Preparation of Nβ-Fmoc-protected aza-β3- amino acids with nonproteinogenic hydrophobic side chains for solid-phase syntheses of pseudopeptides

Article abstract of DOI:10.1055/s-0028-1087969

The preparation of twelve new N^β-Fmoc-protected azaβ³-amino acids (aza-β³aa) with nonproteinogenic hydrophobic side chains is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087969

PAPER
1007
Preparation of Nb-Fmoc-Protected Aza-b3-Amino Acids with Nonproteino-
genic Hydrophobic Side Chains for Solid-Phase Syntheses of Pseudopeptides
b
N
z
a
a-
b
-Amino
t
Acids
h
w
ith Nonpr
o
i
teinog
e
enic
H
ydro
u
phobic Side ChainsLaurencin, Patrick Bauchat,* Michèle Baudy-Floc’h*
Groupe ‘Ciblage et Auto-Assemblages Fonctionnels’, UMR 6226 CNRS, Institut de Chimie, Université de Rennes I, 263 Avenue du
Général Leclerc, 35042 Rennes Cedex, France
Fax +33(2)23236738; E-mail: Michele.Baudy-Floch@univ-rennes1.fr
Received 30 October 2008; revised 12 November 2008
nine (4-Bip), cyclohexylalanine (Cha), diphenylalanine
Abstract: The preparation of twelve new Nb-Fmoc-protected aza-
(Dip), dodecylalanine (Dod), 4-fluorophenylalanine (4-F-
Phe), 4-fluoro-1-naphthylalanine (4-F-1-Nal), 1-naphthyl-
alanine (1-Nal), 2-naphthylalanine (2-Nal), octylalanine
(Oct), 4-pyridylalanine (4-Pal), and 3-pyridylalanine (3-
b3-amino acids (aza-b3aa) with nonproteinogenic hydrophobic side
chains is described.
Key words: aza-b3-amino acid, Fmoc protecting group, peptidomi-
metics, hydrophobic side chains, non-natural amino acid
Pal).
We have previously reported a method with which to pre-
pare aza-b3-amino acids via reductive amination of glyox-
Due to proteolytic degradation, peptides are not ideal can-
didates for pharmaceutical development. For this reason,
ylic acid.21 First, N-substituted Fmoc hydrazones 1 were
obtained by condensing fluoren-9-ylmethyl carbazate
with the appropriate aldehyde or ketone (Scheme 1). For
4-fluoro-1-naphthylalanine, since the corresponding alde-
hyde was not commercially available, 4-fluoro-1-naph-
thalenecarbaldehyde was first synthesized following the
procedure described by Boswell et al.22 Most of these hy-
drazones were not soluble in dichloromethane and precip-
itated immediately after their formation, thus driving the
reaction through a shift in the equilibrium. All these reac-
tions afforded very good yields (Table 2). The condensa-
tion of fluoren-9-ylmethyl carbazate and benzophenone
required heating to reflux in toluene with a Dean–Stark
trap.
numerous research groups try to develop non-natural pep-
tidic analogues in order to enhance metabolic stability,
bioavailability, and biological absorption.1–4 In this class
of peptidomimetics, pseudopeptides either consisting ex-
clusively or including aza-b3-amino acids have emerged
as a promising new class of compounds that favor hydro-
gen bond formation and can enhance biological activi-
ties.5–7 Nb-Fmoc-protected aza-b3-amino acids with both
nonfunctionalized and functionalized side chains that are
analogues of natural proteinogenic amino acids have been
already published,8–10 and we have demonstrated that
pseudopeptides including aza-b3-amino acids can be more
active than the natural parent peptides.6 In light of the in-
stability of aza-b3-Tyr and aza-b3-Trp analogues in a
strongly acidic medium, and in the context of our ongoing
projects on the synthesis of antimicrobial pseudopeptides,
we needed to develop Nb-Fmoc-protected aza-b3-amino
acid building blocks with non-proteinogenic side chains
that are more hydrophobic than natural side chains and
more stable. We already know that Trp residues can be re-
placed by naphthylalanine, pyridylalanine, biphenylala-
nine residues and many other compounds.11–13
Furthermore, lipophilic long alkyl chains are very useful
for enhancing or modifying antimicrobial activities and
cytotoxicity.14–17 Additionally, the incorporation of fluor-
inated amino acids have generated great interest since
such modifications can enhance the activity of antimicro-
bial peptides. Such modifications can also allow structural
NMR studies since fluorine labels are very suitable for an-
alyzing molecular orientations.18–20
R2
R2
O
R1
R1
FmocHN
N
FmocHN NH2
A
1
NaBH3CN
B
R2
R1
FmocHN NH
2
NaBH3CN
OHC-COOH
C
R2
R1
O
N
FmocHN
OH
3
Scheme 1 Synthesis of Fmoc-aza-b3-amino acids. See Table 1 for
R1 and R2
Thus, we describe here a detailed preparation of twelve
new aza-b3-amino acid derivatives (Table 1), with the side
chains of 9-anthracenylalanine (9-Ath), 4,4¢-biphenylala-
In a recent publication on the synthesis of aza-amino
acids, Boeglin et al. described the reduction of acyl
hydrazone intermediates of 1-naphthylalanine, 2-naph-
thylalanine and 4,4¢-biphenylalanine with 10% mol of
Pd(OH)2 on carbon (20% wt) in tetrahydrofuran (THF)
SYNTHESIS 2009, No. 6, pp 1007–1013
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x
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Advanced online publication: 24.02.2009
DOI: 10.1055/s-0028-1087969; Art ID: Z23508SS
© Georg Thieme Verlag Stuttgart · New York

1008
M. Laurencin et al.
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Table 1 Hydrophobic Non-Proteinogenic Side Chains (R1 and R2) of Aza-b3-Amino Acids
a 1-Nal
1-naphthylalanine
b 2-Nal
2-naphthylalanine
c 4-Bip
4¢-biphenylalanine
d Dip
diphenylalanine
e Cha
cyclohexylalanine
f 4-Fpa
4-fluorophenylalanine
F
N
g 9-Ath
9-anthracenylalanine
h 4-F-1-Nal
4-fluoro-1-naphthylalanine
i 3-Pal
3-pyridylalanine
F
N
j 4-Pal
4-pyridylalanine
k Oct
octylalanine
l Dod
dodecylalanine
3
3
under 100 psi H2 pressure.23 The authors reported that at-
tempts to reduce the acyl hydrazone intermediates with
sodium cyanoborohydride were not successful. However,
reduction of these hydrazones with sodium cyanoborohy-
dride in methanol could be performed with the use of an
additional solvent: N,N-dimethylformamide (DMF).
