Ketones aldol stereoselection

The intramolecular reductive aldol reaction of keto-enones was successfully conducted under conditions similar to those described above, employing a cationic Rh complex and PI13P (Scheme 20) [34]. The keto-enone 63 was cyclized in the presence of added K2CO3 to give the ketone-aldol 64 in 72% yield with exclusive ds-selectivity. Dione-enone derivatives, for example 68 and 70, were efficiently cyclized to furnish bicyclic aldol products 69 and 71, respectively, wherein three stereogenic centers of the bicyclic product form stereoselectivity through the intermediacy of a Rh-enolate. 

Detailed investigations indicate that the enolization process (LDA, THF) affords enolates 37 and 38 with at/east 97% (Z)-stereoselection. Related observations have recently been reported on the stereoselective enolization of dialkylthioamides (38). In this latter study, the Ireland-Claisen strategy (34) was employed to assign enolate geometry. Table 10 summarizes the enolization stereo selection that has been observed for both esters and amides with LDA. Complementary kinetic enolization ratios for ketonic substrates are included in Table 7. Recent studies on the role of base structure and solvent are now beginning to appear in the literature (39,40), and the Ireland enolization model for lithium amide bases has been widely accepted, A tabular survey of the influence of the ester moiety (ORj) on a range of aldol condensations via the lithium enolates is provided in Table 11 (eq. [24]). Enolate ratios for some of the condensations illustrated may be found in Table 10. It is apparent from these data that ( )-enolates derived from alkyl propionates (Rj = CH3, t-C4H9) exhibit low aldol stereoselectivity. In contrast, the enolates derived from alkoxyalkyl esters (Rj = CHjOR ) exhibit 10 1 threo diastereo-... 

Aldol reactions Enolate formation from ketones and subsequent aldol reaction give yyn-aldols stereoselectively. 

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. 

Kinetic control. The Zimmerman-Traxler model, as applied to propionate and ethyl ketone aldol additions, is shown in Scheme 5.7 (note the similarity to the boron-mediated allyl additions in Scheme 5.3). Based on this model, we would expect a significant dependence of stereoselectivity on the enolate geometry, which is in turn dependent on the nature of X and the deprotonating agent (see section... 

Figure 5. Synthesis ofsyn- or anti- 2-alkyUI-hydroxy-3-ketones via stereoselective enolboration-aldolization reactions...

Bivalent tin enolates may also be used in cross-aldol condensations between two ketones. In reactions of tin enolates with aliphatic ketones, little stereoselectivity is observed, but with aromatic ketones (such as acetophenone), the major diastereoisomer formed is the threo-xsomtt [equation (51)]. The reaction... 

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at —12°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioseiectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2BOSO2CF3, at low temperatures (D A. Evans, 1979). Both types of trans-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

Butyraldehyde undergoes stereoselective crossed aldol addition with diethyl ketone [96-22-0] ia the presence of a staimous triflate catalyst (14) to give a predominantiy erythro product (3). Other stereoselective crossed aldol reactions of //-butyraldehyde have been reported (15). 

Ideal starting materials for the preparation of. svn-aldols are ketones that can be readily deprotonated to give (Z)-enolates which are known to give predominantly yyu-adducts. Thus, when (5,)-1-(4-methylphenyl)sulfonyl-2-(l-oxopropyl)pyrrolidine is treated with dibutylboryl triflate in the presence of diisopropylethylamine, predominant generation of the corresponding (Z)-boron enolate occurs. The addition of this unpurified enolate to 2-methylpropanal displays not only simple diastereoselectivity, as indicated by a synjanti ratio of 91 9, but also high induced stereoselectivity, since the ratio of syn- a/.vyn-lb is >97 3. 

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. 

The lithium enolate 2a (M = Li ) prepared from the iron propanoyl complex 1 reacts with symmetrical ketones to produce the diastercomers 3 and 4 with moderate selectivity for diastereomer 3. The yields of the aldol adducts are poor deprotonation of the substrate ketone is reported to be the dominant reaction pathway45. However, transmetalation of the lithium enolate 2a by treatment with one equivalent of copper cyanide at —40 C generates the copper enolate 2b (M = Cu ) which reacts with symmetrical ketones at — 78 °C to selectively produce diastereomer 3 in good yield. Diastereomeric ratios in excess of 92 8 are reported with efficient stereoselection requiring the addition of exactly one equivalent of copper cyanide at the transmetalation step45. Small amounts of triphcnylphosphane, a common trace impurity remaining from the preparation of these iron-acyl complexes, appear to suppress formation of the copper enolate. Thus, the starting iron complex must be carefully purified. 

