Access to the noryohimban [6,5,6,5,6] ring system via an intramolecular furan Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4039(03)01179-1

Polycyclic indolic compounds containing the [6,5,6,5,6] ring system were prepared via an intramolecular furan Diels-Alder reaction of α,β-unsaturated amides generated by the N-acylation of 1-(2-furyl)-β-tetrahydrocarbolines. This chemistry can provide access to D(14)-noryohimban derivatives by exploiting the functionality on the C,D,E ring system of the corresponding cycloadducts.

Full text of DOI:10.1016/S0040-4039(03)01179-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5137–5140
Access to the noryohimban [6,5,6,5,6] ring system via an
intramolecular furan Diels–Alder reaction
Demosthenes Fokas,* Jean E. Patterson, Gregory Slobodkin and Carmen M. Baldino
Department of Chemistry, ArQule Inc., 19 Presidential Way, Woburn, MA 01801, USA
Received 14 March 2003; revised 5 May 2003; accepted 5 May 2003
Abstract—Polycyclic indolic compounds containing the [6,5,6,5,6] ring system were prepared via an intramolecular furan
Diels–Alder reaction of a,b-unsaturated amides generated by the N-acylation of 1-(2-furyl)-b-tetrahydrocarbolines. This chemistry
can provide access to D(14)-noryohimban derivatives by exploiting the functionality on the C,D,E ring system of the
corresponding cycloadducts. © 2003 Elsevier Science Ltd. All rights reserved.
The polycyclic indolic [6,5,6,5,6] ring system is usually
Polycyclic indole alkaloids continue to be the target of
constructed by the reductive cyclization2 of N-imido
scientific investigations because of their interesting
physiological, biological and structural properties.1 In
our search for libraries of rigid heterocycles we turned
our attention to the noryohimban [6,5,6,5,6] ring sys-
tem since very little is known about the bio-
logical activities of this unnatural ring system and its
analogs, in contrast with the well studied yohimbine
alkaloids.
tryptamines or by the condensation of tryptamines with
2-carboxybenzaldehyde equivalents.3 However, the
molecules generated by these methods lack any immedi-
ate functionality for further manipulation or introduc-
tion of diversity. Here, we wish to report our studies
leading to functionalized indole polycycles that give
access to D(14)-noryohimban derivatives.
Scheme 1. Reagents and conditions: (a) MeOH, 60°C; (b) (CH2)2Cl2, 70°C, 24 h; (c) THF, NiPr2Et, rt to 60°C; (d) CH3CN,
HBTU, R3R4NH, NEt3; (e) n-BuLi, THF, −78°C, HMPA, CuI then ClCOCO2Me.
* Corresponding author. Fax: (781)-3766019; e-mail: dfokas@arqule.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01179-1

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D. Fokas et al. / Tetrahedron Letters 44 (2003) 5137–5140
We envisioned4 that N-acylation of a secondary fur-
furylamine such as b-tetrahydrocarboline 3 (b-THC)
with maleic anhydride5 would result in the activated
maleamide 5-cis, which could undergo an intramolecu-
lar furan Diels–Alder cycloaddition (IMDAF)6 to give
carboxylic acid 6. Similarly, N-acylation of 3 with acid
chloride 4 followed by an IMDAF cycloaddition of the
intermediate a,b-unsaturated amide 5-trans would give
compound 7 (Scheme 1). If this were the case, then
entry to hexacyclic heterocycles 6 and 7 would require
the synthesis of 3.
HBTU, as shown in Scheme 1, thus introducing an
additional element of diversity.
