Syn-aldol reactions

Aldol reactions.1 Several exotic boron derivatives have been used to prepare boron enolates, of particular interest because of their use for selective syn-aldol reactions. Actually boron enolates can be generated using BC13 and Hiinig s base. Dichloroboron enolates are unusually reactive even at -95°, and show syn-selectivity of 80-95%. Aldol reactions are carried out in CH2C12 by mixing the ketone and BC13 (1 2 equiv.) followed by addition of the base (2 equiv.) and the aldehyde (1 equiv.). Yields are 80-95%. 

The related lactate-derived ketones, 44 [27] and 45 [29], are useful auxiliaries for boron- and titanium-mediated syn aldol reactions, respectively (Scheme 9-14). The effect of the protecting group in both cases is notable. For ketone 44, the use of the boron chloride reagent unexpectedly afforded the syn adduct with good control... 

In a similar manner, syn aldol reactions can be carried out with ethyl ketones using the Ipc2BOTf reagent. We showed that the asymmetric induction using diethyl ketone is reasonable (66-91% ee), with best results for a,jS-unsaturated aldehydes [35]. We also showed that this reaction could be extended to chiral ketones, for example, the stereoselective synthesis of either syn adduct 51 or 52 was achieved, depending on the configuration of IpciBOTf reagent (Scheme 9-17) [II]. 

The second total synthesis of swinholide A was completed by the Nicolaou group [51] and featured a titanium-mediated syn aldol reaction, followed by Tishchenko reduction, to control the C21-C24 stereocenters (Scheme 9-30). The small bias for anri-Felkin addition of the (Z)-titanium enolate derived from ketone 89 to aldehyde 90 presumably arises from the preference for (Z)-enolates to afford anti-Felkin products upon addition to a-chiral aldehydes [52], i.e. substrate control from the aldehyde component. 

The first total synthesis of rutamycin B (138) was reported by Evans et al. in 1993 [62J. In this route, two auxiliary eontrolled syn aldol reactions were used to introduce the stereocenters at C2S/C24 and C3(/C3i of the spiroacetal (Scheme 9-44). In both cases, the same enantiomer of auxiliary 36 was used and, as expected, excellent stereocontrol over the newly formed centers in 139 and 140 was achieved (>99%ds). Elaboration of the aldol adducts to 141 and 144, subsequent coupling and further functionalization afforded the spiroacetal containing vinyl boronic acid 143. 

In the Evans synthesis of the polypropionate region (Scheme 9-45), the boron-mediated anti aldol reaction of -ketoimide ent-25 with a-chiral aldehyde 145 afforded 146 with 97% ds in what is expected to be a matched addition. Adduct 146 was then converted into aldehyde 147 in readiness for union with the C -Cs ketone. This coupling was achieved using the titanium-mediated syn aldol reaction of enolate 148 leading to the formation of 149 with 97% ds. 

In the first total synthesis of bafilomycin A by Evans and Calter [16], the syn aldol reaction between ketone 29 and aldehyde 176 was a pivotal transformation (Scheme 9-51). Using a (Z)-enolate, it could be expected that aldehyde 176 would have a small bias for the desired ann-Felkin adduct, however, control from the ketone component would be needed for high stereoselectivity. Use of common metal enolates led to poor stereocontrol however, model studies indicated that the (Z)-chlorophenyl boron enolate, in conjunction with cyclic protection of the C21-C23 diol, induced high selectivity in the desired sense. In practice, the coupling of the required aldehyde 176 and enolate 77 afforded 178 with >95%ds. Compound 178 was then successfully elaborated to give bafilomycin A]. In the second reported synthesis of bafilomycin A, Toshima et al. carried out the same aldol coupling to form the Cn-Cig bond [68]. 

A popular aldol connection has been a syn reaction to form the C(,-Cj bond (Scheme 9-59). The lithium-mediated syn aldol reactions of ketone 202 were used extensively by the Schinzer group in their synthesis of epothilone A and B [75]. 

In our synthesis, iterative aldol reactions of dipropionate reagent (R)-18 allowed for the control of the C3-C10 stereocenters (Scheme 9-72) [89]. Hence, a tin-mediated, syn aldol reaction followed by an anti reduction of the aldol product afforded 270. Diol protection, benzyl ether deprotection and subsequent oxidation gave aldehyde 271 which reacted with the ( )-boron enolate of ketone (/ )-18 to afford anti aldol adduct 272. While the ketone provides the major bias for this reaction, it is an example of a matched reaction based on Felkin induction from the... 

