A synthetic strategy to access the fused 6–7–6 tricyclic core of hetisine-type C20-diterpenoid alkaloids is reported. This strategy employs a Diels–Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to a vinyl lactone-acetal bearing an aromatic ring in five steps. Aromatic iodination is followed by magnesium–halogen exchange with a trialkyl magnesiate species, which undergoes intramolecular cyclization. Subsequent oxidation provides the desired 6–7–6 tricyclic diketoaldehyde, with carbonyl groups at all three positions for eventual C–N bond formation and subsequent elaboration

deGruyter, Justine N.

Morrill, Louis C.

Perea, Melecio A.

Pflueger, Jason J.

Sarpong, Richmond

Organic Letters

Online Research @ Cardiff

This is a n  Op e n  Acces s  doc u m e n t  dow nloa d e d  fro m  ORCA, Ca r diff U nive r si ty 'sins ti t u tion al r e posi to ry: h t t p s://o rc a .c a r diff.ac.uk/id/e p rin t/10 4 1 8 0/This  is t h e  a u t ho r’s ve r sion  of a  wo rk  t h a t  w as  s u b mi t t e d  to  / a c c e p t e d  forp u blica tion.Cit a tion  for  final p u blish e d  ve r sion:Pflue g er, Jason  J., Mo r rill, Louis  C. ORCID: h t t p s ://o rcid.o r g/00 0 0-0 0 0 2-6 4 5 3-7 5 3 1,  d eGr uyt er, Jus tin e  N., Pe r e a ,  M elecio A. a n d  S a r po n g,  Rich mo n d  2 0 1 7.M a g n e si a t e  a d di tion/ ring-exp a n sion  s t r a t e gy to  a c c e s s  t h e  6-7-6  t ricyclic co r eof h e t isine-typ e  C20-di t e r p e noid  alkaloids.  Or g a nic  Let t e r s  1 9  (17) , p p .  4 6 3 2-4 6 3 5.  1 0.10 2 1/acs.o r gle t t .7 b 0 2 2 6 0  file P u blish e r s  p a g e:  h t t p://dx.doi.or g/10.10 2 1/acs.o rgle t t .7b 0 2 2 6 0< h t t p://dx.doi.o rg/10.10 2 1/acs.o r gl e t t .7 b0 2 2 6 0 >Ple a s e  no t e:  Ch a n g e s  m a d e  a s  a  r e s ul t  of p u blishing  p roc e s s e s  s uc h  a s  copy-e di ting,for m a t ting  a n d  p a g e  n u m b e r s  m ay no t  b e  r eflec t e d  in t his  ve r sion.  For  t h ed efini tive  ve r sion  of t his  p u blica tion,  ple a s e  r ef e r  to  t h e  p u blish e d  sou rc e.  Youa r e  a dvise d  to  cons ul t  t h e  p u blish e r’s ve r sion  if you  wish  to  ci t e  t his  p a p er.This ve r sion  is b ein g  m a d e  av ailable  in  a cco r d a n c e  wit h  p u blish e r  policie s.S e e  h t t p://o rc a .cf.ac.uk/policies.h t ml for  u s a g e  policies.  Copyrigh t  a n d  m o r al  r i gh t sfor  p u blica tions  m a d e  available  in ORCA a r e  r e t ain e d  by t h e  copyrig h thold e r s .Jason J. Pflueger, Louis C. Morrill,† Justine N. deGruyter, Melecio A. Perea, and Richmond Sarpong* Department of Chemistry, University of California, Berkeley, California 94720, United States Supporting Information Placeholder ABSTRACT: A synthetic strategy to access the fused 6–7–6 tricyclic core of hetisine-type C20-diterpenoid alkaloids is reported. This strategy employs a Diels–Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to a vinyl lactone-acetal bearing an aromatic ring in 5 steps. Aromatic iodination is followed by magnesium-halogen exchange with a trialkyl magnesiate species, which undergoes intramolecular cyclization. Subsequent oxidation provides the desired 6–7–6 tricyclic diketoal-dehyde, with carbonyl groups at all three positions for eventual C–N bond formation and subsequent elaboration.Diterpenoid alkaloid natural products have emerged as attrac-tive synthetic targets by virtue of their complex caged skeletons and intriguing biological interactions, particularly with voltage-gated ion channels.1 Among the many structural classifications that have been established, the hetisine-type C20-diterpenoid al-kaloids have emerged as compounds of particular interest. They possess one of the most complex frameworks of any of the diterpenoid alkaloids, with a tertiary amine embedded in a caged heptacyclic core (see nominine (1), Figure 1), and are one of the most prominent diterpenoid alkaloid types, with over 120 known members.2 Furthermore, the hetisine-type alkaloid guan-fu base A (3, Scheme 1) is currently in clinical use in China for the treatment of arrhythmia,3 highlighting the therapeutic poten-tial of these natural products. The observed biological effects of guan-fu base A and many other diterpenoid alkaloid natural products are believed to arise from their interactions with volt-age-gated ion channels, which are emerging as important ther-apeutic targets.4 Figure 1. Hetisine- and Hetidine-type Diterpenoid Alkaloids. To date, only a single hetisine-type diterpenoid alkaloid nat-ural product has succumbed to total synthesis: the mono-hy-droxylated alkaloid nominine (1, Figure 1). This molecule was first synthesized by Natsume and Muratake in 20045 and again by Gin in 2006.6 Despite these initial successes, the synthesis of more highly-oxygenated hetisine-type alkaloids remains elu-sive, and new strategies to access these secondary metabolites with suitable functional group handles are required. The synthe-sis of the related hetidine-type core, which lacks the N–C6 bond (Figure 1), has seen more recent success, with routes from our group7 as well as the labs of Baran8 and Qin.9 While early work by Okamoto suggested a final N–C6 bond could be formed at a