Diastereoselective preparation of Michael adducts

Details Diastereoselective preparation of Michael adducts Diastereoselective preparation of Michael adducts

2000-04-07

2002-11-12

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06479672

ABSTRACT:

SUMMARY OF THE INVENTION
The present invention relates to diastereoselective Michael addition using zinc-amine complex reagent. and further provides a method for the diastereoselective preparation of &agr;-hydroxyacetic acids.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,948,791 discloses fluorine-containing 1,4-disubstituted piperidine derivatives. These compounds are muscarinic M3 receptor antagonists useful for the treatment or prophylaxis of respiratory diseases such as chronic obstructive pulmonary diseases, chronic bronchitis, asthma and rhinitis; digestive diseases such as irritable bowel syndrome, convulsive colitis, diverticulitis and pain accompanying contraction of smooth muscles of the digestive system; urinary disorders like urinary incontinence and frequency in neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystisis; and motion sickness.
Many of the derivatives exemplified in U.S. Pat. No. 5,948,792 are of the formula (A)
where R
X
is defined in the patent as R
2
. Their synthesis requires the common precursor (2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid, which may be prepared according to the methods disclosed in U.S. Pat. No. 5,948,792 and summarized in the following scheme:
The Michael addition of a dioxolanone to a cyclopentenone is the key step in defining the stereochemistry of the phenylacetic acid precursor. The methods described in U.S. Pat. No. 5,948,792 are not suitable for large-scale preparation of the chiral phenylacetic acid—the use of the chiral tricyclic ketone is prohibitively expensive and involves flash pyrolysis requiring specialized equipment, and deprotonation of cyclopentenone using lithium diisopropylamide (LDA) in hexamethylphosphoramide (HMPA) does not impart diastereocontrol to the Michael addition. There is therefore the need for an efficient and stereoselective process amenable to large-scale production to provide the phenylacetic acid precursor of the desired stereochemistry.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the diastereoselective preparation of Michael adducts of a cycloalkenone and a chiral 2,5-disubstituted-1,3-dioxolan-4-one using a zinc-amine complex and the free amine of the zinc-amine complex. The novel process comprises the steps of:
(a) contacting said chiral 2,5-disubstituted-1,3-dioxolan-4-one with a base to provide the corresponding enolate;
(b) contacting said enolate with a zinc-amine complex followed by addition of the free amine component of the zinc-amine complex;
(c) contacting the mixture of step (b) with the cycloalkenone.
The term “diastereoselective” as used herein means that the desired isomer is formed predominantly, i.e. 50% or greater of the diastereomeric mixture.
The chiral 2,5-disubstituted-1,3-dioxolan-4-one is preferably a compound of formula (I):
in which R
1
is an optionally substituted hydrocarbyl group such as optionally substituted aryl, optionally substituted C
1-6
alkyl, optionally substituted C
2-6
alkenyl or optionally substituted C
2-6
alkynyl, where the substituents may be for example hydroxy, thiol, ethers, thioethers, primary, secondary and tertiary amines; R
a
is a bulky group such as t-butyl, phenyl, diphenylmethyl, trityl, trichloromethyl, mesityl, or the like; the asterisk (*) indicates that the chiral center is of defined 3-dimensional configuration.
The base may be any that is capable of generating an enolate of the dioxolanone described above; examples of suitable bases include lithium diisopropylamide (LDA), lithium hexamethyldisilazide, lithium t-butoxide, sodium t-butoxide, DBU and tetramethyguanidine, and the like. Preferably a lithium base is used to generate the lithium enolate.
