Synthesis of spirocyclic

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Synthesis of Spirocyclic
Compounds
Yi He

• Introduction
• Synthetic methodologies
• Syntheses of spirocyclics in natural products
– Gelsemine
– Spirotryprostatin
– Histrionicotoxin
– Ginkgolide B
• Conclusion

Introduction
• “Spirocyclane” introduced by Baeyer in
1900
• Widely present in natural compounds
• Synthetic challenging
– Chiral quaternary carbon center
– Synthesis of two fused rings

Methodologies for Constructing
Spirocenters
•
•
•
•
•

Alkylations
Rearrangement reactions
Cycloadditions
Transition metal catalyzed reactions
Cleavage of bridged systems

Sannigrahi, M. Tetrahedron 1999, 55, 9007-9071.

Alkylation
X
n

n

m

m

Substitution

X

X

n

n
m

m

1,4 - Addition

Alkylation using Bis-acetal
MeO

MeO

OMe

H
H

H

TMSOTf

H

MeO

MeO
MeO

CH2OTs

OTs

MeO

MeO

Solvent

Yield%

A%

B%

CH3CN

77

71

29

52

26

74

H

H

OTs
A

H

MeO

H

O

THF

OTs

MeO

OTs

O
B

Tanaka, T.; Okuda, O; Murakami, K; Yoshino, H.; Mikamiyama, H;
Kanda, A; Iwata, C. Tetrahedron Lett. 1994, 35, 4125-4128.

Alkylation using Ynamine
R
R

O
Me
Ph N

n

O

MgBr, CH3CN, 70 ºC

H

60-70%

O
H

n
O
C
N Me
Ph

Ph
Me N R

R
n

O

+

n

O
Me N O
Ph

O

A

B

n

R

A%

B%

2

CH3

85

15

1

CH3

80

20

1

i-Pr

100

0

(±)-Acoradiene

Ficini, J.; Revial, G.; Genêt, J. P. Tetrahedron Lett. 1981, 22, 629-632.
Kaiser, R.; Naegeli, P. Tetrahedron Lett. 1972, 13, 2009-2012.

Michael Addition
Ph

Ph
N

N

O
CO2Me
EtO2C

N
Boc

O

O

a) DIEPA, CH3CN
b) H2, Pd/C, CH3OH
85% 2 steps

EtO2C

O
N
Boc

H
CO2Me

Ph
N
H

O

EtO2C

N

H

H
O

Manzamine A

Brands, K. M.; DiMichele, L. M. Tetrahedron Lett. 1998, 39, 1677-1680.

Rearrangement Reactions for
Spiroannulation
• Vinylcyclopropanol/Vinylcyclobutanol
rearrangement
• Pinacol-type rearrangement
• Sigmatropic rearrangement

Vinylcyclobutanol/Vinylcyclopropanol
Rearrangement
OR

OR
Lewis acid

n

n

OCH3
OCH3

m

m

OCH3

O

n

n = 1 or 2
m = 1 or 3
m

OCH3

Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 6556-6558.
Trost, B. M.; Chen, D. W. D. J. Am. Chem. Soc. 1996, 118, 12541-12554.

Vinylcyclopropane Rearrangement
OTMS

O

1 eq. TMSOTf, 0.7 eq. pyr

OCH3

OCH3

-40 °C, 0.01M CH2Cl2, 85%

OCH3
85.2% de
O
H

OTMS
OCH3
O

CH3

favored
O
H

OTMS
O CH3

OCH3

H
disfavored

Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 6556-6558.

Prins – Pinacol Rearrangement
Y

R

Y

slow

HO

XR

Y

fast

XR

HO
O
XR

XR
O

XR
XR

TMSO

TMSO
O

Prins-Pinacol Spiroannulation
OMe
t-Bu

OTMS

RuCl3•3H2O

TMSOTf, DTBMP
t-Bu

CH2Cl2, RT, 70%
MeO

O

NaIO4, CCl4
CH3CN, H2O

t-Bu
O

OMe

t-Bu

OMe

CH2Cl2, RT, 28%

O

OMe RuCl3•3H2O

TMSOTf, DTBMP
TMSO
MeO

O

t-Bu
O

NaIO4, CCl4
CH3CN, H2O

t-Bu
O

Me
DTBMP =

t-Bu

Minor, K. P; Overman, L. E. Tetrahedron 1997, 53, 8927-8940.

N

t-Bu

Mechanism for Regioselectivity
XR'

t-Bu

OR
H

t-Bu
X

fast

OR

t-Bu

R'

O

XR'

slow
XR'

XR'

t-Bu
RO
O

t-Bu

XR'

t-Bu

OR
X

t-Bu

OR
t-Bu

R'
XR'

H

O

slow

RO
t-Bu

XR'

t-Bu
XR'
O

Mechanism for Low Yield of AxiallyTethers Electrophile

R'
X
t-Bu
OR

XR'

t-Bu
OR

neither bond anti to the carbocation!

2,3-Sigmatropic Rearrangement

SPh

Ph
CO2Et
S
Rh2(OAc)4

O
CO2Et

PhH, reflux

O

Ph
S

O

EtO2C

N2

PhS CO2Et
O

O

(+)-Acorenone

Kido, F.; Abiko, T.; Kato M. J. J. Chem. Soc. Perkin Trans. 1 1992, 229-233.

Cycloaddition
• [4+2]

+
n

n

X

X

• [3+2]

X

+
Y

• [2+2]

n

n

n

n

n

X

• [2+1]

n

X

Diels-Alder Approach to ShizukaAcoradienol
MeO2C
+

O O

O

CHCl3, 50 °C

O

m-CPBA

MeO2C

300 MPa, 57%

O O

O

MeO2C

xylene, reflux
45%

MeO2C

O

HO

Shizuka-acordienol

Hatsui, T.; Hashiguchi, T.; Takeshita. H. Chemistry Express 1993, 8, 581-584.

[2+1]Cycloaddition in the Total
Synthesis of (-)-Acorenone

N2

Cu powder

HCl

cyclohexane

CHCl3
O

O

O

(-)-Acorenone

Ruppert, J. F.; Avery, M. A.; White, J. D. J. Chem., Soc. Chem. Commun. 1976, 978.

Gelsemine
• Major alkaloid component
of Gelsemium
sempervirens
• Novel hexacyclic cage
structure
• Unique spiro-oxindole
center
O

N
Me

H
N

O

Retrosynthesis of Gelsemine by
Johnson
O

H
N

O
N
N

+
N
N

O

N
O
TMS

Me

OMe

Me

O

N
Me

O

O

N
Me

Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, A. P.
J. Chem. Soc., Chem. Commun. 1994, 763-766.

O

Johnson’s Total Synthesis of Gelsemine
N
N N
OMe

O
N
+

O

n-BuLi (2 equiv.)

N
N N

N
N

N

MeO

O

Me

TMS

+

O

OMe

N

O

Me

O

N
Me

major

MeO

minor

N

N

hv, CH3CN
Pyrex

+

O
N

OMe

O
N

O

O

Me

Me

1

:

O

2

Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, A. P.
J. Chem. Soc., Chem. Commun. 1994, 763-766.

Mechanism of Radical Cyclization
N
N

•

•

N

N•
OCH3