Synthesis of modified phenylalanine peptides by cross enyne metathesis and a diels-alder reaction as key steps

Article abstract of DOI:10.1002/ejoc.201101744

Modified phenylalanine-based di- and tripeptides have been efficiently assembled by cross enyne metathesis and a Diels-Alder reaction as key steps under mild conditions. In all cases, peptide integrity was preserved, no racemisation was observed, and good yields of modified peptides were obtained.

Full text of DOI:10.1002/ejoc.201101744

FULL PAPER
DOI: 10.1002/ejoc.201101744
Synthesis of Modified Phenylalanine Peptides by Cross Enyne Metathesis and
a Diels–Alder Reaction as Key Steps
Sambasivarao Kotha,*[a] Deepti Goyal (née Bansal),[a] Niranjan Thota,[a] and Venu Srinivas[a]
Keywords: Metathesis / Diels–Alder reaction / Peptides / Diversity oriented approach / Synthesis design
Modified phenylalanine-based di- and tripeptides have been
efficiently assembled by cross enyne metathesis and a Diels–
Alder reaction as key steps under mild conditions. In all
cases, peptide integrity was preserved, no racemisation was
observed, and good yields of modified peptides were ob-
tained.
Peptide modifications can be carried out by various
chemical reactions such as C–C bond-forming reactions
Introduction
With the advances in combinatorial chemistry, the diversity (Suzuki–Miyaura cross-coupling),[6] metathesis (ring-clos-
of peptide-based drugs has steadily increased.[1] These ing metathesis),[7] oxidation,[8] cycloaddition ([2+2+2] cy-
methods provide access to peptides with improved bioavail- cloaddition)[9] and biotransformations.[10] However, there is
ability and resistance to cellular peptidases.[2] Among the still a pressing need to devise mild procedures to modify
different strategies available to modify a preformed peptide preassembled peptides that are compatible with a wide
sequence, manipulation of either the backbone[1c,3] or vari- range of functional groups and well suited to library gener-
ous side-chains[4] have been investigated. Such procedures ation. Perhaps the most powerful method to generate modi-
can provide a multitude of peptide analogs, which cannot fied peptides is by restructuring the available amino acid
be prepared from the component amino acids; these pept- equivalents by chemical transformations. As Grubbs cata-
ides are useful for structure–activity relationship (SAR) lysts are both selective and tolerate a wide range of func-
studies.[5] Therefore, such approaches for drug discovery, tional groups, an innovative methodology that employs
which can generate a large number of peptides with diverse cross enyne metathesis (CEM)[11] and a Diels–Alder (DA)
structural, electronic and stereochemical variations from a reaction[12] (Figure 1) to modify preformed peptides is wor-
single presynthesised peptide sequence by the application of thy of systematic investigation. Such a methodology is the
various chemical transformations, are useful to generate first of its kind to be used in the posttranslational modifica-
lead compounds in a combinatorial fashion.
tion of peptides. This diversity-oriented[13] approach would
Figure 1. Retrosynthesis for modified phenylalanine-based peptides.
generate a library of peptides by simply varying one of the
reaction partners during the CEM or DA sequence.
One can also visualise that this strategy could be ex-
tended to assemble a library of modified commercially
available HIV-inhibiting drugs[14] such as Kaletra (I), Reya-
taz (II) and Norvir (III) (Figure 2) to generate new drugs.
[a] Department of Chemistry, Indian Institute of Technology –
Bombay,
Mumbai 400076, India
Fax: +91-22-25767152
E-mail: srk@chem.iitb.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101744.
Eur. J. Org. Chem. 2012, 1843–1850
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Kotha, D. Goyal (née Bansal), N. Thota, V. Srinivas
FULL PAPER
Figure 2. Structures of HIV-inhibiting drugs.
Results and Discussion
Our journey to realise the synthesis of the phenylalanine
(Phe) based peptides depicted in Figure 1 began with the
readily accessible and inexpensive starting material diethyl
acetamidomalonate (1). Propargylation of 1 with Cs2CO3
delivered the acetylene derivative 2.[15] Decarboxylation of
2 with KOH afforded the key building block 3 as a racemic
mixture (Scheme 1). The other key building block 5 re-
quired for peptide coupling was prepared by iodination of
l-phenylalanine (4) with AcOH/H2SO4 in the presence of
I2/NaIO3 followed by treatment with thionyl chloride in
methanol (Scheme 2).[16] Along similar lines, 6 was pre-
pared by treating 4 with thionyl chloride in methanol.[16]
Scheme 2. Synthesis of 5 and 6. Reagents and conditions: (i)
AcOH, H2SO4, I2, NaIO3, 70 °C, 21 h; (ii) SOCl2, MeOH, 0 °C to
r.t., 24 h.
Next, the condensation of 3 with 5 in the presence of N-
[3-(dimethylamino)propyl]-NЈ-ethylcarbodiimide
hydro-
chloride (EDCl) gave a diasteromeric mixture of peptides 7
and 8 (Scheme 3), whose absolute configuration was estab-
lished unequivocally.[17]
Furthermore, we synthesised tripeptide 12 from 8. To
this end, 8 was subjected to hydrolysis to generate the acid
11, which was coupled with l-isoleucine methyl ester hydro-
chloride to furnish the alkyne-based building block 12
(Scheme 4).
