recent advances in stereoselective -cyclopropane …...synthesis of 2 diastereomers ho et tipso...
TRANSCRIPT
![Page 1: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/1.jpg)
Recent Advances in Stereoselective�-Cyclopropane Amino Acid Syntheses
R. Adam MoseyMichigan State University
November 10, 2004
NH2
CO2H
R1
R2
![Page 2: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/2.jpg)
Naturally Occurring �-CyclopropaneAmino Acids
HH O
HN
HO2C H
O
Coronatine
H2N CO2HHN NH2
NH
NH2HO2C
CarnosadineACC1-amino-1-cyclopropane carboxylic acid
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 3: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/3.jpg)
Why Make �-Cyclopropane Amino Acids?
• Drug applications• Reactive intermediates• Cause conformational changes when
placed in proteins• Studying some biosynthetic pathways
![Page 4: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/4.jpg)
Synthesized Compounds With Possible Drug Applications
CO2H
NH2
HO
(+)-(E)-2,3-methano-m-tyrosineDDC Inhibitor
N N
S
O NH
O
N
O
HN
HN
OO
O
CO2H
BILN 2061HCV NS3 Protease Inhibitor
Adams, L.; Aggarwal, V.; Bonnert, R.; Bressel, B; Cox, R.; Shepard, J.; de Vincent, J.; Walter, M.; Whittingham, W.; Winn, C. J. Org. Chem. 2003, 68, 9433.Faucher, A-M.; Bailey, M.; Beaulieu, P.; Brochu, C.; Duceppe, J-S.; Ferland, J-M.; Ghiro, E.;Gorys, V.; Halmos, T.; Kawai, S.; Poirier, M.; Simoneau, B.; Tsantrizos, Y.; Llinas-Brunet, M.Org. Lett. 2004, 6, 2901.
Boehringer Ingelheim Ltd. Compound
![Page 5: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/5.jpg)
Synthesis of 2,3-diaminodihydropyrroles
NHCbz
HO O
NHCbz
H2N S
NHCbz
H2N S
1. EDCI, NH4Cl DMF
2. Lawesson's Reagent THF, 50 oC
MeI, 60 oCacetone
I-
H2N SI
NHCBz
NH
S
NHCBzTautomerization
N S
NHCBz
1 2
34
NHR2
N NR2
NHCBzP
SP
SOMeMeO
S
S
Lawesson's Reagent
Kuduk, S.; Ng, C.; Chang, R.; Bock, M. Tetrahedron Lett. 2003, 44, 1437.
pyrrolothioimidate
![Page 6: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/6.jpg)
Physical Effects of CyclopropaneIntroduction
HN C
R
φ
χ
ψ
HN C
R
HN C
HN C
RR
HN C
RR
I II III IV
O
O O O O
Moye-Sherman, D.; Jin, S.; Ham, I.; Lim, D.; Scholtz, J.; Burgess, K. J. Am. Chem. Soc. 1998, 120, 9435.
![Page 7: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/7.jpg)
Dipeptide Crystal Structures
Nt-Bu
O
HN
O
O
NHi-Pr
Piv-L-Pro-D-c3Val-NHi-Pr
Nt-Bu
O
HN
O
O
NHi-Pr
Piv-L-Pro-L-c3Val-NHi-Pr
Jimenez, A.; Marraud, M.; Cativiela, C. Tetrahedron Lett. 2003, 44, 3147.
βII-turnβII-turn and γ-turn
![Page 8: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/8.jpg)
Specific CaseBiosynthesis of Ethylene
H2N CO2HACC Synthase
PLP, ATP
NH3
CO2
S ACC Oxidase
Ascorbate, FeII, O2, CO2H2C CH2
ACC
NH
O3POO
HN
-2
Pyridoxal 5'-Phosphate (PLP)
Adams, D.; Yang, S. Proc. Natl. Acad. Sci. USA 1979, 76, 170.
