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    • 专利摘要:
    METHODS FOR PREPARATION OF GLYCOSPHINGOLIPIDS AND USES OF THESE. Methods for synthesis and preparation of alpha-glycosphingolipids are provided. Methods are provided for synthesis of 244> -galactosyl-ceramide, and pharmaceutically active analogs and variants thereof. Innovative alpha-glycosphingolipids are provided, where the compounds are immunogenic compounds that serve as ligands for NKT (natural killer T) cells.
    公开号:BR112013017382B1
    申请号:R112013017382-3
    申请日:2012-01-05
    公开日:2021-03-16
    发明作者:Pi-Hui Liang
    申请人:National Taiwan University；
    IPC主号:
    专利说明:

    Cross References to Related Orders
    [001] This application claims the priority of the US Provisional Patent Application Serial Number 61 / 430,117, filed on January 5, 2011, entitled “METHODS FOR PREPARING Glycosphingolipids and Uses of These,” which is incorporated herein by reference . Technical Field of the Invention
    [002] The present invention relates to analogs of innovative glycosphingolipids, intermediates for their production. In particular, the invention relates to innovative processes for the preparation of glycosphingolipids. More particularly, the invention relates to methods for synthesis and uses of innovative alpha-binding glycosphingolipid compounds. History of the Invention
    [003] Studies show that NKT cells, a single lymphocyte subpopulation, are characterized by the coexpression of an invariant antigen receptor and NK receptors. Human NKT cells (Vα24-Jα18) are activated by a specific glycolipid antigen, in a CD1d-dependent manner. CD1d molecules are heterodimeres, composed of a heavy polypeptide chain associated non-covalently with a 2-microglobulin, and have substantial structural similarity to the major proteins of the class I histocompatibility complex (MHC). After activation, NKT cells exhibit MHC-independent antitumor activity against tumor cells in vitro and in vivo through various mechanisms. Activated NKT Vα24 cells produce a high level of cytokines, such as IFN-y, thereby linking innate and adaptive immunity through the activation of other effector cells, including dendritic cells (DC), NK cells and CD8 + T cells. NKTs play a regulatory role in the immune system, so they are attractive targets for immunotherapy.
    [004] Currently, the best studied antigen presented by CD1d is alpha-galactosylceramide (αGalCer, KRN-7000). It first aroused interest when extracts derived from the marine sponge Agelas mauritianus demonstrated innovative anti-tumor properties. Pharmaceutical company Kirin Beer (U.S. Patent Application No. 5849716). This potent activity was later traced to a family of alpha-linked glycosphingolipids (GSLs), from which αGalCer was structurally optimized. GSLs consist of an alpha-bonded sugar moiety with a ceramide, which is formed by a fatty acid amide bond with a long chain base.
    [005] After activation by αGalCer, NKT cells release pro-inflammatory (TH1) and immunomodulatory (TH2) cytokines. Th1 cytokine production is believed to correlate with antitumor, antiviral / antibacterial and adjuvant activities, while TH2 cytokine production is believed to alleviate autoimmune diseases. ΑGalCer has been the subject of clinical trials for its anticancer potential, but these were terminated during phase I. The unspecified nature of the cytokine profile induced by αGalCer, both TH1 and TH2, makes it less efficient as a therapeutic treatment. This interpretation encouraged many groups to focus on research for compounds that increase the selectivity for TH1 or TH2 cytokine response. Wong et al. synthesized a series of glycolipids having aromatic groups on the acyl side chain and found that these molecules deviate the cytokine release profile to a TH1 response (J. Am. Chem. Soc. 2006, 128, 9022-9023. US 2007/0238871) . In vivo experiments in mice with aggressive cancerous lung tumors (cell line TC1) and cancerous breast tumors (cell line 4T1) showed that mice with lung cancer treated with the new glycolipids had significantly prolonged survival times compared to those treated with αGalCer. In mice with breast cancer, treatment with the new glycolipids inhibited the tumor growth rate in 75% of the untreated group, compared with 50% inhibition in mice treated with αGalCer (Proc. Natl. Acad. Sei. USA 2007, 104, 10299-10304).
    [006] Therefore, there is a need for efficient forms of alpha-glycosphingolipid synthesis, such as αGalCer compounds, as well as a need for the synthesis of new alpha-glycosphingolipid compounds with immunomodulatory effects. Summary of the Invention
    [007] The present invention provides innovative methods for synthesizing galactosphingolipids, including innovative compounds related to α-galactosyl ceramides and active analogues thereof, such as C34.

    [008] The invention provides, in one configuration, a compound represented by the structure of formula (1):
    where R1 = OH, NH2, NHCOR2; R2 = H or an alkyl, alkenyl, or alkyl ending in aryl, substituted aryl, heteroaryl, or substituted heteroaryl; X = alkyl, alkenyl group; R3, R4 = H, OH; R5 = aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
    [009] In one embodiment of the invention, the compound of formula 1 can be obtained by a process that includes, inter alia, the step of removing the benzyledene protecting group and hydrogenating the compound represented by the structure of formula (2):
    where PG is a hydroxyl protection group.
    [010] In another configuration, the hydroxyl protecting group may be benzyl.
    [011] In a configuration of the invention, the compound of formula 2, where X = (CH2) 8 R3 = H, R4 - H, R5 = 4-F-phenoxy-phenyl, can be obtained by a process that includes, inter alia, the step of amide bond formation between compounds of formula (3) and formula (4).
    where, in a configuration, PG is benzyl
    where, in one configuration, X = alkyl, alkenyl group, R3 = H, OH, R4 = H, OH, R5 = aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
    [012] In one embodiment of the invention, the compound of formula (3), where R is benzyl, can be obtained by a process that includes, inter alia, the step of: reducing the azide group of a compound represented by the formula structure (5):

    [013] In a configuration of the invention, the compound of formula 5, where PG is benzyl, can be obtained by a process that includes, inter alia, the step of: reaction of a compound represented by the structure of formula (6)
    where PG is a hydroxyl protecting group and LG is an leaving group, with a compound represented by the structure of formula (7)
    where PG is the hydroxyl protecting group, to form an alpha glycosidic bond, thereby obtaining the compound of formula (5). In another configuration, the formula (6) output group can be any one of:

    [014] In one embodiment of the invention, the compound of formula 1 can be obtained by a process that includes, inter alia, the step of removing the benzylidene protecting group and hydrogenating the compound represented by the structure of formula (8):
    where PG is a hydroxyl protection group. In another embodiment, PG can be, inter alia, benzyl.
    [015] In one embodiment of the invention, the compound of formula (8) can be obtained by a process that includes, inter alia, the step of: reacting a compound represented by the structure of formula (9) with a compound represented by acid alkanoic, aryl acid, arylalkanoic acid, substituted arylacanoic acid, and heterocyclic acid.
    where PG is a hydroxyl protection group.
    [016] In one embodiment of the invention, compound (9) can be obtained from the process which includes, inter alia, the step of: reducing the azide of a compound represented by the structure of formula (10)
    where PG is hydroxyl protection group.
    [017] In one embodiment of the invention, compound (10) can be obtained from the process which includes, inter alia, the step of: replacing a compound represented by the structure of formula (11)
    where R is a leaving group, thereby obtaining the compound of formula (11).
    [018] In another configuration, R may be, inter alia, methanesulfonyl or toluenesulfonyl. In one embodiment of the invention, the compound of formula (11) can be obtained by a process that includes, inter alia, the step of: conducting a replacement of the hydroxyl portion of the compound represented by the structure of formula (12)

    [019] In another configuration, the substitution can be carried out in the presence of base and methanesulfonyl chloride or toluenesulfonyl chloride.
    [020] In one embodiment of the invention, the compound (12) can be obtained from the process which includes, inter alia, the step of: hydrolysis of the compound represented by the structure of formula (13)
    where R is a hydroxyl protecting group, in one configuration, R is alkyl ester. In another configuration, R is acetate.
    [021] In one embodiment of the invention, compound (13) can be obtained from the process which includes, inter alia, the step of: forming the amide bond of the compound represented by the structure of formula (14),
    and the compound represented by the structure of formula (4).
    [022] In one embodiment of the invention, compound (14) can be obtained from the process which includes, inter alia, the step of: reducing the azide of a compound represented by the structure of formula (15).

    [023] In one embodiment of the invention, the compound (15) can be obtained from the process which includes, inter alia, the step of: reaction of a compound represented by the structure of formula (16)
    where PG is the hydroxyl protecting group, LG is the leaving group, and R is ester, with a compound represented by the structure of formula (7), where PG is the hydroxyl protecting group, to form an alpha glycosidic bond , thereby obtaining the compound of formula (15).
    [024] In another configuration, the output group can be any one of:

    [025] In a configuration of the invention, the compound of formula (17) can be obtained by the process which includes, inter alia, the step of: removing the hydroxyl protecting group PG1, thereby obtaining the compound of formula (17) , PG1 can be, inter alia, trityl.

    [026] These and other aspects will become apparent from the following description of the preferred configuration taken in conjunction with the following drawings, although variations and modifications of these can be carried out without departing from the spirit and scope of the innovative concepts of the disclosure. Brief Description of Drawings
    [027] The following drawings are part of the present specification and are included to further demonstrate certain aspects of the present disclosure, the inventions of which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific configurations. presented here.
    [028] Figure 1 is a schematic illustration illustrating the synthesis of C34, A15-21. Scheme 1. Reagents and Conditions: (a) TfN, K2CO3, CuSO4, DCM, MeOH, H2O; (b) trityl chloride, triethylamine, toluene; (c) benzyl chloride (BnCl), NaH, DMF, Toluene; (d) HCl, toluene, MeOH; (e) A5, Me2S2-Tf2O, THF, 4 A MS; (f) LiAlH4, THF; (g) RCO2H, HBTU, NMM, DCM; (h) Pd (OH) 2, H2, MeOH, DCM.
    [029] Figure 2 is a schematic illustration illustrating the synthesis of compound A23-A25. Scheme 2. Reagents and conditions: (a) Pd (OH) 2, H2 (80 psi), MeOH, DCM, AcOH; (b) RCO2H, HBTU, NMM, DCM MeOH.
    [030] Figure 3 is a schematic illustration illustrating the synthesis of formula (4). Scheme 3.
    [031] Figure 4 is a schematic illustration illustrating the synthesis of C5-C7 compounds. Scheme 4. Reagents and conditions: (a) PPh3, THF, H2O; (b) Ph (CH2) nCO2H, HBTU, NMM, DCM; (c) Pd (OH) 2, H2, DCM, MeOH.
    [032] Figure 5 is a schematic illustration illustrating the synthesis of compounds C20-C31. Scheme 5. Reagents and conditions: (a) TsCl, pyridine; (b) NaN3, DMF; (c) Ph3, THF, H2O; (d) RCH2CO2H, HBTU, NMM, MeOH, DCM.
    [033] Figure 6 shows glycosphingolipid-induced IL-2 secretion in A20CDld and mNK1.2 cell system. Data are provided as mean ± SD; indicates no compound.
    [034] Figure 7 shows results of INF-gamma cytokine secretion by female C57BL / 6 mouse splenocytes.
    [035] Figure 8 shows results of IL-4 cytokine secretion by female C57BL / 6 mouse splenocytes.
    [036] Figure 9 shows cytokine secretion rates obtained by comparing figures 7 and 8. Detailed Description of the Invention
    [037] The terms used in this specification generally have their common meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are> used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms can be highlighted, for example, using italics and / or quotation marks. The use of highlights has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether it is highlighted or not. It must be appreciated that the same thing can be said in more than one way. Consequently, alternative terminology and synonyms can be used for any one or more terms discussed in this document, just as no special meaning should be taken as to whether or not a term is elaborated or discussed in this document. Synonyms are provided for certain terms. The mention of one or more synonyms does not exclude the use of other synonyms. The use of examples in any part of this specification, including examples of any terms discussed here, is merely illustrative, and in no way limits the scope and meaning of the invention or any exemplified term. Likewise, the invention is not limited to the various configurations presented in this specification.
    [038] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as that normally understood by someone of ordinary skill in the technique to which this invention belongs. In case of conflict, this document, including definitions, will prevail.
    [039] The innovative methods of synthesis of formula (1) generally comprise the bonding of ceramide with saccharide, but it is also possible to bind first with phytosphingosine and then derive the amine group to the amide group to complete formula 1.
    [040] As an example of such a synthesis,) it is also possible to synthesize the compound represented by formula (1) where C6 'galactose is hydroxyl group by means of the following steps (see figure 1-3).
    [041] Phytosphingosine hydrochloride ((2S, 3S, 4R) -2-amino- 1,3,4-octadecanotriol) is a starting material, although there are several methods, as described in Curr. Org. Chem. 2002, 6, 365-391 for the synthesis of phytosphingosine. The commercial source - phytosphingosine hydrochloride is prepared from the appropriate yeast fermentation broth, which can be obtained at a reasonable price in large quantities (EvoniK Degussa Taiwan Ltd.). Isomeric sphingosines, having a different configuration from that of natural sphingosine, can be prepared according to the methods described in Helvetica Chimica Acta 1957, 470, 1145; or Chem. commun. 1991, 820.
    [042] In the first step, the phytosphingosine amine group was converted to an azido group by a diazon transfer reaction by freshly prepared TfN to generate Al. The TfN3 preparation can be found in Tetrahedron Lett 1996, 37, 6029-6032 . The trityl protection of primary alcohol Al generated A2 raw, which was directly subjected to benzylation conditions of NaH and BnCl to generate compound A3. In the present route, while the benzyl group is employed as the protecting group of the hydroxyl group, other suitable groups, such as benzoate, (p-methoxy) -benzyl, or isopropylidene can also be used. Toluene was selected as the solvent to synthesize compounds from A1 to A3. The benzylation reaction of secondary alcohols failed to proceed in toluene as a single solvent. To overcome the low reactivity of benzylation in toluene, a 10% DMF co-solvent system in toluene was employed to improve the solubility of NaH and intermediate alkoxide. After the aqueous procedure, raw A3 was obtained as a solution in toluene and was subjected to acid deprotection to generate the glycosyl acceptor A4. Various acids can be used in the deprotection of the trityl group, such as hydrochloride, sulfuric acid, hydrogen bromide, trifluoroacetic acid, BF3.OEt, nitric acid, acidic resin (for example, Amberlite IR120®) and the like.
    [043] Previously, several glycosylation methods have been applied to glycolipid synthesis, including glycosyl fluoride, glycosyl trichloroacetoimidate, glycosyl bromide and glycosyl iodide Tetrahedron 1998, 54, 3141-3150; J Org Chem 2005, 70, 10260-10270; J Org Chem 2002, 67, 4559-4564; Chem commun 2007, 2336-2338. Glycosyl imidate was initially used in our synthesis with excellent yield (89%) and anomeric selectivity (α / β = 9/1). Due to the fact that the imitate is easily hydrolyzable and should normally be prepared fresh, the use of this glycosylation leaving group in large-scale synthesis can encounter storage and purification problems. Alternatively, thioglycoside A5 as a donor can be obtained using Lewis acid, such as TMSOTf, Tf2O, BF3 • OEt2, TfOH, Me2S2-Tf2O as catalysts and using molecular sieves to dehydrate. The compound A5 contains the azido group that favors glycosylation, while the amine group of phytosphingosine is protected by amide or cabamate (t-butyl carbamate) as seen in US 5849716; US 2007/0238871; J. Am. Chem. Soc. 2004, 126, 13602-13603; J. Org. Chem. 2005, 70, 10260-10270; Tetrahedron 1998, 54, 3141-3150; Sintesis 2004, 847-850; Bioorg. Med. Chem. Lett. 2006, 16, 2195-2199. 2-NH and 1-OH can form an intramolecular hydrogen bond that makes it difficult, as a nucleophile, to attack activated glycosyl and results in low glycosylation yields. After glycosylation between A4 and A5, the purification of the column can generate A6 in both pure α and pure β forms.
    [044] Compound A6, which contains the azido group, can be reduced using a lithium aluminum hydride, sodium borohydride, a borane complex, phosphine complex, enzymatic reduction, hydrogenation, or transfer hydrogenation. Instead of using the phosphine complex, which generates phosphine oxide as a by-product, which is difficult to remove, the reduction of azide by lithium aluminum hydride (LiAlH4) produced amine of higher purity A7. Compound A 7 was linked to several prepared carboxylic acids (see figure 3 for preparation methods) to generate corresponding amide compounds. The global deprotection of these compounds was achieved under hydrogenolysis conditions in the presence of catalytic Pd (OH) 2 and H2 in a mixture of solvents of MeOH and CH2Cl2 to generate analogs of C34, compounds A15-21.
    [045] Reductive dehalogenation of aryl halides in an acyl chain is carried out by the hydrogenation reaction of compounds containing chloro- and bromo-acyl. Therefore, in order to avoid a dehalogenation reaction, A6 was unprotected and reduced by hydrogenation in the presence of catalytic Pd (OH) 2 and H2. Thereafter the resulting amine A22 was linked to appropriate acids (see figure 3 for preparation methods) under the binding conditions, analogs A23-25 (figure 2) were generated. For this process, many reaction methods are known, particularly for amidation. It is also possible to use acyl chloride, and acid anhydride or a carboxylic acid. Carboxylic acid is used in a condensation reaction in the presence of an appropriate condensing agent. The appropriate condensing agent used in the reaction includes dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3'dimethylaminopropyl) carbodiimine (EDC), as well as 2- (1H-benzotriazol-1-yl) -1,1, 3,3- tetramethyluronium hexafluorophosphate (HBTU), hydroxybenzotrazol (HOBt) or similar. In order for the reaction to progress rapidly, an organic base such as triethylamine, pyridine, N-methylmorpholine, dimethylaniline, 4-dimethylaminopyridine, AZ-methylpiperidine, N-methylpyrrolidine, is added. The solvent can be any inert solvent that is not involved in the reaction, such as tetrahydrofuran, ethyl ether, toluene, chloroform, methylene chloride, ethyl acetate, acetone or the like.
    [046] For the preparation of various substituted phenylalkanoic acids, the Wittig reaction is used as can be seen in figure 3. In this process, the cobromoalkanoic acids are mixed with triphenyl phosphine in the presence of the solvent. The reaction is usually carried out with an appropriate solvent, but when the reaction is low, it can be increased by carrying out the reaction in the absence of a solvent. The solvent can be any inert solvent that is not involved in the reaction, for example, toluene, benzene, diglyme, dimethyl sulfide or the like.
    [047] As another example of the synthesis, it is also possible to synthesize the compound represented by the formula (1) by making several substitutions in the galactose position C6 'by means of the following steps (see figure 4-5).
    [048] The synthesis of modified C6 analogs begins with the compound Cl as described in Org Lett 2002, 4, 1267-1270. Reduction of azide, then amidation with different commercial aromatic acids and complete deprotection of C5-C6 (figure 4, diagram 4). In addition, to avoid a tedious protection group interconversion for the preparation from the compound Cl, a different strategy was used in the synthesis of C6 ”and bimodified acyl chain compounds (figure 5). The hydroxyl group C6 ”of A15 can be tosylated or mesylated by sulfonyl toluene chloride in the presence of a base, such as pyridine, dimethylpyridine, triethylamine, diethylpropylamine, DBU or similar, and then the corresponding tosylate or mesylate group can be replaced with azide by sodium azide to generate C18. Staudinger's reduction of azide and amidation with a variety of acids generated C20-31. Use of the compound of the present invention
    [049] The compounds represented by formula (1) exhibit the following physiological activities: they can be used as an immunotherapeutic agent against cancers or as an immunostimulating agent against other diseases.
    [050] APC activation activity: IL-2 secretions can be measured in the A20CDld and mNK1.2 cell system as APC and effector cells, as shown in example 2.
    [051] Immunostimulating activity: secretions of IFN-i and Cytokine Il-4 can be measured as shown in example 2, in which the female C57BL / 6 mouse (16w4d) was sacrificed and the spleen was harvested for the study.
    [052] Antitumor agent: The compound of the present invention has a secretion profile of cytokines with a tendency to TH1 and can be used for antitumor activity and immunostimulating effect.
    [053] While the compounds of the present invention can be used as an immunotherapeutic agent against tumors, they can be used alone or in combination with chemotherapy or radiation therapy.
    [054] The compounds of the present invention as antitumor agents or immunostimulating agents can be administered in any appropriate route of administration. The compound is generally formed in a preparation that is in the form of a dilute and formed with a pharmaceutically acceptable carrier (liposome, or micelle). When the compound of the present invention is used, it can be administered orally or parenterally to humans or mammals. For example, the compounds of the present invention, when used as an injection, can be administered intravenously, intramuscularly, subcutaneously, or by inhalation in forms such as solution, suspension or emulsion with an appropriate solvent. In this case, polysorbates or macrogol, cholesterol can be added as a solubilizing agent, if necessary. When the compounds of the present invention are administered orally, they can be in the form of a tablet, powder, granules, or dry syrup in an appropriate additive. EXAMPLES
    [055] Without the intention to limit the scope of the invention, exemplary instruments, apparatus, methods and their related results, according to the configurations of the present invention, are presented below. Note that titles or subtitles may be used in the examples for the convenience of a reader, and that this should in no way limit the scope of the invention. In addition, certain theories are proposed and presented here; however, they in no way, whether right or wrong, should limit the scope of the invention as long as the invention is practiced in accordance with the invention, without regard to any particular theory or scheme of action. Example 1
    [056] The synthetic method and the physicochemical properties of the compounds of the present invention are described below (with reference to the number of compounds present in the synthesis process, see the reaction schemes as shown in figure 1 - figure 5).
    [057] In the diagrams shown here, the following abbreviations are used: - THF: tetrahydrofuran - DMF: N, N-dimethyl formide - MS-4A: Molecular sieves-4A (dehydrating agent) - CH2Cl2: dichloromethane - NMM: N-methyl morpholine - HBTU: - O-benzotriazole-N, N, N ', N'-tetramethyl-uronium-hexafluor-phosphate TMSOTf: trimethylsilyl trifluoromethanesulfonate - Tf2O: trifluoromethanesulfonic anhydride - nuclear: dl-chloroform: NMR: NMR: NMR: NMR high resolution mass - ESI: electron spray ionization
    [058] The other abbreviations have the same meanings as those present in the diagrams shown above. - Synthetic Scheme 1 (figure 1)
    [059] The routes specifically show the process of preparing compound C34, A13, A14, A15, A16, A18, A19, A20, A21 and the compounds according to the present invention can also be synthesized according to that process.
    [060] Synthesis of (2S, 3S, 4R) -2-azido-D-ribo-octadecane-1,3,4-triol (Al)

