Î²-Hydroxy-Î±-Amino Acids Using - American Chemical Society

Chapter 14

Downloaded by UNIV DE SHERBROOKE on May 3, 2015 | http://pubs.acs.org Publication Date: June 14, 2009 | doi: 10.1021/bk-2009-1009.ch014

Stereoselective Synthesis of anti-β-Hydroxy-α-Amino Acids Using anti-Selective Asymmetric Hydrogenation Yasumasa Hamada and Kazuishi Makino Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

anti-β-Hydroxy-α-amino acids are efficiently synthesized from chirally labile α-amino-β-keto esters using ruthenium- and iridium-catalyzed asymmetric hydrogenation through dynamic kinetic resolution, which is capable of the stereocontrolled construction of two consecutive stereocenters at one reaction.

Introduction P-Hydroxy-oc-amino acids with syn or anti stereochemistry are common structural units widely found as a component of biologically active natural products, especially cyclodepsipeptides (7). Their importance and usefulness as building blocks for synthesis of natural products and medicines have prompted a search for better methods in the stereocontrolled construction of two consecutive stereocenters (2). We have been working on total synthesis of naturally occurring cyclodepsipeptides with biologically interesting activities. In this research we needed an efficient synthesis of a«//-P-hydroxy-a-amino acids. Although to date various methods for synthesis of a«//'-P-hydroxy-a-amino acids have been reported and are roughly classified into asymmetric aldol reactions in a diastereoselective or enantioselective manner (5), diastereoselective synthesis from the Garner aldehyde (4), enantioselective synthesis using Sharpless asymmetric dihydroxylation as a key step (5), and etc (6) as shown in Figure 1, these methods need long reaction steps and/or contain tedious operation. Simple and straightforward synthesis of an//-p-hydroxy-a-amino acids still remains to © 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.

227

228 be developed. In our efforts on synthesis of a«r/-P-hydroxy-a-amino acids, we have found new and efficient asymmetric hydrogenation. In this article we focus on our developed diastereo- and enantioselective synthesis of aw//-P-hydroxy-cxamino acids using asymmetric hydrogenation through dynamic kinetic resolution.


" A O diastereoselective aldol enantioselective aldol

o R ^ H

Garner aldehyde diastereoselective alkylation

Jl

OH

X = CI, Br N=CAr , etc

OH

Boc

FT

O

Y NH

2

"OH 2

anf/-p-hydroxy-a-amino acid

A

A

O ,

OEt

diastereoselective hydrazination

intramolecular allylic alkylation OH

Sharpless A D J-Pr

O OEt

OH

Figure 1. Literature procedures for anti-P-hydroxy-a-amino acids

Synthesis of aifft-P-Hydroxy-a-Amino Acids using Noyori Asymmetric Hydrogenation The dynamic kinetic resolution (DKR) (7) in the asymmetric hydrogenation of racemic ketones is an efficient method for obtaining theoretically optically pure alcohols from racemic ketones in 100% yield, which was reported by Noyori and coworkers for the first time (#). Especially, asymmetric hydrogenation of a-substituted-P-ketoesters via DKR is an excellent procedure with the ability to construct two adjacent stereocenters in a stereocontrolled fashion at one reaction. Noyori and coworkers reported the highly stereoselective synthesis of sjw-P-hydroxy-cc-amino acids from chirally labile oc-acylamino-Pketoesters using this method. At the beginning of our study, we synthesized all four stereoisomers of 3-hydroxyleucine using the Noyori method (9). This method is efficient for obtaining sjw-P-hydroxy-a-amino acids, but for anti-$hydroxy-a-amino acids it has a substantial disadvantage that one more step for


229 the inversion of the C3 stereocenter is needed. Therefore, we focussed on a direct and straightforward construction of a«//-P-hydroxy-a-amino acids by asymmetric hydrogenation via DKR.

