Esters boron enolates

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

An entry to. yyrt-2-methoxy-3-hydroxycarboxylic acids is also opened using similar methodology. Thus the norephedrine derived (4/ ,5S)-3-(2-methoxy-l-oxoethyl)-4-methyl-5-phenyl-1,3-oxazolidine-2-one 23105a, as well as the phenylalanine derived (4S)-4-benzyl-3-(2-methoxy-l-oxoethyl)-l,3-oxazolidin-2-one 25105b, can be added to aldehydes via the boron enolates to give, after oxidative workup, the adducts in a stereoselective manner (d.r. 96 4, main product/sum of all others). Subsequent methanolysis affords the methyl esters. 

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. 

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. 

Boron enolates can be obtained from esters40,41 and amides42 by methods that are similar to those used for ketones. Various combinations of borylating reagents and amines have been used and the E.Z ratios are dependent on the reagents and conditions. In most cases esters give Z-enolates, which lead to syn adducts, but there are exceptions. Use of branched-chain alcohols increases the amount of anti enolate, and with t-butyl esters the product ratio is higher than 97 3. 

These oxazolidinones can be acylated and converted to the lithium, boron, tin, or titanium enolates by the same methods applicable to ketones and esters. For example, when they are converted to boron enolates using di-n-butylboron triflate and triethyl-amine, the enolates are the Z-stereoisomers.125... 

The boron enolates of a-substituted thiol esters also give excellent facial selectivity.135 CH(CH3)2 (CHg"/ -CH2)2BCI... 

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). 

Reagent control This involves the addition of a chiral enolate or allyl metal reagent to an achiral aldehyde. Chiral enolates are most commonly formed through the incorporation of chiral auxiliaries in the form of esters, acyl amides (oxazolines), imides (oxazolidinones) or boron enolates. Chiral allyl metal reagents are also typically joined with chiral ligands. 

Because anti/syn ratios in the product can be correlated to the E(0)/Z(0) ratio of the involved boron enolate mixture,10b initial experiments were aimed at the preparation of highly E(0)-enriched boron enolate. The E(0)/Z(0) ratio increases with the bulk of the alkanethiol moiety, whereas the formation of Z(O) enolates prevails with (S )-aryl thioates. (E/Z = 7 93 for benzenethiol and 5 95 for 2-naphthalene thiol esters). E(O) reagent can be formed almost exclusively by reaction of (5)-3,3-diethyl-3-pentyl propanethioate 64 with the chiral boron triflate. High reactivity toward aldehydes can be retained in spite of the apparent steric demand (Scheme 3-22).43... 

Although this general principle of asymmetric induction has not been demonstrated for boron enolates, the related addition reactions of allylboranes to aldehydes (eq. [115]) (131) have been examined in this context. The reaction of chiral diol 175 with either triallyl-borane or tri- -methallylborane afforded the boronic esters 176 (Ri = H, Me) in yields exceeding 95% (132a). The addition reactions of 176 to representative aldehydes are summarized in Table 40. In all cases reported, the sense of asymmetric induction from the chiral... 

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. 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

Dialkylboron trifluoromethanesulfonates (Inflates) are particularly useful reagents for the preparation of boron enolates from carbonyl compounds, including ketones, thioesters and acyloxazoiidinones. Recentiy, the combination of dicylohexyiboron trifluoromethanesulfonate and triethyiamine was found to effect the enolization of carboxyiic esters. The boron-mediated asymmetric aldoi reaction of carboxyiic esters is particuiariy usefui for the construction of anti p-hydroxy-a-melhyl carbonyl units. The present procedure is a siight modification of that reported by Brown, et ai. ... 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Boron enolates of a-benzyloxy esters.1 The triflate 1 converts alkyl benzyloxy-acetates (2) into the boron enolate, which readily undergoes aldol reactions with high yyn-diastereoselectivity. Somewhat higher syn-selectivity obtains with dicyclopen-tylboryl triflate, whereas use of LDA results in slight anti-selectivity (synlanti=34-37 66-63). Diisopropylethylamine is essential for the aldol reaction. Syn-3 is re-... 

It has been demonstrated that optically active oxetanes can be formed from oxazolidinone 92, a crotonic acid moiety functionalized with Evans chiral auxiliary (Scheme 18) <1997JOC5048>. In this two-step aldol-cyclization sequence, the use of 92 in a deconjugative aldol reaction, with boron enolates and ethanal, led to formation of the syn-aldol 93. This product was then converted to the corresponding oxetanes, 94a and 94b, via a cyclization with iodine and sodium hydrogencarbonate. This reaction sequence was explored with other aldehydes to yield optically active oxetanes in similar yields. Unlike previous experiments using the methyl ester of crotonic acid, in an analogous reaction sequence rather than the oxazolidinone, there was no competing THF formation. 

Boron enolates of thioglycolates. Esters do not form boron enolates because of the low acidity of the a-protons. However, methyl phenylthioacetate (2) forms a boron enolate on treatment with Hunig s base and dibutylboryl triflate, and this enolate undergoes aldol reactions with aldehydes with high syn-diastereoselectiv-ity.1... 

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. 

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