Stereoselective synthesis of vinylogous peptides

TETRAHEDRON

Pergamon

Tetrahedron 57 ;2001) 4903±4923

Stereoselective synthesis of vinylogous peptides

p

Claude Grison, Stephane Geneve, Etienne Halbin and Philippe Coutrot

Â

Á

Â Â Â Â

Institut Nanceien de Chimie Moleculaire FR CNRS 1742, Laboratoire de Chimie Organique II, UMR 7565, Universite Henri Poincare,

Â

Nancy-I, BP 239, 54506 Vandoeuvre-les-Nancy Cedex, France

Received 23 January 2001; revised 3 April 2001; accepted 18 April 2001

AbstractÐA trans or cis ethenyl group has been inserted between the a-carbon and the carboxyl group of a-aminoacids by Horner

stereoselective ole®nation of a-aminoaldehydes. Numerous pure cis and trans vinylogous a-aminoacids have been obtained thus and

coupled with aminopartners by classical methods. The versatility of the method was illustrated by the preparation of a [trans vinylogous-

1. Introduction

the cis CHvCMe group induces the formation of a very

stable intramolecular hydrogen bond closing a nine-

membered pseudocycle that involved an excellent mimic

of the natural b-turn.⁴As a consequence, these vinylogous

aminoacids represent an attractive approach for the

construction of new peptide materials.

During the last few decades, there has been an increasing

effort to rationally design new neuroactive peptides with

controlled conformations and de®ned biological functions.

The principal reason is that the therapeutic applications of

endogenous peptides have been limited severely. They are

subject to poor bioavailibility, rapid proteolytic degra-

dation, and interact competitively with different receptors.

The example of enkephalins is now well known.¹

In this paper, we present a more detailed study of the stereo-

selective syntheses of trans and cis vinylogous dipeptides 1

;a trans vinylgous dipeptide is a dipeptide where R²and H

present a trans relationship on the double bond, a cis vinyl-

ogous dipeptide is a dipeptide where R²and H present a cis

relationship):

Numerous investigations are directed towards the synthesis

of peptide analogs that are protected against proteolytic

attack and speci®c for analgesic receptor. Introduction of

conformational restraint has become a standard strategy

for increasing the receptor selectivity and the duration

action of peptide ligands. A major approach in the develop-

ment of conformationaly restricted aminoacids and peptides

is the synthesis of head-to-fail cyclic peptides.^1g,2Vinyl-

ogous amino acids have hitherto been little explored. A

sole example of trans ethylenic bond has been proposed

by Schreiber as a rigid extension of a peptide residue by

inclusion between the a-carbon and the carbonyl, resulting

in vinylogous aminoacid.³

The strategy is based on stereoselective Horner reactions

applied to a-aminoaldehydes with the stereochemical

control of the ole®nation determined by the choice of the

Horner reagent. Previous results with the lithiated anions

derived from N-substituted ;diethyl-b-ketophosphono)-a-

aminoacids or from 2-diethylphosphono alcanoic acids

and aliphatic, aromatic and glucidic aldehydes have

shown a preference for the formation of the trans ole®ns.⁵

Analogously the direct generation of unsaturated peptides

by reaction between the lithiated anions derived from

N-;diethyl-b-ketophosphono)-a-aminoacids and amino-

aldehydes was considered, but failed, leading to the decom-

position of the aminoaldehydes.

We have recently shown in a short communication that

the insertion of an ethenyl CHvCMe group between the

a-carbon and the carboxyl group of Proline can be used to

control the structure of a peptide.⁴The trans CHvCMe

group leads to an open conformer in which the amide groups

are exposed to solvation in solution or engaged in inter-

molecular hydrogen bonds in the solid state. Conversely,

On the basis of these observations and other previous

works,⁶a stereoselective synthesis of trans vinylogous

aminoacids 4 was then realized using the convenient

reaction between the lithiated dianions 3 derived from

Keywords: vinylogous peptides; Horner stereoselective ole®nation;

neuroactive peptides.

Corresponding author. Tel.: 133-3-8391-2033; fax: 133-3-8391-2393;

e-mail: claude.grison@lco2.uhp-nancy.fr

p

PII: S0040-4020;01)00433-1

4904

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

Scheme 1.

2-diethylphosphono alcanoic acids and a-aminoaldehydes 2

that gave major trans stereomer ;Scheme 1).

the mixture was allowed to warm to room temperature.

After 3 h stirring at 258C, the mixture was then hydrolysed.

Subsequent acidi®cation of the aqueous solution at pH4

with 6 M HCl, followed by extraction with diethylether led

to the expected vinylogous aminoacids 4.

The preparation of cis vinylogous aminoacids 4 needed

another stereoselective synthesis, based on the use of two

systems, either KH/ethyl 2-bis;tri¯uoroethyl)phosphono

alcanoate or BuLi/ethyl 2-diethylphosphono alcanoate.

With a-aminoaldehydes 2 these reagents led to major or

exclusive cis vinylogous amino esters 5. Basic hydrolysis

of these a,b-ethylenic esters 5 led to cis vinylogous amino

acids 4 ;Scheme 1).

The crude products 4 may be used without puri®cation.

Nevertheless a chromatographic puri®cation on a silica gel

column was possible in the cases where R²H, alkyl or aryl.

When R²was a halogen or an ethoxy, the acids 4 presented a

low stability and degraded on the chromatographic column.

The target 1 trans or 1 cis vinylogous peptides were respec-

tively obtained by a classical coupling between the so

obtained trans or cis vinylogous aminoacids 4 and an

aminoacid or a peptide fragment.

First, the Horner reaction was tested with N-Z-protected

alaninal. The expected ole®nation product 4a was obtained

in a low yield with R²CH₃;Table 1).

The replacement of the Z-moiety by Boc led to increasing

yields ;compare 4d and 4a, 4h and 4b). The strategy

allowed the obtention of the double bond with a wide

range of carbon and heteroatom-containing substituents

;R²CH₃, C₅H₁₁, Ph, F, Cl, OC₂H₅). The ethoxy group

was of particular interest for further possible synthetic trans-

formation into a-keto acid. Equally different structures of

aminoaldehydes 4, alaninal ;4a±4i), valinal ;4j), glycinal

;4k, 4l), phenylanalinal ;4m, 4n), prolinal ;4o±4s),

b-alaninal ;4t), have been easily converted into alkenoic

acids. The bulkiness of the substituents decreased the reac-

tivity either of the aminoaldehyde ;phenylanalinal ;4m, 4n))

or the dianion ;R²C₅H₁₁;4e), Ph ;4f)).

2. Results and discussion

2.1. Preparation of the trans vinylogous aminoacids 4

The dilithiated dianions 3 were prepared from 2-diethyl-

phosphono alcanoic acids by treatment with n-butyllithium

in a mixture of hexane±tetrahydrofuran at 2608C in the

cases where R²H, CH₃, C₅H₁₁, C₆H₅or at 2788C for

R²F, Cl. For R²OC₂H₅, the acid was converted into the

corresponding dianion with LDA at 2788C in the same

solvent.

In the cases where R²CH₃;4a, 4d, 4j, 4l, 4n, 4p, 4t), C₅H₁₁

After addition of the aminoaldehyde 2 at the metallation

temperature and stirring for 60 min at this temperature,

;4e), Ph ;4f, 4o) the preferential con®guration of the formed

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

4905

acetic acid in the Horner reaction.⁶The reaction of this

dianion onto an aldehyde is under thermodynamic control.

The more stable intermediate adduct where the carboxylic

group moved away from the amino group, was exclusively

formed and led to the trans ole®n. With a bulky R²;CH₃,

C₅H₁₁, Ph), the difference of stability between the two

intermediates decreased as well as the stereoselectivity

;Scheme 2).

Table 1. Preparation of the vinylogous aminoacids 4 by Horner reaction

between N-protected aminoaldehydes 2 and dianions 3

4

n

R

R¹

R²

Yield ;%)

trans/cis^a

4a

4b

4c

4d

4e

4f

4g

4h

4i

4j

4k

4l

4m

4n

4o

4p

4q

4r

4s

Z

1

H

CH

3

CH

3

CH₃

Cl

H

CH₃

C₅H₁₁

C₆H₅

OC₂H₅

Cl

25

80

71

79

65:35

40:60

.98:2^b

60:40

95:5

The electron withdrawing groups ;R²F ;4i, 4s), Cl ;4h,

4r), OC₂H₅;4g, 4q)) promoted a faster addition of the

dianion onto the carbonyl compound, involving a kinetic

control of the reaction. As a result, the preferred adduct

was this where the carboxylic acid eclipsed the amino

group. In this case, the decomposition of the kinetic inter-

mediate gave a double bond containing a cis arrangement of

the carboxylic acid and the amino group ;Scheme 2).

Boc

1H

1±;CH

CH

i-C

H

3

12

38.5

7145:55

92.5

82

60:40

30:70

35:65

82:18

.98:2^b

75:25

.98:2^b

75:25

82:18

80:20

30:70

35:65

30:70

98:2

F

CH₃

3

₃H₇

79

H

CH

77

H

CH

77

52

35.5

72

80

45

68

62

3

A further column chromatographic puri®cation on silica gel

could give pure trans isomers of the acids 4 if R²is an

electron donating group or an hydrogen. In the case of 4l,

the trans and cis stereomers could be easily separated by

selective precipitation in ether. Only the acid 4l with a trans

con®guration precipitated in ether. The conversion of the

acids 4 into corresponding N-isopropyl amides 4⁰was an

attractive alternative when the acids 4 are unstable ;R²F,

Cl, OEt), because the trans and cis amides can be easily

separated by chromatography without decomposition. The

purity of the ethylenic stereomers was evaluated by ¹H- and

¹³C NMR analysis of the acids.

₂Ph

₂)₃±

H

CH₃

C₆H₅

CH₃

OC₂H₅

Cl

F

CH₃

4t

2

H

70

a

1

trans/cis ratio was determinated by H NMR of the crude product.

b

1

Only one isomer was observed by H- and ¹³C NMR.

double bond is that where the carboxylic acid and the amino

group are trans.

2.2. Preparation of the cis vinylogous aminoacids 4

When R²H ;4c, 4k, 4m), the reaction was completely

stereoselective and gave only the trans isomer. This result

is typical of the dianion derived of the diethylphosphono-

It is known that the electronic effects in¯uence the stereo-

selectivity of the Horner reaction. The formation of cis

Scheme 2.

4906

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

Table 2. Results of the Horner reaction with 6a or 6b and a range of aminoaldehydes 2

5

n

R

R¹

CH

R²

6

5 ;Yield %)

trans/cis^a

5c

5d

5h

5i

5j

5l

5p

5r

5s

5w

5t

5u

5v

1

H

6a

6b

6a

6b

6a

6b

6a

6b

6a

6b

72

79

82

88

95

87

80

85

63

79

7170:30

95

92

25:75

7:93

10:90

2:98

3

CH

CH₃

Cl

F

CH₃

3

CH

3

,2:98^b

10:90

80:20

35:65

14:86

10:90

3

i-C₃H₇

H

CH

3

1

3

1±;CH

2

₂)₃±

CH₃

Cl

F

H

CH₃

Cl

₂)₃±

33:67

,2:98^b

16:84

77

H

9140:60

60

90

H

40:60

16:84

F

97

,2:98^b

a

trans/cis ratio determinated by ¹H NMR of the crude product.

b

1

Only one isomer observed by H and ¹³C NMR.

ole®ns can also be favoured when the phosphorus atom

electrophilicity is increased. Thus, an ef®cient method has

been reported to produce cis-unsaturated esters using bis;tri-

¯uoroethyl)phosphonoesters.⁷Some particular examples of

cis-vinylogous aminoesters have been prepared with bis;tri-

¯uoroethyl)phosphonoesters,⁸but the method lacked gener-

ality and the transformation of cis-vinylogous aminoesters

into vinylogous peptides was not described.⁸The optimal

cis stereoselection could be obtained with the use of a base

having minimally complexing counterions to decrease the

factor reversibility and to facilitate the elimination. KH was

therefore a good candidate for the synthesis of cis-unsatu-

rated esters. In light of these results, we investigated the

formation of cis vinylogous aminoacids 4 from KH/bis;tri-

¯uoroethyl) phosphonoesters and aminoaldehydes 2 in the

cases where the previous procedure could not allowed to

obtain suf®cient amounts of cis acids 4 ;R²H, Me).

An excess of phosphonate 6 was required to obtain an opti-

mum cis/trans product ratio. In the case of 6a, the following

sequence of operations was realized: addition of the phos-

phonate at 08C onto KH/THF; stirring for 15 min at 08C,

addition of the aminoaldehyde at 2788C onto the potassium

anion; stirring for 3 h at 2788C; addition of a solution of 2%

hydrochloric acid at 2788C; extractive work-up; column

chromatography. With the reagents 6b, the procedure was

similar except for the metallation that was effected at 2788C

with BuLi 1.6 M in hexane/THF ;Table 2).

As it can be observed from the results of Table 2, the Horner

reaction afforded in all cases the vinylogous amino esters 5

in good yields. With reagent 6a, the formation of esters 5

proceeded with a good cis-stereoselectivity, which was not

affected by the size of R¹and the nature of R².

On the other hand, it appeared that the behaviour of 6b was

more speci®c, the stereoselectivity depended much on the

nature of the aminoaldehyde except when R²F where pure

cis esters could be obtained in very good yields whatever is

the nature of the aminoaldehyde ;5i, 5s, 5v). When

R²CH₃, the size of R¹had a marked effect on the stereo-

selectivity: with a feebly hindered R¹;Me, H), a high cis

stereoselectivity was observed ;5d, 5l, 5t), while a bulky R¹

involved the trans preference ;5j, 5p). The same trend

was veri®ed in the case R²Cl where the best cis stereo-

selectivity was established with the l-alanine moiety

;R¹Me, 5h) or with the b-alanine moiety ;5u).

In a second time, we decided to reinvestigate with the same

purpose the selectivity of the Horner reaction using the

lithium anions derived of 6b because it has been previously

observed in particular cases by us⁶as others⁹that lithium

ethyl 2-diethylphosphono propanoate ;6b, R²Me) could

lead to cis unsaturated esters whereas the general behaviour

of this last anion was known to give major trans unsaturated

compounds. Analogously, we have noticed during our

precedent investigations using dianions 3 the great capacity

of the lithiated anions derived from ethyl diethylphosphono

halogenoacetic acids ;6b, R²Cl, F) to preferably lead to cis

double bond ;see Table 1).

The stereochemical course of these reactions could be

explained on the basis of the previously proposed mecha-

nism in the case of the dianions 3 ;Scheme 2). In the case

of 6a, the phosphorus electrophilicity combined with the

The reactions were run in THF using 1equiv. of amino-

aldehyde 2, 1.2 equiv. of Horner reagent and 1.2 equiv. of

base ;KH when R⁵CF₃CH₂or Buli when R⁵CH₃CH₂).

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

Table 3. Hydrolysis of cis-vinylogous ester 5 into cis-vinylogous acids 4

4907

4

n

R

R¹

R²

Yield ;%)

4d

4j

4l

4p

4w

4t

1

H

CH

3

i-C₃H₇

H

₂)₃±

H

CH₃

CH

3

CH₃

H

CH₃

88

89

90

80

96

1±;CH

2

H

potassium ion effect and the low temperature promoted the

decomposition of the kinetic adduct to give the cis alkene.

With the lithiated ethyl 2-diethylphosphono propanoate

carbanion 6b, the decrease of the phosphorus electro-

philicity and the use of the cation Li¹decelerated the elimi-

nation of ;EtO)₂P;O)OLi. Combined with the increase of the

bulkiness of R¹these different factors retarded the decom-

position of the kinetic intermediate and permitted the

equilibration with the thermodynamic adduct. The direct

consequence was the reversibility of this ®rst step that

involved the decrease of the cis stereoselectivity ;5j, 5p).

However, with small R¹, the decomposition of the kinetic

adduct remained faster than the interconversion with the

thermodynamic adduct and the cis stereoselectivity was

conserved, as exempli®ed with 5d, 5l, 5t. In these cases, it

was noteworthy that the observed cis stereoselectivity was

either practically identical to the one obtained with 6a ;5d,

5t) or even better ;5l). These results were remarkable

considering the dif®culty to obtain the Horner reagent 6a

compared to the accessibility of 6b.

the pure cis isomers could be easily obtained after a chro-

matographic separation in all the cases where the trans/cis

ratio was ,40:60.

The basic hydrolysis of pure cis-vinylogous N-protected

amino esters 5 was effected with 1N solution of NaOH

;2.5 equiv.) in H₂O/EtOH ;1:2) for 2 h at 208C except for

the ester 5t that exhibited a particular resistance to hydro-

lysis. It was observed that this compound was completely

hydrolysed only after 48 h at room temperature. Subsequent

acidi®cation at pH2 with 1N HCl aqueous solution,

followed by extraction with AcOEt led to the pure cis-vinyl-

ogous N-protected amino acids 4 ;Table 3).

2.3. Coupling of N-protected vinylogous aminoacids 4

with aminoacid derivatives

Pure cis or pure trans or mixture of cis/trans vinylogous

aminoacids 4 were coupled with different aminoacid deri-

vatives in the presence of BOP as coupling reagent and led

to the desired peptides 1 in good yields and with a total

stereospeci®city ;Table 4). The reaction occurred at room

From a practical point of view, it was important to note that

Table 4. Results of the coupling between vinylogous aminoacids 4 and aminoacid derivatives

1

n

R

R¹

R²

R³

R⁴

OCH₃

Yield ;%)

trans/cis^a

1ca

1cb

1ia

1

1H

H

CH

H

F

CH;CH₃)₂

H

76

92

93

80

55

70

78

82

84

76

82

80

87

85

70

.98:2^b

35:65

45:55

60:40

3

H

CH₃

1ga

1da

1db

1ka

1ma

1pa

1pb

1pc

1wd

OC₂H₅

CH₃

CH₂COOMe

60:40

H

₂Ph CH

H

OCH

.98:2^b

,2:98

.98:2^b

,2:98

.98:2^b

,2:98

.98:2^b

25:75

3

1

H

CH₃

OCH₃

1±;CH

₂)₃±

CH₃

H

NHCH;CH₃)₂

O±CH₃

OCH₃

CH₃

CH₂COOMe

CH₃

OCH₃

NHCH₃

a

trans/cis ratio determinated by ¹H NMR on the crude product 1 and identical to this of the starting reagent 4.

b

Only one isomer observed by ¹H- and ¹³C NMR.

4908

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

Scheme 3.

temperature with one equivalent of triethylamine in

dichloromethane and was complete after stirring for two

hours. The formed HMPT was easily removed by chromato-

graphy on silica gel. When a mixture of geometrical isomers

of 4 was used as starting compound the cis/trans ratio was

conserved into the product 1. A further column chromato-

graphic puri®cation using graduated elution gave pure cis or

pure trans isomer of 1 easily. The separation of 1 cis and 1

trans was often easier than acid 4 or ester 5. As a conse-

quence, it could be more convenient to use a mixture of cis/

trans acid 4 as starting reagent than to proceed to a puri®-

cation into pure 4 cis or pure 4 trans after the initial Horner

reaction that produced 4. A large number of acid 4 was

tested ;R²H, CH₃, F, Cl, EtO) with different aminoacids

derivatives ;val-OMe, gly-OMe, asp;OMe)-OMe, ala-

NHiPr, ala-NHMe, ala-OMe). All the yields were high

and the reaction was relatively insensitive to changes in

amino partner or R²substituent.

the so-obtained pure diastereoisomer vinylogous aminoacid

trans 1ca ll compared to the racemic trans 1ca ll, ld

unambiguously demonstrated the con®gurational integrity of

all chiral carbons in the successive reactions used to obtain 1.

2.4. Synthesis of a Leu-enkephalin analogue including

the vinylogous glycine residue ±NH±CH₂±CHvCH±

CO± at position 3

Encouraged by the precedent results, the total synthesis of a

modi®ed Leu-enkephalin was carried out with the aim to

both reduce the ¯exibility of the peptide and increase its

resistance towards endopeptidase.

According to the site of enzymatic degradation of Leu-

enkephalin by the corresponding enkephalinase,¹¹the

replacement of Gly³by the vinylogous glycine residue

±NH±CH₂±CHvCH±CO± should increase the stability

of the peptide towards this metallopeptidase strongly. The

synthetic scheme is presented in Scheme 3.

Although in all cases only two stereomers were observed

and assigned to cis and trans double bond isomers, the

con®gurational stability of the all chiral centres was also

studied. A ®rst source of possible epimerisation was the

Horner reaction, although few examples of the literature

indicate that Boc-protected amino aldehydes may partially

racemise under the C±C bond forming reaction conditions

in which they are employed.¹⁰The other source of possible

epimerisation was the coupling reaction. To study these

eventualities, parallel couplings of pure trans vinylogous

N-Boc-l-alanine-OH with both l-valine-OMe and dl-

The strategy involved the initial preparation of the vinyl-

ogous trans-N-Boc-glycine 4k according to the Table 1. The

synthesis of this aminoacid required careful attention to the

selection of protecting group so that ®nal deprotection

would not cause unwanted chemical transformations of

the double bond. For example, the N-Z-moiety could not

be selectively deprotected with HBr/AcOH or with catalytic

hydrogenation because the addition reactions on the double

bond are faster than the deprotection. The N-Boc moiety

was once more the best protection.

1

valine-OMe were realised. H- and ¹³C NMR analyses of

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

4909

The best activation method was attained with BOP as

coupling reagent. The tripeptide 9 was obtained in excellent

yield ;98%). Removal of the N-terminal t-butoxycarbonyl

protecting group into the unsaturated peptide with anhy-

drous HCl in ether ;better than tri¯uoroacetic acid) yielded

the corresponding chlorhydrate salt 10 ;92%).

backed silica gel-coated plates ;Kieselgel 60-F₂₅₄, Merck

or Alugram^wSil G/UV₂₅₄, Macherey-Nagel), spots were

identi®ed under an UV lamp ;l254 nm) or developed

using iodine. Column chromatographies were performed

on silicagel 60 or 70±230 mesh with the indicated eluent,

dried and distilled shortly before use. IR spectra of solids

were recorded as KBr pellets, and IR spectra of liquids were

recorded as thin ®lms on KBr plates with a Nicolet 210 FT-

IR spectrophotometer. All NMR experiments were recorded

on a Brucker AC spectrometer [250 MHz ;¹H), 235.36 MHz

;¹⁹F) and 62.896 MHz ;¹³C)]. Chemical shifts were given as

d ppm values and J values were given in Hertz ;Hz). Isomer

Coupling of the fragment Boc-Tyr-Gly-OH 12 with the

unsaturated tripeptide 10 was achieved in the presence of

BOP reagent in DMF. No special problem was encountered

during the coupling and the puri®cation of the pentapeptide

13. The presence of the double bond facilitated the solu-

bility of the peptide in usual organic solvent greatly. No side

chain protecting group was necessary. The unsaturated

pentapeptide 13 was easily puri®ed on a silica gel chromato-

graphic column with ethylacetate/acetone: 4:1as solvent.

1

ratios were determined by H NMR on the crude products.

Optical rotations were measured with a Bellingham and

Stanley ADP 220 automatic polarimeter, in chloroform or

methanol solution with 1or 2 dm cells at the designate

concentration in g/100 mL at room temperature. Mass

spectra ;EI, 70 eV and CI) were obtained on a Fison Trio

1000 spectrometer and Mass Spectra ;FAB) were measured

on an Autospec Fited Cesium Gun ;Micromass, Man-

chester). Solvents were puri®ed by standard procedures

just before use.

The hydrolysis of the methyl ester group was achieved with

a 1N solution of NaOH in methanol with stirring for 2 h at

208C. After concentration the residue was acidi®ed at pH 4

with 1N HCl aqueous solution and extracted with ethyl

acetate leading to 14.

Final removal of the N-Boc group with anhydrous HCl in

THF gave the desired fully deprotected Leu-enkephalin

analogue 15 which was fully characterised ;¹H NMR, ¹³C

NMR, FAB MS). This synthesis con®rmed the excellent

feasibility of the introduction of a vinylogous aminoacid

into a peptide chain.

4.2. Typical procedure for the preparation of the

aminoaldehyde 2

Boc-l-Alaninal, Boc-l-valinal and Boc-l-phenylalaninal

were easily prepared from Boc-amino acids according to

Fehrentz and Castro.¹²The Boc-l-prolinal was synthesised

similarly.¹³Some modi®cations were employed in order to

obtain the Boc-glycinal.

