NOTES & REFERENCES

Representative Procedure 4: Preparatory Scale Reaction

1.7 NOTES & REFERENCES

1

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Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; ObstSander, U.; Stahl, M. ChemBioChem 2004, 5, 637–643. (b) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303–319.

(c) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–1029. (d) Müller, K.; Faeh, C.;

Diederich, F. Science 2007, 317, 1881–1886. (e) Kirk, K. L. Org. Process Res. Dev.

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Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330. (h) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369. (i) Qiu, X.-L.; Xu, X.-H.; Qing, F.-L. Tetrahedron 2010, 66, 789–843. (j) Hunter, L. Beilstein J. Org. Chem. 2010, 6, 38.

(k) Vulpettil, A.; Dalvit, C. Drug Discovery Today 2012, 17, 890–897. (l) Wang, J.;

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2

Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752–6756.

3

For reviews on fluorination and trifluoromethylation to construct α-tetrasubstituted

stereocenters on ketones, see: (a) Babbio, C.; Gouverneur, V. Org. Biomol. Chem. 2006, 4, 2065–2075. (b) Prakash, G. K. S.; Beier, P. Angew. Chem., Int. Ed. 2006, 45, 2172–

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Synthesis of (Poly)fluorinated Chiral Building Blocks

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1182. (i) Ueda, M.; Kano, T.; Maruoka, K. Org. Biomol. Chem. 2009, 7, 2005–2012. (j) Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2010, 352, 2708–2732. (k) Cahard, D.; Xu, X.; Couve-Bonnaire, C.; Pannecoucke, X. Chem. Soc. Rev. 2010, 39, 558–568. (l) Zheng, Y.; Ma, J.-A. Adv. Synth. Catal. 2010, 352, 2745–2750. (m) Shibata, N.; Matsnev, A.; Cahard, D. Beilstein J. Org. Chem. 2010, 6, 65. (n) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470–477. (o) Valero, G.; Companyó, X.; Rios, R.

Chem. Eur. J. 2011, 17, 2018–2037. (p) Hollingworth, C.; Gouverneur, V. Chem.

Commun. 2012, 48, 2929–2942. (q) Macé, Y.; Magnier, E. Eur. J. Org. Chem. 2012, 2479–2492. (r) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214–8264. (s) Yang, X.; Wu, T.; Phipps, R. J.; Toste, D. F. Chem. Rev. 2015, 115, 826–

870.

4

For accounts and reviews on palladium-catalyzed allylic alkylation chemistry, see: (a)

Trost, B. M.; Vranken, Van D. L. Chem. Rev. 1996, 96, 395–422. (b) Trost, B. M. Acc.

Chem. Res. 1996, 29, 355–364. (c) Pfaltz, A.; Lautens, M. “Comprehensive Asymmetric Catalysis” III, Vol. 2 (Eds.: Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.), Springer: New York, 1999, pp. 833–884. (d) Helmchen, G. J. Organomet. Chem. 1999, 576, 203–214.

(e) Trost, B. M.; Lee, C. “Catalytic Asymmetric Synthesis”, 2nd ed. (Ed.: Ojima, I.), Wiley: New York, 2000, pp. 593–649. (f) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1–

14. (g) Graening, T.; Schmalz, H.-G. Angew. Chem. 2003, 115, 2684–2688; Angew.

Chem. Int. Ed. 2003, 42, 2580–2584. (h) Trost, B. M. J. Org. Chem. 2004, 69, 5813–

5837. (i) Lu, Z.; Ma, S. Angew. Chem. 2008, 120, 264–303.; Angew. Chem. Int. Ed. 2008,

47, 258–297. (j) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned,

Synthesis of (Poly)fluorinated Chiral Building Blocks

A. W.; Tani, K.; Seto, M.; Ma, S.; Novák, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, Jr. J. A.; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. Eur. J. 2011, 17, 14199–14223. (k) Liu, Y.; Han, S.; Liu, W.;

Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740–751.

5

(a) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int. Ed.

2005, 44, 6924–6927. (b) Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. Angew.

Chem. 2005, 117, 7414–7417.; Angew. Chem. Int. Ed. 2005, 44, 7248–7251. (c) Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M.

