William O. Moss

2-Amino ketene S,S-acetals as α-amino acid homoenolate equivalents. Synthesis of 3-substituted prolines and molecular structure of 2-(N-pivaloylpyrrolidin-2-ylidene)-1,3-dithiane

Allylic deprotonation of the heterocyclic 2-amino ketene S,S-acetal 8a, followed by regioselective γ-alkylation reaction of the resulting organolithium 10(a proline homoenolate equivalent) with electrophiles, leads to adduct 11. Controlled hydrolytic cleavage of 11 gives a series of 3-substituted prolines, including the conformationally-constrained aspartate and glutamate derivatives, 14e and 14f respectively. The bicyclic thiolactam 18 has been prepared in an attempt to provide an asymmetric variant of organolithium 10 but efforts to generate the requisite ketene N,S-acetal 19 were unsuccessful. Extension of the ketene S,S-acetal chemistry to other ring sizes has been examined within the context of substituted azetidine-2-carboxylates. Condensation of the protected amino ester 20 with AIMe3–HS(CH2)3SH was complicated, however, by the reactivity of the four-membered ring and led to the ring-opened adduct 24, with none of the required ketene S,S-acetal 22 being observed.

Generation of α-amino acid homoenolate equivalents. Synthesis of 3-substituted prolines.

Abstract Deprotonation of the N-protected aminoketene-S,S-acetal (6) and reaction of allylic anion (7) with electrophiles leads to adducts (8) which have been converted to 3-substituted prolines (11). Conformationally constrained variants (11d) and (11e) of aspartic and glutamic acid have been prepared.

Ketene-S,S-acetals as 1,3-dipolarophiles reactivity towards electron-deficient azides

Abstract The reactivity of a series of ketene-S,S-acetals (2a-e) towards p-toluenesulphonyl azide and ethoxycarbonyl azide is determined by the nature of the substituents on both the dipolarophile and the 1,3-dipole. With p-toluenesulphonyl azide rearrangement of the 1,3-dithianyl ring is observed to give (4), but with ethoxycarbonyl azide a different pathway is followed leading to β-amino ketene-S,S-acetals (6), albeit in low yield.

Synthesis and lithiation of γ,γ-difunctionalised ketene dithioacetals. Access to a new synthetic equivalent of a β-hydroxy-β-lithioacrylate. X-Ray molecular structure of 2-(1,3-dithian-2-ylidenemethyl)-1,3-dithiane

A series of γ,γ-dithioalkyl or dithioaryl ketene dithioacetals (3a), (3b), and (3c) has been prepared. Attempts to generate allylic anions under a variety of conditions from 1,1,3,3-tetrakis(phenylthio)propene (3a) and 1,1,3,3-tetrakis(methylthio)propene (3b) failed but 2-(1,3-dithian-2-ylidenemethyl)-1,3-dithiane (3c) is readily deprotonated with lithium di-isopropylamide to give anion (4c). This species can function as an equivalent of β-hydroxy-β-lithioacrylate and this equivalence has been illustrated by a synthesis of (±)-dihydrokawain (14). The use of compound (3c) as a reagent in synthesis is, however, limited in some cases by the nature of the conditions required for dithioacetal–ketone conversion. The X-ray crystal structure of compound (3c) has been determined.

Ketene-S,S-acetals as 1,3-dipolarophiles towards azides. A new synthetic entry into cyclic amino acids

Abstract Intramolecular azide cycloaddition reactions of ketene-S,S-acetals proceed to give a reactive imine as the initially-formed intermediate and this mechanism is supported by thermolysis of (18) which gave the stable imine (22). N-Acylation of this intermediate leads to cyclic variants of 2-amino ketene-S,S-acetals (20, 24, 27), which can be viewed as masked α-amino acids, and reduction leads to the corresponding dithiane (21, 25, 29a). Both systems have been converted to cyclic α-amino acids and the scope, in terms of the ring sizes available, and the limitations of this intramolecular cycloaddition process are discussed.

ASYMMETRIC SYNTHESIS OF (2R, 5R)-2,5-DIAMINOHEXAN-1,6-DIOIC ACID

Abstract Schollkopfs auxiliary 16 was added to bis-lactim iodide 21 to give 1,2-bis[(3S,6R)-3,6-dihydro-2,5-dimethoxy-3-isopropylpyrazin-6-yl]ethane22 in 50% d.e. Dimer 22 was separated from its diastereoisomer 23 and deprotected using 6M HCl to afford homochiral (2R,5R)-2,5-diaminohexan-1,6-dioic acid 24.

Ketene S,S-acetals as 1,3-dipolarophiles: application to the synthesis of polyhydroxylated pyrrolidines

Two approaches to the synthesis of the hydroxylated pyrrolidines 3 and 4, based on exploiting the reactivity of a ketene S,S-acetal as a 1,3-dipolarophile, are described. Both routes utilize a carbohydrate starting material and the strategy based on D-erythrose was successfully concluded. The use of D-ribose, although not successful in terms of the synthetic objectives, does serve to probe the scope and limitations of ketene S,S-acetals as highly functionalised dipolarophiles.

Ketene dithioacetals as 1,3-dipolarophiles. Applications to the synthesis of cyclic amino acids

Intramolecular azide cycloaddition reactions of ketene dithioacetals provide a new route to cyclic amino acids and a stereoselective synthesis of (2S,3S,4R)-3,4-dihydroxyproline (14) based on this methodology is described.