Synthesis of N-Substituted Iminosugar Derivatives and Evaluation of Their Immunosuppressive Activities

Accepted Article

Title: Synthesis of N-Substituted Iminosugar Derivatives and

Evaluation of Their Immunosuppressive Activities

Authors: Xinshan Ye and Qin Li

This manuscript has been accepted after peer review and appears as an

Accepted Article online prior to editing, proofing, and formal publication

of the final Version of Record (VoR). This work is currently citable by

using the Digital Object Identifier (DOI) given below. The VoR will be

published online in Early View as soon as possible and may be different

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: ChemMedChem 10.1002/cmdc.201700706

Link to VoR: http://dx.doi.org/10.1002/cmdc.201700706

A Journal of

www.chemmedchem.org

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

Synthesis of N-Substituted Iminosugar Derivatives and

Evaluation of Their Immunosuppressive Activities

Zhuo Lv, Chengcheng Song, Youhong Niu, Qin Li,* and Xin-Shan Ye*^[a]

^[a]Z. Lv, C. Song, Dr. Y. Niu, Prof. Q. Li, Prof. X.-S. Ye

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University

Xue Yuan Rd No. 38, Beijing 100191, China

Fax: +86 10 82802724

E-mail: xinshan@bjmu.edu.cn (X.-S. Ye) or liqin@bjmu.edu.cn (Q. Li)

Supporting information for this article is available on the WWW under http://www.chemmedchem.org or from the author.

Abstract: It is important to find more effective and safer

immunosuppressants because the clinically-used

immunosuppressive agents have signiﬁcant side-effects. A series of

indolizidine alkaloid (bicyclic iminosugar), has been found to

exhibit some immunosuppressive activity and prolong heart

allograft survival in rats.^[9]In recent years, our group has been

N-substituted iminosugar derivatives were designed and synthesized, actively involved in search of iminosugar derivatives with

and their immunosuppressive effects were evaluated by CCK-8

assay. The results revealed that iminosugars 10e and 10i exhibited

the strongest inhibitory effect on mouse splenocyte proliferation (IC₅₀

immunomodulating activities. By

a

series of structural

modifications on iminosugars, such as alteration in the

configuration of the hydroxyl group, N-alkylation and N-arylation,

several synthetic monocyclic iminosugar derivatives (Figure 1,

2–6) with good immunosuppressive activities both in vitro^[10]and

in vivo^[11]have been identified. Among them, N-decyl-1,4-

=

2.16 and 2.48 μM, respectively), whereas the iminosugars

containing an amide group near the hydrophilic head (compounds

10j-n) exhibited no inhibitory effects. Further studies revealed that

the inhibitory effects on splenocyte proliferation may come from the

suppression of both IFN-γ and IL-4 cytokines. Our results suggested

that the synthetic iminosugars, especially compounds 10e and 10i

hold the potential as immunosuppressive agents.

dideoxy-l,4-iminotetritol

(Figure

1,

5)

displayed

immunosuppressive activities in vitro and prolonged the allograft

survival in the mouse skin transplantation experiment.

Recently, spingosine-1-phosphate receptor 1 (S1P₁) has been

actively pursued as an important therapeutic target due to its

essential role in immune regulation.^[12]One of the S1P₁

modulators, Fingolimod (FTY720/Gilenya; Novartis) (Figure 1, 7),

was approved for the treatment of relapsing multiple sclerosis in

2010.^[13]Interestingly, modifications of the carbon chain in 7

resulted in different immune responses and the selectivity

between S1P₁and S1P₃. KRP-203 (Figure 1, 8), an analogue of

FTY720, is a more selective agonist of the S1P1 receptor and is

believed to be safer than FTY720,^[14]thus holding the great

potential in the treatment of autoimmune diseases and in the

prevention of transplant rejection. Compound 9 is another

selective S1P₁agonist. Compared with FTY720, compound 9

exerted good lymphopenia activity in vivo but with weak

influence on heart rate.^[15]KRP-203, compound 9, and FTY720

have some common structural characteristics: they all possess

the same hydrophilic 2-aminopropane-1,3-diol fragment and a

hydrophobic tail.

Introduction

Inhibition of the acute rejection is the key to the success of

organ transplantation.^[1]Although the use of immunosuppressive

agents has greatly improved the transplant survival, the current

immunosuppressants such as cyclosporin A (CSA), tacrolimus,

mycophenolate mofetil, and sirolimus, have significant side-

effects including nephrotoxicity, neurotoxicity, infection, cancer,

new onset post-transplant diabetes mellitus, hyperlipidemia, and

hypertension.^[2]Therefore, it is urgent to find more effective and

safer immunosuppressants.

Iminosugars are carbohydrate mimetics in which the

endocyclic oxygen of sugar ring is replaced by nitrogen.

Because of their structural similarity to sugars, iminosugars can

act as potent inhibitors for a variety of carbohydrate-processing

enzymes involved in important biological events,^[3]hence, they

possess a range of biological activities that spin a wide cross

section of diseases such as tumor metastasis,^[4]diabetes,^[5]viral

infections^[6]and lysosomal storage disorders.^[7]The broad

biological activities of iminosugars have aroused many efforts in

the synthesis of iminosugars and their derivatives.^[8]Some

iminosugars have been already approved as drugs on the

market, for example, Glyset™ and Zavesca™, for the treatment

of noninsulin-dependent diabetes and Gaucher’s disease,

respectively. However, the use of iminosugar derivatives as

immunosuppressive agents is an area that is less explored. To

date, only castanospermine (Figure 1, 1), a naturally-occurring

Inspired by these observations, to find iminosugars with better

activities and to further understand the structure–activity

relationships (SARs) of this type of compounds, we report herein

the synthesis of several N-alkylated iminosugar derivatives and

the evaluation of their immunosuppressive activities.

1

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

The preparation of the key iminosugar intermediate 11 is shown

in Scheme 1. The reaction of D-ribose with acetone in the

presence of

a

catalytic amount of iodine produced

isopropylidene-D-ribose (12) in 84% yield.^[16]After oxidation of

12 by NaIO₄, the unstable aldehyde 13 was immediately

subjected to reductive amination, leading to the formation of

benzylated iminosugar 14 in 86% yield over two steps.

Subsequently, the catalytic hydrogenolysis of 14 yielded

compound 11, which was directly used for the next step without

further purification.^[17]

Figure 1. Structures of some immunoregulatory molecules

Scheme 1. Synthesis of iminosugar 11. Reagents and conditions: (a)

acetone/I₂, overnight, 84% yield; (b) NaIO₄, H₂O, 20 h; (c) BnNH₂,

NaBH₃CN/MeOH, 3 Å MS, 2 h, 86% yield over two steps; (d) Pd(OH)₂/C (20%

Pd), H₂, MeOH, 48 h.

Results and Discussion

Design

Bromides 17a–d were obtained by Friedel−Crafts acylation of

15a–d with bromoacetyl bromide^[18]followed by reduction of the

carbonyl group with dimethylamine-borane in the presence of

titanium tetrachloride (Scheme 2).^[19]

Fourteen N-alkylated 1,4-dideoxy-l,4-iminotetritol derivatives

with side chains containing one or more phenyl or biphenyl

groups (Figure 2, compounds 10a-n) were designed. Since

FTY720, KRP-203, and compound

9 have the same 2-

Compound 17e was prepared as outlined in Scheme 3. p-

Hydroxyacetophenone was first alkylated using n-heptyl bromide

in the presence of K₂CO₃in DMF (70 ^oC), and then the obtained

phenyl ether 15e was subjected to radical bromination with

CuBr₂/EtOAc, affording the desired bromoacetophenone 16e.^[20]

Reduction of the carbonyl group in 16e provided compound 17e.

aminopropane-1,3-diol structure, we want to explore whether the

substitution of this polar head group with a conformation-locking

iminosugar (1,4-dideoxy-l,4-iminotetritol) would improve the

immunosuppressive activity. To further investigate whether the

N-alkylated side chain influences the immunosuppressive

activity or not, various side chains based on the reported

immunoregulatory molecules are chosen. All these target

compounds could be prepared by coupling compound 11 with a

variety of alkyl bromides 17a-n (Figure 2).

Scheme 2. Synthesis of 17a-d. Reagents and conditions: (a) bromoacetyl

bromide, AlCl₃, CH₂Cl₂, 3-5 h, 96-99% yield; (b) Me₂NH·BH₃, TiCl₄, CH₂Cl₂,

overnight, 96-97% yield.

Figure 2. Structures of the designed iminosugars with alkyl chains inserted

phenyl or biphenyl groups.

Scheme 3. Synthesis of 17e. Reagents and conditions: (a) K₂CO₃, DMF, 70

^oC, 9 h, 98% yield; (b) CuBr₂, EtOAc, reflux, overnight; (c) Me₂NH·BH₃, TiCl₄,

CH₂Cl₂, overnight, 85% yield over two steps.

Chemistry

2

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

As shown in Scheme 4, compounds 17f and 17g were

prepared through the intermediates 15f and 15g that were

obtained by the aromatic nucleophilic substitution reaction of 2-

chloro-4-fluoro-acetophenone with p-(n-butyl)phenol or p-(n-

butyl)thiophenol. The radical bromination of compounds 15f and

15g with NBS/p-TsOH^[21]and CuBr₂/EtOAc provided compounds

16f and 16g, respectively. Reduction of the carbonyl group by

dimethylamine-borane/titanium tetrachloride afforded 17f and

17g.

Scheme 6. Synthesis of 17i. Reagents and conditions: (a) (i)

bis(pinacolate)diboron, PdCl₂(Cy₃P)₂, AcOK, dioxane, 100 ^oC; (ii) 1-bromo-4-

iodobenzene, Pd(PPh₃)₄, NaHCO₃, DME/H₂O, 100 ^oC, 53% yield over two

steps; (b) p-toluene thiophenol, Xantphos, Pd₂(dba)₃•CHCl₃, DIPEA, dioxane,

reflux, 87% yield; (c) CuBr₂, EtOAc, reflux, overnight; (d) Me₂NH·BH₃, TiCl₄,

CH₂Cl₂, overnight, 57% yield over two steps.

The biphenyl compound 17h was synthesized from 2-chloro-

4-bromo-acetophenone through Suzuki coupling reaction,^[22]

followed by NBS bromination and reduction (Scheme 5).

The synthesis of diaryl sulfide 17i was described in Scheme 6.

The palladium-mediated Suzuki coupling between 2-chloro-4-

bromo-acetophenone and 1-bromo-4-iodobenzene afforded

biphenyl bromide 19. The bromide 19 was converted to the

A preliminary exploration of S1P related structures has

demonstrated that an amide insertion in the S1P structure is well

tolerated.^[24]Clemens and co-workers also demonstrated that

replacing the ethylene component of FTY720 with an amide

bond allowed for active molecules across S1P receptor subtypes

1, 3, 4, and 5.^[25]As a useful reference for the structure-activity

relationship (SAR) studies, the compounds 17j-n incorporating

an amide bond between the phenyl ring and the methylene were

needed. As shown in Scheme 7, 3-bromonitrobenzene was

treated with 1-octyne/ 1-hexyne in a Sonogashira cross-coupling

reaction^[26]to furnish 15j/15k in high yield. The nitro and alkyne

groups were then reduced by hydrogen using palladium on

charcoal to provide 3-octylaniline/3-hexylaniline (16j/16k).^[27]

When we tried to reduce the nitro group to amino group by

catalytic hydrogenation, the chlorine atom in compound 15l

(Scheme 8) was also reduced to produce compound 16l.

However, the zinc powder reduction could provide the desired

product without affecting the chlorine atom. The anilines

obtained were subsequently treated with 2-bromoacetyl bromide

in the presence of triethylamine in dichloromethane to give

compounds 17j-n.

diaryl sulfide 15i by

a

coupling reaction using 4,5-

bis(diphenylphosphino)-9,9-dimethylxanthene as the phosphine

ligand,^[23]which was followed by bromination and reduction,

affording compound 17i.

Scheme 4. Synthesis of 17f and 17g. Reagents and conditions: (a) K₂CO₃,

DMF, 115 ^oC, 5 h to overnight, yield: 100% for 15f, 85% for 15g; (b) (i) NBS, p-

TsOH, MeCN, 50 ^oC, overnight; (ii) CuBr₂, EtOAc, reflux, overnight; (c)

Me₂NH·BH₃, TiCl₄, CH₂Cl₂, overnight, for 17f: 72% yield over two steps, for

17g: 51% yield over two steps.

Scheme 7. Synthesis of 17j and 17k. Reagents and conditions: (a) 1-octyne

or 1-hexyne, [Pd(PPh₃)₂Cl₂], CuI, Et₃N, 99% yield; (b) H₂(g), Pd/C, MeOH; (c)

bromoacetyl bromide, Et₃N, CH₂Cl₂, overnight; for 17j:36% yield over two

steps; for 17k: 58% yield over two steps.

