Heteroannulation of Arynes with α-Amino Imides: Synthesis of 2,2-Disubstituted Indolin-3-ones and Application to the Enantioselective Total Synthesis of (+)-Hinckdentine A

Article abstract of DOI:10.1002/anie.201800746

A novel heteroannulation reaction between α-amino imides and in situ generated arynes has been developed for the synthesis of 2,2-disubstituted indolin-3-ones. An enantioselective total synthesis of the marine alkaloid (+)-hinckdentine A was subsequently accomplished using this reaction as a key step. A catalytic enantioselective Michael addition of an α-aryl-α-isocyanoacetate to phenyl vinyl selenone was employed for the construction of the enantioenriched α-quaternary α-amino ester.

Full text of DOI:10.1002/anie.201800746

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Heteroannulation of Arynes with α-Amino Imides: Synthesis
of 2,2-Disubstituted Indolin-3-ones and Application to the
Enantioselective Total Synthesis of (+)-Hinckdentine A
Authors: Rubén Omar Torres-Ochoa, Thomas Buyck, Qian Wang, and
Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800746
Angew. Chem. 10.1002/ange.201800746
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10.1002/anie.201800746
Angewandte Chemie International Edition
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a
Heteroannulation of Arynes with -Amino Imides: Synthesis of
2,2-Disubstituted Indolin-3-ones and Application to the
Enantioselective Total Synthesis of (+)-Hinckdentine A
Rubén O. Torres-Ochoa, Thomas Buyck, Qian Wang and Jieping Zhu*
Abstract: A novel heteroannulation reaction between the a-amino
imides and the in situ generated arynes has been developed for
the synthesis of the 2,2-disubstituted indolin-3-ones. An
enantioselective total synthesis of the marine alkaloid (+)-
hinckdentine A was subsequently accomplished featuring this
in turn be synthesized by an organocatalytic enantioselective
Michael addition of methyl a-isocyano acetate 6 to phenyl vinyl
selenone (7).[10] Critical to the success of this synthesis would
rely on the one step synthesis of the indolin-3-one 3 from 4a
and 5. The incorporation of this strategic step into the
synthesis was inspired by the work of Okuma who reported the
synthesis of 9 by reaction of the a-monosubstituted amino
ester 8 with 2 equivalents of 4a (Scheme 1b).[11-12] We report
herein the difficulties encountered in our attempted
heteroannulation between 4a and 5, the subsequent
development of a new heteroannulation protocol and its
implementation in the realization of an enantioselective total
synthesis of (+)-hinckdentine A (1).
reaction as
a key step. A catalytic enantioselective Michael
addition of an a-aryl-a-isocyanoacetate to phenyl vinyl selenone
was employed for the construction of the enantioenriched a-
quaternary a-amino ester.
Hinckdentine A (1, Scheme 1) was isolated by Blackman,
Taylor and co-workers from the bryozoan Hincksinoflustra
denticulata, collected from Tasmanian eastern coast.[1] The
structure, unambiguously determined by single crystal X-ray
analysis, is characterized by a unique brominated indolo[1,2-
Br
O
COOMe
NH2
O
NH
NPCOR
HN
HN
c]quinazoline and
a
hexahydroazepin-2-one motif. The
Br
N
Br
bioactivity of this natural product has not been examined due
to its extremely low availability (isolation yield: 0.0005%).
Nonetheless, the presence of indoline, azepinone and
pyrimidine motifs in the same structure renders it a highly
appealing compound in medicinal chemistry and an intriguing
target for synthetic chemists.[2] The total synthesis of the
racemic 8-desbromo analogue and the natural product itself
have been achieved by the groups of McWhorter[3] and
H2N
O2N
N
1 (+)-hinckdentine A
2
3
(a)
NPCOR
X
CN
O2N
COOMe
+
OTf
O
SeO2Ph
+
H2N
TMS
O2N
4a
5
6
7
Kawasaki,[4]
synthesis of (+)-hinckdentine A, featuring a key asymmetric
dearomative cyclization of functionalized N-acyl
respectively. An elegant enantioselective
O
R
OTf
TMS
COOMe
CsF, MeCN
RT
+
(b)
H2N
R
N
H
4a
8
9
tetrahydrocarbazole, has recently been accomplished by
Kitamura, Fukuyama and co-workers.[5]
Scheme 1. Hinckdentine A and retro-synthetic analysis.
