HBTU mediated 1-hydroxybenzotriazole (HOBt) conjugate addition: Synthesis and stereochemical analysis of β-benzotriazole N-oxide substituted γ-amino acids and hybrid peptides

Article abstract of DOI:10.1039/c4ob01548g

HBTU is a standard coupling agent commonly used for the activation of free carboxylic acids during the solution and solid phase peptide synthesis. 1-Hydroxybenzotriazole (HOBt) plays a significant role in reducing the racemization during peptide synthesis

Full text of DOI:10.1039/c4ob01548g

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HBTU mediated 1-hydroxybenzotriazole (HOBt)
conjugate addition: synthesis and stereochemical
analysis of β-benzotriazole N-oxide substituted
γ-amino acids and hybrid peptides†
Cite this: DOI: 10.1039/c4ob01548g
Sachitanand M. Mali, Mothukuri Ganesh Kumar, Mona M. Katariya and
Hosahudya N. Gopi*
HBTU is a standard coupling agent commonly used for the activation of free carboxylic acids during the
solution and solid phase peptide synthesis. 1-Hydroxybenzotriazole (HOBt) plays a significant role in redu-
cing the racemization during peptide synthesis; hence it is regularly used as a coupling additive. Here, we
are reporting the mild and facile conjugate addition of HOBt to E-vinylogous γ-amino acids mediated by
the HBTU. The reaction is moderately diastereoselective and novel β-benzotriazole N-oxide (β-BtO) sub-
stituted γ-amino acids were isolated in moderate to good yields. The single crystal analysis of methyl
esters of major (anti) and minor (syn) conjugate addition products infers the formation of exclusively
N-alkylated benzotriazole N-oxides instead of O-alkylation of HOBt. In addition, we showed the utilization
of β-BtO substituted γ-amino acids in peptide synthesis and studied their conformations in single crystals.
Received 22nd July 2014,
Accepted 28th August 2014
DOI: 10.1039/c4ob01548g
www.rsc.org/obc
Recently we have reported the synthesis, reactivity, con-
formational analysis and antimicrobial activities of hybrid pep-
Introduction
Nucleophilic conjugate addition is one of the most widely tides containing naturally occurring E-α,β-unsaturated γ-amino
explored reactions in synthetic organic chemistry. The conju- acids.9 All peptide coupling reactions of these E-vinylogous
gate addition offers direct access to a variety of organic com- amino acids have been performed using standard HBTU/HOBt
pounds by the C–X (X = C, N, O, S etc.) bond formation.1 The coupling conditions. The coupling reagent HBTU consists of
regiochemistry of 1,2 or 1,4-nucleophilic addition to α,β-un- both carbodiimide and HOBt components and commonly
saturated carbonyl compounds is generally controlled by the used as a carboxylic acid activating reagent in both solution
relative electrophilicity of the carbonyl group, steric inter- and solid phase peptide syntheses with or without an
actions of both electrophiles and nucleophiles as well as the additional equivalent of HOBt.10 In an accidental encounter in
hard and soft nature of the nucleophiles. Besides the organo- the absence of a free amine coupling partner, we observed a
copper reagents,2 various other transition metal catalyzed HOBt conjugate addition product of the E-α,β-unsaturated
selective conjugate addition reactions have been well docu- γ-amino acid. As unsaturated carboxylic acids have been
mented.3 In comparison with the α,β-unsaturated aldehydes, proven difficult to undergo conjugate addition reactions under
ketones, esters and amides, the unsaturated carboxylic acids mild conditions, the unexpected 1,4 addition products motiva-
have not been well explored in the conjugate addition reac- ted us to investigate the HOBt conjugate addition in detail.
tions. However, the literature survey reveals that strong alkyl- Herein, we are reporting the 1,4 conjugate addition of HOBt to
ating agents such as organolithium4 and organomagnesium various E-α,β-unsaturated γ-amino acids, stereochemical ana-
reagents,5 copper reagents,6 rhodium(I) catalyzed arylboronic lysis of the conjugate addition products, their utility in the syn-
acids,7 and gold(III) catalysts8 have been reported for the selec- thesis of peptides and the crystal conformations of β-BtO
tive 1,4 additions to α,β-unsaturated acids.
substituted γ-amino esters and peptides.
Department of Chemistry, Indian Institute of Science Education and Research,
Dr. Homi Bhabha Road, Pune-411 008, India. E-mail: hn.gopi@iiserpune.ac.in
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
Results and discussion
Ethyl esters of E-vinylogous amino acids (1) were synthesized
starting from α-amino aldehydes using the Wittig reaction as
reported earlier (Scheme 1).9a Saponification of the ethyl esters
of 1a–f, 6a–d, 7a–d, dipeptides, 8 (i, ii)–12(i, ii) and 13, and ORTEP diagrams for
7a, 6a, 6c, 10i and 13. CCDC 1012298–1012302. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4ob01548g
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Scheme 1 Synthesis of α,β-unsaturated γ-amino acids, R = a, –CH2–Ph; b, –CH–(CH3)2; c, –CH2–CH(CH3)2; d, –CH2–C6H4–OBut; e, –CH(CH3)–
CH2–CH3; f, α,β-unsaturated γ-proline.
leads to the free E-vinylogous amino acids (2). The schematic using other coupling additives, pentafluorophenol and
representation of the HOBt conjugate addition in the absence N-hydroxysuccinimide, in the presence of HBTU. Mass spectral
and presence of the free amine coupling partner is shown in analysis of the products reveals no conjugate addition from
Scheme 2. In the absence of the free amine coupling partner, both pentafluorophenol as well as N-hydroxysuccinimide
we isolated the diastereomeric mixture of HOBt conjugate rather we isolated the corresponding active esters.
addition products (4 + 5) in moderate to good yields from the
In order to understand the stereochemistry and the
α,β-unsaturated γ-amino acids, 2a–f (Scheme 2). No conjugate diastereoselectivity, we subjected all major (7) and minor (6)
addition products were observed in the presence of the free diastereoisomers for crystallization. Out of all major and
amine coupling partner. In addition, no HOBt conjugate minor diastereoisomers, we were able to obtain the single crys-
addition products were observed with HBTU alone suggesting tals for minor (6a) and major (7a) diastereoisomers of β-BtO
the requirement of an additional HOBt for the conjugate substituted γ-phenylalanine and the minor isomer of β-BtO-
addition. Though the β-BtO substituted γ-amino acids, (4 + 5) substituted γ-leucine (6c). The crystal structures of these dia-
a–f, were isolated after the simple aqueous work-up, we found stereoisomers are shown in Fig. 1.
it difficult to separate the diastereomeric carboxylic acids 4
The crystal structure analysis reveals that as anticipated anti
and 5 by column chromatography. In order to understand the (7) is the major product and syn addition product (6) is the
diastereomeric ratio, we subjected all HOBt substituted dia- minor. Intriguingly, crystal structures also provide unexpected
stereomeric mixtures, (4 + 5) a–f, to the esterification reaction information regarding the involvement of triazole nitrogen (N)
using methyl iodide and potassium carbonate in DMF to give as a nucleophile in the conjugate addition over the N-hydroxyl
methyl esters 6 and 7 as shown in Scheme 3.
(N-OH) group of HOBt. All three structures displayed N-alkyl-
Out of all methyl esters of diastereoisomers in Scheme 3, ated benzotriazole N-oxides. The participation of the triazole N
we were able to separate the diastereoisomers of the com- in the conjugate addition instead of the free N-OH group of
pounds 6a–d and 7a–d by silica gel column chromatography. the HOBt is not surprising as enormous attention has been
We were unable to separate the diastereoisomers 6e and 7e as paid over the decades regarding the ambidentate reactivity of
well as 6f and 7f. The yield and the diastereomeric ratio of the HOBt. A survey of the literature reveals both N-acylation and
products are given in Table 1. We observed moderate diastereo- O-acylation properties of HOBt and their solvent dependent
selectivity in the conjugate addition and based on the earlier equilibrium properties.12 Furthermore, the crystal structures of
reports on the Michael addition to the E-vinylogous amino HBTU, TBTU and HAPyU also suggest the formation of N-oxide
esters,9c,11 we anticipated that the anti addition product (7) derivatives over their uronium salts. Most of these studies con-
may be the major product compared to the syn addition vincingly suggest that the N-acylation is an intermolecularly
product (6). To understand whether the conjugate addition of driven process. We observed no HOBt conjugate addition
HOBt to E-vinylogous amino acids is specific to the coupling product from the coupling reaction involving HBTU alone,
additive HOBt, we performed two individual control reactions supporting the intermolecular conjugate addition. Based on
Scheme 2 Amide coupling and conjugate addition of HOBt with E-vinylogous γ-amino acids.
