Boronic Ester Intermediates in Synthesis

In 2011, Hartwig and coworkers reported the total synthesis of taiwaniaquinol B (55, Scheme 11.9), a member of a family of diterpenoids that are derived from the abietane skeleton [36]. A key aspect of the Hartwig synthesis of taiwaniaquinol B was the use of the iridium-catalyzed borylation reaction to accomplish the C(5) functionalization of resorcinol derivative 53. This regioselectivity for the overall bromination is complementary to that which would be obtained using a standard electrophilic aromatic substitution (EAS) reaction. In the transformation of 53 to 54, a sterically controlled borylation was first accomplished, which was then followed by treatment of the boronic ester intermediate with cupric bromide to... 

The synthesis in Scheme 13.31 also relies on me.so-2,4-dimethylglutaric acid as the starting material. Both the resolved aldehyde employed in Scheme 13.30 and a resolved half-amide were successfully used as intermediates. The configuration at C-2 and C-3 was controlled by addition of a butenylborane to an aldehyde (see Section 9.1.2). The boronate ester was used in enantiomerically pure form so that stereoselectivity was enhanced by double stereodifferentiation. The allylic additions carried out by the butenylboronates do not appear to have been quite as highly stereoselective as the aldol condensations used in Scheme 13.30, because a minor diastereomer was formed in the boronate addition reactions. 

The synthesis by K. C. Nicolaou and co-workers is summarized in Scheme 13.43. Diels-Alder reactions are prominent in forming the early intermediates. The formation of the A ring in steps A and B involves use of z-cli loroacrylonitrile as a ketene synthon. In step C, the pyrone ring serves as diene. This reaction is facilitated by phenylboronic acid, which brings the diene and dienophile together as a boronate ester, permitting an intramolecular reaction. 

The use of a-halo(alkyl) boronic esters in asymmetric synthesis provides state of the art stereoselection1-3. The diastereomeric ratio of the a-halo boronic esters synthesized as intermediates is routinely in the 100 1 range. However, with the proper choice of chiral director, displacement of the oc-halogen provides a second stcrcodifferentiation step, after which diastereomeric ratios may exceed 1000 1 4. 

The quinoline portion of the target alkaloids was prepared by condensing p-anisidine 9 with ethyl propiolate, followed by bromination. Coupling of 10 with the boronic ester 8 proceeded to give 11, the intermediate for the synthesis of both 1 and 2. Selective direct epoxidation of 11 using the usual reagents failed, but Sharpless asymmetric dihydroxylation was successful, providing the diol in > 96 4... 

The addition of carboxylic acids to alkynes affords enol esters which are useful as intermediates in organic synthesis.470 As in the addition to alkenes, a catalyst is usually required for high conversions of alkynes to enol esters. Simple acid catalysis has been employed (equation 279),471 but the more common catalysts are Lewis acids, such as boron trifluoride etherate,472 silver nitrate,473 zinc acetate474 and zinc oxide (equations 280 and 281),47S-476... 

An improved synthesis of pyridyl boronic esters, valuable synthetic intermediates in crosscoupling reactions, has been reported. The critical element is the use of rr -trimethylsilylborate instead of the usual trialkylborates <03SC795>. 

In a biogenetically patterned synthesis, the cyclization of epoxygeranylgeraniol with boron trifluoride etherate has been shown to afford the compounds (103) and the pimaradienols (104). The cyclization of epoxygeranylgeranyl pyrophosphate by kaurene synthetase affords the epimeric 3-hydroxykaurenes. A cyclization of olefinic jS-keto-esters (105) to the bicyclic compound (106) has formedthe basis of a novel synthesis of A -podocarpen-13-one (107), a compound which is an intermediate in several diterpenoid total syntheses. Synthetic approaches to the... 

It is dear that boron is the most common metal for attaching chiral ligands, and this is mainly due to ease of preparation. However, chiral ligands on titanium can also promote enantioselective aidol reactions. Duthaler s reagent 56 leads to good levels of asymmetric induction with acetate aidol reactions [39] and has been used with ester 57 to give 58, an important intermediate in the total synthesis of tautomycin (Scheme 9-19) [40]. 

The second synthesis of fascaplysin (44), from labs at the CNRS, is also very high in overall yield (157). Palladium-catalyzed cross-coupling of the boronic ester 189 with the halogenated pyridine 190 lead to intermediate 191 (Scheme 20). Metalation of 191 with n-BuLi was regioselective, due in part to the inductive effects of nearby electronegative groups. The double cyclization of 192 to fascaplysin provides the natural product in 76% overall yield. 

The synthesis of 3,4-substituted anisoles [for example, R = R = (CH2)4] has been effected in the manner shown by the reaction of propynylmagnesium bromide with a sulphur-containing a,p-unsaturated ketone derivative to afford an intermediate carbinol. Cyclisation of this with boron trifluoride-etherate in the presence of methanol occurred with loss of methylthiol and desulphurisation by means of Raney nickel gave the final product (ref.86). The same sulphur-containing intermediates have been used with aryl esters to derive 4-methoxy acetophenone (ref. 87,88). Carbonyl derivatives of phenols are considered in detail in Chapter 7. 

Homochiral epoxides are versatile intermediates for the synthesis of a variety of natural products. The four-carbon bifiinctional chiron (i )-l- erNbutyldimethylsilyl-3,4-epoxybut-l-yne (228) is conveniently prepared from 141 as shown in Scheme 53. The conversion of 141 to chloride 225 followed by base-induced chloride elimination in liquid ammonia proceeds without any detectable epimerization (as determined by both hplc and nmr analysis of the corresponding Mosher ester) to provide the i -alcohol 226 in good yield. Subsequent silyl protection followed by treatment with boron tribromide results in a highly stereoselective bromination, together with simultaneous debenzylation to the bromohydrin 227, which under mild basic conditions is converted to epoxide 228. The optical purity of 228 (ee = 99%) demonstrates the high selectivity in this new bromination reaction [80,81]. 

The synthesis of saprisartan, reported by Judd and co-workers, used a Suzuki reaction as a key step to couple a benzofuran-based boronic acid with methyl 2-bromobenzoate in 30% yield. The resulting compound was then brominated and the methyl ester was hydrolyzed to produce the corresponding acid in 92% yield. Conversion of the acid to the Boc protected amine occurred with 18% yield. A second bromination, followed by substitution with a highly functionalized imidazole, gave the desired intermediate in 60% over two steps. Three additional steps were required to generate saprisartan in 1% overall yield. 

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