Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• a 6-step sequence from 3,4-dihydro-2-ethoxy-2H-pyran (58) [50]. Treatment of 58 with a mixture of butyllithium and potassium tert-butoxide in the presence of TMEDA and pentane, followed by reaction with the corresponding alkyl iodides in THF, and finally, acidic cleavage of the generated acetal

Ring-closing metathesis of prochiral oxaenediynes to racemic 4-alkenyl-2-alkynyl-3,6-dihydro-2H-pyrans

• Viola Kolaříková,
• Markéta Rybáčková,
• Martin Svoboda and
• Jaroslav Kvíčala

Beilstein J. Org. Chem. 2020, 16, 2757–2768, doi:10.3762/bjoc.16.226

• with CH2Cl2, and the organic solution was carefully evaporated to give the crude products. If necessary, the products were purified by column chromatography. 4-Ethenyl-(2-prop-2-yn-1-yl)-3,6-dihydro-2H-pyran (12a) According to general procedure A, from oxaenediyne 2a (243 mg, 1.64 mmol) in CH2Cl2 (6 mL

• ), 137.9 (s, 1C, CH=CH2); MS (CI+, m/z): 149.1 [M + H]+ (10), 109.1 [M − C3H3]+ (100), 91.1 [C7H7]+ (45), 81.1 [C5H5O]+ (50); HRMS (CI+, m/z): [M + H]+ calcd for C10H13O, 149.0966; found, 149.0964. 2-(But-2-yn-1-yl)-4-(prop-1-en-2-yl)-3,6-dihydro-2H-pyran (12b) According to general procedure A, from

• − CH2=O + H+]+ (95), 121.1 [M − CH2=O − CH≡CH + H]+ (100); HRMS (EI+, m/z): [M]+ calcd for C12H16O, 176.1201; found, 176.1208. 4-(But-1-en-2-yl)-2-(pent-2-yn-1-yl)-3,6-dihydro-2H-pyran (12c) According to general procedure A, from oxaenediyne 2c (31 mg, 0.15 mmol) in CH2Cl2 (1.2 mL) using G-I (6.2 mg

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• ,6R)-13b. Intermolecular N-methylation of reduction product 7. Synthesis of pyrrolidinyl phosphonic acids 11a–d. Synthesis of tetrahydropyranylphosphonates 13a–f via diastereoselective Henry/acetalyzation reaction. Synthesis of (3,4-dihydro-2H-pyran-5-yl)phosphonate 14. Optimization of the conditions

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• ) gave the C-phenyl glucoside 75 [36]. Notably, the use of oxidants other than BQ gave either the TMS enol ether or the 2,3-dihydro-6-phenyl-4H-pyran-4-one. The C-3 exocyclic methylene group was introduced by a Wittig olefination, and after the manipulation of the protecting groups, a VO(acac)2-catalyzed

One-pot synthesis of substituted pyrrolo[3,4-b]pyridine-4,5-diones based on the reaction of N-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-arylethyl)acetamide with amines

• Valeriya G. Melekhina,
• Andrey N. Komogortsev,
• Boris V. Lichitsky,
• Vitaly S. Mityanov,
• Artem N. Fakhrutdinov,
• Arkady A. Dudinov,
• Vasily A. Migulin,
• Yulia V. Nelyubina,
• Elizaveta K. Melnikova and
• Michail M. Krayushkin

Beilstein J. Org. Chem. 2019, 15, 2840–2846, doi:10.3762/bjoc.15.277

• Federation Lomonosov Moscow State University, Moscow 119991, Russian Federation 10.3762/bjoc.15.277 Abstract The condensation of primary amines with N-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-arylethyl)acetamides was explored. Thus, a previously unknown recyclization of the starting material was

• strongly desirable. In this article, we describe a convenient synthetic method for the preparation of 6-alkyl-2-methyl-7-aryl-6,7-dihydro-1H-pyrrolo[3,4-b]pyridine-4,5-diones 1. Therein, the condensation of N-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-arylethyl)acetamides 2 with a diverse range of

• amines 3 did not only furnish the desired scaffolds in satisfactory yields but also allowed to use a variety of readily available substituted substrates (Scheme 1). Results and Discussion The published synthesis of acetamides 2 includes a one-pot three-component reaction of 4-hydroxy-6-methyl-2H-pyran-2

Catalytic asymmetric oxo-Diels–Alder reactions with chiral atropisomeric biphenyl diols

