Filip Petronijevic Current Literature Presentation April, 24th 2010.

Total Synthesis of (+)-Complanadine A Using an Iridium-Catalyzed Pyridine C-H Functionalization

Daniel F. Fischer and Richmond Sarpong J. Amer. Chem. Soc., ASAP

Synthesis of (+)-Complanadine A, an Inducer of Nerutrophic Factor Excretion

Changxia Yuan, Chih-Tsung Chang, Abram Axelrod, and Dionicio Siegel J. Amer. Chem. Soc., ASAP

NH

Me

N

HN

Me

N

HHComplanadine A

2'3

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Lycopodium Alcaloids and Complanadine A

For review see: Hudlicky, T.; and Reed, J.W. In The Way of Synthesis, 1st ed.; Wiley-VCH, 2007; pp 573-602.. Conroy, H. J. Tetrahedron Lett. 1960, 10, 34. Fisher, D.; Sarpong, R.J. Amer. Chem. Soc. ASAP.

NH

Me

O NH

Me

OOH N

H

Me

N

NH

NH

H

Me

H

HN

NH

H

MeH

H

NH

Me

NHN

Me

N

HH

Lycopodine Fawcettimine Lycodine

Phlegmarine

A

BC

D

1

5

7

8

9

1012

14

15

16

NH

Me

N

HN

Me

N

HHComplanadine A

2'3

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How Does Nature Make Complanadine A: Biosynthesis of Lycopodium Alcaloids

H2N H2N CO2HH

H2N NH2

-CO2 diamine oxidase

H2N O N

-CO2X

O O O

Xmalonyl CoA

NH

X

O

O

HN

O-CO2

cadaverineLys (K)

pelletierine

oxidative

dimerizationHN

NHNH

Me

NH

oxidation

NH

Me

N

lycodine

dimerization NH

Me

N

HN

Me

N

HHcomplanadine A

Hudlicky, T.; Reed, J.W. In The Way of Synthesis, 1st ed.; Wiley-VCH, 2007; pp 573-602 and references therein. Conroy, H. J. Tetrahedron Lett. 1960, 10, 34. Stork, G. Pure Appl. Chem. 1968, 17, 383.

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Retrosynthetic Approaches in the Sarpnog and Siegel Groups

NBoc

Me

N

BO

OBocN

Me

N

HH

TfO

+NBoc

Me

N OTf

N Boc

Me

NH O

N

MeHNMe O

+

Sarpong's group

NR'

Me

N

R'N

Me

N

HH

R3Si1 2

6

34

5

+

R'N

Me

HH

NN

R'

Me

N1 2

6 5

R3Si 34

SiR3

Siegel's group

NH

Me

N

HN

Me

N

HHcomplanadine A

3

45

12

6

Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Amer. Chem. Soc. ASAP. Fisher, D.; Sarpong, R.J. Amer. Chem. Soc. ASAP.

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The Key Step in Siegel’s Synthesis: [2+2+2] Cycloaddition

CpCoL2 (L = CO, PR3, olefin)

L

CpCoL

L

CpCo

CoCp

CoCp

CoCp CoCp

"CpCo"

2

1

2

3

4

56

CoCp

CoCp

CoCpN

CR

NCR

CoCp

NR

N

CpCo

R

"CpCo"

NR

2 CN R

or

3

7 89

10

For an excelent review on pyridine synthesis by metal Mediated cyclotrimerization, see: Varela, J.A.; Saá, C. Chem. Rev. 2003, 103, 3787. Funk. R.L.; Volhardt, K.P.C. J. Amer. Chem. Soc. 1980, 102, 5253.

Benzene and Pyridine Synthesis by Cyclotrimerization

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The Key Step in Sarpong’s Synthesis: Suzuki Reaction

LnPd

LnPdX

R2

LnPdOR

R2

LnPdR1

R2

R2-XL

R1-R2

M+OR-

M+X-

BR2

ORR1

BR2

ORRO

+ LBR2R1 M+OR-+

oxidative addition

transmetallation

reductive elimination

Kurti, L.; Czako, B.In Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA, 2005; pp 448-449.

