Synthesis of the first axially dissymmetric, Cα,α-disubstituted glycine containing a crown ether receptor, and the conformational preferences of a model peptide

FULL PAPER

Synthesis of the First Axially Dissymmetric, C^α,α-Disubstituted Glycine

Containing a Crown Ether Receptor, and the Conformational Preferences of a

Model Peptide

Jean-Paul Mazaleyrat,*^[a]Yolaine Goubard,^[a]Maria-Vittoria Azzini,^[a]

Michel Wakselman,^[a]Cristina Peggion,^[b]Fernando Formaggio,^[b]and Claudio Toniolo^[b]

Keywords: Atropoisomeric amino acids / Axial chirality / C^α,α-disubstituted glycine / Crown compounds / Side-chain

modified amino acids

Racemic and enantiomerically enriched N^α-protected methyl

6-amino-1,11-(20-crown-6)-6,7-dihydro-5H-dibenzo[a,c]-

cycloheptene-6-carboxylates (Boc-[20-C-6]-Bip-OMe) (RS)-

obtained with only 64% ee and 48% ee, respectively, be-

cause of racemization occurring both at the demethylation/

esterification and at the crown formation stages of the syn-

Ia, (R)-Ia and (S)-Ia have been synthesized by phase-transfer thesis. Solution synthesis provided access to: (i) a number of

dialkylation of the 4-chlorobenzylidene derivative of glycine [20-C-6]-Bip/Gly peptides up to the pentapeptide Boc-[20-C-

tert-butyl ester, with both racemic and resolved (both enantio- 6]-Bip-Gly-Gly-[20-C-6]-Bip-Gly-OMe (RR,SS)- and (RS,SR)-

mers) 2,2Ј-bis(bromomethyl)-6,6Ј-dimethoxy-1,1Ј-biphenyl

Va as a mixture of two racemic isomers, and (ii) the hepta-

peptide Boc-[20-C-6]-Bip-(Aib)₆-OtBu (S)-VI. Conforma-

being used as alkylating agents. Demethylation of the re-

sulting (RS)-, (R)- and (S)-H-[MeO]₂-Bip-OtBu, followed by tional analysis of (S)-VI by FT-IR absorption and ¹H NMR

esterification and N^α-Boc protection, gave (RS)-, (R)- and (S)-

indicated a high degree of folding, with spectral patterns typ-

ical of a 3₁₀-helical peptide. The absolute configuration of the

Boc-[HO]₂-Bip-OMe. Cyclization with Cs₂CO₃/DMF and

pentaethylene glycol ditosylate afforded the crown-carrier [20-C-6]-Bip residue was correlated with the CD pattern in

C^α,α-disubstituted glycines (RS)-Ia, (R)-Ia and (S)-Ia, pos- the 200−300 nm region.

sessing only axial dissymmetry. Although (R)-Ia and (S)-Ia

are enantiomerically stable in solution at 110 °C, they were

(

Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,

2002)

Introduction

shown that new cyclic, axially chiral, C^α-tetrasubstituted α-

amino acids of the 1-aminocycloheptane-1-carboxylic acid

(Ac₇c) type, Bip and Bin Ϫ 1,1Ј-biphenyl- and 1,1Ј-binaph-

thyl-substituted analogues of Aib Ϫ behave as helix in-

ducers in short-chain peptides.^[24Ϫ27]

Synthetic α-amino acids bearing crown ether moieties are

of great interest for the preparation of ion-selective molecu-

lar receptors, since they can easily be assembled in supra-

molecular architectures of both bis(crown) and polymeric

crown compounds with a peptide framework.^[1,2]For that

purpose, crown-carrier derivatives of -DOPA,^[1Ϫ12]lys-

ine^[13]and glutamic acid^[14]have been exploited in the past

few years. However, this concept had not yet been applied

to C^α,α-disubstituted glycines,^[15]in spite of their known

ability to induce predictable secondary structures by stabil-

izing either fully extended or folded (turn and helical) con-

formations in polypeptides,^[16Ϫ23]which makes them at-

tractive building blocks for the construction of supramolec-

ular devices with peptides as framework. We have recently

In this paper we report our detailed experimental proced-

ure for the synthesis of the 6-amino-1,11-(20-crown-6)-6,7-

dihydro-5H-dibenzo[a,c]cycloheptene-6-carboxylic acid res-

idue ([20-C-6]-Bip) both in racemic and in enantiomerically

enriched forms, (R)-I and (S)-I (Figure 1).^[28,29]This com-

pound represents the first example of a crown-carrier C^α,α

-

disubstituted glycine with axial dissymmetry. Selected pep-

tides based on the [20-C-6]-Bip residue have also been syn-

thesized by solution methods.

[a]

ˆ

´

SIRCOB, ESA CNRS 8086, Bat. Lavoisier, Universite de

Versailles,

78035 Versailles, France

Fax: (internat.) ϩ 33-1/39254452

E-mail: mazaleyrat@chimie.uvsq.fr

Biopolymer Research Centre, CNR, Department of Organic

Chemistry, University of Padova,

35131 Padova, Italy

[b]

Figure 1. Chemical structure of the enantiomeric crown-carrier,

axially dissymmetric, C^α,α-disubstituted glycyl residue [20-C-6]-Bip

(R)-I and (S)-I

1232

WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0407Ϫ1232 $ 17.50ϩ.50/0 Eur. J. Org. Chem. 2002, 1232Ϫ1247

C^α,α-Disubstituted Glycine Containing a Crown Ether Receptor

FULL PAPER

Results and Discussion

Synthesis and Characterization of Amino Acid Derivatives

Racemic 6,6Ј-dimethoxy-1,1Ј-biphenyl-2,2Ј-dicarboxylic

acid [(R,S)-1; Figure 2] was first prepared from 2-amino-3-

methoxybenzoic acid,^[30]and resolved through its diquinine

salt as previously described.^[31Ϫ33]In our hands, however,

the described resolution procedure could not be reproduced

well and we ended up with enantiomerically enriched but

not enantiomerically pure samples of each enantiomer, (Ϫ)-

(R)-1 (76% yield; 91 Ϯ 5% ee) (ee: enantiomeric excess) and

(ϩ)-(S)-1 (88% yield; 75 Ϯ 5% ee). To avoid racemization,

known to occur relatively easily for the diacid, its sodium

salt and its methyl ester, it has been recommended (by Hall

et al.^[32]) that the subsequent steps be carried out at temper-

atures below ca. 50 °C, with diazomethane in diethyl ether/

ethanol at 0 °C for esterification and LiAlH₄in refluxing

diethyl ether for reduction of the diester to the correspond-

ing diol. As an improvement on such a two-step procedure,

we were able to perform one-step reductions of (Ϫ)-(R)-1

and (ϩ)-(S)-1 to the corresponding diols under mild condi-

tions and in high yields Ϫ giving (Ϫ)-(R)-2 (88% yield; 95

Ϯ 5% ee) and (ϩ)-(S)-2 (77% yield; 71 Ϯ 5% ee) (Figure 2)

Ϫ with BH₃/THF (tetrahydrofuran) at room temperature.

The racemic diacid (R,S)-1 was also successfully reduced to

(R,S)-2 (92% yield) by that method. The crude samples of

diol 2 were then treated with PBr₃in toluene^[32]to give the

dibromides (Ϫ)-(R)-3 (63% yield; 99 Ϯ 5% ee), (ϩ)-(S)-3

(77% yield; 74 Ϯ 5% ee) and (R,S)-3 (56% yield).

The dibromides (R,S)-3, (R)-3 and (S)-3 were used as al-

kylating agents in the solid-liquid phase-transfer dial-

kylation of (4-chlorobenzylidene)glycine tert-butyl es-

ter,^[34,35]prepared as previously described for (4-chloroben-

zylidene)alanine ethyl ester,^[36]with tetrabutylammonium

bromide as catalyst and the mixed base KOH/K₂CO₃in

dichloromethane, according to O’Donnell et al.^[35Ϫ37]De-

protection of the amino group of the resulting C^α,α-dial-

kylated glycine ester Schiff base, performed variously by

transimination,^[38,39]acidic cleavage on silica gel or, more

conveniently, by hydrolysis of the crude reaction product

with 0.5  citric acid in THF, gave H-[MeO]₂-Bip-OtBu

(R,S)-4 in 64% yield. The corresponding amino esters (R)-

4 (61%) and (S)-4 (48%) were obtained in somewhat lower

yields, with side products arising from a further N,N-dial-

kylation of 4 being isolated: (RR)-5 (21%) and (SS)-5

(35%), respectively (Figure 3). We suspect partial degrada-

tion of the starting (4-chlorobenzylidene)glycine tert-butyl

ester during storage, resulting in the presence of unchanged

dibromide 3, which, after hydrolysis of the reaction mixture,

could alkylate the amino function of 4.

Figure 2. Synthesis of racemic and chirally resolved H-[MeO]₂-Bip-

OtBu (4): (i) BH₃, THF, 0 to 25 °C, 5 h; (ii) PBr₃, toluene, 0 to 45

°C; (iii) (4-chlorobenzylidene)glycine tert-butyl ester, KOH powder,

K₂CO₃, CH₂Cl₂, room temp.; (iv) NH₂OH·HCl, AcONa, 95%

[a]

EtOH, room temp.; (v) 0.5  citric acid, THF, room temp.; en-

antiomeric excess (optical purity) determined by comparison of the

optical rotation with the maximum value from literature (see text

[b]

and Exp. Sect.); determined by ¹⁹F NMR of the corresponding

Mosher amide (see text and Exp. Sect.)

Treatment of aliquots of samples of (R)-4 and of (S)-

4 with (Ϫ)-(S)-α-methoxy-α-trifluoromethyl-α-phenylacetic

anhydride, produced by treatment of Mosher’s acid^[40]with

0.5 equiv. of DCC (N,NЈ-dicyclohexylcarbodiimide) in ace-

Figure 3. Chemical structure of the side product (RR)-5

tonitrile as previously described,^[25]provided the diastereo- OtBu with 64 Ϯ 5% de, respectively, as determined by H

isomeric amido esters (S)-Ph(OCH₃)(CF₃)C-CO-(R)- NMR and ¹⁹F NMR. These de values were very similar,

[MeO]₂-Bip-OtBu with 98 Ϯ 2% de (de: diastereoisomeric within experimental error, to the enantiomeric excesses of

excess) and (S)-Ph(OCH₃)(CF₃)C-CO-(S)-[MeO]₂-Bip- the starting dibromides (Ϫ)-(R)-3 (99 Ϯ 5% ee) and (ϩ)-

1

Eur. J. Org. Chem. 2002, 1232Ϫ1247

1233

J.-P. Mazaleyrat et al.

FULL PAPER

(S)-3 (74 Ϯ 5% ee), thus demonstrating absence of racemiz-

ation in the phase-transfer dialkylation reaction.

The observed decreases in the enantiomeric purity of (R)-

6 (56 Ϯ 5% ee) relative to its precursor (R)-4 (98 Ϯ 2% ee)

Demethylation of the 6,6Ј-methoxy groups of (RS)-4, and in that of (S)-6 (37 Ϯ 5% ee) relative to its precursor

(R)-4 and (S)-4 by boron tribromide^[41]in dichloromethane (S)-4 (64 Ϯ 5% ee), demonstrates the occurrence of extensive

was accompanied by cleavage of the tert-butyl ester func- racemization during the demethylation/re-esterification steps.

tion, to give H-[HO]₂-Bip-OH·HBr, which was not isolated

Luckily, racemic (RS)-6 appeared to be only sparingly

but directly esterified in methanol and 98% H₂SO₄

soluble in organic solvents and could be removed almost

(catalyst) at 50Ϫ55 °C to afford the corresponding methyl

completely from samples enriched in either one of the more

6-amino-1,11-dihydroxy-6,7-dihydro-5H-dibenzo[a,c]cyclo-

soluble (R)-6 or (S)-6 enantiomers by fractional crystalliza-

heptene-6-carboxylates (H-[HO]₂-Bip-OMe) (RS)-6 (73%),

tion. Indeed, crystallization of the sample of (R)-6 (55%

(R)-6 (55%) and (S)-6 (75%) (Figure 4). The enantiomeric

yield; 56 Ϯ 5% ee) from CH₂Cl₂provided separated crystals

purities of (R)-6 (56 Ϯ 5% ee) and (S)-6 (37 Ϯ 5% ee) were

of nearly racemic (RS)-6 (27% yield) and nearly enantiom-

determined by comparison of their optical rotations:

erically pure (R)-6 (26% yield; 98 Ϯ 2% ee). In the same

25

[α] ϭ Ϫ74.4, [α] ϭ Ϫ343.0 (c ϭ 0.1; MeOH) for (R)-

436

365

manner, crystals of nearly racemic (RS)-6 (37% yield) and

nearly enantiomerically pure (S)-6 (27% yield; 95 Ϯ 5% ee)

were obtained from the sample of (S)-6 (75% yield; 37 Ϯ

5% ee). For determination of the enantiomeric excesses,

aliquots of the thus obtained (R)-6 and (S)-6 were treated

with excesses of Mosher’s anhydride produced by treatment

of (S)-Ph(OCH₃)(CF₃)C-COOH with 0.5 equiv. of EDC

25

6 and [α] ϭ ϩ51.1, [α]

ϭ ϩ225.8 (c ϭ 0.25; MeOH)

436

365

25

for (S)-6, with the maximum values [α]

ϭ Ϫ136.7,

ϭ ϩ130.5,

436

25

[α]

ϭ Ϫ610.2 (c ϭ 0.1; MeOH) and [α]

365

436

[α]₃²₆⁵₅ϭ ϩ602.1 (c ϭ 0.1; MeOH), respectively, extrapolated

from the optical rotations of samples of known enantiom-

eric excess (see Table 1), determined from the ¹⁹F NMR

spectra of the corresponding Mosher’s amide/half phenyl

ester isomers (vide infra).

[N-ethyl-NЈ-(dimethylaminopropyl)carbodiimide

hydro-

chloride] in acetonitrile. In these cases, however, acylation

not only of the amino group, but also of one of the phenolic

hydroxy groups took place, resulting in two amide/half

phenyl ester isomers: (S)-Ph(OCH₃)(CF₃)C-CO-(R)-

[HO; (S)-Ph(OCH₃)(CF₃)C-COO]-Bip-OMe: (SRS)-7A ϩ

(SRS)-7B from (R)-6 and (S)-Ph(OCH₃) (CF₃)C-CO-(S)-

[HO; (S)-Ph(OCH₃)(CF₃)C-COO]-Bip-OMe: (SSS)-7A ϩ

(SSS)-7B from (S)-6 (Figure 5). The isomer pairs (SRS)-7A

and (SRS)-7B and also (SSS)-7A and (SSS)-7B could easily

be separated on preparative TLC (thin layer chromato-

graphy) silica gel plates. On the other hand, the isomer pairs

(SRS)-7A and (SSS)-7A and also (SRS)-7B and (SSS)-7B,

with close R_fvalues, remained inseparable, but the dia-

stereoisomeric excess could be determined by ¹⁹F NMR.

Similar values were obtained both in series 7A and in series

7B: the (SRS)-7A and (SRS)-7B isomers were obtained

from (R)-6 with 98 Ϯ 2% de over the (SSS)-7A and (SSS)-

7B isomers, respectively, while the (SSS)-7A and (SSS)-7B

isomers were obtained from (S)-6 with 95 Ϯ 5% de over the

(SRS)-7A and (SRS)-7B isomers, respectively.^[42]

Treatment of the samples of H-[HO]₂-Bip-OMe (R)-6 and

(S)-6 with di-tert-butyl dicarbonate (Boc₂O) in acetonitr-

ile,^[43,44]at room temperature to prevent any racemization,

afforded the corresponding N^α-protected α-amino esters

Boc-[HO]₂-Bip-OMe (R)-8 (88%) and (S)-8 (87%), respect-

ively (Figure 4). Enantiomeric excesses identical to those of

the starting materials (R)-6 and (S)-6 can be assumed for

the corresponding samples of (R)-8 (98 Ϯ 2% ee) and (S)-

8 (95 Ϯ 2% ee) with a high degree of confidence, because

of the relatively low temperature and neutral reaction con-

ditions. In a control experiment, a solution of (S)-6 in

MeOH presented complete optical stability after 24 h at 50

°C (only at 110 °C in DMF did racemization occur, with a

half-life of ca. 2 h). In a similar manner, the sparingly sol-

uble racemic α-amino ester (RS)-6 was treated with Boc₂O

in acetonitrile at 75 °C to give (RS)-8 (93%).

