Synthesis of enantiopure, axially chiral, Cα-tetrasubstituted α-amino acids with binaphthyl-based crowned side chains and 3D-structural analysis of their peptides

Article abstract of DOI:10.1016/j.tet.2008.01.019

The syntheses of the terminally protected, crowned, C^α-tetrasubstituted α-amino acids with only axial chirality, the two diastereomers Boc-(S)-Bip[(R)-Binol-22-C-6]-OMe and Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe, and their respective enantiomers Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe and Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe, all derived from 2′,1′:1,2; 1″,2″:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid (Bip), were performed by bis-alkylation with cyclization of racemic (R+S)-Boc-[HO]₂-Bip-OMe, possessing two phenolic OH groups at the 6,6′-positions of the biphenyl frame of Bip, using (+)-(R)- and (-)-(S)-Binol[(OCH₂CH₂)₂OTs] ₂ (2,2′-bis[5-tosyloxy-3-oxa-1-pentyloxy]-1,1′-binaphthyl), respectively, as the alkylating agent followed by chromatographic separation. Two series of terminally protected model peptides to the hexamer level, containing the (R)-Bip[(S)-Binol-22-C-6] residue at i and i+3 positions of the sequence, combined with either l-Ala or l-Ala/Aib, were synthesized by solution methods. Their 3D-structural analyses by FTIR absorption and NMR suggest that these peptides preferentially adopt folded secondary structures.

Full text of DOI:10.1016/j.tet.2008.01.019

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2307e2320
www.elsevier.com/locate/tet
Synthesis of enantiopure, axially chiral, Ca-tetrasubstituted
a-amino acids with binaphthyl-based crowned side chains
and 3D-structural analysis of their peptides
a
a
a
Karen Wright a, , Jean-Franc¸ois Lohier , Michel Wakselman , Jean-Paul Mazaleyrat ,
*
Fernando Formaggio b, Cristina Peggion b, Marta De Zotti b, Claudio Toniolo b,
*
a ILV, UMR CNRS 8180, University of Versailles, F-78035 Versailles, France
b Institute of Biomolecular Chemistry, CNR, Padova Unit, Department of Chemistry, University of Padova, I-35131 Padova, Italy
Received 10 December 2007; accepted 6 January 2008
Available online 11 January 2008
Abstract
The syntheses of the terminally protected, crowned, Ca-tetrasubstituted a-amino acids with only axial chirality, the two diastereomers Boc-
(S)-Bip[(R)-Binol-22-C-6]-OMe and Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe, and their respective enantiomers Boc-(R)-Bip[(S)-Binol-22-C-6]-
OMe and Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe, all derived from 20,10:1,2; 100,200:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid
(Bip), were performed by bis-alkylation with cyclization of racemic (RþS)-Boc-[HO]2-Bip-OMe, possessing two phenolic OH groups at the
6,60-positions of the biphenyl frame of Bip, using (þ)-(R)- and (ꢀ)-(S)-Binol[(OCH2CH2)2OTs]2 (2,20-bis[5-tosyloxy-3-oxa-1-pentyloxy]-
1,10-binaphthyl), respectively, as the alkylating agent followed by chromatographic separation. Two series of terminally protected model
peptides to the hexamer level, containing the (R)-Bip[(S)-Binol-22-C-6] residue at i and iþ3 positions of the sequence, combined with either
L-Ala or L-Ala/Aib, were synthesized by solution methods. Their 3D-structural analyses by FTIR absorption and NMR suggest that these
peptides preferentially adopt folded secondary structures.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Atropoisomerism; Binaphthyl; Biphenyl; Crowned amino acids; Ca-Tetrasubstituted a-amino acids; NMR; Infrared absorption; Peptide conformation
1. Introduction
known to be able to induce folded 310-helical conformations
in short peptide backbones.22e33 Accordingly, we previously
designed crown-carrier Ca-tetrasubstituted a-amino acids as
interesting targets allowing control of the spatial organization
of the crown-ether receptors in short-chain peptide structures
for the construction of new molecular receptors and supra-
molecular devices.34e37 Peptides based on L-Mdp[CROWN]
residues derived from Ca-methyl-L-DOPA (L-Mdp) with
[CROWN]¼[15-C-5], [18-C-6], [Benzo-24-C-8], and [(S)-Bi-
nol-20-C-6] (Fig. 1), the latter containing a binaphthyl unit as
a part of the crown moiety, were shown to have a strong propen-
sity for folded/helical secondary structures.38,39 Other groups
synthesized indane-based,40 as well as a-hydroxymethylser-
ine-based,41,42 achiral, Ca-tetrasubstituted a-amino acid deriv-
atives with various crown-ether side chains. However, X-ray
In the past few years, a series of crown-carrier derivatives of
L-DOPA,1e19 lysine,20 or glutamic acid,21 were synthesized and
shown to be of interest for the construction of peptide receptors
specific for alkali metal, ammonium, and di-ammonium ions,
and for the preparation of artificial ion channels. Application
of this concept to Ca-tetrasubstituted a-amino acids with
well-defined stereochemical properties was expected to result
in more predictable peptide structures, as these residues are
* Corresponding authors. Fax: þ33 01 39 25 44 52 (K.W.); fax: þ39 049 827
5239 (C.T.).
E-mail addresses: wright@chimie.uvsq.fr (K. Wright), claudio.toniolo@
unipd.it (C. Toniolo).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.019

2308
K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
O
O
O
O
O O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O O
O
O
O
Me
Me
N
H
C
O
N
H
C
O
N
H
C
O
N
H
C
O
N
H
C
O
L-Mdp[18-C-6]
L-Mdp[(S)-Binol-20-C-6]
(R)-Bip[20-C-6]
(R)-Bip[(S)-Binol-22-C-6] (S)-Bip[(S)-Binol-22-C-6]
Figure 1. Chemical structures of L-Mdp[18-C-6], L-Mdp[(S)-Binol-20-C-6], (R)-Bip[20-C-6], (R)-Bip[(S)-Binol-22-C-6], and (S)-Bip[(S)-Binol-22-C-6] residues.
diffraction 3D-structural analyses of only single amino acids
or cyclic dipeptides (2,5-dioxopiperazines) have been
performed.40
acid methyl ester Boc-(RþS)-Bip[OH]2-OMe (Fig. 2),
previously obtained from 2,20-bis(bromomethyl)-6,60-dime-
thoxy-1,10-biphenyl,36 served to introduce the (R)- or (S)-bi-
naphthyl-crowned side chain, by using the well established
procedure reported by Voyer and co-workers,3,6,14 with
Cs2CO3 as a base in DMF (N,N-dimethylformamide) at
60 ꢁC, and enantiomerically pure (þ)-(R)- or (ꢀ)-(S)-Bino-
l[(OCH2CH2)2OTs]2 (2,20-bis[5-tosyloxy-3-oxa-1-pentyloxy]-
1,10-binaphthyl)46 as the alkylating agent to afford a mixture
of either Boc-(S)-Bip[(R)-Binol-22-C-6]-OMe (SR)-1 and its
diastereomer Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe (RR)-1
(not shown), or Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe (RS)-1
and its diastereomer Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe
(SS)-1 (Fig. 2), which could be separated by chromatography
on silica gel. The compounds (SR)-1 and (RR)-1 were obtained
from a small-scale experiment in 26% yield (52% of theoretical
yield) and 25% yield (50% of theoretical yield), respectively,47
while (RS)-1 (37% of theoretical yield) and (SS)-1 (45% of
theoretical yield) resulted from a medium-scale experiment in
which repeated chromatography was necessary for efficient
and complete separation.
To the same end, peptides based on the more rigid, cyclic, 6-
amino-1,11-(20-crown-6)-6,7-dihydro-5H-dibenzo [a,c]cyclo-
heptene-6-carboxylic acid (Bip[20-C-6]) residue (Fig. 1) were
previously investigated in our groups.34e36 However, we were
unable to prepare this amino acid in an enantiomerically pure
state, because of extensive racemization occurring at several
stages of the synthesis. Therefore, only limited 3D-structural
information on some of its short peptides could be obtained.36
We envisioned that introduction of either a (R)- or a (S)-bi-
naphthyl unit as a part of the crown receptor would not only im-
part extended chiral barriers to the Bip[20-C-6] residue, as an
amino acid analogue of the famous binaphthyl crown-ether se-
ries designed many years ago by Cram and co-workers,43e46
but could also allow access to the resulting diastereomeric
(R)-Bip[(S)-Binol-22-C-6] and (S)-Bip[(S)-Binol-22-C-6] resi-
dues (Fig. 1), as well as their respective enantiomers (S)-
Bip[(R)-Binol-22-C-6] and (R)-Bip[(R)-Binol-22-C-6] (not
shown), in an enantiomerically pure state.47
In this paper, we wish to present our detailed results of the
synthesis of the binaphthyl-crowned, atropisomeric, terminally
protected, Ca-tetrasubstituted a-amino acid isomers Boc-
(S)-Bip[(R)-Binol-22-C-6]-OMe (Boc, tert-butyloxycarbonyl;
OMe, methoxy), Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe, Boc-
(R)-Bip[(S)-Binol-22-C-6]-OMe, and Boc-(S)-Bip[(S)-Binol-
22-C-6]-OMe. The solution synthesis of two series of terminally
protected model peptides to the hexamer level, where the (R)-
Bip[(S)-Binol-22-C-6] residue is placed at the i and iþ3 posi-
tions of the sequence, combined with either L-Ala or L-Ala/Aib
(a-aminoisobutyric acid), and their 3D-structural analysis by
FTIR absorption and NMR are also presented.
This separation represents a resolution of the Bip part of the
molecule after crown formation with access to both configura-
tions in an enantiopure state. This is especially interesting
since, as pointed out above, racemization was shown previ-
ously to be an inherent process during crown formation by
etherification of the di-cesium salt of the enantiomerically
pure Boc-(R)- or (S)-Bip[OH]2-OMe in DMF at 60 ꢁC, to
afford crowned, a-amino esters Boc-(R)-Bip[20-C-6]-OMe
(Fig. 1) with only ca. 64% ee or Boc-(S)-Bip[20-C-6]-OMe
with only ca. 48% ee, respectively.36
The absolute configuration of (RR)-1 was easily assigned by
considering its relationship with the absolute configurations of
the two products resulting from chemical cleavage of the
ArOeR ether bonds. Treatment of the postulated (RR)-1
isomer with a large excess of boron tribromide in dichlorome-
thane,48 followed by re-esterification of the crude product with
thionyl chloride in methanol (Fig. 3), allowed the recovery of
2. Results and discussion
2.1. Synthesis
The two phenolic hydroxy groups of the racemic, Na-pro-
tected, a-amino ester 6-tert-butyloxycarbonylamino-1,11-dihy-
droxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-6-carboxylic
Binol with [a]2D5 þ29 (c 0.84, THF), and of H-Bip[OH]2-OMe
25
with [a]
436
ꢀ93 (c 0.14, MeOH), both of known absolute
configuration (þ)-(R)46 and (ꢀ)-(R),36 respectively. From this

