Alkylation diastereoselective synthesis

Consecutive Michael additions and alkylations can also be used for the diastereoselective synthesis of 5- and 6-membered ring systems. For instance when 6-iodo-2-hexenoates or 7-iodo-2-heptenoates are employed the enolate of the Michael adduct is stereoselectively quenched in situ to provide the cyclic compound with trans stereochemistry (>94 6 diastereomeric ratio). As the enolate geometry of the Michael donor can be controlled, high stereoselectivity can also be reached towards either the syn or anti configuration at the exocyclic... 

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates . A-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecatboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <0OJHC13O9>. 

A diastereoselective imine alkylation and a palladium-catalysed biaryl coupling were important steps in the diastereoselective synthesis of 6,7-dihydro-5//-dibenz[c,e]azepines (Scheme 7) starting from (R)-l-(2-methoxyphenyl)ethylamine. Selection for the... 

In 2005, a diastereoselective synthesis of m-3-alkyl-l-benzyl-4-ethoxycarbonyl-[S-1 act a ms has been reported to be developed by galvanostatic electrolysis of a solution of acetonitrile containing a tetraalkylammonium salt, as supporting electrolyte and /V-(ethoxycarbonyl)methyl-/V-benzyl-2-bromoalkylcarboxamides [165]. The electrogenerated cyanomethyl anion, at room temperature and under a nitrogen atmosphere, caused the cyclization of the substituted carboxamides. High cis/trans ratios were observed with all the substrates exploited, (Scheme 68). 

This alkylation strategy has been successfully implemented to the diastereoselective synthesis of a number of biologically active compounds,17 19 32 72 73 including the orally active HIV protease inhibitor Crixivan (>95% de)17-19 and nucleoside antibiotic (+)-sinefungin (51) (>99% de).72 The C-6 amine stereochemistry of (+)-sinefungin was set by a highly diastereoselective allylation of (lS,2/ )-l-amino-2-indanol-derived oxazolidinone 52 (Scheme 24.10). 

In 1986, Evans and colleagues introduced tetramethylammonium triacetoxyboro-hydride, a mild reducing reagent for the highly diastereoselective synthesis of 1,3-anft-diols from acyclic (3-hydroxy ketones1 (Scheme 4.2a). The reaction, commonly called the Evans-Chapman-Carreira reduction, is typically carried out in a 1 1 mixture of anhydrous acetic acid and acetonitrile, as the reaction needs to be run at low temperature in the presence of acetic acid. An important observation is that the anti -diastereoselectivity is realized regardless of the stereochemistry of the a-alkyl substituent Both anti - and. vvn-a.-methyl-(3-hydroxy... 

The substrates are available by diastereoselective alkylation of chiral p-hydroxy acids followed by conversion to the aldehyde and Wittig olefination. The overall process provides a diastereoselective synthesis of compounds with three consecutive asymmetric centers. Tetrahydropyridines.5 Danishefsky has used an intramolecular version of the Giese... 

The method has been applied to the diastereoselective synthesis of naturally occurring compounds such as frontalin (84-100% ee) and(—)-malyngolide (95% ee). On the other hand, diastereoselective alkylation of chiral formylaminal with Grignard reagents and the subsequent hydrolysis afford optically active S-a-hydroxyaldehydes with moderate stereoselectivity (60% ee). ... 

Diastereoselective a-alkylations of acetoacetic acid derivatives <1995T10795> and amino acid aldimines 582 (R = GOG(R )N=GHAr) <1995TL4069> were reported. Tandem Reformatsky and Mannich-type reactions provide an efficient diastereoselective synthesis of /3-amino acids <2006JOG3332>. 

Narumi, T., Niida, A., Tomita, K., et al. (2006) A novel one-pot reaction involving organocop-per-mediated reduction/transmetalation/asymmetric alkylation, leading to the diastereoselective synthesis of functionalized (Z)-fluoroalkene dipeptide isosteres. Chem. Commun., 4720-4722. 

Feroci M, Lessard J, Orsini M, Inesi A (2005) Electrogenerated cyanomethyl anion in organic synthesis a simple diastereoselective synthesis of cis-3-alkyl-l-benzyl-4-ethoxycarbonyl-P-lactams. Tetrahedron Lett 46 8517-8519... 

