Wieland-Miescher ketone synthesis

The so-called Wieland-Miescher ketone is a valuable starting materia) used in the synthesis of steroid hormones. How might you prepare it hom 1,3-cycio-hexanedione ... 

The synthesis of S. J. Danishefsky s group is outlined in Scheme 13.55. The starting material is a protected derivative of the Wieland-Miescher ketone. The oxetane ring is formed early in this synthesis. An epoxide is formed using dimethylsulfonium methylide (Step A-3) and opened to an allylic alcohol in Step A-4. The double bond... 

In contrast to the Johnson s D —> A-ring construction approach, Brown devised an A —> D-ring construction approach [22]. Starting from Wieland-Miescher ketone (30), a common source of the A, B-rings in the de novo synthesis of steroids, the C-ring was introduced via hydrazone allylation, ozonolysis, aldol condensation, and olefin isomerization (31 > 32). The D-ring was assembled by a reductive alkylation... 

In contrast, the so-called bis-nor-Wieland-Miescher ketone (2) is a more complex synthetic problem, since the molecule is a multidissonant system with two dissonant bifunctional group relationships (1,4-D and 1,6-D) and two dissonant cyclopentane rings, besides a 1,5-consonant bifunctional group relationship. Its synthesis was only accomplished 30 years after the synthesis of its consonant homologue [5],... 

The product in entry 1 of Scheme 2.10 is commonly known as the Wieland-Miescher ketone and is a useful starting material for the preparation of steroids and terpenes. The Robinson annulation to prepare this ketone can be carried out enantioselectively by using the amino acid L-proline to form an enamine intermediate. The 5-enantiomer of the product is obtained in high enantiomeric excess.89 This compound and the corresponding product obtained from cyclopentane-1,3-dione90 are key intermediates in the enantiose-lective synthesis of steroids.91... 

The key intermediate in the synthesis of the derivatives of 19-F3-androstane is the trifluoro analogue of the Wieland-Miescher ketone. Its preparation involves a Diels-Alder reaction between a trifluoromethyi ketone and a siloxy diene. Another original step is the regioselective reduction of a diketone only the ketone function in P of CF3 (probably activated by this substituent) is reduced (Figure 4.6). " Then, a succession of classical reactions leads to derivatives of androstane from the trifluoro analogue of the Wieland-Miescher ketone (Figure 4.7). ... 

Figure 4.6 Synthesis of the trifluoro analogue of the Wieland-Miescher ketone. ...

This was demonstrated by Fukumoto and co-workers in a synthesis of (+)-albicanol (251), a sesquiterpene with potent hsh antifeedant properties (272,273). Oxime 248 [prepared from the (+)-Wieland-Miescher ketone 247] was subjected to cycloaddition using sodium hypochlorite and gave isoxazoline 249 in very good yield (Scheme 6.95). Conversion of 249 into (3-hydroxyketone 250 was again accomplished by the reductive hydrolysis sequence using Raney Ni and trimethyl... 

Further breakthroughs in enantioselectivity were achieved in the 1970s and 1980s. For example, 1971 saw the discovery of the Hajos-Parrish-Eder-Sauer-Wiechert reaction, i.e. the proline (l)-catalyzed intramolecular asymmetric aldol cyclodehydration of the achiral trione 11 to the unsaturated Wieland-Miescher ketone 12 (Scheme 1.3) [12, 13]. Ketone 12 is an important intermediate in steroid synthesis. 

This reaction is particularly suitable for the preparation of the Wieland-Miescher ketone 96, a very useful building block for construction of a broad variety of biologically active compounds such as steroids, terpenoids, and taxol. On the basis of the proline-catalyzed approach described above Barbas et al. recently reported an optimized procedure for formation of the chiral Wieland-Miescher ketone, 96 [105]. It has been shown that this synthesis (which comprises three reactions) can be performed as a one-pot synthesis. The desired product is obtained in 49% yield with enantioselectivity of 76% ee (Scheme 6.43). Here L-proline functions as an efficient catalyst for all three reaction steps (Michael-addition, cydiza-tion, dehydration). It is also worth noting that although many other amino adds and derivatives thereof were tested as potential alternative catalysts, L-proline had the best catalytic properties for synthesis of 96. This result emphasizes the superior catalytic properties of proline reported after previous comparative studies by the Hajos group [100, 101]. 

