WO2018035416A1 - Réactifs et méthodes de glycosylation - Google Patents

Réactifs et méthodes de glycosylation Download PDF

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WO2018035416A1
WO2018035416A1 PCT/US2017/047519 US2017047519W WO2018035416A1 WO 2018035416 A1 WO2018035416 A1 WO 2018035416A1 US 2017047519 W US2017047519 W US 2017047519W WO 2018035416 A1 WO2018035416 A1 WO 2018035416A1
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compound
salt
certain embodiments
group
alkyl
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PCT/US2017/047519
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Aaron APONICK
Ji LIU
Romain J. MIOTTO
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University Of Florida Research Foundation, Incorporated
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Definitions

  • the present invention provides systems, methods, and regents for the glycosylation of organic molecules and/or the synthesis of more complex carbohydrates.
  • the invention provides methods for glycosylating a hydroxyl-containing organic compound (i.e., a glycosyl acceptor) comprising contacting a glycosyl donor with the hydroxyl-containing organic compound (i.e., the glycosyl acceptor), in the presence of an oxidant, to yield a glycosylated organic compound.
  • the glycosyl donor is a compound of one of the following formulae:
  • the glycosyl donor is:
  • Glycosyl acceptors useful in the methods provided herein are any compounds comprising a free hydroxyl group (i.e.,–OH group).
  • the compound comprising a free hydroxyl group may be a small molecule, large molecule, natural product, pharmaceutical drug, etc.
  • the compound containing a free hydroxyl group may also be a carbohydrate (e.g., monosaccharide, disaccharide, trisaccharide, polysaccharide).
  • sugars comprising free hydroxyl groups can be glycosyl acceptors, such as (but not limited to) compounds of the following formulae:
  • R 1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted carbocyclyl, or optionally substituted acyl.
  • the glycosyl acceptor is the following:
  • Scheme 1 shows a general outline of a certain embodiment of the methods provided herein.
  • the reaction of reagents such as 9 (a glycosyl donor; stereochemistry arbitrarily drawn as glucose as an example) and 10 (glycosyl acceptor; stereochemistry arbitrarily drawn as glucose as an example) provide the disaccharide 11, now containing a“latent glycosyl donor” moiety.
  • Pg is any hydroxyl protecting group, defined herein.
  • the method can further comprise a step of deprotecting the latent glycosyl donor moiety to unveil an active glycosyl donor, which can be used in a subsequent glycosylation step.
  • deprotection of the phenolic ester in 11 can be accomplished to reveal 13, and repeating the steps with a glycosyl acceptor such as 10, or other building blocks, would build up the saccharide.
  • a glycosyl acceptor such as 10, or other building blocks
  • the methods described herein offer the ability to grow the carbohydrate in multiple directions as needed.
  • the ability to form linear or branched substrates relies on tactical protecting group strategies (described herein). Additionally, protecting group choices can allow for predictable substrate control of anomeric selectivity, which is important in carbohydrate synthesis.
  • the present invention provides compounds (e.g., glycosyl donors and glycosyl acceptors), and salts thereof, which are useful in glycosylation reactions and in carbohydrate preparation.
  • the present invention provides kits comprising one or more of the compounds provided herein.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • a formula is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, is absent or a single bond, and or is a single or double bond.
  • the formula is meant to encompass all possible stereoisomers (e.g., enantiomers, diastereomers, epimers) of the compounds.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of 12 C with 13 C or 14 C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C 1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C 7 ), n- octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an“unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1-10 alkyl (such as unsubstituted C 1-6 alkyl, e.g., ⁇ CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)).
  • the alkyl group is a substituted C 1-10 alkyl (such as substituted C 1-6 alkyl, e.g., ⁇ CH 3 (Me), un
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-10 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain
  • heteroC 1-9 alkyl (“heteroC 1-9 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-7 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”).
  • a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an“unsubstituted heteroalkyl”) or substituted (a“substituted heteroalkyl”) with one or more substituents. In certain
  • the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 2 to 9 carbon atoms (“C 2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C 2-7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”).
  • an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In some
  • an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In some
  • an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an“unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkenyl”).
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an“unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C 2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2- 7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In some
  • an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some
  • an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2- propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an“unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C 2-10 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkynyl”).
  • a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2- 8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). In some
  • a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC 2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkynyl”).
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an“unsubstituted heteroalkynyl”) or substituted (a“substituted
  • heteroalkynyl with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
  • carbocyclyl or“carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
  • Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ),
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an“unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3-14 cycloalkyl.
  • the term“heterocyclyl” or“heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”).
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • heteroatoms include, without limitation, triazinyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 pi electrons shared in a cyclic array
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).“Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an“unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted C 6-14 aryl. In certain embodiments, the aryl group is a substituted C 6-14 aryl.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an“unsubstituted heteroaryl”) or substituted (a“substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • “Heteroaralkyl” is a subset of“alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
  • “unsaturated bond” refers to a double or triple bond.
