Practical synthesis of (3S,4S)-3-methoxy-4-methylaminopyrrolidine

Three synthetic methods for the preparation of (3S,4S)-3-methoxy-4-methylaminopyrrolidine, an important intermediate in the synthesis of the novel quinolone antitumor agent, AG-7352, have been developed. By one route, an efficient and large-scale preparation of the chiral pyrrolidine could be achieved through resolution of (±)-1-Boc-3-benzylamino-4-hydroxypyrrolidine, which is prepared from either 3-pyrroline or 1,4-dichloro-2-butene.     

A short, simple and general approach for the synthesis of (3S,4S)-3-methoxy-4-methylamino pyrrolidine and (3S,4R)-3-methoxy-4-methylamino pyrrolidine

A general and efficient stereoselective approach for the synthesis of (3S,4S) and (3S,4R)-3-methoxy-4-methylamino pyrrolidines, a part of the structure of AG-7352, a naphthyridine antitumor agent and quinoline antibacterial compounds has been described.     

Chemoenzymatic synthesis of (3S,4S)- and (3R,4R)-3-methoxy-4-methylaminopyrrolidine

Facile chemoenzymatic enantioselective synthesis of (3S,4S)-3-methoxy-4-methylaminopyrrolidine, a key intermediate for a new quinolone antitumor compound AG-7352 has been described. This methodology illustrates the preparation of 3-azido-1-benzyloxycarbonyl-4-hydroxypyrrolidine starting from diallylamine via 1-benzyloxycarbonyl-3-pyrroline obtained by ring-closing metathesis (RCM) employing Grubbs’ catalyst. Enzymatic transesterification employing PS-C lipase gave (3S,4S)-3-azido-1-benzyloxycarbonyl-4-hydroxypyrrolidine in >99% ee, which upon methylation of the hydroxyl group followed by sequential reactions gave the desired intermediates, (3S,4S)-1-tert-butoxycarbonyl-3-tert-butoxycarbonylamino-4-methoxypyrrolidine.     

An efficient and stereospecific synthesis of (2S,4S)-2,4-diaminoglutaric acid

An efficient and stereospecific synthesis of (2S,4S)-2,4-diaminoglutaric acid 1 starting from trans-4-hydroxy-l-proline 2 is presented. The key step involves the combined application of ruthenium tetroxide (RuO₄) oxidation of 4-(tert-butoxycarbonylamino)proline derivatives 7 and 8 followed by regioselective ring opening of the resulting lactams 9 and 10 with 1 M LiOH.     

Synthesis of D-(6R) - and D-(6S) -(6-2H1) glucose

Chemical synthesis ofD-(6R)- and D(6S)-(6-²H₁) glucose is described comprising (i) formation of 6-²H₁)-3-o-benzyl-5,6-dideoxy-l, 2-0-isopropylidene-α-D-xylo-hex-5-ynofuranose from D-glucose; (ii) stereospecific reduction of the deuterated acetylene functionality to (E)- or (Z)-deuterated olefin; (iii) stereospecific cis-dihydroxylation of the deuterated olefin; and (iv) separation of stereoisomers based on the intrinsic chirality of D-glucose and subsequent deprotection.     

Stereospecific synthesis of differentially protected (2S,4S)-2,4-diaminoglutaric acid suitable for incorporation into peptides

The first synthesis of differentially protected (2S,4S)-2,4-diaminoglutaric acids 2 and 3 suitable for incorporation into peptides has been accomplished in a completely stereospecific manner in seven steps (overall yield 25–28%) from tert-butyl (2S,4S)-4-azido-N-tert-butoxycarbonylprolinate 5.     

Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

Asymmetric synthesis of (−)-pseudoephedrine from (2S,3S)-3-phenyloxiran-2-ylmethanol. Stereospecific interchange of amino and alcohol functions

A ring-opening reaction of N-methylaziridines with Boc₂O/NaI has been applied to the asymmetric synthesis of pseudoephedrine. 3-Methylamino-3-phenyl-1,2-propanediol 1, derived from (2S,3S)-3-phenyloxiran-2-ylmethanol, was converted into the oxazolidin-2-one 4, a precursor of pseudoephedrine. The reaction occurs with a stereospecific interchange of amino and alcohol functions.     

