Protecting Group Strategies -Heterogeneous...

Protecting Group Strategies

- Heterogeneous Catalysis

Nitin Patil

NCL - 14th Dec2012

A) Debenzylation- O Debenzylation of protected sugar 2,3,4,6-tetra-O-benzyl-D-glucopyranose- N-Debenzylation of N-Benzyl-N-α-methylbenzylamine

B) Removal of Benzyloxycarbonyl (Cbz) Protecting Groups

C) Transfer Hydrogenation

- O-benzyl-L-phenylalanine

- N-benzyloxycarbonyl-L-phenylalanine

- O-benzyl-N-benzyloxycarbonyl-L-aspartame

Variables

- Catalyst

- Solvent

- Temperature

- Pressure

De protection – Presentation Theme

O-and N-DebenzylationsA Need for “New Generation” Catalysts

O-Debenzylation of the protected sugar 2,3,4,6-tetra-O-benzyl-D-glucopyranose

N-Debenzylation of N-Benzyl-N-α-methylbenzylamine

Variables

- Catalyst

- Solvent

- Temperature

- Pressure

O

H

BnO

H

BnO

H

OH

OBnHH

OBn

O

H

OH

H

OH

H

OH

OHHH

OH

NH

H2N

Toluene + Ammonia Ethylbenzene + Ammonia

Further reaction masks undesired reaction

Further reaction depletes product

Benzylamine

O-DebenzylationCatalyst Design Variables

- Nature of carbon support

- Size and location of deposited metal particulates

- Active metal precursor

- Metal oxidation state (reduced or unreduced)

- Method of catalyst preparation

2,3,4,6-tetra-O-benzyl-D-glucopyranose

O-DebenzylationEffect of Metal Distribution & Oxidation State

Observations:

- Eggshell, unreduced

catalysts performed better

- Uniform metal distributions

showed low conversions

and/or long reaction times.

Hydrogenation of 2,3,4,6-tetra-O-benzyl-D-glucopyranose at 25oC, 3 bar hydrogen pressure with

5%Pd/C catalysts of different design in ethyl acetate

0

1

2

3

4

5

6

7

8

9

10

0 20 40 60 80 100 120

Time / min

H2 U

ptake / m

l

Eggshell Unreduced Uniform Reduced Uniform Unreduced Eggshell Reduced


O-Debenzylation

Catalyst activity and Selectivity Hydrogenation of 2,3,4,6-tetra-O-benzyl-D-glucopyranose at 25

o C, 3 bar hydrogen pressure

with various Pd/C catalysts in THF

0

6

12

18

24

30

36

0 20 40 60 80 100 120

Time / min

H2 Uptake / m

l

A470129-10 10R39 A405130-5 A470129-5

10R338 A402032-10 A001023-10 Commercial Standard

- reaction rates varied by up to a factor of ten.

- carbon support had large effect on reaction

rate and conversion

- more active catalysts gave complete conversion

- partially debenzylated intermediates were observed with catalysts with slower reaction rates,

Standard Reaction Conditions

• 5% & 10% Pd/C – (equal metal loading)

• 25oC, 3 bar, THF

• H2 uptake, GC and/or HPLC 2,3,4,6-tetra-O-benzyl-D-glucopyranose

O-DebenzylationEffect of Solvent

- Solvents used: THF, ethanol, ethyl acetate, and acetic acid

- Reaction rates (Generally Linear)- fastest in THF- slightly slower in ethanol - slowest in ethyl acetate & acetic acid.

Hydrogenation of 2,3,4,6-tetra-O-benzyl-D-glucopyranose at 25oC, 3 bar hydrogen pressure

using 5%Pd/C A405130-5 in different solvents

0

2

4

6

8

10

12

14

16

0 20 40 60 80 100 120

Time / min

H2 Uptake / m

l

THF Ethyl Acetate Ethanol Acetic Acid

Solvent choice critical for O debenzylation reaction.


O-DebenzylationEffect of Temperature, Pressure and Catalyst Loading

- Increasing temperature from 25 to 50oC increased the reaction rate by a factor of 3.5.