  • saturated refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g.,“substituted” or“unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl,“substituted” or“unsubstituted” alkynyl, “substituted” or“unsubstituted” heteroalkyl,“substituted” or“unsubstituted” heteroalkenyl, “substituted” or“unsubstituted”
  • the term“substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a“substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the invention is not intended to be limited in any manner by the exemplary substituents described herein.
  • Exemplary carbon atom substituents include, but are not limited to, halogen, ⁇ CN, ⁇ NO 2 , ⁇ N 3 , ⁇ SO 2 H, ⁇ SO 3 H, ⁇ OH, ⁇ OR aa , ⁇ ON(R bb ) 2 , ⁇ N(R bb ) 2 , ⁇ N(R bb ) +
  • R aa is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alken
  • each instance of R cc is, independently, selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R dd is, independently, selected from halogen, ⁇ CN, ⁇ NO 2 , ⁇ N 3 , ⁇ SO 2 H, ⁇ SO 3 H, ⁇ OH, ⁇ OR ee , ⁇ ON(R ff ) 2 , ⁇ N(R ff ) 2 , ⁇ N(R ff ) +
  • each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
  • each instance of R gg is, independently, halogen, ⁇ CN, ⁇ NO 2 , ⁇ N 3 , ⁇ SO 2 H, ⁇ SO 3 H, ⁇ OH, ⁇ OC +
  • carbon atom substituents include: halogen, ⁇ CN, ⁇ NO 2 , ⁇ N 3 , ⁇ SO 2 H, ⁇ SO 3 H, ⁇ OH, ⁇ OC 1-6 alkyl, ⁇ ON(C 1-6 alkyl) 2 , ⁇ N(C 1-6 alkyl) 2 , ⁇ N(C 1-6 alkyl) +
  • halo or“halogen” refers to fluorine (fluoro, ⁇ F), chlorine (chloro, ⁇ Cl), bromine (bromo, ⁇ Br), or iodine (iodo, ⁇ I).
  • hydroxyl refers to the group ⁇ OH.
  • amino refers to the group ⁇ NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the“substituted amino” is a monosubstituted amino or a
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from ⁇ N(R bb ) 3 and ⁇ N(R bb ) +
  • sulfonyl refers to a group selected from–SO 2 N(R bb ) 2 ,–SO 2 R aa , and– SO 2 OR aa , wherein R aa and R bb are as defined herein.
  • heteroaryloxy aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1 groups taken together form a 5- to 6-membered heterocyclic ring.
  • acyl groups include aldehydes ( ⁇ CHO), carboxylic acids ( ⁇ CO 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
  • sil refers to the group–Si(R aa ) 3 , wherein R aa is as defined herein.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an“amino protecting group”).
  • heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc , and R dd are as defined herein.
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1- methylethyl
  • TLBOC 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1- methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (C
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)- acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-di
  • diphenylthiophosphinamide Ppt
  • dialkyl phosphoramidates dibenzyl phosphoramidate, diphenyl phosphoramidate
  • benzenesulfenamide o-nitrobenzenesulfenamide
  • Nps 2,4- dinitrobenzenesulfenamide
  • pentachlorobenzenesulfenamide 2-nitro-4- methoxybenzenesulfenamide
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • a nitrogen protecting group is benzyl (Bn), tert- butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).
  • Bn benzyl
  • BOC tert- butyloxycarbonyl
  • Cbz carbobenzyloxy
  • Fmoc 9-flurenylmethyloxycarbony
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an“hydroxyl protecting group”).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • DEIPS diethylisopropylsilyl
  • TDMS t-butyldimethylsilyl
  • TDPS t- butyldiphenylsilyl
  • tribenzylsilyl tri-p-xylylsilyl, triphenylsilyl
  • DPMS diphenylmethylsilyl
  • TMPS t-butylmethoxyphenylsilyl
  • formate benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate
  • an oxygen protecting group is silyl.
  • an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate,
  • methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2- trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a“thiol protecting group”).
  • a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.
  • A“counterion” or“anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F – , Cl – , Br – , I – ), NO –
  • sulfonate ions e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF ⁇
  • carborane anions e.g., CB 11 H –
  • Exemplary counterions which may be multivalent include CO 2 ⁇ 3 ⁇
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the
  • phrase“at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
  • carbohydrate or“saccharide” refers to an aldehydic or ketonic derivative of polyhydric alcohols.
  • Carbohydrates include compounds with relatively small molecules (e.g., sugars) as well as macromolecular or polymeric substances (e.g., starch, glycogen, and cellulose polysaccharides).
  • saccharide refers to monosaccharides, disaccharides, or polysaccharides. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed to smaller carbohydrates.
  • monosaccharides can be represented by the general formula C y H 2y O y (e.g., C 6 H 12 O 6 (a hexose such as glucose)), wherein y is an integer equal to or greater than 3.
