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.     

Total synthesis of khafrefungin using highly stereoselective vinylogous Mukaiyama aldol reaction

[structure: see text] A convergent total synthesis of khafrefungin was accomplished on the basis of (1) the highly stereoselective TiCl4-mediated vinylogous Mukaiyama aldol reaction using vinylketene silyl N,O-acetal and (2) syn-selective aldol reaction of enal 5a and ethyl ketone 6 followed by anti-dehydration under Mitsunobu conditions.     

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.     

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.     

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.     

Concise total synthesis of (-)-myxalamide A

The MIDA touch: A concise and highly convergent protecting-group-free total synthesis of (-)-myxalamide?A involves a stereoselective vinylogous Mukaiyama aldol reaction of a vinylketene silyl N,O-acetal, together with a one-pot Stille/Suzuki-Miyaura cross-coupling reaction using Burke's N-methyliminodiacetic acid (MIDA) boronate to connect left- and right-hand fragments of the molecule (see scheme).     

Hydrogen bond catalyzed enantioselective vinylogous Mukaiyama aldol reaction

[chemical reaction: see text]. The concept of hydrogen bonding catalysis was extended to the vinylogous Mukaiyama aldol reaction, which gives rapid access to polyketide derivatives. The reaction of the silyldienol ether shown and a range of aldehydes catalyzed by TADDOL proceeds regiospecifically to produce the addition products in good yields and enantiomeric excesses.     

Total synthesis and stereochemical reassignment of (+)-dolastatin 19

[reaction: see text] A revised configurational assignment for the cytotoxic marine macrolide dolastatin 19 is proposed and validated by total synthesis. Key features of the route include an asymmetric vinylogous aldol reaction to install the isolated C13 stereocenter and (E)-trisubstituted alkene, two sequential 1,4-syn boron-mediated aldol reactions, and a Mukaiyama glycosylation to append the l-rhamnose-derived pyranoside.     

A catalytic asymmetric vinylogous Mukaiyama aldol reaction

A vinylogous Mukaiyama aldol reaction, conducted using 10 mol % of a BITIP catalyst and B(OMe)3 as an additive, effects an enantioselective four-carbon chain extension to give versatile E-alpha,beta-unsaturated thiol esters.     

Synthetic study of fomitellic acids: construction of the AB ring moiety

Stereocontrolled synthesis of a fully functionalized AB ring moiety of fomitellic acids was accomplished. The tricyclic skeleton was stereoselectively constructed by means of titanium(III)-mediated radical cascade cyclization of epoxypolyene. The stereochemistry at C1 and C3 was controlled by a vinylogous Mukaiyama aldol reaction and a Sharpless asymmetric epoxidation, respectively.     

First total synthesis of salinipyrone A using highly stereoselective vinylogous Mukaiyama aldol reaction

A synthetic approach for the total synthesis of salinipyrone A has been developed. Key steps involve the TiCl₄-mediated vinylogous Mukaiyama aldol reaction (VMAR) of chiral ketene silyl N,O-acetal with propionaldyhyde, an aldol condensation, Witting olefination, and a cyclization. The synthesis proceeds in eight steps.     

Rate enhancement by water in a TiCl4-mediated stereoselective vinylogous Mukaiyama aldol reaction

A remarkable enhancement in the rate of a TiCl₄-mediated stereoselective vinylogous Mukaiyama aldol reaction (VMAR) using vinylketene silyl N,O-acetal 1 was observed in the presence of water.     

Concise Total Synthesis of Nannocystin A

Nannocystin A, a structurally unique 21‐membered macrocyclic depsipeptide with low nanomolar inhibitory activity against elongation factor 1A, was synthesized according to a strategy involving the vinylogous Mukaiyama aldol reaction, Sharpless epoxidation, olefin metathesis, the Mitsunobu reaction, and a palladium‐catalyzed intramolecular Suzuki coupling of a highly complex cyclization substrate. The overall synthesis is efficient and paves the way for preparation of analogues for drug development efforts.     

