Prodigiosin alkaloids: recent advancements in total synthesis and their biological potential

Abstract

Despite recent developments in combinatorial chemistry and related techniques for facilitating drug discovery and development, natural products continue to play a prominent and evolving role for the development of new therapeutic agents. Pyrrole containing natural products constitute an integral part of this strategy. The structure and reactivity of pyrrole along with its propensity to polymerize renders it a relative speciality and certainly not something for the faint of heart. Besides, the well known tetrapyrrolic “Pigments of life,” other fascinating natural products incorporating multiple copies of the pyrrole ring system are attracting the attention of organic medicinal chemists and must be acknowledged.

---

Nisha

Miss Nisha has received her B.Sc degree in non-medical from DAV College, Jalandhar in 2008. In 2010, She joined Guru Nanak Dev University for obtaining her M.Sc. in Applied Chemistry with specialization in Pharmaceuticals. She is currently pursuing her doctoral studies in organic-medicinal chemistry with Dr Vipan Kumar. Her doctoral work comprises of the synthesis of a series of isatin-based molecular conjugates along with their antimalarial, anti-Tubercular, anti-trichomonas and cytotoxic evaluations. She has already published five research papers in international journals with good impact factors.

Kewal Kumar

Mr Kewal Kumar has obtained his B.Sc. degree from SPN College, Mukerian with distinction in Chemistry in 2007. He joined the Department of Applied Chemistry, Guru Nanak Dev University, Amritsar for his master's degree and achieved Gold medal of academic excellence in 2009. Afterwards, he joined Ranbaxy Research Laboratories as Research trainee, where he was awarded for “making a difference and driving excellence” in work in 2010. In the same year, he joined Dr Vipan's research group as INSPIRE Fellow for pursuing his doctoral degree. During his doctoral work, he worked extensively on the synthesis and bio-evaluation of ferrocene/uracil based molecular conjugates. He has published fifteen research papers in journals of international repute and has one US patent.

Vipan Kumar

Vipan kumar Ph.D, has been working as an Assistant Professor in the Department of Chemistry, Guru Nanak Dev University, Amritsar since 2009. He obtained his Ph.D with Prof. MP Mahajan, in the Department of Applied Chemistry, GNDU. In 2007, he moved to the University of Cape Town (UCT), South Africa to pursue his postdoctoral studies with Prof. Kelly Chibale and extensively worked on molecular hybridization protocols for the preparation of molecular conjugates intended for HIV–malaria co-infections. His research interests include the development of diverse synthetic protocols for synthesis of novel molecular frameworks targeting tropical infections. He has also been engaged in the utilization of β-lactam synthon protocols for the synthesis of functionally decorated and biologically relevant heterocycles with medicinal potential.

---

1. Introduction

Prodigiosin (PG) alkaloids represent a family of naturally occurring red pigments produced by Streptomyces and Serratia^1–3 with a common pyrrolylpyrromethene skeleton. From early times, extensive records have indicated the appearance of red colour on bread and wafers which was mis-interpreted in certain religious or symbolic contexts as the miraculous appearance of blood.² The secretion of “blood” like material by S. marcescens caused this considerable confusion and was responsible for many seemingly miraculous (prodigious) events. With an eventual transition from superstition to science, prodigiosins attracted considerable attention from both chemists and biologists because of their synthetically arduous and unique molecular architectures and range of potentially useful biological activities. Prodigiosin-like pigments have been isolated from several bacteria including S. plymuthica, S. rubidaea, S. coelicolor, P. magnesiorubra, V. psychroerythrus and γ-Proteobacteria etc. and have an unusual structure comprising of three pyrrole rings. Two of the pyrrole rings are directly linked to each other, while the third one is attached through a methane bridge 2,3. “Prodigiosin” has a series of close relatives bearing the same pyrrolylpyrromethene (“prodiginine”) core with different alkyl substituents which are often tied back to form medium-sized rings or macrocycles, as shown in Fig. 1.

Fig. 1 Representative members of the prodigiosin family.

Past decade has witnessed the emergence of a number of reports on the impressive biological properties such as immunosuppressive,⁴ antimalarial,^5,6 antimicrobial,⁷ antitumor,^7a,b,8 anticancer,⁹ cell pH regulation by H⁺/Cl⁻ symport/antiport activity,¹⁰ phosphatase inhibition¹¹ and DNA-interchelation activities¹² exhibited by natural and synthetic prodigiosins. Most interesting are their immunosuppressive activities at doses that are not cytotoxic. In vivo studies further suggested that the prodigiosins act synergistically with cyclosporine A or FK506,^4c,13,14 which are presently the dominant drugs in clinical immunosuppressive regimens. Its derivative Obatoclax (GX15-070), commercially developed by the pharmaceutical company Gemin X Pharmaceuticals (recently acquired by Cephalon), is also involved in phase I/II clinical trials on leukemia, lymphoma, and solid tumor malignancies with promising anticancer potential.

Given the immense medicinal potential of prodigiosins and the complexities of their structural assignments, various synthetic chemists have developed novel synthetic approaches for their total synthesis in order to unambiguously confirm their assigned structures. The present review article is an attempt to focus on the developments, the past decade has witnessed, in the total synthesis of prodigiosin alkaloids along with their medicinal potential. The aim will be to provide an inspiration to the marvels and pit falls of constructing the polypyrrole heterocycles with in the complex systems.

2. Biological potential of prodigiosins and their analogues

The emergence of drug-resistant pathogens and the subsequent urgent need for novel effective molecules has resulted in the re-engineering and re-positioning of the known bio-active molecules. Bacterial prodigiosins are considered as remarkable molecules in terms of their effectiveness as anti-tumor, immunosuppressants and antimalarials at non-toxic levels.

2.1. Antimalarial properties of prodigiosins

Although the antimalarial activity of natural prodigiosins was reported several years ago,¹⁵ the parasiticidal activity of prodigiosin analogues was reported only recently, with encouraging results. Many prodigiosins viz. metacycloprodigiosin (5), undecylprodigiosin (7), streptorubin B (4) were shown to exhibit potent in vitro activity against P. falciparum. Papireddy⁶ and co-workers studied the in vitro antimalarial activity of natural and synthetic prodigiosins against P. falciparum pansensitive D6 with chloroquine (CQ) as a reference drug. Assessment results revealed that the prodigiosin (1), undecylprodigiosin (7), metacycloprodigiosin (5), and streptorubin B (4) displayed potent antimalarial activity with very low IC₅₀ values viz. 8, 7.7, 1.7 and 7.8 nM respectively.

Patil et al.¹⁶ evaluated the larvicidal potential of microbial pigment prodigiosin produced by Serratia marcescens NMCC46 against Aedes aegypti and Anopheles stephensi. These results confirmed that these species would be more useful against vectors responsible for diseases of public health importance. Thompson and co-workers¹⁷ synthesized and evaluated prodigiosin complexes with tin, cobalt, boron and zinc (11–14) (Fig. 2). The antimalarial activities of these prodigiosins were evaluated in vitro against the 3D7 strain of P. falciparum. The presence of a nitrogen atom in the A-ring is needed for antimalarial activity while the presence of an alkyl group at the β-position of the C-ring seems detrimental. Dibutyl tin complexes exhibited IC₅₀ values in the nanomolar range with equal or improved activity compared to the free-base prodigiosin ligand, despite the fact that the general toxicity of tin complex is lower than that of the free bases.

Fig. 2 Complexes of prodigiosin with zinc (11), cobalt (12), tin (13) and boron (14).

Mahajan et al.¹⁸ synthesized 53 prodigiosins and assayed their in vitro anti-malarial activity against P. falciparum pansensitive D6, with chloroquine (CQ) as a reference drug. These synthetic prodigiosins having various substituents like –F, –Cl, alkyl, –NH₂, etc. at different positions were also explored in the CoMSIA (Comparative Molecular Similarity Indices Analysis) model in order to explore the role of structural features on the antimalarial activity. The analyses revealed that the lipophilicity, hydrogen donor/acceptor and steric factors of the synthesized prodiginines play crucial role in the design of new analogues. The most active compound of the series 15 displayed an IC₅₀ value of 0.9 nM against D6 strain of P. falciparum (Fig. 3).

Fig. 3 Most active antimalarial synthetic prodigiosin 15.

2.2. Anticancer properties of prodigiosins

Baldino et al.¹⁹ reported the synthesis of novel prodigiosin analogs, formed by the condensation of C-10 methoxybipyrrole aldehyde precursor 16 with indole derivatives (Scheme 1) and evaluated their cytotoxicity against a panel of cancer cell lines viz. A549, DLD-1, HT29, MDA-MB-231 and NCI-H460. The activity data revealed that the metacycloprodigiosin (5) having IC₅₀ 0.3–1.7 μM is approximately 10-fold less potent than the prodigiosin (1) with an IC₅₀ = 0.03–0.17 μM. The compound 19 exhibited greatest inhibition of cellular proliferation similar to metacycloprodigiosin (5), having IC₅₀ in the range between 0.2 and 0.8 μM (Fig. 4). The aliphatically substituted C-ring pyrrole compounds exhibited greatest activity, while the incorporation of the additional pyrrole ring and methoxy substituent appeared to reduce cell proliferation of the chemotype by 100-fold, similar to the indoloprodigiosin analogs.

Scheme 1 Synthesis of prodigiosin analogue 18.

Fig. 4 Most potent compound 19 with greatest inhibition of cellular proliferation.

Sainis and co-workers²⁰ in a recent communication investigated the mechanism of cell death induced by the N-alkylated prodigiosin analogue viz. 2,2′-[3-methoxy-1′-amyl-5′-methyl-4-(1′′-pyrryl)]dipyrryl-methene (MAMPDM) 20 (Fig. 5) in S-180 and EL-4 tumour cell lines. Investigations into the mechanism of cell death by MAMPDM in S-180 cells showed the absence of characteristics of apoptotic cell death such as activation of caspase 3, DNA fragmentation and presence of cells with sub-diploid DNA content. However, rapid loss of membrane integrity was observed as assessed by the uptake of propidium iodide, which is a characteristic of necrosis. In contrast to the induction of necrosis in S-180 cells, MAMPDM has also shown to induce apoptotic cell death in EL-4 cells as evident by activation of caspase 3, fragmentation of DNA and sub-diploid DNA containing cells.

