Showing papers on "Total synthesis published in 2002"
TL;DR: The approach differs strategically from previous routes and contains built-in flexibility necessary to access many other members of the Aspidosperma family of indole alkaloids, which is readily adapted to the asymmetric synthesis of these compounds.
Abstract: Described is a concise, highly stereocontrolled strategy to the Aspidosperma family of indole alkaloids, one that is readily adapted to the asymmetric synthesis of these compounds. The strategy is demonstrated by the total synthesis of (±)-tabersonine (rac-1), proceeding through a 12-step sequence. The basis for this approach was provided by a highly regio- and stereoselective [4 + 2] cycloaddition of 2-ethylacrolein with 1-amino-3-siloxydiene developed in our laboratory. Subsequent elaboration of the initial adduct into the hexahydroquinoline DE ring system was accomplished efficiently by a ring-closing olefin metathesis reaction. A novel ortho nitrophenylation of an enol silyl ether with (o-nitrophenyl)phenyliodonium fluoride was developed to achieve an efficient, regioselective introduction of the requisite indole moiety. The final high-yielding conversion of the ABDE tetracycle into pentacyclic target rac-1 relied on intramolecular indole alkylation and regioselective C-carbomethoxylation. Our approac...
230 citations
TL;DR: The remarkable conversion of 5 --> 6 can be rationalized by the mechanistic pathway shown in Scheme 2 that involves a multistep sequence which includes palladation, cyclization, and rearrangement.
Abstract: The first synthesis of (+)-austamide (1), (+)-deoxyisoaustamide (2), and (+)-hydratoaustamide (10) by a very direct route is described (Scheme 1). Starting from tryptophan methyl ester (3) intermediate 5 is generated in two steps in >98% overall yield. The key step in the synthesis is a novel cyclization of 5 involving organopalladium intermediates which gives the dihydroazocine 6. From this key intermediate the target structures are accessible in just a few steps as shown in Scheme 1. The remarkable conversion of 5 --> 6 can be rationalized by the mechanistic pathway shown in Scheme 2 that involves a multistep sequence which includes palladation, cyclization, and rearrangement.
230 citations
TL;DR: In this paper, a straightforward synthesis of ecteinascidin 743 from readily available l-glutamic acid as a single chiral source was accomplished from a simple linear combination of Heck reaction between a diazonium salt and an enamide, oxidative cleavage of the resulting alkene, and intramolecular ortho substitution of the phenol by an aldehyde.
Abstract: A straightforward synthesis of ecteinascidin 743 was accomplished from readily available l-glutamic acid as a single chiral source. Our novel synthesis features a concise and convergent approach for construction of the B-ring, consisting of a sequence involving a stereoselective Heck reaction between a diazonium salt and an enamide, oxidative cleavage of the resulting alkene, and intramolecular ortho substitution of the phenol by an aldehyde.
228 citations
TL;DR: The first total synthesis of the biologically significant bis-indole alkaloid dragmacidin D has been achieved thanks to a series of palladium-catalyzed Suzuki cross-coupling reactions that furnished the core structure of the complex guanidine- and aminoimidazole-containing dragmacids.
Abstract: The first total synthesis of the biologically significant bis-indole alkaloid dragmacidin D (5) has been achieved. Thermal and electronic modulation provides the key for a series of palladium-catalyzed Suzuki cross-coupling reactions that furnished the core structure of the complex guanidine- and aminoimidazole-containing dragmacidins. Following this crucial sequence, a succession of meticulously controlled final events was developed leading to the completion of the natural product.
210 citations
TL;DR: The enantioselective synthesis of endothelin-A antagonist ABT-546 has been accomplished via the discovery and development of a highly selective catalytic asymmetric conjugate addition of ketoesters to nitroolefins through a complex of bis(oxazoline)-Mg(OTf)(2) complex with an amine cocatalyst.
