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In 1989, the asymmetric Mukaiyama aldol reaction mediated by a Lewis acid consisting of a chiral diamine and Sn(II) triflate was reported. The asymmetric Mukaiyama aldol reaction is now widely used as a versatile tool for the construction of highly advanced, multifunctionalized molecules. In this Personal Account, the history of the development of this powerful methodology and the application of the asymmetric Mukaiyama aldol reaction in the synthesis of natural products are reviewed.

Pyridine-3-carboxylic anhydride (3-PCA) was found to function as an efficient coupling reagent for the preparation of carboxylic esters from various carboxylic acids with alcohols under mild conditions by a simple experimental procedure. This novel condensation reagent 3-PCA was applicable not only for the synthesis of achiral carboxylic esters catalyzed by 4-(dimethylamino)pyridine (DMAP) but also for the production of chiral carboxylic esters by the combination of chiral nucleophilic catalyst, such as tetramisole (=2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b][1,3]thiazole) derivatives. An efficient kinetic resolution of racemic benzylic alcohols with achiral carboxylic acids was achieved by using 3-PCA in the presence of (R)-benzotetramisole ((R)-BTM), and a variety of optically active carboxylic esters were produced with high enantiomeric excesses by this new chiral induction system without using a tertiary amine.

A variety of optically active 2-hydroxyalkanoates and the corresponding 2-acyloxyalkanoates are produced by the kinetic resolution of racemic 2-hydroxyalkanoates by using achiral 2,2-diarylacetic acid with hindered carboxylic anhydrides as the coupling reagents. The combined use of diphenylacetic acid, pivalic anhydride, and (+)-(R)-benzotetramisole ((R)-BTM) effectively produces (S)-2-hydroxyalkanoates and (R)-2-acyloxyalkanoates from the racemic 2-hydroxyalkanoates (s-values=47-202). This protocol directly provides the desired chiral 2-hydroxyalkanoate derivatives from achiral diarylacetic acid and racemic secondary alcohols that do not include the sec-phenethyl alcohol moiety by using the transacylation process to generate the mixed anhydrides from the acid components with bulky carboxylic anhydrides under the influence of the chiral acyl-transfer catalyst. The transition state that provides the desired (R)-2-acyloxyalkanoate from (R)-2-hydroxyalkanoate included in the racemic mixture is disclosed by DFT calculations, and the structural features of the transition form are also discussed.

Various intermediates for the synthesis of erythronolide A, an aglycon of erythromycin A, are prepared from the corresponding seco-acids using 2-methyl-6-nitrobenzoic anhydride (MNBA) in the presence of 4-(dimethylamino)pyridine (DMAP) with or without triethylamine. The efficiency of the MNBA lactonization is assessed by studying this method and comparing the results with those of the other established macrocyclization protocols. It has been finally concluded that (i) the conformationally appropriate substrate for the monomeric cyclization gave the desired lactone in excellent yield under mild reaction conditions in the presence of MNBA and DMAP, (ii) the highly-strained substrate for the cyclization also afforded the monomeric lactone in relatively good yield at 100°C in toluene, and (iii) the seco-acid having stable linear conformation, which preferred dimerizing more than forming the monomeric lactone, provided the corresponding diolide in high yield with the constant ratio of the monomer to dimeric lactone (approximately 1/5). © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 305–320; 2009: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.200900017

A variety of optically active carboxylic esters were produced by kinetic resolution of racemic carboxylic acids by using achiral alcohols, benzoic anhydrides, and Birman's tetramisole-type catalysts. Bis(α-naphthyl)methanol is a very effective reagent for producing the corresponding esters with high ee values in the presence of 4-methoxybenzoic anhydride (PMBA) as the coupling reagent by promotion of benzotetramisole derivatives (BTM, α-Np-BTM, and β-Np-BTM). This protocol directly provides chiral carboxylic esters from free carboxylic acids and achiral alcohols by utilizing a transacylation process to generate the mixed anhydrides from the acid components with benzoic anhydride derivatives in the presence of chiral catalysts.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

We have developed effective methods for the total synthesis of 2-hydroxytetracosanolide and 2-hydroxy-24-oxooctacosanolide, the defensive salivary secretions of termites. The former natural product isolated from Armitermes neotenicus, a species of termite that inhabits Guyana, contains a 25-membered lactone backbone, and the latter, extracted from Pseudacanthoterme springer, an African termite, includes a 29-membered lactone moiety. The key cyclization to produce the 25- or 29-membered lactone core is performed by using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a stoichiometric amount of 4-(dimethylamino)pyridine (DMAP) or a catalytic amount of 4-(dimethylamino)pyridine N-oxide (DMAPO).

