A facile synthesis and crystallographic analysis of N-protected β-amino alcohols and short peptaibols

Article abstract of DOI:10.1039/c0ob01226b

A facile, efficient and racemization-free method for the synthesis of N-protected β-amino alcohols and peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide, tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of β-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III β-turn being observed in the tripeptide alcohol crystals. This method is found to be compatible with Fmoc-, Boc- and other side-chain protecting groups.

Full text of DOI:10.1039/c0ob01226b

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PAPER
A facile synthesis and crystallographic analysis of N-protected b-amino
alcohols and short peptaibols†
Sandip V. Jadhav, Anupam Bandyopadhyay, Sushil N. Benke, Sachitanand M. Mali and Hosahudya N. Gopi*
Received 21st December 2010, Accepted 15th March 2011
DOI: 10.1039/c0ob01226b
A facile, efficient and racemization-free method for the synthesis of N-protected b-amino alcohols and
peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide,
tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of
b-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III b-turn
being observed in the tripeptide alcohol crystals. This method is found to be compatible with Fmoc-,
Boc- and other side-chain protecting groups.
N-Hydroxysuccinimide (HOSu) has been widely used as an
additive in carbodiimide-mediated peptide couplings to reduce
Introduction
racemization.19 Recently, the use of N-hydroxysuccinimide es-
ters in the synthesis of N-protected homoserines starting from
aspartic and glutamic acids has been demonstrated.20 Further,
the combination of carbodiimide and HOSu has been used in
the immobilization of proteins, peptides, antibodies on sensor
surfaces.21 Because of their shelf-stability and slow reactivity, N-
hydroxysuccinimide esters have also been used in the single-step
synthesis of dipeptide acids.22
Herein, we report the synthesis of N-protected-b-amino alco-
hols and peptide alcohols starting from N-hydroxysuccinimide
esters of N-protected amino acids and peptides. This method is
compatible with N-Fmoc, N-Boc and other carboxylic acid, alco-
hol, thiol and guanidine protecting groups. Using chiral HPLC,
we demonstrated that this protocol is free from racemization. In
addition, the crystal conformations of Fmoc-Valol, Boc-Ala-Valol
and the tripeptide alcohol Boc-Aib-Ala-Leuol synthesized using
this method were studied.
b-Amino alcohols are an important C-terminal component of
biologically active peptaibols.1 They have been extensively used
as chiral auxiliaries in asymmetric synthesis,2 precursors for the
synthesis of b-amino acids,3 starting materials for the synthesis
of optically active a-amino aldehydes,4 diamines, triamines5 and
a-halo-b-amines.6 Numerous methods have been reported for the
synthesis of N-protected b-amino alcohols starting from the re-
duction of activated carboxylic group of N-protected amino acids.
A variety of carboxylic-acid-activated derivatives of protected
amino acids including mixed anhydrides,7 acid fluorides,8 acid
chlorides,9 1-hydroxybezotriazole esters,10 1-succinimidyl esters,11
pentafluorophenyl esters,12 N-carboxyanhydrides (UNCAs)13 and
carboxy methyleniminium chlorides14 have been used for reduction
using mild NaBH4. Other mild reducing agents, such as NaBH4–
I2,15 ZnBH4 and Ti(OiPr)4 and (EtO)3SiH,17 have also been
16
reported with protected amino acid derivatives.
We have been interested in the synthesis of peptides containing
g- and functionalized g-amino acids.18 N-Protected b-amino alco-
hols are the starting materials for the synthesis of functionalized
g-amino acids. We followed the most widely used mixed anhydride
protocol for the synthesis; however, in our hands yields were lower
than the expected, and we found up to 15% of the isobutyl ester
as a byproduct.9 In our continuing search for mild, low-cost and
high-yielding methods for the synthesis of N-protected b-amino
alcohols, we envisioned that N-hydroxysuccinimide esters would
be ideal reagents because of their easy accessibility, shelf-stability
and cost-effectiveness.
Results and discussion
A schematic representation of the synthesis of N-protected b-
amino alcohols using N-hydroxysuccinimide is shown in Scheme 1.
