Anti aldol product

The absolute configuration of the major aldol product anti-11, obtained from the corresponding (47 ,55)-oxazolidine and propanal, was determined by its conversion to (3A, 4W)-4-methyl-3-heptanol (12)5. 

Aldol reactions using phosphoramides as organocatalysts The organic base-catalyzed asymmetric intermolecular aldol reaction with ketone-derived donors can be successfully applied to the construction of aldol products with two stereogenic centers [82-86]. Trichlorosilyl enolates of type 51 have been used as nucleophiles. Such enolates are strongly activated ketone derivatives and react spontaneously with several aldehydes at —80 °C. A first important result was that in the aldol reaction of 51 catalytic amounts of HMPA led to acceleration of the rate of reaction. After screening several optically active phosphoramides as catalysts in a model reaction the aldol product anti-53 was obtained with a diastereomeric... 

It should be noted that in the absence of the organocatalyst the E enolate affords mainly the syn adduct (syn/anti ratio 49 1, 92% yield, reaction temperature 0 °C [82, 84]) whereas in the presence of (S,S)-52 by dramatic reversal in diastereoselectivity the anti-aldol product anti-53 is preferentially formed (anti/syn ratio 50 1 anti 93% ee) [84], Other types of chiral phosphoramide, e.g. based on optically active 1,2-cyclohexyldiamine, had less satisfactory catalytic properties. 

Bisprolindiamide 13a proved to be a good catalyst for the aldol reaction of cyclohexanone (57) with 4-nitrobenzaldehyde (2a) (Chart 3.6) [86, 33, 34] Carter et al. designed a proline sulfonamide-derivative possessing a long alkyl chain and applied it to the synthesis of 263 g of the aldol product anti-SSa [87]. Disappointingly, only 63% of the catalyst was recovered. To avoid this drawback, fluorous sulfonamide was synthesized and could be easily recovered from the reaction mixture by fluorous solid-phase extraction [88]. 

In general, syn aldol products are achievable with high selectivity, anti aldols are more difficult... 

A consequence of this mechanism is that the reaction is stereospecific with respect to the E- or Z-configuration of the enolate. The E-enolate will give the anti aldol product whereas the Z-enolate will give the syn aldol. 

A syn-selective asymmetiic nih o-aldol reaction has been reported for structurally simple aldehydes using a new catalyst generated from 6,6-bis[(tiiethylsilyl)ethynyl]BINOL (g in Scheme 3.18). The syn selectivity in the nitro-aldol reaction can be explained by steric hindrance in the bicyclic transition state as can be seen in Newman projection. In the favored h ansition state, the catalyst acts as a Lewis acid and as a Lewis base at different sites. In conbast, the nonchelation-controlled transition state affords anti product with lower ee. This stereoselective nitro-aldol reaction has been applied to simple synthesis of t/ireo-dihydrosphingosine by the reduction of the nitro-aldol product with H2 and Pd-C (Eq. 3.79). 

Overall yield using yields of chromatographed, isomericaliy pure aldol products. b Elimination requires forcing conditions ( )-isomer probably formed by isomerization of the kineticaily formed (Z)-isomer. The anti.anti- and anti.svn-aldol products were not separable. 

R Yield of Aldol Product (%) ee (%) anti Ratio (antijsyn) Config. of 1.3-Diols... 

The (Z)-configuration of the enol ether however is a prerequisite for both high. yyn-selecting and high optical purity of the products23. When, on the other hand, (Z)-2-benzyloxy-l-ethyl-thio-l-trimethylsilyloxy-l-propene is allowed to react with 2-propional in the presence of the diamine 2, the anti-aldol product is obtained in 92% ee42. 

The E-boron enolate from cyclohexanone shows a preference for the anti aldol product. The ratio depends on the boron alkyl groups and is modest (2 1) with di-n-butylboron but greater than 20 1 for cyclopentyl- -hexylboron.16... 

