Enantioselective synthesis of 2-[(3-ethyl-4-piperidyl)methyl]indoles from a phenylglycinol-derived lactam: formal synthesis of Strychnos alkaloids

Article abstract of DOI:10.1016/j.tetlet.2007.07.079

A diastereodivergent synthesis of enantiopure cis- and trans-2-[(3-ethyl-4-piperidyl)methyl]indole (cis-1b and trans-1b) from a common phenylglycinol-derived oxazolopiperidone lactam 3 is reported. The key step is a stereocontrolled conjugate addition, ei

Full text of DOI:10.1016/j.tetlet.2007.07.079

Tetrahedron Letters 48 (2007) 6722–6725
Enantioselective synthesis of 2-[(3-ethyl-4-piperidyl)methyl]-
indoles from a phenylglycinol-derived lactam:
formal synthesis of Strychnos alkaloids
*
*
´
Mercedes Amat, Nu´ria Llor, Begona Checa, Maria Perez and Joan Bosch
˜
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
Received 25 May 2007; accepted 17 July 2007
Available online 21 July 2007
Abstract—A diastereodivergent synthesis of enantiopure cis- and trans-2-[(3-ethyl-4-piperidyl)methyl]indole (cis-1b and trans-1b)
from a common phenylglycinol-derived oxazolopiperidone lactam 3 is reported. The key step is a stereocontrolled conjugate addi-
tion, either under kinetic or thermodynamic control, of the dilithium salt of 2-(2-indolyl)-1,3-dithiane to unsaturated lactam 3.
Ó 2007 Elsevier Ltd. All rights reserved.
cis- and trans-2-[(3-Ethyl-4-piperidyl)methyl]indoles 1
are key intermediates1 in the synthesis of tetracyclic
alkaloids of the uleine group2 and pentacyclic Strychnos
indole alkaloids3 (Scheme 1). All these syntheses have
been conducted in the racemic series, and no precedents
for the enantioselective synthesis of (piperidylmethyl)-
indoles 1 have been reported so far.
After some experimentation, the conjugate addition of
the dilithium salt of 2-(2-indolyl)-1,3-dithiane7,8 (2) to
the easily accessible unsaturated lactam 36c was accom-
plished in excellent yield (90%) and good facial diastereo-
selectivity (4:1) to give the enantiopure cis-isomer
cis-4b when the reaction was performed at ꢀ78 °C for
12 h using an excess (2 equiv) of the nucleophile in
THF solution (Scheme 2).9 The observed stereoselectiv-
ity can be explained by considering that the attack of the
nucleophile takes place, under stereoelectronic con-
trol,10 axial to the electrophilic carbon of the conjugated
double bond of the conformationally rigid lactam 3, and
consequently, cis with respect to the ethyl substituent, as
depicted in Figure 1.
Taking into account that phenylglycinol-derived oxazo-
lopiperidone lactams provide a general solution for
the enantioselective synthesis of piperidines bearing
virtually any type of substitution pattern,4 we planned
to take advantage of these chiral building blocks to
develop a diastereodivergent synthesis of enantiopure
cis- and trans-(piperidylmethyl)indoles cis-1b5 and
trans-1b (3,4-disubstituted piperidine derivatives).
The former is a known synthetic precursor of the Strych-
nos alkaloids tubifoline, tubifolidine, and 19,20-dihydro-
akuammicine.1a,b
In sharp contrast, when the conjugate addition of the
dianion derived from 2 (1.2 equiv) was carried out at
room temperature for a longer reaction time (16 h) in
THF solution, the enantiopure isomer trans-4b was ste-
reoselectively formed as the only product, also in excel-
lent yield (93%).9 This result makes evident that, under
these conditions, the equilibration of the initially formed
kinetic cis-isomer to the thermodynamic trans-isomer
has occurred.
The key step of the synthesis is a stereocontrolled conju-
gate addition of a 2-indolylmethyl anion equivalent to
an unsaturated oxazolopiperidone lactam that incorpo-
rates the ethyl substituent with the required absolute
configuration.6
The conversion of cis-4b to the target cis-(piperidyl-
methyl)indole cis-1b was performed in three steps. Reduc-
tive desulfurization of cis-4b with nickel boride11
(NiCl2ÆH2O, NaBH4, THF–MeOH, 0 °C, 4 h) gave
(94% yield) oxazolopiperidone lactam cis-5, which bears
the required ethyl and 2-indolylmethyl substituents at
the piperidine 3 and 4 positions, respectively (Scheme 3).
Keywords: Phenylglycinol; Strychnos alkaloids; Piperidines; Indoles;
Oxazolopiperidone lactams.
*
Corresponding authors. Tel.: +34 93 4024538; fax: +34 93 4024539
(J.B.); e-mail addresses: amat@ub.edu; joanbosch@ub.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.079

