Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2?ligand: Structure?activity studies and biological evaluation

Article abstract of DOI:10.1016/j.ejmech.2017.05.024

The design, synthesis, and SAR study of a new series of HIV-1 protease inhibitors incorporating stereochemically defined tetrahydrofuran-tertiary amine-acetamide P2-ligand are described. Various substituent effects on the tertiary amine P2-ligand and phenylsulfonamide P2′-ligand were investigated to maximize the ligand-binding site interactions in the protease active site. Most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Inhibitor 20e containing N-(S-tetrahydrofuran)-N-(2-methoxyethyl)acetamide as P2-ligand along with 4-methoxylphenylsulfonamide as P2′-ligand displayed the most potent enzyme inhibitory activity (IC₅₀ = 0.35 nM) and remarkably low cytotoxicity (CC₅₀ = 305 μM).

Full text of DOI:10.1016/j.ejmech.2017.05.024

Accepted Manuscript
Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-
tertiary amine-acetamide as P2−ligand: Structure−activity studies and biological
evaluation
Xiaoguang Bai, Zhiheng Yang, Mei Zhu, Biao Dong, Lei Zhou, Guoning Zhang, Juxian
Wang, Yucheng Wang
PII:
S0223-5234(17)30385-9
10.1016/j.ejmech.2017.05.024
EJMECH 9454
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 21 April 2017
Revised Date: 5 May 2017
Accepted Date: 7 May 2017
Please cite this article as: X. Bai, Z. Yang, M. Zhu, B. Dong, L. Zhou, G. Zhang, J. Wang, Y. Wang,
Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-
acetamide as P2−ligand: Structure−activity studies and biological evaluation, European Journal of
Medicinal Chemistry (2017), doi: 10.1016/j.ejmech.2017.05.024.
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Graphical Abstract:
Ra
O
O
O
N
S
N
N
*
Rb
H
OH
S2-subsite
(Asp29/30)
S2'-subsite
(Asp30')
O
P2-ligand
P2'-ligand
Target compounds (48 prepared)

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Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2−ligand:
structure−activity studies and biological evaluation
a
a
a
a
Xiaoguang Bai a, †, Zhiheng Yang b, †, Mei Zhu , Biao Dong , Lei Zhou , Guoning Zhang , Juxian Wang a, *, Yucheng
Wang a,
*
a
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College,
Beijing 100050, China
b Department of Pharmacy, the First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
* Corresponding author. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union
Medical College, Beijing 100050, China. Tel./Fax: +86-010-6316-5263. E-mail address: imbjxwang@163.com (J Wang);
wangyucheng@imb.pumc.edu.cn (Y Wang).
†
These authors contributed equally to this work.
ABSTRACT
The design, synthesis, and SAR study of a new series of HIV-1 protease inhibitors incorporating stereochemically
defined tetrahydrofuran-tertiary amine-acetamide P2-ligand are described. Various substituent effects on the tertiary
amine P2-ligand and phenylsulfonamide P2΄-ligand were investigated to maximize the ligand-binding site interactions in
the protease active site. Most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Inhibitor 20e
containing N-(S-tetrahydrofuran)-N-(2-methoxyethyl)acetamide as P2-ligand along with 4-methoxylphenylsulfonamide
as P2΄-ligand displayed the most potent enzyme inhibitory activity (IC50 = 0.35 nM) and remarkably low cytotoxicity
(CC50 = 305 µM).
Keywords: HIV-1 protease; Inhibitors; P2 ligand; Enzyme; Design
1. Introduction
HIV/AIDS continues to be one of the most challenging problems in medicine. In 2015, an estimated 36.7 million
people were living with HIV and 1.1 million people died of AIDS-related illnesses [1]. The highly active antiretroviral
therapy treatment (HAART) strategy has significantly reduced HIV/AIDS-related mortality. As critical components of
antiretroviral therapy, HIV-1 protease inhibitors (HIV-1 PIs) continue to play an important role in the treatment of
HIV/AIDS [2‒4]. To date, nine HIV-1 PIs have been approved by the FDA [5]. However, the rapid emergence of
multi-drug-resistant strains of HIV-1 protease (HIV-1 PR) has severely limited long-term treatment options [5‒8]. Thus,
the design of novel HIV-1 PIs with improved potency against resistant viral strains is urgent more than ever.

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One effective design strategy of eliminating drug resistance is to maximize interactions between inhibitor and the
protease, especially promote extensive hydrogen bond interactions with backbone atoms and residues in the protease
active site [9‒14]. For example, the stereochemically defined P2-ligands bis-tetrahydrofuran (THF) of Darunavir (DRV)
[9, 14], mono-THF of amprenavir (APV) [15], tris-THF of GRL-0519 [16] and Tp-THF of GRL-0476 [17] introduce
more hydrogen bonds through cyclic ether oxygens with main chain atoms of the protease residues in S2-subsite, such as
amide NH of Asp29/Asp30. We have recently reported a number of potent inhibitors with a substituted-phenyl-tertiary
amine-acetamide structural template [18], splitting from the bis-THF of DRV by scaffold hopping method, as the
P2-ligand to enhance interactions with the protein backbone in the S2-subsite. One inhibitor containing
N-(2,6-di-methylphenyl)-N-(2-morpholino-2-oxoethyl)acetamide group as P2-ligand along with a
4-methoxylphenylsulfonamide as P2΄-ligand displayed a decent inhibitory activity with enzymatic IC50 of 15 nM (Fig. 1).
However, its potency is not nearly as DRV in low picomolar range.
To further optimize this tertiary amine structural template, our inhibitor design strategy focused on the cyclic ether
oxygen of DRV and APV. In this work, we incorporated a stereochemically defined THF ring utilizing our previous
tertiary amine structural template as the P2-ligand to probe potential favorable interactions to Asp29/Asp30 of the HIV-1
protease backbone (Fig. 1). Two marked differences of this P2 ligand from DRV and APV are included as follows: (a)
the flexible acetamide structure may possess automatic fine tuning function to enhance interactions; (b) Ra substituent on
the tertiary amine including small and with both hydrogen bond-donating and -accepting capability groups may make
additional interactions in the protease active site. Additionally, both modifications of the substitution pattern on the
phenylsulfonamide P2΄-ligand of all series and the configuration of N-THF on P2-ligand of selected inhibitors were
synthesized for the structure activity relationship (SAR) study.
2. Results and discussion
2.1. Chemistry
The syntheses of (S) and (R)-THF-tertiary amine-acetamide P2-ligand are shown in Scheme 1. N-alkylation of
commercially available optically (S)-3-aminotetrahydrofuran hydrochloride (1) with benzyl-2-bromoacetate gave the
requisite (S)-benzyl ester 3a in 56% yield. Similarly, (R)-benzyl ester 3g was prepared from (R)-3-aminotetrahydrofuran
hydrochloride (2) in 61% yield. The further N-alkylations of the resulting secondary amines 3a or 3g as tertiary amine
were accomplished through three different conditions. Compound 3a was heated with bromoalkane in dimethyl
formamide and K2CO3 as a base provided the corresponding tertiary amines 3b-d in 66-77% yields. However, a severe
condition utilizing microwave assisted synthesis was required for N-(2-Methoxyethyl) tertiary amines 3e and 3h. It was
found the reaction could be finished within a short time of 0.5 h with fewer impurities and moderate yield using a

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Microwave Synthesizer at 130 °C under 80 W. Mild N-alkylation of 3a with methylsulfonyl chloride using DIEA/DMAP
in methylene chloride afforded 3f in 78% yield.
In Scheme 2, amines 14‒16 were readily prepared starting from commercial available epoxide 5 as described in the
literature [18, 19], and unreported amines 17‒19 were obtained similarly by coupling 6 with corresponding aryl sulfonyl
chlorides and then Boc-deprotection. At the same time, the so obtained optically (S) and (R)-benzyl esters 3a‒h were
saponified using 3 equivalents of NaOH in methanol/methylene chloride (1:3, v/v) and then acidified with 2 N HCl to
give free acids 4a‒h. Finally, the syntheses of inhibitors 20‒29 were carried out by coupling acids 4a‒h with amines 14‒
19 through an EDCI/HOBt/Et3N mediated coupling method [18]. Catalytic hydrogenation of 21a‒f over 5% Pd/C in
methanol afforded the corresponding aminosulfonamide derivatives 22a‒f. The inhibitor structures are shown in Tables 1
and 2.
2.2. Structure activity relationships
The enzyme inhibitory activity of the synthetic compounds against HIV-1 wild-type protease was evaluated using a
fluorescence resonance energy transfer (FRET) method [20, 21]. As a reference the best marketed compound DRV has
also been included. Various (S)-THF-tertiary amine-acetamide P2-ligands were investigated in combination with other
phenylsulfonamide substituents as P2΄-ligand in the protease S2΄-site. On the basis of the exhibited enzyme inhibitory
potency, selected inhibitors were further evaluated in cytotoxicity assay using a cell counting kit-8 assay [22]. The results
are presented in Tables 1 and 2.
In general, inhibitors with (S)-THF-tertiary amine-acetamide P2-ligand showed impressive enzymatic activity. As
can be seen in Table 1, most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Series of
inhibitors 20e‒26e with N-(S-THF)-N-(2-methoxyethyl)acetamide as P2-ligand were significantly more potent than other
series. Among them, compounds 20e, 22e and 26e displayed very impressive inhibitory activity (IC50 = 0.35‒0.88 nM).
Firstly, we believed that the (S)-THF-substituted tertiary amine P2-ligand was responsible for the generally and
significantly enhanced potency compared to the corresponding inhibitors with phenyl-substituted tertiary amine
P2-ligand in our previous work [18]. This suggested that (S)-THF P2-ligand may make additional interactions with the
backbone atoms and residues in the protease S2-subsite. The ether oxygen of (S)-THF was very likely to form hydrogen
bond interaction with the amide NH of Asp29/Asp30, similar to the cyclic THF of APV [16], DRV [14, 23] and other
cyclic ethers as P2 ligands reported by Ghosh et al [10, 17, 24], and this appears to enhance the affinity of the inhibitor.
Secondly, the substituent Ra on the tertiary amine P2-ligand played a regulatory role on potency. For example, the
potency of inhibitors 20a‒f with different Ra substituents changed dramatically in a range from 0.35 to 44.0 nM of
enzymatic IC50 value. Among them, inhibitor 20e with an N-(2-methoxyethyl) group displayed the most potency of 0.35

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nM than others. Whereas, inhibitors (20b‒d, 20f to 26b‒d, 26f) with N-acetamino or N-methylsulfonyl on the tertiary
amine have shown a sharp reduction in potency, most of them were even inferior to the corresponding inhibitors of 20a‒
26a with no substituent of Ra. However, two thirds of them still remained in the low nanomolar range (IC50 = 9.9‒98.1
nM). We speculated that the relatively massive and rigid structures such as methylsulfonyl and substituted carbamoyl
groups in P2-ligand may not be beneficial to the binding interactions between (S)-THF and the backbone atoms and
residues in the protease S2-subsite. But inhibitors of 20e‒26e with flexible N-(2-methoxyethyl) group might have a
favorable synergistic effect with (S)-THF and form possible water-mediated interactions with some residues in the active
site [10, 14‒17]. Therefore, Ra substituent on the P2-ligand including flexible and with hydrogen bond-accepting
capability groups may make additional interactions in the protease active site.
Meanwhile, functionalized P2΄-phenylsulfonamide ligand also plays a vital role in the potency of inhibitors. As
shown in Table 1, phenylsulfonamide derivatives with 4-methoxyl (20a‒f), 4-amino (22a, 22c, 22e and 22f),
4-hydroxymethyl (23a‒c, 23e and 23f) or 3,4-dioxole (26a‒f) substituent displayed generally higher potency than the
corresponding substituted compounds with 4-trifluoromethoxy (24a‒f), 3,4-dimethoxy (25a‒f) or 4-nitro (21a, 21c, 21e
and 21f) substituent. Among them, inhibitors 20a, 22a, 26a, 20e, 22e and 26e displayed excellent potency in a low
nanomolar range (IC50 = 0.35‒10.2 nM). For the impressive activity of inhibitors 20a, 20e, 26a and 26e, the P2΄ oxygen
atom (OMe and 3,4-OCH2O) of phenylsulfonamide isostere is likely to form hydrogen bond (O···H-N) with the
main-chain amide of Asp30΄ in the protease S2΄-subsite, similar as inhibitors GRL-0489A [10], TMC-126 [10],
GRL-0519A [16], and GRL-0467 [17]. With respect to the impressive activity of inhibitors 22a, 23a‒b, 22e, 23e, and 26e,
we speculated that the terminal amino of aniline (‒C6H4-NH2) moiety and the terminal hydroxyl of benzyl alcohol (‒
C6H4-CH2-OH) moiety might make similar weak hydrogen bond (N-H···N and O-H···N, respectively) and
water-mediated (NHinh···H2O···OOC and OHinh···H2O···OOC, respectively) interactions with the main-chain amide and
side chain oxygen of Asp30΄ in S2΄ binding subsite as does APV [16] or GRL-06579A [19]. However, with respect to the
unsatisfactory activity of inhibitors 21a-f and 24a-f, the strong electron withdrawing group such as 4-nitro or
4-trifluoromethoxy substituent would not only reduce the electron density of the oxygen atom itself via inductive effects
but also the oxygen atom on the sulfonyl group via conjugative effects. This would directly reduce the ability of oxygen
atom as a hydrogen bond-accepting group to form hydrogen bond with the amide of Asp30΄(phenyl-Oinh···N-H) [10, 16,
17] or water-mediated interactions with the amide of Ile50΄ (SO2inh···H2O···N-H) [11, 16] in the generally conserved
protease S2΄-subsite. Therefore, Rb substituent on the P2΄-phenylsulfonamide ligand including electron donating group
and with hydrogen bond-donating or -accepting capability groups could make additional interactions in the protease
active site.

