Oxidation lithium enolate synthesis

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Schreiber found that the monoalkylation of the lithium enolate of cyclonona-none with propene oxide could be cleanly effected by addition of AlMe3 to give the y-hydroxy ketone 145, a key intermediate for the synthesis of recifeiolide [69a]. 

Palladium-catalyzed bis-silylation of methyl vinyl ketone proceeds in a 1,4-fashion, leading to the formation of a silyl enol ether (Equation (47)).121 1,4-Bis-silylation of a wide variety of enones bearing /3-substituents has become possible by the use of unsymmetrical disilanes, such as 1,1-dichloro-l-phenyltrimethyldisilane and 1,1,1-trichloro-trimethyldisilane (Scheme 28).129 The trimethylsilyl enol ethers obtained by the 1,4-bis-silylation are treated with methyllithium, generating lithium enolates, which in turn are reacted with electrophiles. The a-substituted-/3-silyl ketones, thus obtained, are subjected to Tamao oxidation conditions, leading to the formation of /3-hydroxy ketones. This 1,4-bis-silylation reaction has been extended to the asymmetric synthesis of optically active /3-hydroxy ketones (Scheme 29).130 The key to the success of the asymmetric bis-silylation is to use BINAP as the chiral ligand on palladium. Enantiomeric excesses ranging from 74% to 92% have been attained in the 1,4-bis-silylation. 

Full details of Barton s selenofenchone (212 X = Se) and fenchylidenefeachane (212 X = 2-fenchylidene) synthesis (Vol. 6, p. 40) have been published" and Wynberg has discussed the antipodal interaction effect in the reductive dimerization of (+)- and ( )-camphor to bornylidenebornanes (Vol. 7, p. 41)," sensitized photo-oxidation of which has also been reported." The CuCl2-promoted dimerization of camphor-lithium enolate yields the expected mixture of dia-... 

Page et al. (see [298] and references therein) have shown that generally excellent stereocontrol in organic reactions can be obtained by using DITOX (1,3-dithiane-l-oxide) derivatives as chiral auxiliaries. The one-pot stereo-controlled cycloalkanone synthesis given here outlines some aspects of the chemistry worked out for efficient acylation-alkylations steps. Of note are the use of N-acyl imidazoles under mixed base (sodium hexamethyldisilazide/n-butyllithium) conditions to yield the lithium enolates of 2-acyl-l,3-dithiane-l-oxides) and the sequential alkylation-cyclization of the latter (steps (iv) and (v)). 

The trisubstituted (Z)-olefin was introduced by Still-Gennari HWE olefination, as precedented by Schreiber [43, 44, 106], and following silyl protection provided 124. Conversion into the iodide 125 was followed by alkylation with the lithium enolate of aryl ester 126, to complete the C9-C16 subunit 121. The synthesis of the C17-C24 subunit 98 from 120 began with a four-step sequence involving protecting group manipulations and oxidation at C21 to provide aldehyde 127, converging with the earlier route to 98 [55-57],... 

The studies that eventually led to the synthesis of 6 started by installation of one of the all-carbon stereocenters by addition of vinylmagne-sium bromide to the lithium enolate of (i )-carvone oxide 120. This reaction afforded compound 121 as a single isomer, albeit in only 30% isolated... 

Nitrogen heterocycles such as azirines and aziridines are also used effectively as building blocks for the synthesis of a,a-disubstituted amino acids. The aziridine derivative 33 is prepared in optically pure form by addition of the lithium enolate 32 to the chiral sulfinimide 31 (Scheme 7) [42]. After oxidation of the sulfoxide to the sulfone and subsequent hydration, the a-methylated phenylalanine derivative 34 is obtained in good overall yield. 