K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
2309
OH
HO
MeO
OMe
O
O
O
O
O
O
O
O
O
(i)
OTs
(ii)
O
O
+
O
O
+
O
O
OTs
Boc
BrH2C CH2Br
N
H
C OMe
O
O
Boc-(R+S)-Bip[OH]2-OMe
(-)-(S)-Binol[O(CH2CH2)2OTs]2
Boc
Boc
N
H
C OMe
O
N
H
C OMe
O
(RS)-1
(SS)-1
Figure 2. Synthesis of Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe (RS)-1 and Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe (SS)-1. (i) Ref. 36; (ii) Cs2CO3; DMF; 60 ꢁC.
of the dihydroxy-substituted binaphthyl and biphenyl moieties
of the products (R)-Binol and (R)-H-Bip[OH]2-OMe, respec-
tively. Indeed, Binol has been reported to be configurationally
stable at 100 ꢁC for 24 h in dioxane/water, but to racemize to
HO OH
O O
an extent of 72% in a 1.2 N HCl solution.46 It is perhaps there-
fore not surprising that Binol racemizes 15%, and that the
more flexible dihydroxy-biphenyl skeleton of H-Bip[OH]2-
OMe racemizes 32% at room temperature under the acidic
conditions required for both ether cleavage and re-esterifica-
tion. To clarify the question of the enantiomeric purity of
the adducts 1, the Na-Boc protecting group of (SS)-1 and
(RS)-1 was cleaved by acidolysis in TFA (trifluoroacetic
acid)/CH2Cl2 and the resulting free amino esters were reacted
with a large excess of the symmetrical anhydrides resulting
from reaction of both (ꢀ)-(S)-MTPA (Mosher’s reagent,49 a-
methoxy-a-trifluoromethyl-a-phenyl-acetic acid) and (þ)-
(R)-MTPA with a half-equivalent of EDC (N-ethyl, N0-[3-di-
methylaminopropyl]-carbodiimide) in acetonitrile. This led
to the pairs of diastereomeric amido esters S(SS)-1, MTPA/
R(SS)-1, MTPA (Fig. 4) and S(RS)-1, MTPA/R(RS)-1, MTPA
(not shown), respectively. These compounds showed distinct
1H NMR signals in CDCl3 solution for the eCOOMe singlet
(see Section 4) and distinct 19F NMR signals in either
CDCl3 or toluene-d8 solution (with a much better signal sepa-
ration in the latter case) for the eCF3 singlet (Fig. 5), allowing
(+)-(R)-Binol
(i)(ii)
O
O
HO OH
O
O
H2N
(-)-(R)-H-Bip[OH]2-OMe
Boc-HN
(RR)-1
COOMe
COOMe
Figure 3. Cleavage of the postulated (RR)-1 isomer to (þ)-(R)-Binol and (ꢀ)-
(R)-H-Bip[OH]2-OMe. (i) BBr3, CH2Cl2, ꢀ10 ꢁC to rt; (ii) MeOH, SOCl2, rt.
result the absolute configuration of its diastereomer (SR)-1 and
those of their enantiomeric pairs(SS)-1 and (RS)-1 were inferred.
It can be observed that as the maximum value reported for
(þ)-(R)-Binol was [a]D25 þ34 (c 1.1, THF)46 and for (ꢀ)-(R)-
25
436
H-Bip[OH]2-OMe was [a]
ꢀ137 (c 0.1, MeOH),36 these
two compounds were obtained by chemical cleavage of
(RR)-1 with only ca. 85% ee and ca. 68% ee, respectively.
However, we believe that this result does not bring into ques-
tion the ee of the starting (RR)-1, expected to be enantiomeri-
cally pure or nearly so, but rather that it reflects a racemization
O O
O O
O O
(i)(ii)
(iii) (-)-(S)-MTPA
or (iii) (+)-(R)-MTPA
or
O
O
O
O
O
O
O
O
O
O
O
O
Ph
MeO
Ph
F3C
Boc-HN
C C HN
F3C O
C C HN
MeO O
COOMe
COOMe
COOMe
(SS)-1
[+ minor (RR)-1]
S(SS)-1,MTPA
[+ minor S(RR)-1,MTPA]
R(SS)-1,MTPA
[+ minor R(RR)-1,MTPA]
Figure 4. Synthesis of the diastereomeric Mosher’s amides S(SS)-1, MTPA and R(SS)-1, MTPA from (SS)-1. (i) TFA/CH2Cl2 1:3, 0 ꢁC to rt; (ii) EDC, CH3CN, rt.

2310
K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
Peptides based on the (R)-Bip[(S)-Binol-22-C-6] residue
combined with either L-Ala (a series) or L-Ala/Aib (b series)
residues, were prepared by stepwise coupling in solution. The
urethane-protected N-carboxyanhydrides (UNCAs),50,51 Fmoc-
L-Ala-NCA (Fmoc, 9-fluorenylmethyloxycarbonyl), and Boc-
Aib-NCA were used for coupling at the Na-terminus of either
Ca-tetrasubstituted a-amino acid residue, (R)-Bip[(S)-Binol-
22-C-6] or Aib, while coupling of H-L-Ala-OMe or H-L-Ala-
peptide ester at the C-terminus of the (R)-Bip[(S)-Binol-22-C-6]
residue was performed by HATU (2-[7-aza-1H-benzotri-
azole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate)52
activation, more efficient in our hands than the EDC/HOAt
(7-aza-1-hydroxy-1,2,3-benzotriazole) method.53
For the (R)-Bip[(S)-Binol-22-C-6]/L-Ala (a) series (Fig. 6),
saponification of (RS)-1 in 1 N NaOH/MeOH (methanol) at
50 ꢁC gave its C-deprotected analogue Boc-(R)-Bip[(S)-Bi-
nol-22-C-6]-OH, which was coupled with HCl$H-L-Ala-OMe
by the HATU method to afford Boc-(R)-Bip[(S)-Binol-22-
C-6]-L-Ala-OMe 2a in 94% yield. This dipeptide was Na-de-
protected in TFA/CH2Cl2 1:3 and the resulting crude
TFA$H-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-OMe was coupled
with Fmoc-L-Ala-NCA in the presence of an excess of DIEA
(N,N,N-diisopropylethylamine) to give the tripeptide Fmoc-L-
Ala-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-OMe 3a in 63% overall
yield. Coupling of Boc-L-Ala-OH at the deprotected Na-termi-
nus of 3a (using Et2NH/CH3CNeCH2Cl2) by the EDC/HOAt
method gave Boc-{L-Ala}2-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-
OMe 4a in 74% overall yield. Coupling of Boc-(R)-Bip[(S)-
Binol-22-C-6]-OH at the deprotected Na-terminus of 4a
(HCl/dioxane/CH2Cl2) by the HATU method furnished
Boc-(R)-Bip[(S)-Binol-22-C-6]-{L-Ala}2-(R)-Bip[(S)-Binol-
22-C-6]-L-Ala-OMe 5a in 62% overall yield, and coupling
of Fmoc-L-Ala-NCA at the deprotected Na-terminus of 5a
(HCl/dioxane/CH2Cl2) afforded the hexapeptide Fmoc-{L-Ala-
(R)-Bip[(S)-Binol-22-C-6]-L-Ala}2-OMe 6a in 61% yield.
The corresponding (R)-Bip[(S)-Binol-22-C-6]/L-Ala/Aib
(b) series (Fig. 7) was prepared in a different way, as we
expected that competitive cyclization of the Na-deprotected
dipeptide TFA$H-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-OMe to
the corresponding 2,5-dioxopiperazine during coupling with
the more hindered Boc-Aib-NCA (as compared to Fmoc-L-
Ala-NCA) could occur, as we had previously observed in sim-
ilar cases.37 The tripeptide 3b was prepared by first coupling
Boc-Aib-NCA with the fully deprotected crude amino acid
TFA$H-(R)-Bip[(S)-Binol-22-C-6]-OH, which gave Boc-Aib-
(R)-Bip[(S)-Binol-22-C-6]-OH 2b in 69% yield, and then
coupling of 2b with HCl$H-L-Ala-OMe by the HATU method,
which afforded Boc-Aib-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-
OMe 3b in 72% yield. In the next step, Fmoc-L-Ala-NCA
was used for coupling at the hindered, Na-deprotected (using
TFA/CH2Cl2) terminus of 3b, which afforded Fmoc-L-Ala-
Aib-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-OMe 4b in 85% overall
yield. Finally, in a similar manner as in the a series, coupling
of Boc-(R)-Bip[(S)-Binol-22-C-6]-OH at the deprotected
Na-terminus of 4b (using Et2NH/CH3CNeCH2Cl2) by the
HATU method furnished Boc-(R)-Bip[(S)-Binol-22-C-6]-L-
Ala-Aib-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-OMe 5b in 61%
Figure 5. 19F NMR spectra of the Mosher’s amido esters S(SS)-1, MTPA (A)
and R(SS)-1, MTPA (B) in toluene-d8 solution, as compared to the spectrum of
an artificial mixture of both solutions of S(SS)-1, MTPA (major) and R(SS)-1,
MTPA (minor) (C).
localization of the corresponding minor isomers and determi-
nation of the diastereomeric excess (de). An average ꢂ95% de
was found for both pairs of isomers S(SS)-1, MTPA/S(RR)-1,
MTPA and R(SS)-1, MTPA/R(RR)-1, MTPA (Fig. 5) as well
as S(RS)-1, MTPA/S(SR)-1, MTPA and R(RS)-1, MTPA/
R(SR)-1, MTPA (not shown), demonstrating the formation of
the adducts (SS)-1 and (RS)-1 in an enantiopure state or nearly
so, taking into account the synthetic nature (<100% ee) of the
MTPA reagents.

