Phosphoglycolipids and their derivatives

Abstract

Described herein are phosphoglycolipids having a saccharide moiety attached at the 3-position of a phospholipid chain ("3-hydroxy phosphoglycolipids") and derivatives thereof. Also provided are methods for the synthesis of 3-hydroxy phosphoglycolipids and their derivatives.

Description

PHOSPHOGLYCOLIPIDS AND THEIR DERIVATIVESRELATED APPLICATION(S)

[0001] This application claims priority to U.S. Provisional Application No. 63 / 717,516, filed November 7, 2024, which is hereby incorporated by reference in its entirety.STATEMENT OF GOVERNMENT INTEREST

[0002] This invention was made with government support under DE-SC0022403 awarded by the Department of Energy (DOE). The government has certain rights in the invention.TECHNICAL FIELD

[0003] The present disclosure relates to phosphoglycolipids having a saccharide moiety attached at the 3-position of a phospholipid chain (i.e., “3-hydroxy phosphoglycolipids”) and derivatives thereof. Further disclosed are synthetic methods for preparing phosphoglycolipids and derivatives thereof.INTRODUCTION

[0004] Historically, glycolipid syntheses and research efforts have centered around glycolipids with carboxylic acid head groups. To date, there have been no reports of any 3-saccharide phosphoglycolipids, as illustrated below,SUMMARY

[0005] In one aspect, the present disclosure provides phosphoglycolipids and derivatives thereof. The phosphoglycolipids and derivatives thereof may be compounds of formula (I), or salts thereof,wherein:A is a monosaccharide, a disaccharide, a trisaccharide, or an amine or thiol derivative thereof;R1is Ci-isalkyl, C2-isalkenyl, Cz-isalkynyl or hydrogen;RZ, at each occurrence, is -ORX, Rx, -SRX, or -N(RX)2;Rx, at each occurrence, is hydrogen, PG, Ci-ealkyl, Ci-ehaloalkyl, Gla, -Ci-ealkylene-Gla,PG is a hydroxyl protecting group, a thiol protecting group, or an amine protecting group; RY, at each occurrence, is -OCi-4alkyl, -OCi-4haloalkyl, -OH, cyano, -SH, -SCi-4alkyl, -SCi-4haloalkyl, -SGla, -NH2, -NHCi-4alkyl, NHGla, -N(Ci-4alkyl)2, -N(Gla)2, -C(O)OGla, -C(O)OCi-4alkyl, -C(0)NH2, -C(O)NHCi-4alkyl, -C(O)N(Ci-4alkyl)2, -C(O)NHGla, -C(O)N(Gla)2, -SO2Ci-4alkyl, -SO2Gla, -SO2NH2, -SO2NHCi.4alkyl, or -SO2N(Ci-4alkyl)2;R2, at each occurrence, is C1-18alkyl, C2-18alkenyl, C2-18alkynyl or hydrogen;RZ”, at each occurrence, is -ORX, Rx, -SRX, or-N(Rx)2;Rx”, at each occurrence, is hydrogen, PG’, Ci salkyl, Ci-ehaloalkyl, Gla, -Ci ealkylene-G1a”, or-Ci-ealkylene-RY;PG’ is a hydroxyl protecting group, a thiol protecting group, or an amine protecting group; RY, at each occurrence, is -OCi-4alkyl, -OCi-4haloalkyl, -OH, cyano, -SH, -SCi-4alkyl, -SCi-4haloalkyl, -SGla”, -NH2, -NHCi-4alkyl, -NHGla”, -N(Ci-4alkyl)2, -N(Gla”)2, -C(O)OGla”, -C(O)OCi-4alkyl, -C(0)NH2, -C(O)NHCi-4alkyl, -C(O)N(Ci-4alkyl)2, -C(O)NHGla”, C(O)N(Gla”)2, -SO2Ci-4alkyl, -SO2Gla”, -SO2NH2, -SO2NHCi-4alkyl, or-SO2N(Ci-4alkyl)2; andGlaand Gla, at each occurrence, are independently a Ca-scycloalkyl, a 4- to 12-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, wherein Glaand Glaare independently optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, oxo, Ci-4alkyl, Ci-4haloalkyl, -OCi-4alkyl, -OCi-4haloalkyl, -OH, -SCi-4alkyl, -SCi-4haloalkyl, -SH, -NO2, -NH2, -NHCi-4alkyl, -N(Ci-4alkyl)2, cyano, -C(O)OCi-4alkyl, -C(O)NH2, -C(O)NHCi-4alkyl, -C(O)N(Ci-4alkyl)2, -SO2Ci-4alkyl, -SO2NH2, -SO2NHCi-4alkyl, and -SO2N(Ci-4alkyl)2.

[0006] Also disclosed are methods of preparing the phosphoglycolipids and derivatives thereof, the methods comprising:i. preparing an intermediate of formula (I-1B), where X1is O, S, or NH:ii. reacting the intermediate of formula (I- IB) with an intermediate of formula (1-1 C):RZ(I-1C)in the presence of a base to provide an intermediate of formula (I-1D):HX1RZ(LID);iii. in the presence of a glycosylation promoter, reacting the intermediate of formula (I- 1D) with a compound of formula (I-S):wherein:X2is O and PG” is a hydroxyl protecting group; or alternatively,X2is S and PG” is a thiol protecting group;Ralis -CH3, hydrogen, or -CH2X2PG”; andRa4is PG”, a monosaccharide moiety, or a disaccharide moiety,to provide an intermediate of formula (1-1 E):IV. removing the PG” groups from the intermediate of formula (I-1E) to provide a compound of formula (I-F):

[0007] Also disclosed are methods of preparing the phosphoglycolipids and derivatives thereof, the methods comprising:i. preparing an intermediate of formula (I- II):wherein X3is Cl, Br, or I;in the presence of a glycosylation promoter, reacting the intermediate of formula (I- II) with a compound of formula (I-Sl-i):to provide an intermediate of formula (I- 1 J):wherein:X2is O and PG” is a hydroxyl protecting group; or alternatively,X2is S and PG” is a thiol protecting group;R"1is -CH3, hydrogen, or -CH2X2PG”; andR"4is PG”, a monosaccharide moiety, or a disaccharide moiety,iii. at a temperature of 120-200 °C, reacting the intermediate of formula (1-1 J) with a phosphite of formula (I-1K):(RZ)2P-ORX(I-1K),to provide an intermediate of formula (I- IE):iv. removing the PG” groups from the intermediate of formula (LIE) to provide a compound of formula (LF):

[0008] Other aspects and embodiments of the disclosure will become apparent in light of the following description.DETAILED DESCRIPTION

[0009] Before any embodiments of the disclosure are explained in detail, it is to be understood that the disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The disclosure is capable of other embodiments and of being practiced or of being carried out in various way.T. Definitions

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0011] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0012] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0013] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., NewYork, 1989; Carruthers, Some Modern Methods of Organic Synthesis 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0014] The term “alkoxy,” as used herein, refers to a group -O-alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tertbutoxy.

[0015] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “Ci-6alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “Ci-4alkyl” means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, zz-propyl, z.w-propyl, zz-butyl, sec-butyl, zso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, zz-hexyl, 3 -methyl hexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, zz-octyl, zz-nonyl, and zz-decyl.

[0016] The term “alkenyl,” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond.

[0017] The term “alkynyl,” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon triple bond.

