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[reaction: see text] The conversion of N-2,2-dichloropropionyl indole methyl ester into a tetracyclic cycloheptannelated indole model compound for the synthesis of dragmacidin E was accomplished in 10 steps. Key reactions include a Witkop cyclization to fashion a C-C bond at C(4) of the indole nucleus and a subsequent Dieckmann cyclization to deliver the desired cycloheptanoid ring.

[reaction: see text] When subjected to palladium-catalyzed amidation conditions, 2-triflyloxy phenethyl carbonates undergo, in addition to the expected aryl cross-coupling, an additional amidation with net displacement of the carbonate. The result is a one-step synthesis of indolines which may be oxidized to indoles. The utility of the procedure is illustrated by the two- or three-step syntheses of anhydrolycorinone, hippadine, oxoassoanine, and pratosine.

[reaction: see text] Cycloalkanones are easily converted into aryl-substituted cyclic alkenes by the addition of an aryl Grignard reagent followed by dehydration. These alkenes are good substrates for asymmetric epoxidation. We have found that the addition of allylic and benzylic Grignard reagents can occur preferentially at the benzylic position of the derived epoxides to give the quaternary stereogenic center. This approach led to a short synthesis of the nanomolar serotonin re-uptake inhibitor (-)-mesembrine.

[reaction: see text] An application of the phosphine-catalyzed [4 + 2] annulation in the formal synthesis of alstonerine and macroline is reported. A phosphine-catalyzed [4 + 2] reaction between imine 7a and allene 8 formed the D ring of the target indole alkaloids. A subsequent intramolecular Friedel-Crafts acylation provided the C ring of the bridged tetracycle. Deprotection, followed by methylation of the bridged nitrogen, deoxygenation of the C6 ketone, and reduction of the C16 carbethoxy group provided the previously known intermediate 3.

An efficient, convergent synthesis of the core bicyclo[4.3.1]decane ring system of welwitindolinones is described. Key steps in the synthesis include an intramolecular palladium-catalyzed enolate arylation reaction to create the desired bicyclic skeleton and a Curtius rearrangement to install the bridgehead isocyanate unit. [reaction: see text]

A successful structure-based design of a class of non-peptide small-molecule MDM2 inhibitors targeting the p53-MDM2 protein-protein interaction is reported. The most potent compound 1d binds to MDM2 protein with a Ki value of 86 nM and is 18 times more potent than a natural p53 peptide (residues 16-27). Compound 1d is potent in inhibition of cell growth in LNCaP prostate cancer cells with wild-type p53 and shows only a weak activity in PC-3 prostate cancer cells with a deleted p53. Importantly, 1d has a minimal toxicity to normal prostate epithelial cells. Our studies provide a convincing example that structure-based strategy can be employed to design highly potent, non-peptide, cell-permeable, small-molecule inhibitors to target protein-protein interaction, which remains a very challenging area in chemical biology and drug design.

[reaction: see text] Racemic oxodiester 1 undergoes stereoselective cyclocondensation with (S)-tryptophanol, (S)-(3,4-dimethoxyphenyl)alaninol, or the corresponding amino acids, in a process involving a tandem dynamic kinetic resolution/desymmetrization of diastereotopic groups, to give bicyclic lactams, which are cyclized to substituted indolo[2,3-a]- and benzo[a]quinolizidines.

[reaction: see text] A new strategy for the synthesis of the isoschizozygane alkaloid core has been developed that is based on a 1,4-dipolar cycloaddition reaction of a cross-conjugated heteroaromatic betaine. The resulting cycloadduct undergoes loss of COS, and further reduction delivers a 5a-aza-acenaphthylene intermediate that was transformed into the isoschizozygane skeleton upon treatment with acid.

[reaction: see text] A new synthesis of enantiopure 3,3-disubstituted oxindoles by stereoselective Mukaiyama aldol reaction of 3-substituted 2-siloxyindoles and chiral, enantiopure aldehydes having nitrogen or oxygen substituents at the alpha carbon is described. When the C3 substituent of the prochiral nucleophile is aryl or heteroaryl, stereoselectivity is high (10-80:1).

