Stereoretentive Suzuki-Muyaura Coupling of Haloallenes Enables FullyStereocontrolled Access to (−)-Peridinin

Eric M. Woerly, Alan H. Cherney, Erin K. Davis and Martin D. Burke

J. Am. Chem. Soc. (ASAP)

Current LiteratureMay, 2o1o

OO

•OHO OAc

HO1'

1

5

3'

15

15'

11'

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•

AcO OH

OO

OOH

Isolation and Structural Features:

Schütt, F. Ber. Deut. Bot. Ges. 1890, 8, 9.Lieean-Jensen, S. at al J. Am. Chem. Soc. 1971, 93, 1823Johansen, J. E.; Borch, G.; Liaaen-Jensen, S. Phytochemistry 1980, 19, 441Yamano, Y.; Tode, C.; Ito, M. J. Chem. Soc. Perkin Trans. 1 1993, 1599.

(+)-Peridinin

• Isolated in 1890 by Schütt from fresh-water dinoflagelletes (causing red-tide, > 106 cells/mL).

• Later isolated from corals, clams and sea anemones.

• Dinoflagelletes - red pigment important for photosynthesis.

• Full structure and assignment of Peridinin wasn’t achieved till 1971.

• Interesting features:

• (Z)-γ-ylidenebutenolide moiety (anticancer activity?)• C37 nor-carotnoide• Stereogenic allene.

• More recently, Peridinin suggested as 1O2 quencher; associated with atherosclerosis rheumatoid arthritis and cancer, contributing to the aging process.

• 1st Total synthesis of (±)-Perdinin was completed over 100 years later by Ito (1993), confirmed the structure.

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Katsumra’s Total Synthesis:

1'

15

3'15

15'

10' CHOO

TBSO•

AcO OHO

O

OOH

•

H

AcO OH

OH

OOH

OO

HO

2

3

4

O

P+Ph3Br-

OTBS5

R

O AlH

OO

RSonogashiraCoupling

OO

R

R'

LigandExchange

OO

R

PdR'

OO

R Pd

R'

Pd Insertion

OO

RR'

Pd

Red.Elimination

3

Furuichi, N.; Hara, H.; Osaki, T.; Nakano, M.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 7949.Yamano, Y.; Tode, C.; Ito, M. J. Chem. Soc. Perkin Trans. 1 1993, 1599.

“Domino Reaction”

1. 5, nBuLi, 3 h

2. TPP, O2, hv, !78 oC77%, 2 steps

OTBSO

OOOH

OHO

OAllylO1. iPr2NEt, DMSO, 3h, r.t. then AllylBr, r.t., 1 h, 70%

2. CBr4, PPh3, Et3N, ! 60 oC, 1 h, 89%3. TBAF, 81%

4

6b, Pd(Ph3P)4, Et3N, CuI, r.t. 1 h

then HCO2H, 20 h, 49%

3

1. ClCH2P+Ph3Cl-, nBuLi! 30 oC, 3h

2. tBuOK, DMSO, r.t, 20 min53%, 2 steps

OHO

1. 6a, Pd(Ph3P)4, iPr2NH, CuI, r.t. 1 h, 84%

2. DIBAl, 0 oC, 80%

•

H

HO OH

OH1. MnO2, Et2O, 3h2. Ac2O, pyr, 86%, 2 steps

3. NaBH4, MeOH, 98%4 2

CO2MeI6a

I6b

OH

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Katsumra’s Total Synthesis cont.

•

AcO OHO

O

OOH

E/Z 1/3

E/Z > 5/1

Benzener.t. 3 d

50% from aldehyde

NaHMDS

!78 oC dark, 5 min

OOH

OOOHC

•

H

AcO OH

SO2

S

N1. 7, DIAD. PPh3, 78%

2. (NH4)6Mo7O24, aq H2O2, 89%

MnO2

Et2O3

2

HSS

N

7

•

AcO OH

OOH

OO

•

AcO OH

OOH

OO

•

AcO OH

OOH

OO

C33

C35

C39

Katsumura at el Org. Lett. 2009, 11, 5006.

• Peridinin posses large static dipole moment facilitating energy transfer.

