Showing papers on "Total synthesis published in 2009"

Impact of natural products on developing new anti-cancer agents

Abstract: 3.3.1. Potential of the “Metagenome” 3016 3.3.2. Cryptic Clusters in Bacteria and Fungi 3016 3.3.3. Cyanophytes 3017 3.3.4. Marine Microbes (Non-Cyanophytes) 3018 3.3.5. Extremophiles 3018 3.3.6. Microbial Symbionts 3019 3.3.7. Plant Endophytes 3020 3.3.8. Combinatorial Biosynthesis 3020 4. Development of Drugs from Natural Products 3020 4.1. Synthesis Based on Natural Products 3021 4.1.1. Derivatization and Semisynthesis 3021 4.1.2. Total Synthesis 3021 4.1.3. Diverted Total Synthesis 3021 4.2. Natural Product-Inspired Combinatorial Synthesis 3022

High‐Yielding Synthesis of the Anti‐Influenza Neuramidase Inhibitor (−)‐Oseltamivir by Three “One‐Pot” Operations

Abstract: Taking shortcuts: A remarkably short and high-yielding asymmetric total synthesis of (−)-oseltamivir takes advantage of organocatalysis and single-pot domino operations The target, known as the drug Tamiflu, is prepared efficiently in a short time, and also its derivatives can be synthesized effectively

Nine-step enantioselective total synthesis of (+)-minfiensine.

Abstract: An enantioselective total synthesis of the Strychnos alkaloid (+)-minfiensine has been accomplished. Prominent features of this synthesis include (i) a new enantioselective organocatalytic Diels−Alder/amine cyclization sequence to build the central tetracyclic pyrroloindoline framework in four steps from commercial materials and (ii) a 6-exo-dig radical cyclization to forge the final piperidinyl ring system. This total synthesis of (+)-minfiensine was completed in nine chemical steps and 21% overall yield.

Total synthesis of (+)-11,11'-dideoxyverticillin A.

Abstract: The fungal metabolite (+)-11,11'-dideoxyverticillin A, a cytotoxic alkaloid isolated from a marine Penicillium sp., belongs to a fascinating family of densely functionalized, stereochemically complex, and intricate dimeric epidithiodiketopiperazine natural products. Although the dimeric epidithiodiketopiperazines have been known for nearly 4 decades, none has succumbed to total synthesis. We report a concise enantioselective total synthesis of (+)-11,11'-dideoxyverticillin A via a strategy inspired by our biosynthetic hypothesis for this alkaloid. Highly stereo- and chemoselective advanced-stage tetrahydroxylation and tetrathiolation reactions, as well as a mild strategy for the introduction of the epidithiodiketopiperazine core in the final step, were developed to address this highly sensitive substructure. Our rapid functionalization of the advanced molecular framework aims to mimic plausible biosynthetic steps and offers an effective strategy for the chemical synthesis of other members of this family of alkaloids.

Total synthesis and study of 6-deoxyerythronolide B by late-stage C-H oxidation

Abstract: Among the frontier challenges in chemistry in the twenty-first century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. Oxidation reactions of C–H bonds, particularly when applied at late stages of complex molecule syntheses, hold special promise for achieving both these goals. Here we report a late-stage C–H oxidation strategy in the total synthesis of 6-deoxyerythronolide B (6-dEB), the aglycone precursor to the erythromycin antibiotics. An advanced intermediate is cyclized to give the 14-membered macrocyclic core of 6-dEB using a late-stage (step 19 of 22) C–H oxidative macrolactonization reaction that proceeds with high regio-, chemo- and diastereoselectivity (>40:1). A chelate-controlled model for macrolactonization predicted the stereochemical outcome of C–O bond formation and guided the discovery of conditions for synthesizing the first diastereomeric 13-epi-6-dEB precursor. Overall, this C–H oxidation strategy affords a highly efficient and stereochemically versatile synthesis of the erythromycin core. A synthesis of 6-deoxyerythronolide B is reported that uses a late-stage C–H oxidative macrocyclization reaction to forge the key macrocyclic core found in the erythromycins. By installing oxygen at a late-stage, this strategy improves synthetic efficiency by minimizing the ‘oxygen load’, and provides stereochemical versatility at the site of oxidation.

Total synthesis of (-)-nakadomarin A.

Abstract: A short and highly stereoselective synthesis of (-)-nakadomarin A has been developed using combinations of catalyst-controlled bond formations, one-pot multistep procedures, and powerful route-shortening reaction cascades. Several unprecedented chemical transformations were developed, including a highly Z-selective, eight-membered-ring-forming intramolecular Julia-Kocienski reaction, a highly diastereoselective intramolecular furan/iminium ion cyclization, and a sulfonic acid-controlled Z-selective macrocyclic ring-closing metathesis. In conjunction with a diastereoselective nitro olefin Michael addition under bifunctional organocatalysis and a nitro-Mannich/lactamization cascade, these transformations allowed the construction of this architecturally complex natural product in significant quantities in 12 steps (longest linear sequence) from commercially available starting materials.

Design and stereoselective preparation of a new class of chiral olefin metathesis catalysts and application to enantioselective synthesis of quebrachamine: catalyst development inspired by natural product synthesis.