K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
2311
O O
O O
O O
O O
O O
O O
O O
O
O
O
O
O
O
O
O
(iii)
(iv)
(v)
(i)
O O
(vi)
(ii)
H
Me
OMe
O
H
Me
H
Me
OMe
O
H
H
Me
H
Me
OMe
O
Me
Boc
N
H
Boc
N
H
C
O
OMe
Fmoc
N
H
C
O
N
H
C
O
N
H
C
O
N
H
Boc
C
O
N
H
N
H
C
O
N
H
C
O
N
H
(RS)-1
2a
3a
4a
O O
O O
O
O
O O
O O
O
O
O
O
O
O
O
O
O
H
O
O
H
O
O
H
(vii)
(vii)
(iv)
O
(viii)
H
H
H
Me
Me
OMe
O
H
Me
Me
OMe
O
Me
Me
Me
C
O
Boc
N
C
O
N
H
C
O
N
H
C
O
N
H
C
O
N
H
N
H
C
N
H
C
O
N
H
C
O
N
H
Fmoc
N
H
C
O
N
H
H
O
5a
6a
Figure 6. Synthesis of peptides based on (R)-Bip[(S)-Binol-22-C-6] combined with L-Ala (a series). (i) 1 N NaOH, MeOH, 50 ꢁC; (ii) HCl$H-L-Ala-OMe, HATU,
DIEA, CH2Cl2/THF; (iii) TFA/CH2Cl2 1:3; (iv) Fmoc-L-Ala-NCA, DIEA, THF; (v) 10% (v/v) Et2NH/CH3CNeCH2Cl2; (vi) Boc-L-Ala-OH, EDC, HOAt, CH2Cl2;
(vii) HCl/dioxanez4 N, CH2Cl2; (viii) Boc-(R)-Bip[(S)-Binol-22-C-6]-OH, HATU, DIEA, CH2Cl2/THF.
overall yield, and coupling of Boc-Aib-NCA at the deprotected
Na-terminus of 5b (using TFA/CH2Cl2) afforded the hexapep-
tide Boc-{Aib-(R)-Bip[(S)-Binol-22-C-6]-L-Ala}2-OMe 6b in
33% overall yield.
groups of extended conformers was also observed. Upon pep-
tide dilution from 10 to 0.1 mM peptide concentration, the spec-
tra change only slightly (not shown), indicating that the
C]O/HeN H-bonding is almost exclusively of the intramo-
lecular type. A comparison of the spectra for the two peptide
series strongly supports the view that the major finding of this
analysis is the rank order propensities of the three a-amino acids
studied to induce strong intramolecular C]O/HeN H-bonds,
and, as a result, to stabilize folded conformers: Aib>(R)-
Bip[(S)Binol-22-C-6]>L-Ala. In particular, the remarkably
higher helicogenic tendency of Aib compared to L-Ala, already
known,22e33 was confirmed by considering the spectral patterns
of peptide 3a versus 3b, and peptide 4a versus 4b. Moreover, if
the spectra of peptides 3a/4a/5a and 3b/4b/5b are
compared, it stands out clearly that more folding is produced
by the incorporation of an N-terminal (R)-Bip[(S)Binol-
22-C-6] residue than an L-Ala residue in the sequence. The
observation that peptide 3a is not folded, as compared with
the partially folded tripeptide with two L-Ala and one Aib resi-
due,55 points to a greater capability to generate turn species for
Aib than for (R)-Bip[(S)Binol-22-C-6].
2.2. Conformational analysis
1
FTIR absorption and H NMR techniques were used to
assess the preferred conformations of the two terminally pro-
tected (R)-Bip[(S)Binol-22-C-6]/L-Ala 2ae6a and (R)-Bip[(S)-
Binol-22-C-6]/L-Ala/Aib 2be5b oligopeptide series at various
concentrations in the structure supporting solvent CDCl3 (pau-
city of material precluded the analysis of compound 6b).
Figure 8 shows the FTIR absorption spectra of the two
peptide series at 1 mM concentration in the conformationally
informative 3530e3200 cmꢀ1 region. An intense band at
3360e3330 cmꢀ1, assigned to the NeH stretching mode of
strongly H-bonded eCONHe groups,54,55 was seen at the level
of the trimer in the b series, but only at the level of the pentamer
in the a series. The bands found in the regions 3462e3424 cmꢀ1
(with a major contribution at 3434e3424 cmꢀ1) and 3520e
3480 cmꢀ1, the latter seen only in the dipeptide carboxylic
acid 2b, were assigned to the NeH stretching mode of free
(solvated) eCONHe groups and the OeH stretching mode
of the eCOOH group,56 respectively. In the longest peptides
of both series, a band of very low intensity centered near
3395(ꢃ5) cmꢀ1 and associated to weakly H-bonded eCONHe
More detailed information on the conformational prefer-
ences of the longest peptides of the two series was derived
from an NMR analysis in CDCl3 solution (1 mM concentration)
despite the complexity of the spectra in the 7.5e6.5 ppm region
due to overlapping of the informative NH proton signals with
those of the (R)-Bip[(S)Binol-22-C-6] aromatic CH protons.

2312
K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
O O
O O
O O
O O
O
O
O
O
O
O
O
O
(i)(ii)
(iii)
(ii)
(v)
(iv)
O
O
O
O
O
O
O
O
Me
Boc
Me
Boc
Me
Me
H
Me
OMe
O
H
Me Me Me
H
Me
OMe
O
Boc
Fmoc
N
H
C
O
OMe
N
C
O
N
H
N
C
O
N
H
C
O
OH
C
O
N
H
N
H
C
O
N
H
C
O
N
H
C
O
N
H
H
H
(RS)-1
2b
3b
4b
O O
O
O
O O
O
O
O
O
O
O
O
O
H
O
O
O
O
H
(vi)
(vii)
(ii)
(iii)
O
O
O
O
O
O
MeMe
H
H
Me
Me
OMe
O
Me
Me
Me
OMe
O
Me
MeMe
Boc
Boc
N
C
O
N
H
C
O
N
C
N
H
C
O
N
H
C
O
N
C
N
H
C
O
N
H
C
O
N
H
N
H
C
N
H
H
O
H
O
H
O
5b
6b
Figure 7. Synthesis of peptides based on (R)-Bip[(S)-Binol-22-C-6] combined with L-Ala and Aib (b series). (i) 1 N NaOH, MeOH, 50 ꢁC; (ii) TFA/CH2Cl2 1:3;
(iii) Boc-Aib-NCA, DIEA, THF; (iv) HCl$H-L-Ala-OMe, HATU, DIEA, CH2Cl2/THF; (v) Fmoc-L-Ala-NCA, DIEA, THF; (vi) 10% (v/v) Et2NH/CH2Cl2; (vii)
Boc-(R)-Bip[(S)-Binol-22-C-6]-OH, HATU, DIEA, CH2Cl2/THF.
As an illustrative example, Figure 9 presents a section of the
ROESY spectrum of peptide 5a in the region where the amide
NH proton signals are found. The urethane NH proton, NH(1),
is known to be remarkably upfield shifted (y5.0 ppm) with
respect to the amide NH protons in this halohydrocarbon solu-
tion.55 All other NH proton resonances were assigned by virtue
of their peak multiplicities and TOCSY/ROESY experiments.
From an inspection of Figure 9 it is evident that a complete
set of cross-peaks of the NH(i)/NH(iþ1) type is exhibited by
the pentapeptide ester, indicative of the onset of an at least
partially developed helical structure.57 We believe that the
type of helix formed would be most probably of the 310-type
in view of the well established conformational tendencies of
short peptides (with less than six residues) rich in Ca-tetrasub-
stituted a-amino acids.22e33
3. Conclusion
In the present study we prepared all isomers Boc-(S)-
Bip[(R)-Binol-22-C-6]-OMe, Boc-(R)-Bip[(R)-Binol-22-C-6]-
A
B
5b
6a
4b
5a
4a
3b
3a
2a
2b
3500
3400
3300
3200
3500
3400
3300
3200
Wavenumbers [cm-1
]
Wavenumbers [cm-1
]
Figure 8. FTIR absorption spectra in the NeH stretching region of the (R)-Bip[(S)Binol-22-C-6]/L-Ala peptide series 2ae6a (A) and the (R)-Bip[(S)Binol-22-C-6]/
L-Ala/Aib series 2be5b (B) in CDCl3 solution (peptide concentration: 1 mM).

K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
2313
4. Experimental
4.1. General experimental information
Melting points were measured on a Mettler apparatus with
a final temperature raise of 3 ꢁC/min or by means of a capillary
tube immersed in an oil bath (Tottoli apparatus, Buchi) and are
¨
uncorrected. 1H NMR and 13C NMR spectra were recorded on
a Bruker WM300 spectrometer operating at 300 MHz and
77 MHz, respectively, the solvent being used as the internal
standard: CDCl3 (1H: d¼7.27 ppm; 13C: d¼77.00 ppm). Split-
ting patterns are abbreviated as follows: (s) singlet, (d) dou-
blet, (t) triplet, (q) quartet, (m) multiplet. Elemental analyses
were performed by the C.N.R.S. Service of Microanalyses in
Gif-sur-Yvette. High resolution mass spectra were performed
by the Service of Mass Spectrometry of the ENS, Paris.
Mass spectra (electrospray mode) were recorded on a
HewlettePackard HP5989MS spectrometer, by Mr. Vincent
Steinmetz (ILV). Analytical TLC and preparative column
chromatography were performed on Kieselgel F 254 and
Kieselgel 60 (0.040e0.063 mm) (Merck), respectively, with
the following eluant systems: 1% MeOHe99% CH2Cl2 (I);
5% MeOHe95% CH2Cl2 (II); 10% MeOHe90% CH2Cl2 (III);
40% cHex (cyclohexane)e60% EtOAc (ethyl acetate) (IV). UV
light (l¼254 nm) allowed visualization of the spots after TLC
runs for all compounds. Except when noted, all starting mate-
rials and solvents were obtained from commercial suppliers
and were used as received. (þ)-(R)-1,10-Bi(2-naphthol) (Binol)
(ꢂ98% ee) and (ꢀ)-(S)-1,10-bi(2-naphthol) (ꢂ98% ee) were
purchased from Fluka. (ꢀ)-(S)-a-Methoxy-a-trifluoromethyl-
a-phenyl-acetic acid (gold label, 99þ%) and (þ)-(R)-a-
methoxy-a-trifluoromethyl-a-phenyl-acetic acid (ee>99%)
were purchased from Aldrich. Fmoc-L-Ala-NCA and Boc-
Aib-NCA were Fluka and Isochem products, respectively.
Figure 9. Section of the ROESY spectrum of the (R)-Bip[(S)Binol-22-C-6]/L-
Ala pentapeptide 5a in CDCl3 solution (peptide concentration: 1 mM) showing
the NH(i)/NH(iþ1) connectivities.
OMe, Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe, and Boc-(S)-
Bip[(S)-Binol-22-C-6]-OMe, of a new, terminally protected,
Ca-tetrasubstituted a-amino acid with only axial chirality,
characterized by a 2,20,6,60-tetrasubstituted biphenyl architec-
ture and a binaphthyl-based crown-ether side chain. The pres-
ence of a binaphthyl unit as chiral selector allowed resolution
of the biphenyl part of the molecule after crown formation to
afford enantiomerically pure adducts, overcoming the racemi-
zation problems previously encountered in the synthesis of the
related Boc-Bip[20-C-6]-OMe series.36
Model peptides to the hexamer level, based on the (R)-
Bip[(S)-Binol-22-C-6] residue combined with either L-Ala or
L-Ala/Aib and introduced at i and iþ3 positions of the se-
quence, were synthesized by solution methods and shown to
preferentially adopt folded secondary structures, as their bi-
naphthyl-crowned analogues derived from Ca-methyl-L-
DOPA.38,39
The Bip[Binol-22-C-6] residue presents interesting features
for future developments. (i) It belongs to the class of Ca-tetra-
substituted a-amino acids, well known for their high tendency
to induce b-bends and 310-helices in peptides.22e33 (ii) Its
crown-ether receptor site is in a totally rigid and controlled
spatial disposition relative to the Ca atom, in contrast with
the previously described flexible1e21 or semi-rigid38,39
crown-carrier a-amino acids. (iii) The crown-ether side chains
of two residues, introduced at positions i and iþ3 of a peptide
sequence, should be located one on top of the other in the
ternary 310-helix, favoring cooperative cation binding.39 (iv)
As pointed out earlier, Bip[Binol-22-C-6] may be considered
as a building block amino acid equivalent of the well known
binaphthyl crown-ether hosts previously designed by Cram
and co-workers.43e46 Here, the chirality of the binaphthyl
unit could function in synergy with the chirality of the peptide
chain in new peptide-based catalysts58,59 for enhanced chiral
recognition properties in enantioselective crown-ether cata-
lyzed reactions.60e65
4.2. 6-tert-Butyloxycarbonylamino-1,11-(Binol-22-crown-6)-
6,7-dihydro-5H-dibenzo[a,c]cycloheptene-6-carboxylic acid
methyl ester: Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe (RR)-1,
Boc-(S)-Bip[(R)-Binol-22-C-6]-OMe (SR)-1, Boc-(S)-Bip[(S)-
Binol-22-C-6]-OMe (SS)-1, and Boc-(R)-Bip[(S)-Binol-22-C-
6]-OMe (RS)-1
A solution of racemic 6-tert-butyloxycarbonylamino-1,11-
dihydroxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-6-car-
boxylic acid methyl ester Boc-(RþS)-Bip[OH]2-OMe36
(0.101 g; 0.25 mmol) and Cs2CO3 (0.099 g; 0.30 mmol) in de-
gassed MeOH (5 mL) was stirred under argon at 45 ꢁC for
15 min, then evaporated to dryness in vacuo. To the residue
was added DMF (5 mL) under an argon stream and the resulting
solution was evaporated under high vacuum at 45 ꢁC to remove
the residual MeOH. Again, DMF (15 mL) was added to the
residue, generating a greenish-orange solution which was
magnetically stirred under argon at 60 ꢁC while a solution of
2,20-bis[5-tosyloxy-3-oxa-1-pentyloxy]-1,10-binaphthyl (þ)-(R)-
Binol[(OCH2CH2)2OTs]2 (0.200 g; 0.27 mmol), prepared from
(þ)-(R)-Binol according to Cram and co-workers,46 in DMF
(5 mL) was added dropwise over a 1 h period. The solution

