Patrick Metzner

Thiocarbonyl Compounds as Specific Tools for Organic Synthesis

Thiocarbonyl compounds (thioamides, thioesters, thioketones...) react readily with a large variety of reagents (nucleophiles, electrophiles and radicals) due to their weak C=S bond and the aptitude of sulfur to stabilise an adjacent charge or radical centre. Thus, nucleophilic additions, deprotonation, and sigmatropic rearrangements are often more facile than in the oxygen series. Moreover, a number of specific reactions have been uncovered: thiophilic addition of nucleophiles, Michael addition of enethiolates, the Eschenmoser reaction, oxidation to sulfines, a large variety of [4+2] and [3+2] cycloaddition reactions with 1,3-dienes and 1,3-dipoles. Far from being purely exotic species, thiocarbonyl compounds are now efficient and specific tools and have indeed been used in multi-step synthetic schemes leading to various products of biological interest.

Cis-selectivity of the kinetic deprotonation of dithiopropanoates

Abstract Deprotonation of dithiopropanoates with LDA in THF solution at −78°C afforded chiefly the cis lithium thioenolate in contrast with the trans enolization of most of carbonyl compounds. The cis geometry was proved by a thio-Claisen rearrangement.

Recent Synthetic Developments in Thiocarbonyl Chemistry

Abstract Direct oxidation of enethiolizable thioketones and dithioesters with a peroxycarboxylic acid affords the corresponding sulfines quantitatively. This observation stands in contrast with literature expectations, stating that this reaction would lead to divin disulfides. The oxidation shows a high stereoselectivity: delivery of the oxygen proceeds from the side opposite to the alkylthio group of dithioesters and from the side opposite to the more hindered substituent in the case of thioketones. The thermal stability of these sulfines was studied and a novel rearrangement was observed. The second part of this report deals with the thio-Claisen rearrangement of precursors bearing a chiral centre adjacent to the pericyclic nucleus and its use for stereocontrol in the acyclic series. This thermally facile transposition leads to allylated dithioesters with good to excellent yields. A high diastereomeric selectivity was obtained in a number of cases involving either a steric effect with alkyl groups on th...

SOME DIFFICULTIES ENCOUNTERED WITH AM1 AND PM3 CALCULATIONS

Abstract AM1 and PM3 underestimate frontier interactions with respect to steric repulsions. Therefore, if two structures differ by ∼1 kcal/mol, their calculated ordering is unreliable. Activation energies tend to increase with substitution, regardless of electronic effects. Atomic charges are sometimes unrealistic (in enolates, the negative charge is larger on C than on O). At van der Waals distances, acid-base and coulombic interactions can prevail over steric repulsions. At all distances, basicities are overestimated and nucleophilicities underestimated. This may lead to anomalous ion-molecule and transition structures in gas phase reactions. Transition structures are tighter than in ab initio calculations. Optimisations may give chemically unreasonable structures. Minimum energy paths are then difficult to obtain. Usually, but not systematically, PM3 gives more reliable structures and AM1 more realistic energies.

Carbon versus sulfur addition of nucleophiles to sulfines: The case of amines

Abstract Reaction of dithioester sulfines 4 with amines leads to thioamides 5 . Sulfine 7 , obtained from (−)-thiocamphor, reacts with primary amines at room temperature to afford chiral imines 8 . Carbophilic addition, instead of thiophilic addition, has thus been evidenced.

Regioselectivite de l'addition d'enethiolates de composes thiocarbonyles avec les enones

Resume The regiochemistry of the reaction of lithium thioenolates towards non aromatic unsaturated ketones has been examined. The thioenolates have been generated by deprotonation of various thiocarbonyl compounds with lithium diisopropylamide. Thionesters afford mostly carbon 1,4-addition. Thioketones and an enethiol give regioselective sulphur 1,4-addition. N,H-dimethylthioacetamide leads to 1,2-addition. With the latter exception, thioenolates are confirmed as soft nucleophiles yielding conjugate addition. It has also been shown that the deprotonation of an aliphatic thioketone occurs stereoselectively to give the cis thioenolate.

Stereospecific Michael addition of dithioester enethiolates with acyclic enones

Abstract Cis lithium enethiolates, generated from substituted dithioesters, undergo 1,4-addition uith vapious β-monosubstituted α-unsaturated ketones. With acyclic enones one of the tw resulting diastereomeric 5-oxodithioesters is predominantly formed (ratio up to 95 : 5). Its anti configuration was proven by chemical correlation in one case. Evidence for fhe stereospecificity of this Michael, addition is given.

Auto-protonation diastereoselective d' enolates issus de l'addition-1,4 d'nethiolates avec des enones

Abstract 1,4-Addltion reaction of lithiated methyl dithioacetate with alpha,-beta-disubstituted enones affords diastereomeric 5-oxodithioalkanoates. Syn configuration was assigned to the major diastereomer by chemical correlation. High diastereoselectivities were obtained with 2,2,4-trimethyl-4-hexen-3 one and 2-ethylldenecycloalkanones, making this reaction useful for selective synthesis of acyclic or semi-cyclic chains with 1,2-adjacent asymmetric carbons. The stereoehemical course is opposite to the one normally observed for the protonation of acyclic diastereotopic enolates (Houk model). Trapping experiments revealed that the species present prior to hydrolysis is not an enolate but an enethiolate, already bearing the syn stereochemistry. These enefhiolates arise from the following steps : Michael addition gives an elusive enolate which undergoes a fast “auto-protonation” : transfer of the hydrogen alpha to the thiocarbonyl group towards the enolate moiety. Geometry of the enethiolate double bond is unique and probably cis. An intramolecular concerted auto-protonation mechanism is discussed and a pseudo-cyclic transition state is tentatively assigned. An example of a tandem Michael addition/Claisen rearrangement was achieved by S-allylation of the addition intermediate followed by transposition of the resulting unsaturated ketene dithioacetal at room temperature. Diastereoselectivity for the protonation of 1,3-dlastereotopic enolates was also examined.

An efficient and straightforward access to sulfur substituted [2.2]paracyclophanes: application to stereoselective sulfenate salt alkylation.

A straightforward and high-yielding access to various [2.2]paracyclophanes possessing a sulfur-based functional group is reported, the key step being a SEAr reaction mediated by a sulfonium salt. The versatility of the methodology was exemplified by an original application in sulfenate salt chemistry, from which a remarkable chirality transfer was observed.

Cis-homo addition-1,4 thiophile d'organomagnesiens avec des composes thiocarbonyles comportant un groupe carbonyle en β: Synthese stereoselective d'alcoylthio-2 et de bis (alcoylthio)-2,2 cyclopropanols

Abstract Aliphatic Grignard reagents react stereoselectively with β thioxo carbonyl compounds to give substituted cis 2-alkylthio or 2,2-bis (alkylthio) cyclopropanols with good yields. Two types of non-enethiolisable thiocarbonyl compounds of formulae MeCOC(Me) 2 CSR undergo this reaction a thioketone (R = Me) and a number of dithioesters (R = SMe, SEt, S iso Pr). The cis configuration of cyclopropanols has been assigned by 1 H NMR-Eu(fod) 3 . The cyclopropane ring closure is a concerted cis -1,4-homo addition.