Ru syn-selective hydrogenation

0

6-membered cyclic transition state

OR NHR' R' = H

"OR FlH-acyl

OR NH-acyl

R' = acyl


OH O

6

syn-3 Noyori's method

^~Ru NH

Direct anti-selective hydrogenation

OH

0 OR

2

C0 R 2

4

NH

2

anti-Z

5-membered cyclic transition state

Figure 2. Direct anti-Selective Hydrogenation

As shown in Figure 2, we envisioned hydrogenation via the 5-membered cyclic transition state 4 using the 2-amino substituent of a-amino-P-keto ester 1 as a directing group, which would directly produce aAtf/-P-hydroxy-a-amino acid ester in place of the syn product generated via the 6-membered cyclic transition state 2 (10). In fact, asymmetric hydrogenation of cc-amino-P-ketoester hydrochloride 5 with Ru-(5)-BINAP in methanol at 50°C for 48 h gave anti-$hydroxy-ot-amino acid ester 6 in almost perfect diastereoselectivity and moderate enantioselectivity (Table 1, entry 1). With this encouraging result in hand, we extensively surveyed the optimized conditions for the ^/-selective hydrogenation with high enantioselectivity. Methylene chloride is the solvent of choice for the enantioselectivity and isopropanol and «-propanol also give satisfactory results. The ester function affected the chemical yield due to low solubility of the starting hydrochloride salt. Finally, benzyl ester was most effective in terms of chemical yield and enantioselectivity (entry 2). This method was then applied to various substrates to clarify the generality of the hydrogenation. The starting a-amino-P-keto ester hydrochlorides were easily prepared by the following four methods: (1) acid hydrolysis of 4alkoxycarbonyloxazoles derived from carboxylic anhydrides and isocyanoacetic


230 Table I. ^/-Selective Hydrogenation through DKR O

o

o

NH -HCI

5


RUCI

OH

O

2 OR

n

solvent, 50 °C, 48 h

6

2

NH -HCI

BzCI, T E A

OH

^ R T H F , rt, 1 h

2

O OR'

NHBz

R

R

1

Pr

Me

MeOH

71

99:1

56

2

Pr

Bn

CH CI

2

87

>99:1

96 81

entry

a

HoMOOatrrrt H (100 atm) 2(^)-b'nap](dmf) 2

2 [ OR'

1

2

yield [%]

solvent

2

anti:syn

eef%f

3

cyclobutyl

Bn

nPrOH

92

83:17

4

cyclopentyl

Bn

nPrOH

85

97.5:2.5

95

5

cyclohexyl

Bn

CH CI

85

>99:1

97 97

2

2

6

cycloheptyl

Bn

nPrOH

86

97:3

7

b

nPr

Bn

nPrOH

76

97:3

91

8

tBu

Bn

nPrOH

89

96:4

79

9

cyclohexyl

Me

CH CI

92

98:2

95

C

2

2

V a l u e o f the 99:1, 90% ee (87% ee* R = CI, 76%, dr = >99:1, 74% ee R = F, 67%, dr= >99:1, 67% ee OH

OMe NHBz quant. dr=>99:1 9 1 % ee

O OMe

NHBz 33% dr=>99:1 85% ee

The values in the parenthese are the results of thefirst-generationIr catalyst.

in the presence of sodium acetate (1 equiv) in acetic acid under 4.5 atm of hydrogen at 23°C for 96 h. The yields and enantioselectivities were improved in comparison with our previous data by using thefirst-generationIr catalyst. The introduction of an electron-withdrawing group at the para or meta position on the phenyl ring resulted in a slight decrease of the enantionselectivity, but the antiselectivity was excellent. The cationic Ir complex was also applicable to heteroaromatic substrates containing a sulfiir or oxygen atom. In the case of aliphatic substrates, such as R = w-Pr and cyclohexyl substrates, at the C4 position, no or low desired reaction was observed. Surprisingly, hydrogenation of the hindered substrate with ater/-butylgroup efficiently proceeded to provide tfrt//-P-hydroxy-a-amino acid ester with >99:1 diastereoselectivity in quantitative yield and 91% ee. It is noted that this result is the highest value for the terf-butyl substrate and is superior to that of the Ru-BINAP catalyzed orwrt-selective hydrogenation developed by us.


235

Mechanism of the an/i-Selective Asymmetric Hydrogenation


In order to elucidate origin of the extremely high ^//-selectivity, we briefly carried out the hydrogenation of deuterio substrate as shown in Figure 4. In the case of the hydrogenation via the enol form 13, the deuterium at the a-position would be removed by tautomerization and the hydrogen for hydrogenation would be provided from gaseous hydrogen to afford the deuterium-free product 12b instead of the ketone reduction product 12a after workup.