3. Conclusions

4.2.1. N-2t-Butoxycarbonyl)-glycine N-methoxy-N-methyl-

amide. Yield: 85%, white solid; mp 1028C; R_f0.55 ;ethyl

acetate/hexane: 1:1); IR ;KBr ®lm)/cm²¹: n_max3290, 1715

New cis- and trans-vinylogous aminoacids including a bi-

or a tri-substituted double bond were prepared using a

judicious choice of Horner reactions between suitable phos-

phonate anions and N-protected aminoaldehydes. Mainly

trans vinylogous aminoacids were easily obtained with the

lithium dianions derived from 2-diethylphosphono alcanoic

acids whereas cis were mainly obtained from Still reagent

ethyl 2-bis;tri¯uoroethyl)phosphono alcanoate. For certain

cis vinylogous acids a complete reinvestigation of the

behaviour of lithium ethyl 2-diethylphosphono alcanoate

led to a very interesting alternative to the Still reagent, not

easily available. These vinylogous aminoacids could be

easily introduced into a peptide as illustrated with a total

synthesis of the Leu-enkephalin analogue that included the

trans-vinylogous glycine moiety in replacement of the 3

glycine residue. As a consequence a lot of combinations

using cis and trans vinylogous aminoacids and aminoacids

was now possible leading to a various new library of peptide

analogues. Works concerning this last point and appli-

cations in the solid phase peptide synthesis are under

investigation.

1

and 1660; H NMR ;250 MHz, CDCl₃): d_H1.40 [s, 9H,

C;CH₃)₃], 3.15 ;s, 3H, N±CH₃), 3.67 ;s, 3H, O±CH₃), 3.93±

4.06 ;m, 2H, NH±CH₂), 5.27 ;m, 1H, NH±CH₂); ¹³C NMR

;62.696 MHz, CDCl₃): d_C28.2 [3C, C;CH₃)₃], 32.3 ;N±

CH₃), 41.6 ;NH±CH₂), 61.3 ;O±CH₃), 79.5 [C;CH₃)₃],

155.8 ;CO Boc), 170.1 ;CO).

4.2.2. N-2t-Butoxycarbonyl)-glycinal. Lithium aluminium

hydride ;8.6 mL, 1M in ether, 5 equiv.) was added to a

stirred solution of a N-;t-butoxycarbonyl)-glycine N-meth-

oxy-N-methylamide ;6.9 mmol) in THF ;80 mL). Reduction

was complete within 15±20 min. The mixture was hydro-

lysed with a solution of potassium hydrogen sulfate ;1.41 g,

10.35 mmol) in water ;10 mL). Then the mixture was

evaporated and extracted with dichloromethane ;3£

60 mL). The organic phases were combined, washed

successively with 3N HCl ;3£20 mL), with a saturated

aqueous NaCl solution ;1£20 mL), with an aqueous

NaHCO₃solution ;3£20 mL) and with a saturated NaCl

solution ;3£20 mL), and ®nally dried with magnesium sul-

fate. The solvent was evaporated to leave the crude glycinal

which was further used without puri®cation. Yield: 85% as a

colourless oil; R_f0.37 ;ethyl acetate/hexane: 1:1); IR ;KBr

®lm)/cm²¹: n_max3370 and 1695; ¹H NMR ;250 MHz,

CDCl₃): d_H1.42 [s, 9H, C;CH₃)₃], 3.95±4.11 ;m, 2H,

NH±CH₂), 5.37 ;m, 1H, NH±CH₂), 9.62 ;s, 1H, ±CHO);

¹³C NMR ;62.696 MHz, CDCl₃): d_C28.1[3C, C; CH₃)₃],

4. Experimental

4.1. General

Melting Points were determined in a capillary tube in an

Electrothermal apparatus and were uncorrected. Thin layer

chromatography ;TLC) were carried out on aluminium-

4910

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

51.2 ;NH±CH₂), 79.9 [C;CH₃)₃], 155.7 ;CO Boc), 197.5

;CHO).

;CHvCCl±CO), 127.7, 128.1 ;2C), 128.6 ;2C), 135.8

;Ph), 144.2 ;CHvCCl±CO), 156.1 ;CO Boc), 171.2

1

;COOH); cis isomer: H NMR ;250 MHz, CDCl₃): d_H

3

1.35 ;d, J_H±H7.5 Hz, 3H, CH±CH₃), 4.50±5.10 ;m,

4.3. Typical procedure for the preparation of the trans

vinylogous aminoacids 4

2£1H, CH±CH₃and NH±CH), 5.10 ;s, 2H, Ph±CH₂),

3

7.05 ;d, J_H±H11.5 Hz, 1H, CHvCCl±CO), 7.35 ;s, 5H,

Ph), 11.5 ;br s, 1H, ±OH); ¹³C NMR ;62.896 MHz, CDCl₃):

d_C17.8 ;CH±CH₃), 46.5 ;CH±CH₃), 67.9 ;Ph-CH₂), 123.6

;CHvC±Cl±CO), 126.6, 127.7 ;2C), 128.1, 128.6, 135.8

;Ph), 145.7 ;CHvCCl±CO), 155.5 ;CO Boc), 171.8

;COOH).

To a solution of n-butyllithium ;9.22 mL, 14 mmol, 1.56 M

in hexane) in 20 mL THF, was added dropwise at 2608C in

the cases where R²H, CH₃, C₅H₁₁, C₆H₅or at 2788C for

R²F, Cl a solution of 2-diethylphosphono-alcanoic acid

2

;6.8 mmol, 1equiv.) in THF ;10 mL). For R OC₂H₅, the

acid was converted into the corresponding dianion 3 with

LDA at 2788C in the same solvent. In all cases, after 30 min

stirring at the metallation temperature, the aminoaldehyde 2

;6.8 mmol) in THF ;5 mL) was added dropwise at this

temperature. The reaction medium was allowed to warm

to 2608C for 1h, then to room temperature. After stirring

for 3 h, it was hydrolysed with water ;20 mL). The organic

layer was separated and washed with 10% aqueous NaHCO₃

;2£15 mL). The aqueous phases were combined and acidi-

®ed to pH3.5 with 12N HCl and extracted with ether

;2£30 mL). After drying over MgSO₄, the solvent was

removed under vacuum to leave the crude product, which

was puri®ed by column chromatography.

4.3.3. [l-2trans)]-4-[2t-Butoxycarbonyl)amino]-2-pente-

noic acid 4c. Yield: 220 mg ;71%), white solid, mp 788C,

R_f0.56 ;ethyl acetate/hexane: 1:1); IR ;KBr plate)/cm²¹

:

n_max3430, 3050, 2975, 1710 and 1650; ¹H NMR

3

;250 MHz, CDCl₃): d_H1.28 ;d, J_H±H7.0 Hz, 3H, CH±

CH₃), 1.45 [s, 9H, C;CH₃)₃], 4.42 ;m, 1H, CH±CH₃), 4.61

;br s, 1H, NH), 6.11 ;dd, ³J_H±H15.5 Hz and ⁴J_H±H1.5 Hz,

3

1H, CHvCH±CO), 6.97 ;dd, J_H±H15.5 Hz and J_H±H

4.0 Hz, 1H, CHvCH±COOH), 9.50 ;br s, 1H, COOH); ¹³C

NMR ;62.896 MHz, CDCl₃): d_C20.2 ;CH±CH₃), 28.4

[3C, C;CH₃)₃], 47.1; CH±CH₃), 80.0 [C;CH₃)₃], 119.6

;CHvCH±CO), 151.8 ;CHvCH±CO), 154.9 ;CO Boc),

171.0 ;COOH); [a]_D1138 ;c0.3, HCCl₃); MS ;EI¹)

m/z calculated for C₁₀H₁₇NO₄Cl [M]¹215.6, found 215.6

;,2%), 142.9 [[M2tBuO]¹, 17%], 158.0 [[M2tBu]¹,

37%], 96.0 [[M2tBuOCO±OH]¹, 70%], 113.2

[[M2tBuOCO]¹, 76%], 68.7 [[M2tBuOCO±COOH]¹,

100%].

4.3.1. [l-2trans)]/[l-2cis)]-4-[2Benzyloxycarbonyl)amino]-

2-methyl-2-pentenoic acid 4a. Yield: 290 mg ;25%), white

solid, ;trans/cis: 65:35), R_f0.48 ;ethyl acetate/hexane: 1:1)

IR ;KBr plate)/cm²¹: n_max3320, 3025, 1720, 1700 and

1650. MS ;FAB²) m/z calculated for C₁₄H₁₆NO₄[M2H]²

262.1, found 262.1 ;100%). trans Isomer: ¹H NMR

3

4.3.4. [l-2trans)]-4-[2t-Butoxycarbonyl)amino]-2-methyl-

2-pentenoic acid 4d. Yield: 640 mg of a white solid

obtained after a separation on a chromatographic silicagel

column from 1.693 g ;79%) of a ;trans/cis: 60:40) mixture;

mp 1368C; R_f0.39 ;ethyl acetate/hexane: 1:1); IR ;KBr

;250 MHz, CDCl₃): d_H1.24 ;d, J_H±H 6.5 Hz, 3H, CH±

CH₃), 1.92 [s, 3H, CHvC;CH₃)±CO], 4.56 ;m, 1H, CH±

CH₃), 4.96±5.26 ;m, 3H, Ph±CH₂and NH±CH), 6.66 [dd,

4

³J_H±H9.0 Hz and J_H±H1.2 Hz, 1H, CHvC;CH₃)±CO],

7.35 ;br s, 5H, Ph), 9.00 ;br s, 1H, OH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C12.2 [CHvC;CH₃)±CO], 20.3

;CH±CH₃), 45.4 ;CH±CH₃), 67.8 ;CH₂-Ph), 127.1, 128.1

;2C), 128.5 ;2C), 136.2 ;Ph), 141.0 [CHvC;CH₃)±CO],

144.2 [CHvC;CH₃)±CO], 155.5 ;CO Boc), 172.7

;COOH). cis Isomer: ¹H NMR ;250 MHz, CDCl₃):

1

plate)/cm²¹: n_max3320, 1700, 1695 and 1645; H NMR

3

;250 MHz, CDCl₃): d_H1.22 ;d, J_H±H7.0 Hz, 3H, CH±

CH₃), 1.44 [s, 9H, C;CH₃)₃], 1.91 [s, 3H, CHvC;CH₃)±

CO], 4.49 ;m, 1H, CH±CH₃), 4.74 ;br s, 1H, NH),

3

4

6.65 [dd, J_H±H8.15 Hz and J_H±H1.2 Hz, 1H,

CHvC;CH₃)±CO], 7.45 ;br s, 1H, COOH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C11.9 [CHvC;CH₃)±CO], 20.1

;CH±CH₃), 28.0 [3C, C;CH₃)₃], 44.6 ;CH±CH₃),

80.1[ C;CH₃)₃], 127.4 [CHvC;CH₃)±CO], 144.3

[CHvC;CH₃)±CO], 155.1 ;CO Boc), 171.8 ;COOH);

[a]_D1198 ;c0.25, HCCl₃) MS ;EI¹) m/z calculated for

C₁₁H₁₉NO₄[M]¹229.13, found 230.5 [[M11]¹, 10%],

173.6 [[M112tBu]¹, 35%], 129.3 [[M112tBuOCO]¹,

27%], 112.2 [[M112tBuOCO±OH]¹, 100%].

3

d_H1.24 ;d, J_H±H6.5 Hz, 3H, CH±CH₃), 1.92 [s, 3H,

CHvC;CH₃)±CO], 4.86 ;m, 1H, CH±CH₃), 4.96±5.26

3

;m, 3H, Ph±CH₂and NH±CH), 5.73 [d, J_H±H8.0 Hz,

1H, CHvC;CH₃)±CO], 7.35 ;br s, 5H, Ph), 9.00 ;br s,

1H, ±OH); ¹³C NMR ;62.896 MHz, CDCl₃): d_C10.8

[CHvC;CH₃)±CO], 18.2 ;CH±CH₃), 45.4 ;CH±CH₃),

66.9 ;CH₂-Ph), 127.1, 128.1 ;2C), 128.5 ;2C), 136.2 ;Ph),

141.0 [CHvC;CH₃)±CO], 144.2 [CHvC;CH₃)±CO],

155.7 ;CO Boc), 172.7 ;COOH).

4.3.5. [l-2trans)]-4-[2t-Butoxycarbonyl)amino]-2-pentyl-

2-pentenoic acid 4e. Yield: 71mg ;12%), colourless oil

;trans/cis: 95:5); R_f0.62 ;ethyl acetate/hexane: 1:1); IR

4.3.2. [l-2trans)]/[l-2cis)]-4-[2Benzyloxycarbonyl)amino]-

2-chloro-2-pentenoic acid 4b. Yield: 530 mg ;80%),

colourless oil, ;trans/cis: 40:60), R_f0.37 ;ethyl acetate/

hexane: 1:1); IR ;KBr ®lm)/cm²¹: n_max3345, 3025,

1735, 1730, 1700 and 1630; MS ;FAB²) m/z calculated

for C₁₃H₁₃NO₄Cl [M2H]²282.5, found 282.0 ;100%).

1

;KBr ®lm)/cm²¹: n_max3310, 1720, 1715 and 1700; H

3

NMR ;250 MHz, CD₃CN): d_H1.18 ;d, J_H±H5.0 Hz,

3H, CH±CH₃), 1.30±1.41 ;m, 9H, CH₂±CH₂±CH₂±CH₃),

1.41 [s, 9H, C;CH₃)₃], 2.28±2.40 [m, 2H, CHvC;CH₂±

1

trans Isomer: H NMR ;250 MHz, CDCl₃): d_H1.35 ;d,

3

³J_H±H7.5 Hz, 3H, CH±CH₃), 4.50±5.10 ;m, 2£1H, CH±

C₄H₉)±CO], 4.44 ;ddq, J_H±H9.0, 7.0, 5.0 Hz, 1H, CH±

CH₃), 5.28 ;d, ³J_H±H7.0 Hz, 1H, NH±CH), 6.49 [d, ³J_H±H

3

CH₃and NH±CH), 5.10 ;s, 2H, Ph-CH₂), 6.10 ;d, J_H±H

11.0 Hz, 1H, CHvCCl±CO), 7.35 ;s, 5H, Ph), 11.5 ;br s,

1H, ±OH); ¹³C NMR ;62.896 MHz, CDCl₃): d_C18.6

;CH±CH₃), 45.1; CH±CH₃), 66.7 ;Ph-CH₂), 123.6

9.0 Hz, 1H, CHvC;CH₂±C₄H₉)±CO], 11.0 ;br s, 1H,

COOH); ¹³C NMR ;62.896 MHz, CDCl₃): d_C16.3

;CH₂±CH₃), 18.3 ;CH±CH₃), 26.9 ;CH₂±CH₃), 27.9 and

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

4911

28.1;2C, 2 £CH₂), 28.4 [3C, C;CH₃)₃], 31.3 [CHvC;CH₂±

C₄H₉)±CO], 46.7 ;CH±CH₃), 78.3 [C;CH₃)₃], 125.5

[CHvC;C₅H₁₁)±CO], 145.0 [CHvC;C₅H₁₁)±CO], 155.6

;CO Boc), 171.4 ;COOH); MS ;FAB²) m/z calculated for

C₁₅H₂₃NO₄[M2H]²284.2, found 284.1;100%).

C;CH₃)₃], 4.62 ;m, 1H, CH±CH₃), 4.84 ;br s, 1H,

3

NH±CH), 7.05 ;d, J_H±H8.2 Hz, 1H, CHvCCl±CO),

7.90 ;br s, 1H, COOH); ¹³C NMR ;62.896 MHz, CDCl₃):

d_C19.9 ;CH±CH₃), 28.2 [3C, C;CH₃)₃], 45.7 ;CH±CH₃),

81.4 [C;CH₃)₃], 124.5 ;CHvCCl±CO), 144.2 ;CHvCCl±

CO), 156.9 ;CO Boc), 164.0 ;COOH).

4.3.6. [l-2trans)]/[l-2cis)]-4-[2t-Butoxycarbonyl)amino]-

2-phenyl-2-pentenoic acid 4f. Yield: 193 mg ;38.5%);

white solid ;trans/cis: 60:40); R_f0.51;ethyl acetate/hex-

ane: 1:1); IR ;KBr plate)/cm²¹: n_max3330, 1685 and 1645;

MS ;FAB²) m/z calculated for C₁₆H₂₁NO₄[M2H]²290.2,

4.3.9. [l-2trans)]/[l-2cis)]-4-[2t-Butoxycarbonyl)amino]-

2-¯uoro-2-pentenoic acid 4i. Yield: 514 mg ;82%), colour-

less oil ;trans/cis: 35:65); R_f0.58 ;acetone); IR ;KBr ®lm)/

cm²¹: n_max3330, 3115, 1805, 1700, and 1620; MS ;FAB²)

m/z calculated for C₁₀H₁₆NO₄F [M2H]²232.11, found

1

found 290.1;100%). trans Isomer: H NMR ;250 MHz,

3

CD₃COCD₃): d_H1.16 ;d, J_H±H7.0 Hz, 3H, CH±CH₃),

232.10;01%).

cis Isomer: ¹H NMR ;250 MHz,

3

1.38 [s, 9H, C;CH₃)₃], 4.24 ;ddq, J_H±H9.5, 7.0, 7.0 Hz,

CD₃COCD₃): d_H1.30 ;d, J_H±H5.5 Hz, 3H, CH±CH₃),

1.39 [s, 9H, C;CH₃)₃], 4.63 ;m, 1H, CH±CH₃), 6.17 ;dd,

³J_H±F32 Hz and ³J_H±H8.0 Hz, 1H, CHvCF±CO), 6.05±

6.55 ;m, 2£1H, NH±CH and COOH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C20.8 ;CH±CH₃), 28.3 [3C,

3

1H, CH±CH₃), 6.18 ;d, J_H±H7.0 Hz, 1H, NH±CH), 6.94

[d, ³J_H±H9.5 Hz, 1H, CHvC;Ph)±CO], 7.23±7.45 ;m, 5H,

Ph), 11.0 ;br s, 1H, COOH); ¹³C NMR ;62.896 MHz,

CDCl₃): d_C20.8 ;CH±CH₃), 28.2 [3C, C;CH₃)₃], 45.7

;CH±CH₃), 79.6 [C;CH₃)₃], 128.0, 128.3 ;2C), 129.5

;2C), 133.9 [CHvC;Ph)±CO], 144.7 ;Ph), 147.5

[CHvC;Ph)±CO], 154.8 ;CO Boc), 171.3 ;COOH). cis

C;CH₃)₃], 43.3 ;CH±CH₃), 79.3 [C;CH₃)₃], 122.9 ;d,

1

²J_C±F9.0 Hz, 1C, CHvCF±CO), 147.1 ;d, J_C±F

244 Hz, 1C, CHvCF±CO), 156.7 ;CO Boc), 163.9 ;d,

²J_C±F37 Hz, 1C, COOH); ¹⁹F NMR ;235.35 MHz,

1

Isomer: H NMR ;250 MHz, CD₃COCD₃): d_H1.16 ;d,

³J_H±H7.0 Hz, 3H, CH±CH₃), 1.38 [s, 9H, C;CH₃)₃], 4.24

CD₃COCD₃): d_F2124.18 ;d, ³J_F±H32 Hz). trans Isomer:

3

;ddq, J_H±H9.5, 7.0, 7.0 Hz, 1H, CH±CH₃), 6.08 [d,

¹H NMR ;250 MHz, CD₃COCD₃): d_H1.30 ;d, J_H±H

3

³J_H±H9.5 Hz, 1H, CHvC;Ph)±CO], 6.18 ;d, J_H±H

5.5 Hz, 3H, CH±CH₃), 1.39 [s, 9H, C;CH₃)₃], 5.09 ;m,

3

7.0 Hz, 1H, NH±CH), 7.23±7.45 ;m, 5H, Ph), 11.0 ;br s,

1H, COOH).

1H, CH±CH₃), 5.93 ;dd, J_H±F15 Hz and J_H±H9.5 Hz,

1H, CHvCF±CO), 6.05±6.55 ;m, 2£1H, NH±CH and

COOH; ¹⁹F NMR ;235.35 MHz, CD₃COCD₃): d_F

2177.9 ;d, ³J_F±H15 Hz).

4.3.7. [l-2trans)]/[l-2cis)]-4-[2t-Butoxycarbonyl)amino]-

2-ethoxy-2-pentenoic acid 4g. Yield: 320 mg ;71%),

colourless oil ;trans/cis: 45:55); R_f0.66 ;acetone); IR

;KBr ®lm)/cm²¹: n_max3345, 1770, 1700 and 1645; MS

;FAB²) m/z calculated for C₁₂H₂₀NO₅[M2H]²258.1,

4.3.10. [l-2trans)]-4-[2t-Butoxycarbonyl)amino]-2,5-di-

methyl-2-hexenoic acid 4j. 275 mg of a colourless oil

obtained after a chromatographic separation on a silicagel

column of 430 mg ;79%) of a ;trans/cis: 82:18) mixture;

found 258.1;010%).

cis Isomer: ¹H NMR ;250 MHz,

CD₃COCD₃): d_H1.20±1.34 ;m, 2£3H, CH±CH₃and O±

R_f0.41 ;ethyl acetate/hexane: 1:1); IR ;KBr ®lm)/cm²¹

:

3

1

CH₂±CH₃), 1.39 [s, 9H, C;CH₃)₃], 3.95 ;q, J_H±H7.0 Hz,

n_max3325, 1710, 1695 and 1650; H NMR ;250 MHz,

2H, O±CH₂±CH₃), 4.89 ;m, 1H, CH±CH₃), 5.15 [d, ³J_H±H

CDCl₃): d_H0.92 ;d, J_H±H6.8 Hz, 3H, CH±CH₃), 0.96

3

9.5 Hz, 1H, CHvC;OEt)±CO], 6.10 ;br s, 1H, NH±CH),

11.0 ;br s, 1H, COOH); ¹³C NMR ;62.896 MHz, CDCl₃):

d_C14.2 ;O±CH₂±CH₃), 19.6 ;CH±CH₃), 28.2 [3C,

C;CH₃)₃], 52.9 ;CH±CH₃), 68.3 ;O±CH₂±CH₃), 79.8

;d, J_H±H6.6 Hz, 3H, CH±CH₃), 1.44 [s, 9H, C;CH₃)₃],

4

1.78 [m, 1H, CH;CH₃)₂], 1.89 [d, J_H±H1.1 Hz, 3H,

CHvC;CH₃)±CO], 4.26 ;m, 1H, NH±CH), 4.57 ;br s,

3

4

1H, NH±CH), 6.63 [dd, J_H±H9.8 Hz and J_H±H1.1 Hz,

1H, CHvC;CH₃)±CO], 11.0 ;br s, 1H, COOH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C12.8 [CHvC;CH₃)±CO], 18.4

and 18.5 [2C, CH;CH₃)₂], 28.3 [3C, C;CH₃)₃], 32.8

[CH;CH₃)₂], 54.0 ;NH±CH±CHv), 78.7 [C;CH₃)₃], 129.1

[CHvC;CH₃)±CO], 142.3 [CHvC;CH₃)±CO], 155.3 ;CO

Boc), 172.7 ;COOH); MS ;FAB²) m/z calculated for

C₁₃H₂₂NO₄[M2H]²256.2, found 256.0 ;100%). [a]_D

1308 ;c0.20, HCCl₃).

[C;CH₃)₃],

113.7

[CHvC;OEt)±CO],

148.5

[CHvC;OEt)±CO], 155.6 ;CO Boc), 166.9 ;COOH).

trans Isomer: ¹H NMR ;250 MHz, CD₃COCD₃): d_H

1.20±1.34 ;m, 2£3H, CH±CH₃and O±CH₂±CH₃), 1.39

3

[s, 9H, C;CH₃)₃], 3.79 ;q, J_H±H7.0 Hz, 2H, O±CH₂±

CH₃), 4.68 ;m, 1H, CH±CH₃), 6.10 ;br s, 1H, NH±CH),

3

6.20 [d, J_H±H9.0 Hz, 1H, CHvC;OEt)±CO], 11.0 ;br s,

1H, COOH).

