Biogenetically inspired enantioselective approach to indolo[2,3-a]- and benzo[a]quinolizidine alkaloids from a synthetic equivalent of secologanin

Article abstract of DOI:10.1021/ol0505609

(Chemical Equation Presented) Racemic oxodiester 1 undergoes stereoselective cyclocondensation with (S)-tryptophanol, (S)-(3,4- dimethoxyphenyl)alaninol, or the corresponding amino acids, in a process involving a tandem dynamic kinetic resolution/desymmetrization of diastereotopic groups, to give bicyclic lactams, which are cyclized to substituted indolo[2,3-a]- and benzo[a]quinolizidines.

Full text of DOI:10.1021/ol0505609

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2817-2820
Biogenetically Inspired Enantioselective
Approach to Indolo[2,3-a]- and
Benzo[a]quinolizidine Alkaloids from a
Synthetic Equivalent of Secologanin
Oriol Bassas,† Nu´ria Llor,† Maria M. M. Santos,† Rosa Griera,† Elies Molins,‡
Mercedes Amat,† and Joan Bosch*,†
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona,
08028-Barcelona, Spain, and Institut de Cie`ncia de Materials (CSIC),
Campus UAB, 08193-Cerdanyola, Spain
joanbosch@ub.edu
Received March 15, 2005
ABSTRACT
Racemic oxodiester 1 undergoes stereoselective cyclocondensation with (S)-tryptophanol, (S)-(3,4-dimethoxyphenyl)alaninol, or the corresponding
amino acids, in a process involving a tandem dynamic kinetic resolution/desymmetrization of diastereotopic groups, to give bicyclic lactams,
which are cyclized to substituted indolo[2,3-a]- and benzo[a]quinolizidines.
Secologanin (Figure 1) is a secoiridoid glucoside of extraor-
dinary significance because it is a key intermediate in the
biosynthesis of monoterpenoid indole alkaloids as well as
of emetine and related benzo[a]quinolizidine alkaloids,1 many
of them possessing considerable pharmacological and thera-
peutic interest.2 A condensation of secologanin with either
tryptamine (or tryptophan) or dopamine constitutes the initial
step of the biosynthesis of these natural products.
Figure 1. Secologanin and its aglycone.
The pivotal role of secologanin in alkaloid biosynthesis
has stimulated the development of biomimetic syntheses of
alkaloids using this compound as the starting material.3,4
of secologanin,5 and its use in cyclocondensation reactions
with chiral nonracemic amino alcohols 9a and 17a as well
We present here an efficient synthesis of racemic aldehyde
diester 1, which can be envisaged as a synthetic equivalent
(3) For reviews, see: (a) Brown, R. T. In The Chemistry and Biology of
Isoquinoline Alkaloids; Phillipson, J. D., Roberts, M. F., Zenk, M. H., Eds.;
Springer-Verlag: Berlin, 1985; pp 204-212. (b) Brown, R. T. In Indole
and Biogenetically Related Alkaloids; Phillipson, J. D., Zenk, M. H., Eds.;
Academic Press: London, 1980; Chapter 9.
(4) For a recent review on biomimetic synthesis of alkaloids, see: Scholz,
U.; Winterfeldt, E. Nat. Prod. Rep. 2000, 17, 349.
(5) For the synthesis of an analogue of secologanin and its use in the
total synthesis of monoterpenoid isoquinoline alkaloids, see: Brown, R.
T.; Jones, M. F. Tetrahedron Lett. 1984, 25, 3127.
† University of Barcelona.
‡ Institut de Cie`ncia de Materials.
(1) Sto¨ckigt, J.; Ruppert, M. In ComprehensiVe Natural Products; Barton,
D., Nakanishi, K., Eds.; Elsevier: New York, 1999; Vol. 4, pp 109-138.
(2) (a) Neuss, N. In Indole and Biogenetically Related Alkaloids;
Phillipson, J. D., Zenk, M. H., Eds.; Academic Press: London, 1980;
Chapter 17. (b) Dewick, P. Medicinal Natural Products. A Biosynthetic
Approach; Wiley: Chichester, 2002.
10.1021/ol0505609 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/09/2005