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Our depicted synthesis route allowed us to prepare another enantiomer of the THF P2-ligand. In Table 2, we have
also prepared and evaluated the effect of enantiomerically pure ligands with a (R)-THF ring stereochemistry, which
showed a substantial reduction as micromolar potency. And (S)-THF P2-ligand-derived inhibitors exhibited more
impressive enzyme inhibitory potency, consistent with the (S)-THF P2 ligand of APV [15] and 4(S)-Cyclohexyl P2
ligand-derived inhibitors reported by Ghosh et al [16]. It suggested that the (S)-configuration is beneficial to form the
important binding interactions between the P2-ligand and the backbone atoms and residues in the protease active site.
Additionally, (S)-THF ligand-derived inhibitors displayed remarkably low cytotoxicity compared to the corresponding
(R)-THF ligand-derived inhibitors. In particular, the most potent inhibitor 20e in this work exhibited remarkably low
cytotoxic CC50 value compared to DRV (305 µM vs 245 µM).
3. Conclusion
In summary, we have reported the structure-based design of novel HIV-1 protease inhibitors incorporating a
stereochemically defined (S)-THF-tertiary amine-acetamide as the P2-ligands and phenylsulfonamide isostere as the
P2΄-ligand. The inhibitors were designed to make extensive interactions with the protein backbone of the HIV-1 protease
active site. The syntheses of (S) and (R)-tetrahydrofuran-tertiary amine-benzyl acetates were carried out using
enantiomerically pure (S) and (R)-3-aminotetrahydrofuran hydrochlorides as the starting materials. It was found that
inhibitors with (S)-THF-tertiary amine-acetamide P2-ligand had significantly enhanced potency. In particular, inhibitor
20e incorporating N-(S-THF)-N-(2-methoxyethyl)acetamide as P2-ligand and 4-methoxylphenylsulfonamide isostere as
P2΄-ligand displayed remarkable and closest enzyme inhibitory potency (IC50 = 0.35 nM) compared to the best FDA
approved DRV and also exhibited impressive low cytotoxicity (CC50 = 305 µM). SAR studies indicated that the
stereochemistry of (S)-THF ring and the flexibility of the substituent Ra on the tertiary amine P2-ligand are critical to the
ligand’s high enzyme affinity. Extensive interactions with the HIV-1 protease active site might be responsible for
inhibitor 20e’s potent enzymatic activity. Further evaluation on drug-resistance profiles and continued design and
optimization of inhibitors utilizing this molecular insight are in progress.
4. Experimental section
4.1. HIV-1 protease inhibition assays [18]
The HIV-1 protease inhibitory activities of all new designed inhibitors were measured using fluorescence resonance
energy transfer (FRET) method [20, 21]. Peptide (Arg-Glu
(EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Lys(DABCYL)-Arg) purchased from AnaSpec was selected as the substrate.
The energy transfer donor (EDANS) and acceptor (DABCYL) dyes are labeled at two ends of the peptide to perform
FRET. Excitation and emission wavelengths were set at 340 nm and 490 nm. Inhibitors were dissolved in

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dimethylsulfoxide (DMSO) and diluted to appropriate concentrations. HIV-1 protease was cloned and heterologously
expressed in Escherichia coli and purified. The experiment was carried out in 96-well plates. The FRET assay reaction
buffer contained 0.1 M sodium acetate, 1 M sodium chloride, 1 mM ethylenediaminetetraacetic acid (EDTA), 1 mM
dithiothreitol (DTT), 2% DMSO and 1 mg/mL bovine serum albumin (BSA) with an adjusted pH 4.7. Protease and
inhibitor were mixed and incubated for 20-30 min at room temperature and then the substrate was added. Each reaction
was recorded for about 10 min.
4.2. Cytotoxicity assay
Selected inhibitors were further evaluated in cytotoxicity assay using a cell counting kit-8 assay [22].
4.3. General methods
All experiments requiring anhydrous conditions were conducted in flame-dried glassware fitted with rubber septa
under a positive pressure of dry nitrogen, unless otherwise noted. THF was distilled under argon from
sodium-benzophenone ketyl and CH2Cl2 was distilled under argon from calcium hydride. All reactions were monitored
by thin-layer chromatography on silica gel plates (GF-254) and visualized with UV light. Flash column chromatography
was performed on a CombiFlash®Rf 200 system employing silica gel (50-75 µm, Qingdao Haiyang Chemical Co.,Ltd).
Microwave assisted synthesis was carried on a CEM Discover Microwave Synthesizer. Melting points were taken on
MP70 Melting Point System with uncorrected. High resolution mass spectra were obtained on an Autospee Ultima-TOF
spectrometer. 1H NMR and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 on a Bruker AVANCE III 400 MHz,
500 MHz, or 600 MHz spectrometer (Bruker Inc) with tetramethylsilane (TMS) as an internal reference. The chemical
1
shifts are given in δ (ppm) referenced to the respective solvent peak (CDCl3: H, δ = 7.26 ppm, 13C, δ = 77.16 ppm;
1
CD3OD: H, δ = 3.31 ppm, 13C, δ = 49.00 ppm), and coupling constants are reported in Hz. All target compounds were
characterized by 1H and 13C NMRs and HRMS spectra.
4.4. Synthetic experiments
Compounds 6, 7-10 and 14-16 were prepared as previously reported [18, 19].
4.4.1. (S)-Benzyl 2-((Tetrahydrofuran-3-yl)amino)acetate (3a). To a stirred solution of (S)-3-aminotetrahydrofuran
hydrochloride (16.0 g, 130 mmol) in anhydrous THF (250 mL) at 0° C was added dropwise Et3N (41.5 mL, 298 mmol)
within 20 min and stirred another 20 min, then a solution of benzyl 2-bromoacetate (29.6 g, 130 mmol) was added slowly
at 0° C followed by NaI (1.90 g, 13.0 mmol). The reaction mixture was stirred at 0° C for 30 min and then allowed to
warm to room temperature and stirred overnight. The solvent was removed under diminished pressure and the residue
was treated with water (200 mL) and extracted with three 150 mL portions of ethyl acetate. The combined organic
extracts were dried over Na2SO4 and concentrated under diminished pressure. The residue was purified by

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chromatography on a silica gel column (30 × 6 cm). Elution with 3:1 hexanes–ethyl acetate gave 3a as a yellow oil: yield
17.1 g (56.1%). 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.30 (m, 5H), 5.16 (s, 2H), 3.91 (dd, J = 15.6, 7.6 Hz, 1H), 3.80 –
3.74 (m, 2H), 3.57 (dd, J = 9.2, 3.6 Hz, 1H), 3.44 (d, J = 1.2 Hz, 2H), 3.41 – 3.36 (m, 1H), 2.08 – 2.00 (m, 1H), 1.76 –
1.68 (m, 2H); LC-MS (ESI) [M + H]+ m/z 236.2.
4.4.2. (S)-Benzyl 2-((2-Amino-2-oxoethyl)(tetrahydrofuran-3-yl)amino)acetate (3b). To a solution of compound 3a (2.00
g, 8.51 mmol) in DMF (10 mL) was added 2-bromoacetamide (1.17 g, 8.51 mmol) and K2CO3 (2.35 g, 17.0 mmol). The
reaction mixture was stirred for 1~2 h at 90°C. After cooling to room temperature, the reaction mixture was diluted with
60 mL of water and extracted with 100 mL of ethyl acetate. The organic extracts were washed with two 60 mL portions
of water and then 80 mL of saturated brine and dried over Na2SO4 and concentrated under diminished pressure. The
residue was purified by chromatography on a silica gel column (20 × 4 cm). Elution with 10:1 hexanes–ethyl acetate
gave 3b as a colorless oil: yield 2.10 g (76.9%). 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.42 – 7.34 (m, 5H), 6.20 (s,
1H), 5.18 (s, 2H), 3.97 (td, J = 8.4, 4.4 Hz, 1H), 3.76 – 3.66 (m, 3H), 3.62 – 3.55 (m, 1H), 3.53 – 3.43 (m, 2H), 3.33 –
3.22 (m, 2H), 2.12 – 2.04 m, 1H), 1.86 – 1.77 (m, 1H).
4.4.3. (S)-Benzyl 2-((2-(Dimethylamino)-2-oxoethyl)(tetrahydrofuran-3-yl)amino)acetate (3c). The title compound was
obtained through N-alkylation of 3a with N,N-dimethyl-bromoacetamide in 69.3% yield (colorless oil) as described for
3b. 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.30 (m, 5H), 5.13 (s, 2H), 3.94 (td, J = 8.6, 4.2 Hz, 1H), 3.80 – 3.75 (m, 1H),
3.73 – 3.68 (m, 3H), 3.63 – 3.61 (m, 1H), 3.59 – 3.51 (m, 3H), 3.01 (s, 3H), 2.91 (s, 3H), 2.08 – 2.01 (m, 1H), 1.92 – 1.83
(m, 1H); LC-MS (ESI) [M + H]+ m/z 321.3.
4.4.4. (S)-Benzyl 2-((2-Morpholino-2-oxoethyl)(tetrahydrofuran-3-yl)amino)acetate (3d). The title compound was
obtained through N-alkylation of 3a with 2-bromo-1-morpholinoethanone in 66.3% yield (colorless oil) as described for
3b. 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.30 (m, 5H), 5.13 (s, 2H), 3.95 (td, J = 8.8, 4.4 Hz, 1H), 3.74 – 3.72 (m, 2H),
3.69 – 3.53 (m, 12H), 3.49 – 3.44 (m, 2H), 2.09 – 2.01 (m, 1H), 1.90 – 1.81 (m, 1H); LC-MS (ESI, M + H+) m/z 363.3.
4.4.5. (S)-Benzyl 2-((2-Methoxyethyl)(tetrahydrofuran-3-yl)amino)acetate (3e). To a solution of compound 3a (2.00 g,
8.51 mmol) in DMF (8 mL) was added 0.80 mL (1.18 g, 8.51 mmol) of 2-bromo-1-methoxyethane and K2CO3 (2.35 g,
17.0 mmol) and tetrabutyl ammonium iodide (TBAI, 0.31g, 0.85 mmol). The reaction mixture was stirred in a CEM
Discover Microwave Synthesizer for 0.5 h at 130°C under 80 W. After cooling to room temperature, the reaction mixture
was diluted with water (60 mL) and extracted with 100 mL of ethyl acetate. The organic extracts were washed with two
60 mL portions of water and then saturated brine (80 mL) and dried over Na2SO4 and concentrated under diminished
pressure. The residue was purified by chromatography on a silica gel column (20 × 4 cm). Elution with 10:1 hexanes–
ethyl acetate gave 3e as a colorless oil: yield 1.42 g (56.8%). 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.27 (m, 5H), 5.14 (s,

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2H), 3.93 (td, J = 8.8, 4.0 Hz, 1H), 3.83 – 3.76 (m, 1H), 3.72 – 3.63 (m, 3H), 3.52 (d, J = 1.6 Hz, 2H), 3.46 (t, J = 5.6 Hz,
2H), 3.28 (s, 3H), 2.93 – 2.79 (m, 2H), 2.08 – 2.00 (m, 1H), 1.87 – 1.78 (m, 1H); LC-MS (ESI) [M + H]+ m/z 294.2.
4.4.6. (S)-Benzyl 2-(N-(Tetrahydrofuran-3-yl)methylsulfonamido)acetate (3f). To a stirred solution of compound 3a (2.50
g, 10.6 mmol) in anhydrous DCM (30 mL) was added 2.63 mL (2.05 g, 15.9 mmol) of DIEA and DMAP (0.13 g, 1.06
mmol) and cooled to 0 °C. To the mixture, a solution of 1.07 mL (1.58 g, 13.8 mmol) of methanesulfonyl chloride in
DCM (20 mL) was added dropwise at 0 °C. After the addition was done, the reaction was transferred to room
temperature and stirred for 1.5 h. The solvent was removed under diminished pressure and the residue was treated with
water (30 mL) and extracted with three 40 mL portions of ethyl acetate. The combined organic extracts were dried over
Na2SO4 and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column
(20 × 4 cm). Elution with 3:1 hexanes–ethyl acetate gave 3f as a yellow oil: yield 2.60 g (78.3%). 1H NMR (400 MHz,
CDCl3) δ 7.40 – 7.32 (m, 5H), 5.21 – 5.14 (m, 2H), 4.54 – 4.48 (m, 1H), 4.20 (d, J = 18.4 Hz, 1H), 4.11 (d, J = 18.4 Hz,
1H) 3.95 (td, J = 8.8, 4.8 Hz, 1H), 3.83 (dd, J = 10.0, 3.2 Hz, 1H), 3.69 (dd, J = 10.0, 6.4 Hz, 1H), 3.61 (dd, J = 16.8, 8.0
Hz, 1H), 3.07 (s, 3H), 2.33 – 2.25 (m, 1H), 1.96 – 1.88 (m, 1H); LC-MS (ESI) [M + Na]+ m/z 336.2.
4.4.7. (R)-Benzyl 2-((Tetrahydrofuran-3-yl)amino)acetate (3g). The title compound was obtained through N-alkylation of
(R)-3-aminotetrahydrofuran hydrochloride with benzyl 2-bromoacetate in 60.6% yield (light yellow oil) as described for
3a. LC-MS (ESI) [M + Na]+ m/z 258.2.
4.4.8. (R)-Benzyl 2-((2-Methoxyethyl)(tetrahydrofuran-3-yl)amino)acetate (3h). The title compound was obtained
through N-alkylation of 3g hydrochloride with 2-bromo-1-methoxyethane in 63.2% yield (colorless oil) as described for
3e. LC-MS (ESI) [M + Na]+ m/z 316.1.
4.4.9. Tert-butyl
((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-(trifluoromethoxy)phenylsulfonamido)-1-phenylbutan-2-yl)carbamate (11) [18].
To an ice-cooled solution of the secondary amine 6 (5.00 g, 14.9 mmol) in anhydrous THF (40 mL) was added 3.68 mL
(2.11g, 16.3 mmol) of DIEA and DMAP (0.18 g, 1.49 mmol) followed by the addition of
4-(trifluoromethoxy)benzenesulfonyl chloride (4.25 g, 16.3 mmol) solution in anhydrous THF (15 mL) slowly. After
stirring 0.5 h at 0 oC, the reaction mixture was warmed to room temperature and stirred 3~5 h. The solvents were
removed under diminished pressure and the residue was added water (30 mL) and extracted with three 40 mL portions of
ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated under diminished pressure. The
residue was purified by chromatography on a silica gel column (20 × 4 cm). Elution with 5:1 hexanes–ethyl acetate gave
11 as a colorless solid: yield 7.49 g (89.7%), mp 136–138°C. 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.81 (m, 2H), 7.33 (d,
J = 8.4 Hz, 2H), 7.30 – 7.28 (m, 2H), 7.25 – 7.21 (m, 3H), 4.63 (d, J = 6.8 Hz, 1H), 3.82 – 3.76 (m, 2H), 3.13 – 3.11 (m,

