Wangqing Kong Zhu’s group meeting

13th, Aug, 2015

Intramolecular Asymmetric Heck Reaction and Application in Natural Products

Synthesis

Mizoroki-Heck Reaction

Mizoroki (1971)

Heck (1972) 2010 Nobel Prize

Construction of quaternary stereocenters by the intramolecular asymmetric Heck reaction

N

OMe

OH Heck

MeO

OBn

I

NMe

Me

Skeletal Motif

O

O

NO Me

O

O

N

O

Me

I

H

RO OR

OTfBr

Me

OHMeMe

Me

(-)-Oppositol

NMe

O

OH

OH

Morphine

NH

MeO

O

O

O

OHO

O

Me

Fredericamycin

MeOMe OR MeO

Me

OR

OTf

OH

O

OH

O(+)-Vernolepine

Content ： Different Reaction Modes in Asymmetric Heck

R1.

2.

3.

π-allylic-Pd formation

R'

Pd

Nu R'

Nu

R

Intramolecular Reductive Heck Reactions

5. X = H

Oxidative boron Heck-type Reaction4. X = B(OH)2

Fujiwara-Moritani Reaction

X

R

RPd(II)

Pd (0)

O.A. and Insertion

R

R

Masakatsu Shibasaki

Larry E. Overman

The Pioneers in Intramolecular Asymmetric Heck Reaction

MeOOC

I

Pd(OAc)2 (3 mol%)

R-BINAP (9 mol%)

cyclohexene (6 mol%)

Ag2CO3 (2 equiv.)

NMP, 60 oC

H

COOMe

The best result: 74% yield, 46% ee

J. Org. Chem. 1989, 54, 4739-4741.

OTf

O

Pd(OAc)2 (10 mol%)

R,R-DIOP (10 mol%)

Et3N, Benzene, rt

O

The best result: 90% yield, 45% ee

J. Org. Chem. 1989, 54, 5846-5848.

Asymmetric Heck Reaction Mechanism

1. Cationic Pathway:

The cationic pathway was first proposed independently by Cabri and Hayashi to describe the Heck reactions of aryl triflates in the presence of palladium-diphosphine catalyst.

Cabri, W.; Candiani, I.; DeBernardis, S.; Francalanci, F.; Penco, S. J. Org. Chem. 1991, 56, 5796; Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 1417.

triflate dissociation

halide abstraction by Ag(I)

Chiral bidentate ligand always chelated to the palladium center throughout the alkene coordination and migratory insertion steps!!!

High ee

M. Shibasaki. J. Am. Chem. Soc., 1994, 116, 11737.

MeOOC

TfO

Pd(OAc)2 (5 mol%)

R-BINAP (10 mol%)

toluene, 60 oCH

COOMe

K2CO3 (2 equiv.)

54% yield, 91% ee

Pd(OAc)2 (5 mol%)

R-BINAP (10 mol%)

toluene, 60 oC

H

OTBSX

X = I Ag3PO4, CaCO3, 78% yield, 82% ee

NMP, 60 oC

OTBS

X = OTf K2CO3 (2 equiv.) 63% yield, 73% ee

BrMe

OHMeH

Me

Me

(-)-Oppositol

M. Shibasaki, Tetrahedron Lett. 1992, 33, 2593; Tetrahedron: Asymmetry 1995, 6, 757.

OH

O

OH

O(+)-Vernolepine

M. Shibasaki. Tetrahedron Letters, 1993, 34, 4965; J. Org. Chem. 1995, 60, 398.

Lentiginosine

N

H OH

OH

4 steps

Lentiginosine

N

H

N

O

IPd2(dba)3 (5 mol%)

ligand (10 mol%)

Ag zeolite, CaCO3

DMSO/DMF, 0 oC

N

O

H

N

O

H

+

94% yield (1 : 1.4)

86% ee

FePPh2

OH

Asymmetric Heck Reaction

M. Shibasaki. J. Am. Chem. Soc. 1993, 115, 8477.

Zn-Cu, BrCH2CH2Br

OTBDPSI

, Pd(PPh3)4, THF84%

OTBDMS

MeO

OTBDPS

OTBDMS

MeO

BH3-THF, H2O2-NaOH

PPh3, I2, imidazole

OTBDMS

MeO I

74%

TBAF, THF, 0oC

Tf2O, Et3N, DCM MeO

OTBDPS

OTf

88%

(-)-EptazocineHO

Me

N

Me

(-) -Eptazocine

Asymmetric Heck Reaction

(1) TBAF, AcOH, THF, 0 oC

(2) MeNH2, MeOH;

H2, PtO2, MeOH, rt;

Ac2O, AcOH, 100 oC,

MeON

Ac

Me87%

MeOOTBDPS

Pd2(dba)3 (5 mol%)

(R)-BINAP (10 mol%)

K2CO3, THF, 70oC

90% yield, 90% ee

MeO

Me

87%

(1) CrO3, AcOH, H2O

(2) KOH, MeOH, reflux;

(CH2O)n, (CO2H)2, MeOH, 50 oC

NMeO

34%

Pd/C, AcOH, H2; 48% HBr

NaBH4, EtOH;

HO

Me

N

Me

(-) -Eptazocine

Halenaquinone and Halenaquinol

Asymmetric Heck

M.Shibasaki. J. Org. Chem. 1996, 61, 4876.

