Isoxazole functionalization

Isoxazoles-Isothiazoles vs -Diketones

- Acidic methylene (pKa ~13)

- Selective deprotonation at R1 or R2
(to form the dianion) difficult
- Amenable to nucleophilic attack
- Two carbonyls difficult to differentiate
- Acyclic structure

R1

-enamino-amino-hydroxy,-unsaturated
ketones

Group Meeting
8/25/2004

Isoxazoles and Isothiazoles in Organic Synthesis

Christos Mitsos

R2

- Selective deprotonation
feasible
- Not attacked by most nucleophiles
- "Carbonyl" sites C-3 and C-5
readily differentiated
- Rigid planar structure

X N
R1

R2
X = O, S

LDA or

O N

O N

Li

n-BuLi

O N

R
Electrophile

R1
O N

Electriphile: RX, R1COR2, CO2, CS2 - MeI

O N

HO

R2
O N

HO2C

S
Micetich, R.; Can. J. Chem. 1970, 48, 2006.
for a review see: Natale, N. R.; Mirzaei, Y. R.; Org. Prep. Proc. Int. 1993, 25, 515-556.
N O
Cl

THF

Nu-

N O
Nu

25-65 oC

N-

Nu = MeO-, PhS-, PhCH2-,

Stevens, R. V.; Albizati, K. F. Tetrahedron Lett. 1984, 25, 4587.

A-D

NH2 O
R1

O N
R1

R2
E

NH2 O

I
R2

R1

Isothiazole functionalization
R2
S N

G
Ph

O
Ph

NH

R1

O
R2

R1

O
R1

LICA/TMEDA

N S
BnO

OH
R2

R1
G
O
R1

R2

H
R1

OH
R2

R2

S N

OH

Ph
R1

N S

n-BuLi or
LICA/TMEDA

O
NH

R1

Li

R2

R2

Ph

Ph

Alberola, A.; Calvo, L.; Rodriguez, M. T.; Sanudo, M. C. J. Heterocycl. Chem. 1993, 30, 537.

O
R2

S N

n-BuLi or

BnO

N S

Electrophile

BnO

Li

Bunch, L.; Krogsgaard L., P.; Madsen, U. J. Org. Chem. 2002, 67, 2375.
A: H2, Raney Ni
B: Na/NH3, 1 equiv t-BuOH
C: Mo(CO)6, H2O,
D: SmI2, MeOH
E: PhCOCl, Pyr
F: NaBH4
G: H3O+
H: AcOH
I: Na/NH3, 3 equiv t-BuOH
J: Et3O+BF4-

Baraldi, P. G.; Barco. A.; Pollini G. P.; Simoni, D. Synthesis 1987, 857,
and references cited therein.

The Bic protecting group

O
O

N
O

N
R2

R1

Base
aprotic
solvent

O
NC
-

N
R2

R1

pH 7

Kemp, D. S.; Hoyng, C. F. Tetrahedron Lett. 1975, 4625.

O
+
CO2
+
HN
R2

R1

Latent -ketonitriles

O N

Group Meeting
8/25/2004

Isoxazoles as Latent Functionalities

Christos Mitsos

Latent -ketonitriles

NaOH, EtOH
Et 2SO4

CN

NH2

O-

EtO

CN

H2NCONH2
EtONa

CN

Inverse
electron-demand
dienophile

N
N
O
H
Cytosine

O N

Ph

1. LDA, -78 C

Ph

2. TMSCl, -78 C

CN

OHC

TFA

EtO2C

N
H

O N

2. DMF, 100 C
N

Ph

Ph

100 C, 30min

N
Ph

1. KOH, EtOH, H2O

N
H

CH2Cl2

NH2

55%

Ph

Ph

CN

CN

98%

96%

Ph

N
H

Alberola, A.; Gonzalez, A. M.; Gonzalez, B.; Laguna, M. A.; Pulido, F. J.

Tetrahedron Lett. 1986, 27, 4221.