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Näslund, G.; Senning, A.; Lawesson, S.-O. Act. Chem. Scand. 1962, 16, 1324. Koylovich, M.N.; Kukushkin, V.Y.; Haukka, M.; Fransto da Silu, J.J.R.; Pombeiro, A.J.L. Inorg. Chem. 2002, 41, 4798. Liu, K.-M.; Sha, C.-K. Chem. Commun. 2008, 1, 91. Schyster, E.; Jas, G.; Schumann, D. Org. Prep. Proc. Int.. 1992, 24, 670. Fisher, D.; Sarpong, R.J. Amer. Chem. Soc. ASAP.

Sarpong: Precursors Syntheses

O

O OCN

NaOEtEtOH

0 °C to rt

O

O O

CN

p-TsOH 150 °C

53%

OCN

Zn(NO3)2acetone oxime

H2O, 90 °C

O O

NH2

120 °C

vacuum53%

HNMe O

O

Me

O

Me

O

30% H2O2

LiOH, MeOH30 °C94%

(trans/cis 66:34)

PhSH, tAmONaMTBE, reflux

73%(trans/cis 40:60) O

Me

SPh

1. NaBO3, AcOH 40 °C quantitative

2. CaCO3, 80 °C 52% O

Me

1. I2, pyr. DCM, 95%2. AIBN, TBTH acrylonitrile PhH, 70%

O

Me1. (CH2OH)2, H+

2. LiAlH4, Et2O 0 °C, 90%

Me

O

O

H2N

N

Me

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Sarpong: Tricyclic Intermediate Synthesis

HNMe O

70% HClO4dioxane

105 °C, 20 h

O NH2

O

O NH2

O

N

Me

H

H+

NH

MeNH2

OO

NH

MeNH2

OOH

N H

Me

H2NOO

N

Me

NH O

Boc

then Boc2O, Et3N

THF, 60 °C65%

Schyster, E.; Jas, G.; Schumann, D. Org. Prep. Proc. Int.. 1992, 24, 670. Fisher, D.; Sarpong, R.J. Amer. Chem. Soc. ASAP.

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Takagi, J.; Sato, K.; Hartwig, J.F.; Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 43, 5649. Ishiyama, T.; Miyaura, N. Pure Appl. Chem. 2006, 78, 1369. Cho, J.-Y.; Tse, M.K.; Holmes, D.; Maleczka, R.E.; Smith III, M.R. Science 2002, 295, 305. Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N.R.; Hartwig, J.F. J. Amer. Chem. Soc. 2002, 124, 390. Fisher, D.; Sarpong, R.J. Amer. Chem. Soc. ASAP.

Sarpong’s Synthesis: Complanadine A Formation

NN

tBu

tBu

dtBu-dipy

B BO

O O

O

[B(pin)]2

IrN

N

tBu

tBu BpinBpin

COE

Bpin

N

Me

NH O

Boc

Pb(OAc)4CHCl3, rt

84% NBoc

MeHN O

Tf2O, pyridine -78 °C to rt

72%

NBoc

Me

N

cat. [Ir(COD)(OMe)]2 dtBu-dipy[B(pin)]2

THF, 80 °C 75%

NBoc

Me

N

BO

O

NBoc

Me

N OTf

cat. Pd(OAc)2 dppf, HCO2NH4

Et3N, 60 °C

90%

BocN

Me

N

HH

TfO

NBoc

Me

N

BO

O

BocN

Me

N

HH

TfO

+1. PdCl2(dppf), K3PO42. 6N HCl, 70 °C

42% (over 2 steps)

NH

Me

N

HN

Me

N

HHComplanadine A

2'3

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Siegel’s Synthesis: Starting Material Preparation

