DISPIRO TETRAQXANE COMPOUNDS

The present invention relates to dispiro tetraoxane compounds, particularly but not exclusively, for use in the treatment of malaria and/or cancer, and methods for producing such compounds.

The discovery of artemisinin and the establishment that the peroxide pharmacophore is important for antimalarial activity has seen many attempts by chemists to synthesise simple but effective synthetic or semi-synthetic endoperoxides. Artemisinin (2) is a naturally occurring endoperoxide sesquiterpene lactone compound of Artemisia annua, an herbal remedy used in Chinese medicine. Although artemisinin derivatives are extensively used against malaria, cost, supply and high recrudescent rates remain issues with this class of drug. Other known peroxides with antimalarial potency include Yingzhaousu (3), WRl 48999 (4) and steroid amide (5).

Artemisinin (2) Yingzhaosu A (3) WR148999 (4)

The endoperoxides group is an important functional group in medicinal chemistry. It is found in the artemisinin class of antimalarials such as artemether and artesunate, in which its reaction with heme (or free Fe(II)) generates cytotoxic radicals which cause parasite death. More recently, artemisinin derived 1,2,4-trioxane monomers and dimers have been shown to be potent inhibitors of cancer cell proliferation. A disadvantage with the semi-synthetic compounds described is that their production requires artemisinin as starting material. Artemisinin is extracted from the plant Artemisinia annua in low yield, a fact that necessitates significant crop-production. Therefore, there is much need for the development of new and improved approaches to synthetic endoperoxides.

Tetraoxanes were initially used industrially for the production of macrocyclic hydrocarbons and lactones, however, pioneering work by the Vennerstrom group demonstrated that symmetrical tetraoxanes possess impressive antimalarial activity in vitro. Tetraoxanes are believed to have a similar mode of activity as the naturally occurring peroxides such are artemisinin.

The major drawbacks with tetraoxanes that have been synthesized to date include poor stability and low oral antimalarial activity. Apart from some recent success with steroidal-based 1,2,4,5-tetraoxanes such as (5), previously synthesised tetraoxanes all have poor oral bioavailability. Although many of the first generation tetraoxane derivatives are highly lipophilic, suggesting that poor absorption was the key factor affecting bioavailability, it is also apparent that first pass metabolism plays a role in reducing effective drug absorption.

The object of the present invention is to obviate or mitigate one or more of the above problems.

According to a first aspect of the present invention there is provided a compound having the formula (I)

(I) wherein ring A represents a substituted or unsubstituted monocyclic or multicyclic ring; m=any positive integer; n=0-5;

X=CH and Y=^-C(O)NR ¹ R ² , -NR ¹ R ² or -S(O) ₂ R ⁴ , where R ¹ , R ² and R ⁴ are each individually selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or any combination thereof, or R ¹ and R ² are linked so as to form part of a substituted or unsubstituted heterocyclic ring,

or

X=N and Y=^S(O) ₂ R ³ or -C(O)R ³ , where R ³ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring or any combination thereof.

Preferred compounds in accordance with the first aspect of the present invention have unprecedented in vivo levels of antimalarial activity for the tetraoxane class of drug.

A second aspect of the present invention provides a method for the production of a compound according to the first aspect of the present invention, wherein the method comprises reacting a bishydoperoxide compound having formula (Ia) with a ketone having formula (Ib)

(Ia) (Ib)

hi the compound forming the first aspect of the present invention preferably ring A contains 3 to 30 carbon atoms, more preferably 5 to 15 carbon atoms, and most preferably 6, 8, 10 or 12 carbon atoms. Ring A is preferably a substituted or unsubstituted mono- or polycyclic alkyl ring.

Polycyclic alkyl rings, which contain more than one ring system may be "fused", where adjacent rings share two adjacent carbon atoms, "bridged", where the rings are defined by at least two common carbon atoms (bridgeheads) and at least three acyclic chains (bridges) connecting the common carbon atoms, or "spiro" compounds where adjacent rings are linked by a single common carbon atom.

Preferably ring A is selected from the group consisting of a substituted or unsubstituted cyclopentyl ring, a substituted or unsubstituted cyclohexyl ring, a substituted or unsubstituted cyclododecanyl ring, and a substituted or unsubstituted adamantyl group. In a particularly preferred embodiment of the compound forming the first aspect of the present invention, ring A is an adamantyl group.

In a preferred embodiment of the compound according to the first aspect of the present invention X=CH, Y^-C(O)NR ¹ R ² or -NR ¹ R ² , R ¹⁼ H and R ² =alkyl group substituted with an ester group, amine group or amido group.

Said alkyl group may be an ethyl group.

Said amino group may be a diethylaminoethyl group.

Said ester group may be a methylester group.

In a further preferred embodiment of the compound according to the first aspect of the present invention X=CH, Y^-C(O)NR ¹ R ² or -NR ¹ R ² , R ¹ ^H and R ² contains a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring, zero, one or more methylene radicals being provided in between said carbocyclic or heterocyclic ring and the nitrogen atom of group Y.

hi this embodiment R ² preferably contains a substituted or unsubstituted cycloalkyl group containing 3 to 6 carbon atoms. The cycloalkyl group is most preferably bonded directly to the nitrogen atom of group Y.

Alternatively, R ² preferably contains a substituted or unsubstituted heterocyclic group containing 3 to 6 carbon atoms and at least one heteroatom, the or each heteroatom being separately selected from the group consisting of nitrogen, oxygen and sulfur.

The heterocyclic group may be linked to the nitrogen atom of group Y by any appropriate number of methylene radicals, such as one, two, three or four methylene group. It is most preferred that the heterocyclic group is linked to the nitrogen atom of group Y via two methylene radicals.

Said heterocyclic group is preferably selected from the group consisting of a pyrrolidyl group, a piperidyl group, a morpholinyl group, a thiomorpholinyl group and a thiomorpholinyl sulfone group.

In a further preferred embodiment of the compound according to the first aspect of the present invention X=CH, Y^C(O)NR ¹ R ² or -NR ¹ R ² , and R ¹ and R ² are linked so as to form part of a substituted or unsubstituted heterocyclic ring selected from the group consisting of a pyrrolidyl group, a piperidyl group, a morpholinyl group, a thiomorpholinyl group and a thiomorpholinyl sulfone group.

In another preferred embodiment of the compound according to the first aspect of the present invention X=N, Y=-S(O) ₂ R ³ or -C(O)R ³ , and R ³ is a substituted or unsubstituted phenyl group or a substituted or unsubstituted heterocyclic group selected from the group consisting of a pyrrolidyl group, a piperidyl group, a morpholinyl group, a thiomorpholinyl group and a thiomorpholinyl sulfone group.

In a yet further preferred embodiment of the compound forming the first aspect of the present invention m=l, n=0, X=CH and Y=NHR ² , where R ² is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or any combination thereof.

Preferably ring A is an adamantyl group.

In a further preferred embodiment m=l, n=l, X=CH, Y-S(O) ₂ R ⁴ , wherein R ⁴ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or

unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or any combination thereof.

It is preferred that ring A is a C ₄ -C ₁₅ carbocyclic group. More preferably ring A is selected from a cyclohexanyl carbocylic group and an adamantyl group.

In a still further preferred embodiment of the first aspect of the present invention m=l, n=0, X=N and Y^C(O)R ³ , where R is a substituted or unsubstituted amine group or a substituted or unsubstituted heterocyclic ring containing a nitrogen atom where said nitrogen atom connects the heterocyclic ring to the carbonyl carbon atom or group Y.

Where R ³ is an amine group that is substituted, i.e. the nitrogen atom of the amine group is substituted with atoms and/or groups other than hydrogen atoms, the pattern of substitution may be symmetric or unsymetric. One or both amine substituents may be the same or different alkyl or aryl groups, which may themselves be substituted or unsubstituted. Preferably the amine group is substituted with one or two methyl, ethyl or propyl groups. The amine group may be substituted with an aromatic group, such as a phenyl group.

Ring A may be a C ₄ -C ₁₅ carbocyclic group, preferably a cyclohexanyl carbocylic group or an adamantyl group.

Where R ³ is a substituted or unsubstituted heterocyclic ring containing a nitrogen atom in which said nitrogen atom connects the heterocyclic ring to the carbonyl carbon atom, R ³ preferably forms part of a pyrrolidyl group, a piperidyl group, a morpholinyl group, a thiomorpholinyl group and a thiomorpholinyl sulfone group.

As explained below in the Examples, reductive amination of appropriate ketones with various amino compounds afforded compounds 14-19, which represent preferred compounds according to the first aspect of the present invention.

14-19

14 R = CH(CH ₂ ) ₂ 17 R = CH ₂ CH ₂ N(CH ₂ ) ₄ O

15 R = CH ₂ CH ₂ N(CH ₂ ) ₄ 18 R = CH ₂ CH ₂ N(C ₂ H ₅ ) ₂

16 R = CH ₂ CH ₂ N(CH ₂ ) ₅ 19 R = (CH ₂ ) ₄ O

In a still further preferred embodiment of the compound according to the first aspect of the present invention m=l, n=l, X=CH and Y=-C(O)NR ¹ R ² , where R ¹ and R ² are each individually selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or any combination thereof, or R ¹ and R ² are linked so as to form part of a substituted or unsubstituted heterocyclic ring.

Preferably ring A is an adamantyl group.

Preferred compounds according to the first aspect of the present invention are represented below

27c-27i, R ¹ and R ² = (CH ₂ ) ₅

28c-28i, R ¹ and R ² = (CH ₂ )H

29c-29j, R ⁱ and R ² = Adamantylidine, where

27c, R= CH(CH ₂ ) ₂ 28c, R= CH(CH ₂ ) ₂

27d, R = CH ₂ CH ₂ N(CH ₂ ) ₄ 28d, R = CH ₂ CH ₂ N(CH ₂ ) ₄

27e, R = CH ₂ CH ₂ N(CH ₂ ) ₅ 28e, R = CH ₂ CH ₂ N(CH ₂ ) ₅

27f, R = CH ₂ CH ₂ N(CH ₂ ) ₄ O 28f, R = CH ₂ CH ₂ N(CH ₂ ) ₄ O

27g, R= CH ₂ CH ₂ N(C ₂ Hs) ₂ 28g, R= CH ₂ CH ₂ N(C ₂ Hs) ₂

27h, R = (CH ₂ ) ₄ O 28h, R = (CH ₂ ) ₄ O

27i, R = CH ₂ CO ₂ CH ₃ 28i, R = (CH ₂ ) ₄ S

29c, R= CH(CH ₂ ) ₂ 29h, R = (CH ₂ ) ₄ O 29d, R = CH ₂ CH ₂ N(CH ₂ ) ₄ 29i, R = (CH ₂ ) ₄ S 29e, R = CH ₂ CH ₂ N(CH ₂ )S 29j, R = CHCH(CH ₃ ) ₂ CO ₂ CH ₃ 29f, R = CH ₂ CH ₂ N(CH ₂ ) ₄ O 31, R = (CH ₂ ) ₄ SO ₂ , 29g, R= CH ₂ CH ₂ N(C ₂ Hs) ₂ 32, R = (CH ₂ ) ₄ SO ₂ , R'&R^adamantyl

Further aspects of the present invention provide compounds having formulae (II) and

(III)

(II) (πi)

In a further preferred embodiment of the compound according to the first aspect of the present invention m=l, n=0, X=N and Y=-S(O) ₂ R ³ or -C(O)R ³ , where R ³ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring or any combination thereof.

Preferably ring A is an adamantyl group.

Preferred compounds according to the first aspect of the present invention are compounds 39a, 39f, 34p, 40a and 44 which are prepared from the corresponding ketone compound 38a, 38f and 34f, as shown below, some of which are described in more detail in the Examples.

38a 39a TFE

38f 39f

A preferred group of compounds according to the first aspect of the present invention are represented below

39a-i, R ¹ and R ² = adamantylidine 40a-d,R ¹ andR ² = (CH ₂ ) _π where

39a, R = Me 40a, R = Me

39b, R = Et 4Ob ₅ R = Et

39d, R = cyclopropyl 4Od ₅ R = C ₆ H ₅

39e, R = CH ₂ CF ₃

39f,R = C ₆ H ₅

39g ₅ R=p-ClC ₆ H ₄

39h, R=^-FC ₆ H ₄

391,R=P-CF ₃ C ₆ H ₄

In a preferred embodiment of the first aspect of the present invention there is provided a compound having the formula (IX) (corresponding to compound 39b)

(IX)

In a further preferred embodiment of the first aspect of the present invention there is provided a compound having the formula (X) (corresponding to compound 39d)

(X)

A still further preferred embodiment provides a compound having formula (XI) (corresponding to compound 34p)

A further aspect of the present invention provides a compound having the general formula (XII)

(XII) wherein ring A represents a substituted or unsubstituted monocyclic or multicyclic ring; q=any integer; and ring B represents a fused substituted or unsubstituted monocyclic or multicyclic ring.

q may take any appropriate integer value, such as 0 (in which case the ring fused to ring B will contain 5 carbon atoms), 1, 2, 3 or more.

Ring B may be a carbocyclic or heterocyclic ring aromatic or non-aromatic ring. Preferably, ring B is a non-substituted aromatic ring, such as a phenyl group.

Ring A may take any of the optional forms set out above in respect of the first aspect of the present invention. For example, ring A may be an adamantyl group.

Preferred embodiments of the class of compounds of general formula (XII) are compounds (XIII), (XIV) and (XV) corresponding to compounds 35d, 36c and 36d described below respectively.

(XIII) (XIV) (XV)

A still further aspect of the present invention provides a compound having the general formula (XVI)

(XVI)

wherein ring A represents a substituted or unsubstituted monocyclic or multicyclic ring; o=any integer; p=any integer; n=0-5; Z represents a bridging group; and

X=CH and Y=^C(O)NR ¹ R ² , -NR ¹ R ² or -S(O) ₂ R ⁴ , where R ¹ , R ² and R ⁴ are each individually selected from the group consisting of H, substituted or

unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or any combination thereof, or R ¹ and R ² are linked so as to form part of a substituted or unsubstituted heterocyclic ring, or

X=N and Y^S(O) ₂ R ³ or -C(O)R ³ , where R ³ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring or any combination thereof.

Z is any desirable bridging group. Preferably Z is an alkylidene or arylidene group which may be substituted or substituted and may incorporate one or more heteroatoms, such as oxygen, sulfur and/or nitrogen atoms. More preferably Z is a C ₁ -C ₃ alkylidene group, most preferably an ethylidene group.

The various substituents set out above in the general definition of compound (XVI) may take any of the optional or preferred substituents specified above in respect of the first aspect of the present invention.

A preferred embodiment of the class of compounds of general formula (XVI) is compound corresponding to compound (XVII) below.

A further aspect of the present invention provides a salt of the compound according to the first aspect of the present invention. Said salt may be an acid addition salt produced by reacting a suitable compound according to the first aspect of the present invention with an appropriate acid, such as an organic acid or mineral acid.

The present invention further provides a pharmaceutical composition comprising a compound according to the first aspect of the present invention and a pharmaceutically acceptable excipient.

There is still further provided a pharmaceutical composition comprising a compound according to the first aspect of the present invention and a pharmaceutically acceptable excipient for the treatment of malaria.

A further aspect of the present invention provides use of a compound according to the first aspect of the present invention in the preparation of a medicament for the treatment of malaria.

Another aspect of the present invention provides a method of treating malaria in a human or animal patient comprising administering to said patient a therapeutically effective amount of a compound according to the first aspect of the present invention.

A yet further aspect of the present invention provides a pharmaceutical composition for the treatment of a cancer comprising a compound according to the first aspect of the present invention and a pharmaceutically acceptable excipient.

There is further provides use of a compound according to the first aspect of the present invention in the preparation of a medicament for the treatment of cancer.

A still further aspect of the present invention provides a method of treating a cancer in a human or animal patient comprising administering to said patient a therapeutically effective amount of a compound according to the first aspect of the present invention.

The aforementioned second aspect of the present invention provides a method for the production of a compound according to the first aspect of the present invention, wherein the method comprises reacting a bishydoperoxide compound having formula (Ia) with a ketone having formula (Ib)

(Ia) (Ib)

It is preferred that compound (Ia) is prepared by oxidising an appropriate starting material using an oxidising agent and isolating compound (Ia) from any excess unreacted oxidising agent prior to reacting compound (Ia) with compound (Ib).

Any appropriate oxidising agent may used but a preferred oxidising agent is hydrogen peroxide.

It is preferred that oxidation of said appropriate starting material is carried out in the presence of acetonitrile.

Said appropriate starting material is preferably selected from the group consisting of compounds (Ic) and (Id)

(Ic) (Id)

Li a preferred embodiment of the method forming the second aspect of the present invention, the compound to be prepared in accordance with the first aspect of the present invention comprises X=CH and Y-C(O)NR R , and the method for its preparation comprises an amide coupling reaction between NHR R and a compound having formula (IV)

(IV) wherein Z=H or alkyl.

It is preferred that compound (FV) is prepared by reacting compound (V) with compound (Ib)

(V) (Ib)

Preferably compound (V) is prepared by oxidising compound (VI)

(VI)

Oxidation of compound (VI) may be effected using any suitable oxidising agent but it is preferably effected by the addition of hydrogen peroxide.

Where the compound according to the first aspect of the present invention is to be prepared where n=l to 4, it is preferred that compound (VI) is prepared by reacting compound (VII) with compound (VIII) under conditions to facilitate a Wittig reaction between said compounds and subsequently hydrogenating the resulting C=C bond formed as a result of said Wittig reaction.

(VII) (VIII)

In a preferred embodiment of the method for the production of a compound according to the first aspect of the present invention, the method comprises reacting a ketone compound (Ic) with an oxidising agent in a reaction mixture so as to oxidise said ketone (Ic) to provide a bishydoperoxide compound (Ia) and adding a ketone compound (Ib) to said reaction mixture so as to react compound (Ia) with said ketone (Ib), said oxidising reaction and said reaction of compound (Ia) with compound (Ib) being effected in the presence of a fluorinated alcoholic solvent.

(Ic) (Ia)

(Ib)

The fluorinate solvent is preferably l,l,l,3,3,3-hexafluoro-2-propanol.

When any of the foregoing substituents are designated as being optionally substituted, the substituent groups which are optionally present may be any one or more of those customarily employed in the development of pharmaceutical compounds and/or the modification of such compounds to influence their structure/activity, stability, bioavailability or other property. Specific examples of such substituents include, for example, halogen atoms, nitro, cyano, hydroxyl, cycloalkyl, alkyl, alkenyl, haloalkyl, cycloalkyloxy, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio,

alkylsulphinyl, alkylsulphonyl, alkylsulphonato, arylsulphinyl, arylsulphonyl, arylsulphonato, carbamoyl, alkylamido, aryl, aralkyl, optionally substituted aryl, heterocyclic and alkyl- or aryl-substituted heterocyclic groups. A halogen atom may be fluorine, chlorine, bromine or iodine atom and any group which contains a halo moiety, such as a haloalkyl group, may thus contain any one or more of these halogen atoms.

The compound of the first aspect of the present invention may take a number of different forms depending, in particular on the manner in which the compound is to be used. Thus, for example, the compound may be provided in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micelle, transdermal patch, liposome or any other suitable form that may be administered to a person or animal. It will be appreciated that the vehicle of the compound of the invention should be one which is well tolerated by the subject to whom it is given and enables delivery of the compound to the required location.

The compound may be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

The compound of the invention may be used in a number of ways. For instance, systemic administration may be required in which case the compound may, for example, be ingested orally in the form of a tablet, capsule or liquid. Alternatively the compound may be administered by injection into the blood stream. Injections may be intravenous (bolus or infusion) or subcutaneous (bolus or infusion). The compounds may be administered by inhalation (e.g. intranasally).

The compound may also be administered centrally by means of intrathecal delivery.

The compound may also be incorporated within a slow or delayed release device. Such devices may, for example, be inserted on or under the skin and the compound may be released over weeks or even months. The devices may be particularly advantageous when a compound is used which would normally require frequent administration (e.g. at least daily ingestion of a tablet or daily injection).

It will be appreciated that the amount of a compound required is determined by biological activity and bioavailability which in turn depends on the mode of administration, the physicochemical properties of the compound employed and whether the compound is being used as a monotherapy or in a combined therapy. The frequency of administration will also be influenced by the above mentioned factors and particularly the half-life of the compound within the subject being treated.

Optimal dosages of the compound to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.

Known procedures, such as those conventionally employed by the pharmaceutical industry (e.g. in vivo experimentation, clinical trials, etc.), may be used to establish specific formulations of compounds and compositions and precise therapeutic regimes (such as daily doses of the compounds and the frequency of administration).

Generally, a daily dose of between 0.01 μg/kg of body weight and 1.0 g/kg of body weight of the inventive compound may be used depending upon which specific compound is used. More preferably, the daily dose is between 0.01 mg/kg of body weight and 100 mg/kg of body weight.

Daily doses may be given as a single administration (e.g. a daily tablet for oral consumption or as a single daily injection). Alternatively, the compound used may require administration twice or more times during a day. As an example, patients may be administered as two or more daily doses of between 25 mgs and 5000 mgs in tablet form. A patient receiving treatment may take a first dose upon waking and then a second dose in the evening (if on a two dose regime) or at 3 or 4 hourly intervals thereafter. Alternatively, a slow release device may be used to provide optimal doses to a patient without the need to administer repeated doses.

This invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and, preferably, a pharmaceutically acceptable vehicle. In the subject invention a "therapeutically effective amount" is any amount of a compound or composition which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. A "subject" is a vertebrate, mammal, domestic animal or human being. In the practice of this invention the "pharmaceutically acceptable vehicle" is any physiological vehicle known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.

In one embodiment, the amount of the compound in the composition according to the the present invention is an amount from about 0.01 mg to about 800 mg. In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 500 mg. In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 250 mg. hi another embodiment, the amount of the compound is an amount from about 0.1 mg to about 60 mg. hi another embodiment, the amount of the compound is an amount from about 1 mg to about 20 mg.

In one embodiment, the pharmaceutical vehicle employed in the composition of the present invention may be a liquid and the pharmaceutical composition would be in the form of a solution. In another embodiment, the pharmaceutically acceptable vehicle is a solid and the composition is in the form of a powder or tablet. In a further

embodiment, the pharmaceutical vehicle is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound or composition may be formulated as a part of a pharmaceutically acceptable transdermal patch.

A solid vehicle employed in the composition according to the present invention can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet- disintegrating agents; it can also be an encapsulating material. In powders, the vehicle is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid vehicles include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid vehicles may be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions according to the present invention. The compound of the first aspect of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.

The liquid vehicle can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid vehicles for oral and parenteral administration of the compound forming the first aspect of the present invention include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile

liquid vehicles are useful in sterile liquid form compositions for parenteral administration. The liquid vehicle for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.

