1

Maoqun TianBaran Group Meeting

04/16/2016Helvetica Chimica Acta 2015 Special Issue:

Albert Eschenmoser and Organic Synthesis as Art

Albert and Elisabeth Eschenmoser

The issue (December 2015, Volume 98, Issue 11-12) of Helvetica Chimica Acta is dedicated to Albert Eschenmoser and his art of Organic Synthesis.

"Corrin Syntheses – Part I – VI" had been originally planned to be submitted to Helvetica Chimica Acta around 1975, as 'full paper' in the conventional sense with the intention of covering in full detail the workcarried out at the ETH from early 1960 up to the time of the writing.

The series was not intended to include the work on the synthesis of vitamin B12 itself:"The work done at the ETH on the synthesis of vitamin B12 is not to be a part of this series, since it will be subject of a joint publication of the Harvard and the ETH groups, covering the B12 work done at Harvard as well as at the ETH."

N

N

N

N

Me

Me

H2NOC

H2NOC

H2NOC MeMe

CONH2Me

H

HH

H

MeMe

H

CONH2Co

CN

Me

NH

O

OP O

Me

OO O

OH

HOH

N

NMe

Me

H

HH

vitamin B12

CONH2

A B

D C

N

HN

N

NH

Me 1

5

10

15

20A B

CD

Corrin

Influence and assistance of corrin model studies on the B12 syntheses:-information on preparative procedures and the scope of the C,C-coupling by imido ester/enamine condensation-spectroscopic and chemical properties of hemicorrinoids and corrinoids-complexation and decomplexation procedures-introduction of Me groups in meso-positions

-the 'targeted discovery' of the photochemical A/D-secocorrin-corrin cycloisomerization

Synthesis of Corrin Complexes via A-B Ring Closure. Preparation of Hemicorrinoid B/C-Components

Original ideas:

N

N

N

NH

MeA B

CD

N

N

N

NH

Me

CO2Me

CO2Me

CO2Me

N

HN

NH

NHH

Me

CO2Me

CO2Me

CO2Me

O

O

HN

HN

NH

NHH

Me

CO2Me

CO2Me

CO2Me

O

O

O

CH3

Me

HN

HN

NH

NHCH3

HMe

CO2Me

CO2Me

CO2Me

O

O

O

O

O

O

General concept for synthesizing a vinylogous amidine system by imido-ester/enamine C,C- condensation

NH

O

N

OEt

tBuO2C CO2Me

or BrZnCH2CO2Me HN

CO2Me

N

CO2Me

HN N HNGroup seminar: Corrin Chemistry Cliff Notes (Burns, 2007)

2

Maoqun TianBaran Group Meeting

04/16/2016Helvetica Chimica Acta 2015 Special Issue:

Albert Eschenmoser and Organic Synthesis as Art

OH H+, 170 °CCO2H

CO2H

O ONH3, 130 °C

NH

O

OO O OCO2H

SOCl2

O OCl

OO

NO

t-BuOK

290 °C (30%)

or hv (254 nm)Cyclohexane (40-50%)

OO

HN

O

NH3, MeOHN

HN

O

HOt-BuOKN

HN

O

B

C

NH

O

1. AgNO32. i-PrI

N O

NC CO2(t-Bu) HN

CN

O(t-Bu)O

NC

O(t-Bu)O

170 °C

HN

OCN

O(t-Bu)

TFA, 60 °CN

CN

NEtO O

t-BuOK

N

HN

O

B

C

CN

Route A

Route B

(34-47%)

NH

OO O+

320 °C

(50%)

Route C

HNO

KCNHN

O

NC P4S10

HNS

NC

(PhCOO)2

HNO

NS

NC

NH

O

P(OEt)3N

NC

HN

O

t-BuOK N

HN

O

B

C

NH

O O

1. Ag2CO32. C2H5I

NEtO OZn/BrCH2CO2CH3

NH

OMeO2C

N OMeO2C

AgNO3

i-PrI

NH

MeO2C CO2Me

+

NEtO O +

NH

OMeO2C

N

HNCO2Me

O

B

C

MeO2C

Zn/BrCH2CO2CH3

"Responsible for these failures are not the (highly reactive) imido-ester components, but rather the nucleophilic partners which are not enamines but enamides or vinylogous enamides."