4.3.8. [l-2trans)]/[l-2cis)]-4-[2t-Butoxycarbonyl)amino]-

2-chloro-2-pentenoic acid 4h. Yield: 400 mg ;92.5%),

colourless oil ;trans/cis: 30:70); R_f0.68 ;ethyl acetate/hex-

ane: 1:1); IR ;KBr ®lm)/cm²¹: n_max3315, 1700 and 1650.

cis Isomer: ¹H NMR ;250 MHz, CDCl₃): d_H1.31 ;d,

³J_H±H8.8 Hz, 3H, CH±CH₃), 1.46 [s, 9H, C;CH₃)₃], 4.62

;m, 1H, CH±CH₃), 4.84 ;br s, 1H, NH±CH), 6.05 ;m, 1H,

CHvCCl±CO), 7.90 ;br s, 1H, COOH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C18.6 ;CH±CH₃), 27.9 [3C,

C;CH₃)₃], 45.5 ;CH±CH₃), 81.7 [C;CH₃)₃], 124.5

;CHvCCl±CO), 151.4 ;CHvCCl±CO), 156.2 ;CO Boc),

165.2 ;COOH). trans Isomer: ¹H NMR ;250 MHz, CDCl₃):

4.3.11. 2trans)-4-[2t-Butoxycarbonyl)amino]-2-butenoic

acid 4k. Yield: 584 mg ;77%), white solid, mp 1158C,

R_f0.58 ;ethyl acetate); IR ;KBr plate)/cm²¹: n_max3325,

1

1710, 1690 and 1655; H NMR ;250 MHz, CD₃COCD₃):

3

d_H1.43 [s, 9H, C;CH₃)₃], 3.89 ;dd, J_H±H4.8 Hz and

⁴J_H±H2.0 Hz, 2H, CH₂), 5.91;dt, ³J_H±H15.5 Hz and

⁴J_H±H2.0 Hz, 1H, CHvCH±CO), 6.31;br s, 1H, N H),

3

6.91;dd, J_H±H15.5, 4.8 Hz, 1H, CHvCH±CO), 11.0

;br s, 1H, COOH); ¹³C NMR ;62.896 MHz, CDCl₃): d_C

28.3 [3C, C;CH₃)₃], 41.3 ;NH±CH₂), 80.1[ C;CH₃)], 120.6

;CHvCH±CO), 147.3 ;CHvCH±CO), 155.6 ;CO Boc),

170.6 ;COOH); MS ;FAB²) m/z calculated for C₉H₁₄NO₄

[M2H]²200.1, found 200.1 ;100%).

3

d_H1.31 ;d, J_H±H8.8 Hz, 3H, CH±CH₃), 1.46 [s, 9H,

4912

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

4.3.12. 2trans)-4-[2t-Butoxy)carbonyl)amino]-2-methyl-2-

butenoic acid 4l. 410 mg, white solid obtained by precipi-

tation with diethyl ether from 828 mg ;77%) of a ;trans/cis:

75:25) mixture; mp 1178C, R_f0.66 ;ethyl acetate); IR ;KBr

plate)/cm²¹: n_max3370, 1685 and 1650; ¹H NMR

;250 MHz, CDCl₃): d_H1.56 [s, 9H, C;CH₃)₃], 1.99 [d,

[CHvC;CH₃)±CO], 155.1 ;CO Boc), 172.6 ;COOH). cis

Isomer: ¹H NMR ;250 MHz, CD₃COCD₃) d_H1.36 [s, 9H,

4

C;CH₃)₃], 1.96 [d, J_H±H1.5 Hz, 3H, CHvC;CH₃)±CO],

3

2.80 and 2.99 ;2dd, J_H±H13.5, 7.5 Hz, 2£1H, CH±CH₂),

5.13 ;ddt, ³J_H±H9.0, 7.5, 5.0 Hz, 1H, CH±CH₂), 5.96 [dd,

4

³J_H±H9.0 Hz and J_H±H1.5 Hz, 1H, CHvC;CH₃)±CO],

3

⁴J_H±H1.0 Hz, 3H, CHvC;CH₃)±CO], 4.01;t, ³J_H±H

6.16 ;d, J_H±H5.0 Hz, 1H, NH±CH), 7.12±7.38 ;m, 5H,

6.5 Hz, 2H, NH±CH₂), 6.42 ;br s, 1H, NH±CH₂), 6.85 [dt,

Ph), 11.0 ;br s, 1H, COOH); ¹³C NMR ;62.896 MHz,

CDCl₃): d_C20.5 [CHvC;CH₃)±CO], 28.9 [3C,

C;CH₃)₃], 40.7 ;CH±CH₂), 51.3 ;CH±CH₂), 80.3

[C;CH₃)₃], 128.5 [CHvC;CH₃)±CO], 129.4 ;3C), 129.8

;2C) and 136.5 ;Ph), 142.7 [CHvC;CH₃)±CO], 156.3

;CO Boc), 172.4 ;COOH).

4

³J_H±H6.5 Hz and J_H±H1.0 Hz, 1H, CHvC;CH₃)±CO],

9.47 ;br s, 1H, COOH); ¹³C NMR ;62.896 MHz,

CD₃COCD₃): d_C12.9 [CHvC;CH₃)±CO], 29.0 [3C,

C;CH₃)₃], 39.8 ;NH±CH₂), 79.3 [C;CH₃)₃], 129.4

[CHvC;CH₃)±CO], 140.8 [CHvC;CH₃)±CO], 157.1

;CO Boc), 169.3 ;COOH). cis Isomer: IR ;KBr ®lm)/

cm²¹: n_max3330, 1685, 1660 and 1520; ¹H NMR

;250 MHz, CDCl₃): d_H1.43 [s, 9H, C;CH₃)₃], 1.91 [s,

4.3.15. [l-2trans)]/[l-2cis)]-N-2t-Butoxycarbonyl)-2-[2⁰-car-

boxy-2⁰-phenyl-1⁰-ethenyl] pyrrolidine 4o. Yield: 498 mg

;72%), colourless oil ;trans/cis: 82:18). R_f0.43 ;ethyl

acetate/hexane: 1:1); IR ;KBr ®lm)/cm²¹: n_max1670 and

1650. trans Isomer: ¹H NMR ;250 MHz, CDCl₃): d_H1.43

[s, 9H, C;CH₃)₃], 1.58±2.37 ;m, 2£2H, CH±CH₂±CH₂),

3.32±4.01;m, 2H, N±C H₂), 4.63 ;m, 1H, N±CH), 7.09

3

3H, CHvC;CH₃)±CO], 4.05 ;t, J_H±H6.0 Hz, 2H,

NH±CH₂), 5.09 ;br s, 1H, NH±CH₂), 6.05 [m, 1H,

CHvC;CH₃)±CO], 9.47 ;br s, 1H, COOH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C20.0 [CHvC;CH₃)±CO], 28.3

[3C, C;CH₃)₃], 39.7 ;NH±CH₂), 79.9 [C;CH₃)₃], 129.4

[CHvC;CH₃)±CO], 140.9 [CHvC;CH₃)±CO], 156.6

;CO Boc), 171.5 ;COOH); MS ;CI²) m/z calculated for

C₁₀H₁₆NO₄[M2H]²214.12, found 214.0 ;7%), 157.8

[[M2H2tBuO]², 37%], 114.2 [[M2H2tBuOCO]²,

37%], 56.9 [[tBu-H]², 87%], 40.9 [[C₃H₅±H]², 100%].

3

[d, J_H±H9.0 Hz, 1H, CHvC;Ph)±CO], 7.20±7.53 ;m,

5H, Ph), 11.0 ;br s, 1H, COOH); ¹³C NMR ;62.896 MHz,

CDCl₃): d_C24.0 ;CH±CH₂±CH₂), 28.3 [3C, C;CH₃)₃],

32.4 ;CH±CH₂), 47.2 ;N±CH₂), 56.2 ;N±CH), 81.9

[C;CH₃)₃], 127.2, 128.3, 128.4 ;2C), 130.8 ;2C), 137.1

and 138.9 [CHvC;Ph)±CO], 156.1 ;CO Boc), 169.2

1

4.3.13. [l-2trans)]-4-[2t-Butoxycarbonyl)amino]-5-phenyl-

2-pentenoic acid 4m. Yield: 674 mg ;52%), white solid,

mp 1658C, R_f0.41 ;ethyl acetate/hexane: 1:1); IR ;KBr

;COOH). cis isomer: H NMR ;250 MHz, CDCl₃): d_H

1.46 [s, 9H, C;CH₃)₃], 1.58±2.37 ;m, 2£2H, CH±CH₂±

CH₂), 3.32±4.01;m, 2H, N±C H₂), 4.63 ;m, 1H, N±CH),

1

3

plate)/cm²¹: n_max3285, 3060, 1700, 1660 and 1640; H

5.81[d, J_H±H10.5 Hz, 1H, CHvC;Ph)±CO], 7.20±7.53

NMR ;250 MHz, CDCl₃): d_H1.40 [s, 9H, C;CH₃)₃],

;m, 5H, Ph), 11.0 ;br s, 1H, COOH).

2.73±3.04 ;m, 2H, CH±CH₂), 4.37±4.75 ;m, 2£1H, NH±

3

CH), 5.86 ;dd, J_H±H15.5, 4.0 Hz, 1H, CHvCH±CO),

4.3.16. [l-2trans)]-N-2t-Butoxycarbonyl)-2-[2⁰-carboxy-

2⁰-methyl-1⁰-ethenyl]pyrrolidine 4p. Yield: 498 mg,

colourless oil obtained after a chromatographic separation

on a silicagel column from 973 mg ;80%) of a ;trans/cis:

80:20) mixture; R_f0.35 ;ethyl acetate/hexane: 1:1); IR

3

7.01;dd, J_H±H15.5, 4.7 Hz, 1H, CHvCH±CO), 7.15±

7.36 ;m, 5H, Ph), 10.4 ;br s, 1H, COOH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C28.2 [3C, C;CH₃)₃], 40.7

;CH±CH₂), 52.3 ;NH±CH), 80.1[ C;CH₃)₃], 120.5

;CHvCH±CO), 126.9, 128.6, 128.8, 129.1, 129.4 and

136.2 ;Ph), 150.0 ;CHvCH±CO), 155.0 ;CO Boc), 170.9

;COOH); [a]_D1308 ;c0.2, HCCl₃); MS ;EI¹) m/z calcu-

lated for C₁₆H₂₁NO₄[M]¹291.2, found 291.8 ;6%), 191.3

[[M112tBuOCO]¹, 38%], 89.8 [[C₇H₆]¹, 100%].

1

;KBr ®lm)/cm²¹: n_max3070, 1705, 1695 and 1650; H

NMR ;250 MHz, CDCl₃): d_H1.37 [s, 9H, C;CH₃)₃],

1.57±2.26 ;m, 2£2H, CH±CH₂±CH₂), 1.85 [s, 3H,

CHvC;CH₃)±CO], 3.30±3.57 ;m, 2H, N±CH₂), 4.46 ;m,

3

1H, N±CH), 6.71[d, J_H±H8.8 Hz, 1H, CHvC;CH₃)±

CO], 11.0 ;br s, 1H, COOH); ¹³C NMR ;62.896 MHz,

CDCl₃): d_C11.9 [CHvC;CH₃)±CO], 23.7 and 24.3

;CH±CH₂±CH₂), 28.2 [3C, C;CH₃)₃], 31.7 and 32.1

;CH±CH₂), 46.3 and 46.8 ;N±CH₂), 55.1;N± CH),

79.6 [C;CH₃)₃], 125.7 [CHvC;CH₃)±CO], 145.2

[CHvC;CH₃)±CO], 154.4 ;CO Boc), 172.5 ;COOH); MS

;EI¹) m/z calculated for C₁₃H₂₁NO₄[M]¹255.2, found

256.2 [[M11]¹, 41%], 154.1 [[M2tBuOCO]¹, 48%],

200.0 [[M112tBu]¹, 52%], 109.9 [[M112tBuOCO±

COOH]¹, 77%], 137.9 [[M112tBuOCO±OH]¹, 78%],

56.9 [[tBu]¹, 100%].

4.3.14. [l-2trans)]/[l-2cis)]-4-[2t-Butoxycarbonyl)amino]-

2-methyl-5-phenyl-2-pentenoic acid 4n. Yield: 210 mg

;35.5%), white solid ;trans/cis: 75:25). R_f0.61;ethyl ace-

tate/hexane: 1:1); IR ;KBr plate)/cm²¹: n_max3065, 1720,

1715 and 1690; MS ;EI¹) m/z calculated for C₁₇H₂₃NO₄

[M]¹305.16, found 306.2 [[M11]¹, 2%], 249.6 [[M1

12tBu]¹, 20%], 187.0 [[M2tBuOCO±OH]¹, 21%], 112.9

[[M112tBuOCO±OH±Ph]¹, 72%], 89.8 [[C₇H₆]¹, 100%].

1

trans Isomer: H NMR ;250 MHz, CD₃COCD₃): d_H1.36

[s, 9H, C;CH₃)₃], 1.65 [d, ⁴J_H±H1.5 Hz, 3H,

3

CHvC;CH₃)±CO], 2.80 and 2.99 ;2dd, J_H±H13.5,

3

7.5 Hz, 2£1H, CH±CH₂), 4.65 ;ddt, J_H±H9.25, 7.5,

4.3.17. [l-2trans)]/[l-2cis)]-N-2t-Butoxycarbonyl)-2-[2⁰-

carboxy-2⁰-ethoxy-1⁰-ethenyl] pyrrolidine 4q. Yield: 967

mg ;45%), colourless oil ;trans/cis: 30:70); IR ;KBr ®lm)/

cm²¹: n_max1710, 1690 and 1645. trans Isomer: R_f0.19

3

5.0 Hz, 1H, NH±CH), 6.28 ;d, J_H±H5.0 Hz, 1H,

3

4

NH±CH), 6.69 [dd, J_H±H9.25 Hz and J_H±H1.5 Hz,

1H, CHvC;CH₃)±CO], 7.12±7.35 ;m, 5H, Ph), 11.0 ;br

s, 1H, COOH); ¹³C NMR ;62.896 MHz, CDCl₃): d_C12.2

[CHvC;CH₃)±CO], 28.8 [3C, C;CH₃)₃], 41.0 ;CH±CH₂),

50.8 ;CH±CH₂), 80.4 [C;CH₃)₃], 128.5 [CHvC;CH₃)±

CO], 129.0 ;3C), 129.5 ;2C) and 136.2 ;Ph), 142.5

1

;ethyl acetate/hexane: 1:1); H NMR ;250 MHz, CDCl₃):

3

d_H1.37 ;t, J_H±H7.0 Hz, 3H, O±CH₂±CH₃), 1.44 [s, 9H,

C;CH₃)₃], 1.65±2.30 ;m, 2£2H, CH±CH₂±CH₂), 3.22±3.53

;m, 2H, N±CH₂), 3.94±4.83 ;m, 2H, O±CH₂±CH₃), 4.61;m,

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

4913

1H, N±CH), 6.13 [m, 1H, CHvC;OEt)±CO], 11.0 ;br s, 1H,

COOH). cis Isomer: R_f0.38 ;ethyl acetate/hexane: 1:1); ¹H

R_f0.45 ;ethyl acetate/hexane: 1:1); IR ;KBr ®lm)/cm²¹

:

n_max3345, 3075, 1715, 1695 and 1645; ¹H NMR

;250 MHz, CDCl₃): d_H1.46 [s, 9H, C;CH₃)₃], 1.86 [d,

⁴J_H±H1.0 Hz, 3H, CHvC;CH₃)±CO], 2.37±3.61;m, 2H,

3

NMR ;250 MHz, CDCl₃): d_H1.37 ;t, J_H±H7.0 Hz, 3H,

O±CH₂±CH₃), 1.47 [s, 9H, C;CH₃)₃], 1.65±2.30 ;m, 2£2H,

CH±CH₂±CH₂), 3.70±3.88 ;m, 2H, N±CH₂), 3.94±4.83 ;m,

2H, O±CH₂±CH₃), 4.61;m, H1 , N±C H), 4.76 [m, 1H,

CHvC;OEt)±CO], 11.0 ;br s, 1H, COOH).

3

CH₂±CHv), 3.26 ;q, J_H±H6.7 Hz, 2H, NH±CH₂), 4.63

3

;br s, 1H, NH±CH₂), 6.85 [t, J_H±H6.4 Hz, 1H,

CHvC;CH₃)±CO], 10.5 ;br s, 1H, COOH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C12.1 [CHvC;CH₃)±CO], 28.3

[3C, C;CH₃)₃], 29.4 ;CH₂±CHv), 39.3 ;N±CH₂),

80.1[ C;CH₃)₃], 129.5 [CHvC;CH₃)±CO], 140.6

[CHvC;CH₃)±CO], 155.5 ;CO Boc), 172.6 ;COOH); MS

;EI¹) m/z calculated for C₁₁H₁₉NO₄[M]¹229.1, found

230.0 [[M11]¹, 6%], 130.0 [[M2tBuOCO]¹, 30%],

173.9 [[M1H2tBu]¹, 44%], 112.0 [[M1H2tBuOCO±

OH]¹, 68%], 56.9 [[tBu]¹, 100%].

4.3.18. [l-2trans)]/[l-2cis)]-N-2t-Butoxycarbonyl)-2-[2⁰-car-

boxy-2⁰-chloro-1⁰-ethenyl] pyrrolidine 4r. Yield: 385 mg

;68%), colourless oil ;trans/cis: 35:65). R_f0.32 ;ethyl

acetate/hexane: 1:1); IR ;KBr ®lm)/cm²¹: n_max1695 and

1650. trans Isomer: ¹H NMR ;250 MHz, CDCl₃): d_H1.48

[s, 9H, C;CH₃)₃], 1.65±2.39 ;m, 2£2H, CH±CH₂±CH₂),

3.33±3.60 ;m, 2H, N±CH₂), 4.67 ;m, 1H, N±CH), 7.09

;m, 1H, CHvCCl±CO), 8.99 ;br s, 1H, COOH); ¹³C

NMR ;62.896 MHz, CDCl₃): d_C23.7 and 23.8 ;CH±

CH₂±CH₂), 28.2 [3C, C;CH₃)₃], 31.4 and 31.8 ;CH±CH₂),

46.4 and 46.9 ;N±CH₂), 56.3 ;N±CH), 80.5 [C;CH₃)₃],

122.8 ;CHvCCl±CO), 145.0 ;CHvCCl±CO), 154.6 ;CO

Boc), 165.1 ;COOH); cis isomer: ¹H NMR ;250 MHz,

CDCl₃): d_H1.48 [s, 9H, C;CH₃)₃], 1.65±2.39 ;m, 2£2H,

CH±CH₂±CH₂), 3.33±3.60 ;m, 2H, N±CH₂), 4.67 ;m, 1H,

N±CH), 6.04 ;d, ³J_H±H10.4 Hz, 1H, CHvCCl±CO), 8.99

;br s, 1H, COOH); ¹³C NMR ;62.896 MHz, CDCl₃):

d_C24.7 ;CH±CH₂±CH₂), 28.7 [3C, C;CH₃)₃], 30.6 ;CH±

CH₂), 46.4 ;N±CH₂), 55.4 ;N±CH), 81.9 [C;CH₃)₃], 126.0

;CHvCCl±CO), 137.1 ;CHvCCl±CO), 156.0 ;CO Boc),

163.9 ;COOH); MS ;FAB²): m/z calculated for

C₁₂H₁₇NO₄Cl [M2H]²274.6, found 274.1;100%).

4.4. Typical procedure for the preparation of N-iso-

propyl vinylogous aminoamides 4⁰

Triethylamine ;71mg, 1equiv.) was added to a stirred

solution of Boc N-protected vinylogous amino acid 4

;0.705 mmol) in dichloromethane ;10 mL). Then, benzo-

triazol-1-yloxytris-;dimethylamino)-phosphonium

hexa-

¯uorophosphate ;BOP), ;312 mg, 1 equiv.) was added,

followed after a few minutes by amine hydrochloride

;1equiv.) and triethylamine ;80 mg, 1.5 equiv.). The

mixture was stirred at room temperature until TLC analysis

indicated the total consumption of the amino component

;90±20 min, depending to the substrate). The mixture was

then diluted with dichloromethane ;25 mL) and washed

successively with 3N aqueous HCl ;3£5 mL), saturated

NaCl aqueous solution ;5 mL), saturated NaHCO₃solution

;3£5 mL) and saturated NaCl solution ;3£5 mL). The

organic layer was dried over magnesium sulfate and the

solvent evaporated. The crude product was puri®ed by

column chromatography on silica gel.

4.3.19. [l-2trans)]/[l-2cis)]-N-2t-Butoxycarbonyl)-2-[2⁰-car-

boxy-2⁰-¯uoro-1⁰-ethenyl] pyrrolidine 4s. Yield: 147 mg

;62%), colourless oil ;trans/cis: 30:70); IR ;KBr ®lm)/cm²¹

:

n_max1735, 1695, 1670, 1650 and 1635; MS ;FAB²) m/z

calculated for C₁₂H₁₇NO₄F [M2H]²258.1, found 258.1

;100%). trans Isomer: R_f0.19 ;ethyl acetate/hexane:

1:1); ¹H NMR ;250 MHz, CDCl₃): d_H1.46 [s, 9H,

C;CH₃)₃], 1.67±2.35 ;m, 2£2H, CH±CH₂±CH₂), 3.31±

3.55 ;m, 2H, N±CH₂), 4.69 ;m, 1H, N±CH), 6.13 ;dd,

4.4.1. [l-2trans)] or [l-2cis)]-N-2t-Butoxycarbonyl)-2-[2N-

isopropyl)-2⁰-carboxamide-2⁰-ethoxy-1⁰-ethenyl]-pyrro-

lidine 4⁰q. Yield: 145 mg ;78%), colourless oil ;trans/cis:

30:70); IR ;KBr ®lm)/cm²¹: n_max3330, 1690, 1680 and

3

³J_H±F35 Hz and J_H±H8.6 Hz, 1H, CHvCF±CO), 9.30

;br s, 1H, COOH); ¹³C NMR ;62.896 MHz, CDCl₃):

d_C23.6 ;CH±CH₂±CH₂), 28.1[3C, C; CH₃)₃], 31.9 ;CH±

1

1640. cis Isomer: R_f0.58 ;ethyl acetate/hexane: 1:1); H

3

NMR ;250 MHz, CDCl₃₃): d_H1.17 [d, J_H±H6.5 Hz, 2£

CH₂₂), 46.5 ;N±CH₂), 52.0 ;N±CH), 80.5 [C;CH₃)₃], 120.8

3H, CH;CH₃)₂], 1.32 ;t, J_H±H7.0 Hz, 3H, O±CH₂±CH₃),

1.40 [s, 9H, C;CH₃)₃], 1.55±2.41 ;m, 2£2H, CH±CH₂±

CH₂), 3.63±3.78 ;m, 2H, N±CH₂), 4.08 [m, 1H,

CH;CH₃)₂], 4.62±4.83 ;m, 2H, O±CH₂±CH₃), 4.93 ;m,

1H, N±CH), 5.39 [m, 1H, CHvC;OEt)±CO], 8.25 ;m,

1H, iPr-NH); ¹³C NMR ;62.896 MHz, CDCl₃): d_C15.5

;O±CH₂±CH₃), 22.4 [2C, CH;CH₃)₂], 23.8 ;CH±CH₂±

CH₂), 28.4 [3C, C;CH₃)₃], 34.0 ;CH±CH₂), 41.1

[CH;CH₃)₂], 46.7 ;N±CH₂), 52.6 ;N±CH), 69.2 ;O±CH₂±

CH₃), 78.6 [C;CH₃)₃], 115.6 [CHvC;OEt)±CO], 149.1

[CHvC;OEt)±CO], 154.2 ;CO Boc), 162.3 ;CONHiPr);

[a]_D189.28 ;c0.5, HCCl₃). trans Isomer: ¹H NMR

1

;d, J_C±F14 Hz, 1C, CHvCF±CO), 146.7 ;d, J_C±F

271Hz, 1C, CH vCF±CO), 154.7 ;CO Boc), 162.7 ;d,

²J_C±F35 Hz, 1C, COOH); ¹⁹F NMR ;235.35 MHz,

3

CDCl₃): d_F2130.5 ;d, J_F±H35 Hz). cis Isomer: R_f

0.38 ;ethyl acetate/hexane: 1:1); ¹H NMR ;250 MHz,

CDCl₃): d_H1.43 [s, 9H, C;CH₃)₃], 1.67±2.35 ;m, 2£2H,

CH±CH₂±CH₂), 3.31±3.55 ;m, 2H, N±CH₂), 4.81;m, 1H,

3

N±CH), 5.65 ;dd, J_H±F34 Hz and J_H±H9.9 Hz, 1H,

CHvCF±CO), 9.30 ;br s, 1H, COOH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C24.1;CH±CH ₂±CH₂), 28.1

[3C, C;CH₃)₃], 31.4 and 32.8 ;CH±CH₂), 46.4 and 46.5

3

;N±CH₂), 53.0 ;d, J_C±F8.0 Hz, 1C, N±CH), 81.4

;250 MHz, CDCl₃): d_H1.21 [d, J_H±H6.5 Hz, 2£3H,

2

3

[C;CH₃)₃], 122.1 ;d, J_C±F13.5 Hz, 1C, CHvCF±CO),

CH;CH₃)₂], 1.40 ;t, J_H±H7.0 Hz, 3H, O±CH₂±CH₃),

1

148.3 ;d, J_C±F258 Hz, 1C, CHvCF±CO), 155.5 ;CO

1.50 [s, 9H, C;CH₃)₃], 1.49±2.18 ;m, 2£2H, CH±CH₂±

CH₂), 3.17±3.41 ;m, 2H, N±CH₂), 3.76 [m, 1H,

CH;CH₃)₂], 3.85±4.08 ;m, 2H, O±CH₂±CH₃), 4.56 ;m,

1H, N±CH), 5.90 [m, 1H, CHvC;OEt)±CO], 6.91;m, 1H,

iPr-NH); ¹³C NMR ;62.896 MHz, CDCl₃): d_C14.4 ;O±

CH₂±CH₃), 22.7 [2C, CH;CH₃)₂], 23.7 ;CH±CH₂±CH₂),

2

Boc), 162.4 ;d, J_C±F34 Hz, 1C, COOH); ¹⁹F NMR

3

;235.35 MHz, CDCl₃): d_F2128.9 ;d, J_F±H34 Hz).

