Total synthesis of indiacen A using a practical one-pot reaction: Promoted by a key waste product, and its utility in natural products synthesis

Article abstract of DOI:10.1016/j.tetlet.2021.152822

Trialkylammonium salt, recognized as a waste product in the Heck reaction, was found to act as a key catalyst in the practical one-pot Heck-dehydration reaction. A concise synthesis of indiacen A was accomplished in 92% overall yield using a protecting-gr

Full text of DOI:10.1016/j.tetlet.2021.152822

Tetrahedron Letters 66 (2021) 152822
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of indiacen A using a practical one-pot reaction:
Promoted by a key waste product, and its utility in natural products
synthesis
Lihua Wang , Ting Lei , Fusheng Wang , Shizhi Jiang , Guiyang Yan b,
a
a
a
a,
⇑
⇑
a
College of Pharmacy, Dali University, Dali 671000, China
Fujian Provincial Key Laboratory of Featured Materials in Biochemical Industry, Ningde Normal University, Ningde, Fujian 352100, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Trialkylammonium salt, recognized as a waste product in the Heck reaction, was found to act as a key
catalyst in the practical one-pot Heck-dehydration reaction. A concise synthesis of indiacen A was accom-
plished in 92% overall yield using a protecting-group-free and redox-neutral strategy. In this synthesis, a
novel one-pot reaction with high regio- and stereo-selectivity was developed and further application in
the total synthesis of other natural products. This newly established method would be beneficial for the
synthesis of other relevant natural products.
Received 4 November 2020
Revised 23 December 2020
Accepted 3 January 2021
Available online 16 January 2021
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Trialkylammonium salt
Protecting-group-free
Redox-neutral
Indole alkaloid
Regio- and stereo-selectivity
Indiacen A (Scheme 1), an unusual structurally-simplified 3-
formylindole derivative bearing an isoprene-like side chain at the
The crucial step of our outlined synthesis (Scheme 1) was found
to be the coupling of an indole moiety and an olefin side chain. In
this context, the Heck coupling [7] appeared to be the most attrac-
tive for introducing a trans-alkene and could take place without the
participation of the indole enamine moiety and the aldehyde
group. Retrosynthetic analysis revealed 4-bromoindole derivative
2 and allyl alcohol 3 as suitable starting materials to install the
desired carbon skeleton 4 upon Heck coupling. Subsequent or
in situ dehydration of the newly formed tertiary alcohol 4 would
give the desired indiacen A.
It should be noted that the above strategy combining Heck cou-
pling and dehydration had previously been documented in the lit-
erature [3,8–17]. But current methods still possess some
limitations such as high-temperature reaction conditions, long
reaction time as well as the use of instable aryl iodides substrate
or need additional assistance in the dehydration step by MsCl/
4
-position, is a secondary metabolite of the bacterium Sandaracinus
amylolyticus that was isolated in 2012 [1]. It has antibacterial activ-
ity against Gram-positive and Gram-negative bacteria, as well as
antifungal activity against Mucor hiemalis [1]. The fascinating
structural features of indiacen A, along with its potential pharma-
cological activity and our ongoing interest in the total synthesis of
biologically active indole natural products [2], prompted us to
develop a practical approach to synthesize this attractive indole
alkaloid.
Previously, 1 has been produced as a by-product in the synthe-
sis of (±)-6, 7-secoagroclavine [3], Thus far, only one group has
achieved the total synthesis of indiacen A in early 2017 (together
with indiacen B by a versatile method); the product was obtained
in 6 steps and 13.7% overall yield by using Horner-Wadsworth-
Emmons olefination, carboalumination and Vilsmeier-Haack
formylation as key steps [4]. Both the reported syntheses possess
some limitations such as the use of harsh reaction conditions and
highly toxic substrates. Here we disclose an effective one-pot reac-
tion, leading to a concise [5,6] synthesis of indiacen A from readily
available starting materials under mild conditions.
Et
3
N [9], p-TsCl/pyridine [10], acetyl chloride/pyridine [11,12],
/DBU [14] or POCl /pyridine
HCl aqueous solution [13], SOCl
2
3
[15], and thus constitutes a major impediment to the application
of this ingenious method in total synthesis. Additionally, no mech-
anism study or discussion was performed, and the reaction scope
of substrates has not been explored. To this end, designing a prac-
tical and target-orientated strategy is in great demand.
⇑
Corresponding authors.
E-mail addresses: jiangshizhi@dali.edu.cn (S. Jiang), ygyfjnu@163.com (G. Yan).
