Synthesis of ureidomuraymycidine derivatives for structure-activity relationship studies of muraymycins

Article abstract of DOI:10.1021/jo300205b

Figure Persented: One of the key constituents of the muraymycins is the 6-membered cyclic guanidine, (2S,3S)-muraymycidine (or epi-capreomycidine). In order to diversify the structure of the oligopeptide moiety of the muraymycins for thorough structure-activity relationship studies, we have developed a highly stereoselective synthesis of ureidomuraymycidine derivatives with the lactone 4a.

Full text of DOI:10.1021/jo300205b

Article
pubs.acs.org/joc
Synthesis of Ureidomuraymycidine Derivatives for Structure−
Activity Relationship Studies of Muraymycins
Bilal A. Aleiwi, Christopher M. Schneider, and Michio Kurosu*
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison,
Memphis, Tennessee 38163-0001, United States
S
* Supporting Information
ABSTRACT: One of the key constituents of the muraymycins is the 6-membered cyclic guanidine, (2S,3S)-muraymycidine (or
epi-capreomycidine). In order to diversify the structure of the oligopeptide moiety of the muraymycins for thorough structure−
activity relationship studies, we have developed a highly stereoselective synthesis of ureidomuraymycidine derivatives with the
lactone 4a.
A1 (1) against S. aureus was highlighted by the Wyeth research
groups.8 Thus, it is our intent to validate the efficacy of 1 in
vitro and in vivo against M. tuberculosis. In our effort on total
synthesis of muraymycin A1 (1) and D1 (2), and their
analogues for structure−activity relationship studies against
Gram-positive bacteria including M. tuberculosis, it is crucial to
develop an efficient synthesis of -2-amino-2-(2-iminohexahy-
dropyrimidin-4-yl)acetic acid [-muraymycidine (a in Figure 1)]
derivative that can readily be incorporated in the syntheses of
muraymycin analogues. The 6-membered cyclic guanidine
moiety seems to be essential to exhibit strong antibactericidal
activities for the muraymycidins.8b To date, several asymmetric
syntheses of (2S,3R)-capreomycidine (b) have been reported
for the total synthesis or biosynthetic studies of the
capreomycins.9 On the other hand, very few synthetic efforts
on -muraymycidine derivative a have been reported.10 Recently,
Tanino and co-workers reported a synthesis of the amino
alcohol possessing the cyclic guanidine c in which they
accomplished the synthesis of c in 11 steps from an advanced
intermediate with an overall yield of 7.9%.11 In the syntheses of
the 6-membered cyclic guanidine containing α-amino acids
reported to date, selectivities of the asymmetric induction to
generate two consecutive chiral centers were moderate or very
low, and the synthetic schemes required multiple protecting-
group manipulations. Herein, we report an efficient synthesis of
the ureido--muraymycidine derivatives (highlighted in Figure
1) via the optically pure diamino lactone (3S,4S)-3,4-
diaminotetrahydro-2H-pyran-2-one derivative (4a).
INTRODUCTION
■
The increasing resistance among Gram-positive bacteria is
concerning because they are responsible for one-third of
nosocomial infections.1 Multidrug resistance in Gram-positive
cocci (i.e., staphylococci, pneumococci, and vancomycin
resistance in enterococci) and mycobacteria has achieved
great prominence in past 15 years.2 Over the past decade, a
few phase clinical drugs have been developed for Gram-positive
bacterial infections.3 The ultimate goal of the development of
treatment of multidrug resistant strains is to find novel
antibacterial agents which interfere with unexploited bacterial
molecular targets.
Since peptidoglycan (PG) is an essential bacterial cell wall
polymer, the machinery for PG biosynthesis provides a unique
and selective target for antibiotic action. However, only a few
enzymes in PG biosynthesis such as the penicillin binding
proteins (PBPs) have been extensively studied.4 Thus, the
enzymes associated with the early PG biosynthesis enzymes
(i.e., MurA, B, C, D, E, and F, MraY, and MurG) are still
considered to be a source of unexploited drug targets.5 Our
interest in unexploited molecular targets related to PG
biosynthesis is MraY,6 which catalyzes the transformation of
UDP-N-acylmuramyl-L-alanyl-γ-D-glutamyl-meso-diaminopimel-
yl-D-alanyl-D-alanine (Park’s nucleotide) to prenylpyrophos-
phoryl-N-acylmuramyl-L-Ala-γ-D-glu-meso-DAP-D-Ala-D-Ala
(lipid I).7 MraY is inhibited by nucleoside-based complex
natural products such as muraymycin, liposidomycin, capraza-
mycin, and capuramycin. Muraymycins have been isolated from
Streptmyces spp. and possess a common core structure of
capuramycin; however, their structural diversity is observed in
the ester moiety (R in Figure 1) and the appended C5′-ribose
unit. Promising in vivo antibactericidal activity of muraymycin
Received: January 30, 2012
Published: March 29, 2012
© 2012 American Chemical Society
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dipeptides 8 from the lactones in Scheme 1 can be attributed to
the fact that δ-hydroxypentanoic acid derivatives tend to form
δ-lactones even under weak acidic conditions.13 Indeed, the
dipeptides 8a and 8b were relactonized to form 5 and 6,
respectively, during purification by a silica gel chromatography.
In order to improve the conversion of 4 to 3 (Figure 1) and to
realize epimerization of (2R,3S)-diamino lactone derivatives
(e.g., 6 in Scheme 1), we explored suitable N-protecting groups
at the C2-position of lactone 4 (R1 and R2 in Figure 1) in which
we expected that bulky N-protecting groups on (2R,3S)-
diamino lactone would prevent nucleophilic attack on the
carbonyl group to form the undesired dipeptides possessing
2′R-configuration.
We first investigated chemical properties of N-benzyl-N-Cbz-
protected lactones 4a and 4b. The syntheses of 4a and 4b are
illustrated in Scheme 2. The (2S)-aminobutanal derivative 9
was readily synthesized from (2S)-2-amino γ-butyrolactone
according to the reported procedures.14 The aldehyde 9 was
subjected to the Strecker reaction with benzylamine and
TMSCN to form a mixture of 2,3-diaminonitriles 10a and
10b.15 In our extensive reaction screening (9→10), the
Strecker reaction conditions that provided 10 with greater
than 80% yield are summarized in Table 1.
The Strecker reactions with Lewis acids (e.g., ZnI2,
Cu(OTf)2, Sn(OTf)2, La(OTf)3)16 provided the undesired
product 10b as a major product with low yields (<30%) due
probably to instability of the aldehyde 9 under strong Lewis
acidic conditions. The reaction with the thiourea catalyst
provided a 1:3.5 mixture of 10a and 10b in 88% yield
(conditions A). A Ti-mediated Strecker reaction resulted in a
1:1.5 mixture of 10a and 10b (conditions B). It was found that
the Strecker reaction of the benzyl imine 9 with TMSCN could
be achieved via a convenient dehydrating reagent, MgSO4, to
furnish a 1:1 mixture of 10a and 10b in 88% yield (conditions
C). The same Strecker reactions with the known chiral catalysts
such as thioureas and salene−transition-metal complexes
resulted in the formation of a mixture of 10a and 10b in
very poor yield (<30%) with low 10a/10b selectivity.17 The
structure of 10b could unequivocally be determined by
extensive 2D-NMR studies of 4b that was synthesized from
10b.18 With a 1:1 mixture of 10a and 10b in hand, we could
establish the synthesis of 4a in five steps including
epimerization of the C2-center (Scheme 2). Cbz protection
of a mixture of the Strecker products was accomplished under
buffered conditions in CH2Cl2 to afford 11a and 11b in 96%
yield. Hydration of a mixture of the nitriles 11a and 11b was
achieved by using InCl3 in the presence of acetaldoxime at 70
°C to afford a mixture of N-benzyl-N-Cbz-protected primary
Figure 1. Retro-synthesis of muraymycins and structures of
muraymycidine and capreomycidine.
RESULTS AND DISCUSSION
■
Our synthetic strategy to efficiently synthesize ureido-(2S,3S)-
muraymycidine is illustrated in Figure 1. In our preliminary
studies on the synthesis of the dipeptide intermediate 3 (Figure
1), we examined the efficiency of a strategy of lactone-opening
of (2S,3S)-diamino lactone 5 and (2R,3S)-diamino lactone 6
with H-L-Leu-OtBu for the synthesis of 8 (Scheme 1).12 We
observed that the lactone opening of 6 with H-L-Leu-OtBu in
the presence of 2(1H)-pyridinone (7) furnished a 1:1 mixture
of the dipeptides 8a and 8b in very poor yield (<5%). On the
other hand, under the same conditions the lactone 5 yielded the
desired 8a without contamination of 8b in 10−20% yield.