Scheme 3 Esterification of the HOBt conjugate addition product of γ-amino acids, R = a, –CH2–Ph; b, –CH–(CH3)2; c, –CH2–CH(CH3)2; d, –CH2–
C6H4–OBut; e, –CH(CH3)–CH2–CH3; f, α,β-unsaturated γ-proline.
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this experimental evidence the possible reaction mechanism
of the HOBt conjugate addition is outlined in Scheme 4.
We anticipate that the active ester(I) and/or amide (Ia),
obtained after the treatment of HBTU in the presence of a
base, will react further with the HOBt leading to the formation
of the diastereomeric mixture II which will immediately react
further with HOBt to give the active ester III. The hydrolysis of
the active ester III during the aqueous work-up gave the dia-
stereomeric conjugate addition products 4 and 5. Furthermore,
we speculate that the soft nucleophilic nature of triazole nitro-
gen (N) may be preferred for the conjugate addition over the
hard nucleophilic nature of the oxygen in N-OH. This was
further supported by the 1,2 addition of pentafluorophenol
and N-hydroxysuccinimide. Similarly, intramolecular N-alkyl-
ation of unsaturated acids with various carbodiimides leading
to the multisubstituted hydantoins have been recently
reported.13
Table 1 List of β-BtO substituted γ-amino acid methyl esters and their
diastereomeric ratios
AA
a
6 + 7
% Yield (6 + 7)
% Syn (6)
% Anti (7)
75
39
61
b
c
80
83
37
41
63
59
d
70
40
60
Based on the encouraging results from the methyl esters of
HOBt conjugate addition products, we subjected the β-BtO
substituted diastereomeric mixture of 4 and 5 directly to the
Fig. 1 X-ray structures of 7a, 6a and 6c.
Scheme 4 Schematic representation of the conjugate addition of HOBt.
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peptide synthesis, anticipating that it may be possible to separ- and tripeptide 13 and their X-ray structures are shown in
ate the diastereomeric dipeptides once they coupled to the Fig. 2. Instructively, similar to methyl esters, the peptide
α-amino acid esters. In this regard, the conjugate addition pro- crystal structures also revealed N-substituted conjugate
ducts of 2c (4c + 5c) were directly coupled with methyl ester of addition products in the peptides.
Ala in the presence of DCC. The two diastereomeric dipeptides
Crystal structure analysis of the methyl esters of major (7a,
8i and 8ii were isolated in 70% yield and were separated by anti) and minor (6a, syn) products from N-Boc-α,β-unsaturated
column chromatography in the ratios of 41 and 59% respect- γ-phenylalanine reveals that both molecules adopted the un-
ively (Table 2). The dipeptides 9i and 9ii were synthesized favorable staggered conformation along the Cβ–Cγ bond. Mole-
from the coupling reaction between methyl ester of Leu and cule 7a adopted t and g− conformations, while 6a displayed g+
the diastereomeric mixture of 4e and 5e, respectively. Similarly, and t conformations along Cβ–Cγ and Cβ–Cα bonds, respect-
dipeptides 10(i and ii), 11(i and ii) and 12(i and ii) were syn- ively. Similarly, syn addition products 6b and γVal(BtO) in the
thesized from the diastereomeric mixtures of BtO conjugate dipeptide (10i) showed g+ and t conformations. In contrast,
addition products of 2b, 2f and 2a, respectively, by direct coup- anti γLeu(BtO) in the tripeptide 13 follows the general trend of
ling with leucine methyl ester. The overall yield and the dia- tetra alkyl substituted ethane by adopting the gauche confor-
stereomeric ratios of dipeptides are given in Table 2.
mations14 along the Cβ–Cγ bond and displayed the anti(t) con-
We further subjected dipeptide 8ii for the synthesis of the formation along the backbone Cβ–Cα bond. Recently, Alezra
tripeptide Boc-Phe-γLeu(β-BtO)-Ala-OMe (13). The Boc group of et al. reported the conformational diversity of foldamers com-
the dipeptide was deprotected using TFA and the isolated free posed of β-substituted γ-amino acids.15 The Michael addition
amine was coupled to the Boc-Phe using HBTU/HOBt to give of HOBt to the E-vinylogous amino acids reported here may
the tripeptide in good yield. Out of all the HOBt substituted serve as the direct route for the synthesis of β-substituted
peptides, we were able to get single crystals of dipeptide 10i γ-amino acids.
Table 2 List of the peptides synthesized using β-BtO substituted γ-amino acids
Entry
8
Peptides (P)
% Yield
70
% i
% ii
41
59
9
62
38
62
10
11
12
67
58
56
37
41
39
63
59
61
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Fig. 2 The X-ray structures of Boc-γVal(β-BtO)-Leu-OMe (10i) and Boc-Phe-γLeu(β-BtO)-Ala-OMe (13).
General procedure for the synthesis of α,β-unsaturated
γ-amino esters.9a The N-protected amino aldehyde (10 mmol)
Conclusions
In conclusion, we have demonstrated the HBTU mediated was dissolved in dry THF (40 mL) under a N2 atmosphere. To
HOBt conjugate addition to the α,β-unsaturated γ-amino acids. this solution Wittig ylide (11.5 mmol) was added. The progress
Using this mild and facile methodology, various β-BtO substi- of reaction was monitored by TLC. After completion of the
tuted γ-amino acids were synthesized and utilized in the reaction (monitored by TLC), THF was evaporated and
peptide synthesis. Experimental evidence suggests that HOBt the product was purified by column chromatography using the
conjugate addition is an intermolecular reaction with moder- 5 : 95 ethyl acetate–pet ether solvent system.
ate diastereoselectivity. The stereochemistry of the novel β-BtO
Saponification of N-protected α,β-unsaturated γ-amino
substituted γ-amino acids was analyzed using single crystal esters.9a The N-protected vinylogous amino ester (10 mmol)
X-ray structures from both the monomers as well as peptides. was dissolved in 15 mL of ethanol. To this solution, 1 N NaOH
Results also suggest the preference for the N-alkylation over (10 mL) was added drop wise. The reaction mixture was
the anticipated O-alkylation in the conjugate addition. As con- allowed to stir for about 3 h. The progress of reaction was
jugate addition to the unsaturated carboxylic acids has scarcely monitored by TLC. After completion of reaction (3 h), the
been studied due to their inherent limitations, the results solvent ethanol was evaporated and the aqueous layer was
reported here may provide an opportunity to extend this meth- acidified (pH ∼ 2) with 5% aq. HCl. This aqueous solution was
odology to other α,β-unsaturated acids. The β-substituted then extracted with ethyl acetate (30 mL × 3). The organic layer
γ-amino acids reported here can be directly utilized for the was washed with brine, dried over anhydrous Na2SO4 and con-
construction of peptide foldamers.
centrated under reduced pressure to give the N-protected vinyl-
ogous amino acid in average 95% yield.
General procedure for the synthesis of β-BtO substituted
γ-amino acids. The N-protected E-vinylogous amino acid
(1.6 mmol) was dissolved in 2 mL of dry DMF under a N2
atmosphere. To this solution HBTU (1.6 mmol) and HOBt
(3.2 mmol) were added. The reaction mixture was cooled at
0 °C prior to the addition of DIEA (3.2 mmol). This reaction
mixture was allowed to stir for another 12 h. After 12 h, the
reaction mixture was diluted with ethyl acetate and acidified to
pH ∼ 2 using 5% HCl. The aqueous layer was further extracted
with ethyl acetate (3 × 20 mL). The combined organic layer was
then washed with brine, dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give β-BtO substituted
γ-amino acids in moderate to good yields (70–85%) and
directly used for esterification as well as peptide synthesis
without purification.