    [061] To the solution of sodium azide (64.3 g, 989 mmol) in 250 ml of water, dichloromethane (350 ml) was added. The biphasic mixture was cooled to 5 ° C in an ice bath and triflic anhydride (47.5 ml, 283 mmol) was added over 20 minutes, keeping the temperature below 10 ° C. After stirring for 2.5 h in an ice bath, the reaction mixture was quenched with 70 ml of sat. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2 (200 ml). The organic phases were combined to generate a solution of triflil azide in dichloromethane. [Caution! Triflil azide is explosive, and must be stored with solvent.]
    [062] To a solution of cuprous sulfate (0.35 g, 1.4 mmol) in water (150 mL) was added phytosphingosine hydrochloride (highly pure form of phytosphingosine hydrochloride [(2S, 3S, 4R) -2- amino-1,3,4-octadecanotriol] from the appropriate yeast fermentation broth that is commercially available at a reasonable price in large quantities, 50.0 g, 141 mmol), potassium carbonate (29.28 g, 211 , 9 mmol) and methanol (1.0 L). The suspension was cooled to 0-5 ° C in an ice and salt bath, and the triflil azide solution (in 550 ml CH2Cl2) was added over 10 minutes. After stirring the reaction mixture for 12 h at RT [room temperature], the mixture was concentrated. The residue was suspended in water (1.0 L) and stirred at room temperature for 12 h. The precipitate was filtered and washed with water (500 ml x 2). The residue was dried by azeotropic distillation (70-80 ° C, 200-250 mmHg) with toluene (1.5 L) to generate (2S, 3S, 4R) -2-azido-D-ribo-octadecane-1,3 , 4-triol (Al) (47.0 g, 137 mmol, 97%) as off-white solids, mp: 87 ° C. 1H-NMR (CD3OD, 400 MHz) δ 3.85 (dd, J = 11.6, 3.3 Hz, 1H), 3.69 (dd, J = 11.6, 7.9 Hz, 1H), 3.50-3.55 (m, 1H), 3.43-3.47 (m, 2H), 1.22-1.60 (m, 26H), 0.83 (t, J = 6, 4 Hz, 3H). 13C-NMR (CD3OD, 100 MHz) δ 7 4.6, 71.5, 65.3, 61.2, 32.5, 31.7, 29.4, 29.4, 29.1, 25.4 , 22.4, 13.1. HRMS (ESI) calculated for C18H37N3O3Na [M + Na] +: 366.2733, obtained: 366.2729.
    [063] Synthesis of (2S, 3S, 4R) -2-azido-3,4-di-O-benzyl-D-ribo-octadecane-1,3,4-triol (A4)

    [064] To the mixture of (2S, 3S, 4R) -2-azido-D-ribo-octadecane-1,3,4-triol (47.0 g, 137 mmol) in toluene (1.0 L) was added triethylamine (46 ml, 332 mmol) and trityl chloride (42.0 g, 151 mmol). After stirring at 50-55 ° C for 6 h, triethylamine (4.6 mL, 33 mmol) and triphenylmethyl chloride (4.20 g, 15.1 mmol) were added and then stirred for an additional 15 h. Water (1.0 L) was added and the mixture was stirred for 3 min. The organic phase was washed with water (1.0 L, 500 mL) and concentrated to generate crude (2S, 3S, 4R) -2-azido-1-trityl-D-ribo-octadecane-1,2,3-triol (A2). The analytical sample for NMR was purified by column chromatography. 1H-NMR (CDCl3, 400 MHz) δ 7.22-7.47 (m, 15H), 3.62 (dd, J = 3.7, 10.1 Hz, 2H), 3.53 (m, 2H ), 3.40 (dd, J = 6, 10.1 Hz, 1H), 2.35 (brs, 1H), 1.83 (brs, 1H), 1.20-1.52 (m, 26H) , 0.87 (t, J = 6.8 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 143.35, 128.54, 128.01, 127.27, 87.78, 74.19, 72.18, 63.48, 62.31, 31.90, 31.74, 29.67, 29.64, 29.60, 29.55, 29.34, 25.59, 22.67, 14.10.
    [065] To the solution of crude (23,33,4R) -2-azido-1-trityl-D-ribooctadecane-1,3,4-triol (A2) in toluene (750 mL) and DMF (75 mL) ) sodium hydride (60% in mineral oil, 21.9 g, 548 mmol) was added in three portions over 10 minutes. The mixture was stirred for 30 min, after which benzyl chloride (50.5 ml, 0.438 mmol) was added to the reaction mixture. The mixture was heated to 50-60 ° C and stirred for 18 h. The mixture was then cooled to 0 ° C and water (50 ml) was added dropwise. The organic phase was washed with sat. (500 mL x 2) and water (500 mL * 2). The organic phase was filtered through Celite sponges and the filtrate was concentrated to generate (2S, 3S, 4R) -2-azido-2,3-di-benzyl-1-trityl-D-ribooctadecane-1,3, Crude 4-triol (A3).
    [066] To the solution of A3 in toluene / methanol (600 ml, 1/1), aqueous HCl (33%, 6.0 ml) was added. The mixture was heated to 50-60 ° C and stirred for 20 h. The reaction mixture was quenched with 1.0 N NaOH (55 ml) and concentrated. The residue was partitioned with toluene (500 ml) and water (500 ml). The organic phase was concentrated and the residue was purified by column chromatography (crude 100 g, silica gel 500 g, ethyl acetate / n-hexane = 1/10) to generate (2S, 3S, 4R) -2-azido- 2,3-di-benzyl-D-ribo-octadecane-1,3,4-triol (A4) (27.5 g, 52.5 mmol, 38% in 4 steps) as yellow oil. 1H-NMR (CDCl3, 20 MHz) δ 7.26-7.39 (m, 10H), 4.69 (d, J = 1.4 Hz, 2H), 4.59 (d, J = 4 , 3 Hz, 2H), 3.59-3.94 (m, 5H), 1.26-1.61 (m, 26H), 0.88 (t, J = 6.4 Hz, 3H). 13C-NMR (CDCl3, 50 MHz) δ 137.9, 137.6, 128.5, 128.4, 128.1, 127.97, 127.81, 127.10, 80.38, 78.96, 73.59, 72.49, 63.03, 62.20, 21.90, 30.16, 29.66, 29.35, 25.43, 22.67, 14.11. HRMS (ESI) calculated for C32H49N3O3Na [M + Na] +: 546, 3672, obtained: 546.3689.
    [067] Synthesis of 4-methylphenyl 2,3-O-dibenzyl-4,6-O-benzylidene-1-thiol-D-pyranosidic (A5)

    [068] Compound A5 can be prepared according to the method described in Plettenburg, O. et al. J. Org. Chem. 2002, 67, 4559-4564.
    [069] Data for compound A5: 1H-NMR (CDCl3, 400 MHz) δ 7.58 (d, J = 8.1 Hz, 1H), 7.50 (m, 2H), 7.23-7.42 (m, 15H), 6.98 (d, J = 8.0 Hz, 1H), 5.46 (s, 1H), 4.69 (m, 4H), 3.54 (d, J = 9, 5 Hz, 1H), 4.35 (dd, J = 12.3, 1.5 Hz, 1H), 4.12 (d, 7 = 3.2 Hz, 1H), 4.03 (dd, J = 9.8, 3.6 Hz, 1H), 3.82 (t, J = 9.3 Hz, 1H), 3.60 (dd, J = 9.2, 3.4 Hz, 1H), 3, 39 (s, 1H), 2.28 (s, 3H).
    [070] Synthesis of 2-azido-3,4-di-O-benzyl-10- (2,3-di-O-benzyl-4,6-O-benzylidene-α-D-galactopyranosyl) -D-ribo -octadecane-1,3,4-triol (A6)

    [071] To the solution of dimethyl disulfide (10.0 mL, 113 mmol) in dichloromethane (75 mL) was added triflic anhydride (17 mL, 100 mmol) at 0-5 ° C in an ice and salt bath. After stirring the reaction mixture in the ice and salt bath for 30 min, Me2S2-Tf2O was obtained as a 1.0 M solution in dichloromethane and can be stored in an ice bath for 3 hours.
    [072] Compounds A4 (27.3 g, 52.2 mmol), A5 (34.7 g, 62.6 mmol) and 4 A molecular sieve (33 g) were mixed and dried in vacuo by THF ( 520 mL) was added to the mixture. The mixture was cooled to -10 ° C in an ice and salt bath before adding Me2S2-Tf2O (1.0 M solution in CH2Cl2, 94 mL, 94 mmol). After stirring for 20 min, the reaction mixture was quenched with triethylamine (22 ml) and then diluted with dichloromethane (200 ml). The mixture was filtered through Celite and washed with dichloromethane (50 ml). The combined filtrate was concentrated and partitioned with dichloromethane (500 ml) and water (500 ml). The organic phase was concentrated and the residue was purified by column chromatography (raw weight = 153 g, 600 g silica gel, ethyl acetate: n-hexane = 1:15 to 1:12 to 1:10) to generate 2- azido-3,4-di-O-benzyl-10- (2,3-di-O-benzyl-4,6-O-benzylidene-α-D-galactopyranosyl) -D-ribo-octadecane-1,3, 4-triol (A6) (32.07 g, 33.60 mmol, 64%) as off-white wax mp: 59 ° C. 1H-NMR (CDCI3, 400 MHz) δ 7.22-7.50 (m, 25H), 5.44 (s, 1H), 4.96 (d, J = 3.4 Hz, 1H), 4, 85 (d, J = 11, 9 Hz, 1H), 4.79 (d, J = 12.3 Hz, 1H), 4.73 (d, J = 12.3 Hz, 1H), 4.66- 4.69 (m, 2H), 4.59 (d, J = 8.5 Hz, 1H), 4.56 (d, J = 12.8 Hz, 1H), 4.48 (d, J = 11 , 5 Hz, 1H), 4.15 fd, J = 2.8 Hz, 1H), 4.06-4.12 (m, 1H), 3.98-4.04 (m, 3H), 3, 86 (dd, J = 12.5, 1.5 Hz, 1H), 3.68-3.73 (m, 3H), 3.60-3.62 (m, 1H), 3.55 (s, 1H), 1.25-1.55 (m, 26H), 0.87 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCI3, 100 MHz) δ 138.75, 138.36, 138.01, 137.82, 128.85, 128.37, 128.34, 128.26, 128.22, 128.09, 127.90, 127.79, 127.75, 127.70, 127.66, 127.61, 127.50, 127.45, 126.33, 101.05, 99.13, 79.41, 78, 95, 76.68, 75.80, 75.44, 74.66, 73.77, 73.49, 72.06, 72.03, 69.31, 68.43, 62.97, 61.80, 31.91, 30.01, 29.75, 29.69, 29.67, 29.65, 29.63, 29.60, 29, 35, 25, 44, 22, 68, 14, 10, [α ] 25 + 63.1 (c 1.0, CHCl3). HRMS (ESI) calculated for C59H75N3O8Na [M + Na] +: 976.5452, obtained: 976.5483.
    [073] Synthesis of 3,4-di-O-benzyl-10- (2,3-di-O-benzyl-4,6-0-benzylidene-α -D-galactopyranosyl) -2- (11- (4- (4-fluorophenoxy) phenyl) undecanoyl) amino - D-ribo-octadecan-1,3,4-triol (A8)

