Chiral imidodiphosphates and derivatives thereof

Abstract

The invention relates to chiral imidodiphosphates and derivatives thereof having the general formula I, ##STR00001## The compounds are suitable as chiral Brønsted acid catalysts, phase-transfer catalysts, chiral anions for organic salts, metal salts or metal complexes for catalysis.

Claims

1. A chiral imidodiphosphate having the formula (I): ##STR00032## wherein: X and Y are, independently from each other, the same or different and represent one of O, S, Se and NR.sup.N, Z.sup.1 to Z.sup.4 represent O, n stands for 0 or 1, W is a substituent capable of forming an ionic bond with the imidodiphosphate moiety, R.sup.1 to R.sup.4 are, independently from each other, the same or different and are 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.sup.1 and R.sup.2 form a ring system with Z.sup.1 and Z.sup.2 and R.sup.3 and R.sup.4 form a ring system with Z.sup.3 and Z.sup.4, respectively, and R.sup.N is selected from hydrogen, C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, each hydrocarbon optionally being substituted by one or more groups selected from C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, or its tautomeric forms, or ionic forms.

2. The chiral imidodiphosphate according to claim 1, wherein in formula (I), Z.sup.1 to Z.sup.4 represent O, n is 1, R.sup.1 to R.sup.4, R.sup.N, X and Y as well as W are as defined as in claim 1, as represented by formula (II): ##STR00033##

3. The chiral imidodiphosphate according to claim 1, wherein at least one moiety ##STR00034## is a five to ten-membered ring structure and R.sup.1 to R.sup.4, R.sup.N, X and Y as well as W are as defined as in claim 1.

4. The chiral imidodiphosphate according to claim 1, wherein, in formula (I), Z.sup.1 to Z.sup.4 represent O, n is 1, X and Y represent O, R.sup.1 to R.sup.4 as well as W are as defined as in claim 1, as represented by formula (III): ##STR00035##

5. The chiral imidodiphosphate according to claim 4, wherein, in such formula (III), R.sup.1 to R.sup.4, respectively are selected from C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, each hydrocarbon optionally being substituted by one or more groups selected from C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, and W is selected from hydrogen, halogen, a metal, or a cationic organic group, or a substituted silicon —SiR.sup.IR.sup.IIR.sup.III, wherein R.sup.I, R.sup.II and R.sup.III are same or different and each stand for hydrogen, halogen, C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, each hydrocarbon optionally being substituted by one or more groups selected from C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms thereof, or its tautomeric forms, or ionic forms.

6. The chiral imidodiphosphate according to claim 4, wherein, in such formula (III), (R.sup.1 and R.sup.2) and (R.sup.3 and R.sup.4), respectively each form a ring structure which is the same or different and is derived from a bridged, optionally dimeric, aromatic structure, or a partially arene-hydrogenated form of such aromatic ring structure, each of said rings systems optionally being substituted by one or more substituents which are the same or different on each position and are selected from hydrogen, heterosubstituents, C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, each hydrocarbon optionally being substituted by one or more groups selected from C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, and W is as defined as in claim 4, or its tautomeric forms, or ionic forms.

7. The chiral imidodiphosphate according to claim 5, wherein the compound of formula (I) is represented by formula (IV): ##STR00036## wherein in said formula (IV), the substituent R is same or different on each position and is selected from hydrogen, heterosubstituent, C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, each hydrocarbon optionally being substituted by one or more groups selected from C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, and W has the meaning as defined in claim 5.

8. The chiral imidodiphosphate according to claim 4, wherein at least one of said ring structures formed by (R.sup.1 and R.sup.2) or (R.sup.3 and R.sup.4) is chiral, optionally with a C.sub.2 symmetry axis.

9. The chiral imidodiphosphate according to claim 4, wherein the ring structures formed by (R.sup.1 and R.sup.2) or (R.sup.3 and R.sup.4), respectively, are identical.

