BINOL-based foldamers - Access to oligomers with diverse structural architectures

Article abstract of DOI:10.1021/jo070396y

(Chemical Equation Presented) In this article, we report on the synthesis and conformation of a new family of aromatic oligoamide foldamers based on binaphthol (BINOL) monomers. A series of oligomers with differing chirality of the individual BINOL building blocks and mixed sequences of alternate BINOL and pyridyl building blocks has been synthesized and structurally characterized. NMR and quantum chemical calculations on the basis of ab initio MO theory were performed to obtain insight into the conformational features of these oligomers. It is shown that the combination of these inherently chiral aromatic building blocks provides a novel access to a wide variety of conformationally ordered synthetic oligomers with diverse and dazzling structural architectures distinct from those classically observed.

Full text of DOI:10.1021/jo070396y

BINOL-Based FoldamerssAccess to Oligomers with Diverse
Structural Architectures
Pranjal K. Baruah,† Rajesh Gonnade,‡ P. R. Rajamohanan,*,§ Hans-Jo¨rg Hofmann,*,| and
Gangadhar J. Sanjayan*,†
DiVision of Organic Synthesis, Central Material Characterization DiVision, and Central NMR Facility,
National Chemical Laboratory, Doctor Homi Bhabha Road, Pune 411 008, India, and Institut fu¨r
Biochemie, UniVersita¨t Leipzig, Bru¨derstrasse 34, D-04103 Leipzig, Germany
pr.rajamohanan@ncl.res.in; hofmann@rz.uni-leipzig.de; gj.sanjayan@ncl.res.in
ReceiVed February 27, 2007
In this article, we report on the synthesis and conformation of a new family of aromatic oligoamide
foldamers based on binaphthol (BINOL) monomers. A series of oligomers with differing chirality of the
individual BINOL building blocks and mixed sequences of alternate BINOL and pyridyl building blocks
has been synthesized and structurally characterized. NMR and quantum chemical calculations on the
basis of ab initio MO theory were performed to obtain insight into the conformational features of these
oligomers. It is shown that the combination of these inherently chiral aromatic building blocks provides
a novel access to a wide variety of conformationally ordered synthetic oligomers with diverse and dazzling
structural architectures distinct from those classically observed.
Introduction
design, oligomers containing different residues of independent
conformational preferences were recently suggested. For in-
stance, several groups demonstrated that R,â-hybrid peptides
Foldamers are synthetic oligomers with discrete folding
propensities similar to biopolymers.1,2 In the past decade,
foldamer research has attracted immense attention.1-3 Numerous
examples show that foldamers are well-suited to mimic peptide
structures and that they contribute to a deeper understanding of
the structure and function of biopolymers.3-5 The discovery of
foldamers with biological activity6 and special material proper-
ties7 was of particular importance and increased the activities
to find novel foldamers with diverse backbone structures not
easily achievable by their small molecule counterparts.8
Extensive investigations by several groups led to the genera-
tion of a myriad of such synthetic oligomers with diverse
backbone structures.3-5,9 To extend the repertoire of foldamer
(3) (a) Smith, M. D.; Fleet, G. W. J. J. Peptide Sci. 1999, 5, 425-441.
(b) Kirschenbaum, K.; Zuckerman, R. N.; Dill, D. A. Curr. Opin. Struct.
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S.; Iverson, B. L. Curr. Opin. Chem. Biol. 2001, 5, 650-653. (f) Cheng,
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Martinek, T. A.; Fulop, F. Eur. J. Biochem. 2003, 270, 3657-3666. (i)
Sanford, A. R.; Yamato, K.; Yang, X.; Yuan, L.; Han, Y.; Gong, B. Eur.
J. Biochem. 2004, 271, 1416-1425. (j) Seebach, D.; Beck, A. K.; Bierbaum,
D. J. Chem. BiodiV. 2004, 1, 1111-1239. (k) Huc, I. Eur. J. Org. Chem.
2004, 1, 17-29. (l) Cheng, R. P. Curr. Opin. Struct. Biol. 2004, 14, 512-
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Schepartz, A. Bioorg. Med. Chem. 2005, 13, 11-16. (n) Licini, G.; Prins,
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Li, X.; Yang, D. Chem. Commun. 2006, 32, 3367-3379. (r) Franz, N.;
Kreutzer, G.; Klok, H-A. Synlett 2006, 12, 1793-1815. (s) MacKenzie, K.
R. Chem. ReV. 2006, 106, 1931-1977. (t) Seebach, D.; Hook, D. F.; Gla¨ttli,
A. Biopolymers 2006, 84, 23-37. (u) Davis, J. M.; Tsou, L. K.; Hamilton,
A. D. Chem. Soc. ReV. 2007, 36, 326-334.
* Corresponding authors. Tel.: 91-020-25893153; fax: 91-020-25893153.
† Division of Organic Synthesis, National Chemical Laboratory.
‡ Central Material Characterization Division, National Chemical Laboratory.
§ Central NMR Facility, National Chemical Laboratory.
| Universita¨t Leipzig.
