Diastereoselectivity Mukaiyama reaction

In the discussion of the stereochemistry of aldol and Mukaiyama reactions, the most important factors in determining the syn or anti diastereoselectivity were identified as the nature of the TS (cyclic, open, or chelated) and the configuration (E or Z) of the enolate. If either the aldehyde or enolate is chiral, an additional factor enters the picture. The aldehyde or enolate then has two nonidentical faces and the stereochemical outcome will depend on facial selectivity. In principle, this applies to any stereocenter in the molecule, but the strongest and most studied effects are those of a- and (3-substituents. If the aldehyde is chiral, particularly when the stereogenic center is adjacent to the carbonyl group, the competition between the two diastereotopic faces of the carbonyl group determines the stereochemical outcome of the reaction. 

Scheme 2.3 shows reactions of several substituted aldehydes of varying complexity that illustrate aldehyde facial diastereoselectivity in the aldol and Mukaiyama reactions. The stereoselectivity of the new bond formation depends on the effect that reactant substituents have on the detailed structure of the TS. The 3,4-syn stereoselectivity of Entry 1 derives from a Felkin-type acyclic TS. 

Scheme 2.6 shows some examples of the use of chiral auxiliaries in the aldol and Mukaiyama reactions. The reaction in Entry 1 involves an achiral aldehyde and the chiral auxiliary is the only influence on the reaction diastereoselectivity, which is very high. The Z-boron enolate results in syn diastereoselectivity. Entry 2 has both an a-methyl and a (3-benzyloxy substituent in the aldehyde reactant. The 2,3-syn relationship arises from the Z-configuration of the enolate, and the 3,4-anti stereochemistry is determined by the stereocenters in the aldehyde. The product was isolated as an ester after methanolysis. Entry 3, which is very similar to Entry 2, was done on a 60-kg scale in a process development investigation for the potential antitumor agent (+)-discodermolide (see page 1244). 

The aldehyde-aldehyde aldol reactions were first nsed in a natural product synthesis setting by Pihko and Erkkila, who prepared prelactone B in only three operations starting from isobutyraldehyde and propionaldehyde (Scheme 40). Crossed aldol reaction under proline catalysis, followed by TBS protection, afforded protected aldehyde 244 in >99% ee. A highly diastereoselective Mukaiyama aldol reaction and ring closure with aqueous HE completed the synthesis [112]. 

Considerable effort has been devoted to finding Lewis acid or other catalysts that could induce high enantioselectivity in the Mukaiyama reaction. As with aldol addition reactions involving enolates, high diastereoselectivity and enantioselectivity requires involvement of a transition state with substantial facial selectivity with respect to the electrophilic reactant and a preferred orientation of the nucleophile. Scheme 2.4 shows some examples of enantioselective catalysts. 

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. 

To achieve a stereoselective aldol reaction that does not depend on the structural type of the reacting carbonyl compounds, many efforts have been made to use boron enolates. Based on early studies by Mukaiyama et al.8a and Fenzl and K0ster,8b in 1979, Masamune and others reported a highly diastereoselective aldol reaction involving dialkylboron enolates (enol borinates)9... 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

A.V. The Noyori Open-Chain Model. In the Mukaiyama reaction, the Zimmerman-Traxler and Evans models are not satisfactory for predicting diastereoselectivity. Several open (nonchelated) transition states have been considered as useful models. The condensation reaction of carboxylic acid dianions with aldehydes indicated that anti selectivity increased with increasing dissociation of the gegenion (the cation, M+),224 When analyzing an aldol condensation that does not possess the bridging cation required for the Zimmerman-Traxler model, an aldehyde and enolate adapt an eclipsed orientation as they approach. Noyori reported syn selectivity for the reaction of a mixture of (Z)-silyl enol ether 389 and ( )-silyl enol ether 390 with benzaldehyde in the presence of the cationic tris-(diethylamino) sulfonium (TAS).225 xhis reaction is clearly a variation of the Mukaiyama reaction, which does not usually proceed with good diastereoselectivity... 

The presence of a chiral auxiliary can influence the stereochemistry of products formed in a Mukaiyama reaction. A stereogenic center derived from a chiral amino alcohol was incorporated in the enol ether moiety (see 445). When this reacted with benzaldehyde and TiCU. the alcoholate products were 446 and 447 (R = the chiral auxiliary) The diastereoselectivity in this reaction was quite good (95 5 favoring 446) and each product was formed with high enantioselectivity.246 It is also possible to incorporate the stereogenic center into the starting material (a chiral template, as discussed in sec. 10.9).247... 

The aldol reaction and related processes have been of considerable importance in organic synthesis. The control of syn/anti diastereoselectivity, enantioselectivity and chemoselectivity has now reached impressive levels. The use of catalysts is a relatively recent addition to the story of the aldol reaction. One of the most common approaches to the development of a catalytic asymmetric aldol reaction is based on the use of enantiomerically pure Lewis acids in the reaction of silyl enol ethers with aldehydes and ketones (the Mukaiyama reaction) and variants of this process have been developed for the synthesis of both syn and anti aldol adducts. A typical catalytic cycle is represented in Figure 7.1, where aldehyde (7.01) coordinates to the catalytic Lewis acid, which encourages addition of the silyl enol ether (7.02). Release of the Lewis acid affords the aldol product, often as the silyl ether (7.03). 

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],... 

In 1993, a tris(pentafluorophenyl)boron was first recognized by Yamamoto and co-workers as a water-tolerant Lewis acid catalyst in the aldol reaction of silyl enol ethers (237). Subsequently, Kobayashi and co-workers developed the first strategy for catalytic generation of boron enolates, employing catalytic amount of diphenylborinic acid (Ph2BOH) to promote the Mukaiyama aldol reaction in the presence of sodium dodecyl sulfate (SDS) (Scheme 59). The authors presumed that the active species of the reactions are boron enolates. Perhaps it is the first example of catalytic use of a boron source in boron enolatemediated diastereoselective aldol reactions (238). 

Recently, Wang and coworkers developed an efficient asymmetric Mukaiyama reaction using Ga(OTf)3, associated with a chiral semi-crown ligand, as the Lewis acid (Scheme 8.9). Enantioselectivities up to 87% were obtained when the reaction was performed in a mixture of water/ethanol (9 1) or even in neat water, with good chemical yields and high diastereoselectivities. 

Munoz-Muniz, O., Quintanar-Audelo, M. and Juaristi, E., Reexamination of CeCla and InCla as activators in the diastereoselective Mukaiyama aldol reaction in aqueous media, J. Org. Chem., 2003, 68, 1622-1625. 

T. OUevier, J.-E. Bouchard, V. Desyroy, Diastereoselective Mukaiyama aldol reaction of 2-(trimethylsilyloxy)furan catalyzed by bismuth triflate, J. Org. Chem. 73 (2008) 331-334. 

Numerous in-depth mechanistic studies have been performed on the Mukaiyama aldol reaction. " Although various mechanisms exist in the literature that take into account the various roles of the numerous catalysts used for the enantio- and diastereoselective Mukaiyama aldol reaction, the commonly accepted mechanism accounting for bond formation is shown below.The reaction begins with the coordination of a Lewis acid with aldehyde 4 to form complex 5. Due to its enhanced electrophilicity, complex 5 is attacked by the 7t-bond of the enol silane 6, giving rise to resonance stabilized cation 7. At this point, either intermolecular silyl cleavage upon hydrolysis or intramolecular silyl transfer to the product hydroxyl group occurs to give products such as 8 or 9. 

Finally, stereochemical aspects of the mechanism have been extensively studied by Evans and coworkers during their construction of a model to map the diastereoselective induction observed in the course of the aldol reaction. Similarly, mechanistic studies were performed by the Evans group with regards to their bis(oxazolinyl)-pyridine (pybox)-copper(II) complex, a catalyst for the enantioselective Mukaiyama reaction. ... 

A remarkable case of remote asymmetric induction was observed by Kobayashi and coworkers when they extended the Evans method to protocol for a vinylogous aldol addition (Scheme 4.59). For this purpose, the alkenoic imides 251 and 254 were converted into vmylketene sUyl N,0-acetals 252 and 255, respectively. When these silicon enolates, whose fr 5-configuration was assigned based upon NOE experiments, were submitted to a vinylogous Mukaiyama reaction, the adducts 253 and 256 were obtained with excellent diastereoselectivity [131]. 

Oppolzer s sultams also provided a solution to the problem of the asymmetric acetate aldol addition based upon a Mukaiyama reaction of sUyl ketene N,0-acetal 276, derived from N-acetylsultam 92 (R = H). In the titanium tetrachloride-mediated reaction with various aldehydes, the diastereoselectivity is not particularly high - as typical for aldol additions of a-unsubstituted enolates. 

The most versatile and the most frequently applied among the enantioselective catalytic aldol protocols is based upon the Mukaiyama s directed aldol reaction the addition of silicon enolates to aldehydes or ketones [86], in its classic version under activation of the carbonyl group by a chiral Lewis acid. More recently, base-promoted versions of the Mukaiyama reaction were elaborated and also procedures that involve a transmetallation of the silicon enolate. Over the years since the discovery of the reaction, numerous protocols for enantioselective and diastereoselective additions of silicon enolates to aldehydes or ketones under activation by chiral catalysts were elaborated [87], after the group of Mukaiyama itself had made seminal and substantial contributions [88]. 

A Lewis acid-catalyzed vinylogous Mukaiyama aldol reaction between 2-trialkylsilyloxyfurans and a-substituted ketones proceeded diastereoselectively... 

Pro-chiral pyridine A-oxides have also been used as substrates in asymmetric processes. Jprgensen and co-workers explored the catalytic asymmetric Mukaiyama aldol reaction between ketene silyl acetals 61 and pyridine A-oxide carboxaldehydes 62 <06CEJ3472>. The process is catalyzed by a copper(II)-bis(oxazoline) complex 63 which gave good yields and diastereoselectivities with up to 99% enantiomeric excess. 

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>. 

Recent developments of aldol-type reactions with titanium enolates include the a- and /3-C-glycosidation of glycals73 and the diastereoselective addition to 2-acetoxytetrahydrofurans.74 Mukaiyama and co-workers have developed a one-pot procedure for the preparation of unsymmetrical double aldols.75... 

It is significant to note that this reaction is highly unusual since the prochiral element resides entirely on the nucleophile. The chiral Lewis acid exerts control of en-antiofacial selectivity by proctor through tight control of the presumed heterocycloaddition transition state, Scheme 27. In effect, extremely high fidelity is necessary to orient the 2n component with respect to the 4ji component coordinated to the chiral Lewis acid. The factors that control the diastereoselectivity in the Mukaiyama Michael reaction of crotonylimides could also control enantioselectivity in the amination reaction. That selectivities on the order of 99% ee are observed in this reaction is testament to the level of control exerted by these catalysts. 

Based on these results, Kalesse et al. applied the vinylogous Mukaiyama aldol reaction in their total synthesis of ratjadone [33, 34]. In the synthesis of the C14-C24 segment (A-fragment), the vinylogous aldol reaction was used together with different Lewis acids to achieve the addition of this diacetate syn-thon in a diastereoselective manner under Felkin control (Scheme 23). 

Scheme 8 summarizes the introduction of the missing carbon atoms and the diastereoselective epoxidation of the C /C double bond using a Sharpless asymmetric epoxidation (SAE) of the allylic alcohol 64. The primary alcohol 62 was converted into the aldehyde 63 which served as the starting material for a Horner-Wadsworth-Emmons (HWE) reaction to afford an E-configured tri-substituted double bond. The next steps introduced the sulfone moiety via a Mukaiyama redox condensation and a subsequent sulfide to sulfone oxidation. The sequence toward the allylic alcohol 64 was com-... 

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