Synthesis of α, β-unsaturated γ-amino esters with unprecedented high (E)-stereoselectivity and their conformational analysis in peptides

Article abstract of DOI:10.1039/c1ob05732d

Mild, efficient and racemization-free synthesis of N-protected α, β-unsaturated γ-amino esters with unprecedented high E- stereoselectivity is described. This method is found to be compatible with Boc-, Fmoc- and other side chain protecting groups. The crystal conformations of the vinylogous γ-amino esters in monomers and in homo- and mixed dipeptides are studied. Further, the vinylogous homo-dipeptide showed a β-sheet conformation, while mixed α- and α,β-unsaturated γ-hybrid dipeptide adapted an irregular structure in single crystals.

Full text of DOI:10.1039/c1ob05732d

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Organic &
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PAPER
Synthesis of a, b-unsaturated c-amino esters with unprecedented high
(E)-stereoselectivity and their conformational analysis in peptides†
Sachitanand M. Mali, Anupam Bandyopadhyay, Sandip V. Jadhav, Mothukuri Ganesh Kumar and
Hosahudya N. Gopi*
Received 10th May 2011, Accepted 27th June 2011
DOI: 10.1039/c1ob05732d
Mild, efficient and racemization-free synthesis of N-protected a, b-unsaturated g-amino esters with
unprecedented high E- stereoselectivity is described. This method is found to be compatible with Boc-,
Fmoc- and other side chain protecting groups. The crystal conformations of the vinylogous g-amino
esters in monomers and in homo- and mixed dipeptides are studied. Further, the vinylogous
homo-dipeptide showed a b-sheet conformation, while mixed a- and a,b-unsaturated g-hybrid
dipeptide adapted an irregular structure in single crystals.
A range of methodologies including Wittig,12 Julia,13 Horner–
Wadsworth–Emmons reaction,14 and Peterson15 olefination have
Introduction
a,b-Unsaturated g-amino acids (insertion of –CH CH- between
CaH and CO of a-amino acids, vinylogous amino acids) have been
frequently found in many peptide natural products.1 They have
been used as starting materials for the synthesis of g-amino acids2
as well as substrates in a variety of organic reactions including, 1,4-
conjugate addition,3 epoxidation,4 and Diels–Alder reaction5 to
develop the functional derivatives of g-amino acids. The synthetic
and naturally occurring peptides containing vinylogous amino
acid residues (Fig. 1) have been used as inhibitors for serine and
cystine proteases.6 The de novo design of the folded oligomers
from different sources of monomers is a very interesting field
in the perspective of designing biologically relevant protein and
peptidomimetics.7 This endeavor has been elegantly described
in the design of the structured peptides from the homologated
derivatives of a-amino acids such as b-, g- and w-amino acids.8
However, the structures of a, b- unsaturated g-amino acids and
their oligomers have been little explored. Nevertheless, preliminary
work by Schreiber and colleagues gave an insight into the struc-
tures that can be formed by the vinylogous amino acids with E-
double bond.9 Grison et al. and others reported the b-turn mimet-
ics with a nine-membered hydrogen bond using Z-vinylogous
amino acids.10 Recently, Hofmann et al. provided an overview of
the helical structures formed by the vinylogous amino acids using
ab initio MO theory.11 These systematic conformational analyses
are elucidated based on the E and Z geometry of the double bonds.
been reported for the synthesis of a,b-unsaturated esters. However,
Horner–Wadsworth–Emmons reaction, a variant of Wittig reac-
tion has been extensively utilized for the synthesis of vinylogous
amino acids.2c,6,16 In this reaction, alkali metal bases such as
BuLi and NaH are commonly used to generate the reactive
metalated phosphonate intermediate and to achieve the high
levels of stereoselectivity, reactions are also performed in the
presence of metal salts and organic bases.17 Seebach and co-
workers reported the synthesis of methyl esters of N-Boc-protected
a,b-unsaturated g-amino acids with the E/Z ratio of 3 : 1 to
7 : 1 via Horner–Wadsworth–Emmons reaction using NaH as a
base.2 Grison and colleagues used Horner reagents as starting
materials for the stereoselective synthesis of E and Z vinylogous
amino acids.10a,b To achieve the major E-selectivity, lithiated
dianion derivative of 2-diethylphosphonopropanoic acid has been
used, while Z-stereoselectivity has been achieved by KH/ethyl 2-
bis(trifluoroethyl)-phosphonopropanoate or BuLi/ethyl 2-diethyl
phosphonopropanoate. However, these procedures may not be
compatible for the synthesis of vinylogous amino acids containing
commonly used base labile Fmoc-protecting group. Herein, we are
reporting the synthesis of a, b-unsaturated g-amino esters starting
from the N-protected amino aldehydes using Wittig reaction with
exceptional high E-selectivity, their solid state conformational
analysis, and the conformations of homo- and mixed hybrid
dipeptides in single crystals.
