Asymmetric Synthesis and Application of Î±-Amino Acids - American

Chapter 15

Catalyst Screening for the Synthesis of Amino Acids 1

2

David J. Ager , Laurent Lefort , and Johannes G. de Vries

2

Downloaded by EAST CAROLINA UNIV on September 18, 2015 | http://pubs.acs.org Publication Date: June 14, 2009 | doi: 10.1021/bk-2009-1009.ch015

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DSM Pharmaceutical Products, PMB 150, 9650 Strickland Road, Suite 103, Raleigh, NC 27615 DSM Pharmaceutical Products, Innovative Synthesis and Catalysis, P.O. Box 18, 6160 MD, Geleen, The Netherlands

Asymmetric hydrogenation is a powerful method for the synthesis of α-amino acids and was the first transition metal catalyzed reaction to provide high enantioselectivity. Unfortunately, there is no catalyst that can reduce every possible substrate with high enantioselectivity and screening has to be performed to find a useful candidate. The use of monodentate BINOL-based ligands such as MonoPhos™, which can be prepared by a very short synthetic sequence, allows for large libraries of potential ligands to be accessible within a few hours. Further diversity can be created by screening catalysts based on mixtures of these monodentate ligands. These catalysts can then be used to prepare a wide variety of amino acid derivatives.

© 2009 American Chemical Society

In Asymmetric Synthesis and Application of -Amino Acids; Soloshonok, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

239

240

Introduction Amino acids, peptides and peptidomimetics occur in a wide range of biologically active compounds and present a challenge for asymmetric synthesis. Knowles and his coworkers at Monsanto developed the first chemical asymmetric synthesis of amino acids based on rhodium-catalyzed olefin hydrogénation, which rivals enzymatic methods in terms of enantioselectivity and culminated in the production of the drug, L-Dopa (1), for the treatment of Parkinson's disease (Scheme l). The enamide substrate is prepared by the classical Erlenmeyer reaction and the desired Z-isomer 2 crystallizes from the reaction mixture. The asymmetric catalyst is based on the chiral bisphosphine, /?,/?-DIPAMP (3), that has chirality at the phosphorus atoms, and can form a 5membered chelate ring with rhodium. The asymmetric reduction of the Zenamide, proceeds in 96% ee. The pure isomer of the protected amino acid intermediate 4 can be obtained upon crystallizationfromthe reaction mixture as it is a conglomerate.


1

2

3

4

OAc

Scheme 1.


241 Although the catalyst system is amenable to the preparation of a wide variety of amino acids, especially substituted phenylalanine derivatives, a major shortcoming of the approach is the need to have just the Z-enamide isomer 5a as the substrate. Knowles' catalyst gives slow reactions with low asymmetric induction if an £-enamide 5b is used as the substrate. Fortunately, the general method for the preparation of the enamides is stereoselective to the Z-isomer when an aryl aldehyde is used. Other approaches to the alkene are also available such as the Heck or Suzuki reactions. The need to prepare the substrate in a stereoselective manner was overcome by the use of the DuPhos (6) family of ligands. For substrates that possess a single β-substituent (e.g., either R or R = H), the Me-DuPhos-Rh and EtDuPhos-Rh catalysts were found to give enantioselectivities of 95-99% at the alpha-center for a wide range of amino acid derivatives. ' Hydrogénation of just the E- or Z-enamide isomers allows the generation of the β-stereogenic center with high selectivity. The more electron-rich Me-BPE (7, R = Me) catalysts can be used to access β-branched amino acids (Scheme 2, R , R Φ Η ) . 5,6


4

2

3

7 8

2

2

ψ ^ C 0 V

+

[DuPhos-Rh] 2

R

^

R

Τ H (

9

5

910

° 2 R

Τ NHCOR

2

1

3

C

3

%

e

1

e

2

1

2

3

where DuPhos (6) = R

f*

'RR

B

P

E

7

()

=

R y

^

J*

v

'R R

Scheme 2.

The DuPhos reduction has been used to prepare a wide range of amino acids with substituted aromatic, heteroaromatic, alkyl, fluoroalkyl, and other functionalized organic groups. " Polyamino acids can also be accessed. " There is no comprehensive catalyst system to perform an asymmetric hydrogénation under optimal conditions. Although the systems mentioned above, as well as others, provide adequate selectivity and rates across a wide range of enamides, some optimization may be required to obtain an economical, commercial synthesis. For these large-scale reactions, not only does 9

