Enantio aldol reaction

Scheme 2.62. Synthesis of an enantio-enriched indene by a twofold nitro-aldol reaction.

The gold(I) complex of a chiral ferrocenylphosphine complex promotes asymmetric aldol reactions of a-isocyanocarboxylates to form chiral oxazolines in high diastereo- and enantio-selectivities (Scheme 52).225,226 In these reactions, the analogous silver(I) ferrocenylphosphine complex also works well. 

The first iridium-catalyzed reductive aldol reaction was reported in 2001.422 Methyl acrylate reacts with certain aldehydes and diethylmethylsilane with high enantio- and diastereoselectivies (Equation (69)). 

Regio-, Enantio-, and Diastereo-selective Aldol Reactions. 10... 

Marhwald reported that ligand exchange of Ti(rac-BINOLate)(Of-Bu)2 with optically active a-hydroxy acids presents an unexpected and novel approach to enantio-selective direct aldol reactions of aldehydes and ketones (Scheme 12.19). The aldol products have been isolated with a high degree of syn diastereoselectivity. High enantioselectivities have been observed when using simple optically pure a-hydroxy acids. 

Unlike most enantio- and diastereoselective direct aldol processes, the enamine-catalyzed aldol reactions are also feasible with aldehyde donors. In a milestone paper, Northrup and MacMillan reported in 2002 that aldehyde-aldehyde aldol... 

Scheme 6.71 Succinimide-containing substituted thiochromanes obtained from the 12-catalyzed enantio- and diastereoselective domino Michael-aldol reaction between 2-mercaptobenzaldehydes and maleimides.

In 2007, Wang and co-workers published a protocol for an enantio- and diastereoselective domino Michael-aldol reaction using electron-rich and electron-deficient 2-mercaptobenzaldehydes and maleimides as substrates [223]. The conversion was described to proceed smoothly in the presence of bifunctional catalyst 12 (lmol% loading) in xylenes at 0°C reaction temperature producing the desired chiral succinimide-containing substituted thiochromanes 1-5 in high yields (83-96%), in synthetically useful ee values (74—94%), and diastereoselectivities (up to dr 20 1) in 7h reaction time (Scheme 6.71). 

Enantioselective aldol reactions also can be used to create arrays of stereogenic centers. Two elegant ot-amino anion approaches have recently been published. Fujie Tanaka and Carlos F. Barbas III of the Scripps Institute, La Jolla, have shown (Org. Lett. 2004,6,3541) that L-proline catalyzes the addition of the aldehyde 6 to other aldehydes with high enantio- and diastereocontroJ. Keiji Maruoka of Kyoto University has developed (J. Am. Chem. Soc. 2004,126,9685) a chiral phase transfer catalyst that mediates the addition of the ester 9 to aldehydes, again with high enantio- and diastcrcocontrol. 

Boron aldol reactions have been used to stereoselectively construct the anti-3-hydroxy-2-methylcarbonyl system from carboxylate esters,58 and to combine a-hetero-substituted thioacetates with aldehydes or silyl imines enantio- and/or diastereo-selectively.59... 

Optically active 4-alkoxycarbonyl-3-hydroxycyclohexanones (formed in highly enantio- and diastereoselective organocatalytic asymmetric domino Michael aldol reaction of / -keto esters and a,/ -unsaturated ketones) are transformed into corresponding chiral oxepanones under the action of urea-hydrogen peroxide and trifluoroacetic anhydride <2004AGE1272>. 

A catalytic enantio- and diastereo-selective aldol reaction of ketones with ketene (g) silyl acetals, H2C=C(OTMS)-OMe, gives fair to good yields and ee.129 With further substitution of the vinyl function, the reaction is diastereoselective, up to 97%. A highly developed catalyst/promoter protocol is employed a copper fluoride complex is combined with a Taniaphos auxiliary (a chiral ferrocenyldiphosphine), plus (EtO)3SiF. Evidence for the formation of species (EtO)4 SiF (n > 2) as active... 

F. F. Huerta and J. E. Backvall, Enantio-selective synthesis of beta-hydroxy acid derivatives via a one-pot aldol reaction -dynamic kinetic resolution, Org. Lett. 2001, 3(8), 1209-1212. 