Department of Chemistry Indian Institute of Science Education and
Research, Garware Circle Pashan, Pune, Maharashtra, 411021, India.
E-mail: hn.gopi@iiserpune.ac.in
Results and discussions
† Electronic supplementary information (ESI) available: Detailed exper-
imental procedures, characterization data, Crystallographic data, and
copies of 1H and13C NMR and Mass spectra for all compounds are
available. CCDC reference numbers 802255, 825100–825104. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05732d
Synthesis and characterization
As a part of our investigation to understand the structural features
of vinylogous peptides, we sought to utilize the Wittig reaction,
since the target vinylogous amino acids can be obtained at neutral
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Fig. 1 Representative examples of vinylogous amino acids in peptide natural products.
conditions and it can be compatible with a variety N-protecting
groups including base labile Fmoc- group. To understand the
efficacy and the stereochemical output of the Wittig reaction in
the synthesis of vinylogous amino acids, initially, the Boc-alanal
was subjected to the olefination reaction using the ylide, ethyl
(triphenylphosphoranylidene)acetate in dry THF (tetrahydrofu-
ran) at room temperature. The schematic representation of the
synthesis is shown in Scheme 1. The Boc-amino aldehyde was
synthesized from the LAH (lithium aluminium hydride) reduction
of the corresponding Weinreb amide and subjected immediately
to the Wittig reaction.18 Surprisingly, no trace of Z product was
observed in the reaction, while 100% E-isomer (1C) was isolated
in high yield (93%). We speculate that there may be a chance of
cis/trans isomerisation during the column chromatography, which
may lead to the conversion of Z into E product.19
Wittig reaction. The N-Fmoc-amino aldehydes were synthesized
using the corresponding Weinreb amides as described earlier. The
Fmoc-amino aldehydes with a variety of orthogonal side chain
protecting groups were subjected to the Wittig reaction using
the ylide, benzyl (triphenylphosphoranylidene)acetate. The pure
products of benzyl esters of N-Fmoc-vinylogous amino esters
(10C–15C) were isolated after the column chromatography from
moderate to high yields (78–94%) with 100%-(E)-selectivity and
are given in the Table 2.
Overall, both N-Boc-/Fmoc-protected vinylogous amino esters
were isolated in good yields with exceptional E-selectivity using
the Wittig reaction. We speculate that the formation of E-
product may adapted a planar transition state that leads to the
less steric clash between the amino acids side-chains/NHX (I),
while the formation of Z-product should adapt a energetically
unfavourable puckered transition state, that leads to the steric clash
between the amino acid side chains/NHX (II) and the incoming
ethyloxycarbonyl group as shown in Scheme 2.
Scheme 1 Synthesis of a,b-unsaturated g-amino esters using Wittig
reaction.
To further confirm the E- selectivity, we subjected the crude
1
Wittig product before the column purification to the H NMR
1
to observe the cis couplings of vinylic protons. The H NMR
shows the trans coupling of vinylic protons, indicating the presence
of only E- product (1C) in the reaction mixture. Though it has
been reported that the E- double bond is a major product in a
verity of Wittig reactions, we are surprised to see unprecedented
E-selectivity in the synthesis of vinylogous amino acids. Further, to
understand whether the E-selectivity is depending upon the amino
acid side chain, we subjected a variety amino aldehydes (2B–9B),
including proline, Ser(OBut) and a-aminoisobutyric acid (Aib)
to the Wittig reaction. In all these cases, we observed only the
E-selectivity. In addition, except dialkyl amino acid and proline,
all Wittig products (2C–9C) were isolated in high yields (>88%)
and are given in the Table 1. All Wittig reactions of Boc-amino
aldehydes proceeds very smoothly at room temperature in dry
THF.
