Asymmetric Fluoroorganic Chemistry - American Chemical Society

Chapter 7

Stereoselective and Enantioselective Synthesis of New Fluoroalkyl Peptidomimetic Units: Amino Alcohols and Isoserines Ahmed Abouabdellah, Jean-Pierre Bégué, Danièle Bonnet-Delpon, Andrei Kornilov, Isabelle Rodrigues, and Truong Thi Thanh Nga

Downloaded by MONASH UNIV on May 4, 2015 | http://pubs.acs.org Publication Date: December 29, 1999 | doi: 10.1021/bk-2000-0746.ch007

CNRS, URA 1843, Centre d'Etudes Pharmaceutiques, Rue J. B. Clément, 92296 Châtenay-Malabry, France

A concise and stereoselective synthesis of syn and anti fluoroalkyl β-amino alcohols 1 has been performed in three steps from the cheap ethyl trifluoroacetate. Stereoselectivity arises from stereocontrol in the β-amino ketone reduction. The salen -mediated chiral epoxidation of the 1-trifluoromethyl enol ether 4a led to the epoxy ether in a good enantiomeric excess. Reaction with dimethylaluminum amide, followed by a reduction step provided the non-racemic anti amino alcohols 12a and 13a. A stereoselective route to new fluoroalkyl isoserines has been found through the β-lactam chemistry. Cycloaddition of fluoroalkyl imines with benzyloxy ketene provided stereoselectively cis fluoroalkyl azetidinones, and corresponding N-Boc isoserinates after ring opening. From chiral imines, non-racemic syn and anti methyl trifluoromethyl isoserinates could be prepared. These new peptidomimetic units have been used for the design of fluoroalkyl analogues of bioactive compounds.

β-Amino alcohols are important targets which have found use in the treatment of a wide variety of human disorders, as peptidomimetic units and as chirai auxiliaries in organic synthesis. Since the selective introduction of fluorine atoms into a molecule is accompanied by change in physical, chemical and biological properties, fluoroalkyl amino alcohols aroused increasing interest. The fluorinated moiety can be present either α to the hydroxyl group, or α to the amino group. Regioisomers 1 are much more known than regioisomers 2, because of their use as essential key unit for the synthesis of protease inhibitors. On the contrary, the first reports regarding amino alcohols 2 have been published only very recently. " 1

2

3

5

OH

OH 1

84

NH

2

2

© 2000 American Chemical Society

In Asymmetric Fluoroorganic Chemistry; Ramachandran, P.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.

85 α-FIuoroaIkyl β-amino alcohols 1 Fluoroalkyl β-amino alcohols are precursors of the corresponding fluoroalkyl peptidyl ketones which have been shown to be effective inhibitors of proteolytic enzymes, such as serine proteases, (chymotrypsin, elastases, ' trypsin, thrombin, ) aspartyl proteases or cysteine proteases. In some cases fluoroalkyl β-amino alcohols are themselves inhibitors of the same enzymes. This interest in these fluoroalkyl β-amino alcohols 1 aroused efforts for stereoselective and enantioselective synthetic methods. A number of approaches have been reported during these last years, either through the addition of trifluoromethyl equivalent anion to protected aldehyde or through the building block approach. " However the main problem of all these approaches is the diastereoselectivity. We developed a new easy and versatile diastereoseiective synthesis of these amino alcohols. Our synthetic plan was based on the ring opening of trifluoromethyl epoxy ethers 3, which are easily available in two steps from the cheap ethyl trifluoroacetate, and are useful building blocks. The first step, the Wittig olefination of this ester, is possible because of the increased electrophilicity of the ester carbonyl by the fluorinated moiety (Scheme l ) . ' The second step, the epoxidation of the enol ether 4 has been performed with meta-chloroperbenzoic acid. The electron withdrawing character of the C F group stabilizes epoxy ethers towards proteolysis. This stability allows investigations on the oxirane ring opening with various nucleophiles. 7

12

8

1 , 1 4

9 10

11

15

9,14

10ab141619


16

20

11,17

19

21

21,22

3

18,19,22 2 4

Ph

CF -COOEt

*

3

Λ ^ t °' E U

3

"

