Total Synthesis of Epoxyeujindole A

Article abstract of DOI:10.1021/jacs.5b09198

The total synthesis of epoxyeujindole A, a structurally unusual indole diterpenoid isolated from Eupenicillium javanicum, has been accomplished for the first time. The synthesis features a late-stage cationic cyclization strategy, which took advantage of an electron-rich olefinic substrate. The CDE ring system was assembled via an enantioselective conjugate addition/alkylation, a Luche cyclization, and a Nozaki-Hiyama-Kishi reaction. The heavily substituted A ring was constructed through a Suzuki-Miyaura coupling and a cationic cyclization, and the bridged fused B ring was formed through a Prins reaction.

Full text of DOI:10.1021/jacs.5b09198

Subscriber access provided by - Access paid by the | UCSB Libraries
Communication
Total Synthesis of Epoxyeujindole A
Zhaohong Lu, Hailong Li, Ming Bian, and Ang Li
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b09198 • Publication Date (Web): 23 Sep 2015
Downloaded from http://pubs.acs.org on September 24, 2015
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 free 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 accessible to all
readers and 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.
Journal of the American Chemical Society 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
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Total Synthesis of Epoxyeujindole A
Zhaohong Lu,† Hailong Li,† Ming Bian, and Ang Li*
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
State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of Chemistry for
Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
200032, China
Email: ali@sioc.ac.cn
Supporting Information Placeholder
Scheme 1. Retrosynthetic Analysis of Epoxyeujindole A
ABSTRACT: The total synthesis of epoxyeujindole A, a
structurally unusual indole diterpenoid isolated from Eupen-
Me
Me
Me
Me
icillium javanicum, has been accomplished for the first time.
The synthesis features a late-stage cationic cyclization strate-
gy, which took advantage of an electron-rich olefinic sub-
strate. The CDE ring system was assembled via an enantiose-
lective conjugate addition/alkylation, a Luche cyclization,
and a Nozaki−Hiyama−Kishi reaction. The heavily substitut-
ed A ring was constructed through a Suzuki−Miyaura cou-
pling and a cationic cyclization, and the bridged fused B ring
was formed through a Prins reaction.
Me
Me
HN
HN
O
O
21 20
22
21
Y
X
Me
Me
4
: epoxyeujindole A
5
Me
Me
Me
Me
Me
Me
18
O
9
O
Me
Me
Indole terpenoids comprise a large number of biologically
and biosynthetically interesting natural products.1 Recently,
we focused our attentions to a class of indole diterpenoids
first discovered by the Gloer group from Asperigillus, the
parent molecule of which is anominine (1, Figure 1).2 The
syntheses of 1 and its carbazole congener tubingensin A (2)
were reported by Bonjoch, Garg, and us,3–5 while other mem-
bers such as aspernomine2c (3) have not been synthesized to
our knowledge. In 2011, Nakadate et al. reported the isolation
of structurally complex anominine-related compounds from
Eupenicillium javanicum, including epoxyeujindole A (4),
although its absolute configurations were not determined.6 4
possesses a heptacyclic scaffold that is non-trivial to access
from 1 through a biomimetic synthesis.4a Its congested
I
O
O
O
EtO
EtO
EtO
9
8
6
TMS
Me
+
Me
Me
I
Ts
N
12
O
Me
B(OH)2
CHO
O
OH
AlMe3
10
11
7
nature poses a considerable challenge for chemical synthesis.
Here we report the first and asymmetric total synthesis of 4.
As illustrated in Scheme 1, two key disconnections at
C20−C21 and C21−C22 bonds are envisioned in our retrosyn-
thetic analysis. We take advantage of the electron-rich na-
ture of the exocyclic olefin of substrate 5, for two sequential
Prins cyclizations.7 The strategy avoids functionalization at
C21 of 5 and ensures a tetrasubstituted olefin in the product.
