Synthesis of N-Fused Polycyclic Indoles via Ligand-Free Palladium-Catalyzed Annulation/Acyl Migration Reaction

Article abstract of DOI:10.1021/acs.orglett.8b04128

An efficient synthesis of N-fused polycyclic indoles by a palladium-catalyzed annulation/acyl migration cascade reaction is described. The reaction is ligand-free, scalable, and provides access to a diverse range of useful indole scaffolds from readily available starting materials. Supporting mechanistic studies indicate that the reaction likely proceeds via an intramolecular α-arylation mechanism. The synthetic utility of this protocol is demonstrated by a gram-scale reaction and syntheses toward indole alkaloids and a HSP90 inhibitor.

Full text of DOI:10.1021/acs.orglett.8b04128

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of N‑Fused Polycyclic Indoles via Ligand-Free Palladium-
Catalyzed Annulation/Acyl Migration Reaction
Zhan Dong,† Xiao-Wen Zhang,† Weishuang Li, Zi-Meng Li, Wen-Yan Wang, Yan Zhang, Wei Liu,
and Wen-Bo Liu*
Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular
Sciences, Wuhan University, 299 Bayi Road, Wuhan, Hubei 430072, China
S
* Supporting Information
ABSTRACT: An efficient synthesis of N-fused polycyclic indoles by a palladium-catalyzed annulation/acyl migration cascade
reaction is described. The reaction is ligand-free, scalable, and provides access to a diverse range of useful indole scaffolds from
readily available starting materials. Supporting mechanistic studies indicate that the reaction likely proceeds via an
intramolecular α-arylation mechanism. The synthetic utility of this protocol is demonstrated by a gram-scale reaction and
syntheses toward indole alkaloids and a HSP90 inhibitor.
eterocycles are present as core architectures in numerous
bioactive molecules, both natural and synthetic. Among
them, indoles have been recognized as privileged scaffolds for
library design in drug discovery.1 In particular, N-fused
polycyclic indoles (i.e., dihydropyrido[1,2-a]indolones,
DHPIs) are key skeletons2 and crucial synthetic intermediates3
of biologically important compounds (Figure 1). The
al.7b employing the classical Fischer indolization of mono-
phenylhydrazines and α-substituted-1,3-dicarbonyls provided
the desired scaffold efficiently under acid conditions.7
Palladium-catalyzed reactions (i.e., enamine coupling,6f,k
tandem C−N/C−C coupling,6r and intramolecular hetero-
annulation6c,d) provided versatile entries into indole deriva-
tives. An elegant report by Edmondson et al. delivered DHPI
from 1,2-dibromobenzene and vinylogous amide using
Pd2(dba)3/Davephos as catalyst, albeit with only one
substrate.6e Rhodium-catalyzed electrocyclization/acyl migra-
tion of styryl azides and one-pot cyclization of alkyne-tethered
phenylhydrazine/acid-promoted amide formation were also
uncovered recently.6g,h It is rare but more desirable to develop
a protocol with significantly reduced precious metal loading
under ligand-free conditions. Inspired by the fact that the
carbonyl group migrates preferentially over aryl and alkyl
groups in indolenines 26k,7b and the Edmondson’s precedent,6e
we sought to develop a more efficient and straightforward
route to DHPIs 3 by palladium-catalyzed cyclization of readily
accessed enaminones 1 to form 2 followed by acyl migration
(Scheme 1). Herein, we report the results of this synthetic
approach with as low as 0.5 mol % of Pd(OAc)2 alone as the
catalyst.
H
Figure 1. Representative natural products and pharmaceuticals
containing DHPIs.
prominence of DHPIs was highlighted recently in the total
synthesis of indole alkaloids.3a−c Although considerable
progress has been achieved in the preparation of indole
derivatives,4−7 the direct and practical synthesis of N-fused
polycyclic indoles remains a significant challenge.
