Alkoxy group facilitated ring closing metathesis (RCM) of acyclic 1,6-dienes. Convenient synthesis of non-racemic highly substituted cyclopentenols

Alkoxymethyl groups at the C-5 allylic position of 1,6-dienols have been found to accelerate RCM reactions significantly with the Grubbs’ catalyst PhCHRu(PCy₃)₂Cl₂. This phenomenon has been used for direct access to highly substituted cyclopentenols, potential intermediates in the synthesis of carbovir, abacavir and BCA.     

Stereospecific total synthesis of (−)-8-epi-hyperaspine

Condensation of protected δ-hydroxy-β-amino ester 7 with a β-keto ester provides vinylogous urethane 8, which is cyclized under the action of t-BuOK followed by decarboxylation to afford enone 12. Hydrogenation of 12 or its N,O-diprotected derivative 13 gives 2,6-cis-disubstituted piperdines. Using these intermediates, (−)-8-epi-hyperaspine is synthesized.     

Total synthesis of (−)-nakadomarin A: alkyne ring-closing metathesis

A 13-step, highly stereoselective synthesis of (−)-nakadomarin A has been achieved using the combination of a bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, an alkyne ring-closing metathesis/syn-reduction, and furan/iminium ion cyclization/reduction as key steps.     

The first total synthesis of sequosempervirin A through an orthoester Claisen rearrangement—ring closing metathesis sequence

The first total synthesis of sequosempervirin A, a norlignan with a unique spirocyclic structure has been accomplished using an orthoester Claisen rearrangement—ring closing metathesis sequence.     

Stereoselective synthesis of (−)-cytoxazone and (+)-epi-cytoxazone

Optically pure (−)-cytoxazone was synthesized, starting from methyl p-methoxycinnamate, in six steps and in 31% overall yield. The required anti-aminoalcohol configuration was established by combining Sharpless asymmetric aminohydroxylation with the configurational inversion of the intermediate amidoalcohol via an oxazoline. The synthesis of (+)-epi-cytoxazone is also described.     

Expedient asymmetric synthesis of a functionalized 5-7-6 fused tricyclic skeleton present in caribenol A through ring opening-ring closing metathesis of a norbornene derivative

A concise approach towards the synthesis of the highly biologically active terpenoid caribenol A is described involving sequential aldol condensation-ring opening-ring closing metathesis of a norbornene derivative.     

Total synthesis of (±)-erythravine based on ring closing dienyne metathesis

The first total synthesis of (±)-erythravine was achieved in thirteen steps from 3,4-dimethoxyphenethylamine using ring closing dienyne metathesis as the key step.     

Stereoselective synthesis of (8R,8aS)-8-methylhexahydroindolizin-5-one

Catalytic hydrogenation of dihydroindolizidinone occurred preferentially from the endo-face giving rapid entry to (8R,8aS)-8-methylhexahydroindolizin-5-one, a key intermediate in the synthesis of 5,8-disubstituted indolizidines and deoxypumiliotoxin 251H. The selectivity could be improved further by diimide reduction though this also resulted in some oxidation of the alkene to the diene. The basis of the unusual stereoselectivity in the diimide reduction is believed to be stereoelectronic in origin.     

Enantioselective synthesis of (−)-barrenazines A and B

A short enantioselective synthesis of barrenazines A and B is described. Barrenazines A and B are prepared following a common synthetic route in nine steps (19% overall yield) and eight steps (21% overall yield), respectively, from readily available 4-methoxy-3-(triisopropylsilyl)pyridine. The synthesis relies on a highly diastereoselective nucleophilic addition of a Grignard reagent to a chiral acylpyridinium salt, a radical azidation of a silyl enol ether and the assembly of the pyrazine ring by reductive dimerization of a functionalized 5-azidopiperidin-4-one.     