[0018] The term “amide,” as used herein, means -C(O)NR- or -NRC(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0019] The term “amino,” as used herein, means -NRxRy, wherein Rx and Rymay be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any other moiety where amino appends together two other moieties, amino may be -NRX- wherein Rxmay be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0020] The term “aryl,” as used herein, refers to a phenyl or a phenyl appended to the parent molecular moiety and fused to a cycloalkane group (e.g., the aryl may be indan-4-yl), fused to a 6-membered arene group (i.e., the aryl is naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl may be benzo[d][l,3]dioxol-5-yl). The term “phenyl” is used when referring to a substituent and the term 6-membered arene is used when referring to a fused ring. The 6-membered arene is monocyclic (e.g., benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system).

[0021] The term “cycloalkoxy,” as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0022] The term “cycloalkyl” or “cycloalkane,” as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term “cycloalkyl” is used herein to refer to a cycloalkane when present as a substituent. A cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), or a bridged cycloalkyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptanyl). Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[l.l.l]pentanyl.

[0023] The term “cycloalkenyl” or “cycloalkene,” as used herein, means a non-aromatic monocyclic or multicyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. The term “cycloalkenyl” is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthal enyl), or a bridged cycloalkenyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohex enyl or cycloheptenyl.

[0024] The term “carbocyclyl” means a “cycloalkyl” or a “cycloalkenyl.” The term “carbocycle” means a “cycloalkane” or a “cycloalkene.” The term “carbocyclyl” refers to a “carbocycle” when present as a substituent.

[0025] The terms cycloalkylene and heterocyclylene refer to divalent groups derived from the base ring, i.e., cycloalkane, heterocycle. For purposes of illustration, examples of cycloalkylene X.and heterocyclylene include, respectively,and Cycloalkylene andheterocyclylene include a geminal divalent groups such as l,l-C3-ecycloalkylene (i.e.,A further example is 1,1 -cyclopropylene (i.e.,

[0026] The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F.

[0027] The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.

[0028] The term “haloalkoxy,” as used herein, means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.

[0029] The term “halocycloalkyl,” as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms are replaced by a halogen.

[0030] The term “heteroalkyl,” as used herein, means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced by a heteroatom selected from S, O, P and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.

[0031] The term “heteroaryl,” as used herein, refers to an aromatic monocyclic heteroatomcontaining ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). The term “heteroaryl” is used herein to refer to a heteroarene when present as a substituent. The monocyclic heteroaryl are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). The five membered aromatic monocyclic rings have two double bonds, and the six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl is an 8- to 12-membered ring system and includes a fused bicyclic heteroaromatic ring system (i.e., 10ZI electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-l-yl), a monocyclic heteroaryl ring fused to a monocyclic heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic heteroarene (e.g., quinolin-5-yl, indol-4-yl). A bicyclic heteroaryl / heteroarene group includes a 9-membered fused bicyclic heteroaromatic ring system having four double bonds and at least one heteroatom contributing a lone electron pair to a fully aromatic 10D electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or a benzoxadiazolyl. A bicyclic heteroaryl also includes a fused bicyclic ringsystem composed of one heteroaromatic ring and one non-aromatic ring such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom. Other representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-l-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[l,2-a]pyridinyl (e.g., imidazo[l,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-d]pyrimidin-2-yl.

[0032] The term “heterocycle” or “heterocyclic,” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The term “heterocyclyl” is used herein to refer to a heterocycle when present as a substituent. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1, 3 -di thiol any 1, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydrothienyl, thiadi azol inyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. The bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-l-yl). Representative examples of bicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothien-2-yl, l,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3 -dihydro- IH-indol-l-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-l-yl, and 3-oxabicyclo[3.1.0]hexan-6-yl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2, 5 -epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro- 1H- 1,4-methanocyclopenta[c]furan, azaadamantane (l-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocyclyls are connected to the parent molecular moiety at a non-aromatic ring atom.

[0033] The term “hydroxyl” or “hydroxy,” as used herein, means an -OH group.

[0034] The term “hydroxyalkyl,” as used herein, means at least one -OH group, is appended to the parent molecular moiety through an alkylene group, as defined herein.

[0035] The term “nitrile,” as used herein, means any organic compound that has a -C=N functional group.

[0036] Terms such as “alkyl,” “cycloalkyl,” “alkylene,” etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., “Ci-4alkyl,” “C3-ecycloalkyl,” “Ci-4alkylene”). These designations are used as generally understood by those skilled in the art. For example, the representation “C” followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, “Caalkyl” is an alkyl group with three carbon atoms (i.e., 7?-propyl, isopropyl). Where a range is given, as in “C1-4,” the members of the group that follows may have any number of carbon atoms falling within the recited range. A “Ci-4alkyl,” for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0037] The term “substituted” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =0 (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkyl sulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0038] The terms “saccharide,” “sugar,” and “carbohydrate” are used interchangeably herein and generally refer to a mono-, di-, and / or trisaccharide or mixtures thereof.

[0039] The term “monosaccharide” refers to any type of hexose of the formula C6H12O6or a derivative thereof. The ring structure (i.e., ring type) of the monosaccharide can be a pyranose or a furanose. In addition, the monosaccharides can be an a- or P-anomer. Monosaccharide can be a ketonic monosaccharide (i.e., ketose), an aldehyde monosaccharide (i.e., aldose), or any type of hexose of the formula H12O6or a derivative thereof. Non-limiting examples of monosaccharides of the invention include, but are not limited to, allose, altrose, arabinose, fructose, fucose, galactose, glucose, mannose, gulose, idose, lyxose, psicose, rhamnose, ribose, ribulose, sorbose, tagatose, talose, xylose, and xylulose. A monosaccharide may also be an amine or thiol derivative of any monosaccharide. Each monosaccharide may also be independently an (L)-isomer or a (D)-isomer.

[0040] The term “di saccharide” refers to a carbohydrate composed of two monosaccharides. It is formed when two monosaccharides are covalently linked to form a dimer. The linkage can be a (1—4) bond, a (1—6) bond, a (1—2) bond, a (1—3) bond, etc. between the two monosaccharides. In addition, each of the monosaccharides can be independently an a- or P-anomer. Non-limiting examples of disaccharides include, but are not limited to, cellobiose, chitobiose, dirhamnose, gentiobiose, isomaltose, isomaltulose, lactose, lactulose, laminaribose, leucrose, maltose, maltulose, melibiose, nigerose, sophorose, sucrose, trehalose, turanose, and xylobiose. A disaccharide may also be an amine or thiol derivative of any monosaccharide units that are linked to make a disaccharide. Each of the monosaccharides can independently be a ketonic monosaccharide (i.e., ketose), an aldehyde monosaccharide (i.e., aldose), or any type of hexose of the formula C6H12O6or a derivative thereof. Each monosaccharide in a disaccharide may also be independently an (L)-isomer or a (D)-isomer.

[0041] The term "trisaccharide" refers to a carbohydrate composed of three monosaccharides. It is formed when three monosaccharides are covalently linked to form a trimer. Each of the linkage between monosaccharides can be independently a (1—4) bond, a (1—6) bond, a (1—2) bond, a (1—3) bond, etc. In addition, each of the monosaccharides can be independently an a- or P-anomer. Non-limiting examples of tri saccharides include, but are not limited to, cellotriose, isomaltotriose, isopanose, laminaritriose, manninotriose, maltotriose, melezitose, nige-rotriose, panose, raffinose, and xylotriose. A trisaccharide may also be an amine or thiol derivative of any monosaccharide that are linked to make a trisaccharide. Each of the monosaccharides can independently be a ketonic monosaccharide (i.e., ketose), an aldehyde monosaccharide (i.e., aldose), or any type of hexose of the formula C6H12O6or a derivative thereof. Each monosaccharide within a trisaccharide can also be independently an (L)-isomer or a (D)-isomer.

