Subscriber access provided by UNIV OF LOUISIANA
Communication
Twelve-Step Asymmetric Synthesis of (–)-Nodulisporic Acid C Nicole A. Godfrey, Devon Schatz, and Sergey V. Pronin J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Sep 2018 Downloaded from http://pubs.acs.org on September 28, 2018
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
Twelve-Step Asymmetric Synthesis of (–)-Nodulisporic Acid C Nicole A. Godfrey‡, Devon J. Schatz‡, and Sergey V. Pronin* Department of Chemistry, University of California, Irvine, California 92697-2025, United States
Supporting Information Placeholder
ABSTRACT: A short, enantioselective synthesis of (–)nodulisporic acid C is described. The route features two highly diastereoselective polycyclizations en route to the terpenoid core and the indenopyran fragment and a highly convergent assembly of a challenging indole moiety. Application of this chemistry allows for a 12-step synthesis of the target indoloterpenoid from commercially available material.
Me H
Me
Me
OH O
Me Me
OH
Me
O
H
H
Me
H
Me
Me
N OH
O
H nodulisporic acid A (1; LD90 = 1.5 µM, flea feeding assay5) Me H
Me
Me
OH O
Me Me
Nodulisporic acids (e.g., 1, 2, and 3; Figure 1) comprise a group of secondary metabolites isolated from the endophytic fungus Hypoxylon pulicicidum (previously known as Nodulisporium sp.) that exhibit potent insecticidal activities.1–6 These biological effects arise from the specific activation of a subset of ligand-gated chloride ion channels found in arthropods, but not in mammals, resulting in a potentially useful selectivity profile.7 For example, the flagship congener, nodulisporic acid A (1), exhibits high efficacy against fleas while lacking overt toxicity in dogs.5,8 The producing organism has proven difficult to culture.9,10 Nevertheless, detailed investigations of nodulisporic acids as a starting point for the development of new anti-flea medications for companion animals have been performed, resulting in identification of promising lead compounds.11 As a part of broader efforts towards the paxilline indoloterpenoids,12–14 multiple inquiries from organic chemists15 recently culminated in the syntheses of nodulisporic acids B (2), C (3), and D.16,17 In addition to the common indoloterpenoid core, these natural products contain an indenopyran motif found in other members of the paxilline family, such as the janthitrems and shearinines.18,19 Here we demonstrate a 12-step asymmetric synthesis of (–)-nodulisporic acid C (3) enabled by the development and implementation of new polycyclization-based strategies and a highly convergent assembly of a challenging indole moiety. The key transforms in our retrosynthetic analysis of nodulisporic acid C (3) included a late-stage indole assembly to form the C14–C15 and N1–C2 bonds and two polycyclization events to access the terpenoid and inde-
OH
Me
O
Me
N
H
H
Me
H
Me
OH
H nodulisporic acid B (2; LD90 = 150 µM, flea feeding assay5) Me OH H
Me
Me
O
Me Me O
OH
Me H
Me
Me
NH
H
H
OH Me
Me
nodulisporic acid C (3; LD90 = 15 µM, flea feeding assay5) Me H Me 21 O
23
Me
NH 1
H
2
Me
OH O
8
OH
4
Me 22
Me 9
15 14
18
Me
Me
H
7
H
OH
Me Me Key transforms: indole assembly and two polycyclizations
Figure 1. Representative nodulisporic acids and our analysis of nodulisporic acid C.
