(S,S)-(+)-pseudoephedrine as chiral auxiliary in asymmetric aza-Michael reactions. Unexpected selectivity change when manipulating the structure of the auxiliary

[reaction: see text] The asymmetric aza-Michael reaction of metal benzylamides to alpha,beta-unsaturated amides derived from the chiral amino alcohol (S,S)-(+)-pseudoephedrine has been studied in detail. A deep study of the most important experimental parameters (solvent, temperature, nucleophile structure, influence of additives) has been carried out, showing that the reaction usually proceeds with good yields and diastereoselectivities, although the experimental conditions have to be modified depending on the substitution pattern of the conjugate acceptor. Additionally, a very interesting facial selectivity inversion has been observed when manipulating the structure of the chiral auxiliary, which has allowed a diastereodivergent procedure to be set up for performing asymmetric aza-Michael reactions using the same chirality source. Finally, the adducts obtained in the asymmetric aza-Michael reaction have proven to be very versatile synthetic intermediates in the preparation of other interesting compounds such as beta-amino esters, gamma-amino alcohols, and beta-amino ketones in highly enantioenriched form.     

Preparation of protected syn-alpha,beta-dialkyl beta-amino acids that contain polar side chain functionality

We report the synthesis of syn-alpha,beta-dialkyl beta-amino acid derivatives suitably protected for solid-phase synthesis that give rise to residues containing positively charged lysine-like side chains. These amino acids, as well as syn-alpha,beta-dialkyl beta-amino acids that contain diverse hydrophobic side chains, are prepared in good de and ee. The key step in this route involves Davies's protocol for the conjugate addition of a chiral lithium amide to alpha,beta-unsaturated tert-butyl esters (Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 9, 1141). syn-alpha,beta-Dialkyl beta-amino acids are interesting building blocks because of their sheet-forming propensity and because of their presence in bioactive compounds.     

(S,S)-(+)-Pseudoephedrine as chiral auxiliary in asymmetric conjugate addition and tandem conjugate addition/alpha-alkylation reactions

Organolithium reagents undergo highly regio- and diastereoselective 1,4-addition to (S,S)-(+)-pseudoephedrine enamides furnishing the corresponding beta-alkyl-substituted adducts in excellent yields and diastereoselectivities. In addition, the intermediate lithium enolates generated after the conjugate addition step undergo a highly diastereoselective alkylation reaction, furnishing alpha,beta-dialkyl-substituted amides in high yields. The obtained adducts have been converted into chiral nonracemic beta-alkyl- and alpha,beta-dialkyl-substituted carboxylic acids and gamma-alkyl- and beta,gamma-dialkyl-substituted alcohols using very simple and high-yielding procedures.     

Asymmetric synthesis of the stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylate

The stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylate may be prepared stereoselectively from diester derivatives of (E,E)-octa-2,6-diendioc acid, with the key step utilising the conjugate addition of homochiral lithium N-benzyl-N- alpha-methylbenzylamide. The trans-C(1)-C(2)-stereoisomers are readily prepared via a diastereoselective tandem conjugate addition cyclisation protocol with lithium (R)-N-benzyl-N- alpha-methylbenzylamide, with subsequent hydrogenolysis and ester hydrolysis giving the (1R,2R,5R)- and (1R,2R,5S)- beta-amino diacids in good yields. The preparation of the cis-C(1)-C(2)-stereoisomers utilises a protocol involving N-oxidation and Cope elimination of the major diastereoisomeric product arising from conjugate addition and cyclisation, giving homochiral (R)-5-carboxymethyl-cyclopentene-1-carboxylate. Conjugate addition of either lithium (R)- or (S)-N-benzyl-N- alpha-methylbenzylamide to (R)-5-carboxymethyl-cyclopentene-1-carboxylate, and diastereoselective protonation with 2,6-di-tert-butyl phenol gives, after hydrogenolysis and ester hydrolysis, the (1S,2R,5R)- and (1R,2S,5R)- beta-amino diacids in good yield. The use of (S)-N-benzyl-N- alpha-methylbenzylamide in the initial conjugate addition and cyclisation reaction, and subsequent repetition of the elimination and conjugate addition strategy allows stereoselective access to all stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylate.     

Highly enantioselective conjugate additions to alpha,beta-unsaturated ketones catalyzed by a (salen)Al complex

Chiral (salen)Al complex 1a catalyzes the highly enantioselective conjugate addition of carbon- and nitrogen-based nucleophiles to acyclic alpha,beta-unsaturated ketones. This methodology is tolerant of substantial variation of the ketone structure, providing access to a wide range of useful chiral building blocks in high yield and enantiomeric excess. Synthetic manipulations of the conjugate addition products are demonstrated, including the straightforward preparation of beta-amino ketones and highly enantioenriched carbo- and heterocyclic compounds.     