Reagents are available nowadays for acyl anions other than (4). Thus when Heathcock made the ketone (16), which he used in stereoselective aldol reactions, he needed a-hydroxy ketone (17), This required synthon (18) for which an acetylene is not a good choice as there are as yet no means of controlling the reglo-selectivity of hydration of (19). 

Control of Regio- and Stereoselectivity of Aldol Reactions of Aldehydes and Ketones... 

A similar preference for formation of the syn aldol is found for other Z-enolates derived from ketones in which one of the carbonyl substituents is bulky. Ketone enolates with less bulky substituents show a decreasing stereoselectivity in the order r-butyl > i-propyl > ethyl.2c This trend parallels a decreasing preference for stereoselective formation of the Z-enolate. 

From these and many related examples the following generalizations can be made about kinetic stereoselection in aldol additions of lithium enolates. (1) The chair TS model provides a basis for analyzing the stereoselectivity observed in aldol reactions of ketone enolates having one bulky substituent. The preference is Z-enolate syn aldol /(-enolate anti aldol. (2) When the enolate has no bulky substituent, stereoselectivity is low. (3) Z-Enolates are more stereoselective than /(-enolates. Table 2.1 gives some illustrative data. 

The requirement that an enolate have at least one bulky substituent restricts the types of compounds that give highly stereoselective aldol additions via the lithium enolate method. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Whereas ketones with one tertiary alkyl substituent give mainly the Z-enolate, less highly substituted ketones usually give mixtures of E- and Z-enolates.7 (Review the data in Scheme 1.1.) Therefore efforts aimed at increasing the stereoselectivity of aldol additions have been directed at two facets of the problem (1) better control of enolate stereochemistry, and (2) enhancement of the degree of stereoselectivity in the addition step, which is discussed in Section 2.1.2.2. 

Tin enolates are also used in aldol reactions.27 Both the Sn(II) and Sn(IV) oxidation states are reactive. Tin(II) enolates can be generated from ketones and Sn(II)(03SCF3)2 in the presence of tertiary amines.28 The subsequent aldol addition is syn selective and independent of enolate configuration.29 This preference arises from avoidance of gauche interaction of the aldehyde group and the enolate P-substituent. The syn stereoselectivity indicates that reaction occurs through an open TS. 

The overall transformation of this sequence corresponds to the aldol addition of an aldehyde with a cyclic ketone. The actual aldol addition frequently proceeds with low stereocontrol, so this sequence constitutes a method for stereoselective synthesis of the aldol adducts. The reaction has been done with several Lewis acids, including SnCl4, BF3, and Ti(0-/-Pr)3Cl. 

A very interesting organocatalyzed one-pot Michael addition/aldol condensation/Darzens condensation has been reported for the asymmetric synthesis of epoxy-ketones <06JA5475>. An initial asymmetric Michael condensation between 16 and 17 is catalyzed by proline derivative 18. Intermediate 19 then undergoes an aldol condensation followed by a stereoselective Darzens condensation to provide epoxy-ketone 20 in moderate yield and with surprisingly good enantiomeric excess. 

In the case of methyl vinyl ketone (MVK), similar reactivity is observed. Exposure of MVK (150 mol%) and p-nitrobenzaldehyde to basic hydrogenation conditions provides the corresponding aldol product in good yield, though poor dia-stereoselectivity is observed [24a]. Remarkably, upon use of tris(2-furyl)phos-phine as ligand and Li2C03 as basic additive, the same aldol product is formed with high levels of syn-selectivity [24 e]. Addition of MVK to activated ketones such as l-(3-bromophenyl)propane-l,2-dione is accomplished under similar con-... 

Starting from ketone(i )-/(S )-49, the asymmetric aldol reaction with aldehyde in the presence of 45a or 45b affords all four isomers of //-hydroxyl ketone 47, 48, 50, and 51 with high yields and stereoselectivities (Scheme 3-17). 

As illustrated in Scheme 3 20 and Table 3-5, using 55a or 55b as the chiral auxiliary,, vy -aldol adduct 56 can be obtained with high stereoselectivity via aldol reaction of diethyl ketone with various aldehydes.39... 

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