![Page 9: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/9.jpg)
• Ethylene is a plant hormone involved in germination, fruit ripening, and senescence
• Slowing the formation of ethylene during maturation will slow fruit ripening
• Lower ethylene levels allow plants to grow for a longer period before fruit ripening occurs, resulting in larger fruit
• Fruits can be harvested and shipped before ripening has occurred. Ethylene could then be administered to the fruit at place of sale, allowing fruit to ripen when desired.
Effects of Ethylene Production
![Page 10: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/10.jpg)
Stereoselective Syntheses of �-Cyclopropane Amino Acids
• Use of chiral auxiliaries in cyclopropanation– α,�-Didehydroamino acid (DDAA) derivatives as chiral
auxiliaries– Acetomides as chiral auxiliaries
• Cyclopropanation via diazo equivalents – Cyclopropanation via vinyldiazomethane compounds– Cyclopropanation via iodonium ylides– Cyclopropanation via diazo compounds generated in situ
from tosylhydrazone salts
![Page 11: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/11.jpg)
Using α,�-Didehydroamino acid (DDAA)derivatives as chiral auxiliaries
N
BocN O
RPh N
BocN O
RPh RH3N
HO2CHydrolysisCyclopropanation
Abellan, T.; Mancheno, B.; Najera, C.; Sansano, J. Tetrahedron 2001, 57, 6627.
DDAA derivative
![Page 12: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/12.jpg)
Building the Auxiliary
Ph O
NH3+Cl-
Ot-BuNHBoc
OO
THF, Et3N Ph O
HN O
NHBoc
1. HCl/AcOEt2. K2CO33. Boc2O/DMAP (cat) THF, 0oC, 1h
Ph N
BocN O
Ph N
BocN O
H
OTBAB
K2CO3, rt CH2Cl2
1 2
34
Abellan, T.; Mancheno, B.; Najera, C.; Sansano, J. Tetrahedron 2001, 57, 6627.
TBAB = tetra-n-butylammonium bromide
62% overall yield, 98% de
![Page 13: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/13.jpg)
Cyclopropanation and Hydrolysis
N
BocN O
Ph NaH, DMSO, rt N
BocN O
Ph H3N
HO2C3 M HCl, 150oC
4 d
[Me3SO]I-
Abellan, T.; Mancheno, B.; Najera, C.; Sansano, J. Tetrahedron 2001, 57, 6627.
Z:E = 11:170% after chromatography 24%, 98% ee
Corey’s dimethylsulfoxonium
methylide[Me3SO]I- =
![Page 14: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/14.jpg)
Building Four Diastereomers of Coronamic Acid
H2NH
CO2H
EtHO2C
HNH2
Et
H2NEt
CO2H
HHO2C
EtNH2
H
(-)-allo-coronamic acid
(+)-allo-coronamic acid
(-)-coronamic acid
(+)-coronamic acid
Charette, A.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
![Page 15: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/15.jpg)
Building All Stereoisomers of CoronamicAcid
Et
O
OMe
OHChiral Auxiliary Et2Zn, CH2ICl
HOEt
TIPSO
Charette, A.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
Curtius
RearrangementAll Diastereomersof Coronamic Acid
HOEt
TIPSOProtecting Group
Interconversion (If needed)
![Page 16: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/16.jpg)
Et
O
OMe
OHEt
O
OMe
OH
Ph3P, DEAD, THF
CO2H
O2N
Et
O
OMe
Op-NO2BzK2CO3, MeOH, 0 oC
85%
87%
1 2 3
Charette, A.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
Building Starting Allylic Alcohol
![Page 17: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/17.jpg)
Building Protected Diastereomers
Et
O
OMe
OH
1. Acetomide 1, BF3. OEt2 10%
M.S. 4 A, CH2Cl2, -78 oC
