Synthesis of two (S)-indoline-based chiral auxiliaries and their use in diastereoselective alkylation reactions

Two chiral auxiliaries, 2-[(S)-indolin-2-yl]propan-2-ol 1a and (S)-2-(2-methoxypropan-2-yl)indoline 1b, were synthesised from enantiomerically pure (S)-indoline-2-carboxylic acid 3. High diastereoselectivities in alkylations of enolates of the propanoylamides derived from the two auxiliaries are presented. Surprisingly, both auxiliaries induced the same selectivity at the newly created stereogenic centre. The benzyl bromide and n-butyl iodide alkylation reactions showed diastereomeric ratios that were moderate (81:19) to very good (96:4) and with very good yields (86–98%). When LiCl was used as an enolate coordinating agent, in the benzylation of the enolate from propanoylated auxiliary 1a, a very high crude diastereomeric ratio was obtained (99.7:0.3).     

Enantioselective synthesis of (S)-N,N-diethyl-2-formyl-2-(methoxymethoxy)butyramide,a key intermediate for 20(S)-camptothecin analogues,via asymmetric bromolactonization

A new enantioselective synthetic method for enantiomerically pure (S)-N,N-diethyl-2-formyl-2-(methoxymethoxy)butyramide 5, a versatile key intermediate has been developed employing asymmetric bromolactonization using (S)-proline as the chiral auxiliary.     

A highly efficient stereocontrolled synthesis of (S)-2′,6′-dimethyltyrosine [(S)-DMT]

A new, practical and very convenient stereocontrolled synthesis of (S)-2′,6′-dimethyltyrosine [(S)-Dmt] 4 was accomplished in a good yield, starting from the chiral synthon 1,4-N,N-[(S)-phenylethyl]-piperazine-2,5-dione 1. The procedure, which is an extension of our original strategy and occurs with a high level of stereoselectivity (>98%), is simple and inexpensive allowing us to prepare the unnatural α-aminoacid (S)-Dmt also on a multi-gram scale.     

Novel asymmetric total syntheses of (R)-(−)-pyridindolol, (R)-(−)-pyridindolol K1, and (R)-(−)-pyridindolol K2 via a mild one-pot aromatization of N-tosyl-tetrahydro-β-carboline with (S)-2,3-O-isopropylidene-l-glyceraldehyde as the source of chirality

Novel total syntheses of (R)-(?)-pyridindolol 1, (R)-(?)-pyridindolol K1 2, and (R)-(?)-pyridindolol K2 3 are described. By using l-tryptophan methyl ester and (S)-2,3-O-isopropylidene-l-glyceraldehyde as the starting materials, (R)-(?)-pyridindolol 1, (R)-(?)-pyridindolol K1 2, and (R)-(?)-pyridindolol K2 3 were synthesized in 5–7 steps in 66%, 41%, and 55% overall yields, respectively. The characteristic step of the total syntheses is a mild one-pot aromatization of N-tosyl-1,2,3,4-tetrahydro-β-carboline (N-Ts-THBC), which was obtained via Pictet–Spengler reaction of l-tryptophan methyl ester with (S)-2,3-O-isopropylidene-l-glyceraldehyde, and subsequent N-tosylation.     

Stereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl)ethyl]-dihydrofuran-2-one

A short, efficient, and highly diastereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl)ethyl]-dihydrofuran-2-one (1) is described. Use of phthalic anhydride as thiolate scavenger effectively preserves the chiral integrity of the α-aminoketone 4 product obtained from the reaction of organozincate 3 with thioester 2.     

Enzymatic desymmetrization of 2-amino-2-methyl-1,3-propanediol: asymmetric synthesis of (S)-N-Boc-N,O-isopropylidene-α-methylserinal and (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one

We report herein, the novel enzymatic desymmetrization of 2-tert-butoxycarbonylamino-2-methyl-1,3-propanediol 1. This method makes it possible to prepare (S)-N-Boc-N,O-isopropylidene-α-methylserinal 3, which is a chiral building block for the synthesis of a variety of α-substituted alanine derivatives. Moreover, optically active (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one 4, one of the key intermediates in the synthesis of a novel immunosuppressant, has been prepared by this methodology.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Chemoenzymatic synthesis of enantiopure geminally dimethylated cyclopropane-based C2- and pseudo-C2-symmetric diamines