Scheme 1. Synthesis of 3. Reagents and conditions: (i) propargyl
bromide, Cs2CO3, CH3CN, r.t., 18 h; (ii) KOH, MeOH/H2O (5:1),
reflux, 4 h.
Scheme 3. Peptide coupling between 3 and 5 or 6. Reagents and conditions: (i) EDCl, HOBt, Et3N, dry tetrahydrofuran (THF), 0 °C to
r.t., 24 h.
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Modified Phenylalanine Peptides
Scheme 4. Synthesis of 12. Reagents and conditions: (i) 1 n NaOH, MeOH, r.t., 24 h; (ii) l-isoleucine methyl ester hydrochloride, EDCl,
HOBt, Et3N, dry THF, 0 °C to r.t., 24 h.
Scheme 5. General method for the synthesis of 18–23. Reagents and conditions: (i) ethylene, (dihydrolMes)(Cy3P)Cl2Ru=CHPh (G-II)
(10 mol-%), CH2Cl2, r.t., 20–24 h; (ii) (a) toluene, 90 °C, 18–20 h, (b) MnO2, dioxane, reflux, 20–24 h.
We initially chose 7 as a model to carry out CEM with
Having optimised the reaction conditions with 13, the
ethylene as the cross-coupling partner. To this end, cross- next task was to extend this methodology to other alkyne-
metathesis with Grubbs first-generation catalyst (G-I) un- based dipeptides such as 8–10 (Table 1). Compounds 8–10
der different solvent and temperature conditions (CH2Cl2 were subjected to the optimised reaction conditions for the
r.t., CH2Cl2 45 °C, toluene r.t., toluene 90 °C) was at- CEM and DA reaction sequence. Along similar lines, this
tempted, but the desired diene 13 was not obtained in an methodology was extended to tripeptide 12, which was sub-
acceptable yield. However, Grubbs second-generation cata- jected to the CEM and DA reaction sequence to furnish
lyst (G-II) gave 13 in good yield (Scheme 5). Compound 13 the desired tripeptides 22 and 23 with dienophiles dimethyl
was characterised by various spectroscopic methods. The acetylenedicarboxylate and 1,4-naphthoquinone, respec-
disappearance of peaks that corresponded to the acetylenic tively (Table 1). It is gratifying to note that the results ob-
protons and the appearance of new peaks at δ = 5.02–5.34 served with the tripeptide proceed along the expected lines.
1
and 6.33 ppm in the H NMR spectrum indicated the for- In all cases, peptide integrity was preserved, and good
mation of 13.
yields of modified peptides were obtained.
Furthermore, treatment of 13 with a dienophile, such as
dimethyl acetylenedicarboxylate, delivered the DA adduct.
It was necessary to perform the DA reaction at 90 °C; at
higher temperatures, a retro-DA reaction was observed. Ini-
tially, the DA adduct was subjected to 2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone (DDQ) mediated aromatisation;
however, separation of the desired product 18 from the
Conclusions
We have demonstrated an exceptionally simple and ver-
DDQ byproduct was cumbersome. As an alternative, the satile method for the synthesis of modified Phe-based pept-
aromatisation sequence was carried out by using activated ides in high overall yields from the inexpensive starting ma-
MnO2 in boiling dioxane to deliver the desired modified terial diethyl acetamidomalonate (1). As Phe-based pept-
Phe-based peptide 18 in good yield (Table 1). The structure ides are useful for the treatment of several disorders, our
of 18 was confirmed by the presence of seven peaks between methodology is likely to find application in medicinal chem-
δ = 129 and 140 ppm in the 13C NMR spectrum, which was istry and peptide-based drug design. Our approach has
supported by the presence of peaks between δ = 7.00 and combined several diverse points (CEM coupling partners,
8.00 ppm in the 1H NMR spectrum. A peak at m/z = dienophiles and Suzuki–Miyaura cross-coupling). Conse-
611.0918 in the HRMS gave additional support for the for- quently, our approach can provide access to a library of
mation of 18.
Phe peptides, which may be suitable for SAR studies.
Eur. J. Org. Chem. 2012, 1843–1850
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Table 1. Various Phe-based peptides synthesised by the CEM and DA strategy.
discs. H (400 MHz) and 13C NMR (100.6 MHz) spectra were re-
corded with Bruker/Varian spectrometers. HRMS data were re-
corded with a Micromass Q-Tof spectrometer. Melting points were
recorded with a Büchi B-545 apparatus.
1
Experimental Section
General: All reactions were monitored by TLC using an appropri-
ate solvent system for development. Reactions involving air/oxy-
gen-sensitive reagents or catalysts were performed in degassed sol-
vents. The transfer of moisture-sensitive materials was carried out
in a glovebox by using standard syringe–septum techniques and the
reaction mixtures were maintained under nitrogen until workup.
