1. A Career in Pharmaceuticals:
Drug Hunting in The Lipitor Era
Gregg M Kamilar

2. 14C Radiosynthesis
Custom Synthesis of Radiolabeled Compounds
ViTrax – Placentia, CA
2011-2012

3. Labeled ROMP Monomer
High SA Polymer Substrate

4. High % Isotopic Incorporation via “Click Labeling”

5. Addressing Unexpected Isomeric Effects
Tetrahedron. 2004, 60, 11415-11420

6. Boranophosphate Nucleotide
Monomers
Building Blocks for RNAi Oligomer Synthesis
Pfizer, Inc – Cambridge, MA
2008-2009

7. Boranophosphates Delivered
Adenosine (N-BZ) 3.15 g
Cytidine (N-BZ) 3.56 g
Thymidine (N-BZ) 3.32 g
Guanosine (N-PAC)(O-DPC) 3.21 g

8. Optimizing Boranophosphorylation
Partial
purification
preserves
overall yield
Short reaction times
reduces side-
Working in 1 gram batches improves products
reproducibility and yield
Efficient
purification at this
step allows for use
of less pure
substrate
increasing
throughput

9. Protected Thymidine
Nucleosides, Nucleotides and Nucleic Acids, 20:12, 1927 - 1939

10. Protected Guanosine
J. Org. Chem. 2004, 69, 5261-5268

11. Boranophosphorylating Reagent – Literature Method
•3 steps/3 purifications
•Isolation of phosphite
triester was problematic
J. Am. Chem. Soc., 98, 7327 (1976)

12. Boranophosphorylating Reagent – Modified method
•2 steps/2 purifications
•No isolation of phosphite triester
•Scaled successfully to >25 g
•Final salt is highly stable oil @ RT
J. Am. Chem. Soc., 98, 7327 (1976)

13. Literature Synthesis of MNTP Condensing Reagent
Key
Intermediate
Tetrahedron 62 (2006) 3667–3673

14. Alternate Synthesis of The Key Intermediate
Aldrich
D15,780-5
$4.48 - 7.89 / gram
J. Am. Chem. Soc. 1967, 89, 6276–6282

15. Completed Synthesis of MNTP
Aldrich
D15,780-5
$4.48 - 7.89 / gram
J. Am. Chem. Soc. 1967, 89, 6276–6282
Tetrahedron 2006, 62, 3667-3673

16. 2’-Cyclopropyl Nucleotide
A Building Block for RNAi Oligomer Synthesis
Pfizer, Inc – Cambridge, MA
2009

17. Route to 2’-Cyclopropyl U and C
CAN. J. CHEM. VOL. 71, 1993, p 413
J. Org. Chem., Vol. 62, No. 5, 1997

18. Scaled Synthesis of Starting Ketone
Can. J. Chem. Vol 44 , 1966, p. 836

19. Mitsunobu Protection of Uridine O4
J. Org. Chem., Vol. 62, No. 5, 1997

20. Scaled Cycloaddition
Modified from
Org. Syn. 1935, 16, 3
Can. J. Chem. Vol 44 , 1966, p. 836
NH O
H
H3C N N N+
N O-
O

21. Conversion to Cyclopropane
Can. J. Chem. Vol 44 , 1966, p. 836

22. Undesired Glycosidic Cleavage
Can. J. Chem., 1993, 71, 413
Heterocycles, 2003, 59, 207

23. Substrate Effects in Deprotection
Heterocycles, 2003, 59, 207
OEt O
10 : 1
N HN
OBz MeOH : 1 M HCl OBz
O N O N
TBDMSO HO
O OBz O OBz
RT
TBDMSO OMe 83% OH OMe
OEt OEt
N 10 : 1 N OEt
N O MeOH : 1 M HCl HO
N O O N
Si O HO +
O O
O N O
RT 90 ºC OH H
Si O OH

24. New Protection Strategy for Uridine
1) Benzoyl group can be left on until final oligo deprotection
2) Can be removed under mild conditions prior to phosphitylation
3) Installation is a high yielding reaction
J. Am. Chem. Soc. 1992, 114, 4008-4010
J. Med. Chem., 1991, 34, 999-1002

25. Synthesis and SAR of A Bacterial
Translation Inhibitor
Pharmacia, Inc – Kalamazoo, MI
1999-2003

26. A Three Ring Pharmacophore
Ring substitution
Isosteric carboxylic
acid replacements
Linkers
HO
O
Ring substitution
H Other Sulfonamides
Br A N Linkers
B
O
O
S
O
Ring substitution N C Cl
Meta is better
Heterocycles

27. Synthetic Route
R6 R6
R6 R5 COOH R5 CO2Cl
Cl N
R5 COOH H (COCl)2
R4 R2 R4 R2
CH2Cl2 O S O CH2Cl2 O S O
R4 R2
Py N N
SO2Cl
Cl Cl
O CH2Cl2
HO O
O Py O
O
LiOH H R6 R5
H R6 R5
Br N Br NH2
Br N Dioxane R4
R4 40 oC O O
O O R2 S
R2 S O
O N Cl
N Cl

28. Direct o/p Chlorosulfonation
CO2H(Me) CO2H(Me)
G HSO3Cl G
65o-120 oC
SO2Cl
CO2H(Me) CO2H(Me)
HSO3Cl
65o-120 oC
SO2Cl
G G