[0042] The term “saccharide derivative,” “sugar derivative,” or “carbohydrate derivative” refers to any chemical modification of the carbohydrate / sugar. Carbohydrate derivatives includes alkylated carbohydrate, replacement of one or more hydroxyl groups with hydrogen, halide, amine, or a thiol; modification of a hydroxyl group (e g., by esterification, etherification, protection, etc.); as well as other derivatives known to one skilled in the art. The term carbohydrate includes pyranose and furanose carbohydrates. Non-limiting examples of carbohydrate derivatives carbohydrates include, but are not limited to, alkylated carbohydrate (e.g., one or more hydroxyl groups that are methylated, ethylated, acetylated, or benzoylated), thiol carbohydrate (where oneor more hydroxyl groups are replaced with -SH moiety), and deoxy carbohydrates (where one or more -OH groups of the carbohydrate is replaced with -H).

[0043] The term “a thiol derivative” of a sugar refers to a sugar moiety in which the hydroxyl group that links the sugar to the lipid moiety is replaced with a sulfur atom. Similarly, the term “an amine or amino derivative” of a sugar refers to a sugar moiety in which the hydroxyl group that links the sugar moiety to the lipid moiety is replaced with a nitrogen atom.

[0044] The term “phosphoglycolipid,” as used herein, refers to a phospholipid covalently attached to a saccharide by a glycosidic bond.

[0045] The term “phospholipid,” as used herein, refers to a lipid containing a phosphate group in its molecule.Abbreviations:Bn is benzyl;Ac is acetyl or acyl;Me is methyl;Pd / C is palladium on carbon;PG is protecting group;n-BuLi is n-butyllithiumEtOAc is ethyl acetate;Et2O is diethyl ether;DCM is dichloromethane;DBU is 1,8-diazabicyclo(5.4.0)undec-7-ene;NaOMe is sodium methoxide;BF3-Et2O is boron trifluoride diethyl ether;Pd / C is palladium on carbon;THF is tetrahydrofuran;NMR is nuclear magnetic resonance;LRMS is low resolution mass spectrometry;ESI is electron spray ionization;TLC is thin-layer chromatography;4 A MS is 4 angstrom molecular sieves;eq. or equiv. is equivalents;min or min. is minute(s); andh or hr. is hour(s).II. Phosphoglycolipids and Derivatives Thereof

[0046] In one aspect, disclosed herein are phosphoglycolipids and derivatives thereof. In various instances, the phosphoglycolipids or derivatives thereof may be compounds of formula (I),wherein A and B are as defined herein.A. Compounds of Formula (I)

[0047] In the following, numbered embodiments of the compounds of formula (I) and pharmaceutically acceptable salts thereof, are disclosed. The first embodiment is denoted El, and subsequent embodiments are denoted El, El.l, El.2, E2, E2.1, E2.2, E2.3, E3, E4, E4.1, etc.

[0048] El. A compound of formula (I), or a salt thereof,wherein:A is a monosaccharide, a disaccharide, a trisaccharide, or an amine or thiol derivative thereof;R1is C1-18alkyl, C2-18alkenyl, C2-18alkynyl, or hydrogen;RZ, at each occurrence, is -ORX, Rx, -SRX, or -N(RX)2;RX, at each occurrence, is hydrogen, PG, C1-6alkyl, C1-6haloalkyl, G1a, –C1-6alkylene–G1a,PG is a hydroxyl protecting group, a thiol protecting group, or an amine protecting group; RY, at each occurrence, is -OCi-4alkyl, -OCi-4haloalkyl, -OH, cyano, -SH, -SCi-4alkyl, -SCi-4haloalkyl, -SGla, -NH2, –NHC1-4alkyl, –NHG1a, –N(C1-4alkyl)2, –N(G1a)2, –C(O)OG1a, –C(O)OC1-4alkyl, –C(O)NH2, –C(O)NHC1-4alkyl, –C(O)N(C1-4alkyl)2, –C(O)NHG1a,-C(O)N(Gla)2, -SO2Ci-4alkyl, -SO2Gla, -SO2NH2, -SO2NHCi-4alkyl, or -SO2N(Ci-4alkyl)2; R2, at each occurrence, is C1-18alkyl, C2-18alkenyl, C2-18alkynyl or hydrogen;RZ”, at each occurrence, is -ORX, Rx, -SRX, or-N(Rx)2;Rx”, at each occurrence, is hydrogen, PG’, Ci salkyl, Ci ehaloalkyl, Gla, -Ci ealkylene-Gla”, or-Ci-ealkylene-RY;PG’ is a hydroxyl protecting group, a thiol protecting group, or an amine protecting group; RY”, at each occurrence, is -OCi-4alkyl, -OCi-4haloalkyl, -OH, cyano, -SH, -SCi-4alkyl, -SCi-4haloalkyl, -SGla”, –NH2, -NHCi-4alkyl, -NHGla”, -N(Ci-4alkyl)2, -N(Gla”)2, -C(O)OGla”, -C(O)OCi-4alkyl, -C(O)NH2, -C(O)NHCi-4alkyl, -C(O)N(Ci-4alkyl)2, -C(O)NHGla”, C(O)N(Gla”)2, -SO2Ci-4alkyl, -SO2Gla”, -SO2NH2, -SO2NHCi-4alkyl, or-SO2N(Ci-4alkyl)2; and Glaand Gla”, at each occurrence, are independently a C3-8cycloalkyl, a 4- to 12-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, wherein Glaand Glaare independently optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, oxo, Ci-4alkyl, Ci-4haloalkyl, -OCi-4alkyl, -OCi-4haloalkyl, -OH, -SCi-4alkyl, -SCi-4haloalkyl, -SH, -NO2, -NH2, -NHCi-4alkyl, -N(Ci-4alkyl)2, cyano, -C(O)OCi-4alkyl, -C(O)NH2, -C(O)NHCi-4alkyl, -C(O)N(Ci-4alkyl)2, -SO2Ci-4alkyl, -SO2NH2, -SO2NHCi-4alkyl, and -SO2N(Ci-4alkyl)2.

[0049] E1.1. The compound of E1, or the salt thereof, wherein R1is C1-18alkyl, C2-18alkenyl, or hydrogen.

[0050] El. 2. The compound of El or El.l, or the salt thereof, wherein R2is C1-18alkyl, C2-18alkenyl, or hydrogen.

[0051] E2. The compound of any one of El -El.2, or the salt thereof, wherein the saccharide is a monosaccharide.

[0052] E2.1. The compound of E2, or the salt thereof, wherein the monosaccharide is a deoxy hexose, a deoxy hexulose, a deoxy pentose, a deoxy pentulose, or a derivative thereof.

[0053] E2.2. The compound of E2, or the salt thereof, wherein the monosaccharide is a hexose, a deoxy hexose, a hexulose, a uronic acid hexose, or a derivative thereof.

[0054] E2.3. The compound of E2, or the salt thereof, wherein the monosaccharide is a pentose, a deoxy pentose, a pentulose, a uronic acid pentose, or a derivative thereof.

