Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
2000-04-20
2001-07-17
Gitomer, Ralph (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
C556S437000, C549S512000
Reexamination Certificate
active
06262288
ABSTRACT:
BRIEF SUMMARY OF THE INVENTION
The present invention relates to the field of organic synthesis. It relates, more particularly, to novel malonates cited below and their use in the novel synthesis of chiral epoxides of formula
having a cyclanic (1R) configuration, the group in position 2 of the ring having a transconfiguration and the epoxy group having a cis-configuration with respect to the substituent in position 1 of the ring. In the above formula (I), R is a linear or branched alkyl group from C
1
to C
4
and R
1
is a linear or branched alkyl, alkylene or alkynyl group from C
4
to C
6
. The present invention is in particular drawn towards the synthesis of epoxides according to the above formula (I) in which R is a methyl group and R
1
is a (Z)-2-pentenyl group.
BACKGROUND OF THE INVENTION
The epoxides of the above formula (I) are of great interest in the fragrance industry as precursors for the synthesis of ketones of the formula (II), into which they are transformed in a rearrangement reaction which, depending on the conditions chosen, may proceed in a stereochemically selective way.
The ketones of formula (II), which show a (1R)-cis configuration, form a class of fragrant molecules developing a jasmine-like odour which varies depending on the nature of the substituents R and R
1
. It has been found that the molecules possessing the configuration (1R)-cis, as shown in the above formula (II), are exactly those responsible for the typical jasmine odour of the compounds, whereas the other 3 stereoisomers contribute to a much lesser extent to the mentioned, and highly appreciated jasmine odour.
Of particular interest for perfumers are the two molecules of formula (II) in which R is a methyl group and R
1
is either a n-pentyl or a (Z)-2-pentenyl group. These compounds represent best the jasmine odour which is so prized by perfumers. In what concerns the compound in which R
1
is a n-pentyl group, this compound has been synthetically available for some time now, for example by enantioselective hydrogenation of appropriate precursor compounds (see U.S. Pat. No. 5,874,600 and WO 98/52687, both to Firmenich S A). Another synthesis for this compound and for its (Z)-2-pentenyl analogue, which is related to the present invention, is described in U.S. Pat. No. 5,962,706 (applicant: Firmenich S A), which will be discussed in greater detail below.
A process for the synthesis of the epoxides of the above-mentioned formula (I) is described in U.S. Pat. No. 5,962,706 (applicant: Firmenich S A). This synthesis comprises the reaction steps which are outlined in the following scheme I.
The above synthesis, although giving high enantiomeric excesses (ee's), of the order of greater than 95%, and high yields and allowing thus to prepare the desired epoxides (I) having the defined stereochemistry, can still be improved in order to raise the overall yield and reduce the costs of the synthesis. In particular, the synthesis of the ester (III), starting from the chiral alcohol (IV), is hampered by the fact that the intermediate products (designed in brackets) which are obtained after the esterification reaction with an orthoester CH
3
C(OR)
3
have to be treated at a relatively high temperature of above 140° C. in order to induce the Claisen rearrangement reaction which gives the desired ester (III), from which are prepared the epoxides (I). Therefore, in the case where the esterification of the alcohol (IV) is carried out with trimethylorthoacetate (R═CH
3
), an incomplete rearrangement reaction results because the intermediate ester can only be heated to about 115° C., due to its low boiling point. Thus, use of triethylorthoacetate (R═C
2
H
5
), or even higher analogues is required, in which case the intermediate esters show higher boiling points, permitting a complete conversion in the Claisen rearrangement reaction leading towards the ester (III). However, because the most appreciated compounds of formula (II) are the methyl esters (R═CH
3
), a supplementary transesterification or saponification/esterification reaction has to be carried out after the rearrangement reaction has taken place, thus raising costs and lowering yields.
DESCRIPTION OF THE INVENTION
The object of the present invention is to provide a process for the preparation of esters of the above formula (III) which improves on the process described in U.S. Pat. No. 5,962,706.
This object is attained by a process for the preparation of an ester of formula
having a (1R) configuration, and wherein R is an alkyl group from C
1
to C
4
, linear or branched, and R
1
is an alkyl, alkenyl or alkynyl group from C
4
to C
6
, linear or branched, which process comprises the decarboxylation reaction of a compound of formula
wherein R and R
1
have the meaning given above and R′ is hydrogen or a triorganylsilyl group.
In a preferred embodiment of the invention, R is a methyl group, R′ is a trimethylsilyl group, and R
1
is a pentyl or a (Z)-2-pentenyl group.
The compounds (VI) are novel chemical species which are the object of the invention and turn out to be unexpectedly advantageous for the preparation of the desired fragrance ingredients of formula (II) and the intermediates therefor.
The use of these novel compounds (VI) according to the present invention renders it possible to prepare esters (III), and ultimately the epoxides (I), in a simple and very efficient one-pot reaction.
The novel compounds (VI) are used in a decarboxylation reaction leading to the esters (III), which reaction is carried out for example by saponification of one ester function, which saponification may be carried out under basic and acidic conditions. In the case where R′ is an organosilyl group, e.g. a trimethylsilyl group, it was found to be particularly advantageous when N-methylpyrrolidone (NMP) and water were used for the hydrolysis reaction.
Furthermore, we were able to develop original processes for the preparation of malonates (VI). One synthetic route is outlined in the following scheme II, in which R, R′ and R
1
have the meaning given above.
This synthesis starts from the known cyclopentenones (V). The ketone is converted into the novel chiral, mixed malonic ester (VII) having the configuration (1R). This transformation may be carried out in different ways.
According to the invention the ketone is reduced in an enantioselective manner, into the corresponding cyclopentenol having a (1R) cyclanic configuration, and the latter is then esterified with an appropriate derivative of malonic acid, e.g. an ester thereof, the esterification being carried out under conditions which allow the retention of the stereochemistry of the chiral carbon. Specific conditions are described in detail in the examples.
The enantioselective reduction of the keto function is carried out using techniques which are known in the art. Advantageous results could be obtained when using a reductive system of the oxazaborolidine-borane type (see, for example, E. J. Corey et al., J. Amer. Chem. Soc. 1987, 109, 7925; S. Itsuno et al., Bull. Chem. Soc. Jpn. 1987, 60, 395; D. J. Mathre et al., J. Org. Chem. 1991, 56, 751; V. K. Singh, Synthesis 1992, 605).
The cyclopentenones of formula (V) can also be reduced into the desired racemic alcohols by a conventional transformation, followed by esterification into the racemic ester such as, for example, the acetate. The racemic esters are then separated in a biotechnological process which involves the enantioselective saponification into the desired optically active alcohols by means of a lipase. Examples of suitable lipases include
Candida antarctica, Pseudomonas fluorescens, Pseudomonas cepacia, Mucor miehei, Chromabacterium viscosum
and
Mucor javanicus.
The chiral cyclopentenol having the (1R)-configuration is then esterified without racemization into the malonic diester (VII). This esterification is carried out, for example, by using an alkyl malonyl halide such as, for example, methyl malonyl chloride. The use of this reagent is preferred according to the invention, resulting in mixed ma
Fehr Charles
Galindo Jose
Ohleyer Eric
Firmenich SA
Gitomer Ralph
Khare D.
Winston & Strawn
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