We also found that N-acylation of 3 with a crotonyl or
cinnamoyl chloride 4 at room temperature afforded the
a,b-unsaturated amide 5-trans, which converged to
cycloadduct 7 upon heating at 60°C for 5 h (Table 1,
entries 1–5). However, electron-withdrawing sub-
stituents on the phenyl ring of cinnamoyl chlorides
facilitated the cycloaddition process and the corre-
sponding cycloadducts were formed even after stirring
the reaction mixture at room temperature overnight
(entries 4 and 5). Although similar intramolecular
Diels–Alder reactions of furans with a,b-unsaturated
amides9 are usually accelerated by internal hydrogen
bonding, internal coordination with a Lewis acid cata-
lyst or excessive heating, cyclization of a,b-unsaturated
amide 5-trans is presumably entropically favored due to
the rigid tether and the gem-disubstitution effect.10
A direct route to b-THC 3 (R=H) would involve the
Pictet–Spengler reaction of tryptamine 1 with 2-furalde-
hyde. However, the instability of the requisite furalde-
hydes and products towards acidic conditions makes
these substrates inaccessible by this route. We found
that the disubstituted 1-(2-furyl)-1-carboxymethyl-b-tet-
rahydrocarboline 3 (R=CO2Me) was particularly sta-
ble and readily available by
a
Pictet–Spengler
condensation of tryptamine hydrochloride 1 with the
furyl-a-ketoester 2 (Scheme 1). Eight different sub-
strates were prepared in good yields (40–73%, Table 1)
from eight commercially available tryptamines and a-
ketoester 2.7 Ketoester 2 was prepared in multi-gram
quantities from furan in 40–50% yield via a lithiation,
transmetallation with CuI, and quenching the corre-
sponding cuprate with methyl oxalyl chloride.8
The cycloaddition proceeds in a stereocontrolled fash-
ion where an exo-addition of the furan nucleus to the
dienophile prevails. The transition state presumably
involves a conformation where the ester group lies anti
to the furan oxygen due to unfavorable steric repulsions
between the ester carbonyl and the lone pair of elec-
trons on the furan oxygen. The stereochemical outcome
of the cycloaddition was determined by a single X-ray
crystal structure of compound 7a.12
As we had hoped, when disubstituted tetra-
hydrocarboline 3 was treated with maleic anhydride in
dichloroethane (DCE) at 70°C, carboxylic acid 6 was
formed as the sole product. Acid 6 could then be
converted cleanly to amide 8 (Table 1, entries 6–8)
upon treatment with an amine in the presence of
Cycloadducts 6 and 7 contain functionalities, which
allow access to new noryohimban derivatives (Scheme
2). For instance, dihydroxylation of the olefin 7b (con-
ditions a) gave diol 9 while reduction of the ester group
gave alcohol 10 (conditions b). Reduction of both the
Table 1.
Entry
b-THC (Yield%a)
Product
Yielda (%)
1
2
3
4
5
6
7
8
3a R1=6-H (64)
3b R1=6-Cl (55)
3c R1=6-OH (62)
3d R1=6-OBn (73)
3e R1=7-F (60)
3f R1=6-OMe (70)
3g R1=6-Me (65)
3h R1=6-Br (40)
7a R2=Ph
7b R2=Ph
7c R2=Me
7d R2=(2-Cl)Ph
7e R2=(3-CF3)Ph
8a R3–R4=-(CH2)2NPh(3-CF3)(CH2)2-
8b R3=isobutyl, R4=H
8c R3=Ph, R4=H
90
94
70
86
79
72
77
85
a Isolated yields of purified products. All compounds gave satisfactory 1H NMR and mass spectra.11
Scheme 2. Reagents and conditions: (a) OsO4 (cat.), NMMO, acetone–H2O (4:1); (b) EtOH, NaBH4; (c) Me3O+BF4−, CH2Cl2 at
rt then EtOH, NaBH4; (d) Me3O+BF4−, CH2Cl2 at rt then MeOH, NaBH4, 0°C to rt.

D. Fokas et al. / Tetrahedron Letters 44 (2003) 5137–5140
5139
amido carbonyl and the ester group of cycloadduct 7b,
without cleavage of the oxygen bridge of the oxabicyclo
ring system, gave noryohimban 11 (conditions c). Selec-
tive reduction of the amido carbonyl of 7b gave nor-
yohimban 12 (conditions d), which was also converted
to diol 13 (conditions a).