Yields reported are isolated yields. Ruthenium catalysts were pur-
chased from Aldrich and Strem chemicals. All the commercial rea-
gents were used without further purification. IR spectra were re-
corded with a Nicolet Impact-400 FT IR spectrometer as KBr
Preparation of 2: To a solution of diethyl acetamidomalonate (1,
2.0 g, 9.22 mmol) in CH3CN (25 mL) was added propargyl brom-
ide (1.65 g, 13.82 mmol) and Cs2CO3 (3.0 g, 9.22 mmol). The re-
sulting heterogeneous mixture was stirred at r.t. for 18 h. The reac-
tion mixture was filtered and concentrated, the residue was dis-
solved in ethyl acetate (30 mL), washed with water and brine and
dried with Na2SO4. Evaporation of the solvent gave the crude prod-
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Modified Phenylalanine Peptides
uct as a yellowish white solid, which was purified by column
chromatography (30% ethyl acetate/petroleum ether) to give 2 as a
white solid (2.01 g, 85%). We have slightly modified the literature
procedure. 1H and 13C NMR spectroscopic data are consistent with
those in the literature reports. M.p. 90 °C (ref.[15] 91–92 °C).
length 254 nm, reverse-phase C18 column). [α]2D5 = 27.63 (c = 0.08,
CHCl3).
Compound 8: Rf = 0.40 (80% ethyl acetate/petroleum ether). M.p.
1
179–180 °C. H NMR (300 MHz, CDCl3): δ = 2.04 (s, 3 H), 2.06
(t, J = 2.7 Hz, 1 H), 2.52–2.61 (m, 1 H), 2.68–2.76 (m, 1 H), 2.99–
3.15 (m, 2 H), 3.74 (s, 3 H), 4.53–4.59 (m, 1 H), 4.82–4.88 (m, 1
H), 6.28 (d, J = 7.5 Hz, 1 H), 6.67 (d, J = 7.8 Hz, 1 H), 6.99 (d, J
= 8.0 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.4, 23.3, 37.6, 51.5, 52.7, 53.3, 72.1, 79.2,
92.9, 131.5, 135.5, 137.8, 169.6, 170.5, 171.5 ppm. HRMS (QTOF):
calcd. for C17H20N2O4I [M + H]+ 443.0468; found 443.0484. IR
Preparation of 3: KOH (966.3 mg, 17.25 mmol) was added portion-
wise to a well-stirred suspension of 2 (2 g, 7.84 mmol) in MeOH
(160 mL) and H2O (32 mL). The mixture was heated at reflux for
4 h, allowed to cool, and the solvents were evaporated to dryness.
The residue was treated with ethyl acetate and 2 n HCl to pH = 1
(decarboxylation). After separation, the aqueous phase was ex-
tracted with ethyl acetate (3ϫ20 mL), the combined organic layers
were dried with Na2SO4 and the solvents evaporated to yield 3
(KBr): ν = 1647, 1741, 2353 cm–1. HPLC: t = 3.108 min (100%
˜
R
acetonitrile, flow rate 1 mL/min, detector wavelength 254 nm, re-
1
(971 mg, 80%). We have modified the literature procedure. H and
verse-phase C18 column). [α]2D5 = 21.15 (c = 0.08, CHCl3).
13C NMR spectroscopic data are consistent with those in the litera-
ture reports. M.p. 137 °C (ref.[15] 137–139 °C).
Compound 9: Rf = 0.49 (80% ethyl acetate/petroleum ether). M.p.
129–130 °C. 1H NMR (400 MHz, CDCl3): δ = 2.01 (br. s, 4 H),
2.51–2.76 (m, 2 H), 3.07–3.19 (m, 2 H), 3.73 (s, 3 H), 4.53–4.58 (m,
1 H), 4.82–4.87 (m, 1 H), 6.36 (d, J = 7.6 Hz, 1 H), 6.82 (d, J =
7.6 Hz, 1 H), 7.09–7.11 (m, 2 H), 7.23–7.28 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 22.2, 23.2, 37.8, 51.5, 52.6, 53.7,
71.9, 79.4, 127.3, 128.8, 129.4, 135.8, 169.7, 170.5, 171.6 ppm.
HRMS (QTOF): calcd. for C17H21N2O4 [M + H]+ 317.1501; found
Preparation of 5: To a stirred solution of l-phenylalanine (4, 2.0 g,
12.12 mmol) in AcOH (11 mL) and concd. H2SO4 (1.44 mL) was
added powdered I2 (1.22 g, 4.79 mmol) and NaIO3 (507 mg,
2.55 mmol). The mixture was heated at 70 °C until TLC showed
the reaction to be complete, which took 21 h and the addition of
two further portions of NaIO4 (50 mg) at this 2 g scale reaction.