Scheme 2 Schematic representation of the transition states of the
formation of E (I) and Z (II) products.
Further, to understand the chiral integrity in the synthesis of
vinylogous amino esters, we synthesized N-Boc-protected L, D
and ( ) DL mixture of valinals using the protocol described earlier
and then subjected to the Wittig reaction using the ylide, ethyl
(triphenylphosphoranylidene)acetate. The pure ethyl esters of N-
Boc-vinylogous amino acids were subjected to the chiral HPLC
using Daicel CHIRALPAK-AI column. However, all amino ester
enantiomers gave a single peak with the same retention time (tR).
Since all amino esters gave the same tR, we further synthesized three
dipeptides, Boc-Ala-dgV-OEt (D1), Boc-Ala-(D)dgV–OEt (D2)
and Boc-Ala-( DL)dgV-OEt(D3) by coupling of the vinylogous
amino esters to the Boc-alanine using the standard DCC/HOBt
coupling reaction and subjected to the chiral HPLC. The HPLC
profiles of these dipeptides are shown in Fig. 2. Single peaks were
Further, to verify whether or not this method can be applicable
to the synthesis of N-Fmoc-protected vinylogous amino acids, we
subjected a variety of N-Fmoc-amino aldehydes (10B–15B) to the
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Table 1 Synthesis of N-Boc-a, b-dehydro g-amino esters (dg) using Wittig reaction
Entry
Aldehyde(B)
Product (C)
% Yield
93
1
2
3
90
90
4
5
95
92
6
7
75
83
8
9
88
81
observed for the dipeptides D1 and D2 at tR 4.158 and 4.795 min
respectively, whereas dipeptide D3 showed two peaks with tR 4.105
and 4.685 min, corresponding to the individual dipeptides D1
and D2, respectively. These results indicate that the synthesis
of vinylogous amino ester from Wittig reaction is free from the
racemization. Further, out of all vinylogous amino esters in the
Tables 1 and 2, and the dipeptides, we were able to obtain the single
crystals for the amino esters 2C, 4C, 5C, 6C and the dipeptide
D1 after slow evaporation of ethyl acetate, ethyl acetate/hexane
solution as well as upon standing the pure gummy products. The
crystal structure analysis of these vinylogous residues are described
below.
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Table 2 Synthesis of N-Fmoc-a, b-unsaturated g-amino esters using Wittig reaction
Entry
Aldehyde(B)
Product (C)
% Yield
78
10
11
90
12
13
80
90
14
15
80
83
Crystal structure analysis of the vinylogous amino esters and
dipeptides
observed in the dialkyl amino acid residue 6C. The f and y angles
are found to be ~ -90 and ~ ( )180◦, respectively, in the vinylogous
residues 2C, 4C and 5C, while in the case of 6C, the f and y angles
-63 and -3◦, respectively, are observed. The torsional angle q2 is
having the value ~ -180◦ in all vinylogous residues. It should be
noted that the y value in dialkyl vinylogous amino acid is close
to 0◦, whereas in the other vinylogous residues it is close to 180◦,
indicating the rotation around the single bond in the conjugated
ester is possible.
Crystals of Boc-Ala-dgV-OEt (D1) were obtained after slow
evaporation of ethyl acetate solution and the crystal structure
is shown in Fig. 4. Surprisingly, six dipeptide molecules are
observed in the asymmetric unit with a significant variation in the
torsional angles. The torsional values are tabulated in the Table 4.
