Aldol/lactonization reaction acetals

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,... 

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). 

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. 

Synthesis of Butyrolactones.—A chiral synthesis of five- and six-manbered lactones has been reported which involves an initial aldol-type reaction of (/J)-t-butyl (p-tolylsulphinyl)acetate to give the intermediate (136), which is converted into the butyrolactone (138) (in 80% enantiomeric excess) via the nitrile (137), as shown in Scheme 84. ... 

One of the pervasive problems in asymmetric synthesis has been the development of stereoselective acetate ester aldol reactions. Although a number of chiral auxiliaries perform superbly well in diastereoselective propionate aldol additions, these have, with rare exceptions, been unsuccessful in the corresponding additions of unsubstituted acetate-derived enolates [19, 63, 64). Braun s disclosure of a stereoselective acetate aldol addition reaction with 103 was an important milestone in the development of the field (Scheme 4.11) [63, 65]. The diol auxiliary can easily be prepared from mandelic acid esterification of the secondary alcohol is obsei ved, without interference from the tertiary counterpart. Its use has been showcased in a number of syntheses [53]. The high yield and diastereoselectivity generally obtained with 103 were highlighted by investigators at Merck in the construction of the chiral lactone fragment that is common in a number of HMG-CoA reductase inhibitors, such as compactin (105) [66]. 

A special case is the ring-forming reaction in the lactone acetal 568,69. When 5 is treated with trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate TMSOTf) in the presence of triethylamine at 0°C the cisjtrans mixture 6a and 6b is formed in ca. 50% yield. In this intramolecular aldol reaction the probable intermediate is the oxonium ion 7. 

One of the early syntheses of orlistat (1) by Hoffmann-La Roche utilized the Mukaiyama aldol reaction as the key convergent step. Therefore, in the presence of TiCU, aldehyde 7 was condensed with ketene silyl acetal 8 containing a chiral auxiliary to assemble ester 9 as the major diastereomer in a 3 1 ratio. After removal of the amino alcohol chiral auxiliary via hydrolysis, the a-hydroxyl acid 10 was converted to P-lactone 11 through the intermediacy of the mixed anhydride. The benzyl ether on 11 was unmasked via hydrogenation and the (5)-7V-formylleucine side-chain was installed using the Mitsunobu conditions to fashion orlistat (1). 

To make the DERA-catalyzed process commercially attractive, improvements were required in catalyst load, reaction time, and volumetric productivity. We undertook an enzyme discovery program, using a combination of activity- and sequence-based screening, and discovered 15 DERAs that are active in the previously mentioned process. Several of these enzymes had improved catalyst load relative to the benchmark DERA from E. coli. In the first step of our process, our new DERA enzymes catalyze the enantioselective tandem aldol reaction of two equivalents of acetaldehyde with one equivalent of chloroacetaldehyde (Scheme 20.6). Thus, in 1 step a 6-carbon lactol with two stereogenic centers is formed from achiral 2-carbon starting materials. In the second step, the lactol is oxidized to the corresponding lactone 7 with sodium hypochlorite in acetic acid, which is crystallized to an exceptionally high level of purity (99.9% ee, 99.8% de). 

SCHEME 111. Synthesis of y-lactones from tartaric-derivedbis-thioester by aldol reaction and the bis-thioketene acetal obtained by silylation of the intermediate bis-enolate552... 

Kiyooka et al. reported that the 3i-catalyzed aldol reaction of a silyl ketene acetal involving a dithiolane moiety with y3-siloxy aldehyde resulted in the production of syn and anti 1,3-diols with complete stereoselectivity depending on the stereochemistry of the catalyst used [45b]. This methodology was applied to the enantioselective synthesis of the optically pure lactone involving a syn-l,3-diol unit, known to be a mevinic acid lactone derivative of the HMG-CoA reductase inhibitors mevinolin and compac-tin (Sch. 2). 

In the enantioselective total synthesis of p-lactone enzyme inhibitor (-)-ebelactone A and B, I. Paterson and coworkers constructed seven stereocenters and a trisubstituted alkene plus a very sensitive p-lactone ring. The backbone of their strategy applied an aldol reaction / Ireland-Claisen rearrangement sequence and used minimal functional group manipulation. The Ireland-Claisen rearrangement was performed in the presence of an unprotected ketone moiety and set a precedent for this protocol. The diastereoselectivity was 96 4, indicating highly ( )-selective silylketene acetal formation. 