Total syntheses of indoloquinolizidine alkaloid (+/-)-, R-(+)-, and S-(-)-deplancheine are described here. The synthesis features an enantioselective intramolecular formal aza-[3 + 3] cycloaddition for the construction of the quinolizidine CD-ring. This application serves to introduce a new synthetic strategy for the synthesis of indoloquinolizidine alkaloids.

One achiral seco-hydroxycyclopropylbenz[e]indolone (seco-CBI) (12) and seven achiral seco-amino-CBI (11a-g) analogues of CC-1065 and the duocarmycins were designed, synthesized and evaluated for their DNA-binding and anticancer properties. These compounds contain a core 2-chloroethylnaphthalene structure and they do not have a stereocenter. From thermal cleavage gel analyses, compounds 11a-g and 12 demonstrated similar covalent sequence specificity to adozelesin 3 and the racemic seco-CBI-TMI 4 for binding to the 5'-AAAAA(865)-3' site. Continuous exposure of human (K562) and murine (B16, L1210 and P815) cancer cell lines to the compounds demonstrated their significant cytotoxicity, with IC50 values in the sub-micromolar range. Generally, a good leaving group on the ethyl moiety and a free amino or hydroxyl group on the naphthyl moiety are essential for activity. According to NCI's cytotoxicity screen, compounds 11a and 12 were active against human cancer cell lines derived from lung, colon, melanoma, renal system, and breast. At the respective doses of 15 and 20 mg/kg (administered via an ip route), compounds 11a and 12 inhibited the growth of murine B16-F0 melanoma in C57BL/6 mice, with minimal toxicity, and 11a gave a significant anticancer effect. The in vivo anticancer activity of compound 11a was confirmed in a human tumor xenograft study (advanced stage SC-OVCAR-3 ovarian cancer growing in scid mice). Finally, compound 11a was not toxic to murine bone marrow cell growth in culture at a dose that was toxic for the previously reported compound 4.

[structures: see text] The highly convergent stereocontrolled total synthesis of (-)-vincamajinine (7), (-)-11-methoxy-17-epivincamajine (9), and the oxygen-bridged (+)-dehydrovoachalotine (22) are described. Key steps in the synthesis of 7 and 9 involved the stereospecific enolate-driven palladium-catalyzed cross-coupling reaction, a Tollens reaction, an acid-assisted intramolecular cyclization to form the C(7)-C(17) quaternary center, and two stereospecific reductions. The efficiency of this strategy is illustrated by the completion of the synthesis of 7 and 9 in 16 [from d-(+)-tryptophan methyl ester 17] and 17 (from the Schöllkopf chiral auxiliary 27) reaction vessels, respectively. This constitutes the first total synthesis of these indole alkaloids and provides the first regiospecific route to 11-methoxy-substituted ajmaline/vincamajine-related alkaloids. The synthesis of 22 required a novel DDQ-mediated cyclization to furnish the C(6)-O(17) bond, executed in stereospecific fashion. Completion of these syntheses illustrates a concise and versatile strategy for the synthesis of vincamajine-related alkaloids, which has also been employed to prepare the related compounds quebrachidine diol (53), vincamajine diol (56), and vincarinol (59).

[reaction: see text] An intermolecular aza-double Michael reaction leading to functionalized piperidin-2-ones from simple starting materials has been developed. The method allows alpha,beta-unsaturated amides to be used as a synthon of the piperidine nucleus. In addition, the utility of this methodology is demonstrated by its application to a formal synthesis of the indolo[2,3-a]quinolizidine alkaloids, (+/-)-deplancheine, (+/-)-tacamonine, and the antidepressant paroxetine.

An enantiodivergent strategy for the total chemical synthesis of both (+)- and (-)-dragmacidin F beginning from a single enantiomer of quinic acid has been developed and successfully implemented. Although unique, the synthetic routes to these antipodes share a number of key features, including novel reductive isomerization reactions, Pd(II)-mediated oxidative carbocyclization reactions, halogen-selective Suzuki couplings, and high-yielding late-stage Neber rearrangements.

