• 专利附录
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    • 专利摘要:
    The invention relates to chiral imidodiphosphates and derivatives thereof having the general formula I, The compounds are suitable as chiral Brønsted acid catalysts, phase-transfer catalysts, chiral anions for organic salts, metal salts or metal complexes for catalysis.
    公开号:AU2013209048A1
    申请号:U2013209048
    申请日:2013-01-08
    公开日:2014-07-24
    发明作者:Ilija Coric；Benjamin List；Sreekumar Vellalath
    申请人:Studiengesellschaft Kohle mbH；
    IPC主号:C07C317-14
    专利说明:
    WO 2013/104604 PCT/EP2013/050189 - 1 Chiral Imidodiphosphates and Derivatives thereof The present invention relates to chiral imidodiphosphates, their salts and metal complexes as well as derivatives thereof and their use as catalysts. 5 Many chemical transformations are catalyzed by Bronsted acids. In enantioselective organocatalysis, this possibility of metal-free, and in the case of chiral Bronsted acids also enantioselective, catalysis is a rapidly growing field with increasing applications. In this field of organocatalysis, a distinction is made between hydrogen bonding catalysts such 10 as thioureas and also TADDOL and BINOL derivatives and stronger Bronsted acids such as phosphoric acid diesters and derivatives thereof as disclosed in EP 1623971. Bulky phosphates have found wide application in asymmetric catalysis, however, it is challenging to further modify their steric environment because, for example, 3,3' substituents on BINOL radiate away from the active site. Significant synthetic efforts have 15 been undertaken by a number of groups to design alternative backbones that would narrow the chiral environment of the phosphoric acid as discussed in Xu, F. et al. SPINOL-Derived Phosphoric Acids: Synthesis and Application in Enantioselective Friedel Crafts Reaction of Indoles with Imines. J. Org. Chem. 75, 8677-8680 (2010) and Cori6, I., MOller, S. & List, B. Kinetic Resolution of Homoaldols via Catalytic Asymmetric 20 Transacetalization. J. Am. Chem. Soc. 132, 17370-17373 (2010). While the fields of chiral Bronsted acid catalysis and chiral anion directed catalysis have acquired wide popularity and importance in recent years, numerous transformations are still elusive, in particular reactions of small substrates that do not posses sterically 25 demanding protecting groups, large aromatic/planar surfaces, or bulky substituents are still extremely rare. Furthermore reactions including substrates or intermediates lacking spatially defined interactions such as hydrogen bonding with the catalyst are very limited. The reason for these limitations, at least in part, is the inability of current synthetic Bronsted acid catalysts and their respectful anions to provide more variable as well as 30 truly compact chiral microenvironments. The preparation of synthetic Bronsted acid catalysts that display readily tuneable steric environment, as well as the potential for highly sterically demanding chiral microenvironment around their active site is therefore desirable. 35 WO 2013/104604 PCT/EP2013/050189 -2 The present invention provides such new Bronsted acid catalysts by means of new chiral imidodiphosphates, a simple process for preparing chiral imidodiphosphates and also their use in catalysis. 5 On the field of Lewis-base promoted catalysis, imidodiphosphoric tetramide ligand system as a catalytic unit has been disclosed by Hellwig et al. in Tetrahedron Letters 42 (2001), p. 5417-19. Said catalytic system has been reported to be useful for the allylation of aldehydes with trichlorosilane in such a Lewis-base promoted catalysis only. Said ligand structures were not shown to possess beneficial properties, such as improved 10 enantioselectivity, compared to other Lewis base catalysts. Said Lewis-base catalytic systems cannot promote Bronsted acid catalysed and chiral-anion-directed reactions and are thus of limited value for a number of catalytic reactions for which the specific catalytic system of the present invention is suitable. 15 The unknown cyclic imidodiphosphates according to the present invention and the substituted derivatives thereof can be classified as strong Bronsted acids. The conjugated bases of the imidodiphosphates are likewise suitable as chiral anions in enantioselective catalysis. 20 Thus, the present invention provides chiral imidodiphosphates and derivatives thereof having the general formula (1) W Y I x Z1.... N " /....-4 I I R1 z2 z 3 n, R 4 RRZ Z3 R (1 wherein: X and Y may be, independently from each other, the same or different and represent 0, S, 25 Se and NRN
    Z
    1 to Z 4 may be, independently from each other, the same or different and represent 0, S, Se and NRN n stands for 0 or preferably 1, W is a substituent being capable of forming an ionic bond with the imidodiphosphate 30 moiety,
    R
    1 to R 4 may be, independently from each other, the same or different and may be each an aliphatic, heteroaliphatic, aromatic or heteroaromatic group, each optionally being further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic WO 2013/104604 PCT/EP2013/050189 -3 or heteroaromatic groups whereby R 1 and R 2 are forming a ring system with Z' and Z 2 and
    R
    3 and R 4 are forming a ring system with Z 3 and Z 4 , respectively, and RN may be selected from hydrogen, C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C1-C20 5 alkyl, C 2
    -C
    2 0 -alkenyl or C 2
    -C
    20 -alkinyl, C 3
    -C
    8 -heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C,-C 6 )-alkyl, heteroaryl-(C,-C 6 )-alkyl, each hydrocarbon optionally being substituted by one or more groups selected from C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C,-C 20 -alkyl, C2 10 C 20 -alkenyl or C 2
    -C
    20 -alkinyl, C 3
    -C
    8 -heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C-C 6 )-alkyl, heteroaryl-(C-C 6
    )
    alkyl or heterosubstituents, including its tautomeric and ionic forms, and derivatives thereof. 15 The inventors have found out that by forming two ring systems around the imidodiphoshate moiety of the chiral compound, the catalytic site thereof can be protected and is perfectly suitable for highly selective catalytic reactions. In the following, it is to be understood that the above formula (1) comprises its tautomeric 20 forms as represented by the formulae (Ia) or (Ib) w w Y | X Y X SZ4 Z4 R1 z2 Z3 R 4 R( z2n Z3" R 4 R (Ia) R (Ib) wherein X, Y, Z' to Z 4 , n, W, R 1 to R 4 'and RN have the meaning as defined above. In the following, it is to be understood that any of the formulae (II), (Ill), (IV) and (V) below 25 comprises its respective tautomeric forms as represented by formula (Ia) or formula (Ib). In the context of this invention, W is a substituent being capable of forming an ionic bond with the imidodiphosphate moiety. In this respect, the tautomeric forms as well as polarized bonds W+-N- are understood to be covered by said definition. 30 In the present application, the expression "imidodiphosphates" is to be understood to comprise derivatives thereof, wherein one or more of the oxygen atoms of the imidodiphosphate moiety is replaced by S, Se, NRN as defined above.
