The aspidosperma alkaloid goniomitine was synthesized in six steps from 2-ethyl-δ-valerolactam. The convergent strategy features an Ullman coupling to assemble the required carbon atoms. A complexity-generating radical translocation reaction was used to build the indole architecture

Beaudry, Christopher M.

Vellucci, Jessica K.

Undetermined

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Total	  Synthesis	  of	  (±)-­‐Goniomitine	  via	  Radical	  Translocation.	  Jessica K. Vellucci and Christopher M. Beaudry* Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR  97331 Supporting Information Placeholder ABSTRACT: The aspidosperma alkaloid goniomitine was synthesized in six steps from 2-ethyl-δ-valerolactam.  The convergent strategy features an Ullman coupling to assemble the required carbon atoms. A complexity-generating radical translocation reaction was used to build the indole architecture. Goniomitine (1) is a monoterpene alkaloid that was isolated in 1987 by Husson and coworkers from the Madagascan tree Gonioma malagasy.1  Goniomitine belongs to the family of aspidosperma alkaloids, but it has an unusual molecular archi-tecture featuring four angularly fused rings and an aminal functional group.  Husson and coworkers forwarded an in-sightful biogenetic hypothesis suggesting that goniomitine is derived from vincadifformine, which has a more typical aspi-dosperma alkaloid structure (Scheme 1).1 Intermediate 2 was hypothesized to undergo ester hydrolysis and decarboxylation to arrive at tetracycle 3.  Retro-Mannich reaction would pro-duce iminium 4, which could be captured by the indole to pro-duce goniomitine. This biosynthetic hypothesis was substanti-ated by subsequent investigations by Husson,2 and by a bio-mimetic synthesis of goniomitine from vincadifformine fol-lowing this strategy by Lewin and coworkers.3 Scheme 1. Biosynthetic Hypothesis for Goniomitine.              The unusual molecular architecture of goniomitine and its micromolar antiproliferative activity on several cancer cell lines have captivated the attention of many synthetic chem-ists.4,5 In addition to the biosynthetic studies by Husson and Lewin, eight total syntheses of goniomitine have been report-ed.  All of these total syntheses follow two general strategies. In the first strategy4 (Scheme 2), a protected tryptophol start-ing material (5) is functionalized at the C2 position of the in-dole in one or more steps. Additional synthetic transfor-mations are used to build the δ-valerolactam C-ring found in goniomitine.  Finally, reduction of a tethered azide and reduc-tive cyclization with the lactam carbonyl gives the aminal structure and completes the synthesis of goniomitine. Scheme 2. Tryptophol Functionalization Strategy.          The second general strategy for goniomitine5 is exemplified in Scheme 3.  An ortho-substituted aniline 8 is used as a start-ing material for the construction of a 2,3-disubstituted indole 9.6 Several steps are used to append a tethered D-ring in the form of a δ-valerolactam with the quaternary stereocenter in tact.  Activation of the lactam carbonyl in 9 gives an iminium ion (10) that cyclizes to form the aminal functional group in goniomitine. Scheme 3. Indole Functionalization Strategy.              Our interest in aminal-containing molecules led us to goni-omitine.7  Initially, we explored strategies to use aminal radi-cal intermediates for the construction of the goniomitine struc-ture. Radical chemistry is well suited for the synthesis of ni-trogenous molecules, as carbon-centered radicals are generally  tolerant of the nitrogen lone pair and the rich acid-base reac-tivity of the nitrogen atom.8 However, our initial efforts were ultimately unsuccessful because of a general paucity of meth-ods for the preparation of aminals incorporating indole nitro-gen atoms.9 However, we continued to consider radical-based approaches toward the goniomitine structure.   Goniomitine may arise from intermediate 11, which was envisioned to be an immediate precursor to the natural product by way of global hydride reduction (Scheme 4). In a departure from all previous synthetic strategies, we chose to unravel the indole B-ring to give intermediate 12. Intermediate 12 could be prepared from substituted δ-valerolactam 13 using standard cross-coupling methods.   Scheme 4.  Retrosynthetic Analysis of Goniomitine.         The previous syntheses of goniomitine involved 8–28 syn-thetic steps, and many of the transformations were devoted to preparing the central C-ring of the target molecule. In fact, all previous syntheses of goniomitine required construction of the central C-ring. We suspected that beginning our synthesis with a readily available δ-valerolactam starting material (as the C-ring) could result in an expeditious synthesis of the target mol-ecule.     A key consideration in the synthesis of goniomitine is creat-ing the quaternary stereocenter. We initially followed Pagen-kopf’s report that a one step alkylation (or a more robust 4 step sequence) of 14 would give 15, which contains the requisite quaternary carbon (Scheme 5, top).5b We were able to opti-mize the one step conversion to a synthetically useful 63% yield. However, we had substantial difficulty removing the benzyl protecting group to give lactam 13.  After many failed attempts at this transformation with hydrogenolysis10 and other conditions,11 we found that dissolving metal reduction cleanly removed the benzyl group to give 13, which proved to be a sensitive intermediate.  Lactam 13 could be taken into the subsequent coupling with iodide 1612 without purification, but the Ullmann coupling to give 12 was low yielding. Ultimately, although we were able to forge the desired bonds, the chemi-cal yields were disappointing, and an alternative route was investigated.    