Iterative asymmetric allylic substitutions: syn- and anti-1,2-diols through catalyst control

A copper-catalyzed asymmetric allylic boronation (AAB) gives access to syn- and anti-1,2-diols. The method facilitates an iterative strategy for the preparation of polyols, such as the fully differentiated L-ribo-tetrol and protected D-arabino-tetrol. P=protecting group.     

Concise asymmetric synthesis of (+)-CP-99,994 and (+)-L-733,060 via efficient construction of homochiral syn-1,2-diamines and syn-1,2-amino alcohols

An efficient asymmetric synthesis of human NK-1 SP receptor antagonists (+)-CP-99,994 and (+)-L-733,060 was achieved starting from a common chiral intermediate (5). Our route featured the SmI2-induced reductive coupling of N-tert-butanesulfinyl imine (7) with aldehyde (6) as the key step as well as pivotal transformations of the anti-1,2-amino alcohol thus obtained to homochiral syn-1,2-amino alcohol and syn-1,2-diamine for the asymmetric synthesis of 2,3-disubstituted piperidines.     

Regio- and stereochemically controlled formation of hydroxamic acid containing anti- or syn-1,4-cycloalkenols from acylnitroso-derived Diels-Alder adducts

Treatment of acylnitroso hetero Diels-Alder cycloadducts 2 with iron(III) or copper(II) in an alcohol solvent induces ring opening to afford predominantly monocyclic anti-1,4-hydroxamic acids 3. However, treatment of cycloadducts 2 with copper(II) in toluene reverses the stereoselectivity of the ring opening to afford syn-1,4-hydroxamic acids 4. These regio- and stereoselective processes separately provide anti-1,4- and syn-1,4-disubstituted cyclopentenes while regenerating a hydroxamic acid moiety, thus enhancing the chemical versatility of the Diels-Alder cycloadducts.     

Single route to chiral syn- and anti-2-amino-1,2-diphenylethanols via a new stereodivergent opening of trans-1,2-diphenyloxirane

Oxiranyl ring opening of trans-stilbene oxide gave rise to anti- or syn-2-bromo-1,2-diphenylethanols, using either MgBr(2).Et(2)O or MgBr(2).Et(2)O, NaBr, and KBr with Amberlyst 15, respectively. Starting from optically pure (R,R)-trans-stilbene oxide, (1R,2R)- and (1R,2S)-2-amino-1,2-diphenylethanols were obtained in high yield and ee.     

anti-1,2-Diols via Ni-catalyzed reductive coupling of alkynes and alpha-oxyaldehydes

[reaction: see text] Ni-catalyzed reductive coupling of aryl alkynes (1) and enantiomerically enriched alpha-oxyaldehydes (2) afford differentiated anti-1,2-diols (3) with high diastereoselectivity and regioselectivity, despite the fact that the methoxymethyl (MOM) and para-methoxybenzyl (PMB) protective groups typically favor syn-1,2-diol formation in carbonyl addition reactions of this family of aldehydes.     

Asymmetric synthesis of syn- and anti-1,3-amino alcohols

The first application of metalloenamines derived from N-sulfinyl imines is reported for the highly diastereoselective addition to aldehydes. Reduction of the beta-hydroxy-N-sulfinyl imine products with catecholborane and LiBHEt3 provides syn- and anti-1,3-amino alcohol derivatives, respectively, with very high diastereomeric ratios.     

Diastereomer-differentiating hydrolysis of 1,3-diol-acetonides: a simplified procedure for the separation of syn- and anti-1,3-diols

[reaction: see text] A new method to facilitate the separation of diastereomeric syn- and anti-1,3-diols is described. The method relies on the different hydrolysis rates of the corresponding diastereomeric acetonides. Treatment of a dichloromethane solution of syn- and anti-1,3-diol-acetonide with a catalytic amount of diluted aqueous hydrochloric acid leads to the selective cleavage of the anti diastereomer. The resulting anti-1,3-diol can be easily separated from the unchanged syn-1,3-diol-acetonide.     