2314
K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
was stirred at 60 ꢁC overnight and evaporated to dryness under
high vacuum. The residue was dissolved in a mixture of CH2Cl2
(150 mL) and 5% NaHCO3 (100 mL). The decanted CH2Cl2 so-
lution was washed with a 5% NaHCO3 solution (2ꢄ100 mL),
then with H2O (3ꢄ100 mL), dried (MgSO4), filtered, and evap-
orated in vacuo. The crude product (0.200 g) showed two main
spots of close Rf values but well separated in several eluant sys-
tems. It was purified by chromatography on four preparative
TLC plates of silica gel with eluant (I) (five consecutive elu-
tions) to afford 0.052 g (25%) of Boc-(R)-Bip[(R)-Binol-
22-C-6]-OMe (RR)-1 and 0.054 g (26%) of Boc-(S)-Bip[(R)-
Binol-22-C-6]-OMe (SR)-1. In a similar manner, a mixture
of Boc-(RþS)-Bip[OH]2-OMe36 (2.410 g; 6.04 mmol) and
Cs2CO3 (2.340 g; 7.18 mmol) in DMF (150 mL) was treated
with a solution of (ꢀ)-(S)-Binol[(OCH2CH2)2OTs]2 (4.770 g;
6.19 mmol) prepared from (ꢀ)-(S)-Binol,46 in DMF (80 mL)
at 60 ꢁC for 16 h. Extraction as above gave 5.550 g of a brown
foam, which was purified by chromatography on a column of sil-
ica gel (0.040e0.063 mm) with eluant (II). The resulting prod-
uct (4.480 g) was purified by chromatography on a second
column of silica gel (0.020e0.040 mm) with eluant (I), to afford
0.800 g of pure Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe (SS)-1,
0.950 g of pure Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe (RS)-1,
and 0.680 g of a mixture of the two isomers. This mixture was
repeatedly purified by chromatography on preparative TLC
plates of silicagel eluted with eluant (I)(severalconsecutiveelu-
tions) to afford 0.114 g of pure (SS)-1 for a total of 0.914 g(18%)
and 0.171 g of pure (RS)-1 for a total of 1.121 g (23%).
0.1, MeOH) [Note: The experimental absolute values [a]l25
are not the same as for the enantiomer (RR)-1 (vide supra) be-
25
cause of measurement imprecision. Even the sign of [a] is
436
opposite, as compared to (RR)-1, in the sensitive zone close to
zero]. ESIþ MS m/z (relative intensity): 848 (100) [MþNa]þ
Anal. Calcd for C50H51NO10$0.5H2O (834.924): C, 71.92;
H, 6.28; N, 1.68. Found: C, 71.91; H, 6.17; N, 1.36.
4.5. Boc-(S)-Bip[(R)-Binol-22-C-6]-OMe (SR)-1
Amorphous solid, mp 152 ꢁC, Rf 0.14 (I). 1H NMR (CDCl3):
d 8.00 [d, J¼9.0 Hz, 2H, ArH Binol], 7.91 [d, J¼8.0 Hz, 2H,
ArH Binol], 7.42 [d, J¼9.0 Hz, 1H, ArH Binol], 7.41 [d,
J¼8.9 Hz, 1H, ArH Binol], 7.37e7.21 [m, 6H, 4ArH Binol
and 2ArH Bip], 7.15 [d, J¼8.4 Hz, 2H, ArH Binol],
6.87e6.80 [m, 4H, ArH Bip], 4.82 [br s, 1H, NH Bip],
4.22e4.16 [m, 2H, OCH2], 4.00e3.86 [m, 6H, OCH2], 3.75
[s, 3H, OCH3], 3.57e3.33 [m, 8H, OCH2], 3.15 [d,
J¼12.9 Hz, 1H, ArCHA Bip], 2.95 [br s, 2H, ArC0H2 Bip],
2.25 [d, J¼12.9 Hz, 1H, ArCHB Bip], 1.48 [s, 9H, CH3 Boc].
13C NMR (CDCl3): d 173.2 [C]O Bip], 156.4, 156.2, 154.5,
154.0, 153.9 [C]O Boc and CArO], 136.4, 134.2, 129.3,
129.2, 128.3, 128.1, 127.8, 126.2, 125.4, 125.2, 125.0, 123.7,
123.6, 121.9, 121.8, 120.4, 120.3, 115.4, 115.2, 115.1, 111.0,
110.9 [CAr], 80.1 [CeO Boc], 69.6, 69.50, 69.47, 69.2, 67.9,
67.8 [OCH2], 67.7 [Ca Bip], 52.3 [OCH3], 41.5 [ArCH2 Bip],
25
25
37.9 [ArC0H2 Bip], 28.2 [CH3 Boc]. [a]
þ240, [a]
589
578
25
25
25
þ241, [a]
þ284, [a]
þ567, [a]
þ1300 (c 0.1,
546
436
365
MeOH). ESIþ MS m/z (relative intensity): 864 (10) [MþK]þ,
848 (100) [MþNa]þ, 826 (3) [MþH]þ. Anal. Calcd for
C50H51NO10$1.5H2O (852.940): C, 70.40; H, 6.38; N, 1.64.
Found: C, 70.53; H, 6.26; N, 1.64.
4.3. Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe (RR)-1
Amorphous solid, mp 170 ꢁC, Rf 0.18 (I). 1H NMR (CDCl3):
d 7.94 [d, J¼9.0 Hz, 2H, ArH Binol], 7.88 [d, J¼8.2 Hz, 2H,
ArH Binol], 7.53 [d, J¼9.0 Hz, 2H, ArH Binol], 7.35 [m (t-
like), 2H, ArH Binol], 7.27e7.20 [m, 4H, 2ArH Binol and
2ArH Bip], 7.14 [d, J¼8.0 Hz, 2H, ArH Binol], 6.89e6.80
[m, 4H, ArH Bip], 4.77 [br s, 1H, NH Bip], 4.29e4.22 [m,
2H, OCH2], 4.06e3.80 [m, 6H, OCH2], 3.73 [s, 3H, OCH3],
3.60e3.40 [m, 8H, OCH2], 3.14 [d, J¼13.1 Hz, 1H, ArCHA
Bip], 2.91 [br s, 2H, ArC0H2 Bip], 2.21 [d, J¼13.1 Hz, 1H,
ArCHB Bip], 1.45 [s, 9H, CH3 Boc]. 13C NMR (CDCl3):
d 173.1 [C]O Bip], 156.5, 156.3, 154.74, 154.69, 154.5
[C]O Boc and CArO], 136.2, 134.0, 129.6, 129.2, 128.4,
128.2, 127.9, 126.2, 125.5, 125.3, 123.8, 122.2, 122.1, 120.8,
117.2, 117.1, 112.2 [CAr], 80.1 [CeO Boc], 70.6, 70.3, 70.2,
4.6. Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe (RS)-1
Mp, Rf, 1H NMR and 13C NMR (CDCl3): see above (SR)-1.
25
25
25
25
25
[a]
ꢀ236, [a]
ꢀ250, [a]
ꢀ293, [a]
ꢀ586, [a]
589
578
546
436
365
ꢀ1321 (c 0.1, MeOH). ESIþ MS m/z (relative intensity):
848 (100) [MþNa]þ. Anal. Calcd for C50H51NO10$0.5H2O
(834.924): C, 71.92; H, 6.28; N, 1.68. Found: C, 72.14; H,
6.36; N, 1.68.
4.7. Cleavage of (RR)-1 by boron tribromide
To a solution of (RR)-1 (0.045 g; 0.054 mmol) in CH2Cl2
(5 mL) kept under argon atmosphere and cooled to ꢀ10 ꢁC
was added a 1 M solution of BBr3 in CH2Cl2 (1.5 mL;
1.5 mmol). The reaction mixture was stirred at room tempera-
ture for 40 h, cooled to 0 ꢁC, quenched with MeOH (25 mL),
concentrated in vacuo at 30 ꢁC to ca. 15 mL (CH2Cl2 off), and
diluted to ca. 40 mL by addition of MeOH. The solution was
then cooled to 0 ꢁC and SOCl2 (5 mL) was added dropwise.
The reaction mixture was stirred at room temperature for 4
days, and then evaporated in vacuo. To the residue were
successively added ice (ca. 25 mL), H2O (ca. 25 mL), and
EtOAc (ethyl acetate) (ca. 25 mL). The mixture was magneti-
cally stirred and made basic by addition of solid NaHCO3 (by
70.1, 69.9, 68.5 [OCH2], 67.8 [Ca Bip], 52.3 [OCH3], 41.4
25
589
[ArCH2 Bip], 38.0 [ArC0H2 Bip], 28.2 [CH3 Boc]. [a]
25
25
25
25
ꢀ10, [a] ꢀ10, [a] ꢀ14, [a] ꢀ7, [a] þ181 (c 0.1,
578
546
436
365
MeOH). ESIþ MS m/z (relative intensity): 864 (15) [MþK]þ,
848 (100) [MþNa]þ, 826 (3) [MþH]þ. Anal. Calcd for
C50H51NO10$1.5H2O (852.940): C, 70.40; H, 6.38; N, 1.64.
Found: C, 70.75; H, 6.39; N, 1.65.
4.4. Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe (SS)-1
Mp, Rf, 1H NMR and 13C NMR (CDCl3): see above (RR)-1.
25
25
25
25
25
[a] þ10, [a] þ9, [a] þ9, [a] ꢀ4, [a] ꢀ204 (c
589
578
546
436
365