We describe an enantioselective synthetic route to the antiproliferative alkaloid stephacidin B (1) proceeding in 18 steps and 4.0% yield from 4,4-(ethylenedioxy)-2,2-dimethylcyclohexanone (3). Key features of the synthetic sequence include the use of the Corey-Bakshi-Shibata (CBS) reduction to introduce asymmetry early in the synthetic route, use of the novel electrophile N-(tert-butoxycarbonyl)-5-(isopropylsulfonyloxymethyl)-2,3-dihydropyrrole in a stereoselective enolate alkylation, a diastereoselective Strecker-type addition of hydrogen cyanide to an N-Boc enamine substrate in the solvent hexafluoroisopropanol, platinum-catalyzed nitrile hydrolysis under neutral conditions, cyclization of an acylamino radical intermediate to form the diketopiperazine core of stephacidin B, and implementation of a convergent procedure for introduction of the key 3-alkylidene-3H-indole 1-oxide functional group in the final stage of the route to prepare the structure 2, previously proposed to be the fungal metabolite avrainvillamide (17 steps, 4.2% yield). We observed that synthetic (-)-2 dimerized in the presence of triethylamine to form (+)-stephacidin B (>95%). We also obtained evidence that 2 can form 1 under mild conditions, and that 2 reacts with nucleophiles, such as methanol, by conjugate addition.

[reaction: see text] Herbindole B and cis-trikentrin B are naturally occurring indoles having the unusual and synthetically challenging pattern of carbon substitution at the 4-7 and 5-7 positions, respectively, with no substitution at the 1-3 positions. The total syntheses of these polyalkylated indoles have been achieved in 19 and 12 steps, respectively. The synthesis of herbindole B relies on two iterations of a quinine monoimine Diels-Alder reaction, while cis-trikentrin B uses a single cycloaddition of a suitable quinone monoimine. Indolization of the adducts provides suitably substituted benzopyrrole nuclei for elaboration to the natural products.

[reaction: see text] A one-pot procedure was developed to efficiently prepare hexahydroindolinones containing a tethered furan ring. Reaction of a furanyl azide with Bu3P delivered the iminophosphorane, which was allowed to react with 1-methyl-(2-oxocyclohexyl)acetic acid to give the desired hexahydroindolinone ring system. Further treatment with trifluoroacetic acid afforded the tetracyclic lactam skeleton found in the alkaloid (+/-)-selaginoidine.

[reaction: see text] A Brønsted acid-catalyzed highly stereoselective arene-ynamide cyclization is described. These reactions constitute a keteniminium variant of Pictet-Spengler cyclizations, leading to efficient synthesis of nitrogen heterocycles and related alkaloids. Total syntheses of desbromoarborescidines A and C are illustrated here as first applications of this methodology.

We report a novel, facile and asymmetric approach to both enantiomers of the indole alkaloid deplancheine from a readily available, nonracemic chiral template. The natural product and its antipode are isolated with >95% ee.

Inspired by the skeletal diversity of naturally occurring indole alkaloids and the rich potential of chemistry developed by Padwa and co-workers, we conceived a pathway entailing six modes of intramolecular reactions leading to indole alkaloid-like skeletons. In this context, an efficient folding pathway via a rhodium-catalyzed tandem cyclization-cycloaddition involving three of the modes has been developed (two of which are shown above) that affords densely functionalized compounds with three distinct skeletons in a stereocontrolled manner.

Recently, many organometallic complexes, such as palladium, nickel, ruthenium, titanium complexes and others, were used for synthetic organic chemistry. We have developed many novel synthetic methods using these organometallic complexes for synthetic organic chemistry. As the organometallic complexes, nickel, chromium, molybdenum, ruthenium, zirconium, titanium, and palladium complexes, were used. Furthermore, bimetallic complexes having silicon-tin and silicon-zirconium bonds were investigated. On the other hand, utilization of gases in synthetic organic chemistry has been also developed. 1 atm pressure of gases such as CO, CO(2), N(2), ethylene and acetylene, could be used and the reaction procedure is very simple, that a balloon filled with a gas is connected on the top of the flask. Using our novel synthetic methods, we have synthesized many natural products and biologically active substances, such as cephalotaxin, mesembrine, tubifoline, strychnine, stemoamide, lycopodine, pumiliotoxin C, beta-lactam, carbapenam and benzodiazepinone derivatives.