We began our studies with enaminone 1a, prepared from the
condensation of 2-iodoaniline and 1,3-diketone in 88% yield,8
as a model substrate. A brief screen of palladium sources was
To date, only a handful of examples of N-fused indole
syntheses have been reported. A seminal report by Teuber et
Received: December 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04128
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Synthesis of DHPIs by Palladium-Catalyzed
Annulation/Acyl Migration Reaction
Scheme 2. Substrate Scope
initially conducted (see Table S1 in the SI). We were pleased
to find that Pd(OAc)2 alone9 delivered the desired product 3a
in 74% yield (entry 1, Table 1). The use of Pd(PPh3)4 or
Table 1. Optimization of the Reaction Conditions
a
b
entry
[Pd] (x, mol %)
ligand
temp (°C)
yield (%)
1
2
3
4
5
6
7
Pd(OAc)2 (5)
Pd(PPh3)4 (5)
Pd(OAc)2 (5)
Pd2(dba)3 (2.5)
Pd(OAc)2 (1)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.2)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.5)
none
c
c
80
80
80
80
80
80
80
100
120
120
74
54
78
59
77
80
36
93
94
NR
P(o-tol)3
P(o-tol)3
c
c
c
c
c
c
d
8
9
e
f
10
a
Reactions conducted with 0.2 mmol of 1a and 0.3 mmol of K3PO4 in
b
c
1 mL of DMSO. Yield of isolated product. Without the use of
ligand. For 30 min. For 10 min. For 1 h. NR, no reaction. For
d
e
f
additional optimizations, see Tables S1−S4.
complexes derived from palladium precursors and P(o-tol)3
resulted in 54−78% yield (entries 2−4). Reducing the loading
of Pd(OAc)2 obtained essentially the same yield (entries 5 and
6), while further reducing Pd(OAc)2 to 0.2 mol % resulted in a
diminished yield (entry 7). The reaction temperature was
found to affect the reactivity dramatically, and 93% yield was
obtained at 100 °C (entry 8). Although extensive investigation
of reaction parameters was carried out for palladium with
additional phosphine ligands (Tables S2 and S3), ligand-free
system was found to be superior in terms of yield and catalyst
cost (Table S4). Ultimately, treatment of 1a with 0.5 mol % of
Pd(OAc)2 in DMSO at 120 °C (entry 9) was identified as the
optimal condition.
With optimized condition in hand, the substrate scope of the
reaction was then investigated (Scheme 2). We were delighted
to find that an array of substituents on the aryl moiety,
including Me, F, Cl, Br, CF3, and NO2, were well tolerated.
Methyl substituents at the 4- and 5-positions of the anilines
had limited effects on the outcome of the reaction (3c,d), but
sterically encumbered 3-methyl substrate 1b gave a lower yield
to the corresponding 4-methylindole 3b (68% yield),
presumably due to the reduced rate of oxidative addition
step. With electron-deficient substrates (i.e., Br, CF3, and
NO2),10 we found that applying microwave irradiation was
crucial to accelerate the reaction, and the corresponding
products were obtained in 64−72% yield (3h−j). It is
noteworthy that an aryl bromide is amenable to this protocol
and furnished product 3h in 64% yield, accompanied by 12%
of debrominated product (3a). Notably, 7-azaindole 3k was
a
Reactions performed under the conditions of entry 9, Table 1.
b
c
Under microwave irradiation. Yield in the parentheses is the
d
debromination product 3a. With 1 mol % of Pd(OAc)2.
also synthesized in 52% yield, indicating the tolerance for
additional heterocyclic functionality.
The effects of substituents on the enaminone moiety toward
the reactivity were also examined. Substrates bearing alkyl
chains of varying steric bulk and chain length (benzyl,
cyclohexylmethyl, and n-butyl) were well compatible, provid-
ing 3l−n in 89−93% yield. Importantly, benzoxyethyl- and
phthalimide-containing dihydropyrido[1,2-a]indolones 3o and
3p, key precursors in Aspidosperma alkaloids synthesis, were
furnished in 69% and 59% yield, respectively. Aside from
aliphatic substituents, α-aryl-substituted enaminones were also
studied and afforded 3-arylindoles 3q−t in 53−70% yield.
Finally, pyrrolo[1,2-a]indole 3u, present in biologically active
substances and drugs,11 was also accessible from a five-
membered enaminone albeit in low yield.
The intramolecular enaminone couplings were suggested to
operate through two possibilities according previous studies,
namely, α-arylation6k,r and Heck-type olefination.5c Likewise,
mechanisms of our ligand-free reaction12,13 were proposed as
illustrated in Scheme 3a. Oxidative addition of substrate 1a
with a palladium(0) species, generated in situ from Pd-
(OAc)2,12−14 provides intermediate I. Olefin coordination
forms complex II, which can subsequently undergo an α-
arylation pathway (path a) or a Heck-type pathway (path b).
