Asymmetric aza-Diels-Alder reactions of indole 2-carboxaldehydes

Article abstract of DOI:10.1016/S0040-4039(01)02070-6

The aza-Diels-Alder reaction of substituted indole 2-carboxaldehydes with Danishefsky's diene has been investigated. The reaction proceeds with a high degree of diastereoselectivity providing highly functionalized 2-(2-piperidyl)indoles which are further elaborated into novel polycyclic heterocycles.

Full text of DOI:10.1016/S0040-4039(01)02070-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 29–32
Asymmetric aza-Diels–Alder reactions of indole
2-carboxaldehydes
Jeffrey T. Kuethe,* Ian W. Davies, Peter G. Dormer, Robert A. Reamer, David J. Mathre and
Paul J. Reider
Department of Process Research, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 7 September 2001; revised 26 October 2001; accepted 29 October 2001
Abstract—The aza-Diels–Alder reaction of substituted indole 2-carboxaldehydes with Danishefsky’s diene has been investigated.
The reaction proceeds with a high degree of diastereoselectivity providing highly functionalized 2-(2-piperidyl)indoles which are
further elaborated into novel polycyclic heterocycles. © 2001 Elsevier Science Ltd. All rights reserved.
The aza-Diels–Alder reaction has emerged in recent
years as a highly efficient method for the construction
of nitrogen heterocycles.1,2 Most notable successes have
been achieved by reaction of aliphatic and aromatic
imines with Danishefsky’s diene 2 in the presence of a
Lewis acid.1,2 Diastereoselectivities of these reactions
have been investigated with imines derived from carbo-
hydrates,3 amino acids,2b and a-alkoxyimines4. Enan-
tioselective methods employing chiral Lewis acids have
also emerged.5
either enantiomeric form. Attempts to form the imine
of indole carboxaldehyde 58 in situ in the presence of
diene 2 and ZnCl2 or Zn(OTf)2 at 0°C and at rt did not
afford the expected cycloadduct 8.9 Instead, compounds
6 and 7 were isolated in 45 and 25% yields, respectively.
H
N
N
N
N
H
H
H
O
Et
H
Indoles bearing a substituted piperidine ring at the
2-position of the indole ring comprise of a large and
diverse class of naturally occurring and biologically
active compounds. The indolo[2,3-a]quinolizidine ring
system is present in a large number of indole alkaloids
of several structural types including the Corynanthean,
Eburnan, and Rauwolfia families of alkaloids6 (Fig. 1).
In addition, alkaloids lacking the tryptamine bridge
have also been identified.7 Construction of the poly-
cyclic framework found in many of these complex
alkaloids depends on the availability of convenient
methods for the preparation of intermediates in the
enantiomerically pure form. We have investigated the
aza-Diels–Alder reaction of imines derived from substi-
tuted indole 2-carboxaldehydes 1 as a means of prepar-
ing enantiomerically pure, highly functionallized
2-(2-piperidyl)indoles 3 (Fig. 2). In this letter we dis-
close our initial observations.
yohimbane
eburnamonine
OH
OH
H
Me
N
N
N
N
H
MeO2C
H
Et
OH
guettardine
vinoxine
Figure 1.
1. R3NH2
2. ZnCl2
R2
R2
R3
N
N
CHO
N
R1
R1
TMSO
We chose to utilize (S)-(−)-a-methylbenzylamine as the
chiral auxiliary due to it’s low cost and availability in
O
1
3
OMe
2
* Corresponding author. E-mail: jeffrey kuethe@merck.com
–
Figure 2.
