Synthesis of Amino Acid Derivatives via Asymmetric Hydrogenation

Chapter 13

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Synthesis of Amino Acid Derivatives via Asymmetric Hydrogenation Hideo Shimizu, Izuru Nagasaki, Noboru Sayo, and Takao Saito Corporate Research and Development Division, Takasago International Corporation, 1-4-11, Nishi-Yawata, Hiratsuka City, Kanagawa 254-0073, Japan

The development of asymmetric hydrogenation en route to αamino acid derivatives is outlined with regard to the catalyst and substrate scope. The reaction that gives β-amino acid derivatives is also addressed as an extension of this technology.

Introduction Asymmetric hydrogenation to give a-amino acid derivatives has been in the vanguard of asymmetric synthesis. In the development of a new ligand, a key parameter in asymmetric synthesis, the asymmetric hydrogenation of dehydroamino acid derivatives (typically 2-acetamidocinnamic acid and its ester) has frequently been used as a benchmark reaction to investigate the initial performance. Consequently, many promising systems that give a-amino acid derivatives in a highly enantioselective manner have been reported to date (7). In general, asymmetric hydrogenation offers several advantages, including the use of a clean reducing agent and the low generation of waste, the feasibility of a high-density reaction to enable an efficient operation, and a relatively wide scope of reaction substrates. Although the number of industrial applications that use this reaction has increased (2, J), further expansion seems likely, in light of the potential utility of this reaction. Obstacles to such expansion include the cost of adopting the catalysis and development time (4). Considerable effort has been made to improve the value of asymmetric hydrogenation by eliminating these obstacles. This chapter deals with © 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.

203


204 representative examples of these efforts to reduce the cost in terms of the catalyst and substrate scope. The former helps to expand the pool of suitable catalysts and improve its performance, which directly impact the cost of the reaction. On the other hand, the latter should make it possible to apply asymmetric hydrogenation to a process in a suitable form, i.e., without additional adjustment such as protection/deprotection. The ability to skip redundant steps should help to reduce costs. In this chapter, the synthesis of P-amino acid derivatives is also addressed as an expansion of substrate scope in a new direction. Excellent reviews have been published on other efforts to reduce the cost of the catalysis, i.e., on methodologies designed to easily separate and/or reuse catalysts, such as recoverable catalysts (i.e. immobilization ) and unconventional reaction media (i.e. supercritical C 0 and ionic liquid) (5, 6). With regard to development time, high-throughput screening (HTS) has recently become popular for meeting the demand of chemists, especially those in the pharmaceutical industry (7). In this field, the time-to-market pressure has become severe, which forces process chemists to identify the best possible synthetic route in a shorter period of time. Under such circumstances, the time required to identify an optimal condition takes a high priority for asymmetric hydrogenation to be regarded as a potential key reaction. A conventional stepby-step approach with individual reactions can be too slow to meet such a time requirement, particularly in a case where there is no close empirical analogy. On the other hand, with the HTS system, where typically 96 reactions are carried out at a time, parameters such as ligands, catalyst precursors, solvents, and additives can be extensively screened quickly within a few days to identify an optimal system. In addition to identifying the ligand of choice in a short time, HTS has the potential to identify suitable catalyst systems for substrate types that have not yet been investigated. Some of the examples in this chapter were identified by HTS. 2

Progress in Catalyst Parameters Chiral Ligands A large part of the research on the asymmetric hydrogenation of dehydroamino acid derivatives involves the study of chiral ligands. In most cases, ligand development was carried out for the use of Rh catalysis. The development of chiral ligands was motivated by the need for higher performance (selectivity and productivity), easier accessibility and/or the circumvention of existing patents. Here we provide an overview of some representative ligand types that are effective in the asymmetric hydrogenation of dehydroamino acid derivatives,


205 especially those used in Rh catalysis. Excellent reviews provide a detailed discussion for each ligand type (8, 9, 10).


