Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• orientation of p-nitrophenyl units, due to the shielding of the bound aldehyde substrate from the incoming diene. The catalytic inactivity of 5 demonstrated the requirement of macrocyclic character for the potential catalysts. Later in 2009, the same group reported an organocatalyzed diastereoselective aldol

• addition of furan-based silyloxydiene synthons to a variety of achiral aldehydes using four different calix[4]pyrrole macrocycles (3, 4, 11, and 12) as organocatalysts (Figure 3) [38]. These calixpyrrole macrocycles acted as hydrogen-bond donors, activating substrate aldehydes through hydrogen-bonding

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• conjugate alkynylation and consecutive aldol addition (Scheme 49) [91]. The chiral ruthenium complex C2 (Phebox-type)-catalyzed procedure delivered β-hydroxyketone derivatives 192 having α-propargyl groups in good yields, however, only with low diastereoselectivities (up to 3:1). While the syn-diastereomers

• aldol addition step was performed either in a two-component (intramolecular aldol) or a three-component (intermolecular aldol) arrangement. The enantioselective implementation of this methodology was realized by Herraiz and Cramer in 2021 (Scheme 53) [98]. The reaction sequence is initiated by the C–H

Mechanochemical solid state synthesis of copper(I)/NHC complexes with K₃PO₄

• Ina Remy-Speckmann,
• Birte M. Zimmermann,
• Mahadeb Gorai,
• Martin Lerch and
• Johannes F. Teichert

Beilstein J. Org. Chem. 2023, 19, 440–447, doi:10.3762/bjoc.19.34

• why we also tested 5bm in these transformations: The 1,2-reduction of benzaldehyde (14) and acetophenone (15) proceeded with good yields (Scheme 3c). No aldol addition for the acetophenone substrate has been observed although working under strongly basic conditions [68][69]. Conclusion In conclusion

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• stabilization of reactive conformations by chelation or dipole control. Keywords: aldol addition; ketoesters; natural products; total synthesis; Introduction Vicinal ketoesters contain a carbonyl group adjacent to an ester group. One keto group results in α-ketoesters 1 and two vicinal keto groups lead to α,β

• intramolecular aldol addition of ketones such as 7 (Scheme 2) [5]. Brønsted-acid catalysis leads via a transition state 8 to the aldol 9, while the use of chelating Lewis acids results via 10 in the epimeric aldol 11. This review is a collection of total syntheses of natural products where vicinal keto esters

• -tricarbonyl compound 108 to set two stereogenic centers and correct one via an intramolecular aldol addition (108 → 109; Scheme 18) [34]. The vic-tricarbonyl compound 108 was synthesized via DMDO oxidation from α-diazo-β-ketoester 107, which was easily accessible from 5-methoxy-4H-chromen-4-one (106). The

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• predominantly the all-cis product. Similarly, cis- and trans-129 (1:4), generated in situ from methyl 10-undecenoate and an aldehyde 130 via ene reaction, undergo cyclization to form THPs 131 and 132 (Scheme 31). Martín and co-workers reported a general strategy based on a reaction sequence of Evans aldol

• addition to construct a homoallylic alcohol, followed by Prins cyclization to furnish 2,3,4,5,6-pentasubstituted tetrahydropyrans 137 using β,γ-unsaturated N-acyloxazolidin-2-ones 134 as a key precursor [67]. In this Evans aldol−Prins (EAP) protocol, four new σ-bonds and five contiguous stereocenters were

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• previously tested the reactivity of 8 in the intermolecular aldol addition to ethyl glyoxalate [62]. As these attempts met with failure, we have turned our attention to enantioselective fluorination reactions [63][64][65]. Specifically, we decided to explore the enantioselective electrophilic fluorination of

Syn-selective silicon Mukaiyama-type aldol reactions of (pentafluoro-λ⁶-sulfanyl)acetic acid esters with aldehydes

• Anna-Lena Dreier,
• Andrej V. Matsnev,
• Joseph S. Thrasher and
• Günter Haufe

Beilstein J. Org. Chem. 2018, 14, 373–380, doi:10.3762/bjoc.14.25

• cycloadditions of azomethine ylides with pentafluoro-λ6-sulfanyl-substituted acrylic esters and amides [28]. A couple of years ago, we became interested in SF5-substituted ester enolates as reaction intermediates. Thus, in 2016 we reported a highly anti-selective aldol addition of SF5-substituted acetic ester

• addition of ice-water. After work-up 22% of the aldol addition products were formed in a syn/anti-ratio of 97:3 as determined by 19F NMR spectroscopy (Scheme 1). Subsequently, the reaction conditions were optimized (Table 1). Elevation of the reaction temperature (15 h reflux) led to an increase of the

• aromatic and aliphatic aldehydes (Table 2). Table 2 shows that benzaldehyde and five of its derivatives substituted with electron withdrawing groups in para-position gave the desired aldol addition products in fair yields and with diastereoselectivities between 81:19 and 95:5 in favor of the syn-products

Volatiles from the tropical ascomycete Daldinia clavata (Hypoxylaceae, Xylariales)

• Tao Wang,
• Kathrin I. Mohr,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 135–147, doi:10.3762/bjoc.14.9

