Chiral Nβ-Fmoc-amino alkyl isonitriles in Ugi-4CR: An assembly of novel 1,1′-iminodicarboxylated peptidomimetics

Article abstract of DOI:10.1016/j.tet.2011.12.037

Enantiopure N^β-Fmoc-amino alkyl isonitriles and amino acid esters have been employed as building blocks in Ugi four-component reaction (U-4CR) to yield 1,1′-iminodicarboxylated peptidomimetics. By employing trifluoroacetic acid as one of the co

Full text of DOI:10.1016/j.tet.2011.12.037

Tetrahedron 68 (2012) 1992e2000
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral Nb-Fmoc-amino alkyl isonitriles in Ugi-4CR: an assembly of novel
1,10-iminodicarboxylated peptidomimetics
*
N. Narendra, T. M. Vishwanatha, G. Nagendra, Vommina V. Sureshbabu
Room 109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B.R. Ambedkar Veedhi, Bangalore 560001, India
a r t i c l e i n f o
a b s t r a c t
Enantiopure Nb-Fmoc-amino alkyl isonitriles and amino acid esters have been employed as building
blocks in Ugi four-component reaction (U-4CR) to yield 1,10-iminodicarboxylated peptidomimetics. By
employing trifluoroacetic acid as one of the components, a different outcome has been observed and
rationalized. Ugi products are obtained as trifluoroacetamide adducts, which on further reaction under
mild acidic conditions lead to the title compounds. The method has also been proven to be useful for the
preparation of ethyl, benzyl and tert-butyl esters.
Article history:
Received 22 September 2011
Received in revised form 13 December 2011
Accepted 14 December 2011
Available online 4 January 2012
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Nb-Fmoc-amino alkyl isonitriles
Amino acid esters
Trifluoroacetic acid
U-4CR
U-5C-4CR
1,10-Iminodicarboxylic acid tethered
peptidomimetics
1. Introduction
would be of considerable interest in order to obtain various
peptide-like adducts. A thorough literature survey revealed that
The isonitrile based MCRs were developed by Passerini (3CR) in
1921 and then by Ugi (4CR) in 1959.1 Isonitriles have divalent na-
ture and their unique reactivity provides C-nucleophiles toward
imines, resulting in nitrilium electrophiles, enables the wide ap-
plications of Passerini and Ugi reactions to produce diverse array of
products in combinatorial chemistry.2 Ugi reaction has been the
widely recognized MCR, since it has larger flexibility toward gen-
eration of small molecules to larger ones, natural products, pep-
tides, heterocycles and other biologically relevant compounds.3 In
Ugi-4CR, an amine, an aldehyde, an isonitrile, and an acid react in
one-pot leading to the synthesis of a linear peptide-like adduct.
Thus, enantiopure isocyano esters4 have been synthesized and
employed as one of the components in several of the MCRs.5 They
have been employed for the synthesis of complex peptides and
peptidomimetics in one-pot.6 Amino acid derived isocyano ester 1a
remains a focus of much attention, because permutation and
combination of new variants would generate a wide variety of
novel type of molecules as desired by the pharmaceutical industry.7
In this context, the use of C-terminal modified ‘N-protected amino
alkyl isonitriles’ 1b as building blocks in multicomponent reactions
only one derivative namely N-Fmoc/Boc-amino ethyl isonitrile had
been synthesized starting from ethylene diamine in a multistep
approach.8 The above isonitrile was employed for one-pot syn-
thesis of peptide nucleic acids (PNAs). With the objective to in-
corporate isonitrile functionality in place of carboxy group of
optically pure amino acids, we have developed a simple protocol for
conversion of carboxylic acid to formamide, followed by de-
hydration to the isocyanide using Burgess reagent (Fig. 1).9
R
R
NC
CN
COOX
PgHN
(a)
(b)
X = Me, Et, Bn or tBu groups
Pg= Fmoc, Boc or Z groups
Fig. 1. Amino acid derived isonitriles.
Apart from the application of isocyano ester 1a, several studies
have also been made to broaden the scope of enantiopure bi-
functional amino acids/peptides in MCRs.10 Thus, varieties of bi-
ologically active peptidomimetics have been synthesized via Ugi
MCRs by using amino acid derivatives as aldehyde,11 amine12 or
acid component.13 A prominent example for this kind of MCRs is
* Corresponding author. Tel.: þ91 (0)8 2296 1339, 09986312937; e-mail
addresses: sureshbabuvommina@rediffmail.com, hariccb@gmail.com, hariccb@
hotmail.com (V.V. Sureshbabu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.037

N. Narendra et al. / Tetrahedron 68 (2012) 1992e2000
1993
the condensation of amino acid, isonitrile and aldehyde to obtain O-
2. Results and discussion
acyl amide, which then undergoes nucleophillic attack by the al-
coholic solvent (MeOH) to give 1,10-iminodicarboxylic acid de-
rivative (Scheme 1).14
In our approach to obtain the hitherto unreported class of Ugi
peptide adducts, Nb-Fmoc-amino alkyl isonitriles have been syn-
R1
R1
O
R1
R2 R1
O
H
N
MeOH
R3-NC
HN
R2
O
O
+
H2N
COOH
H
R2
HN
R2
R3
N
H
O
O
O
O
N
R3
Scheme 1. General reaction mechanism of U-5C-4CR.
Recently, several other groups have utilized a similar protocol to
obtain 1,10-iminodicarboxylic acid derivatives,15 which were found
to be potent inhibitors toward angiotensin converting enzymes and
Zn2þ containing endopeptidase and occur in naturally occurring
crown gall tumors and poisonous mushrooms.16 They have also
been widely used as chiral ligands. Interestingly, the U-5C-4CR is
strongly influenced by the nucleophillic solvents used. To the best
of our knowledge, only MeOH has been explored as a solvent.
Consequently, the respective Ugi products were obtained as methyl
esters (Scheme 1).
thesized following our previous report.9a In a short note, carboxy
group of Nb-Fmoc-amino acids were directly converted to the
corresponding isocyanates through established protocol,9d which
then undergoes DMAP catalyzed formylation with 98% HCOOH.
The formamides were then dehydrated using Burgess reagent
(Fig. 2).
Considering the successful implementation as well as mecha-
nistic studies of Ugi 5C-4CR, we expected that other nucleophilic
solvents (except MeOH) could give rise to a corresponding ester as
Ugi product. In an initial study, N-FmocePhe-j-[CH2NC] was
Isonirtiles
R1
R1
R1
1. NMM, IBC-Cl
2. NaN3
Burgess reagent
CH2Cl2, 60 oC
COOH
NHCHO
NC
3. toluene, 65 oC
4. 98% HCOOH,
FmocHN
FmocHN
FmocHN
1
DMAP, CH2Cl2, -15 oC
Amino acids employed: Gly, Ala, Phe, Asp(β-Bn), Lys(Z), Pro, Ile, Glu (γ-Bn)
Amines
OH
Ph
Aldehydes
CHO
H2N
COOMe
H2N
COOMe
COOBn
H2N
COOEt
S
OHC
CHO
OH
(HCHO)n
H2N
H2N
COOMe
H2N
COOEt
H2N
COOBn
t
H2N
COOBu
Fig. 2. Building blocks employed for U-4CR.