The earliest exploratory experiments aimed at the synthesis of the B/C component

The most remarkable property of monocyclic ene-lactam

HNO

HN

O

TsOH/DCM 40 °C NO

H

HN

O

HN

HN

O

ONH

NH

O

O

A

D(>95%)

quasi-A/D componentEt3N·HCl, 185 °C (>90%)

C B

BC

NHN

S

NH

S

N NH N(-(S)PR3)N

S

NH

R3PX

3

Maoqun TianBaran Group Meeting

04/16/2016Helvetica Chimica Acta 2015 Special Issue:

Albert Eschenmoser and Organic Synthesis as ArtSynthesis of Corrin Complexes via A-B Ring Closure. Preparation of A/D ComponentsOriginal plan for the synthesis of the A/D component

O

N

NHH

MeA

D

CO2Me

Et

NH

NH

O

HMe

O

Me

H

CO2R

CO2R

NH2

NH2

Me

H

CO2R

CO2R

Me

H

CO2RCO2R

CO2R

CO2RCO2R

RO2C

RO2C

CO2RMe

H+

Me

H

CO2RCO2R

OM(metal)RO

RO OM

Route A (rather long, though instructive)

CO2Me

MeO2C

MeO2C

CO2Me+

190 °C CO2MeCO2Me

CO2Me

CO2Me

Na/NH3 CO2MeCO2Me

CO2Me

CO2Me1. KOH2. Collidine

170 °C

CO2R

CO2R

NH3/EtOH160 °C

CONH2

CONH2

(C2H5)3OBF4

NH

NH

OEtOEt

Br2/DCMNH

OEtH

Br

N

OEt

1. 1N H2SO42. EtONa

O

O

OEtOEt

NH

NOCl/Et3N/Ether-70 °C to 0 °C

O

O

OEtOEt

Ph

Ph

Ph

Ph

Ph

PhHN

NH

Ph

Ph

Nitrosylation

Nitrosylation

A general method for the determination of the relative configuration of substituted aziridines

INCO or Br2

O

NH2H

X

O

O

Route A (cont.) Expectations vs. observations on the way to aziridineNH

OEtH

Br

N

OEt

AgBF4

NH

OEtH

Br

N

OEt

Ag OEt

N

N

OEt

HMe

A

D

NH

OEtH

Br

N

OEt

Ag

N OEt

OEt

HNH

N N OEt

H

EtOMe

H

CO2Et

H

CO2Et

O

1. BnOH2. Pd/H2

NH

NH

H

MeOO

A safe method for converting imido-ester groups into the correspondingamide groups

Route A (cont.)

HMe

HN

CO2Et

CO2EtNaN3/H2SO4MeOH NH2

OEt

C2H4CO2EtH

N3

O

+ NH2

N3

OEt

O

H

EtO2C

N OEt

C2H4CO2EtH

N3

OHHN

OEtH

N3

O

H OEtOH

N

N3

OEt

OH

H

EtO2C

H

hoursdays

HN

OEtH

N3

O

ON

N3

H

EtO2C

HO

EtONaPd/H2NH

NH

O

O

H

Pd/H2

NH2

NH2

OEt

O

H

OEt

O

NH

HN O

OMe

HPd/H2

immediatemixture

4

Maoqun TianBaran Group Meeting

04/16/2016Helvetica Chimica Acta 2015 Special Issue:

Albert Eschenmoser and Organic Synthesis as ArtRoute A (cont.)

CO2EtN3

NH

O

H (Et)3OBF4

CO2EtN3

N

OEt

H

NC

CO2(t-Bu)

CO2EtN3

NH

H Pd/H2

CNO(tBu)

O

NH

NH

H

CNO(tBu)

O

O

TFA NH

NH

H

CN

O

CF3CO2 N

NH

H

CN

OEt

(Et)3OBF4

Route B (short, though inefficient)

A

D

NH

O hv (Hg)

(10%, dr 1:1)NH

NH

HH

O

O

+NH

NH

HH

O

O

N

N

HH

OEt

OEt

(Et)3OBF4CN

CO2(t-Bu)

N

NH

HH

CNO(tBu)

O

OEt

TFAN

NH

HH

CN

OEt

Route C (the efficient route to the A/D component)

NH

Ot-BuOKMeNO2

NH

O

NO2

R4NOHmethyl acrylate NH

COOMeNO2

H

O

dr 1:1

Route C (cont.)

Ni / H2 / 100-300 atm NH

NHH

O

O

(Et)3OBF4 N

NH

OEt

OEt

CN

CO2(tBu) N

NHH

OEt

CN

O

OtBu

TFA N

NHH

OEt

CN

Synthesis of Corrin Complexes via A-B Ring Closure. Coupling of Hemicorrinoid A/D and B/C Components to Corrin by Imido-ester-Enamine Condensations

Pd/H2

CO2EtNH2

N

OEt

H Δ

NHOEtO

N

Me

OEt

HNH

HN O

OMe

H

A

D

A

D

"Dream corrin synthesis": all four peripheral rings would be derived from one single precursor.