Asymmetric synthesis of beta-amino-gamma-substituted-gamma-butyrolactones: double diastereoselective conjugate addition of homochiral lithium amides to homochiral alpha,beta-unsaturated esters

Chiral alpha,beta-unsaturated esters, containing a single, gamma-stereogenic centre, show modest levels of substrate control upon conjugate addition of lithium dibenzylamide. Double diastereoselective conjugate additions of homochiral lithium N-benzyl-N-(alpha-methylbenzyl)amide to the homochiral alpha,beta-unsaturated esters display "matching" and "mismatching" effects. In each case, however, these additions proceed under the dominant stereocontrol of the lithium amide to give the corresponding beta-amino esters in high de. A remarkable reversal in stereoselectivity is noted by changing the ester functionality to an oxazolidinone. Subsequent O-deprotection and cyclisation of the resultant beta-amino adducts gives access to the corresponding beta-amino-gamma-substituted-gamma-butyrolactones in good yield and high de.     

Syntheses of (S,S)-reboxetine via a catalytic stereospecific rearrangement of beta-amino alcohols

The formal total synthesis of (S,S)-reboxetine has been realized by two different approaches using a stereospecific rearrangement of beta-amino alcohols catalyzed by (CF3CO)2O.     

Tandem asymmetric conjugate addition/alpha-alkylation using (S,S)-(+)-pseudoephedrine as chiral auxiliary

Alpha,beta-unsaturated amides derived from the chiral amino alcohol (S,S)-(+)-pseudoephedrine undergo a very clean and diastereoselective tandem conjugate addition/alpha-alkylation reaction. Excellent results have been achieved using a wide range of differently substituted conjugate acceptors, organolithium reagents, and alkyl halides. The chiral auxiliary could be easily removed from the obtained adducts by reduction, furnishing chiral nonracemic alpha,beta-branched alcohols in a very easy and efficient way. [reaction: see text]     

Enantioselective organocatalytic amine conjugate addition

The first enantioselective organocatalytic amine conjugate addition has been successfully developed. The application of LUMO-lowering iminium catalysis has enabled the highly chemo- and enantioselective 1,4-addition of a rationally designed N-silyloxycarbamate nucleophile (HOMO-raised) to alpha,beta-unsaturated aldehydes. Imidazolidinone 2*pTSA was found to catalyze the addition of various orthogonally N-protected silyloxycarbamate nucleophiles to a range of alpha,beta-unsaturated aldehydes, affording synthetically useful beta-amino aldehyde intermediates. The synthetic utility of the protocol was demonstrated in the rapid synthesis of enantioenriched beta-amino acids in one operation and 1,3-amino alcohol derivatives in three operations.     

Regioselective single and double conjugate additions to substituted cyclohexa-2,5-dienone monoacetals

[reaction: see text]. A series of quinone monoacetals bearing electron-withdrawing groups was treated with diethyl malonate and other bifunctional nucleophiles in the presence of KO-t-Bu in THF. Reactions of ethyl 3-nitropropionate or diethyl malonate resulted in single conjugate addition adducts. When ethyl acetoacetate was used as a nucleophile, bridged bicyclic products were obtained in good yields. The regiochemistry of conjugate addition was dependent on the quinone monoacetal substitution.     

Solvent-free Brønsted acid-catalyzed Michael addition of nitrogen- and carbon-containing nucleophiles by ultrasound activation

A new method has been developed for the Michael addition of nitrogen- and carbon-containing nucleophiles to cyclic enones. Using this conjugate addition reaction, a variety of different nucleophiles can react with a range of cyclic enones in the presence of p-toluenesulfonic acid under solvent-free ultrasound irradiation conditions affording the corresponding C–N or C–C adducts in good to excellent yields. Comparatively, performing the reaction under ultrasound irradiation gives higher yields, is more efficient and environmentally benign than performing it at high pressure.     

Electrochemical oxidation of substituted catechols in the presence of pyrazol-5-ones: characterization of products and reaction mechanism

The electrochemical oxidation of substituted catechol derivatives has been investigated in the presence of pyrazol-5-ones as C-H acid nucleophiles by using constant current technique in acetate buffer solution. The results indicate that different reaction mechanisms are involved and not only 1,4-Michael adducts but also 1,6-Michael adducts are formed, depending on the nature of the starting catechols and the nucleophiles, as well as the reaction conditions.     

An efficient synthesis of a new series of acyclonucleosides starting from beta-amino alcohols

A series of new acyclonucleosides analogues 3 has been synthesized very efficiently in three steps starting from beta-amino alcohols 1. The key step of this process is a nucleophilic substitution with various nucleophiles on 2,2'-anhydronucleosides 2. The chemo- and stereoselectivities of this reaction are discussed. AM1 calculations sustained the observed chemoselectivity.     

Urethane N-carboxyanhydrides from beta-amino acids

A general method has been developed for the synthesis of N-tert-butyloxycarbonyl N-carboxyanhydrides from beta-amino acids using Vilsmeier complex. These beta-UNCA are stable, and the reactivity with different nucleophiles (alcohol, amine, lithium enolate) was studied.     

