Towards peptide versions of Cram's host-guest chemistry: The synthesis of Cα,α-disubstituted glycines with binaphthol-based crowned side-chains

Article abstract of DOI:10.1016/S0040-4039(03)00127-8

Dietherification of the hydroxy groups of various α,α-disubstituted α-amino acids or their precursors, possessing either an achiral frame derived from α-hydroxymethylserine, or a 2,2′,6,6′-tetrasubstituted biphenyl frame with only an axial chirality, or a frame with α-carbon chirality derived from α-methyl-(L)-DOPA, using (R)-2,2′-bis-(5-tosyloxy-3-oxa-1-pentyloxy)-1,1′-binaphthyl as alkylating agent, gave a new series of amino acids bearing binaphthol-based crown-ethers, as building blocks for the construction of short-chain peptide helices with topologically well-localized receptors.

Full text of DOI:10.1016/S0040-4039(03)00127-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1741–1745
Towards peptide versions of Cram’s host–guest chemistry: the
a,a
synthesis of C -disubstituted glycines with binaphthol-based
crowned side-chains
Jean-Paul Mazaleyrat,* Karen Wright, Maria-Vittoria Azzini, Anne Gaucher and Michel Wakselman
SIRCOB, UMR CNRS 8086, Baˆtiment Lavoisier, University of Versailles, F-78000 Versailles, France
Received 18 December 2002; revised 14 January 2003; accepted 14 January 2003
We wish to dedicate this paper to the memory of Donald J. Cram
Abstract—Dietherification of the hydroxy groups of various a,a-disubstituted a-amino acids or their precursors, possessing either
an achiral frame derived from a-hydroxymethylserine, or a 2,2%,6,6%-tetrasubstituted biphenyl frame with only an axial chirality,
or a frame with a-carbon chirality derived from a-methyl-(L)-DOPA, using (R)-2,2%-bis-(5-tosyloxy-3-oxa-1-pentyloxy)-1,1%-
binaphthyl as alkylating agent, gave a new series of amino acids bearing binaphthol-based crown-ethers, as building blocks for
the construction of short-chain peptide helices with topologically well-localized receptors. © 2003 Elsevier Science Ltd. All rights
reserved.
Considering the well-documented high tendency of a-
amino acids disubstituted at their a-carbon to induce
b-bends and a/310-helical secondary structures in
polypeptides,1 we have previously designed crown-car-
rier Ch,h-disubstituted glycines2,3 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
supramolecular devices using peptidic frameworks.4 We
have recently reported the synthesis of crowned amino
acids derived from a-methyl-(L)-DOPA,3 as well as the
synthesis of [20-C-6]-Bip,2 another Ca,a-disubstituted
glycine possessing a 2,2%,6,6%-tetrasubstituted biphenyl
frame with only an axial dissymmetry, related to the
1,1%-binaphthyl-crown-ether series developed by Cram
et al.5,6 In such receptors, the presence of extended
steric and chiral barriers imparted complementary bind-
ing features in host–guest chemistry. In the same view,
Figure 1. Structure of some 2,2%-dihydroxy-1,1%-binaphthyl (Binol)-based crown-carrier Ca,a-disubstituted glycines.
Keywords: binaphthol; crown-ethers; Ca,a-disubstituted glycines; modified a-amino acids.
* Corresponding author. Fax: +33-01-3925-4452; e-mail: jean-paul.mazaleyrat@chimie.uvsq.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00127-8

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J.-P. Mazaleyrat et al. / Tetrahedron Letters 44 (2003) 1741–1745
we have now designed a new series of Ch,h-disubstituted
glycines containing binaphthol-based crown-ether side-
chain receptors (Fig. 1).
Various architectures have been considered, involving
either achiral frames derived from a-hydroxymethylser-
ine (Hms)7,8 and 2-amino-5,6-dihydroxyindan-2-car-
boxylic acid (Aic),9,10 or a cyclic Ac7c frame with only
axial chirality,11 derived from [20-C-6]-Bip,2 or a cyclic
frame with chiral g,g%-carbons, derived from (1S,2S)-
dihydroxy-substituted a-aminocyclopentane carboxylic
acid (Ac5c),12 or an acyclic frame with a-carbon chiral-
ity derived from a-methyl-(L)-DOPA (Mdp).3 In the
present paper, we report our preliminary results on the
synthesis of some of these compounds: [(R)-Binol-22-C-
6]-(R)-Bip, [(R)-Binol-22-C-6]-(S)-Bip, [(R)-Binol-21-C-
6]-Hms and [(R)-Binol-20-C-6]-(L)-Mdp (Fig. 1).
