Patent Description:
Spiroketals and oxa-spirolactones are ubiquitous chemical entities found in a myriad of pharmacologically important natural products. In recent times, it has been shown that simplified spiroacetals derived from natural products retain their biological properties. Hence, these scaffolds essentially contribute to biological activities and represent privileged pharmacophores in drug discovery. In the recent years, several bioactive natural products with unsaturated γ-spiroketal-γ-lactone (<NUM>,<NUM>-dioxaspiro[<NUM>]non-<NUM>-en-<NUM>-one) appendage were isolated and have become an important sub-group of spiroketals, which include pyrenolide D (anticancer, IC50 = <NUM>µg/mL against HL-<NUM>), crassalactone D (anticancer, ED50 = <NUM>µg/mL against P-<NUM>, <NUM>µg/mL against KB, <NUM>µg/mL against Col-<NUM>, <NUM>µg/mL against BCA-<NUM> and <NUM>µg/mL against ASK), massarinoline A (active against Bacillus subtilis and Staphylococcus aureus), levantenolide (antibacterial & anticancer), tuberostemonamide (antitussive), papyracillic acid C (anti-biotic), acutissimatriterpene A (herbal medicine),<NUM> aphagrandinoid A (antibacterial) and many others.

Article titled "<NPL> reports TMSOTf-mediated reactions of <NUM>-aryl-<NUM>-(<NUM>-phenylcyclopropyl)ethanones <NUM> with diethyl <NUM>-oxomalonate <NUM> afford a novel method for the synthesis of spiro-γ-lactone derivatives <NUM> in good to excellent yields via a sequential reaction involving a nucleophilic ring-opening reaction of the cyclopropane by H<NUM>O , an aldol-type reaction and a cyclic transesterification mediated by Lewis acid. On the other hand, TMSOTf-mediated reactions of <NUM>-cyclopropyl-<NUM>-arylethanones <NUM> with ethyl <NUM>-oxoacetate <NUM> could also provide the corresponding spiro-γ-lactone derivatives <NUM> in moderate yields along with another spiro-γ-lactone derivatives <NUM> derived from the reaction of <NUM> with two molecules of ethyl <NUM>-oxoacetate.

Article titled "<NPL> reports the SnCl4-mediated reactions of cyclopropyl alkyl ketones with γ-ketoesters afford a novel method for the synthesis of <NUM>,<NUM>-dioxaspiro[<NUM>]-non-<NUM>-en-<NUM>-ones with high stereo selectivities in moderate to good yields. This process is a sequential reaction involving a nucleophilic ring opening reaction of the cyclopropane by H<NUM>O, an aldol-type reaction, and a cyclic transesterification mediated by Lewis acid.

Article titled "<NPL> reports investigation of PdII, PtII, AuI, AuIII, and ReVII have all been investigated for their ability to construct the spiroketal moiety. Recent developments have explored numerous novel cyclisations and their application to the synthesis of spiroketal-containing natural products. Developments include new catalytic protocols, exploration of chiral ligands and the novel application of known reactions to the synthesis of spiroketals. This Perspective covers recent metal-catalysed syntheses of spiroketals (published since <NUM>) in this rapidlydeveloping field.

<NPL>, disclose three sesquiterpenoids Massarinolins A-C (<NUM>-<NUM>) metabolites isolated from liquid cultures of the aquatic fungus Massarina tunicata Shearer & Fallah collected from a twig submerged in a Wisconsin river. Massarinolins A (<NUM>) having tetracyclic ring system, contain one methyl group, five methylene unit, four methine units and one free OH group, was found to be active against Gram positive bacteria (Bacillus subtilis (ATCC <NUM>) affording zone of inhibition of <NUM> and <NUM> respectively and Staphylococcus aureus (ATCC <NUM>), causing a <NUM>-nun zone of inhibition. Further these compounds were not active against the strain of Candida albicans (ATCC <NUM>) at <NUM>µg/disk.

<NPL>, disclose that labdane diterpenoids, isolated from the aerial parts of Croton laui which belongs to the genus Croton (Euphorbiaceae), shows anti-inflammatory activity.

All of these approaches had several limitations such as usage of prefunctionalized starting materials, protection and deprotection sequence, stoichiometric amount of Lewis acids and multiple steps.

Therefore, there is a need for the development of new synthetic approaches for unsaturated γ-spiroketal-γ-lactones is of considerable importance in the fields of both synthetic and medicinal chemistry.

Main objective of the present invention is to provide γ-spiroketal-γ-lactones of formula (<NUM>) to (<NUM>) or a hydrate, solvate or pharmaceutically acceptable salt thereof.