Abstract: The enantioselective synthesis of endothelin-A antagonist ABT-546 has been accomplished via the discovery and development of a highly selective catalytic asymmetric conjugate addition of ketoesters to nitroolefins. Employing just 4 mol % bis(oxazoline)-Mg(OTf)(2) complex with an amine cocatalyst, we obtained the product nitroketone with 88% selectivity at the aryl-bearing stereocenter and in good yield on scales ranging to 13 mol. The effects of ligand structure, metal salt, and solvent on the reaction are described. Particularly important to the reaction is the water content. While water is necessary during the generation of the catalyst, the water must be then removed to maximize stereoselectivity and reactivity. The reaction has been extended to other dicarbonyl substrates, and a variety of substitution patterns are tolerated on the nitroolefin partner. The reaction has also been employed in the synthesis of the antidepressant rolipram. Investigations relating to the mechanism of the reaction are also described.
207 citations
TL;DR: The total synthesis of the isoquinoline natural product decumbenine B has been accomplished in seven steps and 20% overall yield by employing this palladium-catalyzed coupling and cyclization methodology.
Abstract: Monosubstituted isoquinolines and pyridines have been prepared in good to excellent yields via coupling of terminal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in the presence of a palladium catalyst and subsequent copper-catalyzed cyclization of the intermediate iminoalkynes. In addition, isoquinoline heterocycles have been prepared in excellent yields via copper-catalyzed cyclization of iminoalkynes. The choice of cyclization conditions is dependent upon the nature of the terminal acetylene that is employed, as only aryl and alkenyl acetylenes cyclize under the palladium-catalyzed reaction conditions that have been developed. However, aryl-, vinylic-, and alkyl-substituted acetylenes undergo palladium-catalyzed coupling and subsequent copper-catalyzed cyclization in excellent yields. The total synthesis of the isoquinoline natural product decumbenine B has been accomplished in seven steps and 20% overall yield by employing this palladium-catalyzed coupling and cyclization methodology.
198 citations
TL;DR: The inter- and intramolecular Diels-Alder reactions of in situ generated masked o-benzoquinones produced cycloadducts in excellent selectivities and the efficacy of the methodology is demonstrated by several examples of the total synthesis of natural products.
Abstract: An account of the synthetic utility of masked o-benzoquinones is provided. The inter- and intramolecular Diels-Alder reactions of in situ generated masked o-benzoquinones produced cycloadducts in excellent selectivities. New synthetic methodologies have been developed for the synthesis of highly substituted ring systems including bicyclo[2.2.2]octenones, oxatricycles, triquinanes, polysubstituted cyclohexanes, and bicyclo[4.2.2]decenones with complete stereocontrol from easily accessible 2-methoxyphenols via the Diels-Alder reaction of masked o-benzoquinones. Other reactions of adducts derived from masked o-benzoquinones are also described. The efficacy of our methodology is demonstrated by several examples of the total synthesis of natural products.
197 citations
TL;DR: A stereocontrolled total synthesis of (+)-vinblastine was accomplished, featuring preparations of the two indole units by means of a novel indole synthesis via radical cyclization of thioanilide, and a stereoselective coupling of these units.
Abstract: A stereocontrolled total synthesis of (+)-vinblastine was accomplished, featuring preparations of the two indole units by means of a novel indole synthesis via radical cyclization of thioanilide, and a stereoselective coupling of these units.
192 citations
TL;DR: The stereostructure of pinolidoxin, a potent inhibitor of induced phenylalanine ammonia lyase (PAL) activity, is established, making clear that a previous study dealing with the relative and absolute stereochemistry of this phytotoxic agent cannot be correct.
Abstract: A concise approach to a family of potent herbicidal 10-membered lactones is described on the basis of ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. This includes the first total syntheses of herbarumin I (1) and II (2) as well as the synthesis of several possible macrolides of the pinolidoxin series. A comparison of their spectral and analytical data with those of the natural product allowed us to establish the stereostructure of pinolidoxin, a potent inhibitor of induced phenylalanine ammonia lyase (PAL) activity, as shown in 46. This finding, however, makes clear that a previous study dealing with the relative and absolute stereochemistry of this phytotoxic agent cannot be correct. An important aspect from the preparative point of view is the fact that the stereochemical outcome of the RCM reaction can be controlled by the choice of the catalyst. Thus, use of the ruthenium indenylidene complex 16 always leads to the corresponding (E)-alkenes, whereas the secon...