These data clearly indicated that the lactone 6 was epimerized
under the reaction conditions (2(1H)-pyridinone, toluene at
reflux). Importantly, the stereochemistry of the lactone 5 was
intact, and the dipeptide 8a was not epimerized in the 2(1H)-
pyridinone-catalyzed thermal lactone-opening reaction con-
ditions. In addition, reactivity of the lactone 6 against H-L-Leu-
OtBu was poorer than that of 5. Low conversion of the
Scheme 1. Preliminary Studies of Lactone-Opening Reactions
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Scheme 2. Syntheses of Lactones 4a and 4b and Lactone-Opening Reactions
completed in 3 h. The synthesis of the desired dipeptide 3a
could be accomplished via a one-pot operation in which H-L-
Leu-OtBu was added into a solution of the completely
epimerized lactone. We realized that the undesired lactone 4b
could not be opened with H-L-Leu-OtBu even after prolonged
reaction times. Among amine nucleophiles tested, only NH3
could react with 4b at room temperature in the absence of
2(1H)-pyridinone to furnish 13b in quantitative yield. There-
fore, the dipeptide 3a can be synthesized without contami-
nation of the epimer of 3a from a 1:1 mixture of 4a and 4b
through epimerization.
Table 1. Strecker Reactions of the α-Amino Aldedyde 9
In order to obtain more insight into epimerization followed
by opening of the lactone 4b, we examined the lactone-opening
reactions with a wide range of primary amines and α-amino
acids (e.g., H-L-Leu-OtBu, H-L-Leu-OMe, Gly-OMe, H-L-Phe-
OtBu, and others). Table 2 summarizes the selected examples
of 2(1H)-pyridinone-catalyzed lactone-opening reactions of a
mixture of 4a and 4b (1:1). The lactone-opening reactions with
the reactive amines (e.g., NH3, PhCH2NH2, C6H13NH2) were
successfully achieved by addition of the amine nucleophiles
after completion of epimerization (4b→4a) to afford the
corresponding primary or secondary amides with 90−100% yield
(conditions A). On the other hand, lactone-opening reactions
with the α-amino acids did not require adding the nucleophiles
after completion of the epimerization of 4b. In all of the
reactions with α-amino acids summarized in Table 2, (2R,3S)-
diamino lactone 4b did not react with salt-free α-amino acid
esters. Thus, the 2(1H)-pyridinone catalyzed epimerization of
4b to 4a could be completed in the presence of α-amino acid
esters, and only (2S,3S)-diaminolactone 4a was smoothly
amide 12a and 12b in 86% yield.19 Desilylation of 12 followed
by a thermal lactonization of the resulting mixture of 13a and
13b in toluene at refluxing temperature provided 4a and 4b in
75% overall yield. The structure of (2R,3S)-diaminolactone 4b
was established via extensive 2D-NMR techniques (vide supra).
Gratifyingly, the undesired lactone 4b could be epimerized to
the desired lactone 4a with DBU in quantitative yield.
Epimerization of 4b to 4a was also observed under the
conditions (2(1H)-pyridinone, toluene at reflux) used for
opening of the lactone with H-L-Leu-OtBu (5→8a in Scheme
1). Under these conditions, epimerization of 4b to 4a was
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Table 2. Lactone-Opening Reactions with Amines and α-Amino Acid Esters
Scheme 3. Synthesis of Ureidomuraymycidine Tripeptide 19
reacted with α-amino acid esters. Lactone-opening reaction of a
1: 1 mixture of 4a and 4b with H-L-Gly-OMe and 2(1H)-
pyridinone in toluene at reflux for 5 h furnished the desired 3c
exclusively in 80% yield (conditions B).
correlations.21 The syn-isomer 4a is significantly lower in
energy than the anti-isomer 4b; the calculated free energy
difference was 6.86 kcal/mol. Thus, we concluded that
epimerization of 4b could readily be achieved by using
2(1H)-pyridinone in toluene at refluxing temperature. Because
the anti-isomer 4b exists as a pseudoboat conformation, the
amino groups at the C2- and C3-positions hinder the
nucleophilic additions of α-amino acids to the lactone carbonyl
from both re- and si-faces.
Synthesis of the ureido tripeptide 19 was achieved from the
dipeptide 3a (Scheme 3). The primary alcohol of 3a was first
protected as its acetate to afford 14 in quantitative yield. The
N-Bn and N-Cbz groups of 14 were removed by hydrogenation
to generate free amine which was subjected to the urea-forming
reaction with the imidazolium salt 15 to furnish 16 in 70%
Under the same conditions, (2S,3S)-benzyl-2-amino-3-
hydroxy-4-methylpentanoate was reacted with a mixture of
the lactones to furnish 3g in 65% yield (90% yield based on
recovering 4a) without formation of the other diastereomers.
The dipeptide 3g is a valuable intermediate for a total synthesis
of muraymycin A1 (1). The dipeptides 3a−g in Table 2 were
stable under weak acidic and basic conditions (pH 4.0−9.0) at
room temperature; relactonizations of 3a−g to 4a were not
observed. The plausible lowest-energy conformers of 4a and 4b
are illustrated in Scheme 2. Those conformers were obtained
via MM2 calculations20 and supported by the NOESY
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overall yield.22 The Boc group of 16 was removed by using 50%
TFA at 0 °C and the generated salt free amine was coupled
with N,N′-di-tert-butoxycarbonyl-S-methyl isothiourea in the
presence of Et3N and HgCl2 to afford 17 in 62% yield.23
[tBu2Sn(OH)Cl]2-catalyzed deacetylation24 of 17 followed by
an intramolecular Mitsunobu reaction with DIAD and PPh3
completed the synthesis of the fully protected ureidomur-
aymycidine tripeptide 19 in 65% overall yield. The segment 19
possesses ideal protecting groups for a total synthesis of
muraymycin D1 (2).
with pH 8 phosphate buffer solution. The heterogeneous mixture was
filtered, and the filtrate was extracted with CH2Cl2. The generated
Weinreb amide was used in the next step without purification. A
stirred solution of the Weinreb amide (3.60 g, 13.70 mmol) and 2,6-
lutidine (0.92 mL, 27.40 mmol) in CH2Cl2 (55 mL) was cooled to 0
°C. TBSOTf (3.46 mL, 15.10 mmol) was added, and the reaction
mixture was stirred for 30 min. The reaction was quenched with water
and extracted with EtOAc. The extract was washed with 1 N HCl,
brine, dried over Na2SO4, and concentrated in vacuo. Purification by
silica gel column chromatography gave (2S)-tert-butyl (3,9,9,10,10-
pentamethyl-4-oxo-2,8-dioxa-3-aza-9-silaundecan-5-yl)carbamate (4.71
g, 12.50 mmol, 91%) as an amorphous solid: TLC (hexanes/EtOAc
25:75) Rf = 0.7; [α]22 +0.4 (c = 0.9, CHCl3); IR (thin film) νmax
=
D
CONCLUSIONS
■
3323 (br), 2930, 2858, 1716, 1669, 1500, 1390, 1366, 1253, 1173,
1101, 941, 836, 778 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.45 (d, J =
7.7 Hz, 1H), 4.74 (br s, 1H), 3.20 (s, 3H), 1.96 (dd, J = 4.7, 9.0 Hz,
1H), 1.79−1.61 (m, 1H), 0.89 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 155.7, 79.4, 61.7, 59.9, 48.9, 34.9, 32.3,
28.5, 26.0, 18.3, −5.4; HRMS (ESI+) m/z calcd for C17H37N2O5Si [M
+ H] 377.2472, found 377.2472.
LiAlH4 (1 M in THF, 15.90 mmol, 15.90 mL) was slowly added to
a THF solution (40 mL) of (2S)-tert-butyl (3,9,9,10,10-pentamethyl-4-
oxo-2,8-dioxa-3-aza-9-silaundecan-5-yl)carbamate (3.00 g, 7.97 mmol)
at 0 °C. After 1.5 h, the reaction mixture was diluted with Et2O, and
quenched with brine. The precipitates were filtered. The combined
organic solution was dried over MgSO4, and evaporated. This was used
for the next reaction without purification.
General Procedure of Strecker Reaction: Synthesis of a
Mixture of 10a and 10b. A CH2Cl2 (72 mL) solution of aldehyde 9
(2.30 g, 7.24 mmol), benzylamine (0.87 mL, 7.97 mmol), and an
excess of MgSO4 were stirred at room temparature for 2 h. The solids
were then filtered off, and the mixture was concentrated in vacuo to
give an intermediate imine. The imine was dissolved in CH2Cl2 (72
mL), and TMSCN (1.93 mL, 14.50 mmol) was then added. The
reaction was stirred for 1 h then poured into saturated NaHCO3 (aq.).