- Increased pressure & catalyst loadings increased reaction rate

- Little rate or selectivity differences were observed between equivalent 5% or 10%

Pd/C catalysts.


O-DebenzylationConclusions

- Not all Pd/C catalysts are same

- Facile cleavage using Pd/C catalysts at low temperature and pressure, with low catalyst loadings and low catalyst weight percent metal.

- Eggshell unreduced catalysts performed better than uniform and/or reduced catalysts.

- Solvent choice critical for any debenzylation reaction. Fastest with THF

Catalyst: 5% Pd/C A470129-5 and A405130-5; 10% Pd/C 10R39 and A470129-10Solvents: THF, ethyl acetate, ethanol

Temperature: 25 - 50ºC

Pressure: 1 - 10 bar

Catalyst loading: 2 - 10% wrt substrate

Recommendations


N-DebenzylationCatalyst Activity and Selectivity

- Initial reaction rates varied by up to a factor of eight.

- number of catalysts more active than a 20%

Pd(OH)2/C Pearlman’s catalyst standard.

- Free amine products strongly adsorb at active sites,

inhibiting and sometimes completely poisoning the

catalyst.

- Hydrogenolysis of the less bulky benzyl group

occurred with high selectivity in most cases.

- Product degradation pathways were not significant

until >90% conversion; for best selectivity the reaction

needed to be stopped prior to complete conversion.


• 5% -20% Pd/C – (equal metal loading)

• 50oC, 3 bar, Ethanol

• H2 uptake, GC and/or HPLC

Hydrogenation of N-benzyl-N-a-methylbenzylamine with various catalysts in EtOH

0

10

20

30

40

50

60

70

0 30 60 90 120 150 180

Time / mins

Uptake / m

l

5R39 5R394

5R338 A405028-5

A503023-5 A503032-5

20R91 Pearlman 5R398

Hydrogenation of N-benzyl-N-αααα-methylbenzylamine with various catalysts in EtOH

N-Benzyl-N-α-methylbenzylamine

N-Debenzylation

Effect of Pd/C Catalyst Design

Reaction Temperature, Pressure and Catalyst Loading

- Increasing the reaction temperature from 50 to 70oC increased the reaction rate by a

factor of 2.5 but with ~ 50% decrease in selectivity to the desired α -methylbenzylamine

- increased pressure increased rate but decreased selectivity.

- Increased catalyst loadings increased reaction rate.

- Little rate or selectivity differences were observed between equivalent 5% or 10% or 20%

Pd/C catalysts.

- Both eggshell, reduced and eggshell, unreduced catalysts performed well.

- Carbon support had large effect on the initial reaction rate and selectivity

Same catalyst design variables as for

O-debenzylation study investigatedN-Benzyl-N-α-methylbenzylamine

N-DebenzylationEffect of Solvent

- Reaction rates - fastest in ethanol and ethyl acetate - followed by ethanol- slowest in acetic acid but reaction proceeded- premature cessation occurred in THF.

- Selectivity- ~95% in ethanol - ~85% in acetic acid

Mixed solvents- eg. minimizing the amount of HAc(to 2-10% v/v in ethanol) prevented the amine inhibition of the catalyst and preserve the good rates seen in ethanol alone.

Hydrogenation of N-benzyl-N-a-methylbenzylamine using 5R338 catalyst

0

5

10

15

20

25

30

35

40

45

50

55

60

0 30 60 90 120 150

Time / min

Uptake / m

l

5R338 in EtOH

5R338 in EtOAc

5R338 in AcOH

5R338 in THF

Hydrogenation of N-benzyl-N-α-methylbenzylamine using 5R338 catalyst

Solvent choice critical for N- debenzylation reaction. N-Benzyl-N-α-methylbenzylamine

N- Debenzylation O – Debenzylation



- both eggshell, reduced and eggshell, unreduced catalysts performed well.

- solvents, temperatures, pressures, and catalyst loadings have impact on selectivity. Ethanol & Ethyl acetate best solvent

- Selective hydrogenolysis occurs at the less bulky side of the substrate.