Table 2 Yields of the Reactions A, B and C
Side chain type
1-Nal
2-Nal
Dip
A
B
C
99%
97%
95%
98%
96%
97%
96%
87%
87%
99%
87%
91%
96%
96%
99%
99%
91%
98%
99%
99%
57%
45%
88%
91%
96%
98%
85%
93%
92%
96%
94%
96%
85%
86%
92%
95%
In fact, the acyl hydrazone intermediates were insoluble in
many solvents, including dichloromethane and methanol,
and it is this insolubility that prevents the action of the re-
ductive agent. Thus, hydrazones 1 were solubilized in the
minimum amount of DMF and then methanol and sodium
cyanoborohydride (1.5 equiv) were added. Immediately
after the addition, the pH of the solution was adjusted to
pH 3 and the reaction occurred. This addition of DMF is
not necessary for the reduction of all hydrazones and can
be replaced by dichloromethane for the reduction of
diphenylalanine, octyl and dodecylalanine hydrazones.
For all side chains, yields of hydrazone reduction were
very good (>95%; Table 2) except for the two pyridyl res-
idues. Effectively, protonation of the heterocycle during
these reactions could explain the two low yields. We
could isolate the two protonated forms of the acyl hydra-
zone intermediates and N¢-alkyl fluoren-9-ylmethyl car-
bazates of 4-pyridylalanine, and 3-pyridylalanine.
4-Bip
Cha
4-Fpa
9-Ath
4-F-1-Nal
3-Pal
4-Pal
Oct
Dod
In conclusion, we have shown that Fmoc-aza-b3-amino
acids, with chemically diverse hydrophobic side chains,
could be conveniently prepared via reductive amination of
glyoxylic acid. As in our precedent works, these mono-
mers could be anchored to resin, allowing the preparation
of mixed pseudopeptides on solid-phase support. The
solid-phase synthesis of antimicrobial hybrid peptides in-
corporating these analogues will be published later.
With the entire series of twelve N¢-alkyl fluoren-9-yl-
methyl carbazates 2 in hand, we could realize the final re-
ductive amination in the presence of glyoxilic acid to
provide the twelve new Nb-Fmoc-protected aza-b3-amino
acids 3. The reactions gave the expected products with
good to excellent yields from 70 to 98% (Table 2). All
conditions were the same except for Fmoc-aza-b3-9-an-
thracenylalanine, for which addition of some DMF was
necessary in order to solubilize the N¢-anthracen-9-yl
fluoren-9-ylmethylcarbazate before adding the reagents.
NMR spectra were recorded at 200 MHz or 300 MHz (1H) and 75
MHz (13C). 1H chemical shifts are reported in d values in ppm rela-
tive to CHCl3 (d = 7.24 ppm) as internal standard; 13C chemical
shifts are reported in ppm relative to CDCl3 (d = 77.0 ppm). Multi-
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Nb-Fmoc-Protected Aza-b3-Amino Acids with Nonproteinogenic Hydrophobic Side Chains
1009
plicities in 1H NMR are reported as: (br) broad, (s) singlet, (d) dou-
blet, (t) triplet, (q) quartet, and (m) multiplet. For the assignment of
Hz, 1 H, CH), 4.42 (d, J = 6.8 Hz, 2 H, CH2), 7.2–7.6 (m, 5 H, ArH
+ CH), 7.66–7.83 (d, J = 7 Hz, 2 H, ArH), 7.90 (d, J = 7 Hz, 2 H,
ArH), 10.71 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 153.8, 152.4, 144.2, 141.2,
128.1, 127.5, 125.7, 120.6, 65.9, 47.1, 40.4, 30.2, 26.0, 25.5.
signals H, 13C, and H–13C heteronuclear single quantum correla-
tion (HSQC) spectroscopy experiments were used. The analytical
laboratory from the Centre Régional de Mesures Physiques de
l'Ouest performed elemental analyses and electrospray mass spec-
trometry (HR-MS, ESI) studies using an MS/MS mass spectrometer
ZAB Spec TOF. Thin layer chromatography was performed on sil-
ica gel 60 F254 plates (Merck). Flash chromatography was per-
formed on SP silica gel 60 (230–600) mesh ASTM.
1
1
Hydrazone 4-Fpa (1f)
Yield: 97%; mp 200–201 °C.
1H NMR (300 MHz, DMSO-d6): d = 4.35 (t, J = 6.3 Hz, 1 H, CH),
4.54 (d, J = 6.3 Hz, 2 H, CH2), 7.25–7.48 (m, 6 H, ArH), 7.7–7.8
(m, 4 H, ArH), 7.92 (d, J = 6.9 Hz, 2 H, ArH), 8.10 (s, 1 H, CH),
11.29 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 164.95, 161.68 (s), 153.88 (s),
144.18 (s), 143.7, 141.3, 131.49 (s), 129.56, 129.1, 128.16 (d),
127.57 (d), 125.65 (d), 120.6, 116.4, 116.12, 66.26 (t), 47.1.
Condensation; General Procedure
A stirred solution of fluoren-9-ylmethyl carbazate (10.17 g, 40
mmol) in CH2Cl2 (500 mL) and aldehyde (1.1 equiv) was main-
tained under stirring overnight. The mixture was concentrated and
the resulting white powder was triturated in Et2O to give hydrazone
1, which was pure enough for the following steps. If the hydrazone
remains soluble, purification by chromatography on silica gel
(CH2Cl2–EtOAc, 9:1) was required.