Completion was indicated by the I2 colour fading to orange. AcOH
was removed by rotary evaporation, and the residual viscous oil
was diluted with water (40 mL) and washed twice with Et2O
(20 mL) and CH2Cl2 (20 mL). The aqueous solution was neutral-
ised with NaOH to precipitate the crude product, which, after chill-
ing, was collected by filtration and rinsed with water (20 mL) and
ethanol (20 mL). The precipitate was dried in a vacuum desiccator
for 1 h to yield 4-iodo-l-phenylalanine (2.45 g, 75%). M.p. 259 °C
(ref.[16] 261–262 °C). To a suspension of 4-iodo-l-phenylalanine
(1.0 g, 3.43 mmol) in methanol (10 mL) was added thionyl chloride
(0.4 mL, 5.15 mmol) dropwise at 0 °C. The reaction mixture was
stirred at r.t. for 24 h. Evaporation of the methanol gave hydrochlo-
ride 5 as a white solid (1.1 g, 94%). We have slightly modified the
literature procedure for the hydrochloride formation reaction. 1H
and 13C NMR spectroscopic data are consistent with those in the
literature reports. M.p. 198 °C (ref.[16] 199–200 °C). The same pro-
cedure was used to synthesise 6. M.p. 160 °C (ref.[16] 158–160 °C).
317.1490. IR (KBr): ν = 1665, 1746, 2306 cm–1. HPLC: t
=
˜
R
3.252 min (100% acetonitrile, flow rate 1 mL/min, detector wave-
length 254 nm, reverse-phase C18 column). [α]2D5 = 31.94 (c = 0.2,
CHCl3).
Compound 10: Rf = 0.45 (80% ethyl acetate/petroleum ether). M.p.
1
150–151 °C. H NMR (400 MHz, CDCl3): δ = 2.01 (t, J = 2.8 Hz,
1 H), 2.02 (s, 3 H), 2.53–2.67 (m, 2 H), 3.11–3.15 (m, 2 H), 3.73 (s,
3 H), 4.57–4.59 (m, 1 H), 4.86–4.88 (m, 1 H), 6.44 (d, J = 7.2 Hz,
1 H), 6.76 (d, J = 8.0 Hz, 1 H), 7.13–7.15 (m, 2 H), 7.25–7.31 (m,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.5, 23.2, 38.0, 51.5,
52.6, 53.5, 71.9, 79.3, 127.4, 128.8, 129.5, 135.8, 169.6, 170.5,
171.8 ppm. HRMS (QTOF): calcd. for C17H21N2O4 [M + H]+
317.1501; found 317.1492. IR (KBr): ν = 1647, 1742, 2300 cm–1.
˜
HPLC: tR = 3.329 min (100% acetonitrile, flow rate 1 mL/min, de-
tector wavelength 254 nm, reverse-phase C18 column). [α]2D5 = 36.42
(c = 0.2, CHCl3).
Compound 11: Rf = 0.12 (100% ethyl acetate). M.p. 176–177 °C.
1H NMR (400 MHz, CD3OD): δ = 1.96–1.99 (br. s, 4 H), 2.40–
2.57 (m, 2 H), 2.93–3.19 (m, 2 H), 4.48–4.63 (m, 1 H), 4.64–4.89
(m, 1 H), 7.01 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.4 Hz, 2 H) ppm.
13C NMR (100 MHz, CD3OD): δ = 22.5, 22.8, 37.9, 53.4, 54.7,
72.3, 80.2, 92.9, 132.7, 138.1, 138.7, 172.1, 173.4, 174.0 ppm.
HRMS (QTOF): calcd. for C16H18N2O4I [M + H]+ 429.0311;
General Procedure for Peptide Coupling: To a solution of 3
(1.94 mmol) and HOBt (1.83 mmol) in dry THF (10 mL) was
added EDCl (1.83 mmol) at 0 °C. Then, 5 or 6 (1.83 mmol) and
Et3N (0.3 mL, the pH of the reaction mixture was 9) in THF
(10 mL) were added at 0 °C. The reaction mixture was stirred at
r.t. for 24 h. The solvent was evaporated, and the residue was di-
luted with water. The aqueous layer was extracted with ethyl acet-
ate (3ϫ10 mL). The combined organic layers were washed with
water and brine and dried with Na2SO4. Evaporation of the solvent
gave the crude product, which was purified by column chromatog-
raphy (ethyl acetate/petroleum ether) to give the diasteromeric di-
peptides.
found 429.0298. IR (KBr): ν = 1658, 1745, 2320, 3460 cm–1. [α]25
˜
D
= 150.03 (c = 0.1, CH3OH).
Compound 12: Rf = 0.41 (80% ethyl acetate/petroleum ether). M.p.
200–202 °C. 1H NMR (400 MHz, CDCl3): δ = 0.87–0.89 (m, 6 H),
1.48–1.59 (m, 3 H), 2.00–2.03 (br. s, 4 H), 2.53–2.69 (m, 2 H), 3.05
(d, J = 6.8 Hz, 2 H), 3.71 (s, 3 H), 4.49–4.56 (m, 2 H), 4.67–4.72
(m, 1 H), 6.53–6.57 (m, 2 H), 6.98 (d, J = 8.2 Hz, 2 H), 7.05 (d, J
= 8.0 Hz, 1 H), 7.60 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.0, 22.2, 22.9, 23.2, 24.9, 37.7, 41.4, 51.1,
51.9, 52.6, 54.5, 72.1, 79.0, 92.7, 131.6, 136.1, 137.9, 170.0, 170.2,
170.9, 173.0 ppm. HRMS (QTOF): calcd. for C23H31N3O5I [M +
Compound 7: Rf = 0.44 (80% ethyl acetate/petroleum ether). M.p.
