Practical resolution of an atropoisomeric α,α-disubstituted glycine with L-phenylalanine cyclohexylamide as chiral auxiliary

Article abstract of DOI:10.1016/S0957-4166(98)00253-5

L-Phenylalanine cyclohexylamide has been used as a chiral auxiliary for the medium-scale resolution of 2', 1 ':1,2;1_,2' :3,4-dinaphthcyclohepta- 1,3-diene-6-amino-6-carboxylic acid (Bin), an α,α-disubstituted glycine with only axial dissymmetry

Full text of DOI:10.1016/S0957-4166(98)00253-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2701–2713
Practical resolution of an atropoisomeric α,α-disubstituted
glycine with L-phenylalanine cyclohexylamide as chiral auxiliary
Jean-Paul Mazaleyrat,∗ Aurelia Boutboul, Yann Lebars, Anne Gaucher and Michel Wakselman
SIRCOB, Bât. Lavoisier, Université de Versailles, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
Received 11 June 1998; accepted 22 June 1998
Abstract
L-Phenylalanine cyclohexylamide has been used as a chiral auxiliary for the medium-scale resolution of
20,10:1,2;100,200:3,4-dinaphthcyclohepta-1,3-diene-6-amino-6-carboxylic acid (Bin), an α,α-disubstituted glycine
with only axial dissymmetry. Coupling of X–Bin–OH (X=Ac; Bz) with H–(L)-Phe–NH–C6H11 by the EDC/HOBt
method gave the dipeptide diastereoisomers X–(R)-Bin–(L)-Phe–NH–C6H11 and X–(S)-Bin–(L)-Phe–NH–C6H11,
which were separated by crystallization (X=Bz) and/or chromatography. Extensive acidic hydrolysis, followed by
esterification of the resulting free amino acid enantiomers, led to enantiomerically pure (−)-(R)-H–Bin–OMe and
(+)-(S)-H–Bin–OMe with high yields. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
In recent years, the non-proteinogenic open-chain and cyclic α,α-disubstituted-α-amino acids have
acquired considerable importance in the design of peptide analogs, because of their tendency to induce
and stabilize rather well defined secondary structures such as turns, β-sheet-like arrangements and
310- or α-helical conformations, when incorporated into peptides.1 We have recently reported the
synthesis of 20,10:1,2;100,200:3,4-dinaphthcyclohepta-1,3-diene-6-amino-6-carboxylic acid (Bin),2 a new
α,α-disubstituted glycine possessing only an axial chirality due to the hindered rotation along the 1–10
bond of the 1,10-binaphthyl moiety (Fig. 1). The Bin residue was later shown to behave as a helix inducer
in short-chain peptides.3
Although the (S)-Bin enantiomer could be obtained in our previous work,2 we were interested in
the investigation of a practical procedure for the resolution of (RS)-Bin for several reasons. Indeed,
(R)-Bin and (S)-Bin represent useful precursors or building blocks for the synthesis of new chiral
catalysts, applicable to a variety of reactions. Furthermore, access to relatively large quantities of both
enantiomerically pure (R)-Bin and (S)-Bin could allow the use of chirospectroscopic techniques in
∗
Corresponding author. Fax: 331-3925-4452; e-mail: jean-paul.mazaleyrat@chimie.uvsq.fr
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00253-5

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J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 9 (1998) 2701–2713
Fig. 1. Structure of the axially dissymmetric (R)- and (S)-Bin
structural analysis, especially for the study of the as-yet unexplored relationship between axial chirality
and helix handedness in peptides. The impact of the α-carbon chirality of α,α-disubstituted glycines
on the 310-helix screw sense is already known to be side-chain dependent: (S)-amino acids with a
β-branched side chain such as L-(αMe)Val or L-Iva (isovaline) give right-handed helical structures,
the same as shown by protein (S)-amino acids, while (S)-α,α-disubstituted amino acids with a γ-
branched side chain such as L-(αMe)Leu, L-(αMe)Trp, L-(αMe)Phe or L-(αEt)Phe, give rise to opposite
left-handed helicities.4 Finally, the interesting results of Obrecht et al.5 in which L-phenylalanine
cyclohexylamide has been recognized as a simple and powerful chiral auxiliary for the resolution of
open-chain α,α-disubstituted glycines H2N–C(R1)(R2)–COOH (R1=Me; R2=i-Pr, cyclo-Pr, t-Bu, Ph,
PhCH2, 4-MeO–C6H4–CH2) as well as of cyclic ones, all possessing α-carbon chirality, prompted us to
check the ability of this reagent to effect the resolution of an atropoisomeric amino acid.
2. Results and discussion
The racemic Bin amino acid tert-butyl ester (RS)-2 was first prepared on a moderate scale in 68% yield,
by phase transfer bis-alkylation of the 4-chlorobenzylidene derivative of glycine tert-butyl ester, using
racemic 2,20-bis(bromomethyl)-1,10 -binaphthyl (RS)-16 as the alkylating agent (Fig. 2), as previously
described,2 except that the cleavage of the resulting Schiff base was accomplished by acidic hydrolysis
on silica gel.
In order to follow as closely as possible Obrecht’s resolution conditions,5 we chose to protect the amino
function of Bin either by an acetyl or a benzoyl group. Thus the amino ester (RS)-2 was treated with either
acetic anhydride or benzoic anhydride in acetonitrile at room temperature, to give the fully protected
derivatives (RS)-3 in 70% yield after crystallization and (RS)-4 in 83% yield after chromatography.
Acidic cleavage of the tert-butyl ester group of (RS)-3 and (RS)-4 in TFA/CH2Cl2 at room temperature
gave the N-protected amino acids Ac–Bin–OH (RS)-5 in 99% yield (crude) and Bz–Bin–OH (RS)-6 in
86% yield after crystallization. The aminoamide resolving agent L-phenylalanine cyclohexylamide was
readily prepared as previously described,5 by coupling Boc-(L)-phenylalanine with cyclohexylamine by
the mixed anhydride method using ethyl chloroformate and N-methyl morpholine at −15°C, followed by
N-deprotection of the Boc protecting group in TFA/CH2Cl2 at room temperature.
The coupling of Ac–Bin–OH (RS)-5 and Bz–Bin–OH (RS)-6 with L-phenylalanine cyclohexylamide
was first realized on a small scale in order to check the experimental conditions of both reaction and
work-up. This study allowed us to draw the following conclusions:
(i) The desired dipeptides 7 and 8 could be obtained quantitatively as 1:1 mixtures of diastereoisomers,
by using the EDC/HOBt method in CH2Cl2/THF at room temperature.
(ii) In both cases, the two diastereoisomers could be separated by column chromatography on silica
gel, furnishing the pure compounds Ac–(R)-Bin–(L)-Phe–NH–C6H11 7a (87%);7 [α]54625=+92.8 (c
0.13; MeOH) and Ac–(S)-Bin–(L)-Phe–NH–C6H11 7b (97%);7 [α]54625=−5.3 (c 0.16; MeOH) or