NH
Corynanthe
Alkaloids

N
H

N
H

CHO
NC

CN

Latent siloxybutadienes

Indoloquinolizine
O N
Perez, C; Janin, Y. L.; Grierson, D. S. Tetrahedron 1996, 52, 987.

R2
R1

O N

80 C,
15min

NH

CO2Et

CN

Ph

N+ O -

-10 C, 15min

O N

18%

OTMS

Tarsio, P. J.; Nicholl, L. J. Org. Chem. 1957, 22, 192.

Ph

Ph

180 C, 2h

2LDA

ArCN
CN

-10 C

Ar
RX

N
H

NH2

LDA, TMSCl

R
TMSO

CO2Et

CO2Et

OTMS

THF, -78 C

120-140 C
R = H, CN, Me

1. BuLi, THF, -78 C

2. E+, -78 C
3. H3O+
O

75-95%

HO

Y = H, CO2Et

70-81%

E
O
R

CN

NaBH4

OH
R

CN

Vinick, F. J.; Pan, Y.; Gschwend, H. W. Tetrahedron Lett. 1978, 4221.

R
E = Br, Me, Et
Barbero, A.; Pulido, F. J. Synthesis 2004, 401.

Group Meeting
8/25/2004

Natural Products Synthesis

Christos Mitsos
Homotestosterone -Progesterone

Dehydrofukinone

O
O
NaH
O

glyme
O
N

Cl

55%

NaBH4

66%

N
O

H2, Pd/C

N
O

1. MeONa, HCO2Et
2. K2CO3, i-PrI
3. NaH, MeI
4. HCl
5. NaOH

OH

40%

OH

1. Et3OBF4

N
O

2. NaOH

K2CO3, i-PrI

38%

O
OH

OH

1. MeLi
2. HCl
3. POCl3, pyridine

H2, Pd/C
EtOAc/Et3N 3:1

H2, Raney Ni

O
N

EtOH

HO
O

HN

H
Dehydrofukinone

Ohashi, M. Chem. Comm. 1969, 893.

OH

OH
1. MeOH/MeONa,
oxygen free
2. aq. NaOH,

1. Li/NH3

H
60% (4 steps)

O
H

2. MeI
90%

Prostaglandins

MeNO2

CO2Me

O
1. HCCC5H11,
PhNCO, Et3N
CO2Me
NO2

1,1,3,3-TMG

2. K2CO3

1. H+, H2O
H

2. MeOH, NaOH,
80%

H
H

O
Homotestosterone

OMe
1.
2.
2.
3.

K-Selectride, THF
TsOH, PhH,
DIBAL, toluene
BF 3.OEt2, MeOH

Stork, G.; McMurry, J.E. J. Am. Chem. Soc. 1967, 89, 5464.

C5H11

OMe

O
1. Na/NH3,
t -BuOH
N O

Progesterone

N O

70%

82%

OH

CO2H

C5H11

2. TsOH
O
Intermediate in
prostaglandins synthesis

Barco, A.; Benetti, S.; Pollini, G. P.; Baraldi, P. G.; Simoni, D.; Guarneri, M.; Gandolfi, C.
J. Org. Chem. 1980, 45, 3141.

Group Meeting
8/25/2004

Natural Products Synthesis

Christos Mitsos

Garuganin III

3(2H)-Furanone natural products

CO2Me

MeO

MeO

PPh3Br
1. H2, Pd/C, EtOAc (100%)
2. LAH, THF (85%)
3. SOBr2, PhH (86%)
4. PPh3, MeCN (89%)

N O

HO

MeO

1. LiOH
2. MsCl

OAc

OAr

3.ArOH, LiBr

NH2 O

MeCN, H2O

OAr

HO

AcOH, H2O

O
N

MeO
O

67%

MeOH

O
Geiparvarin

MeO
H2, PtO2

96%

MeO

Mo(CO)6

60%

OMe

DMF

N O

MeO

OMe

t-BuOK

HO

O
MeO

Baraldi, P.G.; Barco, A.; Benetti, S.; Guarneri, M. Tetrahedron Lett. 1985 26, 5319.

