Diversity-Oriented Synthesis of Diol-Based Peptidomimetics as Potential HIV Protease Inhibitors and Antitumor Agents

Article abstract of DOI:10.1002/cbic.201800247

Peptidomimetic HIV protease inhibitors are an important class of drugs used in the treatment of AIDS. The synthesis of a new type of diol-based peptidomimetics is described. Our route is flexible, uses d-glucal as an inexpensive starting material, and makes minimal use of protection/deprotection cycles. Binding affinities from molecular docking simulations suggest that these compounds are potential inhibitors of HIV protease. Moreover, the antiproliferative activities of compounds 33 a, 35 a, and 35 b on HT-29, M21, and MCF7 cancer cell lines are in the low micromolar range. The results provide a platform that could facilitate the development of medically relevant asymmetrical diol-based peptidomimetics.

Full text of DOI:10.1002/cbic.201800247

Accepted Article
Title: Diversity-Oriented Synthesis of Diol-Based Peptidomimetics as
Potential HIV Protease Inhibitors and Antitumor Agents
Authors: Paresh M. Vadhadiya, Marc-Alexandre Jean, Chahrazed
Bouzriba, Thomas Tremblay, Patrick Lagüe, Sébastien Fortin,
John Boukouvalas, and Denis Giguere
This manuscript has been accepted after peer review and appears as an
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemBioChem 10.1002/cbic.201800247
Link to VoR: http://dx.doi.org/10.1002/cbic.201800247
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10.1002/cbic.201800247
ChemBioChem
Diversity-Oriented Synthesis of Diol-Based Peptidomimetics as Potential HIV
Protease Inhibitors and Antitumor Agents
Paresh M. Vadhadiya,[a] Marc-Alexandre Jean,[a] Chahrazed Bouzriba,[b, c] Thomas Tremblay,[a] Patrick Lagüe,[d]
Sébastien Fortin,[b, c] John Boukouvalas,[a] and Denis Giguère∗[a]
[a]Département de Chimie, 1045 Avenue de la Médecine, Université Laval, Quebec City, Qc, Canada G1V 0A6, RQRM
[b]CHU de Québec-Université Laval Research Center, Oncology Division, Hôpital Saint-François d’Assise, 10 rue de
l’Espinay, Quebec City, Qc, G1L 3L5, Canada
[c]Faculté de pharmacie, Université Laval, Quebec City, QC, Canada G1V 0A6
[d]Départment de biochimie, de microbiologie et de bio-informatique, 1045, Avenue de la Médecine, Université Laval,
Quebec City, Qc, Canada G1V 0A6
GRAPHICAL ABSTRACT
Sweet peptidomimetics: We prepare a new type of diol-based peptidomimetics starting from
D-hexopyranose.
Molecular docking simulations suggest that these compounds are potential inhibitors for the HIV protease.
Antiproliferative activities exhihibited significant TGI and LC50 showing potent antitumor potencies.
ABSTRACT
Peptidomimetic HIV protease inhibitors are an important class of drugs used in the treatment of AIDS. The synthesis
of a new type of diol-based peptidomimetics is described. Our route is flexible, utilises D-hexose as inexpensive
starting material and makes minimal use of protection/deprotection cycles. Binding affinities from molecular
docking simulations suggest that these compounds are potential inhibitors for the HIV protease. Moreover, the
antiproliferative activities of compounds 33a, 35a and 35b on HT-29, M21 and MCF7 cancer cell lines are in the
low micromolar range. The results provide a platform that could facilitate the development of medically relevant
nonsymmetrical diol-based peptidomimetics.
Keywords:Diversity-oriented synthesis; Protease inhibitors; Carbohydrate approach; Conjugate addition; Peptidomimetics;
cancer therapeutics
∗ Corresponding author. Tel.: +1-418-656-2131; fax: +1-418-656-7916; e-mail: denis.giguere@chm.ulaval.ca
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1. INTRODUCTION
It is well known that the human immunodeficiency virus (HIV) is the causative agent for acquired
immunodeficiency syndrome (AIDS). [1] In the last few decades, advances in antiretroviral therapies have led to
various approved protease inhibitors (PIs) for the treatment of HIV/AIDS. Several PIs have been used successfully
in combination therapy with reverse transcriptase inhibitors and other antiviral drugs, and are among the top 200
drugs sold in the United States. As a consequence, HIV/AIDS can now be perceived as a manageable chronic
infection. Despite major advances in antiretroviral therapies, current drugs have several drawbacks, such as i) high
daily pill burden, ii) poor metabolic profiles, iii) decrease in efficacy through drug interactions, and iv) a high
resistance barrier.[2] The emergence of drug resistance has become a serious problem leading to ineffective
therapies.[3] Because of continuing resistance, there is a pressing need for new PIs with improved properties and
activities.[4]
HIV protease cleaves viral proteins in order to generate mature infectious virions.[5] It is composed of two
subunits where the catalytic active site of the enzyme is the dimer interface comprised of two aspartic acid residues
(Asp25 and Asp25’). Also, the enzyme’s active site possesses distinct subsites S1, S1’, S2, S2’, S3 and S3’.
Different subsites can accommodate hydrophobic or polar side chains.[6] When the PI binds to the active site, it
prevents cleavage of nascent viral proteins, thereby halting viral replication.[7]
First-generation PIs were approved by the Food and Drugs Administration (FDA) in the mid-90’s. Also, this era
marked the beginning of combination therapy for the treatment of HIV/AIDS. Careful inspection of the first-
generation inhibitors 1−5 reveals hydroxyethylene and hydroxyethylamine central cores (Figure 1a). The rapid
emergence of resistance led to the development of second-generation PIs (Figure 1b). Inhibitors 6−8 were
developed not only to overcome drug resistance but also to resolve other challenging issues such as high metabolic
clearance, low half-life and poor oral bioavailability. The pharmaceutical industry reduced substantially their
investment in the development of PIs, because new therapies must demonstrate superiority over existing treatment.
Nevertheless, recent progress in the development of new classes of inhibitors[8] has led to candidates showing
clinical promise.[9] Some diol-based inhibitors have also emerged in recent years (Figure 1c). The diol moiety of
inhibitors 9−11[10] is believed to interact with the two aspartate residues of the binding site. Nonetheless, the
development of new PIs is still ongoing[11] and finding novel PIs with broad-spectrum activities against multidrug-
resistant variants is most certainly the biggest challenge to overcome.[12]
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Figure 1. HIV-1 protease inhibitors: a) First-generation FDA-approved inhibitors 1−5; b) Second-generation FDA-
approved inhibitors 6−8; c) Diol-based inhibitors 9−11
Typically, D
-Mannitol[13] and L-mannonic-γ-lactone[10c, 14] have been used as starting points for the preparation
of PIs. However, this approach generally leads to C2-symmetrical compounds. Since nonsymmetrical inhibitors
have superior activities,[15] new routes from simple chiral building blocks are clearly needed. To date, there is only
one report describing the use of methyl β-D
-mannopyranoside for the synthesis of PIs.[16] Similarly, peptidic diol-
based PIs have been successfully designed for the purpose of probing favorable interactions with the HIV protease
backbone.[10b, 17]
Besides HIV/AIDS, there has been growing interest in repurposing PIs for the treatment of cancer.[18] Although
the mechanism of antitumor action of such drugs is under debate,[19] early clinical trials employing a PI alone or in
combination with radiotherapy[20] have shown promise in treating patients with various types of cancer, including
adenocarcinoma and non-small cell lung cancer (NSCLC).[21]
Herein, we describe the synthesis of novel nonsymmetrical diol-based peptidomimetics of general structure 12
(Scheme 1), which incorporate prominent structural features of the HIV protease inhibitors shown in Figure 1.
From a retrosynthetic perspective, azides 13 were viewed as key intermediates, accessible through aminolysis of
lactones 14 (Scheme 1). The desired benzyl substituent in 14 would be installed in stereodivergent fashion by
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conjugate addition onto α,β−unsaturated lactone 15, derived from inexpensive
D
-glucal 16. Our approach offers
considerable flexibility as it enables parallel assemblage of small molecule libraries with distinct molecular
architectures from chiral and achiral fragments.
Scheme 1. Retrosynthesis of nonsymmetrical diols 12
2. RESULTS AND DISCUSSION
The synthesis began from
D
-glucal 16 following a known 3-step sequence (Scheme 2).[22] Selective
tosylation of the primary alcohol in 16, followed by acetylation of the sec-hydroxyl groups provided intermediate
17 in 70% yield over 2 steps. Next, nucleophilic displacement of the tosylate with azide yielded glycal 18 in high
yield. Treatment of 18 with boron trifluoride and 3-chloroperbenzoic acid (m-CPBA) at −20 °C for 0.5 h led directly
to α,β-unsaturated γ-lactone 19.[23] Attempts to hydrolyze the acetyl ester group in 19 under standard basic
conditions resulted in complete decomposition. Ultimately, the desired hydrolysis to alcohol 20 was successfully
accomplished using Amano Lipase PS from Burkholderia cepacia.[24] Exposure of 20 to benzyl bromide and silver
oxide afforded the rather unstable ether 15 in 59% yield over 2 steps.[25] Conjugate addition of in situ generated
benzyl cuprate onto 15 proceeded with modest diastereoselectivity to afford lactone 14 as an inseparable ~2:1
mixture of isomers, whose respective identities were deduced after ring opening (vide infra).[26] The major isomer
of 14 (not shown) arose by addition trans to the adjacent benyloxy substituent.
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Scheme 2. Synthesis of lactone 14
At this point the isomer mixture 14 was subjected to heating with amines 21−23 in MeOH to generate
gluconamide derivatives 24−26 (Scheme 3).[27] The three amines used, namely, butylamine 21, (S)-tetrahydrofuran-
3-amine 22 and (1S,2R)-cis-1-amino-2-indanol 23, were selected for the purpose of exploring interactions of amides
24−26 with the enzyme backbone, targeting hydrophobic S2/S2’ pockets. Importantly, separation of the resulting
diastereomeric mixtures of amides (24−26) could be readily achieved by flash column chromatography, allowing
both the 3,4-syn (24a−26a, major) and 3,4-anti isomers (24b−26b, minor) to be obtained in pure form.