The gem-dimethyl at C22 may be installed on a ketone pre-
cursor by using Reetz/Trauner’s protocol (methyl addition
followed by cationic methylation of the resultant tertiary
alcohol).8 5 is then disassembled into ketone 6 and boronic
acid 7, and the former may arise from allyl iodide 8. The two-
carbon unit at C9 is expected to be introduced via a Noza-
ki−Hiyama−Kishi coupling with acetaldehyde. Further sim-
plification of 8 results in tricycle 9. The tetrahyrdofuran mo-
tif bearing quaternary C18 could be constructed by Luche
cyclization.9 Thus, 9 is traced back to enone 10, which would
be prepared from enone 11, iodide 12, and Me3Al though a
sequence of asymmetric conjugation and alkylation.10
Figure 1. Selected indole terpenoids of the anominine family.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
Scheme 2. Synthesis of Advanced Intermediate 13a
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
aReagents and conditions: a) Me3Al (1.2 eq), CuTC (2 mol%), 14 (4 mol%), Et2O, −30 °C, 2.5 h; MeLi (1.0 eq), HMPA (2.5 eq), −30
°C, 20 min; 12 (1.3 eq), THF, −30 °C, 24 h, −10 °C, 24 h, 0 °C, 48 h, 65%; b) K2CO3 (2.0 eq), m-CPBA (1.2 eq), CH2Cl2, 0 °C, 1.5 h; c)
TFA/CH2Cl2, 0 °C, 15 min; d) MeONa (3.0 eq), MeOH, 22 °C, 2.5 h, 53% (3 steps); e) HC(OMe)3 (18 eq), TsOH (15 mol%), DMF, 10
°C, 2 h; f) Oxone (1.0 eq), −5 °C, THF, 1.5 h, 51% (2 steps); g) NIS (6.0 eq), ethyl vinyl ether (8.0 eq), CH2Cl2, 0 °C,1.5 h, 94%; h) Zn
(9.0 eq), CuI (2.7 eq), pyridine/water (1:4), 22 °C, 2 h, 68%; i) MsOH (20 mol%), EtOH, 22 °C, 1 h, 89%; j) LiHMDS (2.3 eq),
PhNTf2(1.9 eq), THF, −78 °C, 10 min, 87%; k) Pd(PPh3)4 (10 mol%), Bu3SnCH2OH (2.0 eq), LiCl (2.0 eq), THF, 65 °C, 2 h; l) PPh3
(1.2 eq), I2 (1.2 eq), imidazole (3.0 eq), CH2Cl2, 0 °C, 30 min, 81% (2 steps); m) CrCl2 (5.0 eq), LiI (1.2 eq), 2,6-lutidine (10 eq),
MeCHO (21 equiv), 22 °C, 5 h, 67%; n) Raney Ni, H2 (60 bar), EtOH, 22 °C, 1 h; o) TPAP (10 mol%), NMO(3.0 eq), CH2Cl2, 22 °C,
30 min, 91% (2 steps); p) KHMDS (1.1 eq), PhNTf2 (1.8 eq), THF, −30 °C, 10 min; q) Pd(PPh3)4 (10 mol%), NaHCO3 (1.6 eq), 20 (1.5
eq), toluene/MeOH/water (4:1:1), 22 °C, 30 min, 51% (2 steps).
Based on the above analysis, we first synthesized an ad-
vanced intermediate 13 in an enantioselective manner
(Scheme 1). Inspired by the work of Alexakis, Cramer, and
Cook,11 we carried out an asymmetric conjugate addition (11,
CuTC, Me3Al) with phosphoramidite ligand (R,S,S)-14 to set
the first stereocenter. The resultant enolate was activated in
situ by adding MeLi and HMPA and then quenched by allyl
iodide 12,12 providing ketone 15 with an excellent level of en-
antioselectivity (vide infra). The diastereoselectivity (ca. 3.8:1)
and efficiency (65% yield) of the one-pot reaction are ac-
ceptable at this early stage. Notably, trapping the enolate
with methyl vinyl ketone (MVK) was inefficient (< 20%
yield), presumably due to the severe polymerization of MVK
under these conditions. Thus, 12 served as a suitable alterna-
tive of MVK. Epoxidation of the alkenyl silane with m-CPBA
followed by TFA promoted rearrangement afforded the cor-
responding diketone,13 which underwent aldol condensation
(MeONa) to reach enone 16 in 53% overall yield. The enanti-
omeric excess of 16 was measured to be 95% by HPLC, and
its absolute configurations were determined by comparing
with chiral pool derived 16.4a,14 This compound was subjected
to a known 3-step sequence4a to afford iodide 17. We exam-
ined reductive radical conditions for the next 5-exo-trig cy-
clization: treatment with SmI2 resulted in a moderate yield of
the tricycle along with a large portion of the reductive cleav-
age products, and modified Luche conditions9 (Zn, CuI, pyri-
dine/water) significantly suppressed such side reactions and
improved the yield to 68%. The Luche protocol is more prac-
tical than conventional radical ones in terms of reaction scale
and purification. This diastereomeric acetal mixture (ca. 1.4:1
at C20) was converted to thermodynamically more stable 9
smoothly by exposure to MsOH in EtOH.