NH2

79%

Gingerol
MeO
O

AcOH
H2O

MeO
O

CH2N2
OH

Ph

N O

MeO

MeOH, CHCl3

OMe

MeO

C5H11

BnO

1. H2, PtO2, MeOH

2. BzCl, pyridine

OMe
O

1. NaBH4, MeOH
2. AcOH, H2O
3. H2, Pd/C, MeOH

(+ 3 isomers)
Keseru, G.M.; Dienes, Z; Nogradi, M. J. Org. Chem. 1993, 58, 6725.

C5H11
BnO

MeO

Garuganin III

NH O

OH

HO
OMe

3(2H)-Furanone natural products

N O
Ph

OEt
OH

Barco, A.; Benetti, S.; Baraldi, P. G.; Guarneri, M.; Pollini, G. P.; Simoni, D.
J. Org. Chem. 1980, 45, 3141.

1. H2, Raney Ni
2. HCl
77%

NH2 O
Ph

OH
O

Ph

Bullatenone

Curran, D.P.; Singleton, D.H. Tetrahedron Lett. 1983, 24, 2079.

Studies towards Vitamin B12

Ni(II) Octamethylcorphin
CO2Me
NO2
+
O

(1)

CO2 Me

PhNCO
Et3N
PhH, 50 C

N
O

O
N

96%

HO
N
N O

O
N
O

CO2Me
N
HO (2)

OH

(1)

N O

N O

94%

CO2Me

N
HO

O
(5)

1. 3, t-BuOCl, CH2Cl2,
-78 C to rt
2. 4, Et3N, CH2Cl2, rt

CONMe2

O N

MeO2C

MeO2C

(3)

O
N

1. 1, NCS, DMF, 40 C MeO2C

2. Et3N, Et2O, rt
3. 2, CHCl3, 40 C
O

NO2

NO2

HO N

1. NBS, DMF
2. Et3N,

OH

MeO2C

CO2Me

CO2Me

CONMe2

MeO2C

N
O

2. NH2OH.HCl,
pyridine

N
O

CO2Me

CO2Me
1. THF, H2O, HCl

89%

1. NBS, DMF
2. 1, Et3N
3. THF, H2O, HCl
4. NH2OH.HCl,
pyridine

Group Meeting
8/25/2004

Natural Products Synthesis

Christos Mitsos

CO2 Me

57%

(4) NC

CO2Me

NC
(6)

67-85%
1. 5, t-BuOCl,
CH2Cl2, -78 C
2. Et3N, CH2Cl2,
-78 C to rt
3. 6, rt

67-85%

Vitamin B12

O
CO2Me
H2, Raney Ni
MeOH, pH 7

NH2

Et3N, CHCl3

O NH2 H2N
O

NH

CONH2
H2NOC

O
1. NaOMe, MeOH
2. Ni(ClO4)2

ClO4
O

Ni+
N

CN N
Co

O
1. NH4OAc, MeOH
2. t-BuOK. t-BuOH,

ClO4N

H2NOC

N CN N

MeO2C
O

CONH2

O
O2N

CONMe2

N O N

CO2Me

O N O

MeO2C

Ni+
N

CO2Me

CONH2

93% (3 steps)

HO2C

CONH2

NC

CO2Me

Cobyric acid
Ni(II) Octamethylcorphin

Stevens, R.V.; Christensen, C.G.; Cory, R.M.; Thorsett, E. J. Am. Chem. Soc. 1975, 97, 5940.

Stevens, R.V.; Beaulieu, N.; Chan, W. H.; Daniewski, A. R.; Takeda, T.;Waldner, A.;
Williard, P. G.; Zitter, U. J. Am. Chem. Soc. 1986, 108, 1039.