1
178–179 °C. H NMR (300 MHz, CDCl3): δ = 2.02 (s, 3 H), 2.06
(t, J = 2.7 Hz, 1 H), 2.50–2.59 (m, 1 H), 2.72–2.81 (m, 1 H), 2.98–
3.05 (m, 1 H), 3.11–3.18 (m, 1 H), 3.74 (s, 3 H), 4.49–4.56 (m, 1
H), 4.79–4.86 (m, 1 H), 6.18 (d, J = 7.8 Hz, 1 H), 6.75 (d, J =
7.8 Hz, 1 H), 6.86 (d, J = 8.4 Hz, 2 H), 7.61 (d, J = 8.4 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 22.0, 23.3, 37.4, 51.5 52.7,
53.5, 72.1, 79.3, 92.9, 131.4, 135.5, 137.8, 169.7, 170.5, 171.3 ppm.
H]+ 556.1308; found 556.1288. IR (KBr): ν = 1650, 1731,
˜
2251 cm–1. [α]2D5 = 7.28 (c = 0.6, CHCl3).
HRMS (QTOF): calcd. for C17H20N2O4I [M + H]+ 443.0468; General Procedure for CEM: A solution of the alkyne dipeptide
found 443.0453. IR (KBr): ν = 1644, 1736, 2306 cm–1. HPLC: t
(0.11 mmol) in CH2Cl2 (15 mL) was degassed with nitrogen for
10 min and degassed with ethylene for 10 min. G-II (0.011 mmol,
˜
R
= 3.087 min (100% acetonitrile, flow rate 1 mL/min, detector wave-
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FULL PAPER
10 mol-%) was added, and the reaction vessel was kept under 1 atm
pressure of ethylene (balloon pressure). The reaction mixture was
stirred at r.t. for 20–24 h. After completion of the reaction (TLC
monitoring), the solvent was evaporated, and the crude product
was purified by flash silica gel column chromatography (ethyl acet-
ate/petroleum ether) to give the dipeptide-based diene.
34.2, 37.5, 41.2, 51.1, 52.4, 52.9, 54.2, 92.6, 114.9, 119.3, 126.8,
128.9, 131.6, 136.3, 137.7, 137.8, 141.2, 170.3, 170.9, 171.4,
172.9 ppm. HRMS (QTOF): calcd. for C25H35N3O5I [M + H]+
584.1621; found 584.1628. IR (KBr): ν = 1540, 1641, 1738,
˜
2958 cm–1. [α]2D5 = –14.25 (c = 0.3, CHCl3).
General Procedure for DA Reaction: To a solution of dipeptide-
based diene (0.07 mmol) was added dimethyl acetylenedicarboxyl-
ate (0.16 mmol) in dry toluene (10 mL), and the reaction mixture
was heated at 90 °C for 18–20 h. The solvent was evaporated under
reduced pressure, and the crude product obtained was purified by
flash silica gel column chromatography (ethyl acetate/petroleum
ether) to afford the DA adduct. Oxidation of the DA adduct
(0.03 mmol) was carried out with MnO2 (0.33 mmol) in dioxane
(10 mL) at reflux for 20–24 h. The solvent was removed under re-
duced pressure, and the crude product was purified by flash silica
gel column chromatography using (ethyl acetate/petroleum ether)
to afford the aromatised product.
Compound 13: Rf = 0.46 (80% ethyl acetate/petroleum ether). M.p.
1
126–128 °C. H NMR (400 MHz, CDCl3): δ = 1.97 (s, 3 H), 2.62
(d, J = 7.6 Hz, 2 H), 2.95–3.11 (m, 2 H), 3.72 (s, 3 H), 4.51–4.57
(m, 1 H), 4.75–4.80 (m, 1 H), 5.02 (s, 1 H), 5.09 (s, 1 H), 5.15 (d,
J = 10.8 Hz, 1 H), 5.39 (d, J = 18 Hz, 1 H), 6.07 (d, J = 7.2 Hz, 1
H), 6.33 (dd, J = 17.6, 10.8 Hz, 1 H), 6.56 (d, J = 8.0 Hz, 1 H),
6.86 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 23.1, 34.1, 37.4, 52.0, 52.4, 53.0, 92.6,
114.9, 119.1, 131.3, 135.3, 137.6, 137.7, 141.3, 170.0, 170.7,
171.2 ppm. HRMS (QTOF): calcd. for C19H24N2O4I [M + H]+
471.0781; found 471.0783. IR (KBr): ν = 1621.9, 1681.7, 1743.2,
˜
3052.9 cm–1. [α]2D5 = 28.98 (c = 0.07, CHCl3).
Compound 18: Rf = 0.33 (80% ethyl acetate/petroleum ether). M.p.