The aqueous layer was extracted with CH2Cl2 (3×), and the combined
organic extracts were dried over Na2SO4 and concentrated in vacuo.
Purification by silica gel column chromatography (hexanes/EtOAc
100:0 to 80:20) gave a mixture of 10a and 10b (2.77 g, 6.38 mmol,
88%) as an oil: IR (thin film) νmax = 3332 (br), 3065, 3031, 2932,
2228, 1714, 1505, 1367, 1255, 1172, 837 cm−1; 1H NMR (CDCl3, 400
MHz) δ 7.51−7.17 (m, 5H), 5.42 (d, J = 6.6 Hz, 0.5H), 5.21 (d, J =
8.4 Hz, 0.5H), 2.12−1.70 (m, 3H), 1.46 (s, 9H), 0.93−0.90 (m, 9H),
0.10−0.05 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 155.7, 138.2,
128.6, 128.4, 128.4, 127.6, 119.0, 118.6, 80.0, 60.1, 59.8, 54.3, 52.1,
51.5, 51.3, 50.9, 34.1, 32.3, 28.5, 28.4, 26.1, 25.9, 25.9, 18.2, 18.2, −5.5;
HRMS (ESI+) m/z calcd for C23H40N3O3Si [M + H] 434.2839, found
434.2839.
In summary, we present a highly stereoselctive synthesis of
ureidomuraymycidine tripeptide 19 from a 1:1 mixture of the
lactones 4a and 4b. δ-Lactones have not been widely utilized
for functionalization of alcohols and amines due mainly to
undesired reversible reactions.25 We realized that (2R,3S)-
diamino lactone 4b can readily be epimerized to the
stereoelectronically favored 4a with 2(1H)-pyridinone. In
addition, the lactone 4b was not susceptible to lactone-opening
reactions with α-amino acid derivatives. Thus, epimerization
followed by selective lactone-opening reactions of a mixture of
4a and 4b with α-amino acids can be achieved in the presence
of 2(1H)-pyridinone to furnish the corresponding dipeptides as
a single diastereomer. Relactonizations of the δ-hydroxy
dipeptides synthesized in this program were not observed
under mild acidic and basic conditions; thus, high-yield
dipeptide formations from the lactones 4a and 4b were
achieved.26 The ureidomuraymycidine moiety of the muray-
mycins is an important functionality to show strong
antibacterial activities.27 Thus, the ureidomuraymycidin (high-
lighted in Figure 1) should be retained as the intact
stereochemistry for SAR studies of the muraymycins. As
illustrated in Table 2, we will diversify the structure of
muraymycin A1 and D1 for a thorough SAR study via the
lactone-opening reactions of a 1:1 mixture of 4a and 4b, which
could be synthesized from the known aldehyde 9 in over 50%
overall yield. Total synthesis of muraymycins A1 and D1, and
preliminary SAR of the muraymycins will be reported
elsewhere.
EXPERIMENTAL SECTION
■
All reagents and solvents were of commercial grade and were used as
received without further purification unless otherwise noted.
Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled
from sodium benzophenone ketyl under an argon atmosphere prior to
use. Methylene chloride (CH2Cl2), acetonitrile (CH3CN), benzene,
toluene, and triethylamine (Et3N) were distilled from calcium hydride
under an argon atmosphere. Flash chromatography was performed
with Whatman silica gel (Purasil 60 Å, 230−400 Mesh). Analytical
thin-layer chromatography was performed with 0.25 mm coated
commercial silica gel plates (EMD, silica gel 60F254) visualizing at 254
nm or developed with ceric ammonium molybdate or anisaldehyde
solutions by heating on a hot plate. 1H NMR spectral data were
obtained using 300, 400, and 500 MHz instruments. 13C NMR spectral
data were obtained using 100 and 125 MHz instruments. For all NMR
spectra, δ values are given in ppm and J values in Hz.
tert-Butyl ((3S,4S)-3-(Benzylamino)-2-oxotetrahydro-2H-
pyran-4-yl)carbamate (5). tert-Butyl (1-amino-2-(benzylamino)-5-
hydroxy-1-oxopentan-3-yl)carbamate (40 mg, 0.12 mmol) was
dissolved in toluene (2 mL). The reaction mixture was stirred at
reflux for 24 h and cooled to rt. All volatiles were evaporated in vacuo.
Purification by silica gel column chromatography (hexanes/EtOAc
90:10 to 50:50) yielded product 5 as an amorphous white solid (25
mg, 0.08 mmol, 63%). Data for 5: TLC (hexanes/EtOAc 50:50) Rf =
0.4, [α]22 +36 (c = 0.85, CHCl3); IR (thin film) νmax = 3351 (br),
D
2979, 2929, 1693, 1524, 1459, 1418, 1364, 1259, 1170, 1075, 994, 873,
1
773, 739, 702 cm−1; H NMR (CDCl3, 500 MHz) δ 7.39−7.28 (m,
5H), 5.45 (s, 1H), 4.94 (s, 1H), 4.42 (m, 1H), 4.28 (m, 1H), 4.02 (d, J
= 12.5 Hz, 1H), 3.91−3.77 (ddd, J = 13.5, 12.5, 14.0 Hz, 1H), 3.66 (m,
1H), 3.46−3.38 (dd, J = 7.5, 10.5 Hz, 1H), 2.51−2.49 (m, 1H), 1.98−
1.94 (m, 2H), 1.48 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 172.9,
171.4, 156.2, 155.7, 139.5, 138.7, 128.7, 128.5, 128.1, 127.4, 79.9, 65.8,
65.5, 60.6, 57.9, 51.8, 50.5, 49.6, 45.0, 30.4, 28.4; HRMS (ESI+) m/z
calcd for C17H24N2O4Na [M + Na] 343.1634, found 343.1637.
tert-Butyl ((3R,4S)-3-(Benzylamino)-2-oxotetrahydro-2H-
pyran-4-yl)carbamate (6). tert-Butyl (2R,3S)-1-amino-2-(benzyla-
mino)-5-hydroxy-1-oxopentan-3-ylcarbamate (30 mg, 0.089 mmol)
was dissolved in toluene (2 mL). The reaction mixture was stirred at
(2S)-tert-Butyl (4-((tert-Butyldimethylsilyl)oxy)-1-oxobutan-
2-yl)carbamate (9). MeNHOMe·HCl (1.89 g, 19.4 mmol) was
suspended in CH2Cl2 (97 mL) and cooled to 0 °C. Me2AlCl (1 M in
hexanes, 19.4 mmol, 19.4 mL) was added dropwise, and the reaction
mixture was warmed to rt. After 1 h, the reaction was cooled to 0 °C,
and a solution of 2S-[(tert-butyloxycarbonyl)amino]-4-butyrolactone
(1.95 g, 9.69 mmol) in CH2Cl2 (49 mL) was added via syringe pump
over 15 min. The reaction mixture was stirred for 6 h and quenched
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reflux for 24 h and cooled to rt. All volatiles were evaporated in vacuo.
Purification by silica gel column chromatography (hexanes/EtOAc
90:10 to 50:50) yielded product 6 as an amorphous white solid (15
mg, 0.048 mmol, 53%). Data for 6: TLC (hexanes/EtOAc 50:50) Rf =
mL, 1.74 mmol) in THF (18 mL) was added TBAF (1 M in THF,
6.93 mL, 6.93 mmol). After 1 h at rt, all volatiles were concentrated in
vacuo. Purification by silica gel column chromatography (hexanes/
EtOAc 50:50 to 0:100) gave a mixture of 13a and 13b (1.48 g, 3.13
mmol, 90%). Data for 13a: TLC (hexanes/EtOAc 25:75) Rf = 0.15;
[α]22D −0.3 (c 2.1, CHCl3); IR (thin film) νmax = 3340 (br), 3200 (br),
2963, 2932, 1683, 1498, 1454, 1406, 1367, 1255, 1169, 1123, 1054,
0.4, [α]22 −0.6 (c = 0.75, CHCl3); IR (thin film) νmax = 3351 (br),
D
2979, 2929, 1693, 1524, 1459, 1418, 1364, 1259, 1170, 1075, 994, 873,
1
773, 739, 702 cm−1; H NMR (CDCl3, 500 MHz) δ 7.29−7.19 (m,
1
5H), 5.36 (s, 1H), 4.83 (s, 1H), 4.39−4.32 (m, 1H), 4.23−4.18 (m,
1H), 3.92 (d, J = 12.0 Hz, 1H), 3.82−3.65 (ddd, J = 14.0, 12.5, 13.5
Hz, 1H), 3.55 (m, 1H), 3.37−3.28 (dd, J = 5.0, 10.5 Hz, 1H), 2.43−
2.34 (m, 1H), 2.07−2.02 (m, 1H), 1.39 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 172.9, 171.4, 156.2, 155.7, 139.6, 138.8, 128.7, 128.5,
128.1, 127.5, 79.9, 65.5, 60.6, 57.9, 51.8, 50.5, 49.6, 45.0, 30.36, 28.4,
27.5; HRMS (ESI+) m/z calcd for C17H24N2O4Na [M + Na]
343.1634, found 343.1636.
