Aldol reaction sequential

Robinson annulation reaction (Section 23.12) A synthesis of cyclohexenones by sequential Michael reaction and intramolecular aldol reaction. 

A fourfold anionic sequence which is not initiated by a Michael but an aldol reaction has been reported by the group of Suginome and Ito (Scheme 2.129) [295]. In this approach, the borylallylsilane 2-573 reacts selectively in the presence of TiCl4 with two different aldehydes which are added sequentially to the reaction mixture. First, a Lewis acid-mediated allylation of the aldehyde with 2-573 takes place to form a homoallylic alcohol which reacts with the second aldehyde under formation of the oxenium ion 2-574. The sequence is terminated by a Prins-type cyclization of 2-574 and an intramolecular Friedel-Crafts alkylation of the intermediate 2-575 with formation of the fraws-1,2-be rizoxadeca lines 2-576 as single diastereomers. 

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. 

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]. 

Johnson has developed two linear approaches to synthesize the C-nor-D-homosteroid skeleton (Scheme 2.2). In his first approach [21], tetralone 19, obtained from reduction of 2,5-dimethoxynaphthalene, was used as the source of the C,D-rings. The B- and A-rings were constructed by sequential Robinson annulations (19 —> 20 —> 21). The Cl 1,12 olefin was then introduced to provide 22. Ozonolysis of 22 followed by an aldol reaction of the resulting dialdehyde gave 23. Subsequent deformylation and deoxygenation afforded the cyclopamine skeleton 24. 

In Holton s and Wender s work, the total synthesis was achieved by sequentially forming the AB ring through the fragmentation of epoxy alcohols derived from (—)-camphor and a-pinene. Nicolau s, Danishefsky s, and Kuwa-jima s total syntheses involved B ring closure connecting the A and C rings, whereas in Mukaiyama s synthesis, the aldol reaction was extensively applied to construct the polycyclic system. 

Scheme 1.57). Although the natural donor aldehyde is D-2-deoxyribose-5-phosphate, non-phosphorylated donor aldehydes are also tolerated and the enzyme displays some flexibility towards both donor and acceptor. Importantly, as both donor and acceptor substrates are aldehydes, the enzyme can perform sequential aldol reactions allowing the preparation of a key lactol intermediate to the atorvastatin side chain in a single step. Following substantial modification, this approach is now operated on an industrial scale to... 

This [1,4]-Wittig rearrangement system is applicable to the sequential [l,4]-rearrange-ment/aldol reaction which provides -hydroxy ketones with moderate diastereoselectivity (Table 4). 

According to equation 102, stereochemically homogeneous 3-carbonyl-substimted tetrahydrofurans are constructed in a brick-box system by sequential homoaldol and aldol reaction. The metallated aUyl carbamate serves as an equivalent for the chiral dianion A, which accepts two different aldehydes B and C in a highly controlled manner. ... 

The mechanism of the catalytic cycle is outlined in Scheme 1.37 [11]. It involves the formation of a reactive 16-electron tricarbonyliron species by coordination of allyl alcohol to pentacarbonyliron and sequential loss of two carbon monoxide ligands. Oxidative addition to a Jt-allyl hydride complex with iron in the oxidation state +2, followed by reductive elimination, affords an alkene-tricarbonyliron complex. As a result of the [1, 3]-hydride shift the allyl alcohol has been converted to an enol, which is released and the catalytically active tricarbonyliron species is regenerated. This example demonstrates that oxidation and reduction steps can be merged to a one-pot procedure by transferring them into oxidative addition and reductive elimination using the transition metal as a reversible switch. Recently, this reaction has been integrated into a tandem isomerization-aldolization reaction which was applied to the synthesis of indanones and indenones [81] and for the transformation of vinylic furanoses into cydopentenones [82]. 

Scheme 8.7 Sequential oxidation of MeOH to H2C=0 and aldol reaction with a (5-oxo ester.

The classic C—C bond-forming processes of aldehydes and ketones are aldol reactions. In Scheme 8.7, an iron-catalyzed sequential methanol oxidation to formaldehyde and its aldol reaction with [i-oxo ester 24a is shown [30]. The oxidant is 30% aqueous H202. Curiously for an oxidation, the reaction has to be performed under an atmosphere of Ar in order to prevent a-hydroxylation of the [i-oxo ester [31], The role of benzaldehyde (4f) as substoichiometric additive is not completely clear. 