For the zinc-amine complex, the zinc component may be any zinc (II) compounds such as zinc chloride, zinc bromide, zinc iodide, zinc trifluoromethanesulfonate and the like. The amine component is an amine containing at least two nitrogen atoms separated by 2 to 6 atoms. Preferably the amine is a secondary or tertiary amine, more preferably a tertiary amine; suitable amines are, for example, of the formula (IV):
wherein L is C
2-6
alkylene or C
2-6
alkenyl each of which may be optionally interrupted by a heteroatom selected from O, S and N—R
c
wherein R
c
is H or C
1-6
alkyl; each R
b
is independently H or C
1-4
alkyl or 2 R
b
s together with the N to which they are attached form a 5- or 6-membered ring optionally containing an additional heteroatom selected from O, S and N—R
c
wherein R
c
is H or C
1-6
alkyl. Examples of suitable amines are 4-[2-(dimethylamino)ethyl]morpholine; N,N-diethyl-N′,N′-dimethylethylenediamine; 1-[2(dimethylamino)ethyl]-4-methylpiperazine; N,N,N′,N′-tetramethylethylenediamine; 1-[2(dimethylamino)ethyl]pyrrolidine; 1-[(2-(dimethylamino)ethyl]piperidine; N,N′,N′-tetramethyl-1,3-propanediamine; N,N,N′,N′-tetramethyl-1,4-butanediamine; 1-[3-(dimethylamino)propyl]-4-methylpiperazine; 1-[3-(dimethylamino)propyl]-4-ethylpiperazine; 1-[3-(dimethylamino)propyl]piperidine; 1-[3-(dimethylamino)propyl]pyrrolidine; 1-[3-(dimethylamino)propyl]morpholine; N,N-bis-[2-(dimethylamino)ethyl]-N-methylamine; bis-[2-(dimethylamino)ethyl]ether. The preferred amine is selected from 4-[2-(dimethylamino)ethyl]morpholine; N,N-diethyl-N′,N′-dimethylethylenediamine; 1-[2(dimethylamino)ethyl]-4-methylpiperazine; N,N,N′,N′-tetramethylethylenediamine; 1-[2(dimethylamino)ethyl]pyrrolidine; and 1-[(2-(dimethylamino)ethyl]piperidine.
The cycloalkenone of the present process is a compound of formula (II):
wherein n is 1, 2 or 3.
The novel process, in one embodiment, is illustrated in the following scheme:
In the novel process, the product Michael adduct (III) is obtained as a mixture of diasteromers with the predominant diastereomer being determined by the configuration at the * carbon. For example, when the configuration at the * carbon is R, the predominant diastereomer of the Michael adduct has the R/R configuration at carbon atoms 1/2, and when the configuration at the * carbon is S, the predominant isomer has the S/S configuration at carbon atoms 1/2.
In the present process, the chiral dioxolanone is first treated with a base to generate the corresponding enolate. In one preferred embodiment the chiral dioxolane is a compound of formula (I) wherein R
1
is phenyl and R
a
is t-butyl. Preferably the base is lithium base such as lithium diisopropylamide and lithium hexamethyldisilazide. The base is preferably used in excess relative to the dioxolane, for example up to about 1.5 equivalents. The reaction is carried out under inert atmosphere at a temperature of −25° C. or lower and in an aprotic organic solvent such as tetrahydrofuran, dimethoxyethane, toluene or other aromatic solvents, diethyl ether or methyl t-butyl ether, or a mixture thereof.
The resultant enolate is treated with a zinc-amine complex while maintaining the reaction temperature at below about −30° C., for example from −45 to about −30° C. The zinc-amine complex may be used in from about 0.2 to about 2 equivalents relative to the dioxolane. After about an hour, additional free amine is added to the mixture. The free amine is used in about two to about twenty equivalents relative to the dioxolane, preferably about two to about four equivalents. For the zinc-amine complex, the zinc component is preferably zinc chloride, and the amine is preferably selected from 4-[2-(dimethylamino)ethyl]morpholine; N,N-diethyl-N′,N′-dimethylethylenediamine; 1-[2(dimethylamino)ethyl]-4-methylpiperazine; N,N,N′,N′tetramethylethylenediamine; 1-[2(dimethylamino)ethyl]pyrrolidine; and 1-[(2-dimethylamino)ethyl]piperidine. The reaction mixture is maintained at about −20° to about 0° C. for about 30 min

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