Progress in Heterocyclic Chemistry

By Elsevier Science

Progress in Heterocyclic Chemistry (PHC) is an annual review series commissioned by the International Society of Heterocyclic Chemistry (ISHC). Volumes in the series contain both highlights of the previous year’s literature on heterocyclic chemistry and articles on emerging topics of particular interest to heterocyclic chemists. The chapters in Volume 23 constitute a systematic survey of the important original material reported in the literature of heterocyclic chemistry in 2010.

As with previous volumes in the series, Volume 23 apprises academic/industrial chemists and advanced students of developments in heterocyclic chemistry in a convenient format.

• Covers the heterocyclic literature published in 2010
• Includes specialized reviews
• Features contributions from leading researchers in their fields

• Language: English
• Publisher: Elsevier Science
• Release date: Sep 22, 2011
• ISBN: 9780080968063

Book preview

Chemistry

Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids

Justin M. Lopchuk

---

Dartmouth College, Department of Chemistry, Hanover, NH 03755, USA

[e-mail]

1.1. Introduction

Aspidosperma alkaloids are a subset of the naturally occurring monoterpenoid indole alkaloids that are derived from the fusion of tryptamine and a terpene unit (generally either 9 or 10 carbons). More than 250 different compounds are known and many are of synthetic or biological interest 〈B-09MI311〉. In addition to the significant interest from an organic synthesis perspective, a variety of studies designed toward a better understanding of the biosynthesis of these molecules have become increasingly prevalent in the literature 〈B-10MI977〉.

The synthesis of Aspidosperma alkaloids was previously reviewed in 1998 by Saxton 〈B-98MI2, B-98MI343〉, and a short review of the total syntheses of haplophytine has also been recently published 〈09AG(I)7480〉. This review is not intended to be comprehensive but instead will highlight various strategies for the construction of these complex molecules reported from 2000 to early 2011.

1.2. Aspidospermine and aspidospermidine

Aspidospermine and aspidospermidine (along with tabersonine) are the archetypical members of the Aspidosperma alkaloids. As they comprise the basic core system of the more functional group dense and stereochemically complex members of this family of natural products, they are a popular target and ideal proving ground for new synthetic methods. Heathcock and Toczko reported a racemic synthesis of aspidospermidine in which the key complexity-generating step was the TFA-mediated intramolecular cascade cyclization of precursor 6 to give tetracyclic intermediate 7 in high yield 〈00JOC2642〉. To effect the final ring closure, chloroacetamide 8 was converted to the corresponding iodide. Treatment with silver triflate yielded pentacycle 9 which gave (+/−)-aspidospermidine upon reduction with LiAlH4.

Marino and coworkers reported an enantioselective synthesis of (+)-aspidospermidine 〈02JA13398〉 in which Boc-protected aniline 10 was converted to intermediate 11 in five steps. Lactone 11 was ring-opened with pyrrolidine to give aldehyde 12 which subsequently underwent an intramolecular aldol reaction followed by conversion to chloroamide 13. When key intermediate 13 was treated with NaH, tricycle 14 was formed via a tandem conjugate addition/intramolecular alkylation cascade. The enone was installed with a modified Saegusa reaction; treatment of 15 with 3 M HCl facilitated deprotection of the aniline which underwent immediate conjugate addition to yield tetracycle 16. The synthesis of (+)-aspidospermidine was completed by Wolff–Kishner reduction of the ketone and LiAlH4 reduction of the amide carbonyl.

An intramolecular Schmidt reaction was utilized by Aube et al. to convert intermediate azide 17 to tricyclic amide 18 with TiCl4 〈05JOC10645〉. The enantioselective synthesis of aspidospermidine was completed after seven more steps in an overall yield of 1.1% (longest linear sequence, 22 steps).

Sharp and Zard reported a radial cyclization approach to tricyclic amine 23 which served as a key intermediate in the racemic synthesis of aspidospermidine 〈06OL831〉.

The route to amine 23 began with the Birch reduction of anisole derivative 19 followed by cyclization to yield lactol 20. Radical precursor 22 was treated with ACCN and tributyltin hydride to afford tricyclic amine 23. This radical cyclization was also successfully applied to the Stemona alkaloid core and could see future applications in the synthesis of pyrrolizidine and indolizidine alkaloids.

Waser recently reported a unique approach that utilized the catalytic cyclization of aminocyclopropanes to generate complex tetracyclic indole scaffolds 〈10AG(I)5767〉. Indole derivative 24 was coupled with aminocyclopropane 25 to give cyclization precursor 26. Upon treatment with either TsOH or Cu(OTf)2, 26 underwent cyclization to tetracycle 27. In addition to completing a formal synthesis of aspidospermidine, this methodology was used in the total synthesis of goniomitine. Shishido and coworkers utilized a diastereoselective ring-closing metathesis reaction to synthesize (−)-aspidospermidine 〈03OL749〉 and (−)-limaspermine 〈04H(62)787〉.

1.3. Aspidofractinine

Aspidofractinine was initially isolated in 1963 and first synthesized in 1976 by Ban and coworkers. This highly strained molecule has received comparably little recent attention from the synthetic community despite the challenging carbon skeleton. The most recent synthesis of (+)-aspidofractinine was reported by Gagnon and Spino in 2009 〈09JOC6035〉. Advanced intermediate 28 was prepared from indole and utilized a ring-closing metathesis as one of the key steps to form the tricycle. The α-bromoketone was converted to α-diazoketone 29 with (TsNH)2 and DBU. Upon treatment with CuOTf, 29 underwent chemoselective cyclopropanation to yield 30 in 76% yield. Exposure of 30 to NaI in acetone gave the corresponding iodide which was then treated with AIBN and tributyltin hydride to affect radical cyclization which completed the core pentacyclic structure.