1028, 1005, 771, 739, 698 cm−1; H NMR (DMSO-d6, 400 MHz) δ
7.48−7.14 (m, 10H), 7.00 (br s, 1H), 6.62−6.47 (m, 1H), 5.03 (br s,
2H), 4.64 (br s, 2H), 4.48 (d, J = 16.0 Hz, 1H), 4.30 (br s, 1H), 3.98
(br s, 1H), 3.32 (br s, 2H), 1.57−1.43 (m, 2H), 1.37 (s, 9H); 13C
NMR (DMSO-d6, 100 MHz) δ 171.8, 170.5, 155.3, 128.7, 128.1,
128.0, 127.7, 127.6, 127.1, 126.4, 77.9, 66.6, 60.6, 57.8, 47.6, 35.0, 31.2,
28.4, 28.2, 22.1, 13.9; HRMS (ESI+) m/z calcd for C25H33N3O6Na [M
+ Na] 494.2267, found 494.2268. Data for 13b: TLC (hexanes/EtOAc
Benzyl (Benzyl)((2S)-2-((tert-butoxycarbonyl)amino)-4-((tert-
butyldimethylsilyl)oxy)-1-cyanobutyl)carbamate (12). To a
stirred solution of a 1:1 mixture of 10a and 10b (342 mg, 0.79
mmol) in CH2Cl2 (4 mL) were added aq satd NaHCO3 (4 mL) and
CbzCl (0.23 mL, 1.58 mmol). This reaction mixture was stirred for 1 h
at rt. Upon completion, the aqueous layer was extracted with CH2Cl2
(3×), and the combined organic extract was dried over Na2SO4 and
concentrated in vacuo. The crude mixture was purified by silica gel
column chromatography (hexanes/EtOAc 90:10 to 80:20) to yield a
1:1 mixture of the Cbz-protected products 11a and 11b (430 mg, 0.76
mmol, 96%) as an oil: TLC (hexanes/EtOAc 75:25) Rf = 0.65; IR
(thin film) νmax = 3362 (br), 3034, 2956, 2858, 2247, 1716, 1498,
25:75) Rf = 0.05; [α]22 +0.2 (c = 1.1, CHCl3); IR (thin film) νmax
=
D
3346 (br), 3201 (br), 2976, 2933, 1684, 1513, 1499, 1453, 1404, 1366,
1345, 1258, 1170, 1052, 1029, 768, 737, 698 cm−1; 1H NMR (DMSO-
d6, 400 MHz) δ 7.82 (br s, 1H), 7.48−7.04 (m, 10H), 6.90 (d, J = 5.5
Hz, 1H), 6.53 (d, J = 9.8 Hz, 1H), 5.05−4.95 (m, 1H), 4.91 (br s, 1H),
4.63 (d, J = 16.8 Hz, 1H), 4.54 (d, J = 10.2 Hz, 1H), 4.44−4.30 (m,
2H), 4.07−3.89 (m,1 H), 3.54−3.35 (m, 2H), 1.54 (br s, 2H), 1.34 (s,
9H); 13C NMR (DMSO-d6, 100 MHz) δ 175.4, 170.6, 155.4, 128.0,
127.8, 127.4, 127.0, 126.2, 126.0, 77.5, 66.4, 61.5, 58.1, 46.9, 34.2, 31.2,
28.3, 28.2, 22.1, 13.9; HRMS (ESI+) m/z calcd for C25H33N3O6Na [M
+ Na] 494.2267, found 494.2263. A mixture of these alcohols was used
for the next reaction.
1
1471, 1367, 1254, 1171, 1102, 1003, 837, 777, 698 cm−1; H NMR
(3S,4S)- and (3S,4R)-3,4-Diaminotetrahydro-2H-pyran-2-one
(4a and 4b). A mixture of benzyl (1-amino-3-(tert-butoxycarbonyl)-
amino)-5-hydroxy-1-oxopentan-2-yl)(benzyl)carbamates (117 mg,
0.248 mmol) was dissolved in toluene (5 mL). The reaction mixture
was stirred at reflux for 24 h and cooled to rt. All volatiles were
evaporated in vacuo. Purification by silica gel column chromatography
(hexanes/EtOAc 90:10 to 50:50) yielded 4a and 4b as an amorphous
white solid (94 mg, 0.21 mmol, 83%). Data for 4a: TLC (hexanes/
(CDCl3, 400 MHz) δ 7.46−7.14 (m, 10H), 5.31 (br s, 1H), 5.17 (br s,
2H), 4.87−4.69 (m, 2H), 4.23−4.15 (m, 1H), 4.20 (d, J = 3.9 Hz,
1H), 3.83−3.54 (m, 2H), 1.74 (br s, 1H), 1.57 (br s, 1H), 1.45 (s,
9H), 0.92−0.89 (m, 9H), 0.10−0.03 (m, 6H); 13C NMR (CDCl3, 100
MHz) δ 155.3, 137.0, 135.6, 128.8, 128.6, 128.4, 128.2, 127.7, 127.7,
127.1, 116.4, 80.1, 77.2, 68.6, 65.4, 59.7, 53.1, 50.3, 32.9, 28.6, 28.5,
28.5, 28.4, 28.4, 26.1, 26.1, 26.0, 26.0, 25.9, 18.2, −5.3, −5.4, −5.5;
HRMS (ESI+) m/z calcd for C31H45N3O5SiNa [M + Na] 590.3026,
found 590.3017.
EtOAc 50:50) Rf = 0.4, (benzene/acetone 80:20) Rf = 0.75; [α]22
D
+46 (c = 0.75, CHCl3); IR (thin film) νmax = 3353 (br), 2978, 2932,
To a stirred solution of 11a and 11b (a 1:1 mixture, 2.34 g, 4.12
mmol) in toluene (27 mL) were added InCl3 (137.0 mg, 0.62 mmol)
and acetaldoxime (1.26 mL, 20.6 mmol). The reaction mixture was
heated at 70 °C for 4 h. Upon completion, the reaction was cooled to
rt, and all volatiles were removed. Purification by silica gel column
chromatography (hexanes/EtOAc 90:10 to 50:50) to yielded 12a and
12b (2.03 g, 3.47 mmol, 84%) as an amorphous white solid. Data for
1699, 1519, 1454, 1420, 1366, 1261, 1171, 1075, 993, 871, 771, 737,
1
700 cm−1; H NMR (benzene-d6, 400 MHz) δ 7.37−7.21 (m, 2H),
7.21−7.08 (m, 3H), 7.04 (br s, 5H), 6.62 (d, J = 7.7 Hz, 1H), 5.08−
5.05 (d, J = 12.4 Hz, 1H), 4.94−4.91 (d, J = 12.4 Hz, 1H), 4.49−4.45
(d, J = 16.0 Hz, 1H), 4.39−4.35 (d, J = 15.6 Hz, 1H), 4.11 (br s, 1H),
4.02−3.97 (dd, J = 10.5 Hz, 1H), 3.42−3.39 (d, J = 11.2 Hz, 1H),
3.33−3.31(d, J = 6.8 Hz, 1H), 1.57−1.54 (d, J = 12.0 Hz, 1H), 1.38 (s,
9H), 1.02−0.97 (dd, J = 11.2, 13.8 Hz, 1H); 13C NMR (benzene-d6,
100 MHz) δ 165.6, 157.7, 155.1, 136.7, 136.1, 128.3, 128.1, 127.8,
127.5, 127.3, 127.2, 126.7, 126.5, 78.6, 67.7, 63.8, 59.2, 52.7, 47.9, 27.9,
27.7; HRMS (ESI+) m/z calcd for C25H30N2O6Na [M + Na]
477.2002, found 477.1999. Data for 4b: TLC (hexanes/EtOAc 50:50)
12a: TLC (hexanes/EtOAc 50:50) Rf = 0.5; [α]22 −0.4 (c = 3.1,
D
CHCl3); IR (thin film) νmax = 3350 (br), 2956, 2930, 2857, 2556,
2490, 2406, 1682, 1454, 1412, 1366, 1255, 1169, 1094, 1030, 991, 837,
1
775, 735, 697 cm−1; H NMR (CD3OD, 400 MHz) δ 7.47−7.02 (m,
10H), 6.37 (br s, 1 H), 5.07 (br s, 2H), 4.69 (d, J = 16.0 Hz, 1H),
4.65−4.39 (m, 2H), 4.21 (br s, 1H), 3.55 (br s, 2H), 1.64 (br s, 1H),
1.49 (br s, 1H), 1.39 (s, 9H), 0.86 (s, 9H), 0.00 (br s, 6H); 13C NMR
(CD3OD, 100 MHz) δ173.6, 158.3, 157.7, 157.6, 139.7, 137.5, 129.4,
129.3, 129.1, 128.4, 128.0, 80.2, 68.9, 63.4, 61.1, 36.0, 28.8, 26.5, 19.1,
−5.2, −5.2; HRMS (ESI+) m/z calcd for C31H47N3O6SiNa [M + Na]
608.3132, found 608.3128. Data for 12b: TLC (hexanes/EtOAc
Rf = 0.4 (benzene/acetone 80:20) Rf = 0.8; [α]22 −0.8 (c 2.5,
D
CHCl3); IR (thin film) νmax = 3368 (br), 2977, 2361, 1745, 1712,
1500, 1474, 1455, 1426, 1392, 1366, 1250, 1169, 1079, 992, 911, 865,
1
737, 699 cm−1; H NMR (CDCl3, 400 MHz) δ 7.40−7.18 (m, 10H),
5.12 (d, J = 14.5 Hz, 2H), 4.54 (d, J = 16.0 Hz, 2H), 4.31−4.10 (m,
2H), 4.01 (br s, 1H), 3.71−3.47 (m, 1H), 2.23−1.92 (m, 1H), 1.92−
1.61 (m, 1H), 1.37 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 169.0,
154.9, 136.0, 135.3, 129.0, 128.8, 128.7, 128.7, 128.5, 128.3, 128.1,
127.8, 127.7, 79.9, 77.2, 68.7, 67.9, 66.5, 66.2, 62.1, 61.4, 54.0, 53.1,
49.7, 49.0, 30.2, 28.4; HRMS (ESI+) m/z calcd for C25H30N2O6Na [M
+ Na] 477.2002, found 477.1999.
