Chiral tether

Catalytic alcoholysis of silanes by a variety of transition metal based catalysts is a useful method to form silyl ethers under mild conditions (Scheme 19). The process is atom-economical hydrogen gas is the only byproduct. This mild method has not been fully exploited for the preparation of unsymmetrical bis-alkoxysilanes. A catalytic synthesis using silicon alcoholysis would circumvent the need of bases (and the attendant formation of protic byproducts), and eliminate the need for excess silicon dichlorides in the first silyl ether formation. We sought catalytic methods that would ultimately allow formation of chiral tethers that are asymmetric at the silicon center (Scheme 20). Our method, once developed, should be easily transferable for use with high-value synthetic intermediates in a complex target-oriented synthesis therefore, it will be necessary to evaluate the scope and limitation of our new method. 

We sought catalytic methods that would allow formation of chiral tethers that are asymmetric at the silicon center. Synthesis of the chiral tether by our method would be advantageous for the reasons we described in the Introduction. Chiral information could be transferred during an intramolecular reaction. This would be an example of substrate-controlled transformation. 

Control over the absolute configuration in cyclohexenone photocycloadditions has been achieved by auxiliary-induced diastereoselectivity. In particular, esters related to compound 26, which are derived from a chiral alcohol but not from methanol, lend themselves as potential precursors, from which the chiral auxiliary can be effectively cleaved [42, 43]. In a recent study, the use of additives was advertised to increase the diastereomeric excess in these reactions [44], An intriguing auxiliary-induced approach was presented by Piva et al., who employed chiral 13-hydroxy-carboxylic adds as tethers to control both the regioselectivity and the diastereoselectivity of intramolecular [2 + 2]-photocycloaddition reactions [45]. In Scheme 6.14 the reaction of the (S)-mandelic acid derived substrate 38 is depicted, which led with very good stereocontrol almost exclusively to product 39a, with the other diastereoisomer 39b being formed only in minor quantities (39a/39b = 96/4). Other acids, such as (S)-lactic acid, performed equally well. The chiral tether could be cleaved under basic conditions to afford enantiomerically pure cydobutane lactones in good yields. 

In the same study, maleimides were irradiated in the presence of allyl alcohol and allyl ethyl ether, yielding the respective cyclobutanes with significant exo-preference [115]. Diastereofadal stereocontrol was achieved in the [2 + 2]-photo-cycloaddition of tetrahydrophthalimide by a chiral tether. The valinol-derived sub-... 

Faure, S., Piva-Le-Blanc, S., Bertrand, C., Pete, J.-P., Faure, R., and Piva, O. (2002) Asymmetric intramolecular [2 + 2] photocycloadditions a- and (3-Hydroxy acids as chiral tether groups. Journal of Organic Chemistry, 67, 1061-1070. 

Alternatively, enantioselective intramolecular photocycloisomerizations result from the use of hydroxy acids as chiral tethers, as illustrated in the conversion of 3-oxocyclohexenylcarboxylate 51 to the tricyclic lactone 52 which proceeds with 94% ee [67]. The chiral tether can be recycled by saponification to 53 and this hydroxyacid again converted to lactone 54 without loss of optical purity. 

Some natural compounds offer a chiral structural backbone that biases the outcome of the oxidative coupling of appended aryls (e.g., the ellagitannins). It was plausible to suppose, therefore, that two aryl units could be linked by a non-natural chiral tether to induce atrop-selective coupling upon exposure to an appropriate oxidant. In one of their attempts to realize the total synthesis of calphostin D (200) [136], Merlic and co-workers showed that, in the presence of dioxygen in trifluoroacetic acid (TFA), the precursor 198 affords the coupled compound 199 as a single diastereoisomer. Unfortunately, the relative configuration was incorrect for the calphostin target (Scheme 49). 

With inexpensive hydroxy acids as chiral tethers, only two stereochemic pure head-to-head 118 and head-to-tail 119 cycloadducts were isolated from lactate 117. With the corresponding dihydropyranone 120, the facial select decreased and head-to-head cycloadducts were obtained as a mixture of t diastereoisomers 121 and 122 (Scheme 27). I... 

As expected, the position of the asymmetric center on the tether influence the selectivity, and a lower de is obtained with a- rather than with (3-substitute butyrates [79]. Furthermore, for an identical chiral tether, the selectivity is usualn higher with cyclohexenone than with cyclopentenone derivatives. ... 