Introduction of a 2,2%-dihydroxy-1,1%-binaphthyl (Binol)
unit on the crown-ether side chains of these different
amino acids may result in several interesting features:
(i) transformation of achiral architectures to chiral ana-
logues as in the case of [(R)-Binol-21-C-6]-Hms com-
pared to [19-C-6]-Hms,8 (ii) presence of supplementary
steric and chiral barriers as in the case of [(R)-Binol-20-
C-6]-(L)-Mdp compared to [18-C-6]-(L)-Mdp,3 which
may allow additive asymmetric interactions with chiral
guests, (iii) possibility of resolution of otherwise scarcely
accessible structures, illustrated here by the synthesis
and the chromatographic separation of the [(R)-Binol-
Figure 3. Synthesis of Boc-[(R)-Binol-21-C-6]-Hms-OH (R)-
5: (i) KH; THF; 70°C; 24 h. (ii) 2N HCl; 60°C; 3 h. (iii)
Boc2O; MeCN; rt; 24 h. (iv) CrO3; aq. H2SO4; acetone; 0°C;
1 h. (v) CH2N2; CH2Cl2/Et2O.
22-C-6]-(R)-Bip
and
[(R)-Binol-22-C-6]-(S)-Bip
diastereomers, resulting in resolution of the [C-6]-Bip
part of the molecule (vide infra) which could not be
obtained in an enantiomerically pure state for the par-
ent [20-C-6]-Bip structure in previous studies,2c and (iv)
opportunity for photophysical studies involving
intramolecular energy transfer13 or intramolecular spin
polarization14 in designed peptides, because of the pres-
ence of the photoactive 1,1%-binaphthyl chromophore.
Access to all these compounds required the initial syn-
thesis of 2,2%-bis(5-tosyloxy-3-oxa-1-pentyloxy)-1,1%-
binaphthyl (+)-(R)-1 which was readily obtained in ca.
60% overall yield from optically pure (+)-(R)-Binol, as
previously described (Fig. 2).15
Figure 4. Synthesis of Boc-[(R)-Binol-20-C-6]-(L)-Mdp-OMe
(RS)-7: (i) Cs2CO3; DMF; 60°C; 20 h.
For the synthesis of the [(R)-Binol-21-C-6]-Hms
residue, we used 2,2%-bis(hydroxymethyl)-1-aza-4-oxas-
pirodecane 216 as a convenient starting material, to
apply a reaction pathway similar to the one reported
very recently in the case of achiral crowned Hms.8
Etherification of the two hydroxymethyl groups of 2
with potassium hydride in THF at 70°C and the ditosy-
late (R)-1 as alkylating agent, in highly diluted condi-
tions, gave (R)-317 (Fig. 3) in 16% yield, which upon
acidolysis followed by N-protection using Boc2O in
acetonitrile,18 gave (R)-417 in 88% yield. Finally, oxida-
tion of (R)-4 with Jones reagent, followed by esterifica-
tion of the resulting crude N-protected amino acid with
diazomethane, gave Boc-[(R)-Binol-21-C-6]-Hms-OMe
(R)-517 in 30% yield (not optimized).
Figure 2. Synthesis of the ditosylate (+)-(R)-1: (i) NaH;
DMF; Cl-(CH2)2-O(CH2)2-OTHP; 70°C; 48 h. (ii) MeOH;
HCl; CH2Cl2; 25°C; 2 h. (iii) TsCl; pyridine; −15°C; 16 h.
The (RS) isomer of the [Binol-20-C-6]-Mdp residue was
also prepared from the terminally protected amino acid
Boc-(L)-Mdp-OMe (S)-6 (Fig. 4).3 Applying similar

J.-P. Mazaleyrat et al. / Tetrahedron Letters 44 (2003) 1741–1745
1743
experimental conditions as those previously reported by
Voyer et al.19a,d and then by us,2,3,20 a DMF solution (ca.
0.05 mol/l) of the dicesium salt of (S)-6 was reacted at
60°C with a DMF solution (ca. 0.1 mol/l) of the ditosylate
(R)-1 (1.1 equiv. mol/mol) which was added dropwise
during a 1 h period. The reaction mixture was stirred at
60°C for 20 h, DMF was evaporated in vacuo and the
crude product was purified by preparative TLC on silica
gel with eluent CH2Cl2/MeOH/AcOH 98:1:1, to afford
Boc-[(R)-Binol-20-C-6]-(L)-Mdp-OMe (RS)-717 in 32%
yield.
The absolute configuration of the diastereomers (RR)-9
and (RS)-9 could be attributed with a reasonable degree
of confidence by considering the optical rotations of both
compounds. Indeed, according to the known (+)-(R)
absolute configuration of the common fragment of both
molecules: (R)-Binol[O-(CH2)2-O(CH2)2-OR]2 (R=H or
Ts), with for example [h]25758=+31 (c 1; THF) for (R)-1,15c
and the previously established (−)-(R)/(+)-(S) absolute
configuration of the Boc-[HO]2-Bip-OMe part, with
[h]24536=−394 (c 0.1; MeOH) for (R)-82c and [h]24356=+403
(c 0.1; MeOH) for (S)-8,2c one would expect a positive
rotation for (RS)-9 and either a negative rotation or a
positive one with a lower absolute value for (RR)-9.
