Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from d-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by intramolecular reductive amination of amino-aldehyde.     

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.     

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.     

First enantioselective synthesis of the novel antiinfective TAN-1057A via its aminomethyl-substituted dihydropyrimidinone heterocycle

Enantiomerically pure N²-Z-N²-MeAsnOH [(S)-14], prepared in 8 steps (23% overall yield) from asparaginic acid, was first subjected to a Hofmann degradation with PhI(OCOCF₃)₂ yielding (S)-N²-Z-N²-methyl-2,3-diaminopropanoic acid [N²-Z-N²-Me-L-A₂pr, (S)-15], and this in turn was protected to give N²-Z-N³-Boc-N²-Me-L-A₂pr [(S)-17]. Condensation of (S)-17 with HNC(SMe)NHCONH₂ followed by removal of the tert-butoxycarbonyl protecting group, cyclization and hydrogenolytic removal of the Z-group gave the heterocycle of TAN-1057A [(S)-1] with an e.e. of 87 in 36% yield [from (S)-14]. Coupling of (S)-1 with (S)-tris-Z-β-homoarginine (20a) in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and iPr₂NEt in N,N-dimethylacetamide followed by hydrogenolysis afforded the most active A-diastereomer of the natural antibiotic TAN-1057 in 52% yield (from (S)-1 and 20a). Similarly, starting from (S)-1, a single diastereomer of the potent, less toxic TAN-1057A analogue 22b with a β-lysine side chain has been prepared. All described synthetic steps do not require column chromatography for purification of the products.     

Synthesis of a variety of optically active hydroxylated heterocyclic compounds using epoxide hydrolase technology

Novel epoxide hydrolases in Yarrowia lipolytica have been shown to hydrolyse a variety of functionalised epoxides with good to excellent stereoselectivity and at high volumetric productivities. Individual biotransformation products have been converted into optically active (R)-(tetrahydrofuran-2-yl)methanol (6), (S)-N-benzyl-3-hydroxypyrrolidine (7), (S)-3-hydroxytetrahydrothiophene (8), (S)-N-benzyl-3-acetoxypiperidine (10), (S)-3-hydroxytetrahydrofuran (16) and (R)-[(S)-N-benzylpyrrolidin-2-yl](phenyl)methanol (20).     

On the mechanism of the Fe(CO)5-catalyzed Kbarasch reaction

Addition of BrCCl₃ to methylN-acryloyl-(S)-prolinate (1) catalyzed by Fe(CO)₅ or Fe(CO)₅-PPh₃ at 75–80 °C in benzene solution affords in good total yield methylN-((S)-2-bromo-3,3,3-trichlorobutyryl)-(S)-prolinate (2) and methylN-((R)-2-bromo-3,3,3-trichlorobutyryl)-(S)-prolinate (3) in an ～1.5 : 1 ratio, which does not depend on the catalytic system employed or its concentration. Catalysis by the Fe(CO)₅-PPh₃ system substantially increases the adducts yield.     

Practical and highly stereoselective method for the preparation of several chiral arylsulfinamides and arylsulfinates based on the spontaneous crystallization of diastereomerically pure N-benzyl-N-(1-phenylethyl)-arylsulfinamides

A novel and simple process for the preparation of enantiomerically pure (S_S)-benzenesulfinamide (S_S)-3a, (S_S)-p-toluenesulfinamide (S_S)-3b, (S_S)-p-chloro-benzenesulfinamide (S_S)-3c and (S_S)-p-fluorobenzenesulfinamide (S_S)-3d has been developed. The treatment of arylsulfinyl chlorides with (R)-N-benzyl-1-phenylethanamine in the presence of excess triethylamine gave diastereomeric mixtures of N-benzyl-N-(1-phenylethyl)-arylsulfinamides 1, which underwent spontaneous crystallization to furnish diastereomerically pure (R,S_S)-N-benzyl-N-(1-phenylethyl)-arylsulfinamides (R,S_S)-1a-1d in 28%, 29%, 27% and 31% yields, respectively. The diastereomerically pure compounds (R,S_S)-1 were then converted into four enantiopure (R_S)-methyl arylsulfinates (R_S)-2, and finally into four enantiopure (S_S)-arylsulfinamides (S_S)-3 in good yields.     