B
DOI: 10.1021/acs.orglett.8b04128
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Proposed Reaction Pathways
Scheme 4. Comparison of Fischer Indole Synthesis with
Our Method
a
Isolated yield of Fischer indolization; see the SI for conditions.
Yield of palladium-catalyzed reactions as shown in Scheme 2.
b
methylindole 3b and 6-methylindole 3d, isolated in 55%
overall yield. We were pleased to find that the corresponding
indoles (3b and 3d) were synthesized in 68% and 84% yield,
respectively, using palladium catalysis. With regard to either
bulkier group substituted diketones (R2 = Bn, CH2CH2OBn,
and Ph) or electron-poor arylhydrazines (R1 = CF3 and
NO2),16 the Fischer indolization resulted in lower yields (3l,
3o, and 3q) or no product formation (3i and 3j). In particular,
since the low efficiency of Fischer indolization toward 3o
synthesis (11−33%),7a an alternative route was then
established enabling the total synthesis of monoterpene indole
alkaloids practically albeit in multiple steps.3a,b
We have applied this method to the syntheses of indole
alkaloids and bioactive compounds bearing distinct DHPI
cores (Scheme 5). A gram-scale reaction with substrate 1o was
carried out with 1 mol % of Pd(OAc)2 as catalyst and furnished
DHPI 3o in 74% yield. Notably, Li et al. also developed an
efficient synthesis of 3o with rhodium catalyst and finished the
formal synthesis of goniomitine.6g,17 Here, we offered a
complementary synthetic route to aminal 7 including double
alkylation of 3o and a one-pot anti-Markovnikov hydro-
amination18/reductive cyclization of 6.3a,19 More generally, this
method provides access to versatile synthetic intermediates
that have previously been utilized in alkaloid synthesis.
Hydrazinolysis of phthalimide 3p afforded tryptamine 8 in
84% yield. Protection of the primary amine with methyl
chloroformate furnished indole 9, a synthetic intermediate en
route to conolutinine by the Xie group,20 in 69% yield.
Importantly, tryptamine 8 can also be advanced to 9-
membered lactam 10 under UV irradiation,3d,e which was
previously employed in the total synthesis of a series of
alkaloids in Strychnos, Aspidosperma, and Schizozygane families.
Additionally, the HSP90 inhibitor 1221 was obtained in 53%
overall yield from 3t by a nucleophilic aromatic substitution
and conversion of the nitrile to amide. Finally, N-fused indole
3a itself was used as a key intermediate for the synthesis of FK-
1052, which is a potent serotonin 3 and 4 (5-HT3 and 5-HT4)
dual-receptor antagonist.2
In path a, deprotonation of the enaminone II facilitates a
nucleophilic attack onto palladium to generate six-membered
metallacycle IV. Then reductive elimination of IV provides
indolenine 2a while regenerating the catalytically active
species. In contrast, path b would proceed via a Heck-type
mechanism: 1,2-olefin insertion followed by β-hydride
elimination provides enamine VI. Tautomerization to 2a and
subsequent acyl migration again provide product 3a. A similar
acyl migration step (2a to 3a)15 has been previously observed
by the Ban group3e in the Fischer indole process as well as by
Edmondson et al. in the palladium catalysis.6e We then
performed several experiments in order to gain insight into
which pathway is operative under our conditions. In path a, a
base capable of generating a nucleophilic, anionic species III is
required. Studies probing the role of base emphasized the
importance of K3PO4: weaker bases such as Et3N exhibited a
complete lack of reactivity, whereas substoichiometric K3PO4
resulted in drastically reduced yield (Scheme 3b). Further
experiments with deuterium-labeled substrate D-1r were
carried out, and less than 4% isotope scrambling was observed
(Scheme 3c). The minimal H/D scrambling of the γ-position
of product D-3r indicates that the β-hydride elimination is less
likely involved. While we could not rule out the possibility that
abstraction of the proton on nitrogen of V forms palladium
hydride species and product 2a, the strained geometry of 5-
endo-dig cyclization of the Heck pathway (from II to V) usually
requires high energy thus is generally disfavored in palladium
chemistry.6r Together, these results are in line with previous
observations and support the α-arylation pathway.6k,r
Next, the efficiency of this approach was evaluated by
comparison with Fischer indolization protocols (Scheme 4).4,7
Several DHPIs were prepared following known Fischer
procedures with arylhydrazines 4 and 1,3-diketones 5.7 The
application of meta-substituted arylhydrazines commonly
exhibits poor regioselectivity in the Fischer indole process.