    [074] A solution of compound A7 (32.07 g, 33.61 mmol) in THF (340 mL) was cooled in an ice bath and lithium aluminum hydride (1.910 g, 50.33 mmol) was added in two portions. The mixture was returned to room temperature (rt) and stirred for 70 min. The mixture was cooled to 0 ° C before subsequently quenching with water (1.9 ml), 1.0 N NaOH (3.8 ml) and water (1.9 ml). The mixture was filtered through a Celite sponge and washed with dichloromethane (100 ml). The filtrate was concentrated and partitioned with dichloromethane (350 ml) and water (350 ml).
    [075] 11- (4- (4-fluorophenoxy) phenyl)) undecanoic acid (B4) (11.27 g, 30.26 mmol) was added to the isolated organic phase, followed by NMM (9.2 mL, 84 mmol ) and HBTU (19.12 g, 50.41 mmol). After stirring at room temperature for 12 h, the mixture was filtered and washed with 50 ml CH2Cl2. The combined filtrate was washed with sat. (400 ml) and water (400 ml). The organic phase was concentrated and purified by column chromatography (raw weight = 46 g, 350 g silica gel, ethyl acetate / n-hexane = 1/6 to 1/5 to 1/4) to generate A8 (36.06 g, 28.11 mmol, 84%) as off-white wax. 1H-NMR (CDCl3, 400 MHz) 56.86-7.51 (m, 33H), 5.84 (d, J = 8.0 Hz, 1H), 5.44 (s, 1H), 4.94 (d, J = 3.5 Hz, 1H), 4.83 (d, J = 11.6 Hz, 1H), 4.69-4, 74 (m, 3H), 4.63 (d, J = 11.6 Hz, 1H), 4.57 (d, 7 = 11.6 Hz, 1H), 4.50 (d, 7 = 3.9 Hz, 1H), 4.47 (d, 7 = 3, 9 Hz, 1H), 4,244.31 (m, 1H), 4.16 (d, 7 = 3.1 Hz, 1H) 4.03-4.12 (m, 3H), 3.92 (dd, 7 = 10.3, 3.6 Hz, 2H), 3, 73-3, 7 9 (m, 2H), 3.56 (s, 1H), 3.51-3.53 (m, 1H), 2 .55 (t, 7 = 7.6 Hz, 2H), 1.87-1.91 (m, 2H), 1.19-1.69 (m, 42H), 0.87 (t, 7 = 6 , 6 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 172.89, 159.76, 157.36, 155.36, 153.36, 153.33, 138.63, 138.52, 138.50, 138.38, 137.81, 137.79, 129.53, 128.84, 128.64, 128.42, 128.35, 128.31, 128.29, 128.08, 127.88, 127.80, 127, 69, 127.59, 127.57, 127.55, 126.29, 120.08, 120.00, 118.31, 116.24, 116.01, 100.99, 99.59, 79.81, 79.48, 76.68, 76.14, 75.68, 74.33, 73.81, 73.28, 71.88, 71.69, 69.39, 68.13, 62.91, 60, 36, 50.32, 36.69, 35.17, 31.90, 31.61, 30.24, 29.78, 29.69, 29.67, 29.65, 29.59, 29.56, 29.51, 29.42, 29.35, 29.29, 25.81, 25.68, 22.66, 14.17, 14.10. HRMS (ESI) calculated for C82H105FNO10 [M + H] +: 1282.7723, obtained: 1282.7731.
    [076] Synthesis of 10- (α-D-galactopyranosyl) -2- (11- (4- (4-fluorophenoxy) phenyl) und ecanoyl) amino-D-ribo-octadecane-1,3,4-triol (C34 )

    [077] To the solution of A8 (36.06 g, 28.11 mmol) in dichloromethane / methanol (200 mL, dichloromethane / methanol = 1/1) was added palladium hydroxide (1.8 g). The mixture was stirred in hydrogen (5 bar) at room temperature for 10 h. The reaction mixture was filtered through a Celite sponge and washed with dichloromethane / methanol (100 ml, dichloromethane / methanol = 1/1). The combined filtrate was concentrated and purified by column chromatography (300 g silica gel, dichloromethane / methanol = 15/1 to 10/1) to generate crude C34 (17.46 g, 20.93 mmol, purity = 95.72 area % by HPLC) as off-white solids in 75% yield. Ethanol (87.5 ml) was added to the crude C34 and heated to 50 ° C, acetone (87.5 ml) was then added. The solution was cooled to RT over a period of 3 h and then cooled in an ice bath. The precipitate was filtered and washed with acetone (200 mL) to generate C34 (16.02 g, 19.21 mmol, 68%), purity = 97.15 area% by HPLC) as white solids at 92% recovery, mp : 163 ° C. 1H-NMR (CDCl3 / CD3OD = 1/1, 400 MHz) δ 7.26 (d, J = 8.5 Hz, 2H), 7.07-7.17 (m, 4H), 7.00 (dd , J = 6.6, 2.0 Hz, 2H), 5.03 (d, J = 3.7 Hz, I 1H), 4.33 (q, J = 4.7 Hz, 1H), 4, 05 (d, J = 2.7 Hz, 1H), 4.01 (dd, J = 4.6, 10.8 Hz, 1H), 3.7 9-3, 97 (m, 6H), 3, 64-3.72 (m, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H), 1.29-1.43 (m, 42H), 1.01 ft, J = 6.6 Hz, 3H). 13C-NMR (CDCl3 / CD3OD = 1/1, 100 MHz) δ 173.99, 154.82, 152.97, 137.34, 128.95, 119.39, 119.31, 117.71, 115, 52, 115.29, 99.21, 73.92, 71.28, 70.41, 69.69, 69.17, 68.37, 66.63, 61.12, 49.92, 35.74, 34.50, 31.66, 31.27, 31.02, 29.10, 29.06, 28.99, 28.95, 28.88, 28.85, 28.77, 28.70, 28, 60, 25.28, 25.23, 21.99, 13.10. [α] 25 +57.0 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C47H77FNO3 [M + H] +: 834.5532, found: 834.5595.
    [078] Synthesis of 3,4-di-O-benzyl-10- (2,3-di-O-benzyl-4,6- 0-benzylidene-α -D-galactopyranosyl) -2- (11 - (4 -phenoxyphenyl) undecanoyl) amino-D-ribo-octadecan-1,3,4-triol (A9)

    [079] By the similar procedure of synthesis of A8, compound A6 (100 mg, 0.105 mmol) and compound B12 (33 mg, 0.093 mmol) are the starting materials to generate compound A9 (45 mg, 0.036 mmol, 38 %) as white wax. 1H-NMR (CDCl3, 400 MHz) δ 7.48-7.52 (m, 2H), 7.20-7.41 (m, 25H), 7.12 (d, J = 8.8 Hz, 2H ), 7.06 (t, J = 7.3 Hz, 1H), 6, 96-7.00 (m, 2H), 6, 92 (d, J = 10, 4 Hz, 2H), 5.8 3 fd, 7 = 8.4 Hz, 1H), 5.45 (s, 1H), 4.94 (d, J = 3.6, 1H), 4.84 (d, J = 11.6 Hz, 1H), 4, 69-4.75 (m, 3H), 4.63 (d, J = 11.6 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H), 4, 49 (d, J = 11.6 Hz, 1H), 4.48 (d, J = 11.6 Hz, 1H), 4.24-4.31 (m, 1H), 4.17 (d, J = 3.2 Hz, 1H) 4.03-4.12 (m, 3H), 3.87-3.96 (m, 3H), 3.74-3.80 (m, 2H), 3.56 (s, 1H), 3.50-3.56 (m, 1H), 2.57 (t, J = 7.6 Hz, 2H), 1.82-1, 95 (m, 2H), 1, 15-1.65 (m, 42H), 0.88 (t, J = 6.6 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 172.89, 159, 69, 154.86, 138.62, 138.51, 138.50, 138.38, 137.89, 137.79, 129.60, 129.49, 128.83, 128.41, 128.34, 128.31, 128.29, 128.07, 127.87, 127.82, 127.80, 127.68, 127.57, 127, 55, 126.29, 122.79, 118.92, 118.41, 100.98, 99.60, 79.82, 79.48, 76.14, 75.68, 74.33, 73.80, 73.27, 71.88, 71.69, 69.38, 68.14, 62.91, 50.32, 36.70, 35.21, 31.90, 31.61, 30.24, 29, 78, 29, 69, 29, 67, 29, 65, 29, 59, 29.56, 29.51, 29.41, 29.34, 29.29, 25.80, 25.68, 22.66, 14.10. HRMS (ESI) calculated for C82H106NO10 [M + H] +: 1264.7817, obtained: 1264.7834.
    [080] Synthesis of 3,4-di-O-benzyl-10- (2,3-di-O-benzyl-4,6-O-benzylidene-α-D-galactopyranosyl) -2- (11 - (4 -isopropoxyphenyl) undecanoyl) amino - D-ribo-octadecan-1,3,4-triol (A10)

    [081] By the similar procedure of synthesis of A8, compounds A6 (100 mg, 0.105 mmol) and B13 (30 mg, 0.094 mmol) were used as starting materials to generate A10 (72.0 mg, 0.059 mmol, 63% ) as white wax. 1H-NMR (CDCl3, 400 MHz) δ 7.21-7.55 (m, 25H), 7.06 (d, J = 8.4 Hz, 2H), 7.78-7.84 (m, 2H), 5.86 (d, J = 8.4 Hz, 1H), 5.46 (s, 1H), 4.95 (d, J = 3.2, 1H), 4.85 (d, J = 11.6 Hz, 1H), 4.71 - 4.80 (m, 3H), 4.63 (d, J = 11.6 Hz, 1H), 4.58 (d, J = 11.6 Hz , 1H), 4.46-4.54 (m, 3H), 4.18 (d, J = 3.2 Hz, 1H), 4.05-4.14 (m, 3H), 3.88- 3.97 (m, 3H), 3.75-3.82 (m, 2H), 3.58 (s, 1H), 3.51-3.57 (m, 1H), 2.53 (t, J = 7.6 Hz, 2H), 1.83-1.96 (m, 2H), 1.15-1.71 (m, 48H), 0.89 (t, J = 6.6 Hz, 3H ). 13C-NMR (CDCl3, 100 MHz) δ 172.84, 139.68, 138.60, 138.49, 138.46, 138.36, 137.77, 128.81, 128.39, 128.32, 128.28, 128.26, 128.05, 127.86, 127.79, 127.78, 127.66, 127.54, 126.26, 124.00, 116.89, 116.72, 100, 96, 99.54, 79.75, 79.46, 76.10, 75.66, 74.29, 73.79, 73.25, 71.84, 71.65, 69.35, 68.08, 62.88, 50.28, 36.66, 35.04, 31.87, 31.20, 30.19, 29.75, 29.67, 29.64, 29.50, 29.48, 29, 38, 29.37, 29.31, 29.04, 25.87, 25.64, 22.64, 14.07. HRMS (ESI) calculated for C79H108NO10 [M + H] +: 1230.7973, obtained: 1230.7968.
    [082] Synthesis of 3,4-di-O-benzyl-10- (2,3-di-O-benzyl-4,6-O-benzylidene-α-D-galactopyranosyl) -2- (11- (3 , 4-difluorfenyl) undecanoyl) amino-D-ribo-octadecan-1,3,4-triol (A11)

    [083] By the similar procedure of synthesis of A8, compounds A7 (100 mg, 0.105 mmol) and B14 (28 mg, 0.093 mmol) were used as starting materials to generate A11 (63 mg, 0.052 mmol, 56%). mp: 98 ° C. 1H-NMR (CDCl3, 400 MHz) δ 7.21-7.54 (m, 25H), 6, 92-7.06 (m, 2H), 6.81-6.87 (m, 1H), 5 , 87 (d, J = 8.4 Hz, 1H), 5.45 (s, 1H), 4.95 (d, J = 3.2, 1H), 4.84 (d, J = 11.6 Hz, 1H), 4.69-4.79 (m, 3H), 4.63 (d, J = 11.6 Hz, 1H), 4.58 (d, J = 11.6 Hz, 1H), 4.50 (d, J = 11.6 Hz, 1H), 4.49 (d, J = 11.6 Hz, 1H), 4.25-4.33 (m, 1H), 4.17 (d , J = 2.8) Hz, 1H) 4.04-4.13 (m, 2H), 3.88-3.97 (m, 3H), 3.74-3.81 (m, 2H), 3.57 (s, 1H), 3.51-3.56 (m, 1H), 2.54 (t, J = 7.6 Hz, 2H), 1.82-1, 96 (m, 2H) , 1.15-1.69 (m, 42H), 0.89 (t, J = 6.8 Hz, 3H). 13C-NMR (CDCI3, 100 MHz) δ 172.84, 150.02 (dd, J = 245, 13 Hz), 148.55 (dd, J = 244, 13 Hz), 139.68, 138.60, 138.49, 138.46, 138.36, 137.77, 128.81, 128.39, 128.32, 128.28, 128.26, 128.05, 127.86, 127.79, 127, 78, 127.66, 127.54, 126.26, 124.00, 116.89, 116.72, 100.96, 99.54, 79.75, 79.46, 76.01, 75.66, 74.29, 73.79, 73.25, 71.84, 71.65, 69.35, 68.08, 62.88, 50.28, 36.66, 35.04, 31.87, 31, 20, 30.19, 29.75, 29.67, 29.64, 29.50, 29.48, 29.38, 29.37, 29.31, 29.04, 25.78, 25.64, 22.64, 14.07. HRMS (ESI) calculated for C76H100F2NO9 [M + H] +: 1208.7366, obtained: 1208.7398.
    [084] Synthesis of 3,4-di-O-benzyl-1-O- (2,3-di-O-benzyl-4,6-O-benzylidene-α-D-galactopyranosyl) -2- (11- (2,4-difluorophenyl) undecanoyl) amino-D-ribo-octadecan-1,3,4-triol (A12)

    [085] By the similar process of synthesis of A8, compounds A6 (100 mg, 0.105 mmol) and B15 (28 mg, 0.093 mmol) were used as starting materials to generate A12 (70 mg, 0.058 mmol, 62%) as white wax. 1H-NMR (CDCI3, 400 MHz) δ 7.20-7.55 (m, 25H), 7.04-7.14 (m, 1H), 6.69-6.81 (m, 2H), 5 , 89 (d, J = 8.3 Hz, 1H), 5.45 (s, 1H), 4.95 (d, J = 3.2 Hz, 1H), 4.85 (d, J = U, 6 Hz, 1H), 4.70-4.79 (m, 3H), 4.64 (d, J = 11.6 Hz, 1H), 4.58 (d, J = 11.6 Hz, 1H) , 4.50 (d, J = 11.6 Hz, 1H), 4.49 (d, J = 11.6 Hz, 1H), 4.25-4.33 (m, 1H), 4.17 ( d, J = 2.8 Hz, 1H) 4.04-4.13 (m, 2H), 3.88-3, 97 (m, 3H), 3.74-3, 80 (m, 2H), 3.57 (s, 1H), 3.51-3.56 (m, 1H), 2.57 (t, J = 7.6 Hz, 2H), 1.82-1.96 (m, 2H) , 1.15-1.69 (m, 42H), 0.88 (t, J = 6.6 Hz, 3H). 13C-NMR (CDCI3, 100 MHz) δ 172.90, 162.30, 138.59, 138.50, 138.45, 138.36, 137.78, 130.89, 128.82, 128.40, 128.33, 128.30, 128.27, 128.06, 127.87, 127.79, 127.68, 127.55, 126.27, 110.07, 103.41, 99.53, 79, 75, 79.47, 76.11, 75.67, 74.29, 73.81, 73.27, 71.85, 71.65, 69.36, 68.05, 62.89, 50.29, 36.67, 31.88, 30.19, 30.15, 29.76, 29.67, 29.65, 29.51, 29.37, 29.32, 29.17, 28.38, 25, 78, 25, 66, 22, 65, 14.08. HRMS (ESI) calculated for C76H100F2NO9 [M + H] +: 1208.7366, obtained: 1208.7377.
    [086] Synthesis of 1-0- (α-D-galactopyranosyl) -2- (11- (4-phenoxyphenyl) undecanoyl) amino-D-ribo-1,3,4-octadecanotriol (A15)