The compound forming the first aspect of the present invention can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The inventive compounds may be prepared as a sterile solid composition according to the present invention which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Vehicles are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.

The compound forming part of the present invention is eminently suitable for use in prophylactic treatment. By the term "prophylactic treatment" we include any treatment applied to prevent, or mitigate the effect of a disorder. The prophylactic treatment may be given, for example, periodically to a person who is of a predetermined minimum age or who is genetically predisposed to a disorder. Alternatively the prophylactic treatment may be given on an ad hoc basis to a person who is to be subjected to conditions which might make the onset of a disorder more likely.

The invention will be further described by way of example only with reference to the following non-limiting Examples and Figure 1 which shows single crystal X-ray structures of compounds 27h, 29a, 29c and 29h.

EXAMPLES

Structure A Derivatives

Compounds of formula (I) wherein m=l, n=0, X=CH and Y=NHR ² , where R ² is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or any combination thereof.

The initial target molecule was prepared by the method reported by Iskra et al. (Scheme 1) in which cyclohexanone 5 and 1,4-cyclohexanedione 6 are allowed to react in a two step sequence.

6, R ¹ and R ² = (CH ₂ ) ₅ 10, R ¹ and R ² = (CH ₂ ) _5l 28%

7, R ^{1 a} nd R ² = (CH ₂ )H 11 , R1 a _n d R ² = (CH ₂ )H, 22%

8, R ¹ and R ² = Adamantylidine 12, R ¹ and R ^{2 =} Adamantylidine, 23%

Scheme 1. Reagents and conditions: a) 30% H ₂ O ₂ (2 equiv.), MTO (O.lequiv.) /TFE- 0.5M, b) [l,4-cyclohexanedione-9 (2 equiv.), EtOAc/HBF ₄ (l equiv.)]

The required 1,2,4,5-tetraoxane 10, formed by cross-condensation of the bis- hydroperoxide and the 1,4-cyclohexanedione, was obtained in rather low yield. A significant amount of the symmetrical 1,2,4,5-tetraoxane, resulting from competitive homo-cyclocondensation of bishydroperoxide, was also recovered with a small amount of the trimeric cyclic peroxide.

To avoid the formation of any trimeric product any excess hydrogen peroxide was removed by carrying out a two step synthesis of the tetraoxanes; first by preparing the bishydroperoxide and removing any unreacted hydrogen peroxide followed by the tetraoxane formation reaction (Scheme 2). The yield of the required tetraoxane was improved slightly.

Various methodologies available for the formation of the bishydroperoxide were investigated and the method reported by Ledaal and co workers ¹ was identified. Performing the reaction in acetonitrile led to the elimination of the formation of a solid mass in the flask leading to quantitative conversion of the ketone to the bishydroperoxide.

While some methodologies led to an exclusive formation of the symmetrical tetraoxanes, others led to the formation of compound 13.

Several attempts to close the ring according to existing literature ¹ procedures failed.

6, R and R = (CH ₂ ) _{5 63j R} 1 _{and R} 2 _{= {CH2)5| m} ^ _{R1 and R2 = (CH} ^ _Wo

7, R ^a nd R = (CH ₂ )H 7a, R ^{1 a} nd R ² = (CH ₂ )H, 66% 11, R ^{1 a} nd R ² = (CH ₂ J ₁₁ , 22%

8, R ¹ and R ^z -Adamantylιdιne _{8ai R} 1 _{and R} ² = _Adamant y)idine, 73% ₁₂₍ R1 and R ^{2 =} Adamantylidine, 23%

Scheme 2. Reagents and conditions: a) H ₂ O ₂ 30% (2 equiv.), CH ₃ CN, O ⁰ C, 4min., b) l,4-cyclohexanedione-9 (2 equiv.), EtOAc, HBF ₄ (1 equiv.)

Reductive animation of the ketone with various amino compounds afforded compounds 14-19 in moderate to good yields. (20-85%) (Scheme 3)

14-19

14 R = CH(CH ₂ ) ₂ , 55% 17 R = CH ₂ CH ₂ N(CH ₂ ) ₄ O, 47%

15 R = CH ₂ CH ₂ N(CH ₂ ) ₄ , 85% 18 R = CH ₂ CH ₂ N(C ₂ Hs) ₂ , 20%

16 R = CH ₂ CH ₂ N(CH ₂ ) _S , 60% 19 R = (CH ₂ ) ₄ O, 56%

Scheme 3. Reagents and conditions: a) RNH ₂ (1.3 equiv.), NaBH(OAc) ₃ (1.3 equiv.), CH ₂ Cl ₂ .

Structure B Derivatives

Compounds of formula (I) wherein m=l, n=l, X=CH and Y=^C(O)NR ¹ R ² , where R ¹ and R ² are each individually selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or any combination thereof, or R and R are linked so as to form part of a substituted or unsubstituted heterocyclic ring.

Structure B derivatives were prepared via an alternative route by first carrying out a Wittig reaction between 1,4-cyclohexanedionemo-noethylketal with the appropriate ylide (Scheme 4). Hydrogenation in the presence of Palladium on charcoal afforded the required starting material 17. The bishydroperoxide formed was condensed with various ketones to afford the corresponding tetraoxanes 27a, 28a, 29a, 30a. Hydrolysis, followed by amide coupling reactions led to various water-soluble analogues listed in Table 1.

20 21, R = CH ₃ , 90% 23, R = CH ₃ , 95% 25, R = CH ₃ , 70%

22,R = C ₂ H ₅₎ 92% 24, R = C ₂ H ₅₎ 93% 26, R=C ₂ H ₅ , 88%

27a, R ¹ and R ² = (CH ₂ ) ₅ , R =C ₂ H ₅ , 50% 272c-27i, R ¹ and R ² = (CH ₂ ) ₅

28a, R ¹ and R ² = (CH ₂ ), „ R = C ₂ H ₅ , 33% £$ ^ 28c-28i, R ¹ and R ² = (CH ₂ ), ,

29/3Oa, R ¹ and R ² = Adamantylidine, 29b, 87.8% 29c-29j R ¹ and R ² = Adamantylidine = C ₂ H ₅ /CH ₃ , 50.1/66% ^'

Scheme 4. Reagents and conditions: a) Ph ₃ P=CHCO ₂ R, R = CH ₃ /C ₂ H ₅ (1.1 equiv), benzene/toluene, reflux, 24hrs, b) Pd/C, H ₂ , EtOAc, c) H ₂ WO ₄ (2 equiv.), THF, 30% H ₂ O ₂ (2 equiv.), O ⁰ C, 48hrs d) cyclohexanone/cyclododecanone/adamantanone (2 equiv.), EtOAc, HBF ₄ (1 equiv.), e) KOH (5.5 equiv.), CH ₃ OH, 7O ⁰ C, IHr, f) Et ₃ N (1 equiv.), ClCO ₂ C ₂ H ₅ (1.3 equiv.), c, O ⁰ C, lhr. g) RNH ₂ (2 equiv.), O ⁰ C- r.t.

Table 1. Yields for Amide Synthesis.

27c-27i, , R ¹ and R ² = (CH ₂ ) _S 28c-28i, R ¹ and R ² = (CH ₂ )H 29c-29j, _R ⁱ _{and R} ² = Adamantylidine,

Acid Amide Product Yield (%)

27b 27c, R= CH(CH ₂ ) ₂ 85

27b 27d, R = CH ₂ CH ₂ N(CH ₂ ) ₄ 78

27b 27e, R = CH ₂ CH ₂ N(CH ₂ ) ₅ 81

27b 27f, R = CH ₂ CH ₂ N(CH ₂ ) ₄ O 76

27b 27g, R= CH ₂ CH ₂ N(C ₂ Hs) ₂ 58

27b 27h, R = (CHz) ₄ O 84

27b 27i, R = CH ₂ CO ₂ CH ₃ 45

28b 28c, R= CH(CH ₂ ) ₂ 88

28b 28d, R = CH ₂ CH ₂ N(CH ₂ ) ₄ 81

28b 28e, R = CH ₂ CH ₂ N(CH ₂ ) _S 82

28b 28f, R = CH ₂ CH ₂ N(CH ₂ ) ₄ O 78

28b 28g, R= CH ₂ CH ₂ N(C ₂ Hs) ₂ 74

28b 28h, R = (CH ₂ ) ₄ O 90

28b 28i, R = (CH ₂ ) ₄ S 78

29b 29c, R= CH(CH ₂ ) ₂ 83

29b 29d, R = CH ₂ CH ₂ N(CH ₂ ) ₄ 80

29b 29e, R = CH ₂ CH ₂ N(CH ₂ )S 78

29b 29f, R = CH ₂ CH ₂ N(CH ₂ ) ₄ O 77

29b 29g, R= CH ₂ CH ₂ N(C ₂ Hs) ₂ 66

29b 29h, R = (CH ₂ ) ₄ O 81

29b 29i, R = (CH ₂ ) ₄ S 77

29b 29j, R = CHCH(CH ₃ ) ₂ CO ₂ CH ₃ 69

28b 31; R = (CHz) ₄ SO ₂ 92

29b 32; R = (CH ₂ ) ₄ SO ₂ 88

For analogues 27h, 29a, 29c and 29h crystals were grown by slowly evaporating a dichloromethane/hexane mixture and the single crystal X-ray structures were solved for these two tetraoxanes (Figure 1).

Compounds 28i and 29i were converted into the corresponding sulfones 31 and 32 using excess amount of rø-Chloroperbenzoic acid in dichloromethane in excellent yields.

28i, R ¹ and R ² =(CH ₂ ) ₁₁ 31 , R ¹ and R ² =(CH ₂ )n

29i, R ¹ and R ² = Adamantylidine 32, R ¹ and R ² = Adamantylidine

Scheme 5. Reagents and conditions: (a) m-CPBA (2.2 equiv.), CH ₂ Cl ₂ , room temperature, 4-6hrs.

Preliminary in vitro antimalarial data indicated that the amides containing the adamantylidine group were the most active so the synthesis of a wider range of adamantylidine amides 29k-29w was undertaken (Table 2).

Table 2. Yields for extended amide synthesis

Structure C Derivatives

Compounds of formula (I) where in m=l, n=0, X=N and Y=-S(O) ₂ R ³ or -C(O)R ³ , where R ³ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring or any combination thereof.

Structure C derivatives 39a-i and 40a-d were prepared as shown below. The process involved a one step procedure in which the sulfonyl piperidinones 38a-i were oxidised to the gem-dihydroperoxide in situ using 2 equivalents of hydrogen peroxide and approximately 0.1 mol% of methyltrioxorhenium (MTO). The second ketone was then added along with 2 equivalents OfHBF ₄ to give selectively the non- symmetric tetraoxanes 39a-i and 40a-d in 25-65% yields. The use of fluorous alcohols as the solvent for these reactions is important to this selectivity with l,l,l,3,3,3-hexafluoro-2-propanol (HFIP) being used in this case. This one-pot methodology allows the rapid synthesis of non-symmetrical tetraoxanes without the use of an excess of hydrogen peroxide or the need to isolate the potentially explosive dihydroperoxide intermediate.

b,d

Scheme 6. Reagents and conditions: (a) RSO ₂ Cl, K ₂ CO ₃ , DCM, H ₂ O, rt, overnight (b) H ₂ O ₂ , MTO, HFEP, rt, lh30mins (c) HBF ₄ , adamantanone, rt, Ih (d) HBF ₄ , cyclododecanone, rt, Ih.

Adamantanone and cyclododecanone have both been successfully incorporated in good yields (Table 3 and Table 4). The range of compounds with cyclododecanone incorporated was limited as it rapidly became apparent from preliminary in vitro test results that these compounds were less active than their adamantane counterparts.

Table 3: Yields of adamantane dispiro compounds

Table 4: Yields of cyclododecanone dispiro compounds

Preparation of a further example of a structure C derivative, tetraoxane 34n, was investigated. First, a reflux reaction between 4-piperidinone monohydrate hydrochloride 34a and an appropriate carbonyl chloride afforded the corresponding piperidinone 34h (Scheme 7).

Scheme 7. Reagents and conditions: (a) Toluene, reflux, triethylamine, 12 hours, carbonyl chloride.

R ² = PhCF ₃ , 74%

1,2-dihydroperoxycyclohexane 6a was prepared and condensed with piperidinone 34h to afford the target tetraoxane 34n (Scheme 8).

34h

Scheme 8. Reagents and conditions: (a) HCOOH, CH ₃ CN, 30% H ₂ O ₂ ,0 ⁰ C, 15min (b) EtOAc, HBF ₄ , rip.

Structure D Derivatives

Compounds of formula (I) wherein m=l, n=l, X=CH and Y-S(O) ₂ R ⁴ , where R ⁴ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring or any combination thereof.

The presence of a sulfonyl group in place of the amide was also investigated. Diethylmethyl thiomethyl phosphorane 33a was oxidized using røCPBA to the corresponding sulfone 33b. The sulfone was then reacted with 1,4-cyclohexane dione monoethylene ketal via a Wittig reaction to the corresponding vinyl compound 33c. Hydrogenation afforded the required starting material 33d which was oxidized with hydrogen peroxide to the gem-dihydroperoxide 33e and condensed with cyclohexanone/2-adamantanone to the corresponding tetraoxanes 33f and 33g (Scheme 9).

8%

Scheme 9. Reagents and conditions: (a) mCPBA, CH ₂ Cl ₂ (b) THF, -78 ⁰ C or THF, NaH, -1O ⁰ C (c) ethylacetate, H ₂ , 10% Pd/C (d) THF, H ₃ WO ₄ , O ⁰ C, 48 hours (e) Ketone, ethylacetate, HBF ₄

Structure E Derivatives

Compounds of formula (I) wherein m=l, n=0, X=N and Y-C(O)R ³ , where R ³ is a substituted or unsubstituted amine group or a substituted or unsubstituted heterocyclic ring containing a nitrogen atom where said nitrogen atom connects the heterocyclic ring to the carbonyl carbon atom or group Y.

Further, preparations of Urea type tetraoxanes 34j-o were investigated. First, a reflux reaction between 4-piperidinone monohydrate hydrochloride 34a and an appropriate carbonyl chloride afforded the corresponding piperidinones 34c-g (Scheme 10).

R ² = (CH ₂ ) _4; 63%

34d, X = N, R ¹ and R ² = (C ₂ H _S ) ₂ , 56% 34e, X = N, R ¹ and R ² = (CH ₂ ) _S , 73% 34f, X = N, R ¹ and R ² = (C ₂ H ₄ ) ₂ O, 64% 34g, X = N ₅ R ¹ and R ² =Ph 89%

Scheme 10. Reagents and conditions: (a) Toluene, reflux, triethylamine, 12 hours, carbonyl chloride.

Three pathways were then explored to prepare the urea type tetraoxanes. First, the gem-dihydroperoxide 34i was prepared using the formic acid procedure of the piperidinone 34e and condensed with cyclohexanone or 2-adamantanone to the target tetraoxanes 34j and 34k (Scheme 11).

Scheme 11. Reagents and conditions: (a) HCOOH, CH ₃ CN, 30% H ₂ O ₂ , O ⁰ C, 15min (b) diethylether, BF ₃ OEt ₂

Alternatively, 1,2-dihydroperoxycyclohexane 6a was prepared and condensed with the appropriate piperidinone to afford the target tetraoxanes 341-0 (Scheme 12).

34o,X = N, R ¹ and R ² = Ph, 26%

Scheme 12. Reagents and conditions: (a) HCOOH, CH ₃ CN ₅ 30% H ₂ O ₂ ,0 ⁰ C, 15min (b) EtOAc, HBF ₄ , rip.

An alternative strategy using a one pot methodology for conversion to the gem- dihydroperoxide followed by tetraoxane formation was also investigated to give the morpholine urea 34p (Scheme 13).

Scheme 13. Reagents and conditions: (a) H ₂ O ₂ , MTO, HFlP, lh30min (b) HBF ₄ , Adamantanone, Ih.

Structure F Derivatives

wherein ring A represents a substituted or unsubstituted monocyclic or multicyclic ring; q=any integer; and ring B represents a fused substituted or unsubstituted monocyclic or multicyclic ring.

In addition, we investigated the preparation of the diaspirol,2,4,5-tetraoxanes using 2-indanone 35a and /3-tetralones 36a. The gew-dihydroperoxides 35b and 36b prepared by treating 2-indanone and /3-tetralone with 30% H ₂ O ₂ were condensed with cyclohexanone and 2-adamantanone to give tetraoxanes 35c, 35d, 36c and 36d. The reactions are low yielding. Nevertheless, the required compounds were obtained (Scheme 14).

ne, 20%

6c, R ¹ and R ² = (CH ₂ ) ₅ , 28% 6d, R ¹ and R ² =adamantylidine, 26%

Scheme 14. Reagents and conditions: (a) HCOOH, CH ₃ CN, 30% H ₂ O ₂ , O ⁰ C, 15min (b) EtOAc, HBF ₄ , rtp.

Structure G Derivatives

(XVI) wherein ring A represents a substituted or unsubstituted monocyclic or multicyclic ring; o=any integer; p=any integer; n=0-5; Z represents a bridging group; and X=CH and Y^-C(O)NR ¹ R ² , -NR ¹ R ² or -S(O) ₂ R ⁴ , where R ¹ , R ² and R ⁴ are each individually selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, or any combination thereof, or R ¹ and R ² are linked so as to form part of a substituted or unsubstituted heterocyclic ring, or X=N and Y=-S(O) ₂ R ³ or — C(O)R ³ , where R ³ is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amine, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring or any combination thereof.

The increased activity of the adamantane systems compared to the cyclododecane systems lead us to postulate that the fused, more rigid adamantane ring has a stabilising effect. The effect of having a more rigid ring system at the other end of the molecule was also investigated using tropinone 41a as the starting material. Commercially available tropinone 41a was demethylated, sulfonated and subjected to the one pot reaction described above to give the anticipated tetraoxane 41 d in a reasonable yield (Scheme 15).

Scheme 15. Reagents and conditions: (a) 1-chloroethyl chloroformate, DCE, 12h, reflux (b) triethylamine, Et SO ₂ Cl, DCM, overnight, rt (c) H ₂ O ₂ , MTO, HFP, lh30min, rt (d) HBF ₄ , adamantanone, Ih, rt.

Biological Activity

A selection of the 1,2,4,5-tetraoxanes were tested against the 3D7 strain of the Plasmodium falciparum and the results are summarized in Table 5 below. Most of the analogues have comparable antimalarial IC _5O values to the naturally occurring peroxide artermisinin. The adamantane analogues of the tetraoxanes and their corresponding amide have a better activity than their cyclohexanone and cyclododecanone counterparts.

Table 5. In Vitro Antimalarial Activity of 1,2,4,5-tetraoxanes (10-34k) versus 3D7* strain of Plasmodium falciparum

^a The mean IC ₅₀ was calculated from triplicate results. Antimalarial activities were assessed by a previously published protocol. ³

A 4-day Peter's suppressive test was performed on a selection of the compounds and the results are summarized in Table 6. The adamantylidine analogues 29c, 29h and 291 showed 100% inhibition by oral administration at a dose of 30mg/kg; based on this exciting result, several adamantane analogues are currently undergoing full assessment in the 4-day Peter's test to determine ED ₅₀ and ED ₉₀ values.

Table 6. Peter's suppressive test results verses Plasmodium yoelli in mice

R ²¹

It is clear that the adamantyl based systems 29c, 29h and 291 have unprecedented in vivo levels of antimalarial activity for the tetroxane class of drug.

Compound 29c, 29h and 291 were then subjected to dose response experiment against the P. berghei ANKA and the results are summarized in Table 7 below.

Table 7: In vivo Screening Against the Chloroquine Resistant Strains of the P. Berghei ANKA.

Sulfonamide dispiro 1,2,4,5-tetraoxanes

Table 8: IC ₅₀ values for sulfonamide dispiro 1,2,4,5-tetraoxanes

*Note: ring carbon atoms bonded directly to ring nitrogen atom further linked via briding ethylene moiety.

hi Vitro IC ₅₀ test results show that the majority of these compounds have activity in the 3-30 nM region. There are clear trends in the SAR required for maximum activity. The presence of an adamantyl group 39a-i greatly increases activity. Smaller alkyl groups at R ¹ 39a-e as apposed to larger aromatic groups 39f-i also increase activity (Table 8). The presence of the tropinone group resulted in a loss in activity 41 d. Compounds 39b and 39d were selected for in vivo screening.

Table 9: In vivo screening of 39b and 39d against P. berghei ANKA infected mice

Note: 94% inhibition was found at 30mg/kg with 39b, so the ED90 of 39b is below 30mg/kg but because of the sigmoidal curve calculations is giving 35.48mg/kg

Due to the high in vitro and in vivo activity of compounds 29h and 39b these compounds were selected for further in vitro studies.

Table 10: In Vitro Analysis on 29h and 39b versus Seven Strains of Plasmodium falciparum (AM = Amodiaquine, CQ—Clύoroquine)

DD2 HB3

Kl PH3

GC03

TM4

VlS

Antimalarial Activity

The 3D7 strain of Plasmodium falciparum was used in this study. This strain is known to be CQ resistant Parasites were maintained in continuous culture using the method of Jensen and Trager ⁴ . Cultures were grown in flasks containing human erythrocytes (2-5%) with parasitemia in the range of 1% to 10% suspended in PvPMI 1640 medium supplemented with 25 mM HEPES and 32 mM NaHCθ3, and 10% human serum (complete medium). Cultures were gassed with a mixture of 3% 02, 4% CO2 and 93% N2- Antimalarial activity was assessed with an adaption of the 48- h sensitivity assay of Desjardins et al. ⁵ using [ H]-hypoxanthine incorporation as an assessment of parasite growth. Stock drug solutions were prepared in 100% dimethylsulphoxide (DMSO) and diluted to the appropriate concentration using complete medium. Assays were performed in sterile 96-well microtitre plates, each plate contained 200 μl of parasite culture (2% parasitemia, 0.5% haematocrit) with or without 10 μl drug dilutions. Each drug was tested in triplicate and parasite growth compared to control wells (which consituted 100 % parasite growth). After 24-h incubation at 37 ⁰ C, 0.5 μCi hypoxanthine was added to each well. Cultures were incubated for a further 24 h before they were harvested onto filter-mats, dried for 1 h at 55 C and counted using a Wallac 1450 Microbeta Trilux Liquid scintillation and luminescence counter. IC50 values were calculated by interpolation of the probit transformation of the log dose - response curve.