10. The chiral imidodiphosphate according to claim 1, as represented by the following formula (IVa): ##STR00037## wherein the substituent R is the same or different on each position and is selected from hydrogen, heterosubstituent, C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, each hydrocarbon optionally being substituted by one or more groups selected from C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, and W is selected from hydrogen, halogen, a metal, or a cationic organic group, or a substituted silicon —SiR.sup.IR.sup.IIR.sup.III, wherein R.sup.I, R.sup.II and R.sup.III are same or different and each stand for hydrogen, halogen, C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, each hydrocarbon optionally being substituted by one or more groups selected from C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms thereof, or its tautomeric forms, or ionic forms.

11. The chiral imidodiphosphate according to claim 10, wherein the substituent R is the same on each position.

12. The chiral imidodiphosphate according to claim 1, wherein W is hydrogen.

13. A method comprising conducting an organic synthesis reaction that is catalyzed by a chiral Brønsted acid catalyst, wherein the chiral Brønsted acid catalyst is the chiral imidodiphosphate of the formula (I) according to claim 1.

14. A method comprising conducting a phase-transfer catalysis reaction in the presence of a phase-transfer catalyst, wherein the phase-transfer catalyst comprises the chiral imidodiphosphate of the formula (I) according to claim 1 as a chiral anion.

15. A method comprising conducting an organic synthetic reaction that is catalyzed by a chiral catalyst, wherein the chiral catalyst is the chiral imidodiphosphate of the formula (I) according to claim 1, wherein the organic synthetic reaction is selected from aldol reactions, Mukaiyama-Michael reactions, Michael additions, Mannich reactions, TMSCN additions onto aldehydes and ketones, esterifications, etherifications, pinacol rearrangements, acetalizations, cycloadditions, hydroaminations, hydroalkoxylation, hydrations, haloalkoxylation, haloamination, olefin activations, Friedel-Crafts reactions, epoxide openings, Ritter reactions, nucleophilic substitutions of alcohols, asymmetric ring openings, transfer hydrogenations, alkyne additions, allylations propargylations, reductions, epoxidations, isomerizations, iminium catalysis and enamine catalysis.

16. A process for preparing chiral imidodiphosphates of the formula (V): ##STR00038## comprising the steps of reacting a compound of the formula (VI): ##STR00039## in the presence of a basic compound in an organic solvent with a compound of the formula (VII): ##STR00040## to yield said compound of the formula (V); wherein in said formulae (V), (VI and VII): L represents a leaving group selected from halogen, alkoxy, aryloxy, heteroaryloxy aryl, heteroaryl, OH, and wherein the substituent R is the same or different on each position and is selected from hydrogen, heterosubstituent, C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, each hydrocarbon optionally being substituted by one or more groups selected from C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, and W is selected from hydrogen, halogen, a metal, or a cationic organic group, or a substituted silicon —SiR.sup.IR.sup.IIR.sup.III, wherein R.sup.I, R.sup.II and R.sup.III are same or different and each stand for hydrogen, halogen, C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms, each hydrocarbon optionally being substituted by one or more groups selected from C.sub.1 to C.sub.20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more unsaturated bonds, C.sub.3-C.sub.8-heterocycloalkyl or C.sub.6 to C.sub.20 aromatic hydrocarbon and partially arene-hydrogenated forms thereof.

17. The method according to claim 15, wherein the organic synthetic reaction is selected from the group consisting of vinylic aldol reactions, Mukaiyama aldol reactions, transacetalisations, spiro-acetalisations, asymmetric reductions, and olefin metathesis.