    [087] By a procedure similar to that of C34, A15 (21 mg, 0.026 mmol, 72%) was obtained from A9 (45 mg, 0.036 mmol) as off-white solids, mp: 131 ° C. 1H-NMR (CD3OD / CDCI3 = 1/1, 400 MHz) δ 7.45 (t, J = 8.3 Hz, 2H), 7.28 (d, J = 1.1 Hz, 2H), 7, 20 (t, J = 7.3 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 5.04 ( d, J = 3.3 Hz, 1H), 4.26 (q, J = 1.1 Hz, 1H), 3.79-4.13 (m, 10H), 2.73 (t, J = 1 , 1 Hz, 2H), 2.36 (t, J = 1.5 Hz, 2H), 1,651.82 (m, 4H), 1.41 (brs, 38H), 0.89 (t, J = 7 , 5 Hz, 3H). 13C-NMR (CD3OD / CDCl3 = 1/1, 100 MHz) δ 174.09, 157.18, 154.36, 137.40, 128.98, 128.92, 122.22, 118.25, 117, 71, 99.18, 73.88, 71.30, 70.41, 69.68, 69.17, 68.37, 66.63, 61.10, 60.01, 35.80, 34.56, 31.61, 31.29, 31.04, 29.08, 29.02, 28.91, 28.80, 28.72, 28.64, 25.30, 22.01, 19.90, 13, 15. [α] 25 +37.4 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C47H78NO10 [M + H] +: 816.5626, obtained: 816.5637.
    [088] Synthesis of 1-0- (α-D-galactopyranosyl) -2- (11- (4-isopropoxy) phenyl) undecanoyl) amino-D-ribo-1,3,4-octadecanotriol (A16)

    [089] By a procedure similar to that of C34, compound A16 (34 mg, 0.044 mmol, 74%) was obtained from A10 (72 mg, 0.059 mmol). A16 data: mp: 120 ° C. 1H-NMR (CD3OD / CDCI3 = 1/1, 400 MHz) δ 7.16 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 5, 01 (d, J = 3.7 Hz, 1H), 4.58-4.66 (m, 1H), 4.32 (m, 1H), 4.03 (d, J = 2.6 Hz, 1H ), 3.99 (dd, J = 10.6, 4.8, 1H), 3.88-3.96 (m, 2H), 3.78-3.88 (m, 4H), 3.62 -3.73 (m, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.32 (t, J = 7.4 Hz, 2H), 1.61-1.81 ( m, 4H), 1.32-1.52 (m, 44H), 0.99 (t, J = 6.8 Hz, 3H). 13C-NMR (CD3OD / CDCl3 = 1/1, 100 MHz) δ 174.06, 155.10, 134.52, 128.54, 115.33, 99.16, 73.81.71.25, 70, 40, 69.65, 69.62, 69.12, 68.33, 66.60, 61.04, 35.75, 35.70, 34.35, 31.53, 31.25, 31.08, 29.09, 29.03, 28.97, 28.94, 28.87, 28.85, 28.76, 28.68, 28.59, 25.27, 25.22, 21.96, 21, 08, 20.88, 13.08. [α] 25 +36.2 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C44H79NO10Na [M + Na] +: 804.5602, obtained: 804.5641.
    [090] Synthesis of 1-O- (α-D-galactopyranosyl) -2- (11- (3,4-difluorfenyl) undecanoyl) amino-D-ribo-1,3,4-octadecanotriol (A17)

    [091] By a procedure similar to that of C34, compound A17 (37 mg, 0.049 mmol, 94%) was obtained from A11 (63 mg, 0.052 mmol). A18 data [sic]: mp: 140 ° C. 1H-NMR (CD3OD / CDCI3 = 1/1, 400 MHz) δ 7.06-7.22 (m, 2H), 6, 98-7, 04 (m, 1H), 5.03 (d, J = 3.3 Hz, 1H), 4, 2 9-4, 36 (m, 1H), 4.05 (d, J = 2.5 Hz, 1H), 4.00 (dd, J = 10.5, 4.8, 1H), 3.89-3.96 (m, 2H), 3, 7 8-3, 8 9 (m, 4H), 3, 64-3, 73 (m, 2H), 2, 69 (t, J = 7.5 Hz, 2H), 2.34 (t, J = 7.6 Hz, 2H), 1.63-1.83 (m, 4H), 1, 33-1, 4 8 (m, 38H), 1.00 (t, J = 6.5 Hz, 3H). 13C-NMR (CD3OD / CDCI3 = 1/1, 100 MHz) δ 174, 07, 149.33 (d, J = 2 47, 13 Hz), 14 7, 95 (d, J = 24 4, 13 Hz) , 13 9, 47 7, 123, 56, 116.22, 116.06, 99.18, 73.86, 71.82, 70.40, 69.67, 69.15, 68.34, 66.63 , 61.08, 45.00, 35.78, 35.73, 34.40, 31.58, 31.28, 30.66, 29.12, 29.06, 29.00, 28.91, 28 , 85, 2 8, 7 7, 28, 7 1, 2 8, 4 4, 25, 28, 21.99, 13.12, [α] 25 +44.4 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C41H72F2NO9 [M + H] +: 760.5175, obtained: 760.5222.
    [092] Synthesis of 1-O- (α-D-galactopyranosyl) -2- (11- (2,4-difluorphenyl) undecanoyl 1) amino-D-ribo-1,3,4-octadecanotriol (A18)

    [093] By a procedure similar to that of C34, compound A18 (39 mg, 0.051 mmol, 88%) was obtained from compound A12 (70 mg, 0.058 mmol). A18 data: mp: 149 ° C. 1H-NMR (CD3OD / CDCI3 = 1/1, 400 MHz) δ 7.29 (q, J = 8.1 Hz, 1H), 6, 87-6, 97 (m, 2H), 5.05 (d , J = 3.7 Hz, 1H), 4.30-4.38 (m, 1H), 4.07 (d, J = 2.9 Hz, 1H), 4.03 (dd, J = 10, 6, 4.4 Hz, 1H), 3.91-3.98 (m, 2H), 3.66-3.75 (m, 4H), 3.64-3.73 (m, 2H), 2 , 73 (t, J = 7.5 Hz, 2H), 2.36 (t, J = 7.6 Hz, 2H), 1.65-1.86 (m, 4H), 1.24-1, 60 (m, 38H), 1.02 (t, J = 6.6 Hz, 3H). 13C-NMR (CD3OD / CDCI3 = 1/1, 100 MHz) δ 174, 09, 161.65, 159.20, 130.48, 124.73, 110.06, 102.62, 99.19, 73, 90.71.31, 70.40, 69.69, 69.17, 68.36, 66.66, 61.11, 50.12, 35.81, 35.76, 31.63, 31.30, 29.59, 29.16, 29.14, 29.09, 29.02, 28.92, 28.87, 28.78, 28.76, 28.73, 28.56, 27.72, 25, 30, 22.01, 13.16. [α] 25 +46.0 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C41H71F2NO9Na [M + Na] +: 782.4995, obtained: 782.5034.
    [094] Synthesis of 1-0- (α-D-galactopyranosyl) -2 - ((10R, 11S) - 11- (3,4-difluorphenyl) -10,11-dihydroxyundecanoyl) amino-D-ribo-1, 3,4- octadecanotriol and 10- (α-D-galactopyranosyl) -2 - ((10S, 11R) -11- (3,4-difluorphenyl) - 10,11-hydroxyundecanoyl) amino-D-ribo-1,3 , 4-octadecanotriol (A19) as a mixture of anti-diol isomers

    [095] To the solution of A7 (101 mg, 0.109 mmol) in dichloromethane (3 mL) was added anti-B21 (32 mg, 0.097 mmol), HBTU (62 mg, 0.16 mmol) and NMM (24 pL, 0 , 23 mmol). After stirring at room temperature for 12 h, the mixture was concentrated and the residue was purified by column chromatography (ethyl acetate / n-hexane = 1/4 to 1/2 to 1/1). The resulting white wax was dissolved in dichloromethane / methanol (1/1, 10 ml) and Pd (OH) 2 (10 mg) was then added. After stirring at room temperature in hydrogen for 15 h, the mixture was filtered through a Celite sponge and washed with dichloromethane / methanol (1/1). The filtrate was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 10/1 then 8/1) to generate A19 (34 mg, 0.043 mmol, 44%) as off-white solids, mp: 105 ° C. 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) 57.17-7.40 (m, 3H), 5.01 (d, J = 3.6 Hz, 1H), 4.62 (d, J = 4.8 Hz, 0.75H), 4.50 (d, J = 6.0 Hz, 0.25H), 4.28-4.36 (m, 1H), 4.03 (d, J = 2.8 Hz, 1H), 3.99 (dd, J = 4.8, 10.8 Hz, 1H), 3.87-3.95 (m, 2H), 3,763.87 (m, 4H) , 3.61 - 3.71 (m, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.31 - 1.83 (m, 40H), 0.99 (t, J = 6.9 Hz, 3H). 13C-NMR (CDCI3 / CD3OD = 1/1, 100 MHz) δ 173.97, 149.42 (dd, J = 245, 13 Hz), 148.86 (dd, J = 245, 13 Hz), 136, 65, 122.46, 116.09, 115.77, 115.27, 115.10, 99.16, 75.70, 75.35.74.74, 74.21, 73.94, 71.25, 70.40, 69.65, 69.10, 68.31, 66.52, 61.03, 49.91, 35.63, 31.94, 31.69, 31.23, 31.18, 29, 09, 29.04, 29.00, 28.95, 28.83, 28.76, 28.68, 28.65, 28.53, 25.17, 25.08, 24.96, 21.94, 13.04. [α] 25 +58.3 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C41H71F2NO11Na [M + Na] +: 814.4893, obtained: 814.4859.
    [096] Synthesis of 1-0- (α-D-galactopyranosyl) -2 - ((10S, 11S) - 11- (3,4-difluorphenyl) -10,11-dihydroxyundecanoyl) amino-D-ribo-1, 3,4- octadecanotriol and 1-O- (α-D-galactopyranosyl) -2 - ((10R, 11R) -11- (3,4-difluorphenyl) - 10,11-dihydroxyundecanoyl) amino-D-ribo-1 , 3,4-octadecanotriol, (A20) as a mixture of sin-diol isomers

    [097] To the solution of A7 (101 mg, 0.109 mmol) in dichloromethane (3 mL) was added Sin-A21 (14 mg, 0.042 mmol), HBTU (62 mg, 0.16 mmol) and NMM (24 pL, 0 , 22 mmol). After stirring at room temperature for 12 h, the mixture was concentrated and the residue was purified by column chromatography (ethyl acetate / n-hexane = 1/4 to 1/2 to 1/1). The resulting white wax was dissolved in dichloromethane / methanol (1/1, 10 ml) and Pd (OH) 2 (10 mg) was then added. After stirring at room temperature in hydrogen for 15 h, the mixture was filtered through a Celite sponge and washed with dichloromethane / methanol (1/1). The filtrate was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 10/1 then 8/1) to generate A20 (20 mg, 0.025 mmol, 60%) as white solids, mp: 80 ° C. 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) δ 7.19-7.49 (m, 3H), 5.02 (d, J = 3.6 Hz, 1H), 4.52 (d , J = 6 Hz, 1H), 4.30-4.37 (m, 1H), 4.04 (d, J = 2.8 Hz, 1H), 4.01 (dd, J = 4.4, 10.8 Hz, 1H), 3.89-3.96 (m, 2H), 3.78-3.88 (m, 4H), 3.63-3.73 (m, 3H), 2.33 (t, J = 7.6 Hz, 2H), 1.26-1.84 (m, 40H), 1.01 (t, J = 6.8 Hz, 3H). 13C- NMR (CDCI3 / CD3OD = 1/1, 100 MHz) δ 174.00, 149, 58 (dd, J = 245, 12 Hz), 149.07 (dd, J = 245, 12 Hz), 138, 90, 122.46, 116, 13, 115, 14, 99.21, 75.47, 74.79, 74.01, 71.28, 70.41, 69.69, 69.15, 68.34, 66.57, 61.09, 49.90, 35.67, 31.98, 31.77, 31.27, 29.12, 29.03, 28.98, 28.80, 28.68, 28, 56, 25.20, 25, 00, 21.98, 13.08. [α] 25 + 50.0 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C41H71F2NO11Na [M + Na] +: 814.4893, obtained: 814.4893.
    [098] Synthesis of 1-0- (α-D-galactopyranosyl) -2- (11- (4-bromophenyl) -10,11-dihydroxyxyecanoyl) amino-D-ribo-1,3,4-octadecanotriol (A21)

    [099] By a procedure similar to that of A19, compound A21 (18 mg, 0.024 mmol, 28%) was obtained from A7 (90 mg, 0.094 mmol) and B19 (32 mg, 0.086 mmol). A21 data: whitish wax. 1H-NMR (CD3OD / CDCl3 = 1/1, 400 MHz) δ 7.26-7.51 (m, 5H), 5.02-5.10 (m, 1H), 5.02 (d, J = 4.0 Hz, 1H), 4.23-4.29 (m, 1H), 4.06-4.15 (m, 1H), 3, 97-4.03 (m, 2H), 3.83 -3.96 (m, 6H), 3.68 (t, J = 10.2 Hz, 1H), 2.84-2.89 (m, 1H), 2.52 (t, J = 7.4 Hz, 2H), 1.27-1.89 (m, 40H), 1.02 (t, J = 6.8 Hz, 3H). 13C-NMR (CD3OD / CDCl3 = 1/1, 150 MHz) δ 174.08, 173, 54, I 138.50, 128.72, 127.55, 125.39, 99.10, 72.40, 71 , 92, 70.84, 70.16, 69.92, 69.57, 69.24, 68.23, 63.43, 61.13, 52.30, 43.34, 36.69, 36.39 , 35.91, 35.69, 35.26, 33.69, 32.83, 32.03, 31.67, 31.25, 30.90, 30.59, 29.81, 29.30, 29 , 01, 28.97, 28.86, 28.77, 28.67, 28.54, 28.46, 25.22, 25.00, 24.36, 24.27, 21.97, 13.09 . M15 +22.7 (cl, O, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C41H74NO11 [M + H] +: 778.5081, obtained: 778.5073. - Scheme 2: Synthesis of compounds A23-25
    [0100] Synthesis of 1-O- (α-D-galactopyranosyl) -2-amino-D-ribo-1,3,4-octadecanotriol (A22)

    [0101] To the solution of A7 (520 mg, 0.545 mmol) in dichloromethane / methanol (1/1, 20 mL) was added Pd (OH) 2 (220 mg) and three drops of acetic acid. The reaction mixture was stirred at room temperature in 80 psi hydrogen for 16 h. The mixture was filtered through Celite and the filter cake was washed with methanol. The filtrate was concentrated and dried in vacuo to generate crude A22 (302 mg, quantitative) as white solids. HRMS (ESI) calculated for C24H49NO8H [M + H] +: 480.3536, obtained: 480.3515.
    [0102] Synthesis of 1-0- (α-D-galactopyranosyl) -2- (11- (3,4-dichlorophenyl) undecanol) amino-D-ribo-1,3,4-octadecanotriol (A23)

