Showing papers on "Total synthesis published in 1998"

Enantioselective Total Synthesis of (−)-Taxol

Abstract: Enantioselective total synthesis of taxol has been accomplished. Coupling reaction of the optically pure A-ring hydroxy aldehyde with the aromatic C-ring fragment followed by Lewis acid mediated eight-membered B-ring cyclization gave the desired ABC endo-tricarbocycle. The C-ring moiety of this product was reduced under Birch conditions to the cyclohexadiene derivative, which was oxygenated by singlet oxygen from the convex β-face to give the C4β,C7β-diol stereoselectively. For introduction of the C19-methyl, the cyclopropyl ketone was prepared via cyclopropanation of the C-ring allylic alcohol or conjugate addition of a cyano group to the C-ring enone. Reductive cleavage of the cyclopropane ring followed by isomerization of the resulting enol to the corresponding ketone gave the crucial synthetic intermediate containing the C19-methyl group. Regioselective transformation of three hydroxyl groups of this intermediate, conversion of the C4-carbonyl group to the allyl chloride, and introduction of the C10-o...

Total Synthesis of Roseophilin

Abstract: The first total synthesis of the antitumor agent roseophilin 1 is reported. Its intricate macrotricyclic core 2 is obtained by means of a new palladium-catalyzed manifold for the formation of ansa-bridged pyrroles which proceeds via vinyl oxirane 8 and allyl lactone 11 as key intermediates. After conversion of the latter into pyrrolophane 14, a base-induced elimination of the sulfone group followed by the Michael addition of a zincate onto the resulting enone 18 installs the isopropyl substituent in a stereoselective manner. The pyrrolylfuran side chain 3 of roseophilin is prepared from 4-methoxy-2(5H)-furanone (24) and methyl 4-chloropyrrole-2-carboxylate (26) as the starting materials. The appropriate building blocks 25a and 28 derived thereof are combined via a sequence comprising a directed metal−halogen exchange reaction, transmetalation of the resulting lithiopyrrole to the corresponding organozinc compound, a palladium-catalyzed cross coupling of the latter, and a subsequent acid-catalyzed closure ...

Total Synthesis of (+)-Discodermolide

Abstract: The total synthesis of (+)-discodermolide is described. The approach involves assemblage of three key stereotriad subunits through addition of nonracemic allenyltin, -indium, and -zinc reagents to (S)-3-silyloxy-2-methylpropanal derivatives, followed by reduction of the resulting anti,syn- or syn,syn-homopropargylic alcohol adducts to the (E)-homoallylic alcohols and subsequent Sharpless epoxidation. Addition of methyl cuprate reagents or Red-Al to the resultant epoxy alcohols yielded the key precursors, alkyne 4, aldehyde 9, and alcohol 24. Addition of alkyne 4 (as the lithio species 10) to aldehyde 9 afforded the propargylic alcohol 11 as the major stereoisomer. Lindlar hydrogenation and installation of appropriate protecting groups led to aldehyde 17. This was converted to the (Z)-vinylic iodide 18 upon treatment with α-iodoethylidene triphenylphosphorane. Suzuki coupling of this vinylic iodide with a boranate derived from iodide 25 led to the coupled product 27 with the complete carbon backbone of (+)...

Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Mo-Catalyzed Chromene Formation in Synthesis. Enantioselective Total Synthesis of the Antihypertensive Agent (S,R,R,R)-Nebivolol

Abstract: The first enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol (3) is described. The synthesis includes the efficient (EBTHI)Zr-catalyzed kinetic resolutions of cycloheptenyl styrenyl ethers 8 and 16, which are subsequently treated with 4 mol % Mo(CHCMe2Ph)(N(2,6-(i-Pr)2C6H3))(OCMe(CF3)2)2 to afford chiral nonracemic 2-substituted chromenes (R,R)-9 and (S,R)-17. Since the present retrosynthetic analysis dissects the molecule into two chromene fragments, both the (R) and (S) antipodes of (EBTHI)Zr catalyst are required. Accordingly, Buchwald's efficient resolution process is used to resolve rac-(EBTHI)ZrCl2 (from catalytic hydrogenation of commercially available rac-(EBI)ZrCl2), such that the two requisite transition metal chiral catalysts are obtained by a single process. Other noteworthy features of the synthesis include a highly efficient, regio- and stereoselective Pd-catalyzed opening of cyclic allylic epoxide 7 with diaryloxystannane 15 and a photochemical modification o...

