Z- -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. 

Achiral ketones, for example, 3-pentanone, can be converted predominantly into (Z)-boron enolates [(Z)/( )>97 3] by treatment with (- )-diisopinocampheylboron triflate. Subsequent addition to aldehydes, followed by an oxidative workup procedure, delivers /i-hydroxy ketones with a diastcrcomeric ratio of 95 5 to 98 2 (synjanli) and the xpn-products with 66 to 93% ee33. 

When the related saccharin derived sultam (R)-29 is converted into the (Z)-boron enolate and subsequently treated with aldehydes,. vy -diastereomers 30 result almost exclusively. Thus, the diasteromeric ratios, defined as the ratio of the major product to the sum of all other stereoisomers, surpass 99 1. Hydroperoxide assisted saponification followed by esterification provides carboxylic esters 31 with recovery of sultam 32106a. 

Z-Boron enolates can also be obtained from silyl enol ethers by reaction with the bromoborane derived from 9-BBN (9-borabicyclo[3.3.1]nonane). This method is necessary for ketones such as 2,2-dimethyl-3-pentanone, which give E-boron enolates by other methods. The Z-stereoisomer is formed from either the Z- or E-silyl enol ether.20... 

Enantioselectivity can also be induced by use of chiral boron enolates. Both the (+) and (-) enantiomers of diisopinocampheylboron triflate have been used to generate syn addition through a cyclic TS.132 The enantioselectivity was greater than 80% for most cases that were examined. Z-Boron enolates are formed under these conditions and the products are 2,3-syn. 

Scheme 2.6 shows some examples of the use of chiral auxiliaries in the aldol and Mukaiyama reactions. The reaction in Entry 1 involves an achiral aldehyde and the chiral auxiliary is the only influence on the reaction diastereoselectivity, which is very high. The Z-boron enolate results in syn diastereoselectivity. Entry 2 has both an a-methyl and a (3-benzyloxy substituent in the aldehyde reactant. The 2,3-syn relationship arises from the Z-configuration of the enolate, and the 3,4-anti stereochemistry is determined by the stereocenters in the aldehyde. The product was isolated as an ester after methanolysis. Entry 3, which is very similar to Entry 2, was done on a 60-kg scale in a process development investigation for the potential antitumor agent (+)-discodermolide (see page 1244). 

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. 

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). 

Paquette et al. start with the bis-vinylogation of the same compound 29 [14], by Wittig-Horner reaction, reduction, and oxidation (Scheme 5). For the formation of the C17-C16 bond, the onti-aldol 41 (ds not reported) is obtained by treatment of the aldehyde 39 with the (Z)-boron enolate 40, bearing a dithioketal moiety that is later to be the C51-C54 side chain. 3-Hydroxy-assisted, diastereoselective reduction of the keto group at C15 gives 41, which is converted into intermediate 42 in five more steps. The dethioketalization of 41 is achieved with phenyliodine(m) bis(trifluoroacetate) [16], As in Nicolaou s synthesis, the N12-C13 amide bond is formed first, followed by a low-yielding (21%, even at a concentration of 1 him) macrolactonization to 3. Table 1 summarizes the benchmark data of the two total syntheses of sanglifehrin A (1). 

Stereoselective aldol condensations. Ketones react with 1 in the presence of ethyldiisopropylamine to form (Z)-boron enolates with high stereoselectivity. These derivatives react with aldehydes to afford primarily erythro- -ketols after oxidation and alkaline hydrolysis. ... 

Hoffmann and co-workers completed the first synthesis of both denticulatins via a C9-C10 aldol bond construction (Scheme 9-70) [87], In this case, aldehyde 266 was assembled using asymmetric crotylboration reactions to introduce the C4-CS stereocenters. The (Z)-boron enolate 267 was then reacted with aldehyde 266 to afford the desired anh-Felkin adduct with 80% selectivity where the minor diastereomer resulted from reaction of the enantiomer of the starting ketone. Unfortunately, the C5-PMB ether protecting group could not be removed without epi-merization at C o, and denticulatins A and B were formed in equimolar amounts. 

We (Novartis) reported the first enantioselective synthesis of (27 ,2 7 )-(+)-f/7reo-methylphenidate hydrochloride (1), which involved an asymmetric aldol condensation of 5-chlorovaleraldehyde with the (Z)-boron enolate derived from 7V-phenylacetyl-(7 )-4-phenyl-2-oxazolidinone (29) as the key step to generate both stereogenic centers of 1 with desired absolute configuration (Scheme ll). ... 