Monodentate Ligands (11, 12) The use of chiral monodentate ligands in asymmetric hydrogenation started at 1968 when PPh of the Wilkinson catalyst (RhCl(PPh ) ) was replaced by optically active phosphines (13, 14). In the early stage of its history, a considerably high enantioselectivity (88% ee) was achieved in the asymmetric hydrogenation of a dehydroamino acid by using a monophosphine ligand, CAMP (75). However, monodentate ligands lost their prominent position in ligand development with the appearance of bidentate ligands. Although monodentate ligands continued to be studied (76), it was not until 2000 that ligands in this category were again highlighted. In that year, several groups reported the efficiency of BINOL-based phosphorus ligands (phosphonites (1) (77, 18% phosphites (2) (19) and phosphoramidites (20)) in the Rh-catalyzed asymmetric hydrogenation, to give excellent enantioselectivities comparable to bidentate counterparts. In a kinetic study, monodentate ligands showed rates comparable to DuPHOS, a representative bidentate ligand (27). Many of these ligands can be prepared easily, which promoted their modification. In the case of MonoPHOS ligands, modification of the amine moiety is effective. For example, in many cases, ligands bearing piperidine (PipPHOS) give higher enantioselectivity than the parent MonoPHOS ligand (22). Meanwhile, various modifications of the diol moiety have been implemented to achieve higher performance. Representative examples are H MonoPHOS (23) and SIPHOS (24). A later study showed that the diol moiety is not necessary for high enantioselectivity; ligands derived from catecol and optically active amine such as ligand 3 also give the products with high optical purity (25) (Figure 1). Although the optimal ligand tends to vary with the substrate, this can be overcome by HTS, which identifies the ligand of choice in a short period of time (26, 27). 3

3

3

8

Bidentate Ligands Since DIOP, the first ligand in this category, was reported (28), it has become generally recognized that C symmetry and a bidentate property are the key to success in ligand development, and this has inspired researchers to design and synthesize various chiral bidentate ligands. Bidentate ligands can be classified into several categories. 2



206

H -MonoPHOS 8

SIPHOS-Me

3

Figure 1. Monodentate ligands.

DIPAMP-Type Ligands (P-Chiral Ligands) (29) Soon after the concept of C -symmetric bidentate ligands was reported, Knowles synthesized DIPAMP (30). It was revealed that the bidentate ligand gave higher enantioselectivity than the corresponding monodentate ligands. This success led to the L-Dopa process, the first industrial application to use asymmetric hydrogenation (J/). P-chiral ligands are attractive in the sense that we can expect high enantioselectivity by having chirality on the phosphorus atom, the closest position to the reaction center (metal atom) in the complex. However the development of this ligand type was slow, presumably due to the difficulty of its synthesis. A renaissance of P-chiral ligands was initiated by Imamoto, who reported BisP* (32). Since then, a variety of P-chiral ligands have been reported, such as MiniPHOS (33). Many ligands of this type are trialkylphosphine-type, which are sensitive to air. They are easier to handle when converted to the corresponding salts (34). Recently, it was discovered that the introduction of a quinoxaline backbone (Quinox P*) made the ligand stable in air while maintaining high chiral-recognition ability (55). Other effective P-chiral ligands in the asymmetric hydrogenation of dehydro aminoacid derivatives include TangPhos (36), DuanPHOS (57), DisquareP* (38), and BIPNOR (39) (Figure 2). 2


207

Me ^~ p

>uo-Ani o-Ani

Ph

t-Bu

M-Bu Me

Me - p ^ p . »^-Bu t-Bu

Me

Me-p t-B\i


DIPAMP

BisP*

TangPhos

DuanPhos

MiniPHOS

DiSquareP*

p.»\f-Bu Me

QuinoxP*

BIPNOR

Figure 2. DIPA MP-type ligands.

BINAP-Type Ligands (40) The first application of BINAP, the landmark ligand in a wide array of asymmetric synthesis, was the Rh-catalyzed asymmetric hydrogenation of dehydroamino acids and their esters (41). However, parent ligands with biaryl frameworks (with PPh appendages) often fail to give high enantioselectivity in the reaction of acylated dehydroamino acid esters. Promising ligands with a biaryl backbone are those with dialkylphosphino appendages, such as BICHEP (42) . Those which introduce substituents at the 3,3'-position are also attractive (43) . For example, o-Ph-MeO-BIPHEP gave 98% ee in the asymmetric hydrogenation of methyl 2-acetamidocinnamate, while the parent MeO-BIPHEP gave 21% ee under identical conditions. Alternatively, the use of biheteroaromatic TMBTP reportedly gave high enantioselectivity (44) (Figure 3). 2

DuPHOS-Type Ligands (45) DuPHOS and BPE (46) developed by Burk, are landmarks in this field. These ligands generally give a wide array of natural and unnatural amino acid derivatives with high optical purity (4 7). Catalytic activity is quite high and in some cases reaches a turnover number (TON) of 50,000. The success of these hyperactive ligands ignited the extensive development of their descendants. In the early stage, the comparatively difficult availability of the corresponding 1,4-diol precursor led to the design of alternative ligands derived from easily available Mannitol. RoPHOS (48), KetalPHOS (49) and BASPHOS (50) are among these ligands. A 2,5-diaryl phospholane version of BPE, Ph-BPE, was recently reported to give higher enantioselectivity than the parent alkyl-counterparts (51). Variation of the backbone has also been carried