189 citations
TL;DR: These experiments clearly demonstrated that the geometry of the internal double bond and the presence of an electron-withdrawing group on the diene moiety were essential for the facile and stereoselective formation of the desired cycloadducts.
Abstract: As a prelude to undertaking the total syntheses of the complex manzamine alkaloids, a series of model studies were conducted to establish the scope and limitations of intramolecular [4 + 2] cycloadditions of N-acylated vinylogous ureas with the trienic substrates 17a,b, 28a,b, and 34. These experiments clearly demonstrated that the geometry of the internal double bond and the presence of an electron-withdrawing group on the diene moiety were essential for the facile and stereoselective formation of the desired cycloadducts. The enantioselective syntheses of the manzamine alkaloids ircinol A (75), ircinal A (5), and manzamine A (1) were then completed by employing a convergent strategy that featured a novel domino Stille/Diels-Alder reaction to construct the tricyclic ABC ring core embodied in these alkaloids. Thus, the readily accessible chiral dihydropyrrole 58 was first converted in a single chemical operation into the key tricyclic intermediate 60. Two ring-closing metathesis reactions were then used to form the 13- and 8-membered rings leading to Z-72 and 74, the latter of which was quickly elaborated into ircinal A (5) via ircinol A (75). The synthetic 5 thus obtained was converted into manzamine A (1) following literature precedent. This concise synthesis of ircinal A required a total of 24 operations from commercially available starting materials with the longest linear sequence being 21 steps.
162 citations
TL;DR: The total synthesis of the novel antitumor agent callipeltoside A, as well as several analogues, is accomplished and allows assignment of the stereochemistry not previously established and the excellent chemo- and regioselectivity highlights the synthetic potential of this new ruthenium catalyzed process.
Abstract: The total synthesis of the novel antitumor agent callipeltoside A, as well as several analogues, is accomplished and allows assignment of the stereochemistry not previously established. A convergent strategy is employed wherein the target is dissected into three units-the core macrolactone, the sugar callipeltose, and a cyclopropyl bearing chain. The strategy for the synthesis of the macrolactone derives from employment of diastereoselective aldol reactions that emanate from an 11 carbon piece. The stereochemistry of the latter derives from the chiral pool and two asymmetric reactions-a ketone reduction using CBS-oxazaborolidine and a Pd catalyzed asymmetric allylic alkylation (AAA). The novelty of the latter protocol is its control of regioselectivity as well as absolute configuration. The trisubstituted olefin is generated using an alkene-alkyne coupling to create a trisubustituted olefin with complete control of geometry. The excellent chemo- and regioselectivity highlights the synthetic potential of this new ruthenium catalyzed process. The macrolactonization employs in situ formation of an acylketene generated by the thermolysis of a m-dioxolenone. Two strategies evolved for attachment of the side chain-one based upon olefination and a second upon olefin metathesis. The higher efficiency of the latter makes it the method of choice. A novel one pot olefin metathesis-Takai olefination protocol that should be broadly applicable is developed. The sugar is attached by a glycosylation by employing the O-trichloroacetimidate. This route provided both C-13 epimers of the macrolactone by using either enantiomeric ligand in the Pd AAA reaction. It also provided both trans-chlorocyclopropane diastereomers of callipeltoside A which allows the C-20 and C-21 configuration to be established as S and R, respectively. The convergent nature of the synthesis in which the largest piece, the macrolatone, require only 16 linear steps imparts utility to this strategy for the establishment of the structure-activity relationship. Initial biological testing demonstrates the irrelevance of the chloro substituent and the necessity of the sugar.