Description

EXAMPLES

Catalyst Preparation

Synthesis of imidodiphosphoric acids 1

(S)-2,2′-Dimethoxy-3,3′-bis(2,4,6-triethylphenyl)-1,1′-binaphthalene (5)

(1) ##STR00019##

(2) 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 Ni(PPh.sub.3).sub.2Cl.sub.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.sub.4Cl solution (40 ml) and water (40 ml), and extracted with CH.sub.2Cl.sub.2 (100 ml, 50 ml). The combined organic layers were dried (MgSO.sub.4), filtered, and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel using 10-15% CH.sub.2Cl.sub.2/hexane as the eluent yielding the title compound as a colorless solid (1.22 g, 48%).

(3) .sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): δ 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, 6H), 1.08 (t, J=7.6 Hz, 6H); .sup.13C-NMR (100 MHz, CD.sub.2Cl.sub.2): δ 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.sub.46H.sub.50O.sub.2Na, 657.3703; found, 657.3708.

(S)-3,3′-bis(2,4,6-triethylphenyl)-[1,1′-binaphthalene]-2,2′-diol (6)

(4) ##STR00020##

(5) A 1 M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (7.56 ml, 7.56 mmol) was added dropwise to the solution of (S)-5 (1.20 g, 1.89 mmol) in CH.sub.2Cl.sub.2 (20 ml) at 0° C. under argon. After 40 h at room temperature, the solution was cooled to 0° C., water (50 ml) was carefully added, and the mixture was extracted with CH.sub.2Cl.sub.2 (50 ml). The organic layer was washed with saturated aqueous Na.sub.2CO.sub.3 solution (50 ml), dried (MgSO.sub.4), filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using 20% CH.sub.2Cl.sub.2/hexane as the eluent yielding the title compound as a colorless solid (1.02 g, 89%).

(6) .sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): δ 7.91 (d, J=7.9 Hz, 2H), 7.78 (s, 2H), 7.41-7.37 (m, 2H), 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); .sup.13C-NMR (100 MHz, CD.sub.2Cl.sub.2): δ 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.sub.44H.sub.46O.sub.2Na, 629.3390; found, 629.3387.

(S)-4-chloro-2,6-bis(2,4,6-triethylphenyl)dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxide (7)

(7) ##STR00021##

(8) To a solution of (S)-6 (553 mg, 0.912 mmol) in pyridine (3 ml) under argon was added POCl.sub.3 (255 μl, 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.sub.2Cl.sub.2 as the eluent yielding the title compound as a colorless solid (604 mg, 96%).

(9) .sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): δ 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 (t, J=7.6 Hz, 3H), 1.01 (t, J=7.5 Hz, 3H, overlapped), 0.99 (t, J=7.5 Hz, 3H, overlapped); .sup.13C-NMR (100 MHz, CD.sub.2Cl.sub.2): δ 145.3 (d, J.sub.C-P=11.1 Hz), 145.2 (d, J.sub.C-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, J.sub.C-P=2.5 Hz), 122.48 (d, J.sub.C-P=2.8 Hz), 29.14, 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 .sup.13C—.sup.31P-coupling, some signals are overlapped); .sup.31P-NMR (162 MHz, CD.sub.2Cl.sub.2): δ 8.26 (s); HRMS (ESI+) (m/z): [M+Na] calcd for C.sub.44H.sub.44O.sub.3ClPNa, 709.2609; found, 709.2606.

(S)-4-amino-2,6-bis(2,4,6-triethylphenyl)dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxide (8)

(10) ##STR00022##

(11) To a solution of (S)-6 (464 mg, 0.764 mmol) in pyridine (3 ml) under argon was added POCl.sub.3 (214 μl, 351 mg, 2.29 mmol) at room temperature. After 1.5 h at 60° C., the mixture was cooled to −78° C. 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.sub.2Cl.sub.2 as the eluent yielding the title compound as a colorless solid (500 mg, 98%).