ACCEPTED MANUSCRIPT
2H), 3.03 – 2.86 (m, 4H), 1.92 – 1.82 (m, 1H), 1.35 (s, 9H), 0.90 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H); LC-MS
(ESI) [M + H]+ m/z 561.0.
4.4.10. Tert-butyl ((2S,3R)-3-Hydroxy-4-(N-isobutyl-3,4-dimethoxyphenylsulfonamido)-1-phenylbutan-2-yl)carbamate
(12). The title compound was obtained through N-sulfonylation of 6 with 3,4-dimethoxybenzenesulfonyl chloride in 65.3%
yield (colorless solid) as described for 11, mp 125–126°C. 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 8.5, 2.1 Hz, 1H),
7.31 – 7.20 (m, 6H), 6.93 (d, J = 8.5 Hz, 1H), 4.60 (d, J = 7.0 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.80 – 3.74 (m, 2H),
3.18 – 3.07 (m, 2H), 3.01 (dd, J = 14.1, 4.4 Hz, 1H), 2.97 – 2.91 (m, 2H), 2.85 (dd, J = 13.5, 6.9 Hz, 1H), 1.91 – 1.81 (m,
1H), 1.33 (s, 9H), 0.91 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H); LC-MS (ESI) [M + H]+ m/z 537.0.
4.4.11. Tert-butyl ((2S,3R)-3-Hydroxy-4-(N-isobutylbenzo[d][1,3]dioxole-5-sulfonamido)-1-phenylbutan-2-yl)carbamate
(13). The title compound was obtained through N-sulfonylation of 6 with 1,3-benzodioxole-5-sulphonyl chloride in 71.2%
yield (colorless solid) as described for 11, mp 93–94°C. 1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 8.2, 1.9 Hz, 1H),
7.32 – 7.28 (m, 2H), 7.25 – 7.19 (m, 3H), 7.18 (d, J = 1.8 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.08 (s, 2H), 4.65 (d, J = 7.5
Hz, 1H), 3.78 – 3.75 (m, 2H), 3.08 – 3.06 (m, 2H), 3.01 (dd, J = 14.2, 4.8 Hz, 1H), 2.97 – 2.87 (m, 2H), 2.82 (dd, J =
13.3, 6.8 Hz, 1H), 1.90 – 1.80 (m, 1H), 1.35 (s, 9H), 0.91 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H); LC-MS (ESI) [M
+ H]+ m/z 521.0.
4.4.12. N-((2R,3S)-3-Amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-(trifluoromethoxy)benzenesulfonamide (17) [18]. To
a stirred solution of 11 (5.53 g, 9.87 mmol) in 10 mL of anhydrous DCM was slowly added 10 mL of TFA at 0oC. After
stirring 3 h at room temperature, the mixture was concentrated under diminished pressure. The residue was diluted with
water (50 mL) and alkalized with saturated NaHCO3 until pH ~ 9 with vigorous stirring. A white precipitation was
formed and kept stirring for 0.5 h. A white cake was obtained by filtration and then purified by chromatography on a
silica gel column (20 × 6 cm). Elution with 10:1 DCM–methanol gave 17 as a colorless solid: yield 3.27 g (71.8%), mp
151–152°C. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 8.8 Hz, 2H), 7.72 (s, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.39 –
7.27 (m, 5H), 6.00 – 5.60 (m, 1H), 3.95 (s, 1H), 3.50 – 3.43 (m, 1H), 3.37 (dd, J = 14.8, 4.4 Hz, 1H), 3.04 – 2.93 (m, 3H),
2.80 – 2.73 (m, 2H), 1.93 – 1.86 (m, 1H), 0.82 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H); LC-MS (ESI) [M + H]+ m/z
461.2.
4.4.13. N-((2R,3S)-3-Amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-3,4-dimethoxybenzenesulfonamide (18). The title
compound was obtained through N-Boc deprotection of 12 in 78.2% yield (colorless solid) as described for 17, mp 94–
95°C. 1H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J = 8.0 Hz, 1H), 7.30 – 7.17 (m, 6H), 7.12 (d, J = 8.4 Hz, 1H), 4.77 (s,
1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.49 – 3.45 (m, 2H), 3.02 – 2.95 (m, 2H), 2.87 – 2.80 (m, 3H), 2.37 (dd, J = 12.0, 8.8 Hz,
1H), 1.98 – 1.93 (m, 1H), 0.85 (d, J = 6.4 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H); LC-MS (ESI, M + H+) m/z 437.3.

ACCEPTED MANUSCRIPT
4.4.14. N-((2R,3S)-3-Amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzo[d][1,3]dioxole-5-sulfonamide (19). The title
compound was obtained through N-Boc deprotection of 13 in 80.5% yield (colorless solid) as described for 17, mp 104–
106°C. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 2H), 7.38 – 7.26 (m, 7H), 7.08 (d, J = 8.4 Hz, 1H), 6.19 (s, 2H), 5.68 (d,
J = 2.4 Hz, 1H), 3.98 (s, 1H), 3.50 – 3.47 (m, 1H), 3.36 (dd, J = 14.8, 5.2 Hz, 1H), 3.04 (dd, J = 14.4, 5.6 Hz, 1H), 2.94
(dd, J = 13.6, 8.4 Hz, 1H), 2.87 (dd, J = 14.4, 7.6 Hz, 1H), 2.82 – 2.70 (m, 2H), 1.94 – 1.84 (m, 1H), 0.83 (d, J = 6.4 Hz,
3H), 0.77 (d, J = 6.4 Hz, 3H); LC-MS (ESI) [M + H]+ m/z 421.3.
4.4.15.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl)-2-(((S)-tetrahydrofuran-3-yl)am
ino)acetamide (20a). To a stirred solution containing benzyl ester 3a (0.13 g, 0.55 mmol) in 2 mL of 3:1 DCM–MeOH
was added NaOH (66.0 mg, 1.65 mmol). The reaction mixture was stirred at room temperature for 1 h, and then
concentrated under diminished pressure. The residue was diluted with water (5 mL) and extracted with three 5 mL
portions of ether. The aqueous phase was then acidified with 2 N HCl to pH~3 and extracted with three 5 mL portions of
ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated to dryness under diminished
pressure and gave a crude of acid 4a, which was redissolved into anhydrous DMF (6 mL) and followed by the addition of
1-hydroxybenzotriazole (82.0 mg, 0.61 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (160 mg,
0.83 mmol), and 156 µL (113 mg, 1.10 mmol) of triethylamine. The mixture was stirred at room temperature for 1 h and
then a solution of 14 (220 mg, 0.55 mmol) in 1 mL of anhydrous DMF was added, the solution was stirred at room
temperature for overnight. The reaction mixture was poured onto 30 g of ice-water with stirring. A white precipitation
was formed. A white cake was obtained by filtration and then purified by chromatography on a silica gel column (18 × 2
cm). Elution with 5:1 ethyl acetate–methanol gave 20a as a colorless oil: yield 0.20 g (69.0% over two steps). 1H NMR
(500 MHz, CDCl3) δ 7.76 – 7.72 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.34 – 7.21 (m, 5H), 7.00 (d, J = 9.0 Hz, 2H), 4.20 –
4.15 (m, 1H), 3.94 – 3.91 (m, 1H), 3.89 (s, 3H), 3.85 (dd, J = 16.0, 8.0 Hz, 1H), 3.80 – 3.69 (m, 1H), 3.63 (dd, J = 9.5,
5.5 Hz, 1H), 3.47 (dd, J = 9.0, 3.0 Hz, 1H), 3.22 – 3.14 (m, 2H), 3.11 – 3.07 (m, 2H), 3.05 – 3.00 (m, 1H), 2.98 (dd, J =
14.0, 10.0 Hz, 1H), 2.93 – 2.88 (m, 2H), 1.98– 1.85 (m, 3H), 1.61 – 1.55 (m, 1H), 0.91 – 0.88 (m, 6H); 13C NMR (125
MHz, CDCl3) δ 172.3, 163.0, 138.0, 130.2, 129.5, 129.3, 128.5, 126.6, 114.3, 72.9, 72.8, 66.9, 58.6, 58.5, 55.6, 54.1, 53.2,
50.5, 34.6, 32.6, 27.2, 20.1, 20.0; HRMS (ESI) m/z calcd. for C27H40N3O6S ([M + H]+): 534.2632, found 534.2627.
4.4.16.
2-((2-Amino-2-oxoethyl)((S)-tetrahydrofuran-3-yl)amino)-N-((2S,3R)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonam
ido)-1-phenylbutan-2-yl)acetamide (20b). The title compound was obtained by saponification of 3b to 4b, which was
then coupled with 14 through an EDC/HOBT/Et3N coupling procedure in 73.5% yield over two steps (colorless oil) as

ACCEPTED MANUSCRIPT
described for 20a. 1H NMR (500 MHz, CDCl3) δ 7.77 – 7.73 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.32 – 7.21 (m, 5H), 7.03
– 7.01 (m, 2H), 6.51 (s, 1H), 5.53 (s, 1H), 4.36 – 4.30 (m, 1H), 4.17 (d, J = 3.0 Hz, 1H), 3.98 – 3.95 (m, 1H), 3.94 – 3.92
(m, 1H), 3.90 (s, 3H), 3.63 – 3.57 (m, 3H), 3.35 – 3.32 (m, 1H), 3.25 (dd, J = 15.0, 4.5 Hz, 1H), 3.17 – 3.03 (m, 6H),
2.98 (dd, J = 14.5, 10.5 Hz, 1H), 2.93 (d, J = 7.5 Hz, 2H), 1.98 – 1.88 (m, 2H), 1.69 – 1.64 (m, 1H), 0.91 (d, J = 4.0 Hz,
3H), 0.90 (d, J = 4.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.1, 171.2, 163.1, 138.0, 130.3, 129.4, 129.2, 128.6,
126.6, 114.4, 72.75, 70.7, 67.6, 63.0, 58.4, 56.9, 56.4, 55.6, 53.9, 52.9, 34.8, 28.8, 27.1, 20.1, 20.0; HRMS (ESI) m/z
calcd. for C29H43N4O7S ([M + H]+): 591.2848, found 591.2845.
4.4.17.
2-((2-(((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl)amino)-2-oxoethyl)((S)-tetra
hydrofuran-3-yl)amino)-N,N-dimethylacetamide (20c). The title compound was obtained by saponification of 3c to 4c,
which was then coupled with 14 through an EDC/HOBT/Et3N coupling procedure in 49.4% yield over two steps
(colorless solid) as described for 20a, mp 50.9–51.7°C. 1H NMR (500 MHz, CDCl3) δ 8.61 (d, J = 9.0 Hz, 1H), 7.76 –
7.73 (m, 2H), 7.24 (d, J = 4.0 Hz, 4H), 7.16 (dq, J = 9.0, 4.0 Hz, 1H), 6.98 – 6.95 (m, 2H), 4.32 – 4.28 (m, 1H), 4.24 –
4.19 (m, 1H), 3.92 – 3.87 (m, 2H), 3.86 (s, 3H), 3.57 (dd, J = 16.0, 8.0 Hz, 1H), 3.54 (d, J = 7.0 Hz, 1H), 3.48 (dd, J =
9.5, 4.5 Hz, 1H), 3.32 (s, 1H), 3.32 – 3.26 (m, 2H), 3.18 – 3.01 (m, 5H), 2.97 (dd, J = 13.5, 7.5 Hz, 1H), 2.92 (s, 3H),
2.92 – 2.87 (m, 2H), 2.88 (s, 3H), 2.87 (d, J = 3.0 Hz, 1H), 1.99 – 1.87 (m, 2H), 1.63 – 1.56 (m, 1H), 0.90 (d, J = 4.0 Hz,
3H), 0.89 (d, J = 4.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.0, 170.5, 162.8, 138.6, 130.8, 129.5, 129.3, 128.2,
126.2, 114.2, 72.9, 70.8, 67.6, 63.0, 57.9, 57.5, 55.6, 54.0, 53.9, 52.6, 36.2, 36.0, 34.8, 29.3, 27.0, 20.1, 20.0; HRMS (ESI)
m/z calcd. for C31H46N4O7SNa ([M + Na]+): 641.2979, found 641.2988.
4.4.18.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-morpholino-2-oxoethyl)((
S)-tetrahydrofuran-3-yl)amino)acetamide (20d). The title compound was obtained by saponification of 3d to 4d, which
was then coupled with 14 through an EDC/HOBT/Et3N coupling procedure in 65.3% yield over two steps (colorless oil)
as described for 20a. 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 9.0 Hz, 2H), 7.25 – 7.23 (m,
4H), 7.20 – 7.15 (m, 1H), 6.98 – 6.96 (m, 2H), 4.26 – 4.20 (m, 2H), 3.93 – 3.90 (m, 1H), 3.89 – 3.85 (m, 1H), 3.86 (s,
3H), 3.67 – 3.64 (m, 4H), 3.60 – 3.55 (m, 3H), 3.53 – 3.47 (m, 2H), 3.37 – 3.27 (m, 5H), 3.21 – 3.06 (m, 5H), 2.96 (dd, J
= 13.5, 7.5 Hz, 1H), 2.92 – 2.86 (m, 2H), 1.98 – 1.87 (m, 2H), 1.63 – 1.56 (m, 1H), 0.90 (d, J = 4.0 Hz, 3H), 0.88 (d, J =
4.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.0, 169.3, 162.8, 138.5, 130.7, 129.5, 129.3, 128.3, 126.3, 114.2, 73.0,
70.8, 67.6, 66.8, 66.3, 62.9, 57.9, 57.5, 55.6, 53.9, 53.4, 52.6, 45.0, 42.3, 34., 29.4, 27.1, 20.1, 20.0; HRMS (ESI) m/z
calcd. for C33H48N4O8SNa ([M + Na]+): 683.3085, found 683.3098.

ACCEPTED MANUSCRIPT
4.4.19.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-methoxyethyl)((S)-tetrahy
drofuran-3-yl)amino)acetamide (20e). The title compound was obtained by saponification of 3e to 4e, which was then
coupled with 14 through an EDC/HOBT/Et3N coupling procedure in 63.4% yield over two steps (colorless oil) as
described for 20a. 1H NMR (500 MHz, CDCl3) δ 7.74 – 7.69 (m, 3H), 7.28– 7.17 (m, 5H), 6.98 – 6.95 (m, 2H), 4.46 (d, J
= 2.5 Hz, 1H), 4.15 – 4.10 (m, 1H), 3.89 – 3.82 (m, 2H), 3.85 (s, 3H), 3.58 – 3.53 (m, 2H), 3.47 – 3.43 (m, 1H), 3.38 –
3.33 (m, 1H), 3.29 – 3.21 (m, 3H), 3.26 (s, 3H), 3.11 – 2.98 (m, 4H), 2.95 – 2.86 (m, 3H), 2.63 – 2.58 (m, 1H), 2.51 –
2.47 (m, 1H), 1.94 – 1.85 (m, 2H), 1.55 – 1.48 (m, 1H), 0.89 (d, J = 1.0 Hz, 3H), 0.87 (d, J = 1.0 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 172.5, 162.9, 138.2, 130.5, 129.4, 129.3, 128.5, 126.5, 114.3, 72.8, 70.3, 70.2, 67.7, 62.4, 58.6, 58.4, 55.6,
55.3, 54.2, 53.4, 53.0, 34.6, 29.1, 27.2, 20.1, 20.0; HRMS (ESI)m/z calcd. for C30H45N3O7SNa ([M + Na]+): 614.2870,
found 614.2866.
4.4.20.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl)-2-(N-((S)-tetrahydrofuran-3-yl)
methylsulfonamido)acetamide (20f). The title compound was obtained by saponification of 3f to 4f, which was then
coupled with 14 through an EDC/HOBT/Et3N coupling procedure in 73.6% yield over two steps (colorless solid) as
described for 20a, mp 64.3–66.0°C. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.5 Hz, 2H), 7.29 – 7.18 (m, 5H), 6.97 (d,
J = 9.0 Hz, 2H), 6.40 (d, J = 9.0 Hz, 1H), 4.43 – 4.38 (m, 1H), 4.25 – 4.20 (m, 1H), 3.91 (s, 1H), 3.88 – 3.84 (m, 1H),
3.86 (s, 3H),3.81 (td, J = 8.5, 4.0 Hz, 1H), 3.70 (s, 2H), 3.62 (dd, J = 10.0, 7.0 Hz, 1H), 3.57 (dd, J = 10.0, 4.0 Hz, 1H),
3.51 – 3.46 (m, 1H), 3.13 – 3.10 (m, 3H), 2.95 – 2.87 (m, 2H), 2.85 (s, 3H), 2.83 – 2.80 (m, 1H), 2.06 – 1.99 (m, 1H),
1.90 –1.82 (m, 1H), 1.57 – 1.50 (m, 1H), 0.89 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 169.1, 163.0, 137.7, 130.1, 129.5, 129.3, 128.6, 126.6, 114.4, 72.4, 70.4, 67.2, 58.8, 57.7, 55.6, 53.9, 53.3, 47.1, 38.7,
35.2, 30.5, 27.2, 20.1, 19.9; HRMS (ESI) m/z calcd. for C28H41N3O8S2Na ([M + Na]+): 634.2227, found 634.2226.
4.4.21.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)-2-(((S)-tetrahydrofuran-3-yl)amino)
acetamide (21a). The title compound was obtained by saponification of 3a to 4a, which was then coupled with 15
through an EDC/HOBT/Et3N coupling procedure in 73.3% yield over two steps (colorless solid) as described for 20a, mp
54.5–55.7°C. 1H NMR (500 MHz, CDCl3) δ 8.39 – 8.35 (m, 2H), 8.02 – 7.99 (m, 2H), 7.54 – 7.50 (m, 1H), 7.38 – 7.23
(m, 5H), 4.48 (s, 1H), 4.21 – 4.10 (m, 1H), 3.99 – 3.91 (m, 1H), 3.89 – 3.85 (m, 1H), 3.80 – 3.70 (m, 1H), 3.63 (dd, J =
9.5, 5.0 Hz, 1H), 3.52 (dd, J = 9.0, 2.0 Hz, 1H), 3.47 – 3.44 (m, 1H), 3.37 – 3.32 (m, 1H), 3.28 – 3.15 (m, 3H), 3.14 –
2.94 (m, 5H), 2.02 – 1.90 (m, 2H), 1.65 – 1.59 (m, 1H), 0.94 – 0.87 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 170.5, 150.1,