nopyran motifs. We envisioned a radical-polar crossover cascade initiated by a chemoselective20,21 hydrogen atom transfer (HAT)22–24 to construct the C4–C9 and C8–C7 bonds of the decalin fragment and a gold-catalyzed cycloisomerization25 to construct the C18–C23 and O21– C22 bonds of the dihydropyran fragment. We previously discovered a diastereoselective polycyclization related to the proposed HAT-initiated cascade, which relied on a transient lactolization event to control the relative orientation of the C3–C4 vicinal quaternary stereocenters.13
1 ACS Paragon Plus Environment
Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Implementation of this approach was expected to require multiple manipulations to accommodate both the assembly of the reactant and the late-stage installation of the indole moiety, therefore an alternative solution was sought. The outcome of the polycyclization en route to the indenopyran motif was difficult to predict at the outset of our work.26,27 Our synthesis began with a copper-catalyzed asymmetric conjugate addition of alkylmagnesium bromide 5 to commercially available cyclopentenone 4 (Scheme 1). Scheme 1. Synthesis of the terpenoid fragment 1 5 mol% CuBr"SMe2, 5 6 mol% SL-J015-1, –78 ℃; O
TIPSCl, LiCl, Et3N, HMPA 95%
Me
H Me Me
TIPSO
4
6 (73% ee) Me
BrMg
2 7, InBr3; HCl, 0 ℃ 52%
OTBS 5
N
Me
7
Me
H
3 TMSCN, Sc(OTf)3 4 SeO2, TBHP
Me
H
Me
O TMSO
2
5 DMP, CH2Cl2 40%, 3 steps
O
Me
8
9
6 Fe(acac)3 10, AcOEt (CH2OH)2;
H
Me
Me
OH Me
Ph
HCl; NaOH d. r. 10:1 41% of 11
O
O
H
H
H
Si
O OH
2
TMSO
Me
H
14 (d. r. > 19:1)
H
12 Me
OEt
Me
Me
Me
1 t-BuONO, CuI, 60 ℃; 62% 2 i-PrMgCl, DMF, –78 ℃; 82%
Cl
O
H 2N
OPiv
O
sents an unusual case of efficient differentiation between methyl and linear alkyl substituents and is in stark contrast to the lack of diastereoselectivity observed with the corresponding unprotected cyclopentanone derivative.13 Presence of the pseudo-axial substituent at C2 proved crucial for obtaining high levels of diastereocontrol. Thus, only the trans-decalin is produced during the polycyclization to corresponding tert-alkyl ether 14 while low selectivity was previously observed in the case of the related sec-alkyl ether, which lacked the methyl substituent at C2.13 Furthermore, undesired cis-decalin 15 is favored during the polycyclization of the corresponding dialdehyde, where C2 is sp2 hybridized and the indole N–H group presumably exhibits unfavorable steric interactions en route to the trans-decalin product. Protection of alcohol 11 delivered the corresponding pivalate, which could be obtained in a highly enantioenriched form (97% ee) upon recrystallization from hexanes. The pivalate was subjected to Horner-WadsworthEmmons olefination with phosphonate 12,32 providing access to ketone 13 in eight steps from commercially available material. With the decalin-containing fragment of nodulisporic acid C in hand, we proceeded to assemble the indenopyran motif of the target natural product. We began with a three-step synthesis of arene 17 (Scheme 2), which inScheme 2. Synthesis of the indenopyran fragment Br
H
Me
O 2
Me
Me H
Zn
Me
15 (d. r. ~ 3.5:1)
Me
O
H
Me
H
19 Br
HO TIPSO 26
Extensive screening identified JosiPhos derivative SLJ015-1 as a suitable ligand for production of silyl enol ether 6 in excellent yield and with synthetically useful levels of enantioenrichment.28 Alkenylation of enoxysilane 6 with pentynol derivative 7 was best performed in the presence of sub-stoichiometric amounts of indium(III) bromide and acidic work-up secured access to product 8.13,29 Cyclopentanone 8 was converted to the corresponding protected cyanohydrin, which underwent Sharpless allylic oxidation30 and subsequent double oxidation of the resulting diol to deliver dialdehyde 9. Subjection of intermediate 9 to the conditions of ironmediated HAT20,31 resulted in highly diastereoselective formation of the trans-decalin fragment and subsequent work-up secured direct access to the cyclopentanone functionality of the desired tricyclic product 11. The pronounced preference for the trans-decalin motif repre-
