Synthesis of spirocyclic

Synthesis of Spirocyclic Compounds Yi He... – Chiral quaternary carbon center– Synthesis of two fused rings... OR X R' t-Bu OR XR' neither bond anti to the carbocation!. Mechanism for Lo

Synthesis of Spirocyclic

Compounds

Yi He

– 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.

X

n m

m

n

Substitution

n m

m

n

1,4 - Addition

MeO OMe

CH2OTs MeO

MeO

TMSOTf

MeO

OTs MeO

H

H H

MeO

H MeO H

H

OTs

Tanaka, T.; Okuda, O; Murakami, K; Yoshino, H.; Mikamiyama, H;

Kanda, A; Iwata, C Tetrahedron Lett 1994, 35, 4125-4128.

26 71 A%

74 52

THF

29 77

C N Ph Me

Me

Ph

N

Ph Me

n n

n H

2080

CH31

0100

i-Pr

1

1585

CH32

B %

A %R

N EtO2C O

N O

Boc

Ph

a) DIEPA, CH3CN

b) H2, Pd/C, CH3OH 85% 2 steps N

EtO2C

Boc

N O Ph

CO2Me O

N O Ph

H N

EtO2C H

Rearrangement Reactions for

Spiroannulation

• Vinylcyclopropanol/Vinylcyclobutanol rearrangement

• Pinacol-type rearrangement

• Sigmatropic rearrangement

Vinylcyclobutanol/Vinylcyclopropanol

Rearrangement

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.

OR

OCH3

OCH3m

OR

OCH3m

OCH3m

1 eq TMSOTf, 0.7 eq pyr -40 °C, 0.01M CH2Cl2, 85%

O OCH3OTMS

OCH3OCH3

O CH3

OTMS H

OTMS H

O CH3

H

O OCH3

O OCH3favored

disfavored

85.2% de

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

Vinylcyclopropane Rearrangement

XR

t-Bu OTMS

OMe MeO

CH2Cl2, RT, 28% t-Bu

O

RuCl3•3H2O NaIO4, CCl4

X R'H

OR

X R'

t-Bu

OR

XR'

neither bond anti to the carbocation!

Mechanism for Low Yield of

Axially-Tethers Electrophile

X

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

Diels-Alder Approach to

Shizuka-Acoradienol

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

[2+1]Cycloaddition in the Total

HNO

O Me

O

+

N N N

Sheikh, Z.; Steel, R.; Tasker, A S.; Johnson, A P

J Chem Soc., Chem Commun 1994, 763-766.

O Me

O

+

N N N

+

N

O Me

N MeO

+

N

O Me

N OMe

Johnson’s Total Synthesis of Gelsemine

Sheikh, Z.; Steel, R.; Tasker, A S.; Johnson, A P

J Chem Soc., Chem Commun 1994, 763-766.

O Me

OCH3

O

N NN

N

O Me

O

N MeO

N

O Me

O

N MeO

•

•

O Me

O

O N

Ph

Unexpected Formation of Oxetane

O Me

H N O

Me

O N SEM O

N

OTDS Me

O

OTf Br

Me

O

N OEtO

Retrosynthesis of Gelsemine by

Speckamp

Newcombe, N J.; Ya, F.; Vijn, R J.; Hiemstra, H.; Speckamp, W N

J Chem Soc., Chem Commun 1994, 767-768.

OTDS Me

O

OTf 1) Pd(OAc)2, PPh3, Et3N

CO, 2-bromoaniline DMF, RT, 24 h, 79%

2) NaH, SEMCl, THF

N

OTDS Me

O N SEM

O

Me

H N O

Pd2(dba)3, Et3N PhCH3, refulx, 4h 60%

1) Bu4NF, THF, RT., 2 h 2) HgO, Tf2O, N,N-dimethylaniline

MeNO2, RT, 3 d, 60%, 3 steps 3) NaBH 4 , NaOH, CH 2 Cl 2 , EtOH, 80%

4) Bu4NF, THF, 4 Å MS, reflux, 4 h, 90%;

AlH 3 , THF, -65 - 0 °C

4 h, 50%

TDS = thexyldimethylsilyl de? 60:30

Speckamp’s Total Synthesis of Gelsemine

Newcombe, N J.; Ya, F.; Vijn, R J.; Hiemstra, H.; Speckamp, W N

J Chem Soc., Chem Commun 1994, 767-768.

H N O

N

OH Me

H N O

HN

CO2R Me

H N O X

X

RO2C

NH O

X

RO2C

H N O

N H O X

CO2R

Fukuyama’s Total Synthesis of Gelesmine

OAc

HO

CHO

1) 4-iodooxindole cat piperidine MeOH, RT, 89%

2) DCC, DMSO pyridium trifluoroacetate

Et3N, CH2Cl2, RT, 91%

CO2CH3

O CO2CH3

NH O

I

O

H3CO2C

NH O

Me

H N O

3 CO2C

H N O

H3CO2C

NH O

Spirotryprostatin B

N H

Edmonson, S D.; Danishefsky, S J Angew Chem Int Ed Engl 1998, 37, 1138-1140.

