Sulfur-containing spiroketals from Breynia disticha and evaluations of their anti-inflammatory effect

• Ken-ichi Nakashima,
• Naohito Abe,
• Masayoshi Oyama,
• Hiroko Murata and
• Makoto Inoue

Beilstein J. Org. Chem. 2023, 19, 1604–1614, doi:10.3762/bjoc.19.117

• Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan retired, formerly Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan 10.3762/bjoc.19.117 Abstract Breynia spp. are a key source of sulfur-containing spiroketal glycosides with

• . & G.Forst. (Phyllanthaceae), commonly known as snow bush, is a tropical shrub native to New Caledonia and Vanuatu in the Western Pacific but has been naturalized in many regions globally. Investigations of the phytochemical compositions of several Breynia spp. have revealed sulfur-containing spiroketal

• glycosides [1][2][3], flavan-3-ol glycosides [4], alkaloids [5], and phenolic glycosides [5][6]. Notably, sulfur-containing spiroketal glycosides, represented by breynins and epibreynins, have characteristic sesquiterpenoid-derived structures. The sesquiterpenoid phyllaemblic acid and its glycosides, which

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• versatility of CYPs in plant triterpenoid and steroid metabolism (Figure 6). Diosgenin (13) is a specialised plant natural product with a unique 5,6-spiroketal moiety that serves as an inexpensive raw material for the industrial synthesis of steroidal drugs. Diosgenin (13) biosynthesis from cholesterol (3

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• [98][99]. Compound 142 under refluxing conditions gave spirocyclic compound 143 as the exclusive product (Scheme 42) [99]. Propargylic triols 144 undergo Hg(OTf)2-catalyzed cyclization reaction, to produce monounsaturated spiroketal 145. Finally in the case of 1,2-dihydroxy-3-alkynes 146 comparable

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• (3CR) developed by Barluenga et al. [35] to steroids. The original Barluenga’s 3CR comprises the reaction of salicylaldehyde with an alkyl orthoformate and 4-pentyn-1-ol to obtain a 4-alkylchroman spiroketal as a single diastereomer. However, as shown in Scheme 10, the employment of alkynyl-4,5

• -secocholestan-5-ol 33 in such a metal-catalyzed MCR led to the steroidal chroman-ketal 34 as a mixture of epimers at the center bearing the methoxy group, instead of the expected chroman spiroketal. The authors proposed the initial formation of a 6-membered enol ether, which may subsequently undergo either a

Synthesis of spirocyclic scaffolds using hypervalent iodine reagents

• Fateh V. Singh,
• Priyanka B. Kole,
• Saeesh R. Mangaonkar and
• Samata E. Shetgaonkar

Beilstein J. Org. Chem. 2018, 14, 1778–1805, doi:10.3762/bjoc.14.152

• of palmarumycin CP1 were synthesized later which were showing good thioredoxin–thioredoxin reductase (Trx-1/TrxR) inhibitory activity [129]. It was observed that the introduction of enone functionality in naphthoquinone spiroketal enhances the biological activity of palmarumycin 138. Furthermore, Ley

• ortho-substituted phenolic compounds 155 to spiroketals 156 by Quideau and co-workers [139]. The cyclization reactions were performed in trifluoroethanol and spirocyclic ketals 156 were isolated in useful yields (Scheme 58). Additionally, the synthesized spiroketal 156 (R = iPr; R1 = iPr) was used as

• substrate for the synthesis of natural product (+)-biscarvacrol (157). Koag and Lee [140] reported the synthesis of a spiroketal by radical cyclization of a steroidal alkylamine in presence of PIDA (15) as oxidant and molecular iodine in dichloromethane at low temperature. It is an example of hypoiodite

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• -γ-butyrolactone in DMF at 130 °C [73]. This method could successfully be applied in the synthesis of the spiroketal core of rubromycins 22 and 23. One of the latest publications around the topic is published by Hayashi et al. in 2015 [74]. Starting from diarylmethylamines 24 and arylboroxines, they

