Enantioselective total synthesis of (+)-arborescidine C and related tetracyclic indole alkaloids using organocatalysis

Article abstract of DOI:10.1039/c7ob00473g

A concise and enantioselective synthesis of the tetracyclic indoles, including the naturally occurring compounds (+)-arborescidine C and (+)-arborescidine B, was achieved by the key step of Pictet-Spengler cyclization reaction with a Jacobsen-type thiourea organocatalyst. The synthetic process was further demonstrated in a pot-economy strategy and was achieved in a one-pot operation.

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Enantioselective total synthesis of (+)‐arborescidine C and related
tetracyclic indole alkaloids using organocatalysis
Vishal M. Sheth,a Bor‐Cherng Hong,*,a and Gene‐Hsiang Leeb
Received 00th March 2017,
Accepted 00th March 2017
A concise and enantioselective synthesis of the tetracyclic indoles, including the naturally occurring compounds (+)‐
arborescidine C and (+)‐arborescidine B, was achieved by the key step of Pictet‐Spengler cyclization reaction with a
Jacobsen‐type thiourea organocatalyst. The synthetic process was further demonstrated in a pot‐economy strategy and
was achieved in a one‐pot operation.
DOI: 10.1039/x0xx00000x
www.rsc.org/
The tetracyclic indole alkaloids constitute an important class of isolated from the marine tunicate Pseudodistoma arborescens,
naturally occurring alkaloids (Fig 1). Especially, these classes of which was collected from the North‐East Barrier reef of New
alkaloids exhibited a variety of biological activities, e.g., Caledonia, and also from the sponge Verongula rigida,
antibacterial, antinematode, antiviral, and antidepressant collected from Key Largo, Florida.4 The first total synthesis of
activities, and many of them have been used as medicinal (±)‐arborescidine C was achieved by Koomen and colleagues.5
drugs.1 Consequently, the tetracyclic indole alkaloids have Later, asymmetric synthesis of (–)‐arborescidine C was
received extensive synthetic interest and have resulted in demonstrated by Rawal and his coworkers from
many elegant total syntheses,2 as well as several domino bromotryptamine with the key step of an asymmetric
catalysis approaches.3
hydrogen‐transfer reaction of imine by (S,S)‐TsDPEN–Ru(II)
catalyst in an 8‐step synthesis.6 More recently, Santos and his
coworkers extend the synthesis and studied the
antiproliferative activities of the products.7 Other syntheses
for
the
(±)‐desbromoarborescidine
C
and
(+)‐
desbromoarborescidine C have been reported in a sequence of
multi‐step synthetic reactions.8
Owing to the aforementioned summary of their biological
activities and the synthetic achievements, a concise and
efficient enantioselective preparation of these tetracyclic
indoles is a compelling subject. Therefore, we envisaged that
by taking advantage of the Pictet‐Spengler cyclization reaction
with asymmetric catalysts,9 e.g., Jacobsen‐type thiourea
organocatalyst, as well as by exploitation of a pot‐economy
strategy, we could attain an efficient and enantioselective
synthesis of these alkaloids, Scheme 1.
Fig. 1 Selected examples of the naturally occurring alkaloids with a tetracyclic
indole core.
Scheme 1. Initial synthetic plan toward the cyclic indole system.
(+)‐Arborescidine C, a tetracyclic indole alkaloid, was
Initially, the Pictet‐Spengler reactions were examined with
a. Address here. Department of Chemistry and Biochemistry, National Chung Cheng
University, Chia‐Yi 621, Taiwan, R.O.C. E‐mail: chebch@ccu.edu.tw; fax: +886 5
2721040; Tel: +886 5 2729174
tryptamine 1a and glutaraldehyde by
a
variety of
organocatalysts in different solvents, including CH2Cl2 and H2O
(Scheme 2). However, the reactions were in vain with the
recovery of tryptamine 1a and the decomposition of
glutaraldehyde. In addition, the attempts to conduct the
reaction with tryptaminecarbamate and 5‐hydroxypentanal
b. Instrumentation Center, National Taiwan University, Taipei, 106, Taiwan, R.O.C.
† CCDC 1523958, 1523959 For crystallographic data in CIF or other crystallographic
data see 10.1039/x0xx00000x
‡
Electronic Supplementary Information (ESI) available: Experimental detail,
spectroscopic characterization, HPLC analysis. See DOI: 10.1039/x0xx00000x
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with DPP and TFA in CH2Cl2 was fruitless and gave complicated
mixtures.
the results gave low yields with low ee (Table 1, entries 1‐3), or
did not react over a long reaction time (Table 1, entries 4‐5).
