Intermediate Amino Alcohol Research Articles

Chiral Camphor-Based 1,3- and 1,4-Amino Alcohols and Aminodiols as Ligands for Diethylzinc Addition to Aldehydes

Syntheses of (1R,2S,3R,4S)-1,7,7-trimethyl-2-pyridin-2-ylmethylbicyclo[2.2.1]-heptane-2,3-diol (7), (1R,2S,3R,4S)-1,7,7-trimethyl-2-[(6-methyl)-pyridin-2-ylmethyl-bicyclo-[2.2.1]heptane-2,3-diol (13), and (1R,2S,2’R,4R)-1,7,7-trimethyl-2-piperidin-2-ylmethyl-bicyclo[2.2.1]heptan-2-ol (19b) from commercially available (d)-camphor (1) are described. Key steps of the syntheses involved substrate-controlled diastereoselective alkylation and platinum oxide-catalyzed hydrogenation reactions. These compounds, and other intermediate amino alcohols in their syntheses, were successfully utilized as ligands in enantioselective diethyl zinc (Et2Zn) addition to benzaldehyde with moderate enantioselectivity.

Stereochemistry of condensation and transaldimination of amino acids by pyridoxal

The stereochemistry of the products of condensation and transaldimination of L-α- and D-α- alanines with pyridoxal has been studied. Structure of intermediate amino alcohols, aminals, and of the final Schiff’s bases depends on their fragments location with respect to the pyridine ring plane. Basing on the collected data, we have proposed the reaction mechanism involving the in-plane attack of the carbonyl group, in contrast to commonly accepted out-of-plane attack.

One-pot synthesis of vicinal aminoalkanols from sugar aldehydes

A novel synthetic method of carbohydrate derived vicinal aminoalcohols, from sugar aldehydes and bromonitroalkanes, has been developed. It involves an indium-catalyzed one-pot Henry reaction and nitro group reduction, and proceeds with a remarkably high anti-selectivity. The reaction of the intermediate aminoalcohols with alkylating agents furnished the corresponding carbohydrate-based tertiary aminoalcohols with excellent stereoselectivity. This very simple methodology allows easy access to families of N,N-dialkylated vicinal aminoalkanols, useful intermediates in the synthesis of derivatives of biological interest and sugar-based stereodifferentiating agents for asymmetric catalysis.

Synthesis of an advanced intermediate of alfa-alloenduracididine from allylglycine

α-Alloenduracididine, 3-(2-amino-4,5-dihydro-1Himidazole-4-yl)-2-aminopropionic acid) 1 and its diastereoisomer, enduracididine 2, are two nonproteinogenic amino acids isolated in 1968 from Streptomyces fungicidicus as part of a cyclopeptide the enduracidine, which has antibiotic activity. 1,2 α-Alloenduracididine, which can be viewed as a constrained analogue of arginine, 3 belongs to a family of natural amino acids having the terminal guanidine nitrogen atom linked to the methylene backbone. Most of these amino acids are components of peptide antibiotics isolated from extracts of microorganisms and include: β-hydroxyenduracididine and β-hydroxyalloenduracididine (constituents of (α-e)-mannopeptimycins), 3 tetrahydrolathyrine, capreomycidine (constituent of capreomycins). Our laboratory has recently completed the first total synthesis and determination the absolute configuration of tetrahydrolathyrine. 4 Here, we described an efficient synthetic route to acess the α-alloenduracididine by synthesis of an advanced intermediate amino alcohol 11 , obtained as diastereoisomers mixture (11a and 11b). Amino alcohol intermediate was synthesized, in eight steps, from ethyl (R)-N-Boc-allylglycinate 4 in satisfactory yields from 4 . Studies concerning the oxidation of the amino alcohol to the amino acid and determination of the absolute configuration at C4 of each diastereoisomer are in progress.

