Stereoselectivity with boron enolates

Scheme 1. Zimmerman-Traxler models for aldol stereoselectivity with boron enolates.

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

The general trend then is that boron enolates parallel lithium enolates in their stereoselectivity but show enhanced stereoselectivity. They also have the advantage of providing access to both stereoisomeric enol derivatives. Table 2.3 gives a compilation of some of the data on stereoselectivity of aldol reactions with boron enolates. 

Organoaluminum reagents, 202 1,1,1-Trifluoroacetone, 323 Trityllithium, 338 Zinc chloride, 349 Stereoselective aldol reactions With boron enolates Boron trichloride, 43 Chlorodimethoxyborane, 73 9-(Phenylseleno)-9-borabicyclo-[3.3.1]nonane, 245 With silyl enol ethers... 

Although boron enolates are usually more stereoselective in aldol reactions than lithium enolates, the latter are more readily prepared (e.g., using LDA). To obtain synthetically useful levels of aldol stereoselectivities with lithium enolates, the (E)-(O)- and (Z)-(0)-enolates must be available with high selectivity (> 95 5), and the non-enolized carbonyl group Rmust be large (Table 6.3). ... 

For a closed transition structure, shorter M-O bond lengths amplify the van der Waals interactions between Ri, R2, and X relative to enolates with longer bond lengths, resulting in higher stereoselectivities [16]. With boron enolates for example, Z((9)-enolates are highly syn selective [52]. 

Example 4.3 This example demonstrates a notable difference in stereoselectivity between alkylation and aldol reactions of enolates derived from chiral oxazolidi-nones. Lithium enolates of oxazolines 27 and 28 proved exceptionally efiicient in the control of the stereoselectivity of alkylation (Sect. 3.7.3, Schemes 3.12 and 3.13 ) but react with low stereoselectivity in aldol reactions. Instead, high stereochemical control of aldol reactions is achieved with boronic enolates of chiral oxazolidinones 9-13 (Scheme 4.11). 

Asymmetric aldol additions involving chiral ketones generally furnish products with much higher levels of induction [16, 20], These processes offer an attractive alternative to auxiliary-based methods since additional steps for auxiliary introduction and removal can thus be avoided. In particular, boron enolates have been extensively used. High stereoselectivity obtained with boron enolates is ascribed to the highly ordered nature of the cyclic chair-like transition states involved. The shorter C-B and 0-B bond distances give rise to tighter transition states, in which unfavorable non-bonded interactions between substituents are maximized, in contrast to those formed from other metal enolates [13]. Furthermore, additions of boron enolates are stereospecific, such that cis-boron enolates preferentially furnish 1,2-syn products and trans-boron enolates the 1,2-anti products [13, 14, 16]. 

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. 

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. 

The following C2-symmetric bis-sulfonamide is a more efficient controller of stereoselectivity in aldol additions. The incorporation of this ligand into the bromodiazaborolane, subsequent generation of the boron enolate derived from 3-pentanone, and addition to achiral aldehydes preferentially leads to the formation of ijn-adducts (synjanti 94 6 to >98 2) with 95-98% ee. Chemical yields of 85-95% are achieved51. 

S)-Tricarbonyl(2-methoxyacetophenone)chromium is a starting material which provides remarkable substrate-induced stereoselectivity. Thus, its conversion into a boron enolate and subsequent addition to aldehydes delivers the chromium complexes 7 and 8 with diastereomeric ratios of 92 8 to 95 559. 

Crystalline, diastereomerieally pure syn-aIdols are also available from chiral A-acylsultams. lhe outcome of the induction can be controlled by appropriate choice of the counterion in the cnolate boron enolates lead, almost exclusively, to one adduct 27 (d.r. >97 3, major adduct/ sum of all other diastereomers) whereas mediation of the addition by lithium or tin leads to the predominant formation of adducts 28. Unfortunately, the latter reaction is plagued by lower induced stereoselectivity (d.r. 66 34 to 88 12, defined as above). In both cases, however, diastereomerieally pure adducts are available by recrystallizing the crude adducts. Esters can be liberated by treatment of the adducts with lithium hydroxide/hydrogen peroxide, whereby the chiral auxiliary reagent can be recovered106. 

A somewhat tedious extension of this methodology, which guarantees good induced stereoselectivity, relies on the reversible introduction of an a-substituent which is removed after the aldol addition is performed. For this purpose, the corresponding derivative of (methyl-thio)acetic acid is converted into the boron enolate and subsequently reacted with aldehydes. The... 

The stereoselectivity is not significantly improved if boron enolates are used instead of lithium enolates. For example, the enantiomerically pure aldehyde (—)-(2S,4/ )-4-methoxycarbonyl-2-methylpentanal delivers the diastereomeric thioeslers in a ratio of 3 2 when treated with the indicated boron enolate29. 