Abstract: A total synthesis of the Aspidosperma alkaloid quebrachamine in racemic form is first described. A key catalytic ring-closing metathesis of an achiral triene is used to establish the all-carbon quaternary stereogenic center and the tetracyclic structure of the natural product; the catalytic transformation proceeds with reasonable efficiency through the use of existing achiral Ru or Mo catalysts. Ru- or Mo-based chiral olefin metathesis catalysts have proven to be inefficient and entirely nonselective in cases where the desired product is observed. In the present study, the synthesis route thus serves as a platform for the discovery of new olefin metathesis catalysts that allow for efficient completion of an enantioselective synthesis of quebrachamine. Accordingly, on the basis of mechanistic principles, stereogenic-at-Mo complexes bearing only monodentate ligands have been designed. The new catalysts provide significantly higher levels of activity than observed with the previously reported Ru- or Mo-based complexes. Enantiomerically enriched chiral alkylidenes are generated through diastereoselective reactions involving achiral Mo-based bispyrrolides and enantiomerically pure silyl-protected binaphthols. Such chiral catalysts initiate the key enantioselective ring-closing metathesis step in the total synthesis of quebrachamine efficiently (1 mol % loading, 22 °C, 1 h, >98% conversion, 84% yield) and with high selectivity (98:2 er, 96% ee).

Catalytic Asymmetric Friedel-Crafts Alkylations

Abstract: GENERAL ASPECTS AND HISTORICAL BACKGROUND Introduction General Aspects and Historical Background Catalytic Enantioselective FC Reactions: An Introduction MICHAEL ADDITION Chelating Alpha, Beta-Unsaturated Compounds Simple Alpha, Beta-Unsaturated Substrates Nitroalkenes ADDITION TO CARBONYL COMPOUNDS Aldehydes/Ketones Imines NUCLEOPHILIC ALLYLIC ALKYLATION AND HYDROARYLATION OF ALLENES Introduction Allylic Alkylations Metallo-Catalyzed Hydroarylation of Allenes NUCLEOPHILIC SUBSTITUTION ON CSP3 CARBON ATOMS Ring-Opening of Epoxides Direct Activation of Alcohols UNACTIVATED ALKENES Introduction Early Studies Rh(I)-Catalyzed Enantioselective Hydroarylation of Iminoarenes Pt(II)-Catalyzed Enantioselective Hydroarylation of Alkenylidoles Au(II)-Catalyzed Enantioselective Hydroarylation of Allenylindoles Conclusions and Outlook Experimental: Selected Procedures CATALYTIC ASYMMETRIC FRIEDEL-CRAFTS ALKYLATIONS IN TOTAL SYNTHESIS Introduction Total Synthesis of Indole-Containing Compounds Total Synthesis of Pyrrole-Containing Compounds Friedel-Crafts Alkylation of Furan Derivatives in Total Synthesis Friedel-Crafts Alkylation of Arenes in Total Synthesis Asymmetric Synthesis of Natural Products Based on Diastereoselective Friedel-Crafts Reactions INDUSTRIAL FRIEDEL-CRAFTS IN CHEMISTRY Introduction Green Chemistry and the Friedel-Crafts Reaction Heterogeneous Catalysts for the Friedel-Crafts Reaction Large Scale Hydrocarbon Processing Conclusions and Perspectives

Enantioselective total synthesis of (-)-napyradiomycin A1 via asymmetric chlorination of an isolated olefin.

Abstract: The napyradiomycins are an intriguing family of halogenated natural products with activity against several tumor cell lines as well as some of the worst bacterial strains known to humanity, including methicillin-resistant Staphylococcus aureas and vancomycin-resistant strains of Enterococcus faecium. This communication delineates the first asymmetric total synthesis of (−)-napyradiomycin A1 by a strategy that features a two-step total synthesis of flaviolin, the first highly asymmetric halogenation of a simple alkene, and a Johnson−Claisen rearrangement that generates a quaternary carbon next to a glucal-like oxygen.