    [0103] To the solution of A22 (50 mg, 0.10 mmol) in dichloromethane / methanol (1 / 1.3 mL) was added B16 (34 mg, 0.10 mmol), HBTU (59 mg, 0.16 mmol) ) and NMM (23 pL, 0.21 mmol). The reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 15/1 to 12/1 to 9/1) to generate A23 (16 mg, 0.020 mmol, 20%) as off-white solids, mp: 147 ° C. 1H-NMR (CD3OD / CDCI3 = 1/1, 400 MHz) δ 7.51 (s, 1H), 7.35 (s, 2H), 5.08 (d, J = 3.3 Hz, 1H), 4.43 (m, 1H), 4.08-4.12 (m, 1H), 4.06 (dd, J = 10.7, 4.0 Hz, 1H), 3.82-4.02 ( m, 6H), 3.67-3.77 (m, 2H), 2.8 6 (t, J = 7.6 Hz, 2H), 2.39 (t, J = 7.5 Hz, 2H ), 1.66-1.88 (m, 4H), 1.34 1.60 (m, 38H), 1.06 ft, J = 6.4 Hz, 3H). 13C-NMR (CD3OD / CDCI3 = 1/1, 100 MHz) δ 174.05, 138.47, 133.89, 131.36, 130.64, 128.41, 126.35, 99.25, 73, 99, 71.36, 70.42, 69.74, 69.22, 68.42, 66.71, 61.19, 49.97, 35.82, 32.41, 31.76, 31.34, 29.20, 29.17, 29.12, 29.06, 28.95, 28.91, 28.81, 28.76, 28.69, 25.33, 25.29, 22.06, 13, 21. [α] 25 +46.8 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C41H71Cl2NO9Na [M + Na] +: 814.4404, obtained: 814.4311
    [0104] Synthesis of 1-O- (α-D-galactopyranosyl) -2- (11- (4-chlorophenyl) undecanoyl) amino-D-ribo-1,3,4-octadecanotriol (A24)

    [0105] By procedure similar to that of A23, compound A24 (18 mg, 0.024 mmol, 22%) was obtained from A22 (52 mg, 0.11 mmol) and B17 (32 mg, 0.11 mmol). A24 data: off-white solids, mp: 136 ° C. 1H-NMR (CD3OD / CDCI3 = 1/1, 400 MHz) δ 7.28 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 4, 96 (d, J = 3.6 Hz, 1H), 4.21 - 4.29 (m, 1H), 3.98 (d, J = 2.5 Hz, 1H), 3.95 (dd, J = 10.6, 4.4, 1H), 3.83-3, 90 (m, 2H), 3.72-3.82 (m, 4H), 3.58-3, 68 (m, 2H) , 2.64 (t, J = 7.6 Hz, 2H), 2.28 (t, J = 7.8 Hz, 2H), 1.57-1.77 (m, 4H), 1.20- 1.51 (m, 38H), 0.95 (t, J = 6.7 Hz, 3H). 13C-NMR (CD3OD / CDCl3 = 1/1, 100 MHz) δ 173.99, 140.73, 130.53, 129.08, 127.51, 99.15, 73.79, 71.23, 70, 34, 69.62, 69.17, 68.32, 66.58, 61.06, 49.87, 35.67, 34.52, 1.53, 31.23, 30.73, 29.01, 28.95, 28.87, 28.81, 28.75, 28.65, 28.46, 25.24, 21.94, 13.03. [α] 25 +41.7 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C41H72ClNO9Na [M + Na] +: 780.4793, obtained: 780.4779
    [0106] Synthesis of 1-0- (α-D-galactopyranosyl) -2- (11- (4-bromophenyl) undecanoyl) amino-D-ribo-1,3,4-octadecanotriol (A25)

    [0107] By procedure similar to that of A23, compound A25 (22 mg, 0.027 mmol, 25%) was obtained from A22 (52 mg, 0.11 mmol) and B28 (56 mg, 0.16 mmol). A25 data: whitish wax. 1H-NMR (CD3OD / CDCl3 = 1/1, 400 MHz) δ 7.28 (d, J = 8.4 Hz, 2H), 7.20-7.47 (m, 2H), 5.00 (d , J = 3, 6 Hz, 1H), 4.28-4.33 (m, 1H), 4.02 (d, J = 2.8 Hz, 1H), 3.98 (dd, J = 10, 6, 4.6 Hz, 1H), 3.683-3.94 (m, 2H), 3.77-3.87 (m, 4H), 3.62-3.70 (m, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.31 (t, J = 7.6 Hz, 2H), 1.29-1.81 (m, 42H), 0.98 (t, J = 6.6 Hz, 3H). 13C-NMR (CD3OD / CDCl3 = 1/1, 100 MHz) δ 171.21, 141.18, 130.44, 129.44, 118.39, 99.41.74.54, 70.41, 70, 13, 69.58, 69.50, 69.07, 68.41, 67.22, 60.95, 49.68, 35.58, 34.51, 31.36, 31.18, 30.62, 28.95, 28.90, 28.81, 28.76, 28.68, 28.61, 28.40, 27.00, 25.21, 24.88, 21.89, 19.90, 19, 74, 19, 57, 12, 96. [α] 25 +40.7 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C41H73BrNO9 [M + H] +: 802.4469, obtained: 802.4216. - Synthetic Scheme 3: Synthesis of arylalkanoic acid
    [0108] Synthesis of (9-carboxynonyl) triphenylphosphonium bromide (B2)

    [0109] 10-Bromodecanoic acid (19.65 g, 78.24 mmol) and triphenylphosphine (21.45 g, 81.78 mmol) were mixed and stirred at 150 ° C for 24 h. The Wittig B2 reagent in the form of light yellow syrup was obtained in 100% yield and used without further purification.
    [0110] Synthesis of 11- (4- (4-fluorophenoxy) phenyl)) undecanoic acid (B4)

    [0111] To the mixture of B2 (19.89 g, 38.81 mmol) and THF (150 mL) was added potassium t-butoxide (10.40 g, 92.68 mmol) at 0 ° C. The reaction mixture became a red solution. The reaction mixture was heated to RT and stirred for 1 h. 4- (4-fluorophenoxy) benzaldehyde (Bl) (7.50 g, 34.7 mmol) was added to the reaction mixture at 0 ° C and was stirred for an additional 30 min at RT. The reaction mixture was neutralized with 1.0 N HCl and concentrated. The residue was partitioned with ethyl acetate (200 ml), water (200 ml) (the pH value was adjusted to 5 by the addition of 1.0 N HCl) and brine (200 ml). The organic phase was isolated and concentrated under reduced pressure. The residue was recrystallized from ethanol / water (1/1, 80 mL) and washed with water to generate B3 (9.99 g, 27.0 mmol, 78%) as white solids. B3 was dissolved in ethanol / ethyl acetate (1/1, 80 mL) and Pd / C (10%, 1.08 g) was added later. The mixture was stirred at room temperature under hydrogen for 12h. The reaction mixture was filtered through a Celite sponge and washed with ethyl acetate. The filtrate was concentrated and recrystallized from methanol / water (5/1, 12 mL), filtered and washed with water to generate 11- (4- (4-fluorophenoxy) phenyl)) undecanoic acid (B4) (9,080 g, 24, 38 mmol, 90%) as white solids, mp: 73 ° C. 1H-NMR (CDCl3, 400 MHz) δ 6.85-7.13 (m, 8H), 2.56 (t, J = 7.6 Hz, 2H), 2.33 (t, J = 7.4 Hz, 2H), 1.22-1.65 (m, 16H). 13C-NMR (CDCI3, 100 MHz) δ 179.69, 159.78, 157.38, 155.36, 153.39, 137.88, 129.56, 120.09, 120.01, 118.33, 116.25, 116.02, 35.18, 33.97, 31.59, 29.69, 29.48, 29.44, 29.38, 29.24, 29.20, 29.03, 24, 65. HRMS (ESI) calculated for C23H29FO3Na [M + Na] +: 395.1998, obtained: 395.2003.
    [0112] Synthesis of 11- (4-phenoxy) phenylundecanoic acid

    [0113] Similar to the pathway for compound B4, compound B12 (1.34 g, 3.78 mmol, 97%) was synthesized from B2 (3.47 g, 6.76 mmol) and 4-phenoxybenzaldehyde ( 1.03 g, 5.20 mmol). Compound B12 data: off-white solids, mp: 55 ° C. 1H-NMR (CDCI3, 400 MHz) δ 6.93-7.35 (m, 9H), 2.60 (t, J = 7.4 Hz, 2H), 2.37 (t, J = 7.3 Hz, 2H), 1.65 (m, 4H), 1.33 (m, 12H). 13C-NMR (CDCl3, 100 MHz) δ 180.35, 157.71, 154.83, 137.87, 130.13, 129.51, 122.73, 118.97, 118.32, 35.18, 34.10, 31.55, 29.45, 29.42, 29.36, 29.22, 29.18, 29.00, 24.63. HRMS (ESI) calculated for C23H30O3Na [M + Na] +: 377.2093, obtained: 377.2053.
    [0114] Synthesis of 11- (4-isopropoxy) phenylundecanoic acid (B13)

    [0115] By a similar process to the synthesis of B4, compound B2 (2.25 g, 4.38 mmol) and 4-isopropoxybenzaldehyde (479 mg, 2.92 mmol) were used as starting materials to generate compound B13 (562 mg, 1.75 mmol, 60%) as white solids, mp: 46 ° C. 1H-NMR (CDCl3, 400 MHz) δ 7.04 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 4.48 (m, 1H) , 2.50 (t, J = 7.5 Hz, 2H), 2.32 (t, J = 7.5 Hz, 2H), 1.50-1.61 (m, 4H), 1.25- 1.35 (m, 18H). 13C-NMR (CDCl3, 100 MHz) δ179.73, 155.82, 134.93, 129.20, 115.77, 69.91, 35.04, 34.11, 31.69, 29.50, 29 , 47, 29.40, 29.26, 29.22, 29.12, 29.06, 24.71, 22, 11, 21.88. HRMS (ESI) calculated for C20H32O3Na [M + Na] +: 343.2249, obtained: 343.2227.
    [0116] Synthesis of (10 E or 10Z) acid - 11- (3,4-difluorphenyl) undec-10-enoic ((E) -BI, and (Z) -B7)

    [0117] By procedure similar to that of compound B3, B2 (12.93 g, 25.18 mmol) and THF (80 mL) and 3,4-difluorbenzaldehyde (2.35 g, 16.5 mmol) were starting materials to generate compound B7 (3.77 g, 12.7 mmol, 77%). The products of form Z and form E were separated by recrystallization with n-hexane. (E) -B7 was obtained as white solids, mp: 66 ° C. 1H-NMR (CDCl3, 400 MHz) δ 6.98-7.14 (m, 3H), 6.25 (d, J = 15.8 Hz, 1H), 6.12 (m, 1H), 2, 33 (t, J = 7.5 Hz, 2H), 2.16 (q, J = 7.0 Hz, 2H), 1.61 (m, 2H), 1.43 (m, 2H), 1, 30 (s, 8H). 13C-NMR (CDCI3, 100 MHz) δ 180.57, 150.49 (dd, J = 246, 12 Hz), 149.31 (dd, J = 241, 13 Hz), 135.29, 132.35, 127.88, 121.99, 117.13, 114.18, 34.15, 32.91, 29.31, 29.22, 29.18, 29.08, 24.70. HRMS (ESI) calculated for C17H22F2O2Na [M + Na] +: 319.1486, found: 319.1485. (Z) -B7 was obtained as a colorless oil with 25% inseparable (E) -B7.
    [0118] Synthesis of (3,4-difluorfenyl) undecanoic acid (B14)

    [0119] Compound B7 (1.61 g, 5.43 mmol) was dissolved in ethanol / ethyl acetate (1/1, 30 mL) and Pd / C (10%, 160 mg) was added to the solution. The mixture was stirred at room temperature in hydrogen for 12 h. The mixture was filtered through a Celite sponge and washed with ethyl acetate. The filtrate was concentrated and dried in vacuo. Compound B14 was obtained as white solids (1.61 g, 5.40 mmol, 99%). mp: 51 ° C. 1H-NMR (CDCI3, 400 MHz) 56.90-7.03 (m, 2H), 6.84 (m, 1H), 2.53 (t, J = 1.1 Hz, 2H), 2.33 (t, J = 1.5 Hz, 2H), 1.521.64 (m, 4H), 1.26 (m, 12H). 13C-NMR (CDCl3, 100 MHz) δ 180.24, 150.13 (dd, J = 13, 247 Hz), 148.49 (dd, J = 13, 246 Hz), 147.40, 139.77, 124.05, 116.85, 35.09, 34.01, 31.23, 29.43, 29.36, 29.35, 29.18, 29.05, 29, 01, 24.64. HRMS (ESI) calculated for C17H24F2O2Na [M + Na] +: 321.1642, obtained: 321.1594.
    [0120] Synthesis of 11- (2,4-difluorfenyl) undecanoic acid (B15)

    [0121] By a similar process to the synthesis of B4, the compound B2 (2.76 g, 5.38 mmol) and 2,4-difluorbenzaldehyde (588 mg, 4.14 mmol) were used as starting materials to generate the compound B15 (431 mg, 1.45 mmol, 35%) as off-white solids, mp: 56 ° C. 1H-NMR (CDCI3, 400 MHz) δ 7.05-7.13 (m, 1H), 6.70-6.79 (m, 2H), 2.66 (t, J = 7.6 Hz, 2H ), 2.31 (t, J = 7.4 Hz, 2H), 1.50-1.62 (m, 4H), 1.26 (m, 12H). 13C-NMR (CDCI3, 100 MHz) δ 180.00, 162.19, 159.80, 130.90, 125.31, 110.69, 103.44, 34.11, 30.15, 29.44, 29.36, 29.33, 29.19, 29.16, 29.03, 28.41, 24.69. HRMS (ESI) calculated for C17H24F2O2Na [M + Na] +: 321.1642, obtained: 321.1637.
    [0122] Synthesis of 11- (2,4-dichlorophenyl) undecanoic acid (B16)

    [0123] By a similar process to that of compound B7, B2 (2.25 g, 4.38 mmol) and 2,4-dichlorobenzaldehyde (500 mg, 2.86 mmol) were used as starting materials to generate acid (10 E or 10Z)) - 11- (2,4-dichlorophenyl) undec-10-enoic (B9) (576 mg, 1.75 mmol, 61%). Then, that compound (210 mg, 0.638 mmol) was dissolved in ethyl acetate (10 ml) and Pd / BaSO4 (21 mg) was then added. The mixture was stirred at room temperature in hydrogen for 12 h. The mixture was filtered through a sponge
    [0124] Celite and washed with ethyl acetate. The combined filtrate was concentrated and dried in vacuo to generate compound B16 (210 mg, 0. 634 mmol, 99%) as white solids, mp: 78 ° C. 1H-NMR (CDCI3, 400 MHz) δ 7.32 (d, J = 1.9 Hz, 1H), 7.09-7.15 (m, 2H), 2.65 (t, J = 7.8 Hz, 2H), 2.33 (t, J = 1.5 Hz, 2H), 1.53-1.63 (m, 4H), 1.26 (m, 12H). 13C-NMR (CDCl3, 100 MHz) δ 180.00, 162.19, 159.80, 130.90, 125.31, 110.69, 103.44, 34.11, 30.15, 29.44, 29.36, 29.33, 29.19, 29.16, 29.03, 28.41, 24.69. HRMS (ESI) calculated for C17H24Cl2O2Na [M + Na] +: 353.1051, obtained: 353.1046.
    [0125] Synthesis of 11- (4-chlorophenyl) undecanoic acid

    [0126] By a similar process to the synthesis of B10, compound B2 (2.20 g, 4.28 mmol) and 4-chlorobenzaldehyde (401 mg, 2.85 mmol) were used as starting materials to generate B17 (526 mg, 1.77 mmol, 62%), mp: 93 ° C. 1H-NMR (CDCl3, 400 MHz) δ 7.21 (d, J = 8.4 Hz, 1H), 7.08 (d, 7 = 8.4 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 2.33 (t, J = 7.5 Hz, 2H), 1.53-1.63 (m, 4H), 1.26 (m, 12H). 13C-NMR (CDCl3, 100 MHz) 5179.90, 141.28, 131.21, 129.71, 128.27, 35.26, 34.00, 31.35, 29.69, 29.44, 29 , 39, 29.36, 29, 19, 29, 13, 29.01, 24, 64. HRMS (ESI) calculated for C17H25ClO2Na [M + Na] +: 319.1441, obtained: 319.1435.
    [0127] Synthesis of 11- (4-bromophenyl) undecanoic acid (B18)

    [0128] By a similar process to the synthesis of B10, compound B2 (330 mg, 0.643 mmol) and 4-bromobenzaldehyde (91.5 mg, 0.495 mmol) were used as starting materials to generate B18 (98.0 mg, 0.287 mmol, 58%) as off-white solids, mp: 91 ° C. 1H-NMR (CDCl3, 400 MHz) δ 7.37 (d, J = 8.3 Hz, 1H), 7.02 (d, 7 = 8.3 Hz, 2H), 2.53 (t, 7 = 7.6 Hz, 2H), 2.34 (t, 7 = 7.5 Hz, 2H), 1.52-1.63 (m, 4H), 1.20-1, 37 (m, 12H). 13C-NMR (CDCI3, 100 MHz) δ 179, 94, 141, 79, 141.79, 131.22, 130.14, 119.22, 35.31, 34.11, 31.27, 29.44, 29.38, 29.36, 29.19, 29.12, 29.03, 24.68. HRMS (ESI) calculated for C17H26BrO2 [M + H] +: 341.1111, obtained: 341.1111.
    [0129] 11- (4-Bromophenyl) -10,11- dihydroxyundecanoic acid (B20)

