1. Stereoselective Synthesis of α-
Hydroxy Acids and Application
Towards a Formal Synthesis of
t-Bu
Me t-Bu
i Si
O HO CO2H
O R3 Me R2
R1 R1
AgOTs (10 mol %),
O R2 R3
–25 °C, Tol
ii. HF•Pyr
Me
Me O Me
O O
O HO2C
Me O H O O Me
HO O O
O HO
Me OP O R
N Me
Brett E. Howard
4-3-2009

2. Background: Silylene Transfer
t-Bu O
Si t-Bu
t-Bu
t-Bu Si t-Bu H Ph O
n-Bu n-Bu t-Bu Si Ph
AgOCOCF3 ZnBr n-Bu
(5 mol %) (20 mol %)
100%
73%
d.r. 65:35
• Metal-catalyzed silylene transfer provides silacyclopropanes
t-Bu
OH OH
t-Bu Si O t-BuOOH, CsOH•H2O,
Ph
Bu4NF, DMF, 70 °C Me Ph
Me
Me Me
64%
Single Diastereomer
• Silicon-carbon bonds can be oxidized using modified Tamao
conditions
Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044-6046.
Ćiraković, J.; Driver, T. G.; Woerpel, K. A. J. Org. Chem. 2004, 69, 4007-4012.

3. Silylene Transfer To Esters
t-Bu
1. Si
t-Bu t-Bu
O O
AgOTf (5 mol %) t-Bu Si
O t-Bu O t-Bu
2. TMEDA
67% (1H NMR)
• Non-enolizable esters give silacyclopropanation products
t-Bu
t-Bu
O Si t-Bu Si OH
t-Bu
O i-Pr O
AgOTf
(1 mol%) 45%
t-Bu
t-Bu t-Bu
O Si O Si
t-Bu Me
EtO EtO
AgOCOCF3
(5 mol%) 98% (1H NMR)
Ćiraković, J.; Driver, T. G.; Woerpel, K. A. J. Am. Chem. Soc. 2002, 124, 9370-9371.
Calad, A. S.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 2046-2047.

4. Proposed Silacarbonyl Ylide
t-Bu t-Bu t-Bu t-Bu
TfO Si Si t-Bu
O O O
[AgLn] Si t-Bu
O i-Pr O i-Pr O i-Pr
t-Bu t-Bu
t-Bu t-Bu Si OH
Si O
H
O O
Me Me
t-Bu t-Bu t-Bu t-Bu
O Si Si t-Bu
t-Bu O O Si
EtO Me
AgOCOCF3 EtO EtO
(5 mol%)
Driver, T. G.; Woerpel, K. A. J. Am. Chem. Soc. 2004, 126, 9993-10002.

5. Silacarbonyl Ylide Formation
Me Me Me Me hv (> 460nm) Me Me
hv (254nm) or ∆
SiMes2
Mes2Si + O O SiMes2
hv (254nm) O
Me Me Me Me Me Me
62%
R2
O SiR2 Si
pyrolysis or hv O O O H
R2Si + or SiR2
R' Me
R' Me R' Me R'
24-62%
O
t-Bu t-Bu t-Bu t-Bu
Si Si HF•Pyr
H Ph O O HO OH
Me Me CuI (10 mol%)
Ph Ph Ph Ph
61%, 2 Steps
d.r. 93:7
Ando, W.; Haglwara,K.; Sekiguchi, A. Organometallics 1987, 6, 2270-2271.
Ando, W.; Ikeno, M.; Sekiguchi, A. J. Am. Chem. Soc. 1977, 99, 6447-6449.
Franz, A.K.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 949-957.

