Oxidative cyanation of 2-oxindoles: formal total synthesis of (±)-gliocladin C

Article abstract of DOI:10.1039/c9ob02752a

Efficient oxidative direct cyanations of 3-alkyl/aryl 2-oxindoles using Cyano-1,2-BenziodoXol-3(1H)-one (CBX) (2a) have been reported under 'transition metal-free' conditions to synthesize a wide variety of 3-cyano 3-alkyl/aryl 2-oxindoles sharing an all-carbon quaternary center under additive-free conditions. The application of this process is shown by the formal total synthesis of (±)-gliocladin C (11c) in a few steps.

Full text of DOI:10.1039/c9ob02752a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Maity, A. Roy,
M. K. Das, S. De, M. Naskar and A. Bisai, Org. Biomol. Chem., 2020, DOI: 10.1039/C9OB02752A.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 5
View Article Online
DOI: 10.1039/C9OB02752A
PAPER
Oxidative Cyanation of 2-Oxindoles: Formal Total Synthesis of (±)-
Gliocladin C
Received 00th January 20xx,
Accepted 00th January 20xx
Arindam Maity,§a Avishek Roy,§a Mrinal Kanti Das,a Subhadip De,a Malay Naskar,a and Alakesh
Bisai* a-b
DOI: 10.1039/x0xx00000x
An efficient oxidative direct cyanations of 3-alkyl/aryl 2-oxindoles employing Cyano-1,2-BenziodoXol-3(1H)-one (CBX) (2a)
has been reported under ‘transition-metal free’ condition to furnish a wide variety of 3-cyano 3-alkyl/aryl 2-oxindoles
sharing an all-carbon quaternary center under the additive-free condition. The application of this process is shown by
formal total synthesis of (±)-gliocladin C (11c) in few steps.
constitute a common structural motif in many biologically active
molecules and pharmaceuticals. In this regard, the use of
hypervalent iodine for oxidative cyanide transfer reactions by
Introduction
Cyanide group incorporation in organic molecules is of particularly
significant interest because of their wider abundance in natural
products, pharmaceuticals and materials.1,2 Accordingly, there are
several successful conventional methodologies utilizing cyanide as a
nucleophilic source are reported.3 These include the addition of
cyanide onto a variety of electron-deficient carbonyl compounds,
imines, and ,-unsaturated carbonyls.3 Recently, the utilization of
hypervalent iodine4 reagent under non-classical way via umpolung
reactivity has been emerged for oxidative atom transfer.5 Towards
this direction, in 1995, Zhdankin and co-workers have reported an
elegant direct N-alkyl cyanation of N,N-dialkylarylamines using
Cyano-1,2-BenziodoXol-3(1H)-one (CBX) reagents under oxidative
condition.5a Later, encouraged by the umpolung behaviour of CBX
reagent, Waser,6a-b Zheng,6c and Feng-Liu6d group independently
reported elegant asymmetric electrophilic -cyanations of -
ketoesters and -ketoamides.5 Other reports on oxidative cyanation
include Alcarazo’s hypervalent sulfur-based cyanation of
heteroaromatics, heteroatoms,6f Chen’s asymmetric electrophilic
cyanation of 3-substituted oxindoles using 4-acetyl phenyl
cyanate.6g
Zhdankin and co-workers drew our interest.5a It was hypothesized
that direct cyanation could be achieved through electrophilic
substitution of carbonyl compounds with a hypervalent iodine(III)-
CN reagent. In this work, we report en efficient α-cyanation of 2-
oxindoles using Zhdankin’s cyano benziodoxole (CBX)5a as the
electrophilic cyanating agent for the first time to the best of our
knowledge, as its utilization in formal total synthesis of ()-
gliocladin C (11c).10
Results and discussion
It was envisioned that 2-oxindole methyl-3-carboxylate 1 could
form enolate 7b (via carbanion 7a), which would react with Cyano-
1,2-BenziodoXol-3(1H)-one (CBX) reagent 2a to form hypervalent
iodine intermediate 8a (Scheme 1). This intermediate would then
R2
O
O
O
R2
I
NC
O
O
O
O
NC
I
H
O
condition
+
O
O
+
N
N
R1
1
()-
R1
()-
2a
3-6
Given the prevalence of 2-oxindole and their derivatives in
biologically active molecules7 and pharmaceutically active
ingredients8 significant effort has been directed toward the
synthesis of this structural motif. Particularly, 2-oxindoles bearing
an all-carbon quaternary stereocenter9 at the C-3(a) position
R2
O
R2
O
O
O
R1
O
O
R2
O
O
N
R1
N
O
O
O
N
N
O
R2
8a
O
N
I
I(III)
O
N
8b
(
)
(
)
R1
)
R1
2a
(
)
7b
(
)
7a
(
O
O
+
N
I
O
aDepartment of Chemistry, Indian Institute of Science Education and
Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal - 462 066, Madhya
Pradesh, INDIA.