ACCEPTED MANUSCRIPT
145.2, 137.5, 129.2, 128.7, 128.5, 126.8, 124.3, 72.6, 72.2, 66.9, 58.8, 57.4, 55.0, 52.0, 50.2, 35.0, 32.4, 26.9, 20.0, 19.94;
HRMS (ESI) m/z calcd. For C26H37N4O7S ([M + H]+): 549.2377, found 549.2381.
4.4.22.
2-((2-Amino-2-oxoethyl)((S)-tetrahydrofuran-3-yl)amino)-N-((2S,3R)-3-hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido
)-1-phenylbutan-2-yl)acetamide (21b). The title compound was obtained by saponification of 3b to 4b, which was then
coupled with 15 through an EDC/HOBT/Et3N coupling procedure in 65.2% yield over two steps (light yellow solid) as
described for 20a, mp 57.6–59.3°C. 1H NMR (500 MHz, CDCl3) δ 8.36 (d, J = 9.0 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H),
7.88 (d, J = 8.5 Hz, 1H), 7.32 – 7.22 (m,5H), 6.09 (s, 1H), 5.55 (s, 1H), 4.28 – 4.23 (m, 1H), 4.17 – 4.13 (m, 1H), 3.96 –
3.91 (m, 2H), 3.63 – 3.55 (m, 3H), 3.36 (dd, J = 15.5, 3.5 Hz, 1H), 3.33 – 3.23 (m, 3H), 3.13 – 2.98 (m, 6H), 2.93 (dd, J
= 14.5, 10.5 Hz, 1H), 2.00 – 1.92 (m, 2H), 1.69 – 1.62 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 173.2, 171.7, 150.0, 145.5, 137.7, 129.1, 128.6, 128.5, 126.7, 124.3, 72.1, 70.8, 67.6, 63.3,
57.3, 56.9, 56.1, 54.3, 51.4, 34.8, 29.1, 26.8, 19.9; HRMS (ESI) m/z calcd. for C28H39N5O7SNa ([M + Na]+): 628.2406,
found 628.2396.
4.4.23.
2-((2-(((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)amino)-2-oxoethyl)((S)-tetrahyd
rofuran-3-yl)amino)-N,N-dimethylacetamide (21c). The title compound was obtained by saponification of 3c to 4c, which
was then coupled with 15 through an EDC/HOBT/Et3N coupling procedure in 66.3% yield over two steps (colorless solid)
as described for 20a, mp 60.8–62.5°C. 1H NMR (500 MHz, CDCl3) δ 8.82 (d, J = 8.0 Hz, 1H), 8.33 – 8.29 (m, 2H), 8.02
(d, J = 8.5 Hz, 2H), 7.26 – 7.17 (m, 5H), 4.30 – 4.18 (m, 1H), 4.23 – 4.16 (m, 1H), 3.91 – 3.83 (m, 2H), 3.60 – 3.54 (m,
1H), 3.52 – 3.43 (m, 2H), 3.38 (dd, J = 15.0, 3.3 Hz, 1H), 3.31 (dd, J = 15.0, 9.0 Hz, 2H), 3.22 – 3.18 (m, 1H), 3.14 (dd,
J = 14.0, 8.5 Hz, 2H), 3.06 – 3.00 (m, 1H), 3.00 – 2.95 (m, 2H), 2.92 (s, 3H), 2.91 (s, 3H), 2.90 – 2.87 (m, 1H), 2.01 –
1.92 (m, 2H), 1.69 – 1.62 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
149.8, 146.0, 138.1, 129.2, 128.7, 128.4, 126.4, 124.0, 71.9, 70.8, 67.6, 63.4, 58.0, 56.1, 54.3, 54.2, 50.7, 36.3, 36.0, 34.6,
29.3, 26.6, 20.0, 19.9; HRMS (ESI) m/z calcd. for C30H43N5O8SNa ([M + Na]+): 656.2725, found 656.2727.
4.4.24.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-morpholino-2-oxoethyl)((S)-te
trahydrofuran-3-yl)amino)acetamide (21d). The title compound was obtained by saponification of 3d to 4d, which was
then coupled with 15 through an EDC/HOBT/Et3N coupling procedure in 62.8% yield over two steps (light yellow solid)
as described for 20a, mp 81.1–83.0°C. 1H NMR (500 MHz, CDCl3) δ 8.70 (s, 1H), 8.31 (d, J = 9.0 Hz, 2H), 8.01 (d, J =
9.0 Hz, 2H), 7.28– 7.18 (m, 5H), 4.26 – 4.15 (m, 2H), 3.93 – 3.83 (m, 2H), 3.68– 3.67 (m, 5H), 3.59 – 3.53 (m, 6H), 3.36

ACCEPTED MANUSCRIPT
– 3.20 (m, 6H), 3.13 – 3.09 (m, 2H), 3.01 (dd, J = 14.0, 4.5 Hz, 1H), 2.96 (dd, J = 14.0, 7.0 Hz, 1H), 2.88 (dd, J = 14.0,
10.5 Hz, 1H), 2.00- 1.93 (m, 2H), 1.75 – 1.68 (m, 1H), 0.91 – 0.86 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 167.7, 149.8,
145.8, 138.0, 132.3, 130.9, 129.2, 128.9, 128.7, 128.5, 126.5, 124.1, 67.6, 66.7, 66.27, 65.6, 56.3, 54.4, 53.7, 50.9, 45.1,
42.4, 34.7, 30.6, 29.2, 26.6, 20.0, 19.9; HRMS (ESI) m/z calcd. for C32H45N5O9SNa ([M + Na]+): 698.2830, found
698.2827.
4.4.25.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-methoxyethyl)((S)-tetrahydrof
uran-3-yl)amino)acetamide (21e). The title compound was obtained by saponification of 3e to 4e, which was then
coupled with 15 through an EDC/HOBT/Et3N coupling procedure in 72.9% yield over two steps (light yellow oil) as
described for 20a. 1H NMR (500 MHz, CDCl3) δ 8.33 – 8.31 (m, 2H), 8.00 – 7.97 (m, 2H), 7.76 (d, J = 6.5 Hz, 1H), 7.30
– 7.21 (m, 5H), 4.43 (d, J = 3.5 Hz, 1H), 4.14 – 4.08 (m, 1H), 3.88 – 3.84 (m, 2H), 3.59 – 3.54 (m, 2H), 3.46 (dd, J = 9.0,
4.0 Hz, 1H), 3.40 – 3.34 (m, 2H), 3.32 – 3.30 (m, 2H), 3.29 (s, 3H), 3.21 (dd, J = 15.0, 9.0 Hz, 1H), 3.10 (dd, J = 13.5,
8.0 Hz, 1H), 3.08 – 2.95 (m, 4H), 2.86 (dd, J = 13.5, 10.0 Hz, 1H), 2.70 – 2.65 (m, 1H), 2.53 – 2.48 (m, 1H), 1.98 – 1.88
(m, 2H), 1.54 – 1.47 (m, 1H), 0.90 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.9,
149.9, 145.6, 137.7, 129.2, 128.6, 128.5, 126.7, 124.2, 72.1, 70.3, 70.1, 67.7, 62.5, 58.6, 56.9, 55.1, 54.9, 53.5, 51.4, 34.8,
29.2, 26.8, 19.9; HRMS (ESI) m/z calcd. for C29H42N4O8SNa ([M + Na]+): 629.2616, found629.2617.
4.4.26.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)-2-(N-((S)-tetrahydrofuran-3-yl)met
hylsulfonamido)acetamide (21f). The title compound was obtained by saponification of 3f to 4f, which was then coupled
with 15 through an EDC/HOBT/Et3N coupling procedure in 80.7% yield over two steps (colorless solid) as described for
20a, mp 97.7–99.5°C. 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 9.0 Hz, 2H), 8.00 (d, J = 9.0 Hz, 2H), 7.31 – 7.21 (m,
5H), 6.39 (d, J = 8.0 Hz, 1H), 4.45 – 4.40 (m, 1H), 4.24 – 4.18 (m, 1H), 3.87 (s, 1H), 3.79 (td, J = 8.5, 4.0 Hz, 1H), 3.67
(s, 3H), 3.64 – 3.58 (m, 2H), 3.46 (dd, J = 17.0, 8.5 Hz, 1H), 3.29 (dd, J = 15.0, 3.0 Hz, 1H), 3.19 – 3.09 (m, 2H), 2.99 (d,
J = 7.5 Hz, 2H), 2.90 – 2.88 (m, 1H), 2.85 (s, 3H), 2.04 – 1.97 (m, 1H), 1.95 – 1.87 (m, 1H), 1.47 – 1.40 (m, 1H), 0.89 (d,
J = 1.5 Hz, 3H), 0.87 (d, J = 1.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.4, 150.0, 145.0, 137.3, 129.2, 128.8, 128.6,
126.8, 124.4, 72.0, 70.4, 67.2, 57.9, 57.8, 54.4, 52.3, 47.2, 38.2, 35.3, 30.5, 27.0, 20.0, 19.9; HRMS (ESI) m/z calcd. for
C27H45N3O7SNa ([M + Na]+): 649.1972, found 649.1964.
4.4.27.
N-((2S,3R)-4-(4-Amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-2-(((S)-tetrahydrofuran-3-yl)amin
o)acetamide (22a). A solution of 21a (0.28 mmol, 0.15 g) in 10 mL of methanol was added to a 50 mL of hydrogenated

ACCEPTED MANUSCRIPT
flask and replaced with N2 for three times. Approximately 80 mg of 5% Pd/C was cautiously and slowly added to the
reaction vessel. The reaction mixture was then stirred at room temperature under 40 psi of a hydrogen atmosphere for 1.5
h. Products were isolated by filtering off the catalyst through a pad of Celite 545® and washing with an additional 10 mL
of methanol, and the resulting methanol solution was concentrated under diminished pressure. The residue was purified
by chromatography on a silica gel column (15 × 4 cm). Elution with 5:1 ethyl acetate–methanol gave 22a as a colorless
solid: yield 0.10 g (69.2%), mp 66.1–67.9°C. 1H NMR (500 MHz, CDCl3) δ 7.59 – 7.55 (m, 2H), 7.40 (d, J = 8.5 Hz, 1H),
7.35 – 7.21 (m, 5H), 6.70 (d, J = 8.5 Hz, 2H), 4.21 – 4.14 (m, 2H), 3.93 – 3.90 (m, 1H), 3.85 (dd, J = 15.5, 8.0 Hz, 1H),
3.81 – 3.70 (m, 1H), 3.65 – 3.61 (m, 1H), 3.48 (dd, J = 9.0, 3.0 Hz, 1H), 3.45 – 3.32 (m, 1H), 3.21 – 3.09 (m, 3H), 3.08 –
2.94 (m, 3H), 2.92 – 2.85 (m, 2H), 1.99 – 1.85 (m, 2H), 1.61 – 1.55 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 6.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 172.1, 150.7, 138.1, 129.5, 129.4, 128.7, 128.5, 126.5, 114.1, 72.9, 72.8, 66.9, 58.7,
58.6, 54.0, 53.4, 50.4, 34.6, 32.6, 27.2, 20.2, 20.0; HRMS (ESI) m/z calcd. for C26H39N4O5S ([M + H]+): 519.2636, found
519.2638.
4.4.28.
2-((2-Amino-2-oxoethyl)((S)-tetrahydrofuran-3-yl)amino)-N-((2S,3R)-4-(4-amino-N-isobutylphenylsulfonamido)-3-hydro
xy-1-phenylbutan-2-yl)acetamide (22b). The title compound was obtained by hydrogenation of 21b in 71.0% yield
(colorless solid) as described for 22a, mp 57.6–59.3°C. 1H NMR (500 MHz, CDCl3) δ 7.58 – 7.56 (m, 2H), 7.47 (d, J =
9.0 Hz, 1H), 7.31 – 7.20 (m, 5H), 6.71 (d, J = 9.0 Hz, 3H), 5.71 (s, 1H), 4.35 – 4.30 (m, 1H), 4.25 (s, 1H), 4.18 – 4.14 (m,
1H), 3.97 – 3.96 (m, 1H), 3.91 (td, J = 9.0, 4.5 Hz, 1H), 3.61 – 3.56 (m, 3H), 3.32 – 3.27 (m, 1H), 3.24 (dd, J = 15.0, 4.0
Hz, 1H), 3.15 – 3.06 (m, 5H), 3.04 – 2.92 (m, 3H), 2.92 – 2.86 (m, 2H), 1.95 – 1.87 (m, 2H), 1.68 – 1.61 (m, 1H), 0.91 (d,
J = 7.0 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.5, 171.2, 150.8, 138.1, 129.4, 129.2, 128.5,
126.5, 126.4, 114.1, 72.8, 70.7, 67.6, 62.9, 58.5, 56.8, 56.4, 53.8, 53.0, 35.0, 28.7, 27.1, 20.1, 20.0; HRMS (ESI) m/z
calcd. for C28H41N5O6SNa ([M + Na]+): 598.2670, found 598.2687.
4.4.29.
2-((2-(((2S,3R)-4-(4-Amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-yl)amino)-2-oxoethyl)((S)-tetrahy
drofuran-3-yl)amino)-N,N-dimethylacetamide (22c). The title compound was obtained by hydrogenation of 21c in 63.8%
yield (colorless oil) as described for 22a. 1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 7.58 (d, J = 9.0 Hz, 2H), 7.25 –
7.23 (m, 4H), 7.17 – 7.14 (m, 1H), 6.67 (d, J = 9.0 Hz, 2H), 4.24 – 4.20 (m, 1H), 3.92 – 3.86 (m, 2H), 3.63 – 3.46 (m,
4H), 3.35 (s, 1H), 3.24 (dd, J = 15.0, 3.5 Hz, 2H), 3.13 (dd, J = 14.5, 4.5 Hz, 2H), 3.07 (dd, J = 15.0, 8.5 Hz, 2H), 2.93 (s,
3H), 2.92 – 2.85 (m, 4H), 2.88 (s, 3H), 1.97 –1.90 (m, 2H), 1.68 – 1.57 (s, 1H), 0.89 (d, J = 6.5 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 150.4, 138.7, 129.5, 129.3, 128.2, 126.1, 114.1, 73.0, 67.6 (s), 58.1, 53.9, 52.8, 36.3, 36.0, 34.8, 29.3,