Enantioselective synthesis of (10S)- and (10R)-methyl-anandamides

For the development of novel endocannabinoid templates with potential resistance to hydrolytic and oxidative metabolism, we are targeting the bis-allylic carbons of the arachidonoyl skeleton. Toward this end, we recently disclosed the synthesis and preliminary biological data for the (13S)-methyl-anandamide. We report now the total synthesis of the (10S)- and (10R)-methyl-counterparts. Our synthetic approach is stereospecific, efficient, and provides the analogs without the need for resolution. Peptide coupling, P-2 nickel partial hydrogenation, and cis-selective Wittig olefination are the key steps.     

Stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-ol and its propionate,the sex pheromones of pine sawflies

The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-ol (diprionol) and its propionate, the sex pheromones of pine sawflies (Neodiprion sp. and other), in high enantiomeric purity was achieved from (1R,3S)-2,2-dichloro-3-methylcyclopropanecarboxylic acid. The carbon skeleton of diprionol was formed via copper-catalyzed cross-coupling reactions and diastereoselective methylation of the intermediate chiral α-methylbranched aldehyde with MeTi(Oi-Pr)₃ in the presence of [(R,R)-TADDOL]Ti(Oi-Pr)₂. The latter transformation leads to a syn-adduct with high stereoselectivity, which depends on the presence and configuration of the α-stereogenic center in the aldehyde. The diastereomeric purity of (2S,3S,7S)-diprionol can be substantially increased via crystallization of its 3,5-dinitrobenzoate.     

Expedient asymmetric synthesis of (2S,3S)-Boc-phenylalanine epoxide,a key intermediate for the synthesis of biologically active compounds

The asymmetric synthesis of (2S,3S)-3-(tert-butoxycarbonyl)amino-1,2-epoxy-4-phenylbutane [(2S,3S)-Boc-phenylalanine epoxide] has been achieved in six steps and in 55% overall yield from the N-benzylimine derived from (R)-2,3-O-isopropylidene-glyceraldehyde. The required vic-aminodiol intermediate was obtained through a highly diastereoselective addition of benzylmagnesium chloride to the N-benzylimine in the presence of BF₃·OEt₂ as an imine precomplexing agent.     

Stereoselective synthesis,solution structure and metal complexes of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids

The highly stereoselective synthesis of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids was achieved by addition of dimethyl phosphite to N-protected aminoaldehydes. Relative configuration and solution conformations of (1S,2S)-2-amino-1-hydroxy-alkylphosphonic acids (in D₂O) and their dimethyl esters (in CDCl₃ and CD₃OD) were established by means of NMR basing on the dependence between observed values of coupling constants (³J_HH, ³J_PC, ³J_HP) and corresponding dihedral angles. Potentiometric and spectroscopic methods were used for the evaluation of the structure of the complexes of (1S,2S)-2-amino-1-hydroxy-alkylphosphonic acids with Zn(II) and Cu(II) ions in aqueous solutions.     

Synthesis of (3S,5S)-3,5-diaminopiperidin-2-one as a conformationally restricted surrogate of Dab-Gly dipeptide

An efficient and stereospecific synthesis of chiral 3,5-diaminopiperidin-2-one as a novel conformationally restricted surrogate of 2,4-diaminobutanoyl (Dab)-Gly dipeptide has been achieved. The key steps include (i) ruthenium tetroxide (RuO₄) oxidation of N-Boc-2-azidomethylpyrrolidines with a catalytic amount of RuO₂·xH₂O in a two-phase system of aq NaIO₄/AcOEt and (ii) intramolecular transamidation of the resulting 2-azidomethylpyrrolidin-2-ones with 10% Pd–C in MeOH/H₂O (12/1, v/v) under an H₂ atmosphere (3 atm). This methodology represents a powerful tool for the synthesis of Dab-Gly dipeptide surrogate.     

Transformation of l-phenylalanine to (S)-indoline-2-carboxylic acid without group-protection

(S)-Indoline-2-carboxylic acid was synthesized by use of a nitro amination approach with l-phenylalanine as chiral pool. The first step of the synthesis was nitration of l-phenylalanine, with urea nitrate (UN)/H₂SO₄ as nitrating reagent, to give 2,4-dinitro-l-phenylalanine in 75.7 % yield in one-pot synthesis and 69.1 % yield by step-wise nitration. Intramolecular nitro amination of 2,4-dinitro-l-phenylalanine gave (S)-6-nitro-indoline-2-carboxylic acid in 65.7 % yield and more than 99.5 % enantiomeric excess (ee). The title compound, (S)-indoline-2-carboxylic acid, was obtained in 85.9 % yield and high ee by one-pot transformation of (S)-6-nitroindoline-2-carboxylic acid. The total synthesis consisted of three operations and gave the title compound in 42 % yield and more than 99.5 % ee.     