Focusing on finding a new class of 1,10-iminodicarboxylated
peptidomimetics, we employed Nb-Fmoc-protected amino alkyl
isonitrile 1b and amino acid esters. Peptide adducts obtained from
present method are rich in chiral centers and possesses both N- and
C-termini. Herein to obtain aforementioned peptidomimetics, we
explored U-4CR rather than U-5C-4CR through condensation of
amino acid ester, CF3COOH, isonitrile and aldehyde. The Ugi prod-
ucts 4 were obtained as trifluoroacetamide adducts, which after the
cleavage of trifluoroacetyl group from respective adducts affords
1,10-iminodicarboxylated peptidomimetics 5. In both the steps
a good diastereoselectivity was observed. This work has been
demonstrated not only to obtain new class of peptidomimetics, but
constitutes an alternative to complement the earlier route of U-5C-
4CR involving amino acids providing both amino as well as carboxy
termini.
employed in Ugi 5C-4CR (Scheme 2). Enantiopure L-Ala in MeOH
was cooled to ꢀ30 ꢁC, equimolar amounts of benzaldehyde and N-
FmocePhe-j-[CH2NC] were added. Indeed, after 46 h of vigorous
stirring at 30 ꢁC, we obtained the Ugi product 2 in 59% yield (Table
1, entry a). But only a slight increase in the yield was observed at
60 ꢁC (Table 1, entry b). When the same reaction was performed in
presence of EtOH, the desired product was obtained in 28% yield
(Table 1, entry c) and only 2% was scaled upon reflux (Table 1, entry
d). In contrast, replacing EtOH with benzyl alcohol had no result at
room temperature (Table 1, entry e) and about only 5% of the
product was obtained at 70 ꢁC (Table 1, entry f). However, the use of
tert-butanol affords a trace amount of Ugi product at 30 ꢁC as well
as at 60 ꢁC (Table 1, entries g and h). These results are in accordance
with the known observations that nucleophillic solvents drastically
influence the U-5C-4CR. Further, less reactivity of other alcoholic

1994
N. Narendra et al. / Tetrahedron 68 (2012) 1992e2000
Ph
FmocHN
Ph
*
Ph
H
N
solvent
+
C6H5CHO
+
N
H
COOX
NC
H2N
COOH
FmocHN
O
1
2
Scheme 2. Synthesis of 2 via Ugi 5C-3CR using different nucleophillic solvents under various conditions.
Table 1
TLC analysis), a simple work-up followed by column purification
afforded Ugi product 4c as trifluoroacetamide adduct in good yield
(85%, Table 2).
Results of Ugi 5C-3CR in various solvents from Scheme 2
Entry
Solventa
X
Time (h)
Temp (ꢁC)
Yieldb (%)
In the final step of the study, we carried out cleavage of tri-
fluoroacetyl group of Ugi products 4. For the deprotection, the
widely known base catalyzed cleavage methods employing K2CO3,
a
b
c
d
e
f
MeOH
MeOH
EtOH
Me
Me
Et
Et
Bn
Bn
t-Bu
t-Bu
46
45
58
56
58
55
50
51
30
60
30
70
30
70
30
60
59
61
28
30
d
EtOH
18
Na2CO3 or NH3 are not compatible with Fmoc chemistry. In pur-
BnOH
BnOH
t-BuOH
t-BuOH
suit of an alternative protocol, we followed Li et al., approach which
involves treatment with p-TsOH.19 This method also facilitates the
isolation of product after simple work-up. In the present study
(Scheme 3), Ugi products 4 were treated with p-TsOH in MeOH at
50 ꢁC, and the final product 5 was formed over 30 min (TLC anal-
ysis). A simple work-up led to the isolation of the desired product 5
in good yields (Table 3). However, due to the acidic nature of the
reaction conditions employed, about 10e15% of tert-butyl ester
cleavage was observed in case of 5j and 5k (Table 3, entries 10
and 11).
05
20
24
g
h
a
Ten-fold excess of solvents were taken.
Yields of the crude products.
b
solvents could be expected. This is probably due to steric factors
arising from the cyclic intermediate, which restricts the smooth
nucleophillic attack by the solvent and poor solubility of the amino
acid also.
To circumvent the above drawbacks, it is imperative to choose
an alternative protocol. We might expect that a linear peptide-like
adduct rather than cyclic intermediate can be obtained easily
through U-4CR. While implementing this strategy, selecting strong
acid component finds an attractive objective. Thus, trifluoroacetic
acid (TFA) was chosen as an acid component in our present study.
U-4CR gives linear non cyclic trifluoroacetamide adduct as Ugi
product in less duration of time under mild conditions with good
diastereoselectivities (Scheme 3). In the subsequent step, the title
compounds can be obtained after the removal of trifluoroacetyl
function under mild acidic condition (Scheme 4).
The broad utility of the current version of the strategy to syn-
thesize 1,10-iminodicarboxylated derivatives is demonstrated by
studying the feasibility of the protocol using several functionalized
amino acids viz. Ser, Asp(b-Bn), Lys(Z), Glu(g-Bn), Tyr, Cys and Met
either as isonitrile or as an amino component. In all the cases Ugi
peptide adducts 4 were obtained without any difficulty and prod-
ucts were obtained in good yield within 2e3 h. In addition, we did
not observe any considerable decrease in the yield, when we used
sterically hindered aldehydes. According to the mechanism of the
Ugi-4CR, a mixture of diastereomeric products was obtained, which
arises from the new chiral center created at the quaternary carbon
of the aldehyde. In addition, both the products 4 and 5 had similar
diastereoselectivities and were not separable in column chroma-
tography, although, HPLC had displayed good selectivity of the
products.
To examine the above strategy, a typical reaction has been
conducted using HeAlaeOMe as amino component. To a solution of
HeAlaeOMe (hydrochloride salt was deprotonated by treatment
with Zn dust17) in MeOH, an equimolar amount of isovaleraldehyde
R1
3. Conclusion
R1
R2 R3
NC
R3
FmocHN
R2-CHO
H
N
In conclusion, this report outlines the synthesis of 1,10-imino-
dicarboxylated peptidomimetics. U-4CR was found to be suitable
protocol rather than known U-5C-3CR, provided appropriate acid
component was chosen. Reaction of Nb-Fmoc-amino alkyl iso-
nitriles, amino acid esters, commercially available aldehydes and
trifluoroacetic acid affords trifluoroacetamide peptidomimetic ad-
ducts in good yield. Further, cleavage of trifluoroacetyl functionality
under mild conditions afforded title molecules. An Ugi 4CR using
U-4CR
*
FmocHN
N
COOX
1- 3 h
O
4
COCF3
H2N
COOX
rt, MeOH
CF3COOH
Scheme 3. Preparation of 1,10-iminodicarboxylated peptidomimetics through U-4CR.
R1
R2
R3
R1
R2
*
R3
H
N
H
N
.
p-TsOH H2O
FmocHN
N
H
COOX
FmocHN
* N
COOX
MeOH, TEA
O
30 min, 50 0C
O
COCF3
5a-k
4a-k
Scheme 4. Deprotection of trifluoroacetyl group of Ugi products 4.
was added at room temperature, the reaction mixture was allowed
to stir under the same temperature for 2 h to ensure the imine
trifluoroacetic acid as the carboxylic acid component and a per-
formed amino acid ester as the amine component was found to be
preferable to the known U-5C-3CR in involving solvolysis of the
reaction intermediate.
formation, and then Nb-FmocePhe-
j-[CH2NC] and trifluoroacetic
acid (TFA) were added. After stirring for another 1 h (monitored by

N. Narendra et al. / Tetrahedron 68 (2012) 1992e2000
1995
Table 2
Trifluoroacetamide possessing Ugi adducts isolated from Scheme 2
Product
R1
R2
R3
X
Yielda (%)
Timeb (h)
drc
89:11
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
CH3
CH2Ph
e(CH2)3e
CH2Ph
(CH2)4NHZ
CH2CH(CH3)2
CH(CH3)2
CH2COOBn
CH2CH2COOBn
CH(CH3)CH2CH3
Ph
H
CH2OH
CH2Ph
CH3
CH2CH(CH3)2
CH3
CH3
CH2Ph-pOH
H
Me
Et
Me
Bn
Me
Me
Me
Bn
86
91
85
79
78
83
89
93
87
86
88
1
3
1
2
100:0
79:21
100:0
84:16
75:25
100:0
98:2
100:0
91:9
97:3
CH2CH(CH3)2
H
Ph
Ph
1
2.5
0.5
1.5
3
1.6
3.5
H
C(CH3)3
H
C(CH3)3
CH2CH(CH3)2
CH2CH2SCH3
CH3
CH3
Et
t-Bu
t-Bu
4j
4k
a
Yields of the isolated product.