Imine 32 was generated by allowing 31 to react with sodium and anthracene which both removed the protecting group and ring-opened the cyclopropane. Oxidation with phenylseleninic acid installed the double bond in conjugation with the imine, which tautomerized upon heating to reveal a diene fortuitously setup for a Diels–Alder reaction with phenylvinylsulfone. Cycloaddition adduct 34 was desulfurized with Raney nickel in 67% yield; reduction with LiAlH4 completed the synthesis of (+)-aspidofractinine.

1.4. Tabersonine

Tabersonine was first isolated in 1954 and is believed to be the biosynthetic precursor to most of the Aspidosperma alkaloids including vindoline (and thus also vinblastine and vincristine). Tabersonine is somewhat more complicated than aspidospermidine but necessarily contains the same core structure and so can be accessed by similar methods. A gram-scale asymmetric synthesis of (+)-tabersonine was reported by Rawal and coworkers in 2002 〈02JA4628〉. An endo-selective Diels–Alder reaction of aminosiloxydiene 37 and vinyl aldehyde 38 gave cyclohexene 39 in excellent yield. Wittig olefination yielded intermediate 40 which was subjected to ring-closing metathesis conditions to generate bicycle 41. An ortho-nitrophenyl group was installed using (ortho-nitrophenyl)phenyliodonium fluoride (NPIF) as the arylating reagent.

The indole synthesis was completed by reducing 42 to the intermediate aniline with TiCl3 and NH4OAc which then underwent spontaneous cyclization in 89% yield. The newly generated indole was deprotected with TMSI followed by reaction with 2-bromoethanol to give 45. Attempted conversion of the alcohol to the corresponding mesylate surprisingly gave chloride 46 which smoothly underwent base-promoted cyclization to tetracycle 47. The synthesis of (+)-tabersonine was completed by deprotonation with LDA and quenching with Mander’s reagent. This proved to be a softer acylating reagent which favored the desired C-acylated product over the N-acylated regioisomer.

1.5. Subincanadines

The subincanadines are a unique subset of the Aspidosperma alkaloids isolated from 2002 to 2005 which have a rearranged pentacyclic skeleton. These molecules have received a considerable amount of attention from synthetic chemists due to their novel skeletons, sparse functionality, and interesting biological activity. Zhai and coworkers reported a synthesis of the pentacyclic core of subincanadine B; the key tetracyclic intermediate was formed in seven steps via a sequence of Michael addition, Pictet–Spengler cyclization, and Dieckmann condensation 〈06OL115〉. The first asymmetric total syntheses of (−)-subincanadines A and B were reported in 2006 by Takayama and Suzuki 〈06OL4605〉. Tryptamine 48 and alcohol 49 (derived from (S)-malic acid) were coupled with carbonyldiimidazole to yield hemiaminoacetal 50 which then underwent a TMSCl-promoted intramolecular Pictet–Spengler reaction. Recrystallization gave a single diastereomer in 99% ee. Advanced intermediate 52 was treated with NiCl2 and CrCl2 in DMSO to affect a Nozaki–Hiyama–Kishi reaction which provided two tetracyclic diastereomers 53 and 54. Both diastereomers were deprotected with TMSCl/NaI and converted to the corresponding mesylates which underwent spontaneous cyclization to complete the total synthesis of (−)-subincanadines A and B.

The first total synthesis of subincanadine F was reported by Zhai and coworkers in 2006 〈06JOC9495〉. This short synthesis began with the cycloaddition of tryptamine 57 and ketoester 58 to yield tetracycle 59 in a single step. Treatment with SmI2 fostered a ring-opening to yield intermediate 60 which was mixed with aqueous formaldehyde to give the homologated ring-closed tetracycle 61. The exocyclic double bond was installed via an aldol condensation with LDA and acetaldehyde (followed by treatment with TFAA, DMAP, and DBU to facilitate the dehydration). Deprotection and decarboxylation with either HCl or AlCl3 then HCl completed the racemic synthesis of subincanadine F.

In 2010, Waters and coworkers disclosed their own concise racemic synthesis of subincanadine F 〈10JOC7026〉. This approach is highlighted by the Ti-mediated cyclization of 64 to give Boc-protected tetracycle 65. Deprotection with TFA reveals subincanadine F.

Other approaches to subincanadine F include a Heck cyclization to the tetracyclic core 〈10SL944〉, a racemic protecting group free synthesis utilizing a Dieckmann condensation 〈09JOC7533〉, and the first asymmetric synthesis of (+)-subincanadine F which took advantage of a chemoselective radical cyclization to form the core system 〈10CC8436〉.

1.6. Meloscine

Meloscine is a structurally rearranged alkaloid closely related to the Aspidosperma family. The structure of meloscine was elucidated in 1969 and first synthesized by Overman in racemic form. No new syntheses of this compound were reported until 2008 when Bach and Selig disclosed the first enantioselective total synthesis of (+)-meloscine 〈08AG(I)5082, 09CEJ3509〉. Cyclobutane derivative 68 was generated from the regioselective and stereoselective photocyclization of amine 66 and silyl enol ether 67 with chiral complexing agent 70. Intermediate 68 underwent base-promoted rearrangement to give tricycle 69.