effected by treatment with LiHMDS. Such selectivity was not
observed on C20-epi-9, which indicates a directing effect by
the ethyloxy oxygen, presumably through chelation with
Li/base aggregates. Notably, KHMDS gave no selectivity in
this reaction. The Li enolate was trapped by PhNTf2 to afford
triflate 18 in 87% yield, which then underwent Stille–Migita
coupling [Pd(PPh3)4, Bu3SnCH2OH, LiCl] followed by io-
dination (Ph3P, I2, imidazole) to furnish allyl iodide 8 (81%
yield for the two steps). The introduction of the two-carbon
unit at C9 was achieved by Nozaki−Hiyama−Kishi coupling
(CrCl2, LiI) with acetaldehyde,4d,15 leading to alcohol 19 in
67% yield as a single detectable diastereomer. 19 tends to
cyclize to generate a bridged acetal under the coupling con-
ditions. Thus, 2,6-lutidine is crucial as a buffering additive.
The observed facial selectivity may be attributable to the
conformation of the D ring (see ORTEP of 13 as an indirect
reference), and the configuration at C8 is inconsequential.
Establishing the C10 stereochemistry turned out to be prob-
lematic. Crabtree catalyst directly caused bridged acetal for-
mation because of its acidity. Pd/C resulted in C═C bond
migration and poor diastereoselectivity for hydrogenation.
Silylation of the secondary alcohol increased the steric hin-
drance and inhibited the hydrogenation under the Crabtree
conditions. This issue was solved by Raney Ni mediated hy-
drogenation under a pressure of 60 bar. TPAP oxidation gave
methyl ketone 6 in 91% yield for the two steps. Triflation
followed by Suzuki−Miyaura coupling with boronic acid 7
provided the key intermediate 13, the racemic sample of
which was readily crystallized from EtOAc/petroleum ether
(1:1). The relative stereochemistry of 13 was thus confirmed
by X-ray crystallographic analysis (Scheme 2). The triflate
intermediate is sensitive to basic conditions at elevated tem-
perature, and the acetylene byproduct was formed. There-
Further elaborations of tricycle 9 at C9 led to compound
13, as shown in Scheme 1. Regioselective deprotonation was
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
fore, NaHCO3 was used as a mild base for the cross cou-
pling.16
We then explored the double Prins strategy toward the
take advantage of the strong driving force of electrocycliza-
tion.18,19 Reinstallation of the hemiacetal functionality by
DIBAL-H reduction followed by treatment with TsOH built
the heptacyclic skeleton of the natural product through a
Prins cyclization. Reductive desulfonation with Mg in MeOH
afforded epoxyeujindole A (4) in 84% yield for the three steps,
the structure of which was verified by X-ray crystallographic
analysis using a copper target. The spectra and physical
properties of the synthetic sample are identical with those of
the authentic sample. Thus, the synthesis clarifies the abso-
lute configurations of naturally occurring 4. Notably, we at-
tempted to build the heptacyclic core of 4 directly from 24
through a cascade reaction, which would avoid the unfortu-
nate redox manipulation. However, such endeavors were
unsuccessful.
