Asymmetric reactions anti aldols

Chiral Auxiliaries in Aldol Reaction Asymmetric aldol reactions ntilizing chiral auxiliaries have emerged as one of the most reliable methods in organic synthesis. Both syn-and anti-selective aldol reactions have been developed over the years. The field of asymmetric i yn-aldol reactions has been largely advanced by Evans since his development of dibntylboron enolate aldol chemistry based on amino acid-derived chiral oxazolidinones (Scheme 2.109) [9]. 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

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... 

A yyw-selective asymmetric nitro-aldol reaction has been reported for structurally simple aldehydes using a new catalyst generated from 6,6-bis[(triethylsilyl)ethynyl]BINOL (g in Scheme 3.18).126 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 transition state, the catalyst acts as a Lewis acid and as a Lewis base at different sites. In contrast, the nonchelation-controlled transition state affords anti product with lower ee. This stereoselective nitro-aldol reaction has been applied to simple synthesis of t/ircodihydrosphingosine by the reduction of the nitro-aldol product with H2 and Pd-C (Eq. 3.79). 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

In the synthesis of D-eryt/zro-sphingosine (78 without BOC protection), the key step is the asymmetric aldol reaction of trimethylsilylpropynal 75 with ke-tene silyl acetal 76 derived from a-benzyloxy acetate. The reaction was carried out with 20 mol% of tin(II) triflate chiral diamine and tin(II) oxide. Slow addition of substrates to the catalyst in propionitrile furnishes the desired aldol adduct 77 with high diastereo- and enantioselectivity (syn/anti = 97 3, 91% ee for syn). In the synthesis of protected phytosphingosine (80, OH and NH2 protected as OAc and NHAc, respectively), the asymmetric aldol reaction is again employed as the key step. As depicted in Scheme 3-27, the reaction between acrolein and ketene silyl aectal 76 proceeds smoothly, affording the desired product 80 with 96% diastereoselectivity [syn/anti = 98 2) and 96% ee for syn (Scheme 3-27).50... 

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. 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

By the use of chiral oxazolidines derived from a chiral norephedrine and methyl ketones, an asymmetric aldol reaction proceeds in a highly enantioselective manner. In the case of ethyl or a-methoxy ketones, the corresponding anti aldol products were obtained with high diastereo- and enantioselectivities. A chiral titanium reagent, generated from... 

See the procedure describing the anti-selective asymmetric aldol reaction of carboxylic esters, p. 116. 

ANTI-SELECTIVE BORON-MEDIATED ASYMMETRIC ALDOL REACTION OF CARBOXYLIC ESTERS SYNTHESIS OF (2S, 3R)-2,4-DIMETHYL-1,3-PENTANEDIOL... 

Several methods for the anti-selective, asymmetric aldol reaction recorded in the literature include (i) the use of boron, titanium, or tin(ll) enolate carrying chiral ligands, (ii) Lewis acid-catalyzed aldol reactions of a metal enolate of chiral carbonyl compounds, and (iii) the use of the metal enolate derived from a chiral carbonyl compound. Although many of these methods provide anti-aldols with high enantioselectivities, these methods are not as convenient or widely applicable as the method reported here, because of problems associated with the availability of reagents, the generality of reactions, or the required reaction conditions. 

Dialkylboron trifluoromethanesulfonates (triflates) are particularly useful reagents for the preparation of boron enolates from carbonyl compounds, including ketones, thioesters and acyloxazolidinones.4 Recently, the combination of dicylohexylboron trifluoromethanesulfonate and triethylamine was found to effect the enolization of carboxylic esters.5 The boron-mediated asymmetric aldol reaction of carboxylic esters is particularly useful for the construction of anti (3-hydroxy-a-methyl carbonyl units.6 The present procedure is a slight modification of that reported by Brown, et al.2... 

ANTI-SELECTIVE BORON-MEDIATED ASYMMETRIC ALDOL REACTION OF 116... 

Anti-selective Boron-mediated Asymmetric Aldol Reaction of Carboxylic Esters. 

Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with yS-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92 8 anti. syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508. 

The group of Arai and Nishida investigated the catalytic asymmetric aldol reaction between tert-butyl diazoacetate and various aldehydes under phase-transfer conditions with chiral quaternary ammonium chloride 4c as a catalyst. The reactions were found to proceed smoothly in toluene, even at —40°C, when using 50% RbOH aqueous solution as a base, giving rise to the desired aldol adducts 23 with good enantioselectivities. The resulting 23 can be stereoselectively transformed into the corresponding syn- or anti-P-hydroxy-a-amino acid derivatives (Scheme 2.20) [42],... 

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... 

The myxalamides and the phenalamides have attracted some synthetic attention. A partial synthesis of myxalamide D (4) was reported by Cox and Whiting in which an anti aldol reaction was used to set the C-12/C-13 stereochemistry.4 In addition, a total synthesis of 2 was described by Andrus In this approach, an asymmetric alkylation set the distal stereocenter (C-16), while an asymmetric crotylboration created the anti stereorelationship at C-12/C-13. In contrast to the other synthetic efforts, the approach to 1 described in this chapter would enable a single asymmetric reaction early in the synthesis to produce the anti C-12/C-13 relationship as well as set the distal C-16 stereocenter.5... 

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