0

0

o-'*?

D ND .DCI 2

D

9

ketone

H

0 H

C0 Me

O

gj N H

2

11

2

12a

tautomerization OD R

DO M

H

J^.ND DCI 2

OÔMe

2

t

R

Ai>D

enol reduction 2

HO H

0

R ' > T "OMe

OÔMe

Figure 4. Isotope labeling experiment

Initially, we investigated Ru-catalyzed asymmeric hydrogenation using the cyclohexyl substrates as shown in Figure 5. When the deuterio substrate 14 was hydrogenated with Ru-(5)-BINAP at 50°C for 1 h in methylene chloride, the D/H ratio at the a-position of the product was 18:82, supporting that the Rucatalyzed a/7//-selective asymmetric hydrogenation takes place through the reduction of the enol form. In contrast 5>w-selective asymmetric hydrogenation of 16 as a control experiment gave the D/H ratio of 66:34, the paralell result to the Noyori experiment, which supports that the hydrogenation proceeds via the ketone reduction. These experiments clearly indicate that the syn- and antiselective asymmetric hydrogenations proceed via substantially different mechanism. Next, we carried out the Ir-catalyzed asymmetric hydrogenation using the deuterio aromatic substrate 18. The hydrogenation using the Ir-(5)-MeOBIPHEP-BARF catalyst in the presence of sodium acetate in acetic acid under one hydrogen pressure at 23 °C afforded an equal mixture of two corresponding P-hydroxy-a-amino acid esters 19a and 19c in 17% yield. Surprisingly, 19c has a deuterium at the P-position, which seems to be derived from the D/H exchange on the catalyst (27). However, the D/H ratio at the a-position was 100:0. This


236 antf-Selective Hydrogenation O

O

HQ

H (100 atm) Ru(S)-BINAP 2

2

2

14

HQ

H O

OMe

CH CI 50°C. 1 h 46% yield

D ND DCI

H 0

D NH

2

15a

OMe H NH 15b 82%

2

18%

2

syn-Selective Hydrogenation 0

O

H (100 atm) Ru(S)-BINAP 2

16

2

12% yield

O

O

D ND -DCI 2

18

17b

lr-(S)-MeO-BIPHEP-BARF

Ph-SÔMe

H O

CH CI 50°C,24 h

D NDBz


HQ

2

H

2

(

1

a

t

m

CD3COOD

A c 0 N a >

2

3

HO H O

HQ H 0

Ph^VÔMe

)

C

'

3

h

17% conversion yield

D* NH 19a

34%

2

53%

. , . . via keto form

+

HQ D O

PhAê H NH

19b

2

0%

via enol form

+

PhA^M. g NH

2

47% . , . . via keto form 19c

Figure 5. Isotope labeling experiments using the Ru and Ir Catalysts

result clearly supports that the Ir-catalyzed asymmetric hydrogenation of the aamino-p-keto esters takes place through reduction of the ketone double bond to produce the P-hydroxy-a-amino acid esters with ^//-stereochemistry.

Conclusion The above ^//-selective asymmetric hydrogenation of chirally labile aamino-P-ketoesters using the Ru- and Ir-axially chiral phosphine catalysts provides simple and straightforward access to important a«//-P-hydroxy-a-amino acids. Both processes are complementary each other on their scope and limitation. The Ru-catalyzed asymmetric hydrogenation of a-amino-Pketoesters via DKR is the first example of giving a/7//-P-hydroxy-ot-amino acids and the Ir-catalyzed asymmetric hydrogenation is the first example of hydrogenation via dynamic kinetic resolution by the Ir catalyst. Especially, the second-generation Ir catalyst is robust and can be easily used without care, which undergoes mild hydrogenation under low hydrogen pressure. It is noted that this method does not require special instruments and techniques and can be carried out even by use of the hydrogen-balloon technique. The product a/i/Z-P-hydroxy-


237 a-amino acids are useful as building blocks for the synthesis of various pharmaceuticals and natural products.

References


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238 7.

8.

9.


10. 11. 12. 13. 14.

15. 16. 17. 18. 19. 20. 21.

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Î²-Hydroxy-Î±-Amino Acids Using - American Chemical Society

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