Literature Screening

1

Literature Screening

JACS

Synthesis

February 2nd 2009

Thibaud Gerfaud

2

Oxidative Pd(II)-catalyzed C-H bond amination to Carbazole at ambient

temperature James A. Jordan-Hore, Carin C. C. Johansson, Moises Gulias, Elizabeth M. Beck and Matthew J. Gaunt

H

N RH

N RPd(II) Pd(IV)

- Classical disconnection in C-N bond formation: C-X + NH (Pd(0) and Cu(I) couplings)

- This work: C-H + NH Pd(II) catalysis

- Interest: No prefunctionalization of the aryl group with an halide

- Carbazole motif present in a lot of natural products and medicines:

HN

NNH

O

O

Cl

Cl

O

OH

HO

HO

HO

rebeccamycin

HN

carvidilol

OOH

NH

O

MeO

Gaunt & al., JACS, 2008, 130, 16184-16186

3

Previous work on C-H amination:

Gaunt & al., JACS, 2008, 130, 16184-16186

- Via nitrenes, Rh catalysis

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Driver & al., JACS, 2007, 129, 7500-7501

- Allylic C-H amination, heterobimetallic catalysis

R

H

SS

Ph

OO

Ph

-Pd(OAc)2

(10 mol%)Cr(III)(salen)Cl (6 mol%)

MeOC(O)NHTsBQ, TBME45°C, 72h

RTsN

O

OMe

White & al., JACS, 2008, 130, 3316-3318



- Acetanilide amination, Pd catalysis

Inamoto & al., Org. Lett., 2007, 9, 2931-2934

4

Mechanistic hypothesis:

Optimized reaction conditions:

H

N Bn

H

N BnPd(OAc) 5% mol.

toluene, PhI(OAc)2 (1.2 eq.), rt, 1h

Yield : 96%

Gaunt & al., JACS, 2008, 130, 16184-16186

C H

HN

H R

CH

NH R

Pd(II)

PdII

Pd(II) CH

NH R

PdII [O]C

NR

PdIV -Pd(II)C

H

NR

5

Scope of the reaction

Complex Isolation



H

N R1

H

N R1Pd(OAc) 5-10% mol.

toluene, PhI(OAc)2 (1.2 eq.), rt



H

N Bn

H

N BnPd(OAc) 5% mol.

toluene, PhI(OAc)2, additive, rt

Gaunt & al., JACS, 2008, 130, 16184-16186

6

Application to complex substrates

Conclusion

- New Pd(II) catalyzed intramolecular C-H amination to form carbazoles

- Reaction occurs under mild conditions with a broad scope

- Rare exemple of reductive elimination from a high oxidation state transition

- A non polar solvent seems necessary to promote polynuclear palladacycles

- Useful in natural products synthesis

N-Glycosyl carbazoles

N

HPd(OAc) 20% mol.

toluene, PhI(OAc)2, 50°CO

OAc

OAc

OAc

OAc

NO

AcO OAc

OAc

OAc

72%

NiPr

HPd(OAc) 10% mol.

I2, PhI(OAc)2

CH2Cl2, rt77% yield

N iPr

I

Pd(OAc)2 1% mol.XPhos 2% mol., K3PO4

n-BuOH-H2O, 80°C90% yield

N iPr

Tandem para-iodination, C-H amination followed by Suzuki coupling to give highly functionalized

cabazoles

Gaunt & al., JACS, 2008, 130, 16184-16186

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Direct Catalytic Asymmetric Synthesis of Cyclic Aminals From Aldehydes

Xu Cheng, Sreekumar Vellalath, Richard Goddard and Benjamin List

- Phosphoric acid catalyzed synthesis

- Stereogenic cyclic aminals: very common in drugs, catalysts and pharmaceuticals

- Common synthesis protocol for benzo(thia)diazines: use of an achiral catalyst and HPLC separation

List & al., JACS, 2008, 130, 15786-15787

NH2

O

NH2

OHC

Cat. (10% mol.)

Toluene

NH

O

NH

Yield 86%, 99er (ee= 98%)

O OP

O OH

iPr

iPr

iPriPr

Cat:

NH

NH

O

H2NO2S

Cl

NH

NH

SH2NO2S

Cl

O O

N

N

H

O

HN O

NH

NO

tBu

Aquamox Thiabutazide Physostigmine MacMillan chiral auxiliary

8

Catalyst Screening:

List & al., JACS, 2008, 130, 15786-15787



NH2

O

NH2

OHC

Cat. (10% mol.)

Toluene, 5A MS-45°C, 24h

NH

O

NH

Ar

Ar

O

O

P

OH

O

Ar=

F3C CF3

4a4b 4c

4d 4e 4f

Ph

Ph

O

O

P

O

OH

9

Scope of the reaction:



NH2

O

NH2

4d (10% mol.)