Another objective of the present invention is to provide a pharmaceutical composition containing γ-spiroketal-γ-lactones of formula (<NUM>) to (<NUM>) or a hydrate, solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

Yet another objective of the present invention is to provide a process for the preparation of γ-spiroketal-γ-lactones of formula (<NUM>) to (<NUM>) or a hydrate, solvate or pharmaceutically acceptable salt thereof.

Yet another objective of the present invention is the use of γ-spiroketal-γ-lactones of formula (<NUM>) to (<NUM>) or a hydrate, solvate or pharmaceutically acceptable salt thereof, as anticancer agents.

The present invention provides γ-spiroketal-γ-lactones as claimed or a hydrate, solvate or pharmaceutically acceptable salt thereof.

The present invention further provides one step process for the preparation of γ -spiroketal- γ -lactones as claimed or a hydrate, solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient comprising adding catalyst in the solution of alkynol and α-ketoester in suitable solvent at a temperature ranging from <NUM> to <NUM> followed by stirring the reaction mixture at the temperature ranging from <NUM> to <NUM> for a time period <NUM> to <NUM> hours to obtain γ -spiroketal-γ-lactone as claimed.

The present invention further provides a pharmaceutical composition comprising γ-spiroketal-γ-lactones as claimed or a hydrate, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

The present invention further provides the use of γ-spiroketal-γ-lactones as claimed or a hydrate, solvate or pharmaceutically acceptable salt thereof as anticancer agents.

The present invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.

The present disclosure provides γ-spiroketal-γ-lactones of formula (I) or a stereoisomer, ester, hydrate, solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient,
<CHM>
wherein R, R<NUM>, R<NUM>, R<NUM> and R<NUM> represents independently of each other hydrogen, alkyl, cycloalkyl, alkene, alkyne, alkenyl, aryl, heteroaryl, monocyclic or bicyclic heteroarylene group having at least one heteroatom selected from the group consisting of N, S and O, halogen, hydroxy, cyano, amino, alkoxy; and
X, Y and Z each independently is O.

The present invention relates to γ-spiroketal-γ-lactones selected from the group consisting of <NUM>, <NUM>-Dimethyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Methyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-(<NUM>-Methoxyphenyl)-<NUM>-methyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Methyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-methyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-(<NUM>-methoxyphenyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Methyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>, <NUM>-Diphenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-(<NUM>-Methoxyphenyl)-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Phenyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-(<NUM>-Nitrophenyl)-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>).

In another preferred embodiment, the γ -spiroketal- γ -lactones of formula (<NUM>) to (<NUM>) is used as anticancer agent.

In another embodiment, the present invention provides one step process for the preparation of γ -spiroketal- γ -lactones selected from the group consisting of <NUM>, <NUM>-Dimethyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Methyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-(<NUM>-Methoxyphenyl)-<NUM>-methyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Methyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-methyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-(<NUM>-methoxyphenyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Methyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>, <NUM>-Diphenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-(<NUM>-Methoxyphenyl)-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Phenyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-(<NUM>-Nitrophenyl)-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), and <NUM>-Methyl-<NUM>-phenyl-<NUM>, or a stereoisomer, ester, hydrate, solvate or pharmaceutically acceptable salt thereof; comprising adding catalyst in the solution of alkynol and α-ketoester in suitable solvent at a temperature ranging from <NUM> to <NUM> followed by stirring the reaction mixture at the temperature ranging from <NUM> to <NUM> for a time period <NUM> to <NUM> hours to afford γ - spiroketal-γ-lactone of formula (<NUM>) to (<NUM>), wherein the alkynol is selected from (<NUM>-(But-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol, (<NUM>-(Pent-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol, and (<NUM>-(<NUM>-Phenylprop-<NUM>-yn-<NUM>-yl) cyclohexyl), and
the α -ketoester is selected from ethyl <NUM>-(<NUM>-nitrophenyl)-<NUM>-oxoacetate, ethyl pyruvate, ethyl phenylglyoxylate, ethyl anisylglyoxylate, and ethyl p-tolylglyoxylate.

The catalyst is selected from bismuth triflate Bi(OTf)<NUM>, Copper (II) triflate (Cu(OTf)<NUM>), Scandium(III) triflate (Sc(OTf)<NUM>), Ferric triflate (Fe(OTf)<NUM>), mercuric triflate (Hg(OTf)<NUM>), Ytterbium triflate (Yb(OTf)<NUM>), Iron(III) chloride (FeCl<NUM>), Silver triflate (AgOTf), p-Toluenesulfonic acid (PTSA), Trifluoromethanesulfonic acid (TfOH).