Changing the order of steps proved to be auspicious and more step-economical (Scheme 5, bottom). We found that the Ullmann coupling of ethyl δ-valerolactam with 16 was a high-yielding reaction producing N-aryl lactam 17. Moreover, the installation of the quaternary carbon proceeded smoothly to give 12 in high yield, which avoided the use of the benzyl protecting group altogether. Finally, bromination of the alkene gave key cyclization intermediate 18 as a 2.8:1 mixture of alkene isomers. Notably, this sequence begins from ethyl δ-valerolactam and assembles 18 in just three high-yielding op-erations, and 18 is complete with all the carbons of goniomi-tine and a functional handle for the radical cyclization reac-tion.  Scheme 5.  Preparation of Radical Reaction Substrate.               With 18 in hand, the key radical cyclization reaction was investigated.13 Treatment of 18 with standard radical condi-tions led to the formation of desired indolines 19 and 20 as a 2.4:1 mixture of cis-indoline diastereomers. Presumably, the initial radical species 21 arises from the homolytic cleavage of the C–Br bond.  Radical translocation then gives α-amino radical 22. Intramolecular cyclization gives radical 23, which abstracts a hydrogen atom from Bu3SnH to give the products. Scheme 6.  Radical Translocation.    The combined chemical yield of 19 and 20 in the reaction was quite good, and the production of two diastereomeric in-dolines was acceptable because these stereocenters will be destroyed upon oxidation to the corresponding indole. The pure geometric alkene isomers of 18 were isolated and indi-vidually subjected to the radical reaction; they gave an identi-cal mixture of 19 and 20. This result indicated there is no ste-reospecificity in this reaction, and the alkene geometry of 18 is inconsequential.     The stereochemistry of 19 and 20 is also inconsequential for the goniomitine synthesis; however, the stereochemistry of the major product diastereomer (19) was determined using NOESY methods (see key correlations in Scheme 6). The sim-ilarity of the coupling pattern in 19 and 20 lead us to tentative-ly assign 20 as a trans indoline as well.     Oxidation of 19 and 20 to indole 11 would convert both dia-stereomers to one racemic product, and it would make charac-terizing intermediates from the final steps of the synthesis more convenient. However, the N-acyl group, substitution at both C2 and C3, and the inductively withdrawing carbometh-oxy group in 19 and 20 conspired against this transformation, and no conditions for the indoline oxidation to 11 were found. Most standard reagents (MnO2, DDQ, Pd/C, S8, KMnO4) for indoline oxidation14 were ineffective, returning unreacted start-ing materials. More forcing conditions using CAN (Scheme 7, eq 1) or NBS (eq 2) gave over-oxidation of the indole produc-ing 24 and 25, respectively. Scheme 7.  Attempted Indoline Oxidation.     Of course, the goniomitine structure does not possess an N-acyl indole, so we decided to postpone the indoline oxidation step and perform the required hydride reduction first. Previous goniomitine syntheses utilized a reductive cyclization se-quence of compounds with structure 7 (Scheme 1) that was promoted by LiAlH4. Treatment of 19 and 20 with LiAlH4 in hot THF for 12 hours, followed by an aqueous workup gave a mixture of compounds with spectroscopic characteristics con-sistent with the desired reduction products 26 as a complex mixture of diastereomers. Gratifyingly, intermediates 26 un-derwent smooth oxidation with MnO2 to give the natural prod-uct as the only isolable product. The combined yield of goni-omitine from radical translocation products 19 and 20 was 51%. Scheme 8.  Completion of the Goniomitine Synthesis.           In summary, we have completed a synthesis of the aspido-sperma alkaloid goniomitine. The synthesis requires six syn-thetic transformations from ethyl δ-valerolactam and has an overall yield of 29%, which makes it the most efficient syn-thesis of (±)-goniomitine to date.  Key features of this synthe-sis are the strategic use of a δ-valerolactam starting material and a radical translocation reaction to build the indole B-ring.  Efforts to extend this strategy in other alkaloid targets are un-derway in our laboratory.  ASSOCIATED	  CONTENT	  	  Supporting	  Information	  Experimental procedures, spectroscopic data, depiction of 1H and 13C NMR spectra for all new compounds. This material is availa-ble free of charge via the Internet at http://pubs.acs.org. AUTHOR	  INFORMATION	  Corresponding	  Author	  * christopher.beaudry@oregonstate.edu Author	  Contributions	  The manuscript was written through contributions of all authors.  ACKNOWLEDGMENT	  	  This work was supported by the National Science Foundation under Grant Number 1465287. Any opinions, findings, and con-clusions or recommendations expressed are those of authors and do not necessarily reflect the views of the National Science Foun-dation. REFERENCES	                                                    (1) (a) Randriambola, L.; Quirion, J. –C.; Kan-Fan, C.; Husson, H. –P. Tetrahedron Lett. 1987, 28, 2123.  (2) Hashimoto, C.; Husson, H. –P. Tetrahedron Lett. 1988, 29, 4563. (3) (a) Lewin, G.; Bernadat, G.; Aubert, G.; Cresteil, T. Tetrahedron 2013, 69, 1622. (b) Lewin, G.; Schaeffer, C.; Lambert, P. H. J. Org. Chem. 1995, 60, 3282.  (c)  Lewin, G.; Schaeffer, C. Nat. Prod. Lett. 1995, 7, 227. (4) (a) De Simone, F.; Gertsch, J.; Waser, J.  Angew. Chem. Int. Ed. 2010, 49, 5767. (b) Jiao, L.; Herdtweck, E.; Bach, T. J. Am. Chem. Soc. 2012, 134, 14563. (c) Zhou, S.; Jia, Y. Org. Lett. 2014, 16, 3416. 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Total Synthesis of (±)-Goniomitine via Radical Translocation

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Total Synthesis of (±)-Goniomitine via Radical Translocation

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