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Enantioselective X–H insertion reactions based on carbenoids

Speaker: Shaolong ZhangSupervisor: David Zhigang WangDate: Jan. 3nd, 2014

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Outline

• Background• Construction of C-X bond via metal carbene

N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions

• Application in synthesis• Summary&Acknowlegement

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Outline

• Background• Construction of C-X bond via metal carbene

N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions

• Application in synthesis• Summary&Acknowlegement

4

BackgroundConstruction of C-X bonds:

Transition-metal-catalyzed insertion of carbenes or carbenoids:

2)Transition-metal-catalyzed C-X coupling reactions

Advantages:a)mild reaction conditions;b)high efficiency;c)diverse ligand sources render highenantioselectivily X-H insertion results.

palladium-catalyzed C-N and C-O couplings;Buchwald-Hartwig cross-coupling;stoichiometric amounts of strong base;coulpling partners are limited to aryl iodides or aryl bromides.

Traditional strategy to construct C-X bonds:

1)Uncatalysed nucleophilic displacement reactionsto achieve the substitution of polar X-H bonds.

O

R1 R2

N2

O

R1 R2

MLn

O

R1 R2

H XR3

metal-carbenoid

via:

R3X-H

LnMN2

XY NR2

HR1

amine

+

[L2PdCl2](catalytic)base

NYR1

R1

S. Zhu, Q. Zhou, Acc. Chem. Res. 2012, 1365.

R1X-H Leaving Group-R2+ R1X-R2base

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Background

Carbenoid based X-H insertions remain underdeveloped:

1) The predominant focus in the carbenoid field was insteadcyclopropanation and C-H insertion;

2) There are good ways to achieve the substitution of polarX-H bonds through classical uncatalysed nucleophilicdisplacement reactions.

synthetic chemistry

bond destruction bond construction

Functional group transformationC-H bond activation

task 1 task 2

To achieve this goal:

Carbene chemistry

Key learning points1)X-H insertion is an underexploited process with great potential for further development.2) Metal carbenoids are less reactive than is typically believed and are compatible with a var iety of common functional groups.3)The availability of diverse ligand classes has reinvigorated the study of X-H insertion. Many metals behave poorly or are completely inactive without the right ligand.4)Recent breakthroughs in copper- and iron-catalysed X-H insertion should stimulatefurther development with these metals.5)X-H insertion can be carr ied out in water , opening the door to applications in chemicalbiology.

packed destruction-consructionstrategy

direct destruction-consructionstrategy

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NHN2

OH

O

O

CO2pNB

H

N

OH

O

H0.1 mol%Rh2(OAc)4

80 oCO

CO2pNB

HH

NO

SCHH

H

F3CHO

OOH

OH

NO

SC

HH

H

F3CHO

OOH

HNNH

Faropenem

NO

SC

HH

H

F3CHO

OOH

N

H

CH3HN

NO

SC

HH

H

F3CHO

OO

NN

NN

O

SC

HH

H

F3CHO

OOH

H CH3

NHH

HNH

CH3

H OH

Tmipenem Paniperem

Biapenem Lenapenem

Used industrially by MeckIn synthesis of (+)-Thienamycin

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AcO

Me

H

H

Me

H

O N2

CuO

MeOH

AcO

Me

H

H

Me

H

O OMe

Seminal observations f rom Reichstein in 1950

ON2 Cu, RX-H

OXR

Yates in 1952

R. Casanova, T. Reichstein, Helv. Chim. Acta, 1950, 33, 417.

P. Yates, J. Am. Chem. Soc. , 1952, 74, 5376.

representative products:

O

PhOEt

O

PhXPh

O

PhN

X = N, O, S

P. Teyssie, Tetrahedron Lett., 1973, 14, 2233.

O

OEtN2

Rh2(OAc)4

R-OH

O

OEtOR

R = Me, Et, iPr, tBu

Tetssie in 1973

Background

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General mechanistic study

N2cat. [M]

MR H

[M]

[M]

R H

A concerted mechanism for carbenoids with non-polar bonds(cyclopropanation,

C-H insertion, or Si-H insertion)

MLnNN

R COOR

LnMR

COORN N

LnMCOOR

RXH R

LnMX R

COOR

H R

R COOR

H XR

A

BC

D

prefered stepwise ylide machanisim with polar bonds

(X = N, O, or S)

S. Zhu, Q. Zhou, Acc. Chem. Res. 2012, 1365.

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Metals for carbenoid-transfer reactions. (The font scaling is meant to qualitatively convey the effectiveness of each metal)

Conclution:

elements in the smallest font(Co, Ni, Pd, Pt, Os, Ir) have applied in carbenoidchemistry but have seen little or no use in X-H insertion;It is copper(I) and rhodium(II) that have proven, as yet, most versatile.

