Aldol condensation with boron enolates

Diastereoselective Aldol Condensation with Boron Enolates... 

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

Aldol Condensations of Boron Enolate 142 with Representative Aldehydes (eq. [101]) (115a)... 

Table 9.2 summarises some of the results reported by Evans and coworkers in aldol condensations of boron enolates with benzaldehyde [14]. 

Boron-mediated asymmetric aldol condensation methodology developed by Evans [90] served as an inspiration for preparation of daunosamine starting from chiral oxazoUdinones. It appeared that the choice of chiral auxiUary is quite important for the stereochemical outcome of planned reactions [91]. A successful series of reactions started from N -succinoylation of (R)-3-(l-oxo-3-carbomethoxypropyl)-4-diphenylmethyl)oxazolidin-2-one as a novel chiral auxihary. The chain extension was achieved in aldol condensation with protected lactaldehyde and the key intermediate 132 was converted into the target aminosugar 135, via Curtius rearrangement of carboxyhc acid azide, and reduction of lactone to lactol, as depicted in Scheme 24 [58]. Unexpectedly, boron catalysts were rather ineffective in the aldol condensation step and had to be replaced with more reactive lithiiun enolates (which proved to be non-Evans syn selective). 

Conversion of 74 into a boron enolate 75 and aldol condensation with 71 to form postulated intermediate 76 was followed by appropriate steps to yield 77, the first intermediate that was normally purified by chromatography in the sequence. Debenzyla-tion resulted in the first crystalline sample of stegobiol (78), a minor component of the natural pheromone. However, tests of pure 78 by Wendell Burkholder showed no attractant activity [48], in contrast to the low activity previously reported for oily natural samples. Perruthenate-catalyzed oxidation of 78 with N-methylmorpholine N-ox-ide yielded pure crystalline stegobinone (79) having very high attractant activity. 

One of the most active areas of organoborane chemistry this year has been the application of boron enolates to enantioselective aldol condensations. Thus the enolate (82), derived from (5)-valinol, reacts with aldehydes R CHO to give, after cleavage of the oxazolidinone residue with R OH, the alcohols (83) with an erythro threo selectivity greater than 140 1, whereas the enolate (84), obtained from (IS, 2/ )-norephedrine, gives alcohols (85) with a selectivity of at least 500 1. Somewhat lower levels of selectivity are observed with the azaenolates (86) and (87) which give predominantly threo- and erythro-alcohols (88) and (89), respectively. ... 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

The synthesis of the polyol glycoside subunit 7 commences with an asymmetric aldol condensation between the boron enolate derived from imide 21 and a-(benzyloxy)acetaldehyde (24) to give syn adduct 39 in 87 % yield and in greater than 99 % diastereomeric purity (see Scheme 8a). Treatment of the Weinreb amide,20 derived in one step through transamination of 39, with 2-lithiopropene furnishes enone 23 in an overall yield of 92 %. To accomplish the formation of the syn 1,3-diol, enone 23 is reduced in a chemo- and... 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

A further step towards improved selectivity in aldol condensations is found in the work of David A. Evans. The work of Evans [3a] [14] is based in some early observations from Meyers laboratory [15] and the fact that boron enolates may be readily prepared under mild conditions from ketones and dialkylboron triflates [16]. Detailed investigations with Al-propionylpyrrolidine (31) indicate that the enolisation process (LDA, THE) affords the enolate 32 with at least 97% (Z>diastereoselection (Scheme 9.8). Finally, the observation that the inclusion of potential chelating centres enhance aldol diastereoselection led Evans to study the boron enolates 34 of A(-acyl-2-oxazolidones (33), which allow not only great diastereoselectivity (favouring the 5yn-isomer) in aldol condensations, but offer a possible solution to the problem of enantioselective total syntheses (with selectivities greater than 98%) of complex organic molecules (see below, 9.3.2), by using a recyclisable chiral auxiliary. 