4.3.20. 2trans)-5-[2t-Butoxycarbonyl)amino]-2-methyl-2-

pentenoic acid 4t. Yield: 170 mg ;70%), colourless oil,

4914

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

28.4 [3C, C;CH₃)₃], 34.0 ;CH±CH₂), 41.1 [CH;CH₃)₂],

46.2 ;N±CH₂), 54.7 ;N±CH), 63.4 ;O±CH₂±CH₃),

79.4 [C;CH₃)₃], 108.1 [CHvC;OEt)±CO], 146.9

[CHvC;OEt)±CO], 154.8 ;CO Boc), 162.8 ;CONHiPr).

;R²CH₃). It was synthesized with the appropriate method

when R²Cl¹⁵or F¹⁶.

With the ethyl bis5tri¯uoroethyl)phosphonoalcanoates 6a.

The phosphonate 6a ;1.08 g, 3.12 mmol) was added to a

slurry of oil-free potassium hydride ;125 mg, 3.12 mmol)

in THF ;10 mL) at 08C. The solution was stirred for

15 min at this temperature followed by cooling to 2788C.

Aminoaldehyde 2 ;520 mg, 2.6 mmol) in THF ;5 mL) was

added over 15 min. The reaction mixture was stirred at

2788C for 3 h and then quenched with 2% aqueous HCl

;15 mL). The aqueous phase was extracted with dichloro-

methane ;3£50 mL). The organic layers were combined and

dried with MgSO₄. After ®ltration the solvent was evapo-

rated and the so-obtained crude product was puri®ed by

column chromatography on silica gel.

4.4.2. [l-2trans)]- or [l-2cis)]-N-2t-Butoxycarbonyl)-2-[2N-

isopropyl)-2⁰-carboxamide-2⁰-chloro-1⁰-ethenyl]-pyrro-

lidine 4⁰r. Yield: 365 mg ;84%), colourless oil ;trans/cis:

30:70); IR ;KBr ®lm)/cm²¹: n_max3350, 1700, 1685 and

1

1650. cis Isomer: R_f0.73 ;ethyl acetate/hexane: 1:1); H

3

NMR ;250 MHz, CDCl₃): d_H1.22 [d, J_H±H6.5 Hz,

2£3H, CH;CH₃)₂], 1.46 [s, 9H, C;CH₃)₃], 1.54±2.23 ;m,

2£2H, CH±CH₂±CH₂), 3.31±3.46 ;m, 2H, N±CH₂), 4.09

[m, 1H, CH;CH₃)₂], 4.64 ;m, 1H, N±CH), 5.81;m, 1H,

CHvCCl±CO), 8.88 ;m, 1H, iPr-NH). trans Isomer:

1

R_f0.64 ;ethyl acetate/hexane: 1:1); H NMR ;250 MHz,

3

CDCl₃): d_H1.21 [d, J_H±H6.5 Hz, 2£3H, CH;CH₃)₂],

1.41 [s, 9H, C;CH₃)₃], 1.61±2.29 ;m, 2£2H, CH±CH₂±

With the ethyl 2-diethylphosphonoalcanoates 6b. 1.6 mL of

n-butyllithium ;2.37 mmol, 1.54 M in hexane) were added

dropwise to the phosphonate 6b ;550 mg, 2.37 mmol) in

THF ;10 mL) with stirring at room temperature. After

20 min, the mixture was cooled to 2788C with stirring

and aminoaldehyde 2 ;360 mg, 2.26 mmol) in THF

;10 mL) was added dropwise. After 3 h stirring, the reaction

was quenched with an aqueous saturated ammonium

chloride solution ;12 mL) at 2788C. The aqueous phase

was extracted with diethyl ether ;3£30 mL) and the

combined organic phases were washed with water

;2£5 mL). Then the organic layer was dried over MgSO₄,

®ltered and evaporated under reduced pressure to afford a

crude product, which was puri®ed by column chroma-

tography on silica gel.

CH₂), 3.38±3.61;m, 2H, N±C H₂), 4.09 [m, 1H,

CH;CH₃)₂], 4.61;m, H1, N±C H), 6.39 ;m, 1H,

CHvCCl±CO), 7.05 ;m, 1H, iPr-NH).

4.4.3. [l-2trans)]- or [l-2cis)]-N-2t-Butoxycarbonyl)-2-

[2N-isopropyl)-2⁰-carboxamide-2⁰-¯uoro-1⁰-ethenyl]-

pyrrolidine 4⁰s. Yield: 255 mg ;85%), white solid ;trans/

cis: 35:65); IR ;KBr ®lm)/cm²¹: n_max3310, 1695, 1680,

1665, 1660, 1650 and 1640. cis Isomer: R_f0.6 ;ethyl ace-

1

tate/hexane: 1:1); mp 738C; H NMR ;250 MHz, CDCl₃):

d_H1.21 [d, ³J_H±H7.3 Hz, 2£3H, CH;CH₃)₂], 1.43 [s, 9H,

C;CH₃)₃], 1.61±2.34 ;m, 2£2H, CH±CH₂±CH₂), 3.23±3.51

;m, 2H, N±CH₂), 4.12 [m, 1H, CH;CH₃)₂], 4.79 ;m, 1H,

N±CH), 5.50 ;m, 1H, CHvCF±CO), 8.19 ;m, 1H, iPr-

NH); ¹³C NMR ;62.896 MHz, CDCl₃): d_C21.9 and 22.3

[2C, CH;CH₃)₂], 23.8 ;CH±CH₂±CH₂), 28.3 [3C, C;CH₃)₃],

32.8 ;CH±CH₂), 40.1[ CH;CH₃)₂], 46.7 ;N±CH₂), 53.1;d,

4.5.1. Ethyl [l-2trans)]/[l-2cis)]-4-[2t-butoxycarbonyl)-

amino]-2-pentenoate 5c. Yield: 360 mg ;72%) of a

;trans/cis: 25:75) mixture obtained with phosphonate 6a

;R²H); colourless oil; R_f0.57 ;acetone/ethyl acetate/

hexane: 1:1/1); IR ;KBr ®lm)/cm²¹: n_max3355, 1720,

2

³J_C±F8.0 Hz, 1C, N±CH), 79.9 [C;CH₃)₃], 122.5 ;d, J_C±

1

31.6 Hz, 1C, CHvCF±CO), 148.4 ;d, J_C±H258 Hz,

F

2

1C, CHvCF±CO), 154.8 ;CO Boc), 159.3 ;d, J_C±F

31.8 Hz, 1C, CONHiPr); ¹⁹F NMR ;235.36 MHz,

1

1715, 1705, 1695, 1660 and 1650. cis Isomer: H NMR

3

CD₃COCD₃): d_F2123.5 ;d, J_F±H19 Hz, 1F); [a]_D

;250 MHz, CDCl₃): d_H1.17 ;d, J_H±H7.25 Hz, 3H,

3

1838 ;c0.4, HCCl₃). trans Isomer: R_f0.4 ;ethyl acetate/

hexane: 1:1); mp 1068C; ¹H NMR ;250 MHz, CDCl₃):

CH±CH₃), 1.29 ;t, J_H±H7.0 Hz, 3H, O±CH₂±CH₃), 1.45

3

[s, 9H, C;CH₃)₃], 4.18 ;q, J_H±H7.0 Hz, 2H, O±CH₂±

3

d_H1.21 [d, J_H±H6.5 Hz, 2£3H, CH;CH₃)₂], 1.43 [s,

CH₃), 4.78 ;br s, 1H, NH), 5.16 ;m, 1H, NH±CH), 5.74

3

4

9H, C;CH₃)₃], 1.69±2.24 ;m, 2£2H, CH±CH₂±CH₂),

;dd, J_H±H11.6 Hz and J_H±H0.75 Hz, 1H, CHvCH±

CO), 6.11 ;m 1H, CHvCH±CO); ¹³C NMR

;62.896 MHz, CDCl₃): d_C14.2 ;O±CH₂±CH₃), 20.2

;CH±CH₃), 28.3 [3C, C;CH₃)₃], 45.4 ;NH±CH), 60.2 ;O±

CH₂±CH₃), 79.5 [C;CH₃)₃], 119.5 ;CHvCH±CO), 151.9

;CHvCH±CO), 155.2 ;CO Boc), 165.7 ;COOEt). trans

3.29±3.57 ;m, 2H, N±CH₂), 4.13 [m, 1H, CH;CH₃)₂],

3

4.69 ;m, 1H, N±CH), 6.00 ;dd, J_H±F36 Hz and J_H±

9.2 Hz, 1H, CHvCF±CO), 6.05 ;m, 1H, iPr-NH); ¹³C

H

NMR ;62.896 MHz, CDCl₃): d_C22.3 [2C, CH;CH₃)₂],

23.3 and 24.1;CH±CH ±CH₂), 28.3 [3C, C;CH₃)₃], 31.8

2

1

3

and 32.1;CH± CH₂), 41.4 [CH;CH₃)₂], 46.1;N± CH₂),

Isomer: H NMR ;250 MHz, CDCl₃): d_H1.27 ;d, J_H±H

2

3

53.9 ;N±CH), 79.5 [C;CH₃₁)₃], 116.8 ;d, J_C±F33 Hz, 1C,

7.25 Hz, 3H, CH±CH₃), 1.29 ;t, J_H±H7.0 Hz, 3H, O±

3

CHvCF±CO), 150.0 ;d, J_C±H269 Hz, 1C, CHvCF±

CH₂±CH₃), 1.45 [s, 9H, C;CH₃)₃], 4.19 ;q, J_H±H7.0 Hz,

2

CO), 154.1 ;CO Boc), 159.3 ;d, J_C±F27 Hz, 1C,

2H, O±CH₂±CH₃), 4.31±4.59 ;m, 2£1H, NH and NH±CH),

CONHiPr); ¹⁹F NMR ;235.36 MHz, CD₃COCD₃):

4

5.91;dd,

³J_H±H15.75 Hz and J_H±H1.3 Hz, 1H,

3

d_F2129.8 ;d, J_F±H36 Hz, 1F);); [a]_D26.18 ;c0.25,

CHvCH±CO), 6.88 ;dd, J_H±H15.75 Hz and J_H±H

4.85 Hz, 1H, CHvCH±CO); ¹³C NMR ;62.896 MHz,

CDCl₃): d_C14.2 ;O±CH₂±CH₃), 20.3 ;CH±CH₃), 28.5

[3C, C;CH₃)₃], 45.5 ;NH±CH), 60.4 ;O±CH₂±CH₃), 79.5

[C;CH₃)₃], 118.9 ;CHvCH±CO), 149.3 ;CHvCH±CO),

155.2 ;CO Boc), 165.7 ;COOEt).

HCCl₃).

4.5. Typical procedure for the preparation of the cis

vinylogous aminoesters 5

The bis;tri¯uoroethyl) phosphonoesters 6a were prepared

according to the Savignac method.¹⁴The ethyl 2-diethyl-

phosphonopropanoate 6b was commercially available

4.5.2. Ethyl [l-2trans)]- or [l-2cis)]-4-[2t-butoxycarbonyl)-

amino]-2-methyl-2-pentenoate 5d. Yield: 983 mg ;79%);

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

4915

colourless oil ;trans/cis: 7:93) obtained with phosphonate

6a and 1.05 g ;82%); colourless oil ;trans/cis: 10:90)

obtained with phosphonate 6b. cis Isomer: colourless oil;

4.5.5. Ethyl [l-2trans)]- or [l-2cis)]-4-[2t-butoxycarbonyl)-

amino]-2,5-dimethyl-2-hexenoate 5j. Yield: 740 mg

;63%) of pure cis isomer obtained after a separation on a

silicagel chromatographic column from 1.015 g ;87%) of a

;trans/cis: 10:90) mixture obtained with the phosphonate 6a

and 590 mg ;80%) of a ;trans/cis: 80:20) mixture obtained

with the phosphonate 6b. cis Isomer: colourless oil; R_f0.59

R_f0.54 ;ethyl acetate/hexane: 1:4); IR ;KBr ®lm)/cm²¹

:

1

n_max3360, 1715, 1695 and 1650; H NMR ;250 MHz,

3

CDCl₃): d_H1.25 ;d, J_H±H6.8 Hz, 3H, CH±CH₃), 1.32

3

;t, J_H±H7.1Hz, 3H, O±CH ₂±CH₃), 1.43 [s, 9H,

4

C;CH₃)₃], 1.90 [d, J_H±H1Hz, 3H, CH vC;CH₃)±CO],

;ethyl acetate/hexane: 1:2); IR ;KBr ®lm)/cm²¹: n_max

3

1

4.22 ;q, J_H±H7.1Hz, 2H, O±C H₂±CH₃), 4.53 ;m, 1H,

3370, 1710, 1695 and 1655; H NMR ;250 MHz, CDCl₃):

3

NH), 4.94 ;m, 1H, NH±CH), 5.79 [d, J_H±H8.6 Hz, 1H,

d_H0.91and 0.93 [2d, J_H±H6.7 Hz, 2£3H, CH;CH₃)₂],

CHvC;CH₃)±CO]; ¹³C NMR ;62.896 MHz, CDCl₃):

d_C14.0 ;O±CH₂±CH₃), 20.1[CH vC;CH₃)±CO], 20.6

;CH±CH₃), 28.2 [3C, C;CH₃)₃], 45.7 ;NH±CH), 60.2 ;O±

CH₂±CH₃), 78.9 [C;CH₃)₃], 126.7 [CHvC;CH₃)±CO],

144.5 [CHvC;CH₃)±CO], 154.9 ;CO Boc), 167.1

;COOEt); [a]_D1478 ;c1.0, HCCl₃). MS ;FAB¹): m/z

calculated for C₁₃H₂₃NO₄[M]¹257.2, found 258.2

[[M11]¹, 76%], 202.2 [[M2tBu]¹, 100%]. trans Isomer:

colourless oil; R_f0.5 ;ethyl acetate/hexane: 1:4); IR ;KBr

1.32 ;t, J_H±H7.1Hz, 3H, O±CH ₂±CH₃), 1.43 [s, 9H,

3

4

C;CH₃)₃], 1.87 [m, 1H, CH;CH₃)₂], 1.93 [d, J_H±H

3

1.0 Hz, 3H, CHvC;CH₃)±CO], 4.22 ;q, J_H±H7.1Hz,

2H, O±CH₂±CH₃), 4.60 ;m, 1H, NH), 4.74 ;m, 1H, NH±

3

4

CH), 5.74 [dd, J_H±H9.5 Hz and J_H±H0.5 Hz, 1H,

CHvC;CH₃)±CO]; ¹³C NMR ;62.896 MHz, CDCl₃):

d_C13.9 ;O±CH₂±CH₃), 17.7 and 18.8 [2C, CH;CH₃)₂],

20.4 [CHvC;CH₃)±CO], 28.1[3C, C; CH₃)₃], 32.6

[CH;CH₃)₂], 53.9 ;NH±CH), 60.1;O± CH₂±CH₃),

78.5 [C;CH₃)₃], 128.2 [CHvC;CH₃)±CO], 140.9

[CHvC;CH₃)±CO], 155.2 ;CO Boc), 167.2 ;COOEt).

trans Isomer: colourless oil; R_f0.51;ethyl acetate/hexane:

1:2); IR ;KBr ®lm)/cm²¹: n_max3370, 1700, 1695 and

1

®lm)/cm²¹: n_max3360, 1700, 1680 and 1655; H NMR

3

;250 MHz, CDCl₃): d_H1.17 ;d, J_H±H6.8 Hz, 3H, CH±

3

CH₃), 1.24 ;t, J_H±H7.0 Hz, 3H, O±CH₂±CH₃), 1.34 [s,

9H, C;CH₃)₃], 1.86 [s, 3H, CHvC;CH₃)±CO], 4.14 ;q,

³J_H±H6.8 Hz, 2H, O±CH₂±CH₃), 4.46 ;m, 1H, NH), 4.72

1

3

1655; H NMR ;250 MHz, CDCl₃): d_H0.89 [d, J_H±H

3

4

3

;m, 1H, NH±CH), 6.49 [dd, J_H±H8.9 Hz and J_H±H

6.8 Hz, 2£3H, CH;CH₃)₂], 1.28 ;t, J_H±H7.1Hz, 3H, O±

1.3 Hz, 1H, CHvC;CH₃)±CO]; ¹³C NMR ;62.896 MHz,

CDCl₃): d_C12.4 [CHvC;CH₃)±CO], 14.0 ;O±CH₂±

CH₃), 20.5 ;CH±CH₃), 28.3 [3C, C;CH₃)₃], 44.8 ;NH±

CH), 60.5 ;O±CH₂±CH₃), 78.3 [C;CH₃)₃], 128.0

[CHvC;CH₃)±CO], 142.7 [CHvC;CH₃)±CO], 154.9

;CO Boc), 167.9 ;COOEt); [a]_D2128 ;c0.8, HCCl₃).

CH₂±CH₃), 1.41 [s, 9H, C;CH₃)₃], 1.79 [m, 1H, CH;CH₃)₂],

4

1.90 [d, J_H±H0.5 Hz, 3H, CHvC;CH₃)±CO], 4.22 ;q,

³J_H±H7.1Hz, 2H, O±C H₂±CH₃), 4.51;m, 1H, N H), 4.79

3

4

;m, 1H, NH±CH), 6.49 [dd, J_H±H9.5 Hz and J_H±H

0.5 Hz, 1H, CHvC;CH₃)±CO]; ¹³C NMR ;62.896 MHz,

CDCl₃): d_C13.0 [CHvC;CH₃)±CO], 13.8 ;O±CH₂±

CH₃), 18.5 and 19.1 [2C, CH;CH₃)₂], 28.0 [3C, C;CH₃)₃],

32.9 [CH;CH₃)₂], 55.4 ;NH±CH), 60.6 ;O±CH₂±CH₃),

79.3 [C;CH₃)₃], 128.4 [CHvC;CH₃)±CO], 139.9

[CHvC;CH₃)±CO], 155.3 ;CO Boc), 167.7 ;COOEt).

4.5.3. Ethyl [l-2cis)]-4-[2t-butoxycarbonyl)amino]-2-

chloro-2-pentenoate 5h. Yield: 489 mg ;88%); colourless

oil obtained with phosphonate 6b; R_f0.62 ;ethyl acetate/

hexane: 1:1); IR ;KBr ®lm)/cm²¹: n_max3340, 1715, 1700

and 1690; ¹H NMR ;250 MHz, CDCl₃): d_H1.29 ;d,

4.5.6. Ethyl 2trans)- or 2cis)-4-[2t-butoxycarbonyl)amino]-

2-methyl-2-butenoate 5l. Yield: 1.14 g ;41%) of pure cis

isomer obtained after a separation on a silicagel chromato-

graphic column from 2.37 g ;85%) of a ;trans/cis:35:65)

mixture obtained with the phosphonate 6a and 345 mg

;63%) of a ;trans/cis: 14:86) mixture obtained with the

phosphonate 6b. cis Isomer: colourless oil; R_f0.35 ;ethyl

acetate/hexane: 1:4); IR ;KBr ®lm)/cm²¹: n_max3370,

3

³J_H±H7.15 Hz, 3H, CH±CH₃), 1.36 ;t, J_H±H7.15 Hz,

3

3H, O±CH₂±CH₃), 1.36 [s, 9H, C;CH₃)₃], 4.28 ;q, J_H±H

7.15 Hz, 2H, O±CH₂±CH₃), 4.69 ;m, 1H, NH), 5.00 ;m, 1H,

NH±CH), 6.30 ;d, ³J_H±H8.65 Hz, 1H, CHvCCl±CO); ¹³

C

NMR ;62.896 MHz, CDCl₃): d_C13.8 ;O±CH₂±CH₃), 19.9

;CH±CH₃), 28.1[3C, C; CH₃)₃], 45.7 ;NH±CH), 62.2

;O±CH₂±CH₃), 79.4 [C;CH₃)₃], 122.2 ;CHvCCl±CO),

146.2 ;CHvCCl±CO), 154.8 ;CO Boc), 161.9 ;COOEt).

1

1715, 1695 and 1645; H NMR ;250 MHz, CDCl₃): d_H

3

1.23 ;t, J_H±H7.0 Hz, 3H, O±CH₂±CH₃), 1.37 [s, 9H,

4

4.5.4. Ethyl [l-2cis)]-4-[2t-butoxycarbonyl)amino]-2-

¯uoro-2-pentenoate 5i. Yield: 261mg ;95%); white solid

obtained with phosphonate 6b; mp 64±658C; R_f0.57 ;ethyl

acetate/hexane: 1:3); IR ;KBr ®lm)/cm²¹: n_max3360,

1725, 1685 and 1665; ¹H NMR ;250 MHz, CDCl₃):

C;CH₃)₃], 1.82 [d, J_H±H1.0 Hz, 3H, CHvC;CH₃)±CO],

3

3.93±4.07 ;m, 2H, NH±CH₂), 4.13 ;q, J_H±H7.0 Hz, 2H,

O±CH₂±CH₃), 5.07 ;m, 1H, NH±CH₂), 5.93 [m, 1H,

CHvC;CH₃)±CO]; ¹³C NMR ;62.896 MHz, CDCl₃): d_C

14.0 ;O±CH₂±CH₃), 19.9 [CHvC;CH₃)±CO], 28.2 [3C,

C;CH₃)₃], 39.4 ;NH±CH₂), 60.3 ;O±CH₂±CH₃),

79.1[ C;CH₃)₃], 128.7 [CHvC;CH₃)±CO], 140.2

[CHvC;CH₃)±CO], 155.8 ;CO Boc), 167.2 ;COOEt).

trans Isomer: colourless oil; R_f0.29 ;ethyl acetate/hexane:

1:4); IR ;KBr ®lm)/cm²¹: n_max3370, 1715, 1695 and

3

d_H1.25 ;d, J_H±H7.0 Hz, 3H, CH±CH₃), 1.30 ;t,

³J_H±H7.5 Hz, 3H, O±CH₂±CH₃), 1.37 [s, 9H, C;CH₃)₃],

3

4.26 ;q, J_H±H7.5 Hz, 2H, O±CH₂±CH₃), 4.88 ;m, 1H,

3

NH), 5.01;m, 1H, NH±C H), 5.79 ;dd, J_H±H8.9 Hz and

³J_H±F20 Hz, 1H, CHvCF±CO); ¹³C NMR ;62.896 MHz,

1

3

CDCl₃): d_C14.0 ;O±CH₂±CH₃), 20.8 ;CH±CH₃), 28.2

1655; H NMR ;250 MHz, CDCl₃): d_H1.28 ;t, J_H±H

4

[3C, C;CH₃)₃], 43.0 ;d, J_C±F4.0 Hz, 1C, NH±CH), 61.6

7.0 Hz, 3H, O±CH₂±CH₃), 1.44 [s, 9H, C;CH₃)₃], 1.86 [d,

⁴J_H±H1.0 Hz, 3H, CHvC;CH₃)±CO], 3.82±3.96 ;m, 2H,

NH±CH₂), 4.19 ;q, ³J_H±H7.0 Hz, 2H, O±CH₂±CH₃), 4.73

;O±CH₂±CH₃), 79.4 [C;CH₃)₃], 125.7 ;d, ²J_C±F17 Hz, 1C,

1

CHvCF±CO), 146.5 ;d, J_C±F256 Hz, 1C, CHvCF±

3

4

CO), 154.9 ;CO Boc), 160.3 ;d, J_C±F8.9 Hz, 1C,

;m, 1H, NH±CH₂), 6.64 [dt, J_H±H6.5 Hz and J_H±H

COOEt); ¹⁹F NMR ;235.35 MHz, CDCl₃): d_F2123.6 ;d,

³J_F±H20 Hz).