Stereocontrolled synthesis of all of the four possible stereoisomers of erythro-3,7-dimethyl-pentadec-2-yl acetate and propionate,the sex pheromone of the pine sawflies

All of the four possible stereoisomers of 2,3-erythro-3,7-dimethylpentadecan-2-ol 1 were synthesized by a stereospecific S_N2 oxirane cleavage of (2S,3S)-2,3-epoxybutane or its antipode with lithium di[(R)- or (S)-4-methyldodecyl]cuprate. Their acetates or propionates were prepared to test their pheromone activity.     

A stereocontrolled formal total synthesis of (±)-thienamycin

The stereocontrolled synthesis of a key intermediate 20 for the preparation of (±)-thienamycin 1 is described. The key steps in the synthesis are the formation of the β-lactam ring by cyclization of the amide 5 via a complete S_N2 mechanism, and the stereospecific conversion of the azetidinone 5 to the amide (trans-11) which have the correct relative configurations at three contiguous chiral centres. The mechanism of the conversion of the azetidinone 16E to the N-free azetidinone 17 and the selenide compound 18 is presumed.     

Interaction in the Yb2S3-In2S3 system

A T-x diagram is designed for the Yb₂S₃-In₂S₃ system using physicochemical methods. A complex chemical reaction occurs in the system to yield ternary compounds Yb₃InS₆ (S₁), YbInS₃ (S₂), Yb₃In₅S₁₂ (S₃), and YbIn₃S₆ (S₄). In₂S₃-based limited solid solutions are found. Phases S₁, S₃, and S₄ are formed by peritectic reactions at 1260, 1200, and 1100 K, respectively. Compound S₂ melts congruently at 1390 K. Compound S₃ crystallizes in monoclinic system (a = 10.90 Å, b = 21.01 Å, c = 3.846 Å, β = 96.2°). Compounds S₁ and S₄ crystallize in orthorhombic system (for S₁, a = 16.76 Å, b = 13.70 Å, c = 3.88 Å; for S₄, a = 3.86 Å, b = 11.64 Å, c = 20.98 Å, d _exp = 4.62 g/cm³). Compound S₂ crystallizes in cubic system (a = 10.68 Å).     

Section EuNdGa3S7-EuGa4S7 of the ternary system Nd2S3-Ga2S3-EuS

The section EuNdGa₃S₇-EuGa₄S₇ of the ternary system Nd₂S₃-Ga₂S₃-EuS was studied by physicochemical analysis methods (differential thermal, X-ray powder diffraction, and microstructural analyses and microhardness and density measurements). The data obtained were used to construct the state diagram of the section EuNdGa₃S₇-EuGa₄S₇. The section was found to be a quasi-binary section of the ternary system and is of the eutectic type. The coordinates of the eutectic are 64 mol % EuGa₄S₇ and T _melt = 1170 K. A region of solid solutions based on both components was found.     

Chemoenzymatic synthesis of (3R,4S)- and (3S,4R)-3-methoxy-4-methylaminopyrrolidine

An efficient and a convenient enantioselective synthesis of (3R,4S)-3-methoxy-4-methylaminopyrrolidine has been carried out by a lipase-mediated resolution protocol. This method describes the preparation of (±)-1-Cbz-cis-3-azido-4-hydroxypyrrolidine starting from commercially available diallylamine followed by ring-closing metathesis (RCM) via S_N2 displacement reactions. Pseudomonas cepacia lipase immobilized on diatomaceous earth (Amano PS-D) provides (3R,4S)-11 and (3S,4R)-12 in an excellent enantiomeric excess.     

A synthetic approach toward taxol analogs: studies on the construction of the CD ring

Tricycle 6, containing the CD ring of taxol, is constructed from (S)-(+)-carvone in 21 steps involving a Diels-Alder reaction with isoprene, a Baeyer-Villiger oxidation, an Oppenaurer oxidation and Meerwein-Ponndorf-Verley reduction, a stereospecific Grignard addition, and an intramolecular S_N2 reaction as the key steps.