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 9 (1998) 2701–2713
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Fig. 2. Synthesis and resolution of (RS)-Bin. (i) p-Cl–Ph–CH_N–CH2–COOtBu; KOH powder; K2CO3; nBu4N+Br−;
CH2Cl2; r.t. (ii) SiO2; CH2Cl2/MeOH. (iii) (MeCO)2O; CH3CN/r.t. (iv) (PhCO)2O; CH3CN/r.t. (v) TFA/CH2Cl2; r.t. (vi)
H–(L)-Phe–NH–C6H11; EDC; HOBt; CH2Cl2/THF; r.t. (vii) 35% aq. HCl (10 M)/dioxane (1:1 vol:vol); 110°C; 6–8 days.
(viii) 1. MeOH/98% H2SO4 (cat); reflux; 3 days. 2. Extraction aq. NaHCO3/Et2O
Bz–(R)-Bin–(L)-Phe–NH–C6H11 8a (95%);7 [α]24625=+68.9 (c 0.1; MeOH) and Bz–(S)-Bin–(L)-
Phe–NH–C6H11 8b (90%);7 [α]54625=−22.2 (c 0.13; MeOH), respectively, with excellent yields.
(iii) Attempted crystallizations of the pure diastereoisomers 7a and 7b with an N-acetyl group were
unsuccessful in our hands, both compounds being amorphous solids. However, in the N-benzoyl
series, while the isomer 8b was also an amorphous solid which could not be crystallized, the isomer
8a showed a very high crystallinity from ethyl acetate. Pure crystals suitable for X-ray analysis,
in which EtOAc was included, were obtained with 78% yield after a single crystallization from a
dilute solution.
(iv) The absolute configuration of the binaphthyl unit in the two pairs of diastereoisomers, which was
suspected from the specific rotations of the samples as (+)-(aR,S) for 7a and 8a and (−)-(aS,S) for
7b and 8b, by comparison with previous series of similar compounds Boc–(S)-Bin–(L)-Ala–OMe,3a

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Fig. 3. The X-ray structure of Bz–(R)-Bin–(L)-Phe–NH–C6H11 8a8
was confirmed by the X-ray structural determination of (+)-(aR,S) 8a (Fig. 3),8 as well as by the
further recovery of H–(R)-Bin–OH from 8a and H–(S)-Bin–OH from 8b after acidic hydrolysis
(vide infra).
In view of these results, the N-benzoyl protection was chosen for the resolution procedure on a moder-
ate scale. A combination of crystallization and chromatography of the crude mixture of isomers obtained
after EDC/HOBt coupling of (RS)-6 with H–(L)-Phe–NH–C6H11 led to 8a (92%);7 [α]54625=+67.6 (c
0.1; MeOH) as white crystals containing ca. 1 equivalent mol/mol of EtOAc by 1H NMR and 8b (97%);7
[α]54625=−20.7 (c 0.13; MeOH) as an amorphous white powder. A second crystallization of 8a from
EtOAc did not raise its melting point or specific rotation to a significant extent.
Acid hydrolysis of 8a and 8b was performed in a 1:1 mixture of aqueous 10 N HCl and dioxane
at 110°C for several days, which allowed the cleavage of all the amide functions in a single step.
The resulting free amino acids H–Bin–OH, HCl (R)-9; [α]54625=−418.9 (c 0.19; MeOH) and (S)-9;2
[α]54625=+415.8 (c 0.21; MeOH), respectively, were directly esterified to the corresponding amino
esters H–Bin–OMe in refluxing methanol/H2SO4 in order to allow an easier purification by chromato-
graphy. The pure enantiomers (R)-10 (78.3%); [α]54625=−396.6 (c 0.21; MeOH) and (S)-10 (73.3%);
[α]54625=+393.5 (c 0.21; MeOH), were obtained with excellent yields, although contaminated by a side
product H–Bin–O(CH2)2O(CH2)2–OH (R)-11 or (S)-11 (ca. 3% content by NMR), presumably resulting
from the acidic cleavage of dioxane during the vigorous conditions of hydrolysis of 8a and 8b, which
was quite difficult to remove by chromatography.9
As already pointed out, the absolute configurations of all series of compounds 8–10 were deduced from
both the X-ray analysis of 8a and the sign of the specific rotations of the recovered amino acids (R)-9
and (S)-9, by reference to earlier work.2b The enantiomeric purities of the obtained enantiomers (R)-10
and (S)-10 were shown to be very high: treatment of an aliquot of both samples with (−)-(S)-α-methoxy-
α-trifluoromethyl-α-phenyl-acetic acid anhydride (resulting from the reaction of the Mosher’s acid with
0.5 equiv. of EDC),2b led to the diastereoisomeric amido ester (S)-Ph(OCH3)(CF3)C–CO–(R)-Bin–OMe
with >96% de from (R)-10 and (S)-Ph(OCH3)(CF3)C–CO–(S)-Bin–OMe with >98% de from (S)-10, by

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 9 (1998) 2701–2713
2705
1H NMR and 19F NMR. This demonstrates the absence of racemization of the binaphthyl unit under the
rather drastic experimental conditions of hydrolysis of the dipeptides 8a and 8b, in agreement with the
known very high configurational stability of 2,20-bis(methylene)-substituted-1,10 -binaphthyls.10
In conclusion, the present study has illustrated the extension of the efficient method of Obrecht
et al.5 for the resolution of α,α-disubstituted glycines, using L-phenylalanine cyclohexylamide as a
resolving agent, to an amino acid having an axial chirality instead of an α-carbon chirality. Starting from
the readily available racemic 20,10:1,2;100,200:3,4-dinaphthcyclohepta-1,3-diene-6-amino-6-carboxylic
acid tert-butyl ester (RS)-2, over 1 g samples of the corresponding amino acid methyl ester (R)-10
and (S)-10 of high enantiomeric purity, potentially useful for the synthesis of new catalysts and new
conformationally constrained peptides with atropoisomerism, could be easily obtained in 50% overall
yield.7
3. Experimental section
3.1. General
Racemic 2,20-bis(bromomethyl)-1,10 -binaphthyl (RS)-1 was prepared as previously described.6 Melt-
1
ing points were determined with a temperature raise of 3°C/min and are uncorrected. H NMR and 13
C
NMR spectra were recorded at 300 MHz and 77 MHz, respectively, the solvent CDCl3 or CD3OD being
1
used as an internal standard (δ=7.27 or 3.31 ppm for H and 77.00 or 49.00 ppm for 13C). Splitting
patterns are abbreviated as follows: (s) singlet, (d) doublet, (t) triplet, (q) quartet, (m) multiplet. The
optical rotations were measured with an accuracy of 0.3%, in a 1 dm thermostated cell. Analytical thin
layer chromatography (TLC) and preparative column chromatography were performed on Kieselgel F
254 and on Kieselgel 60 (0.040–0.063 mm) (Merck) respectively, with the following eluent systems:
(I) CH2Cl2; (II) 2.5% MeOH–97.5% CH2Cl2; (III) 5% MeOH–95% CH2Cl2; (IV) 10% MeOH–90%
CH2Cl2; (V) 5% Et2O–95% CH2Cl2; (VI) 10% Et2O–90% CH2Cl2; (VII) 20% Et2O–80% CH2Cl2.
UV light (254 nm) allowed visualization of the spots after TLC runs for all compounds, even at low
concentration.
3.2. 20,10:1,2;100,200:3,4-Dinaphthcyclohepta-1,3-diene-6-amino-6-carboxylic acid tert-butyl ester
(RS)-22b
A mixture of 2,20-bis(bromomethyl)-1,10 -binaphthyl (RS)-1 (8.80 g; 20 mmol), 4-chloro-benzylidene-
glycine-tert-butyl ester (5.97 g; 22 mmol), tetrabutylammonium bromide (1.29 g; 4 mmol), anhydrous
potassium carbonate (27.6 g; 200 mmol) and finely ground KOH pellets (11.2 g; 200 mmol), in CH2Cl2
(300 mL), was magnetically stirred at room temperature for 24 h. The reaction mixture was then
evaporated in vacuo and the residue solubilized in water (250 mL) and diethyl ether (250 mL). The
ethereal phase was washed with water and brine (2×250 mL), dried (MgSO4), filtered and evaporated. To
the resulting orange solid foam was added silica gel (100 g) and a solution of dichloromethane/methanol
[eluent (II)]. The mixture was stirred at 60°C for 2 hours, then evaporated to dryness, left at room
temperature for 4 days and directly chromatographed on a 3×80 cm column of silica gel with eluents (I)
then (II) to give 6.59 g (68.3%) of H–Bin–OtBu (RS)-2 as a pale orange solid foam, which could be used
in the next steps without further purification. 1H NMR (CDCl3): 7.98–7.22 [m, 12H, ArH], 3.13 and 2.39
[2×d, J=13.3, 2H, CH2 β], 3.07 and 2.65 [2×d, J=13.1, 2H, CH2 β0], 1.67 [s (broad), 2H, NH2], 1.48
[s, 9H, OtBu]. 13C NMR (CDCl3): 174.6 (C_O), 136.2, 134.5, 134.2, 133.7, 132.9, 132.7, 131.8, 131.7,