I
O
O
work up
2a
(
)
H
1
()-
O
3
()-
bDepartment of Chemical Sciences, Indian Institute of Science Education and
Research Kolkata, Mohanpur, Nadia - 741 246, West Bengal, INDIA.
Scheme 1. Our hypothesis of cyanation of 2-oxindoles.
Corresponding author: alakesh@iiserb.ac.in; alakesh@iiserkol.ac.in
quickly form another intermediate 8b via O-C migration, from
where a reductive elimination would lead to the formation of
expected product 3 and generation of 2-iodobenzoate as a by-
product. We argued that 2-oxindole 3-carboxylates having a labile
Electronic Supplementary Information (ESI) available: Experimental
procedures,
characterization
data,
NMR
spectra.
See
DOI: 10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 5
ARTICLE
Journal Name
proton with pKa ~14-15 might act as excellent substrates for this
process. At the outset, we choose 1a as our model substrate to
react with hypervalent Cyano-1,2-BenziodoXol-3(1H)-one (CBX) (2a)
and 1-Cyano-3,3-Dimethyl-3-(1H)-1,2-BenziodoXole (CDBX, 2b)
reagents at different temperature and solvents (See, SI for details).
Following exhaustive optimization, we found that oxidative
cyanation of 2-oxindole methyl-3-carboxylate 1a can be realized in
DMF at room temperature to afford compound 3a in 82% without
any additives. Further, it was noted that 1-Cyano-3,3-Dimethyl-3-
(1H)-1,2-BenziodoXole (CDBX, 2b) was inferior over CBX reagent
(2a) under the similar condition. To our delight, oxidative cyanation
works under base-free condition, which probably indicates that the
coordination of CBX reagent to the carbonyl might enhance the
acidity of the -proton of 2-oxindole 3-carboxylates enabling the
deprotonation by the carboxylate without any additives. Therefore,
based on our extensive optimization, we carried out substrate
scope using 1.0 equivalent of 2-oxindole alkyl-3-carboxylates 1 and
1.1 equivalent of CBX reagent (2a) in DMF at room temperature.
Mechanistically, C-3 cyanation of 2-oxindole 3a could take place
with hypervalent iodine reagent CBX (2a) under oxidative conation
as shown in Scheme 1. However, considering the strong oxidizing
properties of CBX reagent, a single electron transfer (SET) pathway
cannot be completely ruled out. To test this hypothesis, we have
carried out the reaction in the presence of stoichiometric amount
of TEMPO, which is a well-known radical trapping agent. However,
this reaction afforded product 3a in 80%, clearly ruled out of the
possibility of a SET mechanism. In fact, EPR study of reaction
mixture also indicates EPR inactive plot (see, SI for details). These
control reactions suggests that the reaction probably goes through
a reductive elimination pathway (Scheme 1) via the carbanion
intermediate.
View Article Online
R'
O
O
DOI: 10.1039/C9ORB'02752A
O
NC
DMF, 25 C
20-30 min
NC
I
O
O
X
X
O
O
O
+
N
upto 87%
N
R
R
1
()-
2a
(
)
3a e
-
4a-f
()-
and
O
O
O
O
Me
Me
Me
Me
NC
NC
NC
NC
O
MeO
Cl
O
O
O
O
O
O
O
N
N
N
Me
N
R
Me
3a
R = Me, ()- , 20 min, 82%
R = Bn, ()- , 25 min, 76%
3d
()- , 25 min, 66%
3e
()- , 30 min, 74%
3c
()- , 30 min, 73%
3b
Me
O
O
O
NC
NC
Me
O
NC
O
O
R1
O
O
Me
O
N
Me
N
N
Me
4f
R
()- , 30 min, 77%
4e
()- , 30 min, 72%
4a
R = Me, R1 = H, ()- , 20 min, 87%
4b
R = Ph, R1 = H, ()- , 30 min, 82%
4c
R = allyl, R1 = H, ()- , 25 min, 73%
4d
R = Me, R1 = OMe, ()- , 25 min, 63%
aReactions were carried out using 0.5 mmol of 1 with 0.55 mmol of 2a in 1
mL N,N-dimethyl formamide (DMF). byields are reported after column
purification.
