The synthesis of functionalized bridged polycycles via C–H bond insertion

• Jiun-Le Shih,
• Po-An Chen and
• Jeremy A. May

Beilstein J. Org. Chem. 2016, 12, 985–999, doi:10.3762/bjoc.12.97

• diazoacetamides (Scheme 8) [61]. He found an important example of a transformation where the ratio of gamma vs beta-lactam formation could be controlled to a significant extent by catalyst choice. In particular, Rh2(4S-MEOX)4 favored the bridged γ-lactam 41 over the fused β-lactam 42 in about a 3:1 ratio. The

Enantioselective carbenoid insertion into C(sp³)–H bonds

• J. V. Santiago and
• A. H. L. Machado

Beilstein J. Org. Chem. 2016, 12, 882–902, doi:10.3762/bjoc.12.87

• transformation was regio and stereoselective where the main product was trans-γ-lactam (56). The chiral rhodium complexes (S)-17, (S)-18 and (S)-23 were also evaluated and yielded similar regio- and diastereoselectivity, however, with lower enantioselectivity when compared to the bis(oxazoline)/CuCl2/NaBARF

• C(sp3)–H catalyzed by (S)-23. Asymmetric insertion of copper carbenoids in C(sp3)–H bonds to prepare trans-γ-lactam. Chiral porphyrin iridium complex catalyzes the carbenoid insertion into bis-allylic C(sp3)–H bonds. Chiral porphyrin iridium complex catalyzes the carbenoid insertion into

New synthetic strategies for xanthene-dye-appended cyclodextrins

• Milo Malanga,
• Andras Darcsi,
• Mihaly Balint,
• Gabor Benkovics,
• Tamas Sohajda and
• Szabolcs Beni

Beilstein J. Org. Chem. 2016, 12, 537–548, doi:10.3762/bjoc.12.53

• -B lactone belongs to the carbonyl stretching of the γ-lactone moiety of the dye and this value is very similar to that found in the carbonyl region of the IR spectrum of Rho-β-CD at 1755.4 cm−1. This last frequency is typical for the carbonyl stretching of a γ-lactam ring [27], thus demonstrating

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• sterically hindred 64 (Scheme 20) [61] in a similar MAO-N/MCR combination. In this way, dipeptide mimics 66 were obtained in good yields (75–83%), however, now with very high diastereomeric (>98%) and enantiomeric excesses (>99%). γ-lactams The γ-lactam unit is an important dipeptide pharmacophore since it

• can induce β-turns. A well-known example was described by Freidinger in 1980, who successfully developed a γ-lactam β-turn mimic of the luteinizing hormone-releasing hormone (LHRH) almost nine times more potent than the original hormone [64]. Since then, these “Freidinger lactams” have been used in

• numerous pharmaceutical and biological active compounds. For example, they are found in compounds used for the treatment of epilepsy [65][66], HIV [67][68], and depression [69]. Multicomponent reactions towards γ-lactam peptidomimetics were earlier described by Ugi [70], Mjalli [71] and Harriman [72

Diastereoselective radical addition to γ-alkyl-α-methylene-γ-butyrolactams and the synthesis of a chiral pyroglutamic acid derivative

• Tomoko Yajima,
• Eriko Yoshida and
• Masako Hamano

Beilstein J. Org. Chem. 2013, 9, 1432–1436, doi:10.3762/bjoc.9.161

• development of stereoselective synthesis of chiral γ-lactams remains a challenge [4][5]. Developing effective and simple synthetic methods is important so that the drug candidates can be screened. A stereoselective addition to a γ-lactam skeleton provides a direct and efficient method for synthesizing various

• γ-lactam derivatives. However, the most commonly used methods for synthesizing chiral γ-lactams are based on the cyclization or cycloaddition of N-containing precursors, which are synthesized stereoselectively, and there are limited studies on the stereoselective additions to γ-lactam skeletons [6

• ][7][8] and no reports on radical addition. We have already investigated diastereoselective alkyl radical additions to α-methylene-γ-phenyl- γ-lactam and reported that the N-unsubstituted lactam yields cis-α,γ-disubstituted lactams using (Me3Si)3SiH under UV irradiation, whereas the reactions of N

α-Bromodiazoacetamides – a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C–H insertion reactions

