Aldol-Lactonization Reactions

Scheme 2.61. Syntnesis of (-)-panclicin D (2-258) and okinonellin B (2-261) employing the domino Mukaiyama aldol/lactonization reaction sequence.

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>. 

Romo and coworkers [1] have extensively studied the domino Mukaiyama-aldol-lactonization reaction of aldehydes and thiopyridyl silyl S,0-ketene acetals,... 

Isotetronic acids were readily assembled through an organocatalyzed domino aldol-lactonization reaction starting from a-keto carboxylic acids and aldehydes [5]. As chiral organocatalyst, the proline-derived benzimidazol pyrrolidine 8 was employed, which proved superior to proUne itself Electron-poor aldehydes were both more reactive and selective. Thus, as a typical example, pyruvate was converted into isotetronic acid 10 in 77% yield and 83% ee upon treatment with para-nitrobenzyldehyde (9) and 10mol% 8 (Scheme 8.3). 

Scheme 8.3 Domino aldol-lactonization reaction for the assembly of isotetronic acids [5].

Similar tandem Aldol/Oxa-Michael/Aldol/Lactonization reactions have been reported in literatures, which include Prof. Nicolaou s total synthesis research of cortistatin A [28, 29]. 

Scheme 36.19 Organocatalytic intramolecular aldol/lactonization reaction.

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. 

Aldol-type reaction of zinc esters. This titanium reagent promotes condensation of (ethoxycarbonylalkyl)iodozinc compounds (13, 220) with aldehydes or ketones to provide hydroxy esters and/or lactones. The active reagent may be (ethoxycarbonyl)alkyltriisopropoxytitanium. 

Base for aldol coupling reactions, and tiie syntiiesis of lactone precursors and ketones. ... 

Asymmetric synthesis in aldol-type reaction involving magnesium ester or lactone enolates has also been reported. Enolate of (—)-menthyl or (-l-)-bornyl acetate reacts with substituted benzophenones or a-naphtophenones to yield, upon hydrolysis of the resulting esters, optically active /3-hydroxyacids. Although these results are interpreted in terms of a steric factor. Prelog s rules are not applicable to these reactions (equation 88). 

Lithium tri-sec-butylborohydride, 21 B-3-Pinanyl-9-borabicyclo[3.3.1]-nonane, 249 Sodium borohydride, 21 (3-Hydroxy esters and lactones By aldol-type reactions (R)-( + )-f-Butyl p-tolylsulfinylace-tate, 59 Cadmium, 60... 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

It is worthy of note that the type of reaction shown in Scheme 6.39, Eq. (1) was reported only recently [102]. In 2001, Romo and co-workers described an intramolecular, nucleophile-catalyzed aldol-lactonization (NCAL) process which contains... 

Diastereoselective /3-lactone formation was also carried out by a tandem Mukaiyama aldol lactonization between an aldehyde 132 and a thiopyridyl ketene acetal 133 (Equation 46) <2005CCL1448>. This reaction gave the /3-lactone 134 as a 10 1 (transacts) mixture of diastereoisomers and the major isomer was converted into (-)-tetrahydrolipstatin by silyl deptotection followed by a Mitsunobu coupling to form the ester. 

A diastereoselective Mukaiyama aldol lactonization between thiopyridylsilylketene acetals and aldehydes was used to form the /3-lactone ring in the total synthesis of (-)-panclicin D <1997T16471>. Noyori asymmetric hydrogenation was a key step in a total synthesis of panclicins A-E and was used to establish the stereocenter in aldehyde 140, which in turn directed the stereochemistry of subsequent reactions <1998J(P1)1373>. The /3-lactone ring was then formed by a [2+2] cycloaddition reaction of 140 with alkyl(trimethylsilyl)ketenes and a Lewis acid catalyst. 

The nucleophile-catalyzed aldol lactonization (NCAL) reaction of carboxyl-derived zwitterions and unactivated aldehydes has been applied to the catalytic asymmetric synthesis of bicyclic /3-lactones (Equation 31)... 

The mechanistic proposal for the formation of these p-laclonc products is related to that for the formation of y-lactones (Scheme 17). Initial formation of the conjugate enamine Ila is followed by a proton transfer from oxygen to carbon thereby forming the enolate V. In an aldol-type reaction this enolate attacks the electrophilic ketone providing zwitte-rions VI. The subsequent cyclization to the lac tone 18 then liberates the NHC catalyst. 

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