The solvent is selected from dicholoromethane (CH<NUM>Cl<NUM>), toluene, acetonitrile (CH<NUM>CN), Tetrahydrofuran (THF), Nitromethane (CH<NUM>NO<NUM>).

The yield of the process of the present invention is <NUM>-<NUM> %.

The above process as shown in following scheme:
<CHM>.

Wherein R, R<NUM>, R<NUM>, R<NUM>, R<NUM> and R<NUM> each independently are hydrogen, alkyl, cycloalkyl, alkene, alkyne, alkenyl, aryl, heteroaryl, monocyclic or bicyclic heteroarylene group having at least one heteroatom selected from the group consisting of N, S and O, halogen, hydroxy, cyano, amino, alkoxy; and
X, Y and Z each independently is O.

In still another embodiment, the present disclosure provides a process of preparation of <NUM>-Methyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM>] tetradec-<NUM>-en-<NUM>-one.

In yet another embodiment, the present invention provides pharmaceutical composition comprising a compound of formula (<NUM>) to (<NUM>) or a stereoisomer, ester, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

In still yet another embodiment, the present disclosure provides a method for treating fungus, bacterial, malarial infection, or cancer in a subject in need thereof; comprising administering to the subject a therapeutically effective amount of the γ -spiroketal- γ -lactones of formula (I) or a stereoisomer, ester, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

The compounds as disclosed herein possess antibacterial activity against a wide spectrum of Gram-positive and Gram-negative bacteria, aerobic and anaerobic organisms such as Staphylococcus, Lactobacillus, Streptococcus, Escherichia, Enterobacter, Pseudomonas, Proteus, Citrobacter, Baccillus, Clostridium, Salmonella, and other organisms. Also, the compounds as disclosed herein possess antibacterial activity against bacterial species resistant to conventional [beta]- lactams, such as MRSA. Further, the compounds as disclosed herein are effective as anti-plasmodium agent for the treatment of malaria. The compound as disclosed herein is present in the composition in an amount which is effective to treat the disease or the condition caused by the bacterial strains mentioned above.

The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres.

In another embodiment, the present disclosure relates to administering 'an effective amount' of the 'composition of invention ' to the subject suffering from said disease. Accordingly, compounds disclosed herein and pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.

Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient may take the form of one or more dosage units. The dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of examples and for purpose of illustrative discussion of preferred embodiments of the invention only.

The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use. The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

Following examples are given by way of illustration therefore should not be construed to limit the scope of the invention.

To the alkynol (<NUM> mmol) and α-ketoester (<NUM> mmol) in <NUM> of anhydrous CH<NUM>Cl<NUM> in a dry round bottom flask, was added Bi(OTf)<NUM> (<NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture at <NUM> for mentioned reaction time. After completion of reaction (typically after <NUM>-<NUM>, monitored by TLC, visualized using UV, anisaldehyde, and KMnO<NUM> staining solutions), the reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate (NaHCO<NUM>) then extracted with CH<NUM>Cl<NUM> (2x10 mL). The combined organic layers were dried over anhydrous sodium sulphate and filtered through sintered glass funnel. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (<NUM>-<NUM> mesh) to afford the corresponding unsaturated γ-spiroketal-γ-lactone.

Following the General Procedure, to the mixture of (<NUM>-(prop-<NUM>-yn1 yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl pyruvate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was add Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM> at <NUM>. Purification of the crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc /hexanes) afforded <NUM>-methyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%). TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(prop-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl phenylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-phenyl-<NUM>,<NUM>-dioxadispiro[<NUM>. <NUM><NUM>. <NUM><NUM>]tetradec-<NUM>-en-one as a crystalline solid (<NUM>, <NUM>%). TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+<NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(prop- <NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl anisylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-(<NUM>-methoxyphenyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%). TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the reaction mixture of (<NUM>-(prop-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl p-tolylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a crystalline solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc /hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM> found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(prop-<NUM>-yn-<NUM>-yl)cyclopentyl)methanol (<NUM>, <NUM> mmol) and ethylpyruvate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-methyl-<NUM>,<NUM>-dioxadispiro[<NUM>. <NUM><NUM>. <NUM><NUM>]tridec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a white solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI): calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(prop-<NUM>-yn-<NUM>-yl) cyclopentyl) methanol (<NUM>, <NUM> mmol) ethyl phenylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc /hexanes) afforded <NUM>-phenyl-<NUM>,<NUM>-dioxadispiro[<NUM>. <NUM><NUM>. <NUM><NUM>]tridec-<NUM>-en-one (<NUM>, <NUM>%). TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc /hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI): calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the reaction mixture of (<NUM>-(prop-<NUM>-yn-<NUM>-yl) cyclopentyl) methanol (<NUM>, <NUM> mmol) and ethyl anisylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc /hexanes) afforded <NUM>-(<NUM>-methoxyphenyl)-<NUM>,<NUM>-dioxadispiro[<NUM>. <NUM><NUM>. <NUM><NUM>]tridec-<NUM>-en-<NUM>-one crystalline solid (<NUM>, <NUM>%). TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc /hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (<NUM>, CDCl<NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM> found <NUM>.

