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

Chapter 6

Novel Chiral Template for Preparation of α-Amino Acids: Practical Synthesis and Application

Downloaded by UNIV LAVAL on September 18, 2015 | http://pubs.acs.org Publication Date: June 14, 2009 | doi: 10.1021/bk-2009-1009.ch006

Kazumi Okuro, Yasuhiro Saka, Ikuhiro Suzuki, and Masaru Mitsuda* Frontier Biochemical and Medical Research Laboratories, Corporate Research and Development Division, Kaneka Corporation, 1-8, Miyamae-machi, Takasago-cho, Takasago, Hyogo 676-8688, Japan

A novel chiral imidazolidinone-type template for synthesizing optically active α-amino acids has been developed. The template was prepared from α-phenylethylamine as a chiral source, 2-chloroacetamide, and 2,6-dichlorobenzaldehyde in 4 steps. The process includes crystallization-induced dynamic resolution (CIDR). The template reacted with electrophiles in a highly stereoselective manner under mild conditions to afford alkylated products that were further transformed in 2 steps into optically active α-amino acids.

Introduction Biotechnology in the post-genomic era has been changing the ways that new drugs are discovered. Information regarding the human genome sequence offers new opportunities in medicinal research, including the field of resultant protein, peptide, and amino acid science. Approximately 20% of the new drugs approved in the last decade contain an a-amino acid moiety in their structure. In particular, © 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.

89


90 non-natural amino acids have attracted a great deal of attention as a key component of peptide mimetic agents, which improve stability and resistance toward metabolic degradation of the pharmaceuticals (/). To date, a number of efficient methods, including biotransformations, for preparing optically active a-amino acids have been established (2). In particular, recent remarkable progress in asymmetric synthesis has provided a wide range of accesses to a-amino acids. Examples include enantioselective hydrogenation of dehydroamino acid derivatives catalyzed by chiral transition metals (3) and enantioselective alkylation of glycinate derivatives by a chiral-phase transfer catalyst (4). The process utilizing chiral glycine templates is also a candidate (5) because such a process is considered to be one of the most straightforward and reliable methodologies from the perspective of simple, quick, and routine procedures (Figure J).

Figure 1. Synthetic outline of a-amino acids synthesis using a chiral glycine template

In this methodology, asymmetric induction is based on diastereoselective alkylation of the enolate generated from an optically active glycine derivative with electrophiles. In 1979, Schollkopf et al. reported their pioneering studies on enantioselective synthesis of optically active a-amino acids using the symmetrical bis-lactim ether of L-alanine as a chiral glycine template (5a). Since then, a variety of glycine derivatives have been developed, some of which, including the bis-lactim ether, are now commercially available in reagent grade (Figure 2).

Schollkopf (5a)

Seebach (5e)

Williams (5g)

Figure 2. Example of commercially available chiral glycine template


91 To our best knowledge (6), however, none of the known chiral glycine templates has been found in any industrial processes. There have been difficulties in their preparation or chemical conversion into a target a-amino acid on a large scale production. In general, extremely low temperature condition, below -60°C, is required in the asymmetric induction process (Scheme 1).


M

E

0

-

N

J

THF/.70»C

W

*

Me0

C0 H 2

2) R X Scheme 1. Standard process to a-amino acid using Shollkopfs template

Development of a New Chiral Glycine Template Under such circumstances, we envisioned the design of a novel chiral glycine template that can tolerate industrial-scale preparation. Consequently, we developed a chiral imidazolidinone 1, a couple of enantiomers, easily converted to various chiral a-amino acids . O N-Boc

(2R,\'R)-l

H (S)-a-amino acid

O

A

,, II

Boc NN-- E

(25,1 'S)-l

H (/?)-a-amino acid

Preparation When a-phenylethylamine (R)-2 was heated with sodium iodide and 2chloroacetamide 3 in acetonitrile, followed by condensation with 2,6dichlorobenzaldehyde 5 in the presence of a catalytic amount of p-toluenesulfonic acid in toluene, a 1:1 diastereomeric mixture of imidazolidinone (2RS, 1 'R)-6 was formed with regard to C-2 of the imidazolidinone ring (Scheme 2).