    WO 2013/104604 PCT/EP2013/050189 -4 In the above formula (1) and the derived formulae below, it is to be understood that any tautomeric form of the inventive chiral imidodiphosphates as well as any charged form thereof including any anionic form is to be comprised by the representation of said formula. It is also to be understood that imidodiphosphates could possess inherent 5 chirality even if all of the groups R' to R 4 are achiral groups. In the above formulae (1), R' to R 4 may be selected each from C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C-C 20 -alkyl, C 2
    -C
    20 -alkenyl or C 2
    -C
    20 -alkinyl, C3-C8 10 heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C-C 6 )-alkyl, heteroaryl-(C-C 6 )-alkyl, each hydrocarbon optionally being substituted by one or more groups selected from C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C-C 20 -alkyl, C 2
    -C
    20 -alkenyl or C 2
    -C
    20 -alkinyl, or C6 to C20 15 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C-C 6
    )
    alkyl, heteroaryl-(C-C 6 )-alkyl or heterosubstituents. In the above formula (1), W is a substituent being capable of forming an ionic bond with the imidodiphosphate moiety such as hydrogen, halogen, a metal such as Li, Na, K, Rb, 20 Cs, Be, Mg, Ca, Sr, Ba, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ru, Rh, Pd, Ag, W, Re, Os, Ir, Pt, Au, Al, Pb, La, Sm, Eu, Yb, U, or a cationic organic group as exemplified in Scheme 2 below. or a substituted silicon such as -SiR'RR'", wherein R', R" and R"' may be same or different and each stand for hydrogen, halogen, C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more 25 unsaturated bonds such as C,-C 20 -alkyl, C 2
    -C
    20 -alkenyl or C 2
    -C
    20 -alkinyl, C3-C8 heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C-C 6 )-alkyl, heteroaryl-(C-C 6 )-alkyl, each hydrocarbon optionally being substituted by one or more groups selected from C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more 30 unsaturated bonds such as C-C 20 -alkyl, C 2
    -C
    20 -alkenyl or C 2
    -C
    20 -alkinyl, C3-C8 heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C-C 6 )-alkyl, heteroaryl-(C-C 6 )-alkyl or a heterosubstituent. The expression "partially arene-hydrogenated forms thereof" is to be understood that in 35 case that the aromatic structure comprises more than one aromatic cycle such as for WO 2013/104604 PCT/EP2013/050189 -5 naphthalene, at least one aromatic cycle, one aromatic cycle remaining, might be partially or fully hydrogenated. The anionic form may be complemented by any cation for forming an ion pair. 5 In one embodiment of the above formulae (1), Z' to Z 4 represent 0, n is 1 and the other definitions are as given before for formula (1), as represented by formula (II): W Y I X 10 (II) R2 R R4 Y In such formulae (1) and (II), the moiety zn- rn R ,z 2 . zs ,R 4 R '2 R 15 might be a five to ten-membered ring structure of (R 1 , R 2 , Z 1 , Z 2 and -PY-) or (R 3 , R 4 , Z 3 ,
    Z
    4 and -PX-), respectively. In one embodiment of the compounds of formula (II), X and Y represent 0 and the other 20 definitions are as given before for formulae (1), as represented by formula (Ill): W 01 0 /0~~~\ N / R 2' 0 0, /R4(1) 25 In such formula (Ill), at least one of (R 1 and R 2 ) and (R 3 and R 4 ) may form a ring structure derived from a bridged aromatic structure such as biphenyl optionally substituted, BINOL, TADDOL, VAPOL, SPINOL, 1,1'-binaphthalene, 1,1'-bianthracene, 1,1-biphenanthrene, as well as the partially arene-hydrogenated forms such as 8H-BINOL, each of said rings 30 systems optionally being substituted by one or more substituents selected from heterosubstituents, C1 to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C,-C 20 -alkyl, C2
    C
    20 -alkenyl or C 2
    -C
    20 -alkinyl, C 3
    -C
    8 -heterocycloalkyl or C6 to C20 aromatic hydrocarbon such as aryl, aryl-(C-C 6 )-alkyl, heteroaryl-(C-C 6 )-alkyl, each hydrocarbon optionally being 35 substituted by one or more heterosubstituents. In such formula (Ill), the ring structure formed by (R 1 and R 2 ) or (R 3 and R 4 ) may be the same or different.
    WO 2013/104604 PCT/EP2013/050189 -6 In another embodiment, the compounds of formula (1) may be represented by formula (IV): R R R R R R R R R R O OIR R R N O R (IV) R R R R R R R R In said formula (IV), the substituent R may be the same or different on each position and 10 may each stand for hydrogen, a heterosubstituent, C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C-C 20 -alkyl, C 2
    -C
    20 -alkenyl or C 2
    -C
    20 -alkinyl, C 3
    -C
    8 -heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C-C 6
    )
    alkyl, heteroaryl-(C-C 6 )-alkyl, each hydrocarbon optionally being substituted by one or 15 more groups selected from C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C,-C 20 -alkyl, C2
    C
    20 -alkenyl or C 2
    -C
    20 -alkinyl, C 3
    -C
    8 -heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C,-C 6 )-alkyl, heteroaryl-(C,-C 6
    )
    alkyl or a heterosubstituent. 20 In said formula (IV), W is defined as given before for formula (1). The substituents on the ring structure proximal to the -Z-P- bond, such as the -0-P-bond, are preferably bulky groups and may be selected from the definitions for RN or 25 heterosubstituents. Basically, any chiral groups are possible as chiral groups for the inventive compounds. If the other group in each case is not chiral, the groups R, to R 4 are any organic group which may be saturated or unsaturated, linear, cyclic or heterocyclic, aromatic and/or 30 heteroaromatic. Three examples of said compound having the formula (IV) are shown below: R R R OR Et Et O O HO O' 35 4N0 P R = - Et - R R Et Et 1 2 3 WO 2013/104604 PCT/EP2013/050189 -7 In organic synthesis, particularly in the synthesis of pharmaceutical active compounds, chiral compounds are frequently used as catalysts in order to obtain the desired product in a high enantiomeric purity or diastereomeric purity. 5 It has been found that the compounds according to the invention are well suited as catalysts for enantioselective synthesis. Here, they function as chiral Bronsted acids or the conjugated bases thereof as chiral anions in enantioselective catalyses directed by counterions. 10 The following definitions for the individual groups R, RN, and R' to R 4 apply equally as follows. A heterosubstituent as defined according to the invention can be selected from OH, F, Cl, 15 Br, I, CN, NO 2 , SO 3 H, a monohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethyl group, CF(CF3) 2 , SF 5 , amine bound through N atom, -0-alkyl (alkoxy), O-aryl, -O-SiRs 3 , S-Rs, S(O)-Rs, S(O) 2 -Rs, COOH, CO 2 -Rs, amide, bound through C or N atom, formyl group, C(O)-Rs, COOM, where M may be a metal such as Na or K. Rs 3 may be, independently from each other, the same or different and may be each an aliphatic, 20 heteroaliphatic, aromatic or heteroaromatic group, each optionally being further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic or heteroaromatic groups. Aliphatic hydrocarbons including alkyl, alkenyl and alkinyl may comprise straight-chain, 25 branched and cyclic hydrocarbons. Heteroaliphatic is a hydrocarbon including alkyl, alkenyl and alkinyl which may comprise straight-chain, branched and cyclic hydrocarbons with one or more carbon atoms substituted with a heteroatom. 30 In more detail, C,-C 20 -Alkyl can be straight chain or branched and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Alkyl might be C 1
    -C
    6 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, likewise pentyl, 1-, 2- or 3-methylpropyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2, 35 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1- WO 2013/104604 PCT/EP2013/050189 -8 ethyl-1 -methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl. Substituted alkyl groups are trifluoromethyl, pentafluoroethyl and 1,1,1-trifluoroethyl. Cycloalkyl might be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. 5 Alkenyl might be C2-C20 alkenyl. Alkinyl might be C2-C20 alkinyl. Said unsaturated alkenyl- or alkinyl groups can be used for linking the inventive compounds to a carrier such as a polymer to serve for an immobilized catalyst. 10 Halogen is F, Cl, Br or I. Alkoxy is preferably C2-C1o alkoxy such as methoxy, ethoxy, propoxy, tert-butoxy etc.