After acylation, compound 71 was deprotected with TFA and exposed to hydrogenation conditions which diastereoselectively reduced the enol double bond and induced cyclization of the amine (which was then reprotected with Boc2O) to yield tetracycle 72. Alcohol 73 was generated by a sequence of acetate hydrolysis, oxidation with IBX,  Wittig olefination, and DIBAL-H reduction in 60% yield over the four steps.

Intermediate alcohol 73 was converted to the methyl ester with trimethyl orthoacetate and hydroquinone in 85% yield. The amine was deprotected with TFA and converted to diene 74 with allyl bromide. Exposure to Grubbs II catalyst affected ring-closing metathesis which gave the core skeleton in near quantitative yield. The methyl ester was reduced in a two-step sequence with DIBAL-H and NaBH4 to yield intermediate 75. The resulting alcohol was eliminated to complete the enantioselective synthesis of (+)-meloscine in 15 steps and 7% overall yield.

A racemic synthesis of meloscine was reported by Mukai and coworkers which coupled aniline derivative 77 with propiolic acid using EDC 〈11OL1778〉. Intermediate 78 was treated with Co2(CO)8 to facilitate the intramolecular Pauson–Khand reaction which generated tetracycle 79 in one step. This intermediate was further elaborated to give (+/−)-meloscine.

1.7. Miscellaneous approaches to the general aspidosperma core

Owing to the congested pentacyclic core structure of the Aspidosperma alkaloids, general approaches to this family of natural products are frequently reported in the literature. A few of these methods are outlined below.

Vanderwal and Martin reported a general approach to the core structure of the Aspidosperma, Strychnos, and Iboga alkaloids 〈09JA3472〉 in which tethered diene 80 underwent intramolecular Diels–Alder reaction with the indole double bond to yield tetracycle 81. The double bond migrated under the basic reaction conditions to remain in conjugation with the aldehyde. This method was utilized successfully in the total synthesis of norfluorocurarine. In 2008, Ishikawa, Saito, and coworkers reported the base-promoted condensation of substituted ketones and vinyl esters to yield a variety of cyclic ketones with quaternary carbon centers (82 and 83) 〈08JOC7498〉. This approach proved exceedingly flexible and was utilized in the total synthesis of (+)-aspidospermidine, (+/−)-galanthamine, (+/−)-lycoramine, and (+/−)-mesembrine.

Coldham and coworkers reported an efficient synthesis of tricyclic amines that are useful intermediates in the synthesis of a variety of alkaloids 〈07AG(I)6159, 09JOC2290〉. Simple ketone 84 was converted into cascade precursor 85 in just four steps. With the addition of glycine and camphorsulfonic acid (CSA) to 85, a cyclization/cycloaddition cascade proceeded to give tricyclic amine 86 after deprotection with HCl. This versatile approach was used to successfully synthesize aspidospermine, aspidospermidine, and quebrachamine.

Various other approaches have been reported, including the use of chiral cyclopentanoids as starting materials 〈09H(77)855〉, 1,3-dipolar cycloadditions of diazo imides with tethered indole 〈09TL3675〉, intramolecular imino Diels–Alder reactions 〈10OL2012〉, intramolecular Heck reactions 〈07OL3101, 08CPB1567〉, Ullmann cross-coupling reactions 〈05OBC213, 05AJC722〉, reductive radical cyclizations 〈04T3273〉, and palladium-catalyzed oxidative amination cascades 〈07OL3913〉.

1.8. Vindoline, vinblastine, and vincristine

The significant synthetic interest in vinblastine and vincristine is due to both their clinical use and structural complexity. Vindoline comprises the more complex half of vinblastine and is a popular target for researchers.

Murphy and coworkers reported a formal synthesis of vindoline 〈02OL443〉 which relies on a tandem radical cyclization to produce the key tetracyclic intermediate (the same group has also published a total synthesis of (+/−)-aspidospermine using radical chemistry 〈99JCS(P1)995〉). In 2007, Fukuyama reported the synthesis of (−)-vindoline 〈00SL883〉. They expanded upon this work with their total synthesis of (+)-vinblastine and generated a number of analogs which were evaluated for biological activity 〈07OL4737〉. Much of the work toward the total synthesis of these alkaloids has been completed by the Boger group who have developed a tandem [4 + 2]/[3 + 2] cycloaddition of a 1,3,4-oxadiazole as the key complexity building step 〈05OL4539, 06JA10596〉. Key intermediate 92 in Boger’s synthesis of vindoline was generated by the coupling of indole 90 and acid 91 with EDC and DMAP in high yield. The tandem cyclization proceeded smoothly first with a Inverse Electron Demand Diels–Alder reaction, loss of N2 to generate the carbonyl ylide 94, followed by the 1,3-dipolar cycloaddition to yield the advanced pentacycle 95.

This impressive sequence forms four new carbon–carbon bonds, three rings, and six stereocenters all in a single step. Compound 95 was further elaborated by installation of an OTIPS group at C7, sulfurization, and desulfurization to remove the carbonyl group. The concise synthesis of (+) and (−) vindoline was completed by reductive cleavage of the bridging oxygen and Mitsunobu elimination to install the final double bond. A similar synthetic plan was also utilized in the total synthesis of (−)- and (+)-4-desacetoxy-5-desethylvindoline 〈07H(72)95〉, minovine 〈05OL741〉, and aspidoalbidine 〈10JA3009〉. Boger and coworkers later reported an improved asymmetric total synthesis of vindoline which took advantage of a shortened tether to significantly improve the key cycloaddition cascade 〈10JA3685, 10JA13533〉.