Iterative Cr-mediated catalytic asymmetric allylation to synthesize syn/syn- and anti/anti-1,3,5-triols

Iterative use of Cr-mediated catalytic asymmetric allylation could give a simple access to 1,3-polyols. Using syn/syn- and anti/anti-1,3,5-triols as representative examples, the feasibility of this approach is studied, thereby demonstrating that (1) the pre-existing TMS-protected alcohol at the beta-position does not give a significant effect on the Cr-mediated catalytic asymmetric allylation and (2) this synthetic route furnishes the expected syn/syn- and anti/anti-1,3,5-triols at the useful level of asymmetric induction and yield.     

Stereocontrolled route to vicinal diamines by [3.3] sigmatropic rearrangement of allyl cyanate: asymmetric synthesis of anti-(2R,3R)- and syn-(2R,3S)-2,3-diaminobutanoic acids

A stereocontrolled route via allyl 1,2-diols to vicinal diamines based on the [3.3] sigmatropic rearrangement of allyl cyanate has been developed. Our approach consists of two consecutive steps: stereoselective construction of allyl anti- and syn-1,2-diols followed by [1,3]-chirality transfer by sigmatropic rearrangement, which allow an access to anti-(2R,3R)- and syn-(2R,3S)-2,3-diaminobutanoic acids. [reaction: see text]     

Development and application of a new general method for the asymmetric synthesis of syn- and anti-1,3-amino alcohols

A general method is described for asymmetric synthesis of both syn- and anti-1,3-amino alcohols. The first application of metalloenamines derived from N-sulfinyl imines is reported for the highly diastereoselective addition to aldehydes. The reduction of the product beta-hydroxy N-sulfinyl imines 2 with catecholborane and LiBHEt(3) provides syn- and anti-1,3-amino alcohols with very high diastereomeric ratios. This method was found to be effective for a variety of substrates incorporating either aromatic or various aliphatic substituents. The convergent and efficient asymmetric syntheses of the two natural products, (-)-8-epihalosaline and (-)-halosaline, were also accomplished.     

Highly stereoselective syntheses of syn- and anti-1,2-amino alcohols

The reduction of N-protected amino ketones can be carried stereoselectively to produce either the syn- or anti-amino alcohol diastereomer. Carbamate-protected amino ketones can be reduced predictably and selectively to anti-amino alcohols with LiAlH(O-t-Bu)3 in ethanol at -78 degrees C. N-Trityl-protected amino ketones can be reduced selectively to syn-amino alcohols with LiAlH(O-t-Bu)3 in THF at -5 degrees C.     

Regio- and stereochemically controlled formation of hydroxamic acids from indium triflate-mediated nucleophilic ring-opening reactions with acylnitroso-Diels-Alder adducts

Treatment of acylnitroso-Diels-Alder [2.2.1] bicyclic adducts 2a-b with indium triflate in an alcohol solvent induces ring-opening reactions to afford monocyclic anti-1,2-, anti-1,4-, and syn-1,4-hydroxamic acids with good to excellent regio- and stereoselectivity (up to 7:86:7). Treatment of [2.2.2] bicyclic nitroso adducts 2c-d under similar reaction conditions generates only anti-1,2- and anti-1,4-hydroxamic acids with anti-1,4-product being predominant (up to 17:83).     

Asymmetric synthesis of anti- and syn-2,3-diamino esters using sulfinimines. Water and concentration effects

[reaction: see text] In the absence of water, an excess of the lithium enolate of N-(diphenylmethylene)glycine ethyl ester (4) adds to sulfinimines to give syn-2,3-diamino esters 6, and in the presence of water, this enolate gives the anti-2,3-diamino esters 5. These unusual results are interpreted in terms of those factors that inhibit the retro-Mannich fragmentation in the diamino esters.     

Three Component syn-1,2-Arylmethylation of Internal Alkynes**

A Pd-catalyzed three-component syn-1,2-arylmethylation of internal alkynes (ynamides/yne-acetates/alkynes) is described. The readily available and bench stable coupling partners iodo-arenes, and methyl boronic acid are successfully used in this coupling strategy to access the methyl-containing tetra-substituted olefins; the scope is broad showing excellent functional-group tolerance. Notably, the transformation is regio- as well as stereoselective. The biologically relevant motifs (BRM) bearing iodo-arenes and ynamides are also used for the late-stage syn-1,2-arylmethylation of alkynes. Aryl-alkylation, aryl-trideuteriomethylation, alkynyl-methylation, and alkenyl-methylation of ynamides are also presented. The Me-substituted alkenes are further transformed into synthetically important β-amino-indenones and α-fluoro-α′-methyl ketones.     

