Pronounced rate enhancements in condensation reactions attributed to the fluorous tag in modified Mukaiyama reagents

The observed rate enhancement for the condensation reaction between 2-phenyl benzoic acid and isopropanol mediated by fluorous Mukaiyama reagents is described. It is shown that Mukaiyama reagents bearing a fluorous tag increase the reaction rate considerably when compared to their non-fluorous tagged counterpart. Furthermore, it is observed that the longer the fluorous chain, the higher the activity of the Mukaiyama reagent.     

A fluorous Mukaiyama coupling reagent for a concise condensation reaction: utility of medium-fluorous strategy

The entire study of condensation reactions using various fluorous Mukaiyama reagents, including a novel medium-fluorous strategy, is described. A Mukaiyama reagent bearing a medium-fluorous content tag, between 40 and 60% fluorine by weight, was prepared and examined in ester and amide-forming condensation reactions. At the end of the reactions, the fluorous pyridone by-product was effectively separated from non-fluorous components by increasing the water content of the crude reaction mixture and subsequent filtration of the precipitate. It is also shown that Mukaiyama reagents bearing a fluorous tag increase the reaction rate considerably when compared to their non-fluorous tagged counterpart. Interestingly, it was observed that the longer the fluorous chain, the higher the activity of the Mukaiyama reagent.     

Thiazolinium salt: an efficient catalyst for the Mukaiyama reaction

Mukaiyama aldol reaction between benzaldehyde and Danishefsky diene is promoted by ionic liquid-type salts. Hence, thiazolinium salts have been found to be the most efficient for this transformation. On a mechanistic point of view, only the Mukaiyama process is observed without any hetero Diels-Alder cycloaddition. In some cases, cyclisation of the Mukaiyama adduct occurred without addition of TFA. Interestingly, the thiazolinium catalyst can be recycled at least 10 times without loss of activity.     

An environmentally friendly procedure for Mukaiyama aldol and Mukaiyama-Michael reactions using a catalytic amount of DBU under solvent- and metal-free conditions

Mukaiyama aldol and Mukaiyama-Michael reactions can proceed smoothly in the presence of a catalytic amount of DBU (20% mmol), to afford the corresponding products in moderate to good yields. This solvent- and metal-free approach provides an environmentally friendly procedure for Mukaiyama reactions.     

Toward the synthesis of γ-pyrone-containing natural products: diastereoselective aldol-type reaction of a γ-pyrone

The diastereoselective aldol-type reaction of a γ-pyrone via a sodium anion has been developed. This reaction is useful for synthesizing γ-pyrone-containing natural products. Also, we applied the Mukaiyama aldol-type reaction of silyl enol ether of γ-pyrone by using TiCl₄. This Mukaiyama aldol-type reaction of γ-pyrone indicated higher anti-aldol selectivity than the aldol-type reaction of a γ-pyrone with NaHMDS.     

Enantioselective total synthesis of convolutamydines B and E

[reaction: see text] The first enantioselective total synthesis of convolutamydines B and E has been achieved using our vinylogous Mukaiyama aldol reaction. The synthesis features highly diastereoselective vinylogous Mukaiyama aldol reaction with isatin instead of aldehydes to construct a chiral center of convolutamydines. Additionally, the absolute configuration of natural convolutamydine B has been determined as R by its CD spectrum.     

Asymmetric vinylogous Mukaiyama aldol reaction of aldehyde-derived dienolates

Unsaturated aldehydes are exquisite building blocks for further transformations in polyketide synthesis. Besides standard transformations that take advantage of the aldehyde functionality, the conjugate addition of hydrides followed by internal protonation allows access to alpha chiral aldehydes. Even though vinylogous Mukaiyama aldol reactions have been used in natural product syntheses before, the first enantioselective Mukaiyama aldol reaction of aldehyde-derived dienolates is described.     

Study of the lanthanide-catalyzed, aqueous, asymmetric Mukaiyama aldol reaction

The development of efficient methods for the asymmetric Mukaiyama aldol reaction in aqueous solution has received great attention. We have developed a new series of chiral lanthanide-containing complexes that produce Mukaiyama aldol products with outstanding enantioselectivities. In this paper, we describe an optimized ligand synthesis, trends in stereoselectivity that result from changing lanthanide ions, and an exploration of substrate scope that includes aromatic and aliphatic aldehydes and silyl enol ethers derived from aromatic and aliphatic ketones.     