As a continuation of our research program dealing with
the total synthesis of indoline-based polycyclic natural
products,[6] we became interested in (+)-hinckdentine A (1).
Our retrosynthetic analysis is outlined in Scheme 1a. We
planned to construct the pentacyclic ring system of 1 from the
We began our synthesis by investigating the
heteroannulation between 4a and racemic a,a-disubstituted a-
amino ester 5a (Scheme 2a).[13] The reaction afforded, under
Okuma’s conditions, the N-phenylated compound 10a as a
major product (76% yield) together with a small amount of the
desired indolin-3-one 3a. Systematic survey of reaction
conditions by varying the fluoride sources (CsF, KF, TBAT,
TBAF), the solvents (THF, dichloroethane, dioxane), the
temperature and the additives (bases or crown ether) failed to
improve the yield of 3a. Suspecting that the presence of the
amide NH in the side chain of 5a could serve as a proton
donor to trap the phenyl anion intermediate 11, the N-2,4-
dimethoxybenzyl protected amino ester 5b was prepared and
submitted to the heteroannulation with 4a. However, N-
phenylated product 10b was again isolated as a major product
in 65% yield. That the protonation of the anionic intermediate
11 outcompeted the desired cyclization was presumably due
to the moderate electrophilicity and the steric hindrance
around the neopentylic methoxycarbonyl group. Indeed, no
example of a-quaternary a-amino esters was reported as
coupling partner in Okuma’s paper. Taking advantage of the
amino ester
2 via a sequence of amidine formation,
lactamization and bromination reactions. Compound 2 could
be prepared from 2,2-disubstituted indolin-3-one 3, which was
envisaged to be prepared by a formal [3+2] heteroannulation
between benzyne generated in situ from ortho-
(trimethylsilyl)phenyl triflate (4a)[7] and a suitably functionalized
a,a-disubstituted a-amino acid derivative 5.[8-9] The latter could
[*]
Dr. R. O. Torres-Ochoa, Dr. T. Buyck, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201800746
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COMMUNICATION
ready access to a-quaternary a-amino ester 10b, its
cyclization via intramolecular Friedel-Crafts acylation was
briefly examined. Unfortunately, no cyclization of 10b was
observed in the presence of various Lewis and Brønsted acids.
Alternatively, we also examined the reaction of 4a with g-
heteroannulation reaction is highly sensitive to the subtle
electrophilicity differences of the carbonyl groups.
In light of the importance of the indoxyl structure in natural
products,[16] its application as building blocks in organic
synthesis[17] and fluorescent dyes,[18] we set out to examine the
generality of this heteroannulation protocol. The synthesis of
imides is depicted in Scheme 3. Hydrolysis of the isocyano
group in 16 followed by reductive lactamization of the w-azido
ester under the Staudinger conditions afforded lactam 17.
Chemoselective acylation of the amide NH (nBuLi, then Ac2O)
furnished the desired N-acyl-3-aminopyrrolidin-2-ones 15 (n =
1) in good to excellent overall yields from 16.[13] The 1-acetyl-
3-amino-3-phenylpiperidin-2-one (15j, R1 = Ph, n = 2) was
similarly synthesized. On the other hand, reductive N-
alkylation of 17a (R1 = Ph, n = 1) with benzaldehyde followed
by imide formation afforded 18.
amino-a,b-unsaturated amide 12 aiming at
a one-step
synthesis of tricycle 13.[14] However, the reaction afforded once
again the N-phenylated product 14 as a major product (67%
yield) together with a trace amount of 13 (Scheme 2b).
NPCOMe
NPCOMe
CsF, MeCN
OMe
OMe
OTf
O
O
+
(a)
NH
H2N
O2N
5a P = H
5b P = 2,4-dimethoxybenzyl 10b P = 2,4-dimethoxybenzyl, 65%
TMS
RT
O2N
10a P = H, 76%
4a
OMe
NPCOMe
O
O
Ac
>c@
N
NH
N
H
NO2
n
R1
O
O2N
NHCOMe
HN
H2N
11
3a
>a, b@
MeOOC
CN
N3
n
O
15
DMB
N
n
R1
O
R1
16
Ac
DMB
N
N
H2N
O
NDMB
+
idem
O
>d, c]
OTf
(b)
O
17
+
Ph
BnHN
N
H
TMS
NH
18
H2N
O2N
O2N
O2N
12
4a
13 trace
14 67%
Scheme 3. Synthesis of N-acyl 3-aminopyrrolidin-2-ones 15 and 18. [a] HCl
in MeOH, RT; [b] PPh3, THF/H2O, 70 °C; [c] nBuLi, Ac2O, THF, -78 °C; [d]
PhCHO, MgSO4, DCM, 0 °C to RT, then NaBH4, MeOH, 0 °C.
