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The left ring system is spiro, and the right-hand substituent is $\mathrm{CH}(\mathrm{OMe})\mathrm{Me}$, not OMe directly attached to the cyclohexene ring. Let $Q$ denote the right cyclohexenyl group bearing that methoxyethyl substituent cis to its linker. The connection to the left alkene carbon is $-(\mathrm{C}{\mathrm{H}}_2{)}_3-\mathrm{Q}$. These observations suggest two Diels–Alder constructions. A left-hand dienehas the original cyclopentane carbon as one terminal diene atom; cycloaddition with an ethylene equivalent gives the spiro six-membered ring. Its residual double bond is between the two internal diene atoms, putting the linker on the required alkene carbon.

Build $Q$ and its four-carbon alcohol appendage first. Protect the OH group of the indicated 4-Bromobutan-1-ol, for example as a THP ether. Convert the primary bromide to its grignard reagent and formylate with DMF, giving $\mathrm{THPOC}{\mathrm{H}}_2(\mathrm{C}{\mathrm{H}}_2{)}_3\mathrm{CHO}$. olefination with an allylidenetriphenylphosphorane, $\mathrm{P}{\mathrm{h}}_3\mathrm{P}=\mathrm{CHCH}=\mathrm{C}{\mathrm{H}}_2$, supplies a conjugated diene $\mathrm{THPOC}{\mathrm{H}}_2(\mathrm{C}{\mathrm{H}}_2{)}_3\mathrm{CH}=\mathrm{CHCH}=\mathrm{C}{\mathrm{H}}_2$; select the required diene geometry rather than assume a single E/Z outcome.

Cycloaddition with methyl vinyl ketone produces a cyclohexene with a protected four-carbon alcohol chain at one saturated ring carbon and an acetyl group at its adjacent ring carbon. Choose and isolate the adjacent-substituent cis regioisomer, matching the two dashed substituent bonds in the target. Endo preference and diene geometry can aid the selection, but an unsymmetrical diene is not guaranteed to give a unique regioisomer. Reduce the acetyl ketone to $\mathrm{CH}(\mathrm{OH})\mathrm{Me}$, then methylate that alcohol with sodium hydride/methyl iodide while the chain-end OH is protected. Remove the THP group under mild acid conditions to reveal $\mathrm{Q}(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{OH}$, preserving the secondary methyl ether and the ring alkene.

Oxidize this primary alcohol to $\mathrm{Q}(\mathrm{C}{\mathrm{H}}_2{)}_3\mathrm{CHO}$. Add vinylmagnesium bromide to give $\mathrm{Q}(\mathrm{C}{\mathrm{H}}_2{)}_3\mathrm{CH}(\mathrm{OH})\mathrm{CH}=\mathrm{C}{\mathrm{H}}_2$, then oxidize the allylic alcohol to the enone $\mathrm{Q}(\mathrm{C}{\mathrm{H}}_2{)}_3\mathrm{C}(=\mathrm{O})\mathrm{CH}=\mathrm{C}{\mathrm{H}}_2$. This carbonyl carbon is the original alcohol-end carbon of 4-bromobutanol; after olefination it will be the linker-bearing carbon of the left ring alkene.

In the other branch, reduce the specified cyclopentanone to cyclopentanol, convert to bromocyclopentane, and react with triphenylphosphine to obtain the cyclopentylphosphonium salt. Deprotonation gives the cyclopentylidene phosphorane, whose ylidic carbon is part of the five-membered ring. Wittig olefination of the just-prepared enone gives the substituted diene displayed above. This carbonyl–ylide pairing keeps the ring carbon terminal in the diene and avoids accidentally constructing a fused ring instead of a spiro ring.

Finally, cycloadd an ethylene equivalent. Ethylene itself requires suitably forcing/high-pressure conditions; a more reactive alternative is phenyl vinyl sulfone, followed by reductive removal of the sulfone substituent using a method compatible with the methyl ether and retained C=C bonds. The latter installs the same two otherwise unsubstituted saturated carbons. Control or separate any additional cycloaddition isomers, and retain the previously selected cis configuration on $Q$.

The carbon count provides a strong check: cyclopentanone supplies five, bromobutanol four, DMF formylation one, the first allylidene ylide three, methyl vinyl ketone four, O-methylation one, vinylmagnesium two, and the final ethylene equivalent two, totalling 22 target carbons. Three original bromobutanol carbons form the linker; its fourth becomes the substituted carbon of the spiro ring's alkene. The proposal is a multistep constitutional/relative-stereochemical route with explicit regioisomer and diastereomer selection, not an unsupported claim of a single quantitative cycloaddition product.

Schwartz reagent adds syn across the terminal alkene, placing zirconium at its terminal carbon and hydrogen at the substituted carbon. The organozirconium intermediate is $\mathrm{PhCH}(\mathrm{OMe})\mathrm{CH}(\mathrm{Me})\mathrm{C}{\mathrm{H}}_2\mathrm{ZrC}{\mathrm{p}}_2\mathrm{Cl}$. The two faces of the achiral starting alkene give enantiomeric organometallic intermediates.

