Synthons allylic alkylation

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

Rhodium-catalyzed allylic alkylation provides an expeditious entry into a variety of useful synthons for asymmetric synthesis. For example, the application of this reaction to a range of enantiomerically enriched allylic carbonates with the sodium salt of methyl phenylsulfonylacetate provides products that represent important synthons for target-directed synthesis (Tab. 10.1) [17]. 

The allylic alkylation products represent useful synthons, as exemplified by the reaction sequence outlined in Scheme 10.4. For example, reductive ozonolysis of the allylic alkylation product 15 afforded the y-lactone 16 as a single diastereoisomer. Sequential alkylation with methyl iodide, and reductive alkylation using lithium naphthalenide with allyl iodide furnished the ternary-quaternary substituted y-lactones 17a/17b in 72% overall yield, as a 10 1 mixture of diastereomers favoring 17a [18]. This method provides a versatile approach to the construction of a variety of a-quaternary-/9-ternary stereogenic centers. 

Ketones. The reagent (1) is a propenoyl anion synthon. After alkylation, enones are released. On the other hand, the adducts undergo allylic displacement with Grignard reagents, and on hydrolytic workup, ketones are formed. The possibility of creating a-bromoalkyl ketones, 1,4-diketones, 2-ethoxy-2-cyclopentenones, and a-keto enamines bespeaks for the versatility of this synthesis. 

Meyers lactams are widely used in synthesis of substituted synthons of interest and their functionalization is carried out under strong base conditions giving C-alkyl derivatives. Alkylation of bicyclic lactam 182 with electrophiles (alkyl, allyl, benzyl halides, chlorophosphonate), and a strong base (j-BuLi, LiHMDS, or KHMDS HMDS = hexamethyldisilazide) in THF at — 78 °C gave an endo-exo mixture of products where the major one is the rro/o-compound 183 in good yields. The ratios were determined by H NMR spectroscopy and are usually up to... 

Therefore, taking into account the potentialities of such lactones as carbohydrate delivery synthons (vide infra), several routes leading to carboxymethyl glycosides (and thus subsequently to the lactones) were investigated, in order to get as many structural variations as possible for widening the scope of their use in synthesis. In addition to the isomaltulose oxidation method (route a), the oxidation of allyl glycosides (route b), and the anomeric alkylation with tert-butylbromoacetate (route c) were studied (Scheme 11). These three methods are detailed in the following sections. 

The anion of 2-(methoxyethoxymethoxy)cyclopropyl phenyl sulfone (methoxyetho-xymethoxy = MEM) is a d -synthon for a,)8-unsaturated aldehydes ". The anion is readily formed by treating 2-(MEM)cyclopropyl phenyl sulfone (359) with n-butyllithium in THE at — 78°C. Treatment of the anion 360 with aliphatic primary bromides or allyl bromide produces the alkylated sulfone 361 in very good yields. Hydrolysis of the MEM-protecting group was readily performed by treatment with aqueous tetrafluoroboric acid to furnish the cyclopropanol sulfone (362). Treatment with aqueous sodium bicarbonate produced the corresponding aldehydes 363 in 70-90 % yields. 

The alkoxydi(sulfonyl)methane shown in Scheme 128 (entry b) has been used as a useful carbonyl 1,1-dipole synthon ( C°-0). Its alkylation with alkyl halides is best achieved using CS2CO3 in DMF at 50 °C, and its palladium-catalyzed allylation requires the use of phase-transfer conditions (Scheme 128, entry b). The unmasking of the carbonyl group was then achieved by reacting the resulting disulfone with boron trichloride (-78 C, CH2CI2) followed by the addition of alcohols or amines to provide esters or amides respectively (Scheme 128, entry b). ... 

Some of the first syntheses of the leukotrienes involved alkynes as intermediates, since these are excellent synthons for the stereospecific formation of alkenes. The alkylation with the allyl bromide occurred quite late in the Merck-Frosst synthesis of 5-HETE (Scheme 43). ... 

By photolyzing a solution of the allyl aryl sulfoxide at slightly elevated temperature at appropriate wavelengths, allyloxy radicals were produced from photolysis of the steady state concentration of the sulfenate. Another study examined the regioselectivity of addition of the alkyl and sulfenyl radicals across olefins and allenes [155], Control of these elements allowed potentially useful synthetic transformations to be designed [156], particularly as the sulfenate may be viewed as an O-H abstraction synthon . 