M. Amat et al. / Tetrahedron Letters 48 (2007) 6722–6725
6723
H
N
H
N
N
H
H
N
H
H
CO2Me
Dihydroakuammicine
CO2Me
Tubotaiwine
R
N
N
H
1a R= Bn
b R= H
R
N
H
H
N
N
H
H
X
X
O
O
R
CH3 Dasycarpidone
Nordasycarpidone
N
H
H
Tubifoline
Tubifolidine (
β-H, α-OH CH3 Dasycarpidol
N,2-dihydro)
CH2
CH3 Uleine
Scheme 1. Synthesis of uleine and Strychnos alkaloids from (piperidylmethyl)indoles 1.
C6H5
O
R
O
N
S
N
H
S
2
S
3
n-BuLi
(2 equiv)
THF
-78 ºC, 12 h
r.t., 16 h
93%
90%
O
C6H5
O
C6H5
N
N
O
N
O
N
S
S
H
S
S
H
trans-4
cis-4
(cis/trans ratio 4:1)
Scheme 2. Diastereodivergent synthesis of enantiopure cis-4 and trans-4.
Nu
1b were coincident with those reported for the racemic
product.1b
O
H
H
Taking into account previous correlations1,12 and that
the stereogenic centers at the piperidine 3 and 4 posi-
tions in cis-1b are configurationally stable, the above
synthesis of cis-1b also represents a formal synthesis of
the alkaloids (ꢀ)-tubifoline, (ꢀ)-tubifolidine, and (ꢀ)-
19,20-dihydroakuammicine.
N
C6H5
O
H
3
Figure 1. Stereoelectronic control in the conjugate addition to 3.
Then, treatment of cis-5 with LiAlH4 (THF, reflux,
30 min) brought about both the reduction of the lactam
carbonyl group and the reductive cleavage of the C–O
bond of oxazolidine ring to give (65% yield) piperidine
cis-6. A subsequent removal of the phenylethanol
moiety by hydrogenolysis [H2, Pd(OH)2, EtOH, 400 psi]
Following a similar reaction sequence, trans-4b was con-
22
verted to trans-(piperidylmethyl)indole trans-1b13 (½aꢁD
ꢀ77.8 (c 0.09, EtOH)) via the enantiopure intermediates
trans-5 and trans-6 (Scheme 4).
led to cis-(piperidylmethyl)indole cis-1b in 85% yield
(½aꢁD ꢀ11.6 (c 1.0, EtOH)). The NMR data of (ꢀ)-cis-
The concise routes (four synthetic steps) developed herein
further illustrate the potential of phenylglycinol-derived
22

