An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• to a β-aminoacid, and a tropinone-type unit bound to a 1,2,4-triazole ring. Relatively simple and straightforward chemical transformations are used to assemble the main fragments of maraviroc such as amide bond formation and reductive amination (Scheme 57) [86]. The triazole ring incorporation is

Total synthesis of (±)-coerulescine and (±)-horsfiline

• Mukund G. Kulkarni,
• Attrimuni P. Dhondge,
• Sanjay W. Chavhan,
• Ajit S. Borhade,
• Yunnus B. Shaikh,
• Deekshaputra R. Birhade,
• Mayur P. Desai and
• Nagorao R. Dhatrak

Beilstein J. Org. Chem. 2010, 6, 876–879, doi:10.3762/bjoc.6.103

• N-oxide (NMO), followed by cleavage of the diol with sodium metaperiodate on silica in methylene chloride. Reductive amination of the aldehyde 12 was conducted using methylamine hydrochloride and NaBH3CN and gave spiro-oxindole 13. The Boc group of 13 was removed by treatment with 2.5 M HCl to give

Development of dynamic kinetic resolution on large scale for (±)-1-phenylethylamine

• Lisa K. Thalén and
• Jan-E. Bäckvall

Beilstein J. Org. Chem. 2010, 6, 823–829, doi:10.3762/bjoc.6.97

• for their preparation that are applicable on multigram scale. They can be prepared by resolution of amines, hydrogenation of prochiral imines and enamines [1][2], alkylation of prochiral imines [3], aminohydroxylation of alkenes [4], transamination of prochiral ketones [5][6][7], and reductive

• amination of prochiral ketones [8]. Of these methods kinetic resolution using enzymes is often favored due to its simplicity [9][10]. The main disadvantages of kinetic resolution are that only a maximum yield of 50% can be achieved and that the remaining unreacted starting material must be removed from the

Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring

• Arumugam Kodimuthali,
• Padala Lakshmi Prasunamba and
• Manojit Pal

Beilstein J. Org. Chem. 2010, 6, No. 71, doi:10.3762/bjoc.6.71

• mediated intramolecular cyclization (Dieckmann reaction) [18] of compound 4 provided the key piperidin-4-one ester 5 which on decarboxylation under Krapcho conditions [19] afforded the desired compound 6 (steps v and vi, Scheme 1). Reductive amination of the ketone followed by Boc protection of the

Efficient and improved synthesis of Telmisartan

• A. Sanjeev Kumar,
• Samir Ghosh and
• G. N. Mehta

Beilstein J. Org. Chem. 2010, 6, No. 25, doi:10.3762/bjoc.6.25

• -formylphenylboronic acid 10 with 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline (11) as the key step (90% yield). The benzimidazole moiety 15 was constructed regioselectively via a reductive amination-condensation sequence, replacing the alkylation of the preformed benzimidazole step in the previously published route

• major bond disconnections. We realized biaryl synthesis and reductive amination are the key steps, and have the potential to overcome both of these weaknesses. Results and Discussion We identified 4-formylphenylboronic acid (10) and 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline (11) [12] as the ideal

• -1,3-oxazol-2-yl)biphenyl-4-carbaldehyde (12) in over 90% yield (Scheme 2). The reductive amination of the biaryl aldehyde 12 with amine 13 (prepared by the literature procedure [13]) was carried out in the presence of p-toluenesulfonic acid in toluene and followed by hydrogenation in methyl alcohol

Synthesis of lipophilic 1-deoxygalactonojirimycin derivatives as D-galactosidase inhibitors

• Georg Schitter,
• Elisabeth Scheucher,
• Andreas J. Steiner,
• Arnold E. Stütz,
• Martin Thonhofer,
• Chris A. Tarling,
• Stephen G. Withers,
• Jacqueline Wicki,
• Katrin Fantur,
• Eduard Paschke,
• Don J. Mahuran,
• Brigitte A. Rigat,
• Michael Tropak and
• Tanja M. Wrodnigg

Beilstein J. Org. Chem. 2010, 6, No. 21, doi:10.3762/bjoc.6.21

• step after brief silica gel purification. The reductive amination and N-deprotection of 11 was carried out under an atmosphere of H2 with benzylamine in methanol and Pd/C as catalyst to produce 3,4-O-isopropylidene-1-deoxy-D-galactonojirimycin (12) in an overall yield of 75% (Scheme 1). Compound 12

Mitomycins syntheses: a recent update

• Jean-Christophe Andrez

Beilstein J. Org. Chem. 2009, 5, No. 33, doi:10.3762/bjoc.5.33

Synthesis and enzymatic evaluation of 2- and 4-aminothiazole- based inhibitors of neuronal nitric oxide synthase

• Graham R. Lawton,
• Haitao Ji,
• Pavel Martásek,
• Linda J. Roman and
• Richard B. Silverman

Beilstein J. Org. Chem. 2009, 5, No. 28, doi:10.3762/bjoc.5.28

• does not need to be diprotected to allow the Mitsunobu reaction with phthalimide as the nucleophile to proceed (28a-c). This is presumably because the thiazole nitrogen is less nucleophilic. Cleavage of the phthalimide group gave amines 29a-c. The syntheses of 4a-c were completed by reductive amination