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J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 9 (1998) 2701–2713
128.7, 128.4, 128.2, 128.1, 128.0, 127.4, 127.2, 127.16, 127.13, 125.7, 125.5, 125.1, 124.9 (CAr), 81.4
(OtBu), 69.0 (Cα), 43.5 (Cβ), 43.2 (Cβ0), 27.9 (OtBu). [Note: (i) yields of 76–78% in other runs have
been previously reported; (ii) the chemical shifts in both 1H NMR and 13C NMR (CDCl3) differ from the
previously reported ones, probably because of a variation of concentration].2b
3.3. 20,10:1,2;100,200:3,4-Dinaphthcyclohepta-1,3-diene-6-acetylamino-6-carboxylic
acid
tert-butyl ester (RS)-3
To a solution of (RS)-2 (0.818 g; 2 mmol) in acetonitrile (30 mL) was added acetic anhydride (0.408
g; 4 mmol). The solution was stirred at room temperature for 24 h and evaporated in vacuo. The residue
was dissolved in EtOAc (100 mL). The solution was extracted with 2 N NaOH (2×50 mL), washed with
water (2×100 mL), dried (MgSO4), filtered and evaporated. The crude product was dissolved in CH2Cl2
(70 mL), hexane (30 mL) was added and the clear solution was concentrated to ca. 25 mL. Crystallization
occurred at room temperature. The solid was filtered, washed with a solution of CH2Cl2 (10 mL)/hexane
(60 mL) and air dried, to give 0.628 g (69.6%) of Ac–Bin–OtBu (RS)-3 as a white crystalline powder.
1
Mp=216°C. Rf=0.12 (I). H NMR (CDCl3): 7.96–7.22 [m, 12H, ArH], 5.55 [s, 1H, NHAc], 3.31 and
2.39 [2×d, J=12.9, 2H, CH2 β], 3.19 and 3.05 [2×d, J=13.8, 2H, CH2 β0], 1.97 [s, 3H, Ac], 1.46 [s,
9H, OtBu]. 13C NMR (CDCl3): 170.9 (C_O), 169.3 (C_O), 134.9, 134.4, 134.3, 133.8, 133.1, 132.9,
131.8, 131.6, 128.3, 127.9, 127.2, 125.9, 125.7, 125.3, 125.2 (CAr), 81.6 (OtBu), 69.9 (Cα), 42.0 (Cβ),
37.9 (Cβ0), 27.9 (OtBu), 23.1 (Ac). Anal. C30H29NO3·1.2H2O: calcd C 76.15, H 6.69, N 2.96; found C
75.82, H 6.26, N 2.77.
3.4. 20,10:1,2;100,200:3,4-Dinaphthcyclohepta-1,3-diene-6-benzoylamino-6-carboxylic acid tert-butyl
ester (RS)-4
A solution of (RS)-2 (6.296 g; 15.4 mmol) and benzoic anhydride (6.96 g; 30.8 mmol) in acetonitrile
(125 mL) was stirred at room temperature for 24 h and evaporated in vacuo. The residue was dissolved in
EtOAc (200 mL). The solution was extracted with 2 N NaOH (2×100 mL), washed with water (2×100
mL), dried (MgSO4), filtered and evaporated. The obtained brown oil was chromatographed on a 3×60
cm column of silica gel with eluents (I) then (II), to give 6.580 g (83.3%) of pure Bz–Bin–OtBu (RS)-
4 as a pale orange solid foam. Another run starting from 1.02 g (2.49 mmol) of (RS)-2 gave 1.096 g
1
(85.7 %) of (RS)-4 after chromatography. Mp=158°C. Rf=0.71 (II). H NMR (CDCl3): 7.97–7.24 [m,
17H, ArH], 6.19 [s, 1H, NHBz], 3.46 and 2.55 [2×d, J=12.9, 2H, CH2 β], 3.35 and 3.19 [2×d, J=13.9,
2H, CH2 β0], 1.50 [s, 9H, OtBu]. 13C NMR (CDCl3): 170.7 (C_O), 168.8 (C_O), 134.9, 134.5, 134.4,
134.3, 133.8, 133.1, 132.9, 131.8, 131.7, 131.6, 128.6, 128.4, 128.3, 128.2, 128.0, 127.9, 127.2, 127.1,
126.9, 125.9, 125.8, 125.3 (CAr), 81.6 (OtBu), 70.1 (Cα), 42.1 (Cβ), 38.1 (Cβ0), 27.9 (OtBu). Anal.
C35H31NO3·0.5H2O: calcd C 79.96, H 6.14, N 2.66; found C 80.29, H 6.09, N 2.61.
3.5. 20,10:1,2;100,200:3,4-Dinaphthcyclohepta-1,3-diene-6-acetylamino-6-carboxylic acid (RS)-5
To a solution of (RS)-3 (0.591 g; 1.31 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The solution
was stirred at room temperature for 3 h and evaporated in vacuo. The residue was dissolved in EtOAc
(100 mL). The solution was washed with 0.5 N HCl (50 mL) then water (2×100 mL), dried (MgSO4),
filtered and evaporated, to give 0.523 g (100%) of crude Ac–Bin–OH (RS)-5 which was used in the
next step without further purification. An analytical sample was obtained by crystallisation of an aliquot
1
from CH2Cl2/hexane. Mp=210°C. Rf=0.43 (III). H NMR (CD3OD): 7.93–7.14 [m, 12H, ArH], 3.11