Scheme 3. Aminolysis of lactone 14
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With the individual diastereoisomers of 24−26 in hand, their transformation to sulfonamides was addressed
(Table 1). First, TiCl4 mediated cleavage of the O-benzyl group[28] provided the corresponding diols 27−29 in
81−89% yield. Compounds 27−29 were subjected to a hydrogen atmosphere with a catalytic amount of palladium
allowing formation of the amine intermediates. The latter were transformed in situ to sulfonamides 30−32 upon
treatment with p-toluenesulfonyl chloride and triethylamine.[29] It is important to note that a sulfonamide residue is
encountered in several known PIs.[8]
Table 1. Synthesis of sulfonamides 30−32
Sulfonamide
(Yield over 2 steps, %)[a]
Starting
material
Entry
1
Diol (Yield, %)[a]
OH
O
H
S
N
N
O
24a
24b
25a
25b
26a
26b
H
OH Bn
O
30a
(89)
(85)
(84)
(88)
(81)
(84)
(70)
(66)
(69)
(68)
2
3
4
5
6
(67)
(65)
[a]Yields refer to isolated products after flash column chromatography.
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The final step of the synthesis of diol-based peptidomimetics is shown in Table 2. Alkylation of sulfonamides
30−32 was carried out using isobutyl bromide under basic conditions at 70 °C. Products 33−35 were isolated in
yields ranging between 89−96%. Installation of a small alkyl group, such as isobutyl, could improve interactions
with the protease backbone. In fact, the structures of our target compounds specifically incorporate features found
in darunavir 6 (Figure 1).
Table 2. Preaparation of peptidomimetics 33−35
Starting
material
Yield
(%)[a]
Entry
1
Product
96
92
89
89
90
93
30a
30b
31a
31b
32a
32b
2
3
4
5
6
[a]Yields refer to isolated products after flash column chromatography.
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The stereochemistries of our peptidomimetics were determined by NMR, based on the crystal structure of diol
33b (Figure 2).[30] This compound was prepared from minor isomer 24b.
OH
O
H
S
N
N
O
OH Bn
O
33b
Figure 2. X-ray derived ORTEP of diol 33b
3. MOLECULAR DOCKING SIMULATIONS
Compounds 33−35 were subjected to molecular docking simulations using Autodock Vina to evaluate their
binding affinities for the HIV protease binding pocket. Such simulations give insight into the binding pattern of the
compounds. The observed interactions between the compounds and the HIV protease and their predicted binding
affinities are depicted in Figure 3. For the sake of comparison, we also examined the docking of Darunavir, found
to have a predicted affinity of -9.5 kcal/mol, with an RMSD of 0.61 Å between the docked and the crystallographic
structure. Overall, peptidomimetics 33−35 docked well into the protease binding pocket, displaying a mix of
hydrophobic interactions with the non-polar residues and between 2 to 5 hydrogen bonds with polar residues.
Although the number of hydrogen bonds between the compounds and the receptor are fewer than for Darunavir, the
non-polar interactions are in general more present. Interestingly, all compounds have at least one hydroxyl group
hydrogen-bonded to at least one of the two catalytic aspartic acids. Compounds 33a and 33b presented the lowest
binding affinities, with predicted values of -9.0 kcal/mol for both compounds. These values are lower than that of
darunavir, suggesting that compounds 33a-b would be probably weaker inhibitors of HIV protease. Because 33a-b
are the most hydrophobic compounds of the set, their docking involved the largest hydrophobic interactions with
the receptor. In contrast, compounds 34a-b and 35a-b had predicted affinities equal or better than Darunavir (Figure
3), with the best affinity predicted for 35a. These findings indicate that 34a-b and 35a-b have the potential for
similar or better inhibitory activities than Darunavir. In agreement with their more hydrophilic character,
compounds 34a and 34b presented the fewest non-polar interactions with the binding pocket residues. Nevertheless,
the pair 35a and 35b presented a good balance between hydrophilic and hydrophobic interactions, leading to the
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best binding affinities. Interestingly, the sulfamoyl moiety of three compounds were involved in hydrogen bonding
with one residue of the binding pocket: the side chain of Asp25A for compound 33b, the backbone amide of Asp29A
for compound 34b and the side chain of Arg8B for compound 35a. This crucial interaction is exemplified with the
binding pose of compound 35a as shown in Figure 4. Finally, while diastereoisomers 33a and 33b display similar
binding affinities, the 3,4-syn-4,5-anti compounds 34a and 35a had slightly better predicted binding affinities than
their respective 3,4-anti-4,5-anti stereoisomers 34b and 35b.
Figure 3. 2D diagram of the interactions between compounds 33−35 and the HIV protease binding pocket
residues from the docking results, as generated by PoseView.[40, 41] Dashed lines are for hydrogen bonds and green
lines are for hydrophobic interactions. The respective predicted binding affinities are also indicated.
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Figure 4. Binding pose of compound 35a. The HIV protease is represented in transparent light gray cartoon,
compound 35a in bold green sticks, the hydrogen-bonding residues in light gray small sticks and the hydrophobic
residues in dark gray small sticks and semi-transparent surfaces. Hydrogen bonds are represented by yellow dashes.
4. ANTIPROLIFERATIVE ACTIVITY
Compounds 29a, 33a, 34ab, and 35ab were evaluated for their antiproliferative activity on human HT-29
colon adenocarcinoma, M21 skin melanoma, and MCF7 breast carcinoma cell lines according to the NCI/NIH
Developmental Therapeutics Program.[31] These particular cell lines were chosen to reflect the types of cancer found
in preclinical[32] and clinical trials[33] with existing HIV PIs. The results are summarized in Table 3; expressed as
the concentration of drug inhibiting cell growth by 50% (IC50), concentration of drug inhibiting totally cell
proliferation (TGI), and concentration of drug killing 50% of the cell population (LC50). It is seen from the results
that the three cancer cell lines displayed similar sensitivity toward the new compounds assessed. Compound 34a
exhibited very weak IC50 ranging from 83 to > 100 µM and compounds 29a and 34b showed no antiproliferative
activity. These results suggest that the tetrahydrofuranyl group is detrimental while the sulfonamide moiety is
required for effective antiproliferative activity. Compounds 33a, 35a and 35b exhibited IC50 ranging from 12 to 36
µM. Moreover, compound 35b bearing an amido indanol group was the most active, with IC50 values of 12 µM, 14
µM and 17 µM against HT-29, M21 and MCF7, respectively. Finally, 35b exhibited TGI ranging from 23 to 29 µM
and LC50 ranging from 32 to 41 µM showing that it is a potent cytotoxic agent.
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Table 3. Antiproliferative activity (IC50), total growth inhibition (TGI) and median lethal concentration (LC50) of
diol-based peptidomimetics 29a, 33a, 34ab, and 35ab on human HT-29 colon adenocarcinoma, M21 skin
melanoma and MCF7 breast carcinoma cancer cells.
IC50 (µM)[a]
M21
> 100
30
TGI (µM)[b]
M21
LC50 (µM)[c]
M21
Compounds
HT-29
> 100
26
MCF7
n.e.d
36
HT-29
> 100
> 100
> 100
> 100
42
MCF7
n.e
HT-29
> 100
> 100
> 100
> 100
> 50
MCF7
n.e
> 100
> 100
> 100
> 100
35
> 100
> 100
> 100
> 100
43
29a
33a
> 100
> 100
> 100
> 50
29
> 100
> 100
> 100
> 50
41
85
83
> 100
> 100
31
34a
34b
35ae
> 100
21
12
> 100
18
14
17
2.2
23
> 10
26
> 10
36
> 10
32
> 10
35b
Topotecan
0.34
0.0037
2.0
> 10
> 0.03
> 10
> 0.03
Paclitaxel
0.0046
0.0027
> 0.03
> 0.03
> 0.03
> 0.03
[a]IC50 is expressed as the concentration of drug inhibiting cell proliferation by 50% after 48 h of treatment.
[b]TGI is expressed as the concentration of drug totally inhibiting cell proliferation after 48 h of treatment.
[c]LC50 is expressed as the concentration of drug killing 50% of the cell population after 48 h of treatment.
[d]n.e.: not evaluated.
[e]The maximum concentration assessed was 50 µM for 35a.
5. CONCLUSION
We have described the synthesis of a series of novel, non-symmetrical diol-based peptidomimetics using a
carbohydrate approach. The synthetic route utilizes conjugate addition as a key step, enabling access to a wide range
of analogues in few chemical steps from inexpensive D-glucal. Final products were subjected to molecular docking
simulations to evaluate their binding affinities for the HIV protease binding pocket. Peptidomimetics 33−35 docked
well into the protease binding pocket, displaying a mix of hydrophobic interactions with the non-polar residues and
between two and five hydrogen bonds with polar residues. It was also shown that the antiproliferative activities of
compounds 33a, 35a and 35b are in the low micromolar range. In addition, compound 35b exhibited significant
TGI and LC50 showing that is a potent antitumor agent. Collectively, the results provide a platform for further
chemical and pharmacological exploration of this new class of diol peptidomimetics.
6. EXPERIMENTAL SECTION
All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions,
unless otherwise noted. Methylene chloride (CH2Cl2) was distilled from CaH2 and N,N′-dimethylformamide (DMF)
from ninhydrin and kept over molecular sieves. Tetrahydrofuran (THF) was distilled from Na/benzophenone
immediately before use. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous
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materials, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without
further purification, unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried
out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and charring with a solution
of 3 grams of PhOH and 5 ml of H2SO4 in EtOH, followed by heating with a heatgun. SiliaFlash® P60 40-63 µm
(230−400 mesh) was used for flash column chromatography. NMR spectra were recorded with an Agilent DD2 500
MHz spectrometer and calibrated using residual undeuterated solvent (CDCl3: 1H δ = 7.26 ppm, 13C δ = 77.16 ppm;
1
1
(CD3)2CO: H δ = 2.05 ppm, 13C δ = 29.84 ppm; CD3OD: H δ = 3.31 ppm, 13C δ = 49.00 ppm) as an internal
reference. Coupling constants (J) are reported in Hertz (Hz), and the following abbreviations were used to designate
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Infrared spectra were
recorded using a Thermo Scientific Nicolet 380 FT-IR spectrometer. The absorptions are given in wavenumbers
(cm−1). High-resolution mass spectra (HRMS) were measured with an Agilent 6210 LC Time of Flight mass
n
+
spectrometer in electrospray mode. Either protonated molecular ions [M + nH] , sodium adducts [M + Na]+ or
ammonium adducts [M + NH4]+ were used for empirical formula confirmation. Optical rotations were measured with a
JASCO DIP-360 digital polarimeter, and are reported in units of 10−1 (deg cm2 g−1).