Although there are many known methodologies (Scheme 2)
such as Suzuki coupling [8,18], Still coupling [18], Hiyama coupling
https://doi.org/10.1016/j.tetlet.2021.152822
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0

L. Wang, T. Lei, F. Wang et al.
Tetrahedron Letters 66 (2021) 152822
3
). Due to concerns that longer reaction time might lead to
increased byproducts, we finally treated the reaction at 115 °C. A
significant increase in yield was observed, and the reaction had
reached completion after 5 h (81%, entry 4), we also noted that
the ratio of the products (4 and 1) in this reaction varied with time
(
and TLC observations), which indicated that the end-product was
formed via the dehydration of the initially formed coupling pro-
duct 4 and not by Heck coupling between 2 and isoprene [22].
However, further increasing the temperature affected the yield
(
72%, entry 5).
Other palladium catalysts, namely, PdCl
were also evaluated (Table 2, entry 1–3); however, Pd(OAc)
2
, Pd(PPh
3
)
4
, Pd
2
(dba)
was
superior to all of them. Interestingly, the representative Pd(0) cat-
alyst Pd(PPh failed to afford any diene 1 after a long reaction
time (10 h, entry 2). When PPh or P(2-furyl) was used instead
of P(o-tol) , the desired product was obtained in moderate or low
3
2
3 4
)
3
3
3
yield (66%, entry 4; 15%, entry 5).
Scheme 1. Retrosynthetic analysis of indiacen A.
Examination of various bases, including organic and inorganic
bases, indicated that varying the base had a dramatic effect on
the reaction (entry 6–9). When trialkylamine was used as the base,
the diene product 1 was obtained in good yield (entry 6–7; Table 1,
entry 4). In particular, in the presence of DIPEA, the yield of pro-
duct 1 reached 85% (entry 6). A slightly decreased yield was
observed when a trialkylated long-chain amine was employed (en-
3
try 7). When inorganic bases such as NaOAc (CH COONa) and
NaHCO were used, both the reactions rate and yields were unsat-
3
isfactory (entry 8–9), presumably due to significant catalyst
decomposition during the coupling reaction.
After ascertaining that trialkylamine was the best base for the
reaction, we then investigated the role of the solvent. A screening
of various solvents, namely, THF, DCE, toluene and DMF revealed
that they all performed well, with THF giving the best result to
afford indiacen A in 83% yield (entry 10). It is well-known that
Heck reactions can be conducted neat under elevated temperature,
we then tried to prepare indiacen A under solvent-free condition,
but the yield was moderate (entry 14).
To gain further insight into the possible mechanism of the
dehydration step, a thorough, but not exhaustive, control experi-
ment was conducted (Table 3). The Heck product 4 was isolated
Scheme 2. Synthetic strategies for install the isoprene group.
(
according to Table 1, entry 4) and then subjected to various pos-
[
19] and reductive/dehydrative from alkynol [20] that could intro-
sible factors in a separate step. Initially, tertiary alcohol 4 was
duce the isoprene group. But the reported syntheses need to inde-
pendently prepare an isoprene intermediate or required multi-
steps to install the isoprene moiety and possess some limitations
such as harsh reaction conditions, highly toxic and expensive start
material. Hence traditional methods are not simple enough.
Our synthetic efforts commenced with 4-bromoindole-3-car-
boxaldehyde 2 as the key starting material; this compound is com-
mercially available, and can also be prepared easily from
inexpensive 4-bromoindole using the Vilsmeier-Haack formylation
heated in the presence of only CH CN (entry 1), a distinct degrada-
tion of the starting material and the diene product were found, and
after one hour, diene 1 was obtained in low yield (17%) and unre-
3
acted alcohol 4 was recovered (10%). When a CH CN solution of 4
3
was heated in the presence of Pd(OAc) (entry 2), the yield was not
2
improved compared to the solvent-only reaction. Furthermore, it is
noteworthy that the presence of P(o-tol)3 or Et N very strongly
3
inhibited the dehydration reaction but also stabilize the reaction
mixture (entry 3–4). This result perhaps because of their weak
alkalinity, and the latter might explain the longer reaction time
[
21]. With bromide 2 in hand, we first tried to prepare indiacen A
via Heck reaction and dehydration at 85 °C under atmospheric
pressure (Table 1). Unfortunately, the desired diene product 1
was not formed, and mainly the unreacted starting material 2
was recovered. However, the initial Heck cross-coupling was
accomplished with high regio- and stereo-selectivity to give alkene
required for the Heck-dehydration reaction when 1.5 eq. Et N
was used [Table 1, entry 4 (1.5 eq., 5 h) versus Table 4, entry 1
(1.0 eq., 1 h)]. Surprisingly, the elimination product was obtained
3
in excellent yield in just 15 min when Et NꢀHBr was used (96%,
3
entry 5). In the presence of catalytic amounts of Et NꢀHBr, the
3
4
in 13% yield. The geometry of the double bond was ascertained as
reaction also proceed well (72%, entry 5). These reactions clearly
1
the E-isomer using H NMR spectroscopy. To our delight, the
desired diene 1 was obtained in 58% yield when this reaction
was conducted in a sealed tube at 95 °C (entry 2), although it
was accompanied by a small quantity of coupling product 4
show that Et NꢀHBr can promote the dehydration reaction and
3
perhaps because the mild acidity it offers.