K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
2315
portions). The diluted organic phase (EtOAc, ca. 100 mL) was
decanted, washed with H2O (2ꢄ100 mL), dried (MgSO4), fil-
tered, and evaporated in vacuo. The crude product was purified
by chromatography on a preparative TLC plate of silica gel us-
ing eluant (II) to afford 0.0084 g (54%) of (R)-Binol, pure by
Jz7.3 Hz, 1H] [23 ArH and NHCO], 4.31e4.22 [m, 2H,
OCH2], 4.10e3.83 [m, 6H, OCH2], 3.73 [s (integra-
tionz1.5%), COOCH3 from the S(SS)-1, MTPA isomer (vide
supra)], 3.67 [s (integrationz98.5%), 3H, COOCH3],
3.62e3.40 [m, 8H, OCH2], 3.31 [m, 3H, OCH3 MTPA], 3.09
[d, J¼12.9 Hz, 1H, ArCHA Bip], 3.08 [d, J¼14.0 Hz, 1H,
ArC0HA Bip], 3.01 [d, J¼14.0 Hz, 1H, ArC0HB Bip], 2.40 [d,
J¼12.9 Hz, 1H, ArCHB Bip]. 19F NMR (CDCl3): ꢀ69.2085
[s, CF3], [CF3 from the S(SS)-1, MTPA isomer at ꢀ69.1680
(vide supra) not seen]. For a better separation of the two signals:
19F NMR (toluene-d8): ꢀ68.9857 [s (integrationz1.5%), CF3
from the S(SS)-1, MTPA isomer (vide supra)], ꢀ69.1275 [s
(integrationz98.5%), CF3].
1H NMR and TLC, with [a] þ29 (c 0.84, THF), maximum
25
589
lit.46 [a]2D5 þ34 (c 1.1, THF), and 0.068 g (42%) of (R)-H-Bi-
p[OH]2-OMe, identified by comparison with an authentic sam-
1
25
436
ple,36 pure by H NMR and TLC, with [a]
ꢀ93 (c 0.14,
25
436
MeOH), maximum lit.36 [a] ꢀ137 (c 0.1, MeOH).
4.8. Mosher’s amido ester derivatives of (SS)-1 and (RS)-1
To a solution of (SS)-1 (16.5 mg; 0.020 mmol) in CH2Cl2
(3 mL) cooled to 0 ꢁC was added TFA (1 mL). The solution
was magnetically stirred at 0 ꢁC for 1 h, then at room tempera-
ture for 2 h, and evaporated in vacuo at 25 ꢁC. The residue was
dissolved in CH2Cl2 (100 mL), the solution was successively
washed with 5% aq NaHCO3 (50 mL) and H2O (50 mL), dried
(MgSO4), filtered, and evaporated in vacuo. The resulting crude
amino ester was dissolved in CH2Cl2 (1 mL) and the solution
divided into two portions of ca. 0.5 mL each, to which were,
respectively, added the symmetrical anhydrides previously pre-
pared in situ by stirring at room temperature for 2 h: (a) a solu-
tion of (ꢀ)-(S)-MTPA (24.5 mg; 0.105 mmol) and EDC
(10.0 mg; 0.052 mmol) in CH3CN (1 mL), and (b) a solution
of (þ)-(R)-MTPA (19.5 mg; 0.083 mmol) and EDC (8.0 mg;
0.042 mmol) in CH3CN (1 mL). The solutions were magneti-
cally stirred at room temperature for 48 h, diluted with
CH2Cl2 (100 mL), successively extracted with 0.5 N HCl
(50 mL), H2O (100 mL), 5% NaHCO3 (50 mL), and H2O
(100 mL), dried (MgSO4), filtered, and evaporated in vacuo.
The crude products were purified by chromatography on
preparative TLC plates of silica gel with eluant (I), care being
taken not to exercise a mechanical separation of one of the
diastereomers on top of the other, to afford: (a) the amido ester
In the same manner, to a solution of (RS)-1 (16.5 mg;
0.020 mmol) in CH2Cl2 (3 mL) cooled to 0 ꢁC was added TFA
(1 mL). The solution was treated as above. The resulting crude
amino ester was dissolved in CH2Cl2 (1 mL) and the solution di-
vided into two portions of ca. 0.5 mL each, which were, respec-
tively, added to the symmetrical anhydrides previously prepared
in situ by stirring at room temperature for 2 h: (a) a solution of
(ꢀ)-(S)-MTPA (20.7 mg; 0.088 mmol) and EDC (8.6 mg;
0.045 mmol) in CH3CN (1 mL), and (b) a solution of (þ)-(R)-
MTPA (19.8 mg; 0.084 mmol) and EDC (8.0 mg; 0.04 mmol)
in CH3CN (1 mL). The solutions were magnetically stirred at
room temperature for 48 h, diluted with CH2Cl2 (100 mL),
and extracted as above. The crude products were purified by
chromatography on preparative TLC plates of silica gel with
eluant (I), care being taken not to exercise a mechanical separa-
tion of one of the diastereomers on top of the other, to afford: (a)
the amido ester S(RS)-1, MTPA (6.2 mg; 66%). 1H NMR
(CDCl3): d 7.99 [d, Jz9.0 Hz, 2H], 7.90 [d, Jz8.1 Hz, 2H],
7.56e7.52 [m, 2H], 7.44e7.20 [m, 11H], 7.14e7.08 [m, 3H],
6.87e6.81 [m, 3H], and 6.77 [d, Jz7.3 Hz, 1H] [23 ArH and
NHCO], 4.24e4.12 [m, 2H, OCH2], 4.02e3.81 [m, 6H,
OCH2], 3.73 [s (integrationz2.5%), COOCH3 from the
S(SR)-1, MTPA isomer (vide infra)], 3.67 [s (integra-
tionz97.5%), 3H, COOCH3], 3.61e3.35 [m, 8H, OCH2],
3.31 [m, 3H, OCH3 MTPA], 3.10 [d, J¼12.9 Hz, 1H, ArCHA
Bip], 3.08 [d, Jz14.1 Hz, 1H, ArC0HA Bip], 3.03 [d,
Jz14.1 Hz, 1H, ArC0HB Bip], 2.40 [d, J¼12.9 Hz, 1H, ArCHB
Bip]. 19F NMR (CDCl3): ꢀ69.2355 [s, CF3], [CF3 from the
S(SR)-1, MTPA isomer at ꢀ69.2018 (vide infra) not seen]. For
a better separation of the two signals: 19F NMR (toluene-d8):
ꢀ68.9924 [s (integrationz2.5%), CF3 from the S(SR)-1,
MTPA isomer (vide infra)], ꢀ69.1477 [s (integrationz97.5%),
1
S(SS)-1, MTPA (6.9 mg; 73%). H NMR (CDCl3): d 7.94 [d,
Jz9.0 Hz, 2H], 7.88 [d, Jz8.1 Hz, 2H], 7.65e7.61 [m, 2H],
7.55e7.46 [m, 5H], 7.37e7.32 [m (t-like), 2H], 7.26e7.19
[m, 2H], 7.16e7.11 [m, 3H], 7.08e7.03 [m (t-like), 2H],
6.88e6.82 [m, 4H], and 6.48 [d, Jz7.1 Hz, 1H] [23 ArH and
NHCO], 4.29e4.21 [m, 2H, OCH2], 4.06e3.83 [m, 6H,
OCH2], 3.73 [s (integrationz97.5%), 3H, COOCH3], 3.67 [s
(integrationz2.5%), COOCH3 from the S(RR)-1, MTPA
isomer (vide infra)], 3.61e3.39 [m, 8H, OCH2], 3.45 [m, 3H,
OCH3 MTPA], 3.25 [d, J¼12.9 Hz, 1H, ArCHA Bip], 2.95 [d,
J¼14.0 Hz, 1H, ArC0HA Bip], 2.86 [d, J¼14.1 Hz, 1H, ArC0HB
Bip], 2.32 [d, J¼12.9 Hz, 1H, ArCHB Bip]. 19F NMR (CDCl3):
ꢀ69.1680 [s, CF3], [CF3 from the S(RR)-1, MTPA isomer at
ꢀ69.2085 (vide infra) not seen]. For a better separation of the
two signals: 19F NMR (toluene-d8): ꢀ68.9857 [s (integra-
tionz97.5%), CF3], ꢀ69.1275 [s (integrationz2.5%), CF3
from the S(RR)-1, MTPA isomer (vide infra)]. (b) The amido
ester R(SS)-1, MTPA (6.4 mg; 68%). 1H NMR (CDCl3):
d 7.94 [d, Jz8.9 Hz, 2H], 7.88 [d, Jz8.1 Hz, 2H], 7.55e7.51
[m, 4H], 7.42e7.32 [m, 5H], 7.23e7.08 [m, 7H], 6.92e6.86
[m (t-like), 2H], 6.81 [d, Jz7.1 Hz, 1H], and 6.75 [d,
1
CF3]. (b) The amido ester R(RS)-1, MTPA (5.9 mg; 63%). H
NMR (CDCl3): d 7.99 [d, Jz8.7 Hz, 2H], 7.89 [d, Jz8.1 Hz,
2H], 7.67e7.60 [m, 2H], 7.51e7.45 [m, 3H], 7.41 [d,
Jz9.1 Hz, 2H], 7.34 [m (t-like), Jz7.3 Hz, 2H], 7.24e7.19
[m, 3H], 7.17e7.10 [m, 3H], 6.89e6.80 [m, 4H], and 6.50 [d,
Jz7.3 Hz, 1H] [23 ArH and NHCO], 4.24e4.11 [m, 2H,
OCH2], 4.01e3.79 [m, 6H, OCH2], 3.73 [s (integra-
tionz97.5%), 3H, COOCH3], 3.67 [s (integrationz2.5%),
COOCH3 from the R(SR)-1, MTPA isomer (vide supra)],
3.60e3.31 [m, 8H, OCH2], 3.42 [m, 3H, OCH3 MTPA], 3.26
[d, J¼13.1 Hz, 1H, ArCHA Bip], 2.97 [d, J¼13.9 Hz, 1H,
ArC0HA Bip], 2.86 [d, J¼13.9 Hz, 1H, ArC0HB Bip], 2.32

