Chiral boron substituent

In addition to BH3, alkyl- and alkoxy-substituted boranes can also undergo insertion into a B-H bond. The higher stability and commercial availability of these boranes (e.g., BBN, catecholborane) has made them attractive as hydroboration reagents. These substituents can also be utilized to effect stereocenters upon insertion. Since hydroboration proceeds with controlled cis stereochemistry, the use of chiral boron substituents... 

Probably the most widely applicable asymmetric imine aziridination reaction reported to date is that of Wulff et al. These workers approached the reaction from a different perspective, utilizing the so-called vaulted , axially chiral boron Lewis acids VANOL and VAPOL [35] to mediate reactions between ethyl diazoacetate and N-benzhydrylimines (Scheme 4.29) [36]. The reactions proceed with impressive enantiocontrol, but there is a requirement that the benzhydryl substituent be present since this group is not an aziridine activator there is, therefore, a need for deprotection and attachment of a suitable activating group. Nonetheless, this method is a powerful one, with great potential for synthesis, as shown by the rapid synthesis of chloroamphenicol by the methodology [37]. 

The facial selectivity in these chiral boron enolates has its origin in the steric effects of the boron substituents. 

The boron atom dominates the reactivity of the boracyclic compounds because of its inherent Lewis acidity. Consequently, there have been very few reports on the reactivity of substituents attached to the ring carbon atoms in the five-membered boronated cyclic systems. Singaram and co-workers developed a novel catalyst 31 based on dicarboxylic acid derivative of 1,3,2-dioxaborolane for the asymmetric reduction of prochiral ketones 32. This catalyst reduces a wide variety of ketones enantioselectively in the presence of a co-reductant such as LiBH4. The mechanism involves the coordination of ketone 32 with the chiral boronate 31 and the conjugation of borohydride with carboxylic acid to furnish the chiral borohydride complex 34. Subsequent transfer of hydride from the least hindered face of the ketone yields the corresponding alcohol 35 in high ee (Scheme 3) <20060PD949>. 

Treatment of N-acyloxazolidinones with di-n-butylboron triflate in the presence of Et3N furnishes the (Z)-(O) boron enolates. These on treatment with aldehydes give the corresponding 2,3-syn aldol products (the ratio of syn- to anti- isomers is typically 99 1 ). On hydrolysis they produce chiral a-methyl-(3-hydroxy carboxylic acids, as exemplified below. The facial selectivity of the chiral boron enolate is attributed to the favored rotomeric orientation of the oxazolidinone carbonyl group, where its dipole is opposed to the enolate oxygen dipole. At the Zimmerman-Traxler transition state, the aldehyde approaches the oxazolidinone appendage from the face of the hydrogen rather than from the benzyl substituent. 

During the total synthesis of rhizoxin D by J.D. White et al., an asymmetric aldol reaction was utilized to achieve the coupling of two key fragments. " The aldol reaction of the aldehyde and the chiral enolate derived from (+)-chlorodiisopinocampheylborane afforded the product with a diastereomeric ratio of 17-20 1 at the CIS stereocenter. During their studies. White and co-workers also showed that the stereochemical induction of the chirai boron substituent and the stereocenters present in the enolate reinforce each other thus representing a matched aldol reaction. 

The spectroscopic evidence for the structure of carbony 1-Lewis acid complexes in solution is obviously quite relevant for elueidation of the transition states of Lewis acid-promoted stereoseleetive reactions. Yamamoto, Ishihara and Gao investigated the boron-substituent-dependent enantioselectivity of the chiral CAB-cata-... 

Reagents developed for the synthesis of 2-anti diol adducts include the chiral [( )-7-alkoxyallyl]indium and [( )-7-alkoxyalIyl]boronate reagents 233 [171J and 234 (Fig. 11-21) [172]. Alternatively, the ( )-allylboron reagents 235-237, which included silicon and boron substituents as hydroxy sunogates, have been independently developed [173-177]. 

Since the first asymmetric reduction of ketones with chiral borohydrides by Itsuno et al. [ 1 ], a number of studies on the asymmetric reduction of ketones with chiral borane reagents have been demonstrated [2]. Corey s oxazaborolidines are some of the most successful reagents [3 ]. The effect of fluorine substituents was examined in the asymmetric reduction of acetophenone with LiBH4 by the use of chiral boronates (73) obtained from substituted phenyl boronic acid and tartaric acid [4]. Likewise, 3-nitro, fluorine, and trifluoromethyl groups on the 3- or 4-position provided enhanced stereoselection (Scheme 5.20). 

Burgi-Dunitz angle of 107°, passing the least sterically hindering a-substituent in its approach (transition state E). In the double asymmetric reactions of a-chiral aldehydes with chiral allylboronates 1-3, the a-stereocenter and the chiral boronate auxiliary both influence the stereochemical outcome of the reaction. 

The group of McQuayde reported a six-membered chiral NHC ligand for allylic borylation of allylic nitrophenol (Scheme 3.58) [86]. The reaction occurs over all)dic nitrophenols bearing silane or boron substituents delivering doubly... 

Hydrolysis of 1,3,2-dioxaborolanes is thermodynamically disfavored, no doubt as a result of the same kinds of entropic factors that favor formation of cyclic acetals in preference to acyclic acetals. Hydrolysis of a 1,3,2-dioxaborolane (1) converts three molecules to two, but hydrolysis of a boronic acid dimethyl ester keeps the total number of molecules at three (Scheme 5). (It m be noted that hydrolysis of a cyclic acetal with one molecule of water keeps the number of reactant and product molecules equal at two, and hydrolysis of an acyclic acetal converts two molecules to three.) Adding base does almost nothing to the equilibrium, since hydroxide ion coordinates to the boronic ester 1 as well as to the boronic acid product. Furthermore, it spears that the trans R° substituents in 1 further stabilize the stmcture. Chiral boronic esters of this series are harder to hydrolyze than pinacol boronic esters, and treatment of pinacol boronic esters with DICHED results in liberation of the pinacol and formation of the DICHED boronic ester. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

An approach to the preparation of asymmetrically 1,2-disubstituted 1,2-diamines has been reported the zinc-copper-promoted reductive coupling of two different N-(4-substituted)phenyl aromatic imines, one bearing a 4-methoxy and the other a 4-chloro substituent, in the presence of either boron trifluoride or methyltrichlorosilane, gave a mixture of the three possible 1,2-diamines, where the mixed one predominated [31 ]. Low degrees of asymmetric induction were observed using 1-phenylethylamine, phenylglycinol and its 0-methyl ether, and several a-amino acid esters as the chiral auxiharies meanwhile the homocoupling process was not avoided (M.Shimizu, personal communication). 

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). 

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... 

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