We synthesized a variety of N-hydroxysuccinimide esters of Fmoc-
amino acids using DCC as a coupling agent in quantitative
yield. In a typical reaction procedure, the succinimide esters were
dissolved in distilled THF and then treated with a solution of
NaBH4 in ice-cold water. The course of the reaction was monitored
by TLC. Intriguingly, it was found that within 5 min the active ester
was completely converted to alcohol; however, we continued the
reaction for another 5 min.
Department of Chemistry, Indian Institute of Science Education and
Research, Garware Circle, Pashan, Pune, 411021, India. E-mail: hn.gopi@
iiserpune.ac.in
† Electronic supplementary information (ESI) available: Detailed experi-
mental procedures; characterization data; crystallographic data; 1H and13C
NMR and mass spectra for all compounds. CCDC reference numbers
794215 (3), 805264 (16) and 794216 (20). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0ob01226b
A list of Fmoc-protected b-amino alcohols synthesized using
this method is given in Table 1. Except Fmoc-Ile-OH (entry 5),
all Fmoc-b-amino alcohols were isolated in yields above 80%.
For comparison, we synthesized the same Fmoc-b-amino alcohols
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Scheme 1 Schematic representation of the synthesis of N-protected-b-amino alcohols using N-hydroxysuccinimide esters.
using mixed anhydride method (‘IBC-Cl’), and these values are
also given in Table 1.
A clear improvement of the yields can be observed for the
N-hydroxysuccinimide method relative to the mixed anhydride
method in the case of side-chain-protected amino acids (entries
6–10). The optical rotation and the melting points of Fmoc-b-
amino alcohols derived from the N-hydroxysuccinimide esters are
in agreement with the mixed anhydride method (Table 1).
To investigate the racemization during the synthesis of b-
amino alcohols, we synthesized Fmoc-b-amino alcohols from
D-, L- and DL-alanine. These amino alcohols were subjected to
chiral HPLC separation using a chiralpack AD column. The
HPLC profiles of Fmoc-protected D-, L- and DL-Alaol is shown
in Fig. 1. Single peaks were obtained for Fmoc-L-Alaol and
Fmoc-D-Alaol at tR 6.24 min and 7.66 min, respectively. For
the DL mixture two peaks with tR at 6.26 and 7.70 min were
observed, corresponding to the individual enantiomers. These
results indicate that no racemization occurred during the syntheses
of the b-amino alcohols.
Given these encouraging results, we extended the same
methodology to the synthesis of Boc-b-amino alcohols. The N-
hydroxysuccinimide esters of Boc-amino acids were prepared
from the coupling reaction of Boc-amino acids and HOSu using
DCC as a coupling agent (Scheme 1). A list of Boc-b-amino
alcohols is given in Table 2 (entries 11–15). The yields and optical
rotations of Boc-b-amino alcohols from the succinimide method
are in agreement with the mixed anhydride method (data not
Fig. 1 Chiral HPLC of Fmoc-protected L-, D- and DL-Alaol. HPLC was
performed on a chiralpack AD column using 90% isopropanol in n-hexane
as the solvent system in the isocratic mode with a flow rate of 1 mL min-1.
HPLC profiles for: a) Fmoc-L-Alaol; b) Fmoc-D-Alaol; c) Fmoc-DL-Alaol.
shown). Except for 15, all Boc-b-amino alcohols were isolated as
oils.
We further explored the N-hydroxysuccinimide method to verify
whether or not it can be used to reduce the peptide acids into the
corresponding peptide alcohols. A variety of methods have been
Table 1 Comparison of Fmoc-protected b-amino alcohol obtained from HOSu and IBC-Cl method
Yield (%)
HOSu
mp (◦C)
HOSu
[a]2D5 (c 1, MeOH)
Entry/Cpd no.