6.1. General procedure I
− lactone opening with various amines
To a solution of lactone 14 (1.0 equiv) in dry MeOH was added amine 21−23 (2.0 equiv). The mixture was
stirred under refluxed for 16 h. After this time, the mixture was concentrated under reduced pressure and purified
by flash column chromatography (hexanes / EtOAc) affording products 24−26.
6.2. General procedure II
− benzyl ether deprotection
To a solution of benzyl ether 24−26 (1.0 equiv) in CH2Cl2 at 0 °C was added TiCl4 (1.0 M in CH2Cl2, 5.0 equiv)
and the mixture was stirred at 0 °C for 3 h. The mixture was poured in cold water and extracted with ethyl acetate
(3 × 10 mL). The combined organic phase were dried over MgSO4, filtered and concentrated under reduced pressure.
Flash chromatography (hexanes / EtOAc) afforded products 27−29.
6.3. General procedure III
− azide functionalization
To a solution of azide 27−29 (1.0 equiv) in MeOH was added Pd/C (10 mol%). The mixture was stirred under a
balloon pressure of hydrogen for 8 h. After this time, the mixture was filtered through a pad of celite and
concentrated under reduced pressure. The amine thus generated was used for the next step without further
purification. To a solution of the resulting amine in CH2Cl2 at 0 °C was added Et3N (1.5 equiv) and p-toluenesulfonyl
chloride (1.2 equiv). The mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure
and purified by flash column chromatography (hexanes / EtOAc) affording products 30−32.
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6.4. General procedure IV
− sulfonamide alkylation
To a solution of the sulfonamide 30−32 (1.0 equiv) in acetonitrile was added K2CO3 (2.0 equiv) and isobutyl
bromide (2.0 equiv). The mixture was heated at 65 °C for 16 h. After this time, the mixture was filtered through
celite and concentrated under reduced pressure. The crude product was purified by flash column chromatography
(hexanes/EtOAc) yielding products 33−35.
6.5. 3,4-di-O-acetyl-6-O-(4-toluenesulfonyl)-
D-glucal (17)
To a solution of D-glucal 16 (1.6 g, 11.0 mmol) in anhydrous pyridine (30 mL) at 0 °C was added p-
toluenesulfonyl chloride (2.3 g, 12.0 mmol, 1.1 equiv). The mixture was stirred vigorously at rt for 3 h, then acetic
anhydride (4.1 mL, 43.8 mmol, 4.0 equiv) was added and the mixture was stirred at rt for 16 h. The mixture was
concentrated under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic solution was washed with
sat aq CuSO4 (3 × 30 mL), water (5 × 30 mL), and brine (1 × 30 mL). The organic solution was dried over MgSO4,
filtered and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography
on silica gel (hexanes / EtOAc, 7 : 3) to give compound 17 (3.2 g, 70%) as colorless oil. The physical and
spectroscopic properties for compound 17 match those reported in the literature[34] : IR (NaCl film)
ν 2958, 2929,
1710, 1653, 1364, 1229, 1177, 1044, 816 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 2H), 7.36 (d, J =
8.0 Hz, 2H), 6.35 (dd, J = 6.1, 1.4 Hz, 1H), 5.30 – 5.23 (m, 1H), 5.17 – 5.10 (m, 1H), 4.82 (dd, J = 6.2, 3.4 Hz, 1H),
4.31 – 4.16 (m, 3H), 2.46 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 169.6, 145.4,
145.3, 132.7, 130.0, 128.2, 99.1, 73.4, 67.1, 66.7, 66.5, 21.8, 21.1, 20.9; HRMS (ESI-TOF) m/z: [M + NH4]+ Calcd
for C17H24NO8S 402.1217; Found 402.1224.
6.6. 3,4-di-O-acetyl-6-deoxy-6-azido-D-glucal (18)
To a solution of compound 17 (6.6 g, 17.2 mmol, 1.0 equiv) in DMF (70 mL) at rt was added sodium azide (4.5
g, 68.7 mmol, 4 equiv). The solution was stirred at 80 °C for 3 h, then cooled to rt and diluted with ethyl acetate
(200 mL). The organic solution was washed with water (3 × 100 mL), dried over MgSO4, filtered and concentrated
under reduced pressure. Flash column chromatography on silica gel (hexanes / EtOAc, 8 : 2) afforded compound
18 (3.7 g, 85%) as a colorless oil. The physical and spectroscopic properties for compound 18 match those reported
in the literature[35] : IR (NaCl film)
ν
2963, 2944, 2105, 1750, 1652, 1558, 1373, 1225, 1046 cm-1; 1H NMR (400
MHz, CDCl3) δ 6.41 (dd, J = 6.2, 1.4 Hz, 1H), 5.23 (dddd, J = 5.5, 3.4, 1.4, 0.8 Hz, 1H), 5.09 (ddd, J = 7.2, 5.4, 0.5
Hz, 1H), 4.80 (ddd, J = 6.1, 3.4, 0.5 Hz, 1H), 4.14 (tdd, J = 7.1, 3.8, 0.9 Hz, 1H), 3.49 (dd, J = 13.3, 7.0 Hz, 1H),
3.36 (dd, J = 13.3, 3.8 Hz, 1H), 2.01 (s, 3H), 1.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 169.4, 145.3, 99.0,
74.7, 67.9, 66.8, 50.0, 20.9, 20.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C10H13N3NaO5 278.0747; Found
278.0735.
6.7. (5S, 6R)-6-(azidomethyl)-5-(acetoxy)-5,6-dihydro-2H-pyran-2-one (19)
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ChemBioChem
To a solution of 80% anhydrous MCPBA (3.8 g, 17.5 mmol, 1.2 equiv) in dry CH2Cl2 (50 mL) at −20 °C was
.
added a cooled solution (−20 °C) of compound 18 (3.7 g, 14.6 mmol, 1.0 equiv) in CH2Cl2 (50 mL). Then, BF3 OEt2
(0.9 mL, 7.29 mmol, 0.5 equiv) was added dropwise at −20 °C and the mixture was stirred for 15 min. The solution
was poured into a sat aq NaHCO3 solution (50 ml) containing 10-20 mg of Na2S2O3. The mixture was extracted
with CH2Cl2 (3 × 50 ml) and the combined organic solutions were concentrated under reduced pressure. The crude
mixture was purified by flash column chromatography on silica gel (hexanes / EtOAc, 7 : 3) affording 19 (2.4 g,
77%) as a white amorphous solid: [α]D = +102.3 (c 1.1, CHCl3); IR (NaCl film)
ν 2948, 2123, 1748, 1733, 1269,
1229, 1058, 818 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.79 (dd, J = 10.0, 2.8 Hz, 1H), 6.11 (dd, J = 10.0, 1.8 Hz,
1H), 5.57 (ddd, J = 8.3, 2.8, 1.8 Hz, 1H), 4.58 (ddd, J = 8.4, 4.7, 3.8 Hz, 1H), 3.62 (dd, J = 13.5, 3.8 Hz, 1H), 3.54
(dd, J = 13.5, 4.7 Hz, 1H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 161.0, 143.8, 122.2, 78.3, 64.3, 51.2,
20.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C8H10N3O4 212.0666; Found 212.0663.
6.8. (5S, 6R)-6-(azidomethyl)-5-(benzyloxy)-5,6-dihydro-2H-pyran-2-one (15)
To a solution of compound 19 (900 mg, 4.26 mmol, 1.0 equiv) in a mixture of diisopropyl ether (40 mL) and
phosphate buffer pH 7 (20 mL) was added amano lipase PS (from Burkholderia cepacia) (916 mg). The mixture
was stirred at rt for 16 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2 × 80 ml).
The combined organic solutions were washed with a sat aq NaHCO3 solution (100 ml) and brine (100 ml), dried
over MgSO4, filtered and concentrated under reduced pressure. The crude alcohol 20 (HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C6H8N3O3 170.0560; Found 170.0558.) was used for the next step without further purification. To
a solution of the crude alcohol 20 in toluene (30 mL) at rt was added benzyl bromide (0.6 mL, 5.11 mmol, 1.2 equiv)
followed by silver (I) oxide (1.5 g, 6.39 mmol, 1.5 equiv). The mixture was stirred for 48 h, then filtered through
celite and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography
on silica gel (hexanes / EtOAc, 75 : 25) to give compound 15 (654 mg, 59% over 2 steps) as a colorless oil: [α]D =
+55.5 (c 0.9, CHCl3); IR (NaCl film)
ν
3063, 3029, 2920, 2851, 2104, 1743, 1496, 1454, 1228, 1073, 749, 699 cm-
1; 1H NMR (500 MHz, CDCl3) δ 7.43 – 7.31 (m, 5H), 6.89 (dd, J = 10.1, 1.7 Hz, 1H), 5.99 (dd, J = 10.0, 1.9 Hz,
1H), 4.71 (d, J = 11.6 Hz, 1H), 4.62 (d, J = 11.6 Hz, 1H), 4.47 – 4.36 (m, 2H), 3.69 (dd, J = 13.5, 2.6 Hz, 1H), 3.56
13
(dd, J = 13.5, 3.6 Hz, 1H); C NMR (125 MHz, CDCl3) δ 162.0, 146.7, 136.6, 128.9, 128.7, 128.3, 120.4, 79.3,
72.6, 69.4, 50.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H14N3O3 260.1030; Found 260.1032.
6.9. Compound (14)
To a solution of lactone 15 (100 mg, 0.39 mmol, 1.0 equiv) in dry THF (5 mL) at –78 °C was added CuBr.Me2S
(79.3 mg, 0.39 mmol, 1.0 equiv) and benzylmagnesium chloride (1.6 mL, 1.4 M in THF, 2.3 mmol, 6.0 equiv) over
10 min. The mixture was stirred at –78 °C for 0.5 h, then quenched by addition of sat aq NH4Cl solution (10 mL).
The mixture was extracted with ethyl acetate (3 × 15 ml) and the combined organic extracts were dried over MgSO4,
filtered and concentrated over reduced pressure. The product was purified by flash column chromatography on silica
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10.1002/cbic.201800247
ChemBioChem
gel (hexanes / EtOAc, 8 : 2) to yield lactone 15 (30 mg) and compound 14 (60 mg, 63% based on recuperated
starting material) as a mixture of diastereoisomers (HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H22N3O3
352.1656; Found 352.1651).