Time refers to complete consumption of isonitriles.
Diastereomeric ratios were established by RP-HPLC analysis of the purified products.
b
c
4. Experimental
4.1. General
hexane/EtOAc, 2:1); RP-HPLC tR 21.1, 21.6 (60e100% ACN; 30 min);
20
[a
]
þ25.3 (c 1.0, CHCl3); IR (KBr) nmax 3025, 2877, 2568, 1751,
D
1735, 1635, 1380 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 2.74 (br s, 1H,
OH Ser), 3.15 (t, J¼2.9 Hz, 2H, NHCH2CH2), 3.26 (t, J¼4.8 Hz, 2H,
NHCH2CH2), 3.65 (s, 3H, OCH3), 3.89e4.01 (m, 2H, CH2 Ser), 4.42 (t,
J¼5.8 Hz, 1H, CH Fmoc), 4.65 (d, J¼3.6 Hz, 2H, CH2 Fmoc), 4.51 (m,
1H, CH Ser), 5.18 (br, 1H, eNH), 5.32 (s, 1H, CH Ph), 5.83 (br, 1H,
All amino acids aldehydes were used as obtained from Sigma-
eAldrich Company, USA. Unless or otherwise mentioned, all amino
acids used were of L-configuration. All the solvents were dried and
purified using recommended procedures in the literature when
necessary. High resolution mass spectra were recorded on
a Micromass Q-TOF micro mass spectrometer using electron spray
ionization mode. IR spectra were recorded on a Schimadzu model
FT-IR spectrometer. 1H NMR and 13C NMR spectra were recorded on
a Bruker AMX 300 MHz and 100 MHz spectrometers, respectively.
19F NMR was recorded on a Bruker AMX 376 MHz (internal stan-
dard CFCl3). Melting points were determined in an open capillary
and are uncorrected. TLC experiments were done using MERCK TLC
aluminum sheets (silica gel 60 F254) and chromatograms were vi-
sualized by exposing in iodine chamber, UV-lamp or spraying with
KMnO4 and heating. Column chromatography was performed on
silica gel (100e200 mesh) using ethyl acetate and hexane mixtures
as eluent.
NH), 7.09e7.48 (m, 13H, HAr); 13C NMR (75 MHz, CDCl3)
d 38.6,
39.1, 46.2, 50.5, 55.3, 57.4, 57.6, 65.8, 112.6, 124.6, 125.9, 127.2, 127.8,
128.0, 128.2, 128.9, 129.0, 135.4, 141.0, 142.6, 154.8, 155.6, 168.2,
170.2; 19F NMR (376 MHz, CDCl3)
d
ꢀ75.44 (s, 3F, COCF3); HRMS
(ESI) calcd for
636.1912.
C
31H30F3N3O7 m/z 636.1934 (MþNa)þ, found
4.3.2. Ethyl 2-(N-(2-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)propy-
lamino)-2-oxoethyl)-2,2,2-trifluoroacetamido)-3-phenylpropanoate
(4b). Pale yellow solid; mp 143e144 ꢁC; Rf 0.48 (n-hexane/EtOAc,
20
2:1); RP-HPLC tR 22.4 (60e100% ACN; 30 min); [
a
]
þ54.6 (c 1.0,
D
CHCl3); IR (KBr) nmax 3030, 2858, 1755, 1741, 1640, 1311 cmꢀ1
;
1H
1.12 (d, J¼5.6 Hz, 3H, CH3 Ala), 1.21 (t,
NMR (300 MHz, CDCl3)
d
J¼9.1 Hz, 3H, OCH2CH3), 2.96e3.08 (m, 2H, CH2 Phe), 3.11e3.23 (m,
2H, CHCH2NH), 3.96 (s, 2H, NHCOCH2N), 4.11 (m, 2H, OCH2CH3),
4.21 (m, 1H, CH Ala), 4.42 (t, J¼3.9 Hz, 1H, CH Fmoc), 4.65 (d,
J¼4.7 Hz, 2H, CH2 Fmoc), 4.72 (m, 1H, CH Phe), 5.65 (br, 1H, NH),
5.94 (br, 1H, NH), 7.11e7.54 (m, 13H, ArH); 13C NMR (75 MHz, CDCl3)
4.2. Typical procedure for synthesis of 2
To a solution of HeAlaeOH (5.0 mmol, 445.5 mg) in 50 mL of
alcohol (MeOH/EtOH/BnOH/t-BuOH) was cooled to ꢀ15 ꢁC. N-
d
13.8, 17.6, 36.2, 45.9, 46.1, 47.3, 49.5, 52.6, 60.4, 67.0, 112.6, 124.8,
FmocePhe-j-[CH2NC] (5.0 mmol, 1.91 g) and benzaldehyde
124.6, 126.0, 126.8, 127.3, 127.8, 128.3, 138.4, 141.1, 143.2, 154.8,
(5.0 mmol, 0.54 mL) were added. The resulting mixture was
stirred at the indicated temperature and time. The mixture was
then concentrated in vacuo and the crude product was
analyzed.
155.0, 169.4, 170.0; 19F NMR (376 MHz, CDCl3)
d
ꢀ74.37 (s, 3F,
COCF3); HRMS (ESI) calcd for C33H34F3N3O6 m/z 648.2297 (MþNa)þ,
found 648.2274.
4.3.3. Methyl 2-(N-(1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-
phenylpropylamino)-4-methyl-1-oxopentan-2-yl)-2,2,2-
trifluoroacetamido)propanoate (4c). White solid; mp 123e124 ꢁC;
Rf 0.61 (n-hexane/EtOAc, 2:1); RP-HPLC tR 19.6, 19.8 (60e100% ACN;
4.3. General procedure for the synthesis of 4
The trifluoroacetic acid (5.0 mmol, 0.683 mL), amino acid ester
(5.1 mmol), and aldehyde (5.1 mmol) were dissolved in MeOH to an
approximate concentration of 1 M each. This solution was then
stirred for 20 min at room temperature, and then Nb-Fmoc-amino
alkyl isonitrile (5.0 mmol) was added in one portion. The resulting
solution was allowed to stir at room temperature for 4 h. When the
reaction was complete by TLC (10% MeOH in CH2Cl2), the solvent
was removed in vacuo, and the residue purified by column
chromatography.
30 min); [
a
]
20 þ34.2 (c 1.0, CHCl3); IR (KBr) nmax 3039, 2860, 1755,
D
1734, 1711, 1639, 1366 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
0.96 [d,
J¼3.9 Hz, 6H, CH(CH3)2], 1.42 (d, J¼7.1 Hz, 3H, CH3 Ala), 1.56 [m, 1H,
CH2CH(CH3)2], 1.87 [m, 2H, CH2CH(CH3)2], 2.32e2.41 (m, 2H, CH2
Phe), 3.11e3.19 (m, 2H, CHCH2), 3.62 (s, 3H, OCH3), 4.23 (t, J¼5.6 Hz,
1H, CH Fmoc), 4.31e4.48 (m, 3H, CH i-Bu, CH Ala, CH Phe), 4.58 (d,
J¼3.8 Hz, 2H, CH2 Fmoc), 5.13 (br, 1H, NH), 5.92 (br, 1H, NH),
7.10e7.52 (m, 13H, ArH); 13C NMR (75 MHz, CDCl3)
d 13.2, 19.6, 20.4,
Note: The spectral characterization data for the compounds
4aek and 5aek corresponding to the major diastereoisomer.
37.6, 39.1, 43.0, 45.6, 46.8, 48.1, 50.1, 52.2, 65.6, 112.3, 125.8, 126.2,
127.1,127.5, 127.9, 128.3,128.5,137.3, 141.6, 143.0,153.2,155.0,169.8,
170.4; 19F NMR (376 MHz, CDCl3)
d
ꢀ76.13 (s, 3F, COCF3); HRMS
4.3.1. Methyl 2-((2-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)ethyl-
amino)-2-oxo-1-phenylethyl)-2,2,2-trifluoroacetamido)-3-
hydroxypropanoate (4a). White solid; mp 138e139 ꢁC; Rf 0.54 (n-
(ESI) calcd for
690.2750.