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02070-6

30
J. T. Kuethe et al. / Tetrahedron Letters 43 (2002) 29–32
Scheme 1.
efficient method for the construction of the 2-(2-pipe-
ridyl)indole framework, we next turned our attention to
further elaboration of the piperidone ring. For example,
removal of the silyl protecting group of 19 with TBAF
followed by bromination (CBr4, PPh3) gave bromide 20
(Scheme 3) in 65% overall yield.16 Interestingly, reduc-
tion of 20 with excess NaBH4 in MeOH gave the novel
bicyclic aza-octane 22 as a single diastereomer in 92%
yield. The unique [2,2,4] aza-octane 22 most likely
arises via an intramolecular alkylation of intermediate
21 followed by a stereoselective reduction of the result-
ing ketone. Intramolecular cyclization also occurred
when 20 was treated with lithium hexamethyldisilyazide
(LiHMDS) at −20°C giving hexahydro-4H-pyrido[2,3-
a]carbazole 23 in 89% isolated yield.17
The presence of 7 clearly indicates that a tandem
Mannich–Michael cyclization pathway is operative.3,10
On the other hand, treatment of the preformed imine of
5 with ZnCl2 at −20°C followed by addition of diene 2
afforded cycloadduct 8 in 96% yield as a 97:3 mixture
of diastereomers (Scheme 1).11 The absolute configura-
tion of 8 was determined by single crystal X-ray analy-
sis which indicated a preferred pseudoaxial orientation
of the indole ring (Fig. 3).12 We also explored the
aza-Diels–Alder reactions of indole 2-carboxaldhydes
10 and 11.13 Treatment of the preformed imines of
these aldehydes followed by exposure to ZnCl2 and
diene 2 gave the desired adducts 12 (76%) and 14 (61%)
although with decreased diastereoselectivity. As in the
case of cycloadduct 8, the minor diastereomers could
easily be separated by crystallization. We assume the
increased diastereoselectivity for 5 is due in large part
to steric influences of the sulfonyl group; however, we
cannot rule out an electronic influence at this time.
In conclusion, we have demonstrated that the aza-
Diels–Alder reaction of substituted indole 2-carbox-
The vast majority of indole alkaloids contain substitu-
tion at the 3-position of the indole ring. In order to
broaden the synthetic utility of the process, we investi-
gated the reactions of imines derived from readily avail-
able indole 2-carboxaldehydes 1614 and 1815 with diene
2 (Scheme 2). In the case of 16, the highly functional-
lized adduct 17 was obtained in 75% isolated yield with
the depicted stereochemistry as shown. The
diastereomeric ratio was determined to be 85:15 by
HPLC analysis of the crude reaction mixture. Exposure
of 18 to the identical reaction conditions afforded 19 in
73% yield. The diastereomeric ratio for 19 was 86:14.
Both 17 and 19 were stable, crystalline solids which
could be obtained in diastereomerically pure form by
either chromatography or crystallization.
Having established that the aza-Diels–Alder reaction
sequence of substituted indole 2-carboxaldehydes is an
Figure 3. X-Ray structure of 8.

J. T. Kuethe et al. / Tetrahedron Letters 43 (2002) 29–32
31
OTBDMS
OTBDMS
1.
H2N
Ph
4
R*
N
MgSO4, PhH, reflux
N
N
CHO
SO2Ph
2. ZnCl2, CH2Cl2, -20 °C
3. 2
SO2Ph
O
16
17 R* = (S)-α-methylbenzyl
OTBDMS
OTBDMS
1.
H2N
Ph
4
R*
N
MgSO4, PhH, reflux
N
N
CHO
SO2Ph
SO2Ph
2. ZnCl2, CH2Cl2, -20 °C
3. 2
O
18
19 R* = (S)-α-methylbenzyl
Scheme 2.
Br
OTBDMS
1. TBAF
R*
N
R*
N
N
N
2. CBr4, PPh3
SO2Ph
SO2Ph
O
O
19 R* = (S)-α-methylbenzyl
20 R* = (S)-α-methylbenzyl
NaBH4, MeOH
LiHMDS, THF
Me
Br
H
N
H
N
OH
O
N
R*
N
PhO2S
Me
N
PhO2S
N
SO2Ph
O
23
21
22
Scheme 3.
aldehydes proceeds with good to excellent diastereose-
lectivity and high yield. Subsequent transformations
allow for the construction of novel heterocyclic ring
systems possessing multiple stereogenic centers. We are
currently examining the use of chiral Lewis acids and
alternative nitrogen protecting groups in order to gain
access to advanced alkaloid ring systems. The results of
our findings will be reported in due course.