4 18, Et2Zn 8 mol% 19 PhMe, –20 ℃ ca. 100%
N OH
Me
18
Me
17
Me
Me
Me
Me
OH
vs. NH
NO2 Br
O
16
H
Cl
3 HNO3, H2SO4, 23 ℃; ca. 100%
H 13 (97% ee)
H
Br
Br
H
effect of substituents at C2:
Me
Me
CO2Et
O
7 Piv2O, Et3N; recrystallize 55% 8 12, LiHMDS 23 ℃; 92%
Me
EtO EtO P
Oi-Pr
H 10
11
H Me
Me OH
Me
O
Page 2 of 5
Me
Cl
5 PdCl2(PPh3)2, 21 CuI, Et3N; 67%
NO2
6 TIPSOTf, Et3N; 71% Me
HO
Me
22
7 12 mol% IPrAuCl, 10 mol% AgSbF6
Me THF, 50 ℃ 90% d. r. > 19:1
20
Me
HO
Bu3Sn
21
O
Cl
Me Me H
8 24, PdCl2(PPh3)2 DMF, 90 ℃ 72%
26
TIPSO
Me 24
O
Cl
Me Me H
NO2
TIPSO
NO2
Br 25 Me
23 Me Me
Me ● Cl
HO Me Me H TIPSO
Me
Me
Me
Me
Me
NO2 Br
Br Me
Cl
26
Br
26 (d. r. > 19:1)
NO2
Me
effect of substituent at C26:
O Me Me H TIPSO
Me
26
NO2
R
27 (d. r. > 19:1) vs. 28 (d. r. ~ 1:1)
27 (R = Br); 28 (R = H)
2 ACS Paragon Plus Environment
Page 3 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
Scheme 3. Synthesis of (–)-nodulisporic acid C (3) Me
Me Me H
Me
OEt
Me
O
H
H
O
NO2
TIPSO
H
Me
Me H
Me
Me OH
Me
Me
NH H
Me
H
H
O OPiv
O
Me
H
H
H H Me Me
Me
O
Me Me 29
Me Me H
2 Zn, AcOH, EtOH, 23 ℃ 3 TASF, DMF, 60 ℃ 4 LiOH, H2O, dioxane, MeOH, 100 ℃ 73% from 30, 3 steps
OH Me
OEt
TIPSO
OH O
Me O
O2N
Me
PhMe, 50 ℃ d. r. 3.5:1 (30:29) 44% of 30 (+ 28% of 13)
Me
Me
H
Me
25 (1.1 equiv.)
13
Me
1 25 mol% RuPhosPdG4 25 mol% RuPhos NaHMDS, Bu3SnCl
Cl
Me Me H
O OPiv
Me
Me
Me Me
TIPSO Me H
Me Me
Me
O
O2N
Me
Me
OEt O
OPiv
H
O
(–)-nodulisporic acid C (3)
Me
H
H
30
cluded iodination of commercially available aniline 16, formylation of the intermediate iodide, and nitration of the resulting arene. Addition of diorganozinc 18 to aldehyde 17 was accomplished in the presence of catalytic amounts of aminoalcohol 19 and efficiently delivered benzyl alcohol 20 with high enantioselectivity.33 Sonogashira cross-coupling34 of dibromide 20 with alkyne 21 proceeded chemoselectively and the intermediate diol was protected to yield cycloisomerization precursor 22. We discovered that treatment of enyne 22 with catalytic amounts of a gold(I) complex in the presence of a halide scavenger resulted in highly efficient and stereoselective formation of dihydropyran 23. The process likely involves the initial nucleophilic attack on the alkyne-gold complex by the isobutenyl fragment and subsequent trapping of the resulting tertiary carbocation with the pendant hydroxyl group. This proposal is supported by the observation of allene 26, which likely results from elimination of an alkenylgold intermediate26 and accumulates in the reaction mixture under anhydrous conditions. Neither dihydropyran 23 nor allene 26 is observed upon treatment of alkyne 22 with acid, but these conditions are competent in converting intermediate 26 to the desired tricyclic product. The presence of the substituent at C26 proved to be crucial for obtaining high levels of stereocontrol during the reaction. Thus, products 23 and 27 are formed as single diastereomers in contrast to dihydropyran 28. Allylic strain between the benzyl ether and the ortho substituent is expected to force rotation of the silyl group35 towards the reaction center in the transition state of the initial cyclization, which can lead to the dramatic enhancement of the diastereoselectivity en route to products 23 and 27. This proposal is consistent with the observed restricted rotation of the siloxybearing fragment in the ortho-substituted substrates. Installation of the prenyl group into the aromatic moiety was best accomplished after the cycloisomerization.
