Iron acyl complexes enolates

I.3.4.2.5. Chiral Enolates of Acyl-Metal Complexes J. S. McCallum and L. S. Liebeskind I.3.4.2.5.I. Chiral Iron-Acyl Complexes... 

The a-alkoxy-substituted iron-acyl complex 8 is prepared by oxidation of the enolate prepared from iron-acetyl complex 6 and subsequent etherification12. 

Hydroxy-substituted iron-acyl complexes 1, which are derived from aldol reactions of iron-acyl enolates with carbonyl compounds, are readily converted to the corresponding /i-methoxy or /1-acetoxy complexes 2 on deprotonation and reaction of the resulting alkoxide with iodomethane or acetic anhydride (Tabic 1). Further exposure of these materials to base promotes elimination of methoxide or acetate to provide the a,/ -unsaturated complexes (E)-3 and (Z)-3 (Table 2). 

Aldol reaction of the a-trimethylsilylated enolate 9 with aldehydes provides nearly equal amounts of chromatographically separable ( )- and (Z)-isomers of iron-acyl complexes 11 via silyloxide elimination from the intermedate aldolate 10 (Table 3). This methodology has been the most commonly employed entry to the (Z)-isomer series. 

The lithium enolate 2a (M = Li ) prepared from the iron propanoyl complex 1 reacts with symmetrical ketones to produce the diastercomers 3 and 4 with moderate selectivity for diastereomer 3. The yields of the aldol adducts are poor deprotonation of the substrate ketone is reported to be the dominant reaction pathway45. However, transmetalation of the lithium enolate 2a by treatment with one equivalent of copper cyanide at —40 C generates the copper enolate 2b (M = Cu ) which reacts with symmetrical ketones at — 78 °C to selectively produce diastereomer 3 in good yield. Diastereomeric ratios in excess of 92 8 are reported with efficient stereoselection requiring the addition of exactly one equivalent of copper cyanide at the transmetalation step45. Small amounts of triphcnylphosphane, a common trace impurity remaining from the preparation of these iron-acyl complexes, appear to suppress formation of the copper enolate. Thus, the starting iron complex must be carefully purified. 

Conducting the aldol reaction at temperatures below —78 "C increases the diastereoselectivity, but at the cost of reduced yields45. Transmetalation of the lithium enolate 2 a by treatment with diethylaluminum chloride generated an enolate species that provided high yields of aldol products, however, the diastereoselectivity was as low as that of the lithium species45. Pre treatment of the lithium enolate 2a with tin(II) chloride, zinc(II) chloride, or boron trifluoridc suppressed the aldol reaction and the starting iron-acyl complex was recovered. 

The a-alkoxy iron-acyl complex 5 may be deprotonated to generate the lithium enolate 6, which undergoes a highly diastereoselective aldol reaction with acetone to generate the adduct 7 as the major product. Deprotonation of acetone by 6 is believed to be a competing reaction 30% of the starting complex 5 is found in the product mixture48 40. 

The lithium enolate of the oc-silyl-substituted iron-acyl complex 19 reacts with aldehydes, however, products of the Peterson elimination process (E)- and (Z)-22 are usually isolat-ed22- 23,36.37 for t[1js anc other preparations of a,/t-unsaturated iron-acyl complexes see Section I.3.4.2.5.I.3.). 

The oxidation of /(-amino-substituted iron acyl complexes which are prepared via condensation reactions of iron-acyl enolates and imines or iminium ions26,5 -47-54 generates /(-lactams 32,33,61. Brief treatment with bromine in dichloromethane at low temperature is the usual procedure. 

Enolate Preparation by Deprotonation of Iron-Acyl Complexes a-Deprotonation of Iron-Acyl Complexes... 

The anion 7 is quite nucleophilic and undergoes exclusive C-alkylation upon reaction with electrophiles including chlorotrimethylsilane °. These reactivity patterns have led to the suggestion that enolates of iron-acyl complexes may be considered to behave similarly to the organic dianion 910- u. 

Most of the work in this area has concerned complexes racemic at iron. Section D.1.3.4.2.5.1.1. details methods for the preparation and resolution of enantiomerically pure iron acyl complexes. The details of alkylation reactions (see Section 1.1.1.3.4.1.3.) and aldol reactions (see Section 1.3.4.2.5.1.2.) of these and other iron acyl enolates are presented later with examples utilizing enantiomerically pure complexes indicated therein. Table 1 illustrates the scope of iron-acyl enolates prepared by deprotonation of complex 10 and its analogs. 

Treatment of the potentially electrophilic Z-xfi-unsaturated iron-acyl complexes, such as 1, with alkyllithium species or lithium amides generates extended enolate species such as 2 products arising from 1,2- or 1,4-addition to the enone functionality are rarely observed. Subsequent reaction of 2 with electrophiles results in regiocontrolled stereoselective alkylation at the a-position to provide j8,y-unsaturated products 3. The origin of this selective y-deproto-nation is suggested to be precoordination of the base to the acyl carbonyl oxygen (see structures A), followed by proton abstraction while the enone moiety exists in the s-cis conformation23536. 

Conditions employed for the generation of extended enolates by y-deprotonation of Z-oc,/ -un-saturated iron-acyl complexes are presented in Table 3. 