Other improvements in the synthesis included a ring-expansion/Kornblum oxidation sequence to generate pentacycle 104 from bridged intermediate 103.

The total synthesis of vinblastine by the direct coupling of catharanthine 105 and vindoline has been explored by a number of research groups over the past 35 years. Most synthetic routes required numerous steps or yielded either multiple diastereomers or a reduced version of vinblastine. Boger and coworkers were able to develop a one-pot direct coupling of catharanthine 105 and vindoline 87 to give (+) and (−)-vinblastine 88 〈08JA420, 09JA4904〉. The reaction proceeded in 66% overall yield giving a 2:1 mixture of diastereomers (β-OH was the major diastereomer).

1.9. Aspidophytine and haplophytine

Aspidophytine and haplophytine are two of the constituents of a traditional insecticidal powder used in various parts of Mexico and Central Mexico. However, it was not until the 1960s that the structures were finally elucidated and took until 1999 for the first total synthesis of aspidophytine to be reported by Corey 〈99JA6771〉. This remarkable synthesis relies on the coupling of tryptamine derivative 108 and dialdehyde 109 and subsequent cascade which constructs three new rings and three stereocenters, including a quaternary center in one step.

Fukuyama and coworkers disclosed their own enantioselective total synthesis of aspidophytine which utilized a Sonogashira coupling to join iodoindole 111 with chiral acetylene 112 〈03OL1891, 03T8571〉. The chiral acetylene was made in 11 steps starting from cyclopentenone.

Advanced intermediate 113 was further elaborated by a cis-selective reduction of the triple bond and a key step which involved an intramolecular Mitsunobu reaction of the o-nosyl protected amine and pendant alcohol to yield macrocycle 115. An intramolecular Mannich reaction and lactonization completed the synthesis of 116.

Marino and Cao utilized chemistry developed during their work on aspidospermidine which allowed them to take functionalized intermediate 117 to the pentacyclic core 119 of aspidophytine in just three steps including a tandem conjugate addition/intramolecular alkylation followed by a modified Saegusa reaction 〈06TL7711〉.

Further functional group manipulation and lactonization completed the synthesis of aspidophytine. Padwa and coworkers took advantage of a different strategy that utilized their well-developed Rh(II)-catalyzed cyclization/dipolar cycloaddition chemistry 〈06OL3275, 06TL8387, 08HCA285〉. Indole acetic acid derivative 120 and diazo compound 121 were joined with (COCl)2 (via the acid chloride) to yield key precursor 122. Upon treatment with Rh2(OAc)4, intermediate 122 underwent decomposition of the diazo group and cyclization to form carbonyl ylide 123. A facile intramolecular [3 + 2]-dipolar cycloaddition of the carbonyl ylide with the indole double bond proceeded smoothly and was followed by treatment with BF3–OEt2 to effect lactonization which completed the construction of the core ring system. The synthesis was finished in eight more steps by installing the C-ring double bond and removal of the E-ring carbonyl.

The most recent asymmetric total synthesis reported by Nicolaou et al. accessed intermediate 128 by Suzuki coupling of known indole boronic acid 126 with vinyl iodide 127 〈08JA14942〉. Treatment of 128 with Tf2O induced a 6-exo-trig-cyclization followed by reduction of the isolable iminium 129 gave tetracyclic compound 130. The primary alcohol was deprotected and converted to xanthate 131, which, upon exposure to n-Bu3SnH and AIBN, underwent radical cyclization to yield pentacycle 132 as a single diastereomer in 58% yield. The synthesis of aspidophytine was completed by TBAF-mediated hydrolysis and oxidative lactonization with K3Fe(CN)6 in a single pot.

Due to the precedent of direct coupling between vindoline and catharanthine, it is not unreasonable to expect that aspidophytine and the left-hand domain of haplophytine could be coupled together as well. Toward this end, Corey and coworkers examined model systems designed to probe this problem 〈06OL3117〉. Unfortunately, this biomimetic route remains a significant unsolved challenge. Haplophytine has long been known to undergo HBr-mediated rearrangement to give 133; researchers working toward the total synthesis of haplophytine used this rearrangement to great effect when constructing the left-hand portion of the molecule.

Despite the first total synthesis of aspidophytine being achieved in 1999, it remained another decade before the first total synthesis of haplophytine was reported in 2009 by Fukuyama and Tokuyama nearly 60 years after it was initially isolated 〈07SL3137, 09AG(I)7600〉.

Tricyclic ketone 137 was prepared from diol 135 (itself prepared in 10 steps from commercially available ketone 134) by a regioselective sulfonylation of the less sterically hindered alcohol followed by PCC oxidation of the other alcohol. The intermediate was treated with Cs2CO3 which promoted intramolecular N-alkylation to give amine 136. Deprotection of the ketone and ethyl ester was achieved by treatment with 1 M HCl. The nosyl group was removed with PhSH, which set the stage for the intramolecular Mannich reaction. The cyclization proceeded upon treatment of the amine with silica gel followed by the addition of trimethylsilyldiazomethane to give tricyclic ketone 137. The second part of the synthesis commenced with 7-benzyloxyindole which was converted to tetrahydro-β-carboline 139 over 10 steps. A further six steps gave key intermediate 140 which was treated with m-CPBA to trigger a skeletal rearrangement in 84% yield.