1
2
3
4
5
6
7
8
synthesis of heptacycle 20 (Scheme 3). Hydrolysis of 13 with
aq. HClO4 (0.50 M) furnished compound 21 (82% yield). The
hemiacetal functionality was considered to be more reactive
than the aldehyde in the following Prins reaction, because of
the ease of oxonium formation. Exposure of 21 to TsOH rap-
idly afforded the bridged tetracycle 22 in 76% yield, which
implies the steric proximity between C20 and C21. The struc-
ture of 22 was confirmed by X-ray crystallographic analysis of
a racemic sample (Scheme 3). Further activation of the alde-
hyde of 22 with BF3•OEt2 gave a cyclization product (72%
yield). However, spectroscopic analysis revealed that it is
naphthalene derivative 23 rather than desired product 20.17
Although the formation of 23 may proceed through the in-
termediacy of 20, we failed to halt the transformation at the
stage of the latter, presumably due to the thermodynamic
preference to the former. The installation the gem-dimethyl
at C20 of the naphthalene scaffold is not straightforward. A
tertiary alcohol was prepared from the aldehyde; however, a
number of side reactions including dehydration occurred
instead of the desired cyclization under acidic conditions.
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
Scheme 4. Completion of the Synthesis of Epoxyeujin-
dole Aa
Me
Me
Me
Me
a) MeMgBr
b) TPAP, NMO
c) MeMgBr, CeCl3
Me
Me
Ts
Ts
N
N
O
O
85% (3 steps)
Me
Scheme 3. Synthesis of Unexpected Heptacycle 23a
OEt
OEt
Me OH
O
13
24
95%
d) aq. HClO4
(2 steps)
e) TPAP, NMO
Me
Me
Me
Me
f) BF3 OEt2
65%
Me
Me
Ts
N
Ts
Ts
Ts
N
O
O
O
Me
+
O
Me OH
Me Me
27
25
Me
Me
Me
Me
Me
+
Me
Ts
N
N
O
O
+
O
O
aReagents and conditions: a) aq. HClO4 (0.50 M), THF, 22 °C,
8 h, 82%; b) TsOH (1.0 eq), CH2Cl2, 22 °C, 30 min, 76%; c)
BF3•OEt2 (2.7 eq), CH2Cl2, 22 °C, 10 min, 72%.
Me
Me Me
Me
28
29
Having encountered the above problems, we swapped the
sequence of the two cyclizations, as depicted in Scheme 4.
Aldehyde 13 was converted to tertiary alcohol 24 through a
three step sequence with good overall efficiency. The second
methyl addition had to rely on a Ceric reagent4b due to the
competitive deprotonation of the methyl ketone substrate. In
order to form the A ring prior to the B ring, we transiently
protect the acetal as a lactone. Acid hydrolysis followed by
TPAP oxidation provided compound 25 in 95% yield for the
two steps; the benzylic tertiary hydroxyl was tolerated under
these conditions. Exposure of 25 to BF3•OEt2 effected a ring
closure to give hexacycle 26 in 65% yield. This vinylogous
Friedel−Crafts reaction may proceed through a pathway illus-
trated in Scheme 4, via the intermediacy of 27 and 28. Inter-
estingly, this reaction shares some features with a 6π electro-
cyclization process, as the postulated cation species 27 can be
considered as a triene form (29). Thus, the ring closure may
Me
Me
Me
Me
4
ORTEP of
Me
Me
N
HN
O
O
g) DIBAL-H
h) TsOH
i) Mg, MeOH
O
Me
Me
Me
Me
26
84% (3 steps)
4
: epoxyeujindole A
aReagents and conditions: a) MeMgBr (2.3 eq), THF, −78 °C,
10 min; b) TPAP (10 mol%), NMO (6.1 eq), CH2Cl2, 22 °C, 30
min; c) MeMgBr (4.2 eq), CeCl3 (5.0 eq), THF, 0 °C, 30 min,
85% (3 steps); d) aq. HClO4 (0.50 M), THF, 22 °C, 5 h; e)
TPAP (10 mol%), NMO (3.0 eq), CH2Cl2, 22 °C, 30 min, 95%
(2 steps); f) BF3•OEt2 (1.5 eq), MeNO2, 75 °C, 5 min, 65%; g)
DIBAL-H (3.0 eq), CH2Cl2, −78 °C, 10 min; h) TsOH (3.0 eq),
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
ies of indole terpenoids from our group: (b) Sun, Y.; Li, R.; Zhang, W.;
CH2Cl2, 22 °C, 30 min; i) Mg (19 eq), MeOH, 22 °C, 1 h, 84% (3
steps).
Li, A. Angew. Chem., Int. Ed. 2013, 52, 9201. c) Sun, Y.; Chen, P.;
Zhang, D.; Baunach, M.; Hertweck, C.; Li, A. Angew. Chem., Int. Ed.