6. Proposed α-Keto Ester
t-Bu t-Bu
O Si Si t-Bu 6π e-
O t-Bu O
O O
Me AgOCOCF3 O
(1 mol%) Me
t-Bu
t-Bu t-Bu t-Bu
O Si t-Bu t-Bu
Si
O O Si
O [3,3]
O = O O
Me O
O Me
Me
•Ireland–Claisen expected to occur through chair TS

7. Silylene Transfer to 1,2
Me
O OMe
MeO O Si
+ Ph O O
Si
Me Ph Ph
Ph
24%
•Addition to 1,2 dicarbonyls has been observed previously
t-Bu
t-Bu t-Bu
O 1 eqv. Si
t-Bu Si
OEt O O
Me
O C6D6, AgOCOCF3
Me OEt
(1 mol%), 15 min, rt
29Si NMR δ 14.2 ppm
Heinicke, J.; Gehrhus, B. J. Organomet. Chem. 1992, 423, 13-21.

8. Silylene Transfer to α-Keto Esters
O O
DCC, DMAP,
OH + O
Ph HO Ph
CH2Cl2, 0 °C
O O
58%
t-Bu t-Bu t-Bu
t-Bu t-Bu
1 eqv. Si Si O Si
O t-Bu O O
O Ph
O
Ph Ph
C6D6, AgOCOCF3 O O
O (1 mol%), 15 min, rt
52% 1H NMR
29Si NMR δ 15.2 ppm
•Intermediate dioxacyclopentene not observed

9. Silylene Transfer Optimization
t-Bu
t-Bu
O O Si
conditions O
O Ph
Ph
O O
Entry Catalyst mol % Silylene Source Silylene eqv Conditions % Yield (1H NMR)
1 AgOCOCF3 1 cyclohexyl 1 15 min, rt 53
2 AgOCOCF3 1 dimethyl 1 15 min, rt 61
3 Ag3PO4 10 cyclohexyl 1 2 h, 50 °C 46
4 Ag3PO4 10 dimethyl 1 20 h 62
5 AgOTs 10 cyclohexyl 1 15 min, rt 63
6 AgOTs 10 dimethyl 1 15 min, rt 73
7 AgOBz 10 cyclohexyl 1 15 min, rt 53
8 AgOBz 10 dimethyl 1 15 min, rt 72
9 Cu(OTf)2 1 cyclohexyl 1 2 h, 50 °C 27
10 AgOTs 10 cyclohexyl 1.3 15 min, rt 64
11 AgOTs 10 cyclohexyl 1.6 15 min, rt 73
12 AgOTs 10 dimethyl 1.6 15 min, rt 80
t-Bu
t-Bu t-Bu
dimethylsilacyclopropane Me Si Si cyclohexylsilacyclopropane
t-Bu
Me

10. Transfer Substrate Scope
t-Bu
Me t-Bu
Si
Me
O i. AgOTs (10 mol %), HO CO2H
–25 °C
O R2
R1 R1
O ii. HF•Pyr, rt R2
≥ 97:3
Entry R1 R2 % Yield
1 Me Ph 70
2 Et Ph 84
3 i-Pr Ph 54
4 t-Bu Ph 47
5 Ph Ph 71
6 Ph Me 62
7 Ph n-Bu 72
8 Ph CH2OTBS 71
9 Et (CH2)2OBn 75

11. Chiral α-Hydroxy Acid Synthesis
i. (COCl)2, DMF,
O O Me
Me CH2Cl2
Me + Me
OH O n-Bu
HO n-Bu ii. Pyr
OTBDPS OTBDPS
40%
> 97% ee
O Me
1. TBAF, THF, –20 °C
Me
O n-Bu
2. DMP, Pyr, CH2Cl2
O
62% yield, 2 steps

12. Chiral α-Hydroxy Acid Synthesis
t-Bu
Me t-Bu
Si t-Bu
Me Si t-Bu
O O
O 4 n-Bu 10 mol % AgOTs 1 O 6π electrocyclization
Me 1 R 1
6
O Me O 4 n-Bu
6
Me
t-Bu
t-Bu t-Bu t-Bu
Si O
Si [3,3] O HO CO2H
O HF•Pyr
O Me
n-Bu Me O Me
6
O 4 n-Bu n-Bu
Me Me
Me
71%, >98% ee

