Danishefsky condensation

A preparation of P-hydroxy thioesters is best carried out in ether within a narrow range of catalyst concentration (ca. 20 mol %) for maximum conversion and enantiomer excess. Dihydropyrones. The Danishefsky condensation gives chiral products in the presence of a BINOL-Ti complex and CFjCOOH. 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

Interest in the total synthesis of the Aspergillus terreus derived quadrone fi06), an antitumor agent has been very intense. Success was first realized in Danishefsky s laboratory Once 601 was reached, its sidechain was elaborated and ring closure effected (Scheme LII). Condensation of 602 with 1-tert-butoxy-l-tcrt-butyl-dimethylsiloxyethylene in the presence of titanium tetrachloride and subsequent desilylation resulted in introduction of an angular acetic acid moiety. The two sidechains were next connected by intramolecular alkylation and the resulting keto add was subjected to selenenylation in order to produce 603. The a, P-unsaturated double bond was used to force enolization to the a position. Indeed, 604 was... 

New possibilities in hetero-Diels-Alder condensation have been opened by the introduction of highly active l-methoxy-3-trimethylsilyloxy-, 4-benzoyIoxy-l-methoxy-3-trimethylsilyloxy-, and 2-acetoxy-l-alkoxy-3-trimethylsilyloxy-l,3-butadienes ( Danishefsky dienes, 5). These compounds readily react under atmospheric pressure, in the presence of Lewis acids, with normal aldehydes (e.g., acetaldehyde, benzaldehyde, furfural) to furnish 2,3-disubstituted or 2,3,5-trisubstituted derivatives of 2,3-dihydro-4H-pyran-4-one 7 capable of readily functionalizing to sugars (Scheme 5) [26]. This approach... 

Fig. 3. Total synthesis by Danishefsky construction of the carbo-bicyclic core structure by aldol condensation and carbopalladation.

Aminoindanol-derived Schiff bases were developed as tridentate ligands for the chromium-catalyzed hetero Diels-Alder reaction between weakly nucleophilic dienes and unactivated aldehydes.24 The generality of the utility of these Schiff bases, readily obtained by condensation of 1 with the corresponding aldehyde, was later demonstrated in the hetero Diels-Alder reaction between Danishefsky s diene and chiral aldehydes,25 in the inverse electron-demand hetero Diels-Alder reaction of a,P-unsaturated aldehydes with alkyl vinyl ethers,26 and in hetero-ene reactions.27... 

The convergent approach to N-glycopeptides was first demonstrated by Peter Lansbury et al. (Scheme 11.4) [52, 53], Condensation of an oligosaccharyl amine with the Asp side chain of a suitably protected peptide was examined in solution phase but can also be carried out in solid phase. However, the drawback of this method is that the Asp unit meant to be coupled to an oligosaccharyl amine is prone to cyclic aspartimide formation with the amide nitrogen atom of the peptide backbone. Samuel Danishefsky and coworkers examined several conditions to overcome... 

In addition to thioesterifications employing the C-terminal condensation with alkyl-thiols, the Danishefsky group demonstrated an alternative type of thioesterification (Scheme 11.6) [74], A suitably side chain-protected peptide acid is condensed with an amino acid 2-dithioethyl phenyl ester. The 2-dithioethyl phenyl ester is prone to rearrangement to a thioester through O S transesterification under reducing (NCL) conditions. 

As part of a study of ring construction through transposition of activated cyclo-propanes, Danishefsky s group has scrutinized the feasibility of intramolecular homoconjugate nucleophilic additon.64 Two of the substrates examined were 34 and 35 and these were found to undergo rather efficient closure to bicyclo[3.3.0]octane derivatives when treated with strong base. The somewhat elevated temperatures allow both the cyclopropane fission and subsequent Dieckmann condensation to proceed at respectable rates. 

The camptothecin synthesis of Shen/Dani-shefsky [16] (Scheme 8) starts with the construction of the D ring reaction of 46 with 47 affords 48. The next step (48 49) introduces the C20 ethyl group. Hydroxymethylation of 49 delivers lactone SO. The B ring of the camptothecin precursor 52 should be accomplished by a Friedlander condensation of 10 with 11. For this purpose, a keto group at C2 of the C,D,E ring building block had to be installed. Shen and Danishefsky solved this problem by combination of an aldol condensation (50 —> 51) and a subsequent ozonolysis (51 11). Important for... 