— ~ ct^rT C K .CI C U, .48 4 8hh ° CH E

2

2

4 (50-80 %)

t

Π

R

°

3 (90 %)

Scheme 1: Preparation of 1-trifluoromethyl epoxy ethers. A n oxirane ring opening of these epoxy ethers by a nitrogen-nucleophile could be a good access to α-amino ketones. Unfortunately, primary amines reacted at high temperature providing JV-monosubstituted ketones which, after enolization by 1-4 prototropy, undergo a rapid degradation leading to an unidentified mixture. Probably, the degradation of the unstable produced JV-monosubstituted amino ketone is faster than the reaction of epoxy ethers with amines. On the contrary, various secondary amines reacted cleanly. The addition occurred, as expected, regioselectively on the less hindered site leading to JV-disubstituted amino ketones which are stable enough to be further reduced. Reduction with sodium borohydride provided selectively the syn amino alcohols. The stereocontrol of the reduction follows the Felkin-Anh transition state model, where the amino group is the bulkier group. As an example, reaction of 3 (R = C H - C H - C H ) with dibenzylamine, followed by reduction, provided exclusively the syn amino alcohol 5, after debenzylation. However, when the R substituent is the bulky isopropyl group, its steric hindrance competes with the steric hindrance of the amino group, leading to only 75 % of the syn isomer (Scheme 2^ 18,19,23 183

183

2

2

6

5


86 CF R #(C H -CH ) NH W NaBH

PP

Bn

3

Μ

%

6

5

2

2

s

Ν

4

Bn NH H , Pd(OH)zCF l 2

2

3 N

R 3 Ex:

Bn Bn

ÔH 5 Overall yield 50%

OH

R = C H - C H - C H Syn/Anti: 100:0 = /so-Propyl 75:25 2

2

6

5

Felkin-Anh model transition state


Scheme 2: Reaction of epoxy ethers 3 with secondary amines and reduction. In order to prepare the anti amino alcohols, it was necessary to reverse the control of the reduction of amino ketones, and so to introduce a strong chelation in the transition state. Aluminum amides, as nitrogen-containing agents for the ring opening, appeared to be good candidates for this purpose: first, as Lewis acids, they can facilitate the reaction under mild conditions; second, they can favour the chelation control in the reduction step. Furthermore the aluminum takes the place of the mobile hydrogen involved in prototropy and renders possible the reaction with a primary amine. However, a competitive reaction of the epoxy ether with Lewis acid could also be expected. Dimethylaluminum amides were prepared in dichloromethane at 0 °C from trimethyl aluminum (Me Al) and a primary amine. Epoxy ethers 3 reacted slowly at room temperature with two equivalents of the dimethyl aluminum benzylamide. After 16 h, reduction step was performed in situ at - 78 °C with N a B H in the presence of ethanol. The use of ethanol as solvent is very important since, in methanol, the reaction failed leading to an inseparable mixture. In ethanol, the JV-monosubstituted amino alcohols anti 6 and syn 7 were obtained in good yields (Scheme 3). No trace of products resulting from ring opening by a methyl group of the aluminum reagent could be detected. Furthermore, nucleophilic substitution occurred at Cp, whatever the R group is, unlike reactions with EtAlCl and M e A l which most often occurred with a Ca-0 bond cleavage. As expected, the diastereoselectivity anti/syn is high, ranging from 97/3 (R = C H ) to 73/27 (R =CH -C H ) (Scheme 3). The anti configuration of the major isomer has been determined by N M R data of the corresponding oxazolidinone (Scheme 4). 26

25

3

4

2

3

26

6

5

2

6

13

15,27

C

F

\

N

£ΤΑ Et-0 Ο 3

,H(i)Me AI-NHCH -C H CH CI 2

2

6

5t

2

e

(ii) NaBH , EtOH, - 78 C *

^ V ^ R OH

4

\ a R=C H 6

75%

5

b R = CH -CH -C H c R = CH -Cyclohexyl d R = n-Hexyl 2

2

H

^ "

2

2

6

5

B n C

*

P

R

'Y^ OH

B n

R

7

anti.syn 97:3

66 % anti.syn 80:20 71 % anti.syn 73:27 62% anti.syn 80:20

Scheme 3: Reaction of epoxy ethers 3 with dimethylaluminum amide and reduction.