A

D

monoperoxy-phthalic acid

MeOH, -20 °C

NH

NH

O

O

NH

NH

O

O

HOMeO

sublimaiton160-215 °C

NH

NH

O

O

ONH

NH

O

O

HO

hv (Hg)Dioxane

-CONH

NH

O

O

NH

NH

O

O

+monomericcomponents + N

NH

O

O

Et

CN

N

NH

R2

R3

NC

OEtA

D

R1

R1N

N

EtO

B

C

more electrophilic

N

N

N

NR3R2 M

R1

R1

CN

OEt

N

N

N

NR3R2

M

R1

R1

CN

Quasi-A/D Components

5

Maoqun TianBaran Group Meeting

04/16/2016Helvetica Chimica Acta 2015 Special Issue:

Albert Eschenmoser and Organic Synthesis as ArtNiII complexes of corrin in the pentamethyl series

N

NH

NC

OEtA

D

N

N

EtO

B

C

H EtONa N

N

N

NNa

CN

OEt

HN

N

N

NNi

CN

H

N

N

N

NNi

CN

H

Ni(ClO4)2

MeCN

OEt

tBuOK/tBuOH 80 °C

ClO4

ClO4

KOHN

N

N

NNi

CN

H

HClO4

D2ON

N

N

N

D2C

D2C

CD2

CD2

Ni

CN

H

CoIII complexes of corrin in the pentamethyl series

N

N

N

NNa

CN

OEt

H1. Co(ClO4)2

MeCN

2. Cu2+

N

N

N

NCo

CN

OEt

HN

Me

N

N

N

NCo

CN

H

OEt

NH

Me

L

1. Co(ClO4)2, EtOH2. KCN, H2O, air

N

N

N

NCo

CN

H

OEt

CN

CN

1. tBuOK/ tBuOH

2. KCN,H2O

N

N

N

NCo

CN

HCN

CN

N

N

N

NNa

CN

OEt

H

Coupling of hemicorrinoid A/D and B/C components to corrin by thioimido-ester enamine condensations

1. H2S/H+

2. Zn(ClO4)2

N

N

N

NZn

CN

H

S

N

N

N

NCo

CN

H

CN

CN

S1. TFA2. Co(ClO)43. KCN/air

t-BuOK/t-BuOHMeI/rt

N

N

N

NCo

CN

H

CN

CN

MeS

N

N

N

NCo

CN

H

CN

CN

SDIPEA/DMF/t-BuOH/150 °C

or 220 °C w/o base

N

N

N

NCo

CN

H

CN

CN

N

N

N

NCo

CN

HNH

Me

190 °C

O

L

Coupling of quasi-A/D and B/C components

N

N

CN

N

NPdO

NH

NH

O

O

Et

CN

N

N

EtO

+

OEt

EtONa100 °C N

N

CN

N

NPdO

hv in CF3CH2OH-CO

N

N

N

N

CN

OEt

Pd

tBuOK/tBuOH 105 °C

(10%)

N

N

N

N

CN

PdEtO N

N

N

N

CN

Pd

(40%)

t-BuOK

(NH4)PdCl4

6

Maoqun TianBaran Group Meeting

04/16/2016Helvetica Chimica Acta 2015 Special Issue:

Albert Eschenmoser and Organic Synthesis as Art

Preparation of Metal-Free Corrin Derivatives via A-B Ring Closure

Methods for the introduction of Me groups in the meso-positions of the corrin chromophoreCoupling of quasi-A/D and B/C components (cont.)

N

N

CN

N

NPdO

OEt

145 °C N

N

CN

NPd

OHNO

hv

N

N

N

N

CN

PdEtO

N

N

N

N

CN

Pd

tBuOK/tBuOH 105 °C N

N

N

N

CN

Pd

N

N

N

NZn

CN

H

S

1. (PhCOO)2TFADCM, r.t2. MeOH

TFAZn(ClO4)2DMF/80 °C

N

N

N

NZn

CN

H

SH

P(Ph)3/TFACHCl3

N

N

N

NZn

CN

H

HN

HN

N

N

CN

H

1.TFA/MeCN2. NaCl orCF3COONa or KBr /H2O

N

N

N

NCo

H

CN

CN

(CH3)2N+=CH2I-N

N

N

NCo

H

CN

CN

CH2N(CH3)2Pd/H2

N

N

N

NCo

H

CN

CN

Ph-S-CH2ClAgBF4DIPEAMeCNN

N

N

NCo

H

CN

CN

CH2SPh

Raney-Ni

(CH3)2N+=CH2I- N

N

N

NCo

H

CN

CN

(H3C)2NH2CPh-S-CH2ClAgBF4DIPEAMeCNN

N

N

NCo

H

CN

CN

Raney-Ni

CH2SPh

+

N

N

N

NCo

H

CN

CN

N

N

N

NCo

H

CN

CN

CH2SPh

+

CH2SPh

CH2SPh

N

N

N

NCo

H

CN

CN

(3%)