Indeed, the use of m-tolylhydrazine afforded a 1:1 mixture of 4-
In conclusion, an efficient synthesis of N-fused polycyclic
indoles was realized by a palladium-catalyzed intramolecular
annulation/acyl migration of enaminones. This expedient
strategy features readily available starting materials, good
compatibility with diverse functional groups, and low catalyst
loadings and does not require expensive phosphine ligands. We
C
DOI: 10.1021/acs.orglett.8b04128
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Notes
Scheme 5. Synthetic Applications
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the NSFC (21772148, 21602160),
the Fundamental Research Funds for the Central Universities
(2042018kf0017), National Program for 1000 Young Talents
of China, and Wuhan University (WHU) for financial support.
Prof. Qiang-Hui Zhou (WHU) and his group are appreciated
for generously sharing their lab space. Prof. Nasri Nesnas
(Florida Tech) and Drs. Kangway Chuang (UCSF) and Yiyang
Liu (Pfizer, Inc.) are thanked for helpful discussions. We also
thank the Xumu Zhang, Guoyin Yin, Aiwen Lei, Chun-Jiang
Wang, and Hong-Ding Tang groups at WHU for instrumenta-
tion and chemicals.
REFERENCES
■
(1) (a) Gribble, G. W. Indole ring synthesis: From natural products to
drug discovery; John Wiley & Sons, Ltd.: West Sussex, UK, 2016.
́
(b) de Sa Alves, F. R.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med.
Chem. 2009, 9, 782. (c) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R.
Curr. Opin. Chem. Biol. 2010, 14, 347.
(2) (a) Nagakura, Y.; Kadowaki, M.; Tokoro, K.; Tomoi, M.; Mori,
J.; Kohsaka, M. J. Pharmacol. Exp. Ther. 1993, 265, 752. (b) Kato, M.;
Ito, K.; Nishino, S.; Yamakuni, H.; Takasugi, H. Chem. Pharm. Bull.
1994, 42, 2546. (c) Kato, M.; Nishino, S.; Ito, K.; Takasugi, H. Chem.
Pharm. Bull. 1995, 43, 1346.
(3) (a) Pritchett, B. P.; Kikuchi, J.; Numajiri, Y.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2016, 55, 13529. (b) Pritchett, B. P.; Donckele, E. J.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2017, 56, 12624. (c) Ban, Y.;
Yoshida, K.; Goto, J.; Oishi, T.; Takeda, E. Tetrahedron 1983, 39,
3657. (d) Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T. J. Am. Chem. Soc.
1981, 103, 6990. (e) Li, H.; Cheng, P.; Jiang, L.; Yang, J.-L.; Zu, L.
Angew. Chem., Int. Ed. 2017, 56, 2754. (f) Yang, Y.; Bai, Y.; Sun, S.;
Dai, M. Org. Lett. 2014, 16, 6216.
(4) (a) Robinson, B. Chem. Rev. 1969, 69, 227. (b) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 2000, 1, 1045.
(5) Selected reviews: (a) Zeni, G.; Larock, R. C. Chem. Rev. 2006,
106, 4644. (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
(c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (d) Platon,
M.; Amardeil, R.; Djakovitch, L.; Hierso, J.-C. Chem. Soc. Rev. 2012,
41, 3929. (e) Gribble, G. W. Pure Appl. Chem. 2003, 75, 1417.
a
Conditions: (A) Pd(OAc)2 (1 mol %), K3PO4, 4 Å MS, DMSO; (B)
(i) LDA, THF, then EtI; (ii) LiHMDS, THF, then allyl bromide; 52%
yield of two steps; (C) one pot: (i) Cp2Zr(H)Cl, NH2OSO3H, THF;
(ii) LiAlH4, THF; (iii) AcOH/H2O; 32% overall yield; (D) N2H4·
H2O, EtOH, 84% yield; (E) Et3N, ClCO2Me, CH2Cl2, 69% yield; (F)
iPr2NEt, DMSO, 71% yield; (G) NaOH, H2O2, dioxane, 74% yield.
anticipate that the wide scope and efficiency of this new
method will find broad utility across the synthetic community.
Further applications in natural product synthesis are currently
under investigation in our laboratory.
̈
̈
̈
(f) Agarwal, S.; Cammerer, S.; Filali, S.; Frohner, W.; Knoll, J.; Krahl,
̈
M. P.; Reddy, K. R.; Knolker, H. J. Curr. Org. Chem. 2005, 9, 1601.
(g) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(h) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.