1.0 Hz, 1H, CHvC;CH₃)±CO]; ¹³C NMR ;62.896 MHz,

CDCl₃): d_C12.5 [CHvC;CH₃)±CO], 14.2 ;O±CH₂±CH₃),

4916

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

28.3 [3C, C;CH₃)₃], 38.8 ;NH±CH₂), 60.7 ;O±CH₂±CH₃),

79.7 [C;CH₃)₃], 129.5 [CHvC;CH₃)±CO], 137.9

[CHvC;CH₃)±CO], 155.3 ;CO Boc), 167.5 ;COOEt); MS

;EI¹): m/z calculated for C₁₂H₂₁NO₄[M]¹243.2, found

244.2 [[M11]¹100%].

CH), 61.9 ;O±CH₂±CH₃), 79.5 [C;CH₃)₃], 123.3

;CHvCCl±CO), 143.3 ;CHvCCl±CO), 155.1 ;CO Boc),

163.0 ;COOEt).

4.5.9.

[l-2cis)]-N-2t-Butoxycarbonyl)-2-[1⁰-ethenyl-2⁰-

¯uoro-2⁰-ethoxycarbonyl]-pyrrolidine 5s. Yield: 261mg

;92%) of pure cis isomer obtained with phosphonate 6b;

colourless oil; R_f0.61;ethyl acetate/hexane: :12); IR

4.5.7. [l-2trans)]- or [l-2cis)]-N-2t-Butoxycarbonyl)-2-[1⁰-

ethenyl-2⁰-methyl-2⁰-ethoxy carbonyl]-pyrrolidine 5p.

Yield: 1.09 g ;50%) of pure cis isomer obtained after a

separation on a silicagel chromatographic column from

1.73 g ;79%) of a ;trans/cis:10:90) mixture obtained with

the phosphonate 6a and 872 mg ;71%) of a ;trans/cis:70:30)

mixture obtained with the phosphonate 6b. cis Isomer:

colourless oil; R_f0.78 ;ethyl acetate/hexane: 1:4); IR

;KBr ®lm)/cm²¹: n_max1730, 1700 and 1670; H NMR

1

3

;250 MHz, CDCl₃): d_H1.35 ;t, J_H±H7.0 Hz, 3H, O±

CH₂±CH₃), 1.40 [s, 9H, C;CH₃)₃], 1.64±2.37 ;m, 2£2H,

CH±CH₂±CH₂), 3.34±3.60 ;m, 2H, N±CH₂), 4.32 ;q,

³J_H±H7.2 Hz, 2H, O±CH₂±CH₃), 5.13 ;dt, J_H±H8.5,

3

5.0 Hz, 1H, N±CH), 5.85 ;dd, J_H±H8.5 Hz and J_H±F

1

;KBr ®lm)/cm²¹: n_max1710, 1695 and 1620; H NMR

20.25 Hz, 1H, CHvCF±CO); ¹³C NMR ;62.896 MHz,

CDCl₃): d_C13.6 ;O±CH₂±CH₃), 23.9 and 23.2 ;CH±

CH₂±CH₂), 27.8 [3C, C;CH₃)₃], 32.5 ;CH±CH₂±CH₂),

3

;250 MHz, CDCl₃): d_H1.30 ;t, J_H±H7.0 Hz, 3H, O±

CH₂±CH₃), 1.39 [s, 9H, C;CH₃)₃], 1.61±2.35 ;m, 2£2H,

4

CH±CH₂±CH₂), 1.90 [CHvC;CH₃)±CO], 3.32±3.57 ;m,

45.9 and 46.3 ;N±CH₂), 52.6 ;d, J_C±F4.0 Hz, 1C, N±

3

2H, N±CH₂), 4.19 ;q, J_H±H7.0 Hz, 2H, O±CH₂±CH₃),

CH), 61.0 ;O±CH₂±CH₃), 78.9 [C;CH₃)₃], 125.4 ;d,

3

1

5.02 ;m, 1H, N±CH), 5.86 [d, J_H±H6.5 Hz, 1H,

²J_C±F7.0 Hz, 1C, CHvCF±CO), 146.1 ;d, J_C±F

CHvC;CH₃)±CO]; ¹³C NMR ;62.896 MHz, CDCl₃): d_C

14.1 ;O±CH₂±CH₃), 20.0 [CHvC;CH₃)±CO], 23.8

;CH±CH₂±CH₂), 28.3 [3C, C;CH₃)₃], 33.0 ;CH±CH₂±

CH₂), 46.4 ;N±CH₂), 56.1;N± CH), 60.1;O± CH₂±CH₃),

77.3 [C;CH₃)₃], 134.2 [CHvC;CH₃)±CO], 145.1

[CHvC;CH₃)±CO], 155.4 ;CO Boc), 167.0 ;COOEt).

trans Isomer: colourless oil; R_f0.65 ;ethyl acetate/hexane:

237 Hz, 1C, CHvCF±CO), 153.9 ;CO Boc), 160.2 ;d,

²J_C±F35 Hz, 1C, COOEt); ¹⁹F NMR ;235.35 MHz,

3

CDCl₃): d_F2124.5 ;d, J_F±H20.2 Hz).

4.5.10. [l-2trans)]- or [l-2cis)]-N-2t-Butoxycarbonyl)-2-[1⁰-

ethenyl-2⁰-ethoxycarbonyl]-pyrrolidine 5w. Yield: 434

mg ;77%); colourless oil ;trans/cis: 16:84); obtained with

phosphonate 6a cis isomer: colourless oil; R_f0.61;ethyl

acetate/hexane: 1:1); IR ;KBr ®lm)/cm²¹: n_max1735, 1695

and 1650; ¹H NMR ;250 MHz, CDCl₃): d_H1.24 ;t,

³J_H±H7.1Hz, 3H, O±CH ₂±CH₃), 1.37 [s, 9H, C;CH₃)₃],

1.58±2.40 ;m, 2£2H, CH±CH₂±CH₂), 3.33±3.61;m, 2H,

1

1:4); IR ;KBr ®lm)/cm²¹: n_max1710, 1695 and 1620; H

3

NMR ;250 MHz, CDCl₃): d_H1.29 ;t, J_H±H7.0 Hz, 3H,

O±CH₂±CH₃), 1.40 [s, 9H, C;CH₃)₃], 1.57±2.36 ;m, 2£2H,

CH±CH₂±CH₂), 1.89 [CHvC;CH₃)±CO], 3.28±3.54 ;m,

3

2H, N±CH₂), 4.20 ;q, J_H±H7.0 Hz, 2H, O±CH₂±CH₃),

3

5.01;m, H1, N±C

H), 6.57 [d, J_H±H6.5 Hz, 1H,

N±CH₂), 4.14 ;q, J_H±H7.1Hz, 2H, O±C H₂±CH₃), 5.25

CHvC;CH₃)±CO]; ¹³C NMR ;62.896 MHz, CDCl₃): d_C

12.7 [CHvC;CH₃)±CO], 14.3 ;O±CH₂±CH₃), 23.1

;CH±CH₂±CH₂), 28.0 [3C, C;CH₃)₃], 32.5 ;CH±CH₂±

CH₂), 45.8 ;N±CH₂), 57.0 ;N±CH), 61.1 ;O±CH₂±CH₃),

77.1[ C;CH₃)₃], 129.7 [CHvC;CH₃)±CO], 137.1

[CHvC;CH₃)±CO], 154.4 ;CO Boc), 169.2 ;COOEt).

;m, 1H, N±CH), 5.69 ;d, J_H±H11.5 Hz, 1H, CHvCH±

3

CO), 6.18 ;m, 1H, CHvCH±CO); ¹³C NMR ;62.896 MHz,

CDCl₃): d_C14.2 ;O±CH₂±CH₃), 24.7 ;CH±CH₂±CH₂),

28.3 [3C, C;CH₃)₃], 32.8 ;CH±CH₂±CH₂), 46.9 ;N±CH₂),

55.3 ;N±CH), 59.9 ;O±CH₂±CH₃), 79.3 [C;CH₃)₃], 118.0

;CHvCH±CO), 152.4 ;CHvCH±CO), 154.6 ;CO Boc),

165.9 ;COOEt) trans isomer: colourless oil; R_f0.44

1

4.5.8. [l-2trans)]-/[l-2cis)]-N-2t-Butoxycarbonyl)-2-[1⁰-

;ethyl acetate/hexane: 1:3); H NMR ;250 MHz, CDCl₃):

3

ethenyl-2⁰-chloro-2⁰-ethoxycarbonyl]-pyrrolidine

5r.

d_H1.21 ;t, J_H±H7.0 Hz, 3H, O±CH₂±CH₃), 1.46 [s,

Yield: 520 mg ;95%); colourless oil ;trans/cis: 33:67)

obtained with phosphonate 6b; R_f0.65 ;ethyl acetate/

hexane: 1:4); IR ;KBr ®lm)/cm²¹: n_max1710, 1695 and

9H, C;CH₃)₃], 1.60±2.41 ;m, 2£2H, CH±CH₂±CH₂),

3

3.30±3.52 ;m, 2H, N±CH₂), 4.21;q, J_H±H7.0 Hz, 2H,

3

O±CH₂±CH₃), 4.46 ;m, 1H, N±CH), 5.82 ;d, J_H±H

1

1620. cis Isomer: H NMR ;250 MHz, CDCl₃): d_H1.35

16.2 Hz, 1H, CHvCH±CO), 6.80 ;m, 1H, CHvCH±

CO); ¹³C NMR ;62.896 MHz, CDCl₃): d_C14.2 ;O±CH₂±

CH₃), 24.0 ;CH±CH₂±CH₂), 28.4 [3C, C;CH₃)₃], 31.7

;CH±CH₂±CH₂), 46.3 ;N±CH₂), 55.4 ;N±CH), 60.3 ;O±

CH₂±CH₃), 79.4 [C;CH₃)₃], 120.5 ;CHvCH±CO), 153.4

;CHvCH±CO], 154.6 ;CO Boc), 165.9 ;COOEt); MS

;FAB¹): m/z calculated for C₁₂H₂₁NO₄[M]¹269.2, found

270.2 [[M11]¹, 60%], 214.2 [[M112tBu]¹, 84%], 170.1

[[M2CHvCH±COOEt]¹, 100%].

3

;t, J_H±H7.2 Hz, 3H, O±CH₂±CH₃), 1.41 [s, 9H,

C;CH₃)₃], 1.64±2.91 ;m, 2£2H, CH±CH₂±CH₂), 3.22±

3

3.51;m, 2H, N±C H₂), 4.46 ;q, J_H±H7.2 Hz, 2H, O±

3

CH₂±CH₃), 5.55 ;m, 1H, N±CH), 6.34 ;d, J_H±H8.3 Hz,

1H, CHvCCl±CO); ¹³C NMR ;62.896 MHz, CDCl₃):

d_C13.6 ;O±CH₂±CH₃), 23.7 ;CH±CH₂±CH₂), 28.0 [3C,

C;CH₃)₃], 32.2 ;CH±CH₂±CH₂), 46.2 ;N±CH₂), 55.9

;N±CH), 61.7 ;O±CH₂±CH₃), 79.3 [C;CH₃)₃], 121.1

;CHvCCl±CO), 146.9 ;CHvCCl±CO), 153.9 ;CO Boc),

161.9 ;COOEt). trans Isomer: ¹H NMR ;250 MHz, CDCl₃):

d_H1.34 ;t, ³J_H±H7.2 Hz, 3H, O±CH₂±CH₃), 1.41 [s, 9H,

C;CH₃)₃], 1.64±2.91 ;m, 2£2H, CH±CH₂±CH₂), 3.22±3.51

4.5.11. Ethyl 2trans)- or 2cis)-5-[2t-butoxycarbonyl)amino]-

2-methyl-2-pentenoate 5t. Yield: 756 mg ;50%) of pure cis

isomer obtained after a separation on a silicagel chromato-

graphic column from 1.750 g ;91%) of a ;trans/cis:40:60)

mixture obtained with the phosphonate 6a and 175 mg

;60%) of a ;trans/cis:40:60) mixture obtained with the phos-

phonate 6b. cis Isomer: colourless oil; R_f0.49 ;ethyl

acetate/hexane: 1:5); IR ;KBr ®lm)/cm²¹: n_max3375,

3

;m, 2H, N±CH₂), 4.46 ;q, J_H±H7.2 Hz, 2H, O±CH₂±

3

CH₃), 4.68 ;m, 1H, N±CH), 6.97 ;d, J_H±H8.3 Hz, 1H,

CHvCCl±CO); ¹³C NMR ;62.896 MHz, CDCl₃): d_C

13.6 ;O±CH₂±CH₃), 24.2 ;CH±CH₂±CH₂), 28.0 [3C,

C;CH₃)₃], 31.5 ;CH±CH₂±CH₂), 46.6 ;N±CH₂), 55.9 ;N±

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

4917

1

1715, 1695 and 1625; H NMR ;250 MHz, CDCl₃): d_H

;NH±CH₂±CH₂), 61.4 ;O±CH₂±CH₃), 79.2 [C;CH₃)₃],

3

1.32 ;t, J_H±H7.1Hz, 3H, O±CH ₂±CH₃), 1.45 [s, 9H,

119.9 ;d, J_C±F19 Hz, 1C, CHvCF±CO), 148.0 ;d,

C;CH₃)₃], 1.92 [CHvC;CH₃)±CO], 2.51±2.73 ;m, 2H,

N±CH₂±CH₂), 3.11±3.34 ;m, 2H, N±CH₂±CH₂), 4.21;q,

³J_H±H7.1Hz, 2H, O±C H₂±CH₃), 4.75 ;m, 1H, NH±CH₂),

¹J_C±F254 Hz, 1C, CHvCF±CO), 155.9 ;CO Boc), 160.5

3

;d, J_H±H50 Hz, 1C, COOEt); ¹⁹F NMR ;235.36 MHz,

3

CD₃COCD₃): d_F2120.3 ;d, J_F±H19 Hz, 1F).

5.90 [t, J_H±H8.0 Hz, 1H, CHvC;CH₃)±CO]; ¹³C NMR

3

;62.896 MHz, CDCl₃): d_C14.2 ;O±CH₂±CH₃), 20.5

[CHvC;CH₃)±CO], 28.3 [3C, C;CH₃)₃], 29.7 ;NH±CH₂±

CH₂), 40.0 ;NH±CH₂±CH₂), 60.3 ;O±CH₂±CH₃),

79.0 [C;CH₃)₃], 129.7 [CHvC;CH₃)±CO], 138.6

[CHvC;CH₃)±CO], 156.0 ;CO Boc), 167.0 ;COOEt); MS

;EI¹): m/z calculated for C₁₃H₂₃NO₄[M]¹257.2, found

258.1[[M 11]¹, 47%], 202.0 [[M112tBu]¹, 56%],

[[M112tBuOCO]¹, 100%]. trans Isomer: colourless oil;

4.6. Typical procedure for the hydrolysis of cis-

vinylogous aminoesters 5 into cis-aminoacids 4

To a solution of pure cis-vinylogous aminoester 5

;1.20 mmol) in ethanol ;6 mL) was added dropwise

2.5 equiv. ;3 mL) of a 1N NaOH aqueous solution. The

mixture was stirred at room temperature until TLC analysis

indicated that all aminoester was reacted ;2±3 h). Then

1equiv. of a 1N HCl aqueous solution was added

;1.2 mL) before the mixture was evaporated to eliminate

ethanol. Then, 1.6 equiv. of a 1N HCl aqueous solution

was added again ;1.6 mL), keeping up the temperature

below 258C, before the aqueous layer was extracted with

ethyl acetate ;3£15 mL). The organic layers were combined

and dried over magnesium sulfate before the solvent was

removed under vacuum to leave the crude product cis-

aminoacid 4.

R_f0.43 ;ethyl acetate/hexane: 1:5); IR ;KBr ®lm)/cm²¹

:

1

n_max3365, 1710 and 1625; H NMR ;250 MHz, CDCl₃):

d_H1.13 ;t, ³J_H±H7.0 Hz, 3H, O±CH₂±CH₃), 1.28 [s, 9H,

C;CH₃)₃], 1.69 [CHvC;CH₃)±CO], 2.15±2.33 ;m, 2H,

N±CH₂±CH₂), 3.01±3.16 ;m, 2H, N±CH₂±CH₂), 4.02 ;q,

³J_H±H7.0 Hz, 2H, O±CH₂±CH₃), 5.01;m, 1H, N H±CH₂),

5.57 [t, J_H±H6.5 Hz, 1H, CHvC;CH₃)±CO]; ¹³C NMR

3

;62.896 MHz, CDCl₃): d_C12.1 [CHvC;CH₃)±CO], 13.9

;O±CH₂±CH₃), 28.0 [3C, C;CH₃)₃], 29.0 ;NH±CH₂±CH₂),

39.0 ;NH±CH₂±CH₂), 60.1;O± CH₂±CH₃), 78.6 [C;CH₃)₃],

129.5 [CHvC;CH₃)±CO], 138.0 [CHvC;CH₃)±CO],

155.6 ;CO Boc), 167.5 ;COOEt).

4.6.1. [l-2cis)]-4-[2t-Butoxycarbonyl)amino]-2-methyl-2-

pentenoic acid 4d. Yield: 218 mg ;88%); colourless oil

obtained from cis-ester 5d; R_f0.42 ;ethyl acetate/hexane:

1:1); IR ;KBr ®lm)/cm²¹: n_max3360, 1700, 1680 and

4.5.12. Ethyl 2trans)/2cis)-5-[2t-butoxycarbonyl)amino]-

2-chloro-2-pentenoate 5u. Yield: 243 mg ;90%); yellow

oil ;trans/cis: 16:84) obtained with phosphonate 6b;

1

3

1640; H NMR ;250 MHz, CDCl₃): d_H1.22 ;d, J_H±H

6.0 Hz, 3H, CH±CH₃), 1.44 [s, 9H, C;CH₃)₃], 1.96 [d,

⁴J_H±H1.3 Hz, 3H, CHvC;CH₃)±CO], 4.52 ;m, 1H, CH±

CH₃), 4.81;br s, 1H, N H±CH), 5.47 [d, ³J_H±H10.2 Hz, 1H,

CHvC;CH₃)±CO], 7.90 ;br s, 1H, COOH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C20.3 and 20.5 [CH±CH₃and

CHvC;CH₃)±CO], 28.2 [3C, C;CH₃)₃], 45.8 ;CH±CH₃),

80.9 [C;CH₃)], 130.1 [CHvC;CH₃)±CO], 138.3

[CHvC;CH₃)±CO], 156.6 ;CO Boc), 170.5 ;COOH);

[a]_D1318 ;c1.1, HCCl₃); MS ;EI¹) m/z calculated for

C₁₁H₁₉NO₄[M]¹229.13, found 230.1 [[M11]¹, 12%],

173.6 [[M112tBu]¹, 39%], 129.3 [[M112tBuOCO]¹,

34%], 112.2 [[M112tBuOCO±OH]¹, 100%].

R_f0.41 ;ethyl acetate/hexane: 1:1); IR ;KBr ®lm)/cm²¹

:

1

n_max3365, 1715, 1700 and 1690. cis Isomer: H NMR

3

;250 MHz, CDCl₃): d_H1.23 ;t, J_H±H7.11 Hz, 3H,

O±CH₂±CH₃), 1.32 [s, 9H, C;CH₃)₃], 2.59±2.71;m, 2H,

N±CH₂±CH₂), 3.09±3.21;m, 2H, N±C H₂±CH₂), 4.16 ;q,

³J_H±H7.11 Hz, 2H, O±CH₂±CH₃), 4.96 ;m, 1H, NH±

CH₂), 6.34 ;t, J_H±H7.9 Hz, 1H, CHvCCl±CO); ¹³C

3

NMR ;62.896 MHz, CDCl₃): d_C13.8 ;O±CH₂±CH₃),

28.1[3C, C; CH₃)₃], 30.3 ;NH±CH₂±CH₂), 39.2 ;NH±

CH₂±CH₂), 61.8 ;O±CH₂±CH₃), 78.9 [C;CH₃)₃], 123.6

;CHvCCl±CO), 140.9 ;CHvCCl±CO), 155.7 ;CO Boc),

162.3 ;COOEt). trans Isomer: ¹H NMR ;250 MHz, CDCl₃):

d_H1.14 ;t, ³J_H±H7.14 Hz, 3H, O±CH₂±CH₃), 1.36 [s, 9H,

C;CH₃)₃], 2.42±2.53 ;m, 2H, N±CH₂±CH₂), 3.21±3.32 ;m,

4.6.2. [l-2cis)]-4-[2t-Butoxycarbonyl)amino]-2,5-dimethyl-

2-hexenoic acid 4j. Yield: 240 mg ;90%) colourless oil

obtained from cis-ester 5j; R_f0.48 ;ethyl acetate/hexane:

1:1); IR ;KBr ®lm)/cm²¹: n_max3325, 1710, 1695 and

3

2H, N±CH₂±CH₂), 3.99 ;q, J_H±H7.14 Hz, 2H, O±CH₂±

CH₃), 4.97 ;m, 1H, NH±CH₂), 6.97 ;t, ³J_H±H7.22 Hz, 1H,

CHvCCl±CO); ¹³C NMR ;62.896 MHz, CDCl₃): d_C13.9

;O±CH₂±CH₃), 28.1[3C, C; CH₃)₃], 30.3 ;NH±CH₂±CH₂),

39.3 ;NH±CH₂±CH₂), 62.0 ;O±CH₂±CH₃), 79.9 [C;CH₃)₃],

121.9 ;CHvCCl±CO), 138.8 ;CHvCCl±CO), 155.7 ;CO

Boc), 162.3 ;COOEt).

1

3

1645; H NMR ;250 MHz, CDCl₃): d_H0.90 ;d, J_H±H

3

6.75 Hz, 3H, CH±CH₃), 0.95 ;d, J_H±H6.7 Hz, 3H, CH±

CH₃), 1.42 [s, 9H, C;CH₃)₃], 1.71 [m, 1H, CH;CH₃)₂], 1.97

[s, 3H, CHvC;CH₃)±CO], 4.14 ;m, 1H, NH±CH±CHv),

3

4.81;br s, H1,

N

H), 5.47 [d, J_H±H10 Hz, 1H,

CHvC;CH₃)±CO], 9.71;br s, H1 , COO H); ¹³C NMR

;62.896 MHz, CDCl₃): d_C18.5 and 18.8 [2C, CH;CH₃)₂],

20.8 [CHvC;CH₃)±CO], 28.3 [3C, C;CH₃)₃], 31.9

[CH;CH₃)₂], 55.7 ;NH±CH±CHv), 81.1 [C;CH₃)₃], 132.3

[CHvC;CH₃)±CO], 134.4 [CHvC;CH₃)±CO], 157.1 ;CO

Boc), 170.4 ;COOH); MS ;FAB²) m/z calculated for

C₁₃H₂₂NO₄[M2H]²256.2, found 256.1;100%). [ a]_D

1428 ;c1.0, HCCl₃).

