Bicyclic ketone substrate

A novel class of chiral indenes (verbindenes) was prepared from enantiopure verbenone by K.C. Rupert and coworkers who utilized the Shapiro reaction and the Nazarov cyciization as the key transformations. The bicyclic ketone substrate was treated with triisopropylbenzenesulfonyl hydrazide to prepare the trisyl hydrazone that was then exposed to n-BuLi. The resulting vinyllithium intermediate was reacted with various aromatic aldehydes to afford the corresponding allylic alcohols. 

The total synthesis of the phenolic sesquiterpene (+)-parviflorine was accomplished by L.A. Maldonado and co-workers. The key step in the synthetic sequence was the reaction of an enamine with acrolein to form a bicyclic intermediate, which was subjected to a Grob fragmentation to afford the eight-membered ring of the natural product. The bicyclic ketone substrate was refluxed in benzene using a Dean-Stark trap and the resulting enamine was taken to the next step as crude material. 

Tri-substituted pyridine derivatives 201 were prepared by Katritzky et al. using a-benzotriazolyl ketones 199 and a,P-unsaturated ketones 200 in the presence of ammonitun acetate in refluxing acetic acid in good yields.Fused 2,3,4,6-tetrasubstituted pyridines 203 were also formed from the appropriate fused bicyclic ketone substrates 202. ... 

Allylic carbonates are most reactive. Their carbonylation proceeds under mild conditions, namely at 50 C under 1-20 atm of CO. Facile exchange of CO2 with CO takes place[239]. The carbonylation of 2,7-octadienyl methyl carbonate (379) in MeOH affords the 3,8-nonadienoate 380 as expected, but carbonylation in AcOH produces the cyclized acid 381 and the bicyclic ketones 382 and 383 by the insertion of the internal alkene into Tr-allylpalladium before CO insertion[240] (see Section 2.11). The alkylidenesuccinate 385 is prepared in good yields by the carbonylation of the allylic carbonate 384 obtained by DABCO-mediated addition of aldehydes to acrylate. The E Z ratios are different depending on the substrates[241]. 

The enzyme derived from Pseudomonas sp. strain HI-70 is able to oxidize a wide range of substrates including C12-C15 ketones, C5 and Cg ketones with methyl substituents, and some bicyclic ketones including decalones (Iwaki et al. 2006). 

Other cyclic or bicyclic ketones do not have a convex side but only a less concave and a more concave side. Thus, a hydride donor can add to such a carbonyl group only from a concave side. Because of the steric hindrance, this normally results in a decrease in the reactivity. However, the addition of this hydride donor is still less disfavored when it takes place from the less concave (i.e., the less hindered) side. As shown in Figure 10.10 (top) by means of the comparison of two reductions of norbomanone, this effect is more noticeable for a bulky hydride donor such as L-Selectride than for a small hydride donor such as NaBH4. As can be seen from Figure 10.10 (bottom), the additions of all hydride donors to the norbomanone derivative B (camphor) take place with the opposite diastereoselectivity. As indicated for each substrate, the common selectivity-determining factor remains the principle that the reaction with hydride takes place preferentially from the less hindered side of the molecule. 

Naturally, the WT of any enzyme has limitations regarding substrate scope (acceptance) and the degree of enantioselectivity. For example, the ee of the desymmetrization of 4-hydroxycyclohexanone 4 catalysed by the WT-CHMO amounts to only 9% in favour of (S)-5. We applied our previous experience with the lipases using epPCR and were able to evolve a mutant showing ee = 90% (S) (Reetz et al. 2004a). Reversal of enantioselectivity was also possible. One of the mutants also displayed fairly large substrate scope, a number of cyclic and bicyclic ketones undergoing desymmetrization with ee > 95% (Mihovilovic et al. 2006). No synthetic catalysts are currently available that allow such transformations (Scheme 2). 

Simple ketone substrates served to demonstrate the process. Thus bicyclic ketone (32) was oxidized at -22 C to generate a mixture of diastereomers (33) in good yield. Good stereoselectivity was observed in the oxidation of steroidal ketone (34) to the hydroxy ketone (35). Application of the procedure in syn-... 

Another example of a highly regio- and enantiospccific microbial Baeyer-Villiger reaction is the transformation of racemic bicyclic ketone 17 by Acinetobacter TD 63433. This leads to chiral lactones 18 and 19 which are of particular interest as synthons for prostaglandin synthesis. Interestingly, each enantiomer of the racemic substrate reacts with a different regioselectivity for the oxygen atom insertion, and the enantioselectivity of the reaction is excellent. 