(i) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29.
ASSOCIATED CONTENT
(6) Selected recent methods for the catalytic synthesis of indoles:
(a) Cera, G.; Piscitelli, S.; Chiarucci, M.; Fabrizi, G.; Goggiamani, A.;
■
S
* Supporting Information
́
Ramon, R. S.; Nolan, S. P.; Bandini, M. Angew. Chem., Int. Ed. 2012,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04128.
51, 9891. (b) Chuang, K. V.; Kieffer, M. E.; Reisman, S. E. Org. Lett.
2016, 18, 4750. (c) Liu, J.; Shen, M.; Zhang, Y.; Li, G.; Khodabocus,
A.; Rodriguez, S.; Qu, B.; Farina, V.; Senanayake, C. H.; Lu, B. Z. Org.
Lett. 2006, 8, 3573. (d) Liu, J.; Zhang, Y.; Li, G.; Roschangar, F.;
Farina, V.; Senanayake, C. H.; Lu, B. Z. Adv. Synth. Catal. 2010, 352,
2667. (e) Edmondson, S. D.; Mastracchio, A.; Parmee, E. R. Org. Lett.
2000, 2, 1109. (f) Chen, C.; Lieberman, D. R.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676. (g) Zhou,
B.; Du, J.; Yang, Y.; Li, Y. Chem. - Eur. J. 2014, 20, 12768. (h) Jones,
C.; Nguyen, Q.; Driver, T. G. Angew. Chem., Int. Ed. 2014, 53, 785.
(i) Kandukuri, S. R.; Schiffner, J. A.; Oestreich, M. Angew. Chem., Int.
Ed. 2012, 51, 1265. (j) Lian, X.-L.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-
H. Org. Lett. 2014, 16, 3360. (k) Marelli, E.; Corpet, M.; Minenkov,
Y.; Neyyappadath, R. M.; Bismuto, A.; Buccolini, G.; Curcio, M.;
Cavallo, L.; Nolan, S. P. ACS Catal. 2016, 6, 2930. (l) Zhang, Z.-Z.;
Liu, B.; Xu, J.-W.; Yan, S.-Y.; Shi, B.-F. Org. Lett. 2016, 18, 1776.
(m) Cai, Q.; Zhao, Z.-A.; You, S.-L. Angew. Chem., Int. Ed. 2009, 48,
Detailed reaction condition optimizations, complete
experimental procedures, characterization, and spectra
for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wenboliu@whu.edu.cn.
ORCID
Wen-Bo Liu: 0000-0003-2687-557X
Author Contributions
†Z.D. and X.-W.Z. contributed equally.
D
DOI: 10.1021/acs.orglett.8b04128
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7428. (n) Cheng, H.-G.; Lu, L.-Q.; Wang, T.; Yang, Q.-Q.; Liu, X.-P.;
Li, Y.; Deng, Q.-H.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed.
2013, 52, 3250. (o) Shevlin, M.; Guan, X.; Driver, T. G. ACS Catal.
2017, 7, 5518. (p) Jana, S.; Clements, M. D.; Sharp, B. K.; Zheng, N.
Org. Lett. 2010, 12, 3736. (q) Huang, H.; Yu, M.; Su, X.; Guo, P.;
Zhao, J.; Zhou, J.; Li, Y. J. Org. Chem. 2018, 83, 2425. (r) Knapp, J.
M.; Zhu, J. S.; Tantillo, D. J.; Kurth, M. J. Angew. Chem., Int. Ed. 2012,
51, 10588. (s) Yao, X.; Shan, X.; Zu, L. Org. Lett. 2018, 20, 6498.
(t) Ma, X.-P.; Li, K.; Wu, S.-Y.; Liang, C.; Su, G.-F.; Mo, D.-L. Green
Chem. 2017, 19, 5761. (u) Zhao, C.-Y.; Li, K.; Pang, Y.; Li, J.-Q.;
Liang, C.; Su, G.-F.; Mo, D.-L. Adv. Synth. Catal. 2018, 360, 1919.
(v) Liu, Y. Y.; Yu, X. Y.; Chen, J. R.; Qiao, M. M.; Qi, X.; Shi, D. Q.;
Xiao, W. J. Angew. Chem., Int. Ed. 2017, 56, 9527. (w) Liu, W. Q.; Lei,
T.; Song, Z. Q.; Yang, X. L.; Wu, C. J.; Jiang, X.; Chen, B.; Tung, C.
