Mukaiyama aldol/lactonization

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>. 

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. 

Notably, the Mukaiyama aldol/lactonization approach has been used in the total synthesis of panclicin D (2-258) [139b,c] and okinonellin B (2-261) (Scheme 2.61) [139d]. I11 the synthesis of 2-258, aldehyde 2-254 and the ketene acetal 2-255 were used to prepare the (3-lactone 2-256 with high simple and induced diastereoselectivity. There follows an esterification with the carboxylic acid 2-257. For the synthesis of 2-261, the aldehydes 2-259 and 2-252b were employed as substrates leading initially to the (3-lactone 2-260. 

A highly diastereoselective, tandem Mukaiyama aldol-lactonization provides chiral... 

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

The synthetic utility of the Mukaiyama aldol reaction is broadened when coupled with other reactions in a tandem fashion. Romo and coworkers developed a highly diastereoselective tandem Mukaiyama aldol-lactonization... 

The p-lactone cyclization precursors come from Romo and Yang s tandem Mukaiyama aldol lactonization (TMAL) process (Scheme 7) [10]. As an example of this, lactone 25 was the product of the ZnCl2-mediated cyclization of a-benzyloxy aldehyde 24 with thio-ketene acetal 23. Ozonolytic cleavage of the alkene gave 26. 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

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). 

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. ... 

The TiCLrmediated Mukaiyama aldol reactions between 7r-allyltricarbonyliron lactone complexes and chiral aldehydes were well documented by Ley and coworkers [37]. (/ )-Trimethylsilyl enol ether 23 (>96% ee) was prepared from the methyl ketone complex 22 by treatment with MesSiOTf/EtsN in CH2CI2 and this was then reacted with (R)- and (5)-2-benzyloxypropanal 24 under the influence of TiCl4 in CH2CI2 at -78 °C. Although the reactions proceeded very slowly and apparent hydrolysis of the silyl enol ether occurred, the aldol products 25 and 26 were isolated in excellent diastereoselectivity in both cases (Scheme 1-8). Interest-... 

Keck et al. have used the lactone annulation procedure developed in their laboratory to install the lactone moiety by reaction of the lithium enolate of methylacetate with a (3-acetoxy aldehyde [108]. The other key steps include a diastereoselective Lewis acid mediated (Z)-crotylstannane aldehyde addition, a highly selective Lewis acid promoted Mukaiyama aldol reaction and an arari-selective Sml2 reduction of a p-hydroxyketone. The preparation of the C8-C15 fragment of (-)-pironetin started with the chelation-controlled addition of (Z)-crotyl tri-n-butylstannane to the (3-benzyloxy-aldehyde 153 in the presence of TiCU [109] to give the... 

Danishefsky s total synthesis of avermectin (3a) was accomplished via an aldol reaction to join the northern and southern segments, intramolecular Nozaki aldol cyclization [138] to construct the southern ring system, Mukaiyama macro-lactonization, deconjugation to the C3-C4 double bond, and NIS-mediated gly-cosidation (Fig. 7). 

Aldol reactions. The Mukaiyama-aldol reaction has been extended to using peroxyacetals and trimethyl orthoformate as acceptors. The latter process serves to introduce the lactonic carbonyl group across the bicyclic core of (+)-CP263114. 

The cross-aldol reaction between propionaldehyde (5a, R =Me in Scheme 4.12) and p-nitrobenzaldehyde gave the corresponding compound anti-29 (> 88% yield, 88% de and 99% ee), which has been used as the asymmetric key step in the synthesis of trichostatin A [76], In a similar way, using propionaldehyde (Sa, R =Me in Scheme 4.12) and an excess isobutyraldehyde (4 equiv, R =j-Pr) catalyzed by proline (10 mol%), product anti-29 (98% de and 99% ee) was obtained. Subsequent diastereoselective Mukaiyama aldol reaction followed by lactonization gave prelactone B [77]. The synthesis of (-)-enterolactone has been achieved by a cross-aldol reaction between methyl 4-oxobutyrate and 3-methoxybenzaldehyde catalyzed by proline (20 mol%) as a key step [78],... 

Mukaiyama aldol reaction of a dienolsilane with a ketone, followed by lactone ring closure (Scheme 2.27). Yields and enantiomeric excesses were satisfactory only with aliphatic methyl ketones. 

Pyrid-2-yl congeners of the reagent have been employed for the synthesis of 8-lactones via a tandem Mukaiyama aldol lac-tonization (TMAL) process. Herein, choice of Lewis acid promoter (zinc(n) chloride or tin(IV) chloride) determines whether cis or trans 8-lactone products are obtained (eq 15). The analogous Mannich initiated sequence provides /3-lactams. ... 

K. Kong, D. Romo, Diastereoselective, vinylogous Mukaiyama aldol additions of silyloxy furans to cyclic Ketones annulation of buteno-lides and y-lactones, Org. Lett. 8 (2006) 2909-2912. 

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