Experimental section
General information
All amino acids, Weinreb amine hydrochloride salt, DCC, LAH,
DIEA, PPh3, ethyl bromoacetate, di- tert-butyldicarbonate,
HOBt, HBTU, THF, DCM, DMF and toluene were used as com-
mercially available. THF was dried over sodium and distilled
prior to use. Column chromatography was performed on silica
gel (100–200 mesh). 1H NMR spectra were recorded on a
400 MHz instrument (100 MHz for 13C NMR) using residual
solvent as the internal standard (CDCl3 δH, 7.24 ppm, δc
77.0 ppm and DMSO-d6 δH, 2.5 ppm δc 40.0 ppm). The chemi-
cal shifts (δ) were reported in ppm and the coupling constant
(J) in Hz. High resolution mass spectra were obtained using
General procedure for the synthesis of methyl ester of β-BtO
substituted N-protected γ-amino acids. Beta-BtO substituted
an ESI-TOF MS spectrometer and
spectrometer.
a
MALDI-TOF/TOF
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γ-amino acid (1.6 mmol) was dissolved in dry DMF (2 mL). To reduced pressure to give the crude tripeptide. The pure tripep-
this solution, K2CO3 (1.6 mmol) was added followed by methyl tide Boc-Phe-γLeu(β-BtO)-Ala-OMe was isolated as a white solid
iodide (3.2 mmol). This reaction mixture was further stirred in 67% yield after column purification in the 80 : 20 (Ethyl
for 8 h. After completion of reaction (monitored by TLC), the acetate–Pet ether) solvent system.
(S,E)-Ethyl
4-((tert-butoxycarbonyl)amino)-5-phenylpent-2-
reaction mixture was diluted with water (70 mL) and extracted
with ethyl acetate (25 mL × 3). The combined organic layer was
washed with saturated solution of Na2S2O3, brine and dried
over anhydrous Na2SO4 and evaporated under reduced
pressure. The two diastereoisomers 6 and 7 were separated by
column chromatography using the 70 : 30 (EtOAc–pet ether)
solvent system.
General procedure for the synthesis of β-BtO substituted
N-protected γ-amino acids containing dipeptides. The hydro-
chloride salt of amino acid methyl ester (HCl·NH2-Xaa-OMe)
(3 mmol) was dissolved in water and pH was adjusted to 12 by
adding solid Na2CO3 under ice cold conditions. The aqueous
solution was then extracted with ethyl acetate (30 mL × 3). The
combined organic layer was then washed with brine and dried
over anhydrous Na2SO4, concentrated to ∼2 mL under reduced
pressure and used in the next step.
The beta-BtO substituted N-protected γ-amino acid
(2 mmol) was dissolved in dry DMF under a N2 atmosphere.
To this solution, methyl ester of the amino acid (∼2 mL, from
the above step) was added. The reaction mixture was cooled to
0 °C and then DCC (2 mmol) was added. The reaction mixture
was allowed to stir for another 12 h and progress of the reac-
tion was monitored by TLC. After completion of reaction, the
reaction mixture was diluted with ethyl acetate (50 mL) and
DCU generated in the reaction was filtered. The filtrate was
then washed with 5% HCl (20 mL), 10% Na2CO3 (20 mL), and
brine and dried over Na2SO4. The organic layer was concen-
trated under reduced pressure to obtain a diastereomeric
mixture (i and ii) of dipeptides. These dipeptides were separ-
ated by column chromatography using the 2 : 98 (MeOH–DCM)
solvent system.
Procedure for the synthesis of tripeptide Boc-Phe-γLeu
(β-BtO)-Ala-OMe (13). NH2-γLeu(β-BtO)-Ala-OMe: Boc-γLeu
(β-BtO)-Ala-OMe (200 mg, 0.4 mmol) was dissolved in 2 mL
DCM and cooled at 0 °C. To this solution TFA (4 mL) was
added. After the completion of reaction (1 h) (monitored by
TLC), TFA was evaporated under reduced pressure. The residue
was dissolved in water and pH of the solution was adjusted to
∼12 by adding solid Na2CO3 under ice cold conditions. This
aqueous solution was then extracted with ethyl acetate (25 mL
× 3), washed with brine, and dried over Na2SO4. The organic
layer was concentrated under reduced pressure to ∼2 mL and
used in the next step.
enoate (1a). White powder (4.01 g, 84%), mp 70 °C, UV (λmax
)
206 nm, 255 nm, [α]2D5 −2.0 (c 1.0, MeOH). H NMR (400 MHz,
CDCl3) δ = 7.30–7.14 (m, 5 H), 6.89 (dd, J = 5.04 Hz, J = 11 Hz,
1 H), 5.83 (d, J = 17.4, 1 H), 4.59 (br, 1 H), 4.52 (m, 1 H), 4.15
(q, J = 6.8 Hz, 2 H), 2.92–2.85 (m, 2 H), 1.37 (s, 9 H), 1.25 (t, J =
7.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 166.2, 155.0,
147.6, 136.4, 129.4, 128.6, 126.9, 121.1, 79.9, 60.5, 52.3, 40.9,
28.3, 14.3 ppm. MALDI TOF/TOF m/z value calcd for
C18H25NO4 [M + Na+] 342.1681; found 342.1657.
1
(S,E)-Ethyl 4-(tert-butoxycarbonylamino)-5-methylhex-2-enoate
(1b). White solid (yield 2.43 g, 90%). mp 59 °C, UV (λmax
)
216 nm, [α]2D5 −3.40 (c 1.0, MeOH). H NMR (400 MHz, CDCl3)
δ = 6.83 (dd, J = 15.8 Hz, J = 5.2 Hz, 1 H) 5.90 (d, J = 15.6 Hz,
1 H), 4.55 (d, J = 6.8 Hz, 1 H), 4.17 (q, J = 6.88 Hz, 2 H),
1.86–1.84 (m, 1 H), 1.42 (s, 9 H), 1.27 (t, J = 7.32 Hz, 3 H), 0.90
(q, J = 6.4 Hz, 6 H) ppm, 13C NMR (100 MHz, CDCl3) δ = 166.3,
155.4, 147.4, 121.5, 79.7, 60.5, 56.7, 32.3, 28.4, 18.9, 17.0,
14.3 ppm. MALDI TOF/TOF m/z calcd for C14H25NO4 [M + Na+]
294.1681; found 294.1686.
1
(S,E)-Ethyl 4-(tert-butoxycarbonylamino)-6-methylhept-2-enoate
(1c). White solid (2.70 g, 95%), mp 55 °C, UV (λmax) 218 nm,
[α]2D5 −25.50 (c 1.0, MeOH). 1H NMR (500 MHz, CDCl3) δ = 6.83
(dd, J = 16 Hz, J = 5.5 Hz, 1 H), 5.91 (d, 1 H, J = 16 Hz), 4.45 (br,
1 H), 4.33 (br, 1 H), 4.19 (q, 2 H, J = 7 Hz), 1.72–1.67 (m, 1 H),
1.44 (s, 9 H), 1.38 (t, 2 H, J = 7 Hz), 1.28 (t, J = 7 Hz, 3 H), 0.94
(d, J = 6.5 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 166.5,
155.1, 148.0, 120.4, 79.7, 60.5, 49.8, 43.9, 28.4, 24.7, 22.7, 22.2,
14.3 ppm. MALDI TOF/TOF m/z calcd for C15H27NO4 [M + Na+]
308.1838; found 308.1840.
(4S,5R,E)-Ethyl 4-(tert-butoxycarbonylamino)-5-methylhept-2-
enoate (1d). White solid (yield 2.62 g, 92%), mp 62 °C, UV
(λmax) 216 nm, [α]2D5 −11.20 (c 1.0, MeOH). H NMR (400 MHz,
1
CDCl3) δ = 6.87 (d, 1 H, J = 15.6 Hz), 5.92 (d, 1 H, J = 15.6 Hz),
4.58 (dd, 1 H, J = 17.9 Hz, J = 9.2 Hz), 4.32 (br, 1 H), 4.2 (q, J =
7.3 Hz, 2 H), 1.66 (m, 2 H), 1.45 (s, 9 H), 1.29 (t, J = 7.1 Hz,
3 H), 1.14 (m, 1 H), 0.91–0.86 (m, 6 H) ppm. 13C NMR
(100 MHz, CDCl3) δ = 166.3, 155.3, 147.1, 121.6, 79.6, 60.4,
55.7, 39.0, 28.4, 25.3, 15.3, 14.2, 11.6 ppm. MALDI TOF/TOF
m/z calcd for C15H27NO4 [M + Na+] 308.1838; found 308.1837.