C
36H40F3N3O6 m/z 690.2767 (MþNa)þ, found

1996
N. Narendra et al. / Tetrahedron 68 (2012) 1992e2000
Table 3
1,10-Iminodicarboxylated peptidomimetics 5 synthesized
Entry
Product 5
Structure
Yielda (%)
drb
Mp (ꢁC)
OH
1
5a
95
88:12
128e130
H
N
FmocHN
FmocHN
FmocHN
N
H
COOMe
COOEt
COOMe
O
2
5b
91
100:0
141e143
H
N
N
H
O
3
5c
88
77:23
158e160
H
N
N
H
O
H
N
4
5
5d
5e
90
88
100:0
109e111
N
H
COOBn
N
Fmoc
O
88:12
135e137
H
N
FmocHN
N
H
COOMe
O
O
ZHN
4
6
7
5f
91
93
96:4
171e173
166e168
H
N
FmocHN
N
H
COOMe
OH
5g
100:0
H
N
FmocHN
FmocHN
FmocHN
N
COOMe
COOBn
H
O
H
N
8
9
5h
5i
95
89
91:9
98e100
N
H
O
COOBn
S
H
N
100:0
113e115
N
H
COOEt
O

N. Narendra et al. / Tetrahedron 68 (2012) 1992e2000
1997
Table 3 (continued )
Entry
Product 5
Structure
Yielda (%)
drb
Mp (ꢁC)
BnOOC
H
10
5j
76
61
95:5
160e162
125e127
N
t
FmocHN
N
H
COOBu
O
H
N
11
5k
96:4
t
FmocHN
N
COOBu
H
O
a
Isolated yield after column purification.
Diastereomeric ratios were determined by RP-HPLC analysis of the purified products.
b
4.3.4. (9H-Fluoren-9-yl)methyl 2-((2-(N-(1-(benzyloxy)-3-methyl-1-
oxobutan-2-yl)-2,2,2-trifluoroacetamido)acetamido)methyl)pyrroli-
dine-1-carboxylate (4d). White solid; mp 181e183 ꢁC; Rf 0.11 (n-
NH), 6.12 (br, 1H, NH), 7.12e7.59 (m, 18H, ArH); 13C NMR (75 MHz,
CDCl3) 13.6, 19.8, 29.4, 31.2, 39.6, 43.2, 45.8, 45.9, 50.6, 51.1, 57.4,
d
64.4, 66.1, 112.1, 119.1, 125.4, 126.8, 127.0, 127.5, 127.8, 128.0, 128.3,
128.8, 129.0, 135.4, 139.2, 141.2, 142.9, 153.2, 153.9, 154.5, 168.4,
hexane/EtOAc, 2:1); RP-HPLC tR 20.1 (60e100% ACN; 30 min);
20
[
a
]
þ79.2 (c 1.0, CHCl3); IR (KBr) nmax 2859, 1751, 1742, 1710,
170.4; 19F NMR (376 MHz, CDCl3)
d
ꢀ75.10 (s, 3F, COCF3); HRMS (ESI)
D
1685, 1631, 1399 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
0.92 [d,
calcd for C43H45F3N3O6 m/z 825.3087 (MþNa)þ, found 825.3050.
J¼4.6 Hz, 6H, (CH3)2 Val], 1.32e1.38 (m, 2H, NCHCH2 Pro),
1.41e1.51 (m, 2H, eNCH2CH2 Pro), 3.12e3.26 [m, 4H, NCH2CH2
(Pro), CHCH2], 3.82 (m, 1H, eNCHCH2, Pro), 3.96 (s, 2H,
NHCOCH2N), 4.16 (d, J¼6.9 Hz, 1H, CH Val), 4.42 (t, J¼8.1 Hz, 1H,
CH Fmoc), 4.59 (d, J¼4.6 Hz, 2H, CH2 Fmoc), 5.14 (s, 2H, OCH2Ph),
5.65 (br, 1H, eNH), 7.12e7.39 (m, 13H, ArH); 13C NMR (75 MHz,
4.3.7. Methyl 2-(N-(2-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-
methylpentylamino)-2-oxoethyl)-2,2,2-trifluoroacetamido)-3-(4-
hydroxyphenyl)propanoate (4g). White solid; mp 183e184 ꢁC; Rf
0.46 (n-hexane/EtOAc, 2:1); RP-HPLC tR 23.9 (60e100% ACN;
20
30 min); [
a]
ꢀ68.5 (c 1.0, CHCl3); IR (KBr) nmax 3069, 2599, 1745,
D
CDCl3)
d
19.9, 22.8, 26.7, 28.6, 40.2, 45.5, 46.2, 50.0, 55.1, 65.1, 66.1,
1739, 1711, 1635, 1388 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 0.94 [d,
66.8, 112.3, 125.9, 126.8, 127.2, 127.5, 128.0, 128.3, 128.9, 139.1,
J¼5.7 Hz, 6H, (CH3)2 Leu], 1.37e1.42 (m, 2H, CH2 Leu), 1.78 (m, 1H,
CH Leu), 3.08e3.18 (m, 2H, CH2 Tyr), 3.29e3.41 (m, 2H, CHCH2NH),
3.67 (s, 3H, OCH3), 3.96 (s, 2H, NHCOCH2N), 4.12 (m, 1H, CH Tyr),
4.42 (t, J¼4.9 Hz, 1H, CH Fmoc), 4.51 (br, 1H, OH Tyr), 4.68 (d,
J¼9.1 Hz, 2H, CH2 Fmoc), 4.76 (m,1H, CH Leu), 5.29 (br,1H, NH), 5.55
(br, 1H, NH), 7.01e7.78 (m, 13H, ArH); 13C NMR (75 MHz, CDCl3)
140.2, 142.2, 154.1, 155.6, 170.0, 170.9; 19F NMR (376 MHz, CDCl3)
d
ꢀ75.38 (s, 3F, COCF3); HRMS (ESI) calcd for C36H38F3N3O6 m/z
688.2610 (MþNa)þ, found 688.2604.
4.3.5. Methyl 2-(N-(2-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-
phenylpropylamino)-2-oxo-1-phenylethyl)-2,2,2-trifluoroacetamido)
propanoate (4e). Pale yellow solid; mp 151e152 ꢁC; Rf 0.58 (n-
hexane/EtOAc, 2:1); RP-HPLC tR¼23.2, 23.4 (60e100% ACN; 30 min);
d
21.6, 22.5, 32.5, 41.5, 43.0, 46.1, 47.1, 49.5, 50.5, 51.3, 65.9, 112.5,
114.8, 127.2, 127.6, 128.0, 128.3, 129.0, 130.5, 141.2, 143.4, 154.5,
154.9, 170.2, 171.5; 19F NMR (376 MHz, CDCl3)
d
ꢀ74.51 (s, 3F,
[
a
]
20 þ82.4 (c 1.0, CHCl3); IR (KBr) nmax 3038, 2855, 1750, 1739, 1716,
COCF3); HRMS (ESI) calcd for C35H38F3N3O7 m/z 692.2560 (MþNa)þ,
D
1645, 1377 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
1.36 (d, J¼5.8 Hz, 3H,
found 692.2542.