4.5.13. Ethyl 2cis)-5-[2t-butoxycarbonyl)amino]-2-¯uoro-

2-pentenoate 5v. Yield: 310 mg ;97%) yellow oil obtained

with phosphonate 6b; R_f0.47 ;ethyl acetate/hexane: 1:1);

IR ;KBr ®lm)/cm²¹: n_max3360, 1730, 1715 and 1695; H

1

3

NMR ;250 MHz, CDCl₃): d_H1.36 ;t, J_H±H7.2 Hz, 3H,

O±CH₂±CH₃), 1.44 [s, 9H, C;CH₃)₃], 2.53±2.78 ;m, 2H,

N±CH₂±CH₂), 3.14±3.32 ;m, 2H, N±CH₂±CH₂), 4.31;q,

³J_H±H7.2 Hz, 2H, O±CH₂±CH₃), 4.64 ;m, 1H, NH±CH₂),

3

5.90 ;dt, J_H±H8.0 Hz and J_H±F21.2 Hz, 1H, CHvCF±

CO); ¹³C NMR ;62.896 MHz, CDCl₃): d_C14.0 ;O±CH₂±

CH₃), 26.2 ;NH±CH₂±CH₂), 28.2 [3C, C;CH₃)₃], 39.7

4.6.3.

2cis)-4-[2t-Butoxycarbonyl)amino]-2-methyl-2-

butenoic acid 4l. Yield: 189 mg ;90%); colourless oil

from cis-ester 5l; R_f0.55 ;ethyl acetate); IR ;KBr ®lm)/

4918

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

cm²¹: n_max3330, 1685, 1660 and 1520; ¹H NMR

;250 MHz, CDCl₃): d_H1.43 [s, 9H, C;CH₃)₃], 1.91 [s,

4.7. Coupling of N-protected vinylogous aminoacids 4

with aminoacid derivatives

3

3H, CHvC;CH₃)±CO], 4.05 ;t, J_H±H6.0 Hz, 2H, NH±

CH₂), 5.09 ;br s, 1H, NH±CH₂), 6.05 [m, 1H,

CHvC;CH₃)±CO], 9.47 ;br s, 1H, COOH); ¹³C NMR

;62.896 MHz, CDCl₃): d_C20.0 [CHvC;CH₃)±CO], 28.3

[3C, C;CH₃)₃], 39.7 ;NH±CH₂), 79.9 [C;CH₃)₃], 129.4

[CHvC;CH₃)±CO], 140.9 [CHvC;CH₃)±CO], 156.6

;CO Boc), 171.5 ;COOH); MS ;CI²) m/z calculated for

C₁₀H₁₆NO₄[M2H]²214.12, found 214.2 ;7%), 157.6

[[M2H±tBuO]², 35%], 114.3 [[M2H±tBuOCO]², 39%],

56.9 [[tBu2H]², 85%], 40.7 [[C₃H₅±H]², 100%].

The procedure was similar to that employed above to

synthesize the vinylogous aminoamides 4⁰. The crude

products 1 were puri®ed on a silica gel chromatographic

column.

4.7.1. 2trans)-N-[42S)-4-[N-2t-Butoxycarbonylamino)]-1-

oxo-2-pentenyl]-l-valine methyl ester 1ca. Yield:

140 mg ;76%); white solid obtained from 4c ;trans/cis

.98:2); mp 1188C; R_f0.47 ;ethyl acetate/hexane: 1:1);

IR ;KBr plate)/cm²¹: n_max3440, 3350, 1735, 1700, 1685

1

4.6.4. [l-2cis)]-N-2t-Butoxycarbonyl)-2-[1⁰-ethenyl-2⁰-methyl-

2⁰-carboxy]-pyrrolidine 4p. Yield: 617 mg ;80%) colour-

less oil from cis-ester 5p; R_f0.48 ;ethyl acetate/hexane:

1:1) IR ;KBr ®lm)/cm²¹: n_max3030, 1715, 1695 and

1640; ¹H NMR ;250 MHz, CDCl₃): d_H1.47 [s, 9H,

C;CH₃)₃], 1.62±2.19 ;m, 2£2H, CH±CH₂±CH₂), 1.99 [s,

3H, CHvC;CH₃)±CO], 3.23±3.57 ;m, 2H, N±CH₂), 4.55

;m, 1H, N±CH), 5.42 [d, J11.0 Hz, 1H, CHvC;CH₃)±

CO], 11.31 ;br s, 1H, COOH); ¹³C NMR ;62.896 MHz,

CDCl₃): d_C21.2 [CHvC;CH₃)±CO], 24.4 ;CH±CH₂±

CH₂), 28.9 [3C, C;CH₃)₃], 32.8 ;CH±CH₂), 47.5

;N±CH₂), 56.2 ;N±CH), 81.9 [C;CH₃)₃], 132.6

[CHvC;CH₃)±CO], 134.5 [CHvC;CH₃)±CO], 156.5

;CO Boc), 171.0 ;COOH); MS ;EI¹) m/z calculated for

C₁₃H₂₁NO₄[M]¹255.2, found 256.2 [[M11]¹, 39%],

154.1 [[M2tBuOCO]¹, 49%], 200.0 [[M112tBu]¹,

55%], 109.9 [[M112tBuOCO±COOH]¹, 75%], 137.9

[[M112tBuOCO±OH]¹, 80%], 56.9 [[tBu]¹, 100%];

[a]_D1258 ;c1.4, HCCl₃).

and 1635; H NMR ;250 MHz, CDCl₃): d_H0.92 and 0.95

3

[2d, J_H±H6.75 Hz, 2£3H, CH;CH₃)₂], 1.26 ;d, J_H±H

6.75 Hz, 3H, CH±CH₃), 1.45 [s, 9H, C;CH₃)₃], 2.20 [m,

1H, CH;CH₃)₂], 3.74 ;s, 3H, O±CH₃), 4.39 ;m, 1H, CH±

3

CH₃), 4.58 ;m, 1H, NH±CH±CH₃), 4.64 [dd, J_H±H8.75,

3

4.75 Hz, 1H, CH±CH;CH₃)₂], 5.94 ;dd, J_H±H15.3,

3

5.25 Hz, 1H, CHvCH±CO), 6.05 ;d, J_H±H8.75 Hz, 1H,

3

NH±CH), 6.75 ;dd, J_H±H15.3, 5.25 Hz, 1H, CHvCH±

CO); ¹³C NMR ;62.896 MHz, CDCl₃): d_C17.8 ;CH±

CH₃), 18.9 and 20.2 [2C, CH;CH₃)₂], 28.3 [3C, C;CH₃)₃],

31.2 [CH;CH₃)₂], 47.0 [CH±CH;CH₃)₂], 52.1; CH±CHv),

57.1;O± CH₃), 79.4 [C;CH₃)₃], 122.7 ;CHvCH±CO),

145.8 ;CHvCH±CO), 155.1 ;CO Boc), 166.2 ;CO±NH),

172.5 ;COOCH₃); [a]_D16.78 ;c1.1, HCCl₃); MS ;EI¹):

m/z calculated for C₁₆H₂₈N₂O₅[M]¹328.2, found 329.3

[[M11]¹,100%].

4.7.2. 2trans)-N-[42S)-4-[N-2t-Butoxycarbonylamino)]-1-

oxo-2-pentenyl]-glycine methyl ester 1cb. Yield: 365 mg

;92%); white solid obtained from 4c ;trans/cis . 98:2); mp

4.6.5. [l-2cis)]-N-2t-Butoxycarbonyl)-2-[1⁰-ethenyl-2⁰-car-

boxy]-pyrrolidine 4w. Yield: 920 mg ;80%) as an oil

obtained from cis-ester 5w; R_f0.10 ;ethyl acetate/hexane:

928C; R_f0.48 ;ethyl acetate); IR ;KBr plate)/cm²¹

:

n_max3435, 3320, 3050, 1750, 1715, 1680 and 1635. trans

1

3

Isomer: H NMR ;250 MHz, CDCl₃): d_H1.26 ;d, J_H±H

1

4:1); IR ;KBr ®lm)/cm²¹: n_max1720, 1695 and 1650; H

7.0 Hz, 3H, CH±CH₃), 1.44 [s, 9H, C;CH₃)₃], 3.77 ;s, 3H,

3

NMR ;250 MHz, CDCl₃): d_H1.41 [s, 9H, C;CH₃)₃], 1.63±

2.39 ;m, 2£2H, CH±CH₂±CH₂), 3.34±3.52 ;m, 2H, N±

CH₂), 4.84 ;m, 1H, N±CH), 5.31;m, 1H, C HvCH±CO),

5.80 ;m, 1H, CHvCH±CO), 9.45 ;br s, 1H, COOH); ¹³C

NMR ;62.896 MHz, CDCl₃): d_C24.2 ;CH±CH₂±CH₂),

28.7 [3C, C;CH₃)₃], 31.4 ;CH±CH₂), 45.3 ;N±CH₂), 55.7

;N±CH), 79.8 [C;CH₃)₃], 127.6 ;CHvCH±CO), 129.5

;CHvCH±CO), 154.3 ;CO Boc), 169.0 ;COOH); [a]_D

1308 ;c1.3, HCCl₃).

O±CH₃), 4.11 ;d, J_H±H5.0 Hz, 2H, CH₂), 4.40 ;m, 1H,

3

CH±CH₃), 4.61;m, 1H, N H±CH±CH₃), 5.96 ;d, J_H±H

3

15.5 Hz, 1H, CHvCH±CO), 6.31;d, J_H±H5.0 Hz, 1H,

3

NH±CH₂), 6.78 ;dd, J_H±H15.5, 5.0 Hz, 1H, CHvCH±

CO); ¹³C NMR ;62.896 MHz, CDCl₃): d_C20.0 ;CH±

CH₃), 28.1[3C, C; CH₃)₃], 40.8 ;CH₂), 46.7 ;CH±CH₃),

51.9 ;O±CH₃), 79.5 [C;CH₃)₃], 121.7 ;CHvCH±CO),

145.5 ;CHvCH±CO), 154.9 ;CO Boc), 165.8 ;CO±NH),

170.3 ;COOCH₃); [a]_D12.28 ;c1.2, HCCl₃); MS ;EI¹):

m/z calculated for C₁₃H₂₂N₂O₅[M]¹286.2, found

287.2 [[M11]¹, 50%], 97.1[[M 2tBuOCONH±l

CH₂COOCH₃]¹, 83%], 231.1 [[M112tBu]¹, 83%].

4.6.6. 2cis)-5-[2t-Butoxycarbonyl)amino]-2-methyl-2-pen-

tenoic acid 4t. Yield: 68 mg ;96%); colourless oil from cis-

ester 5t; R_f0.57 ;ethyl acetate); IR ;KBr ®lm)/cm²¹

:

1

n_max3370, 1695 and 1645; H NMR ;250 MHz, CDCl₃):

4.7.3. 2trans)/2cis)-N-[42S)-4-[N-2t-Butoxycarbonylamino)]-

2-¯uoro-1-oxo-2-pentenyl]-glycine methyl ester 1ia.

Yield: 242 mg ;93%); white solid ;trans/cis: 35:65);

obtained from 4i ;trans/cis: 35:65); R_f0.45 ;ethyl acetate);

IR ;KBr plate)/cm²¹: n_max3355, 3000, 1755, 1695 and

1660; MS ;CI²): m/z calculated for C₁₃H₂₀N₂O₅[M2H]²

303.1, found 303.2 ;100%). trans Isomer: ¹H NMR

4

d_H1.42 [s, 9H, C;CH₃)₃], 2.02 [d, J_H±H1.0 Hz, 3H,

3

CHvC;CH₃)±CO], 2.67 ;dt, J_H±H6.9 Hz, J_H±H

6.9 Hz, 2H, CH₂±CHv), 3.08±3.32 ;m, 2H, NH±CH₂),

4.80 ;br s, 1H, NH±CH₂), 6.01[m, 1H, C HvC;CH₃)±

CO], 10.6 ;br s, 1H, COOH); ¹³C NMR ;62.896 MHz,

CDCl₃): d_C20.5 [CHvC;CH₃)±CO], 28.4 [3C, C;CH₃)₃],

30.1; CH₂±CHv), 39.9 ;N±CH₂), 79.2 [C;CH₃)₃], 128.9

[CHvC;CH₃)±CO], 141.7 [CHvC;CH₃)±CO], 156.2 ;CO

Boc), 172.8 ;COOH); MS ;EI¹) m/z calculated for

C₁₁H₁₉NO₄[M]¹229.1, found 230.2 [[M11]¹, 10%],

130.0 [[M2tBuOCO]¹, 40%], 173.9 [[M1H±tBu]¹, 45%],

112.0 [[M1H±tBuOCO±OH]¹, 63%], 56.9 [[tBu]¹, 1 00%].

3

;250 MHz, CD₃COCD₃): d_H1.28 ;d, J_H±H6.25 Hz, 3H,

CH±CH₃), 1.39 [s, 9H, C;CH₃)₃], 3.71;s, 3H, O±C H₃), 4.38

;m, 1H, CH±CH₃), 4.61;m, 1H, N H±CH±CH₃), 6.01;dd,

3

³J_H±F35 Hz and J_H±H9.0 Hz, 1H, CHvCF±CO), 6.21

3

;d, J_H±H7.5 Hz, 1H, NH±CH), 7.95 ;d, J_H±H6.0 Hz,

1H, NH±CH₂); ¹³C NMR ;62.896 MHz, CDCl₃): d_C20.7

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

4919

;CH±CH₃), 28.3 [3C, C;CH₃)₃], 40.7 ;CH₂), 41.8 ;CH±

173.7 ;COOCH₃); cis isomer: ¹H NMR ;250 MHz,

2

CH₃), 53.4 ;O±CH₃), 79.8 [C;CH₃)₃], 118.4 ;d, J_C±F

3

CDCl₃): d_H1.21 ;d, J_H±H6.8 Hz, 3H, CH±CH₃), 1.45

1

3

8.5 Hz, 1C, CHvCF±CO), 149.5 ;d, J_C±F268 Hz, 1C,

[s, 9H, C;CH₃)₃], 1.46 ;d, J_H±H7.0 Hz, 3H, CH±CH₃),

2

CHvCF±CO), 155.4 ;CO Boc), 159.9 ;d, J_C±F5.8 Hz,

1.92 [s, 3H, CHvC;CH₃)±CO], 3.74 ;s, 3H, O±CH₃),

4.41±4.64 ;m, 2H, CH±CH₃and NH±CH±CH₃), 4.85 ;m,

1C, CO±NH), 169.6 ;COOCH₃); ¹⁹F NMR ;235.36 MHz,

CD₃COCD₃): d_F2127.8 ;d, ³J_F±H35 Hz, 1F). cis Isomer:

1H, CH±CH₃), 5.25 ;d, J_H±H11 Hz, 1H, CHvC;CH₃)±

3

¹H NMR ;250 MHz, CD₃COCD₃): d_H1.28 ;d, J_H±H

CO), 9.27 ;br s, 1H, NH±CH); ¹³C NMR ;62.896 MHz,

6.25 Hz, 3H, CH±CH₃₃), 1.39 [s, 9H, C;CH₃)₃], 3.71;s,

3H, O±CH₃), 4.07 ;d, J_H±H6.0 Hz, 2H, CH₂), 5.21;m,

CDCl₃): d_C18.2

;CH±CH₃), 20.7

and

21.1

[CHvC;CH₃)±CO and CH;CH₃)±CHv], 28.1[3C,

C;CH₃)₃], 44.6 [CH;CH₃)±CHv], 48.1; CH±CH₃), 52.5

;O±CH₃), 79.7 [C;CH₃)₃], 130.5 [CHvC;CH₃)±CO],

144.8 [CHvC;CH₃)±CO], 156.4 ;CO Boc), 168.1 ;CO±

NH), 173.7 ;COOCH₃).

3

1H, CH±CH₃), 5.78 ;dd, J_H±F15 Hz and J_H±H9.0 Hz,

1H, CHvCF±CO), 6.25 ;br s, 1H, NH±CH), 8.28 ;d,

³J_H±H6.0 Hz, 1H, NH±CH₂); ¹³C NMR ;62.896 MHz,

CDCl₃): d_C20.7 ;CH±CH₃), 28.3 [3C, C;CH₃)₃], 41.0

;CH₂), 41.8 ;CH±CH₃), 52.5 ;O±CH₃), 79.8 [C;CH₃)₃],

2

118.4 ;d, J_C±F8.5 Hz, 1C, CHvCF±CO), 149.5 ;d,

4.7.6. 2trans)/2cis)-N-[42S)-4-[N-2t-Butoxycarbonylamino)]-

2-methyl-1-oxo-2-pentenyl]-l-aspartic acid dimethyl

ester 1db. Yield: 194 mg ;70%) colourless oil ;trans/cis:

60:40) obtained from 4d ;trans/cis: 60:40); R_f0.70 ;ethyl

acetate); IR ;KBr plate)/cm²¹: n_max3345, 1750, 1710,

1665 and 1630; MS [EI¹]: m/z calculated for C₁₇H₂₈N₂O₇

[M]¹372.2, found 373.3 [[M11]¹, 72%], 111.0

¹J_C±F268 Hz, 1C, CHvCF±CO), 154.8 ;CO Boc), 159.9

;d, J_C±F5.8 Hz, 1C, CO±NH), 169.6 ;COOCH₃); ¹⁹F

2

3

NMR ;235.36 MHz, CD₃COCD₃): d_F2119.8 ;d, J_F±H

15 Hz, 1F).

4.7.4. 2trans)/2cis)-N-[42S)-4-[N-2t-Butoxycarbonylamino)]-

2-ethoxy-1-oxo-2-pentenyl]-glycine methyl ester 1ga.

Yield: 221mg ;80%); colourless oil ; trans/cis: 45:55);

obtained from 4g ;trans/cis: 45:55); R_f0.55 ;ethyl

acetate/hexane: 4:1); IR ;KBr plate)/cm²¹: n_max3460,

1750, 1700, 1675 and 1645 trans isomer: ¹H NMR

[[M2tBuOCO±HAsp;OCH₃)OCH₃]¹,

100%].

trans

1

3

Isomer: H NMR ;250 MHz, CDCl₃): d_H1.19 ;d, J_H±H

6.7 Hz, 3H, CH±CH₃), 1.40 [s, 9H, C;CH₃)₃], 1.92 [s, 3H,

CHvC;CH₃)±CO], 2.98 ;AB part of an ABX system,

3

n_A2.94, n_B2.96, J_AB17.2 Hz, J_AX4.5 Hz and

³J_BX4.3 Hz, 2H, CH₂±COOCH₃), 3.67 and 3.74 ;2s, 6H,

O±CH₃), 4.46 [m, 1H, CH;CH₃)±CH], 4.62 ;m, 1H, NH±

3

;250 MHz, CDCl₃₃): d_H1.18 ;d, J_H±H7.0 Hz, 3H,

CH±CH₃), 1.32 ;t, J_H±H7.0 Hz, 3H, O±CH₂±CH₃), 1.39

3

[s, 9H, C;CH₃)₃], 3.69 ;s, 3H, O±CH₃), 3.89 ;q, J_H±H

3

CH±CH₃), 4.87 ;ddd, J_H±H7.75, 4.5, 4.3 Hz, 1H, CH±

3

7.0 Hz, 2H, O±CH₂±CH₃), 3.94 ;d, J_H±H6.0 Hz, 2H,

CH₂), 6.20 [d, J_H±H8.3 Hz, 1H, CHvC;CH₃)±CO],

3

CH₂), 4.55 ;m, 1H, CH±CH₃), 5.36 ;d, J_H±H7.0 Hz, 1H,

6.82 ;d, J_H±H7.75 Hz, 1H, NH±CH±CH₂); ¹³C NMR

NH±CH±CH₃), 5.93 [d, ³J_H±H9.0 Hz, 1H, CHvC;OEt)±

;62.896 MHz, CDCl₃): d_C12.6 [CHvC;CH₃)±CO], 18.2

;CH±CH₃), 28.3 [3C, C;CH₃)₃], 35.9 ;CH₂), 45.1

[CH;CH₃)±CHv], 48.6 ;CH±CH₂), 52.0 and 52.7 ;2C,

2£O±CH₃), 79.9 [C;CH₃)₃], 130.2 [CHvC;CH₃)±CO],

138.6 [CHvC;CH₃)±CO], 155.0 ;CO Boc), 168.2 ;CO±

3

CO], 7.21;d, J_H±H6.0 Hz, 1H, NH±CH₂). cis Isomer: ¹H

3

NMR ;250 MHz, CDCl₃): d_H1.18 ;d, J_H±H7.0 Hz, 3H,

3

CH±CH₃), 1.32 ;t, J_H±H7.3 Hz, 3H, O±CH₂±CH₃), 1.39

3

[s, 9H, C;CH₃)₃], 3.69 ;s, 3H, O±CH₃), 3.85 ;q, J_H±H

3

1

7.0 Hz, 2H, O±CH₂±CH₃), 3.94 ;d, J_H±H6.0 Hz, 2H,

CH₂), 4.96 [d, 1H, CHvC;OEt)±CO], 5.08 ;m, 1H, CH±

CH₃), 5.36 ;d, ³J_H±H7.0 Hz, 1H, NH±CH), 7.71;br s, 1H,

NH±CH₂).

NH), 171.2 and 171.6 ;2C, 2£COOCH₃). cis Isomer: H

3

NMR ;250 MHz, CDCl₃): d_H1.25 ;d, J_H±H6.7 Hz, 3H,

CH±CH₃), 1.44 [s, 9H, C;CH₃)₃], 1.88 [s, 3H,

3

CHvC;CH₃)±CO], 2.88 ;d, J_AB6.61Hz, 2H, C H₂±

COOCH₃), 3.67 and 3.71;2s, 6H, O±C H₃), 4.36±4.95 [m,

3

3H, NH±CH±CH₂and NH±CH±CH₃), 5.25 [d, J_H±H

4.7.5. 2trans)/2cis)-N-[42S)-4-[N-2t-Butoxycarbonylamino)]-

2-methyl-1-oxo-2-pentenyl]-l-alanine methyl ester 1da.

Yield: 128 mg ;55%); colourless oil ;trans/cis: 60:40)

obtained from 4d ;trans/cis: 60:40); R_f0.72 ;ethyl acetate);

IR ;KBr plate)/cm²¹: n_max3355, 1760, 1715, 1680 and

1625; MS ;EI¹): m/z calculated for C₁₅H₂₅N₂O₅[M]¹

314.2, found 315.2 [[M11]¹, 14%], 138.0 [[M112

tBuO±HAlaOCH₃]¹or [M112tBuOCONH±COOCH₃]¹,

19%], 83.0 [[M2tBuOCO±CONHCH;CH₃)OCH₃]¹, 21 %],

104.0 [[HAlaOCH₃]¹, 40%], 259.1[[M 2tBu]¹, 50%], 111.1

[[M2tBuOCO±CONHCH;CH₃)OCH₃]¹, 100%]. trans

9.25 Hz, 1H, CHvC;CH₃)±CO], 9.22 ;br s, 1H, NH±

CH±CH₂); ¹³C NMR ;62.896 MHz, CDCl₃): d_C19.9 and

20.9 [CH±CH₃and CHvC;CH₃)±CO], 28.1[3C, C; CH₃)₃],

44.4 [CH;CH₃)±CHv], 48.9 ;CH±CH₂), 51.9 and 52.4 ;2C,

2£O±CH₃), 79.7 [C;CH₃)₃], 130.5 [CHvC;CH₃)±CO],

144.7 [CHvC;CH₃)±CO], 156.4 ;CO Boc), 168.2 ;CO±

NH), 171.2 and 171.6 ;2C, 2£COOCH₃).