Following the General Procedure, to the reaction mixture of (<NUM>-(prop-<NUM>-yn-<NUM>-yl) cyclopentyl) methanol (<NUM>, <NUM> mmol) and ethyl p-tolylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc /hexanes) afforded <NUM>-(p-tolyl)-<NUM>,<NUM>-dioxadispiro[<NUM>. <NUM><NUM>. <NUM><NUM>]tridec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a white solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc /hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM> found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(prop-<NUM>-yn-<NUM>-yl) cyclopentyl) methanol (<NUM>, <NUM> mmol) and ethyl <NUM>-(<NUM>-nitrophenyl)-<NUM>-oxoacetate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) at <NUM> under argon atmosphere and stirred the reaction mixture for <NUM>. Quenched with aqueous NaHCO<NUM> solution (<NUM>), stirred for <NUM> then extracted with CH<NUM>Cl<NUM> (2x5 mL), dried over anhydrous Na<NUM>SO<NUM>, filtered and concentrated. Resulting solid was dissolved in hexanes (<NUM>) and slowly added the minimum amount of CH<NUM>Cl<NUM>. The resulting solution was stand at <NUM> until all solvents were evaporated to form crystalline product <NUM>-(<NUM>-nitrophenyl)-<NUM>,<NUM>-dioxadispiro[<NUM>. <NUM><NUM>. <NUM><NUM>Itridec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%). TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc /hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM>N [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the reaction mixture of pent-<NUM>-yn-<NUM>-ol (<NUM>, <NUM> mmol) and ethyl pyruvate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM> purification of crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc /hexanes) afforded <NUM>-methyl-<NUM>,<NUM>-dioxaspiro[<NUM>]non-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a yellow oily liquid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc /hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM> found <NUM>.

Following the General Procedure, to the mixture of <NUM>-pentyne-<NUM>-ol (<NUM>, <NUM> mmol) and ethyl phenylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM> at <NUM>. Purification of the crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc/hexane) afforded <NUM>-phenyl-<NUM>, <NUM>-dioxaspiro [<NUM>, <NUM>] non-<NUM>-en-<NUM>-one (<NUM>, <NUM>%). TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc /hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of <NUM>-pentyne-<NUM>-ol (<NUM>, <NUM> mmol) and ethyl anisylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM> at <NUM>. Purification of the crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc /hexanes) afforded <NUM>-(<NUM>-methoxyphenyl)-<NUM>,<NUM>-dioxaspiro[<NUM>,<NUM>]non-<NUM>-en-<NUM>-one (3cc) (<NUM>, <NUM>%). TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc /hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI): calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the reaction mixture of pent-<NUM>-yn-<NUM>-ol (<NUM>, <NUM> mmol) and ethyl p-tolylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc /hexanes) afforded <NUM>-(p-tolyl)-<NUM>, <NUM>-dioxaspiro [<NUM>] non-<NUM>-en-<NUM>-one crystalline solid (<NUM>, <NUM>%). TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc /hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM> found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(but-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl pyruvate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction n mixture for <NUM> at <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) gave <NUM>, <NUM>-dimethyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a yellow oil. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(but-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl phenylglyoxylate (<NUM>, <NUM> mmol) in dry CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-methyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro[<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (6ab) (<NUM>, <NUM>%) as a crystalline solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes). <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>); δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(but-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl anisylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-(<NUM>-methoxyphenyl)-<NUM>-methyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a crystalline solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(but-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl p-tolylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) gave <NUM>-methyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a crystalline solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>);<NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(pent-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl pyruvate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) provided <NUM>-ethyl-<NUM>-methyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a colorless oil. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(pent-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl phenylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-ethyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(pent-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl anisylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) gave <NUM>-ethyl-<NUM>-(<NUM>-methoxyphenyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(pent-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl p-tolylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM>. 11mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-ethyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(<NUM>-phenylprop-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl pyruvate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-methyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a white solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(<NUM>-phenylprop-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl phenylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by crystallization (hexane:CH<NUM>Cl<NUM> (<NUM>)) afforded <NUM>, <NUM>-diphenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one, (<NUM>, <NUM>%) as a solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>;HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(<NUM>-phenylprop-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl anisylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-(<NUM>-methoxyphenyl)-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(<NUM>-phenylprop-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl p-tolylglyoxylate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-phenyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a white solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(<NUM>-phenylprop-<NUM>-yn-<NUM>-yl) cyclohexyl) methanol (<NUM>, <NUM> mmol) and ethyl <NUM>-(<NUM>-nitrophenyl)-<NUM>-oxoacetate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexanes) afforded <NUM>-(<NUM>-nitrophenyl)-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>, <NUM>%) as a yellow solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM> ): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM>N [M+H]+ <NUM>, found <NUM>.

