Enantioselective synthesis aldol reaction

The enantioselective nitro-aldol reaction catalyzed by (R)-LLB is effectively applied to the synthesis of three kinds of optically active (3-receptor blocking drugs (5)-metoprolol,123a (S)-propanolol,123b and ( -pindolol1230 (Scheme 3.17). 

Ebelactone A and B. The ebelactones are a small group of / -Iactone enzyme inhibitors isolated from a cultured strain of soil actinomycetes. Our synthesis of ebelactone A (274) and B (275) employed three different types of aldol reactions including the enantioselective syn aldol reaction of diethylketone and ethacrolein which afforded aldol adduct 276 with 86% ee (Scheme 9-74) [90]. Following... 

Although asymmetric organocatalysis is now considered as a powerful tool for the synthesis of chiral compounds this research held experimented its own revolution. It was restricted after the seventies only to the nse of simple a-amino acids as catalyst for the Robinson annulations and above all with the application of proline to the enantioselective intermolecular aldol reaction. 

Aldol reaction using monoclonal aldolase antibodies, generated against a ketosulfone hapten by reactive immunization, was used to catalyze rapid and highly enantioselective retro-aldol reaction of a thiazole aldol, providing optically pure aldol by kinetic resolution. The product was used for the synthesis of epothilone E (Fig. 10.39(b) and (c)). ... 

Scheme 1.31 Regioselective synthesis of N- or O-adduct in enantioselective Nitroso aldol reactions.

Willis et al reported an enantioselective direct aldol reaction for the synthesis of protected aryl P-hydroxy-a-amino acids catalyzed by chiral Mg (I I) complexes (Scheme 4.12) [12]. A catalyst system composed of 10 mol% of Mg(Cl04)2,11 mol% of (S,S)-Ph-Pybox (35), and diisopropylethylamine generated an enolate of a chiral glycine equivalent derived from isothiocyanate-substituted oxazolidinone (33). The... 

This system could be evolved into the catalytic enantioselective vinylogous aldol reactions [10, 11]. For example, the reaction of crotonate-derived dienol ether with benzaldehyde proceeded smoothly in the presence of 2 to give the y-addition product exclusively with rigorous enantiocontrol (Scheme 7.8). This protocol tolerated the use of aliphatic aldehydes such as 3-phenylpropanal as an electrophile and has found fruitful applications in the total synthesis of natural products [12]. 

SCHEME 20.21. The organocatalytic enantioselective transannular aldol reaction in the synthesis... 

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

Krische and coworkers [44] developed a Rh-catalyzed asymmetric domino Michael/aldol reaction for the synthesis of substituted cyclopentanols and cyclohex-anols. In this process, three contiguous stereogenic centers, including a quaternary center, are formed with excellent diastereo- and enantioselectivity. Thus, using an enantiopure Rh-BINAP catalyst system and phenyl boronic acid, substrates 2-108 are converted into the correspondding cyclized products 2-109 in 69-88% yield and with 94 and 95% ee, respectively (Scheme 2.24). 

The synthesis of the BC-ring fragment 26 begins with the enantioselective aldol reaction of aldehyde 22 and chiral boron enolate 23 derived from (—)-DIP-Cl as described by Paterson and Brown [42]. The aldol adduct 24 is converted to the... 

As the t-butyl group can readily be removed upon acidic or basic hydrolysis, this method can also be used for //-hydroxyl acid synthesis. In analogy with allylation reactions, the enolate added preferentially to the Re-face of the aldehydes in aldol reactions. Titanium enolate 66 tolerates elevated temperatures, while the enantioselectivity of the reaction is almost temperature independent. The reaction can be carried out even at room temperature without significant loss of stereoselectivity. We can thus conclude that this reaction has the following notable advantages High enantiomeric excess can be obtained (ee > 90%) the reaction can be carried out at relatively high temperature the chiral auxiliary is readily available and the chiral auxiliary can easily be recovered.44... 

This method has been applied in the enantioselective synthesis of d-erythro-sphingosine and phytosphingosine. Sphingosine became an important substance for studying signal transduction since the discovery of protein kinase C inhibition by this compound.48 Many efforts have been made to synthesize sphingosine and its derivatives.49 Kobayashi et al. reported another route to this type of compound in which a Lewis acid-catalyzed asymmetric aldol reaction was a key step. 

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... 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

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