ACCEPTED MANUSCRIPT
27.1, 20.2, 20.1; HRMS (ESI) m/z calcd. for C30H45N5O6SNa ([M + Na]+): 626.2982, found 626.2974.
4.4.30.
N-((2S,3R)-4-(4-Amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-2-((2-morpholino-2-oxoethyl)((S)-
tetrahydrofuran-3-yl)amino)acetamide (22d). The title compound was obtained by hydrogenation of 21d in 81.6% yield
(colorless solid) as described for 22a, mp 125.6–127.1°C. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.8 Hz, 1H), 7.56 –
7.51 (m, 2H), 7.24 – 7.13 (m, 5H), 6.66 – 6.64 (m, 2H), 4.25 – 4.18 (m, 2H), 3.92 – 3.83 (m, 2H), 3.65 – 3.61 (m, 4H),
3.59 – 3.45 (m, 5H), 3.34 – 3.20 (m, 6H), 3.16 – 3.03 (m, 5H), 2.94 – 2.82 (m, 4H), 1.97 – 1.85 (m, 2H), 1.62 – 1.53 (m,
1H), 0.88 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 171.9, 169.3, 150.6, 138.6, 129.5, 129.3, 128.3, 126.9,
126.2, 114.1, 73.1, 70.9, 67.6, 66.8, 66.3, 62.8, 58.2, 57.5, 53.8, 53.4, 52.9, 45.0, 42.3, 34.8, 29.4, 27.1, 20.2, 20.1;
HRMS (ESI) m/z calcd. for C32H47N5O7SNa ([M + Na]+): 668.3083, found 668.3078.
4.4.31.
N-((2S,3R)-4-(4-Amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-2-((2-methoxyethyl)((S)-tetrahydro
furan-3-yl)amino)acetamide (22e). The title compound was obtained by hydrogenation of 21e in 58.1% yield (colorless
oil) as described for 22a. 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.31 – 7.20 (m,
4H), 6.68 (d, J = 8.5 Hz, 2H), 4.45 (s, 1H), 4.23 – 4.14 (m, 3H), 3.91 – 3.85 (m, 2H), 3.61 – 3.56 (m, 2H), 3.47 (dd, J =
9.5, 4.5 Hz, 1H), 3.40 – 3.35 (m, 1H), 3.34 – 3.30 (m, 2H), 3.28 (s, 3H), 3.21 (dd, J = 15.0, 4.5 Hz, 1H), 3.13 – 3.01 (m,
4H), 2.96 – 2.90 (m, 3H), 2.66 – 2.61 (m, 1H), 2.56 – 2.50 (m, 1H), 1.96 – 1.88 (m, 2H), 1.59– 1.52 (m, 1H), 0.92 (d, J =
5.0 Hz, 3H), 0.90 (d, J = 5.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.4, 150.7, 138.3, 129.4, 129.3, 128.4, 126.8,
126.4, 114.1, 72.8, 70.3, 67.7, 62.5, 58.6, 58.5, 55.4, 54.1, 53.3, 53.2, 34.6, 29.1, 27.2, 20.1, 20.0; HRMS (ESI)m/z calcd.
for C29H44N4O6SNa ([M + Na]+): 599.2868, found 599.2867.
4.4.32.
N-((2S,3R)-4-(4-Amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-2-(N-((S)-tetrahydrofuran-3-yl)me
thylsulfonamido)acetamide (22f). The title compound was obtained by hydrogenation of 21f in 78.0% yield (colorless
solid) as described for 22a, mp 81.9–83.2°C. 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 2H), 7.29 – 7.18 (m, 5H),
6.67 (d, J = 8.0 Hz, 2H), 6.38 (d, J = 8.0 Hz, 1H), 4.45 – 4.38 (m, 1H), 4.26 – 4.18 (m, 1H), 3.93 (s, 1H), 3.86 – 3.80 (m,
3H), 3.71 (s, 2H), 3.64 – 3.55 (m, 2H), 3.52 – 3.47 (m, 1H), 3.12 – 3.04 (m, 3H), 2.93 – 2.87 (m, 2H), 2.85 (s, 3H), 2.80
(dd, J = 13.0, 6.5 Hz, 1H), 2.07 – 2.02 (m, 1H), 1.87 – 1.82 (m, 1H), 1.57 – 1.54 (m, 1H), 0.89 (d, J = 6.5 Hz, 3H), 0.87
(d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.1, 150.7, 137.7, 129.5, 129.4, 128.6, 126.5, 129.4, 114.2, 72.5,
70.4, 67.2, 58.8, 57.7, 53.8, 53.4, 47.2, 38.9, 35.2, 30.6, 27.3, 20.2, 19.9; HRMS (ESI) m/z calcd. for C27H40N4O7S2Na
([M + Na]+): 619.2225, found 619.2216.

ACCEPTED MANUSCRIPT
4.4.33.
N-((2S,3R)-3-Hydroxy-4-(4-(hydroxymethyl)-N-isobutylphenylsulfonamido)-1-phenylbutan-2-yl)-2-(((S)-tetrahydrofuran-
3-yl)amino)acetamide (23a). The title compound was obtained by saponification of 3a to 4a, which was then coupled
with 16 through an EDC/HOBT/Et3N coupling procedure in 71.9% yield over two steps (light yellow oil) as described
for 20a. 1H NMR (400 MHz, CDCl3) δ 7.80 – 7.74 (m, 2H), 7.55 – 7.52 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.35 – 7.22 (m,
5H), 4.79 (s, 2H), 4.20 – 4.11 (m, 1H), 3.93 – 3.89 (m, 1H), 3.87 – 3.83 (m, 1H), 3.77 – 3.69 (m, 1H), 3.65 – 3.61 (m,
1H), 3.48 (dd, J = 9.2, 3.2 Hz, 1H), 3.35 – 3.01 (m, 1H), 3.26 – 3.21 (m, 1H), 3.17 – 3.02 (m, 5H), 3.00 – 2.93 (m, 4H),
2.00 – 1.87 (m, 2H), 1.63 – 1.52 (m, 1H), 0.93 (d,J = 1.2 Hz, 3H), 0.90 (d,J = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 172.2, 146.4, 137.9, 137.5, 129.3, 128.6, 127.5, 127.2, 126.6, 72.8, 72.6, 66.9, 64.1, 58.6, 58.4, 54.2, 53.0, 50.3, 34.6,
32.5, 27.1, 20.1, 19.9; HRMS (ESI) m/z calcd. for C27H40N3O6S ([M + H]+): 534.2632, found 534.2627.
4.4.34.
2-((2-Amino-2-oxoethyl)((S)-tetrahydrofuran-3-yl)amino)-N-((2S,3R)-3-hydroxy-4-(4-(hydroxymethyl)-N-isobutylphenyls
ulfonamido)-1-phenylbutan-2-yl)acetamide (23b). The title compound was obtained by saponification of 3b to 4b, which
was then coupled with 16 through an EDC/HOBT/Et3N coupling procedure in 77.3% yield over two steps (colorless solid)
as described for 20a, mp 57.6–59.3°C. 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H),
7.49 (d, J = 8.5 Hz, 1H), 7.31– 7.21 (m, 5H), 6.57 (s, 1H), 5.69 (s, 1H), 4.78 (s, 2H), 4.27 – 4.21 (m, 1H), 4.06 (s, 1H),
3.93 – 3.88 (m, 2H), 3.61 – 3.56 (m, 1H), 3.54 (d, J = 5.5 Hz, 2H), 3.30 – 3.24 (m, 2H), 3.15 – 2.89 (m, 9H), 1.99 – 1.88
(m, 2H), 1.65 – 1.56 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.6,
171.3, 146.4, 137.9, 137.7, 129.2, 128.6, 127.5, 127.4, 126.6, 72.6, 70.7, 67.6, 64.2, 63.0, 58.0, 56.9, 56.3, 54.0, 52.6,
34.9, 28.9, 27.0, 20.0, 19.9; HRMS (ESI) m/z calcd. for C29H42N4O7SNa ([M + Na]+): 613.2666, found 613.2661.
4.4.35.
2-((2-(((2S,3R)-3-Hydroxy-4-(4-(hydroxymethyl)-N-isobutylphenylsulfonamido)-1-phenylbutan-2-yl)amino)-2-oxoethyl)((
S)-tetrahydrofuran-3-yl)amino)-N,N-dimethylacetamide (23c). The title compound was obtained by saponification of 3c
to 4c, which was then coupled with 16 through an EDC/HOBT/Et3N coupling procedure in 73.0% yield over two steps
(colorless solid) as described for 20a, mp 127.5–128.6°C. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J = 8.5 Hz, 1H), 7.79 (d,
J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.25 – 7.14 (m, 5H), 4.76 – 4.70 (m, 2H), 4.17 (s, 1H), 4.14 – 4.05 (m, 1H),
3.86 (td, J = 8.5, 4.0 Hz, 1H), 3.75 – 3.73 (m, 1H), 3.59 – 3.53 (m, 1H), 3.52 – 3.47 (m, 1H), 3.47 – 3.40 (m, 1H), 3.32 –
3.29 (m, 2H), 3.25 (s, 1H), 3.18 (d, J = 16.5 Hz, 1H), 3.13 – 2.97 (m, 6H), 2.92 (s, 3H), 2.89 (s, 3H), 2.87 – 2.81 (m, 1H),
2.03 – 1.96 (m, 1H), 1.94 – 1.83 (m, 1H), 1.63 – 1.52 (m, 1H), 0.92 (d, J = 3.0 Hz, 3H), 0.91 (d, J = 3.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 146.0, 138.4, 138.3, 129.2, 128.3, 127.5, 127.4, 126.2, 72.5, 70.7, 67.6, 64.4, 57.4, 57.2, 54.1,

ACCEPTED MANUSCRIPT
54.0, 51.9, 36.3, 36.0, 34.4, 29.1, 26.9, 20.1, 20.0; HRMS (ESI) m/z calcd. for C31H46N4O7SNa ([M + Na]+): 641.2979,
found 641.2988.
4.4.36.
N-((2S,3R)-3-Hydroxy-4-(4-(hydroxymethyl)-N-isobutylphenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-morpholino-2-oxo
ethyl)((S)-tetrahydrofuran-3-yl)amino)acetamide (23d). The title compound was obtained by saponification of 3d to 4d,
which was then coupled with 16 through an EDC/HOBT/Et3N coupling procedure in 59.3% yield over two steps
(colorless oil) as described for 20a. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.49
(d, J = 8.4 Hz, 2H), 7.24 – 7.15 (m, 5H), 4.72 (s, 2H), 4.18 – 4.07 (m, 1H), 3.85 (td, J = 8.8, 4.4 Hz, 1H), 3.80 – 3.76 (m,
1H), 3.67 – 3.62 (m, 5H), 3.58 – 3.51 (m, 3H), 3.49 – 3.41 (m, 2H), 3.33 – 3.29 (m, 3H), 3.25 – 3.10 (m, 3H), 3.08 – 2.91
(m, 6H), 2.85 (dd, J = 14.3, 10.8 Hz, 1H), 2.02 – 1.84 (m, 2H), 1.60- 1.51 (m, 1H), 0.91 (d, J = 3.2 Hz, 3H), 0.88 (t, J =
3.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.9, 169.4, 146.2, 138.3, 138.1, 129.2, 128.4, 127.5, 127.4, 126.3, 72.6,
70.8, 67.6, 66.8, 66.3, 64.3, 63.0, 57.5, 57.4, 54.0, 53.6, 52.0, 45.0, 42.3, 34.5, 29.2, 26.9, 20.1, 20.0; HRMS (ESI) m/z
calcd. for C33H48N4O8SNa ([M + Na]+): 683.3085, found 683.3090.
4.4.37.
N-((2S,3R)-3-Hydroxy-4-(4-(hydroxymethyl)-N-isobutylphenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-methoxyethyl)((S)-
tetrahydrofuran-3-yl)amino)acetamide (23e). The title compound was obtained by saponification of 3e to 4e, which was
then coupled with 16 through an EDC/HOBT/Et3N coupling procedure in 68.3% yield over two steps (colorless oil) as
described for 20a. 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 7.0 Hz, 1H), 7.49 (d, J = 8.0 Hz,
2H), 7.28 – 7.18 (m, 5H), 4.74 (s, 2H), 4.34 (d, J = 3.0 Hz, 1H), 4.13 – 4.06 (m, 1H), 3.85 – 3.79 (m, 2H), 3.58 – 3.52 (m,
2H), 3.41 (dd, J = 9.5, 4.5 Hz, 1H), 3.37 – 3.31 (m, 1H), 3.30 – 3.22 (m, 3H), 3.26 (s, 3H), 3.07 – 3.02 (m, 2H), 3.01 –
2.98 (m, 2H), 2.96 – 2.91 (m, 2H), 2.87 (dd, J = 14.5, 10.5 Hz, 1H), 2.78 (s, 1H), 2.63 – 2.58 (m, 1H), 2.50 – 2.45 (m,
1H), 1.96 – 1.85 (m, 2H), 1.53 – 1.46 (m, 1H), 0.90 (d, J = 2.0 Hz, 3H), 0.88 (d, J = 2.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 172.5, 146.3, 138.0, 137.8, 129.3, 128.5, 127.5, 127.2, 126.5, 72.6, 70.3, 70.2, 67.7, 64.2, 62.4, 58.6, 58.1, 55.1,
54.3, 53.4, 52.7, 34.5, 29.0, 27.1, 20.1, 20.0; HRMS (ESI)m/z calcd. for C30H45N3O7SNa ([M + Na]+): 614.2870, found
614.2879.
4.4.38.
N-((2S,3R)-3-Hydroxy-4-(4-(hydroxymethyl)-N-isobutylphenylsulfonamido)-1-phenylbutan-2-yl)-2-(N-((S)-tetrahydrofur
an-3-yl)methylsulfonamido)acetamide (23f). The title compound was obtained by saponification of 3f to 4f, which was
then coupled with 16 through an EDC/HOBT/Et3N coupling procedure in 81.4% yield over two steps (colorless solid) as
described for 20a, mp 67.1–68.6°C. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H),