Reaction of 5-chlorovaleraldehyde with the (Z)-boron enolate derived from 7V-phenylacetyl-(71)-4-phenyl-2-oxazolidinone (29) afforded the desired single diastereomer 30, as confirmed by H NMR, in 78%... 

Other than for the cyclic or /-alkyl ketones we met at the beginning of the chapter, controlling aldol reactions of ketones has been more difficult. Evans boron enolates work well in some cases and it is fortunate that the Z enolates are preferentially formed as these react stereoselectively with aldehydes to give syn aldols whereas the E enolates show poor stereoselectivity. Thus the symmetrical ketone 1 gives almost exclusively (>97 3) the Z boron enolate 27 and hence syn aldol 28 with the enolisable aldehyde n-PrCHO.8... 

Though either enantiomer of a yyn-aldol can be made by using the right auxiliary in an Evans aldol reaction the anti aldols cannot be made this way. The addition of a Lewis acid catalyst transforms the situation.13 Using the valine-derived chiral auxiliary 89, the same Z-boron enolate 111 is used but the aldehyde is added in the presence of a threefold excess of the Lewis acid Et2AlCl. The product is predominantly one enantiomer of an anh-aldol 112. 

Boron or tin (II) Z-enolates are generated by reaction with the corresponding triflates with a carbonyl compound in the presence of tertiary amines like r-P NEt or. M-ethylpiperidine (except when using dicyclopentylboron triflate [407]). E-Enolates are prepared by using dicyclohexyl- or other cyclic chloroboranes in the presence of Et3N or Me NEt [407, 685, 686, 1246, 1247, 1248], Because enolization does not take place under such conditions with esters or aliphatic tertiary amides, thiophenyl esters RGH COSPh have been used as ester/amide substitutes. Furthermore, Z-boron enolates of ketones can be prepared by conjugate addition of acid derivatives of dialkylboranes to a-enones [687],... 

In most boron-mediated aldol reactions, (Z)-boron enolates 7 and ( )-boron enolates 8 stereoselectively afford sy -aldols 9 and nnh-aldols 10, respectively, via a chelation-controlled transition state (Scheme 1). The (Z)-boron enolates 7 can be prepared from 6 by a combination of /i-Bu2BOTf and j-Pr2NEt, while a combination of (c-hex)2BCl and Et3N gives the ( )-boron enolates 8. (Abbreviations are defined in the Appendix at the end of this chapter.)... 

The simplest asymmetric induction involves a reaction of an achiral enolate with a chiral aldehyde. In this case, if the boron enolate geometry and facial selectivity to the aldehyde are well controlled, the stereoselective aldol reaction will proceed. For example, treatment of (Z)-boron enolate 11 with chiral aldehyde 12 effected stereoselective aldol reaction to give sy -aldol adduct 13 as a single product [3]. 

The aldol reaction using chiral a-oxygenated ketones proceeds in a diastereose-lective manner (Scheme 3) (Z)-boron enolate 28 derived from benzyloxy ketone 27 afforded sy -aldol 29 via chelation control, while benzoyloxy ketone 30 afforded anft-aldol 32 via ( )-enolate 31 through a nonchelation transition state [9]. 

In the first total synthesis of elaiophylin (azalomycin B 181), glycosidation of P-hydroxy ketone 178 and glycal 177 was examined (Scheme 26) [111]. NBS-promoted glycosidation [112] followed by debromination with -Bu3SnH-AIBN was first applied to give 179 in only a 30% yield. Then, the Wakamatsu procedure using CSA-MS 4A [113] was found to afford the desired 179 in 80% yield as the sole anomer, which led to 181 via aldol reaction of the (Z)-boron enolate of the ketone 179 with dialdehyde 180. 

CB. The (Z)-boron enolates derived from 9-BBN undergo aldol reactions to provide aldols in >96% syn-selectivity. However, (Z)-boron enolates formed from CB show lower selectivity (syn/anti = 3 1). 

In practice, aldehydes bearing an adjacent stereogenic center, particularly one devoid of a bulky group, typically provide only modest aldol stereoselectivity. For example, consider the reaction of aldehyde 28 with Z boron enolate 27 as shown in Scheme 3a. According to the models just discussed, one would expect this reaction to provide only 1,2-syn products with anti-Felkin- Ahn stereoselectivity. Indeed, that conjecture proved to be true for the most part as exclusively 1,2-syn aldol adducts resulted with 29, a compound whose stereotriad reflected anti-Felkin—Ahn selectivity, constituting the predominant product. However, a fair amount of the alternate 1,2-syn Felkin- Ahn adduct (30) was also observed, such that the final ratio of 29 to 30 was a disappointing 1.75 1. 

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