The first total synthesis of (+)-okaramine C is described. Our previously described selenocyclisation-oxidative deselenation sequence was used to establish a 3a-hydroxy-pyrrolo[2,3-b]indole core, which was modified by selective epimerisation to the common pyrrolo[2,3-b]indole of the okaramines., (Copyright 2004 The Royal Society of Chemistry)

The highly stereoselective asymmetric 6pi-azaelectrocyclization was achieved as a general synthetic method based on the reaction between the (E)-3-carbonyl-2,4,6-trienal compounds and the (-)-7-alkyl-cis-1-amino-2-indanol derivatives which are effective chiral amines. The 7-alkyl-substituted 2-indanol moiety of the cyclized products was efficiently removed by the novel manganese dioxide oxidation under remarkably mild conditions, and the method was successfully applied to the formal synthesis of optically active 20-epiuleine.

[reaction: see text] A systematic study addressed toward the optimization of the Pd-catalyzed alkylation of indoles by allylic carbonates is presented. The protocol uses a catalytic amount of [PdCl(pi-allyl)](2)/phosphine as a promoting agent, providing allylindoles in excellent yields. The regioselectivity of the reaction can be controlled by a proper choice of the base and the reaction media. The method proved to be effective also for intramolecular allylic alkylations of indolyl carbonates, providing a flexible route to fused indole alkaloids.

The enantioselective cyclization of N-acyliminium ions generated in situ from tryptamine is promoted with high enantioselectivity by a new chiral thiourea catalyst. This represents the first successful system for asymmetric catalysis of the Pictet-Spengler reaction.

A five-step formal synthesis of alkaloid cryptotackiene and its 2-formyl, 11-methyl/phenyl derivatives involving conjugate addition of enolate anion from cyclohexanone (or 4-methylcyclohexanone) to bis[(methylsulfanyl)methylene]-2-oxindole followed by heterocyclization in the presence of ammonium acetate as the key step has been developed. The 11-methylsulfanyl group in the initial precursor can be either desulfurized (Raney Ni) or replaced by methyl/phenyl groups via nickel-catalyzed cross-coupling reaction with appropriate Grignard reagents., (Copyright 2004 American Chemical Society)

Securamine A is a structurally intriguing alkaloid possessing a pyrroloindole core joined via a modified isoprene subunit to a functionalized imidazole ring. Recent synthetic efforts in this laboratory have resulted in the efficient construction of key lactone 36, which undergoes tandem azide reduction/ring expansion to macrolactam 37. Macrolactam 37 possesses the complete macrocyclic core of securamine A.

The first total synthesis of (+)-dragmacidin F has been accomplished, establishing the absolute configuration of this biologically important, antiviral marine alkaloid. The convergent route described features a palladium-mediated oxidative pyrrole carbocylization reaction to construct the [3.3.1] bicycle, as well as a highly selective Suzuki coupling to build the carbon skeleton of the natural product. A late-stage Neber rearrangement allows for the facile installation of the aminoimidazole moiety to provide (+)-dragmacidin F.

The synthesis of indoles bearing alkenyl and alkynyl moieties in different positions of the nucleus is described. These compounds are used as substrates for the intermolecular Pauson-Khand reaction leading to tetracyclic cyclopentenones with formation of additional five- to seven-membered rings. Products are related to alkaloids such as mitosenes, clausines, ergotamines, or apogeissochizines., (Copyright 2004 American Chemical Society)

[reaction: see text] An efficient route to benzo[a]carbazoles via a metalation-cross-coupling sequence has been demonstrated and its application to the synthesis of the antitumor and antiviral alkaloid 6-cyano-5-methoxy-12-methylindolo[2,3-a]carbazole has been achieved.

Described is the first enantioselective synthesis of (-)-gilbertine (2), a member of the uleine-type family, and the determination of the absolute configuration of this natural product is reported. The key step employs a cationic cascade reaction for a tetrahydropyrane and piperidine ring formation and the construction of the pentacyclic framework in one step. The synthetic strategy utilizes the Shibasaki reaction to build up the first stereogenic center. A formylation reaction of a 3-substituted cyclohexanone derivative was achieved, giving only the desired regioisomer. The Japp-Klingemann Fischer indole protocol was used successfully as a convergent synthetic approach for the construction of the desired tetrahydrocarbazole (20). Furthermore, an unexpected behavior of this 2,3-disubstituted cyclohexanone derivative during an epimerization process was investigated, resulting in different chemical behavior of the enantiomers and the racemate. The diastereomeric resolution was achieved via the cationic cascade reaction, demonstrating the versatility of this approach. Significantly, the synthetic 17-step sequence was easy to execute, giving (-)-gilbertine in 5.5% overall yield.

