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Build the phenethyl grignard reagent, use one portion to make a phenethyl-substituted ester, and add two further equivalents to that ester. Write ; the target is , so all three carbon substituents must be phenethyl, not benzyl.
hydroboration followed by oxidation of styrene gives : use in a suitable ether, followed by alkaline hydrogen peroxide. The Anti-Markovnikov addition regiochemistry is essential; acid-catalysed Markovnikov addition of water would give the wrong alcohol. Convert the primary alcohol to with phosphorus tribromide, then form with magnesium in dry ether. The organomagnesium reagent must be prepared and used without a protic solvent.
carboxylate one portion with carbon dioxide and acidify to obtain , then esterify with ethanol under acid catalysis to give . Treat the isolated ester with at least two equivalents of another portion of and then perform an aqueous acidic work-up:The first addition to the ester gives a ketone after ethoxide elimination; the second addition gives the tertiary alkoxide. Work-up supplies its OH proton. The extra central carbon comes from carbon dioxide, and each original styrene contributes one intact eight-carbon phenethyl unit. The resulting carbon count is , matching the target skeleton.
B is 4-hydroxy-1-methylpyrrolidin-2-one; C is 1-methylpyrrolidin-3-ol. Their ring connectivities are shown below. Each ring remains five membered; the attached N-methyl group is retained.
For B, a B–H bond of sodium borohydride supplies a hydride equivalent to the ketone carbonyl carbon, and the carbonyl pair moves to oxygen. This gives an alkoxide, whose protonation during the reaction or workup gives the secondary alcohol. The lactam carbonyl remains. Converting one to adds two H atoms and gives .
For C, lithium aluminium hydride reduces that ketone in the same net way and also reduces the lactam. Coordination of the amide oxygen to aluminium assists hydride attack at its carbonyl carbon, giving a tetrahedral intermediate. The N lone pair then forms a C=N bond while the C–O bond breaks to an aluminium-bound oxygen group. A resulting iminium ion accepts a second hydride at carbon, yielding the cyclic tertiary amine. Aqueous workup protonates the ketone-derived alkoxide.
The lactam conversion replaces by ; its oxygen is removed rather than retained as another alcohol. Together with ketone reduction, the net change is , giving . No stereochemistry is specified: the new alcohol stereocentre is formed as a racemic mixture in an achiral environment.
Disconnect the amide into 2-propylhexanoic acid and N-methyl-2-(4-hexylphenyl)ethylamine. This keeps the nitrogen substituents distinct: one is Me and the other is the two-carbon aryl side chain. The acid's alpha carbon must bear both n-butyl and n-propyl groups.
For the acid fragment, esterify the supplied hexanoic acid, form its ester enolate with LDA, and alkylate with 1-iodopropane:hydrolysis gives 2-propylhexanoic acid; conversion with gives the acyl chloride for the final coupling. Limit the alkylating reagent and isolate the monoalkylated ester to avoid overalkylation.
For the aryl fragment, use another portion of hexanoic acid to make hexanoyl chloride. A Friedel-Crafts acylation of bromobenzene with this reagent and gives ortho and para products; isolate the para bromoaryl ketone. A Wolff-Kishner reduction converts into without deliberately hydrogenolyzing the aryl bromide. Acylation followed by carbonyl reduction installs an unrearranged n-hexyl group; direct Friedel–Crafts alkylation is a less reliable way to do that.
Convert the retained aryl bromide into its grignard reagent, open ethylene oxide, and work up to obtain . Oxidize the primary alcohol to under conditions that stop at the aldehyde, then perform reductive amination with methylamine and sodium triacetoxyborohydride. Excess methylamine helps favour the desired secondary amine over further alkylation. Finally acylate that secondary amine with the isolated acyl chloride, using a separate base to capture HCl.
The final amide has an N-methyl group, the para n-hexyl phenethyl group, and the required n-butyl/n-propyl acyl branching. The carbon check is in the acyl fragment plus in the amine fragment, giving overall. No absolute stereochemistry is specified at the acid alpha carbon.
Disconnect the internal Z alkene by a non-stabilized Wittig reaction:The aldehyde carbon becomes the right-hand internal alkene carbon; the ylide carbon becomes the left-hand one. Both the methyl ester and the remote terminal alkene survive the olefination.