OSPh

1. NaH, I(CH2)3OAc DMF, 23 °C, 63%

2. m-CPBA, CH2Cl2 -78 to 23 °C, 77%

O OAc 1. a) TMSCH2CN, n-BuLi b) ethyl salicilate, Et2O -78 °C

2. CsF, CH3CN, 23 °C 45% (over 2 steps)

O OAc

CN

1. HCCMgCl, THF 23 °C, 97%

2. Ac2O, Mg(ClO4)2 23 °C, 97%3. PhCH2NH2, CuCl THF, 66 °C, 92%

OAc

CN

HNPh 1. K2CO3, MeOH

23 °C, 99%

2. PPh3, imidazole CCl4, 77 °C, 75%

HNClCN

HBnMe

NCN

Me

H

Bn NBn

CN

MeH

Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Amer. Chem. Soc. ASAP  

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Siegel’s Synthesis: Cyclotrimerization and Regioselectivity Problem

NBn

CN

MeH TMS

TMS

+CpCo(CO)2

THF, 140 °C82%

NBn

Me

N

H

TMS TMS

NBn

Me

N

H

H

TMS

+

25:1

NBn

Me

N

H

TMS TMS

1. TBAF, THF 66 °C, 85%

2. LiHMDS, TMSCl THF, 23 °C, 90%

CpCo(CO)2

THF, 140 °C82%

NBn

Me

N

H

TMS

NBn

Me

N

H

BnN

Me

N

HH

TMS

Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Amer. Chem. Soc. ASAP  

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Siegel’s Synthesis: End Game

NBn

Me

N

H

TMS

NCHO

CN

MeH

CpCo(CO)2dioxane, 140 °C

NBn

Me

N

H

CHON

Me

N

HH

TMS

NBn

Me

N

H

TMS

OHCN

Me

NH

H

A

B

A : B = 3.3 : 1 (47% yield)with 8 equiv. PPh3 A : B = 1 : 3 (56% yield)

NBn

Me

N

H

TMS

OHCN

Me

NH

H

1. TBAF, dioxane 101 °C, 99%

2. Pd/C, H2, 23 °C MeOH, 78%3. HCl, MeOH 50 °C, 90%

NH

Me

N

H

HN

Me

NH

H

Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Amer. Chem. Soc. ASAP  

Changing the regioselectivity:

“The use of formyl in place of the benzyl group was required as “coupling partners” failed to react” “The ability of PPh3 to change the regioselectivity warrants furhter study”

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CoCp

N

TMS

TMS TMS

TMS

+

N

N

TMS

TMS+

CoCp

TMS

N

TMS

TMS

TMS

~ 0.5 hartree

~ 0.4 hartree

LUMO

CoCp

TMS

N

TMS

biggest lobeof diyne's LUMO

ß to the metal

route 1

route 2

prefered

CoCp

H3Si

H3Si

N

CoCp

H3Si

N

H3Si

Ab initio energies: -789.740069812 -789.746989353prefered

Siegel’s Synthesis: Cyclotrimerization Regioselectivity Explanation

Varela, J.A.; Castedo, L.; Saá, C. J. Amer. Chem. Soc. 1998, 120, 12147. Stockis, A.; Hoffmann, R. j. Amer. Chem. Soc. 1980, 102, 2952.

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Conclusions

• Both syntheses are based on the “symmetry” of Complanadine A: Nature mimicking approaches

• Sarpong’s key step: Hartwig-Miyaura Ir(I)-catalyzed borylation and Suzuki -Miyaura coupling

• Siegel’s key step: Co(I)-catalyzed [2+2+2] cycloaddition – cyclotrimerization

NBoc

Me

N

BO

OBocN

Me

N

HH

TfO

+

R'N

Me

HH

NNR'

Me

N

R3Si

SiR3

• Biological studies in progress: The influence of the compound on primary cultures of rat glial cells and examining the effects on the biosynthesis of neurotrophin mRNA

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