Compound 14: Rf = 0.42 (80% ethyl acetate/petroleum ether). M.p.
1
144–146 °C. H NMR (400 MHz, CDCl3): δ = 1.95 (s, 3 H), 2.92–
1
128–130 °C. H NMR (400 MHz, CDCl3): δ = 1.96 (s, 3 H), 2.57–
2.94 (m, 1 H), 3.03–3.08 (m, 3 H), 3.68 (s, 3 H), 3.88 (s, 6 H), 4.61–
4.63 (m, 1 H), 4.71–4.73 (m, 1 H), 6.14 (d, J = 7.6 Hz, 1 H), 6.39
(d, J = 7.6 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 2 H), 7.36 (d, J = 8.0 Hz,
1 H), 7.49 (s, 1 H), 7.57 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8.0 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.3, 37.5, 37.8, 52.7,
52.8, 52.9, 53.3, 54.1, 92.9, 129.6, 129.9, 130.5, 131.4, 131.9, 132.8,
135.4, 137.8, 140.3, 167.7, 168.1, 170.1, 171.7 ppm. HRMS
(QTOF): calcd. for C25H28N2O8I [M + H]+ 611.0890; found
2.62 (m, 2 H), 2.98–3.03 (m, 2 H), 3.69 (s, 3 H), 4.56–4.57 (m, 1
H), 4.75–4.77 (m, 1 H), 4.95 (s, 1 H), 5.01 (s, 1 H), 5.14 (d, J =
10.8 Hz, 1 H), 5.37 (d, J = 17.6 Hz, 1 H), 6.05 (d, J = 6.8 Hz, 1
H), 6.29 (dd, J = 18.0, 11.2 Hz, 1 H), 6.59 (d, J = 7.6 Hz, 1 H),
6.86 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 23.3, 34.3, 37.6, 52.2, 52.6, 53.2, 92.8,
115.2, 119.1, 131.4, 135.6, 137.9, 141.6, 170.4, 171.1, 171.6 ppm.
HRMS (QTOF): calcd. for C19H24N2O4I [M + H]+ 472.0859;
611.0918. IR (KBr): ν = 1652, 1731, 3055 cm–1. [α]25 = 4.10 (c =
˜
D
found 472.0841. IR (KBr): ν = 1622, 1662, 1748, 3055 cm–1. [α]25
˜
D
0.29, CHCl3).
= 26.51 (c = 0.4, CHCl3).
Compound 19: Rf = 0.31 (80% ethyl acetate/petroleum ether). M.p.
143–144 °C. H NMR (400 MHz, CDCl3): δ = 1.94 (s, 3 H), 2.87–
Compound 15: Rf = 0.50 (80% ethyl acetate/petroleum ether). M.p.
123–125 °C. H NMR (400 MHz, CDCl3): δ = 1.97 (s, 3 H), 2.56–
1
1
2.89 (m, 2 H), 2.91–2.98 (m, 1 H), 3.00–3.15 (m, 1 H), 3.67 (s, 3
H), 3.89 (s, 3 H), 3.90 (s, 3 H), 4.69–4.76 (m, 2 H), 6.17 (d, J =
8.4 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 2 H), 6.69 (d, J = 8.0 Hz, 1 H),
7.28 (d, J = 8.0 Hz, 1 H), 7.52 (s, 1 H), 7.56 (d, J = 8.0 Hz, 2 H),
7.67 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
23.2, 37.5, 37.8, 52.7, 52.9, 53.0, 53.2, 54.1, 92.9, 129.6, 129.9,
130.5, 131.3, 132.0, 132.9, 135.4, 137.9, 140.5, 167.7, 168.2, 170.3,
170.4, 171.4 ppm. HRMS (QTOF): calcd. for C25H28N2O8I [M +
2.65 (m, 2 H), 3.02–3.16 (m, 2 H), 3.72 (s, 3 H), 4.50–4.56 (m, 1
H), 4.77–4.82 (m, 1 H), 5.01 (s, 1 H), 5.06 (s, 1 H), 5.14 (d, J =
10.8 Hz, 1 H), 5.43 (d, J = 18.0 Hz, 1 H), 5.99 (d, J = 7.2 Hz, 1
H), 6.28–6.39 (m, 2 H), 7.08–7.09 (m, 2 H), 7.24–7.30 (m, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 23.3, 34.5, 38.1, 52.2, 52.6,
53.5, 115.3, 119.5, 127.4, 128.8, 129.5, 135.8, 137.8, 141.6, 170.1,
170.8, 171.6 ppm. HRMS (QTOF): calcd. for C19H25N2O4 [M +
H]+ 345.1814; found 345.1808. IR (KBr): ν = 1543, 1650, 1743,
˜
H]+ 611.0890; found 611.0881. IR (KBr): ν = 1652, 1731,
˜
3062 cm–1. [α]2D5 = 6.179 (c = 0.34, CHCl3).
3064 cm–1. [α]2D5 = 29.07 (c = 0.26, CHCl3).
Compound 16: Rf = 0.46 (80% ethyl acetate/petroleum ether). M.p.