Make the aldehyde from pentanal by Stork enamine reaction: form its pyrrolidine enamine, react at carbon with allyl bromide, then hydrolyse to . The original alpha carbon of pentanal now bears allyl and n-propyl substituents. Control the alkylation to avoid multiple substitutions.
The other branch needs a three-carbon extension of the supplied four-carbon bromo alcohol. Protect the OH of as a tetrahydropyranyl ether. Convert the bromide into an organocuprate and add it conjugatively to methyl acrylate:Here the organocopper formula is shorthand for a suitable cuprate preparation, not a claim that an isolated monomer is necessary. The acrylate contributes two methylenes and the ester carbonyl. Remove the THP group, replace the resulting terminal OH by Br, and react with to form . Deprotonate adjacent to phosphorus to generate the non-stabilized ylide. This proton is much more acidic than the ester alpha protons, but controlled base stoichiometry and low temperature remain important.
Add the allylated aldehyde under conditions favouring the usual kinetic Z-selective Wittig olefination, and separate any E isomer. The result isThe four-carbon starting alcohol plus the three-carbon acrylate backbone supplies the seven-carbon acid-derived chain; the ester Me gives an eighth carbon. Pentanal plus allyl gives the other eight. The total is sixteen carbons, including the terminal alkene. A two-carbon extension would produce the wrong chain length.
Disconnect the tertiary alcohol at its bond to the alkenyl group. The required carbonyl partner is ; the other partner is an E-configured organometallic reagent. This disconnection fixes the alkene geometry before the alcohol is made.
First form the ethyl-side enolate of butan-2-one under equilibrating conditions, then trap it with ethyl iodide and isolate the required monoalkylated ketone:The incoming group is Et: methylation would give a carbon skeleton one carbon too short. Because an unsymmetrical ketone can form two enolates and undergo repeated alkylation, regioisomer separation and controlled conversion are part of this step.
Independently perform a halo-Wittig reaction on phenylacetaldehyde using and isolate E- from any geometrical mixture. magnesium insertion in dry ether gives the corresponding vinylmagnesium halide; add the isolated ketone at low temperature and protonate the resulting alkoxide. Addition to C=O preserves the pre-existing C=C geometry:The E alkene and the complete fifteen-carbon skeleton are obtained. No absolute configuration is specified at the newly formed alcohol centre, so an unselected stereoisomeric mixture there is acceptable. An alternative carbon–carbon disconnection is acetylide addition to the same ketone followed by a controlled trans-selective alkyne reduction; the vinyl-reagent route avoids relying on reduction of a tertiary propargylic alcohol.
Open the lactone formally at its acyl–oxygen bond, then replace the resulting secondary alcohol by its ketone precursor. With , the useful sequence of retrosynthetic intermediates isDisconnect the last compound as a Michael addition product of the methyl-side enolate of and ethyl methacrylate:The substituted carbon of the methacrylate becomes the methyl-bearing carbon alpha to the lactone carbonyl. The ketone carbon becomes the oxygen-bearing ring carbon. This checks the six-membered ring connectivity.
The required branched methyl ketone itself comes from butan-2-one by ethyl-side aldol addition to acetone, followed by dehydration and selective hydrogenation:Choose and isolate the aldol regioisomer shown. For the subsequent Michael step, use a bulky base at low temperature to favour its less hindered methyl-side kinetic enolate. Reduce the resulting ketone selectively with while retaining the ester, hydrolyse the ester, then acidify and promote intramolecular esterification with water removal. The hydroxy acid closes to the required six-membered lactone. There is no specified stereochemical relationship to enforce, but a stereochemically pure target would require an additional selectivity or resolution step.
There are three largely independent constructions: a substituted Robinson-annulation core, a protected vicinal diol, and the ester acyl fragment. Disconnect the ester first to an allylic alcohol on the bicyclic ring and the acid . Disconnect the benzylidene acetal to a side chain and benzaldehyde. Reversing 1,2-reduction of the allylic alcohol gives the corresponding bicyclic enone; its six-membered enone ring is a Robinson disconnection back to a suitably alpha-substituted cyclohexanone and methyl vinyl ketone.
