Development of an additive-controlled, SmI₂-mediated stereoselective sequence: Telescoped spirocyclisation, lactone reduction and Peterson elimination

• Brice Sautier,
• Karl D. Collins and
• David J. Procter

Beilstein J. Org. Chem. 2013, 9, 1443–1447, doi:10.3762/bjoc.9.163

• functionalisation of the side chain. The ratio of 2b/4b was optimized by adjusting the SmI2/MeOH ratio and the reaction time to minimise retro-aldol reaction and the formation of saturated ketolactone byproduct 4b (Table 1). Lowering the amount of SmI2 and MeOH used and shortening the reaction time resulted in

Anionic cascade reactions. One-pot assembly of (Z)-chloro-exo-methylenetetrahydrofurans from β-hydroxyketones

• István E. Markó and
• Florian T. Schevenels

Beilstein J. Org. Chem. 2013, 9, 1319–1325, doi:10.3762/bjoc.9.148

• -dichloroethylene is converted into the corresponding chloro-acetylene anion 9 [4][5]. This nucleophilic species adds rapidly, though reversibly, to acetone, leading ultimately to the formation of 5. However, in this case, competitive aldol reaction appears to take place, delivering the adduct 8. The subsequent

• sole base (Scheme 4). In stark contrast, applying this procedure to the keto-alcohol 14 resulted in a mediocre 13% yield of 6, probably due to a rapid retro-aldol reaction of the derived, rather hindered, potassium alkoxide. Applying the LDA/KOt-Bu protocol improved the yield to 41%. It thus transpires

Metal-mediated aminocatalysis provides mild conditions: Enantioselective Michael addition mediated by primary amino catalysts and alkali-metal ions

• Matthias Leven,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2013, 9, 155–165, doi:10.3762/bjoc.9.18

• direct aldol reaction, which is mediated by copper ions and amino acid derivatives [14] or enamine nucleophilic addition to palladium π-allyl electrophiles [15][16][17]. We report the development of new catalysts based on chiral 1,2-diamines and present their application in the asymmetric addition of 4

Reactions of salicylaldehyde and enolates or their equivalents: versatile synthetic routes to chromane derivatives

• Ishmael B. Masesane and
• Zelalem Yibralign Desta

Beilstein J. Org. Chem. 2012, 8, 2166–2175, doi:10.3762/bjoc.8.244

• cascade reaction of salicylaldehyde (5) and malononitrile (20) involving an aldol reaction followed by intramolecular cyclization and finally a dehydration to give intermediate 21. A subsequent Michael addition of the indole (25) to intermediate 21 gives cation 26, which loses a proton to give the product

• reaction between salicylaldehyde (5) and acetonitrile (28) involving an aldol reaction, cyclization and dehydration. A subsequent Michael addition of nitromethane (30) to the product of the cascade reaction gave the desired product 32. Kovalenko and co-workers used a quantitative amount of piperidine in

• (5), followed by an intramolecular aldol reaction and final dehydration to give the desired chromene derivative. Related work involving asymmetric reaction of salicylaldehyde derivatives and α,β-unsaturated carbonyl compounds in the synthesis of 2-phenylchromenes was reported by Li and co-workers

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• , viz. ball-milling and grinding with pestle and mortar. Review Aldol reaction Since the origin of organocatalysis, the asymmetric aldol reaction has been one of the most intensely studied reactions, providing an easy access to chiral β-hydroxycarbonyl compounds, which are important building blocks for

• various bioactive molecules [28]. Among different organocatalysts used for asymmetric aldol reactions, proline and its derivatives emerged as powerful catalysts for the enamine activation of donor aldehyde or ketone. Bolm’s group reported a solvent-free asymmetric organocatalytic aldol reaction under ball

• observed. The ball-milling approach was applied to the (S)-BINAM-L-prolinamide (II) catalysed direct aldol reaction between ketones and aldehydes under solvent-free conditions by Najera and co-workers (Scheme 3) [33][34]. Using 5–10 mol % of II and 10–20 mol % of benzoic acid as additive, the aldol

Determination of the relative configuration of tropinone and granatanone aldols by using TBDMS ethers

• Ryszard Lazny,
• Aneta Nodzewska,
• Katarzyna Sidorowicz and
• Przemyslaw Kalicki

Beilstein J. Org. Chem. 2012, 8, 1877–1883, doi:10.3762/bjoc.8.216

• was determined as exo,syn by comparison of NMR data of the aldol isomers, in particular vicinal coupling constants and shifts corresponding to the side-chain CH group, with data of related TBDMS derivatives and confirmed by single-crystal X-ray diffraction. Keywords: aldol reaction; exo–endo