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10.1021/jo070396y CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/12/2007
J. Org. Chem. 2007, 72, 5077-5084
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Baruah et al.
composed of alternately changing R- and â-amino acid con-
stituents showed convincing evidence for the formation of
special helix types.10 We ourselves have recently provided
theoretical insight into the helix formation propensities in
R,â-, R,γ-, and â,γ-hybrid peptides.11 Furthermore, the poten-
tial of using unconventional foldamer building blocks for the
design of protein secondary structure mimics has also been
described.12
In an effort to augment the repertoire of conformational space
available for foldamer design, we recently suggested novel
hybrid foldamers composed of conformationally constrained
R-amino acid/aromatic amino acid building blocks as sub-
units.13,14 The investigation of hybrid foldamers consisting of
intrinsically constrained amino acid residues of independent
conformational preferences resulted in the discovery of a
foldamer that stabilizes a polymeric array of water clusters held
dexterously by the backbone amide groups of the foldamer with
a peculiar architecture.13 It is noteworthy that the exploration
of conformationally ordered synthetic oligomers interacting with
water molecules enables a better understanding of the much
debated issue of water interaction with anti-freeze proteins
(AFPs) and anti-freeze glyco proteins (AFGPs).15 Our hybrid
foldamer strategy involving the use of constrained R-amino acid/
aromatic amino acid-conjugated building blocks as subunits also
revealed a novel Pro-Amb-derived foldamer with periodic γ-turn
motifs, which is extensively stabilized by intramolecular
hydrogen bondings.14
In this article, we report on the synthesis and conformation
of a new family of BINOL-based foldamers. These foldamers
are characterized by the occurrence of inherently chiral BINOL
building blocks in the backbone. It was anticipated that the
introduction of BINOL building blocks of varying chiralities
in the foldamer backbones would lead to a great number of
oligomers with diverse conformations and intriguing structural
architectures.
Results and Discussion
1,1′-Bi(2-naphthols), popularly known as BINOLs, exhibit
the phenomenon of atropisomerism, a type of stereoisomerism
occurring in systems where the rotation around a single bond
is restricted to allow for different stereoisomers.16 The BINOL
building blocks required for the present study were synthesized
in an optically pure form by starting from 3-hydroxy-2-naphthoic
acid in 12 steps. The oligomers 1a-d were then assembled by
a segment doubling strategy as described in Scheme 1. The
racemic BINOL ester 4, obtained by the oxidative coupling of
a methyl ester of 3-hydroxy-2-naphthoic acid 3, was saponified
to furnish the BINOL bis-acid 5, which was subjected to kinetic
resolution using a leucine methyl ester as the base to afford
both R and S antipodes of 5.17 Both R and S antipodes of the
BINOL acid 6 were subjected to a series of transformations
involving Curtius rearrangement as a key step to furnish the
BINOL bis-amines (R)-9 and (S)-9. The oligomers 1 were made
accessible by coupling excess BINOL amines (R)-9/(S)-9 with
the acid chlorides (S)-7/(R)-7 followed by capping the terminal
amines as trifluoroacetamides (Scheme 1).
All efforts to investigate the solid-state conformation of the
trimers 1a-d by X-ray studies did not succeed since diffraction-
quality crystals could not be grown in any of the cases. There-
fore, NMR and quantum chemical studies were performed to
obtain insight into the conformational features of the oligomers.
All oligomers are highly soluble in nonpolar organic solvents
(.100 mM in CDCl3) at ambient temperature. Thus, it can be
concluded that the polar hydrogen-bonding groups of 1a-d are
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BINOL-Based Aromatic Foldamers
SCHEME 1. Synthesis of BINOL-Based 2-D Foldamers 1a-da
a Reagents and conditions: (i) MeOH, H2SO4 (cat.), reflux, 24 h; (ii) Cu(OH)Cl‚TMEDA (cat.), MeOH, reflux, 48 h; (iii) KOH, MeOH, reflux, 2 h; (iv)
leucine methyl ester (resolution); (v) (a) dimethyl sulfate, K2CO3, acetone, reflux, 6 h and (b) KOH, MeOH, reflux, 2 h; (vi) oxalyl chloride, DCM, DMF
(cat.), rt, 2 h; (vii) NaN3, acetone, water, 15 min; (viii) benzene, reflux, 1 h; (ix) NaOH, benzene, water, reflux, 1 h; (x) (R)-9 (4 equiv), triethylamine, DCM;
(xi) TFA, DCC, DCM; and (xii) (S)-9 (4 equiv), triethylamine, DCM.