6.10. (3R, 4S, 5R)-6-azido-3-benzyl-4-(benzyloxy)-N-butyl-5-hydroxyhexanamide (24a) and (3S, 4S, 5R)-6-azido-
3-benzyl-4-(benzyloxy)-N-butyl-5-hydroxyhexanamide (24b)
Following general procedure I with lactone 14 (110 mg, 0.31 mmol, 1.0 equiv) and butyl amine (0.62 mL, 0.63
mmol, 2.0 equiv) in 4.0 mL of MeOH. Flash column chromatography on silica gel afforded amide 24a (74 mg,
55%) and 24b (37 mg, 28%) as colorless oils. (3R, 4S, 5R)-6-azido-3-benzyl-4-(benzyloxy)-N-butyl-5-
hydroxyhexanamide (24a): [α]D = +12.3 (c 1.0, CHCl3); IR (NaCl film)
ν 3306, 3028, 2930, 2099, 1650, 1495,
1455, 1286, 1094, 747, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.17 (m, 10H), 5.18 (dd, J = 5.9, 5.9 Hz,
1H), 4.56 (s, 2H), 3.93 – 3.83 (m, 1H), 3.61 – 3.45 (m, 3H), 3.41 (dd, J = 12.5, 6.0 Hz, 1H), 3.19 – 3.04 (m, 3H),
2.65 – 2.48 (m, 2H), 2.19 (ddt, J = 15.2, 6.2 Hz, 2H), 1.43 – 1.24 (m, 4H), 0.90 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 172.6, 140.6, 138.2, 129.4, 128.6, 128.2, 128.1, 126.3, 80.4, 73.8, 72.0, 54.6, 39.4, 36.9, 36.0, 31.7,
20.2, 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H33N4O3 425.2547; Found 425.2533. (3S, 4S, 5R)-6-
azido-3-benzyl-4-(benzyloxy)-N-butyl-5-hydroxyhexanamide (24b): [α]D = +31.7 (c 1.0, CHCl3); IR (NaCl film)
ν
3312, 3028, 2930, 2872, 2100, 1644, 1496, 1455, 1293, 1097, 737, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.43 –
7.26 (m, 7H), 7.26 – 7.15 (m, 3H), 5.25 (t, J = 5.3 Hz, 1H), 4.99 (br s, 1H), 4.66 (d, J = 11.3 Hz, 1H), 4.58 (d, J =
11.3 Hz, 1H), 3.69 – 3.60 (m, 1H), 3.55 (dd, J = 9.1, 1.6 Hz, 1H), 3.51 (dd, J = 12.5, 2.7 Hz, 1H), 3.36 (dd, J = 12.5,
5.7 Hz, 1H), 3.16 – 3.07 (m, 2H), 2.92 (dd, J = 13.2, 5.1 Hz, 1H), 2.88 – 2.79 (m, 1H), 2.64 (dd, J = 13.1, 10.4 Hz,
1H), 2.56 (dd, J = 16.0, 8.1 Hz, 1H), 1.99 (dd, J = 16.0, 3.0 Hz, 1H), 1.38 – 1.30 (m, 2H), 1.28 – 1.18 (m, 2H), 0.88
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.2, 139.9, 138.3, 129.3, 128.7, 128.7, 128.0, 127.7, 126.5,
82.0, 74.8, 71.3, 53.9, 39.6, 39.5, 37.4, 34.5, 31.5, 20.1, 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C24H33N4O3 425.2547; Found 425.2541.
6.11. (3R, 4S, 5R)-6-azido-3-benzyl-4-(benzyloxy)-5-hydroxy-N-((S)-tetrahydrofuran-3-yl)hexanamide (25a) and
(3S, 4S, 5R)-6-azido-3-benzyl-4-(benzyloxy)-5-hydroxy-N-((S)-tetrahydrofuran-3-yl)hexanamide (25b)
Following general procedure I with lactone 14 (60 mg, 0.17 mmol, 1.0 equiv), (S)-3-aminotetrahydrofuran
tosylate (89 mg, 0.34 mmol, 2.0 equiv) and Et3N (0.14 mL, 1.02 mmol, 6.0 equiv) in 2.0 mL of MeOH. Flash
column chromatography on silica gel afforded amide 25a (40 mg, 53%) and 25b (20 mg, 27%) as colorless oils.
(3R, 4S, 5R)-6-azido-3-benzyl-4-(benzyloxy)-5-hydroxy-N-((S)-tetrahydrofuran-3-yl)hexanamide (25a): [α]D
=
+17.2 (c 1.0, CHCl3); IR (NaCl film)
ν
3306, 2925, 2866, 2100, 1642, 1546, 1453, 1285, 1073, 745, 700 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.38 – 7.26 (m, 7H), 7.24 – 7.18 (m, 3H), 5.57 (d, J = 7.2 Hz, 1H), 4.55 (q, J = 11.5 Hz,
2H), 4.40 (dtt, J = 10.3, 5.6, 2.9 Hz, 1H), 3.88 – 3.81 (m, 2H), 3.73 (ddd, J = 17.0, 9.1, 5.5 Hz, 2H), 3.57 (dd, J =
12.5, 2.9 Hz, 1H), 3.54 – 3.49 (m, 2H), 3.41 (dd, J = 12.5, 6.0 Hz, 1H), 3.07 (dd, J = 13.4, 5.4 Hz, 1H), 2.65 – 2.58
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10.1002/cbic.201800247
ChemBioChem
(m, 1H), 2.54 (dd, J = 13.4, 9.7 Hz, 1H), 2.26 – 2.15 (m, 3H), 1.72 – 1.64 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
172.4, 140.5, 138.1, 129.4, 128.7, 128.7, 128.1, 128.1, 126.4, 80.4, 73.8, 73.4, 71.8, 66.9, 54.6, 50.4, 39.3, 37.1,
36.1, 33.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H31N4O4 439.2340; Found 439.2677. (3S, 4S, 5R)-6-
azido-3-benzyl-4-(benzyloxy)-5-hydroxy-N-((S)-tetrahydrofuran-3-yl)hexanamide (25b): [α]D = +24.5 (c 0.8,
1
CHCl3); IR (NaCl film)
ν
3307, 2925, 2856, 2101, 1641, 1495, 1453, 1293, 1075, 739, 700 cm-1; H NMR (500
MHz, CDCl3) δ 7.41 – 7.28 (m, 7H), 7.25 – 7.16 (m, 3H), 5.44 (d, J = 7.4 Hz, 1H), 4.75 (d, J = 3.5 Hz, 1H), 4.66
(d, J = 11.3 Hz, 1H), 4.59 (d, J = 11.3 Hz, 1H), 4.36 (dtt, J = 10.3, 5.4, 2.8 Hz, 1H), 3.82 – 3.74 (m, 1H), 3.70 (ddd,
J = 8.7, 7.8, 5.5 Hz, 2H), 3.69 – 3.62 (m, 1H), 3.59 – 3.49 (m, 3H), 3.37 (dd, J = 12.6, 5.7 Hz, 1H), 2.92 (dd, J =
13.4, 4.9 Hz, 1H), 2.83 – 2.76 (m, 1H), 2.62 (dd, J = 13.3, 10.7 Hz, 1H), 2.56 (dd, J = 16.0, 7.8 Hz, 1H), 2.19 – 2.07
(m, 1H), 1.97 (dd, J = 16.0, 3.2 Hz, 1H), 1.57 – 1.48 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 174.0, 139.9, 138.2,
129.3, 128.8, 128.7, 128.1, 127.8, 126.6, 82.0, 74.7, 73.4, 71.3, 66.8, 53.9, 50.6, 39.6, 37.7, 34.5, 33.1; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C24H31N4O4 439.2340; Found 439.2342.
6.12. (3R, 4S, 5R)-6-azido-3-benzyl-4-(benzyloxy)-5-hydroxy-N-((1S, 2R)-2-hydroxy-2,3-dihydro-1H-inden-1-
yl)hexanamide (26a) and (3S, 4S, 5R)-6-azido-3-benzyl-4-(benzyloxy)-5-hydroxy-N-((1S, 2R)-2-hydroxy-2,3-
dihydro-1H-inden-1-yl)hexanamide (26b)
Following general procedure I with lactone 14 (140 mg, 0.40 mmol, 1.0 equiv) and (1S, 2R)-(−)-cis-1-amino-2-
indanol (119 mg, 0.80 mmol, 2.0 equiv) in 5.0 mL of MeOH. Flash column chromatography on silica gel afforded
amide 26a (108 mg, 54%) and 26b (52 mg, 26%) as colorless oils. (3R, 4S, 5R)-6-azido-3-benzyl-4-(benzyloxy)-5-
hydroxy-N-((1S, 2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)hexanamide (26a): [α]D = +15.4 (c 1.0, CHCl3); IR
(NaCl film)
ν
3395, 3026, 2924, 2101, 1646, 1454, 1300, 1090, 750, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35
– 7.17 (m, 14H), 6.21 (d, J = 8.7 Hz, 1H), 5.32 (dd, J = 8.6, 5.1 Hz, 1H), 4.67 (d, J = 11.5 Hz, 1H), 4.55 (d, J = 11.5
Hz, 1H), 4.49 (td, J = 5.2, 2.4 Hz, 1H), 3.81 (ddd, J = 8.6, 5.7, 2.8 Hz, 1H), 3.58 (dd, J = 8.5, 2.0 Hz, 1H), 3.53 (dd,
J = 12.5, 2.7 Hz, 1H), 3.36 (dd, J = 12.5, 5.7 Hz, 1H), 3.06 (ddd, J = 18.1, 14.6, 4.8 Hz, 2H), 2.86 (dd, J = 16.6, 2.5
Hz, 1H), 2.67 – 2.53 (m, 2H), 2.46 – 2.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 173.4, 140.5, 140.4, 140.2, 138.1,
129.5, 128.6, 128.6, 128.4, 128.0, 127.2, 126.3, 125.4, 124.6, 80.1, 74.2, 73.4, 71.4, 57.4, 54.6, 39.6, 39.5, 38.1,
35.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C29H33N4O4 501.2496; Found 501.2496. (3S, 4S, 5R)-6-azido-3-
benzyl-4-(benzyloxy)-5-hydroxy-N-((1S, 2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)hexanamide (26b): [α]D
=
+12.9 (c 1.0, CHCl3); IR (NaCl film)
ν
3395, 3027, 2924, 2101, 1645, 1521, 1455, 1299, 1086, 1055, 750, 699 cm-
1; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.16 (m, 14H), 6.96 (d, J = 7.1 Hz, 1H), 6.07 (d, J = 8.4 Hz, 1H), 5.22 (dd,
J = 8.5, 4.9 Hz, 1H), 4.63 (d, J = 11.3 Hz, 1H), 4.57 (d, J = 11.3 Hz, 1H), 4.53 (td, J = 5.0, 1.8 Hz, 1H), 3.81 (ddd,
J = 8.6, 5.3, 3.7 Hz, 1H), 3.50 (dd, J = 7.9, 2.0 Hz, 1H), 3.45 – 3.38 (m, 2H), 2.98 (ddd, J = 21.2, 15.0, 5.3 Hz, 2H),
2.91 – 2.81 (m, 2H), 2.61 (dd, J = 13.3, 9.8 Hz, 1H), 2.49 (dd, J = 15.6, 8.9 Hz, 1H), 2.13 (dd, J = 15.5, 3.6 Hz,
13
1H); C NMR (100 MHz, CDCl3) δ 174.6, 140.3, 140.2, 139.9, 138.1, 129.2, 128.7, 128.7, 128.4, 128.1, 128.0,
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10.1002/cbic.201800247
ChemBioChem
127.2, 126.5, 125.4, 124.4, 80.6, 73.7, 73.5, 70.8, 57.9, 53.9, 39.3, 38.8, 37.6, 35.6; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C29H33N4O4 501.2496; Found 501.2501.