2. DIBAL-H, CH2Cl23. TIPSOTf, 2,6-lutidine 78%
1. TIPSOTf, 2,6-lutidine2. DIBAL-H, CH2Cl23. Acetomide 1, BF3
. OEt2 10% M.S. 4 A, CH2Cl2, -30 oC4. K2CO3, MeOH
OBnO
BnOOH
O
OBn
Et
H
TIPSO
OBnO
BnOOH
O
OBn
H
Et
TIPSOOBnO
BnOOH
OBn
O
NH
CCl3Acetomide 1 E isomer
Z isomer
OBnO
BnOOH
O
OBn
Et
TIPSO
Et2ZnCH2ICl
Et2ZnCH2ICl
Charette, A.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
![Page 18: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/18.jpg)
Cyclopropanation Step
OBnO
BnOOH
O
OBn
Et
H
TIPSO OBnO
BnOOH
O
OBn
Et
H
TIPSO
entry reagent (equiv) temp (oC) time yield de
1 Et2Zn (7)CH2I2 (5)
-20 18 hr 65% 20:1
2 Et2Zn (7)CH2I2 (5)
0 2 hr >95% 3:1
4 Et2Zn (4)CH2ICl (4)
-60 18 hr 98% 66:1
Reagent
CH2Cl2
Charette, A.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
3 Et2Zn (7)CH2ICl (5)
-20 40 min >95% 25:1
![Page 19: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/19.jpg)
Origin of All Stereoisomers
OBnO
BnOOH
O
OBn
Et
H
TIPSO
OBnO
BnOOH
O
OBn
H
Et
TIPSO
1. Tf2O, pyridine CH2Cl2, -20 oC
2. DMF, pyridine H2O, 120oC
HOEt
H
TIPSO
HOH
Et
TIPSO
Z Cyclopropane
E Cyclopropane
Charette, A.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
![Page 20: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/20.jpg)
Access to the Four Diastereomers
H2NH
CO2H
Et
HO2CH
NH2
Et
H
Et
H
Et
TIPSO
HO
HO
RO
Protecting GroupInterconversion
(-)-allo-coronamic acid
(-)-coronamic acid
H2NEt
CO2H
H
HO2CEt
NH2
H
Et
H
Et
H
TIPSO
HO
HO
RO
Protecting GroupInterconversion
(+)-coronamic acid
(+)-allo-coronamic acid
Charette, A.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
![Page 21: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/21.jpg)
Synthesis of 2 Diastereomers
HOEt
TIPSO
RuCl3, NaIO4H2O, CH3CN, CCl4 R.T., 2 hr 83%
HOEt
TIPSO
O
1. (PhO)2PON3 Et3N, Toluene 0 to 22 oC
BocHN Et
HO
1. PDC, DMF M. S. 4 A2. KMnO4, NaH2PO4 t-BuOH, 3 min
BocHN
CO2H
Et
t-BuO CCl3
NH
BF3.OEt2 cat.
cyclohexane
t-BuOEt
TIPSO
O
1. TBAF, AcOH, THF2. RuCl3, NaIO4 H2O, CH3CN, CCl43. (PhO)2PON3, Et3N, toluene 0o to 22o C4. t-BuOH, 120 oC
t-BuONHBoc
EtO
2. t-BuOH, 120 oC3. TBAF, AcOH THF
(+)-coronamic acid(+)-allo-coronamic acid
Charette, A.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
![Page 22: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/22.jpg)
Synthesis of the Other 2 Diastereomers
HO
TIPSO
RuCl3, NaIO4H2O, CH3CN, CCl4 R.T., 2 hr
HO
TIPSO
O
1. (PhO)2PON3
Et3N, Toluene 0 to 22 oC
BocHN
HO
1. PDC, DMF M. S. 4 A2. KMnO4, NaH2PO4
tBuOH, 3 min
BocHN
CO2H
t-BuO CCl3
NH
BF3.OEt2 cat.
cyclohexane
t-BuO
TIPSO
O
1. TBAF, AcOH, THF2. RuCl3, NaIO4 H2O, CH3CN, CCl43. (PhO)2PON3, Et3N, toluene4. t-BuOH, 120 oC
t-BuONHBoc
O
2. t-BuOH, 120 oC3. TBAF, AcOH THF
(-)-coronamic acid(-)-allo-coronamic acid
Et
Et Et Et
EtEt
Charette, A.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
![Page 23: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/23.jpg)
Cyclopropanation via Vinyldiazomethanes
R1R2
N2
CO2R
+ R1
CO2R
R2
Rh2L4
NH3+Cl-R1
CO2H
All 4 diastereomers
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
R1
N2CO2R
+HH
chiral Cu, Ruor Rh catalystsof C2 symmetry
up to 99% eebut E/Z mixtures
CO2RR1
Not Diastereoselective unless extremely bulky ester groups used.