However, a dramatic disparity was found between Et NꢀHBr
3
and HBr or AcOH (CH COOH) (entry 6–7). The difference cannot
3
(
17%). The spectroscopic data for synthetic 1 were in agreement
be explained by weak acidity. Thus, we hypothesized that, Et3-
with those reported for the natural product [1]. We assumed that
the reaction did not proceed smoothly at 95 °C because of the dif-
ficult hydroxyl elimination. Indeed, when the temperature was
increased to 105 °C, a 71% yield of 1 was observed in 10 h (entry
NꢀHBr may also serve as the buffer and the phase transfer catalyst
in this case, while HBr or AcOH cannot. Based on the above
assumptions, we deduced that the acid could catalyze the dehydra-
tion reaction, the buffer and the phase transfer catalyst could
2

L. Wang, T. Lei, F. Wang et al.
Tetrahedron Letters 66 (2021) 152822
Table 1
Preliminary study in the synthesis of indiacen A.
o
R.S.M. 2%a
yield 4%a
yield 1%a
Entry
T [ C]
t [h]
1
2
3
4
5
85b
95
105
115
125
10
10
10
(1) 5
3
73
–
–
–
–
13
17
trace
(92) -
–
–
58
71
(trace) 81
72
R.S.M. = Recovered Starting Material.
‘
‘–” = Not Detected.
a
Isolated yield.
b
Atmospheric pressure.
Table 2
Investigating the effect of the catalyst, ligand, base and solvent.
Entry
variable
PdCl
Pd(PPh
Pd (dba)
PPh
t [h]
R.S.M. 2%a
yield 4%a
yield 1%a
1
2
3
4
5
6
7
8
9
2
5
–
73
–
–
43
–
–
47
–
62
66
15
85
76
trace
trace
83
71
68
3
)
4
10
10
5
5
5
5
5
5
5
5
3
3
3
23
22
–
10
–
b
2
3
3
P(2-furyl)
3
DIPEAc
(n-C
H
8 17
)
3
N
–
–
d
d
NaOAc
72 (79 )
63 (71 )
- (19 )
d
d
NaHCO
THF
DCE
3
28 (11 )
10
11
12
13
14
–
–
–
–
–
–
–
–
–
–
e
Toluene
DMF
Solvent free
72
59
a
b
c
Isolated yield.
.04 eq.
N,N-diisopropylethylamine.
In DMF.
0
d
e
Dichloroethane.
stabilize and promote the reaction, the three complement each
other, are indispensable. Indeed, performing the dehydration reac-
tion with TBAB (serve as the buffer and the phase transfer catalyst)
resulted in an unacceptably slow conversion rate and low yield
was served as the buffer, the phase transfer catalyst and the acid.
It is worth mentioning that Et
NꢀHBr has been widely recognized
as a waste product in the Heck reaction, and there is little discus-
sion of its use as a reagent in the literature. In this reaction, Et
3
3
-
(
entry 8). By comparison, the combination of TBAB and HBr or
NꢀHBr has been used as a dehydration catalyst to promote
hydroxyl elimination under mild reaction conditions and this can
also explain why the use of trialkylamine as the base led to high
yield.
Taking the above findings into consideration, a high yield of
indiacen A (91%, Table 4, entry 1) was attained in less than one
AcOH (entry 9–10) was effective for the dehydration reaction.
In addition, treatment of 4 with AcOH-NaOAc (serve as the buf-
fer and acid) gave moderate yield of 1 (entry 11). By comparison,
the combination of AcOH-NaOAc and TBAB (serve as the phase
transfer catalyst) give a better result on version of 4 into 1 (entry
1
2).