View Article Online
DOI: 10.1039/C7OB00473G
Table 2. Optimization of the reaction conditions for the acyl‐Pictet‐Spengler reactiona
Scheme 2. Initial synthetic attempt toward to the cyclic indole system.
Due to the observation of the complicated products in the
Pictet‐Spengler reaction and the instability of the corresponding
aldehyde, a protected aldehyde 2a was selected for the reaction
with tryptaminecarbamate 1a in the presence of DPP
(diphenylyphosphate) and MgSO4 (Scheme 3). Encouragingly, the
reaction was feasible and provided the tryptoline 3 in 82% yield.
Reduction of the carbamate with LiAlH4 in THF at room temperature
for 12 h provided 80% yield of the amine 4. Deprotection of 4 with
2N HCl in THF at room temperature for 3 h afforded the cyclization
product (±)‐5 in 78%.
Entry Cat.
Solvent
t
T (h)
Yield
(%)c
60
58
61
Ee (%)d
(°C)b
–60
–60
–60
–60
–60
–60
–60
–60
–60
–60
–60
–60
0
1
2
3
4
V
VI
VII
VIII
IX
X
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
CH2Cl2
THF
toluene
Et2O
Et2O
Et2O
Et2O
23
21
25
18
20
25
30
34
26
16
18
22
8
90
91
90
85
93
na
na
na
na
8
63
69
65
84
84
95
65
70
5
6e
7e
8e
9e
10
11
12
13
14
15
16h
tracef
tracef
traceg
traceg
53
XI
II
XII
IX
IX
IX
IX
IX
IX
IX
58
64
59
65
50
74
Scheme 3. Synthesis of (±)‐5.
–30
–78
–60
14
51
37
Table 1. Exploration of the enantioselective Pictet‐Spengler reaction of carbamate 1a
and aldehyde 2aa
aUnless otherwise noted, the reactions were performed with
tryptamine 1b (1.0 equiv) in 0.05 M concentration with
2 (1.0
equiv) and 5 mol% of the catalyst. bThe final reaction
c
temperature of the second‐step reaction. Yield of
6 isolated.
dDetermined by HPLC with a chiral column (Chiralpak IA). 10
e
f
mol% of the catalyst was used. Around 60% yield of N‐
acetyltryptamine and less than 5% of
6 were observed.
gAround 80% yield of N‐acetyltryptamine and less than 5% of
6
were observed. hReaction at 0.0167 M. nr = no reaction. na =
not available.
Entry Solvent
Cat.
(10mol %)
I
II
II
III
IV
T (h)
Yieldb (%)
ee (%)c
We then turned our attention to the highly
enantioselective catalytic acyl‐Pictet‐Spengler reactions,10 and
delved into the catalytic acyl‐Pictet‐Spengler reactions of
tryptamine 1b and aldehyde 2a with various organocatalysts
(Table 2). We were delighted to find that the reaction with
1
toluene
toluene
CH2Cl2
toluene
toluene
26
16
20
96
96
38
41
65
nr
nr
5
13
4
na
na
2
3
4
5
Jacobsen thiourea organocatalysts (
V‐VIII) provided 58‐65%
a The reactions were performed on 1a (1.0 equiv) with 2a (1.0
yield of the product with good enantioselectivities, ranging
6
b
c
equiv) at room temperature.
Determined by HPLC with a chiral column (Chiralpak IA). nr =
no reaction. na = not available.
Yields of 3 isolated.
from 85‐91% ee (Table 2, entries 1–4). It is noteworthy that
the reaction with a new Jacobsen‐type thiourea organocatalyst
IX, R1=R2=allyl, gave slightly better yields with 93% ee, and the
observations were reproducible and verified on several
occasions (Table 2, entry 5). The exact reason for having a
slightly better isolated yield is not clear yet, possibly owing to
the non‐covalent interaction effect11 or because of the better
Initially, we investigated the enantioselective Pictet‐
Spengler reaction of carbamate 1a and aldehyde 2a with a
series of asymmetric organocatalysts (Table 1). Unfortunately,
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solubility of the catalysts. The same reaction catalyzed by the promotes enantioselective cyclization by formingViewa AcrthicileraOlnlNine‐
squaramide catalyst
, thiourea XI, BINOL‐based chiral acyliminium chloride–thiourea complex.1D2OI: 10.1039/C7OB00473G
X
phosphoric (Akiyama) catalyst II, or cinchonine‐modified
squaramide XII did not take place or only gave trace amounts
of the product
6 (Table 2, entries 6–9). Changing the reaction
media to other solvents, e.g., CH2Cl2, THF and toluene, gave
lesser yields and lower ee (Table 2, entry 10–12). Raising the
final reaction temperature of the second‐step reaction to –30
°C or 0 °C reduced the enantioselectivity to 84% ee and 65% ee,
respectively (Table 2, entry 13‐14), while maintaining the
temperature of the second‐step reaction at –78 °C gave a
much lower yield of product with less ee obtained, as
compared to the reaction with the final temperature at –60 °C.