(S,E)-Ethyl
5-(4-(tert-butoxy)phenyl)-4-((tert-butoxycarbonyl)-
amino)pent-2-enoate (1e). Yellowish oil (3.2 g, 82%), UV (λmax
)
222 nm, 265 nm, 274 nm, 285 nm, [α]2D5 4.0 (c 0.1, MeOH). H
NMR (400 MHz, CDCl3) δ = 7.06 (d, J = 8 Hz, 2 H), 6.90 (m,
3 H), 5.84 (d, J = 16 Hz, 1 H), 4.55 (m, 2 H), 4.17 (q, J = 8 Hz,
2 H), 2.83 (m, 2 H), 1.40 (s, 9 H), 1.33 (s, 9 H), 1.27 (t, J = 8 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 192.3, 166.3, 155.1,
154.3, 131.3, 129.9, 124.3, 121.1, 78.5, 60.5, 28.9, 28.4,
14.3 ppm. HRMS m/z calcd for C22H33NO5 [M + Na+] 414.2251;
found 414.2259.
1
The Boc-Phe-OH (110 mg, 0.4 mmol) and NH2-γLeu(β-BtO)-
Ala-OMe (from the above step) were dissolved in dry DMF. The
reaction mixture was cooled at 0 °C and treated with HBTU
(158 mg, 0.4 mmol) and HOBt (56 mg, 0.4 mmol), followed by
DIEA (0.144 mL, 0.8 mmol). The reaction mixture was allowed
to stir overnight (12 h). After completion of reaction (12 h), the
reaction mixture was diluted with ethyl acetate (75 mL),
washed with 5% HCl, 10% Na2CO3 and brine, and dried over
(S,E)-tert-Butyl-2-(3-ethoxy-3-oxoprop-1-enyl)pyrrolidine-1-carb-
anhydrous Na2SO4. The organic layer was concentrated under oxylate (1f). Colorless oil (2.23 g, 83%), UV (λmax) 214 nm,
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1
[α]2D5 −72.0 (c 1.0, MeOH). H NMR (400 MHz, CDCl3) δ = 6.80 (7b)anti. White powder (0.315 g, 48%), mp 173–175 °C,
(d, J = 15.6 Hz, 1 H), 5.81 (d, J = 15.2 Hz, 1 H), 4.45 (br, 1 H), [α]2D5 −7.2 (c 0.1, MeOH), UV (λmax) 323 nm, IR (neat) ν (cm−1
)
4.19 (q, J = 6.4 Hz), 3.44 (t, J = 6 Hz, 2 H), 2.1 & 1.85 (m, 4 H), 3272, 2966, 2928, 1738, 1690, 1606, 1506, 1423, 1394, 1308,
1.42 (s, 9 H) 1.29 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, 1250, 1167, 1033. 1H NMR (400 MHz, CDCl3) δ = 7.99 (d, J =
CDCl3) δ = 166.4, 154.3, 148.5, 120.4, 79.6, 60.3, 57.8, 46.2, 8.8 Hz, 1 H), 7.64–7.63 (m, 2 H), 7.43–7.38 (m, 1 H), 5.09–5.03
31.7, 28.3, 22.9, 14.2 ppm. MALDI TOF/TOF m/z calcd for (m, 1 H), 4.53(d, J = 12 Hz, 1 H), 4.27–4.21 (m, 1 H), 3.58 (s,
C14H23NO4 [M + Na+] 292.1525; found 292.1520.
3 H), 3.22–3.07 (m, 3 H), 1.45 (s, 9 H), 0.86 (dd, J = 6.8 Hz, 6 H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 171.4, 155.8, 139.3,
134.3, 130.7, 124.6, 115.8, 110.8, 57.8, 57.2, 52.2, 36.1, 31.9,
29.7, 28.3, 22.7, 20.1, 15.8, 14.1 ppm. HRMS (ESI) m/z calcd for
C19H28N4O5 [M + H+] is 393.2138; found 393.2143.
1-((3R,4S)-4-(tert-Butoxycarbonylamino)-1-methoxy-1-oxo-5-phenyl-
pentan-3-yl)-1H-benzo[d][1,2,3]triazole 3-oxide (Boc-γPhe(β-BtO)-
OMe) (6a)syn. White solid (0.204 g, 30%), the diastereomeric
ratio of 6a : 7a is 39 : 61, mp 220–222 °C, [α]2D5 −7.4 (c 0.1,
MeOH), UV (λmax) 323 nm, 274 nm, IR (neat) ν (cm−1) 3362,
2973, 2928, 1736, 1604, 1504, 1458, 1425, 1306, 1208, 1134,
1-((3R,4S)-4-(tert-Butoxycarbonylamino)-1-methoxy-6-methyl-1-
oxoheptan-3-yl)-1H-benzo[d][1,2,3]triazole 3-oxide (Boc-γLeu
748. 1H NMR (400 MHz, CDCl3) δ = 7.99 (d, J = 8 Hz, 1 H), 7.55 (β-BtO)-OMe) (6c)syn. White solid (0.220 g, 33%), the diastereo-
(t, J = 8 Hz, 1 H), 7.42 (t, J = 6 Hz, 1 H), 7.24–7.21 (m, 4 H), 6.91 meric ratio of 6c : 7c is 41 : 59, mp 130–132 °C, [α]2D5 −7.0
(dd, J = 4 Hz, 2 H), 5.54 (d, J = 8 Hz, 1 H), 5.16–5.12 (m, 1 H), (c 0.1, MeOH), UV (λmax) 323 nm, IR (neat) ν (cm−1) 3360, 3267,
4.57–4.49 (m, 1 H), 3.51 (s, 3 H), 3.21 (dd, J = 4 Hz & 12 Hz, 1 2957, 1735, 1704, 1605, 1510, 1460, 1398, 1366, 1317, 1248,
H), 2.98 (dd, 4 Hz & 12 Hz, 1 H), 2.76 (t, J = 8 Hz, 1 H), 2.41 1167, 1035, 749. 1H NMR (400 MHz, CDCl3) δ = 7.97 (d, J =
(dd, J = 4 Hz & 8 Hz, 1 H), 1.42 (s, 9 H) ppm. 13C NMR 8 Hz, 1 H), 7.69–7.62 (m, 2 H), 7.41 (t, J = 6 Hz, 1 H), 5.20–5.15
(100 MHz, CDCl3) δ = 170.7, 155.7, 136.3, 130.5, 129.5, 128.7, (m, 2 H), 4.25–4.19 (m, 1 H), 3.55 (s, 3 H), 3.23 (dd J = 8 Hz,
127.0, 124.9, 115.3, 111.7, 56.8, 54.7, 52.2, 38.5, 36.9, 29.7, 1 H), 3.02 (dd, J = 4 Hz & 12 Hz, 1 H), 1.62–1.56 (m, 1 H), 1.43
28.3 ppm. HRMS (ESI) m/z calcd for C23H28N4O5 [M + H+] is (s, 9H), 1.02 (t, J = 6 Hz, 2H), 0.81 (dd, J = 4 Hz, 6 H) ppm.
441.2138; found 441.2134.
13C NMR (100 MHz, CDCl3) δ = 170.9, 155.8, 135.3, 130.9,
129.5, 124.7, 115.5, 111.0, 79.9, 59.1, 52.1, 51.5, 40.940, 36.1,
29.7, 28.3, 24.7, 23.1, 21.7 ppm. HRMS (ESI) m/z calcd for
C20H30N4O5 [M + H+] is 407.2294; found 407.2300.