50:50) Rf = 0.55; [α]22 +0.6 (c = 1.3, CHCl3); IR (thin film) νmax
=
D
3339 (br), 2956, 2930, 2857, 2541, 2474, 2406, 1683, 1499, 1463,
1407, 1366, 1254, 1172, 1098, 1030, 837, 776, 735, 697, 665 cm−1; 1H
NMR (CD3OD, 400 MHz) δ 7.50−6.90 (m, 9H), 6.28 (d, J = 9.8 Hz,
1H), 5.18 (br s, 1H), 5.13−4.94 (m, 2H), 4.75−4.56 (m, 2H), 4.50(d,
J = 16.0 Hz, 1H), 4.34−4.17 (m, 1H), 3.73 (d, J = 6.3 Hz, 2H), 1.77
(br s, 1H), 1.60 (br s, 1H), 1.40 (s, 9H), 0.91 (s, 9H), 0.06 (s, 6H);
13C NMR (CD3OD, 100 MHz) δ 178.1, 173.3, 157.7, 129.3, 129.2,
128.9, 128.9, 127.8, 127.6, 80.1, 68.8, 63.6, 61.3, 35.9, 28.8, 26.5, 19.1,
−5.3; HRMS (ESI+) m/z calcd for C31H48N3O6Si [M + H] 586.3312,
found 586.3306. A mixture of 12a and 12b was used for the next
reaction.
Epimerization of the Lactone 4b to 4a. To a stirred solution of
the lactone 4b (20 mg, 0.044 mmol) in toluene (2 mL) was added
DBU (14 mg, 0.088 mmol). After 1.5 h at rt, all volatiles were
evaporated in vacuo. Purification by silica gel column chromatography
(hexanes/EtOAc 90:10 to 50:50) gave the lactone 4a as a single
diastereomer.
General Procedure for Lactone-Opening Reaction. To a
stirred solution of a 1:1 mixture of the lactones 4a and 4b (1 equiv) in
toluene (0.4 M) were added 2(1H)-pyridinone (1−2 equiv) and α-
amino acid (2−3 equiv). The reaction mixture was heated at reflux for
Benzyl ((3S)-1-Amino-3-((tert-butoxycarbonyl)amino)-5-hy-
droxy-1-oxopentan-2-yl)(benzyl)carbamate (13). To a stirred
solution of 12a and 12b (1:1, 2.03 g, 3.47 mmol) and HOAc (0.01
3864
dx.doi.org/10.1021/jo300205b | J. Org. Chem. 2012, 77, 3859−3867

The Journal of Organic Chemistry
Article
5 h and cooled to rt. All volatiles were evaporated in vacuo.
Purification by silica gel column chromatography (hexanes/EtOAc
65:35 to 50:50) yielded the desired product (procedure A). To a
stirred solution of a 1:1 mixture of the lactone 4a and 4b (1 equiv) in
toluene (0.4 M) was added 2(1H)-pyridinone (1−2 equiv). After 3 h
at 130 °C, free amine (2−3 equiv) was added. The reaction mixture
was heated at 130 °C for an additional 5 h and cooled to rt. All
volatiles were evaporated in vacuo. Purification by silica gel column
chromatography (hexanes/EtOAc 65:35 to 50:50) yielded the desired
product (procedure B).
(S)-Methyl 2-(-2-(benzyl((benzyloxy)carbonyl)amino)-3-
((tert-butoxycarbonyl)amino)-5-hydroxypentanamido)-4-
methylpentanoate (3b). The dipeptide 3b was synthesized using
general procedure A, 3b (22 mg, 0.036 mmol, 80%): colorless oil;
TLC (hexanes/EtOAc 50:50) Rf = 0.25; [α]22D +0.9 (c = 0.6, CHCl3);
IR (thin film) νmax = 3330 (br), 2969, 2956, 1730, 1634, 1487, 1458,
1415, 1172, 1110, 1052, 1021, 773, 741, 692 cm−1; 1H NMR (DMSO-
d6, 400 MHz) δ 9.15−8.92 (m, 1H), 7.61−7.05 (m, 8H), 6.90 (d, J =
6.7 Hz, 2H), 6.75−6.52 (m, 1H), 5.03 (br s, 1H), 4.95 (br s, 1H), 4.73
(d, J = 5.9 Hz, 2H), 4.49−4.37 (m, 2H), 4.37−4.24 (m, 1H), 4.12−
3.99 (m, 1H), 3.69−3.59 (s, 3H), 3.46 (d, J = 7.4 Hz, 2H), 1.73−1.47
(m, 5H), 1.41 (s, 9H), 0.92 (d, J = 5.9 Hz, 3H), 0.86 (d, J = 6.3 Hz,
3H); 13C NMR (DMSO-d6, 100 MHz) δ 185.6, 172.6, 168.6, 156.4,
155.4, 139.9, 136.5, 127.9, 127.7, 127.2, 127.0, 126.8, 126.2, 125.9,
77.7, 66.5, 61.6, 57.9, 51.9, 47.6, 47.2, 33.7, 28.1, 24.2, 22.9, 21.0;
HRMS (ESI+) m/z calcd for C32H46N3O8 [M + H] 600.3285, found
600.3288.
-Methyl 2-(2-(Benzyl((benzyloxy)carbonyl)amino)-3-((tert-
butoxycarbonyl)amino)-5-hydroxypentanamido)-3-hydroxy-
4-methylpentanoate (3g). The dipeptide 3g was synthesized using
general procedure A, 3g (20 mg, 0.029 mmol, 65%): colorless oil;
TLC (hexanes/EtOAc 50:50) Rf = 0.25; [α]22D +0.6 (c = 0.8, CHCl3);
IR (thin film) νmax = 3350 (br), 3015, 2975, 2962, 1728, 1510, 1464,
1412, 1182, 1109, 1063, 1035, 769, 735, 687 cm−1; 1H NMR (DMSO-
d6, 400 MHz) δ 7.42−7.28 (m, 6H), 7.28−6.86 (m, 9H), 5.17−4.85
(m, 5H), 4.76−4.53 (m, 2H), 4.44−4.26 (m, 2H), 4.01 (d, J = 5.9 Hz,
1H), 3.36 (m, 2H), 1.54 (br s, 2H), 1.34 (s, 9H), 1.24, (br s, 1H),
0.94−0.71 (m, 6H); 13C NMR (DMSO-d6, 100 MHz) δ 169.3, 135.8,
128.5, 128.2, 127.9, 127.8, 127.7, 127.2, 127.1, 126.9, 125.9, 66.5, 66.4,
65.9, 58.0, 54.9, 31.3, 28.2, 28.1, 22.2, 13.9 ; HRMS (ESI+) m/z calcd
for C38H50N3O9 [M + H] 692.3547, found 692.3543.
