Cyclohexenones asymmetric synthesis

Liu H. J., Chew S. Y., Yeh W. L. Facile Selective Diels-Alder Reactions of Chiral 5,5-Dimethyl-4,6-Methano-2-Methoxycarbonyl-2-Cyclohexenone. Application to the Total Synthesis of Qinghaosu. Youji Huaxue 1993 13 314 321 Keywords (-)-/f-pinene, asymmetric synthesis... 

A very effective method for removal of the chiral auxiliary from cyclohexenones 34 involves treatment with I2 in THF-H2O to give the iodolactones 35 (Scheme 9). These highly functionalized chiral cyclohexanones have figured prominently in the asymmetric synthesis of natural products e.g. Scheme 15. Furthermore, selective cleavage of the cyclohexanone ring in 35... 

In the asymmetric synthesis of 4,4-disubstituted cyclohexenones of the type (132) it was possible to raise the optical yield to a maximum of 54 % by varying the structures of the carbonyl compounds 150) and of the proline derivatives (131)151). 

The usefulness of aminosiloxy diene Diels-Alder chemistry to the preparation of different substituted cyclohexenones is demonstrated in Table 11.3 The functionality at the 4 and 5-positions of the cyclohexenones can be easily controlled by the substitution pattern in the dienophile. The differing endo-exo selectivity found in the initial cycloadducts does not impact the usefulness of this route to cyclohexenones, since the amino group is eliminated in the last step. Chiral versions of aminosiloxy dienes provide the opportunity for asymmetric synthesis. Indeed, the diphenylpyrrolidine-substituted diene allows the synthesis of a variety of cyclohexenones, with good to excellent ee s 2b The usefulness of aminosiloxy diene Diels-Alder reactions to natural product synthesis is exemplified through the stereocontrolled synthesis of the pentacyclic indole alkaloid tabersonine 2c... 

It was most convenient to isolate the products after acidic conversion to cyclohexenones. Structures of the products were assigned by chemical correlation and circular dichroism and the enantiomeric purities were based on optical rotations. The selectivities obtained, although impressive for the era, are moderate at best, despite significant attempts to optimize the substrates and reaction conditions. Use of substituted cyclohexanones (29) and other aldehydes (30) lead to optically active products but the extent of enantiomeric induction in these products was not determined. This technology was used for the partial asymmetric synthesis of (+ )-mesembrine (12.1) (29) and (+ )-podocarpic acid (12.2) (31). 

Asymmetric Synthesis of 4,4-Dialkylcyclohexenones from Chiral Bicyclic Lactams. (S)-4-Ethyl-4-allyl-2-cyclohexenone A. I. Meyers and D. Berney, Department of Chemistry,... 

Meyers and his group have published an interesting asymmetric synthesis of chiral 4,4-disubstituted cyclohexenones which depends on the sequential alkylation of the chiral aldehydo-ketone equivalent (18). Because alkylation occurs preferentially from the less hindered, lower face, both enantiomers are available from this... 

Synthetic work on the mesembrane group will no doubt be further stimulated by reports on their central nervous system activity and somewhat surprising biosynthesis. An interesting asymmetric synthesis of unnatural (+ )-mesembrine (38) has been announced (Scheme 4). The key intermediate (35), prepared in nine steps from 1,2-dimethoxybenzene, was treated with L-proline pyrrolidide (36) under conditions typical for the preparation of enamines. The product was not isolated but subjected to reaction with methyl vinyl ketone followed by acid treatment to give the cyclohexenone (37) in 38 % overall yield. The last step in the synthesis [(37) — (38)] was based on previous synthetic work on mesembrine alkaloids. The synthetic (+ )-mesembrine (38) was shown to exhibit a positive Cotton effect and thus an antipodal relationship to natural (— )-mesembrine. The mesembrine analogues (40 = H or OMe, = H, Me, or CHjPh) have... 

Meyers has published aparticularly simple and efficient asymmetric synthesis of cyclohexenones (54) bearing a quaternary stereogenic centre at position 4 which again uses aminodiol (51) as the source of chirality.O i... 

Mori, K., Katoh, T., Suzuki, T., Noji, T., Yamanaka, M., Akiyama, T. (2009). Chiral phosphoric acid catalyzed desymmetrization of meso-l,3-diones asymmetric synthesis of chiral cyclohexenones. Angewandte Chemie International Edition, 48, 9652-9654. 

An improved asymmetric synthesis of (-l-)-tanikolide, a toxic and antifungal 7-lactone metabolite of the marine cyanobacterium Lyngbya majuscula, has been described by Akai et al. ° starting from 2-cyclohexenone. The reaction... 

Significant improvement in the catalytic activity of ALB was realized without any loss of enantioselectivity by using the second-generation ALB [27] generated by the self-assembled complex formation of ALB with alkali metal-malonate or alkoxide. This protocol allowed the catalyst loading to be reduced to 0.3 mol %, for example, the Michael addition of methyl malonate to cyclohexenone catalyzed by the self-assembled complex of (ff)-ALB (0.3 mol %) and KO Bu (0.27 mol %) in the presence of MS 4A gave the adduct in 94% yield and 99% ee [28]. This reaction has been successfully carried out on a 100-g scale wherein the product was purified by recrystallization. The kinetic studies of the reactions catalyzed by ALB and ALB/Na-malonate have revealed that the reactions are second-order to these catalysts (the rate constant ALB = 0.273 M 1h 1 ALB/Na-maionate = 1-66 M 1h 1) [27]. This reaction was used as the first key step for the catalytic asymmetric total synthesis of tubifolidine (Scheme 8D. 11) [28]. 