6.13. (3R, 4S, 5R)-6-azido-3-benzyl-N-butyl-4,5-dihydroxyhexanamide (27a)
Following general procedure II with amide 24a (60 mg, 0.14 mmol, 1.0 equiv) and TiCl4 (0.71 ml, 0.71 mmol,
5.0 equiv) in CH2Cl2 (2.0 mL). Flash column chromatography on silica gel afforded alcohol 27a (42 mg, 89%) as a
colorless oil: [α]D = –16.0 (c 1.0, CHCl3); IR (NaCl film)
ν 3335, 3026, 2930, 2872, 2101, 1624, 1557, 1454, 1291,
1068, 1030, 741, 701 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.23 (m, 2H), 7.24 – 7.15 (m, 3H), 5.47 – 5.34 (m,
2H), 3.84 – 3.67 (m, 3H), 3.59 – 3.49 (m, 1H), 3.31 – 3.10 (m, 2H), 3.04 – 2.91 (m, 1H), 2.64 – 2.50 (m, 3H), 2.31
– 2.22 (m, 2H), 1.50 – 1.40 (m, 2H), 1.35 – 1.25 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.4, 140.6, 129.1, 128.6, 126.4, 75.1, 71.4, 55.5, 39.7, 39.0, 38.8, 33.0, 31.6, 20.2, 13.8; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C17H27N4O3 335.2078; Found 335.2086.
6.14. (3S, 4S, 5R)-6-azido-3-benzyl-N-butyl-4,5-dihydroxyhexanamide (27b)
Following general procedure II with amide 24b (60 mg, 0.14 mmol, 1.0 equiv) and TiCl4 (0.71 ml, 0.71 mmol,
5.0 equiv) in CH2Cl2 (2.0 mL). Flash column chromatography on silica gel afforded alcohol 27b (40 mg, 85%) as
a colorless oil: [α]D = +17.4 (c 1.0, CHCl3); IR (NaCl film)
ν 3329, 3027, 2929, 2872, 2101, 1634, 1557, 1455,
1277, 1074, 745, 701 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.24 (m, 2H), 7.26 – 7.16 (m, 3H), 5.46 (t, J = 5.0
Hz, 1H), 4.19 – 4.06 (m, 1H), 3.74 – 3.44 (m, 5H), 3.29 – 3.09 (m, 2H), 2.84 (dd, J = 13.3, 5.8 Hz, 1H), 2.73 – 2.56
(m, 2H), 2.31 (d, J = 4.7 Hz, 2H), 1.48 – 1.39 (m, 2H), 1.36 – 1.23 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 174.0, 139.9, 129.2, 128.7, 126.5, 74.0, 71.9, 54.7, 39.8, 38.3, 37.7, 34.5, 31.5, 20.2, 13.8; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H27N4O3 335.2078; Found 335.2088.
6.15. (3R, 4S, 5R)-6-azido-3-benzyl-4,5-dihydroxy-N-((S)-tetrahydrofuran-3-yl)hexanamide (28a)
Following general procedure II with amide 25a (30 mg, 0.07 mmol, 1.0 equiv) and TiCl4 (0.34 ml, 0.34 mmol,
5.0 equiv) in CH2Cl2 (1.5 mL). Flash column chromatography on silica gel afforded alcohol 28a (20 mg, 84%) as a
colorless oil: [α]D = –15.3 (c 0.8, CHCl3); IR (NaCl film)
ν 3306, 3025, 2926, 2869, 2101, 1638, 1543, 1453, 1289,
1069, 751, 701, 667 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.23 (m, 2H), 7.25 – 7.14 (m, 3H), 5.68 (d, J = 7.1
Hz, 1H), 5.15 (br s, 1H), 4.47 (tdt, J = 7.6, 5.3, 2.8 Hz, 1H), 3.87 (dt, J = 8.6, 7.3 Hz, 1H), 3.80 – 3.68 (m, 5H), 3.59
– 3.51 (m, 2H), 3.04 – 2.92 (m, 1H), 2.63 – 2.50 (m, 3H), 2.30 – 2.21 (m, 3H), 1.81 – 1.72 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 173.1, 140.4, 129.2, 128.7, 126.5, 75.0, 73.3, 71.3, 66.8, 55.4, 50.7, 38.9, 38.6, 33.1, 33.0; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H25N4O4 349.1870; Found 349.1882.
6.16. (3S, 4S, 5R)-6-azido-3-benzyl-4,5-dihydroxy-N-((S)-tetrahydrofuran-3-yl)hexanamide (28b)
Following general procedure II with amide 25b (20 mg, 0.05 mmol, 1.0 equiv) and TiCl4 (0.23 ml, 0.23 mmol,
5.0 equiv) in CH2Cl2 (1.5 mL). Flash column chromatography on silica gel afforded alcohol 28b (14 mg, 88%) as
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10.1002/cbic.201800247
ChemBioChem
a colorless oil: [α]D = +5.2 (c 0.5, CHCl3); IR (NaCl film)
ν
3311, 2924, 2101, 1636, 1541, 1454, 1286, 1080, 749,
701 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.33 – 7.28 (m, 2H), 7.24 – 7.17 (m, 3H), 5.64 (d, J = 7.2 Hz, 1H), 4.43
(dtt, J = 10.3, 5.4, 2.7 Hz, 1H), 3.88 – 3.47 (m, 10H), 2.85 (dd, J = 13.3, 5.6 Hz, 1H), 2.67 (dd, J = 13.2, 10.1 Hz,
1H), 2.64 – 2.57 (m, 1H), 2.36 – 2.15 (m, 3H), 1.69 – 1.60 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 173.8, 139.8,
129.3, 128.8, 126.6, 74.1, 73.4, 71.9, 66.8, 54.7, 50.7, 38.3, 37.8, 34.4, 33.0; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C17H25N4O4 349.1870; Found 349.1896.
6.17. (3R, 4S, 5R)-6-azido-3-benzyl-4,5-dihydroxy-N-((1S, 2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)hexanamide
(29a)
Following general procedure II with amide 26a (90 mg, 0.18 mmol, 1.0 equiv) and TiCl4 (0.17 ml, 0.90 mmol,
5.0 equiv) in CH2Cl2 (2.5 mL). Flash column chromatography on silica gel afforded alcohol 29a (60 mg, 81%) as a
colorless oil: [α]D = +6.7 (c 0.2, acetone); IR (NaCl film)
ν 3333, 3040, 2920, 2105, 1610, 1560, 1455, 1320, 1067,
1055, 741, 702 cm-1; 1H NMR (500 MHz, (CD3)2CO) δ 7.27 – 7.11 (m, 9H), 5.28 (d, J = 5.1 Hz, 1H), 4.49 (td, J =
5.1, 1.9 Hz, 1H), 3.82 (ddd, J = 9.0, 6.3, 2.6 Hz, 1H), 3.73 (dd, J = 9.0, 1.9 Hz, 1H), 3.56 (dd, J = 12.6, 2.6 Hz, 1H),
3.40 (dd, J = 12.6, 6.4 Hz, 1H), 3.25 (s, 1H), 3.08 (dd, J = 16.3, 5.2 Hz, 1H), 2.97 (dd, J = 13.6, 4.0 Hz, 1H), 2.85
(dd, J = 16.4, 1.9 Hz, 1H), 2.73 – 2.66 (m, 1H), 2.55 – 2.46 (m, 2H), 2.30 (dd, J = 14.9, 3.9 Hz, 1H); 13C NMR (126
MHz, (CD3)2CO) δ 174.7, 142.5, 142.1, 141.7, 130.3, 129.1, 128.5, 127.4, 126.7, 125.8, 125.3, 74.0, 73.4, 72.3,
58.3, 56.0, 40.4, 39.9, 38.2, 34.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H27N4O4 411.2027; Found
411.2021.
