HIGHLY FUNCTIONALIZED FIVE-MEMBERED BICYCLIC -HYDROXY ACIDS FROM SYNTHETIC EQUIVALENT OF GLYCOLIC ACIDS

Five-membered cyclic -hydroxy acids (1-hydroxycycycloalkane-1-carboxylic acids) are important constituents in biologically active natural products and also important precursor molecules for the synthesis of pharmacologically active compounds. This paper presents stereo selective synthesis of polysubstituted fivemembered bicyclic -hydroxy acid derivatives from ,-dialkylated 1,3-dixolan4-one (9). The synthesis was initiated on the -propagylation of 2-(tert-butyl)-5(1-ethenylprop-2-enyl)-1, 3-dixololan-4-one (trans-8) via its enolate, followed by intramolecular Pauson-Khand cyclization. The reaction was stereo selective and afforded two isomers (10a and 10b) in 4:1 ratio out of four possible diastereoisomers of bicyclic -hydroxy acid (bicyclic 1-hydroxycarboxylic acid) derivatives. This method opens a new avenue to prepare synthetically useful highly functionalized stereoselctive synthesis of five-membered bicyclic hydroxy acids using a convenient and very effective method.


INTRODUCTION
Cyclic -hydroxy carboxylic acids are important constituents in pharmacological active natural products and important synthetic building units for the synthesis of various biologically active natural products [1]. Although the research has mainly focused on the development of potential synthetic strategies for the synthesis of acyclic hydroxy acids [2], less attention has been paid on preparation of cyclic -hydroxy acids. Glycolic acids is an easily available, important -hydroxy acid which can be easily converted into the asymmetric acetals, and then it can serve as chiral auxiliaries in selective induction of its -position to prepare asymmetric 1-hydroxycycloalkane-1-carboxylic acid derivatives [3]. In our previous work, we reported stereo selective preparation of 1-hydroxycylclopentene-1-carboxylic acid derivatives (3, Figure 1) using chiral equivalent of glycolate derivatives via metathesis. This method has been successfully applied in the synthesis of natural product, (-)-quinic acid [4]. In another method, we have demonstrated synthesis of polysubstituted 1-hydroxyclyopentane-1-carboxylic acid derivatives (6a and 6b, Figure 2) using chiral equivalent of glycolate derivatives via a group selective radical annulation procedure [5].  Development of synthetic strategies for the preparation of asymmetric bicyclic hydroxy acids is equally important in organic synthesis. Pauson -Khand reaction has emerged as a convenient tool for the synthesis of cyclopentenones, from alkynes and alkene, involving of cobalt carbonyl compounds [6]. In this reaction, the alkyne first reacts with Co(CO)8 to form alkyne-Co2(CO)6 complex and then it reacts with the alkene to form the cyclopentanone. We have planned a synthetic route to bicyclic 1-hydroxycarboxylic acid derivatives based on intramolecular Pauson-Khand cyclization of ,-dialkylated glycolic acid derivatives. As a demonstration of the proposed method, we explain here the synthesis of asymmetric polysubstituted bicyclic 1-hydroxycarboxylic acids (10a and 10b, Figure

Method
The initial compound, ethyl 3-ethenyl-2-hydroxypent-4-enoate (7) to be used in the synthesis of precursor molecule for the targeted Pauson-Khand reaction, was prepared by the reaction of 5-bromo-1,3-pentadine with ethyl gloxylate with the presence of Zn powder and anhydrous AlCl3 (Figure 3) [7], [8]. This compound was then reacted with pivalaldehyde in the presence of acid catalyst to obtain 2- Figure 3) [4]. The trans isomer of 8 (-monosubstituted cyclic acetal of glycolate) which was obtained through column chromatographic purification of the mixture, was deprotonated with LDA in THF at -78 0 C and then followed by alkylation with propagyl bromide to form -disubstituted cyclic acetal of glycolate (9, Figure 4), which was the substrate for the targeted Pauson-Khand cyclization. The stereo selectivity of the formed mixture of bicyclic 1-hydroxycarboxylic acid derivatives was analyzed with the help of gas chromatography and NMR spectroscopy.
The mixture of isomers was separated using preparative HPLC and the structures of the diastereomers along with their relative stereochemistry were determined with the help of NMR studies (NOE difference spectra).

RESULTS AND DISCUSSION
The formation of ethyl 3-ethenyl-2-hydroxypent-4-enoate (7)  Pauson-Khand cyclization of the substrate compound 9 was highly selective and the desired bicyclic 1-hydroxycarboxylic acid derivatives ( Figure 5, 10a and 10b) were formed as a mixture of two diastereomers (4:1) out of four possible diastereomers. This isomeric mixture could be separable only in preparative HPLC. The NOE different spectra supported to determine the relative stereochemistry of the major isomer, 7-[2- The proposed mechanism for the intramolecular cyclization is given below (Figure 8).

CONCLUSION
We have documented here highly functionalized stereo selective and efficient synthesis of five-membered bicyclic 1-hydroxycarboxylic acid derivatives based on Pauson-Khand cyclization. As 1-hydroxycycloalkane-1-carboxylic acids serve as important staring compounds for the preparation of biologically active molecules, this method can be applied in the synthesis of wide range of biologically relevant molecules.

ACKNOWLEDGEMENT
Author is thankful to Swiss National Science foundation and Swiss Federal Commission of Scholarships for providing financial support for this research and to Professor Philippe Renaud, University of Bern, Switzerland for his valuable guidance for the research.