enantiopure lactam 10a11 in 62% yield (Scheme 2). Three
stereogenic centers with a well-defined configuration have
Scheme 1. Synthesis of the Synthetic Equivalent of
Secologanin
Scheme 2. Enantioselective Entry to Substituted
Indolo[2,3-a]quinolizidines
been generated in a single synthetic step. Only minor
amounts (∼10%) of other diastereoisomers were formed.
The observed stereoselectivity can be explained by con-
sidering that the initially formed diastereomeric imines are
in equilibrium via an enamine and that the final irreversible
lactamization of the mixture of equilibrating oxazolidines
occurs faster via a transition state in which all the substituents
in the incipient chairlike six-membered lactam are in an
equatorial disposition (Figure 2).
as amino acids (S)-tryptophan (9b) and (S)-(3,4-dimethox-
yphenyl)alanine (17b), ultimately leading to enantiopure
indolo[2,3-a]- and benzo[a]quinolizidines.
The synthesis of target 1, depicted in Scheme 1, involves
the conjugate addition of 2-methyl-1-propenylmagnesium
bromide to unsaturated diester 2, a bis-homologation of the
resulting diester 3 to diester 8 via diol 4, tosylate 5, and
dinitrile 6, and finally reductive ozonolysis6 of the alkene
moiety. The synthesis can be satisfactorily conducted at a
50-100 g scale, and most of the steps take place in excellent
yield.
On the basis of our experience in related cyclocondensa-
tions using phenylglycinol or other amino alcohols as the
source of chirality,7 we expected that, although synthon 1 is
a racemate, it would undergo a stereoselective cycloconden-
sation with (S)-tryptophanol (9a) in a process involving a
dynamic kinetic resolution,8 with epimerization of the
configurationally labile stereocenter R to the carbonyl group
and simultaneous desymmetrization of the two diastereotopic
acetate chains.9 Advantageously with respect to these cy-
clocondensations, tryptophanol not only would act as a chiral
inductor but also would be incorporated in the target final
products.10 In the event, refluxing a toluene solution of
tryptophanol (9a) and 1 under Dean-Stark conditions gave
Figure 2. Stereoselective lactamization to 10a.
A subsequent intramolecular BF3‚OEt2-promoted R-ami-
noalkylation on the indole 2-position, taking advantage of
the masked N-acyliminium moiety present in the bicyclic
lactam 10a, led to the indolo[2,3-a]quinolizidine derivative
11a12 in 35% yield.
Although cyclocondensation reactions of γ- and δ-ox-
oesters with chiral nonracemic amino alcohols have received
considerable attention,13 since the resulting lactams have
proven to be versatile building blocks for the enantioselective
synthesis of nitrogen-containing derivatives,14 to our knowl-
edge there is no precedent for the use of amino acids in
similar cyclocondensations. For this reason, we decided to
investigate the cyclocondensation of (S)-tryptophan (9b) with
(6) For related ozonolysis, see: Cartier, D.; Le´vy, J. Tetrahedron 1990,
46, 5295.
(7) (a) Amat, M.; Canto´, M.; Llor, N.; Ponzo, V.; Pe´rez, M.; Bosch, J.
Angew. Chem., Int. Ed. 2002, 41, 335. (b) Amat, M.; Bassas, O.; Perica`s,
M. A.; Pasto´, M.; Bosch, J. Chem. Commun. 2005, 1327.
(8) For a recent review, see: Pellissier, H. Tetrahedron 2003, 59, 8291.
(9) For reviews, see: (a) 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; Vol. 1, pp 143-219. (b) Schoffers, E.;
Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769. (c) Willis,
M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765. (d) Danieli, B.; Lesma,
G.; Passarella, D.; Silvani, A. Curr. Org. Chem. 2000, 4, 231.
(10) For the use of tryptophanol in a cyclocondensation reaction with a
simple δ-oxoester, see: Allin, S. M.; Thomas, C. I.; Doyle, K.; Elsegood,
M. R. J. J. Org. Chem. 2005, 70, 357.
(11) Stereochemistry of 10a was assigned taking into account: (i) the
preferential formation of cis H3-H8a oxazolidine isomers in related
cyclocondensations from aldehydes;7,10 (ii) the H8-H8a J value (8.4 Hz),
indicating of a trans relationship; and (iii) the absolute configuration of the
cyclized product 11a (see below).
(12) Absolute configuration of lactams 10b, 11a, and 19a was unambigu-
ously established by X-ray crystallography (see Supporting Information).
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Org. Lett., Vol. 7, No. 14, 2005