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Brückner’s Approach to the Butenolide Moeity:

O

OO

MeO2C

O

OO

MeO2C

4

1

2

EtO2C CO2Et

OH

OH

O

OO

MeO2C

OBu3Sn

OO

MeO2C Br

+

OOHC

41

4-deoxy-4

(!)-diethyl tartrate

• 2 was also prepared in the same fashion.• Later in 2006, used the same methodology to complete the synthesis of Peridinin.

EtO2C CO2Et

O

O

O

O

MeO2C

O

NMe

OMe3 steps 1. NaBH4 (8.0 eqv), 98%

2. Swern [O], 90%O

O

MeO2C3. NaH, THF, 90% E:Z =95:5

P Br

CO2Et

OPhO

PhO

Br

CO2Et

OOHCMeO2C

1. O3, MeOH

2. NaBH43. Sharpless, 67%, 99.8%ee4. Swern [O], 99%

1. LDA, TMSCHN2

2. Bu3SnH, Pd(PPh3)4

OBu3Sn O

OH

MeO2C Br

O

+

1. CuI, Pd2dba3, P(2-furyl)3, 84%2. DEAD, Ph3P, ! 30oC, 52%

1

Amberlyst 15, MeOH reflux, 28 h, 95%

.

Olpp, T.; Brückner, R. Angew. Chem., Int. Ed. 2005, 44, 15533.Olpp, T.; Brückner, R. Angew. Chem., Int. Ed. 2006, 45, 4023.

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Burke’s Work: MIDA Mask

B O

N

OO

OO

H B O

N

OO

OOHOHPMBO

B O

N

OO

OOMeOMeOH

1. Me3OBF4, proton sponge, 82%

2. CAN, 77%

1. DMP, 97%

2. CHI3, CrCl2THF:Dioxane, 74%

2

H2N

OMeO OMe

IOMeOMe

B O

N

OO

O

H2N

O

SnBu3

2

3Br

41 Crocacin C

32, Pd(PPh3)4

CuI, CsF, DMFOMeOMe

B O

N

OO

O

H2N

O62%

4, Pd(OAc)2

SPhos, K3PO477%

1

• Highly unreactive.• Very stable to most C-C conditions.• Easily removable under mild conditions.• Stable to silica chromatography and storage.

• Nine linear steps synthesis of crocacin C

Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716.Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084.

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Title Paper - Key Reaction:

Woerly, E. M.; Cherney, A. H.; Davis, E. K.; Burke, M. D. J. Am. Chem. Soc. (ASAP)Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1985, 50, 3042.

•Pd2(dba)3, Ligand

THF:H2O, rt, 1.5 h

(R)

PhB(OH)2, Ag2OH

R X

H•

H

R Ph

H

(R)

Key Reaction:

OO

•OHO OAc

HO

OTBSO

B O

N

OOO

B1O

O

BrB O

N

OOOB2

B O

N

OOO

I

B3•

OAc

TMSOH

I

B4

Iterative Cross Coupling (ICC)

Stereoretentive SM cross-coupling

R CH

C CH

Xcat. Pd(PPh3)4

PhZn2 or PhZnClR C

HC C

HPh

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Pd(0)-Catalysed Phenylation of 1-Haloallenes:

PdL4

PdL2

PhZnYZnXY

R CH

C CPd

H

L X

LR CH

C CPd

H

Ph L

L

R CH

C CH

PhR C

HC C

HXInversion:

X•

HR

H PdL2

!PdL2

X•

HR

H

PdL2

SN2'

antiH

RH

PdL2X

H•

PdR

H

X

L

L

[1,3]-shift

Retention:

• Oxidative addition to Pd decreases I > Br > Cl, as in vinyl halides.• Heavier metals, group VIII show affinity to heavy halogens.• Possible radical intermediate in which recombination rate is faster.

(retention)

I•

HR

H Pd•

R

H

H

L

LI

(R) (R)

Pd(PPh3)4halide transfer C

HC C H

PdI ILL

cage

H•

XR

H

(R)

Ph•

HR

H

H•

PhR

H

Inversion

Retention

X = I

X = Cl or Br

Proposed catalytic cycle

Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1985, 50, 3042.

