Exploration of a KI-catalyzed oxidation system for direct construction of bispyrrolidino[2,3-: B] indolines and the total synthesis of (+)-WIN 64821

Article abstract of DOI:10.1039/c9cc08646c

A facile and environmentally benign KI(cat.)/NaBO₃·4H₂O oxidation system has been developed for the tandem oxidative aminocyclization/coupling of tryptamines, affording a series of 3a,3a′-bispyrrolidino[2,3-b]indolines with high efficiency (up to 94% yield). This reaction features an electrophilic "I⁺" mechanism, which is importantly quite different from and milder than the typical radical-involving process, and can be readily amplified for the total synthesis of (+)-WIN 64821.

Full text of DOI:10.1039/c9cc08646c

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Exploration of a KI-catalyzed oxidation system
for direct construction of bispyrrolidino[2,3-
b]indolines and the total synthesis of (+)-WIN
Cite this: Chem. Commun., 2020,
56, 121
Received 6th November 2019,
Accepted 25th November 2019
64821†
a
Si-Kai Chen,‡a Ju-Song Yang,‡a Kun-Long Dai,a Fu-Min Zhang,
*
DOI: 10.1039/c9cc08646c
ab
Xiao-Ming Zhang *a and Yong-Qiang Tu
*
rsc.li/chemcomm
A facile and environmentally benign KI(cat.)/NaBO3ꢀ4H2O oxidation synthesis of relatively simple organic compounds, and only a few
system has been developed for the tandem oxidative aminocyclization/ can give access to sterically complex frameworks, such as those
coupling of tryptamines, affording a series of 3a,3a0-bispyrrolidino- with the vicinal all-carbon quaternary centers.7 As indicated in
[2,3-b]indolines with high efficiency (up to 94% yield). This reaction Scheme 1, the oxidation systems mediated by a catalytic amount
features an electrophilic ‘‘I+’’ mechanism, which is importantly quite of iodide have not been expanded to effect the tandem coupling/
different from and milder than the typical radical-involving process, cyclizations of tryptamine or tryptophan to construct the more
and can be readily amplified for the total synthesis of (+)-WIN 64821. complex 3a,3a0-bispyrrolidino[2,3-b]indoline 6, 8 and 11 with vicinal
all-carbon quaternary centers. Instead, they are only applicable to
Oxidation is one of the most important transformations for mediate the simple cyclization to produce the monomer products
organisms to produce functional molecules. In vivo, the oxidation 1–4 (Scheme 1(a)).8 Due to our continuing interest in the synthesis of
of tryptophan or tryptamine can result in a big family of structu- 3a,3a0-bispyrrolidino[2,3-b]indoline alkaloids,9 we thus try to develop
rally complex and biologically important 3a,3a0-bispyrrolidino- an alternative effective iodide-catalyzed oxidative system, which we
[2,3-b]indoline alkaloids (Fig. 1), which show antifungal, antiviral expect will enable the coupling/cyclizations as shown in Scheme 1(b).
and cytostatic acivities.1 Despite its significance for biological and Herein, we describe our research results.
medicinal chemistry, realizing this biotransformation by means
To achieve the hypothesis above, our initial optimization
of organic chemistry, especially with a catalytic amount of assis- started toward the oxidation of tryptamine 5a with screening the
tant oxidation reagent, is still rare and synthetically challenging.2 oxidants and solvents using KI as a catalyst (Table 1). Fortunately,
To date, several groups have devoted much pioneering effort to after testing H2O2 in several solvents, only TFE (trifluoroethanol)
this aspect.3,4 However, most of the current solutions require could generate the desired dimeric products (6a and 6a0) with
either equivalent amounts of transition metals or excess of strong a moderate 44% yield (entry 5), while the other solvents gave
acid or base. Furthermore, these methodologies generally give inferior results (entries 1–4). Subsequently, both organic (entries
insufficient yields. Therefore, the development of a catalytic and 6 and 7) and inorganic oxidants were screened (entries 8 and 9),
transition-metal-free oxidative system for the efficient synthesis of among which, NaBO3ꢀ4H2O gave the best yield (64%, entry 9). In
3a,3a0-bispyrrolidino[2,3-b]indolines under mild condition is in addition, other conditions which involved varying the iodide
demand.
catalysts, additives, concentrations and component equivalents
During the past fifteen years, the iodide-catalyzed oxidative were widely investigated,10 with the conditions in entry 10 giving
reaction has received widespread attention because of its versatile the best result (68% yield).
reactivity and environmentally benign property.5,6 In general,
however, these systems are mostly limited to the application of
a State Key Laboratory of Applied Organic Chemistry and College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China.
