Enolate using NaHMDS

Oxidation of the sodium enolate of 15b, prepared by using NaHMDS, with ( )-2-phenylsulfonyl-3-phenyloxaziridine yielded the desired 7-hydroxy derivative 23 (R = H) and its C(7) epimer with a very low... 

Scheme 1.1 shows data for the regioselectivity of enolate formation for several ketones under various reaction conditions. A consistent relationship is found in these and related data. Conditions of kinetic control usually favor formation of the less-substituted enolate, especially for methyl ketones. The main reason for this result is that removal of a less hindered hydrogen is faster, for steric reasons, than removal of a more hindered hydrogen. Steric factors in ketone deprotonation are accentuated by using bulky bases. The most widely used bases are LDA, LiHMDS, and NaHMDS. Still more hindered disilylamides such as hexaethyldisilylamide9 and bis-(dimethylphenylsilyl)amide10 may be useful for specific cases. 

The reaction sequence is called the Regitz diazo transfer and requires active methylene compounds as substrates/ Hence it is common to use formic esters to create P-carbonyl compounds from ketones or aldehydes in an aldol reaction. These are used as substrates for deformy-lative diazo transfer reactions in which the diazo group is transferred and the formyl group is removed in one concerted step. The mechanism of the deformylative diazo transfer is shown below. In this case the bulky base NaHMDS ensures deprotonation at the less-hindered a-position of 3, forming the so-called kinetic enolate 13. This enolate is formylated by ethyl formate yielding the P-formyl ketone 14, which is used as substrate in the deformylative diazo transfer. 

In the first step of the reaction silyl enol ether 23 is formed. The use of bulky bases like NaHMDS at -78 °C ensures the formation of the so-called kinetic enolate 22, which is obtained by deprotonation of the ketone at the less-hindered a-position. Afterwards, 22 is protected by trimethylsilyl chloride (TMSCl), yielding TMS-enol ether 23. TMS ethers are often unstable under acidic and basic conditions and barely survive the simplest chemical transformation. TMS-enol ethers of this type are often used in Mukaiyama aldol reactions with catalytic amounts of Lewis acids. 

Typically, nonstabilized ylides are utilized for the synthesis of (Z)-alkenes. In 1986, Schlosser published a paper summarizing the factors that enhance (Z)-selectivity. Salt effects have historically been defined as the response to the presence of soluble lithium salts. Any soluble salt will compromise the (Z)-selectivity of the reaction, and typically this issue has been resolved by the use of sodium amide or sodium or potassium hexamethyldisilazane (NaHMDS or KHMDS) as the base. Solvent effects are also vital to the stereoselectivity. In general, ethereal solvents such as THF, diethyl ether, DME and t-butyl methyl ether are the solvents of choice." In cases where competitive enolate fomnation is problematic, toluene may be utilized. Protic solvents, such as alcohols, as well as DMSO, should be avoided in attempts to maximize (Z)-selectivity. Finally, the dropwise addition of the carbonyl to the ylide should be carried out at low temperature (-78 C). Recent applications of phosphonium ylides in natural product synthesis have been extensively reviewed by Maryanoff and Reitz. 

The second step in the above sequence, deprotonation followed by silylation of the resulting enolate, was not successful under standard lithium diisopropylamide (LDA) conditions, presumably because silylation of the lithium enolate was slow. The deprotonation/silylation can be carried out effectively using KHMDS, which is available from Aldrich Chemical Company, Inc., as a 0.5 M solution in toluene. This protocol is quite general for the preparation of various dienes containing different silyl and amino groups as illustrated in Table I.5-7 For preparative scale reactions, such as that described above, the use of NaHMDS was preferred as it is available from Aldrich Chemical Company, Inc., as 1.0 M solution in THF. The procedure described here also provides a convenient and high-yielding preparation of Danishefsky s diene (1-methoxy-3-trimethylsiloxy-1,3-butadiene).8... 