1-((3S,4S)-4-(tert-Butoxycarbonylamino)-1-methoxy-6-methyl-1-oxo-
heptan-3-yl)-1H-benzo[d][1,2,3]triazole 3-oxide (Boc-γLeu(β-BtO)-
1-((3S,4S)-4-(tert-Butoxycarbonylamino)-1-methoxy-1-oxo-5-
phenylpentan-3-yl)-1H-benzo[d][1,2,3]triazole 3-oxide (Boc-γPhe-
(β-BtO)-OMe) (7a)anti. White solid (0.320 g, 45%), mp
190–192 °C, [α]D25 −0.2 (c 0.1, MeOH), UV (λmax) 323 nm,
274 nm, IR (neat) ν (cm−1) 3360, 2971, 2921, 1736, 1604, 1507,
1458, 1425, 1367, 1311, 1209, 1167, 1024, 747. 1H NMR OMe) (7c)anti. White solid (0.317 g, 50%), mp 95–97 °C,
(400 MHz, CDCl3) δ = 7.99 (d, J = 12 Hz, 1 H), 7.74–7.70 (m, [α]2D5 −1.6 (c 0.1, MeOH), UV (λmax) 323 nm, IR (neat) ν (cm−1
)
1 H), 7.62–7.61 (m, 2 H), 7.54 (dd, J = 4 Hz, 1 H), 7.43–7.39 (m, 3360, 3270, 2956, 2927, 2863, 2315, 1737, 1702, 1607, 1506,
1
1 H), 7.29 (d, J = 8 Hz, 1 H), 7.23 (d, J = 6 Hz, 2 H), 7.11 (d, J = 1460, 1424, 1394, 1367, 1262, 1167, 1115, 1038, 749. H NMR
8 Hz, 2 H), 5.57 (br., 1 H), 5.02–4.92 (m, 1 H), 4.22 (t, J = 6 Hz, (400 MHz, CDCl3) δ = 7.89 (d, J = 4 Hz, 1 H), 7.61–7.54 (m,
1 H), 3.57 (s, 3 H), 3.33 (dd, J = 8 Hz, 1 H), 3.03 (dd, J = 16 Hz & 2 H), 7.34 (t, J = 6 Hz, 1 H), 5.40 (br, 1 H), 4.72 (br, 1 H),
J = 4 Hz, 1 H), 2.89–2.77 (m, 2 H), 1.35 (s, 9 H) ppm. 13C NMR 4.03–4.00 (m, 1 H), 3.50 (s, 3 H), 3.29 (dd, J = 4 H & 8 Hz, 1 H),
(100 MHz, CDCl3) δ = 170.6, 155.4, 136.7, 135.6, 130.5, 128.9, 2.87 (dd, J = 4 Hz, 12 Hz, 1 H), 1.60–1.58 (m, 1 H), 1.39 (s, 9 H),
128.6, 126.8, 124.7, 115.3, 111.1, 80.1, 57.9, 55.3, 52.2, 35.7, 0.83 (t, J = 4 Hz, 8 H) ppm. 13C NMR (100 MHz, CDCl3) δ =
29.7, 28.3 ppm. HRMS (ESI) m/z calcd for C23H28N4O5 [M + H+] 170.5, 155.4, 135.7, 130.4, 129.8, 124.5, 115.3, 111.1, 58.3, 52.1,
is 441.2138; found 441.2138.
1-((3R,4S)-4-((tert-Butoxycarbonyl)amino)-1-methoxy-5-methyl-1-
38.0, 35.1, 29.7, 28.3, 24.7, 23.6, 21.1 ppm. HRMS (ESI) m/z
calcd for C20H30N4O5 [M + H+] is 407.2294; found 407.2303.
oxohexan-3-yl)-1H-benzo[d][1,2,3]triazole
3-oxide
(Boc-γVal
1-((3R,
4S)-5-(4-(tert-butoxy)phenyl)-4-((tert-butoxycarbonyl)-
(β-BtO)-OMe) (6b)syn. White powder (0.185 g, 32%), the diaster-
amino)-1-methoxy-1-oxopentan-3-yl)-1H-benzo[d][1,2,3]triazole
eomeric ratio of 6b : 7b is 37 : 63; mp 164–166 °C, [α]D25 −1.0 3-oxide (Boc-Tyr(β-BtO)-OMe)(6d)syn. Yellowish oil (0.152 g,
(c 0.1, MeOH), UV (λmax) 323 nm, IR (neat) ν (cm−1) 2968, 1736, 28%), the diastereomeric ratio of 6d : 7d is 40 : 60. [α]D25 −7.0
1707, 1605, 1503, 1460, 1423, 1390, 1366, 1303, 1241, 1199, (c 0.1, MeOH), UV (λmax) 219 nm, 273 nm, 280 nm, 323 nm,
1
1
1165, 1109, 1022, 749. H NMR (400 MHz, CDCl3) δ = 7.98 (d, IR (neat) ν (cm−1) 3424, 2923, 1609, 1400, 1108, 740, 619. H
J = 8 Hz, 1 H), 7.70–7.63 (m, J = 8 Hz, 2 H), 7.42 (t, J = 8 Hz, NMR (400 MHz, CDCl3) δ = 7.95 (d, J = 8 Hz, 1 H), 7.61–7.56
1 H), 5.5 (d, J = 12 Hz, 1 H), 5.40–5.3 (m, 1 H), 3.90–3.8 (m, (m, 2 H), 7.39–7.36 (m, 1 H), 6.99–6.87 (m, 4 H), 5.54–5.49 (m,
1 H), 3.54 (s, 3 H), 3.18 (dd J = 10 Hz & J = 3.6 Hz, 1 H), 2.96 (dd, 1 H), 4.62–4.57 (m, 1 H), 4.24–4.18 (m, 1 H), 3.54 (s, 3 H),
J = 4 Hz & 12 Hz, 1 H) 1.47 (s, 9 H), 0.89 (dd, J = 4 Hz, 6 H) ppm. 3.36–2.95 (m, 2 H), 2.82–2.71 (m, 2 H), 1.33 (s, 9 H), 1.30 (s, 9
13C NMR (100 MHz, CDCl3) δ = 173.0, 168.9, 156.6, 135.0, 130.9, H) ppm. 13C NMR δ = 170.6, 155.4, 154.3, 1135.7, 131.4, 130.6,
129.3, 124.8, 115.3, 111.6, 59.1, 57.4, 52.4, 50.8, 40.9, 40.3, 30.7, 130.0, 129.4, 124.7, 124.5, 115.5, 111.2, 80.3, 78.6, 57.7, 55.3,
28.4, 24.6, 22.7, 21.2, 20.1, 19.4 ppm. HRMS (ESI) m/z calcd for 52.3, 35.5, 35.0, 29.8, 28.9, 28.3 ppm. HRMS m/z calcd for
C19H28N4O5 [M + H+] is 393.2138; found 393.2147.
1-((3S,4S)-4-(tert-Butoxycarbonylamino)-1-methoxy-5-methyl-1-oxo-
C27H36N4O6 [M + H+] 513.2713; found 513.2717.
1-((3S, 4S)-5-(4-(tert-butoxy)phenyl)-4-((tert-butoxycarbonyl)-
hexan-3-yl)-1H-benzo[d][1,2,3]triazole 3-oxide(Boc-γVal(β-BtO)-OMe) amino)-1-methoxy-1-oxopentan-3-yl)-1H-benzo[d][1,2,3]triazole
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3-oxide (Boc-Tyr(β-BtO)-OMe) (7d)anti. Yellowish oil (0.240 g, (m, 2 H), 1.45 (s, 9 H), 1.17–1.11 (m, 2 H), 0.89 (d, J = 4 Hz,
42%), [α]2D5 +0.2 (c 0.1, MeOH), UV (λmax) 219 nm, 273 nm, 6 H), 0.76 (dd, J = 8 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3)
280 nm, 323 nm, IR (neat) ν (cm−1) 3395, 2923, 1723, 1683, δ = 172.4, 168.7, 156.3, 135.1, 130.8, 129.5, 124.6, 115.4, 111.3,
1609, 1512, 1418, 1370, 1304, 1162, 1108, 895, 740, 618. 1H 57.3, 52.2, 50.9, 41.2, 39.6, 36.6, 29.7, 28.4, 26.3, 24.8, 22.7,
NMR (400 MHz, CDCl3) δ = 7.98 (d, J = 8 Hz, 1 H), 7.55–7.39 21.8, 14.9, 10.6 ppm. MALDI TOF/TOF m/z calcd for
(m, 2 H), 7.24–7.19 (m, 1 H), 6.89–6.77 (m, 4 H), 5.52 (d, J = C26H41N5O6 [M + Na+] is 542.2955; found 542.2957.
