Syntheses of Dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1 via Diastereoselective Epoxidation of N-Protected 4-Aminocyclohex-2-en-1-ols

Brennan, Méabh B.; Csatayová, Kristína; Davies, Stephen G.; Fletcher, Ai M.; Green, Will; Lee, James A.; Roberts, Paul M.; Russell, Angela J.; Thomson, James E.

doi:10.1021/acs.joc.5b00716

Cited by 14 publications

(5 citation statements)

References 42 publications

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“…The lack of diastereoselectivity upon epoxidation of N,N-dibenzyl protected 16 is in direct contrast to the high diastereoselectivities observed upon epoxidation of N,Ndibenzyl protected 3 and N-benzyl-protected 15 under these conditions. This could be the result of a competition between ammonium-directed and hydroxyl-directed pathways in the case of 16 (the N,N-dibenzylammonium moiety likely being a poorer directing group in comparison to the N-benzylammonium moiety, as we have previously established in related systems, 24,25 allowing direction by the ho-…”

Section: Syn Thesismentioning

confidence: 93%

Stereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3

et al. 2017

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Epoxidation of racemic trans-2-(N,N-dibenzylamino)cyclohex-3-en-1-ol, upon treatment with Cl3CCO2H then m-CPBA, proceeded with poor diastereoselectivity (ca. 60:40 dr), whilst epoxidation of racemic trans-2-(N-benzylamino)cyclohex-3-en-1-ol under the same conditions proceeded with high diastereoselectivity (>95:5 dr) and was followed by completely regioselective and stereospecific ring-opening in situ to give, after methanolysis of the intermediate trichloroacetate ester, (1RS,2SR,3SR,4SR)-2-(N-benzylamino)cyclohexane-1,3,4-triol. Use of aq HBF4 as the acid protecting agent gave the amino triol directly. The differing diastereoselectivities of these epoxidation reactions may be due to a predilection towards formation of an intramolecular hydrogen-bond in the former substrate disrupting the ability of the in situ formed ammonium moiety to act as a directing group for the incoming oxidant; the presence of two potential hydrogen-bond donors (i.e., two N–H bonds) in the latter substrate circumvents this limitation. With the criterion for a highly diastereoselective (ammonium-directed) epoxidation in this system established, a synthesis of enantiopure trans-2-(N-benzylamino)cyclohex-3-en-1-ol (>99% ee) was developed and the ammonium-directed epoxidation was then employed as a key synthetic step to facilitate the asymmetric syntheses of enantiopure dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3 (>98% ee in each case) from 1,3-cyclohexadiene.

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Section: Syn Thesismentioning

confidence: 93%

Stereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3

et al. 2017

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“…In contrast, epoxidation of N , N -dibenzyl-protected trans - 20 gave a separable 25:75 mixture of epoxides 22 and 23 , respectively (i.e., the major product 23 results from epoxidation on the face of the olefin syn to the hydroxyl group), suggesting that the hydroxyl group is a better directing group than the N , N -dibenzylammonium moiety in an identical environment. From the results of these studies, it followed that the order of directing group ability is NHBn ≫ OH > NBn 2 , (Scheme ).…”

Section: Introductionmentioning

confidence: 99%

“…The epoxidations of the diastereoisomeric compounds cis - 24 and cis - 25 were also explored . In these cases, the corresponding epoxides 26 and 27 were obtained as the exclusive products, which result from reaction on the face syn to both the amino (ammonium) moiety and the hydroxyl group, as may be expected; in the former case N -benzylation of the crude reaction mixture to facilitate purification gave 27 , which was thus isolated in 59% yield from 24 and 63% yield from 25 (Scheme ).…”

Section: Introductionmentioning

confidence: 99%

“…11, 14 We have recently explored the epoxidations of N-benzyl-and N,N-dibenzyl-protected trans-4-aminocyclohex-2-en-1-ol 19 and 20. 18,19 These are privileged structures within which the relative directing abilities of the various substituents may be evaluated, as in either of the possible half-chair conformations (19A/20A and 19B/20B) of the six-membered rings, the allylic amino (and hence in situ formed ammonium) moiety and the allylic hydroxyl group are located in identical environments (e.g., both pseudoequatorial in the ground states 19A and 20A). Epoxidation of N-benzyl-protected trans-19 resulted in complete diastereoselectivity (>95:5 dr) for production of epoxide 21 (i.e., epoxidation exclusively on the face of the olefin syn to the in situ formed ammonium moiety); N-benzylation of the crude reaction mixture gave 22 in 64% yield.…”

