Aldol cyclization asymmetric

Comparison with the Hajos-Parrish asymmetric version of the Robinson annulation [81] (Scheme 7.25(a)) shows the following distinct differences between the two methods. Firstly, the cycloalkenone in the Cu(OTf)2/ligand 18-catalyzed procedure is the Michael acceptor, whereas the cycloalkanone is the Michael donor in the proline-mediated annulation. Secondly, the asymmetric induction occurs in the 1,4-addition step in the new method, in contrast to the asymmetric aldol-cyclization in the Hajos-Parrish procedure. 

Asymmetric aldol cyclization of the triketone with (S)-(-)-proline can also be effected in solvents other than N,N-dimethylformamide acetonitrile 1s outstanding. ... 

Asymmetric aldol cyclization. Complete details are available for the cyclization of the triketone 1 to the optically active bicyclic aldol product 2, first reported in 1974 (6, 411). The high asymmetric induction is attributed to formation of the rigid intermediate A by virtue of two hydrogen bonds. Other amino acids are considerably less effective for this asymmetric cyclization. ... 

Developed in the early 1970s, this reaction, also called the Hajos-Parrish reaction or Hajos-Parrish-Ender-Sauer-Wiechert reaction, is one of the earliest processes for the stereoselective synthesis of Wieland-Miescher ketone, an important building block for steroids and terpenoid synthesis. This reaction is a proline mediated asymmetric variation to the Robinson annulation. Hajos and Parrish of Hoffmann-La Roche Inc. in 1971 and 1974 published an asymmetric aldol cyclization of triketones such as that of structure 39, which affords optically active annulation products in the presence of catalytic amounts of (S)-proline (Z-proline). One of the early examples is the synthesis of 41 from the triketone 39 (a product of the Michael addition of MVK to the corresponding 2-methylcyclopentane-l,3-dione), the reaction is performed in two steps first by ring formation in the presence of 3 mol % of (iS)-proline in DMF to afford the ketol 40 in 100% yield after crystallization with 93% ee and then by reaction with toluenesulfonic acid to give the dehydrated adduct 41. The formation of the Wieland-Miescher Ketone 44 follows the same synthetic route, starting from the tri-ketone 42 to give the end product in 75% optical purity and 99.8% of optical yield. 

By tethering a,p-enones with another carbonyl-containing moiety, Rrische developed rhodium-catalyzed asymmetric 1,4-addition/aldol cyclization reactions." These reactions proceed with high diastereo- and enantioselectivity, furnishing structurally complex cyclic compounds in a single step [Eqs. (3.11-3.13)]. 

Until 1968, not a single nonenzymic catalytic asymmetric synthesis had been achieved with a yield above 50%. Now, barely 15 years later, no fewer than six types of reactions can be carried out with yields of 75-100% using amino acid catalysts, i.e., catalytic hydrogenation, intramolecular aldol cyclizations, cyanhydrin synthesis, alkylation of carbonyl compounds, hydrosilylation, and epoxidations. 

Asymmetric aldol condensation (6, 410-411 7, 307). Terashima and coworkers have examined the effect of various (S)-amino acids on asymmetric cyclization of the acyclic triketone 1. The course of the cyclization is dependent on the solvent. In ether (R,S)-3 is formed preferentially in water (R,S)-2 is the major product. Several amino acids were found to effect asymmetric cyclization, particularly in the cyclization of 1 to 2. The most interesting result is that addition of (S)-phenylalanine gives (R)-2 in 56% enantiomeric excess and that addition of (S)-histidine gives (S)-2 in 54% enantiomeric excess. As expected (S)-proline exerted an effect, but rather slight. 

Preparative Methods by ring-closure of 3-bromobutyric acid with Sodium Carbonate, or by hydrogenation of Diketene. The optically active forms are obtained in the same manner starting from (J )- or (,S)-3-bromobutyric acid, which may be resolved with the (5) form of I-(I-Naphthyl)ethylamine Asymmetric aldol condensation using an enantiopure iron acetyl complex followed by cyclization, or asymmetric hydrogenation of diketene catalyzed by a chiral ruthenium complex, also gives the optically active p-lactone. 

The mechanism of the proline-catalyzed enantioselective aldol reaction has been studied. An extension of the asymmetric aldolization deals with the cyclization of diketones. Also investigated was the dehydration of racemic p-ketols in the presence of (S)-proline and a kinetic resolution was observed. ... 