1-((4S,8S,9S)-9-sec-Butyl-4-isobutyl-13,13-dimethyl-3,6,11-trioxo-
2,12-dioxa-5,10-diazatetradecan-8-yl)-1H-benzo[d][1,2,3]triazole
3-oxide (Boc-γIle(β-BtO)-Leu-OMe) (9ii). White solid (0.397 g,
8 Hz, 1 H), 5.12 (m, 1 H), 4.51 (m, 1 H), 3.51 (s, 3 H), 3.10 (m,
2 H), 2.54 (m, 2 H), 1.42 (s, 9 H), 1.33 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3) δ 170.7, 155.7, 154.3, 135.4, 131.1, 130.5,
129.4, 124.8, 124.5, 115.3, 111.8, 80.1, 78.6, 56.7, 54.6, 52.1,
37.9, 36.9, 29.7, 28.8, 28.3 ppm. HRMS m/z calcd for
C27H36N4O6 [M + H+] 513.2713; found 513.2730.
37%), mp 193–195 °C, [α]2D5 +32.0 (c 0.1, MeOH), UV (λmax
)
323 nm, IR (neat) ν (cm−1) 2964, 2875, 2314, 2259, 2124, 1740,
1707, 1664, 1545, 1460, 1425, 1369, 1207, 1168, 1022, 992, 825,
1
754, H NMR (400 MHz, DMSO-d6) δ = 8.49 (d, J = 8 Hz, 1 H),
1-((4S,8R,9S)-9-Isobutyl-4,13,13-trimethyl-3,6,11-trioxo-2,12-dioxa-
5,10-diazatetradecan-8-yl)-1H-benzo[d][1,2,3]triazole 3-oxide (Boc-
7.84 (d, J = 8 Hz, 1 H), 7.67 (d, J = 4 Hz, 2 H), 7.42–7.38 (m, 1
γLeu(β-BtO)-Ala-OMe) (8i). White solid (0.273 g, 28%), The dia- H), 7.03 (d, J = 8 Hz, 1 H), 5.28–5.22 (m, 1 H), 4.05–4.0 (m, 1
stereomeric ratio of 8i : 8ii is 41 : 59, mp 135–137 °C, H), 3.86–3.80 (m, 1 H), 3.22 (s, 3 H), 3.05 (dd, J = 4 Hz & 12 Hz,
[α]D25 −62.0 (c 0.1, MeOH), UV (λmax) 323 nm, IR (neat) ν (cm−1
)
1 H), 2.69 (dd, J = 4 Hz & 12 Hz, 1 H), 1.33 (s, 9 H), 0.84 (d, J =
3281, 2960, 2378, 2312, 2112, 1741, 1668, 1525, 1458, 1423, 8 Hz, 3 H), 0.73 (dd, J = 4 Hz & 12 Hz, 6 H), 0.56 (t, J = 8 Hz
1367, 1208, 1164, 1114, 1052, 996, 748. 1H NMR (500 MHz, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6) δ = 172.8, 169.5,
CDCl3) δ = 7.91 (d, J = 4 Hz, 1 H), 7.68 (d, J = 8 Hz, 1 H), 7.59 (t, 156.1, 134.5, 130.6, 129.7, 124.5, 115.2, 112.0, 78.4, 57.5, 51.9,
J = 6 Hz, 1 H), 7.38 (t, J = 8 Hz, 1 H), 6.85 (d, J = 8 Hz, 1 H), 50.8, 35.7, 35.2, 28.6, 24.5, 23.1, 21.5, 16.5, 11.4 ppm. MALDI
5.26 (d, J = 8 Hz, 1 H), 5.24–5.21 (m, 1 H), 4.35–4.30 (m, 1 H), TOF/TOF m/z calcd for C26H41N5O6 [M + Na+] is 542.2955;
4.29–4.25 (m, 1 H), 3.66 (s, 3 H), 3.03–2.93 (m, 2 H), 1.61–1.54 found 542.2950.
1-((4S,8R,9S)-4-Isobutyl-9-isopropyl-13,13-dimethyl-3,6,11-trioxo-
2,12-dioxa-5,10-diazatetradecan-8-yl)-1H-benzo[d][1,2,3]triazole
3-oxide (Boc-γVal(β-BtO)-Leu-OMe) (10i). White solid (0.249 g,
26%), The diastereomeric ratio of 10i : 10ii is 37 : 63, mp
200–202 °C, [α]2D5 +18.0 (c 0.1, MeOH), UV (λmax) 323 nm, IR
(neat) ν (cm−1) 2964, 2312, 2117, 1740, 1542, 1425, 1368, 1311,
1210, 1092, 748. 1H NMR (400 MHz, CDCl3) δ = 7.95 (d, J =
8 Hz, 1 H), 7.70 (d, J = 8 Hz, 1 H), 7.62 (t, J = 8 Hz, 1 H), 7.40 (t,
(m, 1 H), 1.41 (s, 9 H), 1.07 (d, J = 4 Hz, 3 H), 0.79 (t, J = 4 Hz,
6 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 173.1, 168.7, 155.1,
135.3, 130.8, 129.4, 124.8, 115.2, 111.4, 60.0, 52.5, 51.6, 48.1,
41.2, 38.5, 28.3, 24.8, 23.1, 21.7, 17.5 ppm. MALDI TOF/TOF
m/z calcd for C23H35N5O5 [M + Na+] is 500.2485; found
500.2491.
1-((4S,8S,9S)-9-Isobutyl-4,13,13-trimethyl-3,6,11-trioxo-2,12-dioxa-
5,10-diazatetradecan-8-yl)-1H-benzo[d][1,2,3]triazole 3-oxide (Boc-
γLeu(β-BtO)-Ala-OMe) (8ii). White solid (0.393 g, 42%), mp J = 8 Hz, 1 H), 6.54 (d, J = 8 Hz, 1 H), 5.55 (d, J = 12 Hz, 1 H),
98–100 °C, [α]2D5 −66.0 (c 0.1, MeOH), UV (λmax) 323 nm, 5.46–5.42 (m, 1 H), 4.39–4.33 (m, 1 H), 3.99–3.93 (m, 1 H), 3.70
IR (neat) ν (cm−1) 3276, 2958, 2873, 2313, 1740, 1710, 1661, (s, 3 H), 2.89 (d, J = 8 Hz, 2 H), 1.48 (s, 9 H), 1.28–1.24 (m,
1532, 1458, 1423, 1368, 1208, 1166, 1114, 953, 749. 1H NMR 2 H), 0.90 (t, J = 8 Hz, 6 H), 0.69 (d, J = 8 Hz, 3 H) 0.53 (d, J =
(400 MHz, DMSO-d6) δ = 8.52 (d, J = 8 Hz, 1 H), 7.85 (d, J = 4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 173.0, 168.9,
8 Hz, 1 H), 7.67 (t, J = 8 Hz, 1 H), 7.60 (d, J = 8 Hz, 1 H), 7.41 (t, 156.6, 135.0, 130.9, 129.3, 124.8, 115.3, 111.6, 59.1, 57.4, 52.4,
J = 8 Hz, 1 H), 6.94 (d, J = 8 Hz, 1 H), 5.17–5.13 (m, 1 H), 50.8, 40.9, 40.3, 30.7, 28.4, 24.6, 22.7, 21.2, 20.1, 19.4 ppm.
3.95–3.88 (m, 1 H), 3.23 (s, 3 H), 3.03 (dd, J = 4 Hz & 12 Hz, MALDI TOF/TOF m/z calcd for C25H39N5O6 [M + Na+] is
1 H), 2.75 (dd J = 4 Hz & 12 Hz, 1 H), 1.36 (s, 9 H), 1.12(d, J = 528.2798; found 528.2780.
8 Hz, 3 H), 0.77 (t, J = 8 Hz, 6 H) ppm. 13C NMR (100 MHz,
1-((4S,8S,9S)-4-Isobutyl-9-isopropyl-13,13-dimethyl-3,6,11-trioxo-
2,12-dioxa-5,10-diazatetradecan-8-yl)-1H-benzo[d][1,2,3]triazole
3-oxide (Boc-γVal(β-BtO)-Leu-OMe) (10ii). White solid (0.425 g,
DMSO-d6) δ = 173.0, 169.1, 155.8, 135.3, 130.6, 129.6, 124.5,
115.1, 112.0, 78.5, 59.7, 51.7, 48.0, 36.1, 28.6, 24.7, 23.9, 21.4,
17.1 ppm. MALDI TOF/TOF m/z calcd for C23H35N5O5
[M + Na+] is 500.2485; found 500.3464.