NH

O

NH R

RCHO

3

Aldehyde

5

4

3

2

1

6

NH2

O

NH2

OHC

4d (10% mol.)


NH

O

NH

XX

3

Aminobenzamide



10

Conclusion:

- First enantioselective direct synthesis of aminals from aldehydes catalyzed by chiral phosphoric acid

- Catalyst structure:

- Good aldehyde tolerance- All investigated amides gave excellent enantioselectivities- Methodology applied to different structures:

O

O

P

O

OH

Ar

Ar

Ar:

List & al., JACS, 2008, 130, 15786-15787

NH

NH

SH2NO2S

Cl

O O

(R)-ThiabutazideY: 81%, 91%ee

NH

NH

SH2NO2S

Cl

O O

(R)-CyclopenthiazideY: 72%, 91%ee

NH

NH

S

Bn

H2NO2S

F3C

O O

(R)-BendroflumethiazideY: 80%, 92%ee

NH

NH

SH2NO2S

F3C

O O

(R)-PenflutizideY: 74%, 90%ee

NH

NH

O

H2NO2S

Cl

(S)-AquamoxY: 78%, 61%ee

11

Asymmetric Reductive Mannich Reaction to Ketimines Catalyzed by a Cu(I) Complex

Yao Du, Li-Wen Xu, Yohei Shimizu, Kounosuke Oisaki, Motomu Kanai and Masakatsu Shibasaki

- Asymmetric -aminoacids: Mannich reaction is the most straighforward method

- Reaction was limited to the use of aldimines and iminoesters to form -amino acids

- Low reactivity of ketimines

- This work: expand the scope of previous work by the group

Shibasaki & al., JACS, 2008, 130, 16146-16147

R1

N

R2

PPh2

O

R3

O

OR4

CuOAc - Phosphine (5-10 mol %)PinBH or (EtO)3SiH

THF

O

OR4

R3H

R1

NH R2Ph2P

OO

O

O

O

F

F

F

F

PPh2

PPh2

(R)-Difluorphos

12

Previous work by the same group:

- Method limited to acetate-derived enolates as donors

- New method required to achieve the catalytic asymmetric synthesis of -amino acids with a substituent at the -position


R1 R2

N

Xy2P

O

OBu

OTMS

CuOAc- ligand (10 mol %)(EtO)2Si(OAC)2 or (EtO)3SiF

THF, 40°C, 20hR1

NH

Xy2P

O

OBu

O

R2

45-99%77-97% ee


13

Catalytic Diastereoselective Reductive Mannich Reaction of Ketimines

R1

N

R2

PPh2

O

R3

O

OR4

CuOAc (5 mol %)PPh3 (10 mol %)PinBH (1.6 eq.)

THF, rt

O

OR4

R3

R1

NH R2Ph2P

O



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Catalytic Asymmetric Reductive Mannich Reaction of Ketimines

R1

N

PPh2

O

R3

O

OEt

CuOAc (10 mol %)(R)-Difluorphos (10 mol %)

(EtO)3SiH (2.8 eq.)

THF, -30 -50°C

O

OEt

R3

R1

NHPh2P

O

Conversion to 2,2,3-amino acids derivatives

4M HCl aq.EtOH, 50°C, 24h

NaHCO3 aq.

O

OEt

NHPh2P

O

Cl

O

OEt

H2N

Cl74%

Without any racemization and epimerization


15

One-Pot Synthesis of -Siloxy Esters Using a Silylated Masked Acyl Cyanide

Hisao Nemoto, Rujian Ma, Tomoyuki Kawamura, Kenji Yatsuzuka, Masaki Kamiya and Masayuki Shibuya

Nemoto & al., Synthesis, 2008, 23, 3819-3827

R1 R2

O

H

CN

CN

OTBS R3OH

DMAP, Pyridine or PPY

One-PotR1

O

R2

O

OR3

TBS

- -Hydroxycarboxylic acids or esters usually prepared in multiple steps by C-C bond formation using carbanion chemistry

R1 R2

O

R1

R2

OR

Y

OxidationR1

R2

OR

Y

OH

HO

-HY R1

R2

OH

CO2R

R1

R2

OH

Z

YX

R1

R2

OH

CO2H

Kirschning & al., Chem. Eur. J., 1999, 5, 2270

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- One-pot reaction using MAC (Masked Acyl Cyanide)

- Reminder on Passerini reaction:

R1 R2

O

N R6C

R5COOH

One-pot

H2N R6

R1

R2

O

O

R5

O

HN

R6 R1

R2

OH

CO2H

hydrolysis

R1 R2

O

H

CN

CN

OTBS

R3XH

One-Pot

R1

O

R2

O

XR3

TBS

MAC reagent

R1

O

R2

O

NC CN

TBS

R1

OTBS

R2

O

CN

HXR3

X = O or NR4

hydrolysis

R1

OH

R2

CO2H


17

- Esters and tertiary amides which cannot be directly synthesized by Passerini reactions can be synthesized using MAC reagents

- Amines can be used directly: no need to form an isonitrile

Scope of the reaction (selected examples)

R1 R2

O

H

CN

CN

OTBS

DMAP (0.1 eq.) or Pyridine (1 eq.)