36
Thus, Stille cross-coupling of bromide 23 with stannane 24 delivered chloroarene 25 in good yield, completing assembly of the indenopyran motif in eight steps from commercially available starting material and setting the stage for the fragment union. After significant experimentation we discovered that a trialkyltin enolate of ketone 13 could undergo a palladium-catalyzed arylation with nearly stoichiometric quantities of chloroarene 25 (Scheme 3). A RuPhos-based palladium precatalyst37 provided optimal performance and the arylketone was produced in a diastereoselective manner.38 The stereochemical outcome of the reaction proved crucial for the successful completion of the synthesis. Treatment of arylation product 30 with zinc in the presence of acetic acid resulted in efficient formation of the desired indole under mild conditions. In this setting, diastereomer 29 returned the corresponding aminoketone and attempted cyclodehydration under forcing conditions led to elimination of the benzyl ether moiety. The sensitive nature of the indenopyran fragment was previously highlighted in the isolation and synthetic literature.3,17 The facility of conversion of ketone 30 to the desired indole is in stark contrast to the previous reports of cyclodehydrations of relevant aminoketones39 and can be instructive during synthetic planning towards the other paxilline indoloterpenoids. Final manipulations in our synthesis of (–)-nodulisporic acid C (3) included deprotection of the silyl ether and saponification of the intermediate diester, which delivered the natural product in twelve steps from commercially available material (longest linear sequence). In summary, we disclose an enantioselective synthesis of (–)-nodulisporic acid C that proceeds in a highly convergent manner. The relative brevity of our route was enabled by the development of two polycyclizations to rapidly assemble the decalin and indenopyran motifs and a ketone arylation protocol to unite the two complex
3 ACS Paragon Plus Environment
Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
fragments. In these processes, seemingly minor structural modifications within the crowded steric environments have a significant influence on the reactivity and have allowed for complete stereocontrol over the polycyclization events and facile construction of a sensitive indole fragment. The preponderance of these and related structural motifs among the paxilline indoloterpenoids suggests that lessons learned during our synthesis will find application in the assembly of other members of this fascinating family and simplify production of unnatural analogs for biological studies. ASSOCIATED CONTENT Experimental procedures and spectroscopic data for new compounds as well as CIF files for compounds 15, 23, and 26. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author
[email protected] Author Contributions ‡
These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT Financial support from the National Institutes of Health (R01GM121678), the University of California Irvine, the Hellman Foundation, the National Science Foundation (DGE-1321846 to N.A.G.), and the Natural Sciences and Engineering Research Council of Canada (PGSD3-4875062016 to D.J.S.) is gratefully acknowledged. We thank Dr. David George for preparation of compound 15 and Dr. Joseph Ziller and Austin Ryan for X-ray crystallographic analysis. We also thank Professors Larry Overman, Chris Vanderwal, and Scott Rychnovsky for providing routine access to their instrumentation and helpful discussions.