Total Synthesis of Palau’amine†

Abstract: Polycyclic dimeric pyrrole-imidazole alkaloids such as palau’amine (1, Figure 1),1 axinellamine A (2),2 and massadine chloride (3)3 possess daunting structural and physical attributes, including nine or more nitrogen atoms, eight contiguous stereogenic centers, reactive (hemi)aminal moieties, oxidation-prone pyrroles, and highly polar, non-crystalline morphologies. Their unique structures have been the focus of numerous publications from many groups worldwide, and have led to notable advances in synthetic methodology.4 Among the more complex members of this class, only the axinellamines (e.g. 2)5 and the massadines (e.g. 3)6 have succumbed to total synthesis, aided by the invention of a highly chemoselective and controllable late-stage oxidation reaction. Figure 1 Selected pyrrole-imidazole alkaloids, and retrosynthetic analysis of palau’amine (1). Ar = 2-(4,5-dibromopyrrole). In contrast to its siblings (2 and 3), palau’amine (1) possesses a unique chemical challenge: one of the pyrrole-amide sidechains is embedded in an exquisite, hexacyclic core architecture which contains a highly strained trans-azabicyclo[3.3.0]octane substructure (unprecedented among natural products). This is undoubtedly a central reason why the synthesis of palau’amine (1) has thus far eluded organic chemists despite the dozens of Ph.D. theses7 and studies towards publications8 that have appeared since its isolation in 1993 and structural reassignment in 2007.1 Many well-founded and logical plans to secure the idiosyncratic trans-5,5 core of 1 in our laboratory resulted in unfortunate empirical realities. Presumably, the high degree of strain implicit in the hexacyclic architecture thwarted all attempts at a biomimetic closure (N14-C10 and N1-C6 simultaneously)4 or a stepwise closure (N14-C10 followed by N1-C6).9 The lessons learned during those initial attempts inspired an alternative strategy that ultimately led to the total synthesis of 1 presented herein. As depicted in Figure 1, our retrosynthetic analysis relied upon a speculation that hypothetical macrocycle 4, dubbed “macro-palau’amine”, would be a kinetically stable isomer of the natural product core found in 1. It was predicted that an irreversible transannular ring-chain tautomerization would convert 4 into its consitutional isomer 1 via a dynamic equilibrium involving amidine tautomer 4′. Handheld molecular models suggested that 4 might adopt a folded conformation wherein N14 and C10 would be in close proximity to facilitate such a ring closure. A conceptually related late-stage shift of topology between constitutional isomers through dynamic equilibration was a key design element of our recent synthesis of the kapakahines.10 As with 1, “macro palau’amine” (4) exhibits a high level of strain and was believed to be accessible via macrolactamization of the diamine derived from diazide 5. This intermediate was envisioned to arise from the SNAr of a pyrrole (or surrogate thereof) to the bromo-aminoimidazole 6. The total synthesis of 1, outlined in Scheme 1, commences with the readily-available cyclopentane core 7, an intermediate enlisted in the synthesis of the massadines and available in 19 steps from commercially available materials in 1% overall yield.6 Treatment of 7 with aqueous TFA unveiled aminoguanidine 8, which was directly converted in unprotected form to the hemiaminal 10 in 64% isolated yield (along with 17% recovered 8, 130 mg scale)11 using silver(II)-picolinate (9). It is notable that this oxidation reaction takes place with precise regioselectivity – no oxidation of the primary amine is observed under these acidic reaction conditions. Construction of the remaining 2-aminoimidazole took place in 65% yield (251 mg scale)11 to afford 11 using cyanamide in brine (sat. aq. NaCl), a solvent that minimizes displacement of the highly labile chlorine atom.3,6 Subsequent bromination using Br2 in a 1:1 mixture of TFA:TFAA delivered the desired 2-amino-4-bromoimidazole 6 in 54% yield (150 mg scale).11 The introduction of the pyrrole moiety proved challenging, as standard conditions to couple amines to aryl halides using transition metal catalysis failed to produce any detectible amounts of product (even on the Boc-shielded 2-amino-4-bromoimidazole derivatives). In principle, the inherent ambiphilicity of the 2-aminoimidazole could lend itself to a unique reactivity pattern, one that would allow for uncatalyzed nucleophilic attack on the 2-amino-4-bromoimidazole as a possible direct route to the pyrrole-acid intermediate 5. Scheme 1 Total synthesis of palau’amine (1). Counterions are CF3CO2− and are omitted for clarity. Reagents and conditions: a) TFA/H2O (1/1), 50 °C, 12 h, then silver(II)picolinate (2.4 equiv), TFA/H2O (1/9), 23 °C, 5 min, 64% + ... In the event, the nucleophilic pyrrole surrogate 1212 was reacted with 2-amino-4-bromoimidazole 6 buffered with AcOH, followed by treatment with TFA, to deliver the desired N-coupled pyrrole-2-carboxylic acid 5 in a one-pot operation in 44% yield (91 mg scale).11 Presumably, facile N–C bond formation is observed due to the high reactivity of its tautomeric amidine form (6′). This reaction appears to be general and its scope will be reported in the full account of this work. The pyrrole-forming step, mediated by TFA and traversing through oxonium 14, involves no less than five chemical transformations occurring in tandem to deliver 5. In preparation for the key macrolactamization step, the azide groups of 5 were reduced to afford highly polar diamine 15 (4.0 mg scale). The synthesis of “macro-palau’amine” 4 was effected using EDC and HOBt. Heating of the crude reaction mixture in TFA (70 °C) elicited the crucial transannular cyclization (presumably proceeding via amidine tautomer 4′) that fastened the remaining two stereocenters and cemented the hallmark trans-5,5 ring system to deliver palau’amine (1) in 17% overall yield from 5 (one-pot, average of 55% per operation) after repeated purification with reverse phase HPLC (spectroscopically identical to that reported for 1 with the exception of optical rotation).13 Optimization and mechanistic investigation of this final sequence (5 Π 1) is currently underway.9 The journey to 1 (25 steps from commercial material, 0.015% overall yield with current procedures)9 has led not only to useful strategies and methods, but also to an empirical demonstration of numerous guiding principles for synthesis design at the frontiers of chemical complexity.14 Over six years ago our lab embarked on the synthesis of dimeric pyrrole-imidazole alkaloids by methodically applying the logic of biosynthesis where appropriate during the syntheses of sceptrin, oxysceptrin, nakamuric acid, ageliferin, nagelamide, the axinellamines (e.g. 2), and the massadines (e.g. 3).5,6,15 The synthesis of 1 benefited from a tremendous amount of chemical reactivity learned during those endeavours. Our 2004 biosynthetic hypothesis15b led us to pursue the true structure of 1 prior to the realization of its revised structure.1 In an effort to apply redox economic principles16 to this chemical synthesis program, a late-stage, chemoselective, silver-mediated oxidation was invented to circumvent laborious routes to the key hemiaminal unit expressed in 1–3 (C–20, Figure 1). Cascade reactions were incorporated to rapidly assemble complexity (e.g. 6 Π 5 Π 1). Finally, innate reactivity was embraced so as to minimize the use of redundant and orthogonal protecting group operations,17 and instead maximize the discovery of interesting chemical reactivity such as the direct coupling of nucleophiles to unprotected 2-amino-4-bromoimidazoles. An enantioselective, scalable variant of the current synthesis, as well as a full account of this work will be forthcoming.

Total synthesis of the akuammiline alkaloid (+/-)-vincorine.

Abstract: The first total synthesis of the akuammiline alkaloid (±)-vincorine (6) has been accomplished in about 1% overall yield in 31 steps. A concise assembly of the core 1,2-disubstituted 1,2,3,4-tetrahydro-4a,9a-iminoethanocarbazole (1), a distinctive feature of akuammiline and strychnos alkaloids, was developed via a three-step one-pot cascade reaction consisting of copper-catalyzed intramolecular cyclopropanation, ring-opening, and ring closure. The construction of the last seven-membered E-ring in a rigid two-ring moiety (31, 45 to 47) through Heck coupling, Michael addition, π-allyl/Heck or π-allyl/Stille coupling failed, leading us to seek an alternative method. After successful addition of an acetate side chain on C15 of the cyclohexenyl ring (D-ring) in Boc-protected 35b by a Johnson−Claisen rearrangement and multistep modification of the functionality in the rearrangement product 33a, the E-ring formation was then realized for providing pentacyclic lactam 32 through intramolecular condensation of the a...