Key intermediate 144 was deprotected and condensed with tricyclic ketone 137 to ultimately yield Fischer indole product 145 in 47% yield. Treatment of 145 with phenylselenyl anhydride installed the desired C-ring double bond in compound X; removal of the Cbz group was achieved with BBr3. Imine reduction and reductive methylation were achieved with formaldehyde, NaBH3CN, and AcOH, while basic hydrolysis removed the mesyl and methyl ester groups.

Finally, the lactone ring was closed with potassium ferricyanide to yield (+)-haplophytine. In 2007, Nicolaou and coworkers reported a synthesis of the left domain of haplophytine 〈07AG(I)4715〉. This work, along with their prior synthesis of aspidophytine, was utilized to provide the second total synthesis of (+)-haplophytine 〈09AG(I)7616〉. A second generation formal synthesis was reported in 2011 by Chen and coworkers 〈11EJO1027〉.

Tetrahydro-β-carboline 147 (accessed from 7-benzyloxyindole in nine steps) was treated with indoline 148 and phenyliodine-bis-trifluoroacetate in acetonitrile to yield intermediate 149 in 11.5% yield (based on the consumption of 148). Methylation of the phenol gave 150 which underwent hydrolysis of the acetyl group, reprotection with a benzyl group, and finally cleavage of the N,O-acetal with Cs2CO3 and a large excess of methyl iodide to give intermediate 151. Lactam 152 was generated by a sequence of ester hydrolysis, acid chloride formation, and cyclization. Upon treatment with m-CPBA, the skeletal rearrangement proceeded smoothly in 78% yield; the indole double bond was introduced with DDQ to give compound 154.

Boronic ester 155 was coupled with vinyl iodide 127 to produce advanced intermediate 156. The remainder of the synthesis is similar to the chemistry discussed for the total synthesis of aspidophytine; a radical cyclization generated core structure 157 which was taken over six steps to (+)-haplophytine.

1.10. Conophylline and conophyllidine

Conophylline and conophyllidine are bis-indole alkaloids which possess two pentacyclic Aspidosperma core units. They were first isolated in 1992 and have shown both anticancer activity as well as some antidiabetic effects. This biological activity, along with their challenging complex structures, certainly merits attention from the synthetic community.

Two of the core indole units of conophylline were synthesized by Otsuka and coworkers from simple benzene derivatives 〈08JHC1803〉. The first total synthesis of (−)-conophylline and (−)-conophyllidine was completed in 2011 by Fukuyama and coworkers which utilized a Polonovski–Potier reaction as a key step to join the two main pentacyclic units 〈11AG(I)4884〉.

The synthesis of (−)-conophylline commenced from benzene derivative 160 which was converted to isocyanide 161 in 11 steps. Treatment of 161 with n-Bu3SnH, AIBN, and I2 promoted a radical cyclization to form the indole ring system which was further elaborated to yield 162.

Functionalized indole 162 was coupled with dihydrofuran 163 under Mitsunobu conditions to give 164 in 76% yield; the product was exposed to TFA which both deprotected the indole and hydrated the enol ether. Intermediate 165 was treated with pyrrolidine to cleave the 2,4-dinitrobenzenesulfonyl (DNs) group and initiate a cyclization cascade (enamine formation, Michael addition, and Mannich reaction) to furnish advanced pentacycle 167. After indole 167 was reprotected with TrocCl and DMAP, a regioselective dehydration and stereoselective epoxidation were achieved in one-pot with m-CPBA and aq. HClO4. The structure of 168 was confirmed by a global deprotection that gave (−)-taberhanine, a known indole alkaloid.

Oxidation with m-CPBA converted 168 to the corresponding N-oxide 169. A similar synthetic route was utilized to generate pentacycle 170. With both halves of conophylline in hand, the key step, a Polonovski–Potier reaction, could be investigated. Upon exposure to trifluoroacetic anhydride, the electron-rich arene in 170 intercepted the newly generated iminium ion in 169 to give coupled product 171 as a single diastereomer in 50% yield. The ring-closing reaction was achieved by treatment with [Pd(PPh3)4], and exposure to LDA removed both the mesyl and Troc groups to complete the synthesis of (−)-conophylline.

References

B-98MI343 J.E. Saxton, Synthesis of the aspidosperma alkaloids. G.A. Cordell, editor. The Alkaloids: Chemistry and Biology. Vol. 50. San Diego: Academic Press; 1998:343.

B-98MI2 J.E. Saxton. Alkaloids of the aspidospermine group. G.A. Cordell, editor. The Alkaloids: Chemistry and Biology. Vol. 51. San Diego: Academic Press; 1998:2.

B-09MI311 P.M. Dewick. Alkaloids. In: P.M. Dewick, editor. Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition. New York: John Wiley & Sons, Ltd.; 2009:311.

B-10MI977 S.E. O’Connor. Alkaloids. L. Mander, H.-W. Liu, editors. Comprehensive Natural Products II. Vol. 1. Kidlington: Elsevier, Ltd.; 2010:977.

99JA6771 F. He, Y. Bo, J.D. Altom, E.J. Corey. J. Am. Chem. Soc. 1999;121:6771.