1H), 6.15 (d, 1H, J=3.3 Hz), 3.88 (s, 3H), 3.25 (m, 1H),
3.10 (m, 1H), 2.82 (t, 2H, J=5.2, J=6.0 Hz).
8. For the synthesis of 2 via the oxidation of the corre-
sponding a-hydroxy ester, see: (a) Tanaka, M.;
Kobayashi, T.; Sakakura, T. Angew. Chem., Int. Ed.
Engl. 1984, 23, 518; (b) Monenschein, H.; Drager, G.;
Jung, A.; Kirschning, A. Chem. Eur. J. 1999, 5, 2270–
2280. Large quantities of ketoester 2 were made by
metallation of furan as described below: To a dry 2 L
three neck round bottom flask, equipped with a magnetic
stirrer, immersion thermometer, addition funnel and gas
inlet, 600 mL dry THF and furan (27 g, 0.4 mol) were
added. The stirred solution was cooled to −70°C followed
by addition of HMPA (90 g, 0.5 mol) and 160 mL of 2.5
M n-BuLi (0.4 mol). After the mixture was stirred at
−70°C for 1 h, CuI (76 g, 0.4 mol) was added and the
cooling bath was removed. After the stirred mixture was
warmed up to −20°C and CuI dissolved, the resulting
dark homogeneous mixture was cooled to −70°C.
MeOCOCOCl (50 g, 0.41 mol) was then added dropwise
and the mixture was warmed up to room temperature.
After stirring overnight, the mixture was diluted with
toluene (500 mL), quenched with water (500 mL) and
then filtered. After washing the filter cake with toluene
(100 mL), the organic phase of the filtrate was separated
and the aqueous layer was extracted with toluene. The
combined organic layer was washed with water, dried
over Na2SO4 and concentrated. Vacuum distillation of
the resulting residue afforded 25 g (40%) of ketoester 2 as
a yellowish oil which rapidly solidified. Bp 135°C/20 mm
The functionality of intermediates 6, 7, and 8 is
amenable to further chemical diversification through
solution phase parallel synthesis methods13 utilizing the
chemistry depicted in Scheme 1. The preparation of
screening libraries utilizing these compounds as build-
ing blocks towards the synthesis of highly functional-
ized noryohimban derivatives is currently under
investigation and will be communicated in due course.
References
1. For a review of the indole alkaloids, see: (a) Wang, F.-P.;
Liang, X.-T. In Alkaloids: Chemistry and Biology;
Cordell, G. A., Ed.; Academic Press: New York, 2002;
Vol. 59, pp. 2–280; (b) Baxter, E. W.; Mariano, P. S. In
Alkaloids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Springer-Verlag: New York, 1992; Vol. 8, pp.
197–319.
2. (a) Hitchings, G. J.; Helliwell, M.; Vernon, J. M. J.
Chem. Soc., Perkin Trans. 1 1990, 83–87; (b) Rahman,
A.; Ghazala, M.; Sultana, N.; Bashir, M. Tetrahedron
Lett. 1980, 21, 1773–1774.
1
Hg. H NMR (300 MHz, CDCl3): l 7.77 (m, 2H), 6.62
3. (a) Heany, H.; Simcox, M. T.; Slawin, A. M. Z.; Giles, R.
G. Synlett 1998, 640–642; (b) Bailey, P. D.; Cochrane, P.
J.; Fo¨rster, A. H.; Morgan, K. M.; Pearson, D. P. J.
Tetrahedron Lett. 1999, 40, 4597–4600.
(m, 1H), 3.98 (s, 3H).
9. Takebayashi, T.; Iwasawa, N.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1983, 56, 1107–1112.
10. For substitution effects in the intramolecular furan Diels–
Alder reaction, see: Jung, M. E.; Kiankarimi, M. J. Org.
Chem. 1998, 63, 2968–2974 and references cited therein.
11. Typical experimental procedure for the synthesis of
cycloadducts 7: To a solution of b-THC 3 (1 equiv.) and
NiPr2Et (1.2 equiv.) in THF (1:1 acetone–THF for 3c) at
room temperature, acid chloride 4 (1.1 equiv.) was added.
