Metalloporphyrin～as efficient Lewis acid catalysts with a unique reaction-field～
and～Synthetic study toward complex metalloporphyrins～

Literature Seminar
Kenta Saito (D1)1

Topics
Chapter 1～as efficient lewis acid catalysts with a unique reaction-field～

Chapter 2～Synthetic study toward complex metalloporphyrins～

2

Introduction : Metalloporphyrins
What is Porphyrin?
・ Macrocyclic tetrapyrrole in a 18-π aromatic ringsystem・ Four-fold coordination, bind the vast majority ofmetals (Mg, Zn, Cu, Fe …)・ Three-dimensional architectures created from planarframework (π-stacking, linker connected at mesoposition)
M = 2H, Mg, Zn et al.

Phthalocyanine

Corrole3

Introduction : Cytochromes P450
Mono-oxygenases
Major enzymes involved in drug
metabolism

Liver detoxification and hormone biosynthesesref) Chem. Res. Toxicol. 2008, 21, 70
Chem. Res. Toxicol. 2010, 23, 1393

4

Introduction : Oxidative Reaction with P450 / carbonyl byproducts

Step A

Step B

Step B’
Active species

Step A is the rate-limiting
step
Step B is fast, but carbonylcompounds are generated as
the byproducts (Step B’).
ref) J. Am. Chem. Soc. 2010, 132, 7656
J. Am. Chem. Soc. 2003, 125, 3406

5

Introduction : Another possible pathway of generating byproducts

Porphyrin’s metal center behave as a Lewis acid.
・ Large ligand
・ Stabilization of the cationic species by the broad π-conjugated plane

It’s possible to contoribute the unique reaction-field.
Axial ligand, porphyrin : tunableref) Inorg. Chem. 1994, 33, 1731
J. Am. Chem. Soc. 1993, 115, 4641

6

Rearrangement of monoalkyl-substituted epoxides into aldehydes

stoichiometric amount of LiTMP is the only known method.
ref) J. Chem. Soc., Chem. Commun., 1994, 2103

7

Rearrangement of monoalkyl-substituted epoxides into aldehydesref) Tetrahedron Lett. 1999, 40, 7243

8

Rearrangement of monoalkyl-substituted epoxides into aldehydesref) Angew. Chem. Int. Ed. 2008, 47, 6638

9

Rearrangement of α,β-epoxyketone into 1,2-diketoneEx.) ref) J. Am. Chem. Soc. 1980, 102, 2095ref) Synth. Commun. 1993, 23, 1527

10

Rearrangement of α,β-epoxyketone into 1,2-diketone

11Rearrangement of α,β-epoxyketone into 1,2-diketoneref) Chem. Commun. 2002, 2570

12

Rearrangement of 2 or 3-substituted epoxide into ketone or aldehydeEx.) ref) J. Org. Chem. 1996, 61, 1877
J. Org. Chem. 1998, 63, 8212
Tetrahedron Lett. 2000, 41, 1527ref) J. Am. Chem. Soc.. 1989, 111, 6431

13

Rearrangement of 2 or 3-substituted epoxide into ketone or aldehyderef) Chem. Lett. 1996, 1031

14

Rearrangement of 2 or 3-substituted epoxide into ketone or aldehyde

15Rearrangement of 2 or 3-substituted epoxide into ketone or aldehyderef) J. Am. Chem. Soc. 2004, 126, 9554

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Rearrangement of 2 or 3-substituted epoxide into ketone or aldehyde

17Rearrangement of 2 or 3-substituted epoxide into ketone or aldehyde

18Rearrangement of 2 or 3-substituted epoxide into ketone or aldehyde

Lewis acidity

Low

High

Stability bybroad π-plane

19

Rearrangement of 2 or 3-substituted epoxide into ketone or aldehyde

Cr(TBPC)OTf : TON (over 60,000)
Cr(TBPC)OTf is stable and active catalyst.
20

Rearrangement of 2 or 3-substituted epoxide into ketone or aldehyde

Cr(TBPC)OTf is not soluble in hexane.
Cr(TBPC)OTf and target materials are separetable between
each other.
21

Rearrangement of 2 or 3-substituted epoxide into ketone or aldehyderef) Chem. Commun. 2009, 1255

22

Rearrangement of 2,3-diaryl epoxide into 2,3-diaryl aldehyde

Yb is necesarry to maintein selectivity. (Fe and Cr are not suitable)

23

Rearrangement of 2,3-diaryl epoxide into 2,3-diaryl aldehyde

24Rearrangement of 2,3-diaryl epoxide into 2,3-diaryl aldehyderef) Heterocycles. 2009, 77, 365

25

Summery of Chapter 1

Metalloporphyrins are efficient lewis acids for selectivity and activity owing
to ligand’s effects.

They are tunable by changing axial ligands and porphyrin ligands.

Phthalocyanine ligands produce more lewis acidic and π-electronic reaction
fields compared to metalloporphyrin ligands.