87 NH-Bn

C

y

F

R

Scheme 4: Syn configuration: formation of oxazolidinone. The selective formation of anti diastereoisomers confirms that the aluminum atom allows a chelation control in the reduction reaction. The chelated intermediate is quite stable in dichloromethane. Surprisingly, its C N M R spectrum, before addition of NaBH /ethanol, exhibited no signal corresponding to a ketonic group but a quadruplet at 88 ppm ( Jcp 26 Hz), indicating a hemiacetal that was supposed to be the intermediate A (Figure 1). However, the reactive intermediate is likely the complex B , produced immediately on addition of ethanol. Hydride addition takes place on the less hindered face leading to anti amino alcohols 6 (Figure 1). 1 3

4


2

=

Eto R

ο \

R

II

κ ^ C

6

H

κ y^-cn

5

\ Me

/^OEt Me

A

B

Chelation Control

Figure 1 : Stereochemistry of the reduction of amino ketones So, we were able to prepare selectively syn and anti trifluoromethyl amino alcohols. The next step was a search for a chirai approach to these compounds. Two approaches have been investigated to obtain chirai anti amino alcohols: first we performed the reaction of epoxy ethers 3 with the chirai dimethylaluminum amide, prepared from the fZ?,)-phenethylamine and M e A l (Scheme 5). From 3a, the reaction was effective leading, after reduction to the anti diastereoisomers 8a and 9a stereoseiectively (Scheme 5). However, the chirai amine induced no selectivity: anti amino alcohols 8a and 9a were obtained in a 50/50 mixture. Their separation was performed by crystallisation of the mandelate salts. Although this access to homochiral anti amino alcohols is somehow tedious, it is general since oxirane ring opening is efficient whatever the R substituent, and since epoxy ethers, substituted with various fluoroalkyl groups, are available. 3

22

Çe s H

CF

3

\ /

#\ E

t

0

Η

3

6

5

ii) NaBH ,EtOH, -78 °C 4

R

3

i) Me Al-NHCH(CH )C H fft) 2

A 0

r

C F

^ NH^Me 3"Y^R OH

R=C H 70% (50:50) (CH ) -C H 60% (50:50) 6

5

2

2

6

5

8 (R,R*,R*) and 9 (R,S*,S*)

Scheme 5 : Reaction of epoxy ethers with a chirai amide.


88 A second approach, based on the ring opening of homochiral epoxy ethers 10 and 11 has been investigated. Since the preparation of epoxy ethers from enol ethers bearing a chiral auxiliary was disappointing, we turned to the salen-mediated asymmetric epoxidation, largely developed by Jacobsen ' and by Katsuki. Until now chiral epoxidation of CF -substituted double bonds (alkenes, enol ethers) had not been reported. Success of the reaction could, a priori, be limited by the poor The reaction of the enol ether 4a with the (R,R) Mn-salen catalyst, bleach, and 4-phenyl pyridine N-oxide as co-oxidant, under the accurate conditions of pH reported by Jacobsen, has been monitored by G C with an internal standard. The reaction was very slow compared to that of non-fluorinated enol ethers. However epoxy ether 10a was quite stable in the reaction medium in contrast to non-fluorinated epoxy ethers which could not be isolated in this reaction. We noticed that efficiency of the catalyst decreased with the reaction time, and that reaction rate slowed down after some hours. Thus, despite the relative stability of epoxy ether 10a, degradation partially occurred (Figure 2). The best compromise reaction time was 16 h, with about 50-60 % of conversion. The ee (> 80 %) of the resulting epoxy ether 10a could be determined by *H N M R in the presence of the chiral shift reagent Eu(hfc) . The enantiomeric excess has been confirmed by separation of enantiomers on gas chromatography chiral column. The same reaction performed with the (S,S) Mn-salen catalyst led to the epoxy ether 11a. Enol ether 4b (CH -CH -C H ) also reacted under the same conditions, but the degradation of the produced epoxy ether 10b was faster than the disappearance of starting material (Figure 2). 28 29

30

3

29

31


3132

3

2

2

6

5

100 80

f

60 + 40 + 20

-f

0 0

10

20

30

0

10

30

20

Figure 2 : Chiral epoxidation of enol ethers 4a and 4b (% enol ether: % epoxy ether: • ) .

tBu

tBu

Scheme 6 : Chiral epoxidation of enol ether 4a.


