Cycloalkanediols and their use in preparing chiral compounds

Details Cycloalkanediols and their use in preparing chiral compounds Cycloalkanediols and their use in preparing chiral compounds

1996-06-04

1998-04-14

Raymond, Richard L.

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

544329, 549436, 560115, 560189, 560158, C07C27124, C07D31744

Patent

active

057393320

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB94/02194, filed Oct. 7, 1994.


FIELD OF THE INVENTION

This invention relates to cycloalkanediols and their use in preparing chiral compounds. The invention relates also to a process whereby a desired diol can be prepared stereoselectively.


BACKGROUND OF THE INVENTION

2,3-cis-Dihydoxycyclopentane-1-carboxamides linked at the 5-position to a purine or pyrimidine have therapeutic utility. See, for example, EP-A-0368640. In the synthesis of such compounds, control of the chiral centres on the cyclopentane ring is essential.
An important intermediate in such a synthesis, which is protected at the hydroxyl groups as an acetonide, is the final compound in Scheme 1, below; this compound is useful as a synthon for the manufacture of carbocylic compounds having vasodilatory activity, see Chen et al, Tetrahedron Lett, 30:5543-6 (1989). An established route for the synthesis of the acetonide is also shown in Scheme 1.
The geometric constraints provided by the bicyclic nature of the starting for the high stereocontrol of the dihydroxylation onto the exo-face of the starting material. One disadvantage, however, with this route is the need for a pressure reaction to open the amide linkage.
However, despite these disadvantages, it is generally considered that opening of the amide linkage of the starting material results in a loss of the stereocontrol of the dihydroxylation so that a mixture of stereoisomers of the diol results. This is undesirable.


SUMMARY OF THE INVENTION

According to the present invention, a process for the preparation of a 2,3-dihydroxycycloalkene-1-carboxamide, e.g. of formula (1) and most preferably the diol corresponding to the acetonide shown in Scheme 1, comprises stereoselective dihydroxylation of the olefinic precursor thereof. Dihydroxylation takes place anti to the carboxamide function.
The process can be used to prepare a substantially pure diastereomer, either as a single enantiomer, or in racemic form. Indeed the optical purity of the product will reflect the optical composition of the starting cyclopentene.
In view of the understanding in the art as to the importance of a bicyclic structure for achieving high stereocontrol of a reaction of this nature, it is surprising that the process of the invention, i.e. without a bicyclic starting material, achieves just this.


DESCRIPTION OF THE INVENTION

Compounds of the type involved in the novel process are shown in Scheme 2. n may be any suitable number, e.g. 1 or 2, and (CH.sub.2).sub.n may be substituted, e.g. by a primary, secondary, tertiary or cyclic amine function. That may be a purine or pyrimidine ring or a group NR.sub.3 R.sub.4 as shown in formula (1). R.sub.3 and R.sub.4 are each H or a removable blocking group such as tert-butoxycarboxyl or benzyloxycarboxyl.
The starting materials for the process of the invention can be obtained by conventional methods such as amidation of the corresponding carboxylic an amine.
Compounds of formula (1) are specific examples of products of Scheme 2, i.e. of formula (2). The nature of R.sub.1 and R.sub.2 is not critical; R.sub.1 is preferably H, but may be any organic, e.g. hydrocarbyl group, e.g. of up to 20 C atoms. R.sub.2 may be the same or a different organic group, e.g. alkyl such as ethyl. It is most preferred that R.sub.1 is H, methyl or ethyl and R.sub.2 is methyl or ethyl.
An example of the process of the invention is shown in Scheme 3. Starting material is depicted as a salt, but can be in the form of an amino-acid. Introduction of the ethylamido group into the starting material is relatively easy compared with its introduction in Scheme 1 which, as mentioned above, requires a pressure reaction. It may be achieved using (i) (tBuO.sub.2 C).sub.2 O and OH, and (ii) EtOCOC1 and EtNH.sub.2. Conversion of the cyclopentene-carboxamide, the olefinic precursor of the diol, is by cis-dihydroxylation across the double bond, for example by using osmium tetroxide or (potassium) permanganate. In the case of osmium tetroxide, that may be used as a catalyst, wit

REFERENCES:
patent: 5217982 (1993-06-01), Fink et al.
Jen Chen et al., "A Novel and Efficient Route to Chiral 2-Substituted Carbocyclic 5'-N-Ethyl-Carboxamido-Adenosine (C-NECA)", Tetrahedron Letters, vol. 30, No. 41, 1989, pp. 5543-5546.

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