Aldehydes aldol cyclization

Reaction of the potassium salt of salicylaldehyde with chlo-roacetone affords first the corresponding phenolic ether aldol cyclization of the aldehyde with the ketonic side chain affords the benzofuran (1). Reduction of the carbonyl group by means of the Wolf-Kischner reaction affords 2-ethyl-benzofuran. Friedel-Crafts acylation with anisoyl chloride proceeds on the remaining unsubstituted position on the furan ring (2). The methyl ether is then cleaved by means of pyridine hydrochloride (3). lodina-tion of the phenol is accomplished by means of an alkaline solution of iodine and potassium iodide. There is thus obtained benziodarone (4)... 

Krische et al. demonstrated intramolecular reaction with Co(dpm)2 (5mol%) and PhSiH3 (120 mol %) as a hydride donor (Scheme 8) [14-16]. Addition of aldehyde-enone 17 to a solution of the Co catalyst and phenylsi-lane resulted in the formation of the corresponding aldol cyclization product... 

The present tandem nitro aldol-cyclization process is used for the preparation of the enantiomerically pure 4-hydroxy-2-isoxazoline-2-ones. They are prepared starting from chiral a-mesyloxy aldehydes and ethyl nitroacetate under mild reaction conditions (Eq. 8.85).136... 

Though several intermolecular catalytic reductive aldol additions are reported, corresponding reductive cyclizations have received less attention. The first reported reductive aldol cyclization involves use of a (diketonato)cobalt(ll) precatalyst in conjunction with PhSiHj as terminal reductant.48,486 The reductive cyclization is applicable to aromatic and heteroaromatic enone partners to form five- and six-membered rings. As demonstrated by the reductive cyclization of mono-enone mono-aldehyde 65a to afford aldol 65b, exceptionally high levels of ty -diastereoselectivity are observed. Interestingly, exposure of the substrate 65a to low-valent nickel in the presence of excess Et2Zn provides the isomeric homoaldol cyclization product 65c via reductive coupling to the enone /3-position (Scheme 43).47a... 

Most recently, reductive aldol cyclization catalyzed by In(OAc)3 in the presence of PhSiH3 was reported.50 This catalytic system is applicable to both aldehyde and ketone acceptors. As demonstrated by the reductive cyclization of 65a and 68a, cycloaldol products are produced in good yields and excellent ry -diastereoselectivity (Scheme 48). 

This method can also be applied to silyl enol ethers of homologous unsaturated ketones as well as of unsaturated aldehydes or esters [85-87]. While unmodified unsaturated esters give only the corresponding aldehydes without cyclization under tandem hydroformylation/aldol reaction conditions, the corresponding silylated ester enolates smoothly cyclize in a tandem hy-droformylation/ Mukaiyama aldol reaction (Scheme 32) [85-87]. 

Intramolecular Michael-aldol cyclization One route to a hydrindane involves base-catalyzed cyclization of the keto aldehyde 1 to the hydrindene 2. Although Zr(0-/-Pr)4 is useful, Zr(0-n-Pr)4 is the most satisfactory base, both in respect to yield and selectivity. 

It has been demonstrated that optically active oxetanes can be formed from oxazolidinone 92, a crotonic acid moiety functionalized with Evans chiral auxiliary (Scheme 18) <1997JOC5048>. In this two-step aldol-cyclization sequence, the use of 92 in a deconjugative aldol reaction, with boron enolates and ethanal, led to formation of the syn-aldol 93. This product was then converted to the corresponding oxetanes, 94a and 94b, via a cyclization with iodine and sodium hydrogencarbonate. This reaction sequence was explored with other aldehydes to yield optically active oxetanes in similar yields. Unlike previous experiments using the methyl ester of crotonic acid, in an analogous reaction sequence rather than the oxazolidinone, there was no competing THF formation. 

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. 