The six molecules in the asymmetric unit are held together by
intermolecular H-bonds and their parameters are tabulated in the
supporting information. The analysis of the torsional variables
reveals the conformational flexibility of the vinylogous residue
Crystal structures of all vinylogous residues are shown Fig. 3. The
local conformations of these vinylogous residues are determined
by introducing the additional torsional variables q1 (N–Cg –Cb–
Ca) and q2 (Cg –Cb Ca–C) as described by the Hofmann and
colleagues.11
The torsional variables of all vinylogous residues are summa-
rized in Table 3. In the case of 4C, two molecules are appeared
in the asymmetric unit with a slight variation in the torsional
values. The vinylogous residues 2C and 6C adapted orthorhombic
crystal systems, while 4C and 5C exhibited monoclinic crystal
systems. Examination of the crystal structures of all vinylogous
amino esters reveals that the torsional angle q1 is 0◦ or close to
0◦ suggesting the eclipsed conformation of the double bond with
the N–Cg bond. In addition, the local s-cis conformation of the
conjugated ester is observed in 2C, 4C, and 5C, whereas s-trans is
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Table 4 Torsional angles (◦) of the dipeptide Boc-Ala-dgV-OEt(D1)
f1
y1
w
f2
q1
q2
y2
a
b
c
d
e
f
-57
140
157
141
155
139
134
173
173
169
166
177
175
-123
69
-115
69
-122
-112
9
-180
175
179
175
-179
177
-175
9
175
10
-179
-173
-122
-60
127
-9
129
7
-116
-61
-60
-3
esters is observed with the y2 values ~180◦. Interestingly, in the
case of b and d, the Ala adapted extended conformations with the
f1 and y1 value approximately -120, and 155◦, respectively. In
addition, the f2 is found to be 69◦ and q1 is having the values close
to 130◦. Further, the local s-trans conformation of the conjugated
ester is observed with the y2 close to 0◦. It should be noted that
the values of f2, q1 and y2 are different for the two sets of the
peptides in the crystals, indicating that the rotations around the
single bonds are possible. In contrast to the all unsaturated g-
amino ester structures (Table 3), the q1 of the dipeptides b and d
is having the value close to 130◦.
Further, inspired by the interesting results obtained from
the dipeptide D1, we sought to investigate the conformational
behaviour of the vinylogous residues in homo-dipeptides. The
dipeptide Boc-dgL-dgL-OEt (D4), was synthesized by coupling
of N-Boc-vinylogous acid and the free amine of 4C obtained
after the saponification and the Boc-deprotection, respectively.
The coupling reaction was mediated by DCC and HOBt. Crystals
of homo-dipeptide D4 obtained after the slow evaporation of
ethyl acetate solution yield the structure shown in Fig. 5A. In
contrast to the D1, single dipeptide molecule is observed in the
asymmetric unit. Interestingly, the dipeptide D4 adapted a partial
parallel b-sheet character in the crystal structure (Fig. 5B). The
torsional values are given in the Table 3. Analysis of the crystal
structure reveals that the dipeptide molecules are held together
by two intermolecular H-bonding between the C O and NH
groups with N–H---O distances 2.066 [N1H---O2, (N1---O2, 2.872
Fig. 2 Chiral HPLC of dipeptides D1, D2, and D3. The HPLC was
performed on Daicel CHIRALPAK-AI column using 20% isopropanol
in n-hexane as a solvent system at isocratic mode with the flow rate of
1 mL/min.
Table 3 The torsional angles (◦) of vinylogous amino esters and the
dipeptide D4
Compound
Residues f
q1
q2
y
2C
4C
5C
6C
dgV
dgL
dgI
-90
0
-1
0
179
-179
180
177
178
-179
-3
-91
-94
-63
˚
˚
˚
A)] and 2.165 A [N2H---O3, (N2---O3, 3.012 A)] with N–H---O
angles 156 and 168◦, respectively (Fig. 5B). A fully extended
conformation is observed in dgL1 of the dipeptide with f, q1,
q2 and y values -107, 116, 178 and 171◦, respectively, whereas in
the second residue dgL2, q1 is having the eclipsed conformation
with the N–Cg bond (q1 is 0◦), leads to the deviation from the b-
sheet structure. However, the other torsional variables f, q2 and y
showing the extended conformations with the angles of -137, 179
and 180◦, respectively.
dgU
-10
-179
Boc-dgL-dgL-OEt
D4 dgL1
dgL2
-107
-137
116
0
179
179
171
180
in the hybrid dipeptide. Instructively, molecules a, c, e and f in
the Table 4 adapted a very similar conformations in the crystals
with slight variations in the torsional values (highlighted in green
in Fig.4), while dipeptides b and d adapted similar conformations
different from the other four dipeptides (highlighted in blue, Fig.4).
In the case of a, c, e and f, the Ala adapted a semi-extended
conformation by having f1 and y1 angles ~ -60◦ and ~140◦,
respectively. In addition, the vinylogous residues adapted extended
conformations by having f2 ~ -120◦, however, q1 is found to be
close to 0◦. Further, the local s-cis conformation of the conjugated
Further, to understand their conformational signature in
solution, we subjected the dipeptides D1, D2 and D4 for CD
analysis. The CD spectra of the dipeptides are shown Fig. 6.
