Synthesis and hydrogen bonding capabilities of biphenyl-based amino acids designed to nucleate β-sheet structure

Article abstract of DOI:10.1021/jo952194k

The syntheses of 3′-(aminoethyl)-2-biphenylpropionic acid (1) and 2-amino-3′-biphenylcarboxylic acid (2) are described. These residues were designed to nucleate β-sheet structure in aqueous solution when incorporated into small, amphiphilic peptides in place of the backbone of the i + 1 and i + 2 residues of the β-turn. N-Benzyl-3′-(2-(benzylamido)ethyl)-2-biphenylpropamide (3) and N-benzyl-(2-benzylamido)-3′-biphenylamide (4) were synthesized and studied as model compounds to investigate the hydrogen-bonding capabilities of residues 1 and 2, respectively. The X-ray crystal structure of 3 indicates that a 13-membered intramolecular hydrogen-bonded ring is formed, while the remaining amide proton and carbonyl are involved in intermolecular hydrogen bonding. Infrared and variable-temperature NMR experiments indicate that, in solution (CH₂Cl₂), 3 exists as an equilibrium mixture of the 13- and the 15-membered intramolecularly hydrogen-bonded conformers with the 15-membered ring conformer being favored. Amide 4 was shown to exist in solution (CH₂Cl₂) as an equilibrium mixture of the 11-membered intramolecular hydrogen-bonded ring and a nonbonded conformation. No contribution from the 9-membered hydrogen-bonded ring conformation was observed. The X-ray crystal structure of 4 indicated the absence of intramolecular hydrogen bonding in the solid state.

Full text of DOI:10.1021/jo952194k

J . Org. Chem. 1996, 61, 3127-3137
3127
Syn th esis a n d Hyd r ogen Bon d in g Ca p a bilities of Bip h en yl-Ba sed
Am in o Acid s Design ed To Nu clea te â-Sh eet Str u ctu r e
Carey L. Nesloney and J effery W. Kelly*
Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255
Received December 11, 1995X
The syntheses of 3′-(aminoethyl)-2-biphenylpropionic acid (1) and 2-amino-3′-biphenylcarboxylic
acid (2) are described. These residues were designed to nucleate â-sheet structure in aqueous
solution when incorporated into small, amphiphilic peptides in place of the backbone of the i + 1
and i + 2 residues of the â-turn. N-Benzyl-3′-(2-(benzylamido)ethyl)-2-biphenylpropamide (3) and
N-benzyl-(2-benzylamido)-3′-biphenylamide (4) were synthesized and studied as model compounds
to investigate the hydrogen-bonding capabilities of residues 1 and 2, respectively. The X-ray crystal
structure of 3 indicates that a 13-membered intramolecular hydrogen-bonded ring is formed, while
the remaining amide proton and carbonyl are involved in intermolecular hydrogen bonding. Infrared
and variable-temperature NMR experiments indicate that, in solution (CH2Cl2), 3 exists as an
equilibrium mixture of the 13- and the 15-membered intramolecularly hydrogen-bonded conformers
with the 15-membered ring conformer being favored. Amide 4 was shown to exist in solution
(CH2Cl2) as an equilibrium mixture of the 11-membered intramolecular hydrogen-bonded ring and
a nonbonded conformation. No contribution from the 9-membered hydrogen-bonded ring conforma-
tion was observed. The X-ray crystal structure of 4 indicated the absence of intramolecular hydrogen
bonding in the solid state.
In tr od u ction
copolymers have enhanced our understanding of â-sheet
structure, the approach is limited because of competitive
intra- and intermolecular folding which leads to hetero-
geneous aggregated â-sheet structures.18-27 Small hy-
drophobic or amphiphilic peptides are also poor model
systems as they too usually form self-associated â-sheet
structures.10,11,28-36 The ability to prepare a monomeric
â-hairpin structure, where a â-turn reverses the polypep-
tide chain direction allowing two strands to interact with
one another in an antiparallel orientation, would be
advantageous. In principle, this could be accomplished
using a consensus â-turn sequence combined with flank-
ing strand sequences that have a high â-sheet propensity.
The mechanisms of â-sheet folding are under investi-
gation in several laboratories using a variety of ap-
proaches.1-13 While â-sheet structure is commonly ob-
served in proteins, our understanding of this structural
motif is poor relative to what is known about R-helical
secondary structure. This is due, in part, to the difficul-
ties inherent in creating a well-defined peptide model
system for the study of â-sheet formation in aqueous
solution.14-17 Although studies on the conformational
propensities of amino acid homopolymers and sequential
* To whom correspondence should be addressed. E-mail address:
kelly@chemvx.tamu.edu. Fax: (409) 845-9452.
X Abstract published in Advance ACS Abstracts, April 15, 1996.
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S0022-3263(95)02194-3 CCC: $12.00 © 1996 American Chemical Society

3128 J . Org. Chem., Vol. 61, No. 9, 1996
Nesloney and Kelly
F igu r e 1. Structures of biphenyl-based amino acids 3′-(2-
aminoethyl)-2-biphenylpropionic acid (1) and 2-amino-3′-bi-
phenylcarboxylic acid (2).
However, the conformational propensities of known
â-turn sequences do not appear to be sufficient to effect
â-hairpin folding given what is currently known about
the process.2,37-40 In an effort to develop a reliable
strategy to achieve â-sheet folding, we have developed
unnatural amino acids which nucleate folding when
incorporated into an appropriate R-amino acid sequence.
The concept of utilizing a conformationally defined
template to increase the stability of a given conformation
in a predominantly R-amino acid sequence was pioneered
by Hirschmann and his colleagues.41-44 The utility of
Cu(II) binding bipyridine-based amino acids and a diben-
zofuran-based amino acid that employs a hydrogen-
bonded hydrophobic cluster to facilitate â-hairpin folding
in peptides in aqueous solution has been previously
demonstrated by our group.8,45-47
F igu r e 2. Molecular Graphics representation70 of -Leu-1-
Val- demonstrating the hydrophobic cluster conformation in
which the ethyl side chains of 1 are perpendicular to the
aromatic rings and hydrophobic interactions between one ring
and the leucine side chain are present. The structure repre-
sents the lowest energy conformation predicted by molecular
mechanics/molecular dynamics of the peptide H3N-VOL-1-
VOL-C(O)NH2 in aqueous solution: (a) side view; (b) top view.
Here, we present the syntheses of two 2,3′-substituted
biphenyl-based amino acids, 3′-(aminoethyl)-2-biphenyl-
propionic acid (1) and 2-amino-3′-biphenylcarboxylic acid
(2) (Figure 1), which are potential â-sheet nucleators. The
biphenyl skeleton was chosen based on the 4.8 Å distance
between C2 and C3′ which is very similar to the distance
separating two strands of an antiparallel â-sheet (4.85
Å).48,49 Amino acids 1 and 2 were designed to replace
the backbone of the i + 1 and i + 2 residues of a â-turn.
It should be noted that 1 and 2 do not actually mimic a
specific â-turn type. Instead, these residues are meant
to resemble a â-turn only in that they were designed to
reverse the polypeptide chain direction by promoting
intramolecular hydrogen bonding between the flanking
R-amino acid residues. Simple diamide derivatives of 1
and 2 were prepared and studied by variable temperature
1H NMR and FT-IR in an effort to evaluate the hydrogen-
bonding capabilities of the 2,3′-substituted biphenyl-
based amino acid residues. X-ray crystal structures of
these amides (3 and 4) provided additional insight into
the potential abilities of 1 and 2 to serve as templates
for â-sheet nucleation.
Molecular modeling suggests that both amino acids are
expected to have a dihedral angle between the two phenyl
rings of approximately 120° in order to avoid eclipsing
of the ortho substituents. The 2,3′-substituted biphenyl-
based residues 1 and 2 differ in that -CH2CH2- frag-
ments were incorporated into 1 to allow a potentially
favorable hydrophobic interaction to occur between one
or both of the biphenyl rings and the hydrophobic side
chains of the flanking R-amino acid residues, which is
not possible in residue 2. Phenethyl compounds are
known to adopt a low energy conformation in which the
aliphatic carbon-carbon bond is oriented perpendicular
to the plane of the aromatic ring.50,51 In a peptide
incorporating 1, this conformation would orient one of
the aromatic rings perpendicular to the plane of the
resulting â-sheet, allowing the side chains of at least one
of the flanking R-amino acids to pack against the
aromatic skeleton to afford a hydrophobic cluster (Figure
2). This type of hydrophobic cluster has been shown to
be critical for the nucleation of â-sheet structure in
peptides incorporating the 4-(2-aminoethyl)-6-dibenzo-
furanpropionic acid residue.8
(37) Several small peptides are capable of populating a â-turn
conformation; see: refs 2 and 38-43. However, concensus â-turns do
not appear to be sufficient to nucleate folding within sequences which
are known to fold when nucleated by unnatural amino acids such as
the 4-(2-aminoethyl)-6-dibenzofuranpropionic acid. Unpublished re-
sults.
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Acta Crystallogr. 1984, C40, 1572-1576.

