Aldol tandem

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

Q -Phenylthiomethyl-jS-hydroxy esters (50) can be prepared, predominantly as the iyn-isomer, by a stereoselective one-pot Michael-aldol tandem reaction. The seleno analogue can similarly be prepared (again, mainly syn), using PhSeLi in diethyl ether, but phenoxide ion is not sufficiently reactive for this sequence. 

Scheme 6.130 Proposed mechanism of the 121-catalyzed enantioselective thio-Michael-aldol tandem reaction of 2-mercaptobenzaldehydes with a,P-unsaturated oxazolidinones bifunctional activation through thiourea 121.

Scheme 6.131 Typical thiochromanes obtained from the 121-catalyzed asymmetric thio-Michael-aldol tandem reaction between various 2-mercaptobenzaldehydes and a, 3-unsaturated oxazolidinones.

Recently, a similar Michael-aldol tandem sequence has been reported, using catalytic amounts of the organolithium reagent. Reactions of a,f)-unsaturated esters with aldehydes were catalyzed by 0.2 equivalents of lithium phenylthiolate in the presence of phenyl... 

The cyclization, presumably via 160, gave the Michael-aldol tandem cyclization products 161 and 162 in a perfect. vyw-aldol stereoselectivity. The stereochemistry of the tandem reaction is rationalized by the model 164, which is sterically more favorable than 165 (Scheme 51). The oxo-ester 158 reacts in s-cis form and generates the d.v-enolatc, 163,... 

A remarkable example of tandem conjugate addition-aldol reaction has been recently reported by Tomioka and coworkers. The transient lithium enolate, generated by 1,4-addition of benzyl lithium thiolate onto the corresponding a,-unsaturated ester182,595, is followed by an intramolecular aldol tandem cyclization, resulting in a five-membered... 

SCHEME 126. Stereoselective Michael-aldol tandem cyclization reaction177... 

An efficient sulfa-Michael-aldol tandem reaction between 2-mercaptobenzalde-hydes and a,(3-unsaturated A-acyloxazolidin-2-ones catalyzed by thiourea 12 was disclosed by Wang and co-workers [36]. The resulting benzothiopyrans, containing three stereogenic centers, were obtained with high enantio- and diastereoselectivities regardless of the electronic and steric nature of the (3-substituent on the Michael acceptor (Scheme 14.8). 

Stereoselective thio-Michael-aldol tandem reaction has been reported, using a mixture of PhSLi, O -unsaturated ester (148), and aldehyde (149) in CH2CI2 (Scheme 21). The adducts, j0-hydroxy-a-(l-phenylthioalkyl) esters (150), were obtained in moderate... 

Conjugate Addition. Conjugate addition-aldol tandem reaction of Q , S-unsaturated esters in the presence of catalytic amount of lithium phenylthiolate proceeds stereoselectively with the formation of aleohol (after protodesilylation). The aldol reaction of the lithium enolate with aldehyde takes place from the hottom face, anti to the phenylsulfenyl group in the thermodynamic enolate conformation (eq 30). ... 

More than the corresponding enolexo-aldolizations, amine-catalyzed 6-enolmdo aldol reactions have frequently been used synthetically. An early example is the synthesis of Hagemaris ester (89) from formaldehyde and acetoacetate via piperidine-catalyzed Knoevenagel-Michael-aldol tandem-reaction follo ved by decarboethoxylation (Scheme 4.14, Eq. (1)) [83]. Related product 91 vas obtained vhen thiophene-carbaldehyde 90 vas used (Eq. (2)) [84]. 

Fusion of SIX membered nngs by reactnn of cyclanones with vinyl ketones (base or acd catalyzed), a tandem Michael addition aldol condensation... 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

Scli ir 7.14. Enantlocelectli/e tandem conjugate addition-aldol re... 

The present tandem nitro aldol-cyclizadon process is used for the preparadon of the enandomerically pure 4-hydroxy-3-isoxa2olme-3-ones They are prepared starting from chiral ct-mesyloxy aldehydes and ethyl nitroacetate under rruld reacdon conthdons fEq 8 85 ... 