Pd(OAc)2 (5 mol%)

R-BINAP (10 nol%)

K2CO3, THF, 60 oC

OMe

OMe

OTBDPS

78% yield, 87% ee

OMe

OMe

OTf

OTBDPS

(+)-Xestoquinone

Brian A. Keay. J. Am. Chem. Soc. 1996, 118, 10766.

(1) H2, Pd-C

(2) CAN

O

O O

O

Me

Xestoquinone

Pd2(dba)3 (2.5 mol %),

OMe

OMe O

O

Me

+

OMe

OMe O

O

Me

74% (1 : 2) 68% ee

S-BINAP (10 mol %),

PMP (8 equiv),

O

O O

O

Me

Xestoquinone

O

Me

OMe

OMe

OTf

O

A. Hallberg. J. Org. Chem. 1997, 62, 595.

N

HO

TfOPd(OAc)2 (10 mol%)

i-Pr2NEt, toluene

100 oC

N

HO

N

HO

+

R-BINAP 30% yield, 19% ee 14% yield, 20% ee

N

O

PPh2

61% yield, 87% ee 10% yield, 99% ee

This was the first example of an enantioselective intramolecular Heck reaction with a bidentate phosphinamine ligand that proved to be superior to BINAP.

(+)-Minfiensine

L. E. Overman. J. Am. Chem. Soc., 2008, 130, 5368; J. Am. Chem. Soc., 2005, 127, 10186.

TFA, DCM

75% NMeOOC

NBoc

NH N

Me

OH

(+)-Minfiensine

Minfiensine

AB C

Retro-synthesis

N

COOMe

BocHN

Pd(OAc)2 (10 mol%)

PPh2

N

O

(20 mol%)

PMP, Toluene

Microwave

170 oC, 40 min

85% yield, 99% ee

N

OTf COOMe

BocHN

NMeOOC

Pd(OAc)2 (20 mol%)

BINAP (30 mol%)

PMP, toluene or MeCN

80 oC

NHBoc

N

COOMe

BocHN

[Pd]H

N

OTf COOMe

BocHN

L. E. Overman. J. Am. Chem. Soc., 2008, 130, 5368; J. Am. Chem. Soc., 2005, 127, 10186.

N

MeOOCNBoc

(1) 9-BBN, THF, 100oC

H2O2, NaOH

(2) N(C3H7)4RuO4 NMeOOC

NBoc

O

NMeOOC

NBoc

O

+

25% 63%N-Methylmorpholine N-oxide

DCM

NMeOOC

NI

Me

(1) TFA, DCM, rt

(2) MeI

Br

K2CO3, MeCN

65%

O

PdCl2(dppf), K2CO3

MeOH, 70 oC

74%

N

MeOOCN

Me

O NaHMDS, Comins'reagent

THF, -78 oC

86%

N

MeOOCN

Me

OTf

Pd(OAc)2, PPh3, Et3N

CO, MeOH, DMF

89%N

MeOOCN

Me

COOMe (1) LiAlH4, THF, -78 oC

(2) NaOH, MeOH, H2O

100 oC85% (two steps)

NH N

Me

OH

(+)-Minfiensine

dissociation of one arm of the bidentate ligand

2. Neutral Pathway :

Asymmetric Heck Reaction Mechanism

low ee (without Ag(I) salts)

(S, 81% yield, 71% ee)

(R, 77% yield, 66% ee)

This was the first example of a Heck reaction proceeding with good asymmetric induction using aryl iodide in the absence of a silver salt.

L. E. Overman. J. Org. Chem. 1992, 57,4571; J. Am. Chem. Soc. 1998, 120, 6477

The same enantiomer of chiral ligand gave opposite enantiomers.

N

I

Me

O

Me

OTBDMSPd(OAc)2 (10 mol%)

PMP (4 equiv.)

DMA, 100 oC NMe

O

Me OTBDMSHCl, THF/H2O

NaBH4NMe

O

Me OH

PPh2

PPh2

92% ee

PPh2

OTBDMS

23% ee

PPh2

OiPr

27% ee

PPh2

CHPh2

19% ee

Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.Soc. 1998, 120, 6488; Angew. Chem., Int. Ed. 1997, 36, 518.

Bidentate or Monodentate Phosphine Ligands?

Chiral Amplification Study

Catalyst is monomeric Pd-BINAP.

Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.Soc. 1998, 120, 6488; Angew. Chem., Int. Ed. 1997, 36, 518.

Both Phosphanes of BINAP are coordinated to Pd in the enantioselective step

Mechanistic Neutral Pathway ：

X

Reference for pentacoordinate Pd intermediate: V. G. Albano, G. Natile and A. Panunzi, Coord. Chem. Rev., 1994, 133, 67.

The migratory insertion directly from this pentavalent intermediate is less favourable than from a tetra-coordinate Pd complex! References see: Thorn, D. L.; Hoffmann, R. J. Am. Chem. Soc. 1978, 100, 2079; Samsel, E. G.; Norton, J. R. J. Am. Chem. Soc. 1984, 106, 5505.

Conclusion: 1 2 5 4 6

X

X

L. E. Overman. J. Am. Chem. Soc.,1998, 120, 6500; J. Am. Chem. Soc. 1998, 120, 6488; J. Org. Chem. 1993, 58, 6949.

Physostigmine and Physovenine

N

I

Me

O

Me

OTIPS

Pd(OAc)2 (10 mol%)

PMP (4 equiv.)

DMA, 100 oC

N

Me

O

MeOTIPS

N

Me

O

Me

CHO

S-BINAP (20 mol%)

84% yield, 95% ee

THF/H2O

HCl

MeOMeO

MeO

O

O O

Me

I

Cl

I

HO OH

acetone, K2CO3

91% I

OH

O

PIDA, MeOH

83%

O

O

Ph Ph

Ph Ph

O

OP N

Pd(OAc)2 (6 mol%)

(12 mol%)

CHCl3, Cy2NMe

75% yield, 96% ee

O

O

O

Me

B. L. Feringa. J. Am. Chem. Soc., 2002, 124, 184.

Only one substrate in this paper

This is the only reported example to date of a monodentate ligand which has induced good enantioselectivities in the intramolecular asymmetric Heck cyclisation of the cyclohexadienone.

The ligand to Pd ratio in the catalytically active species is as yet unknown but the authors speculate that two ligands are bound to the metal centre.

2. Asymmetric Heck cyclization, π-allylic-Pd formation and nucleophile trapping

M. Shibasaki. J. Org. Chem. 1991, 56, 4093; J. Am. Chem. Soc. 1996, 118, 7108.

OTf

Me

Pd(OAc)2

(S)-BINAP

DMSO, rt

NuH

Me

Bu4NOAc Nu = OAc (89% yield, 80% ee)

BnNH2 Nu = NHBn (76% yield, 81% ee)

COOMe

COOMe92% yield, 83% ee

COOEt

COOEt

TBDPSO77% yield, 87% ee

SO2Ph

SO2Ph

83% yield, 94% ee

Ph

O O

Ph90% yield, 80% ee

Me

O

CO2Me 74% yield, 83% ee

OTf

Me conditions

EtO2C

EtO2C

OTBDPS

Me

HEtO2C

CO2Et

OTBDPS

Me

HMe

Me H

H

(-)-Capnellene

87% ee

11 steps

OTf

Me

N

OBr

R Pd(OAc)2 (5 mol%)

R-BINAP (10 mol%)

HCO2Na (2 equiv.)

MeOH, 100 oC

N

O

R

R1 R1

Yi-Xia Jia. J. Am. Chem. Soc., 2015, 137, 4936.

3. Intramolecular Reductive Heck Reactions

4. Oxidative Boron Heck-type Reaction

K. Akiyama and K. Mikami, Heterocycles, 2007, 74, 827.

The first and only example for the intramolecular oxidative boron Heck-type reactions!

S

B(OH)2Me

O O

N

Ph

Me

Me Pd2(dba)3 (2.5 mol%)

Me

PPh2

PPh2

Me(7.5 mol%)

DMF, O2, 25-50 oC SN

O OPh

MeMe

91% yield (56 : 44)

up to 86% ee

SN

O OPh

MeMe

+

5. Fujiwara-Moritani Reaction

N N

O

L2

J. A. Schiffner, A. B. Machotta and M. Oestreich, Synlett, 2008, 2271; H. Zhang, E. M. Ferreira and B. M. Stoltz, Angew. Chem., Int. Ed., 2004, 43, 6144; J. A. Schiffner, T. H. Woeste and M. Oestreich, Eur. J. Org. Chem., 2010, 174.

R = Me, n = 1, 70% yield, 70% eeR = Ph, n = 1, 16% yield, 68% eeN N

OMeOOC

Summary and outlook

X

RR

Pd(II)Pd (0)

O.A. and Insertion

chiral ligand

*

RR

R

*

R

R

*

R

Reductive Heck

Known Transformations

N

O

N

RH

C-H bond activation

------- ??????

isocyanide insertion

R R

NC

+ Nu