Enantioselective spirocyclizations trom tryptophanol-derived oxazolopiperidone lactams

Article abstract of DOI:10.1021/ol0712327

A straightforward synthetic route to enantiopure spiro[indole-3,3′- indolizidines] is reported. The key step is a Lewis acid promoted cyclization of a N_a-tosyltryptophanol-derived oxazolopiperidone lactam in the presence of Et₃SiH.

Full text of DOI:10.1021/ol0712327

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2907-2910
Enantioselective Spirocyclizations from
Tryptophanol-Derived Oxazolopiperidone
Lactams
Mercedes Amat,*,† Maria M. M. Santos,† Antonia M. Go´mez,† Danica Jokic,†
Elies Molins,‡ and Joan Bosch*,†
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona,
08028-Barcelona, Spain, and Institut de Cie`ncia de Materials de Barcelona (CSIC),
Campus UAB, 08193-Cerdanyola, Spain
amat@ub.edu; joanbosch@ub.edu
Received May 25, 2007
ABSTRACT
A straightforward synthetic route to enantiopure spiro[indole-3,3′-indolizidines] is reported. The key step is a Lewis acid promoted cyclization
of a Na-tosyltryptophanol-derived oxazolopiperidone lactam in the presence of Et3SiH.
Aminoalcohol-derived oxazolopiperidone lactams are ex-
ceptionallyversatilebuildingblocksforthesynthesisofenantio-
pure polysubstituted piperidines bearing virtually any type
of substitution pattern, including structurally diverse natural
products and bioactive compounds.1 These lactams are easily
available by a cyclocondensation reaction of a prochiral or
racemic δ-oxo(di)acid derivative with a chiral nonracemic
aminoalcohol, generally phenylglycinol. This aminoalcohol
constitutes a chiral latent form of ammonia, and a final debenz-
ylation is needed to remove the phenylethanol appendage.2
A substantial advancement on previous work was the use
of (S)-tryptophanol as the aminoalcohol partner in cyclo-
condensation reactions. In these cases, tryptophanol not only
constitutes the source of chirality but also can be used to
assemble complex polycyclic targets, such as substituted
indolo[2,3-a]quinolizidine derivatives, by intramolecular
R-amidoalkylation upon the indole ring3 (Scheme 1).
We report here an alternative mode of cyclization of
tryptophanol-derived oxazolopiperidone lactams, leading to
enantiopure spiro derivatives in a highly stereoselective
process that involves the generation of a quaternary stereo-
center.
This spirocyclization was unexpectedly observed when we
attempted the reductive opening of the oxazolidine ring of
lactam 1. Under the conditions (Et3SiH, TiCl4) satisfactorily
(2) For recent work, see: (a) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´,
M.; Pe´rez, M.; Llor, N.; Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J.
J. Org. Chem. 2000, 65, 3074. (b) Amat, M.; Canto´, M.; Llor, N.; Escolano,
C.; Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67, 5343. (c)
Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem.
2003, 68, 1919. (d) Amat, M.; Pe´rez, M.; Llor, N.; Escolano, C.; Luque, F.
J.; Molins, E.; Bosch, J. J. Org. Chem. 2004, 69, 8681. (e) Amat, M.;
Escolano, C.; Lozano, O.; Go´mez-Esque´, A.; Griera, R.; Molins, E.; Bosch,
J. J. Org. Chem. 2006, 71, 3804. (f) Amat, M.; Bassas, O.; Llor, N.; Canto´,
M.; Pe´rez, M.; Molins, E.; Bosch. J. Chem.-Eur. J. 2006, 12, 7872. (g)
Amat, M.; Lozano, O.; Escolano, C.; Molins, E.; Bosch, J. J. Org. Chem.
2007, 72, 4431. See also references cited therein.
(3) (a) Bassas, O.; Llor, N.; Santos, M. M. M.; Griera, R.; Molins, E.;
Amat, M.; Bosch, J. Org. Lett. 2005, 7, 2817. (b) Allin, S. M.; Thomas, C.
I.; Allard, J. E.; Doyle, K.; Elsegood, M. R. J. Eur. J. Org. Chem. 2005,
4179. (c) Allin, S. M.; Khera, J. S.; Witherington, J.; Elsegood, M. R. J.
Tetrahedron Lett. 2006, 47, 5737. (d) Amat, M.; Santos, M. M. M.; Bassas,
O.; Llor, N.; Escolano, C.; Go´mez-Esque´, A.; Molins, E.; Allin, S. M.;
McKee, V.; Bosch, J. J. Org. Chem. 2007, 72, 5193.
† University of Barcelona.
‡ Institut de Cie`ncia de Materials de Barcelona (CSIC).
(1) For reviews, see: (a) Romo, D.; Meyers, A. I. Tetrahedron 1991,
47, 9503. (b) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1. (c)
Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843. (d) Escolano,
C.; Amat, M.; Bosch, J. Chem.-Eur. J. 2006, 12, 8198.
10.1021/ol0712327 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/29/2007