Hydrazone 9-Ath (1g)
Yield: 96%; mp 249–250 °C.
1H NMR (200 MHz, DMSO-d6): d = 4.36 (t, J = 6.9 Hz, 1 H, CH),
4.59 (d, J = 6.9 Hz, 2 H, CH2), 7.20–7.50 (m, 4 H, ArH), 7.50–7.70
(m, 4 H, ArH), 7.80 (d, J = 7.2 Hz, 2 H, ArH), 7.89 (d, J = 7.2 Hz,
2 H, ArH), 8.11 (d, J = 6.5 Hz, 2 H, ArH), 8.65 (m, 3 H, ArH + CH),
9.27 (m, 1 H, ArH), 11.49 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 154.0, 144.2, 143.8, 141.3,
131.4, 129.9, 129.6, 129.4, 128.2, 127.6, 127.48 (d), 125.9, 125.8,
125.6, 125.2, 120.7, 66.3, 47.2.
Hydrazone 1-Nal (1a)
Yield: 99%; mp 219–220 °C.
1H NMR (200 MHz, DMSO-d6): d = 4.38 (t, J = 6.8 Hz, 1 H, CH),
4.57 (d, J = 6.8 Hz, 2 H, CH2), 7.29–8.05 (m, 14 H, ArH), 8.76 (d,
J = 7.2 Hz, 1 H, ArH), 8.82 (s, 1 H, CH), 11.32 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 154.0, 144.6, 144.2, 141.3,
134.0, 130.6, 130.5, 130.1, 129.2, 128.2, 127.7, 127.6, 126.7, 126.0,
125.6, 124.6, 120.7, 66.3, 47.1.
HRMS (ESI): m/z [M + Na]+ calcd for C26H20N2O2Na: 415.14225;
found: 415.1418.
Hydrazone 4-F-1-Nal (1h)
Yield: 87%; mp 221–222 °C.
1H NMR (200 MHz, DMSO-d6): d = 4.34 (t, J = 6.2 Hz, 1 H, CH),
4.53 (d, J = 6.2 Hz, 2 H, CH2), 7.30–7.47 (m, 5 H, ArH), 7.67–7.91
(m, 7 H, ArH), 8.11 (m, 1 H, ArH), 8.64 (s, 1 H, CH), 8.85 (m, 1 H,
ArH), 11.31 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 160.8, 157.5, 153.9, 144.3,
144.2, 141.3, 131.9, 131.8, 128.8, 128.2, 127.6, 127.5, 126.9, 126.8,
125.6, 125.0, 123.7, 123.5, 121.1, 121.0, 120.6, 110.3, 110.0, 66.4,
47.1.
Hydrazone 2-Nal (1b)
Yield: 97%; mp 235–236 °C.
1H NMR (200 MHz, DMSO-d6): d = 4.33 (t, J = 6.8 Hz, 1 H, CH),
4.53 (d, J = 6.8 Hz, 2 H, CH2), 7.32–7.92 (m, 14 H, ArH), 8.04 (d,
J = 7.2 Hz, 1 H, ArH), 8.25 (s, 1 H, CH), 11.34 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 153.4, 144.4, 143.7, 140.8,
133.5, 132.8, 132.1, 128.1, 128.2, 128.0, 127.7, 127.1, 126.9, 126.6,
125.1, 122.4, 120.1, 65.7, 46.6.
Hydrazone 3-Pal (1i)
Yield: 87%; mp 215–216 °C.
1H NMR (200 MHz, DMSO-d6): d = 4.35 (t, J = 6.7 Hz, 1 H, CH),
4.53 (d, J = 6.7 Hz, 2 H, CH2), 7.30–8.12 (m, 11 H, ArH + CH),
8.59 (d, J = 7 Hz, 1 H, ArH), 8.84 (s, 1 H, ArH), 11.45 (s, 1 H, NH).
HRMS (ESI): m/z [M + Na]+ calcd for C26H20N2O2Na: 415.14225;
found: 415.1419.
Hydrazone 4-Bip (1c)
Yield: 98%; mp 240–241 °C.
13C NMR (75 MHz, DMSO-d6): d = 153.8, 150.7, 148.74, 144.1,
142.0, 141.3, 133.5, 130.8, 128.2, 127.6, 125.6, 124.4, 120.6, 66.3,
47.1.
1H NMR (200 MHz, DMSO-d6): d = 4.32 (t, J = 6.7 Hz, 1 H, CH),
4.55 (d, J = 6.7 Hz, 2 H, CH2), 7.35–7.83 (m, 15 H, ArH), 7.90 (d,
J = 6.8 Hz, 2 H, ArH), 8.10 (s, 1 H, CH), 11.26 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 153.3 (s), 143.9, 143.7, 141.1,
140.8, 139.3, 133.5, 128.8, 127.7, 127.7, 127.2, 127.1, 126.9, 126.6,
125.1, 120.1, 65.7, 46.6.
Hydrazone 4-Pal (1j)
Yield: 99%; mp 215–216 °C.
1H NMR (200 MHz, DMSO-d6): d = 4.37 (t, J = 6.7 Hz, 1 H, CH),
4.62 (d, J = 6.7 Hz, 2 H, CH2), 7.30–8.00 (m, 10 H, ArH), 8.15 (s,
1 H, CH), 8.69 (d, J = 6.1 Hz, 2 H, ArH), 11.90 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 153.8, 150.6, 144.1, 142.4,
142.1, 141.3, 128.2, 127.6, 125.6, 121.4, 120.6, 66.7, 47.1.
Hydrazone Dip (1d)
Yield: 95%; mp 163–164 °C.
1H NMR (200 MHz, CDCl3): d = 4.38 (t, J = 7.4 Hz, 1 H, CH), 4.45
(d, J = 7.4 Hz, 2 H, CH2), 7.27–7.92 (m, 18 H, ArH).