• Åsmund Kaupang and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2013, 9, 1407–1413, doi:10.3762/bjoc.9.157

• Comparing with results obtained using dirhodium(II) catalysis, the α-H-analogue of the azepane derivative 5c was prepared in 67% yield by Doyle et al. from 3d [61]. They could also prepare the analogous azocane-derived α-H-β-lactam in 45% yield, accompanied by a 22% yield of the α-H-γ-lactam. Interestingly

A construction of 4,4-spirocyclic γ-lactams by tandem radical cyclization with carbon monoxide

• Mitsuhiro Ueda,
• Yoshitaka Uenoyama,
• Nozomi Terasoma,
• Shoko Doi,
• Shoji Kobayashi,
• Ilhyong Ryu and
• John A. Murphy

Beilstein J. Org. Chem. 2013, 9, 1340–1345, doi:10.3762/bjoc.9.151

• reaction of 1a with Bu3SnH (2.0 equiv) and AIBN (2,2’- azobisisobutyronitrile, 0.3 equiv) was carried out under CO pressure (80 atm) in THF (0.02 M) at 80 °C for 12 h, which gave the desired 4,4-spirocyclic indoline γ-lactam 2a in 48% yield (Scheme 4). We found that the modest improvement in the yield of

• cyclization due to the longer C–S bonds. We then tried to extend the tandem spirocyclization approach to obtain 4,4-spirocyclic oxindole γ-lactam and tested two substrates, 2-(azidomethyl)-N-benzyl-N-(2-iodophenyl)acrylamide (1f) and the nitrogen-unprotected analogue 1g. The reaction of 1f was smooth to give

• the desired 4,4-spirocyclic oxindole γ-lactam 2f in 62% yield (Table 1, entry 6). On the other hand, the reaction of 1g gave the cyclized product in only a trace amount, and instead THF-incorporating 6-endo cyclization product 3 was obtained in 60% yield (Table 1, entry 7) [28]. Based on the known

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• activity seen with 2 and the inactivity of 3 supported the hypothesis that the bioactive conformation of PLG was a type II β-turn, since the (R)-isomer of the γ-lactam mimics a type II β-turn, while the (S)-isomer supports a type II’ β-turn structure. Although an X-ray structure of 2 showed that the γ

• dopaminergic pathway [26]; (3) antagonism of antipsychotic drug-induced vacuous chewing movements in the rat model of human tardive dyskinesia [27]; and (4) prevention of NMDA receptor antagonist (MK-801)-induced deficits in social interaction in rats [28]. In the initial design of the γ-lactam PLG

• peptidomimetic 2, the isobutyl side chain of the leucyl residue was not incorporated into the structure, in order to simplify the synthesis. The potent activity of γ-lactam peptidomimetic 2 indicated that the isobutyl side chain was not an absolute requirement for modulating dopamine receptors. The synthesis of

A new approach toward the total synthesis of (+)-batzellaside B

• Jolanta Wierzejska,
• Shin-ichi Motogoe,
• Yuto Makino,
• Tetsuya Sengoku,
• Masaki Takahashi and
• Hidemi Yoda

Beilstein J. Org. Chem. 2012, 8, 1831–1838, doi:10.3762/bjoc.8.210

• route to (+)-batzellaside B from L-pyroglutamic acid, which offers the advantages of convenience and simplicity of total synthesis. Results and Discussion The synthesis began with the preparation of N-Boc-protected γ-lactam 8 by stepwise functionalization of L-pyroglutamic acid, using literature

Automated three-component synthesis of a library of γ-lactams

• Erik Fenster,
• David Hill,
• Oliver Reiser and
• Jeffrey Aubé

Beilstein J. Org. Chem. 2012, 8, 1804–1813, doi:10.3762/bjoc.8.206

• process, the management of by-products and excess reagents, the development of an automated parallel sequence, and the adaption of the method to permit the preparation of enantiomerically enriched products. These efforts culminated in the preparation of a library of 169 γ-lactams. Keywords: γ-lactam

• as pharmacological probes and as starting points for drug-discovery campaigns, has primarily fuelled this interest, while enabling technologies, such as diversity-oriented synthesis (DOS), have improved access to small-molecule libraries [1][2][3][4][5]. Compounds containing a γ-lactam moiety have

