Cyclizations intramolecular aldol

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

Intramolecular aldol cyclization of 2,5-heptanedione with aqueous NaOH yields a mixture of two enone products in the approximate ratio 9 1. Write their structures, and show how each is formed. 

Treatment of the minor product formed in the intramolecular aldol cyclization of 2,5-heptanedione (Problems 23.30 and 23.31) with aqueous NaOH converts it into the major product. Propose a mechanism to account for this base-catalyzed isomerization. 

The ozonolysis of cyclobutene derivatives in the preparation of 1,4-diketones was also applied to the total synthesis of eyclopentanoid antibiotics 161 162k The oxidative cleavage of (470) by ozone and reductive work-up yielded the diketone (471) in 73 % yield. Diketone (471) underwent intramolecular aldol cyclization to give the key intermediate (472), which was used to synthesize ( )-xanthocidin161,162), (+)-epi-xanthocidin 162), ( )-p-isoxanthocidin161,162) as well as ( )-desdihydroxy-4,5-didehydroxanthocidin162). 

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. 

Michael addition of tin(II) dienolates.1 The tin(II) dienolates of (3,y-enones undergo y-selective addition to acyclic ot,(3-enones to give frans-l,7-enediones. If the reaction is carried out at high dilution, the intermediate tin(II) enolate can undergo an intramolecular aldol cyclization to give a cyclohexenol. 

DFT methods have been used to explore the nature of the transition states giving rise to stereoselectivity in intramolecular aldol cyclizations catalysed by amino acids.116 Proline and primary amino acids are compared, identifying the factors explaining why proline is better in some cases, but not always. 

The roles of proline and primary amino acids in intramolecular aldol cyclizations are compared in the previous section. 

An intramolecular vinylogous Morita-Baylis-Hillman reaction, followed by intramolecular aldol cyclization,129 is described under Intramolecular Aldols above. 

With the requisite aldehyde 26 in hand, the stage was now set for the key intramolecular aldol cyclization. Thus, treatment of 26 with 4 equivalents of DBU in refluxing benzene gave the cyclized product in a ratio of 14 1, and the major product 27 was isolated in 60% yield by flash column chromatography. The major product in this key reaction was cw-octahydroquinolinone as expected. The stereochemistry of the major product was determined by the NOE experiment shown in Scheme 13. 

A new stereocontrolled synthetic route to the potent proteasome inhibitor omuralide 46 has been developed from methyl pyroglutamate <07JOC10108>. The development of a new convertible isocyanide, indole-isocyanide, for ready access to pyroglutamic acids has culminated in the formal total synthesis of omuralide featuring a stereocontrolled Ugi reaction <07OL3631>. A novel enantioselective total synthesis of 20S proteasome inhibitor salinosporamide A 47 included, as a key feature, an intramolecular aldol cyclization <07OL2289>. A concise total synthesis of ( )-salinosporamide A, ( )-cinnabaramide A, and derivatives via a bis-cyclization process has been documented <07OL2143>. The... 

The major product formed by intramolecular aldol cyclization of 2,5-hejitanedione (Problem 23.30) has two singlet absorptions in the... 

The third and fourth steps in the synthesis of Hagemann s ester from ethyl acetoacetate and formaldehyde (Problem 23.50) are an intramolecular aldol cyclization to yield a substituted cyclohexenone, and a decarboxylation reaction. Write both reactions, and show the products of each step. 

A. Cyclization of a 5,6-dideoxy-6-nitrohexose derivative Cyclization of a 6-dimethoxyphosphorylhexose derivative Intramolecular aldol cyclization... 

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]. 

Aldol reactions involving aluminum species are considered to be of less synthetic value because of the ambiguous isomerization of the aldol products, under the influence of the Lewis-acidic aluminum species. Efforts have been made to generate an aluminum enolate in a regiospecific manner. Addition of dialkylchloroalane and zinc to a mixture of an a-halo ketone (126) and an aldehyde leads to the formation of enolate (127), which subsequently reacts with the aldehyde, as shown in Scheme 53.71 This method is applicable to the construction of medium to large rings by intramolecular aldol cyclization of various a-bromocarboxylates of u)-hydroxy aldehydes (e.g. BiCHRC02(CH2) CH0 where — 9, 11 or 12 and R = H or Me). The macrolactonization proceeds in reasonable yield, as shown in Scheme 53. 

Chiloschyphone (1) is a sesquiterpene ketone isolated from Chiloscyphus polyanthos and its absolute configuration has not been determined (3). The structure of this compound was first reported in 1972 (4), but later a total synthesis of this compound revealed that this original structure was wrong (5). Quite recently the correct structure was proposed by Connolly and his co-workers to be that depicted as in 1 (3). The synthesis of this correct structure has not been achieved yet. We plan to introduce cw-dimethyl groups by 1,4-addition, followed by an intramolecular aldol cyclization to yield a hydrindane skeleton (Scheme 1). The optical resolution must be possible at the stage of compound 4. 

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