6.18. (3S, 4S, 5R)-6-azido-3-benzyl-4,5-dihydroxy-N-((1S, 2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)hexanamide
(29b)
Following general procedure II with amide 26b (45 mg, 0.09 mmol, 1.0 equiv) and TiCl4 (0.09 ml, 0.45 mmol,
5.0 equiv) in CH2Cl2 (2.0 mL). Flash column chromatography on silica gel afforded alcohol 29b (31 mg, 84%) as
a colorless oil: [α]D = +25.7 (c 1.0, MeOH); IR (NaCl film)
ν 3331, 3050, 2922, 2100, 1635, 1524, 1455, 1300,
1053, 748, 701 cm-1; 1H NMR (400 MHz, CD3OD) δ 7.31 – 7.14 (m, 9H), 5.32 (d, J = 5.1 Hz, 1H), 4.57 (td, J =
5.2, 2.3 Hz, 1H), 3.67 (ddd, J = 9.3, 7.0, 2.5 Hz, 1H), 3.46 (dd, J = 12.7, 2.5 Hz, 1H), 3.42 (dd, J = 9.2, 1.9 Hz, 1H),
3.28 (dd, J = 12.8, 7.1 Hz, 1H), 3.13 (dd, J = 16.5, 5.2 Hz, 1H), 2.93 (dd, J = 16.4, 2.2 Hz, 1H), 2.79 (dd, J = 7.4,
13
1.7 Hz, 2H), 2.69 – 2.57 (m, 2H), 2.35 (dd, J = 14.8, 7.0 Hz, 1H); C NMR (100 MHz, CD3OD) δ 176.5, 142.1,
141.8, 141.6, 130.4, 129.4, 129.0, 127.8, 127.1, 126.1, 125.3, 74.0, 72.9, 72.8, 58.9, 55.6, 40.5, 39.8, 38.6, 35.7;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H27N4O4 411.2027; Found 411.2020.
6.19. (3R, 4S, 5R)-3-benzyl-N-butyl-4,5-dihydroxy-6-(4-methylphenylsulfonamido)hexanamide (30a)
Following general procedure III with azide 27a (30 mg, 0.09 mmol, 1.0 equiv) and Pd/C (10 mg, 10 mol%) in
2.0 mL of MeOH. Then, Et3N (18 µL, 0.13 mmol, 1.5 equiv) and TsCl (21 mg, 0.11 mmol, 1.2 equiv) in CH2Cl2
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(2.0 mL) was used to give the desired sulfonamide. Flash column chromatography on silica gel afforded
sulfonamide 30a (29 mg, 70%) as a colorless oil: [α]D = –8.4 (c 0.8, CHCl3); IR (NaCl film) 3321, 3027, 2929,
ν
2872, 1634, 1557, 1454, 1324, 1158, 1092, 753, 701, 664 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz,
2H), 7.33 – 7.21 (m, 4H), 7.22 – 7.13 (m, 3H), 5.69 (t, J = 6.6 Hz, 1H), 5.54 (t, J = 5.7 Hz, 1H), 5.03 (d, J = 2.5 Hz,
1H), 3.71 (s, 2H), 3.56 (s, 1H), 3.31 – 3.07 (m, 4H), 2.95 (d, J = 10.4 Hz, 1H), 2.58 – 2.45 (m, 2H), 2.40 (s, 3H),
2.27 – 2.22 (m, 2H), 1.47 – 1.38 (m, 2H), 1.34 – 1.23 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 173.6, 143.6, 140.6, 136.8, 129.9, 129.3, 128.6, 127.2, 126.2, 74.7, 70.8, 46.9, 39.7, 38.7, 38.6, 33.4, 31.5, 21.7,
20.2, 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H35N2O5S 463.2261; Found 463.2236.
6.20. (3S, 4S, 5R)-3-benzyl-N-butyl-4,5-dihydroxy-6-(4-methylphenylsulfonamido)hexanamide (30b)
Following general procedure III with azide 27b (30 mg, 0.09 mmol, 1.0 equiv) and Pd/C (10 mg, 10 mol%) in
2.0 mL of MeOH. Then, Et3N (18 µL, 0.13 mmol, 1.5 equiv) and TsCl (21 mg, 0.11 mmol, 1.2 equiv) in CH2Cl2
(2.0 mL) was used to give the desired sulfonamide. Flash column chromatography on silica gel afforded
sulfonamide 30b (28 mg, 66%) as a colorless oil: [α]D = +4.5 (c 1.0, CHCl3); IR (NaCl film)
ν 3368, 3027, 2928,
2872, 1726, 1636, 1455, 1288, 1159, 1092, 745, 704, 661 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz,
2H), 7.33 – 7.25 (m, 4H), 7.24 – 7.14 (m, 3H), 5.52 (t, J = 5.7 Hz, 1H), 5.21 (t, J = 6.1 Hz, 1H), 4.45 (br s, 1H),
3.88 (br s, 1H), 3.57 (d, J = 9.2 Hz, 1H), 3.49 – 3.43 (m, 1H), 3.30 – 3.22 (m, 1H), 3.18 – 3.04 (m, 3H), 2.81 (dd, J
= 12.5, 5.0 Hz, 1H), 2.70 – 2.57 (m, 2H), 2.41 (s, 3H), 2.36 (dd, J = 16.2, 6.9 Hz, 1H), 2.17 (dd, J = 16.2, 2.1 Hz,
1H), 1.44 – 1.35 (m, 2H), 1.33 – 1.23 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.3, 143.6,
140.0, 136.8, 129.9, 129.3, 128.7, 127.2, 126.5, 73.6, 71.0, 46.1, 39.7, 38.6, 37.2, 34.1, 31.5, 21.7, 20.1, 13.8; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C24H35N2O5S 463.2261; Found 463.2243.
6.21.
(3R,
4S,
5R)-3-benzyl-4,5-dihydroxy-6-(4-methylphenylsulfonamido)-N-((S)-tetrahydrofuran-3-
yl)hexanamide (31a)
Following general procedure III with azide 28a (20 mg, 0.06 mmol, 1.0 equiv) and Pd/C (7 mg, 10 mol%) in 2.0
mL of MeOH. Then, Et3N (12 µL, 0.09 mmol, 1.5 equiv) and TsCl (13 mg, 0.07 mmol, 1.2 equiv) in CH2Cl2 (1.5
mL) was used to give the desired sulfonamide. Flash column chromatography on silica gel afforded sulfonamide
31a (19 mg, 69%) as a colorless oil: [α]D = –3.3 (c 0.8, acetone); IR (NaCl film)
ν 3355, 2980, 2919, 1715, 1610,
1455, 1362, 1222, 1158 cm-1; 1H NMR (500 MHz, (CD3)2CO) δ 7.80 – 7.74 (m, 2H), 7.43 – 7.37 (m, 2H), 7.28 –
7.21 (m, 2H), 7.19 – 7.13 (m, 3H), 6.27 (t, J = 6.2 Hz, 1H), 5.34 (d, J = 3.4 Hz, 1H), 4.36 (tdt, J = 7.3, 5.7, 3.7 Hz,
1H), 4.27 – 4.15 (m, 2H), 3.82 – 3.65 (m, 3H), 3.65 (br s, 1H), 3.52 (d, J = 8.8 Hz, 1H), 3.46 (dd, J = 9.1, 3.6 Hz,
1H), 3.31 (ddd, J = 12.8, 6.5, 3.9 Hz, 1H), 2.95 (ddd, J = 13.0, 7.0, 6.1 Hz, 1H), 2.89 – 2.83 (m, 1H), 2.57 – 2.48
(m, 1H), 2.46 (dd, J = 13.2, 11.0 Hz, 1H), 2.40 (s, 3H), 2.34 (dd, J = 15.5, 7.5 Hz, 1H), 2.22 – 2.11 (m, 2H), 1.85 –
1.75 (m, 1H); 13C NMR (125 MHz, (CD3)2CO) δ 206.1, 173.6, 143.8, 142.1, 139.0, 130.4, 130.0, 129.1, 127.9,
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126.6, 76.4, 73.4, 71.3, 67.2, 51.2, 48.6, 39.6, 38.4, 33.7, 33.3, 21.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C24H33N2O6S 477.2054; Found 477.2129.
6.22.
(3S,
4S,
5R)-3-benzyl-4,5-dihydroxy-6-(4-methylphenylsulfonamido)-N-((S)-tetrahydrofuran-3-
yl)hexanamide (31b)
Following general procedure III with azide 28b (14 mg, 0.04 mmol, 1.0 equiv) and Pd/C (5 mg, 10 mol%) in 2.0
mL of MeOH. Then, Et3N (8 µL, 0.06 mmol, 1.5 equiv) and TsCl (9 mg, 0.05 mmol, 1.2 equiv) in CH2Cl2 (1.5 mL)
was used to give the desired sulfonamide. Flash column chromatography on silica gel afforded sulfonamide 31b
(13 mg, 68%) as a colorless oil: [α]D = +18.9 (c 0.4, CHCl3); IR (NaCl film) ν 3360, 3004, 2917, 2849, 1714, 1420,
1
1362, 1222, 1161, 1092, 905 cm-1; H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.34 – 7.24 (m, 4H),
7.25 – 7.15 (m, 3H), 5.74 (d, J = 7.6 Hz, 1H), 5.15 (t, J = 6.4 Hz, 1H), 4.39 (tdd, J = 7.1, 6.3, 5.3, 2.6 Hz, 1H), 3.93
– 3.76 (m, 1H), 3.74 (dd, J = 9.2, 5.4 Hz, 2H), 3.60 (d, J = 9.6 Hz, 2H), 3.51 – 3.41 (m, 1H), 3.30 – 3.20 (m, 1H),
3.17 – 3.04 (m, 1H), 2.82 (dd, J = 12.4, 4.7 Hz, 1H), 2.71 – 2.56 (m, 1H), 2.42 (s, 3H), 2.39 – 2.01 (m, 5H), 1.68 –
13
1.56 (m, 1H); C NMR (100 MHz, CDCl3) δ 174.1, 143.7, 139.9, 136.8, 129.9, 129.3, 128.7, 127.2, 126.6, 73.6,
73.3, 71.0, 66.8, 50.7, 47.7, 46.1, 38.7, 37.3, 33.9, 33.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H33N2O6S
477.2054; Found 477.2107.
6.23.