They are useful for economical reactions owing to poor solubility to hexane
and suitable to BTF as the substitution of harogen-contained solvents like
DCM and DCE.

26

Topics
Chapter 1～as efficient lewis acid catalysts with a unique reaction-field～

Chapter 2～Synthetic study toward complex metalloporphyrins～

27Synthetic difficulty of metalloporphyrin-analog
Zn, Mg and 2H (= por) are well used for study offluorescence and artificial photosynthesis. But…
Mg(por) is demetalized by very slight amount of acid orvery weak acid (ex. HCl from CHCl3, silica gel).
Cu(II) has very strong affinity to porphyrin.
Insertion to porphyrin very easily at RT.
Exchange with Zn(por) under heat condition.
It’s difficult to demetalize Cu(por).
(need strong acidic condition. (ex.) H2SO4-TFA)
If you use Cu(II) for reactions, you must Zn(por) to mask porphyrin, and Cu(II) used
reaction must be conducted under mild condition ,and you have to demetalizeZn(por) if you want to synthesize other-metal-contained metalloporphyrins.
28

Synthetic difficulty of metalloporphyrin-analog
Transition metals are introduced to porphyrins under heat condition,
but it’s impossible to replace Zn(por) with M(por) under neutral condition.
Porphyrins have many active C-H bonds.
Many side reactions are occurred in transition-metal-contained reactions.
(many byproducts, difficulty of purification and low yield of target material)

Poor solubility of metalloporphyrins (1.0mM~10mM are favor).
In synthesis of derivative of metalloporphyrins, as many reaction’scondition are optimized to dense concentration (mainly 100mM~1.0M),
the reactions are not suitable to matalloporphyrins as substrates.

It’s need to use more amount of transition metals to conduct transition
metal-catalyzed reaction.
ref) Synlett. 2005, 1306
Chem. Mater. 1999, 11, 2974

29

To solve the difficulties of synthesis of metalloporphyrin-analogEx.1) Sonogashira coupling

without Cu source

It’s difficult to generate Pd-acetylide.

30

Synthetic difficulty of metalloporphyrin-analogref) J. Org. Chem. 1995, 60, 5266

31

Synthetic difficulty of metalloporphyrin-analog

AsPh3 is suitable for the ligand of Sonogashira coupling.
(it is the just ligand for oxidative addition and reductive elimination steps)
32

Synthetic difficulty of metalloporphyrin-analog

33

Synthetic difficulty of metalloporphyrin-analog(Por)-Pd(II) species activate porphyrin’s C-H bond and insert As(PPh3)2 to thestarting material (sometimes it makes difficult to purify the products).
34

Synthetic difficulty of metalloporphyrin-analog
P(o-tolyl)3 is used instead of As(PPh3)3P(o-tolyl)3 provides lower yield of products, but suppresses the generating ofbyproduct.
ref) Chem. Mater. 1999, 11, 2974

35

Synthetic difficulty of metalloporphyrin-analog
Ex.2) Metal-mediated cross-coupling reaction

Nucleophylic organometalic reagents (like R-Li, R-MgX) cause
reduction of por-Br to generate their respective porphyrin radicalanions.
R-Li and R-MgX are not suitable for insertion ofR groups to Br-porphyrins.
ref) J. Am. Chem. Soc. 1993, 115, 2513
J. Org. Chem. 1993, 58, 5983

36

Synthetic difficulty of metalloporphyrin-analog

Without Pd source, SNAr typereaction is occurred.

ref) Acc. Chem. Res.. 2005, 38, 733

37

Synthetic difficulty of metalloporphyrin-analog
Ex.3) Suzuki-Miyaura coupling

dehalogenized compounds
are observed.

Ex.4) Mizoroki-Heck reactionref) J. Am. Chem. Soc. 1998, 120, 12676
Org. Lett. 2001, 3, 4213

38

Synthetic difficulty of metalloporphyrin-analog

39

Synthetic difficulty of metalloporphyrin-analogref) Org. Biomol. Chem. 2006, 4, 902

40

Synthetic difficulty of metalloporphyrin-analog

CuI is must for this Stille coupling.
Porphyrins must be masked by Zn for preventing from insertionof Cu.
ref) Org. Lett. 2005, 7, 5365

41

Summery of Chapter 2
It’s difficult to synthesize porphyrin-derivatives from porphyrins or metalloporphyrins
for active C-H bond and affinity of metals.
use Zn as masking porphyrin’s central site to avoid the connection of Cu.
and reaction’s condition must be mild.
use Cu-free-reaction to synthesize porphyrin’s derivatives.

need special reaction’s condition for porphyrins.
(large amount of solvent, avoidance of side-reactions etc.)42References (Reviews)
1) J. Synth. Org. Chem., Jpn., 2007, 65, 298
2) J. Synth. Org. Chem., Jpn., 2009, 67, 595
3) J. Synth. Org. Chem., Jpn., 2009, 67, 688

43Appendix
Cost of porphyrins

44