Divergent Total Syntheses of Isobatzellines A/B and Batzelline A

Article abstract of DOI:10.1021/acs.orglett.0c01894

Divergent total syntheses of isobatzellines A/B and batzelline A were accomplished. A fully substituted common indole intermediate bearing C-2 methylthio and C-5 chloro groups was constructed via ring expansion of benzocyclobutenone oxime sulfonate with NaSMe and a benzyne-mediated cyclization/functionalization sequence as the key steps. The total synthesis of isobatzelline B was achieved via formation of the iminoquinone structure by the redox-neutral acid-promoted C-5 proto-dechlorination of the common indole intermediate. The total syntheses of isobatzelline A and batzelline A were completed in a divergent manner by oxidation of the common indole intermediate using MnO2 or Mn(OAc)3, respectively.

Full text of DOI:10.1021/acs.orglett.0c01894

pubs.acs.org/OrgLett
Letter
Divergent Total Syntheses of Isobatzellines A/B and Batzelline A
Yumi Yamashita, Louna Poignant, Juri Sakata, and Hidetoshi Tokuyama*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01894
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Divergent total syntheses of isobatzellines A/B and
batzelline A were accomplished. A fully substituted common indole
intermediate bearing C-2 methylthio and C-5 chloro groups was
constructed via ring expansion of benzocyclobutenone oxime
sulfonate with NaSMe and a benzyne-mediated cyclization/
functionalization sequence as the key steps. The total synthesis
of isobatzelline B was achieved via formation of the iminoquinone
structure by the redox-neutral acid-promoted C-5 proto-dechlori-
nation of the common indole intermediate. The total syntheses of
isobatzelline A and batzelline A were completed in a divergent
manner by oxidation of the common indole intermediate using
MnO2 or Mn(OAc)3, respectively.
arine alkaloids with the pyrrolo[4,3,2-de]quinoline
explored, and their total syntheses have only been reported by
Joule’s group.8,9 As part of our ongoing interest in the total
synthesis of pyrroloquinoline alkaloids,5d,10 we herein report
efficient and divergent total syntheses of 1, 2, and 4 featuring
three key processes, including the ring expansion of
benzocyclobutenone oxime sulfonate with NaSMe to construct
2-methylthioindole,11 a benzyne-mediated cyclization/func-
tionalization cascade to form the tetrahydroquinoline ring,12
and a Mn-reagent-dependent oxidative formation of iminoqui-
none and o-benzoquinone.
M
skeleton, such as isobatzellines,1,2 batzellines,1−3 and
makaluvamines,4 have received a great deal of attention in the
fields of drug discovery and organic synthesis owing to their
broad range of biological activities and characteristic structures
(Figure 1). For example, isobatzellines and batzellines isolated
There are two major synthetic challenges to overcome in the
construction of batzellines and isobatzellines family com-
pounds. One is adjusting the oxidation state of the pyrrolo-
[4,3,2-de]quinoline skeleton in the latter stage of the synthesis
without affecting the electron-rich indole skeleton. The other is
the construction of a fully substituted indole skeleton with the
introduction of oxygen, nitrogen, sulfur, and halogen
substituents at the requisite positions. These issues are made
more challenging by the presence of the oxidant-labile
methylthio group. In Joule’s pioneering total synthesis of
2,8,9 oxidation of 2-methylthioindole 12 was executed in the
final step to provide pyrroloiminoquinone 13 in only 30%
yield, whereas the C-2-unsubstituted indole 14 gave
pyrroloiminoquinone 15 in high yield under the same
oxidation conditions (Scheme 1a). For the total syntheses of
1 and 4, C-5 chlorination of indole 16 was attempted (Scheme
Figure 1. Isobatzellines, batzellines, and makaluvamines
from deep-water Caribbean sponge Batzella sp. exhibit
cytotoxic activity against P388 leukemia cells, and the latter
compounds inhibit HIV-1 envelope-mediated cell fusion.2
Furthermore, makaluvamine A exhibits potent in vitro
cytotoxicity against the human colon tumor cell line
HCT116 and inhibitory activity against topoisomerase II.4a