Aldol cyclization. Exposure of the hydroxy ketone 1 to excess potassium t-butoxide and benzophenone in refluxing benzene provides the o,/S-unsaturated ketone 2 directly/ This transformation involves a modified Oppenauer oxidation followed by aldol closure of the resulting keto aldehyde. The product serves as an intermediate in the synthesis of Elaeocarpus alkaloids. 

Aldol cyclization. Although the keto aldehyde 1 is resistant to aldol cyclization under normal, alkaline conditions, this reaction can be accomplished by a method originally developed by Raphael et Reduction of the enol lactone (2), derived from 1, with DIBAH produces a bridged ketol, which is oxidized to 3 with chromic add. This diketone was employed as an intermediate in a synthesis of the sesquiterpene gymnomitrol (4). 

The mechanism is a conjugate addition of the central enolate of the keto-ester to the enal fcw- il5 by an aldol cyclization of the ketone enolate on to the aldehyde and dehydration. 

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 cyclization of keto aldehyde intermediates has been used in several steroid syntheses, as pan of a strategy for conversion of a six-membered o-ring into a five-membered ring. An example is seen in equation (105), a step in the Sarett steroid synthesis. A similar transformation has been utilized by Johnson and coworkers in a steroid synthesis. 

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. 

A number of scenarios, albeit multistep, are conceivable for the transposition of the (3-hydroxy ketone functionality present in lactam 61 to the isomeric version in lactam 60. Lactam 61 could be constructed by an aldol ring closure of 62, which in turn could be fashioned by another aldol-type cyclization within aldehyde 63. Finally, a Diels-Alder cycloaddition of silyloxydiene 65 with the 2-amidoacrolein 64 was expected to furnish 63. It should be noted that this intermolecular cycloaddition was expected to install not only the central 1 -alkyl-1 -aminocyclohexane substructure of FR901483 but also the electrophilic and nucleophilic components, appropriately tuned, for the pending sequential aldol cyclizations. 

The precursor to amidoacrolein 64, 1,3-dioxin 66, was prepared as follows [39] the imine derived from the condensation of 2,2-dimethyl-l,3-dioxan-5-one with aminoacetaldehyde dimethyl acetal was acetylated with acetic anhydride/triethylamine to afford dioxin 66 in 83% yield (Scheme 24). Retro Diels-Alder of dioxin 66 in warm benzonitrile (120 C, 16 h) generated the amidoacrolein 64, which was trapped in situ with the silyloxydiene 65 to afford the desired cycloadduct 63 (64%). An aldol cyclization between the acetamide and neighboring aldehyde functionalities within 63 proceeded smoothly (2 equiv. of KCh-Bu, 10 equiv. of EtOAc, THF, 0 °C, 40 min) and directly afforded the corresponding conjugated lactam. This product was of sufficient purity for the second aldol reaction, which was best accomplished under acidic conditions, presumably proceeding through the achiral keto aldehyde intermediate 62 enroute to the desired, but racemic, (3-hydroxy ketone 61 obtained in 79% yield after the two consecutive ring closures. 

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)". 

In a later study, Ito s group found that TBAF also effected aldol reactions of 1027 and aldehydes to produce oxazolines. Here, the authors proposed fluoride-catalyzed desilylation of 1027 generated an equilibrium mixture of the oxazol-2-yl carbanion 1031 and the isocyanovinyl enolate 1032 (Scheme 1.275). Condensation of 1032 with an aldehyde and cyclization then gave the oxazolines 1028 and 1029. Aromatic aldehydes gave predominately the cw-oxazoline 1029 in good yield. Interestingly, aliphatic aldehydes were unreactive. The authors also prepared 1028 and 1029 directly from an a-isocyanoacetate ester and an aldeyhde, but used only a catalytic amount of TBAF. 

The ease with which cyclopent-2-enones are prepared by intramolecular aldol cyclizations of 1,4-diones has been much exploited in synthesis. A particularly attractive route to y-keto-aldehydes has been described by Martin etal, which has as a key stage the reaction between 2,3-dibromopropene (functioning as a 2-oxopropyl synthon) with an enamine (Scheme 11). In a similar type of approach to... 

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