In order to unambiguously ascertain the Cio stereochemistry, the Hoffmann group elected to separately synthesize both C(o epimers of aldehyde 269 (Scheme 9-73) via aldol additions of both enantiomers of ketone 18 to aldehyde 273 [88]. Notably, the boron-mediated syn aldol reactions of this ketone are non-selective in the absence of chiral ligands (see Scheme 9-8 for selective syn aldol reactions of 18). In this case, the C7 hydroxyl was ultimately oxidized to a ketone, and the Cg stereocenter epimerized during cyclization so the lack of selectivity was not detrimental to the synthesis. 

Ebelactone A and B. The ebelactones are a small group of / -Iactone enzyme inhibitors isolated from a cultured strain of soil actinomycetes. Our synthesis of ebelactone A (274) and B (275) employed three different types of aldol reactions including the enantioselective syn aldol reaction of diethylketone and ethacrolein which afforded aldol adduct 276 with 86% ee (Scheme 9-74) [90]. Following... 

TBS-protection, a second, boron-mediated, syn aldol reaction led to the formation of 277 with 95% ds. In this case, ketone 278 controlled the stereochemical outcome of the reaction, and chiral ligands on boron were not required. A simple steric model accounts for this selectivity (see Scheme 9-11), and a titanium-mediated aldol reaction would be expected to give the same product. Following elaboration, including an Ireland-Claisen rearrangement, aldehyde 279 was prepared. 

Application of asymmetric alkylation with Evans auxiliaries Aldol Reactions with Evans Oxazolidinones The syn aldol reaction with boron enolates... 

Stereoselective syn-aldol reaction syn-3-hydroxy-2-anu.no esters. Reaction of the lithium cnolatc of ethyl N, N-dimethylglycinc (1) with aldehydes in the presence of B(C2I1,), (1 cquiv.) results in vyn-3-hydroxy-2-amino acid esters in >95% de (equation 1). The high diastcreosclcctivity is explained by the exclusive or predominant... 

In the synthesis of the C1-C12 fragment of amphidinolide Tl, syn aldol adduct 77 was prepared in 92% yield as a single diastereomer by the Crimmins modified Evan s strategy (TiCU with (-)-sparteine). This protocol was also used to install the stereocenters at the C4 and C5 in 80 with excellent diastereoselectivity (96% de) in the total synthesis of (-)-bitungolide F. In the total synthesis of cruentaren B, the Crimmins modified condition was used in the Evans syn aldol reaction, giving adduct 82 in excellent yield and diastereoselectivity (92%, 98% de). ... 

S. S. V. Ramasastry, H. Zhang, F. Tanaka, C. F. Barbas, III, J. Am. Chem. Soc. 2007,129, 288-289. Direct catalytic asymmetric synthesis of anti-1,2-amino alcohols and syn-l,2-diols through organocatalytic anti-Mamtich and syn-aldol reactions. 

Asymmetric aldol reactions utilizing chiral auxiliaries or templates have emerged as one of the most reliable methods in organic synthesis. Both syn-and anti-selective aldol reactions have been developed over the years. The field of asymmetric syn aldol reactions has been largely advanced by Evans since his development of dibutylboron enolate aldol chemistry based on amino acid-derived chiral oxazolidinones. This method requires expensive dibutylboron trifiate, hosvever, and the amino acid-derived chiral auxiliary is only readily available in one enantiomer and thus only provides one enantiomer of the syn aldol. Several methods developed on the basis of titanium enolates provide convenient access to both Evans and non-Evans syn aldol products. 

Other chiral auxiliaries used in syn aldol reactions are illustrated in Figure 2.5. Xiang et al. developed N-tosylnorephedrine-based chiral auxiliary 139... 

Ahn and coworkers developed stilbenediamine-derived 1,2,5-thiadiazoli-dine-1,1-dioxide-based chiral auxiliary 140 and demonstrated its utility in syn aldol reactions [49]. Excellent selectivity and yield were observed for a variety of aldehydes, as shown in Table 2.24, entries 1-3. The cyclic sulfa-mide auxiliary is novel in that it is bifunctional and C2-symmetric, so only... 

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