    C
    3
    -C
    8 -Heterocycloalkyl having one or more heteroatoms selected from among N, 0 and S 15 is preferably 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, 20 -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4 pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8 isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl. 25 Optionally substituted means unsubstituted or monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or even further substituted for each hydrogen on the hydrocarbon. 30 Aryl might be phenyl, naphthyl or biphenyl. Arylalkyl might be benzyl. Heteroaryl having one or more heteroatoms selected from among N, 0 and S is preferably 35 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5 pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothia zolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, also preferably 1,2,3-triazol-1 -, -4- or -5 yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4- WO 2013/104604 PCT/EP2013/050189 -9 oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3 thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-Indolyl, 4- or 5 isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6 or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 5 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, also preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl. 10 In a preferred embodiment of the present invention as for example shown in formula (IV), at least one of R proximal to the -O-P- bond is not hydrogen and may be selected from among methyl, ethyl, isopropyl, cyclohexyl, cyclopentyl, phenyl, 2,4,6-triisopropylphenyl, 2,4,6-triethylphenyl, 2,6-diethylphenyl, 2,6-diethylphenyl, 2-isopropylphenyl, 5-methyl-2 15 isopropylphenyl, mesityl, 9-phenanthryl, 9-anthracenyl, ferrocenyl, N (perfluorophenyl)acetamide, N-(4-chlorophenyl)acetamide, N-(naphthalen-1-yl)acetamide, N-benzhydrylacetamide, N-(2,6-diisopropylphenyl)acetamide, 1-anthracenyl, corannulene, porphyrin, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 3,5-(trifluoromethyl)phenyl, 2,6 dimethylphenyl, tert-butyl, tris-methylsilyl, tert-butydimethylsilyl, phenyldimethylsilyl, 20 methyldiphenylsilyl, tris-mesitylsilyl, tris-phenylsilyl, 4-nitrophenyl and 2,6-methyl-4 butylphenyl, trifluoromethyl, unbranched (linear) and branched (C,-C 12 )-perfluoroalkyls, 3,4,5-trifluorophenyl, 1,3-bis(perfluoropropan-2-yl)phenyl, 1,3-bis(perfluorobutyl)phenyl and/or pentafluorophenyl and also chloride, iodide, fluoride, COOH, B(OH) 2 , B(alkyl) 2 , B(O-alkyl) 2 , B(pinacol), BF 3 X where X = Na or K, OTf,. The other groups are preferably 25 hydrogen. The compounds according to the invention can be converted in process steps which are well known per se to those skilled in the art into organic salts, metal salts or metal complexes. In one possible embodiment, the imidodiphosphates are reacted with an 30 appropriate metal salt, for example with the carbonate of the appropriate metal. Examples of organic salts, metal salts and metal complexes are shown in the following Scheme 1 for formula (V): WO 2013/104604 PCT/EP2013/050189 -10 Scheme 1: General examples of metal salts and metal complexes of the imidodiphosphates V. R R R R R R R R 5 | / / 0 O 11 [M+] R R R R R R R R R R R R R R 10 X In Scheme 1, any metals or organic cations, e.g. tertiary ammonium ions, can be represented by M. Even though the compounds are shown as salts in scheme 1, the 15 precise structure with metals is not known; they can also have the structure of metal complexes. The formulation metal salts or metal complexes is therefore used for the purposes of the present invention. The metal compounds are not restricted to particular metal compounds or complexes. Suitable metal compounds are derived from Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ru, Rh, Pd, 20 Ag, W, Re, Os, Ir, Pt, Au, Al, Pb, La, Sm, Eu, Yb, U.
    WO 2013/104604 PCT/EP2013/050189 - 11 Scheme 2: Examples of possible cations M*X R X- X- * R R R R R 5 tertiary carbocation salts secondary carbocation salts primary carbocation salts R R N X N X /R
    H
    2 + N+ IN N N * N H H 10 Ammonium salts R R (primary and Imidazol(in)ium salts Triazolium salts Amidinium salts secondary amines and also ammonia) R NR 2 R N R N XS, R' R -R R X H /N + 1 15 Ammonium salts + X~ H H of tertiary amines H Thiazol(in)ium salts Guanidinium salts Pyridinium salts R R NR X P- X R M*LnX H 2 N N NH 2 R 20 Quaternary Metal salts H Quaternary ammonium salts Pyridinium salts phosphonium salts The imidodiphosphates of the invention and their organic salts, metal salts and metal complexes can be prepared according an exemplary reaction path shown for imido-di 25 (BINOL-phosphate): R O 0 P/ POR l 3 pyrdine NH2 R then NH 3 (1) 0 2 30 OH R RR NaH, THF O OO HO OH R N PO O *N> H ''N 0 OC13 0 pyridine R R R 35R more specifically for the derivative with R = triethylphenyl-: WO 2013/104604 PCT/EP2013/050189 -12 Et Et Et Et Et Br OH Et BBr 3 OMe MgBr OMe 5 OHI Et Ni(PPh 3
    )
    2
    C
    2 OMe Et 89% Et 48% Br 6 Et Et 5
    POC
    3 py, 60 PC OCI py, 60 'C 96% 98 then NH 3 Et Et Et Et Et Et Et Et 10 Et, 0, 1 Et Et Et O O O NaH O //O HO O CI + / NH2 THF 0/P- -N:= O EtEtt /E Et0 76% 7 Et Et 8 Et Et Et Et Et Et 15 Use as catalysts The imidodiphosphates of the invention and their organic salts, metal salts and metal complexes are particularly suitable as strong, chiral Bronsted acid catalysts or chiral 20 Lewis acid catalysts for many reactions, in particular for the activation of ketones, aldehydes, alkenes, imines, enol ethers, ethers, alkynes, and acetals. The reactions in which compounds according to the invention can be used as catalysts include reactions such as aldol reactions, vinylic aldol reactions, Mukaiyama aldol 25 reactions, vinylic Mukaiyama aldol reactions, Mukaiyama-Michael reactions, Michael additions, Mannich reactions, TMSCN additions onto aldehydes and ketones, esterifications, etherifications, pinacol rearrangements, as well as acetalizations, transacetalization, spiroacetalization and related reactions, cycloadditions, hydroaminations, hydroalkoxylation, hydrations, haloalkoxylation, haloamination, olefin 30 activations in general, Friedel-Crafts reactions, epoxide openings, Ritter reactions, nucleophilic substitutions of alcohols, asymmetric ring openings, asymmetric reductions, transfer hydrogenations, alkyne additions, allylations, propargylations, reductions, epoxidations, olefin metathesis, isomerizations, iminium catalysis and enamine catalysis, as exemplified in the following reaction schemes. 35 WO 2013/104604 PCT/EP2013/050189 -13 K _ ___ ___ __ Br 0 OH Br 'bromoetherifications 0 )/OH o spiroacetalizations _- 0 OH O transacetalizations OH 0 OH Iacetalizations OH + o SH 0 C H + O,"( S,-acetalizations SH + O S,S-acetalizations 'SH k-aS WO 2013/104604 PCT/EP2013/050189 -14 O OH PhAlH + allylations O OH Ph HC M propargylations Ph H Ph"LI" OH Ph"'k + [H-] 0 Ph reductions OR Ph + ROH Hydroalkoxylation OH Ph ~ + !H 2 0 Hydration Ph NHR Ph + ± RNH 2 Hydroaminations Ph Ph Friedel-Crafts reactions R OH Nu Ih Ph + Nu Ph Ph Nucleophilic substitution Nu Ph + Nu-H Ph OH Epoxide openings OH + 0 H Ph Friedel-Crafts reactions N Ph H N' WO 2013/104604 PCT/EP2013/050189 -15 O OTBS OTBS 1 H OePh Mukaiyama R+ H Caldol reactions OTBS 'COPr ---- 0 OMukaiyama Michael addition
    NR
    2 OTBS NHR 2
    R
    1 H OMe R1 O 2 Me Indirect Mannich reaction + R--- CHO Diels-Alder CHO P reaction endo exa O9x0 TMSO P HR1 Hetero-Diels R R Alder reactions P o OTBS OTBS OTBS -C"O 2 R CO0 2 1R + OR -- Cycloadditions OH NHAc Ph Ph + CH3CN
    -
    P Ritter reactions 0 0
    HNH
    2 OHN Aminalization H Ph 0 ihe0 ditPh t NPh'~ P -~ Michael addition H H WO 2013/104604 PCT/EP2013/050189 -16 The compounds according to the invention can also be used for preparing a class of spiro acetal compounds. The inventors targeted spiroacetalisations of readily available hydroxyenol ethers catalysed by the inventive chiral Bronsted acid as shown in the following reaction schemes: 5 Et Et Et . Et Et Et N0 0 H 0t I Et :Et 10 Et Et Et Et 0 OH 1 (5 mol%) 01 OH 1 (0.1 mol%) 15 11 Use of the inventive catalyst 1 lead to the first highly enantioselective catalytic spiroacetalisation reaction to obtain (S)-olean 10 from alcohol 9 with an excellent enantiomeric ratio of 98:2. The (R)-enantiomer of olean was easily obtained by using the enantiomer of the catalyst. Compound 12 was obtained from alcohol 11 under similar 20 conditions also with an excellent enantiomeric ratio of 97:3. Imidodiphosphoric acid catalyst 1 proved quite general and various other small spiroacetals were obtained with high enantioselectivity. Consequently, the present invention is also directed to the use of the inventive compounds for preparing spiro-acetals. 25 As it can be seen from the above, the inventors have designed a novel class of Bronsted acids, in particular employing a C 2 -symmetric imidodiphosphate anion. In principle, such a
    C
    2 -symmetric imidodiphosphate moiety has two distinct Bronsted basic sites, 0 and N. The corresponding acid should have a flexible relative positioning of acid/basic pairs due to free P-N rotation. However, the inventor's catalyst design aimed at restricting the 30 imidodiphosphate moiety to a single 0,0-syn conformation preferably between two identical BINOL subunits with bulky 3,3'-substituents. The inventors have found that the inclusion of two BINOL subunits will result in their interlocking due to sterically demanding 3,3'-substituents as shown here: WO 2013/104604 PCT/EP2013/050189 -17 R o' N o0 5R As a direct consequence, the BINOL subunits are unable to freely rotate and the resulting molecular structure possesses a very high rigidity. Importantly, such arrangement also 10 resulted in the sterical blocking of the undesirable alternative Bronsted basic N-site. As the two BINOL subunits are identical, anion is C 2 -symmmetric, and has therefore only a single type of catalytically relevant Bronsted basic site. Consequently, the corresponding Bronsted acid possesses a single catalytically active bifunctional acid/base pair with a fixed geometry. The interlocking of BINOL-subunits could in principle also result in the 15 conformational locking of the imidodiphosphate moiety in the 0,0-anti conformation to give the 0,0-anti-atropisomer. However, the inventors found out that the formation of the corresponding 0,0-anti-atropisomer will be disfavoured with bulky 3,3'-substituents on its backbone due to sterical reasons. 20 The inventors have thus shown here that Bronsted acids with extreme steric demand and chiral pockets reminiscent of those found in enzymes can overcome limitations and solve an important problem in organic synthesis. According to the invention, the concepts as described open the door for the development of asymmetric reactions which include small and/or loosely bound molecules, and will be widely applicable. 25 The invention is further illustrated by the following Examples.