Synthesis of Biphenyl-Based Amino Acids
J . Org. Chem., Vol. 61, No. 9, 1996 3129
ment of 1,3-dibromobenzene with 1.0 equiv of n-butyl-
lithium at -95 °C in THF provided the monolithiated
species. The anion was quenched with trimethylsilyl
chloride to afford 1-bromo-3-(trimethylsilyl)benzene (7)
in 91% yield after vacuum distillation. Minor amounts
of the ortho- and para-isomers were also observed in the
crude product. A second metal-halogen exchange using
1.5 equiv of n-butyllithium at -95 °C in THF followed
by addition of trimethyl borate and acidification afforded
the crude boronic acid 8. The biphenyl compound 9 was
prepared in 92% yield by refluxing 6 and crude 8 in the
presence of catalytic tetrakis(triphenylphosphine)pal-
ladium(II) and aqueous sodium carbonate in dimethyl-
ethyleneglycol. Iododesilylation of 9 was accomplished
using iodine monochloride55 in carbon tetrachloride to
afford 10 in quantitative yield. Subjecting 10 to a
palladium-catalyzed Heck cross-coupling reaction with
acrylic acid56,57 afforded ethyl 3′-(carboxyethenyl)-2-bi-
phenylpropionate (11) in 77% yield. Hydrogenation using
platinum oxide in 1:1 ethanol:acetic acid at 1 atm of H2
afforded 12 in 97% yield. The acid functional group of
12 was transformed into a tert-butyl carbamate group
via a Curtius rearrangement to afford 13 in 70% yield.
Saponification of 13 with lithium hydroxide in ethanol
provided the Boc-protected amino acid 14 in quantitative
yield, which was used directly in solid phase peptide
synthesis and in the preparation of the diamide deriva-
tive 3. The overall yield of 14 from 2-bromocinnamic acid
was 44%. The synthesis of the methyl ester-protected
amino acid 2 (compound 23) began with the conversion
of 3-bromobenzoyl chloride (Figure 4) to 3-bromo-N-tert-
butyl-N-methylbenzamide (17) in quantitative yield fol-
lowed by a metal-halogen exchange employing 1.1 equiv
of sec-butyllithium in THF at -95 °C to give the mono-
lithiated species. Addition of trimethyl borate followed
by acidification afforded the crude boronic acid 18 in 89%
yield. Temperature control was important in this reac-
tion; e.g., metalation at -80 °C resulted in a mixture of
the meta- and ortho-isomers due to the ability of the
amide group to act as an ortho-metalation director.
Boronic acid 18 was coupled to methyl 2-bromobenzoate
in the presence of catalytic tetrakis(triphenylphosphine)-
palladium(II) and aqueous sodium carbonate in dimeth-
ylethylene glycol to afford methyl 3′-(N-tert-butyl-N-
methylamidyl)-2-biphenylcarboxylate (19) in 69% yield.
Saponification of the methyl ester functionality followed
by a Curtius rearrangement afforded a mixture of the
desired tert-butyl carbamate 21 as well as the urea 22.
Compounds 21 and 22 were hydrolyzed in concentrated
HCl to afford the fully deprotected amino acid 2 in 46%
yield from 20. The methyl ester protected amino acid
23 was obtained in quantitative yield by refluxing amino
acid 2 in methanol with excess thionyl chloride. The
overall yield of 23 from 3-bromobenzoyl chloride was 27%.
F igu r e 3. Outline of the synthesis of 3′-(N-(tert-butyloxycar-
bonyl)-2-aminoethyl)-2-biphenylpropionic acid (14). Reaction
conditions: (a) 50 psi H2, 5 mol % Rh(PPh3)3Cl, EtOH, room
temperature, 40-50 h, 94%; (b) 1 mol % p-toluenesulfonic acid,
EtOH, reflux, 22 h, 95%; (c) (i) 1.0 equiv of n-BuLi at -95 °C
in THF, 5 min, (ii) 2.5 equiv of TMSCl, initially at -95 °C,
warmed to -75 °C and stirred 2 h, and then warmed to room
temperature overnight, 91%; (d) (i) 1.5 equiv of n-BuLi at -95
°C in THF, 5 min, (ii) 10.0 equiv of B(OMe)3, initially at -95
°C, warmed to -78 °C and stirred 2 h, and then warmed to
room temperature overnight, (iii) cooled to 0 °C and acidified
to pH 6 with 10% HCl, 107% (crude); (e) 1.6 equiv of boronic
acid, 5 mol % Pd(PPh3)4, 2.0 equiv of Na2CO3, DME, reflux,
22 h, 92%; (f) 2.4 equiv of ICl, 3.0 equiv of K2CO3, CCl4, initially
at 0 °C and then warmed to room temperature, 15 h, quantita-
tive; (g) 2 mol % Pd(OAc)2, 5 mol % PPh3, 2.5 equiv of Et3N,
1.5 equiv of acrylic acid, DMF, 130 °C, 5 h, 77%; (h) 1 atm of
H2, 7 mol % PtO2, 1:1 EtOH:HOAc, room temperature, 6 h,
97%; (i) 1.1 equiv of diphenyl phosphorazidate, 1.2 equiv of
Et3N, t-BuOH, reflux, 24 h, 70%; (j) 10 equiv of 1.0 M aqueous
LiOH, EtOH, room temperature, 2.5 h, quantitative.
Resu lts a n d Discu ssion
Syn th esis of â-Tu r n Mim ics 1 a n d 2. The syntheses
of 1 and 2 are based on the aryl-aryl cross-coup-
ling strategies developed by Suzuki and modified by
Snieckus.52-54 The ethyl 2-bromodihydrocinnamate (6)
required for the synthesis of the Boc-protected derivative
of 1 (compound 14) was obtained by hydrogenating
2-bromocinnamic acid in ethanol (50 psi) to afford 2-bro-
modihydrocinnamic acid (5) in 94% yield (Figure 3).
Esterification using p-toluenesulfonic acid in ethanol
provided the desired aryl bromide (6) in 95% yield. The
required 3-(trimethylsilyl)phenylboronic acid (8) was
obtained in two steps from 1,3-dibromobenzene. Treat-
Syn th esis of th e Dia m id e Der iva tives of 1 a n d 2
for X-r a y Cr yst a llogr a p h y, F T-IR , a n d VT-NMR
An a lysis. Diamides 3 and 4 (Figures 5 and 6, respec-
tively) were prepared from the Boc-protected amino acid
14 and the amino ester 23, respectively. These amide
analogs were prepared to probe the intramolecular
hydrogen-bonding preferences of residues 1 and 2 and
(55) Stock, L. M.; Spector, A. R. J . Org. Chem. 1963, 28, 3272-3274.
(56) Patel, B. A.; Ziegler, C. B., J r.; Cortese, N. A.; Plevyak, J . E.;
Zebovitz, T. C.; Terpko, M.; Heck, R. F. J . Org. Chem. 1977, 42, 3903-
3906.
(57) Plevyak, J . E.; Dickerson, J . E.; Heck, R. F. J . Org. Chem. 1979,
44, 4078-4081.
(52) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513-519.
(53) Unrau, C. M.; Campbell, M. G.; Snieckus, V. Tetrahedron Lett.
1992, 33, 2773-2776.
(54) Snieckus, V. Chem. Rev. 1990, 90, 879-933.

3130 J . Org. Chem., Vol. 61, No. 9, 1996
Nesloney and Kelly
F igu r e 4. Outline of the synthesis of methyl 2-amino-3′-biphenylcarboxylate (23). Reaction conditions: (a) 1.0 equiv of t-BuMeNH,
1.0 equiv of Et3N, CH2Cl2, 0 °C, 2 h and then room temperature overnight, quantitative; (b) (i) 1.1 equiv of s-BuLi at -95 °C in
THF, 10 min, (ii) 3.2 equiv of B(OMe)3, initially at -95 °C, warmed to -80 °C and stirred for 2 h, and then warmed to -10 °C
overnight, (iii) cooled to 0 °C and acidified to pH 6 with 10% HCl, 89%; (c) 2.2 equiv of boronic acid, 3 mol % Pd(PPh3)4, 2.0 equiv
of Na2CO3, DME, reflux, 50 h, 69%; (d) 5.1 equiv of NaOH, MeOH, reflux, 6 h, 95%; (e) 1.2 equiv of diphenyl phosphorazidate, 1.2
equiv of Et3N, t-BuOH, reflux, 22.5 h; (f) concd HCl, phenol, 110 °C, 45 h, 46%; (g) 19.8 equiv of SOCl2, MeOH, initially at 0 °C
and then refluxed, quantitative.
F igu r e 5. Representation of the two possible hydrogen-
bonding conformations of diamide 3.
F igu r e 7. ORTEP depiction of N-benzyl-3′-(2-(benzylamido)-
ethyl)-2-biphenylpropamide (3).
of phenylacetic acid in CH2Cl2 to give the amide. The
crude compound was then hydrolyzed to afford 2-(benz-
ylamido)-3′-biphenylcarboxylic acid (25) in 81% yield
(from 23) after purification by preparative C18 HPLC.
BOP activation of 25 followed by reaction with benzyl-
amine in CH2Cl2 afforded diamide 4 in 96% yield after
purification by flash chromatography. Thus, 4 was
F igu r e 6. Representation of the two possible hydrogen-
bonding conformations of diamide 4.
obtained from 23 in 78% overall yield.
Sin gle Cr ysta l X-r a y An a lysis of Dia m id es 3 a n d
4. Orthorhombic crystals having a space group of Fdd2
were obtained for diamide 3 by dissolving the compound
in hot chloroform and allowing the crystals to grow at
room temperature over 48 h. The ORTEP depiction of
the structure in Figure 7 exhibits an N(2) to O(1) bond
distance of 2.98 Å, indicating that the formation of a 13-
membered ring intramolecular hydrogen bond is pre-
ferred in the solid state (Figure 5, 3a ). An intermolecular
hydrogen bond between N(1) and O(2) having a bond
distance of 2.85 Å was also observed (Figure 8) which
suggests that crystal packing forces may have influenced
the preference for the 13-membered ring intramolecular
to identify the preferred dihedral angle about the carbon-
carbon biphenyl bond in residues 1 and 2. Diamide 3
was prepared by treatment of amino acid 14 with BOP
reagent and benzylamine in DMF to obtain the Boc-
protected amide, N-benzyl-3′-(N-(tert-butyloxycarbonyl)-
2-aminoethyl)-2-biphenylpropamide (15), in 76% yield.