• and enantiomerically pure aldols of tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one) and granatanone (9-methyl-9-azabicyclo[3.3.1]nonan-3-one) (Figure 1) were synthesized by enantioselective deprotonation with lithium amide bases followed by diastereoselective aldol reaction with aldehydes [10][11

• combined with separation on a silica column. The major products of the direct solventless aldol reaction of tropinone and granatanone [20] were assigned the exo,syn configuration on the bases of their NMR data and NMR data of the corresponding TBDMS ethers. The assigned exo,syn configuration of the

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

• Chittaranjan Bhanja,
• Satyaban Jena,
• Sabita Nayak and
• Seetaram Mohapatra

Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191

• 2006, using diarylprolinolether as an effective organocatalyst. This method involved an oxa-Michael attack of salicylaldehydes 1 on the α,β-unsaturated aldehydes 2 activated through an iminium ion formation with the catalyst Ib, followed by an intramolecular aldol reaction and the subsequent water

• solvent, the test reaction provided the chiral chromenes 3 in good yields (up to 98%) and enantioselectivities (99%) at room temperature (Scheme 3). In 2009, Xu et al. [45] developed an efficient protocol for the asymmetric tandem oxa-Michael–aldol reaction using chiral amine/chiral acid organocatalyst

• (>99%). Extending the methodology adopted by Hong et al., the same group [53] reported a diastereoselective domino oxa-Michael–Michael–Michael–aldol reaction as the key step for the construction of the hexahydro-6H-benzo[c]chromene skeleton of the biologically active natural product (+)-conicol (26

Asymmetric total synthesis of smyrindiol employing an organocatalytic aldol key step

• Dieter Enders,
• Jeanne Fronert,
• Tom Bisschops and
• Florian Boeck

Beilstein J. Org. Chem. 2012, 8, 1112–1117, doi:10.3762/bjoc.8.123

• intramolecular aldol reaction as the key step, is described. Smyrindiol was synthesized from commercially available 2,4-dihydroxybenzaldehyde in 15 steps, with excellent stereoselectivity (de = 99%, ee = 99%). In the course of this total synthesis a new and mild coumarin assembly was developed. Keywords: aldol

• intramolecular aldol reaction of O-acetonyl-salicylaldehydes was described by our research group (Scheme 3) [10]. We envisaged that this 5-enolexo aldolization could be utilized to construct the 1,3-diol moiety of smyrindiol, if a coumarin derivative of the O-acetonyl-salicylaldehyde were to be used. The

• addition of a methyl group to the carbonyl of the aldol product would yield smyrindiol (Scheme 4). Unfortunately, all attempts to conduct the intramolecular aldol reaction with the ketoaldehyde 4 failed (Scheme 5). Instead of the expected hydroxy ketone 3, we obtained a complex reaction mixture. This was

Aldol elaboration of 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-ones, masked precursors to acylpyridones

• Raymond C. F. Jones,
• Abdul K. Choudhury,
• James N. Iley,
• Mark E. Light,
• Georgia Loizou and
• Terence A. Pillainayagam

Beilstein J. Org. Chem. 2012, 8, 308–312, doi:10.3762/bjoc.8.33

• condensation to give new 3-alkenyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-ones, which are masked forms related to the acylpyridone natural products. Keywords: aldol reaction; fused-ring systems; heterocycles; isoxazole; metalation; pyridone; Introduction The 3-acyl-4-hydroxypyridin-2-one moiety 1

Synthetic approaches to multifunctional indenes

• Neus Mesquida,
• Sara López-Pérez,
• Immaculada Dinarès and
• Ermitas Alcalde

Beilstein J. Org. Chem. 2011, 7, 1739–1744, doi:10.3762/bjoc.7.204

• immediately by dehydration with acid. This classical condensation process, which is neither simple nor trivial despite its apparent directness, permits an efficient entry to a variety of indene-based molecular modules, which could be adapted to a range of functionalized indanones. Keywords: aldol reaction

Oxidative allylic rearrangement of cycloalkenols: Formal total synthesis of enantiomerically pure trisporic acid B

• Silke Dubberke,
• Muhammad Abbas and
• Bernhard Westermann

Beilstein J. Org. Chem. 2011, 7, 421–425, doi:10.3762/bjoc.7.54

• -oxocyclohex-3-ene-1-carboxylate ((−)-1c, Scheme 1) [21][22]. Results and Discussion Precursor for the synthesis of racemic cyclohexenone (±)-1c is methyl 2-methyl-3-oxopentanoate (5), which upon addition of acrolein undergoes a tandem Michael/aldol-reaction sequence (Scheme 2) [11]. To obtain optically pure β