    [0130] To the solution of B11 (389 mg, 1.15 mmol) in t-butanol / water (4/3, 35 mL) was added NMO (462 mg, 3.94 mmol) and osmium tetroxide (2.5 wt% in t-BuOH, 170 µL, 0.167 mmol). After stirring at room temperature for 15 h, the reaction was quenched with sat. and concentrated. The residue was partitioned with dichloromethane (50 ml) and sat. (50 mL). The organic phase was washed with brine (50 ml), concentrated and purified by column chromatography (ethyl acetate / n-hexane = 1/2 then 1/1) to generate B20 (256 mg, 0.686 mmol, 60%). 1H-NMR (CD3OD / CDCI3 = 1/1, 400 MHz) δ 7.49-7.56 (m, 2H), 7.28-7.37 (m, 2H), 4.59 (d, 5.1 Hz , 0.7H), 4.44 (d, J i = 6.6 Hz, 0.3H), 3.71-3.77 (m, 0.7H), 3.62-3.66 (m, 0.3H), 2.45 (t, 7 = 7.2 Hz, 2H), 1.27-1, 78 (m, 14H). 13C-NMR (CD3OD / CDCI3 = 1/1, 100 MHz) 5169.05, 140.40, 140.16, 130.60, 130.30, 128.18, 120.64, 120.27, 76.44 , 75.80, 74.81, 74.27, 31.88, 30.94, 28.92, 28.78, 28.67, 28.63, 28.56, 28.48, 28.45, 28 , 38, 25.10, 24.88, 24.28. HRMS (ESI) calculated for C17H25BrO4Na [M + Na] +: 395.0834, obtained: 395.0813.
    [0131] Synthesis of L - (-) - Mentile (10E) -11- (3,4-difluorfenyl) - undec-10-enoate (Mentile (E) - B7)

    [0132] To the solution of (E) -B7 (298 mg, 1.01 mmol) in dichloromethane (3 mL) was added L - (-) - menthol (314 mg, 2.01 mmol), EDC ^ HCl (34 7 mg, 1.81 mmol) and DMAP (1.2 mg, 0.010 mmol). The reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 ml), washed with water (20 ml) and concentrated. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/50) to generate Mentile (E) -B7 (112 mg, 0.258 mmol, 26%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ 6.95-7.13 (m, 3H), 6.24 (d, J = 15.6 Hz, 1H), 6.15-6.24 (m, 1H ), 4.11 - 4.20 (m, 1H), 2.27 (t, 7 = 7.6 Hz, 2H), 2.15 (q, 7 = 6.8 Hz, 2H), 1.92 -1.99 (m, 1H), 1.801.89 (m, 1H), 1.55-1, 68 (m, 4H), 1.38-1.50 (m, 3H), 1.22-1 , 35 (m, 10H), 0.771.09 (m, 9H), 0.73 (d, J = 7.0 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 173.34, 150.39 (dd, J = 245, 13 Hz), 149.23 (dd, J = 246, 13 Hz), 135.15, 132.24, 127.77, 121.87, 117.00, 114.08, 73.82, 47.00, 40.93, 34.67, 34.25, 32.82, 31.33, 29.67, 29, 26, 29.14, 29.08, 29.06, 26.22, 25.06, 23.39, 21.97, 20.70, 16.25. HRMS (ESI) calculated for C27H40F2O2Na [M + Na] +: 457.2894, obtained: 457.2863.
    [0133] Synthesis of (10S, 11S) -11- (3,4-difluorfenyl) - 10,11-dihydroxyundecanoic acid (10R, 11R) -11- (3,4-difluorfenyl) -10,11- dihydroxyundecanoic , sin- (B21) as a mixture of sin-diol isomers

    [0134] To the solution of mentile (E) -B7 (110 mg, 0.253 mmol) in t-butanol / water (2/1, 6 mL) was added NMO (103 mg, 0.879 mmol) and osmium tetroxide (2, 5% by weight in t-BuOH, 38 µL, 0.0037 mmol). After stirring at room temperature for 20 h, the reaction mixture was quenched with sat. Na2S2C3. (10 mL). The mixture was concentrated and the residue was dissolved in ethyl acetate (20 ml), washed with sat. Na2S2O3. (20 ml), and brine (20 ml), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/4 then 1/3). The resulting colorless oil was dissolved in methanol (5 ml) and 1.0 N NaOH (5 ml) was then added. After stirring at room temperature for 12 h, the reaction mixture was neutralized with 1.0 N HCl (5 ml) and concentrated. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/2 then 1/1) to generate sin-B21 (35 mg, 0.11 mmol, 43%) as white solids, mp: 104 ° Ç. 1H- NMR (CD3OD, 400 MHz) δ 6, 99-7.25 (m, 3H), 4.36 (d, 7 = 5.6 Hz, 1H), 3.45-3.52 (m, 1H ), 2.18 (t, J = 7.4 Hz, 2H), 1.11-1.54 (m, 14H). 13C-NMR (CD3OD, 100 MHz) δ 177.70, 151.29 (dd, J = 244, 12 Hz), 150.76 (dd, J = 244, 13 Hz), 141.48, 124.36, 117.64, 116.87, 77.23.76.39, 34.39.33.72,30.51, 30.41, 30.27, 30, 15, 26, 80, 26.03. HRMS (ESI) calculated for C17H24F2O4Na [M + Na] +: 353.1540, obtained: 353.1550.
    [0135] Synthesis of (10R, 11S) - and (10S, 11R) -11- (3,4-difluorphenyl) - (10.11) -dihydroxyundecanoic acid, Anti- (B21) as a mixture of anti-diol isomers

    [0136] To the solution of (Z) -B7 (361 mg, 1.22 mmol) in t-butanol / water (2/1, 6 mL) was added NMO (494 mg, 4.22 mmol) and osmium tetroxide (2.5 wt% in t-BuOH, 186 pL, 0.0183 mmol). After stirring at room temperature for 20 h, the reaction mixture was quenched with sat. (15 mL). The mixture was concentrated and the residue was dissolved in ethyl acetate (50 ml), washed with sat. Na2S2O3. (50 ml), and brine (50 ml), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/2 after 1/1) to generate anti-B21 (246 mg, 0.745 mmol, 61%, a mixture of anti-diol isomers) like a colorless oil. 1H- NMR (CD3OD, 400 MHz) δ 7.03-7.25 (m, 3H), 4.36 (d, J = 5.5 Hz, 1H), 3.47-3, 57 (m, 1 H), 2.16-2.22 (m, 2H), 1.18-1.56 (m, 14H). 13C-NMR (CD3OD, 100 MHz) δ 177.73, 151.19 (dd, J = 245, 13 Hz), 150.72 (dd, J = 245, 13 Hz), 141.46, 124.57, 117.49, 117.08, 77.34, 77.25, 76.42, 76.06, 34.95, 33.75, 33.50, 30.63, 30.51, 30.44, 30, 34, 30.20, 26.83, 26.07. HRMS (ESI) calculated for C17H24F2O4Na [M + Na] +: 353.1540, obtained: 353.1566.
    [0137] (4) Synthetic Scheme 4: Synthesis of compound C5C 3,4-di-O-benzyl-10- (6-azido-2,3,4-tri-0-benzyl-6-deoxy-α-D -galactopyranosyl) -2-hexacosanoylamino-D-ribo-octadecan-1,3,4-triol (Cl)

    [0138] Compound Cl can be synthesized according to Zhou, X. T. et al. Org Lett 2002, 4, 1267-1270. Cl data: 1H-NMR (CDCl3, 400 Hz) δ 7.35-7.21 (m, 25H), 5.94 (d, J = 6.0 Hz, 1H), 4.95 (d, J = 11.4 Hz, 1H), 4.82 (d, J = 3.2 Hz, 1H), 4.79-4.91 (m, 4H), 4.63-4.55 (m, 3H) , 4.37-4.48 (m, 2H), 4.18-4.30 (m, 2H), 4.00 (dd, J = 3, 6, 10.1 Hz, 1H), 3.87 -3.81 (m, 7H), 3.52-3.50 (m, 1H), 1.78-1.79 (m, 74H), 0.86 (t, J = 7.0 Hz, 6H ).
    [0139] Synthesis of 1-O- (6-phenylacetamido-6-deoxy-α-D-galactopyranosyl) -2-hexaCOsanoylamino-D-ribo-octadecan-1,3,4-triol (C5)

    [0140] To the solution of Cl (24 mg, 0.018 mmol) in THF / water (10/1, 5 mL) was added triphenylphosphine (10 mg, 0.038 mmol). After stirring at room temperature for 2 days, the mixture was concentrated and dried in vacuo. The residue was dissolved in chloroform (3 ml). Phenylacetic acid (3 mg, 0.02 mmol), NMM (5 qL, 0.05 mmol) and HBTU (10 mg, 0.026 mmol) were added to this solution. After stirring and at room temperature for 12 h, the mixture was concentrated and purified by column chromatography (ethyl acetate / n-hexane = 1/8 to 1/6 to 1/4) to generate compound C2. The resulting C2 intermediate was dissolved in dichloromethane / methanol (1/1, 5 ml) and Pd (OH) 2 (5.0 mg) was then added. After stirring at room temperature in hydrogen for 15 h, the mixture was filtered through a Celite sponge and washed with dichloromethane / methanol (1/1). The filtrate was concentrated and purified by column chromatography (dichloromethane / methanol = 1/1) to generate C5 (4.0 mg, 0.004 mmol, 22%) as a white wax. 1H-NMR (pyridine-d5, 400 Hz) δ 7.24-7.43 (m, 5H), 5.51 (d, J = 3.8 Hz, 1H), 4.50-4, 67 (m , 2H), 4.09-4.51 (m, 8H), 3.89 (s, 2H), 3.82-4.01 (m, 1H), 2.21-2.57 (m, 4H ), 1.08-1, 96 (m, 74H), 0.88 (t, J = 6.1 Hz, 6H). 13C-NMR (pyridine-d5, 150 Hz) δ 173.75, 173.46, 142.53, 129.24, 129.20, 126.75, 101.71, 77.08, 72.95, 71, 64, 71.34, 70.91, 70.50, 68.82, 51.89, 41.50, 38.77, 37.20, 34.81, 32.67, 32.51, 30.78, 30.55, 30.42, 30.39, 30.32, 30.20, 29.99, 26.90, 26, 79, 23.32, 14.66. [α] 25 +39.3 (c 1.0, CH2Cl2 / CH3OH: 1/1). LRMS (ESI) calculated for C58H107N2O9 [M + H] +: 975.80, obtained: 975.67.
    [0141] Synthesis of 1-O- (6- (3-phenylpropylamido) -6-deoxy-α-D-galactopyranosyl) -2-hexacosanoylamino-D-ribo-octadecan-1,3,4-triol (C6)

    [0142] By a process similar to that of C5 synthesis, the compound Cl (24 mg, 0.018 mmol) and 3-phenylpropanoic acid (2.2 mg, 0.018 mmol) were used as starting materials to generate C6 (10 mg, 0.010 mmol, 55%). 1H-NMR (pyridine-d5, 400 Hz) δ 7.29-7.30 (m, 5H), 5.50 (d, J = 3.7 Hz, 1H), 5.20-5.30 (m , 1H), 4.56-4.65 (m, 2H), 4.48 (t, J = 6.6 Hz, 1H), 4.25-4.38 (m, 5H), 4.15- 4.23 (m, 1H), 3.86-3.95 (m, 1H), 3.17-3.26 (m, 2H), 2.74-2.89 (m, 2H), 2, 41-2.55 (m, 2H), 1.08-2.04 (m, 74H), 0.89 (t, J = 6.7 Hz, 3H). 13C-NMR (pyridine-d5, 400 Hz) δ 173.81, 173.52, 149.78, 142.60, 129.32, 129.27, 126.83, 101.78, 77.15, 73, 00, 71.70, 71.41, 70.98, 70.56, 68.88, 51.94, 38.84, 37.26, 34.88, 32.74, 32.58, 30.86, 30, 63, 20.50, 30.47, 30.39, 26, 97, 26, 87, 23.40, 14.74. [α] 25 + 36.0 (c 1.0, CH2Cl2 / CH3OH: 1/1). LRMS (ESI) calculated for C59H109N209 [M + H] +: 989.81, obtained: 989, 60.
    [0143] Synthesis of 1-O- (6- (4-phenylbutyl starch) -6-deoxy-α-D-galactopyranosyl) -2-hexacosanoylamino-D-ribo-octadecan-1,2,3-triol (C7)

    [0144] By a process similar to that of C5 synthesis, the compound Cl (24 mg, 0.018 mmol) and 4-phenylbutanoic acid (2.0 mg, 0.018 mmol) were used as starting materials to generate C7 (9.0 mg , 0.090 mmol, 50%). 1H-NMR (pyridine-d5, 400 Hz) δ 7.27-7.40 (m, 5H), 5.50 (d, J = 3.7 Hz, 1H), 5.21-5.27 (m , 1H), 4.55-4.66 (m, 2H), 4.48 (t, J = 6.6 Hz, 1H), 4.25-4.37 (m, 6H), 4.15- 4.23 (m, 1H), 3.87-3.95 (m, 1H), 3.16-3.25 (m, 2H), 2.74-2.89 (m, 2H), 2, 41-2.55 (m, 2H), 1.02-1.98 (m, 74H), 0.88 (t, J = 7.2 Hz, 6H). 13C-NMR (pyridine-d5, 400 Hz) δ 173.30, 173.02, 142.07, 128.82, 128.70, 126.33, 101.28, 76.66, 72.50, 71, 19, 70.90, 70.48, 70.05, 68.39, 51.44, 41.06, 38.34, 36.77, 34.38, 32.25, 32.10, 30.37, 30.13, 30.01, 29.98, 29.91, 29.79, 29.76, 29.59, 29.58, 26.47, 26.37, 22, 91, 14.25. [α] 25 +36.9 (c 1.0, CH2Cl2 / CH3OH: 1/1). LRMS (ESI) calculated for C60H111N2O9 [M + H] +: 1003.83, obtained: 1003.47. - Synthetic Scheme 5: Synthesis of C20-C31 compounds
    [0145] Synthesis of 1-O- (6-O-toluenesulfonyl-α-D-galactopyranosyl) -2- (11- (3,4-difluorphenyl) undecanoyl) amino-D-ribo-1,3,4-octadeca ntriol (C17)

    [0146] To the solution of A15 (2.58 g, 3.40 mmol) in pyridine (30 mL) was added the solution of p-toluenesulfonyl chloride (712 mg, 3.74 mmol) in pyridine (20 mL) in an ice bath. The reaction mixture was returned to RT. After stirring for 16 h, the solvent was evaporated and the residue was purified by column chromatography (dichloromethane / methanol = 100/1 to 50/1 to 20/1 to 15/1) to generate C17 as yellow wax (782 mg, 0.855 mmol, 25%, 100% BRSM with 2.01 g of starting material recovery). 1H-NMR (CD3OD / CDCI3 = 1/1, 400 MHz) δ 7.96 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7, 10-7.27 (m, 2H), 7.02-7.09 (m, 1H), 5.01 (d, J = 3.2 Hz, 1H), 4.29-4.42 (m, 3H), 4.21 (t, J = 5.9 Hz, 1H), 3.96-4.04 (m, 2H), 3.85-3.95 (m, 2H), 3.81 (dd , J = 4.0, 10.6 Hz, 1H), 3.70-3.76 (m, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.62 (s, 3H), 2,352.43 (m, 2H), 1.67-1.88 (m, 4H), 1.36-1.60 (m, 38H), 1.05 (t, J = 6.7 Hz , 3H). 13C- NMR (CD3OD / CDCI3 = 1/1, 100 MHz) δ 173.84, 149.47 (dd, J = 246, 13 Hz), 148.00 (dd, J = 244, 13 Hz), 144, 74, 139.43, 132.04, 129.32, 127.44, 123.60, 116.22, 114.55, 99.09, 73.87, 71.39, 69.27, 68.98, 68.51, 68.15, 68.07, 66.95, 35.85, 34.46, 31.71, 31.34, 30.72, 29.21, 29.17, 29.12, 29, 06, 28.96, 28.91, 28.82, 28.77, 28.50, 25.30, 22.06, 20.67, 13.22. HRMS (ESI) calculated for C48H78F2NO11S [M + H] +: 914.5264, obtained: 914.5228.
    [0147] Synthesis of l-0- (6-azido-6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4 - difluorfenyl) undecanoyl) amino-D-ribo-1,3,4 - octadecantriol (C18)

