Anti aldol adduct

This stereoselectivity can be improved by use of a very bulky group. 2,6-Dimethylphenyl esters give F-enolates and anti aldol adducts.38... 

On the other hand, the condensation of Gamer s aldehyde574 with the non-chiral lithium enolate of diethylacetamide in non-chelating conditions occurs preferentially on the 57-face with a moderate 37% d.e. The same reaction using the enolate of (R.R)- or (5,5)-pseudoephedrine acetamides resulted in identical anti aldol adducts, but with an amplification of the face recognition of the aldehyde for the matched (R, W )-pscudoephedrine (d.e. = 96%). On the other hand, the mismatched (5,5)-pseudoephedrine gave only 12% d.e. (Scheme 120)575. 

Asymmetric Aldol Reactions. Reaction of (1) with Boron Tribromide in CH2CI2 affords, after removal of solvent and HBr, a complex (5) useful for the preparation of chiral enolates (eq 5). Complex (5) is moisture sensitive and is generally prepared immediately before use. For propionate derivatives, either syn or, less selectively, anti aldol adducts may be obtained by selection of the appropriate ester derivative and conditions. Thus reaction of f-butyl propionate with (5) and triethylamine produces the corresponding E 0) enolate, leading to formation of anti aldol adducts upon addition to an aldehyde (eq 6). Selectivities may be enhanced by substitution of the t-butyl ester with the (+)-menthyl ester. Conversely, reaction of 5-phenyl thiopropionate with (5) and Diisopropylethylamine affords the corresponding Z(0) enolates and syn aldol products (eq 7). ... 

As previously mentioned, certain methyl ketone aldol reactions enable the stereocontrolled introduction of hydroxyl groups in a, 5-anti relationship (Scheme 9-7) [9], and this was now utilized twice in the synthesis. Hence, methyl ketones 48 and 98 were converted to their respective Ipc boron enolates and reacted with aldehydes 97 and 99 to give almost exclusively the, 5-anti aldol adducts 100 and 101, respectively (Scheme 9-34). In the case of methyl ketone 48, the j -silyl ether leads to reduced stereoinduction however, this could be boosted to >97%ds with the use of chiral ligands. In both examples, the y9-stereocenter of the aldehyde had a moderate reinforcing effect (1,3-syn), thus leading to triply matched aldol reactions. Adducts 100 and 101 were then elaborated to the spiro-acetal containing aldehyde 102 and ketone 103, respectively. 

In our synthesis, iterative aldol reactions of dipropionate reagent (R)-18 allowed for the control of the C3-C10 stereocenters (Scheme 9-72) [89]. Hence, a tin-mediated, syn aldol reaction followed by an anti reduction of the aldol product afforded 270. Diol protection, benzyl ether deprotection and subsequent oxidation gave aldehyde 271 which reacted with the ( )-boron enolate of ketone (/ )-18 to afford anti aldol adduct 272. While the ketone provides the major bias for this reaction, it is an example of a matched reaction based on Felkin induction from the... 

The completion of the synthesis of ebelactone A required an anti aldol reaction of a suitable three-carbon unit to proceed with and-Felkin selectivity, i.e. a mismatched reaction. Conversion of thioester 280 into its ( )-enol borinate and reaction with aldehyde 279 gave two anti aldol adducts, unfortunately with little stereochemical preference. The minor isomer 281 from this reaction was used in the successful synthesis of ebelactone A (274), and the same chemistry, now using thioester 282, was employed to complete the first synthesis of ebelactone B (275). 

We have used this methodology in a recent synthesis of the anti-obesity drug tetrahydrolipstatin (283) (Scheme 9-76) [91J. Hence, the ( )-boron enolate of ketone 284 was reacted with aldehyde 285 to afford the desired anti aldol adduct... 

Evans has recently reported the use of structurally well-defined Sn(II) Lewis acids 119 and 120 (Fig. 9)for the enantioselective aldol addition reactions of a-heterosubstituted substrates [83]. These complexes are easily assembled from Sn(OTf)2 and C2-symmetric bisoxazoline Hgands 124 and 126 (Fig. 10). The facile synthesis of these ligands commences with optically active 1,2-amino alcohols 122, which are themselves readily available from the corresponding a-amino acids 121 [84, 85]. The Sn(II) bis(oxazoHne) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, using 10 mol % of 119, thioacetate and thiopropionate derived silyl ketene acetals add at -78 °C in CH2CI2 to glyoxaldehyde to give hydroxy diesters 130 in superb yields and enantioselectivities as well as diastereo-selectivities (Eq. 12). The process represents an unusual example wherein 2,3-anti-aldol adducts are obtained in a stereoselective manner. 

In all cases the anti aldol adducts constituted <1% of the total reaction mixture. 