In 2002, Sasai et al. reported the synthesis of dendritic heterobimetal-lic multi-functional chiral catalysts, containing up to 12 l,l/-bi-2-naphthol (BINOL) units at their terminal positions (Fig. 9) [30]. On treating these functionalized dendrimers with AlMe3 and n-Buli, insoluble metallated Al-Ii-bis(binaphthoxide) generation x (GX-ALB) catalysts were obtained, which showed moderate catalytic activity in the asymmetric Michael reaction of 2-cyclohexenone with dibenzyl malonate (Scheme 4). 

Chiral bicyclic lactams are excellent precursors to a wide variety of chiral, non-racemic carbocycles including cyclopentenones, cyclohexenones, cyclopropanes, indanones, naphthalenones, and asymmetric keto acids.3 Recently they have been applied to the synthesis of chiral, non-racemic pyrrolidines and pyrroiidinones,4 that are medicinally and synthetically important molecules.5 The three-step procedure described here provides an efficient route (overall yield 46%) to (S)-5-heptyl-2-pyrrolidinone of high enantiomeric purity. The scheme below illustrates this reaction. 

Carbonyl-selective asymmetric hydrogenation of simple 2-cyclohexenone is still difficult. The optical yield obtained with [Ir(OCH3)(cod)]2-DIOP is only 25%, while the carbonyl-selectivity is 95% at 65% conversion (Scheme 23) [80]. Hydrogenation of 2,4,4-trimethyl-2-cyclohexenone with a Ru(II)-TolBINAP-4-KOH catalyst system under 8 atm of hydrogen at 0 °C gives 2,4,4-trimethyl-2-cy-clohexenol quantitatively in 96% ee [81, 82]. Notably, the combination of (R)-TolBINAP and (S,S)-4 matched well to give the S alcohol with a high ee. The chiral allylic alcohol is the key intermediate in the synthesis of carotenoid-derived odorants and other bioactive compounds [83]. 

New and continuing efforts towards the total synthesis of dendrobine (59 R = H) have been reported.In one sequence (Scheme 8), the butyric acid (85) was readily transformed into the ketal (86), which was submitted to a Birch reduction and hydrolysis to yield the cyclohexenone (87) as the single diastereomeric product. Acid treatment of (87) gave a stereoisomeric mixture of products (88) which were not separated but subjected to reaction with base to give compound (89). The same compound was obtained directly by treatment of (87) with strong base (Michael and aldol condensations combined). After some discouraging results, the tricyclic compound (89) was transformed into the desired keto-acid (90) via an abnormal ozonolysis reaction. Compound (90) possesses the correct stereochemistry at three asymmetric centres required for elaboration of dendrobine (59 R = H). 

An asymmetric variant makes use of a planar chiral complex. This arene to substituted cyclohexenone conversion has been elegantly used in a synthesis of (-F)-ptilocaulin. (Scheme 5 see also Chap. 8) [22]. The sequence is unusual in that after nucleophilic addition, acid free ClSiMe3 is added. When a strong acid... 

In 1969 Yamada and Otani reported an stereoselective stoichiometric synthesis of 4,4-disubstituted 2-cyclohexenones through an asymmetric Robinson annula-tion between preformed chiral aldehyde L-proline-derived enamines 20 and methyl vinyl ketone (Scheme 2.12) [33]. Surprisingly, only few examples of organocatalyzed Michael additions of aldehydes to enones have been reported since then. 

An early example of an asymmetric domino Michael/Knoevenagel reaction was reported by Jorgensen et al. [167] in 2006, providing the synthesis of chiral cyclohexenones from the reaction of tert-butyl 3-oxobutyrate and a, 3-unsaturated aldehydes catalyzed by chiral diphenylprolinol silyl ether derivative. Soon after, the... 

Ficini, J. Touzin, A. M. "Cycloaddition of an ynamine to cyclohexenones. Synthesis of aminobicyclo[4.2.0]octenones Tetrahedron Lett. 1972, 2093. Ficini, J. Touzin, A. M. "Stereochemical control of an asymmetric center formed a to the carboxyl function by hydrolysis of bicyclic en amines. Stereoselective synthesis of diastereoisomericy-keto acids" Tetrahedron Lett. 1972, 2097. Ficini, J. d Angelo, J. Noire, J. "Stereospecific Synthesis of c//-Juvabione" J. 

The final synthesis we will consider uses asymmetric catalysis to establish absolute stereochemistry. Thus, treatment of cyclohexenone (172) with dimethylzinc and catalytic Cu(I) in the presence of chiral ligand 173 proceeded with good asymmetric induction. Alkylation of the intermediate enolate using allyl acetate in the presence of Pd(0) provided 174 with 96% ee. This ketone was reduced to provide a mixture of alcohols which were separated and converted to 171 by degrading the allylic side chain to a carboxyl group, and displacing the alcohol with a nitrogen nucleophile. 

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