Tandem Aldol-Cyclization Sequence for the Construction of Cyclic Ethers. The Formation of Substituted Tetrahydrofurans

Galatsis, Paul; Millan, Scott D.; Nechala, Patrik; Ferguson, George

doi:10.1021/jo00101a024

Cited by 46 publications

(22 citation statements)

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“…Thes tereochemistry of the diene starting material (E,E-, Z,E-, or E,Z-) had minimal impact on reaction outcomes and rates,a llowing the use of crude substrate mixtures obtained from standard diene syntheses. [12] Ther eductive chemoselectivity of the reaction was assessed by ac omprehensive functional-group compatibility screen ( Figure 2B), which demonstrated that related carbonyl groups (ketones,e sters,a mides), activated and unactivated olefins,o ther dienes,a lkyl halides,e poxides,a nd protic NHand OH-groups are well tolerated (> 60 %product yield with one equivalent of additive and > 85 %r ecovery of additive, see the Supporting Information for complete details). Of the functional groups screened, only alkynes and alkyl bromides were impacted under the standard reaction conditions.…”

Section: Resultsmentioning

confidence: 99%

“…[14] Thestereochemically defined Z-allylic alcohols generated by formic acid mediated reductive coupling are useful building blocks for more complex fragments ( Figure 6). Straight-forward access to 2,5-dihydrofurans (7), [15] epoxide, [16] and aziridine [17] stereotetrads (8,9), tertiary alcohols (10), [18] and tetrasubstituted tetrahydrofurans (11) [12] is possible by the high-yielding stereoselective functionalization of 2a by standard synthetic protocols.…”

Section: Resultsmentioning

confidence: 99%

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Direct Formic Acid MediatedZ‐Selective Reductive Coupling of Dienes and Aldehydes

2019

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Methods for the addition of unsaturated nucleophiles to carbonyls to generate Z-olefin products remain rare and often require either alkylb orane or zinc reductants, limiting their utility.D emonstrated here is that formic acid mediates the Rh-catalyzed, Z-selective coupling of dienes and aldehydes.T he process is distinguished by broad tolerance towards reducible or electrophilic groups.K inetic analysis suggests that generation of the catalytically active Rh intermediate by ligand dissociation is the rate-determining step.The rapid generation and trapping of Rh-allyl intermediates is key to preventing chain-walking isomerization events that plague related protocols.Insights gained through this study mayhave wider implications in selective metal-catalyzed hydrofunctionalization reactions.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Direct Formic Acid MediatedZ‐Selective Reductive Coupling of Dienes and Aldehydes

2019

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“…Galatsis et al45a examined the cyclization of homoallylic alcohols possessing an ester function in the allylic position. Cyclization of compounds 111 in the presence of iodine in acetonitrile at room temperature occurred very slowly (3 days).…”

Section: Preparation Of Oxetanesmentioning

confidence: 99%

Formation of Four-Membered Heterocycles through Electrophilic Heteroatom Cyclization

Robin

Rousseau

2002

Eur. J. Org. Chem.

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“…2,3 its use in two consecutive aldol-aldol reactions is rare 4 and often limited to trimerisation protocols. 5 We have recently outlined the first examples of a highly diastereoselective and widely applicable one-pot dominoaldol-aldol-hemiacetal strategy using metal bisenolates (or polyenolates) 3 and various aldehydes 2 (Scheme 1, top route, R 1 = R 4 ; R 2 = R 5 ) 6 yielding tetrahydropyran-2,4-diols 8 along the E1 + E1 + A route (using only one enol E1 and one aldehyde A).…”

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The elusive aldol reaction of enolates with aldolates—a highly stereoselective process using three different carbonyl components

et al. 2003

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Three different carbonyl components are assembled to tetrahydropyran-2,4-diols by two successive diastereoselective aldol reactions.Contrary to the ample usage of the aldol reaction in domino/ tandem 1 processes. 2,3 its use in two consecutive aldol-aldol reactions is rare 4 and often limited to trimerisation protocols. 5 We have recently outlined the first examples of a highly diastereoselective and widely applicable one-pot dominoaldol-aldol-hemiacetal strategy using metal bisenolates (or polyenolates) 3 and various aldehydes 2 (Scheme 1, top route, R 1 = R 4 ; R 2 = R 5 ) 6 yielding tetrahydropyran-2,4-diols 8 along the E1 + E1 + A route (using only one enol E1 and one aldehyde A). We now wish to report the first case of an E1 + E2 + A aldol-aldol protocol to yield structurally diversified tetrahydropyran-2,4-diols with up to 5 different groups R in a highly stereoselective manner.As 4 is a plausible intermediate (the metal center coordinates both to the aldolate ‡ and enolate) in the E1 + E1 + A reaction, 6 we contemplated realising the elusive E1 + E2 + A aldol-aldol reaction via its structural analogue 7. In such an approach, however, one has to worry that rapid retro-aldol reaction, as observed in the E1 + E1 + A route (4 ? 3 + 2), leads to a disastrous scrambling of the enol components, most likely the reason why any E1 + E2 + A reaction has been intangible so far.Realistically, the E1 + E2 + A aldol-aldol reaction can only be orchestrated when (i) an adequate way to assemble the desired intermediate 7 is found, and (ii) a metal is met that renders the 2. aldol step (Scheme 1) more rapid than retro-aldol reaction. 7 may originate from the reaction of mono-aldolate 5·Li with metal enolate 6. (pathway 1, Scheme 2; X = leaving group) or alternatively from lithium enolate 10 and metal aldolate 9 (pathway 2). Independent of the pathway the aldolate must have the correct relative anti configuration as in the tetrahydropyran-2,4-diol.Following our earlier results, 6 the influence of various metal fragments (MX m + n = TiCl 4 , TiCl 4 -Bu 3 N, Ti(OiPr) 2 Cl 2 , ZrCl 4 , SnCl 4 , InCl 3 , AlCl 3 , and ZnCl 2 ) in the reaction of metal enolate 6a (R 4 = Et, R 5 = Me) with anti 5a·Li 7 (R 1 = Ph, R 2 = Me, R 3 = Ph; d.e. = 75%) to afford 8a as the E1 + E2 + A product was explored (Scheme 3). From the metal fragments, only ZrCl 4 (19%), SnCl 4 (28%), InCl 3 (7%) and ZnCl 2 (14%) afforded 8a in some detectable yield.Most importantly, however, no retro-aldol cleavage of 5a was observed with SnCl 4 , whereas use of ZrCl 4 , InCl 3 , and ZnCl 2 led additionally to tetrahydropyran-2,4-diol 11, propiophenone and b-hydroxyketone 12, in particular at higher temperatures. The formation of the latter compounds unequivocally indicates occurrence of the unwanted retro-aldol reaction. Thus, the reaction was optimized with SnCl 4 varying the temperature, reaction time and stoichiometry. Finally, 8a was furnished in 63% at 40 °C, 4 h using SnCl 4 +enolate+monoaldolate = 1+2+2 attesting that two molecules of 8a form in the coor...

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Tandem Aldol-Cyclization Sequence for the Construction of Cyclic Ethers. The Formation of Substituted Tetrahydrofurans

Cited by 46 publications

References 0 publications

Direct Formic Acid MediatedZ‐Selective Reductive Coupling of Dienes and Aldehydes

Direct Formic Acid MediatedZ‐Selective Reductive Coupling of Dienes and Aldehydes

Formation of Four-Membered Heterocycles through Electrophilic Heteroatom Cyclization

The elusive aldol reaction of enolates with aldolates—a highly stereoselective process using three different carbonyl components

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