Lithium enolates 279 do give a-hydroxy-carbonyl compounds but there is a significant side reaction that is a kind of aldol reaction on the imine product 272 through a six-membered cyclic transition state 280 like those we used to explain the stereoselectivity of aldol reactions in chapter 4. Hence the Na or K disilazide bases NaHMDS or KHMDS are usually used. 

Sterically Hindered Base for Enolate Formation. Like other metal dialkylamide bases, sodium bis(trimethylsilyl)amide is sufficiently basic to deprotonate carbonyl-activated carbon acids and is sterically hindered, allowing good initial kinetic vs. thermodynamic deprotonation ratios. The presence of the sodium counterion also allows for subsequent equilibration to the thermodynamically more stable enolate. More recently, this base has been used in the stereoselective generation of enolates for subsequent alkylation or oxidation in asymmetric syntheses. As shown in eq 1, NaHMDS was used to selectively generate a (Z)-enolate alkylation with lodomethane proceeded with excellent diastereoselectivity. In this case, use of the sodium enolate was preferred as it was more reactive than the corresponding lithium enolate at lower temperatures. 

The reagent has been used for the enolization of carbonyl compounds in a number of syntheses. For ketones and aldehydes which do not have enolizable protons, NaHMDS may be used to prepare the corresponding TMS-imine. ... 

In this event, the addition of 2.1 equivalents of NaHMDS in THF at —78°C converted 17 into a prostereogenic cyclic enolate which then attacked the tartrate-derived dielectrophile 18 with a high level of facial selectivity to generate an intermediate of type 19. Subsequent cyclization was then biased to provide the desired pseudo meso product 20, a compound that was ultimately obtained in 92% yield. In contrast, when the conditions were changed to prevent chelation by using LiHMDS instead of NaHMDS in a solvent mixture of THF and HMPA (hexamethyl-phosphoramide), the C2-symmetric variant of this product (27, see column figures) was formed in 58 % yield. This alternate outcome presumably reflects the preliminary formation of an acyclic lithium dienolate which led to a monoalkylated product corresponding to 26. ... 

Another classic in asymmetric synthesis is Oppolzer s sultam 91 [48], and various JV-acyl derivatives 92 were used - inter alia - for diastereoselective alkylations. Early attempts for enolate generation from amides 92 were plagued by competing deprotonation at carbon 10, adjacent to the sulfonyl group, but regioselective metallation at the a-carbonyl position was achieved by treatment with -butyllithium, LICA, or NaHMDS. The method is applicable not only to the sultam derived from propionic acid 92 (R = Me) but also to substituted and... 

The first report of the use of N-acyl oxazolidinones in asymmetric alkylation was by Evans et al. in 1982. The reactions described were found to proceed with high levels of diastereoselectivity and with very good yields (Table 7.2). The primary factor in determining the stereochemical course of the reaction is the geometry of the enolate intermediate. Studies have shown the level of /Z-enolate control transfers directly to the level of diastereoselectivity of the alkylated product. Conveniently, it has also been established that the use of bulky bases (e.g., EDA and NaHMDS) for the deprotonation of A-acyl oxazolidinones strongly favors formation of the Z-(0)-enolate. Another factor influencing the stereochemical course of the reaction is the nature of the auxiliary itself. In particular, the ability of the... 

Enolates can also be used to assemble bicyclo[4.2.0] octanes (Scheme 19.25). Lee and co-workers treated trien-one 100 with sodium hexamethyldisilazide (NaHMDS) in refluxing 1,2-dimethoxyethane for 12 hours to produce tricyclic product 101 of unspecified stereochemistry in 47% yield. Several features contribute to the interest of this reaction. The 6ti-electrocyclization of the sodium enolate that is derived from 100 evidently does not compete with the 871-electrocyclization. The enolate may facilitate the 8ti-/671-cascade process in a similar way as with the anionic... 

These assumptions were checked using a series of amino ketones 10 prepared from N-tritylated amino acids by the normal route.(7d) These were converted predominantly to the Z-TMS enol ethers 11 with NaHMDS/ TMSC1.(79) A 10 1 ratio of Z,E isomers was evident... 

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