(12) .sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): δ 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), 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); .sup.13C-NMR (100 MHz, CD.sub.2Cl.sub.2): δ 145.9 (d, J.sub.C-P=10.7 Hz), 145.2 (d, J.sub.C-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, J.sub.C-P=2.0 Hz), 122.5 (d, J.sub.C-P=2.0 Hz), 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 .sup.13C—.sup.31P-coupling, some signals are overlapped); .sup.31P-NMR (162 MHz, CD.sub.2Cl.sub.2): δ 13.20 (s); HRMS (ESI+) (m/z): [M+Na] calcd for C.sub.44H.sub.46NO.sub.3PNa, 690.3108; found, 690.3114.

O,O-syn-Imidodiphosphoric acid 1

(13) ##STR00023##

(14) Sodium hydride (60% dispersion of in mineral oil, 84 mg, 2.1 mmol) was added to a 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 HCl 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 20-100% CH.sub.2Cl.sub.2/hexane followed by 2-8% EtOAc/DCM as the eluents giving a colorless solid. The solid was dissolved in CH.sub.2Cl.sub.2 (10 ml) and stirred with 3N aqueous HCl (10 ml) for 4 h. The organic layer was separated, washed with 3N aqueous HCl (10 ml) and concentrated under reduced pressure to give the title compound as a colorless solid (695 mg, 76%).

(15) .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2): δ 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=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.sub.2O), 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, 3H), 0.04 (t, J=7.5 Hz, 3H); .sup.13C-NMR (125 MHz, CD.sub.2Cl.sub.2): δ 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; .sup.31P-NMR (202 MHz, CD.sub.2Cl.sub.2): δ 4.94 (s); HRMS (ESI−) (m/z): [M-H] calcd for C.sub.88H.sub.88NO.sub.6P.sub.2, 1316.6092; found, 1316.6096.

O,O-syn-Imidodiphosphoric acid 2

(16) ##STR00024##

(17) 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 HCl solution (5 ml) and DCM (5 ml) were added to the mixture, which was stirred for 4 h. The 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.sub.2Cl.sub.2 (5 ml) and stirred with 3N aqueous HCl (10 ml) for 4 h. The organic layer was separated, and concentrated under reduced pressure to give the title compound as a colorless solid (76 mg, 61%).

(18) .sup.1H-NMR (500 MHz, acetone-d.sub.6): δ 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=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), 1.37-1.31 (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); .sup.13C-NMR (125 MHz, acetone-d.sub.6): δ 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, 122.8, 28.0, 27.7, 27.4, 27.3, 15.8, 15.4, 15.3, 14.9; .sup.31P-NMR (202 MHz, acetone-d.sub.6): δ 5.73 (s); HRMS (ESI−) (m/z): [M-H] calcd for C.sub.80H.sub.72NO.sub.6P.sub.2, 1204.4840; found, 1204.4846.

O,O-syn-Imidodiphosphoric acid 3

(19) ##STR00025##

(20) 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 added and the mixture was extracted with CH.sub.2Cl.sub.2 (5×10 ml). The organic extracts were washed with brine, dried (MgSO.sub.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.sub.2Cl.sub.2 (10 ml) and washed with 3 N aqueous HCl (10 ml). The organic layer was separated, and concentrated under reduced pressure to give the title compound as a yellowish solid (101 mg, 37%).

(21) .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2): δ 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), 6.91-6.87 (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.sub.2O); .sup.13C-NMR (125 MHz, CD.sub.2Cl.sub.2): δ 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, 124.0, 122.5; .sup.31P-NMR (202 MHz, CD.sub.2Cl.sub.2): δ 13.74 (s); HRMS (ESI−) (m/z): [M-H] calcd for C.sub.96H.sub.56NO.sub.6P.sub.2, 1380.3588; found, 1380.3584.