![Page 24: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/24.jpg)
Access to Either Enantiomer
RPh
N2
CO2Me
+ pentane R
CO2Me
Ph
R
MeO2C
Ph
NSO2R2
O RhRhO
4
H
NSO2R2
O RhRhO
4
H
pentane
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
![Page 25: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/25.jpg)
Cyclopropanation Process
catalyst temp, oC R ee% yield, %
1 25 C6H5 90 792 -78 C6H5 98 681 25 p-ClC6H4 89 912 -78 p-ClC6H4 >97 701 25 p-MeOC6H4 83 872 -78 p-MeOC6H4 90 411 25 AcO 76 402 -78 AcO 95 261 25 EtO 59 832 -78 EtO 93 651 25 n-Bu >90 631 25 Et >95 651 25 i-Pr 95 58
RPh
N2
CO2Me
+pentane R
CO2Me
Ph
cat. 1 or 2
NSO2R
O RhRhO
4
Catalysts1: R=4-(t-Bu)C6H42: R=4-(C12H25)C6H4
H
1.2 eq.
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
Diastereoselectivity drops from 40:1 to 15:1 when simple alkenes used with cat 1.
![Page 26: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/26.jpg)
Alkene Product %ee yield (%)
Me
CO2Me
Ph
Me
Me
CO2Me
Ph
Me
Me
CO2Me
Ph
Me
CO2Me
Ph
O
95
N/A
N/A
86
52
80
0
84
O
Cyclopropanation Process Cont.
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
![Page 27: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/27.jpg)
How is the Selectivity Being Obtained?
O
O
RhO
O Rh
R RO
OR
OR
O
NSO2(C6H4)C12H25
H
O
O
RhO
O Rh
R RO
OR
OR
O
EWG
R2
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
R=
Staggered Conformation
![Page 28: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/28.jpg)
Rh
Rh
How is the Selectivity Being Obtained?
Ar Group
SO2 Group
pyrolidine ring
Rh
Rh
Rh
Rh
Rh
Rh
α,β,α,β form(D2 symmetry)
α,α,β,β form(C2 symmetry)
α,α,α,α form(C4 symmetry)
α,α,α,β form(no symmetry)
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
![Page 29: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/29.jpg)
How is the Selectivity Being Obtained?
EWG
Rh
R2
EWG
Rh
R2
H
HR1
Hδ+
R1
EWG
R2
EWG
Rh
R2
R1
H
H
HEWG
Rh
R2
H
HR1
Hδ+
R1
EWG
R2
R1
H
H
H
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
![Page 30: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/30.jpg)
Access to All Four Stereoisomers
Ph
CO2Me
Ph
Ph
MeO2C
PhAvailable via (S)-catAvailable via (R)-cat
NH3+Cl-Ph
CO2H
CO2HPh
NH3+Cl-
-Cl+H3N Ph
HO2C
HO2C Ph
-Cl+H3N
NSO2R
O RhRhO
4
CatalystR=4-(C12H25)C6H4
H
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
![Page 31: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/31.jpg)
Synthesis of Two Diastereomers
Ph
CO2Me
Ph
CO2HPh
CO2Me
CO2MePh
CO2Me
NHBocPh
CO2Me
NH3+Cl-Ph
CO2H
CO2MePh
NHBoc
CO2HPh
NH3+Cl-
RuCl3. H2O/NaIO4
70%
Me2SO4/K2CO3 94%
1. NaOH, H2O
2. 3 M HCl EtOAC
1. NaOH, H2O
2. 3 M HCl EtOAC
Curtius Rearrangement
1. Ester Hydrolysis2. Curtius Rearrangement
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
![Page 32: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/32.jpg)
Synthesis of Two Diastereomers
Ph
MeO2C
Ph
HO2C Ph
MeO2C
MeO2C Ph
MeO2C
BocHN Ph
MeO2C-Cl+H3N Ph
HO2C
MeO2C Ph
BocHN
HO2C Ph
-Cl+H3N
RuCl3. H2O/NaIO4
Me2SO4/K2CO3 94%
1. NaOH, H2O
2. 3 M HCl EtOAC
1. NaOH, H2O
2. 3 M HCl EtOAC
Curtius Rearrangement
1. Ester Hydrolysis2. Curtius Rearrangement
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
![Page 33: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/33.jpg)
Preparation of Cyclopropane Amino Acids via a Nitrocyclopropane Intermediate
NO2R2
O
OR1O2N
OR1
O
Rh2L4
Alkene, solventPhI(OAc)2 (1.1 eq.)