Oxaziridines. Davis has developed the use of chiral 2-sulfonyloxaziridines derived from camphorsulfonic acid as chiral auxiliaries in the asymmetric oxidation reactions. Although other oxaziridines may be preferable, the camphor-derived oxaziridines can be used for the oxidation of sulfides and disulfides to sulfoxides and thiosulfinates as well as for the epoxidation of alkenes. On the other hand, the camphoryloxaziridines are the preferred reagents for hydroxylation of lithium enolates of esters, amides, and ketones, as utilized in the synthesis of kjellmanianone (eq 17). ... 

Oxidation of the dienolate of (17) with (+)-( ) affords a-hydroxy ester (18), a key intermediate in the enantioselective synthesis of the antibiotic echinosporin (eq 19) whereas oxidation of enolates derived from 1,3-dioxin vinylogous ester (19) gives rise to both a - and y-hydroxylation depending on the reaction conditions (eq 20). With (+)-( ) the lithium enolate of (19) gives primarily the a -hydroxylation product (20), while the sodium enolate gives )/-hydroxylation product (21). Only low levels of asymmetric induction (ca. 16% ee) are found in these oxidations. Birch reduction products are also asymmetrically hydroxylated in situ by (+)-( ) (eq 21). ... 

Sammes and cowoikers devised a promising solution to the synthesis of substituted P-silyl sulfones, which has been exploited in a new approach to the antibiotic bicyclomycin (Scheme 44). In their approach the P-silyl sulfone (125) was prepared by conjugate addition of the lithium enolate of the mono-imino ether derivative (123) of a dioxopiperazine to the unsaturated P-silyl sulfone (124). After oxidative cyclization to the bicyclic system (126), the latent alkene functionality was unleashed in 89% yield on treatment with TBAF in THF at room temperature to give the basic skeleton of bicyclomycin. 

The total synthesis of the immunosuppressant (-)-pironetin (PA48153C) was accomplished by G.E. Keck and co-workers. The six-membered a,(3-unsaturated lactone moiety was installed using a lactone annulation reaction by reacting the advanced aldehyde intermediate with the lithium enolate of methyl acetate. The aldehyde was prepared by the Ley oxidation of the corresponding primary alcohol and was used without purification in the subsequent annulation step. 

The oxidation of titanium enolato complexes, derived from a transmetallation reaction of the corresponding lithium enolates with Cp2TiCl2, by dimethyldioxirane has been investigated as a general, convenient, effective, and chemo- and diastereoselective synthesis of cr-hydroxy carbonyl compounds. The Cp derivative shown in Scheme 601 results in much higher diastereoselectivities than other enolato complexes studied.1556... 

By far the most concise synthesis of 1 has arisen from the work of Schreiber in 1980 (see Scheme 1.8). The lithium enolate 28 was monoalkylated with propylene oxide in the presence of trimethyl aluminum to give keto alcohol 29 in 96% yield (based on recovered 28). The addition of hydrogen peroxide under acidic conditions then made available the hydroperoxide 30 in 99% yield. A ferrous-ion-induced fragmentation then gave the natural product 1 in 96% yield as a single olefin isomer. 

The remaining steps are trivial except for the conversion of the cyanide to a ketone. This was achieved by oxidising the lithium enolate of the cyanide. The methyl groups were removed from the phenols with BBr3 and the final oxidation to the extended quinone was done with oxygen adsorbed onto silica. The whole synthesis took only seven steps and gave a remarkable overall 21% yield. 

TBS-Protected D-lactaldehyde 961 is used as the chiral source for the synthesis of jS-lactam 969, a key intermediate in the synthesis of the antibiotic monobactam Aztreonam [254] (Scheme 131). The cmcial step in the synthesis, the reaction of A/-trimethylsilylimine 962 with the lithium enolate of STABASE (963), affords ra 5-j5-lactam 964 with 98% diaster-eoselectivity. Desilylation, Jones oxidation, and Baeyer—Villiger oxidation provides acetoxy jS-lactam 968, which in itself is a useful intermediate for the preparation of j5-lactam anti-... 

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