Isothiourea-Catalyzed Enantioselective Synthesis of Tetrahydro-α-carbolinones

Article abstract of DOI:10.1021/acs.orglett.9b04615

An isothiourea-catalyzed enantioselective annulation protocol using indolin-2-imines with a series of α,β-unsaturated p-nitrophenyl esters for the synthesis of tetrahydro-α-carbolinones was developed. Using 5 mol % of the isothiourea HyperBTM as the Lewis base catalyst, this process allows the enantioselective preparation of a range of C(4)-substituted tetrahydro-α-carbolinones in good to excellent yield and with high enantioselectivity (20 examples, 32-99% yield and up to 99:1 er).

Full text of DOI:10.1021/acs.orglett.9b04615

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Letter
Isothiourea-Catalyzed Enantioselective Synthesis of Tetrahydro-α-
carbolinones
Honglei Liu, Alexandra M. Z. Slawin, and Andrew D. Smith*
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ABSTRACT: An isothiourea-catalyzed enantioselective annulation
protocol using indolin-2-imines with a series of α,β-unsaturated p-
nitrophenyl esters for the synthesis of tetrahydro-α-carbolinones was
developed. Using 5 mol % of the isothiourea HyperBTM as the
Lewis base catalyst, this process allows the enantioselective
preparation of a range of C(4)-substituted tetrahydro-α-carbolinones
in good to excellent yield and with high enantioselectivity (20
examples, 32−99% yield and up to 99:1 er).
of N-heterocycle that are frequently found in natural
compounds with diverse biological activities.3 Although a
range of methods for the construction of β- and γ-carbolinone
skeletons has been reported,4 limited synthetic routes to α-
carbolinones have been developed, with enantioselective
methods rare. For example, Zhou and coworkers developed a
sequential Michael addition/amidation/reductive cyclization
process using oxindole nucleophiles with Michael acceptors to
give tetrahydro-α-carbolinones in racemic form.5,6 Alterna-
tively, Li and coworkers demonstrated the enantioselective
synthesis of tetrahydro-α-carbolinones through an NHC-
catalyzed formal [4 + 2] cyclization of aza-dienes with an
azolium enolate derived from α-chloroaldehydes.7 Recently, Ye
and coworkers reported an elegant oxidative NHC-catalyzed
annulation of indolin-2-imines with in situ generation of α,β-
unsaturated acyl azolium intermediates for the preparation of
racemic tetrahydro-α-carbolinones bearing C(4)-aryl and
C(4)-alkyl groups (Figure 1B) that served as precedent for
this work.8
itrogen-containing heterocycles are important structural
Nmotifs prevalent in a diverse range of natural products
and medicinal agents. Their importance is readily quantified as
59% of United States FDA approved small-molecule drugs
contain a nitrogen heterocycle,1 with these heterocycles
commonly incorporated into molecules to improve phys-
icochemical properties.2 α-Carbolines and their tetrahydro-α-
carbolinone derivatives (Figure 1A) are a representative class
Isothioureas are versatile and powerful Lewis base catalysts
of broad synthetic utility9 and have been utilized for the in situ
generation of chiral α,β-unsaturated acyl ammonium species
for use in a range of reaction processes.10 In previous work, we
and others have harnessed this intermediate in Michael
addition and subsequent lactonization or lactamization
processes to generate carbo- and heterocycles.10a,f,l,m Building
upon these precedents, this manuscript showcases the use of
isothioureas for the enantioselective synthesis of tetrahydro-α-
carbolinones using indolin-2-imines and α,β-unsaturated esters
as starting materials (Figure 1C).
Received: December 23, 2019
Figure 1. Synthesis of tetrahydro-α-carbolinones.
https://dx.doi.org/10.1021/acs.orglett.9b04615
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Initial investigations studied the proposed annulation
between indolin-2-imine 2 and β-trifluoromethyl α,β-unsatu-
rated p-nitrophenyl (PNP) ester 1 using (2S,3R)-HyperBTM 3
(20 mol %) and an equivalent of iPr2NEt in THF at room
temperature. The desired C(4)-trifluoromethyl substituted
tetrahydro-α-carbolinone product 6 was afforded in 53%
yield with 98:2 er (Table 1, entry 1). Use of alternative
Scheme 1. Variation of the α,β-Unsaturated Aryl Ester
a
Table 1. Optimization of Reaction Conditions
b
c
entry
cat.