Boron trifluoride coordinates the ether oxygen, making the benzylic C–OMe bond susceptible to cleavage. The C–Zr bond then transfers its carbon terminus intramolecularly to the benzylic carbon as the activated methoxy group departs, closing a cyclopropane. This can be represented as a concerted, strongly assisted displacement rather than requiring a freely equilibrating long-lived benzylic carbocation. hydrozirconation fixes the relative disposition of the new C–H and C–Zr bonds, and the preferred closure conformation places the bulky phenyl and methyl groups on opposite faces. The result is racemic trans-1-methyl-2-phenylcyclopropane, with much less steric crowding than the cis alternative. The ring contains the original two alkene carbons and the original benzylic carbon; no carbene carbon is added.

Both free primary allylic alcohols undergo Sharpless asymmetric epoxidation. With slightly more than two equivalents of hydroperoxide, the expected fully oxidized product is the diepoxide, with both original C=C bonds converted to epoxides and both primary alcohols retained. The two central pre-existing stereocentres and their ether substituents are retained.

The stereochemical construction is unambiguous by applying the L-(+)-tartrate mnemonic separately at each end: orient that alkene horizontally with its CH${}_2$OH group at lower right, and deliver oxygen from the back face. In the source's original in-plane orientation this gives the left epoxide oxygen behind the plane and the right epoxide oxygen in front. The methyl and hydroxymethyl groups retain their original relative arrangement about each former double bond. One cannot simply draw both oxygens on the same face of the original extended chain: the two allylic-alcohol ends have opposite drawing orientations. titanium binding to each free hydroxyl directs oxygen transfer; the pre-existing stereocentres can create matched/mismatched rate differences, but the stated reagent control predicts the stereochemistry of both epoxidations. Molecular sieves maintain a dry active titanium–tartrate system.^[ref]

Number the epoxide-bearing ring carbon carrying CH${}_2$OH as C1, then proceed through the other epoxide carbon C2 around the ring to C6. Heating with water opens the epoxide at the less substituted C2 by backside attack: the incoming oxygen becomes C2–OH on the front face, while the original epoxide oxygen remains as C1–OH on the back face. Proton transfers complete formation of the triol. Thus the two original epoxide oxygens' roles are distinct: one is retained from B and the new hydroxyl oxygen comes from water.

Iodine next activates the remaining C4=C5 bond as an iodonium ion. The pendant primary alcohol oxygen attacks intramolecularly at C5 to make the five-membered cyclic ether with path O–CH${}_2$–C1–C6–C5, opening the iodonium anti and leaving iodine at C4 on the opposite face. Bicarbonate removes the oxonium proton and neutralizes acid; it is not the source of the ether oxygen. The folded tether selects the face of closure compatible with the bridged structure, accounting for the ether/iodine stereochemistry.

The remaining two hydroxyl groups react with acid-activated 2,2-dimethoxypropane. Successive oxygen attack, methanol departure and intramolecular closure form the isopropylidene ketal of C, protecting that diol without changing its carbon configurations. The terminal primary hydroxyl has already become the cyclic ether and is not one of the two acetonide oxygens. This atom tracking distinguishes the epoxide hydrolysis, iodoetherification and protection stages.

Silver(I) promotes iodide departure, with precipitation of AgI. The oxygen of dimethyl sulfoxide substitutes at the iodine-bearing carbon to form an alkoxydimethylsulfonium intermediate. Triethylamine removes the hydrogen on that carbon; collapse forms C=O and breaks O–S, releasing dimethyl sulfide. The result is ketone D by a Kornblum oxidation. In arrow terms, the C–H electrons form the carbonyl pi bond as the O–S bond breaks. The carbon bearing iodine becomes the carbonyl carbon; the existing bridged ether and acetonide are spectators. The iodine centre loses its tetrahedral stereochemistry because it becomes trigonal planar.

The terminal ureidopyrimidinone groups supply the association sites. Their urea/pyrimidinone NH donors and carbonyl/ring-nitrogen acceptors can form a self-complementary array of four hydrogen bonds between two UPy units. Joining the two terminal units of one molecule by this noncovalent association closes the ring.

The ether-containing arms provide flexibility and spacing; they are not covalently joined together during ring formation. The ring is therefore a supramolecular conformation of the existing molecule, rather than a new covalent ether macrocycle.

The molecule combines three chemically different binding regions.

These assignments identify the preferred local sites, rather than guaranteeing three independent binding constants: occupancy can alter conformation, electrostatics and the affinity of neighboring sites.

A polymer or oligomer with repeated ether linkages in its main chain.

Tetrahydrofuran is a cyclic ether solvent. Its oxygen can coordinate lithium ions and alter the aggregation of organolithium reagents.

An ether with oxygen directly attached to a vinylic carbon, $\mathrm{R}-\mathrm{O}-\mathrm{CH}=\mathrm{C}{\mathrm{H}}_2$ in the simplest terminal example. oxygen resonance donation strongly differentiates the two alkene carbon shifts.

A dibenzo-gamma-pyrone framework with two outer benzene rings, an endocyclic ether oxygen and an exocyclic ketone oxygen. The outer rings are strongly aromatic; the central ring has a more polarized, partial aromatic description.