Treatment of triisopropylsilyl enol ethers of cyclic ketones with ammonium cerium nitrate (3 equiv) and sodium azide (4.5 equiv) in acetonitrile at — 20 °C gave a-azido ketones in good yields124. By varying the ratio of the reagents the yields were lower or the formation of byproducts, difficult to separate, increased. Mixture of diastereomers (ratio not reported) were generally obtained from substituted substrates, except from the bicyclic ketones 16. 

Enantiomeric and diastereotopic face specific reductions are also readily effected on racemic bicyclic ketones. An illustration of the broad structural range that is amenable to enzyme-catalyzed transformation in this way is given in Scheme 38. While 2-decalones, such as ( )-(81)- 83), and the related heterocyclic analogs ( )-(85) are good substrates for HLADH, the 1-decalone ( )-(84) is not. However, by changing enzymes to MJADH, ( )-(84) becomes a good substrate.Similarly, TBADH is a highly satisfactory catalyst for stereospecific reduction of ( )-(86), but will not accept its dimethyl... 

Exploitation of the complementary specificities of enzymes from different sources towards the same racemic substrate permits very precise control of the product stereochemistry. For example, any one of the three diastereomeric 2-decalols (94)-(96) can be obtained at will from ( )-tra/iJ-2-decalone (81 R = H) using the alcohol dehydrogenases HLADH, MJADH or CFADH, respectively (Scheme 40). The stereospecificities of these three enzymes are well documented and a simple active site model of predictive value is available for each. 55 Racemic bridged bicyclic ketones are similarly discriminated, either... 

Structurally rigid substrate surrogates were added to the cubic section model before more flexible molecules as the following order signifies pentacyclic, tetracyclic, tricyclic, bicyclic ketones, trans/cis-decalones, methyl cyclohexanones and alkyl cyclohexanones. The hydroxyls of cyclohexanols were oriented axially with respect to cyclohexyl rings consistent with the Jones protocol and with the obsen/ation that... 

With the same substrate, silver(I) perchlorate gave solely the bicyclic ketone 6. A reagent consisting of palladium(O) in ethanol was successfully used in the ring expansion of7,7-dihalo-l-phenylbicyclo[4.1.0]heptanes. ... 

Over the past few years, there have been reports of directed evolution of Baeyer-Villiger MOs and their application in synthetic chemistry. In the evolution and synthetic application of these mutated enzymes to previous and new substrates, Mihovilovic and co-workers have improved the selectivity of a variety of CHMOs and CPMOs toward the oxidation of bicyclic ketone rac-87. It was shown that rac-87 provides 99% ee of each lactone 88 and 91 as a 1 1 mixture.50 In addition, it was shown that high % ee s and conversions could be obtained for a variety of substrates for the enzyme-promoted Baeyer-Villiger oxidation.51... 

With the success of our palladium idea behind us, we next turned our attention to the installation of the critical C8-methyl group. Conversion of the hindered ketone group to the C8-methyl group presented several obvious options. We started by using stannane 145 in the palladium cascade to afford bicyclic ketone 146, which we planned to use as the substrate for installing the methyl group and further advance toward vinigrol (Scheme 27). We quickly realized... 

Samarium(n) iodide-promoted intramolecular Barbier-type reactions have also been employed to produce a multitude of cyclic and bicyclic systems. Molander and McKie have enployed an intramolecular Barbier-type reductive coupling reaction to promote the formation of bicyclo[/n.n. l]alkan-l-ols from the corresponding iodo ketone substrates in good yield (eq 15). ... 

Horse liver ADH is a very universal enzyme with a broad substrate specificity and excellent stereoselectivity. Historically, it is the most widely used dehydrogenase in biotransformations [775, 776]. The three-dimensional structure has been elucidated by X-ray diffraction [778]. Although the primary sequence is quite different, the tertiary structure of HLADH is similar to that of YADH [779]. The most useful applications of HLADH are found in the reduction of medium-ring monocyclic ketones (four- to nine-membered ring systems) and bicyclic ketones [780-782]. Sterically demanding molecules which are larger than decalines are not readily accepted and acyclic ketones are usually reduced with modest enantioselec-tivities [783, 784]. 

Hydroxysteroid dehydrogenases (HSDH) are ideally suited enzymes for the reduction of bulky mono- [823] and bicyclic ketones (Scheme 2.121) [824]. This is not surprising if one thinks of the steric requirements of their natural substrates steroids [825, 826]. 

The racemic dihydrocarvone, above, was not tested for regiodivergent RRM behaviour, but the analogous experiment was carried out with several other racemic ketones [28]. Furstoss et al. obtained the best results by incubating Acinetobacter with the cyclobutanones rac-60 or rac-63 as the substrates (Scheme 6.14), resulting in near-perfect enantiodivergence to afford the isomeric lactones 61 and 62, or 64 and 65, respectively [28c]. In the case of the bicyclic ketone rac-66, one of... 

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