Synthesis of enantiomers of exo‐2‐norbornyl‐N‐n‐butylcarbamate and endo‐2‐norbornyl‐N‐n‐butylcarbamate for stereoselective inhibition of acetylcholinesterase

The acetylcholinesterase inhibition by enantiomers of exo‐ and endo‐2‐norbornyl‐N‐n‐butylcarbamates shows high stereoselelectivity. For the acetylcholinesterase inhibitions by (R)‐(+)‐ and (S)‐(?)‐exo‐2‐norbornyl‐N‐n‐butylcarbamates, the R‐enantiomer is more potent than the S‐enantiomer. But, for the acetylcholinesterase inhibitions by (R)‐(+)‐ and (S)‐(?)‐endo‐2‐norbornyl‐N‐n‐butylcarbamates, the S‐enantiomer is more potent than the R‐enantiomer. Optically pure (R)‐(+)‐exo‐, (S)‐(?)‐exo‐, (R)‐(+)‐endo‐, and (S)‐(?)‐endo‐2‐norbornyl‐N‐n‐butylcarbamates are synthesized from condensations of optically pure (R)‐(+)‐exo‐, (S)‐(?)‐exo‐, (R)‐(+)‐endo‐, and (S)‐(?)‐endo‐2‐norborneols with n‐butyl isocyanate, respectively. Optically pure norborneols are obtained from kinetic resolutions of their racemic esters by lipase catalysis in organic solvent. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Synthesis of New exo‐ and endo‐3,8‐Dihydro‐β‐santalols and Other Norbornyl‐Derived Alcohols

Several new and differently functionalized cis‐2,3‐dimethylnorbornane derivatives presenting diverse side‐chain lengths were prepared, the structures of which are related to the natural fragrance β‐santalol. In particular, exo‐ and endo‐3,8‐dihydro‐β‐santalols, with either (E) or (Z) C?C‐bond configuration on the side chain, were synthesized in seven steps and 21–24% overall yields. Several other exo‐ and endo‐norbornyl alcohols with shorter side chains were also prepared in high yields. The olfactory evaluation indicated woody, sandalwood, as well as fruity notes for some of the derivatives.     

Application of NMR spectroscopy for assignment of the absolute configuration of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one

In order to assign the absolute configurations of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one ( 2a , 2b ), their esters ( 5a , 5b , 5c , 5d ) with (R)‐ or (S)‐2‐methoxyphenylacetic acid ( 4a , 4b ) have been synthesized. The absolute configurations of these compounds have been determined on the basis of NOESY correlations between the protons of the tert‐butyl group and the cyclopentane fragment of the molecules. The crucial part of this analysis was assignment of the absolute configuration at C‐5. Additionally, by calculation of the chemical shift anisotropy, δ^RS, for the relevant protons, it was also possible to confirm the absolute configurations at the C‐2 centres of compounds 2a , 2b and 5a , 5b , 5c , 5d . Chirality, 25:422–426, 2013.© 2013 Wiley Periodicals, Inc.     

Synthesis of Novel Camphor‐Derived Bifunctional Thiourea Organocatalysts

Synthesis and catalyst performance of 2,3‐ (types B and C ) and 2,8‐disubstituted (type D ) thiourea bifunctional organocatalysts was attempted. The synthesis of catalyst of type B has, so far, not been realized, while catalysts of type C , i.e., the 2,3‐exo‐ and the 2‐endo‐3‐exo‐thiourea catalysts, were prepared in six steps starting from (+)‐camphor. The catalysts of type D were prepared from (+)‐camphor in eight steps. All the potential catalysts as well as most of the intermediate products were carefully structurally characterized. The thiourea bifunctional organocatalysts were tested in a model reaction of Michael addition of dimethyl malonate to trans‐β‐nitrostyrene. Chirality 27:39–52, 2015. © 2014 Wiley Periodicals, Inc.     

Optically Active α‐Phenylethylamine as Efficient Organocatalyst in the Solvent‐free Reactions Between 2,3‐Butanedione and Conjugated Nitroolefins

(R)‐(+) and (S)‐(?)‐1‐phenylethylamine have been shown to promote highly diastereoselective and complementary enantioselective formal [3 + 2]carbocyclization reactions between 2,3‐butanedione and conjugated nitroalkenes with formation of enantiomerically rich 2‐hydroxy‐3‐nitrocyclopentanone derivatives. The reactions were carried out both in solvent and under solvent‐free conditions. The absolute configurations of the products were assigned by X‐ray and circular dichroism spectra analyses. Chirality 24:1005–1012, 2012. © 2012 Wiley Periodicals, Inc.     