E-mail: tuyq@lzu.edu.cn, zhangfm@lzu.edu.cn, zhangxiaom@lzu.edu.cn
b School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
Shanghai 200240, P. R. China
† Electronic supplementary information (ESI) available. CCDC 1940250. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9cc08646c
Fig. 1 Representative bispyrrolidino[2,3-b]indoline alkaloids.
‡ These authors contributed equally.
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Table
2
Investigation of R6 and X–R7 of tryptamines for oxidative
dimerizationa
Scheme 1 (a) Previous I-catalyzed oxidation of tryptamine or tryptophan;
(b) our design.
Table 1 Optimization of the conditions for the iodide-catalyzed oxidative
dimerization of tryptaminea
Entry
Solvent
Oxidant
Time
Yieldb (%)
c
1
2
3
4
5
6
7
8
CH3CN
Toluene
THF
CH2Cl2
TFE
TFE
TFE
TFE
TFE
TFE
H2O2
24 h
24 h
24 h
24 h
4 h
10 h
10 min
24 h
1.5 h
2 h
NRd
NR
NR
NR
44
H2O2
H2O2
H2O2
H2O2
tBuO2He
m-CPBA
53
NDf
NR
64
g
O2
9
NaBO3ꢀ4H2O
10h
NaBO3ꢀ4H2O
68
a
a
Unless otherwise noted, all reactions were carried out with 5
Unless otherwise noted, reactions were carried out with 5a (0.2 mmol),
(0.2 mmol), KI (10 mol%) and NaBO3ꢀ4H2O (1.2 equiv.) in 2 mL TFE
KI (20 mol%) and oxidant (2.0 equiv.) in 2 mL solvent. The dr was 1.8 : 1
b
c
and reacted for 1 h. Isolated yields and dr were determined by 1H NMR.
determined by 1H NMR. Determined by 1H NMR. 50 wt% in water.
b
c
d
d
h
e
f
g
Reacted for 2 h. No reaction was observed after 24 h. Reacted for
No reaction was observed. 5.5 M in decane. Not detected. 1 atm.
e
3 h. Not detected.
Reaction was carried out with 5a (0.2 mmol), KI (10 mol%) and
NaBO3ꢀ4H2O (1.2 equiv.) in 2 mL TFE.
accompanied by a partial starting material. It was also important
that when tryptophol 5n and 3-indolepropanol 5o were sepa-
rately subjected to the catalytic oxidative systems, interestingly,
the former could react efficiently to give the tetrahydrofuran 6n
with an excellent yield of 94%, while the latter gave a mixture
without hexahydropyran 6o detected.
Next, a wide range of tryptamines with different substituents
on the benzene rings were tested. As shown in Table 3, both EWG
and EDG substituents at C7, C6 and C5 of the benzene rings were
effective for the expected oxidative dimerization reactions and
generally gave satisfactory results (8a–i, 68–94% yield, 1.5:1 to
3.9 : 1 dr). The differences of these examples in the reaction time
revealed that the EDG substituents were more favorable for
reaction rates than the EWGs (8f, 8i vs. 8a, 8c, 8j, and 8k). Notably,
the C4–F and C4–Cl substituted tryptamines 7j and 7k could give 8j
and 8k with excellent diastereoselectivities (11.7 : 1 and 420 : 1 dr)
With the optimal catalytic oxidative system in hand, we then
expanded the tryptamine substrate scope by varying the sub-
stituents R6 and X–R7 (Table 2, 5a–m). Initially, when X–R7 was
selected as N-tosyl, varying the substituents R6 (5b–d) with the
EDGs (electron-donating groups, e.g., methyl, ethyl and allyl)
generally led to excellent reaction results (6b–d, 91–93% yields,
1.4 : 1 to 2.9 : 1 dr), while the EWG (electron-withdrawing group,
e.g., Ac) substituted substrate (5e) remained inactive to give
product 6e. Subsequently, when the optimal methyl was selected
as R6 (as indicated in 6f–l), varying substitution of R7 (X = N) with
the strong EWG sulfonyl (5f–k) and trifluoroacetyl (5l) could
drive the reactions with satisfactory results (6f–l, 75–93% yields,
1.5 : 1 to 2.9 : 1 dr). Exceptionally, when a carbamate was intro-
duced to tryptamine (5m, X–R7 = N-CO2Me), the reaction could
not give the desired product 6m, but gave a complex mixture
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Table 3 Investigation of benzene ring substituted tryptamines for oxida-
tive dimerizationa
Scheme 2 The plausible mechanism.