Scheme 2. Substrates scope of cyanations using CBX reagent (2a).
Later, our successful cyanations with 2-oxindole 3-carboxylates as
substrates further prompted us to test N-alkoxycarbonyl 3-
substituted 2-oxindoles 1, having a labile proton with pKa ~19-20.
These substrates also afforded corresponding cyanation products
5a-d in good to excellent yields (Scheme 3). In particular, product
sharing amino ethyl derivatives might give the opportunity to
access hexahydro[2,3-b]-pyrroloindoline alkaloids with a cyano
group at the pseudobenzylic position (see, 5c, Scheme 3). Since
there are abundant literature reports for indole natural products
bearing 3-arylated-2-oxindole moieties,15 we also utilized few 3-
arylated 2-oxindole substrates for oxidative cyanation reaction to
afford product 5d in 83% yield (Scheme 3).
Under the standard condition, we then probed the oxidative
cyanation of 2-oxindole methyl-3-carboxylates 1 using CBX reagent
(2a). Gratifyingly, a variety of 2-oxindole methyl-3-carboxylates 1
with a variety of N-protected substrate reacted under the standard
condition to furnish cyanation products 3a-e in 66-82% isolated
yields in the absence of base (Scheme 2). Next, the prevalence of
prenylated,
reverse-prenylated(3,
3-dimethylprop-1-ene)
hexahydropyrrolo[2,3-b]indole alkaloids,11 drew our attention.12
These naturally occurring hexahydropyrrolo[2,3-b]indole alkaloids
are reported to show a broad spectrum of biological activities. For
the construction few of these compounds, we envisioned a direct
incorporation of the allyl, methallyl, prenyl, group at the 3-position
of 2-oxindole products via Pd-catalyzed decarboxylative
allylation/methallylation/prenylation, on related esters of 3-cyano
2-oxindoles (Scheme 2). We assumed that these compounds might
serve as the starting point of Tsuji-Trost decarboxylative allylations
(DcA)13 to yield enantioenriched 3-cyano 2-oxindoles following a
dynamic kinetic asymmetric transformation (DYKAT)14 along the
similar line as an efficient DcA on -ketoesters reported by Waser
and co-workers.6b
R'
H
R'
NC
NC
I
O
DMF, 25 C, 3-4 h
O
O
O
+
up to 85%
N
N
R
R
2a
(
)
1
5a-d
( )-

()-
Cbz
NC
NC
N
Me
NC
NC
Ph
Me
OMe
O
O
O
N
O
N
N
N
O
O
tBuO
5a
MeO
5b
O
tBuO
5c
O
tBuO
5d
()- , 85%, 4 h
(
)- , 72%, 4 h
()- , 83%, 3 h
()- , 84%, 4 h
Hence, to test the synthetic viability of this oxidative cyanation
process, we then extended it to a variety of 2-oxindole allyl-3-
carboxylates which were treated with CBX reagents (2a) and the
results are summarized in Scheme 2. Rewardingly, a number of
aReactions were carried out using 0.5 mmol of 1 with 0.55 mmol of 2a in 1
mL N,N-dimethyl formamide (DMF). byields are reported after column
purification.
sensitive 2-oxindole allyl-3-carboxylates
1 reacted under the
Scheme 3. The scope of cyanations using N-alkoxycarbonyl 3-
standard condition to afford a variety of substrates 4a-f in
moderate to good yields (63-87% yields). Worth mentioning here is
that N-benzyl and N-allyl substituted 2-oxindoles, those are
sensitive towards oxidative coupling following a single electron
transfer (SET) mechanism, also afforded products 4b-c in 73-82%
isolated yields (Scheme 2).
substituted 2-oxindoles.