In vivo Antimalarial Screening

Selections of the compounds were screened for in vivo activity. In vivo data (Table 6) was determined using 30 mg/kg oral (po) and subcutaneous (sc) doses in a 4 -days Peter's test. For subcutaneous administration, compounds were dissolved in 10%dimethylsulfoxide (DMSO) 0.05% Tween 80 (Sigma, Dorset, UK) in distilled water. For oral admistration, compounds were dissolved in standard suspending formula (SSV) [0.5% sodium carboxymethylcellulose, 0.5% benzyl alcohol, 0.4% Tween 80, 0.9%NaCl (all Sigma)]. Subcutaneous (s.c) or oral (p.o) treatment was done with 0.2ml of a solution of the test compound two hours (day 0) and on days 1, 2, and 3 post infections. Parasitaemia was determined by microscopic examination of Giemsa stained blood films taken on day 4. Microscopic counts of blood films from each mouse were processed using MICROSOFT@EXCELL spreadsheet (Microsoft Corp.) and expressed as percentage of inhibition from the arithmetic mean parasitaemias of each group in relation to the untreated group.

Cytotoxicity Studies

Table 11: Cellular Cytotoxicity Screens and Theraputic Index (TI) for Selected Lead Tetraoxanes, 29h, 39b and 39d.

HepG2 Human Caucasian hepatocyte carcinoma H9c2(2-1) Myocardium, heart, rat

L6 Sketal muscle myoblast, rat

Vero Kidney, African green monkey, Cercopithecus aethiops

MRC-5 Embryonal lung, diploid, male, Human

Values represent Tox 50 in μM . Cytotoxicity measured by Resazurin reduction.

Single full dose response curves generated using 10 independent drug concentrations. The 100 therapeutic index (TI) is the ration of the TOX 50 to the IC50 for the specific compound against the 3D7 P. falciparum isolate. The primary hepatocytes have demonstrable drug metabolising activity. The tetraoxane derivatives are remarkably non-toxic in these screens with in vitro TIs of between 5000 to 17000!.

Genotoxicity Studies

The potential genotoxicity of selected lead compounds (RKA 216 (29h), GE75 (39b) and GEl 14 (39d)) has been determined by the Salmonella typhimurium SOS/umu assay in two strains (Table 12 and Table 13): TA1535/pSK1002 and NM2009. This assay is based on the ability of DNA damaging agents to induce the expression of the umu operon. The Salmonella strains have a plasmid pSK1002 which carries an umuCλ&cZ fused gene that produces a hybrid protein with /3-galactosidase activity and whose expression is controlled by the umu regulatory region. Since many compounds do not exert their mutagenicity effect until they have been metabolized, the assay was also performed in the presence of rat liver S9-mix. Positive control agents (4-Nitroquinoline-l -oxide (4NNQO) and 2-Aminoanthracene (2Aan)) were used to test the response of the tester strains. Negative results were obtained for GE75 (39b), GEl 14 (39d) and RKA216 (29h) at the highest concentration tested (50μM), both in the absence and in the presence of an in vitro metabolic activation system (S-9 mix).

Table 12. Mutagenic potential on Salmonella typhimurium TA 1535/pSK1002 strain in the absence and presence of S9-mix. (D535 = 4'Chloro N-tertbutyl amodiaquine as an'additional comparitor)

Max Range of

Cmpd in t Co tested -S9 + Rat S9

Max. Fold Potential Max. Fold Potential

Increase genotox Increase genotox

D535 140 140 140-0.27 1.10±0.07 NEG 0.93±0.02 NEG

GE75 50 50 50-0.10 1.03+0.07 NEG 0.98±0.06 NEG

GE114 50 50 50-0.10 1.05±0.09 NEG 0.99±0.09 NEG

RKA216 50 50 50-0.10 1.04+0.04 NEG 0.98±0.02 NEG

(μg/ml_) (//g/mL) (μg/mL)

4NNQO 2 0.25 2-0.004 7.22±0.54 Positive ² 8.68±1.32 Positive

2Aan 5 5 5-0.01 1.10±0.11 NEG 7.34±0.32 Positive

1. MCE: Maximum Co w/o effects on bacteria growth or /J-galactosidase production.

2. Positive response: > 2-fold dose-related increase in β -galactosidase activity over the mean control values.

Table 13. Mutagenic potential on Salmonella typhimurium NM2009 strain in the absence and presence of S9-mix.

Max Range of

Cmpd in t Co tested -S9 + Rat S9

Max. Fold Potential Max. Fold Potential

Increase genotox Increase genotox

D535 140 140 140-0.27 1.04±0.10 NEG 1.05±0.02 NEG

GE75 50 50 50-0.10 1.07±0.03 NEG 0.95±0.03 NEG

GE114 50 50 50-0.10 1.09±0.03 NEG 1.07±0.10 NEG

RKA216 50 50 50-0.10 1.22±0.03 NEG 1.02±0.06 NEG

(μg/mL) (//g/mL) (//g/mL)

4NNQO 2 1 2-0.004 4.80+0.45 Positive ² 8.40+0.50 Positive

2Aan 5 0.31* 5-0.01 1.08±0.01 NEG 6.09±0.29 Positive

1. MCE: Maximum Co w/o effects on bacteria growth or beta-galactosidase production. * In the presence of rat S9, the maximum concentration without effects on bacteria growth or β-galatosidase production (MCE) is 0.31 μg/mL for 2Aan.

2. Positive response: > 2-fold dose-related increase in β-galactosidase activity over the mean control values.

Stability Studies

Chemical Stability

The chemical stability of 29b. and 39b was investigated to confirm stability in aqueous solution and in the presence of acid. As can be seen from the table greater than 95% recovery of the starting tetraoxane was observed in all cases (Table 14). These reactions are based on recovery of material following chromatography on a 50 mg scale reaction. Apart from entry 2, where a minor product appeared on TLC, no other products of decomposition could be detected. In a control to assess column recovery 50 mg yielded 48 mg indicating, that as a percentage control, the endoperoxides examined are completely stable under the conditions tested.

Table 14: Chemical stability studies on 39b and 29h.

Tetraoxane Drug Conditions % Recovery of Tetraoxane

^~ 39b DCM, 7 days, RT 96.2 (99)

39b DCM, 1% formic acid, 7days, RT 92.3 (95)

39b Water, 7 days, 37 ⁰ C 97.8 (100)

39b Phosphate buffer, pH 7.4, 16 hrs, 37°C 93.2 (95)

29h Phosphate buffer, pH 7.4, 16 hrs, 37°C 95.6 (99)

29h Water, 7 days, 37 ⁰ C 98.2 (100)

29h DCM, 7 days, RT 97.2 (99) ^a Figures in brackets refer to recovery as a % of control. (DCM = dichloromethane)

Stability in Presence of Fe(II) ions

Tetraoxane 39f, ozonide 42 (also referred to below as OZ) and trioxane 43 (for structures see below, compounds selected due to UV chromophore to aid TLC analysis) were subjected to 1.0 equivalents Of FeBr ₂ in THF for the set time periods layed out in the table (This combination leads to complete degradation of artemisinin

after 24h). The resulting residue was purified by flash column chromatography and the % recovery of starting endoperoxide calculated (Table 15).

39f

Table 15: Timed iron degradation stability studies.

DRUG % Recovery Of Endoperoxide

4 hrs 8 hrs 24 hrs 48 hrs

TETRAOXANE 39f 88.7 80.5 72.0 69.0 OZONIDE 42 11.0 9.0 2.6 0.0 TRIOXANE 43 96.8 84.9 56.7 43.2

Table 16

IRON % Recovery of Tetraoxane 39f SOURCE

2 hrs 4 hrs 8 hrs 24 hrs

FeSO ₄ JH ₂ O 99 99 98 98

FeCl ₂ .4H ₂ O - - - 97

Tables 15 and 16 demonstrate the remarkable stability of the 1,2,4,5 tetraoxane ring system. The ferrous bromide/THF system has been widely used in the literature for

iron degradation reactions and in studies with artemisinin complete degradation can be achieved in less than 24h. With the OZ heterocycle we observe almost 90% degradation after 4h; the corresponding tetraoxane 39f is only degraded by 10%. Complete loss of OZ material 42 (100 % turnover) is observed after 48 h whereas 69% (31% turnover) can be recovered for 39f. The tetraoxane is also more stable than the corresponding 1,2,4-trioxane 43 which was degraded by 57% after 48h.

Further studies with iron salts known to readily degrade artemisinin and synthetic endoperoxides such as arteflene proved to be ineffective at degrading 39f.

The results confirm that the 1, 2, 4, 5- tetraoxane heterocyle is remarkably stable to decomposition with ferrous iron salts. This contrasts with the synthetic OZ derivatives where instability has contributed to major difficulties in their development.

Experimental Preparation of Inventive Compounds

General procedure for the preparation of bishydroperoxides

Preparation of Cyclohexane- 1,1 -diyl bis-hydro peroxide 6a

A stirred solution of cyclohexanone 6 (5.889g, 60mmol) in formic acid (40ml) was added 30% aqueous hydrogen peroxide (20ml) and the mixture was stirred at room temperature for 4 minutes. The mixture was then poured into ice-cold water and the organic products were extracted by diethyl ether (300ml). After conventional workup, the residue was separated by column chromatography on silica gel to give the bishydroperoxide in 76%.

Preparation of Cyclododecane- 1,1 -diyl bis hydro peroxide 7a

This product was prepared in 72% according to the general procedure for preparing bishydroperoxides.

Preparation of Adamantane-2,2-diyl bishydroperoxide 8a

This product was prepared in 76% according to the general procedure for preparing bishydroperoxides .

General procedure for the preparation of the tetraoxane ketones

Preparation of 7,8, 15 , 16-Tetraoxa-dispiro[5.2.5.2]hexadecan-3 -one 10

A solution of (0.12g, 2mmol) of cyclohexanone 6, (0.05g, 4mmol) of 30% H ₂ O ₂ and (0.0005g, 0.002mmol) of methyltrioxorhenium (MTO) in 4ml of 2,2,2- trifluoroethanol (TFE) was stirred for 2 hours at room temperature. Into the solution, (0.4485g, 4mmol) of 1,4-cyclohexanedione 9 was added, followed by the addition of (0.095g, 2mmol) of 54% ethereal solution of tetrafluoroboric acid. The reaction mixture was left under stirring for an additional hour. Dichloromethane was added and the organic phases washed wish diluted NaHSO ₄ , dried over MgSO ₄ and solvent evaporated under reduced pressure. Products were determined by NMR spectroscopy, isolated by column chromatography (SiO ₂ , CH ₂ Cl ₂ : Hexane = 9:1) to give the tetraoxane in 38%.

Preparation of 7,8,21,22-Tetraoxa-dispiro[5.2.11.2]docosan-3-one 11

This product was prepared in 38% according to the general procedure for preparing tetraoxane ketones

Preparation of adamantane tetraoxane ketone 12

This product was prepared in 40% according to the general procedure for preparing tetraoxane ketones.

General procedure for reductive animation of tetraoxane ketones

Preparation of 4-(7, 8, 15, 16-Tetraoxa-dispiro[5.2.5.2]hexadec-3-yl)-morpholine 19

The 7,8,15, 16-Tetraoxa-dispiro[5.2.5.2]hexadecan-3-one 10 (O.lg, 0.4mmol) and morpholine (0.26g, 0.26ml, 3.03mmol) were mixed in dichloromethane(15ml) before addition of sodiumtriacetoxyborohydride(0.64g, 3.03mmol). The reaction was stirred at room temperature for 18hrs and then washed with distilled water. The organic layer was dried and evaporated under vacuum to dryness. Purification by chromatography afforded the product in 56%.

Preparation of Cyclopropyl-(7,8, 15, 16-tetraoxa-dispiro[5.2.5.2]hexadec-3-yl)-amine 14

This product was prepared in 55% according to the general procedure for reductive amination of tetraoxane ketones.

General procedure for the Wittig reaction

Preparation of (l,4-Dioxa-spiro[4.5]dec-8-ylidene)-acetic acid ethyl ester 22

A solution of 1,4-cycloliexanedionemonoetliylketal 20 (6g, 40mmol) and ethyl- (triphenylphosphoranylidene)acetate 22 (15g, 44mmol) in dry benzene (80ml) were refluxed under argon for 24hours. The solvent was removed under vacuum and product purified by flash chromatography to give the product in 90%.

Preparation of (l,4-Dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester 21

This product was prepared in 93% according to the general procedure for Wittig reactions.

General procedure for hydrogenation reaction

Preparation of (l,4-Dioxa-spiro[4.5]dec-8-yl)-acetic acid ethyl ester 24

A suspension of the compound (3.14g, 13.7mmol) in ethyl acetate (80ml) and Pd-C (10%w/w, 1.97g) was stirred in a hydrogen atmosphere for 3hours. The solvent was removed under vacuum and product purified by flash chromatography to give the product in 90%.

Preparation of (l,4-Dioxa-spiro[4.5]dec-8-yl)-acetic acid methyl ester 23

This product was prepared in 95% according to the general procedure for hydrogenation reaction.

General procedure for the preparation of bishydroperoxide via tungstic acid catalyzed approach

Preparation of (4,4-Bis-hydroperoxy-cyclohexyl)-acetic acid ethyl ester 26

To a solution of the ketal 24 (Ig, 4.4mmol) in dry THF (20ml) was treated with H ₂ O ₂ (30% aq, 20ml) and tungstic acid (2.2g, 8.8mmol) and stirred for 48hrs at O ⁰ C. The reaction mixture was extracted with dichloromethane, washed with brine and dried with MgSO ₄ . Purification by column chromatography gave the product in 73%.

Preparation of (4,4-Bis-hydroperoxy-cyclohexyl)-acetic acid methyl ester 25

This product was prepared in 76% according to the general procedure for preparing bishydroperoxides via tungstic acid catalyzed approach.

General procedure for the preparation of the 1,2,4,5-tetraoxane esters

Preparation of (VjδjlSjlβ-Tetraoxa-dispirofS^.S.lJhexadec-S-ytyacetic acid ethyl ester 27a

A stirred solution of cyclohexanone 6 (1.7g, 7.26mmol) in ethyl acetate was added 54% ethereal solution of HBF ₄ (1.25g, 14.2mmol) to ethyl 2-(4,4- dihydroperoxycyclohexyl)acetate 26 and stirred for 3hrs at room temperature. Purification by column chromatography gave the product in 50%.

Preparation of (7,8,21,22-Tetraoxa-dispiro[5.2.11.2]docos-3-yl)-acetic acid ethyl ester 28a

This product was prepared in 33% according to the general procedure for preparing 1,2,4,5-tetraoxane esters.

Preparation of adamantyl tetraoxane ethylester 29a

This product was prepared in 50% according to the general procedure for preparing 1,2,4,5-tetraoxane esters.

Preparation of adamantyl tetraoxane methyl ester 30a

This product was prepared in 66% according to the general procedure for preparing 1,2,4,5-tetraoxane esters.

General procedure for the preparation of the carboxylic acids

Preparation of 7,8,15,16-Tetraoxa-dispiro[5.2.5.2]hexadec-3-yi)acetic acid 27b

The ethyl ester 27a (1.82g, 5.8mmol) was hydrolyzed in 60ml methanol at 7O ⁰ C with KOH (1.8g, 31.65mmol) and 6ml water. After one hour heating, the reaction mixture was cooled and diluted with 90ml dichloromethane and 30ml water. The aqueous layer was acidified with concentrated HCl (6ml). The aqueous layer was further extracted with DCM. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and evaporated to dryness. Purification by column chromatography gave the pure acid 27b in 75%.

Preparation of (7,8,21, 22-Tetraoxa-dispiro[5.2.11.2]docos-3-yl)-acetic acid 28b

This product was prepared in 66% according to the general procedure for preparing or carbocylic acids.

Preparation of adamantyl tetraoxane carboxylic acid 29b

This product was prepared in 66% according to the general procedure for preparing carboxylic acids.

General procedure for the preparation for the amide coupling reactions

Preparation of 1 -Morpholin-4-yl-2-(7,8, 15, 16-tetraoxa-dispiro[5.2.5.2]hexadec-3-yl)- Ethanone 27h

A solution of 7,8,15, 16-Tetraoxa-ώspiro[5.2.5.2]hexadec-3-yl)acetic acid 27b (O.lg, 0.35mmol) in dry dichloromethane (18ml), with added triethylamine (0.04g, 0.005ml, 0.35mmol) and ethylchloroformate (0,005g, 0.04ml, 0.46mmol) was stirred for 60minutes at O ⁰ C. (0.06g, 0.06ml, 0.70mmol) of morpholine was added, and after 30minutes of stirring the reaction mixture was warmed to room temperature. After 90minutes, it was diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried over anhydrous Na ₂ SO ₄ . The crude product was purified by flash chromatography to give the pure amide in 84%.

Preparation of iV-Cyclopropyl-2-(7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadec -3-yl)- acetamide 27c

This product was prepared in 84% according to the general procedure for the amide coupling reactions.

Preparation of N-(2-Pyrrolidin-l-yl-ethyl)-2-(7,8,15,16-tetraoxa-dispiro[5. 2.5.2]- hexadec-3-yl)-acetamide 27d

This product was prepared in 78% according to the general procedure for the amide coupling reactions.

Preparation of 7V-(2-Piρeridin-l-yl-ethyl)-2-(7,8,15,16-tetraoxa-dispiro[5 .2.5.2]- hexadec-3-yl)-acetamide 27e

This product was prepared in 81% according to the general procedure for the amide coupling reactions.

Preparation of N-(2-Morpholin-4-yl-ethyl)-2-(7,8,15,16-tetraoxa-dispiro[5.2 .5.2]- hexadec-3-yl)-acetamide 27f

This product was prepared in 76% according to the general procedure for the amide coupling reactions.

Preparation of N-(2-Diethylamino-ethyl)-2-(7,8,15,16-tetraoxa-dispiro[5.2.5 .2]- hexadec-3-yl)-acetamide 27g

This product was prepared in 58% according to the general procedure for the amide coupling reactions.

Preparation of (2-7,8,15,16-Tetraoxa-dispiro [5.2.5.2]hexadec-3-yl-acetylamino)- acetic acid methyl ester 27i

This product was prepared in 45% according to the general procedure for the amide coupling reactions.

Preparation of N-Cyclopropyl-2-(7,8,21,22-tetraoxa-dispiro[5.2.11.2]docos-3 -yl)- acet-amide 28c

This product was prepared in 88% according to the general procedure for the amide coupling reactions.

Preparation of 7V-(2-Pyrrolidin- 1 -yl-ethyl)-2-(7,8,21 ,22-tetraoxa-disρiro[5.2.11.2]do- cos-3-yl)-acetamide 29d

This product was prepared in 81% according to the general procedure for the amide coupling reactions.

Preparation of N-(2-Piperidin-l-yl-ethyl)-2-(7,8,21,22-tetraoxadisρiro[5.2 .11.2]- docos-3-yl)-acetamide 28e

This product was prepared in 82% according to the general procedure for the amide coupling reactions.

Preparation of N-(2-Morpholin-4-yl-ethyl)-2-(7,8,21 ,22-tetraoxa-dispiro[5.2.11.2]do- cos-3-yl)-acetamide 28f

This product was prepared in 78% according to the general procedure for the amide coupling reactions.

Preparation of N-(2-Dietriylamino-ethyl)-2-(7,8,21,22-tetraoxa-dispiro[5.2. 11.2]- docos-3-yl)-acetamide 28g

This product was prepared in 74% according to the general procedure for the amide coupling reactions.

Preparation of 1 -Morpholin-4-yl-2-(7,8,21 ,22-tetraoxa-dispiro[5.2.11.2]docos-3-yl)- ethanone 28h

This product was prepared in 90% according to the general procedure for the amide coupling reactions.

Preparation of 2-(7,8,21,22-Tetraoxa-dispiro[5.2.11.2]docos-3-yl)-l-thiomor pholin- 4-yl-ethanone 28i

This product was prepared in 78% according to the general procedure for the amide coupling reactions.

Preparation of adamantyl- N-Cyclopropyl tetraoxane acetamide 29c

This product was prepared in 83% according to the general procedure for the amide coupling reactions.

Preparation of iV-(2-Pyrrolidin-l-yl-ethyl)-[adamantyl] acetamide 29d

This product was prepared in 80% according to the general procedure for the amide coupling reactions.

Preparation of N-(2-Piperidin-l-yl-ethyl)-[adamantyl Jacetamide 29e

This product was prepared in 78% according to the general procedure for the amide coupling reactions.

Preparation of N-(2-Morpholin-4-yl-ethyi)-adaniantyl acetamide 29f

This product was prepared in 77% according to the general procedure for the amide coupling reactions.

Preparation of N-(2-Diethylamino-ethyl)-[adamantly]acetamide 29g

This product was prepared in 66% according to the general procedure for the amide coupling reactions.

Preparation of adamantly- l-Morpholin-4-yl tetraoxane acetamide 29h

This product was prepared in 81% according to the general procedure for the amide coupling reactions.

Preparation of Tetraoxa-dispiro-(adamantly)-thiomorpholin-4-yl-ethanone 29i

This product was prepared in 77% according to the general procedure for the amide coupling reactions.

Preparation of adamantyl acetamide 29j

This product was prepared in 69% according to the general procedure for the amide coupling reactions.

Preparation of tetraoxane 29k

This product was isolated in 83% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using Hexane/ethyl acetate (1:1, v/v, Rf= 0.6) as eluent.

Preparation of tetraoxane 291

This product was isolated in 87% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/methanol (9:1, v/v, Rf= 0.6) as eluent.

Preparation of tetraoxane 29m

This product was isolated in 89% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.7) as eluent.

Preparation of tetraoxane 29n

This product was isolated in 43% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf = 0.2) as eluent.

Preparation of tetraoxane 29o

This product was isolated in 83% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.7) as eluent.

Preparation of tetraoxane 29p

This product was isolated in 76% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.3) as eluent.

Preparation of tetraoxane 29q

This product was isolated in 80% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.5) as eluent.

Preparation of tetraoxane 29r

This product was isolated in 72% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.2) as eluent.

Preparation of tetraoxane 29s

This product was isolated in 87% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.4) as eluent.

Preparation of tetraoxane 29t

This product was isolated in 68% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.3) as eluent.

Preparation of tetraoxane 29u

This product was isolated in 73% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.7) as eluent.

Preparation of tetraoxane 29v

This product was isolated in 77% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.6) as eluent.

Preparation of tetraoxane 29w

This product was isolated in 64% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.7) as eluent.

Preparation of tetraoxane 29x

This product was isolated in 70% according to the general procedure for amide coupling reactions. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.6) as eluent.

General procedure for the preparation of tetraoxane sulfones

Preparation of 1 -(1 , 1 -Dioxo- 1 λ ⁶ -thiomorpholin-4-yl)-2-(7 ₅ 8,21 ,22-tetraoxa- dispiro[5.2.11.2]docos-3-yl)-ethanone 31

A solution of 28i (O.lg, 0.22mmol) and mCPBA (0.1 Ig, 0.66mmol) in 10ml CH ₂ Cl ₂ was stirred at room temperature for 4-6hours. After consumption of the more polar intermediate sulfoxide (monitored by tic) the mixture was poured into a saturated solution of cold 5% K ₂ CO ₃ solution. The mixture was then extracted with CH ₂ Cl ₂ , the organic layer separated, dried over MgSO ₄ and evaporated. Purification was achieved by column chromatography to give the desired sulfone in 92%.

