SmI₂-Promoted Reformatsky-Type Coupling Reactions in Exceptionally Hindered Contexts

Abstract

Highly substituted, very hindered enones were synthesized using a two-step procedure that utilizes a diiodosamarium-promoted Reformatsky-type coupling and dehydration using Martin sulfurane. Both α-chloro-and α-bromoketones were coupled with a variety of carbonyl nucleophiles to form the intermediate β-hydroxyketones, occurring with excellent diastereoselectivity, favoring the syn isomer (R 1 = Me). This technique complements other methods and enables the preparation of enones outside of the scope of current olefination methodology.The β-hydroxyketone and α,β-unsaturated ketone are frequently used as sites of fragment couplings in target-oriented synthesis. 1,2 In numerous natural products, a quaternary alkylsubstituted carbon exists adjacent to this functional group (Figure 1). 3 However despite this prevalence, these highly hindered enones are rarely exploited as a site of fragment assembly. 4,5 The significant steric demand posed by these α-quaternary carbon centers prevents the use of most techniques commonly used to form similar, less sterically hindered systems. 6,7 The Reformatsky reaction is an excellent synthetic tool for site-selective formation and subsequent elaboration of an enolate. 8 Many metals such as magnesium, chromium and zinc can be used to promote this transformation. Nevertheless, only a few examples of such reactions involving quaternary substitution adjacent to the α-bromoketone have been described. Dubois has reported the use of chromium(II) chloride to promote the Reformatsky-type coupling of pinacolone-type α-bromoketones with aldehydes; 9 however, to date this coupling has found limited utility. Other metallic species, namely magnesium 10 and diethylzinc, 11 have been used to promote the pinacolone-type Reformatsky-type coupling, but the low degree of functional group compatibility of these reagents places significant restrictions on these methods. 12 Since the advent of diiodosamarium as a reagent in organic synthesis, it has been extensively employed in intramolecular Reformatsky-type reactions. 13 In contrast, this reagent has found little use in intermolecular Reformatsky-type coupling reactions, presumably due to the numerous side reactions that can occur. 14 Our recent total synthesis of (+)-acutiphycin tfj@mit.edu.

Stereoselective Preparation of (E)‐Configured 1,2‐Disubstituted Propenes from Two Aldehydes by a Two‐Carbon Stitching Strategy: Convergent Synthesis of 18,21‐Diisopropyl‐Geldanamycin Hydroquinone and Its C7 Epimer

“…Given the repeated failure encountered in these attempts, it was gratifying to note that a-bromoketone 15, which was obtained by treatment of ethyl ketone 14 with phenyltrimethyl ammonium tribromide (PTAB), [22] underwent a reductive Reformatsky-type [23] coupling with aldehyde 3. As nicely precedented by the work of Jamison et al, [14] SmI 2 was found to be an excellent reductant for this step. It is noteworthy that a-bromoketone 15, which-in contrast to the tert-alkyl substrates studied by Jamison et al [14c] -contains a sensitive stereogenic center at the second a-position, reacted smoothly and afforded the desired product 16 in up to 81 % yield.…”

“…It was found that 1chloroethyl magnesium chloride nicely serves this purpose and a general method was established, with which aldehydes can be converted into the respective a-chloroethyl ketones. As previously shown by Jamison et al, [14] the latter compounds are in turn capable to undergo a reductive SmI 2 -promoted coupling reaction with aldehydes to provide after dehydration the respective E-configured a,b-unsaturated ketones. When applied to compounds 3 and 4 a successful assembly was possible to an intermediate which was further converted into the title compounds upon reduction at C7 and macrolactamization.…”

“…For the subsequent dehydration step we recurred to the use of the Martin sulfurane [25] reagent, which had been previously used by Jamison et al for the same purpose. [14] The desired enone 17 was obtained as pure E isomer in a yield of 79 %. Although the presented route is a valid solution for the retrosynthetic disconnection presented earlier (Scheme 1), it was not fully satisfying from a preparative point of view.…”

“…Preparation of a-chloroketones and their reductive coupling: An improved route for the preparation of enone 17: In light of the encountered difficulties preparing ketone 15 and being aware of the fact that a-chloroketones had been reported to be an equally potential coupling partner in the SmI 2 -promoted reactions, [14] we considered the possibility to prepare an a-chloroketone related to 15 from aldehyde 4 by direct addition of an a-chloro Grignard reagent and subsequent oxidation. Carbenoids of this type have been shown to be accessible by sulfoxide-magnesium exchange (Scheme 5), the driving force of which has been proposed to be the increased stabilization of the negative charge at the carbon atom by the halogen substituent.…”

A Highly Efficient Large‐Scale Asymmetric Direct Intermolecular Aldol Reaction Employing L‐Prolinamide as a Recoverable Catalyst

“…tertButyl ethyl ketone was prepared following the reported procedure. [15] All reactions were monitored by thin-layer chromatography (TLC) with Haiyang GF254 silica gel plates. Flash column chromatography was carried out using 100-200 mesh silica gel at increased pressure.…”