  • C y H 2y O y e.g., C 6 H 12 O 6 (a hexose such as glucose)
  • y is an integer equal to or greater than 3.
  • Certain polyhydric alcohols not represented by the general formula described above may also be considered monosaccharides.
  • deoxyribose is of the formula C 5 H 10 O 4 and is a monosaccharide.
  • Monosaccharides usually consist of five or six carbon atoms and are referred to as pentoses and hexoses, receptively.
  • monosaccharide contains an aldehyde it is referred to as an aldose; and if it contains a ketone, it is referred to as a ketose.
  • Monosaccharides may also consist of three, four, or seven carbon atoms in an aldose or ketose form and are referred to as trioses, tetroses, and heptoses, respectively.
  • aldotriose and ketotriose sugars are considered to be aldotriose and ketotriose sugars, respectively.
  • aldotetrose sugars include erythrose and threose; and ketotetrose sugars include erythrulose.
  • Aldopentose sugars include ribose, arabinose, xylose, and lyxose; and ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose.
  • aldohexose sugars include glucose (for example, dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; and ketohexose sugars include fructose, psicose, sorbose, and tagatose.
  • Ketoheptose sugars include sedoheptulose. Each carbon atom of a
  • the aldohexose D -glucose for example, has the formula C 6 H 12 O 6 , of which all but two of its six carbons atoms are stereogenic, making D-glucose one of the 16 (i.e., 2 4 ) possible stereoisomers.
  • the assignment of D or L is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the right the molecule is a D sugar, otherwise it is an L sugar.
  • the aldehyde or ketone group of a straight-chain monosaccharide will react reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and exist in equilibrium with the straight-chain form.
  • the carbon atom containing the carbonyl oxygen becomes a stereogenic center with two possible configurations: the oxygen atom may take a position either above or below the plane of the ring.
  • the resulting possible pair of stereoisomers is called anomers.
  • an ⁇ anomer the ⁇ OH substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the ⁇ CH 2 OH side branch.
  • the alternative form, in which the ⁇ CH 2 OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane of the ring, is called a ⁇ anomer.
  • a carbohydrate including two or more joined monosaccharide units is called a disaccharide or polysaccharide (e.g., a trisaccharide), respectively.
  • Exemplary disaccharides include sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, or rutinose.
  • Exemplary trisaccharides include, but are not limited to, isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, and kestose.
  • carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.
  • salt refers to any and all salts, and encompasses pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,
  • salts derived from appropriate bases include alpha-1-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
  • Salts derived from appropriate bases include alpha-1-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanes
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvent refers to a substance that dissolves one or more solutes, resulting in a solution.
  • a solvent may serve as a medium for any reaction or transformation described herein.
  • the solvent may dissolve one or more reactants or reagents in a reaction mixture.
  • the solvent may facilitate the mixing of one or more reagents or reactants in a reaction mixture.
  • the solvent may also serve to increase or decrease the rate of a reaction relative to the reaction in a different solvent.
  • Solvents can be polar or non-polar, protic or aprotic.
  • Common organic solvents useful in the methods described herein include, but are not limited to, acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide N,N-dimethylformamide (DMF), 1,3- dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethylether, 2-ethoxyethyl ether, ethyl acetate, ethyl alcohol, ethylene glycol,
  • “Oxidant,”“oxidizing agent” or“chemical oxidant” refers to a chemical compound or substance that has the ability to oxidize another compound. Oxidation, as will be appreciated by one of skill in the art, is the loss of electrons– and an oxidizing agent is a chemical agent that removes electrons from another compound. In certain embodiments, the oxidant is a two- electron oxidant (i.e., removed two electrons from the other compound). Examples of chemical oxidants can be found in the literature, e.g., Carey and Sundberg. Advanced
  • small molecule refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight.
  • a small molecule is an organic compound (i.e., it contains carbon).
  • the small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.).
  • functional groups e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.
  • the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol.
  • the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible.
  • the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S.
  • the small molecule may also be complexed with one or more metal atoms and/or metal ions.
  • the small molecule is also referred to as a “small organometallic molecule.”
  • Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents.
  • the small molecule is a drug.
  • the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R.
  • A“large organic molecule” or“large molecule” refers to an organic compound that is not a small molecule.
  • the molecular weight of a large molecule is greater than about 2,000 g/mol, greater than about 3,000 g/mol, greater than about 4,000 g/mol, or greater than about 5,000 g/mol.
  • the molecular weight of a large molecule is at most about 100,000 g/mol, at most about 30,000 g/mol, at most about 10,000 g/mol, at most about 5,000 g/mol, or at most about 2,000 g/mol. Combinations of the above ranges (e.g., greater than about 2,000 g/mol and at most about 10,000 g/mol) are also possible.
  • the large molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)).
  • a drug e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)
  • the large molecule may also be complexed with one or more metal atoms and/or metal ions.