late stage through HLF-type chemistry,10 this transformation has not been successfully realized by other investigators, sug-gesting the need for novel strategies that incorporate the for-mation of this N–C6 bond into the synthetic plan. Scheme 1. Synthetic Strategy toward the Hetisine Core  Our research group has identified a central fused 6–7–6 tri-cycle (Scheme 1, highlighted in red) as a key structural motif in the core scaffold of these complex alkaloids. This design choice arises from a network analysis approach to retrosynthesis,11 in which the [2.2.2]bicycle is forged late-stage through a [4+2] cy-cloaddition reaction on a derivative of vinyl arene 5. Further disconnection of the C–N bonds leads both the hetidine and he-tisine cores back to an all-fused 6–7–6 tricycle (6), the key tar-get for our collective synthetic strategies.  Initial efforts in our group utilized a gallium(III)-catalyzed cycloisomerization reaction to convert alkyne 7 into 6–7–6 tri-cycle 8.7 While this reaction proceeds in a high 89% yield, this alkyne takes 13 steps to synthesize (longest linear sequence) and the resulting tricycle is relatively unfunctionalized. Several steps are then required to introduce key functional groups for both the C–N bond forming reactions and the [4+2] cycloaddi-tion. Despite these challenges, the overall strategy was vali-dated with the successful synthesis of the hetidine-type core, which was further elaborated to dihydronavirine (2, Figure 1), the formal hydrogenation product of the natural product navirine. Scheme 2. Efforts toward the Central 6–7–6 Tricycle  On the basis of this precedent, we embarked on a streamlined and higher yielding synthesis of a tricycle that would be more ideally functionalized to access the hetisine-type core. We en-visioned diketoaldehyde 10 as an ideal precursor, with carbonyl groups at all three carbon atoms that form C–N bonds in the hetisine-type alkaloids (Scheme 3). Intramolecular addition of the aromatic ring moiety in 9 was predicted to enable the syn-thesis of this desired tricycle. We envisioned a rapid synthesis of this compound from bicyclic anhydride 11, which could be readily accessed through a Diels–Alder cycloaddition from diene 12 and dienophile 13. Scheme 3. Retrosynthetic Analysis  The synthesis begins with the construction of maleic anhy-dride dienophile 13 (Scheme 4) following a sequence used to synthetize a related compound by Wood and coworkers.12 In this route, benzyl protection of commercially available 3-butyn-1-ol (14) is followed by a palladium-catalyzed dicarboxylation reaction to access diester 16 in 65% yield over two steps after optimization. Saponification of the diester enabled a dehydra-tive cyclization reaction in the presence of acetic anhydride to give dienophile 13 in 4 steps. Diels–Alder cycloaddition with known diene 1213 then affords Diels–Alder adduct 11 in 72% yield as a single diastereomer. Scheme 4. Dienophile Synthesis and Diels–Alder Cycload-dition  After exploring a wide range of nucleophiles, we discovered benzylic ester 17 (readily synthesized through esterification of 3-methoxyphenylacetic acid) adds with complete chemoselec-tivity into the desired carbonyl group. Treatment with HCl then cleaves the silyl ether, and the resulting primary hydroxyl group spontaneously cyclizes to form lactone acetal 18. A Krapcho-type decarboxylation with lithium chloride14 facilitates removal of the methyl ester after which a one-pot alkene hydrogena-tion/benzyl ether hydrogenolysis provides primary alcohol 19. A Grieco elimination completes the installation of the vinyl group needed for eventual formation of the [2.2.2]bicycle, af-fording 9. This sequence proceeds in only 5 steps and 52% over-all yield, allowing rapid access to the cyclization precursor. Scheme 5. Elaboration to Vinyl Lactone-Acetal  We initially explored using a direct Friedel–Crafts cycliza-tion to forge the desired C–C bond. Despite screening a variety of Lewis acids, cyclization was not observed, with most at-tempts simply leading to recovery of starting material. We then turned to the formation of a discreet aromatic nucleophile via metal-halogen exchange of an aryl iodide. An investigation of electrophilic iodination conditions, including iodine monochlo-ride and NIS, with and without Bronsted or Lewis acid addi-tives, identified an indium(III) triflate-catalyzed protocol devel-oped by Romo and coworkers as the most effective,15 producing the desired aryl iodide (21), along with its ortho-positioned iso-mer (20), in a roughly 1:1 mixture (Scheme 6). These isomers were readily separated, and the undesired isomer could be recy- cled through metal-halogen exchange to regenerate vinyl lac-tone-acetal 9 (see the Supporting Information for details). Ulti-mately, a 65% yield of desired aryl iodide 21 (based on recov-ered starting material) could be obtained. Scheme 6. Completion of the Desired 6–7–6 Tricycle  With aryl iodide 21 in hand, conditions for metal-halogen ex-change were then investigated. Lithium-halogen exchange16 proved to be too reactive, leading only to nonspecific decompo-sition products. Direct Grignard formation with magnesium turnings was likewise unsuccessful, returning only starting