Instructively, dipeptide D4 showed the CD negative maxima at
228 nm, indicating a b-sheet character in solution, while the
other dipeptides D1 and D2 exhibiting strange characteristics
by giving almost two mirror image spectra with the CD positive
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Fig. 3 Crystal structures of vinylogous amino esters, Boc-(S, E)-dgV-OEt (2C), Boc-(S, E)-dgL-OEt (4C), Boc-(S, E)-dgI-OEt (5C) and
Boc-(E)-dgU-OEt(6C).
and negative maxima at around 205 and 202 nm, respectively.
For a comparison, the CD spectrum of the a-dipeptide, Boc-
Leu-Leu-OMe (D5) is also shown in Fig. 6. The CD analysis,
however, suggests that the lack of secondary structural elements
in dipeptide D5. We speculate that the red shift of the CD negative
maxima at 228 nm for the dipeptide D4 and the anomalous CD
spectra of the dipeptides D1 and D2 may be due to the conjugated
enamides and esters of vinylogous residues.
Conclusion
In conclusion, we have demonstrated the facile and racemization-
free synthesis of a,b-unsaturated g-amino esters with exceptional
high E-stereoselectivity using Wittig reaction. In addition, this
method was found to compatible with Boc-, Fmoc- and other
side chain protecting groups. Further, the crystal conformations
of vinylogous amino esters and dipeptides were analyzed. The
homo-vinylogous dipeptide D4 showed the partial extended b-
Fig. 4 Crystal structure of dipeptide Boc-Ala-dgV-OEt. Six molecules are
appeared in the asymmetric unit. The intermolecular H-bonding between
the dipeptide units are shown in dotted lines. The types of conformations
sheet characters in single crystals. The knowledge from this work
with significant variation in the torsional values of vinylogous residues are
can be further utilized to construct higher ordered structures of
highlighted in different colours.
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Fig. 5 Crystal structure of dipeptide Boc-dgL-dgL-OEt (D4). A. The ORTEP diagram of the dipeptide. B. The partial b-sheet of character exhibited by
the dipeptide in crystals. C. The side view of the b-sheets.
vinylogous residues as well as for the synthesis biologically active
peptides.
mixture was quenched with 5% HCl. The organic layer was
evaporated under reduced pressure and product was isolated
by extracting with ethyl acetate (50 mL ¥ 3). The combined
organic layer was then washed with brine and dried over Na2SO4.
The oily product of N-protected amino aldehyde was isolated
after evaporating ethyl acetate under reduced pressure and used
immediately for next step without purification. The Wittig ylide,
alkyl(triphenylphosphoranylidene)acetate (22 mmol) was added
to the solution of N-protected amino aldehyde dissolved in 40 mL
dry THF under the N2 atmosphere. The reaction mixture was
stirred overnight and the progress of reaction was monitored
by TLC. After the completion of reaction (~8h) the THF was
evaporated and product was purified by coloumn chromatography
Experimental section
General procedure for the synthesis of N-protected-a,
b-unsaturated-c-amino esters
The solution of N-protected amino acid Weinreb amide (20 mmol)
in 130 mL of THF was cooled to 0 ◦C under N2 atmosphere.
To this solution, LiAlH4 (22 mmol) was added slowly and
the reaction mixture was stirred for further 20 min. After the
completion of reaction, as indicated by the TLC, the reaction
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was washed with brine (3 ¥ 50 mL), 5% HCl (3 ¥ 50 mL), 10%
Na2CO3(3 ¥ 50 mL), brine (30 mL) and dried over Na2SO4. The
organic layer was concentrated under reduced pressure and the
crude product was purified by column chromatography using ethyl
acetate/pet ether to get 1.2 g (40%) of the pure dipeptide D4.