  • the large molecule is also referred to as an“large organometallic compound.”
  • the invention provides a method for glycosylating a hydroxyl-containing organic compound (i.e., a glycosyl acceptor), the method comprising contacting a glycosyl donor with the hydroxyl-containing organic compound, in the presence of an oxidant, to yield a glycosylated organic compound.
  • a glycosyl donor i.e., a glycosyl acceptor
  • “glycosyl donors” useful in the provided methods are of the following formula:
  • each R is independently a substituent on the pyranose backbone.
  • each substituent on the sugar backbone is independently hydrogen, optionally substituted alkyl, optionally substituted hydroxyl, optionally substituted amino, or a carbohydrate.
  • R is hydrogen.
  • R is optionally substituted alkyl.
  • R is optionally substituted hydroxyl.
  • R is optionally substituted amino.
  • R is a carbohydrate (e.g., sugar or polysaccharide).
  • each substituent on the sugar backbone is independently–CH 2 OH,–CH 2 OBn,–OH,–OBn,–OBz,–OFmoc,–OTBS,–NPhth, –CO 2 Bn,–CH 3 ,–H, or a carbohydrate (e.g., a sugar).
  • Bn is aboutCH 2 Ph
  • Fmoc is 9-fluorenylmethyl carbamate
  • TBS is tert-butyldimethylsilyl
  • NPhth is a phthalimide group.
  • the glycosyl donor is of the following formula:
  • glycosyl donor is of one of the following formulae:
  • the glycosyl donor is of the following formula:
  • the glycosyl donor is of the following formula:
  • the glycosyl donor is of the following formula:
  • glycosyl donor is of one of the following formulae:
  • the glycosyl donor is of one of the following formulae:
  • the glycosyl donor is of one of the following formulae:
  • A“glycosyl acceptor” is any hydroxyl-containing organic compound.
  • a hydroxyl- containing organic compound is any organic molecule comprising an–OH group.
  • a hydroxyl-containing organic compound is of the formula R 2 –OH, or a salt thereof, wherein R 2 is an organic compound.
  • R 2 is a small molecule.
  • R 2 is a large molecule.
  • R 2 is a carbohydrate (e.g., a sugar).
  • R 2 is a monosaccharide, disaccharide, trisaccharide, or polysaccharide.
  • the method for glycosylating a hydroxyl-containing organic compound comprises contacting a glycosyl donor provided herein, or a salt thereof, with a hydroxyl-containing organic compound of the formula R 2 –OH, or a salt thereof, in the presence of an oxidant to yield a compound of Formula (S-1):
  • each R is independently a substituent on the pyranose ring, as defined herein.
  • each substituent on the sugar backbone is independently–CH 2 OH,–CH 2 OBn,–OH,–OBn,–OBz,–OFmoc,–OTBS,–NPhth,– CO 2 Bn,–CH 3 ,–H, or another carbohydrate (e.g., a sugar).
  • the grou corres onding to:
  • the grou corres onding to:
  • the grou corres onding to:
  • the grou corres onding to:
  • the grou corres onding to:
  • the grou corres ondin to:
  • the“glycosyl acceptor” is a hydroxyl-containing organic molecule, and may be a hydroxyl-containing carbohydrate (e.g., sugar).
  • the glycosyl acceptor is a hydroxyl-containing monosaccharide
  • the product of the glycosylation is a disaccharide.
  • the glycosyl acceptor is of one of the following formulae:
  • each substituent on the sugar backbone is independently hydrogen, optionally substituted alkyl, optionally substituted hydroxyl, optionally substituted amino, or a carbohydrate.
  • R is hydrogen.
  • R is optionally substituted alkyl.
  • R is optionally substituted hydroxyl.
  • R is optionally substituted amino.
  • R is a carbohydrate (e.g., sugar or polysaccharide).
  • each substituent on the sugar backbone is independently–CH 2 OH,–CH 2 OBn,–OH,–OBn,–OBz,–OFmoc,–OTBS,–NPhth, –CO 2 Bn,–CH 3 ,–H, or a carbohydrate (e.g., a sugar).
  • Bn is aboutCH 2 Ph
  • Fmoc is 9-fluorenylmethyl carbamate
  • TBS is tert-butyldimethylsilyl
  • NPhth is a phthalimide group.
  • the glycosyl acceptor is of one of the following formulae:
  • R 1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted carbocyclyl, or optionally substituted acyl.
  • the glycosyl acceptor is of the formula:
  • the glycosyl acceptor is of the following formula:
  • R 1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted carbocyclyl, or optionally substituted acyl.
  • R 1 is optionally substituted alkyl.
  • R 1 is optionally substituted aryl.
  • R 1 is optionally substituted heteroaryl.
  • R 1 is optionally substituted heterocyclyl.
  • R 1 is optionally substituted carbocyclyl.