Scheme 5. Synthesis of 17h. Reagents and conditions: (a) Pd(PPh₃)₄,

NaHCO₃, DME/H₂O, 65 ^oC, 4 h, quantitative; (b) NBS, p-TsOH, MeCN, 50 ^oC,

overnight; (c) Me₂NH·BH₃, TiCl₄, CH₂Cl₂, overnight, 47% yield over two steps.

3

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

(39.54%) with 5 (57.59%), it seemed that insertion of a phenyl

ring into the alkyl chain of 5 would improve the inhibitory activity,

but the inhibitory rate was decreased gradually with the increase

of the carbon numbers of the linear alkyl chain on the benzene

ring. When the flexible alkyl tail was linked to the benzene ring

by an oxygen atom (compound 10e), the inhibitory rate showed

an enormous leap (87.18%). Thus, to check if the introduction of

another benzene ring would influence the inhibitory activities,

compounds 10f-i were prepared. The experimental data

revealed that the inhibitory activity of 10f and 10g was even

weaker than that of 10a, but the introduction of a biphenyl

moiety into the hydrophobic part was beneficial to enhancement

of the immunosuppressive activity and compound 10i showed

the strongest inhibitory effect (88.37% at 5 μM). The 50%

inhibitory concentrations (IC₅₀) of compounds 10a, 10b, 10c,

10e, 10g, 10h, 10i were further tested and the results were

summarized in Table 1. Iminosugars 10e and 10i showed

promising inhibitory activity, with IC₅₀values of 2.16 μM and 2.48

μM, respectively.

Scheme 8. Synthesis of 17l-n. Reagents and conditions: K₂CO₃, DMF, 70 ^oC,

9 h, 100% yield; (b) H₂(g), Pd/C, MeOH, overnight; (c) Zn, NH₄Cl, MeOH, 45

^oC, 8-10 h; (d) bromoacetyl bromide, Et₃N, CH₂Cl₂, overnight; for 17l: 76%

yield over two steps; for 17m: 90% yield over two steps; for 17n: 65% yield

over two steps; (e) 1-bromoheptane, K₂CO₃, DMF, 70 ^oC, 6 h, 80% yield.

With all substrates in hand, the coupling reaction was

performed. As shown in Scheme 9, the coupling reaction

between iminosugar 11 and the substituted alkyl bromides 17a-n

proceeded smoothly in acetonitrile in the presence of potassium

carbonate, affording compounds 18a-n in 21-98% yields. Finally,

the acid-catalyzed deprotection of acetonide in 18a–n led to the

target compounds 10a–n in 71–90% yields.

120

100

80

60

40

20

0

-20

Figure 3. Effects of compounds 10a-n on Con A-induced mouse splenocytes

proliferation were assessed by the CCK-8 assay. Concentration of CSA was 1

μΜ and concentration of compounds 10a-n was 5 μΜ. Data are means ± SEM

of at least three independent experiments.

Scheme 9. Synthesis of the target compounds 10a-n. Reagents and

conditions: (a) K₂CO₃, MeCN, 50 ^oC, overnight; (b) 6 M HCl, MeOH, H₂O, 50

^oC.

Table 1. IC₅₀determination of compounds 10a, 10b, 10c, 10e, 10g, 10h, 10i

against mouse splenocytes proliferation

Compound

Inhibition of mouse splenocytes proliferation IC₅₀[μM]

Biology

With compounds 10a–n in hand, their effects on Con A-induced

mouse splenocytes proliferation were assessed by the cell

counting kit-8 (CCK-8) assay,^[10a]by which the mitochondrial

dehydrogenase activity of the surviving cells was measured. The

mouse splenocytes were induced by 5 μg mL^-1of Con A and

were cultured in RPMI-1640 medium. After inoculated in 96-well

plates at about 5×10⁵cells per well, the cells were treated with 5

μM concentration of iminosugars 10a-n at 37 ^oC and 5% CO₂for

48 h. The Con A-treated splenocytes were used as the control

and cyclosporine A (CSA, 1 μM, 95.52% inhibitory rate) treated

splenocytes were used as the positive control. The inhibitory

rates of all compounds were shown in Figure 3. Compared with

the control, none of the iminosugars containing an amide group

near the hydrophilic head (compounds 10j-n) exhibited inhibitory

effects on mouse splenocyte proliferation. The levels of cell

proliferation were reduced by 71.90%, 67.60%, 61.40%, 87.18%,

66.14%, 72.54%, 88.37% when including 5 μM of compounds

10a, 10b, 10c, 10e, 10g, 10h, 10i respectively. Among these

compounds with inhibitory activities, 10e (87.18%) and 10i

(88.37%) exhibited strong inhibitory effects. Comparing

compounds 10a (71.90%), 10b (67.60%), 10c (61.40%), 10d

10a

2.34 (±0.63)

10b

10c

10e

10g

10h

10i

2.59 (±0.53)

3.61 (±0.46)

2.16 (±0.24)

3.06 (±0.22)

3.53 (±0.08)

2.48 (±0.16)

To further confirm the immunosuppressive activity of these

compounds, a cytokine-secretion assay was employed.^[27]The

mouse splenocytes induced by Con A were incubated with 5 μM

o

of compounds 10a, 10b, 10c, 10e, 10g, 10h, 10i at 37 C and

5% CO₂for 72 h. The secretion of IFN-γ and IL-4 was detected

from the supernatant of spleen cells using mice IFN-γ and IL-4

ELISA kits, respectively. The data were shown in Figure 4A and

Figure 4B. All of these seven compounds showed inhibition to

the IFN-γ secretion. As compared with the control, the level of

4

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

10h, 10i on IL-4 secretion. Concentration of CSA was 1 μΜ and concentration

of each compound was 5 μΜ. Data are means ± SEM of at least three

independent experiments.

IFN-γ secretion was reduced by 42.44%, 57.57%, 58.59%,

50.53%, 46.73%, 65.97% and 73.13% when including 5 μM of

compounds 10a, 10b, 10c, 10e, 10g, 10h and 10i, respectively

(Figure 4A, 102.93% for CSA at 1 μM). It was found that among

these compounds, compounds 10b, 10c, 10h and 10i displayed

obvious inhibitory effects on the release of cytokine IFN-γ. The

assay on secretion of IL-4 from mice splenocytes was similar to

that of IFN-γ (Figure 4B). As compared with the control, the level

of IL-4 secretion was decreased by 64.91%, 58.11%, 40.18%,

85.04%, 79.03%, 78.07% and 98.31% when using 5 μM of

compounds 10a, 10b, 10c, 10e, 10g, 10h and 10i, respectively

(Figure 4B, 105.81% for CSA at 1 μM). Compound 10i showed

the best inhibition effect on the secretion of both IFN-γ and IL-4.

Compounds 10b, 10h and 10i did not show significant inhibition

selectivity between IL-4 and IFN-γ secretion. Compounds 10a,

10e and 10g showed moderate inhibitory selectivity for IL-4 over

IFN-γ secretion. Compound 10c showed moderate inhibitory

selectivity for IFN-γ over IL-4 secretion.

IFN-γ and IL-4 are the hallmark cytokines of Th1 and Th2 cells,

respectively. Th1 and Th2 cells are two subclasses of T-helper

cells. Th1 cells secret pro-inflammatory cytokines such as IFN-γ,

IFN-, and IL-2l; their responses predominate in organ-specific

autoimmune disorders, acute allograft rejection, and in some

chronic inflammatory disorders. Th2 cells produce cytokines

such as IL-4, IL-5, and IL-6; their responses predominate in

Omann’s syndrome, transplantation tolerance, chronic graft-

versus-host disease, systemic sclerosis, and allergic diseases.

The cytokines that are secreted by Th1 cells (e.g. IFN-γ)

primarily act in cell-mediated response, whereas those that are

secreted by Th2 cells (e.g. IL-4) mainly function in B-cell

activation and humoral response.^[28]From the assay of the

cytokine secretion, it seems that compound 10i suppress both

Th1 and Th2 cells. Therefore, it might show inhibitory activity

toward both humoral response and cell-mediated immune

response, holding the potential to treat different kinds of immune

diseases. Besides, compound 10e showed moderate inhibitory

selectivity toward Th2 cells.

Conclusions

In summary, we report herein the design and synthesis of

fourteen novel N-substituted iminosugar derivatives by using

concise synthetic routes. All the synthetic compounds were

evaluated in vitro for the immunosuppressive activities on Con

A-induced proliferation of mouse splenocytes by the CCK-8

assay. The results demonstrated that iminosugars 10e and 10i

exhibited the strongest inhibition effect (IC₅₀= 2.16 and 2.48 μM,

respectively), whereas the iminosugars containing an amide

group near the hydrophilic head (compounds 10j-n) exhibited no

inhibitory effects on mouse splenocyte proliferation. Further

studies revealed that the inhibitory effects on splenocyte

proliferation may come from the suppression of both IFN-γ and

IL-4 cytokines. Our results suggested that the synthetic

iminosugars, especially compounds 10e and 10i hold the

potential as immunosuppressive agents.

Experimental Section

Chemistry

General method. Solvents were dried according to standard methods.

Analytical thin-layer chromatography (TLC) was carried out on 0.25 mm

silica gel 60 F₂₅₄plates (Merck), employing ultraviolet light and/or staining

with ceric ammonium molybdate for visualization. Column

chromatography was performed employing 200–300 mesh silica gel or C-

18 reversed-phase silica gel (Merck). ¹H NMR and ¹³C NMR spectra were

recorded on Bruker AVANCE III-400 spectrometer at ambient

temperature. Chemical shifts (in ppm) were referenced to the residual

proton signal of the solvent. High resolution mass spectrometry (HRMS)

was performed on Waters Xevo G2 QTof (ESI) or Bruker Solarix XR

(ESI) or Agilent 7980A/5975B GCMS (EI).

General procedure for Friedel−Crafts acylation (taking 4-octyl-α-

bromoacetophenone as an example). Aluminum chloride (126.7 mg, 0.95

mmol) and 1-phenyloctane (0.2 mL, 0.90 mmol) were dissolved in dry

CH₂Cl₂(1.5 mL) and cooled to −10 °C. Bromoacetyl bromide (78 L, 0.90

mmol) was added dropwise, and the mixture was allowed to return to

room temperature while stirring overnight. The mixture was slowly poured

into ice-water (100 mL), and the aqueous phase was extracted with

CH₂Cl₂(3 × 10 mL). The combined organic layers were washed with

saturated sodium bicarbonate solution (10 mL) and brine (10 mL), dried

over Na₂SO₄and concentrated under reduced pressure. The residue was

purified by column chromatography on silica gel (petroleum ether/ethyl

acetate, 70:1) to give the product 16a as a brown and highly viscous oil.

Yield: 2.74 g (98%).

120

A）

100

80

60

40

20

0

CSA 10a 10b 10c 10e 10g 10h 10i

120

B）

100

General procedure for aromatic carbonyl reduction by

dimethylamine borane/titanium tetrachloride. The carbonyl compound

(50 mmol) was dissolved in 50 mL of CH₂Cl₂, cooled to 0 ^oC, and treated

under stirring with 50 mmol of TiCl₄which was added by syringe through

a septum. Dimethylamine-borane (100 mmol) in 25 mL of CH₂Cl₂was

added to the cold solution, and the mixture was allowed to warm to room

temperature. Stirring was continued for 30 min. Thereafter 1N HCl was

added for the destruction of excess reductant and hydrolysis. The

organic layer was separated, and the aqueous layer was extracted with

CH₂Cl₂(2 × 10 mL). The combined organic layers were washed with

saturated aqueous NaCl, dried over Na₂SO₄. The solvent was removed,

80

60

40

20

0

CSA 10a 10b 10c 10e 10g 10h 10i

Figure 4. A) Inhibitory rates of compounds 10a, 10b, 10c, 10e, 10g, 10h, 10i

on IFN-γ secretion. B) Inhibitory rates of compounds 10a, 10b, 10c, 10e, 10g,

5

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

and the product was purified by column chromatography on silica gel

(petroleum ether/ethyl acetate, 150:1) to give the product.

4-(1-Heptyloxyl)-acetophenone (15e). To a solution of 4-hydroxyl-

acetophenone in anhydrous DMF (10 mL) was added 1-bromo-heptane

(0.24 mL, 1.5 mmol). The mixture was stirred at 70 ^oC for 9 h until TLC

indicated completion of the reaction. The mixture was allowed to warm to

room temperature and ethyl acetate (40 mL) was added. The mixture

was washed with water (2 × 10 mL) and brine (1× 10 mL). The combined

organic layers were dried over Na₂SO₄and concentrated under reduced

pressure. The residue was purified by column chromatography

(petroleum ether/ethyl acetate, 20:1) to give the product as a brown oil.