Further, we tested more challenging N-alkyl 3-substituted 2-
oxindoles 1, having a proton with less acidity (pKa ~22-24) (Scheme
4). We found that these substrates were inferior as compared to 2-
oxindole methyl-3-carboxylate 1 (Scheme 2) and N-alkoxycarbonyl
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
areactions were carried out using 0.09 mmol of 4a with in 3 mL Et2O. byields
3-substituted 2-oxindoles 1 (Scheme 3). We believed that acidity of
benzylic proton of N-substituted 2-oxindoles plays a crucial role in
our oxidative cyanation reaction. Therefore, it was decided to use a
stoichiometric amount of base in this process. In fact, as per our
hypothesis, we further established a standard condition for this
challenging N-alkyl/aryl 3-substituted 2-oxindoles 1. Following
exhaustive optimization, it was found that oxidative cyanation
product from these substrates can be obtained in synthetically
useful yields in the presence of 1.1 equiv. of N,N,N’,N’-
tetramethylguanidine (TMG). N-Methyl 3-(o-nitrophenyl) 2-
oxindoles 1 reacted with CBX (2a) without any base to afford
product 6f in 87% in 50 min. This is quite interestingly in a sense
that, N-Methyl 3-(o-nitrophenyl) 2-oxindoles is having a more acidic
proton (with pKa ~14-15) as compared to other 2-oxindole
substrates, thereby, further supporting our hypothesis.
View Article Online
after column purification.
DOI: 10.1039/C9OB02752A
Scheme 5. Catalytic decarboxylative allylation of 4a.
Further,
the
prevalence
of
biologically
relevance
epipolythiodioxopiperazine (ETP) toxins (11a-b, Figure 1) sharing an
indole motif at the pseudobenzylic C(3a)-position of pyrroloindoline
scaffolds,19-20 drew our interest for the application of our oxidative
cyanation methodology. It has been shown by Overman and co-
workers that the simpler alkaloid such as gliocladin C (11c)10 served
as a synthetic precursor of this family of ETPs through three
potentially straightforward transformations, which in turn was
synthesized from aldehyde precursor 12 (Figure 1).
tBuO
R'
O
H
1.1 equiv. TMG
DMF, 25 °C, 30-60 min
R'
NH
NC
I
O
NC
HN
N
HN
H
OH
N
O
O
Me
Me
O
O
N
N
NMe
O
O
+
O
N
N
up to 87%
Me Me
TMG
N
S
NMe
R
OMe
R
R
S
1
2a
)
()-
(
6a-f
()-
Me
N
N
H
O
N
H
O
H
H
tBuO
Overman aldehyde (
O
11c
(+)-gliocladin C (
)
Me
Me
NC
11a
R = H, bionectin A (
R = i-Pr, leptosin D (
)
12
)
NC
Me
11b
)
NC
NC
OMe
O
O
O
O
N
N
N
Me
N
R
Figure 1. Naturally occurring epipolythiodioxopiperazine (ETP) alkaloids 11a-
b, ()-gliocladin C (11c) and Overman aldehyde (12).
Me
H
6a
()- , 30 min, 81%
6c
R= Me, ()- , 60 min, 82%
6e
6b
()- , 60 min, 72%
()- , 30 min, 71%
6d
R= Allyl, ()- , 60 min, 76%
Towards this end, we envisioned a direct incorporation of cyano
group using CBX reagent under the optimized oxidative condition.
Therefore, a number of N-substituted 3-(3-indolyl) 2-oxindoles were
reacted under the standard condition to afford products 14a-g in
72-82% yields (Scheme 6).
NC
NO2
O
N
OH
N
H
O
N
Me
O
O
O
O
N
Me
N
Me
6f
()- , 50 min, 87%
9b
9a
()-
(without any base)
R'
R'
N
N
1.1 equiv. TMG
DMF, 25 C
40-60 min
aReactions were carried out using 0.5 mmol of 1 with 0.55 mmol of 2a and
0.55 mmol of TMG in 1 mL N,N-dimethyl formamide (DMF). byields are
reported after column purification.
NC
I
O
NC
Y
O
Y
+
up to 82%
O
O
N
N
R
2a
(
)
14a-g
()-
13a-g
()-
R
Scheme 4. The scope of cyanation using N-alkyl 2-oxindoles.
HN
HN
HN
R
Gratifyingly, subjecting the unprotected 2-oxindoles to the reaction
conditions, we found that a highly chemoselective cyanation can be
achieved with CBX reagent 2a to afford C-cyanation products 6e in
72% yield in the presence of 1.1 equiv. of N,N,N’,N’-
tetramethylguanidine (TMG) (Scheme 4). The latter clearly depicts
the soft nature of CBX reagents, which predominantly reacted at C-
center nucleophile as compared to N-center (oxindole nitrogen)
nucleophile.