16

17

21


20


242 enantioselectivity have to be considered but turnover number (TON), the amount of catalyst that is required, and turnover frequency (TOF), the amount of time it takes to go round the catalytic cycle, are also important factors. Both of these considerations relate to cost; how much catalyst has to be bought is related by the TON while equipment costs and time are connected to TOF. A different ligand, therefore, may be required for each separate substrate. In addition, the optimal reaction conditions may also vary. As with most process chemistry procedures, the solution comes back to looking at many different conditions; in other words, the variables need to be screened. For the catalysts themselves, there are a number of metals known to perform asymmetric hydrogénations to provide amino acid derivatives although rhodium and iridium are the most common. To achieve high enantioselectivity under optimal conditions, a wide variety of ligands needs to be screened. Many asymmetric hydrogénation catalysts are bisphosphines and prepared by long synthetic sequences. Thus, to obtain a sample of such a ligand requires investment in time and money. Some of these ligands can be bought either as the free ligand or as a metal complex; others require synthesis, as they are not commercially available. Samples of these ligands and catalysts can be kept for future screening use. However, many phosphines are oxygen sensitive and can degrade over time. Although this can be addressed, especially by the use of an inert atmosphere and temperature control, this approach requires careful monitoring and space. In addition, for screening only small amounts of the ligand will be required and dispensing these small amounts can be problematic. An alternative method is to make the ligand and then use it straightaway. This alleviates storage problems. The monodentate MonoPhos family of ligands 8 is set up to fulfill the requirements due to their ready accessibility.

Rhodium-Catalyzed Hydrogénations Rhodium-based catalysts with the monodentate phosphoramidite ligands have been found to provide high enantioselectivities for the asymmetric hydrogénation of dehydroamino acid substrates. Unlike bidentate ligands, there can be a strong solvent effect. The stereogenic backbone of the majority of phosphoramidite ligands is derived from 2,2'-binaphthol (BINOL) (9), which is readlily available as either isomer (Scheme 3). The intermediate phosphoryl chloride 10 is stable enough to be able to use in stock solutions. This convenient phenomenon extends to derivatives of BINOL. The biphenol 9 is derived from dimerization of 2-naphthol and the antipodes are then separated. 2-Naphthol is readily substituted at the 3- and 6positions due to the directing nature of the hydroxy group. Although a little more difficult, substitution can also be introduced at the 4-position. Dimerization and resolution then gives access to the general BINOL-based ligands 11. 22

23,24

25

26



243

11

To alleviate the problems associated with ligand storage and dispensing, a method was sought where the ligand synthesis could be automated. The structure of the ligands themselves allows for coupling to a solid support either through the biphenol (e.g., R attached to a polymer) or the amine (R ). None of these approaches were successful. A polymeric base did provide ligands that gave comparable results in the reduction to when purified ligands were used. However, as the purpose of the base is to drive the synthesis of the phosphoramidite to completion, triethylamine is competent in a solvent, such as toluene, where the resultant salt is insoluble. For asymmetric hydrogénations, the presence of chloride ion can be detrimental, but the triethylamine hydrochloride precipitates out and can be removed by filtration. The addition of the reagents for ligand synthesis can be performed by a robot and the reactions performed in 96-well plates. The use of an oleophobic filter then allows subsequent removal of the salt by-product by application of a vacuum. Comparison studies showed that parallel synthesis of the ligands, with only filtration to remove the salt by-product and no further purification, gave results in the reductions that were close to the analogous reactions with purified ligands. Thus, for the reduction of the enamide (5c) to prepare phenylalanine methyl ester, use of the purified ligand 8 (R = R = Et) gave 99% ee with quantitative conversion in dichloromethane under 5 bar of hydrogen; whereas use of the ligand prepared in the robot from which only the salts were removed by filtration led to 96% ee and 100% conversion under identical conditions. On average ee's are -5% lower using the robot-prepared ligands. However, the 5

1

27

28

27

1

2


244


relative order of selectivity and reactivity remains the same, making this methodology an excellent screening tool. As phosphoramidite ligands are monodentate and simple to prepare, there is a second aspect of the approach that can be exploited. The results from the first round of screening can be used to design and investigate more ligands in a second round of screening. The time required for this series of experiments is the same as the first screen; no long ligand syntheses are required. Thus, multiple rounds of experiments can be performed to not only optimize enantioselectivity but also reaction conditions. This is illustrated in Figure 1.

Figure 1. Iterative approach to ligand screening.

Monodentate ligands such as phosphoramidites and phosphites have a third property, which can be useful and also greatly increases the diversity space. Unlike bidentate bisphosphine ligands, which bind tightly to the metal, monodentate ligands provide a more dynamic system. In these, the most reactive system can be made up from a mixed ligand system. This is illustrated by the reduction of the α,β-unsaturated carboxylic acid 12 in the synthesis of the renin inhibitor, Aliskirin™ (13) (Scheme 4). 29