Removal of the Boc group with TFA followed by reaction
with the HOBt active ester of phenylacetic acid in CH2Cl2
afforded diamide 3 in 53% yield after purification by
preparative C18 HPLC. The overall yield of 3 from 14
was 40%. Diamide 4 was prepared by acylating the
amino group of 23 with an excess of the HOBt active ester

Synthesis of Biphenyl-Based Amino Acids
J . Org. Chem., Vol. 61, No. 9, 1996 3131
F igu r e 8. ORTEP depiction of N-benzyl-3′-(2-(benzylamido)-
ethyl)-2-biphenylpropamide (3) showing the intermolecular
hydrogen bond between N(1) and O(2).
hydrogen bond in the solid state. The structure demon-
strates that the biphenyl system has the R configuration
with a 120.8° dihedral angle between the two phenyl
rings of the biphenyl unit. The aliphatic carbon-carbon
bond of the 3′ side chain of residue 1 is perpendicular to
the plane of phenyl ring 2, and the methylene groups of
the side chain attached to the 2 position are perpendicu-
lar to the plane of ring 1. The average distance between
the 2 and 3′ side chains was calculated to be 4.85 Å,58
which is in excellent agreement with the distance be-
tween two strands of a naturally occurring antiparallel
â-sheet. The bond lengths, angles, and coordinates and
the isotropic and anisotropic displacement factors for the
solid state structure of 3 are available from the Cam-
bridge Crystallographic Data Center. Triclinic crystals
having a space group of P1 were obtained for diamide 4
from a slowly cooled CCl4 solution (Figure 9). Two closely
related conformers were observed in the solid state
structure. The first has an S configuration with a 120.0°
angle between the two phenyl rings of the biphenyl ring
while the second conformer has an R configuration with
an angle of 121.3°. The crystal structure revealed an
intermolecularly hydrogen-bonded system (Figure 10).
The hydrogen bond is formed between O(1) and N(4) with
a distance of 2.86 Å. The average distance between the
2 and 3′ side chains of the S conformer was calculated to
be 5.53 Å while the average distance of the 2 and 3′ side
chains of the R conformer was calculated to be 5.02 Å.59
These distances are slightly larger than the distance
separating two strands of a naturally occurring antipar-
allel â-sheet and than the distance calculated for diamide
3.
F igu r e 9. ORTEP depiction of N-benzyl-2-(benzylamido)-3′-
biphenylamide (4) showing (a) the S conformer and (b) the R
conformer.
free NHs (∆δ/∆T ∼ -3 ppb/K) in CD2Cl2.60-64 Amides
which are undergoing equilibration between the hydrogen-
bonded and nonbonded states have been observed to
exhibit intermediate temperature dependencies (-7 to
-10 ppb/K) and room-temperature chemical shifts in the
range of 5.5-6.5 ppm.62 Since amino acid 1 has been
designed to replace the backbone of the i + 1 and i + 2
residues of a â-turn, a 15-membered ring hydrogen bond
was desired (Figure 5, 3b) for nucleating â-sheet forma-
tion as this is the hydrogen bond which is formed between
the NH and CdO of of the i and i + 3 residues in a
â-hairpin. A proton NMR spectrum of 3 (4.2 mM solution
in CD2Cl2 at room temperature) shows resonances for the
amide protons at δ 6.3 and 6.1 ppm (298 K). The
downfield signal shows a large temperature dependence
(∆δ/∆T ) -10 ppb/K) consistent with an intramolecular
hydrogen bond,
Va r ia ble-Tem p er a tu r e 1H NMR Resu lts for Dia -
m id es 3 a n d 4. Variable temperature 1H NMR spec-
troscopy has been employed to probe intramolecular
hydrogen bonding and was used here to probe the
preferred hydrogen bonds adopted by 3 and 4 in a
noncompetitive solvent (CH2Cl2). Generally, hydrogen-
bonded NHs have downfield chemical shifts (∼7.0-9.0
ppm) relative to non-hydrogen-bonded NHs (∼5.5-6.0
ppm) at 25 °C. In acyclic amides, hydrogen-bonded NHs
typically exhibit a large temperature dependence of the
chemical shift (∆δ/∆T ∼ -10 to -13 ppb/K) relative to
(60) Stevens, E. S.; Sugawara, N.; Bonora, G. M.; Toniolo, C. J . Am.
Chem. Soc. 1980, 102, 7048-7050.
(58) The distances between N(2) and C(15), C(23) and C(13), C(24)
and C(14), C(25) and C(15), and O(1) and O(2) were used to calculate
the average strand distance in diamide 3.
(59) The distances between N(4) and C(41), N(3) and C(49), N(3)
and N(4), and C(42) and C(50) were used to calculate the average
strand distance in the R conformer of diamide 4, and the distances
between N(2) and C(13), N(1) and N(2), N(1) and C(21), and C(14) and
C(22) were used to calculate the average strand distance in the S
conformer of diamide 4.
(61) Gellman, S. H.; Adams, B. R.; Dado, G. P. J . Am. Chem. Soc.
1990, 112, 460-461.
(62) Gellman, S. H.; Dado, G. P.; Liang, G.; Adams, B. R. J . Am.
Chem. Soc. 1991, 113, 1164-1173.
(63) Liang, G.; Dado, G. P.; Gellman, S. H. J . Am. Chem. Soc. 1991,
113, 3994-3995.
(64) Liang, G.; Rito, C. J .; Gellman, S. H. J . Am. Chem. Soc. 1992,
114, 4440-4442.

3132 J . Org. Chem., Vol. 61, No. 9, 1996
Nesloney and Kelly
and the quartet at 3.46 ppm (-CH2CH2NHCOCH2Ph)
and between the NH signal at 6.3 ppm and the doublet
at 4.28 ppm (-CH2CH2CONHCH2Ph) were observed.
Thus, the amide proton exhibiting the larger temperature
coefficient is assigned to the amide proton capable of
forming the 15-membered ring hydrogen bond (3b). The
larger temperature coefficient suggests that the 15-
membered ring (3b) is favored over the 13-membered ring
(3a ) in CH2Cl2 solution. These interpretations are con-
sistent with the solution IR spectroscopy results dis-
cussed below but are opposite to the crystallography
results, most likely owing to crystal packing forces in the
solid state structure. While these data demonstrate the
ability of 1 to hydrogen bond in a non-hydrogen-bonding
solvent, intramolecular hydrogen bonding is less ener-
getically favorable in aqueous solvents. However, slow
amide proton deuterium exchange rates for the R-amino
acids flanking 1 in small peptides indicate that the 15-
membered ring hydrogen bond is preferentially formed
in aqueous solution as well.65 In a peptide incorporating
2, the 11-membered hydrogen-bonded ring conformation
(Figure 6, 4b) is ideal for nucleating â-sheet formation
as it is formed between the NH and CdO of the flanking
F igu r e 10. ORTEP depiction of N-benzyl-2-(benzylamido)-
3′-biphenylamide (4) showing the intermolecular hydrogen
bond between N(4) and O(1).
1
R-amino acid residues. The H NMR spectrum of 4 in
CH2Cl2 at room temperature revealed one amide proton
signal at 6.5 ppm. The remaining amide proton appears
to be buried under the aromatic signals. A DQ COSY
experiment exhibits a cross peak between the amide NH
signal and the doublet at 4.3 ppm (-C(O)NHCH2Ph),
identifying the amide proton at 6.5 ppm (298 K) as that
capable of forming the 11-membered ring hydrogen bond;
Figure 4b. This proton exhibits an intermediate tem-
perature dependence (-6.5 ppb/K) which is consistent
with a proton in rapid equilibrium between the hydrogen-
bonded and nonbonded states (Figure 11b). The remain-
ing amide proton (that derived from residue 2) has a
small temperature dependence (e-3 ppb/K)66 which is
consistent with a non-hydrogen-bonded amide proton.
F T-IR Stu d y of th e Am id e Hyd r ogen Bon d in g of
Dia m id es 3 a n d 4. Intramolecular amide-amide hy-
drogen bonding was also studied in CH2Cl2 by analyzing
the amide NH infrared stretch region (3200-3500 cm-1
)
where a sharp signal at 3400-3500 cm-1 generally
corresponds to a free NH and a broader band at ∼3200-
3400 cm-1 corresponds to a hydrogen-bonded NH.60-64
Infrared studies on diamide 3 (1.7 mM in CH2Cl2) reveal
that intramolecular hydrogen bonding does occur (Figure
12a). Two bands are observed in the amide stretch
region: one having a maximum at 3429 cm-1 (nonbonded
NH) and one having a maximum at 3337 cm-1 (hydrogen-
bonded NH). These results have several possible inter-
pretations. One possibility is that the diamide may exist
entirely in the 15-membered ring hydrogen-bonded con-
formation which is possible; however, the moderate
temperature coefficient for the amide NH capable of
forming the 13-membered suggests that the 13-mem-
bered ring is also a minor conformer. Alternatively,
because the time scale of IR measurements is fast
compared to the equilibration rate of conformers 3a and
3b, it is possible to observe distinct NH stretch absorp-
tions for each of the equilibrating states. Thus, the two
bands observed are likely to result from a mixture of 3a
F igu r e 11. (a) Temperature dependence of chemical shifts of
the amide protons of model compound 3 (4.2-6.3 mM CH2Cl2).
O: the amide proton corresponding to the 15-membered
hydrogen-bonded ring conformation. 0: represent the amide
proton corresponding to the 13-membered ring conformation.
