Catalytic Enantioselective Synthesis of Tetrahydocarbazoles and Exocyclic Pictet-Spengler-Type Reactions

Article abstract of DOI:10.1021/acs.orglett.6b02718

A synthetic strategy for the synthesis of chiral tetrahydrocarbazoles (THCAs) has been developed. The strategy relies on two types of 6-exo-trig cyclization of 3-substituted indole substrates. Enantioselective domino Friedel-Crafts-type reactions leading to THCAs can be catalyzed by chiral phosphoric acid derivatives (with up to >99% ee), and the first examples of exocyclic Pictet-Spengler reactions to form THCAs are reported.

Full text of DOI:10.1021/acs.orglett.6b02718

Letter
pubs.acs.org/OrgLett
Catalytic Enantioselective Synthesis of Tetrahydocarbazoles and
Exocyclic Pictet−Spengler-Type Reactions
Casper L. Hansen,† Ragnhild G. Ohm,† Lasse B. Olsen,† Erhad Ascic,† David Tanner,†
and Thomas E. Nielsen*,†,‡
†Department of Chemistry, Technical University of Denmark, DK-2800 Kgs Lyngby, Denmark
‡Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551, Singapore
S
* Supporting Information
ABSTRACT: A synthetic strategy for the synthesis of chiral tetrahydrocarbazoles
(THCAs) has been developed. The strategy relies on two types of 6-exo-trig
cyclization of 3-substituted indole substrates. Enantioselective domino Friedel−
Crafts-type reactions leading to THCAs can be catalyzed by chiral phosphoric acid
derivatives (with up to >99% ee), and the first examples of exocyclic Pictet−Spengler
reactions to form THCAs are reported.
he classical Pictet−Spengler reaction, in which an amine is
condensed with an aldehyde to form a six-membered N-
heterocycle via an iminium intermediate (Figure 1 path a, 6-
presence of external nucleophiles (type 2), including the
exocyclic Pictet−Spengler reaction. Furthermore, we reasoned
that it should be possible to convert 2 to 3 by reaction with
external nucleophiles, and we envisioned enantioselective
versions of all these processes.6
T
Initial investigations focused on the type 1 conversion of 4 to
THCA 5, but surprisingly, formation of compound 6 (Scheme
2, see also the Supporting Information for a full account of
Scheme 2. Cyclization of Aldehyde 4
Figure 1. Classical Pictet−Spengler reaction (path a) and the exocyclic
Pictet−Spenger reaction (path b).
endo-trig) is a robust and well-established process.1−3 However,
to our knowledge, an exocyclic version of this reaction has not
yet been reported to give the pharmaceutically interesting
indole-containing tetrahydrocarbazole (THCA) skeleton (Fig-
ure 1, path b, 6-exo-trig),4 probably due to the instability of the
starting aldehyde.5
This paper describes the development of exocyclic Pictet−
Spengler reactions and related cyclizations, including a highly
enantioselective route to 1-substituted THCAs. Our overall
plan was to trigger two types of 6-exo cyclization using the same
starting aldehyde (1) (Scheme 1): direct cyclization providing
hydroxyl-containing THCAs (2) (type 1) and cyclization in the
reaction optimization) was observed in most cases. Generally,
strong Brønsted and Lewis acids provided 6; however, the use
of formic acid in acetonitrile/water (1:1) provided a clean
conversion to the desired THCA 5 in excellent yield (93%,
Scheme 3).
Compound 6 could be obtained in reasonably good yield
when 4 was treated with trifluoroacetic acid (TFA) (59%,
Scheme 3). The formation of 6 is accompanied by the
formation of three stereocenters, of which two are formed in a
highly diastereoselective fashion (as evidenced by the crystal
structure of 8, Scheme 4). As an indication of the reactivity of 4,
the formation of 5 and 6 was observed simply upon storage of
the aldehyde at ambient temperature.
Scheme 1. Strategy for the Synthesis of THCAs
To confirm the structure of 6, the imine was reduced to the
corresponding amine (Scheme 4). However, nuclear magnetic
resonance (NMR) analysis indicated occurrence of an addi-
Received: September 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02718
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
phosphate, and the desired THCA 11 was isolated in excellent
yield (92%).
Scheme 3. Selective Cyclizations of Aldehyde 4
Careful monitoring of these reactions via both thin-layer
chromatography (TLC) and liquid chromatography−mass
spectrometry (LC−MS) indicated that the cyclization did
indeed occur first, followed by external nucleophilic attack, in a
domino Friedel−Crafts type of process.7,8 Furthermore, alcohol
5 could be converted to 11 upon reaction with indole and
diphenyl phosphate in CH2Cl2 in 80% yield (Scheme 7), thus
validating the overall strategy outlined in Scheme 1.