REFERENCES (1) Ondeyka, J. G.; Helms, G. L.; Hensens, O. D.; Goetz, M. A.; Zink, D. L.; Tsipouras, A.; Shoop, W. L.; Slayton, L.; Dombrowski, A. W.; Polishook, J. D.; Ostlind, D. A.; Tsou, N. N.; Ball, R. G.; Singh, S. B. J. Am. Chem. Soc. 1997, 119, 8809–8816. (2) Hensens, O. D.; Ondeyka, J. D.; Dombrowski, A. W.; Ostlind, D. A.; Zink, D. L. Tetrahedron Lett. 1999, 40, 5455–5458. (3) Ondeyka, J. G.; Dahl-Roshak, A. M.; Tkacz, J. S.; Zink, D. L.; Zakson-Aiken, M.; Shoop, W. L.; Goetz, M. A.; Singh, S. B. Bioorg. Med. Chem. Lett. 2002, 12, 2941–2944. (4) Ondeyka, J. G.; Byrne, K.; Vesey, D.; Zink, D. L.; Shoop, W. L.; Goetz, M. A.; Singh, S. B. J. Nat. Prod. 2003, 66, 121–124. (5) Singh, S. B.; Ondeyka, J. G.; Jayasuriya, H.; Zink, D. L.; Ha, S. N.; Dahl-Roshak, A.; Greene, J.; Kim, J. A.; Smith, M. M.; Shoop, W. L.; Tkacz, J. S. J. Nat. Prod. 2004, 67, 1496–1506. (6) Bills, G. F.; González-Menéndez, V.; Martín, J.; Platas, G.; Fournier, J.; Peršoh, D.; Stadler, M. PLoS One 2012, 7, e46687. (7) Ludmerer, S. W.; Warren, V. A.; Williams, B. S.; Zheng, Y.; Hunt, D. C.; Ayer, M. B.; Wallace, M. A.; Chaudhary, A. G.; Egan, M. A.; Meinke, P. T.; Dean, D. C.; Garcia, M. L.; Cully, D. F.; Smith, M. M. Biochemistry 2002, 41, 6548–6560.
Page 4 of 5
(8) Shoop, W. L.; Gregory, L. M.; Zakson-Aiken, M.; Michael, B. F.; Haines, H. W.; Ondeyka, J. G.; Meinke, P. T.; Schmatz, D. M. J. Parasitol. 2001, 87, 419–423. (9) Byrne, K. M., Smith, S. K., Ondeyka, J. G. J. Am. Chem. Soc. 2002, 124, 7055–7060. (10) Van de Bittner, K. C.; Nicholson, M. J.; Bustamante, L. Y.; Kessans, S. A.; Ram, A.; van Dolleweerd, C. J.; Scott, B.; Parker, E. J. J. Am. Chem. Soc. 2018, 140, 582–585. (11) Meinke, P. T.; Colletti, S. L.; Fischer, M. H.; Wyvratt, M. J.; Shih, T. L.; Ayer, M. B.; Li, C.; Lim, J.; Ok, D.; Salva, S.; Warmke, L. M.; Zakson, M.; Michael, B. F.; deMontigny, P.; Ostlind, D. A.; Fink, D.; Drag, M.; Schmatz, D. M.; Shoop, W. L. J. Med. Chem. 2009, 52, 3505–3515. (12) (a) Smith, A. B., III; Mewshaw, R. J. Am. Chem. Soc. 1985, 107, 1769–1771. (b) Mewshaw, R.; Taylor, M. D.; Smith, A. B., III J. Org. Chem. 1989, 54, 3449–3462. (c) Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am. Chem. Soc. 1990, 112, 8197– 8198. (d) Smith, A. B., III; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114, 1438–1449. (e) Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am. Chem. Soc. 2000, 122, 11254–11255. (f) Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Minakawa, N.; Rainier, J. D.; Hark, R. A.; Cho, Y. S.; Cui, H.; Moser, W. M. J. Am. Chem. Soc. 2003, 125, 8228–8237. (g) Smith, A. B., III; Cui, H. Org. Lett. 2003, 5, 587–590. (h) Smith, A. B., III; Cui, H. Helv. Chim. Acta 2003, 86, 3908–3938. (i) Enomoto, M.; Morita, A.; Kuwahara, S. Angew. Chem. Int. Ed. 2012, 51, 12833–12836. (j) Teranishi, T.; Murokawa, T.; Enomoto, M.; Kuwahara, S. Biosci. Biotechnol. Biochem. 