  • R 1 is optionally substituted acyl.
  • R 1 is optionally substituted phenyl. In certain embodiments, R 1 is substituted phenyl. In certain embodiments, R 1 is unsubstituted phenyl (i.e.,–Ph).
  • glycosyl acceptor is, in certain embodiments, of one of the following formulae:
  • the glcosl accetor is of one of the formula:
  • the glycosyl acceptor is of the formula:
  • the glycosyl acceptor is of one of the following formulae:
  • the glycosyl acceptor is of one of the following formulae:
  • the glycosyl acceptor is of the following formula:
  • the glycosyl acceptor is of the following formula:
  • the glycosyl acceptor is of the following formula:
  • glycosyl acceptor is of the following formula:
  • the hydroxyl-containing organic compound of the formula R 2 –OH, or a salt thereof, and the glycosylation product is a compound of Formula (S-1):
  • each R is independently a substituent on the pyranose ring.
  • R 2 is of any one of the following formulae:
  • R 2 is of any one of the following formulae:
  • R 2 is of any one of the following formulae:
  • R 2 is of one of the following formulae:
  • R 2 is of one of the following formulae:
  • the methods provided herein comprise a step of glycosylating that is carried out in the presence of an oxidant.
  • the oxidant is a chemical oxidant (i.e., oxidizing agent).
  • the oxidant is a 2-electron oxidant.
  • the oxidant is ceric ammonium nitrate (CAN).
  • the oxidant is a hypervalent iodine reagent.
  • the oxidant is
  • the oxidant may be used in stoichiometric, substoichiometric, catalytic, or excess amounts. In certain embodiments, less than 1 molar equivalent of the oxidant is used relative to the glycosyl donor. In certain embodiments, approximately 1 molar equivalent of the oxidant is used relative to the glycosyl donor. In certain embodiments, more than 1 molar equivalent of the oxidant is used relative to the glycosyl donor (i.e., excess).
  • 1-2 molar equivalents e.g., about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9 molar equivalents
  • approximately 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 equivalents are used.
  • the step of glycosylating may be carried out in the presence of one or more additional agents.
  • the step of glycosylating is carried out in the presence of a Lewis acid.
  • the Lewis acid is a boron species.
  • the Lewis acid is boron trifluoride.
  • the Lewis acid is boron trifluoride diethyletherate (BF 3 •OEt 2 ).
  • the Lewis acid may be used in stoichiometric, substoichiometric, catalytic, or excess amounts. In certain embodiments, less than 1 molar equivalent of the Lewis acid is used relative to the glycosyl donor.
  • the reaction is carried out in the presence of an oxidant and a Lewis acid.
  • the reaction is carried out in the presence of an oxidant and BF 3 •OEt 2 . In certain embodiments, the reaction is carried out in the presence of PIFA and a Lewis acid. In certain embodiments, the reaction is carried out in the presence of PIFA and BF 3 •OEt 2 . In certain embodiments, the reaction is carried out in the presence of approximately 1.1 equivalents of PIFA and 1 equivalent of BF 3 •OEt 2 . In certain
  • the reaction is carried out in the presence of PIFA and BF 3 •OEt 2 , in CH 2 Cl 2 and MeCN. In certain embodiments, the reaction is carried out in the presence of
  • the reaction is carried out in the presence of PIFA and BF 3 •OEt 2 , in CH 2 Cl 2 and MeCN, at room temperature. In certain embodiments, the reaction is carried out in the presence of approximately 1.1 equivalents of PIFA and 1 equivalent of BF 3 •OEt 2 , in CH 2 Cl 2 and MeCN, at room temperature. In certain embodiments, the reaction is carried out in the presence of PIFA and BF 3 •OEt 2 , in CH 2 Cl 2 and MeCN, at room temperature, for 30 minutes or more. In certain embodiments, the reaction is carried out in the presence of approximately 1.1 equivalents of PIFA and 1 equivalent of BF 3 •OEt 2 , in CH 2 Cl 2 and MeCN, at room temperature, for 30 minutes or more.
  • the step of glycosylating is carried out in a solvent.
  • the solvent may be any solvent, including polar and non-polar solvents.
  • the solvent is aprotic.
  • the solvent is a polar solvent.
  • the solvent is an alkyl nitrile.
  • the solvent is acetonitrile (MeCN).
  • the solvent is CH 2 Cl 2 .
  • the solvent is a mixture of CH 2 Cl 2 and MeCN.
  • the solvent is a mixture of CH 2 Cl 2 and MeCN (1/1).
  • the step of glycosylation can be carried out at any temperature.
  • the reaction is carried out at or around room temperature (about 21 °C).
  • the reaction is carried out at a temperature below room temperature.
  • the reaction is carried out at a temperature above room temperature.
  • the reaction is carried out at a temperature between 21 °C and 70 °C.
  • the reaction is carried out at or around 60 °C.
  • the methods described herein yield glycosylated organic molecules with anomeric selectivity.