It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

The asymmetric aldol reaction can also be performed as an enantio- and diastereo-selective reaction forming molecules of type 50 with two stereogenic centers. The principle of this reaction is shown in Scheme 6.25. 

The basic principles of the mechanism of this Lewis-base-catalyzed aldol reaction have already been described in Section 6.2.1.1. With regard to the course of the enantio- and diastereoselective formation of aldol adducts with two stereogenic centers, it is proposed that synthesis of anti-products proceeds via a chair-like transition structure. A distinctive feature of the cationic transition state complex is a hexacoordinated silicon atom bearing two chiral phosphoramide molecules as ligands (Scheme 6.30). 

German, C. Vulpetti, A. Pain, G. Highly enantio- and diastereoselective boron aldol reactions of a-heterosubstituted fhioacetates with aldehydes and silyl imines. Tetrahedron 1997, 53, 5909-5924. 

Five- and six-membered /3-hydroxylactones have been synthesized diastereo- and (g) enantio-selectively from a,/l-unsaturated esters bearing a ketone tethered as the ester R group, in an intramolecular reductive aldol reaction catalysed by chiral bisphosphine complexes of copper .133... 

A new thioester aldol reaction which uses a half-thioester (PhS0C- CHMe-C02H) of methylmalonic acid and a copper-bis(oxazoline) catalyst is highly enantio- and diastereo-selective, while also being mild and tolerant of protic functional groups and enolizable aldehydes.136... 

The indium trichloride-catalyzed Mukaiyama aldol reaction of 3-aminoketoesters with various silylenolethers gave under solvent-free conditions 1,3-amino alcohols with high stereoselectivity [36], Several Robinson annelation reactions have been carried out enantio-selectively using (S)-proline as a chiral catalyst [37]. Remarkably, the enantioselectivity was distinctly higher in the absence of solvent than in DMSO. 

Silver salts or reagents have received much attention in preparative organic chemistry because they are useful catalysts for various transformations involving C-G and C-heteroatom bond formation.309 Especially, the silver(i)/ BINAP (2,2 -bis(diphenylphosphino)-l,T-binaphthalene) system is a very effective catalyst for a variety of enantio-selective reactions, including aldol, nitroso aldol, allylation, Mannich, and ene reactions. Moreover, silver salts are known to efficiently catalyze cycloisomerization and cycloaddition reactions of various unsaturated substrates. Recently, new directions in silver catalysis were opened by the development of unique silver complexes that catalyze aza-Diels-Alder reactions, as well as carbene insertions into C-H bonds. 

The stereoselective chelation-controlled aldol reaction of unsubstituted lithium ester enolates with (7 s)-2-(p-tolylsulfinyl) cyclohexanone A (Figure 16) led to a high enantio-face differentiation (> 90 < 10), while the simple diastereoselection was rather low for prochiral enolates567. The role of the lithium cation acting as a template is here essential, since sodium, potassium, HMPA or even added ZnCl2 resulted in decreased yield and selectivity. 

A chiral Lewis acid derived from Sn(OTf)2 and the proline derivative 17 has proven to catalyze the aldol reaction effectively. As Mukaiyama et al. [7J demonstrated, a high degree of enantio-selectivity was achieved (Scheme 3b). 

The gold(I) complex is prepared in situ by the reaction of (1) with bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate (2), typically in anhydrous dichloromethane. The dihydrooxazolines obtained provide a ready access to enantiomerically pure p-hydroxy-a-amino acid derivatives. High diastereo- and enantios-electivity are generally maintained with a wide variety of substituted aldehydes, and a-isocyanoacetate esters. N,N-Dimethyl-a-isocyanoacetamides and a-keto esters have been substituted for the a-isocyanoacetate ester and aldehyde component, respectively, sometimes with improved stereoselectivity. The effect of both the central and planar chirality of (1) on the diastereo- and enantioselectivity of the gold(I)-catalyzed aldol reaction has been studied. The modification of the terminal di-alkylamino group of (1) can lead to improvements in the stereos-... 

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