Crystal structure analysis of Boc-dgV-OEt. Crystals of Boc-
dgV-OEt were grown by slow evaporation from a solution of
EtOAc and Hexane. A single crystal (0.50¥ 0.35 ¥ 0.20 mm)
was mounted on loop with a small amount of the paraffin
oil. The X-ray data were collected at 200 K temperature on a
Bruker APEX DUO CCD diffractometer using Mo-Ka radiation
˚
(l = 0.71073 A), w-scans (2q = 55.84), for a total of 3650
independent reflections. Space group P21, 2(1), 2(1), a = 9.978(4),
3
˚
b = 10.083(3), c = 16.904(6), V = 1700.7(10) A , Orthorhombic
P, Z = 4 for chemical formula C14H25NO4, with one molecule in
asymmetric unit; r calcd = 1.060gcm-3, m = 0.077 mm-1, F(000) =
592, Rint = 0.0268. The structure was obtained by direct methods
using SHELXS-97.20 The final R value was 0.0581 (wR2 = 0.1589)
1978 observed reflections (F0 ≥ 4s (|F0|)) and 178 variables,
S = 1.011. The largest difference peak and hole were 0.344 and
Fig. 6 Circular Dichroism spectra of dipeptides D1, D2, D4 and D5 in
methanol.
using 5 : 95 ethyl acetate/pet ether solvent system. The pure
products were isolated with an average 85% yield. Individual yield,
1H, 13C and mass spectra of all Wittig products are given the
supporting information.
3
˚
-0.160eA , respectively.
Acknowledgements
Synthesis of Boc-dgL-dgL-OEt (D4)
We thank Department of Science and Technology, Govt. of India
for financial support. S. M. M A. B., S. V. J. and M. G. K are
thankful to CSIR, for Research Fellowship.
(S,E)-4-(tert-butoxycarbonylamino)-6-methylhept-2-enoic acid-
(Boc-dgL-OH). Boc-dgL-OEt, 4C (1.86 g, 6.8 mmol) was dis-
solved in 4 mL of ethanol followed by 10 mL of 1 N NaOH
was added slowly to the solution. The reaction mixture was then
stirred for about 8h. The progress of reaction was monitored by
TLC. After completion of the reaction, the solvent was evaporated
under reduced pressure. The aqueous layer was diluted with water
(50 mL) and then acidified (~pH 3.0) with 5% HCl and extracted
with ethyl acetate (3 ¥ 50 mL). The combined organic layer was
then washed with brine and dried over anhydrous Na2SO4. Product
was concentrated under reduced pressure to get 1.67 g (95%) of
oily Boc-dgL-OH.
References
1 (a) R. G. Linington, B. R. Clark, E. E. Trimble, A. Almanza, L.-D.
Uren, D. E. Kyle and W. H. Gerwick, J. Nat. Prod., 2009, 72, 14–
17; (b) J. E. Coleman, E. D. de Silva, F. Kong, R. J. Andersen and
T. M. Allen, Tetrahedron, 1995, 51, 10653–10662; (c) N. Schaschke,
Bioorg. Med. Chem. Lett., 2004, 14, 855–857; (d) M. Hagihara and
S. L. Schreiber, J. Am. Chem. Soc., 1992, 114, 6570–6571; (e) J. A.
Nieman, J. E. Coleman, D. J. Wallace, E. Piers, L. Y. Lim, M. Roberge
and R. J. Andersen, J. Nat. Prod., 2003, 66, 183–199.
2 (a) T. Hintermann, K. Gademann, B. Jaun and D. Seebach, Helv. Chim.
Acta, 1998, 81, 983–1002; (b) M. Brenner and D. Seebach, Helv. Chim.
Acta, 2001, 84, 1181–1189.
(S,E)-Ethyl 4-amino-6-methylhept-2-enoate(H2N-dgL-OEt).
The solution of Boc-dgL-OEt (1.95 g, 7.2 mmol) in 5 mL of
DCM was cooled to 0 ◦C followed by 5 mL of neat TFA was
added. The reaction mixture was stirred for about 1.5 h at the
same temperature. The progress of the reaction was monitored
by TLC. After completion of the reaction (1.5 h), the solvent
was evaporated under reduced pressure. The residue was then
treated with saturated Na2CO3 solution in cold condition. This
aqueous layer was extracted with ethyl acetate (3 ¥ 50 mL). The
combined organic layer was washed with brine and dried over
anhydrous Na2SO4. The organic layer was concentrated under
reduced pressure to 4 mL.