Notable new general syntheses of butenolides include the addition of the three-carbon synthon Li(PhS)C=CMeC02Me to aldehydes R CHO (R = alkyl or aryl) to yield the thioethers (19), the related reaction of lithio-j8-lithio-acrylates R CLi=CR C02Li with benzaldehyde to give compounds (20 R = H or Me), and the formation of (21) from the iodinated allyl alcohol ICMe=CHCH20H and carbon monoxide in the presence of bis(triphenylphos-phine)palladium(ii) chloride. Chloral reacts with dimethyl (benzylamino)fu-marate to yield the butenolide (22), whereas aromatic aldehydes give hydroxy-pyrrolinones (23). The total synthesis of piperolide (24) has been reported. 

We have developed a completely new synthesis of chiral aldols 12 by formal enantioselelective connection of a C-0 and a C-C bonding at the C3-position of a homoenolate dianion synthon 11 (Scheme 1). Because the natural polarity of the reactants is reversed twice the direct approach is not possible. Therefore we used the allyl amine 1 and enamine 2 as excellent synthesis equivalents of homoenolates, which can be silylated and alkylated, respectively (Scheme 2). 

The mixed vinyl acetylene cuprate (435) has been developed as an ethyl acrylate synthon. Whereas (435) does not react with alkyl bromides and iodides, it is reactive towards allylic (and propargylic) bromides, as exemplified by its reaction with 3-bromo-... 

The synthesis of both R)- and (5)-enantiomers of 4,4,4-trifluoro-3-methyl-1-butanol (19,20) by Jacobs et al. [54] as building blocks for leuko-triene antagonists Scheme 5.12), demonstrates how oxazolidinone auxiliaries (21) and (22), derived from L-valine and (lS,2/ )-norephedrine, respectively, impart complementary selectivity in alkylation of chelated (Z)-enolates. Similarly, Trova et al. [55] have utilized the iV-acyl oxazolidinone (23), from L-phenylalanine and 3-phenylpropanoyl chloride, for the construction of diastereomeric lactones (24) and (25) as synthons for HIV-1 protease inhibitors Scheme 5.12). Following allylation and hydrolytic removal of the auxiliary, stereocomplementary iodolactonization reactions of... 

An easy synthesis of the ergoline synthon 274 has been described by Genet and Grisoni.f i The key step involved C-5/C-6 intramolecular alkylation of allylic nitro compounds. The starting aldehyde 275 was submitted to a Homer-Einmons reaction with... 

Malonic acid labeled with carbon-14 at C2 or at Cl,3 and the corresponding mono- and diesters have become important and highly versatile building blocks for the synthesis of a broad range of labeled compounds, such a,/3-unsaturated acids and esters, cycloalkanes, 8-keto esters, a-amino acids, phenols, dihydropyridines/pyridines, pyrimidines and quinolines. In addition, they are widely used as acetic acid synthons ( CH2COOR CHCOOR) for the extension of carbon chains of alkyl, allyl and benzyl halides as well as of saturated and a,)8-unsaturated carbonyl compounds. This Section discusses aU malonates, wherever labeled, and unlabeled malonates used with carbon-14-labeled reaction partners. However, it is the [2- " C]malonates that have been most often used in radiochemical synthesis. 

Optically active epoxides are useful chiral synthons in the phamaceutical synthesis of prostaglandins. Microbial epoxidation of olefinic compounds was first demonstrated by van der Linden [241]. Subsequently, May et al. [242] demonstrated the epoxidation of alkenes in addition to hydroxylation of alkanes by an m-hydroxylase system. Oxidation of alk-l-enes in the range C6-C12, a,(o-dienes from C6-C12, alkyl benzene, and allyl ettiers were demonstrated using an co-hydroxylase enzyme system from Pseudomonas oleovorans. i -Epoxy compounds in greater than 75% e.e. were produced by epoxidation re tions using the co-hydroxylase system [243,244]. The epoxidation system from Nocardia cor-allina is very versatile, has broad substrate specificity, and reacts with unfunctionalized aliphatic as well as aromatic olefins to produce i -epoxides [245,246]. 

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