Cyclic aldol reaction

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

The aldol reactions of enamines may be formally considered to proceed via acyclic amino aldehyde or amino ketone forms, in spite of the fact that the cyclic enamine forms can also take part in aldol reactions. 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

Jager and coworkers have used the TBAF catalyzed-stereoselective niho-aldol reaction for the synthesis of cyclic amino alcohols such as iminopolyols, imino sugars, and cyclic amino acids. They are important classes of compounds and have the potential utility as anh-diabetic. 

Ring expansion of cyclic ketones via nitro-aldol reaction of a-nitrosiilfides followed by treatment wiih AlCU has been reported fEq 7 35 ... 

The aldol reactions we ve seen thus far have all been intermolecular, meaning that they have taken place between two different molecules. When certain r/zcar-bonyl compounds are treated with base, however, an mtramolecular aldol reaction can occur, leading to the formation of a cyclic product. For example, base treatment of a 1,4-diketone such as 2,5-hexanedione yields a cyclopcntenone... 

An analogous reaction has been carried out using malononitrile and different products derived by a Cross-Aldol reaction of acetone (Scheme 32). The cyclic furanimide 91 was then reacted under microwave irradiation in the presence of NaOEt with a second molecule of malononitrile to give the furanone 92 [66]. The NLO chromophore 93 was prepared using this procedure. 

Reaction progress kinetic analysis offers a reliable alternative method to assess the stability of the active catalyst concentration, again based on our concept of excess [e]. In contrast to our different excess experiments described above, now we carry out a set of experiments at the same value of excess [ej. We consider again the proline-mediated aldol reaction shown in Scheme 50.1. Under reaction conditions, the proline catalyst can undergo side reactions with aldehydes to form inactive cyclic species called oxazolidinones, effectively decreasing the active catalyst concentration. It has recently been shown that addition of small amounts of water to the reaction mixture can eliminate this catalyst deactivation. Reaction progress kinetic analysis of experiments carried out at the same excess [e] can be used to confirm the deactivation of proline in the absence of added water as well to demonstrate that the proline concentration remains constant when water is present. 

Aldol Reactions of Boron Enolates. The matter of increasing stereoselectivity in the addition step can be addressed by using other reactants. One important version of the aldol reaction involves the use of boron enolates.15 A cyclic TS similar to that for lithium enolates is involved, and the same relationship exists between enolate configuration and product stereochemistry. In general, the stereoselectivity is higher than for lithium enolates. The O-B bond distances are shorter than for lithium enolates, and this leads to a more compact structure for the TS and magnifies the steric interactions that control stereoselectivity. 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

The Mukaiyama aldol reaction can provide access to a variety of (3-hydroxy carbonyl compounds and use of acetals as reactants can provide (3-alkoxy derivatives. The issues of stereoselectivity are the same as those in the aldol addition reaction, but the tendency toward acyclic rather than cyclic TSs reduces the influence of the E- or Z-configuration of the enolate equivalent on the stereoselectivity. 

Another group of catalysts consist of cyclic borinates derived from tartaric acid. These compounds give good reactivity and enantioselectivity in Mukaiyama aldol reactions. Several structural variations such as 16 and 17 have been explored.151... 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

Under similar conditions, employing a cationic Rh complex (10mol%) and hydrogen (1 atm), the aldehyde-enone 17 was subjected to the cycli-zation to give the cyclic aldol product 18 in 89% with czs-selectivity up to 10 1 (Scheme 19) [31]. Use of (p-CF3Ph)3P as ligand accelerated the reaction... 

Using a cyclic enone 2-29b and an ester-TMS enolate 2-30 in the presence of catalytic amounts of SmI2(THF)2, the Michael addition and the Mukaiyama/aldol reaction with the added aldehyde 2-32 led to the diastereomeric adducts 2-33 and 2-34 via 2-31 with a dr =80 20 to 98 2 and 70-77% yield (Scheme 2.7) [13]. The major product is the trans-l,2-disubstituted cycloalkanone. 

A facile synthesis of cyclic five-, six-, and seven-membered oxonitriles 7-35 by a combination of an ozono lysis and an aldol reaction has been described by the Fleming group [17]. As starting material the unsaturated oxonitriles 7-33 are used, which are easily accessible by reaction of unsaturated esters 7-32 with LiCHjCN (Scheme 7.11). It can be assumed that 7-34 acts as an intermediate. 

Aldolases catalyze asymmetric aldol reactions via either Schiff base formation (type I aldolase) or activation by Zn2+ (type II aldolase) (Figure 1.16). The most common natural donors of aldoalses are dihydroxyacetone phosphate (DHAP), pyruvate/phosphoenolpyruvate (PEP), acetaldehyde and glycine (Figure 1.17) [71], When acetaldehyde is used as the donor, 2-deoxyribose-5-phosphate aldolases (DERAs) are able to catalyze a sequential aldol reaction to form 2,4-didexoyhexoses [72,73]. Aldolases have been used to synthesize a variety of carbohydrates and derivatives, such as azasugars, cyclitols and densely functionalized chiral linear or cyclic molecules [74,75]. 

The stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

The synthesis of the rare amino acid 3-hydroxy-4-methylproline (8)3 involves an aldol reaction of the oxazoiidinone 5 with methacrolein to provide the a-bromo-0-hydroxy adduct 6. Azide displacement and removal of the chiral auxiliary gives 7. On treatment with dicyclohexylborane, 7 undergoes hydroboration-cycloalkyl-ation to provide, after hydrolysis, the methyl ester hydrochloride (8) of (2S,3S,4S)-3-hydroxy-4-methylproline in >97% de. This cycloalkylation should be a useful route to cyclic amino acids as well as pyrrolidines. 

Scheme 35 Enolboration/hydroformylation/aldol reaction - Diastereoselective access to cyclic aldols...

The medicinally important )3-lactam antibiotic thienamycin (34) has stimulated several investigations into the application of the aldol reaction for the introduction of the hydroxyethyl moiety with the indicated Cg and Cg stereochemistry (29,30). Low-temperature enolization (LDA, THF) of either 35 (29a,b) or 36 (30) and subsequent condensation with excess acetaldehyde afforded the illustrated kinetic aldol adducts (eqs. [22] and [23]). In both examples the modest levels of threo diastereoselection are comparable to related data for unhindered cyclic ketone lithium enolates. Related condensations on the penam nucleus have also been reported (31). 

If a five- or six-membered ring can form, then intramolecular aldol reactions nsnally occnr more rapidly than the corresponding intermolecnlar reactions between two molecnles of snbstrate. This provides a very nsefnl ronte to cyclic componnds (see Box 10.19). 

The proline-mediated intramolecular aldol condensation of dialdehyde substrates was also reported by List in 2003, affording enantioselective synthesis of cyclic p-hydroxy aldehydes via a 6-e ofexo-aldolization reaction (Scheme 11.7d). 

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