(b) Temperature dependence of chemical shift of the amide
proton corresponding to the 11-membered hydrogen-bonded
ring conformation of model compound 4 (4.1-4.7 mM CH2Cl2,
b).
while the upfield signal shows a moderate temperature
dependence (∆δ/∆T ) -8 ppb/K) (Figure 11a). These
values suggest that both the 13- and 15-membered
hydrogen-bonded rings (3a and 3b) are in fast equilib-
rium on the NMR time scale. A DQ COSY experiment
was used to unambiguously assign the amide proton
signals. Crosspeaks between the NH signal at 6.1 ppm
(65) Nesloney, C. L.; Kelly, J . W. Unpublished results.
(66) Value calculated by dividing the width of the aromatic signals
overlapping the amide proton resonance (0.3 ppm) by the temperature
range of the experiment.

Synthesis of Biphenyl-Based Amino Acids
J . Org. Chem., Vol. 61, No. 9, 1996 3133
samples for both the VT NMR and FT-IR studies were
extensively dried (refer to the Experimental Section for
details), the samples of 3 typically contained 5-10 mM
H2O. Studies by Gellman have shown that addition of
up to 30 mM D2O does not appear to significantly affect
the data obtained in these types of studies.62,67
Con clu sion
The biphenyl-based amino acids 1 and 2 have been
synthesized, and simple amide derivatives have been
prepared and studied by X-ray crystallography, FT-IR,
and NMR. Biphenyl-based amino acid 2 can support a
partially hydrogen-bonded conformation which should be
consistent with â-sheet formation but is incapable of
adopting a hydrophobic cluster conformation thought to
be critical for â-sheet nucleation. FT-IR and NMR
studies of the diamide derivative of residue 1 indicate
that it is capable of adopting a 15-membered, intramo-
lecularly hydrogen-bonded conformation which should
support antiparallel â-sheet structure. In addition,
computational modeling based on the solid state struc-
ture of 1 suggests that it should be capable of promoting
hydrophobic cluster formation involving at least one of
the phenyl rings of the biphenyl skeleton and one of the
hydrophobic flanking R-amino acid side chains. Evalu-
ations of peptides containing amino acids 1 and 2 support
these predictions.65
F igu r e 12. FT-IR spectral data of amide derivatives 3 and 4
from the NH stretch region in CH2Cl2. (a) 1.7 mM diamide 3
(maxima at 3337 and 3439 cm-1) and (b) 3.0 mM diamide 4
(maxima at 3387, 3420, and 3449 cm-1). Spectra were obtained
at room temperature and have been corrected for CH2Cl2
contributions.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, materials were
obtained from commercial suppliers and were used without
further purification. Tetrahydrofuran (THF) and diethyl ether
(Et2O) were distilled from sodium/benzophenone ketyl under
nitrogen (N2). Dichloromethane (CH2Cl2), trimethylsilyl chlo-
ride (TMSCl), and trimethyl borate (B(OMe)3) were distilled
from calcium hydride under N2. Triethylamine (TEA) and
diisopropylethylamine (DIEA) were refluxed over ninhydrin,
distilled, and then distilled from calcium hydride. Routine 1H
NMR and 13C NMR spectra were recorded on a Varian XL-
200E spectrometer and are reported in parts per million (δ)
and 3b such that the hydrogen-bonded NHs in 3a and
3b combine to give the observed broad band centered at
3337 cm-1 and the nonbonded NHs in 3a and 3b both
contribute to the band at 3429 cm-1. The most likely
scenario is that 3b is the major conformer with minor
contributions from 3a and perhaps even a small non-
hydrogen-bonded component. This interpretation is con-
sistent with all spectroscopic data including the recent
data collected on peptides in aqueous solution.65
relative to CHCl3 (7.24 ppm).
J values are given in Hz.
Variable-temperature and 2D NMR studies of diamides 3 and
4 were obtained on a Varian XL-400 spectrometer. Data from
the 400 MHz NMR were processed using Varian VNMR
version 5.1 software. Analytical thin layer chromatography
was performed on E. Merck silica gel 60 F254 plates. Column
chromatography was performed as described by Still68 using
forced flow (flash) chromatography with the indicated solvents
on Baxter SIP silica gel 60 Å (230-400 mesh). Melting points
were obtained on a Bristoline apparatus and are uncorrected.
Nominal resolution mass spectra were obtained on a Hewlett-
Packard 5971 mass spectrometer, and high-resolution mass
spectra were obtained on a VG-70S double-focusing high-
resolution mass spectrometer. Preparative HPLC was carried
out on a dual pump system equipped with Altex 110A pumps
and a 420 gradient programmer or a Waters 600 preparative
HPLC. Waters RCM Delta Pak C18 and C4 (15 µm, 300 Å, 25
× 100 mm) columns and a Knauer 86 variable-wavelength
detector were used. Solvent A was composed of 95% water,
5% acetonitrile, and 0.2% TFA. Solvent B was composed of
5% water, 95% acetonitrile, and 0.2% TFA.
The FT-IR of 4 (3.0 mmol, CH2Cl2) reveals three bands
in the amide stretch region having maxima at 3449, 3420,
and 3387 cm-1 (Figure 12b). The first two bands cor-
respond to nonbonded amide protons while the band at
3387 cm-1 corresponds to a hydrogen-bonded NH. These
results are consistent with the 1H NMR data which
suggest that the amide proton capable of forming a
9-membered ring hydrogen-bonded conformation does not
form an intramolecular hydrogen bond while the amide
proton capable of forming an 11-membered ring hydrogen
bond exists in an equilibrium between the hydrogen-
bonded and non-hydrogen-bonded states. That the 11-
membered ring hydrogen-bonded conformer is in equi-
librium with a non-hydrogen-bonded state in the absence
of a 9-membered ring hydrogen-bonded conformation
suggests that the net energetic gain associated with
intramolecular hydrogen bonding in 4 is small. In order
to demonstrate that intramolecular hydrogen bonding
rather than intermolecular hydrogen bonding was being
probed, the concentration dependence of the hydrogen
bonding of 3 and 4 was examined by FT-IR. A concen-
tration dependent increase in hydrogen bonding was not
observed in the IR spectra for samples ranging from 0.34
to 85 mM (3) and 0.18 to 44 mM (4), consistent with a
lack of intermolecular hydrogen bonding. Although the
Syn th esis of 3′-(2-Am in oeth yl)-2-bip h en ylp r op ion ic
Acid Der iva tives. 2-Br om od ih yd r ocin n a m ic Acid (5). To
a solution of 2-bromocinnamic acid (1.08 g, 4.76 mmol) in EtOH
(150 mL) was added tris(triphenylphosphine)rhodium(II) chlo-
ride (0.22 g, 0.24 mmol, 5.0 mol %) in a 500 mL hydrogenation
(67) Dado, G. P.; Gellman, S. H. J . Am. Chem. Soc. 1993, 115, 4228-
4245.
(68) Still, W. C.; Kahn, M.; Maitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

3134 J . Org. Chem., Vol. 61, No. 9, 1996
Nesloney and Kelly
bottle. The resulting light yellow mixture contained some
undissolved, dark red catalyst. The reaction mixture was
hydrogenated at 50 psi (25 °C) for 40-50 h using a Parr
hydrogenator. The bright yellow, homogeneous solution was
concentrated in vacuo to give a light brown oil. The crude
material was purified by flash chromatography (70:29:1 hex-
anes:ethyl acetate:acetic acid) to give 1.02 g (94%) of the fully
saturated compound as a white solid: mp 96-97 °C; 1H NMR
(CDCl3) δ 11.98 (bs, 1 H), 7.56 (d, J ) 7.7, 1 H), 7.31-7.06 (m,
3 H), 3.10 (t, J ) 7.7 Hz, 2 H), 2.74 (t, J ) 7.7 Hz, 2 H); 13C
NMR (CDCl3) δ 179.80, 139.87, 133.46, 130.93, 128.73, 128.15,
124.87, 34.42, 31.60; MS (+FAB, NBA/PEGH) m/z 228.9836
(79Br) and 230.9837 (81Br), [M + H]+ calcd for C9H9O2Br
228.9864.
aqueous layer was washed with ether (2 × 100 mL). The
organic layers were combined, washed with 10% HCl (2 × 125
mL), dried (MgSO4), and concentrated in vacuo. Further
drying under high vacuum afforded 2.88 g (107%) of a crude
white solid. The crude compound was generally used in the
following step without further purification. When required,
pure material was obtained through crystallization from a CH2-
Cl2/hexanes mixture (28% recovery): mp 140-142 °C; 1H NMR
(CDCl3) δ 8.46 (bd, J p ) 0.7, 1 H), 8.25 (dt, J o ) 7.4, J m ) 1.4,
1 H), 7.8 (dt, J o ) 7.3, J m ) 1.4, 1 H), 7.54 (td, J o ) 7.3, J p
)
0.7, 1 H), 0.39 (s, 8 H); 13C NMR (CDCl3) δ 140.86, 139.90,
137.77, 136.15, 129.44, 127.53, -0.98.
Eth yl 3′-(Tr im eth ylsilyl)-2-bip h en ylp r op ion a te (9). A
three-necked, 100 mL round-bottomed flask was fitted with a
reflux condenser, flame-dried under Ar, and charged with ethyl
2-bromodihydrocinnamate (2.26 g, 8.79 mmol), tetrakis(tri-
phenylphosphine)palladium(II) (0.31 g, 0.27 mmol), and 60 mL
of dimethylethylene glycol (DME). The bright yellow solution
was stirred at room temperature in darkness for 20 min.