6724
M. Amat et al. / Tetrahedron Letters 48 (2007) 6722–6725
O
O
C6H5
C6H5
.
N
N
NiCl2 H2O
NaBH4
O
O
N
N
H
S
S
H
94%
cis-5
cis-4
LiAlH4
65%
C6H5
OH
H2
Pd(OH)2
NH
N
R
S
N
85%
N
H
H
cis-1b
cis-6
Scheme 3. Enantioselective synthesis of (piperidylmethyl)indole cis-1b.
O
O
C6H5
C6H5
.
N
N
NiCl2 H2O
NaBH4
O
O
N
N
S
S
H
93%
H
trans-4
trans-5
LiAlH4
65%
C6H5
OH
H2
Pd(OH)2
NH
N
S
S
N
83%
N
H
H
trans-1b
trans-6
Scheme 4. Enantioselective synthesis of (piperidylmethyl)indole trans-1b.
6; (c) Alvarez, M.; Joule, J. A. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, 2001; Vol. 57,
Chapter 4.
oxazolopiperidone lactams for the enantioselective
synthesis of diversely substituted piperidine derivatives.
3. For reviews, see: (a) Bosch, J.; Bonjoch, J. In Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.; Else-
vier: Amsterdam, 1988; pp 31–88; (b) Sapi, J.; Massiot, G.
In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; The
Chemistry of Heterocylic Compounds; Taylor, E. C., Ed.;
Wiley: Chichester, 1994; Supplement to Vol. 25, Part 4,
Chapter 7; (c) Bosch, J.; Bonjoch, J.; Amat, M. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 1996; Vol. 48, pp 75–189.
4. For reviews, see: (a) Romo, D.; Meyers, A. I. Tetrahedron
1991, 47, 9503–9569; (b) Meyers, A. I.; Brengel, G. P.
Chem. Commun. 1997, 1–8; (c) Groaning, M. D.; Meyers,
A. I. Tetrahedron 2000, 56, 9843–9873; (d) Escolano, C.;
Amat, M.; Bosch, J. Chem. Eur. J. 2006, 12, 8198–8207;
For more recent work, see: (e) Amat, M.; Escolano, C.;
Acknowledgments
Financial support from the Ministry of Science and
Technology (Spain)-FEDER (Project CTQ2006-02390/
BQU) and the DURSI, Generalitat de Catalunya
(Grant 2005-SGR-0603) is gratefully acknowledged.
Thanks are also due to the Ministry of Science and
Technology (Spain) for a fellowship to B.C.
References and notes
´
´
1. (a) Wu, A.; Snieckus, V. Tetrahedron Lett. 1975, 2057–
Lozano, O.; Gomez-Esque, A.; Griera, R.; Molins, E.;
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Bosch, J. J. Org. Chem. 2006, 71, 3804–3815; (f) Amat, M.;
`
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Heterocycles 1988, 27, 2883–2890; (c) Gracia, J.; Casa-
Bassas, O.; Llor, N.; Canto, M.; Perez, M.; Molins, E.;
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Bosch, J. Chem. Eur. J. 2006, 12, 7872–7881; (g) Amat,
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M.; Escolano, C.; Gomez-Esque, A.; Lozano, O.; Llor, N.;
Griera, R.; Molins, E.; Bosch, J. Tetrahedron: Asymmetry
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C.; Molins, E.; Bosch, J. J. Org. Chem. 2007, 72, 4431–
4439; (i) Amat, M.; Santos, M. M. M.; Bassas, O.; Llor,
2. For reviews, see: (a) Joule, J. A. In Indoles. The Mono-
terpenoid Indole Alkaloids; Saxton, J. E., Ed.; The Chem-
istry of Heterocyclic Compounds; Weissberger, A., Taylor,
E. C., Eds.; Wiley: New York, 1983; Vol. 25, Part 4,
Chapter 6; (b) Alvarez, M.; Joule, J. A. In Monoterpenoid
Indole Alkaloids; Saxton, J. E., Ed.; The Chemistry of
Heterocyclic Compounds; Taylor, E. C., Ed.; Wiley:
Chichester, 1994; Supplement to Vol. 25, Part 4, Chapter
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N.; Escolano, C.; Gomez-Esque, A.; Molins, E.; Allin, S.
M.; McKee, V.; Bosch, J. J. Org. Chem. 2007, 72, 5193–
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5201; (j) Amat, M.; Perez, M.; Minaglia, A. T.; Peretto, B.;
Bosch, J. Tetrahedron 2007, 63, 5839–5848.

