Titanium and Boron Mediated Aldol Reactions of .beta.-Hydroxy Ketones

Luke, George P.; Morris, Joel

doi:10.1021/jo00115a015

Cited by 46 publications

(22 citation statements)

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“…The following results indicate that the dimerization reaction is quantitative; reaction of the methylketene with aniline afforded approximately 30% of the corresponding amide, and reduction of purified 1 afforded a 70% yield of 3 . While the yield for this reaction sequence is lower than that for the existing route to 3 , the low cost of the starting material (100 g/$18.25 for 2-bromopropionyl bromide from Aldrich) and the lack of intermediate isolations make this route attractive. We are currently exploring the asymmetric dimerization of methylketene generated by alternative means and also different methods for reduction.…”

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confidence: 98%

Catalytic, Asymmetric Dimerization of Methylketene

Calter

1996

J. Org. Chem.

102

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We hope to develop quick, inexpensive routes to biologically important classes of molecules using catalytic, asymmetric transformations. Toward this goal, we are exploring reactions catalyzed by chrial tertiary amines. Tertiary amines are attractive catalysts, as these compounds are generally stable, inexpensive, and less toxic than most transition metals. Although the asymmetric variants of some tertiary amine-catalyzed processes are known, 1 many such reactions have not been attempted with chiral catalysts. One example of the latter case is the tertiary amine-catalyzed dimerization of methylketene (Scheme 1). 2,3 We report here that cinchona alkaloids and their derivatives catalyze the dimerization of methylketene with high enantioselectivity, yielding a product that easily transforms into a useful synthon for polypropionate synthesis.The tertiary amine-catalyzed dimerization of methylketene yields -lactone 1 via a formal Claisen condensation (Scheme 1). We reasoned that a chiral tertiary amine might impose a facial bias on ammonium enolate 2, eventually producing -lactone 1 in an optically enriched form. We were encouraged in this respect by the high enantioselectivity (98% ee) realized by Wynberg in the related cycloaddition of ketene to chloral catalyzed by cinchona alkaloids. 4 We also assumed that 1 would be a useful polypropionate precursor. Accordingly, we studied the dimerization of methylketene catalyzed by various chiral, nonracemic tertiary amines.We used Ward's procedure to prepare a -78°C solution of methylketene in tetrahydrofuran (THF). 5 In this procedure, the ketene distilled away from the reaction pot as it formed, yielding a reactant solution free of any starting materials or byproducts. We then added the ketene solution to 1 mol % of the amine catalyst in THF at -78°C (Scheme 2). The volatility and instability to silica gel of 1 hampered the isolation of this compound, so we added LiAlH 4 to the reaction mixture to produce primary alcohol 3 (Table 1). 6 Either enantiomer of 3 is produced with high enantiocontrol from the dimerization of methylketene with readily available catalysts. Quinidine and its derivatives afford uniformly high enantioselectivities, while quinine and propionylquinine are notably less selective catalysts. This trend is similar to trends observed in numerous processes utilizing cinchona alkaloids as catalysts or ligands. 1 The overall yield for this reaction sequence is 20% based on bromopropionyl bromide, regardless of the identity of the catalyst. The following results indicate that the dimerization reaction is quantitative; reaction of the methylketene with aniline afforded approximately 30% of the corresponding amide, and reduction of purified 1 afforded a 70% yield of 3. While the yield for this reaction sequence is lower than that for the existing route to 3, 7 the low cost of the starting material (100 g/$18.25 for 2-bromopropionyl bromide from Aldrich) and the lack of intermediate isolations make this route attractive. We are currently exploring the asymmetr...