In the proline-mediated Mannich and aldol reactions of propanal as a nucleophile, the aldimine prepared from benzaldehyde and p-anisidine is about 7 times more reactive than the corresponding alde- hyde, benzaldehyde, as an electrophile. This higher reactivity of aldimine over aldehyde is attributed to the carboxylic acid of proline protonating the basic ni- trogen atom of the aldimine more effectively than the oxygen atom of the aldehyde, an explanation which has been both experimentally and theoretically veri- fied.

In 1989, the asymmetric Mukaiyama aldol reaction mediated by a Lewis acid consisting of a chiral diamine and Sn(II) triflate was reported. The asymmetric Mukaiyama aldol reaction is now widely used as a versatile tool for the construction of highly advanced, multifunctionalized molecules. In this Personal Account, the history of the development of this powerful methodology and the application of the asymmetric Mukaiyama aldol reaction in the synthesis of natural products are reviewed.

A practical protocol is developed to directly provide chiral α-acyloxyphosphonates and α-hydroxyphosphonates from (±)-α-hydroxyphosphonates utilizing the transacylation process to generate the mixed anhydrides from acid components and pivalic anhydride in the presence of organocatalysts (s-value = 33–518).

A new method for the total asymmetric synthesis of antitumor agent Taxol is described. Baccatin III, a complex carbon framework, is synthesized by way of B to BC to ABC ring construction. Further, a method of forming Taxol from baccatin III and a β-amino acid is also demonstrated.

The kinetic resolution of racemic alcohols (I) with phenylpropanoic acid (II) is examined and the optimized structure of the oxazole part in substrates (I) is determined.

The first efficient non-enzymatic method for providing optically active 1-heteroarylalkanol derivatives by kinetic resolution is given.

A widely applicable method is developed via generation of mixed anhydrides followed by reaction with bis(9-phenanthryl)methanol in the presence of (+)-benzotetramisole as the catalyst.

Anti-α,β-dihydroxy thioesters are prepared with excellent enantioselectivities by the asymmetric aldol reaction between both achiral aldehydes and silyl enol ethers derived from α-benzyloxy thioesters in the presence of a chiral promoter consisted of chiral diamine coordinated tin(II) triflate and dibutyltindiacetate.

In the presence of a chiral promoter consisting of tin(II) triflate, a chiral diamine, and tributylin fluoride, the silyl enol ether of S-ethyl ethanethioate or S-tert-butyl ethanetioate reacts with aldehydes to afford the corresponding aldol-type adducts in good yields with high enantioselectivities. In the reaction of silyl enol ether of S-ethyl propanethioate with aldehydes, perfect stereochemical control is attained by the combined use of tin(II) triflate, a chiral diamine, and dibutylin diacetate. A wide variety of aldehydes, including aliphatic, α,β-unsaturated, and aromatic aldehydes, are applicable to this reaction. The chiral promoters are characterized by 119 Sn NMR spectra and proved to form the three-component complexes, which behave as chiral Lewis acids. The reaction proceeds directly from silyl enol ethers without any accompanying metal exchange on the enolates

Three types of sugars, 6-deoxy-L-tallose,4-C-methyl-D-ribose, and D-ribose were synthesized from both achiral starting materials, α,β-unsaturated aldehydes and silyl enol ethers of α-benzyloxy thioesters, by successive asymmetric aldol and vicinal dihydroxylation reactions.

syn-α,β-Dihydroxy thioesters are prepared in good yields with high diastereo- and enantioselectivities by the asymmetric aldol reaction of 1-trimethylsiloxy-1-ethylthio-2-t-butyldimethylsiloxyethene with aldehydes using a chiral promoter consisting of tin(II) triflate, a chiral diamine and dibutyltin diacetate.

Various carboxylic esters are prepared in good to excellent yields by the reaction of equimolar amounts of silyl derivatives of carboxylic acids and alcohols by using a catalytic amount of active Lewis acid in hexamethyldisiloxane, a solvent.