[0055] E3. The compound of any one of E2-E2.3, or the salt thereof, wherein the monosaccharide is allose, altrose, arabinose, fructose, fucose, galactose, glucose, mannose, gulose,idose, lyxose, psicose, rhamnose, ribose, 2-deoxy-ribose, ribulose, sorbose, tagatose, talose, xylose, xylulose, or an amine or thiol derivative thereof.

[0056] E4. The compound of El, or the salt thereof, wherein the saccharide is a disaccharide.

[0057] E4.1. The compound of E4, or the salt thereof, wherein the disaccharide comprises two monosaccharides, wherein each monosaccharide is independently a hexose, a hexulose, a deoxy hexose, a uronic acid hexose, or a derivative thereof.

[0058] E5. The compound of E4 or E4.1, or the salt thereof, wherein the disaccharide is cellobiose, chitobiose, dirhamnose, gentiobiose, isomaltose, isomaltulose, lactose, lactulose, laminaribose, leucrose, maltose, maltulose, melibiose, nigerose, sophorose, sucrose, trehalose, turanose, xylobiose, or an amine or thiol derivative thereof.

[0059] E6. The compound of El, or the salt thereof, wherein the saccharide is a trisaccharide.

[0060] E6.1. The compound of E6, or the salt thereof, wherein the trisaccharide comprises three monosaccharides, wherein each monosaccharide independently a hexose, a hexulose, a deoxy hexose, a uronic acid hexose, or a derivative thereof.

[0061] E7. The compound of E6 or E6.1, or the salt thereof, wherein the trisaccharide is cellotriose, isomaltotriose, isopanose, laminaritriose, manninotriose, maltotriose, melezitose, nigerotriose, panose, raffinose, xylotriose, or an amine or thiol derivative thereof.

[0062] E8. The compound of any one of E1-E7, or the salt thereof, wherein the saccharide is a naturally occurring saccharide.

[0063] E9. The compound of any one of E1-E7, or the salt thereof, wherein the saccharide is a synthetically prepared saccharide.

[0064] ElO. The compound of any one of E1-E9, or the salt thereof, wherein A is:wherein:R"' is CH3, CH2X2PG”, CH2X2H, CO2H, or hydrogen;Ra2and Ra3are each independently hydrogen or PG”;Ra4is hydrogen, PG”, a monosaccharide moiety, or a disaccharide moiety;X1is O, S, or NH;X2is O or S; andPG” is a hydroxyl protecting group or a thiol protecting group.

[0065] E10.1. The compound of E10, or the salt thereof, wherein Ra1is –CH3.

[0066] E10.2. The compound of E10 or El 0.1, or the salt thereof, wherein Ra4is hydrogen.

[0067] Ell. The compound of any one of E10-E10.2, or the salt thereof, wherein A is:

[0068] E12. The compound of El 1, or the salt thereof, wherein X2is O.

[0069] E13. The compound of El 2, or the salt thereof, wherein A is:

[0070] E14. The compound of any one of E10-E13, or the salt thereof, wherein X1is O.

[0071] El 5. The compound of any one of El -El 4, or the salt thereof, wherein the compound of formula (I) is a compound of formula (I-a), (I-b), (I-aa), (I-bb), (I-ab), or (I-ba):(I-ba).

[0072] E16. The compound of any one of E1-E15, or the salt thereof, wherein RZ, at each occurrence, is -ORXor Rx.

[0073] E16.1. The compound of El 6, or the salt thereof, wherein -ORXis -OH.

[0074] E17. The compound of any one of E1-E16.1, or the salt thereof, wherein RZ, at each occurrence, is -ORX.

[0075] El 7.1. The compound of El 7, or the salt thereof, wherein -ORXis -OH.

[0076] El 8. The compound of any one of El -El 7.1, or the salt thereof, wherein RZ”, at each occurrence, is -ORXor Rx.

[0077] El 8.1. The compound of El 8, or the salt thereof, wherein RZ, at each occurrence, is ORX.

[0078] E18.2. The compound of El 8 or El 8.1, or the salt thereof, wherein -ORXis -OH.

[0079] E19. The compound of any one of E1-E18.2, or the salt thereof, wherein R1is C1-18alkyl.

[0080] E20. The compound of any one of El -El 9, or the salt thereof, wherein R2is C1-18alkyl.B. Salts

[0081] The disclosed compounds may exist as salts, such as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for administration to a subject (e.g., treatment of disorders) without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound of formula (I) may be dissolved in a suitable solvent and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide asalt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0082] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N, N-dibenzylphenethylamine, 1-ephenamine and N, N’ -dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0083] In some instances, the disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use.C. General Syntheses

[0084] In various instances, compounds of formula (I) or any of its subformulas may be synthesized as shown in the following schemes.

[0085] In some instances, compounds of formula (I) may be prepared as shown in Schemes 1-5.Scheme 1.I-1B 1-1 C I-1D

[0086] As shown in Scheme 1, compounds of formula I-1B may be reacted with compounds of formula I-1C under suitable basic conditions (e.g., in presence of an organolithium base, e.g., n-BuLi) to yield compounds of formula T-1D.Scheme 2.solvent l-S1-i I-S1

[0087] As shown in Scheme 2, PG”-protected saccharides of formula I-Sl-i may be reacted with an alkyl amine (e.g., but- 1 -amine) to yield selectively deprotected saccharides of formula I-Sl. Selectively deprotected saccharides of formula I-Sl may be reacted with tri chloroacetonitrile under suitable conditions (e.g., in the presence of DBU and 4 A MS) to yield compounds of formula I-S.Scheme 3.

[0088] As shown in Scheme 3, compounds of formula I-S maybe reacted with compounds of formula I-1D under suitable glycosylation conditions (e.g., in the presence of BFAE^O and 4 A MS) to yield compounds of formula I-1E.Scheme 4.

[0089] As shown in Scheme 4, compounds of formula I-1E may be subjected to suitable PG” deprotection conditions, thereby removing the PG” groups to yield compounds of formula I-1F.For example, when each PG” is acetyl (Ac), compounds of formula I-1E may be subjected to suitable basic conditions (e.g., NaOMe in MeOH).

[0090] Alternatively, in some instances, compounds of formula (I) may be prepared as shown in Schemes 5-6.Scheme 5.

[0091] As shown in Scheme 5, compounds of formula I-Sl-i may be reacted with compounds of formula I- II under suitable glycosylation conditions (e.g., in the presence of BF3-Et2O) to yield compounds of formula 1-1 J.SchemePG" DeprotectionConditions

[0092] As shown in Scheme 6, PG”-protected saccharides of formula 1-1 J may be reacted with a phosphite of formula I-1K (e.g., triethyl phosphite) under suitable heating conditions (e.g., neat at 120-200 °C) to yield phosphoglycolipid compounds of formula I-1E. The resulting compounds of formula I-1E may then be subjected to suitable PG” deprotection conditions to remove the PG” groups, thereby yielding compounds of formula I-1F.Scheme 7.

[0093] As shown in Scheme 7, compounds of formula I-1E or 1-1F where RZis -OPG may be subjected to suitable PG deprotection conditions, thereby removing the PG groups to yield compounds of formula I-1G or I-1H, respectively. For example, when each PG is benzyl (Bn), the compounds of formula I-1E or 1-1F may be subjected to Pd / C-catalyzed hydrogenation conditions to remove the PG groups.