89 The preparation of an epoxy ether in high optical purity is not the sole condition for the success of this approach, seeing that α-amino ketones easily undergo enolization and consequently racemization. The stability of complex A of hemiketal form of amino ketone (fig. 1) should prevent from enolization. Reaction of 10a and 11a with the aluminum amide prepared from M e A l and the (i?)-phenethylamine and subsequent reduction step occurred with the same excellent anti/syn diastereoselection as precedently, leading respectively to anti amino alcohols 8a and 9a. These amino alcohols were obtained in an excellent purity from 10a (8a/9a = 93/7) and from 11a (9a/8a = 90/10). The stereoisomeric excess is the same as the enantiomeric excess of starting epoxy ethers. No racemization occurred in the reaction: ring opening does not involve a carbenium ion, and no enolization occurs from intermediate A or B. Both enantiomeric amino alcohols 12a and 13a were obtained by debenzylation with palladium hydroxide; unfortunately, we have not been able to assign the absolute configuration of the asymmetric carbons of 8a and 9a (Scheme 7).


3

Me rp

R}

M

EtO >

O

Ji

CH 6

3 5

y^C H 6

10a Catalyst(R,/?)

0

MU

•

5

Τ

H

0 8

a

C 6 H 5

H

8a

[«1546= + 5.5°

12a[a]

5 4 6 =

+

i3.r β

1

2

Μ ο = + 11-2

a

Me NH

ΒΟ

Ν

V

''c H 6

=

5

11a Catalyst(S,S)

6

5

2

13a M

ÔH

H

9a

9a [ο] * + 2.5

13a

546

e

= - 15.1°

[o] = - 1 2 . 1 ° D

I) Me AI-NHCH(CH )-C H (R), CH CI , rt ίί) NaBH , EtOH, - 78 °C. (iii) Pd(OH) /C; H 2

3

6

5

2

2

4

2

2

Scheme 7 : Reaction of chiral epoxy ethers with (R) phenethyl amine.

β-Amino β-fluoroalkyl alcohols 2 Due to the lack of easy access, properties of amino alcohols 2 as peptidomimetic units have never been explored although specific features brought by the fluorinated moiety can be expected: for example the presence of the fluoroalkyl group can increase the stability towards non specific proteolysis and strongly weakens the basicity of the amine function, the latter factor reducing the energy requirements for desolvation. Our interest in these amino alcohols was targeted on the unknown and important trifluoromethyl isoserine 14 and 15. Norstatine, statine, and their analogues have been largely used as peptidomimetic unit in peptide-based inhibitors of aspartyl proteases such as renin and HIV-1 proteases. Fluorinated analogues of these nonproteogenic α-hydroxy β-amino acids could be of great interest, as isosteres of 33

34

35


90

norstatine. Morever, β-substituted isoserine unit is an essential component of taxol derivatives. OH y ^ R NH


2

OH

QH

^f^COOH NH

2

2

1

Y^COOH NH

4

2

1

5

Our approach was based on the ring opening of fluoroalkyl β-lactams. These βlactams can be obtained either through a [2+2] ketene-imine cycloaddition with a fluoroacetaldimine, or by the cyclocondensation of an alkoxy or silyloxy ester enolate on this same fluoroacetaldimine. The preparation of fluoroalkyl β-lactams 16 (RF = CF , C F H and CF C1) and the preparation of homochiral β-lactams and isoserines 14 and 15, have been have investigated with success by these two approaches. The Staudinger reaction of ketenes to aldimines is well known to provide cis~$lactams. However, it had never been studied in the case of fluoroalkyl imines. The trifluoroacetaldimine 17a has been prepared by the usual route from the corresponding ethyl trifluoromethyl hemiketal and p-methoxyaniline. ' Reaction of the benzyloxyketene, generated from α-benzyloxyacetyl chloride, with imine 17a, performed at 45 °C in CH C1 , provided the expected cis azetidinone 16a in 65 % yield (Scheme 8). In azetidinone 16a, the VH.3,H-4 coupling constant of 5 Hz indicates the cis relative configuration. Coupling constants in parent non-fluorinated β-lactams have been reported to be 2 Hz for the trans isomer and 5-6 Hz for the cis one. Condensation of the aldimine 17b with the same ketene led to the cis β-lactam 16b in 72 % yield. The cis β-lactam 16c was obtained in a satisfatory yield (55 %) from the aldimine 17c (Scheme 8). 3