Photocycloaddition of aromatic and aliphatic aldehydes to isoxazoles: Cycloaddition reactivity and stability studies

• Axel G. Griesbeck,
• Marco Franke,
• Jörg Neudörfl and
• Hidehiro Kotaka

Beilstein J. Org. Chem. 2011, 7, 127–134, doi:10.3762/bjoc.7.18

• -1,4-diketones after hydrolysis of the primary photochemical products (photo aldol reaction) [7], whilst the reaction of oxazoles with carbonyl compounds is a convenient protocol for the stereoselective synthesis of α-amino β-hydroxy ketones [8][9] as well as highly substituted α-amino β-hydroxy acids

Stereoselective synthesis of four possible isomers of streptopyrrolidine

• Debendra K. Mohapatra,
• Barla Thirupathi,
• Pragna P. Das and
• Jhillu S. Yadav

Beilstein J. Org. Chem. 2011, 7, 34–39, doi:10.3762/bjoc.7.6

• % yield over six steps starting from D-phenylalanine and L-phenylalanine, respectively. The absolute configuration of the natural product was shown to be (4S,5S) by comparing its spectral and analytical data with the reported values. Keywords: aldol reaction; angiogenesis; cancer; Lewis acid mediated

• could be utilized for the aldol reaction in the presence of different Lewis acids to obtain a better selectivity particularly for (R)-tert-butyl (1-oxo-3-phenylpropan-2-yl)carbamate (6). To our surprise, when the reaction was carried out with the ketene silyl acetate at −78 °C, of the five Lewis acids

The allylic chalcogen effect in olefin metathesis

• Yuya A. Lin and
• Benjamin G. Davis

Beilstein J. Org. Chem. 2010, 6, 1219–1228, doi:10.3762/bjoc.6.140

• previously optimized by our group, compound 25 was efficiently functionalized with an allyl sulfide derived fluorescent probe 26 via CM in aqueous media to demonstrate the utility of functionalization of peptides and proteins by the Mukaiyama aldol reaction (Scheme 10). Allyl selenides are superior

The C–F bond as a conformational tool in organic and biological chemistry

• Luke Hunter

Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38

• enantioselectivity suggesting that the fluorine atom of 35 helps to rigidify the activated intermediate and thereby enhances selectivity. Another fluorinated organocatalyst has recently featured in the first example of an asymmetric transannular aldol reaction (Figure 10) [35]. (S)-proline (39) is able to catalyse

• , Figure 10), with the key transannular aldol reaction (44→45) proceeding in high yield and with impressive enantioselectivity [35]. Fluorine-substituted organocatalysts are also useful in the asymmetric Stetter reaction (Figure 11) [36]. N-Heterocyclic carbene 49 was identified as a promising first

• . The asymmetric transannular aldol reaction catalysed by trans-4-fluoroproline (41), and its application to the total synthesis of (+)-hirsutene (46). The asymmetric Stetter reaction catalysed by chiral NHC catalysts 49–52. The ring conformations of 50–52 are influenced by σCH→σ*CF hyperconjugation. Cy

Can we measure catalyst efficiency in asymmetric chemical reactions? A theoretical approach

• Shaimaa El-Fayyoumy,
• Matthew H. Todd and
• Christopher J. Richards

Beilstein J. Org. Chem. 2009, 5, No. 67, doi:10.3762/bjoc.5.67

• anecdotally refer to a “good“ or “bad“ reaction, there is no system for comparing those reactions with each other. Well-known examples of asymmetric catalysis such as the Sharpless asymmetric dihydroxylation, the Corey oxazaborolidine ketone reduction or the proline-catalysed aldol reaction are almost

• asymmetric hydrogenation, which gives a product of 79% ee, is employed in the industrial multi-tonne synthesis of (S)-metolachlor [3]. An instructive comparison may be made between an antibody capable of catalysing an intramolecular, asymmetric aldol reaction and proline, capable of catalysing the same

Asymmetric reactions in continuous flow

• Xiao Yin Mak,
• Paola Laurino and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2009, 5, No. 19, doi:10.3762/bjoc.5.19

• in the near future. Enantioselective addition of trimethylsilyl cyanide to benzaldehyde. Asymmetric catalytic hydrogenation in a falling-film microreactor. Aldol reaction catalyzed by 5-(pyrrolidine-2-yl)tetrazole. Enantioselective addition of diethylzinc to aryl aldehydes. Glyoxylate-ene reaction in