• Chi-Tung Yeung,
• Wesley Ting Kwok Chan,
• Wai-Sum Lo,
• Ga-Lai Law and
• Wing-Tak Wong

Beilstein J. Org. Chem. 2019, 15, 955–962, doi:10.3762/bjoc.15.92

• diene in standard conditions. The reaction was found to be very sluggish when performed at −40 °C. However, at −20 °C, better yields were obtained. The reactions with organocatalysts 1–4 showed moderate yields (41–64%) of the catalytic product (2,3-dihydro-2-phenyl-4H-pyran-4-one). Unfortunately

• used as catalysts (Table 1, entries 8–11). With 1, the yield and enantioselectivity of the catalytic product (2,3-dihydro-2-tert-butyl-4H-pyran-4-one) were 50% and 12% ee (Table 1, entry 8). The reactivity and enantioselectivity were significantly increased to 66% yield and 72% ee when 2 was employed

Synthesis of the aglycon of scorzodihydrostilbenes B and D

• Katja Weimann and
• Manfred Braun

Beilstein J. Org. Chem. 2019, 15, 610–616, doi:10.3762/bjoc.15.56

• , 152.5, 154.6, 158.1, 205.2; ESIMS m/z (%): 377.2 [M + 1] (100); HRMS (ESI): [M + H]+ calcd for C24H25O4, 377.1753; found, 377.1748. (2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-[3-acetyl-2-(3,4-dimethoxyphenethyl)-4-hydroxyphenoxy]tetrahydro-2H-pyran-3,4,5-triyl triacetate (12): A 50 mL two-necked flask was

Ring-closing-metathesis-based synthesis of annellated coumarins from 8-allylcoumarins

• Christiane Schultze and
• Bernd Schmidt

Beilstein J. Org. Chem. 2018, 14, 2991–2998, doi:10.3762/bjoc.14.278

• completely in this case (Table 4, entries 3 and 4). The beneficial effect of low initial substrate concentrations on RCM reactions with acrylates has previously been described [65] and was later systematically investigated by one of us [66]. A possible access to the pyran-2-one-annellated coumarin

• catalyze allylic and benzylic oxidation reactions through a radical mechanism [70]. To implement this tandem sequence in the synthesis of pyran-2-one-annellated coumarins 15 an isomerization of the 8-allyl substituent to a prop-1-enyl substituent was first required. When 8-allyl-7-hydroxycoumarin (8a) was

• -1-enyl)coumarins 16 were isolated in high overall yields and E-selectivities. Allylation of phenols 16 furnished the RCM precursors 17, which underwent the tandem RCM/allylic oxidation sequence to compounds 15 in fair yields (Table 5). All pyran-2-one-annellated coumarins 15 synthesized in the

Volatiles from the hypoxylaceous fungi Hypoxylon griseobrunneum and Hypoxylon macrocarpum

• Jan Rinkel,
• Alexander Babczyk,
• Tao Wang,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 2974–2990, doi:10.3762/bjoc.14.277

• germination and to cause necrotic lesions in the plant tissue. In other cases, fungal volatiles can have beneficial effects and may even be involved in the induction of systemic resistance in plants, as can be assumed for 6-pentyl-2H-pyran-2-one (5) that is produced by many fungi from the genus Trichoderma

• ) 152.9 (Cq), 152.8 (Cq), 143.5 (Cq), 124.7 (CH), 124.3 (Cq), 108.0 (CH), 60.6 (CH3), 60.3 (CH3), 55.8 (CH3), 15.9 (CH3). Structures of fungal volatiles. Trichodiene (1), aristolochene (2), (R)-oct-1-en-3-ol (3), 3,4-dimethylpentan-4-olide (4), and 6-pentyl-2H-pyran-2-one (5). Total ion chromatogram of a

An overview on recent advances in the synthesis of sulfonated organic materials, sulfonated silica materials, and sulfonated carbon materials and their catalytic applications in chemical processes

• Hashem Sharghi,
• Pezhman Shiri and
• Mahdi Aberi

Beilstein J. Org. Chem. 2018, 14, 2745–2770, doi:10.3762/bjoc.14.253

• -sulfo-1,4-diazabicyclo[2.2.2]octane-1,4-diium) chloride (C4(DABCO-SO3H)2·4Cl, 31) and its applications in the synthesis of spiro-oxindole derivatives 36 and 37 was described. C4(DABCO-SO3H)2·4Cl 31 acted as an efficient, cheap, and reusable nanocatalyst for synthesis of 2-amino-4H-pyran derivatives 36