Scheme 2. Initial attempts on the heteroannulation. Reaction conditions: 4a
(0.2 mmol), 5 (0.1 mmol), CsF (0.3 mmol). Abbreviation: DMB = 2,4-
dimethoxybenzyl.
Ac
O
OTf
Conditions[a]
N
R1
Ar
+
α
α
N
Ar
n
O
R2HN
NHAc
NHAc
TMS
R1
n
Table 1. Optimization of reaction conditions.
R2
4
15 or 18
3
O
Ac
OTf
Conditions>D@
N
O
3a, R = o-NO2, 67%
3b, R = H, 77%
3c, R = o-F, 77%
3d, R = m-Br, 72%
3e, R = p-OMe, 69%
3f, R = p-CF3, 52%
+
O
N
H
R
R
O
TMS
H2N
NHAc
N
H
4a
15b
3b
N
H
3g, R = Me, 70%
3h, R = Bn, 80%
O
F– source
TBAF
KF
Additive
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
t (h)
1
1
Yield (%)[b]
NHAc
Entry
O
O
1
2
3[c]
4
–
18-C-6
–
42
59
54
77
75
75
0
MeO
CsF
24
4
N
Bn
N
H
N
MeO
H
NHAc
4
CsF
–
NHAc
NHAc
5
CsF
4Å MS
3
3j, 75%
3i, 70%
3k, 68%
O
6
CsF
NaHCO3
3
OMe
5
6
O
7
CsF
–
–
24
24
R
8
CsF
THF
0
N
H
7
N
H
NHAc
[a] Reaction conditions: 4a (0.2 mmol), 15b (0.1 mmol), CsF (0.3 mmol),
solvent (c 0.085 M), RT; [b] Yields of isolated products; [c] CsF (0.2 mmol).
NHAc
3m, R = 4-Me/7-Me (2/1), 83%
3n, R = 5-OMe/6-OMe (5/3), 80%
3l, 86%
MeO
MeO
To drive the reaction towards the desired heteroannulation
process, we thought that increasing the electrophilicity of the
ester carbonyl group could be
OTf
Me
OTf
OTf
OTf
TMS
TMS
MeO
TMS
a viable option. Taking
OMe
4c
TMS
advantage of the aminoethyl side chain of compound 5, we
opted a cyclic imide function as a moderately activated form of
the carboxylic acid.[15] To our delight, the formal [3+2]
cycloaddition between 4a and 15b indeed occurred to produce
the desired 2,2-disubstituted indolin-3-one 3b. As it is seen
from Table 1, the best conditions found consisted of
performing the reaction in acetonitrile at room temperature in
the presence of CsF (3.0 equiv, entry 4). Under these
conditions, compound 3b was isolated in 77% yield. The
dramatic reactivity difference between a-amino esters 5 and a-
amino imide 15b indicated that the outcome of the
4b
4d
4e
Scheme 4. Scope of the heteroannulation reaction between 4 and 15 or 18.
Reaction conditions: 4 (0.2 mmol), 15 or 18 (0.1 mmol), CsF (0.3 mmol),
MeCN (c 0.085 M), RT.