(S)-tert-Butyl 2-(2-(Benzyl((benzyloxy)carbonyl)amino)-3-
((tert-butoxycarbonyl)amino)-5-hydroxypentanamido)-3-phe-
nylpropanoate (3d). The dipeptide 3d was synthesized using general
procedure A, 3d (21 mg, 0.031 mmol, 70%): clear oil; TLC (hexanes/
EtOAc 50:50) Rf = 0.25; [α]22D +0.8 (c = 0.7, CHCl3); IR (thin film)
νmax = 3340 (br), 3004, 2969, 2964, 1732, 1642, 1630, 1485, 1474,
1412, 1171, 1118, 1063, 1037, 781, 755, 691 cm−1;1H NMR (DMSO-
d6, 400 MHz) δ 8.92−8.83 (m, 1H), 7.17 (dd, J = 7.0, 15.7 Hz, 13H),
6.94−6.79 (m, 2H), 6.54−6.43 (m, 1H), 5.11−4.82 (m, 3H), 4.71−
4.55 (m, 2H), 4.42−4.20 (m, 3H), 4.04−3.87 (m, 2H), 3.46−3.37 (m,
1H), 3.30−3.25 (m, 1H), 3.03−2.92 (m, 1H), 2.87−2.80 (m, 1H),
1.60−1.50 (m, 1H), 1.43−1.18 (m, 18H), 1.13−1.02 (m, 1H); 13C
NMR (DMSO-d6, 100 MHz) δ 185.6, 170.4, 170.3, 170.1, 168.3,
156.4, 155.4, 155.3, 137.1, 136.1, 127.9, 127.7, 127.4, 127.1, 126.9,
126.5, 126.2, 125.8, 80.9, 80.8, 77.6, 66.4, 61.6, 57.6, 47.7, 46.9, 37.1,
31.3, 27.6, 22.1, 13.9; HRMS (ESI+) m/z calcd for C38H50N3O8 [M +
H] 676.3598, found 676.3597.
Benzyl (Benzyl)(1-(benzylamino)-3-((tert-butoxycarbonyl)-
amino)-5-hydroxy-1-oxopentan-2-yl)carbamate (3e). The
amide 3e was synthesized using general procedure B, 3e (23 mg,
0.04 mmol, 90%): white foam; TLC (hexanes/EtOAc 50:50) Rf =
0.25; [α]22 +0.4 (c = 0.3, CHCl3); IR (thin film) νmax = 3345 (br),
D
3301, 2952, 2954, 1712, 1638, 1452, 1472, 1411, 1169, 1110, 1052,
1033, 774, 748, 691 cm−1; 1H NMR (DMSO-d6, 400 MHz) δ 8.97 (br
s, 1H), 7.48−6.81 (m, 15H), 6.62−6.52 (m, 1H), 4.98 (m, 1H), 4.91
(m, 1H), 4.68−4.62 (m, 1H), 4.58−4.51 (m, 1H), 4.47−4.34 (m, 2H),
4.20−3.97 (m, 3H), 3.49−3.34 (m, 2H), 1.61−1.46 (m, 2H), 1.34 (s,
9H); 13C NMR (DMSO-d6, 100 MHz) δ 185.6, 168.4, 156.3, 155.4,
139.6, 138.8, 136.4, 128.2, 128.0, 127.8, 127.5, 127.4, 127.0, 126.8,
126.1, 126.0, 77.5, 66.4, 61.7, 58.0, 47.4, 46.9, 42.1, 34.0, 31.2, 28.3,
28.2, 22.1; HRMS (ESI+) m/z calcd for C32H40N3O6 [M + H]
562.2917, found 562.2917.
Benzyl (1-Amino-3-((tert-butoxycarbonyl)amino)-5-hy-
droxy-1-oxopentan-2-yl)(benzyl)carbamate (13a). The amide
13a was synthesized using general procedure B, 13a (21 mg, 0.044
mmol, 100%): white foam. Data for 13a: TLC (hexanes/EtOAc
25:75) Rf = 0.15; [α]22 −0.3 (c 2.1, CHCl3); IR (thin film) νmax
=
D
3340 (br), 3200 (br), 2963, 2932, 1683, 1498, 1454, 1406, 1367, 1255,
1169, 1123, 1054, 1028, 1005, 771, 739, 698 cm−1; 1H NMR (DMSO-
d6, 400 MHz) δ 7.48−7.14 (m, 10H), 7.00 (br s, 1H), 6.62−6.47 (m,
1H), 5.03 (br s, 2H), 4.64 (br s, 2H), 4.48 (d, J = 16.0 Hz, 1H), 4.30
(br s, 1H), 3.98 (br s, 1H), 3.32 (br s, 2H), 1.57−1.43 (m, 2H), 1.37
(s, 9H) ; 13C NMR (DMSO-d6, 100 MHz) δ 171.8, 170.5, 155.3,
128.7, 128.1, 128.0, 127.7, 127.6, 127.1, 126.4, 77.9, 66.6, 60.6, 57.8,
47.6, 35.0, 31.2, 28.4, 28.2, 22.1, 13.9; HRMS (ESI+) m/z calcd for
C25H33N3O6Na [M + Na] 494.2267, found 494.2268.
Benzyl Benzyl(3-((tert-butoxycarbonyl)amino)-5-hydroxy-1-
(octylamino)-1-oxopentan-2-yl)carbamate (3f). The amide 3f
was synthesized using general procedure B, 3f (24 mg, 0.042 mmol,
95%): white foam; TLC (hexanes/EtOAc 50:50) Rf = 0.25; [α]22
D
+0.4 (c = 0.6, CHCl3); IR (thin film) νmax = 3355 (br), 2951, 2944,
1
1632, 1451, 1462, 1112, 1051, 1023, 772, 751, 695 cm−1; H NMR
(DMSO-d6, 400 MHz) δ 8.45−8.34 (m, 1H), 7.53−7.28 (m, 2H), 7.19
(d, J = 7.0 Hz, 5H), 7.06 (d, J = 6.7 Hz, 2H), 6.92 (br s, 1H), 6.56−
6.45 (m, 1H), 4.99 (br s, 1H), 4.93−4.85 (m, 1H), 4.66−4.57 (m,
1H), 4.51 (br s, 1H), 4.39 (d, J = 17.6 Hz, 2H), 4.07−3.95 (m, 1H),
3.39 (d, J = 5.9 Hz, 2H), 2.86 (br s, 2H), 1.56−1.42 (m, 2H), 1.34 (s,
9H), 1.30−1.16 (m, 12H), 0.88−0.83 (m, 3H); 13C NMR (DMSO-d6,
100 MHz) δ 185.7, 168.1, 156.3, 155.4, 139.8, 136.5, 128.1, 127.7,
127.5, 127.2, 127.1, 126.9, 126.4, 126.1, 125.9, 77.6, 66.4, 61.8, 58.1,
47.3, 46.9, 31.3, 28.5, 26.4, 22.1, 13.9; HRMS (ESI+) m/z calcd for
C33H50N3O6 [M + H] 584.3700, found 584.3701.
(S)-tert-Butyl 2-(2-(Benzyl((benzyloxy)carbonyl)amino)-3-
((tert-butoxycarbonyl)amino)-5-hydroxypentanamido)-4-
methylpentanoate (3a). To a stirred solution of a 1:1 mixture of 4a
and 4b (37.0 mg, 0.081 mmol) and 2(1H)-pyridinone (15.4 mg, 0.16
mmol) in toluene (0.4 mL) was added H-L-Leu-OtBu (60.0 mg, 0.413
mmol). The reaction mixture was stirred at 130 °C for 5 h and cooled
to rt. Purification by silica gel column chromatography (hexanes/
EtOAc 65:35 to 50:50) provided 3a (43 mg, 0.067 mmol, 82%) as a
colorless oil: TLC (hexanes/EtOAc 50:50) Rf = 0.25; [α]22D +0.8 (c =
0.5, CHCl3); IR (thin film) νmax = 3340 (br), 2965, 2954, 1732, 1634,
1
1498, 1464, 1410, 1172, 1112, 1057, 1031, 771, 745, 697 cm−1; H
NMR (CDCl3, 500 MHz) δ 7.27−7.33 (m, 10H), 6.67 (s, 1H), 5.32
(s, 1H), 5.19 (m, 2H), 4.48−4.56 (m, 3H), 4.28 (m, 2H), 3.64 (br s,
2H), 1.75 (br s, 2H), 1.45 (s, 9H), 1.29 (m, 3H), 0.89 (br s, 6H); 13C
NMR (CDCl3, 125 MHz) δ 171.5, 157.5, 156.3, 137.4, 135.9, 128.8,
128.6, 128.2, 127.9, 81.9, 79.8, 68.1, 64.7, 58.8, 51.5, 47.1, 41.4, 35.3,
28.4, 27.9, 24.9, 22.7, 22.1; HRMS (ESI+) m/z calcd for C35H52N3O8
[M + H] 642.3754, found 642.3756.