Preparation of 1 -( 1 , 1 -Dioxo- 1 λ -tMomorpholin-4-yl)-2-tetraoxa-dispiro-adarnantyl ethanone 32

This product was prepared in 88% according to the general procedure for preparation of tetraoxane sulfones.

Preparation of diethyl methylsulfonylmethylphosphonate 33b

A solution of diethylmethy thiomethyl phosphorane (Ig, 3.8 mmol) and mCPBA (1.4g, 7.98 mmol) in DCM (30 mL) was stirred at room temperature for 4-6 hours. The mixture was poored into a saturated solution of cold K ₂ CO ₃ and then extracted with DCM. The organic layer was separated, dried over MgSO ₄ and concentrated to give the product.

Preparation of 8-(methylsulfonylmethylene)-l,4-dioxaspiro[4.5]decane 33c

To a stirred solution of diethylmethyl sulfonomethylphosphonate (2.4g, 10 mmol) in THF (50 mL) under nitrogen and at -78 _O C was added (6.4g, 9.2mL, lOmmol) of 1.32M ⁿ BuLi in pentane. The resulting solution was stirred at -78 ⁰ C for 15minutes to 3 hours at which time 1,4-cyclohexane dione monoethylene ketal (1.5g, lOmmol) was added in THF (1OmL). The clear solution was stirred at -78 ⁰ C for 1 hour, then allowed to warm to room temperature and stirring was continued at that temperature overnight. The resulting solution was poured into 5OmL saturated solution OfNH ₄ Cl and extracted with ether, washed with water, NaHCO ₃ and brine. The combined extracts were dried over MgSO ₄ and concentrated to give the product in 67%.

Preparation of 8-(methylsulfonylmethyl)-l,4-dioxaspiro[4.5]decane 33d

A suspension of 8-(methylsulfonylmethylene)~l,4-dioxaspiro[4.5]decane (1.6g,

6.7mmol) and 10% Pd/C (Ig) in ethyl acetate (4OmL) was stirred under hydrogen atmosphere for 1 hour. The reaction mixture was filtered off through celite and the filtrated concentrated to give the product in 88%.

Preparation of tetraoxane 33f

To a solution of 8-(methylsulfonylmethyl)-l,4-dioxaspiro[4.5]decane (1.6g, 6.6mmol) in THF (20 niL), 30% H ₂ O ₂ (20 niL) and tungstic acid (3.4g, 13.7mmol) were successively added at O ⁰ C. After 48 hours of stirring with exclusion of light, at O ⁰ C, the mixture was extracted with DCM and the combined organic layers were washed with a saturated solution of NaCl, dried and evaporated in vacuo. The resulting ge/M-dihydroperoxide was dissolved in ethyl acetate (3OmL) and cyclohexanone (0.7g, 6.6mmol) followed by 54% ethereal solution of tetrafluoroboric acid (1.15g, 13.08mmol) were added and the reaction mixture stirred for an hour. The mixture was washed with NaHCO ₃ , dried in MgSO ₄ and the solvent evaporated under reduced pressure. Purification of the crude product by flash column chromatography using Hexane/ethylacetate (1:1, v/v, Rf = 0.6) as eluent gave the required product as white powder in 15%.

Preparation of tetraoxane 33g

This product was isolated in 8% according to the general procedure above. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.7) as eluent.

General procedure for making Piperidinones

Preparation of l-benzoylpiperidin-4-one 34b

To a solution of benzoyl chloride (5g, 4.ImL, 35.6 mmol) and triethylamine (7.2g, 9.9mL, 71.2 mmol) in 50 mL toluene was added 4-piperidinone monohydrate hydrochloride (5g, 29.1 mmol) and heated to reflux for 2-3 hours. The solid was filtered off and the liquid concentrated. Purification by column chromatography using DCM/ethyl acetate (1:1, v/v, Rf = 0.4) gave the pure product as a liquid in 66%.

Preparation of l-(pyrrolidin-l-carbonyl)piperidin-4-one 34c

This product was isolated in 63% according to the general procedure for making the piperidinones. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.4) as eluent.

Preparation of N,N-diethyl-4-oxopiperidine-l-carboxamide 34d

This product was isolated in 56% according to the general procedure for making the piperidinones. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.3) as eluent.

Preparation of l-(piperidine-l-carbonyl)piperidin-4-one 34e

This product was isolated in 73% according to the general procedure for making the piperidinones. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.3) as eluent.

Preparation of l-(morpholine-l-carbonyl)piperidin-4-one 34f

This product was isolated in 64% according to the general procedure for making the piperidinones. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.3) as eluent.

Preparation of 4-oxo-λf,N-diphenylpiperidine-l-carboxamide 34g

This product was isolated in 89% according to the general procedure for making the piperidinones. This product was purified by flash column chromatography using

DCM/ethyl acetate (1:1, v/v, Rf= 0.7) as eluent.

Preparation of l-(4-trifluoromethyl)benzoyl)piperidm-4-one 34h

This product was isolated in 74% according to the general procedure for making the piperidinones. This product was purified by flash column chromatography using Hexane/ethyl acetate (1:1, v/v, Rf= 0.3) as eluent.

Preparation of (4,4-dihydroperoxypiperidin-l-yl)(piperidin-l-yl)methanone 34i

This product was isolated in quantitative yield according to the general procedure for making ge7M-dihydroperoxides. This product was purified by flash column chromatography using Hexane/ethyl acetate (1:1, v/v, Rf= 0.2) as eluent.

Preparation of tetraoxane 34j

A solution of 1,1-diethoxyadamantanone (0.17g, 0.77mmol) in diethylether (5mL) was added to a stirred suspension of(4,4-dihydroperoxypiperidin-l-yl)(piperidin-l- yl)methanone (0.2g, 0.77mmol) and BF3.OEt3 (1.4 equiv.) in diethylether (5mL). The mixture was stirred until the conversion of the gem-dihydroperoxide and then K2CO3 was added. The resulting two-phase system was stirred for 30-60 minutes and the organic phase separated. The aq. Phase was extracted with diethylether and dried with MgSO4, concentrated and chromatographed with DCM/ethylacetate (1:1, v/v, Rf= 0.6) as eluent to give the product in 33%.

Preparation of tetraoxane 34k

This product was isolated in 37% according to the general procedure above. This product was purified by flash column chromatography using Hexane/ethyl acetate (1:1, v/v, Rf= 0.6) as eluent.

Preparation of tetraoxane 34o

This product was isolated in 18% according to the general procedure above. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.5) as eluent.

Preparation of tetraoxane 341

This product was isolated in 19% according to the general procedure above. This product was purified by flash column chromatography using Hexane/ethyl acetate (1:1, v/v, Rf= 0.2) as eluent.

Preparation of tetraoxane 34m

This product was isolated in 32% according to the general procedure above. This product was purified by flash column chromatography using DCM/ethyl acetate (1:1, v/v, Rf= 0.7) as eluent.

Preparation of tetraoxane 34n

To a stirred solution of 1,2-dihydroperoxycyclohexane (0.97g, 6.65mmol) in ethyl acetate (3OmL) was added l-(4-trifluoromethyl)benzoyl)piperidin-4-one (1.8g, 6.54mmoi). A 54% ethereal solution of tetrafluoroboric acid (1.15g, 13.08mmol) was added and the reaction mixture stirred for an hour. The mixture was washed with NaHCO ₃ , dried in MgSO ₄ and the solvent evaporated under reduced pressure. Purification of the crude product by flash column chromatography using Hexane/ethylacetate (1:1, v/v, Rf = 0.6) as eluent gave the required product as white powder in 24%.

Preparation of morpholine urea 1,2,4,5-tetraoxane 34p

A solution of ketone (250 mg, 1.18 mmol), 30% H ₂ O ₂ (0.27 ml, 2.36 mmol, 2.0 eq) and MTO (trace) in HFIP (2.36 ml) was stirred at room temperature for 2 hours. After this time 2-adamantanone (355 mg, 2.36 mol, 2.0 eq) was added followed by dropwise addition of a 54% ethereal solution Of HBF ₄ (0.33 ml, 2.36 mmol, 2.0 eq). The reaction was then stirred at room temperature for 1 hour. Dichloromethane (10 ml) was added and the organic layer washed with a sat. soln. OfNaHCO ₃ , dried over MgSO ₄ and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ , hexane:EtOAc = 9:1) to give the title compound (30.8 mg, 6.6%).

Preparation of tetraoxanes incorporating fused ring moieties

Preparation of indanone tetraoxane 35d

To a solution of 2-indanone (2g, 6.6 mmol) in 10 rnL acetonitrile was added 5 rnL formic acid and 5mL 30% H ₂ O ₂ at O ⁰ C. The mixture was stirred for 15 minutes and DCM added. The organic phase was washed with saturated NaHCO ₃ , dried and concentrated. The resulting gezjj-dihydroperoxide was dissolved in ethyl acetate (3OmL) and 2-adamantanone (3g, 18mmol) followed by 54% ethereal solution of tetrafluoroboric acid (2.7g, 2.3mL, 30.3mmoi) were added and the reaction mixture stirred for an hour. The mixture was washed with NaHCO ₃ , dried in MgSO ₄ and the solvent evaporated under reduced pressure. Purification of the crude product by flash column chromatography using Hexane/ethylacetate (9:1, v/v, Rf = 0.5) as eluent gave the required product as white powder in 20%.

Preparation of tetralone tetraoxane 36c

λλλVO

This product was isolated in 28% according to the general procedure above. This product was purified by flash column chromatography using Hexane/ethyl acetate (9:1, v/v, Rf= 0.6) as eluent.

Preparation of tetralone tetraoxane 36d

This product was isolated in 26% according to the general procedure above. This product was purified by flash column chromatography using Hexane/ethyl acetate (9:1, v/v, Rf= 0.5) as eluent.

General procedure for preparation of sulfonyl piperidones

R'-sulfonyl chloride (17.48 mmol, 1.5 eq) was added to a slurry of 4-piperidone monohydrate hydrochloride salt (2.0Og, 11.65 mmol), K ₂ CO ₃ (4.03g, 29.13 mmol, 2.5 eq), water (16 ml) and chloroform (16 ml). The bi-phasic reaction was stirred at room temperature overnight. The reaction was then quenched with saturated NaHCO ₃ aq. The aqueous layer was separated and extracted with DCM (3 x 30ml). The combined organic extracts were dried over NaSO ₄ and concentrated. The resulting residue was purified by flash column chromatography (SiO ₂ , EtOAc :hexane = 3:2) to give the desired sulfonyl piperidones.

Preparation of l-methanesulfonyl-piperidin-4-one 38a

This product was prepared in 62% according to the general procedure for preparing sulfonyl piperidones.

Preparation of l-ethanesulfonyl-ρiperidin-4-one 38b

This product was prepared in 59% according to the general procedure for preparing sulfonyl piperidones.

Preparation of l-(propane-2-sulfonyl)-piperidin-4-one 38c

This product was prepared in 52% according to the general procedure for preparing sulfonyl piperidones.

Preparation of l-cyclopropylsulfonyl-piperidin-4-one 38d

This product was prepared in 59% according to the general procedure for preparing sulfonyl piperidones.

Preparation of l-(2,2,2-trifluoroethanesulfonyl)-piperidin-4-one 38e

This product was prepared in 62% according to the general procedure for preparing sulfonyl piperidones.

Preparation of l-benzenesulfonyl-piperidin-4-one 38f

This product was prepared in 98% according to the general procedure for preparing sulfonyl piperidones.

Preparation of l-(4-chloro-benzenesulfonyl)-piperidin-4-one 38g

This product was prepared in 99% according to the general procedure for preparing sulfonyl piperidones.

Preparation of l-(4-fluoro-benzenesulfonyl)-piperidin-4-one 38h

This product was prepared in 98% according to the general procedure for preparing sulfonyl piperidones.

Preparation of l-(4-trifluoromethyl-benzenesulfonyl)-piperidin-4-one 38i

This product was prepared in 95% according to the general procedure for preparing sulfonyl piperidones.

General procedure for preparation of adamantyl-l,2,4,5-tetraoxanes

A solution of 1-R ¹ sulfonyl-piρeridin-4-one (1.13 mmol), 30% H ₂ O ₂ (0.26 ml, 2.26 mmol, 2.0 eq) and MTO (trace) in HFIP (2.27 ml) was stirred at room temperature for 2 hours. After this time 2-adamantanone (339 mg, 2.26 mol, 2.0 eq) was added followed by dropwise addition of a 54% ethereal solution of HBF ₄ (368 mg, 2.26 mmol, 2.0 eq). The reaction was then stirred at room temperature for 1 hour. Dichloromethane (10 ml) was added and the organic layer washed with a sat. soln. of NaHCO ₃ , dried over MgSO ₄ and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ , hexane:EtOAc = 9:1) to give the desired dispiro-l,2,4,5-tetraoxane.

Preparation of 1,2,4,5-tetraoxane 39a

This product was prepared in 61% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of 1,2,4,5-tetraoxane 39b

This product was prepared in 60% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of 1,2,4,5-tetraoxane 39c

This product was prepared in 56% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of 1,2,4,5-tetraoxane 39d

This product was prepared in 53% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of 1,2,4,5-tetraoxane 39e

This product was prepared in 51% according to the general procedure for preparing 1 ,2 ,4, 5 -tetraoxanes .

Preparation of 1,2,4,5-tetraoxane 39f

This product was prepared in 35% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of 1,2,4,5-tetraoxane 39g

This product was prepared in 41% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of 1,2,4,5 -tetraoxane 39h

This product was prepared in 38% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of 1,2,4,5-tetraoxane 39i

This product was prepared in 25% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

General procedure for preparation of cyclododecyl-l,2,4,5-tetraoxanes

A solution of 1-R ¹ sulfonyl-piρeridin-4-one () (1.13 mmol), 30% H ₂ O ₂ (0.26 ml, 2.26 mmol, 2.0 eq) and MTO (trace) in HFIP (2.27 ml) was stirred at room temperature for 2 hours. After this time cyclododecanone (412 mg, 2.26 mol, 2.0 eq) was added followed by dropwise addition of a 54% ethereal solution of HBF ₄ (368 mg, 2.26 mmol, 2.0 eq). The reaction was then stirred at room temperature for 1 hour. Dichloromethane (10 ml) was added and the organic layer washed with a sat. soln. of NaHCO ₃ , dried over MgSO ₄ and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ , hexane:EtOAc = 9:1) to give the desired dispiro-l,2,4,5-tetraoxane.

Preparation of 1,2,4,5-tetraoxane 40a

This product was prepared in 36% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of 1,2,4,5-tetraoxane 40b

This product was prepared in 32% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of 1,2,4,5-tetraoxane 40c

This product was prepared in 38% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of 1,2,4,5-tetraoxane 4Od

This product was prepared in 20% according to the general procedure for preparing 1 ,2,4,5-tetraoxanes.

Preparation of tetraoxanes incorporating briding moieties

Preparation of 8-Aza-bicyclo[3.2.1]octan-3-one 41b

A solution of tropinone (4.38 g, 31.51 mmol) in 1,2-dicloroethane (44 ml) was cooled to 4°C, 1-chloroethyl chloroformate (3.77 ml, 34.66 mmol, 1.1 eq) was added and the solution heated at reflux for 12 hours. After cooling the solvent was evaporated and the residue dissolved in methanol (44 ml). The solution was then refluxed for an additional 5 hours. After cooling the solution was evaporated to half its volume and acetone (25 ml) was added. The flask was then placed in the fridge overnight. The product precipitated out of solution and was filtered and dried under vacuum to give the title compound as a pale yellow solid (3.27 g, 83%).

Preparation of S-Ethanesulfonyl-δ-aza-bicyclofS^.lJoctan-S-one 41c

Triethylamine (0.67 ml, 4.80 mmol, 1.5 eq) was added to a solution of ketone (400 mg, 3.20 mmol) in dichloromethane (6.5 ml). The solution was cooled to O ⁰ C and ethane sulfonyl chloride (0.32 ml, 3.84 mmol, 1.2 eq) added. The reaction was then stirred at room temperature overnight and was subsequently quenched with saturated NaHCO ₃ aq. The aqueous layer was separated and extracted with DCM (3 x 10ml).

The combined organic extracts were dried over NaSO ₄ and concentrated. The resulting residue was purified by flash column chromatography (SiO ₂ , EtOAc:hexane = 3:2) to give the title compound (437 mg, 63%).

Preparation of tropinone derived 1,2,4,5-tetraoxane 41d

A solution of ketone (200 mg, 0.92 mmol), 30% H ₂ O ₂ (0.21 ml, 1.84 mmol, 2.0 eq) and MTO (trace) in HFIP (1.89 ml) was stirred at room temperature for 2 hours. After this time 2-adamantanone (335 mg, 1.84 mol, 2.0 eq) was added followed by dropwise addition of a 54% ethereal solution of HBF ₄ (0.25 ml, 1.84 mmol, 2.0 eq). The reaction was then stirred at room temperature for 1 hour. Dichloromethane (10 ml) was added and the organic layer washed with a sat. soln. OfNaHCO ₃ , dried over MgSO ₄ and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ , hexane:EtOAc = 9:1) to give the title compound (128 mg, 35%).

APPENDIX A

Characterisation Data

Cyclohexane-l,l-diyl bis-hydro peroxide 6a

¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.46(m, 2H, cyclohexyl), 1.58(m, 4H, cyclohexyl), 1.84(t, 4H, J = 6.46Hz, cyclohexyl), 8.1(s, 2H, OH), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 22.81, 25.61, 25.69, 29.91, 111.20.

Cyclododecane-l,l-diyl bis hydro peroxide 7a

¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.22-1.44(m, 14H, cyclododecanyl), 1.53(m, 3H, cyclodecanyl), 1.69(d, 4H, cyclododecanyl), 2.47(d, IH, cyclododecanyl), 8.1(s, 2H, OH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 19.39, 21.94, 22.20, 22.27, 24.33, 24.83, 25.93, 25.99, 26.16, 26.51, 40.50, 115.15 MS (ES+) [M + Na] ⁺ (100), 255.2 HRMS calculated 255.1596 C ₁₂ H ₂₄ O ₄ Na found, 255.1607.

Adamantane-2,2-diyl bishydroperoxide 8a

¹ HNMR (400MHz, CDCl ₃ ) δ _H> 1.66-1.73(m, 6H, adamantylidene), 1.88(s, 2H, adamantylidene), 1.96(s, 2H, adamantylidene), 2.0(s, 2H, adamantylidene), 2.36(s, 2H, adamantylidene), 8.02(s, 2H, OH), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 27.42, 31.56, 34.14, 37.44, 112.85 MS (ES+) [M + Na] ⁺ (100), 223.1, HRMS calculated for 223.0970 C ₁₂ H ₁₆ O ₄ Na found, 233.0962.

7,8,15,16-Tetraoxa-dispiro[5.2.5.2]hexadecan-3-one 10

Mpt. 78-8O ⁰ C F _n13x (CHCl ₃ VCm ^"1 1719.8, 2856.2, 2942.3, 3012.7 ¹ HNMR (400MHz, CDCl ₃ ) δ _H> 1.5(m, 6H, cyclohexyl), 1.80(s, 4H, cyclohexyl), 2.15(t, 2H, CH ₂ ), 2.30(t, 2H, CH ₂ ), 2.5(m, 4H, CH ₂ ), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 14.0, 23.07, 25.84, 31.98, 37.25, 106.60, 108.56, 210.77, MS (ES+) [M + Na] ⁺ (100), 265.0, [M + Na + CH ₃ OH] ⁺ (60) 297.1

7,8,21,22-Tetraoxa-dispiro[5.2.11.2]docosan-3-one 11

F _max (CHClsVcm- ¹ 1715.9, 2856.2,> 2926.7, 3012.7 Mpt. 108-110 ⁰ C IHNMR (400MHz, CDCl ₃ ) δ _H 1.2-1.7(m, 18H, cyclododecanyl), 1.96(bs, 4H, cyclodecanyl), 2.28(bs, 2H, CH ₂ ), 2.42(d, 2H, CH ₂ ), 2.66(bs, 2H, CH ₂ ). ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 14.5, 22.98, 25.06, 31.97, 106.94, 113.35, 209.48. MS (ES+) [M + Na] ⁺ (100), 349.6

Adamantane tetraoxane ketone 12

Mpt. 156-158 ⁰ C F _max (CHCl^/cm ^"1 1722.2, 2854.9, 2912.3, 3010.7 ¹ HNMR (400MHz, CDCl ₃ ) δ _H) 1.59-1.83(m, 4H, adamantyl), 1.88-2.13(m, 8H, adamantyl), 2.41-2.52(m, 4H, CH ₂ ), 2.54(bs, 4H, CH ₂ O), 2.68-2.78(m, 2H, CH ₂ ) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 27.38, 27.84, 33.51, 36.69, 37.25, 39.64, 47.36, 106.97, 111.38, 209.63 MS (ES+) [M + Na] ⁺ (100), 317.1 HRMS calculated for 317.1365 C ₁₆ H ₂₂ O ₅ Na, found 317.1331.