13C NMR (75 MHz, CDCl3): d = 153.9, 152.0, 143.7, 141.4, 137.1,
131.8, 130.0, 129.9, 129.7, 128.5, 128.4, 127.8, 127.6, 127.1, 125.5,
120.1, 67.9, 47.0.
Hydrazone Oct (1k)
Yield: 87%; mp 137–138 °C.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 6.4 Hz, 3 H, CH3), 1.32
(m, 8 H, CH2), 1.54 (m, 2 H, CH2), 2.32 (m, 2 H, CH2), 4.31 (t, J = 7
Hz, 1 H, CH), 4.54 (d, J = 7 Hz, 2 H, CH2), 6.75 (m, 1 H, NH), 7.2
(t, J = 5.6 Hz, 1 H, CH), 7.29–7.5 (m, 4 H, ArH), 7.67 (d, J = 7.2
Hz, 2 H, ArH).
Hydrazone Cha (1e)
Yield: 96%; mp 207–208 °C.
1H NMR (300 MHz, DMSO-d6): d = 1.23 (m, 4 H, CH2), 1.60 (m,
2 H, CH2), 1.71 (m, 4 H, CH2), 2.19 (m, 1 H, CH), 4.30 (t, J = 6.8
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M. Laurencin et al.
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13C NMR (75 MHz, CDCl3): d = 153.8, 149.2, 143.7, 141.3, 128.8,
127.1, 125.2, 120.0, 67.1, 47.0, 32.3, 31.7, 29.2, 29.1, 26.6, 22.7,
14.1.
HRMS (ESI): m/z [M + H]+ calcd for C28H25N2O2: 421.1910; found:
421.1910.
N¢-(Diphenyl)fluorenylmethyl Carbazate (2d)
Yield: 99%; translucent oil.
Hydrazone Dod (1l)
Yield: 91%; mp 133–134 °C.
1H NMR (200 MHz, CDCl3): d = 4.24 (t, J = 6.6 Hz, 1 H, CH), 4.45
(d, J = 6.6 Hz, 2 H, CH2), 5.40 (br, 1 H, CH), 6.46 (br, 1 H, NH),
7.27–7.82 (m, 18 H, ArH).
13C NMR (75 MHz, CDCl3): d = 157.3, 143.7, 141.4, 141.2, 128.7,
127.8, 127.7, 127.15, 125.1, 120.1, 68.2, 67.1, 46.2.
1H NMR (300 MHz, CDCl3): d = 0.92 (t, J = 6.4 Hz, 3 H, CH3), 1.30
(m, 16 H, CH2), 1.56 (m, 2 H, CH2), 2.36 (m, 2 H, CH2), 4.32 (t,
J = 6.9 Hz, 1 H, CH), 4.56 (d, J = 6.9 Hz, 2 H, CH2), 6.76 (m, 1 H,
NH), 7.22 (t, J = 5.6 Hz, 1 H, CH), 7.30–7.5 (m, 4 H, ArH), 7.67 (d,
J = 7.1 Hz, 2 H, ArH), 7.81 (d, J = 7.1 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 153.7, 148.9, 143.7, 141.3, 127.8,
127.1, 125.1, 120.0, 67.4, 47.0, 32.2, 31.9, 29.6, 29.5, 29.4, 29.4,
29.2, 26.6, 22.7, 14.1.
N¢-(Cyclohexylmethyl)fluorenylmethyl Carbazate (2e)
Yield: 91%; mp 133–134 °C.
1H NMR (300 MHz, CDCl3): d = 0.96 (m, 2 H, CH2), 1.11–1.33 (m,
3 H, CH2), 1.46 (m, 1 H, CH), 1.68–1.78 (m, 5 H, CH2), 2.72 (m,
2 H, CH2), 4.25 (t, J = 6.7 Hz, 1 H, CH), 4.47 (d, J = 6.7 Hz, 2 H,
CH2), 6.47 (s, 1 H, NH), 7.2–7.6 (m, 4 H, ArH), 7.61 (d, J = 7.1 Hz,
2 H, ArH), 7.79 (d, J = 7.1 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 157.3, 143.8, 141.4, 127.8, 127.1,
125.0, 120.0, 66.9, 58.6, 47.2, 36.3, 31.3, 26.6, 26.0.
Reduction of Hydrazone 1; General Procedure
To a stirred solution of hydrazone 1 (35 mmol) in DMF–MeOH
(50:150 mL), NaBH3CN (2.7 g, 1.2 equiv) was added fractionally
into the above mixture and the pH was adjusted to pH 3 with HCl
(2N). This mixture was maintained under stirring for 1 h, then the
pH was adjusted to pH 1 over 10 min and finally increased to pH 7
with sat. NaHCO3. The mixture was filtered, concentrated, taken up
in EtOAc (150 mL) and washed with H2O (2 × 100 mL) and brine
(100 mL). The organic layer was dried over Na2SO4 and concentrat-
ed to give a crude foam, which was triturated in Et2O to give hydra-
zine 2 as a white powder, which was pure enough for the following
step. For characterization, the crude material was purified by chro-
matography on silica gel (CH2Cl2–EtOAc, 9:1).
N¢-(4-Fluorophenylmethyl)fluorenylmethyl Carbazate (2f)
Yield: 97%; mp 159–160 °C.
1H NMR (300 MHz, CDCl3): d = 3.97 (s, 2 H, CH2), 4.24 (t, J = 6.8
Hz, 1 H, CH), 4.49 (d, J = 6.8 Hz, 2 H, CH2), 6.29 (s, 1 H, NH), 7.03
(m, 2 H, ArH), 7.28–7.46 (m, 6 H, ArH), 7.58 (d, J = 7.2 Hz, 2 H,
ArH), 7.79 (d, J = 7.2 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 162.4, 157.2, 143.8, 141.4, 133.1,
130.7, 130.6, 127.8, 127.1, 124.95, 120.1, 115.5, 115.2, 66.9, 54.9,
47.2.