(S)-tert-Butyl 2-((2S,3S)-5-Acetoxy-2-(benzyl((benzyloxy)-
carbonyl)amino)-3-((tert-butoxycarbonyl)amino)-
pentanamido)-4-methylpentanoate (14). To a stirred solution of
the dipeptide 3a (43 mg, 0.067 mmol) in pyridine (0.1 mL) was added
acetic anhydride (0.1 mL). The reaction mixture was stirred for 6 h at
rt, and all volatiles were evaporated in vacuo. Purification by silica gel
column chromatography (hexanes/EtOAc 80:20 to 50:50) gave 14
(44 mg, 0.064 mmol, 95%) as a white foam: TLC (hexanes/EtOAc
Methyl 2-(2-(Benzyl((benzyloxy)carbonyl)amino)-3-((tert-
butoxycarbonyl)amino)-5-hydroxypentanamido)acetate (3c).
The dipeptide 3c was synthesized using general procedure A, 3c (20
mg, 0.036 mmol, 80%): colorless oil; TLC (hexanes/EtOAc 50:50) Rf
= 0.25; [α]22D +0.8 (c = 0.8, CHCl3); 1H NMR (DMSO-d6, 400 MHz)
δ 8.55−8.38 (m, 1H), 7.45−7.01 (m, 10H), 6.52 (m, 1H), 5.05 (br s,
2H), 4.78−4.65 (m, 2H), 4.51−4.48 (m, 1H), 4.34 (s, 1H), 3.99 (d, J
= 8.5 Hz, 1H), 3.70−3.66 (m, 2H), 3.61 (s, 3H), 3.36−3.25 (m, 2H),
1.48 (m, 2H), 1.36 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 169.6,
156.9, 137.7, 135.9, 128.6, 128.3, 127.3, 79.9, 68.3, 60.6, 58.4, 52.4,
48.7, 40.9, 36.5, 28.4; HRMS (ESI+) m/z calcd for C28H38N3O8 [M +
H] 544.2659, found 544.2657.
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Article
50:50) Rf = 0.7; [α]22 +0.8 (c = 0.75, CHCl3); IR (thin film) νmax
=
concentrated in vacuo to provide the free amine as an oil: TLC
(CH2Cl2/MeOH 90:10) Rf = 0.25. To a stirred solution of the free
amine (15.0 mg, 0.028 mmol) in DMF (0.3 mL) were added N,N′-bis-
tert-butoxycarbonyl-S-methylisothiourea (12.2 mg, 0.042 mmol), Et3N
(8.5 mg, 0.084 mmol), and HgCl2 (11.4 mg, 0.042 mmol). The
reaction mixture was stirred at rt for 14 h. Upon completion, the
reaction mixture was diluted with EtOAc and filtered through Celite.
The combined organic phase was washed with brine (2×), dried over
Na2SO4, and concentrated in vacuo. The crude material was purified
by silica gel column chromatography (hexanes/EtOAc 50:50) to give
17 (13.0 mg, 0.018 mmol, 62%): TLC (hexanes/EtOAc 50:50) Rf =
0.25; [α]22D −3.16 (c = 0.3, CHCl3); IR (thin film) νmax = 3284, 2978,
D
3336, 2974, 1739, 1718, 1677, 1516, 1453, 1367, 1246, 1152, 1043,
1
751, 697 cm−1; H NMR (CDCl3, 500 MHz) δ 7.21−7.30 (m, 10H),
6.72 (s, 1H), 5.18 (s, 2H), 4.61 (d, J = 16.5 Hz, 1H), 4.48 (s, 1H), 4.42
(d, J = 11.0 Hz, 1H), 4.31(m, 1H), 4.19 (m, 2H), 4.12 (m, 2H),
2.05(s, 3H), 1.98 (m, 2H), 1.81 (m, 2H), 1.46 (m, 1H), 1.44 (s, 9H),
1.39 (s, 9H), 0.95 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 171.4,
171.1, 168.1, 157.5, 155.5, 137.8, 135.9, 128.5, 128.1, 127.9, 127.7,
127.3, 81.8, 79.5, 67.9, 64.3, 63.8, 61.4, 51.7, 51.4, 51.3, 50.4, 47.4,
42.1, 41.5, 30.8, 29.8, 28.4, 27.9, 24.9, 24.8, 22.8, 22.4, 22.2, 20.9;
HRMS (ESI+) m/z calcd for C37H54N3O9 [M + H] 684.3860, found
684.3863.
1
1792, 1726, 1639, 1614, 1540, 1369, 1264, 1100, 1058, 737 cm−1; H
(S)-1-((1-Methoxy-3-methyl-1-oxobutan-2-yl)carbamoyl)-3-
methyl-1H-imidazol-3-ium Iodide (15). To a stirred suspension of
the HCl·H-L-Val-OH (500 mg, 2.99 mmol) in CH2Cl2 (0.3M) were
added Et3N (0.92 mL, 6.58 mmol) and DMAP (37 mg, 0.3 mmol),
and N,N-carbonyldiimidazole (534 mg, 3.29 mmol) was added at 0 °C.
The reaction mixture was warmed to rt and stirred for 2 h. The
reaction mixture was diluted with CH2Cl2, and the combined organic
phase was washed with H2O and brine and dried over Na2SO4. The
crude material was purified by basic alumina column chromatography
to give (S)-methyl 2-(1H-imidazole-1-carboxamido)-3-methylbuta-
noate as colorless oil (587 mg, 2.61 mmol, 87%): TLC (CHCl3/
MeOH 90:10) Rf = 0.25; 1H NMR (CDCl3, 500 MHz) δ 8.19 (s, 1H),
7.43 (s 1H), 6.75 (d, J = 8.0 Hz, 1H), 4.59 (m, 1H), 3−81 (s, 3H),
2.28 (m, 1H), 1.01 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 172.1,
148.9, 136.1, 130.7, 115.9, 58.8, 52.6, 31.4, 18.9, 17.9; HRMS (ESI+)
m/z calcd for C10H15N3O3 225.1113, found 225.1115.
NMR (CDCl3, 500 MHz) δ 11.34 (s, 1H,), 8.65 (d, J = 7.5 Hz, 1H),
6.86 (d, J = 8.0 Hz, 1H), 5.03 (d, J = 9.0 Hz, 1H), 4.61 (t, J = 7.0 Hz,
1H), 4.42 (m, 3H), 4.16 (m, 1H), 4.12 (m, 1H), 3.73 (s, 3H), 2.18 (s,
1H), 2.08 (m, 2H), 2.07 (s, 3H), 2.05 (m, 2H), 1.98 (m, 2H), 1.43−
1.53 (m, 27H), 0.91 (m, 12H); 13C NMR (CDCl3, 125 MHz) δ 173.3,
171.5, 171.2, 170.1, 157.9, 156.7, 152.7, 83.6, 81.4, 79.9, 61.3, 60.4,
58.1, 57.8, 51.9, 51.5, 51.4, 41.4, 31.6, 29.1, 28.4, 28.1, 27.9, 24.9, 22.9,
21.9, 20.9, 19.2, 17.9; HRMS (ESI+) m/z calcd for C35H62N6O12
758.4426, found 758.4428.
(S)-tert-Butyl 2-((tert-Butoxycarbonyl)imino)-4-((4R,8S,11S)-
11-isobutyl-4-isopropyl-14,14-dimethyl-3,6,9,12-tetraoxo-
2 , 1 3 - d i o x a - 5 , 7 , 1 0 - t r i a z a p e n t a d e c a n - 8 - y l ) -
tetrahydropyrimidine-1(2H)-carboxylate (19). To a stirred
solution of 17 (12.5 mg, 0.016 mmol) in MeOH (0.5 mL) was
added [tBu2Sn(OH)Cl]2 (0.0008 mmol). After 12 h at rt, all volatiles
were evaporated in vacuo. The crude product was passed through a
silica gel pad (hexanes/EtOAc 50:50) to provide the free alcohol 18
(10.0 mg, 0.014 mmol, 85%) as a white foam: TLC (hexanes/EtOAc
To a stirred solution of (S)-methyl 2-(1H-imidazole-1-carboxami-
do)-3-methylbutanoate (587 mg, 2.61 mmol) in dry CH3CN (13 mL)
were added Et3N (0.40 mL, 2.88 mmol) and MeI (0.18 mL, 2.88
mmol). The reaction mixture was stirred at rt for 18 h. All volatiles
were evaporated in vacuo. The resulting light yellow solid 15 (959 mg)
was used in the following reactions without further purification.