Synthesis of propionate motifs: diastereoselective tandem reactions involving anionic and free radical based processes

Reported herein is a strategy employing a Mukaiyama reaction in tandem with a hydrogen transfer reaction for the elaboration of propionate motifs. The nature of the protecting groups on the chiral beta-alkoxy aldehyde and the type of Lewis acid used are varied to modulate the stereochemical outcome of the tandem reactions. The mode of complexation is thus controlled (monodentate or chelate) for the Mukaiyama reaction to give access to either syn or anti aldol products, precursors of the free radical reduction reaction. The endocyclic effect is subsequently capitalized upon to control the hydrogen transfer step so that the syn-reduced product may be achieved. Proceeding with excellent yield and diastereoselectivity, the synthetic sequence proposed gives access to syn-syn and syn-anti propionate motifs. Also considered is a complementary approach using a chelation-controlled Mukaiyama reaction in tandem with a free radical allylation reaction under the control of the endocyclic effect that leads to the anti-anti product.     

Recent development of vinylogous Mukaiyama aldol reactions

The vinylogous Mukaiyama aldol reaction (VMAR) is a powerful tool of polyketide synthesis, which constructs a large size structure by simultaneous introduction of the stereogenic center(s) and the α,β-unsaturated carbonyl group. A variety of stereocontrolled VMARs have been developed and applied to natural product synthesis. This review is focused on recent development of the vinylogous Mukaiyama aldol reaction using s-trans silyl dienolates.     

Synthesis of 2,3-anti-3,4-anti and 2,3-anti-3,4-syn propionate motifs: a diastereoselective tandem sequence of Mukaiyama and free-radical-based hydrogen transfer reactions

[reaction: see text] Reported herein is a strategy employing a Mukaiyama reaction in tandem with a hydrogen transfer reaction for the elaboration of 2,3-anti-3,4-anti and 2,3-anti-3,4-syn propionate motifs. The mode of complexation is controlled through monodentate or chelate pathways for the Mukaiyama reaction to give access to either syn or anti aldol products, precursors of the free-radical reduction reaction. Boron Lewis acid is used to control the free-radical reaction through the exocyclic pathway.     

Remote asymmetric induction with vinylketene silyl n,o-acetal

A highly regio- and diastereoselective TiCl4-mediated vinylogous Mukaiyama aldol reaction using the chiral vinylketene silyl N,O-acetal has been developed. The present vinylogous Mukaiyama aldol reaction provides a unique and effective means of controlling remote asymmetric induction. The methyl group at the alpha-position is important in achieving a high level of stereoselectivity. From a synthetic point of view, this methodology can provide a one-step construction of delta-hydroxy-alpha,gamma-dimethyl-alpha,beta-unsaturated carbonyl unit that is seen in many natural polyketide products.     

The Impact of the Mukaiyama Aldol Reaction in Total Synthesis

Four decades since Mukaiyama’s first reports on the successful application of silicon and boron enolates in directed aldol reactions, the ability of this highly controlled carbon–carbon bond‐forming method to simultaneously define stereochemistry, introduce complexity, and construct the carbon skeleton with a characteristic 1,3‐oxygenation pattern has made it a powerful tool for natural product synthesis. This Minireview highlights a number of representative total syntheses that demonstrate the impact of the Mukaiyama aldol reaction and discusses the underlying mechanistic rationale that determines the stereochemical outcomes.     

Efficient one-step aldol-type reaction of ketones with acetals and ketals mediated by dibutylboron triflate/diisopropylethyl amine

one-step Mukaiyama aldol type reaction [reaction: see text] A highly efficient one-step Mukaiyama aldol-type reaction has been developed for the synthesis of beta-alkoxy carbonyl compounds starting from ketones and acetals/ketals. The reaction is mediated by a combination of Bu(2)BOTf and i-Pr(2)NEt affording the products in high yields. Formation of the two possible diastereoisomers of the beta-alkoxy ketones from the chiral acetals shows that the condensation takes place by an S(N)1 mechanism, involving prior opening of the acetal to an oxonium ion.     

Total synthesis and stereochemical reassignment of (+)-dolastatin 19, a cytotoxic marine macrolide isolated from Dolabella auricularia

Using conformational analysis and biogenetic considerations, a revised configurational assignment for the cytotoxic marine macrolide dolastatin 19 is proposed, together with its validation by completion of the first total synthesis. Key features of the highly stereocontrolled route include an asymmetric vinylogous Mukaiyama aldol reaction to simultaneously install both the remote C13 stereocenter and the C10-C11 (E)-trisubstituted olefin, two sequential 1,4-syn boron-mediated aldol reactions, and a late-stage, α-selective Mukaiyama glycosylation to append the l-rhamnose-derived pyranoside.     

Precolumn fluorescence tagging reagent for carboxylic acids in high-performance liquid chromatography: 4-substituted-7-aminoalkylamino-2,1,3-benzoxadiazoles.