Scheme 7. Conversion of a Type 1 Product into a Type 2
Product
Scheme 4. Validation of the Structure of 6 and Crystal
Structure of 8
We then addressed the question of enantioselectivity by
using chiral phosphoric acids9,10 to catalyze the type 2
cyclization. After preliminary screening experiments, reaction
conditions were optimized for the use of (R)-3,3′-bis(2,4,6-
triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phos-
phate ((R)-TRIP) in CH2Cl2 at −50 °C.11 When aldehyde 4
was exposed to a range of external nucleophiles, the desired
products were obtained only with electron-rich heterocycles
and thiols (Scheme 8). Attempted reactions with poorer carbon
nucleophiles such as furan and trimethoxybenzene, as well as
with alcohols, gave no conversion to the desired products. As
shown in Scheme 8 (13a−j), the substitution pattern and the
steric bulk of the external indole nucleophile had considerable
impact on both the yields (35−74%) and the enantioselectivity
(11−94% ee). For example, the highest enantioselectivity (94%
ee) was obtained using 2-tert-butylindole, which can be
compared with the 2-methyl analogue (25% ee), the isolated
yields being comparable (Scheme 8, 13b−c). The substituent
pattern of the aldehyde (9b, 12a−d) also proved highly
important, as the products 13k−o were isolated in moderate to
excellent yields (35−94%, generally >78%) and with low to
moderately high ee (6−78%, Scheme 8).
tional reaction, involving the indole nitrogen, giving compound
7 in 80% yield. The structure of 7 was confirmed after acylation
with 3,5-dinitrobenzoyl chloride to give 8 as a single
diastereomer. The crystal structure of 8 is shown in Scheme 4.
Not unexpectedly, the ease of the type 1 cyclization was very
dependent on the electronic properties of the indole (Scheme
5). The electron-rich indoles 9a and 9b gave the desired
Scheme 5. Type 1 Cyclization to THCAs
Returning to reactions of aldehyde 4, reactions of some other
nucleophilic heterocycles and thiols gave good to excellent
yields (up to 95%) but generally low enantioselectivity (46% ee
at best).
Encouraged by the excellent enantioselectivity provided by 2-
tert-butylindole, we explored the possibility of using the
removable trimethylsilyl (TMS) group in the 2-position of
the indole nucleophile (Table 1). When aldehyde 4 was
exposed to a range of readily available 2-TMS-indoles (14a−f),
followed by removal of the TMS group, the desired products
(15a−f) were generally isolated in excellent enantiopurity (95
to >99% ee) and moderate to good yields (33−70%, Table 1,
entries 1−4).
products (10a and 10b) in superb yields (91−95%), while for
the less nucleophilic 9c no conversion was observed, even at
elevated temperatures. Notably, when the aldehyde function-
ality was changed to a ketone, no conversion was observed for
any of the substrates.
The formation of compound 6 indicated that a type 2
reaction (cf. Figure 1) should also be possible (Scheme 6).
Aldehyde 4 was therefore reacted with indole as external
nucleophile in the present of catalytic amounts of diphenyl
Finally, we turned our attention to the long-sought exocyclic
Pictet−Spengler reaction, for which a new optimization study
proved to be necessary.10 As shown in Table 2, a variety of
functional groups are tolerated, and yields are generally
acceptable. Unfortunately, reactions catalyzed by (R)-TRIP
gave only low enantioselectivity (<10% ee), and a synthetically
useful asymmetric version of the exocyclic Pictet−Spengler
reaction remains elusive.
Scheme 6. Type 2 Cyclization to THCAs
B
DOI: 10.1021/acs.orglett.6b02718
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 8. Enantioselective Synthesis of THCAs via Domino Type 2 Cyclization/Friedel−Crafts-Type Reactions
Crafts-type reactions leading to THCAs can be catalyzed by
chiral phosphoric acid derivatives (with up to >99% ee), and
the first examples of exocyclic Pictet−Spengler reactions are
also described.
Table 1. Enantioselective Synthesis of THCAs Using 2-TMS-
indoles
ASSOCIATED CONTENT
* Supporting Information
■
S
a
b
entry
indole
R
product, yield (%)
ee (%)
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02718.
c
1
14a
14b
14c
14d
14e
14f
H
15a, 52
15b, 70
15c, 33
15d, 43
15e, 47
>99
97
97
95
77
22
2
3
4
5
6
5-OBn
5-Cl
Experimental details, procedures, and characterization of
all compounds (PDF)
5-CF3
5-OCF3
6-CO2Me
15f, 12
a
b
AUTHOR INFORMATION
Corresponding Author
Isolated yield after flash column chromatography. Determined by
■
c
chiral NP-HPLC. Reaction temperature −20 °C.
*E-mail: ten@sund.ku.dk.
