Hydroxylated tetracyclic

Recent improvements in the total synthesis of steroids which give as the first tetracyclic products 19-norsteroids bearing a hydroxyl or keto group at C-17 have revived interest in the conversion of androstanes to pregnanes. 

A Pd11- or Ptn-induced polycyclization of compounds containing two or even three C=C-double bonds and a hydroxyl group was described by Gagne and coworkers [179]. Thus, reaction of6/1-377 with equimolar amounts of the Ptn complex 6/1-378 led to the Pt-alkyl complex 6/1-379. Treatment of6/1-379 with NaBH4 provided the tetracyclic 6/1-380 as a 96 3 1 mixture in 86% yield (Scheme 6/1.95). It was proposed that, in the domino process, carbocations are formed as intermediates. 

Triterpenoids (C30 compounds) are the most ubiquitous of the terpenoids and are found in both terrestrial and marine flora and fauna (Mahato et al., 1992). Diterpenoids and triterpenoids rarely occur together in the same tissue. In higher plants, triterpenoid resins are found in numerous genera of broad-leaved trees, predominantly but not exclusively tropical (Mills and White, 1994 105). They show considerable diversity in the carbon skeleton (both tetracyclic and pentacyclic structures are found) which occur in nature either in the free state or as glycosides, although many have either a keto or a hydroxyl group at C-3, with possible further functional groups and/or double bonds in the side-chains. 

It has been shown" that isomerization of the exocyclic allylic system of the five-membered ring D of kaurenols depends on the orientation of the C(15) hydroxyl group. The total synthesis of methyl atis-16-en-19-oate, a tetracyclic diterpenoid possessing a bicyclo[2.2.2]octane skeleton, has been accomplished" using a homoallyl-homoallyl radical rearrangement process of methyl 12-hydroxykaur-16-en-19-oate monothioimid-azolide (280) as the pivotal step. Two plausible mechanisms have been presented" ... 

Mechanism of Action A tetracyclic compound that blocks reuptake norepi nephri ne by CNS presynaptic neuronal membranes, increasing availability at postsynaptic neuronal receptor sites, and enhances synaptic activity. Therapeutic Effect Produces antidepressant effect, with prominent sedative effects and low anticholinergic activity. Pharmacokinetics Slowly and completely absorbed after PO administration. Protein binding 88%. Metabolized in liver by hydroxylation and oxidative modification. Excreted in urine. Unknown if removed by hemodialysis. Half-life 27-58 hr. 

In another study (93), cyclization of optically active substrate 244 gave optically active tetracyclic product 245 with the same optical purity. Since, 245 was converted into Ua-hydroxyprogesterone (246), this work constitutes a total asymmetric synthesis of that steroid. This remarkable asymmetric control is due to the chiral center at C-10 of 244 the relative orientation of the hydroxyl group in the transition state of the cyclization process, controlled by stereoelectronic factors, is such that it yields a product (245) having an equatorial secondary alcohol. 

Vielsmeier-Haack formylation of /-substituted 2-phenylamino-4/7-pyrido[ 1,2-a]pyrimidin-4-ones 470 with a mixture of phosphoryl chloride and dimethylformamide at 95°C for 90 minutes gave a near 1 1 mixture of pyrido[r,2 I,2]pyrimido[4,5-6]quinazolin-12-one 472and -12,13 dione 473 in 23-37% and 22-41% yields, respectively (87JHC329). Compounds 472 and 473 probably formed by the disproportionation of the tetracyclic hydroxyl derivatives 471. If the substituent (R) of 470 was the ethoxycar-bonyl group, only N-ethoxycarbonyl derivative 475 could be obtained (92JHC25). No tetracyclic derivative 472 and/or 473 (R = COOEt) was formed. 

Since the 4 -hydrogen of mevalonic acid is eliminated during biosynthesis, the original dimethylallyl residue would be expected to carry the label from C-2 of the mevalonate in the trans-methyl group. The conversion of 3 to 4 therefore seems to involve hydroxylation at the cis-methyl group followed by cis-trans isomerization at the allylic double bond. Thus, the apparently normal labeling of the tetracyclic clavines in the trans (i.e., C-17) carbon after feeding with [2-14C]-mevalonate is merely the accidental result of a more complex series of reactions. 

When the dipolar cycloadduct 65, derived from the unsubstituted alkenyl dia-zoimide 64, was exposed to BF3 - OEt2, the resulting cyclized product 66 (90%) was identified as the all syn tetracyclic lactam 66 by X-ray crystal analysis. Thus, in contrast to the other three systems, the bridgehead proton of 66 lies syn to the hydroxyl stereocenter of the original cycloadduct. 

If as above we simply represent alicyclic rings sharing two Gs by a vertical line, then we can represent the basic tetracyclic structure of lanosterol as G61G61 G6 C5 (noting that there are two double bonds and various alkyl substituents and also a 3-hydroxyl on the first of the alicyclic rings). Many subsequent reactions yield cholesterol, a major triterpene membrane component that modifies the fluidity of animal cell membranes and is a precursor for synthesis of animal bile acids (fat solubilizing amphipathic detergents) plant triterpenes and steroid hormones such as the corticosteroids cortisol and cortisone, the mineralocorticoid aldosterone and the sex hormones testosterone and 17-(3-oestradiol. The structure and bioactivity of the plant terpenes is sketched below. 

Interesting intra- and intermolecular transformations involving oxonium ions formed by protonation of furan rings were shown to lead to elaborated ring systems. As shown in Scheme 1, interception of a transient cation by the pendant hydroxyl group led to the ketone intermediate 1, which further cyclized to provide the tetracyclic isochro-mene product <2005TL8439>. 

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