Yield: 344.8 mg (98%). ¹H NMR (400 MHz, CDCl₃) δ 7.93-7.91 (m, 2H,

aromatic H), 6.93-6.90 (m, 2H, aromatic H), 4.01 (t, J = 6.6 Hz, 2H,

C₆H₁₃CH₂O-), 2.55 (s, 3H, CH₃CO-), 1.84-1.77 (m, 2H), 1.49-1.42 (m,

2H), 1.40-1.31 (m, 6H), 0.90 (t, J = 6.8 Hz, 3H).

General procedure for removing isopropylidene protecting group.

The substrate was dissolved in a combined solvent of MeOH/6 M HCl

(10:3), and the mixture was heated at 50 ^oC overnight. After TLC analysis

showed the complete disappearance of the starting material, the mixture

was cooled to room temperature and concentrated in vacuo, purified by

column chromatography on silica gel (CH₂Cl₂/MeOH) to provide the final

product.

4-Octyl-α-bromoacetophenone (16a). ¹H NMR (400 MHz, CDCl₃) δ

7.90 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 4.44 (s, 2H), 2.67 (t, J =

7.6 Hz, 2H), 1.65-1.59 (m, 2H), 1.31-1.27 (m, 10H), 0.88 (t, J = 6.1 Hz,

3H). The spectral data are in accordance with the data reported in ref. 29.

1-(2-Bromoethyl)-4-(heptyloxy)benzene (17e). To

a

solution of

compound 15e (344.8 mg, 1.47 mmol) in EtOAc (7 mL) was added CuBr₂

(656.7 mg, 2.94 mmol) and the mixture was heated under reflux

overnight. After TLC analysis showed the complete disappearance of the

starting material, the mixture was cooled to room temperature and filtered.

Saturated Na₂S₂O₃aqueous solution was added into the filtrate, and the

mixture was extracted with EtOAc. The organic layers were combined,

dried (Na₂SO₄), filtered, and concentrated. The residue was used directly

for the next step. The dimethylamine borane/titanium tetrachloride

reduction provided compound 17e as a light yellow oil (381.0 mg, 85%,

over two steps). ¹H NMR (400 MHz, CDCl₃) δ 7.10 (dd, J = 2.2 Hz, 8.6

Hz, 2H, aromatic H), 6.84 (dd, J = 3.0 Hz, 8.5 Hz, 2H, aromatic H), 3.93

(dt, J = 2.9 Hz, 6.5 Hz, 2H), 3.52 (dt, J = 1.8 Hz, 7.6 Hz, 2H), 3.09 (dt, J =

2.1 Hz, 7.7 Hz, 2H), 1.79-1.76 (m, 2H), 1.45-1.44 (m, 2H), 1.31 (br, 6H),

0.90-0.89 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 158.23, 130.88, 129.70,

114.67, 68.09, 38.74, 33.50, 31.90, 29.40, 29.18, 26.13, 22.73, 14.21;

HRMS (ESI): Calcd for C₁₅H₂₄BrO [M+H]⁺, 299.1005; found, 299.1010.

4-n-Decyl-α-bromoacetophenone (16b). Yield: 97%. ¹H NMR (400 MHz,

CDCl₃) δ 7.91 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 4.44 (s, 2H),

2.67 (t, J = 7.6 Hz, 2H), 1.65-1.59 (m, 2H), 1.31-1.26 (m, 14H), 0.88 (t, J

= 6.6 Hz, 3H).

4-n-Dodecyl-α-bromoacetophenone (16c). Yield: 99%. ¹H NMR (400

MHz, CDCl₃) δ 7.91 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 4.44 (s,

2H), 2.67 (t, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.32-1.25 (m, 18H), 1.88

(t, J = 6.6 Hz, 3H).

4-n-Tetradecyl-α-bromoacetophenone (16d). Yield: 96%. ¹H NMR (400

MHz, CDCl₃) δ 7.91 (d, J = 8.2 Hz, 2H，aromatic H), 7.29 (d, J = 8.2 Hz,

2H, aromatic H), 4.44 (s, 2H, BrCH₂-), 2.67 (t, J = 7.6 Hz, 2H), 1.67-1.59

(m, 2H), 1.32-1.25 (m, 22H), 0.88 (t, J = 6.6 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 191.08(BrCH₂CO-), 150.11, 131.79, 129.22, 129.05, 36.22,

32.06, 31.16, 31.09, 29.83, 29.81, 29.79, 29.78, 29.68, 29.58, 29.50,

29.40, 22.83, 14.26; HRMS (ESI), Calcd for C₂₂H₃₅BrNaO [M+Na]⁺,

417.1763; found, 417.1783.

4-(4-Butylphenoxy)-2-chloro-acetophenone (15f). To a solution of p-n-

butyl phenol (1.0 g, 5.80 mmol) in DMF (15 mL) was added K₂CO₃(2.40

g, 17.38 mmol). The mixture was stirred at 50 ^oC for 30 min. Then 2-

chloro-4-fluoro acetophenone (0.98 mL, 6.37 mmol) was added. The

mixture was stirred at 115 ^oC under atmosphere of argon overnight. The

mixture was cooled to room temperature and saturated NH₄Cl was added,

and extracted with EtOAc. The combined extracts were washed with

saturated aqueous NaCl, dried over Na₂SO₄. The solvent was removed,

and the product was purified by column chromatography on silica gel

(petroleum ether/ethyl acetate, 25:1) to give the product as a brown oil.

1-(2-Bromoethyl)-4-octyl benzene (17a). Compound 17a was prepared

from 16a by the procedure described in the general procedure. Yield:

96%. The product was used directly for the next step without purification.

1-(2-Bromoethyl)-4-decyl benzene (17b). Compound 17b was

prepared from 16b by the procedure described in the general procedure.

1

Yield: 97%. H NMR (400 MHz, CDCl₃) δ 7.14-7.09 (m, 4H), 3.53 (t, J =

Yield: 1.98 g (100%). H NMR (400 MHz, CD₃OD) δ 7.63 (d, J = 8.7 Hz,

7.6 Hz, 2H), 3.12 (t, J = 7.7 Hz, 2H), 2.59-2.55 (m, 2H), 1.59-1.57 (m, 2H),

1.30-1.26 (m, 14H), 0.90-0.86 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

141.75, 136.18, 128.75, 128.62, 39.26, 35.75, 33.19, 32.05, 31.63, 29.77,

29.74, 29.66, 29.49, 22.83, 14.26; HRMS (EI): Calcd for C₁₈H₂₉Br [M]⁺,

324.1447; found, 324.1444.

1H), 7.21-7.19 (m, 2H), 6.97-6.95 (m, 3H), 6.87 (dd, J = 2.4 Hz, 8.6 Hz,

2H), 2.64-2.60 (m, 5H), 1.65-1.60 (m, 2H), 1.42-1.33 (m, 2H), 0.95 (t, J =

7.4 Hz, 3H).

4-(4-Butylphenylthio)-2-chloro-acetophenone (15g). Compound 15g

was prepared by the same procedure as 15f from p-n-butyl thiophenol.

Yield: 85%. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 8.2 Hz, 1H,

1-(2-Bromoethyl)-4-dodecy benzene (17c). Compound 17c was

prepared from 16c by the procedure described in the general procedure.

Yield: 96%. ¹H NMR (400 MHz, CDCl₃) δ 7.12 (t, J = 9.3 Hz, 4H), 3.55 (t,

J = 7.6 Hz, 2H), 3.13 (t, J = 7.8 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.61-

1.55 (m, 2H), 1.30-1.25 (m, 18H), 0.88 (t, J = 6.5 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 141.80, 136.22, 128.78, 128.65, 39.29, 35.76, 33.20,

32.08, 31.62, 29.82, 29.74, 29.66, 29.50, 22.84, 14.26; HRMS (EI): Calcd

for C₂₀H₃₃Br [M]⁺, 352.1760; found, 352.1758.

), 7.42-7.39 (m, 2H,

), 7.24-7.22 (m, 2H,

), 7.11 (d, J = 1.8 Hz, 1H,

), 7.01 (dd, J = 1.8 Hz,

1-(2-Bromoethyl)-4-tetradecy benzene (17d). Compound 17d was

prepared from 16d by the procedure described in the general procedure.

Yield: 97%. ¹H NMR (400 MHz, CDCl₃) δ 7.14-7.10 (m, 4H，aromatic H),

3.55 (t, J = 7.8 Hz, 2H ， BrCH₂CH₂-), 3.13 (t, J = 7.8 Hz, 2H ，

BrCH₂CH₂-), 2.57 (t, J = 7.6 Hz, 2H), 1.63-1.55 (m, 2H), 1.30-1.25 (m,

22H), 0.88 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 141.80,

136.22, 128.78, 128.64, 39.29(BrCH₂CH₂-), 35.76 (BrCH₂CH₂-), 33.20,

32.08, 31.62, 29.82, 29.74, 29.66, 29.51, 22.84, 14.26; HRMS (EI): Calcd

for C₂₂H₃₇Br [M]⁺, 380.2073; found, 380.2071.

8.2 Hz, 1H,

), 2.65 (t, J = 7.7 Hz, 2H), 2.61 (s, 3H,

), 1.66-1.59 (m, 2H), 1.42-1.33 (m, 3H), 0.94 (t, J = 7.4 Hz,

6

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

3H); ¹³C NMR (100 MHz, CDCl₃) δ 199.09, 145.30, 144.74, 135.28,

134.60, 132.65, 130.43, 130.11, 128.49, 127.53, 125.29, 35.49, 33.48,

30.76, 22.46, 14.05; HRMS (ESI): Calcd for C₁₈H₂₀OSCl [M+H]⁺,

319.0918; found, 319.0923.

135.97, 132.30, 130.44, 129.26, 129.12, 127.12, 125.37, 35.73, 31.63,

31.21, 30.88, 22.67, 14.15; HRMS (ESI): Calcd for C₁₉H₂₂ClO [M+H]⁺,

301.1354; found, 301.1355.

4-(2-Bromoethyl)-3-chloro-4'-pentyl-1,1'-biphenyl (17h). Compound

17h was synthesized starting from 15h using a similar procedure to that

described in the preparation of 17f, yielding 17h as a light yellow oil (47%

yield over two steps). ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J = 1.8 Hz,

1H), 7.47 (d, J = 8.2 Hz, 2H), 7.43 (dd, J = 1.8 Hz, 7.9 Hz, 1H), 7.30 (d, J

= 7.9 Hz, 2H), 7.25-7.24 (m, 2H), 3.62 (t, J = 7.4 Hz, 2H), 3.32 (t, J = 7.6

Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H), 1.68-1.61 (m, 2H), 1.36-1.33 (m, 4H),

0.90 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 143.00, 141.98,

136.85, 134.94, 134.48, 131.49, 129.13, 128.18, 126.96, 125.55, 37.05,

35.73, 31.68, 31.24, 31.08, 22.69, 14.15; HRMS (EI): Calcd for

C₁₉H₂₂BrCl [M]⁺, 364.0588; found, 364.0586.

4-(4-Butylphenoxy)-2-chloro-α-bromoacetophenone (16f). To

a

solution of compound 15f (346.2 mg, 1.15 mmol) in MeCN ( 10 mL) was

added NBS (214.2 mg, 1.20 mmol) and p-TsOH monohydrate (218.0 mg,

1.15 mmol). The mixture was heated at 50 ^oC overnight until TLC

analysis showed the complete disappearance of the starting material.

The reaction was quenched with saturated NaHCO₃and extracted with

CH₂Cl₂. The CH₂Cl₂layers were combined, dried (Na₂SO₄), filtered, and

concentrated. The residue was purified by column chromatography on

silica gel (petroleum ether/EtOAc 25/1) to provide a light yellow solid

1-(4'-Bromo-3-chloro-(1,1'-biphenyl)-4-yl)ethan-1-one (19). A mixture

of 2-chloro-4-bromo-acetophenone (233.5 mg, 1.0 mmol), bis(neopentyl

glycolato)diboron (248.5 mg, 1.1 mmol), potassium acetate (294.4 mg,

3.0 mmol), and dichlorobis(tricyclohexylphosphine)palladium(II) (36.9 mg,

0.05 mmol) in 1,4-dioxane (4 mL) was heated at 100 ^oC. After 6 h, the

mixture was allowed to cool to room temperature and poured into water.

The mixture was extracted with EtOAc and washed with brine. The

organic layer was dried over Na₂SO₄and concentrated in vacuo. The

residue was used directly for the next step.

1

(430.1 mg, 99%). H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 8.7 Hz, 1H),

7.22 (d, J = 8.4 Hz, 2H), 6.99-6.97 (m, 3H), 6.90 (dd, J = 2.4 Hz, 8.7 Hz,

1H), 4.53 (s, 2H), 2.63 (t, J = 7.6 Hz, 2H), 1.66-1.58 (m, 2H), 1.43-1.33

(m, 2H), 0.95 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 192.26,

162.08, 152.59, 140.28, 133.85, 132.81, 130.22, 129.42, 120.42, 119.10,

115.84, 35.15, 34.70, 33.79, 22.48, 14.07. HRMS (ESI): Calcd for

C₁₈H₁₈BrClNaO₂[M+Na]⁺, 403.0071; found, 403.0084.