ACCEPTED MANUSCRIPT
7.31 – 7.19 (m, 5H), 6.38 (d, J = 9.0 Hz, 1H), 4.77– 4.76 (m, 2H), 4.42 – 4.37 (m, 1H), 4.21 – 4.15 (m, 1H), 3.86 – 3.77
(m, 3H), 3.66 (s, 2H), 3.59 (dd, J = 10.5, 7.0 Hz, 1H), 3.54 (dd, J = 10.5, 4.0 Hz, 1H), 3.51 – 3.46 (m, 1H), 3.16 – 3.06
(m, 3H), 2.96 (dd, J = 13.5, 8.5 Hz, 1H), 2.90 – 2.86 (m, 2H), 2.84 (s, 3H), 2.04 – 1.98 (m, 1H), 1.91 – 1.84 (m, 1H),
1.54 – 1.46 (m, 1H), 0.90 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.1, 146.3,
137.5, 137.4, 129.3, 128.7, 127.6, 127.3, 126.7, 72.2, 70.3, 67.2, 64.2, 58.6, 57.7, 54.0, 53.1, 47.1, 38.6, 35.2, 30.5, 27.2,
20.1, 19.9; HRMS (ESI) m/z calcd. for C28H41N3O8S2Na ([M + Na]+): 634.2222, found 634.2220.
4.4.39.
N-((2S,3R)-3-hydroxy-4-(N-isobutyl-4-((S)-trifluoromethoxy)phenylsulfonamido)-1-phenylbutan-2-yl)-2-(((S)-tetrahydrof
uran-3-yl)amino)acetamide (24a). The title compound was obtained by saponification of 3a to 4a, which was then
coupled with 17 through an EDC/HOBT/Et3N coupling procedure in 63.4% yield over two steps (colorless oil) as
described for 20a. 1H NMR (500 MHz, CDCl3) δ 7.88 – 7.85 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 2H),
7.34 – 7.23 (m, 5H), 4.18 – 4.12 (m, 1H), 4.00 – 3.90 (m, 1H), 3.88 – 3.83 (m, 1H), 3.80 – 3.69 (m, 1H), 3.67 – 3.62 (m,
1H), 3.48 (dd, J = 9.5, 3.0 Hz, 1H), 3.45 – 3.33 (m, 1H), 3.27 (dd, J = 15.0, 3.9 Hz, 1H), 3.23 – 3.12 (m, 3H), 3.10 – 2.93
(m, 6H), 2.00 – 1.88 (m, 2H), 1.62 – 1.56 (m, 1H), 0.90 (d,J = 6.5 Hz,6H); 13C NMR (125 MHz, CDCl3) δ 172.5, 152.2,
137.8, 137.4, 129.4, 129.3, 128.6, 126.7, 121.0, 72.9, 72.6, 66.9, 58.7, 58.1, 54.5, 52.8, 50.5, 34.8, 32.6, 27.1, 20.0, 19.9;
HRMS (ESI) m/z calcd. for C27H37F3N3O6S ([M + H]+): 588.2350, found 588.2340.
4.4.40.
2-((2-Amino-2-oxoethyl)((S)-tetrahydrofuran-3-yl)amino)-N-((2S,3R)-3-hydroxy-4-(N-isobutyl-4-(trifluoromethoxy)pheny
lsulfonamido)-1-phenylbutan-2-yl)acetamide (24b). The title compound was obtained by saponification of 3b to 4b,
which was then coupled with 17 through an EDC/HOBT/Et3N coupling procedure in 69.1% yield over two steps
(colorless solid) as described for 20a, mp 57.6–59.3°C. 1H NMR (500 MHz, CDCl3) δ 7.89 – 7.87 (m, 2H), 7.74 (d, J =
9.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.31 – 7.21 (m, 5H), 6.44 (s, 1H), 5.79 (s, 1H), 4.33 – 4.27 (m, 2H), 3.98 – 3.96 (m,
1H), 3.92 (td, J = 8.5, 4.0 Hz, 1H), 3.62 – 3.55 (m, 3H), 3.34 – 3.29 (m, 2H), 3.21 – 3.15 (m, 2H), 3.12 – 3.05 (m, 4H),
3.03 – 2.91 (m, 3H), 1.98 – 1.90 (m, 2H), 1.69 – 1.62 (m, 1H), 0.90 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) δ 173.5, 171.5, 152.2, 137.9, 137.4, 129.5, 129.2, 128.6, 126.6, 121.0, 72.6, 70.7, 67.6, 63.1,
57.7, 57.0, 56.3, 54.0, 52.3, 34.7, 29.0 (s), 27.0, 20.0, 19.9; HRMS (ESI) m/z calcd. for C29H39F3N4O7SNa ([M + Na]+):
667.2384, found 667.2391.
4.4.41.
2-((2-(((2S,3R)-3-hydroxy-4-(N-isobutyl-4-(trifluoromethoxy)phenylsulfonamido)-1-phenylbutan-2-yl)amino)-2-oxoethyl)
((S)-tetrahydrofuran-3-yl)amino)-N,N-dimethylacetamide (24c). The title compound was obtained by saponification of 3c

ACCEPTED MANUSCRIPT
to 4c, which was then coupled with 17 through an EDC/HOBT/Et3N coupling procedure in 80.3% yield over two steps
(colorless oil) as described for 20a. 1H NMR (500 MHz, CDCl3) δ 8.73 (d, J = 8.5 Hz, 1H), 7.88 – 7.86 (m, 2H), 7.31 –
7.29 (m, 2H), 7.25 – 7.14 (m, 5H), 4.31 – 4.28 (m, 1H), 4.24 – 4.18 (m, 1H), 3.90 – 3.84 (m, 2H), 3.58 – 3.51 (m, 2H),
3.48 (dd, J = 9.5, 4.0 Hz, 1H), 3.38 – 3.32 (m, 2H), 3.29 – 3.25 (m, 1H), 3.19 – 3.15 (m, 2H), 3.11 – 3.02 (m, 4H), 2.93–
2.86 (m, 1H), 2.91 (s, 3H), 2.89 (s, 3H), 2.03 – 1.86 (m, 2H), 1.62 – 1.55 (m, 1H), 0.89 (d, J = 7.0 Hz, 3H), 0.87 (d, J =
7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.2, 170.7, 151.9, 138.4, 138.0, 129.6, 129.2, 128.3, 126.3, 120.8, 72.6,
70.8, 67.6, 63.2, 57.8, 57.1, 54.1, 54.0, 51.8, 36.2, 36.0, 34.7, 29.3, 26.8, 20.0, 19.9; HRMS (ESI) m/z calcd. for
C31H43F3N4O7SNa ([M + Na]+): 695.2697, found 695.2698.
4.4.42.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-(trifluoromethoxy)phenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-morpholino-2-o
xoethyl)((S)-tetrahydrofuran-3-yl)amino)acetamide (24d). The title compound was obtained by saponification of 3d to 4d,
which was then coupled with 17 through an EDC/HOBT/Et3N coupling procedure in 68.3% yield over two steps
(colorless oil) as described for 20a. 1H NMR (500 MHz, CDCl3) δ 8.61 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.33
(d, J = 8.0 Hz, 2H), 7.29 – 7.20 (m, 5H), 4.30 – 4.21 (m, 1H), 3.94 – 3.87 (m, 2H), 3.69 – 3.68 (m, 4H), 3.59 – 3.53 (m,
5H), 3.44 – 3.35 (m, 4H), 3.29 – 3.15 (m, 4H), 3.12 – 3.03 (m, 4H), 2.96 – 2.88 (m, 2H), 2.01 – 1.91 (m, 2H), 1.65 – 1.58
(m, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.1, 169.4, 152.0, 138.3,
137.9, 129.6, 129.2, 128.4, 126.4, 120.8, 72.7, 70.8, 67.5, 66.7, 66.3, 63.1, 57.7, 57.2, 54.1, 53.6, 51.9, 45.0, 42.3, 34.8,
29.3, 26.8, 20.0, 19.9; HRMS (ESI) m/z calcd. for C33H45F3N4O8SNa ([M + Na]+): 737.2802, found 737.2809.
4.4.43.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-(trifluoromethoxy)phenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-methoxyethyl)((
S)-tetrahydrofuran-3-yl)amino)acetamide (24e). The title compound was obtained by saponification of 3e to 4e, which
was then coupled with 17 through an EDC/HOBT/Et3N coupling procedure in 64.9% yield over two steps (colorless oil)
as described for 20a. 1H NMR (500 MHz, CDCl3) δ 7.89 – 7.86 (m, 2H), 7.76 (d, J = 7.5 Hz, 1H), 7.36 – 7.21 (m, 7H),
4.48 (d, J = 2.0 Hz, 1H), 4.19 – 4.11 (m, 1H), 3.92 – 3.85 (m, 2H), 3.61 – 3.56 (m, 2H), 3.48 (dd, J = 9.0, 4.5 Hz, 1H),
3.41 – 3.36 (m, 1H), 3.36 – 3.30 (m, 3H), 3.29 (s, 3H), 3.16 – 3.02 (m, 5H), 2.97 – 2.89 (m, 2H), 2.69 – 2.64 (m, 1H),
2.54 – 2.50 (m, 1H), 2.00 – 1.89 (m, 2H), 1.57 – 1.50 (m, 1H), 0.91 (t, J = 7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
172.6, 152.1, 137.9, 137.7, 129.5, 129.3, 128.5, 126.6, 120.9, 72.5, 70.3, 70.2, 67.6, 62.5, 58.6, 57.7, 55.2, 54.5, 53.4,
52.4, 34.6, 29.1, 27.0, 20.0, 19.9; HRMS (ESI)m/z calcd. for C30H43F3N3O7S ([M + H]+): 646.2768, found 646.2776.
4.4.44.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-(trifluoromethoxy)phenylsulfonamido)-1-phenylbutan-2-yl)-2-(N-((S)-tetrahydrofu

ACCEPTED MANUSCRIPT
ran-3-yl)methylsulfonamido)acetamide (24f). The title compound was obtained by saponification of 3f to 4f, which was
then coupled with 17 through an EDC/HOBT/Et3N coupling procedure in 63.9% yield over two steps (colorless solid) as
described for 20a, mp 51.4–53.1°C. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H),
7.30 – 7.19 (m, 4H), 6.41 (d, J = 8.5 Hz, 1H), 4.44 – 4.40 (m, 1H), 4.25 –4.20 (m, 1H), 3.89 (s, 1H), 3.81 – 3.78 (m, 2H),
3.70 (s, 2H), 3.64 – 3.59 (m, 2H), 3.50 – 3.45 (m, 1H), 3.21 (dd, J = 15.0, 3.0 Hz, 1H), 3.15 – 3.10 (m, 2H), 2.97 – 2.90
(m, 2H), 2.88 (d, J = 10.0 Hz, 1H), 2.85 (s, 3H), 2.07 – 1.98 (m, 1H), 1.93 – 1.85 (m, 1H), 1.53 – 1.43 (m, 1H), 0.88 (d, J
= 4.0 Hz, 3H), 0.87 (d, J = 4.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.2, 152.2, 137.5, 137.1, 129.5, 129.3, 128.7,
126.7, 121.0, 72.3, 70.4, 67.2, 58.4, 57.7, 54.1, 53.0, 47.2, 38.5, 35.3, 30.5, 27.1, 20.0, 19.8; HRMS (ESI) m/z calcd. for
C28H38F3N3O8S2Na ([M + Na]+): 688.1945, found 688.1938.
4.4.45.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-3,4-dimethoxyphenylsulfonamido)-1-phenylbutan-2-yl)-2-(((S)-tetrahydrofuran-3-yl
)amino)acetamide (25a). The title compound was obtained by saponification of 3a to 4a, which was then coupled with 18
through an EDC/HOBT/Et3N coupling procedure in 59.1% yield over two steps (colorless solid) as described for 20a, mp
52.3–53.0°C. 1H NMR (500 MHz, CDCl3) δ 7.44 (dd, J = 8.5, 2.0 Hz, 1H), 7.41 – 7.39 (m, 1H), 7.36 – 7.22 (m, 6H),
6.97 (d, J = 8.5 Hz, 1H), 4.20 – 4.14 (m, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.94 – 3.90 (m, 1H), 3.88 – 3.76 (m, 1H), 3.74 –
3.70 (m, 1H), 3.63 (dd, J = 9.5, 5.5 Hz, 1H), 3.49 – 3.42 (m, 1H), 3.34 – 3.22 (m, 1H), 3.18 – 3.07 (m, 4H), 3.06 – 2.98
(m, 2H), 2.96 – 2.89 (m, 2H), 2.00 – 1.87 (m, 3H), 1.61 – 1.55 (m, 1H), 0.92 (d, J = 5.0 Hz, 3H), 0.92 – 0.90 (m, 3H);
13C NMR (125 MHz, CDCl3) δ 172.2, 152.8, 149.3, 137.9, 130.5, 129.3, 128.5, 126.6, 121.3, 110.8, 110.2, 72.88 (s), 72.7,
66.9, 58.7, 58.4, 56.4, 56.2, 54.3, 53.1, 50.5, 34.7, 32.6, 27.2, 20.1, 20.0; HRMS (ESI) m/z calcd. for C28H42N3O7S ([M +
H]+): 564.2738, found 564.2745.
4.4.46.
2-((2-Amino-2-oxoethyl)((S)-tetrahydrofuran-3-yl)amino)-N-((2S,3R)-3-hydroxy-4-(N-isobutyl-3,4-dimethoxyphenylsulfo
namido)-1-phenylbutan-2-yl)acetamide (25b). The title compound was obtained by saponification of 3b to 4b, which was
then coupled with 18 through an EDC/HOBT/Et3N coupling procedure in 68.0% yield over two steps (colorless solid) as
described for 20a, mp 57.6–59.3°C. 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.0 Hz, 1H), 7.44 (dd, J = 8.5, 2.0 Hz,
1H), 7.31 – 7.20 (m, 6H), 6.97 (d, J = 8.5 Hz, 1H), 6.50 (s, 1H), 5.69 (s, 1H), 4.34 – 4.28 (m, 1H), 4.24 (s, 1H), 3.97 (s,
1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.94 – 3.90 (m, 1H), 3.62 – 3.56 (m, 3H), 3.32 – 3.28 (m, 2H), 3.19 – 3.03 (m, 6H), 3.00
– 2.92 (m, 3H), 1.97 – 1.90 (m, 2H), 1.69 – 1.62 (m, 1H), 0.92 – 0.89 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 173.4,
171.3, 152.7, 149.2, 138.0, 130.5, 129.2, 128.5, 126.6, 121.3, 110.7, 110.0, 72.7, 70.7, 67.6, 63.0, 58.1, 56.9, 56.4, 56.3,
56.2, 53.9, 52.6, 34.7, 28.8, 27.1, 20.1, 20.0; HRMS (ESI) m/z calcd. for C30H44N4O8SNa ([M + Na]+): 643.2766, found

