Homoenolate route

Previously unreported yn-diastereoselectivity in the synthesis of 6-niuoesters (94) from enals (95) and nitroalkenes (96) has been achieved, using an NHC (97, reminiscent of dialkylprolinol TMS ether) designed to avoid the established acyl anion/Stetter pathway and favour the homoenolate route.The method has been further exploited in a mild and elegant one-pot synthesis of 6-lactams (98) from similar starters. 

The recent surge of interests in metal homoenolate chemistry has been stimulated by the recognition that the siloxycyclopropane route can afford novel reactive homoenolate species that are stable enough for isolation, purification, and characterization. The stability of such homoenolates crucially depends on the subtle balance of nucleophilic and electrophilic reactivity of the two reactive sites in the molecule. Naturally, homoenolates with metal-carbon bonds that are too stable do not serve as nucleophiles in organic synthesis. 

Treatment of zinc homoenolates with Me3SiCl in a polar solvent also results in cyclopropane formation Eq. (23). This provides a very mild route to the siloxycyclopropanes [24]. 

The fact that the above reactions allow isolation of 4-hydroxyesters, which are often unstable and lactonize quickly, is a merit of the homoenolate chemistry. Mesylation of the hydroxy group followed by appropriate operations provides stereocontrolled routes to y-lactones and cyclopropane carboxylates [19]. Through application of such methodology steroid total synthesis has been achieved (Section 7). 

Two groups independently reported the formation of titanium homoenolates by the transmetalation reaction of 3-stannyl-propionate esters with TiCl, Eq. (48) [45, 46]. Amide homoenolates become available along this route [47], The trichlorotitanium species thus obtained have been shown ( H NMR) to be similar to that generated along the siloxycyclopropane route and indeed exhibit very similar reactivities. This method does provide a conventient alternative to the siloxycyclopropane route. 

A very practical route to zinc homoenolate involves reduction of 3-iodoesters with zinc/copper couple in the presence of a polar solvent, e.g. DMF, DMA [49] Eq. (51). The nature of the species obtained in this approach is not well-defined, but appears to be essentially the same as the one obtained along the siloxycyclo-propane route. Acylation, arylation, and vinylation reactions have been reported. 

Reaction between a siloxycyclopropane and Cu(BF3)2 in ether gives a product due to symmetrical coupling of two homoenolate moieties (Eq. 53, Table 12) [51]. This is particularly noteworthy as a simple route to 1,6-ketones superior to classical approaches such as the Kolbe electrolysis [52], Several lines of evidence suggest the intermediacy of Cu(II) homoenolates. AgBF3 and CuF2 effect the same reaction albeit with lower yields. The reactions with cupric halides give... 

The title transformation provides an alternative pathway for the construction of the cyclopropane ring from a synthon of three carbons. The intramolecular cyclization of homoenolate anion equivalents is represented in Scheme 11, Eq. (ii). In practice, several routes involving metals such as Mg, Zn, and Ti, as well as different homoenolate precursors, have been developed [17a-e]. 

Ring-opening reactions of cyclopropanone hemiketals are well known. Under appropriate conditions, cleavage of trimethylsilyl protected hemiketals can provide a synthetically useful route to homoenolate anions as noted earlier (Scheme 20). The reaction of an isopropoxy-titanium homoenolate (128) derived from 127 with an aldehyde has recently been used as the key step in the stereocontrolled construction of the steroidal side-chain of depresosterol (Scheme 49) ... 

The Pd- or Ni-catalyzed reaction of tiialkylsilylmethylmetals containing Zn or Mg provides a novel regio- and stereo-controlled route to allylsilanes [82-84] (Scheme 1-26). Another useful application of Pd-catalyzed alkylation is the / -substitution reaction of zinc homoenolates [85-89] (Scheme 1-27) and higher homologues [90]. 

Nitriles and esters are also unreactive in Smh-promoted Barbier reactions. A very useful procedure for lactone synthesis has been developed making use of this fact. Treatment of 7-bromobutyrates or 8-bro-movalerates with Smh in THF/HMPA in the presence of aldehydes or ketones results in generation of lactones through a Barbier-type process (equations 25 and 26). This nicely complements the -metaUo ester or homoenolate chemistry of organosamarium(III) reagents described above (Section 1.9.2.1), and also the Reformatsky-type chemistry promoted by Sml2 (Section 1.9.2.3.2). Further, it provides perhaps the most convenient route to 7- and 8-carbanionic ester equivalents yet devised. 

Taylor, E.C., and Davies, H.M.L., Rhodium(II) acetate-catalyzed reaction of ethyl 2-diazo-3-oxopent-4-enoates. Simple routes to 4-aryl-2-hydroxy-l-naphthoates and P,y-iinsaliiralcd esters. The dianion of ethyl 4-(diethylphosphono)acetoacetate as a propionate homoenolate equivalent, Tetrahedron Lett., 24, 5453. 1983. 

Since the mid-1970s, advances in organometallic chemistry have permitted the preparation and synthetic use of homoenolates. Major efforts have been expended for the exploration of a silyloxycyclopro-pane route,in which silyloxycyclopropanes are cleaved by polyvalent metal salts to obtain reactive metal homoenolates (equation 1). Through such a route, a host of reactive ester, ° ketoneand aldehyde homoenolates have been generated. 

Internal nucleophilic cyclization is one of the most typical reactions of reactive metal homoenolates (equation 3 and Scheme and provides a convenient route to silyloxycyclopropanes (e.g. 8) through cyclization of 3-halo esters. Zinc homoenolates (9) also cyclize to cyclopropanes under suitable conditions. Treatment of the zinc homoenolate in CHCb with an acid chloride at room temperature gives an 0-acylation product (Scheme 6), instead of a 4-keto ester (see Section 1.14.7.1). The reaction of the zinc homoenolate wifo MesSiCl in a polar solvent gives a silyloxycyclopropane (Scheme 6), providing a very mild route to silyloxycyclopropanes. ... 

Reaction of a silyloxycyclopropane and Cu(Bp4)2 in ether results in symmetrical coupling of two homoenolate moieties (Scheme 10). This reaction provides a convenient route to 1,6-diketones. Intermediacy of a copper(II) homoenolate has been suggested. AgBp4 and Cup2 effect the same reaction,... 

Addition of a homoenolate to a carbonyl compound, which may be called a homoaldol reaction , provides a straightforward route to 4-hydroxy esters and y-lactones. Only two classes of well-characterized homoenolates that undergo nucleophilic addition to carbonyl compounds are known, namely titanium and zinc homoenolates of esters. 

Titanium homoenolates can be prepared by transmetallation of 3-stannyl esters wiA TiCU (Scheme 13) 30,31 trichlorotitanium species (10), shows reactivity very similar to that obtained by the silyl-oxycyclopropane route. 

Reduction of 3-iodocarbonyl compounds with a zinc/copper couple in polar solvents (e.g. DMF, DMA) > generates homoenolates of esters, nitriles and ketones - (Scheme 24). These species are not well defined, but they appear to be very similar to those obtained by the silyloxycyclopropane route. 

Commercially available methyl p-hydroxyisobutyrate (16) has been converted to the corresponding halide (17), then either via the silyloxycyclopropane route (A) or via the reductive route (B) to the chiral zinc homoenolate (18 Scheme 28). It is optically stable in ether and has been used for several standard carbon-carbon bond-forming reactions, e.g. carbonyl addition, arylation and acylation. ... 

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