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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 m n m

Substitution

X n m

X n m

1,4 - Addition

Alkylation using Bis-acetal

MeO OMe TMSOTf MeO MeO CH2OTs MeO OTs MeO OTs MeO H H MeO H H

MeO

Solvent CH3CN THF

Yield% 77 52

A% 71 26

B% 29

O

H MeO

H

H

H OTs A

O B

OTs

74

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 H O n MgBr, CH3CN, 70 ºC 60-70% O H C N Me Ph R O Me N O Ph A n + O O B Ph Me N R n n O

(±)-Acoradiene

n 2 1 1

R CH3 CH3 i-Pr

A% 85 80 100

B% 15 20 0

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 N O CO2Me EtO2C N Boc O a) DIEPA, CH3CN b) H2, Pd/C, CH3OH 85% 2 steps EtO2C O O N Boc H CO2Me Ph N

Ph N H EtO2C H O O N H

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 n OCH3 m OCH3 Lewis acid n OR

m

OCH3

n

O 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 1 eq. TMSOTf, 0.7 eq. pyr OCH3 OCH3 85.2% de O H OTMS OCH3 O favored O H OTMS O CH3 H disfavored OCH3 CH3 -40 °C, 0.01M CH2Cl2, 85% O OCH3

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

Prins ­ Pinacol Rearrangement

Y HO R

slow

Y HO

XR

fast

Y

XR

O

XR

XR

O

XR

XR

TMSO

TMSO

O

Prins-Pinacol Spiroannulation

OMe t-Bu OTMS TMSOTf, DTBMP CH2Cl2, RT, 70% MeO OMe t-Bu O RuCl3·3H2O NaIO4, CCl4 CH3CN, H2O t-Bu O O

t-Bu TMSO MeO

TMSOTf, DTBMP OMe CH2Cl2, RT, 28% t-Bu O

OMe RuCl3·3H2O NaIO4, CCl4 CH3CN, H2O t-Bu O

O

Me DTBMP = t-Bu N t-Bu

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

Mechanism for Regioselectivity

XR' fast t-Bu XR' O t-Bu OR H X R' t-Bu OR

slow XR' t-Bu RO t-Bu O XR'

XR'

t-Bu

OR X R' H

t-Bu

OR t-Bu XR' O

slow t-Bu XR' O

RO t-Bu

XR'

Mechanism for Low Yield of AxiallyTethers Electrophile

R' X t-Bu OR t-Bu OR XR'

neither bond anti to the carbocation!

2,3-Sigmatropic Rearrangement

Ph CO2Et S O

CO2Et N2

SPh

Rh2(OAc)4 PhH, reflux

Ph S EtO2C

O

O

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 X n X + Y n n n +

· [3+2] · [2+2] · [2+1]

X

X n n n X

Diels-Alder Approach to ShizukaAcoradienol

MeO2C + O O O O CHCl3, 50 °C 300 MPa, 57% MeO2C

m-CPBA

O O MeO2C

O

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 cyclohexane O

HCl CHCl3

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

H N

N Me

O

Retrosynthesis of Gelsemine by Johnson

O H N O N + N N Me O O O Me N O TMS OMe N

N Me

O Me

N

O

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

Johnson's Total Synthesis of Gelsemine

O N O N Me O TMS + N OMe O + N Me major O N O N Me minor O n-BuLi (2 equiv.) N N N OMe MeO N N N

MeO hv, CH3CN Pyrex O N Me

N

N + O N Me O OMe

O

1

:

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 OCH3 · N· OCH3 · O O · N OCH3

O

O N Me O

N Me

N Me

O rotation

MeO N O N Me O MeO OMe N Me O N O N · ·

O N Me O

Unexpected Formation of Oxetane

· H O H H · O N Me O O N Me

Ph N O N CH2 O · O N Me O

N ·

O

Retrosynthesis of Gelsemine by Speckamp

O H N O OTf O N Me O N Me N SEM Br OTDS O N Me OTDS

TIPSO O N Me OH O H OEt N CH3 +

OH

O

O N CH3

Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767-768.