CN
CN
CN
O
O
O
N
N
N
R
Ph
14a
R = OMe, ()-14d,
45 min, 72%
R = H, ()-
R = Ph, ()-
, 50 min, 76%
14c
()-
, 60 min, 82%
Br
14b
, 40 min, 81%
Me
N
HN
HN
OMe
Later, Pd(0)-catalyzed decarboxylative allylations (Scheme 5)17
through a dynamic kinetic asymmetric transformation (DYKAT)18 of
allyl ester ()-4a (Scheme 2), was investigated in the presence of 2.5
mol% Pd2(dba)3 in combination with 7.5 mol% ligands L1-L5 (See, SI
for details). Following exhaustive optimization, it was found that 2.5
mol% Pd2(dba)3 in combination with 7.5 mol% ligand L4 in diethyl
ether at 0 ˚C afforded product 10 in 56% ee with 94% yield.
CN
CN
CN
O
O
O
N
N
N
Me
14g
()-
, 40 min, 74%
14e
()-
, 60 min, 75%
14f
()- , 50 min, 78%
aReactions were carried out using 0.5 mmol of 13a-g with 0.55 mmol of 2a
and 0.55 mmol of TMG in 1 mL N,N-dimethyl formamide (DMF). yields are
b
reported after column purification.
2.5 mol% Pd2(dba)3,
7.5 mol% ligand L4,
Et2O, 0 °C, 16 h
O
CN
N
Scheme 6. Further scope of chemoselective oxidative cyanations
using CBX.
L4
(S,S)-
NC
O
O
O
O
O
NH HN
94% yield
56% ee
N
Me
Me
P
P
Gratifyingly, sensitive substrates such as N-benzyl and N-allyl
substituted 2-oxindoles were also afforded products 14b-f in
10
()-
Ph
Ph
4a
Ph
Ph
()-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 5
ARTICLE
Journal Name
synthetically useful yields (Scheme 6). To our delight, in these cases In conclusion, we developed a novel entry to direct incorporation of
View Article Online
where substrates containing an indole motif at the C-3 position of a nitrile functionality using CBX reagents unDdOerI:o10x.i1d0a3t9iv/Ce9cOoBn0d2it7i5o2nA.
2-oxindoles, which is capable of undergoing C-2 functionalization
A wide variety of 2-oxindole substrates sharing all-carbon
under oxidative process,22 also afforded products in moderate to quaternary centers have been synthesized under a mild condition in
good yields (Scheme 6).
good to excellent yields. Our study not only offers a vital method
for the oxidative C-C bond construction but also clearly
Finally, for the synthesis of Overman aldehyde 12, we prepared demonstrates the potential of the modular 2-oxindole scaffolds in
compound 13h in gram scale. Isatin was reacted with indole in the the synthesis of important building blocks. Finally, employing our
presence of KOH in methanol to form 3-indolyl-3-hydroxy 2-
oxindole in quantitative yield, which was further reduced with
triethylsilane in the presence of trifluoroacetic acid to furnish 3-
indolyl- 2-oxindole (13h’) in 75% yield over 2 steps (Scheme 7). The
oxidative cyanation of compound 13h was pursued in 1.5 g scale
(3.5 mmol) to afford cyanated product 14h in 92% yield. The latter
was elaborated to Overman aldehyde 12 only in 3 steps namely,
NaBH4 reduction to furnish hemiaminal 15 in quantitative yield,
which was followed by a reaction with HC(OMe)3 in the presence of
BF3.OEt2 to form 16 in 90% overall yields over 2 steps. The cyanide
functionality was reduced using DIBAL-H to afford aldehyde 12 in
23% over 3 steps.23 It is to be noted that DIBAL-H reduction of
cyano group of compound 16 afforded 20-26% yields along with
recovery of 62-70% starting materials, probably indicating the
prominence of neopentyl effect.23 Since aldehyde 12 was used as an
advanced intermediate for the total synthesis of 11c (Figure 1),
therefore, our effort culminated in the formal total synthesis of ()-
gliocladin C (Scheme 7).
methodology, we have shown a formal total synthesis of ()-
gliocladin C clearly demonstrating the potential application of this
methodology.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial supports from the SERB, DST [EMR/2016/000214], MoES
(09-DS/11/2018-PC-IV), and CSIR (02(0295)/17/EMR-II), Govt. of
India, are gratefully acknowledged. A.M, and A.R. thank IISER
Bhopal for SRFs (Senior Research Fellowships) and M.K.D. thanks
IISER Bhopal for I-PDF.