Figure 4. Synthesis of racemic and chirally resolved H-[HO]₂-Bip-

OMe (6) and Boc-[HO]₂-Bip-OMe (8); (i) BBr₃, CH₂Cl₂, room

temp.; (ii) MeOH, 98% H₂SO₄(cat.), reflux; (iii) fractional crystal-

lization of (R,S)-6; (iv) Boc₂O, CH₃CN, room temp. or 75 °C (for

[a]

racemic);

enantiomeric excess (optical purity), determined by

comparison of the optical rotation with the calculated maximum

value (see text and Exp. Sect.); determined by ¹⁹F NMR of the

[b]

corresponding Mosher amides/half phenyl ester isomers (see text

[c]

and Exp. Sect.); assumed (see text)

1234

Eur. J. Org. Chem. 2002, 1232Ϫ1247

C^α,α-Disubstituted Glycine Containing a Crown Ether Receptor

FULL PAPER

Table 1. Optical rotations of the different samples of 6,6Ј-disubstituted-2,2Ј-bridged biphenyl (Bip) derivatives 4, 6, 8 and Ia of known

enantiomeric excess (ee), extrapolated to their maximum values (bold/italic characters)

25

[α]

365

c (MeOH)

0.1

589

578

546

436

(R)-4 ee 98 Ϯ 2%

[α]_max

(S)-4 ee 64 Ϯ 5%

[α]_max

ϩ19.8

؉20.2

Ϫ17.2

؊26.8

ϩ18.8

؉19.2

Ϫ17.7

؊27.6

ϩ14.7

؉15.0

Ϫ17.9

؊27.9

Ϫ7.6

؊7.7

ϩ3.2

؉5.0

Ϫ132.0

؊134.7

ϩ83.8

0.5

؉130.9

(R)-6 ee 98 Ϯ 2%

[α]_max

(S)-6 ee 95 Ϯ 2%

[α]_maxX

Ϫ3.0

؊3.1

ϩ7.0

؉7.4

Ϫ7.6

؊7.7

ϩ7.9

؉8.3

Ϫ15.2

؊15.5

ϩ15.7

؉16.5

Ϫ134.0

؊136.7

ϩ124.0

؉130.5

Ϫ598.0

؊610.2

ϩ572.0

؉602.1

0.1

(R)-8 ee 98 Ϯ 2%

[α]_max

(S)-8 ee 95 Ϯ 2%

[α]_max

Ϫ137.7

؊140.5

ϩ137.8

؉145.0

Ϫ145.5

؊148.5

ϩ146.8

؉154.5

Ϫ174.1

؊177.6

ϩ173.0

؉182.1

Ϫ386.4

؊394.3

ϩ382.9

؉403.0

Ϫ905.0

؊923.5

ϩ917.6

؉965.9

0.1

(R)-Ia ee 64 Ϯ 5%

[α]_max

(S)-Ia ee 48 Ϯ 5%

[α]_max

Ϫ89.0

؊139.1

ϩ72.0

؉150.0

Ϫ94.0

؊146.9

ϩ74.0

؉154.2

Ϫ109.0

؊170.3

ϩ85.0

Ϫ210.0

؊328.1

ϩ162.0

؉337.5

Ϫ399.0

؊623.4

ϩ318.0

؉662.5

0.1

؉177.1

Figure 5. Chemical structures of the four diastereoisomeric Mosher

amides/half phenyl esters 7A and 7B; note: position of the phenyl

ester function in 7A and 7B has been arbitrarily assigned

Figure 6. Synthesis of racemic and chirally resolved Boc-[20-C-6]-

Bip-OMe (Ia) and H-[20-C-6]-Bip-OMe (Ib): (i) Cs₂CO₃, TsO-CH₂-

(CH₂-O-CH₂)₄-CH₂-OTs, DMF, 60 °C; (ii) TFA/CH₂Cl₂(1:3),

room temp.; ^[a]enantiomeric excess determined by ¹⁹F NMR of the

corresponding Mosher amide (see text and Exp. Sect.)

The dicesium salts of (RS)-8, (R)-8 and (S)-8 were treated

with pentaethylene glycol ditosylate in DMF (N,N-di-

methylformamide) at 60 °C under high-dilution conditions,

in a manner similar to that previously reported by Voyer et Ph(OCH₃)(CF₃)C-CO-(S)-[20ϪC-6]-Bip-OMe was ob-

al.,^[7]to give the expected fully protected crown-carrier α- tained from (S)-Ib with a de of only 48 Ϯ 5%. Assuming

amino acid residues Boc-[20-C-6]-Bip-OMe (RS)-Ia (38%), the absence of any racemization during the conversion of

(R)-Ia (49%) and (S)-Ia (49%), respectively (Figure 6).

Ia to Ib, it appears that (R)-Ia and (R)-Ib (64 Ϯ 5% ee)

Cleavage of the Boc protecting group of (RS)-Ia in TFA resulted from (R)-8 (98 Ϯ 2% ee) and that (S)-Ia and (S)-

(trifluoroacetic acid)/CH₂Cl₂(1:3) at room temperature af- Ib (48 Ϯ 5% ee) resulted from (S)-8 (95 Ϯ 2% ee), demon-

forded the free α-amino ester H-[20-C-6]-Bip-OMe (RS)-Ib strating the occurrence of extensive racemization during the

(91%). Aliquots of (R)-Ia and (S)-Ia were also N-depro- cyclisation step with crown ether formation.

tected in the same manner, and the resulting crude samples

No decrease in de was observed by ¹⁹F NMR in a control

of (R)-Ib and (S)-Ib were converted into the corresponding experiment in which a solution of (S)-Ph(OCH₃)(CF₃)C-

Mosher’s amides as above for analysis of their diastereo- CO-(S)-[20-C-6]-Bip-OMe (48 Ϯ 5% de) in [D₈]toluene was

isomeric excess by ¹⁹F NMR. It was found that (S)- kept for one week at 110 °C, reflecting a very high enantiom-

Ph(OCH₃)(CF₃)C-CO-(R)-[20-C-6]-Bip-OMe was obtained eric stability of the [20-C-6]-Bip residue, as would be ex-

from (R)-Ib with a de of only 64 Ϯ 5%, while (S)- pected from racemization studies on related compounds in

Eur. J. Org. Chem. 2002, 1232Ϫ1247

1235

J.-P. Mazaleyrat et al.

FULL PAPER

the literature.^[45,46]Altogether, it appears that racemization N-terminus of (R,S)-Ib, to give Boc-Gly-[20-C-6]-Bip-OMe

only occurred in two steps of the synthesis, in both of which (R,S)-IIIa (70%).

a 6,6Ј-dihydroxy-2,2Ј-bridged biphenyl was being treated in

either an acidic or a basic medium: (i) H-[HO]₂-Bip-

OH·HBr and H-[HO]₂-Bip-OMe in the demethylation

(BBr₃/CH₂Cl₂/room temp.) and esterification (MeOH/

H₂SO₄/50 °C) steps, and (ii) Boc-[HO]₂-Bip-OMe in the

cyclization step (Cs₂CO₃/DMF/60 °C). This result concurs

with both the acid-catalysed and the base-catalysed racem-

ization of 2,2Ј-dihydroxy-1,1Ј-binaphthyl, previously ob-

served and interpreted by Cram et al.^[47]Racemization is

even probably enhanced in the present case, because of the

lower configurational stability of 2,2Ј,6,6Ј-tetrasubstituted

biphenyls relative to the related 2,2Ј-disubstituted 1,1Ј-bi-

naphthyls.

It is noteworthy that, in addition to the absolute config-

Figure 8. Solution synthesis of peptides IϪV: (i) 1  NaOH,

uration of the new series of compounds 4, 6, 8 and Ia, read-

MeOH, 50 °C, 2 h; (ii) EDC, HOBt; (iii) 1  NaOH, MeOH, room

ily established by chemical correlation with the known

temp., 2 h; (iv) TFA/CH₂Cl₂(1:3), room temp., 2.5 h; (v) (1) Boc-

starting diacid 1, diol 2 and dibromide 3 Ϫ all [(Ϫ)-(R);

(ϩ)-(S)]^[33]Ϫ their maximum optical rotations can be es-

timated with a high degree of confidence by extrapolation

from the optical rotation values of samples of known ee,

deduced from the de values of their Mosher derivatives

(Table 1).

Gly-OH (2 equiv.), EDC, CH₃CN, room temp., 1 h; (2) H-[20-C-

6]-Bip-OMe

In the same manner, coupling of H-Gly-OMe by the

EDC/HOBt method at the C-terminus of Boc-Gly-[20-C-

6]-Bip-OH (R,S)-IIIc (84%), obtained after saponification

of (R,S)-IIIa, afforded the tripeptide Boc-Gly-[20-C-6]-Bip-

Gly-OMe (R,S)-IVa (82%). Finally, segment coupling of H-

Gly-[20-C-6]-Bip-Gly-OMe (R,S)-IVb (100%), resulting

from N^α-deprotection of (R,S)-IVa, with Boc-[20-C-6]-Bip-

Gly-OH (R,S)-IIc (54%), resulting from saponification of

(R,S)-IIa, by the EDC/HOBt method afforded the penta-

peptide Boc-[20-C-6]-Bip-Gly-Gly-[20-C-6]-Bip-Gly-OMe

Va (55%) as a mixture of two racemic isomers [(RR,SS) and

(RS,SR)], which could not be separated by chromatography.

We succeeded in the synthesis of only a single peptide

from the corresponding enantiomerically enriched [20-C-6]-

Bip residue; coupling of (S)-Ic, resulting from saponifica-

tion of (S)-Ia (48 Ϯ 5% ee), with H-(Aib)₆-OtBu, obtained

by N^α-deprotection of the corresponding Z (benzyloxycar-

bonyl) precursor^[50]with H₂in the presence of Pd/C in

MeOH, by the EDC/HOAt (1-hydroxy-7-aza-1,2,3-benzo-

triazole) method^[51]afforded the heptapeptide Boc-[20-C-6]-

Bip-(Aib)₆-OtBu (S)-VI (19% yield; assumed 48 Ϯ 5% ee).

Synthesis of Peptides Based on the [20-C-6]-Bip Residue

The synthesis of a few peptides IIϪVI based on the [20-

C-6]-Bip residue I (Figure 7) was performed in order to find

suitable coupling conditions in solution for such an unusual

C^α,α-disubstituted glycine.

Figure 7. Chemical structures of the peptides IϪVI based on the

[20-C-6]-Bip residue

Conformational Characterization of Boc-[20-C-6]-Bip-

(Aib)₆-OtBu (S)-VI

The

EDC/HOBt

(1-hydroxy-1,2,3-benzotriazole)

method^[48]had previously been shown to be efficient for

the coupling of Ala at the C-termini of C^α,α-diphenylglycine

The preferred conformation of the terminally protected

(Dph),^[49]Bip^[26]and Bin,^[27]but to proceed with low yield [20-C-6]-Bip/Aib heptapeptide was determined in a struc-

for the coupling of Ala at the N-terminus of Dph.^[49]It was ture-supporting solvent (CDCl₃) by FT-IR absorption and

chosen by us for coupling of H-Gly-OMe at the C-terminus ¹H NMR at 1 m concentration, at which self association

of racemic Boc-[20-C-6]-Bip-OH (R,S)-Ic, obtained in 96% is absent (results not shown). Figure 9 illustrates the FT-

yield after saponification of (R,S)-Ia with 1  NaOH in IR absorption spectrum (NϪH stretching region), which is

MeOH at 50 °C (Figure 8), to give the dipeptide Boc-[20- characterized by a weak band at 3424 cm^Ϫ1(free, solvated

C-6]-Bip-Gly-OMe (R,S)-IIa (82%). The symmetrical an- NH groups) and an intense band at 3324 cm^Ϫ1(H-bonded

hydride (Boc-Gly)₂O method was used for coupling at the NH groups).^[52,53]

1236

Eur. J. Org. Chem. 2002, 1232Ϫ1247

C^α,α-Disubstituted Glycine Containing a Crown Ether Receptor

FULL PAPER

(i) [N(1)H and N(2)H protons] contained protons with

chemical shifts sensitive to the addition of DMSO. Interest-

ingly, the sensitivity of the N(1)H proton was higher than

that of the N(2)H proton. Class (ii) [N(3)H to N(7)H pro-

tons] contained those displaying behaviour characteristic of

shielded protons (relative insensitivity of chemical shifts to

solvent composition). In summary, the ¹H NMR results al-

lowed us to conclude that, in CDCl₃solution, the N(3)H

to N(7)H protons of the heptapeptide were almost inaccess-

ible to the perturbing agent and so were most probably in-

tramolecularly H-bonded. In view of these findings it was

reasonable to conclude that the most populated structure

adopted by the N- and C-protected heptapeptide in CDCl₃

solution is the 3₁₀-helix. This conclusion is in excellent

agreement with that derived from the FT-IR absorption in-

vestigation discussed above.

Figure 9. FT-IR absorption and inverted second derivative spec-

trum of Boc-(S)-[20-C-6]-Bip-(Aib)₆-OtBu in CDCl₃solution; pep-

tide concentration 1 m

The CD spectra of the (S)-[20-C-6]-Bip heptapeptide VI

and the (R)-[20-C-6]-Bip N^α-protected amino acid derivat-

ive Ic in the 200Ϫ300 nm region are shown in Figure 11.

The consistently positive Cotton effects at longer wave-

lengths and negative Cotton effect at shorter wavelengths

are typical of the (S) compound, whereas an opposite CD

pattern is exhibited by the (R) compound.^[56]Therefore, as

in the related Bin derivatives and peptides,^[27]the CD spec-

trum reflects the configurational properties of the [20-C-6]-

Bip residue, but does not provide any conformational in-

formation.

This analysis provided convincing evidence that intramo-

lecular H-bonding is a factor of paramount importance in

supporting a folded conformation of the heptapeptide in

CDCl₃solution. The ratio of the intensity of the low-fre-

quency band (A_H) relative to the high-intensity band (A_F)

was that expected for an almost fully developed 3₁₀-helical

conformation,^[54]in which the NH groups near the N-ter-

minus are free and all other NH groups are intramolecul-

arly H-bonded.

The assignment of inaccessible (or intramolecularly H-

1

bonded) NH groups of the heptapeptide by H NMR was

performed by using the solvent dependence of NH chemical

shifts, through addition of increasing amounts of the strong

[55]

H-bonding acceptor solvent dimethylsulfoxide (DMSO)

to the CDCl₃solution (Figure 10).

Figure 11. CD spectra of Boc-(S)-[20-C-6]-Bip-(Aib)₆-OtBu VI

(ϪϪϪϪϪ) and the model compound Boc-(R)-[20-C-6]-Bip-OH Ic

(----) in MeOH solution

Conclusions

In this study we have introduced the new C^α,α-disubsti-

tuted amino acid residue [20-C-6]-Bip, characterized by

2,2Ј,6,6Ј-tetrasubstituted biphenyl and crown-ether receptor

architectures, and proposed a route for the synthesis of both

Figure 10. Plot of NH chemical shifts in the ¹H NMR spectrum

of Boc-(S)-[20-C-6]-Bip-(Aib)₆-OtBu as a function of increasing

percentages of DMSO (v/v) added to the CDCl₃solution; peptide

concentration 1 m

The upfield resonance in CDCl₃solution was unambigu- racemic and optically enriched forms.

ously attributable to the urethane N(1)H proton.^[53]By ana-

In the racemic series, the fully protected α-amino ester

logy with a variety of model peptides we were also able to Boc-[20-C-6]-Bip-OMe (R,S)-Ia was readily obtained in ca.

assign the resonance at immediately lower field to the 10% (not optimised) overall yield from 6,6Ј-dimethoxy-1,1Ј-

N(2)H proton.^[54]All other proton resonances fell down- biphenyl-2,2Ј-dicarboxylic acid. However, when resolved

field in a relatively narrow spectral range. In CDCl₃/DMSO samples of this diacid were used, only enantiomerically en-

mixtures, two classes of NH protons were observed. Class riched Ϫ not pure Ϫ (R)-Ia and (S)-Ia could be obtained,

Eur. J. Org. Chem. 2002, 1232Ϫ1247

1237

J.-P. Mazaleyrat et al.

FULL PAPER

uteriochloroform (99.8% D) was purchased from Merck. Solvent

(base line) spectra were recorded under the same conditions.

although their immediate 6,6Ј-dihydroxy precursors Boc-

[HO]₂-Bip-OMe (R)-8 and (S)-8 were enantiomerically pure

or nearly so; this was because of racemization occurring

under the basic conditions needed for the cyclisation step

with crown-ether formation. A better way to proceed would

1

¹H Nuclear Magnetic Resonance: H NMR spectra for conforma-

tional analysis were obtained with a Bruker model AM 400 spectro-

meter. Measurements were carried out in deuteriochloroform

therefore be to carry out the resolution after the final stage (99.96% D; Aldrich) and deuterated DMSO (99.96% D₆; Acros

Organics) with tetramethylsilane as the internal standard.

of the synthesis of [20-C-6]-Bip instead of at an early stage.

We are currently investigating such procedures. In spite of

that failure, a variety of (R) and (S) enantiomerically en-

riched new structures of established absolute configuration,

enantiomeric excess and optical rotation Ϫ 4, 6, 8 and I Ϫ

have been prepared. Short peptides have also been synthe-

sized in order to determine appropriate coupling conditions

for the racemic [20-C-6]-Bip residue in solution, as well as

to probe the postulated 3₁₀-helical conformation of the hep-

tapeptide Boc-[20-C-6]-Bip-(Aib)₆-OtBu (S)-VI by FT-IR

Circular Dichroism: CD spectra were obtained with a Jasco model

J-710 spectropolarimeter. Cylindrical fused quartz cells with path

lengths of 10, 1, 0.2 and 0.1 mm (Hellma) were used. Spectrograde

methanol (Acros Organics) was used as solvent.

Resolution of 6,6Ј-Dimethoxy-1,1Ј-biphenyl-2,2Ј-dicarboxylic Acid

(R,S)-1: According to a previously described procedure,^[31]a solu-

tion of racemic diacid (R,S)-1 (4.146 g, 13.73 mmol), prepared from

2-amino-3-methoxybenzoic acid,^[30]and anhydrous quinine

(8.896 g, 27.46 mmol) in MeOH (100 mL), was concentrated to

dryness in vacuo at 60 °C. The residue was solubilized in boiling

1

absorption and H NMR.

The [20-C-6]-Bip residue presents interesting new fea- acetone (100 mL) and the solution was concentrated to ca. 40 mL,

and then left at room temperature. Crystallization of white crystals

rapidly occurred. The mixture was kept at ϩ4 °C in a refrigerator

overnight, and the crystals were filtered, washed with cold acetone

and dried in vacuo at 25 °C (crystals C₁; yield 6.138 g). The com-

bined acetone solution of supernatant and washings (filtrate F₁)

was heated to reflux and concentrated to ca. 20 mL. After 1 d at

room temperature followed by a few days in a refrigerator, the crys-

tals were collected and dried as above (crystals C₁₁; yield 0.854 g).