The α-hydroxy-α-methyl-β-hydroxy units are enantioselectively prepared by way of asymmetric aldol reactions between both achiral β,β- disubstituted silyl enolates and aldehydes. (-)-2-C-Methyl-D-threono-1,4-lactone is conveniently synthesized by using this reaction

In the presence of a catalytic amount of Lewis acid, various carboxylic esters or S-phenyl carbothioates are prepared in excellent yields by the respective reactions of equimolar amounts of silyl carboxylates and alkyl silyl ethers or phenyl silyl sulfides with 4-trifluoromethylbenzoic anhydride.

Highly diastereo- and enantioselective aldol-type reactions of a silyl enol ether with aldehydes including aromatic, aliphatic, and α,β-unsaturated ones are performed in propionitrile (solvent) by the use of a catalytic amount of chiral tin(II) Lewis acid consisting of tin(II) triflate and a chiral diamine. The asymmetric environments created by the chiral catalysts in the enantioselective aldol reaction are discussed by employing five kinds of chiral diamines.

In the presence of a catalytic amount of titanium(IV) salt, various S-phenyl carbothioates are prepared in excellent yields by the reaction of nearly equimolar amounts of silyl derivatives of carboxylic acids and benzenethiols with p-trifluoromethylbenzoic anhydride.

An efficient method for the synthesis of macrolides directly from ω-hydroxycarboxylic acids is established by using 4-(trifluoromethyl)benzoic anhydride and a catalytic amount of active titanium(IV) salts together with chlorotrimethylsilane under mild conditions.

Various carboxylic esters are prepared in excellent yields from nearly equimolar amounts of free carboxylic acids and alcohols at room temperature by combined use of 4-(trifluoromethyl)benzoic anhydride and a catalytic amount of active titanium(IV) salt together with chlorotrimethylsilane.

In the presence of a catalytic amount of active titanium(IV) salt generated in situ from 1 mol of TiCl4 and 2 mol of AgOTf, weakly nucleophilic anilines react under mild conditions with nearly equimolar amounts of silyl carboxylates to afford the corresponding anilides in excellent yields using 4-(trifluoromethyl)benzoic anhydride. The mixed anhydride formed in situ from trimethylsily acetate and 4-(trifluoxomethyl)benzoic anhydride, a key intermediate of this reaction, was detected by 1H NMR experiment. Further, it was shown that the reaction of the mixed anhydrides and 2-nitroaniline was faster than that of the corresponding homo anhydrides and 2-nitroaniline.

syn- and anti-1,2-Diol units were prepared by using asymmetric aldol reactions of the silyl enol ethers derived from α-alkoxythioacetic S-esters with aldehydes. In the presence of tin(II) triflate, a chiral diamine, and dibutyltin diacetate, (Z)-2-benzyloxy-1-ethylthino-1-(trimethylsiloxy)ethene reacted with aldehydes to afford the corresponding anti-aldol adducts in high yields with excellent diastereo- and enantioselectivities, while syn-adducts were obtained from (Z)-2-(t-butyldimethylsiloxy)-1-ethylthio-1-(trimethylsiloxy)ethene and aldehydes under the same reaction conditions. Thus, both diastereomers can be synthesized in excellent enantiomeric excesses by simply choosing the protective groups of the alkoxyl parts of the silyl enol ethers.

Catalytic Diels-Alder reactions between several 1,3-dienes and α,β-unsaturated ketones are effectively promoted by the combined use of diphenyltin sulfide (Ph2Sn=S) and silver perchlorate or Lawesson’s reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) and silver perchlorate under mild conditions.

1-t-Butyldimethylsiloxy-8,11,11-trimethylbicyclo[5.3.1]undec-7-en-9-one (2) has been synthesized via intramolecular aldol condensation of the precursor 3 by combined use of lithium diisopropylamide (LDA) and CeCl3. The dicarbonyl compound 3 was prepared by allylation of 8-membered ring ketone 6b.

Optically active 3,7-dibenzyloxy-4,8-di-t-butyldimethylsiloxy-5,5-dimethyl-6-p-methoxybenzyloxy-2-octanone (2) has been synthesized by way of diastereoselective aldol reaction between 4-benzyloxy-5-t-butyldimethylsiloxy-2,2-dimethyl-3-p-methoxy-benzyloxypentanal (3) and ketene silyl acetal 4 using MgBr2·OEt2 as a catalyst. The chiral pentanal 3 was synthesized either by asymmetric aldol reaction of both prochiral aldehyde 5 and ketene silyl acetal 4 using a chiral Lewis acid or by diastereoselective aldol reaction between the chiral aldehyde 6 derived from L-serine and the lithium enolate derived from methyl isobutyrate.