ACCEPTED MANUSCRIPT
643.2765.
4.4.47.
2-((2-(((2S,3R)-3-Hydroxy-4-(N-isobutyl-3,4-dimethoxyphenylsulfonamido)-1-phenylbutan-2-yl)amino)-2-oxoethyl)((S)-t
etrahydrofuran-3-yl)amino)-N,N-dimethylacetamide (25c). The title compound was obtained by saponification of 3c to
4c, which was then coupled with 18 through an EDC/HOBT/Et3N coupling procedure in 63.9% yield over two steps
(colorless solid) as described for 20a, mp 52.0–53.6°C. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J = 8.5 Hz, 1H), 7.44 (dd,
J = 8.5, 2.5 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.23 (d, J = 4.5 Hz, 4H), 7.18 – 7.14 (m, 1H), 6.93 (d, J= 8.5 Hz, 1H), 4.25
– 4.20 (m, 1H), 3.93 (s, 3H), 3.93 (s, 3H), 3.92 – 3.89 (m, 1H), 3.86 (dd, J = 8.5, 4.5 Hz, 1H), 3.59 – 3.54 (m, 1H), 3.53
(d, J = 6.5 Hz, 1H), 3.48 (dd, J = 9.0, 3.5 Hz, 1H), 3.35 – 3.30 (m, 3H), 3.19 – 3.15 (m, 2H), 3.12 (dd, J = 10.0, 4.0 Hz,
1H), 3.07 (s, 1H), 2.99 (dd, J = 13.5, 7.5 Hz, 1H), 2.92 (s, 3H), 2.94 – 2.87 (m, 1H), 2.89 (s, 3H), 2.01 – 1.87 (m, 2H),
1.63 – 1.56 (m, 1H), 0.90 (d, J = 6.0 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 152.5, 149.1,
138.6, 131.1, 129.2, 128.2, 126.2, 121.3, 110.6, 110.1, 72.9, 70.8, 67.6, 63.1, 57.6, 56.3, 56.2, 54.0, 53.9, 52.3, 36.2, 36.0,
34.7, 29.3, 27.0, 20.1, 20.0; HRMS (ESI) m/z calcd. for C32H48N4O8SNa ([M + Na]+): 671.3085, found 671.3072.
4.4.48.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-3,4-dimethoxyphenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-morpholino-2-oxoethy
l)((S)-tetrahydrofuran-3-yl)amino)acetamide (25d). The title compound was obtained by saponification of 3d to 4d,
which was then coupled with 18 through an EDC/HOBT/Et3N coupling procedure in 63.0% yield over two steps
(colorless solid) as described for 20a, mp 51.3–52.5°C. 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 8.5 Hz, 1H), 7.45 (d, J
= 8.0 Hz, 1H), 7.32 – 7.19 (m, 5H), 6.95 (d, J = 8.5 Hz, 1H), 4.27 – 4.25 (m, 1H), 3.95 (s, 3H), 3.94(s, 3H), 3.91 – 3.88
(m, 2H), 3.69 – 3.67 (m, 4H), 3.61 – 3.51 (m, 5H), 3.40 – 3.27 (m, 5H), 3.24 – 3.07 (m, 5H), 3.02 – 2.88 (m, 4H), 2.01 –
1.90 (m, 2H), 1.62 – 1.59 (m, 1H), 0.93 – 0.90 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 172.0, 169.3, 152.5, 149.1, 138.5,
131.0, 129.2, 128.3, 126.3, 121.3, 110.6, 110.1, 73.0, 70.8, 68.4, 67.5, 66.8, 66.3, 63.0, 57.7, 57.6, 56.3, 56.2, 53.9, 53.5,
52.4, 45.0, 42.3, 34.8, 29.4, 27.0, 22.9, 20.1, 20.0; HRMS (ESI) m/z calcd. for C34H50N4O9SNa ([M + Na]+): 713.3185,
found 713.3192.
4.4.49.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-3,4-dimethoxyphenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-methoxyethyl)((S)-tetr
ahydrofuran-3-yl)amino)acetamide (25e). The title compound was obtained by saponification of 3e to 4e, which was then
coupled with 18 through an EDC/HOBT/Et3N coupling procedure in 63.2% yield over two steps (colorless oil) as
described for 20a. 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.5, 2.0 Hz, 1H), 7.30 – 7.19 (m,
6H), 6.95 (d, J = 8.5 Hz, 1H), 4.50 (d, J = 2.5 Hz, 1H), 4.18 – 4.12 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.92 – 3.84 (m,

ACCEPTED MANUSCRIPT
2H), 3.60 – 3.55 (m, 2H), 3.46 (dd, J = 9.5, 4.5 Hz, 1H), 3.39 – 3.34 (m, 1H), 3.31 – 3.29 (m, 3H), 3.28 (s, 3H), 3.15 –
3.08 (m, 2H), 3.05 – 2.30 (m, 2H), 2.98 – 2.90 (m, 3H), 2.66 – 2.61 (m, 1H), 2.53 – 2.48 (m, 1H), 1.98 – 1.87 (m, 2H),
1.56 – 1.49 (m, 1H), 0.91 (d, J = 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 172.5, 152.6, 149.2, 138.1, 130.7, 129.3,
128.5, 126.5, 121.3, 110.7, 110.0, 72.7, 70.3, 70.2, 67.7, 62.4, 58.6, 58.1, 56.3, 56.2, 55.3, 54.3, 53.4, 52.8, 34.5, 29.1,
27.1, 20.1, 20.0; HRMS (ESI)m/z calcd. for C31H47N3O8SNa ([M + Na]+): 644.2976, found 644.2965.
4.4.50.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-3,4-dimethoxyphenylsulfonamido)-1-phenylbutan-2-yl)-2-(N-((S)-tetrahydrofuran-3
-yl)methylsulfonamido)acetamide (25f). The title compound was obtained by saponification of 3f to 4f, which was then
coupled with 18 through an EDC/HOBT/Et3N coupling procedure in 74.8% yield over two steps (colorless solid) as
described for 20a, mp 52.8–54.6°C. 1H NMR (500 MHz, CDCl3) δ 7.41 (dd, J = 8.5, 2.0 Hz, 1H), 7.29 – 7.23 (m, 5H),
7.19 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 8.5 Hz, 1H), 4.43 – 4.38 (m, 1H), 4.26 – 4.20 (m, 1H), 3.93
(s, 3H), 3.92 (s, 3H), 3.88 – 3.84 (m, 1H), 3.79 (td, J = 9.0, 4.0 Hz, 1H), 3.69 (s, 2H), 3.61 (dd, J = 10.5, 7.0 Hz, 1H),
3.56 (dd, J = 10.5, 4.0 Hz, 1H), 3.50 – 3.45 (m, 1H), 3.16 (d, J = 6.0 Hz, 2H), 3.12 (dd, J = 14.5, 4.5 Hz, 1H), 2.97 – 2.90
(m, 2H), 2.88 – 2.82 (m, 2H), 2.84 (s, 3H), 2.04 – 1.97 (m, 1H), 1.91 – 1.83 (m, 1H), 1.54 – 1.47 (m, 1H), 0.89 (d, J = 6.5
Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.1, 152.7, 149.2, 137.6, 130.3, 129.3, 128.6, 126.6,
121.4, 110.7, 110.0, 72.3, 70.4, 67.2, 58.6, 57.7, 56.4, 56.2, 54.0, 53.1, 47.2, 38.6, 35.3, 30.5, 27.2, 20.1, 19.9; HRMS
(ESI) m/z calcd. for C29H43N3O9S2Na ([M + Na]+): 664.2335, found 664.2346.
4.4.51.
N-((2S,3R)-3-Hydroxy-4-(N-isobutylbenzo[d][1,3]dioxole-5-sulfonamido)-1-phenylbutan-2-yl)-2-(((S)-tetrahydrofuran-3
-yl)amino)acetamide (26a). The title compound was obtained by saponification of 3a to 4a, which was then coupled with
19 through an EDC/HOBT/Et3N coupling procedure in 80.0% yield over two steps (colorless oil) as described for 20a. 1H
NMR (500 MHz, CDCl3) δ 7.40 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 8.5, 2.0 Hz, 1H), 7.32 – 7.20 (m, 6H), 6.90 (d, J = 8.0
Hz, 1H), 6.09 (s, 2H), 4.19 – 4.13 (m, 1H), 3.94 – 3.90 (m, 1H), 3.85 (dd, J = 15.5, 7.5 Hz, 1H), 3.73 – 3.69 (m, 1H),
3.63 (dd, J= 9.0, 5.5 Hz, 1H), 3.46 (dd, J = 9.0, 3.0 Hz, 1H), 3.22 – 3.17 (m, 2H), 3.13 – 3.02 (m, 4H), 3.00 – 2.96 (m,
1H), 2.94 – 2.92 (m, 2H), 1.98 – 1.85 (m, 2H), 1.61 – 1.55 (m, 1H), 0.91 (d, J = 2.5 Hz, 3H), 0.90 (d, J = 2.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 172.3, 151.4, 148.3, 137.9, 131.9, 129.3, 128.5, 126.6, 123.0, 108.3, 107.6, 102.3, 72.9,
72.8, 66.9, 58.7, 58.6, 54.2, 53.3, 50.5, 34.8, 32.7, 27.2, 20.1, 20.0; HRMS (ESI) m/z calcd. for C27H38N3O7S ([M + H]+):
548.2425, found 548.2424.
4.4.52.
2-((2-Amino-2-oxoethyl)((S)-tetrahydrofuran-3-yl)amino)-N-((2S,3R)-3-hydroxy-4-(N-isobutylbenzo[d][1,3]dioxole-5-sul

ACCEPTED MANUSCRIPT
fonamido)-1-phenylbutan-2-yl)acetamide (26b). The title compound was obtained by saponification of 3b to 4b, which
was then coupled with 19 through an EDC/HOBT/Et3N coupling procedure in 59.8% yield over two steps (colorless solid)
as described for 20a, mp 57.6–59.3°C. 1H NMR (500 MHz, CDCl3) δ 7.56 – 7.52 (m, 1H), 7.38 (dd, J = 8.0, 1.5 Hz, 1H),
7.32 – 7.21 (m, 6H), 6.92 (d, J = 8.0 Hz, 1H), 6.48 (s, 1H), 6.11 (s, 2H), 5.60 (s, 1H), 4.35 – 4.29 (m, 1H), 4.17 – 4.16 (m,
1H), 3.97 – 3.91 (m, 2H), 3.63 – 3.56 (m, 3H), 3.32 (s, 1H), 3.25 (dd, J = 15.0, 4.1 Hz, 1H), 3.18 – 3.04 (m, 6H), 2.99 –
2.93 (m, 3H), 1.99 – 1.89 (m, 2H), 1.75 – 1.65 (m, 1H), 0.92 (d, J = 4.0 Hz, 3H), 0.91 (d, J = 4.0 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 173.4, 171.3, 151.5, 148.3, 137.9, 131.9, 129.2, 128.6, 126.6, 123.1, 108.4, 107.6, 102.4, 72.8, 70.7, 67.6,
63.0, 58.4, 56.9, 56.3, 53.9, 52.9, 34.8, 28.9, 27.1, 20.1, 20.0; HRMS (ESI) m/z calcd. for C29H40N4O8SNa ([M + Na]+):
627.2459, found 627.2457.
4.4.53.
2-((2-(((2S,3R)-3-Hydroxy-4-(N-isobutylbenzo[d][1,3]dioxole-5-sulfonamido)-1-phenylbutan-2-yl)amino)-2-oxoethyl)((S
)-tetrahydrofuran-3-yl)amino)-N,N-dimethylacetamide (26c). The title compound was obtained by saponification of 3c to
4c, which was then coupled with 19 through an EDC/HOBT/Et3N coupling procedure in 80.0% yield over two steps
(colorless solid) as described for 20a, mp 57.6–59.3°C. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J = 8.5 Hz, 1H), 7.37 (dd,
J = 8.5, 2.0 Hz, 1H), 7.24– 7.23 (m, 5H), 7.19 – 7.14 (m, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.06 (s, 2H), 4.28 (s, 1H), 4.24 –
4.18 (m, 1H), 3.93 – 3.85 (m, 1H), 3.88 – 3.85 (m, 1H), 3.60 – 3.52 (m, 2H), 3.48 (dd, J = 9.5, 4.0 Hz, 1H), 3.34 – 3.26
(m, 3H), 3.19 – 3.04 (m, 5H), 2.98 (dd, J = 13.5, 7.5 Hz, 1H), 2.93 (s, 3H), 2.92 – 2.87 (m, 2H), 2.89 (s, 3H), 1.98 –1.87
(m, 2H), 1.63 – 1.56 (m, 1H), 0.91 (d, J = 6.5 Hz, 3H) , 0.90 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.1,
170.6, 151.2, 148.2, 138.6, 132.5, 129.2, 128.2, 126.2, 123.1, 108.2, 107.7, 102.2, 72.9, 70.8, 67.6, 63.0, 57.9, 57.6, 54.0,
53.9, 52.5, 36.2, 36.0, 34.8, 29.4, 27.0, 22.9, 20.1, 20.0; HRMS (ESI) m/z calcd. for C31H44N3O8SNa ([M + Na]+):
655.2772, found 655.2775.
4.4.54.
N-((2S,3R)-3-Hydroxy-4-(N-isobutylbenzo[d][1,3]dioxole-5-sulfonamido)-1-phenylbutan-2-yl)-2-((2-morpholino-2-oxoet
hyl)((S)-tetrahydrofuran-3-yl)amino)acetamide (26d). The title compound was obtained by saponification of 3d to 4d,
which was then coupled with 19 through an EDC/HOBT/Et3N coupling procedure in 70.3% yield over two steps
(colorless solid) as described for 20a, mp 63.9–65.7°C. 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 8.5 Hz, 1H), 7.39 (dd,
J = 8.0, 1.5 Hz, 1H), 7.26 – 7.26 (m, 5H), 7.21 – 7.19 (m, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.09 (s, 2H), 4.27 – 4.16 (m, 2H),
3.95 – 3.87 (m, 2H), 3.69 – 3.67 (m, 4H), 3.60 – 3.49 (m, 5H), 3.41 – 3.29 (m, 5H), 3.24 – 3.21 (m, 1H), 3.16 – 3.08 (m,
4H), 3.00 (dd, J = 13.5, 7.5 Hz, 1H), 2.94 – 2.89 (m, 2H), 2.01 – 1.89 (m, 2H), 1.65 – 1.58 (m, 1H), 0.93 – 0.91 (m, 6H);
13C NMR (125 MHz, CDCl3) δ 172.0, 169.3, 151.3, 148.2, 138.5, 132.4, 129.2, 128.3, 126.3, 123.1, 108.3, 107.7, 102.3,