    [0148] To the solution of C17 (1.63 g, 1.78 mmol) in DMF (15 mL) was added sodium azide (322 mg, 4.95 mmol). The reaction mixture was stirred at 100 ° C for 2 days. The mixture was concentrated and the residue was purified by column chromatography (dichloromethane / methanol = 20/1 to 15/1) to generate crude C18 (1.15 g, 1.47 mmol, 82%) as yellow solids, mp: 101 ° C. 1H-NMR (CD3OD / CDCI3 = 1/1, 400 MHz) δ 7.25-7.51 (m, 3H), 5.36 (d, J = 3.2 Hz, 1H), 4.57-4 , 67 (m, 1H), 4.12-4.42 (m, 6H), 3.94-4.06 (m, 3H), 3.74 (dd, J = 12.8, 4.8 Hz , 1H), 3.00 (t, 2H), 2.60-2.67 (m, 2H), 1.62-2.15 (m, 42H), 1.32 (t, J = 6.8 Hz, 3H). HRMS (ESI) calculated for C41H71F2N4O8 [M + H] +: 785.5240, obtained: 785, 5267.
    [0149] Synthesis of 1-O- (6-amino-6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorfenyl) undecanoyl) amino-D-ribo-1,3,4 - octadecantriol (C19)

    [0150] To the solution of C18 (1.11 g, 1.41 mmol) in THF / water (10/1, 33 mL) was added triphenylphosphine (0.74 g, 2.8 mmol). The reaction mixture was stirred at room temperature for 2 days. The mixture was concentrated and the residue was purified by column chromatography (1% triethylamine, dichloromethane / methanol = 6/1 to 4/1 to 2/1) to generate C19 (566 mg, 0.746 mmol, 53%) as white solids , mp: 161 ° C. 1H-NMR (CD3OD, 400 MHz) δ 6,957.09 (m, 2H), 6.86-6.88 (m, 1H), 4.82 (d, J = 3.2 Hz, 1H), 4, 13-4.19 (m, 1H), 3.83 (dd, J = 10.4, 4.4 Hz, 1H), 3.75 (d, J = 2.0, 1H), 3.63- 3.73 (m, 3H), 3.59 (dd, J = 10.8, 5.6 Hz, 1H), 3.44-3.54 (m, 2H), 2.87 (dd, J = 13.2.7.6 Hz, 1H), 2.72 (dd, J = 13.2.4.4 Hz, 1H), 2.51 (t, J = 7.6 Hz, 2H), 2, 14 (t, J = 1.5 Hz, 2H), 1.50-1.63 (m, 4H), 1.16-1.32 (m, 38H), 0.82 (t, J = 6, 8 Hz, 3H). 13C-NMR (CD3OD, 100 MHz) δ 176, 07, 151.5 (d, J = 246, 13 Hz), 150.8 (d, J = 243, 12 Hz), 141.74, 125.79, 118.16, 118.02, 101.43, 75.90, 73.12, 72.46, 72.02, 71.63, 70.33, 68.35, 52.18, 43.44, 37, 46, 36.20, 33.37, 33.26, 32.68, 31.06, 31.02, 30.96, 30.89, 30.81, 30.73, 30.67, 30.62, 30.39, 27.30, 27.21, 23.29. HRMS (ESI) calculated for C41H73F2N2O8 [M + H] +: 759, 5335, obtained: 759.5319.
    [0151] Synthesis of 10- (6- (4-nitrophenylacetamido) -6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorphenyl) undecanoyl) amino-D-ribo-1,3 .4-octadecantriol (C20)

    [0152] To the solution of C19 (34 mg, 0.045 mmol) in dichloromethane / methanol (1/1, 3 mL) was added 4-nitrophenylacetic acid (8.1 mg, 0.045 mmol), HBTU (34 mg, 0.090 mmol) and NMM (20 pL, 0.18 mmol). After stirring at room temperature for 16 h, the mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 30/1 to 20/1). The crude product was dissolved in dichloromethane / methanol (1/1, 3mL) and Si-carbonate silica gel (HOBT cleaner, 100 mg) was added to the solution. After stirring at room temperature for 1 h, the mixture was filtered and washed with dichloromethane / methanol (1/1). The filtrate was concentrated and dried in vacuo to generate C20 (13 mg, 0.014 mmol, 31%) as a light yellow wax. 1H-NMR (CDCI3 / CD3OD = 1/1, 200 MHz) δ 8.25 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 6, 90-7.21 (m, 3H), 4.94 (d, J = 3.2 Hz, 1H), 4.20-4.26 (m, 1H), 3.77-3.92 (m, 5H), 3.58-3.74 (m, 6H), 2.63 (t, J = 7.4 Hz, 2H), 2.28 (t, J = 7.6 Hz, 2H), 1, 30-1.81 (m, 42H), 0.98 (t, J = 6.8 Hz, 3H). 13C- NMR (CDCl3 / CD3OD = 1/1, 50 MHz) δ 173.93, 170.81, 149.17 (dd, J = 246, 13 Hz), 148.05 (dd, J = 244, 13 Hz ), 14 6, 4 3, 1 42, 53, 13 9, 35, 12 9, 58, 123, 5 9, 122.95, 116.28, 116.11, 98.99, 73.65, 71, 21, 69.35, 69.18, 68.41, 68.14, 66.16, 49.81, 41.69, 39.69, 36.34, 35.69, 34.36, 31.61, 31.25, 30.66, 29.04, 28.74, 28.41, 25, 27, 21.97, 13, 07. [α] 25 +39.3 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C49H78F2N3O11 [M + H] +: 922.5604, obtained: 922.5629.
    [0153] Synthesis of 1-0- (6- (2,4-dinitrophenylacetamido) -6- deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorophenyl) undecanoyl) amino-D-ribo - 1,3,4-octadecantriol (C21)

    [0154] By a similar process to the synthesis of C20, compound C19 (34 mg, 0.045 mmol) and 2,4-dinitrophenylacetic acid (10 mg, 0.045 mmol) were used as starting materials to generate C21 (4.0 mg with inseparable impurities, 0.0041 mmol, 9%). 1H-NMR (CDCI3 / CD3OD = 1/1, 600 MHz) δ 7,397.48 (m, 3H), 6.97-7.17 (m, 3H), 4.98 (d, J = 3.2 Hz , 1H), 4.24-4.31 (m, 1H), 3.593.93 (m, 10H), 2.65 (t, J = 7.4 Hz, 2H), 2.26-2.31 ( m, 2H), 1.14-1.87 (m, 42H), 0.901.02 (m, 3H). 13C-NMR (CDCI3 / CD3OD = 1/1, 150 MHz) δ 173.95, 169, 65, 148, 64, 147.80, 139.33, 134.76, 132.72, 129.90, 129, 13, 123.53, 123.15, 116.92, 116.57, 116.13, 110.69, 99.01, 73.64, 73.42, 71.16, 69.32, 69.08, 68.12, 66.07, 49.80, 39.45, 39.60, 38.18, 38.13, 36.30, 35.66, 34.33, 34.30, 33.63, 32, 01, 31.60, 31.43, 30.67, 30.58, 29.73, 29.23, 28.39, 28.35, 28.23, 26.30, 25.23, 25.17, 23.06, 22.25, 22.20, 21.78, 12, 98. [α] 25 +47.1 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C49H76F2N3O13H11 [M + H] +: 967.5455, obtained: 967.5485.
    [0155] 1-O- (6- (4-tert-butylphenylacetamido) -6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorfenyl) undecanoyl) amino-D-ribo-1 , 3,4- octadecantriol (C22)

    [0156] By a process similar to that of C20 synthesis, compound C19 (34 mg, 0.045 mmol) and 4-tert-butylphenylacetic acid (8.6 mg, 0.044 mmol) were used as starting materials to generate C22 (12 mg , 0.013 mmol, 29%). mp: 170 ° C. 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) δ 7, 47 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6, 98-7.22 (m, 3H), 4.97 (d, J = 3.2 Hz, 1H), 4.29-4.34 (m, 1H), 3.80-3, 95 (m, 5H), 3.76 (dd, J = 10.8, 4.4 Hz, 1H), 3,613.71 (m, 5H), 3.36 (dd, J = 7.8, 13.8 Hz, 1H ), 2.68 (t, J = 7.6 Hz, 2H), 2.33 (t, J = 7.6 Hz, 2H), 1.63-1.82 (m, 4H), 1.31 -1.53 (m, 47H), 1.00 (t, J = 6.5 Hz, 3H). 13C- NMR (CDCl3 / CD3OD = 1/1, 100 MHz) δ 173.91, 172.88, 149.40 (dd, J = 246, 12 Hz), 148.02 (dd, J = 243, 13 Hz ), 139.36, 131.28, 124.96, 123.57, 116.21, 116.05, 99.06, 73.79, 71.30, 69.35, 68.97, 68.40, 68.20, 66.42, 49.84, 41.82, 39.39, 35.72, 34.37, 33.66, 31.66, 31.25, 30.65, 30.38, 29, 14, 29,09, 29,05, 29,03, 28,97, 28,89, 28,83, 28,75, 28,71, 28,68, 28,42, 25,28, 25,24, 21, 96, 13.06. [α] 25 +36.4 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C53H88F2N2O9 [M + H] +: 933, 6380, obtained: 933.6435.
    [0157] Synthesis of 1-O- (6- (4-bromophenylacetamido) -6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorophenyl) undecanoyl) amino-D-ribo- 1 , 3,4-octadecantriol (C23)

    [0158] By a process similar to that of C20 synthesis, compound C19 (34 mg, 0.045 mmol) and 4-bromophenylacetic acid (9.7 mg, 0.044 mmol) were used as starting materials to generate C23 (15 mg, 0.016 mmol, 35%) as off-white solids, mp = 177 ° C. 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) δ 7.54 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6, 97-7.20 (m, 3H), 4.97 (d, J = 3.6 Hz, 1H), 4.28-4.33 (m, 1H), 3.78-3.92 (m, 5H), 3.59-3.74 (m, 6H), 3.37 (dd, J = 7.6, 13.6 Hz, 1H), 2.66 (t, J = 7.6 Hz, 2H ), 2.31 (t, J = 7.6 Hz, 2H), 1.30-1.81 (m, 42H), 0.98 (t, J = 6, 8 Hz, 3H). 13C- NMR (CDCI3 / CD3OD = 1/1, 100 MHz) δ 173.90, 171, 91, 149.53 (dd, J = 247, 13 Hz), 147.86 (dd, J = 245, 12 Hz ), 139.35, 133.70, 130.98, 130.29, 123.58, 120.22, 120.22, 116.18, 116.02, 99.03, 73.77, 71.26, 69.34, 69.08, 68.38, 68.15, 66.32, 49.81, 41.48, 39.51, 35.68, 34.35, 31.63, 31.23, 30, 62, 29.11, 29.08, 29.01, 28.95, 28.87, 28.81, 28, 73, 28, 68, 28, 66, 28, 40, 25.25, 25.22, 21, 94, 13, 03. [α] 25 +42.3 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C49H78BrF2N2O9 [M + H] +: 955.4859, obtained: 955.4920.
    [0159] Synthesis of 10- (6- (4-methoxyphenylacetamido) -6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorophenyl) undecanoyl) amino-D-ribo- 1,3 , 4-octadecantriol (C24)

    [0160] By a process similar to that of C20 synthesis, compound C19 (34 mg, 0.045 mmol) and 4-methoxyphenylacetic acid (7.5 mg, 0.045 mmol) were used as starting materials to generate C24 (15 mg, 0.017 mmol, 38%) as off-white solids, mp: 172 ° C. 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) 57.36 (d, J = 8 Hz, 2H), 7.12-7.26 (m, 2H), 7.01-7, 09 (m, 3H), 5.02 (d, J = 3.6 Hz, 1H), 4.32-4.38 (m, 1H), 3.97 (s, 3H), 3.72-3 , 96 (m, 5H), 3,693.78 (m, 4H), 3.65 (s, 2H), 3.40 (dd, J = 7.8, 14.0 Hz, 1H), 2.74 ( t, J = 7.6 Hz, 2H), 2.38 (t, 7 = 7.6 Hz, 2H), 1.38-1, 89 (m, 42H), 1.05 (t, J = 6 , 8 Hz, 3H). 13C- NMR (CDCI3 / CD3OD = 1/1, 100 MHz) δ 173.91, 173.06, 149.59 (dd, J = 247, 13 Hz), 148.08 (dd, J = 244, 13 Hz ), 158.27, 129.40, 129.66, 126.43, 123.61, 116.29, 116.12, 114.55, 113.62, 99.08, 73.92, 71.39, 61.41, 69.03, 68.41, 68.24, 66.43, 54.47, 49.78, 41.57, 39.46, 35.82, 34.46, 31.80, 31, 33, 30.71, 29.22, 29.17, 29.12, 29.11, 29.05, 28.96, 28.90, 28.82, 28.78, 28.75, 28.49, 25.34, 25.31, 22.04, 13.19. . [α] 25 +44.3 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C50H81F2N2O10 [M + H] +: 907.5859, obtained: 907.5890.
    [0161] Synthesis of 10- (6- (3,4-di (trifluoromethyl) phenyl-acetamido) -6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-ifluorophenyl) undecanoyl) amino -D-ribo-1,3,4- octadecantriol (C25)

    [0162] By a process similar to that of C20 synthesis, compound C19 (34 mg, 0.045 mmol) and 3,4-di (trifluroromethanyl) phenylacetic acid (12 mg, 0.045 mmol) were used as starting materials to generate C25 ( 11 mg, 0.011 mmol, 24%) as off-white solids, mp: 180 ° C 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) δ 7, 98 (s, 2H), 7.91 (s, 1H), 769-7.22 (m, 3H), 5.01 (d, J = 3.6 Hz, 1H), 4.28-4.33 (m, 1H), 3.84-3.99 (m, 5H), 3.83 (s, 2H), 3.78 (dd, J = 4.2, 10.8 Hz, 1H), 3.22-3.32 (m, 3H), 3, 42-3.51 (m, 1H), 2.69 (t, J = 7.6 Hz, 2H), 2.33 (t, J = 7.4 Hz, 2H), 1.3 9-1, 82 (m, 4 2H), 1.00 (t, J = 6, 8 Hz, 3H). (13C-NMR CDCl3 / CD3OD = 1/1, 100 MHz) δ 174.04, 170.56, 143.17, 139.37, 137.65, 131.13, 130.80, 129.10, 124, 18, 123.56, 121.47, 120.09, 116.22, 116.06, 114.50, 99.07, 73.77, 71.32, 69.40, 69.27, 68.42, 68.20, 66.30, 49.99, 41.14, 39.78, 35.75, 34.39, 31.73, 31.27, 30.66, 29.14, 29.09, 29, 04, 28.99, 28.88, 28.75, 28.71, 28, 69, 28.42, 25.29, 25.24, 21.98, 13, 08. [α] 25 + 40.1 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C51H77F8N2O9 [M + H] +: 1013.5501, obtained: 1013.5567.
    [0163] Synthesis of IO- (6- (3,4-difluorophenylacetamido) -6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorophenyl) undecanoyl) amino-D-ribo-1 , 3,4-octadecantriol (C26)