strongly involved in intramolecular hydrogen bonding, prevent-
Conformational investigations in solution by 2-D NOESY
studies (400 MHz, CDCl3) clearly support the existence of
bifurcated hydrogen-bond arrangements in 1a-d. One of the
most characteristic NOE interactions that can be anticipated for
such a bifurcated hydrogen-bonded network with (S)-5- and (S)-
6-type arrangements18 would be the dipolar coupling between
the aryl NH and the adjacent aryloxy methyls. The analysis of
the 2-D NOESY data (Figure 1) indeed revealed the existence
of such dipolar couplings. Furthermore, the characteristic NOE
1
ing the formation of polymeric aggregates.12 The H NMR
spectra (400 MHz) of all oligomers show well-resolved single
sets of signals in CDCl3 at ambient temperature, which confirm
that these oligomers exist in a single conformation. The signal
assignments were made using a combination of 2-D COSY,
HMBC, HSQC (1H-13C), HSQC (1H-15N), and NOESY NMR
experiments (for details, see the Supporting Information). It
should be mentioned that the pairs of enantiomers of the
oligomers (R)(R)(R)/(S)(S)(S) and (R)(S)(R)/(S)(R)(S) show
identical 1H spectra, suggesting their mirror-image architecture.
(18) Etter, M. C. Acc. Chem. Res. 1990, 23, 120-126.
J. Org. Chem, Vol. 72, No. 14, 2007 5079

Baruah et al.
FIGURE 1. Partial 2-D NOESY spectra of 1b (400 MHz, CDCl3) showing characteristic NOE interactions. The chemical structure with selected
labeled atoms is also shown to facilitate the signal assignments.
FIGURE 3. CD spectra of the oligomers 1a-d (8.019 × 10-4 M,
acetonitrile).
Additional support for the prevalence of intramolecular hydro-
gen bonds came from DMSO-d6 titration studies of 1a and 1d
FIGURE 2. Structural architecture of the oligomers 1a-d obtained
as representative examples (for details, see the Supporting Infor-
mation). All the NH signals appear downfield, suggesting their
involvement in extensive hydrogen-bonding interactions. They
show little shifting when the solutions of 1a and 1d were gra-
dually titrated with DMSO-d6 (∆δ < 0.09 ppm), which confirms
their involvement in strong intramolecular hydrogen bonding.
To obtain insight into the backbone structures of 1a-d,
quantum chemical calculations at the HF/6-31G* level of ab
initio MO theory and the B3LYP/6-31G* level of density
functional theory (DFT) were performed. It is noteworthy that
both approximation levels are reliable enough to describe the
conformational characteristics of peptides and peptide foldam-
ers.21,22
at the HF/6-31G* level of ab initio MO theory. The positioning of the
BINOL enantiomers (R and S) is given along with the compound
number.
interactions between aryl-NH and the adjacent O-aryloxymethyls
strongly suggest their syn orientation, thereby making space for
the (S)-5-type hydrogen-bonded arrangement. This is a common
feature in O-alkoxy arylamines and a prerequisite for the
bifurcated hydrogen bonding19 in (S)-5- and (S)-6-type arrange-
ments.18 A strong support of the perpendicular disposition of
the napthyl rings in BINOLs, as seen in their crystal structure,20
is the characteristic nOes observed between the methoxy and
the peripheral aryl protons of the adjacent napthyl rings.
(19) Sanford, A. R.; Yamato, K.; Yang, X.; Yuan, L.; Han, Y.; Gong,
B. Eur. J. Biochem. 2004, 271, 1416-1425.
(20) Li, X.; Hewgley, J. B.; Mulrooney, C. A.; Yang, J.; Kozlowski, M.
C. J. Org. Chem. 2003, 68, 5500-5511.
Both formalisms, the HF/6-31G* level of ab initio MO theory
and the B3LYP/6-31G* level of DFT, provide the conformers
visualized in Figure 2, in perfect agreement. Their detailed
5080 J. Org. Chem., Vol. 72, No. 14, 2007

BINOL-Based Aromatic Foldamers
SCHEME 2. Synthesis of BINOL Pyridine-Based Hybrid Foldamers 2a,ba
a Reagents and conditions: (i) triethylamine, THF, rt; (ii) NaI, TMSCl, acetonitrile, 2 h and then MeOH reflux, 1 h; and (iii) triethylamine, THF, 50 °C,
4 h.
structural data are given in the Supporting Information. The
calculations validate two sets of intramolecular bifurcated
hydrogen bonds with (S)-5- and (S)-6-type arrangements,18
as evidenced from NMR studies (vide supra). It should be noted
that conformational alternatives of the methoxy groups do not
influence the backbone conformation as long as the intramo-
lecular hydrogen bonds are allowed to be maintained. Obviously,
the bifurcated hydrogen-bonded networks with (S)-5- and (S)-
6-type arrangements18 and the conformationally locked naphthyl
rings restrict the conformational space considerably and fix the
backbone structure of the oligomers, alleviating alternate
conformers. A closer inspection further reveals that the four
oligomer sets are composed of two oligomer subsets with their
non-superimposable mirror-images ((R)(R)(R) vs (S)(S)(S) and
(R)(S)(R) vs (S)(R)(S)); a fact that is clearly vindicated by their
mirror-image circular dichroism (CD) profiles (vide infra).