Diastereoselective Synthesis of γ-Butenolides Catalyzed by Potassium tert-Butoxide

Potassium tert-butoxide (0.1 mol%) catalyzed a vinylogous Mukaiyama aldol reaction between aromatic and aliphatic aldehydes with 2-(trimethylsilyloxy)furan. The corresponding γ-butenolides were obtained in good yields with good diastereoselectivities.     

Simple diastereoselectivity of the BF3.OEt2-catalyzed vinylogous Mukaiyama aldol reaction of 2-(trimethylsiloxy)furans with aldehydes

[reaction: see text] A comprehensive scan of the transition state space for the reaction of 2-(trimethylsiloxy)furan and methacrolein (24 combinations) offered a satisfactory explanation of the high like diastereoselectivity obtained experimentally in the Mukaiyama vinylogous aldol reaction of these and related partners. It was determined that the syn-gamma-hydroxyalkylbutenolides are formed preferentially following a g(+) orientation of the two reactants with the aldehyde in the s-trans conformation. Diastereoselectivity is shown to be caused by a combination of subtle effects favoring the formation of the like product.     

Short and efficient synthesis of cryptophycin unit A

[reaction: see text] Two short synthetic approaches toward cryptophycin unit A comprise a catalytic asymmetric dihydroxylation as the sole source of chirality, while all further stereogenic centers are introduced under substrate control. The key step of the first route is a vinylogous Mukaiyama aldol addition, which introduces the alpha,beta-unsaturated ester moiety with defined configuration at the delta-carbon atom. Likewise, allylation with allyltributylstannane diastereoselectively gives the homoallylic alcohol that can be converted by a metathesis reaction to a unit A precursor.     

γ-Oxygenation of α,β-unsaturated esters by vinylogous O-nitroso Mukaiyama aldol reaction

A practical procedure has been developed for γ-oxygenation of α,β-unsaturated esters by a vinylogous O-nitroso Mukaiyama aldol reaction followed by a one-pot N-O bond heterolysis of the in situ generated γ-aminoxy-α,β-unsaturated esters.     

Toward the development of a general chiral auxiliary. Enantioselective alkylation and a new catalytic asymmetric addition of silyloxyfurans: application to a total synthesis of (-)-rasfonin

An enantioselective total synthesis of the apoptosis-inducing natural product, (-)-rasfonin, is described. Camphor lactam-mediated asymmetric alkylation reactions enabled the installation of three stereogenic centers with >95:5 diastereoselectivity. A modified Corey-Peterson olefination was employed in the construction of the (E,E)-diene system. A highly diastereoselective, asymmetric vinylogous Mukaiyama aldol addition was conducted using a chiral cationic oxazaborolidine catalyst. The pyranone core of the natural product was prepared via a DBU-promoted rearrangement of a furanol to its corresponding pyranol with concomitant [1,4]-silyl transfer.     

Asymmetric total synthesis and structural elucidation of NFAT-68

Total synthesis of NFAT-68 (7) has been achieved and its relative stereochemistry has been determined. A key step thereof is the utilization of the chelation-controlled vinylogous Mukaiyama aldol reaction (VMAR) to stereoselectively synthesize the syn-aldol product 8. This developed chemistry is anticipated to have wider application in total syntheses of many other natural products.     

New enantioselective entry to cycloheptane amino acid polyols

[reaction: see text] A diversity-oriented protocol has been developed for the assembly of densely hydroxylated cycloheptane amino acids via succession of a vinylogous Mukaiyama aldol reaction (VMAR), a Morita-Baylis-Hillman reaction (MBHR), and an intramolecular pinacol coupling reaction (IPCR). The plan utilizes D- or L-configured glyceraldehyde derivatives as "chiral" surrogates of glyoxal and N-[(tert-butoxycarbonyl)-2-(tert-butyldimethylsilyl)oxy]pyrrole as the synthetic equivalent of the alpha,gamma-dianion of gamma-aminobutanoic acid. The parallel, asymmetric syntheses of four cycloheptane representatives proceed with high diastereocontrol and virtually complete enantioselectivity in ten steps and overall yields of 15-37%.