N

O

N O

4Å MS, PhCH3

N H

EtO2C

O

N O

Ph Ph

O

Me

Me MeO

HN

CO2Et O

[1,3]-dipolar cycloaddition 82%

N O

Ph Ph

O HN

Me MeO Me O

CO2Et H

O

Sebahar, P R.; Williams R M J Am Chem Soc 2000, 122, 5666-5667.

Williams’ 1,3-Dipolar Cycloaddition

Approach

N O

O

I

I

η 3-allypalladium capture

asymmetric Heck cyclization

Overman, L E.; Rosen, M D Angew Chem Int Ed Engl 2000, 39, 4596-4599.

Overman’s Retrosynthesis of

Spirotryprostatin B

3) Dess-Martin

4) A, t-BuOK

I

N SEM O

NH

N O

O H

[Pd2(dba)3]•CHCl3(otol)3P, KOAc THF, 70 °C

SEMN

N

O

N O

Me2AlCl DIEPA (93%)

Me2AlCl DIEPA (93%)

HN

N

O

N O

HN

N

O

N O

B

C

N NH

Overman, L E.; Rosen, M D Angew Chem Int Ed Engl 2000, 39, 4596-4599.

Daly, J W.; Karle, I.; Myer, C W.; Tokuyama, T.; Walters, J A.; Witkop, B.

Proc Natl Acad Soc U S A 1971, 68, 1870.

O 1) O3 , PPh 3

2) (Ph3P+CH2I)I-, NaN(TMS)2 HMPA, THF, 52%

I

I

HN HO

1) Ph 3 P, CBr 4 , ether, 2h, 53%

2) NH4Cl, AlMe3, PhH, 40 °C, 18h 3) Ac2O, Pry, DMAP, 70%

O

I I

Stork’s Synthesis of (-)-Histrionicotoxin

Stork, G.; Zhao, K J Am Chem Soc 1990, 112, 5875-5876.

Retrosynthesis of (-)-Histrionicotoxin by

Holmes

Williams, G, M.; Roughley, S D.; Davies, J E.; Holmes, A B

J Am Chem Soc 1999, 121, 400-401.

N H

Holmes’ Synthesis of (-)-HistrionicotoxinO

X

(CH2)3OTBDPS

O X NHOH (CH2)3OTBDPS

NaN(TMS) 2

1-chloro-1-nitrosocyclohexane THF, then HCl (aq), 70%

N X

(CH2)3OTBDPS

Ph

N BnO

O Ph

N H

HO

1) Zn, AcOH, 30 min, 98%

2) K2CO3, MeOH, 94%

Williams, G, M.; Roughley, S D.; Davies, J E.; Holmes, A B

J Am Chem Soc 1999, 121, 400-401.

O O

Me

HO

HO

Retrosynthesis of Ginkgolide B’s Synthetic Intermediate by Corey

Corey, E J.; Kang, M.-C.; Desai, M J.; Ghosh, A K.; Houpis, I N

J Am Chem Soc 1988, 110, 648-651

O O

O Me

A =

O HO

O

O O O

CMe3

O O Me HO

HO

1) t-Bu2Cu(CN)Li2, Et2O -78 to -45 °C

2) TMSCl, Et3N, -45 to -10 °C 3) 1,3,5-trioxane TiCl4, CH2Cl2 -78 °C, 65% 3 steps;

1) LDA, DME, -78 to 0 °C then PhNTf2, 0 to RT, 80%

2) A, Pd(PPh3)4, CuI, n-PrNH2

PhH, 16 °C, 84%;

1) (Cy-Hex)2BH, THF, 0 °C 2) AcOH, H2O2, pH 10 3) 1 N HCl, pH 3 4) pH 11, 4 h, pH 3 86% 4 steps

1) (COCl2)2, PhH

2) n-Bu3N, PhCH3 80% two steps

Corey’s Total Synthesis of Ginkgolide B

Corey, E J.; Kang, M.-C.; Desai, M J.; Ghosh, A K.; Houpis, I N

J Am Chem Soc 1988, 110, 648-651

O OMe

O O Me

HO

Et3SiO CMe3

O EtO2C

Retrosynthesis of Ginkgolide B’s Synthetic Intermediate by Crimmins

Crimmins, M T.; Pace, J M.; Nantermet, P G.; Kim-Meade, A S.; Thomas, J B

Watterson, S H.; Wagman, A S J Am Chem Soc 1999, 121, 10249-10250.

Et 3 SiO CMe 3

O EtO2C

O HO

dimethyldioxirane

H2O, p-TSA, 94%

O O

O

O OH

OH CMe3OH

1) MeOH, p-TSA

CH(OMe)3, 95%

2) CS2, MeI, DBU 3) Bu3SnH, AIBN

60 °C, 78% 2 steps

O O

O

O OMe

OMe CMe3

O HO

O

O O O

CMe3

O O Me HO

HO

(EtO 2 CCH 2 CH 2 ) 2 ZnCu

Crimmins’ Total Synthesis of Ginkgolide B

Crimmins, M T.; Pace, J M.; Nantermet, P G.; Kim-Meade, A S.; Thomas, J B

Watterson, S H.; Wagman, A S J Am Chem Soc 1999, 121 10249-10250.

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