R1

O

R2

O

OMe

TBS

MeOHrt

R1 R2 Time Yield

4-MeC6H4 H 5 min 96%

4-NCC6H4 H 2h 98%

(E)-MeCH=CH H 2h 79%

Me3C H 5h 30%

4-O2NC6H4 Me 0.5h 90%

4-MeC6H4 Me 24h 77%

Me3C Me 48h 0%


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- Electron density on aromatic rings did not influence the reaction

- Sterically hindered aldehydes and ketones are not good substrates for the reaction

- On cyclohexen-2-one; competition between 1,2 and 1,4 addition

H

CN

CN

OTBS

O

CN

CN

OTBS

TBSO CO2Me

38%

TBSO CO2Me

32%

Alcohol scope

H

O

H

CN

CN

OTBS

DMAP (0.1 eq.)

O

O

OR3

TBS

R3OHrt

R3 Yield

i-Pr 90%

Bn 88%

Allyl 92%

Ph 93%

t-Bu 0%

- No reaction with hindered tert-butyl alcoholNemoto & al., Synthesis, 2008, 23, 3819-3827

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Conclusion

- One-pot reaction to afford -siloxy esters

- A tertiary amine is necessary, in case of sterically hindered substrates DMAP can improve the yield

- Trialkylamines unsuitables for the reaction because of decomposition of the MAC reagents

- MAC reagents are the only acyl anions equivalents that allow one pot reactions to create -hydroxy carbonyl compounds


20

A Concise Asymetric Total Synthesis of Aspidophytine

K. C. Nicolaou, Stephen M. Dalby and Uptal Majumber

Nicolaou & al., JACS, 2008, 130, 14942-14943

N

Me

N

O

O

H

MeO

OMe

NO

HO

N

Me

O

- Isolated from Haplophyton cimicidium in 1953

- Structure disclosed in 1973

- Acid-mediated degradation lead to the right-hand constituent aspidophytine:

Haplophytine Haplophyton cimicidium

- First total synthesis: Corey 1999

N

Me

N

O

O

H

MeO

OMe

A B C

DE

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Retrosynthetic Analysis

N

Me

N

O

O

H

MeO

OMe

A B C

DE

N

Me

N

H

MeO

OMe

A B C

N

Me

N

MeO

OMe

CO2TMSE

COO

H

OMeS

S

N

Me

N

MeO

OMe

CO2TMSE

B(OH)2

O

TBSO

I

A

B

Nicolaou & al., JACS, 2008, 130, 14942-14943

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Synthesis of A

HN

O

a) NaH, TBSO I

b) LDA,

MeO

O

OBn

Me

N

O

TBSO

O

OBn

Me

KHMDS,

Br CO2TMSE

N

O

TBSO

O OBn

Me

CO2TMSE

1) H2, Pd(OH)2, 82%

2) NaBH4; NaIO4, 79%

N

O

TBSOH

O

CO2TMSE

I

PPh3I

NaHMDSN

O

TBSO

CO2TMSE

I

A

68%

89%

66%

88%

4:1

Nicolaou & al., JACS, 2008, 130, 14942-14943

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Fragment coupling and elaboration to Aspidophytine

Longest linear sequence: 12 steps

5% overall yield

Nicolaou & al., JACS, 2008, 130, 14942-14943

MeO

OMe

t-Buli, B(OMe)3, NH4Cl

69%NMeO

OMe

N B(OH)2

N

O

I

TBSO

CO2TMSE

PdCl2(dppf), Cs2CO3, H2O MeO

OMe

N

Me

N

O

TBSO

CO2TMSE86%

Tf2O, DTBMP

MeO

MeO N

Me

N

TBSO

CO2TMSE

6-exo-trig cyclization

NaBH4

88%

MeO

MeO N

Me

N

TBSO

CO2TMSE

H

>95:5

1) HF.py

2) NaH, CS2, MeI

83% (2 steps)

MeO

MeO N

Me

N

CO2TMSE

H

O

S

MeS

n-Bu3SnH, AIBN

MeO

MeO N

Me

N

CO2TMSE

H

58%

TBAF, THF

K3Fe(CN)6t-BuOH / H2O

63%

N

Me

N

O

O

H

MeO

OMe

A

aspidophytine3:1

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Other interesting articles

Communications:

- Three Component Coupling of α-Iminoesters via Umpolung Addition of Organometals: Synthesis of α,α-Disubstituted α-Amino Acids

Kozlowski & al., JACS, 2008, 130,15794-15795

Full Papers:

-Total Synthesis of (−)-Pseudolaric Acid

Trost & al., JACS, 2008, 130,16424-16434

Literature Screening

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