    WO 2013/104604 PCT/EP2013/050189 -18 Examples Catalyst Preparation 5 Synthesis of imidodiphosphoric acids 1 (S)-2,2'-Dimethoxy-3,3'-bis(2,4,6-triethylphenyl)-1,1'-binaphthalene (5) Et Et 10 Et 10 -OMe OMe Et Et Et 15 To magnesium turnings (583 mg, 24 mmol) activated with 1,2-dibromoethane in diethyl ether (4 ml), 2-bromo-1,3,5-triethylbenzene (3.86 g, 16 mmol) and diethylether (20 ml) were added alternately during 30 min. After complete addition the mixture was refluxed (oil bath heating) for 21 h. After cooling to ambient temperature, the solution was added to a mixture of (S)-3,3'-dibromo-2,2'-dimethoxy-1,1'-binaphthalene (4, 1.89 g, 4.0 mmol) and 20 Ni(PPh 3
    )
    2 Cl 2 (393 mg, 0.60 mmol) in anhydrous diethyl ether (40 ml). The reaction mixture was refluxed for 28 h, cooled to ambient temperature, carefully treated with saturated aqueous NH 4 CI solution (40 ml) and water (40 ml), and extracted with CH 2 Cl 2 (100 ml, 50 ml). The combined organic layers were dried (MgSO 4 ), filtered, and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel 25 using 10-15% CH 2 Cl/hexane as the eluent yielding the title compound as a colorless solid (1.22 g, 48%). 'H-NMR (400 MHz, CD 2 Cl 2 ): 6 7.89 (d, J= 8.1 Hz, 2H), 7.74 (s, 2H), 7.44-7.40 (m, 2H), 7.32-7.25 (m, 4H), 7.06 (s, 2H), 7.05 (m, 2H), 3.10 (s, 6H), 2.70 (q, J= 7.6 Hz, 4H), 2.51 (q, J= 7.6 Hz, 4H), 2.46 (q, J= 7.6 Hz, 4H), 1.30 (t, J= 7.6 Hz, 6H), 1.15 (t, J= 7.6 Hz, 30 6H), 1.08 (t, J= 7.6 Hz, 6H); 13 C-NMR (100 MHz, CD 2 Cl 2 ): 6 155.0, 144.0, 142.9, 142.8, 134.9, 134.4, 134.2, 131.4, 130.8, 128.3, 126.4, 125.9, 125.4 (2C), 125.3, 125.0, 60.1, 29.1, 27.4, 27.3, 15.8, 15.6, 15.4; HRMS (ESI+) (m/z): [M+Na] calcd for C 46
    H
    50
    O
    2 Na, 657.3703; found, 657.3708.
    WO 2013/104604 PCT/EP2013/050189 -19 (S)-3,3'-bis(2,4,6-triethylphenyl)-[1,1'-binaphthalene]-2,2'-diol (6) Et Et ~ Et 5 H tOH Et Et Et 10 A 1 M solution of BBr 3 in CH 2 0 2 (7.56 ml, 7.56 mmol) was added dropwise to the solution of (S)-5 (1.20 g, 1.89 mmol) in CH 2 Cl 2 (20 ml) at 0 0C under argon. After 40 h at room temperature, the solution was cooled to 0 0C, water (50 ml) was carefully added, and the mixture was extracted with CH 2 0 2 (50 ml). The organic layer was washed with saturated aqueous Na 2
    CO
    3 solution (50 ml), dried (MgSO 4 ), filtered, and the solvent was removed 15 under reduced pressure. The residue was purified by column chromatography on silica gel using 20% CH 2 Cl 2 /hexane as the eluent yielding the title compound as a colorless solid (1.02 g, 89%). 'H-NMR (400 MHz, CD 2 Cl 2 ): 6 7.91 (d, J= 7.9 Hz, 2H), 7.78 (s, 2H), 7.41-7.37 (m, 2H), 20 7.35-7.31 (m, 2H), 7.24-7.22 (m, 2H), 7.09-7.07 (m, 4H), 5.06 (s, 2H), 2.70 (q, J= 7.6 Hz, 4H), 2.57-2.31 (m, 8H), 1.30 (t, J= 7.7 Hz, 6H), 1.10 (t, J= 7.6 Hz, 6H), 1.02 (t, J= 7.6 Hz, 6H); 13 C-NMR (100 MHz, CD 2 Cl 2 ): 6 150.9, 145.0, 143.9, 143.8, 133.9, 132.2, 131.5, 129.6, 129.4, 128.7, 127.1, 126.2, 124.6, 124.2, 113.5, 29.1, 27.37, 27.36, 15.7, 15.6, 15.5 (+1 aromatic C, overlapped); HRMS (ESI+) (m/z): [M+Na] calcd for C 44
    H
    4 6
    O
    2 Na, 25 629.3390; found, 629.3387. (S)-4-chloro-2,6-bis(2,4,6-triethylphenyl)dinaphtho[2,1-d:1',2'-I][1,3,2] dioxaphosphepine 4-oxide (7) Et Et 30 Et O t O/EC Et Et Et WO 2013/104604 PCT/EP2013/050189 - 20 To a solution of (S)-6 (553 mg, 0.912 mmol) in pyridine (3 ml) under argon was added
    POC
    3 (255 pl, 420 mg, 2.74 mmol) at room temperature. The mixture was stirred at 60 'C for 1.5 h and then concentrated to dryness under vacuum. The residue was passed through a short silica gel column (10 g) using CH 2 Cl 2 as the eluent yielding the title 5 compound as a colorless solid (604 mg, 96%). 'H-NMR (400 MHz, CD 2 Cl 2 ): 6 8.01-7.98 (m, 2H), 7.96 (s, 1H), 7.92 (s, 1H), 7.59-7.54 (m, 2H), 7.38-7.30 (m, 4H), 7.11-7.12 (m, 2H, two overlapped doublets with small J), 7.05 (d, J= 1.2 Hz, 1H), 7.02 (d, J= 1.2 Hz, 1H), 2.74-2.69 (m, 4H), 2.55-2.29 (m, 8H), 1.32 (t, J= 7.6 Hz, 3H, overlapped), 1.31 (t, J= 7.6 Hz, 3H, overlapped), 1.26 (t, J= 7.5 Hz, 3H), 1.18 10 (t, J = 7.6 Hz, 3H), 1.01 (t, J = 7.5 Hz, 3H, overlapped), 0.99 (t, J = 7.5 Hz, 3H, overlapped); 13 C-NMR (100 MHz, CD 2 Cl 2 ): 6 145.3 (d, JC-P = 11.1 Hz), 145.2 (d, JC-P = 9.1 Hz), 144.9, 144.6, 143.6, 143.3, 142.9, 142.8, 133.4, 132.53, 132.49, 132.46, 132.44, 132.2, 132.0, 131.91, 131.90, 131.79, 131.77, 131.73, 128.8, 127.5, 127.3, 127.2, 126.8, 125.9, 125.5, 125.4, 125.0, 122.54 (d, JC-p = 2.5 Hz), 122.48 (d, JC-p = 2.8 Hz), 29.14, 15 19.12, 27.8, 27.3, 27.18, 27.15, 16.3, 15.57, 15.55, 15.49, 15.1, 14.9 (including additional peaks due to unassigned 13C-31 P-coupling, some signals are overlapped); 3 1 P-NMR (162 MHz, CD 2 Cl 2 ): 6 8.26 (s); HRMS (ESI+) (m/z): [M+Na] calcd for C 44
    H
    44 0 3 CIPNa, 709.2609; found, 709.2606. 20 (S)-4-amino-2,6-bis(2,4,6-triethylphenyl)dinaphtho[2,1-d:1',2'-I][1,3,2] dioxaphosphepine 4-oxide (8) Et Et Et 0' 0 25 o 0 NH 2 Et Et Et To a solution of (S)-6 (464 mg, 0.764 mmol) in pyridine (3 ml) under argon was added 30 POC 3 (214 pl, 351 mg, 2.29 mmol) at room temperature. After 1.5 h at 60 'C, the mixture was cooled to -78 0C and anhydrous ammonia gas was condensed into the reaction flask (ca. 10 ml). The cooling bath was removed and the mixture was allowed to warm to room temperature. The reaction mixture was then concentrated to dryness under vacuum. Residue was passed through short silica gel column (10 g) using CH 2 0 2 as the eluent 35 yielding the title compound as a colorless solid (500 mg, 98%).