    [0164] By a similar process to that of C20 synthesis, compound C19 (34 mg, 0.045 mmol) and 3,4-difluorophenylacetic acid (7.7 mg, 0.045 mmol) were used as starting materials to generate C26 (17 mg , 0.019 mmol, 42%) as off-white solids, mp: 182 ° C 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) δ 6, 97-7.43 (m, 6H), 4.97 (d , J = 3.6 Hz, 1H), 4.28 (q, J = 4.4, 9.6 Hz, 1H), 3.83-4.01 (m, 4H), 3.80 (dd, J = 3.2, 10.0 Hz, 1H), 3.71 (dd, J = 4.4, 10.6 Hz, 1H), 3.60-3, 68 (m, 3H), 3.59 (s, 2H), 3.38 (dd, J = 8.0, 13.6 Hz, 1H), 2.66 (t, J = 7.6 Hz, 2H), 2.30 (t, J = 7.6 Hz, 2H), 1.32-1.81 (m, 42H), 0.97 (t, J = 6.8 Hz, 3H). 13C-NMR CDCI3 / CD3OD = 1/1, 100 MHz) δ 173.92, 171.63, 150.67, 150.03, 149.13, 148.25, 147.65, 146.72, 139.34 , 131.81, 124.72, 123.54, 117.52, 117.34, 116.97, 116.59, 116.42, 116.25, 116.08, 115.93, 99.02, 73 , 75, 71.23, 69.34, 69.15, 68.38, 68.14, 66.24, 49.82, 41.06, 39.57, 35.66, 34.33, 31.63 , 31.23, 30.61, 29.10, 29.07, 29.00, 28.94, 28.85, 28.79, 28.71, 28, 65, 28.38, 25.24, 25 , 20, 21.93, 13.01. [α] 25 +53.8 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C49H77F4N2O9 [M + H] +: 913.5565, obtained: 913.5606.
    [0165] Synthesis of IO- (6- (3-trifluoromethylphenyl-acetamido) - 6-deoxy-α-D-galactopyranosyl) -2- (ll- (3,4-difluorophenyl) undecanoyl) amino-D-ribo- 1 , 3,4- octadecantriol (C27)

    [0166] By a process similar to that of C20 synthesis, compound C19 (34 mg, 0.045 mmol) and 3-trifluoromethylphenylacetic acid (9.2 mg, 0.045 mmol) were used as starting materials to generate C27 (12 mg, 0.013 mmol, 29%) as off-white solids, mp: 157 ° C. 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) δ 6.96-7.82 (m, 7H), 4.96 (d, J = 3.6 Hz, 1H), 4.25-4 , 30 (m, 1H), 4.03-4.10 (m, 1H), 3.77-3.91 (m, 5H), 3.53-3.74 (m, 5H), 3.36 -3.44 (m, 1H), 2.65 (t, J = 7.6 Hz, 2H), 2.29 (t, J = 7.6 Hz, 2H), 1.27-1.76 ( m, 42H), 0.97 (t, J = 6.8 Hz, 3H). 13C-NMR (CDCI3 / CD3OD = 1/1, 100 MHz) δ 174.52, 172.19, 150.04 (dd, J = 247, 13 Hz), 148.52 (dd, J = 244, 13 Hz ), 139.90, 136.43, 132.64, 129.02, 127.67, 125.80, 124.17, 116.76, 116.60, 111.27, 99.64, 74.33, 71.87, 69.93, 69.73, 68.98, 68.76, 66.90, 60.57, 50.44, 42.27, 40.16, 36.25, 34.92, 32, 20, 31.82, 31.21, 29, 68, 29, 65, 29.59, 29.53, 29, 44, 29.38, 29.30, 29.24, 28, 97, 25.83, 25.80, 22.52, 13, 60. [α] 25 +47.4 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C50H78F5N209 [M + H] +: 945.5627, obtained: 945.5611.
    [0167] Synthesis of 1-O- (6- (4-methylphenylacetamido) -6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorophenyl) undecanoyl) amino-D-ribo- 1 , 3,4-octadecantriol (C28)

    [0168] By a process similar to that of C20 synthesis, compound C19 (34 mg, 0.045 mmol) and 4-methylphenylacetic acid (6.8 mg, 0.045 mmol) were used as starting materials to generate C28 (11 mg, 0.012 mmol, 27%) as off-white solids, mp: 171 ° C. 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) δ 7.28-44 (m, 4H), 7.12-7.26 (m, 2H), 7.03-7, 08 (m, 1H), 5.01 (d, J = 3.6 Hz, 1H), 4.32-4.41 (m, 1H), 3.83-3.95 (m, 5H), 3, 67-3 , 79 (m, 3H), 3.66 (s, 2H), 3.40 (dd, J = 7.6, 13.6 Hz, 1H), 2.73 (t, J = 7.6 Hz, 2H), 2.37 (t, J = 7.6 Hz, 2H), 1.32-1.87 (m, 42H), 1.05 (t, J = 6.8 Hz, 3H). 13C-NMR (CDCI3 / CD3OD = 1/1, 100 MHz) 5173.94, 172.96, 149.83 (dd, J = 247, 13 Hz), 148.02 (dd, J = 244, 13 Hz) , 139.42, 136.24, 131.26, 128.86, 128.47, 123.42, 116.31, 116.15, 99.10, 73.89, 71.43, 69.40, 68 , 98, 68.41, 68.25, 66.49, 49.82, 42.07, 39.42, 35.83, 34.47, 31.78, 31.34, 30.73, 29.23 , 29,19, 29,12, 29,06, 28,97, 28,92, 28,84, 28,80, 28,77, 28,51, 25,35, 25,32, 22,06, 20 , 10, 13.22. [α] 25 +31.8 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C50H81F2N2O9 [M + H] +: 891.5910, obtained: 891.5988.
    [0169] Synthesis of 1-O- (6- (3-methylphenylacetamido) -6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorophenyl) undecanoyl) amino-D-ribo- 1 , 3,4-octadecantriol (C29)

    [0170] By a process similar to that of C20 synthesis, compound C19 (34 mg, 0.045 mmol) and 3-methylphenylacetic acid (6.8 mg, 0.045 mmol) were used as starting materials to generate C29 (14 mg, 0.016 mmol, 35%) as off-white solids, mp: 167 ° C. 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) 57.18-7.51 (m, 7H), 5.08 (d, J = 4.0 Hz, 1H), 4.36-4, 43 (m, 1H), 3.91 - 4.02 (m, 5H), 3, 23-3.35 (m, 4H), 3.73 (s, 2H), 3.47 (dd, J = 7.8, 13.8 Hz, 1H), 2.79 (t, J = 7.8 Hz, 2H), 2.57 (s, 3H), 2.43 (t, J = 7.6 Hz, 2H), 1.46-1.94 (m, 42H), 1.11 (t, J = 6.8 Hz, 3H). 13C-NMR (CDCI3 / CD3OD = 1/1, 100 MHz) δ 173.96, 172.85, 149.52 (dd, J = 245, 13 Hz), 148.13 (dd, J = 243, 13 Hz ), 139.43, 137.90, 134.27, 129.41, 128.13, 127.37, 125.61, 123.67, 116.35, 116.19, 99.15, 73.99, 71.49, 69.44, 69.00, 68.41, 68.30, 66.53, 49.88, 42.50, 39.46, 35.89, 34.52, 31.91, 31, 39, 30.76, 29.28, 29.23, 29.11, 29.01, 28.96, 28.88, 28.84, 28.81, 28.55, 25.38, 25.36, 22.11, 13.29. [α] 25 +36.8 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C50H81F2N2O9 [M + H] +: 891.5910, obtained: 891.5950.
    [0171] Synthesis of 1-O- (6- (2-methylphenylacetamido) -6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorophenyl) undecanoyl) amino-D-ribo- 1 , 3,4-octadecantriol (C30)

    [0172] By a process similar to that of C20 synthesis, compound C19 (34 mg, 0.045 mmol) and 2-methylphenylacetic acid (6.8 mg, 0.045 mmol) were used as starting materials to generate C30 (16 mg, 0.018 mmol, 40%) as off-white solids, mp: 182 ° C. 1H-NMR (CDCI3 / CD3OD = 1/1, 400 MHz) δ 7.31-7.37 (m, 4H), 7.01-7.26 (m, 3H), 4.99 (d, J = 3.6 Hz, 1H), 4.30-4.35 (m, 1H), 3.83-3, 94 (m, 5H), 3.68-3.75 (m, 6H), 3.40 (dd, J = 8.0, 13.8 Hz, 1H), 2.72 (t, J = 7.8 Hz, 2H), 2.45 (s, 3H), 2.36 (t, J = 7.6 Hz, 2H), 1.32-1.87 (m, 42H), 1.04 (t, J = 6.8 Hz, 3H). 13C-NMR (CDCI3 / CD3OD = 1/1, 100 MHz) δ 173.86, 172.42, 149.48 (dd, J = 246, 13 Hz), 147.94 (dd, J = 243, 13 Hz ), 139.41, 136.38, 132.67, 129.91, 129.65, 126.99, 125.79, 123.63, 116.28, 116.11, 99.15, 73.91, 71.38, 69.38, 69.11, 68.35, 68.20, 66.56, 49.74, 40.27, 39.49, 35.80, 34.45, 31.78, 31, 32, 30.70, 29.21, 29.16, 29.10, 29.04, 28.95, 28.90, 28.81, 28.77, 28.74, 28, 48, 25.33, 25.29, 22.03, 18, 65, 13.17. [α] 25 +38.3 (c 1.0, CH2Cl2 / CH3OH: 1/1). HRMS (ESI) calculated for C50H81F2N2O9 [M + H] +: 891.5910, obtained: 891.5987.
    [0173] Synthesis of 1-O- (6- (2-naphthylacetamido) -6-deoxy-α-D-galactopyranosyl) -2- (11- (3,4-difluorophenyl) undecanoyl) amino-D-ribo-1 , 3,4- octadecantriol (C31)

    [0174] By a process similar to that of C20 synthesis, compound C19 (34 mg, 0.045 mmol) and 2-naphthylacetic acid (8.4 mg, 0.045 mmol) were used as starting materials to generate C31 (12 mg, 0.013 mmol, 29%) as a white solid, mp: 178 ° C. 1H-NMR (CDCI3 / CD3OD = 1/1, 40 MHz) δ 7, 85-8, 04 (m, 3H), 7.40-7.69 (m, 4H), 7.05-7, 29 (m, 3H), 5.03 (d, J = 3.6 Hz, 1H), 4.31 - 4.40 (m, 1H), 3.87-4.01 (m, 6H), 3 , 72-3.81 (m, 4H), 3.46 (dd, J = 7.8, 14.0 Hz, 1H), 2.76 (t, J = 7.6 Hz, 2H), 2, 38 (t, J = 8.0 Hz, 2H), 1.32-1.90 (m, 42H), 1.08 (t, J = 6, 6 Hz, 3H). 13C-NMR (CDCI3 / CD3OD = 1/1, 150 MHz) δ 173, 92, 172.58, 149.54 (dd, J = 244, 12 Hz), 147, 93 (dd, J = 240, 13 Hz ), 142.73, 139.39, 133.06, 131.96, 127.78, 127.34, 127.01, 126.97, 126.48, 125.61, 125.20, 123.60, 123, 30, 12 3, 14, 1 17, 04, 1 1 6, 2 4, 1 1 6, 0 9, 110.83, 99.07, 73.85, 71.38, 69.38, 69, 05, 68.42, 68.21, 66.45, 49.81, 42.35, 39.52, 35.75, 34.41, 31.74, 31.29, 30.67, 29.72, 29.18, 29.13, 29.07, 29.01, 28.92, 28.68, 28.78, 28.72, 28.45, 25.30, 25.28, 22.00, 13, 12. [α] 25 +8.3 (c 1.0, CH2Cl2 / CH3OH: 1/1).
    [0175] Synthesis of compounds of formula (1)
    [0176] A number of glycosphingolipids have been synthesized and tested for activation of NKT cells. The structures of the compounds are according to formula 1.
    where compound No. (R) is selected from table 1 to provide the corresponding compounds. TABLE 1
    Example 2
    [0177] Activation of antigen presenting cells (APC - Antigen Presenting Cell)
    [0178] A20CD1d cells and mNK1.2 cells were used as APC and effector cells, respectively. The Guava ViaCount reagent was used to determine the viability and viable number of cells with Guava EasiCite Plus. The Mouse IL-2 DuoSet ELISA Development System was used to detect IL-2 production. Cells and glycolipids were co-cultured at 37 ° C and the supernatant was collected 24 h after culture. And, two days after culture, the cells were harvested to determine viability and the results showed that these glycosphingolipids are non-toxic. as shown in figure 6, in this connection, all test compounds exhibited APC activation activities. Cytokine secretions IFN-y and Il-4
    [0179] Female C57BL / 6 mouse (16s4d) was sacrificed and the spleen was harvested for the trial. Cells and glycolipids were co-cultured at 37 ° C for 3 days and the supernatant was collected on the third day (~ 6 h) after culture. Then, Blue alarm (5% / 200pl) was added and the cells were cultured for 7h to determine cell proliferation. Mouse IL-4 and IFN-i Duo Set ELISA Development System were used to detect cytokine production. In this assay, DMSO was a negative control and KRN-7000 was a positive control. as shown in figures 7-9, the compounds showed a secretion profile of cytokines prone to Thl, indicating their applicability to antitumor, antiviral / antibacterial and adjuvant activities.
    [0180] All publications and patent applications cited in this specification are incorporated herein by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
    [0181] Although the above invention has been described in detail by way of illustrations and examples for the purposes of clarity and understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications can be made without distancing itself from the spirit and scope of the attached claims.
    权利要求:
    Claims (15)
    [0001]
    1. METHOD OF PREPARING A COMPOUND OF FORMULA (5)
    [0002]
    2. METHOD, according to claim 1, characterized by the fact that it still comprises the step of: b) reducing the compound of formula (5) to obtain a compound of formula (3):
    [0003]
    3. METHOD, according to claim 2, characterized by the fact that it still comprises the step of: c) coupling the compound of formula (3) with the compound of formula (4):
    [0004]
    4. METHOD, according to claim 3, characterized by the fact that it still comprises the step of: d) deprotection of a compound of formula (2), with hydrogen under hydrogenation catalysis, to generate the compound of formula (1):
    [0005]
    5. METHOD, according to claim 4, characterized by the fact that the hydrogenation catalyst of step (d) is selected from Pd / C, Pd (OH2), or Raney-Ni.
    [0006]
    6. METHOD, according to claim 2, characterized in that the reduction of step (b) is obtained using aluminum and lithium hydride, sodium borohydride, a borane complex, enzymatic reduction, hydrogenation, or transfer hydrogenation.
    [0007]
    7. METHOD, according to claim 1, characterized by the fact that Lewis acid is selected from TMSOTf, Tf2O, BF3O ^ Et2, TfOH and Me2S2-Tf2O.
    [0008]
    8. METHOD, according to claim 1, characterized by the fact that the leaving group containing thiol is tiotoluene (- STol).
    [0009]
    9. METHOD according to any one of claims 1 to 8, characterized in that the compound of formula (6) is:
    [0010]
    10. METHOD according to any one of claims 1 to 9, characterized in that the compound of formula (7) is: N3 OBn
    [0011]
    11. METHOD according to any one of claims 1 to 10, characterized in that the compound of formula (5) is:
    [0012]
    12. METHOD according to any one of claims 2 to 11, characterized in that the compound of formula (3) is:
    [0013]
    13. METHOD according to any one of claims 3 to 12, characterized in that the compound of formula (4) is:
    [0014]
    14. METHOD according to any one of claims 3 to 13, characterized in that the compound of formula (2) is:
    [0015]
    15. METHOD, according to claim 4, characterized in that the compound of formula (1) is 1-O- (α-D-galactopyranosyl) -2- (11- (4- (4-fluorophenoxy) phenyl) undecanoyl) amino-D-ribooctadean-1,3,4-triol (C34), of the formula: or a salt of the same.
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    法律状态:
    2016-10-11| B15I| Others concerning applications: loss of priority|Free format text: PERDA DA PRIORIDADE US 61/430,117 DE 05/01/2011 REIVINDICADA NO PCT/US2012/020388, CONFORME AS DISPOSICOES PREVISTAS NA LEI 9.279 DE 14/05/1996 (LPI) ART. 167O, ITEM 28 DO ATO NORMATIVO 128/97 E NO ART. 29 DA RESOLUCAO INPI-PR 77/2013. ESTA PERDA SE DEU PELO FATO DE O DEPOSITANTE CONSTANTE DA PETICAO DE REQUERIMENTO DO PEDIDO PCT ("NATIONAL TAIWAN UNIVERSITY") SER DISTINTO DAQUELE QUE DEPOSITOU A PRIORIDADE REIVINDICADA E NAO FOI APRESENTADO DOCUMENTO COMPROBATORIO DE CESSAO, CONFORME AS DISPOSICOES PREVISTAS NA LEI 9.279 DE 14/05/1996 (LPI) ART. 166O, ITEM 27 DO ATO NORMATIVO 128/97 E NO ART. 28 DA RESOLUCAO INPI-PR 77/2013. |
    2017-01-10| B12F| Appeal: other appeals|
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-07-03| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2020-04-28| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-05-19| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
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    2021-03-16| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/01/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201161430117P| true| 2011-01-05|2011-01-05|
    US61/430,117|2011-01-05|
    PCT/US2012/020388|WO2012094540A2|2011-01-05|2012-01-05|Methods for preparation of glycosphingolipids and uses thereof|
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