1. “Synthesis of 12-S-HETE using asymmetric phase-transfer catalysis” Spring 2009 ACS Meeting Mike A. Christiansen, Merritt B. Andrus Brigham Young University Department of Chemistry & Biochemistry

2. Obtaining Asymmetrically Pure C-C Bonds
Three ways of obtaining asymmetrically pure products:
Using optically pure starting materials from nature (the “chiral pool”)
Separating racemates (classical resolution, crystallization, kinetic resolution using an enzyme)
Asymmetric synthesis (enzyme-mediated, non-catalytic, catalytic)
Enzyme-Mediated Asymmetric Bond Formation: 1
Ankati, H. et al. J. Org. Chem. 2008, 73,
Non-Catalytic Asymmetric C-C Bond Formation: 3 4 2
Crimmins, M. T. et al. Org. Lett. 2000, 2, Ager, D. J. et al. Chem. Rev. 1996, 96,

3. Catalytic C-C Bonds Via Asymmetric Alkylation
Catalytic Asymmetric Synthesis

4. Catalytic C-C Bonds Via Asymmetric Phase-Transfer-Catalyzed (PTC) Alkylation6 5 7
Figure 1. The mechanism of phase-transfer catalyzed alkylation, aldol, or Michael addition reactions1
CH3Cl, PhMe, 50% KOH 8
10: 98% y, 94% ee2
R = CH3, H, CH2COOEt,
or CH2COOH
9 (10 mol%)
Hicken, E. J. Ph.D. thesis, Brigham Young University, Provo, UT, 2005.
(a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am Chem. Soc. 1984, 106, (b) Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.; Schoenewaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52,

5. Asymmetric Phase-Transfer-Catalyzed (PTC) Alkylation
BnBr, CH2Cl2, 50% NaOH 11
O’Donnell et al. J. Am. Chem. Soc. 1989, 111,
13: 75%, 66% ee1
12 (10 mol %)
BnBr, Catalyst (10 mol%), conditions 11 15 14 * *
Lygo2
50% eq. KOH, PhMe, 25ºC
18 h, 68%, 91% ee
Corey3
CsOH (H2O), CH2Cl2, -78ºC
23 h, 87%, 94% ee
Lygo: R = H, X =Cl
Corey: R = allyl, X = Br
Lygo, B. et al. Tetrahedron Lett. 1997, 38,
Corey, E. J. et al. J. Am. Chem. Soc. 1997, 119,

6. Asymmetric Phase-Transfer-Catalyzed (PTC) Alkylation
Andrus group attempts:
Base, BnBr, catalyst
Low yield/selectivity 15 16
Alternative Approach:
Base, BnBr
catalyst
Baeyer-Villiger
oxidation 17

7. Asymmetric PTC Alkylation with 18
Andrus, M. B.; Hicken, E. J.; Stephens, J. C. Org. Lett. 2004, 6,

8. The Asymmetric Total Synthesis of Kurasoin A
24% yield
over seven steps
Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K. J. Org. Chem. 2006, 71,

9. Attempts at Kurasoin B Evans’ work: . MeI, DMF, 60 C, 24 h
. Nuc (-) at rt 24 25
(a) Evans, D. A et al. J. Am. Chem. Soc. 2005, 127, (b) Org. Lett. 2006, 8, (c) Org. Lett. 2006, 8,
Nuc = ROH, RNH2, morph.

10. The Results: Selective Alkylation of Substrate 25
MeOTf, CH2Cl2
MeOH, NaOMe
quant., no racemization
26, CsOH•H2O,
CH2Cl2, RBr -40 °C 25 27 28
= NAP
DDQ, rt, 5h, 70%
(for R=Bn only) R=
%yield
%ee 90 88 85 91 84 86
>99 75 92 80 77 79
S - 292
[α]D – 6.25°
Lit. [α]D –6.8° 26 A
Andrus, M. B.; Christiansen, M. A.; Hicken, E. J.; Gainer, M. J.; Bedke, D. K.; Harper, K. C.; Mikkelson, S. R.; Dodson, D. S.; Harris, D. T. Org. Lett. 2007, 9, 4865.
Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc. 1998, 120,