The solution of H2N-dgL-OEt in ethyl acetate (4 mL) was added
to the ice-cold solution of Boc-dgL-OH (1.67 g, 6.5 mmol) in DMF
(4 ml). The reaction mixture was then treated with DCC (1.34 g,
6.5 mmol) followed by HOBt (0.884 g, 6.5 mmol). The reaction
mixture was stirred for about 12 h at room temperature and the
progress of the reaction was monitored by TLC. After completion
of reaction, the reaction mixture was diluted with ethyl acetate
(100 mL) and DCU formed in reaction was filtered. This filtrate
3 (a) M. M. M. Santos and R. Moreira, Mini-Rev. Med. Chem., 2007, 7,
1040–1050; (b) J. S. Plummer, L. A. Emery, M. A. Stier and M. J. Suto,
Tetrahedron Lett., 1993, 34, 7529–7532.
4 Y. Fu, B. Xu, X. Zou, C. Ma, X. Yang, K. Mou, G. Fu, Y. Lu and P.
Xu, Bioorg. Med. Chem. Lett., 2007, 17, 1102–1106.
5 M. T. Reetz, Angew. Chem., Int. Ed. Engl., 1991, 30, 1531–1546.
6 (a) R. P. Hanzlik and S. A. Thompson, J. Med. Chem., 1984, 27, 711–
712; (b) H. M. M. Bastiaans, J. L. van der Baan and H. C. J. Ottenheijm,
J. Org. Chem., 1997, 62, 3880–3889; (c) S. Liu and R. P. Hanzlik,
J. Med. Chem., 1992, 35, 1067–1075; (d) J-S. Kong, S. Venkatraman,
K. Furness, S. Nimkar, T. A. Shepherd, Q. M. Wang, J. Aube’ and
R. P. Hanzlik, J. Med. Chem., 1998, 41, 2579–2587; (e) A. Breuning, B.
Degel, F. Schulz, C. Buchold, M. Stempka, U. Machon, S. Heppner, C.
Gelhaus, M. Leippe, M. Leyh, C. Kisker, J. Rath, A. Stich, J. Gut, P. J.
Rosenthal, C. Schmuck and T. Schirmeister, J. Med. Chem., 2010, 53,
1951–1963; (f) N. Schaschke and C. P. Sommerhoff, ChemMedChem,
2010, 5, 367–370.
7 (a) D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes and Jeffrey S. Moore,
Chem. Rev., 2001, 101, 3893–4011; (b) S. H Gellman, Acc. Chem. Res.,
1998, 31, 173–180; (c) I. C. Kim and A. D. Hamilton, Org. Lett., 2006,
8, 1751–1754; (d) N. J. Brown, C. W. Wu, S. L. Seurynck-Servoss and
A. E. Barron, Biochemistry, 2008, 47, 1808–1818.
8 (a) D. Seebach and J. Gardiner, Acc. Chem. Res., 2008, 41, 1366–1375;
(b) W. S. Horne and S. H. Gellmann, Acc. Chem. Res., 2008, 41, 1399–
1408; (c) P. G. Vasudev, S. Chatterjee, N. Shamala and P. Balaram, Acc.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6566–6574 | 6573
©

View Article Online
Chem. Res., 2009, 42, 1628–1639; (d) J. L. Price, W. S. Horne and S. H.
Gellman, J. Am. Chem. Soc., 2010, 132, 12378–12387; (e) D. Seebach,
D. F. Hook and A. Glattli, Biopolymers, 2006, 84, 23–37; (f) R. P.
Cheng, S. H. Gellman and W. F. DeGrado, Chem. Rev., 2001, 101,
3219–3232; (g) G. V. M. Sharma, B. S. Babu, K. V. S. Ramakrishna, P.
Nagendar, A. C. Kunwar, P. Schramm, C. Baldauf and H. J. Hofmann,
Chem.–Eur. J., 2009, 15, 5552–5566; (h) I. M. Mandity, E. Weber, T. A.
Martinek, G. Olajos, G. K. Toth, E. Vass and F. Fulop, Angew. Chem.,
Int. Ed., 2009, 48, 2171–2175 and references sited therein.