Total Synthesis of Platensimycin and Related Natural Products

Abstract: Platensimycin is the flagship member of a new and growing class of antibiotics with promising antibacterial properties against drug-resistant bacteria. The total syntheses of platensimycin and its congeners, platensimycins B1 and B3, platensic acid, methyl platensinoate, platensimide A, homoplatensimide A, and homoplatensimide A methyl ester, are described. The convergent strategy developed toward these target molecules involved construction of their cage-like core followed by attachment of the various side chains through amide bond formation. In addition to a racemic synthesis, two asymmetric routes to the core structure are described: one exploiting a rhodium-catalyzed asymmetric cycloisomerization, and another employing a hypervalent iodine-mediated de-aromatizing cyclization of an enantiopure substrate. The final two bonds of the core structure were forged through a samarium diiodide-mediated ketyl radical cyclization and an acid-catalyzed etherification. The rhodium-catalyzed asymmetric reaction invo...

Asymmetric [4 + 3] Cycloadditions between Vinylcarbenoids and Dienes: Application to the Total Synthesis of the Natural Product (−)-5-epi-Vibsanin E

Abstract: The total synthesis of (−)-5-epi-vibsanin E (2) has been achieved in 18 steps. The synthesis combines the rhodium-catalyzed [4 + 3] cycloaddition between a vinylcarbenoid and a diene to rapidly generate the tricyclic core with an effective end game strategy to introduce the remaining side-chains. The [4 + 3] cycloaddition occurs by a cyclopropanation to form a divinylcyclopropane followed by a Cope rearrangement to form a cycloheptadiene. The quaternary stereogenic center generated in the process can be obtained with high asymmetric induction when the reaction is catalyzed by the chiral dirhodium complex, Rh2(S-PTAD)4.

Total synthesis of (+)-haplophytine.

Abstract: Despite the many impressive accomplishments in the field of total synthesis in recent years, a number of natural products have proven stubbornly resistant to its advances. Among them is haplophytine (1, Scheme 1a), which has only very recently succumbed to synthesis following the elegant work of Fukuyama, Tokuyama and co-workers. Haplophytine was first isolated by Snyder and co-workers in 1952, and identified as the principle bioactive component of the wild flower Haplophyton cimicidum, valued for centuries by the Aztecs and subsequent settlers of Central America for its insecticidal properties. A heterodimeric indole alkaloid, haplophytine features a particularly complex polycyclic array of ten rings, six stereocenters (five of which are quaternary) and a highly congested carbon carbon bond adjoining the two distinct halves of the molecule. The tetracyclic left-hand domain features a unique bridged ketone structure, while the righthand domain consists of the naturally occurring aspidosperma alkaloid, aspidophytine (2, Scheme 1b). A complete appreciation of haplophytine s molecular structure was only reached some 21 years subsequent to its isolation, following extensive chemical degradation, spectroscopic, and X-ray crystallographic studies from the groups of Cava, Yates, and Zacharias, which included identification of the dihydrobromide derivative 3 (Scheme 1a). As depicted, this compound is formed through a unique acid-mediated skeletal rearrangement of the left-hand domain involving the 1,2-shift of an aminal C N bond. Under basic conditions, however, this process can be reversed such as to return haplophytine through a complementary semi-pinacol type mechanism. As

Nazarov Cyclization Initiated by Peracid Oxidation: The Total Synthesis of (±)-Rocaglamide

Abstract: The total syntheses of aglafolin, rocagloic acid, and rocaglamide using Nazarov cyclization are described. Generation of the necessary oxyallyl cation intermediate was accomplished via peracid oxidation of an allenol ether to generate an unusual oxycarbenium ion species that undergoes cyclization. The synthesis is efficient, highly diastereoselective, and strategically distinct from previous syntheses of rocaglamide.