1-((4S,8R,9S)-9-sec-Butyl-4-isobutyl-13,13-dimethyl-3,6,11-trioxo-
2,12-dioxa-5,10-diazatetradecan-8-yl)-1H-benzo[d][1,2,3]triazole
41%), mp 230–232 °C, [α]2D5 +40.0 (c 0.1, MeOH), UV (λmax
)
323 nm, IR (neat) ν (cm−1) 2962, 2928, 2314, 1737, 1543, 1459,
1424, 1368, 1310, 1208, 1169, 1089, 1038, 747. 1H NMR
(400 MHz, DMSO-d6) δ = 8.47 (d, J = 8 Hz, 1 H), 7.84 (d, J =
3-oxide (Boc-γIle(β-BtO)-Leu-OMe) (9i). White solid, (0.254 g, 8 Hz, 1 H), 7.697–7.662 (m, 2 H), 7.40 (t, J = 8 Hz, 1 H), 7.08 (d,
25%), The diastereomeric ratio of 9i : 9ii is 39 : 61, mp J = 8 Hz, 1 H), 5.17 (t, J = 8 Hz, 1 H), 4.032–3.98 (m, 1 H),
230–232 °C, [α]2D5 +20.0 (c 0.1, MeOH), UV (λmax) 323 nm, 3.91–3.86 (m, 1 H), 3.19 (s, 3 H), 3.00 (t, J = 12 Hz, 1 H), 2.70
IR (neat) ν (cm−1) 2963, 2381, 2313, 2112, 1738, 1660, 1509, (d, J = 20 Hz, 1 H), 1.37 (s, 9 H), 0.91–0.85 (m, 2 H) 0.82 (d, J =
1459, 1424, 1368, 1310, 1207, 1167, 749. 1H NMR (400 MHz, 8 Hz, 3 H), 0.75 (d, J = 4 Hz, 3 H), 0.71 (d, J = 4 Hz, 6 H) ppm.
CDCl3) δ = 7.96 (d, J = 8 Hz, 1 H), 7.66–7.58 (m, 2 H), 7.39 (t, J = 13C NMR (100 MHz, DMSO-d6) δ = 172.7, 169.5, 156.3, 134.6,
8 Hz, 1 H), 6.08 (d, J = 8 Hz. 1 H), 5.47–5.43 (m, 2 H), 4.42–4.36 130.7, 129.6, 124.5, 115.2, 112.1, 78.5, 57.8, 51.9, 50.8, 36.5,
(m, 1 H), 4.01–3.95 (m, 1 H), 3.44 (s, 3 H), 2.99 (dd, J = 4 Hz & 28.6, 24.5, 23.1, 21.6, 20.4, 17.2 ppm. MALDI TOF/TOF m/z
12 Hz, 1 H), 2.87 (dd, J = 4 Hz & J = 12 Hz, 1 H), 1.61–1.50 calcd for C25H39N5O6 [M + Na+] is 528.2798; found 528.2535.
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1-((R)-1-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-3-((S)-1-methoxy- J = 8 Hz, 3 H), 7.16 (d, J = 4 Hz, 4 H), 7.03 (d, J = 12 Hz, 1 H),
4-methyl-1-oxopentan-2-ylamino)-3-oxopropyl)-1H-benzo[d][1,2,3]tri-
azole 3-oxide (Boc-γPro(β-BtO)-Leu-OMe) (11i). White solid
(0.242 g, 23%), the diastereomeric ratio of 11i : 11ii is 41 : 59,
mp 110–112 °C, [α]D25 −22.0 (c 0.1, MeOH), UV (λmax) 323 nm,
IR (neat) ν (cm−1) 2966, 2313, 1740, 1687, 1544, 1507, 1455,
1368, 1210, 1164, 907, 748. 1H NMR (400 MHz, CDCl3) δ = 7.94
(d, J = 8 Hz, 1 H), 7.62 (d, J = 8 Hz, 1 H), 7.52 (t, J = 6 Hz, 1 H),
7.37 (t, J = 8 Hz, 1 H), 6.39 (d, J = 8 Hz, 1 H), 5.87–5.83 (m, 1
H), 4.41–4.36 (m, 1 H), 4.27–4.23 (m, 1 H), 3.40 (s, 3 H),
5.34–5.29 (m, 1 H), 4.10.4.06 (m, 2 H), 3.28 (s, 3 H), 3.16 (dd,
J = 4 Hz & 12 Hz, 1 H), 2.94 (dd, J = 4 Hz & 12 Hz, 1 H),
2.73–2.65 (m, 2 H), 1.24 (s, 9 H), 0.79 (d, J = 8 Hz, 3 H), 0.74 (d,
J = 8 Hz, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6) δ = 172.9,
169.3, 155.6, 138.9, 135.3, 130.5, 129.4, 128.5, 126.5, 124.4,
115.2, 112.0, 78.5, 60.2, 59.4, 55.3, 52.0, 50.8, 36.0, 35.5, 28.6,
24.5, 23.2, 21.5, 14.5 ppm. MALDI TOF/TOF m/z calcd for
C29H39N5O6 [M + Na+] is 576.2798; found 576.4337.
1-((4S,8S,9S,12S)-12-Benzyl-9-isobutyl-4,16,16-trimethyl-3,6,11,14-
3.23–3.21 (m, 2 H), 2.87 (dd, J = 4 Hz & 12 Hz, 1 H), 2.24–2.20 tetraoxo-2,15-dioxa-5,10,13-triazaheptadecan-8-yl)-1H-benzo[d]-
[1,2,3]triazole 3-oxide (Boc-Phe-γLeu(β-BtO)-Ala-OMe) (13).
White solid (0.175 g, 67%), UV (λmax) 323 nm, 1H NMR
(400 MHz, DMSO-d6) δ = 8.52 (d, J = 8 Hz, 1 H), 7.91 (d, J =
8 Hz, 2 H), 7.80 (d, J = 8 Hz, 1 H), 7.68 (t, J = 8 Hz, 1 H), 7.35 (t,
J = 6 Hz, 1 H), 7.22 (t, J = 8 Hz, 3 H), 7.15 (d, J = 8 Hz, 1 H),
6.93 (d, J = 8 Hz, 1 H), 5.15–5.10 (m, 1 H), 4.27 (d, J = 8 Hz,
(m, 1 H), 2.05–2.00 (m, 4 H), 1.45 (s, 9 H), 0.88 (t, J = 4 Hz, 6 H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 172.6, 168.5, 157.0,
155.2, 139.3, 135.7, 130.3, 124.6, 115.0, 114.1, 111.6, 60.5, 57.0,
52.1, 51.0, 47.0, 41.0, 37.4, 33.8, 31.9, 29.7, 28.4, 25.8, 24.8,
22.8, 21.8, 14.1 ppm. MALDI TOF/TOF m/z calcd for
C25H37N5O6 [M + Na+] is 526.2642; found 526.2652.
1-((S)-1-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-3-((S)-1-methoxy- 1 H), 4.06–4.99 (m, 1 H), 3.86–3.80 (m, 1 H), 3.50 (s, 3 H),
4-methyl- 1-oxopentan-2-ylamino)-3-oxopropyl)-1H-benzo[d][1,2,3]tri-
azole 3-oxide (Boc-γPro(β-BtO)-Leu-OMe) (11ii). White solid
(0.349 g, 35%), mp 132–134 °C, [α]2D5 −18.0 (c 0.1, MeOH), UV
(λmax) 323 nm, IR (neat) ν (cm−1) 3023, 2967, 2129, 1739, 1653,
1509, 1443, 1368, 1221, 1022, 990, 763. 1H NMR (400 MHz,
DMSO-d6) δ = 8.50 (d, J = 8 Hz, 1 H), 7.79 (br. 2 H), 7.63 (t, J = 8
Hz, 1 H), 7.36 (t, J = 8 Hz, 1 H), 5.12–5.05 (br. 1 H), 4.11–4.09
(m, 2 H), 3.53 (s, 3 H), 3.19 (dd, J = 12 Hz, 1 H), 2.84 (d, J = 16
Hz, 1 H), 1.97–1.81(m, 4 H), 1.08 (s, 9 H), 0.71 (d, J = 4 Hz, 3
H), 0.33 (d, J = 4 Hz, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6)
δ = 173.2, 169.0, 135.1, 124.4, 114.9, 111.9, 58.7, 52.2, 50.2,
31.8, 29.5, 28.0, 24.3, 24.2, 20.7 ppm. MALDI TOF/TOF m/z
calcd for C25H37N5O6 [M + Na+] is 526.2642; found 526.2639.