Accordingly, tremendous effort has been devoted to develop
reliable synthetic routes for construction of the highly
functionalized pyrrolo[4,3,2-de]quinoline skeleton, and several
total syntheses have been reported.5−7 However, synthetic
routes to isobatzellines A (1) and B (2) and batzellines A (4)
and B (5) bearing the C2-methylthio group have not been fully
Received: June 5, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01894
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 1. Joule’s Total Syntheses of Isobatzellines A (1)
Scheme 2. Retrosynthetic Analysis
and B (2) and batzelline A (4)
via regioselective [2 + 2] cycloaddition of benzyne 2714 and
ketene silyl acetal 26.15
Our synthesis commenced with the [2 + 2] cycloaddition of
ketene silyl acetal 26 and the benzyne species 27 generated
from 4-bromoveratrole 30 by treatment with LiTMP, which
provided benzocyclobutenone 32 with perfect regioselectivity
after HF-mediated ring opening of tricyclic adduct 31 (Scheme
3). The resultant primary alcohol 32 was converted to Ns
Scheme 3. Synthesis of Oxime Sulfonate 25
1b). However, reaction with NCS only provided the fully
aromatized compound 17, presumably triggered by undesired
S-chlorination of the methylthio group. Although this
undesired aromatization was bypassed by the early stage of
C-5 chlorination prior to sulfenylation, oxidation of 21 to
pyrroloiminoquinone in the final step was also not
straightforward, and a mixture of isobatzelline A (26%),
batzelline A (22%), and aromatized product 22 (27%) was
obtained after one-pot amination (Scheme 1c).
With these synthetic issues in mind, we conducted
retrosynthetic analysis (Scheme 2). We set indoles 12 and
21 as precursors of isobatzellines A (1), B (2), and batzelline A
(4) hoping that mild and methylthio-group-compatible
oxidation conditions could be identified. Chlorination or
protonation of the aryl anion species 23 generated by our
benzyne-mediated cyclization/functionalization protocol using
4-bromoindole 24 would provide 12 or 21, respectively.10 For
construction of the highly substituted 2-methylthioindole, we
planned to expand the scope of our indole synthesis using the
ring expansion of benzocyclobutenone oxime sulfonate
developed in the course of our synthetic studies on (+)-CC-
1065. Thus, based on our ring-expansion reaction of oxime
sulfonates with hydride and cyanide ion sources (Scheme
2b),11 we envisaged that 1,2-addition of methanethiolate to
oxime sulfonate 25 followed by ring expansion with
concomitant N-O bond cleavage would provide 2-methyl-
thioindole 24.13 Oxime sulfonate 25 should be easily accessible
amide 33 under Mitsunobu conditions using NsNHBoc16 and
DMEAD.17 Bromination of 33 followed by condensation of
the resultant bromide 34 with hydroxylamine at high
temperature (100−130 °C) with undesired loss of the Boc
group gave oxime 35.18 Finally, sulfonylation of oxime 35 and
subsequent Boc protection furnished the desired oxime
sulfonate 25.18
Given the highly strained oxime sulfonate 25, we focused on
the key ring-expansion reaction triggered by nucleophilic
addition of thiolate. First, 25 was treated with NaSMe (5.0
equiv) in DMSO or DMF at room temperature based on our
B
https://dx.doi.org/10.1021/acs.orglett.0c01894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
previously established conditions.11 The expected reaction and
concomitant removal of the Ns group proceeded to give indole
24 and a small amount of side product 38 due to ipso
substitution on the Ns group (Table 1, entries 1 and 2).19
pivotal aryl anion species 40. Aqueous workup of the reaction
mixture with aq. NH4Cl afforded the C-5-unsubstituted indole
41, whereas addition of hexachloroethane to the reaction
mixture gave 5-chloroindole 42. Finally, the Boc group was
removed to afford pyrroloindoles 12 and 21, respectively.21
With pyrroloindoles 12 and 21 in hand, we focused on the
crucial oxidative skeletal transformation toward isobatzellines
A (1) and B (2) and batzelline A (4). Based on Joule’s total
synthesis of isobatzelline B (2), C5−H indole 12 was treated
with CAN to afford the desired pyrroloiminoquinone 13.