4.7.7. 2trans)-N-[4-[N-2t-Butoxycarbonylamino)]-1-oxo-

2-butenyl]-glycine methyl ester 1ka. Yield: 377 mg

;78%); colourless oil; R_f0.40 ;ethyl acetate); IR ;KBr

plate)/cm²¹: n_max3310, 1750, 1685, 1680 and 1635; MS

;EI¹): m/z calculated for C₁₂H₂₀N₂O₅[M]¹272.1,

found 273.1[[M 11]¹, 8%], 126.9 [[M112tBu±

NH₂CH₂COOCH₃]¹, 17%], 156.1 [[M2tBuOCONH]¹,

23%], 217.1 [[M112tBu]¹, 44%], 83.1[[M 2tBuO-

CONH±CH₂COOCH₃]¹, 100%].¹H NMR ;250 MHz,

CDCl₃): d_H1.42 [s, 9H, C;CH₃)₃], 3.67 ;s, 3H, O±CH₃),

3.76±3.85 ;m, 2H, CH₂±CHv), 4.02 ;d, ³J_H±H6.0 Hz, 2H,

NH±CH₂), 6.12 ;dt, ³J_H±H15.3 Hz and ⁴J_H±H1.5 Hz, 1H,

CHvCH±CO), 6.21;br s, 1H, N H±CH₂±CHv), 6.75 ;dt,

1

3

Isomer: H NMR ;250 MHz, CDCl₃): d_H1.24 ;d, J_H±H

6.5 Hz, 3H, CH±CH₃), 1.45 [s, 9H, C;CH₃)₃], 1.46 ;d,

³J_H±H7.0 Hz, 3H, CH±CH₃), 1.97 [s, 3H, CHvC;CH₃)±

CO], 3.78 ;s, 3H, O±CH₃), 4.41±4.64 ;m, 2H, CH±CH₃and

NH±CH±CH₃), 4.65 ;m, 1H, CH±CH₃), 6.22 ;m, 1H, NH),

3

6.35 ;d, J_H±H7.5 Hz, 1H, CHvC;CH₃)±CO); ¹³C NMR

;62.896 MHz, CDCl₃): d_C12.7 [CHvC;CH₃)±CO], 18.3

;CH±CH₃), 20.9 [CH;CH₃)±CHv], 28.3 [3C, C;CH₃)₃],

45.1[ CH;CH₃)±CHv], 48.1; CH±CH₃), 52.5 ;O±CH₃),

79.5 [C;CH₃)₃], 130.5 [CHvC;CH₃)±CO], 138.1

[CHvC;CH₃)±CO], 155.0 ;CO Boc), 168.1 ;CO±NH),

4920

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

³J_H±H15.3, 4.25 Hz, 1H, CH₂±CHvCH), 7.62 ;br s, 1H,

NH±CH₂); ¹³C NMR ;62.896 MHz, CDCl₃): d_C28.1[3C,

C;CH₃)₃], 40.9 ;2C, CH₂), 52.1;O± CH₃), 79.4 [C;CH₃)₃],

122.9 ;CHvCH±CO), 141.3 ;CHvCH±CO), 155.7 ;CO

Boc), 165.7 ;CO±NH), 170.5 ;COOCH₃).

;N±CH₂), 49.2 ;CH±CH₃), 55.5 ;N±CH), 78.1[ C;CH₃)₃],

130.5 [CHvC;CH₃)±CO], 134.0 [CHvC;CH₃)±CO],

155.7 ;CO Boc), 170.2 ;CO±NH), 172.2 ;CONHiPr);

[a]_D0.08 ;c0.9, HCCl₃); MS ;EI¹): m/z calculated

for C₁₉H₃₃N₃O₅[M]¹367.2, found 368 [[M11]¹,

9%], 238 [[M2NHCH;CH₃)CONHiPr]¹, 22%], 181

[[M2tBuOCO±CONHiPr]¹, 61%], 138 [[M2tBuOCO±

NHCH;CH₃)CONHiPr]¹, 85%], 57 [[M2tBu]¹, 100%].

4.7.8. 2trans)-N-[42S)-4-[N-2t-Butoxycarbonylamino)]-1-

oxo-5-phenyl-2-pentenyl]-glycine methyl ester 1ma.

Yield: 328 mg ;82%); white solid; mp 1308C; R_f0.52

;ethyl acetate); IR ;KBr plate)/cm²¹: n_max3430, 3315,

3035, 1750, 1715, 1685 and 1635; MS ;CI²): m/z calculated

4.7.10. 22S)-2trans)- or 22S)-2cis)-N-2t-Butoxycarbonyl)-2-

[2⁰-methyl-3⁰-oxo-1⁰-propenyl-3⁰-l-2O-methyl-alaninyl)]-

pyrrolidine 1pb. Trans isomer: yield: 68 mg ;80%); colour-

less oil obtained from pure trans-4p; R_f0.24 ;ethyl acetate/

hexane: 1:1); IR ;KBr plate)/cm²¹: n_max3325, 1745, 1695,

1

for C₁₉H₂₅N₂O₅[M2H]²361.2, found 361.3 ;100%). H

NMR ;250 MHz, CDCl₃): d_H1.39 [s, 9H, C;CH₃)₃], 2.88

;d, ³J_H±H5.7 Hz, 2H, CH₂-Ph), 3.77 ;s, 3H, O±CH₃), 4.10

3

1

;d, J_H±H5.1Hz, 2H, C H₂), 4.38±4.71;m, 2 £1H, NH±

1675 and 1630; H NMR ;250 MHz, CDCl₃): d_H1.43 [s,

3

CH±CHv), 5.86 ;d, J_H±H15.1 Hz, 1H, CHvCH±CO),

9H, C;CH₃)₃], 1.44 ;d, J_H±H6.7 Hz, 3H, CH±CH₃), 1.94

6.03 ;br s, 1H, NH±CH₂), 6.83 ;dd, ³J_H±H15.1, 4.5 Hz, 1H,

CHvCH±CO), 7.09±7.35 ;m, 5H, Ph); ¹³C NMR

;62.896 MHz, CDCl₃): d_C28.3 [3C, C;CH₃)₃], 41.0

and 41.3 ;2C, CH₂and CH₂-Ph), 52.4 ;O±CH₃), 79.9

[C;CH₃)₃], 122.7 ;CHvCH±CO), 126.8, 128.5 ;2C),

129.4 ;2C) and 136.5 ;Ph), 144.3 ;CHvCH±CO), 155.0

;CO Boc), 165.2 ;CO±NH), 170.4 ;COOCH₃).

[s, 3H, CHvC;CH₃)±CO], 1.61±2.25 ;m, 2£2H, CH±

CH₂±CH₂), 3.35±3.57 ;m, 2H, N±CH₂), 3.77 ;s, 3H, O±

CH₃), 4.58 ;m, 1H, N±CH±CH₂), 4.64 ;m, 1H, CH±CH₃),

6.09±6.47 [m, 2£1H, NH±CH±CH₃and CHvC;CH₃)±

CO]; ¹³C NMR ;62.896 MHz, CDCl₃): d_C12.6

[CHvC;CH₃)±CO], 18.4 ;CH±CH₃), 23.7 and 24.7 ;CH±

CH₂±CH₂), 28.3 [3C, C;CH₃)₃], 31.9 and 32.5 ;CH±CH₂±

CH₂), 46.4 ;N±CH₂), 48.1; CH±CH₃), 52.4 ;O±CH₃), 55.0

;N±CH), 79.6 [C;CH₃)₃], 129.4 [CHvC;CH₃)±CO], 137.9

[CHvC;CH₃)±CO], 154.6 ;CO Boc), 168.2 ;CO±NH),

173.6 ;COOCH₃); [a]_D2198 ;c0.82, HCCl₃); MS

;EI¹): m/z calculated for C₁₇H₂₈N₂O₅[M]¹340.2, found

341.4 [[M11]¹, 12%], 240.4 [[M2tBuOCO]¹, 14%],

239.3 [[M112HAlaOCH₃]¹, 22%], 285.1[[M 112tBu]¹,

79%], 137.3 [[M2tBuOCO±HAlaOCH₃]¹, 98%]. cis

Isomer: yield: 46 mg ;82%); white solid obtained from

pure cis-4p; mp 1 486C; R_f0.50 ;ethyl acetate/hexane:

1:1); IR ;KBr plate)/cm²¹: n_max3245, 3050, 1670 and

1645; ¹H NMR ;250 MHz, CDCl₃): d_H1.45 [s, 9H,

4.7.9. 22S)-ꢀtrans)- or 22S)-2cis)-N-2t-Butoxycarbonyl)-2-

[2⁰-methyl-3⁰-oxo-1⁰-propenyl-3⁰-2N-isopropyl-l-alaninyl-

amido)]pyrrolidine 1pa. Trans isomer: yield: 178 mg

;84%) white solid obtained from pure trans-4p; mp

1148C; R_f0.42 ;ethyl acetate); IR ;KBr plate)/cm²¹

:

1

n_max3330, 1695, 1660 and 1620; H NMR ;250 MHz,

3

CDCl₃): d_H1.12 [d, J_H±H8.5 Hz, 6H, CH;CH₃)₂], 1.36

3

;d, J_H±H7.0 Hz, 3H, CH±CH₃), 1.37 [s, 9H, C;CH₃)₃],

1.88 [s, 3H, CHvC;CH₃)±CO], 1.53±2.18 ;m, 2£2H,

CH±CH₂±CH₂), 3.27±3.57 ;m, 2H, N±CH₂), 4.01[m, 1H,

CH;CH₃)₂], 4.47 ;m, 1H, CH±CH₃), 4.60 ;m, 1H, N±CH),

3

6.25 ;m, 1H, NH±CH±CH₃), 6.76 [d, J_H±H7.5 Hz, 1H,

C;CH₃)₃], 1.46 ;d, J_H±H7.2 Hz, 3H, CH±CH₃), 1.92 [d,

3

CHvC;CH₃)±CO], 7.01;d, J_H±H7.0 Hz, 1H, NH-iPr);

⁴J_H±H1.3 Hz, 3H, CHvC;CH₃)±CO], 1.57±2.20 ;m,

¹³C NMR ;62.896 MHz, CDCl₃): d_C12.7 ;CH±CH₃),

19.4 [CHvC;CH₃)±CO], 22.5 [CH;CH₃)₂], 23.6 ;CH±

CH₂±CH₂), 28.4 [3C, C;CH₃)₃], 32.6 ;CH±CH₂±CH₂),

41.3 [CH;CH₃)₂], 46.4 ;N±CH₂), 49.0 ;CH±CH₃), 55.0

;N±CH), 79.3 [C;CH₃)₃], 129.2 [CHvC;CH₃)±CO],

138.0 [CHvC;CH₃)±CO], 154.2 ;CO Boc), 168.2 ;CO±

NH), 171.5 ;CONHiPr); [a]_D229.68 ;c0.4, HCCl₃);

MS ;FAB¹): m/z calculated for C₁₉H₃₃N₃O₄[M]¹367.2,

found 368.2 [[M1H]¹, 30%], 735.5 [[M1H1M]¹, 28%],

500.1[[M 1H1NHCH;CH₃)CONHiPr]¹, 40%], 312.2

2£2H, CH±CH₂±CH₂), 3.38 ;pt, J_H±H6.5 Hz, 2H, N±

3

CH₂), 3.73 ;s, 3H, O±CH₃), 4.50 ;dq, J_H±H6.5 , 6.3 Hz,

1H, CH±CH₃), 5.04 ;m, 1H, N±CH±CH₂), 5.34 [dd,

4

³J_H±H10.8 Hz and J_H±H1.3 Hz, 1H, CHvC;CH₃)±

3

CO], 9.72 ;d, J_H±H6.3 Hz, 1H, NH±CH±CH₃); ¹³C

NMR ;62.896 MHz, CDCl₃): d_C16.7 ;CH±CH₃), 20.7

[CHvC;CH₃)±CO], 23.8 ;CH±CH₂±CH₂), 28.4 [3C,

C;CH₃)₃], 33.6 ;CH±CH₂±CH₂), 47.0 ;N±CH₂), 48.2

;CH±CH₃), 52.0 ;O±CH₃), 55.0 ;N±CH), 79.8 [C;CH₃)₃],

130.7 [CHvC;CH₃)±CO], 133.6 [CHvC;CH₃)±CO],

155.3 ;CO Boc), 169.5 ;CO±NH), 174.0 ;COOCH₃);

[a]_D11468 ;c0.55, HCCl₃); MS ;EI¹): m/z calculated

for C₁₇H₂₈N₂O₅[M]¹340.2, found 341.1 [[M11]¹, 70%],

241.0 [[M112tBuOCO]¹, 80%], 137.3 [[M2tBuOCO±

HAlaOCH₃]¹, 100%].

[[M1H±tBu]¹,

44%],

138.1

[[M1H2tBuOCO±

NHCH;CH₃)CONHiPr]¹, 100%]. cis Isomer: yield: 69 mg

;76%); white solid obtained from pure cis-4p; mp 998C;

R_f0.47 ;ethyl acetate); IR ;KBr plate)/cm²¹: n_max3400,

1

3305, 1695, 1660 and 1620; H NMR ;250 MHz, CDCl₃):

3

d_H1.01 [d, J_H±H6.5 Hz, 2£3H, CH;CH₃)₂], 1.39 ;d,

³J_H±H6.0 Hz, 3H, CH±CH₃), 1.46 [s, 9H, C;CH₃)₃], 1.93

4.7.11. 22S)-2trans)- or 22S)-2cis)-N-2t-Butoxycarbonyl)-2-

[2⁰-methyl-3⁰-oxo-1⁰-propenyl-3⁰-l-2O,O-dimethylaspar-

tyl)]-pyrrolidine 1pc. Trans isomer: yield: 45 mg ;87%);

colourless oil obtained from pure trans-4p; R_f0.32 ;ethyl

acetate/hexane: 1:1); IR ;KBr ®lm)/cm²¹: n_max3345,

4

[d, J_H±H1.0 Hz, 3H, CHvC;CH₃)±CO], 1.57±2.12 ;m,

2£2H, CH±CH₂±CH₂), 3.27±3.46 ;m, 2H, N±CH₂), 4.06

[m, 1H, CH;CH₃)₂], 4.40 ;m, 1H, CH±CH₃), 4.57 ;m, 1H,

3

N±CH), 5.29 [d, J_H±H10.5 Hz, 1H, CHvC;CH₃)±CO],

6.73 ;d, ³J_H±H7.0 Hz, 1H, NH-iPr), 9.45 ;d, ³J_H±H7.0 Hz,

1H, NH±CH±CH₃); ¹³C NMR ;62.896 MHz, CDCl₃):

d_C16.2 ;CH±CH₃), 21.0 [CHvC;CH₃)±CO], 22.8 and

23.0 [2C, CH;CH₃)₂], 24.1;CH±CH ₂±CH₂), 28.7 [3C,

C;CH₃)₃], 32.9 ;CH±CH₂±CH₂), 41.3 [CH;CH₃)₂], 47.1

1745, 1695, 1680 and 1635; H NMR ;250 MHz, CDCl₃):

1

d_H1.40 [s, 9H, C;CH₃)₃], 1.91 [s, 3H, CHvC;CH₃)±CO],

1.57±2.19 ;m, 2£2H, CH±CH₂±CH₂₃), 2.94 ;AB part of an

3

ABX pattern, n_A2.93, n_B2.95, J_AB17.2 Hz, J_AX

3

4.6 Hz and J_BX4.3 Hz, 2H, CH₂±COOCH₃), 3.32±3.58

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

4921

;m, 2H, N±CH₂), 3.67 and 3.74 ;2s, 2£3H, 2£O±CH₃), 4.48

4.8. Synthesis of a leu-enkephalin analogue

3

;m, 1H, N±CH±CH₂), 4.87 ;ddd, J_H±H7.8, 4.5, 4.3 Hz,

1H, NH±CH±CH₂), 6.29 ;br s, 1H, NH±CH±CH₂), 6.82

[m, 1H, CHvC;CH₃)±CO]; ¹³C NMR ;62.896 MHz,

After the preparation of the essential synthon, trans-N-Boc

vinylogous glycine 4k as described above, three kinds of reac-

tions were used: ;i) BOP-coupling reaction as also described

above excepted in the use of DMF instead of dichloromethane

as solvent; ;ii) in a manner similar to that used for the prepara-

tion of 4v, the hydrolysis of the ester protection was realized

with a sodium hydroxide solution 1M in alcohol; ;iii) the

hydrolytic cleavage of the Boc group was performed with

an hydrochloride acid gaseous barbotage in diethyl ether.

CDCl₃): d_C12.4 [CHvC;CH₃)±CO], 24.1;CH±CH

±

2

CH₂), 28.4 [3C, C;CH₃)₃], 32.5 ;CH±CH₂±CH₂), 36.0

;CH₂±COOCH₃), 46.5 ;N±CH₂), 48.6 ;CH±CH₃), 51.9

and 52.7 ;2C, 2£O±CH₃), 55.0 ;N±CH), 79.4 [C;CH₃)₃],

129.1 [CHvC;CH₃)±CO], 138.1 [CHvC;CH₃)±CO],

154.3 ;CO Boc), 168.3 ;CO±NH), 171.2 and 171.6 ;2C,

2£COOCH₃); [a]_D1118 ;c0.45, HCCl₃); MS ;EI¹):

m/z calculated for C₁₉H₃₀N₂O₇[M]¹398.2, found 399.6

;, 2%), 324.6 [[M112tBuO]¹, 3%], 279.8 [[M112tBu-

2£OCH₃]¹or [M22£COOCH₃]¹, 4%], 297.5 [[M2

tBuOCO]¹, 5%], 237.0 [[M112tBuOCO±2£OCH₃]¹,

5%], 267.1[[M 112tBu±OCH₃]¹, 6%], 343.6 [[M112

tBu]¹, 10%], 181.0 [[M112tBuOCO±2£COOCH₃]¹,

11%], 136.4 [[M112tBuOCO±HAsp;OCH₃)OCH₃]¹,

100%]. cis Isomer: Yield: 46 mg ;85%) colourless oil

obtained from pure cis-4p; R_f0.38 ;ethyl acetate/hexane:

1:1); IR ;KBr ®lm)/cm²¹: n_max3340, 3050, 1745, 1670 and

1645; ¹H NMR ;250 MHz, CDCl₃): d_H1.45 [s, 9H,

C;CH₃)₃], 1.92 [s, 3H, CHvC;CH₃)±CO], 1.57±2.19 ;m,

4.8.1. N-t-Butoxycarbonyl-l-phenylalanyl-l-leucine methyl

ester 7. Yield: 1.136 g ;95%); white solid; mp 1088C;

R_f0.85 ;ethyl acetate/hexane: 1:1); IR ;KBr plate)/cm²¹

:

1

n_max3500±3100, 1740, 1695, 1650; H NMR ;250 MHz,

3

CDCl₃): d_H0.89 [d, J_H±H5.0 Hz, 3H, CH;CH₃)₂], 0.91

3

[d, J_H±H5.0 Hz, 3H, CH;CH₃)₂], 1.41 [s, 9H, C;CH₃)₃],

1.46±1.68 [m, 3H, CH₂±CH;CH₃)₂], 3.07 ;d, ³J_H±H6.5 Hz,

3

2H, CH₂₃-Ph), 3.69 ;s, 3H, O±CH₃), 4.34 ;dt, J_H±H

8.25 Hz, J_H±H6.5 Hz, 1H, CH±CH₂-Ph)), 4.45±4.65 [m,

3

1H, CH±CH₂±CH;CH₃₃)₂], 4.99 ;d, J_H±H8.25 Hz, 1H,

NHBoc), 6.27 ;d, J_H±H8.00 Hz, 1H, NH±CH±

COOCH₃), 7.15±7.35 ;m, 5H, Ph).

3

2£2H, CH±CH₂±CH₂), 2.88 ;d, J_H±H6.6 Hz, 2H, CH₂±

COOCH₃), 3.37 ;pt, ³J_H±H6.75 Hz, 2H, N±CH₂), 3.70 and

3.73 ;2s, 2£3H, 2£O±CH₃), 4.87±5.03 ;m, 2£1H, N±CH±

4.8.2. l-Phenylalanyl-l-leucine methyl ester hydro-

chloride 8. Yield: 945 mg ;95%); white solid; H NMR

3

1

CH₂and NH±CH±CH₂), 5.33 [d, J_H±H10.7 Hz, 1H,

3

CHvC;CH₃)±CO], 976 ;d, J_H±H7.4 Hz, 1H, NH±CH±

;250 MHz, CD₃OD): d_H0.94 [d, J_H±H6.0 Hz, 3H,

CH₂); ¹³C NMR ;62.896 MHz, CDCl₃): d_C20.8

[CHvC;CH₃)±CO], 23.8 ;CH±CH₂±CH₂), 28.3 [3C,

C;CH₃)₃], 32.6 ;CH±CH₂±CH₂), 36.0 ;CH₂±COOCH₃),

46.9 ;N±CH₂), 48.9 ;CH±CH₃), 51.8 and 52.2 ;2C,

2£OCH₃), 54.9 ;N±CH), 79.8 [C;CH₃)₃], 131.0

[CHvC;CH₃)±CO], 133.3 [CHvC;CH₃)±CO], 155.2

;CO Boc), 169.4 ;CO±NH), 170.4 and 171.7 ;2C,

2£COOCH₃); [a_D]11898 ;c1.05, HCCl₃); MS ;EI¹):

m/z calculated for C₁₉H₃₀N₂O₇[M]¹398.2, found 398.5

;, 6%), 237.0 [[M112tBuOCO±2£OCH₃]¹, 9%], 267.1

[[M112tBuOCO±OCH₃]¹, 10%], 279.6 [[M112tBu±

2£OCH₃]¹or [M22£COOCH₃]¹, 18%], 181.0 [[M112

tBuOCO±2£COOCH₃]¹, 18%], 136.4 [[M112tBuOCO±

HAsp;OCH₃)OCH₃]¹, 94%].

3

CH;CH₃)₂], 0.97 [d, J_H±H6.0 Hz, 3H, CH;CH₃)₂], 1.50±

3

1.80 [m, 3H, CH₂±CH;CH₃)₂], 2.97 ;d, J_H±H8.5 Hz, 1H,

CH₂-Ph), 3.03 ;d, ³J_H±H8.5 Hz, 1H, CH₂-Ph), 3.71;s, 3H,

O±CH₃), 4.11 ;dd, ³J_H±H8.5 Hz, ³J_H±H5.25 Hz, 1H, CH±

CH₂-Ph), 4.50 [t, ³J_H±H7.0 Hz, 1H, CH±CH₂±CH;CH₃)₂],

7.20±7.40 ;m, 5H, Ph).

4.8.3. 2trans)-N-[4-N-2t-Butoxycarbonylamino)-1-oxo-2-

butenyl)]-phenylalanyl-leucine methyl ester 9. Yield:

645 mg ;99%); white solid; mp 728C; R_f0.50 ;ethyl

acetate/hexane: 1:1); IR ;KBr plate)/cm²¹: n_max3400,

1

3305, 1735, 1700, 1680 and 1640; H NMR ;250 MHz,

3

CDCl₃): d_H0.87 [d, J_H±H5.5 Hz, 2£3H, CH;CH₃)₂],

1.45 [s, 9H, C;CH₃₃)₃], 1.48±1.60 [m, 3H, CH₂±

CH;CH₃)₂], 3.04 ;dd, J_H±H13.5, 7.5 Hz, 1H, CH-Ph),

3

4.7.12. 22S)-2trans)/22S)-2cis)-N-2t-Butoxycarbonyl)-2-[3⁰-

oxo-1⁰-propenyl-3⁰-l-2N-methyl alaninylamido)]-pyrro-

lidine 1wd. Yield: 90 mg ;70%); colourless oil ;trans/cis:

25:75); cis isomer: R_f0.18 ;ethyl acetate/hexane: 3:1); IR

;KBr plate)/cm²¹: n_max3330, 1695, 1680, 1665 and 1630;

3.15 ;dd, J_H±H13.5, 6.0 Hz, 1H, CH-Ph), 3.70 ;s, 3H,

O±CH₃), 3.81±3.94 ;m, 2H, NH±CH₂), 4.48 [m, 1H,

CH±CH₂±CH;CH₃)₂], 4.62 ;m, 1H, CH±CH₂-Ph), 4.75

3

;d, J_H±H4.5 Hz, 1H, NH±CH₂), 5.92 ;d, J_H±H15.5 Hz,

3

1H, CHvCH±CO), 6.10 ;d, J_H±H8.0 Hz, 1H, NH±CH±

3

¹H NMR ;250 MHz, CDCl₃): d_H1.34 ;d, J_H±H7.0 Hz,

3

COOCH₃), 6.20 ;d, J_H±H7.5 Hz, 1H, NH±CHv), 6.55

3

3H, CH±CH₃), 1.38 [s, 3£3, C;CH₃)₃], 1.52±2.19 ;m,

;dt, J_H±H15.5, 5.0 Hz, 1H, CHvCH±CO), 7.15±7.35

3

;m, 5H, Ph); ¹³C NMR ;62.896 MHz, CDCl₃): d_C21.9

and 22.7 [2C, CH;CH₃)₂], 24.7 [CH;CH₃)₂], 28.0 [3C,

C;CH₃)₃], 38.3 ;CH₂-Ph), 41.3 [CH₂±CH;CH₃)₂], 50.9

[CH±CH₂±CH;CH₃)₂], 52.3 ;O±CH₃), 54.3 ;CH±CH₂-

Ph), 79.9 [C;CH₃)], 123.1 ;CHvCH±CO), 127.0, 128.6

;2C), 129.3 ;2C) and 136.3 ;Ph), 141.5 ;CHvCH±CO),

155.6 ;CO Boc), 165.0 ;CHvCH±CO), 170.6 ;CONH),

172.7 ;COOCH₃); [a]_D2168 ;c0.6, HCCl₃); MS

;FAB¹) m/z calculated for C₂₅H₃₇N₃O₆[M]¹475.3, found

476.0 [[M11]¹, 100%].