• from an α-cleavage next to the alcohol function. To verify this structural proposal for 11a, racemic 2-methylbutanal (18) was reacted in an aldol addition with the enolate anion of pentan-3-one (23) which produced a racemic mixture of all four diastereomers 11a–d (Scheme 4). All eight stereoisomers of

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

Total syntheses of the archazolids: an emerging class of novel anticancer drugs

• Stephan Scheeff and
• Dirk Menche

Beilstein J. Org. Chem. 2017, 13, 1085–1098, doi:10.3762/bjoc.13.108

• stereoselective elimination and decarboxylation in situ. The corresponding aldehyde 22 was then homologated by an Abiko–Masamune anti-aldol addition [74] with ephedrine-derived ester 23, which proceeded with excellent yield and stereoselectivity. However, the subsequent removal of the sterically hindered chiral

• . Synthesis of the north-western fragment As shown in Scheme 10, the synthesis of stannane 39 started with aldehyde 48 which was derived from propargyl alcohol in five steps [82]. After DMP oxidation the generated aldehyde 48 underwent a syn-selective Evans aldol addition with oxazolidinone 47 to obtain the

• the Menche group. Synthesis of north-eastern fragment 5 through a Paterson anti-aldol addition and multiple Still–Gennari olefinations. Synthesis of 4 through an Abiko–Masamune anti-aldol addition. Thiazol construction and synthesis of the southern fragment 6. Completion of the total synthesis of

Enantioselective addition of diphenyl phosphonate to ketimines derived from isatins catalyzed by binaphthyl-modified organocatalysts

• Hee Seung Jang,
• Yubin Kim and
• Dae Young Kim

Beilstein J. Org. Chem. 2016, 12, 1551–1556, doi:10.3762/bjoc.12.149

• of organocatalysts [38][39][40][41][42][43][44][45], we have reported the catalytic asymmetric decarboxylative aldol addition reaction of isatins with benzoylacetic acids catalyzed by chiral binaphthyl-based squaramide [46]. Here we wish to report the enantioselective addition reaction of diphenyl

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• salinosporamide A (199) (Scheme 27) [160][161]. Based on gene cluster analysis, it was proposed that both heterocycles of this PKS–NRPS hybrid product, an oxetan-2-one and a pyrrolidin-2-one, are formed by a bicyclisation mechanism. Aldol addition of the amino acid α-position on the carbonyl gives the pyrrolidin

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• enantioselectivities (up to 99% ee, Scheme 10) [26]. The reaction involved a decarboxylation and an Yb(OTf)3/PyBox (L6)-catalyzed aldol addition. 4 Å Molecular sieves were found to be able to enhance the stereoselectivity. Steric hindrance between substituents and the metal/ligand complex slightly decreased the ee

• amine of the catalyst and ketone substrate and protonation of the tertiary amino group. The protonated amine then served as hydrogen bond donor to activate the carbonyl group of isatin substrates, thereby facilitating the aldol addition. Interestingly, the authors obtained the R-/S-enantiomer by using

• . Substituents attached to the isatins and ketones had little effect on the yields and enantioselectivity, regardless of their electronic properties and positions. Amino alcohol catalysts In 2014, Evano and co-workers reported a concise synthesis of the macrocyclic core of TMC-95A using the asymmetrc aldol

Scope and mechanism of the highly stereoselective metal-mediated domino aldol reactions of enolates with aldehydes

• M. Emin Cinar,
• Bernward Engelen,
• Martin Panthöfer,
• Hans-Jörg Deiseroth,
• Jens Schlirf and
• Michael Schmittel

Beilstein J. Org. Chem. 2016, 12, 813–824, doi:10.3762/bjoc.12.80

• with benzaldehyde (PhCHO) is followed by the exergonic first aldol addition showing a small activation barrier of 1.82 kcal mol−1 via a half−chair like transition state (TS-C-A1), which is in accord with the anti-selective aldol addition of titanium enolates [53][54]. TS-C-A1 leads to the formation of

• radius of the B3+ ion is very small (25 pm). In the case of tin(II), a high yield of 6a (up to 90%) was observed but formation of 5a was not detected which indicates a hindrance for the second aldol addition. Presumably due to the low charge density of the Sn2+ ions the second carbonyl function is not

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• give uridine-5'-aldehyde 99. Aldehyde 99 then supposedly undergoes an aldol addition with glycine 100 as the enol(ate) component, thus furnishing the amino acid–nucleoside hybrid 5'-C-glycyluridine (GlyU, 101). Alkylation of the 6'-amino group is then achieved by reaction with S-adenosyl methionine

• glycine (100). Hence, LipK was revealed to be a transaldolase mediating a retro-aldol reaction of L-threonine (119) towards the enol(ate) and acetaldehyde (120), followed by a stereoselective aldol addition of the former to uridine-5'-aldehyde 99 (Scheme 12). Using synthetic reference compounds, it could