[0094] Complete or partial deprotection of the PG groups and / or the PG” groups is possible depending on the specific groups and deprotection methods. For example, regarding the PG” deprotection of compounds of formula I-1E, depending on the specific sugar moiety, different rates of PG” deprotection may occur. Accordingly, in some instances, compounds having partially deprotected sugar moieties may be prepared (not shown). In other instances, compounds having fully deprotected sugar moieties, e.g., compounds of formula 1-1F or 1-1G, may be prepared. As another example, compounds of formula I-1E or 1-1F where each RZis -OPG and PG is benzyl may be subjected to Pd / C conditions to remove both PG groups. Alternatively, the compounds of formula I-1E or 1-1F where each RZis -OPG and PG is benzyl may be reacted with bromotrimethylsilane (TMSBr) to remove only one PG group.

[0095] The compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel’s Textbook of Practical Organic Chemistry,” 5th edition (1989), by Fumiss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England.

[0096] A disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like.

[0097] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Llnless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above-described schemes or the procedures described in the synthetic examples section.

[0098] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[0099] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[0100] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0101] It can be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.III. Applications

[0102] Exemplary phosphoglycolipids and derivatives thereof described herein may be used as metal chelators / extractants, surfactants, and / or antimicrobial agents. In some instances, the phosphoglycolipids and derivatives thereof described herein may be used as a surfactant in various products, such as detergents, wetting agents, emulsifiers, foaming agents, and dispersants.IV. EXAMPLESExample 1: Synthesis of Example 2-Hydroxyphospholipid Intermediate-78 to 0 °C

[0103] Dibenzyl (2-hydroxytridecyl)phosphonate: Under a N2 atmosphere, n-butyllithium (1.1 equiv) was added to dry THF (0.2 M), and the resulting solution was cooled to -78 °C. Methyl dibenzylphophonate (1.15 equiv) was then added dropwise to the cooled solution over 20-30 minutes, and stirred for an additional 20 min at -78 °C. The reaction vessel was then fitted with a dropping funnel charged with dodecylaldehyde (1.0 equiv) and an equal volume of dry THF. The aldehyde solution was then added dropwise to the reaction mixture with vigorous stirring over 30-45 minutes. The reaction mixture was then stirred for 2 hours at -78 °C and for 2 hours at 0 °C or until complete by TLC. Then the reaction was quenched by the addition of excess saturated NH4C1 (aq), and condensed to remove most of the THF. The residue was then added to a separatory funnel with EtOAc and brine. The phases were separated, the aqueous layers were extracted with EtOAc, and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed, and the product was purified by crystallization from cold hexane and / or column chromatography (1:1 EtOAc: Hexane). 75-90% yields. 'H NMR (300 MHz, CDC13) 6 (ppm): 0.87 (t, 3H), 1.20-1.26 (m, 18H), 1.41 (m, 2H), 1.77-2.02 (dd, JP-H 11.2), 3.38 (m, 1H), 5.30 (d, JP-H 5.5), 7.32-7.52 (m, 10H).I3C{31P} NMR (400 MHz, CDC13) 6 (ppm): 14.1, 22.7, 28.8, 29.3-25.1 (overlapping signals), 31.9, 43.7, 56.6, 68.4, 127.4, 127.8, 129.0, 135.4. LRMS-ESI (m / z)+: calcd for C27H41O4P [460.3] found: 461.4 [M+H],Example 2: Synthesis of an Example Sugar Fragment

[0104] Rhamnose peracetate (1 equiv) was dissolved in THF (-1-0.5M) at room temperature. n-Butylamine (1.5 equiv) was then added in a single portion. The reaction was stirred until complete conversion of the peracetate, approximately 3-12 h. The reaction mixture was then condensed to remove most of the THF, and the resulting syrup was dissolved in ethyl acetate(approximately 3-5 mL / g of starting material) and added to a separatory funnel. The organic phase was then washed with 2* IM HC1, water 2*, and brine. The organic phase was then separated, dried over sodium sulfate, and condensed. The crude product was then crystallized from diethyl ether in a -40 °C freezer overnight, with iterative crystallization after condensing the crystallization liquor and cooling again. The solid product was then collected by vacuum filtration, air dried, and further dried under vacuum. 80-90% yields. This product was then added to a dry round bottom flask with stirrer and dissolved in DCM under an inert atmosphere. Activated 4A molecular sieves (1 g / g starting material) and tri chloroacetonitrile were then added under inert atmosphere and the solution was cooled to 0 °C in an ice bath and stirred for 20 minutes. To the cooled solution was then added l,8-diazabicyclo(5.4.0)undec-7-ene (DBU) (0.1 equiv) dropwise. The reaction was then stirred until complete conversion of the starting material (15-60 min). The resulting solution was filtered to remove the sieves, and then added to a separatory funnel and washed 2 x with ice water, then washed with brine, then dried over sodium sulfate. After condensing, the crude material was purified by column chromatography with 2:1 EtOAc / hexane.70-80% yields. Spectral data matched existing literature reports.Example 3: Glycosylation

[0105] To a well-dried round bottom flask was added phospholipid chain fragment (37.0 g, 81.1 mmol, 1.0 equiv), sugar donor (45.0 g, 105.4 mmol, 1.3 equiv), activated crushed 4A molecular sieves (40 g), and dry DCM (500 mb) under a nitrogen atmosphere. The reaction was allowed to stir 20-30 min at room temperature then cooled to -40 °C. To this solution was then added BFs OEt (13.0 mb, 105.4 mmol, 1.3 equiv) dropwise over 20-30 min, and the reaction mixture was then stirred for 1 h at -40 °C, and warmed to 0 °C over 30 min. The reaction was then filtered through a pad of celite rinsing with 3 x 50 mL DCM and then poured into a separatory funnel. The organic phase was washed with 2 x 100 mL water, 100 mL saturated sodium bicarbonate, and 100 mL brine. The organic phase was then dried over sodium sulfate and condensed. The product was then purified by column chromatography eluting with EtOAc / Hexane (10% — >100%). 39 g (66%yield). 'HNMR (300 MHz, CDCh) 8 (ppm): 0.88 (t, 3H), 1.12 (d, 3H), 1.20-1.26 (m, 18H), 1.38 (m, 2H), 1.75-2.00 (dd, JP-H 10.7), 1.18 (s, 3H), 2.02 (s, 3H), 2.05 (s, 3H), 3.03 (m, 1H), 4.29 (m, 1H), 4.58 (dd, 1H), 4.88 (dd, 1H), 5.14 (dd, 1H), 5.29 (d, JP-H 5.5), 5.97 (d, 1H), 7.32-7.47 (m, 10H).13C{31P] NMR (400 MHz, CDCh) 8 (ppm): 14.1, 17.2, 20.8-21.1 (overlapping signals), 22.8, 29.3-29.6 (overlapping signals), 29.9, 32.4, 37.2, 41.9, 58.4, 65.7, 70.9, 72.1, 72.3, 80.9, 105.9, 127.1, 127.6, 128.9, 134.4, 170.1, 170.2. LRMS-ESI (m / z)+calcd for C39H57O11P [732.4] found: 755.1 [M+Na],Example 4: Deprotection