To obtain insight into the CD signature of these novel
oligomers, we recorded their CD spectra (Figure 3). CD
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Baruah et al.
organic solvents (.100 mM in CDCl3) at ambient temperature,
suggesting the involvement of the pre-organized hydrogen-
bonding groups in intramolecular hydrogen-bonded interactions.
Thus, the formation of polymeric aggregates can again be
excluded.12
The characteristic nOes supporting the bifurcated hydrogen-
bonding arrangement and the perpendicular orientation of the
napthyl rings in BINOLs are clearly visible (for details, see the
Supporting Information). Besides, the strong involvement of all
amide NHs in intramolecular hydrogen bonding is supported
by DMSO-d6 titration studies (for details, see the Supporting
Information).
The structures obtained at the HF/6-31G* and B3LYP/6-31G*
levels are in good agreement. Figure 4 shows that the hybrid
oligomers 2a and 2b have strongly different shapes, although
they only differ in the chirality of the same building block. In
both foldamers, extensive hydrogen-bonding interactions of the
three-centered (S)-4-type are visible, which is a common feature
found in bis-acylated 2,6-aminopyridines.24 In addition to the
(S)-4-type interactions, bifurcated hydrogen-bonding interactions
can also be seen involving the amino pyridine NHs.
FIGURE 4. Structural architecture of the hybrid oligomers 2a (left)
and 2b (right) obtained at the HF/6-31G* level of ab initio MO theory.
The two oligomers consisting of three BINOL building blocks differ
only in the positioning of the BINOL enantiomers (R and S). 2a: [(S)-
(S)(S)] and 2b: [(S)(R)(S)].
Conclusion
spectroscopy is a useful tool to investigate the secondary
structure of peptides and synthetic oligomers.23 The CD spectra
of the BINOL foldamers 1a-d were recorded in acetonitrile at
8.019 × 10-4 M. As expected, mirror-image CD profiles are
clearly evident for the oligomers with opposite chirality. It
should be mentioned that the pairs of enantiomers (R)(R)(R)/
(S)(S)(S) and (R)(S)(R)/(S)(R)(S), respectively, show identical
1H NMR spectra, which further confirms their mirror-image
architecture at the oligomer level.
For a further demonstration of the overwhelming ability of
BINOL foldamer building blocks to breed dazzling structural
architectures, we designed and synthesized the BINOL pyridine-
based hybrid foldamer structures 2a and 2b, which differ only
in their chirality (Scheme 2).
It is shown that aromatic oligoamide foldamers based on
BINOL building blocks are able to form conformationally
ordered structures even in short oligomers. By different
combinations of the enantiomers of the same building block, it
becomes possible to induce controlled changes of the direction
of the oligomeric strands obtaining access to a great number of
diverse structural architectures distinct from those classically
observed. In principle, such an immense conformational diver-
sity could be achieved by all rigid aromatic building blocks,
whose backbones are inherently chiral. Apart from the vast
family of conformationally restricted biaryls,25 spirobiindanols26
and conformationally restricted aryl amides27 might also be
suited for the design of such novel foldamer structures.
Currently, we are working in this direction.
Again, the synthesis was based on the segment doubling
strategy. Reaction of excess mono-boc-2,6-diaminopyridine 1024
with the (S)-BINOL acid chloride (S)-7 gave the bis-boc-
protected diamine 11, which after mono-boc-deprotection with
trimethyl silyl iodide followed by coupling with the BINOL
acid chloride (S)-7 provided the hybrid foldamer 2a, wherein
all three BINOLs are in the S configuration. The hybrid foldamer
2b was made accessible by reacting the mono-boc-protected
amine 12 with BINOL acid chloride (R)-7. Herein, the three
BINOL building blocks have an (S)(R)(S) configuration. Also,
for the oligomers 2a and 2b, single crystals suitable for X-ray
studies could not be obtained. Thus, their conformation was
investigated again on the basis of NMR and quantum chemical
studies.
Experimental Section
N3,N3′-Bis-(R,R)-(2,2′-dimethoxy-3′-(2,2,2-trifluoroacetamido)-
1,1′-binaphthyl-3-yl)-(R)-2,2′-dimethoxy-1,1′-binaphthyl-3,3′-di-
carboxamide 1a. To a solution of 2,2′-dimethoxy-1,1′-binaphthyl-
3,3′-dicarboxylic acid (R)-617,28 (0.52 g, 1.3 mmol, 1 equiv) in dry
DCM (5 mL), oxalyl chloride (0.45 mL, 5.2 mmol, 4 equiv) and a
catalytic amount of DMF were added. The reaction mixture was
stirred for 2 h at room temperature. The solvent was stripped off
under reduced pressure and dried under high vacuum. The resulting
acid chloride was dissolved in dry DCM (3 mL) and slowly added
to a solution of 2,2′-dimethoxy-1,1′-binaphthyl-3,3′-diamine (R)-
929 (1.78 g, 5.2 mmol, 4 equiv) in dry DCM (10 mL) containing
triethylamine (0.9 mL, 6.5 mmol, 5 equiv). The reaction mixture
was stirred at room temperature for 12 h. The solvent was stripped
off under reduced pressure, and a solution of dry DCM (10 mL)
containing trifluoroacetic acid (1.15 mL, 15.5 mmol, 12 equiv) and
dicyclohexylcarbodiimide, DCC (3.20 g, 15.5 mmol, 12 equiv) was
The arguments for the existence of an extensive intramo-
lecular hydrogen-bonding network coming from experimental
studies on the oligomers 1a-d can be repeated for the hybrid
foldamers 2a and 2b. Both are highly soluble in nonpolar
(23) (a) Buffeteau, T.; Ducasse, L.; Poniman, L.; Delsuc, N.; Huc, I.