2015, 79, 11–15. (k) Sharpe, R. J.; Johnson, J. S. J. Am. Chem. Soc. 2015, 137, 4968–4971. (l) Sharpe, R. J.; Johnson, J. S. J. Org. Chem. 2015, 80, 9740–9766. (13) George, D. T.; Kuenstner, E. J.; Pronin, S. V. J. Am. Chem. Soc. 2015, 137, 15410–15413. (14) For recent reviews see: (a) Corsello, M. A.; Kim, J.; Garg, N. K. Chem. Sci. 2017, 8, 5836–5844. (b) Zou, Y.; Smith, A. B., III. J. Antibiot. 2018, 71, 185–204. (15) (a) Magnus, P.; Mansley, T. E. Tetrahedron Lett. 1999, 40, 6909–6912. (b) Smith, A. B., III; Ishiyama, H.; Cho, Y. S.; Ohmoto, K. Org. Lett. 2001, 3, 3967–3970. (c) Smith, A. B., III; Cho, Y. S.; Ishiyama, H. Org. Lett. 2001, 3, 3971–3974. (d) Smith, A. B., III; Davulcu, A. H.; Kürti, L. Org. Lett. 2006, 8, 1665–1668. (e) Smith, A. B., III; Davulcu, A. H.; Kürti, L. Org. Lett. 2006, 8, 1669–1672. (f) Smith, A. B., III; Kürti, L.; Davulcu, A. H. Org. Lett. 2006, 8, 2167– 2170. (g) Smith, A. B., III; Kürti, L.; Davulcu, A. H.; Cho, Y. S. Org. Process Res. Dev. 2007, 11, 19–24. (h) Smith, A. B., III; Davulcu, A. H.; Cho, Y. S.; Ohmoto, K.; Kürti, L.; Ishiyama, H. J. Org. Chem. 2007, 72, 4596–4610. (i) Smith, A. B., III; Kürti, L.; Davulcu, A. H.; Cho, Y. S.; Ohmoto, K. J. Org. Chem. 2007, 72, 4611–4620. (16) Zou, Y.; Melvin, J. E.; Gonzales, S. S.; Spafford, M. J.; Smith, A. B., III. J. Am. Chem. Soc. 2015, 137, 7095–7098. (17) Zou, Y.; Li, X.; Yang, Y.; Berritt, S.; Melvin, J.; Gonzales, S.; Spafford, M.; Smith, A. B., III. J. Am. Chem. Soc. 2018, 140, 9502– 9511. (18) (a) de Jesus, A. E.; Steyn, P. S.; van Heerden, F. R.; Vleggaar, R. J. Chem. Soc. Perkin Trans. I 1984, 0, 697–701. (b) Wilkins, A. L.; Miles, C. O.; Ede, R. M.; Gallagher, R. T.; Munday, S. C. J. Agric. Food Chem. 1992, 40, 1307–1309. (19) (a) Belofsky, G. N.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. Tetrahedron 1995, 51, 3959–3968. (b) Xu, M.; Gessner, G.; Groth, I.; Lange, C.; Christner, A.; Bruhn, T.; Deng, Z.; Li, X.; Heinemann, S. H.; Grabley, S.; Bringmann, G.; Sattler, I.; Lin, W. Tetrahedron 2007, 63, 435–444. (20) (a) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 1304. (b) Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C.-M.; Baran, P. S. Nature 2014, 516, 343. (c) Lo, J. C.; Kim, D.; Pan, C.-M.; Edwards, J. T.; Yabe, Y.; Gui, J.; Qin, T.; Gutiérrez, S.; Giacoboni, J.; Smith, M. W.; Holland, P. L.; Baran, P. S. J. Am. Chem. Soc. 2017, 139, 2484– 2503. (21) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 12692–12714. (22) For pioneering work on relevant hydrofunctionalizations see: (a) Mukaiyama, T.; Yamada, T. Bull. Chem. Soc. Jpn. 1995, 68, 17
4 ACS Paragon Plus Environment
