Diastereoselective thiol conjugate addition on δ-alkylated-γ-silylated-α , β-unsaturated-δ-lactones

The silicon atom at the γ position of α-pyrone 1a plays a dramatic role in directing thiol conjugate additions in a diastereoselective way. We describe here a stereoselective access to γsilylated-β-thio-δ-lactones.


(Scheme 1)
Since the palladium(0) catalyzed first step totally transfers the chirality 3 and the alkylation second step is highly distereoselective, 4 this stereoselective one-pot transformation is a valuable synthetic tool.
Of course δ-lactones 1 are interesting because of the wide occurrence of this skeleton among pharmacological and / or natural compounds [5][6][7] and also because they display different highly reactive chemical functionalities.In particular, we focused recently on diastereoselective conjugate additions which may be followed by electrophilic trapping. 1We demonstrated that these two former reactions can be included in a four-step one-pot transformation of α,β-epoxyγ,δ-vinyl-silanes 2, directly into tetra-substituted δ-lactones 3. 1 3)Nu

Scheme 2
We are also interested in the conjugate addition of nucleophiles, other than carbanions, on δlactone 1a.In this paper we describe the conjugate addition of various thiols derivatives and the confirmation of the structural assessment of the 1,4-adducts with the anti relative configuration of the silicon and the sulfur atoms.

Results and Discussion
][10] Some of the studies, especially with the cysteine system are closely related to the investigation of the biological mechanism responsible for the carcinogenicity of lactones. 11The thiol reagent often plays the role of solvent in thiol conjugate additions on δ-lactones in the presence of a basic amine.Piperidine is used at high temperature to perform the addition of aromatic thiols on aromatic δ-lactones. 12Mevilonin and its analogs could react on thio-acids, thio-alcohols or thiols at room temperature with triethylamine to afford δ-lactones bearing a sulfur atom on the β position. 13Recently high stereoselectivity of these thiol 1,4-additions has been observed on α,β-unsaturated esters by using external chiral ligands which give the adducts with high ees. 14n the case of the δ-lactone 1a, the presence of the trialkylsilyl substituent should again direct the incoming of the heteronucleophile, then unequivocally creating an anti/anti relationship between the three substituents.Independent from the structural interest, this brought the advantage of functionalizing our substrate with an heteroatom which could be oxidized 15 , eliminated or reduced, for instance by a radical transformation. 16Therefore, we ran some experiments consisting of adding thiols in a 1,4-process on lactone 1a.Table 1 shows that the same diastereomer is obtained either exclusively (entries 1,2,4,5,7) or as the major product (entry 3).Yields of the thiophenol addition depend very much on the basic conditions.Use of butyllithium (entry 1) may be optimized in the presence of ether / boron trifluoride complex, but still the yield does not reach beyond 28% (entry 2).Triethylamine gives a better yield of 81% at 90°C (entry 3) and lowering the temperature to 70°C improves the diastereomeric excess to 98% (entry 4).The absence of reactivity for tert-butyl-thiol (entry 6) indicates some steric control of the reaction and p-nitro-thiophenol (entry 8) fails to react probably because of its weak nucleophilicity.In the case of n-butyl-thiol and p-methoxy-thiophenol (entries 5,7) the conjugate addition is probably reversible as formerly reported. 17 1 NMR experiments, especially NOE studies, did not allow us to elucidate the relative configuration of the sulfur and the silicon atoms in thioethers 4-6.Structural determination of the diastereomer obtained in the experiments outlined in table 1 was accomplished with the X-ray analysis of compound 4.These X-ray results show the sulfur atom clearly in an anti relative configuration to the silicon atom, therefore syn to the iso-propyl group (Figure 1).Dihedral angles between C 5 -H 5 and C 4 -H 4 bonds and between C 3 -H 3 and C 4 -H 4 bonds are respectively 166° and 129°, which proves important distortion of this conformationaly stable δ-lactone compared to a cyclohexane chair.Therefore, we were not surprised by the value of the 1 HNMR coupling constants for protons H 4 and H 5 (J = 10.83Hz) and for protons H 4 and H 3 (J = 2.46Hz).Our conclusion points out the directing effect of the silicon group at the γ-position of the δlactone 1a and the possibility of reacting it with thiols in a diastereoselective conjugate addition.This links a sulfur atom, anti to the silicon atom and creates a new stereogenic center on the lactone ring which bears a heteroatom.We have previously studied the desilylation of our substrates and ascertained that, after desilylation, we obtained tri-substituted δ-lactones with substituents at the β and the δ positions which are syn to each other.This is interesting according to the existing literature providing the anti relative configuration of these substituents. 18ynthetic developments of our γ-silylated-β-thio-δ-lactones 4-6 are currently under investigation in our group.

Experimental Section
General Procedure.Compounds 4-6.δ-Lactone 1a (1 equiv), thiol (5 equiv) and triethylamine (0.3 equiv) are successively introduced in a flask equipped with a condenser.The mixture is heated at 70°C and stirred for 48 hours.Hydrolysis with a saturated aqueous solution of ammonium chloride, followed by extraction with dichloromethane and washing of the organic phase with brine leads to a crude material which was purified on silica gel by flash chromatography with petroleum ether / ethyl acetate 95 /5.