General points on catalysts

G. Dennis *, F. Na, Chem. Soc. Rev., 2013, 42, 4918.

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Outline

• Background• Construction of C-X bond via metal carbene

N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions

• Application in synthesis• Summary&Acknowlegement

11

Outline

• Background• Construction of C-X bond via metal carbene

N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions

• Application in synthesis• Summary&Acknowlegement

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N-H bond insertions

N2

MeOEt

O

PhNH2+

5 mol% CuCl6 mol% (Sa,S,S)-SpiroBox

6 mol% NaBArF4CH2Cl2, 25 oC, 2 h

94 %, 98 % ee

NHPh

MeOEt

O

N

O

O

N Ph

Ph

SpiroBox

NHPhMe OBn

On

NHPhPh OBn

On

NHPhOBn

OMe

Me

NHPhOBn

O

NHPhTBSO OBn

On

OEt

O

NHPhEtO

O

95 %, 88% een = 4, 83 %, 98 % een = 6, 75 %, 98 % ee84 %, 95 % ee

72 %, 91 % een = 1, 62 %, 96 % een = 2, 87 %, 96 % ee

n = 1, 83 %, 98 % een = 2, 87 %, 98 % een = 3, 75 %, 98 % een = 4, 77 %, 97 % ee

B. Liu, S. Zhu, W. Zhang, C. Chen, Q. Zhou, J. Am. Chem. Soc. 2007, 5834.

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BocHN COOMe

N25 mol% (S)- COOH

OH

Rh2(OAc)4, 0 oC, DCM45 % ee

NBoc

COOMe

NBoc

COOMe

HCO2Me

HNHBoc BocHN

COOMe

2.6 1.31: :C. F. Garci, M. A. McKervey, T. Ye, Chem. Commun. 1996 , 1465.

S. Bachmann, D. Fielenbach, K. A. Jorgensen, Org. Biomol. Chem. 2004, 3044.

NH2 N2

CO2EtNH

CO2Et

+

10 mol% CuPF6Ligand

N

OPR2

R =

Me

Me

75%, 26% ee.

N-H bond insertions

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N-H bond insertions

N2

MeOBn

O

+

1 mol% CuCl1.2 mol% (Sa,S,S)-SpiroBox

1.2 mol% NaBArF4CH2Cl2, 25 oC, 2 h

92 %, 98 % eeNH

MeOBn

O

N

O

O

N Ph

Ph

SpiroBox

OMeNH2

OMe

NH2

MeOBn

O

TCCAMeCN, H3O

70 %, 97 % ee

N

N

N

O

O O

Cl

Cl

Cl

TCCATrichloroisocyanuric acid

This copper-catalyzed asymmetric N-H insertion shows a high potential for wide applications in the preparation of optically active -amino acid derivatives.

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Outline

• Background• Construction of C-X bond via metal carbene

N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions

• Application in synthesis• Summary&Acknowlegement

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O-H bond insertions

N2

OMe

O+ nBuOH

OnBuOMe

O

5 mol% FeCl2.4H2O6 mol% (Sa,S,S)-SpiroBox

6 mol% NaBArFCHCl3, 40 oC, 15 h

93%, 98% ee

N

O

O

N iPr

iPr

SpiroBox

OOMe

O

OOMe

O

MeO

OMe

O

Ph

OOMe

O

Me

Me

Me

OOMe

O

Me

Me

Me

24 h, 88%, 95% ee 24 h, 91%, 95% ee

12 h, 90%, 95% ee3 h, 92%, 93% ee48 h, 86%, 89% ee

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O-H bond insertions

P

N2

OMe

OOMeX n-BuOH+

5 mol% CuOTf6 mol% (Sa,S,S)-SpiroBox

6 mol% NaBArFCH2Cl2, 25 oC P

OOMe

OOMeX

nBu

X = F, Cl, Me, MeO, etc. 45-89% yield84-98% ee

P

OOMe

OOMe

TMS BF3.OEt2CH2Cl2, rt.