Page 5 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society and references therein. For a recent review see: (b) Crossley, S. W. M.; Martinez, R. M.; Obradors, C.; Shenvi, R. A. Chem. Rev. 2016, 116, 8912–9000. Shenvi and Herzon propose HAT as the initial step in their related hydrogenations: (c) Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W. M.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 1300. (d) King, S. M.; Ma, X.; Herzon, S. B. J. Am. Chem. Soc. 2014, 136, 6884. For similar mechanistic considerations see: (e) Eisenberg, D. C.; Norton, J. R. Isr. J. Chem. 1991, 31, 55–66. (23) For relevant aldol reactions see: Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 2005–2008. (24) For recent examples of HAT-initiated cyclizations in synthesis see: (a) Deng, H.; Cao, W.; Liu, R.; Zhang, Y.; Liu, B. Angew. Chem. Int. Ed. 2017, 56, 5849–5852. (b) Lu, Z.; Zhang, X.; Guo, Z.; Chen, Y.; Mu, T.; Li, A. J. Am. Chem. Soc. 2018, 140, 9211–9218. It is plausible that the peroxyradical cyclization en route to (+)-cardamom peroxide is initiated via HAT: Hu, X.; Maimone, T. J. J. Am. Chem. Soc. 2014, 136, 5287–5290. (25) For recent examples of gold-catalyzed cascades in synthesis see: (a) Yue, G.; Zhang, Y.; Fang, L.; Li, C.-c.; Luo, T.; Yang, Z. Angew. Chem. Int. Ed. 2014, 53, 1837-1840. (b) McGee, P.; Bétournay, G.; Barabé, F.; Barriault, L. Angew. Chem. Int. Ed. 2017, 56, 6280–6283. (c) Ferrer, S.; Echavarren, A. M. Org. Lett. 2018, 20, 5784–5788. (26) Harrak, Y.; Simonneau, A.; Malacria, M.; Gandon, V.; Fensterbank, L. Chem. Commun. 2010, 46, 865–867. (27) Sanjuán, A. M.; Martínez, A.; García-García, P.; FernándezRodríguez, M. A.; Sanz, R. Beilstein J. Org. Chem. 2013, 9, 2242– 2249. Me H
Me
(28) For relevant asymmetric cuprate additions see: Calvo, B. C.; Madduri, A. V. R.; Harutyunyan, S. R.; Minnaard, A. J. Adv. Synth. Catal. 2014, 356, 2061–2069. (29) In this setting, the corresponding catalytic alkenylation proved less efficient: Holmbo, S. D.; Godfrey, N. A.; Hirner, J. J.; Pronin, S. V. J. Am. Chem. Soc. 2016, 138, 12316–12319. (30) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526. (31) Obradors, C.; Martinez, R. M.; Shenvi, R. A. J. Am. Chem. Soc. 2016, 138, 4962–4971. (32) Prepared in two steps from ethyl tiglate as described in SI. (33) (a) Nugent, W. A. Chem. Commun. 1999, 35, 1369–1370. (b) Lurain, A. E.; Maestri, A.; Kelly, A. R.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 13608–13609. (34) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46–49 and references therein. (35) Wilcox, C. S.; Babston, R. E. J. Org. Chem. 1984, 49, 1451– 1453. (36) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771–1780 and references therein. (37) Bruno, N. C.; Niljianskul, N.; Buchwald, S. L. J. Org. Chem. 2014, 79, 4161–4166. (38) Relative configuration of the newly formed stereocenter was established by NOE experiments. See SI for details. (39) See references 12 (a), (b), (c), (k), and (l).
Me
OH H
Me
Me O
Me
O
Me OH
Me
Me
Me
O
Me
OH
NH H
Me
H
H
Me O
Me
OH Me
OH
Me
NH H
H
H
OH
Me
nodulisporic acid C
Me
Me
Me
Key transforms: indole assembly and two polycyclizations
5 ACS Paragon Plus Environment