an intermediate spiroindoleninium cation B, which is trapped
intermolecularly5 by the reductant.
Scheme 1. Enantioselective Entry to the
Indolo[2,3-a]quinolizidine System
The regioselectivity of the above cyclization is in ac-
cordance with previous observations for the electrophilic
substitution in 3-substituted indoles,6 although some reports
indicate that cyclization can occur by direct attack at the
indole 2-position.7 Interestingly, whereas N-acyliminium
cation A undergoes spirocyclization faster than reduction,
in the presence of Et3SiH the resultant N-tosyl spiroindole-
ninium cation B undergoes reduction to spiro tetracycle 4
instead of the usual rearrangement to an indolo[2,3-a]-
quinolizidine. This probably reflects that in the N-tosyl series
the 3f2 migration is slower than in the above unsubstituted
indole series.
used for the selective cleavage of the C-O bond in related
phenylglycinol-derived oxazolopiperidone lactams, tryp-
tophanol-derived lactam 1 underwent cyclization to indolo-
quinolizidine 2, thus making evident that the TiCl4-promoted
amidoalkylation reaction on the indole 2-position occurs
faster than the reduction of the initially formed intermediate
N-acyliminium cation. To deactivate the indole ring toward
the electrophilic attack, lactam 13d was converted (92% yield)
to the N-tosyl derivative 3 under the usual phase transfer
conditions (TsCl, Bu4NCl, NaOH, CH2Cl2). To our surprise,
treatment of 3 with Et3SiH-TiCl4 in refluxing CH2Cl2 for 3
days led to a single spiro derivative 4 (73% yield) instead
of to the expected piperidone 5. The chemical yield of 4
was even higher when TFA (86%) or BF3‚Et2O (85%) was
used as the Lewis acid in the reductive process. As illustrated
in Scheme 2, these results can be accounted for by consider-
The relative configuration of 4 was deduced from NOESY
experiments (Figure 1) and can be rationalized on the basis
Figure 1. Key NOESY correlations of 4.
of a stereoelectronically controlled axial approach8 of the
indole ring to the electrophilic carbon center in the confor-
mation A1 depicted in Figure 2, via a transition state in which
the A1,3 strain between the CH2OH/CO and Et/dCH groups
is minimized. The alternative mode of cyclization from
conformation A2 would suffer from strong interaction
between these groups.
Scheme 2. Enantioselective Spirocyclization
The hydroxymethyl substituent plays a decisive role as a
stereocontrol element in determining the relative stereo-
chemistry of the stereocenters generated in the cyclization
step.9 This was demonstrated since a similar spirocyclization
with TiCl4 in the presence of Et3SiH from tosyl lactam 7,
which lacks the ethyl substituent at the piperidine â-position,
led again to a single enantiopure spiro derivative 8 in
(5) (a) For the trapping of a spiroindoleninium cation, generated via a
Pummerer reaction, by water, see: Padwa, A.; Kuethe, J. T. J. Org. Chem.
1998, 63, 4256. For examples of intramolecular trapping of a spiroindole-
ninium intermediate by a nucleophilic residue to furnish polycyclic indolines,
see: (b) Bu¨chi, G.; Matsumoto, K. E.; Nishimura, H. J. Am. Chem. Soc.
1971, 93, 3299. (c) Biswas, K. M.; Dhara, R. N.; Halder, S.; Mallik, H.;
Sinha-Chaudhuri, A.; De, P.; Brahmachari, A. S. Synth. Commun. 1993,
23, 379. (d) van Maarseveen, J. H.; Scheeren, H. W.; Kruse, C. G.
Tetrahedron 1993, 49, 2325. (e) Wilkins, D. J.; Jackson, A. H.; Shannon,
P. V. R. J. Chem. Soc., Perkin Trans. 1 1994, 299. (f) Nyerges, M.; Rudas,
M.; Bitter, I.; To¨ke, L.; Sza´ntay, C. J., Jr. Tetrahedron 1997, 53, 3269. (g)
He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
6771. (h) Liu, J.-L.; Hino, T.; Tsuruoka, A.; Harada, N.; Nakagawa, M. J.
Chem. Soc., Perkin Trans. 1 2000, 3487. (i) Turet, L.; Marko´, I. E.; Tinant,
B.; Declercq, J.-P.; Touillaux, R. Tetrahedron Lett. 2002, 43, 6591.
(6) For reviews, see: (a) Ungemach, F.; Cook, J. M. Heterocycles 1978,
9, 1089. (b) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797.
(7) (a) Casnati, G.; Dossena, A.; Pochini, A. Tetrahedron Lett. 1972,
5277. (b) Kowalski, P.; Bojarski, A. J.; Mokrosz, J. L. Tetrahedron 1995,
51, 2737.
ing an electrophilic attack of the initially formed N-
acyliminium4 species A on the indole 3-position to generate
(4) For a recent review on cyclizations of N-acyliminium ions, see:
Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C.
A. Chem. ReV. 2004, 104, 1431.
(8) Deslongchamps, P. In Stereoelectronic Effects in Organic Chemistry;
Baldwin, J. E., Ed.; Pergamon: Oxford, 1983.
2908
Org. Lett., Vol. 9, No. 15, 2007