92

(R)-2

CH CN 86% 3

" (y R

92%

4

(2RS,VR)-6 2RJ2S=\/\


Scheme 2. Preparation of(2RS, 1 'R)-6

Simple crystallization of (2RS, 1 'R)-6 from acetonitrile successfully increased the diastereomeric purity in up to 98% de, with (2R,\ 7?)-6 being isolated in 25%. Finally, it was treated with B o c 0 , followed by recrystallization to furnish our target chiral molecule (2/?,l 7?)-l as a single diastereomer (>99.8% de). A n isomer (25,1 'R)-\ could also be isolated by crystallization of the diastereomeric mixture of 1, which originated from the filtrate of crystallization of(2/?,l 'R)-6 (Scheme 3). 2

Reaction The reaction of (2/?,l'/?)-l with benzylbromide using L D A as a base in T H F at -20 °C afforded alkylated product 7a. Acid hydrolysis of crude 7a and subsequent hydrogenolysis on Pd(OH) -C under the atmospheric pressure of H delivered phenylalanine with 99.5% ee in 46% overall yield from (2/?,17?)-l, whose absolute configuration was found to be S (Scheme 4). It should be noted that the alkyation proceeded highly stereoselectively even at -20 °C, whereas alkylation of the chiral glycine templates previously developed are typically carried out below -60 °C in order to achieve satisfactory stereoselectivity. When the preparation of phenylalanine was repeated employing (2S, \ 7?)-l instead of (2/?,l 7?)-l, (#)-amino acid was produced in 99.8% ee. The stereochemical outcomes of the reactions using (2R,VR)-l and (2S,T/?)-!, respectively, suggest that diastereoselectivity in the alkylation should be controlled by the chirality at C-2 on the imidazolidinone ring. In contrast, the diastereoselection of the alkylation could be explained by considering a chelated enolate intermediate, as shown in Figure 3. The metal cation originating from the base employed would form a chelation with two carbonyl oxygens. It is reasoned that on the basis of this model, the re-face might be shielded by a 2,6dicholorophenyl group, resulting in exclusive attack to an electrophile from the 5 /-face. 2

2

5


93 O 1

0 l)Boc 0(1.2eq.) Et N(1.5eq.) | DMAP(0.05eq.)Ph^N-^/

A-

2

crystallization [ NH CH CN P h ^ N - ~ V 3

3

C 1

N

(2RS,VR)-6Cl

precipitate o

2 5

j 2) recrystallization \=/ 8

(2R,VR)-6 98% de 0

/ o

filtrate Downloaded by UNIV LAVAL on September 18, 2015 | http://pubs.acs.org Publication Date: June 14, 2009 | doi: 10.1021/bk-2009-1009.ch006

i

P h ^ N ^ / Boc 0 Et N DMAP

N

4

%

B

o c

c

,

r \

C

W « H > 99.8% de O

^crystallization P h ^ , N 32%

2

C 1

Cl

3

(2S,l'R)-l > 99.8% de

(2RS,l'R)-\

Scheme 3. Preparation of (2R, 1 'R)- and (2S, 1 'R)-l by simple crystallization

1) L D A

_

-20°C

P h ^ W E \

(2R,VR)-l

2) P h C H B r

r

°.

C

60°C

/

• 2

)

H

2 (

L

A

T

M

)

/ . C O O H T N

"

2

Pd(OH) /C (^-Phenylalanine 50 °C 46% yield 99.5% ee 2

+

1) L D A -20 °C o n i (25,1 R)-l

B

\=J 7a

-20 °C thenO°C

n

2

C l — / >

2

+

1)H 0,H

V - A 1)H 0,H Jj N-Boc o V ^ ( Cl (/^-Phenylalanine : \ / 31% yield , _ J \ 2)H (latm) 99.8% ee 2

P P

V

• 2) P h C H B r 2

h

6

h

c

c

2

-20 °C then 0 °C

0

N

?

\ = /

Pd(OH) /C

b

50 °C

2

Scheme 4. Synthesis ofphenylalanine using (2R, 1 "R) and (2S, 1 'R)-l


94

+ Electrophile V* ~O

tBu

v

Y

»S7-face. CL

-O'

N

(R)-l-phenylethyl

R:

Re-face


Figure 3. Plausible mechanism of diastereoselective alkylation

Another interesting transformation to a-amino acids from the alkylated products could also be found that did not require hydrogenolysis to cleave the CN bond at a a-phenylethylamino moiety. Upon exposure of 7a to concentrated H S 0 in chlorobenzene at room temperature for 1 hour could effect removal of a a-phenylethyl group on N - l . Successively, hydrolysis by the addition of water completed the conversion to (^-phenylalanine in 83% yield with no substantial loss of optical purity. We succeeded in isolating an intermediate, 5-benzyl-3(2,6-dichlorophenyl)imidazolidinone 8, in 69% yield by work-up under basic conditions after treatment of 7a with concentrated H S 0 (Scheme 5). 2