4-(7,8,15,16-Tetraoxa-dispiro[5.2.5.2]hexadec-3-yl)-morph oline l9

F _ma x CCHClsycm ^"1 1444.5, 2859.1, 2931.2, 3011.3 ¹ HNMR (400MHz, CDCl ₃ ) δ _H 1.4- 1.5(m, 4H, cyclohexyl), 1.6(bs, 6H, cyclohexyl), 1.7-1.9(m, 6H, cyclohexyl), 2.15- 2.3(m, 2H, cyclohexyl), 2.35(m, IH, CH) ₅ 2.55(t, 4H ₅ J = 4.61Hz ₅ NCH ₂ ), 3.7(t ₅ 4H ₅ J = 4.61Hz ₅ NCH ₂ ) ¹³ CNMR (100MHz ₅ CDCl ₃ ), δ _c 22.39, 24.20, 25.31, 25.76, 30.06, 30.63, 32.76, 33.38, 34.95, 35.00, 50.14, 50.41, 62.50, 67.74, 107.99, 108.72. MS (ES+) [M + H] ⁺ (100) 314.2 [M - H + Na] ⁺ (50) 336.1, HRMS (CI+) calculated for 314.19675 C ₁₆ H ₂₈ O ₅ N found, 314.19687

Cyclopropyl-(7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadec-3 -yl)-amine 14

F _max (CHClsVcm ^"1 14445.3, 2856.2, 2934.5, 3012.7, 3443.2 ¹ HNMR (400MHz, CDCl ₃ ) δ _H ¹³ CNMR 0.36(m, 2H, cyclopropyl), 0.47(m, 2H ₅ cyclopropyl), 1.37- 1.37(m, 4H, cyclohexyl), 1.52-1.66(m, 6H, cyclohexyl), 1.84-1.99(m, 4H, cyclohexyl), 2.14(m, IH, CH), 2.18-2.49(m, 4H, cyclohexyl), 2.75(m, IH, CH), 5.7(bs, IH, NH) (100MHz, CDCl ₃ ), δ _c 8.54, 22.38, 24.19, 25.76, 27.76, 28.64, 28.82, 30.09, 30.52, 32.47, 32.95, 34.99, 56.00, 108.18, 109.62 MS (ES+) [M + H] ⁺ (100),283.8 HRMS (CI+) calculated for 284.18616 C ₁₅ H ₂₆ O ₄ N found 284.18622,

(l,4-Dioxa-spiro[4.5]dec-8-ylidene)-acetic acid ethyl ester 22

F _max (neatycrn ¹ 926.3, 1104.9, 1169.1, 1237.8, 1269.8, 1301.9, 1352.3, 1430.2, 1650.1, 1709.6, 2876.1, 2949.4 ¹ HNMR (400MHz, CDCl ₃ ) δ _H, 1.28ft 3H.. J = 7.15Hz, CH ₃ ), 1.77(m, 4H, cyclohexyl), 2.38(t, 2H ₅ J = 6.68Hz, CH ₂ ), 3.0(t, 2H, J = 7.47Hz, CH ₂ ), 3.98(s, 4H, OCH ₂ ), 4.15(q, 2H, J = 7.15Hz, CH ₂ ), 5.7(s, IH, CH), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 14.3I ₅ 26.09, 34.61, 35.01, 35.81, 59.63, 64.47,

108.06, 114.37, 160.14, 166.56. MS (CI) [M + H] ⁺ (100), 227 [M + NH ₄ ] ⁺ (95), 244, HRMS calculated for 227.1283 C ₁₂ H ₁₉ O ₄ found, 227.1280.

(l,4-Dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester 21

F _max (neatycnϊ ¹ 860.1, 908.0, 1028.0, 1084.0, 1120.0, 1168.0, 1204.01272.0, 1432.0, 1652.0, 1716.0, 2879.9, 2943.9 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.73-1.80(m, 4H, cyclcohexyl), 2.38(dt, 2H, J = 6.45Hz, cyclohexyl), 3.0(dt, 2H, J = 6.46Hz, cyclohexyl), 3.68(s, 3H, OCH ₃ ), 3.97(s, 4H, OCH ₂ ), 5.68(s, IH, CH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 26.39, 34.90, 35.31, 36.10, 51.13, 64.75, 108.27, 114.20, 160.82, 167.18 MS (CI) [M + H] ⁺ (60), 227 [M + NH ₄ ] ⁺ (100), 230, HRMS calculated for 213.1127 C ₁₁ H ₁₇ O ₄ found, 213.1122

(l,4-Dioxa-spiro[4.5]dec-8-yl)-acetic acid ethyl ester 24

F _max (neatycm ^"1 926.3, 1031.6, 1104.9, 1169.9, 1237.8, 1288.2, 1375.2, 1443.9, 1728.0, 2876.1, 2931.0, ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.25(t, 3H ₃ J = 7.15Hz, CH ₃ ), 1.33(m, 2H, cyclohexyl), 1.56(m, 2H, cyclohexyl), 1.74(d, 4H, J = 6.99Hz, cycloheyxl), 2.2(d, 2H, J = 6.99Hz, CH ₂ CO), 3.93(s, 4H, OCH ₂ ), 4.13(q, 2H, J = 7.15Hz, CH ₂ ), 5.7(s, IH, CH), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 14.29, 30.02, 30.16, 33.34, 33.50, 34.16, 34.48, 41.01, 60.35, 64.25, 108.62, 172.87. MS (CI) [M + H] ⁺ (100), 229 [M + NH ₄ ] ⁺ (30), 246, HRMS calculated for 229.1440 C ₁₂ H ₁₉ O ₄ found, 229.1440.

(l,4-Dioxa-spiro[4.5]dec-8-yl)-acetic acid methyl ester 23

F _max (neatycm ^"1 932.1, 1032.0, 1108.0, 1164.0, 1240.0, 1288.0, 1436.0, 1732.0, 2879.9, 2935.9, ¹ HNMR (400MHz, CDCl ₃ ) δ _H) 1.24-1.37(m, 2H, cyclohexyl), 1.56(dt, 2H, J = 12.91H,z, 12.52Hz, cyclohexyl), 1.73(4H, J = 9.49Hz, cyclohexyl), 1.79-1.90(m, IH ₅ CH), 2,24(d, 2H, J = 7.02Hz, CH ₂ CO), 3.67(s, 3H, OCH ₃ ), 3.94(s, 4H, OCH ₂ ) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 30.31, 33.75, 34.59, 41.03, 51.66, 64.53, 108.85, 173.56 MS (CI) [M + H] ⁺ (100), 215 [M + NH ₄ ] ⁺ (40), 232, HRMS calculated for 215.1283 C ₁₁ H ₁₉ O ₄ found, 215.1283.

(4,4-Bis-hydroperoxy-cyclohexyl)-acetic acid ethyl ester 26

¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.26(t, 3H, . J = 7.15Hz, CH ₃ ), 1.62(m, 2H, cyclohexyl), 1.78(m, 4H, cyclohexyl), 1.92(m, 2H, cyclohexyl), 2.22(d, 2H, J = 13.51Hz, CH ₂ CO), 2.4(m, IH, CH), 4.14(q, 2H, J = 7.15Hz, OCH ₂ ), 8.55(bs, 2H, OH), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 14.20, 24.78, 28.19, 41.76, 60.67, 109.58

(4,4-Bis-hydroperoxy-cyclohexyl)-acetic acid methyl ester 25

F _m3x (CHCl ₃ VCm ^"1 1111.7, 1166.0, 1243.0, 1292.8, 1351.7, 1437.7, 1709.7, 2858.9, 2940.4, 3393.2 ¹ HNMR (400MHz, CDCl ₃ ) δ _H) 1.22-1.34(m, 2H, cyclohexyl), 1.52(dt, 2H, J = 13.09Hz, 13.66Hz, cyclohexyl), 1.70(dd, 2H, J ₅ 3.42Hz, cyclohexyl), 1.80-1.94(m, 3H, cyclohexyl/CH), 2.27(d, 2H ₅ J = 7.03Hz, CH ₂ CO) ₅ 3.68(3H, OCH3), 9.72(bs, 2H, OH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 25.89, 28.79, 29.19, 34.07, 40.97, 51.98, 110.11, 174.24 MS (ES+) [M + Na] ⁺ (100), 243.1 HRMS calculated

for 243.0845 C ₉ H ₁₆ O ₆ Na found, 243.0891

(7,8,15, 16-Tetraoxa-dispiro[5.2.5.2]hexadec-3-yl)acetic acid ethyl ester 27a

F _max (CHCy/cm ^"1 1444.8, 1731.6, 2853.8, 2926.4, 3014.3 ¹ HNMR (400MHz, CDCl ₃ ) δ _H) 1.25(t, 4H, J = 7.15Hz, CH ₃ ), 1.4-1.84(m, 14H, cyclohexyl), 1.9(m, 2H, CH ₂ ), 2.14-2.50(m, 4H, cyclohexyl), 3.09(bs, IH, CH), 4.13(q, 2H, J = 4.45Hz, CH ₂ ) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 14.65, 22.57, 25.75, 28.75, 29.10, 31.46, 34.07, 41.12, 60.79, 108.15, 108.70, 173.07 MS (ES+) [M + Na] ⁺ (100), 337.2 [2M + Na] ⁺ , 651.4 HRMS calculated for 337.1627 C ₁₂ H ₂₀ O ₆ Na found, 337.1615

(7,8,21,22-Tetraoxa-dispiro[5.2.11.2]docos-3-yl)-acetic acid ethyl ester 28a

F _max (CHCy/cm ^"1 1450.0, 1723.0, 2849.8, 2936.8, 3020.4, 3435.3 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.25(t, 3H, J = 7.21Hz, CH ₃ ), 1.26-1.40(m, 16H, CH ₂ ), 1.40- 1.49(m, 4H, CH ₂ ), 1.50-1.62(m, 4H, CH ₂ ), 1.64-1.81(m, 6H, CH ₂ ), 1.83-1.99(m, IH, CH), 1.23(d, 2H, J - 4.56Hz, CH ₂ CO), 4.13(q, 2H, J = 7.21Hz, OCH ₂ ) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 14.67, 22.65, 22.97, 24.62, 24.99, 25.15, 25.77, 26.29, 26.39, 27.82, 34.10, 40.79, 41.15, 60.71, 107.94, 112.81, 173.11 MS (ES+), m/z 398.53 [M + Na] ⁺ (100), 421. IHRMS calculated for421.2566 C ₂₂ H ₃₈ O ₆ Na found, 421.2581.

Adamantyl tetraoxane efhylester 29a

Mpt. 60-62 ⁰ C F _max (CHCy/cm ^"1 1446.8, 1718.5, 2858.9, 2922.3, 3003.8 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.25(t, 3H, J = 7.31Hz, CH ₃ ), 1.28-1.37(m, 2H, CH ₂ ), 1.48-

1.79(m, 1OH, CH ₂ ), 1.87(bs, 2H, CH ₂ ), 1.91-2.20(m, 9H, CH ₂ /CH), 2.23(d, 2H, J = 6.83Hz, CH ₂ CO), 4.13(q, 2H, J = 7.21Hz, CH ₂ ) ¹³ CNMR (lOOMHz, CDCl ₃ ), δ _c 14.62, 27.48, 27.87, 34.10, 36.72, 37.37, 39.65, 41.12, 47.38, 60.62, 107.99, 110.78, 173.00 MS (ES+), [M + Na] ⁺ (100), 389.1 [2M + Na] ⁺ 755.2 HRMS calculated for 389.1940 C ₂₀ H ₃₀ O ₆ Na found, 389.1954.

Adamantyl tetraoxane methyl ester 30a

F _max (neatycm ^"1 921.5, 994.0, 1043.81102.6, 1161.5, 1238.5, 1446.8, 1736.6, 2849.8, 29.13.2 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.18-1.37(m, 2H, adamantly), 1.50-1.77(m, 12H, CH2), 1.80-1.89(m, 4H, CH ₂ ), 1.90-2.03(m, 5H, CH), 2.25(d, 2H, J = 6.64Hz, CH ₂ CO), 3.68(s, 3H, OCH ₃ ) ¹³ CNMR (lOOMHz, CDCl ₃ ), δ _c 27.48, 32.61, 33.54, 34.08, 34.60, 35.32, 36.87, 37.37, 40.85, 51.85, 107.96, 110.79, 173.41 MS (ES+), [M + Na] ⁺ (100), 375.1 HRMS calculated for 375.1784 C ₁₉ H ₂₈ O ₆ Na found, 375.1774.

7,8,15, 16-Tetraoxa-dispiro[5.2.5.2]hexadec-3-yl)acetic acid 27b

¹ HNMR (400MHz, CDCl ₃ ) δ _H) 1.2-1.37(m, 4H, cyclohexyl), 1.46(m, 2H, cyclohexyl), 1.57(bs, 6H, cyclohexyl), 1.75(m, 4H, cyclohexyl), 1.88(m, IH, CH), 2.27(d, 2H, J = 6.3Hz, CH ₂ CO), 2.12-2.39(m, 2H, cyclohexyl) ¹³ CNMR (lOOMHz, CDCl ₃ ), δ _c 23.12, 25.76, 25.80, 25.92, 28.97, 30.02, 30.24, 30.95, 32.28, 33.86, 40.63, 107.51, 108.04, 178.42 MS (ES+), [M - H] ⁺ (IOO), 285.1, [2M -H] ⁺ , 571.1

(7,8,21,22-Tetraoxa-dispiro[5.2.11.2]docos-3-yl)-acetic acid 28b

F _max (CHCl ₃ VCm ^"1 1692.8, 2851.1, 2931.2, 3019.3, 3355.7 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.22-1.45(m, 22H, CH ₂ ), 1.51-1.64(m, 4H, CH ₂ ), 1.65-1.77(m, 4H, CH ₂ ), 1.90-1.90(m, IH, CH), 2.28(d, 2H, J = 7.03Hz, CH ₂ CO), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 19.77, 22.41, 22.98, 24.70, 25.06, 25.20, 26.37, 29.77, 40.81, 107.30, 118.89, 177.48

Adamantyl tetraoxane carboxylic acid 29b

F _max (CHCl ₃ VCm ^"1 991.8, 1057.5, 1446.7, 1694.3, 2844.0, 2924.8, 3005.7 3355.7 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.22-1.46(m, 2H, CH ₂ ), 1.50-1.90(m, 12H, CH ₂ ), 1.01-2.05(m, 4H, CH ₂ ), 2.06-2.15(m, 5H, CH), 2.29(d, 2H, J = 6.83Hz, CH ₂ CO), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 27.47, 27.84, 33.52, 33.86, 36.69, 37.35, 39.65, 40.75, 47.34, 108.89, 110.79, 178.23. MS (ES+), [M - H] ⁺ (100), 337.2 HRMS calculated for 337.1651 C ₁₈ H ₂₅ O ₆ found, 337.1663

1 -Morpholin-4-yl-2-(7 ,8,15,16-tetraoxa-dispiro [5.2.5.2]hexadec-3 -yl)-ethanone 27h

F _H13x (CHCl ₃ VCm ^"1 1444.5, 1632.7, 2851.1, 2931.2, 3011.3 Mpt. 126-128 ⁰ C ¹ HNMR (400MHz, CDCl ₃ ) δ _H> 1.19-1.35(m, 4H, cyclohexyl), 1.46(bs, 2H, cyclohexyl), 1.57(bs, 6H, cyclohexyl), 1.77(m, 4H, cyclohexyl), 1.98(m, IH, CH) 2.16-2.35(m, 4H, CH ₂ /cyclohexyl), 3.45(t, 2H, J = 4.76Hz, NCH ₂ ), 3.59-3.67(m, 6H, CH ₂ O). ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 25.76, 34.20, 39.22, 67.35, 108.21, 108.69, 170.9 MS (ES+), [M + Na] ⁺ (100) 378.2, [2M + Na] ⁺ 733.4 HRMS calculated for 378.1893 C ₁₈ H ₂₉ NO ₆ Na found, 378.1886.

N-Cyclopropyl-2-(7,8,l 5 , 16-tetraoxa-dispiro[5.2.5.2]hexadec-3-yl)-acetamide 27c

V _max (CHCh)hm ^A 1444.6, 1535.6, 1636.7, 2851.1, 2939.2, 3019.3, 3299.6 Mpt. 148- 15O ⁰ C ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 0.47(m, 2H, cyclopropyl), 0.77(m, 2H, cyclopropyl), 1.25(m, 4H, cyclohexyl), 1.46(m, 2H, cyclohexyl), 1.57(bs, 6H, cyclohexyl), 1.72(m, 4H, cyclohexyl), 1.94(m, IH, CH), 2.02(d, 2H, J = 5.04Hz, CH ₂ CO), 1.96-2.08(m, 2H, cyclohexyl), 2.71(m, IH, CH-cyclopropyl), 5.7(bs, IH, NH) ¹³ CNMR (100MHz, CDCl ₃ ) δ _c 7.03, 22.99, 25.75, 34.43, 43.49, 108.20, 108.67, 173.54 MS (ES+), [M + Na ] ⁺ (100) 348.2, [2M + Na]+ 673.3 HRMS calculated for 348.1787 C ₁₇ H ₂₇ O ₅ NNa found, 348.1791.

N-(2-Pyrrolidin- 1 -yl-ethyl)-2-(7,8, 15,16-tetraoxa-disρiro[5.2.5.2]-hexadec-3-yl)- acetamide 27d

F _H - _13X (CHCl ₃ VCm ^"1 1444.6, 1512.6, 1652.8, 2859.2, 2931.2, 3011.3, 3315.6 Mpt. 110- 112 ⁰ C ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.2-1.34(m, 4H, cyclohexyl), 1.47(m, 2H, cyclohexyl), 1.57(bs, 6H, cyclohexyl), 1.73(m, 4H, cyclohexyl), 1.83-2.1(m, 5H, CHICH ₂ ), 2.16(d, 2H, J = 6.99Hz, CH ₂ CO), 2.23-2.32(m, 2H,cyclohexyl), 2.68- 2.79(m, 2H, CH ₂ N), 2.86(t, 4H, J = 6.04Hz, NCH ₂ ), 3.49(q, 2H, J = 5.88Hz, NHCH ₂ ), 6.98(bs, IH, NH). ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 15.01, 23.77, 23.82, 25.75, 34.42, 37.26, 43.33, 54.42, 55.57, 108.23, 108.61, 172.79 MS (ES+), m/z 382.49 [M + H] ⁺ (74.77) 383.1, [M + Na] ⁺ (100) 405.1 HRMS calculated for 383.2546 C ₂₀ H ₃₅ O ₅ found, 383.2553 and 405.2365 C ₂₀ H ₃₄ N ₂ O ₅ Na, found, 405.2364.

N-(2-Piperidin-l-yl-ethyl)-2-(7,8,15,16-tetraoxa-dispiro[ 5.2.5.2]-hexadec-3-yl)- acetamide 27e

F _n13x (CHCl ₃ VCm- ¹ 1444.4, 1508.6, 1648.8, 2856.2, 2934.5, 3012.7, 3325.8 Mpt. 68- 78 ⁰ C ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.25(t, 4H, J = 7.16Hz, cyclohexyl), 1.47(m, 4H, cyclohexyl/piperidyl), 1.57(bs, 6H, cyclohexyl), 1.65(m, 4H, cyclohexyl), 1.74(m, 4H, piperidyl), 1.94(m, IH, CH), 2.15(d, 2H, J = 7.0Hz, CH ₂ CO), 2.30(m, 2H, cyclohexyl), 2.53(m, 2H, NCH ₂ ), 2.66(m, 4H, CH ₂ N), 3.45(q, 2H, J = 5.73Hz, NHCH ₂ ), 6.94(bs, IH, NH). ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 20.08, 21.53, 21.99, 22.75, 23.41, 32.11, 33.24, 35.34, 41.07, 52.26, 52.39, 55.38, 55.77, 58.78, 105.89, 106.27, 170.30 MS (ES+), [M + H] ⁺ (66.29) 397.1, [M + Na] ⁺ (100) 419.1 HRMS calculated for 397.2702 C ₂₁ H ₃₇ N ₂ O ₅ found, 397.2704, and for 419.2522 C ₂₁ H ₃₆ N ₂ O ₅ Na found 419.2518.

N-(2-Morpholin-4-yl-ethyl)-2-(7,8,15,16-tetraoxa-dispiro[ 5.2.5.2]-hexadec-3-yl)- acetamide 27f

V _max (CHCl^/cm- ¹ 1444.4, 1508.6, 1656.8, 2811.1, 2851.1, 2931.2, 3307.6 ¹ HNMR (400MHz, CDCl ₃ ) δ _H, 1.25(m, 4H, cyclohexyl), 1.47(m, 2H, cyclohexyl), 1.58(m, 6H, cyclohexyl), 1.70-1.78(m, 4H, cyclohexyl), 1.94(m, IH, CH), 2.1(d, 2H, J = 7.15Hz, CH ₂ CO), 2.13-2.37(m, 2H, cyclohexyl), 2.41-2.51(m, 6H, CH ₂ N/NCH ₂ ), 3.36(q, 2H, J = 5.88Hz, NHCH ₂ ), 3.7(m, 4H, CH ₂ O), 5.98(bs, IH, NH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 15.03, 25.74, 34.44, 35.92, 43.66, 53.75, 57.52, 67.25, 67.29,

108.20, 108.68, 172.16 MS (ES+), [M + Na] ⁺ (100) 421.1, HRMS calculated for 421.2315 C ₂₀ H ₃₄ O ₆ N ₂ Na found, 421.2323.

λH2-Diethylamino-ethyl)-2-(7,8, 15, 16-tetraoxa-disρiro[5.2.5.2]-hexadec-3-yl)- acetamide 27g

F _n13x (CHCl ₃ VCm ^"1 1444.5, 1508.6, 1652.8, 2859.1, 2939.2, 3011.4, 3323.6 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.02(t, 3H, J = 7.15Hz, CH ₃ ), 1.05(t, 3H, J = 7.15Hz, CH ₃ ), 1.25(m, 4H, cyclohexyl), 1.46(m, 2H, cyclohexyl), 1.59(bs, 6H, cyclohexyl), 1.74(m, 4H, cyclohexyl), 1.94(m, IH, CH), 2.1(d, 2H, J = 7.16Hz, CH ₂ CO), 2.14-2.35(m, 2H, cyclohexyl), 2.57(m, 6H, CH ₂ N/NCH ₂ ), 3.23(q, IH, J = 5.88Hz, NHCH ₂ ), 3.33(q, IH, J = 6.2Hz, NHCH ₂ ), 6.30(bs, IH, NH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 11.76, 11.98, 15.02, 25.73, 34.43, 36.95, 43.60, 47.19, 51.99, 52.33, 108.21, 108.60, 172.25 MS (ES+), [M + H] ⁺ (100) 385.2, HRMS calculated for 385.2702 C ₂₀ H ₃₇ N ₂ O ₅ found, 385.2695.

(2-7,8,15,16-Tetraoxa-dispiro [5.2.5.2]hexadec-3 -yl-acetylamino)- acetic acid methyl ester 27i

F _n13x (CHCl ₃ VCm ^"1 1440.5, 1516.6, 1692.8, 1744.9, 2859.1, 2931.2, 3011.3, 3419.7 ¹ HNMR (400MHz, CDCl ₃ ) δ _H 1.24(m, 4H, cyclohexyl), 1.46(bs, 2H, cyclohexyl), 1.51, bs, 4H, cyclohexyl), 1.90(m, IH, CH), 2.18(d, 2H, J = 7.15Hz, CH ₂ CO), 2.20- 2.48(m, 2H, cyclohexyl), 3.70(s, 3H, OCH ₃ ), 4.05(d, 2H, J = 5.08Hz, NCH ₂ ), 6.04(s, IH, NH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 22.44, 25.75, 33.89, 41.56, 43.25, 51.14, 52.74, 108.17, 108.68, 170.86, 172.51 MS (ES+), [M + Na] ⁺ (100) 380.1 HRMS calculated for 380.1685 C ₁₇ H ₂₇ NO ₇ Na found, 380.1778.