Four new 2,1,3-benzoxadiazole amine reagents having different functional groups at the 4- and 7-positions, [4-nitro-7-N-piperazino-2,1,3-benzoxadiazole (NBD-PZ), 4-(N,N-dimethylaminosulphonyl)-7-N-piperazino-2,1,3-benzoxad iazole (DBD-PZ), 4-(N,N-dimethylaminosulphonyl)-7-N-cadaverino-2,1,3-benzoxad iazole (DBD-CD) and ammonium 7-N-piperazino-2,1,3-benzoxadiazole-4-sulphonate (SBD-PZ)] were synthesized as fluorogenic tagging reagents for carboxylic acids in high-performance liquid chromatography. The reagents, except SBD-PZ, reacted with carboxylic acid at room temperature in the presence of activation agents to produce fluorescent adducts. The maximum wavelengths of arachidic acid tagged with DBD-PZ, DBD-CD and NBD-PZ were 569 nm (excitation, 440 nm), 561 nm (excitation, 437 nm) and 541 nm (excitation, 470 nm), respectively. Among various activation agents tested [diethyl phosphorocyanidate (DEPC), diphenyl phosphoroyl azide (DPPA), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-pyridine, 2.2'-dipyridyl disulphide-triphenylphosphine (Mukaiyama A) and 2-chloro-1-methylpyridinium iodide-triethylamine (Mukaiyama B)], DEPC and Mukaiyama A were more effective than the others. When the piperazino reagents (DBD-PZ and NBD-PZ) were used as the tagging reagents, the derivatization reaction in the presence of Mukaiyama A was faster than that in the presence of DEPC. Although the reaction in the presence of Mukaiyama A was completed after 30 min, an unknown peak derived from the activation agent appeared on the chromatograms. The fluorescence peak intensities were compared in the presence of DEPC. The order of the fluorescence peak areas obtained after reaction for 6 h in the presence of DEPC was DBD-PZ greater than DBD-CD greater than NBD-PZ. Thirteen saturated free fatty acids (FFAs) derivatized with DBD-PZ (or DBD-CD) and DEPC (or Mukaiyama A) in acetonitrile were separated completely by linear gradient elution on a reversed-phase ODS column. Eight drugs (ibuprofen, indomethacin, dinoprost, prostaglandin E1, dehydrocholic acid, ursodesoxycholic acid, hydrocartisone succinate and prednisolone succinate) were also tagged with DBD-PZ in the presence of DEPC and separated by isocratic elution. The detection limits (signal-to-noise ratio = 3) of FFAs tagged with DBD-PZ were in the range 3.2-4.7 fmol, whereas those of drugs were in the range 3.9-14 fmol.     

N-heterocyclic carbene-catalyzed Mukaiyama aldol reactions

N-Heterocyclic carbenes were shown to be highly effective catalysts to promote Mukaiyama aldol reactions. In the presence of only 0.5 mol % of N-heterocyclic carbene (5), various aldehydes and 2,2,2-trifluoroacetophenone underwent Mukaiyama aldol reactions in THF with trimethylsilyl ketene acetal (2) at 23 degrees C as well as with trimethylsilyl enol ether (7) at 0 degrees C to afford aldol adducts in good yields. These conditions are extremely mild and operationally simple and tolerate various functional groups. [reaction: see text]     

The Mukaiyama Aldol Reaction: 40 Years of Continuous Development

A directed cross‐aldol reaction of silyl enol ethers with carbonyl compounds, such as aldehydes and ketones, promoted by a Lewis acid, a reaction which is now widely known as the Mukaiyama aldol reaction. It was first reported in 1973, and this year marks the 40th anniversary. The directed cross‐aldol reactions mediated by boron enolates and tin(II) enolates also emerged from the Mukaiyama laboratory. These directed cross‐aldol reactions have become invaluable tools for the construction of stereochemically complex molecules from two carbonyl compounds. This Minireview provides a succinct historical overview of their discoveries and the early stages of their development.     

Synthesis of the C1-C23 fragment of Spirastrellolide A

Synthesis of the C1-C23 fragment in spirastrellolide A is described, featuring a cyclic acetal-tethered RCM for stereoselective constructions of spiroketal, and a 1,3- anti aldol involving methyl ketone enolate and Mukaiyama conditions.     

An environmentally friendly Mukaiyama aldol reaction catalyzed by a strong Brønsted acid in solvent-free conditions

o-Benzenedisulfonimide, a new strong bench-stable Br?nsted acid, has been shown to efficiently catalyze the Mukaiyama aldol reaction of aldehydes or dimethyl acetals with silyl enol ethers under mild solvent-free reaction conditions.