Natural products from microbes associated with insects

• Christine Beemelmanns,
• Huijuan Guo,
• Maja Rischer and
• Michael Poulsen

Beilstein J. Org. Chem. 2016, 12, 314–327, doi:10.3762/bjoc.12.34

• )), sesquiterpenes with an unprecedented carbon skeleton that are most likely built up by an enzymatic Aldol addition. In a similar example, new cytotoxic furanone analogues (e.g., paraconfuranone A (39)) were obtained from the fungus Paraconiothyrium brasiliense isolated from the gut of the grasshopper Acrida

Copper-catalyzed cascade reactions of α,β-unsaturated esters with keto esters

• Zhengning Li,
• Chongnian Wang and
• Zengchang Li

Beilstein J. Org. Chem. 2015, 11, 213–218, doi:10.3762/bjoc.11.23

• aldolization followed by a lactonization. This method provides a facile approach to prepare γ-carboxymethyl-γ-lactones and δ-carboxymethyl-δ-lactones under mild reaction conditions. Keywords: aldol addition; cascade reaction; catalysis; conjugate reduction; copper; lactonization; Introduction Paraconic acid

• unsaturated diester followed by a sequential aldol addition and lactonization reaction [13]. To address aforementioned challenges, we have recently reported the first example of a copper-catalyzed reductive aldolization–lactonization cascade reaction of α,β-unsaturated diesters with ketones [14] and imines

New sesquiterpene hydroquinones from the Caribbean sponge Aka coralliphagum

• Qun Göthel and
• Matthias Köck

Beilstein J. Org. Chem. 2014, 10, 613–621, doi:10.3762/bjoc.10.52

• an aldol addition from a precursor with an acyclic sesquiterpene side chain (Figure 7). The aromatic ring system of proposed precursor 3-ox in Figure 7 also appeared in the known compound siphonodictyal B3 (8) [5] isolated from the same sponge source as well as the newly identified compound 3. There

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• enantioselective lithiation and subsequent hydroxyalkylation. 4. Recently, Pansare [40] reported the synthesis of L-733,060, CP-99,994 and a hydroxypipecolic acid through asymmetric organocatalytic vinylogous aldol addition as the key step. While the syntheses by Charette [38] and Pansare [40] are restricted to

Total synthesis and cytotoxicity of the marine natural product malevamide D and a photoreactive analog

• Werner Telle,
• Gerhard Kelter,
• Heinz-Herbert Fiebig,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2014, 10, 316–322, doi:10.3762/bjoc.10.29

• multigram quantities within five steps from Cbz-valine (8), adapting a convenient sequence developed for dolaisoleuine by Pettit and co-workers [5]. Cbz-protected N-methylvalinol (4) [6] was oxidized to the aldehyde 5 under Parikh–Doering conditions, followed by aldol addition of the lithium enolate of t

Biosynthesis of rare hexoses using microorganisms and related enzymes

• Zijie Li,
• Yahui Gao,
• Hideki Nakanishi,
• Xiaodong Gao and
• Li Cai

Beilstein J. Org. Chem. 2013, 9, 2434–2445, doi:10.3762/bjoc.9.281

• significantly cheaper starting material D-gulono-1,4-lactone instead of expensive L-glucose. In our previous work, we discovered that two rare sugars, D-sorbose and D-psicose, were simultaneously generated when L-rhamnulose-1-phosphate aldolase (RhaD, EC 4.1.2.19) [47] catalyzed the aldol addition between DHAP

• -phosphate (or the analogues) is synthesized by aldol addition catalyzed by L-fuculose-1-phosphate aldolase (FucA). Then, L-fuculose is produced after dephosphorylation by acid phosphatase (EC 3.1.3.2). Finally, L-fuculose is converted to L-fucose by L-fucose isomerase (EC 5.3.1.25). The procedure may be

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

• four steps by the route shown in Scheme 3, involving palladium-catalysed decarboxylative ring opening of cyclic carbonates [23]. Thus the enolate of α-tetralone was added to propenal in an aldol addition (LDA, THF, −78 °C; 86%). The second step involved the reduction of the intermediate β-hydroxyketone

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

• plays a coordinating role in the extended Mukaiyama aldol addition resulting in an endo-like transition state.[11] In the known cases [3][18] of N-alkyl silyloxypyrroles successfully reacting with simple aldehydes just mentioned, a more hindered α-asymmetric benzyl centre on nitrogen was used which

Pd-catalysed [3 + 3] annelations in the stereoselective synthesis of indolizidines

• Olivier Y. Provoost,
• Andrew J. Hazelwood and
• Joseph P. A. Harrity

Beilstein J. Org. Chem. 2007, 3, No. 8, doi:10.1186/1860-5397-3-8

• compares well with a close analogue reported by Knapp and co-workers suggesting that the aldol addition reaction proceeds under Felkin-Anh control [see Supporting Information File 1]). In conclusion, we have shown that functionalised indolizidinone intermediates can be generated through the Pd-catalysed [3

• indolizidines (Scheme 5). [3 + 3] Annelation approach to indolizidine skeleta. Enantiospecific aziridine synthesis (ADDP: 1,1'-(azodicarbonyl)dipiperidine). Diastereoselective aldol addition. Indolizidinone formation. Preparation of a functionalised indolizidine. Investigation of the [3 + 3] annelation reaction