An efficient way to protect the side chain before annulation is to prepare 4-(bromomethyl)-2-phenyl-1,3-dioxolane from and benzaldehyde with mild acid and water removal. The desired five-membered acetal protects the adjacent hydroxyl groups, while its external primary bromide remains an alkylating site. Alpha alkylation of the indicated cyclohexanone with this bromide gives a ring bearing in the benzylidene-protected form. There is no need to expose the eventual ring enone to a nonselective late dihydroxylation.
Generate the enolate at the other, less substituted alpha position of the cyclohexanone and add methyl vinyl ketone. Hydrolysis of an enamine-mediated Michael variant or direct enolate trapping gives the appropriate 1,5-dicarbonyl. Intramolecular aldol condensation closes a six-membered ring onto the original cyclohexanone carbonyl. Dehydration gives the fused bicyclic enone, with the protected three-carbon side chain on the adjacent carbon of the original ring. Regioselecting the initial Michael addition is essential: reaction at the side-chain-bearing alpha site would place that substituent at the wrong fusion position.
Reduce the new enone carbonyl by 1,2-addition, for example sodium borohydride with cerium(III) chloride under Luche-type conditions, to retain the displayed ring C=C bond and produce the allylic alcohol. The benzylidene acetal should be maintained through these neutral/basic operations. The target has no wedge/dash assignments, so a constitutional solution does not require a claim of a unique fused-ring/alcohol diastereomer; isolate the required constitutional annulation product.
For the acyl branch, form the enolate of the indicated methyl butanoate, add acetone, then dehydrate the beta-hydroxy ester:Hydrogenate this isolated alkene before coupling it to the bicyclic substrate, giving . saponification gives ; activate it as its acid chloride or use a mild ester-coupling reagent, then acylate the bicyclic allylic alcohol. Performing the hydrogenation on the separate acyl branch avoids reducing the target ring alkene. Strong acid should be avoided during the final esterification because the benzylidene group is acid-labile.
The carbon audit is particularly useful: the fused rings contain six carbons from cyclohexanone plus four from methyl vinyl ketone; the side chain has three carbons from the protected bromodiol; the benzylidene unit supplies its acetal carbon and phenyl group. In the acyl fragment, the four butanoate acyl carbons plus three acetone carbons give seven; the starting ester methoxy carbon is lost during hydrolysis.
Original modular disconnections separating protected side-chain installation, regioselected Robinson annulation and synthesis of the seven-carbon acyl group
. Details. Both side chains have the order ring–, and both printed double bonds have the Z geometry. The two carbon side chains are cis to one another; equivalently the labelled ring H and ring Me are cis on the opposite face. A useful common late precursor therefore has two cis ring– substituents, which can undergo two Z-selective ethylidene Wittig reactions.
Use the starting 2-methylcyclohex-2-en-1-one in a reductive alpha-alkylation. Conjugate reduction under dissolving-metal/enolate-trapping conditions, followed by a primary electrophile , installs a protected two-carbon alcohol side chain at the original methyl-bearing alpha carbon. This gives 2-methyl-2-(2-siloxyethyl)cyclohexanone. The carbon at that position is now quaternary, with its original methyl retained. Alternatively, reduce the enone to 2-methylcyclohexanone and deliberately form/select its more substituted enolate before alkylation; its opposite kinetic enolate would give the wrong regioisomer.
Convert the remaining ring ketone to an exocyclic enoate by Horner–Wadsworth–Emmons olefination with a phosphonoacetate:Hydrogenate this sole alkene to give ring– at that carbon. Select the diastereomer with this substituent cis to the pre-existing protected hydroxyethyl side chain, so the newly installed ring H is cis to ring Me. Less hindered-face hydrogenation can assist this relationship, but the route should include separation/verification of the desired cis product rather than assert complete stereoselectivity without data.
Reduce the ester with lithium aluminium hydride to ring– and remove the TBS group from the other side chain. Both appendages are now two-carbon primary alcohols. Oxidize them to aldehydes under non-overoxidizing conditions, for example Dess–Martin oxidation, obtaining the cis dialdehyde with two ring– groups. Treat with excess salt-controlled, nonstabilized ethylidenetriphenylphosphorane under conditions favouring kinetic Z olefination; isolate the Z,Z product. Each aldehyde carbon becomes the inner vinylic carbon of its crotyl group, while the ylide supplies .