Synthesis of D-fructose-derived spirocyclic 2-substituted-2-oxazoline ribosides

• Madhuri Vangala and
• Ganesh P. Shinde

Beilstein J. Org. Chem. 2015, 11, 2289–2296, doi:10.3762/bjoc.11.249

• the nitrile group. In all the low yielding reactions, spiroketals are observed in 15–20% yield. This was evidenced by activating 3a and 5a with TMSOTf (1 equiv) in toluene in the absence of a nucleophile. While 3a gave a symmetric spiroketal 3ab with a single set of protons in 75% yield (Scheme 3

Recent applications of ring-rearrangement metathesis in organic synthesis

• Sambasivarao Kotha,
• Milind Meshram,
• Priti Khedkar,
• Shaibal Banerjee and
• Deepak Deodhar

Beilstein J. Org. Chem. 2015, 11, 1833–1864, doi:10.3762/bjoc.11.199

• -alkoxyfurans by employing [4 + 2] and/or [4 + 3] cycloaddition reactions. Further, they used a RRM protocol in the presence of catalyst 2 to generate the spiroketal derivative 281 (Scheme 58). Ikoma and co-workers [59] have reported a short synthetic sequence to cis-fused heterocycles by employing the 7

• systems. Ugi-RRM protocol for the synthesis of 2-aza-7-oxabicyclo system. Synthesis of spiroketal systems via RRM protocol. RRM approach to cis-fused heterotricyclic system. RRM protocol to functionalized bicyclic systems. ROM/RCM/CM cascade to generate bicyclic scaffolds. RCM of ROM/CM product. RRM

Structure and conformational analysis of spiroketals from 6-O-methyl-9(E)-hydroxyiminoerythronolide A

• Ana Čikoš,
• Irena Ćaleta,
• Dinko Žiher,
• Mark B. Vine,
• Ivaylo J. Elenkov,
• Marko Dukši,
• Dubravka Gembarovski,
• Marina Ilijaš,
• Snježana Dragojević,
• Ivica Malnar and
• Sulejman Alihodžić

Beilstein J. Org. Chem. 2015, 11, 1447–1457, doi:10.3762/bjoc.11.157

• Park, Harlow, CM19 5AW, United Kingdom 10.3762/bjoc.11.157 Abstract Three novel spiroketals were prepared by a one-pot transformation of 6-O-methyl-9(E)-hydroxyiminoerythronolide A. We present the formation of a [4.5]spiroketal moiety within the macrolide lactone ring, but also the unexpected

• ; spiroketal; Introduction Macrolide antibiotics are natural or semi-synthetic products of polyketide origin, containing one or more desoxy sugars attached to a macrocyclic lactone aglycon. This large and structurally diverse category of compounds has traditionally been divided into classes based on the

• . As a structural subunit, spiroketal ring systems [16][17] are present in a wide range of natural compounds. Their rigidity makes them useful for conformational control in heterocycles, but also for stabilizing a highly specific conformation within otherwise flexible larger natural compounds. For

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• and 51 µM, respectively) [60][61][124]. Berkelic acid (2009) Berkelic acid (15) (Figure 10) is a spiroketal isolated from a fungus of the Penicillium species that grows in an unusual and harsh environment, Berkeley Pit Lake, an abandoned open-pit copper mine filled with acidic, metal-contaminated

Synthesis of the spiroketal core of integramycin

• Evgeny. V. Prusov

Beilstein J. Org. Chem. 2013, 9, 2446–2450, doi:10.3762/bjoc.9.282

• Evgeny. V. Prusov Department of Medicinal Chemistry, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany 10.3762/bjoc.9.282 Abstract A concise synthetic strategy towards the spiroketal core of the HIV-integrase inhibitor integramycin (1) was developed. The

• , respectively. Structurally, the molecule architecture of integramycin features four distinct elements: a 3,5-dihydroxy-substituted aromatic ring, a spiroketal core, a highly functionalized octalin moiety and a 5-hydroxylated 3-acyltetramic acid. Studies on the syntheses of the spiroketal core [2][3] and the