  • “Anomeric selectivity” refers to the amount of one anomer formed in a reaction as compared to the amount of the opposite anomer formed in the reaction.“Anomers” are sugar stereoisomers that are isomeric with respect to the
  • Anomers are either alpha ( ⁇ ) or beta ( ⁇ ) anomers.
  • ⁇ and ⁇ anomeric forms are shown for compounds of Formula (S-1) below:
  • the step of glycosylating yields a glycosylated organic molecule (e.g., a compound of Formula (S-1)) in a ⁇ : ⁇ anomeric ratio greater than 1:1.
  • the ⁇ : ⁇ anomeric ratio is greater than 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 60:1, 70:1, 80:1, 90:1, or 100:1.
  • the ⁇ : ⁇ anomeric ratio is greater than 3:1. In certain embodiments, the ⁇ : ⁇ anomeric ratio is greater than 5:1. In certain embodiments, the ⁇ : ⁇ anomeric ratio is greater than 10:1. In certain embodiments, the ⁇ : ⁇ anomeric ratio is greater than 15:1. In certain embodiments, the ⁇ : ⁇ anomeric ratio is greater than 20:1. In certain embodiments, the ⁇ : ⁇ anomeric ratio is greater than 25:1.
  • the step of glycosylating yields a glycosylated organic molecule (e.g., a compound of Formula (S-1)) in a ⁇ : ⁇ anomeric ratio greater than 1:1.
  • the ⁇ : ⁇ anomeric ratio is greater than 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 60:1, 70:1, 80:1, 90:1, or 100:1.
  • the ⁇ : ⁇ anomeric ratio is greater than 3:1. In certain embodiments, the ⁇ : ⁇ anomeric ratio is greater than 5:1. In certain embodiments, the ⁇ : ⁇ anomeric ratio is greater than 10:1. In certain embodiments, the ⁇ : ⁇ anomeric ratio is greater than 15:1. In certain embodiments, the ⁇ : ⁇ anomeric ratio is greater than 20:1. In certain embodiments, the ⁇ : ⁇ anomeric ratio is greater than 25:1.
  • the glycosylated compound can be isolated in any chemical yield.
  • the compound is isolated in from 1-10%, 10-20% 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield.
  • the compound is produced in approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% yield.
  • the product may be purified via one or more purification steps.
  • the product is purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art.
  • the compound is carried forward to a subsequent synthetic step without purification (i.e., crude).
  • the glycosyl acceptor employed in the glycosylation reaction is a sugar that comprises a“latent glycosyl donor” moiety.
  • “latent glycosyl donor” moiety is a protected phenol moiety of the following formula:
  • “latent glycosyl donor” moiety is a protected phenol moiety of the following formula:
  • a method for glycosylating a hydroxyl-containing organic compound described herein further comprises the steps of:
  • step (b) contacting the compound provided in step (a) with a hydroxyl-containing organic compound (e.g., a compound of the formula R 2 –OH), or a salt thereof, in the presence of an oxidant, thereby glycosylating the hydroxyl organic compound.
  • a hydroxyl-containing organic compound e.g., a compound of the formula R 2 –OH
  • Step (b) above is a glycosylation reaction, and therefore any reagents or conditions described herein for a step of glycosylating may be used in this step.
  • any reagents or conditions may be used in the step of deprotecting.
  • the step of deprotecting is carried out in the presence of a nucleophile or base. In certain embodiments, the step of deprotecting is carried out in the presence of an alcohol. In certain embodiments, the step of deprotecting is carried out in the presence of hydroxide (e.g., NaOH, KOH, LiOH). In certain embodiments, the step of deprotecting is carried out in the presence of an alkoxide (e.g., methoxide, ethoxide). In certain embodiments, the step of deprotecting is carried out in the presence of ethanolamine. In certain embodiments, the step of deprotecting is carried out in the presence of sodium methoxide.
  • hydroxide e.g., NaOH, KOH, LiOH
  • an alkoxide e.g., methoxide, ethoxide
  • the step of deprotecting is carried out in the presence of ethanolamine. In certain embodiments, the step of deprotecting is carried out in the presence of sodium methoxide.
  • the step of deprotecting is carried out in a solvent.
  • the solvent may be any solvent, including polar and non-polar solvents.
  • the solvent is a polar solvent.
  • the solvent is an alcohol.
  • the solvent is methanol.
  • the solvent is THF.
  • the deprotection is carried out in the presence of ethanolamine. In certain embodiments, the deprotection is carried out in the presence of excess ethanolamine (i.e., greater than 1 equivalent). In certain embodiments, the
  • deprotection is carried out in the presence of excess ethanolamine in THF. In certain embodiments, the deprotection is carried out in the presence of excess ethanolamine, in THF, at around room temperature.