Direct, Chemoselective N‐tert‐Prenylation of Indoles by C ? H Functionalization

Abstract: Prenylated indole alkaloids have long been targets for total synthesis, possessing a broad range of medicinal properties and intriguing architectures.1 Our interest in this family began with the stephacidin family of indole alkaloids2 during which the fortuitous finding shown in Figure 1A was made. Thus, in 2003, during an attempt to convert N-Boc-tryptophan methyl ester (1) to the C-2 prenylated tryptophan 2 directly using 2-methyl-2-butene via electrophilic palladation3 and olefin capture, we instead observed small amounts (<10%) of a non-polar compound identified as N-tert-prenylated indole 3. Whereas many elegant methods have been invented for accomplishing the direct prenylation of indoles,4–7 no methods currently exist for the direct N-tert-prenylation of indoles (Figure 1B).8 Inspired by our initial findings (Figure 1A), this communication delineates a mild, highly chemoselective, scalable, and one-step route to these biologically relevant motifs via C–H functionalization. Figure 1 Inspiration from a failed campaign in the stephacidin total synthesis (A), currently known direct prenylation modalities (B), and the known route to N-tert-prenyl indoles compared to the C–H functionalization alternative (C). Boc = tert-butoxycarbonyl, ... The only known route to N-tert-prenylated indoles requires a four step sequence, three of which involve non-strategic redox-fluctuations9 (Figure 1C): 1) reduction of the indole to the indoline, 2) propargyl substitution via CuI-catalysis, 3) oxidation back to the indole, 4) and finally Lindlar reduction of the alkyne to the olefin. This chemistry has been successfully incorporated into a number of total syntheses.9 Building off of our initial observations (Figure 1A), we envisioned a direct, one-step procedure to synthesize N-tert-prenylated indoles without the use of pre-functionalized starting materials and superfluous redox steps – well known tenets of C–H functionalization logic.10 Such a strategy would be orthogonal to routes that involve nucleophilic prenylation that in this case would not be applicable.11 Specifically, C–H activation of indoles are known to occur at C-2 or C-3, involving the direct coupling of arenes12 and electron-deficient olefins13 and annulations,2,9,14 even in the presence of free N-H indoles.15 Pd-catalyzed allylic C–H aminations16 have been accomplished; however, there have been only a few reports involving the intermolecular coupling of amines and allylic olefins.17 The fundamental mechanistic insights and reaction designs of Stahl18a and Yu19 were instrumental in transforming our esoteric 2003 observations into a useful method for synthesis. Selected results of extensive optimization with the N-Phth-tryptophan methyl ester 4 are outlined in Table 1. The work of Stahl pointed us to the use of CH3CN as a solvent while research from the Yu lab inspired the use of Cu(OAc)2 and AgOTf in concert. Ultimately, we found that 40 mol% of a Pd source (either 40 mol% Pd(OAc)2 or 20 mol% Pd2dba3•CHCl3) with 30 eq of 2-methyl-2-butene in the presence of Cu(OAc)2 and an AgI source (AgOTf or AgTFA) as the co-oxidants in CH3CN was optimal for this transformation. Table 1 Optimization of the direct indole N-tert-prenylation. With these conditions in hand, the synthetic utility could be immediately demonstrated by applying it to known intermediates in total synthesis (Figure 2). For example, compound 3, an intermediate in the okaramine N synthesis9c requiring the aforementioned four step sequence (50% overall yield), could be obtained in 66% yield on a gram-scale and in a single step with no other regioisomers observed under these conditions. Similarly, N-Cbz-tryptophan methyl ester (6) was converted to 7, an intermediate towards the synthesis of the rufomycins,9b in 61% yield (gram-scale) as compared to 60% over 4 steps. Indole 3-carboxaldehyde (8) was prenylated to give 9 on a gram-scale, an intermediate in a cyclomarin synthesis,9d in 68% yield versus 70% (4-step sequence from indoline). The use of methyl acrylate18a and 3-NO2-pyridine12b,14 (possibly as stabilizing ligands of Pd0) was needed when an electron-withdrawing group was occupied at C-3. The natural product 11, isolated from Aporpium caryae,20 has been synthesized previously starting from indoline9a and indole9e in 60% yield over 5 steps and 34% over 7 steps, respectively. The current approach starts from commercially available methyl indole 3-carboxylate (10) and leads to 11 in a single step in 83% yield (gram-scale). Figure 2 Scalable, one-step routes to previously employed N-tert-prenyl indole intermediates. As delineated in Table 1, this mild reaction exhibits broad functional group tolerance. For example, tryptophan derivatives with various protecting groups can be prenylated (Table 2, 13a–i). Peptides containing tryptophan also undergo prenylation (13a, 13h), including a tripeptide (13b). The presence of amides, particularly at the tryptophan nitrogen (13d, 13h), reduces the reactivity, possibly due to ligation of the amides onto electrophilic PdII. However, a sterically hindered amide substrate does lead to an increased yield (13e) compared to other amide substrates. A tryptamine derivative (13j) is also prenylated, albeit in lower yield, but starting material can be recovered. Free alcohol, acid, and protected phenols substrates are well tolerated under the reaction conditions (13i, 13k, and 13m respectively). Halogenated substrates (13f–g), including those incorporated in the indole ring (13l) work well, and are not oxidatively cleaved under these conditions. Table 2 Scope of N-tert-prenylation. To gain insight into the mechanism of this transformation, we studied the interactions that Pd may have with both the indole and the olefin. We initially believed that the indole was being palladated at C-2, thus providing proximal delivery of the prenyl group to nitrogen.3,13 When a methyl group occupied the C-2 position, there was less than 5% conversion to the desired product (Figure 3A). However, when deuterium was placed on C-2 (16), we found that the deuterium was fully incorporated in product 17. We also found that 1,1,1-d3-3-methyl-2-butene reacted at the same rate as its protio isomer with PdII, consistent with Bercaw’s mechanistic studies of allylic C–H activation (the C-H activation step is not rate-determining).21 Figure 3 Mechanistic probe experiments (A), and postulated mechanism (B). Based on these results, we have proposed the following mechanism (Figure 3B). First, C–H activation of the olefin with PdII gives intermediate 18. The palladated olefin reacts with indole in three possible modes. The first involves direct coordination of the indole nitrogen to Pd leading to 19. Alternatively, indole palladation at C-3 takes place to give 20 which rearranges to the product by a metallo-Clasien rearrangement.22 Finally, a Wacker-type mechanism (21) may also be operative.16a All three intermediates are plausible, although intermediate 20 may explain the regioselectivity more convincingly. The Pd0 species then undergoes oxidation with AgI and CuII to close the cycle. In order to rule out initial allylic oxidation of the olefin to prenyl acetate a control experiment was performed using prenyl acetate in place of 2-methyl-2-butene (following Method A). The reaction did not provide the desired product, but rather produced 22 in ca. 10% yield (tentative assignment). The use of cis-butene substituted for 2-methyl-2-butene did afford desired products in decent yield (23, 24). This method is obviously not without limitations. For example, terminal olefins provided only enamine products. Lowering the loading of palladium to 10–20% or reducing the equivalents of olefin added (5 equiv.) led to diminished yields (<30%). With regard to indole substrate scope, substitution at C–3 is required, diketopiperazine ring systems give lower yields of product, and pyrroles are too reactive under these conditions. While the current method is by no means atom-economic, it is direct, scalable, and selective even on complex substrates. It compares favorably to the only other method known for the synthesis of these compounds.23 Finally, our attempts to utilize prenyl acetate (or similar derivatives) in concert with various transition metals has not led to indole N-tert-prenylation.24 In conclusion, a simplified, redox-conserving route to N-tert-prenylated indoles using PdII-mediated C–H functionalization has been developed. Contrary to the known reactivity of indoles, prenylation occurs exclusively at N-1. Although substitution at C-2 hindered reactivity and the use of stoichiometric AgI and CuII salts are required, this method is amenable to gram-scale synthesis using a variety of indoles, including formal syntheses of a number of natural products and the synthesis of antifungal natural product 11 in a single step. The high level of chemoselectivity exhibited in this reaction bodes well for further applications in both the early and advanced stages of prenylated indole total synthesis endeavors.