Total Synthesis and Immunosuppressive Activity of (−)-Pateamine A and Related Compounds: Implementation of a β-Lactam-Based Macrocyclization

Abstract: The asymmetric synthesis of the potent immunosuppressive agent (−)-pateamine A isolated from the marine sponge Mycale sp. is described. A key strategy employed in the synthesis was a β-lactam-based macrocyclization to form the 19-membered dilactone macrolide. The synthesis confirms the relative and absolute stereochemistry as 3R,5S,10S,24S and sets the stage for studies into the mechanism of action of pateamine A. Other studies and findings made in the course of the synthesis and described herein include the following: (1) a Stille coupling can be competitive with π-allyl formation, (2) SmI2 effects a mild N−O cleavage of N-benzyloxy-β-lactams, (3) the synthesis of a pateamine A-dexamethasone hybrid molecule for use in a yeast three-hybrid assay was accomplished, and (4) IC50 values were determined for synthetic and natural pateamine A and related compounds in the interleukin 2 reporter gene assay.

Oxidative Intramolecular Phenolic Coupling Reaction Induced by a Hypervalent Iodine(III) Reagent: Leading to Galanthamine-Type Amaryllidaceae Alkaloids

Abstract: By extending our oxidative phenol-coupling reactions using a hypervalent iodine(III) reagent, a versatile synthetic procedure for the galanthamine-type Amaryllidaceae alkaloids was accomplished. The first total synthesis of (±)-sanguinine and the total syntheses of (±)-galanthamine, (±)-narwedine, (±)-lycoramine, and (±)-norgalanthamine were also successfully carried out.

The First Total Syntheses of Ircinol A, Ircinal A, and Manzamines A and D.

Abstract: In 1986, Higa, Jefford, and co-workers reported the isolation of a structurally novel polycyclic alkaloid, manzamine A, 1, from a sponge harvested near the coast of Okinawa.1 The unique structure of 1 consists of a β-carboline heterocycle attached to a novel pentacyclic diamine core containing both eight- and thirteen-membered rings on a pyrrolo[2,3-i]isoquinoline framework. The cytotoxic activity (IC50 = 0.07 µg/mL against P-388 mouse leukemia cells) and unique structure of 1 have stimulated considerable interest and activity directed toward the total synthesis of manzamine A which has not yet been successfully achieved to date.2 The intramolecular vinylogous amide photoaddition/fragmentation/Mannich closure sequence that we have developed has been applied to the stereoselective synthesis of complex structural types including mesembrine and the aspidosperma alkaloids from simple precursors.3 We have described the application of this methodology to the construction of the tetracyclic core of the manzamine alkaloids, in which the single stereocenter on the unsaturated eight-membered ring template 2 dictates all of the requisite stereochemical relationships embodied in 3, which represents the tetracyclic core of manzamine A.4 Outlined herein is the extension of these preliminary investigations to the first total synthesis of manzamine A.