- Free amine products strongly adsorb at active sites, inhibiting and sometimes completely poisoning the catalyst.



- Eggshell unreduced catalysts performed better than uniform and/or reduced catalysts.

- Solvent choice critical for any debenzylation reaction. Fastest with THF

Debenzylation - Conclusions

N- Debenzylation O – Debenzylation

Catalyst:

Solvents:

Temp:

Pressure:

Catalyst

loading:

5% Pd/C types 39, 394, 338, A405028-5, A405032-5 and A503130-5

Alcohols (+H+), ethyl acetate, acetic acid

30 - 100ºC

1 - 10 bar

2 - 10% wrt substrate

5% Pd/C A470129-5 and A405130-5; 10% Pd/C 10R39 and A470129-10

THF, ethyl acetate, ethanol

25 - 50ºC

1 - 10 bar


Debenzylation - Recommendations

Removal of Benzyloxycarbonyl (Cbz) Protecting Groups

N-benzyloxycarbonyl-L-phenylalanine

HN

OH

O

O

O

NH2

OH

O

NHCbz

SHO

O

NH2

SHO

O

N-benzyloxycarbonyl-S-benzyl-L-cysteine

Model Reactions


• 5% Pd/C – (equal metal loading)

• 25oC, 3 bar

• Rxn Time 1.5 hrs



• 5% Pd/C – (equal metal loading)

• 30oC, 3 bar

• Rxn Time 10 hrs


Removal of Benzyloxycarbonyl (Cbz) Protecting GroupsCatalyst Activity and Selectivity

- 5%, 10% Pd/C and 5% Pd/Al2O3 catalysts

screened for each reaction.

- Difficult to follow the course of either

reaction by H2 uptake as a mole of CO2 is

generated for each mole of H2 consumed.

- the most active catalysts proceeded with

complete conversion and high selectivity to

the deprotected product.

- Not all Pd/C are the same

Hydrogenation of N-benzyloxycarbonyl-S-benzyl-L-cysteine

at 30°C, 3 bar H2 pressure

with various catalysts in ethyl acetate

0

10

20

30

40

50

60

70

80

90

100

5%Pd/C

A503129-5

5%Pd/C

A405028-5

5%Pd/C

A470129-5

5%Pd/C

5R39

10%Pd/C

10R87L

10%Pd/C

10R37

10%Pd/C

10R458

Catalyst Types% Conversion (10 hour reaction tim

e)

%Selectivity to S-benzyl-L-cysteine

% Conversion

% Selectivity


Removal of Benzyloxycarbonyl (CBZ) Protecting GroupsEffect of Solvent

- For the L-phenylalanine reaction:

- Reaction rates - fastest in acetic acid and methanol, - slower in ethanol and ethyl acetate.

For the L-cysteine reaction:

- Reaction rates - fastest in ethyl acetate and ethyl acetate/acetic acid solvent mixture-slower in ethanol and acetic acid.

Hydrogenation of N-benzyloxycarbonyl-L-phenylalanine

at 25°C, 3 bar H2 pressure in different solvents

0

10

20

30

40

50

60

70

80

90

100

Acetic Acid Methanol Ethanol Ethyl Acetate

Solvent

% Conversion (1.5 hour reaction tim

e)

5%Pd/C A503023-5

5%Pd/C A102023-5

HN

OH

O

O

O

NH2

OH

O

NHCbz

SHO

O

NH2

SHO

O



Effect of Reaction Temperature, Pressure and Catalyst Loading

For the L-phenylalanine

- Increasing the reaction temp from 25 to 50oC increased the reaction rate by ~3.

- reaction rate is proportional to catalyst loading

For the L-cysteine

- increased reaction temp, pressure and catalyst loading increased reaction rate

but decreased selectivity to the desired S-benzyl-L-cysteine product.

- For both the L-phenylalanine and L-cysteine deprotection reactions, eggshell, reduced and eggshell, unreduced catalysts performed better than uniform catalysts.

- Carbon supported catalysts performed better than those on alumina supports.


