- Chiral Synthesis via Organoboranes. 6. Hydroboration. 74. Asymmetric Hydroboration of Representative Heterocyclic Olefins with Diisopinocamphenylborane. Synthesis of Heterocyclic Boronates and Heterocyclic Alcohols of Very High Enantiomeric Purity
-
The hydroboration of representative heterocycles bearing an endocyclic double bond with diisopinocamphenylborane (Ipc2BH) was investigated systematically to establish the asymmetric induction achieved in the reaction.The hydroboration of 2,3- and 2,5-dihydrofurans, 1,4-epoxy-1,4-dihydronaphthalene, and 2,3-dihydrothiophene with Ipc2BH in THF at -25 deg C proceeded very cleanly to afford the corresponding trialkylboranes.These trialkylboranes readily eliminate α-piene on treatment with acetaldehyde to give the corresponding boronates, R*B(OR)2.Oxidation afforded in high yields the corresponding heterocyclic alcohols of 100percent ee.N-(Carbobenzyloxy)-3-pyrroline could not be hydroborated with Ipc2BH below 0 deg C.The oxidation of the intermediate trialkylborane gave N-(carbobenzyloxy)-3-pyrrolidinol in 89percent ee.Similarly, six-membered heterocyclic olefins, namely, 3,4-dihydropyran and 3,4-dihydrothiapyran, were hydroborated with Ipc2BH at 0 deg C in THF.The resulting trialkylboranes on treatment with acetaldehyde followed by oxidation yielded 3-hydroxytetrahydropyran and 3-hydroxytetrahydrothiapyran of 83percent and 66percent ee, respectively.N-(Carbobenzyloxy)-1,2,3,6-tetrahydropyridine, hydroborated with Ipc2BH at 0 deg C, followed by oxidation, afforded the corresponding 3- and 4-piperidinols in an 85:15 ratio.The asymmetric induction achieved during hydroboration was 70percent.The five-membered heterocyclic boronates of very high optical purity, highly versatile synthetic intermediates, were isolated both as the diethyl and the diethanolamine esters.
- Brown, Herbert C.,Prasad, J. V. N. Vara
-
-
Read Online
- Stereo-complementary bioreduction of saturated N-heterocyclic ketones
-
The asymmetric bioreduction of several saturated N-heterocyclic ketones is demonstrated in a stereo-complementary fashion using the ketoreductases READH and ChKRED20 for the production of (S)- and (R)-alcohols, respectively. The reaction accepts substrates with a five-, six- or seven-membered ring, and exhibits excellent stereoselectivity when using 2-propanol as both the ultimate reducing agent and cosolvent, achieve >99% ee in the majority of cases for both enantiomers.
- Li, Chao,Liu, Yan,Pei, Xiao-Qiong,Wu, Zhong-Liu
-
-
Read Online
- Enantioselective reduction of heterocyclic ketones with low level of asymmetry using carrots
-
A whole spectrum of biocatalysts for asymmetric reduction of prochiral ketones is well known including the Daucus carota root. However, this type of reaction is still challenging when pro-chiral ketones present low level of asymmetry, like heterocyclic ketones. In this work, 4,5-dihydro-3(2H)-thiophenone (1), 2-methyltetrahydrofuran-3-one (2), N-Boc-3-pyrrolidinone (3), 1-Z-3-pyrrolidinone (4) and 1-benzyl-3-pyrrolidinone (5) were studied in order to obtain the respective enantioselective heterocyclic secondary alcohols. Except for 5, the corresponding alcohols were obtained in high values of conversion and with high selectivity. In order to circumvent the low isolated yield of the corresponding chiral alcohol from 2, we observed that the use of carrots in the absence of water is feasible. Addition of co-solvents was needed to the water-insoluble ketones 3 and 4. Comparatively, baker’s yeast was used for bio reductions of 1, 3 and 4. And in terms of conversion, selectivity and work-up, the use of carrots were a more efficient biocatalyst, as well as a viable method for obtaining 5-member heterocyclic secondary alcohols.