Fmoc-AA-OH
IBC-Cl
IBC-Cl
HOSu
IBC-Cl
1
2
Fmoc-Alaol
Fmoc-D-Alaol
Fmoc-Valol
Fmoc-Leuol
Fmoc-Ileol
Fmoc-Thr(OtBu)ol
Fmoc-Asp(OtBu)ol
Fmoc-Lys(Boc)ol
Fmoc-Asn(Trt)ol
Fmoc-Gln(Trt)ol
90
85
90
81
65
85
92
75
90
85
70
NSa
76
68
50
55
47
64
65
72
150–153
148–151
121–122
133–135
114–116
Oil
150–153
—
124–127
135–136
108–110
Oil
95–96
114
132–134
73–77
-2.0
-1.5
—
+2.0
-13.0
-20.1
-11.7
+6.1
-7.4
3
-13.6
-17.0
-13.0
+6.4
-7.0
-6.0
-10.3
-6.7
4
5
6
7
93–96
8
136–138
155–159
74–77
-6.9
-12.3
-5.8
9
10
a NS: Not synthesized.
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Table 2 Boc-protected b-amino alcohols and di-, tri-, and pentapeptide
alcohols synthesized using the N-hydroxysuccinimide method
(21) was purified by reverse-phase HPLC using a C18 column. The
1H, 13C NMR and HPLC profiles are given in the ESI†. Out of
all the peptides, we were able to obtain single crystals for Boc-
Ala-Valol (16) and Boc-Aib-Ala-Leuol (20). The conformation of
these peptide alcohols is described below.
Entry/Cpd
no.
[a]2D5 (c 1,
MeOH)
Alcohol
Yield (%)
11
12
13
14
15
16
17
18
19
20
21
Boc-Alaol
Boc-Valol
Boc-Leuol
Boc-Prool
80
70
85
78
75
86
82
82
76
79
65
-8.5
-17.6
-23.2
-45.7
-22.2
-22.2
-34.7
-35.9
-34.5
-13.6
NDa
Crystal structures of b-amino alcohol and dipeptide and tripeptide
alcohols
Boc-Trpol
Boc-Ala-Valol
Boc-Val-Valol
Boc-Val-Leuol
Boc-Ala-Leu-Valol
Boc-Aib-Ala-Leuol
Boc-Val-Leu-Ala-Val-Leuol
Crystals of Fmoc-Valol were obtained after slow evaporation
of ethyl acetate, and the crystal structure is shown in Fig. 2A.
The molecule adopted an extended-sheet type of assembly by
the intermolecular H-bonding of NH and OH groups with
the urethane carbonyl of the neighboring molecule (see ESI†).
Crystals of the dipeptide alcohol 16 obtained in methanol solution
yield the structure shown in Fig. 2B. Two molecules appear in
the asymmetric unit, with significant variation in the torsional
values (given in the ESI†). The dipeptide alcohol adopted an
irregular structure in the crystal packing. Notably, an energetically
unfavorable cis-Boc–urethane bond is observed in the molecule B
(Fig. 2B).
a ND: Not determined.
reported in the literature for the synthesis of peptide alcohols,
including the nucleophilic substitution of free amino alcohols
in N-protected amino acid benzotriazoles,23 O–N acyl transfer
of peptide esters,24 and the coupling reaction of N-protected
amino acids and free amino alcohols using standard coupling
reaction conditions.25 To extend this methodology to peptide
alcohols, we synthesized the following methyl esters of Boc-
protected dipeptides using a DCC and HOBt protocol – Boc-Ala-
Val-OMe, Boc-Val-Val-OMe and Boc-Val-Leu-OMe. The pure
dipeptide acids were obtained after the saponification of methyl
esters using 1 N NaOH. The conversion of dipeptide acid to its
alcohol is shown in Scheme 2.
The dipeptide acids were converted to N-hydroxysuccinimide
active esters using DCC and HOSu in ice-cold THF. The separated
DCU was filtered, and the filtrate containing Boc-dipeptide active
ester was reduced in situ using NaBH4 in water. As anticipated,
all peptide alcohols were isolated in pure form without column
purification in high yields (Table 2, entries 16, 17 and 18). The 1H,
13C NMR and HPLC profiles are given in the ESI†. The results
from both 1H-NMR and HPLC reveal single enantiomers as the
products, indicating that the synthesis is free from racemization.