ma-terial. Classic magnesium-halogen exchange17 with iso-propyl magnesium chloride or with the Turbo Grignard reagent18 like-wise proved to be too unreactive to lead to product formation. Lithium trialkylmagnesiates, developed by Oshima and coworkers,19 gratifyingly facilitated magnesium-halogen ex-change as well as a subsequent 1,2-addition of the resulting magnesiate into the lactone carbonyl. The resulting adduct ex-ists as an equilibrium of hemiacetal structures; as such, the crude reaction mixture was directly oxidized with Dess-Martin periodinane following a modified protocol reported by Nico-laou,20 providing diketoaldehyde 10, the structure of which was confirmed by an X-ray crystallographic study of a single crys-tal. This sequence proceeds in 59% yield over 2 steps and can be readily performed on gram-scale, allowing for rapid material throughput. This route to diketoaldehyde 10 represents the next step in our group’s evolving strategy to rapidly access the 6–7–6 fused tricyclic core of hetidine- and hetisine-type diterpenoid alkaloid natural products. Building upon our previous synthetic studies, we have now designed an efficient route to a highly functional-ized 6–7–6 tricycle. This route features a highly diastereoselec-tive Diels–Alder cycloaddition, chemoselective addition of a benzyl enolate nucleophile, and a finely-tuned magnesiate ad-dition/ring-expansion/oxidation sequence to access the desired tricycle. This tricycle possesses key functional groups at strate-gic locations, with carbonyl groups at all three carbon atoms bearing C–N bonds in the hetisine-type alkaloids, as well as the aromatic ring and vinyl group required for the eventual [4+2] cycloaddition reaction. Further studies will focus on the selec-tive derivatization and elaboration of this tricycle into the hetis-ine-type core, selected natural products, and structural deriva-tives for biological evaluation. The Supporting Information is available free of charge on the ACS Publications website.  Experimental details and spectroscopic data (PDF) *rsarpong@berkeley.edu †School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK The authors declare no competing financial interests.  We are grateful to the NIH (NIGMS R01 GM084906) for financial support. We thank the NSF and Eli Lilly for graduate fellowships to J.J.P. and the Amgen Scholars Program for summer fellowships to J.N.D. and M.A.P.  We also thank A. DiPasquale (UC Berkeley) for solving the crystal structure of 10 (displayed with CYLView), supported by the NIH Shared Instrumentation Grant (S10-RR027172). (1) (a) Liu, X.-Y.; Qin, Y. Asian J. Org. Chem. 2015, 4, 1010–1019. (b) Ameri, A. Prog. Neurobiol. 1998, 56, 211–235. (2) (a) Wang, F.-P.; Liang, X.-T. C20-Diterpenoid Alkaloids. In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Elsevier: Am-sterdam, Netherlands, 2002; Vol. 59, pp 1–280. (b) Wang, F.-P.; Chen, Q.-H.; Liu, X.-Y. Nat. Prod. Rep. 2010, 27, 529–570. (3) Jin, S.-S.; Guo, Q.; Xu, J.; Yu, P.; Liu, J.-H.; Tang, Y.-Q. Chin. J. Nat. Med. 2015, 13, 361–367. (4) (a) Catterall, W. A.; Cestèle, S.; Yarov-Yarovoy, V.; Yu, F. H.; Konoki, K.; Scheuer, T. Toxicon 2007, 49, 124–141. (b) Camerino, D. C.; Tricarico, D.; Desaphy, J.-F. Neurotherapeutics 2007, 4, 184–198. (c) Ahuja, S. et al. Science 2015, 350, aac5464. (5) Muratake, H.; Natsume, M. Angew. Chem. Int. Ed. 2004, 43, 4646–4649. (6) (a) Peese, K. M.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 8734–8735. (b) Peese, K. M.; Gin, D. Y. Chem. Eur. J. 2008, 14, 1654–1665. (7) Hamlin, A. M.; Lapointe, D.; Owens, K.; Sarpong, R. J. Org. Chem. 2014, 79, 6783–6800. (8) Cherney, E. C.; Lopchuk, J. M.; Green, J. C.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 12592–12595. (9) Li, X.-H.; Zhu, M.; Wang, Z.-X.; Liu, X.-Y.; Song, H.; Zhang, D.; Wang, F.-P.; Qin, Y. Angew. Chem. Int. Ed. 2016, 55, 15667–15671. (10) (a) Yatsunami, T.; Isono, T.; Hayakawa, I.; Okamoto, T. Chem. Pharm. Bull. 1975, 23, 3030–3032. (b) Yatsunami, T.; Furuya, S.; Oka-moto, T. Chem. Pharm. Bull. 1978, 26, 3199–3207. (11) (a) Corey, E. J.; Howe, W. J.; Orf, H. W.; Pensak, D. A.; Pe-tersson, G. J. Am. Chem. Soc. 1975, 97, 6116–6124. (b) Heathcock, C. H. Angew. Chem. Int. Ed. 1992, 31, 665–681. (12) Spiegel, D. A.; Njardarson, J. T.; Wood, J. L. Tetrahedron 2002, 58, 6545–6554. (13) (a) Marth, C. J.; Gallego, G. M.; Lee, J. C.; Lebold, T. P.; Kulyk, S.; Kou, K. G. M.; Qin, J.; Lilien, R.; Sarpong, R. Nature 2015, 528, 493–498. (b) Kou, K. G. M.; Li, B. X.; Lee, J. C.; Gallego, G. M.; Lebold, T. P.; DiPasquale, A.; Sarpong, R. J. Am. Chem. Soc. 2016, 138, 10830–10833. (14) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E.; Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978, 43, 138–147. (15) Zhou, C.-Y.; Li, J.; Peddibhotla, S.; Romo, D. Org. Lett. 2010, 12, 2104–2107.  (16) Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1998, 352, 1–46.  (17) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem. Int. Ed. 2003, 42, 4302–4320. (18) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333–3336. (19) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333–4339. (20) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; Choi, H.-S. J. Am. Chem. Soc. 2002, 124, 2190–2201. 

