Aldol cycloaddition

On the other hand, silver salts can act as a mild Lewis acid, promoting various reactions such as allylations, aldolizations, cycloadditions, and cyclizations. Silver salts can also be used as halide scavengers, acting as cocatalysts in cross-coupling reactions catalyzed by other metals, especially palladium. In the latter context, the exact role of silver salts is far from clear and may be more complex than just halide... 

A decade has now passed since the studies of my laboratory and those of David MacMillan s refocused the considerable attention of the conununity on the profound potential of small organic molecules to catalyze asymmetric reactions. In this time, the scope of organocatalysis has enlarged considerably with respect both to the type of reactions catalyzed (aldol, cycloaddition, redox, asymmetric assembly and domino reactions, conjugate addition reactions, etc.) and the mechanisms used... 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

The mechanism of the cycloaddition reaction of benzaldehyde 2a with Danishefsky s diene 3a catalyzed by aluminum complexes has been investigated theoretically using semi-empirical calculations [14]. It was found that the reaction proceeds as a step-wise cycloaddition reaction with the first step being a nucleophilic-like attack of Danishefsky s diene 2a on the coordinated carbonyl compound leading to an aldol-like intermediate which is stabilized by interaction of the cation with the oxygen atom of the Lewis acid. The next step is the ring-closure step, giving the cycloaddition product. 

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. 

A series of chiral boron catalysts prepared from, e.g., N-sulfonyl a-amino acids has also been developed and used in a variety of cycloaddition reactions [18]. Corey et al. have applied the chiral (S)-tryptophan-derived oxazaborolidine-boron catalyst 11 and used it for the conversion of, e.g., benzaldehyde la to the cycloaddition product 3a by reaction with Danishefsky s diene 2a [18h]. This reaction la affords mainly the Mukaiyama aldol product 10, which, after isolation, was converted to 3a by treatment with TFA (Scheme 4.11). It was observed that no cycloaddition product was produced in the initial step, providing evidence for the two-step process. 

The dihydropyrones are not produced directly in the initial BINOL-titanium(IV)-cat-alyzed reaction. The major product at this stage is the Mukaiyama aldol product which is subsequently cyclized by treatment with TFA [19fj. The formal cycloaddition product 3d (97% ee) obtained from a-(benzyloxy)acetaldehyde is an important intermediate for compactin and mevinolin. Scheme 4.13 outlines how the structural subunit 13 is available in three steps via this cycloaddition approach [19 fj. 

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. 

The major developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes have been presented. A variety of chiral catalysts is available for the different types of carbonyl compound. For unactivated aldehydes chiral catalysts such as BINOL-aluminum(III), BINOL-tita-nium(IV), acyloxylborane(III), and tridentate Schiff base chromium(III) complexes can catalyze highly diastereo- and enantioselective cycloaddition reactions. The mechanism of these reactions can be a stepwise pathway via a Mukaiyama aldol intermediate or a concerted mechanism. For a-dicarbonyl compounds, which can coordinate to the chiral catalyst in a bidentate fashion, the chiral BOX-copper(II)... 

A two-step sequence of nitrile oxide-olehn cycloaddition and reduction of the resulting A -isoxazolines offers a unique and attractive alternative to the classical aldol reaction and its many variants (2J). The procedure bypasses traditional problems, including enolate equilibrium and cross condensation (20). 

Another example of a [4S+1C] cycloaddition process is found in the reaction of alkenylcarbene complexes and lithium enolates derived from alkynyl methyl ketones. In Sect. 2.6.4.9 it was described how, in general, lithium enolates react with alkenylcarbene complexes to produce [3C+2S] cycloadducts. However, when the reaction is performed using lithium enolates derived from alkynyl methyl ketones and the temperature is raised to 65 °C, a new formal [4s+lcj cy-clopentenone derivative is formed [79] (Scheme 38). The mechanism proposed for this transformation supposes the formation of the [3C+2S] cycloadducts as depicted in Scheme 32 (see Sect. 2.6.4.9). This intermediate evolves through a retro-aldol-type reaction followed by an intramolecular Michael addition of the allyllithium to the ynone moiety to give the final cyclopentenone derivatives after hydrolysis. The role of the pentacarbonyltungsten fragment seems to be crucial for the outcome of this reaction, as experiments carried out with isolated intermediates in the absence of tungsten complexes do not afford the [4S+1C] cycloadducts (Scheme 38). 