1-(2-Bromoethyl)-4-(4-butylphenoxy)-2-chlorobenzene

(17f).

Compound 17f was prepared from 16f by the procedure described in the

general procedure as a colorless oil. Yield: 72%. ¹H NMR (400 MHz,

CDCl₃) δ 7.19-7.15 (m, 3H), 6.98 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.4 Hz,

2H), 6.84 (dd, J = 2.5 Hz, 8.4 Hz, 1H), 3.56 (t, J = 7.5 Hz, 2H), 3.23 (t, J =

7.5 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H), 1.64-1.56 (m, 2H), 1.41-1.32 (m, 2H),

0.94 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 157.86, 154.10,

138.96, 134.65, 131.91, 130.60, 129.90, 119.56, 119.22, 116.75, 36.64,

35.09, 33.85, 31.30, 22.47, 14.08; HRMS (EI): Calcd for C₁₈H₂₀OBrCl

[M]⁺, 366.0381; found, 366.0377.

The product obtained from above, 1-bromo-4-iodobenzene (278.7 mg,

0.99 mmol) and NaHCO₃(470.5 mg, 5.6 mmol) in 1,2-dimethoxyethane

(6

mL)

and

water

(2

mL)

was

added

tetrakis-

(triphenylphosphine)palladium(0) (22.0 mg, 0.02 mmol). After stirring at

100 ^oC for 8 h, 1-bromo-4-iodobenzene (133.0 mg, 0.47 mmol) and

tetrakis(triphenylphosphine)palladium(0) (11.6 mg, 0.01 mmol) was

added to the mixture. The mixture was stirred at 100 ^oC for another 8 h

and extracted with EtOAc. The organic layer was washed with brine,

dried over Na₂SO₄, and concentrated in vacuo. Purification of the residue

by column chromatography on silica gel (petroleum ether /EtOAc 25:1)

gave the title compound as a brown solid. Yield: 164.1 mg, 53%. ¹H NMR

(400 MHz, CDCl₃) δ 7.66 (d, J = 8.0 Hz, 1H), 7.60-7.57 (m, 3H), 7.49 (dd,

J = 1.7 Hz, 8.0 Hz, 1H), 7.46-7.42 (m, 2H), 2.68 (s, 3H).

1-(2-Bromoethyl)-4-(4-butylphenylthio)-2-chloro-benzene (17g). To a

solution of compound 15g (319.2 mg, 1.0 mmol) in EtOAc (7 mL) was

added CuBr₂(447.2 mg, 2.0 mmol) and the mixture was heated under

reflux overnight. After TLC analysis showed the complete disappearance

of the starting material, the mixture was cooled to room temperature and

filtered. Saturated Na₂S₂O₃aqueous solution was added into the filtrate,

and the mixture was extracted with EtOAc for three times. The organic

layers were combined, dried (Na₂SO₄), filtered, and concentrated. The

residue was treated directly by the procedure described in the general

procedure. Yield: 195.3 mg (51%, over two steps). ¹H NMR (400 MHz,

CDCl₃) δ 7.34 (d, J = 8.1 Hz, 2H), 7.20-7.12 (m, 4H), 7.06 (dd, J = 1.8 Hz,

8.0 Hz, 1H), 3.55 (t, J = 7.4 Hz, 2H), 3.23 (t, J = 7.5 Hz, 2H), 2.62 (t, J =

7.7 Hz, 2H), 1.64-1.56 (m, 2H), 1.41-1.31 (m, 2H), 0.93 (t, J = 7.3 Hz,

3H); ¹³C NMR (100 MHz, CDCl₃) δ 143.64, 138.60, 134.60, 134.18,

133.23, 131.56, 129.84, 129.81, 129.56, 127.45, 36.84, 35.45, 33.57,

31.00, 22.49, 14.09; HRMS (ESI): Calcd for C₁₈H₂₁BrClS [M+H]⁺,

383.0230; found, 383.0212.

1-(3-Chloro-4'-(p-tolylthio)-(1,1'-biphenyl)-4-yl)ethan-1-one (15i).

A

mixture of 19 (327.3 mg, 1.06 mmol), _P-toluene thiophenol (148.4 mg,

1.20 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct

(27.4 mg, 0.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

(Xantphos, 30.6 mg, 0.05 mmol), and N,N-diisopropylethylamine (0.36

mL, 2.11 mmol) in 1,4-dioxane (10.0mL) was refluxed overnight. After

being poured into water, the mixture was extracted with EtOAc. The

organic layer was washed with brine, dried over Na₂SO₄, and

concentrated in vacuo. Purification of the residue by column

chromatography on silica gel (petroleum ether/dichloromethane 1:2) gave

the title compound as a pale-yellow solid. Yield: 325.4 mg, 87%. ¹H NMR

(400 MHz, CDCl₃) δ 7.67-7.64 (m, 1H), 7.60-7.57 (m, 1H), 7.49-7.44 (m,

3H), 7.36 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.0 Hz,

2H), 2.67 (s, 3H), 2.37 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 199.69,

144.58, 139.05, 138.44, 137.19, 136.24, 133.25, 132.34, 132.32, 130.47,

130.39, 129.39, 128.97, 127.70, 125.23, 30.83, 21.31; HRMS (ESI):

Calcd for C₂₁H₁₇OSCl [M+H]⁺, 353.0762; found, 353.0775.

1-(3-Chloro-4'-pentyl-(1,1'-biphenyl)-4-yl)ethan-1-one (15h). A mixture

of 2-chloro-4-bromo-acetophenone (233.5 mg, 1.0 mmol), 4-

pentylphenylboronic

acid

(230

mg,

1.19

mmol),

tetrakis(triphenylphosphine)palladium(0) (12.0 mg, 0.010 mmol), and

NaHCO₃(504 mg, 5.99 mmol) in 1,2-dimethoxyethane (6.0 mL) and

water (2.0 mL) was heated at 65 ^oC for 4 h. Water was added to the

reaction mixture, and the resulting mixture was extracted with EtOAc.

The organic layer was washed with brine, dried over Na₂SO₄, and

concentrated in vacuo. Purification of the residue by column

chromatography on silica gel (toluene/MeCN 300:1) gave the title

compound (450 mg, 80%) as a light yellow solid. ¹H NMR (400 MHz,

CDCl₃) δ 7.68-7.63 (m, 2H), 7.54-7.49 (m, 3H), 7.28 (d, J = 8.1 Hz, 2H),

2.69-2.63 (m, 5H), 1.68-1.61 (m, 2H), 1.36-1.32 (m, 2H), 0.90 (t, J = 6.6

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 199.85, 145.46, 143.86, 136.93,

(4'-(2-Bromoethyl)-3'-chloro-(1,1'-biphenyl)-4-yl)(p-tolyl)sulfane (17i).

Compound 17i was synthesized starting from 15i using a similar

procedure to that described in the preparation of 17e, yielding 17i as a

light yellow oil. Yield: 118.0 g, 57% over two steps. ¹H NMR (400 MHz,

CDCl₃) δ 7.56-7.55 (m, 1H), 7.46-7.43 (m, 2H), 7.40 (dd, J = 1.7 Hz, 8.0

Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.31-7.28 (m, 3H), 7.17 (d, J = 7.9 Hz,

2H), 3.61 (t, J = 7.4 Hz, 2H), 3.31 (t, J = 7.5 Hz, 2H), 2.36 (s, 3H); ¹³C

NMR (100 MHz, CDCl₃) δ 141.14, 138.16, 137.64, 137.43, 135.35,

134.59, 133.15, 132.88, 131.62, 130.34, 129.88, 128.08, 127.63, 125.44,

7

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

36.98, 31.03, 21.31; HRMS (ESI): Calcd for C₂₁H₁₉BrClS [M+H]⁺,

417.0074; found, 417.0078.

complete disappearance of the starting material, the mixture was filtered

and the filtrate was concentrated in vacuo, the residue was used directly

for the next step. The crude product was dissolved in 5 mL of CH₂Cl₂,

bromoacetyl bromide (42.4 μL, 0.53 mmol) and Et₃N (76.1 μL, 0.55

mmol) were added dropwise at 0 ^oC. The mixture was warmed to room

temperature and stirred overnight. The mixture was concentrated in

vacuo and purified by column chromatography on silica gel (petroleum

ether/EtOAc 5:1) to provide 17l (137.7 mg, 76%) as a light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (br, 1H), 7.47-7.43 (m, 2H), 7.14-7.12

(m, 2H), 6.99-6.95 (m, 2H), 6.92-6.88 (m, 2H), 4.01 (s, 2H), 2.58 (t, J =

7.6 Hz, 2H), 1.62-1.55 (m, 2H), 1.40-1.31 (m, 2H), 0.93 (t, J = 7.3 Hz,

3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.60, 155.02, 154.99, 138.21,

132.02, 129.73, 122.06, 119.15, 118.85, 35.01, 33.87, 29.56, 22.44,

14.07; HRMS (ESI): Calcd for C₁₈H₂₁NO₂Br [M+H]⁺, 362.0751; found,

362.0756.

2-Bromo-N-(3-octylphenyl)acetamide (17j). 3-Bromo nitrobenzene

(2.02 g, 10 mmol) and [Pd(PPh₃)₂Cl₂] (140 mg, 0.2 mmol) were dissolved

in dry Et₃N (10 mL), and the solution was argon-degassed for 10 min.

Then CuI (76.2 mg, 0.4 mmol) was added, and the solution was argon-

degassed for another 10 min after which 1-octyne (1.7 mL, 11.8 mmol)

was added via a syringe. The reaction was stirred under an atmosphere

of argon overnight at 60 °C and was then quenched with water, extracted

with heptane, washed with brine, dried (Na₂SO₄), evaporated to dryness

and the crude product was purified by column chromatography on silica

gel (petroleum ether/ethyl acetate, 50/1). The product 1-nitro-3-

octynylbenzene (15j) was obtained as brown oil (2.2 g, 95%).

Compound 15j (220.5 mg, 0.95 mmol) was dissolved in MeOH (5 mL)

and Pd/C (10%, 100 mg) was added, and the mixture was hydrogenated

at 0.4 MPa of H₂(g) overnight. The Pd/C was removed by filtration on

celite and the filtrate was evaporated to drynesss, affording 3-octylaniline

(16j). The residue was used directly for the next step.

2-Bromo-N-(4-(4-butylphenoxy)-2-chloro-phenyl)acetamide

(17m).

To a solution of compound 15l (76.4 mg, 0.25 mmol) in MeOH ( 2.5 mL)

was added zinc powder (163.5 mg, 2.5 mmol) and NH₄Cl solid (133.7 mg,

2.5 mmol). The mixture was stirred at 45 ^oC for 8 h. After TLC analysis

showed the complete disappearance of the starting material, the mixture

was diluted with EtOAc, filtered, and the filtrate was concentrated in

vacuo. The residue was treated directly by the same procedure as for the

preparation of 17l to provide compound 17m (89.3 mg, 90%) as white

solid. ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H),

7.16 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 2.7 Hz, 1H), 6.94-6.91 (m, 3H), 4.07

(s, 2H), 2.60 (t, J = 7.6 Hz, 2H), 1.63-1.56 (m, 2H), 1.41-1.32 (m, 2H),

0.94 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.39, 155.04,

154.26, 138.91, 129.91, 129.04, 124.73, 122.69, 119.26, 118.96, 117.57,

35.06, 33.84, 29.67, 22.45, 14.08; HRMS (ESI): Calcd for C₁₈H₂₀BrClNO₂

[M+H]⁺, 396.0360; found, 396.0349.

The crude product above was dissolved in 5 mL of CH₂Cl₂and the

mixture was cooled to 0 ^oC. Bromoacetyl bromide (42.4 μL, 0.53 mmol)

and Et₃N (76.1 μL, 0.55 mmol) were added dropwise at 0 ^oC, and the

reaction mixture was stirred overnight while being allowed to warm to

room temperature. The mixture was concentrated in vacuo and the

residue was purified by column chromatography on silica gel (petroleum

ether/EtOAc 5/1) to provide 17j as a white solid. Yield: 172.0 mg, 58%.

¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.36-7.34 (m, 2H), 7.27-7.23

(m, 1H), 6.99 (d, J = 7.5 Hz, 1H), 4.01 (s, 2H), 2.59 (t, J = 7.6 Hz, 2H),

1.61-1.58 (m, 2H), 1.29-1.26 (m, 10H), 0.89-0.86 (m, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 163.43, 144.36, 136.95, 129.05, 125.50, 120.13, 117.49,

36.06, 32.01, 31.52, 29.69, 29.59, 29.45, 29.37, 22.79, 14.24; HRMS

(ESI): Calcd for C₁₆H₂₅NOBr [M+H]⁺, 326.1115; found, 326.1118.