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confidence: 98%

Catalytic, Asymmetric Dimerization of Methylketene

Calter

1996

J. Org. Chem.

102

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“…Therefore, the mixture of 16 and 17 was taken on via a 4-step route involving NaOH hydrolysis of the silyl ether to form ketone 18 , Horner–Wadsworth–Emmons olefination, 23 Pd-catalyzed stereoselective hydrogenation, and AlMe 3 -mediated Weinreb amide formation. 24 At this point, the desired Weinreb amide 19 could be separated from the regioisomeric mixture obtained from the cyclopropene/cyclopentadiene Diels–Alder reaction. Treatment with vinylmagnesium bromide 25 then KHMDS, TBSOTf 26 provided Z -siloxydiene 9 , the 4π-component for the second key Diels–Alder cycloaddition below.…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis, Relay Synthesis, and Structural Confirmation of the C18-Norditerpenoid Alkaloid Neofinaconitine

et al. 2013

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The first total synthesis of the C18-norditerpenoid aconitine alkaloid neofinaconitine and relay syntheses of neofinaconitine and 9-deoxylappaconitine from condelphine are reported. A modular, convergent synthetic approach involves initial Diels–Alder cycloaddition between two unstable components, cyclopropene 10 and cyclopentadiene 11. A second Diels–Alder reaction features the first use of an azepinone dienophile 8, with high diastereofacial selectivity achieved via rational design of the siloxydiene component 36 with a sterically-demanding bromine substituent. Subsequent Mannich-type N-acyliminium and radical cyclizations provide the complete hexacyclic skeleton 33 of the aconitine alkaloids. Key endgame transformations include installation of the C8-hydroxyl group via conjugate addition of water to a putative strained bridghead enone intermediate 45, and one-carbon oxidative truncation of the C4 sidechain to afford racemic neofinaconitine. Complete structural confirmation was provided by a concise relay synthesis of (+)-neofinaconitine and (+)-9-deoxylappaconitine from condelphine, with X-ray crystallographic analysis of the former clarifying the NMR spectral discrepancy between neofinaconitine and delphicrispuline, which were previously assigned identical structures.

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“…followed by i Pr 2 EtN (2.4 equiv.) according to the procedure 70 of Luke and Morris and led to the isolation of three aldol adducts: meso 99a (60%), (AE)-99b (6%), and (AE)-99e (4%). 61 Further optimization of the conditions using Ti(O i Pr)Cl 3 in place of TiCl 4 and adding the i Pr 2 EtN in two portions produced 99a in excellent yield with remarkable stereoselectivity (dr > 30).…”

Section: Diastereoselective Reactions With Chiral Aldehydesmentioning

confidence: 99%

“…71 Although the optimized conditions for each substrate were slightly different, in each case the reaction occurred with substantial MKE to give one of the eight possible adducts with high selectivity (indicated dr refers to major:others) with the same overall stereoselectivity (i.e., major adducts result from a cis-anti-Felkin aldol reaction). We presume that the high propensity for cis addition of the enolate to the Felkin diastereoface of the aldehyde with anti relative topicity results from reaction of a cyclic enolate 70 via the 'closed' transition state 100.…”

Section: Diastereoselective Reactions With Chiral Aldehydesmentioning

confidence: 99%

The thiopyran route to polypropionates

Ward

2011

Chem. Commun.

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The strategic use of thiopyran templates to facilitate polypropionate synthesis was first demonstrated in Woodward's landmark total synthesis of erythromycin A in 1981 where the topology of a fused bicyclic system was exploited. In the ensuing three decades, various alternative strategic applications of thiopyran motifs to achieve key stereoselective transformations have emerged including, inter alia, unique substrates for chemoenzymatic syntheses, surrogates for 3-pentanone in enantioselective aldol reactions, and templates for enantiotopic group selective reactions. This review summarizes these developments.

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Titanium and Boron Mediated Aldol Reactions of .beta.-Hydroxy Ketones

Cited by 46 publications

References 2 publications

Catalytic, Asymmetric Dimerization of Methylketene

Catalytic, Asymmetric Dimerization of Methylketene

Total Synthesis, Relay Synthesis, and Structural Confirmation of the C18-Norditerpenoid Alkaloid Neofinaconitine

The thiopyran route to polypropionates

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