We further extended this methodology to the synthesis of Boc-
protected tripeptide alcohols, Boc-Ala-Leu-Valol (19), Boc-Aib-
Ala-Leuol (20) and a pentapeptide alcohol, Boc-Val-Leu-Ala-Val-
Leuol (21). Most peptaibols are Aib (a,a-dimethyl glycine)-rich
peptides,1,26 so we included Aib in peptaibol 20 to mimic the C-
terminal sequences of peptaibols. The tri- and pentapeptide acids
were obtained after the saponification of the C-terminal methyl
esters. These peptide acids were converted to active esters as
described for the dipeptide acids and subjected to in situ reduction.
The tripeptide alcohols (19 and 20) were isolated in pure form
without column purification in good yields, while the peptaibol
Colourless crystals of peptaibol 20 were obtained after slow
evaporation of CHCl3, and the X-ray diffraction analysis is
described below. Interestingly, a well-folded structure of the tripep-
tide alcohol is observed in the crystals, as shown in the ORTEP
diagram (Fig. 2C). The crystallographic asymmetric unit contains
four molecules of tripeptide alcohol and four solvent CHCl3
molecules. Intriguingly, two peptaibols are connected by inter-
molecular hydrogen bonding, while the other two are independent
(Fig. 2D). Two intramolecular hydrogen bonds correspond to
Boc C O ◊ ◊ ◊ NH Leuol(3), and Ala(2) C O ◊ ◊ ◊ OH Leu(3)ol
observed in the crystal structure (Fig. 2C). As a consequence
of the two intramolecular C10 hydrogen bonds, two types of b-
bends are observed. The relevant torsional angles and hydrogen
bond parameters are tabulated in Tables 3 and 4, respectively. A
ten-membered H-bond between the urethane carbonyl and the
Leu NH (1→4) leading to the formation of a type III b-turn
with torsional angles f1 = -60◦, y1 = -30◦, f2 = -61◦ and y2
=
-25◦.27 Interestingly, the type III b-turn was further stabilized by
another C10 H-bond between the Ala2 carbonyl and the terminal
OH (Fig. 2C).28 The solvent CHCl3 interacted with the peptaibol
Table 3 Torsion angles (◦) in 20
Residue
f
y
w
c1
c2
c3
Aib1
Ala2
Leuol3
-60
-30
-25
58
179
172
—
—
175
-55
—
—
-179
—
—
-53
-61
-110
Scheme 2 Schematic representation of the synthesis of peptide alcohols using N-hydroxysuccinimide active esters.
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Fig. 2 Crystal structures of Fmoc-Valol (3), Boc-Ala-Valol (16) and Boc-Aib-Ala-Leuol (20). The H-atoms are not labeled for clarity. A: The crystal
structure of Fmoc-Valol. B: ORTEP diagram showing the two molecules of 16 (A and B) in the asymmetric unit. C: ORTEP diagram showing the
conformation of the tripeptide alcohol in crystals. Two intramolecular H-bonds are shown by dotted lines. The interaction of solvent molecule (CHCl3)
with peptide through a CH ◊ ◊ ◊ O hydrogen bond is also shown. D: The unit cell showing four molecules of tripeptide alcohol and four molecules of CHCl3
in the asymmetric unit. All side-chain H-atoms are omitted for clarity.
Table 4 Intra- and intermolecular H-bonding in crystals of the tripeptide
20
between the CHCl3 molecules is not observed in the structure (the
˚
Cl ◊ ◊ ◊ Cl distance is 3.9 A). It appears that the solvent is stabilizing
the crystal packing by filling the vacant space. The two folded
conformers of the tripeptide alcohol are held together by two
intermolecular hydrogen bonds between Aib(1)NH and Ala(2)CO
and between the Boc-urethane oxygen O1 and Ala2CaH in the
crystals (Fig. 2D). Overall, we observed an irregular structure
in the dipeptide alcohol and a well-defined type III b-turn in
the tripeptide alcohol. The type III b-turn in the tripeptide
alcohol may be induced by the presence of the conformationally
restricted dialkyl amino acid residue (Aib) at the N-terminus of the
tripeptide. Toniolo et al. and others have also shown the formation
of type III and III¢ b-turns by di- and tripeptides containing dialkyl
amino acids.27,29
DonorAcceptor
A ◊ ◊ ◊ H D ◊ ◊ ◊ A D–H ◊ ◊ ◊ A
(D)
(A)
Type
(◦)
˚
(A)
˚
(A)
N1
N3
O5
O4
O2
O3
Intermolecular (NH ◊ ◊ ◊ O C) 2.142 2.994 171
Intramolecular (NH ◊ ◊ ◊ O C) 2.203 2.974 149
Intramolecular (O–H ◊ ◊ ◊ O C)2.188 2.914 148
C10 O1
Intermolecular (C–H ◊ ◊ ◊ O)
2.548 3.505 165
C19a O4
Intermolecular (C–H ◊ ◊ ◊ O C) 2.126 3.102 171
a Solvent CHCl3.