29. m/o Chlorosulfonation via Diazotization
CO2Me HCl CO2Me CuCl . 2H2O CO2Me
AcOH SO2(g)
+ NaNO2 -
H2O Cl AcOH
+
G NH2 -10 oC G N
N 5 oC G SO2Cl
CO2Me HCl CO2Me CuCl . 2H2O CO2Me
G AcOH G SO2(g) G
+ NaNO2 -
H2O Cl AcOH
+
NH2 -10 oC N 5 oC SO2Cl
N
Organic Syntheses, Vol 60, p.121, (1981)

30. Convergent Synthesis of Cyanoanthranilic Acids
COOH
COOH
Cl
HO
H H
1) (COCl)2 / DMF N
SO2Cl O O
N NaCNBH3 N O S O CH2Cl2
S
H O
AcOH MeOH N C N
Cl Cl N
Et3N 2) LiOH
Dioxane O
Cl
PHA-xxx523
SAUR MIC 0.125 g/mL
2 g/mL in 5% serum
Br COOMe N C COOMe
+ CuCN
NMP Ratio = 16
Reflux
NH2 NH2

31. Synthesis of a Versatile Intermediate
OEt OH Cl
OEt further DMF
O O O
O ClSO3H N heating N (COCl)2 N
N
O O O
O 80 °C CH2Cl2
O O O
S S S
Cl Cl O Cl O
O
PHA-xxx228
External CRO
HO
O
PO H
PG
O R2 N N O
O
R2 NH2 H
R2 N N O O
1) HNR'R", base
CH2Cl2 O 2) Deprotect acid O S O
Py
N
O S R'
O R"
~ 15 gram scale Cl

32. Parallel Routes Afford Diversity
t-BuO
METHOD A O
t-BuO O
N C NH N O
NH2 1. HNR'R"
X HO
O 2. TFA O
O N C
N
O O S N C NH N O
O
O CH2Cl2, reflux Cl
S O
Cl O
X = OH N C BnO
1. HNR'R" O S
(COCl)2 O O
2. H2, Pd/C
DMF NH2 N
X = Cl N C NH R'
CH2Cl2 N O R"
BnO O
METHOD B O
O S O
Cl

33. Synthesis of A Novel
Bacterial Gyrase Inhibitor
Pharmacia, Inc – Kalamazoo, MI
2004-2005

34. Mechanism of Alkylidene Cyclization
O O
HN NH HN NH
-
O O O O
[1,5] Hydride Shift
O2N O2N
H
+
N N
O O
O
H O
HN NH N
O
- NH
O O O2N
O2N H H O
H N
+
N O
O
Verboom, W.; Reinhoudt, D. N.;
Visser, R.; Harkema, S. J. Org.
Chem. 1984, 49, 269-276.

35. Classical Morpholine Synthesis
 2,6-Dimethylmorpholine is the only commercial 2,6-disubstituted morpholine.
 Beilstein search reveals only 2 other 2,6-disubstituted morpholines.
 Symmetrical cis morpholines are meso.
 Non-symmetrical morpholines have regioselectivity problems in final step.
Intermediates Made by Classical Morpholine Synthesis-
O O
OH OH H2SO4
H
N N
R R 150 ºC N
H
Bn
 Cis and trans isomers difficult to separate.
J. Het.Chem. 1977, 14, 899-904
 Asymmetric synthesis is highly unlikely.
 Morpholines are volatile.

36. Racemic Non-Symmetrical Analogs
H O H O H O
N N N
O O O
O2N NH O2N NH O2N NH
H H H
O O O
N N N
O O O
CF3
H O H O H O
N N N
O O O
O2N NH O2N NH O2N NH
H H H
O O O
N CF3 N N
O O O

37. Finishing the Asymmetric Synthesis
F O
O
H
O
Cl O
O N O
Unpublished N O Cl NO2
H
1) CH2Cl2, RT N Hunig's
HCl K2CO3
2) MeOH, reflux
CH3CN NO2
reflux
(2S,6S)-(-) (2S,6S)-(-)
O
H O
HN NH N
O
O2N NH
O O
H
O
N
CH3OH
reflux O
(2S,4S,4aS)-(-)-

38. Regioselectivity via Non-Symmetrical Morpholines
O
H O
HN NH N
-
O
O O O2N NH
Favored?
O2N H
H O
H N Me
O Me
+
N O
HN NH O
CF3
-
O O CF3
[1,5] hydride
O2N shift
H
+ Me
N O
O
H O
HN NH N
CF3 O
- NH
O O O2N
O2N H
H O
H N CF3
+ CF3
N O
O
Me
Me

39. A Regioselective Synthesis
O
NH2 HO Br
O
O OH N
CH3CN H TEA
+ + Br F3C
F3C RT N Cl CH2Cl2
F3C
0o C
Racemic
Commercial
F O
H
F3C O Cl O
F3C O
NaH/THF LAH/THF F3C O
O Cl NO2
N O N HCl
60o N
0o - RT
H K2CO3
CH3CN
reflux
O O
O NH NH
F3C O O O
O2N NH NH
HN NH O2N
H H
N O O O
O O N CF3
N
H O O
MeOH CF3
reflux
NO2
88 : 12

40. [1,5] Hydride Shift Mechanism
O
O O
HN NH H Ha H O H
NH H N N
O O H Ha O
O O O2N NH
O2N NH O2N
O2N Ha [1-5] shift Hb O
O NH
Hb CH3 CH3
Me N N O Hb CH3
N O irreversible N O O
CH3 CH3
O CH3
1 10a 11
Me
bond rotation
O O
HN HN
O NH O NH
O Hb
O2N O2N
O2N H HbO N O
N
Me
N Ha H CH3
Ha H CH3
O O
O CH3
9 Me 10b CH3
12
PNU-286607