Total synthesis of the 5-epimers of naturally occurring (−)-hyacinthacine A5 and unnatural (+)-hyacinthacine A4

(1R,2S,3R,5S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 10 [(+)-5-epihyacinthacine A₅] and (1R,2S,3R,5S,7aS)-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 17 [ent-5-epihyacinthacine A₄] have been synthesized by either Horner–Wadsworth–Emmons (HWE) or Wittig methodology using aldehydes 6 and 13, prepared from (2R,3S,4R,5R)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 5 (partially protected DALDP) and (2R,3S,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine 12 (partially protected DGADP), respectively, and the appropriated ylide, followed by cyclization through an internal reductive amination process of the corresponding intermediate pyrrolidinic ketones 7 and 14 and subsequent deprotection.     

C-Galactosylceramide diastereomers via Sharpless asymmetric epoxidation chemistry

C-Glycoside analogs of α-galactosylceramide (KRN7000) were synthesized in 19 linear steps with Sharpless asymmetric epoxidation as a key reaction. Opening of a hydroxy epoxide with sodium azide provided an anti vicinal azido diol with inversion of configuration at the azide-bearing carbon while opening with Ti(O-i-Pr)₂(N₃)₂ gave syn vicinal azido diol with retention. The latter, unusual outcome could be rationalized either by invoking Ti-catalyzed intramolecular double S_N2 inversion or by epoxide opening/intramolecular delivery of azide from the Ti complex.     

Reactions of β-substituted amines-IV: Kinetics and stereochemistry of the thermal to (r) 3-chloro-1-ethylpiperidine,and the stereo-chemical course of their reactions with nucleophiles

The rate of the thermal rearrangement of (S) 2 chloromethyl-1-ethylpyrrolidine [(S)-1a] to (R)-3-chloro-1-ethylpiperidine [(R) 2a] has been examined at three temperatures in benzene by PMR and polarimetry. The rearrangement was shown to be completely stereospecific and to obey a simple first order rate law. The calculated E_a ΔH3 and ΔS3 were 22 ± 2 $\text{kcal}\text{mole}$ (25°), 21 ± 2.5 $\text{kcal}\text{mole}$ (25°) and - 10 ± 2 e.u. (0°K) respectively. The effect of solvents having differing dielectric constants was also studied. A transition state 9'a and an ion pair intermediate 3a are suggested for the rearrangement. The stereochemical course of the reactions of (S)-1a, (R)-2a and (S)-2a with hydroxide and methoxide ions have been shown to be 100% stereospecific with an uncertainty of about 1%. The absolute configurations of all optically active reactants and products [(S)- and (R)-4a, (S)-4b (R)- and (S)-5a, (R)-5b, (S,S')-6a, (S,R')-7a and (R,R')-8a] were established by chemical correlations with known compounds or by ORD and chemical inference. The ring opening of both the primary and secondary aziridinium ion positions of 1-azonia-1-ethylbicyclo [3.1.0]hexane [(S)-3a] by nucleophiles proceeds entirely by S_N2 processes. The conversion of (R)-1-ethyl-3-hydroxypiperidine [(R)-5a] to (S)-2a. HCl with thionyl chloride in chloroform proceeds by inversion with 4.8% racemization, whereas the thermal rearrangement of (S)-1a to (R)-2a occurs with complete retention of absolute configuration.     

Ring opening of chiral 2-(1-aminoalkyl)epoxides by aliphatic thiols with total selectivity: synthesis of enantiopure 3-amino-1-(alkylthio)alkan-2-ols

We have studied the thiolysis of (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides 1 or 2 in the presence of BF₃·OEt₂. The ring opening took place at C-3 with complete regioselectivity, affording the corresponding enantiopure (2R,3S)- or (2S,3S)-3-amino-1-(alkylthio)alkan-2-ols 3 or 4 in good or high yield. The structures of compounds 3 and 4 have been proposed based on HMBC NMR experiments.     

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.     

Novel enantiopure non-C2-symmetric NCN-pincer palladium complexes with l-proline chiral auxiliaries: mer η3-N,C,N versus square planar η4-N,C,N,O coordination

