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

Recent Advances in Stereoselective�-Cyclopropane Amino Acid Syntheses

R. Adam MoseyMichigan State University

November 10, 2004

NH2

CO2H

R1

R2

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.

Why Make �-Cyclopropane Amino Acids?

• Drug applications• Reactive intermediates• Cause conformational changes when

placed in proteins• Studying some biosynthetic pathways

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

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

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.

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

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.

• 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

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

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

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


TBAB = tetra-n-butylammonium bromide

62% overall yield, 98% de

Cyclopropanation and Hydrolysis

N

BocN O

Ph NaH, DMSO, rt N

BocN O

Ph H3N

HO2C3 M HCl, 150oC

4 d

[Me3SO]I-


Z:E = 11:170% after chromatography 24%, 98% ee

Corey’s dimethylsulfoxonium

methylide[Me3SO]I- =

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.

Building All Stereoisomers of CoronamicAcid

Et

O

OMe

OHChiral Auxiliary Et2Zn, CH2ICl

HOEt

TIPSO


Curtius

RearrangementAll Diastereomersof Coronamic Acid

HOEt

TIPSOProtecting Group

Interconversion (If needed)

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


Building Starting Allylic Alcohol

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


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


3 Et2Zn (7)CH2ICl (5)

-20 40 min >95% 25:1

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


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


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


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


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.

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


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.


Diastereoselectivity drops from 40:1 to 15:1 when simple alkenes used with cat 1.

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.


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


R=

Staggered Conformation

Rh

Rh


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)



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


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


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


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


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


Access to Cyclopropane via IodoniumYlides

NO2R2

O

OR1

O2NOR1

O

Rh2L4


O2NOR1

O

IPh


Iodonium Ylides as Alternatives to DiazoCompounds

O2N

N2

OR1

O

NO2R2

O

OR1 O2NOR1

O

Rh2L4

Alkene, solvent

Rh2L4



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.


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


Reduction of the Nitro Group

NO2R1

O

OR

NH2R1

O

OR

?

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


Attempted Reductions of Nitro Group

NO2Ph

O

OMe

Pd

Raney Ni

Fe/HCl

Zn/Ac2O


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


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


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


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

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


NR2R3

CO2R1

Ph NN

Ts

Na+

Ph

CO2R1

NR2R3

Ph CO2R1


Catalyst

(+) Z-cyclopropane (+) E-cyclopropane

ClFeTPP = meso-tetraphenylporphyrin iron (III) chloride

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)


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


Z Selectivity With Catalyst

MeO

HN

O

O

Ph

Fe

H

HH

Ph NN

Ts

NHAc

CO2Me

+Na

ClFeTPP MeO2C

AcHN Ph


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


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

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


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


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

Utilizing Chiral Auxiliaries

N

BocN O

RPh N

BocN O

RPh RH3N

HO2CHydrolysisCyclopropanation


DDAA Derivative

[Me3SO]I-


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

Cyclopropanation via Diazo Compounds or their Equivalents

R1R2

N2

CO2R

+ R1

CO2R

R2

Rh2L4

NH3+Cl-R1

CO2H

All 4 diastereomers


O

O

RhO

O Rh

R RO

OR

OR

ONSO2(C6H4)C12H25

H

R=

Oxidative CleavageCurtius Rearrangement

NO2R2

O

OR1O2N

OR1

O

Rh2L4


Nitro ReductionNH2

R2

O

OR1



NR2R3

CO2R1

R3 NN

Ts

Na+

R3

CO2R1

NR2R3

R3 CO2R1


Catalyst(+) Z-cyclopropane (+) E-cyclopropane


dehydroamino acid


Using Fe Catalyst Without Catalyst

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.

Thank you• Dr. Tepe• Dr. Borhan

• Group Members– Arantxa– Chris– Jason– Mahesh– Manasi– Sam– Vasudha

Documents

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