During 1989-93 lithium perchlorate iethyl ether (LiC104 EtiO, LP-DE) was studied as a reaction medium in organic synthesis when it was observed that cycloadditions, sigmatropic rearrangements, Michael additions and aldol condensations carried out in LP-DE occurred quickly and selectively under mild reaction conditions [33]. In addition, LP-DE allowed the reaction and subsequent work-up to be carried out under essentially neutral conditions. 

Johnson J. S., Evans D. A. Chiral Bis(Oxazoline) Copper(II) Complexes Versatile Catalysts for Enantioselective Cycloaddition, Aldol, Michael, and Carbonyl Ene Reactions Acc. Chem. Res. 2000 33 325-335... 

Togni A., Pastor S. D. Cooperativity of Chirality in Homogeneous Catalysis The Gold(I)-Catalyzed Aldol Reaction and the Vanadium(IV)-Catalyzed Hetero-Diels-Alder Cycloaddition Chirality 1991 3 331-340... 

The cyclobutanone is the important aspect. We shall want to make it by ketene cycloaddition (the key reaction) (Chapter T 33) and this we can do after an aldol disconnection. 

In practice simple alkenes give poor cycloaddition so diene (49) was the chosen starting material and the aldol was protected and hydrogenated to give (48). Note that (50) is emphatically bowl shaped (Chapter T 34) so that substituents (OR) or reagents (Hg) prefer to be on the outside of the bowl. The regioselectivity of the addition of Cl2C=C=0 to the diene (49) is correct. Synthesis ... 

Ramachary, D.B. Barbas, C.R III (2004) Towards Organo-Click Chemistry Development of Organocatalytic Multicomponent Reactions Through Combinations of Aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen Cycloaddition Reactions. Chemistry A European Journal, 10, 5323-5331. 

Since the number of domino processes which start with a Diels-Alder reaction is rather large, we have subdivided this section of the chapter according to the second step, which might be a second Diels-Alder reaction, a 1,3-dipolar cycloaddition, or a sigmatropic rearrangement. However, there are also several examples where the following reaction is not a pericyclic but rather is an aldol reaction these examples will be discussed under the term Mixed Transformations . 

Deslongchamps and coworkers [26] used a combination of a transannular Diels-Alder cycloaddition and an intramolecular aldol reaction in the synthesis of the unnatural enantiomer of a derivative of the (+)-aphidicolin (4-74), which is a diterpe-noic tetraol isolated from the fungus Cephalosporium aphidicolia. This compound is an inhibitor of DNA polymerase, and is also known to act against the herpes simplex type I virus. In addition, it slows down eukaryotic cell proliferation, which makes it an interesting target as an anticancer agent... 

Vassilikogiannakis and coworkers described a simple sequential process for the biomimetic synthesis of litseaverticillol B (4-159) which includes a cycloaddition of 4-158 and singlet oxygen to give 4-160, followed by ring opening to afford the hydro-genperoxide 4-161 (Scheme 4.34) [55]. Reduction of 4-161 led to the hemiacetal 4-162, which underwent an aldol reaction to afford 4-159. 

In this section are described those domino reactions which start with a retro-pericy-clic reaction. This may be a retro-Diels-Alder reaction, a retro-l,3-dipolar cycloaddition, or a retro-ene reaction, which is then usually followed by a pericyclic reaction as the second step. However, a combination is also possible with another type of transformation as, for example, an aldol reaction. 

A remarkable combination of a photochemical [2+2] cycloaddition with a retro-aldol reaction and cyclization is the so-called de Mayo reaction. Biichi and coworkers have used this method for the total synthesis of loganin (5-35). Thus, reac-... 

It can be assumed that, upon irradiation, tautomer 5-40-II reacts with the alkene 5-41 in a highly regioselective [2+2] cycloaddition to give the cyclobutane 5-42 as an intermediate. Subsequent retro-aldol-type reaction and hemiacetal formation produces 5-44 via 5-43. After addition of the Lewis acid (BF3-Et20), cyclization takes place to give the desired products. It should be noted that the excess of alkene must be removed under reduced pressure before addition of the Lewis acid in order to avoid polymerization. 

The nitro-aldol reaction followed by dehydration gives 2-nitro-l,3-dienes, which are useful reagents for cycloaddition (Eq. 3.45).70... 

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>. 

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