- Machado, Naira Vieira,Omori, álvaro Takeo
-
-
Read Online
- Regio- and stereoselective biohydroxylations with a recombinant escherichia coli expressing P450pyr monooxygenase of sphingomonas Sp. HXN-200
-
A recombinant Escherichia coli expressing P450pyr monooxygenase of Sphingomonas sp. HXN-200 was developed as a useful biocatalyst for regio- and stereoselective hydroxylations, with no side reaction and easy cell growth. The resting E. coli cells showed an activity of 4.1 U/g cdw and 9.9 U/g cdw for the hydroxylation of N-benzylpyrrolidin-2-one 1 and N-benzyloxycarbonylpyrrolidine 3, respectively, being as active as the wide-type strain. Biohydroxylation of N-benzylpyrrolidin-2-one 1 with the resting cells gave (S)-N-benzyl-4- hydroxypyrrolidin-2-one 2 in >99% ee and 10.8 mM, a 2.6 times increase of product concentration in comparison with the wild-type strain. Biohydroxylation of N-tert-butoxycarbonylpiperidin-2-one 5, N-benzylpiperidine 7 and N-tert-butoxycarbonylazetidine 9 with the E. coli cells afforded the corresponding 4-hydroxypiperidin-2-one 6, 4-hydroxypiperidine 8, and 3-hydroxyazetidine 10 in 14 mM, 17 mM, and 21 mM, respectively. Moreover, hydroxylation of (-)-β-pinene 11 with the recombinant E. coli cells showed excellent regio- and stereoselectivity and gave (1R)-trans-pinocarveol 12 in 82% yield and 4.1 mM, which is over 200 times higher than that obtained with the best biocatalytic system known thus far. The recombinant strain was also able to hydroxylate other types of substrates with unique selectivity: biohydroxylation of norbornane 13 gave exo-norbornaeol 14, with exo/endo selectivity of 95%; tetralin 15 and 6-methoxytetralin 17 were hydroxylated at the non-activated 2-position, for the first time, with regioselectivities of 83-84%. Copyright
- Zhang, Wei,Tang, Weng Lin,Wang, Zunsheng,Li, Zhi
-
-
Read Online
- Ultrafast chiral separations for high throughput enantiopurity analysis
-
Recent developments in fast chromatographic enantioseparations now make high throughput analysis of enantiopurity on the order of a few seconds achievable. Nevertheless, routine chromatographic determinations of enantiopurity to support stereochemical investigations in pharmaceutical research and development, synthetic chemistry and bioanalysis are still typically performed on the 5-20 min timescale, with many practitioners believing that sub-minute enantioseparations are not representative of the molecules encountered in day to day research. In this study we develop ultrafast chromatographic enantioseparations for a variety of pharmaceutically-related drugs and intermediates, showing that sub-minute resolutions are now possible in the vast majority of cases by both supercritical fluid chromatography (SFC) and reversed phase liquid chromatography (RP-LC). Examples are provided illustrating how such methods can be routinely developed and used for ultrafast high throughput analysis to support enantioselective synthesis investigations.
- Barhate, Chandan L.,Joyce, Leo A.,Makarov, Alexey A.,Zawatzky, Kerstin,Bernardoni, Frank,Schafer, Wes A.,Armstrong, Daniel W.,Welch, Christopher J.,Regalado, Erik L.
-
supporting information
p. 509 - 512
(2017/01/13)
-
- BRUTON'S TYROSINE KINASE INHIBITORS
-
Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (BTK). Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the BTK inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions. (Formula I)
- -
-
Page/Page column 81; 82
(2014/05/24)
-
- Sulfonylcarbamate as a versatile and unique hydroxy-protecting group: A protecting group stable under severe conditions and labile under mild conditions
-
The sulfonylcarbamate group is a unique hydroxyl protecting group. In contrast to typical acyl protecting groups, the sulfonylcarbamate group is stable under harsh basic conditions, while showing labile behavior under mild basic conditions. Its compatibility with other hydroxyl protecting groups and application to carbohydrate chemistry is demonstrated.
