Selective Construction of Carbocyclic Eight‐Membered Rings by Ring‐Closing Metathesis of Acyclic Precursors

Michaut, Antoine; Rodríguez, Jean

doi:10.1002/anie.200600787

Cited by 188 publications

(68 citation statements)

References 89 publications

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“…In spite of the reported challenges faced during the formation of eight-membered rings [57] by ring-closing metathesis (RCM), the cyclization proceeded smoothly in the case of 18 and 19, probably due to the conformationally predisposed allyl chains. [58,59] The metathesis reaction, first-and second-generation Grubbs' catalyst were found to be equally effective, afforded 20 and 21 in good yield of 64 and 79 %, respectively, as white solids. Subsequent hydrogenation with palladium on charcoal at atmospheric pressure yielded the doubly halogenated key building blocks 4b and 4c almost quantitatively.…”

Section: Synthesismentioning

confidence: 98%

Synthesis of Rotationally Restricted and Modular Biphenyl Building Blocks

Vonlanthen¹,

Rotzler²,

Neuburger³

et al. 2009

Eur J Org Chem

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A series of modular biphenyl building blocks with stepwise adjusted torsion angles and terminally functionalized with leaving groups have been synthesized. The two phenyl rings of the biphenyl synthon are clamped by alkyl chains of various lengths. The desired building blocks 3 and 4 were obtained by copper-mediated C-C biaryl coupling reactions followed by the construction of interlinking alkyl bridges. The key intermediates 14 and 15 were transformed into the corresponding cycloheptadienones 16 and 17, which were reduced to the desired propyl-bridged biphenyls 3b and 3c. The butyl-bridged derivatives 4b and 4c were obtained from

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Section: Synthesismentioning

confidence: 98%

Synthesis of Rotationally Restricted and Modular Biphenyl Building Blocks

Vonlanthen¹,

Rotzler²,

Neuburger³

et al. 2009

Eur J Org Chem

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“…80% isolated yield at dilutions tenfold higher. Unprotected alcohol groups, particularly those in allylic and homoallylic positions, can have beneficial or negative effects in RCM [104]. The potential benefits of hydrogen-bonding interactions in epothilone synthesis were noted above [106].…”

Section: Protecting Groups As Tunable Gearing Elementsmentioning

confidence: 93%

“…Protection of protic functionalities (e.g. hydroxyl and primary or secondary amines) can improve the performance of Ru metathesis catalysts [78,104,105], as noted above: this can also offer a highly modular means of introducing such conformational constraints. Specific examples of protecting group effects relevant to synthesis of epothilones have also been reviewed; beneficial effects in some cases associated with the unprotected alcohols were attributed to the stabilization of desired conformations by hydrogen-bonding interactions [106].…”

Section: Protecting Groups As Tunable Gearing Elementsmentioning

confidence: 97%

Ring-Closing Metathesis Synthesis of Medium and Large Rings: Challenges and Implications for Sustainable Synthesis

Monfette

Fogg

2010

Green Metathesis Chemistry

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Synthesis of medium-sized and macrocyclic rings by ring closing metathesis (RCM) reactions of dienes involves challenges not found in synthesis of the more common five-and six-membered rings. This review discusses factors that determine the probability and efficiency of cyclization, and experimental methods that have been used to increase selectivity for RCM products, with specific reference to the concentrations at which RCM can be achieved. These issues have important implications for the environmental and economic sustainability of large-scale synthetic processes utilizing RCM for assembly of rings larger than six members.

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“…[13] Ultimately, this problem was circumvented by addition of allyllithium, derived from allyltriphenyltin [14] by transmetalation, to d-lactone 14 to give the b,g-enone 20 (Scheme 5). Use of the latter intermediate was premised on a designed tandem isomerization/RCM process guided by the known reluctance of RCM to provide eight-membered rings [15] and the ability of the ruthenium-hydride species generated from the Grubbs catalyst to promote olefin isomerization. [16] As predicted, upon heating diene 20 with the second generation Grubbs catalyst in toluene, the desired cycloheptenone was formed in 95 % yield, thus indicating that olefin isomerization was faster than RCM, a situation which would have led to a cyclooctenone.…”

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confidence: 99%

Total Synthesis of (+)‐Omphadiol

Romo

2011

Angew Chem Int Ed

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Omphadiol (1) is a sesquiterpene isolated from the basidiomycete omphalotus illudens and the edible fungus clavicorona pyxidata (Scheme 1).[1] As a member of the africanane family of sesquiterpenes, which all possess a 5-7-3 tricyclic core, omphadiol contains six contiguous stereogenic centers, which makes it a challenging synthetic target. Comparison with structurally similar terpenoids, including pyxidatol (2) and africanol (not shown), [2] reveals a large family of sesquiterpenes and diterpenes that share a common tetrasubstituted cyclopentane ring (highlighted in red). Notably, many of these natural products display potent biological activities. For example, rossinone B (3) shows anti-inflammatory, antiviral, and antiproliferative activities [3] while chinesin (4) possesses antimicrobial and antiviral activity.[4] Tomoeone F (5) displays significant cytotoxicity against KB cells.[5] While synthetic studies toward members of this family including a recent biomimetic synthesis of (AE )-rossinone B have appeared, [6] no further biological studies have been described. Full biological evaluation of omphadiol was precluded owing to insufficient quantities isolated from natural sources.[1a] As part of a program to demonstrate the utility of b-lactones as synthetic intermediates, we set out to develop a scaleable route to the common cyclopentane core (highlighted in red) found in these terpenoids as a prelude to biological studies and investigations into their likely biosynthetic interconnectivity. Herein we report a three-step synthesis of a versatile, carvone-derived bicyclic b-lactone, which constitutes the key intermediate for the described ten-step synthesis of (+)-omphadiol. This total synthesis also features several efficient CÀC bond-forming reactions, novel single-pot, sequential and tandem processes, and the highly stereocontrolled introduction of all six stereogenic centers.Our synthetic strategy was premised on a late-stage facially selective cyclopropanation of the C2 À C4 double bond governed by the topology of the [5.3.0] bicycle 6 (Scheme 2). The cycloheptenone would in turn be constructed by ring-closing metathesis (RCM) of diene 7, which could be derived from bromide 8 by a sequential one-pot intra-/ intermolecular dialkylation. The key intermediate for the synthesis of omphadiol and related terpenes was identified as the bicyclic b-lactone 9. We anticipated that this versatile intermediate could be constructed by the reorganization of the carbon skeleton of (R)-carvone through a nucleophilepromoted aldol lactonization process of a derived keto acid.The synthesis of (+)-omphadiol commenced with a [Mn III (dpm) 3 ]-catalyzed (dpm = dipivaloylmethanato) formal hydration of the enone moiety of (R)-carvone to afford the hydroxy ketone 11 in a chemo-and regioselective manner and as an inconsequential mixture of diastereomers (d.r. 2:1; Scheme 3).[7] Subsequent oxidative cleavage of the a-hydroxyketone by periodic acid delivered ketoacid 12. Upon activation of the carboxylic acid with tosyl chloride, and...

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Selective Construction of Carbocyclic Eight‐Membered Rings by Ring‐Closing Metathesis of Acyclic Precursors

Cited by 188 publications

References 89 publications

Synthesis of Rotationally Restricted and Modular Biphenyl Building Blocks

Synthesis of Rotationally Restricted and Modular Biphenyl Building Blocks

Ring-Closing Metathesis Synthesis of Medium and Large Rings: Challenges and Implications for Sustainable Synthesis

Total Synthesis of (+)‐Omphadiol

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