2014, 53, 9012. (d) Lu, Z.; Yang, M.; Chen, P.; Xiong, X.; Li, A. Angew.
Chem., Int. Ed. 2014, 53, 13840. (e) Meng, Z.; Yu, H.; Li, L.; Tao, W.;
Chen, H.; Wan, M.; Yang, P.; Edmonds, D. J.; Zhong, J.; Li, A. Nat.
Commun. 2015, 6, 6096. (f) Zhou, S.; Zhang, D.; Sun, Y.; Li, R.; Zhang,
W.; Li, A. Adv. Synth. Catal. 2014, 356, 2867. (g) Zhou, S.; Chen, H.;
Luo, Y.; Zhang, W.; Li, A. Angew. Chem., Int. Ed. 2015, 54, 6878. (h)
Xiong, X.; Zhang, D.; Li, J.; Sun, Y.; Zhou, S.; Yang, M.; Shao, H.; Li, A.
Chem. Asian J. 2015, 10, 869.
(5) Selected syntheses of indole diterpenoids from other groups:
(a) Smith, A. B., III; Mewshaw, R. J. Am. Chem. Soc. 1985, 107, 1769. (b)
Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am.
Chem. Soc. 1990, 112, 8197. (c) Smith, A. B., III; Kanoh, N.; Ishiyama,
H.; Hartz, R. A. J. Am. Chem. Soc. 2000, 122, 11254. (d) Enomoto, M.;
Morita, A.; Kuwahara, S. Angew. Chem., Int. Ed. 2012, 51, 12833. (e)
Zou, Y.; Melvin, J. E.; Gonzales, S. S.; Spafford, M. J.; Smith, A. B., III.
J. Am. Chem. Soc. 2015, 137, 7095. (c) Sharpe, R. J.; Johnson, J. S. J. Am.
Chem. Soc. 2015, 137, 4968.
1
2
3
4
5
6
7
8
In summary, we have accomplished the first and asymmet-
ric synthesis of epoxyeujindole A, a heptacyclic indole
diterpenoid from the anominine family. The key C−C bond
formations at an early stage include an enantioselective con-
jugate addition/alkylation, a Luche cyclization, a Noza-
ki−Hiyama−Kishi reaction, and a Suzuki−Miyaura coupling.
The assembly of the highly substituted A and B rings relies
on sequential cationic cyclizations. The synthesis provides an
efficient access to epoxyeujindole A and potentially other
relevant anominine congeners as well, which may facilitate
the biological studies of these structurally intriguing mole-
cules.
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
ASSOCIATED CONTENT
Supporting Information
(6) (a) Nakadate, S.; Nozawa, K.; Horie, H.; Fujii, Y.; Yaguchi, T.
Heterocycles 2011, 83, 351. (b) Nakadate, S.; Nozawa, K.; Yaguchi, T.
Heterocycles 2011, 83, 1867. Compound 4 was named "8,21-dehydro-
17,20-epoxyeujindole" by the isolation team, and here we rename it
"epoxyeujindole A" just for simplification.
(7) Han, X.; Peh, G. R.; Floreancig, P. E. Eur. J. Org. Chem. 2013,
1193. For synthetic applications of Prins cyclization from our group,
see refs 4b–d.
(8) (a) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41,
1569. (b) Reetz, M. T.; Westerman, J. J. Org. Chem. 1983, 48, 254.
(9) (a) Petrier, C.; Dupuy, C.; Luche, J. L. Tetrahedron Lett. 1986,
27, 3149. (b) Wang, L.; Wang, H.; Li, Y.; Tang, P. Angew. Chem., Int.
Ed. 2015, 54, 5732.
(10) Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M.
Chem. Rev. 2008, 108, 2796.
(11) (a) Vuagnoux-d'Augustin, M. V.; Alexakis, A. Chem. Eur. J.
2007, 13, 9647. (b) Ngoc, D. T.; Albicker, M.; Schneider, L.; Cramer, N.
Org. Biomol. Chem. 2010, 8, 1781. (c) Zhu, C.; Cook, S. P. J. Am. Chem.
Soc. 2012, 134, 13577.
Experimental procedures and compound characterization
(cif, pdf). This material is available free of charge via the In-
ternet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
ali@sioc.ac.cn
Author Contributions
†These authors contributed equally.
