Aldol chelation-controlled

Noyori "Open" Transition State for non-Chelation Control Aldols... 

The Lewis acid mediated addition of silyl enol ethers or silylketcne acetals to oc-alkoxyaldehydcs is the most versatile and reliable method of providing chelation control in aldol-type additions3. The stereochemical outcome is as predicted by Cram s cyclic model11 ... 

The Mukaiyama variation of the aldol reaction also allows 1,3-induced chelation control. Thus, the reaction of the enolsilane or silylketene acetal with (5 )-3-benzyloxybutanal results in both cases in the predominant formation of the cwt/ -adduct (92 8 and 90 10), respectively14. 

The stereochemical outcome of the Mukaiyama reaction can be controlled by the type of Lewis acid used. With bidentate Lewis acids the aldol reaction led to the anti products through a Cram chelate control [366]. Alternatively, the use of a monoden-tate Lewis acid in this reaction led to the syn product through an open Felkin-Anh... 

The key step in the synthesis of A-ring fragment 50 [56] is the chelation-controlled addition of allylstannane 53 to aldehyde 52, which sets the C7 stereocenter and introduces the C8 gem-dimethyl moiety. Aldehyde 52 is itself prepared from 1,3-propanediol using the author s protocol for titanium-catalyzed enantioselective allylstannation [57], which sets the C5 stereocenter, followed by chelation-controlled Mukaiyama aldol addition [58] to establish the C3 stereocenter (Scheme 5.6). 

LA represents Lewis acid in the catalyst, and M represents Bren sled base. In Scheme 8-49, Bronsted base functionality in the hetero-bimetalic chiral catalyst I can deprotonate a ketone to produce the corresponding enolate II, while at the same time the Lewis acid functionality activates an aldehyde to give intermediate III. Intramolecular aldol reaction then proceeds in a chelation-controlled manner to give //-keto metal alkoxide IV. Proton exchange between the metal alkoxide moiety and an aromatic hydroxy proton or an a-proton of a ketone leads to the production of an optically active aldol product and the regeneration of the catalyst I, thus finishing the catalytic cycle. 

Other studies have provided additional data on the relative stabilities of the lithium aldolates 14 and 15 derived from the condensation of dilithium enediolates 13 (Rj = alkyl, aryl) with representative aldehydes (eq. [ 10]) (16). Kinetic aldol ratios were also obtained for comparison in this and related studies (16,17). As summarized in Table 4, the diastereomeric aldol chelates 14a and ISa, derived from the enolate of phenylacetic acid 13 (R = Ph), reach equilibrium after 3 days at 25° C (entries A-D). The percentage of threo diastere-omer 15 increases with the increasing steric bulk of the aldehyde ligand R3 as expected. It is noteworthy that the diastereomeric aldol chelates 14a and 15a (Rj = CH3, C2HS, i-C3H7) do not equilibrate at room temperature over the 3 day period (16). In a related study directed at delineating the stereochemical control elements of the Reformatsky reaction, Kurtev examined the equilibration of both... 

An example of a chelation-controlled titanium tetrachloride-catalyzed aldol condensation has been featured in a recent synthesis of pestalotin (eq. [86]) (100). The condensation illustrated afforded... 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

The design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

The conjugate reduction of a,(3-unsaturated carbonyl compounds is a potentially useful way of accessing Sm(III) enolates that has yet to be widely exploited. Cabrera reported a cyclodimerisation sequence of a,(3-unsaturated ketones using Sml2 that involves a diastereoselective aldol cyclisation.163 For example, treatment of chalcone 158 with Sml2 generates cyclopentanol 160 in quantitative yield after chelation-controlled aldol cyclisation of Sm(III) enolate 159 (Scheme 5.104). 

Procter reported the diastereoselective spirocyclisation of unsaturated ketones 163 using Sml2-43 165 The cyclisation proceeds by conjugate reduction, Sm(III) enolate generation and chelation-controlled aldol cyclisation to give, vyrt-spirocyclic cyclopentanols 164 in good yield (Scheme 5.106). It is important... 

On the other hand, chelation-controlled aldol reactions usually provide the awh -Cram aldol. This has been early illustrated by Heathcock and coworkers76 who reported that the proportion of the exclusive syn condensation products B and C (>98%) of the bulky enolate A (Scheme 116) was completely reversed when a chelating group was present on the aldehyde backbone (although the chelating ability of the f-butyl dimethylsilyloxy group is questionable566). 