several δ-oxoesters and δ-oxodiesters, including the secolo-
ganin equivalent 1. Thus, racemic oxoester 1215 and prochiral
oxodiester 137a were converted to the corresponding enan-
tiopure lactams 14 and 15 by treatment with (S)-tryptophan
in refluxing toluene, although the yields were quite moderate
(35% based on consumed aldehyde for 14) as a consequence
of the insolubility of the starting amino acid and a competi-
tive decarboxylation process (Scheme 3). In both cases, the
smoothly in excellent yield (90%) by treatment of 10b with
TFA at room temperature.
The secologanin equivalent synthon 1 was also satisfac-
torily used to provide an enantioselective entry to substituted
benzo[a]quinolizidine derivatives.17
Cyclocondensation of 1 with dimethoxyphenylalaninol
17a18 in refluxing toluene under Dean-Stark conditions took
place in excellent yield (80%) to give a mixture of stereoi-
someric lactams, from which the enantiopure isomer 18a was
isolated in 60% yield. A subsequent cyclization of 18a with
BF3‚OEt2 led to benzo[a]quinolizidine 19a12 in 40% yield
(Scheme 4).
Scheme 3. Cyclocondensation Reactions Using the Amino
Acid (S)-Tryptophan
Scheme 4. Enantioselective Entry to Substituted
Benzo[a]quinolizidines
respective enamides 16a or 16b, resulting from decarboxy-
lation of the initially formed oxazolidinones,16 were isolated
to a considerable extent (30-50%). The yield of the process
was improved to 65% (77% based on consumed aldehyde;
2:1 mixture of 15 and its 8,8a-diastereomer), and the
undesired formation of enamide was reduced (∼5%), when
the cyclocondensation of 13 was carried out in refluxing
benzene. Similarly, cyclocondensation of (S)-tryptophan with
1 in refluxing benzene took place in 42% yield to give a
mixture of lactams, from which enantiopure piperidone 10b12
was isolated in 30% yield. In this series, cyclization to the
corresponding indolo[2,3-a]quinolizidine 11b occurred
As observed in the above cyclocondensations with (S)-
tryptophan, reaction of the amino acid 17b with oxodiester
1 was less efficient, and the expected bicyclic lactam 18b
was isolated in low yield (∼15%; 30% based on recovered
aldehyde), enamide 20 being the major product (42%) when
the reaction was carried out in refluxing toluene. Cyclization
of 18b with BF3‚OEt2 provided benzo[a]quinolizidine 19b
in 82% yield.
(13) For reviews, see: (a) Meyers, A. I.; Brengel, G. P. Chem. Commun.
1997, 1. (b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843.
For more recent work, see: (c) 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. (d) Nieman, J. A.; Ennis, M. D. Org. Lett.
2000, 2, 1395. (e) Amat, M.; Canto´, M.; Llor, N.; Escolano, C.; Molins,
E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67, 5343. (f) Allin, S. M.;
James, S. L.; Elsegood, M. R. J.; Martin, W. P. J. Org. Chem. 2002, 67,
9464. (g) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org.
Chem. 2003, 68, 1919. (h) Amat, M.; Escolano, C.; Lozano, O., Llor, N.;
Bosch, J. Org. Lett. 2003, 5, 3139. (i) Penhoat, M.; Levacher, V.; Dupas,
G. J. Org. Chem. 2003, 68, 9517. (j) Allin, S. M.; Thomas, C. I.; Allard,
J. E.; Duncton, M.; Elsegood, M. R. J.; Edgar, M. Tetrahedron Lett. 2003,
44, 2335. (k) Amat, M.; Pe´rez, M.; Llor, N.; Escolano, C.; Luque, F. J.;
Molins, E.; Bosch, J. J. Org. Chem. 2004, 69, 8681.
(14) For related work, see: (a) Roa, L. F.; Gnecco, D.; Galindo, A.;
Tera´n, J. L. Tetrahedron: Asymmetry 2004, 15, 3393. (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. (c)
Agami, C.; Dechoux, L.; Hebbe, S.; Me´nard, C. Tetrahedron 2004, 60,
5433.
The straightforward route to substituted indolo[2,3-a]-
and benzo[a]quinolizidines reported herein significantly
expands the potential of amino alcohol-derived bicyclic
lactams as chiral synthons for the enantioselective con-
struction of complex piperidine-containing derivatives.
The amino alcohol (or amino acid) used as the chiral inductor
in the cyclocondensation reaction not only constitutes
the source of chirality but also is used to assemble the
final target polycyclic products. In conjunction with this, the
use of an appropriately substituted racemic δ-oxodiester
(17) For a recent review on the asymmetric synthesis of isoquinoline
alkaloids, see: Chrzanowska, M.; Rozwadowska, M. D. Chem. ReV. 2004,
104, 3341.
(15) Norman, M. H.; Heathcock, C. H. J. Org. Chem. 1988, 53, 3370.
(16) (a) Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. J. Chem. Soc.,
Chem. Commun. 1987, 49. (b) Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka,
S. Bull. Chem. Soc. Jpn. 1987, 60, 4079.
(18) For the use of 17a in a cyclocondensation reaction with a simple
δ-oxoester, see: Allin, S. M.; Vaidya, D. G.; James, S. L.; Allard, J. E.;
Smith, T. A. D.; Mckee, V.; Martin, W. P. Tetrahedron Lett. 2002, 43,
3661.
Org. Lett., Vol. 7, No. 14, 2005
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allows the direct generation of enantiopure lactams that
already incorporate carbon substituents on the hetero-
cyclic ring, in a process involving a tandem dynamic
kinetic resolution-desymmetrization of diastereotopic acetate
chains.
fellowship to O.B., and the Fundac¸ao para a Cieˆncia e
Tecnologia (Portugal) for a postdoctoral Grant to M.M. M.S.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra of compounds 1, 10, 11, 14, 15, 18, and 19; complete
X-ray crystallographic data for 10b, 11a, and 19a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the
Ministry of Science and Technology (Spain)-FEDER through
project BQU2003-00505. Thanks are also due to the DURSI,
Generalitat de Catalunya, for Grant 2001-SGR-0084, the
Ministry of Education, Culture and Sport (Spain) for a
OL0505609
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Org. Lett., Vol. 7, No. 14, 2005