1-((4S,8R,9S)-9-Benzyl-4-isobutyl-13,13-dimethyl-3,6,11-trioxo-
2,12-dioxa-5,10-diazatetradecan-8-yl)-1H-benzo[d][1,2,3]triazole
3-oxide (Boc-γPhe(β-BtO)-Leu-OMe) (12i). White solid, (0.240 g,
23%), The diastereomeric ratio of 12i : 12ii is 39 : 61, mp
175–177 °C, [α]2D5 +42.0 (c 0.1, MeOH), UV (λmax) 323 nm, 274,
IR (neat) ν (cm−1) 2960, 2130, 1739, 1655, 1526, 1505, 1458,
1425, 1368, 1209, 1164, 1022, 991, 749. 1H NMR (400 MHz,
DMSO-d6) δ = 8.50 (d, J = 8 Hz, 1 H), 7.86 (d, J = 8 Hz, 1 H),
7.70–7.61 (m, 2 H), 7.42 (t, J = 8 Hz, 1 H), 7.25–7.16(m, 5 H),
7.07–7.05 (d, J = 8 Hz 1 H), 5.33–5.28 (m, 1 H), 4.14–4.05 (m,
2 H), 3.54 (s, 3 H), 3.18 (dd, J = 4 Hz & 12 Hz, 1 H), 2.88 (dd, J
4 Hz, & J = 12 Hz, 1 H), 2.69–2.66 (m, 2 H), 1.25 (s, 9 H), 0.67
(d, J = 8 Hz, 3 H) 0.28 (d, J = 8 Hz, 3 H) ppm. 13C NMR
(100 MHz, DMSO-d6) δ = 173.2, 169.1, 155.4, 138.9, 135.3, 130.3,
129.5, 128.4, 126.5, 124.4, 114.9, 112.6, 78.1, 60.2, 55.9, 52.2,
50.2, 28.4, 24.3, 23.3, 20.6, 14.5 ppm. MALDI TOF/TOF m/z
calcd for C29H39N5O6 [M + Na+] is 576.2798; found 576.2814.
1-((4S,8S,9S)-9-Benzyl-4-isobutyl-13,13-dimethyl-3,6,11-trioxo-
2,12-dioxa-5,10-diazatetradecan-8-yl)-1H-benzo[d][1,2,3]triazole
3.17–3.03 (m, 1 H), 2.79 (dd, J = 4 Hz & 12 Hz, 1 H), 2.38 (dd,
J = 4 Hz & 12 Hz, 1 H), 2.07 (dd, J = 4 Hz & 8 Hz, 1 H),
1.67–1.59 (m, 1 H), 1.27 (s, 9 H), 1.10 (d, J = 4 Hz, 3 H), 0.82 (d,
J = 4 Hz, 3 H), 0.74 (d, J = 8 Hz, 3 H) ppm. 13C NMR (100 MHz,
DMSO-d6) = 173.3, 172.2, 168.9, 155.7, 138.8, 135.3, 129.5,
128.4, 124.5, 115.0, 112.6, 78.4, 59.8, 56.5, 48.0, 36.1, 28.5,
24.1, 21.3 ppm. MALDI TOF/TOF m/z calcd for C32H44N6O7
[M + Na+] is 647.3169; found 647.3171.
Crystal structure analysis
Crystal structure analysis of Boc-γF(β-BtO)-OMe (7a). Crys-
tals of peptide were grown by slow evaporation from a solution
of 2-propanol. A single crystal (0.15 × 0.04 × 0.012 mm) was
mounted on a loop with a small amount of the paraffin oil.
The X-ray data were collected at 173 K on a Bruker APEX DUO
CCD diffractometer using Cu Kα radiation (λ = 1.54178 Å),
ω-scans (2θ = 65.16°), for a total of 3950 independent reflec-
tions. Space group P2(1)2(1)2(1), a = 5.2262(5), b = 10.1445(9),
c = 41.525(3), V = 2201.5(3) Å3, orthorhombic P, Z = 4 for the
chemical formula C23H29N4O5 with one molecule in the asym-
metric unit; ρcalcd = 1.428 g cm−3, μ = 0.781 mm−1, F(000) =
968, Rint = 0.0201. The structure was obtained by direct
methods using SHELXS-97. The final R value was 0.0831
(wR2 = 0.2275), 3712 observed reflections (F0 ≥ 4σ (|F0|)) and
281 variables, S = 1.224. The largest difference peak and holes
were 1.376 and −0.726 e Å−3, respectively.
Crystal structure analysis of Boc-γF(β-BtO)-OMe (6a). Crys-
tals of peptides were grown by slow evaporation from a solu-
tion of toluene and methanol. A single crystal (0.15 × 0.04 ×
0.012 mm) was mounted on a loop with a small amount of the
paraffin oil. The X-ray data were collected at 100 K on a Bruker
APEX DUO CCD diffractometer using Cu Kα radiation (λ =
3-oxide (Boc-γPhe(β-BtO)-Leu-OMe) (12ii). White solid (0.377 g, 1.54178 Å), ω-scans (2θ = 72.28°), for a total of 3950 indepen-
33%), mp 153–155 °C, [α]2D5 +32.0 (c 0.1, MeOH), UV (λmax
dent reflections. Space group P2(1)2(1)2(1), a = 9.0179 (3), b =
)
323 nm, 274 nm, IR (neat) ν (cm−1) 3026, 2966, 2313, 1739, 11.9971 (4), c = 21.7378 (7), V = 2351.78 (13) Å3, orthorhombic
1653, 1542, 1524, 1456, 1425, 1368, 1210, 1022, 992, 757. 1H P, Z = 4 for the chemical formula C23H29N4O5 with one mole-
NMR (400 MHz, DMSO-d6) δ = 8.53 (d, J = 8 Hz, 1 H), 7.86 (d, cule in the asymmetric unit; ρcalcd = 1.247 g cm−3, μ =
J = 8 Hz, 1 H), 7.69–7.61 (m, 2 H), 7.42 (t, J = 6 Hz, 1 H), 7.23 (t, 0.731 mm−1, F(000) = 940, Rint = 0.056. The structure was
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obtained by direct methods using SHELXS-97. The final R value was 0.0451 (wR2 = 0.0917) for 6805 observed reflections
value was 0.0479 (wR2 = 0.1263) 4083 observed reflections (F0 ≥ (F0 ≥ 4σ(|F0|)) and 413 variables, S = 1.083. The largest differ-
4σ (|F0|)) and 293 variables, S = 1.049. The largest difference ence peak and holes were 0.225 and −0.217 e Å−3, respectively.
peak and holes were 0.213 and −0.219 e Å3, respectively.
Crystal structure analysis of Boc-γL(β-BtO)-OMe (6c). Crys-
tals of peptides were grown by slow evaporation from a solu-
tion of EtOAc. A single crystal (0.2 × 0.05 × 0.01 mm) was
Acknowledgements
mounted on a loop with a small amount of the paraffin oil. We thank IISER-Pune for financial support. S. M. M. and M. G
The X-ray data were collected at 100 K on a Bruker APEX DUO are thankful to CSIR, Govt. of India, for Senior Research
CCD diffractometer using Mo Kα radiation (λ = 0.71073 Å), Fellowship.
ω-scans (2θ = 56.56°), for a total of 5506 independent reflec-
tions. Space group P2(1)2(1)2(1), a = 9.730(5), b = 10.761(5), c =
21.944(10), V = 2297.7(19) Å3, orthorhombic P, Z = 4 for the
chemical formula C20H30N4O5 with one molecule in the asym-
References
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