A very short and efficient synthesis based on the desymmetrization principle is shown in Scheme 13.39. mc.vo-2,4-Dimethylglularaldchyde reacted selectively with the diethylboron enolate derived from a bornanesultam chiral auxiliary. This reaction established the stereochemistry at the C(2) and C(3) centers. The dominant aldol product results from an anti-Felkin stereoselectivity with respect to the C(4) center. 

In 2000, Morken et al. reported the first examples of catalytic asymmetric reductive aldol reactions [21]. Using Rh(BINAP) (5mol%) as catalyst and Et2MeSiH as reductant, the syn-selective (1.7 1) coupling of benzalde-hyde and methyl acrylate produced the diastereomers 35-syn and 35-anti in 91% ee and 88% ee, respectively. Using phenyl acrylate as the nucleophilic partner, a favorable yield of 72% was obtained for the aldol product 36 (Scheme 12). Several aldehydes were examined, which exhibit higher levels of syn-selectivity. Expanding the scope of substrates and acrylates under... 

Z)-enolates. The product was subjected to selective deprotection of the C4,C4 -methyl ethers with Mgl2, providing the natural structure of hypocrellin A as the major product. The two newly formed stereocenters in the 7-membered ring were determined to conform to the predicted helical (/ -stereochemistry and the syn-aldol stereochemistry. The minor ( )-enolate afforded the anti aldol product, which matched the diastereomeric natural product shiraiachrome A (8). With this step, the first total syntheses of hypocrellin A and shiraiachrome A (symanti = 10 1 syn diastereomer, 92 % ee) were completed. 

Accordingly, Liu et al.4 have designed two types of aldol reagents that can lead to opposite stereochemistry in aldol condensation reactions. In the following structures, compound 4 can be used for obtaining anti- Ao products, and compound 5 can be employed for synthesizing syn-aldol products (Scheme 3-3). 

In summary, boryl enolate 38 can be obtained via in situ O-borylation of N-propionylsultam 37 and converted to aldol product 40 upon treatment with aliphatic, aromatic, or a,/l-unsaturatcd aldehdyes at - 78°C in the presence of TiCU- As aldol product 40 can normally be obtained in crystalline form, in most cases diastereomerically pure anti- Ao 40 can also be obtained after the recrystallization. 

Treating boron reagent 45a with an oxazoline compound gives the azaeno-late 52. Subsequent aldol reaction of 52 with aldehyde yields mainly threo-product (anti-53) with good selectivities (Scheme 3-18).38... 

Besides the silyl enolate-mediated aldol reactions, organotin(IY) enolates are also versatile nucleophiles toward various aldehydes in the absence or presence of Lewis acid.60 However, this reaction requires a stoichiometric amount of the toxic trialkyl tin compound, which may limit its application. Yanagisawa et al.61 found that in the presence of one equivalent of methanol, the aldol reaction of an aldehyde with a cyclohexenol trichloroacetate proceeds readily at 20°C, providing the aldol product with more than 70% yield. They thus carried out the asymmetric version of this reaction using a BINAP silver(I) complex as chiral catalyst (Scheme 3-34). As shown in Table 3-8, the Sn(IY)-mediated aldol reaction results in a good diastereoselectivity (,anti/syn ratio) and also high enantioselectivity for the major component. 

The same natural product was synthesized by Paterson et al. [45] who assembled the carbon skeleton of the macrolide from three larger subunits as well. Instead of the Evans-Metternich variant they used their boron-mediated antz-selective aldol strategy which relies as the Evans-Metternich aldol on stereo-induction from the a-chiral center and translates the E-enolate geometry, established due to the use of Cy2BCl, to the anti aldol product (Scheme 33). 

Ketone donors bearing a-heteroatoms are particularly useful donors for the enamine-catalyzed aldol reactions (Scheme 18). Both anti and syn aldol products can be accessed in remarkably high enantioselectivities using either proline or proline-derived amide, sulfonamide, or peptide catalysts. The syn selective variant of this reaction was discovered by Barbas [179]. Very recently, Luo and Cheng have also described a syn selective variant with dihydroxyacetone donors [201], and the Barbas group has developed improved threonine-derived catalysts 71 (Scheme 18) for syn selective reactions with both protected and unprotected dihydroxyacetone [202]. 

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