DE19706273A1 - Optically active beta-oxy-gamma-butyrolactam and beta-oxy-gamma-lactone derivatives preparation - Google Patents

Abstract

Preparation of non-racemic beta -oxy- psi -butyrolactams and beta -oxy- psi -lactones of formula (I) by asymmetric catalytic hydrogenation of tetramic or tetronic acid derivatives of formula (II) in the presence of an optically active rhodium, ruthenium or iridium complex containing a chiral diphosphine as ligands: R1 = H, 1-10C alkyl or 1-10C acyl; R2 = H, 1-10C acyl or benzyl; X = NR3 or O; R3 = H, 1-10C acyl, benzyl or an amino protecting group.

Description

The present invention relates to a process for producing optically active (non-race mixers) β-oxy-γ-butyrolactams and -lactones by asymmetric hydrogenation of the ent speaking tetramic and tetronic acid derivatives. The invention can be produced verbin have the general formula

wherein R¹ is hydrogen, C _1-10 -alkyl or C _1-10 -acyl,
R² is hydrogen, C _1-10 -acyl or benzyl,
X is a group of the formula NR 3 or oxygen
and R³ is hydrogen C _1-10 acyl, benzyl or an amino protecting group.

C _1-10 -alkyl are here and below to be understood as meaning linear and branched primary, secondary and tertiary alkyl groups having up to 10 carbon atoms. Accordingly, C _1-10 acyl is to be understood as meaning carbonyl groups which carry hydrogen or linear or branched primary, secondary or tertiary alkyl groups having up to 9 carbon atoms, for example formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, octanoyl or decanoyl. Amino-protective groups are to be understood as meaning the groups customary in peptide chemistry (see, for example, E. Wünsch, Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952- ?, Vol. 15/1, P. 46-314), especially groups such as tert-butoxycarbonyl ("Boc") or benzyloxycarbonyl ("Cbz").

Compounds of this class are important building blocks for the synthesis of a range of bio Logically active substances such as 4-amino-3-hydroxybutyric acid ("GABOB") and L-carnitine (Seebach, D., et al., Synthesis 1985, 424), ipsdienol (K.Mori et al., Tetrahedron, 1979, 35, 933) or aplysistatin (H.M. Shieh et al., Tetrahedron Lett. 1982, 23, 4643). Because the Compounds on (for R¹ = H) or two (R¹ ≠ H) contain asymmetric centers and usually only one of the possible stereoisomers is needed, it is desirable to be able to produce this targeted. Previous manufacturing process are based, for example, on the synthesis of chiral starting materials (K.-C. Luk et al. Synthesis 1988, 226) or on the enzymatic reduction of acetoacetic esters (D. Seebach et al. Synthesis 1986, 37). For industrial scale production here the generally high price of the chiral starting materials and the  enzymatic processes usually low space-time yield and consuming Product isolation disadvantage.

The object of the present invention was not a chemical process for the preparation provide racemic β-oxy-γ-butyrolactams and lactones (I), which increases from easy to go outgoing achiral compounds and through a good space-time yield suitable for large-scale production.

According to the invention the object is achieved by the method according to claim 1.

It has been found that tetramic and tetronic acid derivatives of the general formula

wherein R¹, R² and X have the abovementioned meaning, in the presence of catalytic effective optically active rhodium, ruthenium or iridium complexes with chiral Diphosphines can be hydrogenated asymmetrically as ligands.

The tetramic and tetronic acid derivatives (II) are known compounds or analogous to can be prepared (see, for example, R.C.F. Jones et al., Tetrahedron Lett. 1983, 24 (43), 4755).

Preferred chiral diphosphines are those with metallocene structure, in particular the disubstituted ferrocenes of the general formula

wherein R ^4a , R ^4b , R ^5a and R ^5b are each independently C _1-12 alkyl, C _5-7 cycloalkyl or optionally substituted phenyl, and their mirror images. By substituted phenyl are meant phenyl groups substituted, for example, with one or more C _1-4 alkyl or C _1-4 alkoxy groups, with one or more halogen atoms, amino groups, carboxyl groups, sulfo groups, phosphono groups, trialkylsilyl groups and the like. Examples of such chiral diphosphines with ferrocene structure can be found in EP-A 0 564 406 and EP-A 0 612 758.

Very particular preference is given to (R) -1 - [(S) -2- (diphenylphosphino) ferrocenyl] ethyl-di-tert-butylphosphine (R ^4a = R ^4b = tert-butyl, R ^5a = R ^5b = phenyl) and the (R) -1 - [(S) -2- (diphenylphosphino) ferrocenyl] ethyl dicyclohexylphosphine (R ^4a = R ^4b = cyclohexyl, R ^5a = R ^5b = phenyl) and their mirror images. The preparation of these ligands is described in EP-A-0 564 406.

The catalytically active optically active rhodium complexes are advantageously in situ prepared from a suitable precursor complex and the chiral diphosphine. The precursor complex used is preferably an olefin complex. Especially preferred are complexes with non-conjugated cyclic dienes such as those commercially available bis (1,5-cyclooctadiene) -dirhodium (I) dichloride ([Rh (COD) Cl] ₂), the is advantageously reacted in a molar ratio of 1: 2 with the chiral diphosphine, and bis-norbornadiene rhodium (I) tetrafluoroborate.

The asymmetric hydrogenations according to the invention are preferably at 1-50 bar carried out. The reaction temperature is preferably 0-100 ° C. As a solvent are preferably lower alcohols such as methanol, ethanol or iso propyl alcohol or esters such as ethyl acetate.

The process of the invention is preferably suitable for the preparation of those Ver Compounds (I) in which R¹ is hydrogen.