(Table 2, entry 15 and entry 5). Reaction at dilute conditions
(from 0.05 M to 0.0167M) gave the same results with a slight
(+)‐7
(+)‐5
increase in isolated yield and enantioselectivity of product
6
(Table 2, entry 5 and 16). After 37 hours at that reaction
condition, the starting compound tryptamine and aldehyde (2a
were completely consumed. Further prolong reaction, of
course, did not improve the yield.
Fig. 1 Stereoplots of the X‐ray crystal structures of (+)‐7 and (+)‐5. C,
gray; O, red; N, blue.
)
Table 3. Optimal examples of the acyl‐Pictet‐Spengler reactiona
Entry Aldehyde RC(O)Cl
Product
T
Yieldb Eec
(h)
28
32
37
34
34
(%)
64
74
74
70
64
(%)
86
92
95
92
74
1
2b n=1 AcCl
2c n=2 AcCl
2a n=3 AcCl
2d n=4 AcCl
2a n=3 MeOC(O)Cl
7 R=Me
8 R=Me
6 R=Me
9 R=Me
3 R=OMe
2
3
4
5
Fig. 2 Proposed mechanism for the asymmetric catalytic acyl‐Pictet‐
Spengler reaction reaction.
aThe reactions were performed on tryptamine 1b (1.0 equiv,
With respect to efficiency, the sequential transfer process
of acyl‐Pictet‐Spengler reaction of tryptamine 1b with
aldehyde 2a can be done in a one‐pot operation to give 63%
0.0167 M) with aldehyde
2 (1.0 equiv) and 5 mol % of catalyst
IX. bYield isolated for the product. cDetermined by HPLC with a
chiral column (Chiralpak IA). d Reaction at 0.025 M.
yield of
6 with 93% ee (Scheme 4, A). Reduction of the amide 6
with LiH2BH3 afforded amine 10 in 69% yield. Reductive
amination of 10 and formaldehyde with NaBH3CN, followed by
hydrolysis of the acetal and the cyclization reaction gave a 72%
yield of desbromoarborescidine C (5) with 97% ee. The
structure and the absolute configuration of (+)‐5 was revealed
by X‐ray crystallographic analysis (Figure 1). Dehydration of the
With the optimal reaction conditions in the hand (Table 2,
entry 16), a series of acetaldehydes
2 was applied with the
optimal conditions for the acyl‐Pictet‐Spengler reaction (Table
3). The results were promising with the yields ranging from 64
to 74% and enantioselectivities from 86 to 95% ee (Table 3,
entries 1–4). For the reaction with aldehyde 2b, probably due
to the steric congestion of the reaction center caused by the
closely attached acetal group, the reaction yield and
enantioselectivity were the lowest in this series (Table 3, entry
1). Alternatively, when the acetyl chloride at the last step was
replaced by methyl chloroformate, the reaction with aldehyde
2a gave a lesser yield (64% vs 74%) and enantioselectivity (74%
ee vs 95% ee), Table 3, entries 5 and 3. The structure as well as
alcohol
provided the desbromoarborescidine B (11) in 72% yield
(Scheme 4, ). Alternatively, product was prepared in 64%
yield from the methylformyl‐Pictet‐Spengler reaction of
tryptamine 1b with aldehyde 2a (Scheme 4, ). However, the
enantioselectivity of obtained in this methylformyl‐Pictet‐
Spengler reaction was lower than the aforementioned acyl‐
Pictet‐Spengler reaction (74% ee of vs 93% ee of ). Formate
was reduced to methylamine by LiAlH4 in 84% yield,
followed by the acidic hydrolysis and cyclization to provide in
80% yield (Scheme 4, ). With the appropriate synthetic
5 by the treatment with MsCl and Et3N in CH2Cl2 for 2 h
