Highly stereoselective aldol reactions of titanium enolates from ethyl α-silyloxyalkyl ketones

Figueras, Sergi; Martin, R. H.; Romea, Pedro; Urpı́, Fèlix; Vilarrasa, Jaume

doi:10.1016/s0040-4039(97)00108-1

Cited by 35 publications

(12 citation statements)

References 14 publications

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“…[21] Der Wechsel von einem Bor-zu einem Titanreagens (TiCl 4 ) [22] und intensive Optimierungen von Reaktionszeiten und -temperaturen führten zu deutlich verbesserten Ergebnissen (Tabelle 1). Erfreulicherweise entstand das gewünschte Hydroxyketon 21 unter den optimierten Bedingungen in einer Ausbeute von 88 % und guter Selektivität zugunsten des gewünschten Diastereomers.…”

Section: Methodsunclassified

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Totalsynthese von Thuggacin B

2008

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Section: Methodsunclassified

“…[22] Die diastereofaciale Selektivität wird durch elektrostatische Abstoßung zwischen der a-OTBS-Gruppe und dem Enolat gesteuert. Die korrekte 1,4-Stereoinduktion wurde durch Analyse der Mosher-Ester von Hydroxyketon 21 bestätigt.…”

Section: Methodsunclassified

Totalsynthese von Thuggacin B

2008

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“…Initial experiments with the boron enolate afforded the aldol product in only moderate yield and selectivity. [21] After switching from boron to titanium (TiCl 4 ) [22] and substantially optimizing the reaction time and temperature, we could significantly improve the outcome of the reaction (Table 1). To our delight, the desired hydroxyketone 21 was formed in 88 % yield with good selectivity for the desired diastereoisomer under the optimized conditions.…”

Section: Dedicated To Ernst Schaumann On the Occasion Of His 65th Birmentioning

confidence: 99%

“…[22] Facial selectivity is governed by electrostatic repulsion between the enolate and the a-OTBS group. The correct 1,4-stereoinduction was confirmed by analysis of the Mosher esters prepared from hydroxyketone 21.…”

Section: Angewandte Chemiementioning

confidence: 99%

Total Synthesis of Thuggacin B

Böck¹,

Dehn²,

Kirschning³

2008

Angew Chem Int Ed

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Final proof of the complete structures of thuggacins A–C was gained by a highly convergent and flexible total synthesis. Notable features include a substrate‐controlled, titanium‐mediated aldol reaction, a cross‐metathesis approach for converting terminal alkenes into the corresponding vinyl iodides, and the cross‐coupling of a complex vinyl iodide and terminal alkyne in the Sonogashira reaction.

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“…While we are still exploring the nature of the diastereoselectivity, one possible explanation could be a transition state which minimizes the dipoles of the C 21 C-O σ bond and the enolate. 7 The alternate 18S diastereomer can be obtained by performing the reaction at higher temperatures (−40 °C, 1.2:1 dr 5:6). Silyl protection of alcohols 5 and 6 separately using TESCl/ DMAP yielded the silyl ether compounds 17 and 18, respectively.…”

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confidence: 99%

Total Synthesis of Cytotoxic Macrolide Amphidinolide B₁ and the Proposed Structure of Amphidinolide B₂

2008

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Amphidinolide B 1 (1) and its C 18 epimer amphidinolide B 2 (2) have generated significant attention from the synthetic community 1,2 because of their potent cytotoxic activity against several cancer cell lines. In fact, macrolide 1 is the most potent member of this family with a reported IC 50 value of 0.14 ng/mL against L1210 murine leukemia cell line. 3 Despite these efforts, their total syntheses remain elusive targets. Macrolides 1 and 2 represent considerable synthetic challenges because of their highly substituted C 13 -C 15 diene functionality, 1c,4 the densely functionalized C 21 -C 26 right-hand portion, the labile C 6 -C 9 epoxy alkene, and a 26-membered lactone. Our retrosynthetic strategy starts by disconnection at C 8,9 to reveal the aldehydes 3 and 4 (Scheme 1). Further cleavage of the ester linkage at C 25 would lead to the alcohols 5 and 6 and the keto phosphonate 7. The C 18 -C 19 bond should be available via a diastereoselective aldol reaction with the aldehyde 8 and α-oxy ketone 9. We have previously reported a chelation strategy for the synthesis of the 18S stereochemistry present in amphidinolide B 1 1b,c,5 and this approach has been used by others in the field, 6 including Fürstner's recent total syntheses of amphidinolide G and H. 6a Herein, we report a nonchelation strategy for construction of the C 18 stereochemistry and its application to the total syntheses of cytotoxic macrolide amphidinolide B 1 (1) and the proposed structure of amphidinolide B 2 (2).Our syntheses of the aldehyde and methyl ketone subunits commenced with the previously reported intermediates 11 and 14 (Scheme 2). 1a,c Conversion of the C 9 nitrile 11 into the corresponding acetate 12 followed by selective functionalization of the C 18,19 alkene using AD mix β* provided the C 18,19 diol as an inconsequential 6:1 mixture of diastereomers. 1c Cleavage of the resultant diol with sodium periodate provided the desired aldehyde 8. For the synthesis of the Eastern subunit 9, Horner-Wadsworth-Emmons olefination of aldehyde 14 followed by dihydroxylation yielded the diol 16. Next, bis-silylation followed by selective C 25 TES deprotection yielded the free alcohol at C 25 . Finally, Mitsunobu inversion of the alcohol followed by saponification and TMS protection revealed the ketone 9.The key diastereoselective aldol coupling is shown in Scheme 3. Treatment of ketone 9 under our standard LDA, Et 2 O/THF conditions that proved effective with the C 21 OPMB series 1c resulted in low conversion and poor diastereoselectivity favoring the 18S stereochemistry [approximately 1.5:1 dr (5:6)]. Interestingly, addition of TMEDA led to a dramatic rate acceleration and a reversal of the selectivity [2:1 dr (6:5)]. Additional cooling of the reaction to −100 °C led to improved diastereoselectivity [8:1 dr (6:5)] in reasonable yield (65% overall). While we are still exploring the nature of the diastereoselectivity, one possible explanation could be a transition state which minimizes the dipoles of the C 21 C-O σ bond and the enolate. temperatur...

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Highly stereoselective aldol reactions of titanium enolates from ethyl α-silyloxyalkyl ketones

Cited by 35 publications

References 14 publications

Totalsynthese von Thuggacin B

Totalsynthese von Thuggacin B

Total Synthesis of Thuggacin B

Total Synthesis of Cytotoxic Macrolide Amphidinolide B₁ and the Proposed Structure of Amphidinolide B₂

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Highly stereoselective aldol reactions of titanium enolates from ethyl α-silyloxyalkyl ketones

Cited by 35 publications

References 14 publications

Totalsynthese von Thuggacin B

Totalsynthese von Thuggacin B

Total Synthesis of Thuggacin B

Total Synthesis of Cytotoxic Macrolide Amphidinolide B1 and the Proposed Structure of Amphidinolide B2

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Product

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Total Synthesis of Cytotoxic Macrolide Amphidinolide B₁ and the Proposed Structure of Amphidinolide B₂