Such aldolase-catalyzed bidirectional chain elongation ( tandem aldolization) of simple, readily available dialdehydes has been developed into an efficient method for the generation of higher carbon sugars (e.g. (87)/(89)) by simple one-pot operations (Figure 10.32) [126,156]. The choice offuranoid (87) or pyranoid (89) nature of the products can be determined by a suitable hydroxyl substitution pattern in a corresponding cycloolefinic precursor (86) versus (88)). The overall specific substitution... 

Figure 10.32 Applications of bidirectional chain extension for the synthesis of disaccharide mimetics and of annulated and spirocyclic oligosaccharide mimetics using tandem enzymatic aldol additions, including racemate resolution under thermodynamic control.

A tandem enzymatic aldol-intramolecular Homer-Wadsworth-Emmons reaction has been used in the synthesis of a cyclitol.310 The key steps are illustrated in Scheme 8.33. The phosphonate aldehyde was condensed with dihydroxyacetone phosphate (DHAP) in water with FDP aldolase to give the aldol adduct, which cyclizes with an intramolecular Horner-Wadsworth-Emmons reaction to give the cyclo-pentene product. The one-pot reaction takes place in aqueous solution at slightly acidic (pH 6.1-6.8) conditions. The aqueous Wittig-type reaction has also been investigated in DNA-templated synthesis.311... 

It has also been shown that dimethylsilyl enolates can be activated by diisopropylamine and water and exhibit a high reactivity toward iV-tosyl imines to give Mannich-type reaction products in the absence of a Fewis acid or a Bronsted acid.51 For example, the reaction of [(1-cyclohexen-l-yl)oxy]dimethylsilane with 4-methyl-A -(phenylmethylene)benzene sulfonamide gave re/-4-methyl-N- (f )-[(15)-(2-oxocyclohexyl)phenyl-methyl] benzenesulfonamide (anti-isomer) in 91% yield stereoselectively (99 1 anti syn) (Eq. 11.30). On the other hand, Fi and co-workers reported a ruthenium-catalyzed tandem olefin migration/aldol and Mannich-type reactions by reacting allyl alcohol and imine in protic solvents.52... 

Shibasaki has also extended the use of LLB catalyst to tandem nitro-aldol reactions providing bicyclic adducts with 65% ee (Eq. 3.75).124... 

Combining, in tandem, the nitro-aldol reaction with the Michael addition using thiophenol is a good method for the preparation of P-nitro sulfides as shown in Eqs. 4.2 and 4.3. This reaction is applied to a total synthesis of tuberine. Tuberine is a simple enamide isolated from Streptomyces amakusaensis and has some structural resemblance to erbastatin, an enamide which has received much attention in recent years as an inhibitor of tyrosine-specific kinases. The reaction of p-anisaldehyde and nitromethane in the presence of thiophenol yields the requisite P-nitro sulfide, which is converted into tuberine via reduction, formylation, oxidation, and thermal elimination of... 

Figure 14.12 Asymmetric tandem aldol reaction using 2-deoxyribose-5-phosphate aldolase (DERA) and its application for production of Atorvastatin...

Derivatives of the pyrrolo[2,l, 5-z/r quinolizinc system 88 were obtained from 2-benzoyl-iV-acetonylpyridinium bromide 86 in a single step through a tandem process of intramolecular aldol condensation and deprotonation, leading to intermediate 87, followed by 1,3-dipolar cycloaddition and oxidation (Scheme 6) <2001JPI1820>. 

The zinc chloride-mediated tandem Mukaiyama aldol-lactonization reaction of aldehydes 21 and thiopyridylketene acetals 22 gave mainly the trans isomer 23. However, if the catalyst is stannic chloride and the reaction is carried out at -78 °C, then the cyclization is highly diastereoselective and yields the cis-isomer 24 <990L1197>. 

Allylic alcohols react with aldehydes, in the presence of catalytic amounts of Fe(CO)s under photochemical activation conditions, to give mainly aldol products (Scheme 11).33 This novel tandem iosmerization-aldolization reaction is a process with a perfect atom economy, proceeding under neutral conditions. 

Tandem aldol reaction/siloxy-Cope rearrangement equivalent 181... 

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