Chem. Commun. 2006, 2714-2716. (b) Woody, R. W. In Circular
Dichroism Principles and Applications; Nakanishi, K.; Berova, N.; Woody,
R. W., Eds.; VCH Publishers: New York, 1994; Ch. 17. (c) Circular
Dichroism and the Conformational Analysis of Biopolymers; Fasman, G.
D., Ed.; Plenum Publishing: New York, 1996.
(25) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359-1469.
(26) Molteni, V.; Rhodes, D.; Rubins, K.; Hansen, M.; Bushman, F. D.;
Siegel, J. S. J. Med. Chem. 2000, 43, 2031-2039.
(27) Ates, A.; Curran, D. P. J. Am. Chem. Soc. 2001, 123, 5130-5131.
(28) Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S. J. Org.
Chem. 1999, 64, 2264-2271.
(24) Berl, V.; Huc, I.; Khoury, R. G.; Lehn, J.-M. Chem.sEur. J. 2001,
7, 2798-2809.
(29) Hungerhoff, B.; Metz, P. Tetrahedron 1999, 55, 14941-14946.
5082 J. Org. Chem., Vol. 72, No. 14, 2007

BINOL-Based Aromatic Foldamers
added to the residue at 0 °C. After stirring the reaction mixture for
12 h at room temperature, DCU was filtered off, and the solvent
was evaporated under vacuum to afford a crude product, which
was further purified by column chromatography. Yield: 2.13 g
(68.7%); mp 229-231 °C; [R]D ) -124.6 (c ) 1.01, THF); IR
(CHCl3) ν (cm-1): 3396.4, 3305.8, 3018.4, 2935.5, 2856.4, 1726.2,
1699.2, 1664.5, 1529.5, 1350.1, 1309.6, 1215.1, 1002.9; 1H NMR
(400 MHz, CDCl3): δ 10.85 (s, 2H), 9.41 (s, 2H), 9.06 (s, 2H),
8.95 (s, 2H), 8.88 (s, 2H), 8.13 (m, 2H), 7.99 (m, 2H), 7.90 (m,
2H), 7.54 (m, 2H), 7.42 (m, 6H), 7.20 (m, 6H), 7.10 (m, 4H), 3.53
(s, 6H), 3.30 (s, 6H), 3.11 (s, 6H); 13C NMR (100 MHz, CDCl3):
δ 163.6, 155.2, 154.9, 154.5, 154.1, 153.3, 147.2, 146.4, 135.7,
134.6, 131.3, 131.0, 130.3, 130.2, 129.7, 128.9, 128.4, 127.7, 126.6,
126.1, 126.0, 125.9, 125.7, 125.5, 125.4, 125.1, 123.1, 122.6, 119.9,
118.9, 118.8, 117.0, 114.2, 111.3, 62.1, 61.0, 60.7; MALDI-TOF
MS: 1270.3 (M + Na), 1286.4 (M + K); Anal. Calcd for
C72H52F6N4O10: C ) 69.34, H ) 4.20, N ) 4.49; Found: C )
69.09, H ) 4.01, N ) 4.62.
60.9; MALDI-TOF MS: 1270.2 (M + Na); Anal. Calcd for
C72H52F6N4O10: C ) 69.34, H ) 4.20, N ) 4.49; Found: C )
69.29, H ) 4.35, N ) 4.67.
tert-Butyl 6-(3′-(6-(tert-Butyloxycarbonylamino)pyridin-2-yl-
carbamoyl)-(S)-2,2′-dimethoxy-1,1′-binaphthyl-3-carboxamido)-
pyridin-2-ylcarbamate 11. To a solution of 2,2′-dimethoxy-1,1′-
binaphthyl-3,3′-dicarboxylic acid (S)-617,29 (2.5 g, 6.2 mmol, 1
equiv) in dry DCM (15 mL), oxalyl chloride (2.17 mL, 24.9 mmol,
4 equiv) and a catalytic amount of DMF were added. The reaction
mixture was stirred for 2 h at room temperature. The solvent was
stripped off under reduced pressure, and the residue was dried under
high vacuum. The resulting diacid chloride (S)-7 was dissolved in
dry THF (10 mL) and added slowly to a solution of mono-boc-
2,6-diaminopyridine 1024 (2.6 g, 12.4 mmol, 2 equiv) in dry THF
(15 mL) containing triethylamine (2.6 mL, 18.6 mmol, 3 equiv).