Another key event in the history of organocatalytic reaction was the discovery of efficient r-proline-mediated asymmetric Robinson annulation reported during the early 1970s. The so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction (an intramolecular aldol reaction) allowed access to some of the key intermediates for the synthesis of natural products (Scheme 1.4) [37, 38], and offered a practical and enantioselective route to the Wieland-Miescher ketone [39]. It is pertinent to note, that this chemistry is rooted in the early studies of Langenbeck and in the extensive investigations work of Stork and co-workers on enamine chemistry... 

The availability of 38C2 as a broad scope, enantioselective, efficient aldolase enzyme has had a significant impact on organic synthesis. Some of the molecules we have synthesized with 38C2 include the natural products ( + ) —frontalin [( + )— 27] (List et al., 1999), some brevicomins [( —) —28 and (—) —29] (List etal., 1998a), epothilones A (30) and C (31) (Sinha et al., 1998), and the Wieland-Miescher ketone [( ) — ( + )—32] (Hoffmann et al., 1998 Zhong et al., 1997). The brevicomin examples represent the first use of a catalytic antibody to decrease the total number of synthetic steps and increase the enantioselectivity of natural product syntheses. 

The starting material for the present synthesis was Wieland-Miescher ketone (24), which was converted to the known alcohol (25) by the published procedure [10], Tetrahydropyranylation of alcohol (25) followed by hydroboration-oxidation afforded the alcohol (26), which on oxidation produced ketone (27). Reduction of (27) with metal hydride gave the alcohol (28) (56%). This in cyclohexane solution on irradiation with lead tetraacetate and iodine produced the cyclic ether that was oxidized to obtain the keto-ether (29). Subjection of the keto-ether (29) to three sequential reactions (formylation, Michael addition with methyl vinyl ketone and intramolecular aldol condensation) provided tricyclic ether (30) whose NMR spectrum showed it to be a mixture of C-10 epimers. The completion of the synthesis of pisiferic acid (1) did not require the separation of epimers and thus the tricyclic ether (30) was used for the next step. The conversion of (30) to tricyclic phenol (31) was... 

Wieland-Miescher ketone)5,6 1s a versatile building block for the synthesis of steroids7 and terpenoids. The (S) enantiomer, 3-S, was first obtained by microbiological means9 and by classical resolution via a derived... 

A standard reaction that gives substituted decalins is the Robinson annelation (Chapter 29J. A Robinson annelation product available in quantity is the keto-enone known sometimes as the Wieland-Miescher ketone and used widely in steroid synthesis. The non conjugated keto group can be protected or reduced without touching the more stable conjugated enone. 

We achieved the first total synthesis of (+)-halenaquinol 2 and (+)-halenaqui-none 1 as follows.l The carbonyl group at the 1-position of the optically pure (8a/ )-(-)-Wieland-Miescher ketone 33, -98.96° (c 1.039, benzene), was... 

In the case of the total synthesis of halenaquinol (12b5)-(+)-2 and halenaquinone (12b5)-(+)-l, we started from the Wieland-Miescher ketone (8a/ )-(-)-33, as discussed above. Therefore, it is evident that the synthetic sample of halenaquinol dimethyl ether (+)-17 has the (12b5) absolute configuration. 19 if the theoretical determination of the absolute stereochemistry of the halenaquinol family is correct, the chiroptical data of [ ]d and CD spectra of the synthetic sample should be identical with those of the authentic sample of (+)-17 derived from... 

In the synthesis of occidentalol (ref. 13), a eudesmane-type compound consisting of a cis-fused decalin containing a homoannular 1,3-diene system, dihydrocarvone was converted by a typical Robinson annellation reaction to the basic reguired bicyclic structural unit. (It is of interest that a related bicyclic methyldecalenone structure, the Wieland-Miescher ketone, has been employed for the synthesis of longifolene (ref.14), copaene (ref.15) and sativene (ref.16) by three totally different strategies outside the present concept of the semi-synthetic approach). 

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