base
solvent
yield (%)
er (%)
1
2
3
4
5
6
7
8
3
4
5
3
3
3
3
3
3
3
3
3
3
3
iPr2NEt
iPr2NEt
iPr2NEt
Et3N
Na2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
−
THF
THF
THF
THF
THF
THF
toluene
CH2Cl2
dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
53
37
6
98:2
98:2
15:85
98:2
>99:1
>99:1
98:2
98:2
83:17
97:3
97:3
96:4
40
12
68
81
80
80
91
65
83
99
99
9
10
11
12
13
14
d
NaHCO3
NaHCO3
NaHCO3
de
,
97:3
97:3
a
de f
, ,
Isolated yield given; er determined by HPLC analysis on a chiral
b
a
stationary phase. Carried out in THF using (E)-cinnamic (isopropyl
carbonic) anhydride 17 and iPr2NEt.
Unless indicated otherwise, reactions were carried out in 1 mL of
solvent using 0.1 mmol of 1, 0.1 mmol of 2, and 0.1 mmol of base in
b
the presence of 20 mol % of catalysts 3−5 at rt. Isolated yield given.
c
Determined by HPLC analysis on a chiral stationary phase and given
esters gave the corresponding products 18−21 in good to
excellent yields and with high enantioselectivity. Notably,10g
challenging C(3)-aliphatic substituents that are typically
recalcitrant when using α,β-unsaturated PNP esters are also
tolerated, giving the desired products 22−24 in moderate yield
(38−59%) but with excellent enantioselectivity. While the
corresponding C(3)-phenyl-substituted ester provided 25 in
53% yield but poor 57:43 er, the use of the corresponding
isopropyl carbonic anhydride using iPr2NEt as base in THF
gave 25 in 40% yield and improved 88:12 er. Other C(3)-
substituted esters containing C(3)-ester and C(3)-amide
functional groups gave the corresponding products 26−27 in
good yield and good to excellent enantioselectivity.
Further work probed the scope of this transformation
through structural variation of the N-substituent and aryl
substitution pattern within the indolin-2-imine component
(Scheme 2). N-Benzyl substitution led to decreased yield over
the N-Me variant, giving 37 in 32% yield but excellent 96:4 er.
Aryl substituent variation proved more tolerant to steric and
electronic variation, with various indolin-2-imines incorporat-
ing both electron-withdrawing halogen or electron-donating
methyl substituents tolerated. Notably, the substitution pattern
has an interesting influence on the observed reactivity. 6-
Substituted indolin-2-imines gave the products 38−39, 42, and
d
e
as a ratio of (S):(R). 5 mol % of 3 used. 0.12 mmol of 2 used.
f
Carried out at 0 °C.
isothiourea catalysts (R)-BTM 4 and (S)-tetramisole hydro-
chloride 5 gave lower product conversion and yield, despite
promising enantioselectivity with BTM (entries 2−3). Further
optimization varied both base and solvent (entries 4−10).
Variation of base showed that NaHCO3 gave improved yield
and excellent er in THF. A screen of solvents showed that an
excellent 91% isolated yield of 6 with 97:3 er was observed in
acetonitrile (entry 10). Carrying out the reaction without
additional base provided a lower isolated yield (65%, entry 11).
Decreasing the catalyst loading to 5 mol % gave 6 in still
excellent yield and enantioselectivity (entry 12). Finally,
improved yield while maintaining high enantioselectivity was
observed (up to 99% yield and 97:3 er) when using a small
excess (1.2 equiv) of imine 2 at room temperature or at 0 °C
(entries 13 and 14).
Using the optimal reaction conditions, variation of the C(3)-
substituent within the α,β-unsaturated PNP ester to construct
C(4)-substituted tetrahydro-α-carbolinones was explored
(Scheme 1). C(3)-Chlorodifluoromethyl-, -bromodifluoro-
methyl-, -difluoromethyl-, and -perfluoroethyl-substituted
B
https://dx.doi.org/10.1021/acs.orglett.9b04615
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Letter
a
Scheme 2. Variation of Indolin-2-imine Component
Scheme 3. Gram-Scale Experiment and Derivatizations
a
Isolated yield given; er was determined by HPLC analysis on a chiral
stationary phase.
44 in good 72−76% yield with 95:5−99:1 er. In contrast,
incorporation of substituents into the 4-, 5-, or 7-position of
the indolin-2-imine substrate led to the corresponding
products 40, 41, 43, and 45 in moderate 37−54% yield but
with good enantioselectivity (up to 98:2 er).