CH3 Ala), 2.36e2.48 (m, 2H, CH2 Phe), 3.11e3.23 (m, 2H, CHCH2NH),
3.68 (s, 3H, OCH3), 4.31 (t, J¼7.6 Hz, 1H, CH Fmoc), 4.43 (m, 1H, CH
Ala), 4.55 (m, 1H, CH Phe) 4.67 (d, J¼6.8 Hz, 2H, CH2 Fmoc), 5.31 (m,
1H, CH Ph), 5.65 (br, 1H, NH), 5.91 (br, 1H, NH), 7.10e7.48 (m, 18H,
4.3.8. Benzyl 2-(N-(1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-
methylbutylamino)-3,3-dimethyl-1-oxobutan-2-yl)-2,2,2-
trifluoroacetamido)acetate (4h). White solid; mp 129e130 ꢁC; Rf
0.51 (n-hexane/EtOAc, 2:1); RP-HPLC tR 24.4, 24.7 (60e100% ACN;
ArH); 13C NMR (75 MHz, CDCl3)
d 13.2, 38.6, 43.2, 44.6, 46.1, 50.1,
52.6, 57.2, 66.8, 112.0, 124.8, 125.6, 126.4, 126.8, 127.1, 127.5, 128.0,
128.5,128.9,129.0,135.2, 137.1, 141.0,143.2,154.5,154.8,167.2,170.2;
30 min); [
a
]
20 þ58.2 (c 1.0, CHCl3); IR (KBr) nmax 3089, 2586, 1750,
D
1745, 1710, 1631, 1388 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
0.92 [d,
19F NMR (376 MHz, CDCl3)
d
ꢀ74.91 (s, 3F, COCF3); HRMS (ESI) calcd
J¼4.8 Hz, 6H, (CH3)2 Val], 0.98 [s, 9H, (CH3)3 t-Bu], 2.12 (m, 1H, CH
Val), 3.09e3.19 (m, 2H, CHCH2NH), 3.98 (s, 2H, CH2 Gly), 4.11 (m,1H,
CH Val), 4.44 (t, J¼4.8 Hz, 1H, CH Fmoc), 4.51 (s, 1H, CH t-Bu), 4.62
(d, J¼6.1 Hz, 2H, CH2 Fmoc), 5.11 (s, 2H, OCH2Ph), 5.67 (br, 1H, NH),
5.98 (br, 1H, NH), 7.11e7.74 (m, 13H, ArH); 13C NMR (75 MHz, CDCl3)
for C38H36F3N3O6 m/z 710.2454 (MþNa)þ, found 710.2441.
4.3.6. Methyl 2-(N-(2-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-6-
(benzyloxycarbonyl)hexylamino)-2-oxo-1-phenylethyl)-2,2,2-
trifluoroacetamido)propanoate (4f). White solid; mp 171e172 ꢁC; Rf
d
16.4, 23.9, 29.5, 31.4, 41.8, 44.1, 46.5, 57.0, 67.1, 67.9, 70.8, 112.2,
0.21 (n-hexane/EtOAc, 2:1); RP-HPLC tR 18.5, 18.8 (60e100% ACN;
125.8, 126.2, 127.7, 127.9, 128.0, 128.3, 128.9, 139.5, 141.2, 143.0,
20
30 min); [
a
]
þ51.2 (c 1.0, CHCl3); IR (KBr) nmax 3020, 2877, 1755,
154.2, 155.2, 168.2, 170.4; 19F NMR (376 MHz, CDCl3)
d
ꢀ75.05 (s, 3F,
D
1745, 1715, 1641, 1369 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
1.11e1.15
COCF3); HRMS (ESI) calcd for C37H42F3N3O6 m/z 704.2923 (MþNa)þ,
(m, 2H, NHCHCH2CH2 Lys), 1.21 (d, J¼3.9 Hz, 3H, CH3 Ala), 1.41e1.49
(m, 4H, CH2CH2CH2CH2 Lys), 2.78 (t, J¼9.1 Hz, 2H, CH2 NHZ),
3.09e3.19 (m, 2H, CHCH2NHe), 3.64 (s, 3H, eOCH3), 3.98e4.11 (m,
2H, CH Lys, Ala), 4.38 (t, J¼5.9 Hz, 1H, CH Fmoc), 4.62 (d, J¼2.9 Hz,
2H, CH Fmoc), 5.18 (s, 2H, CH2 Z), 5.22 (m, 1H, CH Ph), 5.81 (br, 1H,
found 704.2904.
4.3.9. Benzyl-3-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2-(2,2,2-
trifluoro-N-(1-methoxy-4-(methylthio)-1-oxobutan-2-yl)acetamido)
acetamido)butanoate (4i). White solid; mp 111e113 ꢁC; Rf 0.47 (n-

1998
N. Narendra et al. / Tetrahedron 68 (2012) 1992e2000
20
hexane/EtOAc, 2:1); RP-HPLC tR 20.4 (60e100% ACN; 30 min); [
a
]
(5a). White solid; mp 128e139 ꢁC; Rf 0.30 (CHCl3/MeOH, 8:2); RP-
D
20
ꢀ24.4 (c 1.0, CHCl3); IR (KBr) nmax 3059, 2599,1755,1743, 1711,1632,
HPLC tR 8.2, 8.8 (60e100% ACN; 30 min); [
a
]
þ3.8 (c 1.0, CHCl3);
D
1390 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
1.12 (t, J¼4.5 Hz, 3H,
IR (KBr) nmax 3054, 2875, 1741, 1738, 1659, 1588, 1390 cmꢀ1; 1H NMR
(300 MHz, CDCl3) 2.98 (br, 1H, OH Ser), 3.26e3.32 (m, 2H,
OCH2CH3), 1.92 (s, 3H, SCH3), 2.04e2.09 (m, 2H, CH2CH2SCH3), 2.17
(t, J¼3.1 Hz, 2H, CH2CH2SCH3), 2.28e2.37 (m, 2H, CH2 Asp),
3.12e3.22 (m, 2H, CHCH2NH), 4.01 (s, 2H, NHCOCH2N), 4.09 (m, 2H,
OCH2CH3), 4.28 (t, J¼6.8 Hz, 1H, CH Fmoc), 4.43 (t, J¼6.4 Hz, 1H, CH
Met), 4.61 (d, J¼8.6 Hz, 2H), 4.72 (m, 1H, CH Asp), 5.16 (s, 2H,
OCH2Ph), 5.67 (br, 1H, NH), 5.91 (br, 1H, NH), 7.08e7.79 (m, 13H,
d
NHCH2CH2), 3.41e3.49 (m, 2H, NHCH2CH2), 3.57 (m, 1H, CH Ser),
3.71 (s, 3H, OCH3), 3.86 (m, 1H, CH2 Ser), 4.00 (m, 1H, CH2 Ser), 4.43
(t, J¼7.2 Hz, 1H, CH Fmoc), 4.65 (d, J¼8.6 Hz, 2H, CH2 Fmoc), 4.88 (m,
1H, CH(Ph)), 5.92 (br, 1H, NH), 6.68 (br, 2H, NH), 7.06e7.76 (m, 13H,
ArH); 13C NMR (75 MHz, CDCl3)
d 42.1, 43.4, 46.6, 52.3, 60.0, 62.4,
HAr); 13C NMR (75 MHz, CDCl3)
d
13.4, 16.1, 26.9, 29.2, 38.0, 41.2,
46.3, 49.9, 50.3, 58.7, 60.0, 66.5, 67.3, 112.0, 121.4, 125.8, 127.5, 127.9,
128.0, 128.5, 128.9, 139.4, 141.2, 143.6, 154.5, 154.9, 170.2, 170.9,
66.9, 72.1, 126.3, 126.9, 128.2, 128.4, 128.7, 129.2, 129.5, 135.5, 141.2,
143.6, 155.8, 169.9, 170.7; HRMS (ESI) calcd for C29H31N3O6 m/z
540.2111 (MþNa)þ, found 540.2118.
171.2; 19F NMR (376 MHz, CDCl3)
d
ꢀ74.79 (s, 3F, COCF3); HRMS
(ESI) calcd for C37H40F3N3O8S m/z 766.2386 (MþNa)þ, found
4.4.2. (S)-Ethyl 2-(2-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)pro-
pylamino)-2-oxoethylamino)-3-phenylpropanoate (5b). White solid;
mp 141e143 ꢁC; Rf200.18 (CHCl3/MeOH, 8:2); RP-HPLC tR 7.5 (60e100%
766.2355.
