The Aldol Cyclization

The biomimetic cationic domino cyclization of an acyclic unsaturated substrate to give the tetracyclic scaffold of triterpenes and steroids is intensively described in the literature.1121 The concept has recently been used by Corey et al. to prepare enanti-opure (+)-dammarenediol II 18 in an exceptional short way.1131 The synthesis demonstrates the power of the combination of cation-olefin polyannulation with the aldol cyclization for tetraannulation (scheme 4). Successive treatment of the acylsilane 13 with 2-propenyllithium 14 and the iodoalkane 15 efficiently yidds the epoxytriene 16. The Lewis acid... 

A further example of the use of 2//-thiopyrans as surrogates for m-substituted dienes involves the use of the protected 3,4-dihydio-3-(3-oxobutyl)A//-thiopyranA-onc, 3-[2-(2-methyl-l,3-dioxolan-2-yl)ethyl]-4-[tris(l-methy-lethyl)silyl)oxy-2//-thiopyran 328 as an equivalent of l-ethenyl-2-methylcyclohexene in Diels-Alder reactions. The thiopyran reacted with various maleimides to yield the endo cycloadducts and with methyl propenoate to give the exo adduct under either thermal or Lewis-acid-catalyzed conditions. In the latter case concomitant release of the protected ketone functions occurs, acid-catalyzed cyclization of which generates a fused cyclohexenone ring (Scheme 67). Desulfurization, preferably before the aldol cyclization, leads to derivatives of 2,3,4,4a,5,6,7,8-octahy-dro-4a-methylnaphthalenes < 1997CJC681 >. 

Enolization can be part of an aldol condensation. We examined the aldol cyclization of compound 52 to 53 catalyzed by the bis-imidazole cyclodextrin artificial enzymes, and again saw that the A,D isomer was the preferred catalyst [139]. This was not an obvious result the rate-limiting step in this case is cyclization of the enol, which is... 

This principle is often applied to molecules. If a nucleophile is joined to the carbonyl group it is to attack by a short chain of covalent bonds, it may be able to reach only one side of the carbonyl group. An example from a familiar reaction concerns the Robinson annelation. The first step, Michael addition, creates a stereo genic centre but no relative stereochemistry. It is in the second step—the aldol cyclization—that the stereochemistry of the ring junction is decided. 

Aldol condensation. This reagent is uniquely effective in catalyzing the aldol cyclization of the dialdehyde 1. Elimination of the tetrahydropyranyloxy group with other amine-acid combinations is a complication. 

The final stage in the synthesis of the second compound must be an aldol reaction as the produ is an enone. That leaves us with a diketone (the aldol cyclization is shown with a dotted arrow) ar., this could be made by two different conjugate additions. 

The aldol cyclization step and the dehydration are sometimes separated from the conjugate addition and from each other and sometimes not. It depends to some extent on the conditions. Very mild conditions in this example allowed each step to be performed separately and in good yield but notice the exceptionally mild conditions for the conjugate addition (just mix in water ) which are possible only because of the two carbonyl groups in the enol component. 

For effecting the aldol cyclization of the methyl ketone (5) to (6), a key intermediate in the total synthesis of cedrol. Stork and Clarke used potassium t-butoxide in... 

However, other structural features can provide a thermodynamic selection of one stereoisomer. Intramolecular aldolization of 2,2 -0-methylene-bis-D-glycerose (109) under weakly basic conditions affords only two of the four possible aldols, (110) and (111) (Scheme 4). The (110) (111) ratio greatly favors the former, and conditions were found under which only isomer (110) is produced. It was proposed that the aldol cyclization is under thermodynamic control, and that the initial products are trapped as their intramolecular hemiacetals (112) and (113). The other two possible aldols cannot form such hemiacetals. Isomer (112) is presumably favored over (113) because of the normal equatorial preference of a hydroxy group that is hydrogen-bonded to water. 

Why was benzylammonium trifluoroacetate chosen to induce the Aldol cyclization reaction This appears to be an unusual reagent and deserves comment. The bromoacetate moiety remains a problems since it might react with the enolate anion generated during the Aldol condensation. 