99JCS(P1)995 O. Callaghan, C. Lampard, A.R. Kennedy, J.A. Murphy. J. Chem. Soc., Perkin Trans.. 1999;1:995.

00JOC2642 M.A. Toczko, C.H. Heathcock. J. Org. Chem.. 2000;65:2642.

00SL883 S. Kobayashi, Y. Ueda, T. Fukuyama. Synlett. 2000;6:883.

02JA4628 S.A. Kozmin, T. Iwama, Y. Huang, V.H. Rawal. J. Am. Chem. Soc.. 2002;124:4628.

02JA13398 J.P. Marino, M.B. Rubio, G. Cao, A. de Dios. J. Am. Chem. Soc.. 2002;124:13398.

02OL443 S-z. Zhou, S. Bommezijn, J.A. Murphy. Org. Lett.. 2002;4:443.

03OL749 Y-i. Fukuda, M. Shindo, K. Shishido. Org. Lett.. 2003;5:749.

03OL1891 S. Sumi, K. Matsumoto, H. Tokuyama, T. Fukuyama. Org. Lett.. 2003;5:1891.

03T8571 S. Sumi, K. Matsumoto, H. Tokuyama, T. Fukuyama. Tetrahedron. 2003;59:8571.

04H(62)787 Y. Fukuda, M. Shindo, K. Shishido. Heterocycles. 2004;62:787.

04T3273 H. Tanino, K. Fukuishi, M. Ushiyama, K. Okada. Tetrahedron. 2004;60:3273.

05AJC722 M.G. Banwell, D.W. Lupton, A.C. Willis. Aust. J. Chem.. 2005;58:722.

05JOC10645 R. Iyengar, K. Schildknegt, M. Morton, J. Aube. J. Org. Chem.. 2005;70:10645.

05OBC213 M.G. Banwell, D.W. Lupton. Org. Biomol. Chem.. 2005;3:213.

05OL741 Z.Q. Yuan, H. Ishikawa, D.L. Boger. Org. Lett.. 2005;7:741.

05OL4539 Y. Choi, H. Ishikawa, J. Velcicky, G.I. Elliot, M.M. Miller, D.L. Boger. Org. Lett.. 2005;7:4539.

06JA10596 H. Ishikawa, G.I. Elliot, J. Velcicky, Y. Choi, D.L. Boger. J. Am. Chem. Soc.. 2006;128:10596.

06JOC9495 P. Gao, Y. Liu, L. Zhang, P.-F. Xu, S. Wang, Y. Lu, M. He, H. Zhai. J. Org. Chem.. 2006;71:9495.

06OL115 Y. Liu, S. Luo, X. Fu, F. Fang, Z. Zhuang, W. Xiong, X. Jia, H. Zhai. Org. Lett.. 2006;8:115.

06OL831 L.A. Sharp, S.Z. Zard. Org. Lett.. 2006;8:831.

06OL3117 P.D. Rege, Y. Tian, E.J. Corey. Org. Lett.. 2006;8:3117.

06OL3275 J.M. Mejia-Oneto, A. Padwa. Org. Lett.. 2006;8:3275.

06OL4605 K. Suzuki, H. Takayama. Org. Lett.. 2006;8:4605.

06TL7711 J.P. Marino, G. Cao. Tetrahedron Lett.. 2006;47:7711.

06TL8387 X. Hong, J.M. Mejia-Oneto, A. Padwa. Tetrahedron Lett.. 2006;47:8387.

07AG(I)4715 K.C. Nicolaou, U. Majumder, S.P. Roche, D.Y.-K. Chen. Angew Chem. Int. Ed.. 2007;46:4715.

07AG(I)6159 I. Coldham, A.J.M. Burrell, L.E. White, H. Adams, N. Oram. Angew. Chem. Int. Ed.. 2007;46:6159.

07H(72)95 H. Ishikawa, D.L. Boger. Heterocycles. 2007;72:95.

07OL3101 J. Pereira, M. Barlier, C. Guillou. Org. Lett.. 2007;9:3101.

07OL3913 R. Beniazza, J. Dunet, F. Robert, K. Schenk, Y. Landais. Org. Lett.. 2007;9:3913.

07OL4737 T. Miyazaki, S. Yokoshima, S. Simizu, H. Osada, H. Tokuyama, T. Fukuyama. Org. Lett.. 2007;9:4737.

07SL3137 K. Matsumoto, H. Tokuyama, T. Fukuyama. Synlett. 2007;20:3137.

08AG(I)5082 P. Selig, T. Bach. Angew. Chem. Int. Ed.. 2008;47:5082.

08CPB1567 Y. Yasui, H. Takeda, Y. Takemoto. Chem. Pharm. Bull.. 2008;56:1567.

08HCA285 J.M. Mejia-Oneto, A. Padwa. Helv. Chim. Acta. 2008;91:285.

08JA420 H. Ishikawa, D.A. Colby, D.L. Boger. J. Am. Chem. Soc.. 2008;130:420.

08JA14942 K.C. Nicolaou, S.M. Dalby, U. Majumder. J. Am. Chem. Soc.. 2008;130:14942.

08JHC1803 S. Ando, Y. Okamoto, K. Umezawa, M. Otsukam. J. Heterocycl. Chem.. 2008;45:1803.

08JOC7498 T. Ishikawa, K. Kudo, K. Kuroyabu, S. Uchida, T. Kudoh, S. Saito. J. Org. Chem.. 2008;73:7498.

