Synthesis of hexahydroindole carboxylic acids by intramolecular Diels-Alder reaction

Article abstract of DOI:10.1055/s-2008-1032085

By applying an intramolecular Diels-Alder reaction highly functionalized Δ^6,7-hexahydroindoles were prepared in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032085

LETTER
589
Synthesis of Hexahydroindole Carboxylic Acids by Intramolecular
Diels–Alder Reaction
Synthesis of
H
exah
n
ydroindole
n
A
e
cids Friedrich, Manuel Jainta, Carl F. Nising, Stefan Bräse*
Institute of Organic Chemistry, University of Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)608858; E-mail: braese@ioc.uka.de
Received 23 November 2007
This method has been used for the construction of various
natural products. However, during the course of our study,
we realized that hexahydroindoles can be prepared in an
even more straightforward way using an intramolecular
Diels–Alder reaction.6 A similar approach for the synthe-
sis of octahydroquinolines had already been developed by
Oppolzer et al.7
Abstract: By applying an intramolecular Diels–Alder reaction
highly functionalized D6,7-hexahydroindoles were prepared in good
yields.
Key words: Diels–Alder reactions, heterocycles, rostratins,
hexahydroindoles
Octahydroindoles represent a common scaffold in many
natural products (Figure 1). Rostratins A–D were isolated
from the whole broth of the marine-derived fungus Exse-
rohilum rostratum, a fungal strain found associated with a
marine cyanobacterial mat [Figure 1, rostratin C (1)]. The
highly symmetrical cyclic diketopiperazine disulfides
show in vitro cytotoxicity against human colon carcinoma
(HCT-116) with an IC50 value of 0.76 mg/mL.1 The struc-
tural motif of octahydroindoles can also be found in a cou-
ple of other natural products. Prominent examples are
tuberostemonine or trandolapril (2; Figure 1).2
O
H
O
OH
dimerization
H
S
N
OMe
MeO
N
S
H
OH
O
H
O
rostratin C (1)
CO2Me
O
H
H
O
CO2R
N
R
N
OH
HO
H
Me
O
H
H
OH
4
3
O
Scheme 1 Retrosynthetic analysis of rostratin C (1)
O
H
NH
N
O
OH
O
The required precursor to 11–17, compound rac-10, was
prepared in five steps as depicted in Scheme 2. The as-
sembly of the amino acid8 rac-8 was followed by the con-
densation of hydrochloride rac-9 with crotonaldehyde to
receive the somewhat unstable imine in excellent yield. In
the course of our studies, it turned out that in situ genera-
tion of the free amine and condensation with the aldehyde
in the presence of molecular sieves was the best way to
prepare imine rac-10 (E-isomer) since this compound
could only be stored for a short period without decompo-
sition.
H
H
Me
S
O
N
OMe
MeO
N
S
H
H
H
O
OH
O
OH
rostratin C (1)
trandolapril (2)
Figure 1 Structures of some naturally occurring octahydroindoles:
rostratin C (1) and trandolapril (2)
Due to their interesting structure and the prominent bio-
logical activity, we became interested in the total synthe-
sis of these compounds.3 The overall retrosynthetic
analysis of rostratin C (1) is shown in Scheme 1. After re-
moval of the disulfide bridge, the highly symmetric dike-
topiperazine can easily be divided into two identical D6,7-
hexahydroindoles 4. Therefore we started a program di-
rected towards the synthesis of highly functionalized
hexahydroindoles. Hexahydroindoles have been prepared
by Wipf et al. starting from tyrosine or its derivatives.4,5
With imine 10 in hand, we focused on incorporating a
number of protecting groups in order to allow orthogonal
deprotection on a later stage, transferring the imine into a
butadienyl amine (Scheme 3). After considerable experi-
mentation with a large number of carboxylic acid deriva-
tives and bases, we found that N,N-diethylaniline was the
base of choice and only acid chlorides were suitable elec-
trophiles. Using these conditions, the Diels–Alder precur-
sors rac-11–17 were prepared in good to excellent yields9
and with complete E-stereochemistry (Scheme 3).