  • the step of deprotecting can be carried out at any temperature. In certain embodiments,
  • the reaction is carried out at or around room temperature (about 21 °C). In certain embodiments, the reaction is carried out at a temperature below room temperature. In certain embodiments, the reaction is carried out at a temperature above room temperature. In certain embodiments, the reaction is carried out at a temperature between 21 °C and 100 °C.
  • the deprotected product can be isolated in any chemical yield. In certain aspects,
  • the compound is isolated in from 1-10%, 10-20% 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield.
  • the compound is produced in approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% yield.
  • the product may be purified via one or more purification steps.
  • the product is purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art.
  • the compound is carried forward to a subsequent synthetic step without purification (i.e., crude).
  • any of the methods described herein may further comprise the steps of:
  • step (d) using the glycosyl acceptor produced in step (c) in a subsequent glycosylation reaction.
  • Any of the methods provided herein may further comprise any number of iterative glycosylating/deprotecting steps to provide a trisaccharide, polysaccharide, glycan, etc.
  • the method include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more iterations.
  • the present invention also provides compounds that are useful as glycosyl donors or glycosyl acceptors in the methods provided herein. Provided herein around compounds of the following formula:
  • the provided compound is of one of the following formulae:
  • the provided compound is of one of the following formulae:
  • the provided compound is of the following formulae:
  • the provided compound is of the following formulae:
  • the present invention provides compound of the following formula:
  • the provided compound is of one of the following formulae:
  • the provided compound is of one of the following formulae:
  • the present invention provides compounds the following formulae:
  • a provided compound is of one of the following formulae:
  • a provided compound is of one of the following formulae:
  • R 1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted carbocyclyl, or optionally substituted acyl.
  • the provided compound is of the following formula:
  • the provided compound is of the following formula:
  • the provided compound is of the following formulae:
  • the provided compound is of the formula:
  • the provided compound is of the formula:
  • the provided compound is of one of the following formulae:
  • the provided compound is of one of the following formulae:
  • the provided compound is of the following formula:
  • the provided compound is of the following formula:
  • the provided compound is of the following formula:
  • the provided compound us of the following formula:
  • kits comprising one or more compounds provided herein; optionally one or more reagents provided herein; and optionally instructions for use.
  • the kit comprises one or more glycosyl donors, one or more glycosyl acceptors; optionally a chemical oxidant (e.g., PIFA); and optionally instructions for use.
  • PIFA chemical oxidant
  • An important feature of this invention is use of these compounds in an iterative process, capitalizing on the active/latent properties designed into the system.
  • the next goal was to use the 2-O-benzoyl reagent 48 with a free C6 hydroxyl group as acceptor (Scheme 8), since it contains a latent glycosyl donor (which can be uncovered after the removal of the phenolic benzoyl group).
  • Compound 48 was prepared from glucal 43. Acceptor 48 can react with 30 under the conditions established above (Scheme 4) followed by selective benzoyl deprotection with ethanolamine to yield 50 (Scheme 9; (a) PIFA, BF 3 •OEt 2 , CH 3 CN; (b) ethanolamine, THF). Note that 30 was prepared from 49 under these deacylation conditions. Simple two-step sequences will then sequentially add monosaccharides to the chain to build the linear carbohydrate. These types of iterative glycosylations are provided and described herein. Scheme 9
  • a set of common monosaccharide building blocks are needed to prepare both branched and linear glycan structures. It is important to have a protecting group strategy that is common to all reagents to allow them to be used in a mix-and-match approach.
  • the prevalent motif observed in carbohydrate oligomers is for each monosaccharide in the chain to have two or three points of attachment to the neighboring residues (one for terminal branches).
  • every building block needs to have four types of protecting groups: (1) anomeric protection; (2) protecting groups that will only be removed in a global deprotection step at the end of the sequence; (3) a single temporary protecting group; and (4) no protecting group– a free glycosyl acceptor.
  • Benzyl groups will be utilized to protect alcohols that will be revealed in the final step; Fmoc groups will be used to protect alcohols that will be immediately revealed after glycosylation to act as glycosyl acceptors to introduce branching; Free hydroxyl groups will be revealed directly before use in glycosylation reactions and will largely be protected as silyl ethers during preparation of the building blocks (Scheme 8).
  • Seeberger has used an informatics approach to identify the most common building blocks needed to access the largest majority of known mammalian glycans (Seeberger, P. H. “The Logic of Automated Glycan Assembly”, Acc. Chem. Res.2015, 48, 1450-1463; Werz, D. B.; Ranzinger, R.; Herget, S.; Adibekian, A.; Von der Lieth, C-W.; Seeberger, P. H. “Exploring the Structural Diversity of Mammalian Carbohydrates (‘Glycospace’) by Statistical Databank Analysis”, ACS Chem. Bio.2007, 2, 685-691; Adibekian, A.;
  • Table 3 shows a set of building blocks for use in the present invention, categorized by monosaccharide type. These molecules are latent donors and can be fed into the reaction as acceptors to be glycosylated at the free hydroxyl groups. It is to be understood that all of these compounds can be protected at the free hydroxyl group (with a hydroxyl protecting group) and treated with ethanolamine to produce the corresponding donor molecules.