2

2

36

37 38

2

2

39

OBn Ο II BnO

x

Λ , CI

Et N 3

i

C II

ο

RF 0

RF

w 17

B

N

RF = C F 3

(65 %) CF H (72%) CF CI (55%)

'N

PMP

2

CH CI , 45 °C PMP (PMP = p-methoxyanlline) 16 2

2

2

Scheme 8 : Preparation of the cw-fluoroalkyl azetidinones 16. Classical, but tricky steps of deprotection, protection and azetidinone ring opening have been optimized for the preparation of fluoroalkyl isoserinates, and of properly protected β-lactams 21 for a further coupling (Scheme 9). The best order is first the removal of the 4-methoxyphenyl group with eerie ammonium nitrate (CAN) (65-87 %). The reaction had to be carefully monitored and stopped as soon as azetidinones 16 reacted, because of the fast degradation of the deprotected azetidinones in the presence of excess of C A N . These resulting azetidinones were converted into N-Boc derivatives 18a-c. In the case of 16c, a low temperature of reaction (- 50 °C) for the protection with Boc, was absolutely required to obtain 18c in good yield. Only at this stage, the azide-catalyzed ring opening by methanol was performed providing esters 19a-c. Further debenzylation by catalytic hydrogénation 40


91 followed by the Boc cleavage led to methyl isoserinates 20a-c. In these three series, CF , C F H , CF C1, each step was performed in fairly good yields (Scheme 9). Protected azetidinones 21a-c were prepared by reductive cleavage of benzyl group in azetidinones 18 and protection of the hydroxyl group by reaction with ethyl vinyl ether (EVE) in presence ofp-toluene sulfonic acid (Scheme 9). 3

2

2

OBn

?

R c

0

Β " ™ A 19

H Λ

m

""Toe' B

0

OH

C

0

20

MeOH, NaN T 3


RP

OBn RF f CAN )

]

OBn * OBn RF OH RF f (Boc) 0 ]—f H /Pd-C^ V _ / EVE 2

2

Ο ο Boc B o c ' 18 a RF = CF3, b RF = CF2H, c RF = CF2CI

PMP „ Ο 16

Ο

OEE ^-S

Boc

° 21

Scheme 9 : Preparation of methyl isoserines 20 and protected azetidinones 21. Azetidinones 18 can been used to prepare tri- and tetrapeptide isosteres 22. As example, cleavage of the azetidinone ring has been performed with esters of simple amino acids such as tryptophan, phenylalanine or esters of dipeptides. Interestingly, these very simple compounds exhibit an inhibition of HIV-1 protease with an I C of about micromolar range. So without any recognising element on the N-terminal site and no accurate design on the C-terminal part the activity is significant. 50

W

AA-OMe V y NaN , DMF NJH Ο 3

C

H , P d / C > ,|

F

2

V V IJ

H

AA-OMe IC (μΜ; 50 Leu-OMe Val-Phe-OMe 50 Phe-Phe-OMe 1 3 Tryp-OMe 7 Tyr-OMe Phe-OMe 9 50

Boc'

Ο

Boc

18 (80%)

éoc 22

(70%)

(-90%)