Recommendations

N-benzyloxycarbonyl-L-

phenylalanine


Catalyst:

Solvents:

Temp:

Pressure:

Catalyst

loading:

5% Pd/C types A405023-5, A503038-5,

A503129-5 and 5R394

Acetic acid, methanol

25 - 50ºC

2 - 5 bar


5% Pd/C types A405129-5 and 5R39; 10%

Pd/C A402032-10 and 10R458

Ethyl acetate, ethyl acetate/acetic acid

25 - 50ºC

2 - 5 bar


Transfer HydrogenationUse of hydrogen donor rather then gas phase hydrogenation


- 5% Pd/C - 5% wrt substrate, or equal metal loading

- Temperature: Solvent reflux or 50oC

- Pressure: Atmospheric N2

- Reaction Monitoring: GC and/or HPLC

Model Reactions

NH2

O

O

NH2

OH

O

HNOH

O

O

O

NH2

OH

O

NH

O

CBzHN

OO

O

OBnNH

O

H2N

OO

O

OH

- Advantages

- no pressure equipment requirement

- no need for H2 storage

- chemoselectivity advantages (e.g. deprotection in the presence of an aryl chloride).

- Selection of hydrogen donors

O-benzyl-L-phenylalanine


O-benzyl-N-benzyloxycarbonyl-L-aspartame.

Transfer HydrogenationCatalyst Activity and Selectivity


- O-benzyl-L-phenylalanine: Eggshell reduced catalysts better

- N-benzyloxycarbonyl-L-phenylalanine Catalysts on acidic carbon supports performed best

- O-benzyl-N-benzyloxycarbonyl-L-aspartame: Eggshell reduced and unreduced catalysts better

- wide range of 5%- 20% Pd/C catalysts screened

- both L-phenylalanine reactions complete conversion to the fully deprotected product.

- For the L-aspartame , depending on catalyst and solvent choice,

- removal of both/selective the benzyl and benzyloxycarbonyl protecting groups

Different and/or beneficial reaction selectivity by Transfer Hydrogenation instead of

Hydrogen gas

O-benzyl-L-phenylalanine


O-benzyl-N-benzyloxycarbonyl-L-aspartame.

Transfer HydrogenationEffect of Solvent and Hydrogen Transfer Agent

Solvents : methanol, ethanol, ethyl acetate, THF and/or water)

Hydrogen transfer agents - ammonium formate- sodium hypophosphite hydrate- hydrazine hydrate

- Typically more than one equivalent of a hydrogen donor is required as some decomposition of the transfer agent over the catalyst occurs.

Reaction rates - fastest in methanol and ethanol when using two or more molar equivalents of ammonium formate.

- slower in other solvents and with other hydrogen transfer agents.

Solvent and hydrogen transfer agent choice are critical for any deprotection reaction.

Transfer Hydrogenation

- facile cleavage using Pd/C catalysts at low temperature and pressure via transfer hydrogenation.

- not all Pd/C catalysts are equal

- solvents, hydrogen transfer agents influence activity and selectivity

Different and/or beneficial reaction selectivity using a hydrogen transfer agent instead of hydrogen gas.

Solvents: Methanol, ethanol

Temperature: 25 - 50ºC

Hydrogen Transfer Agent: Ammonium formate (> 2 equiv.)

Catalyst loading: 2 - 10% wrt substrate

Conclusions

Typical recommended conditionsO-benzyl deprotection N-benzyloxycarbonyl deprotection Concomitant O-benzyl and N-

benzyloxycarbonyl deprotection

Catalyst 5% Pd/C 5R39, 5R394, 5R338, A405028-

5, A405032-5 & A503130-5

10% Pd/C A501023-10, A501129-10 &

A101023-10;

5% Pd/C A405032-5, A102129-5 and 5R394;

10% Pd/C - 10R338 and 10R487

5% Pd/C A405032-5, A503129-5;

10% Pd/C - 10R338 and A402032-10

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-H2 +H2

-CO

+CO

C-C

+H2 +CO

+O2

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