Notes
Table 2. Exocyclic Pictet−Spengler Reactions
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Technical University of Denmark, the Lundbeck
Foundation, and the DSF Center for Antimicrobial Research
(CAR) are gratefully acknowledged for financial support.
time
(h)
product,
a
entry substrate
R1
R2
R3
yield (%)
1
2
3
4
5
6
7
8
9
4
H
Bn
Bn
Bn
Bn
Ph
Ph
Bn
Bn
20
20
20
2
16a, 61
16b, 62
16c, 53
16d, 77
16e, 15
16f, 76
16g, 24
16h, 43
16i, 61
4
H
allyl
REFERENCES
4
H
CH2CH2OTBS
■
(1) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030−
2036.
4
H
CH2CO2Et
4
H
Et
2
(2) For selected reviews on the Pictet−Spengler reaction, see:
4
H
H
20
20
74
48
(a) Stockigt, J.; Antonchick, A. P.; Wu, F.; Waldmann, H. Angew.
̈
12b
12d
12d
4-Br
Bn
Me
Bn
Chem., Int. Ed. 2011, 50, 8538−8564. (b) Cox, E. D.; Cook, J. M.
Chem. Rev. 1995, 95, 1797−1842. (c) Nielsen, T. E.; Diness, F.;
Meldal, M. Curr. Opin. Drug. Discovery Devel. 2003, 6, 801−814.
(d) Laine, A. E.; Lood, C.; Koskinen, A. M. P. Molecules 2014, 19,
1544−1567.
7-Me Bn
7-Me Bn
a
Isolated yield after flash column chromatography.
(3) For reviews on iminium ion cyclization, see: Maryanoff, B. E.;
Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev.
2004, 104, 1431−1628. (b) Royer, J.; Bonin, M.; Micouin, L. Chem.
Rev. 2004, 104, 2311−2352. (c) Speckamp, W. N.; Moolenaar, M. J.
In conclusion, we have developed a synthetic strategy for the
synthesis of chiral tetrahydrocarbazoles (THCAs) which relies
on 6-exo-trig cyclizations. Enantioselective domino Friedel−
C
DOI: 10.1021/acs.orglett.6b02718
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Tetrahedron 2000, 56, 3817−3856. (d) Le Quement, S. T.; Petersen,
R.; Meldal, M.; Nielsen, T. E. Biopolymers 2010, 94, 242−256.
(4) For selected reviews on THCAs, see: (a) Bergman, J.; Pelcman,
B. Pure Appl. Chem. 1990, 62, 1967−1976. (b) Knolker, H.-J.; Reddy,
̈
K. R. Chem. Rev. 2002, 102, 4303−4427. (c) Schmidt, A. W.; Reddy,
K. R.; Knolker, H.-J. Chem. Rev. 2012, 112, 3193−3328.
̈
(5) Blair, L. M.; Sperry, J. Synlett 2013, 24, 1931−1936.
(6) For noteworthy examples of catalytic enantioselective Pictet−
Spengler reactions, see: (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem.
Soc. 2004, 126, 10558−10559. (b) Seayad, J.; Seayad, A. M.; List, B. J.
Am. Chem. Soc. 2006, 128, 1086−1087. (c) Wanner, M. J.; van der
Haas, R. N. S.; de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H.
Angew. Chem., Int. Ed. 2007, 46, 7485−7847.
(7) Tietze, L. F. Chem. Rev. 1996, 96, 115−136.
(8) For selected reviews on the Friedel−Crafts reaction, see:
(a) Sartori, G.; Maggi, R. Chem. Rev. 2006, 106, 1077−1104.
(b) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903−
2915. (c) Rueping, M.; Nachtsheim, B. J. Beilstein J. Org. Chem. 2010,
6, 6−29.
(9) For selected reviews on chiral phosphoric acids, see: (a) Akiyama,
T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999−1010.
(b) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190−
2201. (c) Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Org.
Biomol. Chem. 2010, 8, 5262−5276. (d) Schenker, S.; Zamfir, A.;
Freund, M.; Tsogoeva, S. B. Eur. J. Org. Chem. 2011, 2011, 2209−
2222.
(10) For recent examples of use of chiral phosphoric acids in the
Friedel−Crafts reaction, see: (a) Uraguchi, D.; Sorimachi, K.; Terada,
M. J. Am. Chem. Soc. 2004, 126, 11804−11805. (b) Wang, Y.-Q.; Song,
J.; Hong, R.; Li, H.; Deng, L. J. J. Am. Chem. Soc. 2006, 128, 8156−
8157. (c) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L.
Angew. Chem., Int. Ed. 2007, 46, 5565−5567. (d) Zhuo, M.-H.; Jiang,
Y.-J.; Fan, Y.-S.; Gao, Y.; Liu, S.; Zhang, S. Org. Lett. 2014, 16, 1096−
1099.
(11) See the SI for details.
D
DOI: 10.1021/acs.orglett.6b02718
Org. Lett. XXXX, XXX, XXX−XXX