Synthesis of 3,4-Dihydroisoquinolines by a C(sp3) ? H Activation/Electrocyclization Strategy: Total Synthesis of Coralydine

Abstract: Dihydroisoquinolines (DHIQ) constitute synthetically strategic molecules in this context, since they are precursors to both isoquinolines and tetrahydroisoquinolines. Whereas a range of new methods have been developed for the synthesis of 1,2-DHIQ, efforts have focused on the parent 3,4-DHIQ to a much lesser extent. Classical syntheses of 3,4-DHIQ involve Bischler-Napieralski-type reactions that rely on an electrophilic aromatic substitution (SEAr) step. [5] However, for the purpose of introducing broader structural diversity onto this motif, the development of conceptually different synthetic alternatives is of great interest. We envisioned the construction of a variety of 3-aryl-3,4-DHIQ 5 from iminoBCB 4 (BCB = benzocyclobutene) by thermal tandem electrocyclic ring-opening/6p-electrocyclization via o-xylylene intermediate A (Scheme 1). 7] In turn, imines 4 would arise from amino-BCB 3, which should be accessible from BCBesters 2 by hydrolysis and Curtius rearrangement. BCB 2 can be readily synthesized from bromobenzenes 1 by the palladium-catalyzed C H activation of methyl groups that was developed recently in our group. Amino-BCB 3a–d (Table 1) were synthesized from the corresponding aryl bromides 1. The construction of the cyclobutene ring by Pd-catalyzed C H activation/intramolecular C C coupling was carried out in good yield as described earlier (Scheme 1, step a). After ester hydrolysis (Scheme 1, step b), the corresponding carboxylic acids underwent a Curtius rearrangement in the presence of diphenylphosphoryl azide (DPPA, Scheme 1, step c). Amino-BCB 3e (Table 1, entry 12) was obtained from the corresponding BCB-nitrile by hydrolysis to the primary amide and PhI(OCOCF3)2-mediated Hofmann rearrangement [10] (see the Supporting Information). Amino-BCBs, such as 3, have limited thermal stability when R = H, and therefore they have very rarely been isolated and employed in synthesis. In this case, the presence of a quaternary benzylic carbon (R1⁄46 H), which is also necessary for the C H activation step (a), stabilized the molecule, probably by raising the energy barrier for the cyclobutene ring-opening, which allowed us to isolate the free amines 3 and to engage them in the next step. Thus amino-BCB 3 was treated with one equivalent of an aromatic aldehyde (Scheme 1, step d) and the corresponding imines 4 underwent the thermal tandem electrocyclic ringopening/ring-closing process (Scheme 1, step e). It was anticipated that the presence of the R alkyl substituent would favor inward rotation of the imine group to give the Z isomer of the o-xylylene intermediate (Scheme 1, A) that was Scheme 1. Overall strategy for the synthesis of dihydroisoquinolines. Reagents and conditions: a) Pd(OAc)2 (10 mol%), P(tBu)3 (20 mol%), K2CO3, DMF, 140 8C; b) NaOH, MeOH/H2O, reflux; c) diphenylphosphoryl azide (DPPA), Et3N, toluene, reflux, then aq. HCl, 80 8C; d) ArCHO (1 equiv), MgSO4, CH2Cl2, reflux; e) DMF, 160 8C.

Total Synthesis of (±)-Rhazinal Using Novel Palladium-Catalyzed Cyclizations

Abstract: A concise synthesis of (±)-rhazinal that hinges on novel oxidative Heck cyclizations and palladium-catalyzed direct couplings is described. An X-ray structure of N-MOM-rhazinal, which provides insight into the conformation of the strained 9-membered lactam ring, is described.

Total Syntheses of Amphidinolides B1, B4, G1, H1 and Structure Revision of Amphidinolide H2

Abstract: Nature is a pretty unselective "chemist" when it comes to making the highly cytotoxic amphidinolide macrolides of the B/G/H series. To date, 16 different such compounds have been isolated, all of which could now be approached by a highly convergent and largely catalysis-based route (see figure). This notion is exemplified by the total synthesis of five prototype members of this family.Dinoflagellates of the genus Amphidinium produce a "library" of closely related secondary metabolites of mixed polyketide origin, which are extremely scarce but highly promising owing to the exceptional cytotoxicity against various cancer cell lines. Because of the dense array of sensitive functionalities on their largely conserved macrocyclic frame, however, these amphidinolides of the B, D, G and H types elapsed many previous attempts at their synthesis. Described herein is a robust, convergent and hence general blueprint which allowed not only to conquest five prototype members of these series, but also holds the promise of making "non-natural" analogues available by diverted total synthesis. This notion transpires for a synthesis-driven structure revision of amphidinolide H2. The successful route hinges upon a highly productive Stille-Migita cross-coupling reaction at the congested and chemically labile 1,3-diene site present in all such targets, which required the development of a modified chloride- and fluoride-free protocol. The macrocyclic ring could be formed with high efficiency and selectivity by ring-closing metathesis (RCM) engaging a vinyl epoxide unit as one of the reaction partners. Because of the sensitivity of the targets to oxidizing and reducing conditions as well as to pH changes, the proper adjustment of the protecting group pattern for the peripheral -OH functions also constitutes a critical aspect, which has to converge to silyl groups only once the diene is in place. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) turned out to be a sufficiently mild fluoride source to allow for the final deprotection without damaging the precious macrolides.