The scope of the heteroannulation reaction was next
examined (Scheme 4). For the a-amino imides, aromatic
substituents (R1) bearing the electron donating (MeO) or
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10.1002/anie.201800746
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withdrawing groups (NO2, F, Br, CF3) as well as the alkyl
substituents (R1 = Me, Bn) at the Ca position of 15 were
compatible with the reaction conditions to afford the
corresponding 2,2-disubstituted indolin-3-ones in good to high
yields (3a-3h). Secondary amine 18 participated in the
reaction to furnish 3i in 70% yield. Pleasingly, 1-acetyl-3-
amino-3-phenylpiperidin-2-one (15j, R1 = Ph, n = 2) underwent
annulation efficiently with benzyne to afford the C2-
aminopropyl substituted indolinone 3j in 75% yield. Reaction of
4,5-dimethoxy-2-(trimethylsilyl)phenyl triflate (4b) with 15b
afforded 3k without event. Interestingly, the reaction of 3-
methoxy-2-(trimethylsilyl)phenyl triflate 4c with 15b afforded 4-
methoxy indolin-3-one 3l as a single regioisomer in 86%
yield.[8] By inductive effect, the MeO group can stabilize the
neighbouring phenyl anion intermediate contributing therefore,
together with steric effect, to the observed regioselectivity. In
line with this reasoning, the reaction involving 6-methyl-2-
(trimethylsilyl)phenyl triflate (4d) afforded 4- and 7-methyl
indolin-3-ones 3m in a 2/1 ratio in 83% yield. Similarly, 5-
methoxy and 6-methoxy indolin-3-ones 3n were formed in a
5/3 ratio from 4-methoxy-2-(trimethylsilyl)phenyl triflate (4e).
The lack of the regioselectivity in these cases is inherent to the
benzyne-based annulation reaction.
in good overall yield with an e.r. of 98.5:1.5 after
recrystallization (CH2Cl2/petroleum ether). The absolute
configuration of (S)-17a was confirmed by single crystal X-ray
diffraction analysis.[21] Conversion of (S)-17a to the N-Boc
imide 22 followed by its reaction with 4a furnished indolin-3-
one 23 in moderate overall yield.[22] Reduction of the nitro
group followed by treatment of the resulting aniline with methyl
orthoformate in the presence of AcOH afforded tetracycle 24.
The Wittig reaction of 25 followed by 1,4-reduction of the
resulting enoate with magnesium in MeOH[23] provided the
desired amino ester 25 (d.r. = 10:1) which, after N-protection
furnished 26.
CO2Me
PhO2Se
O
NH
CO2Me
CN
O2N
a
b-d
CN
NH2
NO2
6
+
O2N
(S)-21
SeO2Ph
(S)-17a
7
Boc
N
O
O
e
f
g
NH2
NO2
N
H
NO2
NHBoc
22
23
NHBoc
MeO2C
NBoc2
MeO2C
N
NHBoc
R
10
A remarkable feature of the new protocol is that it allows
direct access to the aminoethyl or aminopropyl substituted
indolin-3-ones, found in many bioactive compounds.[16] While
the incorporation of the versatile amino group in a side chain is
highly beneficial, this is also a limitation of the methodology.
To further extend the general applicability of our approach, we
decided to examine other moderately activated carboxylic acid
derivatives that were compatible with the presence of an
unprotected a-amino group. This is highly challenging since
the activated a-amino esters are known to undergo facile
dimerization to afford the 2,5-diketopiperazines.[19] Gratefully, it
was found that the trifluoroethyl ester 19 served well for this
purpose. As it is shown in Scheme 5, reaction of 4a with 19[13]
under standard conditions afforded the corresponding indolin-
3-ones 3o-3r in good yields. It’s worth noting that the
diketopiperazine formation was not observed in all these
O
i
h
2
N
N
R 8
N
N
N
H
Boc
26, R = H
27, R = Br
24
25
j
O
O
Br
Br
NH
NH
k
m
R
Br
N
N
Br
Br
N
N
H
28, R = H
29, R = Br
1 (+)-hinckdentine A
l
OH
OnBu
N
examples.