SYNLETT 2008, No. 4, pp 0589–0591
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032083; Art ID: G39507ST
© Georg Thieme Verlag Stuttgart · New York
Starting with these protected enamines, we explored the
intramolecular Diels–Alder reaction. After prolonged

590
A. Friedrich et al.
LETTER
Bu4NHSO4,
CH2Cl2,
10% NaOH
Table 1 Synthesis of Hexahydroindoles rac-18–21 (Pressure Ves-
sel)
CPh2
N
CPh2
N
EtO2C
Br
+
Yield (%)a
r.t., 4.5 h
91%
R
Time (d) T (°C)
EtO2C
CO2Et
CO2Et
7
5
6
18
19
20
21
p-BrC6H4CO
ClCH2CO
Cbz
9
9
6
6
210
190
210
130
57
53
62
51
1) KOH, EtOH,
reflux, 1 h
2) 15% citric acid ,
THF, r.t., 1 h
NH2
CO2H
SOCl2, MeOH
HO2C
COOMe
42%
r.t., 88 h
>99%
a Yield after column chromatography.
8
NOE
Me
MeO2C
H
Me
O
H
NH2·HCl
Et3N
NOE
CO2Me
N
MeO2C
CO2Me
N
CH2Cl2, r.t.
MeO2C
H
R
O
CO2Me
15 h
94%
9
10
Figure 2 Diagnostic NOE correlations for D6,7-hexahydroindoles
rac-18–21
Scheme 2 Synthesis of Diels–Alder precursor rac-109
Me
modified to access different stereoisomers. The use of
enantiomeric precursors offers an asymmetric access to
functionalized hexahydroindole systems.12 Further stud-
ies directed towards the total synthesis of 1 and other
rostratins13 as well as an evaluation of their biological ac-
tivity are ongoing and will be reported in due course.
RCl, PhNEt2
toluene
R
N
N
MeO2C
0 °C, 12 h
MeO2C
CO2Me
CO2Me
10
96% (11)
p-BrC6H4CO 86% (12)
R = Cbz
Acknowledgment
CO2Me
COCH2Cl
COCHCl2
COi-Pr
59% (13)
57% (14)
40% (15)
61% (16)
45% (17)
Financial support from the Landesgraduiertenförderung Baden-
Württemberg (fellowship for A. Friedrich) and the Scheringstiftung
(fellowship for C. Nising) is gratefully acknowledged.
Alloc
Scheme 3 Synthesis of Diels–Alder precursors rac-11–17
References and Notes
heating of the starting material in toluene [30 mM] in the
presence of N,O-bistrimethylsilylacetamide (BSA),10 the
D6,7-hexahydroindoles were obtained in good yields
(Scheme 4 and Table 1) and excellent stereoselectivity.11
According to NMR and TLC analyses of the reaction mix-
ture only one diastereomer was formed in the Diels–Alder
reaction. The structure of compounds 18–21 was unequiv-
ocally confirmed by NMR NOESY experiments
(Figure 2).
(1) Tan, R. X.; Jensen, P. R.; Williams, P.; Fenical, W. G. J. Nat.
Prod. 2004, 67, 1374.
(2) Wiseman, L. R.; McTavish, D. Drugs 1994, 48, 71.
(3) For an independent synthetic study, see: Liu, Z.; Rainier, J.
D. Org. Lett. 2006, 8, 459.
(4) Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995,
117, 11106.
(5) Wipf, P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225.
(6) (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. E. Angew. Chem. Int. Ed. 2002, 41,
1668. (b) Stocking, E. M.; Williams, R. M. Angew. Chem.
Int. Ed. 2003, 43, 3078. (c) Takao, K.; Munakata, R.;
Tadano, K. Chem. Rev. 2005, 105, 4779.
CO2Me
(7) (a) Oppolzer, W.; Flaskamp, E. Helv. Chim. Acta 1977, 60,
204. (b) Oppolzer, W.; Fröstl, W. Helv. Chim. Acta 1975, 58,
590. (c) Oppolzer, W.; Flaskamp, E.; Bieber, L. W. Helv.
Chim. Acta 2004, 840, 141.
(8) (a) Allan, R. D. J. Chem. Res., Synop. 1980, 392. (b) Allan,
R. D.; Duke, R. K.; Hambley, T. W.; Johnston, G. A. R.;
Mewett, K. N.; Quickert, N.; Tran, H. W. Aust. J. Chem.
1996, 49, 785. (c) O’Donnell, M. J.; Boniece, J. M.; Earp, S.