Nitro ReductionNH2
R2
O
OR1
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 34: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/34.jpg)
Access to Cyclopropane via IodoniumYlides
NO2R2
O
OR1
O2NOR1
O
Rh2L4
Alkene, solventPhI(OAc)2 (1.1 eq.)
O2NOR1
O
IPh
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 35: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/35.jpg)
Iodonium Ylides as Alternatives to DiazoCompounds
O2N
N2
OR1
O
NO2R2
O
OR1 O2NOR1
O
Rh2L4
Alkene, solvent
Rh2L4
Alkene, solventPhI(OAc)2 (1.1 eq.)
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 36: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/36.jpg)
Access to Nitrocyclopropane Carboxylates
O2N
N2
OR
O
NO2R'
O
OR O2NOR
O
Method A[Rh(Octanoate)2]2 (0.5 mol%)
Method B[Rh(OPiv)2]2 (0.5 mol%)
Alkene (1-2 eq.)CH2Cl2, rt, 2-4 hr.
PhI(OAc)2 (1.1 eq.)Alkene (3-5 eq.), 2 hr.
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 37: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/37.jpg)
Access to Nitrocyclopropane Carboxylates
O2N
N2
OR
O
NO2R'
O
OR
O2NOR
O
Method A[Rh(Octanoate)2]2 (0.5 mol%)Alkene (1-2 eq.)CH2Cl2, rt, 2-4 hr.
Method B[Rh(OPiv)2]2 (0.5 mol%)PhI(OAc)2 (1.1 eq.)Alkene (3-5 eq.), 2 hr.
CO2Et
NO2Ph
CO2Me
NO2
TBDPSO
CO2Me
NO2
CO2Me
NO2
Ph
CO2Et
NO2H
H
CO2Me
NO2
entry cyclopropane method E:Z ratio yield (%)
1 93:790
84
A
B
2 92:8 92
3 91:987
80
A
B
4 53:47 70
5 97:379
83
A
B
6 NA83
73
A
B
A
A
Cl
E:Z Ratio Varies less than +2% between methods
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 38: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/38.jpg)
Reduction of the Nitro Group
NO2R1
O
OR
NH2R1
O
OR
?
![Page 39: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/39.jpg)
Hydrogenolysis of the Cyclopropane Ring
NO2Ph
O
OMe
10% Pd/C, H2 (1 atm)
1 N HCl, MeOHPh
NH2
OMe
O
10% Pd/CHCO2NH4 (10 eq.)
1:1 MeOH:THF, 25 minPh
HN
OMe
O
OH
20% Pd(OH)2/C
H2 (100 psi)MeOH, 24 hr
Ph
NH2
OMe
O
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 40: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/40.jpg)
Attempted Reductions of Nitro Group
NO2Ph
O
OMe
Pd
Raney Ni
Fe/HCl
Zn/Ac2O
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 41: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/41.jpg)
Tertiary Nitro Reductions
NO2R1
O
OR
NH2R1
O
OR
Zinc dust (20 eq.)
1 N HCl (10 eq.)i-PrOH (0.05 M), 2 h
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 42: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/42.jpg)
Tertiary Nitro Reductions
NO2R1
O
OR
NH2R1
O
OR
Zinc dust (20 eq.)