Magnesiate addition/ring-expansion strategy to access the 6-7-6 tricyclic core of hetisine-type C20-diterpenoid alkaloids

Jason J. Pflueger

Louis C. Morrill

Justine N. deGruyter

Melecio A. Perea

Richmond Sarpong

Crossref

Magnesiate Addition/Ring-Expansion Strategy To Access the 6–7–6 Tricyclic Core of Hetisine-Type C<sub>20</sub>-Diterpenoid Alkaloids

A synthetic strategy to access the fused 6-7-6 tricyclic core of hetisine-type C20-diterpenoid alkaloids is reported. This strategy employs a Diels-Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to a vinyl lactone-acetal bearing an aromatic ring in five steps. Aromatic iodination is followed by magnesium-halogen exchange with a trialkyl magnesiate species, which undergoes intramolecular cyclization. Subsequent oxidation provides the desired 6-7-6 tricyclic diketoaldehyde, with carbonyl groups at all three positions for eventual C-N bond formation and subsequent elaboration

Pflueger, Jason J

Morrill, Louis C

deGruyter, Justine N

Perea, Melecio A

eScholarship - University of California

Magnesiate Addition/Ring-Expansion Strategy To Access the 6–7–6 Tricyclic Core of Hetisine-Type C20-Diterpenoid Alkaloids

http://orca.cf.ac.uk/104180/1/Magnesiate%20Paper-Final%20Version.pdf

Magnesiate addition/ring-expansion strategy to access the 6-7-6 tricyclic core of hetisine-type C20-diterpenoid alkaloids

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eScholarship - University of California