  • the building blocks are broken up by monosaccharide and it can be seen that there are clearly more prevalent substitution patterns for some types than others.
  • OAr is OC 6 H 4 p- OBz.
  • the synthesis of 32a begins from the known phthalimide 56 (See, e.g., Ferrier, R. J.; Hay, R. W.; Vethaviyasar, N.“A potential versatile synthesis of Glycosides,” Carbohydr. Res.1973, 27, 55–61).
  • Oxidative deprotection and introduction of the hydroquinone using the trichloroacetimidate method should afford 60 (see, e.g., Komarova, B.S.; Orekhova, M.V.; Tsvetkov, Y.E.; Nifantiev, N.E. Is an acyl group at O-3 in glucosyl donors able to control ⁇ -stereoselectivity of glycosylation? The role of conformational mobility and the protecting group at O-6”, Carb. Res.2014, 384, 70-76.
  • the hydroquinone will be introduced using the Schmidt method followed by benzoylation of the phenolic hydroxyl group and deprotection of the TBS group using TBAF to provide the target molecule 53a (see, e.g., Schmidt, R. R.; Michel, J.“Facile Synthesis of ⁇ - and ⁇ -O-Glycosyl Imidates; Preparation of Glycosides and Disaccharides”, Angew. Chem. Int. Ed.1980, 19, 731–732).
  • TMS tetramethylsilane
  • CDCl3 7.26 ppm
  • Coupling constants (J) are reported in Hz.
  • Multiplicities are reported using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet; b, broad; Carbon-13 nuclear magnetic resonance ( 13 C NMR) spectra were recorded using a Varian Unity Inova 500 MHz at 125 MHz.
  • Scheme 9 shows examples of an iterative glycosylation/deprotection/glycosylation reacrtions to access polysaccharides. Another example of this is shown below in Scheme 15.
  • glycosyl donor 50 (0.058 mmol) and glycosyl acceptor 48 (0.064 mmol) in a mixture of CH 2 Cl 2 (0.5 mL) and CH 3 CN (0.5 mL) was added BF 3 .Et 2 O (0.058 mmol, 7 ⁇ L) followed by PIFA (0.064 mmol, 28 mg) in one portion at room temperature. After 1 hour, the mixture was quenched with a saturated aqueous solution of NaHCO 3 (2 mL) then diluted with CH 2 Cl 2 (20 mL).
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.
  • the invention, or aspects of the invention is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein.

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Abstract

L'invention concerne des méthodes et des réactifs pour la glycosylation de molécules organiques. Selon un aspect, l'invention concerne une méthode de glycosylation d'un composé organique contenant un hydroxyle (c'est-à-dire, un accepteur de glycosyle) consistant à mettre en contact un donneur de glycosyle avec le composé organique contenant un hydroxyle, en présence d'un oxydant, pour obtenir un composé organique glycosylé. Selon certains modes de réalisation, les méthodes de l'invention fournissent des produits de glycosylation à haute sélectivité anomérique. Les méthodes peuvent être appliquées à la synthèse de disaccharides, de trisaccharides, de polysaccharides, de glycanes, etc. L'invention concerne également des composés (par exemple, des donneurs et des accepteurs de glycosyle) qui sont des éléments constitutifs utiles dans les réactions obtenues.
PCT/US2017/047519 2016-08-19 2017-08-18 Réactifs et méthodes de glycosylation WO2018035416A1 (fr)

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CN115073540A (zh) * 2022-07-28 2022-09-20 四川大学 一种菊粉型蔗果低聚糖单体的合成方法

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US6245902B1 (en) * 1999-08-09 2001-06-12 University Of Iowa Research Foundation C-glycoside analogs and methods for their preparation and use
US20150099870A1 (en) * 2013-10-04 2015-04-09 Trustees Of Tufts College Glycosylation Reactions Using Phenyl(trifluoroethyl)iodonium Salts

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Publication number Priority date Publication date Assignee Title
US6245902B1 (en) * 1999-08-09 2001-06-12 University Of Iowa Research Foundation C-glycoside analogs and methods for their preparation and use
US20150099870A1 (en) * 2013-10-04 2015-04-09 Trustees Of Tufts College Glycosylation Reactions Using Phenyl(trifluoroethyl)iodonium Salts

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DATABASE Pubchem [O] 28 April 2015 (2015-04-28), XP028042015, Database accession no. 91696864 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115073540A (zh) * 2022-07-28 2022-09-20 四川大学 一种菊粉型蔗果低聚糖单体的合成方法
CN115073540B (zh) * 2022-07-28 2023-08-25 四川大学 一种菊粉型蔗果低聚糖单体的合成方法

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