TL;DR: The antitumor agent (-)-rhazinilam was synthesized in three major steps, namely the pyrrole synthesis, selective C[bond]H bond activation, and direct macrolactam formation.
Abstract: The antitumor agent (−)-rhazinilam was synthesized in three major steps, namely the pyrrole synthesis, selective C−H bond activation, and direct macrolactam formation. The key step involved asymmetric C−H bond functionalization (dehydrogenation) of the diethyl group segment in intermediate 6. This was achieved by the attachment of chiral platinum complexes to the proximal nitrogen atom. A high degree of selectivity (60−75% ee) was achieved via the use of oxazolinyl ketone chiral auxiliaries.
TL;DR: A concise synthesis of the guanidine alkaloids, (+/-)-martinelline and (+/-- Martinellic acid, using a protic acid catalyzed 2:1 hetero Diels-Alder coupling reaction between N-Cbz 2-pyrroline and methyl 4-aminobenzoate is described.
TL;DR: The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved as discussed by the authors, which includes a convergent union of the ABC and EFGH ring fragments via a developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and a late-stage introduction of the sensitive triene side chain by use of Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling.
Abstract: The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B --> AB --> ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which SmI(2)-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1).
TL;DR: The manzacidins represent a small family of structurally unique secondary metabolites found only sparingly in nature as discussed by the authors, and the path to these targets showcases for the first time the distinct power of catalytic C−H bond amination methodology for simplifying problems in alkaloid total synthesis.
Abstract: The manzacidins represent a small family of structurally unique secondary metabolites found only sparingly in nature Efforts to probe the pharmacological profile of these intriguing bromopyrrole alkaloids have been precluded by a deficiency of available material Access to substantive quantities of both manzacidins A and C is now made possible through a rapid, enantioselective, and highly efficient synthesis that is described herein The path to these targets showcases for the first time the distinct power of our catalytic C−H bond amination methodology for simplifying problems in alkaloid total synthesis Application of this chemistry enables the facile and enantiospecific installation of tetrasubstituted carbinolamine stereocenters, functionality common to all of the manzacidins The requisite materials for implementing our plan are assembled using modern tools for catalytic asymmetric synthesis that include both carbonyl-ene and directed hydrogenation reactions In addition, a new protocol for tetrahy
TL;DR: An efficient synthesis of the antitumor alkaloid (+/-)-strychnofoline is documented and 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.
Abstract: 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.
TL;DR: The preparation of the diastereomerically pure beta-tetralone ketal 4 is reported and the key step in this synthesis was the bis-intramolecular cyclization of keto aldehyde 2 to give the tetracyclic intermediate 20.
Abstract: The preparation of the diastereomerically pure beta-tetralone ketal 4 is reported. Intramolecular alkylidene C-H insertion followed by hydrolysis of 4 proceeded to give the enantiomerically pure cyclopentene 15. The key step in this synthesis was the bis-intramolecular cyclization of keto aldehyde 2 to give the tetracyclic intermediate 20. Enone 20 was converted over several steps to (-)-morphine 1.
TL;DR: The first total syntheses of higher-order members of the polypyrrolidinoindoline alkaloid family are reported and rigorously confirms its relative and absolute configuration.
Abstract: The first total syntheses of higher-order members of the polypyrrolidinoindoline alkaloid family are reported. The synthesis of quadrigemine C (1) and psycholeine (3) begins with synthetic meso-chimonanthine (4), which is synthesized from commercially available oxindole and isatin in 13 steps and 35% overall yield. Double Stille cross coupling of diiodide 7, available in three steps from 4, with vinylstannane 8 produces dibutenanilide 9. Double catalytic asymmetric Heck cyclization of 9 simultaneously installs the two peripheral quaternary stereocenters and desymmetrizes this advanced meso precursor to deliver the chiral, decacyclic intermediate 11 in 62% yield and 90% ee. In two additional steps, 11 is converted to 1, which upon treatment with acid generates 3. The synthesis of quadrigemine C (1), which rigorously confirms its relative and absolute configuration, was executed in 19 linear steps (2% overall yield) from commercially available starting materials.