2. (a) Bertilsson, S. K.; Ekegren, J. K.; Modin, S. A.;
Andersson, P. G. Tetrahedron 2001, 57, 6399 and refer-
ences cited therein; (b) Kirschbaum, S.; Waldmann, H. J.
Org. Chem. 1998, 63, 4936 and references cited therein.
3. (a) Pfrengle, W.; Kunz, H. J. Org. Chem. 1989, 54, 4261;
(b) Kunz, H.; Pfrengle, W. Angew. Chem., Int. Ed. Engl.
1989, 28, 1067.
4. Midland, M. M.; Koops, R. W. J. Org. Chem. 1992, 57,
1158.
5. (a) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49,
1749; (b) Waldmann, H. Synthesis 1994, 535; (c) Hattori,
K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264.
6. (a) Kisakurek, M. V.; Leeuwenberg, A. J. M.; Hesse, M.
In Alkaloids: Chemical and Biological Perspectives; Pel-
letier, S. W., Ed.; John Wiley and Sons: New York, 1983;
Vol. 1, Chapter 5; (b) Attaur-Rahman; Basha, A. In
Biosynthesis of Indole Alkaloids; Clarendon Press:
References
1. (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; New York: Academic,
1987; (b) Weinreb, S. M. In Comprehensive Organic Syn-
thesis; Trost, B. M.; Flemming, T., Eds.; Oxford: Perga-
mon, 1991; Vol. 5, pp. 401–415.

32
J. T. Kuethe et al. / Tetrahedron Letters 43 (2002) 29–32
12. The authors have deposited crystallographic data under
Oxford, 1983; (c) Woodson, R. R.; Youngken, H. W.;
Schlittler, E.; Schneider, J. A. In Rauwolfia: Botany,
Pharmacognosy, Chemistry and Pharmacology; Little
Brown and Co.: Boston, 1957.
the number CCDC–170495. Copies of the data can be
obtained, free of charge, on application to CCDC, Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or
email: deposit@ccdc.cam.ac.ul].
7. For leading references for the molecules depicted in Fig.
1 see: (a) Diez, A.; Merce, T.; Rugiralta, M. Tetrahedron
1990, 46, 4393; (b) Bennasar, M.-L.; Alvarez, M.; Lavilla,
R.; Zulaica, E.; Bosch, J. J. Org. Chem. 1990, 55, 1156.
8. Saulnier, M. G.; Gribble, G. W. J. Org. Chem. 1982, 47,
757.
9. Lin, Y. M.; Oh, T. Tetrahedron Lett. 1997, 38, 727.
10. (a) Domingo, L. R.; Oliva, M.; Andre´s, J. J. Org. Chem.
2001, 66, 6151; (b) Waldmann, H.; Braun, M. J. Org.
Chem. 1992, 57, 4444.
13. Barbier, M.; Devys, M.; Tempete, C.; Kollmann, A.;
Bousquet, J. F. Synth. Commun. 1993, 23, 3109.
14. Gribble, G. W.; Keavy, D. J.; Davis, D. A.; Saulnier, M.
G.; Pelcman, B.; Barden, T. C.; Sibi, M. P.; Olson, E. R.;
BelBruno, J. J. J. Org. Chem. 1992, 57, 5878.
15. Prepared by directed lithiation of the known 1-(O-tert-
butyldimethylsilyl)-2-[3-(1-N-phenylsulfonyl)indolyl]-eth-
anol, see: Hirschmann, R.; Nicolaou, K. C.; Pietranico,
S.; Leahy, E. M.; Salvino, J.; Arison, B.; Cichy, M. A.;
Spoors, P. G.; Shakespeare, W. C.; Sprengeler, P. A.;
Hamley, P.; Smith, III, A. B.; Reisine, T.; Raynor, K.;
Maechler, L.; Donaldson, C.; Vale, W.; Freidinger, R.
M.; Cascieri, M. R.; Strder, C. D. J. Am. Chem. Soc.