Total Synthesis of Chloropeptin II (Complestatin) and Chloropeptin I

Abstract: The first total synthesis of chloropeptin II (1, complestatin) is disclosed. Key elements of the approach include the use of an intramolecular Larock indole synthesis for the initial macrocyclization, adopting conditions that permit utilization of a 2-bromoaniline, incorporating a terminal alkyne substituent (-SiEt(3)) that sterically dictates the indole cyclization regioselectivity, and benefiting from an aniline protecting group (-Ac) that enhances the atropdiastereoselectivity and diminishes the strained indole reactivity toward subsequent electrophilic reagents. Not only did this key reaction provide the fully functionalized right-hand ring system of 1 in superb conversion (89%) and good atropdiastereoselectivity (4:1 R:S), but it also represents the first reported example of what will prove to be a useful Larock macrocyclization strategy. Subsequent introduction of the left-hand ring system enlisting an aromatic nucleophilic substitution reaction for macrocyclization with biaryl ether formation completed the assemblage of the core bicyclic structure of 1. Intrinsic in the design of the approach and by virtue of the single-step acid-catalyzed conversion of chloropeptin II (1) to chloropeptin I (2), the route also provides a total synthesis of 2.

A Stereoselective Synthesis of the Bromopyrrole Natural Product (―)-Agelastatin A