Enantiopure (−)-(1S,3S)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxamide 2 and (+)-(1R,3R)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxylic acid 3 were easily obtained from a multigram scale biotransformation of racemic amide or nitrile in the presence of Rhodococcus erythropolis AJ270 whole cell catalyst under very mild conditions. Coupled with efficient and convenient chemical manipulations, comprising mainly of the Curtius rearrangement, oxidation, and reduction reactions, chiral C₂-symmetric (1S,2S)-3,3-dimethylcyclopropane-1,2-diamine 6 and ((1R,3R)-3-(aminomethyl)-2,2-dimethylcyclopropyl)methanamine 8 and pseudo-C₂-symmetric (1S,3S)-3-(aminomethyl)-2,2-dimethylcyclopropanamine 11 were prepared. These were also transformed into the corresponding chiral salen derivatives 12, 13, and 14, respectively, in almost quantitative yields.     

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F 3 was achieved from the chiral bithiazole-type primary alcohols [(S)- and (R)-4-ethoxycarbonyl-2′-(1-hydroxymethylethyl)-2,4′-bithiazoles 8], which were obtained based on the enzymatic resolution of racemic alcohol 8 and its acetate 9. From a direct comparison by means of chiral HPLC between natural cystothiazole F 3 and synthetic compounds [(4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles 3], natural cystothiazole F 3 was found to be a 33:67 diastereomeric mixture [(4R,5S,6E,14S)-3:(4R,5S,6E,14R)-3 = 33:67].     

Synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal: the common aggregation pheromone of flour beetles

The synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal 1 and 1a has been achieved connecting the chiral building block (R)-2-methyl-1-bromobutane 4 with (R)- and (S)-citronellol derivatives. The key intermediate 4 was obtained optically pure in five steps from methyl (S)-3-hydroxy-2-methylpropionate 2.     

Synthesis of chiral 1,5-disubstituted pyrrolidinones via electrophile-induced cyclization of 2-(3-butenyl)oxazolines derived from (1R,2S)- and (1S,2R)-norephedrine

Starting from (1R,2S)- and (1S,2R)-norephedrine, enantiomers of the corresponding 2-(3-butenyl)oxazolines were prepared in a two-step process. The cyclization of the intermediate alkenylamides with phenylselenyl bromide afforded cyclic imidates instead of the expected pyrrolidinones. The electrophile-induced cyclizations of 2-alkenyloxazolines with bromine or iodine produced diastereomeric mixtures of chiral 1,5-disubstituted pyrrolidinones. The ring closure of the all-cis (1R,2S,5R)-diastereomer 7 with NaH resulted in the tetrahydropyrrolo[2,1-b]oxazol-5-one derivative 18, which was alternatively prepared by the cyclocondensation of (1R,2S)-norephedrine with levulinic acid.     

Synthesis of chiral ligands containing the N-(S)-α-phenylethyl group and their evaluation as activators in the enantioselective addition of Et2Zn to benzaldehyde

The synthesis of chiral ligands 4–18 derived from N-[(S)-α-phenylethyl]-trans-β-aminocyclohexanols (S,S,S)-1a and (R,R,S)-2 is described. Addition of diethylzinc to benzaldehyde catalyzed by ligands 4–18 (6 mol %) proceeds in fair to good yield (45–86%), and low to good enantioselectivities (1–76% ee). Highest enantioselectivities were induced by ligands (S,S,S)-4 and (S,S,S,S,R,R)-18 (76% and 68% ee, respectively). The configuration of the major enantiomer of carbinol 3 is (R) in both cases.     

The reaction of (Sp)-2-(diphenylphosphino)ferrocenecarboxylic acid with carbodiimide reagents: Characterisation of the acid anhydride and urea products

Interaction of (S_p)-2-(diphenylphosphino)ferrocenecarboxylic acid [(S_p)-1] with N,N′-dicyclohexylcarbodiimide (DCC) and N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide (EDC) have been investigated in order to study the reacting system itself and to characterise side-products typically arising during the diimide-promoted condensation of acid (S_p)-1 with nucleophiles. The reaction between (S_p)-1 and DCC was found to give preferentially the respective urea derivative in the absence of a base, and (S_p)-2-(diphenylphosphino)ferrocenecarboxylic anhydride [(S_p,S_p)-3] when the same reaction was performed in the presence of 4-(dimethylamino)pyridine (DMAP). With EDC, the preference for a reaction pathway was less pronounced: whereas the reaction without the base afforded exclusively the corresponding urea, that in the presence of DMAP yielded a mixture of the urea and anhydride (S_p,S_p)-3.     