If a chiral aldehyde, e.g., methyl (27 ,4S)-4-formyl-2-methylpentanoate (syn-1) is attacked by an achiral enolate (see Section 1.3.4.3.1.), the induced stereoselectivity is directed by the aldehyde ( inherent aldehyde selectivity ). Predictions of the stereochemical outcome are possible (at least for 1,2- and 1,3-induction) based on the Cram—Felkin Anh model or Cram s cyclic model (see Sections 1.3.4.3.1. and 1.3.4.3.2.). If, however, the enantiomerically pure aldehyde 1 is allowed to react with both enantiomers of the boron enolate l-rerr-butyldimethylsilyloxy-2-dibutylboranyloxy-1-cyclohexyl-2-butene (2), it must be expected that the diastereofacial selec-tivitics of the aldehyde and enolate will be consonant in one of the combinations ( matched pair 29), but will be dissonant in the other combination ( mismatched pair 29). This would lead to different ratios of the adducts 3a/3b and 4a/4b. 

Excellent stereoselectivity is attained with the optically active boron enolate 7, prepared from the corresponding A-acyloxazolidinone (see Appendix) and diethylboron trifluoromethanesul-fonate177. The reaction presumably proceeds via a transition state similar to 5. 

Stereochemical Control Through Reaction Conditions. In the early 1990s it was found that the stereochemistry of reactions of boron enolates of N-acyloxazolidinones can be altered by using a Lewis acid complex of the aldehyde or an excess of the Lewis acid. These reactions are considered to take place through an open TS, with the stereoselectivity dependent on the steric demands of the Lewis acid. With various aldehydes, TiCl4 gave a syn isomer, whereas the reaction was... 

Scheme 2.7 gives some examples of the control of stereoselectivity by use of additional Lewis acid and related methods. Entry 1 shows the effect of the use of excess TiCl4. Entry 2 demonstrates the ability of (C2H5)2A1C1 to shift the boron enolate toward formation of the 2,3-anti diastereomer. Entries 3 and 4 compare the use of one versus two equivalents of TiCl4 with an oxazoldine-2-thione auxiliary. There is a nearly complete shift of facial selectivity. Entry 5 shows a subsequent application of this methodology. Entries 6 and 7 show the effect of complexation of the aldehyde... 

In Step D another thiazoline chiral auxiliary, also derived from cysteine, was used to achieve double stereodifferentiation in an aldol addition. A tin enolate was used. The stereoselectivity of this reaction parallels that of aldol reactions carried out with lithium or boron enolates. After the configuration of all the centers was established, the synthesis proceeded to P-D lactone by functional group modifications. 

Diboration of a,/ -unsaturated ketones is promoted by platinum(O) complexes. Reaction of 4-phenyl-3-buten-2-one with bis(pinacolato)diboron in the presence of a platinum catalyst affords a boryl-substituted (Z)-boron enolate, that is, a 1,4-diboration product, in high yield with high stereoselectivity (Scheme 8). The isolated boron enolate is easily hydrolyzed by exposure to water, giving / -boryl ketones in high yields.66 Similar diboration of a,/ -unsaturated ketones has also been achieved with Pt(bian)(dmfu) (bian = bis(phenylimino)acenaphthene, dmfu = dimethyl fumarate).67 Although the... 

Usually, (Z)-boron enolates can be prepared by treating /V-acyl oxazolidones with di-K-butylboron triflate and triethylamine in CH2CI2 at 78°C, and the enolate then prepared can easily undergo aldol reaction at this temperature to give a, vy -aldol product with more than 99% diastereoselectivity (Scheme 3-4). In this example, the boron counterion plays an important role in the stereoselective aldol reaction. Triethylamine is more effective than di-wo-propylethyl amine in the enolization step. Changing boron to lithium leads to a drop in stereoselectivity. 

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

The is-boron enolates of some ketones can be preferentially obtained with the use of dialkylboron chlorides.17 The data in Table 2.3 pertaining to 3-pentanone and 2-methyl-3-pentanone illustrate this method. Use of boron triflates with a more hindered amine favors the Z-enolate. The contrasting stereoselectivity of the boron triflates and chlorides has been discussed in terms of reactant conformation and the stereoelectronic requirement for perpendicular alignment of the hydrogen being removed with the carbonyl group.18 The... 

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 ... 

Catalyzed aldol additions do not generally proceed with high diastereoselectivity at ambient temperature. Improved stereoselectivity can be achieved by using preformed, diastereomerically pure enolates at low temperatures (Entry 5, Table 7.2). This strategy enables the solid-phase preparation of stereochemically defined polyketides. On cross-linked polystyrene, the observed diastereoselectivity in the addition of boron enolates to aldehydes is the same as that in the homogeneous phase reaction [14,18]. 

Ab initio MO methods have been used to predict the stereochemistry of aldol-type addition of boron enolates to imines, with due allowance for the degree and type of substitution, and the geometry (E or Z) of both the enolate and imine reactants.39 Only two important transition states were identified—both cyclic—one chair-like and the other boat-like. The results are compared with the stereoselections reported in various experimental methodologies. 

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