Fig. 5 N-Alkylated prodigiosin analogue, 2,2′-[3-methoxy-1′-amyl-5′-methyl-4-(1′′-pyrryl)]dipyrryl-methene (MAMPDM).

Antiproliferative activities of prodigiosins derived from Serratia marcescens against HT-29 and T47D cancer cell lines was reported by Samadi et al.²¹ using MTT assay. The evaluation studies clearly elucidated the potential of PG as potent apoptotic agents in human colon adenocarcinoma exhibiting an IC₅₀ value of 400 nM; better than doxirubicin.

Thomson²² and co-workers synthesized prodigiosin analogues 21 bearing an additional methyl and a carbonyl group at the C-ring. In vitro anticancer activity (NCI) and the study of modes of action (copper-mediated cleavage of double-stranded DNA and transmembrane transport of chloride anions) showed that the presence of the methyl group is not detrimental to their activity (Fig. 6). Although the presence of an ester conjugated to the prodigiosin C-ring have shown to decrease both pK_a and chloride transport efficacy compared to the natural product, these analogues still exhibited a high rate of chloride ion transport. All synthesized analogues exhibited good in vitro anticancer activity and reduced toxicity as compared to the natural product with an acute systemic toxicity of 100 mg kg⁻¹ in mice vs. 4 mg kg⁻¹ for prodigiosin suggesting a larger therapeutic window of synthetic analogues than for the natural product.

Fig. 6 Prodigiosin analogues with anticancer activity.

Thompson et al.⁹ further synthesized a novel series of prodigiosin analogues 22 incorporating pendent functional esters and β-carbonyl substituents on the C-ring and evaluated for their anticancer activities (Fig. 7). The synthesized prodigiosin analogues retained the activity of prodigiosin in 60 human cancer cell lines with no reduction in efficacy being observed by the introduction of conjugated β-carbonyl group or the pendent ester.

Fig. 7 Anticancer Prodigiosin analogues with pendent functional esters and β-carbonyl substituents on the C-ring.

2.3. Immunosuppresant properties of prodigiosins

Immunosuppression plays a potential role in the therapy of autoimmune diseases and is required to reduce detrimental immune reactions. Main indications of immunosuppressive therapy are prevention and treatment of acute and chronic allogeneic organ transplant rejection and graft-versus-host disease (GVHD). Although the use of cyclosporin A (CyA) has been considered as a major advancement in organ transplantation,^23,24 current immunosuppressive therapies²⁵ still have strong limitations because of its low efficacy and relevant side effects on transplant recipients. One of the most attractive properties of prodigiosins are their immunosuppressive activities at doses that are not cytotoxic. In vivo studies suggested that the prodigiosins act synergistically with cyclosporine A or FK506 (Tacrolimus), which are presently the dominant drugs in clinical immunosuppressive regimens.

Sainis²⁶ and co-workers have also reported immunosuppressive activity of N-alkylated prodigiosin analogue, 2,2′-[3-methoxy-1′-amyl-5′-methyl-4-(1′′-pyrryl)]dipyrryl-methene (MAMPDM) 20 in mitogen stimulated spleen cells (Fig. 5). An increase in the accumulation of interlukin-2 (IL-2) and induction of apoptotic cell death was observed in these studies. Since IL-2 regulates both cellular proliferation and activation induced cell death (AICD), the effect of MAMPDM on the expression of IL-2 regulated genes involved in these two opposite processes was further investigated. The mitogen stimulated mouse spleen cells did not undergo a single division in presence of proliferation inhibitory concentrations of MAMPDM. An increase in the percentage of apoptotic cells was observed in the undivided cell population. The cells were arrested in G1 phase independent of the p53 expression. Expression of IL-2 regulated genes such as CD71, proliferating cell nuclear antigen (PCNA) and cyclin D was suppressed while the expression of Fas remain unchanged. MAMPDM therefore selectively inhibited the pro-mitogenic signaling without affecting proapoptotic signaling by IL-2. The induction of apoptosis in presence of MAMPDM was the effect rather than cause for the antiproliferative activity.

Kim et al.²⁷ compared the inhibitory potency and mode of action of Prodigiosin with cyclosporine A (CsA) in a mouse model. PG efficiently inhibited T cell proliferation with an IC₅₀ of 3.37 ng mL⁻¹, while CsA exhibited an IC₅₀ of 2.71 ng mL⁻¹. PG has shown to inhibit only IL-2Ra expression and not IL-2 expression, whereas CsA inhibited both. Exogenously added IL-2 reversed the suppressive activity of CsA, but not that of PG. Further although both PG and CsA markedly reduced mortality rates in lethal acute graft-versus-host disease (GVHD), the combined treatment was shown to be more effective than either drug alone. These results clearly demonstrated that PG and CsA have similar inhibitory potencies, but different modes of action suggesting the potential use of PG as a supplementary immunosuppressant in combination with CsA for the treatment of GVHD.

3. Total synthesis of prodigiosins

From a structural point of view, streptorubin B (4) and metacycloprodigiosin (5) possess highly strained pyrrolophane cores formed by oxidative ring closure of undecylprodigiosin (7). Prodigiosin R1 (6) has a structural similarity to metacycloprodigiosin (5) and is considered as an interesting link between these scaffolds and roseophilin (3).

3.1. Total synthesis of butylcycloheptylprodigiosin

Butylcycloheptylprodigiosin 2 is a secondary metabolite originally isolated from Streptomyces sp. Y-42, Streptomyces abikoensis and a culture broth of Streptomyces coelicolor mutants.^28,29 Historically, there has been considerable doubt about the existence of butylcycloheptylprodigiosin (2) as a natural product. Gerber and co-workers in 1975,²⁸ first proposed the structure 2 for a pink pigment isolated from Streptomyces sp. Y-42 and S. rubrireticuli. The structure, however was reassigned to that of streptorubin B (4) in 1978. Likewise, Floss in 1985, isolated a pink pigment from S. coelicolor which was structurally assigned as 2.²⁹ However, Weyland and co-workers isolated another pink pigment from actinomycete and showed that their sample was the meta-bridged isomer streptorubin B 10 rather than the ortho-annulated compound 2.³⁰ However, Weyland's conclusions looked premature on the basis of ¹H NMR spectra where meta-pyrrolophanes exhibited a characteristic fingerprint. The rigidity of the ten-membered ring in 4 forces one of the protons of the ansa-chain to reside within the anisotropy cone of the pyrrole ring resulting in a substantial upfield-shift to δ = −1.55 in 4 and −1.88 ppm in core-segment 23, shown in Fig. 8.³¹ Since no such signal was identified in case of butylcycloheptylprodigiosin 2, it was suspected that 2 exists as a natural product distinct from 4.

Fig. 8 High-field shift of an aliphatic proton as a characteristic signature of the ¹H NMR spectrum of compound with a rigid meta-pyrrolophane structure.

3.1.1. Furstner's total synthesis of butylcycloheptylprodigiosin. In order to unequivocally establish the structure of butylcycloheptylprodigiosin, Furstner and co-workers have successfully attempted its total synthesis in a 16-step sequence with an approximate yield of 1.5%.³²

Retrosynthetically, the assembly of the pyrrolopyrromethane 2 was envisaged from the corresponding building blocks 24–26 by successive condensation and cross-coupling reactions as shown in Fig. 9.^33,34 Because of ease of availability of 25 and 26, the success of this synthesis entirely hinged upon the synthesis of aldehyde 24.

Fig. 9 Retrosynthetic analysis of butylcycloheptylprodigiosin 2.

For the preparation of aldehyde 24, cyclononadienylacetone 27 was considered as the optimal substrate because of (1) the presence of two double bonds increasing the number of reactive encounters during Narasaka–Heck cyclization; (2) the remaining double bond that should provide a handle for the introduction of the butyl side chain; and (3) the symmetrical structure, facilitating its large scale preparation.

The total synthesis of desired butylcycloheptylprodigiosin 2 started with an initial reduction of (Z,Z)-cyclononadienone^5a,28 27 using diisobutyl-aluminium hydride (DIBAL-H) with subsequent acetylation to result in the corresponding acetate 28 in quantitative yields (Scheme 2). The treatment of 28 with methyl acetoacetate in the presence of NaH and catalytic amount of [Pd(PPh₃)₄] interestingly led to the isolation of Z-configured 29, advocating the notion that the two allylic sites in 28 were uncoupled during Tsuji–Trost reaction.³⁵ Krapcho decarboxylation³⁶ of 29 yielded the cyclononadienylacetone 30 which was converted to pentafluorobenzoyl oxime ester 31 under standard conditions. The synthesized oxime ester 31 underwent Narasaka–Heck cyclization³⁷ in the presence of a catalyst prepared in situ from Pd(OAc)₂ and [P(o-tolyl)₃] in DMF at 110 °C, to yield the unsaturated bicyclic imine 32 in good yields. In order to aromatize the product 32, potassium 3-aminopropylamide³⁸ (KAPA) in 1,3-diaminopropane was used. This, through a series of thermodynamic deprotonation/reprotonation resulted in the selective shift of the 9,10 double bond to deliver the highly sensitive pyrrole 33, which was immediately N-Boc protected to yield 34.³⁹

Scheme 2 Synthesis of the ortho-pyrrolophane core structure.

The functionalization of alkene in 34 by using BH₃·THF followed by stepwise oxidation with H₂O₂ and Dess–Martin periodinane yielded ketone 35 as anti-Markovnikov isomer (Scheme 3).^40,41 Wittig olefination of 35 delivered the product 36 which was subsequently selectively reduced with [Ir(pyridine)(cod)(PCy₃)]PF₆ (ref. 42) to yield 37. Subsequent oxidation of methyl substituent in 37 was optimized by the use of cerium ammonium nitrate (CAN) in CHCl₃/H₂O mixture using a small amount of 1,2-dimethoxy ethane (DME) as a phase transfer catalyst to yield the product 38.

Scheme 3 Total synthesis of butylcycloheptylprodigiosin.

Base promoted condensation of aldehyde 38 with commercially available lactam 25 with subsequent cleavage of the N-Boc protecting group led to the formation of 39. The reaction of 39 with Tf₂O (Tf = trifluoromethanesulfonyl) induced a re-organization of the π-system yielding the corresponding triflate 40 as the substrate for Suzuki coupling. The treatment of boronic acid 26 with 40 in the presence catalytic amounts of [Pd(PPh₃)₄] and LiCl afforded butycycloheptylprodigiosin 2 in 70% yield as a deeply red–pink colored solid.

