Aldehyde stereoselective reactions

The condensation of aldehydes or ketones with secondary amines leads to "encunines via N-hemiacetals and immonium hydroxides, when the water is removed. In these conjugated systems electron density and nudeophilicity are largely transferred from the nitrogen to the a-carbon atom, and thus enamines are useful electroneutral d -reagents (G.A. Cook, 1969 S.F. Dyke, 1973). A bulky heterocyclic substituent supports regio- and stereoselective reactions. 

In contrast to the 2-butenylboranes, 2-butcnylboronates have found widespread application in acyclic diastereoselective synthesis owing to their ease of preparation (Section 1.3.3.3.3.1.1.), configurational stability and highly stereoselective reactions with aldehydes3 4. The results of reactions of substituted allylboronates and representative achiral aldehydes are summarized in Table 1. 

Finally, 2-allyl-4,5-tra ,s-diphenyl-l,3-bis(4-methylphenylsulfonyl)-l,3,2-diazaborolidincs have been used74. The 2-propenyl derivative undergoes highly stereoselective reactions with achiral aldehydes (95 - 97% ee) the ( )-2-butenyl derivatives (91-95% ee) and the analogous 2-chloro- and 2-bromo-2-propenyl derivatives (84-99% ee) also give excellent results in reactions with achiral aldehydes. 

Butenyl(trimethyl)silane reacts with aldehydes in the presence of titanium(IV) chloride to give sj/77-products with excellent stereoselectivity. Reactions of the (Z)-2-butenylsilane are less stereoselective although jyn-products are still preferred23. 

The Horner-Wittig reaction of a-phosphoryl sulphoxides 442, which are chemically stable, results in the formation of a, -unsaturated sulphoxides 443 in high yields (equation 264). The reaction has been found to be non-stereoselective, mixtures of E and Z isomers being formed from aldehydes and unsymmetrical ketones . In the case of aromatic aldehydes this reaction can also be advantageously performed in a two-phase catalytic system even without the usual PTC catalysts (Table 24). Intramolecular Horner-Wittig reaction of a-phosphoryl-5-oxosulphoxides 444 leads to a, -unsaturated cyclic sulphoxides 445 (equation 265). Starting from optically active 0,0-... 

Mg11 is often employed in stereoselective reactions. In hetero Diels-Alder reactions of aldehydes with Danishefsky s diene, Mg11 results in good acceleration and stereoselection, and 2,3-coproducts are obtained exclusively (Scheme 6).26 Milder Lewis acidity is necessary for obtaining higher yield and higher stereoselectivity in this reaction, which occurs through a cyclic transition state. 

Scheme 13.32. Preparation of 2-trimethylsilyloxy-r 3-crotyltitanocene and stereoselective reactions with aldehydes.

Stereoselective reaction with aldehydes. Both (E)- and (Z)-l react with aldehydes to give syn-adducts as the major products (12,146). In an effort to improve the diastereoselectivity, (E)- and (Z)-l have been converted into pentacoordinated allylsilicates (2) by reaction with dilithium catecholate. Reaction of an aryl aldehyde with both (E)- and (Z)-2 shows essentially complete diastereoselectivity. 

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. 

The real promise of this catalytic reaction is the eventual development of an efficient enantioselective allylboration catalyzed by chiral Lewis acids. A stereoselective reaction using a substoichiometric amount of a chiral director has been reported, but only modest levels of stereo-induction were achieved with an aluminum-BINOL catalyst system (Eq. 19)P Recently, a chiral Brpnsted acid catalyzed system has been devised based on a diol-tin(IV) complex (Eq. 80). In this approach, aliphatic aldehydes provide enantioselectivities (up to 80% ee) higher than those of aromatic aldehydes when using the optimal complex 114. Although the levels of absolute stereoselectivity of this method remain too low for practical uses, promising applications are possible in double diastereoselection (see section on Double Diastereoselection ). 

Notably, as illustrated in Scheme 124, enantiofaces of aldehydes can be differentiated by a chiral rhenium template to result in stereoselective reaction with cyanide ion (297). The rhenium Lewis acid element forms stereoisomeric it complexes with aldehydes, which are convertible via... 

Stereoselective Reaction of Peptide Aldehydes with Trifluoroiodomethane/Zmc... 

Stereoselective reactions with aldehydes. The related (E)-2-pentenyltin reagent 2 also reacts with aldehydes to form predominantly erythro adducts such as 3. This reaction was used for a stereoselective synthesis of an aggregation pheromone (4) of the European elm bark beetle.1... 

As an extension of this highly enantioselective Michael addition of silyl nitronates with a, p-unsaturated aldehydes, the reactions with cyclic a,p-unsaturated ketones as a Michael acceptor were also tested (Scheme 9.15). Cyclohexenone and cyclohepte-none were employed as a useful Michael acceptor with various silyl nitronates in the presence of catalyst (R,R)-6c, and gave the corresponding enol silyl ethers 28 with excellent stereoselectivities [30]. 