The role of an aromatic group in remote chiral induction during conjugate addition of α-sulfonylallylic carbanions to ethyl crotonate

• Shlomo Levinger,
• Ranjeet Nair and
• Alfred Hassner

Beilstein J. Org. Chem. 2008, 4, No. 32, doi:10.3762/bjoc.4.32

• -(2-thienyl)ethanamine (6d) was prepared from 2-acetylthiophene 7d by a modified Leuckart reaction [5][6], while amines 6b, 6f, 6g and 6i were obtained through Borch reductive amination of the corresponding methyl ketones 7 with sodium cyanoborohydride and ammonium acetate in methanol (Scheme 3) [7][8

• ]. 9-Acetylanthracene does not lend itself to the Borch reductive amination, which entails a nucleophilic addition step of ammonia (or amine) to the carbonyl function [7]. Conjugation between the anthracene nucleus and an acyl substituent at position 9 is sterically inhibited by the flanking hydrogen

• atoms are omitted for clarity. Transmission of asymmetry in the conjugate addition of allyl sulfones to ethyl crotonate depending on the presence of a remote aromatic nucleus. Preparation of donor precursors for conjugate addition (1), bearing a remote stereogenic center. Borch reductive amination of

Combining two-directional synthesis and tandem reactions, part 11: second generation syntheses of (±)-hippodamine and (±)-epi-hippodamine

• Annabella F. Newton,
• Martin Rejzek,
• Marie-Lyne Alcaraz and
• Robert A. Stockman

Beilstein J. Org. Chem. 2008, 4, No. 4, doi:10.1186/1860-5397-4-4

• -hippodamine are presented which are able to shorten the syntheses by up to two steps. Conclusions Key advances include a two-directional homologation by cross metathesis and a new tandem reductive amination / double intramolecular Michael addition which generates 6 new bonds, 2 stereogenic centres and two

• -Grubbs second generation catalyst in dichloromethane at room temperature for 3 days, giving ketodiester 9 [14]. We tried a range of reductive amination conditions for the formation of quinolizidine 7. The ammonia equivalents tried were ammonium acetate, ammonium chloride and ammonium formate, along with

• chromatography over Brockmann Grade (III) neutral alumina. See Supporting Information File 1 for full experimental data. The tandem reductive amination / double intramolecular Michael addition generates 6 new bonds, 2 stereogenic centres and two rings, giving a single diastereomer. In conclusion, we have

Synthesis of the Benzo- fused Indolizidine Alkaloid Mimics

• Daniel L. Comins and
• Kazuhiro Higuchi

Beilstein J. Org. Chem. 2007, 3, No. 42, doi:10.1186/1860-5397-3-42

• 14 in 22% yield. The furan ring of 8a was converted to a carboxylic acid by ozonolysis to afford 15. The reductive amination of 8a with benzylamine provided 16α and 16β in good yield. The stereochemistry of these compounds was determined by NOESY NMR analysis. These functional groups, such as

The enantiospecific synthesis of (+)-monomorine I using a 5-endo- trig cyclisation strategy

• Malcolm B. Berry,
• Donald Craig,
• Philip S. Jones and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2007, 3, No. 39, doi:10.1186/1860-5397-3-39

• groups and an intramolecular reductive amination reaction we were able to prepare (+)-monomorine I in just 11 steps from commercially available D-norleucine in a completely stereoselective manner. Background The abundance in natural products and drug candidates of saturated five-membered heterocycles

• findings described above dictated that an alternative cyclisation strategy be investigated. It was anticipated that intramolecular reductive amination of a pendant methyl ketone would furnish the correct diastereoisomer, because the hydride source would be expected to approach the iminium ion from the less

• intramolecular reductive amination to give the desired indolizidine 26-syn as a single diastereoisomer in 18% yield for the two steps. Whilst the yield of this unoptimised reaction was not satisfactory, we were pleased to observe that only the desired diastereoisomer was formed. Oxidation of the terminal alkene

Synthesis and glycosidase inhibitory activity of new hexa- substituted C8-glycomimetics

• Olivia Andriuzzi,
• Christine Gravier-Pelletier,
• Gildas Bertho,
• Thierry Prangé and
• Yves Le Merrer

Beilstein J. Org. Chem. 2005, 1, No. 12, doi:10.1186/1860-5397-1-12

• subsequent reductive amination. This strategy involving the nucleophilic opening of a cis-cyclic sulfate by sodium azide is to our knowledge the first example in C8-series. It revealead to be an efficient alternative to the nucleoplilic opening of an epoxide moiety which proved unsuccessful in this

• purification by ion-exchange chromatography, the targeted aminocyclitol 15 [20] (95% overall yield from 11). Alternatively, to obtain an analog of voglibose, the amine function of 13 could be alkylated via a reductive amination [39] with a dihydroxyacetone derivative. Thus, treatment of the amine 13 by the

• . According to this strategy and to the nature of the ketones involved in the final reductive amination, various aminocyclitols could be synthesized. Thus, in this study two carbasugars and four aminocyclitols were obtained. Biological evaluation of these compounds towards 24 commercially available