TL;DR: The first total synthesis of (+/-)-ingenol has been achieved with key features of the use of a highly diastereoselective Michael reaction to fix the C-11 methyl stereochemistry and the incorporation of the dimethylcyclopropane via diasterenetic carbene addition to the Delta13,14 olefin.
Abstract: The first total synthesis of (±)-ingenol has been achieved. The key features of the synthesis include the use of a highly diastereoselective Michael reaction to fix the C-11 methyl stereochemistry and the incorporation of the dimethylcyclopropane via diastereoselective carbene addition to the Δ13,14 olefin. The intramolecular dioxenone photoaddition-fragmentation sequence leads to the establishment of the critical C-8/C-10 trans intrabridgehead stereochemistry, a central challenge in the synthesis of ingenanes. The completion of the synthesis proceeds using the C-6α hydroxymethyl group as the sole handle for oxidation of seven contiguous carbon centers.
TL;DR: The enantioselective total synthesis of (-)-strychnine was accomplished through the use of the highly practical catalytic asymmetric Michael reaction as well as a tandem cyclization that simultaneously constructed B- and D-rings.
Abstract: The enantioselective total synthesis of (−)-strychnine was accomplished through the use of the highly practical catalytic asymmetric Michael reaction (0.1 mol % of (R)-ALB, more than kilogram scale, without chromatography, 91% yield and >99% ee) as well as a tandem cyclization that simultaneously constructed B- and D-rings (>77% yield). Moreover, newly developed reaction conditions for thionium ion cyclization, NaBH3CN reduction of the imine moiety in the presence of Lewis acid to prevent ring opening reaction, and chemoselective reduction of the thioether (desulfurization) in the presence of exocyclic olefin were pivotal to complete the synthesis. The described chemistry paves the way for the synthesis of more advanced Strychnos alkaloids.
TL;DR: In this paper, the title compound of merrilactone A was synthesized in 20 steps using a free radical cyclization of vinyl bromide 29 to afford 30, and the synthesis also features an efficient Diels−Alder reaction of 2,3-dimethylmaleic anhydride with 1-(tert-butyldimethylsiloxy)-butadiene.
Abstract: The total synthesis of the title compound has been accomplished in 20 steps. The key step is a free radical cyclization of vinyl bromide 29 to afford 30. The synthesis also features an efficient Diels−Alder reaction of 2,3-dimethylmaleic anhydride with 1-(tert-butyldimethylsiloxy)-butadiene. The oxetane moiety of merrilactone A is fashioned via a Payne-like rearrangement of a hydroxyepoxide (see 2 → 1).
TL;DR: Ring closing alkyne metathesis (RCAM) followed by Lindlar reduction of the resulting cycloalkynes 37 and 38 opens a convenient and stereoselective entry into this class of compounds.
Abstract: The first total synthesis of three naturally occurring cyclophane derivatives belonging to the turriane family of natural products is described. Their sterically hindered biaryl entity is formed by reaction of the Grignard reagent derived from aryl bromide 10 with the oxazoline derivative 18, and the macrocyclic tether of the targets is efficiently forged by ring closing metathesis. While conventional RCM catalyzed by the ruthenium-carbene complexes 33 or 34 invariably leads to the formation of mixtures of both stereoisomers with the undesirable (E)-alkene prevailing, ring closing alkyne metathesis (RCAM) followed by Lindlar reduction of the resulting cycloalkynes 37 and 38 opens a convenient and stereoselective entry into this class of compounds. RCAM can either be accomplished by using the tungsten alkylidyne complex [(tBuO)3 [triple bond] WCCMe3] or by means of a catalyst formed in situ from [Mo(CO)6] and para-trifluoromethylphenol. The latter method is significantly accelerated when carried out under microwave heating. Furthermore, the judicious choice of the protecting groups for the phenolic -OH functions turned out to be crucial. PMB-ethers were found to be compatible with the diverse reaction conditions en route to 3-5; their cleavage, however, had to be carried out under carefully optimized conditions to minimize competing O-C PMB migration. Turrianes 3-5 are shown to be potent DNA cleaving agents under oxidative conditions when administered in the presence of copper ions.