[0106] The fully protected phosphoglycolipid (10 g) was dissolved in THF (50 mL) with stirring and to the mixture was added Pd / C (1 g, 10 wt% Pd). A balloon of H2 was then attached and the reaction was stirred 16 hours. The reaction mixture was filtered through a plug of Celite to remove the Pd / C rinsing the filter cake with 3 x 25 mL THF. The product was carried on without purification. The crude product was dissolved in dry methanol (50 mL) and NaOMe was added portion-wise until the pH was -10-11. The reaction was stirred for 2 h, at which time acidic resin (Dowex®) was added until the pH reached -2-3. The resin was then filtered off, washed with 3 x 50 mL methanol, and the solution condensed to afford the product as an off-white foam (5.9 g, quant, yield). *HNMR (300 MHz, CDCh) S (ppm): 0.88 (t, 3H), 1.11 (d, 3H), 1.20-1.26 (m, 18H), 1.39 (m, 2H), 1.67-1.92 (dd, JP-H 12.6), 3.21 (m, 1H), 3.60 (dd, 1H), 3.68-3.72 (m, 2H), 4.51-4.88 (br m, 5H), 5.44 (d, 1H). ).13C{31P] NMR (400 MHz, CDCh) 8 (ppm): 14.4, 16.9, 22.7, 29.3-29.6 (overlapping signals), 31.9, 32.4, 37.7, 46.2, 57.6, 72.4, 72.5, 73.7, 74.1, 109.4. LRMS-ESI (m z)~: calcd for C19H39O8P [426.2] found: 425.2 [M-H],Example 5: Synthesis of an Example Alternative Sugar Fragment

[0107] To a well-dried round bottom flask was added dry DCM (700 mL), l-bromodocan-2-ol (83 g, 331 mmol, 1.0 equiv), and rhamnose peracetate (134 g, 402 mmol, 1.3 equiv). The solution was stirred until dissolved and then cooled in an ice bath. To this chilled solution was then slowly added BF3 OEt2 (50 mL, 402 mmol, 1.3 equiv), and the resulting solution was allowed to warm to rt overnight. The solution was then washed with 2 x 500 mL water, 1 x 500 mL sat’d sodium bicarbonate solution, and brine. The organic phase was then dried over sodium sulfate, filtered, and condensed to provide a pale yellow oil (the crude product). The crude product was then purified by column chromatography (9:1 to 1:1 hexane / EtOAc) to afford the title compound as a clear viscous oil. 138 g, 76% yield. 'H NMR (300 MHz, CDCI3) 8 (ppm): 0.89 (t, 3H), 1.10 (t, 3H), 1.22-1.28 (m, 16H), 1.39 (m, 2H), 2.02 (s, 3H), 2.05 (s, 3H), 2.10 (s, 3H), 3.60 (m, 2H), 3.90 (m, 1H), 3.96 (m, 1H), 4.29 (1H, m), 5.26 (m, 1H), 5.36 (m, 1H), 5.66 (m, 1H).13C{31P} NMR (500 MHz, CDCI3) 8 (ppm): 14.1, 15.5, 20.7, 21.0, 22.7, 24.7, 29.4-29.3 (overlapping signals), 30.7, 31.9, 34.3, 38.7, 62.3, 63.3, 65.2, 74.9, 77.0, 99.5, 170.0, 170.3, 171.0. LRMS-ESI (m z) calc’d for C24H4iBrOs [536.2], found: 559.2 [M+Na],Example 6: Synthesis of Example Protected Phosphoglycolipid

[0108] In a thick-walled glass pressure flask equipped with Teflon screw cap was added 1-bromo-dodecyl-2-rhamnoside peracetate (66.3 g, 123 mmol, 1 equiv) and triethyl phosphite (25 mL, 148 mmol, 1.2 equiv). The vessel was equipped with a Teflon-coated stir bar, sealed, and heated to 170 °C for 6h. Upon completion, the reaction was then evacuated at a temperature to remove excess phosphite, then allowed to cool to rt. The crude product was then purified by column chromatography (100:0 to 70:30 EtOAc / acetone) to afford the product as a clear viscousoil. 63 g, 85.8% yield. 'H NMR (300 MHz, CDCh) 6 (ppm): 0.89 (t, 3H), 1.10 (t, 3H), 1.22-1.28 (m, 16H), 1.36 (q, 6H), 1.39 (m, 2H), 1.76-2.01 (m, 2H, JP-H 10.7) 2.02 (s, 3H), 2.05 (s, 3H), 2.10 (s, 3H), 3.38 (m, 2H), 3.90 (m, 1H), 3.96 (m, 1H), 4.19 (t, 4H), 4.29 (1H, m), 5.26 (m, 1H), 5.36 (m, 1H), 5.66 (m, 1H).13C{31P} NMR (500 MHz, CDCh) 6 (ppm): 14.1, 16.3, 15.5, 20.7, 21.0, 22.7, 24.7, 29.4-29.3 (overlapping signals), 30.7, 31.9, 34.3, 38.7, 61.9, 62.3, 63.3, 65.2, 74.9, 77.0, 99.5, 170.0, 170.3, 171.0. LRMS-ESI (m / z)+calc’d for C28H51O11P [594.32], found: 617.31 [M+Na],

[0109] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0110] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

[0111] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0112] Clause 1. A compound of formula (I), or a salt thereof,wherein:A is a monosaccharide, a disaccharide, a tri saccharide, or an amine or thiol derivative thereof;R1is Ci-isalkyl, C2-isalkenyl, C2-isalkynyl or hydrogen;RZ, at each occurrence, is -ORX, Rx, -SRX, or -N(RX)2;Rx, at each occurrence, is hydrogen, PG, Ci-ealkyl, Cnehaloalkyl, Gla, -Ci-ealkylene-Gla,PG is a hydroxyl protecting group, a thiol protecting group, or an amine protecting group; RY, at each occurrence, is -OCi-4alkyl, -OCi-4haloalkyl, -OH, cyano, -SH, -SCi-4alkyl, -SCi-4haloalkyl, -SGla, -NH2, –NHC1-4alkyl, –NHG1a, –N(C1-4alkyl)2, –N(G1a)2, –C(O)OG1a, –C(O)OC1-4alkyl, –C(O)NH2, –C(O)NHC1-4alkyl, –C(O)N(C1-4alkyl)2, –C(O)NHG1a, -C(O)N(Gla)2, -SO2Ci-4alkyl, -SO2Gla, -SO2NH2, -SO2NHCi-4alkyl, or -SO2N(Ci-4alkyl)2;R2, at each occurrence, is C1-18alkyl, C2-18alkenyl, C2-18alkynyl or hydrogen;RZ”, at each occurrence, is -ORX”, Rx, -SRX, or-N(Rx)2;Rx, at each occurrence, is hydrogen, PG’, Ci-6alkyl, Ci-6haloalkyl, Gla, -Ci-6alkylene-Gla, or-Ci-fialkylene-R'1;PG’ is a hydroxyl protecting group, a thiol protecting group, or an amine protecting group; RY”, at each occurrence, is -OCi-4alkyl, -OCi-4haloalkyl, -OH, cyano, -SH, -SCi-4alkyl,-C(O)N(Gla)2, -SO2Ci-4alkyl, -SO2Gla', -SO2NH2, -SO2NHCi-4alkyl, or-SO2N(Ci-4alkyl)2; and Glaand Gla”, at each occurrence, are independently a C3-8cycloalkyl, a 4- to 12-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, wherein Glaand G1aare independently optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, oxo, Ci-4alkyl, Ci-4haloalkyl, -OCi-4alkyl, -OCi-4haloalkyl, -OH, -SCi-4alkyl, -SCi-4haloalkyl, -SH, -NO2, -NH2, -NHCi-4alkyl, -N(Ci-4alkyl)2, cyano, -C(O)OCi-4alkyl, -C(O)NH2, -C(O)NHCi-4alkyl, -C(O)N(Ci-4alkyl)2, -SO2Ci-4alkyl, -SO2NH2, -SO2NHCi-4alkyl, and -SO2N(Ci-4alkyl)2.