T. Ohmizu, H. A novel synthesis of a key intermediate for penems and carbapenems utilizing lipase-catalyzed kinetic resolution. Tetrahedron Asymmetry 1996, 7,1241-1244. Shinozuka, T. Kikori, Y. Asaoka, M. Takei, H. Stereoselective reaction of arylsulfanyl-stabi-lized homoenolates with aldehydes. J. Chem. Soc. Perkin Trans. 11996, 119-120. 

Chiral acetals of ArCHO.1 The chiral acetal (1) of Cr(CO)3-complexed benz-aldehyde undergoes a highly stereoselective reaction with (CH3)3A1 and TiCl4 (1 equiv.) to provide (R,R,R)-2 in 72% yield and 97.5% de. A subsequent Ritter... 

The /3-lactone was formed by the cyclization of a 3-hydroxycarboxylic acid with sulfonyl chloride. An alternative synthesis attempted to control all stereochemical relationships in the molecule using the properties of silyl moieties attached to substrates and reagents <20040BC1051>. Stereoselective reactions of this type included the use of silyl groups in enolate alkylations, hydroboration of allylsilanes, and an anti Se2 reaction of an allenyl silane with an aldehyde and ry -silylcupration of an acetylene. The /3-lactone was again formed by the standard sulfonyl chloride cyclization method. 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

The stereochemical course of several Co2(CO)6-mediated reactions has been studied. For example, although alkynyl aldehydes undergo crossed aldol condensation with trimethylsilyl enol ethers with little stereoselectivity, their hexacarbonyldicobalt derivatives react with moderate to excellent syn diastereoselectivity.96 101 The mechanism behind this selectivity has not been fully elucidated and is complicated by the lluxional nature of the intermediate cations. This stereoselective reaction has been successfully applied to the synthesis of /3-lactam antibiotics.100... 

In Ugi s four-component condensation, imine formation from an aldehyde 1 and an amine 2 is likewise the initiating step [5, 6] a carboxylic acid 9 and an isonitrile 10 are the other reaction components, which finally yield the bisamide 11. Both for this reaction and the Strecker synthesis, the galactosylamine 12 is particularly suitable for carrying out a stereoselective reaction (synthesis of 13) [4d-e, 5f. With an aminoglucopyranose as a chiral auxiliary, the stereoselectivity of the reaction can be further increased [5b]. Amino acids as condensation components yield particularly impressive results. For instance, the imino-... 

Chiral Auxiliary. Chiral 1,2-diamines have often been used as chiral auxiliaries in various carbon-carbon bond-forming reactions. The reaction of a diamine with an aldehyde gives a chiral aminal which can undergo stereoselective reactions. This was applied in the synthesis of enantiomerically pure a-hydrazino aldehydes by stereoselective addition of carbon nucleophiles onto the aminal of glyoxal monohydrazone (eqs 2 and 3). In this reaction, the use of 1,2-diaminocyclohexane gave lower diastereomeric excesses than with the related 1,2-diphenyl ethylenediamine. 

Chiral Ligand for other Stereoselective Reactions. The effect of the addition of dihydroquinidine-derived alkaloids on the product enantioselectivity has also been investigated in the addition reaction of Diethylzinc to aldehydes, in the addition of aromatic thiols to conjugated cycloalkenones, and in the heterogeneous hydrohalogenation of a,a-dichlorobenzazepinone-2. In these cases, the dihydroquinidine derivatives were not the optimal ligands. 

Catalytic reactions have the advantage over the methods discussed so far in that the chiral catalyst need not be added in stoichiometric amounts, but only in very small quantities, which is important if not only the metal (very often a precious one) but also the chiral ligand are expensive. Among the ferrocenes, phosphines are by far the most important catalysts for stereoselective reactions, and are covered in Chapter 2 of this book. We will therefore focus here mainly on the catalytic applications of chiral ferrocenes not containing phosphine groups. Only recently, some progress has been made with such compounds, mainly with sulfides and selenides, and with amino alcohols in the side chain (for this topic, see Chapter 3 on the addition of dialkyl zinc to aldehydes). 

Arenetellurolates, ethenetellurolates, and alkanetellurolates prepared by reduction of diorgano ditellurium compounds with sodium borohydride in ethanol, THF/ethanol, or DMSO add to acetylenes in regioselective and tran.v-stereoselective reactions to produce aryl ethenyl tellurium products either predominantly or exclusively as fZ)-isomers. The yields are almost always higher than 70%. In reactions with acetylenic aldehydes, ketones, carboxylic acids, and esters the arenetellurolate becomes bonded to the carbon atom in a fi-position to the carbonyl group. 

D-Glucose ([52], Fig. 9) has served as an intriguing educt for preparation (31) of the Corey lactone equivalent [59] (32). The iodo compound [53] was readily available from glucose in four steps. Reductive fragmentation, induced by zinc in ethanol, gave the unsaturated aldehyde [54]. Reaction with N-methylhydroxylamine was followed by a spontaneous nitrone cycloaddition to provide the oxazolidine [55]. Catalytic reduction of the N-O bond was accompanied by the unexpected loss of tosylate and aziridine formation. Olefin formation from [56] via the N-oxide and chain extension gave acid [57]. lodolactonization and tri-n-butyltin hydride reduction in the standard fashion led to lactone [58]. After saponification of the benzoates, stereoselective epoxide formation gave epoxy lactone [59]. 

---