4.3.10. Benzyl 4-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-(2-(N-(1-
tert-butoxy-1-oxopropan-2-yl)-2,2,2-trifluoroacetamido)-3,3-
dimethylbutanamido)pentanoate (4j). White solid; mp 92e93 ꢁC; Rf
ACN; 30 min); [
a
]
ꢀ18.6 (c 1.0, CHCl3); IR (KBr) nmax 3050, 2864,
D
1740, 1735, 1631, 1511, 1384 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 1.28
(m, 6H, CH3 Ala, OCH2CH3), 2.92 (m, 1H, CH2 Phe), 3.12 (m, 1H, CH2
Phe), 3.29 (m, 1H, CHCH2NH), 3.38e3.44 (m, 4H, CHCH2NH,
COCH2NH), 3.69 (m,1H, CH Phe), 4.03 (m, 2H, OCH2CH3), 4.21 (m,1H,
CH Ala), 4.44 (t, J¼7.4 Hz, 1H, CH Fmoc), 4.68 (d, J¼8.6 Hz, 2H, CH2
Fmoc), 5.81 (br, 1H, NH), 6.73 (br, 2H, NH), 7.06e7.78 (m, 13H, ArH);
0.61 (n-hexane/EtOAc, 2:1); RP-HPLC tR 20.0, 20.4 (60e100% ACN;
20
30 min); [
a]
ꢀ8.4 (c 1.0, CHCl3); IR (KBr) nmax 3065, 2859, 1752,
D
1738, 1710, 1640, 1375 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 0.92 [s,
9H, (CH3)3 t-Bu], 1.34 [s, 9H, O(CH3)3], 1.39 (d, J¼11.2 Hz, 3H, CH3
Ala), 1.73e1.79 (m, 2H, CH2CH2COO), 2.09 (t, J¼11.6 Hz, 2H,
CH2CH2COO), 3.12e3.19 (m, 2H, CHCH2NH), 3.96 (m, 1H, CH Ala),
4.42 (t, J¼5.6 Hz, 1H, CH Fmoc), 4.47 (m, 1H, CH t-Bu), 4.52 (m, 1H,
CH Glu), 4.68 (d, J¼3.9 Hz, 2H, CH2 Fmoc), 5.21 (s, 2H, OCH2Ph), 5.68
(br, 1H, NH), 6.15 (br, 1H, NH), 7.16e7.79 (m, 13H, ArH); 13C NMR
13C NMR (75 MHz, CDCl3)
d 13.3, 17.8, 35.2, 45.3, 46.1, 46.9, 48.7, 57.3,
59.2, 66.4, 125.8, 126.3, 126.9, 127.3, 127.6, 127.9, 128.4, 139.8, 140.9,
143.2, 155.1, 170.2, 170.9; HRMS calcd for C31H35N3O5 m/z 552.2474
(MþNa)þ, found 552.2481.
(75 MHz, CDCl3)
49.7, 66.9, 67.0, 68.5, 81.4, 112.8, 125.6, 126.4, 126.8, 127.8, 127.9,
128.2, 128.5, 139.8, 141.7, 143.2, 153.6, 154.0, 169.9, 170.2, 171.5; 19
d
13.8, 23.4, 26.5, 27.0, 27.9, 33.4, 44.5, 46.1, 46.9,
4.4.3. (S)-Methyl 2-(1-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)-
3-phenylpropylamino)-4-methyl-1-oxopentan-2-ylamino)prop-
anoate (5c). White solid; mp 158e160 ꢁC; Rf 0.18 (CHCl3/MeOH,
F
20
NMR (376 MHz, CDCl3)
C
d
ꢀ75.29 (s, 3F, COCF3); HRMS (ESI) calcd for
8:2); RP-HPLC tR 9.8, 10.4 (60e100% ACN; 30 min); [
a
]
D
þ113.2 (c
42H50F3N3O8 m/z 804.3448 (MþNa)þ, found 804.34421.
1.0, CHCl3); IR (KBr) nmax 3040, 2898, 1758, 1721, 1641, 1575,
1388 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
0.98 [d, J¼5.6 Hz, 6H,
4.3.11. tert-Butyl 2-(N-(1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-
3-methylpentylamino)-4-methyl-1-oxopentan-2-yl)-2,2,2-
trifluoroacetamido)propanoate (4k). White solid; mp 120e123 ꢁC;
Rf 0.63 (n-hexane/EtOAc, 2:1); RP-HPLC tR 20.0, 20.4 (60e100%
CH(CH3)2], 1.24 (d, J¼6.8 Hz, 3H, CH3 Ala), 1.57 [m, 2H,
CH2CH(CH3)2], 1.78 [m, 1H, CH2CH(CH3)2], 2.92 (m, 1H, CH2 Phe),
3.03 (m, 1H, CH2 Phe), 3.21 (m, 1H, CHCH2), 3.37 (m, 1H, CHCH2),
3.58e3.68 (m, 2H, CH i-Bu, CH Ala), 3.71 (s, 3H, OCH3), 4.41 (t,
J¼7.7 Hz, 1H, CH Fmoc), 4.52 (m, 1H, CH Phe), 4.67 (d, J¼8.1 Hz, 2H,
CH2 Fmoc), 5.78 (br, 2H, NH), 6.41 (br, 1H, NH), 7.08e7.81 (m, 13H,
ACN; 30 min); [
a
]
20 þ120.8 (c 1.0, CHCl3); IR (KBr) nmax 3089, 2577,
D
1750, 1742, 1725, 1630, 1390 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
0.83
(t, J¼4.8 Hz, 3H, CH3CHCH2CH3 Ile), 0.94 [d, J¼5.6 Hz, 6H, (CH3)2 i-
Pr], 1.01 (d, J¼11.2 Hz, 3H, CH3CHCH2CH3 Ile), 1.11e1.19 (m, 2H, CH2
Ile), 1.32 [s, 9H, O(CH3)3], 1.41 (d, J¼5.4 Hz, 3H, CH3 Ala), 1.51e1.62
(m, 3H, CH2 i-Bu, CH i-Pr), 2.11 (m, 1H, CHCH3 Ile), 3.12e3.19 (m ,2H,
CHCH2NH), 4.04 (m, 1H, CH Ile), 4.43 [m, 1H, CH(i-Bu)], 4.58e4.61
(m, 2H, CH Fmoc, CH Ala), 4.64 (d, J¼5.5 Hz, 2H, CH2, Fmoc), 5.55 (br,
1H, NH), 6.13 (br, 1H, NH), 7.21e7.85 (m, 8H, ArH); 13C NMR
ArH); 13C NMR (75 MHz, CDCl3)
d 16.8, 19.2, 20.1, 38.6, 39.6, 42.3,
46.2, 52.1, 52.8, 53.9, 55.7, 66.3, 125.3, 126.4, 127.8, 128.1, 128.5,
128.9, 136.2, 140.2, 143.1, 156.3, 170.2, 170.8; HRMS (ESI) calcd for
C
34H41N3O5 m/z 594.2944 (MþNa)þ, found 594.2946.
4.4.4. (S)-(9H-Fluoren-9-yl)methyl 2-((2-((S)-1-(benzyloxy)-3-
methyl-1-oxobutan-2-ylamino)acetamido)methyl)pyrrolidine-1-
carboxylate (5d). Pale yellow solid; mp 109e111 ꢁC; Rf 0.21 (CHCl3/
(75 MHz, CDCl3)
d 10.8, 14.0, 14.9, 21.4, 21.8, 24.6, 27.8, 37.6, 38.1,
41.1, 46.7, 47.0, 48.5, 55.0, 64.8, 81.4, 113.4, 126.7, 127.9, 128.4, 128.8,
MeOH, 8:2); RP-HPLC tR 6.9 (60e100% ACN; 30 min); [
a
]
20 ꢀ89.4 (c
D
139.8, 141.1, 143.2, 153.6, 154.0, 170.4, 171.1; 19F NMR (376 MHz,
1.0, CHCl3); IR (KBr) nmax 3048, 2879, 1740, 1731, 1660, 1551,
1386 cmꢀ1; 1H NMR (300 MHz, CDCl3) 0.98 [d, J¼5.2 Hz, 6H, (CH3)2
Val], 1.28e1.60 (m, 4H, NCH2CH2CH2 Pro), 2.56 (m, 1H, CH(CH3)2
Val), 3.28e3.49 (m, 7H, NCH2 Pro, NCHCH2 Pro, COCH2NH, CH Val),
3.80 (m, 1H, NCH Pro), 4.41 (t, J¼7.1 Hz, 1H, CH Fmoc), 4.68 (d,
J¼8.8 Hz, 2H, CH2 Fmoc), 5.12 (s, 2H, OCH2Ph), 6.32 (br, 1H, NH),
6.79 (br, 1H, NH), 7.16 (s, 5H, ArH), 7.31e7.83 (m, 8H, ArH); 13C NMR
CDCl3)
d
ꢀ75.69 (s, 3F, COCF3); HRMS (ESI) calcd for C36H48F3N3O6
m/z 698.3319 (MþNa)þ, found 698.3311.