This order postpones both stereodefined alkenes until after hydrogenation, so they are not accidentally saturated. It also avoids assuming that a crotyl grignard reagent adds without allylic transposition or that direct alcohol deoxygenation fixes the required ring stereochemistry. An achiral synthesis gives a racemic mixture pair with the specified relative configuration.
The left ring system is spiro, and the right-hand substituent is , not OMe directly attached to the cyclohexene ring. Let denote the right cyclohexenyl group bearing that methoxyethyl substituent cis to its linker. The connection to the left alkene carbon is . 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 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 . olefination with an allylidenetriphenylphosphorane, , supplies a conjugated diene ; 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 , 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 , preserving the secondary methyl ether and the ring alkene.
Oxidize this primary alcohol to . Add vinylmagnesium bromide to give , then oxidize the allylic alcohol to the enone . 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 .
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.
Let . The useful disconnections are benzoate formation, carbonyl reduction and thiol conjugate addition:The sulfur-bearing carbon is the enone beta carbon, so this is a Michael disconnection, not attack of thiophenol on the alcohol-derived central carbon. Reduce the saturated ketone with sodium borohydride after installing SPh, then benzoylate the alcohol with benzoyl chloride and pyridine or a tertiary amine.
Disconnect the enone to and formaldehyde. Kinetic deprotonation on the methyl side of the hindered unsymmetrical ketone, trapping with formaldehyde, and dehydration gives . This order leaves the substituted side unchanged. An alpha-methylenation/Mannich-base-elimination variant is an equivalent way of installing the terminal enone.
Finally, disconnects by alpha alkylation to butan-2-one and 1-iodopropane. Use the more substituted, ethyl-side enolate of butan-2-one for this step, rather than its usual methyl-side kinetic enolate; an equilibrated/regioisomerically selected enolate or enol derivative is required, and the desired monoalkylated ketone should be isolated. Three carbons from propyl iodide and one from formaldehyde increase the original four-carbon ketone to the required eight-carbon alcohol/thioether skeleton. Choosing ethyl iodide here would leave the target short by one carbon.
This is a constitutional synthesis: the target drawing specifies no configuration at either newly formed stereogenic site, so no unproved stereoselective reduction or alkylation is needed. Regioisomeric enolate alkylation and competing overalkylation are the practical selectivity issues to control, rather than something that follows from writing “base”.
Open the cyclic ester at its acyl–oxygen bond. The resulting delta-hydroxy acid isOxidation-state reversal at the benzylic alcohol gives . This identifies the key Michael disconnection between the central and groups:The nucleophile is the enolate or enamine of the phenyl ketone. The electrophile's propyl substituent must be alpha to its ester carbonyl; using a beta-propyl acrylate would move the substituent to the wrong ring position.
Disconnect further to the indicated acetophenone. Crossed aldol addition to acetone followed by dehydration gives ; selective conjugate reduction or controlled alkene hydrogenation then gives . This avoids requiring an efficient SN2 alkylation with a secondary isopropyl halide. The alpha-propyl acrylate can be obtained by alpha-hydroxymethylation/dehydration of ethyl pentanoate, , using formaldehyde.
In the forward direction, perform the Michael coupling, reduce the phenyl ketone selectively with sodium borohydride while retaining the ordinary ester, hydrolyse the ester, and cyclize the delta-hydroxy acid by controlled acid-catalysed lactonization or an activated-acid coupling. The six-membered ring then has the order carbonyl–––––O. This atom order checks all three substituent positions. No relative configuration is specified, so the scheme does not imply a single diastereomer from the Michael addition or reduction.
Product 5 is 1-methylcyclohexan-1-ol. The tertiary ring C–H bond of methylcyclohexane is replaced by C–OH. This is a single constitutional product; the two ring paths at that carbon are equivalent, so no new stereocenter is created there.
The manganese–oxo species abstracts the relatively weak tertiary hydrogen, then hydroxyl rebound converts the carbon radical into the tertiary alcohol. The unfunctionalized catalyst has no crown-ether receptor to preassociate the ammonium substrate. Its selectivity therefore mainly follows intrinsic C–H reactivity: the tertiary site of methylcyclohexane outcompetes the secondary C–H sites of the linear chain. The cationic ammonium group also electronically deactivates nearby sites. This explains the dominant product under the idealized selectivity described in the question.