Synthesis of new C^α-tetrasubstituted α-amino acids

• Andreas A. Grauer and
• Burkhard König

Beilstein J. Org. Chem. 2009, 5, No. 5, doi:10.3762/bjoc.5.5

• prepared from aliphatic aldehydes. Results and Discussion The major difference between the previously used aromatic aldehydes and their aliphatic counterparts is their ability to undergo an aldol reaction under the strongly basic conditions necessary for the formation of the tetrahydrofuran ring system

Stereoselective synthesis of (2S,3S,4Z)-4-fluoro- 1,3-dihydroxy- 2-(octadecanoylamino)octadec- 4-ene, [(Z)-4-fluoroceramide], and its phase behavior at the air/water interface

• Gergana S. Nikolova and
• Günter Haufe

Beilstein J. Org. Chem. 2008, 4, No. 12, doi:10.3762/bjoc.4.12

• fatty acid amide functions. Results In a short synthetic route (2S,3S)-4-fluorosphingosine and 4-fluoroceramide, the fluorinated analogues of the natural products, D-erythro-sphingosine and ceramide, have been prepared. The key step of the synthetic sequence is an asymmetric aldol reaction of (Z)-2

• formation of multi-layers was observed for natural ceramide. Conclusions Asymmetric aldol reaction proved to be successful for the preparation of enantiopure 4-fluoroceramide. Surface/pressure isotherms and hysteresis curves of ceramide and its 4-fluoro derivative showed that the presence of fluorine leads

• recently for the preparation of long chain α-fluoro-α,β-unsaturated carboxylic acid esters [29] and fluorinated 2,4-dienecarboxylic acid esters [30]. The key step of the synthesis is an asymmetric aldol reaction of the fluorinated aldehyde 3 with the enantiopure iminoglycinate 4 (Scheme 1). The latter

Vinylogous Mukaiyama aldol reactions with 4-oxy-2-trimethylsilyloxypyrroles: relevance to castanospermine synthesis

• Roger Hunter,
• Sophie C. M. Rees-Jones and
• Hong Su

Beilstein J. Org. Chem. 2007, 3, No. 38, doi:10.1186/1860-5397-3-38

• Roger Hunter Sophie C. M. Rees-Jones Hong Su Department of Chemistry, University of Cape Town, Private Bag, Rondebosch, Cape Town 7701, South Africa 10.1186/1860-5397-3-38 Abstract Background The diastereoselectivity of a vinylogous Mukaiyama aldol reaction of a series of N-substituted 4-oxy-2

• castanospermine synthesis using a Mukaiyama aldol reaction as a key step. Thus it was decided to investigate the influence of changing both the O-protecting group as well as substituting the 4-oxy substituent with hydrogen. Deprotection of a methyl ether to its hydroxyl group requires aggressive conditions that

• have utilized a convergent stategy via a C-8/C-8a disconnection (Figure 3). Thus, Gallagher,[25] Martin [26][27] and Casiraghi [4] have all attempted syntheses involving either a carbanion at C-8a or a Lewis-acid promoted aldol reaction as in Scheme 1 to form the C-8/C-8a bond. All the syntheses have

Tether- directed synthesis of highly substituted oxasilacycles via an intramolecular allylation employing allylsilanes

• Peter J. Jervis and
• Liam R. Cox

Beilstein J. Org. Chem. 2007, 3, No. 6, doi:10.1186/1860-5397-3-6

• -NMR spectroscopy) by a method described by Heathcock et al. (Scheme 5). [18] We were concerned, however, that the steric bulk of the aryl ester in 5b, which is required to impart the complete anti selectivity on the aldol reaction, would make unmasking of the aldehyde difficult owing to unfavourable

One-pot synthesis of novel 1H-pyrimido[4,5-c][1,2]diazepines and pyrazolo[3,4-d]pyrimidines

• Dipak Prajapati,
• Partha P. Baruah,
• Baikuntha J. Gogoi and
• Jagir S. Sandhu

Beilstein J. Org. Chem. 2006, 2, No. 5, doi:10.1186/1860-5397-2-5

• hot acid produces pyrazolo [3,4-d]pyrimidines, most likely by hydrolytic ring opening at the 'hydrazone' bond followed by a retro-aldol reaction and ring closure.[25][33][34] In contrast, we synthesised the corresponding pyrazolo [3,4-d]pyrimidines in high yields under mild conditions without heating