1-(Heptyloxy)-4-nitrobenzene (15n). To a solution of 4-nitro-phenol

(556.4 mg, 5.0 mmol) and 1-bromoheptane (0.79 mL, 5.0 mmol) in DMF

o

(10 mL) was added K₂CO₃. The mixture was stirred at 70 C for 6 h until

TLC showed the completion of the reaction. The mixture was cooled to

room temperature and neutralized with saturated NH₄Cl aqueous solution

and extracted with EtOAc for three times. The organic layers were

combined and washed with brine, dried (Na₂SO₄), filtered, and

concentrated. The residue was purified by column chromatography on

silica gel (petroleum ether/EtOAc 20:1) to afford 15n as a yellow oil. Yied:

949.2 mg, 80%. ¹H NMR (400 MHz, CDCl₃) δ 8.22-8.18 (m, 2H), 6.96-

6.92 (m, 2H), 4.05 (t, J = 6.5 Hz, 2H), 1.86-1.79 (m, 2H), 1.50-1.43 (m,

2H), 1.40-1.29 (m, 6H), 0.90 (t, J = 6.8 Hz, 3H).

2-Bromo-N-(3-hexylphenyl)acetamide (17k). Compound 17k was

synthesized starting from 3-bromo nitrobenzene and 1-hexyne using a

similar procedure to that described in the preparation of 17j, yielding 17k

as a white solid. Yield: 107.4 mg, 36%. ¹H NMR (400 MHz, CDCl₃) δ 8.28

(s, 1H), 7.35 (s, 2H), 7.24 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H),

3.99 (s, 2H), 2.58 (t, J = 7.8 Hz, 2H), 1.61-1.55 (m, 2H), 1.29 (br, 6H),

0.88-0.86 (M, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.71, 144.29, 136.98,

128.99, 125.45, 120.16, 117.53, 36.01, 31.79, 31.44, 29.65, 29.07, 22.69,

14.19; HRMS (ESI): Calcd for C₁₄H₂₁NOBr [M+H]⁺, 298.0802; found,

298.0812.

2-Bromo-N-(4-(heptyloxy)phenyl)acetamide (17n). Compound 17n

was synthesized starting from 15n (936.6 mg, 3.95 mmol) using a similar

procedure to that described in the preparation of 17m, yielding 17n as a

white solid. Yield: 842.8 mg, 65% over two steps. ¹H NMR (400 MHz,

CDCl₃) δ 8.04 (s, 1H), 7.42-7.40 (m, 2H), 6.89-6.87 (m, 2H), 4.02 (s, 2H),

3.94 (t, J = 6.6 Hz, 2H), 1.80-1.73 (m, 2H), 1.48-1.41 (m, 2H), 1.39-1.26

(m, 6H), 0.89 (t, J = 6.7 Hz, 3H).

4-(4-Butylphenoxy)-2-chloro-1-nitrobenzene (15l). To a solution of 2-

fluoro-4-chloronitrobenzene (263.3 mg, 1.5 mmol) in DMF (10 mL) was

added 4-butylphenol (0.25 mL, 1.65 mmol) and K₂CO₃(310.9 mg, 3.0

mmol). The mixture was stirred at 70 ^oC overnight. After TLC analysis

showed the complete disappearance of the starting material, the mixture

was cooled to room temperature, neutralized with saturated NH₄Cl

aqueous solution, extracted with EtOAc. The EtOAc layers were

combined, dried (Na₂SO₄), filtered, and concentrated. The residue was

purified by column chromatography on silica gel (petroleum ether/EtOAc

35:1) to provide 15l (458.6 mg, 100%) as a light yellow solid. ¹H NMR

(400 MHz, CDCl₃) δ 7.96 (d, J = 9.1 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H),

7.03 (d, J = 2.6 Hz, 1H), 6.99-6.97 (m, 2H), 6.90 (dd, J = 2.6 Hz, 9.1 Hz,

1H), 2.64 (t, J = 7.7 Hz, 2H), 1.66-1.59 (m, 2H), 1.43-1.34 (m, 2H), 0.95 (t,

J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.18, 152.14, 141.90,

140.78, 130.38, 129.73, 128.07, 120.50, 119.62, 115.54, 35.14, 33.75,

22.46, 14.07; HRMS (ESI): Calcd for C₁₆H₁₇ClNO₃[M+H]⁺, 306.0891;

found, 306.0897.

(3R,4S)-3,4-Di-O-isopropylidene-1-(4-octylphenylethyl)pyrrolidine

(18a). To a solution of compound 17a (117.1 mg, 0.39 mmol) and

compound 11 (91.9 mg, 0.39 mmol) in anhydrous acetonitrile (10 mL)

was added potassium carbonate (54.4 mg, 0.39 mmol). The mixture was

stirred at 50 ^oC overnight until TLC analysis showed the complete

disappearance of the starting material. The mixture was cooled to room

temperature, filtered and concentrated in vacuo. The residue was purified

by column chromatography on silica gel (petroleum ether/acetone 15:1)

to provide compound 18a (53.8 mg, 38%) as a light yellow oil. ¹H NMR

(400 MHz, CDCl₃) δ 7.12-7.06 (m, 4H), 4.66-4.63 (m, 2H), 3.14 (d, J =

11.2 Hz, 2H), 2.79-2.75 (m, 2H), 2.65-2.61 (m, 2H), 2.55 (t, J = 7.6 Hz,

2H), 2.15-2.12 (m, 2H), 1.59-1.54 (m, 2H), 1.52 (s, 3H), 1.32-1.26 (m,

13H), 0.87 (t, J = 6.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 140.69,

137.54, 128.65, 128.42, 111.16, 79.49, 60.18, 57.72, 35.68, 34.84, 32.00,

2-Bromo-N-(4-(4-butylphenoxy)phenyl)acetamide (17l). To a solution

of compound 15l (153.0 mg, 0.5 mmol) in MeOH (5 mL) was added 10%

Pd/C (53.2 mg, 0.05 mmol). The mixture was stirred under 0.4 MPa of H₂

pressure at room temperature overnight. After TLC analysis showed the

8

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

31.69, 29.60, 29.48, 29.37, 26.38, 24.88, 22.78, 14.22; HRMS (ESI):

Calcd for C₂₃H₃₈NO₂[M+H]⁺, 360.2898; found, 360.2897.

(3R,4S)-3,4-Di-O-isopropylidene-1-(4-dodecylphenylethyl)pyrrolidine

(18c). Compound 18c was prepared from 17c as described in the

preparation of compound 18a. Yield: 43% as a light yellow oil after

1

column chromatography (petroleum ether/acetone 15:1). H NMR (400

(3R,4S)-1-(4-Octylphenylethyl)pyrrolidine-3,4-diol (10a). Compound

10a was prepared from 18a by the procedure described in the general

procedure as a light yellow solid (86% yield). ¹H NMR (400 MHz, MeOD)

MHz, CDCl₃) δ 7.11 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 4.65-

4.63 (m, 2H), 3.15 (d, J = 11.1 Hz, 2H), 2.78-2.74 (m, 2H), 2.65-2.61 (m,

2H), 2.54 (t, J = 7.7 Hz, 2H), 2.15-2.13 (m, 2H), 1.57-1.56 (m, 2H), 1.51

(s, 3H), 1.31-1.25 (m, 21H), 0.88 (t, J = 6.2 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 140.60, 137.41, 128.59, 128.37, 111.11, 79.41, 60.06, 57.64,

35.63, 34.72, 31.99, 31.64, 29.75, 29.71, 29.67, 29.60, 29.43, 26.29,

24.81, 22.76, 14.20; HRMS (ESI): Calcd for C₂₇H₄₆NO₂[M+H]⁺,

416.3524; found, 416.3522.

δ 7.17-7.10 (m, 4H, aromatic H ), 4.31 (s, 2H,

), 3.11-3.03

(3R,4S)-1-(4-Dodecylphenylethyl)pyrrolidine-3,4-diol

(10c).

Compound 10c was prepared from 18c as described in the preparation

of compound 10a. Yield: 97% as a light yellow solid after column

chromatography. ¹H NMR (400 MHz, CD₃OD) δ 7.15 (d, J = 7.9 Hz, 2H),

7.10 (d, J = 7.8 Hz, 2H), 4.31-4.27 (m, 2H), 3.44-3.40 (m, 2H), 3.27-3.24

(m, 4H), 2.93 (t, J = 8.6 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 1.58-1.51 (m,

2H), 1.27-1.24 (m, 18H), 0.86 (t, J = 6.6 Hz, 3H); ¹³C NMR (100 MHz,

CD₃OD) δ 142.88, 135.17, 129.90, 129.69, 71.10, 59.32, 59.17, 36.48,

33.04, 32.72, 32.67, 30.74, 30.71, 30.56, 30.43, 30.28, 23.70, 14.44;

HRMS (ESI): Calcd for C₂₄H₄₂NO₂[M+H]⁺, 376.3211; found, 376.3216.

(m,

6H,

),

2.90-2.86

(m,

2H,

), 2.56 (t,

J

=

7.5 Hz, 2H,

), 1.60-1.56 (m, 2H), 1.31-1.28 (m, 10H),

0.89 (t, J = 6.7 Hz, 3H); ¹³C NMR (100 MHz, MeOD) δ 142.46, 136.47,

(3R,4S)-3,4-Di-O-isopropylidene-1-(4-

tetradecylphenylethyl)pyrrolidine (18d). Compound 18d was prepared

from 17d as described in the preparation of compound 18a. Yield: 44%

as a yellow solid after column chromatography (petroleum ether/ acetone

15:1). ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.05 (m, 4H), 4.65-4.61 (m, 2H),

3.15 (d, J = 11.1 Hz, 2H), 2.78-2.74 (m, 2H), 2.65-2.61 (m, 2H), 2.54 (t, J

= 7.7 Hz, 2H), 2.13 (d, J = 9.6 Hz, 2H), 1.61-1.51 (m, 5H), 1.31-1.25 (m,

25H), 0.88 (t, J = 6.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 140.56,

137.37, 128.57, 128.34, 111.09, 79.38, 60.03, 57.62, 35.62, 34.69, 31.99,

31.63, 29.74, 29.66, 29.59, 29.42, 26.26, 24.79, 22.74, 14.18; HRMS

(ESI): Calcd for C₂₉H₅₀NO₂[M+H]⁺, 444.3837; found, 444.3838.

129.75,

60.41(

36.48(

129.61,

71.36(

),

59.39(

(3R,4S)-1-(4-Tetradecylphenylethyl)pyrrolidine-3,4-diol

(10d).

Compound 10d was prepared from 18d as described in the preparation

of compound 10a. Yield: 89% as a light yellow solid after column

chromatography. ¹H NMR (400 MHz, CD₃OD) δ 7.18 (d, J = 7.8 Hz, 2H),

7.12 (d, J = 7.7 Hz, 2H), 4.33 (s, 2H), 3.48 (dd, J = 4.7 Hz, 11.4 Hz, 2H),

3.35–3.27 (m, 4H), 2.99–2.95 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 1.58 (br,

2H), 1.28 (br, 22H), 0.89 (t, J = 6.5 Hz, 3H); ¹³C NMR (100 MHz, CD₃OD)

δ 142.79, 135.19, 129.86, 129.70, 71.09, 59.31, 59.04, 36.51, 33.06,

32.67, 30.76, 30.60, 30.46, 30.33, 23.72, 14.50; HRMS (ESI): Calcd for

C₂₄H₄₆NO₂[M+H]⁺, 404.3524; found, 404.3516.

), 33.94, 33.00, 32.73, 30.55, 30.38, 30.29,

23.69, 14.42; HRMS (ESI): Calcd for C₂₀H₃₄NO₂[M+H]⁺, 320.2585; found,

320.2589.

(3R,4S)-3,4-Di-O-isopropylidene-1-(4-decylphenylethyl)pyrrolidine

(18b). Compound 18b was prepared from 17b as described in the

preparation of compound 18a. Yield: 35% as a light yellow oil after

column chromatography (petroleum ether/acetone 15:1). ¹H NMR (400

MHz, CDCl₃) δ 7.12-7.06 (m, 4H), 4.65 (m, 2H), 3.15 (d, J = 10.8 Hz, 2H),

2.78-2.74 (m, 2H), 2.65-2.61 (m, 2H), 2.55 (t, J = 8.0 Hz, 2H), 2.14-2.12

(m, 2H), 1.58-1.52 (m, 5H), 1.31-1.26 (m, 17H), 0.88-0.87 (m, 3H); ¹³C

NMR (100 MHz, CDCl₃) δ 140.54, 137.40, 128.55, 128.32, 111.07, 79.39,

60.06, 57.60, 35.60, 34.72, 31.94, 31.61, 29.67, 29.64, 29.56, 29.38,

26.29, 24.81, 22.71, 14.16; HRMS (ESI): Calcd for C₂₅H₄₂NO₂[M+H]⁺,

388.3211; found, 388.3205.