N¢-(1-Naphthylmethyl)fluorenylmethyl Carbazate (2a)
Yield: 96%; mp 136–137 °C (Lit.23 136–137 °C).
1H NMR (200 MHz, CDCl3): d = 4.27 (t, J = 6.7 Hz, 1 H, CH), 4.51
(m, 4 H, 2 × CH2), 6.43 (br, 1 H, NH), 7.30–7.39 (m, 2 H, ArH),
7.40–7.49 (m, 4 H, ArH), 7.50–7.70 (m, 4 H, ArH), 7.75–7.96 (m,
4 H, ArH), 8.31 (d, J = 8.4 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 46.9, 53.1, 66.7, 119.7, 123.6,
124.7, 125.0, 125.5, 126.1, 126.8, 127.5, 127.6, 128.2, 128.3, 131.7,
132.4, 133.5, 141.0, 143.3, 156.9.
N¢-(9-Anthracenylmethyl)fluorenylmethyl Carbazate (2g)
Yield: 99%; mp 208–210 °C.
1H NMR (200 MHz, DMSO-d6): d = 4.26 (t, J = 6.9 Hz, 1 H, CH),
4.44 (d, J = 6.9 Hz, 2 H, CH2), 4.87 (s, 2 H, CH2), 7.28–7.58 (m,
8 H, ArH), 7.71 (d, J = 7.2 Hz, 2 H, ArH), 7.88 (d, J = 7.2 Hz, 2 H,
ArH), 8.07 (d, J = 8 Hz, 2 H, ArH), 8.53 (s, 1 H, ArH), 8.56 (s, 2 H,
ArH), 8.98 (br, 1 H, NH).
HRMS (ESI): m/z [M + Na]+ calcd for C26H22N2O2Na: 417.15790;
13C NMR (75 MHz, DMSO-d6): d = 157.9, 144.3, 141.2, 135.0,
131.5, 131.1, 129.2, 128.1, 127.7, 127.55, 126.4, 125.8, 125.55,
125.3, 120.6, 66.3, 53.45, 47.3.
found: 417.1581.
N¢-(2-Naphthylmethyl)fluorenylmethyl Carbazate (2b)
Yield: 96%; mp 128–129 °C (Lit.23 128–129 °C).
1H NMR (200 MHz, CDCl3): d = 4.20 (m, 2 H, CH2), 4.25 (t, J = 6.8
Hz, 1 H, CH), 4.49 (m, 2 H, CH2), 6.45 (br, 1 H, NH), 7.39–7.38 (m,
2 H, ArH), 7.44 (t, J = 7.4 Hz, 2 H, ArH), 7.48–7.55 (m, 3 H, ArH),
7.57–7.63 (m, 2 H, ArH), 7.77–7.81 (m, 2 H, ArH), 7.82–7.91 (m,
3 H, ArH).
13C NMR (75 MHz, CDCl3): d = 156.9, 143.3, 141.0, 134.5, 133.0,
132.6, 127.9, 127.5, 127.4, 126.8, 126.6, 125.8, 125.6, 124.7, 119.7,
66.7, 55.4, 46.8.
N¢-(4-Fluoro-1-naphthylmethyl)fluorenylmethyl Carbazate
(2h)
Yield: 99%; mp 150–152 °C.
1H NMR (200 MHz, CDCl3): d = 4.13 (t, J = 6.7 Hz, 1 H, CH), 4.30
(s, 2 H, CH2), 4.39 (d, J = 5.9 Hz, 2 H, CH2), 6.23 (br, 1 H, NH),
6.96 (m, 1 H, ArH), 7.15–7.68 (m, 10 H, ArH), 8.02–8.06 (m, 2 H,
ArH), 8.15 (d, J = 7 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 160.5, 157.2, 143.6, 141.4, 133.35,
128.7, 127.8, 127.7, 127.3, 127.1, 126.15, 125.0, 124.1, 124.1,
121.15, 120.1, 108.75, 67.0, 58.0, 53.0, 47.2.
HRMS (ESI): m/z [M + H]+ calcd for C26H23N2O2: 395.1754; found:
395.1755.
N¢-(3-Pyridylmethyl)fluorenylmethyl Carbazate (2i)
Yield: 57%; mp 133–134 °C.
N¢-(Biphenyl-4-ylmethyl)fluorenylmethyl Carbazate (2c)
Yield: 99%; mp 140–141 °C (Lit.23 140–141 °C).
1H NMR (200 MHz, CDCl3): d = 4.03 (s, 2 H, CH2), 4.23 (t, J = 6.7
Hz, 1 H, CH), 4.49 (d, J = 6.7 Hz, 2 H, CH2), 7.03 (s, 1 H, NH),
7.20–7.47 (m, 5 H, ArH), 7.58 (m, 2 H, ArH), 7.65 (s, 1 H, ArH),
7.78 (d, J = 7 Hz, 2 H, ArH), 8.47 (d, J = 4 Hz, 1 H, ArH), 8.57 (s,
1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 157.4, 150.2, 148.7, 143.7, 141.3,
136.7, 133.3, 127.8, 127.1, 125.0, 123.4, 120.4, 66.8, 52.9, 47.2.
1H NMR (200 MHz, CDCl3): d = 4.09 (m, 2 H, CH2), 4.27 (m, 1 H,
CH), 4.51 (m, 2 H, CH2), 6.44 (br, 1 H, NH), 7.30–7.52 (m, 9 H,
ArH), 7.55–7.68 (m, 6 H, ArH), 7.80 (d, J = 7.5 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 156.8, 143.3, 141.0, 140.4, 140.2,
136.0, 129.1, 128.5, 127.5, 127.4, 127.0, 126.9, 126.8, 124.7, 119.7,
66.6, 55.0, 46.5.
Synthesis 2009, No. 6, 1007–1013 © Thieme Stuttgart · New York

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Nb-Fmoc-Protected Aza-b3-Amino Acids with Nonproteinogenic Hydrophobic Side Chains
1011
N¢-(4-Pyridylmethyl)fluorenylmethyl Carbazate (2j)
Yield: 45%; mp 127–128 °C.
