Tricyclic natural products

Benzocyclobutenediones are of interest on their own as well as for their usefulness as versatile intermediates. The synthesis of adriamycin analogs has been attempted and the syntheses of the similar tricyclic natural products islandicin 180 and digitopurpurone 181 (Scheme 45) are examples of this approach (77JOC2371). 

Iodophenethylamine derivatives were found to undergo palladium catalysed cyclization to indolines.45 Starting from the appropriate tetrahydro-isoquinoline derivative the reaction was extended by Buchwald to the preparation of tricyclic natural products (3.37.),46... 

Cyclopentenones. A recent synthesis of (+)-albene (5), a tricyclic natural product, from the Diels-Alder adduct (1) of cyclopentadiene and 2,3-dimethylmaleic anhydride required transformation of a succinic anhydride group to a cyclopehtenone (4). This was accomplished via a protected keto aldehyde 3 in four steps as formulated in 51% overall yield.1... 

Often used in concert with mass spectrometry, NMR spectroscopy remains an invaluable structural diagnostic tool of particular importance to tricyclic natural products chemistry. For example, the tricyclic phenolic compound moracin P (3) was one of eight previously known compounds identified together with two new isoprenoid-substituted flavanones in isolates of the root bark of mulberry trees <89H(29)807>. In a series of studies of 6-7-5 tricyclic natural products, ID and 2D H and l3C NMR spectroscopy were employed extensively in the structure determination of sesquiterpene lactones (4)—(8) found among the aerial natural products of toxic plants (85P1378,90P551, 90P3875). 

The synthetic studies summarized here cover the partially developed and fully completed programs to build FR901483 and TAN1251 alkaloids, which together with the marine alkaloids cylindricines [80] and lepadiformine [81] are all the tricyclic natural products embodying the 1-azaspiro[4.5]decane ring to be isolated so far. 

Pauson-Khand Reaction As shown in Eq. 14.67, this reaction leads to substituted cyclopentanones in which the bulkiest substituent of the alkyne usually ends up alpha to the carbonyl.In the following application by Schreiber (Eq. 14.68), a complex tricyclic natural product is constructed. [W(CO)5(thf)] is a useful catalyst for the Pauson-Khand reaction. ... 

Bromo-A -tosylindole (8) has been converted to arcyriacyanin A (9) by Steglich. Similarly, Rapapport used 3,4-dibromoindole (10) to construct the ergot alkaloid tricyclic core (11), and Murakami reported a relatively short route to costaclavine." Similar uses in other natural product syntheses continue to appear in the literature. ... 

The importance of the 1,3-dipolar cycloaddition reaction for the synthesis of five-membered heterocycles arises from the many possible dipole/dipolarophile combinations. Five-membered heterocycles are often found as structural subunits of natural products. Furthermore an intramolecular variant makes possible the formation of more complex structures from relatively simple starting materials. For example the tricyclic compound 10 is formed from 9 by an intramolecular cycloaddition in 80% yield ... 

For the construction of the I ring, the vinylic group introduced to activate the y-hydroxy epoxide moiety of 28 towards cyclization is an acrylic ester residue, which concomitantly allows cyclization on the allylic position, with formation of the tricyclic compound 29 containing the IJK fragment of the natural product, and fur-... 

Cl0H2 eO Tricyclic Ar ether Natural product (2) T347... 

One of the most readily available easily oxidized sulfides is tetrathiafulva-lene (TTF) and this material readily transfers electrons to good electrophiles such as arene diazonium salts. This reaction has been used to form the tricyclic precursor to the natural product aspidospermidine, stereospe-cifically (Scheme 1.16). Since water is very inert towards attack by free... 

An enantiospecific synthesis of longifolene was done starting with camphor, a natural product available in enantiomerically pure form (Scheme 13.31) The tricyclic ring was formed in Step C by an intramolecular Mukaiyama reaction. The dimethyl Multistep Syntheses substituents were formed in Step E-l by hydrogenolysis of the cyclopropane ring. 

Classical cannabinoids (CCs) are tricyclic terpenoid derivatives bearing a benzopyran moiety. This class includes the natural product (-)-delta-nine-tetrahydrocannabinol (Fig. 8, 1) and the other pharmacologically active constituents of the plant Cannabis sativa. 