ion intermediate A.3g,8b,11 Subsequently, the active intermediate A
underwent an intramolecular cyclization to generate the 3-iodo-
hexahydropyrroloindole compound B, which was then transferred
to indolium C and released iodide for further catalytic cycles.
Finally, the indolium C could couple with another tryptamine
(5 or 7) through an electrophilic addition/cyclization process via
either favorable model M-1 or a sterically hindered model M-2 to
give the major product 6 or 8 and the minor one 60 or 80,
respectively. It is worth noting that this stereo-control model was
also consistent with the diastereoselectivities obtained from our
reactions.10
To verify the utility of this methodology, the pharmacologi-
cally promising agent (+)-WIN 64821 was chosen as a synthetic
target (Scheme 3).12 The efficient construction of the 3a,3a0-
bispyrrolidino[2,3-b]indoline motif was the key to approach a
concise total synthesis of (+)-WIN 64821. That could be conveniently
realized by using our newly developed catalytic oxidative meth-
odology. Initially, we synthesized the precursor 10 for the key
reaction from commercially available (L)-tryptophan 9. Then,
compound 10 was successfully applied, at the gram-scale, to
a
Unless otherwise noted, all reactions were carried out with 5 (0.2 mmol),
KI (10 mol%) and NaBO3ꢀ4H2O (1.2 equiv.) in 2 mL TFE and reacted for
1
1 h. Isolated yields and dr were determined by H NMR.
and acceptable yields (72% and 46%), probably due to the steric the KI-catalyzed oxidative coupling/cyclization reaction to give the
3a,3a0-bispyrrolidino[2,3-b]indoline 11 with satisfactory results (79%
0
interaction between F or Cl and C3a or C3a
.
In order to elucidate the mechanism of this catalytic oxidative yield, 1.2 : 1 dr). Subsequent deprotections of p-nitrobenzene sulfonyl
coupling/cyclization reaction, we also conducted some additional and allyl of 11 successively afforded the dimeric diamine 13, which
control experiments (Scheme S1, ESI†).10 According to the experi- could be easily condensed with N-Cbz-L-phenylalanine over three
mental results, addition of the radical scavengers such as TEMPO steps4d,13 to finally give (+)-WIN 64821.
(2,2,6,6-tetramethylpiperidinooxy) or DMPO (5,5-dimethyl-1-pyrroline
In conclusion, we have successfully established an iodide-
N-oxide) was found to have little influence on the reaction, while catalyzed oxidative coupling/cyclization approach for the dimer-
use of the electrophilic iodide reagent NIS (N-iodosuccinimide) ization of tryptamine, tryptophol and tryptophan analogues. This
could efficiently promote the desired reaction with similar results protocol features a plausible catalytic cycle comprising iodide
(77% yield, 2.8 : 1 dr) compared to the standard reaction (Table 2, 6b). and hypoiodite catalyst states, the use of inexpensive and readily
Therefore, an electrophilic ‘‘I+’’ mechanism (Scheme 2) rather than available as well as an environmentally benign system (KI and
the classical radical process was proposed.6i As shown in Scheme 2, NaBO3ꢀ4H2O) and mild reaction conditions. Particularly, it provides
the reaction would begin with the oxidation of ‘‘Iꢁ’’; thereafter, a practical solution for the construction of synthetically challenging
the resulting electrophilic ‘‘I+’’ species could readily interact with vicinal all-carbon quaternary motifs. Although it gives moderate
the nucleophilic tryptamine (5 or 7) to form a cyclic iodonium diastereoselectivities in some cases, we have optimized it up to
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We thank the NSFC (No. 21502080, 21772071, 21871117,
21772076, 21971095), STCSM (19JC1430100) and the ‘‘111’’
Program of MOE for their financial support. We also thank Prof.
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Conflicts of interest
There are no conflicts to declare.
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