The reaction mixture was stirred at room temperature
overnight and then heated at 60°C for 4–5 h. The reac-
tion mixture was then concentrated and the resulting
residue dissolved in CHCl3 and washed with 1N HCl and
aq. NaHCO3. The organic phase was then isolated, dried
over Na2SO4, filtered and concentrated to give the crude
product. Purification by silica gel flash chromatography
or preparative TLC with EtOAC–Hex as eluent afforded
4. At the time this work was completed, the synthesis of
similar hexacyclic systems via a tandem N-acyliminium/
Pictet–Spengler/IMDAF reaction by maleic anhydride
acylation of imines from tryptamine and furaldehydes
was reported: Paulvannan, K.; Hale, R.; Mesis, R.; Chen,
T. Tetrahedron Lett. 2002, 43, 203–207.
5. For the reaction of secondary furfuryl amines with maleic
anhydride, see: (a) Bilovic, D. Croat. Chim. Acta 1968,
40, 15–22; (b) Prajapati, D.; Borthakur, D. R.; Sandhu, J.
S. J. Chem. Soc., Perkin Trans. 1 1993, 1197–1200; (c)
Zylber, J.; Tubul, A.; Brun, P. Tetrahedron: Asymmetry
1995, 6, 377–380; (d) Murali, R.; Rao, H. S. P.; Scheeren,
H. W. Tetrahedron 2001, 57, 3165–3174.
6. For a review on the synthetic applications of IMDAF,
see: Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetra-
hedron 1997, 53, 14179–14233.
1
the desired product. H NMR (300 MHz, CDCl3) for 7a:
l 8.35 (s, 1H), 7.50 (d, 1H, J=8.0 Hz), 7.37 (d, 1H,
J=8.2 Hz), 7.30–7.05 (m, 7H), 6.80 (d, 1H, J=5.8 Hz),
6.40 (d, 1H, J=6.0 Hz), 5.12 (d, 1H, J=4.4 Hz), 4.65
(dd, 1H, J=4.7, J=12.9 Hz), 3.92 (s, 3H), 3.85 (t, 1H,
J=4.1, J=4.4 Hz), 3.18 (m, 1H), 3.02–2.80 (m, 3H).
Typical experimental procedure for the synthesis of
cycloadducts 8: A solution of b-THC 3 (1 equiv.) and
maleic anhydride (1.2 equiv.) in DCE (2:1 CH3CN–DCE
for 3c) was heated at 70°C for 24 h. The reaction mixture
was concentrated to give acid 6 which was then dissolved
in CH3CN and treated consecutively with an amine (1.2
equiv.), NEt3 (2 equiv.) and HBTU (1.2 equiv.). After
stirring at room temperature overnight, the reaction mix-
ture was concentrated and the resulting residue dissolved
7. A solution of tryptamine hydrochloride (1 equiv.) and
ketoester 2 (1.5 equiv.) in MeOH (MeOH–AcOH when
R1=5-OBn) was heated at 60°C overnight. The mixture
was concentrated and the resulting residue was parti-
tioned between CHCl3 and 1N NaOH. The organic layer
was isolated and the aqueous basic phase was washed
with CHCl3. The combined organic layer was then dried
over Na2SO4 and concentrated to give the desired b-THC
3. It could be further purified, if necessary, by a quick
filtration of an EtOAc or CHCl3 solution over silica gel.