13. Confirmation of Stereochemistry
NH3
Ph Me
HO CO2
Me
Me
n-Bu

14. Chiral α-Hydroxy Acid Synthesis
NH2 NaNO2, AcOH, OH i. TBSCl, DMF, imid OTBS
Me Me Me
CO2H CO2H ii. KOH, MeOH, H O CO2H
H2O 2
OBn OBn OBn
71% 97%
Cl O
Cl
Cl Cl OTBS 1. TBAF, THF, –20 °C O
Me O Ph Me O Ph
cinnamyl alcohol, 2. DMP, Pyr, CH2Cl2
DMAP,NEt3, OBn O OBn O
PhH
54% 56%,
> 98% ee

15. Chiral α-Hydroxy Acid Synthesis
t-Bu
Me t-Bu t-Bu t-Bu
Si
Me Si
O O HO CO2H
O
10 mol % AgOTs Me
Me O 4 Ph 6 Ph
1 O 4
6
OBn O OBn Ph
Me OBn
H
63%,
80% diastereoselectivity

16. Silylene Transfer to Imines
t-Bu t-Bu
O Si Si t-Bu 6π e-
NR t-Bu O
O NR
AgOCOCF3 O
(1 mol%)
t-Bu
t-Bu t-Bu t-Bu
O Si t-Bu t-Bu
Si
O O Si
N R [3,3]
O = R N N R
O
O

17. Silylene Transfer to Imines
OH Cl Ph O H5IO6, THF O
HO2C OH
CO2H Ph O Ph O
OH NEt3, DMF OH OH
2
100%, complex
61% mixture of oligomers
NH2Bn, CH2Cl2 O
MgSO4
Ph O
NBn
H2N
O
OMe
Ph O
CH2Cl2, MgSO4 NPMP

18. Silylene Transfer to Imines
t-Bu
Me t-Bu
Si
Me
O
AgOTs (10 mol %),
Ph O Decomp.
NBn –25 °C, Tol
t-Bu
Me t-Bu
Si
t-Bu
Me t-Bu
O PMPN Si
AgOTs (10 mol %), O
Ph O
NPMP –25 °C, Tol Ph O
48%
• p-methoxyphenyl group provided transfer product

19. Methodology Limits
t-Bu
Me t-Bu
Si
Me
i. AgOTs (10 mol %),
O O –25 °C HO CO2H
O Ph
Ph ii. HF•Pyr, rt
O O
Me HO CO2H
Me
O O
O Ph
O
Ph
O O
O
Me
Me
O
HO CO2H
O Me
Ph
Ph
O Me
Me Me

20. (+)-Latifoline
Me
Me O
O
Me O H O
HO O
O
Me
N
• Anti leukemia and solid tumor activity
• Activity arises from DNA-Protein or DNA interstrand
crosslinking
• Synthesized by Wood in 2001
Crowley, H. C.; Culvenor, C. C. J. Aust. J. Chem. 1962, 15, 139–144.
Rajski, S. R.; Williams, R. M. Chem. Rev. 1998, 98, 2723–2795.

21. (+)-Latifoline Retrosynthesis
Me
Me O
O
Me O H O
HO O
O
Me
N
(+)-latifoline
Me
Me HO OH O
H HO2C
Me + +
O
OH HO
O N
Me
angelic acid retronecine (+)-latifolic acid

22. (+)-Latifoline Retrosynthesis
O O R
Me Me O
Me
O OH O Me
HO2C HO2C OP
HO2C
HO Me HO OP O R
Me HO Me
OP
Me OH + HO Me
OP O R
O Me
R

23. α-Keto Ester Synthesis
Cl O
Cl
OTBS OTBS
OH Cl Cl
Me + Me O Me
CO2H
Me Et DMAP,NEt3, PhH
OBn OBn O Et
86%
O
1. TBAF, THF –20 °C
Me O Me
2. DMP, Pyr, CH2Cl2
OBn O Et
71%, 2 steps

24. Silylene Transfer
t-Bu
Me t-Bu
Si
Me
O i. AgOTs (10 mol %), HO2C OH
Me O Me –25 °C Me Et
OBn O Et ii. HF•Pyr, rt OBn Me
50:50 dr, 72%