Nat. Chem. 2012, 4, 130–133. (d) Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B.

M. J. Am. Chem. Soc. 2006, 128, 11348–11349.

6

Shibata, N.; Suzuki, S.; Furukawa,T.; Kawai, H.; K. Adv. Synth. Catal. 2011, 353, 2037–2041.

7

Tolnai, G.L.; Szekely, A.; Mako, Z.; Gati, T.; Daru, J.; Bihari, T.; Stirling, A.; Novak, Z. Chem. Commun., 2015, 51, 4488–4491.

8

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9

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10

Shibata, N.; Suzuki, S.; Furukawa, T.; Kawai, H.; Tokunaga, E.; Yuan, Z.; Cahardb, D.

Adv. Synth. Catal. 2011, 353, 2037–2041.

11

Absolute configuration of 5c was determined by comparison of the optical rotation of

the same compound to the known literature value, see: Nakamura, M.; Hajra, A.; Endo,

K.; Nakamura, E. Angew. Chem. 2005, 117, 7414–7417.; Angew. Chem. Int. Ed. 2005,

44, 7248–7251. The absolute configuration of all other products generated herein was

Synthesis of (Poly)fluorinated Chiral Building Blocks

assigned by analogy to the absolute configuration of 5c. For full details, see the Supporting Information.

12

With the consideration of heating requirements for some less reactive substrates, toluene was assigned as the best solvent.

13

A de-fluorinated side product was obtained in the presence of Pd(PPh

3

)

4

for preparing racemic standards. Therefore, racemic samples were prepared in the presence of Pd

₂

(dba)

₃

(or Pd

₂

(pmdba)

₃

) and achiral Gly-PHOX for fluoro-allyl products. For full details, see the Supporting Information.

14

Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.

Organometallics 1996, 15, 1518–1520.

15

Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc., 2007, 129, 11340–11341.

16

Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth. 2009, 86, 181–205.

17

McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett. 2010, 51, 5550–5554.

18

Rambla, M.; Duroure, L.; Chabaud, L.; Guillou, C. Eur. J. Org. Chem. 2014, 7716–

7720.

19

Tolnai, G. L.; Szekely, S.; Mako, Z.; Gati, T.; Daru, J.; Bihari,T.; Stirling, A; Novak, Z. Chem. Commun., 2015, 51, 4488–4491.

20

Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348–11349.

21

King, S.; Ma, X.; Herzon, S. B. J. Am. Chem. Soc. 2014, 136, 6884−6887.

Synthesis of (Poly)fluorinated Chiral Building Blocks

22

Shibata, N.; Suzuki, S.; Furukawa, T.; Kawai, H.; Tokunaga, E.; Yuan, Z.; Cahardb, D.

Adv. Synth. Catal. 2011, 353, 2037–2041.

23

Smith, A. M. R.; Rzepa, H. S.; White, A. J. P.; Billen, D.; Hii, K. K. J. Org. Chem.

2010, 75, 3085–3096.

24

Craig, R. A.; Loskot, S. A.; Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M.

Org. Lett. 2015, 17, 5160−5163.

25

Bennett, N. B.; Duquette, D. C.; Kim, J.; Liu, W.; Marziale, A. N.; Behenna, D. C.;

Virgil, S. C.; Stoltz, B. M. Chem. Eur. J. 2013, 19, 4414–4418.

26

Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M.

Nature Chem. 2012, 4, 130–133.

27

Bélanger, É.; Cantin, K.; Messe, O.; Tremblay, M.; Paquin, J.-F. J. Am. Chem. Soc.

2007, 129, 1034–1035.

28

Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem. Int. Ed. 2005, 44, 7248–7251.

29

Shibata, N.; Suzuki, S.; Furukawa, T.; Kawai, H.; Tokunaga, E.; Yuan, Z.; Cahardb, D.

Adv. Synth. Catal. 2011, 353, 2037–2041.

APPENDIX 1

Spectra Relevant to Chapter 1:

Palladium-Catalyzed Enantioselective

Csp

³

–Csp

³

Cross-Coupling for the Synthesis

of (Poly)fluorinated Chiral Building Blocks

O O

O CF3 4a Figure A1.1.1 H NMR (500 MHz, CDCl3) of compound 4a.

Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound 4a.

Figure A1.3. ¹³C NMR (101 MHz, CDCl3) of compound 4a.

Figure A1.4. ¹⁹F NMR (282 MHz, CDCl3) of compound 4a.

O O

O CF3 4b Figure A1.5.1 H NMR (500 MHz, CDCl3) of compound 4b.

Figure A1.6. Infrared spectrum (Thin Film, NaCl) of compound 4b.

Figure A1.7. ¹³C NMR (101 MHz, CDCl3) of compound 4b.

Figure A1.8. ¹⁹F NMR (282 MHz, CDCl3) of compound 4b.

O O

O F 4c Figure A1.9.1 H NMR (500 MHz, CDCl3) of compound 4c.

Figure A1.10. Infrared spectrum (Thin Film, NaCl) of compound 4c.

Figure A1.11. ¹³C NMR (101 MHz, CDCl3) of compound 4c.

Figure A1.12. ¹⁹F NMR (282 MHz, CDCl3) of compound 4c.

NO

O N Cl 9 Figure A1.13.1 H NMR (500 MHz, CDCl3) of compound 9.

Figure A1.14. Infrared spectrum (Thin Film, NaCl) of compound 9.

Figure A1.14. ¹³C NMR (101 MHz, CDCl3) of compound 9.

O O

O Cl 10 Figure A1.16.1 H NMR (500 MHz, CDCl3) of compound 10.

Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 10.

Figure A1.18. ¹³C NMR (101 MHz, CDCl3) of compound 10.

O O

O F Cl 4d Figure A1.19.1 H NMR (500 MHz, CDCl3) of compound 4d.

Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 4d.

Figure A1.21. ¹³C NMR (101 MHz, CDCl3) of compound 4d.

Figure A1.22. ¹⁹F NMR (282 MHz, CDCl3) of compound 4d.

NO

O N F 11 Figure A1.23.1 H NMR (500 MHz, CDCl3) of compound 11.

Figure A1.24. Infrared spectrum (Thin Film, NaCl) of compound 11.

Figure A1.25. ¹³C NMR (101 MHz, CDCl3) of compound 11.

Figure A1.26. ¹⁹F NMR (282 MHz, CDCl3) of compound 11.

O O

O F 12 Figure A1.27.1 H NMR (500 MHz, CDCl3) of compound 12.

Figure A1.28. Infrared spectrum (Thin Film, NaCl) of compound 12.

Figure A1.29. ¹³C NMR (101 MHz, CDCl3) of compound 12.

Figure A1.30. ¹⁹F NMR (282 MHz, CDCl3) of compound 12.

O O

O F

Me 4e Figure A1.31.1 H NMR (500 MHz, CDCl3) of compound 4e.

Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 4e.

Figure A1.33. ¹³C NMR (101 MHz, CDCl3) of compound 4e.

Figure A1.34. ¹⁹F NMR (282 MHz, CDCl3) of compound 4e.

O O O CF3 4g Figure A1.35.1 H NMR (500 MHz, CDCl3) of compound 4g.

Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 4g.

Figure A1.36. ¹³C NMR (101 MHz, CDCl3) of compound 4g.

Figure A1.36. ¹⁹F NMR (282 MHz, CDCl3) of compound 4g.

O O O CF3 4h Figure A1.39.1 H NMR (500 MHz, CDCl3) of compound 4h.

Figure A1.40. Infrared spectrum (Thin Film, NaCl) of compound 4h.

Figure A1.41. ¹³C NMR (101 MHz, CDCl3) of compound 4h.

Figure A1.42. ¹⁹F NMR (282 MHz, CDCl3) of compound 4h.

O O OF 15 Figure A1.43.1 H NMR (500 MHz, CDCl3) of compound 15.

Figure A1.44. Infrared spectrum (Thin Film, NaCl) of compound 15.

Figure A1.45. ¹³C NMR (101 MHz, CDCl3) of compound 15.

Figure A1.46. ¹⁹F NMR (282 MHz, CDCl3) of compound 15.

O O OF F 4i Figure A1.47.1 H NMR (500 MHz, CDCl3) of compound 4i.