Although the results are easily rationalised in the case of the a-alkylation (attack of the electrophile at the Re face, i.e., attack from the less hindered a face), in the aldol condensation it is somewhat more difficult to rationalise and several factors should be considered. According to Evans [14] one possible explanation for the diastereofacial selection observed for these chiral enolates is illustrated in Scheme 9.14. In the aldol reactions, the more basic carbonyl group of the aldehyde partner interacts with the chelated boron enolate 45 to give the "complex" A which may... 

Notice that the aldol condensation of the boron enolate 49 with the aldehyde (S)-53 affords, after recrystallisation, the diastereomerically homogenous 5yn-anti-Cram aldol adduct 52a. The stereochemical control in this process is remarkable. 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

This dual behaviour must allow control of the configuration at the a carbon atom in an aldol reaction, provided that one can control whether or not the metal is chelated at the time the aldol condensation occurs. Thornton and Nerz-Stormes [35] reported an approach to this problem by using titanium enolates to obtain "non-Evans" 5jn-aldols. On the other hand, Heathcock and his associated found that aldehydes react with chelated boron enolates 100b to afford the anh-aldols 102 or the "non-Evans" i yn-aldols 103 depending upon the reaction conditions (Scheme 9.32). 

Vinyloxyboranes (boron enolates) are obtained in quantitative yield by reaction of silyl enol ethers with dialkylboron triflates in CH2C12 at —22 . The products can be used for stereoselective aldol condensations.3 Example ... 

Boron enolates bearing menthol-derived chiral ligands have been found to exhibit excellent diastereo- and enantio-control on reaction with aldehydes34 and imines.35 Highly diastereo- and enantio-selective aldol additions of geometrically defined trichlorosilyl ketone enolates (31) and (32) have been achieved by promoting the reactions with chiral Lewis bases, of which (,S., S )-(33) proved to be the most effective.36 Moderate enantiomeric excesses have been achieved by using chiral ammo alcohols as catalysts for the Baylis-Hillman condensation of aldehydes with methyl vinyl ketone the unexpected pressure effect on the reaction has been rationalized.37... 

In 1992 Ghosh and co-workers provided the first example of the utility of rigid cis-1 -amino-2-indanol-derived oxazolidinone 36 as the chiral auxiliary in the asymmetric. vv//-aldol reaction.60-61 Aldol condensation of the boron enolate of 37 with various aldehydes proceeded with complete diastereofacial selectivity. Effective removal and recovery of the chiral auxiliary was carried out under mild hydrolysis conditions (Scheme 24.6). As both enantiomers of the chiral auxiliary were readily available, both enantiomers of the. yyn-aldol could be prepared with equal asymmetric induction. 

An asymmetric synthesis of the aminocyclopentitol has been achieved from an acylated oxazolidinone (Scheme 38).110 Thus, the acylated oxazolidinone 295 was subjected to boron triflate-catalyzed condensation with 3-butenal to yield the syn aldol product 297 in 63% yield. Similarly, the A-acyloxazoI idineth ione 296 delivered the aldol adduct 298 in 75% yield when enolized with TiCl4-(—)-sparteine and then... 

Regio- and stereoselective aldol condensations. The enol boronates of ketones, obtained by reaction with 1 and diisopropylethylamine (1 equiv.), react with both aliphatic and aromatic ketones at —78° to —15° to form p-hydroxy ketones with high sy/t-dia-stereoselectivity.2... 

Hexafluoroacetone has also demonstrated unusual reactivity when condensed with the boron cnolatc of an optically active oxazolidinone or the boron enolate of the sultam derived from camphorsulfonic acid s to give products 3 and 4, respectively. The absolute stereochemistry of the products 3 and 4 is the opposite of that formed on addition to nonfluorinated ketones and aldehydes. This change was attributed to the involvement of an open transition state in the aldol reaction, a consequence of the diminished basicity of fluorinated carbonyl oxygens. 

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