TL;DR: A Pd-catalyzed DYKAT on carbonates derived from Baylis-Hillman adducts, followed by a reductive Heck reaction, allows the enantio- and diastereoselective construction of dihydrobenzofurans in a very efficient manner.
Abstract: Baylis−Hillman adducts are easily accessible building blocks; the lack of asymmetric versions of the Baylis−Hillman reaction has however precluded their widespread use in asymmetric synthesis. A Pd...
TL;DR: The scope, generality, and mechanism of the Dess-Martin periodinane-mediated cyclization reaction of unsaturated anilides discovered during the total synthesis of the CP-molecules (phomoidrides A and B) are delineated.
Abstract: The scope, generality, and mechanism of the Dess−Martin periodinane-mediated cyclization reaction of unsaturated anilides discovered during the total synthesis of the CP-molecules (phomoidrides A and B) are delineated. A plethora of heterocyclic compounds are accessible by employing γ,δ-unsaturated amides (derived from anilines and carboxylic acids), urethanes, or ureas (derived from isocyanates and allylic alcohols and amines) as substrates. Optimization of the reaction led to room-temperature conditions, while isotope labeling studies allowed a mechanistic rationale for this cascade reaction.
TL;DR: All silicon protecting groups were removed by treatment of the penultimate intermediate 65 with TAS-F (tris(dimethylamino)sulfonium difluorotrimethylsilicate), thereby completing the total synthesis of (-)-bafilomycin A(1).
Abstract: A highly stereoselective total synthesis of (-)-bafilomycin A(1), the naturally occurring enantiomer of this potent vacuolar ATPase inhibitor, is described. The synthesis features the highly stereoselective aldol reaction of methyl ketone 8b and aldehyde 60c and a Suzuki cross-coupling reaction of the highly functionalized advanced intermediates 12 and 39. Vinyl iodide 12 was synthesized by a 14-step sequence starting from the readily available beta-alkoxy aldehyde 14, while the vinylboronic acid component 39 was synthesized by a nine-step sequence from beta-hydroxy-alpha-methyl butyrate 44 via a sequence involving the alpha-methoxypropargylation of chiral aldehyde 49 with the alpha-methoxypropargylstannane reagent 54. Syntheses of fragments 12 and 39 also feature diastereoselective double asymmetric crotylboration reactions to set several of the critical stereocenters. The Suzuki cross-coupling of 12 and 39 provided seco ester 40, which following conversion to the seco acid underwent smooth macrolactonization to give 41. The success of the macrocyclization required that C(7)-OH be unprotected. The Mukaiyama aldol reaction between aldehyde 60c and the TMS enol ether generated from 8b provided aldol 65 with high diastereoselectivity. Finally, all silicon protecting groups were removed by treatment of the penultimate intermediate 65 with TAS-F (tris(dimethylamino)sulfonium difluorotrimethylsilicate), thereby completing the total synthesis of (-)-bafilomycin A(1).
TL;DR: A new strategy was developed for the enantiospecific synthesis of aspidosperma alkaloids that involves a novel ketene-lactonization reaction of a chiral vinyl sulfoxide to efficiently set up the quaternary carbon center, and a tandem Michael addition-alkylation reaction sequence to form the polycyclic core structure.
Abstract: A new strategy was developed for the enantiospecific synthesis of aspidosperma alkaloids. The key steps involve a novel ketene-lactonization reaction of a chiral vinyl sulfoxide to efficiently set up the quaternary carbon center, and a tandem Michael addition-alkylation reaction sequence to form the polycyclic core structure. This new strategy was employed in the total synthesis of natural product (+)-aspidospermidine.