11. The Total Synthesis of Kurasoin B
(COCl)2, morph.,
16 h, 73%
20h, 134% crude yield
86%
(84% from BnOH
BuLi 31 32 ° 30
26, CH2Cl2,
CsOH, -40°C, 3.5 h
98%, >99% ee
. MeOTf, CH3CN (2 h)
. MeOH, DBU (4 h)
94%, 88% ee
BCl3,
THF, -78°C  -20 °C
18 h, 100%
HN(OCH3)CH3
AlMe3, reflux
18 h, 92% 34 ° ° 35
-2.5 °
TESCl, imidazole, DMF, rt, 2 h, 70%
kurasoin B
+45 °
43% yield over 10 steps
BnMgCl
THF, 0°C, 99%
TBAF, THF
87% 36
+8.16 37 °
Christiansen, M. A.; Butler, A. W.; Hill, A. R. Andrus, M. B. Synlett. 2009, 4,

12. The Total Synthesis of (S)-Naproxen38 41
48% yield
(five steps)
Andrus, M. B.; Harper, K. C.; Christiansen, M. A.; Binkley, M. A. J. Org Chem. submitted for publication.

13. Proposed Total Synthesis of (S)-Equol42 43 46 45 44 47
Andrus group, unpublished work

14. An Introduction to 12-S-HETE
12(S)-hydroxy-6(E),8(Z),10(E),14(Z)-eicosatetraenoic acid (12-S-HETE)
A product of the 12-lipoxygenase pathway from arachidonic acid
Discovered by Hamberg and Samuelsson in 1974 (see Proc. Natl. Adam. Sci. U.S.A. 1974, 71, 3400)
Plays a role in multiple biological pathways and conditions, including angiogenesis, cancer metastasis, atherogenesis, coronary thrombosis, type I diabetes, inflammation, psoriasis, and apoptosis (see Org. Lett. 2000, 2, ).
It possesses potential as a pharmaceutical lead in investigating and treating various clinical processes and conditions.

15. Total Syntheses of 12-S-HETE48 49 50 51 52 53 54 55 56 57 59
Corey, E. J. et al. J. Am. Chem. Soc. 1978, 100, 60 61 62

16. Total Syntheses of 12-S-HETE (continued)
Two racemic syntheses:
Gunn, B. P.; Brooks, D. W. J. Org. Chem. 1985, 50,
Rodríguez, A.; Nomen, M. Spur, B. W.; Godfroid, J. J.; Lee, T. H. Tetrahedron 2001, 57,
Separation of racemates by classic resolution:
Shimazaki, T.; Kobayashi, Y.; Sato, F. Chem. Lett. 1988,
Separatiion of racemates by kinetic resolution using an enzyme:
Suh, Y.-G.; Min, K.-H.; Lee, Y.-S.; Seo, S.-Y.; Kim, S.-H.; Park, H.-J. Tetrahedron Lett. 2002, 43, 64 63 65 67
(±)-12-HETE

17. Our Proposed Approach to 12-S-HETE
red. 68 30 69 70 71 64 72 73
Our initial screens: 75 74 68

18. Improving the Synthesis of Electrophile 6875 74 78 77 75 74
= 68 68 30 69

19. Optimizing the Catalyst and Conditions68 30 69

20. Our Total Synthesis of 12-S-HETE to Date75 74 68 30 69 70 64 73 71 72

21. Conclusions
A new method of asymmetric phase-transfer-catalyzed alkylation has been described.
The synthetic utility of this method has been demonstrated with the total syntheses of kurasoin A, kurasoin B, and S-naproxenTM, with current work toward S-equol.
This methodology is currently being applied to an improved asymmetric total synthesis of the natural compound 12-S-HETE.

22. Acknowledgements 2007-2008 Garth L. Lee Fellowship
Professor Merritt Andrus, Erik Hicken, Morgan Gainer, Karl Bedke, Kaid Harper, Aaron Butler, Amanda Hill, Meisha Binkley, Jason Nielson, and Adam Calvert
Financial Support Provided by:
Department of
Chemistry
& Biochemistry
Garth L. Lee Fellowship
BYU Graduate Research Presentation Award
Roland K. Robins Graduate Research Fellowship
Telford and Frank Woolley Memorial Research Award
Charles E. and Margaret P. Maw Fellowship

23. How the Catalyst Work 14 (10 mol%), CsOH (H2O), * CH2Cl2, BnBr 11 S-13‡
14 (10 mol%),
CsOH (H2O),
CH2Cl2, BnBr * 11
S-13
-78ºC, 23 h,
94% ee, 87% yield 14
Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,