H.; Wu, L. Z. Org. Lett. 2017, 19, 3251. (x) Inman, M.; Moody, C. J.
Chem. Commun. 2011, 47, 788.
(7) (a) Pritchett, B. P.; Kikuchi, J.; Numajiri, Y.; Stoltz, B.
Heterocycles 2017, 95, 1245. (b) Teuber, H.-J.; Cornelius, D.; Worbs,
E. Tetrahedron Lett. 1964, 5, 331. (c) Teuber, H.-J.; Worbs, E.;
Cornelius, D. Arch. Pharm. 1982, 315, 388.
(8) See the Supporting Information for details.
(9) Hydrolysis of 3a to acid was observed following prolonged
exposure to reaction conditions or with wet DMSO as solvent.
(10) Attempts to synthesize of enaminone subsrates by the
condensation of electron-rich anilines (i.e., 4-methoxy-2-iodoaniline)
with diketones were failed.
(11) (a) Monakhova, N.; Ryabova, S.; Makarov, V. J. Heterocyclic
Chem. 2016, 53, 685. (b) Piou, T.; Neuville, L.; Zhu, J. Tetrahedron
2013, 69, 4415.
(12) (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(b) Jeffery, T.; David, M. Tetrahedron Lett. 1998, 39, 5751. (c) Reetz,
M. T.; Westermann, E.; Lohmer, R.; Lohmer, G. Tetrahedron Lett.
1998, 39, 8449. (d) de Vries, A. H. M.; Parlevliet, F. J.; de
Vondervoort, L. S.-V.; Mommers, J. H. M.; Henderickx, H. J. W.;
Walet, M. A. M.; de Vries, J. G. Adv. Synth. Catal. 2002, 344, 996.
(e) Yao, Q.; Kinney, E. P.; Yang, Z. J. Org. Chem. 2003, 68, 7528.
(f) Reetz, M. T.; de Vries, J. G. Chem. Commun. 2004, 1559.
(13) (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009. (b) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
(14) (a) Phan, N. T. S.; van der Sluys, M.; Jones, C. W. Adv. Synth.
Catal. 2006, 348, 609. (b) de Vries, J. G. Dalton Trans. 2006, 421.
(15) A mechanism of base-promoted acyl migration was proposed
following the previously described pathway in refs 3d and 5i; see
Scheme S2.
(16) Simmons, B. J.; Hoffmann, M.; Champagne, P. A.; Picazo, E.;
Yamakawa, K.; Morrill, L. A.; Houk, K. N.; Garg, N. K. J. Am. Chem.
Soc. 2017, 139, 14833.
(17) For selected total syntheses of goniomitine, see: (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) Wagnieres, O.; Xu, Z.; Wang, Q.; Zhu, J. J. Am. Chem. Soc.
2014, 136, 15102. (d) Li, H.; Cheng, P.; Jiang, L.; Yang, J.-L.; Zu, L.
Angew. Chem., Int. Ed. 2017, 56, 2754. (e) Bin, H-Y.; Wang, K.; Yang,
D.; Yang, X.-H.; Xie, J.-H.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2019,
58, 1174. (f) Alves, J. C. F. ISRN Org. Chem. 2013, 2013, 1.
(18) (a) For the development of anti-Markovnikov hydroamination,
see: Strom, A. E.; Hartwig, J. F. J. Org. Chem. 2013, 78, 8909. (b) For
the application of this method in total synthesis, see ref 3a.
(19) For the removal of Bn protecting group: Xu, Z.; Wang, Q.; Zhu,
J. Angew. Chem., Int. Ed. 2013, 52, 3272.
(20) Feng, X.; Jiang, G.; Xia, Z.; Hu, J.; Wan, X.; Gao, J.-M.; Lai, Y.;
Xie, W. Org. Lett. 2015, 17, 4428.
(21) (a) Bureau, P.; Founier, J.-H.; Jaquith, J. B.; Laurent, A.; Rose,
Y.; Proulx, M. WO 2011/035417 A1, 2011. (b) Bureau, P.; Founier,
J.-H.; Jaquith, J. B.; Laurent, A.; Rose, Y.; Proulx, M.; Morris, S. WO
2012/126084 A1, 2012.
E
DOI: 10.1021/acs.orglett.8b04128
Org. Lett. XXXX, XXX, XXX−XXX