Enol intramolecular alkylation

Scheme 1.8 shows some intramolecular enolate alkylations. The reactions in Section A involve alkylation of ketone enolates. Entry 1 is a case of a-alkylation of a conjugated dienolate. In this case, the a-alkylation is also favored by ring strain effects because y-alkylation would lead to a four-membered ring. The intramolecular alkylation in Entry 2 was used in the synthesis of the terpene seychellene. 

Intramolecular alkylation of enolates can be used to synthesize bi- and tricyclic compounds. Identify all the bonds in the following compounds that could be formed by intramolecular enolate alkylation. Select the one that you think is most likely to succeed and suggest reasonable reactants and reaction conditions for cyclization. 

By using this strategy, intramolecular alkylations to unusual enol ethers 37 are easily accessible (equation 14). ... 

Intramolecular alkylation of enolates leads to formation of cyclic products. In addition to the other factors that govern C/O-alkylation ratios, the element of stereo elec -tronic control comes into play in such cases. The following reactions illustrate this point.51... 

Intramolecular alkylation of enolates has been used to advantage in synthesis of bi-and tricyclic compounds. Indicate how such a procedure could be used to synthesize each of the following molecules by drawing the structure of a suitable precursor. 

Interest in the total synthesis of the Aspergillus terreus derived quadrone fi06), an antitumor agent has been very intense. Success was first realized in Danishefsky s laboratory Once 601 was reached, its sidechain was elaborated and ring closure effected (Scheme LII). Condensation of 602 with 1-tert-butoxy-l-tcrt-butyl-dimethylsiloxyethylene in the presence of titanium tetrachloride and subsequent desilylation resulted in introduction of an angular acetic acid moiety. The two sidechains were next connected by intramolecular alkylation and the resulting keto add was subjected to selenenylation in order to produce 603. The a, P-unsaturated double bond was used to force enolization to the a position. Indeed, 604 was... 

Other examples of the formation of six-membered rings by means of an intramolecular alkylation of an ester enolate are given in Table 7. Entry 6, i.e., stereoselective transformation of the epoxy ester into the cyclohexane derivative, should be discussed briefly as a representative for the other cases. The probable reason for the unexpectedly high selectivity i.e., the nonappearance of the diastereomer 8, can be demonstrated by the two transition-state-like conformations 9 and 10. 9 displays a very severe 1,3-diaxial interaction in comparison to 10, thus, formation of the diastereomer 7 from conformation 10 is highly favored113. 

Table 7. Formation of Six-Membered Rings by Intramolecular Alkylation of Ester Enolates...

Intramolecular alkylations of y-lactone enolates are merely variants of the examples mentioned in the previous sections (Section 1.1.1.3.2.2.1.). A striking feature of these reactions is their efficiency with mild bases such as l,8-diazobicyclo[5.4.0]undec-7-ene (DBU) or potassium er -butoxide instead of the lithium amides. 

Intramolecular alkylation of phenol with diazoketone [14] can be analyzed as the following The carbenoid center acts first as an acceptor and then a donor. Since the resulting cyclopropane derivative is vicinally substituted with an acceptor (C=0) and a donor (enol), fragmentation follows instantaneously (vide infra). 

Intramolecular alkylation, although it is enticing, has not been developed as a method for cyclohexanone construction. Joseph P.A. Harrity of the University of Sheffield reports (J. Org. Chem. 68 4392, 2003) that TiCl smoothly transforms the enol ether 10, prepared from the corresponding alkynyl phosphonium salt, into the 2-aryl cyclohexanone 11. Alkynyl ethers such as 10 are readily prepared in enantiomerically-enriched form. Would the enantiomeric excess be maintained on cyclization ... 

For the most part, alkynic and allenic ketones have found limited use in conjugate addition-enolate trapping sequences 69,81-83 their analogous esters have been used with far greater frequency (vide infra). Alkynic ketones, in particular, have found use in development of a new anionic polycyclizadon method consisting of intramolecular Michael addition followed by intramolecular alkylation (equation 15).84... 