Furthermore, acidic phase transfer catalyst (Bu
3, serve as the buffer, the phase transfer catalyst and the acid)
NꢀHCl, entry 14), were also tested
showed a moderate result with 42% isolated yield
the low yield perhaps because the too strong acidity it offers)
3
hour by adopting a reduced dose of Et N (1.0 eq.). To evaluate
4
4
NHSO , entry
the efficacy of this reaction at a larger-scale, the reaction was car-
ried out using 2 g of substrate 2. Pleasingly, indiacen A was isolated
in excellent yield (92%) without loss of efficacy compared to the
small-scale reaction. Nevertheless, we were not satisfied with the
use of a sealed tube, which is not ideal for large-scale synthesis.
Therefore, further investigation was undertaken to develop a more
practical method. Process development demonstrated that the
reaction could also be well achieved at atmospheric pressure in
DMF (80%), with no need for higher temperature to compensate
for the reduction in reaction pressure. Microwave assisted
1
and other triethylamine salt (Et
and Bu NHSO
(
3
4
4
and Et
3
NꢀHCl was found to be as effective as Et NꢀHBr for the
3
dehydration reaction. Hence, research results verified the rational-
ity of the hypothetical.
Importantly, these results demonstrate that Et
3
NꢀHBr plays a
significant role in the one-pot Heck-dehydration reaction which
3

L. Wang, T. Lei, F. Wang et al.
Tetrahedron Letters 66 (2021) 152822
Table 3
Probe into the dehydration factors and mechanism.
Entry
factor
CH CN
Pd(OAc)
P(o-tol)
t
R.S.M. 4%a
yield 1%a
1
2
3
4
5
6
7
8
9
3
1 h
1 h
4 h
4 h
15 min
10 min
12 h
12 h
15 min
12 h
10
9
81
95
–
17
12
2
(0.08 eq.)
(0.2 eq.)
3
trace
–
Et
Et
3
N (1.5 eq.)
b
3
NꢀHBr (1.0 eq.; 0.1 eq.)
96 ; 72
HBr (0.01 eq.)
AcOH (0.1 eq.)
–
14
18
36
57
63
41
62
42
68
12
28
–
c
TBAB (1.0 eq)
TBABc + HBr
10
11
12
13
14
TBABc + AcOH
9
AcOH(0.7 eq.)-NaOAc(0.3 eq.)
12 h
12 h
30 min
15 min
27
20
–
TBABc + AcOH-NaOAc
Bu
Et
4
NHSO
NꢀHCl (0.1 eq.)
4
(1.0 eq.)
3
–
a
b
c
Isolated yield.
At 85 °C.
Tetrabutylammonium bromide.
Table 4
Further study in the synthesis of indiacen A.
Entry
1
2
3
4
variable
Et N (1.0 eq.)
Microwave
Pd(OAc) (0.04 eq.)
Et N (0.8 eq.)
t
R.S.M. 2%a
yield 4%a
yield 1%a
b
c
3
1 h
(3 min) 2 h
3 h
–
–
–
16
–
91(92 )(80 )
c
(89) 25
–
–
(–) 62
88
67
2
3
3 h
a
b
c
Isolated yield.
2
g scale.
Atmospheric pressure, in DMF.
synthesis of indiacen A was also conducted. In result, the Heck cou-
pling reaction time was shortened to 3 min, but the dehydration
reaction rate was low (entry 2). Furthermore, using only 4 mol%
catalyst also exhibited good performance (88%, entry 3). However,
ity of this reaction, we turned our attention to the total synthesis of
natural product 1e [23] and the analogue of natural product (TMC-
205) 1f [18,24]. We were delighted to find that the desired prod-
ucts could be prepared conveniently in just one step from commer-
cial available aryl bromides using the above one-pot reaction.
Further application of this newly established method to the total
synthesis of other natural products (such as 1g-1o [10,18,25–27]
and so on) are under investigation and will be reported in due
course.
3
further decreasing the dose of Et N to 0.8 eq. negatively affected
the yield (67%, entry 4).
With optimized reaction conditions in hand, we set out to
explore the scope of the above one-pot reaction. As shown in
Table 5, the reaction proceeded well with a wide range substrates,
thus delivering a series of desired isoprene products in moderate to
excellent yields (1a-1d). To further demonstrate the synthetic util-
In summary, a concise and practical total synthesis of indiacen
A was achieved in one step and 92% yield from readily available
4

L. Wang, T. Lei, F. Wang et al.
Tetrahedron Letters 66 (2021) 152822
Table 5
Scope of the one-pot reaction.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
J.-Z. J. thanks the NSFC (31860098), Basic Joint Project of Yun-
nan Provincial Science and Technology Department (grant number
2
017FH001-019) and the Innovation Team Project of Dali Univer-
sity for Development and Utilization of Characteristic Medicinal
Plants in Western Yunnan & Bai Nationality Medicines (grant num-
ber ZKLX2019106) for financial support.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152822. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
References
[
1] H. Steinmetz, K.I. Mohr, W. Zander, R. Jansen, K. Gerth, R. Müller, J. Nat. Prod.