[0113] Clause 2. The compound of clause 1, or the salt thereof, wherein the saccharide is a monosaccharide.

[0114] Clause 3. The compound of clause 2, or the salt thereof, wherein the monosaccharide is allose, altrose, arabinose, fructose, fucose, galactose, glucose, mannose, gulose, idose, lyxose, psicose, rhamnose, ribose, 2-deoxy-ribose, ribulose, sorbose, tagatose, talose, xylose, xylulose, or an amine or thiol derivative thereof.

[0115] Clause 4. The compound of clause 1, or the salt thereof, wherein the saccharide is a di saccharide.

[0116] Clause 5. The compound of clause 4, or the salt thereof, wherein the disaccharide is cellobiose, chitobiose, dirhamnose, gentiobiose, isomaltose, isomaltulose, lactose, lactulose,laminaribose, leucrose, maltose, maltulose, melibiose, nigerose, sophorose, sucrose, trehalose, turanose, xylobiose, or an amine or thiol derivative thereof.[001171 Clause 6. The compound of clause 1, or the salt thereof, wherein the saccharide is a tri saccharide.

[0118] Clause 7. The compound of clause 6, or the salt thereof, wherein the trisaccharide is cellotriose, isomaltotriose, isopanose, laminaritriose, manninotriose, maltotriose, melezitose, nigerotriose, panose, raffinose, xylotriose, or an amine or thiol derivative thereof.

[0119] Clause 8. The compound of any one of clauses 1-7, or the salt thereof, wherein the saccharide is a naturally occurring saccharide.

[0120] Clause 9. The compound of any one of clauses 1-7, or the salt thereof, wherein the saccharide is a synthetically prepared saccharide.

[0121] Clause 10. The compound of any one of clauses 1-9, or the salt thereof, wherein A is:wherein:Ralis -CH3, -CH2X2PG”, -CH2X2H, -CO2H, or hydrogen;R"2and Ra3are each independently hydrogen or PG”;Ra4is hydrogen, PG”, a monosaccharide moiety, or a disaccharide moiety;X1is O, S, or NH;X2is O or S; andPG” is a hydroxyl protecting group or a thiol protecting group.

[0122] Clause 11. The compound of clause 10, or the salt thereof, wherein A is:

[0123] Clause 12. The compound of clause 11, or the salt thereof, wherein X2is O.

[0124] Clause 13. The compound of clause 12, or the salt thereof, wherein A is:

[0125] Clause 14. The compound of any one of clauses 10-13, or the salt thereof, wherein X1is O.

[0126] Clause 15. The compound of any one of clauses 1-14, or the salt thereof, wherein the compound of formula (I) is a compound of formula (I-a), (I-b), (I-aa), (I-bb), (I-ab), or (I-ba):ba).

[0127] Clause 16. The compound of any one of clauses 1-15, or the salt thereof, wherein RZ, at each occurrence, is -ORXor Rx.

[0128] Clause 17. The compound of any one of clauses 1-16, or the salt thereof, wherein RZ, at each occurrence, is -ORX.

[0129] Clause 18. The compound of any one of clauses 1-17, or the salt thereof, wherein RZ, at each occurrence, is -ORXor Rx.

[0130] Clause 19. The compound of any one of clauses 1-18, or the salt thereof, wherein R1is C1-18alkyl.

[0131] Clause 20. The compound of any one of clauses 1 -19, or the salt thereof, wherein R2is C1-18alkyl.

[0132] Clause 21. A method of preparing the compound of any one of clauses 1-20, or the salt thereof, the method comprising:i. preparing an intermediate of formula (I- IB), where X1is O, S, or NH:X1R A1H (LIB);ii. reacting the intermediate of formula (I- IB) with an intermediate of formula (I- 1 C):in the presence of a base to provide an intermediate of formula (LID):iii. in the presence of a glycosylation promoter, reacting the intermediate of formula (I- 1D) with a compound of formula (I-S):wherein:X2is O and PG” is a hydroxyl protecting group; or alternatively,X2is S and PG” is a thiol protecting group;Ralis -CH3, hydrogen, or -CH2X2PG”; andR'4is PG”, a monosaccharide moiety, or a disaccharide moiety,to provide an intermediate of formula (LIE):removing the PG” groups from the intermediate of formula (I- IE) to provide a compound of formula (I-F):

[0133] Clause 22. The method of clause 21, wherein the glycosylation promoter is boron trifluoride etherate.

[0134] Clause 23. The method of clause 21 or 22, wherein the base is an organolithium base.

[0135] Clause 24. The method of any one of clauses 21-23, wherein the compound of formula (I-S) is prepared by reacting a compound of formula (I-Sl-i):with trichloroacetonitrile in the presence of a base.

[0136] Clause 25. The method of clause 24, wherein the base comprises 1,8-di azabi cyclo[5.4.0]undec-7-ene.

[0137] Clause 26. A method of preparing the compound of any one of clauses 1-20, or the salt thereof, the method comprising:i. preparing an intermediate of formula (I-1I):wherein X3is Cl, Br, or I;in the presence of a glycosylation promoter, reacting the intermediate of formula (1-11) with a compound of formula (LSl-i):to provide an intermediate of formula (1-1 J):wherein:X2is O and PG” is a hydroxyl protecting group; or alternatively,X2is S and PG” is a thiol protecting group;R"1is -CFh, hydrogen, or -CH2X2PG”; andR“4is PG”, a monosaccharide moiety, or a disaccharide moiety,iii. at a temperature of 120-200 °C, reacting the intermediate of formula (1-1 J) with a phosphite of formula (I-1K):(RZ)2P–ORX(I-1K),to provide an intermediate of formula (1-1 E):removing the PG” groups from the intermediate of formula (LIE) to provide a compound of formula (LF):

[0138] Clause 27. The method of clause 26, wherein the phosphite of formula (T- 1 K) is P(ORX)3.

