Intramolecular alkylation, enol derivatives

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... 

Intramolecular diastereoselective alkylation of the exocyclic enolate derived from compound 6 results in cyclization yielding bicyclic 7 in 94%. 

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. 

Inter- and intramolecular reactions between a propargyiic carbocation equivalent stabilized by Co2(CO)6-coordination and enol derivatives also provide a good method for the carbon-carbon bond formation at the propargyiic carbon of propargyiic alcohols and their derivatives. Many diastereoselective and enantioselective propargyiic alkylation reactions at the propargyiic position take place between chiral propargyiic cation equivalents and enol derivatives. 

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). 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

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... 

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. 

Path a can be considered as a C-alkylation by the Mannich base of enamine or enol derivatives the latter acts in the presence, for example, of hydroxylamine, followed by intramolecular condensation leading to ring closure and formation of the aromatic nucleus 340. " By contrast, path b involves amino group replacement by arylamine (N-alkylation by the Mannich base) producing the P-arylaminoketone 341, directly obtainable also by Mannich synthesis. " ... 

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... 

Lewis acid catalyzed reactions of silyl enol derivatives of esters (ketene acetals) with 5n1-reactive alkylation agents are well known, but space limitations have prevented coverage of this subject here. The reaction shown in equation (11), which was employed by Pattenden and coworkers in their synthetic studies on forskolin, provides an example of an intramolecular Mukaiyama reaction of a silyl enol ester derivative. 

Schering-Plough Corp, has used an oxazolidinone in its synthesis of the cholesterol adsorption inhibitor (+)-SCH 54016 (24) (Scheme 7) [51], Condensation of an acid chloride intermediate with the (7 )-phenylglycine-derived Evans auxiliary followed by reaction of the titanium enolate with -(4-methoxybenzyh-dene)anihne gave the intermediate 25. This was silylated and treated with TBAF, resulting in removal of the auxiliary and cyclization to form the 2-azetidinone ring. The stereochemistry was exclusively trans. The azetidinone was then converted to the bromide, followed by intramolecular alkylation to form SCH 50416 in > 99% ee. 

Abstract The A(1,2) and A(1,3) strains and their control on the conformational and reactivity profiles of substrates are discussed. The application of A(1,3) strain to the facial selectivity of reactions such as [2,3] and [3,3] sigmatropic shifts, intramolecular SN2 reactions, hydroboration, enolate alkylation, etc. is highlighted. The high diastereoselectivity observed in the reactions of enolates derived from 4-substituted /V-al kanoyl-1,3-oxazolidinones (Evans enolates) with electrophiles is discussed. 

The y-extended enolate anion derived from (40) can in principle undergo intramolecular alkylation at either the a- or the y-position to yield (41) or (42) respectively. Piers etal. have shown that careful choice of the reaction conditions can lead to almost exclusive formation of the desired isomer. ... 

In a study of the intramolecular alkylation which the enone (153) undergoes when treated with base, Piers etal. have found that careful choice of the reaction medium can ensure almost exclusive formation of either (154), the product derived from the kinetic enolate, or (155), the product derived from the thermodynamic enolate. An intramolecular alkylation [(156) (157)] is also a key... 

Regio- and stereo-selectivity in the intramolecular cyclization of enolates derived from 4,5-, 5,6-, and 6,7-epoxy-1-phenylalkan-l-ones (18a,b-2 a,b) has been explored. Competition between C- and O-alkylation routes have been discussed. The LHMDS-Sc(OTf)3 protocol seems to be a valuable tool for obtaining the corresponding y-hydroxy ketones stereoselectively from (18a,b) and (20a,b) whereas (19a,b) reacted cleanly only under alternative basic conditions, and yielded products of O-alkylation. 

Intramolecular alkylation of w-bromo-enolates is a useful synthetic route to substituted cyclohexanones (Scheme 15) with some limitations it is also applicable to the synthesis of cycloheptanone derivatives. ... 

The plan was to assemble the first carbocyclic ring of 3 by intramolecular aldol condensation of the keto aldehyde 15. The enantiomericaUy-pure secondary methyl substituent of 15 derived from the commercial monoester 10. Activation as the acid fluoride followed by selective reduction led to the volatile lactone 11. Opening of the lactone with HjCONHCHj HCl gave, after protection, the Weinreb amide 12. Alkylation of the derived hydrazone 13, selectively on the methyl group, led, after deprotection, to 15. The intramolecular aldol condensation of 15 did dehver the imstable cyclohexenone 1. Under the acidic conditions of the aldol condensation, the enol derived from the piperidone added in a Michael sense, from the axial direction on the newly-formed ring, to give the frans-fused bicyclic diketone 2. 

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