Aldol reactions. The Mukaiyama aldol reaction employing 1-triisopropoxy-l-r-butylthioethene as donor displays exceptional Cram-type selectivity, thus the bulk of the silyl group has a crucial effect on the level of 1,2-asymmetric induction. Bicyclic lactones are formed by treatment of a hydroxyalkylalkyne substituted with tungsten and also carrying an acetal side chain. ... 

On the basis of the structures of the three isolated important intermediates 119-121, we proposed a reaction mechanism for the production of lactone 114 (Scheme 41). In this mechanism, catalytic amounts of water or TfOH would play an important role. Oxonium 120 may be obtained by an intramolecular aldol reaction of the intermediate 122. Compound 122 may be derived from olefin 119 by acidic hydration, subsequent fragmentation, and isomerization. Oxonium 120 may undergo intramolecular cyclization to give acetal 123 then fragmentation... 

The aldehyde was then used in an aldol reaction with the anion from 3-isopropylbut-2-enolide. [The lactone was prepared in the following way bromination of 3-methyl-2-butanone under kinetic conditions (-15 °C) afforded the 1-bromo derivative. The bromine was displaced by acetate on refluxing a solution in acetone with anhydrous KOAc. Reaction of the resulting keto-acetate with the anion from triethylphosphonoacetate afforded the desired butenolide in 55% yield.] The anion was generated in tetrahydrofuran from the butenolide and lithium diisopropylamide and was cooled to -78 °C before addition of the aldehyde. The temperature was maintained below -70 °C for 5h and the reaction was quenched with ammonium chloride at this temperature. Under these conditions (kinetic) the 22R23R intermediate (3) was obtained in 65% yield (26). 

Transformation into a protected form of 187 is straightforward oxidation with household bleach gives the lactone 192, displacement with cyanide ion, acetal formation and esterification with trimethylsilyl diazomethane gives 193. The synthesis of atorvastatin from 193 was already known. The next section discusses 1,3-control in non-enzymatic aldol reactions. 

N,P P, P] Danishefsky and Simoneau utilized the sequential Michael-aldol reaction for the synthesis of compactin and ML-236A (51.1 and 51.2 in Scheme 51) (101). In this context, the HgI2-promoted addition of the rerf-butyldimethylsilyl ketene acetal derived from ethyl acetate to cyclohex-enone 51.3 followed by reaction with crotonaldehyde and acidic work-up produces 35-42% of lactone 51.4 as one stereoisomer. As enone 51.3 is available in optically pure form from quinic acid (102), the naturally occurring enantiomer of compactin can be obtained. 

The synthesis of the C29-C43 EF segment 479 is summarized in Scheme 68. Methylation of 467 under Prater s conditions stereoselectively afforded 2,3-anti compound 468 (dr = 5-8 1). After TES protection followed by thioester reduction, aldol reaction of the resulting aldehyde with thioketene acetal afforded a-alcohol 469 under Felkin-Anh selectivity. TES deprotection and silver-mediated lactonization followed by TES protection and lactone reduction gave lactol 470. Dehydration, debenzylation, and oxidation furnished aldehyde 471, which was transformed to benzotriazolyl amide 472. 

Cyclic ketene silyl acetal 536 has been used in a synthesis of the chiral -lactone 541 (Scheme 76). The chelation-controlled aldol reaction of 536 with 464 gives 5y -adduct 537 as the sole product [173]. 

Oxidative Cleavage Reactions. Among the numerous methods for 1,2-diol cleavage there exist only a few that involve catalytic ruthenium reagents, for example Ruthenium(III) Chloride with Sodium Periodate Attempted selective monooxidation of a 1,2-diol to the hydroxy aldehyde with catalytic TPAP and NMO resulted in carbon-carbon bond cleavage to provide the aldehyde (eq 11). Furthermore, attempted oxidation of an anomeric a-hydroxy ester failed instead, in this case decarboxy-lation/decarbonylation and formation of the lactone was observed (eq 12). However, Dimethyl Sulfoxide-Acetic Anhydride provided the required a-dicarbonyl unit. Retro-aldol fragmentations can also be a problem. ... 

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