A
3
B
3
3
6
the absolute configuration of the product (+)‐
7 was
3
4
determined by X‐ray crystallographic analysis (Figure 1). A
rational mechanism of the asymmetric catalytic acyl‐Pictet‐
5
B
Spengler reaction of the tryptamine 1b and aldehyde, e.g., 2a
,
pathway established, the same reaction sequence of the acyl‐
Pictet‐Spengler reaction was applied in the synthesis of
is proposed as shown in Figure 2, where the thiourea catalyst
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arborescidine C (15) and arborescidine B (16), starting from
bromotryptamine 12 and aldehyde 2a (Scheme 4, ). However,
View Article Online
DOI: 10.1039/C7OB00473G
C
the acyl‐Pictet‐Spengler reaction in Et2O gave 92% ee of the
product 13, though in only 20% isolated yield. The low yield
was due to the low solubility in Et2O of the iminium
intermediate, formed from 12 and 2a. The reaction yield was
increased to 54% in the reaction of Et2O–CH2Cl2 (9:1), albeit
with a lower enantioselectivity (83% ee). Apparently, the
solvent effect plays an important role in excerting the
enantioselectivity of the acyl‐Pictet‐Spengler reaction. Amide
13 was successfully transformed to arborescidine C (15) and
arborescidine B (16) with the sequence of reduction, reductive
formylation, and hydrolysis reactions (Scheme 4,
C
).
O
O
(1)
(A)
O
2a
O
NH
N
O
NH2
Na2SO4, CH2Cl2–Et2O (3:1)
rt, 2h
LiH2NBH3
N
N
H
H
(2)
THF, 0 °C to 60 °C
4 h; 69%
cat. IX, 2,6-lutidine, AcCl
Et2O, –78 °C to –60 °C,
37 h; 74%; 95% ee
Scheme 5. Synthesis of 18 and 20
.
6
N
O
O
10
H
1b
O
One-pot, 63% yield; 93% ee
The same reaction sequence was properly applied in the
synthesis of tetrahydro‐1H‐pyrido[3,4‐b]indoles 22 and 24, via
and 9, respectively (Scheme 5). However, all attempts in the
Me
Me
N
N
(1) NaBH3CN, 37% HCHO
MeOH, 0 °C to rt, 12 h
H
H
MsCl, Et3N
N
N
7
CH2Cl2, 2 h; 72%
(2) aq. 2N HCl, THF, 3 h; 72%
HO
11
5
subsequent acidic hydrolysis and cyclization of 22 and 24 were
in vain, with recovery of the aldehyde product or of
complicated mixtures. The difficulty of these cyclizations was
probably due to the small‐ring strain that occurred in the
cyclization of 22 and the entropy disfavor of the
97% ee
(B)
O
O
(1)
(2)
2a
O
O
N
NH2
Na2SO4, CH2Cl2–Et2O (3:1)
rt, 2h
OMe
LiAlH4, THF
rt, 12 h; 84%
N
H
cat. IX, 2,6-lutidine, MeOCOCl
Et2O, –78 °C to °60 °C,
34 h; 64%
macrocyclization of 24
.
N
3
1b
H
O
One-pot
74% ee
O
Me
N
Me
N
H
N
H
aq. 2 N HCl, THF
rt, 3 h; 80%
N
5
78% ee
HO
4
O
O
O
O
O
(C)
(1)
(2)
NH
N
2a
O
NH2
Na2SO4, CH2Cl2–Et2O (3:1)
rt, 2h
N
N
Br
Br
LiH2NBH3
THF
0 °C to 60 °C
4 h; 67%
H
H
cat. , 2,6-lutidine, AcCl
Et2O–CH2Cl2 (9:1)
–78 °C to –60 °C
26 h; 54%
IX
13
83% ee
N
O
O
14
Br
H
O
O
12
Me
N
H
Me
N
(1) NaBH3CN, 37% HCHO
MeOH, 0 °C to rt, 12 h
H
MsCl, Et3N
CH2Cl2, 2 h; 79%
N
N
Br
Br
(2) aq. 2N HCl, THF, 3 h; 76%
HO
16
15
86% ee
Scheme 4. Synthesis of desbromoarborescidine C (5) and arborescidine C (15).
On the other hand, the acyl‐Pictet‐Spengler reaction of
tryptamine 1b and aldehyde 2c gave a 74% yield of with 92%
ee (Scheme 5). Reduction of the amide with LiH2BH3 afforded
8
Scheme 6. One‐pot synthesis of (+)‐5.