Product 6 is a remotely oxidized ketone of the undecylammonium chain, retaining the ammonium group and its counterion. Number from the ammonium-bearing carbon as C1. Crown-mediated recognition positions the remote C8–C9 region near the Mn–oxo center. A representative major-site product is the C8 ketone,Its adjacent possible regioisomer is the C9 ketone . The precise single-site assignment is a limitation discussed below.
The crown ether binds the primary ammonium end through several N–H···O hydrogen bonds. This host–guest complex holds a folded portion of the chain close to the manganese oxidant, so the effective local concentration of a remote secondary C–H bond can overcome the intrinsic advantage of a free tertiary C–H bond. Such recognition-driven reversal of substrate preference is experimentally established.[ref]
The key intermediates are the crown-bound ammonium–Mn=O assembly, a remote carbon radical after H abstraction, and the rebound secondary alcohol. A second oxidation removes the remaining hydrogen on the carbinol carbon to give the ketone. The overall oxygen-equivalent count isThus one ketone requires two equivalents of peroxide, explaining a maximum near 50% ketone yield with one equivalent and near-complete conversion with two.
The primary remote-oxidation study reports preference for C8 and C9, not a universally unique carbon. The schematic catalyst drawing and the oxygen budget alone cannot distinguish those positions quantitatively. The “single product” wording is therefore treated as an idealized remote-site assignment; a uniquely verified C8:C9 ratio is not invented.[ref]
Without a competing hydrocarbon and without a crown receptor, catalyst 1 can still oxidize accessible secondary C–H bonds in the chain. Expect a less site-selective mixture of secondary oxidation products, predominantly ketones when two peroxide equivalents are effectively used, rather than the recognition-selected remote product pattern of catalyst 2.
The strongly electron-withdrawing, protonated ammonium end makes nearby C–H bonds less reactive, so the distribution need not be statistically uniform over every methylene. More distant secondary positions are comparatively favorable, while primary terminal C–H oxidation is generally harder. alcohol intermediates, incomplete conversion and unproductive peroxide consumption are also possible. Exact regioisomer ratios or a guaranteed quantitative yield cannot be predicted from the supplied conditions.
The first step is an endo-selective Diels-Alder reaction of the pyrone diene with the electron-poor acrylamide. Number the pyrone , and the acrylamide carbons and , with next to its carbonyl. The favored polar connection is C3–C and C6–C, leaving C4=C5 and the original C2–O1 lactone bridge intact.
Lithium allyloxide, generated from n-Butyllithium and allyl alcohol, attacks the bridging lactone carbonyl. Collapse of the tetrahedral intermediate cleaves its acyl–oxygen bond. proton transfer converts the former O1 bridge into an OH substituent at C6 and leaves the former pyrone carbonyl as an allyl ester attached to C3. The morpholine amide is retained.
Thus C is allyl 1,4-dihydroxy-2-(morpholine-4-carbonyl)cyclohex-5-ene-1-carboxylate, with the stereochemistry described below. In this product numbering C1 is the former pyrone C3, C2 is the acrylamide , C3 is , and C4 is the former pyrone C6.
The bridge fixes the former C3 carboxyl group and C6 oxygen on the same face. An endo acrylamide places its amide substituent on that face too. Accordingly COallyl at C1, the C2 amide and the C4 OH are cis; the C1 OH is on the opposite face. The alternative face of attack gives the enantiomer, so achiral reagents give a racemate. The band is consistent with the newly formed ester, while the strong lower-frequency band is consistent with the retained, strongly polarized amide carbonyl. These bands support carbonyl-class retention; they do not independently prove the predicted regioisomer or stereochemistry.
Pendant alcohols can form reversible borate bridges, schematically and , where P and P′ belong to different chains. Tetrahedral borate species are also possible depending on pH and water content. A bridge must connect different network strands to act as a cross-link; an intrachain loop does not contribute equivalently to elasticity.
Between cross-links, stretching reduces the number of accessible chain conformations. A simple incompressible rubber elasticity model gives the nominal tensile stresswhere is the extension ratio and the density of elastically active strands. The initial response is soft; stronger extension gives increasing stress and ultimately finite-chain extensibility. Reversible borate exchange permits stress relaxation, rate dependence and a loading–unloading hysteresis loop, rather than permanent ideal elasticity at arbitrarily long times.
