Product PTS TPGS-750-M Product PTS TPGS-750-M TBS t-bu 88% 91% t-bu 72% 74% TBS 70% 74% TBS 7 t-bu 95% 95% 78% 82% Ts 99% 99% eactions run with 2 mol % Grubbs 2nd Generation Catalyst, 2.5% surfactant/water at room temperature for 22 hours.

18 Effect of ph on Cross tathesis s s Cl u Cl PCy Ph (2 mol %) TBS 2.5% sufactant/water 22 ºC TBS surfactant TPGS-750-M TPGS-750-M, 0.02 M KHS 4 PTS, 0.02 M KHS 4 time 12 h 4 h 4 h yield 74% 9% 91% s s Cl Cl u PCy Ph KHS 4 rate determing step s s Cl u Cl Ph Active Catalyst H PCy Lowering the ph of the Aqeous Phase Increases the Amount of Active Catalyst

19 oom Temperature egishi-like Couplings -X '-Br 0.5 mol % PdCl 2 (Amphos) 2 TMEDA (1 eq.) Zn dust ( eq.) 2% surfactant/water, T ' Product PTS TPGS-750-M Product PTS TPGS-750-M Et 2 C Cy 51% 75% Bn n-c 7 H 15 85% >99:1 E:Z 84% >99:1 E:Z Et 2 C C 2 Et 48% 71% n-c 7 H 15 8% 77:2 E:Z 90% 88:12 E:Z Et 2 C 7 91% 89% 4 C 2 Et 74% 96:4 E:Z 87% >99:1 E/Z Surfactant likely insulates organozinc species from water to prevent aqueous protonation and successfully transmetallate to palladium.

20 ecycling of TPGS-750-M Ts Grubbs 2nd Gen. (2 mol %) TPGS-750-M/H 2 (2.5 wt %) T, 2 h Ts Cycles (Conversions in blue) >99% >99% >99% >99% >99% >99% 99% 99% Aqueous phase was extracted three times with diethyl ether and fresh substrate was added to the aqueous phase. Conversions were determined by proton M.

21 Summary Hydrostatic pressure significantly effects conjugate additions of nitroalkanes to sterically congested enones. 5 mol % cat. 2 (2 eq.) Ph, 20 h 2 1 bar = < 2% yield 10 bar = 80% yield, 98% ee Second-generation surfactant allows for organic solvent-free medium for various metal-catalyzed couplings at room temperature. n (n = ca. 16) enables reactions in T Heck, Suzuki-Miyuara, aminations borylations, silylations, egishi-like, olefin metathesis reactions TPGS-750-M