The combined acetone solution of the corresponding filtrate F₂was

heated to reflux and concentrated to ca. 15 mL. No crystallization

tures: (i) the receptor site is in a totally rigid and controlled

spatial disposition relative to the C^αatom, in contrast with

the previously described flexible crown-carrier α-amino

acids,^[1Ϫ14](ii) as emphasized earlier, it belongs to the class

of C^α,α-disubstituted glycines, well known for their very

high tendency to induce β-bends and α/3₁₀-helices in

peptides,^[16Ϫ23]which would be expected to allow control

over the spatial organisation of these receptors in short pep-

tide structures. Indeed, the parent 6,6Ј-unsubstituted Bip

residue itself behaves as helix inducer in short-chain pep- occurred after several days at ϩ4 °C. The solution was concen-

tides,^[26](iii) [20-C-6]-Bip is the lead compound for new

trated to dryness in vacuo at 25 °C, to give 6.500 g (100%) of the

more soluble diquinine salt (filtrate F₂) as a white, amorphous

crown-carrier α-amino acids with only axial dissymmetry re-

25

solid. M.p. 105 °C; [α]²_D⁵ϭ Ϫ41.0, [α] ϭ Ϫ44.6, [α] ϭ Ϫ52.5,

578

546

lated to the 1,1Ј-binaphthyl/crown ether series developed by

Cram et al.,^[57]in which the opportunity to incorporate

steric and chiral barriers is of great interest for the design

of complementary binding features in host-guest chemistry.

[α]

ϭ Ϫ127.9, [α]

ϭ Ϫ675.3 (c ϭ 0.8; CHCl₃); ref.^[31]m.p.

25

436

365

98Ϫ100 °C; [α]²_D⁰ϭ Ϫ60 (c ϭ 0.8; CHCl₃). The crystals C₁(6.14 g)

were recrystallized from acetone (30 mL) as above, to give crystals

25

C₂{3.691 g; m.p. 179 °C; [α]²_D⁵ϭ ϩ111, [α]

ϭ ϩ116, [α]

ϭ

578

546

ϩ138, [α] ϭ ϩ215, [α] ϭ ϩ507 (c ϭ 1; CHCl₃); ref.^[31]m.p.

25

436

365

178Ϫ179 °C; [α]²_D⁰ϭ ϩ111.0 (c ϭ 1; CHCl₃); ref.^[33]m.p. 176Ϫ178

°C; [α]_Dϭ ϩ110 (c ϭ 2.6; CHCl₃)}, and a filtrate F₁₁. From the

concentrated acetone solution of combined C₁₁and F₁₁we ob-

tained crystals C₁₂(2.70 g), which were recrystallized from acetone

to give crystals C₁₃{2.126 g; m.p. 176 °C; [α]²_D⁵ϭ ϩ113.0 (c ϭ 1;

CHCl₃)}, for a total C₂ϩ C₁₃of 5.817 g (89%) of pure less soluble

diquinine salt. The crystals of the less soluble salt (5.817 g) were

triturated in the presence of 1.25  NaOH (90 mL). Et₂O (100 mL)

was added to the obtained suspension, and the mixture was mag-

netically stirred at room temperature until two clear, colourless

phases were obtained (ca. 3 h). The separated aqueous phase was

extracted with several portions of Et₂O, and then with cold CHCl₃

and then again with Et₂O. [Note: In our hands, direct extraction

of the suspension of the less soluble salt with cold CHCl₃as in the

literature^[31]resulted in extraction of both quinine and the disodium

salt of the diacid enantiomer (Ϫ)-(R)-1 in the organic phase. Et₂O,

as opposed to CHCl₃, was found to be the solvent of choice for

extraction of quinine alone, with final salt decomposition indicated

by complete solubilization of the initial suspension. On the other

hand, no particular problem was encountered in the CHCl₃extrac-

Experimental Section

General: Melting points were determined by means of a capillary

tube immersed in an oil bath (Tottoli apparatus, Büchi) with a final

temperature increase of 3 °C/min and are uncorrected. ¹H NMR

and ¹³C NMR spectra were recorded at 300 MHz and 75 MHz,

respectively, with the CDCl₃solvent being used as internal standard

(δ ϭ 7.27 for ¹H and δ ϭ 77.00 for ¹³C). Splitting patterns are

abbreviated as follows: (s) singlet, (d) doublet, (t) triplet, (q) quad-

ruplet, (m) multiplet. The optical rotations were measured with an

accuracy of 0.3%, in a 1-dm thermostatted cell. Analytical TLC

and preparative column chromatography were performed on F 254

Kieselgel and on 60 Kieselgel (0.040Ϫ0.063 mm) (Merck), respect-

ively, with the following eluent systems: 2.5% MeOH/97.5%

CH₂Cl₂(I); 5% MeOH/95% CH₂Cl₂(II); 10% MeOH/90% CH₂Cl₂

(III); 20% MeOH/80% CH₂Cl₂(IV). UV light (254 nm) allowed

viewing of the spots after thin layer chromatography (TLC) runs

for all compounds.

Infrared Absorption: FT-IR absorption spectra were recorded with tion of quinine from the decomposed more soluble salt, probably

a

PerkinϪElmer model 1720X spectrophotometer, nitrogen-

because of much weaker interactions between quinine and the di-

acid enantiomer (ϩ)-(S)-1]. The resulting clear, colourless, aqueous

flushed, equipped with a sample-shuttle device, at 2 cm^Ϫ1nominal

resolution, averaging 100 scans. Cells with path lengths of 0.1, 1.0 basic solution was cooled to ca. 0 °C and acidified with an excess

and 10 mm (with CaF₂windows) were used. Spectrograde de-

of ice-cold 6  HCl (25 mL), to afford a gel-like precipitate that

Eur. J. Org. Chem. 2002, 1232Ϫ1247

1238

C^α,α-Disubstituted Glycine Containing a Crown Ether Receptor

turned into a white solid suspension upon trituration. The solid [α] ϭ Ϫ111.3, [α] ϭ Ϫ202.4, [α] ϭ Ϫ346.5 (c ϭ 0.98; acet-

FULL PAPER

21

546

21

436

21

365

was filtered, abundantly washed with water and air-dried to afford one), corresponding to 93 Ϯ 5% optical purity; and 0.271 g (76%);

21

0.995 g of pure (Ϫ)-(R)-1 as a white powder {m.p. 294 °C; [α]²_D¹

ϭ

[α]²_D¹ϭ Ϫ90.0, [α] ϭ Ϫ94.5, [α] ϭ Ϫ108.9, [α] ϭ Ϫ198.2,

578 546 436

21

Ϫ105.0, [α]₅²₇¹₈ϭ Ϫ111.4, [α]₅²₄¹₆ϭ Ϫ133.4, [α]₄²₃¹₆ϭ Ϫ267.9, [α]₃²₆¹₅ϭ [α]

ϭ Ϫ337.1 (c ϭ 1.10; acetone), corresponding to 91 Ϯ 5%

365

Ϫ539.2 (c ϭ 0.38; acetone), corresponding to 89% optical purity optical purity, respectively}.

(estimated experimental error: Ϯ5%); ref.^[31]m.p. 291Ϫ292 °C;

[α]²_D⁰ϭ Ϫ114.9 (c ϭ 0.38; acetone); ref.^[32]m.p. 291Ϫ292 °C;

[α]²_D⁰·⁵ϭ Ϫ117.8 (c ϭ 0.88; acetone); ref.^[33]m.p. 288Ϫ290 °C;

[α]_Dϭ Ϫ105 (c ϭ 2.75; acetone)}. The aqueous acidic solution of

filtrate was extracted with several portions of CH₂Cl₂(total ca.

500 mL) until the diacid spot was no longer detectable by UV in

the extracts. The combined organic phases were washed with water,

dried (MgSO₄) and filtered, and the solvents were evaporated in

vacuo at 30 °C to give 0.576 g of pure (Ϫ)-(R)-1 as a white solid

2,2Ј-Bis(hydroxymethyl)-6,6Ј-dimethoxy-1,1Ј-biphenyl

[(؉)-(S)-

2]:^[32]The same experimental and workup conditions as above,

when applied to (ϩ)-(S)-1 (1.829 g, 6.05 mmol, 75 Ϯ 5% ee) gave

crude (ϩ)-(S)-2 (1.280 g, 77%) as a white solid, with [α]²_D¹ϭ ϩ70.3,

21

[α] ϭ ϩ73.3, [α] ϭ ϩ84.6, [α] ϭ ϩ153.7, [α] ϭ ϩ261.8

578

546

436

365

(c ϭ 1.08; acetone), corresponding to 71 Ϯ 5% optical purity;

ref.^[32][α]¹_D⁸ϭ ϩ98.0 (c ϭ 0.95; acetone).

[(R,S)-3]:^[32]

21

{m.p. 297 °C; [α]²_D¹ϭ Ϫ107.6, [α]

ϭ Ϫ115.6, [α]

ϭ Ϫ136.5,

2,2Ј-Bis(bromomethyl)-6,6Ј-dimethoxy-1,1Ј-biphenyl

578

546

According to a previously described procedure,^[32]a solution of

phosphorous tribromide (9 mL) in toluene (11 mL) was added

dropwise over 30 min to a magnetically well-stirred, ice-cooled

milky suspension of the racemic diol (RS)-2 (3.591 g, 13.10 mmol)

in toluene (50 mL) [Note: benzene was used in the literature pro-

cedure] under argon. The resulting clarified, but still turbid, solu-

tion was stirred at room temperature for 1 h and at 40 °C for 1 h,

and was then poured onto ice. The cold mixture was magnetically

stirred and made basic by addition of a large excess of solid

NaHCO₃in small portions, and was then extracted with EtOAc (2

ϫ 150 mL). The organic phase was washed with H₂O (4 ϫ

150 mL), dried (MgSO₄) and filtered, and the solvents were evapor-

ated in vacuo to give 2.471 g of crude (R,S)-3 as a white solid. A

duplicate run starting from (RS)-2 (3.498 g, 12.76 mmol) gave

3.637 g of crude (R,S)-3 as a yellowish solid. These combined

samples were solubilized in CH₂Cl₂, and absolute EtOH (50 mL)

was added. The resulting clear solution was concentrated to ca.

10 mL and left at room temperature. Crystallization rapidly oc-

curred. The mixture was kept at ϩ 4 °C in a refrigerator overnight,

the crystals were filtered, washed with cold abs. EtOH and air-

dried (yield 5.397 g). More crystals (0.378 g) were obtained after

concentration of the mother liquor, to give a total of 5.775 g (56%)

of pure (R,S)-3 as white, shiny crystals. R_fϭ 0.85 (I). ¹H NMR

(CDCl₃): δ ϭ 7.49 [dd (t-like), J ഠ 7.9 and 8.1 Hz, 2 H, ArH^4,4Ј],

7.31 (dd, J ഠ 7.7 and 1.0 Hz, 2 H, ArH^5,5Ј), 7.03 (dd, J ഠ 8.2 and

1.0 Hz, 2 H, ArH^3,3Ј), 4.33 and 4.29 (d, J ഠ 10.3 Hz and d, J ഠ

10.3 Hz, 4 H, ArCH₂), 3.78 (s, 6 H, OMe]. ¹³C NMR (CDCl₃):

δ ϭ 156.6 (C_ArϪO), 137.4, 129.2, 123.9, 122.3, 100.5 (C_Ar), 55.5

(ArOCH₃), 31.8 (ArCH₂Br).

21

[α] ϭ Ϫ275.8, [α] ϭ Ϫ555.1 (c ϭ 0.39; acetone), correspond-

436

365

ing to 91 Ϯ 5% optical purity}, for a total yield of 1.571 g (76%).

Decomposition of the more soluble salt (6.500 g) by trituration in

the presence of NaOH (1.25 , 90 mL) and extraction of quinine

by four portions of cold CHCl₃(total 200 mL), followed by acid-

ification with cold 6  HCl (25 mL), trituration of the gel-like pre-

cipitate, filtration of the resulting white solid, washing with water

and drying gave 1.466 g of a white powder. Extraction of the acidic

aqueous filtrate by several portions of CH₂Cl₂(total ca. 500 mL),

washing of the combined organic phases with water, drying

(MgSO₄), filtration and concentration in vacuo at 30 °C gave

0.392 g of a white solid, which was combined with the former

sample to give a total of 1.858 g (90%) of pure (ϩ)-(S)-1 {m.p. ca.

21

300 °C; [α]²_D¹ϭ ϩ87.9, [α]

ϭ ϩ94.0, [α] ϭ ϩ111.6, [α]

ϭ

578

546

436

21

ϩ225.0, [α] ϭ ϩ451.8 (c ϭ 0.36; acetone), corresponding to 75

365

Ϯ 5% optical purity; ref.^[31]m.p. 291Ϫ292 °C; [α]²_D⁰ϭ ϩ108.5 (c ϭ

0.37; acetone); ref.^[32]m.p. 290Ϫ292 °C; [α]²_D³ϭ ϩ116.8 (c ϭ 0.96;

acetone)}.

2,2Ј-Bis(hydroxymethyl)-6,6Ј-dimethoxy-1,1Ј-biphenyl [(R,S)-2]:^[32]

The racemic diacid (RS)-1 (4.187 g, 13.8 mmol) was solubilized in

THF (175 mL). The resulting solution was stirred under argon for

20 min at 0 °C (ice/water bath) and a 1  solution of BH₃in THF

was slowly added by syringe. The cooling bath was removed, and

the resulting turbid mixture clarified after a few minutes to give a

clear, colourless solution, which was stirred at room temperature

overnight. The solution was again cooled to 0 °C and hydrolysed

under a stream of argon by slow addition of water followed by 0.5

 HCl. The acidic mixture was extracted with EtOAc (3 ϫ

150 mL), and the clear, colourless organic phase was washed with

water (2 ϫ 150 mL), dried (MgSO₄) and filtered. The solvents were

evaporated in vacuo to give 3.498 g (92%) of crude (R,S)-2 as a

white solid, pure by NMR and TLC, which was used without fur-

ther purification in the next step. R_fϭ 0.10 (I). ¹H NMR (CDCl₃):

δ ϭ 7.39 [dd (t-like), J ഠ 7.7 Hz, 2 H, ArH^4,4Ј], 7.15 (dd, J ഠ 7.7

and 1.0 Hz, 2 H, ArH^5,5Ј), 6.96 (dd, J ഠ 8.3 and 1.0 Hz, 2 H,

ArH^3,3Ј), 4.24 and 4.18 (d, J ഠ 11.6 Hz and d, J ഠ 11.6 Hz, 4 H,

ArCH₂), 3.70 (s, 6 H, OMe).

2,2Ј-Bis(bromomethyl)-6,6Ј-dimethoxy-1,1Ј-biphenyl [(؊)-(R)-3]:^[32]

The same experimental and workup conditions as for the synthesis

of (R,S)-3, when applied to (Ϫ)-(R)-2 (0.696 g, 2.54 mmol, 95 Ϯ

5% ee) gave, after solubilization of the crude product in CH₂Cl₂/

abs.EtOH, concentration of the solution (all CH₂Cl₂off) to a very

small volume (ca. 0.5 mL) in vacuo at Ͻ 35 °C (resulting in crystal-

lization at room temperature) and then at ϩ4 °C overnight, elim-

ination of the cold supernatant and drying of the crystals in vacuo,

pure (Ϫ)-(R)-3 (0.635 g, 63%) as a white crystalline powder. {m.p.

21

2,2Ј-Bis(hydroxymethyl)-6,6Ј-dimethoxy-1,1Ј-biphenyl

[(؊)-(R)-

114 °C; [α]²_D¹ϭ Ϫ79.9, [α]

ϭ Ϫ84.3, [α]

ϭ Ϫ98.7, [α]

ϭ

578

546

436

2]:^[32,33]The same experimental and workup conditions as above, Ϫ198.6, [α] ϭ Ϫ408.1 (c ϭ 0.98; acetone), corresponding to 99

21

365

when applied to (Ϫ)-(R)-1 (0.943 g, 3.12 mmol, 91 Ϯ 5% ee), gave Ϯ 5% optical purity; ref.^[32]m.p. 116Ϫ117 °C; [α]²_D²ϭ Ϫ80.7 (c ϭ

crude (Ϫ)-(R)-2 (0.707 g, 83%) as a white solid with [α]²_D¹ϭ Ϫ94.1,

1.02; acetone)}. Duplicate runs starting from (Ϫ)-(R)-2 (0.378 g,

[α] ϭ Ϫ98.7, [α] ϭ Ϫ113.8, [α] ϭ Ϫ206.5, [α] ϭ Ϫ351.8 1.38 mmol, 93 Ϯ 5% ee and 0.287 g, 1.05 mmol; 91 Ϯ 5% ee), gave

21

578

21

546

21

436

21

365

(c ϭ 1.24; acetone), corresponding to 95 Ϯ 5% optical purity;

ref.^[32][α]¹_D⁹·⁵ϭ Ϫ98.7 (c ϭ 1.02; acetone); ref.^[33][α]_Dϭ Ϫ63.5

(c ϭ 2.0; EtOH). Duplicate runs starting from (Ϫ)-(R)-1 (0.491 g,

pure (Ϫ)-(R)-3 as a white crystalline powder {0.338 g (61%); m.p.

21

115 °C; [α]²_D¹ϭ Ϫ80.3, [α]

ϭ Ϫ84.7, [α]

ϭ Ϫ99.2, [α]

ϭ

578

546

436

21

Ϫ199.7, [α] ϭ Ϫ410.3 (c ϭ 0.98; acetone), corresponding to 99

365

1.62 mmol, 91 Ϯ 5% ee and 0.395 g, 1.31 mmol, 91 Ϯ 5% ee) gave Ϯ 5% optical purity; and 0.172 g (41%); m.p. 115 °C; [α]²_D¹ϭ Ϫ80.1,

crude (Ϫ)-(R)-2 {0.390 g (88%); [α]²_D¹ϭ Ϫ92.1, [α]

ϭ Ϫ96.6, [α] ϭ Ϫ84.5, [α] ϭ Ϫ98.8, [α] ϭ Ϫ198.8, [α] ϭ Ϫ408.7

21

578

578 546 436 365

Eur. J. Org. Chem. 2002, 1232Ϫ1247

1239

J.-P. Mazaleyrat et al.

