Catalytic asymmetric synthesis of both syn- and anti-3,5-dihydroxy esters: application to 1,3-polyol/alpha-pyrone natural product synthesis

[reaction: see text] We describe a catalytic asymmetric synthesis of both syn- and anti-3,5-dihydroxy esters. The method relies upon catalytic asymmetric epoxidation of alpha,beta-unsaturated imidazolides and amides, using lanthanide-BINOL complexes, and diastereoselective reduction of ketones. The method was applied to the enantioselective syntheses of 1,3-polyol/alpha-pyrone natural products 9a, 9b, and strictifolione (10). The absolute stereochemistry of 9a and 9b was also determined.     

Unusual regioselection in the Mitsunobu reactions of syn-2,3-dihydroxy esters: synthesis of statine and its diastereomer

Mitsunobu reactions of syn-2,3-dihydroxy esters exhibit a complete regioselection for the beta-hydroxyl group. Benzoylation, azidation, and tosylation have been performed under these conditions. Beta-functionalizations of syn-2,3-dihydroxy esters are uncommon, and the Mitsunobu reactions are complementary to other diol chemistries in the regioselection. In addition, the configurational inversion accompanying the Mitsunobu protocol offers a means for diastereochemical diversity, as exemplified by a synthesis of statine and its anti diastereomer. These findings will further expand the synthetic utilities of the Sharpless AD process.     

Biomimetic oxidation of 3,5-di-tert-butylcatechol by dioxygen via Mn-enhanced base catalysis

The 6-coordinate dioximatomanganese(II) complex [Mn(HL)(CH3OH)]+ (2, where H2L is [HON=C(CH3)C(CH3)=NCH2CH2]2NH), formed by instant solvolysis of [Mn2(HL)2](BPh4)2 (1) in methanol, accelerates the triethylamine (TEA)-catalyzed oxidation of 3,5-di-tert-butylcatechol (H2dtbc) by O2 to the corresponding o-benzoquinone. Significantly, 2 alone has no catalytic effect. The observed rate increase can be explained by the interaction of 2 with the hydroperoxo intermediate HdtbcO2- formed from Hdtbc- and O2 in the TEA-catalyzed oxidation. The kinetics of the TEA-catalyzed and Mn-enhanced reaction has been studied by gas-volumetric monitoring of the amount of O2 consumed. The initial rate of O2 uptake (V(in)) shows a first-order dependence on the concentration of 2 and O2 and saturation kinetics with respect to both H2dtbc and TEA. The observed kinetic behavior is consistent with parallel TEA-catalyzed and Mn-enhanced oxidation paths. The 3,5-di-tert-butylsemiquinone anion radical is an intermediate detectable by electron spin resonance (ESR) spectroscopy. The dimeric catalyst precursor has been characterized by X-ray diffraction and electrospray ionization mass spectrometry and the monomeric catalyst by ESR spectroscopy.     

Highly enantioselective hydrogenation of 3,5-diketo esters: a formal synthesis of tetrahydrolipstatin

Compound 4, obtained via a sequence of two consecutive alkylations of methyl 3,5-dioxohexanoate (5), was transformed into the enantiomerically pure lactone (3S,4S,6R)-2 being the precursor of tetrahydrolipstatin (1). The reaction sequence involves asymmetric catalytic hydrogenation of 4 as a crucial step.     

Expeditious synthesis of phenanthridines from benzylamines via dual palladium catalysis

A method for the synthesis of phenanthridines from benzylamines and aryl iodides which uses a dual palladium-catalyzed process is developed. The domino sequence ends via an intramolecular amination and an oxidative dehydrogenation. No protecting group or prefunctionalization of the amine is required, and the process uses dioxygen as the terminal oxidant.     

A highly enantioselective and diastereoselective synthesis of cyclobutanes via boronic esters

[formula: see text] Deprotonation of enantiopure (R,R)-1,2-dicyclohexyl-1,2-ethanediol 1-chloro-4-cyanobutylboronates 5 with LDA followed by treatment with anhydrous magnesium bromide yields (R)-(trans-2-cyanocyclobutyl)boronic esters 7 in high diastereomeric and enantiomeric purity. No cyclobutane formation has been observed in the absence of at least a catalytic amount of magnesium halide.     

An enantioselective synthesis of nitrogen protected 3-arylserine esters

A method for the preparation of (2R,3S) nitrogen protected arylserine esters is described. The method consists of rhodium mediated insertion of tert-butylcarbamate into the corresponding 3-keto-2-diazoester, affording the N-protected α-amino-β-ketoester, followed by asymmetric reduction/dynamic resolution to afford the corresponding N-protected 3-arylserine esters in good chemical yield, and in most cases high enantiomeric excess.     

Concise enantioselective synthesis of 3,5-dialkyl-substituted indolizidine alkaloids via sequential cross-metathesis-double-reductive cyclization

An efficient stereoselective synthesis of two 3,5-dialkyl-substituted indolizidine alkaloids is reported. The convergent syntheses are based on a novel sequence of a cross-metathesis (CM) reaction of an alpha,beta-unsaturated ketone and a chiral homoallylic amine followed by a domino reaction involving hydrogenation, N-deprotection, and two diastereoselective reductive aminations. Our concept presents one of a few examples of a highly selective CM reaction in the synthesis of a natural product.     