    WO 2013/104604 PCT/EP2013/050189 - 21 'H-NMR (400 MHz, CD 2 Cl 2 ): 6 7.99-7.94 (m, 2H), 7.91 (s, 1H), 7.84 (s, 1H), 7.55-7.50 (m, 2H), 7.37-7.31 (m, 4H), 7.10 (d, J= 1.5 Hz, 1H), 7.08 (d, J= 1.4 Hz, 1H), 7.05 (d, J= 1.5 Hz, 1H), 6.99 (d, J= 1.4 Hz, 1H), 2.74-2.63 (m, 6H), 2.58-2.28 (m, 8H), 1.31 (t, J= 7.6 Hz, 3H, overlapped), 1.28 (t, J= 7.6 Hz, 3H, overlapped), 1.25 (t, J= 7.6 Hz, 3H, overlapped), 5 1.17 (t, J = 7.6 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H, overlapped), 0.99 (t, J = 7.5 Hz, 3H, overlapped); 13 C-NMR (100 MHz, CD 2 Cl 2 ): 6 145.9 (d, JC-P = 10.7 Hz), 145.2 (d, JC-p = 8.1 Hz), 144.7, 144.2, 143.8, 143.6, 142.8, 142.1, 133.1, 132.88, 132.85, 132.68, 132.64, 132.61, 132.5, 132.41, 132.38, 131.7, 131.6, 128.7, 128.6, 127.4, 127.3, 126.8, 126.7, 126.2, 126.1, 125.8, 125.6, 125.3, 124.8, 122.8 (d, Jc-p = 2.0 Hz), 122.5 (d, JC-P = 2.0 Hz), 10 29.1 (2C), 27.8, 27.3, 27.21, 27.17, 16.5, 15.53, 15.51, 15.4, 15.2, 14.9 (including additional peaks due to unassigned 13C-31 P-coupling, some signals are overlapped); 31
    P
    NMR (162 MHz, CD 2 Cl 2 ): 6 13.20 (s); HRMS (ESI+) (m/z): [M+Na] calcd for
    C
    44
    H
    4 6
    NO
    3 PNa, 690.3108; found, 690.3114. 15 0,0-syn-Imidodiphosphoric acid 1 Et Et Et Et Et Et 0 HO 20 0 / N E Et Et Et Et Et Sodium hydride (60% dispersion of in mineral oil, 84 mg, 2.1 mmol) was added to a 25 solution of (S)-8 (464 mg, 0.764 mmol) and (S)-7 (577 mg, 0.84 mmol) in THF (5 ml) under argon at room temperature. After 14 h at room temperature, 10% aqueous HCI solution (10 ml) and DCM (10 ml) were added, and the mixture was stirred for 1 h. The organic layer was separated and the solvent was removed under reduced pressure. The residue was purified by column chromatography on aluminum oxide (activity I) using 20 30 100% CH 2 Cl/hexane followed by 2-8% EtOAc/DCM as the eluents giving a colorless solid. The solid was dissolved in CH 2 Cl 2 (10 ml) and stirred with 3N aqueous HCI (10 ml) for 4 h. The organic layer was separated, washed with 3N aqueous HCI (10 ml) and concentrated under reduced pressure to give the title compound as a colorless solid (695 mg, 76%). 35 'H-NMR (500 MHz, CD 2 Cl 2 ): 6 7.90 (d, J= 8.2 Hz, 1H), 7.87 (d, J= 8.2 Hz, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 7.51 (t, J= 7.5 Hz, 1H), 7.46-7.38 (m, 3H), 7.23-7.20 (m, 1H), 7.05 (d, J WO 2013/104604 PCT/EP2013/050189 - 22 -8.6 Hz, 1H), 6.97 (s, 1H), 6.863 (s, 1H), 6.856 (s, 1H), 6.61 (broad s, 1.8H, acidic H +
    H
    2 0), 6.39 (s, 1H), 2.65-2.50 (m, 4H), 2.32-2.12 (m, 5H), 2.07-2.00 (m, 1H), 1.92-1.82 (m, 1H), 1.20 (t, J= 7.6 Hz, 3H, overlapped), 1.19 (t, J= 7.6 Hz, 3H, overlapped), 1.17-1.10 (m, 1H, overlapped), 1.08 (t, J= 7.5 Hz, 3H), 0.95 (t, J= 7.5 Hz, 3H), 0.82 (t, J= 7.5 Hz, 5 3H), 0.04 (t, J= 7.5 Hz, 3H); 13 C-NMR (125 MHz, CD 2 Cl 2 ): 6 146.4, 145.8, 144.2, 144.0, 143.8, 143.5, 143.4, 142.5, 133.1, 133.0, 132.94, 132.86, 132.82, 132.5, 132.4, 132.1, 131.6, 131.3, 128.6, 128.5, 127.6, 127.1, 126.5, 126.4, 125.9, 125.7, 125.6, 125.4, 124.72, 124.70, 122.7, 122.2, 29.0, 28.9, 27.28, 27.25, 26.99, 26.97, 15.85 (2C), 15.77, 15.3, 15.2, 14.9; 3 1 P-NMR (202 MHz, CD 2 Cl 2 ): 6 4.94 (s); HRMS (ESI-) (m/z): [M-H] calcd 10 for C 88
    H
    88
    NO
    6
    P
    2 , 1316.6092; found, 1316.6096. O,0-syn-Imidodiphosphoric acid 2 Et Et Et Et 15 Et Et Et Et 0 + 'p ' O NH2 CI% N P Et Et Et Et Et Et Et Et 13 14 2 20 Sodium hydride (60% dispersion of in mineral oil, 13.7 mg, 0.34 mmol) was added to a solution of (S)-13 (70 mg, 0.114 mmol) and (S)-14 (114 mg, 0.18 mmol) in THF (2 ml) under argon at room temperature. After 2.5 days at room temperature 10% aqueous HCI solution (5 ml) and DCM (5 ml) were added to the mixture, which was stirred for 4 h. The 25 organic layer was separated and the solvent removed under reduced pressure. The residue was purified by column chromatography on aluminum oxide (activity I) using 0 12% EtOAc/DCM as the eluent giving a colorless solid. The solid was dissolved in CH 2 0 2 (5 ml) and stirred with 3N aqueous HCI (10 ml) for 4 h. The organic layer was separated, and concentrated under reduced pressure to give the title compound as a colorless solid 30 (76 mg, 61%). 'H-NMR (500 MHz, acetone-d 6 ): 6 8.05 (d, J= 8.2 Hz, 2H), 8.02 (d, J= 8.2 Hz, 2H), 7.89 (s, 2H), 7.69 (s, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.40 (d, J= 8.7 Hz, 2H), 7.28 (t, J= 7.7 Hz, 2H), 7.18 (t, J= 7.6 Hz, 2H), 7.11 (t, J= 35 7.6 Hz, 2H), 7.07 (d, J= 8.6, 2H), 7.04 (d, J= 7.6 Hz, 2H), 7.00 (d, J= 7.4 Hz, 2H), 6.93 (d, J= 7.4 Hz, 2H), 6.65 (d, J= 7.6 Hz, 2H), 2.33-2.07 (m, 12H), 1.96-1.89 (m, 2H), 1.37- WO 2013/104604 PCT/EP2013/050189 - 23 1.31 (m, 2H), 1.05 (t, J = 7.7 Hz, 6H), 1.03 (t, J = 7.7 Hz, 6H), 0.79 (t, J = 7.5 Hz, 6H), 0.01 (t, J= 7.5 Hz, 6H); 13 C-NMR (125 MHz, acetone-d 6 ): 6 146.7, 146.4, 144.0, 143.6, 143.3, 142.7, 136.1, 136.0, 133.5, 133.1, 133.0, 132.8, 132.5, 132.0, 131.7, 129.2, 129.1, 128.6, 128.5, 127.5, 127.3, 127.1, 127.1, 126.8, 126.5, 126.4, 125.9, 125.5, 125.3, 123.2, 5 122.8, 28.0, 27.7, 27.4, 27.3, 15.8, 15.4, 15.3, 14.9; 31 P-NMR (202 MHz, acetone-d 6 ): 6 5.73 (s); HRMS (ESI-) (m/z): [M-H] calcd for CoH 72 N0 6
    P
    2 , 1204.4840; found, 1204.4846. O,0-syn-Imidodiphosphoric acid 3
    NH