3.1.2. Concise total synthesis of butylcycloheptylprodigiosin using Narasaka–Heck reaction. In another report, Furstner and co-workers^31a described the total synthesis of this complex alkaloid via catalysis based approach featuring the first application of a Narasaka–Heck reaction in natural product chemistry.^43–45 Retro-synthetically, the pyrrolopyrromethane portion of 2 could be assembled via successive condensation/cross coupling steps with aldehyde 24 as the key building block (Fig. 10).^33a,34 The preparation of 24 is non-trivial because of the disfavoured thermodynamic and kinetic grounds.⁴⁶ Thus, the preferred strategy comprised of the annulation of the pyrrole nucleus to the pre-existing cyclononane via palladium promoted intramolecular aza-Heck reaction of 42 having two synthetically equivalent double bonds.^43–45,47

Fig. 10 Retrosynthetic analysis of butylcycloheptylprodigiosin 2.

The synthetic methodology involved an initial ring expansion of cyclooctanone 44 using ethyl diazoacetate in the presence of Meerwein salt (Et₃O⁺BF₄⁻)⁴⁸ resulting in the isolation of ketoester 45 (Scheme 4). Krapcho decarboxylation³⁶ of ketoester 45 ensured the synthesis of cyclononanone 46. Cyclononanone 46 was converted to acetal 47 which when reacted with Br₂ led to the isolation of corresponding dibromide 48 as the major product. Potassium tert-butoxide promoted dehydrobromination of 48 transformed it into (Z,Z)-configured di-unsaturated ketal 51 along with the isomeric diene 50 as a minor product. trans-Deacetalization of this reaction mixture with acetone in the presence of catalytic amount of pyridinium p-toluene sulfonate afforded the desired (Z,Z)-cyclononadiene 27.

Scheme 4 Large-scale adaptable synthesis of cyclononadienone 27.

Treatment of 27 with diisobutylaluminium hydride (Dibal-H) afforded the corresponding doubly allylic alcohol 52 which was subsequently acetylated to yield 28 (Scheme 5). Reaction of 28 with methylacetoacetate in the presence of NaH and catalytic amount of [Pd(PPh₃)₄] afforded 29 as the major isomer along with small amount of conjugated diene isomer 53. Krapcho decarboxylation³⁶ of 29 with subsequent conversion of the resulting cyclononadienylacetone 30 into the pentafluorobenzoyl oxime ester 31 via the corresponding oxime 54 set the stage for Narasaka–Heck cyclization (Scheme 5).³⁷ Pd(OAc)₂ and P(o-tolyl)₃ promoted transformation of 31 delivered the unsaturated bicyclic imine 32. Reluctancy of 32 to undergo spontaneous aromatization promoted the workers to deprotonate the compound at the bridge head position α to nitrogen which will form a stable aza-pentadienylanion. Thus, the treatment of 32 with KAPA (potassium 3-aminopropylamide)³⁸ led to the formation of labile 33 via a series of thermodynamic deprotonation/re-protonation events. The highly labile 33 was immediately N-Boc protected to yield the compound 34.

Scheme 5 Synthesis of the ortho-pyrrolophane core structure 34.

Hydrogenation of 34 with BH₃·THF followed by stepwise oxidation with H₂O₂ and subsequent treatment with Dess–Martin periodinane⁴¹ furnished ketone 35 and the un-conjugated regio-isomer 55 (Scheme 6). Wittig olefination of 35 in boiling toluene delivered the corresponding olefin 36 as a mixture of both stereoisomers. The synthesized tri-substituted alkene was hydrogenated using [(cod)(pyridine)Ir(Pcy₃)]PF₆ (ref. 42) to give the desired ortho-pyrrolophane 37 without reducing the pyrrole ring.

Scheme 6 Total synthesis of butylcycloheptylprodigiosin.

The oxidation of 37 with CAN⁴⁹ in the presence of dimethoxyethane (DME) afforded the desired aldehyde 38a in good yields along with minor quantities of alcohol 38b. Base promoted condensation of 38a with commercially available lactam 25 with subsequent deprotection resulted in the synthesis of 39. Treatment of 39 with Tf₂O induced re-organization of the π-system resulted in the corresponding triflate 40 as the substrate for the final Suzuki coupling.⁵⁰ Treatment of 40 with boronic acid 26 in the presence of catalytic amounts of [Pd(PPh₃)₄] and LiCl afforded prodigiosin 2 in 61% yield. A comparison of the spectrum of the synthesized prodigiosin 2 and authentic sample showed an excellent match confirming the fact that butylcyclohepytylprodigiosin 2 is a natural product distinct from streptorubin B 4.

3.1.3. Reeves' concise synthesis of butylcycloheptylprodigiosin. Reeves and co-workers in 2007 have reported a concise total synthesis of butylcycloheptylprodigiosin 2 in 5 steps from cyclononenone.^51a The retrosynthetic analysis of 2 as depicted in Fig. 11, included an O-triflation/Suzuki cross-coupling simplification of 2 to lactam 56 with subsequent condensation to result in the key formylpyrrole 24.^31–33

Fig. 11 Reeves' retrosynthetic analysis of 2.

Total synthesis of 2 was initiated by the oxidation of commercially available cyclononanone with IBX (o-iodoxybenzoate) to yield cyclononenone 58 as reported by Nicolaou and co-workers.^51b CuI-catalyzed addition of n-BuMgCl to 58 proceeded efficiently in THF at −40 °C (Scheme 7).⁵² The resulting enolate was trapped with 59, obtained by partial reduction of commercially available ethyl-4-oxazole carboxylate, to give 57 as a single diastereomer. The treatment of 57 with MsCl/Et₃N in THF resulted in the synthesis of desired formyl pyrrole 24 in good yields. The elaboration of 24 into 2 was done in three steps viz. the condensation of 24 with commercially available pyrrolinone 25 to yield 56, the treatment of 56 with Tf₂O to yield the corresponding triflate 40, Suzuki cross coupling of 40 with boronic acid 26 with subsequent hydrolysis to yield (±)butylcycloheptyl prodigiosin 2 in good yields (5 steps, 23% overall yield).^31a,32,34

Scheme 7 Total synthesis of butylcycloheptylprodigiosin from cyclononenone 58.

Following these synthetic studies, Challis and co-workers⁵³ isolated a cyclic prodigiosin from S. coelicolor M511 and assigned it as streptorubin B (4). The findings by Challis and co-workers did not match with the report by Floss and the structural confirmation by both Furstner and Reeves, thus creating a doubt whether BCHP (2) is a natural product or not. Thomson and co-workers,⁵⁴ in a recent communication reported the detailed studies regarding the electron impact (EI) mass spectra of synthetic BCHP (2) and streptorubin B (4). These studies motivated by a proposed evolutionary hypothesis have concluded that BCHP (2) was not the compound isolated from S. coelicolor A3 by Floss and infact was streptorubin B, as indicated by identical EI-MS fragmentation patterns with report of Challis and co-workers. The combination of mass spectral comparisons with genetic and biochemical data provided evidence that BCHP (2) is not a natural product produced by S. coelicolor.

3.2. Total synthesis of roseophilin

Roseophilin, isolated from the culture broth of Streptomyces griseoviridis, is a macrocyclic pigment that exhibit potent cytotoxicity against human cancer cell lines.⁵⁵ The presence of unique ansa-bridged cyclopenta[b]pyrrole structural core of roseophilin has attracted the attention of synthetic organic chemists towards its partial or total synthesis.⁵⁶ The first total synthesis of racemic roseophilin was reported by Furstner^56o while the asymmetric synthesis of ent(−)roseophilin and the natural enantiomer was reported by Boger and Tius.^56m,n A number of protocols have been developed on the formal synthesis of roseophilin, focused largely on the construction of macrotricyclic core 3.

3.2.1. Remote stereo-controlled Nazarov cyclization protocol. Occhiato et al. has reported the synthesis of 3 via highly stereocontrolled Nazarov reaction of divinyl ketones in which one of the double bonds have been embedded in properly substituted N-heterocyclic structure.⁵⁷ Retrosynthetic approach for the synthesis of macrotricyclic core 3 is depicted in Fig. 12 involving the synthesis of ketopyrrole 63 in an enantiopure form by electrocyclization of pyrroline 65. The presence of correctly oriented buten-3-yl chain on the heterocycle would control the absolute stereochemistry in the Nazarov product 64.

Fig. 12 Retrosynthetic analysis of roseophilin 3.

Thus the treatment of enantiopure 69 with allyl magnesium bromide,⁵⁸ under refluxing in the THF⁵⁹ led to the synthesis of 70 which was subsequently N-tosylated to yield 71. The lactam 71 was converted to vinyl triflate 72 which was subjected to Pd-catalyzed coupling with α-ethoxydienyl boronate 67 to yield ethoxytriene 73 in good yields (Scheme 8).⁶⁰ The hydrolysis of 73 to furnish desired 63 did not proceed under mild acidic conditions while the harsh conditions (80 °C with 20% H₂SO₄) were not compatible with the delicate moieties involved, thus abandoning the developed approach.⁶¹

Scheme 8 Synthesis of ethoxytriene 73.

Another approach developed by the same workers included a linear sequence starting from enantiopure (R)-pyrrolidine 74 which after O-TBDMS-protection was transformed into the corresponding vinyl triflate and carbonylated (10% Pd(OAc)₂, Ph₃P, Et₃N, CO)⁶² in the presence of methanol to yield 76 and 77 (Scheme 9). The synthesized esters viz. 76 and 77 were transformed into corresponding Horner–Emmons–Wadsworth reagents 79 and 80 as per the protocol developed by Chiu for related carbacyclic systems olefination⁶³ yielding the corresponding dienone 82 and 83 which were directly used for electrocyclization in cold TFA. The reaction on completion furnished cyclopentafused 84 and 85 albeit in 40% and 27% yields respectively with subsequent oxidation with DDQ⁶⁴ to form 63. The key intermediate 63 in the synthesis of roseophilin was obtained in eight steps from compound 69 in 3% overall yield.

Scheme 9 Synthesis of enantiopure bicyclic ketopyrrole 63 via electrocyclization of pyrroline 65.