Since the product of the aldol reaction still contains an aldehyde function, it is readily available for further reactions. Wong and co-workers very elegantly used a DERA mutant (Ser238Asp) for a sequential one-pot aldol condensation towards the synthesis of atorvastatin (Fig. 37) [195], a process also being applied by DSM [196]. When using wild-type DERA, the choice of residues in the acceptor aldehyde... 

Naphthoquinone and 2-acylbenzenethiols react by sequential conjugate addition, aldol reaction, and atmospheric oxidation to produce 1277-benzo[3]thioxanthene quinones 423. The exact conditions required depend on the nature of the thiol, but are quite mild (Equation 123) <2004BCJ2095>. 

In 2002, Skrydstrup reported the diastereoselective construction of functionalised prolines using a Sml2-mediated aldol cyclisation.162 Treatment of p-lactam-derived a-benzoyloxy esters, such as 155, with Sml2 led to the generation of a Sm(III) enolate 156, aldol cyclisation and addition of the resultant samarium alkoxide to the (3-lactam carbonyl. The efficient sequential reaction gave proline derivatives, such as 157, with high diastereoselectivity and in good yield (Scheme 5.103).162 This example illustrates how the presence of a protic cosolvent does not necessarily interfere with the intramolecular aldol reaction and can in fact be crucial to the success of the cyclisation. 

Sequential (tandem) conjugate additions and aldol reactions build complex molecules in a few steps... 

Conditions for aldol reactions are very similar to those required for conjugate addition so that it is not unusual for conjugate addition and cyclization to occur sequentially without isolation of any intermediates. When we described one Michael addition a few pages back, we were not telling you the whole truth. The product isolated from this reaction was actually the enone from cyclization. 

This sequential process of Michael-aldol reaction leading to a new six-membered ring is known as the Robinson annelation. It was, in fact, Robinson who invented the idea of using a Mannich product in conjugate additions because he wanted to develop this important reaction. There are now thousands of examples used to make all kinds of compounds, especially steroids (Chapter 49). 

A particularly elegant application of DERA is the sequential synthesis of thermodynamically stable cyclic hemiacetal. Two DERA-catalyzed aldol reactions convert one equivalent of acceptor and two equivalents of acetaldehyde into this stable compound. A mild subsequent oxidation yielded the corresponding lactone in ex-... 

In DERA reactions, where acetaldehyde is the donor, products are also themselves aldehydes. In certain cases a second aldol reaction will proceed until a product has been formed that can cyclize to a stable hemiacetal.71 For example, when a-substituted aldehydes were used, containing functionality that could not cyclize to a hemiacetal after the first aldol reaction, these products reacted with a second molecule of acetaldehyde to form 2,4-dideoxyhexoses, which then cyclized to a hemiacetal, preventing further reaction. Oxidation of these materials to the corresponding lactone, provided a rapid entry to the mevinic acids and compactins (Scheme 5.43). Similar sequential aldol reactions have been studied, where two enzyme systems have been employed72 (Scheme 5.44). The synthesis of 5-deoxy ketoses with three substitutents in the axial position was accomplished by the application of DERA and RAMA in one-pot (Scheme 5.44). The long reaction time required for the formation of these thermodynamically less stable products, results in some breakdown of the normally observed stereoselectivity of the DERA and FDP aldolases. In a two-pot procedure, DERA and NeuAc aldolase have... 

Thiosalicylaldehydes afford chiral thiochromene-3-carbaldehydes 39 on reaction with a,P-unsaturated aldehydes catalysed by a chiral pyrrolidine silyl ether. Initial activation of the enal triggers sequential Michael and aldol reactions and dehydration completes the highly enantioselective synthesis <06JA10354, 06TL8547>. In a similar manner, cyclic enones afford cycloalkanone[ ]thiochromenes <06TL8679>. 

A very short asymmetric synthesis of the bryostatin C1-C9 segment was achieved by use of three sequential 3f-promoted aldol reactions under reagent control [43f]. This synthetic methodology is based on the direct asymmetric incorporation of two acetate and one isobutyrate synthones into a framework (Sch. 1). 

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