May 2005 Chem. Pharm. Bull. 53(5) 457—470 (2005) 457 Review Development of a Novel Synthetic Method for Ring Construction Using Organometallic Complexes and Its Application to the Total Syntheses of Natural Products1) Miwako MORI Health Sciences University of Hokkaido; Tobetsu, Hokkaido 061–0293, Japan. Received December 2, 2004 Organometallic complexes are useful tools in synthetic organic chemistry. We investigated a novel synthetic method for ring construction using organometallic complexes and synthesized natural products and biologically active substances using these methods. Metalacycles formed from an early transition metal and diene, enyne, and diyne are stable under the reaction conditions and they are easily converted into compounds with functional groups by the addition of various agents. We have developed a novel synthetic method of heterocycles from enyne ؎ ؎ ؊ and diene using Cp2ZrBu2. The total syntheses of ( )-dendrobine, ( )-mecembrane, and ( )-mecembrine were achieved using this procedure. To synthesize these natural products as a chiral form, a novel palladium-catalyzed asymmetric allylic amination was developed, and chiral 2-arylcyclohexenylamine derivatives were synthesized. -From these compounds, the total syntheses of (؊)-mesembrane, (؊)-mesembrine, (؉)-crinamine, (؊)-haeman -thidine, and (؉)-pretazetine were achieved. By further development of this procedure, a chiral 2-siloxymethylcy clohexenylamine derivative could be synthesized and the novel synthesis of indole derivatives was developed from .this compound. From this indole derivative, (؊)-tsubifoline and (؊)-strychnine were synthesized Key words organometallic complex; palladium catalyst; natural product synthesis; strychnine; mesembrine; zirconocene Organometallic complexes are useful tools in synthetic or- forded the cyclized compound 3 (Chart 1). ganic chemistry. In particular, they play an important role in Negishi et al. also found a synthetic method of dibutylzir- carbon–carbon bond formation. A metalacycle, i.e., a ring conocene (Cp2ZrBu2) from zirconocenedichloride (Cp2ZrCl2) compound containing a transition metal, is a useful interme- and butyl lithium, and dibutylzirconocene is easily converted diate in synthetic organic chemistry. Oxidative cyclization of into zirconocene coordinated by a butene ligand in situ at unsaturated hydrocarbons, such as alkene, alkyne, carbonyl room temperature4) (Eq. 3). compounds, or nitrile, using a low-valent transition metal is a useful reaction for synthesis of metalacycles. It is known that a metalacycle formed from a late transition metal and unsatu- (3) rated hydrocarbons is not stable and is easily converted into the reductive elimination product or b-hydrogen elimination This was a great discovery in zirconium chemistry because product (Eq. 1). Since the low-valent metal complex is regen- it is difficult to isolate zirconocene with no ligand. We were erated in this reaction, the reaction proceeds with a catalytic interested in those results and attempted to form carbon–car- amount of the transition metal. On the other hand, the meta- bon bonds between the unsaturated hydrocarbons, such as lacycle formed from an early transition metal and unsatu- enyne and diene, using zirconocene. rated hydrocarbons is fairly stable and can be converted into various compounds with functional groups by treatment with Synthesis of Heterocycles Using Zirconium-Mediated Cy- ؊ various agents (Eq. 2). Therefore a stoichiometric amount of clization and Total Synthesis of ( )-Dendrobine the metal complex is required in this reaction. The zirconacycles 2 were easily synthesized in situ from Cp2ZrCl2 and diene, enyne, or diyne 1. To a THF solution of Cp2ZrCl2 and unsaturated hydrocarbon 1 was added BuLi at (1) Ϫ78 °C under argon gas, and the solution was stirred at room (2) Negishi et al.2) and Nugent and Calabrese3) reported the syntheses of zirconacycles 2 from diene, enyne, and diyne 1 Chart 1. Formation of Zirconacycles from Unsaturated Hydrocarbons and using zirconocene (Cp2Zr). Hydrolysis of zirconacycle af- Cp2ZrBu2 ∗ To whom correspondence should be addressed. e-mail: [email protected] © 2005 Pharmaceutical Society of Japan 458 Vol. 53, No. 5 temperature for 1 to 2 h to form zirconacycle 2. We reacted The reaction of diene 7a with Cp2ZrBu2 was carried out, enyne 1a with dibutylzirconocene (Cp2ZrBu2), and bicyclic and the perhydroindole derivative 9a was obtained in high compound 3a was obtained in high yield after hydrolysis. An yield. Treatment of diene 7a with Cp2ZrBu2 and then conver- intermediary zirconacycle should be tricyclic complex 2a. sion of the atmosphere to carbon monoxide afforded tricyclic Since the reaction proceeded in a highly stereoselective man- ketone 10a in 94% yield.6) The stereochemistry of 9a and ner, the addition of iodine into the solution of 2a gave iodi- 10a could not be determined at this stage. nated compounds 5a and 5b. Interestingly, the atmosphere of Since tricyclic ketone 10a was obtained from 7a in a