(c ϭ 0.91; acetone), corresponding to 99 Ϯ 5% optical purity, 81.2 (OCMe₃), 67.1 (Cα), 55.73, 55.71 (ArOCH₃), 43.4 (Cβ), 42.2

FULL PAPER

respectively}.

(CβЈ), 27.9 (OCMe₃). C₂₂H₂₇NO₄·0.25H₂O (373.948): calcd. C

70.66, H 7.41, N 3.75; found C 70.73, H 7.36, N 3.91. In duplicate

experiments, crude NMR-pure (RS)-4 could be obtained in higher

yields with no chromatography needed. For example, a mixture of

(RS)-3 (2.698 g, 6.75 mmol), (4-chlorobenzylidene)glycine tert-bu-

tyl ester (2.565 g, 10.12 mmol), tetrabutylammonium bromide

(0.435 g, 1.35 mmol), anhydrous potassium carbonate (9.31 g,

67.5 mmol) and freshly ground KOH pellets (3.78 g, 67.5 mmol) in

CH₂Cl₂(100 mL) was magnetically stirred at room temperature for

24 h, and then concentrated in vacuo. The residue was solubilized

in H₂O/Et₂O and extracted as above. The resulting orange solid

foam was solubilized in THF (60 mL), and aqueous citric acid (0.5

, 150 mL) was added. The mixture was magnetically stirred at

room temperature for 16 h and then concentrated in vacuo at 25

°C to ca. 50 mL, diluted with H₂O (ca. 150 mL) and extracted with

Et₂O (2 ϫ 200 mL). The clear, colourless acidic aqueous phase was

retained. The combined, dark orange ethereal phase was washed

with 5% NaHCO₃(100 mL) and then H₂O (2 ϫ 200 mL), dried

(MgSO₄), filtered and concentrated. Analytical TLC of this neutral

extract showed the presence of a main UV-positive spot corres-

ponding to 4-chlorobenzaldehyde and only traces of other unidenti-

fied spots, but none corresponding to (RS)-4. The initial acidic

aqueous phase obtained after extraction with Et₂O was made basic

by addition of a large excess of solid NaHCO₃in small portions,

and then extracted with EtOAc (3 ϫ 100 mL). The combined or-

ganic phasees were washed with H₂O (3 ϫ 200 mL), dried (MgSO₄)

and filtered, and the solvents were evaporated in vacuo to give a

basic extract consisting of crude (R,S)-4 (2.108 g, 85%) as a pale

yellow glass, pure by NMR and TLC, which was used in the next

step without further purification.

2,2Ј-Bis(bromomethyl)-6,6Ј-dimethoxy-1,1Ј-biphenyl [(؉)-(S)-3]:^[32]

The same experimental and workup conditions as for the synthesis

of (Ϫ)-(R)-3, when applied to (ϩ)-(S)-2 (1.268 g, 4.63 mmol; 71 Ϯ

5% ee), gave pure (ϩ)-(S)-3 (1.425 g, 77%) as a white crystalline

powder, with m.p. 109 °C; [α]²_D¹ϭ ϩ60.0, [α] ϭ ϩ62.5, [α]

ϭ

21

578

546

ϩ73.1, [α]₄²₃¹₆ϭ ϩ147.1, [α]₃²₆¹₅ϭ ϩ303.1 (c ϭ 1.01; acetone), corres-

ponding to 74 Ϯ 5% optical purity; ref.^[32]m.p. 117Ϫ118.5 °C;

[α]²_D⁰ϭ ϩ80.6 (c ϭ 1.05; acetone).

(4-Chlorobenzylidene)glycine tert-Butyl Ester:^[34,35]According to a

previously described procedure,^[36]a suspension of glycine tert-bu-

tyl ester hydrochloride (16.75 g, 100 mmol) and MgSO₄(18 g,

150 mmol) in

a solution of 4-chlorobenzaldehyde (14.05 g,

100 mmol) and CH₂Cl₂(350 mL) was stirred at room temperature

under argon while a solution of Et₃N (27.8 mL, 200 mmol) in

CH₂Cl₂(50 mL) was added dropwise over 1.5 h. The reaction mix-

ture was stirred for 20 h and filtered through fritted glass, and the

solvents were evaporated in vacuo at 40 °C. The resulting white

solid residue was triturated in Et₂O (400 mL) and the mixture was

filtered through fritted glass, the white solid precipitate of

Et₃N·HCl being washed several times with Et₂O (3 ϫ 100 mL).

The clear, colourless ether filtrate was successively washed with 5%

NaHCO₃(2 ϫ 100 mL), a solution of 2  NaOH containing 2 g/

100 mL of NH₂OH·HCl (2 ϫ 200 mL) and 1% NaHCO₃(2 ϫ

200 mL), dried (MgSO₄) and filtered. The solvents were evaporated

in vacuo to give 24.15 g (95%) of crude (4-chlorobenzylidene)gly-

cine tert-butyl ester as a colourless glassy oil, pure by NMR, which

was used in the next step without further purification. This sample

crystallized upon cooling to give a white solid that could be stored

for months at ca. Ϫ20 °C. ¹H NMR (CDCl₃): δ ϭ 8.23 (s, 1 H,

ArCHϭN), 7.72 (d, J ഠ 8.5 Hz, 2 H, ArH), 7.39 (d, J ഠ 8.4 Hz, 2

H, ArH), 4.31 (s, 2 H, NCH₂CO), 1.50 (s, 9 H, OCMe₃).

tert-Butyl 6-Amino-1,11-dimethoxy-6,7-dihydro-5H-dibenzo[a,c]cy-

cloheptene-6-carboxylate [(R)-4]: A mixture of (Ϫ)-(R)-3 of 99 Ϯ

5% ee (1.135 g, 2.84 mmol), (4-chlorobenzylidene)glycine tert-butyl

ester (0.863 g, 3.40 mmol), tetrabutylammonium bromide (0.183 g,

0.57 mmol), anhydrous potassium carbonate (3.92 g, 28.4 mmol)

and freshly ground KOH pellets (1.59 g, 28.4 mmol) in CH₂Cl₂

(50 mL) was magnetically stirred at room temperature for 20 h and

then concentrated in vacuo. Extraction with Et₂O/H₂O as above for

(RS)-4 provided a crude product, which was solubilized in CH₂Cl₂/

MeOH (50 mL). Silica gel (9 g) was added, and the mixture was

stirred at room temperature for one week and then concentrated in

vacuo at 30 °C. The resulting mixture of crude product and silica

gel was chromatographed on a 14 ϫ3 cm silica gel column. Elution

with CH₂Cl₂and then with eluent I gave 3 fractions: Fraction 1:

0.336 g of 4-chlorobenzaldehyde with minor unidentified impurit-

ies. Fraction 2: 0.300 g (35%) of a side product identified as (RR)-

tert-Butyl 6-Amino-1,11-dimethoxy-6,7-dihydro-5H-dibenzo[a,c]cy-

cloheptene-6-carboxylate [(RS)-4]: CH₂Cl₂(20 mL) was added to a

mixture of (RS)-3 (0.492 g, 1.23 mmol), (4-chlorobenzylidene)gly-

cine tert-butyl ester (0.374 g, 1.47 mmol), tetrabutylammonium

bromide (0.080 g, 0.248 mmol), anhydrous potassium carbonate

(1.70 g, 12.3 mmol) and freshly ground KOH pellets (0.69 g,

12.3 mmol). The suspension was magnetically stirred at ca. 1000

rev/min at room temperature for 21 h. The reaction mixture was

then concentrated in vacuo and the residue was solubilized in H₂O/

Et₂O. The separated Et₂O solution (150 mL) was washed with H₂O

(2 ϫ 100 mL), dried (MgSO₄) and filtered, and the solvents were

evaporated in vacuo. Silica gel (5 g of 60 Kieselgel, 0.063Ϫ0.2 mm)

and a solution of CH₂Cl₂/MeOH (50 mL) were added to the re-

sulting crude product (orange solid foam, 0.642 g). The mixture

was stirred in a water bath at 50 °C for several hours and the solv-

ents were evaporated in vacuo. The resulting mixture of crude prod-

uct and silica gel was chromatographed on a 21 ϫ 3.3 cm column

of silica gel with eluent I to give 0.248 g of a pure fraction and

0.055 g of a fraction that was further purified by preparative TLC

on silica gel with eluent I, to afford in total 0.290 g (64%) of analyt-

ically pure H-[MeO]₂-Bip-OtBu (RS)-4. R_fϭ 0.25 (I). ¹H NMR

(CDCl₃): δ ϭ 7.32 [dd (t-like), J ഠ 8 Hz, 1 H, ArH], 7.25 [dd (t-

like), J ഠ 8 Hz, 1 H, ArH], 6.98 (d, J ഠ 8 Hz, 1 H, ArH), 6.93

(two superimposed d, J ഠ 8 Hz, 2 H, ArH), 6.90 (d, J ഠ 8 Hz, 1

H, ArH), 3.82 (s, 6 H, ArOCH₃), 2.95 and 2.45 (d, J ϭ 13.2 Hz, 1 H

and d, J ϭ 13.2 Hz, 1 H, ArCH₂β), 2.95 and 2.24 (d, J ϭ 13.2 Hz, 1

H and d, J ϭ 13.2 Hz, 1 H, ArCH₂βЈ), 1.46 (s, 9 H, OCMe₃). ¹³C

1

5. R_fϭ 0.45 (CH₂Cl₂). H NMR (CDCl₃): δ ϭ 7.5Ϫ6.9 (m, 12 H,

ArH), 3.90 (m, 12 H, ArOCH₃), 4.22 and 3.57 (d, J ϭ 12.6 Hz, 2

H and d, J ϭ 12.6 Hz, 2 H, ArCH₂N), 3.51 and 2.44 (d, J ϭ

11.9 Hz, 1 H and d, J ϭ 11.9 Hz, 1 H, ArCH₂β), 3.43 and 2.62 (d,

J ϭ 14.5 Hz, 1 H and d, J ϭ 14.5 Hz, 1 H, ArCH₂βЈ), 1.39 (s, 9

H, OCMe₃). ESI^ϩMS m/z (%): 608 (100) [MH]^ϩ. C₃₈H₄₁NO₆·H₂O

(625.732): calcd. C 72.93, H 6.92, N 2.24; found C 73.19, H 6.87,

N 2.08. Fraction 3: 0.590 g of the desired amino ester (R)-4, which

was further purified by column chromatography on silica gel with

eluent I to afford 0.502 g (48%) of pure (R)-4 as a pale orange

glass, identified by ¹H NMR [see (RS)-4], with [α]²_D⁵ϭ ϩ19.8,

[α]₅²₇⁵₈ϭ ϩ18.8, [α]₅²₄⁵₆ϭ ϩ14.7, [α]₄²₃⁵₆ϭ Ϫ7.6, [α]₃²₆⁵₅ϭ Ϫ132.0 (c ϭ

0.1; MeOH), corresponding to 98 Ϯ 2% ee as determined by ¹⁹F

NMR of the corresponding Mosher amides (vide infra).

NMR (CDCl₃): δ ϭ 174.4 (CϭO), 156.8, 156.6 (C_ArϪO), 138.4, tert-Butyl 6-Amino-1,11-dimethoxy-6,7-dihydro-5H-dibenzo[a,c]cy-

137.0, 128.4, 127.9, 124.8, 124.4, 122.2, 122.1, 110.1, 109.8 (C_Ar), cloheptene-6-carboxylate [(S)-4]: A mixture of (ϩ)-(S)-3 of 74 Ϯ

1240

Eur. J. Org. Chem. 2002, 1232Ϫ1247

C^α,α-Disubstituted Glycine Containing a Crown Ether Receptor

5% ee (1.409 g, 3.52 mmol), (4-chlorobenzylidene)glycine tert-butyl

FULL PAPER

128.43, 128.37, 128.29, 125.8, 124.9, 122.2, 121.9, 110.6, 110.3

ester (1.072 g, 4.22 mmol), tetrabutylammonium bromide (0.227 g, (C_Ar), 83.8 (CF₃), 81.7 (OCMe₃), 68.2 (Cα), 55.8 (ArOCH₃), 54.8

0.70 mmol), anhydrous potassium carbonate (4.86 g, 35.2 mmol)

and freshly ground KOH pellets (1.97 g, 35.2 mmol) in CH₂Cl₂

(OCH₃MTPA), 41.3 (Cβ), 37.0 (CβЈ), 27.8 (OCMe₃). ¹⁹F NMR

(CDCl₃): Ϫ68.85 [s (Ͻ 1%), CF₃of the (SS) isomer], Ϫ69.17 [s (Ͼ

(60 mL) was magnetically stirred at room temperature for 20 h and 99%), CF₃]. From (S)-4, the amido ester (S)-Ph(OCH₃)(CF₃)C-

then concentrated in vacuo. Extraction with Et₂O/H₂O afforded a

crude product, which was treated with silica gel (10 g) in CH₂Cl₂/

MeOH (50 mL) at room temperature for one week, as for (R)-4.

CO-(S)-[MeO]₂-Bip-OtBu (0.0081 g, 97%) was obtained with 64%

de (estimated experimental error: Ϯ5%). ¹H NMR (CDCl₃): δ ϭ

7.67 (m, 2 H, ArH MTPA), 7.47 (m, 3 H, ArH MTPA), 7.25 [dd

Chromatography on a 14 ϫ 3 cm silica gel column, with CH₂Cl₂(t-like), J ഠ 8 Hz, 1 H, ArH], 7.09 [dd (t-like), J ഠ 8 Hz, 1 H,

and then with eluent I, gave 3 fractions. Fraction 1: 0.504 g of a

mixture of 4-chlorobenzaldehyde and a small proportion of re-

maining C^α,α-dialkylated glycine ester Schiff base precursor of (S)-

4 (incomplete hydrolysis on silica gel). This fraction was dissolved

in 95% ethanol (20 mL) and stirred at room temperature for 3 d in

the presence of NH₂OH·HCl (0.695 g, 10 mmol) and sodium acet-

ArH], 6.94 (d, J ϭ 8.2 Hz, 1 H, ArH), 6.90 (d, J ϭ 8.0 Hz, 1 H,

ArH), 6.81 (d, J ϭ 7.7 Hz, 1 H, ArH), 6.74 (s, 1 H, NH), 6.41 (d,

J ϭ 7.1 Hz, 1 H, ArH), 3.80 (s, 3 H, ArOCH₃), 3.79 (s, 3 H, Ar-

OCH₃), 3.48 (m, 3 H, OCH₃MTPA), 3.14 and 2.34 (d, J ϭ

12.6 Hz, 1 H and d, J ϭ 12.8 Hz, 1 H, ArCH₂β), 3.01 and 2.88 (d,

J ϭ 13.9 Hz, 1 H and d, J ϭ 14.2 Hz, 1 H, ArCH₂βЈ), 1.49 (s, 9

ate (0.820 g, 10 mmol). Transimination was complete after 3 d. Eth- H, OCMe₃) all signals corresponding to the (SR) isomer (vide su-

anol was evaporated and the residue was extracted with Et₂O

pra) also present in the proportion of ca. 20%. ¹³C NMR (CDCl₃):

(75 mL) in the presence of 5% NaHCO₃(75 mL). The ethereal so- δ ϭ 169.8 (CϭO), 165.0 (CϭO MTPA), 156.8, 156.7 (C_ArϪO),

lution was dried (MgSO₄) and filtered, and the solvents were evap- 137.2, 135.5, 132.6, 129.5, 128.4, 128.3, 127.5, 124.9, 124.7, 122.0,

orated in vacuo. The residue was chromatographed on preparative 121.8, 110.7, 110.3 (ca. 20%), 110.1 (C_Ar), 83.6 (CF₃), 81.8

TLC plates with eluent I to afford 0.126 g of (S)-4 containing mi-

(OCMe₃), 68.0 (Cα), 55.8 (ArOCH₃), 55.0 (OCH₃MTPA), 41.2

nor impurities. Fraction 2: 0.228 g (21%) of the side product (SS)-

(Cβ), 37.0 (ca. 20%), 36.7 (CβЈ), 27.8 (OCMe₃). ¹⁹F NMR (CDCl₃):

1

5, identified by H NMR (see (RR)-5). Fraction 3: 0.882 g of im- δ ϭ Ϫ68.84 [s (ca. 82%), CF₃], Ϫ69.17 [s (ca. 18%), CF₃of the

pure amino ester (S)-4. This fraction and the sample of (S)-4 ob-

tained from Fraction 1 (0.126 g) were combined and further puri-

fied by column chromatography on silica gel with eluent I to afford

0.790 g (61%) of pure (S)-4 as a pale orange glass, identified by ¹H

(SR) isomer].

Methyl

6-Amino-1,11-dihydroxy-6,7-dihydro-5H-dibenzo[a,c]cy-

cloheptene-6-carboxylate [(RS)-6]: A solution of BBr₃(1  in

CH₂Cl₂, 5 mL, 5 mmol) was slowly added by syringe to a solution

of (RS)-4 (0.205 g, 0.55 mmol) in CH₂Cl₂(25 mL), cooled to Ϫ10

°C (ice/salt bath) and magnetically stirred under argon. The re-

sulting orange-brown suspension was stirred under argon between

Ϫ10 °C and 0 °C for 3 h and then at room temperature for 3 d.

