Aza-Diels-Alder/intramolecular Heck cyclization approach to the tetrahydro-β-carboline skeleton of the ajmaline/sarpagine alkaloids

Article abstract of DOI:10.1016/S0040-4039(02)00668-8

The aza-Diels-Alder reactions of 2-iodo-3-indoleacetaldehydes in the presence of zinc triflate provides 2-(2-iodoindolylmethyl)-4-pyridones in high yield. Palladium-mediated intramolecular Heck cyclization gives access to the tetracyclic tetrahydro-β-carb

Full text of DOI:10.1016/S0040-4039(02)00668-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3871–3874
Aza-Diels–Alder/intramolecular Heck cyclization approach to the
tetrahydro-b-carboline skeleton of the ajmaline/sarpagine
alkaloids
Jeffrey T. Kuethe,* Audrey Wong, Ian W. Davies and Paul J. Reider
Department of Process Research, Merck & Co., PO Box 2000, Rahway, NJ 07065, USA
Received 14 March 2002; revised 3 April 2002; accepted 4 April 2002
Abstract—The aza-Diels–Alder reactions of 2-iodo-3-indoleacetaldehydes in the presence of zinc triflate provides 2-(2-iodoindolyl-
methyl)-4-pyridones in high yield. Palladium-mediated intramolecular Heck cyclization gives access to the tetracyclic tetrahydro-b-
carboline framework of the ajmaline/sarpagine alkaloids. © 2002 Elsevier Science Ltd. All rights reserved.
There have been more than 90 ajmaline/sarpagine-
related indole alkaloids isolated from various species of
Alstonia and Rauwolfia.1,2 Due to the diverse biological
properties and challenging structural complexities of
these alkaloids, they have received a great deal of
attention in recent years.1,2 Common to all of these
alkaloids is the tetracyclic tetrahydro-b-carboline
framework 5 (Fig. 1). Methods for the preparation of
this subunit generally employ the Pictet–Spengler/
Dieckmann cyclization protocol outlined by Cook and
co-workers.1,2 A number of alternative routes have also
been employed.1–5
Our studies on aza-Diels–Alder reactions of substituted
indole carboxaldehydes led us to consider readily acces-
sible 2-(2-iodoindolylmethyl)-4-pyridones such as 7 as
potential precursors for the rapid entry to the core
framework of this unique family of alkaloids (Fig. 2).6
In this letter we disclose our initial findings in this area.
The pseudoaxial orientation of substituents at the 2-
position of 4-pyridones is well established.7 We rea-
soned that the indolyl ring of 7 would be in a favorable
position for intramolecular 1,4-attack of the 6-position
of the pyridone ring.8 In order to initiate our studies on
intramolecular cyclizations of 7, we utilized an aza-
Diels–Alder reaction of 2-iodo-3-indoleacetaldehydes
12 and 13 (Scheme 1). The synthesis of 12 and 13 began
with indoles 89 and 9.10 Treatment of 8 with n-BuLi in
refluxing MTBE followed by addition of I2 at 0°C
afforded N-methyl-2-iodotryptophol 10. In similar
fashion, treatment of 9 with LDA and then I2 gave
N-phenylsulfonyl-2-iodotryptophol 11. Dess–Martin
oxidation11 provided aldehydes 12 and 13 in 57 and
43% overall yield from 8 and 9, respectively. The aza-
Diels–Alder reaction of each of these aldehydes was
conducted at rt by the sequential addition of benzyl-
amine, zinc triflate, and Danishefsky’s diene 14.12 Fol-
lowing workup and chromatography on silica gel, the
desired 2-(2-iodoindolylmethyl)-4-pyridones 15 (70%)
and 16 (74%) were obtained as stable crystalline
solids.13–15
H
H
H
H
OH
O
N
NR
NH
N
N
R
Me
H
H
R'
2 R = Me, R = Et sauveoline
3 R = H, R' = H sellowiine
1 R = Me macroline
HO
OH
H
N
N
H
N
N
4 sarpagine
5 tetrahydro-β-carboline
Figure 1.