M. Amat et al. / Tetrahedron Letters 48 (2007) 6722–6725
6725
5. For synthetic routes to racemic cis-1b, see Refs. 1a,b.
6. For stereoselective conjugate additions to phenylglycinol-
derived d-lactams, see: (a) Amat, M.; Bosch, J.; Hidalgo,
extracts were dried and concentrated, and the resulting
residue was chromatographed (9:1 to 1:4 hexane–EtOAc)
to give compounds cis-4 (2.58 g, 73%) and trans-4 (0.60 g,
17%). Operating as above (reaction conditions: 16 h at
room temperature), from dithiane 2 (2.33 g, 9.9 mmol) and
lactam 3 (2 g, 8.2 mmol) was obtained trans-4 (3.6 g, 93%)
after flash chromatography.
´
´
J.; Canto, M.; Perez, M.; Llor, N.; Molins, E.; Miravitlles,
C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074–
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3084; (b) Amat, M.; Perez, M.; Llor, N.; Bosch, J.; Lago,
E.; Molins, E. Org. Lett. 2001, 3, 611–614; (c) Amat, M.;
´
Perez, M.; Llor, N.; Escolano, C.; Luque, F. J.; Molins, E.;
10. (a) Deslongchamps, P. In Stereoelectronic Effects in
Organic Chemistry; Baldwin, J. E., Ed.; Pergamon: Oxford,
1983; (b) Perlmutter, P. Conjugate Addition Reactions in
Organic Synthesis; Pergamon Press: Oxford, 1992; p 25.
11. (a) Back, T. G.; Yang, K.; Krouse, H. R. J. Org. Chem.
1992, 57, 1986–1990; (b) Back, T. G.; Baron, D. L.; Yang,
K. J. Org. Chem. 1993, 58, 2407–2413.
Bosch, J. J. Org. Chem. 2004, 69, 8681–8693; See also Ref.
4j. For related conjugate additions, see: (d) Forns, P.;
Diez, A.; Rubiralta, M.; Solans, X.; Font-Badia, M.
Tetrahedron 1996, 52, 3563–3574; (e) Allin, S. M.; Duffy,
L. J.; McKee, V.; Edgar, M.; Amat, M.; Bassas, O.;
Santos, M. M. M.; Bosch, J. Tetrahedron Lett. 2006, 47,
´
5713–5716; (f) Garcıa, E.; Lete, E.; Sotomayor, N. J. Org.
12. (a) Dadson, B. A.; Harley-Mason, J.; Foster, G. H. J.
Chem. Soc., Chem. Commun. 1968, 1233; (b) Ban, Y.;
Yoshida, K.; Goto, J.; Oishi, T.; Takeda, E. Tetrahedron
1983, 39, 3657–3668; (c) Amat, M.; Coll, M.-D.; Bosch, J.;
Espinosa, E.; Molins, E. Tetrahedron: Asymmetry 1997, 8,
935–948.
Chem. 2006, 71, 6776–6784; (g) Deiters, A.; Pettersson,
M.; Martin, S. F. J. Org. Chem. 2006, 71, 6547–6561.
7. Rubiralta, M.; Casamitjana, N.; Grierson, D. S.; Husson,
H.-P. Tetrahedron 1988, 44, 443–450.
8. For a recent review on 1,3-dithianes in natural product
synthesis, see: Yus, M.; Najera, C.; Foubelo, F. Tetrahe-
dron 2003, 59, 6147–6212.
13. Spectroscopic data of trans-1b: 1H NMR (300 MHz,
CDCl3) d 0.92 (t, J = 7.2 Hz, 3H, CH3), 1.26–1.39 (m,
1H, H-3), 1.50–1.79 (m, 5H, CH2, H-5 and H-4), 2.35–2.64
(m, 3H, CH2 ind, H-2 and H-6 ax), 3.11–3.33 (m, 3H, CH2
ind, H-2 and H-6 eq), 4.20 (br s, 1H, NH), 6.21 (s, 1H, H-3
ind), 7.04–7.14 (m, 2H, H-5 and H-6 ind), 7.29–7.33 (m,
1H, H-4 ind), 7.52 (dd, J = 7.3, 1.2 Hz, H-7 ind), 8.49 (br s,
1H, NH ind). 13C NMR (75.4 MHz, CDCl3) d 10.0 (CH3),
23.0 (CH2), 27.7 (C-5), 31.2 (CH2 ind), 38.9 (C-4), 39.1 (C-
3), 43.5 (C-6), 47.0 (C-2), 100.3 (C-3 ind), 110.6 (C-7 ind),
119.4 and 119.6 (C-4 and C-5 ind), 120.8 (C-6 ind), 128.7
(C-3a ind), 135.9 (C-2 ind), 136.7 (C-7a ind).
´
9. Experimental procedure for the preparation of cis-4
and trans-4: A solution of n-BuLi in hexane (21 mL of a
1.6 M solution, 32.8 mmol) was slowly added at ꢀ78 °C
to a solution of 2-(2-indolyl)-1,3-dithiane (2; 3.86 g,
16.4 mmol) in anhydrous THF (50 mL). The mixture
was stirred at ꢀ30 °C for 2 h and added at ꢀ78 °C, via a
canula, to a solution of lactam 3 (2 g, 8.2 mmol) in
anhydrous THF (20 mL). The resulting mixture was
stirred at ꢀ78 °C for 12 h, poured into saturated aqueous
NH4Cl, and extracted with EtOAc. The combined organic