09AG(I)7480 E. Doris. Angew. Chem. Int. Ed.. 2009;48:7480.

09AG(I)7600 H. Ueda, H. Satoh, K. Matsumoto, K. Sugimoto, T. Fukuyama, H. Tokuyama. Angew. Chem. Int. Ed.. 2009;48:7600.

09AG(I)7616 K.C. Nicolaou, S.M. Dalby, S. Li, T. Suzuki, D.Y.-K. Chen. Angew Chem. Int. Ed.. 2009;48:7616.

09CEJ3509 P. Selig, E. Herdtweck, T. Bach. Chem. Eur. J.. 2009;15:3509.

09H(77)855 M. Hayashi, K. Motosawa, A. Satoh, M. Shibuya, K. Ogasawara, Y. Iwabuchi. Heterocycles. 2009;77:855.

09JA3472 D.B.C. Martin, C.D. Vanderwal. J. Am. Chem. Soc.. 2009;131:3472.

09JA4904 H. Ishikawa, D.A. Colby, S. Seto, P. Va, A. Tam, H. Kakei, T.J. Rayl, I. Hwang, D.L. Boger. J. Am. Chem. Soc.. 2009;131:4904.

09JOC2290 A.J.M. Burrell, I. Coldham, L. Watson, N. Oram, C.D. Pilgram, N.G. Martin. J. Org. Chem.. 2009;74:2290.

09JOC6035 D. Gagnon, C. Spino. J. Org. Chem.. 2009;74:6035.

09JOC7533 P. Chen, L. Cao, C. Li. J. Org. Chem.. 2009;74:7533.

09TL3675 H. Nambu, M. Hikime, J. Krishnamurthi, M. Kamiya, N. Shimada, S. Hashimoto. Tetrahedron Lett.. 2009;50:3675.

10AG(I)5767 F. De Simone, J. Gertsch, J. Waser. Angew. Chem. Int. Ed.. 2010;49:5767.

10CC8436 P. Chen, L. Cao, W. Tian, X. Wang, C. Li. Chem. Commun.. 2010;46:8436.

10JA3009 E.L. Campbell, A.M. Zuhl, C.M. Liu, D.L. Boger. J. Am. Chem. Soc.. 2010;132:3009.

10JA3685 D. Kato, Y. Sasaki, D.L. Boger. J. Am. Chem. Soc.. 2010;132:3685.

10JA13533 Y. Sasaki, D. Kato, D.L. Boger. J. Am. Chem. Soc.. 2010;132:13533.

10JOC7026 X. Cheng, C.M. Duhaime, S.P. Waters. J. Org. Chem.. 2010;75:7026.

10OL2012 N.T. Tam, E.-J. Jung, C.-G. Cho. Org. Lett.. 2010;12:2012.

10SL944 D. Sole, M.-L. Bennasar, I. Jimenez. Synlett. 2010;6:644.

11AG(I)4884 Y. Nah-ya, H. Tokuyama, T. Fukuyama. Angew. Chem. Int. Ed.. 2011;50:4884.

11EJO1027 W. Tian, L.R. Chennamaneni, T. Suzuki, D.Y.-K. Chen. Eur. J. Org. Chem. 2011;(6):1027.

11OL1778 Y. Hayashi, F. Inagaki, C. Mukai. Org. Lett.. 2011;13:1778.

Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation

Dmytro Tymoshenko*, Gyorgy Jeges**, Brian T. Gregg*

---

* AMRI, 30 Corporate Circle, Albany, NY 12203, USA

** AMRI Hungary, Zahony u. 7, 1031 Budapest, Hungary

[e-mail]

[e-mail]

[e-mail]

2.1. Introduction and scope of the review

Palladium-catalyzed reactions are versatile and efficient methods for the synthesis of a large number of heterocycles. Annulations of cyclic and bicyclic alkenes 〈C/C-Het palladium-catalyzed annulation sequences (route iv). Several examples of such transformations were included in general palladium-catalyzed amination 〈98AGE2046, 98ACR805, 99JOM125〉 and palladium-catalyzed cyclization 〈04CSY47, 06CRV4644〉 discussions.

Scheme 1

The current review covers advances in palladium-catalyzed intramolecular heteroarylations (route iii) reported over the past 15 years. Mechanistic details of the transformation are well documented 〈06CRV4644〉; thus this survey involves the synthetic aspects of the N-aryl bond forming cyclizations. The review is organized by the size of the rings formed with further partition into subsections based on number of heteroatoms on the ring or fused ring systems. A separate section deals with tandem sequences and cascades.

2.2. Annulation of five-membered aza-rings

2.2.1 Indolines and Indoles

The pioneering work of Buchwald and coworkers 〈96T7525〉 for the synthesis of indolines, oxindoles, and their six- and seven-membered homologs from secondary amine or carbamate precursors served as a touchstone of the intramolecular palladium-catalyzed processes. Usually, these reactions require a suitable ortho-halo-substituted precursor and the proper choice of palladium catalyst, ligand, and base. The original reaction conditions (Scheme 2) result in good yields of cyclized products and include (i) for secondary amines, Pd(PPh)4 in toluene (or DMF) with superior results when K2CO3 or its mixture with t-BuONa was used as a base; (ii) for secondary amides, Pd2(dba)3 as a source of palladium, with P(2-furyl)3 as a ligand with cesium carbonate as a base in toluene; (iii) the reverse amides 5 required Pd2(dba)3 as a source of palladium, with more hindered P(o-Tol)3 ligand with potassium carbonate as a base 〈96T7525〉. It was noted that the coordination chemistry involving the oxidative addition complexes of aryl iodides and aryl bromides is substantially different in intermolecular cases; however, for intramolecular cases, no differences were detectable.