Resolution of 1‐n‐Butyl‐3‐Methyl‐3‐Phospholene 1‐Oxide With TADDOL Derivatives and Calcium Salts of O,O'‐Dibenzoyl‐(2R,3R)‐ or O,O'‐di‐p‐Toluoyl‐(2R,3R)‐tartaric Acid

The resolution methods applying (?)‐(4R,5R)‐4,5‐bis(diphenylhydroxymethyl)‐2,2‐dimethyldioxolane (“TADDOL”), (?)‐(2R,3R)‐α,α,α',α'‐tetraphenyl‐1,4‐dioxaspiro[4.5]decan‐2,3‐dimethanol (“spiro‐TADDOL”), as well as the acidic and neutral Ca²⁺ salts of (?)‐O,O'‐dibenzoyl‐ and (?)‐O,O'‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid were extended for the preparation of 1‐n‐butyl‐3‐methyl‐3‐phospholene 1‐oxide in optically active form. In one case, the intermediate diastereomeric complex could be identified by single‐crystal X‐ray analysis. The absolute P‐configuration of the enantiomers of the phospholene oxide was also determined by comparing the experimentally obtained and calculated CD spectra. Chirality 26:174–182, 2014. © 2014 Wiley Periodicals, Inc.     

Stereoselective Synthesis of (R)‐3‐Methylthalidomide by Piperidin‐2‐one Ring Assembly Approach

A simple and stereoselective synthesis of 3‐methylthalidomide, a configurationally stable thalidomide analog, is presented. Herein we describe the synthesis of (R)‐3‐methylthalidomide starting from (S)‐alanine by piperidin‐2‐one ring assembly approach in high yield and enantiomeric purity without using a chiral auxiliary or reagent. Starting from (R)‐alanine, the corresponding (S)‐3‐methylthalidomide can be prepared using the same methodology. Chirality 27:619–624, 2015. © 2015 Wiley Periodicals, Inc.     

Room temperature and highly enantioselective additions of alkyltitanium reagents to aldehydes catalyzed by a titanium catalyst of (R)‐h8‐binol

Three alkyltitanium reagents of RTi(O‐i‐Pr)₃ (R = Cy ( 1a ), i‐Bu ( 1b ), and n‐Bu ( 1c )) were prepared in good yields. The high‐resolution mass spectroscopy showed that 1b and 1 c in the gas phase are monomeric species. However, the solid state of 1a revealed a dimeric structure. Asymmetric additions of 1a , 1b , 1c to aldehydes catalyzed by a titanium catalyst of (R)‐H₈‐BINOL were studied at room temperature. The reactions produced desired secondary alcohols in good yields with good to excellent enantioselectivities of up to 94% ee. Reactivity and enantioselectivity differences, in terms of steric bulkiness of the R nucleophiles, are herein described. The addition reactions of secondary c‐hexyl to aldehydes were slower than the reactions of primary i‐butyl or n‐butyl nucleophiles. For the primary alkyls, lower enantioselectivities were obtained for products from addition reactions of the linear n‐butyl as compared with the enantioselectivities of products from the addition reactions of the branched i‐butyl group. The same stereochemistry of RTi(O‐i‐Pr)₃ addition reactions as the addition reactions of organozinc, organoaluminum, Grignard, or organolithium reagents directly supports the argument of that titanium‐catalyzed addition reactions of aldehydes involve an addition of an organotitanium nucleophile. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

Chiral syntheses of methyl (R)‐2‐Sulfanylcarboxylic esters and acids with optical purity determination using HPLC