• homogeneous conditions (Scheme 5). After this successful application, catalyst 31 was tested in the synthesis of bis(2-amino-4H-pyran) derivatives 39–44 via a one-pot multicomponent reaction of dialdehydes 38 (instead of isatin and acenaphthenequinone substrates), a variety of C–H activated acids 20a,b, 23

• , 34a–c and malononitrile (35) under the same reaction conditions. The observations showed that bis(2-amino-4H-pyran) derivatives 39–44 are constructed in excellent yields during very short reaction times with a higher amount of the catalyst (4 mol %, Scheme 6). The recyclability of this homogeneous

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers

• Zsanett Benke,
• Melinda Nonn,
• Márton Kardos,
• Santos Fustero and
• Loránd Kiss

Beilstein J. Org. Chem. 2018, 14, 2698–2707, doi:10.3762/bjoc.14.247

• , 100 MHz) δ 21.4, 25.3, 28.4, 46.8, 55.6, 78.7, 79.8, 125.9, 129.0, 154.6, 173.0; MS (ESI, pos) (m/z): 288 [M + 1], 168 [M – Boc]; anal. calcd for C14H21NO4: C, 62.90; H, 7.92; N, 5.24; found, C, 63.22; H, 7.59; N, 4.88. tert-Butyl ((S*)-1-((3R*,6S*)-2-oxo-6-vinyltetrahydro-2H-pyran-3-yl)but-3-en-1-yl

Synthesis of pyrimido[1,6-a]quinoxalines via intermolecular trapping of thermally generated acyl(quinoxalin-2-yl)ketenes by Schiff bases

• Svetlana O. Kasatkina,
• Ekaterina E. Stepanova,
• Maksim V. Dmitriev,
• Ivan G. Mokrushin and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2018, 14, 1734–1742, doi:10.3762/bjoc.14.147

• quinoxalin-2-ylideneacetates [9], multicomponent Mannich–Ritter transformations of quinoxalin-2(1H)-ones under the action of nitriles and 3,4-dihydro-2H-pyran [10] and a microwave-assisted cascade strategy via in situ-generated N-acyliminium ion precursors and amines [11] (Figure 2). To develop a new

Heterogeneous acidic catalysts for the tetrahydropyranylation of alcohols and phenols in green ethereal solvents

• Ugo Azzena,
• Massimo Carraro,
• Gloria Modugno,
• Luisa Pisano and
• Luigi Urtis

Beilstein J. Org. Chem. 2018, 14, 1655–1659, doi:10.3762/bjoc.14.141

• recycling of the catalyst. Results and Discussion Taking 2-phenylethanol (1a) as a model compound, we investigated its conversion into the corresponding THP ether 3a by reacting 4 M solutions of this alcohol with a slight excess (1.1 equiv) of 3,4-dihydro-2H-pyran (2, DHP) in the presence of several acidic

• starting materials, was detected. aNo reaction in the presence of comparable amounts of NH4Br or SiO2. b1e is almost insoluble in CPME. c1:1 mixture of diastereoisomers. Deprotection of THP ether 3i. One-pot synthesis of 3-[4-(tetrahydro-2H-pyran-2-yl)oxymethylphenyl]-3-pentanol (4fa). One-pot synthesis of

• 4-(tetrahydro-2H-pyran-2-yloxymethyl)benzyl alcohol (4fb). Synthesis of 2-(2-phenylethoxy)tetrahydro-2H-pyran (3a). Supporting Information Supporting Information File 256: Full experimental details, copies of IR spectra of fresh and recycled NH4HSO4@SiO2 and copies of 1H and 13C NMR spectra.

Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates

• Yuichi Yoshimura,
• Hideaki Wakamatsu,
• Yoshihiro Natori,
• Yukako Saito and
• Noriaki Minakawa

Beilstein J. Org. Chem. 2018, 14, 1595–1618, doi:10.3762/bjoc.14.137

• oxocarbenium ion 101 to serve as an intermediate, giving a nucleoside 102. First, we attempted model reactions of the oxidative coupling to enol ether using a TMSOTf/PhI(OAc)2 system. After several attempts, we found that the reaction of 3,4-dihydro-2H-pyran (DHP, 103) with PhI(OAc)2 and TMSOTf, starting at

Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: synthesis of axitinib

• Jingbo Yu,
• Zikun Hong,
• Xinjie Yang,
• Yu Jiang,
• Zhijiang Jiang and
• Weike Su

