Chiral boron intermediates

S.M.A. Elgendy etal, US Patent 5,596,123 (January 21, 1997) Assignee Thrombosis Research Institute Utility Chiral Boron Intermediates... 

Many intermediate dialkylboranes derived from hydroboration with IpcBH2 can be recrystallized to enantiomeric purities approaching 100%, thus giving alcohols of 98-99% ee upon oxidation. If, instead of being oxidized in situ, the dialkylbo-rane intermediate is treated with Acetaldehyde, a-pinene is displaced for recovery and a chiral boronate bearing the R group of the alkene is obtained (eq 7). 

The Claisen rearrangement has attracted much attention as an attractive tool for the construction of new carbon-carbon bonds. Taguchi et al. reported the enantioselective and regioselective aromatic Claisen rearrangement of catechol mono allylic ether derivatives by means of Corey s chiral boron reagent (Eq. 70) [53a,54]. The mechanism of enantioselectivity is that a rigid five-membered cyclic intermediate is formed by reaction of catechol mono allylic ethers with the chiral boron reagent and this is fol-... 

Alternatively, a similar borate intermediate can be obtained by the reaction of organoborate with chloromethyl- or (dichloromethyl)lithiums (eq (22) and (23)). When a chiral diol ester reacts w ith (dichloromethyl)lithium, an optically active a-chloroalkylboronate is produced with an excellent enantiomeric excess [34] (eq (23)). The C-Cl bond is then displaced readily w ith alkyl, aryl, or 1-alkenyl nucleophiles with inversion of configuration. The procedure has been extensively used for the preparation of chiral boronates, which have been used in organic syntheses [30]. 

By hydroboration of natural products such as a-pmene, H. C. Brown and coworkers have prepared mono- 2.15 (R = H) and diisopinocampheylboranes 2.16 (R = H). These reagents promote highly enantioselective hydroborations [580, 583], The two a-pinene enantiomers are available, so both enantiomers of these reagents can be used. The intermediate di- or trialkylboranes formed in these hydroborations are treated with MeCHO. This forms a chiral boronate 2.17, and the a-pinene is freed for recovery and recycling. From 2.17, it is possible to obtain many functionalized compounds. Additionally, new chiral boranes 2.18 are available, and these are precursors of many chiral compounds bearing the R group [169, 580, 583, 585-588] (Figure 2.2). 

Jacobi and co-workers have applied the above Schreiber/Evans chiral boron enolate methodology to afford stereoselective routes to precursors of biologically important tetrapyr-roles [187], pyrromethanenones (114) (Scheme 4-59) [188], phycocyanin and phytochrome precursors, and P-amino acids [189], versatile intermediates for P-lactams of the carbapenem class. Generally, reaction of achiral or matched enolates with racemic cobalt complexes gave excellent selectivity. With a careful choice of mis-matched chiral enolate, moderate to good anti selectivity could also be achieved, leading to a formal total synthesis of thienamycin [190]. 

A postulated six-membered intermediate (Figure 2), formed by the attachment of the chiral boron reagent 1 to the phenolic hydroxy group, and the subsequent coordination of the ethereal oxygen to the boron atom can be used to explain the stereochemical outcome of the rearrangement. The 5r face of the difluorovinyl ether moiety is shielded by the tolylsulfonyl groups thus, the allyhc moiety approaches preferably from the Re face to avoid steric interaction with the aromatic group in the chair-like transition state. 

Only reaction 1 provides a direct pathway to this chiral molecule the intermediate 2-methyl-butanal may be silylated and reacted with formaldehyde in the presence of the boronated tartaric ester described on page 61. The enantiomeric excess may, however, be low. 

The cyclohexyloxy(dimethyl)silyl unit in 8 serves as a hydroxy surrogate and is converted into an alcohol via the Tamao oxidation after the allylboration reaction. The allylsilane products of asymmetric allylboration reactions of the dimethylphenylsilyl reagent 7 are readily converted into optically active 2-butene-l, 4-diols via epoxidation with dimethyl dioxirane followed by acid-catalyzed Peterson elimination of the intermediate epoxysilane. Although several chiral (Z)-y-alkoxyallylboron reagents were described in Section 1.3.3.3.3.1.4., relatively few applications in double asymmetric reactions with chiral aldehydes have been reported. One notable example involves the matched double asymmetric reaction of the diisopinocampheyl [(Z)-methoxy-2-propenyl]boron reagent with a chiral x/ -dialkoxyaldehyde87. 

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

The use of expensive and unstable ZnPli2 in the preparation of chiral di-arylmethanol derivatives, with electronically and sterically similar aryl rings, made this approach less attractive for the enantioselective synthesis. In order to avoid this inconvenience, other alternative preparations of arylzinc reagents were evaluated.As a first choice, Yus et al. proposed the use of arylboronic adds as a viable source of phenyl (Scheme 4.19). Thus, the reaction of various boronic acids with an excess of ZnEt2 at 70 °C gave the corresponding arylzinc intermediates (probably aryl(ethyl)zincs), which were trapped by reaction with dif-... 

The C(9)-C(14) segment VI was prepared by Steps D-l to D-3. The formation of the vinyl iodide in Step D-3 was difficult and proceeded in only 25-30% yield. The C(15)-C(21) segment VII was synthesized from the common intermediate 17 by Steps E-l to E-6. A DDQ oxidation led to formation of a 1,3-dioxane ring in Step E-l. The A-methoxy amide was converted to an aldehyde by LiAlH4 reduction and the chain was extended to include C(14) and C(15) using a boron enolate of an oxazo-lidinone chiral auxiliary. After reductive removal of the chiral auxiliary, the primary alcohol group was converted to a primary iodide. The overall yield for these steps was about 25%. 

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