13 (a) M. Julia and J. M. Paris, Tetrahedron Lett., 1973, 14, 4833–4836;
(b) J. B. Baudin, G. Hareau, S. A. Julia and O. Ruel, Tetrahedron Lett.,
1991, 32, 1175–1178; (c) P. J. Kocienski, Phosphorus Sulfur Relat. Elem.,
1985, 24, 97–127; (d) P. R. Blakemore, J. Chem. Soc., Perkin Trans. 1,
2002, 2563–2585.
14 (a) D. P. Rotella, J. Am. Chem. Soc., 1996, 118, 12246–12247;
(b) S. Oishi, T. Kamano, A. Niida, Y. Odagaki, N. Hamanaka, M.
Yamamoto, K. Ajito, H. Tamamura, A. Otaka and N. Fujii, J. Org.
Chem., 2002, 67, 6162–6173; (c) V. R. Chintareddy, A. Ellern and
J. G. Verkade, J. Org. Chem., 2010, 75, 7166–7174 and references sited
therein.
9 M. Hagihara, N. J. Anthony, T. J. Stout, J. Clardy and S. L. Schreiber,
J. Am. Chem. Soc., 1992, 114, 6568–6570.
10 (a) C. Grison, P. Coutrot, S. Gen´eve, C. Didierjean and M. Marraud,
J. Org. Chem., 2005, 70, 10753–10764; (b) C. Grison, S. Gen´eve, E.
Halbin and P. Coutrot, Tetrahedron, 2001, 57, 4903–4923; (c) T. K.
Chakraborty, A. Ghosh, S. K. Kumar and A. C. Kunwar, J. Org. Chem.,
2003, 68, 6459–6462.
11 (a) C. Baldauf, R. Gunther and H. J. Hofmann, J. Org. Chem., 2005,
70, 5351–5361; (b) C. Baldauf, R. Gunther and H. J. Hofmann, Helv.
Chim. Acta, 2003, 86, 2573–2588.
12 (a) G. Wittig and G. Geissler, Justus Liebigs Ann. Chem., 1953, 580,
44–68; (b) G. Wittig and U. Schollkopf, Chem. Ber., 1954, 87, 1318–
1330; (c) G. Wittig, Science, 1980, 210, 600–604; (d) A. Maerckar, Org.
React., 1965, 14, 270–490; (e) B. E. Maryanoff and A. B. Reitz, Chem.
Rev., 1989, 89, 863–927; (f) O. I. Kolodiazhnyi, Phosphorus Ylides,
Chemistry and Application in Organic SynthesisWiley-VCH, Weinheim,
Germany, 1999; (g) E. Vedejs and C. F. Marth, J. Am. Chem. Soc.,
1990, 112, 3905–3909; (h) A. El-Batta, C. Jiang, W. Zhao, R. Anness,
A. L. Cooksy and M. Bergdahl, J. Org. Chem., 2007, 72, 5244–5259
and references sited therein.
15 (a) D. J. Peterson, J. Org. Chem., 1968, 33, 780–784; (b) D. J. Ager,
Synthesis, 1984, 384–398; (c) D. J. Ager, Org. React., 1990, 38, 1–
223.
16 L. K. Blasdel and A. G. Myers, Org. Lett., 2005, 7, 4281–
4283.
17 (a) T. D. W. Claridge, S. G. Davies, J. A. Lee, R. L. Nicholson, P. M.
Roberts, A. J. Russell, A. D. Smith and S. M. Toms, Org. Lett., 2008, 10,
5437–5440; (b) M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld,
S. Masamune, W. R. Roush and T. Sakai, Tetrahedron Lett., 1984, 25,
2183–2186; (c) M. W. Rathke and M. Nowak, J. Org. Chem., 1985, 50,
2624–2626.
18 A. Bandyopadhyay, N. Agrawal, S. M. Mali, S. V. Jadhav and H. N.
Gopi, Org. Biomol. Chem., 2010, 8, 4855–4860.
19 E. C. Dunne, E. J. Coyne, P. B. Crowley and D. G. Gilheany, Tetrahedron
Lett., 2002, 43, 2449–2453.
20 (a) SHELXS-97, G. M. Sheldrick, Acta Crystallogr. Sect A, 1990, 46,
467–473; (b) G. M. Sheldrick, SHELXL-97, Universita¨t Go¨ttingen,
(Germany) 1997.
6574 | Org. Biomol. Chem., 2011, 9, 6566–6574
This journal is
The Royal Society of Chemistry 2011
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