8
amine 17 in 61% yield. (Scheme 5). Reductive amination of 17
and formaldehyde with NaBH3CN, followed by hydrolysis of
acetal and cyclization reaction produced an isomeric mixture
of 18 and 19 in 39% and 31% yield, respectively. Dehydration
of the alcohols 18 and 19 by the treatment with MsCl and Et3N
in CH2Cl2 for 2 h afforded the alkene 20 in 78% yield (Scheme
5).
The three‐pot sequence for the synthesis of (+)‐5 (Scheme
) can be improved with a two‐pot operation (without the
isolation of 10), affording a 33% yield of (+)‐ with 94% ee
(Scheme 6). Moreover, the complete synthesis from
tryptamine 1b and aldehyde 2a can be achieved in a one‐pot
operation,13 without the need of extraction or isolation of
intermediates, to give (+)‐5 in 19% yield and 91% ee.14 This
procedure attained the impressive result of five reaction steps
in a one‐pot sequence.
4,
A
5
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8
9
Y. Zhang, R. P. Hsung, X. Zhang, J. Huang, B. VWiew. ASrtliaclfeeOr,nliAne.
Davis, Org. Lett., 2005, , 1047–1050. DOI: 10.1039/C7OB00473G
7
In summary, a highly enantioselective synthesis of (+)‐
arborescidine C (15) and the related tetracyclic indole alkaloids
has been achieved by a Jacobsen‐type thiourea organocatalyst.
The synthetic sequences proved to be the shortest synthesis
toward these tetracyclic indole alkaloids with high total yields
(up to 35% total yields) and high enantioselectivities (up to
97% ee). The synthesis also utilized a pot‐economy strategy
and has been demonstrated in a one‐pot process. The
structures, including the absolute configuration, of the
synthetic intermediates, (+)‐5 and (+)‐7, were unambiguously
revealed by their single crystal X‐ray analyses. Further studies
to extend these results toward more elaborated pentacyclic
indole alkaloids are in progress in our laboratories.
For a recent review in small organic molecule‐catalyzed
reactions, see: B.‐C. Hong in Encyclopedia of Physical Organic
Chemistry, Vol 2, Chap 24, p 1223–1298, Z. Wang, U. Wille, E.
Juaristi, Eds. Wiley 2017.
10 (a) M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc., 2004, 126
,
10558–10559. (b) M. S. Taylor, N. Tokunaga, E. N. Jacobsen,
Angew. Chem. Int. Ed., 2005, 44, 6700 –6704. (c) I. T.
Raheem, P. S. Thiara, E. A. Peterson, E. N. Jacobsen, J. Am.
Chem. Soc., 2007, 129, 13404–13405. (d) I. T. Raheem, P. S.
Thiara, E. N. Jacobsen, Org. Lett., 2008, 10, 1577–1580. (e) D.
J. Mergott, S. J. Zuend, E. N. Jacobsen, Org. Lett., 2008, 10
,
745–748. (f) S. Lin,E. N. Jacobsen, Nat. Chem., 2012, 4, 817–
824.
11 S. J. Zuend, E. N. Jacobsen, J. Am. Chem. Soc., 2009, 131
,
15358–15374.
12 For related mechanism study: (a) I. T. Raheem, P. S. Thiara, E.
A. Peterson, E. N. Jacobsen, J. Am. Chem. Soc., 2007, 129
,
13404–13405. (b) M. S. Taylor, N. Tokunaga, E. N. Jacobsen,
Angew. Chem. Int. Ed., 2005, 44, 6700–6704. (c) S. J. Zuend, E.
N. Jacobsen, J. Am. Chem. Soc., 2009, 131, 15358–15374. (d)
Competing interests
The authors declare no competing financial interest.
S. Lin, E. N. Jacobsen, Nat. Chem., 2012, 4, 817–824. (e) X. Liu,
L. Lin, X. Feng, Chem. Commun., 2009, 6145–6158.
13 For recent reviews of one‐pot synthesis or pot economy
Acknowledgements
We acknowledge the financial support for this study from the
Ministry of Science and Technology (MOST, Taiwan) and thank
the instrument center of MOST for analyses of compounds.
strategy, see: (a) Y. Hayashi, Chem. Sci., 2016, 7, 866–880. (b)
B.‐C. Hong, A. Raja, V. M. Sheth, Synthesis, 2015, 47, 3257–
3285. (c) M. Charles, Chem. Soc. Rev., 2012, 41, 7712–7722
.
14 Refer to Supporting Information for detail procedure.
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