- Manabe, Shino,Yamaguchi, Masanori,Ito, Yukishige
-
supporting information
p. 8332 - 8334
(2013/09/23)
-
- An efficient dynamic kinetic resolution of N-heterocyclic 1,2-amino alcohols
-
A chemoenzymatic dynamic kinetic resolution (DKR) of N-heterocyclic amino alcohols is described. Various lipases were studied as biocatalysts for the kinetic resolution of N-heterocyclic 1,2-amino alcohols. The influence of the support of the enzymes on t
- Lihammar, Richard,Millet, Renaud,Baeckvall, Jan-E.
-
supporting information; scheme or table
p. 2321 - 2327
(2011/10/19)
-
- PROCESS FOR PRODUCING ESTER OR ALCOHOL
-
Provided is a process for producing an ester or alcohol using a fluoroimidinium sulfonate derivative represented by the general formula (9) or a fluoroimidinium carboxylate derivative represented by the general formula (6) and using as a raw material alcohol involving inversion of steric configuration. Further provided are a fluoroimidinium sulfonate derivative represented by the general formula (9), and a process for producing the same.
- -
-
Page/Page column 42
(2009/04/23)
-
- Synthesis of conformationally restricted acetylcholine analogues. Comparing lipase-mediated resolution with simulated moving bed chromatography of arylated β-hydroxy-pyrrolidines
-
The enantiodivergent synthesis of new, conformationally restricted acetylcholine analogues was accomplished using arylated endocyclic enecarbamates as key intermediates. Stereoselective hydroboration of the aryl enecarbamates provided the corresponding ar
- Barreto, Ricardo de L.,Carpes, Marcos J.S.,Santana, Cesar C.,Correia, Carlos R.D.
-
p. 435 - 442
(2007/10/03)
-
- 1,2,4-OXADIAZOLE DERIVATIVES AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
-
The present invention is directed to novel 1,2,4-oxadiazole derivatives which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
- -
-
-
- CYCLOHEXYLALANINE DERIVATIVES AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
-
The present invention is directed to novel cyclohexylalanine derivatives which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
- -
-
-
- PHENYLALANINE DERIVATIVES AS DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
-
The present invention is directed to phenylalanine derivatives which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
- -
-
-
- Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors
-
Amides derived from fluorinated pyrrolidines and 4-substituted cyclohexylglycine analogues have been prepared and evaluated as inhibitors of dipeptidyl dipeptidase IV (DP-IV). Analogues which incorporated (S)-3-fluoropyrrolidine showed good selectivity for DP-IV over quiescent cell proline dipeptidase (QPP). Compound 48 had good pharmacokinetic properties and was orally active in an oral glucose tolerance test in lean mice.
- Caldwell, Charles G.,Chen, Ping,He, Jiafang,Parmee, Emma R.,Leiting, Barbara,Marsilio, Frank,Patel, Reshma A.,Wu, Joseph K.,Eiermann, George J.,Petrov, Aleksandr,He, Huaibing,Lyons, Kathryn A.,Thornberry, Nancy A.,Weber, Ann E.
-
p. 1265 - 1268
(2007/10/03)
-
- Stability against enzymatic hydrolysis of endomorphin-1 analogues containing β-proline
-
The enantiomer of endomorphin-1 (Tyr-Pro-Trp-PheNH2) and the analogues containing (S)-or (R)-β-proline have been synthesized, and their affinities towards μ-opioid receptors have been measured. As expected, the incubations of the different peptides with some commercially available enzymes showed that the presence of D-residues gave strong resistance towards digestion. The presence of β-proline alone is sufficient to confer good resistance against the hydrolysis of the biologically strategic Pro-Trp bond.
- Cardillo, Giuliana,Gentilucci, Luca,Tolomelli, Alessandra,Calienni, Maria,Qasem, Ahmed R.,Spampinato, Santi
-
p. 1498 - 1502
(2007/10/03)
-
- A dirhodium(II)-carbenoid route to (-)- and (+)-Geissman-Waiss lactone: Synthesis of (1R,7R,8R)-(-)-turneforcidine
-
(-)- and (+)-Geissman-Waiss lactone, 4b, was efficiently prepared via the intramolecular C-H insertion reaction of the chiral nonracemic diazoacetates (-)-5a and (+)-5b catalyzed by dirhodium(II) tetrakis[methyl (5R and 5S)-3-phenylpropanoyl-2-imidazolidinone-5-carboxylate]. The cyclization was found to proceed with excellent regioselectivity and cis-diastereoselectivity. The bicyclic lactone (-)-4b was successfully used in the synthesis of the necine base, (-)-turneforcidine 2.