Substrate Preparation

4-(3,4-Dihydro-2H-pyran-6-yl)butan-1-ol (9)

(22) ##STR00026##

(23) A 2.5 M solution of n-butyl lithium in hexane (2 ml, 5 mmol) was added dropwise to a solution of 3,4-dihydro-2H-pyran (457 μl, 420 mg, 5 mmol) in THF (2 ml) at 0° C. under argon atmosphere. After being stirred at 50° C. 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° C. The mixture was heated to 50° C. for 1.5 h, cooled to room temperature, and filtered through celite and aluminum oxide (5 g, activity III) using hexane 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 III) using Et.sub.2O as the eluent. The solvent was removed under reduced pressure and the residue was purified by column chromatography on aluminum oxide (activity III) using 10% EtOAc/hexane as the eluent giving a colorless oil, 349 mg, 45%.

(24) .sup.1H-NMR (500 MHz, C.sub.6D.sub.6): δ 4.45 (t, J=3.7 Hz, 1H), 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); .sup.13C-NMR (125 MHz, C.sub.6D.sub.6): δ 154.8, 95.3, 66.0, 62.6, 34.6, 32.6, 23.7, 22.8, 20.6; HRMS (EI (FE)) (m/z): [M] calcd for C.sub.9H.sub.16O.sub.2, 156.1150. found, 156.1149.

3-(4,5-Dihydrofuran-2-yl)propan-1-ol (11)

(25) ##STR00027##

(26) 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 μl, 350 mg, 5 mmol) in THF (2 ml) at −78° C. under argon atmosphere. After being stirred at 0° C. for 30 min, the mixture was cooled to −78° C. and diluted with THF (3 ml). Oxetane (650 μl, 581 mg, 10 mmol) was added to this mixture followed by the dropwise addition of BF.sub.3.OEt.sub.2 (634 μl, 710 mg, 5 mmol). The mixture was stirred for 15 min at −78° C., and Et.sub.3N (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 III, preconditioned with Et.sub.2O) using 5% MeOH/Et.sub.2O as eluent. The solvent was removed under reduced pressure and the residue was purified by column chromatography on aluminum oxide (activity III) using 20% EtOAc/hexane as the eluent giving a colorless oil, 483 mg, 97%.

(27) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ 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); .sup.13C-NMR (100 MHz, DMSO-d.sub.6): δ 158.2, 93.3, 69.0, 60.1, 29.6, 29.4, 23.9; HRMS (EI (FE)) (m/z): [M] calcd for C.sub.7H.sub.12O.sub.2, 128.0837; found, 128.0836.

Catalytic Tests

General Procedure for the Catalytic Asymmetric Spiroacetalisation

(28) ##STR00028##

(29) Solvent (7 ml) and molecular sieves were cooled to the reaction temperature in a vial 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.sub.3N (50 μl).

(30) Purification was performed by chromatography as described for individual case. Solutions of products after chromatography were carefully concentrated to ca. <0.1 ml, and immediately dissolved in C.sub.6D.sub.6 (3 ml). Yield was determined by .sup.1H NMR analysis using 1 ml of this solution and Ph.sub.3CH (20.4 mg, 0.0833 mmol) as internal standard, integration of Ph.sub.3CH vs. product —CH.sub.2O—. NMR spectra without remaining solvent are obtained after concentrating the other 2 ml of the C.sub.6D.sub.6 solution (previously used for optical rotation measurement) to <0.3 ml and diluting with C.sub.6D.sub.6. Alternatively, after concentration to <50 mg, part of the sample was directly used for optical rotation measurement, and the rest immediately used for NMR analysis, and yield corrected for residual solvent by integration in .sup.1H NMR spectrum. Due to the volatility of the products some imprecision in the determination of yields and optical rotation values is expected.

(31) Absolute configuration of (S)-10 was determined by comparison with literature value and configurations of other products were assigned by analogy.

S)-1,7-Dioxaspiro[5.5]undecane ((S)-10

(32) ##STR00029##

(33) Reaction conditions: catalyst loading, 5 mol %; solvent, tert-butyl-methyl ether; molecular sieves, 4 Å (50 mg); temperature, −25° C., 24 h. Purification: mixture concentrated to <1 ml, silica gel column using 5% Et.sub.2O/pentane as eluent. Colorless liquid, yield 77%.