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Application in Synthesis:

Lera’s Synthesis of Peridinin:

• X

H

AcO OH

Oxidative addition • PdL2X

H

AcO OH

Transmatalation then Reductive Elimination Product with Retention

"PdL2"

• PdL2X

H

AcO OHHO OHPdL2X

anti-SN2' displacement of Br

superfacial1,3-shift

Transmatalation then Reductive Elimination Product with Inversion

HO OH

1. CuBr, NH4Br HBr, Et2O, 85%

2. Ac2O, pyr, 85%

• Br

H

AcO OH

[Pd(PhCN)2Cl2],

(iPr)2NEt, DMF:THF 64%

Bu3Sn SO2BT•

AcO OH

SO2BT

6'-epi-Peridinin6'

Haloallene Natural Products:

O

OH

H

OMs

H

LiCuBr2

O

OH

HH

•

HBr

H

Panacene

O

OH

H

Br

H

• HBr

H

H

O

Br Br

BrBr

O

H

H

Br

H

OH

Laurellene

Vaz, B.; Domínguez, M.; Alvarez, R.; de Lera, A. R. Chem.-Eur. J. 2007, 13, 1273.K. S. Feldman, C. C. Mechem, L. Nader, J. Am. Chem. Soc. 1982, 104, 4011.M. T. Crimmins, E. A. Tabot, J. Am. Chem. Soc. 2000, 122, 5473.

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Title Paper: Forward Synthesis

Woerly, E. M.; Cherney, A. H.; Davis, E. K.; Burke, M. D. J. Am. Chem. Soc. (ASAP)Furuichi, N.; Hara, H.; Osaki, T.; Nakano, M.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 7949.Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857.

OTBSO

OTBSO

B O

N

OO

OB1

pinBH

Cy2BH81%

OTBSO

B O

OHO2C

MeN

CO2H

DMSO, 3 cycles73%

OO

•OHO OAc

HO OTBSO

B O

N

OOO

B1

OO

BrB O

N

OOOB2

B O

N

OOO

I

B3

•

OAc

TMSOH

I

B4

Iterative Cross Coupling (ICC)

Stereoretentive SM cross-coupling

B O

N

OO

O

Bu3SnHMo. cat

THF84%

Bu3SnB O

N

OO

O

OO

BrB O

N

OO

O

1, Pd2(dba)3, Ph3As

THF77% B2

OO

Br Br

1

Structure confirmed by X-rayMo cat = [Mo(allyl)Br(CO)2(CH3CN)2]

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Total Synthesis of (-)-Peridinin: Final Steps

Woerly, E. M.; Cherney, A. H.; Davis, E. K.; Burke, M. D. J. Am. Chem. Soc. (ASAP)

B O

N

OO

OIB O

N

OO

O

1. Br2, CH2Cl2

2. DBU, MeCN67%

B O

N

OO

OBr

1. 2, PdCl2(PPh3)2, DMF:THF, 74%

2. I2, MeOH, 77%B O

N

OO

OI

1. 2, Pd(PPh3)4, CuTc, DMF, 58%

2. I2, MeOH, 75%B3

OTBSO

B O

N

OO

O

1. NaOH, THF:H2O, 95%

2. B2, Pd(OAc)2, XPhos, K3PO4, Tol:THF, 79%

OO

OTBSO

B O

N

OO

O

1. pinacol, NaHCO3, MeOH, 99%

2. B3, PdCl2(PPh3)2, Ag2O, DMSO, 45%

OO

OTBSO

B O

N

OO

O

1. B4, Pd(OAc)2, XPhos, NaOH, THF:H2O, 60%

2. HF.pyr, THF, 65%

OO

•OHO OAc

HO

OO

BrB O

N

OOOB2

•

OAc

TMSOH

I

B4

(-)-Peridinin

Et3Ge SnBu32

iPrPCy2

iPr

iPr

= XPhos

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Conclusion:

• Synthesis of (+)-Peridinin focused on a late stage construction of olefins, which proved problematic due to

the E/Z isomerization.

• Burke’s strategy proved successful in avoiding the isomerization using a different approach, SM cross coupling, in

his synthesis of (-)-Peridinin.

• Combination of bulky substituent and ligand promoted stereoretention in SM cross coupling of Iodo-allenes.

• Using a more stable MIDA boronates which has a lot of advantageous in the modern synthetic chemistry.

• Achieved 1st Stereoselective total synthesis of (−)-Peridinin.

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