4.4. General procedure for the synthesis of 5
Trifluoroacetamide Ugi product 4 (5.0 mmol) was dissolved in
MeOH (8.0 mL), p-TsOH$H2O (5.5 mmol,1.045 g) was added and the
resulting solution was refluxed at 50 ꢁC for 30 min. The reaction
mixture was then cooled to room temperature, TEA (5.5 mmol,
0.56 mL) was added, and stirring was continued for another 5 min
to neutralize the tosylate salt. The solvent was removed in vacuo
and the residue was purified by column chromatography.
(75 MHz, CDCl3)
d 16.4, 21.0, 26.2, 29.8, 42.1, 46.3, 47.2, 49.8, 55.2,
59.8, 64.2, 66.9, 126.4, 126.9, 127.2, 127.5, 128.0, 128.2, 128.6, 141.0,
141.6, 143.2,155.8,169.9, 170.3; HRMS (ESI) calcd for C34H39N3O5 m/
z 592.2787 (MþNa)þ, found 592.2796.
4.4.5. (S)-Methyl 2-(2-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)-
3-phenylpropylamino)-2-oxo-1-phenylethylamino)propanoate
(5e). Pale yellow solid; mp 135e137 ꢁC; Rf 0.41 (CHCl3/MeOH, 8:2);
4.4.1. (2S)-Methyl 2-(2-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)eth-
ylamino)-2-oxo-1-phenylethylamino)-3-hydroxypropanoate
20
RP-HPLC: tR 11.2, 11.5 (60e100% ACN; 30 min); [
a]
þ69.8 (c 1.0,
D

N. Narendra et al. / Tetrahedron 68 (2012) 1992e2000
1999
CHCl3); IR (KBr) nmax 3048, 2881, 1742, 1736, 1660, 1581, 1380 cmꢀ1
1H NMR (300 MHz, CDCl3)
;
1.0, CHCl3); IR (KBr) nmax 3048, 2865, 1745, 1740, 1732, 1654, 1555,
1380 cmꢀ1 1H NMR (300 MHz, CDCl3)
d
1.19 (d, J¼8.6 Hz, 3H, CH3 Ala), 2.92 (m,
;
d
1.27 (t, J¼6.6 Hz, 3H,
1H, CH2 Phe), 3.03 (m, 1H, CH2 Phe), 3.26 (m, 2H, CHCH2NH),
3.34e3.42 (m, 2H, CHCH2NH, CH Ala), 3.68 (s, 3H, OCH3), 4.41 (t,
J¼7.9 Hz, 1H, CH Fmoc), 4.58 (m, 1H, CH Phe), 4.67 (d, J¼6.8 Hz, 2H,
CH2 Fmoc), 4.71 (s, 1H, CH Ph), 5.98 (br, 2H, NH), 6.63 (br, 1H, NH),
OCH2CH3), 2.01 (s, 3H, SCH3), 2.12 (m, 2H, CH2CH2SCH3), 2.38 (m,
3H, CH2CH2SCH3, CH2 Asp), 2.51 (m,1H, CH2 Asp), 3.32e3.51 (m, 5H,
CHCH2NH, COCH2NH, CH Met), 4.09 (m, 2H, OCH2CH3), 4.44 (t,
J¼7.0 Hz, 1H, CH Fmoc), 4.67 (d, J¼8.2 Hz, 2H, CH2 Fmoc), 4.74 (m,
1H, CH Asp), 5.10 (s, 2H, OCH2Ph), 5.71 (br, 1H, NH), 5.96 (br, 1H,
7.04e7.80 (m, 18H, ArH); 13C NMR (75 MHz, CDCl3)
d 16.4, 39.6,
42.4, 44.8, 52.1, 52.9, 53.7, 6.09, 66.7, 126.0, 126.4, 127.4, 127.6, 127.8,
128.2, 128.3, 128.4, 128.6, 128.8, 138.2, 139.6, 140.8, 143.1, 155.6,
169.8, 170.2; HRMS (ESI) calcd for C36H37N3O5 m/z 614.2631
(MþNa)þ, found 614.2638.
NH), 6.43 (br, 1H, NH), 7.16 (s, 5H, ArH), 7.25e7.78 (m, 8H, ArH); 13
C
NMR (75 MHz, CDCl3)
d 13.8, 16.9, 29.8, 31.0, 38.4, 44.2, 46.3, 50.2,
51.1, 57.9, 59.8, 66.9, 67.5, 126.5, 126.9, 127.4, 127.9, 128.2, 128.6,
128.9, 141.0, 141.3, 143.5, 155.8, 169.8, 170.1, 172.3; HRMS calcd for
C
35H41N3O7S m/z 670.2563 (MþNa)þ, found 670.2571.
4.4.6. (2S)-Methyl 2-(2-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)-6-
(benzyloxycarbonyl) hexylamino)-2-oxo-1-phenylethylamino)prop-
4.4.10. (S)-Benzyl 4-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-(2-((S)-
anoate (5f). White solid; mp 171e173 ꢁC; Rf 0.17 (CHCl3/MeOH,
1-tert-butoxy-1-oxopropan-2-ylamino)-3,3-dimethylbutanamido)
20
8:2); RP-HPLC tR 5.6, 5.9 (60e100% ACN; 30 min); [
a
]
ꢀ109.7 (c
pentanoate (5j). White solid; mp 160e162 ꢁC; Rf 0.55 (CHCl3/
D
20
1.0, CHCl3); IR (KBr) nmax 3051, 2870, 1739, 1735, 1655, 1589,
MeOH, 8:2); RP-HPLC tR 9.1, 9.7 (60e100% ACN; 30 min); [a]
D
1390 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
1.26 (d, J¼5.5 Hz, 3H, CH3
ꢀ24.4 (c 1.0, CHCl3); IR (KBr) nmax 3051, 2855, 1751, 1745, 1738, 1655,
1540, 1369 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
1.01 [s, 9H, (CH3)3 t-
Ala) 1.28e1.45 [m, 6H, NHCH2(CH2)3 Lys], 2.44 [m, 2H,
NHCH2(CH2)3 Lys], 3.26 (m, 1H, NHCHCH2NH), 3.59 (m, 2H,
NHCHCH2NH, CH Ala), 3.69 (s, 3H, OCH3), 4.44 (m, 2H, CH Fmoc, CH
Lys) 4.65 (d, J¼7.0 Hz, 2H, CH2 Fmoc), 4.78 (m, 1H, CH Ph), 5.08 (s,
2H, CH2 Z), 5.74 (br, 2H, NH), 6.64 (br, 1H, NH), 7.08e7.79 (m, 18H,
d
Bu],1.23 (d, J¼6.8 Hz, 3H, CH3 Ala),1.38 [s, 9H, O(CH3)3],1.78 (m, 2H,
CH2CH2COO), 2.13 (t, J¼6.1 Hz, 2H, CH2CH2COO), 3.23 (m, 1H,
CHCH2NH), 3.29 (m, 1H, CHCH2NH), 3.61 (s, 1H, CH t-Bu), 3.74 (m,
1H, CH Ala), 4.36 (m, 1H, CH Glu), 4.42 (t, J¼6.4 Hz, 1H, CH Fmoc),
4.65 (d, J¼8.0 Hz, 2H, CH2 Fmoc), 5.14 (s, 2H, OCH2Ph), 5.92 (br, 1H,
NH), 6.73 (br, 2H, NH), 7.13 (s, 5H, ArH), 7.23e7.35 (m, 4H, ArH), 7.51
(d, J¼7.1 Hz, 2H, HAr), 7.75 (d, J¼7.2 Hz, 2H, ArH); 13C NMR (CDCl3,
ArH); 13C NMR (75 MHz, CDCl3)
d 16.9, 20.2, 27.7, 29.1, 40.3, 46.5,
47.2, 47.8, 52.3, 54.3, 59.6, 61.2, 66.8, 119.7, 124.9, 125.3, 126.8, 127.5,
127.7,127.9,128.3,128.9,129.4,139.2,140.2,141.1,143.6,155.7,156.4,
170.1, 171.3; HRMS (ESI) calcd for C41H46N4O7 m/z 729.3264
(MþNa)þ, found 729.3270.