1 N HCl (10 eq.)i-PrOH (0.05 M), 2 h
CO2Et
NH2Ph
CO2Me
NH2
TBDPSO
CO2Me
NH2
CO2Me
NH2
Ph
CO2Et
NH2H
H
CO2Me
NH2
entry cyclopropaneReductionyield (%)
1 77
2 74
3 76
4 93
5 79
6 54
Cl
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 43: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/43.jpg)
One Pot Procedure!
NH2R1
O
OR2. Zinc dust (20 eq.) 1 N HCl (10 eq.) i-PrOH (0.05 M), 2 h
1. [Rh(OPiv)2]2 (0.5 mol%) Alkene (5 eq.) PhI(OAc)2 (1.1 eq.), 2.5 hr
O2NOR
O
NH2Ph
O
OMe2. Zinc dust (20 eq.) 1 N HCl (10 eq.) i-PrOH (0.05 M), 2 h
1. [Rh(OPiv)2]2 (0.5 mol%) Styrene (5 eq.) PhI(OAc)2 (1.1 eq.), 2.5 hr
O2NOMe
O
65%, E:Z = 65:35
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
![Page 44: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/44.jpg)
Cyclopropane Synthesis via DiazoCompounds Generated in Situ
NR2R3
CO2R1
R3 NN
Ts
Na+
R3
CO2R1
NR2R3
R3 CO2R1
NR2R3+Phase Transfer
Catalyst(+) Z-cyclopropane (+) E-cyclopropane
Adams, L.; Aggarwal, V.; Bonnert, R.; Bressel, B; Cox, R.; Shepard, J.; de Vincent, J.; Walter, M.; Whittingham, W.; Winn, C. J. Org. Chem. 2003, 68, 9433.
dehydroamino acid
![Page 45: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/45.jpg)
Developing Cyclopropanation Chemistry
entry dehydroamino acid
condmetalcatalyst(mol%)
yield
(%)E:Z product
1 (a) - 68 94:6
2 (b) 1 12 49:51
3 (b) 10 35 17:83
4 (c) 1 79 36:64
5 (c) 10 53 36:64
6 (a) - 50 95:5
7 (c) 1 73 43:57
8 (a) - 48 85:15
9 (c) 1 84 19:81
10 (c) 10 84 16:84
Reaction Conditions
(a) BnEt3N+Cl- (0.05 eq.), toluene, 40oC, 60h
(b) Rh2(OAC)4, BnEt3N+Cl- (0.1 eq.), 1,4-dioxane, 30oC, 60h
(c) ClFeTPP, BnEt3N+Cl- (0.05 eq.), toluene, 40oC, 60h
NHBoc
CO2Me
NHBoc
CO2PNB
NHAc
CO2Me
Ph
CO2Me
NHBoc
Ph
CO2PMB
NHBoc
Ph
CO2Me
NHAc
Adams, L.; Aggarwal, V.; Bonnert, R.; Bressel, B; Cox, R.; Shepard, J.; de Vincent, J.; Walter, M.; Whittingham, W.; Winn, C. J. Org. Chem. 2003, 68, 9433.
NR2R3
CO2R1
Ph NN
Ts
Na+
Ph
CO2R1
NR2R3
Ph CO2R1
NR2R3+Phase Transfer
Catalyst
(+) Z-cyclopropane (+) E-cyclopropane
ClFeTPP = meso-tetraphenylporphyrin iron (III) chloride
![Page 46: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/46.jpg)
Access to E and Z Cyclopropanes
entry condyield
(%)E:Z
1 (a) 50 95:5
2 (c) 84 19:81
3 (a) 72 95:5
4 (c) 52 12:88
5 (a) 62 87:13
6 (c) 82 15:85
7 (a) 76 66:34
8 (c) 82 8:92
9 (b) 47 96:4
10 (d) 44 16:84
Reaction Conditions
(a) BnEt3N+Cl- (0.05 eq.), toluene, 40oC, 60h
(b) Starting with RCH=NNTs; (i) LiHMDS, THF, -78oC to RT (ii) BnEt3N+Cl- (0.05 eq.), toluene, 40oC, 60h
(c) ClFeTPP (0.01 eq.), BnEt3N+Cl- (0.05 eq.), toluene, 40oC, 60h
(d) Starting with RCH=NNTs; (i) LiHMDS, THF, -78oC to RT (ii) ClFeTPP (0.01 eq.), BnEt3N+Cl- (0.05 eq.), toluene, 40oC
R
MeO
F
OTBS
Ph
Ph
NHAc
CO2Me
R NN
Ts
Na
R
CO2R1
NR2R3
R CO2R1
NR2R3
Z SelectiveE Selective
NHBoc
CO2PNB
(a) or (b) (c) or (d)
Adams, L.; Aggarwal, V.; Bonnert, R.; Bressel, B; Cox, R.; Shepard, J.; de Vincent, J.; Walter, M.; Whittingham, W.; Winn, C. J. Org. Chem. 2003, 68, 9433.