Pyrazoles

Natural products Synthesis (last but not least)

MeO
MeO

1. Raney Ni
2. NaBH4
3. Ac2O. Pyr
4. dil. NaOH

N
S

MeO

CO2Me

N O

MeO

N
S

Group Meeting
8/25/2004

Synthesis of Heterocycles

Christos Mitsos

1. Mo(CO)6
MeCN, H2O

Ar
MeO

NHAc

N
N

MeO

Ar

2. H3O+

N NH

H2NNH2H2O

Ar

75-84%

81-93%
Skacani, I.; Fisera, L.; Bartovicova, M.; Varkonda, S.; Hyblova, O.;
Collect. Czech. Chem. Comm. 1991, 56, 1926.

OH

OH O

OH
Colchicine

Woodward synthesis of colchicine (racemic)

Imidazoles
SSSMe
O

N O
N
O

AcO

HO
O

MeO2CHN

TMS

OH

NH

Calicheamicin 1

NH2

H2, Pd/C

N
H

98%

NH

BnNH2, EtOH,

80%

O
NHBn

N
H

Nicolaou synthesis of calicheamicinone

Synthesis of Heterocycles

N O

BnN

H
O

NH2 O

BnN

Pyrrolidinones

O
NaOH, EtOH,
75%

H2, Pd/C

NaOH, EtOH,

NBn

92%

NBn

O
OMe
NHBoc

N
78%

Calicheamicinone

NaOH, EtOH,

O
R

CO2Et
NHBoc

1. TFA
2. EDCI, HOSu,
DMF

Reiter, L.A. J. Org. Chem. 1987, 52, 2714.

O

N
H

1. H2, Pd/C
2. NaOH
O
Jones, R. C. F.; Dawson, C. E.; OMahony, M. J.
Synlett, 1999, 873.

N
H

O
R1

Mo(CO)6

O N O
Ar
R2

HO
R

Pyrones

MeCN, H2O
54-95%

R1

NH2 O

aq. HCO2H
Ar

R2

AcOH

R2
R1

Ar

49-90%

Li, C.-S.; Lacasse, E. Tetrahedron Lett. 2002, 43, 3565.

Pyridines
O

Pyrroles

O
H2, Pd/C

O
NaNO2, HCl

MeO

Et3N

O
MeO

Group Meeting
8/25/2004

Synthesis of Heterocycles

Christos Mitsos

O N

MeO
N

N
H

LeGoff, E.; Williams, P.D. Heterocycles 1984, 22, 269.

1. H2, Pd/C
2. Acetate buffer,

EtO2C

80%

CO2Et

Zn, HOAc

99%

63% (2 steps)
O

1:1 EtOH/Et3N

EtO2C

NH2 O

H2, Rh/C
R

N
H

NOH

Pyrroles and bicyclic lactams

Ohashi, M.; Kamachi, S.; Kakisawa, H.; Stork, G. J Am. Chem. Soc. 1967, 89, 5460.
EtO2C
N O

Pyridones
O

EtO2C
O
N

OMe

LDA
79%

O N

EtO2C

DBU

EtO2C

42%

CO2Et

1. H2, Pt2O

92%

O
NH2 O

OMe
EtO2C

OH
1. CH2N2, 45%
N

2. LDA, n-BuONO
45%

EtO2C

NOH

N
N

CO2Et

H2, Pd/C

59%

2. AcOH,

N
H

CO2Et

BF3OEt2
O

200 C
56%

N
H

CO2Et

H
Doleschall, G.; Seres, P.; Parkanyi, L.; Toth, G.; Almasy, A.; Bihatsi-Karsai, E.
J. Chem. Soc., Perkin Trans. 1 1986, 927.

Caerulomycin
Alreja, B.D.; Kattige, L.S.; Lal, B.; deSouza, N.J. Heterocycles 1986, 24, 1637.

Flavones
OH

O
O N

1. LDA
2. RCO2Me

N O

Mo(CO)6
R

MeCN, H2O,

N O

H2, Raney Nickel

Ph

N
H

Nitta, M.; Higuchi, T. Heterocycles, 1994, 38, 853.

64%

OH

OH O

AcOH
Ph

HCl,
95%

Ph

Thomsen, I.; Torssell, K.B.G. Acta Chem. Scand. B 1988, 42, 303.