Some recent applications of olefin metathesis in organic synthesis: A review

Abstract: A review is given of a selection of papers published in the past year in this rapidly expanding field. Such papers may be divided into four groups: (i) those in which ring-closing metathesis (RCM) has been used as a key step in the total synthesis of a natural product: ( R )-(+)-lasiodiplodin, dactylol, (−)-stemoamide, and epothilone A; (ii) those in which RCM has been used to make a sub-unit of a natural product: the marine toxins brevetoxin B, brevetoxin A, and maitotoxin; (iii) those in which RCM has been used to make compounds of known biological activity: fluvirucin B 1 (Sch 38516); (iv) those in which metathesis reactions have been used to make compounds of potential synthetic importance: crown ethers, aza sugars (polyhydroxylated pyrrolidines), β -lactams, chromenes, and aminoacids. The catalysts used have been one of the following four metal carbene complexes: the Schrock catalyst Mo(CHCMe 2 Ph)(NC 6 H 3 -2,6- i -Pr 2 )[OCMe(CF 3 ) 2 ] 2 ; the Grubbs catalysts Ru(CHCHCPh 2 )Cl 2 (PCy 3 ) 2 and Ru(CHPh)Cl 2 (PCy 3 ) 2 , where Cy=cyclohexyl; and the Tebbe reagent which behaves as Ti(CH 2 )Cp 2 , where Cp=cyclopentadienyl. In this paper these are denoted by Mo-1, Ru-1, Ru-2, and Ti-1, respectively. Ti-1 is especially useful for effecting RCM by the carbonyl–olefination reaction, while the RCM of enynes, catalyzed by Ru-2, is another valuable metathesis reaction.

Asymmetric Synthesis of Bryostatin 2.

Abstract: The potent bryostatin antitumor agents are currently in phase II clinical trials for the treatment of a variety of forms of cancer. Aldol reactions and directed reductions are among the essential steps for the formation of fragments A-C in the total synthesis of the title compound. Coupling of these fragments by sulfone-based olefination and alkylation reactions was followed by macrocyclization and introduction of the enoate moieties on rings B and C.

Total Synthesis of Vancomycin Aglycon—Part 3: Final Stages

Abstract: A triazene-based synthetic strategy for the construction of the complex biaryl ethers and a Suzuki coupling reaction were the key steps in the synthesis of precursor 1 of the aglycon of vancomycin, which already contains the complete skeleton of the target compound. The cleavage of the triazene unit from the D ring and the removal of the other protecting groups led to the aglycon of vancomycin. These strategies should be particularly valuable for the synthesis of other naturally occurring glycopeptide antibiotics and offer opportunities for the synthesis of combinatorial libraries of compounds of the vancomycin family for chemical biology studies.

Total Synthesis of Vancomycin Aglycon-Part 2: Synthesis of Amino Acids 1-3 and Construction of the AB-COD-DOE Ring Skeleton.

Abstract: A triazene-based synthetic strategy for the construction of the complex biaryl ethers and a Suzuki coupling reaction were the key steps in the synthesis of precursor 1 of the aglycon of vancomycin, which already contains the complete skeleton of the target compound. The cleavage of the triazene unit from the D ring and the removal of the other protecting groups led to the aglycon of vancomycin. These strategies should be particularly valuable for the synthesis of other naturally occurring glycopeptide antibiotics and offer opportunities for the synthesis of combinatorial libraries of compounds of the vancomycin family for chemical biology studies.

Total Synthesis of (±)-Methyl Atis-16-en-19-oate via Homoallyl−Homoallyl Radical Rearrangement

Abstract: Total synthesis of (±)-methyl atis-16-en-19-oate (5c), a tetracyclic diterpenoid possessing a bicyclo[2.2.2]octane ring system, was accomplished. Intramolecular Diels−Alder reaction of tetraene 14 was employed in a construction of kaurene skeleton 13. The pivotal step involved a homoallyl−homoallyl radical rearrangement process of (±)-methyl 12-hydroxykaur-16-en-19-oate monothioimidazolide 12, which led to 5c in good yield. Interestingly, treatment of methyl 12-oxo-kaur-16-en-19-oate 30 with hydrazine monohydrate in the presence of KOH in bis(ethylene glycol) at 200 °C resulted in cyclopropanation to furnish, directly, trachyloban-19-oic acid (4b), together with kaur-16-en-19-oic acid (6b).