Scheme 2

Later developments (Scheme 3) 〈99OL35, 06SL115〉 indicated that ligands capable of chelation, such as bis-phosphines or ligands with heteroatoms capable of coordination, are superior in many instances for the palladium-catalyzed cyclization of secondary amides and carbamates.

Scheme 3

Thus, in the case of o-bromo benzylamide 5 (n = 1), the reaction proceeded smoothly in 82% yield when (±)-MOP 9 was used as a ligand and K2CO3. Synthesis of indolines 8 (n = 1) requires Cs2CO3 as a base and DPEphos 10 as a ligand 〈99OL35〉. A comparative study of ligands for the formation of oxindole 6 (n = 1, dioxane, Cs2CO3) revealed superior results for phosphine 12a in contrast to ligands 12b and 12c 〈06SL115〉. A similar transformation using X-Phos (13a) and optimized conditions [(Pd(OAc)2, K2CO3, t-BuOH)] allowed synthesis of pharmaceutically valuable intermediate 14 in 90% yield 〈04TL8535, 07BML3421〉.

(S)-N-Acetylindoline-2-carboxylate 19, a key intermediate in the synthesis of the ACE inhibitor 20, has been approached in a similar fashion by Buchwald and coworkers 〈97JA8451, 03JA5139〉. Methyl ester 19 was obtained by a palladium-catalyzed intramolecular coupling of the optically active phenylalanine derivative 17a, which was prepared by a Heck coupling reaction of o-bromoiodobenzene 15 with methyl 2-acetamidoacrylate followed by a rhodium-catalyzed asymmetric hydrogenation of the resulting enamide 16 (Scheme 4) 〈97JA8451〉. Alternatively, tert-butyl ester 17b was obtained by the asymmetric alkylation of 18 with commercially available o-bromobenzyl bromide in the presence of a chiral spiro quaternary ammonium phase-transfer catalyst. Subsequent hydrolysis with citric acid and N-acetylation afforded 17b in 86% yield with 99% ee (S) 〈03JA5139〉. In contrast to an intermolecular process, which results in partial or full racemization upon treatment with Pd2(dba)3/P(oN coupling afforded almost enantiopure 19 (94%, 99% ee).

Scheme 4

Another example of enantiomerically pure substituted 2-carboxy indolines 22 (n = 0) was reported by Jackson and coworkers 〈02J(P1)733〉. The two-step procedure included a palladium-catalyzed coupling of amino functionalized organozinc reagents with 2-bromoiodobenzene, followed by a palladium-catalyzed intramolecular amination reaction. The yields in the initial coupling were modest (36–52%), while the cyclization gave good to excellent yields of the chiral products with > 99% ee (Scheme 5).

Scheme 5

A new and flexible procedure for the synthesis of indolines has been reported 〈03EJO2888〉. The target compounds can be synthesized with high diversity from three building blocks, that is, ortho-bromo- or ortho-chloro-iodobenzenes 23, terminal alkynes, and primary amines. The synthetic strategies include Sonogashira couplings and Cp2TiMe2-catalyzed hydroaminations of alkynes 24 (Scheme 6). The key palladium-catalyzed intramolecular amination of o-halo-substituted phenethylamines 25 and 2-benzyl pyrrolidines 27 results in good to excellent yields of indolines 26. Depending on the nature of the halide (Br or Cl), different catalyst systems are used. The bromo derivatives are treated with t-BuONa and [Pd(PPh3)4], while the chloro derivatives required the presence of t-BuOK, [Pd2(dba)3], and a carbene ligand generated in situ from imidazolium salt 28.

Scheme 6

Analogous synthesis of chiral N-Boc indolines 26 [R¹ = 4-Cl(Br), R² = (S)-Me, i-Pr, Bn, CH2OTBS, R³ = Boc] has been reported using Pd(OAc)2, DPE-Phos, and Cs2CO3 in toluene at 100 °C resulting in 51–97% yields of the products 〈09TL1920〉.

N-Protected-R-aminoacyl-5,7-dinitroindolines 30 are inaccessible through the direct acylation of 5,7-dinitroindoline 31 due to its low reactivity (Scheme 7). Nevertheless, they can be prepared in good yields from phenethyl amides 29 by intramolecular amide N-arylation. Although initial attempts using CuI or Pd2(dba)3/Xantphos failed, reactions succeeded under microwave irradiation using 2-dicyclohexylphosphino-2′-methylbiphenyl (Me-Phos) 32 as a ligand and Pd2(dba)3 as a palladium source. Basic reaction conditions are not compatible with an Fmoc-protecting group, but they tolerate N-Boc, N-Cbz, and serine O-t-Bu protection 〈09JOC4519〉.

Scheme 7

Intramolecular reaction of intermediate 33 in the presence of Pd2(dba)3, P(o-Tol)3, and t-BuONa in toluene at 80 °C cleanly afforded the tricyclic indoline 34 which, when treated with 10 mol% Pd/C in the presence of ammonium formate, gave indole 35 as a product of debenzylation and spontaneous oxidation. The latter serves as an intermediate in the total syntheses of marine alkaloids damirone 36 and makaluvamine 37 (Scheme 8)