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 9 (1998) 2701–2713
2707
and 2.60 [2×d, J=13.1, 2H, CH2 β], 3.26 and 3.05 [2×d, J=13.7, 2H, CH2 β0], 1.96 [s, 3H, Ac]. 13C
NMR (CD3OD): 175.6 (C_O), 172.8 (C_O), 136.7, 135.5, 135.3, 134.7, 134.5, 134.3, 132.8, 129.3,
129.24, 129.21, 129.1, 128.7, 127.9, 127.8, 126.73, 126.70, 126.3, 126.1 (CAr), 70.5 (Cα), 42.0 (Cβ),
37.8 (Cβ0), 22.4 (Ac). Anal. C26H21NO3·H2O: calcd C 75.53, H 5.61, N 3.39; found C 75.85, H 5.75, N
3.04.
3.6. 20,10:1,2;100,200:3,4-Dinaphthcyclohepta-1,3-diene-6-benzoylamino-6-carboxylic acid (RS)-6
To a solution of (RS)-4 (6.540 g; 12.75 mmol) in CH2Cl2 (25 mL) was added TFA (25 mL). The
solution was stirred at room temperature for 2 h and evaporated in vacuo. The residue was dissolved
in CH2Cl2 and the solution evaporated in vacuo at 50°C. This was repeated several times in order to
remove most of the remaining TFA. EtOAc (100 mL) was then added to the residue, which remained
insoluble. The mixture was stirred at 50°C for 0.5 h and left in a refrigerator overnight. The solid
was filtered, washed with cold EtOAc and air dried to give 3.08 g of a white crystalline powder. The
filtrate was evaporated to dryness and diethyl ether (50 mL) was added to the residue. The solution
was concentrated and allowed to crystallize, to give 1.665 g of crystals. More crystals (0.231 g) were
obtained after concentration of the filtrate and crystallization, to give a total of 4.976 g (85.4%) of pure
1
Bz–Bin–OH (RS)-6. Mp=263.9°C. Rf=0.33 (IV). H NMR (CDCl3): 7.97–7.26 [m, 17H, ArH], 6.35
[s, 1H, NHBz], 3.63 and 2.55 [2×d, J=13.1, 2H, CH2 β], 3.42 and 3.19 [2×d, J=14.0, 2H, CH2 β0].
13C NMR (CDCl3): 173.7 (C_O), 168.6 (C_O), 134.8, 134.2, 133.9, 133.4, 133.2, 133.1, 132.4, 131.9,
131.6, 128.8, 128.5, 128.4, 128.3, 128.2, 127.6, 127.3, 127.2, 127.1, 126.1, 125.8, 125.6, 125.5 (CAr),
70.3 (Cα), 41.7 (Cβ), 37.9 (Cβ0). Anal. C31H23NO3·0.5H2O: calcd C 79.81, H 5.18, N 3.00; found C
79.83, H 5.17, N 2.95.
3.7. N-tert-Butyloxycarbonyl-(L)-phenylalanine cyclohexylamide
According to the procedure of Obrecht et al.5, a solution of Boc-(L)-phenylalanine (10.60 g; 40 mmol)
in EtOAc (150 mL) was strirred at −15°C (ice–salt bath) for 15 min and N-methylmorpholine (4.04 g; 40
mmol) was added, followed by ethyl chloroformate (4.34 g; 40 mmol). The resulting white suspension
was stirred at −15°C for 20 min and cyclohexylamine (3.96 g; 40 mmol) was added. The mixture was
stirred from −15°C to +10°C for 2 h and at room temperature for 1 h, then poured onto crushed ice (300
g). After addition of more EtOAc, the organic phase (300 mL) was extracted successively with 0.5 N HCl
(3×100 mL), 5% NaHCO3 (2×100 mL) then water (2×100 mL), dried (MgSO4), filtered and evaporated
in vacuo. The crude product (13.35 g; 96.5%) was recrystallized from tert-butyl methyl ether (300 mL).
The white crystals were filtered, washed with cold tBuOMe and air dried to give 10.30 g (74.4%) of pure
Boc–(L)-Phe–NHC6H11. 1H NMR (CDCl3): 7.32–7.19 [m, 5H, ArH], 5.57 [d (broad), 1H, NH Phe], 5.19
[d (broad), 1H, NHC6H11], 4.23 [m, 1H, Hα Phe], 3.68 [m, 1H, CHC5H10], 3.09 [dd, J=6.3 and 13.6, 1H,
HβA Phe] and 2.97 [dd, J=7.9 and 13.6, 1H, HβB Phe], 1.9–0.8 [m, 10H, C5H10], 1.42 [s, 9H, Boc]. 13
C
NMR (CDCl3): 169.8 (C_O), 155.2 (C_O Boc), 136.89, 129.3, 128.5, 126.8 (CAr), 79.9 (OtBu Boc),
56.0 (Cα Phe), 38.9 (Cβ Phe), 48.0, 32.7, 32.6, 25.3, 24.6 (C6H11), 28.2 (tBu Boc). Mp=143.1°C (lit.5
mp=143.0–143.5°C). [α]58925=+9.8; [α]57825=+9.4; [α]54625=+11.8; [α]43625=+9.4; [α]36525=+15.3 (c
0.2; CHCl3), lit.5 [α]589=+5.0 (c 0.2; CHCl3).

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3.8. L-Phenylalanine cyclohexylamide5
A solution of Boc-(L)-phenylalanine cyclohexylamide (10.04 g; 29 mmol) in CH2Cl2 (60 mL) was
stirred at 0°C and TFA (30 mL) was added. The solution was stirred at 0°C for 1 h, then at room
temperature for 2 h and evaporated in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and a
solution of saturated NaHCO3 (150 mL) was added. After shaking and decantation, the aqueous layer
was extracted with CH2Cl2 (2×100 mL). The combined organic layer was dried over MgSO4, filtered
and evaporated in vacuo. The obtained white solid was recrystallized from tert-butyl methyl ether, to
1
give 6.47 g (90.6%) of pure H-(L)-Phe–NHC6H11 as white crystals. H NMR (CDCl3): 7.35–7.21 [m,
5H, ArH], 7.07 [d (broad), 1H, NHC6H11], 3.76 [m, 1H, Hα Phe], 3.59 [m (broad), 1H, CHC5H10],
3.25 [dd, J=4.0 and 13.6, 1H, HβA Phe] and 2.71 [dd, J=9.0 and 13.6, 1H, HβB Phe], 1.9–1.0 [m,
10H, C5H10]. 13C NMR (CDCl3): 173.0 (C_O), 137.9, 129.2, 128.5, 126.6 (CAr), 56.3 (Cα Phe),
41.0 (Cβ Phe), 47.5, 32.9, 32.8, 25.4, 24.7 (C6H11). Mp=100.3°C (lit.5 mp=99–101°C). [α]58925=−55.8;
[α]57825=−65.0; [α]54625=−73.8; [α]43625=−148.3; [α]36525=−261.2 (c 0.2; CHCl3), lit.5 [α]589=−70.0
(c 0.2; CHCl3). Another run in the same conditions gave, after just one extraction, a crude white solid with
mp=99.8°C and [α]58925=−58.2; [α]57825=−64.0; [α]54625=−71.3; [α]43625=−147.4; [α]36525=−268.7
(c 0.2; CHCl3).
3.9. Coupling of (RS)-5 and (RS)-6 with L-phenylalanine cyclohexylamide
To a solution of (RS)-5 (0.198 g; 0.5 mmol), H-(L)-Phe–NHC6H11 (0.246 g; 1 mmol) and HOBt
(N-hydroxybenzotriazole) (0.135 g; 1 mmol) in CH2Cl2 (5 mL) and THF (5 mL), was added EDC
(N-ethyl-N0-dimethylaminopropyl-carbodiimide hydrochloride) (0.115 g; 0.6 mmol). The solution was
stirred at room temperature for 3 days and evaporated in vacuo. The residue was dissolved in EtOAc
(150 mL) and the solution extracted successively with 0.5 N HCl (2×100 mL), H2O (100 mL), 5%
NaHCO3 (2×100 mL), H2O (2×100 mL), then dried (MgSO4), filtered and evaporated in vacuo. The
residue was chromatographed on a 2.5×70 cm column of silica gel with eluents (VI) then (VII), to give
0.136 g (87%)7 of pure diastereoisomer Ac–(R)-Bin–(L)-Phe–NHC6H11 7a and 0.152 g (97%)7 of pure
diastereoisomer Ac–(S)-Bin–(L)-Phe–NHC6H11 7b. Attempts for crystallization of 7a and 7b in EtOAc,
MeOH or CH2Cl2/hexane were unsuccessful. No crystals deposited even from highly concentrated
solutions and evaporation to dryness led to an amorphous white solid in both cases.
3.10. Ac–(R)-Bin–(L)-Phe–NHC6H11 7a
Amorphous white powder. Mp=197.2°C. Rf=0.19 (VII). 1H NMR (CDCl3): 7.90 [m (t-like), 3H, ArH],
7.77 [d, J=8.3, 1H, ArH], 7.38 [m, 2H, ArH], 7.27 [m, 10H, ArH], 6.75 [d, J=8.3, 1H, ArH], 6.53 [d,
J=8.l, 1H, NHC6H11], 6.47 [d, J=8.3, lH, NH Phe], 5.65 [s, 1H, NHAc], 4.66 [ddd, J=8.3, 5.3 and 8.6,
1H, Hα Phe], 3.68 [m, 1H, CHC5H10], 3.36 [dd, J=5.3 and 14.1, 1H, HβA Phe] and 3.02 [dd, J=8.6
and 14.1, 1H, HβB Phe], 2.78 and 2.31 [2×d, J=12.9, 2H, CH2 β Bin], 3.20 and 3.09 [2×d, J=13.8,
2H, CH2 β0 Bin], 1.97 [s, 3H, Ac], 1.8–1.0 [m, 10H, C5H10]. 13C NMR (CDCl3): 171.0, 170.7, 169.5
(C_O Phe, C_O Bin, C_O Ac), 137.6, 134.7, 134.5, 133.9, 133.2, 132.9, 132.8, 131.7, 131.5, 129.3,
128.7, 128.33, 128.26, 128.20, 128.1, 127.7, 127.6, 127.1, 127.0, 126.0, 125.8, 125.4 (CAr), 70.8 (Cα
Bin), 54.3 (Cα Phe), 48.5 (NHCHC5H10), 42.9 (Cβ Phe), 37.6 (Cβ Bin), 36.2 (Cβ0 Bin), 32.7, 32.5,
25.4, 25.0, 24.9 (C5H10), 23.7 (Ac). [α]58925=+72.3; [α]57825=+76.2; [α]54625=+92.8; [α]43625=+261.1;
[α]36525=+1082.4 (c 0.13; MeOH). Anal. C41H41N3O3·0.2H2O: calcd C 78.49, H 6.65, N 6.70; found C
78.46, H 6.66, N 6.59.