Figure A1.48. Infrared spectrum (Thin Film, NaCl) of compound 4i.

Figure A1.49. ¹³C NMR (101 MHz, CDCl3) of compound 4i.

Figure A1.50. ¹⁹F NMR (282 MHz, CDCl3) of compound 4i.

O O OF Me 4j Figure A1.51.1 H NMR (500 MHz, CDCl3) of compound 4j.

Figure A1.52. Infrared spectrum (Thin Film, NaCl) of compound 4j.

Figure A1.53. ¹³C NMR (101 MHz, CDCl3) of compound 4j.

Figure A1.54. ¹⁹F NMR (282 MHz, CDCl3) of compound 4j.

BzN

O O

O CF3 4k Figure A1.55.1 H NMR (500 MHz, CDCl3) of compound 4k.

Figure A1.56. Infrared spectrum (Thin Film, NaCl) of compound 4k.

Figure A1.57. ¹³C NMR (101 MHz, CDCl3) of compound 4k.

Figure A1.58. ¹⁹F NMR (282 MHz, CDCl3) of compound 4k.

BzN

O O

O F 17 Figure A1.59.1 H NMR (500 MHz, CDCl3) of compound 17.

Figure A1.60. Infrared spectrum (Thin Film, NaCl) of compound 17.

Figure A1.61. ¹³C NMR (101 MHz, CDCl3) of compound 17.

Figure A1.62. ¹⁹F NMR (282 MHz, CDCl3) of compound 17.

BzN

O O

O F

Me 4l Figure A1.63.1 H NMR (500 MHz, CDCl3) of compound 4l.

Figure A1.64. Infrared spectrum (Thin Film, NaCl) of compound 4l.

Figure A1.65. ¹³C NMR (101 MHz, CDCl3) of compound 4l.

Figure A1.66. ¹⁹F NMR (282 MHz, CDCl3) of compound 4l.

N

O O

O BnO CF3O 4m Figure A1.67.1 H NMR (500 MHz, CDCl3) of compound 4m.

Figure A1.68. Infrared spectrum (Thin Film, NaCl) of compound 4m.

Figure A1.69. ¹³C NMR (101 MHz, CDCl3) of compound 4m.

Figure A1.70. ¹⁹F NMR (282 MHz, CDCl3) of compound 4m.

BzN

O O

O CF3 4n Figure A1.71.1 H NMR (500 MHz, CDCl3) of compound 4n.

Figure A1.72. Infrared spectrum (Thin Film, NaCl) of compound 4n.

Figure A1.73. ¹³C NMR (101 MHz, CDCl3) of compound 4n.

Figure A1.74. ¹⁹F NMR (282 MHz, CDCl3) of compound 4n.

OCF3 5a Figure A1.75.1 H NMR (500 MHz, CDCl3) of compound 5a.

Figure A1.76. Infrared spectrum (Thin Film, NaCl) of compound 5a.

Figure A1.77. ¹³C NMR (101 MHz, CDCl3) of compound 5a.

Figure A1.78. ¹⁹F NMR (282 MHz, CDCl3) of compound 5a.

O

CF3 5b Figure A1.79.1 H NMR (500 MHz, CDCl3) of compound 5b.

Figure A1.80. Infrared spectrum (Thin Film, NaCl) of compound 5b.

Figure A1.81. ¹³C NMR (101 MHz, CDCl3) of compound 5b.

Figure A1.82. ¹⁹F NMR (282 MHz, CDCl3) of compound 5b.

O F 5c Figure A1.83.1 H NMR (500 MHz, CDCl3) of compound 5c.

Figure A1.84. Infrared spectrum (Thin Film, NaCl) of compound 5c.

Figure A1.85. ¹³C NMR (101 MHz, CDCl3) of compound 5c.

Figure A1.86. ¹⁹F NMR (282 MHz, CDCl3) of compound 5c.

O F Cl 5d Figure A1.87.1 H NMR (500 MHz, CDCl3) of compound 5d.

Figure A1.88. Infrared spectrum (Thin Film, NaCl) of compound 5d.

Figure A1.89. ¹³C NMR (101 MHz, CDCl3) of compound 5d.

Figure A1.90. ¹⁹F NMR (282 MHz, CDCl3) of compound 5d.