New chiral NCN-pincer palladium complexes containing proline ester moieties as chiral auxiliaries have been synthesized. The parent ligands 2,6-bis{[(S)-2-(methoxycarbonyl)-1-pyrrolidinyl]methyl}-1-bromobenzene L^Me and 2,6-bis{[(S)-2-(benzoxycarbonyl)-1-pyrrolidinyl]methyl}-1-bromobenzene L^Bn were prepared in a single synthetic step and were obtained enantiomerically pure. Neutral arylpalladium bromide complexes 1a and 1b, formed upon treatment of the respective ligands L^Me and L^Bn with [Pd₂(dba)₃]·CHCl₃, were isolated as mixtures of three stereoisomers (S_NS_NS_CS_C, R_NS_NS_CS_C and R_NR_NS_CS_C). The ratio of stereoisomers is approximately 1:1:0.6 in the case of methyl ester derivative 1a, whereas the bulkier benzyl ester derivative 1b predominantly forms the (S_NS_NS_CS_C)-stereoisomer. Upon abstraction of the bromide ion from unresolved mixtures of 1a and 1b, cationic complexes 2 and 3, respectively, form as single diastereoisomers in which one of the ester prolinate carbonyl groups is coordinated to palladium according to X-ray crystal structure determination. This coordination of a carbonyl group to the metal has a substantial influence on the stereochemistry and results in the formation of a single diastereoisomer, having the (R_NR_NS_CS_C)-configuration, regardless of the stereochemistry or ratio of stereoisomers of the starting bromide compound. The structures of compounds 2 and 3 were somewhat unexpected since formation of the corresponding cationic [Pd(NCN)(OH₂)]⁺ complexes was anticipated. In preliminary tests of these cationic complexes as catalysts in the enantioselective aldol condensation of benzaldehyde with methyl isocyanoacetate, modest selectivities were observed.     

Enantiomerically pure cyclopalladated diazaphospholidine

Enantiomerically pure (S)-2-(anilinomethyl)pyrrolidine (S)-2 was obtained from (S)-proline using a modified four-step procedure in a total yield of 56%. Diamine (S)-2 was converted to diazaphospholidine (S)-1 using ^oTolP(NMe₂)₂. The enantiomeric purity of ligand (S)-1 and diamine (S)-2 was determined by ³¹P and ¹H NMR spectroscopy, respectively, using a CN-palladacycle for their chiral derivatization. Direct cyclopalladation of (S)-1, using Pd(OAc)₂ in toluene under mild conditions regioselectively afforded the cyclopalladated complex with the (sp²)C–Pd bond. The aromatic C–H bond activation was confirmed by NMR spectral data and X-ray diffraction study of the PPh₃ derivative of the new P¹,C¹,N¹-chiral phosphapalladacycle.     

Diels–Alder reactions of enantiopure [(1S)-isoborneol-10-sulfinyl]- and [(1S-exo)-2-bornylsulfinyl]vinylcyclohexenes with maleimides

Uncatalyzed cycloadditions of enantiopure [(1S)-isoborneol-10-sulfinyl]- and [(1S-exo)-2-bornylsulfinyl]vinylcyclohexenes with N-phenylmaleimide occur with good facial diastereoselectivity, controlled by the sulfur configuration, even if the extent of this stereoselection appears influenced by the structural features of the terpene residue directly linked to the sulfoxide moiety. Complete endo diastereoselectivity is observed in LiClO₄ catalyzed cycloadditions of (R_S)-1-{1-[(1S)-isoborneol-10-sulfinyl]- and (S_S)-1-{1-[(1S-exo)-2-bornylsulfinyl]vinyl}cyclohexenes 4 and 5, respectively. The Diels–Alder reactivity of 5 and (S_S,E)-1-{2-[(1S-exo)-2-bornylsulfinyl]vinyl}cyclohexene 7, with the chiral auxiliary being in a different position with respect to the diene moiety, is also compared, and the results obtained comfirm that 1-sulfinyldienes are less reactive than 2-sulfinyldienes. SnCl₄ catalyzed cycloaddition of 7 with N-methylmaleimide is also performed.     

Synthesis of four enantiomers of 2,3-di(N-Boc-amino)-1-hydroxypropylphosphonates

Enantiomerically pure diethyl (1S,2R)-, (1S,2S)-, (1R,2R)- and (1R,2S)-2,3-di(tert-butoxycarbonyl)amino-1-hydroxypropylphosphonates were synthesised from diethyl (1S,2R,1′S)-, (1S,2S,1′R)-, (1R,2R,1′S)- and (1R,2S,1′R)-[N-(1-phenylethyl)]-2,3-epimino-1-hydroxypropylphosphonates, respectively, via aziridine ring opening with neat TMSN₃ followed by hydrogenolysis in the presence of Boc₂O. A plausible mechanism for the aziridine ring opening in 2,3-epimino-1-hydroxypropylphosphonates involving the intermediate aziridinium ions was proposed. Significant differences in the rates of the aziridine ring opening between diastereoisomeric phosphonates (1S,2R,1′S) and (1S,2S,1′R) were rationalised taking into account different conformations of the 1-phenylethyl group in both diastereoisomers.     