Alkylation of the enolate of (138) with methallyliodide gave the product (149) whose stereochemistry was assigned on the basis of equilibration experiment. It was converted to the dione (150) by oxidation with osmium tetrooxide and sodiumperiodate. The aldol cyclization of (150) effected with sodium hydride and trace of t-amyl alcohol in refluxing benzene afforded the enone (151) in 88% yield. Normal protic conditions (sodium hydroxide, ethanol) were not effective in this transformation. All attempts for its conversion to aphidicolin (148) by intermolecular additions proved fruitless and therefore were turned to intramolecular methods. Molecular models show clearly that the top face of the carbonyl group is less hindered to nucleophilic attack than is the bottom face. Thus the reduction of (151) with lithium aluminium hydride afforded the alcohol (152) whose vinyl ether (153) was subjected to pyrolysis for 2 hr at 360 C in toluene solution containing a small amount of sodium t-pentoxide to obtain the aldehyde (154) in 69% yield. Reduction and then tosylation afforded the alcohol (155) and tosylate (156) respectively. Treatment of this tosylate with Collman s reagent [67] (a reaction that failed in the model system) afforded the already reported ketoacetonide (145) whose conversion to aphidicolin (148) has been described in "Fig (12)". 

Assuming that dehydration occurs, write the structures of the two other products that might have resulted from the aldol cyclization just given. (One of these products will have a five-membered ring and the other will have a seven-membered ring.)... 

Cyclizations via Aldol Condensations 876 [ A MECHANISM FOR THE REACTION ] The Aldol Cyclization 877... 

The Aldol Cyclization 877 The Conjugate Addition of HCN 879 The Conjugate Addition of an Amine 879 The Michael Addition 880 The Mannich Reaction 882... 

Krische disclosed an intramolecular tandem 1,4-addition/aldol process in the presence of water (Scheme 8.40) [118]. Here, the rate of the aldol cyclization was faster than the competing hydrolysis of the rhodium enolate, so that 150 was isolated in 88% yield and 88% enantioselectivity. The configuration observed for the aldol reaction could be accounted for by the Zimmerman-Traxler-type transition state of the (Zj-enolate. 

Fleet s group have examined the utility of carbohydrate-derived 2-azido- and 2-iodo-lactones for synthesis of novel, highly functionalized cyclopentanes and cyclohexanes. The azido lactone 11 undergoes KF-catalysed intramolecular aldol reaction to give 12 (major) and 13 (minor). The minor isomer arises through epimerization at C5 prior to the aldol cyclization. Lactone hydrolysis of the major isomer leads to 15. Similar hydrolysis of the minor isomer yields 16, and thus epimerization via retro-aldol must precede lactone ring opening via the intermediacy of 14. 

Sterics can influence the stereochemical outcome of the aldol cyclization, as in the case of the synthesis of the ketol 52 from the triketone... 

The three C22 natural quassinoids known in the literature have a butenolide moiety attached to the A ring, presumably originating from the aldol cyclization of a a-acetoxycarbonyl moiety from the normal C20 skeleton. In this series, sergeolide has attracted much attention due to its very good antimalarial potential (Fig. 125.4) [7]. 

Other Syntheses of Six-membered Rings.—The aldol cyclization of keto-alde-... 

Cooper and Dolby have outlined a general synthesis of rethrolones which has, as an essential feature, the aldol cyclization of keto-aldehyde (88) with K2CO3 in aqueous dioxan in the presence of a catalytic amount of thiophenol. The attempted cyclization of (88) in the absence of thiophenol instead led to -keto-aldehyde (89),... 

Chen et al. reported that oxindole-type a-isothiocyanato imides 271 had high activities in the aldol-cyclization reaction with inactive simple ketones. With the promotion of thiourea catalyst 1401, the cascade process of either aromatic or aliphatic ketones 206 with 3-isothiocyanato oxindoles 271 proceeded smoothly to afford spirooxindoles 272 bearing a quaternary stereogenic center with perfect stereoselectivity (Scheme 2.72) [102],... 

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