However, as anticipated, the yield was very low (Scheme 5).
Table 1. Ring-Expansion Reaction of 25
Scheme 5. Total Synthesis of Isobatzelline B (2)
a
b
b
b
entry
solvent
time (h)
24 (%)
37 (%)
38 (%)
c
1
2
3
4
5
6
DMSO
DMF
THF
CH2Cl2
MeOH
MeCN
3.5
4.5
2
3
23
1.5
56
45
49
42
−
−
−
−
−
44
−
<9
c
<17
−
−
−
Instead, we found another way to obtain pyrroloiminoquinone
13 from C-5 chloroindole 21. Upon subjection of C-5
chloroindole 21 to TFA at 50 °C, dechlorinative pyrroloimi-
noquinone formation occurred to afford 13 in 81% yield. This
is a Brønsted acid promoted redox-neutral proto-dechlorina-
tion process because C-5 chloroindole 21 has the same formal
oxidation state as 13.22 The total synthesis of isobatzelline B
(2) was achieved by introduction of an amino group by
addition−elimination reaction.
Next, the final stage of isobatzelline A (1) and batzelline A
(4) synthesis was carefully investigated. As reported, CAN
oxidation/amination treatment of 21 resulted in low yields of
batzelline A (4) and isobatzelline A (1) and many byproducts,
such as the fully aromatized compound 22 (Scheme 6a). In
sharp contrast, we successfully established a switchable
oxidation protocol to selectively provide isobatzelline A (1)
or batzelline A (4) depending on the manganese oxidant
86
c
trace
a
b
0.1 M concentration. Isolated yield. Isolated with trace amount of
inseparable unidentified byproducts.
Switching solvent to THF or CH2Cl2 did not increase the yield
of 24 (Table 1, entries 3 and 4), while reaction in MeOH did
not afford indole 24 at all, instead providing thiooxime 37 due
to substitution on the oxime sp2 nitrogen atom (Table 1, entry
5).20 Further screening revealed that MeCN was the best
choice of solvent, providing 24 as the sole product in high yield
(86%) (Table 1, entry 6).
Having established a new protocol for construction of 2-
methylthioindole, we then constructed the fully substituted
piperidine ring-fused indole skeletons 12 and 21 by our
benzyne-mediated cyclization/functionalization protocol
(Scheme 4). After N-methylation of indole 24, the resultant
compound 39 was treated with excess LiTMP to promote the
benzyne generation/cyclization cascade that provides the
Scheme 6. Total Syntheses of Isobatzelline A (1) and
Batzelline A (4)
Scheme 4. Syntheses of Indoles 12 and 21
C
https://dx.doi.org/10.1021/acs.orglett.0c01894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
reagent used. Thus, treatment of indole 21 with Mn(OAc)3 in
AcOH under an O2 atmosphere afforded batzelline A (4) in
acceptable yield along with a trace amount of 22 (Scheme
6b).23 Conversely, reaction using MnO2 in AcOH gave
pyrroloiminoquinone 43 as the main product in high yield,
which was then converted to isobatzelline A (1) by
introduction of an amino group (Scheme 6b).
Platform Project for Supporting Drug Discovery and Life
Science Research (BINDS) from AMED (JP19am0101100).
The authors are grateful to Professor emeritus Tohru
Fukuyama of the University of Tokyo for his valuable
suggestion on the Mn-mediated oxidation.
REFERENCES
■
In summary, divergent total syntheses of isobatzellines A and
B and batzelline A were accomplished by the rapid assembly of
the highly substituted pyrrolidine-fused common 2-methyl-
thioindole by ring expansion reaction of benzocyclobutenone
oxime sulfonates with NaSMe and a benzyne-mediated
cyclization/functionalization protocol. The total synthesis of
isobatzelline B was achieved via TFA-promoted proto-
dechlorination of the common intermediate. Selective
derivatization to isobatzelline A and batzelline A was made
possible by the manganese-oxidant-dependent oxidation of
piperidine-fused 2-methylthioindole to the benzoquinone or
iminoquinone derivative. To the best of the authors’
knowledge, this is the first report of the use of manganese
reagents for the highly chemoselective oxidative transformation
of electron-rich indole skeletons to the pyrrolo[4,3,2-de]-
quinoline skeleton. The efficiencies of our total syntheses are
demonstrated by the dramatically improved total yields of the
products compared to those achieved in previous total
syntheses,9 i.e., isobatzelline A yields from 0.51% to 13%,
isobatzelline B yields from 2.3% to 19%, and batzelline A yields
from 1.1% to 12%.