(3R,
4S,
5R)-3-benzyl-4,5-dihydroxy-N-((1S,
2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-6-(4-
methylphenylsulfonamido)hexanamide (32a)
Following general procedure III with azide 29a (60 mg, 0.15 mmol, 1.0 equiv) and Pd/C (16 mg, 10 mol%) in
2.0 mL of MeOH. Then, Et3N (30 µL, 0.22 mmol, 1.5 equiv) and TsCl (33 mg, 0.18 mmol, 1.2 equiv) in CH2Cl2
(2.0 mL) was used to give the desired sulfonamide. Flash column chromatography on silica gel afforded
sulfonamide 32a (53 mg, 67%) as a colorless oil: [α]D = +7.5 (c 1.0, MeOH); IR (NaCl film)
ν 3359, 3050, 2924,
1636, 1522, 1455, 1323, 1158, 1092, 1054, 749, 702, 666 cm-1; 1H NMR (400 MHz, CD3OD) δ 7.78 (d, J = 8.2 Hz,
2H), 7.38 (d, J = 8.0 Hz, 2H), 7.30 – 7.12 (m, 9H), 5.25 (d, J = 5.0 Hz, 1H), 4.48 (td, J = 5.2, 2.0 Hz, 1H), 3.70 –
3.56 (m, 2H), 3.37 – 3.23 (m, 2H), 3.09 (dd, J = 16.5, 5.0 Hz, 1H), 2.96 – 2.83 (m, 3H), 2.71 – 2.58 (m, 1H), 2.50
– 2.35 (m, 5H), 2.25 (dd, J = 14.7, 4.3 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 175.7, 144.7, 142.2, 142.1, 141.7,
138.7, 130.8, 130.5, 129.3, 128.9, 128.2, 127.9, 127.0, 126.1, 125.5, 74.7, 73.9, 71.7, 58.8, 48.4, 40.5, 40.2, 38.1,
34.5, 21.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C29H35N2O6S 539.2210; Found 539.2228.
6.24.
(3S,
4S,
5R)-3-benzyl-4,5-dihydroxy-N-((1S,
2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-6-(4-
methylphenylsulfonamido)hexanamide (32b)
Following general procedure III with azide 29b (30 mg, 0.07 mmol, 1.0 equiv) and Pd/C (8 mg, 10 mol%) in 2.0
mL of MeOH. Then, Et3N (15 µL, 0.11 mmol, 1.5 equiv) and TsCl (17 mg, 0.09 mmol, 1.2 equiv) in CH2Cl2 (1.5
mL) was used to give the desired sulfonamide. Flash column chromatography on silica gel afforded sulfonamide
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32b (26 mg, 65%) as a colorless oil: [α]D = +11.2 (c 0.5, MeOH); IR (NaCl film)
ν
3350, 3020, 2923, 1635, 1522,
1455, 1321, 1156, 1091, 1052, 749, 701, 663 cm-1; 1H NMR (400 MHz, CD3OD) δ 7.73 (d, J = 8.2 Hz, 2H), 7.36
(d, J = 8.0 Hz, 2H), 7.28 – 7.12 (m, 9H), 5.30 (d, J = 5.1 Hz, 1H), 4.56 (td, J = 5.2, 2.3 Hz, 1H), 3.52 (td, J = 8.5,
2.9 Hz, 1H), 3.29 – 3.22 (m, 2H), 3.13 (dd, J = 16.4, 5.3 Hz, 1H), 2.92 (dd, J = 16.4, 2.3 Hz, 1H), 2.78 – 2.66 (m,
3H), 2.63 – 2.48 (m, 2H), 2.41 (s, 3H), 2.30 (dd, J = 14.7, 6.8 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 176.5,
144.6, 142.1, 141.8, 141.6, 138.7, 130.7, 130.4, 129.4, 129.0, 128.2, 127.8, 127.1, 126.1, 125.3, 74.0, 73.6, 72.0,
58.9, 47.9, 40.6, 39.9, 38.6, 35.7, 21.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C29H35N2O6S 539.2210; Found
539.2219.
6.25. (3R, 4S, 5R)-3-benzyl-N-butyl-4,5-dihydroxy-6-(N-isobutyl-4-methylphenylsulfonamido) hexanamide (33a)
Following general procedure IV with amine 30a (25 mg, 0.05 mmol, 1.0 equiv), K2CO3 (15 mg, 0.11 mmol, 2.0
equiv) and isobutyl bromide (15 mg, 0.11 mmol, 2.0 equiv) in MeCN (1.5 mL). Flash column chromatography on
silica gel afforded product 33a (27 mg, 96%) as a colorless oil: [α]D = –22.2 (c 0.5, CHCl3); IR (NaCl film) ν 3379,
2959, 2871, 1635, 1557, 1455, 1331, 1155, 1089, 757, 701, 656 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J =
8.3 Hz, 2H), 7.36 – 7.24 (m, 4H), 7.25 – 7.15 (m, 3H), 5.51 (d, J = 2.8 Hz, 1H), 5.39 (t, J = 5.4 Hz, 1H), 3.77 (t, J
= 8.9 Hz, 1H), 3.65 (d, J = 2.3 Hz, 1H), 3.55 (d, J = 8.5 Hz, 1H), 3.38 (dd, J = 15.2, 2.1 Hz, 1H), 3.31 – 3.09 (m,
4H), 3.01 (dd, J = 13.4, 3.7 Hz, 1H), 2.79 (dd, J = 13.2, 5.9 Hz, 1H), 2.70 – 2.62 (m, 1H), 2.61 – 2.52 (m, 1H), 2.43
(s, 3H), 2.30 – 2.24 (m, 2H), 2.03 – 1.91 (m, 1H), 1.49 – 1.40 (m, 2H), 1.36 – 1.27 (m, 2H), 0.97 (d, J = 6.6 Hz,
3H), 0.92 (t, J = 7.3 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.7, 143.7, 140.9, 135.5,
129.9, 129.3, 128.5, 127.5, 126.2, 76.2, 71.1, 59.3, 55.1, 39.7, 39.1, 38.8, 33.3, 31.6, 27.2, 21.7, 20.4, 20.2, 20.0,
13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H43N2O5S 519.2887; Found 519.2891.
6.26. (3S, 4S, 5R)-3-benzyl-N-butyl-4,5-dihydroxy-6-(N-isobutyl-4-methylphenylsulfonamido) hexanamide (33b)
Following general procedure IV with amine 30b (25 mg, 0.05 mmol, 1.0 equiv), K2CO3 (15 mg, 0.11 mmol, 2.0
equiv) and isobutyl bromide (15 mg, 0.11 mmol, 2.0 equiv) in MeCN (1.5 mL). Flash column chromatography on
silica gel afforded product 33b (26 mg, 92%) as white needle after crystallisation: mp (CH2Cl2/MeOH) 140−142
°C; [α]D = –2.4 (c 0.5, CHCl3); IR (NaCl film)
ν 3375, 2959, 2929, 1636, 1455, 1330, 1155, 1090, 755, 701, 656
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.3 Hz, 2H), 7.34 – 7.24 (m, 4H), 7.24 – 7.16 (m, 3H), 5.50 (t, J =
5.6 Hz, 1H), 5.13 (d, J = 8.3 Hz, 1H), 4.05 (d, J = 2.6 Hz, 1H), 3.64 (t, J = 8.2 Hz, 1H), 3.44 – 3.33 (m, 2H), 3.30 –
3.12 (m, 3H), 3.08 (dd, J = 13.3, 8.8 Hz, 1H), 2.85 (ddd, J = 22.3, 13.4, 6.5 Hz, 2H), 2.72 (dd, J = 13.6, 9.6 Hz,
1H), 2.65 – 2.56 (m, 1H), 2.53 (dd, J = 15.9, 2.8 Hz, 1H), 2.42 (s, 3H), 2.25 (dd, J = 16.0, 6.2 Hz, 1H), 2.07 – 1.95
(m, 1H), 1.52 – 1.38 (m, 2H), 1.39 – 1.25 (m, 2H), 0.95 – 0.90 (m, 6H), 0.84 (d, J = 6.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 174.0, 143.7, 140.3, 135.6, 129.9, 129.3, 128.6, 127.5, 126.3, 74.1, 72.7, 59.1, 54.5, 39.8, 37.8,
37.6, 35.1, 31.6, 27.0, 21.7, 20.3, 20.2, 20.0, 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H43N2O5S
519.2887; Found 519.2884.
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6.27. (3R, 4S, 5R)-3-benzyl-4,5-dihydroxy-6-(N-isobutyl-4-methylphenylsulfonamido)-N-((S)-tetrahydrofuran-3-
yl)hexanamide (34a)
Following general procedure IV with amine 31a (12 mg, 0.03 mmol, 1.0 equiv), K2CO3 (7 mg, 0.05 mmol, 2.0
equiv) and isobutyl bromide (7 mg, 0.05 mmol, 2.0 equiv) in MeCN (1.5 mL). Flash column chromatography on
silica gel afforded product 34a (12 mg, 89%) as a colorless oil: [α]D = –2.4 (c 0.8, CHCl3); IR (NaCl film)
ν 3365,
2959, 2926, 2871, 1642, 1541, 1454, 1330, 1155, 1089, 735, 702, 656 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.70 (d,
J = 8.3 Hz, 2H), 7.35 – 7.24 (m, 4H), 7.24 – 7.17 (m, 3H), 5.64 (d, J = 7.5 Hz, 1H), 5.29 (s, 1H), 4.45 (tdt, J = 7.6,
5.5, 2.9 Hz, 1H), 3.92 – 3.83 (m, 1H), 3.82 – 3.72 (m, 3H), 3.64 (broad s, 1H), 3.60 – 3.52 (m, 2H), 3.37 (dd, J =
15.3, 2.1 Hz, 1H), 3.25 (dd, J = 15.3, 8.7 Hz, 1H), 3.13 (dd, J = 13.2, 9.1 Hz, 1H), 3.02 (dd, J = 13.7, 4.1 Hz, 1H),
2.79 (dd, J = 13.2, 6.0 Hz, 1H), 2.67 (broad s, 1H), 2.57 (dd, J = 13.7, 11.4 Hz, 1H), 2.44 (s, 3H), 2.34 – 2.20 (m,
3H), 2.03 – 1.91 (m, 1H), 1.82 – 1.72 (m, 1H), 0.97 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 173.5, 143.8, 140.7, 135.4, 129.9, 129.3, 128.6, 127.5, 126.3, 76.1, 73.3, 71.2, 66.9, 59.4, 55.0,
50.7, 39.0, 38.6, 33.2, 33.1, 27.2, 21.7, 20.4, 20.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H41N2O6S
533.2680; Found 533.2763.