The as)rmmetric proline-catalyzed intramolecular aldol cyclization, known as the Hajos-Par-rish-Eder-Sauer-Wiechert reaction [106,107], was discovered in the 1970s [108,109,110,111]. This reaction, together with the discovery of nonproteinogenic metal complex-catalyzed direct asymmetric aldol reactions (see also Sect 5.5.1) [112,113,114], led to the development by List and co-workers [115,116] of the first proline-catalyzed intermolecular aldol reaction. Under these conditions, the reaction between a ketone and an aldehyde is possible if a large excess of the ketone donor is used. For example, acetone reacts with several aldehydes in dimethylsulfoxide (DMSO) to give the corresponding aldol in good yields and enantiomeric excesses (ee) (O Scheme 17) [117]. 

Scheme 6.49 illustrates an asymmetric cycloaddition of an enamino diene developed in the Enders laboratory [200]. In this case the auxiliary, 2-methoxy-methyl pyrrolidine, has Cs symmetry, and excellent selectivity is achieved with P-nitrostyrenes as dienophiles, although the yields are modest. The diastereoselectivity in the cycloaddition is >98% in each case, however hydrolysis of the enamine on workup affords a mixture of 2-methyl diastereomers with 75-95% ds. The proposed transition state for the cycloaddition is shown in the inset, although an alternative two step mechanism (Michael addition followed by aldol cyclization) has not been ruled out [200]. 

Michael addition of (2) to (1) gives the trione (3) in almost quantitative yield. The next step, conversion of (3) to optically active (4), is based on the procedure of Eder et al and Hajos and Parrish for asymmetrical aldolization. These chemists found that asymmetric cyclization of (I) to optically active (II) or the... 

Development of asymmetric syntheses involving chirality transfer to pro-chiral substrates, in particular the use of amino acids as catalysts in chirally directed aldol cyclizations. 

A double cyclization of the aminophosphonoacetate derived -hydroxy acids 181 was utilized by Miller et al. [67] in the synthesis of the bicyclic -lactams 182 as potent antibiotics. The carbon framework for the carbapenems was constructed by an asymmetric aldol condensation utilizing the cysteine-derived thiazolidinethione and subsequent direct coupling of the resulting -hydroxy acid equivalent 183 with dimethyl aminophosphonoacetate (Scheme 43). Two... 

The catalyst we will use Is the amino acid L-proline—no derivatization or protection required. It was actually back in 1971 that it was first noted that L-proline will catalyse asymmetric aldols, but until the year 2000 examples were limited to this one cyclization. Treatment of a triketone with proline leads to selective cyclization onto one of the two enantiotopic carbonyl groups. A molecule of proline must condense with the least hindered ketone, and in this case an enamine (rather than an iminium ion) can form. The chiral enamine can select to react with only one of the two other carbonyl groups, and it turns out that it chooses with rather high selectivity the one coloured green in the scheme below. Cyclization, in the manner of a Robinson annelation, and hydrolysis of the resulting iminium ion follow on, releasing the molecule of L-proline to start another catalytic cycle. The isolated product is the bicyclic ketone, in 93% ee. 

Regardless of the precise structure of the chosen half southern synthon, the two main problems to be solved are the establishment of the carbon skeleton and the introduction of the necessary chirahty into the molecule. The published approaches have introduced chirality either by resolution, by starting with a chiral precursor, or via use of asymmetric synthesis techniques. The carbon skeleton has been established by use of a wide variety of techniques including the Diels-Alder and other cycloaddition reactions, heteroatom induced cyclizations, intramolecular Michael or Aldol cyclizations, intramolecular ether formation, and radical cyclization. 

Floreancig completed the total synthesis of (+)-dactylohde via a sequential Peterson olefination and an intramolecular Hosomi-Sakurai-Prins cycli-zation of the acetal-linked substrate (Scheme 32). Macrocychzation was performed by Horner-Emmons olefination as Smith did (Sect. 3.2.1). The key element of 2,6-cfs-tetrahydropyran in 155 was constructed via the sequential cyclization starting from acetal 156, which involved aldehyde 157 and 1,3-diol 158, synthesized via Denmark s asymmetric aldol reaction and Stille coupling. 

The Hajos-Parrish-Eder-Sauer-Wiechert synthesis (Scheme 5) was the first example of an intramolecular proline-catalyzed asymmetric aldol reaction. Systematically, this reaction can be described as a 6-enolendo cyclization. In 2003, List et al. described the first example of an intramolecular enolexo aldolization 85). This approach was then used by Pearson and Mans for the synthesis of (-i-)-cocaine 92, starting from the weso-dialdehyde 90 on treatment with (S)-12 86). This desymmetrization process gave 91 as a mixture of epimers with good enantio-selectivity. The tropane skeleton 91 could be further transformed into +)-92 by conventional means (Scheme 21). 

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