25. Transition State Analysis
t-Bu t-Bu
Si O R R R
4 120° 4 120° 4
6 O Et Me rotation Et Me rotation Et Me
Me O 1 R O R O R
O 4 1
Et 1
Me OBn H Me BnO H
BnO H H Me
Me BnO
σC–Me σ∗C–C
R = dioxosilacyclopentyl
4
Et Me HO2C OH
HO2C OH Me Et
1
BnO OBn Me
H
Me

26. Transition State Analysis
t-Bu t-Bu
Et
Si Et
O R HO CO2H
Et O 4 4
Me Me Me
6 Me R O HO CO2H
O 4 1 1
OBn Me Et
Me OBn BnO H BnO H
H Me Me
σC–Me σ∗C–C
R = dioxosilacyclopentyl
Et A value 1.75
Me A Value 1.70

27. Transition State Analysis
CF3 O CF3 OTMS CF3 O
i. LDA PdCl2(PhCN)2
1
i-Pr O i-Pr O i-Pr OH
ii. TMSCl reflux
6 4 6 4
74% yield, 88% syn
O CH3 O O CH3 OTMS O CH3 O
i. LDA PdCl2(PhCN)2
1
Me2N O Me2N O Me2N OH
ii. TMSCl reflux
6 4 6 4
71% yield, 1:1
Yamazaki, T.; Ichige, T.; Takei, S.; Kawashita, S.; Kitazume, T.; Kubota, T. Org. Lett. 2001, 3, 2915–2918.

28. Confirmation of Chair
t-Bu
Me t-Bu
Si
Me
O i. AgOTs (10 mol %), HO2C OH HO CO2H
Me O Me –25 °C Me Et Me
+
ii. HF•Pyr, rt
OBn O Et OBn Me OBn Me Et
HO2C OH H HO2C OH H
Me α β Et Me α β H
OBn H Me H OBn Me H Et

29. Increasing Steric Bulk
O O R
Me Me O
Me
O OH O Me
HO2C HO2C OP
HO2C
HO Me HO OP O R
Me HO Me

30. Increasing Steric Bulk
O O R
Me Me O
Me
O OH O Me
HO2C HO2C OP
HO2C
HO Me HO OP O R
Me HO Me
O
Me O Me
OBn O t-Bu

31. Increasing Steric Bulk
t-Bu
Me t-Bu
Si
Me
O O i. AgOTs (10 mol %),
Me O Me
+ Me O Me –25 °C
OBn O t-Bu OBn O t-Bu ii. HF•Pyr, rt
50 : 50
HO2C OH HO CO2H HO CO2H
Me t-Bu Me + Me t-Bu
+
OBn Me OBn Me t-Bu OBn Me
25 : 25 : 50

32. Vicinal Stereocontrol
t-Bu t-Bu
Si
O O HO CO2H Me
O O
Me O Me Me HO
Me
O
OBn Me O
OBn O OBn HO2C
Me
H Me
t-Bu t-Bu
Si
O O Me HO CO2H Me
O O
Me O Me HO Me
O
O O
OBn Me
OBn O Me
Me OBn HO2C HO2C
H Me
O
HO
t-Bu t-Bu
Si O
Me
O HO2C OH Me
O O
Me O Me Me HO2C (+)-latifolic acid
Me
O O
OBn O OBn Me HO
BnO Me Me
H
t-Bu t-Bu
O Me Si O HO2C OH Me
O O
Me O Me HO2C
O O
OBn O Me OBn Me HO
BnO Me Me
H

33. Lactone Synthesis
O
HO CO2H
conditions HO O
R1
R1
R2
R2 X
Entry R1 R2 X Conditions Yield d.r.
1 Ph H I NaHCO3, I2, CH3CN, 0 °C 91% 3:2
2 Et n-Bu OH H2O, t-BuOH, AD mix NR -
3 Et n-Bu Br NBS, THF, 0 °C 76% 5:1
4 Et n-Bu I NIS, THF, 0 °C 92% 3:1
5 Et n-Bu OH OsO4, NMO, CH2Cl2 73% 1:0
6 Et n-Bu OH m-CPBA, CH2Cl2 56% 0:1