Sequential addition of boronic acid 15 (2.88 g, 13.9 mmol) and
Na2CO3 (8.8 mL of a 2.0 M aqueous solution, 18 mmol) resulted
in a light brown solution and the formation of a white
precipitate. The reaction mixture was heated at reflux for 22
h. The mixture was cooled, concentrated in vacuo, and taken
up in CH2Cl2 (75 mL) and H2O (150 mL). The layers were
separated, and the aqueous layer was washed with three
additional 75 mL portions of CH2Cl2. The combined organic
layers were dried (MgSO4) and concentrated in vacuo. Further
drying under high vacuum afforded a dark yellow oil. The
crude material was purified by flash chromatography (70:30
hexanes:CHCl3) to give 2.65 g (92%) of a clear oil: 1H NMR
(CDCl3) δ 7.55-7.20 (m, 8 H), 4.05 (q, J ) 7.1, 2 H), 2.92 (m,
2 H), 2.44 (m, 2 H), 1.18 (t, J ) 7.1, 3 H), 0.28 (s, 8 H); 13C
NMR (CDCl3) δ 172.84, 142.26, 140.66, 140.39, 137.98, 133.91,
131.89, 130.25, 129.45, 129.06, 127.54, 127.48, 126.21, 60.29,
35.56, 28.39, 14.15, -1.13; EI MS m/ z 326.1700, M+ calcd for
C20H26O2Si 326.1702.
Eth yl 3′-Iod o-2-bip h en ylp r op ion a te (10). A 250 mL
round-bottomed flask was flame-dried under Ar and charged
with ethyl 3′-(trimethylsilyl)-2-biphenylpropionate (2.57 g, 7.87
mmol), K2CO3 (3.26 g, 23.6 mmol), and CCl4 (50 mL, dried over
MgSO4). The solution was cooled to 0 °C. The ICl (1.0 mL,
19 mmol) was transferred via a Teflon cannula to a graduated
cylinder which had been flame-dried under Ar and charged
with CCl4 (6.4 mL, 2.6 M solution). The solution was then
transferred to the reaction flask via the Teflon cannula. The
graduated cylinder and cannula were rinsed with three
additional 4 mL portions of CCl4. The cooling bath was
removed after 30 min, and the red wine colored solution was
stirred at room temperature, in darkness overnight (15 h). The
reaction mixture was poured into 200 mL of a 10% Na2S2O3
solution. This was diluted with 100 mL of CH2Cl2 and
vigorously stirred. Additional solid Na2S2O3 was added, and
the mixture was stirred until light yellow. The mixture was
transferred to a separatory funnel, and the layers were
separated. The aqueous layer was washed with CH2Cl2 (3 ×
75 mL). The combined organic layers were washed with 10%
Na2S2O3 (3 × 120 mL), 10% NaHCO3 (3 × 120 mL), 10% HCl
(3 × 120 mL), and H2O (2 × 100 mL). The colorless organic
layer was then dried (MgSO4), concentrated in vacuo, and
further dried under high vacuum to afford 3.01 g (101%) of a
yellow oil. An analytical sample was obtained by preparative
C4 HPLC as a clear oil: 1H NMR (CDCl3) δ 7.72-7.66 (m, 2
H), 7.31-7.10 (m, 6 H), 4.06 (q, J ) 7.1, 2 H), 2.91 (m, 2 H),
2.42 (m, 2 H), 1.19 (t, J ) 7.1, 3 H); 13C NMR (CDCl3) δ 172.68,
143.65, 140.31, 137.94, 137.80, 136.02, 130.05, 129.85, 129.06,
128.39, 128.02, 126.32, 94.19, 60.40, 35.32, 28.18, 14.18; EI
MS m/ z 380.0266, M+ calcd for C17H17O2I 380.0273.
Eth yl 2-Br om od ih yd r ocin n a m a te (6). An oven-dried,
Ar-purged, 25 mL round-bottomed flask was charged with
2-bromodihydrocinnamic acid (0.73 g, 3.2 mmol) and absolute
EtOH (15 mL). To the light yellow solution was added
p-toluenesulfonic acid (6.0 mg, 0.03 mmol). The flask was
fitted with a condenser, and the system was flushed with Ar.
The solution was heated at reflux for 22 h. The EtOH was
removed in vacuo, and the resulting light brown oil was taken
up in ether (100 mL). The organic layer was washed with H2O
(3 × 75 mL), 5% NaHCO3 (3 × 75 mL), and 5% Na2S2O5 (2 ×
75 mL) and then dried (MgSO4). The pale yellow etheral
solution was concentrated under reduced pressure. Further
drying under high vacuum afforded 0.78 g (95%) of a light
yellow oil: 1H NMR (CDCl3) δ 7.52 (d, J ) 8.2, 1 H), 7.27-
7.17 (m, 2 H), 7.12-7.02 (m, 1 H), 4.13 (q, J ) 7.2, 2 H), 3.06
(t, J ) 7.8, 2 H), 2.63 (t, J ) 7.8, 2 H), 1.23 (t, J ) 7.2, 3 H);
13C NMR (CDCl3) δ 172.63, 139.81, 132.87, 130.46, 128.04,
127.52, 124.36, 60.48, 34.12, 31.42, 14.19; MS (+FAB, NBA/
PEGH) m/z 257.0176, [M + H]+ calcd for C11H13O2Br 257.0177.
1-Br om o-3-(tr im eth ylsilyl)ben zen e (7). A 50 mL round-
bottomed flask was flame-dried under Ar and charged with
1,3-dibromobenzene (1.8 mL, 15 mmol) and freshly distilled
THF (30 mL). The clear solution was cooled to -95 °C
(methanol/liquid N2 bath). Addition of n-BuLi (11.5 mL of a
1.3 M solution in hexanes, 15 mmol) over 15 min resulted in
a pale yellow solution. The mixture was stirred at -95 °C for
5 min and then quenched with TMSCl (4.7 mL, 37 mmol). The
pale yellow solution was stirred at -75 °C (methanol/dry ice)
for an additional 2 h and then allowed to warm to 25 °C
overnight. After 12-16 h, the reaction mixture was at room
temperature, and the pale yellow solution contained a white
solid. The mixture was concentrated in vacuo and then
partitioned between ether and H2O (75 mL each). The layers
were separated, and the organic layer was washed with two
additional 75 mL portions of H2O, dried (MgSO4), and con-
centrated under reduced pressure. The crude material (3.57
g, 105% of a light yellow oil) was purified by vacuum distil-
lation. The fraction boiling at 79.0-79.5 °C (1.7 mmHg) (lit.69
bp 50 °C (0.05 mmHg)) was collected as a clear oil (3.09 g,
91%): 1H NMR (CDCl3) δ 7.66-7.61 (m, 1 H, Ar H2), 7.51-
7.40 (m, 2 H), 7.22 (t, J ) 7.7, 1 H) 0.27 (s, 8 H); 13C NMR
(CDCl3) δ 144.25, 136.44, 132.22, 132.04, 129.96, 123.39, -0.86.
3-(Tr im et h ylsilyl)p h en ylb or on ic Acid (8). A 500 mL
round-bottomed flask was flame-dried under Ar and charged
with 1-bromo-3-(trimethylsilyl)benzene (3.18 g, 13.9 mmol) and
freshly distilled THF (75 mL). The clear solution was cooled
to -95 °C (methanol/liquid N2 bath). Addition of n-BuLi (16.0
mL of a 1.3 M solution, 21 mmol) over a 20 min period resulted
in a yellow solution. After 5 min of stirring at -95 °C, the
solution was quenched with B(OMe)3 (15.8 mL, 139 mmol).
The colorless solution was kept at -78 °C for 2 h and then
allowed to warm to room temperature overnight (12-16 h).
The mixture was then cooled to 0 °C and acidified to pH 6
with 10% HCl. A white precipitate formed. The mixture was
stirred at 0 °C for 1 h and then concentrated in vacuo to yield
a white slurry. The slurry was partitioned between ether and
10% HCl (150 mL each). The layers were separated, and the
Eth yl 3′-(Ca r boxyeth en yl)-2-bip h en ylp r op ion a te (11).
The iodobiphenyl compound 10 (2.90 g, 7.63 mmol) was dried
under high vacuum in an oven-dried, 50 mL round-bottomed
flask. Palladium acetate (30.2 mg, 0.13 mmol) and triphen-
ylphosphine (94.5 mg, 0.36 mmol) were added to the flask
which was fitted with an oven-dried condenser. The system
was alternately evacuated under high vacuum and purged
with Ar (four cycles). The DMF (8 mL), triethylamine (2.7 mL,
(69) Klusener, P. A. A.; Hanskamp, J . C.; Brandsma, L.; Schleyer,
P. v. R. J . Org. Chem. 1990, 55, 1311-1321.
(70) This figure was prepared with MolScript; see: Kraulis, P. T.
J . Appl. Crystallogr. 1991, 24, 946-950.

Synthesis of Biphenyl-Based Amino Acids
J . Org. Chem., Vol. 61, No. 9, 1996 3135
19 mmol), and acrylic acid (0.86 mL, 11 mmol) were added
via syringe. The dark brown solution was immersed in a 55
°C oil bath. The temperature was increased to 150 °C over
70 min. The reaction mixture was kept at 150 °C for 5 min
and then cooled to 130 °C. After 5 h at 130 °C, the reaction
mixture was cooled and diluted with CH2Cl2 (100 mL) and H2O
(200 mL). The aqueous layer was washed with CH2Cl2 (5 ×
75 mL). The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. Further drying under
high vacuum afforded 2.95 g (119%) of a dark brown oil.