Pressure independence of stereomutation and fragmentation in the bis-spirocyclobutanes, anti- and syn-2,9-dicyanodispiro[5.0.5.2]tetradeca-1,8-dienes

Pressure dependent rate constants and volumes of activation for stereomutational interconversions of the cyclobutanes, anti- and syn-2,9-dicyanodispiro[5.0.5.2]tetradeca-1,8-dienes (anti-6 and syn-6), and for their fragmentation to 1-cyano-3-methylenecyclohexene (5) have been determined. Although fragmentations might have been expected to have larger and thus more positive volumes of activation than stereomutation, both processes have essentially identical volumes of activation within experimental uncertainties at 50.1 degrees C over the pressure range, 1-3000 bar: DeltaV(not equal) = (+7.4 to +9.9) +/- 2.0 cm3 mol(-1). While these positive values are consistent with the rate of entry into the hypothetical caldera being determined by breaking the weakest bond in the cyclobutanes, the insensitivity of the product-determining exit channels argues against the obligatory second bond-breaking being a significant factor in fragmentation.     

Stereoselective synthesis of 1,2-disubstituted beta-amino alcohols by nucleophilic addition to N-tert-butanesulfinyl alpha-alkoxyaldimines

N-tert-Butanesulfinyl alpha-alkoxyaldimines are readily prepared from protected (S)-lactals without epimerization at the alpha-stereocenter. Addition of ethyl and phenyl Grignard reagents, as well as the titanium enolate of methyl acetate, to the N-tert-butanesulfinyl aldimines provides 1,2-disubstituted beta-amino alcohols in good yields (73-98%) and with high diastereoselectivities. Either syn- or anti-amino alcohol products can be obtained by the appropriate choice of alcohol protecting groups and/or reaction conditions. Finally, deprotection of the addition products provides straightforward access to either syn- or anti-1,2-amino alcohols.     

Gem-difluorinated homoallyl alcohols, beta-hydroxy ketones, and syn- and anti-1,3-diols via gamma,gamma-difluoroallylboronates

Gamma,gamma-difluoroallylboronates have been prepared from trifluoroethanol and utilized for the allylboration of a variety of aldehydes to provide gem-difluorinated homoallylic alcohols. Alpha-chiral aldehydes were allylborated in 4:1-13:1 diastereoselectivity favoring the anti-isomer. A representative series of difluorinated hydroxyl enol ethers were converted to the corresponding alpha,alpha-difluoro-beta-hydroxy ketones. Diastereoselective reduction of one of these to either syn- and anti-1,3-diol was also studied.     

An efficient, stereoselective approach to syn-1,2-diols protected as cyclic carbonates

Enantioenriched 4-hydroxyalk-2-ynyl carbonates (or benzoates) have been prepared by stereoselective zinc-mediated addition of alkyl 2-propynyl carbonates (or their benzoate analogues) to aldehydes. Their partial reduction to Z-olefins followed by cyclization under mild Pd-catalyzed conditions allowed a straightforward access to enantioenriched syn-1,2-diols protected as cyclic carbonates.     

Synthesis of enantiomerically pure anti-1,2-diaryl and syn-1,2-alkylaryl vic-selenoamines

Phenylselenyl benzylcarbanion stabilized by an (S)-2-p-tolylsulfinyl group evolves in a highly stereoselective way in the reactions with (S)-N-(p-tolylsulfinyl)imines at -98 °C affording diastereomerically pure 1,2-selenoamino derivatives in good yields. The syn or anti relationship of the obtained compounds depends on the alkyl or aryl character of the imine. They are easily transformed into enantiomerically pure (1R,2S)-1-aryl[or (1S,2S)-1-alkyl]-2-(phenylseleno)-2-phenylethylamines by reaction with t-BuLi and subsequent methanolysis of the generated sulfinamide derivatives with TFA.     

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.