Fmoc-aza-b3-2-Nal-OH (3b)
Yield: 98%; mp 130–132 °C.
1H NMR (200 MHz, CDCl3): d = 3.99 (s, 2 H, CH2), 4.21 (t, J = 6.4
Hz, 1 H, CH), 4.51 (d, J = 6.4 Hz, 2 H, CH2), 6.92 (s, 1 H, NH),
7.20–7.50 (m, 5 H, ArH), 7.59 (m, 2 H, ArH), 7.75 (s, 1 H, ArH),
7.78 (d, J = 7.1 Hz, 2 H, ArH), 8.47 (d, J = 6.1 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 157.4, 149.7, 147.0, 143.6, 141.4,
127.8, 127.1, 124.9, 123.7, 120.6, 66.8, 54.2, 47.2.
1H NMR (200 MHz, DMSO-d6): d = 3.69 (s, 2 H, CH2), 4.05–4.30
(m, 5 H, 2 × CH2 and CH), 7.18–7.96 (m, 15 H, ArH), 8.73 (br, 1 H,
NH), 12.51 (br, 1 H, COOH).
13C NMR (75 MHz, DMSO-d6): d = 171.1, 155.1, 143.6, 140.6,
135.3, 132.75, 132.35, 127.6, 127.5, 127.4, 127.3, 127.25, 127.0,
125.9, 125.6, 125.2, 120.0, 65.4, 59.5, 57.3, 46.6.
HRMS (ESI): m/z [M + Na]+ calcd for C28H25N2O4Na: 475.1634;
found: 475.1636.
HRMS (ESI): m/z [M + K]+ calcd for C28H24N2O4K: 491.1373;
found: 491.1382.
N¢-(Octyl)fluorenylmethyl Carbazate (2k)
Yield: 88%; mp 111–112 °C.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 6.3 Hz, 3 H, CH3), 1.32
(m, 10 H, CH2), 1.47 (m, 2 H, CH2), 2.88 (m, 2 H, CH2), 4.27 (t,
J = 6.7 Hz, 1 H, CH), 4.50 (d, J = 6.7 Hz, 2 H, CH2), 6.42 (s, 1 H,
NH), 7.30–7.5 (m, 4 H, ArH), 7.63 (d, J = 7 Hz, 2 H, ArH), 7.81 (d,
J = 7 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 157.25 (s), 143.75 (s), 141.36 (s),
127.78 (d), 127.09 (d), 125.01 (d), 120.04 (d), 66.95 (t), 52.06 (t),
47.24 (d), 31.86 (t), 29.53 (t), 29.28 (t), 27.79 (t), 27.08 (t), 22.70
(t), 14.15 (q).
Fmoc-aza-b3-4-Bip-OH (3c)
Yield: 93%; mp 144–146 °C.
1H NMR (200 MHz, DMSO-d6): d = 3.66 (s, 2 H, CH2), 4.11–4.25
(m, 5 H, 2 × CH2 and CH), 7.22–7.96 (m, 17 H, ArH), 8.75 (br, 1 H,
NH), 12.51 (br, 1 H, COOH).
13C NMR (75 MHz, DMSO-d6): d = 171.5, 155.15, 143.7, 140.7,
139.9, 138.9, 136.9, 129.5, 128.8, 127.5, 127.2, 127.0, 126.5, 126.3,
125.2, 120.0, 65.4, 59.1, 57.6, 46.6.
N¢-(Dodecyl)fluorenylmethyl Carbazate (2l)
Yield: 91%; mp 105–106 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C30H26N2O4Na: 501.1790;
1H NMR (300 MHz, CDCl3): d = 0.95 (t, J = 6.8 Hz, 3 H, CH3), 1.32
(m, 18 H, CH2), 1.47 (m, 2 H, CH2), 2.89 (m, 2 H, CH2), 4.27 (t,
J = 6.6 Hz, 1 H, CH), 4.5 (d, J = 6.6 Hz, 2 H, CH2), 6.60 (s, 1 H,
NH), 7.30–7.5 (m, 4 H, ArH), 7.63 (d, J = 7 Hz, 2 H, ArH), 7.8 (d,
J = 7 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 157.3, 143.8, 141.4, 127.8, 127.1,
125.0, 120.0, 66.9, 52.1, 47.3, 32.0, 29.8, 29.75, 29.7, 29.65, 29.6,
29.4, 27.8, 27.1, 22.8, 14.2.
found: 501.1789.
HRMS (ESI): m/z [M + K]+ calcd for C30H26N2O4K: 517.1530;
found: 517.1540.
Fmoc-aza-b3-Dip-OH (3d)
Yield: 85%; mp 138–140 °C.
1H NMR (200 MHz, CDCl3): d = 3.75 (s, 2 H, CH2), 4.06 (t, J = 7
Hz, 1 H, CH), 4.28 (d, J = 7 Hz, 2 H, CH2), 5.37 (s, 1 H, CH), 6.72
(br, 1 H, NH), 7.27–7.92 (m, 18 H, ArH).
13C NMR (75 MHz, CDCl3): d = 173.4, 156.7, 143.4, 141.2, 140.2,
128.95, 127.8, 127.7, 127.15, 125.1, 119.9, 74.3, 67.7, 55.9, 47.0.
HRMS (ESI): m/z [M + Na]+ calcd for C30H26N2O4Na: 501.1790;
found: 501.1800.
Reductive Amination; General Procedure
To a stirred solution of substituted fluorenylmethyl carbazate (32
mmol) in CH2Cl2–MeOH (80:150 mL), glyoxylic acid monohy-
drate (1.2 equiv) was added. NaBH3CN (1.5 equiv) was added frac-
tionally into the above mixture, which was maintained under
stirring for 1 h, then the pH was adjusted to pH 1 over 10 min and
finally increased to pH 4 with sat. NaHCO3. The mixture was fil-
tered, concentrated, taken into EtOAc (100 mL) and washed with
acid water (0.5 M HCl; 2 × 100 mL) and brine (75 mL). The organic
layer was dried over Na2SO4 and concentrated to give a crude foam,
which was triturated in Et2O to give the crude product (13.7 g). All
monomers were purified by chromatography on silica gel (CH2Cl2–
MeOH, 9:1).