After stirring the reaction mixture for 4 h at room temperature, it
was filtered and directly purified by column chromatography.
Yield: 3.49 g (71.6%); mp 285 °C; [R]D ) +186.2 (c ) 0.992,
THF); IR (CHCl3) ν (cm-1): 3423.4, 3330.8, 3018.4, 2979.8,
2937.4, 1730.0, 1672.2, 1585.4, 1504.4, 1454.2, 1303.8, 1215.1,
N3,N3′-Bis-(S,S)-(2,2′-dimethoxy-3′-(2,2,2-trifluoroacetamido)-
1,1′-binaphthyl-3-yl)-(S)-2,2′-dimethoxy-1,1′-binaphthyl-3,3′-di-
carboxamide 1b. Compound 1b was synthesized according to the
procedure described for 1a (Scheme 1). Yield: 2.3 g (74%); mp
223-226 °C; [R]D ) +124.0 (c ) 0.91, THF); IR (CHCl3) ν
(cm-1): 3396.4, 3315.4, 3064.7, 3014.5, 2941.2, 2873.7, 1726.2,
1666.4, 1581.5, 1537.2, 1492.6, 1458.1, 1411.8, 1350.1, 1244.00,
1211.2, 1151.4, 1002.9; 1H NMR (400 MHz, CDCl3): δ 10.84 (s,
2H), 9.40 (s, 2H), 9.05 (s, 2H), 8.94 (s, 2H), 8.87 (s, 2H), 8.12 (m,
2H), 7.99 (m, 2H), 7.89 (m, 2H), 7.54 (m, 2H), 7.42 (m, 6H), 7.2
1
1155.3; H NMR (400 MHz, CDCl3): δ 10.31 (s, 2H), 8.96 (s,
2H), 8.11 (m, 4H), 7.75 (m, 2H), 7.69 (m, 2H), 7.52 (m, 2H), 7.39
(m, 2H), 7.14 (m, 2H), 3.41 (s, 5H), 1.49 (s, 18H); 13C NMR (100
MHz, CDCl3): δ 163.2, 153.2, 152.2, 150.5, 149.8, 140.5, 135.5,
134.5, 130.2, 129.7, 128.9, 126.0, 125.6, 125.3, 125.2, 108.8, 108.0,
80.9, 62.0, 28.1; ESI mass: 785.2 (M + 1), 807.2 (M + Na); Anal.
Calcd for C44H44N6O8: C ) 67.33, H ) 5.65, N ) 10.71; Found:
C ) 67.14, H ) 5.82, N ) 10.69.
(m, 6H), 7.09 (m, 4H), 3.52 (s, 6H), 3.29 (s, 6H), 3.10 (s, 6H); 13
C
tert-Butyl 6-(3′-(6-Aminopyridin-2-ylcarbamoyl)-(S)-2,2′-
dimethoxy-1,1′-binaphthyl-3-carboxamido)pyridine-2-ylcarbam-
ate 12. To a solution of 11 (1.5 g, 1.9 mmol, 1 equiv) and sodium
iodide (0.86 g, 5.7 mmol, 3 equiv) in dry acetonitrile (20 mL), dry
TMSCl (0.37 mL, 2.9 mmol, 1.5 equiv) was slowly added, and the
mixture was stirred for 2 h. The reaction mixture was stripped off
the solvent, and the residue was dissolved in methanol (40 mL)
and heated to reflux for 1 h to decompose the unstable silylated
amine. The solvent was then evaporated under reduced pressure,
and the crude product 12 obtained was dried and used for the next
step without further purification. ESI mass: 685.1 (M + 1).