(1) Sun, H. H.; Sakemi, S.; Burres, N.; McCarthy, P. Isobatzellines
A, B, C, and D. Cytotoxic and Antifungal Pyrroloquinoline Alkaloids
from the Marine Sponge Batzella Sp. J. Org. Chem. 1990, 55, 4964−
4966.
(2) Chang, L. C.; Otero-Quintero, S.; Hooper, J. N. A.; Bewley, C.
A. Batzelline D and Isobatzelline E from the Indopacific Sponge
Zyzzya fuliginosa. J. Nat. Prod. 2002, 65, 776−778.
(3) Sakemi, S.; Sun, H. H. Batzellines A, B, and C. Novel
Pyrroloquinoline Alkaloids from the Sponge Batzella Sp. Tetrahedron
Lett. 1989, 30, 2517−2520.
(4) (a) Radisky, D. C.; Radisky, E. S.; Barrows, L. R.; Copp, B. R.;
Kramer, R. A.; Ireland, C. M. Novel Cytotoxic Topoisomerase II
Inhibiting Pyrroloiminoquinones from Fijian Sponges of the Genus
Zyzzya. J. Am. Chem. Soc. 1993, 115, 1632−1638. (b) Carney, J. R.;
Scheuer, P. J.; Kelly-Borges, M. Makaluvamine G, a Cytotoxic
Pigment from an Indonesian Sponge Histodermella Sp. Tetrahedron
1993, 49, 8483−8486. (c) Schmidt, E. W.; Harper, M. K.; Faulkner,
D. J. Makaluvamines H-M and Damirone C from the Pohnpeian
Sponge Zyzzya fuliginosa. J. Nat. Prod. 1995, 58, 1861−1867.
(d) Venables, D. A.; Concepcion, G. P.; Matsumoto, S. S.; Barrows,
L. R.; Ireland, C. M. Makaluvamine N: A New Pyrroloiminoquinone
from Zyzzya fuliginosa. J. Nat. Prod. 1997, 60, 408−410. (e) Casapullo,
A.; Cutignano, A.; Bruno, I.; Bifulco, G.; Debitus, C.; Gomez-Paloma,
L.; Riccio, R. Makaluvamine P, a New Cytotoxic Pyrroloiminoqui-
none from Zyzzya cf. fuliginosa. J. Nat. Prod. 2001, 64, 1354−1356.
For a recent review, see: (f) Hu, J.-F.; Fan, H.; Xiong, J.; Wu, S.-B.
Discorhabdins and Pyrroloiminoquinone-Related Alkaloids. Chem.
Rev. 2011, 111, 5465−5491.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01894.
(5) Total synthesis of isobatzelline C, see: (a) Tao, X. L.; Cheng, J.-
F.; Nishiyama, S.; Yamamura, S. Synthetic Studies on Tetrahydro-
pyrroloquinoline-Containing Natural Products: Syntheses of Disco-
rhabdin C, Batzelline C and Isobatzelline C. Tetrahedron 1994, 50,
2017−2028. (b) Yamada, F.; Hamabuchi, S.; Shimizu, A.; Somei, M.
Simple Total Syntheses of Marine Alkaloids, Batzelline C, Isobatzel-
line C, Damirone A, and Makaluvamine A. Heterocycles 1995, 41,
1905−1908. (c) Roberts, D.; Joule, J. A. Synthesis of Pyrrolo[4,3,2-
de]quinolines from 6,7-Dimethoxy-4-methylquinoline. Formal Total
Syntheses of Damirones A and B, Batzelline C, Isobatzelline C,
Discorhabdin C, and Makaluvamines A−D. J. Org. Chem. 1997, 62,
568−577. (d) Oshiyama, T.; Satoh, T.; Okano, K.; Tokuyama, H.
