SmI₂/Pd(0)-Mediated Intramolecular Coupling between Propargylic Esters and Tethered Aldehydes or Ketones

Abstract

A SmI(2)/Pd(0)-promoted intramolecular coupling between propargylic esters and carbonyl compounds is described. The reaction affords homopropargyl cycloalkanol products. Cyclopentanols are formed in high yields when ketones are employed as the carbonyl components, but aldehydes are found not to be suitable partners in these reactions. Particularly remarkable is the efficient formation of products with adjacent functionalized quaternary centers. These cyclizations take place with low diastereoselectivity about the newly created propargylic and carbinol stereogenic centers except when these two centers are quaternary or in the presence of groups capable of both chelating trivalent samarium and facilitating retroaldol-aldol-type equilibria in the product. In this latter case, the strategic combination of chemoselective carbonyl addition and SmI(2)/Pd(0)-promoted cyclization provides ready and convenient stereocontrolled access to functionalized cyclopentanols from unprotected 1,5-dicarbonyl starting materials. The analogous formation of cyclohexanols is limited by low cyclization yields and lack of stereoselectivity.

Carbohydrate to Carbocycle Conversions via Intramolecular Propargylation with Et2Zn/Pd(0)/Yb(OTf)3

“…However, the major diastereoisomer formed displayed instead a trans relationship between those groups implying that open transition states 18 are probably involved in the formation of 16. One reasonable explanation for this behavior is that coordination of the carbonyl group to the strong Lewis acid Yb(OTf) 3 10 is the stereocontrolling factor 11,12 in our reactions.…”

“…ZnCl 2 , TiCl 4 and TMSCl gave inferior results and TMSOTf led only to degradation. As for the Pd(0) catalyst, Pd(PPh 3 ) 4 , Pd(OAc) 2 •4PBu 3 and Pd 2 (dba) 3 •4PBu 3 were all found to give good yields of 16. Pd 2 (dba) 3 •4PPh 3 and Pd(OAc) 2 •4PPh 3 gave inferior results while PdCl 2 (dppf) 2 and Pd(OAc) 2 •PPh 3 8 were ineffective.…”

“…CH 2 Cl 2 has also been effective but its generalized use was not explored. For practical purposes, the combination of Yb(OTf) 3 as Lewis acid with a Pd(OAc) 2 •4PBu 3 catalyst and benzene as solvent gave the best results in terms of combined yields and diastereoselectivities. 9 Under these conditions, one diastereoisomer was obtained as a single or very major product in preparatively useful yields (Scheme 4).…”

Catalyst‐ and Solvent‐Dependent Stereodivergence in the Intramolecular Et2Zn/Pd0‐Promoted Carbonyl Propargylation: Mechanistic Implications

“…Substrates 1 a-e, including simple acyclic secondary or tertiary propargylic esters with a tethered aldehyde or ketone, were prepared by using synthetic routes that parallel those previously reported for 1 d and 1 e. [8] Details are given in the Supporting Information.…”

“…The intramolecular propargylation of aldehydes and ketones (Scheme 1, path a) provides an entry to cyclic compounds of type I containing a homopropargyl alcohol unit, a structural motif present in a variety of biologically active compounds, as well as a versatile functionality that is susceptible to useful synthetic transformations. [1][2][3] Although relatively little explored, [4][5][6][7][8][9][10][11][12][13] this type of strategy presents some dis-tinct and interesting features. For example, the regiochemical problems associated with methods based on the traditional oxirane alkynylation (Scheme 1, path b) are avoided, and the Lewis acidity of the metal associated to the carbanionic moiety can be potentially used as a tunable element for stereocontrol by using the nature of the metal and/or Lewis acid additives as variables.…”