- Wee
-
p. 8513 - 8517
(2007/10/03)
-
- Process for making 3-amino-pyrolidine derivatives
-
The invention is concerned with a process for making a compound of formula STR1 wherein R1 is hydrogen, alkyl, cyclo-alkyl, alkenyl, aryl or an amino protecting group; and R2, R3 each independently is hydrogen, alkyl, cyclo-alkyl, alkenyl or aryl; by reacting a compound of the formula STR2 wherein X is a protected hydroxy group; with R1 NH2 to form a compound of formula STR3 wherein X and R1 are described herein above; and then reacting the compound of formula III with R2 R3 NH under pressure to form the compound of formula I. These compounds are valuable intermediates useful in making cephalosporin derivatives.
- -
-
-
- Constrained β-alanine based GpIIb/IIIa antagonists
-
The concepts of centrally constrained and peptide based fibrinogen receptor antagonists have been successfully combined into a single series of analogs which have been demonstrated to be potent inhibitors of platelet aggregation.
- Klein, Scott I.,Czekaj, Mark,Molino, Bruce F.,Valeria, Chu
-
p. 1773 - 1778
(2007/10/03)
-
- Quinolone antibacterial agents. Synthesis and structure-activity relationships of a series of amino acid prodrugs of racemic and chiral 7-(3- amino-1-pyrrolidinyl)quinolones. Highly soluble quinolone prodrugs with in vivo pseudomonas activity
-
A series of amino acid prodrugs of racemic and chiral 7-(3-amino-1- pyrrolidinyl)-6-fluoro-1,8-naphthyridine-3-carboxylic acids, 1-cyclopropyl- 6,8-difluoro-3-quinolinecarboxylic acids, 1-cyclopropyl-6-fluoro-3- quinolinecarboxylic acids, and 5-amino-1-cyclopropyl-6,8-difluoro-3- quinolinecarboxylic acids have been prepared and evaluated for comparative antibacterial activity. Compounds were prepared by acylation of the 3-amino group of the pyrrolidine with common amino acids using standard peptide chemistry. This series has been compared with the parent compounds for antibacterial activity in vitro and in vivo as well as for comparative solubility. The amino acid analogues were less active in vitro, but had equal or increased efficacy in vivo. Indeed, it was proven that these compounds, which were stable to acid and base under the reaction conditions for their preparation, were rapidly cleaved in serum to give the parent quinolones. The amino acid derivatives showed a 3-70 times improved solubility when compared to the parent compounds. The most active compound of the series was [S- (R*,R*)]-7-[3-[(2-amino-1-oxopropyl)-amino]-1-pyrrolidinyl]-1-cyclopropyl- 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (PD 131112).
- Sanchez,Domagala,Heifetz,Priebe,Sesnie,Trehan
-
p. 1764 - 1773
(2007/10/02)
-
- CHIRAL SYNTHESIS VIA ORGANOBORANES. 19. THE SUCCESSFUL ONE-CARBON HOMOLOGATION OF HETEROCYCLIC BORONATE ESTERS WITH HIGH OPTICAL PURITY
-
An exploratory study was undertaken to establish the applicability of the one-carbon homologation to heterocyclic boronic esters.This procedure involves the use of (cloromethyl)lithium, LiCH2Cl, generated in situ by the reaction of bromochloromethane and n-BuLi in THF at -78 deg C in the presence of an enantiomerically pure heterocyclic boronic ester.These heterocyclic boronic esters were prepared via asymmetric hydroboration of representative heterocyclic olefins bearing either an endocyclic or exocyclic double bond with either Ipc2BH or IpcBH2 in THF.
- Brown, Herbert C.,Gupta, Ashok K.,Rangaishenvi, Milind V.,Vara Prasad, J. V. N.
-
p. 283 - 294
(2007/10/02)
-