HIV-1 Protease Inhibition

Scheme 10 : Trifluoromethyl isoserine derivatives, HIV-1 protease inhibition. Azetidinones 21 are suitable synthons for coupling with alcohols, such as baccatin III, in view of the preparation of fluorinated docetaxel analogues. β-Lactam 21a has been coupled with the properly protected baccatin III, in the group of Prof. Ojima providing an analogue of docetaxel, where the 3'-phenyl group has been replaced by a C F group. The compound presents a higher cytotoxicity in vitro towards human tumoral cell lines than docetaxel. ' As already observed in the baccatin series, the reaction occurred with a good kinetic resolution. Using 2 equivalents of the racemic βlactam 21a, only the f3#,4$-isomer reacted, leading to the C F analogue of docetaxel, 3

3


92 with the natural configuration of the isoserine chain. Coupling with azetidinones 21b (CF H) and 21c (CF C1) are under investigation in Stony Brook. 2

2

In order to prepare chiral 4-CF azetidinones, we first studied the cyclocondensation of chiral ester enolates with trifluoroacetaldimine 17a, since the lithium ester enolate-imine cyclocondensation has been demonstrated to occur in high yields and with high enantiomeric purity. However, the ester cyclocondensation of enolate of benzyloxy esters with the trifluoroacetaldimine 17a failed. We finally succeeded in the preparation of the cis β-lactam 23 by using the more reactive triisopropylsilyloxy esters 24, as reported by Ojima (Scheme 11). β-Lactams obtained in this reaction have in most cases the cis configuration. Results were disappointing when reaction was performed with chiral esters 24b,c : the azetidinone 23 was not obtained from 24b, and yield from 24c was very low. 3

36b4 3 , 4 6

47

46


44,45

OSi/Pr Ο π , P R

3

S ,

°—C^

i) LDA J ^ Q R

jj)

1

7

Χ 1 (

a

N

PMP

24

/ Γ

,_ , (68%) 0

a R = Mesityl

_^ 23

3

Ο

b R = ^Menthyl c R = (tjtrans 2-phenylcyclohexyl

/

(0%) (20%)

Scheme 11 : Cyclocondensation route to azetidinone 23. Although the asymmetric Staudinger reaction, controlled by a chiral iV-substituent on imines, is seldom diastereoselective, because of the relatively long distance between chiral and reaction centers, we turned all the same towards the [2+2] ketene-imine cycloaddition with the chiral trifluoroacetaldimine 25, prepared from trifluoroacetaldehyde hemiketal and the (5)-phenethylamine. The reaction of benzyloxyketene with imine 25 was efficient leading to the mixture of azetidinones 26 and 27 in 90 % yield. High cis/trans stereoselectivity was observed, with only 3-5 % of trans azetidinones formed. As expected, the chirality transfer was low with a diastereoisomeric excess of only 10 %. Fortunately, it was possible to easily separate the two diastereoisomers by crystallization in ethanol of the crude mixture. Stereoisomer 26 crystallized in ethanol and was obtained in an excellent diasteroisomeric purity (> 99 %). Stereoisomer 27 could be isolated in 95 % diastereoisomeric purity after S i 0 chromatography and crystallization (Scheme 12). 47

2

CF >

y

3

Crystallization v-»f yauaiiwccmuii

Qf^

|f

OBn Ο Ε*3Ν BnO^(X

C j

if C II ο

;

3

CF J

^OBn

3

ιj

C H v^N—W 6

5

V * U CH % ) CH J ^ ^ s ) Ο ^ Μ CH CI 40'C CH CF3I, (90%)de10% I I Chromatography y ïnêrï CH crystallization o 3

2 5

9

B

7

0

n

9

Q

26

5

e

0

ιr

0 =

+

1

3

2

2>

3

6

&

3

( 9 5

/ o )

( c t ] D =

Scheme 12 : Non racemic trifluoromethyl azetidinones 26 and 27.


,.OBn Ο 27 . o 3 J

93 Azetidinones 26 and 27 underwent the acidic methanolysis leading to methyl isoserinates 28 and 29. The X-ray diffraction diagram of crystals of 28 indicated unambiguously the configuration (2R,3R) for this isomer. Catalytic debenzylation of isoserinates 28 and 29 in the presence of (Boc) 0 provided the two pure enantiomers of methyl syn N-Boc isoserinates 30 and 31 (Scheme 13). 47

2

CF

Boc

OBn

3

NH

CF

„COOMe

CF

Asymmetric Fluoroorganic Chemistry - American Chemical Society

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