(2R,6S,7S)-Methyl 7-(2-Acetoxyethyl)-6-(((S)-1-tert-butoxy-4-
methyl-1-oxopentan-2-yl)carbamoyl)-2-isopropyl-11,11-di-
methyl-4,9-dioxo-10-oxa-3,5,8-triazadodecan-1-oate (16). To a
stirred solution of 14 (100.0 mg, 0.15 mmol) in MeOH (30 mL) were
added AcOH (20 μL) and Pd(OH)2/C (25 wt % 10 mg) under N2.
H2 gas was introduced via a double-folded balloon, and the reaction
mixture was stirred for 6 h under H2. Upon completion, the solution
was filtered through Celite. The crude mixture was dissolved in EtOAc
and washed with aq satd NaHCO3. The combined organic extracts
were dried over Na2SO4 and concentrated in vacuo to yield the desired
primary amine. To a stirred solution of the primary amine in CH2Cl2
(0.5 mL) was added a solution of imidazolium salt 15 (2.5 equiv) in
CH3CN (0.5 mL) at rt. After 12 h, the reaction mixture was diluted
with EtOAc, washed with NaHCO3 (aq) and brine, and dried over
Na2SO4. The crude material was purified by silica gel column
chromatography to give 16 as white foam (79.0 mg, 0.13 mmol, 87%):
TLC (hexanes/EtOAc 50:50) Rf = 0.25; [α]22D −2.5 (c = 0.5, CHCl3);
IR (thin film) νmax = 3356, 2983, 1741, 1684, 1631, 1572, 1275, 1260,
50:50) Rf = 0.20; [α]22D −2.13 (c = 0.5, CHCl3); IR (thin film) νmax
=
3273 (br), 2929, 2927, 1732, 1645, 1556, 1430, 1369, 1264, 1210,
1155, 1050, 1075, 1020, 764, 669 cm−1; 1H NMR (CDCl3, 500 MHz)
δ 11.39 (s, 1H), 8.82 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 9.0 Hz, 1H), 6.25
(s, 1H), 5.14 (d, J = 9.0 Hz, 1H), 4.62 (m, 1H), 4.59 (m, 1H), 4.59
(m, 2H), 4.39 (m, 1H), 3.73 (s, 3H), 3.68 (m, 1H), 3.55 (t, 1H), 2.16
(m, 1H), 1.95 (m, 1H), 1.74 (s, 9H), 1.51 (s, 9H), 1.47 (s, 9H), 0.96
(m, 12H); 13C NMR (CDCl3, 100 MHz) δ 173.4, 172.0, 170.1, 162.6,
157.5, 156.6, 152.6, 83.6, 82.0, 79.6, 58.4, 57.9, 56.4, 52.1, 51.3, 51.1,
41.6, 34.9, 31.3, 29.7, 28.2, 28.1, 27.9, 24.8, 23.0, 21.6, 19.1, 17.9;
HRMS (ESI+) m/z calcd for C33H61N6O11 [M + H] 717.4398, found
717.4399. The alcohol 18 (10.0 mg, 0.014 mmol) was dissolved in
THF (0.3 mL), and PPh3 (36.7 mg, 0.14 mmol) and DIAD (28.3 mg,
0.14 mmol) were added. The reaction mixture was stirred at rt for 18
h. Upon completion, the crude mixture was concentrated in vacuo, and
the crude product was purified by silica gel chromatography (hexanes/
EtOAc 60:40) to yield 19 (7.0 mg, 0.011 mmol, 76%) as a colorless
oil: TLC (hexanes/EtOAc 50:50) Rf = 0.30; [α]22 −2.15 (c = 0.1,
D
CHCl3); IR (thin film) νmax = 3276, 2933, 1728, 1637, 1617, 1544,
1
1372, 1276, 1105, 1063, 739 cm−1; H NMR (CD3OD, 500 MHz) δ
4.63 (m, 1H), 4.55 (m, 2H), 4.33 (m, 1H), 4.21 (d, J = 5.0 Hz, 1H),
3.72 (s, 3H), 3.63 (m, 1H), 3.59 (m, 1H), 2.13 (m, 1H), 1.91 (m, 1H),
1.62 (m, 2H), 1.59 (m, 1H), 1.56 (s, 9H), 1.46 (s, 18H), 1.31 (m,
2H), 0.87−0.98 (m, 12H); 13C NMR (CD3OD, 100 MHz) δ 174.7,
173.2, 172.1, 164.1, 160.1, 158.3, 153.9, 84.8, 82.8, 80.6, 59.8, 58.9,
57.3, 52.9, 52.5, 41.5, 36.4, 32.2, 28.6, 28.3, 28.2, 25.9; HRMS (ESI+)
m/z calcd for C33H58N6O10 [M + H] 699.4293, found 699.4291.
1
764 cm−1; H NMR (CDCl3, 500 MHz) δ 6.82 (d, J = 8.0 Hz, 1H),
6.36 (s, 1H), 5.13 (d, J = 7.6 Hz, 1H), 5.01 (d, J = 8.0 Hz, 1H), 4.51
(m, 1H), 4.42 (m, 1H), 4.38 (m, 1H), 4.38 (m, 1H), 4.29 (m, 1H),
3.74 (s, 3H), 2.09 (m, 1H), 2.06 (s, 3H), 1.93 (d, J = 5.5 Hz, 1H), (m,
2H), 1.56−1.58 (m, 2H), 1.46 (s, 9H), 1.42 (s, 9H), 0.94 (m, 12H);
13C NMR (CDCl3, 125 MHz) δ 173.3, 171.8, 171.5, 170.2, 157.7, 81.8,
80.1, 61.5, 58.4, 57.3, 52.1, 51.5, 50.1, 41.6, 41.2, 31.4, 28.3, 28.2, 27.9,
24.9, 24.8, 22.8, 22.7, 22.1, 21.1, 19.1, 17.9; HRMS (ESI+) m/z calcd
for C29H52N4O10 616.3683, found 616.3686.
ASSOCIATED CONTENT
■
S
* Supporting Information
(8S,9S,13R)-Methyl 8-(2-Acetoxyethyl)-9-(((S)-1-tert-butoxy-
4-methyl-1-oxopentan-2-yl)carbamoyl)-6-((tert-
butoxycarbonyl)amino)-13-isopropyl-2,2-dimethyl-4,11-
dioxo-3-oxa-5,7,10,12-tetraazatetradec-5-en-14-oate (17). To a
stirred solution of 16 (20.0 mg, 0.033 mmol) was added cooled TFA
(50% in CH2Cl2, 1 mL). The reaction mixture was stirred at 0 °C for
30 min, warmed to rt, diluted with CH2Cl2 (10 mL), and poured into
NaHCO3 solution. The aqueous layer was extracted with CHCl3 (3×).
The combined organic extracts were dried over Na2SO4 and
1H and 13C NMR spectra and NOESY data. This material is
available free of charge via the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mkurosu@uthsc.edu.
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Article
(15) Herranz, R.; Suarez-Gea, M. L.; Vinuesa, S.; Garcia-Lopez, M. T.
J. Org. Chem. 1993, 58, 5186.
Notes
The authors declare no competing financial interest.
(16) Merino, P.; Marques
Tetrahedron 2009, 65, 1219.
́ ́
-Lopez, E.; Tejero, T.; Herrera, R. P.
ACKNOWLEDGMENTS
(17) (a) Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E.
N. Nature 2009, 461, 968. (b) Vachal, P.; Jacobsen, E. N. Org. Lett.
2000, 2, 867. (c) Martens, J. Chem. Cat. Chem. 2010, 2, 379 and
references cited therein..
(18) The NOESY correlations of one of most lower energy
conformers of 4b are illustrated in the Supporting Information.
(19) Kim, E. S.; Lee, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett.
2010, 51, 1589.
■
The National Institutes of Health is greatly acknowledged for
financial support of this work (AI084411-02). We also thank
the University of Tennessee for generous financial support.
NMR data were obtained on instruments supported by the
NIH Shared Instrumentation Grant.
(20) MM2 calculations were performed using SPARTAN on a
Silicon Graphics O2 workstation.
(21) See the Supporting Information.
(22) (a) Batey, R. A.; Santhakumar, V.; Yoshina-Ishii, C.; Taylor, S.
D. Tetrahedron Lett. 1998, 39, 6267. (b) Maresca, K. P.; Hillier, S. M.;
Femia, F. J.; Keith, D.; Barone, C.; Joyal, J. L; Zimmerman, C. N.;
Kozikowski, A. P.; Barrett, J. A.; Eckelman, W. C.; Babich, J. W. J. Med.
Chem. 2009, 52, 347.
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