(5%) (25%)

N

N

N

N

CN

HM

N

N

N

NCo

H

CN

CN

1 equiv. CF3COODt-BuOD, D2O, N2

5

105,10 mono- or dideuteration = 0.6

k(H-->D)C5k(H-->D)C10

= 2.1HC5

HC10

LiI, ZnII, CdII, BeII

CoIII, RhIII, CuII, NiII, PdII

N

N

N

NZn

CN

H

S

N

N

N

NZn

CN

H

SPhOCO

N

N

N

NZn

CN

H

S

N

N

N

NZn

CN

H

SO

7

Maoqun TianBaran Group Meeting

04/16/2016Helvetica Chimica Acta 2015 Special Issue:

Albert Eschenmoser and Organic Synthesis as ArtCorrin Synthesis via A-D Ring Closure. The Construction of A/D-Secocorrin Chromophore Systems by the Sulfide Contraction Method

NO

CO2Me

H

Me

MeO

O

HN

O

CO2Me

H MeMeC

B

N

HNMeMe

H

H

O

O

MeMe

CO2Me

CO2Me

O

B

C

Origin of "sulfide contraction"

NC CO2(t-Bu)

HN

CO2Me

H

Me

MeO

O

NCCO2t-Bu

HDimmerizaiton

Synthesis of metal complexes of A/D-secocorrinate

NH

SNC

(PhCO2)2 N

HN

O

NS

CNN

SNC +

N

HN

O

SNNCt-BuOK

Ph3P BF3 HN

HN

N

O

CN

Ag2O HN

AgN

N

O

CN

(Et)3OBF4

HN

N

N

EtO

CN

Synthesis of metal complexes of A/D-secocorrinate (cont.)HN

CN

Ni(ClO4)2, K2CO3

45%

N

N

N

NNi

CN

NC

t-BuOK N

N

N

NNi

CN

Improvement by alkylative coupling

N

HN

O

NIS

81%

N

HN

O

I NH

SNC N

HN

O

SNNC

70%

A B

CD

Synthesis of by the A/D-secocorrinate BC+D+A strategy

N

HN

O

NCB

C

Et3OBF4

NN

HN

NC

NHD

t-BuOK N

HNNH

NH

SNC

1. I22. t-BuOK

N

HNNH

SN 1. PPh3N

N

N

NZn

CN

NC2. Zn(ClO4)2

t-BuOKN

N

N

NZn

CN

N H

SX

N NHN

S

NH

S

N NH N(-(S)PR3)

R3P

NH

O

HNO

HN

O

NH

A B

CD

N

N

N

N

A B

CD

sulfide contraction

sulfide contraction

imidoester/enamine condensationor

N

N

N

NH

Strategy of a corrin synthesis via the photochemical A-D ring closure

M M

Et

8

Maoqun TianBaran Group Meeting

04/16/2016Helvetica Chimica Acta 2015 Special Issue:

Albert Eschenmoser and Organic Synthesis as Art

The Photochemical A/D-Secocorrin-Corrin Cycloisomerization: The Central Step in the Synthesis of Corrins via A-D Ring Closure

N

HN

N

N

CN

HH2CH

N

HN

N

N

antarafacial thermally forbidden[1,16]-sigmatropic H-shift

antarafacial, thermally allowed[1,15]-electrocyclization

HN

HN

N

O

NH

O-2H2O

NH

O

N

HN

N

NO

NH

-H2O-H2O

-H2O

N

HN

N

N

N

HN

N

NH H

Isomerize

Corphin Corrin

N

N

N

NMH H

N

N

N

NMH

sunlight or tungsten lamp 200 W

DCM or benzene

no cyclization

fast cyclization

slow cyclization

The first experiments testing the existence of the A/D-secocorrin-corrin cycloisomerization

N

N

N

NMH H

N

N

N

NMH

M = Ni, no reaction (hv or Δ)M = Pd, sunlight 4 h, 89%

Dependence of cycloisomerization from the nature of the coordinating metal ion

H

X 3