Notes and references
O
tBuO
HN
N
i) KOH, MeOH
ii) Et3SiH, TFA
CH2Cl2, 0 C
aDepartment of Chemistry, Indian Institute of Science Education and
Research Bhopal, Bhopal, MP 460 066, India. Corresponding author:
alakesh@iiserb.ac.in
N
(Boc)2O, DMAP
CH2Cl2, 4 h
H
+
O
H
H
78 %
75%
(over 2 step)
O
O
O
N
N
N
H
bDepartment of Chemical Sciences, Indian Institute of Science Education and
H
O
(
)-13h'
13h
()-

tBuO
Research Kolkata, Mohanpur, Nadia
- 741 246, West Bengal, INDIA.
O
O
Corresponding author: alakesh@iiserkol.ac.in
tBuO
N
tBuO
N
BF3.Et2O, CH(OMe)3
Et2O, rt, 20 min
NaBH4, MeOH
0 C, 30 min
2a
CBX ( ), DMF
†Electronic Supplementary Information (ESI) available: Experimental
25 C, 30 min
procedures,
characterization
data,
NMR
spectra,
See
CN
CN
OH
DOI: 10.1039/b000000x/
O
quant
92%
90%
(over 2 step)
N
N
O
O
§Both authors have contributed equally to this work.
tBuO
tBuO
15
()-
14h
()-
gram scale
1.5 g
O
O
1. (a) A. J. Fatiadi, Preparation and Synthetic Applications of Cyano
Compounds; Wiley: New York, 1983; (b) F. F. Fleming, L. Yao, P. C.
Ravikumar, L. Funk and B. C. Shook, J. Med. Chem., 2010, 53, 7902; (c) T.
Wang and N. Jiao, Acc. Chem. Res., 2014, 47, 1137; (d) D. R. Buckle, B. C. C.
Cantello, H. Smith and B. A. Spicer, J. Med. Chem., 1977, 20, 265.
tBuO
N
tBuO
N
O
DIBAL-H, CH2Cl2
-78 C, 2 h
2 steps
ref. 21
O
NMe
O
CN
OMe
+
H
N
26%
OMe
N
N
OMe
12
()-
16
()-
O
2. (a) Z. Rappoport, Chemistry of the cyano group; Interscience: New York,
1970; (b) F. F. Fleming, Nat. Prod. Rep., 1999, 16, 597; (c) A. Kleemann, J.
Engel, B. Kutscher and D.Reichert, Pharmaceutical substances: syntheses,
patents, applications; Thieme: Stuttgart, 1999; (d) J. S. Miller and J. L.
Manson, Acc. Chem. Res,. 2001, 34, 563; (e) F. F. Fleming, L. Yao, P. C.
Ravikumar, L. Funk and B. C. Shook, J. Med. Chem., 2010, 53, 7902.
O
tBuO
tBuO
Overman aldehyde
O
HN
NMe
O
N
3. For reviews: (a) N. Kurono and T. Ohkuma, ACS Catal., 2016, 6, 989; (b) H.
Pellissier, Adv. Synth. Catal., 2015, 357, 2745; (c) M. North, D. L. Usanov and
C. Young, Chem. Rev., 2008, 108, 5146.
N
H
O
H
11c
()-gliocladin C (
)
4. (a) T. V. Hughes, S. D. Hammond and M. P. Cava, J. Org. Chem., 1998, 63,
401; (b) T. V. Hughes and M. P. Cava, J. Org. Chem., 1999, 64, 313; (c) Y.-q.
Wu, D. C. Limburg, D. E. Wilkinson and G. S. Hamilton, Org. Lett., 2000, 2,
795; (d) P. Anbarasan, H. Neumann and M. Beller, Chem. –Eur. J., 2010, 16,
4725 and references cited.
Scheme 7. Formal total synthesis of ()-gliocladin C (11c).