Scheme 3. Enantioselective Synthesis of
Spiro[indole-3,3′-indolizidine] Derivative 10
Figure 2. Stereochemical outcome of spirocyclization of 3.
excellent yield (88%). Lactam 7 was easily prepared (93%
yield) by tosylation of the known3b tryptophanol-derived
lactam 6. The absolute configuration of 8 was confirmed by
X-ray crystallographic analysis10 (Figure 3).
Strychnos, and oxindole11 (Figure 4) alkaloids, many of them
with strong bioactivity profiles, we decided to study if the
above spiro cyclizations would represent a general synthetic
entry to this tetracyclic ring system.
Figure 3. Molecular structure of spiro derivative 8.
Illustrating the synthetic utility of the methodology, the
removal of the hydroxymethyl appendage of 8 to give the
enantiopure spiroindoline 9 was satisfactorily accomplished
(59% overall yield), following the procedure recently de-
veloped by Allin,3b by oxidation to a carboxylic acid 8′
followed by a radical reductive decarbonylation via a seleno
derivative. The subsequent removal of the tosyl substituent
gave 10 (Scheme 3).
Figure 4. Representative oxindole alkaloids.
For this reason, we selected the known3d lactam 11
(Scheme 4), which incorporates the propionate chain present
Taking into account that the spiro[indole-3,3′-indolizidine]
moiety is present in a large number of Aspidosperma,
(9) For related cyclizations where a substituent R to the amide nitrogen
acts as an element of stereocontrol, see: (a) Maryanoff, B. E.; McComsey,
D. F.; Duhl-Emswiler, B. A. J. Org. Chem. 1983, 48, 5062. (b) Maryanoff,
B. E.; McComsey, D. F.; Almond, H. R., Jr.; Mutter, M. S.; Bemis, G. W.;
Whittle, R. R.; Olofson, R. A. J. Org. Chem. 1986, 51, 1341. (c) Huizenga,
R. H.; Pandit, U. K. Tetrahedron 1992, 48, 6521. (d) Allin, S. M.; Northfield,
C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron Lett. 1998, 39, 4905. (e)
Heaney, H.; Taha, M. O. Tetrahedron Lett. 2000, 41, 1993. (f) Bahajaj, A.
A.; Vernon, J. M.; Wilson, G. D. J. Chem. Soc., Perkin Trans. 1 2001,
1446. (g) Nielsen, T. E.; Meldal, M. J. Org. Chem. 2004, 69, 3765. See
also ref 3.
Scheme 4. Stereocontrolled Access to
Spiro[indole-3,3′-indolizidine]-8′-propionate Derivatives
(10) The experiment was done on a Enraf-Nonius CAD4 diffractometer
using graphite monochromated Mo KR radiation. The structure was solved
by direct methods (SHELXS-86) after applying Lorentz, polarization, and
absorption (empirical PSI scan method) corrections. Full matrix least-squares
refinement (SHELXL-93) using anisotropic thermal parameters for non-H
atoms and riding thermal parameters for H atoms (positioned at calculated
positions) converged to an R factor of 0.0377 (calculated for the reflections
with I > 2σ(I)). Crystal data: C23H26N2O4S, orthorhombic, space group
P212121, a ) 10.055(2) Å, b ) 10.084(2) Å, c ) 20.606(2) Å, V ) 2089.3-
(6) Å3, µ(Mo KR) ) 0.188 mm-1, Dc ) 1.356 mg/m3. Approximate
dimensions: 0.32 × 0.28 × 0.10 mm3. Data collection was up to a resolution
of 2θ ) 49.9° producing 3970 reflections. Maximum and minimum heights
at the piperidine 3-position in the oxindole alkaloid vincatine,
and lactam 15 (Scheme 5), which bears an acetate chain at
the piperidine 4-position, as does isorhynchophylline. The
required lactam 15 was prepared in 74% yield by cyclocon-
at the final difference Fourier synthesis were 0.155 and -0.177 e‚Å-3
.
Org. Lett., Vol. 9, No. 15, 2007
2909