(3R,4S)-3,4-Di-O-isopropylidene-1-(4-

heptyloxylphenylethyl)pyrrolidine (18e). Compound 18e was prepared

from 17e as described in the preparation of compound 18a. Yield: 93%

as a yellow solid after column chromatography (petroleum ether/ acetone

1

7:1). H NMR (400 MHz, CDCl₃) δ 7.10 (d, J = 8.0 Hz, 2H), 6.80 (d, J =

8.1 Hz, 2H), 4.63 (s, 2H), 3.91 (t, J = 6.3 Hz, 2H), 3.13 (d, J = 10.8 Hz,

2H), 2.75-2.71 (m, 2H), 2.62-2.58 (m, 2H), 2.12 (d, J = 10.0 Hz, 2H),

1.79-1.72 (m, 2H), 1.52 (s, 3H), 1.47-1.40 (m, 2H), 1.36-1.25 (m, 9H),

0.90-0.87 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 157.55, 132.29, 129.62,

114.41, 111.11, 79.46, 68.03, 60.15, 57.83, 34.33, 31.87, 29.40, 29.15,

26.38, 26.10, 24.87, 22.68, 14.17; HRMS (ESI): Calcd for C₂₂H₃₆NO₃

[M+H]⁺, 362.2690; found, 362.2692.

(3R,4S)-1-(4-Decylphenylethyl)pyrrolidine-3,4-diol (10b). Compound

10b was prepared from 18b as described in the preparation of compound

10a. Yield: 77% as a light yellow solid after column chromatography. ¹H

NMR (400 MHz, CD₃OD) δ 7.20 (d, J = 7.7 Hz, 2H), 7.14 (d, J = 7.9 Hz,

2H), 4.37 (s, 2H), 3.53-3.49 (m, 2H), 3.42-3.35 (m, 4H), 3.00 (t, J = 8.4

Hz, 2H), 2.57 (t, J = 7.5 Hz, 2H), 1.60-1.56 (m, 2H), 1.30-1.28 (m, 14H),

0.91-0.87 (m, 3H); ¹³C NMR (100 MHz, MeOD) δ 142.94, 134.85, 129.91,

129.72, 71.04, 59.21, 59.08, 36.46, 33.00, 32.64, 32.47, 30.67, 30.55,

30.39, 30.26, 23.68, 14.43; HRMS (ESI): Calcd for C₂₂H₃₈NO₂[M+H]⁺,

348.2898; found, 348.2906.

(3R,4S)-1-(4-Heptyloxylphenylethyl)pyrrolidine-3,4-diol

Compound 10e was prepared from 18e as described in the preparation

of compound 10a. Yield: 60% as white solid after column

(10e).

a

chromatography. ¹H NMR (400 MHz, CD₃OD) δ 7.20 (d, J = 8.5 Hz, 2H),

6.88 (d, J = 8.6 Hz, 2H), 4.36 (s, 2H), 3.94 (t, J = 6.4 Hz, 2H), 3.47-3.43

(m, 4H), 2.99 (t, J = 8.5 Hz, 2H), 1.79-1.72 (m, 2H), 1.49-1.42 (m, 2H),

1.40-1.33 (m, 6H), 0.91 (t, J = 6.7 Hz, 3H); ¹³C NMR (100 MHz, CD₃OD)

δ 159.82, 130.85, 129.14, 115.96, 71.03, 69.02, 59.00, 32.95, 31.88,

9

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

30.38, 30.17, 27.11, 23.64, 14.40; HRMS (ESI): Calcd for C₁₉H₃₂NO₃

[M+H]⁺, 322.2377; found, 322.2383.

(m, 6H), 2.60 (t, J = 7.6 Hz, 2H), 1.62-1.54 (m, 2H), 1.39-1.30 (m, 2H),

0.92 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CD₃OD) δ 144.90, 139.84,

135.49, 134.59, 134.28, 132.57, 130.81, 130.21, 128.79, 71.24, 59.78,

57.26, 36.21, 34.67, 31.42, 23.33, 14.30; HRMS (ESI): Calcd for

C₂₂H₂₉NO₂SCl [M+H]⁺, 406.1603; found, 406.1605.

(3R,4S)-3,4-Di-O-isopropylidene-1-(4-(4-butylphenoxy)-2-

chlorophenylethyl)pyrrolidine (18f). Compound 18f was prepared from

17f as described in the preparation of compound 18a. Yield: 38% as a

yellow oil after column chromatography (petroleum ether/ acetone 20:1).

¹H NMR (400 MHz, CDCl₃) δ 7.20 (d, J = 8.4 Hz, 1H), 7.16-7.12 (m, 2H),

6.96 (d, J = 2.5 Hz, 1H), 6.93-6.89 (m, 2H), 6.81 (dd, J = 2.5 Hz, 8.4 Hz,

1H), 4.68-4.65 (m, 2H), 3.18 (d, J = 11.4 Hz, 2H), 2.91-2.87 (m, 2H),

2.68-2.64 (m, 2H), 2.59 (t, J = 7.6 Hz, 2H), 2.23-2.20 (m, 2H), 1.63-1.56

(m, 2H), 1.51 (s, 3H), 1.41-1.33 (m, 2H), 1.32 (s, 3H), 0.93 (t, J = 7.4 Hz,

3H); ¹³C NMR (100 MHz, CDCl₃) δ 156.92, 154.47, 138.62, 134.46,

132.15, 131.59, 129.81, 119.26, 119.17, 116.97, 111.29, 79.49, 59.98,

55.51, 35.07, 33.87, 31.87, 26.34, 24.88, 22.47, 14.09; HRMS (ESI):

Calcd for C₂₅H₃₃NO₃Cl [M+H]⁺, 430.2144; found, 430.2142.

(3R,4S)-3,4-Di-O-isopropylidene-(1-(2-(3-chloro-4'-pentyl-(1,1'-

biphenyl)-4-yl)ethyl)pyrrolidine (18h). Compound 18h was prepared

from 17h as described in the preparation of compound 18a. Yield: 21%

as a yellow oil after column chromatography (petroleum ether/ acetone

9:1). ¹H NMR (400 MHz, CDCl₃) δ 7.55 (s, 1H), 7.46 (d, J = 7.9 Hz, 2H),

7.38 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 7.9 Hz, 2H),

4.67 (s, 2H), 3.18 (d, J = 10.9 Hz, 2H), 2.96 (t, J = 7.4 Hz, 2H), 2.70-2.61

(m, 4H), 2.20 (d, J = 10.5 Hz, 2H), 1.68-1.64 (m, 2H), 1.52 (s, 3H), 1.34-

1.33 (m, 7H), 0.90 (t, J = 6.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

142.70, 140.93, 137.11, 136.55, 134.40, 131.22, 129.05, 127.83, 126.91

125.39, 111.26, 79.58, 60.15, 55.44, 35.72, 32.43, 31.68, 31.30, 26.48,

25.00, 22.70, 14.19; HRMS (ESI): Calcd for C₂₆H₃₅NO₂Cl [M+H]⁺,

428.2351; found, 428.2365.

(3R,4S)-1-(4-(4-Butylphenoxy)-2-chlorophenylethyl)pyrrolidine-3,4-

diol (10f). Compound 10f was prepared from 18f as described in the

preparation of compound 10a. Yield: 90% as a yellow viscous oil after

(3R,4S)-1-(2-(3-Chloro-4'-pentyl-(1,1'-biphenyl)-4-yl)ethyl)pyrrolidine-

3,4-diol (10h). Compound 10h was prepared from 18h as described in

the preparation of compound 10a. Yield: 74% as a white solid after

1

column chromatography. H NMR (400 MHz, CD₃OD) δ 7.25, (d, J = 8.5

1

column chromatography. H NMR (400 MHz, CD₃OD) δ 7.62-7.69 (m,

1H), 7.51-7.48 (m, 3H), 7.39-7.36 (m, 1H), 7.26-7.24 (m, 2H), 4.22-4.19

(m, 2H), 3.15-3.13 (m, 2H), 3.03-3.00 (m, 2H), 2.91-2.83 (m, 4H), 2.63 (t,

J = 7.0 Hz, 2H), 1.68-1.62 (m, 2H), 1.40-1.35 (m, 4H), 0.93-0.89 (m, 3H);

¹³C NMR (100 MHz, CD₃OD) δ 143.96, 142.79, 137.94, 136.25, 135.35,

132.40, 130.08, 128.58, 127.70, 126.68, 71.45, 60.37, 57.62, 36.49,

32.60, 32.34, 23.59, 14.38; HRMS (ESI): Calcd for C₂₃H₃₁NO₂Cl [M+H]⁺,

388.2038; found, 388.2036.

Hz, 1H,

), 7.14 (d, J = 8.4 Hz, 2H,

), 6.86 (d, J = 8.4 Hz, 2H,

), 6.90 (d, J =

2.4 Hz, 1H,

), 6.80 (dd,

), 2.95-

(3R,4S)-3,4-Di-O-isopropylidene-1-(2-(2-chloro-4-(p-tolylthio)-phenyl-

1-yl)ethyl)pyrrolidine (18i). Compound 18i was prepared from 17i as

described in the preparation of compound 18a. Yield: 61% as a yellow oil

after column chromatography (petroleum ether/ acetone 9:1) ¹H NMR

(400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.35-7.28 (m,

6H), 7.17 (d, J = 7.8 Hz, 2H), 4.66 (s, 2H), 3.17 (d, J = 11.0 Hz, 2H), 2.95

(t, J = 7.4 Hz, 2H), 2.68 (t, J = 8.0 Hz, 2H), 2.36 (s, 3H), 2.19 (d, J = 10.0

Hz, 2H), 1.51 (s, 3H), 1.32 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 140.13,

138.06, 137.78, 137.15, 137.02, 134.52, 132.75, 131.35, 130.91, 130.31,

129.93, 127.75, 127.60, 125.29, 111.25, 79.55, 60.12, 55.34, 32.41,

26.46, 24.98, 21.32; HRMS (ESI): Calcd for C₂₈H₃₁NO₂SCl [M+H]⁺,

480.1759; found, 480.1771.

J = 2.4 Hz, 8.4 Hz, 1H,

), 4.30 (s, 2H,

2.91 (m, 6H), 2.80-2.76 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 1.60-1.52 (m,

2H), 1.38-1.29 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz,

CD₃OD) δ 158.72, 155.42, 139.94, 135.35, 132.82, 131.96, 130.84,

120.34, 119.82, 117.93, 71.50, 61.10, 57.45, 35.85, 34.92, 32.17, 23.28,

14.31; HRMS (ESI): Calcd for C₂₂H₂₉NO₃Cl [M+H]⁺, 390.1831; found,

390.1840.

(3R,4S)-1-(2-(2-Chloro-4-(p-tolylthio)-phenyl-1-yl)ethyl)pyrrolidine-

3,4-diol (10i). Compound 10i was prepared from 18i as described in the

preparation of compound 10a. Yield: 80% as a white solid after column

(3R,4S)-3,4-Di-O-isopropylidene-1-(4-((4-butylphenyl)thio)-2-

chlorophenylethyl)pyrrolidine (18g). Compound 18g was prepared

from 17g as described in the preparation of compound 18a. Yield: 77%

as a yellow oil after column chromatography (petroleum ether/ acetone

10:1). ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.29 (m, 2H), 7.22 (d, J = 1.8 Hz,

1H), 7.18-7.13 (m, 3H), 7.05 (dd, J = 1.9 Hz, 8.0 Hz, 1H), 4.67-4.63 (m,

2H), 3.15 (d, J = 11.3 Hz, 2H), 2.88 (t, J = 7.2 Hz, 2H), 2.65-2.58 (m, 4H),

2.20-2.17 (m, 2H), 1.63-1.55 (m, 2H), 1.49 (s, 3H), 1.40-1.33 (m, 2H),

1.31 (s, 3H), 0.93 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

143.15, 136.70, 136.17, 134.56, 132.56, 131.35, 130.77, 130.10, 129.66,

128.15, 111.27, 79.50, 59.99, 55.18, 35.40, 33.56, 32.18, 26.38, 24.95,

22.46, 14.05; HRMS (ESI): Calcd for C₂₅H₃₃NO₂SCl [M+H]⁺, 446.1916;

found, 446.1917.