N-Cyclopropyl-2-(7,8,21,22-tetraoxa-dispiro[5.2.11.2]doco s-3-yl)-acet-amide 28c

Mpt. 136-138 ⁰ C F _n13x (CHCl ₃ )ZCnI ^"1 1523.8, 1637.0, 2849.8, 2931.3, 3003.8, 3311.7 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 0.46(m, 2H, cyclopropyl), 0.77(m, 2H, cyclopropyl), 1.14-1.47(m, 22H, CH ₂ ), 1.50-1.84(m, 8H, CH ₂ ),1.94(m, IH, CH), 2.02(d, 2H, J = 7.02Hz, CH ₂ CO), 2.70(m, IH, CH), 5.6(bs, IH, NH), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 7.04, 8.88, 22.43, 22.72, 23.00, 26.33, 26.39, 28.74, 29.56, 34.46, 43.51, 107.99, 112.77, 173.54 MS (ES+), [M + Na] ⁺ (100), 432.2 [2M + Na] ⁺ , 841.4 HRMS calculated for 432.2726 C ₂₃ H ₃₉ O ₅ Na found, 432.2723.

N-(2-Pyrrolidin-l-yl-ethyl)-2-(7,8,21,22-tetraoxa-dispiro [5.2.11.2]do-cos-3-yl)- acetamide 29d

Mpt. 108-110 ⁰ C F _max (CHCl^/crn ¹ 1548.6, 1628.7, 2859.1, , 2931.5, 3003.7, 3327.1 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.10-1.49(m, 22H, CH ₂ ), 1.5O-1.83(m, 8H, CH ₂ ),1.94-2.00(m, 5H, CH), 2.16(d, 2H, J = 7.03Hz, CH ₂ CO), 2.81-3.18 (m, 6H, NCH ₂ /CH ₂ N), 3.51(q, 2H, J = 5.70Hz, NHCH ₂ ), 7.1(bs, IH, NH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 18.60, 19.74, 22.34, 22.70, 23.77, 26.30, 26.37, 28.58, 29.40, 31.54, 34.41, 37.14, 43.28, 54.42, 55.48, 107.97, 112.67, 172.88 MS (ES+), [M + H] ⁺ (100), 467.3 HRMS calculated for 467.3485 C ₂₆ H ₄₇ O ₅ N ₂ found, 467.3487.

N-(2-Piperidin-l -yl-ethyl)-2-(7,8,21 ,22-tetraoxadispiro[5.2.11.2]-docos-3-yl> acetamide 28e

Mpt. 96-98 ⁰ C F _max (CHCl^/crn ¹ 1505.7, 1650.6, 2849.0, 2931.3, 3019.3, 3320.8 ¹ HNMR (400MHz, CDCl ₃ ) δ _H, 1.18-1.64(m, 30H, CH ₂ ), 1.65-1.79(m, 6H, CH ₂ ), 1.89-1.86-1.90(m,lH, CH)1.13(d, 2H, J = 7.02Hz, CH ₂ CO), 2.49-2.62(m, 6H, CH ₂ N/NCH ₂ ), 3.41(q, 2H, J = 5.88Hz, MϊCH ₂ ), 6.20(bs, IH, NH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 22.72, 24.17, 25.51, 26.39, 34.50, 35.81, 43.55, 54.65, 57.69, 108.03, 112.73, 172.47 MS (ES+), [M + Na] ⁺ (100), 5.5.2 [M + H] ⁺ , 481.2 HRMS calculated for 503.3461C ₂₇ H ₄₈ ON ₂ Na found, 503.3449.

N-(2-Morpholin-4-yl-eth.yl)-2-(7,8,21,22-tetraoxa-dispiro [5.2.11.2]do-cos-3-yl)- acetamide 28f

Mpt. 78-8O ⁰ C F _max (CHCl ₃ VCm ^"1 1533.1, 1643.0, 2806.2, 2850.2, 2920.5, 3315.9 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.10-1.49(m, 22H, CH ₂ ), 1.50-1.80(m, 8H, CH ₂ ),1.86(m, IH, CH), 2.1 l(d, 2H, J = 7.03Hz, CH ₂ CO), 2.42-2.51(m, 6H, NCH ₂ /CH ₂ N), 3.37(q, 2H, J = 5.88Hz, NHCH ₂ ),3.72(t, 4H, J = 4.55Hz, CH ₂ O), 6.0(bs, IH, NH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 19.67, 19.73, 19.81, 22.33, 2251, 22.59, 26.28, 26.35, 26.54, 26.59, 26.98, 27.06, 28.77, 29.21, 29.49, 29.80, 31.86, 34.70, 35.87, 44.01, 53.72, 57.50, 67.26, 107.47, 112.14, 172.55 MS (ES+), [M + H] ⁺ (100), 483.3 [M + Na] ⁺ , 505.2 HRMS calculated for 483.3434 C ₂₆ H ₄₇ O ₆ N ₂ found, 483.3424.

N-(2-Diethylamino-ethyl)-2-(7,8,21,22-tetraoxa-dispiro[5. 2.11.2]-docos-3-yl)- acetamide 28g

Mpt. 64-66 ⁰ C V _max (CHCl ₃ VCm ^"1 1446.6, 1660.8, 2812.3, 2931.2, 3003.8, 3251.6 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.15(t, 6H, J = 7.21Hz, CH ₃ ), 1.23-1.49(m, 22H, CH ₂ ), 1.50-1.79(m, 8H, CH ₂ ), 1.85(m, IH, CH), 2.12(d, 2H, J = 7.02Hz, CH ₂ CO), 2.73(q, 6H, J = 7.02Hz, NCH ₂ /CH ₂ N), 3.42(q, 2H, J = 5.89Hz, NCH ₂ ), 6.30(bs, IH, NH) ¹³ CNMR (lOOMHz, CDCl ₃ ), δ _c 10.97, 19.70, 19.76, 19.79, 22.40, 22.59, 22.67, 26.33, 26.38, 26.56, 26.62, 27.04, 27.11, 28.77, 29.21, 29.47, 31.86, 34.61, 36.44, 43.80, 47.51, 51.08, 52.38, 107.49, 112.11, 172.90 MS (ES+), [M + H] ⁺ (100), 469.3 [M + Na] ⁺ , 491.3 HRMS calculated for 469.3641 C ₂₆ H ₄₉ O ₅ N ₂ found, 469.3659.

l-Morpholin-4-yl-2-(7,8,21,22-tetraoxa-dispiro[5.2.11.2]d ocos-3-yl)-ethanone 28h

Mpt. 118-12O ⁰ C F _n13x (CHCl ₃ )/^ ¹ 1437.7, 1632.5, 2858.9, 2931.3, 3003.7 ¹ HNMR (400MHz, CDCl ₃ ) δ _H, 1.15-1.49(m, 22H, CH ₂ ), 1.50-1.84(m, 8H, CH ₂ ),1.98(m, IH, CH), 2.23(bs, 2H, CH ₂ ), 3.45(m, 2H, morpholine), 3.65(m, 6H, morpholine), ¹³ CNMR (lOOMHz, CDCl ₃ ), δ _c 22.25, 22.72, 26.33, 26.39, 29.52, 31.61, 34.23, 39.23, 42.37, 46.60, 67.06, 67.37, 107.99, 112.79, 170.92 MS (ES+), [M + Na] ⁺ (100), 462.2 [2M + Na] ⁺ , 901.4 HRMS calculated for 462.2832 C ₂₄ H ₄₁ O ₆ Na found, 462.2834.

2-(7,8,21 ,22-Tetraoxa-dispiro[5.2.11.2]docos-3-yl> 1 -thiomorpholin-4-yl-ethanone 28i

Melting pointt. 108-110 ⁰ C F _max (CHCy/cm ^"1 1169.6, 1182.1, 1290.0, 1422.8, 1443.6, 1464.3, 1638.7, 2854.8, 2921.2 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.29-1.50(m, 24H, CH ₂ ), 1.51-1.66(m, 4H, CH ₂ ), 1.71-1.81(m, m, 2H, CH ₂ ), 1.91-2.03(m, IH, CH), 2.22(bs, 2H, CH ₂ CO), 2.60(t, 4H, CH ₂ S), 3.74(2H, J = 4.36Hz, NCH ₂ ), 3.89(bs, 2H, NCH ₂ ) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 22.41, 22.73, 25.86, 26.33, 26.40, 27.86, 28.36, 29.67, 34.1839.57, 44.73, 48.84, 108.00, 112.79, 170.65. MS (ES+), [M + H] ⁺ (100), 478.2HRMS calculated for 478.2603 C ₂₄ H ₄₁ O ₅ Na found, 478.2605.

Adamantyl- JV-Cyclopropyl tetraoxane acetamide 29c

Mpt. 140-142 ⁰ C F _ma χ (CHCl^/cm ^"1 1496.6, 1664.2, 2858.9, 2922.3, 3012.8, 3320.8 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 0.48(m, 2H, cyclopropyl), 0.78(m, 2H, cyclopropyl), 1.14-1.38(m, 2H, CH ₂ ), 1.40-1.80(m, 14H, CH ₂ ),1.88(bs, 2H, CH ₂ CO), 1.83-2.05(m, 7H, CH/CH ₂ ), 2.70(m, IH, CH-cyclopropyl), 5.5(bs, IH, NH), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 7.05, 8.89, 23.00, 27.47, 27.49, 33.54, 33.56, 34.46, 37.37, 39.48, 43.52, 108.09, 110.80, 173.53 MS (ES+), [M + Na] ⁺ (100), 400.2 [2M + Na] ⁺ , 777.4 HRMS calculated for 400.21 C ₂₁ H ₃ i0 ₅ NNa found, 400.2083

iV-(2-Pyrrolidin-l-yl-etriyl)- [adamantyl] acetamide 29d

Mpt. 142-144 ⁰ C F _n13x (CHCl ₃ VCm ^"1 1446.7, 1559.9, 1641.1, 2859.1, 2931.2, 2937.7, 3260.8 ¹ HNMR (400MHz, CDCl ₃ ) δ _H 1.19-1.35(m, 2H, CH ₂ ), 1.50-1.83(m, 14H, CH ₂ ), 1.83-1.89(m, 4H, CH ₂ ), 1.90-2.04(m, 5H, CH), 2.12(d, 2H, J = 7.02Hz, CH ₂ CO), 2.50-2.67(m, 6H, NCH ₂ /CH ₂ N), 3.3 l(q, 4H, J = 5.50Hz, CH ₂ ), 6.55(bs, IH, NH), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 23.81, 23.83, 27.47, 27.85, 28.61, 33.52, 33.53, 34.45, 36.69, 37.35, 37.95, 39.64, 39.80, 43.51, 47.36, 50.89, 54.29, 55.33, 55.57, 61.06, 108.12, 110.74, 172.53 MS (ES+), [M + Na] ⁺ (100), 457.2 [2M + Na] ⁺ , 891.3 HRMS calculated for 457.2678 C ₂₄ H ₃₈ O ₅ N ₂ Na found, 457.268

N-(2-Piperidin-l-yl-ethyl)-[adamantyl Jacetamide 29e

Mpt. 119-121 ⁰ C F _n13x (CHCl ₃ VCm ^'1 1446.7, 1541.3, 1650.3, 2794.9, 2846.8, 2919.4, 3324.1 ¹ HNMR (400MHz, CDCl ₃ ) δ _H) ) 1.22-1.41 (m, 2H, CH ₂ ), 1.45-1.79(m, 16H, CH ₂ ), 1.86(bs, 2H, CH ₂ ), 1.89-2.17(m, 9H, CH/CH ₂ ), 2.24(d, 2H, J = 6.83Hz, CH ₂ CO), 3.10(t, 6H, J = 5.50Hz, CH ₂ N/NCH ₂ ), 3.68(q, 2H, J = 5.31Hz, NHCH ₂ ), 8.15(bs, IH, NH), ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 22.44, 22.94, 27.50, 33.55, 34.16, 34.48, 37.40, 43.05, 54.64, 58.15, 108.10, 110.70, 173.46 MS (ES+), [M + Na] ⁺ (100), 471.2 HRMS calculated for 471.2835 C ₂₅ H ₄₀ O ₅ N ₂ Na found, 471.2854

N-(2-Morpholin-4-yl-ethyl)-adamantyl acetamide 29f

F _max (neatVcm ^"1 1446.2, 1539.6, 1648.6, 2858.9, 2913.2, 2926.4, 3331.1 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.42-1.79(m, 14H, CH ₂ ), 1.80, 1.99(m, 2H, CH ₂ ), 1.99- 2.20(m, 5H, CH), 2.30-2.07(m, 2H, CH ₂ ), 2.09(d, 2H, J = 7.02Hz, CH ₂ CO), 3.28(q, 2H, J = 5.51Hz, CH ₂ N/NCH ₂ ), 3.67-3.73(m, 4H, CH ₂ O), 6.0(bs, IH, NH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 27.45, 27.47, 33.53, 33.55, 34.46, 35.94, 37.35, 43.68, 53.74,

67.28, 108.08, 110.80, 172.23 MS (ES+), m/z 450.57 [M + Na] ⁺ (100), 473.2 [M + H/K] ⁺ , 451.2/489.2 HRMS calculated for 473.2628 C ₂₄ H ₃₈ O ₆ N ₂ Na found, 473.2649

N-(2-Diethylamino-ethyl)-[adamantly] acetamide 29g

K _n18x (neatycm ^"1 1446.7, 1524.1, 1660.6, 2812.3, 2928.4, 2957.5, 3341.5 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 1.18(t, 6H, J = 7.21Hz, CH ₃ ), 1.22-1.40(m, 2H, CH ₂ ), 1.50- 1.78(m, 14H, CH ₂ ), 1.80-1.88(m, 2H, CH ₂ ), 1.90-2.04(m, 5H, CH), 2.15(d, 2H, J = 7.02Hz, CH ₂ CO), 2.76-2.85(m, 6H, NCH ₂ /CH ₂ N), 3.45(m, 2H, NCH ₂ ), 7.18(bs, IH, NH) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 10.68, 27.47, 33.53, 34.43, 37.36, 43.39, 47.56, 50.99,52.39, 52.51, 108.10, 110.10, 172.86 MS (ES+), m/z 436.58 [M + H] ⁺ (100), 437.2 [M + Na] ⁺ , 459.2 HRMS calculated for 437.3015 C ₂₄ H ₄₁ O ₅ N ₂ found, 437.3035

Adamantly- 1 -Morpholin-4-yl tetraoxane acetamide 29h

Mpt. 139-14O ⁰ C F _m3x (CHCl ₃ VCm ^"1 1442.3, 1632.5, 2858.9, 2913.2, 3003.8 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , l.ll-1.38(m, 2H, CH ₂ ), 1.50-1.82(m, 12H, CH ₂ ), 1.85(bs, 2H, CH ₂ ), 1.90-2.18(m, 5H, CH), 2.30(d, 2H, J = 7.02Hz, CH ₂ CO), 3.46(t, 2H, J = 4.56Hz, NCH ₂ ), 3.60-3.69(m, 6H, NCH ₂ /CH ₂ O) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 26.52, 27.47, 27.49, 28.94, 30.69, 33.54, 33.56, 33.82, 34.25, 35.20, 37.37, 39.21, 42.37, 46.60, 67.07, 67.37, 108.10, 110.81, 170.92 MS (ES+), [M + Na] ⁺ (100), 430.2 [2M + Na] ⁺ , 837.4 HRMS calculated for 430.2206 C ₂₂ H ₃₃ O ₆ NNa found, 430.2213

Tetraoxa-dispiro-(adamantly)-thiomorpholm-4-yl-ethanone 29i

Melting point 150-152 ⁰ C F ^" _max (CHCl ₃ )/^ ¹ 955.9, 992.4, 1056.5, 1102.2, 1184.5, 1285.2, 1417.8, 1445.2, 1632.7, 2848.0, 2921.1 ¹ HNMR (400MHz, CDCl ₃ ) δ _H, 1.17- 1.50(m, 16H, CH ₂ ), 1.50-1.67(m, 4H, CH), 1.71-1.86(m, 2H, CH ₂ ), 1.91-2.04(m, IH, CH), 2.16-2.35(m, 2H, CH ₂ CO), 3.04(bs, 4H, CH ₂ S), 3.97(bs, 2H, NCH ₂ ), 4.11(bs, 2H, NCH ₂ ) ¹³ CNMR (400MHz, CDCl ₃ ), δ _c 14.60, 22.67, 26.30, 26.38, 34.05, 39.26, 40.65, 44.32, 52.55, 52.69, 107.83, 112.89, 170.83. MS (ES+), [M + Na] ⁺ (100), 446.0 HRMS calculated for 446.1977 C ₂₂ H ₃₃ O ₅ NSNa found, 446.1974.

Adamantyl acetamide 29j

Mpt. 108-110 ⁰ C F _max (CHCl ₃ VCm ^'1 1536.3, 1650.3, 2859.1, 2919.4, 2931.2, 3376.0 ¹ HNMR (400MHz, CDCl ₃ ) δ _H , 0.87-0.99(m, 6H, CH ₃ ), 1.25(t, 2H, J = 7.21Hz, CH ₂ ), 1.49-1.80(m, 12H, CH ₂ ), 1.86(bs, 2H, CH ₂ ), 1.90-2.03(m, 5H, CH), 2.06- 2.22(m, 5H, CH/CH ₂ ), 3.76(s, 3H, OCH ₃ ), 4.57(dd, IH, J = 4.94Hz, CH), 5.92(d, IH, J = 8.54Hz, NH), ¹³ CNMR (400MHz, CDCl ₃ ), δ _c 18.13, 18.21, 19.34, 27.48, 31.62, 33.55, 34.43, 37.38, 43.62, 52.50, 57.32, 108.07, 110.77, 172.10, 173.00 MS (ES+), [M + Na] ⁺ (100), 474.2 HRMS calculated for 474.2468 C ₂₄ H ₃₇ O ₇ NNa found, 474.2448.

1 -(1 ,1 -Dioxo-1 λ ⁶ -thiomorpholin-4-yl)-2-(7,8,21 ,22-tetraoxa-dispiro[5.2.11.2]docos- 3-yl)-ethanone 31

Melting point 170-172 ⁰ C F _n13 X (CHCl ₃ VcIn ^"1 859.8, 946.7, 1065.6, 1120.5, 1170.8, 1285.2, 1321.7, 1431.5, 1463.5, 1637.3, 2857.1, 2930.3, 3012.6 ¹ HNMR (400MHz, CDCl ₃ ) δ _H, 1.50-1.82(m, 24H, CH ₂ ), 1.86(bs, 2H, CH ₂ ), 1.91-2.04(m, 5H, CH ₂ /CH), 2.18-2.28(m, 2H, CH ₂ CO), 2.60(t, 4H, J = 4.93Hz, CH ₂ S), 3.73(t, 2H, J = 4.93Hz, NHCH ₂ ), 3.89(bs, 2H, NCH ₂ ) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 27.46, 27.46, 27.86, 28.36, 33.53, 33.55, 33.83, 36.77, 37.34, 39.55, 44.73, 48.85, 108.12, 110.83, 170.68 MS (ES+), [M + Na] ⁺ (100), 510.0 HRMS calculated for 510.2501 C ₂₄ RuO ₇ NNa found, 510.2489.

1 -(1 , 1 -Dioxo- 1 λ -thiomoφholin-4-yl)-2-tetraoxa-dispiro-adamantyl ethanone 32

Melting pointl 89-191 ⁰ C F _n13x (CHCl ₃ VCm ^"1 905.7, 1068.8, 1119.0, 1169.2, 1273.7, 1428.5, 1461.9, 1633.4, 2847.5, 2914.4 ¹ HNMR (400MHz, CDCl ₃ ) δ _H 1.20-1.37(m, 4H, adamantylidine), 1.50-1.82(m, 14H, CH ₂ ), 1.90-2.05(m, 2H, CH ₂ CO), 3.03(q, 4H, J = 4.94Hz, CH ₂ SO ₂ ), 4.97(t, 2H, J = 4.74Hz, NCH ₂ ), 4.07-4.16(m, 2H, NCH ₂ ) ¹³ CNMR (100MHz, CDCl ₃ ), δ _c 27.01, 27.03, 29.70, 33.12, 33.14, 33.66, 36.91, 38.85, 40.24, 43.91, 52.13, 52.28, 107.53, 110.54, 170.44 MS (ES+), [M + Na] ⁺ (100), 478.0 HRMS calculated for 478.1875 C ₂₂ H ₃₃ O ₇ NSNa found, 4578.1864.

Tetraoxane 29k

¹ H NMR (400MHz, CDCl ₃ ) δ _H) 1.19 (d, 6H, J = 6.5Hz, CH ₃ ), 1.37 (d, 6H, J = 6.8Hz, CH ₃ ), 1.22-1.30 (m, 4H, adamantylidene), 1.50-1.81 (m, 12H, adamantylidene/CH ₂ ), 1.86 (bs, 2H, CH ₂ ), 1.91-2.06 (m, 5H, adamantylidene/CH), 2.19 (d, 2H, J = 6.5Hz, CH ₂ CO), 3.89-4.01 (m, 2H, CH) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 21.2, 21.4, 21.5, 27.5, 33.6, 34.3, 37.4, 41.4, 46.1, 108.3, 110.8, 171.1. MS (ES+), [M + Na ] ⁺ (100), 444.2 [2M + Na ] ⁺ 865.5 HRMS calculated for 444.2726 C ₂₄ H ₃₉ O ₅ NNa, found 444.2713.

Tetraoxane 291

¹ H NMR (400MHz, CDCl ₃ ) δ _H , 1.10-1.30 (m, 4H, adamantylidene), 1.45-1.75 (m, 12H, adamantylidene/CH ₂ ), 1.79 (bs, 2H, CH ₂ ), 1.84-1.98 (m, 5H, adamantylidene/CH), 2.16 (bs, 2H, CH ₂ CO), 2.24 (s, 3H, CH ₃ ), 2.27-2.34 (m, 4H, CH ₂ N), 3.38-3.45 (m, 2H, NCH ₂ ), 3.54-3.60 (m, 2H, NCH ₂ ) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 27.5, 33.6, 34.3, 37.4, 39.4, 41.9, 44.0, 46.2, 46.5, 55.1, 55.2, 55.6, 108.2, 110.8, 170.7. MS (ES+), [M + H ] ⁺ (100), 421.3 [M + Na ] ⁺ 443.1 HRMS calculated for 443.2522 C ₂₃ H ₃₆ O ₅ N ₂ Na, found 443.2526.