P

OHOMe

OOMe

89.7% ee 93% yield89.2% ee(R)

an efficient approach not only to -alkoxy phosphonates but also to the more useful -hydroxyphosphonates.

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O-H bond insertions

N2

MeOR

O+

OH

X

5 mol% CuCl6 mol% (Sa,S,S)-SpiroBox6 mol% NaBArF, 5A MS

CHCl3, 25 oC, 3 h N

O

O

N Ph

Ph

SpiroBox

O

MeOR

O

X

68-88%95%-99.6% ee

O

MeOEt

O

aq. KOHEtOH, 0 oC

O

MeOH

O99% ee 100%

OH

TMS

N2

OMe

O

2.0 mol% Cu(OTf)23.8 mol% (+)-Fu's Ligand

4.0 mol% H2ODCE, rt.+

94%, 90% ee

PhOMe

O

HOTMS

Me Me

MeMe

Fe

Me

N N

FeMe Me

MeMe

Me

Fu's Ligand

BF3.Et2OCH2Cl2

98%Ph

OMe

O

HHO

T. C. Maier, G. C. Fu, J. Am. Chem. Soc. 2006, 128, 4594.

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O-H bond insertions

N2

ArOMe

O

+ H2O

5 mol% FeCl2.4H2O6 mol% (Sa,S,S)-SpiroBox

6 mol% NaBArFCHCl3, 40 oC

OH

ArO

OMe

OH

O

OMe

87%, 94% ee

OH

O

OMe

90%, 91% ee

S

OHOMe

O

66%, 92% ee

The challenges of asymmetric O-H insertion of water are mainly attributed to two aspects:First , the active transition metal catalysts are generally sensitive to water. Second, the small molecular structure of water makes chiral discrimination quite difficult.

OH

O

OMeCl

95% ee

NsClDMAP, Et3NCH2Cl2, 0oC

90%

ONs

O

OMeCl

S

NCH2

2

Acetone, 20 oC85%, 93% ee

CO2Me

N

Cl

S

Clopidogrel

S. Zhu, Y. Cai, H. Mao, J. Xie, Q. Zhou, Nat. Chem. 2010 , 546.

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OH

N2

CO2Rn

5 mol% CuOTf6 mol%(Sa,S,S)-SpiroBox

6 mol% NaBArFCH2Cl2, 25 oC O

CO2Rn

O

CO2Bn

O

CO2Bn

O

CO2Bn

OCO2Bn

OCO2Bn

OCO2Me

OCO2Bn

80%, 93% ee 89%, 90% ee 77%, 88% ee

81%, 88% ee 80%, 95% ee 79%, 97% ee 14%, 95% ee70%, 83% ee*

N

O

O

N tBu

tBu

SpiroBox

*obtained by using SpiroBox-iPr

double bond is compatible in the chain,no competitive cyclopropanation reaction are abserved.

competitive -H elimination reaction

O-H bond insertions

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Outline

• Background• Construction of C-X bond via metal carbene

N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions

• Application in synthesis• Summary&Acknowlegement

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S-H bond insertions

N2

R1 OR2

O

+ R3 SH

5 mol% CuCl6 mol%(Sa,S,S)-SpiroBox

6 mol% NaBArFCHCl3, 80 oC

SR3

R1 OR2

O*

S

MeOBn

O*

XS

OBn

O*

X

S

MeOBn

O*

X

70-87%68-85% ee

59-88%44-77% ee

76-92%60-72% ee

S

MeOBn

O*

S

MeOBn

O

S

MeOBn

O

S

MeOBn

O

Ph

PhPh

* * *

86%, 17% ee 84%, 32% e 85%, 61% ee 57%, 77% ee

S

MeOBn

O

Ph

PhPh

*

TFA/Et3SiHCH2Cl2, r.t.

SH

MeOBn

O*

81%, 77% ee77% ee

The low level of enantiocontrol maybe partially attr ibuted to:The high coordination ability of the sulfur atom;The relatively high stability of sulfoniumylide may facilitate the degenerationof metal-associated ylide to free ylide.