With an efficient method for the preparation of the
required 2-(2-iodoindolylmethyl)-4-pyridones in hand,
we explored conditions for effecting intramolecular
cyclization. Treatment of either 15 or 16 under stan-
* Corresponding author. E-mail: jeffrey kuethe@merck.com
–
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00668-8

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J. T. Kuethe et al. / Tetrahedron Letters 43 (2002) 3871–3874
cantly faster than intramolecular cyclization onto the
double bond of the pyridone ring. On the other hand,
when 15 was subjected to standard Heck conditions
N
employing
a stoichiometric amount of palladium
N
PhO2S
I
(PdCl2(CH3CN)2, 2 equiv. P(t-Bu)3, CH3CN, reflux),
the desired product 20 was obtained in 85% isolated
yield. During the course of the reaction, palladium
black is quickly deposited indicating a rapid decompo-
sition of intermediates 19a and 19b. Under identical
reaction conditions, tetracyclic indole 21 was formed in
83% yield from 18.19 While the use of stoichiometric
palladium clearly has limitations, it did provide access
to these complex alkaloid ring systems in a stereocon-
trolled manner and in a limited number of steps.
O
N
N
R
O
N
6
N
R
I
O
7
Figure 2.
The majority of ajmaline/sarpagine alkaloids contain a
hydroxymethyl group at the C-16 position of the tetra-
hydoro-b-carboline skeleton. In order to gain access to
this functionality, we also investigated the intramolecu-
lar Heck reactions of iodoindoles 22 and 23 (Scheme 3).
Deprotonation of either 15 or 16 (LiHMDS, THF,
−20°C) followed by the addition of paraformaldehyde
gave 22 (67%) and 23 (73%). This alkylation was
extremely diastereoselective (>90% d.e.) with only trace
amounts of the corresponding cis-diastereomers in the
crude NMR.7 Minor diastereomers of 22 and 23 were
effectively removed by chromatography.
Interestingly, reaction of 22 under Heck cyclization
conditions (Pd2(dba)3, P(t-Bu)3, DMF, 100°C) gave a
mixture of the desired product 25 (33%) and exocyclic
methylene compound 26 (29%). We assume that com-
pound 26 arises from intermediate 24c8d and compound
O
O
N
N
HSnBu3
N
R
N
R
I
or t-BuLi
Scheme 1.
17 R = Me
18 R = SO2Ph
15 R = Me
16 R = SO2Ph
Pd2Cl2(CH3CN)2
P(t-Bu)3,CH3CN
reflux
dard radical initiation conditions (Bu3SnH, cat. AIBN,
toluene, reflux) failed to bring about 1,4-addition to the
C-6 position of the pyridone ring. In each case, only the
reduced indoles 17 and 18 were obtained as the only
identifiable products (Scheme 2). In addition, treatment
of either 15 or 16 under anionic cyclization conditions
with t-BuLi (−78°C, THF) gave reduced indoles 17 and
18 as the only isolated products.
H
H
NBn
N
NBn
N
R
OPdLn
O
H
R
H
PdLn
19a
19b
We next chose to investigate
a transition-metal
approach. Since there is no b-hydrogen available in
intermediates 19a or 19b8d,16 for completion of the
Heck17 catalytic cycle, we chose to investigate a number
of reductive Heck18 conditions; however, in all attempts
reduced indoles 17 or 18 were formed as the sole
products with no detectable amounts of the desired
products in the crude NMR. Evidently the reduction of
the intermediate 2-indolyl-palladium species is signifi-
N
N
R
O
20 R = Me
21 R = SO2Ph
Scheme 2.

J. T. Kuethe et al. / Tetrahedron Letters 43 (2002) 3871–3874
3873
rials into complex natural products. In addition, we are
examining the use of chiral auxiliaries which will allow
for the asymmetric synthesis of these targets.15 The
results of our findings will be reported in due course.
O
O
HO
N
N
LiHMDS
(CH2O)n
N
R
I
N
R
I
Me
O
22 R = Me
23 R = SO2Ph
15 R = Me
16 R = SO2Ph
N
Zn(OTf)2, BnNH2
TMSO Me
13
Pd2(dba)3, P(t-Bu)3
DMF, 100 °C
N
I
OMe
SO2Ph
29
OH
H
OH
O
H
30
NBn
N
NBn
N
R
OPdLn
H
R
H
PdLn
10 mol% Pd2(dba)3
24b
24a
N
N
P(t-Bu)3, CH3CN
Ph2OS
O
reflux
H2C
H
31
OH
OH
NBn
N
N
R
N
R
Scheme 4.
O PdLn
O
H
24c
25 R = Me
27 R = SO2Ph
References
H
1. (a) Lounasmaa, M.; Hanhinen, P.; Westersund, M. In
The Alkaloids; Cordell, G. A., Ed. The sarpagine group
of indole alkaloids; Academic Press: San Diego, 1999;
Vol. 52; (b) Bi, Y.; Hamaker, L. K.; Cook, J. M. In
Studies in Natural Products Chemistry, Bioactive Natural
Products, Part A; Basha, F. Z.; Rahman, A., Eds. The
synthesis of macroline related alkaloids; Elsevier Science:
Amsterdam, 1993; Vol. 13, p. 383; (c) Hamaker, L. K.;
Cook, J. M. In Alkaloids: Chemical and Biological Per-
spectives; Pelletier, S. W., Ed. The synthesis of macrolin
related sarpagine alkaloids; Elsevier Science: New York,
1995; Vol. 9, p. 23.