3.2.2. Dudley's ring expansion approach. Dudley and co-workers have reported palladium catalyzed annulation/oxidative cleavage sequence for the synthesis of cyclopentanone fused pyrrolophane which serves as a model for the tricyclic core of roseophilin.⁶⁵ Retrosynthetic approach for the synthesis of roseophilin is depicted in (Fig. 13) and features oxidative cleavage of a bridged bicyclic system as a synthetic strategy to reveal an appropriately functionalized precursor to the ansa-bridged ketopyrrole.

Fig. 13 Retrosynthetic analysis of tricyclic core of roseophilin.

The methodology initiated with the synthesis of requisite bicycle via Buono's enamine bis-allylation protocol.⁶⁶ Addition of LDA resulted in an efficient conversion of 91 to 92. Rubottom oxidation⁶⁷ of 92 provided an easy access to 93 which was subjected to subsequent epoxidation using m-CPBA to yield 94 in good yields.

The oxidative cleavage of 94 using lead tetraacetate in methanol afforded the corresponding ketoester 95 which served as an aldehyde equivalent for pyrrole condensation (Scheme 10). Treatment of 95 with ammonium acetate under Paal–Knorr conditions with subsequent saponification of the methyl ester afforded the desired model system 98 via an intramolecular Friedel–Crafts acylation reaction.

Scheme 10 Synthesis of roseophilin's ketopyrrole unit 98.

3.2.3. Frontier's formal synthesis of (±)roseophilin. A formal synthesis of (±)-roseophilin was reported by Frontier.⁶⁸ The retro-synthesis was elucidated in Fig. 14 and involved the preparation of macrocyclization precursor 99, obtained via Nazarov cyclization⁶⁹ of pyrrolyl-vinyl ketone 100 which in turn could be assembled via [3 + 2]cycloaddition/chelotropic extension of the alkynyl ester 101.⁷⁰

Fig. 14 Retrosynthetic analysis of 3.

The synthesis involved an initial desymmetrization of cyclohexene 102 with subsequent Jones oxidation of the intermediate aldehyde to provide carboxylic acid 103 (Scheme 11).⁷¹ The refluxing of 103 with trifluoroacetic anhydride and N-tosylpyrrole resulted in the selective acylation to form ketopyrrole.⁷² Reductive deoxygenation of ketopyrrole using zinc iodide and sodium cyanoborohydride provided the corresponding ester 104.⁷³ The treatment of 104 with DIBAL-H with subsequent Swern oxidation provided the corresponding aldehyde 105 which was converted to α,β-unsaturated ester 106 via reaction with methyldiethyl phosphonoacetate using Horner–Wadsworth–Emmons⁷⁴ conditions.

Scheme 11 Synthesis of α,β-unsaturated ester 106.

The synthesized 106 upon Vilsmeier–Haack formylation⁷⁵ led to the formation of pyrrolyl carboxaldehyde 107 which upon Corey–Fuchs transformation⁷⁶ afforded gem-dibromoalkene 108 (Scheme 12).

Scheme 12 Synthesis of isoxazoline-4-methyl ester 114.

Reduction of 108 with DIBAL-H and subsequent silylation of alcohol 109 yielded gem-dibromoalkene 110 which was converted to corresponding alkyne 111. Corey–Fuchs sequence selective deprotonation of 111 with lithium hexamethyldisilazide and subsequent addition of methylchloroformate yielded alkynyl ester 112. [1,3]-Dipolar cycloaddition reaction of 112 with nitrone 113 provided the corresponding isoxazole 114.

The synthesis of Nazarov cyclization precursor was affected by treatment of 114 with a slight excess of m-chloroperbenzoic acid (m-CPBA) at 0 °C affording the β-ketoester 115 (Scheme 13). The silyl protecting group in the Nazarov substrate 115 was exchanged with an acetyl protecting group to yield 116 which was subsequently heated with the catalytic amount of scandium(III)triflate and 1 eq. of perchlorate providing the Nazarov product 117.⁷⁷

Scheme 13 Synthesis of Nazarov cyclized product 117.

The addition of sodium enolate of 117 to a refluxing solution of tetrakis(triphenylphosphine)palladium provided a 4 : 1 mixture of macrocycle 118 to a product resulting from β-hydride elimination A as shown in Scheme 14.

Scheme 14 Palladium(0)-promoted macrocyclization of 117.

Recrystallization led to the isolation of 118 which upon hydrogenation and subsequent deprotection of the pyrrole nitrogen furnished the macrocyclic β-ketoester 119 (Scheme 15). Krapcho dealkoxy carbonylation of 119 in the final step delivered 60 in good yields.

Scheme 15 Synthesis of macrotricyclic core 60 of roseophilin.

3.2.4. Chang's convergent formal synthesis of (±)macrotricyclic core of roseophilin. A facile convergent synthesis of tricyclic core of roseophilin was reported by Chang and co-workers⁷⁸ involving tandem pyrrole acylation–Nazarov cyclization reaction as the key step for the for the formation of cyclopenta[b]pyrrole moiety (i.e. 122 + 123 → 121) as shown in the retrosynthetic analysis.^69b A late stage intramolecular Tsuji–Trost reaction in case of 120 eventually will close the 13-membered ring affording 60 as shown in Fig. 15.

Fig. 15 Retrosynthetic analysis of roseophilin.

The methodology involved a regioselective acylation of N-tosylpyrrole 126 with 6-heptenoic acid⁷⁹ in the presence of TFAA to yield acylpyrrole 127.⁷² Reduction of carbonyl in 127 using borane-tert-butylamine complex in the presence of aluminium trichloride⁸⁰ led to the synthesis of 2-(6′-hetenyl)-pyrrole 123.

Another precursor 2-methoxy carbonyl-4-methyl pentenoic acid 122 was obtained via Knoevenagel condensation⁸¹ between tert-butyl methyl malonate and isobutyraldehyde with subsequent removal of protecting group with TFA (Scheme 16). Tandem pyrrole acylation–Nazarov cyclization between 122 and 123 using TFAA resulted in the formation of variety of products. A variety of Lewis acids were employed to improve the yield of desired cyclopenta[b]pyrrole derivative 121. FeCl₃ proved to be the most useful in the formation of 121 in 75% isolated yield. Cross olefin metathesis reaction of 121 with allylacetate gave 120 whose palladium catalyzed intramolecular Tsuji–Trost reaction^56e,h resulted in 128 in moderate yields.

Scheme 16 Synthesis of roseophilin's macrotricyclic core 60.

3.2.5. Total synthesis of (±)roseophilin via its 2-azafulvene prototropisomer. Harran et al. reported the total synthesis of (±)-roseophilin via 2-azafulvene prototropisomer.⁸² Retrosynthetically, the approach involved two generic components viz. 130 and 131 linked in such a manner that C₉ in 129 would be at the oxidation state of a ketone. The α-olefin in 131 would incorporate the third component viz. 132 via alkene metathesis (Fig. 16).

Fig. 16 Design and assembly of seco precursors.

The synthetic approach initiated with lithiation of methoxyfuran 133 with its subsequent ZnBr₂–Pd catalyzed carboxylation to yield the corresponding carboxylic acid 134 (Scheme 17).⁸³ Condensation of 134 with 1-(methanesulfonyl)-1H-benzotriazole afforded the corresponding amide which was acylated with 2-(8-nonenyl)pyrroleby using TiCl₄ (ref. 84) to yield the corresponding bis-heteroaryl ketone 135 in high yields. Treatment of 135 with KH and diethylchlorophosphite gave the N-phosphinyl derivative which was oxidized to corresponding phosphoramide 136.⁸⁵ Metathesis of 136 with isopropyl ketone 137 (ref. 86) with subsequent in situ Pd-catalyzed hydrosilylation⁸⁷ gave the ketone 138 as an amber oil. The treatment of 138 with crown ether/KHMDS combination at 55 °C resulted in the gradual formation of pyrrolophane 141, probably via a kinetic enolate 139 in equilibrium with hindered aldol salt 140. The elimination of potassium diethyl phosphate from 141 afforded 142. Hydrogenation of 142 in the presence of catalyst generated from Rh(cod)₂OTf and a Josiphos ligand led to the isolation of cis-β-pyrrolyl ketone 144 with high diastereoselectivity (>25 : 1). Cyclo-dehydration of 144 using [ReBr-(CO)₃(thf)]₂ smoothly afforded the unstable 2-azafulvene 145. The unstable 2-azafulvene 145 was not isolated and treated in situ with dry HCl and substiochiometric amounts of t-BuOH to yield roseophilin hydrochloride 3 in 32% over all yields.

Scheme 17 Total Synthesis of (+)-roseophilin 3.

3.3. Total synthesis of streptorubin B

3.3.1. Chang's synthesis of streptorubin B core. Chang and co-workers have reported the synthesis of streptorubin B core starting from trans-4-hydroxyproline using intramolecular ring closing metathesis as the key step.⁸⁸ Retrosynthesis of streptorubin B core is as depicted in Fig. 17 and envisioned to involve a series of functional group transformations of trans-4-hydroxyproline 151 (ref. 89) to yield 2-substituted pyrrolidin-4-one 150. Grignard addition to 150 with subsequent intramolecular ring closing metathesis would result in the formation of 147. A sequence of hydrogenation dehydration reactions led to the synthesis of bicyclic pyrrole segment 147, reported previously by Furstner and co-workers,³⁹ whose acid catalysed condensation with a known bipyrrole aldehyde 146 may result in the streptorubin B.

Fig. 17 Retrosynthetic analysis of streptorubin B.

Synthetic protocol initiated with the synthesis of prolinol 152 from trans-4-hydroxyproline 151 via a sequence of four step reaction including esterification, tosylation, silylation and reduction. Prolinol 152, thus obtained was transformed into α,β-unsaturated ethyl ester 153 via Swern oxidation and subsequent Wittig olefination (Scheme 18). Hydrogenation of 153 using hydrogen and catalytic amount of 10% palladium on carbon followed by reduction using lithium aluminium hydride resulted in the isolation of alcohol 154. Pyridinium chlorochromate promoted oxidation of 154 with subsequent olefination with methyltriphenylphosphonium iodide gave the corresponding olefin 155. The olefin 155 was desilylated with tetra-n-butylammonium fluoride and oxidized with pyridinium chlorochromate to result in the synthesis of ketone 150. Grignard addition of 1-nonenyl-5-magnesium bromide 156 to the ketone 150 with subsequent ring closing metathesis using second generation Grubbs catalyst resulted in 157 in 58% yield. The product 157 was then transformed to known Furstner's intermediate 148 via hydrogenation with 10% Pd on carbon with subsequent dehydration by using boron triflouride etherate.