tert-Butyl 6-(3′-(6-(3′-(6-(3′-(6-(tert-Butyloxycarbonylamino)-
pyridin-2-ylcarbamoyl)-(S)-2,2′-dimethoxy-1,1′-binaphthyl-3-
carboxamido)pyridin-2-ylcarbamoyl)-(S)-2,2 ′-dimethoxy-1,1′-
binaphthyl-3-carboxamido)pyridin-2-ylcarbamoyl)-(S)-2,2′-
dimethoxy-1,1′-binaphthyl-3-carboxamido)pyridine-2-
ylcarbamate 2a. To a solution of 2,2′-dimethoxy-1,1′-binaphthyl-
3,3′-dicarboxylic acid (S)-6 (0.2 g, 0.5 mmol, 1 equiv) in dry DCM
(5 mL), oxalyl chloride (0.17 mL, 2 mmol, 4 equiv) and a catalytic
amount of DMF were added. The reaction mixture was stirred for
2 h at room temperature. The solvent was stripped off under reduced
pressure, and the residue was dried under high vacuum. The
resulting diacid chloride (S)-7 was dissolved in dry THF (5 mL)
and added slowly to a solution of 12 (0.71 g, 1 mmol, 2.1 equiv)
in dry THF (10 mL) containing triethylamine (0.2 mL, 1.5 mmol,
3 equiv) at room temperature. The reaction mixture was warmed
at 50 °C for 4 h, filtered, and directly adsorbed on silica gel and
purified by column chromatography. Yield: 0.59 g (68.4%); mp
>300 °C; [R]D ) -186.1 (c ) 1.3, THF); IR (CHCl3) ν (cm-1):
3421.5, 3334.7, 3018.4, 2979.8, 2939.2, 1730.0, 1681.8, 1583.5,
1504.4, 1454.2, 1305.7, 1217.0, 1153.4; 1H NMR (400 MHz,
CDCl3): δ 10.22 (s, 2H), 10.14 (s, 2H), 10.10 (s, 2H), 8.97 (s,
2H), 8.90 (s, 2H), 8.85 (s, 2H), 8.26 (m, 4H), 8.04 (m, 8H), 7.89
(m, 2H), 7.73 (m, 2H), 7.64 (m, 2H), 7.50 (m, 2H), 7.37 (m, 8H),
7.24 (m, 2H), 7.05 (m, 8H), 3.39 (s, 3H), 3.36 (s, 6H), 1.44 (s, 18
H); 13C NMR (100 MHz, CDCl3): δ 163.0, 153.1, 152.9, 151.9,
150.1, 150.0, 149.4, 140.6, 135.4, 135.2, 134.5, 134.3, 130.1, 130.0,
129.7, 129.6, 128.9, 128.7, 126.1, 125.3, 125.1, 110.8, 110.5, 108.9,
107.9, 80.9, 61.9, 28.0; MALDI-TOF MS: 1758.4 (M + Na),
1774.5 (M + K); Anal. Calcd for C102H86N12O16: C ) 70.58, H )
4.99, N ) 9.68; Found: C ) 70.40, H ) 5.13, N ) 9.46.
NMR (100 MHz, CDCl3): δ 163.6, 155.2, 154.8, 154.5, 154.1,
153.3, 147.2, 146.4, 135.7, 134.6, 131.3, 131.2, 131.0, 130.3, 130.2,
129.7, 128.9, 128.4, 127.7, 126.6, 126.1, 126.0, 125.9, 125.7, 125.5,
125.4, 125.3, 125.1, 123.1, 122.6, 119.9, 118.9, 118.8, 117.0, 114.2,
111.3, 62.1, 61.0, 60.7; MALDI-TOF MS: 1270.3 (M + Na),
1286.2 (M + K); Anal. Calcd for C72H52F6N4O10: C ) 69.34, H
) 4.20, N ) 4.49; Found: C ) 69.13, H ) 4.31, N ) 4.59.
N3,N3′-Bis-(S,S)-(2,2′-dimethoxy-3′-(2,2,2-trifluoroacetamido)-
1,1′-binaphthyl-3-yl)-(R)-2,2′-dimethoxy-1,1′-binaphthyl-3,3′-di-
carboxamide 1c. Compound 1c was synthesized according to the
procedure described for 1a (Scheme 1). Yield: 2.1 g (67.7%); mp
239-241 °C; [R]D ) -43.5 (c ) 1.1, THF); IR (CHCl3) ν (cm-1):
3396.4, 3317.3, 3062.8, 3018.4, 2943.2, 2871.8, 2837.1, 1728.0,
1666.4, 1581.5, 1537.2, 1492.8, 1454.2, 1411.8, 1350.1, 1309.6,
1217.0, 1151.4, 1001.0; 1H NMR (400 MHz, CDCl3): δ 10.69 (s,
2H), 9.40 (s, 2H), 9.03 (s, 2H), 8.97 (s, 2H), 8.90 (s, 2H), 8.10 (m,
2H), 8.00 (m, 2H), 7.92 (m, 2H), 7.47 (m, 6H), 7.36 (m, 2H), 7.24
(m, 4H), 7.18 (m, 4H), 7.10 (m, 2H), 3.55 (s, 6H), 3.32 (s, 6H),
3.22 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 163.7, 155.1, 154.8,
154.4, 154.0, 153.1, 147.4, 146.4, 135.5, 134.5, 131.3, 131.0, 130.9,
130.3, 129.6, 128.7, 128.3, 127.7, 126.6, 126.2, 126.0, 125.9, 125.8,
125.7, 125.4, 125.2, 125.1, 123.2, 122.4, 119.9, 119.1, 118.9, 117.0,
114.1, 111.3, 62.1, 61.0, 60.9; MALDI-TOF MS: 1270.5 (M +
Na), 1286.6 (M + K); Anal. Calcd for C72H52F6N4O10: C ) 69.34,
H ) 4.20, N ) 4.49; Found: C ) 69.57, H ) 4.29, N ) 4.71.