1
Compound 20: Rf = 0.26 (80% ethyl acetate/petroleum ether). M.p.
125–127 °C. H NMR (400 MHz, CDCl3): δ = 1.97 (s, 3 H), 2.59
1
124–125 °C. H NMR (400 MHz, CDCl3): δ = 1.93 (s, 3 H), 2.98–
(d, J = 7.2 Hz, 2 H), 3.11–3.15 (m, 2 H), 3.71 (s, 3 H), 4.57–4.59
(m, 1 H), 4.77–4.79 (m, 1 H), 4.94 (s, 1 H), 5.01 (s, 1 H), 5.14 (d,
J = 11.2 Hz, 1 H), 5.39 (d, J = 17.6 Hz, 1 H), 6.11 (d, J = 7.2 Hz,
1 H), 6.35 (dd, J = 18.0, 11.2 Hz, 1 H), 6.49 (d, J = 7.6 Hz, 1 H),
7.11–7.13 (m, 2 H), 7.24–7.33 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 23.3, 34.6, 38.0, 52.3, 52.6, 53.5, 115.2, 119.2, 127.4,
128.9, 129.4, 135.8, 137.8, 141.6, 170.2, 171.0, 171.8 ppm. HRMS
(QTOF): calcd. for C19H25N2O4 [M + H]+ 345.1814; found
3.13 (m, 4 H), 3.69 (s, 3 H), 3.88 (s, 6 H), 4.73–4.78 (m, 2 H), 6.19
(d, J = 8.0 Hz, 1 H), 6.41 (d, J = 7.3 Hz, 1 H), 7.01–7.05 (m, 2 H),
7.21–7.37 (m, 4 H), 7.49 (d, J = 1.6 Hz, 1 H), 7.64 (d, J = 7.9 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.2, 37.9, 52.6, 52.7,
52.8, 53.5, 54.0, 127.4, 128.8, 129.3, 129.5, 129.9, 130.5, 132.0,
132.8, 135.7, 140.4, 167.8, 168.1, 170.1, 170.2, 171.4 ppm. HRMS
(QTOF): calcd. for C25H29N2O8 [M + H]+ 485.1936; found
485.1924. IR (KBr): ν = 1660, 1741, 2926 cm–1. [α]25 = 16.69 (c =
345.1812. IR (KBr): ν = 1540, 1658, 1745, 3060 cm–1. [α]25 = 37.04
˜
D
˜
D
0.38, CHCl3).
(c = 0.6, CHCl3).
Compound 17: Rf = 0.45 (80% ethyl acetate/petroleum ether). M.p.
197–198 °C. 1H NMR (400 MHz, CDCl3): δ = 0.88–0.90 (m, 6 H),
1.52–1.55 (m, 3 H), 1.97 (s, 3 H), 2.57–2.61 (m, 2 H), 3.00–3.02 (m,
Compound 21: Rf = 0.24 (80% ethyl acetate/petroleum ether). M.p.
129–131 °C. H NMR (400 MHz, CDCl3): δ = 1.94 (s, 3 H), 2.95–
3.13 (m, 4 H), 3.68 (s, 3 H), 3.88 (s, 6 H), 4.68–4.80 (m, 2 H), 6.13
1
2 H), 3.69 (s, 3 H), 4.35–4.41 (m, 1 H), 4.46–4.51 (m, 1 H), 4.61– (d, J = 7.9 Hz, 1 H), 6.54 (d, J = 7.8 Hz, 1 H), 6.95–6.97 (m, 2 H),
4.66 (m, 1 H), 4.96 (s, 1 H), 5.03 (s, 1 H), 5.15 (d, J = 10.8 Hz, 1 7.00–7.29 (m, 4 H), 7.48 (d, J = 1.56 Hz, 1 H), 7.64 (d, J = 7.9 Hz,
H), 5.31 (d, J = 17.7 Hz, 1 H), 6.05 (br. s, 1 H), 6.29 (dd, J = 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.2, 37.9, 52.6, 52.8,
17.6 Hz, J = 10.9 Hz, 1 H), 6.44 (d, J = 7.5 Hz, 1 H), 6.58 (d, J =
7.6 Hz, 1 H), 6.95 (d, J = 8.2 Hz, 2 H), 7.61 (d, J = 8.0 Hz, 2 H)
52.9, 53.4, 54.0, 127.5, 128.9, 129.3, 129.6, 129.9, 130.5, 131.9,
132.8, 135.7, 140.5, 167.8, 168.2, 170.2, 170.3, 171.7 ppm. HRMS
ppm. 13C NMR (100 MHz, CD3Cl3): δ = 21.9, 22.9, 23.1, 24.9, (QTOF): calcd. for C25H29N2O8 [M + H]+ 485.1924; found
1848
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1843–1850

Modified Phenylalanine Peptides
485.1909. IR (KBr): ν = 1665, 1739, 2928 cm–1. [α]25 = 26.26 (c =
0.19, CHCl3).
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grove, P. R. Hanson, Tetrahedron 2000, 56, 9781.
˜
D
Compound 22: Rf = 0.30 (80% ethyl acetate/petroleum ether). M.p.
