Tetracyclic diol

L.A. Paquette and co-workers accomplished the first total synthesis of the antileukemic agent jatrophatrione. " This natural product has a [5.9.5] fused tricyclic skeleton with a trans-BIC ring fusion. The key step in their approach was the Grab fragmentation to obtain the tricyclo[5.9.5] skeleton. The tetracyclic 1,3-diol was monomesylated on the less hindered hydroxyl group and then treated with potassium fert-butoxide, triggering the concerted fragmentation to afford the desired tricyclic product in almost quantitative yield. 

Strictosamide was converted (Scheme 6) into a stereoisomeric mixture of tetracyclic diols (28). These in turn were obtained from tetrahydrovallesiachot-amine (25) and its C-20-epimer by a series of reductions beginning with reduction of the enamide grouping, as shown for (25) — (29). 

One of the first uses of the allylic sulfoxide-sulfenate interconversion was made by Jones and coworkers64, who reported exclusive suprafacial rearrangement of the allyl group in the steroidal sulfoxide 17 shown in equation 13. Two other examples are shown in equations 1465 and 1566. Evans and coworkers have demonstrated the utility of the suprafacial allylic sulfoxide-sulfenate rearrangement in a new synthesis of the tetracyclic alcohol 24 (equation 16)67, as well as in a synthesis of prostaglandin intermediates as shown in equation 1768. The stereospecific rearrangement of the unstable sulfenate intermediate obtained from the cis diol 25 indicates the suprafacial nature of this process. 

The key cyclization in Step B-2 was followed by a sequence of steps that effected a ring expansion via a carbene addition and cyclopropyl halide solvolysis. The products of Steps E and F are interesting in that the tricyclic structures are largely converted to tetracyclic derivatives by intramolecular aldol reactions. The extraneous bond was broken in Step G. First a diol was formed by NaBH4 reduction and this was converted via the lithium alkoxide to a monomesylate. The resulting (3-hydroxy mesylate is capable of a concerted fragmentation, which occurred on treatment with potassium f-butoxide. 

A practical method for the synthesis, resolution and determination of the absolute configuration of 9,9 -binaphtha(2,l- >)furanyl-8,8 -diol was reported as shown below <06TS1275>. A rearrangement of 4-acetoxy-9-furanylnaphtho[2,3- >]furans to tetracyclic naphthodifurans was achieved under acidic conditions <06TL4117>. 

An alternative new synthetic approach to chrysene 1,2-dihydro-diol based on Method IV has recently been developed (60). This method (Figure 12) entails synthesis of 2-chrysenol via alkylation of 1-1ithio-2,5-dimethoxy-1,4-cyclohexadiene with 2-(1-naphthyl) e-thyl bromide followed by mild acid treatment to ge nerate the diketone 12. Acid-catalyzed cyclization of 12 gave the unsaturated tetracyclic ketone 13 which was transformed to 2-chrysenol via dehydrogenation of its enol acetate with o-chloranil followed by hydrolysis. Oxidation of 2-chrysenol with Fremy s salt gave chrysene... 

Tetracyclization. The Heathcock group1 has described a remarkably short and efficient synthesis of the skeleton of Daphniphyllum alkaloids (2) by reaction of the dialdehyde 1 with gaseous ammonia and then dissolution in acetic acid at 70°. The yield is 77%, based on the diol precursor to 1. The azadiene a and the imine b have both been isolated and identified. The conversion of a to b is an intramolecular Diels-Alder type reaction. The tetracyclization may well be involved in the biosynthesis of alkaloids such as Daphnilactone A (3). 

The first synthesis50 of akagerine (67) makes use of the tetracyclic lactam (68a), previously synthesized. Formation of the ( )-dilactam (69) was observed from both (68a) and its (Z)-isomer. Preferential opening of the Nb,21 lactam function in (69) was followed by reduction stages to the diol (70), which was then oxidized preferentially at the allylic alcohol function to give akagerine (Scheme 10). 