75 MHz)
d 16.8, 23.8, 25.3, 26.7, 28.9, 36.2, 43.8, 45.7, 49.3, 55.1,
65.6, 67.4, 73.6, 81.2, 126.2, 126.9, 127.2, 127.7, 128.1, 128.4, 128.8,
140.8, 141.2, 143.0, 155.4, 169.2, 170.3, 170.5; HRMS (ESI) calcd for
4.4.7. (S)-Methyl 2-(2-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)-
C
40H51N3O7 m/z 708.3625 (MþNa)þ, found 708.3629.
4-methylpentylamino)-2-oxoethylamino)-3-(4-hydroxyphenyl)prop-
anoate (5g). White solid; mp 166e168 ꢁC; Rf 0.11 (CHCl3/MeOH,
4.4.11. (S)-tert-Butyl 2-(1-((2S,3S)-2-(((9H-fluoren-9-yl)methoxy)car-
bonyl)-3-methylpentylamino)-4-methyl-1-oxopentan-2-ylamino)
propanoate(5k). White solid; mp 125e127 ꢁC; Rf 0.47 (CHCl3/MeOH,
20
8:2); RP-HPLC: tR 5.2 (60e100% ACN; 30 min); [
a]
ꢀ29.4 (c 1.0,
D
CHCl3); IR (KBr) nmax 3038, 2868, 1742, 1736, 1655, 1538, 1394 cmꢀ1
1H NMR (300 MHz, CDCl3)
0.98 [d, J¼4.2 Hz, 6H, (CH3)2 Leu], 1.37
;
d
8:2); RP-HPLC tR 8.6, 8.9 (60e100% ACN; 30 min); [
a
]
20 ꢀ22.0 (c 1.0,
D
(m, 2H, CH2 Leu),1.76 (m,1H, CH Leu), 2.97 (m,1H, CH2 Tyr), 3.13 (m,
1H, CH2 Tyr), 3.28 (m, 1H, CHCH2NH), 3.41 (s, 2H, COCH2NH), 3.47
(m, 1H, CHCH2NH), 3.71 (s, 3H, OCH3), 3.79 (m, 1H, CH Tyr), 3.99 (m,
1H, CH Leu), 4.43 (t, J¼7.0 Hz, 1H, CH Fmoc), 4.68 (d, J¼78.1 Hz, 2H,
CH2 Fmoc), 4.98 (br, 1H, OH Tyr), 5.97 (br, 2H, NH), 6.61 (br, 1H, NH),
6.76 (d, J¼7.2 Hz, 2H, ArH), 6.93 (d, J¼7.1 Hz, 2H, ArH), 7.31e7.79 (m,
CHCl3); IR (KBr) nmax 3048, 2849, 1742, 1740, 1738, 1661, 1538,
; d 0.89e1.01 [m, 12H,
1355 cmꢀ1 1H NMR (CDCl3, 300 MHz)
CH3CHCH2CH3 Ile, (CH3)2 i-Pr], 1.31 (m, 5H, CH3 Ala, CH2 Ile), 1.37 [s,
9H, O(CH3)3],1.49 (m, 2H, CH2 i-Bu),1.71 (m,1H, CH i-Pr), 2.13 (m,1H,
CHCH3 Ile), 3.27 (m, 1H, CHCH2NH), 3.32 (m, 1H, CHCH2NH), 3.58 [m,
1H, CH(i-Bu)], 3.74 (m, 1H, CH Ala), 4.33 (m, 1H, CH Ile), 4.43 (t,
J¼6.6 Hz, 1H, CH Fmoc), 4.63 (d, J¼8.2 Hz, 2H, CH2 Fmoc), 5.67 (br,
1H, NH), 6.69 (br, 2H, NH), 7.21e7.32 (m, 4H, ArH), 7.50 (d, J¼7.0 Hz,
2H, ArH), 7.78 (d, J¼7.0 Hz, 2H, ArH); 13C NMR (CDCl3, 75 MHz)
8H, ArH); 13C NMR (75 MHz, CDCl3)
d 21.7, 22.6, 35.3, 40.7, 42.1, 46.2,
47.4, 49.6, 52.1, 58.3, 65.4, 115.6, 126.6, 128.0, 128.2, 128.7, 129.0,
131.2, 141.1, 143.2, 155.9, 156.3, 170.3, 173.8; HRMS calcd for
C
33H39N3O6 m/z 596.2737 (MþNa)þ, found 596.2748.
d 12.3, 14.6, 16.7, 21.4, 23.2, 26.4, 29.1, 37.3, 40.9, 42.1, 48.6, 56.2, 56.4,
58.1, 66.3, 81.8, 125.4, 126.3, 126.7, 127.2, 141.2, 143.4, 155.7, 169.3,
170.2; HRMS (ESI) calcd for C34H49N3O5 m/z 602.3570 (MþNa)þ,
found 602.3573.
4.4.8. Benzyl 2-(1-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-
methylbutylamino)-3,3-dimethyl-1-oxobutan-2-ylamino)acetate
(5h). White solid; mp 98e100 ꢁC; Rf 0.46 (CHCl3/MeOH, 8:2); RP-
20
HPLC tR 12.4, 12.9 (60e100% ACN; 30 min); [
a
]
D
þ74.5 (c 1.0,
Acknowledgements
CHCl3); IR (KBr) nmax 3048, 2868, 1745, 1740, 1664, 1579, 1389 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
0.98 [d, J¼4.8 Hz, 6H, (CH3)2 Val], 1.08
We thank the Department of Science and Technology, Govt. of
India (Grant No. SR/S1/OC-26/2008) for financial assistance.
[s, 9H, (CH3)3 t-Bu], 2.38 (m, 1H, CH Val), 3.22 (m, 1H, CHCH2NH),
3.37e3.50 (m, 4H, CHCH2NH, CH t-Bu, CH2 Gly), 4.18 (m,1H, CH Val),
4.41 (t, J¼7.0 Hz, 1H, CH Fmoc), 4.68 (d, J¼7.5 Hz, 2H, CH2 Fmoc),
5.12 (s, 2H, OCH2Ph), 5.49 (br, 1H, NH), 6.18 (br, 2H, NH), 7.15 (s, 5H,
HAr), 7.26e7.35 (m, 4H, ArH), 7.54 (d, J¼6.9 Hz, 2H, ArH), 7.76 (d,
References and notes
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d 16.3, 23.8, 29.6, 35.2,
42.3, 46.8, 47.1, 57.8, 66.1, 67.3, 74.8, 126.2, 126.8, 127.3, 127.6, 128.0,
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1-methoxy-4-(methylthio)-1-oxobutan-2-ylamino)acetamido)buta-
noate (5i). Pale yellow solid; mp 113e115 ꢁC; Rf 0.58 (CHCl3/MeOH,
20
8:2); RP-HPLC tR 13.1, 13.8 (60e100% ACN; 30 min); [
a]
þ28.9 (c
D

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