    2 CI /N 0 -~- 0- - 0 0 15 15 16 3 Sodium hydride (60% dispersion of in mineral oil, 24 mg, 0.60 mmol) was added to a solution of (S)-15 (140 mg, 0.20 mmol) and (S)-16 (173 mg, 0.24 mmol) in THF (2 ml) under argon at room temperature. After 4 days at room temperature, water (5 ml) was 20 added and the mixture was extracted with CH 2 Cl 2 (5 x 10 ml). The organic extracts were washed with brine, dried (MgSO 4 ), filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using 0-4% EtOAc/DCM as the eluent giving a colorless solid. The solid was dissolved in CH 2 Cl 2 (10 ml) and washed with 3 N aqueous HCI (10 ml). The organic layer was separated, and 25 concentrated under reduced pressure to give the title compound as a yellowish solid (101 mg, 37%). 'H-NMR (500 MHz, CD 2 Cl 2 ): 6 8.21 (s, 2H), 8.06 (d, J= 8.4 Hz, 4H), 7.91 (s, 2H), 7.87 (d, J= 8.2 Hz, 2H), 7.83 (d, J= 8.6 Hz, 2H), 7.80 (s, 2H), 7.74-7.64 (m, 14H), 7.53 (t, J= 7.6 Hz, 2H), 7.48-7.39 (m, 8H), 7.36-7.33 (m, 2H), 7.31-7.27 (m, 6H), 7.11-7.10 (m, 4H), 6.91 30 6.87 (m, 2H), 5.87 (t, J= 7.4 Hz, 2H), 5.59-5.56 (m, 2H), 5.15 (broad s, 2.43H, acidic H +
    H
    2 0); 13 C-NMR (125 MHz, CD 2 Cl 2 ): 6 146.5, 146.4, 146.4, 146.1, 146.1, 146.0, 133.9, 133.1, 133.0, 132.8, 131.9, 131.4, 131.2, 131.1, 131.0, 131.0, 130.8, 130.7, 130.4, 130.3, 130.2, 130.2, 130.0, 129.0, 129.0, 128.8, 128.7, 128.5, 128.1, 127.5, 127.4, 127.3, 127.2, 127.1, 127.1, 126.8, 126.6, 126.2, 126.1, 125.5, 125.4, 125.2, 125.1, 124.4, 124.2, 124.0, 35 124.0, 122.5; 3 1 P-NMR (202 MHz, CD 2 Cl 2 ): 6 13.74 (s); HRMS (ESI-) (m/z): [M-H] calcd for C 96
    H
    56
    NO
    6
    P
    2 , 1380.3588; found, 1380.3584.
    WO 2013/104604 PCT/EP2013/050189 - 24 Substrate Preparation 4-(3,4-Dihydro-2H-pyran-6-yl)butan-1-ol (9) 5 0 1) n-BuLi 0 OH 51 , OTBS , OH 2) TBAF A 2.5 M solution of n-butyl lithium in hexane (2 ml, 5 mmol) was added dropwise to a 10 solution of 3,4-dihydro-2H-pyran (457 pl, 420 mg, 5 mmol) in THF (2 ml) at 0 'C under argon atmosphere. After being stirred at 50 0C for 1 h, the mixture was cooled to -10 C. A solution of the tert-butyl(4-iodobutoxy)dimethylsilane (5 mmol) in THF (2 ml) was added to the mixture at -10 0C. The mixture was heated to 50 0C for 1.5 h, cooled to room temperature, and filtered through celite and aluminum oxide (5 g, activity Ill) using hexane 15 as the eluent. The solvent was removed under reduced pressure and the residue was treated with 1 M solution of tetrabutylammonium fluoride (6 mmol, 6 ml) for 1 h 45 min. The mixture was then diluted with hexane (10 ml) and filtered through celite and aluminum oxide (5 g, activity Ill) using Et 2 0 as the eluent. The solvent was removed under reduced pressure and the residue was purified by column chromatography on aluminum oxide 20 (activity Ill) using 10% EtOAc/hexane as the eluent giving a colorless oil, 349 mg, 45 %. 'H-NMR (500 MHz, C 6
    D
    6 ): 6 4.45 (t, J= 3.7 Hz, 1 H), 3.77-3.75 (m, 2H), 3.37-3.34 (m, 2H), 2.06 (t, J = 7.5 Hz, 2H), 1.83-1.80 (m, 2H), 1.60-1.54 (m, 2H), 1.49-1.45 (m, 2H), 1.44 1.39 (m, 2H), 0.69 (t, J = 5.2 Hz, 1H); 13 C-NMR (125 MHz, C 6
    D
    6 ): 6 154.8, 95.3, 66.0, 62.6, 34.6, 32.6, 23.7, 22.8, 20.6; HRMS (El (FE)) (m/z): [M] calcd for CH 16 0 2 , 156.1150; 25 found, 156.1149. 3-(4,5-Dihydrofuran-2-yl)propan-1-ol (11) 3 t-BuLi 0 30 Q4/ - OH
    BF
    3 xOEt 2 A 1.7 M solution of tert-butyl lithium in pentane (2.94 ml, 5 mmol) was added dropwise to a solution of dihydrofuran (378 pl, 350 mg, 5 mmol) in THF (2 ml) at -78 'C under argon atmosphere. After being stirred at 0 0C for 30 min, the mixture was cooled to -78 0C and 35 diluted with THF (3 ml). Oxetane (650 pl, 581 mg, 10 mmol) was added to this mixture followed by the dropwise addition of BF 3 -OEt 2 (634 pl, 710 mg, 5 mmol). The mixture was WO 2013/104604 PCT/EP2013/050189 - 25 stirred for 15 min at -78 0C, and Et 3 N (2 ml) was added dropwise and the mixture was allowed to warm to room temperature. The mixture was filtered through aluminum oxide (10 g, activity Ill, preconditioned with Et 2 0) using 5% MeOH/Et 2 O as eluent. The solvent was removed under reduced pressure and the residue was purified by column 5 chromatography on aluminum oxide (activity Ill) using 20% EtOAc/hexane as the eluent giving a colorless oil, 483 mg, 97 %. 'H-NMR (400 MHz, DMSO-d 6 ): 6 4.59-4.57 (m, 1H), 4.39 (t, J= 5.2 Hz, 1H), 4.20 (t, J= 9.4 Hz, 2H), 3.38 (q, J = 6.0 Hz, 2H), 2.54-2.49 (m, 2H, overlap with solvent), 2.07-2.03 (m, 2H), 1.59-1.52 (m, 2H); 13 C-NMR (100 MHz, DMSO-d 6 ): 6 158.2, 93.3, 69.0, 60.1, 10 29.6, 29.4, 23.9; HRMS (El (FE)) (m/z): [M] calcd for C 7
    H
    12 0 2 , 128.0837; found, 128.0836. Catalytic Tests General procedure for the catalytic asymmetric spiroacetalisation 15 Et Et Et Et Et Et 20 HO Et Et E 20 0 Et Et Et Et00 C / OH solvent, molecular sieves n1 0.025 M qn'1 f n 2 Solvent (7 ml) and molecular sieves were cooled to the reaction temperature in a vial 25 closed with a septum. A solution of substrate (0.25 mmol) in solvent (2 ml) was added, and the mixture stirred for 5-10 min allowing it to reach the reaction temperature. To the mixture a solution of catalyst 1 in solvent (1 ml) was added dropwise. After 12-24 h at the designated temperature the reaction was quenched with Et 3 N (50 pl). Purification was performed by chromatography as described for individual case. Solutions 30 of products after chromatography were carefully concentrated to ca. <0.1 ml, and immediately dissolved in C 6