Syntheses of two isotopically labeled CB1 receptor antagonists

Synthesis of deuterium‐labeled CB1 receptor antagonist 2‐d9 was accomplished in three steps by alkylation of 2‐nitrophenylacetonitrile with cyclopentyl‐d9 bromide, reductive cyclization of the resulting secondary nitrile into the 3‐cyclopentyl indole‐d9 and its N‐sulfonylation with corresponding p‐amidosulfonyl chloride. Another, structurally related, CB1 receptor antagonist 1 was radiolabeled with carbon‐14 by oxidative cleavage of 3‐cyclopentyl indole followed by the ring closure of o‐acyl substituted N‐formylaniline with potassium cyanide‐[14C], in situ reduction‐elimination of the intermediate amino alcohol, and N‐sulfonylation of the resulting 3‐cyclopentyl indole‐2‐[14C].

ChemInform Abstract: Oxidative Fragmentation of Oxiranes to Nitriles with Hypervalent Iodine(V) Reagents in Aqueous Ammonia.

AbstractNucleophilic ring‐opening of the starting epoxides with aqueous ammonia followed by oxidation of the intermediate amino alcohol with IBX results in formation of the corresponding nitriles.

Chemical Development on the Chiral Auxiliary (S)-4-(Phenylmethyl)-2-oxazolidinone Utilizing Automated Synthesis and DoE

Enantiopure 4-substituted oxazolidinones are well-known chiral auxiliaries for asymmetric synthesis of carboxylic acid derivatives. The 4-(phenylmethyl)-substituted oxazolidinones derived from d- or l-phenylalanine are known to be particularly useful. We have conducted chemical development studies toward an efficient and scaleable “one-pot” process for production of (S)-4-(phenylmethyl)-2-oxazolidinone 2. The first step in the process employed a sodium borohydride reduction of phenylalanine mediated by an additive. The second step utilized triphosgene as a phosgene source to effect cyclization of the intermediate amino alcohol. Both chemical steps and workup procedures were screened and optimized utilizing statistical design of experiments (DoE) and parallel synthesis. The procedure was further characterized in an automated reactor system that provided heat flow measurements and modeled production at the plant scale. The efficiency of this process was compared to those of others previously reported on the basis of raw material cost, time requirements, safety, and hazardous waste generation.

Aziridinium ions from phenylglycinol — A new approach to the synthesis of chiral diamines

A new two-step method [(i) N, N-dialkylation; (ii) aziridinium ion formation followed by amine attack] for the synthesis of chiral diamines from phenylglycinol is described. The two steps can be carried out sequentially without isolation of the intermediate amino alcohols to give diamines in good yields (62–76%). An improved protocol for the N, N-dialkylation of phenylglycinol is also reported.

High pressure and lanthanide catalyzed synthesis of enamino compounds

The synthesis of enaminoketones from the condensation of bulky amines with ethyl acetoacetate or 2,4-pentanedione is described. The reaction can be activated either by high pressure or catalysis by ytterbium triflate. However, the pressure route is of wider applicability. The method is limited by the kinetic competition between the formation of the intermediate aminoalcohol and the dehydration step.

The synthesis of a 4-phenylisoquinoline from a 3-phenylisoquinoline by utilization of a nitrogen analog of the pinacol rearrangement

The nitrogen analog of the pinacol rearrangement has been utilized for the preparation of a 4-phenylisoquinoline 9 from the intermediate amino alcohol 8.

Hydrolysis of α-cyanobenzylideneanilines. Part I. Kinetic studies in acidic media

The hydrolysis of α-cyanobenzylideneanilines was studied kinetically in aqueous sulphuric acid (H0–2 to –6), 40% aqueous acetonitrile (pH 3–0), and 60% aqueous dioxan (H0 1·5 to –2) at 25°. Benzoyl cyanide was demonstrated to be an intermediate. The rate of hydrolysis exhibited a maximum at H0ca.–1 to –2. The effect of substituents on the reaction rate and the Bunnett–Olsen ϕ values suggested that the hydration of the protonated substrate is rate determining on the less acidic side of the rate maximum and that the decomposition of the intermediate amino-alcohol is rate determining under more acidic conditions. It is suggested, from consideration of the shape of the acidity–rate profile, that aniline is expelled only from the dipolar form (or zwitterionic form) of the amino-alcohol intermediate, because the tendency for aniline to separate is weakened by the electronwithdrawing cyano-group.