• asymmetric organocatalyzed reaction in the Michael addition step, (b) combining the individual three steps, and (c) automating the process to produce a demonstrative 256 member γ-lactam library. Asymmetric organocatalyzed Michael addition The success of pyrrolidine as the organocatalyst for the Michael

Synthesis of conformationally restricted glutamate and glutamine derivatives from carbonylation of orthopalladated phenylglycine derivatives

• Esteban P. Urriolabeitia,
• Eduardo Laga and
• Carlos Cativiela

Beilstein J. Org. Chem. 2012, 8, 1569–1575, doi:10.3762/bjoc.8.179

• by Beck [18], and this process affords the γ-lactam displayed in Scheme 4. Assuming the mechanism shown in Scheme 1, it seems that, in the absence of any other nucleophile, the intramolecular C–N coupling takes place with concomitant formation of a N,N-dimethylisoindolinonium salt, which undergoes

An intramolecular inverse electron demand Diels–Alder approach to annulated α-carbolines

• Zhiyuan Ma,
• Feng Ni,
• Grace H. C. Woo,
• Sie-Mun Lo,
• Philip M. Roveto,
• Scott E. Schaus and
• John K. Snyder

Beilstein J. Org. Chem. 2012, 8, 829–840, doi:10.3762/bjoc.8.93

• efficient turnover. The intramolecular cycloaddition of 13a, the alkyne-tethered triazine, was studied under various conditions (Scheme 4, Table 3). Ultimately, it was found that the IEDDA reaction proceeded smoothly under microwave irradiation, in diglyme (120 °C, 20 min; Table 3, entry 3) to give the γ

• -lactam annulated α-carboline 14a in quantitative yield. The microwave reaction conditions were preferred over the more traditional heating (Table 3, entry 1) due to the shorter reaction time. Attempts to lower the temperature and/or shorten the reaction time led to lower yields (Table 3, entries 2, 4 and

N-Heterocyclic carbene/Brønsted acid cooperative catalysis as a powerful tool in organic synthesis

• Rob De Vreese and
• Matthias D’hooghe

Beilstein J. Org. Chem. 2012, 8, 398–402, doi:10.3762/bjoc.8.43

• variation of the used acid led to improved yields. Finally, the most efficient trans-γ-lactam synthesis has been achieved using cyclohexyl-substituted carbene precursor 17 (20 mol %) and sodium o-chlorobenzoate (18, 20 mol %) in the presence of molecular sieves at 0 °C and with acrylonitrile as solvent

• be formed in good yield and high diastereo- and enantioselectivity. A number of different enals 15 as suitable substrates has been explored as well (variation of R3), affording the trans-γ-lactam products 16 in moderate to good yields and stereoselectivities. It is important to underline the fact

• that this approach provides an unprecedented trans selectivity in the synthesis of 4,5-disubstituted γ-lactam systems. The occurrence of hydrogen-bonding intermediates 19 (Figure 1) has been invoked to explain the reaction mechanism, and the phenomenon of hydrogen bonding in NHC catalysis has indeed

Tandem catalysis of ring-closing metathesis/atom transfer radical reactions with homobimetallic ruthenium–arene complexes

• Yannick Borguet,
• Xavier Sauvage,
• Guillermo Zaragoza,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2010, 6, 1167–1173, doi:10.3762/bjoc.6.133

• demonstrated that homobimetallic ruthenium–indenylidene complex 1 is a suitable catalyst precursor for the tandem RCM/ATRC of polyhalogenated α,ω-dienes 4 and 8 into the corresponding bicyclic γ-lactam derivatives. A more complex cascade sequence involving RCM and ATRA reactions afforded γ-lactone 18 starting

Synthesis of fluorinated δ-lactams via cycloisomerization of gem-difluoropropargyl amides

• Satoru Arimitsu and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2010, 6, No. 48, doi:10.3762/bjoc.6.48

• -difluoromethylene moiety has been reported to improve their biological activities. For example, a gem-difluoro-γ-lactam can inhibit γ-lactamase, which is responsible for bacterial resistance to γ-lactam antibiotics [2][3][4]. Additionally, α,α-difluoro lactams are precursors of some biologically active compounds [5