Scheme 18 Synthesis of streptorubin B core structure (Furstner's intermediate 148).

3.3.2. Thomson's enantioselective synthesis. Although, the structure and identity of streptorubin is beyond any doubt, Weyland and co-workers³⁰ noted an element of planar stereochemistry which may lead to the presence of two potential atropdiastereomers depending upon the relative stereochemistry of the butyl side chain and the bis pyrrole side arm (Fig. 18).

Fig. 18 Atropisomerism within streptorubin B.

To solve this problem, Thomson and co-workers⁹⁰ has recently described the enatioselective total synthesis of streptorubin B involving a one pot enatioselective aldol cyclization/Wittig reaction and an anionic oxy-cope rearrangement as the key steps. The retrosynthesis devised for the preparation of streptorubin involved an initial disconnection of the bis-pyrrole side arm to generate the pyrrolophane core 158 (Fig. 19). Paal–Knorr simplification of 158 with subsequent functional group interconversions led to the cyclodecanone 159, containing the full retron for the anionic oxy-cope rearrangement.⁹¹ The functionalized cyclohexanol precursor 160 could be assessed via a proline-catalysed enantioselective desymmetrizing intramolecular aldol reaction of dialdehyde 162 (ref. 92) with subsequent in situ Wittig reaction to form 161.

Fig. 19 Synthetic plan for the preparation of streptorubin B.

Thus the treatment of 164, obtained in a single step⁹³ from commercially available cycloheptene 163, with 10 mol% (s)-proline with subsequent addition of ylide 166 resulted in the isolation of homoallylic alcohol 161 as a major diastereomer (98 : 2 mixture of enantiomers). 161 upon oxidation followed by addition of the vinyl anion 167 (ref. 94) gave the precursor 160 required for anionics oxy-Cope rearrangement with an 97 : 3 ee. Treatment of alcohol 160 with KHDMS and 18-crown-6 yielded the desired 10-membered ring 159 with an enantiopurity of 97 : 3. The alkene reduction in 159 with concomitant benzyl ether cleavage, oxidation of the liberated alcohol to the aldehyde and the Paal–Knorr pyrrole synthesis afforded the pyrrole core 158. Acid promoted condensation between pyrrole 158 and aldehyde 169,⁹⁵ with subsequent removal of the Boc group via methanolysis yielded 4 in an enantioselective manner (Scheme 19). The streptorubin B 4 was prepared in nine steps from 163 in 20% overall yield. The comparison between CD spectra of synthesized and natural sample of streptorubin B coupled with X-ray crystallography confirmed the absolute stereochemistry of this prodigiosin.

Scheme 19 Enantioselective total synthesis of streptorubin B.

3.4. Total synthesis of metacycloprodigiosin

3.4.1. Enantioselective synthesis of metacycloprodigiosin via merged conjugate addition/oxidative coupling approach. The first enantioselective synthesis of the biologically active metacycloprodigiosin 5 was devised by Thomson and co-workers.⁹⁶ The success of this protocol was hinged upon the controlled oxidative coupling of unsymmetrical silyl bis-enol intermediates⁹⁷ followed by 1,4-addition of Grignard reagent.

The synthesis of metacycloprodigiosin was initiated with the treatment of ethyl magnesium bromide to enone 170 using 6 mol% (R,S)-Josi Phos leading to an intermediate which was trapped with chlorosilane 171 yielding silyl bis-enol ether 172 (Scheme 20). 172 was directly subjected to the oxidative bond formation using ceric ammonium nitrate and di-tert-bu-pyridine affording dione 173 as a mixture of diastereomers. The treatment of dione 173 with 10 mol% of Grubbs second generation catalyst⁹⁸ led to the synthesis of 12-membred ring 174. Subsequent hydrogenation with H₂/Pd(OH)₂ gave the fully saturated system which was converted to pyrrole 175 upon treatment with ammonium acetate. Trimethyl silyltriflate-mediated aldol coupling of 176 with 25 (ref. 99) gave ether 177 which upon treatment with HCl in THF afforded the requisite lactam 178. Triflation of 178 with subsequent Suzuki cross-coupling with pyrrole 26 afforded metacycloprodigiosin 5 in 76% yields.

Scheme 20 Enantioselective Synthesis of Metacycloprodigiosin 5.

3.5. Total synthesis of marineosins

Marineosin is a macrocyclic spiroaminal alkaloid isolated from marine-derived Streptomyces related actinomycete and exist as marineosin A and marineosin B.¹⁰⁰ Marineosin A displays potent inhibition against colon carcinoma cell growth, with an IC₅₀ of 0.5 μM in HCT-166 cells.¹⁰⁰

3.5.1. Lindsley's attempted total synthesis marineosins. The biosynthesis of marineosin A and B, as proposed by Fenical,¹⁰⁰ include an inverse electron demand hetero-Diels–Alder reaction to form the pyran ring and spiroaminal in a single step. In order to test the proposed biosynthesis, Lindsley and co-workers¹⁰¹ have reported the total synthesis of acyclic biosynthetic intermediate and attempted the biomimetic synthesis of marineosin. Retrosynthetically, the approach would involve the condensation between the bis-pyrrole 146 and the enone containing pyrrole 179 to deliver the Diels–Alder substrate 180. Intramolecular inverse-electron-demand hetero-Diels–Alder reaction of 180 would afford the desired spiroaminal core 181 with subsequent reduction as depicted in Fig. 20.

Fig. 20 Retrosynthetic approach for the synthesis of marineosin A and B.

The synthetic methodology involved an initial Vilsmeier–Haack haloformylation of 4-methoxy-3-pyrrolin-2-one 25 to yield the bromoenamine 183. Suzuki coupling of 183 with Boc-1H-pyrrol-2yl-boronic acid 26 afforded the Boc-protected analogue 169 in 48% yields (Scheme 21).

Scheme 21 Synthesis of C1–C9 protected bis-pyrrole 169.

Another intermediate 179, was prepared by a sequence of synthetic steps as shown in Scheme 22 involving the addition of Grignard 185 to pyrrole–aldehyde 184 to yield the corresponding secondary alcohol 186. Ley oxidation of 186 yielded the ketone 187 which upon Muchowski's one-pot cascade synthesis led to the isolation of 188.¹⁰² Cross-metathesis of 188 with 189 in the presence of Grubbs II catalyst¹⁰³ resulted in the isolation of desired 179 along with the conjugate addition products 190 and 191. Interestingly, increasing catalyst loading and lowering the temperature from 0.5 to 30 mol% improved the yield of cross-metathesis product 179 (40% yield).

Scheme 22 Synthesis of C1–C25 Diels–Alder substrate 179.

Acid promoted condensation of biosynthetic fragments 179 and 169 delivered the C1–C25 acyclic precursor 180, required for the proposed inverse-electron-demand hetero-Diels–Alder reaction. However, the use of varied reaction conditions (heat, microwave, photochemical, Lewis acid catalysis, mineral acid, solvent and additives) to carry out the inverse-electron-demand hetero-Diels–Alder reaction failed to deliver 181 from 180, which was further supported by modelling studies (Scheme 23).

Scheme 23 Synthesis of C1–C25 Diels–Alder substrate 180.

3.5.2. Lindsley's enantioselective total synthesis of macrotricyclic pyran core of marineosin A. Lindsley and co-workers,¹⁰⁴ in a recent communication reported the enantioselective construction of the 12-membered macrocyclic pyrrole core of marineosin A from (s)-propylene oxide. Retrosynthesis of marineosin 8 relied upon the synthesis of spiroaminal 192 via acid mediated cyclization of intermediate 193 (Fig. 21).

Fig. 21 Retrosynthesis of marineosin A 8.

A Paal–Knorr pyrrole synthesis with subsequent ring closing metathesis (RCM) would facilitate the formation of macrocycle 194 from 1,4-diketone 195. 195 in turn, would be obtained via key setter reaction from 196 which is a critical intermediate derived from Evan's auxillary phosphonate 197, vinyl magnesium bromide and (s)-propylene oxide as depicted in Scheme 24. The synthetic protocol involved a copper catalyzed Grignard addition to (s)-propylene oxide 198 with subsequent in situ silylation of the resulting alcohol to yield olefin 200. Ozonolysis of 200 resulted in the corresponding aldehyde 201 which upon Horner–Wadsworth–Emmons olefination with Evan's auxillary phosphonate, prepared in two steps from (R)-oxazolidinone 204, yielded acyloxazolidinone 205. Cu-promoted conjugate addition of allyl magnesium bromide to 205 delivered 206 with >20 : 1 dr.

Scheme 24 Synthesis of advanced intermediate 206.

Another intermediate 207 was prepared via an initial mono-PMB protection of cis-butene-1,4-diol to yield alcohol 208 with subsequent oxidation using MnO₂ to yield 209. TiCl₄-mediated aldol reaction of 206 with 209 under Crimmin's conditions delivered Evan's syn product 210 with 10 : 1 dr as shown in Scheme 25.^105,106 Hydrolysis of the auxillary with LiBH₄ generated corresponding alcohol which was immediately protected as TIPS silyl ether 211 (Scheme 25). VO(acac)₂-promoted epoxidation of 211 yielded the oxirane 212 as a single stereoisomer.¹⁰⁷ The secondary alcohol functionality in 212 was protected as the benzyl ether while subsequent removal of PMB group using DDQ led to the formation of primary alcohol 213. The ring opening of epoxide using Red-Al yielded 1,3-diol 214 with >20 : 1 ratio over the 1,2-diol congener.¹⁰⁸ The primary hydroxyl group in 214 was subsequently protected as a pivalate while secondary alcohol was converted to methyl ester affording 197 as a key intermediate.

Scheme 25 Synthesis of key intermediate 197.

Deprotection of TIPS in 197 using BF₃·OEt₂ resulted in the formation of primary alcohol 215 which upon oxidation by using Parikh–Doering condition led to the aldehyde 216 (Scheme 26).^109,110 A two step sequence viz. addition of vinyl Grignard reagent with subsequent Dess–Martin periodinane oxidation resulted in the corresponding α,β-unsaturated ketone 217. Reaction of 217 with 6-heptenal under Stetter conditions yielded 218 which upon ring closing metathesis using Grubbs I catalyst (30%) afforded the desired RCM product 219. Microwave promoted reaction of 219 using ammonium acetate in methanol delivered the desired macrocyclic pyrrole moiety 194 of marineosin 8 in 5.1% overall yield.