O F 5e Figure A1.91.1 H NMR (500 MHz, CDCl3) of compound 5e.

Figure A1.92. Infrared spectrum (Thin Film, NaCl) of compound 5e.

Figure A1.93. ¹³C NMR (101 MHz, CDCl3) of compound 5e.

Figure A1.94. ¹⁹F NMR (282 MHz, CDCl3) of compound 5e.

O CF3 5f Figure A1.95.1 H NMR (500 MHz, CDCl3) of compound 5f.

Figure A1.96. Infrared spectrum (Thin Film, NaCl) of compound 5f.

Figure A1.97. ¹³C NMR (101 MHz, CDCl3) of compound 5f.

Figure A1.98. ¹⁹F NMR (282 MHz, CDCl3) of compound 5f.

O CF3 5g Figure A1.99.1 H NMR (500 MHz, CDCl3) of compound 5g.

Figure A1.100. Infrared spectrum (Thin Film, NaCl) of compound 5g.

Figure A1.101. ¹³C NMR (101 MHz, CDCl3) of compound 5g.

Figure A1.102. ¹⁹F NMR (282 MHz, CDCl3) of compound 5g.

O CF3 5h Figure A1.103.1 H NMR (500 MHz, CDCl3) of compound 5h.

Figure A1.104. Infrared spectrum (Thin Film, NaCl) of compound 5h.

Figure A1.105. ¹³C NMR (101 MHz, CDCl3) of compound 5h.

Figure A1.106. ¹⁹F NMR (282 MHz, CDCl3) of compound 5h.

O F

F 5i Figure A1.107.1 H NMR (500 MHz, CDCl3) of compound 5i.

Figure A1.108. Infrared spectrum (Thin Film, NaCl) of compound 5i.

Figure A1.109. ¹³C NMR (101 MHz, CDCl3) of compound 5i.

Figure A1.110. ¹⁹F NMR (282 MHz, CDCl3) of compound 5i.

O F 5j Figure A1.111.1 H NMR (500 MHz, CDCl3) of compound 5j.

Figure A1.112. Infrared spectrum (Thin Film, NaCl) of compound 5j.

Figure A1.113. ¹³C NMR (101 MHz, CDCl3) of compound 5j.

Figure A1.114. ¹⁹F NMR (282 MHz, CDCl3) of compound 5j.

N

O Bz

CF3 5k Figure A1.115.1 H NMR (500 MHz, CDCl3) of compound 5k.

Figure A1.116. Infrared spectrum (Thin Film, NaCl) of compound 5k.

Figure A1.117. ¹³C NMR (101 MHz, CDCl3) of compound 5k.

Figure A1.118. ¹⁹F NMR (282 MHz, CDCl3) of compound 5k.

N

O Bz F 5l Figure A1.119.1 H NMR (500 MHz, CDCl3) of compound 5l.

Figure A1.120. Infrared spectrum (Thin Film, NaCl) of compound 5l.

Figure A1.121. ¹³C NMR (101 MHz, CDCl3) of compound 5l.

Figure A1.122. ¹⁹F NMR (282 MHz, CDCl3) of compound 5l.

N

O BnO O

CF3 5m Figure A1.123.1 H NMR (500 MHz, CDCl3) of compound 5m.

Figure A1.124. Infrared spectrum (Thin Film, NaCl) of compound 5m.

Figure A1.125. ¹³C NMR (101 MHz, CDCl3) of compound 5m.

Figure A1.126. ¹⁹F NMR (282 MHz, CDCl3) of compound 5m.

N

O CF3Bz 5n Figure A1.127.1 H NMR (500 MHz, CDCl3) of compound 5n.

Figure A1.128. Infrared spectrum (Thin Film, NaCl) of compound 5n.

Figure A1.129. ¹³C NMR (101 MHz, CDCl3) of compound 5n.

Figure A1.130. ¹⁹F NMR (282 MHz, CDCl3) of compound 5n.

asymmetric allylic alkylation and ring contraction

CHAPTER 2

Synthesis of enantioenriched 2,2-disubstituted pyrrolidines via sequential asymmetric allylic

alkylation and ring contraction

^*