In contrast, the closely related palladium acetate-promoted intramolecular alkylation of alkenes by tri-methylsilyl enol ethers (Scheme 4)6,7 has been used to synthesize a large number of bridged carbocyclic systems (Table 1). In principle, this process should be capable of being made catalytic in palladium(II), since silyl enol ethers are stable to a range of oxidants used to carry the Pd° -> Pd11 redox chemistry required for catalysis. In practice, catalytically efficient conditions have not yet been developed, and the reaction is usually carried out using a full equivalent of palladium(II) acetate. This chemistry has been used in the synthesis of quadrone (equation 2).8 With the more electrophilic palladium(II) trifluoroace-tate, methyl enol ethers underwent this cyclization process (equation 3).9... 

Intramolecular alkylation of the enol forms of 4- and 5-bromoacyl silanes has been observed upon heating at 100 °C in a polar aprotic solvent, inducing cyclization to give 2-silyldihydrofurans and 2-silyldihydropyrans, respectively195. Similar transformation of the thiono analogues, 4- to 7-halothioacyl silanes, induced by sodium hydroxide, gave the 2-silylated sulphur heterocycles in excellent yields (vide supra Section IV.A.4)196. 

The intramolecular alkylation of the enolate derived from phenylalanine derivatives 22a,b to form P-lactams 23a,b has also been achieved using Taddol as a chiral phase-transfer catalyst (Scheme 8.11) [23]. In this process, the stereocenter within enantiomerically pure starting material 22 is first destroyed and then regenerated, so that the Taddol acts as a chiral memory relay. Taddol was found to be superior to other phase-transfer catalysts (cinchona alkaloids, binol, etc.) in this reaction, and under optimal conditions (50 mol % Taddol in acetonitrile with BTPP as base), P-lactam 23b could be obtained with 82% et. The use of other amino acids was also studied, and the... 

Another type of cydization which follows Baldwin s rules is the intramolecular alkylation of enolates. Cyclopentanones cannot usually be prepared this way because the electrophilic carbon atom cannot approach the nucleophilic carbon atom sufficiently (Scheme 9.4). If the C-C double bond of the enolate remains exocyclic,... 

Intermediate samarium enolates derived from ketones 1522 or 1525 could stereoselectively be trapped with allyl halides, leading to tricycles 1524 and 1526. The intramolecular alkylation by the chloroalkyl terminus of compound 1527 led to tetracyclic compound 1528 with satisfactory efficiency. These cascade reactions selectively generate three continuous stereogenic centers, including a quaternary carbon atom at the 3-position of the dihydroindole moiety, a structural motif of many indole alkaloids. 

In conclusion, C-C bond formation on carbohydrates has absorbed lots of widely used methods from general synthetic organic chemistry. Typical among these methods are intramolecular alkylation and intramolecular condensation of aldehyde with enolates, phosphonates, and nitro-stabilized anions. Metal-mediated radical reactions, cycloadditions, and rearrangements have also been applied frequently. 

Ring expansions of appropriately a-substituted ketones via their vinyl carbinol derivatives has also been carried out under cationic conditions. The basic sequence, outlined in Scheme 66, begins with the addition of a vinyl organometallic to an a-substituted ketone, where X is carbon or a heteroatom. Departure of a leaving group Y then produces a cationic species, which may react further to form products. Two main pathways appear to be operative one is a cationic alkene cyclization, followed by a pinacol-like rearrangement while the other is a 3,3 or 3,3-like rearrangement, followed by an intramolecular alkylation of the intermediate enol. 

Lewis acid catalyzed intramolecular alkylations of silyl enol ethers containing 5n1-reactive functionality provide useful routes to a variety of carbocyclic systems. - Smith et al have employed an intramolecular Mukaiyama reaction of the enol derivative (76) to produce the tetracyclic system (77) (equation 7). This transformation was a key step in their elegant synthesis of jatrophone. The synthesis... 

As shown in Scheme 69, Kim and coworkers have reported highly stereoselective routes to ci5-1,2-dialkylcycloalkanecarboxylates by intramolecular alkylations of tosyloxy esters such as (142). The reaction appears to proceed via the eclipsed conformations of the enolate (143), rather than the bisected one that would result from a 180 rotation about the a, 3-sigma bond. 

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