Note that the diastereoselective synthesis of cis-l,2-dialkyicyclopropanol is considerably improved by using (i-PrOljTiCl or (i-PrO) Ti with RCHjCH MgBr (where R > H). The procedure is further simplified by adding an alkyl bromide to a mixture of the ester, (i-PrOljTiCl, and Mg in THF at room temperature, thus obviating the preparation of the Grignard reagent. In the presence of a chiral TADDOLate, the reaction becomes enantioselective. 

The final fragment is a simple chiral carboxylic acid, so we need a method for its asymmetric synthesis. The most obvious choice is probably an asymmetric alkylation using Evans oxazolidinone auxiliary formation of the appropriate derivative of hexanoic acid is simple, and the enolate will be alkylated diastereoselectively by methyl iodide. You would probably take this approach if you need to make a few grams for initial studies. 

Reductive lithiation of a diastereoisomeric mixture (dr 92 8) of the bicyclic 2-phenyl-l,3-oxazolidine 189 followed by alkylation allowed the highly diastereoselective synthesis of N-(a-alkyl-substituted)benzyl-2-hydroxymethylpiperidines 190 and 191 <01TL129>. 

Only recently, the diastereoselective synthesis and preparative separation of the enantiomers of galaxolide (Givaudan) have been described. [169] The titanium tetrachloride-catalysed Friedel-Crafts alkylation of 1,1,2,3,3-pentamethylin-dane with (S)-propylene oxide produces two epimeric alcohols (whereby no racemisation is observed) with paraformaldehyde and catalytic amounts of sulfuric acid, these are converted into the desired isochroman diastereomers. The separation of the epimers is accomplished by means of the corresponding chro-... 

A multigram-scale diastereoselective synthesis of 1,2-dioxanes involved a Mn(III)-promoted [2 + 2 + 2] cycloaddition reaction of P-keto esters, 1,1-disubstituted alkenes, and molecular oxygen (14EJO1607). The same catalyst was used in the aerobic oxidation of 3-alkyl-substituted pyrrolidin-ediones in the presence of 1,1-diarylethenes to provide 1,2-dioxane derivatives in high yields (Scheme 83) (14JHC579). 

The scope of the ruthenium-catalysed asymmetric transfer hydrogenation methodology was very recently extended to a-alkyl-substituted )S-ketoamides by Limanto et Indeed, the first enantio- and diastereoselective synthesis of various syn a-alkyl-substituted jS-hydroxyamides via highly efficient Ru-cata-lysed hydrogenation through DKR of the corresponding ) -ketoamides has been successfully demonstrated. As shown in Scheme 2.31, excellent diastereo-and enantioselectivities of up to 98% de and > 99% ee, respectively, were observed when the process was performed in CH2CI2 or toluene as the solvent. 

Diastereoselective synthesis of a-aminophosphinates has been achieved by alkylation of iminomethylenephosphinates possessing a (l,l-diethoxyethyl)phosphinyl moiety. The feature of the synthesis is high diastereoselective control by the asymmetric phosphorus atom. The asymmetric addition of diethylzinc to A -diphenylphosphinoylimines afforded Ai-diphenylphosphinoylamides with enan-tioselectivity of up to 90% ee in the presence of a catalytic amount of chiral ligand (S)-iV-ferrocenoyl-2-[(diphenylphosphino)methyl]pyrrolidine (244) and Cu(OTf)2. ... 

Alkyl, cycloalkyl, arylalkyl acids and their derivatives. A facile, diastereoselective synthesis of highly functionalized y-lactone phosphonate esters (76) has been achieved in the reaction of trifluoromethylated-1,3-diones with dimethyl acetylenedicarboxylates in the presence of triphenyl... 

Both cis (10) and irons diastereoisomers of aryl and alkyl chiral oxazolidine sulfonium salts derived from (-)-(/ )-2-phenylglycinol have been demonstrated to be good to excellent chiral auxiliaries for the diastereoselective synthesis of (2/ ,35)-tra j -epoxyamides (11, Scheme A) The diastereoselective outcome depends on the stereochemistry of the chiral centre at the C(4) position of the oxazole moiety (<98% de with R configuration). 

A two-step approach for the diastereoselective synthesis of 4-carboxymethyl-3-alkyl (aryl)oxazolidin-2-ones (391) which proceeds via the intermediate formation of carboxy-methyl-3-alkyl(aryl)-tV-r-butoxycarbonylaziridines (390), has been described " see... 

Alkyl allenoates react with diaryl 1,2-diones in the presence of phosphine, leading to the diastereoselective synthesis of fully substituted cyclopentenones (Scheme 6.10). It may be mentioned that 4-hydroxycyclopentenones are of pharmacological importance [12]. 

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