Accessible chiral syntheses of 3 types of (R)‐2‐sulfanylcarboxylic esters and acids were performed: (R)‐2‐sulfanylpropanoic (thiolactic) ester (53%, 98%ee) and acid (39%, 96%ee), (R)‐2‐sulfanylsucciinic diester (59%, 96%ee), and (R)‐2‐mandelic ester (78%, 90%ee) and acid (59%, 96%ee). The present practical and robust method involves (i) clean S_N2 displacement of methanesulfonates of (S)‐2‐hydroxyesters by using commercially available AcSK with tris(2‐[2‐methoxyethoxy])ethylamine and (ii) sufficiently mild deacetylation. The optical purity was determined by the corresponding (2R,5R)‐trans‐thiazolidin‐4‐one and (2S,5R)‐cis‐thiazolidin‐4‐one derivatives based on accurate high‐performance liquid chromatography analysis with high‐resolution efficiency. Compared with the reported method utilizing AcSCs (generated from AcSH and CsCO₃), the present method has several advantages, that is, the use of odorless AcCOSK reagent, reasonable reaction velocity, isolation procedure, and accurate, reliable optical purity determination. The use of accessible AcSK has advantages because of easy‐to‐handle odorless and hygroscopic solid that can be used in a bench‐top procedure. The Ti(OiPr)₄ catalyst promoted smooth trans‐cyclo‐condensation to afford (2R,5R)‐trans‐thiazolidin‐4‐one formation of (R)‐2‐sulfanylcarboxylic esters with available N‐(benzylidene)methylamine under neutral conditions without any racemization, whereas (2S,5R)‐cis‐thiazollidin‐4‐ones were obtained via cis‐cyclo‐condensation and no catalysts. Direct high‐performance liquid chromatography analysis of methyl (R)‐mandelate was also performed; however, the resolution efficiency was inferior to that of the thaizolidin‐4‐one derivatizations.     

Enhanced diastereoselective synthesis of t‐Butyl 6‐cyano‐(3R,5R)‐dihydroxyhexanoate by using aldo‐keto reductase and glucose dehydrogenase co‐producing engineered Escherichia coli

t‐Butyl 6‐cyano‐(3R,5R)‐dihydroxyhexanoate ((3R,5R)‐ 2 ) is a key chiral diol precursor of atorvastatin calcium (Lipitor®). We have constructed a Kluyveromyces lactis aldo‐keto reductase mutant KlAKR‐Y295W/W296L (KlAKRm) by rational design in previous research, which displayed high activity and excellent diastereoselectivity (de_p > 99.5%) toward t‐butyl 6‐cyano‐(5R)‐hydroxy‐3‐oxohexanoate ((5R)‐ 1 ). To realize in situ cofactor regeneration, a robust KlAKRm and Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) co‐producer E. coli BL 21(DE3) pETDuet‐esgdh (MCS1)/pET‐28b (+)‐klakrm was constructed in this work. Under the optimized conditions, AKR and GDH activities of E. coli BL 21(DE3) pETDuet‐esgdh (MCS1)/pET‐28b (+)‐klakrm peaked at 249.9 U/g DCW (dry cellular weight) and 29100 U/g DCW, respectively. It completely converted (5R)‐ 1 at substrate loading size of up to 60.0 g/L (5R)‐ 1 in the absence of exogenous NADH, which was one‐fifth higher than that of the separately prepared KlAKRm and EsGDH under the same conditions. In this manner, a biocatalytic process for (3R,5R)‐ 2 with productivity of 243.2 kg/m³ d was developed. Compared with the combination of separate expressed KlAKRm with EsGDH, co‐expression of KlAKRm and EsGDH has the advantages of alleviating cell cultivation burden and elevating substrate load. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1235–1242, 2017     

Synthesis and Properties of a Novel Pyridineoxazoline Containing Optically Active Helical Polymer as a Catalyst Ligand for Asymmetric Diels–Alder Reaction

A novel pyridineoxazoline (PyOx) containing helical polymer, poly{(–)‐(S)‐4‐tert‐butyl‐2‐[5‐(4‐tert‐butylphenyl)‐3‐vinylpyridin‐2‐yl]‐oxazoline} ( PA ), was designed and synthesized to approach the effect of chain conformation on the catalytic property. Its complex with Cu(OTf)₂, i.e., Cu(II)-PA , was employed to catalyze the homogeneous Diels–Alder (D–A) reaction of alkenoyl pyridine N‐oxides with cyclopentadiene in tetrahydrofuran. Compared with the previously reported copper complex, Cu(II)-P1 (RSC Advances, 2015, 5 , 2882), which was derived from a nonhelical poly[(–)‐(S)‐4‐tert‐butyl‐2‐(3‐vinylpyridin‐2‐yl)‐oxazoline], Cu(II)-PA exhibited a remarkably enhanced enantioselectivity and reaction rate. However, its enantioselectivity was lower than the Cu(II) complex of (–)‐(S)‐4‐tert‐butyl‐2‐[5‐(4‐tert‐butylphenyl)‐3‐vinylpyridin‐2‐yl]‐oxazoline ( Cu(II)-A ), a low molar mass model compound. Chirality 27:523–531, 2015. © 2015 Wiley Periodicals, Inc.     