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 9 (1998) 2701–2713
2709
3.11. Ac–(S)-Bin–(L)-Phe–NHC6H11 7b
1
Amorphous white powder. Mp=177.8°C. Rf=0.11 (VII). H NMR (CDCl3): 7.92 [m, 4H, ArH],
7.53–7.25 [m, 8H, ArH], 6.90 [m (t-like), 1H, ArH], 6.74 [m (t-like), 2H, ArH], 6.64 [m (d-like), 2H,
ArH], 6.73 [d, J=8.8, 1H, NHC6H11], 5.98 [d, J=8.6, 1H, NH Phe], 5.83 [s, 1H, NHAc], 4.68 [ddd,
J=8.6, 5.2 and 6.6, 1H, Hα Phe], 3.70 [m, 1H, CHC5H10], 3.34 [dd, J=5.2 and 13.6, 1H, HβA Phe] and
2.72 [dd, J=6.6 and 13.8, 1H, HβB Phe], 3.45 and 2.29 [2×d, J=12.7, 2H, CH2 β Bin], 3.11 and 2.54
[2×d, J=12.8, 2H, CH2 β0 Bin], 1.94 [s, 3H, Ac], 1.8–1.1 [m, 10H, C5H10]. 13C NMR (CDCl3): 170.6,
169.7, 169.2 (C_O Phe, C_O Bin, C_O Ac), 136.7, 136.1, 134.7, 134.1, 133.7, 133.5, 133.2, 133.0,
131.7, 131.6, 129.3, 128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 127.3, 127.1, 127.0, 126.8, 126.2, 126.0,
125.6 (CAr), 70.0 (Cα Bin), 53.5 (Cα Phe), 48.7 (NHCHC5H10), 41.7 (Cβ Phe), 36.8 (Cβ Bin), 32.8
(Cβ0 Bin), 32.7, 32.4, 25.4, 25.0, 24.5 (C5H10), 23.5 (Ac). [α]58925=0.0; [α]57825=−0.6; [α]54625=−5.3;
[α]43625=−66.2; [α]36525=−545.2 (c 0.16; MeOH). Anal. C41H41N303·0.7H2O: calcd C 77.38, H 6.72,
N 6.60; found C 77.31, H 6.76, N 6.62.
In a similar manner, a solution of (RS)-6 (0.229 g; 0.5 mmol), H–(L)-Phe–NHC6H11 (0.246 g; 1
mmol), HOBt (0.135 g; 1 mmol) and EDC (0.115 g; 0.6 mmol) in CH2Cl2 (5 mL)/THF (5 mL) was
stirred at room temperature for 3 days and evaporated in vacuo. Extraction as above followed by
chromatography on a 2×60 cm column of silica gel with eluents (V) then (VI), gave 0.162 g (95%)7
of pure diastereoisomer Bz–(R)-Bin–(L)-Phe–NHC6H11 8a, 0.130 g (76%)7 of pure diastereoisomer
Bz–(S)-Bin–(L)-Phe–NHC6H11 8b with [α]54625=−22.2 (c 0.13; MeOH) and 0.050 g (14%)7 of 8b
contaminated with traces of 8a. Attempts to purify the contaminated sample of 8b by crystallization were
again unsuccessful since no crystals could be obtained from concentrated solutions in various solvents.
Crystallization from CH2Cl2/hexane gave only an amorphous solid. On the other hand, ca. 40 mL of
boiling EtOAc was necessary to dissolve the pure isomer 8a (0.162 g) and when the dilute clear colorless
solution was left at room temperature overnight, a large amount of high quality shiny white crystals
were deposited. The crystals were filtered, washed with cold EtOAc and air dried to give 0.142 g (78%
yield for the crystallization process) of 8a as EtOAc solvate (by 1H NMR and X-ray), with mp=275.2°C;
[α]54625=+68.9 (c 0.1; MeOH). More crystals (ca. 0.025 g) were obtained after concentration of the
mother liquor.
In a second run on a medium scale, a solution of (RS)-6 (4.972 g; 10.9 mmol), H–(L)-Phe–NHC6H11
(3.743 g; 15.2 mmol), HOBt (2.080 g; 15.4 mmol) and EDC (2.523 g; 13.2 mmol) in CH2Cl2 (300
mL)/THF (200 mL) was stirred at room temperature for 30 hours. More CH2Cl2 (200 mL) was added
and the organic solution was extracted successively with 0.5 N HCl (2×200 mL), H2O (200 mL), 5%
NaHCO3 (2×200 mL), H2O (2×200 mL), then dried (MgSO4), filtered and evaporated in vacuo. The
obtained crude product (7.91 g) could not be totally solubilized in 200 mL of boiling EtOAc. After
addition of CH2Cl2 (200 mL) and more EtOAc (100 mL), the resulting clear solution was concentrated
at 90°C with complete elimination of dichloromethane. When crystallization started to occur from the
boiling solution (ca. 200 mL), the flask was left at room temperature overnight. The white shiny crystals
were filtered, washed with 150 mL of cold EtOAc and air dried to give 3.745 g (89.1%)7 of pure
1
diastereoisomer Bz–(R)-Bin–(L)-Phe–NHC6H11 8a as EtOAc solvate by H NMR, with mp=273.9°C;
[α]54625=+67.4 (c 0.1; MeOH). Recrystallization of these crystals (3.714 g) from EtOAc/(CH2Cl2) as
1
above led to 3.643 g of crystals (8a:EtOAc ca. 1:1 mol:mol by H NMR), with the same melting
point, mp=273.9°C, and similar optical rotation [α]54625=+72.1 (c 0.l; MeOH). The mother liquor from
the first crop of crystals was evaporated in vacuo and the residue, dissolved in CH2Cl2 (10 mL), was
chromatographed on a 3×56 cm column of silica gel with eluents (VI) then (VII), to give three fractions:
(A) 0.323 g, consisting of a ca. 1:1 mixture of 8a and 8b (by TLC), (B) 0.844 g, consisting of 8b with