One-pot synthesis of optically active allyl esters via lipase-vanadium combo catalysis

The combination of vanadium-oxo compounds (3 or 4) with a lipase produced the regio- and enantioconvergent transformation of racemic allyl alcohols (1 or 2) into optically active allyl esters. In this system, the vanadium compounds catalyzed the continuous racemization of the alcohols along with the transposition of the hydroxyl group, while the lipase effected the chemo- and enantioselective esterification to achieve the dynamic kinetic resolution.     

Practical enantioselective synthesis of beta-substituted-beta-amino esters

[reaction: see text] A practical, large-scale synthesis of a beta-amino ester 1 was developed. A chiral imine derived from (S)-phenylglycinol and 3-trimethylsilylpropanal was coupled with the Reformatsky reagent 3 with high diastereoselectivity (de > 98%) to give (SS)-4a as the major isomer. The amino alcohol residue of the coupling product 4 was oxidatively cleaved with sodium periodate in the presence of methylamine. An unusual selective oxidative cleavage of the (SS)-isomer was observed and the imine 6 was obtained with ee > 99% while the (RS)-4b isomer was not cleaved. Reaction with p-toluenesulfonic acid monohydrate allowed for the hydrolysis of the imine and the isolation of the amine as its salt. The title compound 1 was then obtained by transesterification, desilylation, and hydrochloride salt formation in a one-pot process. The method was successfully applied toward the synthesis of a wide variety of beta-amino esters.     

De novo synthesis of galacto-sugar δ-lactones via a catalytic osmium/palladium/osmium reaction sequence

A highly efficient route to various 1,5-galacto-sugar lactones from dienoates has been developed by using three catalytic reactions. These reactions include (i) an enantioselective osmium-catalyzed dihydroxylation, (ii) a regio- and diastereoselective palladium-catalyzed π-allyl alkylation with p-methoxyphenol for alcohol differentiation and protection, and (iii) a diastereoselective dihydroxylation that can be improved using matched enantioselective osmium-catalyzed dihydroxylation condition.     

An enantioselective route to alpha-methyl carboxylic acids via metal and enzyme catalysis

Dynamic kinetic resolution of allylic alcohols to allylic acetates followed by copper-catalyzed allylic substitution gave alkenes in high yields and high optical purity. Subsequent oxidative C-C double bond cleavage afforded pharmaceutically important alpha-methyl substituted carboxylic acids in high ee.     

A short enantioselective synthesis of (+)-L-733,060 via Shi epoxidation of a homoallylic carboxylate

A short and efficient enantioselective synthesis of (+)-L-733,060 in 92% ee via Shi epoxidation of a homoallylic carboxylate is described. Johnson-Claisen rearrangement was employed to obtain the required carbon backbone, whilst intramolecular reductive O-to-N-ring expansion of a δ-azidolactone was used in the construction of the piperidine moiety.     

A highly enantioselective chemoenzymatic synthesis of syn-3-amino-2-hydroxy esters: key intermediates for taxol side chain and phenylnorstatine

Starting from the bromination of α-ketoesters to obtain 3-bromo-2-oxoalkanoates and bioreduction with Saccharomyces cerevisiae entrapped in calcium alginate pellets with double gel layers, syn-(2R,3S)-β-bromo-α-hydroxy esters were obtained regioselectively in high yields and high ee. These chiral bromohydrins were cyclized to epoxides that were transformed into oxazolidines and finally opened by acidic hydrolysis to give syn-(2S,3S)-β-amino-α-hydroxy esters in high overall yields and high ee. The enantiomeric excesses of all the intermediates were maintained during the reaction sequence.     

A remarkably efficient synthesis of pure cis-stilbenoid hydrocarbons using trans-dibromoalkenes via palladium catalysis

A remarkably versatile synthesis of cis-stilbenoid hydrocarbons containing highly functionalized phenyl groups is developed via an efficient palladium-catalyzed coupling of aryl Grignard reagents with trans-1,2-dibromoalkenes (generally obtained via bromination of the corresponding dialkylacetylenes) in tetrahydrofuran.     

An efficient enantioselective synthesis of florfenicol via asymmetric aziridination

An efficient enantioselective synthesis of florfenicol is accomplished in 44.7% overall yield from commercially available p-(methylsulfonyl)benzaldehyde. Key features of this synthesis are the asymmetric aziridination reaction mediated by the Wulff’s catalyst in situ derived from (R)-VANOL and diastereoselectively ring-opening of (2S,3S)-fluoroaziridine 13.     

Highly efficient and economic synthesis of new substituted amino-bispyridyl derivatives via copper and palladium catalysis

A convenient route for the synthesis of a variety of amino-bispyridyl compounds is introduced. Bispyridylamines were prepared in three steps from commercially available 2,6-dibromopyridine, via a copper mediated alkylation followed by two consecutive N-arylation reactions catalyzed by copper and palladium, respectively.     

Formation of bi-aryls via a domino palladium catalysis

Synthesis of bi-aryls via a domino Pd-catalyzed reaction of 1-(2-bromophenyl)-2-methylpropan-1-ones/(2-bromophenyl)(cyclohexyl)methanones is presented. The mechanism of the reaction is believed to proceed through a five membered palladacycle that combines with a second molecule of halo-arene to yield the bi-aryls. This method is quite successful to deliver highly sterically crowded bi-aryls with dense functionalities on the aromatic rings.     

N-arylation of carbamate-protected glycine derivatives via palladium catalysis

A synthesis of N-aryl and N-heteroaryl amino acid derivatives using palladium catalysis is described. Several carbamate-protected glycine derivatives react with aryl and heteroaryl halides using a palladium/Xantphos catalyst system to access the desired synthons.