Purification by flash chromatography (75:24:1 hexanes:ethyl
acetate:acetic acid) afforded 1.91 g (77%) of a light brown oil:
1H NMR (CDCl3) δ 7.82 (d, J ) 16.0, 1 H), 7.57-7.16 (m, 8 H),
6.48 (d, J ) 16.0, 1 H), 4.05 (q, J ) 7.1, 2 H), 2.93 (m, 2 H),
2.43 (m, 2 H), 1.17 (t, J ) 7.1, 3 H); 13C NMR (CDCl3) δ 172.79,
172.32, 146.91, 142.30, 140.95, 137.83, 134.05, 131.51, 130.10,
129.12, 129.03, 128.90, 127.98, 127.00, 126.40, 117.68, 60.44,
35.37, 28.24, 14.18; MS (+FAB, NBA/PEGH) m/ z 325.1457,
[M + H]+ calcd for C20H20O4 325.1440.
Eth yl 3′-(Ca r boxyeth en yl)-2-bip h en ylp r op ion a te (12).
The biphenyl compound 11 (0.38 g, 1.2 mmol) was dissolved
in 50 mL of 1:1 ethanol:acetic acid in an oven-dried, 100 mL
round-bottomed flask. To the clear solution was added PtO2
(18.5 mg, 0.08 mmol). The system was alternately evacuated
under reduced pressure and flushed with H2. The reaction
mixture was vigorously stirred under positive H2 pressure
(using a balloon) for 6 h. The PtO2 was removed by filtration,
and the pale yellow filtrate was concentrated under reduced
pressure. The crude material was taken up in CH2Cl2 (30 mL)
and washed with H2O (3 × 40 mL). The organic layer was
dried (MgSO4), concentrated under reduced pressure, and dried
under high vacuum to afford 0.37 g (97%) of the desired
compound as an opaque oil: 1H NMR (CDCl3) δ 9.81 (bs, 1 H),
7.39-7.12 (m, 8 H), 4.08 (q, J ) 7.1, 2 H), 3.02 (m, 2 H), 2.94
(m, 2 H), 2.72 (m, 2 H), 2.44 (m, 2 H), 1.20 (t, J ) 7.1, 3 H);
13C NMR (CDCl3) δ 177.28, 173.73, 141.84, 141.59, 139.98,
137.73, 130.16, 129.27, 128.94, 128.58, 127.55, 127.15, 127.00,
126.25, 60.68, 35.77, 35.38, 30.94, 28.36, 14.11; MS (+FAB,
NBA/PEGH) m/ z 327.1585, [M + H]+ calcd for C20H22O4
327.1596.
E t h yl 3′-(N-(ter t-Bu t yloxyca r b on yl)-2-a m in oet h yl)-2-
bip h en ylp r op ion a te (13). Compound 12 (1.52 g, 4.66 mmol)
was dissolved in t-BuOH (18.0 mL) in an oven-dried, Ar cooled,
50 mL cone-shaped flask. The flask was flushed with Ar, and
diphenyl phosphorazidate (1.05 mL, 5.21 mmol) and Et3N (0.75
mL, 5.4 mmol) were added. The flask was fitted with an oven-
dried condenser, and the system was again flushed with Ar.
The slightly yellow solution was heated at reflux for 24 h. The
reaction mixture was concentrated under reduced pressure and
dried under high vacuum to afford the crude material as an
orange oil (3.71 g, 200%). The pure compound (1.30 g, 70%)
was obtained after flash chromatography (80:20 hexanes:ethyl
acetate) as a colorless oil: 1H NMR (CDCl3) δ 7.39-7.11 (m, 8
H), 4.75 (bs, 1 H), 4.08 (q, J ) 7.1, 2 H), 3.39 (m, 2 H), 2.93
(m, 2 H), 2.83 (m, 2 H), 2.40 (m, 2 H), 1.42 (s, 8 H), 1.17 (t, J
) 7.1, 3 H); 13C NMR (CDCl3) δ 172.89, 155.89, 141.84, 141.66,
139.06, 137.88, 130.15, 129.63, 129.07, 128.43, 127.56, 127.50,
127.15, 126.26, 79.20, 60.35, 36.27, 36.19, 35.43, 28.50, 28.41,
14.15; MS (+FAB, NBA/PEGH) m/ z 398.2334, [M + H]+ calcd
for C24H21O4N 398.2331.
3′-(N -(t er t -B u t y lo x y c a r b o n y l)-2-a m in o e t h y l)-2-b i-
p h en ylp r op ion ic Acid (14). The ester carbamate 13 (162.0
mg, 0.41 mmol) was dissolved in absolute ethanol (6.2 mL) in
an oven-dried, 10 mL round-bottomed flask. Addition of 1.0
M aqueous LiOH (4.0 mL, 4.0 mmol) to the clear solution
resulted in the reaction mixture becoming turbid. The mixture
was stirred under Ar at room temperature for 2.5 h. The
mixture was diluted with 100 mL of 1 M citric acid and washed
with ethyl acetate (3 × 75 mL). The combined organic layers
were washed with ice-cold H2O (3 × 100 mL), dried (MgSO4),
and concentrated under reduced pressure. Further drying
under high vacuum afforded the desired compound in quan-
titative yield as a clear oil: 1H NMR (CDCl3) δ 10.03 (bs, 1
H), 7.40-7.13 (m, 8 H), 4.83 (bs, 1 H), 3.39 (m, 2 H), 2.98 (m,
2 H), 2.83 (m, 2 H), 2.45 (m, 2 H), 1.45 (s, 8 H); 13C NMR
(acetone-d6) δ 175.62, 172.03, 143.27, 142.94, 140.95, 139.51,
131.19, 130.86, 130.35, 129.47, 128.71, 128.06, 127.34, 78.97,
73.85, 43.60, 43.02, 37.18, 35.81; MS (+FAB, NBA/PEGH) m/ z
370.2036, [M + H]+ calcd for C22H27O4N 370.2018.
N-Ben zyl-3′-(N-(ter t-bu tyloxyca r bon yl)-2-a m in oeth yl)-
2-bip h en ylp r op a n a m id e (15). Compound 14 (96.0 mg, 0.26
mmol), BOP reagent (0.19 g, 0.43 mmol), and DMF (8 mL)
were cooled to 0 °C in an oven-dried, 50 mL cone-shaped flask.
Freshly distilled benzylamine (0.60 mL, 5.5 mmol) was added,
and the solution was warmed to ambient temperature. The
reaction mixture became opaque. The mixture was stirred at
room temperature under Ar for 40 h and then diluted with
CH2Cl2 (40 mL). The organic solution was washed with 1 M
citric acid (3 × 25 mL), 5% NaHCO3 (3 × 25 mL), and H2O (6
× 25 mL), dried (MgSO4), and concentrated under reduced
pressure. After the solution was dried under high vacuum,
182 mg (151%) of the crude material was obtained as an
opaque yellow oil. Purification by flash chromatography (65:
35 hexanes:ethyl acetate) afforded 0.09 g (76%) of the pure
compound as a white foam: 1H NMR (CDCl3) δ 7.35-7.05 (m,
13 H), 6.08 (bs, 1 H), 4.94 (bs, 1 H), 4.30 (d, J ) 5.7, 2 H), 3.31
(m, 2 H), 2.98 (m, 2 H), 2.76 (m, 2 H), 2.29 (m, 2 H), 1.38 (s, 9
H); 13C NMR (CDCl3) δ 172.06, 156.02, 141.74, 139.15, 138.40,
138.17, 130.12, 129.64, 129.51, 128.54, 128.44, 127.64, 127.53,
127.25, 127.03, 126.25, 79.16, 43.33, 41.92, 37.66, 36.27, 29.37,
28.39; MS (+FAB, NBA/TROITON) m/ z 459.2656, [M + H]+
calcd for C29H37O3N2 459.2648.
N-Ben zyl-3′-(2-a m in oet h yl)-2-b ip h en ylp r op a n a m id e
(16). Compound 15 (0.57 mmol) was dissolved in CH2Cl2 (21.0
mL) in an oven-dried, 100 mL round-bottomed flask. TFA (9.0
mL of a 30% solution in CH2Cl2) was added to the flask, and
the clear solution was stirred at room temperature under Ar
for 1.5 h. The resulting slightly yellow solution was concen-
trated to a yellow oil. The oil was dissolved in CH2Cl2 (60 mL),
and the solution was washed with 10% NaHCO3 (4 × 50 mL).
The organic layer was dried (MgSO4), concentrated, and
further dried under high vacuum to afford 0.212 g (104%) of
the crude compound as an opaque yellow oil: 1H NMR (CDCl3)
δ 7.35-7.02 (m, 13 H), 5.93 (t, J ) 5.7, 1 H), 4.30 (d, J ) 5.7,
2 H), 2.94 (m, 4 H), 2.79 (m, 2 H), 2.25 (m, 2 H), 1.60 (s, 2 H);
13C NMR (CDCl3) δ 171.92, 141.83, 141.63, 139.73, 138.29,
138.11, 130.08, 129.65, 129.44, 128.60, 128.41, 127.66, 127.52,
127.35, 126.89, 126.29, 43.39, 43.18, 39.43, 37.74, 29.53; MS
(+FAB, NBA/PEGH) m/ z 359.2130, [M + H]+ calcd for C24H26
ON2 359.2123.