ACCEPTED MANUSCRIPT
72.9, 70.9, 67.6, 66.8, 66.3, 62.9, 58.0, 57.6, 53.9, 53.4, 52.6, 45.0, 42.3, 34.8, 29.4, 27.04, 20.1, 20.0; HRMS (ESI) m/z
calcd. for C33H46N4O9SNa ([M + Na]+): 697.2878, found 697.2880.
4.4.55.
N-((2S,3R)-3-Hydroxy-4-(N-isobutylbenzo[d][1,3]dioxole-5-sulfonamido)-1-phenylbutan-2-yl)-2-((2-methoxyethyl)((S)-t
etrahydrofuran-3-yl)amino)acetamide (26e). The title compound was obtained by saponification of 3e to 4e, which was
then coupled with 19 through an EDC/HOBT/Et3N coupling procedure in 79.0% yield over two steps (colorless oil) as
described for 20a. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.31 – 7.19 (m,
6H), 6.89 (d, J = 8.5, 1H), 6.08 (s, 2H), 4.47 (d, J = 3.0 Hz, 1H), 4.17 – 4.10 (m, 1H), 3.91 – 3.84 (m, 2H), 3.60 – 3.55
(m, 2H), 3.47 (dd, J = 9.5, 4.5 Hz, 1H), 3.40 – 3.35 (m, 1H), 3.30 – 3.24 (m, 3H), 3.29 (s, 3H), 3.12 – 3.01 (m, 4H), 2.98
– 2.89 (m, 3H), 2.67 – 2.62 (m, 1H), 2.54 2.49 (m, 1H), 1.97 – 1.88 (m, 2H), 1.57 – 1.50 (m, 1H), 0.91 (d, J = 6.5 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ 172.5, 151.4, 148.3, 138.1, 132.1, 129.3, 128.5, 126.5, 123.0, 108.3, 107.6, 102.3,
72.8, 70.3, 70.2, 67.7, 62.4, 58.6, 58.4, 55.3, 54.3, 53.4, 53.0, 34.6, 29.1, 27.1, 20.1, 20.0; HRMS (ESI)m/z calcd. for
C30H43N3O8SNa ([M + Na]+): 628.2657, found 628.2641.
4.4.56.
N-((2S,3R)-3-Hydroxy-4-(N-isobutylbenzo[d][1,3]dioxole-5-sulfonamido)-1-phenylbutan-2-yl)-2-(N-((S)-tetrahydrofuran
-3-yl)methylsulfonamido)acetamide (26f). The title compound was obtained by saponification of 3f to 4f, which was then
coupled with 19 through an EDC/HOBT/Et3N coupling procedure in 60.9% yield over two steps (colorless solid) as
described for 20a, mp 161.3–163.5°C. 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 8.0 Hz, 1H), 7.30 – 7.24 (m, 4H), 7.21
– 7.18 (m, 2H), 6.88 (d, J = 8.0 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.08 (s, 2H), 4.45 – 4.38 (m, 1H), 4.26 – 4.18 (m, 1H),
3.86 – 3.81 (m, 3H), 3.70 (s, 2H), 3.62 (dd, J = 10.0, 7.0 Hz, 1H), 3.57 (dd, J = 10.0, 3.5 Hz, 1H), 3.51 – 3.46 (m, 1H),
3.14 – 3.06 (m, 3H), 2.95 – 2.84 (m, 3H), 2.86 (s, 3H), 2.06 – 2.01 (m, 1H), 1.88 – 1.84 (m, 1H), 1.54 – 1.51 (m, 1H),
0.90 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.1, 151.5, 148.3, 137.6, 131.8,
129.3, 128.6, 126.6, 123.2, 108.4, 107.6, 102.3, 72.5, 70.4, 67.2, 58.8, 57.7, 53.9, 53.4, 47.2, 38.7, 35.3, 30.5, 27.3, 20.1,
19.9; HRMS (ESI) m/z calcd. for C28H39N3O9S2Na ([M + Na]+): 648.2025, found 648.2019.
4.4.57.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl)-2-(((R)-tetrahydrofuran-3-yl)am
ino)acetamide (27g). The title compound was obtained by saponification of 3g to 4g, which was then coupled with 14
through an EDC/HOBT/Et3N coupling procedure in 76.8% yield over two steps (colorless oil) as described for 20a. 1H
NMR (500 MHz, CDCl3) δ 7.76 – 7.73 (m, 2H), 7.45 (d, J = 8.5 Hz, 1H), 7.31 – 7.20 (m, 5H), 7.01 – 6.98 (m, 2H), 4.23
– 4.18 (m, 1H), 3.92 – 3.89 (m, 1H), 3.88 (s, 3H), 3.87 – 3.85 (m, 1H), 3.75 – 3.71 (m, 1H), 3.55 (dd, J = 9.5, 5.0 Hz,

ACCEPTED MANUSCRIPT
1H), 3.49 (dd, J = 9.5, 2.5 Hz, 1H), 3.23 – 3.18 (m, 1H), 3.15 – 3.06 (m, 5H), 2.96 – 2.91 (m, 3H), 2.01 – 1.87 (m, 2H),
1.62 – 1.57 (m, 1H), 0.91 (d, J = 1.5 Hz, 3H), 0.89 (d, J = 1.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.0, 162.9,
138.0, 130.3, 129.4, 129.3, 128.5, 126.5, 114.3, 72.6, 72.3, 66.9, 58.7, 58.4, 55.6, 53.7, 53.0, 50.4, 34.5, 32.8, 27.2, 20.1,
20.0; HRMS (ESI) m/z calcd. for C27H40N3O6S ([M + H]+): 534.2638, found 534.2639.
4.4.58.
N-((2S,3R)-3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl)-2-((2-methoxyethyl)((R)-tetrahy
drofuran-3-yl)amino)acetamide (27h).The title compound was obtained by saponification of 3h to 4h, which was then
coupled with 14 through an EDC/HOBT/Et3N coupling procedure in 63.5% yield over two steps (colorless oil) as
described for 20a. 1H NMR (500 MHz, CDCl3) δ 7.72 – 7.69 (m, 3H), 7.28 – 7.15 (m, 5H), 6.96 – 6.93 (m, 2H), 4.46 (s,
1H), 4.16 – 4.11 (m, 1H), 3.85 – 3.81 (m, 1H), 3.80 (s, 3H), 3.58 – 3.51 (m, 2H), 3.46 – 3.43 (m, 1H), 3.38 – 3.33 (m,
1H), 3.33 – 3.27 (m, 3H), 3.25 – 3.24 (m, 1H), 3.24 (s, 3H), 3.23 – 3.21 (m, 1H), 3.09 – 3.01 (m, 3H), 2.95 – 2.82 (m,
4H), 2.61 – 2.57 (m, 1H), 2.50 – 2.45 (m, 1H), 1.95 – 1.78 (m, 2H), 1.55 – 1.48 (m, 1H), 0.86 (d, J = 6.5 Hz, 6H); 13C
NMR (125 MHz, CDCl3) δ 172.3, 162.8, 138.1, 130.5, 129.4, 129.2, 128.4, 126.4, 114.2, 72.54 (s), 70.7, 70.1, 67.7, 62.3,
58.6, 58.1, 55.6, 55.2, 53.9, 53.7, 52.8, 34.5, 28.5, 27.1, 20.1, 19.0; HRMS (ESI) m/z calcd. for C30H46N3O7SNa ([M +
Na]+): 614.2876, found 614.2879.
4.4.59.
N-((2S,3R)-4-(4-Amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-2-(((R)-tetrahydrofuran-3-yl)amin
o)acetamide (28g). The title compound was obtained by saponification of 3g to 4g, which was then coupled with 15
through an EDC/HOBT/Et3N coupling procedure as described for 20a and finally by hydrogenation of nitro group as
described for 22a in 59.6% yield over three steps (colorless oil). 1H NMR (500 MHz, CDCl3) δ 7.58 – 7.55 (m, 2H), 7.43
(d, J = 8.5 Hz, 1H), 7.30 – 7.19 (m, 5H), 6.70 – 6.67 (m, 2H), 4.23 – 4.16 (m, 3H), 3.91 – 3.84 (m, 2H), 3.74 – 3.71 (m,
1H), 3.56 (dd, J = 9.5, 5.0 Hz, 1H), 3.48 (dd, J = 9.5, 2.5 Hz, 1H), 3.17 (dd, J = 15.0, 4.5 Hz, 1H), 3.13 (s, 2H), 3.10 –
3.04 (m, 3H), 2.96 – 2.88 (m, 3H), 2.00 – 1.86 (m, 2H), 1.61 – 1.55 (m, 1H), 0.91 (d, J = 4.0 Hz, 3H), 0.89 (d, J = 4.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 172.0, 150.8, 138.0, 129.5, 129.3, 128.5, 126.5, 126.4, 114.1, 72.7, 72.4, 66.9, 58.7,
58.6, 53.6, 53.2, 50.5, 34.5, 32.8, 27.2, 20.2, 20.0; HRMS (ESI) m/z calcd. for C26H39N4O5S ([M + H]+): 519.2636, found
519.2664.
4.4.60.
N-((2S,3R)-4-(4-Amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-2-((2-methoxyethyl)((R)-tetrahydr
ofuran-3-yl)amino)acetamide (28h). The title compound was obtained by saponification of 3h to 4h, which was then
coupled with 15 through an EDC/HOBT/Et3N coupling procedure as described for 20a and finally by hydrogenation of

ACCEPTED MANUSCRIPT
nitro group as described for 22a in 73.1% yield over three steps (colorless solid), mp 36–37°C. 1H NMR (500 MHz,
CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.30 – 7.19 (m, 5H), 6.67 (d, J = 8.5 Hz, 2H), 4.49 (s, 1H),
4.24 – 4.13 (m, 3H), 3.90 – 3.84 (m, 2H), 3.62 – 3.56 (m, 2H), 3.42 – 3.30 (m, 3H), 3.28 (s, 3H), 3.22 (dd, J = 15.5, 4.5
Hz, 1H), 3.12 – 3.03 (m, 3H), 2.98 – 2.86 (m, 4H), 2.64 – 2.51 (m, 2H), 1.96 – 1.87 (m, 2H), 1.59 – 1.52 (m, 1H), 0.91 (d,
J = 3.0 Hz, 3H), 0.90 (d, J = 3.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.3, 150.8, 138.2, 129.5, 129.3, 128.5, 126.6,
126.5, 114.1, 72.7, 70.7, 70.2, 67.7, 62.3, 58.7, 58.4, 55.2, 54.0, 53.7, 53.1, 34.4, 28.6, 27.2, 20.2, 20.0; HRMS (ESI) m/z
calcd. for C29H44N4O6SNa ([M + Na]+): 599.2868, found 599.2874.
4.4.61.
N-((2S,3R)-3-Hydroxy-4-(N-isobutylbenzo[d][1,3]dioxole-5-sulfonamido)-1-phenylbutan-2-yl)-2-(((R)-tetrahydrofuran-3
-yl)amino)acetamide (29g). The title compound was obtained by saponification of 3g to 4g, which was then coupled with
19 through an EDC/HOBT/Et3N coupling procedure in 64.4% yield over two steps (colorless solid) as described for 20a,
51–53oC. 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 8.0, 2.0 Hz, 1H), 7.30 – 7.2 (m, 6H), 6.89
(d, J = 8.5 Hz, 1H), 6.09 (s, 2H), 4.44 (s, 1H), 4.22 – 4.16 (m, 1H), 3.3.91 – 3.85 (m, 2H), 3.75 – 3.71 (m, 1H), 3.55 (dd,
J = 9.0, 5 Hz, 1H), 3.48 (dd, J = 9.0, 2.5 Hz, 1H), 3.21 (dd, J = 15.0, 4.0 Hz, 1H), 3.12 (d, J = 1.5 Hz, 2H), 3.09 – 3.04
(m, 3H), 2.96 – 2.88 (m, 3H), 2.01 – 1.86 (m, 2H), 1.61 – 1.55 (m, 1H), 0.90 (d, J = 6.5 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 172.2, 151.4, 148.3, 137.9, 131.9, 129.3, 128.5, 126.6, 123.0, 108.4, 107.6, 102.3, 72.7, 72.4, 66.9, 58.7, 58.5,
53.7, 53.1, 50.5, 34.5, 32.9, 27.2, 20.1, 20.0; HRMS (ESI) m/z calcd. for C27H38N3O7S ([M + H]+): 548.2426, found
548.2464.
4.4.62.
N-((2S,3R)-3-Hydroxy-4-(N-isobutylbenzo[d][1,3]dioxole-5-sulfonamido)-1-phenylbutan-2-yl)-2-((2-methoxyethyl)((R)-t
etrahydrofuran-3-yl)amino)acetamide (29h).The title compound was obtained by saponification of 3h to 4h, which was
then coupled with 19 through an EDC/HOBT/Et3N coupling procedure in 66.2% yield over two steps (light yellow oil) as
described for 20a. 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.0, 2.0 Hz, 1H), 7.28 – 7.16 (m,
6H), 6.85 (d, J = 8.0 Hz, 1H), 6.04 (s, 2H), 4.45 (d, J = 3.5 Hz, 1H), 4.16 – 4.11 (m, 1H), 3.88 – 3.79 (m, 2H), 3.59 –
3.52 (m, 2H), 3.40 – 3.35 (m, 1H), 3.33 – 3.29 (m, 2H), 3.27 – 3.26 (m, 1H), 3.26 (s, 3H), 3.24 – 3.23 (m, 1H), 3.11 –
3.00 (m, 3H), 2.97 – 2.82 (m, 5H), 2.63 – 2.46f (m, 2H), 1.96 – 1.83 (m, 2H), 1.56 – 1.50 (m, 1H), 0.89 (d, J = 5.0 Hz,
3H), 0.87 (d, J = 5.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.3, 151.3, 148.2, 138.0, 132.1, 129.2, 128.5, 126.5,
123.0, 108.3, 107.5, 102.3, 72.6, 70.7, 70.1, 67.7, 62.3, 58.6, 58.1, 55.2, 54.0, 53.8, 52.8, 34.5, 28.5, 27.1, 20.1, 20.0;
HRMS (ESI) m/z calcd. for C30H45N3O8SNa ([M + Na]+): 628.2657, found 628.2664.
Acknowledgement

ACCEPTED MANUSCRIPT
This work was supported by the National Natural Science Foundation of China (Nos. 81473099, 81302644
and 81473098); and the CAMS Innovation Fund for Medical Sciences (Nos. CIFMS 2016-I2M-3-014 and
CIFMS 2016-I2M-1-011).
Appendix A. Supplementary data
Supplementary data associated with this article can be found in the online version, at http://. These data include
characterization data and MOL files of most compounds described in this article.
References
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