Enamines from terminal epoxides and hindered lithium amides

A new reactivity mode of lithium amides with epoxides leads to hindered enamines. The reaction of some of these enamines with unactivated primary and secondary alkyl halides is described, which expands the range of electrophiles that one can use in the synthesis of mono-alkylated aldehydes.     

A New Route to 1,3-Dienes: TMSI Elimination of 2-Ene-1,4-diols

Iodotrimethylsilane effects conversion of acyclic bis-secondary 2-ene-1,4-diols to 1,3-dienes in moderate yield. The reaction with 3-hexene-2,5-diol favors anti elimination but is largely nonstereospecific.     

Substituted epoxides by lithiation of terminal epoxides

Diamine-ligand-assisted direct hydrogen-lithium exchange allows the generation of nonstabilized (H-substituted) oxiranyllithium species and their subsequent trapping by Bu(3)SnCl and carbonyl-based electrophiles. This reaction provides a new concise route to alpha,beta-epoxystannanes and substituted epoxides.     

Alkenes from terminal epoxides using lithium 2,2,6,6-tetramethylpiperidide and organolithiums or grignard reagents

E-Alkenes (including arylated alkenes, dienes, and allylsilanes) are efficiently prepared by alpha-deprotonation of terminal epoxides using lithium 2,2,6,6-tetramethylpiperidide, followed by in situ trapping with organolithiums or Grignard reagents.     

Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen)Co(III) complexes. Practical synthesis of enantioenriched terminal epoxides and 1,2-diols

The hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by chiral (salen)Co(III) complex 1 x OAc affords both recovered unreacted epoxide and 1,2-diol product in highly enantioenriched form. As such, the HKR provides general access to useful, highly enantioenriched chiral building blocks that are otherwise difficult to access, from inexpensive racemic materials. The reaction has several appealing features from a practical standpoint, including the use of H(2)O as a reactant and low loadings (0.2-2.0 mol %) of a recyclable, commercially available catalyst. In addition, the HKR displays extraordinary scope, as a wide assortment of sterically and electronically varied epoxides can be resolved to > or = 99% ee. The corresponding 1,2-diols were produced in good-to-high enantiomeric excess using 0.45 equiv of H(2)O. Useful and general protocols are provided for the isolation of highly enantioenriched epoxides and diols, as well as for catalyst recovery and recycling. Selectivity factors (k(rel)) were determined for the HKR reactions by measuring the product ee at ca. 20% conversion. In nearly all cases, k(rel) values for the HKR exceed 50, and in several cases are well in excess of 200.     

Enantioselective preparation of C2-symmetrical 1,4-diols

The catalytic enantioselective addition of functionalized dialkylzincs to the γ-alkoxyaldehydes 5, 6 and 7 provides 1,4-diols 1–3 with 73–99 %ee. After a simple reaction sequence, these diols are converted to chiral γ-alkoxyaldehydes which undergo a second catalytic enantioselective addition of the same diorganozinc providing C₂-symmetrical 1,4-diols 10a–f with excellent diastereoselectivity (up to 97 : 3).     

Stereoselective dimerization of 3-arylisoxazoles to cage-shaped bis-β-lactams syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.0]octan-4,8-diones induced by hindered lithium amides

3-Arylisoxazoles react with hindered lithium amides giving syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.0^2,5]octan-4,8-diones in good to fair yields. Stereochemistry of the so-obtained cage-shaped bis-β-lactams was assigned by X-ray diffraction analysis. Concerning the mechanism of formation of such hitherto unknown molecules, dimerization of an azetinone anion intermediate stereoselectively induced by Li⁺ chelation is suggested.     

Hydroamination of cinnamyl alcohol using lithium amides

Hydroamination of cinnamyl alcohol is possible by reaction with lithium amides derived from primary or cyclic secondary amines.     

Highly stereoselective approach to alk-2-yne-1,4-diols by oxazaborolidine-mediated reduction of alk-2-yne-1,4-diones

We performed the borane-mediated reduction of a series of symmetrical alk-2-yne-1,4-diones (5) in the presence of the oxazaborolidine (R)-6 to afford (R,R)-alk-2-yne-1,4-diols ((R,R)-1) in good yields and high stereoselectivities (up to 99.9% ee). In some cases, the stereochemical purity of 1 was improved by a two-step process: (i) temporary transformation of 1 into its vic-dibromo derivatives 9, which allowed us to remove the minor meso isomer by chromatography, and (ii) regeneration of the enantioenriched diols 1 with SmI2. Reduction of the hexacarbonyldicobalt complexes 8 derived from 5 was also successful.     

Asymmetric synthesis of 2-substituted butane-1,4-diols by hydrogenation of homochiral fumaramide derivatives

Diastereoselective hydrogenation of homochiral fumaramides 1 derived from (2R)-Oppolzer’s sultam was observed by analysis of the ¹H NMR spectra of the succinamide mixtures with de’s of 77–88%. Reduction of these succinamides using LiAlH₄ gave the corresponding (2S)-butane-1,4-diols and established that addition of hydrogen takes place selectively on the re-face of fumaramides 1. The stereoselectivity was confirmed by estimating the ee’s from the ¹⁹F NMR spectra of the Mosher’s diesters of the diols. This methodology was applied to the synthesis of selected pyrrolidine natural products in homochiral form.     

Facile aminolysis of epoxides with diethylaluminum amides

Treatment of an epoxide with a diethylaluminum amide in dichloromethane at room temperature affords the corresponding β-amino alcohol in good yield.     

Deprotonation-electrophile trapping of terminal epoxides

Organolithium-induced deprotonation of terminal epoxides in the presence of appropriate diamine ligands allows trapping with a range of electrophiles, yielding functionalised di- and tri-substituted epoxides in good yields and with control of stereochemistry at the epoxide.     

Asymmetric 1,4-reductions of hindered beta-substituted cycloalkenones using catalytic SEGPHOS-ligated CuH

The reagent combination of catalytic amounts of copper hydride ligated by a nonracemic SEGPHOS ligand leads in situ to an extremely reactive species capable of effecting asymmetric hydrosilylations of conjugated cyclic enones in very high ees. An unprecedented substrate-to-ligand ratio as high as 275 000:1 for this transformation has been documented. [reaction: see text]     

Synthesis of aminopyridines from 2-fluoropyridine and lithium amides

Lithium amides promote the amination of 2-fluoropyridine under mild reaction conditions, providing 2-aminopyridines in good yields and purity. Treatment of 2-fluoropyridine with 1 equiv of lithium amide at room temperature affords complete conversion after 2 h. To our knowledge, this is the first study of lithium amide-promoted amination of fluoropyridines that are not further activated by electron-withdrawing groups.     

Intramolecular cyclopropanation of unsaturated terminal epoxides

Efficient lithium amide-induced intramolecular cyclopropanation of bishomoallylic and trishomoallylic epoxides is described. The methodology is used in an asymmetric synthesis of sabina ketone.     

Chemoenzymatic synthesis of enantiomerically pure terminal 1,2-diols

A new practical method for the enzymatic synthesis of 1,2-diols has been developed by employing a lipase catalyzed one-pot transesterification protocol. A series of substituted -acetoxyphenylethanones 3a–g have been reduced to the corresponding alcohols under mild conditions employing sodium borohydride and moist neutral alumina, and further subjected for lipase catalyzed irreversible transesterification in the same pot to give mono- and diacetate diols (R)-4 and (S)-5, which on hydrolysis afforded terminal 1,2-diols, (R)- and (S)-6 in high enantiomeric excess.