2316
K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
[d, J¼12.9 Hz, 1H, ArCHB Bip]. 19F NMR (CDCl3): ꢀ69.2018
[s, CF3], [CF3 from the R(SR)-1, MTPA isomer at ꢀ69.2355
(vide supra) not seen]. For a better separation of the two signals:
19F NMR (toluene-d8): ꢀ68.9924 [s (integrationz97.5%),
CF3], ꢀ69.1477 [s (integrationz2.5%), CF3 from the R(SR)-
1, MTPA isomer (vide supra)].
concentrated, then CH2Cl2 was added twice to the residue and
the resulting solution was evaporated in vacuo. The residue
was dissolved in THF (7 mL) and cooled on an ice bath.
DIEA (0.12 mL; 0.70 mmol) and Fmoc-L-Ala-NCA (237 mg;
0.70 mmol) were added. The mixture was stirred at room tem-
perature for 48 h. The mixture was concentrated and the result-
ing residue was taken up in CH2Cl2. The solution was washed
successively with 0.5 N HCl, water, and a saturated NaHCO3 so-
lution, dried over MgSO4, filtered, and evaporated. The residue
was purified by column chromatography (IV) to give 3a
(191 mg; 63%). Amorphous solid, mp 152 ꢁC, Rf 0.32 (IV).
1H NMR (CDCl3): d 7.99 [d, J¼13.8 Hz, 2H, ArH Binol],
7.88 [d, J¼12.1 Hz, 2H, ArH Binol], 7.79e7.01 [m, 17H,
ArH], 6.91e6.70 [m, 5H, ArH], 6.06 [br s, 1H, NH], 5.32 [br
s, 1H, NH], 4.55 [m, 1H, CHa Ala], 4.36 [m, 2H, CH2 Fmoc],
4.21e4.15 [m, 3H, CHa Ala, OCH2], 4.06e3.84 [m, 7H, CH
Fmoc, OCH2], 3.72 [s, 3H, OCH3], 3.47e3.26 [m, 8H,
OCH2], 3.24e2.96 [m, 3H, ArCH2 Bip], 2.27 [d, J¼12.9 Hz,
1H, ArC0H2 Bip], 1.39e1.30 [m, 6H, 2 CH3 Ala]. 13C NMR
(CDCl3): d 173.8, 172.2, 171.2 [C]O], 156.6, 156.3, 154.3,
154.2 [CArO], 143.9, 141.5, 137.3, 136.3, 134.5, 129.6, 129.5,
128.5, 128.4, 128.0, 127.4, 127.3, 126.5, 125.6, 125.6, 125.2,
123.8, 122.7, 121.9, 120.7, 120.6, 120.2, 115.6, 115.4, 111.4,
111.1 [CAr], 69.8, 69.7, 69.7, 69.5, 69.4, 69.1, 68.0, 67.3 [CH2
Fmoc, Ca Bip, OCH2], 52.4 [OCH3], 51.5, 48.5 [Ca Ala], 47.3
[CH Fmoc], 42.2 [ArCH2 Bip], 36.3 [ArC0H2 Bip], 18.1, 17.9
4.9. Boc-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-OMe (2a)
The amino ester (RS)-1 (360 mg; 0.43 mmol) was dissolved
in a mixture of THF (10 mL) and MeOH (7 mL), and water
(3.5 mL) was added. Sodium hydroxide (300 mg) was added,
and the mixture was heated on a 50 ꢁC bath for 16 h. The mix-
ture was allowed to cool, and the organic solvents were removed
under reduced pressure. The resulting mixture was cooled on an
ice bath, and the pH was adjusted to z1 by addition of 1 N HCl.
The mixture was diluted with water and extracted with CH2Cl2
three times. The combined organic extracts were dried over
MgSO4, filtered, and evaporated to give Boc-(R)-Bip[(S)-Bi-
nol-22-C-6]-OH (354 mg; 99%), which was pure by TLC, Rf
0.21 (II), and was not characterized further. This compound
(246 mg; 0.29 mmol) was dissolved in THF (7 mL) and
CH2Cl2
(7 mL),
and
HCl$H-L-Ala-OMe
(121 mg;
0.876 mmol) was added. The mixture was cooled on an ice
bath, and DIEA (0.3 mL) and HATU (165 mg; 0.435 mmol)
were added. The mixture was stirred at room temperature for
16 h. The mixture was concentrated and the resulting residue
was taken up in CH2Cl2. The solution was washed successively
with 0.5 N HCl, water, and a saturated NaHCO3 solution, dried
over MgSO4, filtered, and evaporated. The residue was purified
by column chromatography (IV) to give 2a (246 mg; 94%).
Amorphous solid, mp 148 ꢁC, Rf 0.43 (IV). 1H NMR
(CDCl3): d 7.99 [d, J¼8.8 Hz, 2H, ArH], 7.88 [d, J¼8.1 Hz,
2H, ArH], 7.43e7.11 [m, 10H, ArH], 6.91e6.78 [m, 5H,
ArH, NH], 4.69 [br s, 1H, NH], 4.61 [m, 1H, CHa Ala],
4.23e4.12 [m, 2H, OCH2], 3.99e3.82 [m, 6H, OCH2], 3.77
[s, 3H, OCH3], 3.58e3.35 [m, 8H, OCH2], 3.17 [d,
J¼13.1 Hz, 1H, ArCH2], 2.98e2.94 [br m, 2H, ArCH2 Bip],
2.17 [d, J¼12.9 Hz, 1H, ArC0H2], 1.47 [s, 9H, CH3 Boc],
1.39 [d, 3H, CH3 Ala]. 13C NMR (CDCl3): d 174.6 [C]O],
156.6, 156.3, 154.8, 154.2 [C]O Boc, CArO], 143.7, 136.7,
134.5, 129.5, 129.5, 128.4, 128.0, 126.5, 125.6, 123.8, 121.9,
120.6, 115.5, 115.4, 111.2 [CAr], 81.3 [CO Boc], 69.7, 69.7,
69.4, 69.4, 68.0, 67.9 [Ca Bip, OCH2], 52.5 [OCH3], 50.5 [Ca
Ala], 42.5 [ArCH2 Bip], 39.9 [ArC0H2 Bip], 28.5 [CH3 Boc],
25
25
25
25
[CH3 Ala]. [a]
ꢀ173, [a]
ꢀ183, [a]
ꢀ213, [a]
589
578
546
436
ꢀ430, [a] ꢀ996 (c 0.2, CH2Cl2). ESIþ MS m/z (relative in-
25
365
tensity): 1128 (26) [MþK]þ, 1112 (100) [MþNa]þ. Anal. Calcd
for C66H63N3O12$H2O (1108.204): C, 71.53; H, 5.91; N, 3.79.
Found: C, 71.34; H, 5.88; N, 3.58.
4.11. Boc-L-Ala-L-Ala-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-OMe
(4a)
The tripeptide 3a (144 mg; 0.132 mmol) was dissolved in
CH2Cl2 (5 mL) and diethylamine (1 mL) was added. The mix-
ture was stirred at room temperature for 7 h. The mixture was
concentrated, then CH2Cl2 was added twice to the residue and
the solution was evaporated in vacuo. The resulting residue
was dissolved in CH2Cl2 (7 mL), and Boc-L-Ala-OH (50 mg;
0.264 mmol) was added. The mixture was cooled on an ice
bath, and HOAt (36 mg; 0.264 mmol) and NMM (0.08 mL)
were added. The mixture was stirred for 10 min, and EDC
(76 mg; 0.396 mmol) was added. The mixture was then stirred
at room temperature for 48 h. The mixture was diluted with
CH2Cl2, washed successively with 0.5 N HCl, water, then a sat-
urated NaHCO3 solution, dried over MgSO4, filtered, and evap-
orated. The residue was purified by column chromatography (II)
to give 4a (101 mg; 74%). Amorphous solid, mp 138e141 ꢁC,
Rf 0.30 (II). 1H NMR (CDCl3): d 7.99 [d, J¼8.8 Hz, 2H, ArH Bi-
nol], 7.88 [d, J¼8.1 Hz, 2H, ArH Binol], 7.42e7.04 [m, 10H,
ArH], 6.87e6.80 [m, 4H, ArH], 6.30 [br s, 1H, NH Bip], 4.99
[br s, 1H, NH Ala], 4.52 [m, 1H, CHa Ala], 4.18e4.09 [m,
4H, 2 CHa Ala, OCH2], 3.97e3.79 [m, 6H, OCH2], 3.75 [s,
3H, OCH3], 3.55e3.38 [m, 8H, OCH2], 3.15 [2d, 2H, ArCH2
Bip], 2.98 [d, J¼13.9 Hz, 1H, ArC0H2 Bip], 2.27 [d,
25
25
25
18.1 [CH3 Ala]. [a]
ꢀ187, [a]
ꢀ196, [a]
ꢀ227,
589
578
546
[a] ꢀ454, [a] ꢀ1057 (c 0.2, CH2Cl2). ESIþ MS m/z (rel-
25
25
436
365
ative intensity): 919 (100) [MþNa]þ. Anal. Calcd for
C53H56N2O11$H2O (915.01): C, 69.56; H, 6.39; N, 3.06. Found:
C, 69.19; H, 6.33; N, 3.09.
4.10. Fmoc-L-Ala-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-OMe (3a)
The dipeptide 2a (252 mg; 0.28 mmol) was dissolved in
CH2Cl2 (6 mL) and the solution was cooled on an ice bath.
TFA (1.5 mL) was added. The mixture was kept at 0 ꢁC for
15 min, then at room temperature for 2 h. The mixture was