Total Synthesis of Batzelline C and Isobatzelline C. RSC Adv. 2012, 2,
5147−5149.
1
Full experimental procedure; H and 13C spectra of
compounds 1, 2, 4, 12, 13, 21, 24, 25, 32, 33, 34, 36, 37,
38, 39, 41, 42 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Hidetoshi Tokuyama − Graduate School of Pharmaceutical
Sciences, Tohoku University, Sendai 980-8578, Japan;
orcid.org/0000-0002-6519-7727; Email: tokuyama@
mail.pharm.tohoku.ac.jp
Authors
(6) Total synthesis of batzelline C and batzelline D, see:
Yumi Yamashita − Graduate School of Pharmaceutical Sciences,
Tohoku University, Sendai 980-8578, Japan
Louna Poignant − Graduate School of Pharmaceutical Sciences,
Tohoku University, Sendai 980-8578, Japan
Juri Sakata − Graduate School of Pharmaceutical Sciences,
Tohoku University, Sendai 980-8578, Japan
̈
Backenkohler, J.; Spindler, S.; Spiteller, P. Total Synthesis of
Damirone C, Makaluvamine O, Makaluvone, Batzelline C and
Batzelline D. ChemistrySelect 2017, 2, 2589−2592.
(7) For selected total synthesis of makaluvamines, see: (a) Izawa, T.;
Nishiyama, S.; Yamamura, S. Total Syntheses of Makaluvamines A, B,
C, D and E, Cytotoxic Pyrroloiminoquinone Alkaloids Isolated from
Marine Sponge Bearing Inhibitory Activities against Topoisomerase
II. Tetrahedron 1994, 50, 13593−13600. (b) White, J. D.; Yager, K.
M.; Yakura, T. Synthetic Studies of the Pyrroloquinoline Nucleus of
the Makaluvamine Alkaloids. Synthesis of the Topoisomerase II
Inhibitor Makaluvamine D. J. Am. Chem. Soc. 1994, 116, 1831−1838.
(c) Sadanandan, E. V.; Pillai, S. K.; Lakshmikantham, V.; Billimoria,
A. D.; Culpepper, J. S.; Cava, M. P. Efficient Syntheses of the Marine
Alkaloids Makaluvamine D and Discorhabdin C: The 4,6,7-
Trimethoxyindole Approach. J. Org. Chem. 1995, 60, 1800−1805.
(d) Iwao, M.; Motoi, O.; Fukuda, T.; Ishibashi, F. New Synthetic
Approach to Pyrroloiminoquinone Marine Alkaloids. Total synthesis
of Makaluvamines A, D, I, and K. Tetrahedron 1998, 54, 8999−9010.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01894
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by KAKENHI
(JP16H01127, JP16H00999, JP26253001, JP18H02549,
JP18H04231, JP18H04379, JP18K18462) from JSPS and
D
https://dx.doi.org/10.1021/acs.orglett.0c01894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(e) Kraus, G. A.; Selvakumar, N. Synthetic Routes to Pyrroloimino-
quinone Alkaloids. A Direct Synthesis of Makaluvamine C. J. Org.
Chem. 1998, 63, 9846−9849. (f) Kita, Y.; Egi, M.; Tohma, H. Total
Synthesis of Sulfur-Containing Pyrroloiminoquinone Marine Product,
( )-Makaluvamine F Using Hypervalent Iodine(III)-Induced Re-
actions. Chem. Commun. 1999, 143−144.
(16) Fukuyama, T.; Cheung, M.; Kan, T. N-Carboalkoxy-2-
Nitrobenzenesulfonamides: A Practical Preparation of N-Boc-, N-
Alloc-, and N-Cbz-Protected Primary Amines. Synlett 1999, 1999,
1301−1303.
(17) (a) Sugimura, T.; Hagiya, K. Di-2-methoxyethyl Azodicarbox-
ylate (DMEAD): An Inexpensive and Separation-Friendly Alternative
Reagent for the Mitsunobu Reaction. Chem. Lett. 2007, 36, 566−567.