endo/exo Stereoselectivity in DielsAlder Reactions of α,β‐Dialkylated Conjugated Enals to Cyclic 1,3‐Dienes: Intermediates in the Synthesis of (−)‐β‐Santalol and Its Analogs

Highly exo‐selective [4+2] cycloadditions of cyclopenta‐1,3‐diene 2a to α,β‐dialkyl conjugated enals 5 are compared with the analogous endo‐favored Diels? Alder reaction of cyclohexa‐1,3‐diene 7 . The exo‐stereoselectivity is lower in the homologous case of methylcyclopenta‐1,3‐diene 9 . This diastereoselectivity is discussed either in terms of a retro‐homo‐Diels? Alder reaction, associated with thermodynamic control, or with respect to either a competing hetero‐Diels? Alder/Claisen or Cope domino pathway, or retro‐Claisen/retro‐hetero‐Diels? Alder of the endo‐homo‐cycloadducts. These hypothetical mechanisms have been examined by DFT calculations at the MPW1K(CH₂Cl₂)/6‐31+G** level of theory for the AlCl₃‐mediated cycloadditions of 5d to 2a and 7 . Application of Corey's methodology to the γ‐halogeno‐α‐methyl‐substituted dienophiles 5a and 5b allowed an enantioselective preparation of known and useful intermediates for the synthesis of either the naturally occurring (?)‐β‐santalol or its potentially olfactive structural analogs.     

Production of (R)‐1‐phenylethanols through bioreduction of acetophenones by a new fungus isolate Trichothecium roseum

A total of 120 fungal strains were isolated from soil samples and evaluated in the bioreduction of substituted acetophenones to the corresponding (R)‐alcohols. Among these strains, isolate Trichothecium roseum EBK‐18 was highly effective in the production of (R)‐alcohols with excellent enantioselectivity (ee > 99%). Gram scale preparation of (R)‐1‐phenylethanol is reported. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Diastereomeric resolution of p‐chloromandelic acid with (R)‐phenylethylamine

The optical resolution of p‐chloromandelic acid using (R)‐α‐phenylethylamine as resolving agent was presented. The effect of solvents, molar ratio of racemate to the resolving agent, filtration temperature as well as the amount of solvent on resolution was investigated by orthogonal experimentation. The binary melting point phase diagram and crystal structure analysis of diastereomeric salts rationalized the success of the resolution. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Pyriculins A and B,two monosubstituted hex‐4‐ene‐2,3‐diols and other phytotoxic metabolites produced by Pyricularia grisea isolated from buffelgrass (Cenchrus ciliaris)

Pyricularia grisea has been identified as a foliar pathogen on buffelgrass (Cenchrus ciliaris ) in North America and was studied as a potential source of phytotoxins for buffelgrass control. Two monosubstituted hex‐4‐ene‐2,3‐diols, named pyriculins A and B, were isolated from its culture filtrate organic extract together with (10S ,11S )‐(−)‐epipyriculol, trans ‐3,4‐dihydro‐3,4,8‐trihydroxy‐1(2H )‐napthalenone, and (4S )‐(+)‐isosclerone. Pyriculins A and B were characterized by spectroscopic (essentially nuclear magnetic resonance [NMR], High‐resolution electrospray ionization mass spectrometry [HRESIMS]) and chemical methods such as (4E )‐1‐(4‐hydroxy‐1,3‐dihydroisobenzofuran‐1‐yl)hex‐4‐ene‐2,3‐diols. The relative and absolute configuration of these compounds was determined by a combination of spectroscopic (NMR, electronic circular dichroism [ECD]) and computational tools. When bioassayed in a buffelgrass coleoptile and radicle elongation test, (10S ,11S )‐(−)‐epipyriculol proved to be the most toxic compound. Seed germination was much reduced and slowed with respect to the control and radicles failed to elongate. All five compounds delayed germination, but only (10S ,11S )‐(−)‐epipyriculol was able to prevent radicle development of buffelgrass seedlings. It had no effect on coleoptile elongation, while the other four compounds caused significantly increased coleoptile development relative to the control.     