Stockman and coworkers [329] developed a straightforward synthesis of a tricyclic compound 2-636 which has some resemblance to the spirocyclic portion of the natural product halichlorine (2-637) [330]. On treatment of the symmetrical ketone 2-633, accessible in five steps from alcohol 2-632, with hydroxylamine hydrochloride the spiro piperidine 2-636 could be obtained in 62% yield (Scheme... 

The [6.5.5]-ring fused tricyclic motif is found in many natural products, and has therefore become an important target in synthesis. A convenient access to this structural framework is offered by a radical domino procedure published by the Nagano group [41]. This reaction of optical pure dibromoacetal 3-85 led to the desired tricycle 3-87 via 3-86 as a single diastereoisomer in a very respectable yield of 94% by applying classical radical conditions (excess tributyltin hydride/AIBN, irradia-... 

The same authors also used this approach for an enantioselective synthesis of the natural product (-i-)-royleanone (4-54), a member of the abietane diterpenoid family [17]. The enantiopure sulfoxide 4-50 was oxidized using DDQ to give crude 1,4-ben-zoquinone 4-51, which by reaction with the diene 4-52 in CH2C12 under high pressure led to the tricyclic compound 4-53 with 97 % ee and 60% yield based on 4-50 (Scheme 4.11). Hydrogenation of the unconjugated double bond in 4-53 afforded 35% of the desired compound 4-54 after crystallization to separate it from the unwanted cis-isomer. 

The procedure has been used for the total synthesis of the natural product stypol-dione (5-18) starting from 5-16 to give the 6/6/6-membered tricyclic compound 5-17 which was further manipulated (Scheme 5.4) [7]. 5-17 was obtained as a mixture of two diastereomers in low yield ranging from 20 to 30% [8, 9]. However, three... 

Kraus has reported the synthesis of a tricyclic indole related to the pyrroloiminoquinone marine natural products (Scheme 10.9), in which an intramolecular SNAr and the reductive cyclization of a nitro aldehyde are involved as key steps.94 Related target compounds have been prepared by Joule and coworkers via a similar strategy.95... 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

The number of natural products containing these tricyclic systems is relatively small, viz. a few alkaloids from marine (compound 293), fungal (compound 282), amphibian (compound 395), insect (compound 387), and plant sources (compound 288) and also some iridoid molecules (compounds 98-100). Some of those Myrmkaria alkaloids (from ants Section 12.16.6.5.2) which contain the 5 5 6 fused-ring system are perhaps the most extensively studied of these natural products, with several successful syntheses now recorded. 

Reviews of the syntheses of marine natural products, including marine isonitriles, have appeared recently [72]. After the early synthetic challenges of the tricyclic 9-isocyanopupukeanane (76) [73, 74] and 2-isocyanopupukeanane (78) [75] were met in 1979, additional syntheses of marine isonitriles were reported during 1986-1991. These were ( )-7,20-diisocyanoadociane (95) [63], ( )-axisonitrile-1 (1) and ( )-axamide-l (3) [76], the axisonitrile-4 triad (7-9) [78], and ( )-8,15-diisocyano-ll(20)-amphilectene (96) [79], and theonellin isocyanide (85) [80],... 

Cycloaddition reactions of furans are still widely used as key steps in the construction of complex molecules including natural products. As an example, the intramolecular Diels-Alder cycloaddition of 2-amido substituted furans provides a useful tool for the synthesis of fused, nitrogen-containing poly-heterocycles. Thus, thermolysis of 3-substituted amidofuran produces tricyclic indolinone 39 as a 2 1 mixture of diastereomers via amidofuran cycloaddition-rearrangement methodology, which serves as a key intermediate in the total synthesis of ( )-dendrobine, a major component of the Chinese ornamental orchid Dendrobium nobile . 

A total synthesis of the sesquiterpene ( )-illudin C 420 has been described. The tricyclic ring system of the natural product is readily quickly assembled from cyclopropane and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide—olefin cycloaddition (463). 

This reaction has also opened a rapid access to various polycyclic compounds, as illustrated by the transformation of a mixture of diastereomers 373 into tricyclic compound 374 as a single diastereomer, through a completely stereo-convergent process (Scheme 92). Interesting entries into the syntheses of carane family natural products have also been disclosed by Ftirstner with AuC 331 and by Marco-Contelles with PtCl2.332... 

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