(b) Hagiya, K.; Muramoto, N.; Misaki, T.; Sugimura, T. DMEAD: A
New Dialkyl Azodicarboxylate for the Mitsunobu Reaction.
Tetrahedron 2009, 65, 6109−6114.
(18) Oxime 35 and oxime sulfonates 36 and 25 were obtained as a
single isomer. The stereochemistry of the oxime derivatives were not
determined.
(8) Alvarez, M.; Bros, A.; Joule, J. A. Synthesis of Isobatzelline B.
Tetrahedron Lett. 1998, 39, 679−680.
(9) Alvarez, M.; Bros, A.; Gras, G.; Ajana, W.; Joule, J. A. Syntheses
of Batzelline A, Batzeline B, Isobatzelline A, and Isobatzelline B. Eur. J.
Org. Chem. 1999, 1999, 1173−1183.
(10) Oshiyama, T.; Satoh, T.; Okano, K.; Tokuyama, H. Total
Synthesis of Makaluvamine A/D, Damirone B, Batzelline C,
Makaluvone, and Isobatzelline C Featuring One-Pot Benzyne-
Mediated Cyclization−Functionalization. Tetrahedron 2012, 68,
9376−9383.
(19) Wuts, P. G. M.; Northuis, J. M. T. A Cautionary Note on the
Use of p-Nitrobenzenesulfonamides as Protecting Groups. Tetrahe-
dron Lett. 1998, 39, 3889−3890.
(20) For selected examples on SN2 reaction on oxime nitrogen, see:
(a) Kusama, H.; Yamashita, Y.; Narasaka, K. Synthesis of Quinolines
via Intramolecular Cyclization of Benzylacetone Oxime Derivatives
Catalyzed with Tetrabutylammonium Perrhenate (VII) and Trifluor-
omethanesulfonic Acid. Chem. Lett. 1995, 24, 5−6. (b) Tsutsui, H.;
Hayashi, Y.; Narasaka, K. Preparation of Primary Amines by the
Copper(I) Catalyzed Reaction of 4,4’-Bis(trifluoromethyl)benzo-
phenone O-Methylsulfonyloxime and Alkyl Grignard Reagents.
Chem. Lett. 1997, 26, 317−318. (c) Mori, S.; Uchiyama, K.;
Hayashi, Y.; Narasaka, K.; Nakamura, E. SN2 Substitution on sp2
Nitrogen of Protonated Oxime. Chem. Lett. 1998, 27, 111−112.
(21) Lott, R. S.; Chauhan, V. S.; Stammer, C. H. Trimethylsilyl
Iodide as a Peptide Deblocking Agent. J. Chem. Soc., Chem. Commun.
1979, 495−496.
(22) Roberts, D.; Alvarez, M.; Joule, J. A. Synthesis of 6-Chloro-
1,3,4,5-tetrahydro-7,8-dimethoxy-1-methylpyrrolo[4,3,2-de]quinoline
from a Quinoline; Formal Total Syntheses of Batzelline C,
Isobatzelline C, Discorhabdin C and Makaluvamine D. Tetrahedron
Lett. 1996, 37, 1509−1512.
(23) Nishino, H.; Itoh, N.; Nagashima, M.; Kurosawa, K. Choice of
Manganese(III) Complexes for the Synthesis of 4,4’-Biphenyldiols
and 4,4’-Diphenoquiones. Bull. Chem. Soc. Jpn. 1992, 65, 620−622.
(11) Imaizumi, T.; Yamashita, Y.; Nakazawa, Y.; Okano, K.; Sakata,
J.; Tokuyama, H. Total Synthesis of (+)-CC-1065 Utilizing Ring
Expansion Reaction of Benzocyclobutenone Oxime Sulfonate. Org.
Lett. 2019, 21, 6185−6189.
(12) (a) Noji, T.; Fujiwara, H.; Okano, K.; Tokuyama, H. Synthesis
of Substituted Indoline and Carbazole by Benzyne-Mediated
Cyclization−Functionalization. Org. Lett. 2013, 15, 1946−1949.
(b) Moro-oka, Y.; Fukuda, T.; Iwao, M. The First Total Synthesis
of Veiutamine, A New Type of Pyrroloiminoquinone Marine Alkaloid.