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S-H bond insertions

SOMe

O

O

1 mol% [Ir(COD)Cl]2PhNH2, CH2Cl2

NHOMe

O

91%

NBoc

O SO Cl O

SO

NHBoc

1 mol% [Ir(COD)Cl]2CH2Cl2

NBoc

O

I. K. Mangion, I. K. Nwamba, M. Shevlin, M. A. Huffman, Org. Lett. 2009, 3566.

O

OO

F3C

NO2

SO2N3base

O

OO

F3CNN

NSHO2Ar

ONN

NO

ArO2S

F3CO

O

ON

N

ORX

Ocat. Rh2(Oct)4

ArSO3N3base

Rh2(Oct)4RXH

RXH

O

F3C NSHO2Ar

+

B. H. Brodsky, J. D. Bois, Org. Lett. 2004, 2619.

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Outline

• Background• Construction of C-X bond via metal carbene

N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions

• Application in synthesis• Summary&Acknowlegement

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Si-H bond insertionsN2

OMe

- 78oCEt3SiH

NSO2

nC4F9

CO2

H4

Rh2

0.65% mol%

OMeH

Et3Si

94% ee

M. Ge, E. J. Corey, Tetrahedron Lett. 2006, 2319.

R1 R2

R3N2CO2Me

+ TBDMSiH

N

H O

O

Rh

RhSO2Ar 4

pentane, - 78oC

77-95% ee

R1 R2

R3Me2tBuSi

CO2Me

H. M. L. Davies,T. Hansen,J. Rutberg, P. R. Bruzinski, Tetrahedron Lett. 1997, 1741.

CO2Me

N2

Cl N

Cl

N

Cl

Cl

10 mol%, [CuOTf]2C6H6H-SiMe2Ph, CH2Cl2, - 40oC

88%, 83% eeCO2Me

Me2SiH2PhL. A. Dakin, S. E. Schaus, E. N. Jacobsen, J. S. Panek, Tetrahedron Lett.1998, 8947.

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N2

O

OMe+ Me2PhSi-H

5 mol% Cu(OTf)26 mol% SpiroZhou

CH2Cl2, 0 oCSiPhMe2

O

OMe

N

N

SpiroZhou

Cl

Cl

Cl

Cl

95%, 93% ee

SiPhMe2

O

OMeSiPhMe2

O

OEt

SiPhMe2

O

OiPrSinPr3

O

OMe

95%, 97% ee95%, 97% ee

92%, 98% ee92%, 98% ee

Si-H bond insertions

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Outline

• Background• Construction of C-X bond via metal carbene

N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions

• Application in synthesis• Summary&Acknowlegement

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Application in synthesis

NHN2

OH

O

O

CO2pNB

H

N

OH

O

H0.1 mol%Rh2(OAc)4

80 oCO

CO2pNB

Me MeOH

O

OP

N2

O OEtOEt

OMOMMe

Me MeO

O

Me

OMOM

O

P OOEt

EtO

Rh2(OAc)4PhH60 %

Me MeOH

HO

OMOMMe

J. X. Gong, G. A. Lin, W. B. Sun, C. C. Li, Z. Yang, J. Am. Chem. Soc. , 2010, 132 , 16745.

MeMe

O

O O

O

OH Me

Maoecrystal V

NH

OH

O

O

CO2pNB

H

N

OH

O

H

S

CO2H

NH2HHHH

(+)-Thienamycin

T. N. Salzmann, R. W. Ratcliffe, B. G. Christensen, F. A. Bouffard, J. Am. Chem. Soc. , 1980, 102 , 6161.

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Application in selective protein labeling

NH

HN

ONH

Ph

N2

OOMe

3

100 uM Rh2(OAc)480 %H2O/ethylene glycol N

H

HN

ONH

CO2R

Ph

N

HN

ONH

CO2RPh

tryptophan-containingproteins at 100 uM

buffer salt, PH, and temperatureare varied depending on the protein

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Summary

MLnNN

R COOR

LnMR

COORN N

LnMCOOR

RXH R

LnMX R

COOR

H R

R COOR

H XR

A

BC

D

prefered stepwise ylide machanisim with polar bonds

(X = N, O, or S)

preparation of optically active a-amino acid derivatives;an efficient approach not only to a-alkoxy phosphonates

but also to the more useful a-hydroxyphosphonates;introduction of sulfur and silicon atom into certain position.

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Thank you for your attention