Speckamp's Total Synthesis of Gelsemine

O OTf O N Me O SEM N

1) Bu4NF, THF, RT., 2 h 2) HgO, Tf2O, N,N-dimethylaniline MeNO2, RT, 3 d, 60%, 3 steps 2) NaH, SEMCl, THF 1) Pd(OAc)2, PPh3, Et3N CO, 2-bromoaniline DMF, RT, 24 h, 79%

O OTDS N Me

N SEM Br OTDS

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

O

H N

O N Me de? 60:30 OTDS

O N Me O

3) NaBH4, NaOH, CH2Cl2, EtOH, 80% 4) Bu4NF, THF, 4 Å MS, reflux, 4 h, 90%;

O

H N TDS = thexyldimethylsilyl

AlH3, THF, -65 - 0 °C 4 h, 50%

N Me

O

Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767-768.

Retrosynthesis of Gelsemine by Fukuyama

O H N O H N O X H N

N Me

O

N Me

HN OH Me CO2R

X O NH

X O H N CO2R

X RO2C RO2C

O

N H

Fukuyama, T.; Liu G. Pure & Appl. Chem. 1997, 69(3), 501-505.

Fukuyama's Total Synthesis of Gelesmine

OAc CHO HO CO2CH3 O

1) 4-iodooxindole cat. piperidine MeOH, RT, 89% 2) DCC, DMSO pyridium trifluoroacetate Et3N, CH2Cl2, RT, 91%

NH

O

CO2CH3

I O H N

O

1) PhCH3/CH3CN, 1:1 90 ºC, 45 min, 98% 2) n-Bu3SnH, cat. AIBN 95 ºC, 1 h, 85%

O

NH N

H3CO2C

O

Me

O O NH O CO2CH3 H N

O O NH

O

I

H3CO2C

I

H3CO2C

I

Fukuyama, T.; Liu G. Pure & Appl. Chem. 1997, 69(3), 501-505.

Spirotryprostatins

· Isolated from the fermentation broth of Aspergillus fumigatus · Inhibits cell cycle at G2/M phase · Spiro-oxindole rings

O HN N H3CO O O N HN N O O O N

Spirotryprostatin A

Spirotryprostatin B

Cui. C. B.; Kakeya, H.; Osasa, H. Tetrahedron 1996, 51, 12651-12666. Cui. C. B.; Kakeya, H. l.; Osasa, H. Tetrahedron 1997, 53, 59-72.

Danishefsky's Pinacol-type Rearrangement Approach

CO2CH3 N H NBoc H2O, AcOH SPh Br NBS, THF N H O H CO2CH3 NBoc SPh

O HN CO2CH3 NBoc SPh H3CO HN

O

H N

O N

O

Spirotryprostatin A

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

Williams' 1,3-Dipolar Cycloaddition Approach

Ph Ph Ph Ph HN O O

OHC Me OMe Me

Ph Me Ph MeO N Me O HN O H O

O N O CO2Et [1,3]-dipolar cycloaddition 82%

4Å MS, PhCH3

EtO2C

Me MeO

Me O HN

CO2Et

O N H

O HN N

O N

O

Spirotryprostatin B

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

Overman's Retrosynthesis of Spirotryprostatin B

O HN N

O

N

3-allypalladium capture

O HN HN

O

N

O

O L2Pd I I RN HN O O O N

asymmetric Heck cyclization

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

Overman's Intramolecular Heck Approach

H O N H OTBDPS 1) SEM-Cl, NaH 2) TBAF 3) Dess-Martin 4) A, t-BuOK I

O N N HN

N O

O [Pd2(dba)3]·CHCl3 (otol)3P, KOAc THF, 70 °C (72%, B:C = 1:1)

NH

I

N O SEM

O SEMN

O

O N N O

Me2AlCl DIEPA (93%)

O B

O SEMN N O N

O HN

O N N

A=

H N O

Me2AlCl DIEPA (93%)

O

NH PO(OMe)2

O

O

C

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

(-)-Histrionicotoxin

· Isolated from the skin of frog Dendrobates histrionicus · Novel spiro-piperidine structure

OH

H N (-)-Histrionicotoxin

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.