E. Tetrahedron Lett. 1978, 2641.
H
BSA
toluene
R
N
CO2Me
MeO2C
see Table 2
N
CO2Me
H
R
rac-11–14
rac-18–21
Scheme 4 Preparation of D6,7-hexahydroindoles rac-18–21
(9) Solvents and chemicals used for reactions were purchased
from commercial suppliers. Solvents were dried under
standard conditions and chemicals were used without further
purification. All reactions were carried out under Ar in
In summary, we have developed a straightforward con-
cept for the construction of the 2,4-difunctional hexahy-
droindole ring system. The overall approach can easily be
Synlett 2008, No. 4, 589–591 © Thieme Stuttgart · New York

LETTER
flame-dried glassware. Evaporation of solvents and
Synthesis of Hexahydroindole Carboxylic Acids
591
the filtrate was concentrated. The residue was purified by
column chromatography.
Dimethyl 5-[N-Buta-1,3-dienyl(methoxy-
concentration of reaction mixtures were performed in vacuo
at 40 °C on a Büchi rotary evaporator. TLC was carried out
on silica gel plates (Kieselgel 60, F254, Merck) with
detection by UV and visualization by spraying with the
Seebach solution. Normal-phase silica gel (Silica gel 60,
230–400 mesh, Merck) was used for preparative
chromatography. Melting points were determined on a
Laboratory Devices Inc. Mel-Temp II instrument and are
uncorrected. IR spectra were recorded on a Bruker IFS88
spectrometer. Absorption is reported as n values in cm–1. 1H
NMR and 13C NMR spectra were recorded at 346
K(rotamers) on a Bruker-AC-250, AM-400 or DRX 500
spectrometer. Chemical shifts are reported as d values (ppm)
downfield from internal TMS in the indicated solvent.
Coupling constants (J) are given in Hz; s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad,
p = primary C. High-resolution mass spectra (HRMS) were
determined on a Finnigan MAT90 instrument. The apparatus
used for elemental analysis was Heraeus CHN-O-Rapid.
Dimethyl 5-[(E)-Buta-1,3-dienyl]aminohex-2-
enedicarboxylate (10): In a round-bottomed flask with
rubber septum hydrochloride 9 (4.13 g, 18.5 mmol) and Et3N
(2.60 mL, 1.87 g, 18.5 mmol) were dissolved in CH2Cl2 (200
mL) and stirred at r.t. for 3 h. The mixture was filtered and
the filtrate was concentrated under reduced pressure. The
residue was diluted with Et2O (150 mL), filtrated and the
filtrate was concentrated. The residue was dissolved in
CH2Cl2 (50 mL) and crotonaldehyde (1.34 mL, 1.16 g, 16.61
mmol) as well as molecular sieves (7.00 g) were added.
After stirring at r.t. for 15 h the mixture was filtered and the
filtrate was concentrated to give 10 as a pale yellow oil
which was used without further purification.
IR (neat): 3434, 2999, 2953, 2850, 1726, 1656, 1620, 1437,
1378, 1273, 1201, 1175, 1103, 1039, 985, 722 cm–1. 1H
NMR (500 MHz, CDCl3): d = 1.90 (d, J = 5.1 Hz, 3 H, Me),
2.63–2.70 (m, 1 H, CH2), 2.77–2.83 (m, 1 H, CH2), 3.68 (s,
3 H, OMe), 3.70 (s, 3 H, OMe), 3.86 (dd, J = 5.4, 8.0 Hz, 1
H, CH), 5.85 (d, J = 15.4 Hz, 1 H, H-A), 6.25–6.27 (m, 2 H,
H-2, H-3), 6.78 (dd, J = 7.4, 15.4 Hz, 1 H, H-B), 7.78 (d, J =
8.0 Hz, 1 H, H-1). 13C NMR (125 MHz, CDCl3): d = 18.6
(Me), 36.1 (CH2), 51.5 (OMe), 52.4 (OMe), 71.6 (CH),
124.0 (C-A) 132.4 (C-2), 143.4 (C-3), 144.0 (C-B), 166.0
(C-1), 166.5 (C=O), 171.4 (C=O). MS (EI, 70 eV): m/z
(%) = 239 (8) [M]+, 180 (100), 140 (31), 80 (46). HRMS:
m/z calcd for C12H17NO4: 239.1158; found: 239.1160.