New chiral phosphorus catalysts derived from (S)-binaphthol for highly enantioselective reduction of acetophenone by borane

New chiral (+)-2,2′-O,O-(1,1′-binaphthyl)-dioxo-N,N-diethylphospholidine 1 and its borane complex 3 were prepared from (S)-binaphthol and their use as catalysts in enantioselective borane reductions of prochiral acetophenone were investigated. Enantiomeric excesses of up to 98.5% have been obtained using 6 mol% of 1 at room temperature and using 6 mol% of 3 at 100°C.     

Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.     

Synthesis of (S)-, (R)-, and (rac)-2-amino-3,3-bis(4-fluorophenyl)propanoic acids and an evaluation of the DPP IV inhibitory activity of Denagliptin diastereomers

The non-proteinogenic amino acid (2S)-2-amino-3,3-bis(4-fluorophenyl)propanoic acid [(S)-1] is a key intermediate required for the synthesis of Denagliptin (2a). Denagliptin is a dipeptidyl peptidase IV (DPP IV) inhibitor that is being developed for the treatment of type-2 diabetes mellitus. A diastereoselective, cost-efficient synthetic procedure for (S)-1 was developed by alkylating a Ni(II) glycine equivalent derived from (S)-2-[(N-benzylprolyl) amino] benzophenone [(S)-BPB]. The alkylated product was then decomposed to isolate the target amino acid (S)-1 (ee >99%) and ligand (S)-BPB, which can be reused in subsequent reactions. The enantiomer (R)-1 and racemate (rac)-1 were synthesized from their corresponding Ni(II) glycine equivalents. Denagliptin diastereomers (2), derived from the key intermediates (S)-1, (R)-1, and (rac)-1 were synthesized, and their dipeptidyl peptidase IV inhibitory activities were investigated. These findings are important in the design and synthesis of DPP IV inhibitors.     

Catalytic asymmetric borane reduction of prochiral ketones by the use of diazaborolidine catalysts prepared from chiral β-diamines

The catalytic asymmetric borane reduction of prochiral ketones was examined in the presence of chiral diazaborolidine catalysts prepared in situ from chiral β-diamines and borane. Chiral secondary alcohols were obtained with modest to high enantiomeric excesses (up to 92% ee) using (S)-2-[(4-trifluoromethyl)anilinomethyl]indoline 2f.     

Enantiospecific synthesis of the sugar amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid

An enantiospecific synthesis of the tetrahydrofuran amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid 1 is reported. The sugar enone 2-(S)-octyl 6-O-acetyl-3,4-dideoxy-α-d-glycero-hex-3-enopyranosid-2-ulose 2a, derived from galactose, was employed as a chiral precursor. The enone 2a was converted by chemical manipulation of the functional groups into the 6-azido-2-O-tosyl-3,4,6-trideoxy-d-erythro-hexono-1,5-lactone 9 as key intermediate. Methanolysis of 9 induced the opening of the lactone and the attack of the hydroxyl group at C-5 to C-2 with the displacement of the tosylate. This reaction led to the formation of the tetrahydrofuran ring of methyl (2S,5S)-5-(azidomethyl)-tetrahydrofuran-2-carboxylate 10, which was readily converted into 1. The overall yield of the sequence was 35%, and all the intermediates and the final product have been fully characterized. In addition, the preferential conformations in solution of lactone 9 and target molecule 1 have been established.     

Diastereoselective route to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone component of the wasp Paravespula vulgaris

A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3, derived from the enantiomers of ethyl β-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.     

Efficient preparation of enantiomerically pure (E)-4-(tributylstannanyl)but-3-en-2-ol via lipase-mediated resolution

The practical preparation of enantiomerically pure (E)-4-(tributylstannanyl)but-3-en-2-ol 1 from 3-butyn-2-ol 2 is reported. A modified Guibé's Pd-catalyzed hydrostannation of 2 provided the racemic γ-hydroxy vinylstannane 1 in a good yield. The enzymatic esterification of 1, with an inexpensive lipozyme, afforded (R)-3 and (S)-1 with very high enantiomeric excesses and chemical yields. This procedure is suitable for the multigram scale preparation of the potential chiral building blocks, (R)-1 and (S)-1.