Conclusions
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
5. (a) V. V. Zhdankin, C. J. Kuehl, A. P. Krasutsky, J. T. Bolz, B. Mismash, J. K. 16. (a) S. Ghosh, S. De, B. N. Kakde, S. Bhunia and A. Bisai, Org. Lett., 2012,
Woodward and A. J. Simonsen, Tetrahedron Lett., 1995, 36, 7975; (b) Y. F. 14, 5864; (b) S. Ghosh, S. Chaudhuri and A. Bisai, Org. Lett., 2V0i1ew5,A1rt7ic,l1e3O7n3li.ne
DOI: 10.1039/C9OB02752A
Wang, J. S. Qiu, D. J. Kong, Y. T. Gao, F. P. Lu, P. G. Karmaker and F. X. Chen,
Org. Biomol. Chem., 2015, 13, 365; (c) T. Nagata, H. Matsubara, K. Kiyokawa 17. Ligand L2-L5: (a) B. M. Trost and D. L. Van Vranken, Angew. Chem. Int.
and S. Minakata, Org. Lett. 2017, 19, 4672; (d) M.-X. Sun, Y.-F. Wang, B.-H. Ed., 1992, 31, 228; PHOX ligands L1: (b) G. Helmchen and A. Pfaltz, Acc.
Xu, X.-Q. Ma and S.-J. Zhang, Org. Biomol. Chem., 2018, 16, 1971; Reviews: Chem. Res., 2000, 33, 336.
(e) A. Yoshimura and V. V. Zhdankin, Chem. Rev., 2016, 116, 3328; (f) Y. Li, D.
P. Hari, M. V. Vita and J. Waser, Angew. Chem., Int. Ed. 2016, 55, 4436; (g) T. 18. (a) A. Roy, M. K. Das, S. Chaudhuri and A. Bisai, J. Org. Chem., 2018, 83,
Govender, P. I. Arvidsson, G. E. M. Maguire, H. G. Kruger and T. Naicker, 403; (b) J. D. Weaver, III, A. Recio, A. J. Grenning and J. A. Tunge, Chem. Rev.
Chem. Rev., 2016, 116, 9375.
, 2011, 111, 1846.
6. (a) R. Chowdhury, J. Schörgenhumer, J. Novacek and M. Waser, 19. K. M. Block, H. Wang, L. Z. Szabo, N. W. Polaske, L. K. Henchey, R.
Tetrahedron Lett., 2015, 56, 1911; (b) For CBX Reagent Preparation, See:M. Dubey, S. Kushal, C. F. Laszlo, J. Makhoul, Z. Song, E. J. Meuillet and B. Z.
C. Vita, P. Caramenti and J. Waser, Org. Lett., 2015, 17, 5832; (c) M. Chen, Z. Olenyuk, J. Am. Chem. Soc., 2009, 131, 18078.
T. Huang and Q. Y. Zheng, Org. Biomol. Chem., 2015, 13, 8812; (d) B. Ma, X.
Lin, L. Lin, X. Feng and X. J. Liu, J. Org. Chem., 2017, 82, 701; (e) For CDBX 20. (a) D. Griner, T. Bonaldi, R. Eskeland, E. Roemer and A. Imhof, Nat. Chem.
Reagent Preparation, See: F. L. Vaillant, M. D. Wodrich and J. Waser, Chem. Biol., 2005, 1, 143; (b) D. M. Vigushin, N. Mirsaidi, G. Brooke, C. Sun, P. Pace,
Sci., 2017, 8, 1790; (f) G. Talavera, J. Pena and M. Alcarazo, J. Am. Chem. Soc. L. Inham, C. J. Moody and R. C. Coombes, Med. Oncol., 2004, 21, 21.
2015, 137, 8704; (g) J. Qiu, D. Wu, P. G. Karmaker, G. Qi, P. Chen, H. Yin and
F-X. Chen, Org. Lett. 2017, 19, 4018; (h) Y-L. Liu, F. Zhou, J-J. Cao, C-B. Ji, M. 21 . J. E. DeLorbe, S. Y. Jabri, S. M. Mennen, L. E. Overman and F-L. Zhang, J.
Ding and J. Zhou, Org. Biomol. Chem., 2010, 8, 3847; (i) Y. Ogura, M. Am. Chem. Soc., 2011, 133, 6549.
Akakura, A. Sakakura and K. Ishihara, Angew. Chem. Int. Ed. 2013, 52, 8299.