2710
J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 9 (1998) 2701–2713
traces of 8a and (C) 2.772 g, consisting of pure 8b with [α]54625=−20.7 (c 0.13; MeOH). Fraction (A)
was dissolved in CH2Cl2 (20 mL) and EtOAc (40 mL) was added. Upon concentration at 90°C to ca.
2 mL, with complete elimination of dichloromethane as above, crystallization started to occur and was
completed at room temperature. The white shiny crystals were filtered, washed with abundant cold EtOAc
and air dried to give 0.123 g of pure 8a with [α]54625=+67.6 (c 0.1; MeOH), for a total amount of 3.868
g (92.0%).7 The mother liquor was evaporated in vacuo and the residue, combined with fraction (B), was
chromatographed on a 3×56 cm column of silica gel with eluents (V) then (VI) then (VII), to give 0.830
g of pure 8b for a total amount of 3.602 g (96.7%).7
3.12. Bz–(R)-Bin–(L)-Phe–NHC6H11 8a
1
White crystals (EtOAc solvate). Mp=273.9°C. Rf=0.21 (VI). H NMR (CDCl3): 7.94–7.79 [m, 4H,
ArH], 7.66–7.58 [m, 3H, ArH], 7.51–7.20 [m, 14H, ArH], 6.73 [d, J=8.3, 1H, ArH], 6.78 [d, J=8.4,
1H, NHC6H11], 6.41 [d, J=8.1, 1H, NH Phe], 6.13 [s, 1H, NHBz], 4.72 [ddd, J=8.1, 5.1 and 9.2,
1H, Hα Phe], 4.12 [q, J=7.1, 2H, EtOAc], 3.72 [m, 1H, CHC5H10], 3.46 [dd, J=5.1 and 14.1, 1H,
HβA Phe] and 2.98 [dd, J=9.2 and 14.1, 1H, HβB Phe], 2.81 and 2.45 [2×d, J=12.8, 2H, CH2 β
Bin], 3.29 and 3.23 [2×d, J=14.1, 2H, CH2 β0 Bin], 2.05 [s, 3H, EtOAc], 1.9–1.1 [m, 10H, C5H10],
1.27 [t, J=7.1, 3H, EtOAc]. 13C NMR (CDCl3): 171.1, 170.5, 169.4, 168.0 (C_O EtOAc, C_O Phe,
C_O Bin, C_O Bz), 137.7, 134.7, 134.6, 133.9, 133.2, 133.1, 132.9, 132.7, 132.5, 131.7, 131.6, 129.3,
128.9, 128.7, 128.4, 128.3, 128.2, 128.1, 127.8, 127.2, 127.1, 127.0, 126.0, 125.8, 125.4 (CAr), 71.0
(Cα Bin), 60.4 (EtOAc), 54.6 (Cα Phe), 48.5 (NHCHC5H10), 43.3 (Cβ Phe), 37.5 (Cβ Bin), 36.4 (Cβ0
Bin), 32.8, 32.5, 25.5, 25.1, 24.9 (C5H10), 21.0 (EtOAc), 14.2 (EtOAc). [α]58925=+55.8; [α]57825=+57.8;
[α]54625=+72.1; [α]43625=+213.4; [α]36525=+909.1 (c 0.1; MeOH) (∆ necessary for dissolution). Anal.
C46H43N3O3·0.4EtOAc (after drying at 50°C/0.1 mm): calcd C 79.28, H 6.46, N 5.83; found C 79.54, H
6.46, N 5.97.
3.13. Bz–(S)-Bin–(L)-Phe–NHC6H11 8b
1
Amorphous white powder. Mp=222.6°C. Rf=0.14 (VI). H NMR (CDCl3): 7.96 [m, 4H, ArH], 7.64
[m (d-like), 2H, ArH], 7.56–7.26 [m, 11H, ArH], 6.89 [m (t-like), 1H, ArH], 6.70 [m, 4H, ArH], 6.97 [d,
J=8.1, 1H, NHC6H11], 6.38 [s, 1H, NHBz], 6.01 [d, J=8.6, 1H, NH Phe], 4.76 [ddd, J=8.6, 5.1 and 6.3,
1H, Hα Phe], 3.75 [m, 1H, CHC5H10], 3.37 [dd, J=5.1 and 13.6, 1H, HβA Phe] and 2.77 [dd, J=6.3 and
13.6, lH, HβB Phe], 3.60 and 2.42 [2×d, J=12.7, 2H, CH2 β Bin], 3.15 and 2.67 [2×d, J=12.9, 2H, CH2
β0 Bin], 1.9–1.1 [m, 10H, C5H10]. 13C NMR (CDCl3): 171.1, 169.3, 167.6 (C_O Phe, C_O Bin, C_O
Bz), 136.1, 134.8, 134.1, 133.8, 133.5, 133.3, 133.2, 133.1, 132.3, 131.8, 131.6, 129.3, 128.7, l28.6,
128.5, 128.4, 128.3, 128.2, 128.1, 127.2, 127.1, 127.0, 126.8, 126.3, 126.1, 125.7, 125.6 (CAr), 70.2 (Cα
Bin), 53.4 (Cα Phe), 48.7 (NHCHC5H10), 41.9 (Cβ Phe), 37.4 (Cβ Bin), 36.7 (Cβ0 Bin), 32.9, 32.5, 25.6,
25.1 (C5H10). [α]58925=−14.8; [α]57825=−16.3; [α]54625=−22.2; [α]43625=−108.0; [α]36525=−647.0 (c
0.13; MeOH). Anal. C46H43N3O3·0.5H2O: calcd C 79.51, H 6.38, N 6.05; found C 79.18, H 6.37, N
5.88.
3.14. Acidic hydrolysis of 8a and 8b
To a solution of Bz–(S)-Bin–(L)-Phe–NHC6H11 8b (3.408 g; 4.97 mmol) in dioxane (40 mL) was
added 35% (10 N) HCl (40 mL), resulting in the formation of a white precipitate. The mixture was
magnetically stirred at 110°C and the precipitate gradually disappeared to give a clear pale yellow

