1,3-Diastereocontrolled O-Displacement of Enolates

Abstract

Acyclic diastereoselection of 1,3-relative centers is a topic of great interest1 and has important implication in the synthesis of polyether and macrolide antibiotics.2 Impressive progress has been made in special cases such as in the conversion of metal-chelated j3-hydroxyl ketones to 1,3-diol derivative^.^ However, high levels of asymmetric induction are less documented for substrates which do not involve metal-chelated c~mplexes.~ Geometrical constraints imposed by intramolecular cyclization reactions provide attractive means to control the newly-formed asymmetric centers in the process of ring as~embly,~ and acyclic stereocontrol would then result if the temporary ring can be subsequently elaborated.We describe here a new approach employing rigid fivemembered ring systems for diastereoselective constitution of stereocenters via intramolecular SN' reactions. It was presumed that enolates 1 would undergo O-displace-ment6 with the formation of enol ethers 2 which, after simple hydrolysis, would afford hemiacetals 3 or y-hydroxy ketones 4 with resulting stereocontrol of remote stereogenic centers (Scheme 1).We were initially intrigued with the possibility of stereoselective formation of bicyclic enol ether 7a via intramolecular SN' displacements (Scheme 2). In fact, treatment of cyclohexanone derivative 5l with potassium hydride gave a single isomer of vinyl ether product 7a which was similarly obtained from trans olefin 6.7 Thus, (1) For reviews, see: (a) Bartlett, P. A. Molander, G. A.; Etter, J . B.; Harring, L. S.; Thorel, P.-J. J. Am. Chem. SOC. 1991, 113, 8036. (d) Murakami, M.; Suginome, M.; Fujimoto, K.; Nakamura, H.; Andersson, P.; Ito, Y. J. Am. Chem. SOC. 1993, 115, 6487. (6) For palladium-catalyzed 0-displacment of acetoacetate derivatives, see: Trost, B. M.; Runge, T. A. J . Am. Chem. SOC. 1981, 103, 7550 and 7559.(7) By using 1 equiv of sodium hydride at 0 "C, monoalkylation of 2-phenylcyclohexanone with cisor trans-1,4-dibromide-2-butene gave the corresponding intermediates 5 and 6 in 45% and 65% yields, respectively. 0022-3263/95/1960-2668$09.00/0 Scheme 1 1 2 3 4 Scheme 2 5 l a 6 Scheme 3the olefin geometry of the starting materials has little influence on the resulting stereochemistry of the final product. The preference for 0rather than C-alkylation, which derives from stereoelectronic considerations, has been well documented for the process of five-membered ring formations.s Molecular modeling studiesg were performed to elucidate the nature of these results. In assessing the contribution of various transition states, we have chosen early transition state structures in which the new bond formation is stereodetennining (Scheme 3). In structures 5b and 6b, there are strong 1,3-interactions between phenyl and vinyl groups regardless of the geometry of the double bond. Therefore, the preferred transition states are Sa and 6a in which the vinyl group is oriented away from the phenyl during the five-membered ring formation, thus leading to an efficient 1,3-diastereoselection.An interesting feature of...

Authors' reply

“…In sharp contrast with recent results on the reactivity of 2‐substituted cyclohexanone anions,15b the olefin geometry has a great influence on the outcome of the overall process when stabilized enolates, derived from cyclic ketones 1 a , d – h , are concerned. Indeed, while ( Z )‐1,4‐dichloro‐2‐butene ( 2 e ) gives exclusively a tandem C−C cycloalkylation (Table 1, entries 1, 2), the reaction with its trans ‐isomer 2 n furnishes a clean C−O cycloalkylation (Table 3).…”

“…This simple pathway, applied to more elaborated substrates, could easily give access to stereodefined and highly functionalized reduced furan structures30 which abound in nature and have attracted considerable attention 31. Moreover, related vinyl derivatives have been used as powerful reactive intermediates in many interesting stereoselective synthetic transformations such as thermal14a, 32 and palladium33‐catalyzed rearrangements, simple addition reactions34 and tandem addition–fragmentation sequences 14b,14c,15b…”

“…Therefore the stereochemical outcome of the overall transformation could well result from destabilization of transition state J by 1,3‐interaction between the ring junction carbomethoxy group and the forming vinyl group as postulated by Zhao (Figure 7). 15b…”

Our Recent Contribution to the Field of Anionic Domino Transformations

“…Unfortunately, while Tania had a hard time with the hydration and some other transformations, 55 a series of papers from Zhao's group 56 reported a similar preparation of closely related cyclic enol ethers and their elegant synthetic utilization in the acyclic 1,3-diastereocontrol and in the preparation of medium-sized lactones. In light of this report, we focused our attention on the [3,3] sigmatropic rearrangement.…”

Synthesis and palladium-catalysed isomerisation of fused polycyclic tetrahydrofurans: efficient and stereoselective one-pot domino construction of functionalised bridged bicyclo[n.2.1] ring systems

“…In this context, one-pot sequential and domino reactions [7] have emerged as modern synthetic powerful tools [8][9] because of significant advantages, such as high atom-economy [10][11], bondforming efficiency [12][13], selectivity, molecular complexity and diversity [14][15][16], and environmental prevency. In this family, domino reactions of monoanions [17], dianions and masked dianion equivalents [18][19] derived from β-dicarbonyl compounds have been extensively studied. However, in spite of the synthetic usefulness of these systems, the synthetic potential of anions derived from readily available 1,3-diactivated ketones has been less explored [20][21].…”