    D
    6 (3 ml). Yield was determined by 1 H NMR analysis using 1 ml of this solution and Ph 3 CH (20.4 mg, 0.0833 mmol) as internal standard, integration of Ph 3 CH vs. product -CH 2 0-. NMR spectra without remaining solvent are obtained after concentrating the other 2 ml of the C 6
    D
    6 solution (previously used for optical rotation 35 measurement) to <0.3 ml and diluting with C 6
    D
    6 . Alternatively, after concentration to <50 mg, part of the sample was directly used for optical rotation measurement, and the WO 2013/104604 PCT/EP2013/050189 - 26 rest immediately used for NMR analysis, and yield corrected for residual solvent by integration in 'H NMR spectrum. Due to the volatility of the products some imprecision in the determination of yields and optical rotation values is expected. Absolute configuration of (S)-10 was determined by comparison with literature value and 5 configurations of other products were assigned by analogy. (S)-1,7-Dioxaspiro[5.5]undecane ((S)-10) c 0x0 10 Reaction conditions: catalyst loading, 5 mol%; solvent, tert-butyl-methyl ether; molecular sieves, 4 A (50 mg); temperature, -25 IC, 24 h. Purification: mixture concentrated to <1 ml, silica gel column using 5% Et 2 0/pentane as eluent. Colorless liquid, yield 77%. 'H-NMR (400 MHz, C 6
    D
    6 ): 6 3.71-3.64 (m, 2H), 3.57-3.52 (m, 2H), 2.03-1.91 (m, 2H), 15 1.68-1.62 (m, 2H), 1.51-1.30 (m, 6H), 1.27-1.22 (m, 2H); 13 C-NMR (100 MHz, C 6
    D
    6 ): 6 94.9, 60.2, 36.3, 25.8, 19.1; HRMS (El (FE)) (m/z): [M] calcd for CqH 16 0 2 , 156.1150; found, 156.1151; [a] 2 5 = +121.5 0 (c = 0.85 in pentane, er 98:2) (Literature value for (R) 10: [a]"= -122.8 , c = 3.2 in pentane, e.r. >97.5:2.5); Chiral GC (Column: 25 m Lipodex G (octakis-(2,3-di-0-pentyl-6-0-methyl)-y-cyclodextrin), i.D. 0.25 mm; Detector: FID; 20 Temperature: injector 230 OC, detector 350 OC, oven 100 OC; gas: 0.5 bar H 2 ), tminor = 4.86 min, tmaor = 5.36 min, er = 98:2. (R)-1,7-Dioxaspiro[5.5]undecane ((R)-10) 25 6 00 Reaction conditions: catalyst loading, 5 mol%; solvent, tert-butyl-methyl ether; molecular sieves, 4 A (50 mg); temperature, -25 0C, 12 h. Purification: mixture concentrated to <1 ml, silica gel column using 5% Et 2 0/pentane as eluent. Colorless liquid, yield 70%. 30 1 H-NMR (500 MHz, C 6
    D
    6 ): 6 3.70-3.65 (m, 2H), 3.57-3.53 (m, 2H), 2.02-1.92 (m, 2H), 1.67-1.63 (m, 2H), 1.50-1.30 (m, 6H), 1.27-1.22 (m, 2H); 13 C-NMR (125 MHz, C 6
    D
    6 ): 6 94.9, 60.2, 36.3, 25.8, 19.1; [a]2= -96.3 0 (c = 0.91 in C 6
    D
    6 , er 97.5:2.5); Chiral GC (Column: 25 m Lipodex-G (octakis-(2,3-di-0-pentyl-6-0-methyl)-y-cyclodextrin), i.D. 0.25 mm; Detector: FID; Temperature: injector 230 0C, detector 350 OC, oven 100 0C; gas: 0.5 35 bar H 2 ), tmajor = 4.53 min, tminor = 5.05 min, er = 97.5:2.5.
    WO 2013/104604 PCT/EP2013/050189 - 27 (S)-1,6-dioxaspiro[4.4]nonane (12) 5 Reaction conditions: catalyst loading, 0.1 mol%; solvent, CH 2 Cl 2 ; molecular sieves, 3 A (125 mg); temperature, -55 0C, 12 h. Purification: To the mixture Et 3 N (0.5 ml) was added, mixture concentrated to <1 ml, silica gel column using 10% Et 2 0/pentane as eluent. Colorless liquid, yield 62%. 10 "H-NMR (400 MHz, C 6
    D
    6 ): 6 3.93-3.87 (m, 2H), 3.74-3.68 (m, 2H), 2.01-1.83 (m, 4H), 1.69-1.61 (m, 2H), 1.58-1.48 (m, 2H); 13 C-NMR (100 MHz, C 6
    D
    6 ): 6 114.6, 66.9, 34.8, 25.0; HRMS (El (FE)) (m/z): [M] calcd for C 7
    H
    12 0 2 , 128.0837; found, 128.0838; [a]2= +182.4 0 (c = 0.44 in pentane, er 96:4); Chiral GC (Column: 25 m Lipodex-G (octakis-(2,3 di-0-pentyl-6-0-methyl)-y-cyclodextrin), i.D. 0.25 mm; Detector: FID; Temperature: 15 injector 230 0C, detector 350 0C, oven 95 0C; gas: 0.5 bar H 2 ), tmlnor = 2.82 min, tmajor = 3.00 min, er = 96:4.
    权利要求:
    Claims (16)
    [1] 1. A chiral imidodiphosphate having the general formula (1) W Y I x 5 Z, \ . N, // Z 4 m I 1 4 R 2'Z~ ZmRERl wherein: X and Y may be, independently from each other, the same or different and 10 represent 0, S, Se and NRN Z 1 to Z 4 may be, independently from each other, the same or different and represent 0, S, Se and NRN n stands for 0 or 1, W is a substituent being capable of forming an ionic bond with the 15 imidodiphosphate moiety, R 1 to R 4 may be, independently from each other, the same or different and may be each an aliphatic, heteroaliphatic, aromatic or heteroaromatic group, each optionally being further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic or heteroaromatic groups whereby R 1 and R 2 are forming 20 a ring system with Z' and Z 2 and R 3 and R 4 are forming a ring system with Z 3 and Z 4 , respectively, and RN may be selected from hydrogen, C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C,-C 20 -alkyl, C 2 -C 2 0 -alkenyl or C 2 -C 20 -alkinyl, C 3 -C 8 -heterocycloalkyl or C6 25 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C,-C 6 )-alkyl, heteroaryl-(C-C 6 )-alkyl, each hydrocarbon optionally being substituted by one or more groups selected from C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C-C 20 -alkyl, C 2 -C 20 -alkenyl or C 2 -C 20 -alkinyl, C 3 -C 8 -heterocycloalkyl 30 or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C,-C 6 )-alkyl, heteroaryl-(C -C 6 )-alkyl or heterosubstituents, including its tautomeric and ionic forms, and derivatives thereof.
