Boronic ester, diastereoselective reactions

Diastereoselective homologation of chiral alkylboronates (cf. 12, 80-81). Investigations of this reaction have been carried out mainly on boronic esters (1)... 

In three separate papers, the use of chiral boronic esters in 1,3-dipolar cycloadditions with nitrile oxides have been described (316-318). The reaction of 203 with nitrile oxides proceeded with low diastereoselectivities (Scheme 12.58). 

Boronic ester homologation. (R,R)-2,3-Butanediol- and (-(- )-pinanediol have been used as the chiral adjuncts in a diastereoselective homologation of dichloromethaneboronic esters (1) to the (aS)-a-chloroboronic esters (2). Reaction of 1 with an alkyllithium produces a borate complex (a), which rearranges diastereoselectively in the presence of ZnCl, to 2 with introduction of a chiral center adjacent to boron. The reaction permits... 

Diastereoselective allylation of optically pure sulfinyl dienal complexes using tributyl allyltin can be obtained (Scheme 138). 2,4-Hexadien-1,6-dial iron tricarbonyl complex (88) undergoes nucleophilic addition reactions with diaUcylzincs in the presence of a catalytic amount of an optically active amino alcohol (Scheme 139). Very high enantio-and diastereoselectivity is observed. Related reactions of (88) with chiral allyl boronic esters give allylated alcohols in very high enantiomeric excess. 

An effective control of the simple diastereoselectivity in boron-mediated aldol reactions of various propionate esters (162) was achieved by Abiko and coworkers (equation 45) °. They could show that under usual enolization conditions (dialkylboron triflate and amine) enol borinates are formed, which allowed the selective synthesis of 5yw-configured aldol products (Table 11). The enolization at low temperature (—78 °C) generated a (Z)-enolate selectively, which afforded mainly the syn diastereomer 164 after reaction with isobu-tyraldehyde (163), following a Zimmerman-Traxler transition-state. The anti diastereomer 164 instead was obtained only in small amounts (5-20%). 

TABLE 11. Diastereoselective onate esters (equation 45) boron-mediated aldol reactions of propi-... 

The transfer of the allylic moieties from boron to the electrophilic carbonyl carbon proceeds via rearrangement to form intermediate boronic esters C and D (see below). The reaction is highly diastereoselective. The ( )-crotylboronate reacts to give the anfr-homoallylic alcohol and the (Z)-crotylboronate reacts to afford the syn-homoallylic alcohol.This behavior has been interpreted in terms of the Zimmerman-Traxler chair-type transition state model.Because of the double bond geometry, coordination of the (Ei-crotylboronic ester places the Me preferentially equatorial, whereas coordination of the (Z)-crotylboronic ester places the Me axial, as illustrated in the cyclohexane chair-form transition state conformations A and B, respectively. In both cases, the R moiety of the aldehyde must occupy a pseudo-equatorial position to avoid steric repulsion by one of the OR substituents on boron. 

R.A. Batey and co-workers developed a modification of the Petasis-boronic acid-Mannich reaction that occurs via N-acyliminium ions derived from A/-protected-2,3-dihydroxypyrrolidine and 2,3-dihydroxypiperidine derivatives. This method was utilized in the total synthesis of (+)-deoxycastanospermine. The formation of the A/-acyliminium ion was achieved by treating A/-Cbz-2,3-pyrrolidine with BF3-OEt2. ° Subsequent vinyl transfer from the alkenylboronic ester provided the product with excellent yield and diastereoselectivity. 

Impressively short is a total synthesis by Ian Paterson [281], who uses a lactate ester as chiral auxiliary. This is subsequently converted into a ketone via a Grignard reaction with its Weinreb amide. The boron-mediated aldol reaction, after an oxidative work-up, gives the aldol with a diastereoselectivity of >98 %. Since also the reaction with propionaldehyde shows the same diastereoselectiv-... 

The synthesis began with Prins qrchzation of the symmetric vinylo-gous ester 273, prepared from heptadienol 272, followed by hydrolysis of the resulting trifluoroacetate and benzylation, to afford the desired 2,6-cis-tetrahydropyran 274 with 92 8 diastereoselection at C5 [113], By this novel desymmetrization, 2,4,6-all-ci5 trisubstituted pyran was efficiently provided. Boron-enolate aldol reaction, as Carreira did, of the methyl ketone 274 with aldehyde 275 gave hydroxy ketone 271 as a single isomer. In contrast to Car-reira s result, samarium-catalyzed intramolecular Tishchenko reduction [114]... 

The first synthesis of an (a-haloalkyl)boronic ester [8], a free radical addition of a tetrahalomethane, was followed by mechanistic studies that indicated the potential for stereospecific alkylation with Grignard reagents via borate intermediates [9], if only there had been a way to obtain asymmetric examples. The discovery of the efficient reaction of (dichloromethyl)lithium with boronic esters to form (a-chloroalkyl)boron-ic esters by insertion of a CHCl group into the B-C bond opened a new opportunity [10]. Boronic esters of pinanediol, prepared from (+)-a-pinene by osmium tetroxide catalyzed oxidation, were soon found to undergo the insertion reaction with a strong asymmetric bias, with diastereomeric selectivities frequently in the 90-95% range [llj. It was subsequently found that anhydrous zinc chloride promotes the reaction and increases diastereoselectivity to as high as 99.5% in some cases [12]. 

Scheme. 20 Diastereoselective reaction of (a-haloalkyl)boronic esters with an ester enolate.

In a related papCT, high diastereoselectivity with secondary amines was cOTifmned, while the use of chiral primary amines generally gives products with low to moderate diastereoselectivity [17], Factors affecting the efficiency and stereoselectivity of this reaction, in particular of the structure of the boronate ester and amine, were also determined. 

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). 

This radical cyclization strategy was utilized for the synthesis of the smaller fragment silyl ether 54 as well (Scheme 8). Evans aldol reaction of the boron eno-late derived from ent-32 with aldehyde 33, samarium(III)-mediated imide methyl ester conversion, and protecting group exchange led to tosylate 51. Elaboration of 51 to ketone 53 was achieved under the conditions used for construction of the second tetrahydrofuran moiety of 49 from 46. A highly diastereoselective reduc-... 

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. 

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. 

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