N O

Ph

NH2 O

H2

O N

NH2

60 %

N
H

O
NH3 removal

R'

OH

HO

Ph

Ph

8:2

H2O removal

O N
EtO2C

2. P4S10

50-55%
Allyl
N

1. Mo(CO)6

HO

OH

EtO2C

Allyl
N

O N
N
H

N
Allyl

Ph

or
OH

OH

1. Et3SiH, TFA

HO

3.

OH

1. NaH
2. n-BuLi

O N
EtO2C

Allyl
N

Br

HCl

Ph

NH2 O

Group Meeting
8/25/2004

Synthesis of Phenol Derivatives

Christos Mitsos

MeI, 80 C

2. H2O, H+

N
H

OH
EtO2C

N
H

50-60% (4 steps)
NAllyl

Ph

N O

H2

O N

N O

Ph

EtO2C

NH2

HCl

OH

Ph

NH2 O

H2

OH

HO

100%

Ph

H2

NH2 O

OMe
PDE-II

Sundberg, R.J.; Hamilton, G.S.; Laurino, J.P. J. Org. Chem. 1988, 53, 976.
CO2Me

Ph

O
Fe2(CO)9

O N
N O

OH

HCl

Ph

N O

O
N
H

90%
OH

N O

OH

Me

controlled
hydrogenation

HO2C

Me

N
H

NH2

NH2

R1

R2

H2O, C6H6

NH2

R1

R2

HCl

Ph

OH
MeO2C

CO2Me

CO2Me

R1

KF, AcOH
benzene

R2

21-51% (2 steps)

90%
OH

NH2 O

O
OH

Ph

+
H2N

HO

Ph

Me

O N

as above
O
37%

OH
CO2Me

1. NaOH
2.

Me
81%

96 : 4
Arruchio, S.; Morrocchi, S.; Ricca, A. TL 1974, 33, 2793.

OH

O
Me
Mellein

Takeuchi, N.; Goto, K.; Sasaki, Y.; Fujita, T.; Okazake, K.; Kamata, K.; Tobinaga, S.
Heterocycles 1992, 33, 357.

Studies towards tetracyclines

Isothiazole C-Nucleosides
Ph

Ph

HO

O N
OBn

1, Et3N, DMF

TrO

O N

OBn O

2. HCHO,
NaBH3CN

OH

1. RONO, NaH,
DME
2. H3O+
3. TsCl, DME

CN

1. HCl

OBn
CO2Me

50 C

CO2Me

Group Meeting
8/25/2004

Isoxazoles and Isothiazoles in Organic Synthesis

Christos Mitsos

O
O

OTs

NC

TrO

HSCH2CO2Et
Et3N, EtOH

O
N

O N

S
OH

1. NaH,

OBn
CO2Me
OBn OH

2. H2, Pd/C
OBn OH

OH O

TrO

1. HC(OEt)3,
2. NH3
O

NH

TrO

NH2

NH2

CO2Et

12-Deoxytetracycline
Stork, G.; Hagedorn, A.A. JACS 1978, 100, 3609.

1. PhCONCS, CH2Cl2
2. NaH, CH2Cl2
3. MeI

1. 1,2,4-Triazole,
POCl3, pyr
2. NH3, MeOH

Isoxazole C-Nucleosides
S

O
TBSO

NO2

O
O

HCCOEt

O
O

TBSO

TBSO

H2, Raney Ni, BCl3

O

H2O, MeOH

H
N

OEt

O
O

NH

N
N

O
O

Kozikowski, A.P.; Goldstein, S. JOC 1983, 48, 1141.

NH3, MeOH,

OH

TrO
O

TBSO

O
O

NHCOPh

MeS
O

TrO

OEt

PhNCO, Et3N

TrO

H2N

CO2Et

NH2
Wamhoff, H.; Berressem, R.; Nieger, M.
J. Org. Chem. 1993, 58, 5181; ibid. 1994, 59, 1912.