ACKNOWLEDGMENT
We thank Prof. Shou Nakadate for providing the authentic
1H and 13C NMR spectra of epoxyeujindole A and Prof.
Douglass Taber for helpful discussions. Financial support was
provided by Ministry of Science
&
Technology
(12) Gawley, R. E. Synthesis 1976, 777.
(2013CB836900), National Natural Science Foundation of
China (21290180, 21172235, and 21222202), and Shanghai Sci-
ence and Technology Commission (15JC1400400).
(13) (a) Stork, G.; Jung, M. E. J. Am. Chem. Soc. 1974, 96, 3682. (b)
Dudley, G. B.; Engel, D. A.; Ghiviriga, I.; Lam, H.; Poon, K. W. C.;
Singletary, J. A. Org. Lett. 2007, 9, 2839.
(14) Cuesta, X.; González, A.; Bonjoch, J. Tetrahedron: Asymmetry
1999, 10, 3365.
(15) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem.
Soc. 1977, 99, 3179.
(16) Xie, J.; Okano, A.; Pierce, J. G.; James, R. C.; Stamm, S.; Crane,
C. M.; Boger, D. L. J. Am. Chem. Soc. 2012, 134, 1284.
(17) Bekkam, M.; Mo, H.; Nichols, D. E. Org. Lett. 2012, 14, 296.
(18) (a) Bishop, L. M.; Barbarow, J. E.; Bergman, R. G.; Trauner, D.
Angew. Chem., Int. Ed. 2008, 47, 8100. (b) Bishop, L. M.; Roberson, R.
E.; Bergman, R. G.; Trauner, D. Synthesis 2010, 2233.
(19) For synthetic applications of 6π electrocyclization from our
group, see: (a) Lu, Z.; Li, Y.; Deng, J.; Li, A. Nat. Chem. 2013, 5, 679. (b)
Li, J.; Yang, P.; Yao, M.; Deng, J.; Li, A. J. Am. Chem. Soc. 2014, 136,
16477. (c) Yang, M.; Li, J.; Li, A. Nat. Commun. 2015, 6, 6096. (d) Wan,
M.; Yao, M.; Gong, J.; Yang, P.; Liu, H.; Li, A. Chin. Chem. Lett. 2015,
26, 272. Also see refs 4a and 4e.
REFERENCES
(1) (a) Terpene Indole Alkaloid Biosynthesis; O'Connor, S. E.;
McCoy, E. In Recent Advances in Phytochemistry, Vol. 40, Romeo, J.
T., Ed.; Elsevier, 2006; pp 1–22. (b) Finefield, J. M.; Frisvad, J. C.;
Sherman, D. H.; Williams, R. M. J. Nat. Prod. 2012, 75, 812. (c) Marcos,
I. S.; Moro, R. F.; Costales, I.; Basabe, P.; Díez, D. Nat. Prod. Rep. 2013,
30, 1509. d) Baunach, M.; Franke, J.; Hertweck, C. Angew. Chem., Int.
Ed. 2015, 54, 2604.
(2) (a) Gloer, J. B. Acc. Chem. Res. 1995, 28, 343. (b) Gloer, J. B.;
Rinderknecht, B. L.; Wicklow, D. T.; Dowd, P. F. J. Org. Chem. 1989,
54, 2530. (c) TePaske, M. R.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J.
Org. Chem.1989, 54, 4743. (d) Staub, G. M.; Gloer, J. B.; Wicklow, D.
T.; Dowd, P. F. J. Am. Chem. Soc. 1992, 114, 1015.
(3) (a) Bradshaw, B.; Etxebarria-Jardí, G.; Bonjoch, J. J. Am. Chem.
Soc. 2010, 132, 5966. (b) Goetz, A. E.; Silberstein, A. L.; Corsello, M.
A.; Garg, N. K. J. Am. Chem. Soc. 2014, 136, 3036.
(4) (a) Bian, M.; Wang, Z.; Xiong, X.; Sun, Y.; Matera, C.; Nicolaou,
K. C.; Li, A. J. Am. Chem. Soc. 2012, 134, 8078. Related synthetic stud-
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
TOC
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
5
ACS Paragon Plus Environment