Enantioselective Total Synthesis of (−)-Chlorothricolide via the Tandem Inter- and Intramolecular Diels−Alder Reaction of a Hexaenoate Intermediate

Abstract: An enantioselective total synthesis of (−)-chlorothricolide (1) has been completed via a route involving the tandem inter- and intramolecular Diels−Alder (IMDA) reaction of hexaenoate 19 and the chiral dienophile (R)-12. This reaction, which establishes seven asymmetric centers in a single operation, is feasible only by virtue of the high diastereofacial and exo selectivity of dienophile 12. The C(9)-trimethylsilyl steric directing group of 19 also plays a key role by controlling the stereochemical course of the IMDA reaction leading to the bottom half octahydronaphthalene unit. Hexaenoate 19 was prepared in 32% overall yield by a 10-step sequence starting from the known acetylenic ketone 33. Key steps include the asymmetric reduction of 33 using Alpine Borane (up to 94% ee), the Suzuki cross coupling of α-iodo vinylsilane 20 with vinylboronic acid 21, and the Horner-type olefination of aldehyde 41 with dienylic phosphonate 22. The key tandem inter-intramolecular Diels−Alder reaction was performed by heat...

Total Synthesis of Macrolactin A with Versatile Catalytic, Enantioselective Dienolate Aldol Addition Reactions.

Abstract: A highly convergent total synthesis of macrolactin A (1) utilizes modern asymmetric catalytic C–C coupling methods. The longest linear sequence in the route is 16 steps with an average yield of 86% per step. This total synthesis is valuable, because 1, which has been shown to possess activity against HIV, is not readily accessible from its natural source, a taxonomically unclassified deep-sea bacterium.

Total Synthesis of Himastatin: Confirmation of the Revised Stereostructure.

Abstract: A stereoisomer of the natural product and not himastatin, an unusual dimeric depsipeptide with promising antibiotic and antitumor properties, was obtained from pyrroloindoline anti-cis-1 This result led to a revision of the proposed stereostructure The new stereostructure was confirmed by the total synthesis, which involves stereoselective access to the pyrroloindoline syn-cis-1 and the 5-hydroxypiperazic acid subunit and features a Stille coupling for the formation of the central carbon-carbon bond

Asymmetric Total Synthesis of Callystatin A: Asymmetric Aldol Additions with Titanium Enolates of Acyloxazolidinethiones

Abstract: A number of highly cytotoxic polyketides, including the anguinomycins,1 leptofuranins,2 leptomycin,3 and kazusamycin,4 having similar gross chemical structures have been isolated from Streptomyces strains. Recently, a structurally related polyketide, callystatin A 1, was isolated from the marine sponge, Callyspongia truncata, in the Nagasaki Prefecture.5 Callystatin A shows remarkable in vitro cytotoxicity (IC50 ) 0.01 ng/mL) against KB cells. The relative and absolute stereostructure of callystatin A was established by a combination of spectroscopic methods and chemical synthesis.5-7 The limited quantities of callystatin A available from natural sources, as well as the possibility for carrying out syntheses and structure elucidation of the related antitumor antibiotics, prompted us to pursue a total synthesis of callystatin A.8 Here we disclose the asymmetric total synthesis of (-)-callystatin A exploiting our recently developed asymmetric aldol protocol with chlorotitanium enolates of acyl oxazolidinethiones.9 Strategically, E-selective olefination10 of aldehyde 2 (Scheme 1) with the phosphorane derived from tributylphosphonium salt 3 appeared to offer the most convergent assembly of callystatin A. Aldehyde 2 representing C1 to C12 would be constructed from a similar olefination between the masked pyranone aldehyde 4 (Scheme 2) and phosphonium salt 5 (Scheme 3). The C13 to C22 propionate fragment 3 was to be constructed through consecutive asymmetric aldol additions9 employing acyl oxazolidinethione 6 (Scheme 4). The synthesis of aldehyde 4 began with S-glycidol 7 as illustrated in Scheme 2. Protection of S-glycidol as its TBDPS ether followed by copper-catalyzed epoxide opening with vinylmagnesium bromide provided the alcohol 8 in 85% overall yield. Conversion of the secondary alcohol to the isopropoxy propenyl ether provided a mixed acetal which was exposed to the Grubbs catalyst11 to effect ring-closing metathesis to dihydropyran 9 (71% overall). Removal of the TBPDS protecting group with n-Bu4-

The Total Synthesis of Spirotryprostatin A.