Beilstein J. Org. Chem. 2018, 14, 786–795, doi:10.3762/bjoc.14.66

• -2H-pyran-2-yl)-1H-indazole (3q) in 90% yield. Next, sequential two-step Heck coupling and Migita coupling under ball milling conditions selectively afforded THP-axitinib 7. Finally, deprotection of 7 with p-TsOH gave axitinib in a total yield of 44% (41% [66]). Comparing to previous synthetic

Volatiles from the xylarialean fungus Hypoxylon invadens

• Jeroen S. Dickschat,
• Tao Wang and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 734–746, doi:10.3762/bjoc.14.62

• , Agaricus bisporus, and other delicacies from the fungal world such as the oyster mushroom, the penny bun, and shiitake [2][3]. The ecological function of most fungal volatiles is unknown, but for the alcohol 1 (Figure 1) a germination inhibitory function has been reported [4]. For 6-pentyl-2H-pyran-2-one

• ; MS (EI, 70 eV) m/z (%): 218 (81) [M]+, 204 (13), 203 (100), 137 (53), 136 (17), 108 (21), 67 (26), 43 (23), 39 (13). Structures of the widespread fungal volatiles oct-1-en-3-ol (1) and 6-pentyl-2H-pyran-2-one (2), the stereoisomers α-muurolene (3), α-amorphene (4) and α-cadinene (5), and the

Electrochemical Corey–Winter reaction. Reduction of thiocarbonates in aqueous methanol media and application to the synthesis of a naturally occurring α-pyrone

• Ernesto Emmanuel López-López,
• José Alvano Pérez-Bautista,
• Fernando Sartillo-Piscil and
• Bernardo A. Frontana-Uribe

Beilstein J. Org. Chem. 2018, 14, 547–552, doi:10.3762/bjoc.14.41

• -(pent-1-enyl)-α-pyrone and trans-6-(pent-1,4-dienyl)-α-pyrone, which are naturally occurring metabolites isolated from Trichoderma viride and Penicillium, in high chemical yield and with excellent stereo selectivity. Keywords: Corey–Winter reaction; electrosynthesis; 6-pentyl-2H-pyran-2-ones; reduction

• (Scheme 1) [4]. Despite this advantage, the low availability and high cost of this reagent [5] makes this reaction difficult to be used in industry. Previously, starting from the versatile chiron 7,3-lactone-xylofuranose (7,3-LXF) [6], the first non-biological synthesis of chiral 6-pentyl-2H-pyran-2-ones

• convert thiocarbonates derived from 1,2-diols containing the 6-pentyl-2H-pyran-2-one framework to trans-alkenes by means of electrochemical reduction in an H-type separated cell was developed. The thiocarbonate functional group can be reduced using a vitreous carbon electrode in MeOH/H2O 80:20 with AcOH

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• -pyrazolo[3,4-d]pyrimidin-6-yl)aniline 214 by NO2 group reduction with H2, Pd/C followed by Boc protection, coupling with tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (213) and subsequent Boc deprotection with TFA in DCM. Pyrazolo[3,4-d]pyrimidinylaniline 214 was used to synthesize pyrazolo[3,4-d

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

• natural product is 6-nonyl-2H-pyran-2-one. The antimicrobial and cytotoxic effects of the synthetic volatiles are also reported. Keywords: enantioselective synthesis; gas chromatography; mass spectrometry; natural products; volatiles; Introduction A large variety of volatile organic compounds from

• widespread fungal volatile is 6-pentyl-2H-pyran-2-one (2) that was first isolated from Trichoderma and exhibits a strong coconut aroma [5]. For fungi producing 2 a plant-growth promoting effect and an induction of systemic resistance in plants has been observed which makes these fungi interesting as

• . clavata, showed a mass spectrum that was not included in our database (Figure 5A). However, the mass spectrum of 6-propyl-5,6-dihydro-2H-pyran-2-one (Figure 5B) is very similar, and the mass difference for the molecular ion of 28 Da suggested the structure of 6-methyl-5,6-dihydro-2H-pyran-2-one for

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• allowing access to various β-trifluoromethyl ketones 24 featuring aryl, alkyl, functionalised alkyl, alkenyl, acetal, silylated alcohol, pyran, and piperidine functionalities (R group in 24). Mechanistic studies by 19F NMR allowed to identify CF3 complexes of copper(I) and copper(III) and the predominance

Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

• Anna Kuźnik,
• Roman Mazurkiewicz and
• Beata Fryczkowska

Beilstein J. Org. Chem. 2017, 13, 2710–2738, doi:10.3762/bjoc.13.269

• –71%, respectively (Scheme 29) [42]. An interesting example of the application of ylides derived from vinylphosphonium salts in the enantioselective synthesis of pyran derivatives was reported by Ley et al. in 2010. β-Hydroxyaldehyde 43 as the oxygen nucleophile was obtained here in the asymmetric

• , followed by the intramolecular Wittig reaction gave the corresponding 3,6-dihydropyran derivatives 44 in yields of 34–56% and a high enantioselectivity of 95–98% (Scheme 30) [43]. Pyran derivatives are structural elements of many natural biologically active compounds [44][45][46][47]. 2.2.2. Reactions with

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• product [30] (Scheme 6). The analogous reaction with phenyl vinyl sulfide (22) gave the expected cyclobutane 23 exclusively. However, in the absence of ZnCl2, a mixture of 23 and 3,4-dihydro-2H-pyran 24 was obtained, with the latter compound formed through a competitive hetero-Diels–Alder reaction [30

• ]. The competitive formation of cyclobutane and pyran derivatives was also observed in reactions of E-1b or Z-1b with ethyl prop-1-enyl ether performed in CDCl3 at room temperature [31]. The reaction of N-vinylcarbazole (25) with E-1b or Z-1b in boiling benzene gave mixtures of four diastereoisomers of

• carried out [45][48][50][51]. A stepwise reaction has also been suggested for the formal [4 + 2]-cycloaddition of E- and Z-1b with ethyl prop-1-enyl ether leading to a mixture of the corresponding 3,4-dihydro-2H-pyran and cyclobutane derivatives in a non-stereospecific manner [31]. A mechanism with the

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• ]. Mechanochemical methods of the Mannich reaction, Paal–Knorr synthesis, Bigineli reaction, Hantzsch reaction, and syntheses of substituted pyran, thiophene, isoquinoline derivatives, etc. are also reported [104][107][112][113]. Isocyanide-based multi-component reactions are also well known [114][115]. Recently, in

• example, a) at higher frequency (800 min−1) for 45 min lower yield with less selectivity was observed and b) using lower frequency, 200 min−1 for 8 h led to 82% of yield with high selectivity. In the traditional method of pyran synthesis the use of transition metal catalyst, corrosive acid, longer

Pd(OAc)₂/Ph₃P-catalyzed dimerization of isoprene and synthesis of monoterpenic heterocycles

• Dominik Kellner,
• Maximilian Weger,
• Andrea Gini and
• Olga García Mancheño

Beilstein J. Org. Chem. 2017, 13, 1807–1815, doi:10.3762/bjoc.13.175

• simple screw cap vials or schlenks, leading to the desired dimer in good yields. Finally, the synthetic potential of this method for the synthesis of valuable heterocyclic terpenic derivatives was demonstrated with the preparation of several pyran, tetrahydroisobenzofurane and pyrrolidine derivatives by

• (gradient: hexane to hexanes/EtOAc 4:1) and distillation (90 °C, ≈6 mbar), to provide pyran 5 as colorless oil (106.0 mg, 0.64 mmol, 64%). 4-Methyl-2-(3-methylbut-3-en-1-yl)-5,6-dihydro-2H-pyran (5) [42] 1H NMR (400 MHz, CDCl3) δ 5.37–5.31 (m, 1H, H-2), 4.80–4.63 (m, 2H, H-11), 4.04–3.90 (m, 2H, H-2 + H-6a

Conformational impact of structural modifications in 2-fluorocyclohexanone

• Francisco A. Martins,
• Josué M. Silla and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2017, 13, 1781–1787, doi:10.3762/bjoc.13.172

• study [19], the introduction of an endocyclic oxygen in 2-fluorocyclohexanone to give the 3-fluorodihydro-2H-pyran-4(3H)-one was expected to favor the axial orientation of the fluorine substituent because of the prospective gauche arrangement with the endocyclic oxygen, giving rise to the fluorine

• transition state) or in the ligand assessment to an enzyme binding site. Thus, the replacement of the endocyclic oxygen in 3-fluorodihydro-2H-pyran-4(3H)-one, as well as of the carbonyl oxygen, with other groups, can shift the conformational equilibrium of the resulting molecule towards the equatorial or the