Ligand design for dual enantioselective control in Cu-catalyzed asymmetric conjugate addition of R2Zn to cyclic enone

A new chiral N-heterocyclic carbene (NHC) ligand derived from a natural α-aminoester has been designed and synthesized. The coupling of N-methylbenzimidazole with an α-chloroacetamide derivative, which was prepared from chloroacetyl chloride and (S)-serine methyl ester, gave the corresponding ester/amide-functionalized azolium compound 20. The reaction of 2-cyclohexen-1-one (17) with Et₂Zn in the presence of catalytic amounts of Cu(OTf)₂ and 20 produced (R)-3-ethylcyclohexanone (18) as a major product. In contrast, the enantioselective conjugate addition (ECA) reaction catalyzed by Cu(OTf)₂ under the influence of a hydroxy-amide-functionalized azolium compound 15, which was derived from (S)-tert-leucinol, produced (S)-18 in preference to (R)-18. A series of azolium salts were synthesized from (S)-serine esters, and the reaction conditions for the ECA reaction were optimized to produce (R)-18 with 69% ee. The best results were obtained in the case of the reaction of 4,4-dimethyl-2-cyclohexen-1-one (34) with Et₂Zn catalyzed by Cu(OTf)₂ in combination with azolium compounds. When the reaction of 34 with Et₂Zn was carried out in the presence of catalytic amounts of Cu(OTf)₂ and 20, (S)-3-ethyl-4,4-dimethylcyclohexanone (35) was obtained with 97% ee, whereas the ECA reaction under the influence of hydroxy-amide-functionalized azolium 15 afforded (R)-35 with >99% ee. In this manner, the reversal of enantioselectivity was achieved by controlling the structure of chiral ligands.     

Polyhydroxylated pyrrolizidines. Part 4: Total asymmetric synthesis of unnatural hyacinthacines from a protected derivative of DGDP

(1R,2R,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine [(+)-3-epi-hyacinthacine A₃] 1 and (1R,2R,3S,7aR)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine [(+)-3-epi-hyacinthacine A₂] 2 have been synthesized by Wittig's methodology using aldehyde 6, prepared from (2R,3R,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl) pyrrolidine 3 (a partially protected DGDP), and the appropriated ylides, followed by cyclization through an internal reductive amination process of the resulting α,β-unsaturated ketone 7 and aldehyde 8, respectively, and total deprotection.     

Asymmetric halolactonisation reaction—4: Asymmetric synthesis of optically active α,β-epoxyaldehydes from α,β-unsaturated acids

The bromolactones (5) stereoselectively produced by the asymmetric bromolactonisation of (S)-N-(α,β-unsaturated) acylprolines(3), were elaborated to highly optically active 2(R),3(S)-epoxyaldehydes(8)(84–98% ee) by successive epoxide formation and reductive cleavage of the proline moiety. The overall process constitutes a highly efficient asymmetric synthesis of 8 from α,β-unsaturated acids(1).     

Synthesis of chiral 1- and 2-(p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-dienes and their behaviour in Diels–Alder cycloadditions

The synthesis of (±)-(E)-1-(p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-diene 1 and (S_S)-2-(p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-diene 2 and their reactions with cyclic dienophiles are described. Cycloaddition of diene 1 with N-methylmaleimide 10 was performed under pressure affording a complex reaction mixture from which two epimers at C-3′, (±)-11a and (±)-11b [2,3,3a,4,5,7a-hexahydro-2-methyl-7a-(1-methylsuccinimide-3-yl)-1H-isoindole-1,3,5-triones], were isolated in equal amounts. Diene (±)-1 cycloadded to the more reactive 4-methyl-1,2,4-triazoline-3,5-dione 14 at atmospheric pressure and room temperature. However, nothing can be said about the stereochemical outcome of this addition since the loss of the chiral auxiliary via the sulfoxide–sulfenate rearrangement gave the bicyclic α,β-unsaturated ketone 17 (2-methyl-2,3,5,6-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1,3,6-trione). Diels–Alder cycloaddition of enantiopure diene 2 with 10 occurred under pressure leading to a diastereomeric mixture of adducts where the trimethylsilyl enol ether moiety spontaneously evolved to the ketone function. The major enantiopure product 18a [(3aS,6S,7aR,R_S)-2-methyl-6-(p-tolylsulfinyl)perhydroisoindole-1,3,5-trione] was isolated and characterized. Cycloadditions of both dienes to dienophile 10 appear highly stereoselective.