N3,N3′-Bis-(R,R)-(2,2′-dimethoxy-3′-(2,2,2-trifluoroacetamido)-
1,1′-binaphthyl-3-yl)-(S)-2,2′-dimethoxy-1,1′-binaphthyl-3,3′-di-
carboxamide 1d. Compound 1d was synthesized according to the
procedure described for 1a (Scheme 1). Yield: 1.9 g (61.3%); mp
242-244 °C; [R]D ) +40.9 (c ) 1.05, THF); IR (CHCl3) ν (cm-1):
3398.3, 3307.7, 3064.7, 3020.3, 2943.2, 1726.2, 1664.5, 1581.5,
1541.0, 1492.8, 1458.1, 1411.8, 1350.1, 1309.6, 1215.1, 1001.0;
1H NMR (400 MHz, CDCl3): δ 10.69 (s, 2H), 9.39 (s, 2H), 9.02
(s, 2H), 8.95 (s, 2H), 8.89 (s, 2H), 8.08 (m, 2H), 7.98 (m, 2H),
7.90 (m, 2H), 7.44 (m, 6H), 7.34 (m, 2H), 7.20 (m, 8H), 7.09 (m,
2H), 3.54 (s, 6H), 3.31 (s, 6H), 3.21 (s, 6H); 13C NMR (100 MHz,
CDCl3): δ 163.8, 155.2, 154.9, 154.5, 154.1, 153.1, 147.4, 146.4,
135.6, 134.6, 131.4, 131.1, 130.9, 130.4, 130.3, 129.7, 128.7, 128.4,
127.8, 126.7, 126.2, 126.1, 126.0, 125.9, 125.7, 125.5, 125.2, 125.1,
123.2, 122.5, 119.9, 119.2, 118.9, 117.0, 114.2, 111.3, 62.1, 61.1,
J. Org. Chem, Vol. 72, No. 14, 2007 5083

Baruah et al.
tert-Butyl 6-(3′-(6-(3′-(6-(3′-(6-(tert-Butyloxycarbonylamino)-
pyridin-2-ylcarbamoyl)-(S)-2,2′-dimethoxy-1,1′-binaphthyl-3-
carboxamido)pyridin-2-ylcarbamoyl)-(R)-2,2′-dimethoxy-1,1′-
binaphthyl-3-carboxamido)pyridin-2-ylcarbamoyl)-(S)-2,2′-
dimethoxy-1,1′-binaphthyl-3-carboxamido)pyridine-2-
ylcarbamate 2b. Compound 2b was synthesized according to the
procedure described for 2a (Scheme 2). Yield: 0.57 g (66%); mp
>300 °C; [R]D ) +62.3 (c ) 1.02, THF); IR (CHCl3) ν (cm-1):
3334.7, 3020.32, 2983.7, 2941.2, 1730.0, 1677.9, 1583.5, 1504.4,
(m, 2H), 7.89 (m, 6H), 7.64 (m, 2H), 7.53 (m, 4H), 7.45 (m, 4H),
7.39 (m, 2H), 7.31 (m, 6H), 7.03 (m, 6H), 3.36 (s, 6H), 3.32 (s,
6H), 3.27 (s, 6H), 1.36 (s, 18 H); 13C NMR (100 MHz, CDCl3): δ
163.7, 163.4, 153.0, 152.8, 152.7, 152.0, 150.2, 149.9, 140.7, 140.6,
135.7, 135.6, 135.3, 134.6, 133.5, 130.2, 130.1, 130.0, 129.7, 129.5,
128.9, 128.8, 126.6, 126.2, 126.0, 125.5, 125.4, 125.3, 125.2, 110.8,
110.5, 108.9, 108.1, 81.0, 62.1, 62.0, 61.9, 28.0; MALDI-TOF
MS: 1758.5 (M + Na), 1774.6 (M + K); Anal. Calcd for
C
102H86N12O16: C ) 70.58, H ) 4.99, N ) 9.68; Found: C )
1
1454.2, 1303.8, 1215.1, 1155.3; H NMR (400 MHz, CDCl3): δ
10.06 (s, 2H), 10.00 (s, 2H), 9.95 (s, 2H), 8.99 (s, 2H), 8.90 (s,
2H), 8.45 (s, 2H), 8.30 (m, 2H), 8.24 (m, 2H), 8.11 (m, 2H), 8.03
70.64, H ) 5.06, N ) 9.51.
Quantum Chemical Calculations. All calculations were per-
formed employing the program package Gaussian 03.30 Numerical
data and structural details are given in the Supporting Information.
(30) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
revision C.02; Gaussian Inc.: Pittsburgh, PA, 2004.
Acknowledgment. This work was supported, in part, by the
New Idea Fund, CSIR, New Delhi, the International Foundation
for Science, Sweden (IFS Grant F/4193-1), and the Deutsche
Forschungsgemeinschaft (Projects HO 2346/1-3 and SFB 610).
P.K.B. thanks CSIR, New Delhi for a Senior Research Fellow-
ship. We also thank Dr. G. V. M. Sharma (IICT, Hyderabad)
for providing us with the CD spectra.
Supporting Information Available: 1H, 13C, and 2-D NMR
data (2-D NOESY, HMBC, and HSQC); ESI/MALDI mass spectra
of all oligomers; and B3LYP/6-31G* structural data of 1a,c and
2a,b. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070396Y
5084 J. Org. Chem., Vol. 72, No. 14, 2007