N
catalyst 20
(S)-17a
O
OTf
CsF (3.0 equiv)
R1 R2
H2N
COOCH2CF3
R2
R1
+
MeCN (c 0.085 M)
TMS
Scheme 6. Total synthesis of (+)-hinckdentine A. [a] 20 (0.1 equiv), toluene,
4 Å M.S., -20 °C, 95%, e.r. 82:18; [b] NaN3 (1.5 equiv), DMF, 40 °C; [c] HCl
in MeOH, RT, 1 h; [d] PPh3 (1.1 equiv), THF/H2O (v/v = 99:1), 70 °C, 53%
overall yield from (S)-21; [e] Boc2O (1.75 equiv), DMAP (0.15 equiv), THF,
RT; [f] 4a (2.0 equiv), CsF (2.0 equiv), MeCN, RT, 38% from (S)-17a; [g]
Raney nickel, H2, MeOH, RT then AcOH (3.0 equiv), HC(OMe)3, RT, 83%;
[h] methyl (triphenylphosphoranylidene)acetate (5.0 equiv), toluene, reflux
then Mg (10.0 equiv), MeOH, RT, 52%; [i] Boc2O (5.0 equiv), KHMDS (2.5
equiv), toluene, 0 °C then RT, 83%; [j] NBS (2.7 equiv), DMF, 0 °C then RT,
75%; [k] CH2Cl2/TFA (v/v = 2:3), RT, then K2CO3 (18.0 equiv), MeOH, RT,
91%; [l] nBu4NBr3 (1.0 equiv), DMF, 0 °C, quantitative; [m] TPAP (0.2 equiv),
NMO (1.4 equiv), 0 °C, 81%. Abbreviations: NMO = N-methyl morpholine
oxide, TPAP = tetrapropylammonium perruthenate.
N
H
3
RT
4a
19
O
O
O
O
Ph
Ph
Ph
N
H
N
H
N
H
N
H
3p 60%
3q 65%
3r 66%
3o 66%
Scheme 5. Heteroannulation of trifluoroethyl a-amino esters.
Enantioselective total synthesis of (+)-hinckdentine
A
featuring this heteroannulation reaction as a key step is shown
in Scheme 6. Catalytic asymmetric Michael addition of methyl
a-(2-nitrophenyl)-a-isocyanoacetate (6) to phenyl vinyl
The selective bromination of 26 turned out to be
challenging in accordance with previous observations.[3-5] After
having screened different reagents and conditions, we
achieved the synthesis of the C8, C10-dibrominated
compound 27 in 75% yield by performing the bromination of 26
in DMF at 0 °C using NBS (2.7 equiv) as brominating reagent.
All efforts on the tribromination of 26 failed at this stage.
selenone (7) in the presence of
a
quinidine-derived
bifunctional catalyst 20 (0.1 equiv) afforded (S)-21 in excellent
yield with moderate ee.[20] Nucleophilic substitution of the
selenonyl group by azide followed by hydrolysis of the
isocyano
to
the
amino
group
and
Staudinger
reduction/cyclization converted (S)-21 to pyrrolidinone (S)-17a
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10.1002/anie.201800746
Angewandte Chemie International Edition
COMMUNICATION
Yoshida, K. Takaki, Synlett 2012, 23, 1725; f) A. V. Dubrovskiy, N. A.
Markina, R. C. Larock, Org. Biomol. Chem. 2013, 11, 191.
For reviews on the application of benzyne chemistry in natural
product synthesis, see: a) C. M. Gampe, E. M. Carreira, Angew.
Chem. 2012, 124, 3829; Angew. Chem. Int. Ed. 2012, 51, 3766; b) P.
M. Tadross, B. M. Stoltz, Chem. Rev. 2012, 112, 3550; For a recent
example, see: c) M. A. Corsello, J. Kim, N. K. Garg, Nat. Chem. 2017,
9, 944.
Removal of N-Boc groups from 27 followed by a base
promoted lactamization afforded pentacycle 28 in 91% yield.
Selective C2-bromination of 28 was again a difficult task. After
many unsuccessful trials, we were able to realize this
[9]
transformation in
a quantitative yield by performing the
reaction in DMF at 0 °C using tetrabutylammonium tribromide
as a mild brominating reagent. Finally, oxidation of amine to
imine (NMO, TPAP) afforded (+)-hinckdentine A (1) in 81%
yield {[a]D + 269 (c 1.0, CHCl3), lit:[5] [a]D + 274 (c 2.0, CHCl3)}.
The physical and spectroscopic data of our synthetic
compound were identical to those reported for the natural
product.
[10] T. Buyck, Q. Wang, J. Zhu, Angew. Chem. 2013, 125, 12946; Angew.
Chem. Int. Ed. 2013, 52, 12714.
[11] a) K. Okuma, N. Matsunaga, N. Nagahora, K. Shioji, Y. Yokomori,
Chem. Commun. 2011, 47, 5822; For earlier work using amino esters
as coupling partners, see: b) D. C. Rogness, R. C. Larock,
Tetrahedron Lett. 2009, 50, 4003; c) R. D. Giacometti, Y. K.