The scalability of this process was demonstrated by
performing the reaction of indolin-2-imine 2 with β-
trifluoromethyl α,β-unsaturated PNP ester 1 on a gram scale,
giving 6 in excellent 87% yield and 97:3 er (Scheme 3A). To
further demonstrate the utility of the α-carbolinone products, 6
was derivatized to a range of compounds (Scheme 3B).
Treatment of 6 with Mg/methanol gave ring-opened product
46 in 99% yield and 97:3 er.8 Oxidation of 6 with m-CPBA
gave the corresponding epoxide in situ with subsequent
rearrangement yielding spirolactone 47 as a single diaster-
eoisomer in moderate isolated yield but high er. The absolute
configuration of 47 was determined by single crystal X-ray
diffraction, which also served to assign the absolute
configuration at C(4) within 6, with all other α-carbolinone
products assigned by analogy.11 Alternatively, sequential
reduction with LiAlH4 and triethylsilane gave tetrahydropryr-
anoindole 48 in 68% yield and 97:3 er,7 while dehydrogenation
of 6 was also readily achieved with Pd/C, giving 49 in 57%
yield.8
Figure 2. Proposed mechanism.
enolate 52. Subsequent proton transfer gives zwitterion 53.
Finally, lactamization yields the product 6 and regenerates the
isothiourea HyperBTM 3. The stereochemical outcome of the
reaction can be rationalized by the α,β-unsaturated acyl
isothiouronium 50 adopting an s-cis conformation with a 1,5-
S···O interaction between the acyl O and catalyst S providing a
conformational lock.12 Enantioselective conjugate addition of
the enamine anion to the α,β-unsaturated acyl isothiouronium
50 takes place anti- to the stereodirecting pseudoaxial phenyl
substituent of the acylated HyperBTM isothiourea catalyst and
determines the configuration at C(4) within the products.
In conclusion, an isothiourea-catalyzed enantioselective
annulation protocol of indolin-2-imines with a series of α,β-
unsaturated p-nitrophenyl esters for the synthesis of tetrahy-
dro-α-carbolinones was developed. Using 5 mol % of
isothiourea HyperBTM 3, this protocol allows the enantiose-
lective preparation of a range of C(4)-substituted tetrahydro-α-
Based upon our previous mechanistic investigations in this
area, a simple catalytic cycle is proposed (Figure 2).10a
Catalysis is initiated through rapid and reversible acylation of
HyperBTM 3 by the α,β-unsaturated ester 1 to give α,β-
unsaturated acyl isothiouronium ion pair 50. The addition of
enamine anion 51, generated from indoline-2-imine 2, to the
α,β-unsaturated acyl isothiouronium 50 gives isothiouronium
C
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carbolinones in moderate to excellent yield and with excellent
enantioselectivity (20 examples, 32−99% yield and up to 99:1
er). The scope of the process was demonstrated through
variation in C(3) substitution within the α,β-unsaturated p-
nitrophenyl ester as well as the N-substituent and aryl
substitution pattern within the indolin-2-imine component.
Further investigations from within our laboratory are
concerned with alternative applications of isothioureas and
harnessing the utility of α,β-unsaturated acyl ammonium
intermediates.13
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04615.
Experimental details, compound characterization, NMR
spectra, and HPLC traces (PDF)
Accession Codes
CCDC 1973369 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Andrew D. Smith − EaStCHEM, School of Chemistry,
University of St Andrews, St Andrews, Fife KY16 9ST, U.K.;
orcid.org/0000-0002-2104-7313; Email: ads10@st-
andrews.ac.uk
Authors
Honglei Liu − EaStCHEM, School of Chemistry, University of
St Andrews, St Andrews, Fife KY16 9ST, U.K.
Alexandra M. Z. Slawin − EaStCHEM, School of Chemistry,
University of St Andrews, St Andrews, Fife KY16 9ST, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04615
Author Contributions
The manuscript was written by H.L. and A.D.S. All authors
have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research leading to these results was funded by the Royal
Society (Newton Fellowship Programme, H.L.). A.D.S. thanks
the Royal Society for a Wolfson Research Merit Award.
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D. Angew. Chem., Int. Ed. 2020 DOI: 10.1002/anie.201914421. Also
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chalcogen-bonding interactions see: (h) Pascoe, D. J.; Ling, K. B.;
Cockroft, S. L. J. Am. Chem. Soc. 2017, 139, 15160.
(13) The research data underpinning this publication can be found
at DOI: DOI: 10.17630/46afe239-6329-434e-b590-f53fe3f7de66.
E
https://dx.doi.org/10.1021/acs.orglett.9b04615
Org. Lett. XXXX, XXX, XXX−XXX