Scheme 26 Synthesis of marineosin A's macrocyclic pyrrole 194.

3.5.3. Synthesis of spiroiminal moiety of marineosin A and B by Snider. Snider et al.¹¹¹ reported the total synthesis of spiroiminal moiety of marineosins A and B starting from methyl valerolactone. The retrosynthetic route is as depicted in Fig. 22 and involved the spiroiminal formation from 220 which in turn was obtained from ketoisoxazoline 221 via hydrogenolysis of the N–O bond over RANEY® nickel with spontaneous formation of the hemi-iminal and subsequent O-methylation. Isoxazoline 221 would be obtained via nitrile N-oxide cycloaddition of vinylmagnesium bromide to lactone 222.

Fig. 22 Retrosynthesis of the marineosin.

The synthetic protocol was initiated by the addition of vinyl magnesium bromide to the readily available lactone 223 to yield the hydroxyketone 224.¹¹² The hydroxyketone 224 was subsequently protected as its triethyl silyl ether to afford the corresponding enone 225 as shown in Scheme 27. Reaction of 225 with benzaldehyde oxide, N-chlorosuccinimide and triethylamine provided the corresponding isoxazoline 226a which upon hydrogenolysis over RANEY® nickel led to the formation of hemi-iminal 227a as a mixture of isomers. Sodium hydride promoted methylation of 227a gave the methyl ether iminal 228a with subsequent hydrolysis of triethyl silyl ether to result in the desired spiroiminals 230a, 231a and 233a. The major isomer 230a showed equilibration in 2 weeks to give 19 : 1 mixture of 230a and 232a, establishing the identical stereochemistry at C-4 and C-7 (Scheme 28). The methodology developed for the synthesis of phenyl-substituted spiroiminals was further extended towards the synthesis of spiroaminals with a pyrrole substituent. Thus, the treatment of 225 with the oxime of N-SEM-pyrrole-2-carboxaldehyde¹¹³ NCS and Et₃N at −78 °C in THF afforded isoxazoline 226c in <30% yield. However, the reaction of N-SEM-pyrrole-2-carboxaldehyde oxime with 5% aqueous NaOCl¹¹⁴ generated the nitrile N-oxide which gave 226c in 73% yield. Hydrolysis of triethyl silyl ether functionality in 228c with 2 M aqueous hydrochloric acid gave the protected spiroaminals 230c in an inseparable equilibrium mixture with 231c and 233c. Deprotection of 230c with TBAF and molecular sieves in THF at 60 °C afforded spiroaminal 230b in 54% yields.

Scheme 27 Preparation of iminal 228.

Scheme 28 Preparation of spiroiminlas 230a,c, 231a,c and 232a,c.

3.6. Total synthesis of cycloprodigiosin

Cycloprodigiosin is a red pigment obtained from the bacterial strains Pseudoalteromonas (Alteromonas) rubra, Pseudoalteromonas denitrificans, and Vibrio gazogenes.¹¹⁵ Although this natural product was known for a long time, its true structure was only secured in 1983.¹¹⁶ Cycloprodigiosin has been reported as a potent proapoptotic anticancer compound¹¹⁷ and immunosuppressant.¹¹⁸ The first synthesis of cycloprodigiosin, was reported by Wasserman in 1984.¹¹⁹

3.6.1. Sarpong's total synthesis of cycloprodigiosin. Sarpong and co-workers¹²⁰ in a recent communication disclosed the total synthesis of cycloprodigiosin via Rh-trimethylenemethane variants generated from the interaction of a Rh-carbenoid with an allene. The synthetic methodology initiated with an enantioenriched allenylalkyne 235, prepared in six steps from alkyne 234 as a mixture of diastereomers.¹²¹ The treatment of 235 with TsN₃ in the presence of copper(I) thiophene-2-carboxylate (CuTc) and Rh₂(oct)₄ resulted in the isolation of a mixture of α,β-unsaturated imine 236 and the desired pyrrole 237 (Scheme 29). Lithium aluminium hydride (LAH) promoted removal of tosyl group led to the formation of pyrrole 238.¹²² Condensation of 238 and 169 under Lindsley's¹⁰¹ condition afforded cycloprodigiosin 10 in 71% overall yield.

Scheme 29 Synthesis of cycloprodigiosin 10.

4. Conclusion

Prodigiosins (PGs) constitute a family of natural red pigments isolated mostly from Gram-negative bacteria, with promising therapeutic potential and characterized by a common pyrryldipyrrylmethene core with varying side chains. These scaffolds display a broad spectrum of activities such as anti-microbial, anti-malarial, anti-cancer and immunosuppressive. In vitro, prodigiosins essentially target the cancer cells irrespective of the p53 status with little or no effect on the normal cells. In addition, prodigiosins are considered useful in cancer cells associated with multidrug resistance phenotype and defects in apoptotic pathways, substantiating their role as attractive candidates for further development. Mechanistically, prodigiosins have been found to target different signaling pathways probably through induction of DNA double strand breaks and/or neutralization of pH gradients leading to changes in cell cycle proteins and apoptosis. PGs are also attracting increasing attention as immunosuppressive agents for preventing allograft rejection and autoimmunity. Unlike the well-known immunosuppressant cyclosporin A, PGs do not inhibit the secretion of IL-2 but inhibit the mitogenic signaling from IL-2, suggestive of a different mechanism of action. Therefore, PrGs appear to be potential candidates for pharmaceutical development as immunosuppressants and also as anti-cancer agents. Prodigiosin is currently under preclinical trials for pancreatic cancer treatment while its derivative Obatoclax (GX15-070) Fig. 23, commercially developed by the pharmaceutical company Gemin X Pharmaceuticals, is in phase I/II clinical trials on leukemia, lymphoma, and solid tumor malignancies.

Fig. 23 Prodigiosin derivative Obatoclax (GX15-070).

The synthetically strenuous prodigiosins with enthralling biological potential will always be an attraction for synthetic organic chemists. The examples cited in the review, summarizes both the achievements and contribution of organic synthesis in total synthesis of bacterial prodigiosins. Note-worthy are the explicit assignment of structures to prodigiosins and the remarkable control of stereoselectivity demonstrated in some synthesis.

One of the crucial factors impeding the clinical development of prodigiosins is their high synthetic cost and therefore the development of simple and concise routes for the enantioselective synthesis of prodigiosins and their analogues with biological relevance is indeed desirable.