Much interest has been shown in Amaryllidaceae alkaloids as synthetic targets due to their wide range of biological activities. Over 100 alkaloids have been isolated from members of the Amaryllidaceae family; most of them can be classified into eight skeletally homogeneous groups. We have succeeded in the first asymmetric total syntheses of the crinane-type alkaloids (+)-crinamine (1), (-)-haemanthidine (2), and (+)-pretazettine (3). The starting cyclohexenylamine 14 was obtained from allyl phosphonate 11c by palladium-catalyzed asymmetric amination in 82% yield and with 74% ee. The product was recrystallized from MeOH. Interestingly, (-)-14 with 99% ee was obtained from the mother liquor (74% recovery). Intramolecular carbonyl-ene reaction of (-)-10 proceeds in a highly stereoselective manner to give hexahydroindole derivative 9 as the sole product. In the Lewis-acid-catalyzed carbonyl-ene reaction, an interesting rearrangement product, 20, was isolated in high yield. From 9, (+)-crinamine was synthesized. Thus, the asymmetric total synthesis of (+)-crinamine was achieved in 10 steps from 11c, and the overall yield is 19%. The total synthesis of (-)-haemanthidine was also achieved from 9 by a short sequence of steps.

The first total syntheses of (-)-vincamajinine (5) (from Na-methyl-d-tryptophan methyl ester) and (-)-11-methoxy-17-epivincamajine (6) (from Na-methyl-6-methoxy-d-tryptophan ethyl ester) are described. The syntheses have been completed in a highly stereocontrolled manner (>98% ee). Key steps included the asymmetric Pictet-Spengler reaction, enolate-mediated palladium cross-coupling reaction, and acid-catalyzed formation of the C(7)-C(17) bond. In addition, the triethylsilane/TFA-mediated incorporation of the 2alpha-H (11 to 12) and the borohydride generation of the C(17) hydroxyl function (R) were also stereospecific. The unique highly conjested carbon skeletons of the two alkaloids were completed in a concise manner and in regiospecific fashion.

The harman-1,4-dihydropyridines 1 and 2, which constitute the originally proposed structures for the indole alkaloids lyaline and lyadine, have been synthesized, and their NMR data have been compared with those available for the natural products. Due to the discrepancies in the spectral data, the structures of lyadine and lyaline should be revised.

Hinckdentine A is a structurally unique marine alkaloid containing an 11b,12,13,14,15,16-hexahydroazepino[4',5':2,3] indolo[1,2-c]quinazoline ring system. This review covers the literature on hinckdentine A. The indolo[1,2-c]quinazoline ring system is the foundation of the hinckdentine A structure. The literature on the chemistry of indoloquinazolines until the end of 1994 has been reviewed by Billimoria and Cava. Therefore, we review the research carried out on the synthesis of indolo[1,2-c]quinazolines and related ring systems in which hinckdentine A is described from 1995 to present. The construction of the quaternary center is the primary synthetic challenge posed by the hinckdentine A structure. We will present a selection of methods applicable to the synthesis of 2,2-disubstituted indolines. Finally, we present the three most significant attempts to synthesize hinckdentine A.

The first total synthesis of (+)-Na-methyl-16-epipericyclivine (9) was completed [from d-(+)-tryptophan methyl ester] in an overall yield of 42% (eight reaction vessels). The optical rotation [[alpha]D +22.8 (c 0.50, CHCl3)] obtained on this material confirmed that the reported optical rotation [[alpha]D 0 (c 0.50, CHCl3)]47 was biogenetically unreasonable. The total syntheses of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q3, (-)-panarine, and (+)-Na-methylvellosimine are also described. Moreover, a mixed sample (1:1) of synthetic (-)-panarine and natural (-)-panarine yielded only one set of signals in the 13C NMR; this indicated that the two compounds are identical and further confirmed the correct configuration of (+)-vellosimine, (+)-normacusine B, and (-)-alkaloid Q3. In this approach, the key templates, (-)-Na-H,Nb-benzyltetracyclic ketone 15a and (-)-Na-methyl,Nb-benzyltetracyclic ketone 43 were synthesized on multihundred gram scale by the asymmetric Pictet-Spengler reaction and a stereocontrolled Dieckmann cyclization via improved sequences. An intramolecular palladium (enolate-mediated) coupling reaction was employed to introduce the C(19)-C(20) E-ethylidene function in the sarpagine alkaloids for the first time in stereospecific fashion.