General Procedure for the Synthesis of Enamines 11–17:
Imine 10 was dissolved in toluene (10 mL/mmol) and added
dropwise to a flask containing diethylaniline (1.50 equiv)
and the acid chloride (1.20 equiv) at 0 °C. The reaction
mixture was warmed to r.t. and stirred overnight. The
resulting precipitate was filtered off, washed with Et2O and
carbonyl)amino]hex-2-enedicarboxylate (13): IR (neat):
3621, 3453, 3088, 2954, 2850, 1736, 1647, 1606, 1544,
1441, 1384, 1220, 895, 854, 771, 724, 653, 607 cm–1. 1H
NMR (500 MHz, CDCl3): d = 2.77–2.94 (m, 1 H, CH2),
3.01–3.06 (m, 1 H, CH2), 3.71 (s, 3 H, OMe), 3.74 (s, 3 H,
OMe), 3.79 (s, 3 H, OMe), 4.74 (br s, 1 H, CH), 4.92 (d, J =
10.2 Hz, 1 H, H-4), 5.08 (d, J = 16.9 Hz, 1 H, H-5), 5.49–
5.56 (m, 1 H, H-2), 5.88 (d, J = 15.6 Hz, 1 H, H-A), 6.22–
6.29 (m, 1 H, H-3), 6.86 (ddd, J = 7.6, 7.6, 15.2 Hz, 1 H, H-
B), 6.88–7.04 (m, 1 H, H-1). 13C NMR (125 MHz, CDCl3):
d = 31.3 (CH2), 51.5 (OMe), 52.8 (OMe), 52.8 (OMe), 56.4
(CH), 112.8 (C-2), 114.7 (C-4), 124.0 (C-A), 129.5 (C-1),
134.6 (C-3), 143.6 (C-1), 154.0 (C=O), 166.4 (C=O), 169.9
(C=O). MS (EI, 70 eV): m/z (%) = 297 (100) [M]+, 266 (29)
[M – OMe]+, 238 (63) [M – CO2Me]+, 111 (75). HRMS:
m/z calcd for C14H19NO6: 297.1210; found: 297.1210.
General Procedure for the Diels–Alder Cyclization: In a
pressure vessel the enamine (1 mmol) was dissolved in
toluene (10 mL) and N,O-bistrimethylsilylacetamide (1
mmol) was added. The reaction mixture was heated at 130–
210 °C for 6–9 d. After cooling to r.t, the solvent was
evaporated and the crude product was purified by column
chromatography.
Trimethyl 2,3,3a,4,5,7a-Hexahydroindole-1,2,4-
tricarboxylate (21): IR (neat): 3496, 2954, 2852, 1734,
1703, 1451, 1384, 1304, 1240, 1197, 1176, 1116, 1083,
1015, 877, 774, 690 cm–1. 1H NMR (500 MHz, DMSO-d6,
346 K): d = 1.74–1.82 (m, 1 H, H-3), 2.26 (br s, 2 H, H-3, H-
5), 2.34–2.41 (m, 1 H, H-5), 2.67–2.80 (m, 2 H, H-3a, H-4),
3.61 (s, 3 H, OMe), 3.64 (s, 6 H, OMe), 4.29–4.33 (m, 2 H,
H-2, H-7a), 5.67–5.69 (m, 1 H, H-6), 5.76–5.78 (m, 1 H, H-
7). 13C NMR (125 MHz, DMSO-d6, 346 K): d = 22.5 (s, C-
5), 36.2 (s, C-3), 36.2 (t, C-3a), 38.1 (t, C-4), 51.1 (p, OMe),
51.2 (p, OMe), 51.6 (p, OMe), 54.0 (t, C-2), 57.6 (t, C-7a),
124.6 (t, C-6), 125.4 (t, C-7), 154.2 (q, C=O), 171.8 (q,
C=O), 173.6 (q, C=O). MS (EI, 70 eV): m/z (%) = 297 (6)
[M]+, 266 (5) [M – OMe]+, 238 (100) [M – CO2Me]+, 179 (3)
[M – 2 × CO2Me]+. HRMS: m/z calcd for C14H19NO6:
279.1212; found: 279.1211. Anal. Calcd for C14H19NO6: C,
56.56; H, 6.44; N, 4.71. Found: C, 56.54; H, 6.54; N, 4.88.
(10) El-Khawaga, A. M.; Hoffmann, H. M. R. J. Prakt. Chem.
1995, 337, 332.
(11) Diels–Alder cyclization of enamines 15–17 was
unsuccessful due to poor solubility in various solvents.
(12) Park, H.-G.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-
K.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-S. Angew. Chem. Int. Ed.
2002, 41, 3036; Angew. Chem. 2002, 114, 3162.
(13) For a model dimer, see: Friedrich, A.; Jainta, M.; Nieger, M.;
Bräse, S. Synlett 2007, 2127.
Synlett 2008, No. 4, 589–591 © Thieme Stuttgart · New York

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