4

2

O

O

I N - B o c H 2S O° 4 P h ^ N ^ y ^ H

^

b

H N ^ /

a

I

4

j

/

c i — /

\

N

H

\ Cl I

H

2

° "

(^-Phenylalanine 83% yield

PhCl \

ci-

7a

8

Scheme 5. Transformation to a-amino acids by acid treatment

Toluene could also be used as solvent in place of chlorobenzene. However, toluene underwent sulfonation by H S 0 , producing toluenesulfonic acid as a side product, which may cause difficult separation of the pure amino acid from the reaction mixture. No such sulfonation was observed for chlorobenzene. Some examples have appeared upon acid-promoted removal of arylmethyl or a-arylethyl groups on nitrogen, but this is limited to the case in which the leaving group is activated by a methoxy group on the aromatic ring (7) unless the nitrogen is substituted by another electron-withdrawing group such as an acyl or 2

4


95 carbamoyl group (#). This unprecedented transformation under extremely mild conditions is undoubtedly useful for substrates having substituents sensitive to hydrogenolysis or heteroaromatic groups deactivating heterogeneous Pd catalyst.

Application of New Chiral Template for a-Amino Acid Synthesis Table I. a-amino acid synthesis using (2/?,l'5)-l Downloaded by UNIV LAVAL on September 18, 2015 | http://pubs.acs.org Publication Date: June 14, 2009 | doi: 10.1021/bk-2009-1009.ch006

O R X (1.5-2.0 eq.) \^\ 1)H S0 NaHMDS (l.leq.) I N~Boc PhCl - m^N-^y ^ R

2

(2R VRyi 9

1 2 3 4 5 6 7 8 9 10 11 a

NH =

a

THF,-20°C

entry

4

RX

i

y^l

2)H 0

product (amino acid)

Mel EtI /-PrI /7-Bul n-BuBr PhCH Br 4-FC H CH Br 4-FC H CH Cl 4-ClC H CH Br 4-ClC H CH Cl 4-BrC H CH Br 2

6

4

2

6

4

2

6

4

2

6

4

2

6

4

2

(5)-alanine (5)-2-aminobutanoic acid (5)-valine (5)-norleucine (5)-norleucine (^-phenylalanine (iS)-4-fluorophenylalanine (5)-4-fluorophenylalanine (S)-4-chlorophenylalanine (5)-4-chlorophenylalanine (5)-4-bromophenylalanine

2

COOH

2

a

b

yield(%)

ee(%)

95 96 90 91 82 83 90 86 87 81 70

96 93 98 98 99 99 97 96 98 97 77

Based on (2R, 1' / ? ) - ! . Determined by H P L C using a chiral column. b

Under optimal conditions, a variety of a-amino acids were prepared that are recorded in Table I. Both alkyl and benzylic-type a-amino acids were obtained with high enantiomeric excess in excellent overall yield except for (5)-4bromophenylalanine (entry 11). A significant drop in enantiomeric excess was observed in the case of 4-bromophenylalanine synthesis. It appears that although the alkylation with 4-bromobenzylbromide proceeded highly stereoselectively as


96 with the reaction of other halides, a decrease in optical purity might occur in the conversion to the amino acid, and that this behavior is inherent in this substrate. Sterically hindered alkyl halide, /-propyl iodide, was also successfully employed, with L-valine being formed in 90% yield and 98% ee (entry 3).


Application of New Chiral Template for a,a-Disubstituted Amino Acid Synthesis We next examined the construction of a,a-disubstituted a-amino acids, which have recently received a great deal of attention due to their importance in the field of peptide chemistry (9). When the first alkylation product 7a was subjected to a second alkylation with methyl iodide, the precursor 9 of amethylphenylalanine 10 was produced with high stereoselectivity (Scheme 6). The absolute configuration is obviously determined in the second alkylation step; thus, the methyl group will be introduced from the less hindered face opposite to the 2,6-dichlorophenyl group based on the discussion of stereocontrol, which is consistent with the fact that the final amino acid has an R configuration.

1) L D A , -20 °C 2) P h C H B r 90 o -20 C then0°C 2

r

(2fl,17?)-l

h

? O '> 1 '

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

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