Scheme 1.4. Selective synthesis of (k)- and (fC)-bis[di(ethoxycarbonyl)methano][60]fuIlerene by diastereoselective tether-directed bis-cyclopropanation of Cgo and subsequent transesterification under removal of the chiral tether auxiliary.

The IMDA reaction of pyrone 167, which bears a chiral tether proceeded in a highly diastereoselective fashion to provide 168a-e t/o in 68% yield (95% based on a 72% conversion of 167), upon heating at 110 °C in toluene (Scheme 43) <06AG(E)>. 

Asymmetric Buchner reactions using chiral auxiliary have also been undertaken. The diazoketo substrate 126 for the chiral tethered Buchner reaction is prepared from optically pure (2/ ,4/f)-2,4-pentanediol in three steps the Mitsunobu reaction with 3,5-dimethylphenol, esterification with diketene, and diazo formation/deacetylation. Treatment of 126 with rhodium(II) acetate results in a quantitative yield of 127 with more than 99% ee. This compound is reduced with lithium aluminium hydride, and the resulting diol 128 undergoes epoxidation and concurrent acetal formation to give 129 as a single diastereomer. Hydrogenation of 129 with Raney nickel proceeds stereoselectively to yield saturated diol 130, which is converted to aldehyde 132 via acid hydrolysis followed by oxidation. Compound 132 is a versatile intermediate for natural product synthesis. 

Branched hydroformylation inttoduces a new stereogenic centre and, therefore, there is the opportunity to control the new centre by the use of chiral ligands. An early application of this concept is in an industrial synthesis of the anti-inflammatory drug, naproxen 4.193 from the corresponding styrene (Scheme 4.69). The ligand for the hydroformylation reaction, chiraphite 4.194, consisted of two bulky phosphates linked by a chiral tether. Many other chiral ligands have been developed. A problem with generating aldehydes with an a-chiral centre is their facile racemization via their enol or enolate form. One solution to this problem is to protect the product as its acetal 4.195 in situ (Scheme 4.70). ... 

Very high stereoselectivity caused by the chiral tether is observed when the ketene derived from FVP of diazo ester 428 followed by a Wolff rearrangement adds intramolecularly to give dioxepane-containing cyclobutanone 429 (Scheme 91 2003TL3115). 

Xia and Yamamoto have applied the axially chiral tethered bis-(8-quinolinolato) (TBOx) chromium catalyst 28 in the NHK allylation of a range of aldehydes (Scheme 12.25)." ... 

For the AC of chiral Ceo fuUerene cis-3 bisadducts, there had been many controversies among research groups. Cis-3 bisadducts with different chiral tethers were synthesized, and the energies of possible diastereomers were calculated by the molecular mechanics force field method to determine the AC because it was assumed that the product obtained should be the most stable diastereomer. From the calculation results, the absolute configurations of cis-3 bisadducts were assigned. However, the reported ACs and CD data were inconsistent among research groups. 

Piva et al. have established removable chiral tethers that attach an alkene to an enone and render the intramolecular [2-1-2]-photocycloaddition between these groups highly diastereoselective. Chiral a-and P-hydroxy acids such as (S)-lactic acid, (S)-phenyllactic acid, or (S)-mandelic acid proved to be highly effective auxiliaries. Butenyl lactate 1 was converted regioselectively to the straight adduct 2. The diastereoselectivity reached 94% DE at -40°C, albeit with a reduction in yield. At -20 C, 92% DE and 78% yield were obtained (Scheme 2). 

Faure, S. and Piva, O., Application of chiral tethers to intramolecular [2-1-2] photocycloadditions synthetic approach to (-)-italicene and (-l-)-isoitalicene. Tetrahedron Lett., 42, 255, 2001. 

The use of removable chiral tethers between the reacting double bonds could be an interesting solution for the synthesis of enantiomerically pure cycloadducts. Derivatives of inexpensive chiral hydroxy acids such as lactic and (i-hydroxy acids allow high asymmetric inductions with cyclohexenone derivatives. Unfortunately, the diastereoselectivities obtained during the photochemical step with the corresponding cyclopentenones were considerably lower (Scheme 13). ... 

Furthermore, the method was extended to an intramolecular [2-1-2]-photocycloaddition of imides linked to an allyhc alcohol or a propargyl alcohol by a chiral tether (Scheme 22). Interestingly, when l-valinol was used as a chiral auxihary, a high diastereoselectivity was also observed for the cycloaddition of the unsaturated anhydride with an alkenyl or an alkynyl unit. 

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