(E)-Cycloalkenes and (E,E)-cycloalkadienes by ring closing diyne- or enyne-yne metathesis/semi-reduction

A concise, practical and stereoselective entry into macrocyclic (E)-alkenes is outlined comprising a sequence of ring closing alkyne metathesis (RCAM), trans-selective hydrosilylation of the resulting cycloalkynes catalyzed by [Cp^∗Ru(MeCN)₃]PF₆, and a protodesilylation of the ensuing vinylsilanes with AgF in aq. THF/MeOH. Moreover, the first examples of intramolecular enyne-yne metathesis reactions catalyzed by the Schrock alkylidyne complex (tBuO)₃WCCMe₃ are reported; the resulting cyclic enynes can be converted along similar lines into the corresponding (E,E)-configured 1,3-dienes in good overall yields. Cycloalkyne 4 and the (E)-configured cyclic olefins 6 and 21 were characterized by X-ray crystallography.     

Stereoselective synthesis of new glycooxathiecinone using vic-cyclic thionocarbonate haloalkylation and ring closing metathesis as key steps

Herein, we describe the first glycoconjugate macrocyclic thiolcarbonate namely (Z)-10(S)-[3′-O-acetyl-1′,2′-O-isopropylidene-4′-deoxy-d-erythrofuranose]-4,7,9-trihydro-10H-8-thia-1,3-oxathiecin-2-one (17a) using a strategy based on two key steps synthesis: (i) a haloalkylation of vic-diol via their cyclic thionocarbonate derivatives; (ii) a macrocyclisation using ring closing metathesis reaction. Detailed here is a newly developed extension of vic-diol halogenation via the cyclic thionocarbonate function but using a range of alkyl halides other than the customarily used MeI. For example, with 1,2-O-isopropylidene-5,6-O-thionocarbonate-d-glucose (1) and allyl bromide, the 5-allylthiolcarbonate-6-bromo-6-deoxy-d-glucose derivative 6 was obtained in good yield. The later submitted to 6-allythioetherification and ring closing metathesis (RCM) with Grubbs second generation gave stereoselectively the target oxathiecinone 17a in 75% yield for the RCM step.     

Total synthesis of (−)-Englerin A

A novel and efficient total synthesis of Englerin A is reported. The synthesis featured an intramolecular olefin metathesis ring closure reaction and a highly stereoselective oxygen bridge formation induced by an iodonium ion. This strategy can be used for the synthesis of natural products Englerin A and Englerin B and can provide flexibility in the preparation of various 9-substituted analogues of Englerin A for further structure–activity relationship studies.     

Facile synthesis of (−)-6-acetoxy-5-hexadecanolide by size-selective ring-closing/cross metathesis

A total synthesis of (−)-6-acetoxy-5-hexadecanolide, in six steps and 37% overall yield from (2R,3S)-1,2-epoxy-4-penten-3-ol is reported. The key synthetic step is a size-selective ring-closing/cross metathesis reaction in which lactone formation and alkyl chain extension are accomplished in an efficient one-pot process.     

Enantioselective synthesis of (R)-deoxydysibetaine and (−)-4-epi-dysibetaine

Enantioselective synthesis of (R)-deoxydysibetaine and (−)-4-epi-dysibetaine was achieved by employing a samarium iodide-promoted reductive carbon-nitrogen bond cleavage of a proline derivative, as a key reaction.     

Total synthesis of (s)-(+)-citreofuran by ring closing alkyne metathesis

A concise total synthesis of citreofuran 4 is described, a structurally unique octaketide derivative belonging to the curvularin family. Key steps involve the elaboration of orsellinic acid methyl ester 5 to acid 14, which converts, on attempted formation of the corresponding acid chloride, to the 3-alkoxyisocoumarin derivative 20. This heterocycle can be used as an activated ester to give ketone 21 on treatment with 3-pentynylmagnesium bromide in the presence of TMSCl as the activating agent. Ring- closing alkyne metathesis (RCAM) of diyne 21 catalyzed by (tBuO)(3)W[triple bond]CCMe(3) affords the strained cycloalkyne 22. Treatment with acid renders its triple bond susceptible to nucleophilic attack by the adjacent carbonyl group, thus leading to a transannular cycloaromatization with formation of the intact skeleton of citreofuran. An X-ray crystallographic study reveals conformational details about this natural product. Finally, it is shown that 4 as well as its protected precursor 23 are able to cleave double-stranded DNA under oxidative conditions.     