Therefore, theisomerwith[h]24356=−7(c0.1;MeOH)could
be assumed to be (RR)-9 while the other isomer with
[h]24536=+567 (c 0.1; MeOH) was assumed to be (RS)-9.
In the same manner, treatment of racemic methyl 6-tert-
butyloxycarbonylamino - 1,11 - dihydroxy - 6,7 - dihydro-
5H-dibenzo[a,c]cycloheptene-6-carboxylate Boc-[HO]2-
Bip-OMe (R+S)-8 (Fig. 5), previously obtained in five
steps from 2-amino-3-methoxybenzoic acid,2c by the
ditosylate (R)-1 in similar experimental conditions as
above, allowed access to the [Binol-22-C-6]-Bip residue.
This attribution was unambigously confirmed by chem-
ical derivation: cleavage of the ArOꢀR ether bonds of the
postulated (RR)-9 isomer by treatment with a large excess
of boron tribromide in dichloromethane,22 followed by
re-esterification of the crude product with thionyl chloride
inmethanol(Fig. 6), allowedtherecoveryof(+)-(R)-Binol
with [h]2D5=+29 (c 0.84; THF)23 and of H-[HO]2-Bip-OMe
10 with [h]24356=−93 (c 0.14; MeOH),23 corresponding to
the previously established (−)-(R) absolute configura-
tion.2c
Furthermore, the obtained ca. 1:1 mixture of
diastereomers presented close but distinct TLC spots on
silica gel (eluent CH2Cl2/MeOH 99:1) and could be
separated using preparative TLC after several consecutive
elutions, leading to Boc-[(R)-Binol-22-C-6]-(R)-Bip-
OMe (RR)-917 in 25% yield (50% of theoretical yield) and
Boc-[(R)-Binol-22-C-6]-(S)-Bip-OMe (RS)-917 in 26%
yield (52% of theoretical yield).21 Such separation repre-
sents a resolution of the Bip part of the molecule after crown
formation, with access to both of its enantiomers, which
is especially interesting since we have previously observed
that racemization was an inherent process during the
etherification of the dicesium salt of Boc-[HO]2-Bip-OMe
8 in DMF at 60°C, with partly racemized protected amino
esters Boc-[20-C-6]-(R)-Bip-OMe and Boc-[20-C-6]-(S)-
Bip-OMe being respectively obtained from nearly enan-
tiomerically pure (R)-8 and (S)-8.2c
The presently described small-scale synthesis of Ca,a-dis-
ubstituted glycines with binaphthol-based crown-ether
side-chain receptors, is to be extended to other structures
such as [(R)-Binol-20-C-6]-Aic or [(R)-Binol-20-C-6]-
(1S,2S)-Ac5c (Fig. 1). Binaphthol is likely to be intro-
duced as well into crowned (L)-DOPA itself,19 and into
crowned b3-(L)-DOPA20 with, in the latter case, the aim
of favoring stable 314-helical secondary structures in
derived polycrown peptides. The easy access to the (R)
and (S) enantiomers of binaphthol (both commercially
available) will be exploited to prepare a variety of isomers
such as the protected [(S)-Binol-20-C-6]-(L)-Mdp residue
(SS)-7 to be compared with (RS)-7. Larger [Binol-C-8]-
crowned amino acids will also be prepared as interesting
targets for the study of new peptidic pseudorotaxanes
which could result from host–guest complexes between
bis-crown peptides and diammonium ions.19i
Figure 5. Synthesis of the diastereomeric Boc-[(R)-Binol-22-C-
6]-(R)-Bip-OMe (RR)-9 and Boc-[(R)-Binol-22-C-6]-(S)-Bip-
OMe (RS)-9 from racemic Boc-[HO]2-Bip-OMe (R+S)-8: (i)
Cs2CO3; DMF; 60°C; 20 h.
Figure 6. Cleavage of the postulated (RR)-9 isomer to (+)-(R)-
Binol and H-[HO]2-Bip-OMe (−)-(R)-10: (i) BBr3; CH2Cl2;
−10°C to rt; 48 h. (ii) MeOH; SOCl2; rt; 1 week.