Also preferred is the preparation of compounds (I) wherein R² is C _2-6 acyl.

The following examples illustrate the implementation of the invention Procedure, without any limitation.

example 1 4-benzyloxypyrrolidin-2-one

In an autoclave, 2 g (10.5 mmol) of 4-benzyloxy-1,5-dihydro-2H-pyrrol-2-one ("tetramic acid benzyl ester", prepared according to CH-A 668 422), 10.4 mg (0, 02 mmol) of bis (1,5-cyclooctadiene) -dirhodium (I) dichloride and 23 mg (0.04 mmol) of (R) -1 - [(S) -2- (diphenylphosphino) ferrocenyl] ethyl-di Tert-butylphosphine placed under argon and treated with 20 ml ent guest methanol. The autoclave was purged with hydrogen three times, then 50 bar of hydrogen was injected and hydrogenated at 70 ° C for 18 hours. After cooling, the reaction mixture was concentrated and placed in the refrigerator to crystallize.
Yield: 2.1 g (~ 100%) brownish solid

[α] = -0.9 (c = 1, CHCl₃)

1 H NMR (CDCl₃, 400 MHz) δ = 2.42 (dd, 1H) 2.58 (dd, 1H) 3.41 (dd, 1H) 3.60 (dd, 1H) 4.32 (m, 1H) 4.50 (m, 2H) 6.62 (m, 1H) 7.22-7.30 (m, 5H)

Example 2 1-benzyl-4-acetoxypyrrolidin-2-one

In an autoclave, 6 g (26.0 mmol) of 1-benzyl-4-acetoxy-1,5-dihydro-2H-pyrrole 2-one, 52.4 mg (0.14 mmol) bis (norbornadiene) rhodium (I) tetrafluoroborate and 114 mg (0.21 mmol) of (R) -1 - [(S) -2- (diphenylphosphino) ferrocenyl] ethyl di-tert-butylphosphine in Submitted argon and treated with 50 ml of degassed ethyl acetate. The autoclave was Rinsed three times with hydrogen, then 50 bar of hydrogen were injected and at 65 h at Room temperature hydrogenated. After cooling, the reaction mixture was concentrated and chromatographed on silica gel with hexane / ethyl acetate (2: 8).

crude:
Yield: 5.97 g (99%) of white solid

[α] = + 20.35 (c = 1, CHCl₃), ee = 46%, R-configuration

For purification, the product was recrystallized from ethanol.
Yield: 62%
[α] = +29.14 (c = 1, CHCl₃), ee = 65%

1 H NMR (CDCl₃, 400 MHz) δ = 2.02 (s, 3H) 2.57 (dd, 1H) 2.81 (dd, 1H) 3.21 (dd, 1H) 3.60 (dd, 1H) 4.50 (m, 2H) 5.24 (m, 1H) 7,20-7,38 (m, 5H)

Example 3 4-Acetoxydihydro-2 (3H) -furanone

In an autoclave, 83.3 mg (0.22 mmol) of bis (norbornadiene) rhodium (I) tetrafluoroborate and 184.2 mg (0.34 mmol) of (R) -1 - [(S) -2- ( Diphenylphosphino) ferrocenyl] ethyl-di-tert-butylphosphine under argon and treated with a degassed solution of 6.0 g (42.2 mmol) of 4-acetoxy-2 (5H) -furanone in 64 ml of ethyl acetate. The autoclave was purged with hydrogen three times, then 50 bar of hydrogen was injected and hydrogenated at room temperature for 48 hours. After cooling, the reaction mixture was concentrated, filtered through a little silica gel and distilled in a Kugelrohr (100 ° C, 0.02 mbar).
Yield: 5.04 g (83%) of colorless liquid

[α] = + 45.84 (c = 1, CHCl₃)
ee = 59% (GC on Lipodex® E), R configuration

1 H NMR (CDCl₃, 400 MHz) δ = 2.10 (s, 3H) 2.60 (dd, 1H) 2.88 (dd, 1H) 4.36 (dd, 1H) 4.52 (dd, 1H) 5.42 (m, 1H)

Claims (5)

1. A process for the preparation of non-racemic β-oxy-γ-butyrolactams and lactones of the general formula wherein R¹ is hydrogen C _1-10 alkyl or C _1-10 acyl,
R² is hydrogen C _1-10 acyl or benzyl,
X is a group of the formula NR 3 or oxygen
and R³ is hydrogen C _1-10 acyl, benzyl or an amino protecting group, characterized in that a tetramic or tetronic acid derivative of the general formula wherein R¹, R² and X have the abovementioned meanings, is hydrogenated asymmetrically in the presence of a kata lytically effective optically active rhodium, ruthenium or iridium complex with a chiral diphosphine ligands. 2. The method according to claim 1, characterized in that as chiral diphosphine a diphosphine with metallocene structure of the general formula wherein R ^4a , R ^4b , R ^5a and R ^5b are each independently C _1-12 alkyl, C _5-7 cycloalkyl or optionally substituted phenyl, or their mirror image is used. 3. The method according to claim 2, characterized in that the diphosphine with metal locenstruktur (III) a diphosphine is used, wherein R ^5a and R ^{5b are the} same and are phenyl and R ^4a and R ^{4b are the} same and tert-butyl or cyclohexyl , 4. The method according to any one of claims 1 to 3, characterized in that a β-oxy-γ- butyrolactam or lactone (I) is prepared in which R¹ is hydrogen. 5. The method according to any one of claims 1 to 4, characterized in that a β-oxy-γ-butyrolactam or lactone (I) is prepared, in which R² is C _2-6 acyl.