2£2H, CH±CH₂±CH₂), 2.71;d, J_H±H5.0 Hz, 3H, NH±

CH₃), 3.22±3.40 ;m, 2H, N±CH₂), 4.39 ;m, 1H, CH±

3

CH₃), 4.76 ;m, 1H, N±CH), 5.61;dd, J_H±H11.6 Hz and

3

10.3 Hz, 1H, CHvCH±CO), 5.76 ;d, J_H±H11.6 Hz, 1H,

3

CHvCH±CO), 6.85 ;m, 1H, NH-Me), 8.97 ;pd, J_H±H

6.5 Hz, 1H, NH±CH); ¹³C NMR ;62.896 MHz, CDCl₃):

d_C16.6 ;CH±CH₃), 23.9 ;CH±CH₂±CH₂), 26.2 ;NH±

CH₃), 28.4 [3C, C;CH₃)₃], 32.2 ;CH±CH₂±CH₂), 46.9

;N±CH₂), 49.2 ;CH±CH₃), 54.9 ;N±CH), 80.2 [C;CH₃)₃],

124.5 [CHvCH±CO], 138.5 [CHvCH±CO], 155.2 ;CO

Boc), 167.1 ;CO±NH), 173.2 ;CONHiPr); MS ;CI²): m/z

calculated for C₁₆H₂₆N₃O₄[M2H]²325.2, found 325.3

;100%).

4.8.4. 2trans)-N-24-Amino-1-oxo-2-butenyl)-phenylalanyl-

leucine methyl ester hydrochloride 10. Yield: 500 mg

4922

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

3

2H, Ph±OH), 7.10±7.30 ;m, 5H, Ph), 7.31;d, J_H±H

;92%, crude); white solid; IR ;KBr plate)/cm²¹: n_max

3

3270, 3055, 1740, 1710, 1665 and 1630; ¹H NMR

8.5 Hz, 2H, Ph-OH), 7.64 ;d, J_H±H8.0 Hz, 1H, NH±

CH±CH₂-Ph), 7.70±7.85 [m, 3H, NH±CH₂, NH±CH₂±

CHv and NH±CH±CH₂±CH;CH₃)₂], 8.25 ;br s, 1H, Ph-

OH); ¹³C NMR ;62.896 MHz, CDCl₃): d_C22.0 and 22.6

[2C, CH;CH₃)₂], 24.7 [CH;CH₃)₂], 28.4 [3C, C;CH₃)₃], 38.3

;2C, CH₂-Ph and CH₂-Ph±OH), 39.7 ;NH±CH₂), 40.7

;NH±CH₂±CHv), 42.9 [CH₂±CH;CH₃)₂], 51.4 [CH±

CH₂±CH;CH₃)₂], 52.3 ;O±CH₃), 55.3 ;CH±CH₂-Ph), 56.4

;CH±CH₂-Ph±OH), 80.5 [C;CH₃)], 115.7 ;2C, Ph-OH),

123.8 ;CHvCH±CO), 127.0, 127.2 ;C±OH), 128.6 ;2C),

129.3 ;2C), 130.4 ;2C) and 136.7 ;Ph), 139.6 ;CHvCH±

CO), 155.6 ;CO Boc), 165.9 ;CHvCH±CO), 169.1, 172.3

and 172.6 ;3C, CONH), 172.9 ;COOCH₃); MS ;FAB¹): m/z

calculated for C₃₆H₄₈N₅O₉[M]¹695.4, found 696.3

[[M11]¹, 56%], 1391.0 [[M111M]¹, 73%], 596.2 [[M1

12tBuOCO]¹, 100%].

3

;250 MHz, CD₃OD): d_H0.80 [d, J_H±H6.0 Hz, 3H,

3

CH;CH₃)₂], 0.85 [d, J_H±H6.0 Hz, 3H, CH;CH₃)₂], 1.47±

2

1.65 [m, 3H, CH₂±CH;CH₃)₂], 2.79 ;dd, J_H±H14.5 Hz,

2

³J_H±H9.5 Hz, 1H, CH-Ph), 3.10 ;dd, J_H±H14.5 Hz,

³J_H±H5.25 Hz, 1H, CH-Ph), 3.56±3.60 ;m, 5H, O±CH₃

3

and NH±CH₂), 4.26 [t, J_H±H7.25 Hz, 1H, CH±CH₂±

CH;CH₃)₂], 4.68 ;m, 1H, CH±CH₂-Ph), 6.14 ;d,

3

³J_H±H15.5 Hz, 1H, CHvCH±CO), 6.57 ;dt, J_H±H

3

15.5 Hz, J_H±H6.3 Hz, 1H, CHvCH±CO), 7.02±7.21

;m, 5H, Ph); ¹³C NMR ;62.896 MHz, CD₃OD): d_C19.8

and 21.3 [2C, CH;CH₃)₂], 23.9 [CH;CH₃)₂], 37.0 ;CH₂-Ph),

39.1;NH± CH₂±CHv), 39.5 [CH₂±CH;CH₃)₂], 50.2 [CH±

CH₂±CH;CH₃)₂], 50.7 ;O±CH₃), 53.8 ;CH±CH₂-Ph), 125.8

;CHvCH±CO), 127.0, 127.4 ;2C), 128.3 ;2C) and 136.3

;Ph), 140.5 ;CHvCH±CO), 162.1 and 163.5 ;2C,

CHvCH±CO and CONH), 171.8 ;COOCH₃).

4.8.8. 2trans)-N-2t-Butoxycarbonyl)-l-tyrosylglycyl-N-24-

amino-1-oxo-2-butenyl)-phenyl alanyl-leucine 14. Yield:

101 mg ;70%); white solid; mp 1198C; R_f0.2 ;methanol);

IR ;KBr plate)/cm²¹: n_max3280, 1770, 1645 and 1590; ¹H

NMR ;250 MHz, CD₃COCD₃): d_H0.90 [d, ³J_H±H6.0 Hz,

4.8.5. N,O-di-t-Butoxycarbonyl-l-tyrosylglycine methyl

ester 11. Yield: 810 mg ;86%); white solid; mp 458 C;

R_f0.66 ;ethyl acetate/hexane: 3:1); IR ;KBr plate)/cm²¹

:

n_max3500±3150, 1740±1660; ¹H NMR ;250 MHz,

CDCl₃): d_H1.41 [s, 9H, C;CH₃)₃], 1.55 [s, 9H, C;CH₃)₃],

3.08 ;d, ³J_H±H6.25 Hz, 2H, CH₂-Ph), 3.74 ;s, 3H, O±CH₃),

3

3H, CH;CH₃)₂], 0.91[d, J_H±H6.0 Hz, 3H, CH;CH₃)₂],

1.36 [s, 9H, C;CH₃)₃], 1.50±1.70 [m, 3H, CH₂±

CH;CH₃)₂], 2.80±3.24 ;m, 4H, CH₂-Ph±OH and CH₂-Ph),

3.80±3.94 ;m, 4H, NH±CH₂and NH±CH₂±CHv), 4.37

2

3

3.95 ;dd, J_H±H18.0 Hz, J_H±H6.25 Hz, 1H, CH₂±

2

3

COOCH₃), 4.03 ;dd, J_H±H18.0 Hz, J_H±H5.25 Hz, 1H,

3

CH₂±COOCH₃), 4.39 [dt, J_H±H7.0 Hz, J_H±H6.25 Hz,

;dd, J_H±H7.0 Hz, J_H±H7.0 Hz, 1H, CH±CH₂-Ph±OH),

3

1H, CH±CH₂-Ph], 5.00 ;d, J_H±H7.0 Hz, 1H, NH

4.54 [m, 1H, CH±CH₂±CH;CH₃)₂], 4.85 ;m, 1H, CH±CH₂-

3

CH±CH₂-Ph), 6.49 ;dd, J_H±H5.25 Hz, J_H±H6.25, 1H,

Ph), 6.00 ;d, J_H±H15.5 Hz, 1H, CHvCH±CO), 6.27 ;m,

3

NH±CH₂±COOCH₃), 7.10 ;d, J_H±H8.5 Hz, 2H, Ph),

1H, NH±CH±CH₂-Ph±OH), 6.63 ;dt, J_H±H15.5, 4.8 Hz,

3

7.22 ;d, J_H±H8.5 Hz, 2H, Ph) [a]_D21.18 ;c0.9,

1H, CHvCH±CO), 6.78 ;d, J_H±H8.5 Hz, 2H, Ph-OH),

3

HCCl₃).

7.10±7.30 ;m, 5H, Ph), 7.31;d, J_H±H8.5 Hz, 2H, Ph-

OH), 7.64 ;m, 1H, NH±CH±CH₂-Ph), 7.70±7.85 [m,

3H, NH±CH₂, NH±CH₂±CHv and NH±CH±CH₂±

CH;CH₃)₂], 8.25 ;br s, 1H, Ph-OH), 11.5 ;br s, 1H,

COOH); ¹³C NMR ;62.896 MHz, CDCl₃): d_C21.0 and

22.1[2C, CH; CH₃)₂], 24.3 [CH;CH₃)₂], 27.4 [3C,

C;CH₃)₃], 37.8 ;2C, CH₂-Ph and CH₂-Ph±OH), 39.0

;NH±CH₂), 40.4 ;NH±CH₂±CHv), 42.2 [CH₂±

CH;CH₃)₂], 50.2 [CH±CH₂±CH;CH₃)₂], 56.3 ;CH±CH₂-

Ph), 57.4 ;CH±CH₂-Ph±OH), 78.6 [C;CH₃)], 114.8 ;2C,

Ph±OH), 123.4 ;CHvCH±CO), 126.1, 127.9 ;C±OH),

129.1 ;2C), 130.1 ;2C), 130.7 ;2C) and 137.4 ;Ph), 139.4

;CHvCH±CO), 155.8 ;CO Boc), 168.2 ;CHvCH±CO),

169.3, 170.1 and 170.4 ;3C, CONH); MS ;FAB¹): m/z

calculated for C₃₅H₄₇N₅O₉[M]¹681.3, found 682.3

[[M11]¹, 100%].

4.8.6. N-t-Butoxycarbonyl-l-tyrosylglycine 12. Yield:

381mg ;94%); white solid; mp 80 8C; R_f0.46 ;methanol);

1

IR ;KBr plate)/cm²¹: n_max3100±2800, 1710±1630; H

NMR ;250 MHz, CD₃CO CD₃): d_H1.21 [s, 9H,

3

2

C;CH₃)₃], 2.70 ;dd, J_H±H8.75 Hz, J_H±H14.0 Hz, 1H,

3

2

CH₂-Ph), 2.97 ;dd, J_H±H5.00 Hz, J_H±H14.0 Hz, 1H,

3

CH₂-Ph), 3.85 ;d, J_H±H5.75 Hz, 2H, CH₂±COOH), 4.22

3

;ddd, J_H±H8.00 Hz, J_H±H5.00 Hz, J_H±H5.75 Hz, 1H,

3

CH±CH₂-Ph), 5.88 ;d, J_H±H8.0 Hz, 1H, NH Boc), 6.61

;d, ³J_H±H8.5 Hz, 2H, Ph), 6.98 ;d, ³J_H±H8.5 Hz, 2H, Ph),

3

7.41;dd, J_H±H5.75 Hz, 1H, NHCH₂COOH), 8.01;s, 1H,

PhOH), 12.0 ;s, 1H, COOH) [a]_D21.18 ;c0.9, HCCl₃).

4.8.7. 2trans)-N-2t-Butoxycarbonyl)-l-tyrosylglycyl-N-24-

amino-1-oxo-2-butenyl)-phenyl alanyl-leucine methyl

ester 13. Yield: 207 mg ;61.5%); white solid; mp 1108C;

4.8.9. 2trans)-l-Tyrosylglycyl-N-24-amino-1-oxo-2-butenyl)-

phenylalanyl-leucine 15. Yield: 76 mg ;98%); white solid;

IR ;KBr plate)/cm²¹: n_max3265, 3065, 1690, 1680, 1670,

1660, 1650 and 1645; ¹H NMR ;250 MHz, CD₃OD):

R_f0.42 ;ethyl acetate/acetone 4:1); IR ;KBr plate)/cm²¹

:

1

n_max3410, 3290, 1745, 1710, 1665 and 1615; H NMR

3

;250 MHz, CD₃COCD₃): d_H0.90 [d, J_H±H6.0 Hz, 3H,

3

CH;CH₃)₂], 0.91[d, J_H±H6.0 Hz, 3H, CH;CH₃)₂], 1.36

d_H0.90 [2d, J_H±H6.0 Hz, 3H, CH;CH₃)₂], 0.94 [2d,

[s, 9H, C;CH₃)₃], 1.50±1.70 [m, 3H, CH₂±CH;CH₃)₂],

2.80±3.24 ;m, 4H, CH₂-Ph±OH and CH₂-Ph), 3.69 ;s, 3H,

O±CH₃), 3.80±3.94 ;m, 4H, NH±CH₂and NH±CH₂±

³J_H±H6.0 Hz, 3H, CH;CH₃)₂], 1.60±1.72 [m, 3H, CH₂±

CH;CH₃)₂], 2.86±3.22 ;m, 4H, CH₂-Ph±OH and CH₂-Ph),

3.52±3.63 ;m, 2H, NH±CH₂), 3.85±4.11 ;m, 3H, NH±

CH₂±CHv and CH±CH₂-Ph±OH), 4.43 [m, 1H, CH±

CH₂±CH;CH₃)₂], 4.78 ;m, 1H, CH±CH₂-Ph), 6.08 ;d,

3

CHv), 4.37 ;m, 1H, CH±CH₂-Ph±OH), 4.54 ;dd, J_H±H

7.5 Hz, ³J_H±H7.5 Hz, 1H, CH±CH₂-Ph), 4.85 [dd, ³J_H±H

3

5.0 Hz, J_H±H8.0 Hz, 1H, CH±CH₂±CH;CH₃)₂], 6.00 ;d,

³J_H±H15.5 Hz, 1H, CHvCH±CO), 6.64 ;dt, J_H±H15.5,

3

³J_H±H15.5 Hz, 1H, CHvCH±CO), 6.27 ;d, ³J_H±H7.0 Hz,

5.0 Hz, 1H, CHvCH±CO), 6.78 ;d, J_H±H8.5 Hz, 2H,

3

1H, NH±CH±CH₂-Ph±OH), 6.63 ;dt, J_H±H15.5 Hz,

Ph-OH), 7.12±7.33 ;m, 5H, Ph), 7.31;d, J_H±H8.5 Hz,

³J_H±H4.8 Hz, 1H, CHvCH±CO), 6.78 ;d, J_H±H8.5 Hz,

2H, Ph-OH); ¹³C NMR ;62.896 MHz, CD₃OD): d_C21.0

3

C. Grison et al. / Tetrahedron 57 52001) 4903±4923

4923

Á

4. Coutrot, Ph.; Grison, C.; Geneve, S.; Didierjean, C.; Aubry,

A.; Vicherat, A.; Marraud, M. Lett. Pept. Sci. 1997, 4, 41 5±

422.

and 22.1[2C, CH; CH₃)₂], 24.2 [CH;CH₃)₂], 28.9 [CH₂±

CH;CH₃)₂], 35.9 and 37.1;2C, CH₂-Ph and CH₂-

PhvOH), 42.5 ;NH±CH₂), 46.7 ;NH±CH₂±CHv), 50.2

[CH±CH₂±CH;CH₃)₂], 53.6 ;2C, CH±CH₂-Ph and CH±

CH₂-Ph±OH), 115.2 ;2C, Ph-OH), 124.7 ;CHvCH±CO),

125.7 ;C±OH), 126.1, 127.9 ;2C), 129.0 ;2C), 130.0 and

137.9 ;Ph), 138.1 ;CHvCH±CO), 164.0, 167.9, 168.4,

171.4 and 173.8 ;5C, CO).

Â

5. ;a) Coutrot, Ph.; Grison, C.; Gerardin-Charbonnier, C.;

Lecouvey, M. Tetrahedron Lett. 1993, 34, 2767±2770.

;b) Coutrot, Ph.; Grison, C.; Lecouvey, M. Bull. Soc. Chim.

1997, 134, 27±45.

6. ;a) Savignac, Ph.; Snoussi, M.; Coutrot, Ph. Synth. Commun.

1978, 8, 19±25. ;b) Coutrot, Ph.; Ghribi, A. Synthesis 1986,

Ã

790±792. ;c) Coutrot, Ph.; Grison, C.; Sauvetre, R.

Acknowledgements

J. Organomet. Chem. 1987, 332, 1±8. ;d) Coutrot, Ph.; Grison,

C.; Lecouvey, M. Phosphorus Sulfur Silicon 1994, 97, 47±56.

7. ;a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405±

4408. ;b) Marshall, J. A.; Lebreton, J.; DeHoff, B. S.; Jenson,

T. M. J. Org. Chem. 1987, 52, 3883±3889. ;c) Danishefsky,

S. J.; Deninno, M. P.; Chen, S. J. Am. Chem. Soc. 1988, 110,

3929±3940. ;d) Overman, L. A.; Thompson, A. S. J. Am.

Chem. Soc. 1988, 110, 2248±2256. ;e) Boeckman, Jr., R. K.;

Weidner, C. H.; Perni, R. B.; Napier, J. J. J. Am. Chem. Soc.

1989, 111, 8036±8037.

We are very grateful to Dr A. Van Dorsselaer, University

Louis Pasteur, Strasbourg, for exact mass measurements.

References

1. ;a) Hambrook, T. J.; Morgan, B. A.; Rance, M. J.; Smith, C. F.

Nature 1976, 262, 782±783. ;b) Knight, M.; Klee, W. A.

J. Biol. Chem. 1978, 253, 3843±3847. ;c) Hazum, E.;

Chang, K.-J.; Cuatrecasas, P. Life Sci. 1979, 24, 137±144.

;d) Marley, J. S. Ann. Rev. Pharmacol. Toxicol. 1980, 20,

8. ;a) Hensel, M. J.; Fuchs, P. L. Synth. Commun. 1986, 16,

1285±1295. ;b) Hippeli, C.; Reissig, H.-U. J. Org. Chem.

1988, 53, 3886±3888. ;c) Jako, I.; Uiber, P.; Mann, A.;

Taddei, M.; Wermuth, C. G. Tetrahedron Lett. 1990, 31,

1011±1014. ;d) Sakai, N.; Ohfune, Y. J. Am. Chem. Soc.

1992, 114, 998±1010. ;e) Poss, M. A.; Reid, J. A. Tetrahedron

Lett. 1992, 33, 1411±1414. ;f) RuÈbsam, F.; Evers, P.; Michel,

C.; Giannis, A. Tetrahedron 1997, 53, 1707±1714. ;g) Pihko,

P. M.; Koskinen, A. M. P. J. Org. Chem. 1998, 63, 92±98.

9. ;a) Etemad-Moghadam, G.; Seyden-Penne, J. Tetrahedron

1984, 40, 5153±5166. ;b) Etemad-Moghadam, G.; Seyden-

Penne J. Bull. Soc. Chim. Fr. 1985, 448±454. ;c) Thenappan,

A.; Burton, D. J. J. Org. Chem. 1990, 55, 4639±4642.

;d) Rodriguez, M.; Heitz, A.; Martinez, J. Tetrahedron Lett.

1990, 31, 7319±7322. ;e) Sano, S.; Ando, T.; Yokoyama, K.;

Nagao, Y. Synlett 1998, 777±779.

È

81±110. ;e) Konig, H. Angew. Chem., Int. Ed. Engl. 1980,

19, 749±840. ;f) Schwartz, J. C.; Malfroy, B.; De La

Baume, S. Life Sci. 1981, 29, 1715±1739. ;g) Rapaka, R. S.

Life Sci. 1986, 39, 1825±1843. ;h) Gootschlich, R. Kontakte

1990, 1, 3±12. ;i) Schorderest, M. Pharmacologie, Editions

Slatkine 1992, 321±336. ;j) Noble, F.; Roques, B. P. C. R. Soc.

Â

Biol. 1992, 186, 37±60. ;k) Llorens±Cortes, C. Enkephalines,

Á

neuropeptides et neurotransmetteurs, 27eme Edition,

INSERM ed.; 1995, 115 ;l) Amadeo, P.; Naider, F.; Picone,

D.; Tancredi, T.; Tenussi, P. A. J. Pept. Sci. 1998, 4, 253.

2. ;a) Mosberg, H. I.; Hurst, R.; Hruby, V. J.; Gee, K.;

Yamamura, H. I.; Galligan, J. J.; Burks, T. F. Proc. Natl.

Acad. Sci. USA 1983, 80, 5871±5874. ;b) Schiller, P. W.;

Nguyen, T. M. D.; Maziak, L. A.; Lemieux, C. Biochem.

Biophys. Res. Commun. 1985, 127, 558±564. ;c) Hassan,

M.; Goodman, M. Biochemistry 1986, 7596±7606.

;d) Fletcher, M. D.; Campbell, M. M. Chem. Rev. 1988, 98,

10. ;a) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109,

236±239. ;b) Miles, N. J.; Sammes, P. G.; Kennewell, P. D.;

Westwood, R. J. Chem. Soc., Perkin Trans. 1 1985, 2299±

2305.

Â

763±795. ;e) Gacel, G.; Dauge, V.; Breuze, P.; Delay-Goyet,

P.; Roques, B. P. J. Med. Chem. 1988, 31, 1891±1897.

;f) Mierke, D. F.; Yamazaki, T.; Said-Nejad, O. E.; Felder,

E. R.; Goodman, M. J. Am. Chem. Soc. 1989, 111, 6847±6849.

;g) Gante J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699±

1720. ;h) Goodman, M.; Ro, S. Burger's Medicinal Chemistry

and Drug Discovery, Vol. 1; Wiley: New York, 1995: pp

803±861. ;i) Hruby, V. J.; Li, G.; Haskell-Luevano, C.;

Shenderavich, M. Biopolymers 1997, 43, 219±266.

Â

11. ;a) Fournie-Zaluski, M.-C; Prange, T.; Pascard, C.; Roques,

B. P. Biochem. Biophys. Res. Commun. 1977, 79, 1199±1206.

;b) Schwartz, J. C.; Malfroy, B.; De la Baume, S. Life Sci.

1981, 29, 1715±1739.

12. Fehrentz, J. A.; Castro, B. Synthesis 1983, 676±678.

13. Le Coz, S.; Mann, A.; Thareau, F.; Taddei, M. Heterocycles

1993, 36, 2073±2080.

14. Patois, C.; Savignac, Ph.; About-Jaudet, N.; Collignon, N.

Synth. Commun. 1991, 21, 2391±2396.

3. ;a) Hagihara, M.; Anthony, N. S.; Stout, T. J.; Clardy, J.;

Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 6568±6570.

;b) Hagihara, M.; Schreiber, S. L. J. Am. Chem. Soc. 1992,

114, 6570±6571.

15. Teulade, M. P.; Savignac, P.; Aboujaoude, E.; Collignon, N.

J. Organomet. Chem. 1985, 287, 145±156.

16. Kresze, G.; Runge, W.; Ruch, E. Ann 1972, 756, 112.

Article Doi

Stereoselective synthesis of vinylogous peptides

DOI: 10.1016/S0040-4020(01)00433-1

Source and publish data:

Authors:

Article abstract of DOI:10.1016/S0040-4020(01)00433-1

Full text of DOI:10.1016/S0040-4020(01)00433-1

Products guided by the article

R&D Labs maybe for 128121-02-8

Relevant to this article

Hot Product