102–103 °C. 1H NMR (400 MHz, CDCl3): δ = 0.86–0.88 (m, 6 H),
1.41–1.54 (m, 3 H), 1.95 (s, 3 H), 2.76–3.15 (m, 4 H), 3.69 (s, 3 H),
3.89 (s, 3 H), 3.90 (s, 3 H), 4.43–4.62 (m, 2 H), 4.63–4.72 (m, 1 H),
6.34 (d, J = 7.4 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 6.62 (d, J =
8.4 Hz, 1 H), 6.78 (d, J = 8.2 Hz, 2 H), 7.28–7.29 (m, 1 H), 7.50
(s, 1 H), 7.56 (d, J = 8.28 Hz, 2 H), 7.68 (d, J = 7.96 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 21.9, 22.9, 23.1, 24.9, 37.3, 37.5,
41.2, 51.2, 52.5, 52.8, 52.9, 54.1, 54.8, 92.8, 128.7, 129.7, 129.8,
130.6, 131.5, 131.9, 132.9, 135.9, 137.9, 140.3, 167.6, 168.2, 169.9,
170.5, 170.9, 172.9 ppm. HRMS (QTOF): calcd. for C31H39N3O9I
[7]
[M + H]+ 724.1731; found 724.1760. IR (KBr): ν = 1637, 1734,
˜
2926 cm–1. [α]2D5 = –9.4 (c = 0.18, CHCl3).
Compound 23: Rf = 0.30 (60% ethyl acetate/petroleum ether). M.p.
158–161 °C. 1H NMR (400 MHz, CD3OD): δ = 0.85–0.95 (m, 6
H), 1.59–1.87 (m, 3 H), 1.89 (s, 3 H), 2.75–3.11 (m, 4 H), 3.68 (s,
3 H), 4.41–4.45 (m, 3 H), 6.95 (d, J = 8.3 Hz, 2 H), 7.51 (d, J =
8.3 Hz, 2 H), 7.56–7.58 (m, 1 H), 7.87–7.89 (m, 2 H), 8.10 (d, J =
1.6 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.28–8.31 (m, 2 H) ppm.
HRMS (QTOF): calcd. for C35H37N3O7I [M + H]+ 738.1676;
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found 738.1674. IR (KBr): ν = 1458, 1654, 1936 3002 cm–1. [α]25
=
˜
D
–11.5(c = 0.12, CH3OH).
[9]
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H/13C NMR spectra of all new products.
[10]
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Acknowledgments
We thank the Department of Science and Technology, New Delhi
for financial support and the Sophisticated Analytical Instrument
Facility, IIT-Bombay for recording spectroscopic data. S. K. thanks
the Department of Science and Technology for the award of a J. C.
Bose fellowship. D. G. thanks the University Grants Commission,
New Delhi for the award of a research fellowship.
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The diasteromeric nature of the products was confirmed by the
presence of two singlets of almost equal intensity at δ = 3.725
1
and 3.736 ppm (–OCH3 protons) in the H NMR spectrum of
Eur. J. Org. Chem. 2012, 1843–1850
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1849

S. Kotha, D. Goyal (née Bansal), N. Thota, V. Srinivas
FULL PAPER
the crude reaction mixture. Percolation of the reaction mixture
through a silica gel column with ethyl acetate/petroleum ether
(3:7) resulted in the separation of the diasteromeric dipeptides
7 and 8. The structures of these two dipeptides were established
by IR, 1H NMR, and 13C NMR spectroscopy and MS. The
presence of singlets at δ = 3.736 and 3.725 ppm in the 1H NMR
spectra of 7 and 8, respectively, indicate the successful separa-
tion of the two diasteromers by column chromatography.
HPLC further supports the purity of the two diasteromers. The
2D NMR spectra (COSY and NOESY) of 7 and 8 were not
of much help in the assignment of their stereochemistry, and
therefore, we undertook an independent synthesis of these two
diasteromers to establish their absolute stereochemistry. In this
regard, we acetylated commercially available (S)-propargyl-
glycine and (R)-propargylglycine according to a literature pro-
cedure.[18] (S)-Ac-propargylglycine and (R)-Ac-propargyl-
glycine were treated with the p-iodomethyl ester hydrochloride
of (S)-phenylalanine 5. These dipeptides were characterised
1
and compared with 7 and 8 by inspection of the Rf, H NMR
and [α]D values. Based on this data, it was concluded that 7 is
the (R,S)-dipeptide, and 8 is an (S,S)-dipeptide. The configura-
tions of 9 and 10 were established along similar lines.
[18] a) J. P. Scannell, D. L. Pruess, T. C. Demny, F. Weiss, T. Wil-
liams, J. Antibiot. 1971, 24, 239; b) T. L. Mindt, R. Schibli, J.
Org. Chem. 2007, 72, 10247; c) H. K. Chenault, J. Dahmer,
G. M. Whitesides, J. Am. Chem. Soc. 1989, 111, 6354.
Received: December 3, 2011
Published Online: February 3, 2012
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1843–1850