-
N-Ben zyl-3′-(2-(ben zyla m id o)eth yl)-2-bip h en ylp r op a n -
a m id e (3). The crude compound 16 (0.57 mmol), phenyl acetic
acid (216.0 mg, 1.59 mmol), and DIEA (362 µL, 2.08 mmol)
were dissolved in CH2Cl2 (42 mL) in an oven-dried, Ar purged,
100 mL round-bottomed flask. The slightly cloudy solution
was cooled to 0 °C, and BOP reagent (0.71 g, 1.6 mmol) was
added. The reaction mixture was stirred at 0 °C for 0.5 h and
then at room temperature for 21 h. The material was
concentrated to a yellow oil, dissolved in DMSO, and purified
by preparative C18
HPLC to afford 144.7 mg (53%) of the
desired diamide as a white solid: 1H NMR (CDCl3) δ 7.31-
6.97 (m, 18 H), 6.56 (m, 1 H), 6.32 (m, 1 H), 4.28 (d, J ) 5.7,
2 H), 3.51-3.39 (m, 4 H), 2.97 (m, 2 H), 2.73 (m, 2 H), 2.25
(m, 2 H);
13C NMR (CDCl3) δ 172.76, 171.90, 141.72, 141.66,
138.85, 137.97, 134.70, 130.12, 129.56, 129.40, 129.31, 128.84,
128.59, 128.39, 127.84, 127.73, 127.56, 127.45, 127.36, 127.23,
127.13, 126.41, 43.48, 43.22, 40.84, 37.57, 35.58, 29.56; MS
(+FAB, NBA/PEGH) m/ z 477.2548, [M + H]+ calcd for
C32H32O2N2 477.2542.
Syn th esis of 2-Am in o-3′-bip h en ylca r boxylic Acid a n d
Der iva tives. 3-Br om o-N-ter t-bu tyl-N-m eth ylben za m id e
(17). A solution of tert-butylmethylamine (10.0 mL, 83.4
mmol) in CH2Cl2 (100 mL) was cooled to 0 °C under N2 in a
250 mL round-bottomed flask. To the clear solution was added
triethylamine (11.8 mL, 84.7 mmol) followed by slow addition
of 3-bromobenzoyl chloride (11.0 mL, 83.3 mmol). After 2 h
at 0 °C, the reaction mixture contained a white precipitate.
The mixture was stirred at room temperature overnight. The
reaction mixture was transferred to a separatory funnel and
diluted with 100 mL each of CH2Cl2 and H2O. The aqueous
layer was washed with CH2Cl2 (3 × 100 mL). The combined
organic layers were washed with H2O, 5% acetic acid, and 5%

3136 J . Org. Chem., Vol. 61, No. 9, 1996
Nesloney and Kelly
aqueous NaOH (3 × 100 mL each). The clear, pale yellow
organic layer was dried (MgSO4), concentrated under reduced
pressure, and dried under high vacuum to afford 23.01 g
(102%) of the crude product as a white solid: mp 41-44 °C;
1H NMR (CDCl3) δ 7.53-7.43 (m, 2 H), 7.34-7.17 (m, 2 H),
2.81 (s, 3 H), 1.46 (s, 9 H); 13C NMR (CDCl3) δ 171.25, 141.00,
132.35, 130.18, 129.96, 125.72, 122.35, 56.69, 35.21, 27.63; MS
(0.85 mL, 6.1 mmol) and diphenyl phosphorazidate (1.55 mL,
7.2 mmol) were added at room temperature. The resulting
dark orange solution was heated at reflux under N2 for 22.5
h. The reaction mixture was concentrated under reduced
pressure. The dark brown oil was taken up in Et2O (150 mL)
and washed with 1 M citric acid and 5% NaOH (3 × 100 mL
each). The etheral layer was dried (MgSO4), concentrated
under reduced pressure, and dried under high vacuum to
afford 2.02 g (100%) of a 1.6:1.0 mixture of the desired
carbamate (21) and the corresponding urea compound (22) as
a light brown foam. Analytical samples of both compounds
were obtained by preparative C18 HPLC. The desired car-
bamate was obtained as a yellow oil: 1H NMR (CDCl3) δ 7.92
(bd, J o ) 8.3, 1 H), 7.54-7.14 (m, 7 H), 6.65 (bs, 1 H), 2.94 (s,
3 H), 1.53 (s, 9 H), 1.43 (s, 9 H); 13C NMR (CDCl3) δ 174.06,
153.69, 138.82, 137.90, 134.83, 130.78, 130.13, 129.35, 128.69,
127.69, 126.13, 124.04, 120.12, 120.02, 80.93, 57.97, 35.70,
28.18, 27.73.
(+FAB, NBA/PEGH) m/ z 270.0506, [M + H]+ calcd for C12H16
-
ONBr 270.0494.
3-(N-ter t-Bu t yl-N-m et h yla m id yl)p h en ylb or on ic Acid
(18). A 500 mL round-bottomed flask was flame-dried under
Ar and charged with 17 (6.80 g, 25.2 mmol) in 150 mL of THF.
The clear solution was cooled to -95 °C. Addition of s-BuLi
(20.2 mL, 27.7 mmol) resulted in a brown solution. After 10
min at -95 °C, the reaction mixture was treated with B(OMe)3
(9.2 mL, 81 mmol). The resulting dark yellow solution was
kept at -80 °C for 2 h and then warmed to -10 °C overnight.
The reaction mixture was stirred at room temperature for 1
h, cooled to 0 °C, and acidified to pH 6 with 10% HCl. The
resulting pale green mixture was stirred at 0 °C for 1.5 h. The
THF was removed under reduced pressure, and the material
was taken up in CH2Cl2 and H2O (150 mL each). The aqueous
layer was washed with CH2Cl2 (3 × 100 mL). The combined
organic layers were washed with 10% HCl (3 × 100 mL) and
saturated NaCl (2 × 200 mL). The organic layer was dried
(MgSO4), concentrated under reduced pressure, and dried
under high vacuum to afford 5.24 g (89%) of a yellow foam:
1H NMR (CDCl3) δ 8.11-8.07 (m, 1 H), 7.74-7.10 (m, 3 H),
2.86-2.85 (m, 3 H), 1.50 (s, 9 H); 13C NMR (CDCl3) δ 173.76,
138.08, 136.00, 133.51, 129.39, 128.27, 127.11, 56.48, 35.41,
27.80.
2-Am in o-3′-bip h en ylca r boxylic Acid (2). The crude
mixture of 21 and 22 (2.02 g, 5.9 mmol) was dissolved in
concentrated HCl in a 250 mL round-bottomed flask. Phenol
(5 drops) was added, and the solution was heated at 110 °C
under Ar for 45 h. After being cooled to 0 °C, the material
was filtered. The filtrate was diluted with H2
O and neutral-
ized with NaOH (total volume of 800 mL). The aqueous
solution was extracted with CHCl3 (8 × 75 mL). The combined
organic layers were dried (MgSO4), concentrated under re-
duced pressure, and dried under high vacuum to afford 0.58 g
(46%) of a beige solid. The material was purified by prepara-
tive C18
HPLC to obtain a white solid: 1H NMR (CDCl3) δ
8.11-8.10 (m, 1 H), 7.98 (dd, J o ) 7.6, J m ) 1.4, 1 H), 7.62-
6.70 (m, 7 H), 6.61 (bs, 2 H); 13C NMR (CDCl3) δ 168.67, 143.41,
139.64, 133.39, 131.41, 130.40, 128.77, 128.53, 126.55, 126.10,
118.64, 115.74, 114.85; MS (+FAB, NBA/PEGH) m/z 214.0852,
[M + H]+ calcd for C13H11O2N 214.0868.
Meth yl 3′-(N-ter t-Bu tyl-N-m eth yla m id yl)-2-bip h en yl-
ca r boxyla te (19). An oven-dried, three-necked, 100 mL
round-bottomed flask was charged with methyl 2-bromoben-
zoate (2.17 g, 10.1 mmol) and DME (20 mL). The flask was
fitted with
a condenser and purged with N2. Tetrakis-
Meth yl 2-Am in o-3′-biph en ylcar boxylate (23). The amino
acid 2 (0.12 g, 0.56 mmol) was suspended in anhydrous MeOH
in an oven-dried, 5 mL round-bottomed flask. The slightly
yellow suspension was cooled to 0 °C, and thionyl chloride (60
µL, 0.69 mmol) was added. The mixture immediately became
clear and slightly darker. The reaction was heated at reflux
for 10 h. Additional aliquots of SOCl2 were added (a total of
0.90 mL, 10 mmol), and refluxing was continued over 90 h.
The reaction mixture was partitioned between CHCl3 and 5%
NaHCO3 (30 mL each). The aqueous layer was washed with
CHCl3 (2 × 30 mL) and Et2O (3 × 40 mL). The combined
organic layers were dried (MgSO4), concentrated in vacuo, and
further dried under high vacuum to afford 0.13 g (100%) of a
yellow oil: 1H NMR (CDCl3) δ 8.14 (t, J ) 1.8, 1 H), 8.04-
7.98 (m, 1 H), 7.69-7.64 (m, 1 H), 7.49 (t, J ) 7.7, 1 H), 7.25-
7.13 (m, 2 H), 6.94-6.84 (m, 2 H), 4.64 (bs, 2 H), 3.90 (s, 3 H);
13C NMR (CDCl3) δ 166.93, 141.86, 139.47, 133.69, 130.76,
130.51, 130.27, 128.95, 128.48, 127.45, 119.85, 116.69, 52.20;
MS (+FAB, NBA/PEGH) m/z 227.0956, M+ calcd for C20H23O3N
227.0946.
2-(Ben zylam ido)-3′-biph en ylcar boxylic Acid (24). Phen-
ylacetic acid (0.84 g, 6.2 mmol) and BOP reagent (2.77 g, 6.3
mmol) were dissolved in 30 mL of freshly distilled CH2Cl2 in
an oven-dried, Ar-flushed, 100 mL round-bottomed flask.