    [2] 2. A chiral imidodiphosphate and derivatives thereof according to claim 1, wherein in 35 formula (1), Z' to Z 4 represent 0, n is 1, R 1 to R 4 , R, X and Y as well as W are as defined before, as represented by formula (II): WO 2013/104604 PCT/EP2013/050189 - 29 w Y I x 0 N" /(1 I I I R 2 R 4 5
    [3] 3. A chiral imidodiphosphate according to claim 1 or 2, wherein at least one moiety X Z/" or R 'R Zn Zlo R R4 10 is a five to ten-membered ring structure and R' to R 4 , R, X and Y as well as W are as defined before.
    [4] 4. A chiral imidodiphosphate according to any of claims 1 to 3 wherein, in formula (1), Z' to Z 4 represent 0, n is 1, X and Y represent 0, R' to R 4 as well as W are as 15 defined before, as represented by formula (Ill): w N\N, / 20
    [5] 5. A chiral imidodiphosphate according to claim 4, wherein, in such formula (Ill), R' to R 4 , respectively may each be selected from C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C,-C 20 -alkyl, C 2 -C 20 -alkenyl or C 2 -C 2 0 -alkinyl, C3-C8 heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene 25 hydrogenated forms such as aryl, aryl-(C,-C 6 )-alkyl, heteroaryl-(C,-C 6 )-alkyl, each hydrocarbon optionally being substituted by one or more groups selected from C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C,-C 2 0 -alkyl, C 2 -C 20 -alkenyl or C2 C 2 0 -alkinyl, C 3 -C 8 -heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially 30 arene-hydrogenated forms such as aryl, aryl-(C-C 6 )-alkyl, heteroaryl-(C-C 6 )-alkyl or heterosubstituents, and W may be selected from hydrogen, halogen, a metal such as Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ru, Rh, Pd, Ag, W, Re, Os, Ir, Pt, Au, Al, Pb, La, Sm, Eu, Yb, U, or a cationic organic group, or a 35 substituted silicon -SiR'R"R'", wherein R', R" and R"' may be same or different and each stand for hydrogen, halogen, C, to C20 straight chain, branched chain or WO 2013/104604 PCT/EP2013/050189 - 30 cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C,-C 20 -alkyl, C 2 -C 2 0 -alkenyl or C 2 -C 20 -alkinyl, C 3 -C 8 -heterocycloalkyl or C6 to Co aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C,-C 6 )-alkyl, heteroaryl-(C,-C 6 )-alkyl, each hydrocarbon optionally being 5 substituted by one or more groups selected from C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C,-C 20 -alkyl, C 2 -C 20 -alkenyl or C 2 -C 20 -alkinyl, C 3 -C 8 -heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms thereof, such as aryl, aryl-(C-C 6 )-alkyl, heteroaryl-(C-C 6 )-alkyl, or heterosubstituents, 10 including its tautomeric and ionic forms, and derivatives thereof.
    [6] 6. A chiral imidodiphosphate according to claim 4 or 5, wherein, in such formula (Ill), (R 1 and R 2 ) and (R 3 and R 4 ), respectively each form a ring structure which may be the same or different and is derived from a bridged, optionally dimeric, aromatic 15 structure such as biphenyl optionally substituted, BINOL, TADDOL, VAPOL, SPINOL, 1,1'-binaphthalene, 1,1'-bianthracene, 1,1-biphenanthrene, or a partially arene-hydrogenated form of such aromatic ring structure such as 8H-BINOL, each of said rings systems optionally being substituted by one or more substituents which may be the same or different on each position and may each be selected 20 from hydrogen, heterosubstituents, C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C,-C 20 -alkyl, C 2 -C 2 0 -alkenyl or C 2 -C 20 -alkinyl, C 3 -C 8 -heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C,-C 6 )-alkyl, heteroaryl-(C,-C 6 )-alkyl, each hydrocarbon optionally being 25 substituted by one or more groups selected from C, to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds such as C-C 20 -alkyl, C 2 -C 20 -alkenyl or C 2 -C 20 -alkinyl, C 3 -C 8 -heterocycloalkyl or C6 to C20 aromatic hydrocarbon and partially arene-hydrogenated forms such as aryl, aryl-(C,-C 6 )-alkyl, heteroaryl-(C-C 6 )-alkyl or a heterosubstituent, and 30 W is as defined before, including its tautomeric and ionic forms, and derivatives thereof.
    [7] 7. A chiral imidodiphosphate according to claim 5 or 6, wherein the compound of formula (1) may be represented by formula (IV): 35 WO 2013/104604 PCT/EP2013/050189 -31 R R R R R R R R R (IV) R ON,0 0 R R R R R N R N 0 - R W 5 R R R R R R R R wherein in said formula (IV), the substituent R may be same or different on each position and may be heterosubstituent or RN as defined in claim 1, and W has the meaning as defined in claim 5. 10
    [8] 8. A chiral imidodiphosphate according to any of claims 4 to 7, wherein at least one of said ring structures formed by (R 1 and R 2 ) or (R 3 and R 4 ) is chiral, preferably with a C2 symmetry axis. 15
    [9] 9. A chiral imidodiphosphate according to any of claims 4 to 7, wherein the ring structures formed by (R' and R 2 ) or (R 3 and R 4 ), respectively, are identical.
    [10] 10. A chiral imidodiphosphate according to claim 1, as represented by the following formula (IVa): 20 S R R O 0 0 0 (IVa) O 0 N 0 R R9 25 wherein the substituent R may be the same or different on each position and may be defined as in claim 7 W is as defined in claim 5. including its tautomeric and ionic forms, and derivatives thereof. 30
    [11] 11. A chiral imidodiphosphate according to claim 10, wherein the substituent R is the same on each position.
    [12] 12. A chiral imidodiphosphate according to any of the preceding claims, wherein W is 35 hydrogen. WO 2013/104604 PCT/EP2013/050189 - 32
    [13] 13. A process for preparing chiral imidodiphosphates of the general formula (V) comprising the steps of reacting a compound of the general formula (VI) in the presence of a basic compound in an organic solvent with a compound of the general formula (VII) to yield a compound of the general formula (V) as shown in 5 the following reaction scheme R R R R R R R R R O 1 1 O R R RR R O PL + HN RR ' 5;O' H 00 R~ R RR R R R R (VI) (Vll) R R R R R R R R R OVI) 00 R R (V) 15 R R R N R R R R R R R R R wherein in said formulae (V), (VI and Vll): L represents a leaving group selected from halogen, alkoxy, aryloxy, heteroaryloxy 20 aryl, heteroaryl, OH, and R and W are as defined in claim 10.
    [14] 14. The use of a chiral imidodiphosphate of the general formula (1) as a chiral Bronsted acid catalyst in organic synthesis. 25
    [15] 15. The use of a chiral imidodiphosphate of the general formula (1) as a chiral anion in phase-transfer catalysis, or as chiral anion for organic salts, metal salts or metal complexes as catalysts. 30
    [16] 16. The use of a chiral imidodiphosphate of the general formula (1) as a chiral catalyst in organic synthesis, wherein the synthetic reaction is selected from aldol reactions, vinylic aldol reactions, Mukaiyama aldol reactions, vinylic Mukaiyama aldol reactions, Mukaiyama-Michael reactions, Michael additions, Mannich reactions, TMSCN additions onto aldehydes and ketones, esterifications, 35 etherifications, pinacol rearrangements, as well as acetalizations, transacetalisations, spiro-acetalisations and related reactions, cycloadditions, WO 2013/104604 PCT/EP2013/050189 - 33 hydroaminations, hydroalkoxylation, hydrations, haloalkoxylation, haloamination, olefin activations in general, Friedel-Crafts reactions, epoxide openings, Ritter reactions, nucleophilic substitutions of alcohols, asymmetric ring openings, asymmetric reductions, transfer hydrogenations, alkyne additions, allylations, 5 propargylations, reductions, epoxidations, olefin metathesis, isomerizations, iminium catalysis and enamine catalysis.
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    法律状态:
    2017-08-24| FGA| Letters patent sealed or granted (standard patent)|
    优先权:
    申请号 | 申请日 | 专利标题
    EP12150663.8A|EP2615098A1|2012-01-10|2012-01-10|Chiral imidodiphosphates and derivatives thereof|
    EP12150663.8||2012-01-10||
    PCT/EP2013/050189|WO2013104604A1|2012-01-10|2013-01-08|Chiral imidodiphosphates and derivatives thereof|
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