Notes and references

1. N. N. Gerber, Crit. Rev. Microbiol., 1974, 3, 469.
2. J. W. Bennett and R. Bentley, Adv. Appl. Microbiol., 2000, 47, 1.
3. R. A. Manderville, Curr. Med. Chem.: Anti-Cancer Agents, 2001, 1, 195.
4. (a) A. Nakamura, K. Nagai, K. Ando and G. J. Tamura, Antibiotica, 1985, 39, 1155; (b) R. F. Tsuji, M. Yamamoto, A. Nakamura, T. Katoka, J. Magae, K. Nagai and M. J. Jamasaki, Antibiotica, 1990, 43, 1293; (c) S. M. Stepkowski, R. A. Erwin-Cohen, F. Behbod, M. E. Wang, X. Qu, N. Tejpal, Z. S. Nagy, B. D. Kahan and R. A. Kirken, Blood, 2002, 99, 680; (d) S. M. Stepkowski, Z. S. Nagy, M. E. Wang, F. Behbod, R. Erwin-Cohen, B. D. Kahan and R. A. Kirken, Transplant. Proc., 2001, 33, 3835; (e) J. Magae, J. W. Miller, K. Nagai and G. M. Shearer, J. Antibiot., 1996, 49, 86; (f) R. D'Alessio, A. Bargiotti, O. Carlini, F. Colotta, M. Ferrari, P. Gnocchi, A. Isetta, N. Mongelli, P. Motta, A. Rossi, M. Rossi, M. Tibolla and E. Vanotti, J. Med. Chem., 2000, 43, 2557; (g) K. Tanigaki, T. Sato, Y. Tanaka, A. Nishikawa, K. Nagai, H. Kawashima and S. Ohkuma, FEBS Lett., 2002, 524, 37; (h) S. B. Han, H. M. Kim, Y. H. Kim, C. W. Lee, E. S. Jang, K. H. Son, S. U. Kim and Y. K. Kim, Int. J. Immunopharmacol., 1998, 20, 1.
5. (a) N. J. Gerber, Antibiotica, 1975, 28, 194; (b) D. E. Davidson Jr, D. O. Johnsen, P. Tanticharoenyos, R. L. Hickman and K. E. Kinnamon, Am. J. Trop. Med. Hyg., 1976, 25, 26; (c) M. Isaka, A. Jaturapat, J. Kramyu, M. Tanticharoen and Y. Thebtaranonth, Antimicrob. Agents Chemother., 2002, 46, 1112; (d) J. E. H. Lazaro, J. Nitcheu, R. Z. Predicala, G. C. Mangalindan, F. Nesslany, D. Marzin, G. P. Concepcion and B. J. Diquet, Nat. Tox., 2002, 11, 367.
6. K. Papireddy, M. Smilkstein, J. X. Kelly, S. M. Shweta Salem, M. Alhamadsheh, S. W. Haynes, G. L. Challis and K. A. Reynolds, J. Med. Chem., 2011, 54, 5296.
7. (a) K. Kojiri, S. Nakajima, H. Suzuki, A. Okura and H. Suda, J. Antibiot., 1993, 46, 1799; (b) D. L. Boger and M. J. Patel, J. Org. Chem., 1988, 53, 1405; (c) F. Alihosseini, K. S. Ju, J. Lango, B. D. Hammock and G. Sun, Biotechnol. Prog., 2008, 24, 742.
8. R. P. Williams and W. R. Hearn, Antibiotics, 1967, 2, 410.
9. J. Regourd, A. Al-Sheikh Ali and A. Thompson, J. Med. Chem., 2007, 50, 1528.
10. (a) R. I. Saes Dias, J. Regourd, P. V. Santacroce, J. T. Davis, D. L. Jakeman and A. Thompson, Chem. Commun., 2007, 2701; (b) J. L. Seganish and J. T. Davis, Chem. Commun., 2005, 5781; (c) M. S. Melvin, J. T. Tomlinson, G. Park, C. S. Day, G. S. Saluta, G. L. Kucera and R. A. Manderville, Chem. Res. Toxicol., 2002, 15, 734; (d) H. Matsuya, M. Okamoto, T. Ochi, A. Nishikawa, S. Shimizu, T. Kataoka, K. Nagai, H. H. Wasserman and S. Ohkuma, Biochem. J., 1998, 334, 731.
11. A. Furstner, K. Reinecke, H. Prinz and H. Waldmann, ChemBioChem, 2004, 5, 1575.
12. (a) M. S. Melvin, D. C. Ferguson, N. Lindquist and R. A. Mandervile, J. Org. Chem., 1999, 64, 6861; (b) B. C. Cavalcanti, H. V. N. Junior, M. H. R. Seleghim, R. G. S. Berlinck, G. M. A. Cunha, M. O. Moraes and C. Pessoa, Chem.-Biol. Interact., 2008, 174, 155.
13. S. M. Stepkowski, Z. S. Nagy, M. E. Wang, F. Behbod, R. Erwin-Cohen, B. D. Kahan and R. A. Kirken, Transplant. Proc., 2001, 33, 3272.
14. M. Ferrari, P. Gnocchi, M. C. Fornasiero, F. Colotta, R. D'Alessio and A. M. Isetta, WO98/11894A1, Pharmacia&UpjohntransChem. Abstr., 1998, 128, 275.
15. A. J. Castro, Nature, 1967, 213, 903.
16. C. D. Patil, S. V. Patil, B. K. Salunke, H. Stetter and R. B. Salunkhe, Parasitol. Res., 2011, 109, 1179.
17. E. Marchal, D. A. Smithen, M. I. Uddin, A. W. Robertson, D. L. Jakeman, V. Mollard, C. D. Goodman, K. S. MacDougall, S. A. McFarland, G. I. McFadden, H. Stetter and A. Thompson, Org. Biomol. Chem., 2014, 12, 4132.
18. D. T. Mahajan, V. H. Masand, K. N. Patil, T. B. Hadda, R. D. Jawarker, S. D. Thakur and V. Rastija, Bioorg. Med. Chem. Lett., 2012, 22, 4827.
19. C. M. Baldino, J. Parr, C. J. Wilson, S.-C. Ng, D. Yohannes and H. H. Wasserman, Bioorg. Med. Chem. Lett., 2006, 16, 701.
20. A. A. Deorukhkar, R. Chander, R. Pandey and K. B. Sainis, Cancer Chemother. Pharmacol., 2008, 61, 355.
21. D. Dalili, S. Fouladdel, N. Rastkari, N. Samadi, R. Ahmadkhaniha, A. Ardavan and E. Azizi, Nat. Prod. Res., 2012, 26, 2078.
22. S. Rastogi, E. Marchal, I. Uddin, B. Groves, J. Colpitts, S. A. McFarland, J. T. Davis and A. Thompson, Org. Biomol. Chem., 2013, 11, 3834.
23. N. H. Sigal and F. J. Dumont, in Fundamental Immunology, ed. W. E. Paul, Raven Press, New York, 1993, p. 903.
24. J. Liu, Immunol. Today, 1993, 14, 290.
25. (a) D. A. Gerber, C. A. Bonham and A. W. Thomson, Transplant. Proc., 1998, 30, 1573; (b) E. Mor, A. Yussim and L. C. Schwartz, BioDrugs, 1997, 8, 469; (c) N. G. Singer and W. J. Mccune, Curr. Opin. Rheumatol., 1998, 10, 169.
26. R. Pandey, R. Chander and K. B. Sainis, Indian J. Biochem. Biophys., 2007, 44, 295.
27. S. B. Han, C. W. Lee, Y. D. Yoon, J. S. Kang, K. H. Lee, W. K. Yoon, Y. K. Kim, K. Lee, S. K. Park and H. M. Kim, Biochem. Pharmacol., 2005, 70, 1518.
28. N. N. Gerber and D. P. Stahly, Appl. Microbiol., 1975, 30, 807.
29. S. W. Tsao, B. A. M. Rudd, X. G. He, C. J. Chang and H. G. Floss, J. Antibiot., 1985, 38, 128.
30. H. Laatsch, M. Kellner and H. Weyland, J. Antibiot., 1991, 44, 187.
31. (a) A. Furstner, K. Radkowski, H. Peters, G. Seidel, C. Wirtz, R. Mynott and C. W. Lehmann, Chem.–Eur. J., 2007, 13, 1929; (b) A. Furstner, J. Grabowski, C. W. Lehmann, T. Kataoka and K. Nagai, ChemBioChem, 2001, 2, 60.
32. A. Furstner, K. Reinecke and H. Peters, Angew. Chem., Int. Ed., 2005, 44, 2777.
33. (a) A. Furstner, J. Grabowski and C. W. Lehmann, J. Org. Chem., 1999, 64, 8275; (b) A. Furstner and H. Krause, J. Org. Chem., 1999, 64, 8281.
34. R. D'Allessio and A. Rossi, Synlett, 1996, 513.
35. DFT optimization of the conformation of the presumed pallylpalladium intermediate corroborate this interpretation.
36. (a) A. P. Krapcho, Synthesis, 1982, 805; (b) A. P. Krapcho, Synthesis, 1982, 893.
37. (a) H. Tsutsui, M. Kitamura and K. Narasaka, Bull. Chem. Soc. Jpn., 2002, 75, 1451; (b) H. Tsutsui and K. Narasaka, Chem. Lett., 1999, 28, 45; (c) S. Zaman, M. Kitamura and K. Narasaka, Bull. Chem. Soc. Jpn., 2003, 76, 1055; (d) H. Tsutsui and K. Narasaka, Chem. Lett., 2001, 30, 526; (e) S. Chiba, M. Kitamura, O. Saku and K. Narasaka, Bull. Chem. Soc. Jpn., 2004, 77, 785.
38. C. A. Brown and P. K. Jadhav, Org. Synth., 1987, 65, 224.
39. A. Furstner, H. Szillat, B. Gabor and R. Mynott, J. Am. Chem. Soc., 1998, 120, 8305.
40. M. Zaidlewicz, J. Organomet. Chem., 1985, 293, 139.
41. (a) D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155; (b) S. D. Meyer and S. L. Schreiber, J. Org. Chem., 1994, 59, 7549.
42. R. H. Crabtree, H. Felkin, T. Fillebeen-Khan and G. E. Morris, J. Organomet. Chem., 1979, 168, 183.
43. K. Narasaka and M. Kitamura, Eur. J. Org. Chem., 2005, 4505.
44. S. Zaman, K. Mitsuru and A. D. Abell, Org. Lett., 2005, 7, 609.
45. S. Brse and A. de Meijere, in Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and F. Diederich, Wiley-VCH, Weinheim, 2nd edn, 2004, vol. 1, pp. 217–315.
46. C. Galli and L. Mandolini, Eur. J. Org. Chem., 2000, 3117.
47. I. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009.
48. H. Meerwein, Org. Synth., 1966, 46, 120.
49. (a) G. A. Molander, Chem. Rev., 1992, 92, 29; (b) T. L. Ho, Synthesis, 1973, 347; (c) A. M. Khenkin and R. Neumann, J. Am. Chem. Soc., 2004, 126, 6356.
50. (a) A. Suzuki, J. Organomet. Chem., 1999, 576, 147; (b) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
51. (a) J. T. Reeves, Org. Lett., 2007, 9, 1879; (b) K. C. Nicolaou, T. Montagnon, P. S. Baran and Y. L. Zhong, J. Am. Chem. Soc., 2002, 124, 2245.
52. (a) G. Stork and J. d'Angelo, J. Am. Chem. Soc., 1974, 96, 7114; (b) K. K. Heng and R. A. J. Smith, Tetrahedron, 1979, 35, 425; (c) R. J. K. Taylor, Synthesis, 1985, 364; (d) M. Suzuki, T. Kawagishi, A. Yanagisawa, T. Suzuki, N. Okamura and R. Noyori, Bull. Chem. Soc. Jpn., 1988, 61, 1299; (e) K. C. Nicolaou, W. Tang, P. Dagneau and R. Faraoni, Angew. Chem., Int. Ed., 2005, 44, 3874.
53. S. Mo, P. K. Sydor, C. Corre, M. M. Alhamadsheh, A. E. Stanley, S. W. Haynes, L. Song, K. A. Reynolds and G. L. Challis, Chem. Biol., 2008, 15, 137.