HRMS (ESI): m/z [M + K]+ calcd for C30H26N2O4K: 517.1530;
found: 517.1519.
Fmoc-aza-b3-Cha-OH (3e)
Yield: 92%; translucent oil.
1H NMR (300 MHz, CDCl3): d = 0.86 (m, 2 H, CH2), 1.11–1.33 (m,
2 H, CH2), 1.38 (m, 1 H, CH), 1.64 (m, 4 H, CH2), 1.81 (m, 2 H,
CH2), 2.67 (d, J = 6.1 Hz, 2 H, CH2), 3.62 (s, 2 H, CH2), 4.16 (t,
J = 6.7 Hz, 1 H, CH), 4.42 (d, J = 6.7 Hz, 2 H, CH2), 7.17 (s, 1 H,
NH), 7.24–7.40 (m, 4 H, ArH), 7.53 (d, J = 7.2 Hz, 2 H, ArH), 7.71
(d, J = 7.2 Hz, 2 H, ArH), 10.45 (br, 1 H, COOH).
13C NMR (75 MHz, CDCl3): d = 172.85, 157.0, 143.6, 141.3, 127.8,
127.1, 125.0, 120.0, 67.1, 64.5, 59.3, 47.1, 35.8, 31.2, 26.5, 25.9.
HRMS (ESI): m/z [M + Na]+ calcd for C24H28N2O4Na: 431.1947;
found: 431.1950.
Fmoc-aza-b3-1-Nal-OH (3a)
Yield: 96%; mp 175–176 °C.
1H NMR (200 MHz, DMSO-d6): d = 3.75 (s, 2 H, CH2), 4.08–4.27
(m, 3 H, CH2 + CH), 4.52 (d, J = 6.7 Hz, 2 H, CH2), 7.28–7.74 (m,
8 H, ArH), 7.77 (d, J = 7 Hz, 2 H, ArH), 7.80–7.98 (m, 4 H, ArH),
8.62 (d, J = 7.3 Hz, 1 H, ArH), 8.78 (br, 1 H, NH), 12.58 (br, 1 H,
COOH).
13C NMR (75 MHz, DMSO-d6): d = 171.72, 155.73, 144.20,
141.17, 133.83, 133.57, 132.64, 128.59, 128.34, 128.09, 127.53,
126.35, 126.14, 125.76, 125.68, 125.62, 120.52, 65.96, 57.97,
57.50, 58.60, 47.14.
HRMS (ESI): m/z [M + H]+ calcd for C28H25N2O4: 453.18143;
found: 453.1806.
Fmoc-aza-b3-4-Fpa-OH (3f)
Yield: 96%; mp 135–136 °C.
1H NMR (300 MHz, CDCl3): d = 3.56 (s, 2 H, CH2), 3.90 (s, 2 H,
CH2), 4.01 (t, J = 6.6 Hz, 1 H, CH), 4.28 (d, J = 6.6 Hz, 2 H, CH2),
6.74 (s, 1 H, NH), 6.85 (m, 2 H, ArH), 7.02–7.52 (m, 8 H, ArH),
7.63 (d, J = 7 Hz, 2 H, ArH), 8.82 (br, 1 H, COOH).
13C NMR (75 MHz, CDCl3): d = 173.5, 162.5, 156.4, 143.5, 141.35,
133.1, 131.0, 127.9, 127.1, 124.9, 120.1, 115.5, 67.2, 60.2, 56.7,
47.1.
HRMS (ESI): m/z [M + Na]+ calcd for C28H24N2O4Na: 475.16338;
found: 475.1637.
Synthesis 2009, No. 6, 1007–1013 © Thieme Stuttgart · New York

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M. Laurencin et al.
PAPER
HRMS (ESI): m/z [M + Na]+ calcd for C24H21N2O4FNa: 443.1383;
found: 443.1378.
Fmoc-aza-b3-Oct-OH (3k)
Yield: 92%; mp 102 °C.
HRMS (ESI): m/z [M + K]+ calcd for C24H21N2O4FK: 459.1122;
found: 459.1126.
1H NMR (300 MHz, CDCl3): d = 0.78 (t, J = 6 Hz, 3 H, CH3), 1.16
(m, 10 H, CH2), 1.35 (m, 2 H, CH2), 2.74 (t, J = 7 Hz, 2 H, CH2),
3.54 (s, 2 H, CH2), 4.10 (t, J = 6.7 Hz, 1 H, CH), 4.40 (d, J = 6.7 Hz,
2 H, CH2), 6.54 (br, 1 H, NH), 7.16–7.36 (m, 4 H, ArH), 7.47 (d,
J = 7.1 Hz, 2 H, ArH), 7.66 (d, J = 7.1 Hz, 2 H, ArH), 8.78 (br, 1 H,
COOH).
13C NMR (75 MHz, CDCl3): d = 173.0, 156.9, 143.5, 141.3, 127.8,
127.1, 125.0, 120.0, 67.2, 58.8, 57.7, 47.2, 31.8, 29.4, 29.2, 27.1,
26.9, 22.6, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C25H32N2O4Na: 447.2260;
found: 447.2274.
HRMS (ESI): m/z [M + K]+ calcd for C25H32N2O4K: 463.1999;
found: 463.2013.
Fmoc-aza-b3-9-Ath-OH (3g)
Yield: 94%; mp 219–220 °C.