Tryprostatin B was synthesized in 32% overall yield from the readily available dipeptide anhydride cyclo-(l-Trp-l-Pro). Its tandem C-3 prenylation/cyclization gave the corresponding pentacyclic pyrroloindole systems bearing a prenyl group at the indole C-3 position. These compounds were then submitted to acid-catalyzed opening of the newly formed ring, with concomitant migration of the prenyl group to the indole C-2 position. The alanine analogue of tryprostatin B was also prepared using a similar sequence. The successful implementation of this strategy strengthens the case for a biosynthetic route for the tryprostatins along similar lines.

[structure: see text] The structurally intriguing cell-cycle inhibitor spirotryprostatin A has been synthesized utilizing an azomethine ylide dipolar cycloaddition reaction as the key step. This pentacyclic alkaloid contains a prenylated tryptophan-derived oxindole moiety that has been created in a regiocontrolled and stereocontrolled manner in a single step.

A method of palladium-catalyzed asymmetric allylic substitution for synthesizing 2-substituted cyclohexenylamine derivatives was established. Treatment of a 2-silyloxymethylcyclohexenol derivative with ortho-bromo-N-tosylaniline in the presence of Pd(2)dba(3).CHCl(3) and (S)-BINAPO in THF afforded a cyclohexenylamine derivative with 84% ee in 80% yield. The Heck reaction was carried out to produce an indolenine derivative in good yield. Using this method, we synthesized indolenine derivative 7, which was recrystallized from EtOH to give an optically pure compound. From this compound, tetracyclic ketone 13, which should be a useful intermediate for the synthesis of indole alkaloids, could be synthesized. The total syntheses of (-)-dehydrotubifoline, (-)-tubifoline, and (-)-strychnine were achieved from 13. All ring constructions for the syntheses of these natural products were achieved using a palladium catalyst.

The synthesis of 2-substituted isomers of the meridianins, a familiy of bioactive indole alkaloids isolated from the tunicate Aplidium meridianum, was undertaken. The synthetic route comprises six steps, with a microwave promoted Fischer cyclization as the key reaction.

An efficient strategy is described for the total synthesis of the sarpagine-related indole alkaloids (-)-(E)16-epiaffinisine (1), (+)-(E)16-epinormacusine B (2), and (+)-dehydro-16-epiaffinisine (4). A key step employed the chemospecific and regiospecific hydroboration/oxidation at C(16)-C(17); this method has also resulted in the synthesis of (+)-dehydro-16-epinormacusine B (5). The oxy-anion Cope rearrangement followed by protonation of the enolate that resulted under conditions of kinetic control has been employed to generate the key asymmetric centers at C(15), C(16), and C(20) in alkaloid G (7) in a highly stereocontrolled fashion (>43:1). Conditions that favor control of the sarpagine stereochemistry at C(16) vs the epimeric ajmaline configuration at the same stereocenter have been determined. The formation of the required cyclic ether in 4, 5, and 7 was realized with complete control from the top face on treatment of the corresponding alcohols with DDQ/THF or DDQ/aq THF in excellent yields.