Section: ■ Introductionmentioning

confidence: 99%

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Probing Competitive and Co-operative Hydroxyl and Ammonium Hydrogen-Bonding Directed Epoxidations

et al. 2017

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The diastereoselectivities and rates of epoxidation (upon treatment with ClCCOH then m-CPBA) of a range of cis- and trans-4-aminocycloalk-2-en-1-ol derivatives (containing five-, six-, and seven-membered rings) have been investigated. In all cases where the two potential directing groups can promote epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted by hydrogen-bonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In contrast to the relative directing group abilities already established for the six-membered ring system (NHBn ≫ OH > NBn), an N,N-dibenzylammonium moiety appeared more proficient than a hydroxyl group at directing the stereochemical course of the epoxidation reaction in a five- or seven-membered system. In the former case, this was rationalized by the drive to minimize torsional strain in the transition state being coupled with assistance from hydrogen-bonding to the ammonium moiety. In the latter case, this was ascribed to the steric bulk of the ammonium moiety disfavoring conformations in which hydrogen-bonding to the hydroxyl group results in direction of the epoxidation to the syn face. In cases where the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of epoxidation diastereoselectivity was not observed, while introduction of a second, allylic heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the nucleophilicity of the olefin by the second, inductively electron-withdrawing heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form hydrogen-bonds to two directing groups rather than one is clearly unable to overwhelm it.

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“…The only source of these biologically interesting amino polyols is by means of laboratory synthesis, as none of the conduramine family themselves are naturally occurring . Unsurprisingly, therefore, several routes to these compounds and their derivatives have been reported, although these are often rather lengthy and give rise to only one or two conduramine products. , Given our previous experience concerning the synthesis of dihydroconduramines, − we proposed that epoxidation (treatment with H + then m -CPBA) of allylic amino alcohols 7 , derived from the ring-opening of benzene oxide, would give the corresponding ring-opened products 8 and 9 , i.e., conduramines (R = H) or their N -protected derivatives (R ≠ H) directly. This approach to these compounds would be attractive in that it may allow the preparation of several diastereoisomers of the targets for biological profiling in very short order, and in any case would provide further insight into the relative abilities of the ammonium functionality versus the hydroxyl functionality to direct the epoxidation reaction .…”

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confidence: 99%

Synthesis of (−)-Conduramine A1, (−)-Conduramine A2 and (−)-Conduramine E2 in Six Steps from Cyclohexa-1,4-diene

et al. 2019

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A method to enable the synthesis of conduramines and their N-substituted derivatives (enantiopure or racemic form) in six steps (five steps for N-substituted derivatives) from cyclohexa-1,4-diene is reported. Key features of this reaction sequence include a preparation of benzene oxide that is amenable to multigram scale, and its efficient ring-opening upon treatment with a primary amine. Epoxidation of the resultant amino alcohols (40% aq HBF4 then m-CPBA) is accompanied by hydrolytic ring-opening in situ to give the corresponding N-substituted conduramine derivatives directly. These may undergo subsequent N-deprotection to give the parent conduramines, as demonstrated by the preparation of enantiopure (−)-conduramine A1, (−)-conduramine A2, and (−)-conduramine E2 (the latter two for the first time). The selectivity of the epoxidation reaction is proposed to be the result of competitive ammonium-directed and hydroxyl-directed epoxidation processes, followed by either direct (SN2-type) or conjugate (SN2′-type) ring-openings of the intermediate epoxides.

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Syntheses of Dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1 via Diastereoselective Epoxidation of N-Protected 4-Aminocyclohex-2-en-1-ols

Cited by 14 publications

References 42 publications

Stereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3

Stereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3

Probing Competitive and Co-operative Hydroxyl and Ammonium Hydrogen-Bonding Directed Epoxidations

Synthesis of (−)-Conduramine A1, (−)-Conduramine A2 and (−)-Conduramine E2 in Six Steps from Cyclohexa-1,4-diene

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