54. B. T. Jones, D. X. Hu, B. M. Savoie and R. J. Thomson, J. Nat. Prod., 2013, 76, 1937.
55. Y. Hayakawa, K. Kawakami, H. Seto and K. Furihata, Tetrahedron Lett., 1992, 33, 2701.
56. (a) S. H. Kim and P. L. Fuchs, Tetrahedron Lett., 1996, 37, 2545; (b) S. H. Kim, I. Figueroa and P. L. Fuchs, Tetrahedron Lett., 1997, 38, 2601; (c) A. Furstner and H. Weintritt, J. Am. Chem. Soc., 1997, 119, 2944; (d) A. Furstner and H. Weintritt, J. Am. Chem. Soc., 1998, 120, 2817; (e) T. Mochizuki, E. Itoh, N. Shibata, S. Nakatami, T. Katoh and S. Terashima, Tetrahedron Lett., 1998, 39, 6911; (f) J. Robertson and R. J. D. Hatley, Chem. Commun., 1999, 1455; (g) M. A. Fagan and D. W. Knight, Tetrahedron Lett., 1999, 40, 6117; (h) A. Furstner, T. Gastner and H. Weintritt, J. Org. Chem., 1999, 64, 2361; (i) J. Robertson, R. J. D. Hatley and D. J. Watkin, J. Chem. Soc., Perkin Trans. 1, 2000, 3389; (j) S. J. Bamford, T. Luker, W. N. Speckamp and H. Hiemstra, Org. Lett., 2000, 2, 1157; (k) B. M. Trost and G. A. Doherty, J. Am. Chem. Soc., 2000, 122, 3801; (l) P. E. Harrington and M. A. Tius, J. Am. Chem. Soc., 2001, 123, 8509; (m) D. L. Boger and J. Hong, J. Am. Chem. Soc., 2001, 123, 8515; (n) E. M. E. Viseux, P. J. Parsons, J. B. J. Pavey, C. M. Carter and I. Pinto, Synlett, 2003, 1856; (o) A. Furstner, Angew. Chem., Int. Ed., 2003, 42, 3582.
57. E. G. Occhiato, C. Prandi, A. Ferrali and A. Guarna, J. Org. Chem., 2005, 70, 4542.
58. Y. Nakagawa, K. Matsumoto and K. Tomioka, Tetrahedron, 2000, 56, 2857.
59. D. F. Taber, P. B. Deker and M. D. Gaul, J. Am. Chem. Soc., 1987, 109, 7488.
60. (a) E. G. Occhiato, C. Prandi, A. Ferrali, A. Guarna and P. Venturello, J. Org. Chem., 2003, 68, 9728; (b) C. Prandi, A. Ferrali, A. Guarna, P. Venturello and E. G. Occhiato, J. Org. Chem., 2004, 69, 7705; (c) E. G. Occhiato, A. Trabocchi and A. Guarna, Org. Lett., 2000, 2, 1241; (d) E. G. Occhiato, A. Trabocchi and A. Guarna, J. Org. Chem., 2001, 66, 2459; (e) E. G. Occhiato, C. Prandi, A. Ferrali, A. Guarna, A. Deagostino and P. Venturello, J. Org. Chem., 2002, 67, 7144.
61. J. P. Quintard, B. Elissondo, T. Hattich and M. Pereyre, J. Organomet. Chem., 1985, 285, 149.
62. K. C. Nicolaou, G. Q. Shi, K. Namoto and F. Bernal, Chem. Commun., 1998, 1757.
63. P. Chiu and S. Li, Org. Lett., 2004, 6, 613.
64. Y. K. Shim, J. I. Youn, J. S. Chun, T. H. Park, M. H. Kim and W. J. Kim, Synthesis, 1990, 753.
65. S. G. Salamone and G. B. Dudley, Org. Lett., 2005, 7, 4443.
66. F. Buono and A. Tenaglia, J. Org. Chem., 2000, 65, 3869.
67. G. M. Rubottom, J. M. Gruber, H. D. Juve Jr and D. A. Charleson, Org. Synth., 1986, 64, 118.
68. A. Y. Bitar and A. J. Frontier, Org. Lett., 2009, 11, 49.
69. (a) P. Harrington and M. Tius, Org. Lett., 1999, 1, 649; (b) C. Song, D. W. Knight and M. A. Whatton, Org. Lett., 2006, 8, 163.
70. (a) A. Padwa, D. N. Kline and J. Perumattam, Tetrahedron Lett., 1987, 28, 913; (b) A. Padwa, U. Chiacchio, D. N. Kline and J. Perumattam, J. Org. Chem., 1988, 53, 2238.
71. R. E. Claus and S. L. Schreiber, Org. Synth., 1986, 7, 168.
72. C. Song, D. W. Knight and M. A. Whatton, Tetrahedron Lett., 2004, 45, 9573.
73. C. K. Lau, C. Dufresne, P. C. Bélanger, S. Piétré and J. Scheigetz, J. Org. Chem., 1986, 51, 3038.
74. S. Masanori and K. Mori, Eur. J. Org. Chem., 2001, 503.
75. R. X. Xu, H. J. Anderson, N. J. Gogan, C. E. Loader and R. McDonald, Tetrahedron Lett., 1981, 22, 4899.
76. L. F. Tietze, G. Kettschau and K. Heitmann, Synthesis, 1996, 38, 851.
77. J. A. Malona, J. M. Colbourne and A. J. Frontier, Org. Lett., 2006, 8, 5661.
78. C. Song, H. Liu, M. Hong, Y. Liu, F. Jia, L. Sun, Z. Pan and J. Chang, J. Org. Chem., 2012, 77, 704.
79. E. K. Starostin, D. B. Furman, A. V. Ignatenko, A. P. Barkova and G. I. Nikishin, Russ. Chem. Bull., Int. Ed., 2006, 55, 2016.
80. D. M. Ketcha, K. P. Carpenter, S. T. Atkinson and H. R. Rajagopalan, Synth. Commun., 1990, 20, 1647.
81. B. C. Ranu and R. Jana, Eur. J. Org. Chem., 2006, 3767.
82. J. H. Frederich and P. G. Harran, J. Am. Chem. Soc., 2013, 135, 3788.
83. C. S. Yeung and V. M. Dong, J. Am. Chem. Soc., 2008, 130, 7826.
84. A. R. Katritzky, K. Suzuki, S. K. Singh and H. Y. He, J. Org. Chem., 2003, 68, 5720.
85. K. Lee and D. F. Wiemer, J. Org. Chem., 1991, 56, 5556.
86. D. A. Oare, M. A. Henderson, M. A. Sanner and C. H. Heathcock, J. Org. Chem., 1990, 55, 132.
87. Y. Sumida, H. Yorimitsu and K. Oshima, J. Org. Chem., 2009, 74, 7986.
88. M. Y. Chang, C. L. Pai and H. P. Chen, Tetrahedron Lett., 2005, 46, 7705.
89. P. Remuzon, Tetrahedron, 1996, 52, 13803.
90. D. X. Hu, M. D. Clift, K. E. Lazarski and R. J. Thomson, J. Am. Chem. Soc., 2011, 133, 1799.
91. D. A. Evans and A. M. Golob, J. Am. Chem. Soc., 1975, 97, 4765.
92. C. Pidathala, L. Hoang, N. Vignola and B. List, Angew. Chem., Int. Ed., 2003, 42, 2785.
93. B. C. Hong, H. C. Tseng and S. H. Chen, Tetrahedron, 2007, 63, 2840.
94. Z. Huang and E. Negishi, Org. Lett., 2006, 8, 3675.
95. L. N. Aldrich, E. S. Dawson and C. W. Lindsley, Org. Lett., 2010, 12, 1048.
96. M. D. Clift and R. J. Thomson, J. Am. Chem. Soc., 2009, 131, 14579.
97. (a) M. Schmittel, A. Burghart, W. Malisch, J. Reising and R. Sollner, J. Org. Chem., 1998, 63, 396; (b) M. Schmittel and A. J. Haeuseler, Organomet. Chem., 2002, 661, 169; (c) M. D. Clift, C. N. Taylor and R. J. Thomson, Org. Lett., 2007, 9, 4667; (d) C. T. Avetta, L. C. Konkol, C. N. Taylor, K. C. Dugan, C. L. Stern and R. J. Thomson, Org. Lett., 2008, 10, 5621.
98. M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1, 953.
99. (a) C. Curti, A. Sartori, L. Battistini, G. Rassu, P. Burreddu, F. Zanardi and G. Casiraghi, J. Org. Chem., 2008, 73, 5446; (b) C. W. Downey and M. W. Johnson, Tetrahedron Lett., 2007, 48, 3559.
100. C. Boonlarppadab, C. A. Kauffman, P. R. Jensen and W. Fenical, Org. Lett., 2008, 10, 5505.
101. L. N. Aldrich, E. S. Dawson and C. W. Lindsley, Org. Lett., 2010, 12, 1048.
102. R. Greenhouse, C. Ramirez and J. M. Muchowski, J. Org. Chem., 1985, 50, 2961.
103. A. K. Chatterge, J. P. Morgan, M. Scholl and R. H. Grubbs, J. Am. Chem. Soc., 2000, 122, 3783.
104. L. N. Aldrich, C. B. Berry, B. S. Bates, L. C. Konkol, M. So and C. W. Lindsley, Eur. J. Org. Chem., 2013, 4215.
105. D. A. Evans, J. Bartoli and T. L. Shih, J. Am. Chem. Soc., 1981, 103, 2127.
106. M. T. Crimmins and J. She, Synlett, 2004, 8, 1371.
107. T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1980, 102, 5974.
108. J. M. Finan and Y. Kishi, Tetrahedron Lett., 1982, 23, 2719.
109. J. R. Parikh and W. E. Doering, J. Am. Chem. Soc., 1967, 89, 5505.
110. (a) H. Stetter, Angew. Chem., 1976, 88, 695; (b) H. Stetter, Angew. Chem., Int. Ed., 1976, 15, 639.
111. X.-C. Cai, X. Wu and B. B. Snider, Org. Lett., 2010, 12, 1600.
112. N. Cohen, B. L. Banner, J. F. Blount, G. Weber, M. Tsai and G. Saucy, J. Org. Chem., 1974, 39, 1824.
113. J. M. Muchowski and D. R. Solas, J. Org. Chem., 1984, 49, 203.
114. G. A. Lee, Synthesis, 1982, 508.
115. J. S. Lee, Y.-S. Kim, S. Park, J. Kim, S.-J. Kang, M.-H. Lee, S. Ryu, J. M. Choi, T.-K. Oh and J.-H. Yoon, Appl. Environ. Microbiol., 2011, 77, 4967.
116. (a) N. N. Gerber, Tetrahedron Lett., 1983, 24, 2797; (b) H. Laatsch and R. H. Thomson, Tetrahedron Lett., 1983, 24, 2701.
117. (a) R. Pandey, R. Chander and K. B. Sainis, Curr. Pharm. Des., 2009, 15, 732; (b) K. Kamata, S. Okamoto, S. Oka, H. Kamata, H. Yagisawa and H. Hirata, FEBS Lett., 2001, 507, 74; (c) C. Yamamoto, H. Takemoto, K. Kuno, D. Yamamoto, A. Tsubura, K. Kamata, H. Hirata, A. Yamamoto, H. Kano, T. Seki and K. Inoue, Hepatology., 1999, 30, 894; (d) D. Yamamoto, Y. Uemura, K. Tanaka, K. Nakai, C. Yamamoto, H. Takemoto, K. Kamata, H. Hirata and K. Hioki, Int. J. Cancer, 2000, 88, 121; (e) D. Yamamoto, K. Tanaka, K. Nakai, T. Baden, K. Inoue, C. Yamamoto, H. Takemoto, K. Kamato, H. Hirata, S. Morikawa, T. Inubushi and K. Hioki, Breast Cancer Res. Treat., 2002, 72, 1.
118. R. Pandey, R. Chander and K. B. Sainis, Indian J. Biochem. Biophys., 2007, 44, 295.
119. H. H. Wasserman and J. M. Fukuyama, Tetrahedron Lett., 1984, 25, 1387.
120. E. E. Schultz and R. Sarpong, J. Am. Chem. Soc., 2013, 135, 4696.
121. T. Magauer, H. J. Martin and J. Mulzer, Angew. Chem., Int. Ed., 2009, 48, 6032.
122. N. A. LeBel and N. Balasubramanian, J. Am. Chem. Soc., 1989, 111, 3363.

---