• products with tetramic acid fragments we embarked on the development of a concise and modular approach towards integramycin and related natural products. According to the retrosynthetic analysis, which is outlined in Figure 2, the target molecule may be assembled from an appropriate spiroketal advanced

Gold(I)-catalyzed enantioselective cycloaddition reactions

• Fernando López and
• José L. Mascareñas

Beilstein J. Org. Chem. 2013, 9, 2250–2264, doi:10.3762/bjoc.9.264

• -workers reported another example of a highly enantioselective gold-catalyzed cyclopropanation reaction by using diazo compounds as a source of gold carbenes. In particular, the authors demonstrated that the chiral bisgold complex Au6, derived from the spiroketal bisphosphine ligand, was a very efficient

Thermochemistry and photochemistry of spiroketals derived from indan-2-one: Stepwise processes versus coarctate fragmentations

• Götz Bucher,
• Gernot Heitmann and
• Rainer Herges

Beilstein J. Org. Chem. 2013, 9, 1668–1676, doi:10.3762/bjoc.9.191

• stepwise mechanisms may compete. Keywords: coarctate reaction; fragmentation; matrix isolation; photolysis; pyrolysis; spiroketal; Introduction Pericyclic reactions, according to the original definition, are characterized by a cyclic array of bond making and bond breaking [1][2][3]. At each atom

• spiroketal linkage. The relative ratio of carbon dioxide and carbon monoxide being formed (CO2/CO = 1:27) indicates that a coarctate fragmentation of 1 can play a minor role only, if any. The composition of the product mixture is best rationalized by a series of stepwise processes, which starts with either a

• spiroketal 1 by the fact that two energetically unfavourable products would have to be formed (a quinodimethane and a carbene), whereas the fragmentation of the norbornadiene ketal gives benzene and a carbene. The mechanism for the thermal decomposition of 2 is likely to be similar. The high yield of

Thiourea-catalyzed Diels–Alder reaction of a naphthoquinone monoketal dienophile

• Carsten S. Kramer and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 1414–1418, doi:10.3762/bjoc.9.158

• quarternary center in alpha-position to the obstructed spiroketal center, rendering the long reaction times valid. Conclusion In summary, we screened a variety of different organocatalysts to promote the naphthoquinone monoketal Diels–Alder reaction. Thereby we found that thioureas 10 and 12 facilitate the

Some aspects of radical chemistry in the assembly of complex molecular architectures

• Béatrice Quiclet-Sire and
• Samir Z. Zard

Beilstein J. Org. Chem. 2013, 9, 557–576, doi:10.3762/bjoc.9.61

• xanthates can be reductively removed by treatment with stoichiometric amounts of peroxide in isopropanol as the solvent, and the resulting product 117 saponified and cyclised with acid into spiroketal 118. By choosing a vinyl or a homoallyl ester as the alkene partner, spiroketals of various ring sizes can

• be easily constructed. Spiroketals 119 and 120 are two such examples. The former was used in the total enantioselective synthesis of (+)-broussonetine G (121) [50]. If one of the alkenes contains a masked aldehyde, a bis-spiroketal such as 122 may be accessed. Furthermore, placing a 1,2- or a 1,3

On the proposed structures and stereocontrolled synthesis of the cephalosporolides

• Sami F. Tlais and
• Gregory B. Dudley

Beilstein J. Org. Chem. 2012, 8, 1287–1292, doi:10.3762/bjoc.8.146

• strategy for controlling the stereochemistry of oxygenated 5,5-spiroketals. The same strategy likewise enables the first stereocontrolled synthesis of cephalosporolide E, which is typically isolated and prepared admixed with its spiroketal epimer, cephalosporolide F. Keywords: cephalosporolides; chelation