Following the General Procedure, to the mixture of (<NUM>-(<NUM>-phenylprop-<NUM>-yn-<NUM>-yl) cyclopentyl) methanol (<NUM> gm, <NUM> mmol) and ethyl pyruvate (<NUM>, <NUM> mmol) in anhydrous CH<NUM>Cl<NUM> (<NUM>) was added Bi(OTf)<NUM> (<NUM>, <NUM> mmol) under argon atmosphere at <NUM> and stirred the reaction mixture for <NUM>. Purification of the crude product by silica gel column chromatography (SiO<NUM>, <NUM>% EtOAc/hexane) afforded <NUM>-methyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>. <NUM><NUM>. <NUM><NUM>] tridec-<NUM>-en-<NUM>-one one (<NUM>, <NUM>%) as a solid. TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexane); <NUM>H NMR (CDCl<NUM>, <NUM>,): δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H] <NUM>, found <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (m, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM>N [M+H]+ <NUM>, found <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H] + <NUM>, found <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM>N [M+H]+ <NUM>, found <NUM>.

<NUM>H NMR(CDCl<NUM>, <NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>(d, <NUM>), <NUM> (d, J =<NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>, <NUM>.

<NUM>H NMR(CDCl<NUM>, <NUM>) δ <NUM>-<NUM>(m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>(d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>(d, J = <NUM>, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>;HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+<NUM>, found <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>) δ171. <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; Diastereomer-<NUM>:TLC: Rf = <NUM> (SiO<NUM>, <NUM>% EtOAc/hexanes); <NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>) δ171. <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>;HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM>[M+H]+<NUM>,found <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Minor diastereomer : <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (qd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (AB q, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Data for minor diastereomer (α-isomer): <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s. , <NUM>), <NUM> (s, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>;HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (d, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

Data for partially separable minor diastereomer: <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>- <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>); <NUM>C NMR (CDCl<NUM>, <NUM>): δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+ <NUM>, found <NUM>.

<NUM>HNMR (CDCl<NUM>, <NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d,J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>) <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>. -<NUM> (m, <NUM>);<NUM>C NMR (CDCl<NUM>, <NUM>) δ169. <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM>[M+H]+<NUM>, found <NUM>.

<NUM>H NMR(CDCl<NUM>, <NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>- <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d,J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>);<NUM>C NMR (CDCl<NUM>, <NUM>)<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>; HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+<NUM>, found <NUM>.

<NUM>H NMR(CDCl<NUM>, <NUM>) δ7. <NUM>-<NUM> (s, <NUM>), <NUM> - <NUM> (td, J = <NUM><NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM> ), <NUM>-<NUM> (m, <NUM>),<NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>);<NUM>C NMR (CDCl<NUM>, <NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>;HRMS (ESI) m/z calcd for C<NUM>H<NUM>O<NUM> [M+H]+<NUM>, found <NUM>.

Claim 1:
A γ -spiroketal- γ -lactones compound selected from the group consisting of <NUM>, <NUM>-Dimethyl-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Methyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-(<NUM>-Methoxyphenyl)-<NUM>-methyl-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Methyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-methyl-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-(<NUM>-methoxyphenyl)-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Ethyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Methyl-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>, <NUM>-Diphenyl-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-(<NUM>-Methoxyphenyl)-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), <NUM>-Phenyl-<NUM>-(p-tolyl)-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), and <NUM>-(<NUM>-Nitrophenyl)-<NUM>-phenyl-<NUM>, <NUM>-dioxadispiro [<NUM>.<NUM><NUM>.<NUM><NUM>] tetradec-<NUM>-en-<NUM>-one (<NUM>), having following structure:
<CHM>
<CHM>
<CHM>
<CHM>
or a hydrate, solvate or pharmaceutically acceptable salt thereof