1H NMR (300 MHz, CDCl3) for 3a: l 8.48 (s, 1H), 7.55
(d, 1H, J=8.0 Hz), 7.40 (s, 1H), 7.38 (d, 1H, J=8.0 Hz),
7.23 (t, 1H, J=7.7 Hz), 7.12 (t, 1H, J=7.7 Hz), 6.30 (m,

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D. Fokas et al. / Tetrahedron Letters 44 (2003) 5137–5140
in EtOAc and washed with 1N HCl. The organic phase
J=5.8 Hz), 6.20 (dd, 1H, J=1.1, J=5.5 Hz), 5.08 (dd,
1H, J=1.1, J=4.4 Hz), 3.90 (s, 3H), 3.45 (m, 2H), 3.30
(m, 2H), 3.0 (m, 2H), 2.60 (m, 2H). Diol 13: 1H NMR
(300 MHz, CD3OD): l 7.50–7.15 (m, 7H), 7.05 (dd, 1H,
J=2.2, J=8.5 Hz), 4.32 (d, 1H, J=5.5 Hz), 4.25 (d, 1H,
J=6.1 Hz), 3.92 (d, 1H, J=6.3 Hz), 3.78 (s, 3H), 3.42–
3.18 (m, 4H), 3.12–2.80 (m, 3H), 2.58 (dd, 1H, J=3.0,
J=15.4 Hz).
was then isolated, dried over Na2SO4, filtered and con-
centrated to give the crude product. Purification by silica
gel flash chromatography or preparative TLC with
EtOAC–Hex as eluent afforded the desired product. 1H
NMR (300 MHz, CDCl3) for 8b: l 8.20 (s, 1H), 7.28 (d,
2 H, J=8.2 Hz), 7.05 (dd, 1H, J=1.6, J=8.2 Hz), 6.70
(d, 1H, J=6.0 Hz), 6.55 (dd, 1H, J=1.9, J=6.0 Hz), 6.45
(t, 1H, J=4.9 Hz), 5.15 (d, 1H, J=1.7 Hz), 4.60 (m, 1H),
3.90 (s, 3H), 3.25–2.70 (m, 7H), 2.42 (s, 3H), 1.72 (m,
1H), 0.85 (t, 6H).
12. Crystals for cycloadduct 7a were grown from EtOAc–
acetone. We are pleased to acknowledge the contribution
to this project provided by Dr. John C. Huffman and the
X-ray crystallography laboratory of Indiana University.
Spectroscopic data for selected compounds. Diol 9: 1H
NMR (300 MHz, CDCl3): l 9.15 (s, 1H), 7.50 (d, 1H,
J=1.6 Hz), 7.40–7.10 (m, 7H), 4.55 (dd, 1H, J=4.4,
J=12.9 Hz), 4.48 (d, 1H, J=5.2 Hz), 4.25 (d, 1H, J=6.0
Hz), 4.18 (d, 1H, J=6.0 Hz), 3.82 (s, 3H), 3.65 (t, 1H,
J=5.2, J=5.5 Hz), 3.20 (d, 1H, J=5.5 Hz), 3.10 (m, 1H),
3.0–2.78 (m, 2H). Compound 10: 1H NMR (300 MHz,
CD3OD): l 7.45 (d, 1H, J=2.2 Hz), 7.35-7.15 (m, 6 H),
7.03 (m, 2H), 6.27 (dd, 1H, J=1.6, J=6.0 Hz), 5.03 (dd,
1H, J=1.6, J=4.7 Hz), 4.50 (dd, 1H, J=5.2, J=13.2
Hz), 4.35 (d, 1H, J=12.1 Hz), 4.12 (d, 1H, J=12.1 Hz),
3.65 (t, 1H, J=4.1, J=4.4 Hz), 3.25 (m, 2H), 2.78 (m,
2H). Compound 11: 1H NMR (300 MHz, CD3OD): l 7.40
(d, 1H, J=1.6 Hz), 7.25–7.08 (m, 6 H), 6.97 (m, 2H), 6.15
(dd, 1H, J=1.6, J=5.8 Hz), 4.92 (dd, 1H, J=1.6, J=4.7
Hz), 4.07 (d, 1H, J=11.0 Hz), 3.90 (d, 1H, J=11.0 Hz),
3.40–3.12 (m, 4H), 2.95 (m, 2H), 2.50 (m, 2H). Compound
1
12: H NMR (300 MHz, CDCl3): l 8.30 (s, 1H), 7.47 (d,
13. Baldino, C. M. J. Comb. Chem. 2000, 2, 89–103.
1H, J=1.6 Hz), 7.25 (m, 4H), 7.10 (m, 3H), 6.57 (d, 1H,