Abstract: Agelastatin A and its congeners are a structurally intriguing class of bromopyrrole-based natural products comprised of a densely functionalized cyclopentane core adorned with four contiguous nitrogen substituent groups (Figure 1).[1] Agelastatin A and B were first isolated in 1993 from the Coral Sea marine sponge Agelas dendromorpha.[2] Subsequently, agelastatin C and D were identified in extracts from the Australian sponge Cymbastela sp.[3] The unique structural features of these compounds together with their powerful cytotoxic activities against certain human cancer cell lines have fueled efforts aimed at their de novo synthesis.[4,5] To date, seven completed syntheses of agelastatin A have appeared, each presenting a decidedly different strategy for assembly of the natural product.[6,7] For our purpose, structures such as agelastatin A serve to inspire the development of new catalytic methods for oxidative C–N bond formation. In this report, we detail an 11-step synthesis of this natural product made possible with the advent of a highly selective and efficient intramolecular olefin aziridination method.[8,9] The unique heterocyclic intermediate generated in this sequence is easily manipulated through two selective nucleophilic ring-opening reactions to afford the substituted cyclopentane core of the target. The finished work offers a flexible and highly efficient preparation of (–)-agelastatin A, easily amenable to analogue design.[10] Figure 1 The agelastatin family of natural products. Recent work from our lab and others has demonstrated that homoallyl and bis-homoallyl sulfamate esters react under oxidative conditions to furnish unique bicyclic aziridine derivatives (Figure 2).[8,11,12] This process generally affords high levels of diastereocontrol with both cyclic and acyclic starting materials. The products can be smoothly converted to polyfunctionalized amine derivatives through sequential, regioselective ring opening. For the purpose of assembling (–)-agelastatin A, an attractive plan emerged that would capitalize on such a sequence of steps to establish the trans-substituted vicinal diamine unit embedded at C4 and C8 (Figure 3). Prior to initiating these investigations, we had little sense if a substrate such as 3 would undergo chemoselective oxidation to generate the unusual tricyclic structure 2 and whether such a product would be isolable. Selectivity in the subsequent aziridine displacement reaction presented an additional concern. This plan, however, could be quickly assessed due to the ready availability of sulfamate 3. Figure 2 Rh-catalyzed aziridination: a versatile method for assembling polyfunctionalized amines. Figure 3 Retrosynthetic analysis of (–)-agelastatin A. Optically enriched lactam 4 is prepared on industrial scale and may be obtained in either antipode at a relatively inexpensive cost (Figure 4).[13] In two high yielding transformations, this material can be converted to alcohol 5, also an item of commerce. Sulfamoylation of 5 following a standard protocol that involves in situ generation of ClSO2NH2 is then easily accomplished.[14] Figure 4 Homoallylic sulfamate synthesis from commercial lactam. Exposure of sulfamate 6 to a dimeric Rh(II) catalyst, 1.1 equiv of PhI(OAc)2, and MgO, affords aziridine 7 as a single diastereomer in 95% yield (Figure 5). Less than 1% of the 5-membered ring product of allylic C–H insertion is obtained in this transformation. By capitalizing on our recently developed Rh2(esp)2 catalyst, loadings as low as 0.06 mol% (>1500 turnovers) can be used, thus enabling the reaction to be easily and inexpensively scaled.[15] The novel tricylic structure is quite stable and can be isolated in pure form following chromatography on silica gel. When treated with NaN3 in aqueous isopropanol, regioselective attack at C4 (agelastatin numbering) proceeds at ambient temperature to yield predominantly the bridging [1,2,3]-oxathiazepane-2,2-dioxide 8 (C4/C8 regioselectivity = 9:1).[16,17] This versatile intermediate incorporates three of the four stereogenic carbamine centers found in the natural product, all differentially masked. Accordingly, this aziridination/ring opening reaction sequence should offer ready access to several derivative forms of agelastatin. Figure 5 Catalytic aziridination and regioselective ring-opening affords the desired oxathiazepane heterocycle 8. Rh2(esp)2 = Rh2(α,α,α’,α’-1,3-benzenediproprionate)2. To forward the synthetic plan, a series of maneuvers was needed that would ultimately enable a single carbon excision and introduction of the C5 ketone (see Figure 3). Six- and seven-membered ring cyclic sulfamates possess intrinsic reactivity as electrophilies, which can be modulated as a result of N-functionalization.[14b,18] Taking advantage of this property, oxathiazepane 8 was first treated with diethyl pyrocarbonate to furnish the N-acylated species 9; subsequent introduction of NaSePh (prepared in a separate reaction vessel) displaces the oxathiazepane C–O bond to afford in a single operation selenide 10 (Figure 6). Access to this product in just 4 steps from 5 underscores the effectiveness of our aziridination process for the rapid assembly of stereochemically complex, orthogonally protected polyamine intermediates. Figure 6 Oxathiazepane 8 activation and ring opening. Oxidation of selenide 10 and elimination of the transient selenoxide was intended to furnish the C5 exo-methylene product 11 (Figure 7). Such a reaction does occur, however, the resulting allylic azide undergoes facile [3,3]-sigmatropic rearrangement to afford cyclopentene 12.[19] As it was not possible to prevent this isomerization process, a decision was made to postpone exo-methylene introduction until the latter steps of the synthesis. Accordingly, we opted to fashion first the requisite pyrrole unit from 10 (Figure 8). Removal of the Boc-group with CF3CO2H precedes an efficient Paal-Knorr condensation, which employs tricarbonyl 13 and mild acid catalysis to forge the heterocycle.[20,21] The desired pyrrole 14 is generated in 85% yield over this two-step sequence. Figure 7 Rearrangement of allylic azide 11 necessitates strategic modification. Figure 8 Paal-Knorr condensation installs pyrrole unit. To complete the agelastatin synthesis, azide 14 is reduced chemoselectively under Staudinger conditions (Me3P, THF/H2O, Scheme 1). Once reduction is complete, MeNCO is added to the reaction flask to produce urea 15. This compound is easily purified by normal-phase silica gel chromatography in spite of the presence of the polar N-methyl urea moiety. Exposure of 15 to m-CPBA induces selenide to selenoxide conversion and subsequent elimination to afford alkene 16. While attempts to cleave the C5 exo-methylene unit under ozonolytic conditions gave only intractable mixtures of products, successful installation of the C5 carbonyl was realized using a combination of 2.5 mol% OsO4 and NaIO4. Once the C5-ketone is exposed, addition of the urea is highly favored and the product is isolated exclusively as hemi-aminal 17. Scheme 1 a) Me3P, THF/H2O; then MeNCO, 81%; b) m-CPBA, DCE, 0 °C; then Et3N, 80 °C, 89%; c) 2.5 mol % OsO4, NaIO4, THF/H2O, 45 °C, 81%; d) KOtBu, tAmOH, 45 °C, 77%; e) NBS, THF/MeOH, 0→25 °C, 75%. m-CPBA = meta-chloroperbenzoic ... The stability of the hemi-aminal in 17 obviates protection as the N,O-acetal. As such, assembly of the final target can be accomplished by first exposing 17 to KOtBu in t-amyl alcohol (Scheme 1).[22] This protocol generates the desired six-membered lactam with concomitant cleavage of the ethyl carbamate. Having intercepted the penultimate intermediate formed in prior syntheses of agelastatin A, a literature procedure using N-bromosuccinimde smoothly and selectively brominates the pyrrole unit and gives the natural product as a white, crystalline solid.[6e] This material matches reported spectral and optical rotation data in all respects.[2,6e] Starting from commercial 5, the 11-step sequence has been executed in a single pass to prepare >200 mg of the natural product (15% overall yield). An efficient, easily scaled, and flexible route to (–)-agelstatin A has been made possible following the development and application of a selective Rh-catalyzed aziridination method. With the aid of Rh2(esp)2, this reaction is made to proceed in high yield at negligible catalyst loadings. The resulting tricyclic product 7 represents a unique heterocyclic structure that is efficiently transformed into a differentially protected cyclopentyltriamine. New protocols for manipulating the intermediate oxathiazepane and for crafting the pyrrole lactam also distill from this work. Overall, the preparation of agelastatin A is illustrative of the manner in which modern oxidative methods for C–N bond formation can alter the retrosynthetic logic of complex chemical synthesis.[23]

Combined directed remote metalation-transition metal catalyzed cross coupling strategies: the total synthesis of the aglycones of the gilvocarcins V, M, and E and arnottin I.

Abstract: A key directed remote metalation (DreM)-carbamoyl migration strategy was applied in an efficient synthesis of the naturally occurring 6H-naphtho[1,2-b]benzopyran-6-one defucogilvocarcin V (1a, Scheme 11). The required biarylcarbamate 33d was best prepared by a high yielding Suzuki coupling reaction of 31a with the differentially protected trioxygenated naphthalene coupling partner 32d which was synthesized using a selective acylation of a juglone derivative. In the late stages of the synthesis, the triflate 39 served as the common intermediate to install the required C-8 vinyl group of 1a (Stille coupling) as well as the required substituents for the preparation of defucogilvocarcins M (1b) and E (1c). A variety of protecting group strategies were investigated and provided insight into which groups are preferred for the DreM-carbamoyl migration process. The strategic lessons learned from this total synthesis were applied in the successful total synthesis of the structurally similar natural product arnottin I (2).

Total synthesis and biological evaluation of cortistatins A and J and analogues thereof.

Abstract: Total syntheses of the highly selective antiproliferative natural products cortistatins A (1) and J (5) in their naturally occurring enantiomeric forms are described. The modular and convergent str...