DIEA (1.6 mL, 9.2 mmol) was added, and the clear solution
was cooled to 0 °C. Addition of 23 (0.14 g, 0.62 mmol in 30
mL of CH2Cl2) resulted in a very pale yellow solution. After
0.5 h at 0 °C, the solution was stirred at room temperature
for 68 h. N,N ′-Dimethylethylene (1.7 mL, 16 mmol) was
added to the dark yellow solution to destroy the excess active
ester. After 48 h at room temperature, the solution was
transferred to a separatory funnel and partitioned between
CH2Cl2 and 1 M citric acid (75 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 75 mL). The combined organic
layers were washed with 1 M citric acid (4 × 75 mL), 5%
NaHCO3 (3 × 75 mL), and H2O (2 × 75 mL). The organic layer
was dried (MgSO4), concentrated in vacuo, and further dried
under high vacuum to afford 0.92 g of the crude product as an
orange oil. The crude material was dissolved in MeOH (20
mL) in an oven-dried, Ar-flushed, 50 mL round-bottomed flask.
To the orange solution was added aqueous LiOH (4.4 mL of a
(triphenylphosphine)palladium(II) (0.34 g, 0.29 mmol) was
weighed out under N2 and added to the flask. The resulting
yellow solution was stirred at room temperature for 15 min.
Sequential addition of the boronic acid 18 (5.17 g, 22.0 mmol
in 10 mL of DME) and Na2CO3 (10.1 mL of a 2.0 M aqueous
solution, 20 mmol) resulted in a biphasic reaction mixture. The
mixture was heated at reflux for 50 h, and the solvents were
removed in vacuo. The resulting residue was taken up in
CH2Cl2 and H2O (150 mL each). The aqueous layer was
washed with CH2Cl2 (3 × 150 mL). The combined organic
layers were washed with saturated NaCl (3 × 100 mL), dried
(MgSO4), concentrated under reduced pressure, and dried
under high vacuum. The crude material was purified by flash
chromatography (80:19:1 hexanes:ethyl acetate:acetic acid) to
afford 2.25 g (69%) of a yellow oil: 1H NMR (CDCl3) δ 7.86-
7.81 and 7.52-7.29 (m, 8 H), 3.62 (s, 3 H), 2.88 (s, 3 H), 1.49
(s, 9 H); 13C NMR (CDCl3) δ 172.86, 168.73, 141.94, 141.37,
138.91, 131.39, 130.76, 130.59, 129.94, 129.32, 128.06, 127.42,
127.18, 126.12, 56.50, 51.94, 35.33, 27.73; MS (+FAB, NBA/
PEGH) m/z 326.1765, [M + H]+ calcd for C20H23O3N 256.1756.
3′-(N-ter t-Bu t yl-N-m et h yla m id yl)-2-b ip h en ylca r b ox-
ylic Acid (20). A 50 mL round-bottomed flask was charged
with compound 19 (1.22 g, 3.75 mmol), NaOH (0.77 g, 19
mmol), and 20 mL of absolute MeOH. The mixture was heated
at reflux under N2 for 6 h. The reaction mixture was diluted
with CH2Cl2 (35 mL) and 1 M citric acid (100 mL). The
aqueous layer was washed with CH2Cl2 (5 × 35 mL). The
combined organic layers were dried (MgSO4), concentrated
under reduced pressure, and dried under high vacuum to
afford 1.1 g (95%) of a white solid: 1H NMR (CDCl3) δ 7.92
(dd, J o ) 7.8, J m ) 1.4, 1 H), 7.58-7.50 (m, 1 H), 7.45-7.28
(m, 6 H), 2.82 (s, 3 H), 1.47 (s, 9 H); 13C NMR (CDCl3) δ 173.08,
172.12, 142.67, 141.15, 138.38, 137.29, 132.05, 131.10, 130.64,
129.78, 129.41, 128.17, 127.45, 126.17, 56.70, 35.30, 27.73; MS
(+FAB, NBA/PEGH) m/z 312.1605, [M + H]+ calcd for
C19H21O3N 312.1600.
2-(N-(ter t-Bu t yloxyca r b on yl)a m in o)-3′-b ip h en ylyl-N-
m eth yl-N-ter t-bu tyla m id e (21). The biphenyl acid amide
20 (1.83 g, 5.9 mmol) was dissolved in dry t-BuOH (25 mL) in
an oven-dried, 50 mL round-bottomed flask. Triethylamine

Synthesis of Biphenyl-Based Amino Acids
J . Org. Chem., Vol. 61, No. 9, 1996 3137
1.0 N solution, 4.4 mmol). After 18.5 h at room temperature,
the solution was concentrated to an orange oil and redissolved
in CHCl3 (75 mL) and 1 M citric acid (75 mL). The aqueous
layer was washed with CHCl3 (3 × 50 mL) and CH2Cl2 (3 ×
50 mL). The combined organic layers were dried over MgSO4
and concentrated under reduced pressure. Further drying
under high vacuum afforded 0.89 g of the crude product as an
orange oil. Purification by preparative C18 HPLC afforded 0.17
g (81%) of the pure material as a white solid: 1H NMR (CDCl3)
δ 8.34 (d, J o ) 8.2, 1 H), 8.06 (dt, J o ) 7.6, J m ) 1.6, 1 H), 7.84
(s, 1 H), 7.43-7.00 (m, 10 H), 3.64 (s, 2 H); 13C NMR (CDCl3)
δ 170.57, 169.21, 138.07, 134.54, 134.05, 133.48, 131.18,
130.57, 130.10, 129.96, 129.38, 129.17, 128.89, 128.70, 127.64,
126.74, 124.50, 121.18, 44.95; MS (+FAB, thiogly) m/z 332.1282,
[M + H]+ calcd for C21H17O3N 332.1287.
a temperature range of -72 to +30 °C. The DQCOSY was
run on a 4.2 mM sample. The dichloromethane used for the
IR study was freshly distilled from CaH2. Diamide 3 was
0.34-85 mM in concentration. IR spectra were collected on a
Galaxy 6021 spectrometer using CaF2 solution cells with an
optical pathlength of 3 mm or 0.02 mm (85 mM sample).
1H NMR a n d F T-IR Stu d ies of Dia m id e 4. Diamide 4
was dried under high vacuum in the presence of P2O5 for 3-5
days prior to use. All samples were prepared under Ar. The
CD2Cl2 used for the 1H NMR studies was purchased from
Aldrich. Variable-temperature 1H NMR measurements and
the DQCOSY were obtained on a Varian XL-400 spectrometer
using residual CH2Cl2 (5.32 ppm) as the chemical shift
reference. Concentrations of 4 for the VT experiment were
4.1-4.7 mM, and spectra were obtained at 6° increments over
a temperature range of -72 to +30 °C. The DQCOSY was
run on a 4.7 mM sample. The dichloromethane used for the
IR study was freshly distilled from CaH2. Diamide 4 was
0.18-44 mM in concentration. IR spectra were collected on a
Galaxy 6021 spectrometer using CaF2 solution cells with an
optical pathlength of 3 mm or 0.02 mm (44 mM sample).
N-Ben zyl-2-(ben zyla m id o)-3′-bip h en yla m id e (4). An
oven-dried, Ar-flushed, 50 mL round-bottomed flask was
charged with 24 (0.07 g, 0.2 mmol) and BOP reagent (0.10 g,
0.23 mmol) in dry CH2Cl2 (10 mL). Freshly distilled benzyl-
amine (0.50 mL, 4.6 mmol) was added, and the light yellow
solution was stirred at room temperature for 12 h. The
solution was concentrated under reduced pressure, and a crude
yellow oil was obtained. Purification by flash chromatography
(70:30 hexanes:ethyl acetate) afforded 0.085 g (96%) of a white
Ack n ow led gm en t. We thank Dr. J oe Riebenspies
for determining the X-ray crystal structures of 3 and 4,
Professor Donald Darensbourg for providing access to
FT-IR facilities, and Dr. Wayne R. Fiori for assistance
in preparing Figure 2. We gratefully acknowledge
financial support from the National Institutes of Health
(R01 GM51105), the Robert A. Welch Foundation,
Searle Scholars Program/The Chicago Community Trust
(J .W.K.), and the Camille and Henry Dreyfus Founda-
tion Teacher Scholars Program (J .W.K.). We would also
like to thank the reviewers for their insightful com-
ments.
solid: 1H NMR (CDCl3) δ 8.30 (d, J o ) 8.2, 1 H), 7.80 (dt, J o
)
7.8, 1 H), 7.48 (t, J ) 7.8, 1 H), 7.39-6.96 (m, 16 H), 6.34 (bs,
1 H) 4.66 (d, J ) 5.7, 2 H), 3.58 (s, 2 H); 13C NMR (CDCl3) δ
168.99, 166.45, 138.12, 137.99, 136.59, 134.93, 134.61, 133.61,
131.84, 131.33, 129.92, 129.30, 129.26, 129.15, 128.87, 128.84,
128.05, 127.80, 127.55, 127.24, 126.66, 124.39, 121.16, 44.98,
44.25; MS (+FAB, NBA) m/z 421.1905, [M + H]+ calcd for
C28H24O2N2 421.1916.
1H NMR a n d F T-IR Stu d ies of Dia m id e 3. Diamide 3
was dried under high vacuum in the presence of P2O5 for 3-5
days prior to use. All samples were prepared under Ar or in
a drybox under N2. Despite the extensive dying and very
careful sample preparation, up to 5-10 mmol of H2O was still
observed during the variable-temperature 1H NMR studies.
The CD2Cl2 used for the NMR studies was purchased from
Aldrich. Variable-temperature 1H NMR measurements and
the DQCOSY were obtained on a Varian XL-400 spectrometer
using residual CH2Cl2 (5.32 ppm) as the chemical shift
reference. Concentrations of 3 for the VT experiment were
4.2-6.3 mM, and spectra were obtained at 6° increments over
Su p p or tin g In for m a tion Ava ila ble: The 200 MHz 1H
and 13C spectra of new compounds lacking combustion data
(44 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O952194K