Retrosynthesis of (-)-Histrionicotoxin by Stork

HO N H

HN

HO

CONH2

Br

R HO CO2Me OTBS + R H O H Br OTBS

O O

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

Stork's Synthesis of (-)-Histrionicotoxin

CO2Me OTBS

LDA

O O OTBS

1) O3, PPh3 2) (Ph3P CH2I)I , NaN(TMS)2 HMPA, THF, 52% 3) 5% HCl, THF

+ -

+ O H O O OH H Br

43%

1) Ph3P, CBr4, ether, 2h, 53% 2) NH4Cl, AlMe3, PhH, 40 °C, 18h

AcO

CONH2

Br

I

I I

3) Ac2O, Pry, DMAP, 70%

I

1) (CF3CO2)2IPh CH3CN, H2O, 3 d 2) Et3N, ClCH2CH2Cl 65-70 °C, 2h, 31%

AcO

HN

I HO

HN

I

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

Retrosynthesis of (-)-Histrionicotoxin by Holmes

N R O HO R'

N H

R

N O

R'

R

NH OH

R'

Williams, G, M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B. J. Am. Chem. Soc. 1999, 121, 400-401.

Holmes' Synthesis of (-)-Histrionicotoxin

O X (CH2)3OTBDPS

X = (+)-10,2-camphorsultam THF, then HCl (aq), 70% NaN(TMS)2 1-chloro-1-nitrosocyclohexane

O X NHOH (CH2)3OTBDPS

CN

1) PHCH3, 80 °C, 6 h 2) styrene, 75 °C 85%, 2 steps

X O

(CH2)3OTBDPS N O Ph

BnO

N O Ph TMS TMS

PHCH3 sealed tube

BnO

BnO N O CN

N CN O O N

1) Zn, AcOH, 30 min, 98% 2) K2CO3, MeOH, 94%

N H HO

Williams, G, M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B. J. Am. Chem. Soc. 1999, 121, 400-401.

Ginkgolide B

· Isolated from Ginkgo biloba · Complex structure

­ Six ring in a confined space ­ Eleven stereogenic carbons ­ Four contiguous quaternary centers ­ Ten oxygenated carbons

O HO HO O O O Me HO O O CMe3 O

Retrosynthesis of Ginkgolide B's Synthetic Intermediate by Corey

O t-Bu H H O · MeO O t-Bu MeO O t-Bu

O

CO2H

MeO O t-Bu O O

OMe OMe

Corey, E. J.; Kang, M.-C.; Desai, M. J.; Ghosh, A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988, 110, 648-651

Corey's Total Synthesis of Ginkgolide B

OMe OMe O

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;

MeO O t-Bu O

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%;

MeO O t-Bu OO O Me

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

MeO O t-Bu

1) (COCl2)2, PhH 2) n-Bu3N, PhCH3 80% two steps

CO2H

O MeO O t-Bu H · H O O

A = Me O O O

O t-Bu O Me O

HO

HO O

O CMe3

HO O

O

Corey, E. J.; Kang, M.-C.; Desai, M. J.; Ghosh, A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988, 110, 648-651

Retrosynthesis of Ginkgolide B's Synthetic Intermediate by Crimmins

O O OMe O OMe CMe3 Et3SiO CMe3 Et3SiO CMe3 O CO Et 2 O O CO2Et O

Me O HO O

EtO2C Et3SiO CMe3

O

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.

Crimmins' Total Synthesis of Ginkgolide B

O EtO2C Et3SiO CMe3 O O CO Et 2 O O O H O O

dimethyldioxirane

O

(EtO2CCH2CH2)2ZnCu

CO2Et

O

h, 366 nm hexane. 100%

Et3SiO

CMe3 O OH O O OH OH CMe3 O

H2O, p-TSA, 94%

Et3SiO

CMe3

CMe3

O

1) MeOH, p-TSA CH(OMe)3, 95% 2) CS2, MeI, DBU 3) Bu3SnH, AIBN 60 °C, 78% 2 steps

O O

OMe O OMe

O Me

O

HO

HO O

O CMe3

HO O

CMe3

O

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.

Conclusions

· Structure diversity of spirocyclic compounds · Various approaches to spirocenters

Thanks

· Kiessling Group Members

Information

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