The Sml2-mediated Barbier cyclisation of alkyl halides bearing cyclic ketones has been used extensively to form bicyclic systems.103 When the alkyl halide tether is attached a to the cyclic ketone carbonyl, cyclisation typically proceeds to give syn products. For example, Cook used such a cyclisation in a two-directional strategy for the synthesis of tetracyclic polyquinines treatment of bis-bromide 111 with Sml2 in THF-HMPA gave diol 112 in 68% yield (Scheme 5.80).133... 

Intramolecular Marschalk reaction. Ai. intramolecular Marschalk reaction (9, 376) can be used to effect a synthesis of anthracvclinones from anthraquinones. Thus the oi-hydroxy aldehyde 2, formed on saponification of the a-hydroxydichloride 1, on reduction of the quinone group cyclizes in the alkaline medium to the tetracyclic tran.s- and ci/j-diols(3and4)inaboutequal amounts. Cyclization underphase-transfer conditions results in improved yields and, more importantly, can alter the stereoselectivity. Triton B is the most effective catalyst for stereoselective cyclization to the desired natural tran -diol. 

The C-glycoside 178 was used by Boyd and Sulikowski [87] in the total synthesis of enantiomerically pure urdamycinone B (182) and 104-2 (183) making use of the diene 107 derived from shikimic acid (Scheme 29) and the NMO oxidation to generate the C-5 phenols (Scheme 40). Thus, the bromonaphthoquinone 179 (prepared by treatment of phenol 178 with NBS) formed the tetracycle 180 through a Diels-Alder reaction with the diene 107 in analogy to sugar-free reactants. Osmylation to a cis-diol, deprotection, oxidation, and acetalization gave the acetonide 181. The decisive step in the aromatization to 182 and 183 was the reaction with NMO (Scheme 46). Aromatization was also effected by direct periodane oxidation of adduct 180 to derive 182 after deprotection. 

Dihydroxykaurenolide, previously isolated as a microbiological transformation product of steviol, has been found as a metabolite of a strain of Fusarium monoliforme. The acyloin condensation of the keto-ester (76) under carefully-controlled conditions affords a means of reconstructing the tetracyclic kauranoid skeleton (77). The diol (77) was converted into steviol, which was accompanied by only small amounts of the isomeric beyerane diol. 

In the final stages of the total synthesis of (+)-cephalotaxine by M.E. Kuehne et al., a tetracyclic c/s-vicinal diol was oxidized to the a-diketone. Using PCC, pyridine/SOs or the Swem protocol did not yield the desired product. However, by applying the Corey-Kim protocol, NCS-DMS in dichloromethane at -42 °C, afforded the diketone in 89% yield. 

Fuchs also prepared ( )-ll hydroxycephalotaxine (26), Scheme 8, starting from tetracyclic lactam 84-cji which was treated with lithium diisopro-pylamide followed by 5-phenyl benzenethiosulfonate to give monosulfenyl-ated lactam 85 (37). Treatment of 85 with lithiated hexamethyldisilazane (LiHMDS), followed by molecular oxygen, afforded a-keto lactam 86. Reduction with BH3/THF, acylation, and deprotection of the diol yielded 87, which was oxidized under Swem conditions. Treatment with 2,2-dhmethoxy-... 

A further group of trinervitene (126) diterpenoids have been isolated from the frontal glands of a termite soldier, Nasutitermes rippertii. These include the 9/8-mono-ol, the 2/8,3a-diol and its acetates, the 2/3,3a,9o -triol and its triacetate, the 2j8,3a,13a-triol and its triacetate, and the 13-oxotrinervi-j8,3a-diol and its diacetate. Isotrinervi-2jS-ol has been obtained from the defensive secretions of T. gratiosus. Kempene-1 (127) and kempene-2 (128) are tetracyclic diterpenoids of a related type which were obtained from another Nasutitermes species. The structure (128) was established by A-ray analysis. 

Snider was interested in the synthesis of tetracyclic diterpenes. For that purpose, he examined the radical cyclization of tetraene precursor 55 to give highly valuable intermediate 56 for the total synthesis of isosteviol and beyer-15-ene-3,19-diol (Scheme 19). After the initial 6-enr/o-trig cyclization, a subsequent i-endo-ing cyclization involving the unsubstituted ene partner was responsible for the erosion of the yield [33]. 

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