Optically active 7-t-butyldimethylsiloxy-4,8-dibenzyloxy-6,6-dimethyl-5-p-methoxybenzyloxy-2-cycloocten-1-one (1) was synthesized from 3,7-dibenzyloxy-4,8-di-t-butyldimethylsiloxy-5,5-dimethyl-6-p-methoxybenzyloxy-2-octanone (2) by way of intramolecular Reformatsky-type reaction using SmI2.

Various carboxylic esters are prepared in good to high yields from equimolar amounts of free carboxylic acids and alcohols by the combined use of octamethylcyclotetrasiloxane and a catalytic amount of TiCl(OTf)3.

Optically active 9-t-butyldiphenylsiloxy-11,11-dimethyl-5-methoxymethoxy-1,2,6-tribenzyloxybicyclo[5.3.1]undec-3,7-diene (12) was synthesized from diketone 9 via an intramolecular aldol reaction. The diketone 9 was synthesized from 7-t-butyldimethylsiloxy-4,8-dibenzyloxy-6,6-dimethyl-5-p-methoxy-benzyloxy-2-cycloocten-1-one (1) by way of a two-step sequence using diastereoselective allylation with allylmagnesium bromide followed by Wacker oxidation.

Optically active novel taxoids were efficiently synthesized from 8-membered ring compound 3 by successive constructions of BC and ABC ring systems via each intramolecular aldol and intramolecular pinacol coupling reactions.

Optically active 2α,10β-dibenzyloxy-11β-(t-butyldimethylsiloxy)-7β-hydroxy-1α-(4-methoxybenzyloxy)–8β,15,15-trimethyl-4-methylene-trans-bicyclo[6.4.0]dodecan-9-one 2 that corresponds to BC ring system of Taxol was prepared from 8-membered ring enone 3 in high yield via stereoselctive Michael addition and successive intramolecular aldol cyclization. The above 8-membered ring enone 3 was synthesized from the linear optically active polyoxy-compound 4 by SmI2-mediated intramolecular aldol cyclization.

Total asymmetric synthesis of Taxol was completed by dehydration condensation between a protected N-benzoylphenylisoserine 4 or 9 and 7-TES baccatin III which was prepared from 8-membered ring enone. Taxol side chains 4, 7, 9 and 11, optically active protected N-benzoylphenylisoserines, were successfully synthesized by enantioselective aldol reaction from two achiral starting materials, benzaldehyde and an enol silyl ether derived from S-ethyl benzyloxyethanethioate.

Baccatin III was efficiently synthesized from the BC ring system of Taxol,2α,10β-dibenzyloxy-11β-(t-butyldimethylsil-oxy)-7β-hydroxy-1α-(4-methoxybenzyloxy)-8β,15,15-trimethyl-4-methylene-trans-bic...

An efficient method for the synthesis of (−)-cephalosporolide D was established via successive enantioselective aldol reaction and effective construction of 8-membered ring lactone moiety.

Various carboxylic esters were obtained in high yields from free carboxylic acids and several alcohols including bulky ones by using O,O′-di(2-pyridyl) thiocarbonate and a catalytic amount of DMAP.

The reductive coupling reaction of aromatic and aliphatic ketones including acyclic aliphatic ketones proceeded smoothly to give the corresponding pinacols in good to high yields below room temperature by the combined use of titanium(II) chloride and zinc in the presence of pivalonitrile. Meso-selective formation of the coupling products was observed in the cases with some acyclic aliphatic ketones.

Stereoselective Diels-Alder reaction between several α,β-unsaturated ketones and acetoxy-1,3-butadienes is effectively performed by the promotion of diethylaluminum ethoxide under mild conditions. This reaction is successfully applied to the synthesis of optically active bicyclo[6.4.0]dodecanone 9 which corresponds to the BC ring system of 10-deoxy taxane derivatives from the 8-membered ring enone 7 and diene 2.

Optically active novel 18-demethyltaxiods were successfully synthesized from 2α,10β-dibenzyloxy-11β-(t-butyldimethylsiloxy)-7β-hydroxy-1α-(p-methoxybenzyloxy)-8β,15,15-trimethyl-4-methylene-trans-bicyclo[6.4.0]dodecan-9-one (2) which corresponds to the BC ring system of Taxol by stereoselective allylation and intramolecular aldol condensation reactions.