one- a solution of 2a was changed from argon to carbon monox- pot reaction in high yield, the total synthesis of (Ϫ)-den- ide, and the solution was stirred at room temperature to give drobine was planned. (Ϫ)-Dendrobine was first isolated from tricyclic keto-aldehyde 4a after hydrolysis. Furthermore, Dendrobium nobile lindle by Suzuki et al.7) and Inubushi et 8) Ϫ enyne 1b was treated with Cp2ZrBu2 in a similar manner to al. Total syntheses of ( )-dendrobine were achieved by give bicyclic compound 3b in high yield. The atmosphere of several groups.9,10) Our retrosynthetic analysis is shown in intermediary zirconacycle 2b was changed from argon to Chart 4. Kende et al. previously synthesized (Ϫ)-dendrobine oxygen, and the solution was stirred at room temperature to from compound 11.10) This compound should be synthesized give alcohol 6-D after treatment with 10% DCl. Treatment of from tricyclic ketone 10b, which would be obtained from 2b with carbon monoxide afforded tricyclic ketone 4b.5) diene 7b using our zirconium-mediated cyclization. Al- though the stereochemistry of the 5,5-membered ring junc- tion of the tricyclic ketone was not clear, we believed it to be cis on the basis of common sense. Chart 3. Reaction of Diene with Cp2ZrBu2 Chart 2. Synthesis of Bi- or Tricyclic Compounds Using Zirconium-Me- diated Cyclization Chart 4. Retrosynthetic Analysis of (Ϫ)-Dendrobine Dr. Miwako Mori was obtained her Ph. D. degree in 1971 (Supervisor, Professor Yoshio Ban) from Hokkaido University. She joined the Faculty of Pharmaceutical Sciences, Hokkaido University as an instructor in 1971, and was promoted to Associate Professor in 1987 and was promoted to Professor in 1992. In 2004, she was retired from Hokkaido Uni- versity and is an emeritus professor of Hokkaido University from 2004. In 2005, she moved to Health Sciences University of Hokkaido. Her research interest is in the area of organometallic chemistry toward synthetic organic chemistry, asymmetric synthesis, synthesis of heterocycles using molecular nitrogen and uti- lization of carbon dioxide. She was awarded the Pharmaceutical Society of Japan Award for Young Scientist in 1980, Saruhashi Prize (Superior Women’s Scientist) in 1991, Synthetic Organic Chemistry Miwako Mori Award in 2001, the Akiyama foundation Award in 2001, and the Pharmaceutical Society of Japan Award in 2004. May 2005 459 Fig. 1. Chart 6. Synthesis of trans-5,5-Fused Bicyclic Compound Chart 5. Formal Total Synthesis of (Ϫ)-Dendrobine ϩ Treatment of ( )-carvone with NaBH4 followed by the Mitsunobu reaction11) gave the cyclohexenylamine derivative 12. Detosylation of 12 followed by allylation afforded diene 7b in high yield. Cyclization of diene 7b with Cp2ZrBu2 fol- lowed by hydrolysis gave the perhydroindole derivative 9b in 58% yield. The stereochemistry of the cyclized compound was determined to be 9b in an NOE experiment, and this means that the stereochemistry of the intermediary zircona- cycle should be 8b. Treatment of 8b, obtained from 7b and Cp2ZrBu2, with carbon monoxide gave the tricyclic ketone 10b in 47% yield. Deoxygenation of the keto-carbonyl group Fig. 2. X-Ray Crystallography of trans-10c؅ was carried out to give 13, of which TsOH isomerized the double bond in dichloroethane to afford 14. Hydroboration of 14 followed by conversion of the N-benzyl group into the N- ring is cis because of the steric factor. Thus we further inves- methyl group gave 15, which was converted into a,b-unsatu- tigated the stereochemistry of the ring junction of the fused 14) rated ketone 11. The spectral data and [a]D value of this 5,5-membered ring of the zirconacycle. When diene 7c compound agreed with those of Kende et al.’s intermedi- was treated with Cp2ZrBu2 and then 10% HCl was added, the ate.10) Thus we succeeded in the formal total synthesis of two perhydroindole derivatives trans-9c and cis-9c were ob- (Ϫ)-dendrobine using zirconium-mediated cyclization as a tained in a ratio of 2 to 1. Furthermore, treatment of the zir- key step.12,13) conacycles with carbon monoxide gave the two tricyclic ke- In the reaction of diene 7a with Cp2ZrBu2, the perhydroin- tones trans-10c and cis-10c in a ratio of 2 to 1. Since the dole derivative 9a was obtained. To determine the stereo- trans-fused 5,5-membered ring compound is rare, conversion -chemistry of 9a, an N-benzyl group of 9a was converted into of trans-10c into trans-10c؅ was performed and X-ray analy a N-tosyl group and X-ray analysis of this crystallized com- sis was carried out (Fig. 2). pound was carried out. The stereochemistry of this com- It is clear that the ring junction of the fused 5,5-membered pound was determined to be 9a؅ (Fig. 1). Thus the stereo- ring of zirconacycle trans-10c؅ is trans. This is the second chemistry of 9a was confirmed. This means that the ring example of the X-ray crystallography of a trans-fused 5,5- junction of the fused 5,5-membered ring of zirconacycle 8a membered ring compound.14) is trans and that of the tricyclic ketone 10a should also be trans.