through a CH ◊ ◊ ◊ O hydrogen bond havi◦ng an H ◊ ◊ ◊ O distance
˚
of 2.126 A and a C–H ◊ ◊ ◊ O angle of 171 . However, interaction
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Crystal structure of Boc-Aib-Ala-Leuol (20)
colourless crystal with approximate dimensions 1.2
Conclusion
A
¥
In conclusion, we have developed
a facile, efficient and
0.55 ¥ 0.15 mm had the following characteristics: formula
C18H35N3O5·CHCl3; crystal class orthorhombic; space group
racemization-free protocol for the synthesis of N-protected b-
amino alcohols and peptaibols. This method was found to be
compatible with Fmoc, Boc, and other side-chain protecting
groups. Further, the crystal conformations of the b-amino alcohol,
di- and tripeptide alcohols were analyzed, and the tripeptide
alcohol found to adopt a type III b-turn. This b-turn was further
stabilized by a C10 hydrogen bond with the terminal alcohol and
carbonyl of Ala2.
˚
P212121; a = 10.578(4); b = 11.206(4); c = 23.306(8) A; a = b =
◦
3
˚
g = 90 ; V = 2762.◦7(17) A ; T = 296(2) K; Z = 4; rcalc = 1.185 Mg
m-3; 2qmax = 56.56 ; Mo-Ka l = 0.71073 A. A fine-focus sealed
˚
tube source with a graphite monochromator was used. Treatment
of H atoms was mixed-type. R = 0.0673 (for 1573 reflection I >
2s(I)), wR = 0.1608, which was refined against |F2| and S = 0.715
for 280 parameters and 6526 unique reflections. The structure
was obtained by direct methods using SHELXS-97.30 All non-
hydrogen atoms were refined anisotropically. The hydrogen atoms
were fixed geometrically in the idealized position and refined in the
final cycle of refinement as riding over the atoms to which they are
bonded; m = 0.361 mm-1; minimum/maximum residual electron
Experimental section
1. General procedure for the synthesis of N-protected b-amino
alcohols from N-hydroxysuccinimide
-3
˚
density -0.233/0.444 e A .
To a solution of Fmoc- or Boc-protected amino acid (2 mmol)
and N-hydroxysuccinimide (0.345 g, 3 mmol) at 0 ◦C in THF
(5 mL), was added DCC (0.413 g, 2 mmol), and reaction was
stirred at this temperature for 1h. Precipitated DCU was filtered
and washed with THF (3 ¥ 2 mL), combined organic layer was
cooled to ice temperature and the solution of NaBH4 (0.152 g,
4 mmol) in water (1 mL) was added in one portion which leads to
the vigorous evolution of gas. After 10 min. 5 mL of 0.5 N HCl
was added to quench unreacted NaBH4. Reaction mixture was
extracted in EtOAc (3 ¥ 10 mL), and combined organic layer was
washed with 5% Na2CO3 (3 ¥ 10 mL), brine (3 ¥ 10 mL), dried
over Na2SO4, and concentrated in vacuo. After aqueous work up,
N-protected b-amino alcohols were obtained as pure product over
80–90% yield.
Acknowledgements
We thank the Indian Institute of Science Education and Research,
Pune, and the Department of Science and Technology, Govt. of
India, for financial support. S. V. J., A. B., and S. M. M. are
thankful to CSIR for Junior Research Fellowships.
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