34. Potential Targets
HO O HO O
Me Me
OMe PPh3, I2, Imid,
O
PMBO O O
O O CH2Cl2, reflux
HO PMBO
H OH
HO
OH
(-) delesserine 95%
O
Me O Me
Me O Me OAc
O O Me
OH O
O Me Me
O OH
Me Me
H Me Me O
Me O OAc OH
O
O
Ferupennin F Trilobolide

35. Acknowledgements
Support Crew
UCI Weiss Lab Scott Chiou
Dr. Keith Woerpel Dr. Allison Olszewski Mike Ciriza
Dr. Gregory Weiss Dr. Aron Levin Lynda Ciriza
Dr. David Van Vranken Dr. Sara Chiou LOTC
Dr. Birte Feld Dr. Yemi Adesokan
Dr. John Greaves Woerpel Lab My eternal roommate: Dr. Matt
Dr. Phil Dennison Current and Past Woerpel Morin
Dr. Joseph Ziller Members Vicky Cox
UCI Staff + Faculty Dr. Tim Clark Chris Carol
Laura Bourque Craig Bottolfson
Rainier Lab Walter Salamant Tom Campobello
Dr. Jon Rainier
Joey Georges
Dr. Jason Cox Christian Ventocilla Dr. David Colby
Dr. Jason Imbriglio Kay Buchner Dr. Rob Bahde
Dr. Scott Roberts Dr. Susan Billings Dr. David France
Dr. Shawn Allwein Dr. Stacie Calad Dr. Kevin Bahnck
Mike Taday Catt Edgley TMS Crew
Dr. Ryan Hadley Andrew Thomas DSK
Dr. Jennifer Krumper Brandon Maggs
Dr. Michael Yang This is a big horse HSN guy
Dr. Laura Anderson Rockband 2, Guitar Hero 3
Dr. Pamela Haile
Dr. Renee Link
Dr. Nick Leonard
Dr. Tony Romero

36. Acknowledgements
Support Crew
UCI Weiss Lab Scott Chiou
Dr. Keith Woerpel Dr. Allison Olszewski Mike Ciriza
Dr. Gregory Weiss Dr. Aron Levin Lynda Ciriza
Dr. David Van Vranken Dr. Sara Chiou LOTC
Dr. Birte Feld Dr. Yemi Adesokan
Dr. John Greaves Woerpel Lab My eternal roommate: Dr. Matt
Dr. Phil Dennison Current and Past Woerpel Morin
Dr. Joseph Ziller Members Vicky Cox
UCI Staff + Faculty Dr. Tim Clark Chris Carol
Laura Bourque Craig Bottolfson
Rainier Lab Walter Salamant
Matt Beaver Tom Campobello
Dr. Jon Rainier
Joey Georges
Dr. Jason Cox Christian Ventocilla Dr. David Colby
Dr. Jason Imbriglio Kay Buchner Dr. Rob Bahde
Dr. Scott Roberts Dr. Susan Billings Dr. David France
Dr. Shawn Allwein Dr. Stacie Calad Dr. Kevin Bahnck
Mike Taday Catt Edgley TMS Crew
Dr. Ryan Hadley Andrew Thomas DSK
Dr. Jennifer Krumper Brandon Maggs
Dr. Michael Yang This is a big horse HSN guy
Dr. Laura Anderson Rockband 2, Guitar Hero 3
Dr. Pamela Haile
Dr. Renee Link
Dr. Nick Leonard
Dr. Tony Romero

37. Acknowledgements
Mark and Bonnie Howard
Kevin and Kristin Howard
Howard, Aunt Julie, Uncle Steve

38. CA Peeps

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40. More CA Peeps

42. Phx Peeps

43. Fam

44. Tucson Peeps