![Page 47: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/47.jpg)
E Selectivity without catalyst
Ph NN
Ts
NHBoc
CO2Me
PhC
NNH
C CH
H CO2Me
NHBoc
HOMO
LUMO
+ NN
CO2Me
PhH
NHBoc
Na-N2 Ph CO2Me
NHBoc
Adams, L.; Aggarwal, V.; Bonnert, R.; Bressel, B; Cox, R.; Shepard, J.; de Vincent, J.; Walter, M.; Whittingham, W.; Winn, C. J. Org. Chem. 2003, 68, 9433.
![Page 48: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/48.jpg)
Z Selectivity With Catalyst
MeO
HN
O
O
Ph
Fe
H
HH
Ph NN
Ts
NHAc
CO2Me
+Na
ClFeTPP MeO2C
AcHN Ph
Adams, L.; Aggarwal, V.; Bonnert, R.; Bressel, B; Cox, R.; Shepard, J.; de Vincent, J.; Walter, M.; Whittingham, W.; Winn, C. J. Org. Chem. 2003, 68, 9433.
![Page 49: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/49.jpg)
Tosylhydrazone Chemistry Utilized in Synthesis of (+)-coronamic acid
OTsNH2NH2 (1.15 eq.)
MeOH, rt, 10 min 68%
N
HN
Ts
1. LiHMDS (1 eq.), THF, -78oC to rt
2. BnEt3N+Cl- (0.05 eq.), A (2 eq.), toluene, 40oC, 60h 36%
NHBoc
CO2PNB
NHBoc
CO2Me
A
H2 (1 atm), Pd(OH)2/C,MeOH, rt, 79%
NHBoc
CO2H
1 N HCl, MeOH, rt, 44h
89%
NH3+Cl-
CO2H
(+)-coronamic acid
acrolein
Adams, L.; Aggarwal, V.; Bonnert, R.; Bressel, B; Cox, R.; Shepard, J.; de Vincent, J.; Walter, M.; Whittingham, W.; Winn, C. J. Org. Chem. 2003, 68, 9433.
![Page 50: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/50.jpg)
Making the Process Enantioselective!
Aggarwal, V.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem. Int. Ed. 2001, 40, 1433.
R2
R1
Ph NN
Ts
Na+
Ph
R2
R1
Rh2(OAc)4 (1 mol%)BnEt3N+Cl- (20 mol%)
1,4-dioxane, 40oCsulfide (20 mol%)
S
O
Entry R1 R2 Yield (%) d.r. (E:Z) %ee Absolute config.
1 N-succinimide CO2Et 55 1:7 91 1S,1S
2 N(Boc)2 CO2Me 72 1:6 92 1S,1S
![Page 51: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/51.jpg)
How is the Enantioselectivity Obtained?
O
S
H H Ph
H
O
S
H H H
Ph
O
S
H H
H Ph
H N(Boc)2
CO2Me
O
S
H H H
Ph
N(Boc)2
CO2Me
O
S
H H
MeO2C
(Boc)2N Ph
O
S
H HH
Ph
Aggarwal, V.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem. Int. Ed. 2001, 40, 1433.