1

chromatography. H NMR (400 MHz, CD₃OD) δ 7.62 (d, J = 1.8 Hz, 1H,

), 7.52-7.49 (m, 3H), 7.40 (d, J = 8.0 Hz, 1H,

),

7.31 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H),

4.27 (s, 2H,

(s, 3H,

), 3.17-3.13 (m, 2H), 3.08-2.98 (m, 6H), 2.34

(3R,4S)-1-(4-((4-Butylphenyl)thio)-2-chlorophenethyl)pyrrolidine-3,4-

diol (10g). Compound 10g was prepared from 18g as described in the

preparation of compound 10a. Yield: 85% as a white solid after column

chromatography. H NMR (400 MHz, CD₃OD) δ 7.31-7.29 (m, 2H), 7.24

(d, J = 8.1 Hz, 1H), 7.19-7.17 (m, 2H), 7.14 (d, J = 1.9 Hz, 1H), 7.06 (dd,

J = 1.9 Hz, 8.0 Hz, 1H), 4.28-4.24 (m, 2H), 3.28-3.24 (m, 2H), 3.06-2.97

); ¹³C NMR (100 MHz, CD₃OD) δ 142.08, 139.42,

1

138.84, 138.54, 136.21, 135.48, 133.82, 132.53, 132.01, 131.24, 130.84,

128.61, 128.46, 126.70, 71.46, 60.41, 57.36, 49.64, 32.05,

10

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

2-((3R,4S)-3,4-Dihydroxypyrrolidin-1-yl)-N-(3-hexylphenyl)acetamide

(10k). Compound 10k was prepared from 18k as described in the

preparation of compound 10a. Yield: 86% as a light yellow viscous oil

after column chromatography. ¹H NMR (400 MHz, CD₃OD) δ 7.44-7.42

(m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 4.27-4.22 (m,

2H), 3.40 (s, 2H), 2.92-2.86 (m, 4H), 2.56 (t, J = 7.6 Hz, 2H), 1.60-1.55

(m, 2H), 1.32-1.29 (m, 6H), 0.88 (t, J = 6.4 Hz, 3H); ¹³C NMR (100 MHz,

CD₃OD) δ 171.06, 144.83, 139.02, 129.64, 125.65, 121.35, 118.78,

72.26, 60.62, 60.36, 36.90, 32.82, 32.54, 29.99, 23.62, 14.43; HRMS

(ESI): Calcd for C₁₈H₂₉N₂O₃[M+H]⁺, 321.2173; found, 321.2178.

21.13(

); HRMS (ESI): Calcd for C₂₅H₂₇NO₂SCl [M+H]⁺,

440.1449; found, 440.1448.

2-((3aR,6aS)-2,2-Dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-

yl)-N-(3-octylphenyl)acetamide(18j). Compound 18j was prepared from

17j as described in the preparation of compound 18a. Yield: 58% as a

yellow solid after column chromatography (petroleum ether/ acetone 7:1)

¹H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 7.40-7.35 (m, 2H), 7.22 (t, J =

7.7 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 4.71-4.68 (m, 2H), 3.26 (s, 2H),

3.19 (d, J = 11.4 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H), 2.36 (d, J = 10.2 Hz,

2H), 1.61-1.60 (m, 5H), 1.35 (s, 3H), 1.29-1.26 (m, 10H), 0.89-0.86 (m,

3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.30, 144.16, 137.73, 128.96,

124.47, 119.46, 116.78, 110.90, 79.46, 59.99, 57.23, 36.11, 32.03, 31.47,

29.62, 29.47, 29.38, 26.72, 24.46, 22.81, 14.25; HRMS (ESI): Calcd for

C₂₃H₃₇N₂O₃[M+H]⁺, 389.2899; found, 389.2804.

N-(4-(4-Butylphenoxy)phenyl)-2-((3aR,6aS)-2,2-dimethyltetrahydro-

5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)acetamide (18l). Compound 18l was

prepared from 17l as described in the preparation of compound 18a.

Yield: 92% as a light yellow oil after column chromatography (petroleum

ether/ acetone 10:1). ¹H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 7.52 (d, J

= 8.8 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.89 (d, J

= 8.4 Hz, 2H), 4.68 (s, 2H), 3.26 (s, 2H), 3.18 (d, J = 11.0 Hz, 2H), 2.58 (t,

J = 7.6 Hz, 2H), 2.35 (d, J = 10.2 Hz, 2H), 1.62-1.55 (m, 5H), 1.38-1.31

(m, 5H), 0.93 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.25,

155.34, 153.83, 137.75, 133.07, 129.57, 120.84, 119.35, 118.47, 110.72,

79.33, 59.85, 56.96, 34.92, 33.83, 29.30, 26.66, 24.31, 22.36, 14.02;

HRMS (ESI): Calcd for C₂₅H₃₃N₂O₄[M+H]⁺, 425.2435; found, 425.2431.

2-((3R,4S)-3,4-Dihydroxypyrrolidin-1-yl)-N-(3-

octylphenyl)acetamide(10j). Compound 10j was prepared from 18j as

described in the preparation of compound 10a. Yield: 86% as a yellow

1

solid after column chromatography. H NMR (400 MHz, CD₃OD) δ 7.44-

N-(4-(4-Butylphenoxy)phenyl)-2-((3R,4S)-3,4-dihydroxypyrrolidin-1-

yl)acetamide (10l). Compound 10l was prepared from 18l as described

in the preparation of compound 10a. Yield: 74% as a light yellow solid

after column chromatography. ¹H NMR (400 MHz, CD₃OD) δ 7.57-7.53

7.42 (m, 2H,

), 7.21 (t, J = 7.7 Hz, 1H,

),

6.94 (d, J = 7.5 Hz, 1H,

), 4.34 (s, 2H,

(m, 2H,

), 7.14-7.12 (m, 2H,

), 6.91-6.89 (m, 2H,

3.84 (s, 2H,

), 3.21 (br, 2H), 2.57 (t, J = 7.6 Hz, 2H), 1.99 (br,

2H), 1.59-1.57 (m, 2H), 1.30-1.27 (m, 10H), 0.88 (t, J = 6.6 Hz, 3H); ¹³C

), 6.87-6.85 (m, 2H,

), 4.28 (br, 2H,

),

NMR

(100

MHz,

CD₃OD)

δ

168.10(

),

3.57 (s, 2H,

), 3.02 (br, 4H), 2.57 (t, J = 7.6 Hz, 2H), 1.61-1.53

(m, 2H), 1.39-1.30 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz,

144.92(

), 138.88, 129.72, 125.79, 121.20, 118.64,

CD₃OD)

δ

169.72(

), 156.55(

),

71.83(

), 60.19, 59.80, 36.87, 32.97, 32.54, 30.52, 30.34,

155.65(

), 139.08, 134.27, 130.68, 123.04, 119.77, 119.63,

30.28, 23.66, 14.43; HRMS (ESI): Calcd for C₂₀H₃₃N₂O₃[M+H]⁺,

349.2486; found, 349.2498.

72.08(

), 60.44, 60.14, 35.84, 35.05, 23.29, 14.30; HRMS

(ESI): Calcd for C₂₂H₂₉N₂O₄[M+H]⁺, 385.2122; found, 385.2113.

2-((3aR,6aS)-2,2-Dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-

yl)-N-(3-hexylphenyl)-acetamide (18k). Compound 18k was prepared

from 17k as described in the preparation of compound 18a. Yield: 77%

as a yellow solid after column chromatography (petroleum ether/ acetone

7:1). ¹H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 7.40 (s, 1H), 7.37 (d, J =

8.0 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 6.93, (d, J = 7.6 Hz, 1H), 4.71-4.67

(m, 2H), 3.25 (s, 2H), 3.19 (d, J = 10.9 Hz, 2H), 2.56 (t, J = 7.6 Hz, 2H),

2.36 (d, J = 10.2 Hz, 2H), 1.61-1.56 (m, 5H), 1.35-1.27 (m, 9H), 0.88 (t, J

= 6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.34, 144.14, 137.72,

128.95, 124.45, 119.44, 116.76, 110.86, 79.46, 59.97, 57.21, 36.07,

31.84, 31.40, 29.10, 26.71, 24.45, 22.70, 14.22; HRMS (ESI): Calcd for

C₂₁H₃₃N₂O₃[M+H]⁺, 361.2486; found, 361.2487.

N-(4-(4-Butylphenoxy)-2-chlorophenyl)-2-((3aR,6aS)-2,2-

dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)acetamide

(18m). Compound 18m was prepared from 17m as described in the

preparation of compound 18a. Yield: 98% as a yellow solid after column

chromatography (petroleum ether/ acetone 10:1). ¹H NMR (400 MHz,

CDCl₃) δ 9.49 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H),

7.02 (d, J = 2.7 Hz, 1H), 6.94-6.90 (m, 3H), 4.72-4.70 (m, 2H), 3.31-3.28

(m, 4H), 2.59 (t, J = 7.7 Hz, 2H), 2.35 (d, J = 10.2 Hz, 2H), 1.63-1.55 (m,

5H), 1.41-1.33 (m, 5H), 0.93 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 168.41, 154.61, 154.19, 138.56, 129.82, 129.75, 124.60,

123.00, 119.13, 118.98, 117.67, 110.99, 79.43, 60.39, 58.78, 35.04,

11

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

33.87, 26.27, 24.18, 22.45, 14.09; HRMS (ESI): Calcd for C₂₅H₃₂N₂O₄Cl

[M+H]⁺, 459.2046; found, 459.2044.

(br, 2H,

), 3.94 (t, J = 10.4 Hz, 2H,

),

N-(4-(4-Butylphenoxy)-2-chlorophenyl)-2-((3R,4S)-3,4-

dihydroxypyrrolidin-1-yl)acetamide (10m). Compound 10m was

prepared from 18m as described in the preparation of compound 10a.

Yield: 71% as white solid after column chromatography. ¹H NMR (400

3.53 (s, 2H,

), 3.01-2.98 (m, 2H), 2.95-2.94 (m, 2H), 1.79-1.72

(m, 2H), 1.50-1.43 (m, 2H), 1.41-1.33 (m, 6H), 0.91 (t, J = 6.7 Hz, 3H);

¹³C NMR (100 MHz, CD₃OD)

δ

170.16(

),

MHz, CD₃OD) δ 7.84 (d, J = 8.9 Hz, 1H,

), 7.16 (d, J = 8.3

), 6.90-6.85

157.58(

72.18(

), 131.80, 123.07, 115.57(

Hz, 2H,

(m, 3H,

), 6.99 (d, J = 2.6 Hz, 1H,

), 69.15(

), 60.42, 59.39, 32.88,

30.36, 30.13, 27.05, 23.58, 14.41; HRMS (ESI): Calcd for C₁₉H₃₁N₂O₄

[M+H]⁺, 351.2279; found, 351.2280.

), 4.26 (s, 2H,

), 3.42 (s, 2H,

), 2.96 (br, 2H), 2.88-2.86 (m, 2H), 2.58 (t, J = 7.6 Hz, 2H),

1.61-1.53 (m, 2H), 1.39-1.30 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); ¹³C NMR

Biology

All laboratory animal experiments were performed according to the

national guidelines and approved by the Institutional Animal Care and

Use Committee of Peking University.

(100 MHz, CD₃OD) δ 171.73(

), 156.99(

),

Preparation of mouse splenocytes suspension

155.50(

), 140.04, 130.89, 130.22, 128.39, 126.68, 120.26,

Splenocytes suspensions were prepared from male BALB/c mouse.

Mouse splenocytes were plated on 96-well microplates at a density of

5×10⁵cells/well and cultured in RPMI-1640 media (Hyclone) containing

10% fetal bovine serum (FBS), 2.5 µg/mL concanavalin A alone or along

with 5 µM of synthetic iminosugar compounds at 37 °C, 5% CO₂for 48 h.

119.77, 118.05, 72.17(

), 60.92, 60.08, 35.83, 34.89, 23.26,

14.27; HRMS (ESI): Calcd for C₂₂H₂₈N₂O₄Cl [M+H]⁺, 419.1733; found,

419.1732.

Proliferation assays

Proliferation of the mouse splenocytes was assayed using the CCK-8

reduction method. CCK-8 (20 mL) was added to each well and the plates

were incubated for 2 h at 37 °C. Optical density was measured using a

Microplate Reader at 450 nm. All data were presented as mean ± SEM.

N-(2-Chloro-4-(heptyloxy)phenyl)-2-((3aR,6aS)-2,2-

dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)acetamide (18n).

Compound 18n was prepared from 17n as described in the preparation

of compound 18a. Yield: 79% as a light yellow oil after column

chromatography (petroleum ether/ acetone 2.5:1). ¹H NMR (400 MHz,

CDCl₃) δ 9.16 (s, 1H), 7.46 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.9 Hz, 2H),

4.70-4.67 (m, 2H), 3.93 (t, J = 6.6 Hz, 2H), 3.25 (s, 2H), 3.18 (d, J = 11.3

Hz, 2H), 2.35 (d, J = 10.2 Hz, 2H), 1.80-1.73 (m, 2H), 1.59 (s, 3H), 1.48-

1.40 (m, 2H), 1.35-1.24 (m, 9H), 0.89 (t, J = 6.6 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 168.05, 155.95, 130.94, 120.96, 115.00, 110.87, 79.47,

68.45, 60.01, 57.17, 31.91, 29.41, 29.19, 26.75, 26.12, 24.47, 22.74,

14.21; HRMS (ESI): Calcd for C₂₂H₃₅N₂O₄[M+H]⁺, 391.2592; found,

391.2592.