(34) .sup.1H-NMR (400 MHz, C.sub.6D.sub.6): δ 3.71-3.64 (m, 2H), 3.57-3.52 (m, 2H), 2.03-1.91 (m, 2H), 1.68-1.62 (m, 2H), 1.51-1.30 (m, 6H), 1.27-1.22 (m, 2H); .sup.13C-NMR (100 MHz, C.sub.6D.sub.6): δ 94.9, 60.2, 36.3, 25.8, 19.1; HRMS (EI (FE)) (m/z): [M] calcd for C.sub.9H.sub.16O.sub.2, 156.1150. found, 156.1151; [α].sub.D.sup.25=+121.5° (c=0.85 in pentane, er 98:2) (Literature value for (R)-10: [α].sub.D.sup.19=−122.8°, c=3.2 in pentane, e.r. >97.5:2.5); Chiral GC (Column: 25 m Lipodex-G (octakis-(2,3-di-O-pentyl-6-O-methyl)-γ-cyclodextrin), i.D. 0.25 mm; Detector: FID; Temperature: injector 230° C., detector 350° C., oven 100° C.; gas: 0.5 bar H.sub.2), t.sub.minor=4.86 min, t.sub.major=5.36 min, er=98:2.

R)-1,7-Dioxaspiro[5.5]undecane ((R)-10

(35) ##STR00030##

(36) Reaction conditions: catalyst loading, 5 mol %; solvent, tert-butyl-methyl ether; molecular sieves, 4 Å (50 mg); temperature, −25° C., 12 h. Purification: mixture concentrated to <1 ml, silica gel column using 5% Et.sub.2O/pentane as eluent. Colorless liquid, yield 70%.

(37) .sup.1H-NMR (500 MHz, C.sub.6D.sub.6): δ 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); .sup.13C-NMR (125 MHz, C.sub.6D.sub.6): δ 94.9, 60.2, 36.3, 25.8, 19.1; [α].sub.D.sup.25=−96.3° (c=0.91 in C.sub.6D.sub.6, er 97.5:2.5); Chiral GC (Column: 25 m Lipodex-G (octakis-(2,3-di-O-pentyl-6-O-methyl)-γ-cyclodextrin), i.D. 0.25 mm; Detector: FID; Temperature: injector 230° C., detector 350° C., oven 100° C.; gas: 0.5 bar H.sub.2), t.sub.major=4.53 min, t.sub.minor=5.05 min, er=97.5:2.5.

(S)-1,6-dioxaspiro[4.4]nonane (12)

(38) ##STR00031##

(39) Reaction conditions: catalyst loading, 0.1 mol %; solvent, CH.sub.2Cl.sub.2; molecular sieves, 3 Å (125 mg); temperature, −55° C., 12 h. Purification: To the mixture Et.sub.3N (0.5 ml) was added, mixture concentrated to <1 ml, silica gel column using 10% Et.sub.2O/pentane as eluent. Colorless liquid, yield 62%.

(40) .sup.1H-NMR (400 MHz, C.sub.6D.sub.6): δ 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); .sup.13C-NMR (100 MHz, C.sub.6D.sub.6): δ 114.6, 66.9, 34.8, 25.0; HRMS (EI (FE)) (m/z): [M] calcd for C.sub.7H.sub.12O.sub.2, 128.0837; found, 128.0838; [α].sub.D.sup.25=+182.4° (c=0.44 in pentane, er 96:4); Chiral GC (Column: 25 m Lipodex-G (octakis-(2,3-di-O-pentyl-6-O-methyl)-γ-cyclodextrin), i.D. 0.25 mm; Detector: FID; Temperature: injector 230° C., detector 350° C., oven 95° C.; gas: 0.5 bar H.sub.2), t.sub.minor=2.82 min, t.sub.major=3.00 min, er=96:4.