A diastereodivergent strategy for the asymmetric syntheses of (−)-martinellic acid and (−)-4-epi-martinellic acid

Asymmetric syntheses of (−)-martinellic acid and (−)-4-epi-martinellic acid were achieved in 20 steps from commercially available starting materials using a diastereodivergent strategy. The conjugate addition of lithium (R)-N-allyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl (E)-3-[2′-(N,N-diallylamino)-5′-bromophenyl]propenoate and alkylation of the resultant β-amino ester with methyl bromoacetate were used as the key steps to install the C(9b) and C(3a) stereogenic centres, respectively. Subsequent cyclisation to the corresponding pyrroloquinolin-2-one and reduction of the C(4)-carbonyl group was followed by two complementary procedures for olefination and concomitant intramolecular Michael addition, which gave both C(4)-epimers of this tricyclic molecular architecture in >99:1 dr. Subsequent elaboration of these templates provided access to (−)-martinellic acid and, for the first time, (−)-4-epi-martinellic acid.     

Novel methodology for the synthesis of the benz[a]anthracene skeleton of the angucyclines using a Suzuki-Miyaura/isomerization/ring closing metathesis strategy

The synthesis of the benz[a]anthracene skeleton of the angucyclines is described. Key steps involve the Suzuki-Miyaura reaction, isomerization of an aromatic allyl substituent to the corresponding styrene, and the use of the ring closing metathesis reaction to construct a benzene ring. For example, exposure of 3-allyl-2-bromo-1,4,5-trimethoxynaphthalene to (2-formyl-4-methoxyphenyl)boronic acid under palladium catalysis conditions resulted in the formation of 2-(3-allyl-1,4,5-trimethoxynaphthalen-2-yl)-5-methoxybenzaldehyde. This 2-naphthyl benzaldehyde then underwent a Wittig reaction to furnish 3-allyl-1,4,5-trimethoxy-2-(4-methoxy-2-vinylphenyl)naphthalene. Isomerization of the allyl group of this compound afforded the diene, (E)-1,4,5-trimethoxy-2-(4-methoxy-2-vinylphenyl)-3-(prop-1-en-1yl)naphthalene. Exposure of the formed diene to the Grubbs II catalyst resulted in the formation of the benzanthracene, 3,7,8,12-tetramethoxytetraphene, which was easily oxidized to the corresponding quinone.     

Stereoselective synthesis of (−)-microcarpalide

A stereoselective approach for the synthesis of the bio-active decanolactone (−)-microcarpalide was achieved from chiral pool tartaric acid. The synthesis of pivotal intermediates en route to the decanolactone was achieved from α-benzyloxy aldehydes derived from l- and d-tartaric acid.     

A new synthesis of (−)-thioambrox and its 8-epimer

This new and straightforward synthesis of (−)-thioambrox 2, a sulphur compound whose odour resembles ambergris, starts from sclareolide 4. The stereoselectivity of the final cyclization is independent of the catalyst selected, and compound 2 is always favoured over (+)-iso-thioambrox 3. With hydrochloric acid as catalyst, the cyclization is unexpectedly stereospecific to give 2 in high yield at room temperature.     

A concise synthesis of (−)-cytoxazone and (−)-4-epi-cytoxazone using chlorosulfonyl isocyanate

A concise synthesis of (−)-cytoxazone and its stereoisomer (−)-4-epi-cytoxazone, novel cytokine modulators, has been accomplished each in six steps from readily available p-anisaldehyde with good diastereoselectivity. Key steps in the synthesis include the regioselective and diastereoselective amination of anti- and syn-1,2-dimethyl ethers with chlorosulfonyl isocyanate and the subsequent regioselective cyclization of the diol to construct the oxazolidin-2-one core. The diastereoselectivity of amination reaction using CSI was explained by the Cieplak electronic model via S_N1 mechanism and neighboring group effect, leading to the retention of the configuration.