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 9 (1998) 2701–2713
2711
solution after 20 h. The solution was stirred at 110°C for 6 days, then evaporated to dryness in vacuo at
80°C. Water (ca. 40 mL) was added to the residue and the mixture was evaporated again in vacuo at 80°C,
this operation being repeated several times in order to remove most of the excess of HCl. The residue
was then triturated in water (40 mL) to give a solid precipitate and a turbid supernatant which clarified
upon standing at room temperature overnight. The solid was filtered on a Büchner funnel, washed with
water, air dried for ca. 2 h, then washed with abundant ether and triturated, then air dried, to give 2.250
g of a pale yellow–brown crystalline powder. The crude solid was dissolved in boiling MeOH (200 mL),
activated charcoal was added and the mixture was filtered on paper, the filter was washed with abundant
hot methanol. The solution was then evaporated to dryness in vacuo for elimination of possible residual
water, the residue was dissolved in methanol (50 mL) and the solution was concentrated to near dryness
(ca. 2 mL) at 60°C. Crystallization rapidly occurred at room temperature. The mixture was left in a
refrigerator overnight, then diluted with a cold solution of MeOH:Et2O 1:1 (10 mL). The crystals were
filtered, rapidly washed with a cold solution of MeOH:Et2O (1:1) (10 mL) and air dried, to give 0.482
g (24.8%) of pure H–Bin–OH, HCl (S)-9 as a white crystalline powder. Another sample of (S)-9 (1.537
g) contaminated by several impurities was also recovered after evaporation of the mother liquor. Both
samples of pure (0.471 g) and impure (1.537 g) amino acid (S)-9 were separately esterified in refluxing
MeOH (100 mL)/98% H2SO4 (2 mL) for 3 days. In both cases, the solution was concentrated in vacuo
at 30°C to ca. 10 mL and crushed ice (100 mL) then water (50 mL) were added to the stirred mixture,
followed by small portions of solid NaHCO3 up to a large excess. The basic aqueous phase was extracted
with ether (250 mL), the organic phase was washed with water (3×200 mL), dried (MgSO4), filtered and
evaporated in vacuo. The obtained crude product of the run involving impure (S)-9 had to be repeatedly
chromatographed on 2.3×60 cm columns of silica gel with eluent (II), then on preparative TLC plates,
in order to allow the separation of the side product (S)-11 [Rf close to the one of the desired compound
(S)-10]. Chromatography of both crude products gave the following combined samples:
(1) Bz–(S)-Bin–OMe resulting from incomplete hydrolysis (0.015 g; 0.6%), Rf=0.70 (II), identified
1
by H NMR (CDCl3): 7.93 [m, 4H, ArH], 7.72 [m, 2H, ArH], 7.46 [m, 9H, ArH], 7.27 [m, 2H, ArH],
6.31 [s, 1H, NH], 3.78 [s, 3H, OCH3], 3.50 and 2.57 [2×d, J=13.0, 2H, CH2 β Bin], 3.33 and 3.21 [2×d,
J=13.8, 2H, CH2 β0 Bin] as the first side product;
1
(2) H–Bin–OCH2CH2OCH2CH2–OH (S)-11 (0.009 g; 0.4%), Rf=0.23 (II), identified by H NMR
(CDCl3): 7.92 [m, 4H, ArH], 7.56 [m, 2H, ArH], 7.44 [m, 2H, ArH], 7.36 [m, 2H, ArH], 7.24 [m, 2H,
ArH], 4.31 [m (t-like), 2H, OCH2], 3.71 [m, 2H, OCH2], 3.64 [m, 2H, OCH2], 3.50 [m, 2H, OCH2], 3.19
and 2.41 [2×d, J=13.2, 2H, CH2 β Bin], 3.06 and 2.70 [2×d, J=13.2, 2H, CH2 β0 Bin], 1.79 [s, 3H, NH2
and OH] as the second side product;
(3) H–Bin–OMe (S)-10 (0.772 g; 42.3%), Rf=0.28 (11);
(4) H–Bin–OMe (S)-10 (0.567 g; 3 l.0%) contaminated by ca. 5% (by 1H NMR) of (S)-11.
In the same manner, to a solution of Bz–(R)-Bin–(L)-Phe–NHC6H11 8a:EtOAc ca. 1:1 (3.622 g; 4.68
mmol) in dioxane (50 mL) was added 35% (10 N) HCl (50 mL), resulting in the formation of a white
precipitate. The mixture was magnetically stirred at 110°C and the precipitate gradually disappeared to
give a clear pale yellow solution after 20 h. The solution was stirred at 110°C for 8 days, then evaporated
to dryness in vacuo at 80°C. The solid residue was treated exactly as above, to give 0.770 g (42.1%) of
pure H–Bin–OH, HCl (R)-9 as a white crystalline powder and 1.003 g (54.9%) of (R)-9 contaminated
by several impurities. Both samples of pure and impure amino acid (R)-9 were separately esterified in
refluxing MeOH (100 mL)/98% H2SO4 (2 mL) for 3 days. Work-up as above followed by repeated
chromatography with eluent (II), led for the combined two runs, to small amounts of Bz–(R)-Bin–OMe
and H–Bin–OCH2CH2OCH2CH2–OH (R)-11, both identified only by TLC, to 0.704 g (41.0%) of pure
H–Bin–OMe (R)-10 and to 0.642 g (37.3%) of (R)-10 contaminated by ca. 5% (by 1H NMR) of (R)-11.

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J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 9 (1998) 2701–2713
3.15. 20,10:1,2;100,200:3,4-Dinaphthcyclohepta-1,3-diene-6-amino-6-carboxylic acid (S)-9
Crystalline white powder. Mp=251.8°C (decomp.). [α]58925=+349.4; [α]57825=+363.8;
[α]54625=+415.8; [α]43625=+687.5; [α]36525=+481.2 (c 0.21; MeOH), lit.2b for H–(S)-Bin–OH,
TFA salt: [α]54625=+375.0 (c 0.62; MeOH). Anal. (C24H19NO2·0.3HCl): calcd C 79.11, H 5.62, N 3.84;
found C 78.87, H 5.84, N 3.84.
3.16. 20,10:1,2;100,200:3,4-Dinaphthcyclohepta-1,3-diene-6-amino-6-carboxylic acid (R)-9
Crystalline white powder. Mp=256.1°C (decomp.). [α]58925=−352.l; [α]57825=−367.8;
[α]54625=−418.9; [α]43625=−691.6; [α]36525=−482.1 (c 0.19; MeOH). Anal. (C24H19NO2·0.5HCl):
calcd C 77.56, H 5.56, N 3.77; found C 77.58, H 5.71, N 3.79.
3.17. 20,10:1,2;100,200:3,4-Dinaphthcyclohepta-1,3-diene-6-amino-6-carboxylic acid methyl ester (S)-10
1
White solid foam. Mp=106.6°C. H NMR (CDCl3): 7.93 [m, 4H, ArH], 7.55 [m, 2H, ArH], 7.45
[m, 2H, ArH], 7.37 [m, 2H, ArH], 7.24 [m, 2H, ArH], 3.73 [s, 3H, OCH3], 3.17 and 2.41 [2×d,
J=13.2, 2H, CH2 β Bin], 3.07 and 2.69 [2×d, J=13.3, 2H, CH2 β0 Bin], 1.73 [s, 2H, NH2]. 13C
NMR (CDCl3): 175.9 (C_O); 135.9, 134.3, 134.1, 133.8, 132.9, 132.8, 131.8, 128.4, 128.24, 128.21,
128.13, 128.10, 127.7, 127.2, 125.8, 125.6, 125.2, 125.1 (CAr); 68.8 (Cα); 52.2 (OCH3); 43.5 (Cβ); 43.0
(Cβ0). [α]58925=+331.3; [α]57825=+345.1; [α]54625=+393.5; [α]43625=+630.0; [α]36525=+311.2 (c 0.21;
MeOH), lit.2b for H–(S)-Bin–OEt and H–(S)-Bin–OtBu: [α]54625=+376.8 and +358.4 (c 0.5; MeOH),
respectively. Anal. C25H21NO2·0.3H2O: calcd C 80.53, H 5.84, N 3.76; found C 80.57, H 5.87, N 3.65.
3.18. 20,10:1,2;100,200:3,4-Dinaphthcyclohepta-1,3-diene-6-amino-6-carboxylic acid methyl ester
(R)-10
1
White solid foam. Mp=105.9°C. H NMR and 13C NMR (CDCl3): see above. [α]58925=−333.2;
[α]57825=−348.1; [α]54625=−396.6; [α]43625=−634.1; [α]36525=−307.9 (c 0.21; MeOH). Anal.
C25H21NO2: calcd C 81.72, H 5.76, N 3.81; found C 81.52, H 5.61, N 3.75.
3.19. Coupling of (R)-10 and (S)-10 with (−)-(S)-α-methoxy-α-trifluoromethyl-α-phenyl-acetic acid
To a solution of (−)-(S)-α-methoxy-α-trifluoromethyl-α-phenyl-acetic acid (Aldrich, 99+%) (0.117
g; 0.5 mmol) in acetonitrile (4 mL) was added EDC (0.048 g; 0.25 mmol). After stirring at room
temperature for 1 h the clear colorless solution of the resulting MTPA anhydride was divided into two
portions of 2 mL each, which were added to samples of (R)-10 (0.0183 g; 0.05 mmol) and (S)-10 (0.0184
g; 0.05 mmol), respectively. The resulting clear colorless solutions were stirred at room temperature
for 3 days. After addition of ether (100 mL) the organic phases were successively extracted with 5%
NaHCO3 (2×50 mL), then water (2×100 mL), dried (MgSO4), filtered and evaporated in vacuo. The
residues were chromatographed on preparative TLC plates of silica gel with eluent (I), care being taken
not to exercise a mechanical separation of one of the diastereoisomers over the other. From (R)-10 was
obtained the amido ester (S)-Ph(OCH3)(CF3)C–CO–(R)-Bin–OMe (0.025 g; 86.2%) with >96% de: 1H
NMR (CDCl3): 7.95–7.10 [m, 17H, ArH], 6.90 [s, 1H, NH], 3.76 [s (>98%), 3H, OCH3 Bin], 3.70 [s
(<2%), OCH3 Bin of the (S,S) isomer], 3.44 [m, 3H, OCH3 MTPA], 3.43 (masked) and 2.53 [2×d,
J=12.9, 2H, CH2 β Bin], 3.17 and 3.11 [2×d, J=14.2, 2H, CH2 β0 Bin]. 19F NMR (CDCl3): −68.87