Enantioselective synthesis and antioxidant activity of 3‐(3,4‐dihydroxyphenyl)‐glyceric acid—Basic monomeric moiety of a biologically active polyether from Symphytum asperum and S. caucasicum

The racemic and enantioselective synthesis of a novel glyceric acid derivative, namely, 2,3‐dihydroxy‐3‐(3,4‐dihydroxyphenyl)‐propionic acid as well as the antioxidant activities is described. The virtually pure enantiomers, (+)‐(2R,3S)‐2,3‐dihydroxy‐3‐(3,4‐dihydroxyphenyl)‐propionic acid and (?)‐(2S,3R)‐2,3‐dihydroxy‐3‐(3,4‐dihydroxyphenyl)‐propionic acid were synthesized for the first time via Sharpless asymmetric dihydroxylation of trans‐caffeic acid derivatives using the enantiocomplementary catalysts, (DHQD)₂‐PHAL and (DHQ)₂‐PHAL. The determination of enantiomeric purity of the novel chiral glyceric acid derivatives was performed by high‐performance liquid chromatographic techniques on the stage of their alkylated precursors. The novel glyceric acid derivatives show strong antioxidant activity against hypochlorite and N,N‐diphenyl‐N‐picryl‐hydrazyl free radical. Their antioxidant activity is about 40‐fold higher than that of the corresponding natural polyether and three‐fold higher of trans‐caffeic acid itself. Chirality, 2010. © 2010 Wiley‐Liss, Inc.     

Practical access to the proline analogs (S,S,S)- and (R,R,R)-2-methyloctahydroindole-2-carboxylic acids by HPLC enantioseparation

An efficient methodology for the preparation of the α‐tetrasubstituted proline analog (S,S,S)‐2‐methyloctahydroindole‐2‐carboxylic acid, (S,S,S)‐(αMe)Oic, and its enantiomer, (R,R,R)‐(αMe)Oic, has been developed. Starting from easily available substrates and through simple transformations, a racemic precursor has been synthesized in excellent yield and further subjected to HPLC resolution using a cellulose‐derived chiral stationary phase. Specifically, a semipreparative (250 mm × 20 mm ID) Chiralpak® IC column has allowed the efficient resolution of more than 4 g of racemate using a mixture of n‐hexane/tert‐butyl methyl ether/2‐propanol as the eluent. Multigram quantities of the target amino acids have been isolated in enantiomerically pure form and suitably protected for incorporation into peptides. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

Synthesis of a protected trihydroxyindolizidine 3-carboxylate via a hetero-Diels–Alder addition of ethyl 2-nitrosoacrylate to a d-ribose-derived exo-glycal

A protected trihydroxyindolizidine 3-carboxylate was prepared by a 6-endo epoxide cleavage, which in turn was intermediately formed from the hetero-Diels–Alder adduct of ethyl 2-nitrosoacrylate to a d-ribose-derived exo-glycal.     

An Eco‐Friendly Enantioselective Access to (R)‐Naringenin as Inhibitor of Proinflammatory Cytokine Release

(RS)‐Naringenin is a flavanone well‐known for its beneficial health‐related properties, such as its anti‐inflammatory activity. The preparative enantioselective chromatographic resolution of commercial (RS)‐naringenin was performed on a Chiralpak AD‐H column (500×50 mm i.d., d_p 20 μm) using MeOH as eluent. The developed method is in accordance with the principles of green chemistry, since the environmental impact was lowered by recycling of the eluent, and allowed the production of gram amounts of each enantiomer with high purity (chemical purity >99%, enantiomeric excess (ee) >94%). Racemic and enantiomeric naringenin were subjected to an exhaustive in vitro investigation of anti‐inflammatory activity, aimed at evaluating the relevance of chirality. The assay with cultured human peripheral blood mononuclear cells (hPBMC) activated by phytohemagglutinin A revealed that (R)‐naringenin was more effective in inhibiting T‐cell proliferation than the (S)‐enantiomer and the racemate. Moreover, (R)‐naringenin significantly reduced proinflammatory cytokine levels such as those of TNF‐α and, with less potency, IL‐6. These results evidenced the anti‐inflammatory potential of naringenin and the higher capacity of (R)‐naringenin to inhibit both in vitro hPBMC proliferation and cytokine secretion at non toxic doses. Thus, (R)‐naringenin is a promising candidate for in vivo investigation.     

Electrophilic [N—F]+ catalysed asymmetric allylation of (E)‐N,1‐diphenylmethanimine

New efficient catalysts based on electrophilic N‐fluoro quaternary ammonium salts are reported for catalytic allylation of (E)‐N,1‐diphenylmethanimine. The chiral version of the catalyst based on cinchonidine (F‐CD‐BF₄) shows high catalytic activity with approximately 94% ee and TOF (>800 h^?1). The F‐CD‐BF₄ is prepared from cinchonidine and Selectfluor by one‐step transfer fluorination.