The aldol reaction and related processes have been of considerable importance in organic synthesis. The control of syn/anti diastereoselectivity, enantioselectivity and chemoselectivity has now reached impressive levels. The use of catalysts is a relatively recent addition to the story of the aldol reaction. One of the most common approaches to the development of a catalytic asymmetric aldol reaction is based on the use of enantiomerically pure Lewis acids in the reaction of silyl enol ethers with aldehydes and ketones (the Mukaiyama reaction) and variants of this process have been developed for the synthesis of both syn and anti aldol adducts. A typical catalytic cycle is represented in Figure 7.1, where aldehyde (7.01) coordinates to the catalytic Lewis acid, which encourages addition of the silyl enol ether (7.02). Release of the Lewis acid affords the aldol product, often as the silyl ether (7.03). 

The tin(II) enolate prepared from (1), tin(II) trifluoromethane-sulfonate, and 1-ethylpiperidine reacts with aldehydes in the presence of A(, fY,fV -tetramethylethylenediamine (TMEDA) to afford the anti aldol adducts in good yields with good selectivities (eq 1). Interestingly, syn selective reactions proceed in the absence of TMEDA. Optically active antf aldol adducts can be obtained in the presence of chiral diamine (2) instead of TMEDA. 

With the Zr-BINOL catalyst, the anti-aldol adduct was obtained independently on the geometry of the employed silyl enolates E- and Z-(19) (Equation 5) [8]. These features, the detailed NMR analyses and theoretical calculations suggest the acyclic transition state in the reaction (Figure 15.1). 

Control of stereoselectivity and double diastereodifferentiation was further investigated using resin-bound p-enolate 4 and both enantiomers of chiral aldehyde 8. After a sequence of aldol reaction as described previously, alcohol protection, and DDQ-mediated spiroketalization, reactions with aldehyde 8a(25) provided pure single diastereoisomer of the spiroketal 9. However, the reaction of 4 with aldehyde 8b(2l ) yielded 10 as the major diastereomer along with minor inseparable isomers (Scheme 7.2). Thus, although in both aldol reactions of the chiral enolate 4 with the enantiomeric aldehydes 8a and 8b the anti-aldol adduct is formed as the major product, the combination of 4 and 8a represents the matched case and the combination of 4 and 8b the mismatched case. 

Addition of aldehydes to the lithium enolate derived from propanoyl complex 6 requires prior transmetallation for optimum results. In particular, the use of diethylaluminium chloride has proved to be most valuable when the anti-aldol adduct 14 is required, whilst copper cyanide is the transmetallation reagent of choice when the syn-aldol adduct 15 is the target (Scheme 4.8). Oxidative cleavage and formation of the threo and erythro -hydroxy acids, respectively, is easily achieved by treatment with aqueous bromine solution or CAN. The aluminium(III)-mediated sequence has been employed in the synthesis of an enantiomerically pure degradation product of a marine cyclic peroxide, thereby proving its absolute configuration. ... 

Aldol Reactions. The title reagent and its various congeners continue to find application in Mukaiyama-t3fpe aldol reactions as versatile nucleophilic propionate synthons with predictable behavior.For example, the ( )-isomer of the reagent produced the expected major isomer in a boron trifiuoride etherate mediated addition to a complex aldehyde en route to a C19-C35 subunit of swinholide A (eq 14). Remote stereoinduction in Mukaiyama aldol reactions of the reagent with (2-sulfinylphenyl)acetaldehydes was recently observed anti aldol adducts were obtained preferentially regardless of the geometry of the silyl ketene thioacetal employed. ... 

Duthaler and cosvorkers also reported asymmetric syn aldol methodology based on their titanium complex 146 [52]. Heathcock demonstrated the capacity of 2,6-dimethylphenyl propionate-derived lithium enolates to undergo addition to a range of aldehydes affording racemic anti aldol adduct 151... 

To obtain either syn or anti aldol adducts selectively it is important to generate boron enolates with the appropriate geometry (E or Z), that is, (Z) enolates 11 react with a variety of aldehydes to yield predominantly syn aldols 13, whereas (E) enolates 14 react somewhat less stereoselectively to give anti aldol adducts 16 as the major products (Figure 3.1 and Table 3.1). 

As an application of the stereoselective synthesis of anti-aldol adducts, the asymmetric total synthesis of octalactins, peculiar eight-membered polyketides, was accomplished starting from these chiral templates generated by enantioselective aldol reaction using Sn(II) catalysts (Scheme 10.44) [68]. Details of the asymmetric... 

Trimethylsilyl ketene acetals 92 react in a similar way (note that a bulky trialkylsilyl group works well) ketene acetals derived from t-Bu esters proved to exhibit slightly higher enantioselectivities than their Me, Et, or Ph counterparts (Scheme 15.18 and Table 15.5) [83]. Owing to the higher reactivity of ketene acetals, the catalyst loading could be reduced to 1-5 mol%. However, in contrast to the trichlo-rosilyl enolates, this reaction is believed to proceed via an open transition state, since both (E) and (Z) isomers 92b,c produce anti-aldol adducts 93 with high diastereo- and enantioselectivity (Scheme 15.18 and Table 15.6) [83]. 

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