Claims

1. CLAIMS1. A compound of formula (I), or a salt thereof,6. 8.wherein:9.A is a monosaccharide, a disaccharide, a trisaccharide, or an amine or thiol derivative thereof;11. 13.R1is Ci-isalkyl, C2-isalkenyl, C2-isalkynyl or hydrogen;14.RZ, at each occurrence, is -ORX, Rx, -SRX, or -N(RX)2;15.RX, at each occurrence, is hydrogen, PG, C1-6alkyl, C1-6haloalkyl, G1a, –C1-6alkylene–G1a,18. 20.PG is a hydroxyl protecting group, a thiol protecting group, or an amine protecting group; RY, at each occurrence, is -OCi-4alkyl, -OCi-4haloalkyl, -OH, cyano, -SH, -SCi-4alkyl, -SCi-4haloalkyl, -SGla, -NH2, -NHCi-4alkyl, -NHGla, -N(Ci-4alkyl)2, -N(Gla)2, -C(O)OGla, -C(O)OCi-4alkyl, -C(O)NH2, -C(O)NHCi-4alkyl, -C(O)N(Ci-4alkyl)2, -C(O)NHGla, -C(O)N(Gla)2, -SO2Ci-4alkyl, -SO2Gla, -SO2NH2, -SO2NHCi-4alkyl, or -SO2N(Ci-4alkyl)2;21.R2, at each occurrence, is C1-18alkyl, C2-18alkenyl, C2-18alkynyl or hydrogen;22.RZ”, at each occurrence, is -ORX”, Rx”, -SRX”, or-N(Rx)2;23.Rx”, at each occurrence, is hydrogen, PG’, Ci-ealkyl, Ci-ehaloalkyl, Gla, -Ci-ealkylene-Gla”, or-Ci-6alkylene-RY;24.PG’ is a hydroxyl protecting group, a thiol protecting group, or an amine protecting group; RY, at each occurrence, is -OCi-4alkyl, -OCi-4haloalkyl, -OH, cyano, -SH, -SCi-4alkyl, -SCi-4haloalkyl, -SGla”, -NH2, -NHCi-4alkyl, -NHGla”, -N(Ci-4alkyl)2, -N(Gla”)2, -C(O)OGla”, -C(O)OCi-4alkyl, -C(O)NH2, -C(O)NHCi-4alkyl, -C(O)N(Ci-4alkyl)2, -C(O)NHGla”, -C(O)N(Gla”)2, -SO2Ci-4alkyl, -SO2Gla”, -SO2NH2, -SO2NHCi-4alkyl, or-SO2N(Ci-4alkyl)2; and Glaand Gla”, at each occurrence, are independently a Ca-scycloalkyl, a 4- to 12-membered heterocyclyl, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, wherein Glaand Glaare independently optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, oxo, Ci-4alkyl, Ci-4haloalkyl, -OCi-4alkyl, -OCi-4haloalkyl, -OH, -SCi-4alkyl, -SCi-4haloalkyl, -SH, -NO2, -NH2, -NHCi-4alkyl, -N(Ci-4alkyl)2, cyano, -C(O)OCi-4alkyl, -C(O)NH2, -C(O)NHCi-4alkyl, -C(O)N(Ci-4alkyl)2, -SO2Ci-4alkyl, -SO2NH2, -SO2NHCi-4alkyl, and -SO2N(Ci-4alkyl)2.

2. The compound of claim 1, or the salt thereof, wherein the saccharide is a monosaccharide.

3. The compound of claim 2, or the salt thereof, wherein the monosaccharide is allose, altrose, arabinose, fructose, fucose, galactose, glucose, mannose, gulose, idose, lyxose, psicose, rhamnose, ribose, 2-deoxy-ribose, ribulose, sorbose, tagatose, talose, xylose, xylulose, or an amine or thiol derivative thereof.

4. The compound of claim 1, or the salt thereof, wherein the saccharide is a disaccharide.

5. The compound of claim 4, or the salt thereof, wherein the disaccharide is cellobiose, chitobiose, dirhamnose, gentiobiose, isomaltose, isomaltulose, lactose, lactulose, laminaribose, leucrose, maltose, maltulose, melibiose, nigerose, sophorose, sucrose, trehalose, turanose, xylobiose, or an amine or thiol derivative thereof.

6. The compound of claim 1, or the salt thereof, wherein the saccharide is a trisaccharide.

7. The compound of claim 6, or the salt thereof, wherein the trisaccharide is cellotriose, isomaltotriose, isopanose, laminaritriose, manninotriose, maltotriose, melezitose, nigerotriose, panose, raffinose, xylotriose, or an amine or thiol derivative thereof.

8. The compound of claim 1, or the salt thereof, wherein the saccharide is a naturally occurring saccharide.

9. The compound of claim 1, or the salt thereof, wherein the saccharide is a synthetically prepared saccharide.

10. The compound of claim 1, or the salt thereof, wherein A is:

37. 39.wherein:40.Ralis -CH3, -CH2X2PG”, -CH2X2H, -CO2H, or hydrogen;41.R"2and Ra3are each independently hydrogen or PG”;42.Ra4is hydrogen, PG”, a monosaccharide moiety, or a disaccharide moiety;43.X1is O, S, or NH;44.X2is O or S; and45.PG” is a hydroxyl protecting group or a thiol protecting group.

11. The compound of claim 10, or the salt thereof, wherein A is:

48.

12. The compound of claim 11, or the salt thereof, wherein X2is O.

13. The compound of claim 12, or the salt thereof, wherein A is:

52.

14. The compound of claim 10, or the salt thereof, wherein X1is O.

15. The compound of claim 1, or the salt thereof, wherein the compound of formula (I) is a compound of formula (I-a), (I-b), (I-aa), (I-bb), (I-ab), or (I-ba):

60.

16. The compound of claim 1, or the salt thereof, wherein RZ, at each occurrence, is -ORXor Rx.

17. The compound of claim 16, or the salt thereof, wherein RZ, at each occurrence, is -ORX.

18. The compound of claim 1, or the salt thereof, wherein RZ”, at each occurrence, is -ORXor Rx.

19. The compound of claim 1, or the salt thereof, wherein R1is C1-18alkyl.

20. The compound of claim 1, or the salt thereof, wherein R2is C1-18alkyl.

21. A method of preparing the compound of claim 1, or the salt thereof, the method comprising: i. preparing an intermediate of formula (I-1B), where X1is O, S, or NH:

69. 71.ii. reacting the intermediate of formula (I- IB) with an intermediate of formula (I- 1 C):

73. 75.in the presence of a base to provide an intermediate of formula (I-1D):76.HX177.RZ(I- ID);78.iii. in the presence of a glycosylation promoter, reacting the intermediate of formula (I- 1D) with a compound of formula (I-S):

80. 82.wherein:83.X2is O and PG” is a hydroxyl protecting group; or alternatively,84.X2is S and PG” is a thiol protecting group;85.Ralis -CH?, hydrogen, or -CH2X2PG”; and86.Ra4is PG”, a monosaccharide moiety, or a disaccharide moiety,87.to provide an intermediate of formula (1-1 E):

90. 92.removing the PG” groups from the intermediate of formula (I- IE) to provide a compound of formula (I-F):

94.

22. The method of claim 21, wherein the glycosylation promoter is boron trifluoride etherate.

23. The method of claim 21, wherein the base is an organolithium base.

24. The method of claim 21, wherein the compound of formula (I-S) is prepared by reacting a compound of formula (I-Sl-i):

102. 104.with trichloroacetonitrile in the presence of a base.

25. The method of claim 24, wherein the base comprises 1,8-diazabicyclo[5.4.0]undec-7-ene.

26. A method of preparing the compound of claim 1, or the salt thereof, the method comprising:107.preparing an intermediate of formula (I- II):108.XqH109.k, X:

111. 113.wherein X3is Cl, Br, or I; in the presence of a glycosylation promoter, reacting the intermediate of formula (I- II) with a compound of formula (I-Sl-i):

116. 118.to provide an intermediate of formula (I- 1 J):

122. 124.wherein:125.X2is O and PG” is a hydroxyl protecting group; or alternatively, X2is S and PG” is a thiol protecting group;126.Ralis -CH3, hydrogen, or -CH2X2PG”; and127.Ra4is PG”, a monosaccharide moiety, or a disaccharide moiety,128.vn. at a temperature of 120-200 °C, reacting the intermediate of formula (1-1 J) with a phosphite of formula (1-1K):129.(RZ)2P–ORX(I-1K),130.to provide an intermediate of formula (I- IE):

134. 136.vin. removing the PG” groups from the intermediate of formula (I- IE) to provide a compound of formula (I-F):

138.

27. The method of claim 26, wherein the phosphite of formula (I-1K) is P(ORX)3.

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