Synthetic steroids. Part XI. Stereochemistry of the Tiffeneau—Demjanov ring expansion of 5α-cholestan-3-one

The reaction of 5α-cholestan-3-one with acetone cyanohydrin has been shown to give a mixture of epimers (II and III; R = H) containing at least 80% of the epimer with the axial cyano-group. Each of these cyanohydrins has been converted into its acetate and then, by reduction, into the corresponding amino-alcohol, both of which have been deaminated with nitrous acid. Epimer (II; R = H) gives as the sole product of rearrangement the A-homo-ketone (VI), whereas the epimer (III; R = H) furnishes the same ketone (VI) along with an exocyclic epoxide by-product (X). Each of the intermediate amino-alcohols (IV and VII; R = NH2) has been synthesised independently from the appropriate epoxide (IX or X) and the stereochemistry of the deamination reactions is discussed.

Studies on Girard Hydrazone. IV. Effect of Cupric Ion on the Hydrolysis of Girard Hydrazone

It has been found that cupric ion retards the rates of hydrolysis of Girard T hydrazones formed from aliphatic carbonyl compounds. The reduced rates approach to the magnitude expected for the rate-determining hydronium ion catalyzed decomposition of the intermediate amino-alcohols. Cupric ion has almost no effect of the hydrolysis of the Girard T hydrazone of acetophenone or the Girard D hydrazone of acetone. The results are interpreted in terms of an inhibition of hydrolysis through the dipolar form of amino-alcohol intermediate by cupric ion.

Reaction between streptomycin and benzylamine. Equilibrium of reactions

1. The equilibrium constants of the reaction between streptomycin and benzylamines at different concentrations and pH values have been determined. 2. The formation of azomethine proceeded according to the general synthesis scheme with the formation of a polarographically inactive intermediate amino alcohol. 3. Compounds were formed from benzylamine and two streptomycin molecules of the dimethylol derivative type in acidic medium and in the presence of streptomycin. 4. At pH 9.5–10.0, it has been expedient to carry out the reaction with a benzylamine excess and with a temperature reduction toward the end of the reaction.

Studies on Girard hydrazones. Part III. Further kinetic studies on the hydrolysis of Girard hydrazones

The hydrolysis of Girard T and D hydrazones of several aldehydes and ketones has been studied kinetically in aqueous solution (containing 2% ethanol) by a polarographic method. In the hydrolysis of Girard hydrazones derived from aliphatic carbonyl compounds, a change in the rate-determining step from the rate-determining decomposition of the intermediate amino-alcohol in the highly acid region to a rate-determining attack of water (or hydroxide ion) on the substrate in slightly acidic, neutral, and alkaline regions, is demonstrated, which is similar to the hydrolysis of other azomethines. Four lines of evidence, however, strongly suggest that the pH-independent hydrolysis observed in the neutral region is the rate-determining attack of water on the neutral substrate in contrast to the hydrolysis of other azomethines. In the case of an aromatic Girard hydrazone, only rate-determining decomposition of intermediate is observed. In the decomposition of the intermediate amino-alcohol to the substrate, intramolecular general acid catalysis of an eight-membered ring is suggested in the hydrolysis of Girard D hydrazone that has a dissociable proton on its terminal nitrogen atom. The kinetic results do not indicate any essential difference between the mechanisms of hydrolysis of ketone and aldehyde Girard hydrazones which is responsible for the so-called selective hydrolysis of ketone hydrazone. The two types of pH–rate profile (inflexion type and bell-type) are discussed.