245

The initial screen was performed with eight different phosphoramidite ligands. Although the enantioselectivity was lower than required, it was the reaction rate that gave cause for concern. However, it could be seen that the use of 3,3'-disubstituted BINOL gave the best stereoselection. A second screen was performed but with 96 different achiral electron-donating ligands being added to the system; MonoPhos™ itself (8, R = R = Me) was used as the phosphoramidite. The results showed that the addition of an arylphosphine not only increased the reaction rate but also provided better enantioselectivity. Further rounds of screening lead to the use of the piperidine ligand 11 (R*,R = -(CH ) -, R = Me, R = R = H) with tri(/w-tolyl)phosphine in a ratio of 2:1. As stated above, the monodentate ligands lead to complex equilibria being established. The presence of an achiral ligand can give rise to a rhodium complex, which is viable to perform the reduction but would lead to racemic product. From the initial screening results the complex arisingfromtwo moles of 11 interacting with the metal leads to a system that is slow in performing the desired asymmetric hydrogénation. The use of the 2:1 ratio gives enough of the "mixed" ligand complex, which is the active catalyst to result in good reaction rate while not compromising the enantioselectivity. The use of mixed ligand systems provides an extremely large number of possibilities. Just 10 different ligands provide 55 different combinations. In independent studies, Reetz and coworkers independently found that mixtures of monodentate ligands can provide improved enantioselectivity in selected cases. This phenomenon has been applied to the reduction of β-amino acid derivatives where the use of a mixed ligand system gave much better rates and enantioselectivity compared to the use of two moles of a single ligand (Scheme 5). Phosphoramidites based on a BINOL backbone have proven to be extremely useful ligands for a wide variety of asymmetric hydrogénations, as summarized in Table I. Unlike most bidentate ligands, there can be a marked solvent effect for these reductions. The enantioselectivity for the reduction of the dehydroamino ester 5c with MonoPhos (8, R = R = Me) was 70% in methanol but a simple switch to dichloromethane resulted in an ee of >95%. Thus, a 1

2

2

3

2

4

5

29

5

30

31

32,33

1

2

22


246 1

Ν H Ac R

Rh(COD) BF . L L 2

A^,C0 Me 2

H

2

NHAc

4

2

R

A ^ C 0

2

M e

where R = Me or Ph


Scheme 5.

change in solvent can be used to advantage. An increase in hydrogen pressure increases the reaction rate for hydrogénations with 11, but does not adversely affect the stereoselectivity of the reduction.

Iridium Catalysts For the asymmetric reduction of enamides 5c to α-amino acid derivatives, the much cheaper metal iridium can be used rather than rhodium (Scheme 6). Based on the work of Crabtree, [Ir(cod)Cl] was treated with two equivalents of a MonoPhos ligand to provide [Ir(cod)LCl], which, in turn, was treated with a second ligand. No viable hydrogénation catalysts were found until a bulky ligand was used and the chloride was not displaced by a second ligand. Further screening studies showed that the BINOL backbone was not required and a simple bisphenol could be used as long as there was a large group in the 3- and 3'-positions. Subsequent studies suggest that there is only one phosphoramidite ligand bound to the metal in the active species; the precursor only has one present, the addition of more ligand does not give a rate acceleration, non-linear effects are absent, and there is no mixed ligand effect. 2

42

Summary In summary, the monodentate phosphoramidite ligands have been established as a versatile family of ligands to perform asymmetric hydrogénations. * The ease of synthesis and ready access to a very large number of family members provides for the screening of many ligands and mixtures without taking a large amount of time. The second advantage is the simple synthesis keeps costs for the ligand to a minimum. These systems have been, and continue to be, implemented at industrial scale. However, work still needs to be performed to understand the mechanism of the reductions and provide more insight into the controlling factors. 43

46


247 Table I. Asymmetric hydrogénations with phosphoramidite ligands based on the BINOL backbone. Substrate C0 H 2

Ar

C0 H 2

Ar

22,34,35 NHAc


Ν H Ac C0 R 2

Ar

C0 R 2

Ar

22,24,27,34-36

Ν H Ac

NHAc

C0 H

C0 H

2

R

2

22,34,35 NHAc

Ν H Ac C0 R

C0 R

1

NHAc

A ^ C 0

2

1

R

R

C0 R

A ^ C 0

2

27,37

1

R

C0 R

1

2

AcHN

1

2

AcHN

38 R

R C0 H 2

C0 H 2

R

39

R

R'

H0 C 2

C0 H

22,24,35

H0 C 2

C0 H 2

2

1

R 0 C^A^^ C0 R D

2

2

1

R 0 C^L, C0 R 2

NHAc

24,35,40

R

Ar

OAc

OAc

Ar

Ar OCONMe „R

22

2

NHAc

Ar

22,34-36

NHAc

Ν H Ac NHAc

Ar

1

2

2

R

Reference(s)

Product

OCONMe

2

Ar

41

R

R

2

41


248 C0 Me

[lr(COD)(L)CI]

2

Ph

C H C I , H (5 bar) 2

2

Ph

C0 Me 2

2

NHAc

NHAc

5c

ee 98%


where L =

Scheme 6.

References 1. 2. 3. 4. 5. 6.

7. 8. 9. 10. 11. 12.

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Asymmetric Synthesis and Application of Î±-Amino Acids - American

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