Aldol condensation chiral boron enolate

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. 

Evans DA, Bartroli J et al (1981) Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates. J Am Chem Soc 103 2127-2129... 

The groups of Masamune [4] and Evans [5] reported the synthesis of optically active p-hydroxycarboxylic acids by means of stereoselective chiral aldol condensation via boron enolates. (S)- and (i )-p-Hydroxyisobutyric acid of high optical purity (98% e.e.) were obtained by means of Masamune s method. However, these methods do not seem favorable for industrial production of p-hydroxycarboxylic acids because these reactions need equal amounts of the chiral starting material for the synthesis of optically active p-hydroxycar-boxylic acids (Scheme 2). 

The rate of publication of investigations into systems for carrying out diastereo- and enantio-selective aldol condensations has continued unabated during the year (cf. 9, 241). Chiral boron enolates continue to invoke much interest the dimethylborolane enolates of thioesters form adducts in which the anti-aldols... 

Chiral boron enolates are effective in enantioselective aldol condensations, a transition-state model being proposed for the moderate chirality transfer exhibited (Scheme 57). ° Diastereoselection with chiral lithium enolates has also been demonstrated by a highly stereoselective synthesis of the Prelog-Djerassi lactonic acid. ... 

Masamune S, Choy W, Kerdesky AJ, ImperiaU B. Stereoselective aldol condensation. Use of chiral boron enolates. J. Am. Chem. Soc. 1981 103 1566-1568. 

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-... 

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... 

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... 

The control of the three consecutive asymmetric centers in a-alkylated y-amino-p-hydroxy acids is achieved by aldol condensation of a chiral aldehyde and a chiral reagent (Scheme 17 and Table 6), e.g. boron enolate 43,150 79 oxazolidinones of Evans type lit80 or 45 [68>69>801 or Brown s or Roush s crotylorganoboron reagents 46[81 and 47J81,82 respectively. 

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. 

Asymmetric. syn-aldol condensation reactions employing chiral auxiliaries were reported in 1981 by both Masamune et al.2 and Evans et al.3 Masamune et al. introduced boron enolates obtained from (.S )-mandclic acid, which underwent... 

CAB 2, R = H, derived from monoacyloxytartaric acid and diborane is also an excellent catalyst (20 mol %) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. The reactivity of aldol-type reactions can, furthermore, be improved, without reducing the enantioselectivity, by use of 10-20 mol % of 2, R = 3,5-(CF3)2C6H3, prepared from 3,5-bis(trifluoromethyl)phenyl-boronic acid and a chiral tartaric acid derivative. The enantioselectivity could also be improved, without reducing the chemical yield, by using 20 mol % 2, R = o-PhOCgH4, prepared from o-phenoxyphenylboronic acid and chiral tartaric acid derivative. The CAB 2-catalyzed aldol process enables the formation of adducts in a highly diastereo- and enantioselective manner (up to 99 % ee) under mild reaction conditions [47a,c]. These reactions are catalytic, and the chiral source is recoverable and re-usable (Eq. 62). 

Another example of this methodology has appeared recently from Masamune and coworkers in connection with a total synthesis of bryostatin (equation 67). The salient point here is the demonstrated utility of the thiol ester, prepared directly through stereoselective boron enolate aldol condensation. Notice Aat no further activation or removal of a chiral auxiliary is necessary for this transformation, unlike other related aldol methodology. 

Boron reagents such as ( + )- or (-)-(Ipc)2BOTf are chiral promoters in aldol condensations. " Enolization of an achiral ketone with (Ipc)2BOTf forms a chiral enolate and thus imparts diastereofacial selectivity (DS) for condensation with a chiral aldehyde. If the ketone is chiral, the DS of the reagent may be matched or mismatched with the... 

Boron enolates generated from a-heterosubstituted thioacetates by treatment with 105 undergo highly enantioselective and diastereoselective condensations. On the other hand, chiral esters 106 and 107, and amides 108 behave differently. V-Acyl derivatives of the bicyclic isoxazolidine 109 ° readily undergo syn-selective aldol reactions via enol borates. 

B-C bonds are shorter than other metals with oxygen and carbon, the six membered Zimmerman-Traxler transition state in the aldol condensation tends to be more compact which accentuates steric interactions, thus leading to higher diastereoselectivity. When this feature is coupled with a boron enolate bearing a chiral auxiliary, high enantioselectivity is achieved. Boron enolates are generated from a ketone and boron triflate in the presence of an organic base such as triethylamine. Reviews (a) Abiko, A. Acc. Chem. Res. 2004, 57, 387-395. (b) Cowden, C. J. Org. React. 1997, 51, 1-200. 

The Masamune aldol condensation, in common with the Evans aldol condensation, involves a boron enolate of an ester containing a norephedrine derived chiral auxiliary however, unlike the latter, the Masamune aldol delivers a 3-hydroxy-2-methyl carbonyl moiety with the an/z-stereochemistry. Crucial to the success of this reaction is the use of dicyclohexylboron triflate to generate the boron enolate. Note in the Evans aldol condensation, dibutylboron triflate is utilized. 

Enantioselective aldol condensation by means of an oxazolidone chiral auxiliary and boron enolate (see 1 st edition). 

The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, and amides. Of particular importance are several modified amides, such as those derived from oxazolidinones, that can be used as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, tin, and titanium derivatives have all been used. Because of their usefulness in aldol additions and other synthetic methods (see especially Section 6.4.2.3, Part B), there has been a good deal of interest in the factors that control the stereoselectivity of enolate formation from esters. For simple esters such as ethyl propanoate, the E-enolate is preferred under kinetic conditions using a strong base such as EDA in THE solution. Inclusion of a... 

Reaction C in Fig. 4 is an aldol condensation between an achiral aldehyde and an ester enol borinate featuring a bidentate chiral substituent at the boron atom [24]. Upon enolate-boron/aldehyde-oxygen co-ordination, two chair-like TS can be formed, both featuring the aldehyde phenyl group in a pseudo-equatorial position. Preferential attack on the aldehyde Si face is determined by the spatial arrangement of the metal ligand. The almost exclusive formation of the anti diastereoisomers arises from control of the enolate geometry. 

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