![Page 52: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/52.jpg)
CO2Et
N
Ph NN
Ts
Na+
Rh2(OAc)4 (1 mol%)BnEt3N+Cl- (20 mol%)
1,4-dioxane, 40oC, 24 hrchiral sulfide (20 mol%) 7:1 (Z:E) 55%
O
O
CO2Et
NO
O
Ph
CO2H
NH3+Cl -Ph
CO2Et
NO
O
Ph
Recrystallization
90% ee, 48% (Z only)
100% ee, 40% yield
6 N HCl, reflux, 4 hr.
Enantioselective Synthesis of a Single Stereoisomer
Aggarwal, V.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem. Int. Ed. 2001, 40, 1433.
![Page 53: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/53.jpg)
Pulling Everything Together
• Stereoselective sytheses of α-cyclopropaneamino acids can be performed in various manners, including:– Use of chiral auxiliaries
– Chiral catalyst mediated cyclopropanation via diazo compounds or their equivalents
![Page 54: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/54.jpg)
Utilizing Chiral Auxiliaries
N
BocN O
RPh N
BocN O
RPh RH3N
HO2CHydrolysisCyclopropanation
Abellan, T.; Mancheno, B.; Najera, C.; Sansano, J. Tetrahedron 2001, 57, 6627.
DDAA Derivative
[Me3SO]I-
![Page 55: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/55.jpg)
Charette, A.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
Et
O
OMe
OHAcetomide Et2Zn, CH2ICl
HOEt
TIPSO
Chiral Auxiliary
Curtius
RearrangementAll Diastereomersof Coronamic Acid
HOEt
TIPSOProtecting Group
Interconversion (If needed)
Utilizing Chiral Auxiliaries
OBnO
BnOOH
OBn
O
NH
CCl3Acetomide 1
![Page 56: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/56.jpg)
Cyclopropanation via Diazo Compounds or their Equivalents
R1R2
N2
CO2R
+ R1
CO2R
R2
Rh2L4
NH3+Cl-R1
CO2H
All 4 diastereomers
Davies, H.; Bruzinski, P.; Lake, D.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897.
O
O
RhO
O Rh
R RO
OR
OR
ONSO2(C6H4)C12H25
H
R=
Oxidative CleavageCurtius Rearrangement
![Page 57: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/57.jpg)
NO2R2
O
OR1O2N
OR1
O
Rh2L4
Alkene, solventPhI(OAc)2 (1.1 eq.)
Nitro ReductionNH2
R2
O
OR1
Wurz, R.; Charette, A. Org. Lett. 2003, 5, 2327.
Cyclopropanation via Diazo Compounds or their Equivalents
![Page 58: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/58.jpg)
NR2R3
CO2R1
R3 NN
Ts
Na+
R3
CO2R1
NR2R3
R3 CO2R1
NR2R3+Phase Transfer
Catalyst(+) Z-cyclopropane (+) E-cyclopropane
Adams, L.; Aggarwal, V.; Bonnert, R.; Bressel, B; Cox, R.; Shepard, J.; de Vincent, J.; Walter, M.; Whittingham, W.; Winn, C. J. Org. Chem. 2003, 68, 9433.
dehydroamino acid
Cyclopropanation via Diazo Compounds or their Equivalents
Using Fe Catalyst Without Catalyst
![Page 59: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/59.jpg)
Conclusion
• α−Cyclopropane amino acids are important molecules, and they need to be synthesized due to their low natural abundance
• Various new stereoselective syntheses have been produced to make these molecules
• New methods have been adopted to overcome the hazards associated with diazo chemisty. These methods may allow for new industrial preparations.
![Page 60: Recent Advances in Stereoselective -Cyclopropane …...Synthesis of 2 Diastereomers HO Et TIPSO RuCl3, NaIO4 H2O, CH3CN, CCl4 R.T., 2 hr 83% HO Et TIPSO O 1. (PhO)2PON3 Et3N, Toluene](https://reader030.vdocuments.us/reader030/viewer/2022040616/5f1b60103057a643a5225698/html5/thumbnails/60.jpg)
Thank you• Dr. Tepe• Dr. Borhan
• Group Members– Arantxa– Chris– Jason– Mahesh– Manasi– Sam– Vasudha