Addition of MeOH (40 mL) afforded a clear orange-brown solu-

25

NMR [see (RS)-4], with [α]²_D⁵ϭ Ϫ17.2, [α]

ϭ Ϫ17.7, [α]

ϭ

578

546

Ϫ17.9, [α]₄²₃⁵₆ϭ ϩ3.2, [α]₃²₆⁵₅ϭ ϩ83.8 (c ϭ 0.5; MeOH), correspond-

ing to 64 Ϯ 5% ee as determined by ¹⁹F NMR of the corresponding

Mosher amides (vide infra).

Coupling of (R)-4 and (S)-4 with (؊)-(S)-α-Methoxy-α-phenyl-α-tri-

fluoromethylacetic Acid: DCC (0.0148 g, 0.071 mmol) was added to tion of the free amino acid H-[HO]₂-Bip-OH·HBr, which was con-

a

solution of (Ϫ)-(S)-MTPA (α-methoxy-α-trifluoromethyl-α-

centrated to ca. 20 mL (CH₂Cl₂off) in vacuo at 30 °C, and then

diluted to ca. 70 mL with more MeOH and stirred at room temper-

ature while 98% H₂SO₄(2.5 mL) was added dropwise. The solution

phenylacetic acid; Aldrich, 99%; 0.0336 g, 0.143 mmol) in aceton-

itrile (1.1 mL), which immediately resulted in the formation of a

white precipitate of DCU (N,NЈ-dicyclohexylurea). After this had was heated under reflux under argon for 48 h, and then cooled to

stirred at room temperature for 15 min, the resulting solution of

the MTPA anhydride was filtered through a pipette capped with

cotton wool, and divided into two portions of 0.5 mL each, which

were added to samples of (R)-4 (0.0053 g, 0.014 mmol) and (S)-4

room temperature and poured onto ice. The obtained cold, pale

orange, acidic, clear solution (ca. 300 mL) was made basic by slow

addition of a very large excess of solid NaHCO₃in small portions

and then extracted with EtOAc (2 ϫ 125 mL). The organic phase

(0.0052 g, 0.014 mmol). The resulting clear, colourless solutions was washed with water (100 mL), dried (MgSO₄) and filtered, and

were stirred at room temperature for 16 h and then diluted with

Et₂O (100 mL each). The organic phases from both procedures

were successively extracted with 5% NaHCO₃(2 ϫ 50 mL) and

then water (2 ϫ 100 mL), dried (MgSO₄) and filtered, and the solv-

the solvents were evaporated in vacuo. The crude product (0.156 g)

was solubilized in ca. 5 mL of EtOAc/CH₂Cl₂(1:1) (sparingly sol-

uble in CH₂Cl₂) and chromatographed on a 37 ϫ 1.5 cm silica gel

column with eluent I to afford 0.121 g (73%) of pure H-[HO]₂-Bip-

ents were evaporated in vacuo. The residues were chromatographed OMe (RS)-6 as a white solid. Crystallization from CH₂Cl₂gave an

1

on preparative TLC plates of silica gel with CH₂Cl₂as eluent, care analytical sample (white crystals). M.p. 217 °C. R_fϭ 0.20 (II). H

being taken not to exercise a mechanical separation of one of the

NMR (CDCl₃): δ ϭ 7.29 [dd (t-like), J ഠ 7.4 Hz, 1 H, ArH], 7.23

diastereoisomers over the other. From (R)-4, the amido ester (S)- [dd (t-like), J ഠ 7.7 Hz, 1 H, ArH], 7.02 (dd, J ϭ 8.2 Hz and

Ph(OCH₃)(CF₃)C-CO-(R)-[MeO]₂-Bip-OtBu (0.0076 g, 91%) was 1.1 Hz, 1 H, ArH), 6.99 (dd, J ϭ 7.9 Hz and 1.1 Hz, 1 H, ArH),

1

obtained with Ͼ 98% de (estimated experimental error: Ϯ2%). H

6.97 [d (broad), J ഠ 8 Hz, 1 H, ArH], 6.92 [d (broad), J ഠ 8 Hz, 1

NMR (CDCl₃): δ ϭ 7.56 (m, 2 H, ArH MTPA), 7.40 (m, 3 H, ArH H, ArH], 3.74 (s, 3 H, OCH₃), 3.05 and 2.53 (d, J ϭ 13.2 Hz, 1 H

MTPA), δ ϭ 7.30 [dd (t-like), J ഠ 8 Hz, 1 H, ArH], 7.25 [dd (t- and d, J ϭ 13.2 Hz, 1 H, ArCH₂β), 2.91 and 2.20 (d, J ϭ 13.2 Hz,

like), J ഠ 8 Hz, 1 H, ArH], 7.07 (s, 1 H, NH), 6.98 (d, J ϭ 7.9 Hz, 1 H and d, J ϭ 13.2 Hz, 1 H, ArCH₂βЈ]. ¹H NMR (CDCl₃ϩ 10%

1 H, ArH), 6.95 (d, J ϭ 7.9 Hz, 1 H, ArH), 6.86 (d, J ϭ 7.4 Hz, 1 CD₃OD): δ ϭ 7.14 [dd (t-like), J ഠ 7.5 Hz, 1 H, ArH], 7.07 [dd (t-

H, ArH), 6.85 (d, J ϭ 7.4 Hz, 1 H, ArH), 3.83 (s, 3 H, ArOCH₃), like), J ഠ 7.5 Hz, 1 H, ArH], 6.91 (dd, J ϭ 8.1 Hz and 1.1 Hz, 1

3.81 (s, 3 H, ArOCH₃), 3.30 (m, 3 H, OCH₃MTPA), 3.18 and 2.39 H, ArH), 6.85 (dd, J ϭ 8.3 Hz and 1.1 Hz, 1 H, ArH), 6.78 (dd, J ϭ

(d, J ϭ 12.8 Hz, 1 H and d, J ϭ 12.8 Hz, 1 H, ArCH₂β), 3.07 and

7.4 Hz and 1.1 Hz, 1 H, ArH), 6.73 (dd, J ϭ 7.4 Hz and 1.1 Hz, 1

3.02 (d, J ഠ 14 Hz, 1 H and d, J ഠ 14 Hz, 1 H, ArCH₂βЈ), 1.49 [s H, ArH), 3.64 (s, 3 H, OCH₃), 2.90 and 2.39 (d, J ϭ 13.2 Hz, 1 H

(Ͻ 1%), OCMe₃of the (SS) isomer] and 1.40 [s (Ͼ 99%), 9 H, and d, J ϭ 13.1 Hz, 1 H, ArCH₂β), 2.83 and 2.09 (d, J ϭ 13.2 Hz,

OCMe₃]. ¹³C NMR (CDCl₃): δ ϭ 170.0 (CϭO), 165.0 (CϭO

1 H and d, J ϭ 13.2 Hz, 1 H, ArCH₂βЈ). ¹³C NMR (CDCl₃ϩ 10%

MTPA), 156.8, 156.7 (C_ArϪO), 137.2, 135.7, 131.9, 129.4, 128.6, CD₃OD): δ ϭ 175.1 (CϭO), 153.0, 152.6 (C_ArϪO), 138.2, 136.7,

Eur. J. Org. Chem. 2002, 1232Ϫ1247 1241

J.-P. Mazaleyrat et al.

FULL PAPER

128.6, 128.3, 123.7, 123.2, 122.4, 122.1, 116.2, 115.7 (C_Ar), 66.7

(Cα), 52.1 (OCH₃), 43.3 (Cβ), 41.8 (CβЈ). C₁₇H₁₇NO₄·0.25 H₂O ϩ15.7, [α] ϭ ϩ124.0, [α] ϭ ϩ572.0 (c ϭ 0.1; MeOH), corres-

(303.818): calcd. C 67.20, H 5.81, N 4.61; found C 66.76, H 5.68,

N 4.66. In duplicate experiments under the same experimental con- NMR of the corresponding Mosher amide/half phenyl ester iso-

¹H NMR (CDCl₃): see (RS)-6. [α]²_D⁵ϭ ϩ7.0, [α]₅²₇⁵₈ϭ ϩ7.9, [α]₅²₄⁵₆ϭ

25

436

365

ponding to 95 Ϯ 5% enantiomeric excess as determined by ¹⁹F

ditions, starting from (i) 2.330 g (6.31 mmol) and (ii) 2.562 g

(6.94 mmol) of crude NMR-pure (RS)-4 (vide supra), samples of

(i) 1.009 g (53%) and (ii) 1.037 g (50%) of pure (RS)-6 were ob-

tained after chromatography.

mers (vide infra). C₁₇H₁₇NO₄·0.5H₂O (308.322): calcd. C 66.22, H

5.88, N 4.54; found C 66.62, H 5.55, N 4.47. A duplicate run start-

ing from (S)-4 of 64 Ϯ 5% ee (0.238 g, 0.645 mmol), carried out

under identical experimental and workup conditions, afforded

0.104 g (54%) of (S)-6 after chromatography, and then after frac-

tional crystallization, 0.025 g (13%) of almost racemic (RS)-6 and

Methyl

6-Amino-1,11-dihydroxy-6,7-dihydro-5H-dibenzo[a,c]cy-

0.041 g (21%) of enantiomerically enriched (S)-6 with [α]²_D⁵

ϭ

cloheptene-6-carboxylate [(R)-6]: A solution of (R)-4 of 98 Ϯ 2% ee

(0.490 g, 1.33 mmol) in CH₂Cl₂(50 mL) was treated with a solution

of BBr₃(1  in CH₂Cl₂, 10 mL, 10 mmol) and the obtained free

amino acid H-[HO]₂-Bip-OH·HBr was stirred under argon at

50Ϫ55 °C for 48 h in MeOH (90 mL) containing 98% H₂SO₄

(2.5 mL), under the same experimental and workup conditions as

for the preparation of (RS)-6. Chromatography on a 37 ϫ 1.5 cm

25

ϩ10.0, [α]

ϭ ϩ11.0, [α]

ϭ ϩ18.1, [α]

ϭ ϩ130.6, [α]

ϭ

578

546

436 365

ϩ584.4 (c ϭ 0.1; MeOH), corresponding to 97 Ϯ 5% optical purity

25

by comparison with the extrapolated maximum value [α]

ϩ602.1 (c ϭ 0.1; MeOH) (see Table 1).

ϭ

365

Racemization Tests on (S)-6: A solution of (S)-6 of 37 Ϯ 5% ee

silica gel column with eluents I and then II afforded 0.218 g (55%) (0.00109 g) in MeOH (1.0 mL) was kept at 50 °C in the thermo-

25

of pure (R)-6 as a white solid, with [α]²_D⁵ϭ Ϫ2.4, [α]

ϭ Ϫ4.3, statted cell of a polarimeter and the following optical rotations

578

25

50

[α] ϭ Ϫ9.7, [α] ϭ Ϫ74.4, [α] ϭ Ϫ343.0 (c ϭ 0.1; MeOH), [α] (c ϭ 0.1; MeOH) were recorded at the time intervals stated:

546

436

365

corresponding to 56 Ϯ 5% optical purity by comparison with the ϩ279.8 (initial), ϩ279.8 (1 h), ϩ281.7 (2 h), ϩ280.7 (3 h), ϩ285.3

25

extrapolated maximum values [α]

ϭ Ϫ136.7, [α]

ϭ Ϫ610.2 (19 h), ϩ281.7 (21 h), ϩ283.5 (24 h). In a similar manner, a solu-

436

365

(c ϭ 0.1; MeOH) (see text and Table 1). This sample was solubil-

ized in CH₂Cl₂(ca. 50 mL) and the solution was concentrated to senting an initial optical rotation [α]₄²₃⁵₆ϭ ϩ84.7 was kept in an oil

ca. 4Ϫ5 mL in vacuo at 30 °C, and then allowed to cool to room bath at 110 °C for 1 h, allowed to cool to room temperature and

temperature. The resulting mixture of white crystals and clear, pale transferred to the thermostatted cell of a polarimeter. Its optical

tion of (S)-6 of 37 Ϯ 5% ee (0.00248 g) in DMF (2.0 mL) pre-

yellow supernatant was stored in a freezer for 3 weeks, diluted with

cold Et₂O (ca. 100 mL), filtered through a Büchner funnel, rapidly

rotation was recorded, and it was transferred back to the initial

flask, kept again at 110 °C for a second cycle of 1 h and so on,

25

washed with cold Et₂O and air-dried, to afford 0.108 g (27%) of with the following results: [α] (c ϭ 0.12; DMF) ϭ ϩ84.7 (initial),

436

almost racemic (RS)-6 as white crystals, with [α]²_D⁵ϭ 0, [α] ϭ 0, ϩ63.7 (1 h), ϩ41.9 (2 h), ϩ31.4 (3 h), ϩ19.3 (4 h).

25

578

25

[α]

ϭ Ϫ1.9, [α]

ϭ Ϫ13.4, [α]

ϭ Ϫ65.1 (c ϭ 0.1; MeOH).

546

436

365

Coupling of (R)-6 and (S)-6 with (؊)-(S)-α-Methoxy-α-phenyl-α-

(trifluoromethyl)acetic Acid: EDC (0.0073 g, 0.038 mmol) was ad-

ded to a solution of (Ϫ)-(S)-MTPA (0.0176 g, 0.075 mmol) in ace-

tonitrile (1 mL). The solution was stirred at room temperature for

1 h and divided into two portions of 0.5 mL each, which were ad-

ded to aliquots of samples of (R)-6 (0.0019 g, 0.006 mmol) and (S)-

6 (0.0023 g, 0.007 mmol), obtained after removal of most (RS)-6 by

crystallization (vide supra). The resulting clear, colourless solutions

were stirred at room temperature for 16 h and then diluted with

Et₂O (100 mL each). The organic phases from both experiments

were washed with 0.5  HCl (50 mL) and then water (2 ϫ 100 mL),

The filtrate from the crystallization was concentrated in vacuo at

30 °C, to afford 0.104 g (26%) of analytically pure (R)-6 as a white,

amorphous solid. M.p. 208 °C. ¹H NMR (CDCl₃): see (RS)-6.

25

[α]²_D⁵ϭ Ϫ3.0, [α]

ϭ Ϫ7.6, [α]

ϭ Ϫ15.2, [α]

ϭ Ϫ134.0,

578

546

436

25

[α] ϭ Ϫ598.0 (c ϭ 0.1; MeOH), corresponding to 98 Ϯ 2% ee

365

as determined by ¹⁹F NMR of the corresponding Mosher amide/

half phenyl ester isomers (vide infra). C₁₇H₁₇NO₄·0.25H₂O

(303.818): calcd. C 67.20, H 5.81, N 4.61; found C 67.25, H 5.64,

N 4.47.

Methyl

6-Amino-1,11-dihydroxy-6,7-dihydro-5H-dibenzo[a,c]cy-

cloheptene-6-carboxylate [(S)-6]: A solution of (S)-4 of 64 Ϯ 5% ee dried (MgSO₄) and filtered, and the solvents were evaporated in

(0.506 g, 1.37 mmol) in CH₂Cl₂(50 mL) was treated with a solution vacuo. The residues, which presented two main well-separated, UV-

of BBr₃(1  in CH₂Cl₂, 10 mL, 10 mmol), and the obtained free positive spots (R_fϭ 0.65 and 0.50) on analytical TLC with eluent

amino acid H-[HO]₂-Bip-OH·HBr was stirred under argon at I, were chromatographed on preparative TLC plates of silica gel

50Ϫ55 °C for 48 h in MeOH (100 mL) containing 98% H₂SO₄with eluent I/CH₂Cl₂(1:1). The two corresponding bands were sep-

(2.5 mL), under the same experimental and workup conditions as

arated, providing after workup two compounds arbitrarily desig-

for the preparation of (RS)-6. Chromatography on a 41 ϫ 1.5 cm

nated as 7A and 7B (Figure 5), readily identified as the two ex-

1

silica gel column with eluents I and then II afforded 0.308 g (75%) pected (S)-MTPA amide/half ester isomers of 6 by H NMR and

of pure (S)-6 as a white solid, with [α]²_D⁵ϭ ϩ2.3, [α]

ϭ ϩ2.7, ¹⁹F NMR. From (R)-6 there were obtained the following isomers:

25

578

25

1

[α] ϭ ϩ6.9, [α] ϭ ϩ51.1, [α] ϭ ϩ225.8 (c ϭ 0.25; MeOH), (SRS)-7A: R_fϭ 0.65 (I). H NMR (CDCl₃): δ ϭ 7.5Ϫ6.7 (several

546

436

365

corresponding to 37 Ϯ 5% optical purity by comparison with the m, 16 H, 6 ArH and 10 ArH MTPAc, 5.00 (s, 1 H, NH), 3.69 (s,

25

extrapolated maximum values [α]

ϭ ϩ130.5, [α]

ϭ ϩ602.1 3 H, OCH₃), 3.43 (m, 3 H, OCH₃MTPA ester), 3.33 (m, 3 H,

436

365

(c ϭ 0.1; MeOH) (see text and Table 1). This sample was crystal-

lized from CH₂Cl₂(concentrated solution), stored for a few days J ϭ 13.0 Hz, 1 H, ArCH₂β), 3.05 [s (broad), 2 H, ArCH₂βЈ]. ¹⁹F

in a freezer, diluted with cold Et₂O and filtered through a Büchner NMR (CDCl₃): δ ϭ Ϫ70.2058 [s (100%), CF₃MTPA amide], signal

funnel as above for (R)-6, to afford 0.141 g of almost racemic (RS)- of CF₃MTPA amide of isomer (SSS)-7A at δ ϭ Ϫ70.1158 not

OCH₃MTPA amide), 3.37 and 2.39 (d, J ϭ 13.1 Hz, 1 H and d,

25

6 as white crystals, with [α]²_D⁵ϭ 0, [α] ϭ 0, [α] ϭ 0, [α]

ϭ

seen, Ϫ73.0830 [s (99.07%), CF₃MTPA ester], Ϫ72.7903 [s (0.93%),

578

546

436

25

0, [α] ϭ ϩ6.7 (c ϭ 0.1; MeOH). More crystals (0.011 g) of al-

most racemic (RS)-6 were obtained from the concentrated filtrate (SRS)-7B: R_fϭ 0.50 (I). H NMR (CDCl₃): δ ϭ 7.5Ϫ6.7 (several

CF₃MTPA ester of isomer (SSS)-7A], corresponding to Ͼ 98% de.

365

1

by the same operations, to provide a total of 0.152 g (37%). Finally,

m, 16 H, 6 ArH and 10 ArH MTPA), 4.93 (s, 1 H, NH), 3.68 (s, 3

the new filtrate was concentrated in vacuo at 30 °C, to afford H, OCH₃), 3.45 (m, 3 H, OCH₃MTPA ester), 3.27 (m, 3 H, OCH₃

0.109 g (27%) of analytically pure (S)-6 as a white amorphous solid.

MTPA amide), 3.28 and 3.11 (d, J ϭ 13.9 Hz, 1 H and d, J ϭ

Eur. J. Org. Chem. 2002, 1232Ϫ1247

1242

C^α,α-Disubstituted Glycine Containing a Crown Ether Receptor

13.8 Hz, 1 H, ArCH₂β), 3.07 and 2.58 (d, J ϭ 13.0 Hz, 1 H and d,

FULL PAPER

chromatographed on a 41 ϫ 1.5 cm silica gel column with eluent

J ϭ 13.0 Hz, 1 H, ArCH₂βЈ]. ¹⁹F NMR (CDCl₃): δ ϭ Ϫ70.0302 (s II to give 0.171 g (87%) of analytically pure (S)-8 as a white,

1

(100%), CF₃MTPA amide], signal of CF₃MTPA amide of isomer amorphous solid. H NMR (CDCl₃): see (RS)-8. [α]²_D⁵ϭ ϩ137.8,

(SSS)-7B at δ ϭ Ϫ69.8006 not seen, Ϫ73.1775 [s (99.3%), CF₃[α]₅²₇⁵₈ϭ ϩ146.8, [α]₅²₄⁵₆ϭ ϩ173.0, [α]₄²₃⁵₆ϭ ϩ382.9, [α]₃²₆⁵₅ϭ ϩ917.6

MTPA ester], Ϫ72.7903 [s (0.7%), CF₃MTPA ester of isomer

(SSS)-7B], corresponding to Ͼ 98% de. From (S)-6 were obtained

(c ϭ 0.1; MeOH), corresponding to 95 Ϯ 5% (assumed) enantiom-

eric excess. C₂₂H₂₅NO₆·0.25H₂O (403.932): calcd. C 65.41, H 6.36,

the following isomers: (SSS)-7A: R_fϭ 0.65 (I). ¹H NMR (CDCl₃): N 3.47; found C 65.25, H 5.94, N 3.34.

δ ϭ 7.6Ϫ6.6 (several m, 16 H, 6 ArH and 10 ArH MTPA), 4.94 (s,

Methyl 6-tert-Butyloxycarbonylamino-1,11-(20-crown-6)-6,7-dihy-

1 H, NH), 3.74 (s, 3 H, OCH₃), 3.40 (m, 3 H, OCH₃MTPA ester),

3.36 (m, 3 H, OCH₃MTPA amide), 3.57 and 2.33 (d, J ϭ 13.4 Hz,

1 H and d, J ϭ 13.1 Hz, 1 H, ArCH₂β), 3.00 and 2.87 (d, J ϭ

14.1 Hz, 1 H and d, J ϭ 14.3 Hz, 1 H, ArCH₂βЈ). ¹⁹F NMR

(CDCl₃): δ ϭ Ϫ70.1158 [s (100%), CF₃MTPA amide], signal of

CF₃MTPA amide of isomer (SRS)-7A at δ ϭ Ϫ70.2058 not seen,

Ϫ72.7903 [s (95.7%), CF₃MTPA ester], Ϫ73.0830 [s (4.3%), CF₃

MTPA ester of isomer (SRS)-7A], corresponding to ca. 92% de.

dro-5H-dibenzo[a,c]cycloheptene-6-carboxylate [(RS)-Ia]: Experi-

mental conditions as previously reported by Voyer et al.^[7]were

applied: A solution of (RS)-8 (0.040 g, 0.10 mmol) and Cs₂CO₃

(0.038 g, 0.11 mmol) in degassed MeOH (2 mL) was stirred under

argon at 45 °C for 15 min and then concentrated to dryness in

vacuo. DMF (2 mL) was added to the residue under a stream of

argon, and the resulting solution was concentrated under high va-

cuum at 45 °C to remove the residual methanol. Again, DMF

(5 mL) was added to the residue, generating a greenish-orange solu-

tion that was magnetically stirred under argon at 60 °C while a

solution of pentaethylene glycol ditosylate (Aldrich, 95%) (0.056 g,

0.10 mmol) in DMF (3 mL) was added dropwise over a 1 h period.

The solution was stirred at 60 °C overnight and the solvents were

evaporated to dryness under high vacuum. The residue was solubil-

ized in CH₂Cl₂(100 mL) and 5% NaHCO₃(50 mL). The decanted

CH₂Cl₂solution was washed with 5% NaHCO₃(2 ϫ 50 mL) and

then with H₂O (2 ϫ 100 mL), dried (MgSO₄) and filtered, and the

solvents were evaporated in vacuo. The crude product (0.055 g) was

chromatographed on preparative silica gel TLC plates with eluent

I (two elutions) to afford 0.023 g (38%) of analytically pure Boc-

[20-C-6]-Bip-OMe (RS)-Ia as a pale yellow glass. R_fϭ 0.20 (II);

0.50 (III). ¹H NMR (CDCl₃): δ ϭ 7.28 (dd, J ϭ 8.3 Hz and 7.5 Hz,

1 H, ArH), 7.21 (dd, J ϭ 8.3 Hz and 7.5 Hz, 1 H, ArH), 6.96 (dd,

J ϭ 8.8 Hz and 1.1 Hz, 1 H, ArH) 6.91 (dd, J ϭ 8.8 Hz and 1.1 Hz,

1 H, ArH), 6.84 (dd, J ϭ 7.4 Hz and 1.1 Hz, 1 H, ArH), 6.83 (dd,

J ϭ 7.4 Hz and 1.1 Hz, 1 H, ArH), 4.79 (s, 1 H, NH), 4.17 (m, 2

H, OCH₂), 4.06 (m, 2 H, OCH₂), 3.79Ϫ3.75 (m, 4 H, OCH₂),

3.75Ϫ3.60 (m, 12 H, OCH₂), 3.74 (s, 3 H, OCH₃), 3.15 and 2.24

(d, J ϭ 13.1 Hz, 1 H and d, J ϭ 13.1 Hz, 1 H, ArCH₂β), 2.94 [m

(broad), 2 H, ArCH₂βЈ], 1.45 (s, 9 H, CMe₃Boc). ¹³C NMR

(CDCl₃): δ ϭ 173.2 (CϭO), 156.4, 156.1 (C_ArϪO), 154.5 (CϭO

Boc), 136.3, 128.4, 128.2, 125.3, 125.1, 122.0, 121.9, 111.3 (C_Ar),

80.1 (OϪC Boc), 70.8, 70.7, 70.6, 70.5, 69.8, 69.7, 67.9, 67.8 (OCH₂

and Cα), 52.3 (OCH₃), 41.5 (Cβ), 38.0 (CβЈ), 28.2 (CH₃Boc). ESI^ϩ

MS: m/z (%) ϭ 640 (9) [MK]^ϩ, 624 (100) [MNa]^ϩ, 602 (3) [MH]^ϩ.

C₃₂H₄₃NO₁₀·0.5H₂O (610.680): calcd. C 62.93, H 7.26, N 2.29;

found C 62.96, H 7.24, N 2.14. In a duplicate run, treatment of

(RS)-8 (0.327 g, 0.82 mmol) and Cs₂CO₃(0.320 g, 0.98 mmol) in

DMF (50 mL) with pentaethylene glycol ditosylate (0.477 g,

0.87 mmol) under the same experimental and workup conditions

as above afforded 0.189 g (38%) of (RS)-Ia after chromatography.

1

(SSS)-7B: R_fϭ 0.50 (I). H NMR (CDCl₃): δ ϭ 7.6Ϫ6.7 (several

m, 16 H, 6 ArH and 10 ArH MTPA), 4.87 (s, 1 H, NH), 3.76 (s, 3

H, OCH₃), 3.52 (m, 3 H, OCH₃MTPA ester), 3.34 (m, 3 H, OCH₃

MTPA amide), 3.12 and 2.45 (d, J ϭ 13.0 Hz, 1 H and d, J ϭ

13.1 Hz, 1 H, ArCH₂β), 3.07 [s (broad), 2 H, ArCH₂βЈ]. ¹⁹F NMR

(CDCl₃): δ ϭ Ϫ69.8006 [s (98.1%), CF₃MTPA amide], Ϫ70.0347

[s (1.9%), CF₃MTPA ester of isomer (SRS)-7B], Ϫ72.7903 [s

(99.1%), CF₃MTPA ester], Ϫ73.1730 [s (0.9%), CF₃MTPA ester

of isomer (SRS)-7B], corresponding to ca. 96Ϫ98% de.

Methyl 6-tert-Butyloxycarbonylamino-1,11-dihydroxy-6,7-dihydro-

5H-dibenzo[a,c]cycloheptene-6-carboxylate [(RS)-8]: A suspension

of (RS)-6 (0.149 g, 0.50 mmol) and Boc₂O (0.218 g, 1.00 mmol) in

acetonitrile (20 mL) was stirred at 75 °C for 1 h, and the resulting

clear solution was stirred at room temperature for 10 d and then

concentrated in vacuo. The crude product was chromatographed

on a 40 ϫ 1.5 cm silica gel column with eluent II to give 0.184 g

(93%) of analytically pure Boc-[HO]₂-Bip-OMe (RS)-8 as a white,

crystalline powder. M.p. 156 °C. R_fϭ 0.30 (II). ¹H NMR (CDCl₃):

δ ϭ 7.72 [s (broad), 2 H, ArOH], 7.20 [s (broad), 1 H, ArH], 7.13

[dd (t-like), J ϭ 7.8 Hz, 1 H, ArH], 7.02 [dd (t-like), J ഠ 8 Hz, 2

H, ArH], 6.78 (d, J ϭ 7.4 Hz, 2 H, ArH), 5.01 [s (broad), 1 H,

NH], 3.72 (s, 3 H, OCH₃), 3.05 and 2.21 (d, J ϭ 12.9 Hz, 1 H and

d, J ϭ 12.8 Hz, 1 H, ArCH₂β), 2.92 [m (broad), 2 H, ArCH₂βЈ],

1.46 (s, 9 H, CMe₃Boc). ¹³C NMR (CDCl₃): δ ϭ 173.5 (CϭO),

154.8 (CϭO Boc), 152.6, 152.2 (C_ArϪO), 137.3, 136.6, 129.0, 128.8,

123.5, 123.2, 122.9, 122.6, 116.6, 116.5 (C_Ar), 80.6 (OϪC Boc), 68.1

(Cα), 52.6 (OCH₃), 41.5 (Cβ), 37.8 (CβЈ), 28.2 (CH₃Boc).

C₂₂H₂₅NO₆·0.5 H₂O (408.436): calcd. C 64.69, H 6.42, N 3.43;

found C 64.94, H 6.21, N 3.59.

Methyl 6-tert-Butyloxycarbonylamino-1,11-dihydroxy-6,7-dihydro-

5H-dibenzo[a,c]cycloheptene-6-carboxylate (R)-8: A solution of (R)-

6 of 98 Ϯ 2% ee (0.097 g, 0.32 mmol) and Boc₂O (0.142 g,

0.65 mmol) in acetonitrile (25 mL) was stirred at room temperature

for 10 d and then concentrated in vacuo. The crude product was

chromatographed on a 41 ϫ 1.5 cm silica gel column with eluent

II to give 0.115 g (88%) of analytically pure (R)-8 as a white,

Methyl 6-tert-Butyloxycarbonylamino-1,11-(20-crown-6)-6,7-dihy-

dro-5H-dibenzo[a,c]cycloheptene-6-carboxylate [(R)-Ia]: Treatment

of (R)-8 of 98 Ϯ 2% assumed ee (0.113 g, 0.28 mmol) with Cs₂CO₃

(0.111 g, 0.34 mmol) and pentaethylene glycol ditosylate (0.171 g,

0.31 mmol) in DMF (23 mL), under the same experimental and

workup conditions as for the preparation of (RS)-Ia, afforded

1

amorphous solid. H NMR (CDCl₃): see (RS)-8. [α]²_D⁵ϭ Ϫ137.7,

[α]₅²₇⁵₈ϭ Ϫ145.5, [α]₅²₄⁵₆ϭ Ϫ174.1, [α]₄²₃⁵₆ϭ Ϫ386.4, [α]₃²₆⁵₅ϭ Ϫ905.0

(c ϭ 0.1; MeOH), corresponding to 98 Ϯ 2% (assumed) enantiom-

eric excess. C₂₂H₂₅NO₆·0.25H₂O (403.932): calcd. C 65.41, H 6.36,

N 3.47; found C 65.21, H 6.24, N 3.34.

0.084 g (49%) of (R)-Ia after chromatography, as a pale yellow

glass. ¹H NMR (CDCl₃): see (RS)-Ia. [α]²_D⁵ϭ Ϫ89.0, [α]

ϭ

25

578

Methyl 6-tert-Butyloxycarbonylamino-1,11-dihydroxy-6,7-dihydro-

5H-dibenzo[a,c]cycloheptene-6-carboxylate [(S)-8]: A solution of

Ϫ94.0, [α]₅²₄⁵₆ϭ Ϫ109.0, [α]₄²₃⁵₆ϭ Ϫ210.0, [α]₃²₆⁵₅ϭ Ϫ399.0 (c ϭ 0.1;

MeOH), corresponding to 64 Ϯ 5% ee as determined by ¹⁹F NMR

(S)-6 of 95 Ϯ 5% ee (0.147 g, 0.49 mmol) and Boc₂O (0.215 g, of the Mosher amides of the N^α-deprotected amino ester (R)-Ib

0.98 mmol) in acetonitrile (25 mL) was stirred at room temperature (vide infra). C₃₂H₄₃NO₁₀·0.25H₂O (606.176): calcd. C 63.40, H

for 10 d and then concentrated in vacuo. The crude product was

7.23, N 2.31; found C 63.32, H 7.34, N 2.30.

Eur. J. Org. Chem. 2002, 1232Ϫ1247

1243

J.-P. Mazaleyrat et al.

FULL PAPER

Methyl 6-tert-Butyloxycarbonylamino-1,11-(20-crown-6)-6,7-dihy-

dro-5H-dibenzo[a,c]cycloheptene-6-carboxylate [(S)-Ia]: Treatment

to exercise a mechanical separation of one of the diastereoisomers

over the other. From (R)-Ib the amido ester (S)-Ph(OCH₃)(CF₃)C-

of (S)-8 of 95 Ϯ 5% assumed ee (0.169 g, 0.42 mmol) with Cs₂CO₃CO-(R)-[20-C-6]-Bip-OMe was obtained with 64% de (estimated

(0.111 g, 0.34 mmol) and pentaethylene glycol ditosylate (0.171 g, experimental error: Ϯ5%). ¹H NMR (CDCl₃): δ ϭ 7.54 (m, 2 H,

0.31 mmol) in DMF (23 mL), under the same experimental and ArH MTPA), 7.41 (m, 3 H, ArH MTPA), 7.27 [dd (t-like), J ഠ

workup conditions as for the preparation of (RS)-Ia, afforded

8 Hz, 1 H, ArH], 7.22 [dd (t-like), J ഠ 8 Hz, 1 H, ArH], 7.09 (s, 1

0.126 g (49%) of (S)-Ia after chromatography, as a pale yellow glass. H, NH), 6.98 (d, J ഠ 8 Hz, 1 H, ArH), 6.95 (d, J ഠ 8 Hz, 1 H,

¹H NMR (CDCl₃): see (RS)-Ia. [α]²_D⁵ϭ ϩ72.0, [α]

ϭ ϩ74.0, ArH), 6.83 (d, J ഠ 7.5 Hz, 1 H, ArH), 6.78 (d, J ഠ 7.5 Hz, 1 H,

25

578

[α]₅²₄⁵₆ϭ ϩ83.0, [α]₄²₃⁵₆ϭ ϩ162.0, [α]₃²₆⁵₅ϭ ϩ318.0 (c ϭ 0.1; MeOH), ArH), 4.18 (m, 2 H, OCH₂), 4.07 (m, 2 H, OCH₂), 3.8Ϫ3.6 (m, 16

corresponding to 48 Ϯ 5% ee as determined by ¹⁹F NMR of the H, OCH₂), 3.68 (s, 3 H, OCH₃), 3.32 (m, 3 H, OCH₃MTPA), 3.12

Mosher amides of the corresponding N^α-deprotected amino ester

(S)-Ib (vide infra). C₃₂H₄₃NO₁₀·0.25H₂O (606.176): calcd. C 63.40,

H 7.23, N 2.31; found C 63.41, H 7.45, N 2.17.

and 2.43 (d, J ϭ 13.2 Hz, 1 H and d, J ϭ 12.9 Hz, 1 H, ArCH₂β),

3.10 and 3.05 (d, J ϭ 13.8 Hz, 1 H and d, J ϭ 13.8 Hz, 1 H,

ArCH₂βЈ), all signals corresponding to the (SS) isomer (vide infra)

also present in a proportion of ca. 20%. ¹⁹F NMR (CDCl₃): δ ϭ

Ϫ69.0245 [s (ca. 18.5%), CF₃of the (SS) isomer], Ϫ69.0695 [s (ca.