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 9 (1998) 2701–2713
2713
[s (>98%), CF3], −68.95 [s (<2%), CF3 of the (S,S) isomer]. 13C NMR (CDCl3): 171.8, 165.8 (C_O
Bin, C_O MTPA), 134.4–125.4 (CAr), 83.5 [q, J=26, CF3], 69.2 (Cα Bin), 55.09 and 55.07 (OCH3
MTPA), 52.6 (OCH3 Bin), 41.6 (Cβ Bin), 37.9 (Cβ0 Bin). From (S)-10 was obtained the amido ester
(S)-Ph(OCH3)(CF3)C–CO–(S)-Bin–OMe (0.026 g; 89.6%) with >98% de: 1H NMR (CDCl3): 7.96–7.24
[m, 17H, ArH], 7.14 [s, 1H, NH], 3.70 [s (>99%), 3H, OCH3 Bin], 3.76 [s (<1%), OCH3 Bin of the (S,R)
isomer], 3.30 [m, 3H, OCH3 MTPA], 3.31 (masked) and 2.62 [2×d, J=12.9, 2H, CH2 β Bin], 3.33 and
3.22 [2×d, J=14.1, 2H, CH2 β0 Bin], 19F NMR (CDCl3): −68.96 [s (>99%), CF3], −68.88 [s (<1%),
CF3 of the (S,R) isomer]. 13C NMR (CDCl3): 171.8, 165.8 (C_O Bin, C_O MTPA), 134.5–125.4 (CAr),
83.9 [q, J=26, CF3], 69.4 (Cα Bin), 54.82 and 54.80 (OCH3 MTPA), 52.5 (OCH3 Bin), 41.9 (Cβ Bin),
37.6 (Cβ0 Bin).
References
1. For some recent leading references on open-chain and cyclic α,α-disubstituted-α-amino acids, see: (a) Toniolo, C. Janssen
Chimica Acta 1993, 11(28) 10–16. (b) Benedetti, E. Biopolymers 1996, 40, 3–44. (c) Karle, I. L. Biopolymers 1996, 40,
157–180. (d) Toniolo, C.; Crisma, M.; Formaggio, F.; Benedetti, E.; Santini, A.; Iacovino, R.; Saviano, M.; Di Blasio, B.;
Pedone, C.; Kamphuis, J. Biopolymers 1996, 40, 519–522.
2. (a) Mazaleyrat, J.-P.; Gaucher, A.; Wakselman, M.; Tchertanov, L.; Guilhem, J. Tetrahedron Lett. 1996, 37, 2971–2974.
(b) Mazaleyrat, J.-P.; Gaucher, A.; Šavrda, J.; Wakselman, M. Tetrahedron: Asymmetry 1997, 8, 619–631.
3. (a) Mazaleyrat, J.-P.; Gaucher, A.; Wakselman, M.; Toniolo, C.; Crisma, M.; Formaggio, F. Peptides 1996, R. Ramage and
R. Epton, Eds.; Mayflower Worldwide 1997, in press. (b) Toniolo, C.; Crisma, M.; Formaggio, F.; Pispisa, B.; Flippen-
Anderson, J. L.; Mazaleyrat, J. P.; Wakselman, M. Peptides. Chemistry, Structure and Biology. Proceedings of the 15th
American Peptide Symposium, 1998, in press.
4. For leading references, see: (a) Toniolo, C.; Crisma, M.; Formaggio, F.; Valle, G.; Cavicchioni, G.; Precigoux, G.; Aubry,
A.; Kamphuis, J. Biopolymers 1993, 33, 1061–1072. (b) Crisma, M.; Valle, G.; Pantano, M.; Formaggio, F.; Bonora, G. M.;
Toniolo, C.; Kamphuis, J. Recl. Trav. Chim. Pays-Bas 1995, 114, 325–331. (c) Doi, M.; Ishida, T.; Polese, A.; Formaggio,
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M.; Crisma, M.; Bonora, G. M.; Toniolo, C.; Kamphuis, J. J. Chem. Soc., Perkin Trans. 2 1995, 1097–1101. (e) Yoder,
G.; Keiderling, T. A.; Formaggio, F.; Crisma, M.; Toniolo, C.; Kamphuis, J. Tetrahedron: Asymmetry 1995, 6, 687–690.
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1666–1696. (b) Obrecht, D.; Bohdal, U.; Broger, C.; Bur, D.; Lehmann, C.; Ruffieux, R.; Schönholzer, P.; Spiegler, C.;
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6. Maigrot, N.; Mazaleyrat, J.-P. Synthesis 1985, 317–320.
7. Yield based on the half amount of the starting racemic compound.
8. Tchertanov, L.; Guilhem, J.; Mazaleyrat, J.-P.; Gaucher, A.; Wakselman, M. Acta Cryst. (B) 1998, in press.
9. Separation of compounds 10 and 11 was partly accomplished in the present study, but could be avoided if the desired final
product was N-protected Bin rather than C-protected Bin: N-protection of a mixture of 10 and 11 by Boc or Z followed by
saponification of the ester functions of the resulting mixture,2b would lead to Boc (or Z)-Bin–OH as a single product.
10. (a) Hall, D. M.; Turner, E. E. J. Chem. Soc. 1955, 1242–1251. (b) Dixon, W.; Harris, M. M.; Mazengo, R. Z. J. Chem. Soc.
(B) 1971, 775–778.