Tetraoxane 29m

¹ H NMR (400MHz, CDCl ₃ ) δ _H , 1.20-1.35(m, 4H, adamantylidene), 1.49-1.80 (m, 18H, adamantylidene/CH ₂ ), 1.86 (bs, 2H, CH ₂ ), 1.91-2.03 (m, 5H, adamantylidene/CH/CH ₂ CO), 2.24 (d, 2H, J = 7.22 Hz, CH ₂ CO), 3.39 (t, 2H, J = 5.4 Hz, NCH ₂ ), 3.56 (t, 2H, J = 5.4 Hz, NCH ₂ ) ¹³ C NMR (lOOMHz, CDCl ₃ ), δ _c 25.0,

26.1, 27.0, 27.5, 33.6, 34.4, 37.4, 39.4, 43.1, 47.3, 108.2, 110.8, 170.5 MS (ES+), [M + Na ] ⁺ (100), 428.1 [2M + Na ] ⁺ 883.1 HRMS calculated for 428.2413 C ₂₃ H ₃₅ O ₅ NNa, found 428.2416.

Tetraoxane 29n

¹ H NMR (400MHz, CDCl ₃ ) δ _H , 1.20-1.36 (m, 4H, adamantylidene), 1.50-1.82 (m, 12H, adamantylidene/CH ₂ ), 1.86(bs, 2H, CH2), 1.91-2.05 (m, 5H, adamantylidene), 2.29 (d, 2H, J = 6.8Hz, CH2CO), ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 27.5, 30.1, 33.6, 34.0, 37.4, 40.5, 107.9, 110.9, 177.3 MS (ES+), [M + Na ] ⁺ (100), 360.0 HRMS calculated for 360.1787 C ₁₈ H ₂₇ O ₅ NNa, found 360.1776.

Tetraoxane 29o

¹ H NMR (400MHz, CDCl ₃ ) δ _H) 1.20-1.31(m, 4H, adamantylidene), 1.34(s, 9H, CH ₃ ) 1.50-1.78 (m, 13H, adamantylidene/CH ₂ ), 1.86 bs, 2H, CH ₂ ), 1.91-2.04 (m, 6H, adamantylidene/CH/CH ₂ CO), 5.20 (bs, IH, NH) ¹³ C NMR (100MHz, CDCl ₃ ), θ _c 26.5, 27.5, 28.2, 29.3, 30.0, 33.5, 34.5, 37.4, 39.7, 44.7, 51.6, 108.2, 110.8, 171.5 MS (ES+), [M + Na ] ⁺ (100), 416.2 HRMS calculated for 416.2413 C ₂₂ H ₃₅ O ₅ NNa, found 416.2397.

Tetraoxane 29p

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.20-1.36 (m, 4H, adamantylidene), 1.42-1.80 (m, 14H, admantylidene/CH ₂ ), 1.81-1.89 (m, 8H, CH ₂ ), 1.90-2.04 (m, 5H, adamantylidene/CH), 2.24 (d, 2H, J = 7.22 Hz, CH ₂ CO), 2.62-2.73 (m, 4H, NCH ₂ ),

3.05 (t, IH, J = 11.6 Hz, NH), 3.85 (t, 2H, J = 13.5 Hz, NCH ₂ ), 4.56 (t, 2H, J = 13.5 Hz, NCH ₂ ) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 23.7, 27.5, 31.0, 32.0, 33.6, 34.4, 37.4, 39.4, 40.7, 44.8, 51.7, 62.1, 108.2, 110.8, 170.5 MS (ES+), [M + Na] ⁺ (100), 475.3 HRMS calculated for 475.3172 C ₂₇ H ₄₃ O ₅ N ₂ Na, found 475.3163.

Tetraoxane 29q

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.20-1.36 (m, 4H, adamantylidene), 1.52-1.83 (m, 12H, adamantylidene/CH ₂ ), 1.86 (s, 2H, CH ₂ ), 1.90-2.02 (m, 5H, adamantylidene/CH), 2.29-2.37 (m, 2H, CH ₂ CO), 2.48 (t, 4H, J = 6.0 Hz, CH ₂ CO), 3.76 (t, 2H, J = 6.3 Hz, NCH ₂ ), 3.90 (t, 2H, J = 6.3 Hz, NCH ₂ ) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 27.5, 33.5, 33.6, 34.2, 37.3, 39.5, 41.2, 41.7, 44.6, 108.1, 110.8, 171.1, 207.1 MS (ES+), [M + Na + CH ₃ OH] ⁺ (100), 474.2 [2M + Na + CH ₃ OH] ⁺ 925.5 HRMS calculated for 474.2468 C ₂₄ H ₃₇ O ₇ NNa, found 474.2480.

Tetraoxane 29r

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.20-1.42 (m, 4H, adamantylidene), 1.50-1.82 (m, 12H, adamantylidene/CH ₂ ), 1.86 (bs, 2H, CH ₂ ), 1.90-2.05 (m, 5H, adamantylidene/CH), 2.64 (d, 2H, J = 6.8 Hz, CH ₂ CO), 6.81 (bs, 2H, NH ₂ ), 8.46 (bs, IH, NH) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 27.5, 28.2, 33.6, 34.3, 36.7, 38.0, 39.5, 41.4, 108.0, 110.9, 173.0 MS (ES+), [M + Na] ⁺ (100), 375.2 HRMS calculated for 375.1896 C ₁₈ H ₂₈ O ₅ N ₂ Na, found 375.1891.

Tetraoxane 29s

¹ H NMR (400MHz, CDCl ₃ ) δ _H> 0.89 (m, 6H, J = 6.46Hz, CH ₃ ), 1.17-1.36 (m, 2H, adamantylidene), 1.50-1.84 (m, 14H, adamantylidene/CH ₂ ), 1.86 bs, 2H, CH ₂ ), 1.90- 2.04 (m, 6H, CH), 2.08 (d, 2H, J = 7.40Hz, CH ₂ CO), 2.20-2.27 (m, 2H, NCH ₂ ), 2.35 (t, 4H, CH ₂ N), 3.45(t, 2H, J - 4.74Hz, NCH ₂ ), 3.62(t, 2H, J = 4.74Hz, NCH ₂ ) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 21.2, 25.8, 27.4, 33.5, 34.4, 37.3, 39.4, 42.1, 46.3, 53.7, 54.2, 67.2, 108.2, 110.8, 170.7 MS (ES+), [M + Na] ⁺ (100), 463.3 HRMS calculated for 463.3172 C ₂₆ H ₄₃ O ₅ N ₂ Na, found 4632.3187.

Tetraoxane 29t

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.22-1.36 (m, 4H, adamantylidene), 1.50-1.82 (m, 13H, adamantylidene/CH ₂ ), 1.86 (bs, 2H, CH ₂ ), 1.91-2.04 (m, 5H, adamantylidene/CH), 2.26 (bs, 2h, CH2CO), 3.40-3.76 ( m, 8H, NCH ₂ /CH ₂ N), 7.38- 7.46 (m, 5H, Ar) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 27.5, 33.5, 33.6, 34.2, 37.4, 39.5, 53.2, 108.1, 110.8, 127.5, 129.0, 130.4, 135.6, 171.0 MS (ES+), [M + Na] ⁺ (100), 533.1 HRMS calculated for 533.2628 C ₂₉ H ₃₈ O ₆ N ₂ Na, found 533.2653.

Tetraoxane 29u

¹ H NMR (400MHz, CDCl ₃ ) δ _H 0.92 (d, 6H, J = 6.6 Hz, CH ₃ ), 1.20-1.35 (m, 4H, adamantylidene), 1.50-1.82 (m, 13H, adamantylidene/CH ₂ ), 1.86 (bs, 2H, CH ₂ ), 1.90-2.04 (m, 5H, adamantylidene/CH), 2.09 (d, 2H, J = 7.22 Hz, CH ₂ CO), 3.09 (t, 2H, J = 6.2 Hz, NCH ₂ ), 5.41 (s, IH, NH) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 20.5, 27.5, 28.9, 33.5, 34.5, 37.4, 44.0, 47.2, 108.1, 110.8, 172.1 MS (ES+), [M + Na] ⁺ (100), 416.1, [2M + Na] ⁺ 809.2 HRMS calculated for 416.2413 C ₂₂ H ₃₅ O ₅ NNa, found 416.2392.

Tetraoxane 29v

¹ H NMR (400MHz, CDCl ₃ ) δ _H> 1.22-1.36 (m, 4H ₅ adamantylidene), 1.50-1.80 (m, 12H, adamantylidene/CH ₂ ), 1.86 (bs, 2H, CH ₂ ), 1.91-2.06 (m, 5H, adamantylidene/CH), 2.28 (d, 2H, J = 7.2 Hz, CH ₂ CO), 3.15 (t, 4H,J = 4.9 Hz, NCH ₂ ), 3.63 (t, 4H, J = 4.9 Hz, CH ₂ N), 3.79 (t, 2H, J = 4.8 Hz, NCH ₂ ), 6.88-6.95 (m, 2H, Ar), 7.25-7.31 (m, 2H, Ar) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 27.5, 33.6, 34.4, 37.4, 39.4, 42.0, 46.1, 49.9, 50.2, 108.I ₅ 110.8, 117.0, 121.0, 130.0, 151.3, 171.0 MS (ES+), [M + Na] ⁺ (100), 523.3 [2M + Na] ⁺ 1024.6 HRMS calculated for 523.2584 C ₂₈ H ₃₇ O ₅ N ₂ Na, found 523.2568.

Tetraoxane 29w

¹ H NMR (400MHz, CDCl ₃ ) δ _Hl 1.22-1.35 (m, 4H, adamantylidene), 1.51-1.82 (m, 12H, adamantylidene/CH ₂ ), 1.86 (bs, 2H, CH ₂ ), 1.91-2.06 (m, 5H, adamantylidene/CH), 2.28 (d, 2H, J = 7.2 Hz, CH ₂ CO), 3.15 (t, 4H ₅ J = 4.9Hz, NCH ₂ ), 3.63 (t, 4H, J = 4.9 Hz, CH ₂ N), 3.77 (t, 2H, J = 4.8 Hz, NCH ₂ ), 6.88-6.95 (m, 3H, Ar), 7.25-7.31(m, 2H, Ar) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 27.5, 33.6, 34.4, 37.4, 39.4, 42.0, 46.2, 49.9, 50.2, 108.1, 110.8, 117.0, 121.0, 129.6, 151.3, 170.8 MS (ES+), [M + Na ] ⁺ (100), 483.2 HRMS calculated for 483.2859 C ₂₈ H ₃₉ O ₅ N ₂ Na, found 483.2881.

Tetraoxane 29x

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.21-1.39 (m, 4H, adamantylidene), 1.51-1.81 (m, 12H, adamantylidene/CH ₂ ), 1.86 (bs, 2H, CH ₂ ), 1.91-2.06 (m, 5H, adamantylidene/CH), 2.16 (d, 2H, J = 7.21 Hz, CH ₂ CO), 6.60 (s, IH ₅ NH), 6.75-6.84

(m, IH, Ar), 6.90 (t, 2H, J = 6.5 Hz, Ar), 7.19-7.19 (m, 2H, Ar), 8.60 (bs, IH, NH) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 27.0, 33.1, 33.2, 33.9, 36.9, 40.9, 107.6, 110.5, 113.6, 121.5, 129.4, 147.9, 171.9 MS (ES+), [M + Na] ⁺ (100), 451.3 [2M + Na] ⁺ 879.6 HRMS calculated for 451.2209 C ₂₄ H ₃₂ O ₅ N ₂ Na, found 451.2213.

Diethyl methylsulfonylmethylphosphonate 33b

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.38 (t, 6H, J = 7.0 Hz, CH ₃ ), 3.21 (s, 3H, SO ₂ CH ₃ ), 3.60 (s, IH, SO ₂ CH ₂ ), 3.64 (s, IH, SO ₂ CH ₂ ), 4.21-4.29 (m, 4H, OCH ₂ ). ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 16.3, 42.7, 51.6, 53.0, 63.8 MS (CI+), [M + NH ₄ ] ⁺ (100), 248 HRMS calculated for 231.0456 C ₆ Hi ₆ O ₅ SP, found 231.0453

8-(methylsulfonylmethylene)-l ,4-dioxaspiro[4.5]decane 33c

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.81 (t, 4H, J = 6.5 Hz, CH ₂ ), 2.42 (t, 4H, J = 6.5 Hz, CH ₂ ), 2.96 (s, 3H, SO ₂ CH ₃ ), 3.98 (s, 4H, OCH ₂ ), 6.17 (s, IH, CH) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 26.1, 35.9, 44.6, 65.0, 107.6, 124.3, 159.6 MS (ES+), [M + Na] ⁺ (100), 255.1 [2M + Na] ⁺ 487.2 HRMS calculated for 255.0667 Ci ₀ H ₁₆ O ₄ SNa, found 255.0648.

8-(methylsulfonylmethyl)-l ,4-dioxaspiro[4.5]decane 33d

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.41-1.79 (m, 5H, cyclohexyl), 1.94-2.18 (m, 4H, cyclohexyl), 2.92 (s, 3H, SO ₂ CH ₃ ), 2.96 (d, 2H, J = 6.5 Hz, CH ₂ SO ₂ ), 3.95 (s, 4H, OCH ₂ ) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 28.5, 29.5, 40.4, 58.6, 62.6, 106.2 MS (ES+), [M + Na ] ⁺ (100), 257.1 HRMS calculated for 257.0824 C ₁₀ H ₁₈ O ₄ SNa, found 257.0836.

Tetraoxane 33f

¹ U NMR (400MHz, CDCl ₃ ) δ _H 1.36-1.50 (m 4H, CH ₂ ), 1.51-1.68 (m, 1OH, CH ₂ ), 1.71-2.34 (m, 5H, CH ₂ /CH), 2.92 (s, 3H, SO ₂ CH ₃ ), 2.95 (d, 2H, CH ₂ SO ₂ ) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 23.8, 26.2, 30.0, 30.2, 32.3, 35.5, 43.0, 60.9, 107.9, 109.4 MS (ES+), [M + Na ] ⁺ (100), 343.1 HRMS calculated for 343.1191 C ₁₄ H ₂₄ O ₆ SNa, found 343.1198.

Tetraoxane 33g

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.06-1.38 (m, 4H, adamantylidene), 1.41-1.78 (m, 12H, adamantylidene/CH ₂ ), 1.87 (bs, 2H, CH ₂ ), 1.91-2.06 (m, 5H, adamantylidene/CH), 2.92 (s, 3H, SO ₂ CH ₃ ), 2.95 (d, 2H, J = 5.9 Hz, CH ₂ SO ₂ ) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 26.1, 27.5, 29.0, 31.8, 33.1, 33.5, 37.3, 42.5, 60.5, 107.3, 111.0 MS (ES+), [M + Na ] ⁺ (100), 395.2 HRMS calculated for 395.1504 C ₁₈ H ₂₈ O ₆ SNa, found 395.1482.

l-benzoylpiperidin-4-one 34b

u _max (neatycm ^"1 3089.1, 2958.5, 2877.0, 1714.0, 1632.5, 1433.2, 1365.3, 1315.5, 1274.7, 1243.0, 1143.4, 708.7 ¹ H NMR (400MHz, CDCl ₃ ) δ _H 2.50 (bs, 4H, CH ₂ CO), 3.89 (bs, 4H, NCH ₂ ), 7.41-7.49 (m, 5H, Ar) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 41.6, 42.4, 127.4, 129.0, 130.6, 135.6, 171.3, 207.0

1 -(pyrrolidin- 1 -carbonyl)piperidin-4-one 34c

υ _max (neatycm ^'1 2963.9, 2871.3, 1714.6, 1629.8, 1467.8, 1421.6, 1340.6, 1228.8, 1190.2, 1132.4, 750.6 ¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.85-1.90 (m, 4H, CH ₂ ), 2.49 (t, 4H, J = 6.3 Hz, CH ₂ CO), 3.43 (t, 4H, J = 6.7Hz, NCH ₂ ), 3.58 (t, 4H, J = 6.3 Hz, CH ₂ N) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 25.9, 41.8, 46.0, 48.3, 48.9, 162.6, 208.6

iV,iV-diethyl-4-oxopiperidine- 1 -carboxamide 34d

υ _ma χ (neatycm ^"1 2965.8, 2928.3, 2872.1, 1714.8, 1639.8, 1419.7, 1358.8, 1260.5, 1166.8, 1101.2, 979.4, 773.4 ¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.16 (t, 6H, J = 7.0 Hz, CH ₃ ), 2.49 (t, 4H, J = 6.3 Hz, CH ₂ CO), 3.29 (q, 4H, J = 7.0 Hz, NCH ₂ ), 3.50 (t, 4H, J = 6.1 Hz, CH ₂ N) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 13.3, 41.4, 42.0, 46.7, 164.0, 208.1 MS (CI+), [M + H ] ⁺ (100), 199 HRMS calculated for 199.1447 C ₁₀ H ₁₉ O ₂ N ₂ , found 199.1452

1 -(piperidine- 1 -carbonyl)piperidin-4-one 34e

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.50-1.68 (m, 6H, CH ₂ ), 2.48 (t, 4H, J = 6.3 Hz, CH ₂ CO), 3.27 (t, 4H, J = 5.7 Hz, NCH ₂ ), 3.52 (t, 4H, J = 6.1Hz, NCH ₂ ) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 25.1, 26.1, 41.8, 46.9, 48.3, 164.2, 208.4

1 -(Morpholine-4-carbonyl)-piperidin-4-one 34f

δ _H (400 MHz, CDCl ₃ ), 3.75 (4H, m, 4Hl), 3.60 (4H, t, J 6.3, 4H3), 3.31 (4H, m, 4H2), 2.50 (4H, t, J 6.2, 4H4); δ _c (100MHz, CDCl ₃ ), 207.8, 163.8, 67.0, 47.8, 46.7, 41.6; m/z (CI, +ve, NH ₃ ), 213 ([M+H] ⁺ , 100%); Found [M+H] ⁺ , 213.12448, C ₁₀ H ₁₇ N ₂ O ₃ requires 213.12392.

4-oxo-λζ JV-diphenylpiperidine- 1 -carboxamide 34g

IW (neatVcm ^"1 3013.4, 2965.8, 2861.1, 1711.9, 1650.0, 1588.2, 1493.0, 1412.1, 1264.5, 1212.2, 755.3 ¹ HNMR (400MHz, CDCl ₃ ) δ _H 2.3 (t, 4H, J = 6.3 Hz, CH ₂ CO), 3.63 (t, 4H, J = 6.3 Hz, CH ₂ N), 7.09 (d, 2H, J = 7.4 Hz, Ar), 7.15 (t, 4H, 7.4 Hz, Ar), 7.32 (t, 4H, 7.4 Hz, Ar) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 41.1, 45.1, 125.7, 129.8,

160.3, 207.5, MS (ES+), [M + Na + CH ₃ OH] ⁺ (100), 349.1 HRMS calculated for 349.15289 C ₁₉ H ₂₂ O ₃ N ₂ Na, found 349.1513.

1 -(4-trifluoromethyl)benzoyl)piperidin-4-one 34h

υ _max (neatycm ^"1 2964.1, 2908.5, 2871.4, 1712.2, 1638.0, 1512.8, 1438.6, 1322.7, 1123.3, 1016.6, 974.9, 849.7 ¹ H NMR (400MHz, CDCl ₃ ) δ _H 2.53 (bs, 4H, CH ₂ CO), 3.60-4.14 (m, 4H, CH ₂ N), 7.59 (d, 2H, J = 8.0 Hz, Ar), 7.72 (d, 2H, J = 8.0 Hz, Ar) ¹³ C NMR (IOOMHZ, CDCl ₃ ), δ _c 41.4, 46.5, 125.4, 126.2, 126.2, 127.7, 139.1, 169.8, 206.3 MS (ES+), [M + Na + CH ₃ OH ] ⁺ (100), 326.1 HRMS calculated for 326.0980 C ₁₄ Hi ₆ O ₃ NF ₃ , found 326.0982.

(4 ₅ 4-dihydroperoxypiperidin-l-yl)(piperidin-l-yl)methanone 34i

¹ HNMR (400MHz, CDCl ₃ ) δ _H 1.42-1.59 (m, 6H, CH ₂ ), 1.74 (t, 4H ₅ J = 5.7Hz, CH ₂ ), 3.01-3.15 (m, 4H, NCH ₂ ), 3.28-3.35 (m, 4H, NCH ₂ ), 11.13 (s, 2H, OH), ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 24.6, 25.7, 29.9, 43.7, 47.6, 107.1, 163.4 MS (ES+), [M + Na ] ⁺ (100), 283.1 [2M + Na ] ⁺ 543.1 HRMS calculated for 283.1270 C ₁₁ H ₂₀ O ₅ N ₂ Na, found 283.1282.

Tetraoxane 34j

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.50-1.90 (m, 14H, adamantylidene/CH ₂ ), 1.91-2.05 (m, 8H, CH ₂ ), 3.15-3.22 (m, 4H, CH ₂ N), 3.26-3.37 (m, 4H, NCH ₂ ) ¹³ C NMR (100MHz, CDCl ₃ ), δc 25.1, 26.1, 27.7, 33.5, 34.2, 36.2, 36.7, 37.3, 39.7, 107.1,

111.1, 164.4 MS (ES+), [M + Na ] ⁺ (100), 415.2 [2M + Na ] ⁺ 807.5 HRMS calculated for 415.2209 C ₂₁ H ₃₂ O ₅ N ₂ Na, found 415.2209

Tetraoxane 34k

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.44-1.51 (m, 4H, CH2), 1.52-1.65 (m, 12H, CH ₂ ), 2.15-2.51 (m, 4H, CH ₂ ), 3.17-3.21 (m, 4H, CH ₂ N), 3.26-3.33 (m, 4H, NCH ₂ ) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 22.4, 25.1, 25.7, 26.1, 30.1, 32.1, 48.3, 107.2, 109.0, 164.4 MS (ES+), [M + Na ] ⁺ (100), 363.2 [2M + Na ] ⁺ 703.4 HRMS calculated for 363.1896 C ₁₇ H ₂₈ O ₅ N ₂ Na, found 363.1879.

Tetraoxane 341

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.36-1.51 (m, 2H, CH ₂ ), 1.54-1.75 (m, 12H, CH ₂ ), 1.79-1.88 (m, 4H, CH ₂ ), 2.20-2.50 (m, 4H, NCH ₂ ), 3.36 (t, 4H, J = 6.7 Hz, CH ₂ N) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 21.3, 24.7, 25.7, 28.7, 34.0, 48.8, 107.2, 109.0, 162.9 MS (ES+), [M + Na ] ⁺ (100), 349.1 [2M + Na ] ⁺ 675.2 HRMS calculated for 349.1739 C ₁₆ H ₂₆ O ₅ N ₂ Na, found 349.1737.

Tetraoxane 34m

¹ H NMR (400MHz, CDCl ₃ ) δ _H) 1.12 (t, 6H, J = 7.2 Hz, CH ₃ ), 1.43-1.81 (m, 6H, cyclohexyl), 2.20-2.51 (m, 4H, cyclohexyl), 3.20 (q, 4H, J = 7.0Hz, NCH ₂ ), 3.28 (bs, 4H, NCH ₂ ), ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 13.6, 22.4, 25.7, 30.1, 31.8, 42.3, 44.4,

107.2, 109.0, 164.6 MS (ES+), [M + Na ] ⁺ (100), 351.1 [2M + Na ] ⁺ 679.3 HRMS calculated for 351.1896 C ₁₆ H ₂₈ O ₅ N ₂ Na, found 351.1899.

Tetraoxane 34n

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.13-1.19 (m, 1OH, CH ₂ ), 2.14-2.66 (m, 4H, CH ₂ ), 3.44 (bs, 2H, CH ₂ N), 3.82 (bs, 2H, CH ₂ N), 7.52 (d, 2H, J = 8.1 Hz, Ar), 7.69 (d, 2H, J = 8.1 Hz, Ar) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 22.4, 25.7, 29.9, 30.6, 44.8, 106.6, 109.4, 132.4, 125.4, 127.7, 126.1, 139.6, 169.3 MS (ES+), [M + Na ] ⁺ (100), 424.1 [2M + Na ] ⁺ 825.2 HRMS calculated for 424.1348 C ₁₉ H ₂₂ O ₅ NNa, found 424.1364.

Tetraoxane 34o

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.56-1.76 (m, 4H, adamantylidene) 1.83-2.24 (m, 19H, adamantylidene/CH ₂ ), 3.45(t, 4H, J = 5.9Hz, CH ₂ N), 7.04 (d, 2H, J = 7.4Hz, Ar), 7.13 (t, IH, J = 7.4Hz, Ar), 7.30 (t, 2H, J = 7.4Hz, Ar) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 27.4, 27.9, 31.38, 33.5, 36.7, 37.3, 39.7, 106.7, 111.2, 125.3, 125.5, 129.7, 145.3, 160.1 MS (ES+), [M + Na ] ⁺ (100), 499.2 HRMS calculated for 499.2209 C ₂₈ H ₃₂ O ₅ N ₂ Na, found 499.2206.

Tetraoxane 34p

δ _H (400 MHz, CDCl ₃ ), 3.70 (4H, t, J4.3, 4H3), 3.30 (4H, m, 4Hl), 3.20 (4H, t, J4.5, 4H4), 2.50 (2H, bs, 2H2a), 1.50-2.05 (16H, m, 2H2b and adamantane); δ _c (100MHz, CDCl ₃ ), 163.9, 111.2, 106.8, 67.0, 47.8, 42.5, 37.3, 33.5, 31.8, 30.6, 27.4; m/z (ES, +ve, CH ₃ OH), 417 ([M+Na] ⁺ , 100%); Found [M+Na] ⁺ , 417.1982, C ₂₀ H ₃₀ N ₂ O ₆ Na requires 417.2002.

Tetraoxane 35d

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.55-2.21 (m, 14H, adamantylidene), 3.07 (bs, 2H ₅ CH ₂ ), 3.81(bs, 2H, CH ₂ ), 7.17 (bs, 4H, Ar) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 27.5, 32.7, 33.6, 37.5, 41.1, 110.2, 111.1, 125.2, 127.2, 139.5 MS (ES+), [M + Na ] ⁺ (100), 337.1[2M + Na ] ⁺ 651.2 HRMS calculated for 337.1416 C ₁₉ H ₂₂ O ₄ Na, found 337.1416.

Tetraoxane 36c

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.34-1.66 (m, 6H, cyclohexyl), 1.70-1.98 (m, 4H, cyclohexyl), 2.19-2.46 (m, 2H, CH ₂ ), 2.76-3.04 (m, 4H, CH2), 7.11 (bs, 4H, Ar) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 22.5, 23.1, 25.8, 27.9, 31.9, 35.8, 108.2, 109.0, 126.2, 129.3, 133.9, 136.6 MS (ES+), [M + Na ] ⁺ (100), 299.1 [2M + Na ] ⁺ 575.2 HRMS calculated for 299.1259 Ci ₆ H ₂₀ O ₄ Na, found 199.1271.

Tetraoxane 36d

¹ H NMR (400MHz, CDCl ₃ ) δ _H 1.20-1.34 (m, 4H, adamantylidene), 1.55-1.80 (m, 6H, adamantylidene), 1.86 (bs, 2H, CH ₂ ), 1.91-2.07 (m, 4H, CH), 2.55-2.35(m, 4H, CH ₂ ), 7.14 (bs, 4H, Ar) ¹³ C NMR (100MHz, CDCl ₃ ), δ _c 23.1, 27.5, 32.0, 33.6, 37.4, 108.8, 110.9, 128.7, 129.3, 133.7, 136.4 MS (ES+), [M + Na ] ⁺ (100), 351.1 [2M + Na ] ⁺ 679.3 HRMS calculated for 351.1572 C ₂₀ H ₂₄ O ₄ Na, found 351.1567.

1 -methanesulfonyl-piperidin-4-one 38a

δ _H (400 MHz, CDCl ₃ ), 3.60 (4H, m, 4Hl), 2.91 (3H, s, CH ₃ ), 2.55 (4η, m, 4H2); δ _c (100MHz, CDCl ₃ ), 205.8, 46.0, 41.5, 37.2; m/z (CI, +ve, NH ₃ ), 195 ([M+NH ₃ ] ⁺ , 100%); Found [M+NH ₃ ] ⁺ , 195.08052, C ₆ Hi ₅ N ₂ O ₃ S requires 195.08035.

1 -ethanesulfonyl-piperidin-4-one 38b

δ _H (400 MHz, CDCl ₃ ), 3.71 (4H, m, 4Hl), 3.10 (2H, q, J 7.4, CH ₂ ), 2.62 (4η, m, 4H2), 1.45 (3H, t, J7.4, CH ₃ ); δ _c (100MHz, CDCl ₃ ), 206.3, 46.2, 46.1, 42.2, 8.4; m/z (CI, +ve, NH ₃ ), 209 ([M+NH ₃ ] ⁺ , 100%); Found [M+NH ₃ ] ⁺ , 209.09640, C ₇ H ₁₇ N ₂ O ₃ S requires 209.09599.

l-(propane-2-sulfonyl)-piperidin-4-one 38c

δ _H (400 MHz, CDCl ₃ ), 3.68 (4H, m, 4Hl), 3.25 (IH, m, CH(CH ₃ ) ₂ ), 2.55 (4H, m, 4H2), 1.35 (6H, d, J6.9, (CH ₃ ) ₂ ); δ _c (100MHz, CDCl ₃ ), 206.7, 54.6, 46.6, 42.7, 17.7.

1 -cyclopropylsulfonyl-piperidin-4-one 38d

δ _H (400 MHz, CDCl ₃ ), 3.65 (4H, m, 4Hl), 2.55 (4H, m, 4H2), 2.31 (IH, m, CH ₂ CHCH ₂ ), 1.20 (2H, m, CH ₂ CHCH ₂ ), 1.05 (2H, m, CH ₂ CHCH ₂ ); δ _c (100MHz, CDCl ₃ ), 206.1, 46.3, 41.7, 27.7, 5.1; m/z (CI, +ve, NH ₃ ), 221 ([M+NH ₃ ] ⁺ , 100%); Found [M+NH ₃ ] ⁺ , 221.09643, C ₈ H ₁₇ N ₂ O ₃ S requires 221.09599.

1 -(2,2,2-trifluoroethanesulfonyl)-piperidin-4-one 38e

δ _H (400 MHz, CDCl ₃ ), 3.94 (2H, m, CH ₂ CF ₃ ), 3.71 (4η, m, 4Hl), 2.59 (4H, m, 4H2); δ _c (100MHz ₅ CDCl ₃ ), 205.1, 122.2, 54.4, 54.1, 45.7, 41.9; m/z (ES, -ve,

CH ₃ OH), 244 ([M-H] ^" , 100%); Found [M-H] ^" , 244.0255, C ₈ H ₉ NO ₃ F ₃ S requires 244.0246.

1 -benzenesulfonyl-piperidin-4-one 38f

δ _H (400 MHz, CDCl ₃ ), 7.84-7.51 (5H, m, aromatic), 3.45 (4H, m, 4Hl), 2.50 (4H, m, 4H2); δ _c (100MHz, CDCl ₃ ), 205.8, 133.6, 129.7, 127.9, 127.4, 46.3, 41.1; m/z (CI, +ve, NH ₃ ), 257 ([M+NH ₃ ] ⁺ , 100%); Found [M+NH ₃ ] ⁺ , 257.09645, C ₁₁ H ₁₇ N ₂ O ₃ S requires 257.09598.

1 -(4-fluoro-benzenesulfonyl)-piperidin-4-one 38g

δ _H (400 MHz, CDCl ₃ ), 7.90-7.15 (4H, m, aromatic), 3.40 (4H, m, 4Hl), 2.55 (4H, m, 4H2); δ _c (100MHz, CDCl ₃ ), 205.5, 130.6, 130.5, 117.1, 116.9, 46.2, 41.1; m/z (CI, +ve, NH ₃ ), 275 ([M+NH ₃ ] ⁺ , 100%); Found [M+NH ₃ ] ⁺ , 275.08711, C ₁₁ H ₁₆ FN ₂ O ₃ S requires 275.08655.

1 -(4-chloro-beiizenesulfonyl)-piperidin-4-one 38h

δ _H (400 MHz, CDCl ₃ ), 7.80-7.45 (4H ₅ m, aromatic), 3.40 (4H, m, 4Hl), 2.55 (4H, m, 4H2); δ _c (100MHz, CDCl ₃ ), 205.4, 140.3, 135.6, 130.1, 129.3, 46.2, 41.1; m/z (CI, +ve, NH ₃ ), 291 ([M+NH ₃ ] ⁺ , 100%); Found [M+NH ₃ ] ⁺ , 291.05742, C ₁₁ H ₁₆ ClN ₂ O ₃ S requires 291.05704.

1 -(4-trifluoromethyl-benzenesulfonyl)-piperidin-4-one 38i

δ _H (400 MHz, CDCl ₃ ), 8.25-7.70 (4H, m, aromatic), 3.45 (4H, m, 4Hl), 2.55 (4H, m, 4H2); δ _c (100MHz, CDCl ₃ ), 205.1, 128.4, 128.0, 127.4, 127.3, 126.9, 46.2, 41.1; m/z (CI, +ve, NH ₃ ), 325 ([M+NH ₃ ] ⁺ , 100%); Found [M+NH ₃ ] ⁺ , 325.08377, Ci ₂ H ₁₆ F ₃ N ₂ O ₃ S requires 325.08337.

1,2,4,5-tetraoxane 39a

δ _H (400 MHz, CDCl ₃ ), 3.22-3.45 (4H, m, 4Hl), 2.80 (3H, s, CH ₃ ), 2.52 (2η, s, 2H2a), 1.51-2.23 (16H, m, 2H2b and adamantane); δ _c (100MHz, CDCl ₃ ), 111.6, 105.8, 41.6, 37.2, 36.2, 34.2, 33.5, 31.4, 27.4, 26.2. m/z (ES, +ve, CH ₃ OH), 382 ([M+Naf, 100%); Found [M+Na] ⁺ , 382.1313, C ₁₆ H ₂₅ NO ₆ NaS requires 382.1300.

1, 2,4,5 -tetraoxane 39b

δ _H (400 MHz, CDCl ₃ ), 3.22-3.45 (4H, m, 4Hl), 2.95 (2H, q, J 7.4, CH ₂ CH ₃ ), 2.50 (2H, s, 2H2a), 1.51-2.23 (16H, m, 2H2b and adamantane), 1.35 (3H, t, J 7.4, CH ₂ CH ₃ ); δ _c (lOOMηz, CDCl ₃ ), 111.5, 106.0, 44.9, 37.2, 36.2, 33.5, 31.35, 30.6, 27.4, 8.3. m/z (ES, +ve, CH ₃ OH), 396 ([M+Na] ⁺ , 100%); Found [M+Naf, 396.1447, C ₁₇ H ₂₇ NO ₆ NaS requires 396.1457.

l,2,4,5-tetraoxane 39c

δ _H (400 MHz, CDCl ₃ ), 3.22-3.35 (4H, m, 4Hl), 3.15 (IH, m, CH ₃ CHCH ₃ ), 2.50 (2H, s, 2H2a), 1.51-2.10 (16H, m, 2H2b and adamantane), 1.31 (6H, d, J 6.9, CH ₅ CHCH ₃ ); δ _c (lOOMηz, CDCl ₃ ), 111.5, 106.0, 54.1, 44.9, 37.3, 33.5, 32.0, 27.4, 23.0, 17.1, 14.5. m/z (ES, +ve, CH ₃ OH), 410 ([M+Naf, 100%); Found [M+Naf, 410.1600, C ₁₈ H ₂₉ NO ₆ NaS requires 410.1613.

1,2,4,5-tetraoxane 39d

δ _H (400 MHz, CDCl ₃ ), 3.30-3.50 (4H, m, 4Hl), 2.50 (2H, s, 2H2a), 2.20 (IH, m, CH ₂ CHCH ₂ ), 1.51-2.10 (16H, m, 2H2b and adamantane), 1.15 (2H, m, CH ₂ CHCH ₂ ), 0.95 (2H, m, CH ₂ CHCH ₂ ); δ _c (lOOMηz, CDCl ₃ ), 111.5, 106.0, 54.1, 44.9, 37.3,

33.5, 32.0, 27.4, 26.5, 4.8. m/z (ES, +ve, CH ₃ OH), 408 ([M+Naf, 100%); Found [M+Naf, 408.1438, C ₁₈ H ₂₇ NO ₆ NaS requires 408.1457.

1,2,4,5-tetraoxane 39e

δ _H (400 MHz, CDCl ₃ ), 3.70 (2H, q, J 9.3, CH ₂ CF ₃ ), 3.30-3.60 (4H, m, 4Hl), 2.50 (2H, s, 2H2a), 1.51-2.23 (16H, m, 2H2b and adamantane); δ _c (100MHz ₅ CDCl ₃ ), 110.2, 104.3, 52.2, 51.9, 35.9, 32.1, 31.35, 30.6, 27.4, -1.0. m/z (ES, +ve, CH ₃ OH), 450 ([M+Naf, 100%); Found [M+Na] ⁺ , 450.1156, C ₁₇ H ₂₄ NO ₆ F ₃ NaS requires 450.1174.

1,2,4,5-tetraoxane 39f

δ _H (400 MHz, CDCl ₃ ), 7.50-7.85, (5H, aromatics), 3.01-3.25, (4H, m, 4Hl), 2.51, (2H, s, 2H2a), 1.51-2.20 (16H, m, 2H2b and adamantane); δ _c (100MHz, CDCl ₃ ), 136.6, 133.4, 129.6, 128.0, 111.5, 105.8, 47.4, 39.7, 37.2, 36.7, 33.4, 27.8, 27.3; m/z (ES, +ve, CH ₃ OH), 444 ([M+Naf, 100%); Found [M+Naf, 444.1445, C ₂₁ H ₂₇ NO ₆ NaS requires 444.1457.

1,2,4,5-tetraoxane 39g

δ _H (400 MHz, CDCl ₃ ), 7.10-7.80, (4H, aromatics), 3.05-3.25, (4H, m, 4Hl), 2.55, (2H, s, 2H2a), 1.55-2.10 (16H, m, 2H2b and adamantane); δ _c (100MHz, CDCl ₃ ), 130.7, 130.6, 117.0, 116.7, 111.5, 105.6, 47.4, 39.7, 37.2, 36.7, 33.4, 32.0, 27.3; m/z (ES, +ve, CH ₃ OH), 462 ([M+Naf, 100%); Found [M+Naf, 462.1341, C ₂₁ H ₂₆ NO ₆ FNaS requires 462.1363.

1,2,4,5-tetraoxane 39h

δ _H (400 MHz, CDCl ₃ ), 7.50-7.85, (4H, aromatics), 3.05-3.25, (4H, m, 4Hl), 2.55, (2H, s, 2H2a), 1.55-2.10 (16H, m, 2H2b and adamantane); δ _c (100MHz ₅ CDCl ₃ ), 140.0, 129.9, 129.4, 124.0, 111.5, 105.6, 47.4, 39.7, 37.2, 36.7, 33.4, 32.0, 27.3; m/z (ES, +ve, CH ₃ OH), 478 ([M+Naf, 100%); Found [M+Naf, 478.1081, C ₂₁ H ₂₆ NO ₆ NaSCl requires 478.1067.

1,2,4,5-tetraoxane 39i

δ _H (400 MHz, CDCl ₃ ), 7.75-7.95, (4H, aromatics), 3.05-3.25, (4H, m, 4Hl), 2.55, (2H, s, 2H2a), 1.55-2.10 (16H, m, 2H2b and adamantane); δ _c (100MHz, CDCl ₃ ), 128.4, 128.0, 127.3, 127.3, 126.9, 116.8, 111.4, 47.4, 39.7, 37.2, 36.7, 33.4, 32.0, 27.3; m/z (ES, +ve, CH ₃ OH), 512 ([M+Na] ⁺ , 100%); Found [M+Na] ⁺ , 512.1346, C ₂₂ H ₂₆ NO ₆ F ₃ NaS requires 512.1331.

1,2,4,5-tetraoxane 40a

δ _H (400 MHz, CDCl ₃ ), 3.25-3.42, (4H, m, 4Hl), 2.80, (3H, s, CH ₃ ), 2.50 (2H, bs, 2H2a), 2.25 (2H, m, 2H3a), 1.85 (2H, bs, 2H2b), 1.60 (2H, m, 2H3b), 1.21-1.49 (18H, m, dodecane ring); δ _c (100MHz, CDCl ₃ ), 113.5, 105.7, 43.3, 42.1, 35.5, 29.9, 29.5, 26.3, 22.6, 19.8, 18.4; m/z (ES, +ve, CH ₃ OH), 414 ([M+Naf, 100%); Found [M+Naf, 414.1926, C ₁₈ H ₃₃ NO ₆ NaS requires 414.1926.

1,2,4,5-tetraoxane 40b

δ _H (400 MHz, CDCl ₃ ), 3.31-3.50, (4H, m, 4Hl), 2.95, (2H, q, J 7.4, CH ₂ CH ₃ ), 2.50 (2H, bs, 2H2a), 2.25 (2H, bs, 2H3a), 1.85 (2H, bs, 2H2b), 1.60 (2H, m, 2H3b), 1.28 (3H, t, J 7.4, CH ₂ CH ₃ ), 1.31-1.49 (18H, m, dodecane ring); δ _c (lOOMHz, CDCl ₃ ), 113.5, 106.0, 44.9, 42.1, 35.5, 29.9, 26.4, 26.2, 22.6, 19.8, 8.26; m/z (ES ₅ +ve, CH ₃ OH), 428 ([M+Naf, 100%); Found [M+Naf, 428.2100, C ₁₉ H ₃₅ NO ₆ NaS requires 428.2083.

1,2,4,5-tetraoxane 40c

δ _H (400 MHz, CDCl ₃ ), 3.31-3.50, (4H, m, 4Hl), 3.15, (2H, m, CH ₃ CHCH ₃ ), 2.50 (2H, bs, 2H2a), 2.25 (2H, bs, 2H3a), 1.85 (2H, bs, 2H2b), 1.60-1.20 (26H, m, 2H3b, CH ₃ CHCH ₃ , dodecane ring); δ _c (100MHz, CDCl ₃ ), 113.5, 105.9, 54.2, 44.8, 42.0, 35.3, 29.9, 26.3, 26.1, 22.6, 19.7, 17.7; m/z (ES, +ve, CH ₃ OH), 442 ([M+Naf, 100%); Found [M+Naf, 442.2256, C ₂₀ H ₃₇ NO ₆ NaS requires 442.2239.

1,2,4,5-tetraoxane 4Od

δ _H (400 MHz, CDCl ₃ ), 7.95-7.45 (5H, m, aromatics), 3.05-3.35, (4H, m, 4Hl), 2.50 (2H, bs, 2H2a), 2.25 (2H, bs, 2H3a), 1.85 (2H, bs, 2H2b), 1.62 (2H, m, 2H3b), 1.21- 1.49 (18H, m, dodecane ring); δ _c (100MHz, CDCl ₃ ), 136.5, 133.4, 129.6, 128.0, 113.4, 105.7, 43.7, 42.4, 31.6, 29.7, 26.5, 26.2, 23.1, 19.7; m/z (ES, +ve, CH ₃ OH),

476 ([M+Naf, 100%); Found [M+Naf, 476.2097, C ₂₃ H ₃₅ NO ₆ NaS requires 476.2083.

8-Aza-bicyclo[3.2.1]octan-3-one 41b

δ _H (400 MHz, CDCl ₃ ), 10.45 (IH, bs, NH), 4.35, (2H, m, 2H2), 3.30 (2H, m, 2HIa), 2.51 (2H, m, 2HIb), 2.40 (2H, m, 2H3a), 1.90 (2H, m, 2H3b); δ _c (100MHz, CDCl ₃ ), 202.4, 55.2, 46.7, 27.6; m/z (CI, +ve, NH ₃ ), 126 ([M+H] ⁺ , 100%); Found [M+H] ⁺ , 126.09203, C ₇ H ₁₂ NO requires 126.09189.

δ-Ethanesulfonyl-δ-aza-bicyclofS^.ljoctan-S-one 41c

δ _H (400 MHz, CDCl ₃ ), 4.40, (2H, m, 2H2), 3.10 (2H, q, J 7.4, CH ₂ CH ₃ ), 2.80 (2H, m, 2HIa), 2.41 (2H, m, 2HIb), 2.15 (2H, m, 2H3a), 1.80 (2H, m, 2H3b), 1.39 (3H, t, J 7.4, CH ₂ CH ₃ ) ; δ _c (100MHz, CDCl ₃ ), 207.2, 56.7, 50.3, 48.8, 30.5, 8.8; m/z (CI, +ve, NH ₃ ), 235 ([M+NH ₃ ] ⁺ , 100%); Found [M+NH ₃ ] ⁺ , 235.11197, C ₉ H ₁₉ N ₂ O ₃ S requires 235.11163.

Tropinone derived 1,2,4,5-tetraoxane 4 Id

δ _H (400 MHz, CDCl ₃ ), 4.30, (2H, bs, 2H2), 3.20 (2H, m, 2HIa) ₃ 3.10 (2H, m, 2HIb), 3.00 (2H, q, J 7.3, CH ₂ CH ₃ ), 2.15 (2H, m, 2H3a), 1.50-2.01 (16H, m, 2H3b and adamantane), 1.39 (3H, t, J7.3, CH ₂ CH ₃ ); δ _c (100MHz, CDCl ₃ ), 111.1, 106.9, 56.2, 48.8, 38.0, 37.3, 36.5, 33.5, 30.1, 27.4, 8.8; m/z (ES, +ve, CH ₃ OH), 422 ([M+Naf, 100%); Found [M+Na] ⁺ , 422.1592, Ci ₉ H ₂₉ NO ₆ NaS requires 422.1613.

REFERENCES

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