22. Indoles are prone to dimerize at C-2 and C-3 position under the oxidative
7. For a recent review on 2-oxindoles, see: (a) L. Chen, X.-P. Yin, C.-H. Wang conditions, see; (a) Z. Liang, J. Zhao and Y. Zhang, J. Org. Chem., 2010, 75,
and J. Zhou, Org. Biomol. Chem., 2014, 12, 6017; (b) R. Dalpozzo, Org. Chem. 170–177; (b) Y. Li, W.-H. Wang, S.-D. Yang, B.-J. Li, C. Feng and Z.-J Shi,
Front., 2017, 4, 2063 and references cited.
Chem. Commun., 2010, 46, 4553.
8. (a) W. Luo, Q. S. Yu, M. Zhan, D. Parrish, J. R. Deschamps, S. S. Kulkarni, H. 23. A similar type of neopentyl effect, see; S. De, M. K. Das, A. Roy and A.
W. Holloway, G. M. Alley, D. K. Lahiri, A. Brossi and N. H. Greig, J. Med. Bisai, J. Org. Chem., 2016, 81, 12258.
Chem., 2005, 48, 986; (b) J. J. Badillo, N. V. Hanhan and A. K. Franz, Curr.
Opin. Drug Discovery Devel., 2010, 13, 758; (d) Z.-Y. Cao, Y.-L. Zhao and J.
Zhou, Chem. Commun., 2016, 52, 2537; (e) Z-Y. Cao, F. Zhou and J. Zhou,
Acc. Chem. Res. 2018, 51, 1443; (f) R. Dalpozzo, Adv. Synth. Catal. 2017, 359,
1772.
9. (a) C. J. Douglas and L. E. Overman, Proc. Natl. Acad. Sci., U. S. A. 2004,
101, 5363; (b) A. W. G. Burgett, Q. Li, Q. Wei and P. G. Harran, Angew.
Chem. Int. Ed., 2003, 42, 4961; (d) B. M. Trost and J. Quancard, J. Am. Chem.
Soc., 2006, 128, 6314; (e) A. W. Schammel, G. Chiou and N. K. Garg, J. Org.
Chem., 2012, 77, 725.
10. a) L. Furst, J. M. R. Narayanam and C. R. J. Stephenson, Angew. Chem.
Int. Ed. 2011, 50, 9655; b) S. Hajra, S. Maity and R. Maity, Org. Lett. 2015, 17,
3430; c) T. R. Hodges, N. M. Benjamin and S. F. Martin Tetrahedron. 2018,
74, 3329; d) M. Tayu, Y. Hui, S. Takeda, K. Higuchi, N. Saito and T. Kawasaki,
Org. Lett. 2017, 19, 6582; e) C. Jing, D. Xing, C. Wang, W. Hu, Tetrahedron.
2015. 71. 3597.
11 . (a) Y. -H. Wang, C. -L. Long, F. -M. Yang, X. Wang, Q. -Y. Sun, H. -S. Shi, Y.
-N. Wang and G. -H. Tang, J. Nat. Prod., 2009, 72, 1151; (b) S. J. Rochfort, S.
Moore, C. Craft, N. H. Martin, R. M. Van Wagoner and J. L. C. Wright, J. Nat.
Prod., 2009, 72, 1773.
12. (a) B. M. Trost, S. Malhotra and W. H. Chan, J. Am. Chem. Soc., 2011,
133, 7328; (b) J. Ruchti and E. M. Carreira, J. Am. Chem. Soc., 2014, 136,
16756.
13. (a) J. Tsuji, Palladium Reagents and Catalysis; Wiley: Chichester, UK,
2004; (b) B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921.
14. (a) B. M. Trost and D. R. Fandrick, Aldrichimica Acta, 2007, 40, 59; (b) B.
M. Trost and M. Osipov, Angew. Chem. Int. Ed., 2013, 52, 9176; (c) S. Ghosh,
S. Bhunia, B. N. Kakde, S. De and A. Bisai, Chem. Commun., 2014, 50, 2434.
15. (a) A. W. G. Burgett, Q. Li, Q. Wei and P. G. Harran, Angew. Chem. Int.
Ed., 2003, 42, 4961; (b) Q. –X. Wu, M. S. Crew, M. Draskovic, J. Sohn, T. A.
Johnson, K. Tenney, F. A. Valeriote, X. –J. Yao, L. F. Bjeldanes and P. Crews,
Org. Lett., 2010, 12, 4458.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins