Diastereoselective synthesis Mukaiyama aldol reactions

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). 

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]. 

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]. 

The asymmetric total syntheses of mtamycin B and oligomycin C was accomplished by J.S. Panek et al. In the synthesis of the C3-C17 subunit, they utilized a Mukaiyama aldol reaction to establish the C12-C13 stereocenters. During their studies, they surveyed a variety of Lewis acids and examined different trialkyl silyl groups in the silyl enol ether component. They found that the use of BFs OEta and the sterically bulky TBS group was ideal with respect to the level of diastereoselectivity. The stereochemical outcome was rationalized by the open transition state model, where the orientation of the reacting species was anti to each other, and the absolute stereochemistry was determined by the chiral aldehyde leading to the anti diastereomeric Felkin aldol product. 

The synthesis of the C1-C9 fragment 120 began with an auxiliary controlled aldol reaction of the chloroacetimide 121, where chlorine is present as a removable group to ensure high diastereoselectivity in what would otherwise have been a non-selective addition (Scheme 9-39). The Lewis acid-catalyzed, Mukaiyama aldol reaction of dienyl silyl ether 122 with / -chiral aldehyde 123 proceeded with 94%ds, giving the 3-anti product 124, as predicted by the opposed dipoles model [3]. Anti reduction of the aldol product and further manipulation then provided the C1-C9 fragment 120 of the bryostatins. 

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],... 

The synthesis of the carboxylic acid 9a commenced with silylation of known alcohol 16 followed by reductive removal of the chiral auxiliary to give the aldehyde 17 (Scheme 3). Vinylogous Mukaiyama aldol reaction" " of 17 with Chan s diene 18" afforded the alcohol 19 in 95% yield with 10 1 diastereoselectivity. Treatment of 19 with PPTS in MeOH resulted in cleavage of the silyl ether and spontaneous methyl acetalization to provide the methyl acetal 20. Protection of the hydroxyl group of 20 by using MPM trichloroacetimidate in the presence of La(OTf >3" gave the MPM ether 21. Hydrolysis of the methyl ester of 21 afforded the carboxylic acid 9a. 

In contrast, the Mukaiyama aldol reaction used in the Heathcock synthesis of the C29-C44 fragment of spongistatin proceeded with comparatively reduced diastereoselectivity. The stereochemically complex enol silane 30 was eoupled to 29, a 2,3-57 -p-alkoxy aldehyde, resulting in... 

Remote asymmetric induction can be obtained through the use of chiral auxiliaries, such as valine derived oxazolidinones, within the framework of the vinylogous Mukaiyama aldol reaction. During the synthesis of khafrefungin, an antifungal agent, Kobayashi and coworkers reacted the vinylketene silyl A. O-acetal 56 with the aldehyde 57 to yield the a r/-aldol adduct 58 in excellent yield (98%) and high diastereoselectivity (> 20 1). ... 

Cyclohepta-3,5-dienone)iron complexes can be stereoselectively methylated and hydroxylated. The electrophile adds exclusively anti to the tricarbonyliron fragment. Double methylation or hydroxylation of the a and a positions is accomplished in high overall yield (Scheme 4-146). Silyl enol ethers adjacent to tricarbonyl(Ti -diene)iron units can be subjected to Mukaiyama aldol reaction with aldehydes to provide aldol adducts with varying diastereoselectivity. This methodology has, for example, been applied to the enantioselective synthesis of the dienetriols streptenol C and D (Scheme 4-147). ... 

In investigations of double diastereodifferentiating Mukaiyama aldol reactions, Evans demonstrated that the coupling of end silane 195 either to aldehyde 196 or to aldehyde 198 affords the Felkin products 197 and 199, respectively, with excellent diastereoselectivity (Scheme 4.21) [36]. Because of the involvement of open transition states in these aldol reactions, no direct correlation was found between the starting end silane geometry and the observed simply selectivity (syn versus anti). This contrasts with the simple diastereoselectivity typically observed for cis- and trans-metal enolates that react through cyclic Zimmerman-Traxler transition states. By this strategy, the addition of enol silane 201 to 200 provided an advanced intermediate 202 in the synthesis of 6-deoxyerythronolide B (187, Scheme 4.22) [97]. 

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. 

Mukaiyama and Kobayashi et al. have developed the use of Sn(OTf)2 in diastereose-lective and enantioselective aldol-type reactions [26,27]. Initially, the stereoselective aldol reactions were performed with a stoichiometric amount of Sn(OTf)2 [28], The reaction between 3-acylthiazolidine-2-thione and 3-phenylpropionaldehyde is a representative example of a diastereoselective syn-aldol synthesis (Eq. 17). 

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). 

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