S(N)2 reaction of sulfur nucleophiles with hindered sulfamidates: enantioselective synthesis of alpha-methylisocysteine

The work described here demonstrates that the five-membered cyclic alpha-methylisoserine-derived sulfamidate, (R)-1, behaves as an excellent chiral building block for the ring-opening reaction by S(N)2 attack with sulfur nucleophiles at the quaternary carbon. As a synthetic application of this methodology, and to show that this sulfamidate is a valuable starting material, the synthesis of two new alpha-methylisocysteine derivatives has been carried out to cover the lack of alpha- and beta-methylated amino acids that incorporate the cysteine or isocysteine skeleton. These compounds are two new alpha,alpha-disubstituted beta-amino acids (beta(2,2)-amino acids), and the synthetic routes involve nucleophilic ring opening followed by acid hydrolysis.     

An efficient synthesis of pyrimidines from beta-amino alcohols

[reaction: see text] Pyrimidinones 3 were chemoselectively reduced by using metal-catalyzed hydrogenation and stereoselectively substituted by various nucleophiles. Starting from beta-amino alcohols 1, the overall process allows efficient access to substituted pyrimidines 4 and 6.     

Preparation of syn-delta-hydroxy-beta-amino esters via an intramolecular hydrogen bond directed diastereoselective hydrogenation. Total synthesis of (3S,4aS,6R,8S)-hyperaspine

Hydrogenation of delta-hydroxy-beta-ketoester-derived enamines 8 produces syn-delta-hydroxy-beta-amino esters 9 diastereoselectively, which may be directed by the formation of an intramolecular hydrogen bond between the delta-hydroxyl and beta-amino groups. By using this method and a Dieckmann reaction as the key steps, (3S,4aS,6R,8S)-hyperaspine, a new type of ladybird alkaloid, is synthesized. [reaction: see text]     

Asymmetric Synthesis via Acetal Templates. 14. Preparation of Enantiomerically Pure (3S,4S)- and (3S,4R)-Statine Derivatives

Several (3S,4S)- and (3S,4R)-statine derivatives have been prepared by attack of nucleophiles on crystalline, epimeric N-BOC-lactams 7a and 7b. The key step in the synthesis of the lactams was the TiCl₄-catalyzed coupling reactions of acetals derived from (R)-1,3-butanediol with allyltrimethylsilane.

Several enantiometrically pure (3S,4S- and (3S, 4R)-statine derivatives were made by sodium cyanide-catalyzed reaction of nucleophiles with the lactams 3a and 3b which were synthesized by the scheme 1 → 2 → 3.     

Evaluation of an immunoaffinity extraction column for enrichment of adducts between human serum albumin and hexahydrophthalic anhydride in plasma

An immunoaffinity extraction (IAE) column was prepared for extraction of adducts between human serum albumin (HSA) and hexahydrophthalic anhydride (HHPA). HHPA is a strong sensitizer inducing immunoglobulin E antibodies in vivo. Polyclonal antibodies from a rabbit immunized with keyhole limpet hemocyananin-HHPA conjugate were purified using a Protein A Sepharose gel. To obtain antibodies with optimal affinity towards HHPA-protein adducts, HHPA-specific antibodies were selected using an N-hydroxysuccinimide-Sepharose column coupled with albumin-HHPA conjugate. Antibodies eluted from this column at pH 2.2 were selected to prepare the IAE column. The column was evaluated using 2 mL plasma spiked with HSA-HHPA conjugate. The column was eluted with glycine buffer at pH 2.0. The conjugates in the eluate were hydrolyzed to the corresponding HHP acid and quantified by mass spectrometry. The average recovery of HHPA adducts in 11 experiments was 68% with a coefficient of variation (CV) of 7%. The column's capacity to bind protein-HHPA adducts was found to be linear in the range of 0.15-1.2 nmol conjugate. The evaluation showed that the IAE column had adequate affinity towards the HHPA adducts and that the adducts could be extracted with good recovery and precision from a large volume of plasma.     

S(N)1-like reactions of bicyclic alpha-amino ethers with sulfur,nitrogen, and carbon nucleophiles. Synthesis of 1-azabicyclo[3.2.2]nonanes functionalized at carbon C2 and C6 with complete stereocontrol

[reaction: see text] In the presence of nucleophiles, Lewis acid mediated cleavage of alpha-amino ethers derived from quincorine and quincoridine affords a variety of C2-substituted and C6-vinylated 1-azabicyclo[3.2.2]nonanes. These are enantiopure and are formed in S(N)1-like reactions with complete stereocontrol. There is no leakage into 2-Nu en route to product 1-Nu or vice versa. Me(3)SiCN provides new Strecker-type alpha-amino nitriles. In the presence of TTMPP-BF(3).OEt(2), the ketene acetal Me(2)C=C(OMe)OSiMe(3) delivers enantiopure bicyclic beta-amino acid esters.