1993, 115, 12550. To a solution of LDA, prepared by
from diisopropylamine (3.10 g, 30.60 mmol) and n-butyl-
lithium (2.5 M in hexane, 12.0 mL, 30.00 mmol), in 50
mL of THF at −78°C was added dropwise 1-(O-tert-
butyldimethylsilyl)-2-[3-(1-N-phenylsulfonyl)indolyl]-eth-
anol (8.34 g, 20.01 mmol) in 15 mL of THF. The mixture
was allowed to stir at −78°C for 30 min and then allowed
to warm to rt and stirred for 1 h. The mixture was cooled
to −78°C and DMF (7.30 g, 100 mmol) was added in one
portion. The reaction mixture was allowed to warm to rt
and quenched with sat. NH4Cl. The mixture was
extracted with EtOAc, dried, and chromatographed on
silica gel to give 5.34 g (63%) of 18 as a colorless solid:
mp 67–68°C (EtOAc/hexane); 1H NMR (CDCl3, 400
MHz): l −0.20 (s, 6H), 0.72 (s, 9H), 3.19 (t, 2H, J=6.3
Hz), 3.80 (t, 2H, J=6.3 Hz), 7.34 (m, 3H), 7.52 (m, 2H),
7.71 (m, 3H), 8.23 (d, 1H, J=8.7 Hz), 10.6 (s, 1H); 13C
NMR (CDCl3, 100 MHz): l −5.6, 18.2, 28.7, 63.1, 115.6,
122.8, 124.6, 126.7, 129.1, 129.2, 130.8, 134.1, 134.4,
137.2, 184.7.
11. General procedure for the aza-Diels–Alder reaction of 5
with diene 2: To a solution of of 5 (379 mg, 1.32 mmol)
in 5 mL of toluene was added amine 4 (177 mg, 1.46
mmol) and 150 mg of MgSO4. The mixture was heated at
reflux for 12 h, cooled, and filtered over a pad of solka
flok (filter aid). The toluene was removed under reduced
pressure and the crude imine redissolved in 10 mL of
CH2Cl2 and the mixture cooled to −20°C. To the solution
was added 2.0 mL of a 1.0 M solution of ZnCl2 and the
mixture stirred for 10 min. Diene 2 (273 mg, 1.58 mmol,
Aldrich) was then added dropwise and the mixture main-
tained at −20°C for 2 h. The reaction mixture was
quenched with 5 mL of 1.0 M HCl and allowed to reach
rt. The layers were separated and the aqueous layer was
extracted with an additional 10 mL of CH2Cl2. The
combined organic extracts were dried, and chro-
matographed on silica gel to give 510 mg (96%) of 8 as a
colorless solid: [h]2D3 −32.8 (c 0.04, CDCl3); mp 146–147°C
1
(EtOAc/hexane); H NMR (CDCl3, 400 MHz) d 1.45 (d,
3H, J=6.9 Hz), 2.71 (dd, 1H, J=16.6 and 3.0 Hz), 2.96
(dd, 1H, J=16.6 and 7.7 Hz), 4.47 (q, 1H, J=6.9 Hz),
4.98 (d, 1H, J=7.7 Hz), 5.58 (dd, 1H, J=7.7 and 3.0
Hz), 6.74 (s, 1H), 7.10 (d, 1H, J=7.7 Hz), 7.18–7.56 (m,
11H), 7.63 (d, 2H, J=8.2 Hz), 8.17 (d, 1H, J=8.4 Hz);
13C NMR (CDCl3, 100 MHz): l 19.0, 42.0, 52.9, 61.9,
98.4, 112.2, 115.4, 121.2, 124.3, 125.3, 126.1, 127.2, 128.4,
129.0, 129.3, 129.5, 134.3, 138.0, 138.8, 139.7, 150.9,
189.5. Anal calcd. for C22H24N2O3S: C, 71.03; H, 5.30; N,
6.14. Found: C, 69.92; H, 5.29; N, 6.12.
16. Gribble, G. W.; Barden, T. C. J. Org. Chem. 1985, 50,
5900.
17. The related ring system of isovincane has been obtained
by thermolysis of 1,2-dehydroaspidospermidine: Hugel,
G.; Royer, D.; Sigaut, F.; Levy, J. J. Org. Chem. 1991,
56, 4631.
.