81.5%), CF₃]; for better separation of the 2 signals: ¹⁹F NMR

([D₈]toluene): δ ϭ Ϫ68.9948 [s (ca. 18%), CF₃of the (SS) isomer],

Ϫ69.1479 [s (ca. 82%), CF₃]. From (S)-Ib, the amido ester (S)-

Ph(OCH₃)(CF₃)C-CO-(S)-[20-C-6]-Bip-OMe was obtained with 48

Methyl 6-Amino-1,11-(20-crown-6)-6,7-dihydro-5H-dibenzo[a,c]cy-

cloheptene-6-carboxylate [(RS)-Ib]: TFA (2.5 mL) was added to a

solution of (RS)-Ia (0.130 g, 0.22 mmol) in CH₂Cl₂(7.5 mL). The

solution was stirred at room temperature for 1 h and the solvents

were evaporated to dryness in vacuo. The residue was solubilized

in CH₂Cl₂(100 mL). The solution was washed with 5% NaHCO₃

(100 mL) and then H₂O (2 ϫ 100 mL), dried (MgSO₄) and filtered,

and the solvents were evaporated in vacuo, to afford 0.099 g (91%)

of crude H-[20-C-6]-Bip-OMe (RS)-Ib, which was used without fur-

ther purification in the next step. R_fϭ 0.30 (III). ¹H NMR

(CDCl₃): δ ϭ 7.28 (dd, J ϭ 8.3 Hz and 7.4 Hz, 1 H, ArH), 7.22

(dd, J ϭ 8.3 Hz and 7.5 Hz, 1 H, ArH), 6.96 [d (broad), J ϭ 8.3 Hz,

1 H, ArH], 6.91 [d (broad), J ϭ 7.4 Hz, 1 H, ArH], 6.90 (dd, J ϭ

8.4 Hz and 1.0 Hz, 1 H, ArH), 6.87 (dd, J ϭ 7.4 Hz and 1.0 Hz, 1

H, ArH), 4.17 (m, 2 H, OCH₂), 4.05 (m, 2 H, OCH₂), 3.83Ϫ3.71

(m, 8 H, OCH₂), 3.71Ϫ3.59 (m, 8 H, OCH₂), 3.72 (s, 3 H, OCH₃),

3.00 and 2.24 (d, J ϭ 13.1 Hz, 1 H and d, J ϭ 13.2 Hz, 1 H,

ArCH₂β), 2.93 and 2.51 [d (broad), J ഠ 13 Hz, 1 H and d, J ϭ

13.4 Hz, 1 H, ArCH₂βЈ].

1

Ϯ 5% de. H NMR (CDCl₃): δ ϭ 7.63 (m, 2 H, ArH MTPA), 7.47

(m, 3 H, ArH MTPA), 7.23 [dd (t-like), J ϭ 8.0 Hz, 1 H, ArH],

7.13 [dd (t-like), J ϭ 7.9 Hz, 1 H, ArH], 6.92 (d, J ഠ 8 Hz, 2 H,

ArH), 6.88 (d, J ϭ 8.1 Hz, 1 H, ArH), 6.85 (s, 1 H, NH), 6.52 (d,

J ϭ 7.0 Hz, 1 H, ArH), 4.16 (m, 2 H, OCH₂), 4.05 (m, 2 H, OCH₂),

3.8Ϫ3.6 (m, 16 H, OCH₂), 3.73 (s, 3 H, OCH₃), 3.43 (m, 3 H,

OCH₃MTPA), 3.28 and 2.34 (d, J ϭ 12.9 Hz, 1 H and d, J ϭ

12.9 Hz, 1 H, ArCH₂β), 2.99 and 2.88 (d, J ϭ 14.0 Hz, 1 H and d,

J ϭ 14.0 Hz, 1 H, ArCH₂βЈ), all signals corresponding to the (SR)

isomer (vide supra) also present in a proportion of ca. 25%. ¹⁹F

NMR (CDCl₃): δ ϭ Ϫ69.0245 [s (ca. 73.5%), CF₃], Ϫ69.0695 [s

(ca. 26.5%), CF₃of the (SR) isomer]; for better separation of the

two signals: ¹⁹F NMR ([D₈]toluene): δ ϭ Ϫ68.9948 [s (ca. 74%),

CF₃], Ϫ69.1479 [s (ca. 26%), CF₃of the (SR) isomer]. This ratio

of the CF₃signals of the two diastereoisomers (ca. 74:26) remained

unchanged when the ¹⁹F NMR spectrum was recorded again after

the NMR tube containing the [D₈]toluene solution had been intro-

duced into an oil bath kept at 110 °C for 24 h and 8 d.

Methyl 6-Amino-1,11-(20-crown-6)-6,7-dihydro-5H-dibenzo[a,c]cy-

cloheptene-6-carboxylate [(R)-Ib]: A solution of (R)-Ia (0.0074 g,

0.012 mmol) in CH₂Cl₂(3 mL) was treated with TFA (1 mL) under

the same experimental and workup conditions as for the prepara-

tion of (RS)-Ib to afford 0.0058 g (94%) of crude (R)-Ib, pure by

¹H NMR and TLC (see (RS)-Ib). An aliquot of that sample was

used without further purification for the preparation of the corres-

ponding Mosher amide (vide infra).

6-tert-Butyloxycarbonylamino-1,11-(20-crown-6)-6,7-dihydro-5H-

dibenzo[a,c]cycloheptene-6-carboxylic Acid [(RS)-Ic]: NaOH (1 ,

10 mL) was added to a solution of (RS)-Ia (0.060 g, 0.10 mmol) in

MeOH (10 mL). The solution was stirred at room temperature for

17 h and then at 50 °C for further 2 h, in order to complete the

saponification reaction, its progress being monitored by TLC on

silica gel with eluent III. Methanol was evaporated in vacuo at 40

°C. The resulting aqueous basic solution was cooled by addition of

ice and then acidified by addition of a large excess of 0.5  HCl

and extracted with CH₂Cl₂(3 ϫ 50 mL). The combined organic

phases were washed with H₂O (2 ϫ 100 mL), dried (MgSO₄) and

filtered, and the solvents were evaporated in vacuo to afford 0.056 g

(96%) of crude Boc-[20-C-6]-Bip-OH (RS)-Ic as a white, amorph-

Methyl 6-Amino-1,11-(20-crown-6)-6,7-dihydro-5H-dibenzo[a,c]cy-

cloheptene-6-carboxylate [(S)-Ib]: A solution of (S)-Ia (0.0098 g,

0.016 mmol) in CH₂Cl₂(3 mL) was treated with TFA (1 mL) under

the same experimental and workup conditions as for the prepara-

tion of (RS)-Ib to afford 0.0080 g (98%) of crude (S)-Ib, pure by

¹H NMR and TLC (see (RS)-Ib). An aliquot of that sample was

used without further purification for the preparation of the corres-

ponding Mosher amide (vide infra).

Coupling of (R)-Ib and (S)-Ib with (؊)-(S)-α-Methoxy-α-phenyl-α-

(trifluoromethyl)acetic Acid: EDC (0.0123 g, 0.064 mmol) was ad- tion. R_fϭ 0.30 (III). H NMR (CDCl₃): δ ϭ 7.27 [dd (t-like), J ഠ

ded to a solution of (Ϫ)-(S)-MTPA (0.0300 g, 0.128 mmol) in ace- 8 Hz, 1 H, ArH], 7.22 [dd (t-like), J ϭ 7.9 Hz, 1 H, ArH], 6.97 (d,

ous solid, which was used in the next step without further purifica-

1

tonitrile (2 mL). The solution was stirred at room temperature for

1 h and divided in two portions of 1 mL each, which were added

to aliquots of crude (R)-Ib (0.0035 g, 0.007 mmol) and crude (S)-Ib

J ϭ 8.1 Hz, 1 H, ArH), 6.93 [d (broad), J ഠ 7.5 Hz, 1 H, ArH],

6.92 [d (broad), J ϭ 8.3 Hz, 1 H, ArH], 6.83 (d, J ϭ 7.4 Hz, 1 H,

ArH), 4.87 [s (broad), 1 H, NH], 4.22Ϫ4.00 (m, 4 H, OCH₂),

(0.0060 g, 0.012 mmol) (vide supra). The resulting clear, colourless 3.85Ϫ3.61 (m, 16 H, OCH₂), 3.23 and 2.25 (d, J ϭ 12.9 Hz, 1 H

solutions were stirred at room temperature for 48 h and then di- and d, J ϭ 13.1 Hz, 1 H, ArCH₂β), 3.01 and 2.92 [d (broad), J ഠ

luted with EtOAc (100 mL each). The organic phases from both

13 Hz, 1 H and d, J ϭ 12.9 Hz, 1 H, ArCH₂βЈ], 1.47 (s, 9 H, CMe₃

procedures were washed with 0.5  HCl (50 mL) and then water Boc). ¹³C NMR (CDCl₃): δ ϭ 176.5 (CϭO), 156.3, 155.9 (C_ArϪO),

(2 ϫ 100 mL), dried (MgSO₄) and filtered, and the solvents were

evaporated in vacuo. The residues were chromatographed on pre-

parative silica gel TLC plates with eluent II, care being taken not

155.2 (CϭO Boc), 137.1, 128.2, 128.1, 125.6, 125.5, 122.7, 122.3,

111.8, 111.7 (C_Ar), 80.0 (OϪC Boc), 70.6, 70.4, 69.7, 68.5, 68.0

(OCH₂and Cα), 41.4 (Cβ), 38.0 (CβЈ), 28.3 (CH₃Boc).

1244

Eur. J. Org. Chem. 2002, 1232Ϫ1247

C^α,α-Disubstituted Glycine Containing a Crown Ether Receptor

FULL PAPER

6-tert-Butyloxycarbonylamino-1,11-(20-crown-6)-6,7-dihydro-5H- Boc-[20-C-6]-Bip-Gly-OH (RS)-IIc: A solution of (RS)-IIa (0.039

dibenzo[a,c]cycloheptene-6-carboxylic Acid [(R)-Ic]: A solution of

g, 0.06 mmol) in MeOH (10 mL) and NaOH (1 , 10 mL) was

(R)-Ia (0.079 g, 0.13 mmol) in MeOH (20 mL) and NaOH (1 , stirred at room temperature for 2 h, the reaction progress being

20 mL) was stirred at 50 °C for 4 h. The crude product obtained

after the same workup procedure as for the preparation of (RS)-

monitored by TLC on silica gel with eluent III. The same workup

procedure as for the preparation of (RS)-Ic was applied, to afford

Ic was triturated in hexane. The supernatant hexane solution was 0.021 g (55%) of crude (RS)-IIc as a white, amorphous solid, pure

discarded, and the decanted solid was dried in vacuo at 40 °C to

by TLC, which was used in the next step without further purifica-

afford 0.0057 g (74%) of pure (R)-Ic as a white, amorphous solid.

tion. R_fϭ 0.05 (III); 0.10 (IV).

¹H NMR (CDCl₃): see (RS)-Ic. [α]²_D⁵ϭ Ϫ94.3, [α]

ϭ Ϫ99.5,

ϭ Ϫ424.7 (c ϭ 0.1;

5% ee (assumed).

25

578

Boc-Gly-[20-C-6]-Bip-OMe (RS)-IIIa: EDC (0.076 g, 0.40 mmol)

was added to a solution of Boc-Gly-OH (0.141 g, 0.80 mmol) in

acetonitrile (5 mL). The solution was stirred at room temperature

for 1 h [complete formation of the symmetrical anhydride (Boc-

Gly)₂O assumed] and then transferred by pipette into a flask con-

taining (RS)-Ib (0.099 g, 0.20 mmol). The resulting clear, colourless

solution was stirred at room temperature for 20 h, and the solvents

were evaporated in vacuo. The residue was solubilized in EtOAc

(100 mL) and HCl (0.5 , 50 mL) with stirring. The separated or-

ganic phase was extracted with HCl (0.5 , 50 mL), H₂O (100 mL),

5% NaHCO₃(2 ϫ 50 mL) and H₂O (2 ϫ 100 mL), dried (MgSO₄)

and filtered, and the solvents were evaporated in vacuo. The crude

product was chromatographed on a 1.5 ϫ 36 cm silica gel column

with eluents II and then III, to afford 0.091 g (70%) of analytically

pure (RS)-IIIa as a white, amorphous solid. R_fϭ 0.45 (III). ¹H

NMR (CDCl₃): δ ϭ 7.24 [dd (t-like), J ϭ 7.5 Hz, 1 H, ArH], 7.21

[dd (t-like), J ϭ 7.5 Hz, 1 H, ArH], 6.94 (d, J ϭ 7.7 Hz, 1 H, ArH),

6.91 (d, J ϭ 7.7 Hz, 1 H, ArH), 6.85 (d, J ϭ 7.5 Hz, 1 H, ArH),

6.81 (d, J ϭ 7.4 Hz, 1 H, ArH), 6.49 [s, 1 H, NH (20-C-6)-Bip],

5.21 [m (broad), 1 H, NH Gly], 4.15 (m, 2 H, OCH₂), 4.03 (m, 2

H, OCH₂), 4.15 and 3.99 [dd (partly masked), J ϭ 18.4 Hz and

5.5 Hz, 1 H and dd, J ϭ 18.4 Hz and 5.0 Hz, 1 H, CH₂Gly],

3.77Ϫ3.59 (m, 18 H, OCH₂and masked CH₂Gly), 3.69 (s, 3 H,

OCH₃), 3.20 and 2.29 (d, J ϭ 13.0 Hz, 1 H and d, J ϭ 12.8 Hz, 1 H,

ArCH₂β), 2.94 and 2.89 (d, J ϭ 13.8 Hz, 1 H and d, J ϭ 13.9 Hz, 1

H, ArCH₂βЈ), 1.42 (s, 9 H, CMe₃Boc). ¹³C NMR (CDCl₃): δ ϭ

172.6, 168.9 (CϭO Gly and [20-C-6]-Bip), 156.4, 156.1 (C_ArϪO

and CϭO Boc), 136.4, 136.0, 128.6, 128.3, 125.3, 125.1, 121.9,

121.8, 111.4 (C_Ar), 80.2 (OϪC Boc), 70.8, 70.7, 70.6, 70.5, 69.8,

69.7, 67.8, 67.5 (OCH₂and Cα [20-C-6]-Bip), 52.4 (OCH₃), 44.3

(CH₂Gly), 41.0 (Cβ [20-C-6]-Bip), 37.9 (CβЈ [20-C-6]-Bip), 28.2

(CH₃Boc). C₃₄H₄₆N₂O₁₁·0.5H₂O (667.732): calcd. C 61.15, H 7.10,

N 4.20; found C 60.91, H 7.31, N 4.51.

25

[α]

ϭ Ϫ116.0, [α]

ϭ Ϫ223.2, [α]

546

436

365

MeOH), corresponding to 64

Ϯ

C₃₁H₄₁NO₁₀·0.5H₂O (596.654): calcd. C 62.40, H 7.09, N 2.35;

found C 62.14, H 7.28, N 2.19.

6-tert-Butyloxycarbonylamino-1,11-(20-crown-6)-6,7-dihydro-5H-

dibenzo[a,c]cycloheptene-6-carboxylic Acid [(S)-Ic]: A solution of

(S)-Ia (0.114 g, 0.19 mmol) in MeOH (25 mL) and NaOH (1 ,

25 mL) was stirred at 50 °C for 4 h. The same workup procedure

as for the preparation of (R)-Ic was applied, to afford 0.0064 g

(57%) of pure (S)-Ic as a white, amorphous solid. ¹H NMR

25

(CDCl₃): see (RS)-Ic. [α]²_D⁵ϭ ϩ91.7, [α]

ϭ ϩ93.5, [α]

ϭ

578

546

ϩ114.3, [α]₄²₃⁵₆ϭ Ϫ220.0, [α]₃²₆⁵₅ϭ ϩ432.2 (c ϭ 0.1; MeOH), corres-

ponding to 48 Ϯ 5% ee (assumed). [Note: The recorded optical

rotations of (S)-Ic with an assumed ee of 48 Ϯ 5% are ca. 20Ϫ25%

too high relative to those of (R)-Ic with 64 Ϯ 5% assumed ee. Slight

differences in the purification processes for the two samples by trit-

uration/precipitation from hexane may account for this discrep-

ancy, since either an increase or a decrease of enantiomeric purity

might result from solubility differences between racemic and en-

antiomerically pure Ic]. C₃₁H₄₁NO₁₀(587.646): calcd. C 63.36, H

7.03, N 2.38; found C 63.11, H 7.48, N 2.07.

Boc-[20-C-6]-Bip-Gly-OMe

(RS)-IIa:

Et₃N

(triethylamine,

0.034 mL, 0.24 mmol) was added to a suspension of (RS)-Ic

(0.0474 g, 0.08 mmol), HCl·H-Gly-OMe (0.0304 g, 0.24 mmol) and

HOBt (0.022 g, 0.16 mmol) in THF (tetrahydrofuran) (2 mL) and

CH₂Cl₂(3 mL), followed by a solution of EDC (0.0230 g,

0.12 mmol) in CH₂Cl₂(2 mL). The mixture was stirred at room

temperature overnight, and the solvents were evaporated to dryness

in vacuo. The residue was solubilized in EtOAc (100 mL) and HCl

(0.5 , 50 mL) with stirring. The separated organic phase was ex-

tracted with HCl (0.5 , 50 mL), H₂O (100 mL), 5% NaHCO₃(2

ϫ 50 mL) and H₂O (2 ϫ 100 mL), dried (MgSO₄) and filtered,

and the solvents were evaporated in vacuo. The crude product was

chromatographed on a 35 ϫ 1.5 cm silica gel column with eluents

II and then III, to give 0.0435 g (82%) of analytically pure (RS)-

IIa as a pale yellow, glassy solid. R_fϭ 0.40 (III). ¹H NMR

(CDCl₃): δ ϭ 7.27 [dd (t-like), J ഠ 8 Hz, 1 H, ArH], 7.23 [dd (t-

like), J ഠ 8 Hz, 1 H, ArH], 7.00 [m (broad), 1 H, NH Gly], 6.97

(d, J ϭ 7.7 Hz, 2 H, ArH), 6.90 (d, J ϭ 8.3 Hz, 1 H, ArH), 6.82

(d, J ϭ 6.8 Hz, 1 H, ArH), 4.74 [s, 1 H, NH (20-C-6)-Bip],

Boc-Gly-[20-C-6]-Bip-OH (RS)-IIIc: A solution of (RS)-IIIa (0.087

g, 0.13 mmol) in MeOH (10 mL) and NaOH (1 , 10 mL) was

stirred at 50 °C for 2 h, the reaction progress being monitored by

TLC on silica gel with eluent III. The same workup procedure as

for the preparation of (RS)-Ic was applied, to afford 0.071 g (84%)

of crude (RS)-IIIc as a white, amorphous solid, pure by TLC,

which was used in the next step without further purification. R_fϭ

0.05 (III); 0.15 (IV).