A short and general approach to the cis-3a-aryloctahydroindole alkaloids has been developed on the basis of a key stereocontrolled ZnBr(2)-catalyzed rearrangement of 2,3-aziridino alcohols. Two representative members, (+/-)-crinane and (+/-)-mesembrine, have been synthesized in 15% and 11% overall yields, respectively. [reaction: see text]

The first enantioselective total synthesis of a member of the okaramine family of bis-indole alkaloids, okaramine N (1), has been accomplished via intermediates 2-7, as outlined. The N-prenylated derivative of (S)-tryptophan methyl ester (2) was coupled with Fmoc-protected N-tert-prenylated tryptophan (3) to form the amide 4 in 70% yield. Pd(II)-mediated cyclization/rearrangement, a key step in the synthesis, transformed 4 into the indoloazacine 5 (44%), which was deprotected and cyclized in a single step to give the hexacyclic diketopiperazine 6 (95%). In the following novel and key sequence, 6 was transformed into 1: (1) selective ene reaction with N-methyltriazolinedione, (2) photooxidation of the remaining tert-prenylated indole subunit to provide 7, and (3) thermal retroene reaction of 7 to afford okaramine N (70% from 6).

A concise synthesis of (+)-geissoschizine (1), a biosynthetic precursor of a variety of monoterpenoid indole alkaloids, from d-tryptophan (19) was performed as a critical prelude to achieving the first biomimetic, enantioselective synthesis of the sarpagine alkaloid (+)-N(a)-methylvellosimine (5). The approach to (+)-geissoschizine was designed to address the dual problems of stereocontrolled formation of the E-ethylidene moiety and the correct relative configuration at C(3) and C(15). Key steps in the synthesis involve a vinylogous Mannich reaction to prepare the carboline 22, which has the absolute stereochemistry at C(3) corresponding to that in 1 and 5, and an intramolecular Michael addition that leads to the tetracyclic corynantheane derivative 24, which possesses the correct stereochemical relationship between C(3) and C(15). Compound 24 was then transformed into 27, the pivotal intermediate in the syntheses of 1 and 5, by a sequence that allowed the stereospecific introduction of the E-ethylidene moiety. Selective reduction of the lactam in 27 followed by removal of the C(5) carboxyl group by radical decarbonylation gave deformylgeissoschizine (2) that was converted into (+)-geissoschizine (1) by formylation. The common intermediate 27 was then converted via a straightforward sequence of reactions into the alpha-amino nitrile 39. The derived silyl enol ether 40 underwent ionization upon exposure to BF(3).OEt(2) to give the intermediate iminium ion 41 that then cyclized in a biomimetically inspired intramolecular Mannich reaction to deliver (+)-N(a)-methylvellosimine (5). This transformation provides experimental support for the involvement of such a cyclization as one of the key steps in the biosynthesis of the sarpagine and ajmaline alkaloids.

Tryptamine was subjected to a series of reactions with derivatives of L-Ala, L-Val that ended with final diketopiperazines 9 and 10, having (R) configuration on the newly created, via 1,4-chirality transfer, stereogenic center. On the other hand, when L-Pro was used the opposite chirality sense was formed at this position.

The manzamine alkaloids such as manzamine A, B, and C belongs to a unique family of cyctotoxic beta-carbline linked azacycles, which have been isolated from several marine sponges. Manzamine A has recently been shown to exhibit in vivo antimalarial activity against parasite Plasmodium berghei. Further progress was added recently by the isolation of the new and closely related members such as nakadomarin A, as well as an ingenious proposal for their biosynthetic pathway. Martefragin A, isolated from the Japan sea alga Martensia fragilis Harvey, has been shown to have a potent inhibitory activity against lipid peroxidation. Our recen, efforts to develop total synthesis entries to manzamine A, manzamine B, manzamine C, nakadomarin A, and martefragin A are presented.

[reaction: see text] The first stereospecific total synthesis of the sarpagine indole alkaloids (E)16-epiaffinisine (1), (E)16-epinormacusine B (2), and dehydro-16-epiaffinisine (4) has been completed; this method has also resulted in the synthesis of dehydro-16-epinormacusine B (5). The formation of the required ether in both 4 and 5 was realized with complete control from the top face on treatment of the corresponding alcohols with DDQ/THF in 98% and 95% yields, respectively.

An efficient synthesis of the antitumor alkaloid (+/-)-strychnofoline is documented. Key to the development of the highly convergent strategy delineated is the coupling of a cyclic imine with spiro[cyclopropan-1,3'-oxindole], which takes place in a highly diastereoselective manner. The ability to conduct annulation reactions of spirocyclopropyloxindoles with functionalized cyclic imines provides new avenues for the preparation of this important class of biologically active structures.