208

"PPh „PPh

2

p

2

p

Cy Cy

2

2

"PPh .PPh

MeO MeO

2

2

sDownloaded by UNIV OF CALIFORNIA SANTA BARBARA on September 18, 2015 | http://pubs.acs.org Publication Date: June 14, 2009 | doi: 10.1021/bk-2009-1009.ch013

BINAP

BICHEP

R = H: MeO-BIPHEP Ph: o-Ph-MeO-BIPHEP

TMBTP

Figure 3. BINAP-type ligands. out (Figure 4). UIluPHOS, with a thiophene backbone, has a geometry similar to that of DuPHOS, but has greater electronic availability, and provides a qualitatively faster reaction than DuPHOS (52). CaMSium M (MalPHOS) has a wider bite angle than Me-DuPHOS, and gives higher performance in some cases (53). Me-f-KetalPHOS, which shows high catalyst productivity, is also promising (54).

R = Me: Me-DuPHOS Et: Et-DuPHOS n-Pr: Pr-DuPHOS

BASPHOS

R = Me: Me-BPE Ph: Ph-BPE

UIluPHOS

RoPHOS

KetalPHOS

catASium M

Me-f-KetalPHOS

Figure 4. DuPHOS-type ligands. Other phosphacycle ligands inspired by DuPHOS, such as ligand 4 (55), iPrBeePHOS (56), and Me-FerroTANE (57), have also been reported (Figure 5).

Josiphos-Type Ligands (58) The Josiphos family is one of the largest ligand libraries (59). Its modifications with various appendages can be easily prepared stereospecifically


209

i-Pr

Bn

Fe


a .

»

6

Bn

iPr-BeePHOS

4

Me-FerroTANE

Figure 5. Other Phosphacycle ligands.

from an identical intermediate, which provides wide screening options. Success with the Josiphos family has led to other ferrocene-based diphosphine ligand families, including Taniaphos (60), Walphos (61) and Mandyphos (62). Many ligands in these families show promise in the asymmetric hydrogenation of dehydroamino acid derivatives. TRAP, a trans chelating ligand (63), is also an effective ligand in this reaction (Figure 6).

vPR'2

R P " Fe " \ 2

NMe R = P h , R' = Cy: Josiphos

RoP

Ph

Ph

2

Walphos

Taniaphos

,vPR

R P ° 2

V

2

6R' P 2

MandyPHOS

TRAP

R, R' = alkyl, aryl, heteroaryl

Figure 6. Josiphos-type ligands.

DIOP-Type Ligands (Including Bisphosphine Ligands with Other Chiral Backbones) (64) As previously noted, DIOP offered several guidelines for subsequent ligand development (28). These included the introduction of a chiral backbone, which made synthesis of chiral ligands much easier. Since DIOP, numerous other ligands with diversified backbones, which are effective in a-amino acid synthesis by asymmetric hydrogenation, have been


210 Bn

Ph P" 2

Ph P 2

PPh

2

Ph P 2

Ph P 2

PPh


DIOP

PPh

2

PPh

Ph P 2

y

H ^PPh

2

2

2

BDPP

Pyrphos (Deguphos)

Norphos

BICP

^Ph PPh

2

PPh

2

Ph PHANEPHOS

Ph-o-NAPHOS

Figure 7. Ligands with various chiral backbones.

reported. Representative examples include BDPP (65), Norphos (66), Pyrphos (67), BICP (68), PHANEPHOS (69), and Ph-o-NaPHOS (70) (Figure 7).

Bisphosphine Ligands Based on Self-Assembly. A new category of bidentate ligands based on self-assembly through hydrogen bonding or coordination bonding has recently been developed (71), and some have been applied to the asymmetric hydrogenation of dehydroamino acid derivatives. A representative example is depicted in Figure 8. An adeninethymine base pair analogue was used for the scaffold of the bidentate ligand, which enabled the selective formation of heterodimeric ligands. With m aminopyridine ligands and n isoquinolone ligands, the screening of (m x n) combinations was feasible, and this could identify the ligand that gave ultimate enantioselectivity in the asymmetric hydrogenation of 2-acetamidoacrylate (72).

Ligands Other Than Bisphosphine (73) Diphosphorus ligands other than diphosphine ligands also form a large category of bidentate ligands. Many ligands can be prepared from readily available diols, amino alcohols and diamines. These ligands have been applied to the asymmetric hydrogenation of dehydroamino acid derivatives, and give moderate to excellent enantioselectivities. Backbones similar to those for diphosphine ligands are frequently adopted. Some representative examples are depicted in Figure 9 (BoPhoz (74), Ph-

Synthesis of Amino Acid Derivatives via Asymmetric Hydrogenation

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