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J.-P. Mazaleyrat et al. / Tetrahedron Letters 44 (2003) 1741–1745
As the feasibility of solution synthesis of peptides based
on crowned Ca,a-disubstituted glycines has previously
been evaluated,2c,3 there seems to be no obstacle to the
6. For a review on molecular recognition, asymmetric catal-
ysis and new materials involving 1,1%-binaphthyl dimers,
oligomers and polymers, see: Pu, L. Chem. Rev. 1998, 98,
2405–2494.
construction of
a variety of binaphthol-crowned
derived polypeptides, in which 310-helical secondary
structures should be favored in principle, even in the
case of short-chain oligomers. In such molecules, the
crown-ether receptors should be in a topologically well-
defined and predictable spatial situation relative to the
helical main chain in the case of the a,a-cyclic frames
present in Bip (i.e. 9), Hms (i.e. 5), Aic or Ac5c, while
more flexibility is expected for the a,a-acyclic frame
present in Mdp derivatives (i.e. 7).
7. For the synthesis of Hms, see: (a) O’Connor, M. J.;
Brush, J. R.; Theo, S.-B. Aust. J. Chem. 1977, 30, 683–
684; (b) Stasiak, M.; Wolf, W. M.; Leplawy, M. T. J.
Pept. Sci. 1998, 4, 46–57. For the conformational analysis
of Hms(Ipr) homooligomers, see: (c) Wolf, W. M.;
Stasiak, M.; Leplawy, M. T.; Bianco, A.; Formaggio, F.;
Crisma, M.; Toniolo, C. J. Am. Chem. Soc. 1998, 120,
11558–11566.
8. For the synthesis of achiral crowned Hms, see:
Be˘lohradsky´, M.; C´ısarˇova´, I.; Holy´, P.; Pastor, J.;
Za´vada, J. Tetrahedron 2002, 58, 8811–8823.
Altogether, as pointed out earlier, the presence of a
binaphthyl unit in the crown-ether moiety of these
9. Aic: 2-aminoindan-2-carboxylic acid.
C
a,a-disubstituted glycines makes them amino acid
10. For the synthesis of achiral crowned Aic, see: Kotha, S.;
Brahmachary, E. Indian J. Chem. 2001, 40B, 1–4.
11. For the conformational analysis of peptides based on the
Ac7c residues Bip and Bin possessing only an axial chiral-
ity, see: (a) Formaggio, F.; Crisma, M.; Toniolo, C.;
Tchertanov, L.; Guilhem, J.; Mazaleyrat, J. P.; Gaucher,
A.; Wakselman, M. Tetrahedron 2000, 56, 8721–8734; (b)
Formaggio, F.; Peggion, C.; Crisma, M.; Toniolo, C.;
Tchertanov, L.; Guilhem, J.; Mazaleyrat, J. P.; Goubard,
Y.; Gaucher, A.; Wakselman, M. Helv. Chim. Acta 2001,
84, 481–501.
analogs of the very famous binaphthyl crown-ether
series previously designed by Cram5 in order to impart
structural chiral recognition properties to hosts. Here,
hopefully, the chirality of the binaphthyl unit could
function in synergy with the chirality of the peptidic
chain in new crown or poly-crown catalysts with
enhanced chiral recognition properties.6 Finally, the
binaphthyl unit is subject to structural modifications,
especially at the 3,3%-, 4,4%- and 7,7%-positions,5d,24 which
might be of interest for introducing extra functionalities
in view of designed peptidic supramolecular devices.25
12. For the conformational analysis of Ac5c homooligomers,
see: Toniolo, C.; Benedetti, E. Macromolecules 1991, 24,
4004–4009.
13. Toniolo, C.; Formaggio, F.; Crisma, M.; Mazaleyrat, J.
P.; Wakselman, M.; George, C.; Deschamps, J. R.; Flip-
pen-Anderson, J. L.; Pispisa, B.; Venanzi, M.; Palleschi,
A. Chem. Eur. J. 1999, 5, 2254–2264.
14. Corvaja, C.; Sartori, E.; Toffoletti, A.; Formaggio, F.;
Crisma, M.; Toniolo, C.; Mazaleyrat, J. P.; Wakselman,
M. Chem. Eur. J. 2000, 6, 2775–2782.
15. (a) Helgeson, R. C.; Timko, J. M.; Moreau, P.; Peacock,
S. C.; Mayer, J. M.; Cram, D. J. J. Am. Chem. Soc. 1974,
96, 6762–6763; (b) Kyba, E. P.; Helgeson, R. C.; Madan,
K.; Gokel, G. W.; Tarnowski, T. L.; Moore, S. S.; Cram,
D. J. J. Am. Chem. Soc. 1977, 99, 2564–2571; (c) Kyba,
E. P.; Gokel, G. W.; de Jong, F.; Koga, K.; Sousa, L. R.;
Siegel, M. G.; Kaplan, L.; Sogah, G. D. Y.; Cram, D. J.
J. Org. Chem. 1977, 42, 4173–4184.
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25
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MeOH)2c for (−)-(R)-10, these compounds were presently
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ca. 85% and ca. 68% ee, respectively. However, this result
does not question the enantiomeric purity of the starting
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