Cytokine measurement

The 96-well microplates were incubated for 48 h in 5% CO₂at 37 °C, and

the plates were centrifuged at 4 °C, 1500×g for 15 min to precipitate the

cells. The supernatant was taken, and stored at −20 °C before the

measurement of the cytokines. The samples, which had been frozen,

were thawed to room temperature before the measurements of IL-4 and

INF-γ were taken. The amounts of cytokines were measured with

enzyme-linked immunosorbent assay (IL-4 ELISA kit, Bender

MedSystems, Vienna, Austria; INF-γ ELISA kit, San Diego, USA)

procedures according to the manufacturer's directions.

N-(2-Chloro-4-(heptyloxy)phenyl)-2-((3R,4S)-3,4-dihydroxypyrrolidin-

1-yl)acetamide (10n). Compound 10n was prepared from 18n as

described in the preparation of compound 10a. Yield: 90% as a light

yellow solid after column chromatography. ¹H NMR (400 MHz, CD₃OD) δ

Acknowledgements

This work was financially supported by the National Natural

Science Foundation of China (Grant No. 21232002) and Beijing

Natural Science Foundation (715085).

7.49-7.47 (m, 2H,

), 6.88-6.86 (m, 2H,

), 4.28

12

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

Circulation 2005, 111, 222-229; (b) J. Fujishiro, S. Kudou, S. Iwai, M.

Takahashi, Y. Hakamata, M. Kinoshita, S. Iwanami, S. Izawa, T. Yasue,

K. Hashizume, T. Murakami, E. Kobayashi, Transplantation 2006, 82,

804-812.

Keywords: iminosugar; immunosuppressant; N-alkylation;

synthesis

References:

[15] Y. Tian, J. Jin, X. Wang, W. Han, G. Li, W. Zhou, Q. Xiao, J. Qi, X. Chen,

D. Yin, Med. Chem. Comm. 2013, 4, 1267-1274.

[16] P. Srihari, B. Kumaraswamy, J. S. Yadav, Tetrahedron 2009, 65, 6304-

6309.

[1]

[2]

X. M. Gao, A Foundation Course of Immunology, Higher Education

Press, Beijing, 2006.

[17] a) T. M. Chapman, S. Courtney, P. Hay, B. G. Davis, Chem. Eur. J. 2003,

9, 3397-3414; b) A. J. Steiner, A. E. Stuetz, C. A. Tarling, S. G. Withers,

T. M. Wrodnigg, Aust. J. Chem. 2009, 62, 553-557; c) C. Matassini, S.

Mirabella, X. Ferhati, C. Faggi, I. Robina, A. Goti, E. Moreno-Clavijo, A.

J. Moreno-Vargas, F. Cardona, Eur. J. Org. Chem. 2014, 5419-5432; d)

G. Malik, A. Ferry, X. Guinchard, T. Cresteil, D. Crich, Chem. Eur. J.

2013, 19, 2168-2179; e) F. Oulaidi, S. Front-Deschamps, E. Gallienne,

E. Lesellier, K. Ikeda, N. Asano, P. Compain, O. R. Martin,

ChemMedChem 2011, 6, 353-361.

a) J. M. Smith, T. L. Nemeth, R. A. McDonald, Pediatr. Clin. North Am.

2003, 50, 1283-1300; b) M. P. Gallagher, P. J. Kelly, M. Jardine, V.

Perkovic, A. Cass, J. C. Craig, J. Eris, A. C. Webster, J. Am. Soc.

Nephrol. 2010, 21, 852-858.

[3]

a) A. Mehta, N. Zitzmann, P. M. Rudd, T. M. Block, R. A. Dwek, FEBS

Lett. 1998, 430, 17-22; b) N. Asano, R. J. Nash, R. J. Molyneux, G. W.

J. Fleet, Tetrahedrom Asym. 2000, 11, 1645-1680; c) N. Asano, A. Kato,

A. A. Watson, Mini-Rev. Med. Chem. 2001, 1, 145-154; d) T. M.

Wrodnigg, Monatshefte Fur Chemie 2002, 133, 393-426; e) N. Asano,

Curr. Top. Med. Chem. 2003, 3, 471-484; f) M. Jung, M. Park, H. C.

Lee, Y. H. Kang, E. S. Kang, S. K. Kim, Curr. Med. Chem. 2006, 13,

1203-1218; g) N. Asano, Cell. Mol. Life Sci. 2009, 66, 1479-1492; h) D.

D'Alonzo, A. Guaragna, G. Palumbo, Curr. Med. Chem. 2009, 16, 473-

505; i) K. Suzuki, T. Nakahara, O. Kanie, Curr. Top. Med. Chem. 2009,

9, 34-57; j) R. J. Nash, A. Kato, C.-Y. Yu, G. W. J. Fleet, Future Med.

Chem. 2011, 3, 1513-1521; k) M. E. C. Caines, S. M. Hancock, C. A.

Tarling, T. M. Wrodnigg, R. V. Stick, A. E. Sttz, A. Vasella, S. G.

Withers, Natalie C. J. Strynadka, Angew. Chem. Int. Ed. 2007, 46,

4474-4476; l) T. M. Gloster, P. Meloncelli, R. V. Stick, D. Zechel, A.

Vasella, G. J. Davies, J. Am. Chem. Soc. 2007, 129, 2345-2354.

P. E. Goss, M. A. Baker, J. P. Carver, J. W. Dennis, Clin. Cancer Res.

1995, 1, 935-944.

[18] N. He, B. Li, H. Zhang, J. Hua, S. Jiang, Synth. Met. 2012, 162, 217-224.

[19] E. V. Dehmlow, T. Niemann, A. Kraft, Synth. Commun. 1996, 26, 1467-

1472.

[20] K.-W. Jeong, J.-H. Lee, S.-M. Park, J.-H. Choi, D.-Y. Jeong, D.-H. Choi,

Y. Nam, J.-H. Park, K.-N. Lee, S.-M. Kim, J.-M. Ku, Eur. J. Med. Chem.

2015, 102, 387-397.

[21] W. Borzecka, I. Lavandera, V. Gotor, J. Org. Chem. 2013, 78, 7312-

7317.

[22] M. Hamada, M. Nakamura, M. Kiuchi, K. Marukawa, A. Tomatsu, K.

Shimano, N. Sato, K. Sugahara, M. Asayama, K. Takagi, K. Adachi, J.

Med. Chem. 2010, 53, 3154-3168.

[23] D. S. Im, J. Clemens, T. L. Macdonald, K. R. Lynch, Biochemistry 2001,

40, 14053-14060.

[4]

[5]

[6]

[7]

[8]

[24] J. J. Clemens, M. D. Davis, K. R. Lynch, T. L. Macdonald, Bioorg. Med.

Chem. Lett. 2003, 13, 3401-3404.

A. A. Watson, G. W. J. Fleet, N. Asano, R. J. Molyneux, R. J. Nash,

Phytochemistry 2001, 56, 265-295.

[25] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 4467-

4470.

D. Durantel, N. Branza-Nichita, S. Carrouee-Durantel, T. D. Butters, R.

A. Dwek, N. Zitzmann, J. Virol. 2001, 75, 8987-8998.

[26] a) S. Fortin, E. Moreau, A. Patenaude, M. Desjardins, J. Lacroix, J. L. C.

Rousseau, R. C-Gaudreault, Bioorg. Med. Chem. 2007, 15, 1430-1438;

(b) J. K. Sorensen, J. Fock, A. H. Pedersen, A. B. Petersen, K. Jennum,

K. Bechgaard, K. Kilsa, V. Geskin, J. Cornil, T. Bjornholm, M. B.

Nielsen, J. Org. Chem. 2011, 76, 245-263.

P. Compain, O. R. Martin, Iminosugars: From Synthesis to Therapeutic

Applications; John Wiley & Sons: New York, 2007.

a) G. M. J. Lenagh-Snow, S. F. Jenkinson, S. J. Newberry, A. Kato, S.

Nakagawa, I. Adachi, M. R. Wormald, A. Yoshihara, K. Morimoto, K.

Akimitsu, K. Izumori, G. W. J. Fleet, Org. Lett. 2012, 14, 2050-2053; b)

G. M. J. Lenagh-Snow, N. Araujo, S. F. Jenkinson, R. F. Martinez, Y.

Shimada, C.-Y. Yu, A. Kato, G. W. J. Fleet, Org. Lett. 2012, 14, 2142-

2145; c) W. Zhang, K. Sato, A. Kato, Y.-M. Jia, X.-G. Hu, F. X. Wilson,

R. van Well, G. Horne, G. W. J. Fleet, R. J. Nash, C.-Y. Yu, Org. Lett.

2011, 13, 4414-4417; d) A. Kato, I. Nakagome, S. Nakagawa, K.

Kinami, I. Adachi, S. F. Jenkinson, J. Desire, Y. Bleriot, R. J. Nash, G.

W. J. Fleet, S. Hirono, Org. Biomol. Chem. 2017, 15, 9297-9304; e) B.

J. Ayers, A. F. G. Glawar, R. F. Martinez, N. Ngo, Z. Liu, G. W. J. Fleet,

T. D. Butters, R. J. Nash, C.-Y. Yu, M. R. Wormald, S. Nakagawa, I.

Adachi, A. Kato, S. F. Jenkinson, J. Org. Chem. 2014, 79, 3398-3409.

a) S. Walter, K. Fassbender, E. Gulbins, Y. Liu, M. Rieschel, M. Herten,

T. Bertsch, B. Engelhardt, J. Neuroimmunol. 2002, 132, 1-10; b) P. M.

Grochowicz, A. D. Hibberd, Y. C. Smart, K. M. Bowen, D. A. Clark, W.

B. Cowden, D. O. Willenborg, Transpl. Immunol. 1996, 4, 275-285.

[27] X. S. Ye, F. Sun, M. Liu, Q. Li, Y. H. Wang, G. S. Zhang, L. H. Zhang, X.

L. Zhang, J. Med. Chem. 2005, 48, 3688-3691.

[28] V. K. Singh, S. Mehrotra, S. S. Agarwal, Immunol. Res. 1999, 20, 147-

161.

[29] R. S. Shaikh, S. S. Schilson, S. Wagner, S. Hermann, P. Keul, B.

Levkau, M. Schaefers, G. Haufe, J. Med. Chem. 2015, 58, 3471-3484.

[9]

[10] a) G.-L. Zhang, X.-J. Zheng, L.-H. Zhang, X.-S. Ye, Med. Chem.

Commun. 2011, 2, 909-917; b) G.-L. Zhang, C. Chen, Y. Xiong, L.-H.

Zhang, J. Ye, X.-S. Ye, Carbohydr. Res. 2010, 345, 780-786; c) J. Zhou,

Y. Zhang, X. Zhou, J. Zhou, L.-H. Zhang, X.-S. Ye, X.-L. Zhang, Bioorg.

Med. Chem. 2008, 16, 1605-1612.

[11] G.-N. Wang, Y. Xiong, J. Ye, L.-H. Zhang, X.-S. Ye, ACS Med. Chem.

Lett. 2011, 2, 682-686.

[12] M. Matloubian, C. G. Lo, G. Cinamon, M. J. Lesneski, Y. Xu, V.

Brinkmann, M. L. Allende, R. L. Proia, J. G. Cyster, Nature 2004, 427,

355-360.

[13] V. Brinkmann, M. D. Davis, C. E. Heise, R. Albert, S. Cottens, R. Hof, C.

Bruns, E. Prieschl, T. Baumruker, P. Hiestand, C. A. Foster, M.

Zollinger, K. R. Lynch, J. Biol. Chem. 2002, 277, 21453-21457.

[14] a) H. Shimizu, M. Takahashi, T. Kaneko, T. Murakami, Y. Hakamata, S.

Kudou, T. Kishi, K. Fukuchi, S. Iwanami, K. Kuriyama, T. Yasue, S.

Enosawa, K. Matsumoto, I. Takeyoshi, Y. Morishita, E. Kobayashi,

13

10.1002/cmdc.201700706

ChemMedChem

FULL PAPER

Entry for the Table of Contents

A series of N-substituted iminosugar derivatives were designed and synthesized. The immunosuppressive effects evaluated by CCK-

8 assay revealed that iminosugars 10e and 10i exhibited the strongest inhibitory effect on mouse splenocyte proliferation (IC₅₀= 2.16

and 2.48 μM, respectively).

14

Article Doi

Synthesis of N-Substituted Iminosugar Derivatives and Evaluation of Their Immunosuppressive Activities

DOI: 10.1002/cmdc.201700706

Source and publish data:

Authors:

Article abstract of DOI:10.1002/cmdc.201700706

Full text of DOI:10.1002/cmdc.201700706

Products guided by the article

R&D Labs maybe for 448959-85-1

Relevant to this article

Hot Product