K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
2317
J¼12.9 Hz, 1H, ArC0H2 Bip], 1.42 [s, 9H, CH3 Boc], 1.37e1.24
[m, 9H, 3 CH3 Ala]. 13C NMR (CDCl3): d 173.9, 173.3, 171.9,
171.4 [C]O], 156.6, 156.3, 154.3, 154.2 [C]O Boc and
CArO], 137.4, 136.3, 134.5, 129.6, 129.5, 129.5, 128.5, 128.3,
128.1, 126.6, 126.5, 125.6, 125.6, 125.2, 123.8, 122.7, 122.1,
120.7, 120.6, 115.6, 115.4, 115.4, 111.4, 111.1 [CAr], 80.6
[CeO Boc], 69.8, 69.7, 69.7, 69.6, 69.5, 69.4, 69.1, 68.0
[OCH2], 66.7 [Ca Bip], 52.5 [OCH3], 50.2, 48.5 [Ca Ala],
42.2 [ArCH2 Bip], 36.1 [ArC0H2 Bip], 28.5 [CH3 Boc], 17.9,
1754.7181. Anal. Calcd for C103H105N5O20$H2O (1750.926):
C, 70.65; H, 6.16; N, 4.00. Found: C, 70.59; H, 6.11; N, 4.21.
4.13. Fmoc-{L-Ala-(R)-Bip[(S)-Binol-22-C-6]-L-Ala}2-OMe
(6a)
The pentapeptide 5a (29 mg; 0.017 mmol) was dissolved in
CH2Cl2 (5 mL) and the solution was cooled on an ice bath. A
solution of HCl in dioxane (appx. 4 N; 0.5 mL) was added.
The mixture was kept at 0 ꢁC for 15 min, then at room temper-
ature for 5 h. The mixture was concentrated, then CH2Cl2 was
added twice to the residue and the solution was evaporated in
vacuo. The residue was dissolved in THF (2 mL) and cooled
on an ice bath. DIEA (0.015 mL) and Fmoc-L-Ala-NCA
(17 mg; 0.05 mmol) were added. The mixture was stirred at
room temperature for 48 h. The mixture was concentrated
and the resulting residue was taken up in CH2Cl2. The solution
was washed successively with 0.5 N HCl, water, then a satu-
rated NaHCO3 solution, dried over MgSO4, filtered, and evap-
orated. The residue was purified by column chromatography
(II) to give 6a (20 mg; 61%). Amorphous solid, mp
25
25
25
17.7, 17.6 [CH3 Ala]. [a] ꢀ287, [a] ꢀ301, [a] ꢀ349,
589
578
546
25
436
25
365
[a] ꢀ683, [a] ꢀ1466 (c 0.23, MeOH). ESIþ MS m/z (rel-
ative intensity): 1061 (100) [MþNa]þ. Anal. Calcd for
C59H66N4O13$H2O (1057.166): C, 67.03; H, 6.48; N, 5.30.
Found: C, 66.61; H, 6.17; N, 4.85.
4.12. Boc-(R)-Bip[(S)-Binol-22-C-6]L-Ala-L-Ala-(R)-Bip[(S)-
Binol-22-C-6]-L-Ala-OMe (5a)
The tetrapeptide 4a (60 mg; 0.058 mmol) was dissolved in
CH2Cl2 (5 mL) and the solution was cooled on an ice bath. A so-
lution of HCl in dioxane (approx. 4 N; 1 mL) was added. The
mixture was kept at 0 ꢁC for 15 min, then at room temperature
for 2 h. The mixture was concentrated, then CH2Cl2 was added
twice to the residue and the solution was evaporated in vacuo.
The residue was dissolved in THF (2 mL) and CH2Cl2 (2 mL),
and Boc-(R)-Bip[(S)-Binol-22-C-6]-OH (50 mg; 0.061 mmol)
was added. The mixture was cooled on an ice bath, and DIEA
(0.06 mL) and HATU (33 mg; 0.087 mmol) were added. The
mixture was stirred at room temperature for 16 h. The mixture
was concentrated and the resulting residue was taken up in
CH2Cl2. The solution was washed successively with 0.5 N
HCl, water, then a saturated NaHCO3 solution, dried over
MgSO4, filtered, and evaporated. The residue was purified by
TLC (II) to give 5a (63 mg; 62%). Amorphous solid, mp
1
169e172 ꢁC, Rf 0.38 (II). H NMR (CDCl3): d 7.99 [d, 4H,
ArH], 7.88 [d, 4H, ArH], 7.73 [m, 2H, ArH], 7.40e7.09 [m,
25H, ArH], 6.95e6.53 [m, 9H, ArH], 6.36 [br s, 1H, NH],
6.05 [br s, 1H, NH], 4.58 [m, 1H, CHa Ala], 4.18 [m, 9H, 3
CHa Ala, CH2 Fmoc, OCH2], 3.94e3.76 [m, 13H, CH
Fmoc, OCH2], 3.70 [s, 3H, OCH3], 3.52e3.24 [m, 16H,
OCH2], 3.04e2.90 [m, 3H, ArCH2 Bip], 2.73 [d, 1H, ArCH2
Bip], 2.56 [d, 2H, ArCH2 Bip], 2.37 [m, 2H, ArCH2 Bip],
25
25
1.44e1.34 [m, 12H, 4 CH3 Ala]. [a]
ꢀ159, [a]
ꢀ166,
589
578
[a] ꢀ194, [a] ꢀ400 (c 0.23, CH2Cl2). ESIþ MS m/z (rel-
25
25
546
436
ative intensity): 986.0 (100) [Mþ2Na]2þ. HR-ESI-TOF MS
m/z calcd for C116H112N6O21Na: 1947.7778; found: 1947.7802.
Anal. Calcd for C116H112N6O21$3H2O (1980.152): C, 70.35;
H, 6.01; N, 4.25. Found: C, 70.24; H, 6.17; N, 4.25.
1
191e194 ꢁC, Rf 0.45 (II). H NMR (CDCl3): d 7.99 [d, 4H,
ArH Binol], 7.89 [d, 4H, ArH Binol], 7.42e7.12 [m, 20H,
ArH], 6.94e6.74 [m, 8H, ArH], 6.59 [br s, 1H, NH], 6.50 [br
s, 1H, NH], 4.95 [br s, 1H, NH], 4.55 [m, 1H, CHa Ala], 4.16
[m, 6H, 2 CHa Ala, OCH2], 3.96e3.76 [m, 12H, OCH2], 3.74
[s, 3H, OCH3], 3.56e3.25 [m, 18H, ArCH2 Bip, OCH2], 3.21
[d, J¼14.6 Hz, 1H, ArCH2 Bip], 3.05 [d, J¼13.8 Hz, 1H,
ArCH2 Bip], 2.76 [2d, 2H, ArCH2 Bip], 2.43 [d, J¼12.9 Hz,
1H, ArCH2 Bip], 2.13 [d, J¼12.5 Hz, 1H, ArCH2 Bip], 1.44
[s, 9H, CH3 Boc], 1.38 [m, 9H, 3 CH3 Ala]. 13C NMR
(CDCl3): d 174.0, 173.1, 172.7, 172.2, 171.7 [C]O], 156.8,
156.4, 156.2, 156.1, 154.3, 154.2, 154.1 [C]O Boc and
CArO], 137.8, 136.8, 134.4, 129.5, 129.4, 128.0, 126.5, 125.6,
123.8, 122.6, 120.6, 120.5, 115.6, 115.5, 115.4, 115.2, 111.4,
111.2, 111.1 [CAr], 81.3 [CeO Boc], 69.7, 69.6, 69.3, 69.1,
68.0 [Ca Bip, OCH2], 52.3 [OCH3], 51.0, 50.9, 48.4 [Ca Ala],
42.4, 42.2, 38.7, 35.8 [ArCH2 Bip], 28.5 [CH3 Boc], 17.7,
4.14. Boc-Aib-(R)-Bip[(S)-Binol-22-C-6]-OH (2b)
The amino ester (RS)-1 (171 mg; 0.207 mmol) was dissolved
in a mixture of THF (6 mL), and MeOH (4 mL) and water
(2 mL) was added. Sodium hydroxide (250 mg) was added,
and the mixturewas heated on a 50 ꢁC bath for 16 h. The mixture
was allowed to cool, and the organic solvents were removed
under reduced pressure. The resulting mixture was cooled on
an ice bath, and the pH was adjusted to z1 with 1 N HCl. The
mixture was diluted with water and extracted with CH2Cl2 three
times. The combined organic extracts were dried over MgSO4,
filtered, and evaporated to give crude Boc-(R)-Bip[(S)-Binol-
22-C-6]-OH. This compound was dissolved in CH2Cl2 (6 mL)
and the solution was cooled on an ice bath. TFA (2 mL) was
added. The mixture was kept at 0 ꢁC for 10 min, then at room
temperature for 3 h. The mixture was concentrated, then
CH2Cl2 was added twice to the residue and the solution was
evaporated in vacuo to give crude TFA$H-(R)-Bip[(S)-Binol-
22-C-6]-OH as a light brown solid, which was not characterized
further. To this compound was added THF (7 mL), and the
mixture was cooled on an ice bath. DIEA (0.1 mL) and
25
25
25
17.2, 16.8 [CH3 Ala]. [a] ꢀ219, [a] ꢀ230, [a] ꢀ268,
589
578
546
ꢀ551, [a]
ꢀ1304 (c 0.27, CH2Cl2). ESIþ MS m/z
25
[a]
436
25
365
(relative intensity): 1755.7 (5) [MþNa]þ, 897.4 (24)
[MþKþNa]2þ, 889.4 (100) [Mþ2Na]2þ. HR-ESI-TOF MS
m/z calcd for
C103H105N5O20Na: 1754.7251; found:

2318
K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
Boc-Aib-NCA (142 mg; 0.62 mmol) were added. The mixture
was kept at 0 ꢁC for 5 min then stirred at 50 ꢁC for 60 h. The
mixture was concentrated and the resulting residue was taken
up in CH2Cl2. The solution was washed with 0.5 N HCl, the
phases separated, and the aqueous phase was extracted twice
with CH2Cl2. The combined organic phases were dried over
MgSO4, filtered, and evaporated. The residue was purified by
column chromatography (II) to give 2b (128 mg; 69%). Amor-
phous solid, mp 229 ꢁC, Rf 0.57 (III). 1H NMR (CDCl3): d 7.99
[d, J¼13.1 Hz, 2H, ArH], 7.88 [d, J¼12.2 Hz, 2H, ArH],
7.43e7.10 [m, 9H, ArH], 6.96e6.79 [m, 5H, ArH Bip], 5.38
[br s, 1H, NH Aib], 4.15e4.11 [m, 2H, OCH2], 3.91e3.74 [m,
6H, OCH2], 3.47e3.39 [m, 8H, OCH2], 3.16 [br d, 1H, ArCHA
Bip], 2.87 [br s, 2H, ArC0H2 Bip], 2.07 [br d, 1H, ArCHB Bip],
1.43e1.31 [m, 15H, 2CH3 Aib, CH3 Boc]. 13C NMR (CDCl3):
d 177.9, 174.6 [C]O], 156.4, 156.0, 155.1, 154.3, 154.2
[C]O Boc and CArO], 139.3, 138.1, 134.4, 129.5, 129.4,
128.1, 126.5, 125.6, 125.2, 123.8, 120.7, 120.6, 115.6, 110.6
[CAr], 80.4 [CeO Boc], 69.6, 69.3 [OCH2], 67.9 [Ca Bip],
4.16. Fmoc-L-Ala-Aib-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-OMe
(4b)
The tripeptide 3b (79 mg; 0.08 mmol) was dissolved in
CH2Cl2 (3 mL) and the solution was cooled on an ice bath.
TFA (0.75 mL) was added. The mixture was kept at 0 ꢁC for
15 min, then at room temperature for 3 h. The mixture was
concentrated, then CH2Cl2 was added twice to the residue and
the solution was evaporated in vacuo. The residue was dissolved
in THF (3 mL) and cooled on an ice bath. DIEA (0.04 mL) and
Fmoc-L-Ala-NCA (81 mg; 0.24 mmol) were added. The
mixture was stirred at room temperature for 72 h. The mixture
was concentrated and the resulting residue was taken up in
CH2Cl2. The solution was washed successively with 0.5 N
HCl, water, then a saturated NaHCO3 solution, dried over
MgSO4, filtered, and evaporated. The residue was purified by
TLC (II) to give 3a (80 mg; 85%). Amorphous solid, mp
1
163e165 ꢁC, Rf 0.43 (II). H NMR (CDCl3): d 7.99 [d, 2H,
ArH], 7.89 [d, 2H, ArH], 7.75 [d, 2H, ArH], 7.61 [m, 2H,
ArH], 7.42e7.11 [m, 14H, ArH], 6.80e6.65 [m, 4H, ArH],
6.45 [br d, 1H, NH], 5.38 [br s, 1H, NH], 4.52 [m, 2H, CHa
Ala], 4.29e4.15 [m, 4H, CH2 Fmoc, OCH2], 3.95e3.76 [m,
7H, CH Fmoc, OCH2], 3.67 [s, 3H, OCH3], 3.49e3.38 [m,
8H, OCH2], 3.22 [d, 1H, ArCH2 Bip], 3.10 [d, 1H, ArCH2
Bip], 3.01 [d, 1H, ArCH2 Bip], 2.35 [d, 1H, ArCH2 Bip],
1.48e1.27 [m, 12H, 2 CH3 Aib, 2 CH3 Ala]. 13C NMR
(CDCl3): d 174.4, 173.1, 172.6, 171.8 [C]O], 156.7, 156.4,
156.0, 154.3, 154.2 [CArO], 144.4, 143.6, 141.5, 141.4, 138.7,
136.5, 134.4, 129.5, 129.5, 129.4, 128.2, 128.0, 128.0, 127.9,
127.8, 127.2, 126.5, 125.8, 125.6, 125.5, 125.4, 125.3, 125.2,
123.8, 123.0, 122.5, 120.7, 120.6, 120.1, 115.6, 115.4, 111.3,
110.7 [CAr], 69.8, 69.7, 69.7, 69.5, 69.4, 69.1, 68.9, 68.0,
67.9, 67.6 [CH2 Fmoc, Ca Bip, OCH2], 57.4 [Ca Aib], 52.1
[OCH3], 51.4, 48.4 [Ca Ala], 47.1 [CH Fmoc], 42.9 [ArCH2
Bip], 34.4 [ArC0H2 Bip], 27.7, 23.1 [CH3 Aib] 17.3, 17.1
57.0 [Ca Aib], 28.5 [CH3 Boc], 26.4, 25.0 [CH3 Aib]. [a]
25
589
25
578
25
546
25
436
25
365
ꢀ138, [a] ꢀ146, [a] ꢀ171, [a] ꢀ364, [a] ꢀ937 (c
0.2, CH2Cl2). ESIþ MS m/z (relative intensity): 941 (29)
[Mþ2Na]þ, 919 (100) [MþNa]þ. Anal. Calcd for
C53H56N2O11$2.5H2O (942.034): C, 67.57; H, 6.52; N, 2.97.
Found: C, 67.64; H, 6.51; N, 2.64.
4.15. Boc-Aib-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-OMe (3b)
The dipeptide 2b (90 mg; 0.1 mmol) was dissolved in THF
(3 mL) and CH2Cl2 (3 mL), and HCl$H-L-Ala-OMe (41 mg;
0.3 mmol) was added. The mixture was cooled on an ice bath,
and DIEA (0.1 mL) and HATU (57 mg; 0.15 mmol) were added.
The mixture was stirred at room temperature for 48 h and then
evaporated. The resulting residue was taken up in CH2Cl2. The
solution was washed successively with 0.5 N HCl, water, then
a saturated NaHCO3 solution, dried over MgSO4, filtered, and
evaporated. The residue was purified by TLC (II) to give 3b
25
25
25
25
[CH3 Ala]. [a]
ꢀ161, [a]
ꢀ170, [a]
ꢀ198, [a]
589
578
546
436
ꢀ409, [a] ꢀ970 (c 0.26, CH2Cl2). ESIþ MS m/z (relative
25
365
(71 mg; 72%). Amorphous solid, mp 157 ꢁC, Rf 0.63 (II). H
intensity): 1198 (100) [MþNa]þ. Anal. Calcd for
C70H70N4O13$2H2O (1211.324): C, 69.40; H, 6.16; N, 4.62.
Found: C, 69.49; H, 5.98; N, 4.65.
1
NMR (CDCl3): d 7.99 [d, 2H, ArH], 7.88 [d, 2H, ArH],
7.60e7.09 [m, 11H, ArH], 6.83e6.78 [m, 3H, ArH Bip], 6.68
[br d, 1H, NH], 6.16 [br s, 1H, NH], 4.85 [br s, 1H, NH], 4.57
[m, 1H, CHa Ala], 4.48e4.11 [m, 2H, OCH2], 4.00e3.79 [m,
6H, OCH2], 3.76 [s, 3H, OCH3], 3.56e3.36 [m, 8H, OCH2],
3.15 [br s, 2H, ArCH2 Bip], 2.87 [d, 1H, ArCH2 Bip], 2.25 [d,
1H, ArCH2 Bip], 1.50e1.43 [m, 18H, CH3 Aib, CH3 Ala, CH3
Boc]. 13C NMR (CDCl3): d 174.4, 172.9, 171.2 [C]O], 156.5,
156.0, 155.3, 154.3, 154.1 [C]O Boc and CArO], 138.6,
136.0, 134.4, 134.4, 129.5, 129.5, 129.4, 128.4, 128.0, 126.5,
126.4, 125.6, 125.1, 123.8, 122.9, 122.5, 120.7, 120.6, 115.6,
115.3, 111.4, 110.7 [CAr], 81.3 [CeO Boc], 69.9, 69.8, 69.6,
69.4, 69.4, 68.5, 68.0 [OCH2, Ca Bip], 57.3 [Ca Aib], 52.2
[OCH3], 48.4 [Ca Ala], 28.4 [CH3 Boc], 27.7, 23.4 [CH3 Aib],
4.17. Boc-(R)-Bip[(S)-Binol-22-C-6]-L-Ala-Aib-(R)-Bip[(S)-
Binol-22-C-6]-L-Ala-OMe (5b)
The tetrapeptide 4b (23 mg; 0.019 mmol) was dissolved in
CH2Cl2 (2 mL) and diethylamine (0.5 mL) was added. The mix-
ture was stirred at room temperature for 5 h. The mixture was
concentrated, then CH2Cl2 was added twice to the residue and
the solution was evaporated in vacuo. The residue was dissolved
in THF (1 mL) and CH2Cl2 (1 mL), and Boc-(R)-Bip[(S)-Binol-
22-C-6]-OH (20 mg; 0.025 mmol) was added. The mixture was
cooled on an ice bath, and DIEA (0.05 mL) and HATU (14 mg,
0.037 mmol) were added. The mixture was stirred at room tem-
perature for 16 h. The mixture was concentrated and the result-
ing residue was taken up in CH2Cl2. The solution was washed
successively with 0.5 N HCl, water, then a saturated NaHCO3
solution, dried over MgSO4, filtered, and evaporated. The
25
25
25
25
17.2 [CH3 Ala]. [a] ꢀ154, [a] ꢀ162, [a] ꢀ190, [a]
589
578
546
436
ꢀ385, [a] ꢀ920 (c 0.23, CH2Cl2). ESIþ MS m/z (relative
25
365
intensity):1020(22) [MþK]þ, 1004(52)[MþNa]þ. Anal.Calcd
for C57H63N3O12$H2O (1000.114): C, 68.45; H, 6.55; N, 4.20.
Found: C, 68.38; H, 6.71; N, 3.91.

K. Wright et al. / Tetrahedron 64 (2008) 2307e2320
2319
1
residue was purified by TLC (II) to give 5b (21 mg; 61%).
4.20. H NMR analysis
Amorphous solid, mp 202e205 ꢁC, Rf 0.43 (II). 1H NMR
(CDCl3): d 7.99 [d, 4H, ArH], 7.88 [d, 4H, ArH], 7.42e7.03
[m, 21H, NH, ArH], 6.86e6.64 [m, 9H, NH, ArH], 5.07 [br s,
1H, NH], 4.53 [m, 1H, CHa Ala], 4.13 [m, 4H, OCH2], 3.93e
3.87 [m, 7H, CHa Ala, OCH2], 3.81e3.62 [m, 6H, OCH2],
3.72 [s, 3H, OCH3], 3.48e3.33 [m, 17H, ArCH2 Bip, OCH2],
3.23e2.98 [m, 4H, ArCH2 Bip], 2.55 [d, 1H, J¼13.7 Hz,
ArCH2 Bip], 2.40 [d, J¼12.7 Hz, 1H, ArCH2 Bip], 2.11 [d,
J¼12.5 Hz, 1H, ArCH2 Bip], 1.51e1.47 [m, 9H, 2CH3 Aib,
The NMR spectra for conformational analysis were re-
corded with a Bruker AM 400 spectrometer. Measurements
were performed in deuteriochloroform (99.96% D, Acros
Organics) with tetramethylsilane as the internal standard.
References and notes
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3. Voyer, N. J. Am. Chem. Soc. 1991, 113, 1818e1821.
CH3 Ala], 1.43 [s, 9H, CH3 Boc], 1.38 [m, 3H, CH3 Ala]. 13
C
NMR (CDCl3): d 175.1, 173.5, 173.1, 172.8, 171.9 [C]O],
156.6, 156.2, 155.9, 154.3, 154.2, 154.1, 153.4 [C]O Boc
and CArO], 136.8, 136.4, 134.4, 129.5, 129.4, 128.3, 128.1,
126.5, 126.4, 125.7, 125.6, 125.5, 123.8, 121.7, 120.8, 120.7,
120.5, 115.8, 115.6, 111.2, 111.1 [CAr], 80.9 [CeO Boc],
69.7, 69.6, 69.5, 69.3, 69.1, 68.9, 68.5, 68.2, 68.1, 68.0, 67.9,
67.8 [Ca Bip, OCH2], 57.4 [Ca Aib], 52.3 [OCH3], 50.8, 48.2
[Ca Ala], 42.8, 41.4, 36.8, 34.3 [ArCH2 Bip], 28.5 [CH3 Boc],
ˆ
4. Voyer, N.; Deschenes, D.; Bernier, J.; Roby, J. J. Chem. Soc., Chem.
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5. Voyer, N.; Lamothe, J. Tetrahedron 1995, 51, 9241e9284.
ˆ
6. Voyer, N.; Roby, J.; Deschenes, D.; Bernier, J. Supramol. Chem. 1995, 5,
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8. Voyer, N.; Guerin, B. Chem. Commun. 1997, 2329e2330.
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25
25
27.6, 23.3 [CH3 Aib] 17.3 [CH3 Ala]. [a] ꢀ184, [a] ꢀ194,
589
578
[a] ꢀ226, [a] ꢀ459, [a] ꢀ1085 (c 0.25, CH2Cl2). ESIþ
25
546
25
436
25
365
10. Meillon, J.-C.; Voyer, N. Angew. Chem. 1997, 109, 1004e1006; Angew.
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MS m/z (relative intensity): 912 (14) [Mþ2K]2þ, 904 (63)
[MþKþNa]2þ, 896 (100) [Mþ2Na]2þ. HR-ESI-TOF MS m/z
calcd for C104H107N5O20Na: 1768.7407; found: 1768.7404.
Anal. Calcd for C104H107N5O20$3H2O (1800.984): C, 69.35; H,
6.32; N, 3.89. Found: C, 69.31; H, 6.31; N, 3.89.
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ˆ ´
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The pentapeptide 5b (9 mg; 0.005 mmol) was dissolved in
CH2Cl2 (1 mL) and the solution was cooled on an ice bath.
TFA (0.3 mL) was added. The mixture was kept at 0 ꢁC for
15 min, then at room temperature for 4 h. The mixture was con-
centrated, then CH2Cl2 was added twice to the residue and the
solution was evaporated in vacuo. To this residue was added
THF (1 mL), and the mixture was cooled on an ice bath. DIEA
(0.05 mL) and Boc-Aib-NCA (15 mg, 0.065 mmol) were added.
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mp 229 ꢁC, Rf 0.59 (II). [Note: 1H NMR and 13C NMR spectra,
optical rotation [a]2l5 measurements, and elemental analysis
were not performed because of the low amount of compound
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[Mþ2Na]2þ. HR-ESI-TOF MS m/z calcd forC108H114N6O21Na:
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