6.28. (3S, 4S, 5R)-3-benzyl-4,5-dihydroxy-6-(N-isobutyl-4-methylphenylsulfonamido)-N-((S)-tetrahydrofuran-3-
yl)hexanamide (34b)
Following general procedure IV with amine 31b (7 mg, 0.01 mmol, 1.0 equiv), K2CO3 (4 mg, 0.03 mmol, 2.0
equiv) and isobutyl bromide (4 mg, 0.03 mmol, 2.0 equiv) in MeCN (1.5 mL). Flash column chromatography on
silica gel afforded product 34b (7 mg, 89%) as a colorless oil: [α]D = –35.6 (c 0.5, CHCl3); IR (NaCl film)
ν 3360,
2958, 2924, 2870, 1776, 1641, 1547, 1453, 1331, 1156, 1089, 736, 702, 656 cm-1; 1H NMR (500 MHz, CDCl3) δ
7.68 (d, J = 8.3 Hz, 2H), 7.34 – 7.26 (m, 4H), 7.24 – 7.18 (m, 3H), 5.65 (d, J = 7.4 Hz, 1H), 4.83 (s, 1H), 4.45 (tdt,
J = 7.7, 5.5, 2.9 Hz, 1H), 4.06 (broad s, 1H), 3.92 – 3.84 (m, 1H), 3.84 – 3.73 (m, 2H), 3.68 – 3.61 (m, 2H), 3.45 –
3.33 (m, 2H), 3.25 (dd, J = 15.3, 7.5 Hz, 1H), 3.08 (dd, J = 13.3, 8.7 Hz, 1H), 2.86 (ddd, J = 24.7, 13.4, 6.4 Hz,
2H), 2.72 (dd, J = 13.7, 9.9 Hz, 1H), 2.65 – 2.58 (m, 1H), 2.48 (dd, J = 16.0, 2.9 Hz, 1H), 2.43 (s, 3H), 2.31 – 2.18
13
(m, 2H), 2.05 – 1.98 (m, 1H), 1.75 – 1.66 (m, 1H), 0.91 (d, J = 6.6 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H); C NMR
(125 MHz, CDCl3) δ 173.9, 143.7, 140.2, 135.6, 129.9, 129.3, 128.7, 127.5, 126.4, 74.0, 73.4, 72.8, 66.9, 59.2, 54.4,
50.8, 37.9, 37.7, 34.9, 33.0, 27.0, 21.7, 20.3, 20.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H41N2O6S
533.2680; Found 533.2664.
6.29. (3R, 4S, 5R)-3-benzyl-4,5-dihydroxy-N-((1S, 2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-6-(N-isobutyl-4-
methylphenylsulfonamido)hexanamide (35a)
Following general procedure IV with amine 32a (30 mg, 0.06 mmol, 1.0 equiv), K2CO3 (15 mg, 0.11 mmol, 2.0
equiv) and isobutyl bromide (15 mg, 0.11 mmol, 2.0 equiv) in MeCN (1.5 mL). Flash column chromatography on
silica gel afforded product 35a (30 mg, 90%) as a white amorphous solid: [α]D = –16.7 (c 0. 5, CHCl3); IR (NaCl
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ChemBioChem
film)
ν
3300, 2958, 2927, 2857, 1728, 1458, 1287, 1273, 1122, 1072, 1040, 742 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.70 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.31 – 7.16 (m, 9H), 6.18 (d, J = 8.2 Hz, 1H), 5.33 (dd, J = 8.1,
5.1 Hz, 1H), 5.13 (d, J = 3.4 Hz, 1H), 4.59 (broad s, 1H), 3.81 (ddd, J = 8.8, 6.5, 2.3 Hz, 1H), 3.66 (d, J = 2.8 Hz,
1H), 3.62 (dd, J = 8.9, 2.1 Hz, 1H), 3.38 (dd, J = 15.3, 2.1 Hz, 1H), 3.27 (dd, J = 15.3, 8.7 Hz, 1H), 3.19 – 3.10 (m,
2H), 3.05 (dd, J = 13.0, 3.3 Hz, 1H), 2.91 (dd, J = 16.5, 2.4 Hz, 1H), 2.81 (dd, J = 13.3, 6.1 Hz, 1H), 2.74 – 2.61
13
(m, 3H), 2.48 – 2.34 (m, 5H), 2.02 – 1.92 (m, 1H), 0.97 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H); C NMR
(125 MHz, CDCl3) δ 174.4, 143.8, 140.7, 140.2, 140.0, 135.4, 129.9, 129.4, 128.6, 127.6, 127.5, 126.3, 125.6,
124.8, 75.9, 73.5, 71.1, 59.3, 57.8, 54.9, 39.8, 39.1, 38.9, 33.5, 27.2, 21.7, 20.4, 20.0; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C33H43N2O6S 595.2836; Found 595.2838.
6.30. (3S, 4S, 5R)-3-benzyl-4,5-dihydroxy-N-((1S, 2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-6-(N-isobutyl-4-
methylphenylsulfonamido)hexanamide (35b)
Following general procedure IV with amine 32b (25 mg, 0.05 mmol, 1.0 equiv), K2CO3 (13 mg, 0.09 mmol, 2.0
equiv) and isobutyl bromide (13 mg, 0.09 mmol, 2.0 equiv) in MeCN (1.5 mL). Flash column chromatography on
silica gel afforded product 35b (26 mg, 93%) as a white amorphous solid: [α]D = +11.7 (c 0.3, CHCl3); IR (NaCl
1
film)
ν
3320, 3026, 2959, 2924, 2853, 1738, 1636, 1522, 1456, 1260, 1155, 1090, 1048, 750, 702, 656 cm-1; H
NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.34 – 7.25 (m, 5H), 7.27 – 7.12 (m, 6H), 6.27 (d, J = 8.4 Hz,
1H), 5.36 (dd, J = 8.6, 5.1 Hz, 1H), 4.70 – 4.63 (m, 1H), 4.33 (d, J = 7.9 Hz, 1H), 4.09 (d, J = 3.8 Hz, 1H), 3.82 –
3.69 (m, 1H), 3.50 – 3.37 (m, 2H), 3.22 – 3.08 (m, 2H), 3.07 – 2.85 (m, 4H), 2.81 – 2.70 (m, 2H), 2.54 (dd, J =
16.0, 2.3 Hz, 2H), 2.46 – 2.35 (m, 4H), 2.06 – 1.96 (m, 1H), 0.88 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 174.8, 143.7, 140.2, 140.1, 135.6, 129.9, 129.4, 128.7, 128.5, 127.5, 127.4, 126.4, 125.5,
124.6, 74.4, 73.5, 73.0, 59.0, 57.8, 53.9, 39.9, 38.1, 37.7, 35.1, 27.0, 21.7, 20.3, 20.0; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C33H43N2O6S 595.2836; Found 595.2818.
6.31. Molecular docking
Compounds 33–35 were built in PyMOL Molecular Graphics System (Version 1.8.5.0 Schrödinger, LLC)
based on the Darunavir structure, and energy minimized using ConfBuster.[36] Docking simulations were performed
using Autodock VINA 1.1.2.[37] The crystal structure coordinates of the wild-type HIV protease in complex with
Darunavir were taken from PDB 4LL3.[38] Hydrogen atoms were added using PyMOL for Darunavir and the reduce
software version 3.23 for the protease.[39] One crystallographic water molecule, located in the binding pocket and
hydrogen-bonded to the amine of ILE50 of both subunits, was kept for the dockings. Docking simulations were
carried out using a rigid receptor for the protein with flexibility for the ASP30 and ILE84 side chains, a search space
centered on Darunavir from the crystallographic structure of size of 22.5 Å along the X and Y axis and 26.5 Å along
the Z axis, and an exhaustiveness of 48. Validation of the docking protocol was carried out using self-docking of
Darunavir, leading to an RMSD of 0.61 Å between the docked and crystallographic structures. Because compounds
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10.1002/cbic.201800247
ChemBioChem
33–35 have a scaffold similar to Darunavir, no further optimization of the docking protocol was considered. In
presence of multiple poses with a similar score, the pose with the highest similarity with the Darunavir
crystallographic structure was considered as the best pose. The interactions between the compounds and the HIV
protease has been analyzed using the Poseview tool from the ProteinsPlus server.[40, 41]
6.32. Cell lines culture
Human HT-29 colon adenocarcinoma and MCF7 breast carcinoma cancer cells were purchased from the
American Type Culture Collection (Manassas, VA) while M21 human skin melanoma cells were kindly provided
by Dr. David Cheresh (University of California, San Diego School of Medicine). All cell lines were maintained in
high-glucose Dulbecco’s minimal essential medium (DMEM, Gibco, Thermo Fisher Scientific) supplemented with
5 % (v/v) fetal bovine serum (FBS, Gibco, Thermo Fisher Scientific) and they were grown at 37 °C in a moisture-
saturated atmosphere containing 5% CO2.
6.33. Antiproliferative activity assay
The growth inhibition potency of all compounds was assessed using the procedure recommended by the National
Cancer Institute (NCI) Developmental Therapeutics Program for its drug screening program with slight
modifications.[31] Briefly, 96-well Costar microtiter clear plates were seeded with 75 µL of a suspension of either
HT-29 (5 x 103), M21 (3 x 103), or MCF7 (3.5 x 103) cells per well in medium. Plates were incubated for 24 h.
Freshly solubilised drugs in DMSO (40 mM) were diluted in fresh medium and 75 µL aliquots containing serially
diluted concentrations of the drug were added. Final drug concentrations ranged from 100 µM to 78 nM. DMSO
concentration was kept constant at < 0.5% (v/v) to prevent any related toxicity. Plates were incubated for 48 h, after
which growth was stopped by the addition of cold trichloroacetic acid to the wells (10% w/v, final concentration).
Afterward, plates were incubated at 4 °C for 1 h. Then, plates were washed 5-times with distilled water and a
sulforhodamine B solution (0.1% w/v) in 1% acetic acid was added to each well. After 15 min at room temperature,
the exceeding dye was removed and was washed 5-times with a solution of 1% acetic acid. Bound dye was
solubilized in 20 mM Tris base and the absorbance was read using an optimal wavelength (530-580 nm) with a
SpectraMax® i3x (Molecular Devices). Data obtained from treated cells were compared to the control cell plates
fixed on the treatment day and the percentage of cell growth was thus calculated for each drug. The experiments
were done at least twice in triplicate. The assays were considered valid when the coefficient of variation was < 10%
for a given set of conditions within the same experiment.
AKCNOWLEDGMENTS
This work was supported by the Réseau Québécois de Recherche sur les Médicaments (RQRM), the Natural
Sciences and Engineering Research Council of Canada (NSERC), , the Fonds de Recherche du Québec – Nature et
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10.1002/cbic.201800247
ChemBioChem
Technologies (FRQNT), Université Laval and CHU de Québec-Université Laval Research Center. Finally, T. T.
acknowledge PROTEO for a postgraduate fellowship.
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