2. (a) Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.;
Soerens, D.; Grubisha, D.; Bennett, D.; Cook, J. M. J.
Am. Chem. Soc. 1999, 121, 6998 and references cited
therein; (b) Zhao, S.; Liao, X.; Cook, J. M. Org. Lett.
2002, 4, 687.
NBn
N
R
O
H
26 R = Me
28 R = SO2Ph
Scheme 3.
25 is derived from either intermediates 24a or 24b8d,e
Reaction of 23 gave similar results where 27 was iso-
lated in 29% yield and 28 was isolated in 25% yield.
.
We also prepared iodoindole 30 which was expected to
undergo a catalytic intramolecular Heck cyclization
followed by b-hydride elimination to provide enone 31
(Scheme 4). Iodoindole 30 was synthesized from 13 by
an aza-Diels–Alder reaction with diene 2920 providing
30 in 52% yield. When subjected to catalytic Heck
cyclization conditions (10 mol% Pd2(dba)3, 20 mol%
P(t-Bu)3, DMF, 100°C, 24 h), the desired product 31
was obtained as the only product in 85% yield based on
recovered starting material.
3. (a) Bailey, P. D.; Hollinshead, S. P.; Moore, M. H.;
Morgan, K. M.; Smith, D. I.; Vernon, J. M. Tetrahedron
Lett. 1994, 35, 3585; (b) Bailey, P. D.; Collier, I. D.;
Hollinshead, S. P.; Moore, M. H.; Morgan, K. M.;
Smith, D. I.; Vernon, J. M. J. Chem. Soc., Perkin Trans.
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V. Synlett 1998, 58.
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Wolinsky, J.; Tamm, R.; Aldrich, P. E. J. Am. Chem.
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Wada, K.; Worth, B. R. J. Am. Chem. Soc. 1978, 100,
938.
In conclusion, we have demonstrated that the aza-
Diels–Alder/intramolecular Heck cyclization reactions
of 2-(2-iodoindolylmethyl)-4-pyridones provides rapid
entry into the tetracyclic tetrahydro-b-carboline skele-
ton of the ajmaline/sarpagine alkaloids. Work is cur-
rently in progress to identify a catalytic procedure for
the conversion of these readily accessible starting mate-

3874
J. T. Kuethe et al. / Tetrahedron Letters 43 (2002) 3871–3874
C27H23N2IO3S: C, 55.68; H, 3.98; N, 4.81. Found: C,
6. Kuethe, J. T.; Davies, I. W.; Dormer, P. G.; Reamer, R.
55.30; H, 3.84; N, 4.63.
A.; Mathre, D. J.; Reider, P. J. Tetrahedron Lett. 2002,
15. Preliminary investigations reveal that the asymmetric
aza-Diels–Alder reaction of 13 with (S)-a-methylbenzyl-
43, 29.
7. Comins, D. L.; Joseph, S. P. In Advances in Nitrogen
Heterocycles; Moody, C. J., Ed.; JAI Press: Greenwich,
CT, 1996; Vol. 2, pp. 251–294 and references cited
therein.
amine gave compound 32 as
a 92:8 mixture of
diastereomers (63%).
8. For leading references, see: (a) Comins, D. L.; Joseph,
S. P.; Zhang, Y. Tetrahedron Lett. 1996, 37, 793; (b)
Comins, D. L.; Zhang, Y. J. Am. Chem. Soc. 1996, 118,
12248; (c) Friestad, G. K.; Branchaud, B. P. Tetra-
hedron Lett. 1995, 36, 7047; (d) Kirschbaum, S.; Wald-
mann, H. J. Org. Chem. 1998, 63, 4936. (e) Pays, C.;
Mangeney, P. Tetrahedron Lett. 2001, 42, 589 and refer-
ences cited therein.
9. Rahman, A.; Sultana, M.; Hassan, I. Tetrahedron Lett.
1983, 24, 1845.
16. Friestad, G. K.; Branchaud, B. P. Tetrahedron Lett.
1995, 36, 7047.
10. Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy,
E. M.; Slvino, J.; Arison, B.; Cichy, M. A.; Spoors, P.
G.; Shakespeare, W. C.; Sprengeler, P. A.; Hamley, P.;
Smith, A. B., III; 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.
17. (a) Heck, R. F. Org. React. 1982, 27, 345–390; (b) Heck,
R. F. Palladium Reagents in Organic Synthesis; Aca-
demic Press: London, 1985; (c) Hegedus, L. S. Angew.
Chem. 1988, 100, 1147; (d) Hegedus, L. S. In
Organometallics in Synthesis—A manual; Schlosser, M.,
Ed. Palladium in organic synthesis; Wiley: New York,
1994; pp. 383–459.
11. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
12. Lin, Y. M.; Oh, T. Tetrahedron Lett. 1997, 38, 727.
13. The structure assigned to each new compound is in full
accord with its 1H and 13C NMR and elemental analy-
sis.
18. (a) Schmidt, B.; Hoffmann, H. M. R. Tetrahedron 1991,
47, 9357; (b) Clayton, S. C.; Regan, A. C. Tetrahedron
Lett. 1993, 34, 7493.
19. General procedure for the preparation of tetracyclic tetra-
hydro-b-carboline 21: To a solution of 16 (500 mg,
0.858 mmol) in 35 mL of CH3CN was added 223 mg
(0.858 mmol) of PdCl2(CH3CN)2 followed by tri-t-
butylphosphine (347 mg, 1.72 mmol). The resulting mix-
ture was heated to reflux for 1.5 h, cooled to rt, and
filtered over a pad of Celite. The mixture was concen-
trated under reduced pressure and chromatographed on
silica gel to give 325 mg (83%) of 21 as a colorless solid:
mp: 166–167°C (MTBE); 1H NMR (CDCl3, 400 MHz)
l 2.30 (d, 1H, J=15.4 Hz), 2.54 (d, 1H, J=17.1 Hz),
2.91 (m, 1H), 2.95 (m, 1H), 3.09 (m, 2H), 3.72 (d, 1H,
J=14 Hz), 3.75 (d, 1H, J=14 Hz), 4.85 (m, 1H), 7.27
(m, 1H), 7.37 (m, 9H), 7.52 (m, 1H), 7.58 (d, 2H, J=8.2
Hz), 8.12 (d, 1H, J=8.2 Hz); 13C NMR (CDCl3, 100
MHz) l 23.3, 46.0, 48.3, 52.1, 54.0, 57.0, 114.6, 118.8,
123.8, 125.2, 126.3, 127.6, 128.2, 128.7, 129.4, 129.5,
133.8, 134.9, 138.4, 138.8, 208.5. Anal. calcd for
C27H24N2O3S: C, 71.03; H, 5.30; N, 6.14. Found: C,
70.67; H, 5.12; N, 5.90.
14. General procedure for the aza-Diels–Alder reaction of
13 with diene 14: To a solution of 13 (600 mg, 1.41
mmol) in 25 mL of CH2Cl2 was added benzylamine (166
mg, 1.55 mmol), Zn(OTf)2 (564 mg, 1.55 mmol), and
diene 14 (316 mg, 1.83 mmol). The resulting mixture
was stirred at rt for 3 h and poured into 15 mL of 0.5
M HCl. The aqueous layer was extracted with CH2Cl2
and the combined organic extracts dried over MgSO4.
The solvent was removed under reduced pressure and
the residue chromatographed on silica gel to give 608
mg (74%) of 16 as a colorless solid: 1H NMR (CDCl3,
400 MHz) l 2.07 (d, 1H, J=16.2 Hz), 2.57 (dd, 1H,
J=16.2 and 6.6 Hz), 2.86 (dd, 1H, J=13.9 and 7.2 Hz),
3.30 (dd, 1H, J=13.9 and 7.9 Hz), 3.75 (m, 2H), 4.01
(d, 2H, J=14.9 Hz), 5.07 (d, 1H, J=7.1 Hz), 7.00 (m,
3H), 7.31 (m, 8H), 7.48 (t, 1H, J=7.5 Hz), 7.85 (m,
2H), 8.33 (m, 1H); 13C NMR (CDCl3, 100 MHz) l 27.0,
39.9, 55.1, 58.6, 80.5, 97.7, 16.1, 118.7, 124.3, 125.6,
126.8, 127.2, 127.6, 128.4, 128.7, 129.0, 129.2, 130.8,
134.2, 136.4, 138.1, 139.2, 152.3, 190.1. Anal. calcd for
20. Clive, D. L. J.; Bergstra, R. J. J. Org. Chem. 1991, 56,
4976.