double bond by sequential attack of an N-acyliminium
species and a hydride ion. These stereoselective spirocy-
clizations significantly expand the potential of tryptophanol-
derived oxazolopiperidone lactams as chiral building blocks
for the enantioselective synthesis of complex piperidine-
containing derivatives. The starting lactams are easily
accessible by a cyclocondensation reaction of (S)-tryptopha-
nol with an appropriate prochiral or racemic δ-oxo(di)ester,
and by simply modulating the reactivity of the indole ring
by tosylation, they undergo regio- and stereocontrolled
cyclization reactions at either the 2- or 3-indole position,
providing straightforward access to the indolo[2,3-a]quino-
lizidine13 and spiro[indole-3,3′-indolizidine] frameworks
characteristic of several groups of indole alkaloids.
Scheme 5. Regio- and Stereocontrolled Cyclizations of
Lactams 15 and 16
Acknowledgment. Financial support from the Ministry of
Science and Technology (Spain)-FEDER (Project CTQ2006-
02390/BQU) and the DURSI, Generalitat de Catalunya
(Grant 2005SGR-0603), is gratefully acknowledged. Thanks
are also due to the Fundac¸a˜o para a Cieˆncia e Tecnologia
(Lisbon, Portugal) and the Ministry of Education and Science
(Spain) for a postdoctoral Grant to M.M.M.S. and D.J.,
respectively.
Supporting Information Available: 1H NMR and 13C
NMR spectra for compounds 3, 4, 7, 8, 8′, 10, 12, 13, and
15-18. Crystallographic data in CIF format for 8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
densation of tryptophanol with prochiral oxodiester 14, in a
process that involves the desymmetrization12 of two enan-
tiotopic acetate chains. Satisfactorily, tosylation of lactams
11 and 15 followed by treatment of the resulting N-
tosylindoles 12 and 16 with BF3‚Et2O in the presence of Et3-
SiH gave the respective spiroindolines 13 and 17 as single
isomers in good yields. Finally, to fully illustrate the
versatility of tryptophanol-derived oxazolopiperidone lac-
tams, lactam 15 was cyclized (62% yield) to indoloquino-
lizidine 18 by treatment with HCl in methanol.
OL0712327
(12) (a) For related desymmetrizations, see ref 2f. See also: (b) Tite,
T.; Lallemand, M.-C.; Poupon, E.; Kunesch, N.; Tillequin, F.; Gravier-
Pelletier, C.; Le Merrer, Y.; Husson, H.-P. Bioorg. Med. Chem. 2004, 12,
5091. For reviews, see: (c) Ward, R. S. Chem. Soc. ReV. 1990, 19, 1. (d)
Danieli, B.; Lesma, G.; Passarella, D.; Riva, S. In AdVances in the Use of
Synthons in Organic Chemistry; Dondoni, A., Ed.; JAI Press: London, 1993;
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Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769.
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B.; Lesma, G.; Passarella, D.; Silvani, A. Curr. Org. Chem. 2000, 4, 231.
(i) Garc´ıa-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. ReV. 2005, 105, 313.
(13) For the conversion of indolo[2,3-a]quinolizidines to oxindole
derivatives, see: (a) Ito, M.; Clark, C. W.; Mortimore, M.; Goh, J. B.;
Martin, S. F. J. Am. Chem. Soc. 2001, 123, 8003. (b) Deiters, A.; Pettersson,
M.; Martin, S. F. J. Org. Chem. 2006, 71, 6547.
The unprecedented method of generating spiroindolines
reported herein involves a formal addition to the indole 2,3-
(11) (a) Southon, I. W.; Buckingham, J. In Dictionary of Alkaloids;
Chapman and Hall: London, 1989; pp 922, 1129. (b) Brown, R. T. Indoles,
The Monoterpenoid Indole Alkaloids. In The Chemistry of Heterocyclic
Compounds; Saxton, J. E., Weissberger, A., Taylor, E. C., Eds.; Wiley:
New York, NY, 1983; Vol. 25, Part 4, pp 85-97. (c) For a review on the
construction of the spiro[pyrrolidine-3,3′-oxindole] moiety present in
oxindole alkaloids, see: Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003,
2209.
2910
Org. Lett., Vol. 9, No. 15, 2007