Tetrahedron Lett. 1999, 40, 1713−1716.
(13) For selected examples on 2-alkylthioindole synthesis, see:
(a) Nakagawa, K.; Somei, M. Lithiation of 3-Dimethylaminomethyl-
and 3-Dimethylaminoethyl-1-methoxylndole Derivatives. Heterocycles
1994, 39, 31−34. (b) Hamel, P.; Girard, Y.; Atkinson, J. G. Acid-
Catalyzed Isomerization of 3-Indolyl Sulfides to 2-Indolyl Sulfides:
First Synthesis of 3-Unsubstituted 2-Arylthioindoles. Evidence for a
Complex Intermolecular Process. J. Org. Chem. 1992, 57, 2694−2699.
(c) Plate, R.; Ottenheijm, H. C. J. Synthesis of 2-(Alkylthio)indoles.
Tetrahedron 1986, 42, 4511−4516. (d) Hartke, K.; Teuber, D.;
Gerber, H.-D. Indole- and Pyrrole-Sulfonium Ylides. Tetrahedron
1988, 44, 3261−3270.
(14) For selected examples on [2 + 2] cycloaddition of benzyne, see:
(a) Stevens, R. V.; Bisacchi, G. S. An Efficient and Remarkably
Regioselective Synthesis of Benzocyclobutenones from Benzynes and
1,1-Dimethoxyethylene. J. Org. Chem. 1982, 47, 2393−2396.
(b) Liebeskind, L. S.; Lescosky, L. J.; McSwain, C. M., Jr. Synthesis
of Substituted Benzocyclobutenediones. J. Org. Chem. 1989, 54,
1435−1439. (c) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.;
Matsumoto, T.; Suzuki, K. [2 + 2] Cycloaddition of Benzyne and
Ketene Silyl Acetal as an Efficient Route to Benzocyclobutenones.
Synlett 1995, 1995, 177−179. (d) Hamura, T.; Hosoya, T.;
Yamaguchi, H.; Kuriyama, Y.; Tanabe, M.; Miyamoto, M.; Yasui,
Y.; Matsumoto, T.; Suzuki, K. Facile Access to Versatile Polyaromatic
Building Blocks: Selectively Protected Benzocyclobutenedione
Derivatives via Regioselective [2 + 2] Cycloaddition of α-
Alkoxybenzyne and Ketene Silyl Acetal. Helv. Chim. Acta 2002, 85,
3589−3604. (e) Maurin, P.; Ibrahim-Ouali, M.; Parrain, J.-L.; Santelli,
M. Structure of Substituted o-Benzynes and Their Cycloaddition to
Ketene Dialkyl Acetals. J. Mol. Struct.: THEOCHEM 2003, 637, 91−
100. (f) Chen, P.-H.; Savage, N. A.; Dong, G. Concise Synthesis of
Functionalized Benzocyclobutenones. Tetrahedron 2014, 70, 4135−
4146. For review, see: (g) Takikawa, H.; Nishii, A.; Sakai, T.; Suzuki,
K. Aryne-based Strategy in the Total Synthesis of Naturally Occurring
Polycyclic Compounds. Chem. Soc. Rev. 2018, 47, 8030−8056.
(15) (a) Hosoya, T.; Kuriyama, Y.; Suzuki, K. Convenient Synthesis
of Phthalides via Regioselective Baeyer−Villiger Oxidation of
Benzocyclobutenones. Synlett 1995, 1995, 635−638. (b) Oisaki, K.;
Suto, Y.; Kanai, M.; Shibasaki, M. A New Method for the Catalytic
Aldol Reaction to Ketones. J. Am. Chem. Soc. 2003, 125, 5644−5645.
(c) Hatano, M.; Ishihara, K. Sodium Phenoxide−Phosphine Oxides as
Extremely Active Lewis Base Catalysts for the Mukaiyama Aldol
Reaction with Ketones. Org. Lett. 2007, 9, 4527−4530.
E
https://dx.doi.org/10.1021/acs.orglett.0c01894
Org. Lett. XXXX, XXX, XXX−XXX