Abstract: Eight concise steps suffice for the first total synthesis of the title compound 1, which inhibits the transitions from the G2 and M phases into the next phases of the cell cycle. Key steps in the synthesis are a stereocontrolled oxidative rearrangement of an indole to form the chiral spiroindolinone nucleus and a regioselecitve sulfoxide elimination.

Total Synthesis of (−)-Solanapyrone A via Enzymatic Diels−Alder Reaction of Prosolanapyrone

Abstract: The syntheses of prosolanapyrones I (6) and II (7) via the aldol reactions of pyrone and dienal segments have been achieved in five steps in 31% overall yield for 6 and seven steps in 5% overall yield for 7. An improved synthetic route starting from vinylpyrone 27 provided 7 in 11 steps in 12% overall yield. The enzymatic Diels−Alder reaction of 7 affords (−)-solanapyrone A (1) with high enantioselectivity and with good exo-selectivity, which is difficult to attain by chemical methods. In addition, a crude enzyme preparation from Alternaria solani has been used to perform a kinetic resolution of (±)-3.

A New Magnesium-Catalyzed Doubly Diastereoselective anti-Aldol Reaction Leads to a Highly Efficient Process for the Total Synthesis of Lactacystin in Quantity

Abstract: A new process is described for metal-catalyzed doubly diastereoselective Mukaiyama aldol coupling of a chiral tertiary α-amino aldehyde and an achiral silyl enol ether to form selectively an anti-aldol product. The metal requirement is strict, since of several salts tested only MgI2 functions as an effective catalyst. The MgI2-catalyzed aldol greatly facilitates the total synthesis of lactacystin (1) and the corresponding β-lactone (2), microbial products which are potent and selective inhibitors of proteasome function, cell cycle progression, and gene regulation. The method also allows the synthesis of analogues of 1 in which the 7β-methyl group of lactacystin is replaced by higher alkyl or aralkyl groups. Detailed experimental procedures are presented for the optimized synthesis of lactacystin on the scale required to meet the current needs of many hundreds of biological laboratories.

Total Synthesis of Eleutherobin and Eleuthosides A and B

Abstract: The total synthesis of the cytotoxic marine natural products eleutherobin (1) and eleuthosides A (2) and B (3) is described. The strategy involves glycosidation of the (+)-carvone-derived intermediate 7 with the arabinose-derived trichloroacetimidate 9 followed by base-induced ring closure and elaboration to afford the dihydroxy eneynone 19. Selective hydrogenation of 19 led to the generation and intramolecular collapse of dienone 20 furnishing 21 and thence 22 with the required structural framework of the target molecules. Finally, esterification with mixed anhydride 24 followed by deprotection gave eleutherobin (1) which served as a precursor to eleuthosides A (2) and B (3). The α-glycoside anomer of eleutherobin, compound 27, was also synthesized by application of the developed chemistry, demonstrating the flexibility of the sequence in generating designed analogues for biological screening.

The antibody catalysis route to the total synthesis of epothilones

Abstract: An efficient monoclonal aldolase antibody that proceeds by an enamine mechanism was generated by reactive immunization. Here, this catalyst has been used in the total synthesis of epothilones A (1) and C (3). The starting materials for the synthesis of these molecules have been obtained by using antibody-catalyzed aldol and retro-aldol reactions. These precursors were then converted to epothilones A (1) and C (3) to complete the total synthesis.

Asymmetric Total Synthesis of (+)-Tolterodine, a New Muscarinic Receptor Antagonist, via Copper-Assisted Asymmetric Conjugate Addition of Aryl Grignard Reagents to 3-Phenyl-prop-2-enoyl-oxazolidinones

Abstract: Asymmetric Total Synthesis of (+)-Tolterodine, a New Muscarinic Receptor Antagonist, via Copper-Assisted Asymmetric Conjugate Addition of Aryl Grignard Reagents to 3-Phenyl-prop-2-enoyl-oxazolidinones

The Total Synthesis of Eleutherobin: A Surprise Ending.

Abstract: An "sp2 -sp3 Stille coupling" of the vinyl triflate 1 and the stannyl compound 2 is a key step toward the completion of the total synthesis of eleutherobin, a natural product exhibiting taxol-like cytotoxic activity.