2- Butanone aldol reaction

With aldehydes 73 and 74 in hand, two alternatives were considered for the completion of the synthesis of preswinholide A, i.e. carrying out the butanone aldol reaction on either the methyl or the ethyl side first (see Scheme 9-24). Initially, the former option was investigated. While the reaction of the kinetic boron enolate of butanone with aldehyde 73 did not favour the desired Felkin adduct 83, the addition of allyl silane 84 (a masked butanone equivalent) proved selective in the desired sense (Scheme 9-27). This change in selectivity indicates the stereochemical reversal possible when switching from a cyclic to an acyclic transition state. 

Aldol reaction of the campholenic aldehyde with 2-butanone gives the intermediate ketones from condensation at both the methyl group and methylene group of 2-butanone (Fig. 6). Hydrogenation results in only one of the two products formed as having a typical sandalwood odor (160). 

In contrast, highly stereoselective aldol reactions are feasible when the boron etiolates of the mandelic acid derived ketones (/ )- and (5,)-l- t,r -butyldimethylsiloxy-l-cyclohexyl-2-butanone react with aldehydes33. When these ketones are treated with dialkylboryl triflate, there is exclusive formation of the (Z)-enolates. Subsequent addition to aldehydes leads to the formation of the iyn-adducts whose ratio is 100 1 in optimized cases. 

In general, the product ratio of a mixed aldol condensation will depend upon the individual reaction rates. Most ketones show a pattern similar to butanone in reactions with aromatic aldehydes. Base catalysis favors reaction at a methyl position over a methylene group, whereas acid catalysis gives the opposite preference. 

HYDR0XY-3-NETHYL-1-PHENYL-1-BUTAN0NE BY CROSSED ALDOL REACTION (1-Butanone, 3-hydroxy-3-methyl -1-phenyl -)... 

HYDROXY-3-METHYL-1-PHENYL-1-BUTANONE BY CROSSED ALDOL REACTION... 

S)-Proline-catalyzed aldol reactions involving 2-butanone afforded the products of C-C bond formation at the methyl group, the less substituted a-position of the ketone as the major regioisomers (Fig. 2.1) [6, 9]. The regioselectivity of the aldol reaction of 2-butanone was reversed using a proline amide derivative as the catalyst, as shown in Scheme 2.2 [13]. The (S)-proline-catalyzed aldol reactions of cyclohexanone and of cyclopentanone afforded both anti- and syn-products (anti syn 2 1) with moderate enantioselectivities (63-89% ee) [6]. The selectivity... 

Fig. 2.1 Products of (S)-proline 1- and 4-catalyzed aldol reactions of 2-butanone [6, 9].

In the aldol reaction between butanone and benzaldehyde it is important to note that butanone can form more than one enolate. Under the reaction conditions given, formation of the more substituted and thermodynamically more stable enolate will be produced, and this can be either E- or Z-configured. Moreover, nucleophilic attack at the aldehyde group of the planar benzaldehyde can take place both from the Re or Si sides. Four products are therefore obtained. From the Z enolate the /-configured enantiomers A and B are the preferred products, whilst the E enolate gives predominately the w-configured enantiomers C and D. 

Gennari et al. developed a computational model to reproduce the experimental syn/anti setereoselectivity for the aldol reactions of Z and E enol borinates of butanone with acetaldehyde.13 For the reaction of Z-enol borinate 8Z, the chair transition state TS Z-chair A dominates over other three-transition states (Scheme 2.XI). When a Boltzmann distribution was calculated for the competing transition structures, a complete syn/anti selectivity of 99 1 was predicted. The aldol reaction of E-enol borinate 8E with acetaldehyde is, however, calculated to have four transition structures of similar energy (Scheme 2.XII). Although... 

Swinholide A. The swinholides are a series of complex macrodiolides isolated from the marine sponge Theonella Swinhoei, which display potent cytotoxicity against a range of human tumour cell lines. Swinholide A (71) provided an excellent opportunity to showcase the synthetic utility of a range of aldol reactions. For its total synthesis by our group in 1994 [50] the fully protected preswinholide A 72 was considered to be an essential late-stage intermediate, which appeared accessible via two directed aldol reactions of a suitable butanone equivalent with aldehydes 73 and 74 (Scheme 9-24). 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

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). 

Base-promoted reactions of unsymmetrical methyl ketones often give C-1 substituted products in high yield an example of such a case is shown in equation (55). A clue to the source of this behavior is seen in the two aldol reactions presented in equations (56) and (57). Under the milder set of conditions, benz-aldehyde reacts with butanone to give a mixture of aldols resulting from attack at C-1 and C-3 (equation 56). When the reaction is carried out at higher temperature and for a longer period, the C-1 condensation product is obtained in nearly quantitative yield (equation 57). ... 

McKervey and coworkers have used lithium iodide as a catalyst for mixed aldol reactions several examples are shown in equation (60). In all cases studied, 2-butanone reacts solely at C-1. The process is also applicable to other ketones, but they react much more slowly than do methyl ketones. For... 

Aldol reaction. Asymmetric aldol reaction of chloroacetone with electron-deficient ArCHO gives mainly the ant -3-chloro -hydroxy-2-butanones, in the presence of 1. The... 

The PTAD-diene protected 22-aldehyde analog has been used by Williams and Eyley to synthesize 24,25-dihydroxy derivatives via an aldol reaction with the tetra-hydropytanyl ether of 3-hydroxy-3-methyl-2-butanone followed by NaBH4/pyridine reduction [scheme (9)] The same starting aldehyde is also a precursor for synthesis of the 25,26-dihydroxy-5,7-diene [scheme (10)] ... 

The diastereoselectivity of the Baylis-Hillman reaction was investigated by attaching chiral auxiliaries to a,-unsaturated ketones [216]. The use of the 4-isopropyloxazoladinone chiral auxiliary in [EMIM][OTf] gave rise to very low di-astereomer ratios (45 55) (Scheme 5.2-88). The authors also describe a proline -catalyzed aldol reaction of acetone, butanone, hydroxyacetone and chloroacetone with a chiral imine and obtain up to 9 1 diastereomer ratios. 

You have a choice here either you first form an enol(ate) from butanone and do an aldol reaction with the aromatic ketone or you first make an imine and then form enamines from that. In either case, you would expect enol or enamine formation on the more substituted side in acid but the less substituted side in base. 

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