• ; spiroketals; stereocontrol; zinc chloride; Introduction The spiroketal moiety is common in natural products of marine, plant, insect, and bacterial origins [1][2][3][4][5][6][7][8][9][10][11]. The rigidity of the spiroketal provides defined orientation of pendant functional groups, and there is a strong

• correlation between bioactivity and spiroketal stereochemistry in many natural spiroketals. For example, cephalostatin and ritterazine feature thermodynamically disfavored spiroketals that are more cytotoxic than their stereoisomers [12]. Other prominent cytotoxic spiroketals include spongistatin [7] and

Synthesis and antifungal properties of papulacandin derivatives

• Marjolein van der Kaaden,
• Eefjan Breukink and
• Roland J. Pieters

Beilstein J. Org. Chem. 2012, 8, 732–737, doi:10.3762/bjoc.8.82

• spiroketal unit, which is introduced in a palladium-catalyzed cross-coupling reaction of a glycal silanolate and an aryl iodide followed by an oxidative spiroketalization. Four different variants were made, differing in the nature of the acyl side chain with respect to the length, and in the number and

• stereochemistry of the double bonds. Moderate biological activity was observed for the derivatives with a side chain based on palmitic acid and linoleic acid. Keywords: antifungal agents; carbohydrate; papulacandins; spiroketal; Introduction In recent years, a steady increase in the incidence of opportunistic

• resistance [1]. Clearly, there is a need for new antifungal therapeutics. The papulacandins are a series of naturally occurring antifungal agents whose isolation and characterization were initially reported by Traxler and co-workers in 1977 (Figure 1) [3][4]. They contain a benzannulated spiroketal unit

Recent advances in the gold-catalyzed additions to C–C multiple bonds

• He Huang,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2011, 7, 897–936, doi:10.3762/bjoc.7.103

• enantiomer) in excellent yields (Scheme 6). A range of variously substituted triols was prepared which were cyclized to give substituted 5- and 6-membered ring spiroketals. Similarly, the synthesis of the bisbenz-annelated spiroketal core 35 of natural bioactive rubromycins via a gold-catalyzed double

A gold-catalyzed alkyne-diol cycloisomerization for the synthesis of oxygenated 5,5-spiroketals

• Sami F. Tlais and
• Gregory B. Dudley

Beilstein J. Org. Chem. 2011, 7, 570–577, doi:10.3762/bjoc.7.66

• cephalosporolides. Gold(I) chloride in methanol induced the cycloisomerization of a protected alkyne triol with concomitant deprotection to give a strategically hydroxylated 5,5-spiroketal, despite the potential for regiochemical complications and elimination to furan. Other late transition metal Lewis acids were

• of common reaction conditions. Conversely, the use of alkynes in the synthesis of spiroketals introduces regiochemistry concerns as to which of the two alkyne carbons becomes the spiroketal carbon, and the kinetic stability of alkynes must be overcome when alkyne reactivity is desired. As an off

• the reported structure of cephalosporolide H (1) is outlined in Scheme 2. We recently demonstrated the use of inter-cycle chelation effects to control the spiroketal stereochemistry [28][29]. However, formation of the requisite oxygenated spiroketals (by cycloisomerization) posed significant

A divergent asymmetric approach to aza-spiropyran derivative and (1S,8aR)-1-hydroxyindolizidine

• Jian-Feng Zheng,
• Wen Chen,
• Su-Yu Huang,
• Jian-Liang Ye and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2007, 3, No. 41, doi:10.1186/1860-5397-3-41

• methodology. Background Spiroketals of general structure A (Scheme 1) constitute key structural features of a number of bioactive natural products isolated from insects, microbes, fungi, plants or marine organisms. [1][2][3] The corresponding aza-spiroketal (cf: general structure B) containing natural

• stereoselectively to either hydroxylactams F or G under appropriate conditions. [36][37][38] It was envisioned that if a C4-bifunctional Grignard reagent was used, both aza-spiroketal H (such as aza-spiropyran, n = 1, path a) and indolizidine ring systems I (path b) could be obtained. The synthesis of aza