5 (2012) 1803–1805.
2] S.Z. Jiang, X.Y. Zeng, X. Liang, T. Lei, K. Wei, Y.R. Yang, Angew. Chem. Int. Ed. 55
2016) 4044–4048.
7
[
(
[
3] M. Somei, F. Yamada, Chem. Pharm. Bull. 32 (1984) 5064–5065.
[
4] K.K. Anantoju, B.S. Mohd, T.C. Maringanti, Tetrahedron Lett. 58 (2017) 1499–
1
500.
5] N.Z. Burns, P.S. Baran, R.W. Hoffmann, Angew. Chem. Int. Ed. 48 (2009) 2854–
867.
[
2
[
[
[
[
6] C.G. Hui, F. Chen, F. Pu, J. Xu, Nat. Rev. Chem. 3 (2019) 85–107.
7] M. Oestreich, The Mizoroki-Heck Reaction, Wiley, Chichester, 2009.
8] L. Gao, J.G. Han, X.G. Lei, Org. Lett. 18 (2016) 360–363.
9] D.H. Dethe, R.D. Erande, A. Ranjan, J. Am. Chem. Soc. 133 (2011) 2864–2867.
[
[
[
10] J. Reisch, A. Wickramasinghe, D.B. Mahinda Wickremaratne, Liebigs Ann.
Chem. 2 (1990) 209–210.
11] C.F. Chee, Y.K. Lee, M.J.C. Buckle, N.A. Rahman, Tetrahedron Lett. 52 (2011)
1
797–1799.
12] P.J. Harrington, L.S. Hegedus, K.F. McDaniel, J. Am. Chem. Soc. 109 (1987)
335–4338.
4
[
13] E. Alacid, C. Nájera, Adv. Synth. Catal. 349 (2007) 2572–2584.
[
14] J.G. Han, X. Li, Y. Guan, W. Zhao, W.D. Wulff, X.G. Lei, Angew. Chem. 126 (2014)
9411–9415.
[
15] L.T. Lepovitz, S.F. Martin, Org. Lett. 20 (2018) 7875–7878.
[
16] A. Sauza, J.A. Morales-Serna, M. García-Molina, R. Gaviño, J. Cárdenas,
Synthesis 44 (2012) 272–282.
[
[
[
17] P. Liu, Y.M. Pan, K. Hu, X.C. Huang, Y. Liang, Tetrahedron 69 (2013) 7925–7930.
18] Y. Gao, S. Osman, K. Koide, ACS Med. Chem. Lett. 5 (2014) 863–867.
19] Y. Nakao, H. Imanaka, J.S. Chen, A. Yada, T. Hiyama, J. Organometal. Chem. 692
starting materials (2g scale). The trans-(3-methyl-l, 3-butadienyl)
unit was effectively introduced via a novel one-pot reaction with
high regio- and stereo-selectivity. Through investigation, trialky-
lammonium salt, which was a waste product of the initial Heck
couping, was found to play three important roles in the subsequent
dehydration reaction. Based on this reaction, a wide variety of iso-
prene products could be synthesized in moderate to excellent
yields and the total synthesis of another two natural products
has also been achieved. What’s more, this newly established
method would be beneficial for the synthesis of other relevant
important natural products.
(
2007) 585–603.
[
20] D.M. Cui, K. Zhu, L. Chen, L.J. Qi, C.Z. Zhang, C. Zhang, Synth. Commun. 43
(2013) 2380–2384.
[
[
21] R. Lauchli, K.J. Shea, Org. Lett. 8 (2006) 5287–5289.
22] Isoprene may be formed from already existing 1, 1-dimethylallyl alcohol by
dehydration reaction.
[23] M.N. Nwaji, S.O. Onyiriuka, JCS Chem. Commun. 6 (1972) 327.
[
24] M. Sakurai, J. Kohno, M. Nishio, K. Yamamoto, T. Okuda, K. Kawano, N.
Nakanishi, J. Antibiot. 54 (2001) 628–634.
[
25] T. Asai, T. Yamamoto, Y. Oshima, Tetrahedron Lett. 52 (2011) 7042–7045.
[26] D.H. Dethe, R.D. Erande, B.D. Dherange, Org. Lett. 16 (2014) 2764–2767.
[27] M.J. Smith, K.D. Reichl, R.A. Escobar, T. Heavey, D.F. Coker, S.E. Schaus, J.A.
Porco, J. Am. Chem. Soc. 141 (2019) 148–153.
5