Let , so B is . Its hydroxyl group initiates ring-opening polymerization of lactide, givingEach lactide contributes two lactyl repeat units. Dry monomer, exclusion of water and an alcohol-compatible catalyst such as tin(II) 2-ethylhexanoate under heating provide a practical route. Alcohol/metal-alkoxide exchange followed by lactide coordination and acyl–oxygen cleavage extends the ester chain while retaining a terminal hydroxyl group.
Heating C under oxygen-free conditions homolytically cleaves its benzylic C–O bond to the nitroxide, releasing a benzylic radical and TEMPO. The radical adds styrene repeatedly; reversible trapping by TEMPO controls the active radical concentration. D is therefore a poly(lactide)–polystyrene block copolymer with junction and the hydroxyl end of PLA retained. This is nitroxide-mediated polymerization; a temperature around 120–130 °C is a representative condition for a TEMPO/styrene system, rather than an exact universal optimum.
Hydroxide attacks a PLA ester carbonyl, moving the electrons onto oxygen. Collapse of the tetrahedral intermediate expels an alkoxide; proton transfer produces an alcohol and a carboxylate. The carboxylate stabilizes the hydrolysis products and makes this saponification effectively irreversible under the basic conditions. Repetition cleaves the PLA block, including its terminal ester linkage to the junction alcohol, while the carbon–carbon polystyrene backbone remains intact.
The principal surviving polymer is a polystyrene chain bearing the junction end and its nitroxide-derived distal end. In gel permeation chromatography, the intact block copolymer normally elutes earlier than this smaller surviving polystyrene coil. Lactate and short hydrolysis fragments elute later still, provided the column and detector resolve such small solutes. The polymer peak therefore shifts to larger elution volume; its height need not remain constant under a mass-sensitive detector. Elution reflects hydrodynamic volume, so calibration against polystyrene standards does not supply an exact absolute mass for the original mixed block.
A hydroxyl-directed Evans–Saksena reduction gives the required anti-1,3-diol. A suitable reagent is tetramethylammonium triacetoxyborohydride in an acidic medium, for example acetic acid/acetonitrile. Ligand exchange between the pre-existing alcohol and an acetoxyborohydride group tethers the reducing reagent to the substrate. Intramolecular hydride delivery to the ketone then proceeds through a six-membered arrangement, converting C=O to an alkoxide while conserving all existing stereocentres. Hydrolysis releases the second hydroxyl group.
The preferred directed transition-state conformation minimizes crowding by the larger carbon-chain substituents. It delivers the new C–H bond on the face that leaves the two hydroxyl groups anti, as in B: with the original hydroxyl drawn as a wedge in the printed zigzag, the new hydroxyl is dashed. The intervening methyl stereocentre is retained. Choosing an undirected borohydride reduction would not by itself rationalize this strong substrate-controlled relationship.
The secondary alcohol of H condenses with the aldehyde under acid catalysis to form a hemiacetal, then loses water to an oxocarbenium ion. Its tethered E alkene attacks the aldehyde-derived carbon through a chair-like six-membered arrangement: the alkene carbon farther from the alcohol forms the new C–C bond, placing a carbocation at the nearer alkene carbon. Trifluoroacetate captures that cation; the basic methanolic work-up cleaves the trifluoroacetate ester to reveal the ring hydroxyl group. This is a Prins cyclization.
Number the product ring from oxygen through the aldehyde-derived carbon as C2, then the alkene-derived methyl-bearing carbon C3, the hydroxyl-bearing carbon C4, the intervening methylene C5 and the original alcohol carbon C6. A chair keeping the bulky C2 side chain and C6 hydroxymethyl group equatorial predicts 2,6-cis substitution. Suprafacial alkene capture preserves the E-alkene-derived relationship, giving 2,3-trans between the C2 side chain and C3 methyl. Preferred equatorial trapping of the C4 cation gives 3,4-trans, hence the 2,4,6-cis arrangement of the substituent-bearing bonds in the favoured chair. In the printed flat-ring orientation, draw the C2 side chain, C4 hydroxyl and C6 hydroxymethyl behind the plane, and C3 methyl in front. Existing stereocentres in the aldehyde side chain and at C6 are retained; they anchor the absolute face of this assignment.