1H NMR (200 MHz, DMSO-d6): d = 3.71 (s, 2 H, CH2), 4.07 (t, J =
6.8 Hz, 1 H, CH), 4.18 (d, J = 6.8 Hz, 2 H, CH2), 5.05 (m, 2 H,
CH2), 7.23–7.60 (m, 8 H, ArH), 7.80 (d, J = 7.3 Hz, 2 H, ArH), 7.83
(d, J = 7.3 Hz, 2 H, ArH), 8.05 (d, J = 8.5 Hz, 2 H, ArH), 8.57 (br,
1 H, ArH), 8.73 (br, 2 H, ArH).
13C NMR (75 MHz, DMSO-d6): d = 171.6, 155.4, 143.6, 140.6,
131.2, 130.9, 128.6, 128.2, 127.7, 127.5, 127.0, 125.9, 125.2, 125.1,
125.0, 120.0, 65.6, 56.2, 51.4, 46.5.
HRMS (ESI): m/z [M + Na]+ calcd for C32H26N2O4Na: 525.1790;
found: 525.1777.
HRMS (ESI): m/z [M + 2Na]+ calcd for C28H25N2O4Na2: 547.1610;
Fmoc-aza-b3-Dod-OH (3l)
Yield: 95%; mp 100 °C.
found: 547.1644.
1H NMR (300 MHz, CDCl3): d = 0.92 (t, J = 6.3 Hz, 3 H, CH3), 1.28
(m, 18 H, CH2), 1.48 (m, 2 H, CH2), 2.88 (t, J = 7 Hz, 2 H, CH2),
3.68 (s, 2 H, CH2), 4.22 (t, J = 6.6 Hz, 1 H, CH), 4.51 (d, J = 6.6 Hz,
2 H, CH2), 6.83 (s, 1 H, NH), 7.30–7.45 (m, 4 H, ArH), 7.59 (d,
J = 7.2 Hz, 2 H, ArH), 7.77 (d, J = 7.2 Hz, 2 H, ArH), 11.19 (s, 1 H,
COOH).
13C NMR (75 MHz, CDCl3): d = 173.5, 156.9, 143.6, 141.4, 127.85,
127.1, 125.0, 120.1, 67.2, 58.6, 57.5, 47.2, 32.0, 29.7, 29.7, 29.7,
29.65, 29.5, 29.4, 26.9, 22.8, 14.2.
Fmoc-aza-b3-4-Fluo-1-Nal-OH (3h)
Yield: 96%; mp 190–192 °C.
1H NMR (200 MHz, DMSO-d6): d = 3.72 (s, 2 H, CH2), 4.13 (m,
1 H, CH), 4.22 (br, 2 H, CH2), 4.44 (br, 2 H, CH2), 7.14–7.60 (m,
9 H, ArH), 7.84 (d, J = 7.2 Hz, 2 H, ArH), 8.04 (d, J = 7.2 Hz, 2 H,
ArH), 8.62 (d, J = 7.8 Hz, 1 H, ArH), 8.71 (br, 1 H, NH), 12.58 (br,
1 H, COOH).
13C NMR (75 MHz, DMSO-d6): d = 171.2, 159.4, 156.1, 155.2,
143.65, 140.6, 133.4, 129.55 130.0, 127.85, 127.75, 127.55, 127.0,
126.3, 125.5, 125.2, 123.1, 122.9, 120.0, 119.9, 108.8, 108.5, 65.3,
59.7, 57.0, 46.6.
HRMS (ESI): m/z [M + Na]+ calcd for C29H40N2O4Na: 503.2886;
found: 503.2873.
References
HRMS (ESI): m/z [M + Na]+ calcd for C28H23N2O4FNa: 493.1540;
found: 493.1537.
HRMS (ESI): m/z [M + K]+ calcd for C28H23N2O4FK: 509.1279;
found: 509.1270.
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66, 4923.
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Fmoc-aza-b3-3-Pal-OH (3i)
Yield: 85%; white foam.
1H NMR (200 MHz, CDCl3): d = 3.75 (s, 2 H, CH2), 4.11 (s, 2 H,
CH2), 4.21 (t, J = 6.4 Hz, 1 H, CH), 4.35 (d, J = 6.4 Hz, 2 H, CH2),
7.27–7.81 (m, 10 H, ArH), 8.42 (d, J = 4.2 Hz, 1 H, ArH), 8.65 (s,
1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 173.7, 155.9, 147.5, 146.1, 143.7,
141.3, 139.6, 134.4, 127.8, 127.1, 125.0, 124.4, 120.0, 66.9, 57.7,
57.2, 47.1.
HRMS (ESI): m/z [M + Na]+ calcd for C23H21N3O4Na: 426.1430;
found: 426.1448.
Fmoc-aza-b3-4-Pal-OH (3j)
Yield: 86%; white foam.
1H NMR (200 MHz, CDCl3): d = 3.67 (s, 2 H, CH2), 4.05 (s, 2 H,
CH2), 4.16 (t, J = 6.6 Hz, 1 H, CH), 4.31 (d, J = 6.6 Hz, 2 H, CH2),
7.20–7.80 (m, 10 H, ArH), 8.45 (d, J = 6.3 Hz, 2 H, ArH).
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7, 425.
13C NMR (75 MHz, CDCl3): d = 173.7, 156.2, 150.2, 146.6, 143.6,
141.4, 127.8, 127.1, 124.9, 124.6, 120.0, 66.8, 59.6, 57.4, 47.1.
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Regoli, D.; Salvadori, S. J. Med. Chem. 2008, 51, 655.
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Formaggio, F.; Crisma, M.; Toniolo, C.; Bodo, B.; Rebuffat,
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HRMS (ESI): m/z [M + H]+ calcd for C23H22N3O4: 404.1610; found:
404.1609.
HRMS (ESI): m/z [M + Na]+ calcd for C23H21N3O4Na: 426.1430;
found: 426.1432.
HRMS (ESI): m/z [M + K]+ calcd for C23H21N3O4K: 442.1170;
found: 442.1194.
Synthesis 2009, No. 6, 1007–1013 © Thieme Stuttgart · New York

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Nb-Fmoc-Protected Aza-b3-Amino Acids with Nonproteinogenic Hydrophobic Side Chains
1013
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