Hydroxy lactone moiety

A novel one-pot Dess-Martin oxidation was developed for the construction of the y-hydroxy lactone moiety of the CP-molecules in the laboratory of K.C. Nicolaou. Bicyclic 1,4-diol was treated with 10 equivalents of DMP in dichloromethane for 16h to promote a tandem reaction first, the bridgehead secondary alcohol was selectively oxidized to the ketone, followed by a ring closure to afford the isolable hemiketal, which was further oxidized by DMP to give a keto aldehyde. Trace amounts of water terminated the cascade to give a stable diol, which was not further oxidized with DMP. Subsequent TEMPO oxidation furnished the desired y-hydroxy lactone. 

Finally, the more complicated structures of tricyclic compounds that present the hydroxy ketone and hydroxy lactone moieties can be substrates for the enantioselective resolution process and some examples are presented in Scheme 52 [237,238]. 

In order to replace the chlorine atom by the desired hydroxy functionality, di-isobutylaluminum hydride (DIBAL-H) reduction followed by an acid-catalyzed acetalization with isopropanol in refluxing benzene had to be performed to protect the lactone moiety as an acetal and provided the thermodynamically preferred a-anomer 38 together with 5-8% of the other epimer. The conversion of the... 

Dideoxy-D-eryt/zro-hexopyranose (172) has been obtained from 3-deoxy-D-eryt/zro-pentose (171, Scheme 51)248 as an intermediate for the synthesis of the lactone moiety of inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, that lowers cholesterol levels. 

Another approach to the reduction in blood cholesterol levels has been the development of pravastatin (50) and its congeners as potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase, the rate-limiting enzyme in cholesterol biosynthesis.52 It has also been discovered that the biological activity of such compounds is dependent largely on the P-hydroxy-8-lactone moiety within the compound.53 This led to the development of more potent compounds, such as NK-104 (51), a congener of pravastatin. 

An excellent application of the Narasaka reduction is a diastereoselective synthesis by Merck scientists of 7, a structurally novel analog of the natural product compactin (8)7, which is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase8 (Scheme 4.1e). The key step in the construction of the P-hydroxy-8-lactone moiety in 7 is the highly diastereoselective reduction of the P-hydroxy ketone 9 using a triethyl borane/sodium borohydride system. The yyn-diol 10 was obtained in high yield and with a remarkably high level of diastereoselectivity. 

Camptothecin (CRT, 6, Figure 2.2) was first isolated from the Chinese ornamental tree Camptotheca acuminata Decne, also known as the tree of joy and tree oflove. It occurs in different plant parts such as the roots, twigs, and leaves. It is a member of the quinoline alkaloid group and consists of a pentacyclic ring structure that includes a pyrrole quinoline moiety and one asymmetric center within the a-hydroxy lactone... 

Figure 2. Examples of Various Lactone Moieties in Annonaceous Acetogenins an a, p-Unsaturated-y-lactone [Annonin I (4)], a C(4)-Hydroxylated a, P-Unsaturated-y-lactone [Bullatacin (5)], a Rearranged Acetonyl Butanolide [Bullatacinone (6)], and a Saturated p-Hydroxy-y-lactone [Itrabin (7)].

A diastereoselective epoxidation of a tetrasubstituted double bond was accomplished with mCPBA in the total synthesis of (-)-21-isopentenylpaxilline by A.B. Smith et al." The tetracyclic lactone substrate containing the tetrasubstituted double bond was exposed to mCPBA in toluene at room temperature. The reaction mixture also contained sodium bicarbonate to neutralize the by-product m-chloro benzoic acid. The epoxidation exclusively took place from the less hindered a-face of the molecule. At a later stage, this epoxide was converted to the y-hydroxy enone moiety present in the natural product. 

The labeling pattern of the (3 lactone moiety could be easily explained by Claisen condensation of octanoyl-CoA (33) with 3-hydroxy-5,8-tetradecanoyl-CoA (32) obtained by (3 oxidation of linoleic acid, as opposed to polyketide-type biosynthesis from low-molecular-weight fragments64... 

Their structures were mainly determined by spectral studies using EI-MS, IR, H-NMR, NOE, and CD spectra (75). They consist of a main spiroether moiety, corresponding to 1-oxaspiro[5. 5]undec-4-ene-8-one ring system, (including seven asymmetric centers and possessing a (Z)-olefin, a mefa-substituted phenol, and a P-ketocarboxylic acid functions) and a P-hydroxy-y-lactone moiety. Oscillatoxin Ds are present as esters of both moieties. On the other hand, aplysiatoxins are present as macro bis-lactones including a spiroacetal. We are interested in the relationship between oscillatoxins and aplysiatoxins from a biosynthetic point of view. 

Hydroxy-y-lactone moieties, segment Cl and segment C2, are known compounds whose syntheses have been reported. Therefore, we followed the reported methods and could readily synthesize both segment Cs. 

This interpretation appears to be complemented by the findings that the hydroxy carbonic acid of digitoxigenin, formed by saponification of the lactone moiety, and the similar derivative with -CH=CH-COO at C-17y5 are virtually inactive [19]. This may be assumed to result from the presence of a repellant negative charge in the lactone binding site, which could represent the counter ion in the two-point attachment suggested by Thomas et al. [19]. 

A full account has been given about the tactical installation of the C-4-C-6 furan ring of montanin A from an a,P-unsaturated lactone moiety, and the elaboration of the resulting furan unit into an a,p-unsaturated y-hydroxy lactone for preparing teuscorolide (14H2091). 

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