The stereoselective chelation-controlled aldol reaction of unsubstituted lithium ester enolates with (7 s)-2-(p-tolylsulfinyl) cyclohexanone A (Figure 16) led to a high enantio-face differentiation (> 90 < 10), while the simple diastereoselection was rather low for prochiral enolates567. The role of the lithium cation acting as a template is here essential, since sodium, potassium, HMPA or even added ZnCl2 resulted in decreased yield and selectivity. 

Acylation, Alkylation, and Aldolization (Acyl Species-+ a-, P-, or a/fi-Functionalized Acyl Product) Alkylation reactions of sodium enolates of various lV-acyl-a-methyltoluene-2,a-sultams with selected (both activated and nonactivated ) alkyl iodides and bromides proceed with good C(a)-re stereocontrol (90-99% de). Analogous acylations with various acid chlorides can also be performed, giving p-keto products (97-99% de). Selective reduction of these latter products with Zinc Borohydride (chelate controlled, 82.6-98.2% de) or N-Selectride (nonchelate controlled, 95.8-99.6% de) can provide syn- and anft-aldol derivatives, respectively. ... 

P-Keto esters and -keto amides, each substituted between the two carbonyl units with a 2-[2-(tri-methylsilyl)methyl] group, also undergo Lewis acid catalyzed, chelation-controlled cyclization. When titanium tetrachloride is used, only the product possessing a cis relationship between the hydroxy and ester (or amide) groups is product yields range from 65 to 88% (Table 8). While loss of stereochemistry in the product and equilibration of diastereomers could have occurred via a Lewis acid promoted retro aldol-aldol sequence, none was observed. Consequently, it is assumed that the reactions occur under kinetic, rather than thermodynamic, control. In contrast to the titanium tetrachloride promoted process, fluoride-induced cyclization produces a 2 1 mixture of diastereomeric products, and the nonchelating Lewis acid BF3-OEt2 leads to a 1 4.8 mixture of diastereomers. 

LiC104 was shown to be a more compatible Lewis acid for chelation in an ethereal solvent—when TiCU, a typical chelation agent for a-alkoxyaldehydes, was used in EtaO for alkylation of 79, moderate diastereoselectivity (68 32) was obtained. Rapid injection NMR studies of the TiCU-promoted chelation-controlled Mukaiyama aldol reaction and the Sakurai reaction show that an acyclic transition state must be involved in which the silyl groups never reach the carbonyl oxygen atom. In LPDE-mediated enolsilane additions silylated products predominate. Obviously, the mechanism is different—it is a group-transfer aldol reaction [107]. 

The relative rate increase with LiC104 (3 mol %) in CH2CI2 was also observed in a case involving the aldolization of A jA -dibenzyl-protected aminoaldehyde, where anti-product predominates, as a result of non-chelation control. When attempted in Et20, the transformation is successful only when 5.0 m LPDE is used. Moreover, a reaction time of 18 h at room temperature sufficed for complete conversion of iso-butyraldehyde, while reacting less rapidly to the desirable product [108]. 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

FIGURE 10.20 Chelate control in aldol reaction of L-quebrachitol pyruvate 231 (Scheme 10.78, Ref. [162]). 

The orientation of the enolate and aldehyde in the transition state of the aldol reaction, open transition state vs. the ordered, chelate-controlled transition state... 

Reetz, M. T., Raguse, B., Marth, C. F., Huegel, H. M., Bach, T., Fox, D. N. A. A rapid injection NMR study of the chelation controlled Mukaiyama aldol addition TiCl4 versus LiCI04 as the Lewis acid. Tetrahedron 1992, 48, 5731-5742. 

The Eu-catalyst Eu(dppm)3 provides a remarkable level of chemoselectivity but is only effective for the Mukaiyama-aldol reaction of aldehydes with several ketene silyl acetals (KSA) (Table 2-3) [55]. When ketones and aldehydes are treated, respectively, with KSA and ketone-derived silyl enol ethers, no reaction results. The rate enhancement by chelation control (entry 4, Table 2-3) is intriguing. This is a feature common to other Lewis acids such as TiC [56] or LiC104 [57],... 

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