Gordon and Danishefsky [112] used the reaction of a chromium Fischer car-bene complex 164 with a cycloalkine 163 to build the naphthoquinone core 165 (Dotz reaction, review [113]), a procedure often used for synthesis of the linearly condensed anthracyclinones (e.g., [114]). The quinone ketone 165 has nucleophilic and electrophilic centers correctly positioned to furnish a ben-zo[fl]anthraquinone. However, treatment with NaH or Triton B gave the spiro-compounds 166 as a mixture of two stereoisomers. These products evidently arose from Michael addition of the ketone enolate to the naphthoquinone double bond. But the weaker base DBU induced cyclization at ambient temperature to the benzo[a]anthraquinone 167 in 65% yield (Scheme 42). The primary aldol adduct apparently eliminated water and the resulting dihydrobenzo[a]anthraquinone aromatized under basic conditions in the presence of air. This is an instructive example of the influence of the base on the cyclization mode. 

Most recently, the immunosuppressive agent FK-S06 (416) has been the target of total synthesis. To date several approaches to the trisubstituted alkene region at C-19 and C-20 have appeared. These preliminary studies allow the comparison between the Warren phosphine oxide approach and the Julia coupling. In the first total synthesis of FK-S06, Jones and coworkers at Merck formed the the alkene deprotonadon of the phosphine oxide (418) and condensation with the aldehyde (417). The hydroxy-phosphine oxides were formed in a ratio of 1 1 in 77% yield. The less polar diastereomer was treat with base to obtain the ( )-alkene (419) in 32% overall yield from the aldehyde (equation 96). Danishefsky utilized the Julia coupling for the formation of the trisubstituted alkene region. The sulfone anion (420) was treated with isobu raldehyde as a model, followed by acetylation and reductive elimination to... 

Aza Diels-Alder reactions. The p-tol-BINAP ligand is used to promote asymmetric condensation between the IV-tosyl derivative of ethyl glyoxylate and Danishefsky s diene at -78°. 

The ZnCh reaction seems to pass through a pericylic mechanistic pathway while the BF3-OEt2-cata-lyzed reaction resembles a Mukaiyama aldol reaction. Danishefsky described the process in which an activated diene is condensed with an aldehyde as a cyclocondensation reaction, thus avoiding the implication of a concerted reaction pathway in cases where aldol products are unambiguously isolated (Scheme 2). 

Since the investigations which used ZnCb and BF3-OEt2 as catalysts, other Lewis acids have been shown to catalyze the cyclocondensation reaction. MgBr2, for example, was used by Pearson and Danishefsky to add the power of chelation control to the reaction. When chiral a-alkoxy aldehydes are condensed with dienes under the influence of MgBr2, products derived from an ACF transition state predominate. The chelation of the metal by the a-alkoxy group of the aldehyde forces the aldehyde side chain to occupy the same side of the aldehyde as the metal. The diene, therefore, can attack the aldehyde from the least hindered exo face giving rise to the trans-KC product (Scheme 5). When an aldehyde is used that cannot form a chelate to the metal (such as benzaldehyde) syn (endo) selectivity is observed. 

Observations first made by Danishefsky and later confirmed by Sims and coworkers showed that nu-cleophiiic dienes such as (32) react with a, 3-unsaturated aidehydes exclusively at the aldehyde functional group. Sims and coworkers have exploited this observation by condensing cinnamaldehyde (15d) with diene (32) to produce (37), an a-pyrone isolated from the kava plant (Scheme 13). ... 

Hetero-Diels-Alder reaction. The zirconium complexes of 3,3 -diaryl-BINOL are effective chiral catalysts for the smooth condensation of aldimines with a Danishefsky diene. Linkage of the BINOL moiety to polymer support also provides viable catalysts. 

Dihydro-4-pyridones. These are the hydrolytic products from the condensation of Danishefsky s diene and imines. The condensation is efficeintly achieved at room temperature in the presence of Bi(OTf >3. 

Hetero-Diels-Alder reaction. The condensation of Danishefsky s diene with imines to generate TV-substituted 2-aryl-2,3-dihydro-4-pyridones at room temperature is effected by this salt. A mixture of aldehydes, amines, and the dehydrant MgS04 can be employed instead of imines. 

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