4.22Ϫ3.95 (m, 4 H, OCH₂), 4.15 and 3.99 [dd (partly masked), J ϭ Boc-Gly-[20-C-6]-Bip-Gly-OMe (RS)-IVa: A mixture of (RS)-IIIc

18.4 Hz and 5.5 Hz, 1 H and dd, J ϭ 18.4 Hz and 5.0 Hz, 1 H, (0.071 g, 0.11 mmol), HCl·H-Gly-OMe (0.042 g, 0.33 mmol),

CH₂Gly], 3.79Ϫ3.60 (m, 16 H, OCH₂), 3.76 (s, 3 H, OCH₃), 3.28 HOBt (0.030 g, 0.22 mmol), Et₃N (0.046 mL, 0.33 mmol) and EDC

and 2.21 (d, J ϭ 12.9 Hz, 1 H and d, J ϭ 13.0 Hz, 1 H, ArCH₂β), (0.032 g, 0.17 mmol) in THF (3 mL) and CH₂Cl₂(4 mL), was

3.06 and 2.95 [d (broad), J ഠ 13 Hz, 1 H and d, J ϭ 13.2 Hz, 1 H, treated at room temperature for 24 h under the same experimental

ArCH₂βЈ], 1.46 (s, 9 H, CMe₃Boc). ¹³C NMR (CDCl₃): δ ϭ 172.8, and workup conditions as for the preparation of (RS)-IIa. The

170.4 (CϭO Gly and [20-C-6]-Bip), 156.4, 156.0 (C_Ar-O), 154.7 crude product was chromatographed on a 36 ϫ 1.5 cm silica gel

(CϭO Boc), 136.8, 136.6, 128.3, 125.4, 125.0, 122.6, 121.8, 111.3

column with eluents III and then IV, to afford 0.065 g (82%) of

(C_Ar), 80.4 (OϪC Boc), 70.8, 70.7, 70.6, 70.5, 69.8, 68.5, 67.8 analytically pure (RS)-IVa as a white, amorphous solid. R_fϭ 0.15

(OCH₂and Cα [20-C-6]-Bip), 52.2 (OCH₃), 41.9 (CH₂Gly), 41.4 (II); 0.40 (III); 0.60 (IV). ¹H NMR (CDCl₃, Boc-Gly¹-[20-C-6]-

(Cβ [20-C-6]-Bip), 36.9 (CβЈ [20-C-6]-Bip), 28.2 (CH₃Boc).

C₃₄H₄₆N₂O₁₁·0.5H₂O (667.732): calcd. C 61.15, H 7.10, N 4.20;

found C 61.16, H 7.14, N 4.55.

Bip²-Gly³-OMe): δ ϭ 7.36 (t, J ϭ 5.3 Hz, 1 H, NH Gly³), 7.23 [dd

(t-like), J ϭ 7.9 Hz, 2 H, ArH], 6.98 (d, J ϭ 7.4 Hz, 1 H, ArH),

6.94 (d, J ϭ 7.9 Hz, 1 H, ArH), 6.91 (d, J ϭ 8.3 Hz, 1 H, ArH),

Eur. J. Org. Chem. 2002, 1232Ϫ1247

1245

J.-P. Mazaleyrat et al.

FULL PAPER

6.80 (d, J ϭ 7.2 Hz, 1 H, ArH), 6.51 [s, 1 H, NH (20-C-6)-Bip²], 135.5, 128.6, 128.5, 128.1, 125.5, 125.44, 125.36, 125.3, 125.0,

5.37 [m (broad), 1 H, NH Gly¹], 4.20Ϫ3.94 (m, 4 H, OCH₂and 124.7, 124.5, 122.8, 122.7, 122.4, 122.1, 121.7, 121.4, 111.7, 111.6,

masked dd, 1 H, CH Gly³), 3.90 (dd, J ϭ 18.0 Hz and 5.3 Hz, 1 111.4, 111.2, 110.7 (C_Arof 2 isomers), 81.7, 81.6 (OϪC Boc of 2

H, CH Gly³), 3.80Ϫ3.59 (m, 18 H, OCH₂and masked CH₂Gly¹),

isomers), 70.8, 70.7, 70.5, 69.8, 69.7, 69.1, 68.9, 68.3, 68.1, 67.7,

3.72 (s, 3 H, OCH₃), 3.35 and 2.29 [d (broad), J ഠ 12.5 Hz, 1 H 67.5 (OCH₂and Cα [20-C-6]-Bip of two isomers), 52.0 (OCH₃of

and d, J ϭ 12.9 Hz, 1 H, ArCH₂β], 3.09 and 2.98 (d, J ϭ 13.8 Hz, two isomers), 44.2, 43.7, 42.1, 41.8, 41.6 (CH₂Gly of two isomers),

1 H and d, J ϭ 13.6 Hz, 1 H, ArCH₂βЈ), 1.42 (s, 9 H, CMe₃Boc). 41.4, 41.3 (Cβ [20-C-6]-Bip of two isomers), 38.4, 36.8, 36.3, 36.2

¹³C NMR (CDCl₃): δ ϭ 172.3, 170.4, 169.7 (CϭO Gly¹, [20-C-6]-

Bip²and Gly³), 156.4, 156.0 (C_ArϪO and CϭO Boc), 136.7, 136.4,

128.4, 125.5, 125.1, 122.7, 121.8, 111.7 (C_Ar), 80.6 (OϪC Boc),

(CβЈ [20-C-6]-Bip of two isomers), 28.2 (CH₃Boc of two isomers).

ESI^ϩMS: m/z (%) ϭ 1280 (3) [MK]^ϩ, 1264 (35) [MNa]^ϩ, 1242

(3) [MH]^ϩ, 652 (17) [MKNa]^ϩϩ, 644 (100) [MNa₂]^ϩϩ, 633 (13)

70.7, 70.6, 70.51, 70.46, 69.8, 69.7, 68.8, 68.0 (OCH₂and Cα [20- [MHNa]^ϩϩ, 437 (4) [MNa₃]^ϩϩϩ. C₆₄H₈₃N₅O₂₀·2H₂O (1278.376):

C-6]-Bip²), 52.1 (OCH₃), 45.1, 41.6 (CH₂Gly¹and Gly³), 41.3 (Cβ calcd. C 60.13, H 6.86, N 5.48; found C 60.05, H 6.75, N 5.81.

[20-C-6]-Bip²), 37.0 (CβЈ [20-C-6]-Bip²), 28.2 (CH₃Boc). ESI^ϩMS:

Boc-[20-C-6]-Bip-Aib-Aib-Aib-Aib-Aib-Aib-OtBu (S)-VI: Pd/C

(10%, 0.025 g) was added to a solution of Z-(Aib)₆-OtBu^[50](0.055

g, 0.076 mmol) in MeOH (40 mL). The mixture was hydrogenated

in a Parr apparatus at room temperature for 5 h and filtered

through paper, and the solvents were evaporated in vacuo at 40 °C

to give 0.045 g (100%) of crude H-(Aib)₆-OtBu. A mixture of this

sample (0.045 g, 0.076 mmol), crude Boc-[20-C-6]-Bip-OH (S)-Ic

of 48 Ϯ 5% assumed ee (vide supra) (0.054 g, 0.092 mmol), HOAt

(0.018 g, 0.132 mmol) and EDC (0.025 g, 0.131 mmol) in CH₂Cl₂

(5 mL), was treated at room temperature for 4 weeks under the

same experimental and workup conditions as for the preparation

of (RS)-IIa. The crude product was chromatographed on a prepar-

ative TLC plate of silica gel with eluent III, and the collected frac-

tion of the desired product was purified by further TLC on silica

gel with eluent EtOAc (6 consecutive elutions), to afford 0.017 g

(19%) of analytically pure (S)-VI of 48 Ϯ 5% assumed ee, as a pale

yellow, amorphous solid after trituration in hexane and concentra-

m/z (%) ϭ 754 (9) [MK]^ϩ, 738 (100) [MNa]^ϩ, 716 (3) [MH]^ϩ, 381

(15) [MNa₂]^ϩϩ. C₃₆H₄₉N₃O₁₂(715.776): calcd. C 60.40, H 6.90, N

5.87; found C 60.32, H 6.68, N 5.59.

H-Gly-[20-C-6]-Bip-Gly-OMe (RS)-IVb: A solution of (RS)-IVa

(0.039 g, 0.054 mmol) in CH₂Cl₂(6 mL) was treated with TFA

(2 mL) at room temperature for 3 h under the same experimental

and workup conditions as for the preparation of (RS)-Ib, to afford

0.034 g (100%) of crude (RS)-IVb, which was used in the next step

1

without further purification. R_fϭ 0.05 (III); 0.10 (IV). H NMR

(CDCl₃, H-Gly¹-[20-C-6]-Bip²-Gly³-OMe): δ ϭ 7.81 (broad t, 1 H,

NH Gly³), 7.74 [broad s, 1 H, NH (20-C-6)-Bip²], 7.24 [dd (t-like),

J ϭ 7.7 Hz, 2 H, ArH], 7.05 (d, J ϭ 7.2 Hz, 1 H, ArH), 6.95 (d,

J ϭ 8.8 Hz, 1 H, ArH), 6.92 (d, J ϭ 8.4 Hz, 1 H, ArH), 6.85 (d,

J ϭ 7.0 Hz, 1 H, ArH), 4.23Ϫ4.01 (m, 4 H, OCH₂and masked dd,

1 H, CH Gly³), 3.97 (dd, J ϭ 18.2 Hz and 5.1 Hz, 1 H, CH Gly³),

3.80Ϫ3.59 (m, 18 H, OCH₂and masked CH₂Gly¹), 3.75 (s, 3 H,

OCH₃), 3.34 (broad s, 2 H, NH₂Gly¹), 3.65 and 2.29 [d (masked),

1 H and d, J ϭ 13.4 Hz, 1 H, ArCH₂β], 3.15 and 2.95 (d, J ϭ

14.0 Hz, 1 H and d, J ϭ 13.8 Hz, 1 H, ArCH₂βЈ).

1

tion to dryness in vacuo. R_fϭ 0.40 (III); 0.10 (EtOAc). H NMR

(CDCl₃): δ ϭ 7.77 (s, 1 H, NH Aib), 7.69 (s, 1 H, NH Aib), 7.58

(s, 1 H, NH Aib), 7.39 (s, 2 H, 2 H Aib), 7.32 [dd (t-like), J ϭ

7.5 Hz, 1 H, ArH], 7.20 [dd (t-like), J ϭ 7.7 Hz, 1 H, ArH], 7.01

(d, J ϭ 8.1 Hz, 1 H, ArH), 6.93 (d, J ϭ 8.3 Hz, 1 H, ArH), 6.77

(d, J ϭ 7.0 Hz, 1 H, ArH), 6.75 (d, J ഠ 7 Hz, 1 H, ArH), 6.60 (s,

1 H, NH Aib), 5.03 [s, 1 H, NH (20-C-6)-Bip], 4.23Ϫ4.06 (m, 4 H,

OCH₂), 3.86Ϫ3.60 (m, 16 H, OCH₂), 3.07 and 2.27 (d, J ϭ 13.8 Hz,

1 H and d, J ϭ 13.2 Hz, 1 H, ArCH₂β), 3.01 and 2.71 [d (broad),

J ഠ 13 Hz, 1 H and d, J ϭ 14.0 Hz, 1 H, ArCH₂βЈ], 1.64Ϫ1.48

(m, 36 H, CH₃of 6 Aib), 1.44 (s, 18 H, CMe₃Boc and CMe₃

COOtBu). ¹³C NMR (CDCl₃): δ ϭ 175.3, 174.7, 174.2, 174.0, 172.2

(CϭO Aib and [20-C-6]-Bip), 156.6, 156.1, 155.6 (C_ArϪO and Cϭ

O Boc), 136.1, 135.7, 128.7, 128.1, 125.3, 124.7, 122.3, 121.5, 111.6

(C_Ar), 81.6, 79.7 (OϪC Boc and COOtBu), 70.9, 70.8, 70.6, 70.6,

70.5, 69.9, 68.4, 68.0 (OCH₂and Cα [20-C-6]-Bip), 56.8, 56.7, 56.6,

56.5 (Cα Aib), 42.0 (Cβ [20-C-6]-Bip), 37.3 (CβЈ [20-C-6]-Bip),

28.2, 27.9 (CH₃Boc and COOtBu), 26.1 (broad), 25.5, 25.1, 24.8,

Boc-[20-C-6]-Bip-Gly-Gly-[20-C-6]-Bip-Gly-OMe (RR,SS)-

؉

(RS,SR)-Va: A mixture of Boc-[20-C-6]-Bip-Gly-OH (RS)-IIc

(0.020 g, 0.031 mmol), H-Gly-[20-C-6]-Bip-Gly-OMe (RS)-IVb

(0.032 g, 0.052 mmol), HOBt (0.010 g, 0.074 mmol) and EDC

(0.012 g, 0.062 mmol) in THF (2 mL) and CH₂Cl₂(3 mL) was

treated at room temperature for 24 h under the same experimental

and workup conditions as for the preparation of (RS)-IIa. The

crude product was chromatographed on a 35 ϫ 1.5 cm silica gel

column with eluents III and then IV, to afford 0.021 g (55%) of an

analytically pure ca. 1:1 mixture (by ¹H NMR) of diastereoisomers

(RR,SS)- ϩ (RS,SR)-Va as a white amorphous solid. R_fϭ 0.10

(III); 0.45 (IV). ¹H NMR (CDCl₃): δ ϭ 8.08 (broad t, 1 H, NH

Gly of 2 isomers), 7.32Ϫ6.62 (m, 15 H, 12 ArH, 2 masked NH Gly

and masked NH Bip of 2 isomers), 5.05 [s, 1 H, (Boc) NH (20-C-

6)-Bip of 2 isomers], 4.18Ϫ3.58 (m, 46 H, 20 OCH₂and 3 masked

CH₂Gly of 2 isomers), 3.71 and 3.68 (s, 3 H, OCH₃of 2 isomers),

3.28 and 2.54 (d, J ϭ 12.3 Hz, 0.5 H and d, J ϭ 13.2 Hz, 0.5 H),

3.24 and 2.37 (d, J ϭ 12.5 Hz, 0.5 H and d, J ϭ 13.0 Hz, 0.5 H),

3.17 and 3.09 (d, J ϭ 13.8 Hz, 0.5 H and d, J ϭ 13.6 Hz, 0.5 H),

3.10 and 3.01 (d, J ϭ 13.6 Hz, 0.5 H and d, J ϭ 13.6 Hz, 0.5 H),

3.05 and 2.08 (d, J ϭ 13.6 Hz, 0.5 H and d, J ϭ 13.2 Hz, 0.5 H),

3.01 and 2.18 (d, J ϭ 13.6 Hz, 0.5 H and d, J ϭ 13.0 Hz, 0.5 H),

2.91 and 2.73 (d, J ϭ 13.6 Hz, 0.5 H and d, J ϭ 13.6 Hz, 0.5 H),

2.80 and 2.63 (d, J ϭ 13.6 Hz, 0.5 H and d, J ϭ 14.3 Hz, 0.5 H)

(ArCH₂β and ArCH₂βЈ of 2 [20-C-6]-Bip residues of 2 isomers),

1.43 and 1.42 [s and s (ratio ca. 1:1), 9 H, Boc of 2 isomers]. ¹³C

NMR (CDCl₃): δ ϭ 173.8, 173.3, 172.6, 170.8, 170.7, 170.6, 169.0,

168.9 (CϭO from 3 Gly and 2 [20-C-6]-Bip residues of 2 isomers),

156.6, 156.5, 156.2, 156.1, 155.93, 155.91, 155.8, 152.2 (C_ArϪO and

CϭO Boc of 2 isomers), 137.4, 136.7, 136.6, 136.5, 136.0, 135.7,

25

24.5 (broad) (CH₃Aib). [α]²_D⁵ϭ ϩ69.7, [α]

ϭ ϩ71.3, [α]

ϭ

578

546

ϩ80.9, [α] ϭ ϩ153.9, [α] ϭ ϩ293.0 (c ϭ 0.1; MeOH). ESI^ϩ

25

436

365

MS: m/z (%) ϭ 1176 (12) [MNa]^ϩ, 599.9 (100) [MNa₂]^ϩϩ

.

C₅₉H₉₁N₇O₁₆(1154.374): calcd. C 61.38, H 7.95, N 8.49; found C

61.31, H 8.07, N 7.77.

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1247

Article Doi

Synthesis of the first axially dissymmetric, Cα,α-disubstituted glycine containing a crown ether receptor, and the conformational preferences of a model peptide

DOI: 10.1002/1099-0690(200204)2002:7<1232::AID-EJOC1232>3.0.CO;2-I

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Full text of DOI:10.1002/1099-0690(200204)2002:7<1232::AID-EJOC1232>3.0.CO;2-I

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