Reaction of Z-a./j-unsaturated iron-acyl complexes with bases under conditions similar to those above results in exclusive 1,4-addition, rather than deprotonation, to form the extended enolate species. However, it has been demonstrated that in the presence of the highly donating solvent hexamethylphosphoramide, y-deprotonation of the -complex 6 occurs. Subsequent reaction with electrophiles provides a-alkylated products such as 736 this procedure, demonstrated only in this case, in principle allows access to the a-alkylatcd products from both Z- and it-isomers of a,/j-unsaturated iron-acyl complexes. The hexamethylphosphoramide presumably coordinates to the base and thus prevents precoordination of the base to the acyl carbonyl oxygen, which has been suggested to direct the regioselective 1,4-addition of nucleophiles to -complexes as shown (see Section 1.1.1.3.4.1.2.). These results are also consistent with preference for the cisoid conformations depicted. 

Iron acyl complexes bearing an a,/ -unsaturated acyl ligand possess multiple sites of electrophilic reactivity. Strong bases may be induced to react with the acyl ligand, and in Section 1.1.1.3.4.1.1. the chemoselective y-deprotonation of Z-a,/i-unsaturated acyl ligands to generate enolate species was addressed. The profoundly different reactivity of the unsubstituted complex 1 and E-a,/ -unsaturated acyl complexes, such as 2, is discussed here. 

Representative examples of enolates produced by 1,4-addition of alkyllithium reagents to E-a,/ -unsaturated iron-acyl complexes are presented in Table 4. 

Methods for the preparation of the requisite -2,/l-unsaturaied iron-acyl complexes are presented in Section D.1.3.4.2.5., but it is noted here that several examples of 1,4-alkylative preparations of a-enolates from in situ generated fi-complexes, such as 9, have been reported in which the alkyllithium base employed acts both as a base to produce the unsaturated species via elimination and subsequently, as a nucleophile to afford alkylation products 10 and 1244. 

Table 6. Alkylation of a-Enolates 2 of Chiral Iron-Acyl Complexes 1 by Carbon Electrophiles...

Treatment of -a,/ -unsaturated iron-acyl complexes, such as 33, with alkyllithinms or lithium amides results in exclusive diastereoselective 1,4-nucleophilic addition to generate the elaborated enolate species 34 (see Houben-Weyl, Volume 13/9a, p416, and Section 1.1.1.3.4.1.2.)... 

Electrophiles that have been used for the second alkylation of this tandem Michael addition -alkylation sequence are limited to primary iodoalkanes, (bromomethyl)benzenes and 3-bromo-propenes. Tables 9 and 10 provide details of the alkylations of enolate species prepared by 1,4-additions of -a,/j-unsaturated iron-acyl complexes by anionic carbon nucleophiles and anionic nitrogen nucleophiles, respectively. 

General methods for the preparation of a.jS-unsaturated iron-acyl complexes are deferred to Section D 1.3.4.2.5.1.1. examples of the alkylation of enolates prepared via Michael additions to ii-0 ,/ -unsaturated complexes prepared in situ are included here. Typical reaction conditions for these one-pot processes involve the presence of an excess of alkyllithium or lithium amide which first acts as base to promote elimination of alkoxide from a /f-alkoxy complex to generate the -a,)S-unsaturated complex which then suffers 1,4-nucleophilic addition by another molecule of alkyllithium or lithium amide. The resulting enolate species is then quenched with an electrophile in the usual fashion. The following table details the use of butyllithium and lithium benzylamide for these processes44,46. 

Iron-acyl complex 47 illustrates the diastereoselective a-alkylation of the 3-methyl-l-oxobutyl-substituted enolate 46, prepared by two iterations of the elimination-Michael addition sequence three alkylations are conducted in a single reaction vessel44. 

The origin of the third diastereomer produced, complex 12, is of particular mechanistic interest. The configuration at Ca of 12 is opposite to that of the other two products 10 and 11 indicating that the opposite face of the enolate 6 has been approached by the epoxide. Two possible alterations of the geometry of enolate 6 inay be invoked to account for this, adoption of the 5yn- -conformer or adoption of the anti-Z-conformer. Examination of the different structures shown reveals that the observed minor product 12 could arise from a matched reaction pair of the ivn-E-enolate and epoxide (Newman Projection G) or from a mismatched reaction pair of the anti-Z-enolate and epoxide (Newman projection I). The absence of diastereomer 13 strongly suggests that the minor product 12 arises from reaction of the. ryn- -enolate, underscoring the extreme reluctance of iron-acyl complexes to form Z-enolates on deprotonation (see scheme on p 955). 

Iron acyl complexes are among the most widely studied of the organometallic iron species, especially as applied to organic synthesis. As previonsly mentioned they are prepared to provide access to iron alkyls (via decarbonylation), and because iron acyls can be deprotonated to form enolates much like any carbonyl they have been utilized as chiral auxiliaries in asymmetric synthesis. Also, iron acyls are an important entry point for the preparation of iron carbenes. 

The a-protons of iron acyl complexes are acidic and these can be deprotonated with Lithium diisopropylamide (LDA) or with n-butyllithimn. Thus the corresponding enolates are readily functionalized and undergo reaction with alkyl halides, aldehydes, disulfides, trimethylsilyl chloride, and epoxides to afford the corresponding a-derivatized products. " Early work on racemic complexes revealed that these transformations occur in a highly diastereoselective fashion,... 

Enolates of iron-acyl complexes have been studied extensively, especially by Davies and Liebeskind and their respective coworkers. The chiral complex [T) -CpFe(PPh3)(CO)COCH2R] is usually used it can be prepared in racemic or optically active form. The enolate usually has the anti conformation with regard to CO and Copper (Z)-enolates give predominantly syn aldols, whereas diethylalumin-... 

The final example of asymmetric enolates concerns the iron acyl complexes developed by the Davies group. t O] These complexes give excellent enantioselectivity in a wide variety of asymmetric reactions but unfortunately the auxiliary can only be obtained by a tedious resolution procedure, is very expensive and cannot readily be recycled. 

---