Ramtohul, Synlett 2009, 2010; Using a-aminoketones: d) A. Bunescu,
C. Piemontesi, Q. Wang, J. Zhu, Chem. Commun. 2013, 49, 10284.
[12] For other selected annulation reactions initiated by nucleophilic
addition of amines/anilines to benzynes, see: a) J. Zhao, R. C.
Larock, J. Org. Chem. 2007, 72, 583; b) C. D. Gilmore, K. M. Allan, B.
M. Stoltz, J. Am. Chem. Soc. 2008, 130, 1558; c) D. C. Rogness, R.
C. Larock, J. Org. Chem. 2010, 75, 2289; d) D. C. Rogness, R. C.
Larock, J. Org. Chem. 2011, 76, 4980; e) S. D. Vaidya, N. P. Argade,
Org. Lett. 2013, 15, 4006.
In summary, we have developed a new heteroannulation
reaction of a-amino imides with arynes for the synthesis of
a,a-disubstituted indolin-3-ones. An enantioselective total
synthesis of (+)-hinckdentine A (1) featuring this reaction as a
key step was subsequently developed demonstrating the high
synthetic potential of this methodology.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
[13] See Supporting Information for the details of the synthesis.
[14] For a related transformation, see: X. Huang, T. Zhang, J. Org. Chem.
2010, 75, 506.
[15] Aryne insertion to amides, see: a) D. G. Pintori, M. F. Greaney, Org.
Lett. 2010, 12, 168; b) Aryne insertion to imides, see: A. C. Wright, C.
K. Haley, G. Lapointe, B. M. Stoltz, Org. Lett. 2016, 18, 2793.
[16] Selected examples, see: a) P. S. Steyn, Tetrahedron Lett. 1971, 12,
3331; b) D. D. O’Rell, F. G. H. Lee, V. Boekelheide, J. Am. Chem.
Soc. 1972, 94, 3205; c) J.-F. Liu, Z.-Y. Jiang, R.-R. Wang, Y.-T.
Zheng, J.-J. Chen, X.-M. Zhang, Y.-B. Ma, Org. Lett. 2007, 9, 4127;
d) D.-B. Zhang, D.-G. Yu, M. Sun, X.-X. Zhu, X.-J. Yao, S.-Y. Zhou,
J.-J. Chen, K. Gao, J. Nat. Prod. 2015, 78, 1253; e) G.-G. Cheng, D.
Li, B. Hou, X.-N. Li, L. Liu, Y.-Y. Chen, P.-K. Lunga, A. Khan, Y.-P.
Liu, Z.-L. Zuo, X.-D. Luo, J. Nat. Prod. 2016, 79, 2158; f) Y.-W.
Chang, C.-M. Yuan, J. Zhang, S. Liu, P. Cao, H.-M. Hua, Y.-T. Di, X.-
J. Hao, Tetrahedron Lett. 2016, 57, 4952.
Acknowledgements
We thank EPFL and the Swiss National Science Foundation
(SNSF) for financial support. Dr. R. O. Torres-Ochoa
acknowledges CONACyT (México) for a fellowship (CVU
256937). We are grateful to Dr. Farzaneh Fadaei Tirani and Dr.
Rosario Scopelliti for X-ray crystallographic analysis.
Keywords: Benzyne • heteroannulation • hinckdentine A •
natural product • oxindole
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10.1002/anie.201800746
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
Natural Product Synthesis
O
R
O
Br
O
R1
OTf
NH
Rubén O. Torres-Ochoa, Thomas Buyck,
Qian Wang and Jieping Zhu*__________
Page – Page
CsF, MeCN
RT
N
Ar
+
Ar
Br
NHCOR
n
R1
N
R2
O
TMS
n
N
R2HN
Br
N
(+)-hinckdentine A
Heteroannulation of Arynes with
Amino Imides: Synthesis of 2,2-
Disubstituted Indolin-3-ones and
a
-
Reaction of α-amino imides with the in situ generated arynes afforded the 2,2-disubstituted indolin-3-
ones in good to excellent yields. The reaction was implemented as a key step in a concise
enantioselective total synthesis of (+)-hinckdentine A, a halogenated marine natural product.
Application to the Enantioselective
Total Synthesis of (+)-Hinckdentine A
This article is protected by copyright. All rights reserved.